MX2008015434A - Combinations of monoamine reuptake inhibitors and potassium channel activators. - Google Patents

Abstract

This invention provides pharmaceutical compositions comprising therapeutically effective amounts of a monoamine reuptake inhibitor and an SK inhibitor. In another aspect the invention provides novel benzoimidazole derivatives for use according to the invention.

Description

COMBINATIONS OF MONOAMINE RECAPTATION INHIBITORS AND POTASSIUM CHANNEL ACTIVATORS FIELD OF INVENTION This invention provides pharmaceutical compositions comprising therapeutically effective amounts of a monoamine reuptake inhibitor and an SK inhibitor. In another aspect the invention provides novel benzoimidazole derivatives for use in accordance with the invention. BACKGROUND OF THE INVENTION Mono-aminergic (mA) neurons are located in limited numbers in different areas of the brain: dopaminergic neurons in the ventral tegmental area (VTA) and compact black substance (SNc), serotonergic neurons in the raphe nucleus and neurons noradrenergic in the locus coeruleus. All MA neurons exert a wide variety of modulating neurotransmission in the brain, with the dopaminergic systems that project to the nucleus accumbens, prefrontal cortex and the limbic system (VTA) and the stratium (SNc). The serotonergic neurons of the raphe and the noradrenaline neurons in the locus coeruleus project both to the complete proncephalus. Monoaminergic neurotransmission is central in the treatment of a large number of psychiatric disorders and No. Ref. : 198157 neurological, such as depression, bipolar disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, Parkinson's disease, Huntington's disease, etc. The molecular targets involved are post and presynaptic MA receptors as well as the presynaptic MA reuptake systems, which are essential in controlling the intensity and synchronization of MA signaling.

Depression is treated with a plethora of drugs that act on MA's presynaptic reuptake systems: the oldest of these compounds, tricyclic antidepressants such as imipramine, are also the least selective, inhibit all MA reuptake systems as well as some MA recipients, and have a number of adverse effects in the clinic. The second-generation compounds, in this case selective serotonin reuptake inhibitors (SSRIs) such as Fluoxetine and Paroxetine, are widely used and have substantially fewer classic side effects than tricyclic compounds (decreased libido remains a problem), although The prolonged time of action in combination with a significant proportion of non-responders limits their therapeutic use. The third generation of MA inhibitors represents compounds with several selectivity profiles of selective norepinephrine reuptake inhibitors (SNRIs), such as Reboxetine, for dual-action inhibitors (SA) and NA) such as Venlafaxine and Duloxetine. Triple-action compounds (SA, NA, DA) for depression have not yet been commercialized, although such compounds are generally assumed to have a faster onset of action. The strengthening of MA transmission by reuptake inhibitors is an established antidepressant principle in the clinic. Preclinically, depression models include acute desperation models (the suspension of the tail and forced swimming tests) as well as more chronic models (the chronic moderate tension model and the olfactory bulbectomy model). In addition, there are pharmacological models of support, which show interaction with different MA systems (serotonin syndrome by facilitating nialamide of locomotor activity, noradrenaline syndrome by preventing reboxetine from ptosis induced by tetrabenazine, and dopamine syndromes such as stereotypy induced by methylphenidate and locomotor activity). Increased MA transmission can be achieved by increasing the electrical firing or firing pattern of MA neurons. In general, MA neurons fire irregularly, determined by relative excitatory and inhibitory presynaptic drives, as well as their endogenous rhythmic activity. The action potentials that reach the presynaptic terminals increase the release of MA much more effectively than the action potentials that come in a single discharge pattern: The differential afferent modulation of the VTA firing pattern strongly regulates the equilibrium between the transmission of tonic and phasic dopamine in the nucleus accumbens. The blocking of small conductance calcium activated potassium channels (SK channels) with the selective bee venom peptide component, apamina, also effectively changes regular pacemaker-type dopaminergic neurons to a mode in dense burst, both in vitro and in vivo after local administration. However, due to the poor permeability of the blood-brain barrier of apamin, this compound is not appropriate for behavioral testing. SUMMARY OF THE INVENTION The present invention provides a new principle for the treatment of a large number of psychiatric and neurological diseases based on the signaling of altered MAs in various regions of the brain. The invention focuses on the combined therapeutic effect of an activity on all or a subset of MA reuptake mechanisms and on the same blocks one or more of the presynaptic SK channels (SKI, SK2, and preferably SK3, which is the subtype Predominant SK expressed in MA neurons). This therapeutic effect can be achieved using a monoamine reuptake inhibitor simultaneously with an SK inhibitor, in this case using two separate compounds. It can, however, also be achieved by using an active therapeutic ingredient that has this dual therapeutic activity. Also in accordance with the present invention, we have found organic compounds of small molecules with potent (nM) inhibition of dual MA and actions that inhibit the SK channel. Therefore, in its first aspect, the invention provides pharmaceutical compositions comprising a therapeutically effective amount of an active pharmaceutical ingredient (API) selected from A) a monoamine reuptake inhibitor; and B) an SK inhibitor; together with one or more adjuvants, excipients, carriers and / or diluents. In another aspect the invention provides benzoimidazole derivatives of Formula I an isomer thereof or a mixture of its isomers, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3 and R4, independently of one another, represent hydrogen, halo, trifluoromethyl, trifluoromethoxy cyano, alkyl, alkoxy, amino, N -alkylamino or N, N-dialkyl amino; Z represents hydrogen, alkyl or benzyl, the benzyl can optionally be replaced one or more times with halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino and / or N, N-dialkylamino; X represents CH-A ', N-A', or C = A ''; where A 'represents a group of the formula o or Ib: (the); or (Ib); wherein B represents CH2, 0 or S; Y represents hydrogen, fluoro, hydroxy or alkoxy; and R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 independently of each other, represents hydrogen, halo trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy amino, N-alkylamino or N, N- dialkyl amino; and A "represents a group of the Formula Ic: (Ic); where R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14, independently of one another, represents hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino or N, N-dialkyl-amino. Other objects of the invention will be apparent to a person skilled in the art of the following description and detailed examples. BRIEF DESCRIPTION OF THE DRAWINGS The present invention is further illustrated by reference to the attached Figures, in which: Figure 1 shows the 5HT syndrome in NMRI mice (n = 4); score of the 5-HT syndrome (maximum = 16) versus Time (min.), after administration s.c. of 50 mg / ml of nialamide at t = -120 minutes, followed by p.o. of the test compound (0.3, 1.3 mg / kg,) and / or citalopram (1 mg / kg); and Figure 2 shows PBZ ptosis in NMRI mice (n = 6); Score (maximum ptosis = 24; maximum Bison = 6) against dose of the test compound (0.3, 1 and 3 mg / kg) at t = -60 minutes, and p.o. of reboxetine (0.1 mg / kg) at t = -60 minutes, followed by i.p. of 40 mg / kg TBZ at t = -30 min. DETAILED DESCRIPTION OF THE INVENTION Pharmaceutical Compositions In its first aspect the invention provides the pharmaceutical compositions comprising a therapeutically effective amount of an active pharmaceutical ingredient (API) selected from A) a monoamine reuptake inhibitor; and B) an SK inhibitor; together with one or more adjuvants, excipients, carriers and / or diluents. The carriers must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof. In a preferred embodiment the active pharmaceutical ingredients (API) show biological activity at the submicromolar level (in this case, below 1 μm), preferably at the low nanomolar level (in this case below 0.1 μm). In another preferred embodiment, the monoamine reuptake inhibitor is a dopamine uptake inhibitor, in particular bupropion, sertraline, nomifensin, or mazindol, or vannoxerin, or a noradrenaline uptake inhibitor, in particular Amoxapine, Atomotoxin, reboxetine, or a serotonin reuptake inhibitor, in particular Citalopram, Escitalopram, Fluoxetine, fluvoxamine maleate, Paroxetine, Sertraline or Zimelidin. In a more preferred embodiment the monoamine reuptake inhibitor is a selective inhibitor of serotonin reuptake (SSRI) selected from the group consisting of citalopram (Celexa, Cipramil, Emocal, Sepram), escitalopram oxalate (Lexapro, Cipralex, Esertia), fluoxetine (Prozac, Fontex, Seromex, Seronil, Sarafem, Fluctin (EUR) ), fluvoxamine maleate (Luvox, Faverine), paroxetine (Paxil, Seroxat, Aropax, Deroxat) and sertraline (Zoloft, Lustral, Serlain). In a third preferred embodiment, the SK inhibitor to be used according to the invention is a benzoimidazole derivative of Formula I as defined below. In yet another preferred embodiment the pharmaceutical composition of the invention comprises a compound having the dual activity of a monoamine reuptake inhibitor and of a SK inhibitor as the sole active pharmaceutical ingredient (API). In a more preferred embodiment the API having the dual activity of a monoamine reuptake inhibitor and an SK inhibitor is a benzoimidazole derivative of the Formula I as defined below. In another more preferred embodiment the API having the dual activity of a monoamine reuptake inhibitor and an SK inhibitor show dual biological activity at the submicromolar level (in this case below 1 μm), preferably at the low nanomolar level (in this case, under 0.1 μ?).

While a chemical compound of the invention for use in therapy can be administered in the form of a crude chemical compound, it is preferred to introduce the active ingredient, optionally in the physiologically acceptable salt form, or in the form of a prodrug, into a composition pharmaceutical together with one or more usual adjuvants, excipients, carriers, buffers, diluents, and / or other pharmaceutical auxiliaries. The pharmaceutical composition of the invention can be administered by any convenient route, which satisfies the desired therapy. Preferred routes of administration include oral administration, in particular in tablets, in capsules, in dragees, in powder, or in liquid form, and parenteral administration, in particular injection, cutaneous, subcutaneous, intramuscular, or intravenous. The pharmaceutical composition of the invention can be prepared by any person skilled in the art, by the use of standard methods and conventional techniques, suitable for the desired formulation. When desired, the compositions are adapted to give sustained release of the active ingredient to be employed. Further details on techniques for formulation and administration can be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).

The actual dosage depends on the nature and severity of the disease being treated, and is within the discretion of the physician, and can be varied by adjusting the dose to the particular circumstances of this invention to produce the desired therapeutic effect. Benzoimidazole Derivatives In another aspect the invention provides novel benzoimidazole derivatives. The benzoimidazole derivatives of the invention can be characterized by Formula I an isomer thereof or a mixture of its isomers, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3 and R4, independently of one another, represent hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino , N-alkyl-amino or N, N-dialkylamino; and Z represents hydrogen, alkyl or benzyl, the benzyl can optionally be substituted one or more times with halo, trifluoride, or tr, luoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino and / or N, N-dialkyl-amino; X represents CH-A ', N-A', or C = A ''; where represents a group of Formula la or Ib (the); or (Ib); wherein B represents CH2, 0 or S; Y represents hydrogen, fluoro, hydroxy or alkoxy; and R5, R6, R8, R9, R10, R11, R12, R13 and R14, independently of one another, represent hydrogen, halo, trifluoromethyl, trifluorome t oxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino or N, N- di to 1 qui 1-amino; and A "represents a group of the Formula Ic: (Ic); wherein R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13 and R 14, independently of one another, represent hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, 1 amino, N-alkyl-amino or N, -dialkyl-amino. In a particular embodiment, however, the benzoimidazole derivative of the invention is not 2- (4-Benzylpiperidin-1-yl) -5,6-dimethoxy-1H-benzoimidazole; 2- [- (4-Chlorobenzyl) piperazin-1-yl] -1-propyl-1H-benzoimidazole; 2- [4- (4-Chlorobenzyl) piperazin-1-yl] -1-isopropyl-1H-benzoimidazole; 2- [4- (2, 5-Dimethyl-benzyl) piperazin-1-yl] -6-trifluoromethyl-1H-benzoimidazole; ß-Trifluoromethyl-2- [4- (2-trifluoromethyl-benzyl) -piperazin-1-yl] -lH-benzoimidazole; 2- [4- (4-tert-Butylbenzyl) piperazin-1-yl] -6-trifluoromethyl-1H-benzoimidazole; 2- [4- (2,6-Dichlorobenzyl) piperazin-1-yl] -6-trifluoromethyl-1H-benzoimidazole; 2- (4-Benzhydrylpiperazin-1-yl) -1- (4-chlorobenzyl) -1H-benzoimidazole; 2- (4-Benzylpiperazin-1-yl) -1-pentyl-1H-benzoimidazole; 2- (4-Benzhydrylpiperazin-1-yl) -1-benzyl-1H-benzoimidazole; 2- (4-Benzhydrylpiperazin-1-yl) -1-methyl-1H-benzoimidazole; or 2- (4-Benzylpiperazin-1-yl) -lH-benzoimidazole. In a first preferred embodiment, the derivative of The benzoimidazole of the invention is a compound of the formulas I-IV, wherein R1, R2, R3 and R4, independently of one another, represent hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl -amino or N, N-dialkyl-amino. In a more preferred embodiment two of R1, R2, R3 and R4, independently of one another, represent halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino or N, N-dialkylamino; and the remaining two of R1, R2, R3 and R4 all represent hydrogen. In an even more preferred embodiment the two of R1, R2, R3 and R4 representing halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino or N, N-dialkyl-amino are R1 and R2, or R1 and R3, or R2 and R3. In another more preferred embodiment two of R1, R2, R3 and R4 independently of one another, represent halo, trifluoromethyl, trifluoromethoxy or cyano; and the remaining two of R1, R2, R3 and R4 all represent hydrogen. In an even more preferred embodiment the two of R1, R2, R3 and R4 representing halo, trifluoromethyl, trifluoromethoxy or cyano are R1 and R2, or R1 and R3, or R2 and R3. In yet another more preferred embodiment one of R1, R2, R3 and R4 independently of each other, represents halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino or N, N-dialkylamino; and the three remaining of R1, R2, R3 and R4 all represent hydrogen. In an even more preferred embodiment one of R1, R2, R3 and R4 representing halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino or N, N-dialkylamino is R1 or R2 or R3 . In yet another preferred embodiment one of R1, R2, R3 and R4, independently of one another, represent halo, trifluoromethyl, trifluoromethoxy or cyano; and the remaining three of R1, R2, R3 and R4 all represent hydrogen. In an even more preferred embodiment one of R1, R2, R3 and R4 represents halo, trifluoromethyl, trifluoromethoxy or cyano R1 or R2 or R3. In a most preferred embodiment R1, R2, R3 and R4 all represent hydrogen. In a second preferred embodiment the benzoimidazole derivative of the invention is a compound of Formulas I-IV, wherein Z represents hydrogen, alkyl or benzyl, benzyl optionally can be replaced one or more times with halo, trifluoromethyl, trifluoromethoxy, cyano , alkyl, alkoxy, amino, N-alkyl-amino and / or N, N-dialkyl-amino. In a more preferred embodiment Z represents hydrogen, alkyl or benzyl, which benzyl can be optionally substituted once or twice with halo, trifluoromethyl and / or trifluoromethoxy. In an even more preferred embodiment Z represents hydrogen, alkyl or benzyl, which benzyl can optionally be substituted once or twice with halo and / or trifluoromethyl. In a preferred embodiment Z represents hydrogen, alkyl or benzyl, the benzyl can be optionally substituted once or twice with fluoro, chloro and / or trifluoromethyl. In still a more preferred embodiment Z represents hydrogen or alkyl. In a further more preferred embodiment Z represents benzyl, it may be optionally substituted once or twice with fluoro, chloro and / or trifluoromethyl. In a third preferred embodiment, the benzoimidazole derivative of the invention is a compound of Formulas I-IV, wherein X represents CH-A 'or N-A', and A 'is as defined above. In a more preferred embodiment X represents CH-A ', and A is as defined above. In another more preferred embodiment X represents N-A ', and A' is as defined above. In a fourth preferred embodiment, the benzoimidazole derivative of the invention is a compound of Formula II, an isomer thereof or a mixture of its isomers, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8 and R9, independently of one another, represents hydrogen, halo, trifluoromethyl , trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino or N, N-dialkyl-amino; Z represents hydrogen, alkyl or benzyl, the benzyl can be optionally substituted one or more times with halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino and / or N, N-dialkylamino; X represents CH or N; and B represents CH2, 0 or S. In a more preferred embodiment R1, R2, R3, R4, R5, R6, R7, R8 and R9, independently of one another, represent hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino or N, N-dialkylamino. In an even more preferred embodiment R1, R2, R3, R4, R5, R6, R7, R8 and R9, independently of one another, represent hydrogen, halo or trifluoromethyl. In still a more preferred embodiment R1, R2, R3, R4, R5, R6, R7, R8 and R9, independently of one another, represent hydrogen or halo, and particularly fluoro or chloro. In another more preferred embodiment Z represents hydrogen, alkyl or benzyl, the benzyl can be optionally substituted one or more times with halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino and / or N, N- dialkyl-amino. In an even more preferred embodiment Z represents hydrogen or benzyl, the benzyl can be optionally substituted once or twice with halo, particularly fluoro or chloro, and / or trifluoromethyl. In a third more preferred embodiment X represents CH or N. In still a more preferred embodiment X represents CH. In another even more preferred embodiment X represents N. In a fourth preferred embodiment B represents CH2, 0 or S. In an even more preferred embodiment B represents 0 or S. In yet a more preferred embodiment B represents CH2. In a still more preferred third embodiment B represents 0. In a still more preferred fourth embodiment B represents S. In a most preferred embodiment, the benzoimidazole derivative of the invention is 2- (4-Benzylpiperidin-1-yl) -lH- benzoimidazole; 2- (4-Benzylpiperidin-1-yl) -1- [4-chloro-3- (trifluoromethyl) benzyl] -lH-benzoimidazole; 2- (4-Benzylpiperidin-1-yl) -1- (3,4-difluorobenzyl) -1H-benzoimidazole; 2- [4- (3,4-Dichlorophenoxy) piperidin-1-yl] -lH-benzoimidazole; 2- [4- (3,4-Dichlorophenylsulfanyl) piperidin-1-yl] -1H-benzoimidazole; 2- [4- (3,4-Dichlorobenzyl) piperidin-1-yl] -1H-benzoimidazole; 2- (-Benzylpiperazin-1-yl) -lH-benzoimidazole; 1- (3,4-Difluorobenzyl) -2- [4- (3, 4-difluorobenzyl) piperazin-1-yl] -lH-benzoimidazole; or 2- [4- (3, 4-Difluorobenzyl) piperidin-1-yl] -1H-benzoimidazole; or an enantiomer or a mixture of its enantiomers, or a pharmaceutically acceptable salt thereof. In a fifth preferred embodiment, the benzoimidazole derivative of the invention is a compound of formula III, an isomer thereof or a mixture of its isomers, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14, independently one of another, represents hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino or N, N-dialkylamino; Z represents hydrogen, alkyl or benzyl, which benzyl can optionally be replaced one or more times with halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino and / or N, N-dialkylamino; X represents CH or N; and Y represents hydrogen, fluoro, hydroxy or alkoxy. In a more preferred embodiment R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Ru, R12, R13 and R14, independently of one another, represent hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino or N, N-dialkylamino. In a more preferred embodiment R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14, independently of one another, represent hydrogen, halo or trifluoromethyl. In yet a more preferred embodiment R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14, independently of one another, represent hydrogen or halo, and particularly fluoro or chloro. In another preferred embodiment Z represents hydrogen, alkyl or benzyl, which benzyl can optionally be replaced one or more times with halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino and / or N, -dialkyl- Not me . In a more preferred embodiment Z represents hydrogen or alkyl. In an even more preferred embodiment Z represents hydrogen. In a third more preferred embodiment X represents CH or N. In an even more preferred embodiment X represents CH. In still a more preferred embodiment X represents N. In a fourth most preferred embodiment Y represents hydrogen, fluoro, hydroxy or alkoxy. In a more preferred embodiment Y represents hydrogen or hydroxy.

In a most preferred embodiment, the benzoimidazole derivative of the invention is [1- (1H-Benzoimidazol-2-yl) -piperidin-4-yl] diphenylmethanol; 2- (4-Benzhydryl-piperidin-1-yl) -lH-benzoimidazole; 2- (4-Benzhydrylpiperazin-1-yl) -lH-benzoimidazole; or 2-. { 4- [Bis- (4-fluorophenyl) methyl] piperazin-1-yl} -1H-benzoimidazole; or an enantiomer or a mixture of its enantiomers, or a pharmaceutically acceptable salt thereof. In a sixth preferred embodiment, the benzoimidazole derivative of the invention is a compound of formula IV, an isomer thereof or a mixture of its isomers, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14, independently from one of the other, represents hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino or N, N-dialkylamino; and Z represents hydrogen, alkyl or benzyl, which benzyl can optionally be replaced one or more times with halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino and / or N, N-dialkylamino. In a more preferred embodiment R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14, independently of one another, represent hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl , alkoxy, amino, N-alkyl-amino or N, N-dialkyl-amino. In a more preferred embodiment R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14, independently of one another, represent hydrogen, halo or trifluoromethyl. In yet a more preferred embodiment R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14, independently of one another, represent hydrogen or halo, and particularly fluoro or chloro. In another more preferred embodiment Z represents hydrogen, alkyl or benzyl, which benzyl can optionally be replaced one or more times with halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino and / or N, N- dialkyl-amino. In a more preferred embodiment Z represents hydrogen or alkyl. In an even more preferred embodiment Z represents hydrogen. In a most preferred embodiment, the benzoimidazole derivative of the invention is 2- (4-Benzhydrylidene-piperidin-1-yl) -lH-benzoimidazole; or an enantiomer or a mixture of its enantiomers, or a pharmaceutically acceptable salt thereof. Any combination of two or more of the embodiments described herein are considered within the scope of the present invention. Definition of substituents In the context of this invention halo represents fluoro, chloro, bromo or iodo. Thus, a trihalomethyl group represents, for example, a trifluoromethyl group, a trichloromethyl group, and similar trihalo-substituted methyl groups. In the context of this invention an alkyl group designates a straight or branched saturated univalent hydrocarbon chain. The hydrocarbon chain preferably contains from one to eighteen carbon atoms' (alkyl-Ci_i8), more preferred from one to six carbon atoms (alkyl-Ci_i6); lower alkyl), including pentyl, isopentyl, tertiary pentyl, hexyl and isohexyl. In a preferred embodiment alkyl represents an alkyl-Ci_4 group, including butyl, isobutyl, secondary butyl, and tertiary butyl. In another preferred embodiment of this invention the alkyl represents an alkylCi-3 group, which can be particularly methyl, ethyl, propyl or isopropyl. In the context of this invention an alkoxy group designates an "alkyl-O" group, wherein alkyl is as defined above. Examples of the preferred alkoxy groups of the invention include methoxy and ethoxy. In the context of this invention, a group of N-alkyl-amino designates an amino group (secondary), monosubstituted with an alkyl group as defined above. In the context of this invention, an N, N-dialkyl-amino group designates an (tertiary) amino group, disubstituted with the alkyl groups as defined above. Pharmaceutically acceptable salts The chemical compound of the invention can be provided in any convenient form for the intended administration. Suitable forms include pharmaceutically (in this case physiologically) acceptable salts, and pre or prodrug forms of the chemical compound of the invention. Examples of pharmaceutically acceptable addition salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the hydrochloride, the hydrobromide, the nitrate, the perchlorate, the phosphate, the sulfate, the format, the acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, derivative of naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p-sulfonate, and similar. Such salts can be formed by well known procedures and described in the prior art. Examples of pharmaceutically acceptable cationic salts of a chemical compound of the invention include, without limitation, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, choline, lysine, and salt thereof. ammonium, and the like, of a chemical compound of the invention containing an anionic group. Such cationic salts can be formed by methods well known and described in the prior art. Isomers It will be appreciated by persons skilled in the art that the compounds of the present invention can exist in different stereoisomeric forms, including enantiomers, diastereomers, as well as geometric isomers (cis-trans isomers). The invention includes all isomers and any mixture thereof including racemic mixtures.

The racemic forms can be resolved in the optical antipodes by known methods and techniques. One way of separating the enantiomeric compounds (including enantiomeric intermediates) is by using an optically active amine, and releasing the resolved diastereomeric salt, by treatment with an acid. Another method for resolving racemates in the optical antipodes is based on chromatography in an active optical matrix. The racemic compounds of the present invention can thus be solved in their optical antipodes, for example, by fractional crystallization of D- or L- salts (tartrates, mandelates, or camphorsulfonate) for example. Additional methods for resolution of optical isomers are known in the prior art. Such methods include those described by Jaques J, Collet A, & ilen S in "Enantiomers, Racemates, and Resolutions", Juan iley and Sons, New York (1981). The active optical compounds can also be prepared from the active optical starting materials or intermediates. Prodrugs The benzoimidazole derivative of the invention can optionally be administered in the form of a convenient prodrug. In the context of this invention the term "prodrug" means a compound, which is a drug precursor and which, after administration and absorption, releases the prodrug in vivo via some metabolic process. Particularly favored prodrugs are those that increase the bioavailability of the compounds of the invention, for example by allowing an orally administered compound that will be more readily absorbed in the blood, or that enhances the release of the original compound to a specific biological compartment, for example the brain or lymphatic system.

Thus examples of suitable prodrugs of the benzoimidazole derivative of the invention include compounds modified in one or more reactive or rivalent groups of the parent compound. Of particular interest are compounds modified in a carboxyl group, a hydroxyl group, or an amino group. Examples of suitable derivatives are esters or amides. Methods of preparation The benzoimidazole derivatives of the invention can be prepared by conventional methods for chemical synthesis, for example those described in the working examples. The starting materials for the processes described in the present application are known or can be easily prepared by conventional methods of commercially available chemistries. Also a compound of the invention can be converted to another compound of the invention using conventional methods. The final products of the reactions described herein can be isolated by conventional techniques, for example by extraction, crystallization, distillation, chromatography, etc. Biological Activity Three subtypes of small conductance calcium activated potassium channels (SK channels) have been identified, in this case SKI, SK2 and SK3 (corresponding to KCNN1-3 using the genomic nomenclature). The novel benzoimidazole derivatives of the invention are found to be potent inhibitors of SK channels, including SKI, SK2, and in SK3. In addition, the preferred compounds of the invention show a dual activity of being a potent monoamine reuptake inhibitor and an inhibitor of small conductance calcium activated potassium channels (SK channels). Preferred compounds of the invention show a dual biological activity at the submicromolar level (in this case below 1 μm), preferably at the low nanomolar level (in this case below 0.1 μm). Due to its biological activity the benzoimidazole derivatives of the invention can be used for the treatment, prevention or alleviation of a disease or disorder or condition of a mammal, including a human being, whose disease, disorder or condition is sensitive to the inhibition of the reuptake of the monoamine neurotransmitter in the central nervous system and / or inhibition of SKCa channels- Such diseases, disorders and conditions include depression, pseudodementia, Ganser syndrome, obsessive-compulsive disorder (OCD), panic disorder, deficit of memory, loss of memory, hyperactivity disorder attention deficit, obesity, anxiety, eating disorder, Parkinson's disease, parkinsonism, dementia, dementia due to aging, senile dementia, dementia complex of acquired immunodeficiency syndrome, memory dysfunction in aging, social phobia, drug addiction , drug abuse, cocaine abuse, tobacco abuse, alcoholism, pain, migraine pain, bulimia, premenstrual syndrome, late luteal phase syndrome, post-traumatic syndrome, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervous, sleep disorders, autism, mutism, trichotillomania, narcolepsy, Gilles de la Tourettes disease, inflammatory bowel disease or irritable bowel syndrome. In a preferred embodiment the disease, disorder or condition is depression, obsessive-compulsive disorder (OCD), mood disorders, body dysmorphic disorder, bulimia nervosa, premenstrual dysphoric disorder, panic disorder, ADHD, eating disorder, anxiety, anxiety, panic disorders, panic attacks, phobias, irritable bowel syndrome (IBS) or premature ejaculation. In another preferred embodiment the disease, disorder or condition is depression, pseudodementia, Ganser syndrome, obsessive compulsive disorders (OCD), panic disorders, memory deficit, attention deficit hyperactivity disorder, obesity, anxiety, an eating disorder or Parkinson's disease. Methods of therapy In another aspect the invention provides a method for the treatment or alleviation of diseases or disorders or conditions of living animal bodies, including humans, whose disease, disorder or condition is sensitive to inhibition of reuptake of the monoamine neurotransmitter in the central nervous system and / or inhibition of SKCa channels. The preferred medical indications contemplated according to the invention are those indicated above. Examples The invention is further illustrated with reference to the following examples, which do not in any way attempt to limit the scope of the invention as claimed. General: The procedures represent the generic procedures used to prepare the compounds of the invention. The abbreviations used are as follows: Ac: acetyl DMF: N, N-dimethylformamide DMSO: dimethylsulfoxide Et: ethyl eq: equivalent (s) LCMS: liquid chromatography mass spectrometry Me: methyl mp: melting point MW: microwave ta: room temperature Procedure A 2-Chlorobenzimide zol and the piperidine or piperazine derivative required (commercially available or prepared via literature procedure) were suspended in acetonitrile in a closed flask and heated to 170-200 ° C for 20-40 minutes by the use of MW irradiation. After cooling to rt the precipitated solid was filtered, washed with acetonitrile and recrystallized to give the desired product. Alternatively, the crude product of the reaction mixture was purified by column chromatography or by preparative LCMS to give the desired product as the free base. An example of process A, the preparation of 2- [4- (3,4-dichlorobenzyl) piperidin-1-yl] -lH-benzoimide zol, is shown in Reaction Scheme 1.

Reaction scheme 1 Procedure B A stirred solution of 2-chlorobenzimidazole in dry DMF (under N2 atmosphere) was cooled to 0 ° C and NaH (1.3 eq) was added. After stirring for 30 minutes at rt the required benzyl halide was added dropwise and the reaction mixture was stirred at rt overnight. The saturated aqueous NaHC03 was added and the mixture was extracted with EtOAc. The combined organic phases were dried (MgSO.sub.4), filtered and concentrated in vacuo to give the desired 2-c 1 -o-1 -benzylbenzene derivative or desired. This intermediate was subsequently dissolved in acet oni tri, the required derivative of piperidine or piperazine (1-2 eq) was added and heated by irradiation of MW at 190-200 ° C in a sealed vial for 15-40 Min. The reaction mixture was evaporated to dryness and the crude product purified by preparative LCMS or column chromatography to give the desired product as the free base. An example of procedure B, the preparation of 2- (4-benzylpiperidine-1-yl) -1- (3, -difluorobenzyl) -1H- benzoimidazole, is shown in Reaction Scheme 2. Reaction Scheme 2 Example 1 2- [4- (3,4-Dichlorobenzyl) piperidin-1-yl] -lH-benzoimidazole The title compound was prepared as described in procedure A. The precipitated solid from the reaction mixture was filtered and washed with acetonitrile to give the title compound as a hydrogen chloride salt (mp 268-270 ° C). MS (ES +) m / z 360 (M +, 100). Example 2 2- (4-Benzylpiperidin-1-yl) -lH-benzoimidazole The title compound was prepared as described in procedure A. The precipitated solid from the reaction mixture was filtered and washed with acetonitrile to give the title as the free base (mp 193-194 ° C). MS (ES +) m / z 292 ([M + 1] +, 100). Example 3 [1- (1H-Benzoimidazol-2-yl) -piperidin-4-yl] diphenylmethanol The title compound was prepared from 2-chlorobenzimidazole and a- (4-piperidyl) benzhydrol available in the trade as described in procedure A. The title compound was isolated under basic aqueous analysis as the free base (mp 237-239 ° C). MS (ES +) m / z 384 ([M + 1] 100). Example 4 2- (4-Benzylpiperidin-1-yl) -1- [4-chloro-3- (trifluoromethyl) benzyl] -lH-benzoimidazole The title compound was prepared in two steps as described in procedure B. Crude product was purified by preparative LCMS to give the title compound as the free base (mp 124-125.5 ° C). MS (ES +) m / z 484 (M +, 100). Example 5 2- (4-Benzylpiperidin-1-yl) -1- (3, 4-difluorobenzyl) -1H-benzoimidazole The title compound was prepared in two steps as described in Procedure B. The crude product was purified by Preparative LCMS to give the title compound as the free base (mp 155-155.5 ° C). MS (ES +) m / z 418 Example 6 2- (4-Benzhydrylpiperazin-1-yl) -lH-benzoimidazole The title compound was prepared from the commercially available 2-chlorobenzimidazole and 1- (diphenylmethyl) piperazine as described in process A. The precipitated solid of the reaction mixture was filtered to give the compound of the title as the free base (mp> 230 ° C (decomp.)). MS (ES +) m / z 369 ([M + 1] +, 100). Example 7 2- (4-Benzylpiperazin-1-yl) -lH-benzoimidazole The title compound was prepared as described in procedure A and isolated on examination in the basic aqueous medium as the free base (mp 235-237 ° C). MS (ES +) m / z 369 ([M + 1] +, 100). Example 8 1- (3,4-Difluorobenzyl) -2- [4- (3, 4-difluorobenzyl) piperazin-1-yl] -lH-benzoimidazole The title compound was prepared in two steps as described in process B The crude product was purified by preparative LCMS to give the title compound as the free base (yellowish gum). 1NMR (CDC13) d 2.56 (br s, 4H), 3.25-3.30 (m, 4H), 3.51 (s, 2H), 5.15 (s, 2H), 6.86-6.91 (m, 1H), 6.96-7.24 (m , 8H), 7.65 (d, 1H). MS (ES +) m / z 455 ([M + 1] +, 100). Example 9 2-. { 4- [Bis- (4-fluorophenyl) methyl] piperazin-1-yl} -1? -benzoimidazole The title compound was prepared from commercially available 2-chlorobenzimidazole and 1- (4, '-difluorobenzhydryl) piperazine as described in procedure A. The precipitated solid of the mixture of The reaction was filtered to give the title compound as the hydrochloride salt (mp> 240 ° C (decomp.)). MS (ES +) m / z 405 ([M + 1] +, 100). EXAMPLE 10 2- [4- (3,4-Dichlorophenoxy) piperidin-1-yl] -lH-benzoimidazole The title compound was prepared from 2-chlorobenzimidazole and 4 - (3,4-di-1-orofenox i) pipe Ri di na and as described in procedure A. The precipitated solid from the reaction mixture was filtered and washed with acetonitrile to give the title compound as the hydrochloride salt (mp 297-298 ° C). MS (ES +) m / z 363 ([M + 1] +, 100). EXAMPLE 11 2- [4- (3,4-Dichlorophenylsulfanyl) piperidin-1-yl] -1H-benzoimidazole The title compound was prepared from 2-chlorobenzimidazole and 4- (3,4-di c 1 or of in i 1 its 1 fa i 1) pipe ri di na and as described in procedure A. The crude product was purified by preparative LCMS to give the title compound as the free base. 1 MR (DMSO- CÍ 6) d 1.50-1.62 (m, 2H), 1.95-2.03 (m, 2H), 3.12-3.21 (m, 2H), 3.65-3.70 (m, 1H), 3.95-4.04 (m , 2H), 6.85-6.96 (m, 2H), 7.10-7.21 (m, 2H), 7.41 (d, 1 H), 7.58 (d, 1 H), 7.69 (s, 1 H), 11.3 (s, 1 HOUR) . MS (ES +) m / z 378 (M +, 100).

Example 12 2- (4-Benzhydrylidene-piperidin-1-yl) -lH-benzoimidazole [1- (1H-Benzoimidazol-2-yl) -piperidin-4-yl] diphenylmethanol (prepared as described above) was dissolved in acid trifluoroacetic and was stirred by lh a ta. The reaction mixture was evaporated to dryness, saturated aqueous NaHCO3 was added and extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to give the crude product which was recrystallized from MeOH / water to give the title compound as the free base (mp 229-230 ° C). MS (ES +) m / z 366 ([M + 1] +, 100). Example 13 2- (4-Benzhydryl-piperidin-1-yl) -lH-benzoimidazole 2- (-Benzhydrylidene-piperidin-1-yl) -lH-benzoimidazole (prepared as described above) was dissolved in ethanol, one was added catalytic amount of 10% Pd / C and was hydrogenated at rt with hydrogen gas. The reaction mixture was filtered through celite, evaporated to dryness and the crude product purified by LCMS to give the title compound as the free base (mp 256-258 ° C). MS (ES +) m / z 368 ([M + 1] +, 100). Example 14 2- [4- (3, 4-Difluorobenzyl) piperidin-1-yl] -lH-benzoimidazole The title compound was prepared as described in procedure A. The precipitated solid of the reaction mixture was filter and wash with acetonitrile to give the title compound as a hydrogen chloride salt. S (ES +) m / z 328 ([M + 1] +, 100). HR-MS: 328.1621 ([M + 1] +, Ci 9 H 2 or F 2 N 3; cale 328.162528). Example 15 Biological activity Preclinical data in our laboratories have shown that the combination of a selective inhibitor of SK channels, 1, 3-Bis- (3,4-difluoro-benzyl) -1,3-dihydro-benzo-imidazol-2-ylideneamine, hereinafter referred to as the test compound, shows more than 100 times of selectivity for the inhibition of SK3 channels in patch electrophysiology on the inhibition of [3H] DA, reuptake [3HJ5-HT and [3H] NA in vi tro), with a subthreshold dose of the selective serotonin reuptake inhibitor (SSRI), citalopram , improved the ability of the latter to induce symptoms analogous to serotonin syndrome, after pre-treatment with the amine oxidase inhibitor of monoamine, nialamide. Nialamide induced by the 5-HT syndrome paradigm is widely considered to reflect the ability of a compound to inhibit 5-HT reuptake of the synapse. Method: Mice were administered with nialamide (50 mg / kg, sc, -120 minutes) followed by the test compound (0.3-3 mg / kg, ip) and citalopram (1 mg / kg, po) in the range of Time 0 Min. The presence of behaviors of head contractions, abduction of the hind legs, swinging of the head, and playing the piano were then scored by a trained observer who used a recognized rating scale: maximum score / mouse = 4, minimum score / mouse = 0. Results of this experiment are presented in Figure 1. Thus, these data suggested that blocking of SK channels in combination with SSRI induced a monoamine neurotransmission higher than that of SSRI alone. According to this theory, data from our laboratories have also shown that the combination of an inhibitor of SK channels with a subthreshold dose of the noradrenaline reuptake inhibitor (NRI), reboxetine, improved the ability of the latter to reverse induced ptosis. by tetrabenazine. The inversion of ptosis induced by tetrabenazine is widely considered to reflect the ability of a compound to inhibit the reuptake of noradrenaline from the synapse. Method: Mice were administered the test compound (0.3-3 mg / kg, ip) and reboxetine (0.1 mg / kg, po) in the time interval -60 minutes, followed by tetrabenazine (40 mg / kg, ip , -30 minutes). The presence of ptosis was then noted by a trained observer who used a recognized rating scale: maximum score / mouse = 4, minimum score / mouse = 0. The results of this experiment are presented in Figure 2. Thus, these data suggested that blockade of the SK channels in combination with the NRI induced a higher monoamine neurotransmission than that of the NRI alone. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (25)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of an active pharmaceutical ingredient selected from A) a monoamine reuptake inhibitor; and B) in SK inhibitor; together are one or more adjuvants, excipients, carriers and / or diluents.
2. 2. The pharmaceutical composition according to claim 1, characterized in that it comprises a compound having the dual activity of a monoamine reuptake inhibitor and an SK inhibitor such as the API alone.
3. 3. The use of A) a compound selected from the group of monoamine reuptake inhibitors; and B) a compound selected from SK inhibitors; For the manufacture of a pharmaceutical composition / medicament.
4. 4. A benzodimidazole derivative of Formula I an isomer thereof or a mixture of its isomers, or a salt pharmaceutically acceptable thereof, characterized in that R1, R2, R3 and R4, independently of one another, represent hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino or N, N-dialkylamino; Z represents hydrogen, alkyl or benzyl, the benzyl can be optionally substituted one or more times with halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino and / or N, -dialkylamino; and X represents CH-A ', N-A', or C = A ''; where A 'represents a group of the formula o or Ib: gives); or (Ib); where B represents CH2, 0 or S; Y represents hydrogen, I Luoro, hydroxy or alkoxy; and R10, R11, R12, R13 and R14, independently of one another, represents hydrogen, halo, trifluoromethyl, trifluoride, oxy, cyano, alkyl, alkoxy, amino, Nalkylamino or N, N- dialkyl 1-amino; Y A "represents a group of the Formula Ic: (le) wherein R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14, independently of one another, represents hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl -amino or N, N-dialkyl-amino.
5. 5. The benzoimidazole derivative according to claim 4, an isomer thereof or a mixture of its isomers, or a pharmaceutically acceptable salt thereof, characterized in that R1, R2, R3 and R4, independently of one another, represent hydrogen , halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino or N, N-dialkylamino.
6. 6. The benzoimidazole derivative according to claim 4, an isomer thereof or a mixture of its isomers, or a pharmaceutically acceptable salt thereof, characterized in that Z represents hydrogen, alkyl or benzyl, the benzyl can be optionally substituted one or more times with halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino and / or N, N-dialkylamino.
7. 7. The benzoimidazole derivative according to claim 4, an isomer thereof or a mixture of its isomers, or a pharmaceutically acceptable salt thereof, characterized in that X represents CH-A 'or NA', and A 'is as defined in claim 4.
8. 8. The benzoimidazole derivative according to claim 4, characterized in that it is represented by Formula II, an isomer thereof or a mixture of its isomers, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8 and R9, independently of one another, represents hydrogen, halo, trifluoromethyl , trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino or N, N-dialkylamino; Z represents hydrogen, alkyl or benzyl, the benzyl can optionally be replaced one or more times with halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino and / or N, N-dialkylamino; X represents CH or N; and B represents CH2, 0 or S.
9. 9. The benzoimidazole derivative according to claim 8, an isomer thereof or a mixture of its isomers, or a pharmaceutically acceptable salt thereof, characterized in that R1, R2, R3, R4, R5, R6, R7, R8 and R9, independently of one another, represents hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino or N, -dialkyl-amino.
10. 10. The benzoimidazole derivative according to claim 8, an isomer thereof or a mixture of its isomers, or a pharmaceutically acceptable salt thereof, characterized in that Z represents hydrogen, alkyl or benzyl, the benzyl optionally can be substituted or more times with halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino and / or N, -dialkylamino.
11. 11. The benzoimidazole derivative according to claim 8, an isomer thereof or a mixture of its isomers, or a pharmaceutically acceptable salt thereof, characterized in that X represents CH or N.
12. 12. The benzoimidazole derivative according to claim 8, an isomer thereof or a mixture of its isomers, or a pharmaceutically acceptable salt thereof, characterized in that B represents CH 2, 0 or S.
13. 13. The benzoimidazole derivative according to claim 4, characterized in that it is represented by Formula III, an isomer thereof or a mixture of its isomers, or a pharmaceutically acceptable salt thereof, wherein p R 2 R 4 R 5 R 6 p 7 p 8 R 9 R 10 p R 12 p 3 R 14 independently of one another, represents hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino or N, N-dialkylamino; Z represents hydrogen, alkyl or benzyl, the benzyl of which can optionally be substituted one or more times with halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino and / or N, N-dialkyl Not me; X represents CH or N; and Y represents hydrogen, fluoro, hydroxy or alkoxy.
14. 14. The benzoimidazole derivative according to claim 13, an isomer thereof or a mixture of its isomers, or a pharmaceutically acceptable salt thereof, characterized in that neither Tj2 p3 R4 R5 R6 D7 R8 R9 R10 p R12 R13 R14 independently of one another, represents hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino or N, N-dialkyl-amino.
15. 15. The benzoimidazole derivative according to claim 13, an isomer thereof or a mixture of its isomers, or a pharmaceutically acceptable salt thereof, characterized in that Z represents hydrogen, alkyl or benzyl, which benzyl optionally may be substituted more times with halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino and / or N, N-dialkyl-amino.
16. 16. The benzoimidazole derivative according to claim 13, an isomer thereof or a mixture of its isomers, or a pharmaceutically acceptable salt thereof, characterized in that X represents CH or N.
17. 17. The benzoimidazole derivative according to claim 13, an isomer thereof or a mixture thereof. isomers, or a pharmaceutically acceptable salt thereof, characterized in that Y represents hydrogen, fluoro, hydroxy or alkoxy.
18. 18. The benzoimidazole derivative according to claim 4, characterized in that it is represented by Formula IV, an isomer thereof or a mixture of its isomers, or a pharmaceutically acceptable salt thereof, wherein Rl R2 R3 R4 R5 R6 R7 R8 R9 R10 Rll R12 R13 R14 independently of one another, they represent hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino or N, -dialkylamino; and Z represents hydrogen, alkyl or benzyl, which benzyl can optionally be replaced one or more times with halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino and / or N, N-dialkylamino.
19. 19. The benzoimidazole derivative according to claim 18, an isomer thereof or a mixture of its isomers, or a pharmaceutically acceptable salt thereof, characterized in that R1, R2, R3, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14, independently of one another, represent hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino or, N-dialkyl-amino.
20. 20. The benzoimidazole derivative according to claim 18, an isomer thereof or a mixture of its isomers, or a pharmaceutically acceptable salt thereof, characterized in that Z represents hydrogen, alkyl or benzyl, which benzyl optionally can be substituted one or more times with halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, alkoxy, amino, N-alkyl-amino and / or N, N-dialkyl-amino.
21. 21. The benzoimidazole derivative according to claim 4, characterized in that it is 2- (4-Benzylpiperidin-1-yl) -lH-benzoimidazole; 2- (4-Benzylpiperidin-1-yl) -l- [4-chloro-3- (trifluoromethyl) benzyl] -lH-benzoimidazole; 2- (4-Benzylpiperidin-1-yl) -1- (3,4-difluorobenzyl) -1H-benzoimidazole; 2- [4- (3,4-Dichlorophenoxy) piperidin-1-yl] -lH-benzoimidazole; 2- [4- (3, -Dichlorophenylsulphane) piperidin-1-yl] -1H-benzoimidazole; 2- [4- (3,4-Dichlorobenzyl) piperidin-1-yl] -1H-benzoimidazole; 2- (4-Benzylpiperazin-1-yl) -lH-benzoimidazole; 1- (3, 4-Difluorobenzyl) -2- [4 - (3,4-difluorobenzyl) piperazin-1-yl] -lH-benzoimidazole; [1- (1 H-Benzoimidazol-2-yl) -piperidin-4-yl] diphenylmethanol; 2- (4-Benzhydryl-piperidin-1-yl) -lH-benzoimidazole; 2- (4-Benzhydrylpiperazin-1-yl) -lH-benzoimidazole; 2- . { 4- [Bis- (4-fluorophenyl) methyl] piperazin-1-yl} -1? -benzoimidazole; or 2- (4-Benzhydrylidene-piperidin-1-yl) -lH-benzoimidazole; or an enantiomer or a mixture of its enantiomers, or a pharmaceutically acceptable salt thereof.
22. 22. A pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of a benzoimidazole derivative according to any of claims 4-21, or a pharmaceutically acceptable addition salt thereof, or a prodrug thereof, together with one or more adjuvants, excipients, carriers and / or diluents. The use of a benzoimidazole derivative according to any of claims 4-21, or a pharmaceutically acceptable addition salt thereof, or a prodrug thereof, for the manufacture of a pharmaceutical composition for treatment, prevention or relief of a disease or disorder or condition of a mammal, including a human, whose disease, disorder or condition is sensitive to inhibition of monoamine neurotransmitter reuptake in the central nervous system and / or inhibition of SKCa channels. 24. The use according to claim 23, wherein the disease, disorder or conditions is depression, pseudodementia, Ganser syndrome, obsessive-compulsive disorder (OCD), panic disorder, memory deficit, memory loss, hyperactivity of attention deficit, obesity, anxiety, eating disorder, Parkinson's disease, parkinsonism, dementia, dementia due to aging, senile dementia, dementia complex of acquired immunodeficiency syndrome, memory dysfunction in aging, social phobia, addiction to drugs, drug abuse, cocaine abuse, tobacco abuse, alcoholism, pain, migraine pain, bulimia, premenstrual syndrome, late luteal phase syndrome, post-traumatic syndrome, chronic fatigue syndrome, premature ejaculation, erectile difficulty , anorexia nervosa, sleep disorders, autism, mutism, trichotillomania, narcolepsy, Gilíes de la Tourettes disease , inflammatory bowel disease or irritable bowel syndrome. 25. A method of treating, preventing or alleviating a disease or disorder, or a condition of a body of a living animal, including a human being, whose disease, disorder or condition is sensitive to the inhibition of monoamine neurotransmitter reuptake. in the system central nervous and / or inhibition of SKCa channels characterized in that it comprises the step of administering to such a living animal body the need for a therapeutically effective amount of a bezoimidazole derivative according to any of claims 4-21, or a pharmaceutically acceptable addition salt thereof, or a prodrug thereof.