RS20050924A - N-Pyrrolidin-3-IL-AMID DERIVATIVES AS SEROTONIN AND NORADRENALINE RESORPTION INHIBITORS - Google Patents

Abstract

A compound of Formula (I) and pharmaceutically and/or veterinarily acceptable derivatives thereof, wherein R1 is H, C1_6alkyl, -C(X) Y, C3_8cycloalkyl, aryl, het, aryl-Cl_4alkyl or het-Cl_4alkyl, wherein the cycloalkyl, aryl or het groups are optionally substituted by at least one substituent independently selected from C1_8allkyl, C1_8alkoxy, OH, halo, CF3, OCF3, SCF3, hydroxy-Cl_6alkyl, C1_ 4alkoxy-C1_6alkyl and C1_4alkyl-S-C1_4alkyl; R2 is aryl or heteroaryl, each optionally substituted by at least one substituent independently selected from C1_8alkyl, C1_8alkoxy, OH, halo, CF3, OCF3, SCF3, hydroxy-C1_6alkyl, C1_4alkoxy-C1_6alkyl and C1_4alkyl-S-C1_4alkyl; R3 is C1_6alkyl, C3_8cycloalkyl, C3_8cycloalkyl-C1_6alkyl, aryl, het, aryl-Cl_4alkyl or het-C1_4alkyl, wherein the cycloalkyl, aryl or het groups are optionally substituted by at least one substituent independently selected from C1_6alkyl, C1_6alkoxy, OH, halo, CF3, OCF3, SCF3, hydroxy-C1_6alkyl, C1_4alkoxy - C1_6alkyl and C1_4alkyl-S­C1_4alkyl; X is S or O; Y is H, C1_6alkyl, aryl, het, aryl-C1_4alkyl or het-C1_ 4alkyl; and n is 1 or 2, provided that when n is 1, m is 0 or 1 and when n is 2, m is 0, wherein if m is 0, then * represents a chiral center. The compounds of the invention exhibit activity as both serotonin and noradrenaline re-uptake inhibitors and therefore have utility in a variety of therapeutic areas, for example urinary incontinence.

Description

DERIVATIVES OF PYRROLIDIN-3-YL AMIDE AS RESORPTION INHIBITORS

SEROTONIN AND NORADRENALINE

The present invention relates to amide compounds that inhibit the reabsorption of monoamines,

to the procedures for obtaining them, to the pharmaceutical preparations that contain them and to their application in medicine.

The compounds of the invention show activity as reuptake inhibitors of serotonin and

noradrenaline and accordingly find application in various therapeutic areas. For example, the compounds of the invention find application in the treatment of disorders implicated in the regulation of monoamine transporter function; more specifically, diseases in which the reabsorption of serotonin or noradrenaline is implicated; and especially disorders in which the inhibition of both serotonin and noradrenaline is implicated.

According to a first aspect, the invention describes compounds of formula (I),

and its pharmaceutical and/or veterinary acceptable derivatives, where:

R<1>, H, C1-6 alkyl, -C(X)Y, C3-8cycloalkyl, aryl, het, aryl-C1-4alkyl or het-CMalkyl, where the cycloalkyl, aryl and het groups are optionally substituted with at least one substituent independently selected from C1-galky, C1-alkoxy, OH, halo, CF3, OCF3, SCF3, hydroxy-C1-4alkyl, C1-4alkyl-C1-6alkyl. and C 1-6 alkyl-S-C 1-4 alkyl;

R 2 is aryl or heteroaryl optionally substituted with at least one substituent independently selected from C 1-6 alkyl, C 1-6 methoxy, OH, halo, CF 3 , OCF 3 , SCF 3 , hydroxy-C 1-6 alkyl, C 1-4 alkoxy-C 1-6 alkyl and C 1-4 alkyl-S-C 1-6 alkyl;

R 3 is C 1-6 cycloalkyl C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, aryl, het, aryl-C 1-6 alkyl or het-C 1-6 alkyl, where the cycloalkyl, aryl or het groups are optionally substituted with at least one substituent independently selected from C 1-6 alkyl, C 1-6 alkoxy, OH, halo, CF3, OCF3, SCF3, hydroxy-C 1-6 alkyl, C 1-4 hydroxy-C 1-6 alkyl and C 1 -C 1 -C 1 alkyl;

X is S or O;

Y is H, C 1-4 alkyl, C 1-4 alkoxy, aryl, het, aryl-C 1-4 alkyl or het-C 1-4 alkyl;

nje 1 or 2, provided that when n is 1, then m is 0 or 1, and when n is 2, then m is 0, and when m is 0, then<*>represents a chiral center;

aryl is phenyl, naphthyl, anthracyl or phenanthryl;

heteroaryl is an aromatic 5- or 6-membered heterocycle containing at least one N, O or S heteroatom, optionally fused with an aryl group; and

het is an aromatic or non-aromatic 4-, 5- or 6-membered heterocycle containing at least one N, O or S atom, optionally fused with a 5- or 6-membered carbocyclic group or another 4-, 5- or 6-membered heterocycle containing at least one N, O or S heteroatom.

In one embodiment of the invention, R<1> is H and R<2>, R<3> and m are as previously defined.

In another embodiment of the invention, m is 0 and R , R , and R are as previously defined. When m is 0, then<*>represents the S enantiomer.

In another embodiment, R1, R3 and m are as previously defined, and R2 is phenyl, naphthyl or quinoline, each optionally substituted with at least one substituent independently selected from C1-8alkyl, C1-galkoxy, OH, halo, CF3, OCF3, SCF3, hydroxy-C1-4alkyl, C1-4alkyl-C1-6alkyl and C1-4alkyl-S-C1-4alkyl. In the following approach, the substituents may be selected from halo, OH, C 1-4 alkyl, C 1-4 alkoxy and CF 3 . If necessary, the phenyl, naphthyl or quinoline group can be substituted with one, two or three substituents, independently selected from halo, OH and C1-4alkyl. In the next embodiment, R2 is phenyl and is substituted with two substituents selected from chloro, fluoro, OH and C1-4alkyl. In another embodiment, R 2 is dihydrogenyl.

In another embodiment, R , R and m are as previously defined and R is C 1-6 alkyl, C 3-6 cycloalkyl or C 3-8 cycloalkyl-C 1-4 alkyl, R 3 is C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 cycloalkyl-C 1-4 alkyl.

In the next embodiment of the invention, a compound of Formula II is described

and its pharmaceutical and/or veterinary acceptable derivatives, where:

R4, is phenyl, naphthyl or quinoline, each optionally substituted with at least one substituent independently selected from C1-galky, C1-galkoxy, OH, halo, CF3, OCF3, SCF3, hydroxy-C1-6alkyl, C1-4alkyl-C1-6alkyl and C1-4alkyl-S-C1-4alkyl;

R5 is Ci_6alkyl, C3.8cycloalkyl, C3.8cycloalkyl-Ci-ealkyl, aryl or aryl-Ci-6alkyl where the cycloalkyl and aryl groups are optionally substituted with at least one substituent independently selected from Ci.6alkyl, Ci.6alkyl, OH, halo CF3, OCF3, SCF3, hydroxy-C,.6alkyl, Ci.4alkoxy-Ci.6alkyl and C,. 4alkyl-S-C].4alkyl; and

m is 0 or 1, in the case where m is 0, then<*>represents the R or S enantiomer.

In another embodiment, R5 and m are as previously defined, and R4 is phenyl, 1-naphthyl or 3-naphthyl, each optionally substituted with at least one substituent independently selected from C1-8alkyl, C1-8alkyl, OH, halo, CF3, OCF3, SCF3, hydroxy-C1-6alkyl, CMalkoxy-C1-6alkyl and C1-4alkyl-S-C1-4alkyl. Substituents may be selected from C 1-6 alkyl, C 1-6 alkoxy, OH, halo and CF 3 as needed. Phenyl or naphthyl groups can be substituted with one, two or three substituents. In an embodiment, the phenyl and naphthyl groups are substituted with two substituents independently selected from chloro, fluoro, C 1-4 alkyl and OH. In the following embodiment, the phenyl or naphthyl groups are substituted with two chloro groups. In another embodiment, R<4> and m are as previously defined and R5 is C1-6alkyl, C3-6cycloalkyl or C3-6cycloalkyl-C1-6alkyl.

In yet another embodiment, R<4> and R5 are as previously defined, and m is 0. In this embodiment,

<*>represents the R or S enantiomer. In another embodiment, m is 0 and<*>represents the S enantiomer.

In the following embodiment, a compound of Formula III is described

and its pharmaceutical and/or veterinary acceptable derivatives, where:

R<6>, phenyl, naphthyl or quinolinyl, each optionally substituted with at least one substituent independently selected from halo, OH, C1-6 alkyl, C1-6 alkoxy and CF3;

R 7 is C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, aryl or aryl-CH 2 -, where the cycloalkyl and aryl groups are optionally substituted with at least one substituent independently selected from halo, OH, C 1-4 alkyl, C 1-4 alkoxy and CF 3 ; and

<*>represents R il and S enantiomer.

In another embodiment, R and<*> are as previously defined and R is phenyl, 1-naphthyl or 2-naphthyl, each optionally substituted with at least one substituent independently selected from halo, OH, C 1-6 alkyl, C 1-6 alkoxy and CF 3 . Substituents may be selected from chloro, fluoro, C 1-4 alkyl, Ome and OH as needed. Phenyl and naphthyl groups can be substituted with one, two or three substituents. In another embodiment, the phenyl and naphthyl groups are substituted with one, two or three halo groups, independently selected from fluoro or chloro.

In another embodiment, R 6 and<*>are as previously defined and R<7> is C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 cycloalkyl-C 1-4 alkyl. In another embodiment, R 7 is C 1-6 alkyl optionally C 3-6 alkyl. When R<7> is C 3-6 alkyl, it may be branched C 3-6 alkyl.

In another embodiment, R<6> and R7 are as previously defined and<*>represents the S enantiomer.

In the following embodiment, a compound of Formula IV is described:

and its pharmaceutical and/or veterinary acceptable derivatives, where:

R , phenyl optionally substituted with 1-3 halo substituents;

R<9> is C1-6alkyl; and

<*>represents the R or S enantiomer.

Optionally, R 8 is dichlorophenyl, R 9 is branched C 3-4 alkyl and<*>represents the S enantiomer. R<9> can be an isobutyryl group.

In a further embodiment, the invention relates to compounds selected from:

2, 3-Dichloro-N-isobutyl-N-[(36)-pyrrolidin-3-yl]benzamide;

2,4-Dichloro-N-isobutyl-N-[(3S)-pyrrolidin-3-yl]benzamide;

2-chloro-3-methyl-N-isobutyl-N-[Q5)-pyrrolidin-3-yl]benzamide;

3-Fluoro-2-methyl-N-isobutyl-N-[(35)-pyrrolidin-3-yl]benzamide;

3-Methoxy-2-methyl-N-isobutyl-N-[(35)-pyrrolidin-3-yl]benzamide;

3- Chloro-N-isobutyl-N-[(3S)-pyrrolidin-3-yl]benzamide;

4- Chloro-N-isobutyl-N-[(3S)-pyrrolidin-3-yl]benzamide;

3,4-Dichloro-N-isobutyl-N-(35)-pyrrolidin-3-yl]benzamide;

N-(2-Naphthyl methyl)-N-(3S)-pyrrolidin-3-yl]benzamide;

N-(2-Naphthylmethyl)-N-[(3R)-pyrrolidin-3-yl]benzamide;

N-isobutyl-N-(3S)-pyrrolidin-3-yl]-2-naphthamide;

N-Butyl-N-[(3S)-pyrrolidin-3-yl]-1-naphthamide;

4-Chloro-N-(3,4-dichlorobenzyl)-N-[(3R)-pyrrolidin-3-yl]benzamide; 4-Chloro-N-(2,3-dichlorobenzyl)-N-[(3R)-pyrrolidin-3-yl]benzamide;

1 their pharmaceutical and/or veterinary acceptable derivatives.

Further, non-limiting examples of compounds encompassed by the present invention are: N-Pyrrolidin-3-yl-N-(5,6,7,8-tetrahydro-naphthalen-1-ylmethyl)-benzamide; N-(2,4-Dichloro-benzyl)-N-pyrrolidin-3-yl-benzamide;

N-(3-chloro-4-methyl-benzyl)-2-fluoro-N-pyrrolidin-3-yl-benzamide; Naphthalene-2-carboxylic acid butyl-pyrrolidin-3-yl-amide; Naphthalene-2-carboxylic acid isobutyl-pyrrolidin-3-yl-amide; Naphthalene-2-carboxylic acid (2,2-dimethyl-propyl)-pyrrolidin-3-yl-amide; 3-chloro-N-isobutyl-4-methyl-N-pyrrolidin-3-yl-benzamide; N-isobutyl-2,3-dimethyl-N-pyrrolidin-3-yl-benzamide;

3-chloro-N-(2,2-dimethyl-propyl)-2-methyl-N-pyrrolidin-3-yl-benzamide;

2-chloro-4-fluoro-N-isobutyl-N-pyrrolidin-3-yl-benzamide; 2-chloro-N-isobutyl-N-pyrrolide and n-3-yl-benzamide; 3-chloro-2-fluoro-N- and cobutyl-N-pyrrolide in-3-yl-benzamide; 3-chloro-4-fluoro-N-isobutyl-N-pyrrolidin-3-yl-benzamide; N-Butyl-2,4-dichloro-N-pyrrolidin-3-yl-benzamide; 2, 4-Dichloro-N-cyclobutyl methyl-N-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-N-cyclopentyl methyl-N-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-N-(2,2-dimethyl-propyl)-2-methyl-N-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-N-(2-ethyl-butyl)-N-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-N-(3-methyl-butyl)-N-pyrrolide n-3-yl-benzamide; 2,3,4- Trichloro-N-isobutyl-N-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-N-(2-cyclopropyl-ethyl)-N-pyrrolidin-3-yl-benzamide; naphthalene-1-carboxylic acid isobutyl-pyrrolidin-3-yl-amide; 2,4-Dichloro-5-fluoro-N-isobutyl-N-pyrrolide n-3-yl-benzamide; 2,3-Dichloro-N-(2,2-dimethyl-propyl)-N-pyrrolidin-3-yl-benzamide; 2,3-Dichloro-N-(3-methyl-butyl)-N-pyrrolidin-3-yl-benzamide; 2.3- Dichloro-N-cyclobutyl methyl-N-pyrrolidin-3-yl-benzamide; 3.4-Dichloro-N-cyclopentyl-N-pyrrolidin-3-yl-benzamide; 2.3- Dichloro-N-(1,2-dimethyl-propyl)-N-pyrrolidin-3-yl-benzamide; 2.4- Dichloro-N-(1,2-dimethyl-propyl)-N-pyrrolidin-3-yl-benzamide; 2, 3-Dichloro-N-cyclohexyl-N-pyrrolidin-3-yl-benzamide; 2, 4-Dichloro-N-cyclopentyl-N-pyrrolidin-3-yl-benzamide; 3, 4-Dichloro-N-cyclopentyl-N-pyrrolidin-3-yl-benzamide; naphthalene-1-carboxylic acid sec-butyl-pyrrolidin-3-yl-amide; N-sec-Butyl-2,3-dichloro-N-pyrrolidin-3-yl-benzamide; N-sec-B util-2,4-dichloro-N-pyrrolide yn-3-yl-benzamide; 2,3-Dichloro-N-(1-ethyl-propyl)-N-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-N-(1-ethyl-propyl)-N-pyrrolidin-3-yl-benzamide; Naphthalene-1-carboxylic acid (1-ethyl-propyl)-pyrrolidin-3-yl-amide; 2.3-Dichloro-N-cyclobutyl-N-pyrrolidin-3-yl-benzamide; 2.4-Dichloro-N-cyclobutyl-N-pyrrolidin-3-yl-benzamide; 2, 4-Dichloro-N-cyclopentyl-N-pyrrolidin-3-yl-benzamide; 2,3-Dichloro-N-pyrrolidin-3-yl-N-(1,2,2-trimethyl-propyl)-benzamide; N-tert-Butyl-2, 3-dichloro-N-pyrrolidin-3-yl-benzamide; naphthalene-1-carboxylic acid cyclopentyl-pyrrolidin-3-yl-amide; 2, 3-Dichloro-N-phenyl-N-pyrrolidin-3-yl-benzamide; 3, 4-Dichloro-N-(2,2-dimethyl-propyl)-2-methyl-N-pyrrolidin-3-yl-benzamide: 3-chloro-N-isobutyl-2-methyl-N-pyrrolidin-3-yl-benzamide; N-Butyl-2,3-dichloro-N-pyrrolidin-3-yl-benzamide; N-Butyl-3,4-dichloro-N-pyrrolidin-3-yl-benzamide; naphthalene-2-carboxylic acid cyclobutylmethyl-pyrrolidin-3-yl-amide; naphthalene-1-carboxylic acid cyclobutylmethyl-pyrrolidin-3-yl-amide; 3,4-Dichloro-N-cyclobutylmethyl-N-pyrrolidin-3-yl-benzamide; 4- Chloro-N-isobutyl-2-methoxy-N-pyrrolidin-3-yl-benzamide; 4-chloro-N-isobutyl-3-methyl-N-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-N-isobutyl-3-methyl-N-pyrrolidin-3-yl-benzamide; Naphthalene-1-carboxylic acid (3-methyl-butyl)-pyrrolidin-3-yl-amide; Naphthalene-1-carboxylic acid (2,2-dimethyl-propyl)-pyrrolidin-3-yl-amide; 3,4-Dichloro-N-(3-methyl-butyl)-N-pyrrolidin-3-yl-benzamide; 2.3- Dichloro-N-(4-fluoro-phenyl)-N-pyrrolidin-3-yl-benzamide; 2.4- Dichloro-N-(4-fluoro-phenyl)-N-pyrrolidin-3-yl-benzamide; Naphthalene-1-carboxylic acid (4-fluoro-phenyl)-pyrrolidin-3-yl-amide; N-Butyl-2, 3, 4-trichloro-N-pyrrolidine-3-yl-benzamide; 2,3,4- Trichloro-N-cyclobutyl methyl-N-pyrrolidin-3-yl-benzamide; N-Pyrrolidin-3-yl-N-(3-trifluoromethyl-benzyl)-benzamide; 2,4-Dichloro-N-phenyl-N-pyrrolidin-3-yl-benzamide; 3,4-Dichloro-N-phenyl-N-pyrrolidin-3-yl-benzamide; 2,3,4-Trichloro-N-(2,2-dimethyl-propyl)-N-pyrrolidin-3-yl-benzamide; phenyl-pyrrolidin-3-yl-amide of naphthalene-1-carboxylic acid; 2.3.4- Trichloro-N-(2-cyclopropyl-ethyl)-N-pyrrolidin-3-yl-benzamide; 2.3-Dichloro-N-(2-cyclopropyl-ethyl)-N-pyrrolidin-3-yl-benzamide; 2-Bromo-4-chloro-N-isobutyl-N-pyrrolidin-3-yl-benzamide;

4-chloro-2-ethoxy-N-isobutyl-N-pyrrolidin-3-yl-benzamide;

3- Bromo-4-chloro-N-isobutyl-N-pyrrolidin-3-yl-benzamide;

3, 4-Dichloro-N-isobutyl-2-methyl-N-pyrrolidin-3-yl-benzamide; 2.4-dichloro-3-fluoro-N-isobutyl-N-[pyrrolidin-3-yl]benzamide;

2, 3-dichloro-4-fluoro-N-isobutyl-N-[pyrrolidin-3-yl] benzamide;

2, 3-dichloro-5-fluoro-N-isobutyl-N-[pyrrolidin-3-yl] benzamide;

2,4;5-trichloro-N-isobutyl-N-[pyrrolidin-3-yl]benzamide; 2.5-dichloro-N-isobutyl-N-[pyrrolidine and n-3-yl]benzamide;

2,5-dichloro-4-fluoro-N-isobutyl-N-[pyrrolidin-3-yl]benzamide;

2.3.5-trichloro-N-isobutyl-N-[pyrrolidin-3-ylbenzamide;

2, 3-dichloro-6-fluoro-N-isobutyl-N-[pyrrolidin-3-yl]benzamide;

3,4,-dichloro-6-fluoro-N-isobutyl-N-[pyrrolidin-3-yl]benzamide;

3, 4-dichloro-2-fluoro-N-isobutyl-N-[pyrrolidin-3-yl].benzamide;

2-chloro-3,6-difluoro-N-isobutyl-N-[pyrrolidin3-yl]benzamide;

2,4-Dichloro-5-fluoro-N-isobutyl-N-f(3S)-pyrrolidin-3-yl]benzamide;

and their pharmaceutical and/or veterinary acceptable derivatives.

By pharmaceutical and/or veterinary acceptable derivatives are meant pharmaceutical or veterinary acceptable salts, solvates, esters or amides, salts or solvates of given esters or amides, compounds of the formula (I), (II), (III) or (IV) or other compounds that after administration to the patient can provide (directly or indirectly) the compound of the formula (I), (II), (III) or (IV) or its active metabolite or residue.

For pharmaceutical or veterinary use, the foregoing salts would be pharmaceutically or veterinary acceptable salts, but other salts may be used, for example, to prepare compounds of formula (I), (II), (III) or (IV) and their pharmaceutically or veterinary acceptable salts.

The aforementioned pharmaceutically or veterinary acceptable salts are also their acid and base addition salts.

Suitable acid addition salts are obtained from acids that form non-toxic salts. Examples are the following salts: acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, camsylate, citrate, edisilate, hemidesisylate, esylate, fumarate, gluceptate, gluconate, glucuronate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, pamoate, phosphate/acid phosphate/dihydrogen phosphate, sucrose, stearate, succinate, tartrate and tosylate.

The corresponding base salts are obtained from bases which form non-toxic salts. Examples are: aluminum, 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). Pharmaceutically acceptable salts of compounds of formula (I), (II), (III) or (IV) can be readily obtained by mixing a solution of the compound and the desired acid or base, as appropriate. Salts can settle out of solution and be collected by filtration or regenerated by evaporation of the solvent. The degree of ionization of a salt can vary from fully ionized to almost non-ionized salt.

Pharmaceutically acceptable solvates according to the invention are hydrates and solvates of compounds of formula (I), (II), (III) or (IV).

This invention also includes complexes, such as clathrates, drug-host (host) inclusion complexes, where, in contrast to the previously mentioned solvates, the drug and the host (host) are present in stoichiometric or non-stoichiometric amounts. The present invention also encompasses pharmaceutical drug complexes containing two or more organic and/or inorganic components that may be in stoichiometric or non-stoichiometric amounts. The obtained complexes can be ionized, partially ionized or non-ionized. A review of such complexes is given in J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

Any functional groups of compounds of formula (I), (II), (III) or (IV) can be modified to obtain their pharmaceutically or veterinary acceptable derivatives. Examples of these 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 (incorporated herein by reference) and include: esters, ester carbonates, hemi-esters, phosphate esters, nitro esters, ester sulfates, sulfoxides, amides, sulfonamides, carbamates, azo compounds, phosphamides, glycosides, ethers, acetals, and ketals.

One of ordinary skill in the art will appreciate the fact that certain groups known in the art as "pro-groups" and described among others by H. Bundgaard in "Design of Prodrugs" (ibid) can be placed on the corresponding functional groups when these functional groups are present in the compounds of the invention.

Compounds of formula (I), (II), (III) or (IV) may also contain one or more chiral centers, due to the presence of an asymmetric carbon atom defined by certain meanings of R<1> to R<9> (e.g. s-butyl), or values of the number m. These compounds occur in numerous stereoisomeric forms (e.g. in the form of a pair of optical isomers, or enantiomers). It should be noted that the subject invention includes all isomers of the compounds of the invention, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. tautomeric or racemic mixtures).

The compounds of the invention may occur in one or more tautomeric forms. All tautomers and mixtures thereof are encompassed by the present invention. For example, the claim relating to 2-hydroxydipyridinyl also covers its tautomeric form α-pyridonyl.

It should be noted that the present invention also includes radioactively labeled compounds of formula (I), (II), (III) or (IV).

Compounds of formula (I), (II), (III) or (IV) and their pharmaceutically and veterinary acceptable derivatives may also occur in more than one crystalline form, a property known as polymorphism. All these polymorphic forms ("polymorphs") are covered by the present invention. Polymorphism generally occurs in response to changes in temperature or pressure or both, and may also result from variations in the crystallization process. Polymorphs differ in physical properties, namely in diffraction gratings, solubility, and melting point of compounds.

Unless otherwise indicated, each alkyl group can be straight or branched and 1 of 8 carbon atoms, namely 1 to 6 carbon atoms or 1 to 4 carbon atoms, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group. In the case where the alkyl group contains more than one carbon atom, it may be unsaturated. Thus, the term C1-6alkyl includes C2-6alkenyl and C2-6alkynyl. Similarly, the term C 1-8 alkyl includes C 2-8 alkenyl and C 2-8 alkynyl, and the term C 1-8 alkyl includes C 2-4 alkenyl and C 2-4 alkynyl.

The term halogen refers to fluorine, chlorine, bromine or iodine.

Unless otherwise indicated, the term het includes any aromatic, saturated or unsaturated 4-, 5- or 6-membered heterocycle containing up to 4 heteroatoms selected from N, O and S. Examples of such heterocyclic groups are furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, sulfolanyl, tetrazolyl, triazinyl, azepinyl, oxazapinyl, thiazepinyl, diazepinyl, and thiazolinyl. Further, the term heterocycle includes fused heterocyclyl groups, for example, benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl, dihydroquinazdinyl, benzothiazolyl, phthalimido, benzodiazepine, indolyl, and isoindolyl. The terms het, heterocyclyl and heterocyclic should be interpreted similarly.

For the avoidance of doubt, unless otherwise indicated, the term substituted refers to the substitution of one or more of the indicated groups. In the case where a group can be selected from a number of alternative groups, the selected groups may be the same or different. Further, the term independently means that in the case where more than one substituent is selected from a range of possible substituents, then these substituents may be the same or different.

Further, the compounds of formula (I), (II), (III) and (IV) and their pharmaceutically and veterinary acceptable derivatives, their radiolabeled analogues, their isomers, and polymorphs are designated as "compounds of the invention".

In one embodiment of the invention, the compounds of the invention are pharmaceutically and veterinary acceptable derivatives of compounds of formula (I), (II), (III) or (IV), such as pharmaceutically or veterinary acceptable salts or solvates of compounds of formula (I), (II), (III) or (IV), (e.g. pharmaceutically or veterinary acceptable salts of compounds of formula (I), (II), (III) or (IV)).

In a further embodiment of the invention, there is provided a compound of the invention which is an inhibitor of reabsorption of serotonin and/or noradrenaline monoamine with SRJ or NRIIC50 values of 200nM or less. In another embodiment, the compound has an SRI and/or NRI IC50 value of 100nM or less. And in yet another embodiment, the compound has an SRI or NRI IC50 value of 50 nM or less. In another embodiment, the compound has SRI and NRI IC 50 values of 50 nM or less. In another embodiment of the invention, the compound has SRI and NRI IC50 values of 25 nM or less.

According to Scheme 1, compounds of Formula (V) can be obtained from compounds of Formula (VI) by reaction with aldehyde R<3>CHO, then reaction with an acid or acid chloride R<2>COX (where X is , OH or halo) and removal of protection (deprotection).

In the above scheme, R<2> and m are as previously defined, PG is a protecting group and the -CH 2 R group satisfies the definition for R .

( a) - Reductive Amination

The reaction of 1° amine (VI) with aldehyde to give 2° amine (VII) is a reductive amination reaction, where dehydration of the amine and aldehyde is followed by reduction of the obtained imine with a metal hydride reagent or hydrogenation, in a suitable solvent at room temperature.

In this reaction, equimolar amounts of amine and aldehyde are usually treated with either sodium triacetoxyborohydride (STAB), NaCN(BH)3 or NaBH4, in an appropriate solvent (eg DCM, THF) at room temperature for 1 to 24 hours. Alternatively, an excess of reducing agent (e.g., NaBH4, LiAlH4, STAB) in an appropriate solvent (e.g., THF, MeOH, EtOH) was added after the amine and aldehyde were stirred for 1-18 hours, if necessary in the presence of a drying agent (e.g., molecular sieve) or by removing water using a Dean-Stark apparatus with an appropriate solvent (e.g., toluene, xylene). Another alternative involves catalytic hydrogenation in the presence of palladium or nickel catalysts (e.g. Pd/C, Raney® Ni) in an H2 atmosphere, if necessary at elevated temperature and pressure, in a suitable solvent (e.g. EtOH).

A more specific example of reductive amination involves the reaction of an aldehyde with an amine in the presence of either 10% Pd/C, if necessary in the presence of triethylamine, in ethanol under a hydrogen pressure of about 415 kPa (about 60psi) at room temperature for 18 hours, or excess sodium borohydride in methanol at room temperature for 6 hours.

( b) - Formation of amides

The formation of a peptide bond between an acid or an acid halide and an amine (VII) can occur using either: (i) an acyl halide and an amine (VII), with an excess of an acid acceptor in a suitable solvent, or (ii) an acid, if necessary with a conventional coupling agent, and an amine (VII), if necessary in the presence of a catalyst, with an excess of an acid acceptor in a suitable solvent.

Examples of these reactions are as follows:

(i) Chloral anhydride (generated in-situ if necessary) reacts with excess amine (VII), if necessary with excess 3° amine, such as Et3N, Hiinig's base or NMM, in DCM or dioxane, if necessary at elevated temperature for up to 24 hours; (ii) acid, WSCDI / DCCI / TBTU and HOBT / HOAT react with excess amine (VII) and excess NMM, Et3N, Hunig's base in THF, DCM or EtOAc, at room temperature for 4 to 48 hours; or (iii) the acid and PYBOP<®>/PyBrOP<®>/Mukaiyama reagent are reacted with excess amine (VII) and excess NMM, Et3N, Hiinig's base in THF, DCM, or EtOAc, n room temperature, for 4 to 24 hours.

When the halide-anhydride is chloroanhydride (i.e. X=C1), it can be formed in-situ according to standard methodology and then reacted with amine (VII) and triethylamine in dichloromethane at 70°C for 90 minutes.

(c) - Removal of protection (deprotection)

In the case where the PG is an appropriate amine-protecting group, preferably BOC, trifluoroacetate, or benzyl, removal of the PG from (VIII), yielding the unprotected amine (V), is performed according to a protecting-group-selective method as described in 'Protective Groups in Organic Synthesis', 3<rd>edition, by TW Greene and PGM Wuts. John Wiley and Sons, Inc., 1999, incorporated herein by reference.

Examples of such deprotection reactions are as follows:

When PG is BOC, deprotection involves reaction of (VIII) with a strong acid (eg, HCl, TFA) in excess, at room temperature in a suitable solvent (eg, DCM, EtOAc, dioxane).

When PG is trifluoroacetate, deprotection involves reaction (VIII) with a base (e.g. K2CO3, Na2CO3, NH3, Ba(OH)2) in an alcoholic solvent (e.g. MeOH, EtOH), if necessary with water and if necessary at an elevated temperature.

When PG is Bz, deprotection includes either transfer hydrogenation with a transition metal or a transition metal salt as a hydrogenation catalyst (e.g. Pd/C, Pd(OH)2) in the presence of a hydrogen donor (e.g. NH/HCOV) in a polar solvent (e.g. tetrahydrofuran, ethanol, methanol) as needed at elevated temperature and/or pressure, or catalytic hydrogenation in the presence of a palladium or nickel catalyst (e.g. Pd/C, Raney® Ni) in an H2 atmosphere, if necessary at elevated temperature and pressure, in a suitable solvent.

More details:

When PG is BOC, deprotection involves reaction with either excess 4M hydrochloric acid in dioxane for 18 hours at room temperature. Or with TFA in DCM for 4.5 hours at RT (room temperature).

When PG is trifluoroacetate, deprotection involves reaction with K2C03 in a mixture of methanol and water (5:1 to 10:1) at room temperature for 18 hours.

When PG is Bz, deprotection involves reaction with NH/HCO2" and 10% Pd/C in ethanol under gentle reflux for between 6 and 20 hours.

According to Scheme 2, compounds of Formula (IX) can be obtained from compounds of Formula (VI) by reaction with R - L, where L is a leaving group, under suitable conditions. The resulting compound of Formula (IX) can then be converted to a compound of Formula (II), by amide formation and deprotection in a manner analogous to that previously described in Scheme 1.

In this scheme, R 2 , R 3 and m are as previously defined, PG is an appropriate protecting group and L is a leaving group, the meaning of which will inter alia depend on the nature of the reaction and the specific reaction conditions. Suitable leaving groups will be apparent to one of ordinary skill in the art and are described in a number of standard organic chemistry texts, for example: "Advanced Organic Chemistrv", Jerry March, Third Edition, Wiley (1985), page 587, herein incorporated by reference, and may be halogen (e.g., Br) and sulfonate esters (e.g., methanesulfonate or trifluoromethanesulfonate).

Accordingly, R 3 is an aryl group, L is Br and reaction (d) takes place in a suitable solvent at elevated temperatures in the presence of palladium as a catalyst. These catalyst-mediated aryl amination reactions are known to one of ordinary skill in the art.

A more specific example of the process according to Scheme 2 includes the reaction of aryl boramide and amine of Formula (VI) in the presence of tris(dibenzylideneacetone)dipalladium, 2,2'-bis(diphenylphosphino)-1,r-binaphthyl and sodium tert-butoxide in toluene at 100°C for 8 hours.

According to Scheme 3, compounds of Formula (IX) can be obtained from ketones of Formula (XII) by reaction with a primary amine R -NH 2 under suitable conditions. The resulting compounds of Formula (IX) can then be converted to compounds of Formula (II) by amide formation and deprotection in a manner analogous to that previously described in Scheme 1.

In the preceding Scheme, R 2 , R 3 and m are as previously defined, and PG is a protecting group.

The reaction (e) of the primary amine R2-NH2 with the ketone (XII) can simply be a reductive amination reaction where the dehydration of the amine and ketone is followed by the reduction of the resulting imine, for example, with a metal hydride reagent or hydrogenation, under appropriate conditions. Furthermore, the reaction of amine and ketone takes place in the presence of titanium (IV) tetraisopropoxide in THF at room temperature for 18 hours, followed by reduction with excess sodium borohydride in methanol at room temperature for 5 hours.

A person skilled in the art can choose a synthetic route to obtain the desired compound Formula (I), (II), (III) or (IV), which corresponds to the above. Of course, the previously given Schemes can be modified if necessary in accordance with the general knowledge of an average expert.

For example, one of ordinary skill will appreciate that the hydrogen bonded to the piperidine or pyrrolidine nitrogen (depending on the value of m) of the protected amide (II) or (V) can be replaced with alternative groups as desired to give a compound of Formula (I) where n is 1 and m is 0 or 1, using conventional synthetic methodologies.

Furthermore, the compounds of Formula (I) where n is 2 and m is 0, can be obtained according to processes analogous to those previously described starting from the appropriate starting materials.

One of ordinary skill will recognize that one or more sensitive functional groups must be protected during the synthesis of compounds of Formula (I), (II), (III) or (IV). This can be accomplished by conventional techniques as described in "Protective Groups in Organic Synthesis", 3<rd>edition, by TW Greene and PGM Wuts. John Wiley and Sons, Inc., 1999, herein incorporated by reference in its entirety, which also describes methods of removing these groups.

It will be apparent to the person skilled in the art that certain derivatives of the compounds of the invention, which can be obtained before the last stage, as such have no pharmacological activity, in certain cases, can be administered orally or parenterally and then metabolized in the body to give pharmacologically active compounds of the invention. These derivatives can therefore be described as prodrugs. Further, certain compounds of the invention may act as prodrugs or other compounds of the invention.

Accordingly, according to the following aspect of the invention, there is provided a procedure (process) for obtaining compounds of Formula (I), (II), (III) or (IV), which includes the reaction of compounds of formula (X) where R<3>, n and m are as previously defined, and Y is R<1> or a protecting group, with an acid or an acyl halide (acyl halide): R<2>COX, where X is , OH or halo, and deprotection, if necessary.

Where R comprises a methylene group directly attached to a nitrogen atom, then a compound of Formula (X) can be obtained by reacting a compound of Formula (XXI) with an aldehyde R<3>CHO (where

-CH2R satisfies the definition for R).

Alternatively, a compound of Formula (X) can be obtained by reacting a compound of Formula (XXI) with a compound R<3->L, where L is a leaving group, optionally selected from halides, methanesulfonates and trifluoromethanesulfonates.

Furthermore, the compound of Formula (X) can be obtained by reacting the compound of Formula (XXII) with the compound R -NH2.

Certain of the previously described intermediates are novel compounds and it should be noted that all of the novel intermediates disclosed herein constitute additional aspects of the present invention.

Racemic compounds can be separated either by preparative HPLC and a column with a chiral stationary phase or resolved to give the individual enantiomers using methods known to one of ordinary skill in the art. Furthermore, chiral intermediates can be separated and used to obtain chiral compounds of the invention.

According to a further aspect of the invention, one or more metabolites of a compound of the invention when obtained in vivo are provided.

Peonalaska compounds are useful and possess pharmacological activity in mammals, including humans. Furthermore, they are useful for the treatment or prevention of diseases in which the regulation of monoamine transporter function is involved, that is, diseases in which the resorption of serotonin or noradrenaline is involved, and especially those in which the inhibition of resorption of serotonin and noradrenaline is involved.

Accordingly, the compounds of the invention are useful for the treatment of urinary incontinence, such as true stress incontinence (GSI), urinary stress incontinence (USI) or urinary incontinence in the elderly; overactive bladder (OAB), including idiopathic detrusor muscle instability, detrusor overactivity secondary to neurological disease (eg, Parkinson's disease, multiple sclerosis, spinal cord injury and stroke) and detrusor overactivity secondary to bladder outflow obstruction (eg, benign prostatic hyperplasia (BPH), uterine stricture or stenosis); mocturnal enuresis; urinary incontinence caused by a combination of the aforementioned conditions (eg true stress incontinence associated with an overactive bladder); and urinary symptoms, such as frequency and urge to urinate frequently.

In view of the above pharmacological activities, the compounds of the invention are also useful for the treatment of depression, such as major depression, recurrent depression, single episode depression, subsyndromal symptomatic depression, depression in cancer patients, depression in Parkinson's disease patients, postmyocardial infarction depression, pediatric depression, depression induced by childhood abuse, depression in infertile women, post parum depression, premenstrual dysphoria and "grumpy old man" syndrome.

In terms of the aforementioned pharmacological activity, the compounds of the invention are also useful for the treatment of cognitive disorders such as dementia, especially degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeld-Jakob disease) and vascular dementia (including multi-infarct dementia), as well as dementia related to the intracranial space including lesions, trauma, infections and related conditions (including HIV infection), metabolism, toxins, anoxia and vitamin deficiency; mild age-related cognitive impairment, especially age-related memory impairment (AAMI), amnestic disorders and age-related cognitive deficit (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, mild anxiety and depression; personality disorders such as avoidant 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); an eating disorder, such as anorexia nervosa and bulimia nervosa; obesity, appetite suppression, chemical dependencies resulting from drug addiction or substance abuse, such as addiction to nicotine, alcohol, cocaine, heroin, phenobarbital and benzodiazepines; withdrawal syndrome, such as those that can arise from the previously mentioned chemical addictions; cephalic pain, such as migraine, cluster headache, chronic paroxysmal hemicarnia, headache associated with vascular disease, headache resulting from chemical dependence and tension headache; pain; Parkinson's disease, such as dementia in Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesia); endocrine disorders, such as hyperprolactinemia; vasospasm, such as cerebral vasculature; cerebral ataxia; Tourette's syndrome;

trichotillomania; kleptomania; emotional lability; pathological crying; sleep disorder (cateplexy) and shock.

In view of the aforementioned pharmacological activities, the compounds of the invention are also useful in the treatment of numerous other conditions and disorders, including hypertension; disorders of the gastrointestinal tract (including changes in motility 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 (GORD or synonymous 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 terms of the aforementioned pharmacological activity, the compounds of the invention may also be useful for the treatment of pain. For example, strain/sprain pain, post-operative pain (pain after any type of surgery), post-traumatic pain, burns, myocardial infarction, acute pancreatitis and renal colic. Also symptoms of acute pain associated with cancer which usually arise from therapeutic interactions such as chemotherapy toxicity, immunotherapy, hormonal therapy and radiotherapy. Further examples include pain associated with a tumor (eg, leg pain, headache and facial pain, visceral pain) or related to cancer therapy (eg, post-chemotherapy syndromes, chronic postoperative pain syndrome, post-radiation syndromes), back pain due to herniated or ruptured intervertebral disc or joint abnormalities of the lumbar fascia, sacroiliac joints, paraspinal muscles, posterior longitudinal ligaments.

Additionally, the compounds of the invention may be useful for the treatment of neuropathic pain. This is better defined as pain initiated or caused by primary lesions or dysfunctions in the nervous system (IASP definition). Nerve damage can be caused by trauma or disease, and thus the term 'neuropathic pain' includes numerous disorders with different etiologies. This includes, but is not limited to, diabetic neuropathy, post herpetic neuralgia, back pain, cancerous neuropathy, chemotherapy-induced neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, chronic alcoholism, hypothyroidism, trigeminal neuralgia, uremia, trauma-induced neuropathy, or vitamin deficiency.

Other types of pain including but not limited to:

inflammatory pain, such as arthritic pain, including rheumatoid arthritis (RA) and

osteoarthritis (OA) and irritable bowel syndrome (IBD);

musculoskeletal disorder including but not limited to myalgia,

fibromyalgia, spondylitis, ser-negative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis, pyomyositis;

central pain or "thalamic" pain caused by lesions or dysfunctions of the nervous system including, but not limited to, central post-stroke pain, 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, scleroderma, 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 headache; and

orofacial pain including, but not limited to, dental pain,

temporomandibular myofacial pain.

Disorders of particular importance are urinary incontinence, such as combined incontinence, GSI and USI; bo; depression; anxiety disorders, such as obsessive compulsive disorder and post-traumatic stress disorder; personality disorder, such as ADHD; sexual dysfunction; and chemical dependencies and withdrawal symptoms resulting from chemical dependencies.

Therefore, according to further aspects, the invention provides:

(i) the compound of the invention for use in human and veterinary medicine; (ii) a compound of the invention for use in the treatment of disorders in which the regulation of monoamine transporter function is implicated, such as urinary incontinence; (iii) application of the compound for the production of a drug for the treatment of a disorder in which the regulation of monoamine transporter function is implicated; (iv) the compound of the invention for use in the treatment of a disorder in which the regulation of serotonin or noradrenaline is implicated; (v) using a compound of the invention for the production of a medicament for the treatment of a disorder in which the regulation of serotonin or noradrenaline is implicated; (vi) a compound of the invention for use in the treatment of disorders in which the regulation of serotonin and noradrenaline is implicated; (vii) use of the compound of the invention for the manufacture of a medicament for the treatment of disordered disorders in which the regulation of serotonin or noradrenaline is implicated; (viii) a compound of the invention for use in the treatment of urinary incontinence, such as a GSI

or USI;

(ix) application of the compound of the invention for the production of a drug for the treatment of urinary

incontinence, such as GSI or USI;

(x) procedure for the treatment of a disorder in which a disorder of the regulation of the function of the monoamine transporter is implicated, which includes the administration of a therapeutically effective

amounts of compounds of the invention to a patient in need of such treatment;

(xi) a method of treating a disorder involving the regulation of serotonin or noradrenaline, which comprises administering a therapeutically effective amount

compounds of the invention to a patient in need of such treatment;

(xii) a method of treating a disorder involving the regulation of serotonin or noradrenaline, which includes administering a therapeutically effective amount

compounds of the invention to a patient in need of such treatment;

(xiii) a method of treating urinary incontinence, such as GSI or USI, comprising administering a therapeutically effective amount of a compound of the invention to a patient in need of such treatment;

It should also be emphasized that all references to treatment include curative, palliative and prophylactic treatment, unless otherwise indicated.

The compounds of the invention may be administered alone or as part of a combination therapy. If a combination of therapeutic agents is administered, then the active ingredients may be administered one after the other or simultaneously in separate or combined pharmaceutical formulations.

Examples of suitable adjunctive therapy agents include:

Estrogen agonist or selective estrogen receptor modulator (eg HRT therapy or lasofoxifene); An alpha-adrenergic receptor agonist, such as phenylpropanolamine or R-450; Alda-adrenergic receptor antagonists (eg, phentolamine, doxazasin, tamsulosin, terazasin and prazasin) including selective alpha1-adrenergic receptor antagonists (eg, Example 19 in WO98/030560); Beta-adrenergic agonist (eg clenuterol); Muscarinic receptor antagonist / eg. tolterodine or oxybutynin) including muscarinic M3 receptor antagonists (eg 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 (eg, NK1, NK2, or NK3 antagonist); Beta 3 receptor agonist; 5HTi ligand (eg, buspirone); a 5HT agonist, such as a triptan (eg, sumatriptan or naratriptan); a dopamine receptor agonist (eg, apomorphine, discussed as a pharmaceutical preparation found in US-A-5945117), including a dopamine D2 receptor agonist (eg, premiprixal, Pharmacia Upjohn compound number PNU95666; or ropinirole): a melanocortin receptor agonist (eg, melanotan II); PGE receptor antagonist; PGE1 agonist (eg, alprostadil); Other monoamine transporter inhibitors, such as a noradrenaline reuptake inhibitor (eg, reboxetine), a serotonin reuptake inhibitor (eg, sertraline, fluoxetine or paroxetine) or dopamine reuptake inhibitors; 5-HT3 receptor antagonist (eg, ondansetron, granisetron, tropietron, azasetron, dolasetron, or alosetron); a phosphodiesterase (PDE) inhibitor, such as a PDE2 inhibitor (eg, erythro-9-(2-hydroxyl-3-nonyl)-adenine of Example 100 in EP 0771799, incorporated herein by reference) and especially a PDE5 inhibitor e.g. sildenafil; 1-{[3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f-as-trazin-2-yl)-4-ethoxyphenyl]sulfonyl}-4-ethylpiperazine, i.e. vardenafil, also known as Bayer BA 38-9456; or Icos Lilly's IC351, see structure below).

In a further aspect, the invention provides a combination comprising a compound of the invention, together with other therapeutic agents.

For human use, the compounds of the invention should be administered alone, but in human treatment they will generally be administered in admixture with appropriate pharmaceutical excipients or carriers selected according to the desired route of administration and standard pharmaceutical practice.

For example, the compounds of the invention may be administered orally, buccally, or sublingually in the form of tablets, capsules (including soft gel capsules), ovules, elixirs, solutions, or suspensions, which may contain flavors and colors, for immediate-, delayed-, modified-, continuous-, dual-, controlled-release, or pulsatile distribution. The compounds of the invention may also be administered by intracavernous injection. The compounds of the invention can be administered by rapid dispersing or rapid dissolving dosage forms.

Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, chromium or tapioca starch), disintegrants such as starch sodium glycolate, croscarmellose sodium and certain complex silicates and granulacin binders such as polyvinylpyrrolidone, hydroxypropylmethycellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, glidants such as magnesium stearate, stearic acid, glyceryl behenate and talc may be added.

Solid preparations of any type can also be used as fillings for gelatin capsules. Preferred excipients for this purpose are lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycol. For aqueous suspensions and/or elixirs, the compounds of the invention and their pharmaceutically acceptable salts may be combined with various sweeteners or flavors, colors, emulsifiers or suspending reagents and with diluents such as water, ethanol, propylene glycol and glycerin and combinations thereof.

Modified or pulsed release dosage forms may contain excipients such as those provided for immediate release dosage forms together with additional excipients that act as release modifiers, where these may be applied as a coating fdm and/or contained in the dosage form. Release rate modifiers include, but are not limited to, hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, xanthan gum, carbomer, ammonium methacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer, and mixtures thereof. Modified-release and pulsatile-release dosage forms may contain one or more combinations of excipients that modify the rate of release. Excipients that modify the release rate can also be present in the dosage form, i.e. as part of the matrix and/or on its surface, i.e. on the surface or as part of the coating film.

Fast Dispersing or Dissolving Dose Formulations (FDDF) 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 flavor, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol. The term dispersion or dissolution is used here to describe that FDDFs depend on the solubility of the drug used ie. when the drug is insoluble, a fast-dispersing dosage form can be prepared, and in the case when the drug is soluble, a fast-dissolving dosage form can be prepared.

The compounds of the invention may also be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously, or may be administered by infusion techniques. For parenteral administration, it is better to use them as sterile solutions that may contain other substances, for example, enough salt or glucose to make the solution isotonic with blood. Aqueous solutions should be buffered (preferably pH 3 to 9), as needed. Obtaining a suitable parenteral formulation under sterile conditions is readily accomplished by standard pharmaceutical techniques known to one of ordinary skill in the art.

For oral administration to human patients, the daily dose level of a compound of the invention or a salt or solvate thereof will range from 10 to 500 mg (in one or more divided doses).

Thus, for example, tablets or capsules of the compounds of the invention or their salts or solvates may contain from 5 to 250 mg of the active compound for administration at once or two or more times, as needed. In any case, the doctor will determine the dose that will be suitable for each patient and will vary with the age, weight and reaction of the patient. The above doses are given as examples for an average case. There will also be cases where higher or lower doses are preferred and are also within the scope of this invention. One of ordinary skill will also appreciate that for the treatment of certain conditions (including PE), the compounds of the invention may be taken in a single dose or "as needed" (ie, as desired).

Examples of tablet formulations

In general, tablet formulations should typically contain from 0.10 mg to about 500 mg of a compound of the present invention (or a salt thereof), while the tablet weight ranges from 50 mg to 1000 mg. An example of a 10 mg tablet formulation is:

The compounds of the invention can also be administered intranasally or by inhalation and are usually delivered as a dry inhalation powder or aerosol spray from a pressurized container, pump, spray or nebulizer using a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoroalkane such as 1,1,1,2-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 pressurized aerosols, the unit of measure can be determined with the help of a valve that dispenses a metered quantity. A pressurized container, pump, spray or nebulizer may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and prolean as a solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made, for example, of gelatin) for use in inhalers or insufflators can be formulated to contain a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch.

Aerosol or dry formulations are adjusted so that each metered dose or "puff" contains from 1 to 50 mg of compound for distribution to the patient. The total daily dose with an aerosol will range from 1 to 50 mg and may be administered in one or, more commonly, in multiple divided doses throughout the day.

The compounds of the invention may also be formulated for distribution via an atomizer. Atomizer formulations may contain the following ingredients as solvents, emulsifiers or suspending agents: water, ethanol, glycerol, propylene glycol, low molecular weight polyethylene glycols, sodium chloride, hydrofluorocarbons, polyethylene glycol ethers, sorbitan trioleate, oleic acid.

Alternatively, the pronal compounds may be administered as suppositories or pessaries or may be applied topically as gels, hydrogels, lotions, solutions, creams, salves or powders. The compounds of the invention can also be administered dermally or transdermally, for example, by applying a patch. They can also be administered ocularly, pulmonaryly, or rectally.

For ophthalmic use, the compounds may be formulated as micronized suspensions in isotonic, pH-adjusted, sterile saline solutions or preferably, as isotonic, pH-adjusted, sterile saline solutions in combination with preservatives such as benzalkonium chloride. Alternatively, they can be formulated as ointments in petrolatum.

For application topically to the skin, the compounds of the invention may 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 ingredients: mineral oil, petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they may be formulated as a lotion or cream, suspended or dissolved in, for example, a mixture with one or more of the following ingredients: mineral oil, sorbitan monostearate, 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. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Drug-cyclodextrin complex formation can modify the dissolution rate, bioavailability and/or stability of the drug molecule. Drug-cyclodextrin complexes are generally useful for the most common dosage forms and routes of administration. As an alternative to direct complexation with the drug, cyclodextrin can be used as an auxiliary additive, e.g. as a carrier, diluent and solvent. 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 dosage level of the compounds of formula (I) and their pharmaceutically acceptable salts will range from 0.01 to 30 mg/kg (in one or more divided doses) and ideally will range from 0.01 to 5 mg/kg. The tablets will accordingly contain 1mg to 0.4g of the compound for administration once or twice or more, as required. In any case, the doctor will determine the dose that will be suitable for each patient and will vary with the age, weight and reaction of the patient. The above doses are given as examples for an average case. There will also be cases where higher or lower doses are preferred and are also within the scope of this invention.

For veterinary use, a compound of the invention is administered as an acceptable formulation in accordance with normal veterinary practice and the veterinary surgeon will determine the dosage regimen and route of administration most appropriate for a given animal.

Thus, according to the following aspect, the invention provides a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable adjuvant, diluent and carrier.

The aforesaid combinations may also be practically recommended for use in the form of pharmaceutical formulations, wherein these formulations contain combinations as defined above with a pharmaceutically acceptable adjuvant, diluent or carrier, thus forming the next aspect of the invention. The individual components of such combinations can be administered either sequentially or simultaneously in separate or combined formulations.

When a compound of the invention is used in combination with another therapeutic, then the dosage of each compound may vary from that when the compound is used alone. A person skilled in the art will readily appreciate the appropriate dosages.

The invention is illustrated by the following non-limiting examples, in which the following abbreviations and definitions are used:

APCI Chemical ionization at atmospheric pressure

Arbacel® filter agent

no wide

BOC /<?t/-butoxycarbonyl

CDI carbons Idiimidazole

5 Chemical shift

d doublet

And the warm-up

DCCl dicyclohexylcarbodiimide

DCM dichloromethane

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

ES<+>Positive scan electrospray ionisation

ES" Negative scan electrospray ionisation

h hours

HOAT 1 -hydroxy-7-azabenzotriazole

HOBT 1-hydroxybenzotriazole

HPLC Liquid chromatography under high pressure

m/z Peak (maximum) of the mass spectrum

minutes minutes

MS mass spectrum

NMM N-methyl morpholine

NMR nuclear magnetic resonance

q quartet

with a singlet

t triplet

TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate

Tf trifluoromethanesulfonyl

TFA Trifluoroacetic acid

THF tetrahydrofuran

TLC Thin Layer Chromatography

TS<+>Positive thermal spray ionization scan

WSCDI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

The preparations and Examples that follow illustrate the invention but do not limit it in any way. All temperatures are in °C. Flash column chromatography was performed on Merck silica gel 60 (9385). Solid phase extraction (SPE) chromatography was performed on Varian Mega Bond Elut (Si) cartridges (Anachem) under a vacuum of 15 mmHg. Thin layer chromatography (TLC) was performed on Merck silica gel 60 plates (5729). The melting point was determined on a Gallenkamp MPD350 apparatus and the values given are uncorrected. NMR was measured on a Varian-Unity Inova 400MHz nmr spectrometer or a Varian Mercury 400MHz nmr spectrometer. Mass spectroscopy was performed on a Finnigan Navigator single quadrupole electrospray mass spectrometer or a Finnigan aQa APCI mass spectrometer.

Preparation 1

tert-Butyl(3R)-1-(trifluoroacetyl)pyrrolidine-3-ylcarbamate

(3i?)-3-( tert -Butoxycarbonylamino)pyrrolidine (3.0g, 16.1mmol - purchased from Flurochem) and pyridine (3.87mL, 48.3mmol) were dissolved in dichloromethane (55mL) and the reaction mixture was stirred under a stream of nitrogen at 0°C for 1 hour. A solution of trifluoroacetic anhydride (2.74 mL, 32.2 mmol) in dichloromethane (5 mL) was added dropwise to the reaction mixture over 10 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was diluted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate solution, water and then brine. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. The crude product was azeotroped with toluene (2x3OmL) to give the desired product.

<1>HNMR(DMSO-D6, 400MIIz): 1.40(s, 911), 1.82(dd, IH), 2.08(dd, IH), 3.33(m, IH), 3.46(m, IH), 3.59-3.77(brm, 2H), 4.06(m, IH), 7.22(m, IH)

MS ES+m/z281 [MH]<+>

Preparation 2

(3R)-]-(Trifluoroacetyl)pyrrolidine-3-amine hydrochloride

The Boe protected amine of preparation 1 (4.59g, 16.1mmol) was dissolved in dichloromethane (100mL) and the reaction mixture was stirred at 0°C for 1 hour. Chloro hydrogen gas was blown through the solution for 10 minutes and the reaction mixture was allowed to warm to room temperature. Hydrogen chloride gas and nitrogen gas were blown through the solution for 15 and 10 minutes, respectively, and the reaction mixture was concentrated in vacuo to give the desired product.

'HNMRCDCb, 400MHz): 1.27(m, 2H), 1.65(m, IH), 1.81(m, IH), 2.10(m, 2H), 3.32(m, 2H), 3.61(m, IH)

MS ES+m/z183 [MH]+

Preparation 3

tert-Butyl (35V3-(isobutylamino)pyrrolidine-1 4x:carboxylate

(3S)3-Amino-pyrrolidine-1-carboxylic acid tert-butyl ester (3g, 16.1mmol) was added to a solution of isobutyraldehyde (1.61mL, 17.7mmol) and 10% Pd/C (360mg) in ethanol (60mL) and the reaction mixture was left under 415 kPa (about 60psi) of hydrogen gas for 18 hours. The reaction mixture was filtered through Arbocel®, washing thoroughly with ethyl acetate. The filtrate was concentrated in vacuo and the crude product was purified by chromatography on a silica gel column, eluting with ethyl acetate pentane, giving the desired product, 2.8g, (73%).

HNMR (CDC13, 400MHz): 0.92 (d, 6H), 1.44 (s, 9H), 1.63 (m, 2H), 2.00 (m, IH), 2.39 (m, 2H), 3.02 (m, IH), 3.25 (m, 2H), 3.48 (m, 2H), 3.60 (m, IH)

MS APCI+ 243 [MH<+>]

Preparation 4

GSVA^-Butyl-l-ftrifluoroacetiDpyrrolidine-S-amine

Triethylamine (1.9mL, 13.72mmol) and butanal (1.3mL, 14.41mmol) were added to a solution of (S)-1-(trifluoroacetyl)pyrrolidin-3-ylamine (3.0g, 13.72mmol) (J. Med. Chem., 1996, 39(14), p. 2771, No. 6) in ethanol (60mL). 10% Pd/C (300mg) was added to the reaction mixture and the mixture was subjected to a hydrogen pressure of 415 kPa (about 60psi) at room temperature for 18 hours. The reaction mixture was filtered through Arbocel®, washed extensively with ethyl acetate. The filtrate was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography eluting with ethyl acetate:pentane:triethylamine 25:75:0 to 100:0:0 to 99:0:1 to give the desired product.

HNMR(CDC13, 400MHz): 1.01(t, 3H), 1.38(m, 2H), 1.47(m, 2H), 1.86-2.09(m, 2H), 2.62(m, 2H), 3.38-3.87(brm, 6H)

MS APCI+ m/z 239 [MH]<+>

Preparation 5

( 3»SV./ y- Isobutyl- 1 - ( trifluoroacetyl) pyrrolidine- 3 - amine

This compound was obtained according to a method similar to that described for preparation 4 using isobutyraldehyde.

HNMR(CDC13, 400MHz): 0.9l(t, 6H), 1.26(d, 2H), 1.47(m, 2H), 1.72(m, 1H), 2.42(m, 2H), 3.39(m, 2H), 3.77(m, 1H), 4.09(m, 1H)

MS APCI+ m/z 239 [MH]<+>

Preparation 6

(3Zl-Benzyl-Al-(2-methylmethyl)pyrrolidin-3-amine

A solution of 2-naphthaldehyde (2.0g, 12.8mmol) and (35)-l-benzyl-3-amino-pyrrolidine (2.37g, 13.4mmol) in methanol (30mL) was stirred under a stream of nitrogen at room temperature for 6 hours. Sodium borohydride (969mg, 25.6mmol) was added and the reaction mixture was left at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (x3) and the organic fractions were combined, dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with dichloromethane methanol 100:0 to 97:3 to give the desired product, 4.01g.

HNMR(CDC13, 400MHz): 1.62(m, 1H), 2.19(m, 1H), 2.48(m, 2H), 2.80(m, 2H), 3.42(m, 1H), 3.63(s, 2H), 3.92(m, 2H), 7.26(m, 5H), 7.44(m, 3H), 7.78(m, 4H) MS APCI+m/z317[MH]+

Preparation 7

(3R)-1-Benzyl-Af-(2-naphthylmethyl)pyrrolidin-3-amine

This compound was obtained according to a method similar to that described for preparation 6 using (3R)-[benzyl-3-amino-pyrrolidine].

'HNMRfCDCl, 400MHz): 1.65(m, IH), 2.18(m, IH), 2.5l(m, 2H), 2.78(m, 2H), 3.41 (m, IH), 3.63(m, 2H), 3.94(s, 2H), 7.22(m, IH), 7.28(m, 4H), 7.43(m, 3H), 7.79(m, 4H) MS APCI+m/z317 [MH]+

Preparation 8

(3j?)-Af-(3,4-Dichlorobenzyl)-1-(trifluoroacetyl)pyrrolidin-3-amine

This compound was obtained by a method similar to that described for preparation 6 using the amine from preparation 2 and 3,4-dichlorobenzaldehyde.

HNMR(DMSO-D6, 400MHz): 1.88(m, 2H), 2.63(m, 1H), 3.36-3.78(m, 7H), 7.32(m, 1H), 7.59(m, 2H)

MS APCI+ m/z341 [MH]<+>

Preparation 9

(3i?)-7N-('2,3-Dichlorobenzyl)-1-(trifluoroacetyl)pyrrolidin-3-amine

This compound was obtained by a method similar to that described for preparation 6 using the amine from preparation 2 and 2,3-dichlorobenzaldehyde.

HNMR(DMSO-D6, 400MHz): 1.92(m, 2H), 3.29-3.74(m, 7H), 3.83(m, 1H), 7.27(m, 1H), 7.5 l(m, 2H)

MS APCI+m/z341 [MH]<+>

Preparations 10- 12

The corresponding carboxylic acid, RCO2H (lmmol), was dissolved in dichloromethane (5mL), cooled in an ice bath, and the cooled solution treated with oxalyl chloride (0.248mL, 2.5mmol) and 1 drop of N,N-dimethylformamide. The ice was removed and the reaction mixture was allowed to warm to room temperature and then stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the product added to a solution of triethylamine (0.229mL, 1.64mmol) and the amine from preparation 3 (200mg, 0.83mmol) in dioxane (10mL). The reaction mixture was heated for 45 minutes at 70°C and then allowed to cool to room temperature. The reaction mixture was concentrated in vacuo and dichloromethane was added to the product and the solution was washed with 10% citric acid solution and 2M sodium hydroxide solution. The organic layer was separated and concentrated in vacuo. The crude product was purified by chromatography on a silica gel column, eluting with dichlorometammethanol 100:0 to 98:2 to give the desired products.

Preparation 13

tert-Butyl (3l$ l- 3-[f2, 3- dichlorobenzoyl)(isobutyl) amino1pyrrolidine-l- carboxylate

The amine from preparation 3 (200mg, 0.826mmol) was added to a solution of triethylamine (0.229mL, 1.652mmol) and in dioxane (5mL) and 2,3-dichloro-benzoyl chloride (207mg, 0.99mmol) was added to the reaction mixture. The reaction mixture was heated to 70°C and stirred for 90 minutes. The reaction mixture was concentrated in vacuo and dichloromethane was added to the product and the mixture was washed with 2M sodium hydroxide and 10% citric acid solution. The organic fractions were separated and concentrated in vacuo. The crude product was purified by chromatography on a silica gel column, eluting with dichloromethane, giving the desired product, 278mg, (81%).

MS APCI+m/z315 [MH]+

Preparations 14- 17

The following compounds of the above general formula were obtained by a method similar to that described in Preparation 13 using the amine of Preparation 3 and the corresponding acid chloride:

Preparation 18N -\( 3S )- 1 - Benzylpyrrolidin- 3-yl- A^-( 2- naphthylmethyl) benzamide

Benzoyl chloride (0.12mL, 1.043mmol) was added to a solution of the amine from Preparation 6 (300mg, 0.948mmol) and triethylamine (0.26uL, 1.896mmol) in dichloromethane (5mL) and the reaction mixture was left under a stream of nitrogen at room temperature for 18 hours. The reaction mixture was washed with water and then brine, dried over magnesium sulfate and concentrated in vacuo to give the desired product, 380mg.

<1>HNMR(CDC13, 400MHz): 1.83-2.62(brm, 4H), 2.84(m, 2H), 3.62(m, 2H) 4.56(m, IH), 5.05(m, 2H), 7.24(m, 4H), 7.31-7.60(m, 9H), 7.78(m, 4H)

MS ES+m/z421 [MH]<+>

Preparation 19

N -\( 3R )- 1 - Benzylpyrrolidine-3 - or - N -( 2- naphthylmethyl) benzamide

The title compound was obtained using a procedure similar to that described for preparation 18 using the amine from preparation 7

HNMR (CDC13, 400MHz): 1.94-2.58 (brm, 6H), 2.86 (m, 2H), 3.62 (m, 1H), 5.08 (m, 2H), 7.23 (m, 4H), 7.34-7.60 (m, 9H), 7.79 (m, 4H)

MS APCI+m/z421 [MH]<+>

Preparation 20

jV- Butyl- iV- [( 351- 1 - (trifluoroacetyl) pyrrolidine- 3 - or - 1 - naphthamide

The title compound was obtained using a procedure similar to that described for Preparation 18 using the amine from Preparation 4 and naphthoyl chloride.

HNMR (CDCl3, 400MHz): 0.61 (m, 2H), 0.98 (m, 3H), 1.32-1.60 (brm, 4H), 3.06 (m, 2H), 3.27-3.76 (m, 4H), 5.28 (m, IH), 7.39 (m, IH), 7.45 (m, 3H), 7.72 (m, 1H), 7.89 (m, 2H) MS APCI+ m/z 393 [MH]<+>

Preparations 21

A^ 4isobutyl- V4( 3^- 1-( trifluoroacetinpyrrolidin- 3- yl1- 2- naphthamide)

The title compound was obtained using a procedure similar to that described for preparation 18 using naphthoyl chloride and the amine of preparation 3.

'HNMR (CDC13, 400MHz): 0.84 (m, 8H), 2.00 (m, 1H), 3.25 (m, 2H), 3.93 (m, 2H), 4.38 (brm, 1H), 5.31 (m, 2H), 7.24 (m, 2H), 7.38-7.62 (m, 5H)

MS APCI+ m/z 393 [MH]<+>

Preparation 22

4- Chloro- A^-(3, 4-dichlorobenzyl)- A^-[( 3i?)- 1-(trifluoroacetyl) pyrrolidin-3- yl1benzamide

The amine from preparation 8 (180 mg, 0.58 mmol) was dissolved in dichloromethane (3 mL) and the reaction mixture treated with triethylamine (0.16 mL, 1.16 mmol). The reaction mixture was cooled to 0 °C and 4-chlorobenzoyl chloride (0.08 mL, 0.63 mmol) was added dropwise. The reaction mixture was stirred under a nitrogen atmosphere for 18 hours. The reaction mixture was diluted with more dichloromethane and washed with water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with dichloromethanemethanol 100:0 to 95:5 to afford the title product.

HNMR (DMSO-D6, 400MHz): 2.02 (m, 2H), 3.37-3.72 (m, 4H), 4.61 (m, 2H), 5.68 (m, 1H), 7.22-7.59 (m, 7H)

MS APCI+ m/z 479 [MH]<+>

Preparation 23

4-Chloro-7β-(2,3-dichlorobenzyl)-AL[P?)-1-(trifluoroacetyl)pyrrolidin-3-yl]benzamide

The title compound was obtained using a procedure similar to that described for preparation 22 also using the amine from preparation 9.

HNMR (DMSO-D6, 400MHz): 2.04 (m, 2H), 3.37-3.76 (m, 4H), 4.46-4.76 (m, 3H), 7.22-7.58 (brm, 7H)

MS APCI+ m/z 479 [MH]<+>

Example 1

2, 3-Dichloro-Amisobutyl-AL[f3S>pyrrolidin-3-yl1benzamide citrate

The protected Boe product from Preparation 13 (10.55 g, 25.4 mmol) was dissolved in dichloromethane (20 mL) under nitrogen and the mixture was treated with trifluoroacetic acid (20 mL, 260.5 mmol). The reaction mixture was then stirred at room temperature for 4.5 hours. The reaction mixture was concentrated in vacuo and the residue taken up in dichloromethane and washed with 1M sodium hydroxide solution (100 mL). The organic phases were separated, dried over magnesium sulfate and concentrated in vacuo. The residue was azeotroped with ethyl acetate (10x) and then dried in vacuo to give the free base of the title product as a colorless oil, 7.291 g (91%). A portion of this product (3.327 g, 10.56 mmol) was treated with a solution of citric acid (2.028 g, 10.56 mmol) in methanol, concentrated in vacuo and dried under high vacuum to afford the title product as a pink solid, 4.71 g.

HNMR (MeOD, 400MHz): 0.80 (t, 6H), 1.89 (m, 2H), 2.11 (brm, 2H), 2.53 (m, 2H), 2.68-2.91 (m, 4H), 3.59 (m, IH), 3.82 (m, 2H), 4.37 (m, IH), 7.40 (m, 2H), 7.61 (m, 1H) MS APCI+ m/z 315 [MH+]

Example 2

2, 4- Dichloro- 7v'- isobutyl- A/- r( 36f)- pyrrolidine- 3- ylbenzamide hydrochloride

The protected BOC product of preparation 14 (157 mg, 0.561 mmol) was added to a solution of 4M hydrochloric acid in dioxane (1 mL) in dichloromethane (5 mL) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo and the product azeotroped with dichloromethane and ether and then triturated in the presence of ether to give the title product, 103.3 mg, (87%).

'HNMR (MeOD, 400MHz): 0.80 (m, 6H), 1.89 (m, IH), 2.51 (m, 2H), 2.90 (m, IH), 3.20 (m, 2H), 3.52 (m, IH), 3.78 (m, 2H), 4.30 (m, IH), 7.40 (m, IH), 7.46 (d, IH), 7.58 (s, IH) MS APCI+ m/z 315 [MH+]

Examples 3- 8

The following compounds of the general formula pyrcasane above were obtained by a procedure similar to that described in Example 2 to obtain the hydrochloride salts of the compounds shown.

Example 9 7N-(2-Naphthylmethyl)-A^-r(35Y)-pyrrolidine-3-inbenzamide hydrochloride

A solution of the protected benzyl product from Preparation 18 (370 mg, 88 mmol), ammonium formate (555 mg, 8.798 mmol) and 10% Pd/C (40 mg) in ethanol (5 mL) was refluxed under nitrogen for 6 h. The reaction mixture was filtered through Arbocel®, washed with ethanol, and the filtrate concentrated in vacuo. The crude product was purified by chromatography on a silica gel column eluting with a mixture of dichloromethane:ethanol:0.88 ammonia 100:0:0 to 90:10:1. The product was dissolved in a minimal amount of ethereal hydrochloric acid solution in dichloromethane and concentrated in vacuo. The product was triturated with ether (x 3) and dried in vacuo to give the title product, 120 mg, (36%).

HNMR(DMSO-D6, 400MHz): 2.06(m, 2H), 2.98(brs, IH), 3.79(m, 3H), 4.43(m, IH), 4.71(m, 2H), 7.25-7.59(m, 9H), 7.78(m, IH), 7.93(m, 3H)

MS APCI+m/z331 [MH]<+>

Example 10

A^-(2-Naphthylmethyl)-Af-[(3i?)-pyrrolidin-3-ylberizamide hydrochloride

The title compound was obtained using a procedure similar to that described for example 9 using the protected benzyl product of preparation 19 as starting material. Obtained jel60 mg, (47%) of the title product.

HNMR (DMSO-D6, 400MHz): 2.11 (m, 2H), 3.00 (m, IH), 3.35 (brm, 3H), 4.44 (m, IH), 4.78 (m, 2H), 7.28-7.56 (brm, 9H), 7.81 (m, IH), 7.96 (m, 3H)

MS ES+m/z331 [MH]<+>

Example 11

N-Isobutyl-N-[(35f)-pyrrolidin-3-yl]-2-naphthamide hydrochloride

Potassium carbonate (92 mg, 0.66 mmol) was added to a solution of the protected trifluoroacetate product from Preparation 21 (130 mg, 0.33 mmol) in water (0.5 mL) and methanol (5 mL) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the crude product dissolved in a mixture of 10% potassium carbonate solution:ethyl acetate solution 1:1 (25 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude product was dissolved in ethyl acetate, treated with 1M hydrochloric acid in ether and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to give the title product.

'HNMR (MeOD, 400MHz): 0.79 (d, 6H), 1.93 (m, IH), 2.56 (m, 2H), 3.25 (m, 3H), 3.55 (t, IH), 3.80 (m, 2H), 4.36 (m, IH), 7.48 (d, IH), 7.59 (m, 2H), 7.96 (m, 4H)

MS ES+ m/z 298 [MH<+>]

Example 12

jV- Butyl-^- r( 3^- pyrrolidine- 3- yl1- l- naphthamide hydrochloride

The compound was obtained using a procedure similar to that described for Example 11 using the protected trifluoroacetate product of Preparation 20 as starting material

HNMR (MeOD, 400MHz): 0.62 (m, 3H), 1.04 (m, 2H), 1.72 (m, 2H), 2.65 (m, 2H), 3.07 (m, 2H), 3.21 (m, 1H), 3.59 (m, 1H), 3.87 (m, 2H), 4.42 (m, 1H), 7.30 (s, m, IH), 7.57 (m, 3H), 7.78 (m, IH), 8.00 (m, 2H)

MS ES+ m/z 297 [MH]<+>

Example 13

4- Chloro- A^-( 3, 4- dichlorobenzyl)- A^-[( 3i?)- pyrrolidine- 3- yl- l- benzamide hydrochloride

The compound was obtained using a procedure similar to that described for Example 11 using the protected trifluoroacetate product of Preparation 22 as starting material. 75 mg (47%) of the title product was obtained.

!HNMR(DMSO-D6, 400MHz): 1.58 (m, IH), 1.83 (m, IH), 2.60 (m, IH), 2.81 (m, IH), 3.42 (m, 2H), 4.61 (m, 2H), 7.25 (m, IH), 7.39-7.59 (m, 7H).

Example 14

4- Chloro- A /-( 2, 3- dichlorobenzyl)- 7V-|"( 3i?)- pyrrolidin- 3- yl]- 1 - benzamide hydrochloride

The compound was obtained using a procedure similar to that described for Example 11 using the protected trifluoroacetate product of Preparation 23 as starting material. 90 mg (52%) of the title product was obtained.

HNMR (DMSO-D6, 400MHz): 1.62 (m, IH), 1.88 (m, IH), 2.61 (m, 2H), 2.85 (m, 2H), 4.28 (m, IH), 4.59 (t, 2H), 7.24 (m, IH), 7.36 (m, IH), 7.4-7.58 (m, 6H).

MS ES+ m/z 385 [MH]<+>

Example 15

2, 4- Dichloro- 5- fluoro- A^- isobutyl- A,-|'( 3y)- pyrrolidine- 3- yl1- 1 - benzamide hydrochloride

tert -Butyl3-3-[(2,4-dichloro-5-fluorobenzoyl)(isobutyl)amino]pyrrolidine-1-carboxylate was prepared by a procedure similar to that described in Preparation 13 using the amine from Preparation 3 and 2,4-dichloro-5-fluorobenzoyl chloride to give the desired product, 340 mg.

MS ES+ m/z 455 [MNaph]

2,4-Dichloro-5-fluoro-N-isobutyl-N-[(31S)-pyrrolidin-3-yl]-1-benzamide hydrochloride was prepared from the preceding compound by a procedure similar to that described in Example 2 to afford the title product as an off-white solid, 100 mg.

MS ES+ m/z 333 [MH]<+>

Found: C, 47.22; H, 5.87; N, 7.08 %. Calcd for C15H19CI2FN2O.HCLO.7H2O: C, 47.17; H, 5.64; N, 7.33%.

Example 16

The NRI and SRI IC50 of the compounds of Examples 1 to 14 were determined as follows. The results are shown below in Table 1.

Biological activity

The biological activity of the compounds was investigated through their ability to inhibit the uptake of serotonin and/or noradrenaline by human serotonin and/or noradrenaline transporters as follows.

(i) Cell culture

Human embryonic kidney (HEK-293) cells stably transfected with either the human serotonin transporter (hSERT), noradrenaline transporter (hNET), or dopamine transporter (hDAT) were cultured using standard cell culture techniques (cells were grown at 37 °C and 5% CO2 or in Dulbecco's Modified Eagle Medium (DMEM) cell culture medium supplemented with 10% dialyzed fetal bovine serum). calf serum (FCS), with 2 mM L-glutamine and 250 ug/ml geneticin (hSERT and hNET cells) or DMEM cell culture medium supplied with 5% FCS, 5% newborn calf serum, 2 mM L-glutamine and 2.5 mg/ml puromycin (hDAT) cells). Before the assay, cells were collected by dissociation using cell dissociation solution (Sigma) and centrifugation, and resuspended in standard assay buffer (see below) at a floating cell density of 750,000 cells/ml.

(i) Determination of inhibitory potency

All tested compounds were dissolved in 100% DMSO at 4 mM and diluted in 1% DMSO in water to obtain a suitable concentration. Assays were performed in 96-cell bottom filter plates. Cells expressing the appropriate human potein transporter (75,000 cells/assay cell) were pre-incubated at 25 °C in standard assay buffer containing either the test compound, a standard inhibitor (positive control) or vehicle compound (DMSO in water, final DMSO concentration was 0.1% in each assay cell) for 5 minutes. The reactions were initiated by the addition of the substrate either<3>H-serotonin,<3>H-noradrenaline or<3>H-dopamine. All reactions were performed at 25 °C in a vibrating incubator. Incubation times were 5 minutes for hSERT and hDAT assays and 15 minutes for hNET assays. Reactions were terminated by the addition of ice-cold wash buffer (see below), followed by filtration of the assay mixture using multiple filtration and a rapid wash with ice-cold wash buffer. The amount of <3>H-substrate incorporated into the cells was then quantified: Filtered/washed assay plates were dried at 45 °C for 1 hour, scintillation fluid was added, and radioactivity was measured with a scintillation counter. The potency of the tested compounds was quantified as IC50 values (the concentration of the tested compound required to inhibit the specific uptake of the radiolabeled substrate in the cells by 50% relative to the maximal (vehicle compound only) and minimal (complete inhibition by the standard inhibitor) response.

(ii) Standard composition of the analysis buffer:

Tris (hydroxymethyl) amino methane hydrochloride (26 mM)

NaCl(124 mM)

KC1 (4.5 mM)

KH2PO4(1.2 mM)

MgCl2.6H20(1.3 mM)

Ascorbic acid (1.136 mM)

Glucose (5.55 mM)

pH 7. 40

CaCl2(2.8 mM)

Pargyline (100 uM)

Note: The pH of the buffer was adjusted to 7.40 with 1M NaOH before the addition of CaCl2i pargyline.

Composition of the wash buffer:

Tris (hydroxymethyl) methylamine (26 mM)

NaCl(124 mM)

KC1 (4.5 mM)

KH2PO4(1.2 mM)

MgCl2.6H20(1.3 mM)

Ascorbic acid (1.136 mM)

pH 7. 40 at 4 °C with 6M HCl

(iv) Overview of analysis parameters

For convenience, the compounds of the invention are isolated during the manufacturing process in free base form, but pharmaceutically acceptable acid addition salts can be obtained using conventional means. Solvates (eg, hydrates) of compounds of the invention may be formed during the manufacturing process of one of the aforementioned process steps.

When the compounds are prepared in the manner described for the above Example, one of ordinary skill will appreciate that it may still be necessary or desirable to use a different manufacturing process or purification conditions.

Claims (24)

1. Compound of Formula (I) and its pharmaceutical and/or veterinary acceptable derivatives, where R<1>, H, C1-6alkyl, -C(X)Y, C3-gcycloalkyl, aryl, het, aryl-C1-4alkyl or het-C1-4alkyl, wherein the cycloalkyl, aryl or het groups are optionally substituted by at least one substituent independently selected from C1-galalkyl, C1-galkoxy, OH, halo, CF3, OCF3, SCF3, hydroxy-C3-alkyl, C 1 -C 1 -C 4 alkyl and C 1 -C 1 -C 4 alkyl; R is aryl or heteroaryl, each optionally substituted with at least one substituent independently selected from C 1-6 alkyl, C 1-6 methoxy, OH, halo, CF 3 , OCF 3 , SCF 3 , hydroxy-C 1-6 alkyl, C 1-4 alkoxy-C 1-6 alkyl and C 1-4 alkyl-S-C 1-4 alkyl; R<3> is Ci-6alkyl, C3.gcycloalkyl, C3.gcycloalkyl-Ci.6alkyl, aryl, het, aryl-Ci.4alkyl or het-Ci-6alkyl, where the cycloalkyl, aryl or het groups are optionally substituted by at least one substituent independently selected from Ci-6alkyl, C1-6alkyl, OH, halo, CF3, OCF3, SCF3, hydroxy-Ci-6alkyl, d.4-Ci-6alkyl, and C1-4alkyl-S-C1-4alkyl; XjeSiliO; Y is H, C 1-6 alkyl, aryl, het, aryl-C 1-4 alkyl or het-C 1-4 alkyl; nj 1 or 2, provided that n is 1, m is 0 or 1 and when n is 2, m is 0, where, if m is 0, then<*>represents a chiral center; aryl is phenyl, naphthyl, anthracyl or phenanthryl; heteroaryl is an aromatic 5- or 6-membered heterocycle containing at least one N, O or S heteroatom, optionally fused with an aryl group; het is an aromatic or non-aromatic 4-, 5- or 6-membered heterocycle containing at least one N, O or S heteroatom, optionally fused with a 5- or 6-membered carbocyclic group or another 4-, 5- or 6-membered heterocycle containing at least one N, O or S heteroatom. 2. Compound according to Claim 1, characterized in that R<1>, H. 3. A compound according to Claim 1 or Claim 2, characterized in that m is 0 and represents an R or S enantiomer. 4. The compound according to Claim 3, characterized in that<*>represents the S enantiomer. 5. A compound according to one of the preceding claims, characterized in that R<2> is phenyl, naphthyl or quinolinyl, each optionally substituted by at least one substituent independently selected from d.8alkyl, C.sub.8alkyl, C.sub.1-alkyl, OH, halo, CF.sub.3, OCF.sub.3, SCF.sub.3, hydroxy-C.sub.4 alkyl, C.sub.4 alkyl-C.sub.4 alkyl and C.sub.4 alkyl-S-C.sub.4 alkyl. 6. A compound according to Claim 5, characterized in that R is phenyl or naphthyl each optionally substituted with one, two or three substituents independently selected from halo, OH, C1-4alkyl and CF3. 7. A compound according to one of the claims, characterized in that R 3 is C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl or aryl-C 1-4 alkyl. 8. A compound according to Claim 7, characterized in that R<3> is C1-6alkyl, C3-6cycloalkyl, C3. 6cycloalkyl-C1-2alkyl, phenyl-CH2- or naphthyl-CH2-. 9. Compound according to Claim 1, characterized in that R'jeH; R 2 is phenyl or naphthyl each optionally substituted with one, two or three substituents independently selected from halo, OH, C 1-4 alkyl and CF 3 ; R3 is C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl-CH2- or naphthyl-CH2-; and m is 0. 10. A compound according to Claim 1, characterized in that it is selected from: 2.3-Dichloro-γN-isobutyl-A'-[(35)-pyrrolidin-3-yl]benzamide; 2.4-Dichloro-N-isobutyl-7N-[(35)-pyrrolidin-3-yl]benzamide; 2- Chloro-3-methyl-N-isobutyl-N-[(3S)-pyrrolidin-3-yl]benzamide; 3-Fluoro-2-methyl-N-isobutyl-N-[(3S)-pyrrolidin-3-yl]benzamide; 3-Methoxy-2-methyl-N-isobutyl-7-[(3S)-pyrrolidin-3-yl]benzamide; 3- Chloro-Ar-isobutyl-N-[(3S)-pyrrolidin-3-yl]benzamide; 4-Chloro-nN-isobutyl-7Y-[(3S)-pyrrolidin-3-yl]benzamide; 3,4-Dichloro- N -isobutyl-7 H -[(3S)-pyrrolidin-3-yl]benzamide; 7 N -(2-Naphthylmethyl)- N -[(3S)-pyrrolidin-3-yl]benzamide; N -(2-Naphthylmethyl)- N -[(3 H )-pyrrolidin-3-yl]benzamide; N-Isobutyl-7n7-[(350-pyrrolidin-3-yl]-2-naphthamide; Ar-Butyl-V-[(35,)-pyrrolidin-3-yl]-l-naphthamide; 4-Chloro-A^-(3,4-dichlorobenzyl)-A<r->[(3/?)-pyrrolidin-3-yl]benzamide; N-Pyrrolidin-3-yl-N-(5,6,7,8-tetrahydro-naphthalen-1-ylmethyl)-benzamide; N-(2,4-Dichloro-benzyl)-N-pyrrolidin-3-yl-benzamide; N-(3-Chloro-4-methyl-benzyl)-2-fluoro-N-pyrrolidin-3-yl-benzamide; Naphthalene-2-carboxylic acid butyl-pyrrolidin-3-yl-amide; Isobutyl-pyrrolidin-3-yl-amide; naphthalene-2-carboxylic acid (2,2-dimethyl-propyl)-pyrrolidin-3-yl-amide naphthalene-2-carboxylic acid; 3-Chloro-N-isobutyl-4-methyl-N-pyrrolidin-3-yl-benzamide; N-Isobutyl-2,3-dimethyl-N-pyrrolidin-3-yl-benzamide; 3-Chloro-N-(2,2-dimethyl-propyl)-2-methyl-N-pyrrolidin-3-yl-benzamide; 2-Chloro-4-fluoro-N-isobutyl-N-pyrrolidin-3-yl-benzamide; 2- Chloro-N-isobutyl-N-pyrrolidin-3-yl-benzamide; 3- Chloro-2-fluoro-N-isobutyl-N-pyrrolidin-3-yl-benzamide; 3-Chloro-4-fluoro-N-isobutyl-N-pyrrolidin-3-yl-benzamide; N-Butyl-2,4-dichloro-N-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-N-cyclobutylmethyl-N-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-N-cyclopentylmethyl-N-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-N-(2,2-dimethyl-propyl)-2-methyl-N-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-N-(2-ethyl-butyl)-N-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-N-(3-methyl-butyl)-N-pyrrolidin-3-yl-benzamide; 2,3,4-Trichloro-N-isobutyl-N-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-N-(2-cyclopropyl-ethyl)-N-pyrrolidin-3-yl-benzamide; Naphthalene-1-carboxylic acid isobutyl-pyrrolidin-3-yl-amide; 2,4-Dichloro-5-fluoro-N-isobutyl-N-pyrrolidin-3-yl-benzamide; 2,3-Dichloro-N-(2,2-dimethyl-propyl)-N-pyrrolidin-3-yl-benzamide; 2,3-Dichloro-N-(3-methyl-butyl)-N-pyrrolidin-3-yl-benzamide; 2,3-Dichloro-N-cyclobutylmethyl-N-pyrrolidin-3-yl-benzamide; 2.3- Dichloro-N-cyclopentyl-N-pyrrolidin-3-yl-benzamide; 3.4- Dichloro-N-cyclopentyl-N-pyrrolidin-3-yl-benzamide; 2.3- Dichloro-N-(1,2-dimethyl-propyl)-N-pyrrolidin-3-yl-benzamide; 2.4- Dichloro-N-(1,2-dimethyl-propyl)-N-pyrrolidin-3-yl-benzamide; 2.3- Dichloro-N-cyclohexyl-N-pyrrolidin-3-yl-benzamide; 2.4- Dichloro-N-cyclopentyl-N-pyrrolidin-3-yl-benzamide; 3,4-Dichloro-N-cyclopentyl-N-pyrrolidin-3-yl-benzamide; Naphthalene-1-carboxylic acid sec-butyl-pyrrolidin-3-yl-amide; N-sec-Butyl-2,3-dichloro-N-pyrrolidin-3-yl-benzamide; N-sec-Butyl-2,4-dichloro-N-pyrrolidin-3-yl-benzamide; 2.3- Dichloro-N-(1-ethyl-propyl)-N-pyrrolidin-3-yl-benzamide; 2.4- Dichloro-N-(1-ethyl-propyl)-N-pyrrolidin-3-yl-benzamide; Naphthalene-1-carboxylic acid (1-ethyl-propyl)-pyrrolidin-3-yl-amide; 2.3- Dichloro-N-cyclobutyl-N-pyrrolidin-3-yl-benzamide; 2.4- Dichloro-N-cyclobutyl-N-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-N-cyclopentyl-N-pyrrolidine-3-yl-benzamide; 2.3- Dichloro-N-pyrrolidin-3-yl-N-(1,2,2-trimethyl-propyl)-benzamide; N-tert-Butyl-2,3-dichloro-N-pyrrolidin-3-yl-benzamide; Naphthalene-1-carboxylic acid cyclopentyl-pyrrolidin-3-yl-amide; 2,3-Dichloro-N-phenyl-N-pyrrolidin-3-yl-benzamide; 3.4- Dichloro-N-(2,2-dimethyl-propyl)-2-methyl-N-pyrrolidin-3-yl-benzamide; 3-Chloro-N-isobutyl-2-methyl-N-pyrrolidin-3-yl-benzamide; N-Butyl-2,3-dichloro-N-pyrrolidin-3-yl-benzamide; N-Butyl-3,4-dichloro-N-pyrrolidin-3-yl-benzamide; Naphthalene-2-carboxylic acid cyclobutylmethyl-pyrrolidin-3-yl-amide; Naphthalene-1-carboxylic acid cyclobutylmethyl-pyrrolidin-3-yl-amide; 3,4-Dichloro-N-cyclobutylmethyl-N-pyrrolidin-3-yl-benzamide; 4-Chloro-N-isobutyl-2-methoxy-N-pyrrolidin-3-yl-benzamide; 4-Chloro-N-isobutyl-3-methyl-N-pyrrolidine-3- and 1-benzamide; 2,4-Dichloro-N-isobutyl-3-methyl-N-pyrrolidin-3-yl-benzamide; (3-methyl-butyl)-pyrrolidin-3-yl-amide of naphthalene-1-carboxylic acid (2,2-dimethyl-propyl)-pyrrolidin-3-yl-amide of naphthalene-1-carboxylic acid; 3,4-Dichloro-N-(3-methyl-butyl)-N-pyrrolidin-3-yl-benzamide; 2.3- Dichloro-N-(4-fluoro-phenyl)-N-pyrrolidin-3-yl-benzamide; 2.4- Dichloro-N-(4-fluoro-phenyl)-N-pyrrolidin-3-yl-benzamide; Naphthalene-1-carboxylic acid (4-fluoro-phenyl)-pyrrolidin-3-yl-amide; N-Butyl-2,3,4-trichloro-N-pyrrolidin-3-yl-benzamide; 2,3,4-Trichloro-N-cyclobutylmethyl-N-pyrrolidin-3-yl-benzamide; N-Pyrrolidin-3-yl-N-(3-trifluoromethyl-benzyl)-benzamide; 2,4-Dichloro-N-phenyl-N-pyrrolidin-3-yl-benzamide; 3,4-Dichloro-N-phenyl-N-pyrrolidin-3-yl-benzamide; 2,3,4-Trichloro-N-(2,2-dimethyl-propyl)-N-pyrrolidin-3-yl-benzamide; Naphthalene-1-carboxylic acid phenyl-pyrrolidin-3-yl-amide; 2,3,4-Trichloro-N-(2-cyclopropyl-ethyl)-N-pyrrolidin-3-yl-benzamide; 2.3- Dichloro-N-(2-cyclopropyl-ethyl)-N-pyrrolidin-3-yl-benzamide; 2- Bromo-4-chloro-N-isobutyl-N-pyrrolidin-3-yl-benzamide; 4-Chloro-2-ethoxy-N-isobutyl-N-pyrrolidin-3-yl-benzamide; 3- Bromo-4-chloro-N-isobutyl-N-pyrrolidin-3-yl-benzamide; 2.4-Dichloro-5-fluoro-N-isobutyl-N-[(3S)-pyrrolidin-3-yl]benzamide; 3,4-Dichloro-N-isobutyl-2-methyl-N-pyrrolidin-3-yl-benzamide; 2,4-dichloro-3-fluoro-A<f->isobutyl-A</->[pyrrolidin-3-yl]benzamide; 2,3-dichloro-4-fluoro-N-isobutyl-N-[pyrrolidin-3-yl]benzamide; 23-dichloro-5-fluoro-A<A->isobutyl-A<f->[pyrrolidin-3-yl]benzamide; 2,4,5-trichloro-A</->isobutyl-A<A->[pyrrolidin-3-yl]benzamide; 2,5-dichloro-A<A->isobutyl-A<A->[pyrrolidin-3-yl]benzamide; 2,5-dichloro-4-fluoro-α-isobutyl-α-[pyrrolidin-3-yl]benzamide; 2,3,5-trichloro-[y->isobutyl-A<7->[pyrrolidin-3-yl]benzamide; 2.3-dichloro-6-fluoro-Ar-isobutyl-AA-[pyrrolidin-3-yl]benzamide; S-rdichloro-n-fluoro-N-isobutyl-N-tripyrrolidineO-ylbenzamide; 3.4-Dichloro-2-fluoro-N-isobutyl-N-[pyrrolidin-3-yl]benzamide; 2-Chloro-3,6-difluoro-N-isobutyl-N-[pyrrolidin-3-yl]benzamide; and 4-Chloro-N-(2,3-dichlorobenzyl)-N-[(3?)-pyrrolidin-3-yl]benzamide, or their pharmaceutical and/or veterinary acceptable derivatives. 11. The compound according to Claim 10, characterized in that it is 2,3-Dichloro-A</->isobutyl- /V-[(35)-pyrrolidin-3-yl]benzamide or its pharmaceutical and/or veterinary acceptable derivatives. 12. Pharmaceutical preparation, characterized in that it contains a compound according to one of Claims 1 to 11 and a pharmaceutically acceptable adjuvant, diluent or carrier. 13. A compound according to one of Claims 1-11, characterized in that it is for use as a medicine. 14. Use of a compound according to one of Claims 1-11 for the production of a drug for the treatment of disorders where the regulation of monoamine transporter function is implicated. 15. Use of a compound according to one of Claims 1-11 for the production of a drug for the treatment of disorders involving the regulation of serotonin or noradrenaline, in mammals. 16. Use according to Claim 15, wherein the regulation of serotonin and noradrenaline is implied. 17. Use of a compound according to one of Claims 1-11 for the production of a medicament for the treatment of urinary disorders, depression, pain, premature ejaculation, ADHD or fibromyalgia in mammals. 18. Use of a compound according to Claim 17 for the treatment of urinary incontinence, such as GSI or USI, in a mammal. 19. A method of treating a disorder where regulation of monoamine transporter function is implicated, comprising administering a therapeutically effective amount of a compound according to one of Claims 1-11 to a patient in need of such treatment. 20. A method of treating a disorder involving the regulation of serotonin or noradrenaline, comprising administering a therapeutically effective amount of a compound according to one of Claims 1-11 to a patient in need of such treatment. 21. The method according to Claim 20, where the regulation of serotonin and noradrenaline is implied. 22. A method of treating urinary disorders, depression, pain, premature ejaculation, ADHD or fibromyalgia, comprising administering a therapeutically effective amount of a compound according to one of Claims 1-11 to a patient in need of such treatment. 23. The method according to Claim 22, characterized in that the urinary disorder is urinary incontinence, such as GSI or USI. 24. A process for obtaining a compound according to one of Claims 1-11, characterized in that it includes the reaction of a compound of formula (X): where R 1 , n and m are as previously defined, and Y is R 1 or an azaprotecting group, with an acid or an acyl halide: R COX, where X is OH or halo, and if necessary or desirable, deprotection. 1. Compound of Formula (I) and its pharmaceutical and/or veterinary acceptable derivatives, where R^H, R is aryl or heteroaryl, each optionally substituted with at least one substituent independently selected from C 1 -galalkyl, C 1 -galkoxy, OH, halo, CF 3 , OCF 3 , SCF 3 , hydroxy-C 1-4 alkyl, C 1-4 alkoxy-C 1-6 alkyl and C 1-4 alkyl-S-C 1-4 alkyl; R<3> is C1-6alkyl, C1-6cycloalkyl, C3-8cycloalkyl-C1-6alkyl, aryl, het, aryl-C1-6alkyl or het-C1-4alkyl, where the cycloalkyl, aryl or het groups are optionally substituted by at least one substituent independently selected from C1-6alkyl, C1-6alkyl, OH, halo, CF3, OCF3, SCF3, hydroxy-C1-6alkyl, C1-4alkyl, and C1-4alkyl-S-C1-4alkyl; XjeSiliO; Y is H, C1-6alkyl, aryl, het, aryl-C1-4alkyl or het-C1-4alkyl; n 1 or 2, provided that n is 1, m is 0 or 1 and when n is 2, m is 0, where, if m is 0, then<*>represents a chiral center; aryl is phenyl, naphthyl, anthracyl or phenanthryl; heteroaryl is an aromatic 5- or 6-membered heterocycle containing at least one N, O or S heteroatom, optionally fused with an aryl group; het is an aromatic or non-aromatic 4-, 5- or 6-membered heterocycle containing at least one N, O or S heteroatom, optionally fused with a 5- or 6-membered carbocyclic group or another 4-, 5- or 6-membered heterocycle containing at least one N, O or S heteroatom; provided that: the compound is not N-methyl-N-piperidin-4-ylbenzamide or N-methyl-N-piperidin-4-ylbenzamide; and when R<2> is -and then R is not 2. A compound according to Claim 1, characterized in that m is 0 and<*>represents the R or S enantiomer. 3. A compound according to Claim 2, characterized in that<*>represents the S enantiomer. 4. A compound according to one of the preceding claims, indicated by the fact that R is phenyl, naphthyl or quinolinyl, each optionally substituted with at least one substituent independently selected from C1-alkyl, C1-galkoxy, OH, halo, CF3, OCF3, SCF3, hydroxy-C1-6 alkyl, C1-4 alkoxy-C1-6 alkyl and CMalkyl-S-C1-6 alkyl. 5. A compound according to Claim 4, characterized in that R<2>, phenyl or naphthyl is each optionally substituted with one, two or three substituents independently selected from halo, OH, C1-6 alkyl and CF3. 6. A compound according to one of the claims, characterized in that R<3> is C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl or aryl-C1-4alkyl. 7. A compound according to claim 6, characterized in that R<3> is C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-2 alkyl, phenyl-CH2- or naphthyl-CH2-. 8. A compound according to Claim 1, characterized in that: R\H; R 2 is phenyl or naphthyl each optionally substituted with one, two or three substituents independently selected from halo, OH, C 1-4 alkyl and CF 3 ; R3 is C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl-CH2- or naphthyl-CH2-; and m is 0. 9. A compound according to Claim 1, characterized in that it is selected from: 2.3-Dichloro-Af-isobutyl-Af-[(35)-pyrrolidin-3-yl]benzamide; 2.4-Dichloro-Amisobutyl-A4(3S)-pyrrolidin-3-yl]benzamide; 2- Chloro-3-methyl-AA-isobutyl-Ar-[(3S)-pyrrolidin-3-yl]benzamide; 3-Fluoro-2-methyl-N-isobutyl-N-[(3S)-pyrrolidin-3-yl]benzamide; 3-Methoxy-2-methyl-N-isobutyl-N-[(3S)-pyrrolidin-3-yl]benzamide; 3- Chloro-N-isobutyl-N-[(3S)-pyrrolidin-3-yl]benzamide; 4- Chloro-Amisobutyl-N-[(3S)-pyrrolidin-3-yl]benzamide; 3,4-Dichloro-N-isobutyl-N-[(3S)-pyrrolidin-3-yl]benzamide; N-(2-Naphthylmethyl)-N-[(3S)-pyrrolidin-3-yl]benzamide; N -(2-Naphthylmethyl)- N -[(3 N )-pyrrolidin-3-yl]benzamide; Air-Isobutyl-N-[(3S)-pyrrolidin-3-yl]-2-naphthamide; .alpha.-Butyl-n-tCS^-pyrrolidine-S-yl-1-naphthamide; 4-Chloro-A<L>(3,4-dichlorobenzyl)-A</->[(3i^)-pyrrolidin-3-yl]benzamide; N-Pyrrolidin-3-yl-N-(5,6,7,8-tetrahydro-naphthalen-1-ylmethyl)-benzamide; N-(2,4-Dichloro-benzyl)-N-pyrrolidin-3-yl-benzamide; N-(3-Chloro-4-methyl-benzyl)-2-fluoro-N-pyrrolidin-3-yl-benzamide; Naphthalene-2-carboxylic acid butyl-pyrrolidin-3-yl-amide; Naphthalene-2-carboxylic acid isobutyl-pyrrolidin-3-yl-amide; Naphthalene-2-carboxylic acid (2,2-dimethyl-propyl)-pyrrolidin-3-yl-amide; 3-Chloro-N-isobutyl-4-methyl-N-pyrrolidin-3-yl-benzamide; N-Isobutyl-2,3-dimethyl-N-pyrrolidin-3-yl-benzamide; 3-Chloro-N-(2,2-dimethyl-propyl)-2-methyl-N-pyrrolidin-3-yl-benzamide; 2-Chloro-4-fluoro-N-isobutyl-N-pyrrolidin-3-yl-benzamide; 2- Chloro-N-isobutyl-N-pyrrolidin-3-yl-benzamide; 3- Chloro-2-fluoro-N-isobutyl-N-pyrrolidin-3-yl-benzamide; 3-Chloro-4-fluoro-N-isobutyl-N-pyrrolidin-3-yl-benzamide; N-Butyl-2,4-dichloro-N-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-N-cyclobutylmethyl-N-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-N-cyclopentylmethyl-N-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-N-(2,2-dimethyl-propyl)-2-methyl-N-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-N-(2-ethyl-butyl)-N-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-N-(3-methyl-butyl)-N-pyrrolidin-3-yl-benzamide; 2,3,4-Trichloro-N-isobutyl-N-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-N-(2-cyclopropyl-ethyl)-N-pyrrolidin-3-yl-benzamide; Naphthalene-1-carboxylic acid isobutyl-pyrrolidin-3-yl-amide; 2,4-Dichloro-5-fluoro-N-isobutyl-N-pyrrolidin-3-yl-benzamide; 2,3-Dichloro-N-(2,2-dimethyl-propyl)-N-pyrrolidin-3-yl-benzamide; 2,3-Dichloro-N-(3-methyl-butyl)-N-pyrrolidin-3-yl-benzamide; 2,3-Dichloro-N-cyclobutylmethyl-N-pyrrolidin-3-yl-benzamide; 2.3- Dichloro-N-cyclopentyl-N-pyrrolidin-3-yl-benzamide; 3.4- Dichloro-N-cyclopentyl-N-pyrrolidin-3-yl-benzamide; 2.3-Dichloro-N-(1,2-dimethyl-propyl)-N-pyrrolidin-3-yl-benzamide; 2.4- Dichloro-N-(1,2-dimethyl-propyl)-N-pyrrolidin-3-yl-benzamide; 2.3- Dichloro-N-cyclohexyl-N-pyrrolidin-3-yl-benzamide; 2.4- Dichloro-N-cyclophenyl-N-pyrrolidin-3-yl-benzamide; 3,4-Dichloro-N-cyclopentyl-N-pyrrolidin-3-yl-benzamide; Naphthalene-1-carboxylic acid sec-butyl-pyrrolidin-3-yl-amide; N-sec-Butyl-2,3-dichloro-N-pyrrolidin-3-yl-benzamide; N-sec-Butyl-2,4-dichloro-N-pyrrolidin-3-yl-benzamide; 2.3- Dichloro-N-(1-ethyl-propyl)-N-pyrrolidin-3-yl-benzamide; 2.4- Dichloro-N-(1-ethyl-propyl)-N-pyrrolidin-3-yl-benzamide; Naphthalene-1-carboxylic acid (1-ethyl-propyl)-pyrrolidin-3-yl-amide; 2.3- Dichloro-N-cyclobutyl-N-pyrrolidin-3-yl-benzamide; 2.4- Dichloro-N-cyclobutyl-N-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-N-cyclopentyl-N-pyrrolidin-3-yl-benzamide; 2,3-Dichloro-N-pyrrolidin-3-yl-N-(1,2,2-trimethyl-propyl)-benzamide; N-tert-Butyl-2,3-dichloro-N-pyrrolidin-3-yl-benzamide; Naphthalene-1-carboxylic acid cyclopentyl-pyrrolidin-3-yl-amide; 2.3- Dichloro-N-phenyl-N-pyrrolidin-3-yl-benzamide; 3.4- Dichloro-N-(2,2-dimethyl-propyl)-2-methyl-N-pyrrolidin-3-yl-benzamide; 3- Chloro-N-isobutyl-2-methyl-N-pyrrolidin-3-yl-benzamide; N-Butyl-2,3-dichloro-N-pyrrolidin-3-yl-benzamide; N-Butyl-3,4-dichloro-N-pyrrolidin-3-yl-benzamide; Naphthalene-2-carboxylic acid cyclobutylmethyl-pyrrolidin-3-yl-amide; Naphthalene-1-carboxylic acid cyclobutylmethyl-pyrrolidin-3-yl-amide; 3,4-Dichloro-N-cyclobutylmethyl-N-pyrrolidin-3-yl-benzamide; 4- Chloro-N-isobutyl-2-methoxy-N-pyrrolidin-3-yl-benzamide; 4-Chloro-N-isobutyl-3-methyl-N-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-N-isobutyl-3-methyl-N-pyrrolidin-3-yl-benzamide; (3-methyl-butyl)-pyrrolidin-3-yl-amide of naphthalene-1-carboxylic acid (2,2-dimethyl-propyl)-pyrrolidin-3-yl-amide of naphthalene-1-carboxylic acid; 3,4-Dichloro-N-(3-methyl-butyl)-N-pyrrolidin-3-yl-benzamide; 2.3- Dichloro-N-(4-fluoro-phenyl)-N-pyrrolidin-3-yl-benzamide; 2.4- Dichloro-N-(4-fluoro-phenyl)-N-pyrrolidin-3-yl-benzamide; Naphthalene-1-carboxylic acid (4-fluoro-phenyl)-pyrrolidin-3-yl-amide; N-Butyl-2,3,4-trichloro-N-pyrrolidin-3-yl-benzamide; 2,3,4-Trichloro-N-cyclobutylmethyl-N-pyrrolidin-3-yl-benzamide; N-Pyrrolidin-3-yl-N-(3-trifluoromethyl-benzyl)-benzamide; 2,4-Dichloro-N-phenyl-N-pyrrolidin-3-yl-benzamide; 3,4-Dichloro-N-phenyl-N-pyrrolidin-3-yl-benzamide; 2,3,4-Trichloro-N-(2,2-dimethyl-propyl)-N-pyrrolidin-3-yl-benzamide; Naphthalene-1-carboxylic acid phenyl-pyrrolidin-3-yl-amide; 2.3.4- Trichloro-N-(2-cyclopropyl-ethyl)-N-pyrrolidin-3-yl-benzamide; 2.3- Dichloro-N-(2-cyclopropyl-ethyl)-N-pyrrolidin-3-yl-benzamide; 2- Bromo-4-chloro-N-isobutyl-N-pyrrolidin-3-yl-benzamide; 4-Chloro-2-ethoxy-N-isobutyl-N-pyrrolidin-3-yl-benzamide; 3- Bromo-4-chloro-N-isobutyl-N-pyrrolidin-3-yl-benzamide; 2.4-Dichloro-5-fluoro-Ar-isobutyl-N-[(3S)-pyrrolidin-3-yl]benzamide; 3,4-Dichloro-N-isobutyl-2-methyl-N-pyrrolidin-3-yl-benzamide; 2.4-Dichloro-3-fluoro-N-isobutyl-AA-[pyrrolidin-3-yl]benzamide; 2,3-Fichloro-4-fluoro-N-isobutyl-N-[pyrrolidin-3-yl]benzamide; 2,3-Fichloro-5-fluoro-N-isobutyl-N-[pyrrolidin-3-yl]benzamide; 2.4.5- Trichloro-N-isobutyl-N-[pyrrolidin-3-yl]benzamide; 2.5-Dichloro-N-isobutyl-N-[pyrrolidin-3-yl]benzamide; 2,5-Dichloro-4-fluoro-A<A->isobutyl-A/<r->[pyrrolidin-3-yl]benzamide; 2,3,5-Trichloro-A</->isobutyl-A</>^-[pyrrolidin-3-yl]benzamide; 2.3-Dichloro-6-fluoro-Ar-isobutyl-N-[pyrrolidin-3-yl]benzamide; 3,4,-Dichloro-6-fluoro-N-isobutyl-N-[pyrrolidin-3-yl]benzamide; 3.4- Dichloro-2-fluoro-AA-isobutyl-N-[pyrrolidin-3-yl]benzamide; 2-Chloro-3,6-difluoro-A</->isobutyl-A,'-[pyrrolidin-3-yl]benzamide; and 4-Chloro-N-(2,3-dichlorobenzyl)-N-[(3^)-pyrrolidin-3-yl]benzamide, or their pharmaceutical and/or veterinary acceptable derivatives. 10. The compound according to Claim 9, indicated by the fact that it is 2,3-Dichloro-A<r>isobutyl-A^-[(3S)-pyrrolidin-3-yl]benzamide or its pharmaceutical and/or veterinary acceptable derivatives. 11. Pharmaceutical preparation, characterized in that it contains a compound according to one of Claims 1 to 10 and a pharmaceutically acceptable adjuvant, diluent or carrier. 12. A compound according to any one of Claims 1-10, characterized in that it is for use as a medicine. 13. Use of the compound according to one of Claims 1-10 for the production of a drug for the treatment of disorders in which the regulation of monoamine transporter function is implicated, in mammals. 14. Use of a compound according to one of Claims 1-10 for the production of a drug for the treatment of disorders involving the regulation of serotonin or noradrenaline in mammals. 15. Use according to Claim 14, wherein the regulation of serotonin and noradrenaline is implied. 16. Use of a compound according to one of Claims 1-10 for the production of a medicament for the treatment of urinary disorders, depression, pain, premature ejaculation, ADHD or fibromyalgia in mammals. 17. Use of a compound according to Claim 16 for the treatment of urinary incontinence, such as GSI or USI, in a mammal. 18. A method of treating a disorder where regulation of monoamine transporter function is implicated, comprising administering a therapeutically effective amount of a compound according to one of Claims 1-10 to a patient in need of such treatment. 19. A method of treating a disorder involving the regulation of serotonin or noradrenaline, comprising administering a therapeutically effective amount of a compound according to one of Claims 1-10 to a patient in need of such treatment. 20. The method according to Claim 19, wherein the regulation of serotonin and noradrenaline is implied. 21. A method of treating urinary disorders, depression, pain, premature ejaculation, ADHD or fibromyalgia, comprising administering a therapeutically effective amount of a compound according to one of Claims 1-11 to a patient in need of such treatment. 22. The method according to Claim 21, characterized in that the urinary disorder is urinary incontinence, such as GSI or USI. 23. A method for obtaining a compound according to one of Claims 1-10, characterized in that it includes the reaction of a compound of formula (X): where R<J>, n and m are as previously defined, and Y is R<1>or an azaprotecting group, with an acid or acyl halide: R<2>COX, where X is OH or halo, and if necessary or desirable, deprotection.