WO2007028849A1

WO2007028849A1 - Pyrazolecarboxamide derivatives, method of obtaining same and use thereof as inverse antagonists/agonists of the cannabinoid cb1 and opioid mu receptor

Info

Publication number: WO2007028849A1
Application number: PCT/ES2006/070132
Authority: WO
Inventors: Nadine Jagerovic; Cristina FERNÁNDEZ FERNÁNDEZ; Maria Pilar Goya Laza; Luis Felipe Callado Hernando; Jose Javier Meana Martinez
Original assignee: Consejo Superior De Investigaciones Científicas; Universidad Del Pais Vasco
Priority date: 2005-09-08
Filing date: 2006-09-07
Publication date: 2007-03-15
Also published as: ES2289888B1; ES2289888A1

Abstract

The invention relates to a pyrazolecarboxamide derivative having cannabinoid and opioid antagonist properties. The invention also relates to compositions containing same and to the use thereof in relation to disorders and diseases involving cannabinoid receptors and, more specifically, subtype CBi, and for the prevention and/or treatment of disorders and diseases involving opioid receptors and, more specifically, subtype mu, including the treatment of obesity and opioid drug dependency.

Description

TITLE

DERIVATIVES OF PIRAZOLCARBOXAMIDA, ITS OBTAINING PROCEDURE AND ITS APPLICATIONS AS INVESTED ANTAGONISTS / AGONISTS OF THE CANNABINOID CBi AND OPIODE MU RECEIVER

SECTOR OF THE TECHNIQUE

Pharmaceutical sector. The present invention relates to new pyrazole-3-carboxamide derivatives as cannabinoid inverse agonists and their use as pharmacological tools and as drugs for the treatment of diseases in which cannabinoid and opioid receptors are involved.

STATE OF THE TECHNIQUE Today two subtypes of cannabinoid receptors have been identified and cloned: CBi and CB ₂ (Howlett A. C et al., Pharmacol. Rev., 2002, 5_4, 161-202). CBi cannabinoid receptors are found in the central nervous system while CB ₂ cannabinoid receptors reach significant densities in different types of immune cells. These two receptor subtypes transmit their signal through the activation of pertussis toxin-sensitive G proteins to inhibit the adenylate cyclase system leading to a decrease in intracellular cyclic adenosyl monophosphate levels.

(Petrocellis, L et al., Br. J. Pharmacol. 2004, 141,

765-774). Following the discovery of an endogenous system, synthetic cannabinoid ligands have been prepared. Thus, various families of compounds that modulate the activity of cannabinoid receptors have appeared in the literature (Hertzog DL, Expert. Opin. Ther. Patents, 2004, 14, 1435-1452) (Regio PH, Curr. Pharm. Des. , 2003, 9, 1607-1633) (Pertwee RG, Exp. Opin. Invest. Drugs, 2000, 9, 1553-1551). The present invention relates to pyrazole-3-carboxamide derivatives. In the bibliography several pyrazole-3-carboxamide derivatives with cannabinoid activity have been described (FR2789078, WO2005037199, WO0129007, US2005080087, WO2004052864, WO2004058744, WO03020217, US6509367, WO0046209, EP0656354, WO2005037199, US974892799, 0997299279, 0997799279, 0997299279, 0997799279909, 979979979979979979997, 99779927997, 997799279909, 979979979979979979979997, 9799799799799799799299299299299999 Two of them are particularly relevant: a CBi cannabinoid receptor inverse antagonist / agonist, SR141716 (Rinaldicarmona M. et al., FEBS Lett., 1994, 350, 240-244) and a CB ₂ cannabinoid receptor inverse antagonist / agonist, SR144528 ((Rinaldicarmona M. et al., J. Pharmacol. Exp. Ther., 1998, 284, 644-650).

Compounds that interact with cannabinoid receptors may have therapeutic applications in various diseases such as appetite stimulants, anti- emetics, analgesics, antiglaucoma agents, in the treatment of neurodegenerative disorders such as multiple sclerosis. Antagonists and inverse agonists of CBi cannabinoid receptors, in particular, will be useful for the treatment of obesity, for tobacco addiction, for dependency treatments (cannabis, opiates or alcohol), to treat cerebral ischemia and trauma. craniocerebral

In the present invention, the pyrazole-3- carboxamide derivatives of Formula A act as a potent inverse agonist on CBi cannabinoid receptors. Today, no cannabinoid ligand has been published with such a marked inverse agonist activity. Most of the compounds that act as CBi cannabinoid receptor antagonists are inverse agonists (Makriyannis A. et al., Neuropharmacology 2005, 48, 1068-1071) (Pertwee RG, Life Sci., 2005, 76, 1307-1324) ( Lange JHM et al., Drug Discovery Today, 2005, 10, 693-702). However, the compounds described to date show an inverse agonist effect in itself less important than the antagonistic effect they produce on CBi receptor agonists either in vitro or in vivo.

Today there is no precedent for compounds that incorporate two cannabinoid and opioid pharmacoforic groups in the same structure. However, numerous pharmacological studies (Navarro M. et al., Neuroreport, 1998, 9, 3397-3402. Pickel, V. et al., Neuroscience 2004, 127, 101-112. RÍOS, C et al., Br J Pharmacol 2006, 148, 387-395 Christie, MJ Br J Pharmacol 2006, 148, 385-386) show the interactions between the cannabinoid and opioid systems.

DESCRIPTION OF THE INVENTION Brief Description An object of the present invention is a pyrazolecarboxamide derivative with cannabinoid properties, hereinafter compound of the invention, based on the following formula (A):

Formula A

in which :

- X represents an alkyl, dicyclohexyl, aryl or xylene group, or an isomer, derivative or solvate thereof. In a particular embodiment, said compound of formula (A) belongs, by way of illustration and without limiting the scope of the invention, to the following table I:

Table I

5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (3- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) propyl) -4-methyl-lH - pyrazol-3-carboxamide,

5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (4- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) butyl) -4-methyl-lH - pyrazol-3-carboxamide,

5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (6- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) hexyl) -4-methyl-lH - pyrazol-3-carboxamide,

5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (1- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) heptyl) -4-methyl-lH - pyrazol-3-carboxamide,

(5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (8- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) octyl) -4-methyl- lH- pyrazol-3-carboxamide,

5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (9- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) nonyl) -4-methyl-lH - pyrazol-3-carboxamide,

5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (12- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) dodecyl) -4-methyl-lH - pyrazol-3-carboxamide,

5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (3- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) phenyl) -4-methyl-lH - pyrazol-3-carboxamide,

5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (3- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) methyl benzyl) -4-methyl- lH-pyrazol-3-carboxamide,

5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (4- ((4- (N- (1- phenethylpiperidin-4-yl) propionamido) cyclohexyl) methyl) cyclohexyl) -4- methyl-lH-pyrazol-3-carboxamide, and

5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (5- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) pentyl) -4-methyl-lH - pyrazol-3-carboxamide. Another object of the invention is a process for the preparation of the compound of the invention, hereinafter the method of the invention, according to what is described in the reaction scheme represented in Figure 1.

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (A) for the treatment of and / or prevention of disorders or diseases in which cannabinoid receptors are involved, and more specifically the CBi subtype, and for the prevention and / or treatment of disorders in which opioid receptors are involved, specifically the mu subtype, and more specifically in the treatment of opioid drug dependence, together with, optionally, one or more pharmaceutically acceptable excipients.

In a particular embodiment, said pharmaceutical composition is a composition comprising a compound of formula (A), by way of illustration and without limiting the scope of the invention, belonging to Table I, and mixtures thereof, together with, optionally, one or more pharmaceutically acceptable excipients.

The invention also relates to the use of a compound of formula (A), preferably a compound of Table I, in a method for the prevention and / or treatment of disorders or diseases in which cannabinoid receptors are involved, and more specifically the CBi subtype, and for the prevention and / or treatment of disorders or diseases in which opioid receptors are involved, and, more specifically, the mu subtype.

A particular embodiment of the invention relates to the use of a compound of formula (A) for the prevention and / or treatment of disorders or diseases in which the CB _x cannabinoid receptor is involved, and more specifically to a disorder or disease belonging, by way of illustration and without limiting the scope of the invention, to the following group: appetite suppression, reduction of dyskinesia caused by

L-dopa in Parkinson's patients, the treatment of acute schizophrenia, the treatment of cognitive and memory dysfunctions associated with the disease of

Alzheimer's disease, obesity treatment, tobacco addiction treatment, dependency treatment

(cannabis, opiates or alcohol), to treat cerebral ischemia and head trauma.

A particular embodiment of the invention relates to the use of a compound of formula (A) for the prevention and / or treatment of disorders or diseases in which the opioid receptor mu is involved, and more specifically, with the treatment and prevention from drug addiction to opiates.

Detailed description

The present invention relates to pyrazolecarboxamide derivatives with cannabinoid properties and more specifically with a strong inverse agonist activity by CBi receptors and by mu opioid receptors.

Therefore, an object of the present invention is a pyrazolecarboxamide derivative with cannabinoid properties, hereinafter the compound of the invention, based on the following formula A:

Formula A

in which :

- X represents an alkyl, dicyclohexyl, aryl or xylene group, or an isomer, derivative or solvate thereof.

The compounds of the present invention represented by the formula (A) described above may include isomers, depending on the presence of multiple bonds (eg, Z, E), including optical or enantiomeric isomers, depending on the presence of chiral centers. The individual isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention. The individual enantiomers or diastereoisomers, as well as mixtures thereof, can be separated by conventional techniques.

As used herein, the term "derivative" includes both pharmaceutically acceptable compounds, that is, derivatives of the compound of formula (A) that can be used in the manufacture of a medicament, as pharmaceutically unacceptable derivatives since these may be useful. in the preparation of pharmaceutically acceptable derivatives. The nature of the pharmaceutically acceptable derivative is not critical as long as it is pharmaceutically acceptable. Also, within the scope of this invention are the prodrugs of the compounds of formula (A). The term "prodrug" as used herein includes any compound derived from a compound of formula (A), for example, esters, including carboxylic acid esters, amino acid esters, phosphate esters, metal salt sulphonate esters, etc., carbamates, amides, etc., which, when administered to an individual, is capable of providing, directly or indirectly, said compound of formula (A) in said individual. Advantageously, said derivative is a compound that increases the bioavailability of the compound of formula (A) when administered to an individual or that enhances the release of the compound of formula (A) in a biological compartment. The nature of said derivative is not critical as long as it can be administered to an individual and provides the compound of formula (A) in a biological compartment of an individual. The preparation of said prodrug can be carried out by conventional methods known to those skilled in the art.

The compounds of the invention may be in crystalline form as free compounds or as solvates and it is intended that both forms are within the scope of the present invention. In this sense, the term "solvate", as used herein, includes both pharmaceutically acceptable solvates, that is, solvates of the compound of formula (A) that can be used in the manufacture of a medicament, as pharmaceutically acceptable solvates, which may be useful in the preparation of pharmaceutically acceptable solvates or salts. The nature of the pharmaceutically acceptable solvate is not critical as long as it is pharmaceutically acceptable. In a particular embodiment, the solvate is a hydrate. Solvates can Obtained by conventional methods of solvation well known to those skilled in the art.

For their application in therapy, the compounds of formula (A), their isomers, salts, prodrugs or solvates, will preferably be found in a pharmaceutically acceptable or substantially pure form, that is, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and not including material considered toxic at normal dosage levels. The purity levels for the active ingredient are preferably greater than 50%, more preferably greater than 70%, and more preferably greater than 90%. In a preferred embodiment, they are greater than 95% of the compound of formula (A), or of its salts, solvates or prodrugs.

Unless otherwise indicated, the compounds of the invention also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having said structure, except for the replacement of a hydrogen with a deuterium or tritium, or the replacement of a carbon with a carbon enriched in ¹³ C or ¹⁴ C or a nitrogen enriched in ¹⁵ N, are within of the scope of this invention.

In a particular embodiment, said compound of formula (A) belongs, by way of illustration and without limiting the scope of the invention, to the following table I: Table I

5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (5- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) pentyl) -4-methyl-lH - pyrazol-3-carboxamide. Another object of the invention is a process for the preparation of the compound of the invention, hereinafter the method of the invention, according to what is described in the reaction scheme represented in Figure 1 and comprising the following steps: a) synthesis of 5- (4-chlorophenyl) -1- (2, 4- dichlorophenyl) -4-methyl-lH-pyrazol-3-carboxylic acid according to the synthetic procedures described in the literature and, in particular with the published experimental part by Krishnamurthy et al., Bioorg. Med. Chem., 2004, 12, 393-404, b) treatment of a) carboxylic acid with thionyl chloride to give 5- (4- chlorophenyl) -1- (2,4-dichlorophenyl) acid chloride -4-methyl-lH-pyrazol-3-carboxylic acid, c) preparation of the N- (1- (2-phenethyl) piperidin-4- yl) propionamides (Montero et al., Bioorg. Med. Chem., 2002, K ^, 1009-1018 and Dardonville et al., Bioorg. Med. Chem. Lett., 2004, L4, 491-493) by reductive amination of 1- (2-phenethyl) -4-piperidone with one of the monoprotected starting diamines followed by an N-acylation to introduce the propionyl group and, finally, by a deprotection of the protected amine group, and d) reaction of the acid chloride 5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl ) -4-methyl-lH-pyrazol-3-carboxylic acid with a

N- (1- (2-phenethyl) piperidin-4-yl) propionamide.

In the present invention, the cannabinoid activity of the compounds of the general formula (A) was assessed by carrying out in vitro radioligand displacement assays in brain membranes (fraction P ₂ ) of human cortex, and guanosine-5'-binding assays 0- (3- [ ³⁵ S] uncle) triphosphate) ([ ³⁵ S] GTPγS) in brain membranes (fraction P ₂ ) of human cortex. Thus, it was observed that the new compounds showed a significant affinity for the CBi receptor. The derivatives of formula A wherein X represents a butyl group (Example 3), hexyl (Example 4), heptyl (Example 5) and octyl (Example 6) exhibited a higher affinity with K ₁ values of 569 + 201, 2289+ 1857, 701 + 567 and 3991 + 1366 nM, respectively; while the reference compound SR141716 showed an affinity for CBi cannabinoid receptors with a K ₁ value of 3.73 + 2.5 nM (see Example 12).

The compounds 5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) - N- (6- (N- (1- (2-phenethyl) piperidin-4-yl) propionamido) hexyl) -4-methyl -lH-pyrazol-3-carboxamide (Example 4) and 5- (4- chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (6- (N- (1- (2- phenethyl) piperidin-4) -il) propionamido) heptyl) -4-methyl-lH- pyrazol-3-carboxamide (Example 5) had a very pronounced agonist effect of the CBL cannabinoid receptor very pronounced in the [ ³⁵ S] GTPYS fixation assays in brain membranes (fraction P ₂ ) of human cortex (Figure 2, Example 12).

To assess the opioid activity of the new compounds, radioligand displacement assays [ ³ H] -DAMGO, a mu- opioid receptor agonist, were performed in vitro on brain membranes (fraction P ₂ ) of human cortex. The new compounds showed a moderate to good affinity for the mu-opioid receptor. The compounds 5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (6- (N- (1- (2-phenethyl) piperidin-4-yl) propionamido) hexyl) -4-methyl - lH-pyrazol-3-carboxamide (Example 4) and 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -N- (6- (N- (1- (2-phenethyl) piperidin-4) - il) propionamido) heptyl) -4-methyl-lH-pyrazol-3-carboxamide (Example 5) exhibited an affinity with values of K ₁ 295 + 59 and 6543 + 947 nM respectively.

On the other hand, the results obtained in mice allow us to affirm that the compounds of the invention have a dual cannabinoid and opioid action whose efficacy in vivo is a consequence of the synergy that develops when the opioid and cannabinoid activity coincide in the same molecule, behaving in vivo as cannabinoid antagonists and opioid antagonists (Example 14 and 15; Figure 3, 4 and 5 ); although in the latter case contrary to what is planned taking into account the fentanyl part (opioid agonist) that is incorporated into the structure of the new compounds. In this sense, and in order to analyze said antagonistic activity, mediated by CBl receptors, the anorexigenic effect of the compounds of the invention was evaluated by means of tests of intake measures in male rats (Example 15), it being observed that the compound of Example 4 and of Example 5 produce a decrease in food intake (Figure 5).

These new compounds of the present invention could be useful as antagonists of the effect of both natural (synthetic THC) and synthetic (WIN 55212-2 or CP 55940) agonists. The compounds according to the invention, inverse agonists and antagonists of CBi cannabinoid receptors, can be used as a drug for the manufacture of a medicament for the treatment and / or prevention of disorders in which cannabinoid receptors are involved, and, more specifically, the subtype CBi. The fact that the compounds of the present invention bind to both opioid and cannabinoid receptors as antagonists widens their therapeutic applications to the treatment of opioid drug dependence. In addition, the compounds of the present invention whose opioid agonist functionality could be confirmed in vivo, could be used for the treatment of pain and in particular for the treatment of chronic pain (see Example 13).

In addition, the use of the compounds of the present invention have a particular interest in the characterization and study of cannabinoid receptors and ligands.

Accordingly, in another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (A) for the treatment of and / or prevention of disorders or diseases in which cannabinoid receptors are involved, and more specifically the CBi subtype , and for the prevention and / or treatment of disorders in which opioid receptors are involved, specifically the mu subtype, and more specifically in the treatment of opioid drug dependence, together with, optionally, one or more pharmaceutically acceptable excipients.

As used herein, the term "disorders or diseases in which cannabinoid receptors are involved, and more specifically the CBi subtype", refers to a disorder or disease, by way of illustration and without limiting the scope of the invention. , belonging to the following group: appetite suppression, reduction of dyskinesia caused by L-dopa in Parkinson's patients, treatment of acute schizophrenia, treatment of cognitive and memory dysfunctions associated with Alzheimer's disease, treatment of obesity, treatment of tobacco addiction, dependency treatments (cannabis, opiates or alcohol), to treat cerebral ischemia and head trauma.

In the sense used in this description, the term "pharmaceutically acceptable excipient" refers to those substances, or combination of substances, known in the pharmaceutical sector, used in the preparation of pharmaceutical forms of administration and includes adjuvants, solids or liquids, solvents , surfactants, etc. In a particular embodiment, said pharmaceutical composition is a composition comprising a compound of formula (A), by way of illustration and without limiting the scope of the invention, belonging to Table I, and mixtures thereof, together with, optionally, one or more pharmaceutically acceptable excipients. If desired, said pharmaceutical composition may contain, in addition, one or more natural, recombinant or synthetic therapeutic agents - which, eventually, enhance the therapeutic action of said compound of formula (A), for example, of the compounds of Table I or that increase their spectrum of action.

The compound of formula (A) will be present in the pharmaceutical composition in a therapeutically effective amount, that is, in an amount appropriate to exert its therapeutic effect. In a particular embodiment, the pharmaceutical composition provided by this invention contains between 0.01% and 99.99% by weight of a compound of formula (A), such as a compound selected from the compounds of Table I and mixtures thereof. , and can be presented in any pharmaceutical form of appropriate administration depending on the route of administration chosen, for example, oral, parenteral or topical. A review of the different pharmaceutical forms for drug administration and their preparation methods can be found, for example, in the Tratado de Farmacia Galenica, C. Fauli i Trillo, I Edition, 1993, Luzan 5, SA de Ediciones.

Said pharmaceutical composition can be used to prevent and / or treat diseases in which cannabinoid receptors are involved, and more specifically the CBi subtype, and for the prevention and / or treatment of disorders in which opioid receptors are involved, and more specifically the mu subtype, as opioid antagonists.

Therefore, the invention also relates to the use of a compound of formula (A), preferably a compound of Table I, in a method for prevention and / or the treatment of disorders or diseases in which cannabinoid receptors are involved, and more specifically the CBi subtype, and for the prevention and / or treatment of disorders or diseases in which opioid receptors are involved, and, more specifically, e 1 subtype mu.

A particular embodiment of the invention relates to the use of a compound of formula (A) for the prevention and / or treatment of disorders or diseases in which the CBI cannabinoid receptor is involved, and more specifically to a disorder or disease belonging to , by way of illustration and without limiting the scope of the invention, to the following group: appetite suppression, reduction of dyskinesia caused by L-dopa in Parkinson's patients, treatment of acute schizophrenia, treatment of dysfunctions Cognitive and memory associated with Alzheimer's disease, the treatment of obesity, the treatment of tobacco addiction, the dependence treatments (cannabis, opiates or alcohol), to treat cerebral ischemia and traumatic brain injury.

DESCRIPTION OF THE FIGURES The invention is illustrated with reference to the accompanying Figures, in which:

Figure 1 represents the synthetic scheme of the preparation of the compounds of the present invention of Formula A.

Figure 2 illustrates the effects of the compound of Example 4 (5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (6- {N- (1- (2- phenethyl) piperidin-4-yl) propionamido) hexyl) -4-methyl-lH-pyrazol-3-carboxamide) and Example 5 (5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (7- (N- (1- (2-phenethyl) piperidin-4- yl) propionamido) heptyl) -4-methyl-l-pyrazol-3-carboxamide) in the [ ³⁵ S] GTPγS (0 fixation assays) , 5 nM) in brain membranes (fraction P ₂ ) of human cortex. Each point represents the average of 2-3 experiments performed in duplicate plus the standard error of the mean. Figure 3 illustrates the effects of the compound of Example 5 (5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (7- (N- (1- (2- phenethyl) piperidin-4- il) propionamido) heptyl) -4-methyl-IH-pyrazol-3-carboxamide). WIN55, 212-2 (WIN): 1.5 mg / kg, Compound of Example 5 (Ex. 5), 5 mg / kg. mean ± SEM (n = 10). (#) p <0.05;(##) p <0.01;(###) p <0.001. (**) p <0.01; (***) p <0.001.

Figure 4 illustrates the effect of the compounds of Example 4 (5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (6- {N- (1- (2- phenethyl) piperidin-4 -yl) propionamido) hexyl) -4-methyl-IH-pyrazol-3-carboxamide) and Example 5 (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -N- (7- (N - (1- (2-Phenethyl) piperidin-4- yl) propionamido) heptyl) -4-methyl-lH-pyrazol-3-carboxamide) in the hot plate test. The bars represent the maximum possible effect% (mean ± SEM, n ≤ 10) produced by morphine at 10 mg / kg, compound of Example 4 at 10 mg / kg, compound of Example 5 at 10 mg / kg, morphine 10 mg / kg after a treatment with the compound of Example 4 at 10 mg / kg, morphine 10 mg / kg after a treatment with the compound of Example 5 at 10 mg / kg, or morphine 10 mg / kg after a treatment with naloxone at 1 mg / kg. (##) p <0.01.

Figure 5 shows the intake control after administration of the compound of Example 5 (5- (4- chlorophenyl) -1- (2,4-dichlorophenyl) -N- (7- (N- (1- (2 - phenethyl) piperidin-4-yl) propionamido) heptyl) -4-methyl- IH- pyrazol-3-carboxamide) at 0.1, 1 and 2 mg / kg of animal and at times of 30, 60, 120 and 240 minutes.

EXAMPLES OF EMBODIMENT OF THE INVENTION The following examples illustrate the present invention. However, these examples are not limiting.

The following abbreviations are used in the preparation schemes and in the examples: AcOEt: ethyl acetate, Anal .: elemental analysis, CH ₂ Cl ₂ : dichloromethane, CHCl ₃ : chloroform, DMAP: 4- dimethylaminopyridine, g: gram, MS : mass spectrometry, HCl: hydrochloric acid, LiHMDS: lithium hexadimethylsilazane, MeOH: methanol, min: minutes, mL: milliliter, M: molar, MgSO ₄ : magnesium sulfate, NaBH ₃ CN: sodium cyanoborohydride, NaCl: sodium chloride , NH ₃ : ammonia, Mp .: melting point, Rto: yield, ASD: triethylamine, THF: tetrahydrofuran.

Example 1.- Preparation and obtaining 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -N- (3- ((N- (1- (2-phenethyl) piperidin-4- yl) propionamido ) methyl) benzyl) -4-methyl-lJϊ-pyrazol-3- carboxamide

A) Ethyl 5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -4-methyl-l-pyrazol-3-carboxylate

A solution of 1.55 g of 4-chloropropyrophenone in anhydrous THF is cooled to -78 ° C. 9.3 mL of LiHMDS (IM in THF) are added and the solution is allowed to stir at the same temperature for 45 min. After that time it is brought to -20 ° C and then cooled again to -78 ° C to add 1.46 mL of diethyl oxalate. The reaction mixture is allowed to stir at room temperature for 20 hours. It is evaporated, diluted in ether, washed with IM HCl. The organic phase is separated, dried over MgSO ₄ and evaporated under reduced pressure to give the ethyl 2, 4-dioxo-3-methyl-4- (4- chlorophenyl) butanoate salt as a yellow oil. The crude is dissolved in ethanol (24 mL) and 1.27 g of 2,4-dichlorophenylhydrazine and 1.25 inL of triethylamine. The reaction mixture is heated at reflux overnight. It is cooled, washed with a saturated NaCl solution and extracted with AcOEt. Purification is carried out by medium pressure chromatography on silica gel using hexane-AcOEt (1: 0 -> 20: 1) as eluent to give 841 mg of product. Rto. = 22%, orange solid Pf. =: 122-124 ° C. ¹ H NMR (CDCl ₃ ) δ: 7.38 (d, J = 2.3 Hz, IH); 7.34 (d, J = 7.3 Hz, IH); 7.29 (td, J = 9.5 Hz, J = 2.1 Hz, 2H); 7.27 (dd, J = 7.3 Hz, J = 2.3 Hz, IH); 7.07 (td, J = 9.5 Hz, J = 2.1 Hz); 4.45 (c, 2H, J = 7.9 Hz); 2.33 (s, 3 H); 1.42 (t, 3H, J = 7.9 Hz). MS (ES ⁺ ) m / z = 409 (90%) [M + H] ⁺ .

B) 5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -4-methyl-lH-pyrazol-3-carboxylic acid A solution of 120 mg of 5- (4- chlorophenyl) -1 chloride - (2, 4-Dichlorophenyl) -4-methyl-lH-pyrazol-3-carboxylic acid in 10 mL of ethanol and 10 mL of water, 116 mg of NaOH is added and it is left stirring for 3 hours. The reaction mixture is acidified with HCl (IM) and extracted with AcOEt, washed with saturated NaCl, dried over MgSO ₄ and evaporated under reduced pressure to give 115 mg of product. Rto. 99%, yellow solid Mp = 205-208 ° C. ¹ H NMR (CD ₃ OD) δ: 7.76 (d, J = 2.2 Hz, IH); 7.72 (d, J = 8.5 Hz, IH); 7.63 (dd, J = 6.3 Hz, J = 2.2 Hz, IH); 7.56 (td, J = 8.3 Hz, J = 1.8 Hz, 2H); 7.40 (td, J = 8.3 Hz, J = 1.8 Hz, 2H); 2.49 (s, 3 H). MS (ES ⁺ ) m / z = 380 (100%) [M + H] ⁺ .

C) 3- (Aminomethyl) benzyl tere-butyl carbamate

A solution of 654 mg of B0C2O in 15 mL of CHCl _{3 is added} dropwise over 2 mL (d = 1.032) m-xylylenediamine dissolved in 75 mL of CHCl ₃ cooled to 0 ° C. The reaction mixture is stirred at room temperature overnight. The solution is filtered over celite and the solvent is evaporated. The purification of the reaction crude is carried out by medium pressure chromatography on silica gel eluting with CH ₂ Cl ₂ -Me0H / NH ₃ (100: 10) to obtain 681 mg of desired compound. Rto. 96%, transparent oil. ¹ H NMR (CDCl ₃ ) δ: 7.34-7.13 (m, 4H); 5.34 (sa, IH); 4.24 (m, 2H); 3.74 (s, 2H); 2.73 (sa, 2 H); 1.42 (s, 9H). MS (ES ⁺ ) m / z = 237 (80%) [M + H] ⁺ . D) 3- ((1- (2-Phenethyl) piperidin-4-ylamino) methyl) benzyl tere-butyl carbamate

To a solution of 681 mg of tere-butyl 3- (aminomethyl) benzyl carbamate in dry methanol (5 inL), 331 mg of 1- (2-phenethyl) -4-piperidone and 1.40 g of NaBH _{3 are added} CN on 3 Á molecular sieve. The pH is adjusted to 6-7 with concentrated acetic acid throughout the reaction. The solution is maintained at room temperature 72 hours. The reaction mixture is filtered over celite and the filtrate is concentrated. Purification is carried out by flash chromatography on silica gel with CH ₂ Cl ₂ : MeOH / NH ₃ (100: 0-100: 5) as eluents on a prewash column with CH ₂ Cl ₂ / TEA (100: 1) , obtaining 600 mg of desired compound. Rto.

49%, transparent oil. ¹ H NMR (CDCl ₃ ) δ: 7.29-7.16 (m, 9H); 5.12 (sa, IH); 4.26 (m, 2H); 3.80 (sa, 2 H); 3.06 (m, 2H); 2.84 (m, 2 H); 2.70 (m, 2 H); 2.28 (ta, 2H, J = 10.7 Hz); 1.99 (da, 2H, J = 11.5 Hz); 1.61 (of, 2H, J = 2.9 Hz, J = 10.2 Hz); 1.43 (s, 9H). MS (ES ⁺ ) m / z = 424 (100%) [M + H] ⁺ .

EJ 3- [{N- (1- (2-Phenethyl) piperidin-4- yl) propionamido) methyl] tere-butyl benzyl carbamate 0.18 mL of propionic anhydride is added to a solution of 400 mg of 3- [ (1- (2-Phenethyl) piperidin-4- ylamino) methyl] benzyl tere-butyl carbamate, 11 mg of DMAP _cat , and 0.36 mL of pyridine in 6 mL of dry CH ₂ Cl ₂ . The reaction is allowed to stir for 4 days at room temperature. The reaction mixture is concentrated in vacuo. Purification is carried out by medium pressure flash chromatography on silica gel eluting with CH ₂ Cl ₂ : MeOH / NH ₃ (100: 0-100: 2), on a prewash column with CH ₂ Cl ₂ / TEA (100 :one). 283 mg of desired compound are obtained. Rto. 63%, transparent oil. ¹ H NMR (CDCl ₃ ) δ: 7.32-7.08 (m, 9H); 4.84 (sa, IH); 4.66 (m, 0.7H); 4.58 (s, 0.6H); 4.51 (s, 1.4H); 4.29 (m, 2H); 3.65 (m, 0.3H); 3.02 (da, 2H); 2.74 (m, 2 H); 2.58 (m, 2 H); 2.24 (c, 1.4H, J = 7.3 Hz); 2.20-1.70 (m, 4H); 1.65 (m, 2 H); 1.47 (s, 9H); 1.24 (t, 0.9H, J = 7.3 Hz); l, ll (t, 2, IH, J = 7.3 Hz). MS (ES ⁺ ) m / z = 480 (100%) [M + H] ⁺ .

FJ N- [3- (Aminomethyl) benzyl) -N- (1- (2-phenethyl) piperidin-4- yl] propionamide

A solution of 283 mg of 3- [(N- (I- (2- phenethyl) piperidin-4-yl) propionamido) methyl] benzyl tere-butyl carbamate in TFA / CH ₂ C1 ₂ (50/50) is stirred at room temperature for 30 minutes. The solvent is removed under reduced pressure. Diethyl ether is added to the reaction crude and the solvent is evaporated again. 354 mg of the desired compound are obtained as a salt of trifluoro acetic acid. Rto. 100%, yellow oil. ¹ H NMR

(CDCl ₃ ) δ: 7.68-7.40 (m, 9H); 4.85 (s, 0.8H) 4.81 (s, 1.2H); 4.49 (m, 0.6H); 4.32 (s, 1.2H); 4.27 (s, 0.8H); 3.84 (da, 2H, J = 12.0 Hz); 3.50 (m, 2 H); 3.47-3.28 (m, 4H); 2.86 (c, 0.8H, J = 7.3 Hz); 2.52 (c, 1.2H, J = 7.3 Hz); 2.32 (c, 2H, J = 12.5 Hz); 2.12 (da, 2H, J = 12.9 Hz); 1.40 (t, 1.2H, J = 7.3 Hz); 1.28 (t, 1.8H, J = 7.3 Hz). MS (ES ⁺ ) 380 (100%) [M + H] ⁺ . Anal. (C ₂₄ H ₃₃ N ₃ O- 2TFA-4H ₂ O) theoretical% (experimental%) C: 52.56 (52.09); H: 6.13 (6.40); N: 6.99 (6.51).

G) 5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- [3- ((N- (1- (2- phenethyl) piperidin-4-yl) propionamido) methyl) benzyl] - 4-methyl-lH-pyrazol-3-carboxamide

To a solution of 57 mg of 5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -4-methyl-1H-pyrazol-3-carboxylic acid in 6 mL of toluene is added 2mL of thionyl chloride. The reaction mixture is heated at reflux for 3 hours. The solvent is evaporated under reduced pressure. The residue is dissolved in toluene and the solvent is removed again in vacuo. The solid obtained is dissolved in dry CH ₂ Cl ₂ (5 mL) and added dropwise over a solution of 26 μL of TEA and N- (3- (aminomethyl) benzyl) -N- (1- (2-phenethyl) piperidin-4-yl) propionamide in 2 inL of dry CH2CI2 at 0 ° C The reaction mixture is stirred at room temperature for 16 hours. The purification is carried out by flash chromatography on silica gel with CH ₂ Cl ₂ : MeOH (NH ₃ ) (0-2%) as eluent. 65 mg of desired compound are obtained. Rto. 60%, yellowish solid Mp = 83-85 ° C. ¹ H NMR (CDCl ₃ ) δ:

7.40-7.06 (m, 16H); 4.60 (m, 4 H); 4.51 (m, IH); 3.67 (m, IH); 3.00 (m, 2 H); 2.74 (m, 2 H); 2.55 (m, 2 H); 2.48 (c,

0.5H, J = 7.3 Hz); 2.40 (s, 3 H); 2.23 (c, 1.5H, J = 7.3

Hz); 2.11 (m, 2H); 1.79 (m, 2 H); 1.65 (m, 2 H); 1.20 (t, IH,

J = 7.3 Hz); 1.07 (t, 2H, J = 7.3 Hz). MS (ES ⁺ ) 742 (100%)

[M + H] ⁺ . Anal. (C ₄ IH ₄₂ Cl ₃ N ₅ O ₂ ^• 1 / 2H ₂ O) theoretical% (experimental%) C: 65, 47 (65, 18): H: 5, 76 (5, 66); N: 9, 31

(9, 35).

Example 2.- Preparation and obtaining 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -N- (3- (N- (1- (2-phenethyl) piperidin-4- yl) propionamido) propyl) -4-methyl-lJϊ-pyrazol-3-carboxamide

A) N- (3-Aminopropyl) -N- (1- (2-phenethyl) piperidin-4- yl) propionamide

The desired compound is prepared according to the embodiment described in steps A-F of Example 1 from 1,3-diaminopropane.

B) 5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (3- {N- (1- (2- phenethyl) piperidin-4-yl) propionamido) propyl) -4-methyl -lH- pyrazol-3-carboxamide

The desired compound is prepared according to the embodiment described in step G of Example 1, from 60 mg of 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-lH- pyrazol-3-carboxylic acid and 30 mg of N- (3- aminopropyl) -N- (1- (2-phenethyl) piperidin-4-yl) propionamide.

45 mg of desired compound are obtained. Rto. 44% oil yellow. ¹ H NMR (CDCl ₃ ) δ: 7.43-7.04 (m, 12H); 4.46 (m, IH); 3.43 (m, 2 H); 3.37 (t, 2H, J = 7.1 Hz); 3.28 (m, 2 H); 3.1 (m, 2H); 2.77 (m, 2 H); 2.59 (m, 2 H); 2.35 (s, 3 H); 2.32 (m, 2 H); 2.05 (m, 2H); 1.84 (m, 2 H); 1.69 (m, 2 H); 1.10 (t, 3H, J = 7.3). MS (ES ⁺ ) 680 (100%) [M + H] ⁺ . Anal. (C ₃₆ H ₄₀ Cl ₃ N ₅ O ₂ -IH ₂ O)% theoretical (experimental%) C: 61.85 (62.21); H: 6.06 (6.17); N: 10.02 (10.06).

Example 3.- Preparation and obtaining 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -N- (4- (N- (1- (2-f-enethyl) piperidin-4- yl) propionamido ) butyl) -4-methyl-lJϊ-pyrazol-3-carboxamide

A) N- (4-Aminobutyl) -N- (1- (2-phenethyl) piperidin-4- yl) propionamide

The desired compound is prepared according to the embodiment described in steps A-F of Example 1 from 1,4-diaminobutane.

B) 5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (4- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) butyl) -4-methyl -lH- pyrazol-3-carboxamide. The desired compound is prepared according to the embodiment described in step G of Example 1, from 60 mg of 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-lH- pyrazol-3-carboxylic and N- (4-aminobutyl) -N- (1- (2- phenethyl) piperidin-4-yl) propionamide. 103 mg of desired compound are obtained. Rto. 99%, yellowish solid Pf. = 80-

82 ° C ¹ H NMR (CDCl ₃ ) δ: 7.42-7.05 (m, 12H); 4.51 (m, IH);

3.43 (m, 2 H); 3.23 (m, 2 H); 2.89 (m, 2 H); 2.78 (m, 2 H);

2.61 (m, 2 H); 2.37 (s, 3 H); 2.32 (m, 2 H); 2.10 (m, 2H);

1.92 (m, 2 H); 1.64 (m, 2 H); 1.12 (t, 3H, J = 7.3 Hz). MS (ES ⁺ ) 696 (100%) [M + H] ⁺ . Anal. (C ₃₇ H ₄₂ Cl ₃ N ₅ O ₂ ^• 3 / 2H ₂ O)% theoretical (experimental%) C: 61.54 (61.38); H: 6.28 (6.14);

N: 9.70 (9.43).

Example 4.- Preparation and obtaining 5- (4-chlorophenyl) -1-

(2,4-Dichlorophenyl) -N- (6- (N- (1- (2-phenethyl) piperidin-4- yl) propionamido) hexyl) -4-methyl-lJϊ-pyrazol-3-carboxamide. A) N- (6-Aminohexyl) -N- (1- (2-phenethyl) piperidin-4- yl) propionamide

The desired compound is prepared according to the embodiment described in steps A-F of Example 1 from 1,6-diaminohexane

B) 5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (6- {N- (1- (2- phenethyl) piperidin-4-yl) propionamido) hexyl) -4-methyl -lH- pyrazol-3-carboxamide

The desired compound is prepared according to the embodiment described in step G of Example 1, from 60 mg of 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-lH- pyrazol-3-carboxylic and N- (6-aminohexyl) -N- (1- (2- phenethyl) piperidin-4-yl) propionamide. 86 mg of desired compound are obtained. Rto. 54%, white solid Mp = 69-71 ° C. ¹ H NMR (CDCl ₃ ) δ: 7.43-6.92 (m, 12H,); 4.46 (m, 0.6H); 3.55 (m, 0.4H); 3.41 (m, 2 H); 3.20-3.04 (m, 4H); 2.79 (m, 2 H); 2.59 (m, 2 H); 2.37 (s, 3 H,); 2.32 (m, 2H,); 2.06 (ta, 2H, J = 11.7 Hz); 1.86 (de, 2H, J = 3.4 Hz, J = 12.2 Hz); 1.68 (ma, 2 H); 1.60, 1.54, 1.39 and 1.31 (m, 8H); 1.14 (m, 3 H). MS (ES ⁺ ) 724 (100%) [M + H] ⁺ . Anal. (C ₃₉ H ₄₆ Cl ₃ N ₅ O ₂ )% theoretical (experimental%) C: 64.77 (64.40); H: 6.41 (6.08); N: 9.98 (9.49).

Example 5.- Preparation and obtaining 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -N- (7- (N- (1- (2-phenethyl) piperidin-4- yl) propionamido) heptyl) -4-methyl-lJϊ-pyrazol-3-carboxamide.

A) N- (7-Aminoheptyl) -N- (1- (2-phenethyl) piperidin-4- yl) propionamide

The desired compound is prepared according to the embodiment described in steps A-F of Example 1 from 1, 7-diaminoheptane.

B) 5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (1- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) heptyl) -4-methyl - IH- pyrazol-3-carboxamide The desired compound is prepared according to the embodiment described in step G of Example 1, from 60 mg of 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-lH- pyrazol-3-carboxylic and N- (7-aminoheptyl) -N- (1- (2- phenethyl) piperidin-4-yl) propionamide. 48 mg of desired compound are obtained. Rto. 55%, orange oil. ¹ H NMR

(CDCl ₃ ) δ: 7.41-6.91 (m, 12H); 4.45 (m, 0.7H); 3.53 (m, 0.3H); 3.39 (q, 2H, J = 7.0 Hz); 3.17 (t, 2H, J = 8.0 Hz); 3.10 (m, 2H); 2.79 (m, 2 H); 2.60 (m, 2 H); 2.36 (s, 3 H); 2.30 (m, 2 H); 2.05 (ta, 2H, J = 11.7 Hz); 1.84 (c, 2H, J = 11.3 Hz); 1.67 (da, 2H, J = 10.7 Hz); 1.58, 1.51, 1.35 and 1.26 (m, 10H); 1.30 (m, 3 H). MS (ES ⁺ ) 738 (100%) [M + H] ⁺ . Anal. (C ₄₀ H ₄₈ Cl ₃ N ₅ O ₂ -1 / 2H ₂ O)% theoretical (experimental%) C: 64.38 (64.26); H: 6.62 (6.62); N: 9.39 (9.30).

Example 6.- Preparation and obtaining 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -N- (8- (N- (1- (2-phenethyl) piperidin-4- yl) propionamido) octyl) -4-methyl-lJϊ-pyrazol-3-carboxamide A) N- (8-Aminooctyl) -N- (1- (2-phenethyl) piperidin-4- yl) propionamide

The desired compound is prepared according to the embodiment described in steps A-F of Example 1 from 1,8-diaminooctane. B) 5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (8- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) octyl) -4-methyl - IH- pyrazol-3-carboxamide.

The desired compound is prepared according to the embodiment described in step G of Example 1, from 60 mg of 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-lH- pyrazol-3-carboxylic acid and 40 mg of N- (8-aminooctyl) -N- (1- (2-phenethyl) piperidin-4-yl) propionamide. 65 mg of desired compound are obtained. Rto. 87%, orange solid. Mp = 59-60 ° C. ¹ H NMR (CDCl ₃ ) δ: 7.40-6.93 (m, 12H); 4.45 (m, 0.8H); 3.45 (m, 0.2H); 3.38 (m, 2 H); 3.12 (m, 2H); 3.04 (m, 2 H); 2.79 (m, 2 H); 2.61 (m, 2 H); 2.35 (s, 3 H); 2.31 (m, 2 H); 2.02 (m, 2H); 1.87 (m, 2 H); 1.68 (m, 2 H); 1.56-1.28 (m, 12H); 1.13 (m, 3 H). MS (ES ⁺ ) 750 (100%) [M + H] ⁺ . Anal. (C _4I H ₅₀ Cl ₃ N ₅ O ₂ -H ₂ O)% theoretical (experimental%) C: 64.02 (64.12); H: 6.81 (6.81); N: 9.10 (9.20).

Example 7.- Preparation and obtaining 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -N- (9- (N- (1- (2-phenethyl) piperidin-4- yl) propionamido) nonyl) -4-methyl-lJϊ-pyrazol-3-carboxamide A) N- (9-Aminononyl) -N- (1- (2-phenethyl) piperidin-4- yl) propionamide

The desired compound is prepared according to the embodiment described in steps A-F of Example 1 from 1, 9-diaminononan. B) 5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (9- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) nonyl) -4-methyl - IH- pyrazol-3-carboxamide.

The desired compound is prepared according to the embodiment described in step G of Example 1, from 60 mg of 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-lH- pyrazol-3-carboxylic acid and 30 mg of N- (9-aminononyl) -

N- (1- (2-phenethyl) piperidin-4-yl) propionamide. 45 mg of desired compound are obtained. Rto. 85%, yellow oil. ¹ H NMR

(CDCl ₃ ) δ: 7.73-6.92 (m, 12H); 4.45 (m, 0.7H); 3.53 (m,

0.3H); 3.39; 3.10 (m, 2H); 3.07 (m, 2 H); 2.80 (m, 2 H); 2.57 (m, 2 H); 2.35 (s, 3 H); 2.30 (m, 2 H); 2.08 (m, 2H); 1.84 (c, 2H, J = 12.2 Hz); 1.67 (m, 2 H); 1.58, 1.49 and 1.26 (m, 14H); 1.13 (m, 3 H). MS (ES ⁺ ) 764 (100%) [M + H] ⁺ . Anal. (C ₄₂ H ₅₂ Cl ₃ N ₅ O ₂ -5 / 4CH ₂ Cl ₂ )% theoretical (experimental%) C: 59.61 (59.24); H: 6.30 (6.26); N: 8.04 (8.11).

Example 8.- Preparation and obtaining 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -N- (12- (N- (1- (2-phenethyl) piperidin-4- yl) propionamido) dodecyl) -4-methyl-lJϊ-pyrazol-3-carboxamide. A) N- (12-Aminododecyl) -N- (1- (2-phenethyl) piperidin-4- yl) propionamide

The desired compound is prepared according to the embodiment described in steps A-F of Example 1 from 1,112-diaminododecane.

B) 5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (12- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) dodecyl) -4-methyl - IH- pyrazol-3-carboxamide

The desired compound is prepared according to the embodiment described in step G of Example 1, from 60 mg of 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-lH- pyrazol-3-carboxylic acid and 30 mg of N- (12-aminododecyl) -N- (1- (2-phenethyl) piperidin-4-yl) propionamide.

143 mg of desired compound are obtained. Rto. 99%, orange oil. ¹ H NMR (CDCl ₃ ) δ: 7.40-6.91 (m, 12H); 4.41 (m,

IH); 3.36 (c, 2H, J = 7.5 Hz); 3.14-2.96 (m, 4H); 2.78 (m,

2H); 2.58 (m, 2 H); 2.30 (m, 3 H); 2.23 (m, 2 H); 1.97 (m, 2 H);

1.80 (m, 2 H); 1.62 (m, 2 H); 1.55-1.19 (m, 20H); 1.08 (m,

3H). MS (ES ⁺ ) 808 (100%) [M + H] ⁺ . Anal. (C ₄₅ H ₅₈ Cl ₃ N ₅ O ₂ -IH ₂ O) theoretical% (experimental%) C: 65.49 (65.61); H: 7.33 (7.20); N: 8.49 (8.64).

Example 9.- Preparation and obtaining 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -N- (3- (N- (1- (2-phenethyl) piperidin-4- yl) propionamido) phenyl) -4-methyl-lJϊ-pyrazol-3-carboxamide

A) N- [1- (2-Phenethyl) -4-piperidyl] -N- (3-nitrophenyl) amine

To a solution of 2.44 g of 2-nitroaniline in dry methanol (30 mL), 3.0 g of 1- (2-phenethyl) -4-piperidone and 1.40 g of NaBH ₃ CN on molecular sieve are added of 3 A. The pH is adjusted to 6-7 with concentrated acetic acid throughout the reaction. The solution is maintained at room temperature 72 hours. The reaction mixture is filtered over celite and the filtrate is concentrated. Purification is carried out by flash chromatography on silica gel with hexane: AcOEt (1: 1-0: 1) as eluents, obtaining 980 mg of desired compound. Rto. = 21%, yellow solid Mp = 115-119 ° C. ¹ H NMR

(CDCl ₃ ) δ: 7.41 (t, IH, J = 2 Hz); 7.34-7.38 (m, IH); 7.30-7.33 (m, IH); 7.20-7.29 (m, 3H); 7.13-7.18 (m, IH); 7.02 (ddd, IH, J = 8 Hz, J = 2 Hz, J = I Hz); 3.40 (m, IH); 2.96 (da, 2H, J = 11.5 Hz), 2.77 (m, 2H), 2.56 (m, 2H), 2.22 (ta, 2H, J = 11.8 Hz); 2.01 (m, 2H); 1.52 (of, 2H, J = 3.4 Hz, J = 11.2 Hz). MS (ES ⁺ ) m / z = 326 (100%) [M + H] ⁺ . B) N- [1- (2-Phenylethyl) -4-piperidyl] -N- (3- nitrophenyl) propanamide.

A solution of 800 mg of N- [1- (2-phenethyl) -A-piperidyl] -N- (3-nitrophenyl) amine (2.45 mmol) of propionic anhydride (80 mL) is heated at reflux for 24 hours . The propionic anhydride is evaporated under reduced pressure. The reaction crude is purified by medium pressure chromatography on silica gel eluting with CH ₂ Cl ₂ : MeOH

(100: 1-100: 2-100: 4) to obtain 170 mg of desired compound.

Rto. 18%, yellow solid. Mp = 142-143 ° C. ¹ H NMR (CDCl ₃ ) δ: 8.27 (ddd, IH, J = 8 Hz, J = 2 Hz, J = 1 Hz); 7.98 (t, IH, J _m = 2Hz); 7.63 (t, IH, J = 8 Hz); 7.46 (ddd, IH, J = 8 Hz, J = 2 Hz, J = I Hz); 7.28-7.23 (m, 2H); 7.20-7.13 (m, 3H); 4.72 (m, IH); 3.00 (da, 2H, J = 11.5 Hz); 2.69 (m, 2 H); 2.54 (m, 2 H); 2.18 (ta, 2H, J = 11.8 Hz); 1.93-1.80 (m, 4H); 1.38 (c, 2H, J = 11.2 Hz); 1.05 (t, 3H, J = 7.6 Hz). MS (ES ⁺ ) m / z = 382 (100%) [M + H] ⁺ .

CJ N- (3-Aminophenyl) -N- [1- (2-phenylethyl) -A-piperidyl] propanamide.

170 mg of N- [1- (2-phenylethyl) -A-piperidyl] -N- (3-nitrophenyl) propanamide dissolved in absolute MeOH (5 mL) was hydrogenated under 35-40 psi pressure in the presence of 10 mg of C-Pd (10%) for 5 hours. The reaction mixture is filtered and the solvent is removed under reduced pressure. Purification is carried out by medium pressure chromatography on silica gel with CH ₂ Cl ₂ : MeOH (NH ₃ ) (100: 0-100: 2-100: 5-100: 10), 40 mg of compound are obtained wanted. Rto. 32%, yellow oil. ¹ H NMR (CDCl ₃ ) δ: 7.38-6.44 (m, 9H); 4.68 (m, IH); 3.06 (da, 2H, J = 10.7 Hz); 2.79 (m, 2 H); 2.61 (m, 2 H); 2.21 (m, 2 H); 2.07 (c, 2H, J = 7.4 Hz); 1.85 (m, 2 H); 1.55 (ta, 2H, J = 11.3 Hz); 1.09 (t, 3H, J = 7.4 Hz). MS (ES ⁺ ) m / z = 352 (100%) [M + H] ⁺ .

D) 5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (12- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) docile) -4-methyl - IH- pyrazol-3-carboxamide

The desired compound is prepared according to the embodiment described in step G of Example 1, from 60 mg of 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-lH- pyrazol-3-carboxylic acid and 35 mg of N- (3-aminophenyl) - N- [1- (2-phenylethyl) -4-piperidyl] propanamide. 31 mg of desired compound are obtained. Rto. 48%, solid yellow. Mp = 105-108 ° C. ¹ H NMR (CDCl ₃ ) δ: 7.53-6.73 (m, 16H); 4.58 (m, IH); 2.91 (da, 2H, J = 10.5 Hz); 2.61 (m, 2 H); 2.43 (m, 2 H); 2.33 (s, 3 H); 2.07 (ta, 2H, J = 11.5 Hz); 1.91 (m, 2 H); 1.75 (ta, 2H, J = 14Hz); 1.39 (m, 2 H); 0.94 (t, 3H, J = 7.5 Hz). MS (ES ⁺ ) m / z = 716 (100%) [M + H] ⁺ . Anal. (C ₃₉ H ₃₈ Cl ₃ N ₅ O ₂ -SH ₂ O)% theoretical (experimental%) C: 60.90 (60.46); H: 5.77 (5.93); N: 9.10 (9.11).

Example 10.- Preparation and obtaining 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -N- (4- ((4- (N- (l-phenethylpiperidin-4- yl) propionamido) cyclohexyl ) methyl) cyclohexyl) -4-methyl-IH- pyrazol-3-carboxamide

A) N- (4- (-Aminocyclohexyl) methyl) cyclohexyl) -N- (1- (2- phenethyl) piperidin-4-yl) propionamide.

The desired compound is prepared according to the embodiment described in steps A-F of Example 1 from 4,4'-methylenebis (cyclohexylamine).

B) 5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (4- ((4- (N- (1- phenethylpiperidin-4- il) propionamido) cyclohexyl) methyl) cyclohexyl) -4-methyl-IH-pyrazol-3-carboxamide.

The desired compound is prepared according to the embodiment described in step G of Example 1, from 49 mg of 5- (4-chlorophenyl) -4-methyl-1H-pyrazole-3-carboxylic acid and 70 mg of N -(4-(((-

Aminocyclohexyl) methyl) cyclohexyl) -N- (1- (2- phenethyl) piperidin-4-yl) propionamide. 50 mg of the desired compound are obtained. Rto. 52% white solid. ¹ H NMR (CDCl ₃ ) δ: 7.36-6.69 (m, 12H); 4.12 (m, IH); 3.84 (m, IH); 3.47 (m,

IH); 3.05 (m, 2H); 2.57 (m, 2 H); 2.53 (m, 2 H); 2.31 (s,

3H); 2.27 (m, 2 H); 2.02 (m, 2H); 1.86 (m, 2 H); 1.79-1.31

(m, 24H); 1.19 (m, 3 H). MS (ES ⁺ ) 816 (100%) [M + H] ⁺ .

Anal. (C ₄₆ H ₅₆ Cl ₃ N ₅ O ₂ )% theoretical (experimental%) C: 64.36 (64.25); H: 6.27 (6.15); N: 9.88 (9.80).

Example 11.- Preparation and obtaining 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -N- (5- (N- (1- (2-phenethyl) piperidin-4- yl) propionamido) pentyl) -4-methyl-lJϊ-pyrazol-3-carboxamide A) N- (5-Aminopentyl) -N- (1- (2-phenethyl) piperidin-4- yl) propionamide

The desired compound is prepared according to the embodiment described in steps A-F of Example 1 from 1,5-diaminopentane. B) 5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (5- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) pentyl) -4-methyl -lH- pyrazol-3-carboxamide

The desired compound is prepared according to the embodiment described in step G of Example 1, from 49 mg of 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-lH- acid pyrazol-3-carboxylic acid and 81 mg of N- (5- aminopentyl) -N- (1- (2-phenethyl) piperidin-4-yl) propionamide.

61 mg of desired compound are obtained. Rto. 73%, white solid. ¹ H NMR (CDCl ₃ ) δ: 7.40-6.92 (m, 12H); 5.80 (m, 0.4H); 4.55 (m, 0.3H); 3.83 (m, 0.6H); 3.70 (m, 0.7H); 3.44 (m, 2H); 3.10 (m, 2H); 2.74 (m, 2 H); 2.56 (m, 2 H); 2.35 (s,

3H); 2.30 (m, 2 H); 2.07 (m, 2H); 1.80 (m, 2 H); 1.65-1.30

(m, 8H), 1.12 (m, 3H). MS (ES ⁺ ) 710 (100%) [M + H] ⁺ .

ADaL (C ₄₆ H ₅₆ Cl ₃ N ₅ O ₂ )% theoretical (experimental%) C: 64.36 (64.25); H: 6.25 (6.15); N: 9.88 (9.80).

Example 12.- Tests of cannabinoid activity of the compounds of the invention

In the present invention, the cannabinoid activity of the compounds of general formula (A) was assessed by carrying out in vitro radioligand displacement assays in brain membranes (fraction P ₂ ) of human cortex.

First, the radioligand displacement [ ³ H] -CP55940, a CBi receptor agonist, was evaluated by the new derivatives described in the present invention. The values of the inhibition constants (K ₁ ) obtained from the joint analysis of different competition experiments for each compound were determined. The new derivatives showed a significant affinity for the CBi receptor. Derivatives of formula A wherein X represents a propyl group (Example 2), butyl (Example 3 of the present invention), hexyl (Example 4), heptyl

(Example 5), octyl (Example 6) and methyldicyclohexyl (Example 10) exhibited greater affinity with K ₁ values of 1925 + 705, 569 + 201, 2289 + 1857, 701 + 567, 3991 + 1366 and 2059 + 605 nM respectively. In these radioligand competition tests, the reference compound SR141716 showed an affinity for CBi cannabinoid receptors with a K ₁ value of 3.73 + 2.5 nM.

Cannabinoid receptors are part of the family of G protein-coupled receptors. Thus, the agonist, antagonist or inverse agonist efficacy of the new derivatives of the present invention can be studied by guanosine-5'-0- binding assays. (3- [ ³⁵ S] uncle) triphosphate) ([ ³⁵ S] GTPYS) in brain membranes

(fraction P ₂ ) of human cortex. The tests were performed following the methodology previously described by González et al. (Gonzalez-Maeso et al., Eur J Pharmacol., 2000, 390, 25-36), in aliquots of diluted membranes to a concentration of 0.1 mg of protein / ml, in a test buffer containing 0.5 nM [ ³⁵ S] GTPYS and the corresponding new compound (10 ^{~ 1: L} -10 ^{~ 3} M). Incubation began by adding the membrane suspension (40 μg) in a final volume of 550 μl. The test tubes were incubated for 120 minutes at 30 ° C with stirring. After that, the reaction was stopped by rapid dilution with 3 ml of buffer at 4 ° C. The separation between the radioligand bound to the membrane fraction and the free one was carried out by filtration. The radioactivity present in the filters was quantified by a liquid scintillation counter. Non-specific binding was determined in the presence of GTPγS at a concentration of 10 μM.

The compounds 5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (6- (N- (1- (2-phenethyl) piperidin-4-yl) propionamido) hexyl) -4-methyl -lH-pyrazol-3-carboxamide (Example 4) and 5- (4- chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (6- [N- (1- (2- phenethyl) piperidin-4 -il) propionamido) heptyl) -4-methyl-lH- pyrazol-3-carboxamide (Example 5) had a very pronounced inverse agonist effect in the [ ³⁵ S] GTPYS fixation assays in brain membranes (fraction P ₂ ) of human cortex (Figure 2). The compound of Example 4 showed an EC ₅₀ of 5.11 + 0.35 μM and the compound of Example 5 an EC ₅₀ of 0.26 + 0.03 μM. The potency and efficacy of the new compounds were evaluated by comparing with the inverse reference agonist SR141716. In the fixation tests of

[ ³⁵ S] GTPγS, reference compound SR141716 had an EC ₅₀ of 9.9 + 0.24 μM.

Example 13.- Opioid activity assays of the compounds of the invention In addition, in the present invention the opioid activity of the compounds of the general formula (A) was assessed by carrying out radioligand displacement assays [ ³ H] -DAMGO, a mu-opioid receptor agonist, In vitro in brain membranes (fraction P ₂ ) of human cortex. The values of the inhibition constants (K ₁ ) obtained from the joint analysis of different competition experiments for each compound of the invention were determined. The new compounds showed a moderate to good affinity for the mu-opioid receptor. The derivatives of formula A where

X represents a propyl group (Example 2), butyl (Example

3), pentyl (Example 11), hexyl (Example 4), heptyl

(Example 5), octyl (Example 6), nonyl (Example 7), dodecyl (Example 8), cyclohexyl (Example 10) exhibited an affinity with K ₁ values of 3809 + 392, 1287 + 428, 166 + 97 and 295 +59, 6543 + 947, 1243 + 789, 108 + 57, 6897 + 1580 and 661 + 371 nM, respectively. In these radioligand competition tests, the reference opioid compound Fentanyl showed an affinity for mu-opioid receptors with a K ₁ value of 2.9 ± 1.5 nM. Thus, the compounds of the present invention can be used for the treatment of pain and in particular for the treatment of chronic pain. In addition, the fact that the compounds of the present invention bind to both opioid and cannabinoid receptors extend their therapeutic applications to the treatment of opioid drug dependence.

Example 14.- Cannabinoid activity of the compounds of the invention in mice A set of four assays were performed in vivo in mice to analyze cannabinoid activity: rectal temperature, catalepsy, acute hot plate analgesia and spontaneous activity. After intraperitoneal administration at a dose up to 10 mg / kg of the compound of Example 5 (5 - (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (7- (N- (1- (2-Phenethyl) piperidin-4-yl) propionamido) heptyl) -4-methyl-l-pyrazol-3-carboxamide), no significant differences are observed with respect to the control, which rules out a possible intrinsic cannabinoid agonist activity in vivo. However, the compound of Example 5 (5 mg / kg) reverses the effects produced by the cannabinoid agonist WIN55212-2 (1.5 mg / kg) (Figure 3) so it can be affirmed that the compounds object of this patent are antagonists CBL cannabinoid in vivo. In vivo titration of the opioid activity of the compounds of the invention was carried out using the hot plate test at a temperature of 55 ° C in mice. The compound of Example 4 (10 mg / kg) and Example 5 (10 mg / kg) antagonize the antinociceptive effect of morphine (Figure 4). From these results it can be concluded that the compounds object of the present patent are opioid antagonists.

Therefore, the results obtained so far make it possible to affirm that the compounds of Example 4 and Example 5 have a dual cannabinoid and opioid action whose efficacy in vivo is a consequence of the synergy that develops when the opioid activity coincides in the same molecule and cannabinoid In vivo they behave as cannabinoid antagonists and opioid antagonists.

Example 15.- Studies on the intake in rats of the compounds of the invention

On the other hand, the anorexic effect (intake suppressant) of cannabinoid antagonists mediated by CBl receptors is known. The anorexigenic effect of the compounds object of the invention was evaluated by testing intake measures in male rats. Each of the compounds of Example 4 and Example 5 were injected intraperitoneally at different doses (0.10 mg / kg; 1 mg / kg and 10 mg / kg) to male rats previously deprived of food for 24 hours. The food intake was counted during the first 4 hours, observing that the compounds of Example 4 and Example 5 produce a decrease in food intake (Figure 5). Therefore, the compounds object of the present invention significantly reduce the intake of food in rats.

Claims

1.- Compound derived from pyrazole characterized by the general formula A:

Formula A

in which:

2. A compound according to claim 1 characterized in that it belongs to the following group:

5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (3- {N- (1- (2- phenethyl) piperidin-4-yl) propionamido) propyl) -4-methyl-lH - pyrazol-3-carboxamide,

5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -N- (4- {N- (1- (2- phenethyl) piperidin-4-yl) propionamido) butyl) -4-methyl-lH - pyrazol-3-carboxamide, - 5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (6- {N- (1- (2- phenethyl) piperidin-4-yl) propionamido) hexyl) -4-methyl-lH- pyrazol-3-carboxamide, 5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (7- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) heptyl) -4-methyl-lH - pyrazol-3-carboxamide,

5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (8- {N- (1- (2- phenethyl) piperidin-4-yl) propionamido) octyl) -4-methyl-lH - pyrazol-3-carboxamide,

5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (9- {N- (1- (2- phenethyl) piperidin-4-yl) propionamido) nonyl) -4-methyl-lH - pyrazol-3-carboxamide, - 5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (12- {N- (1- (2- phenethyl) piperidin-4-yl) propionamido) dodecyl) -4-methyl-lH- pyrazol-3-carboxamide,

5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (5- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) pentyl) -4-methyl-lH - pyrazol-3-carboxamide.

3. Pharmaceutical composition characterized in that it comprises a compound of formula (A) according to claim 1, together with, optionally, one or more pharmaceutically acceptable excipients.

4. Composition according to claim 3 characterized in that the compound of formula (A) is selected from

5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (3- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) propyl) -4-methyl-lH - pyrazol-3-carboxamide, 5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (4- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) butyl) -4-methyl-lH - pyrazol-3-carboxamide,

5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (6- {N- (1- (2- phenethyl) piperidin-4-yl) propionamido) hexyl) -4-methyl-lH - pyrazol-3-carboxamide,

5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (7- {N- (1- (2- phenethyl) piperidin-4-yl) propionamido) heptyl) -4-methyl-lH - pyrazol-3-carboxamide, - 5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (8- {N- (1- (2- phenethyl) piperidin-4-yl) propionamido) octyl) -4-methyl-lH- pyrazol-3-carboxamide,

5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (3- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) methyl benzyl) -4-methyl- lH-pyrazol-3-carboxamide, - 5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (4- ((4- (N- (1- phenethylpiperidin-4-yl) propionamido) cyclohexyl) methyl) cyclohexyl) -4-methyl-lH-pyrazol-3-carboxamide, and

5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (5- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) pentyl) -4-methyl-lH - pyrazol-3-carboxamide; and their mixtures.

5. Composition according to any of claims 3 and 4 characterized in that it further comprises one or more therapeutic agents.

6. Use of a compound of formula (A) in a method for the prevention and / or treatment of disorders or diseases in which cannabinoid receptors are involved and for the prevention and / or treatment of disorders or diseases in which they are involved opioid receptors.

7. - Use of a compound of formula (A) according to claim 6 characterized in that the disorder or disease is related to the CBi cannabinoid receptor.

8. Use of a compound of formula (A) according to claim 7 characterized in that the disorder or disease belongs to the following group: appetite suppression, reduction of dyskinesia caused by L-dopa in Parkinson's patients, treatment of acute schizophrenia, the treatment of cognitive and memory dysfunctions associated with the disease of

(cannabis, opiates or alcohol), to treat cerebral ischemia and head trauma.

9. Use of a compound of formula (A) according to claim 6 characterized in that the disorder or disease is related to the opioid receptor subtype mu.

10. Use of a compound of formula (A) according to claim 9 characterized in that the disorder or disease belongs to the following group: opioid drug dependence.

11. Use of a compound of formula (A) according to claims 6 to 10, characterized in that said compound of formula (A) is selected from:

5- (4-Chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (3- {N- (1- (2- phenethyl) piperidin-4-yl) propionamido) propyl) -4-methyl-lH - pyrazol-3-carboxamide, 5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (4- (N- (1- (2- phenethyl) piperidin-4-yl) propionamido) butyl) -4-methyl-lH - pyrazol-3-carboxamide,

12. Process for the preparation of the compound according to claims 1 and 2 characterized by the following steps: a) synthesis of 5- (4-chlorophenyl) -1- (2, 4- dichlorophenyl) -4-methyl-lH-pyrazol-3-carboxylic acid, b) treatment of a) carboxylic acid with thionyl chloride to give place to 5- (4- chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3- carboxylic acid chloride, c) preparation of the N- (1- (2-phenethyl) piperidin-4-yl) propionamides by reductive amination of 1- (2-phenethyl) -4-piperidone with one of the monoprotected starting diamines followed by an N-acylation to introduce the propionyl group and finally by a group deprotection protected amine, and d) reaction of the 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1 H -pyrazol-3-carboxylic acid chloride with an N- (1- (2-phenethyl) ) piperidin-4-yl) propionamide.