MXPA99005669A - Novel compounds with analgesic effect - Google Patents

Abstract

Compounds of general formula (I), wherein m is 0 or 1, and n is 1 or 2, are disclosed and claimed in the present application, as well as their pharmaceutically acceptable salts, pharmaceutical compositions comprising the novel compounds and their use in therapy, in particular in the management of pain.

Description

NOVEDO COMPOUNDS WITH ANALGESIC EFFECT FIELD OF INVENTION The present invention relates to novel ring compounds with nitrogen, with a process for their preparation, with their use and with pharmaceutical compositions comprising the novel compounds. The novel compounds are useful in therapy, and in particular for the treatment of pain.

BACKGROUND AND PREVIOUS TECHNIQUE The receptor d has been identified as receptors that have a role in many bodily functions such as the circulatory system and pain. Therefore, the ligands for the receptor d find potential use as analgesics and / or antihypertensive agents. It has also been shown that ligands for the d receptor possess immunomodulatory activities. The identification of at least three different populations of opioid receptors (μ, d and K) has now been well established and all three are evident in the central and peripheral nervous systems of many species, including the REF. 30452 man Analgesia has been observed in various animal models when one or more of these receptors have been activated. With some exceptions, the selective opioid ligands d currently available are peptidic in nature and are not suitable for administration by systemic routes. For some time, some non-peptide antagonists have been available (see Takemori and Portoghese, 1992, Ann.Rev. Pharmacol. Tox., 32: 239-269, for a review). These compounds, for example naltrindol, suffer from a rather poor selectivity (ie, <10 times) for the receptor d versus the μ receptor binding and do not show analgesic activity, a fact which underlines the need given by the development of highly selective non-peptidic ligands. Therefore, the problem underlying the present invention is to find novel analgesics having improved analgesic effects, but also with an improved side effect profile with respect to current agonists μ as well as with potential oral efficacy. Analgesics that have been identified and that exist in the prior art have many disadvantages in that they exhibit poor pharmacokinetics and are not analgesic when administered by systemic routes. Furthermore, it has been documented that preferred documents, described within the prior art, show significant convulsive effects when administered systemically. The aforementioned problem has been solved by developing novel compounds which possess a piperidine ring, which may be a 5 membered, 6 membered or 7 membered nitrogen ring, as will be described in the following.

DESCRIPTION OF THE INVENTION The novel compounds according to the present invention are defined by the general formula (I) where m is 0 or 1; n is 1 or 2; R1 is selected from hydrogen; linear or branched Ci-Cg alkyl; C3-C8 cycloalkyl; (C 4 -C 8 alkylcycloalkyl), wherein alkyl is C 1 -C 6 alkyl, and cycloalkyl is C 3 -C 6 cycloalkyl; benzyl; wherein G is a hydroaromatic or heteroaromatic group having 5 or 6 atoms, and wherein the heteroatoms are selected from O, S and N; Y and where n = 0 or 1; C6-C10 aryl; or heteroaryl having from 5 to 10 atoms which are selected from any of C, S, and O; wherein the aryl and heteroaryl optionally can be independently substituted by 1 or 2 substituents which are independently selected from any of hydrogen, CH3, (CH2) pCF3, halogen, CONR5R4, COOR5, COR5, (CH2) pNR5R4, (CH2) pCH3 ( CH2) pSOR5R4, (CH2) pS02R5, and (CH2) pS02NR5, wherein R4 and R5 are each independently as defined for R1 before, and p is 0, 1 or 2; (C1-C2 alkyl) - (C6-C10 aryl); or (C ^ C2 alkyl) heteroaryl, the heteroaryl moieties have 5 to 10 atoms which are selected from any of C, S, N, and O, wherein the aryl or heteroaryl may optionally be independently substituted by 1 or 2 substituents which are independently select any of hydrogen, CH3, CONR5R4, COOR5, COR5, (CH2) qNR5R4, (CH2) qCH3 (CH2) qSOR5R4, (CH2) qS02R5, (ChP) qS0: NR5, and (CH2) q0R4, where R4 and R5 are defined, each independently, for R1 above, and q is 0, 1 or 2; A is wherein R6, R0 R8, R9, R10, Ru, R12, R13, R14, R15, R16, R1 ^ and R18 are each and independently as defined for R1 before and wherein the phenyl ring of each substituent A may be optionally and independently substituted by 1 or 2 substituents Z1 and Z2 which are each and independently selected from hydrogen, CH3, (CH2) rCF3, halogen, CONR2R3, C02R2, COR2, (CH2) rNR2R3, (CH2) rCH3 (CH2 ) rSOR2, (CH2) rS02R2, and (CH2) rS02NR2R3, wherein R2 and R3 are each independently defined for R1 above, and wherein r is 0, 1 or 2; X is O, S or NR19, wherein R19 is as defined for R1, B is an aromatic, heteroaromatic, hydroaromatic or substituted or unsubstituted heterohydroaromatic portion having from 5 to 10 atoms which are selected from any of C, S, N and O, optionally and independently substituted by 1 or 2 substituents which are independently selected from hydrogen, CH3, (CH2) tCF3, halogen, (CH2) tCONR5R \ (CH2) tNR5R4, (CH2) tCOR5, (CH2) tCOOR5, OR5 , (CH2) tSOR5, (CH2) tS02R5, and (CH2) tS02NR5R4, where R4 and R5 are each independently defined for R1 above, and where t is 0, 1, 2 or 3; . Within the scope of the invention are also the pharmaceutically acceptable salts of the compounds of the formula (I), as well as isomers, hydrates, isoforms and prodrugs thereof. Preferred compounds according to the invention are compounds of the formula (I) wherein R 1 is selected from benzyl; - (CH2) n-G wherein G is a hydroaromatic group or a heteroaromatic group having 5 or 6 atoms, and wherein the heteroatoms are selected from 0, S and N; Y and where n = 0 or 1; A is selected from any of , 17 wherein R6, R0 R8, R9, R16, R17 and R18 is each and independently as defined for R1 in the foregoing; and Z1, Z2 and X is each and independently as defined in the foregoing; B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, pyrryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, pyrrolidinyl, and indazolinyl, each optionally and independently substituted by 1 or 2 substituents which are independently selected from hydrogen, CH3, CF3, halogen, - (CH2) tCONR5R4, - (CH2) tNR5R \ - (CH2) tC0R5, - (CH2) tC02Rs, and - OR5, where t is 0 or 1; and wherein R4 and R5 is as defined above. Especially preferred compounds are compounds of the formula (I), wherein R 1 is (C 1 -C 2 alkyl) phenyl and hydrogen; A is wherein R6, R7, R8, R9 is each an ethylene group; and Z1 and Z2 are as defined above; B is phenyl or naphthalene; and m and n is each 1, or m is 1 and n is 0. Substituents A and B respectively, may optionally be substituted at any position on the ring. By "halogen" we mean chlorine, fluorine, bromine, and iodine. By "aryl" we mean an aromatic ring having from 6 to 10 carbon atoms, such as phenyl and naphthyl. By "heteroaryl" we mean an aromatic ring in which 1 or more of the 5-10 atoms in the ring are elements other than carbon, such as N, S and 0. By "hydroaromatics" we mean an aromatic ring structure partially or completely saturated that has 5-10 carbon atoms in the ring. By "heterohydroaromatic" we mean a partially or fully saturated aromatic ring structure in which 1 or more than 5-10 ring atoms are elements other than carbon, such as N, S and 0. By "isomers" we mean compounds of the formula (I) which differ by the position of their group and / or functional orientation. By "orientation" we mean stereoisomers, diastereoisomers, regioisomers and enantiomers. By "isoforms" we mean compounds of the formula (I) which differ by their crystalline network, such as crystalline compounds and amorphous compounds. By "promedicamento" we mean pharmacologically acceptable derivatives, for example, esters and amides, so that the biotransformation product resulting from the derivative is an active medicament. The reference by Goodman and Gilmans, The Pharmacological Foundation of Therapeutics, 8th ed., McGra-Hill, Int. Ed. 1992, "Biotransformation of Drugs," pp. 13-15, describes general-purpose promedications, and is incorporated in the present as reference The novel compounds of the present invention are useful in therapy, especially for the treatment of various pain conditions such as chronic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain, etc. However, this list should not be considered as limiting The compounds of the invention are useful as immunomodulators, especially for autoimmune diseases such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for Use as anti-oral agents and antiviral agents.

The compounds of the invention are useful in the disease state where the degeneration or dysfunction of opioid receptors is present or is involved in that paradigm. This may involve the use of isotopically labeled versions of the compounds of the invention in diagnostic and imaging application techniques such as positron emission tomography (PET). The compounds of the invention are useful for the treatment of diarrhea, depression, urinary incontinence, various mental illnesses, cough, pulmonary edema, various gastrointestinal disorders, spinal cord damage and drug addiction, which includes the treatment of alcohol, nicotine, opioids and other drugs of abuse, and for disorders of the sympathetic nervous system, for example hypertension. The compounds of the invention are useful as an analgesic agent for use during general anesthesia and the monitored care of anesthesia. Combinations of agents with different properties are often used to obtain a balance of effects necessary to maintain the anesthetic state (for example, amnesia, analgesia, muscle relaxation and sedation). These include a combination of inhaled anesthetics, hypnotic substances, anxiolytics, neuromuscular blockers and opioids. The compounds of the present invention in isotopically-labeled form are useful as diagnostic agents.

Also within the scope of the invention is the use of any of the compounds according to formula (I) above, for the manufacture of a medicament for the treatment of any of the conditions discussed above. A further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions described above, whereby an effective amount of a compound according to formula (I) above is administered to a patient in need. of such treatment.

METHODS OF PREPARATION The compounds of the formula (I), as described above, can be obtained by the arylation of an amine of formula (II) wherein R1, m and n are as defined in formula (I) above, and W is A or B as defined in formula (I) above, by an arylating agent of formula (III) W - Z (III) wherein W is A or B, as defined in formula (I) above, and Z is a suitable substituent, that is, a reactive component suitable for use in the defined process, which will be appreciated by a person familiar in the technique, preferably halogen, triflate (CF3S03-), mesylate (CH3S03-), tosylate (CH3 (C6H4) S03-), tributyltin, triacetoxylated, diarylbismuth, borate (B (OH) 2), cuprate, or other such groups known in the art. The arylation can be catalyzed by metals, preferably Cu, Ni, Pd or suitable salts, complexes, oxides or hydroxides thereof. The 4-aminopiperidine of formula (II) above can be converted completely or partially to its corresponding anion by treatment with bases, preferably triethylamine, 4-dimethylaminopyridine, K2C03, NaOH, "NaH, lithium diisopropylamide, sodium tert-butoxide or the like , before one during the arylation process The reaction can be carried out in the presence of reagents that form "plejos", preferably triphenylphosphine, triphenylarsine, dibenzylidene ketone, 2,2'-bis (diphenylphosphino) -1,1'-biphenyl, 1,1'-bis (diphenylphosphino) -ferrocene, oxygen and other such compounds known in the art The reaction can optionally be carried out in the presence of one or more solvents such as toluene, dichloromethane, tetrahydrofuran, dimethylformamide, dioxane, acetonitrile or dimethyl sulfoxide, or in mixtures of solvents, R1, and substituents in A and B of compound (I), as defined above, can be modified earlier during the preparation of (I) to from (II) and (III) by methods known in the art, for example reduction, oxidation and alkylation. The amine of the formula (II) can be prepared by reductive amination of a ketone of the formula (IV) wherein R1, R2, R3 m and n are as defined in formula (I) above, with an arylamine (V) substituted W-NH2 (V) where W is as defined in formula (II) above. Reductive amination can be carried out in a one- or two-step process involving a Brønstedt or Lewis acid and a reducing agent. Suitable acids are sulfuric acid, polyphosphoric acid, 4-toluenesulfonic acid, titanium isopropoxide, aluminum trichloride, diethyl boron trifluoride etherate, or the like. Suitable reducing agents are hydrogen in the presence of catalyst, preferably Pd, Pd-C, Pd (0H) 2, Pt02, Rh-C or Raney nickel, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, diborane, hydride of di-iso-butylaluminum, or the like. The reaction can be carried out in the presence of one or more solvents which may be organic or inorganic, such as toluene, dichloromethane, ethers, alcohols, acetic acid, water, or in solvent mixture. R1 and the W substituents of compound (II), as defined above, can be modified after or during the preparation of (I) from (II) and (III), by methods known in the art, by example, reduction, oxidation, and alkylation, after or during the preparation of (II) from (IV) and (V).

The compounds of formula (III), (IV), and (V) may be commercially available, may be prepared by methods in the literature or may be prepared by methods known in the art. The invention will now be described in greater detail by means of the following examples, which should not be considered in any way as limiting the invention.

EXAMPLES EXAMPLE 1 (i) Preparation of 4- [N- (l-benzyl-p-perxdln-4-yl) amino-N, N-diethylbenzamide (compound 1) (1) Ti (Oi-Pr) 4 (14.8 ml, 50 mmol) is added to a mixture of 4-amino- (N, N-diethyl) -benzamide (4.81 g, 25 mmol) and l-benzyl-4- piperidone (6.95 ml, 37.5 mmol) at room temperature. The mixture is sonicated at 40 ° C for 2 h and stirred at 60 ° C for 15 h. The mixture is cooled in an ice bath and EtOH (100 ml) and granules of NaBH 4 (3.5 g, 91 mmol) are added. After stirring for 1 h at 0 ° C and 20 h at room temperature, 1M NH 4 OH (50 ml) is added. The mixture is stirred at room temperature for 30 min, and diluted with CH2C12 (100 ml) and filtered through a pad of Celite ™. The layers in the filtrate are separated, the aqueous layer is extracted with CH2C12 (100 ml) and the combined organic phases are washed with NaHCO3 (aqueous, saturated, 100 ml) and dried over K2C03. The mixture is filtered, concentrated and the residue purified by chromatography (gradient, PhMe to Me2CO) and crystallization (PhMe) to give the title compound 1 (7.48 g, 82%) as a beige solid. IR (KBr): 3343, 2939, 1608, 1528, 1458, 1422, 1339, 1285, 1174, 1091, 981, 827, 735 cirf1. XH NMR (CDC13): 7.32 (d, 4H), 7.26 (t, 1H), 7.23 (d, 2H), 6.54 (d, 2H), 3.72 (broad s, 1H), 3.53 (s, 2H), 3.42 (broad d, 4H), 3.32 (broad s, 1H), 2.84 (d, 2H), 2.15 ( t, 2H), 2.02 (d, 2H), 1.48 (c, 2H), 1.17 (t, 6H). 13 C NMR (CDCl 3): 171.7, 148.1, 138.3, 129.1, 128.5, 128.2, 127.0, 125.3, 112.2, 63.1, 52.2, 49.8, 41.5 (broad), 32.4, 13.6 (broad). An analytical sample was prepared by recrystallization from PhMe. Analysis calculated for C23H31N30: C, 75.58; H, 8.55; N, 11.50 found: C, 75.58; H, 8.63; N, 11.31 (ii) Preparation of 4- [N- (1-benzyl-piperidin-4-yl) -anilino] -N, N-diethylbenzamide (compound 2) (2) A mixture of 4- [N- (1-benzyl-piperidin-4-yl) -amino] -N, N-diethylbenzamide (compound 1) (0.58 g, 1.59 mmole), Ph3Bi (0.84 g, 1.90 mmole) and Cu (OAc) 2 (0.43 g, 2.38 mmole) in PhMe (25 ml) is heated at 110 ° C for 15 h. Ph3Bi is added (0.84 g, 1.90 mmol) and Cu (OAc) 2 (0.43 g, 2.38 mmol), and the mixture is stirred at reflux for 6 h. Ph3Bi (0.84 g, 1.90 mmol) and Cu (OAc) 2 (0.43 g, 2.38 mmol) are added, the mixture is stirred at reflux for 15 h, allowed to cool and suspended with 1M NH 4 OH (5 mL). The mixture is stirred at room temperature for 30 min, diluted with EtOAc (25 ml) and filtered through a pad of Celite ™. The layers in the filtrate are separated, the dark blue aqueous layer is extracted with EtOAc (25 ml) and the combined organic phases are washed with H20 (50 ml) and brine (25 ml) and dried over K2C03.

The mixture is filtered, concentrated and the residue purified by chromatography (gradient, PhMe to Me2C0) to give the title compound 2 (0.33 g, 47%) as a colorless oil. x NMR (CDC13): 7.53 (t, 2H), 7.29-7.18 (m, 8H), 7.01 (d, 2H), 6.58 (d, 2H), 3.85 (t, 1H), 3.49 (s, 2H), 3.42 (d, 4H), 2.95 (d, 2H), 2.11 (t, 2H), 1.92 (d, 2H), 1.51 (c, 2H), 1.17 (t, 6H). 13 C NMR (CDCl 3): 171.5, 149.0, 143.6, 138.2, 129.5, 129. 1, 128.7, 128.2, 128.1, 127.0, 126.7, 125.4, 116.0, 63.1, 55.5, 53.3, 40 (broad), 30.7, 13 (broad). An analytical sample such as the hydrochloride is obtained by adding a solution of the base-free in ether / EtOH to ethereal HCl diluted in cold ice.

IR (KBr): 3423, 2975, 2934, 2529, 1606, 1458, 1285, 1094, 750, 705 crn-1. Analysis calculated for C29H35N30 * HC1 * H20: C, 70.21; H, 7.72; N, 8.47 Found: C, 70.02; H, 7.61; N, 8.35 EXAMPLE 2 Preparation of 4- [N-benzyl-piperidin-4-yl) -4-metxl-anilino] -N, N-diethylbenzamide (compound 3) (3) A mixture of 4- [N- (1-benzyl-piperidin-4-yl) -amino] -N, N-diethylbenzamide (compound 1) (0.37 g, 1.00 mmol), tri-4-tolyl bismuth (1.59 g, 3.30 mmoles) and Cu (0Ac) 2 (0.54 g, 3.00 mmoles) in PhMe (20 ml) is heated to reflux for 16 h. The mixture is allowed to cool and is suspended with H20 (2 ml).

The mixture is stirred for 1 h, diluted with EtOAc (25 mL) and filtered ugh a pad of Celite ™. The layers in the filtrate are separated, the aqueous layer is extracted with EtOAc (25 ml) and the combined organic phases are washed with H20 (50 ml) and brine (25 ml) and dried over MgSO4. The mixture is filtered, concentrated and the residue is purified by chromatography (gradient, CH2C12 at 8% Me0H / CH2Cl2) to give the title compound 3 (0.09 g, 20%) as a colorless oil. XH NMR (CDC13): 7.30-7.16 (m, 9H), 6.94 (d, 2H), 6.52 (d, 2H), 3.83 (t, 1H), 3.48 (s, 2H), 3.42 (d, 4H), 2.93 (d, 2H), 2.36 (s, 3H), 2.07 (t, 2H), 1.90 (d, 2H), 1.50 (c, 2H), 1.16 (t, 6H). 13 C NMR (CDCl 3): 171.6, 149.7, 140.4, 138.2, 136.1, 130. 2, 130.2, 129.0, 128.1, 128.0, 126.9, 125.3, 113.8, 63.0, 55.4, 41 (broad), 30.5, 21.0, 13 (broad). An analytical mixture is obtained as a hydrochloride by adding an ethereal solution of the free base to dilute and cooled ice-cold HCl. IR (KBr): 2936, 2528, 1605, 1510, 1457, 1428, 1284, 1094, 952, 742, 701 was "1. Analysis calculated for C30H37N3O * HCl * 0.5 H20: C, 71.91; H, 7.84; N, 8.39 Found: C, 71.75; H, 7.83; N, 8.32 EXAMPLE 3 Preparation of 4- [N- (l-benzyl-piperidin-4-yl) -1-naphthylamino] -N, N-dxethylbenzamide (compound 4) (4) A mixture of 4- [N- (1-benzyl-piperidin-4-yl) -amino] -N, N-diethylbenzamide (compound 1) (0.37 g, 1.00 mmol) of tri-1-naphthyl bismuth (0.53 g, 1.20 mmoles) and Cu (0Ac) 2 (0.27 g, 1.50 mmoles) in PhMe (20 ml) is heated to reflux for 17 h. Tri-1-naphthylbismuth (0.53 g, 1.20 mmol) and Cu (0Ac) 2 (0.27 g, 1.50 mmol) are added at room temperature. The mixture is stirred at reflux for 22 h, allowed to cool and suspended with 1M NH 4 OH (5 mL). The mixture is stirred for 30 min, diluted with EtOAc (25 mL) and filtered ugh a pad of Celite ™. The layers in the filtrate are separated, the dark blue aqueous layer is extracted with EtOAc (25 ml) and the combined organic phases are washed with H20 (50 ml) and brine (25 ml) and dried over K2C03. The mixture is filtered, concentrated and the residue purified by chromatography (gradient PhMe to Me2CO) to give the title compound 4 (0.41 g, 83%) as a brown solid. IR (KBr): 2939, 2796, 1619, 1511, 1456, 1420, 1346, 1282, 1180, 1099, 783 crn-1. XH NMR (CDC13): 7.83 (t, 2H), 7.79 (d, 1H), 7.51 (t, 1H), 7.46 (t, 1H), 7.37 (t, 1H), 7.31 (d, 1H), 7.28-7.19 (m, 5H), 7.17 (d, 2H), 6.41 (d, 2H), 4.08 (t , 1H), 3.46 (s, 2H), 3.40 (d, 4H), 2.89 (d, 2H), 2.11 (t, 2H), 2.08 (s broad, 2H), 1.50 (s broad, 2H), 1.14 (t, 6H). • 13C NMR (CDCI3): 171.7, 149.8, 138.9, 138.1, 135.0, 133. 4, 129.1, 129.0, 128.3, 128.2, 128.1, 128.0, 127.0, 126.4, 126.2, 126.1, 124.6, 124.5, 112.2, 63.0, 56.5, 53.3, 40 (broad), 30.4, 13.5 (broad). An analytical sample is obtained by recrystallization from EtOH. Analysis calculated for C33H37N30: C, 80.61; H, 7.59; N, 8.55 Found: C, 80.48; H, 7.41; N, 8.52 EXAMPLE 4 Preparation of 4- [N- (1-benzyl-piperidin-4-yl) -2-naphthylamino] -N, N-diethylbenzamide (compound 5) (5) A mixture of 4- [N- (1-benzyl-piperidin-4-yl) -amino] -N, N-diethylbenzamide (compound 1) (0.67 g, 1.83 mmol), tri-2-naphthyl bismuth (0.97 g, 2.20 mmoles) and Cu (0Ac) 2 (0.50 g, 2.75 mmol) in PhMe (35 ml) is heated at reflux for 15 h. Tri-2-naphthylbismuth (0.97 g, 2.20 mmol) and Cu (OAc) 2 are added. (0.50 g, 2.75 mmol), and the mixture is stirred at reflux for 22 h. Tri-2-naphthylbismuth (0.97 g, 2.20 mmol) and Cu (OAc) 2 (0.50 g, 2.75 mmol) are added. After refluxing for 70 h, the mixture is allowed to cool and is suspended with 1M NH 4 OH (10 ml). The mixture is stirred for 30 min, diluted with EtOAc (35 ml) and filtered through a pad of Celite ™. The layers in the filtrate are separated, the dark blue aqueous layer is extracted with EtOAc (35 ml) and the combined organic phases are washed with H20 (75 ml) and brine (35 ml) and dried over MgSO4. The mixture is filtered, concentrated and the residue purified by chromatography (gradient, PhMe to Me 2 CO) to give the title compound 5 (0.63 g, 70%) as a brown oil which solidifies upon standing. IR (KBr): 2935, 2807, 1614, 1510, 1424, 1248 crn-1. 01 NMR (CDC13): 7.83-7.78 (m, 2H), 7.74 (d, 1H), 7.48-7.42 (, 3H), 7.27-7.21 (m, 7H), 7.10 (dd, 1H), 6.66 (d, 2H), 3.94 (t, 1H), 3.48 (s, 2H), 3.43 (broad s, 4H), 2.94 (d, 2H), 2.14 (t, 2H), 1.99 (s, 2H), 1.57 (, 2H) ), 1.17 (t, 6H). 13 C NMR (CDCl 3): 171.4, 148.8, 141.3, 138.1, 134.2, 131.2, 131.2, 129.2, 129.0, 128.1, 128.0, 127.5, 127.4, 127.2, 126.9, 126.2, 125.4, 125.3; 116.8, 63.0, 55.8, 53.3, 41 (broad) 30.7, 13.6 (broad). An analytical sample is obtained from MeOH. Analysis calculated for C.H37N30: C, 80.61; H, 7.59; N, 8.55 Found: C, 80.35; H, 7.59; N, 8.46 EXAMPLE 5 Preparation of N, N-diethyl-4- (N-piperidin-4-yl-anilino) benzamide (compound 6) (6) A solution of 4- [N- (1-benzyl-piperidin-4-yl) -anilino] -N, N-diethylbenzamide (compound 2) (1.21 g, 2.74 mmol) in MeOH (25 ml) is hydrogenated at 4.2 kg. / cm2 (60 psi) for 4 d in the presence of a catalytic amount of Pd (OH) 2 in carbon. The mixture is filtered through a pad of Celite ™, concentrated and the residue is purified by chromatography (gradient, CH2C12 to CH2Cl2 / MeOH (9: 1) to CH2Cl2 / MeOH / NH4OH (concentrated, aqueous) (80:18: 2) to give compound 6 of the title (0.62 g, 64%) as a colorless oil XH NMR (CDC13): 7.37 (t, 2H), 7.25-7.22 (m, 3H), 7.01 (d, 2H), 6.61 (d, 2H), 3.98 (t, 1H), 3.42 (broad d, 4H), 3.17 (d, 2H), 2.78 (t, 2H), 2.00 (d, 2H), 1.71 (s broad, 1H), 1.41 (c, 2H), 1.18 (t, 6H). • 13C NMR (CDCI3): 171.4, 148.2, 143.1, 129.8, 128.0, 127.9, 127.7, 125.7, 116.9, 53.5, 44.4, 41 (broad), 28.7, 13.5 (broad). An analytical sample such as the hydrochloride is obtained by adding an ethereal solution of the free phase to ethereal HCl diluted cold with ice. IR (KBr): 3426, 3359, 2936, 2722, 1603, 1473, 1281, 1091, 708, 503 cm "1. Analysis calculated for C22H29N30 * HC1 * H20: C, 65.09; H, 7.95; N, 10.35 Found: C, 65.37; H, 7.94; N, 10.38 EXAMPLE 6 Preparation of N, N-diethyl-4- ([N-piperidin-4-yl] -1-naphthylamino benzamide (compound 7) (7) A solution of 4- [N- (1-benzyl-piperidin-4-yl) -naphthylamino] -N, N-diethylbenzamide (compound 4) (0.22 g, 0.45 mmol) in EtOH (20 ml) is hydrogenated at 4.2 kg. / cm2 (60 psi) for 64 h in the presence of a catalytic amount of Pd (OH) 2 in carbon. The mixture is filtered through a pad of Celite ™, concentrated and the residue purified by chromatography (gradient, CH2C12 to CH2Cl2 / MeOH (9: 1) to CH2Cl2 / MeOH / NH4OH (concentrated aqueous) (80: 18: 2 )) to provide compound 7 of the title (0.12 g, 67%) as a colorless oil that solidifies upon standing. IR (KBr): 2942, 1609, 1512, 1448, 1280 crrf0 XH NMR (CDC13): 7.86 (t, 2H), 7.80 (d, 1H), 7.50 (t, 1H), 7.45 (t, 1H), 7.36 (t, 1H), 7.30 (d, 1H), 7.18 (d, 2H), 6.42 (d, 2H), 4.20 (t, 1H), 3.40 (broad d, 4H), 3.06 (d, 2H), 2.79-2.63 (m, 3H), 2.03 (broad s, 2H), 1.39 (broad s, 2H), 1.14 (t, 6H). 13 C NMR (CDCl 3): 171.6, 149.4, 138.7, 134.8, 133.3, 128. 7, 128.2, 128.1, 127.9, 126.3, 126.1, 126.0, 124.4, 124.2, 112.1, 56.1, 46.0, 41 (broad), 31.3, 13.4 (broad). Analysis calculated for C 26 H 31 N 30 * 1.25 H 20: C, 73.64; H, 7.96; N, 9.91 Found: C, 73.77; H, 7.54; N, 9.96 EXAMPLE 7 Preparation of N, N-diethyl-4- ([N-piperidin-4-yl] -2-naphthylamino benzamide (compound 8) (8) Chloroformate (1-chloroethyl) (58 μl, 0. 53 mmole) was added to a solution of 4- [N- (1-benzyl-piperidin-4-yl) -2-naphthylamino] -N, N-diethylbenzamide (compound 5) (105 mg, 0.21 mmol) in dichloroethane (2.5 ml. ) at room temperature. The mixture is refluxed for 17 h and then allowed to cool to room temperature and concentrated. Methanol (2.5 ml) is added and the mixture is heated at reflux for 2.5 h, allowed to cool and concentrate. The residue is partitioned between CH2C12 (10 mL) and 1M NH4 OH (10 mL). The layers are separated and the organic phase is washed with H20 (10 ml) and brine (10 ml), and dried over K2C03. The mixture is filtered, concentrated and the residue is purified by chromatography (gradient, CH2C12 to CH2Cl2 / MeOH / NH4OH (aqueous, concentrated) (85: 13.5: 1.5) and CLAP (LiChroPrep RP-18, elution with increasing amounts of 0.1% TFA / MeCN in 0.1% TFA / H2O) to provide the title compound 8 (30 mg) as the trifluoroacetate.RTM. (pure): 3420, 1680, 1600 cm "1.? NMR (CDC13, salt of TFA) d: 1.10 (6H, m), 1.78 (2H, m), 2.10 (2H, m, CH (CH) CH (N) CH (CH)), 3.00 (2H, m, CH (CH) NHCH ( CH)), 3.35 (6H, m), 4.15 (1H, m), 6.65 (2H, m), 7.00 (1H, m), 7.20 (2H, m), 7.40 (3H, m), 7.75 (3H, sea) .

EXAMPLE 8 Preparation of 4- [N- (1- [2-phenylethyl] -piperidin-4-yl) anilino] -N, N-diethylbenzamide (compound 9) O) (2-Bromoethyl) benzene (0.18 ml, 1.30 mmol) is added with stirring to an ice-cooled solution of N, N-diethyl-4- (N-piperidin-4-yl-anilino) benzamide (compound 6) (0.21 g, 0.59 mmol), Et3N (0.10 mL, 0.75 mmol) and a catalytic amount of 4-dimethylaminopyridine in CH2C12 (5 mL). The stirred mixture is allowed to reach room temperature for 5 h, is heated at reflux for 16 h, allowed to cool to room temperature, diluted with CH2C12 (10 ml) and washed with H20 (15 ml), brine ( 15 ml) and dried over K2C03. The mixture is filtered, concentrated and the residue purified by chromatography (gradient, PhMe to PhMe / Me2CO (2: 1)) to give the title compound 9 (0.11 g, 40%) as a colorless oil which solidifies the let rest. IR (KBr): 2928, 1612, 1504, 1437, 1280, 1980, 754 cpT0 ^ NMR (CDC13): 7.36 (t, 2H), 7.30-7.15 (m, 8H), 7.01 (d, 2H), 6.61 ( d, 2H), 3.88 (t, 1H), 3.42 (broad d, 4H), 3.08 (d, 2H), 2.76 (m, 2H), 2.57 (m, 2H), 2.17 (t, 2H), 1.97 ( d, 2H), 1.55 (c, 2H), 1.18 (t, 6H). 13 C NMR (CDCl 3): 171.5, 149.0, 143.5, 140.3, 129.6, 128. 6, 128.4, 128.1, 126.8, 126.1, 125.4, 116.1, 60.6, 55.5, 53.5, 41 (broad), 33.9, 30.7, 13.6 (broad). Analysis calculated for C30H37 3O * 0.2 C3H60: C, 78.66; H, 8.24; N, 8.99 Found: C, 78.55; H, 7.75; N, 8.91 EXAMPLE 9 (i) Preparation of 3- [N- (l-benzyl-piperidin-4-yl) amino] -N, N-diethylbenzamide (compound 10) (10) Ti (0i-Pr) 4 (0.70 ml, 2.37 mmol) is added to a mixture of 3-amino- (N, N-diethyl) benzamide (150 mg, 0.78 mmol) and l-benzyl-4-piperidone (0.18 ml. , 0.97 mmole) at room temperature. The mixture is sonicated at 40 ° C for 6 h and stirred at room temperature for 15 h. The mixture is cooled in an ice bath and EtOH (5 ml) and NaBH 4 (75 mg, 1.98 mmol) are added. After stirring for 1 h at 0 ° C and 2 d at room temperature, 2M NH 4 OH (5 ml) is added. The mixture is stirred at room temperature for 30 min, diluted with CH2C12 (10 mL) and filtered through Celite ™. The layers are separated in the filtrate, extract the aqueous layer with CH2C12 (3x10 ml). The combined organic phases are washed with 10% HCl (2x15 ml). The pH is adjusted in the combined aqueous extracts to 10 with 2N NaOH, and extracted with CH2C12 (3x10 ml). The combined organic extracts are dried over Na 2 SO 4, filtered, concentrated and the residue purified by chromatography (9: 1: 0.1 EtOAc: heptane: Et 3 N) to give the title compound 10 (173 mg, 61%) as an oil. thick light yellow. IR (pure): 3333, 1612 cm'0 XH NMR (CDC13): 7.40-7.10 (7H, m), 6.55 (2H, m), 3.50 (4H, m), 3.22 (4H, m), 2.80 (2H , m), 2.12 (2H, m), 2.00 (2H, m), 1.43 (2H, m), 1.20 (3H, m), 1.05 (3H, m). 13C NMR (CDCI3): 171.6, 147.1, 138.3, 138.2, 129.1, 129.0, 128.1, 126.9, 114.6, 113.8, 110.6, 63.0, 52.2, 49.8, 43.1, 38.9, "32.4, 14.1, 12.8 Analysis calculated for C23H31N30 * HC1 * 2.1 H20: C, 63.07; H, 8.28; N, 9.59 Found: C, 63.19; H, 7.94; N, 9.25 (ii) Preparation of 3- [N- (l-benzyl-piperidin-4-yl) -anilino] -N, N-diethylbenzamide (compound 11) (eleven) A mixture of 3- [N- (1-benzyl-piperidin-4-yl) -amino] -N, N-diethylbenzamide (compound 10) (360 mg, 0.98 mmol), Ph3Bi (1.10 g, 2.50 mmol) and Cu (OAc) 2 (0.45 g, 2.48 mmol) in toluene (10 ml) is heated at 110 ° C for 12 h. Another portion of Cu (OAc) 2 (0.45 g) is added and the mixture is heated at 110 ° C for an additional 12 h and allowed to cool to room temperature. Water (10 ml) is added and the mixture is filtered through Celite ™. The layers in the filtrate are separated, and the organic phase is washed with water, brine, dried over Na 2 SO 4 and concentrated. Chromatography of the residue (9: 1 EtOAc / heptane) gives the title compound 11 (255 mg, 59%) as a thick, light yellow oil. IR (pure): 3056, 3010, 2937, 2810, 1629 crn-1. XH NMR (CDC13): 7.40-6.60 (14H, m), 3.80 (1H, m), 3.43 (s broad, 4H), 3.20 (2H, broad s), 2.90 (2H, m), 2.05 (2H, m), 1.90 (2H, m), 1.48 (2H, m), 1.20 (3H, broad s) , 1.00 (3H, broad s). 13 C NMR (CDCl 3): 171.3, 147.3, 144.4, 138.1, 129.3, 129.0, 128.0, 126.9, 126.4, 123.9, 119.7, 117.5, 116.5, 62.9, 55.3, 53.2, 43.0, 39.0, 30.6, 14.0, 12.7. Analysis calculated for C29H35N30 * 1.25HC1 * 0.5 H20: C, 70.15; H, 7.41; N, 8.47; Cl 8 94 Found: C, 69.69; H, 7.34; N, 8.25; Cl 8.96 EXAMPLE 10 Preparation of N, N-diethyl-3- (N-piperidin-4-yl-anilino) benzamide (compound 12) (12) A solution of 3- [N- (1-benzyl-piperidin-4-yl) -anilino] -N, N-diethylbenzamide (compound 11) (102 mg, 0.23 mmole) in EtOH (15 ml) is hydrogenated at 2.8 kg. / cm2 (40 psi) in the presence of a catalytic amount of Pd (OH) 2 in carbon, during 2 h. The mixture is filtered through Celite ™ and concentrated. The residue is purified by chromatography (9: 1: 0.5 EtOAc / heptane / Et3N) to yield the title compound 12 (50 mg, 81%) as a light yellow viscous oil. IR (hydrochloride salt, pure): 3421, 1597, 1494 cm "1.? NMR (CDC13): 7.80-6.50 (9H, m), 4.00 (1H, m), 3.21 (2H, broad s) 3.30 (2H, m), 3.20 (2? -, s broad), 2.90 (2H, m), 2.05 (2H, m), 1.70 (2H, m), 1.17 (3H, broad s), 1.00 (3H, broad s). 13 C NMR (CDCl 3): 171.0, 143.7, 140.7, 138.0, 129.5, 129.2, 128.2, 124.5, 119.7, 117.9, 116.5, 53.2, 43.1, 41.1, 39.0, 28.7, 14.0, 8.9. An analytical sample is obtained as a clohydrate by adding an ethereal solution of the free base to HCl diluted cold with ice. Analysis calculated for C28H33N30 * HC1 * 1.3 H20: C, 62.30; H, 8-08; N, 9.91 Found: C, 62.40; H, 7.67; N, 9.80 EXAMPLE 11 (i) Preparation of 4- [N- (l-benzyl-piperxdin-3-yl) amino] -N, N-diethylbenzamide (compound 13) (13) Ti (Oi-Pr) 4 (2.2 ml, 7.45 mmol) is added to a mixture of 4-amino- (N, N-diethyl) benzamide (0.36 g, 1.87 mmol) and l-benzyl-3-piperidone. (0.70 g, 3.69 mmol) at room temperature. The mixture is sonicated at 40 ° C for 1 h, and stirred at room temperature for 15 h. The mixture is cooled in an ice bath and EtOH (15 ml) and NaBH 4 (0.21 g, 5.55 mmol) are added. After stirring for 16 h at room temperature, 2M NH 4 OH (15 ml) is added. The mixture is stirred at room temperature for 30 min, diluted with CH2C12 (10 ml) and filtered through a pad of Celite ™. The layers in the filtrate are separated, the aqueous layer is extracted with CH2C12 (3x15 ml). The combined organic phases are washed with 10% HCl (2x20 ml). The pH in the combined aqueous extracts is adjusted to 10 with 2N NaOH, and extracted with CH2C12 (3x10 ml). The combined organic extracts are dried over Na 2 SO 4, filtered and concentrated. The residue is purified by chromatography (9: 1: 0.1 EtOAc / Et3N) to give the title compound 13 (0.32 g, 47%) as a thick, light yellow oil. IR (pure) 3320, 1736, 1608 cm "1. XH NMR (CDC13): 7.20 (7H, m), 6.50 (2H, m), 4.22 (1H s broad), 3.60-3.30 (7H, m), 2.60 (1H, m), 2.35 (3H, m), 1.65 (2H, m), 1.50 (2H, m), 1.10 (6H, m). 13 C NMR (CDCl 3): 171.7, 147.9, 138.1, 128.7, 128.4, 128.1, 126.9, 124.9, 112.1, 63.0, 58.6, 53.5, 48.3, 41.4, 28.6, 22.3, 13.4. Analysis calculated for C23H31N30 * HC1 * 2.1 H20: C, 62.81; H, 8.30; N, 9.55 Found: C, 62.75; H, 7.94; N, 9.63 (ii) Preparation of 4- [N- (l-benzyl-pxperxdin-3-xl) anilino] -N, N-diethylbenzamide (compound 14) (14) A mixture of 4- [N- (1-benzyl-piperidin-3-yl) -amino] -N, N-diethylbenzamide (compound 13) (0.29 mg, 0.79 mmol), Ph3Bi (0.87 g, 1.98 mmol) and Cu (OAc) 2 (0.36 g, 1.98 mmol) in toluene (5 ml), heated at 110 ° C for 12 h, and allowed to cool to room temperature. Water (5 ml) is added and the mixture is filtered through Celite ™. The layers in the filtrate are separated and the organic phase is washed with water, brine, dried over Na 2 SO 4 and concentrated. Chromatography of the residue (9: 1 EtOAc / heptane) gives the title compound 14 (0.24 g, 67%) as a light yellow viscous oil. IR (pure): 3056, 3012, 2938, 2800, 1613, 1492 c "1. XH NMR (CDC13): 7.40-7.10 (10H, m), 6.95 (2H, d), 6.55 (2H, d), 4.05 (1H, m), 3.45 (2H, s), 3.38 (4H, broad s), 3.19 (1H), 2.75 (1H, m), 1.90 (1H, m), 1.80-1.60 (4H, m), 1.12 (6H, m). An analytical sample is obtained as a hydrochloride by adding an ethereal solution of the free base to ethereal HCl diluted cold. 13C NMR (CDCI3): 171.4, 148.8, 143.4, 138.2, 129.3, 128.7, 128.6, 128.4, 128.0, 127.8, 126.8, 125.3, 123.9, 115.7, 62.9, 57.2, 54.4, 53.2, 42 (b), 29.8, 25.9 , 13.4 (b). Analysis calculated for C29H35N30 * 1.25HC1 * 0.5 H20: C, 70.15; H, 7.41; N, 8.47; Cl, 8.94 Found: C, 70.30; H, 7.30; N, 8.43; Cl, 8.34 EXAMPLE 12 Preparation of N, N-diethyl-4- (N-piperidin-3-yl-anilino) benzamide (compound 15) (fifteen) A solution of 4- [N- (1-benzene-piperidin-3-yl) -anilino] -N, N-diethylbenzamide (compound 14) (0.28 g, 0.63 mmol) in EtOH (10 mL) is hydrogenated at 2.1 kg / cm2 (30 psi) in the presence of a catalytic amount of Pd (OH) 2 in carbon, during 6 h. The mixture is filtered through Celite ™, concentrated and the residue purified by chromatography (gradient 9: 1: 0 to 9: 1: 0.5 EtOAc / heptane / Et3N) to give the title compound 15 (80 mg, 36 %) as a light yellow viscous oil. IR (pure): 3300-3500, 1464 c "1.

X H NMR (CDCl 3): 7.35 (2 H, m), 7.18 (3 H, m), 6.95 (2 H, m), 6.56 (2 H, m), 4.30 (1 H, broad s), 4.0 (1 H, m), 3.38 (4H, broad s), 2.95 (1H, m), 2.35 (2H, m), 1.95 (1H, m), 1.70 (2H, m), 1.15 (2H, m), 1.10 (6H, m). 13 C NMR (CDCl 3): 171.3, 148.5, 142.8, 129.3, 128.5, 127.7, 126.4, 125.5, 115.4, 54.1, 49.3, 45.4, 44-38 (b), 29.9, 25.6, 13.3 (b). Analysis calculated for C 22 H 29 N 3 O * HCl * 0.4 H 20: C, 66.87; H, 7.86; N, 10.63 Found: C, 66.85; H, 7.68; N, 10.44 EXAMPLE 13 (i) Preparation of 3- [N- (1-benzyl-piperidin-3-yl) amino] -N, N-diethylbenzamide (compound 16) (16) 13C NMR (CDCI3): 171.4, 146.9, 138.1, 137.9, 128.9, 128.6, 127.9, 126.7, 114.1, 113.5, 110.4, 62.8, 58.5, 53.3, 48.3, 42.9, 38.7, 28.6, 22.2, 13.9, 12.6 . (ii) Preparation of 3- [N- (1-benzyl-piperidin-3-yl) -anilino] -N, N-diethylbenzamide (compound 17) (17) A mixture of 3- [N- (1-benzyl-piperidin-3-yl) -amino] -N, N-diethylbenzamide (compound 16) (0.25 g, 0.68 mmol), Ph3Bi (0.75 g, 1.70 mmole) and Cu (0Ac) 2 (0.31 mg, 1.70 mmole) in toluene (5 ml) is heated at 110 ° C for 14 h and allowed to cool to room temperature. Water (5 ml) is added and the mixture is filtered through Celite ™. The layers in the filtrate are separated and the organic phase is washed with water and brine, dried over Na 2 SO 4 and concentrated. Chromatography of the residue (9: 1 EtOAc / heptane) gives the title compound 17 (0.16 g, 52%) as a pale yellow, viscous oil. IR (pure): 3010, 2930, 1630, 1610 cm "1. XH NMR (CDC13): 7.40-6.60 (14H, m), 4.05 (1H, m), 3.45 (4H, broad s), 3.18 (2H, m), 2.75 (1H, m), 1.90 (1H, m), 1.80-1.60 (4H, m), 1.18 (3H, broad s), 1.00 (3H, broad s) .13C NMR (CDCI3): 171.3, 147.1, 144.5, 138.3, 138.1, 129.3, 129.1, 128.8, 128.1, 126.9, 125.9, 123.7, 119.8, 117.8, 116.9, 63.0, 57.5, 54.4, 53.2, 43.1, 39.0, 29.9, 25.0, 14.1, 12.8. for C29H35N30 * 1.4HC1 * 0.5 H20: C, 69.38; H, 7.46; N, 8.37; Cl, 9.91 Found: C, 69.11; H, 7.14; N, 8.08; Cl, 10.12.

EXAMPLE 14 Preparation of N, N-diethyl-3- (N-piperidin-3-yl-anilino) benzamide (compound 18) (18) A solution of 3- [N- (1-benzyl-piperidin-3-yl) -anilino] -N, N-diethylbenzamide (compound 17) (50 mg, 0.11 mmol) in EtOH (5 ml) is hydrogenated at 2.1 kg. / cm2 (30 psi) in the presence of a catalytic amount of Pd (OH) 2 in carbon, during 6 h. The mixture is filtered through Celite ™, concentrated and the residue purified by chromatography. (gradient, 9: 1: 0 to 9: 1: 0.5 EtOAc / heptane / Et3N) to give the title compound 18 (15 mg, 36%) as a pale yellow, viscous oil. ^ NMR (CDC13): 7.40-6.60 (9H, m), 4.40 (1H, m), 3.60 (2H, m), 3.40 (2H, broad s), 3.15 (3H, m), 2.50 (2H, m) , 1.80 (2H), 1.20 (2H, m), 1.18 (3H, broad s), 0.95 (3H, broad s). 13 C NMR (CDCl 3): 171.2, 146.9, 144.0, 138.0, 129.4, 126.4, 124.3, 119.7, 117.8, 116.5, 54.1, 45.1, 43.1, 39.0, 30.0, 14.0, 12.7. • An analytical sample such as hydrochloride is obtained by adding an ethereal solution of the free base to dilute and ice-cooled etheral HCl. IR (pure): 3412, 1598, 1493 cm "1 Analysis calculated for C22H29N30 * HC1 * H20: C, 65.09; H, 7.95; N, 10.35 Found: C, 65.03; H, 7.80; N, 10.02 EXAMPLE 15 (i) Preparation of 4- [N- (1-benzyl-piperidin-3-yl) amino] -N, -diethylbenzamide (compound 19) (19) Ti (Oi-Pr) 4 (3.1 ml, 10.4 mmol) is added to a mixture of 4-amino- (N, N-diethyl) benzamide (0.50 g, 2.51 mmol) and l-benzyl-3-pyrrolidone. (0.85 ml, 5.30 mmol) at room temperature. The mixture is sonicated at 40 ° C for 3 h, and stirred at room temperature for 16 h. The mixture is cooled in an ice bath and EtOH (30 ml) and NaBH 4 (0.30 g, 8.00 mmol) are added. After stirring for 16 h at room temperature, 2M NH 4 OH (20 ml) is added. The mixture is stirred at room temperature for 30 min, diluted with CH2C12 (20 ml) and filtered through a pad of Celite ™. The layers in the filtrate are separated, the aqueous layer is extracted with CH2C12 (3x20 ml). The combined organic phases are washed with 10% HCl (2x20 ml). The pH in the combined aqueous extracts is adjusted to 10 with 2N NaOH, and extracted with CH2C12 (3x20 ml). The combined organic extracts are dried over Na 2 SO 4, filtered, concentrated and the residue purified by chromatography (gradient, 9: 1: 0.5 to 9: 0: 1 EtOAc / heptane / Et 3 N) to give compound 19 of the title (0.40. g, 44%) as a light yellow viscous oil. IR (pure): 3322, 1609, 1527, 1455 cm "1. XH NMR (CDC13): 7.40-7.10 (7H, m), 6.60-6.40 (2H, m), 4.20 (1H, m), 3.95 (1H , m), 3.55 (2H, s), 3.35 (4H, broad s), 2.70 (2H, m), 2.50-2.35 (2H, m), 2.25 (1H, m), 1.60 (1H, m), 1.15 (6H, broad t). 13 C NMR (CDCl 3): 171.4, 148.2, 138.4, 128.5, 128.2, 128.1, 126.7, 126.1, 113.8, 112.1, 60.5, 59.9, 52.5, 51.9, 41 (b), 32.2, 13.3. (ii) Preparation of 4- [N- (1-benzyl-piperidin-3-yl) -amino] -N, N-diethylbenzamide (compound 20) (twenty) A mixture of 4- [N- (1-benzyl-pyrrolidin-3-yl) -amino] -N, N-diethylbenzamide (compound 19) (0.40 g, 1.14 mmole), Ph3Bi (1.25 g, 2.84 mmole), and Cu (0Ac) 2 (0.52 g, 2.86 mmol) in toluene (10 ml) is heated at 110 ° C for 16 h and allowed to cool to room temperature. Water (5 ml) is added and the mixture is filtered through Celite ™. The filtrate is washed with water, brine, dried over Na 2 SO 4 and concentrated. Chromatography of the residue (95: 5 EtOAc / MeOH) gives the title compound 20 (0.19 g, 40%) as a light yellow viscous oil. 2 H NMR (CDC13): 7.40-7.18 (10H, m), 7.05 (2H, m), 6.70 (2H, m), 4.57 (1H, m), 3.60 (1H, broad d), 3.40 (5H, m) , 2.80 (1H, m), 2.60 (1H, m), 2.58 (2H, m), 2.20 (1H, m), 1.90 (1H, m), 1.18 (6H, broad s). 13C NMR (CDCI3): 171.4, 149.3, 145.2, 138.9, 129.4, 128.4, 128.1, 128.0, 127.7, 127.2, 126.7, 125.0, 117.1, 60.3, 58.3, 57.8, 53.0, 41 (b), 29.5, 13.4. An analytical sample is obtained as a hydrochloride by adding an ethereal solution of the free base to ethereal HCl diluted cold with ice. IR (pure): 3430, 1610, 1457 cm "1. Analysis calculated for C28H33N30 * HC1 * 1.3 H20: C, 68.99; H, 7.24; N, 8.62 Found: C, 68.99; H, 7.57; N, 8.62 EXAMPLE 16 Preparation of N, N-diethyl-4- (N-pyrrolidin-3-yl-anilino) benzamide (compound 21) (twenty-one) A mixture of compound 20 (90 mg, 0.2105 mmol), NH40, CH (27 mg, 0.4282 mmol) and a catalytic amount of 10% Pd / C in MeOH (5 mL) is stirred vigorously at room temperature overnight. The catalyst is removed through Celite ™ and the filtrate condensed in vacuo to give a crude sample which is purified through MPLC (100: 0 to 9: 1 CH2Cl2 / MeOH (10% TEA) in silica gel 60) to provide the title compound 21 (30 mg, 42%) as a thick, light yellow oil.

IR (hydrochloride salt, film) v: 3428 (NH), 1607 (CONEt2) cm "1. XH NMR (free amine, 400 MHz, CDC13) d: 1.06 (6H, m, 2xCH2CH3), 1.90 (1H, m, ArCHCH (CH) CH2), 2.30 (1H, m, ArNCHCH (CH) CH2), 2.58 (2H, m, ArNCHCH2CH2N), 2.95 (1H, m, NHCH (CH) CH2), 3.23 (lh, m, NHCH ( CH) CH2), 3.40 (4H, broad s, 2xCH2CH3), 4.70 (1H, m, ArNCH), 6.68 (2H, m, Ar), 7.22 (3H, m, Ar), 7.38 (2H, m, Ar) 13C NMR (free amine, 100 Hz, CDC13) d: 13.4, 29.7, 41.9, 54.6, 57.9, 59.3, 117.5, 125.5, 127.9, 128.0, 129.7, 144.8, 149.2, 171.2 Elemental analysis calculated for C21H29N30C12.1.5H20 : C, 57.66; H, 7.37; N, 9.61 Found: C, 57.86; H, 7.38; N, 9.03 EXAMPLE 17 (i) Preparation of 4- [N- (1-benzyl-piperidin-4-yl) amino] -N, N-diethylbenzenesulfonamide (compound 22) (22) Ti (0-i-Pr) 4 (2.10 ml, 7.10 mmol) is added to a mixture of 4-amino- (N, N-diethyl) benzenesulfonamide (0.81 g, 3.55 mmol) and l-benzyl-4-piperidone ( 0.99 ml, 5.32 mmol) at room temperature. The mixture is sonicated at 40 ° C for 40 min, and stirred at 60 ° C for 18 h. The dark mixture is cooled in an ice bath and EtOH (15 ml) is added followed by NaBH4 granules (0.5 g, 13.2 mmol). After stirring for 1 h at 0 ° C and 20 h at room temperature, 1 M NH 4 OH (5 ml) is added. The mixture is stirred at room temperature for 30 min, diluted with CH2C12 (25 ml) and filtered through a pad of Celite ™. The layers in the filtrate are separated, the aqueous layer is extracted with CH2C12 (15 ml), and the combined organic phases are washed with NaHCO3. (saturated aqueous, 25 ml) and dried over K2C03. The mixture is filtered, concentrated and the residue is purified by chromatography (gradient, PhMe to Me2CO) to provide the title compound 22 (0.91 g, 46%) as a tan solid. IR (KBr): 2942, 1560, 1520, 1321, 1146, 920 cm "1. XH NMR (CDC13): 7.55 (d, 2H), 7.34-7.23 (m, 5H), 6.54 (d, 2H), 4.08 (d, 1H), 3.53 (s, 2H), 3.29 (broad s, 1H), 3.17 (c, 4H), 2.85 (d, 2H), 2.16 (t, 2H), 2.01 (d, 2H), 1.51 (c, 2H), 1.11 (t, 6H). 13C NMR (CDCI3): 150.2, 138.2, 129.1, 129.0, 128.2, 127.0, 126.8, 63.0, 52.1, 49.6, 41.9, 32.2, 14.1. (ii) Preparation of 4- [N- (l-benzyl-piperidin-4-yl) amino] -N, N-diethylbenzenesulfonamide (compound 23) (23) A mixture of 4- [N- (1-benzyl-piperidin-4-yl) -amino] -N, N-diethylbenzenesulfonamide (compound 22), (0.44 g, 1.10 mmol), Ph3Bi (0.58 g, 1.31 mmoles) and Cu (OAc) 2 (0.30 g, 1.64 mmoles) in PhMe (20 ml) is heated to reflux for 24 h. Ph3Bi (0.58 g, 1.31 mmoles) and Cu (OAc) 2 (0.30 g, 1.64 mmoles) are added. The mixture is stirred at reflux for 24 h and Ph3Bi (0.58 g, 1.31 mmol) and Cu (OAc) 2 (0.30 g, 1.64 mmol) are added. After refluxing for 24 h, the mixture is allowed to cool and is suspended with 1M NH 4 OH (5 mL). The mixture is stirred at room temperature for 30 min, diluted with EtOAc (25 ml) and filtered through a pad of Celite ™. The layers in the filtrate are separated, the dark blue aqueous layer is extracted with EtOAc (25 ml) and the combined organic phases are washed with H20 (50 ml) and brine (25 ml) and dried over K2C03. The mixture is filtered, concentrated and the residue purified by chromatography (gradient, PhMe to Me2C0) to provide the title compound 23 (50 mg, 10%) as a brown oil. XH NMR (CDC13): 7.51 (d, 2H), 7.43 (t, 2H), 7.35 (t, 1H), 7.30-7.22 (m, 5H), 7.07 (d, 2H), 6.48 (d, 2H), 3.86 (t, 1H), 3.48 (s, 2H), 3.18 (c, 4H), 2.94 (d, 2H), 2.11 (t, 2H), 1.91 (d, 2H), 1.50 (c, 2H), 1.11 (t, 6H). 13 C NMR (CDCl 3): 151.8, 141.5, 138.1, 131.1, 129.9, 129.1, 128.6, 128.1, 127.5, 127.0, 125.9, 112.7, 63.0, 55.8, 53.1, 42.0, 30.6, 14.2.

Purification by CLAP (LiChroPrep RP-18, elution with increasing amounts of 0.1% TFA / MeCN in 0.1% TFA / H, O) provides an analytical sample as a white solid. IR (KBr): 3433, 1677, 1586, 1496, 1324, 1196, 1148, 719 c -1. Analysis calculated for C28H35N302S * 1.25CF3COOH: C, 59.07; H, 5.89; N, 6.78 Found: C, 59.00; H, 6.01; N, 7.01 EXAMPLE 18 Preparation of N, N-diethyl-4- (N-piperidxn-4-yl-anilino) benzenesulfonamide (compound 24) (24) (1-Chloroethyl) chloroformate (10 μl, 0.1 mmol) is added to a solution of 4- [N- (1-benzyl-piperidin-4-yl) -anilino] -N, N-diethylbenzenesulfonamide (compound 23) (19 mg, 40 μmol) in toluene (1 ml) at room temperature. The mixture is stirred at reflux for 16 h, allowed to cool to room temperature and concentrated. Methanol (1 ml) is added and the mixture is heated at reflux for 4 h, allowed to cool and concentrated. The residue is partitioned between CH2C12 (5 ml) and 1M NH4OH (5 ml). The layers are separated and the organic phase is washed with H20 (5 ml) and brine (5 ml) and dried over K2C03. The mixture is filtered, concentrated and the residue purified by CLAP (LiChroPrep RP-18, elution with increasing amounts of 0.1% TFA / MeCN in 0.1% TFA / H2O) to provide the title compound 24 (13 mg, 84%) such as trifluoroacetate. IR (KBr): 3420, 1658, 1199, 1146, 714 crn "1 .2H NMR (CD3OD) d: 7.66-7.63 (m, 4H), 7.55 (t, 1H), 7.28 (d, 2H), 6.76 ( d, 2H), 4.50 (t, 1H), 3.54 (d, 2H), 3.35-3.23 (m, 6H), 2.34 (d, 2H), 1.73 (c, 2H), 1.19 (t, 6H). NMR (CD3OD) d: 153.4, 142.4, 132.8, 131.7, 130.1, 129.7, 128.8, 114.4, 53.6, 45.2, 43.6, 29.2, 14.9 Analysis calculated for C28H35N302Sx2CF3COOHxl.5H20: C, 46.73; H, 5.33; N, 6. 54 Found: C, 46.54; H, 5. 01; N, 6. 71 The best mode of carrying out the invention, known so far, is to use the compounds of examples 1, 2, 3 , 4, 5, 6, 7, 17 and 18.

PHARMACEUTICAL COMPOSITIONS The novel compounds according to the present invention can be administered orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracically, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints. A preferred route of administration is orally, intravenously or intramuscularly. The dosage will depend on the route of administration, the severity of the disease, the age and weight of the patient, and other factors normally considered by the attending physician, when determining the individual regimen and the dosage level as the most appropriate for a particular patient. To prepare pharmaceutical compositions from the compounds of this invention, the inert and pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.

A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspension improving agents, binders or agents that disintegrate the tablet; It can also be an encapsulating material. In powder form, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the desired shape and size. To prepare suppository compositions, a low melting point wax, such as a mixture of fatty acid glycerides and cocoa butter, is first melted, and the active ingredient is dispersed therein, for example, by stirring. The homogeneous molten mixture is then poured into conveniently sized molds and allowed to cool and solidify. Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, peptin, dextrin, starch, tragacanth, methylcellulose, carboxymethylcellulose, a wax with a low melting point, cocoa butter and the like. The pharmaceutically acceptable salts are acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium acetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisilate, estolate, esylate, fumarate, glucaptate, gluconate, glutamate, glycolylaminosanilate, hexylresorcinate , baminohydrate, bromohydrate, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methylnitrate, methyl sulfate, mucate, napsylate, nitrate, parmoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, Silicalate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, triethiodide, benzathine, chloroprocaine, choline diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred pharmaceutically acceptable salts are the hydrochlorides, trifluoroacetates and bitartrates. The term composition is considered to include the formulation of the active component with an encapsulating material as a carrier that provides a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with the same. Similarly, cachets or sachets may be included. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.

The liquid of the compositions includes solutions, suspensions and emulsions. The sterile solutions in water or water-propylene glycol of the active compounds can be mentioned as examples of liquid preparations suitable for parenteral administration. The liquid compositions can also be formulated in solution, in an aqueous solution of polyethylene glycol. Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers and thickening agents as desired. Aqueous suspensions for use can be manufactured by dispersing the finely divided active component in water together with a viscous material such as synthetic or natural gums, resins, methylcelluloses, sodium carboxymethylcellulose and other suspension-improving agents known in the art. pharmaceutical formulations. Preferably, the pharmaceutical compositions are in a unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package contains separate amounts of the preparations, for example, packed tablets, capsules and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet or tablet itself, or it can be an appropriate amount of any of these packaged forms.

BIOLOGICAL EVALUATION A) IN VITRO MODEL Cell culture Human 293S cells expressing the cloned human μ, d and K receptors and neomycin resistance are grown in a suspension at 37 ° C and 5% C02 in shake flasks containing 10% calcium DMEM FBS, 5% BCS, pluronic F-68 0.1% and 600 μg / ml geneticin.

Membrane Preparation Cells were plated and resuspended in lysis buffer (50 mM Tris, Ph 7.0, 2.5 mM EDTA with PMSF added just before use at 0.1 mM from a 0.1 M concentrate in ethanol), incubated on ice during 15 min and then homogenized with a polytron for 30 sec. The suspension was centrifuged at 1000 g (max) for 10 in at 4 ° C. The supernatant was kept on ice and the pellets were resuspended and centrifuged as above. The supernatants from both centrifugations were combined and centrifuged at 46,000 g (max) for 30 min. The pellets were resuspended in cold Tris buffer (50 mM Tris-Cl, pH 7.0) and centrifuged again. The final pellets were resuspended in membrane buffer (50 mM Tris, 0.32 M sucrose, pH 7.0). Aliquots (1 ml) were frozen in polypropylene tubes in dry ice / ethanol and stored at -70 ° C until use. Protein concentrations were determined by a Lowry assay and modified with SDS.

Union tests The membranes are reheated to 37 ° C, chilled on ice, passed three times through a gauge needle and diluted in binding buffer (50 mM Tris, 3 mM MgCl 2, 1 mg / ml BSA (Sigma A-7888), pH 7.4, which is stored at 4 ° C after filtration after a 0.22 filter. m, and to which 5 μg / ml of aprotinin, 10 μM bestatin, 10 μM diprotin A, without DTT has recently been added). Aliquots of 100 μl (for μg of protein see table 1) are added to 12 x 75 mm polypropylene tubes, on ice, containing 100 μl of the appropriate radioligand (see Table 1), and 100 μl of test peptides, at various concentrations. The total (TB) and non-specific (NS) junction was determined in the absence and presence of 10 μM naloxone, respectively. The tubes were vortexed and incubated at 25 ° C for 60-75 min, after which time the contents are quickly vacuum filtered and washed with approximately 12 ml / tube of ice wash buffer (50 mM Tris, pH 7.0, 3 mM MgCl2) through GF / B filters (Whatman), pre-rinsed for at least 2 h in 0.1% polyethylenimine. The radioactivity retained (dpm) in the filters is measured with a beta counter after wetting the filters for at least 12 h, in minifrasks containing 6-7 ml of scintillation fluid. In the assay that is established in well plates of 96 places, the filtration is on single filters rinsed with PEI of 96 places, which were washed with 3 x 1 ml washing buffer and dried in an oven at 55 ° C during 2 h. The filter plates were counted in a TopCount (Packard) kit after adding 50 μl of MS-20 / well scintillation fluid.

Analysis of data The specific binding (SB) was calculated as TB-NS and the SB in the presence of various test peptides are expressed as a percentage of SB control. IC50 values and Hill coefficient (nH) were calculated for radioligand displacement ligands specifically bound from logit graphs of curve fitting programs such as Ligand, GraphPad Prism, SigmalPlot or Fit receptor. The Kx values were calculated from the Cheng-Prussoff equation. Means are reported + M.E.E. (mean standard error) of IC50,? 0 and nH for ligands tested in at least three displacement curves.

Receiver Saturation Experiments Kd values of radioligand were determined by performing the binding assays on cell membranes with the appropriate radioligands at concentrations ranging from 0.2 to 5 times the estimated K6 (up to 10 times if the amounts of radioligand needed were feasible). The specific binding of radioligands is expressed as pmol / mg membrane protein. The values of Kd and ßmax are obtained for individual experiments from non-linear adjustments of specifically bound radioligand (B) vs free nM (F) of the individual, according to the model of a site.

B) BIOLOGICAL MODEL (IN VIVO MODEL) COMPLETE FREUND ADJUVANT (FCA) AND ASCTIC NERVE SLEEVE THAT INDUCES MECHANO-ALODINIA IN RAT Animals Male Sprague-Da law rats (Charles River, St-Constant, Canada) weighing 175-200 g at the time of surgery were used. They were housed in groups of three in rooms maintained thermostatically at 20 ° C with light / dark cycle of 12:12 h and with free access to food and water. After arrival, animals were allowed to acclimate for at least two days before surgery. The experiments were approved by the Medical Ethics Committee appropriate for animal studies.

EXPERIMENTAL PROCEDURE COMPLETE FREUD ADJUVANT The rats were anesthetized first in a Halothane chamber after which 10 μl of FCA s.c. was injected. in the dorsal region of the left leg, between the second and third external digits. Subsequently the animals were allowed to recover from the anesthesia under observation in their own cage.

SQUARE NERVE SLEEVE The animals were prepared according to the method described by Mosconi and Kruger (1996). Rats are anesthetized with a mixture of ketamine / xylazine i.p. (2 ml / kg) and placed on its right side, an incision was made along the axis of the lateral side of the left femur. The muscles of the upper quadricep were separated to show the sciatic nerve in which a plastic sleeve was placed (PE-60 pipe 2 mm long). The wound is closed in two layers with vicril sutures and 3-0 wax.

DETERMINATION OF MECANO-ALODINIA USING THE TEST FROM VON FREY The test was performed using 0.8: 00 and 16:00 h using the method described by Chaplan et al. (1994). Rats were placed in a Plexiglas cage on top of a wire mesh bottom which allowed access to the plants, and they were allowed to become accustomed for 10-15 min. The test area was the plant of the left rear quarter in the part of the middle floor, avoiding the pads of the less sensitive legs. The leg plant was played with a series of Von Frey 8 hairs with logarithmically greater rigidity (0.41, 0.69, 1.20, 2.04, 3.63, 5.50, 8.51 and 15.14 grams; Stoelting, 111, USA). Von Frey hair is applied from the floor of the mesh perpendicular to the surface of the plant with sufficient force to cause a slight rejection against the leg, and it was maintained for approximately 6-8 sec. A positive response was observed if the pad was removed quickly. The recoil immediately before hair removal was also considered as a positive response. Walking was considered an ambiguous response and in such cases the stimulus is repeated.

PROTOCOL OF PROOF Animals were tested on postoperative day 1 for the group treated with ACF and on day 7 postoperatively for the group with the cuff in the sciatic nerve. The 50% withdrawal threshold was determined using the top-down method of Dixon (1980). The test starts with 2.04 g hair, in the middle part of the series. The stimuli were always presented consecutively, either ascending or descending. In the absence of a paw withdrawal response to the hair initially selected, a stronger stimulus was present; in the case of withdrawal from the leg plant, the next weakest stimulus was chosen. The calculation of the optimal threshold by this method requires a response in the immediate vicinity of the 50% threshold, and the continuation of these 6 responses begins when the first change in response occurs, for example when the threshold is crossed for the first time. In the cases in which the thresholds are outside the stimulus interval, values of 15.14 (normal sensitivity) or 0.41 (maximum allodynic) were assigned respectively. The resulting pattern of positive and negative responses is tabulated using a conventional gradation, X = no withdrawal; O = withdrawal, and the 50% withdrawal threshold is interposed using the formula: 50% g threshold = 10 < xf + d, / 10,000 where Xf = value of the last von Frey hair used (logarithmic units); k = tabular value (de Chaplan et al. (1994)) for the pattern of positive / negative responses; and d = mean difference between stimuli (logarithmic units). In this case, d = 0.224. The thresholds of Von Frey are converted to percent of possible maximum effect (% MPE), according to Chaplan et al., 1994. The following equation is used to calculate% MPE:% MPE = threshold treated with drugs (g) - threshold with allodynia (g) X 100 control threshold (g) - threshold with allodynia (g) ADMINISTRATION OF PROOF SUBSTANCE Rats were injected (subcutaneously, intraperitoneally or orally) with a test substance before performing the von Frey test, the time of administration of the test compound and the von Frey test varied based on the nature of the compound of proof. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (24)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property

1. A compound of the formula (I) characterized in that: m is 0 or 1; n is 1 or 2; R1 is selected from hydrogen; linear or branched C1-C6 alkyl; C3-C8 cycloalkyl; (C4-C8 alkyl-cycloalkyl), wherein alkyl is C-L-C alkyl; and cycloalkyl is C3-C6 cycloalkyl; benzyl; wherein G is a hydroaromatic or heteroaromatic group having 5 or 6 atoms, and wherein the heteroatoms are selected from O, S and N; Y and where n = 0 or 1; C6-C10 aryl; or heteroaryl having from 5 to 10 atoms which are selected from any of C, S, N and O; wherein the aryl and heteroaryl optionally can be independently substituted by 1 or 2 substituents that are independently selected from any of hydrogen, CH3, (CH2) pCF3, halogen, CONR5R4, COOR5, COR5, (CH2) pNR5R4, (CH2) pCH3 ( CH2) pSOR5R \ (CH2) pS02R5, and (CH2) pS02NR5, wherein R4 and R5 are each independently as defined for R1 before, and p is 0, 1 or 2; (C1-C2 alkyl) - (C6-C10 aryl); or (Cx-C2 alkyl) heteroaryl, the heteroaryl moieties have 5 to 10 atoms which are selected from any of C, S, N and O, wherein the aryl or heteroaryl may optionally be independently substituted by 1 or 2 substituents which are independently select any of hydrogen, CH3, CONR5R4, COOR5, COR5, (CH2) qNR5R4, (CH2) qCH3 (CH2) qSOR5R4, (CH2) qS02R5, (CH2) qS02NR5, and (CH2) qOR4, wherein R4 and R5 they are defined, each and independently, for R1 above, and q is 0, 1 or 2; A is , 17 wherein R6, R0 Rs, R9, R10, R11, R12, R13, R14, R15, R16, R1"1 and R18 are each and independently as defined for R1 before and wherein the phenyl ring of each substituent A may be optionally and independently substituted by 1 or 2 substituents Z1 and Z2 which are each and independently selected from hydrogen, CH3, (CH2) rCF3, halogen, CONR: R3, C02R2, COR2, (CH2) rNR2R3, (CH2) rCH3 (CH2) rSOR2, (CH2) rS02R2, and (CH2) rS02NR2R3, wherein R2 and R3 are each independently defined for R1 above, and wherein r is 0, 1 or 2; X is O, S or NR19, wherein R19 is as defined for R1, B is an aromatic, heteroaromatic, hydroaromatic or substituted or unsubstituted heterohydroaromatic portion having from 5 to 10 atoms which are selected from any of C, S, N and O, optionally substituted and independently by 1 or 2 substituents which are independently selected from hydrogen, CH3, (CH2) tCF3, halogen, (CH2) tCONR5R4, (CH2) tNR5R4, (CH2) tCOR5, (CH 2) tCOOR5, OR5, (CH2) tSOR5, (CH,) tS02R5, and (CH2) tS02NR5R4, wherein R4 and R5 are each independently defined for R1 above, and wherein t is 0, 1, 2 or 3; as well as pharmaceutically acceptable salts of the compounds of formula (I) and isomers, hydrates, isoforms and prodrugs thereof.

2. The compound according to claim 1, characterized in that: R1 is selected from benzyl; wherein G is a hydroaromatic or heteroaromatic group having 5 6 6 atoms, and wherein the heteroatoms are selected from 0, S and N; Y and where n = 0- or 1; A is selected from any of wherein R6, R7, R8, R9, R16, R17 and R18 is each and independently as defined for R1 in the foregoing; and Z1, Z2 and X is each and independently as defined in the foregoing; B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, pyrryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tet rahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, pyrrolidinyl, and indazolinyl, each optionally and independently substituted by 1 or 2 substituents which are independently selected from hydrogen, CH3, CF3, halogen, - (CH2) tCONR5R4, - (CH2) tNR5R4, - (CH2) tC0R5, - (CH2) tC02R5, and - OR5, where t is 0 or 1; and wherein R4 and R5 is as defined for R1.

3. A compound according to claim 2, characterized in that: R1 is (Cx-C2 alkyl) phenyl and hydrogen; A is wherein R6, R7, R8, R9, is each an ethylene group; and Z1, Z2, are as defined in the above; B is phenyl or naphthalene; and m and n are each l or is l and n is O.

4. The compound according to formula (I) according to claim 1, characterized in that it is selected from any of 10 25

5. The compound according to any of the preceding claims, characterized in that it is in the form of its hydrochloride, bitartrate or trifluoroacetate salt.

6. The compound according to any of the previous claims, characterized in that it is used in therapy.

7. The compound according to claim 6, characterized in that the therapy is pain management.

8. The compound according to claim 6, characterized in that the therapy is directed towards gastrointestinal disorders.

9. The compound according to claim 6, characterized in that the therapy is directed towards damage to the spinal cord.

10. The compound in accordance with the claim 6, characterized in that the therapy is directed to disorders of the sympathetic nervous system.

11. The use of a compound according to formula (I) according to claim 1, characterized in that it is used for the manufacture of a medicament for use in the treatment of pain.

12. The use of a compound according to formula (I) according to claim 1, characterized in that it is used for the manufacture of a medicament for use in the treatment of gastrointestinal disorders.

13. The use of a compound according to formula (I) according to claim 1, characterized in that it is used for the manufacture of a medicament for use in the treatment of damage to the spinal cord.

14. The compound according to any of claims 1 to 5, further characterized in that it is isotopically labeled.

15. The use of a compound according to claim 14, characterized in that it is used as a diagnostic agent.

16. A isotopically-labeled compound characterized in that it is of formula (I) in accordance with the claim 1.

17. A diagnostic agent, characterized in that it comprises a compound of the formula (I), according to claim 1.

18. A pharmaceutical composition, characterized in that it comprises a compound of the formula (I), according to claim 1, as an active ingredient, together with a pharmacologically and pharmaceutically acceptable carrier.

19. A process for the preparation of a compound of formula (I) according to claim 1, characterized in that: (i) a ketone of the formula (IV) is subjected where R1, m and n are as defined in the formula (I) according to claim 1, at reductive amination with a substituted arylamine of the formula (V) W - NH2 (V) wherein it is as defined in formula (I) according to claim 1, optionally in the presence of a solvent, which provides a compound of the formula (ID) wherein R1, m and n are as defined in formula (I) above, and is A or B, as defined in formula (I) above; (ii) R1 and in the formula (II), optionally are modified after or during the preparation of (II) from (IV) and (V); (iii) the compound of the formula (II) obtained in step (i) is subjected to an arylation reaction, by reaction with an arylating agent of the formula (III) - Z (III) wherein W is A or B, as defined in formula (I) above, and Z is a suitable substituent, optionally in principle of a catalyst, which provides a compound of formula (I) according to claim 1; and (iv) R0 and substituents in A and B, optionally are further modified.

20. A compound of the formula characterized in that R1, m and n are as defined in formula (I) according to claim 1, and W is as defined for A or B in formula (I) according to claim 1.

21. The compound of formula (II) according to claim 17, characterized in that it is selected from any of

22. A method for the treatment of pain, characterized in that an effective amount of a compound of formula (I) according to claim 1 is administered to a subject in need of pain management.

23. The method for the treatment of gastrointestinal disorders, characterized in that an effective amount of a compound of formula (I) according to claim 1 is administered to a subject suffering from a gastrointestinal disorder.

24. The method for the treatment of damage to the spinal cord, characterized in that an effective amount of a compound of formula (I) according to claim 1 is administered to a subject suffering from damage to the spinal cord.