MXPA06004434A

MXPA06004434A - Novel medical uses of compounds showing cb1.

Info

Publication number: MXPA06004434A
Application number: MXPA06004434A
Authority: MX
Inventors: Chris Kruse
Original assignee: Solvay Pharm Gmbh
Priority date: 2003-10-24
Filing date: 2004-10-22
Publication date: 2006-06-20
Also published as: CA2543338A1; WO2005039550A3; EP1753413A2; AU2004283056A1; RU2006117627A; BRPI0415851A; JP2007513872A; WO2005039550A2

Abstract

The present invention relates to a novel medical use of compounds with CB1- -receptor activity selected from the group of 4,5-dihydro-1H-pyrazole derivatives, 1H-lmidazole derivatives, thiazole derivatives and/or 1H-1,2,4-triazole-3- -carboxamide derivatives, as each defined in the specification, or of a prodrug thereof, a tautomer thereof or a salt thereof, in the manufacture of medicaments for the treatment and/or prophylaxis of CB1, receptor related diseases in juvenile patients and/or for the treatment and/or prophylaxis of drug induced obesity in juvenile, as well as in adolescent, patients. Furthermore, the invention pertains to the use of said compounds with CB1-receptor activity in combination with lipase inhibitors. Said compounds are particularly suitable in combination with lipase inhibitors in the manufacture of medicaments for the treatment and/or prophylaxis of obesity in adolescent or in juvenile patients and/or for the treatment and/or prophylaxis of drug induced obesity in juvenile as well as in adolescent patients. Preferred lipase inhibitors are orlistat, panclicins, ATL-962 and/or lipstatin.

Description

NOVEL MEDICAL USES OF COMPOUNDS SHOWING CBTA ANTAGONISTIC ACTIVITY AND COMBINATION TREATMENT INVOLVING SUCH COMPOUNDS The present invention relates to new therapeutic and / or prophylactic uses of compounds exhibiting CBi antagonist activity and to pharmaceutical compositions containing one or more of these compounds as an active component for new uses. The compounds addressed by this invention show antagonistic activity in the Cannabis-1 receptor (CBi) and can provide exceptional utility for new medical uses provided by the present invention. In addition, according to one embodiment of the present invention, such compounds with CBi antagonist activity can be used in combination with another active ingredient and pharmaceutical compositions containing at least one of these CBi antagonist compounds in combination with said additional active ingredient for treatment and / or prophylaxis of obesity. The combination provided by the present invention of said compounds having antagonist activity in the Cannabis-1 receptor (CBi) with said additional active ingredient are of particular utility for the treatment of obesity. Cannabinoids are present in the Indian hemp Cannabis Sativa L. and have been used as medicines for centuries (Mechoulam R., Feigenbaum, J.J. Prog. Med. Chem. 1987, 24, 159). However, it has only been in the last ten years that research in the area of cannabinoids has revealed fundamental information about cannabinoid receptors and their (endogenous) agonists and antagonists. The discovery and subsequent cloning of two different subtypes of cannabinoid receptors (CBi and CB2) stimulated the search for new cannabinoid receptor antagonists (Munro, S., Thomas, KL, Abu-Shaar, M. Nature 1993, 365, 61 Matsuda, LA; Bonner, TI Cannabinoid Receptors, Pertwee, RG Ed. 1995, 117, Academic Press, London). In addition, the pharmaceutical companies were interested in the development of cannabinoid drugs for the treatment of diseases connected with disorders of the cannabinoid system. The wide distribution of CBi receptors in the brain, in combination with the strictly peripheral location of the CB2 receptor, makes the CBi receptor a very interesting molecular object for medical research directed to the central nervous system (CNS) in several medical indications for example psychiatric and neurological disorders described in the art as being of interest (Consroe, P. Neurobiology of Disease 1998, 5, 534 Pop, E. Curr Opin., In CPNS Investigational Drugs 1999, 1, 587. Greenberg, DA Drug News Perspect, 1999, 12, 458). From the application documents of the international patents WO 03/026647, WO 03/027076, WO 03/078413, WO 03/078413, and the recently filed international patent application document which is going to be published in March / April of 2004 and which is based on the European prior application of European patent document EP 02078966.5 with priority date 19.09.2002, compounds known to be useful for the treatment of diseases related to disorders of the cannabinoid system are known. Thus these compounds show activity in the CBX cannabis receptor showing for example antagonist activity to CBlr and have the formulas (I), (II), (III), (IV) or (V) as defined herein below. In particular, said compounds with activity in the cannabis CB1 receptor have been suggested for use in the treatment of psychiatric disorders such as psychosis, anxiety, depression, attention deficit, memory disorders, cognitive disorders, appetite disorders, obesity, addition. , appetite, drug dependency and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremors, epilepsy, multiple sclerosis, traumatic brain injury, cardiovascular accident, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral apoplexy, craniocerebral trauma, cardiovascular accident, spinal cord damage, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, disorders related to demillenization, as well as for the treatment of pain disorders, including neuropathic pain disorders, and other diseases involving cannabinoid neurotransmission, which includes the treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases , gastrointestinal disorders, gastric ulcers, diarrhea and cardiovascular disorders. International patent application WO 03/026647 describes a group of novel compounds which are 4,5-dihydro-1H-pyrazole derivatives and have the formula (I) defined later. These 4,5-dihydro-lH-pyrazole derivatives are potent antagonists of the cannabinoid receptor (CBi) with utility in the treatment of diseases connected with disorders of the cannabinoid system. The compounds have the general formula (I) wherein the symbols have the meaning given later in the description, and show in particular potent CBi antagonist activity. International patent application WO 03/027076 describes a group of novel compounds which are derivatives of lH-imidazole and have the formula (II) defined later. These γ-imidazole derivatives are potent agonists of the cannabinoid receptor (CBi), partial agonists or antagonists, useful in the treatment of psychiatric and neurological disorders, as well as other diseases involving cannabinoid neurotransmission. The compounds have the general formula (II) wherein the symbols have the meanings given later in the description. The international patent application document WO 03/026648 describes a group of new compounds that are also 4,5-dihydro-1H-pyrazole derivatives and have one of the formulas (III) defined later. These 4,5-dihydro-lH-pyrazole derivatives are again cannabinoid receptor (CBi) antagonists with utility in the treatment of diseases connected with disorders of the cannabinoid system. In particular, the compounds have the general formula (Illa) or (Illb) wherein the symbols have the meaning given later in the description. The international patent application document WO 03/078413 describes a group of new compounds which are thiazole derivatives and have the formula (IV) defined later. These thiazole derivatives are potent antagonists, agonists or partial agonists of the cannabinoid receptor CBi, with utility in the treatment of diseases connected with disorders of the cannabinoid system. The compounds have the general formula (IV) wherein the symbols have the meanings given later in the description. The recently filed international patent application document, which is going to be published in March / April 2004 and which is based on the priority of the European patent application document EP 02078966.5 with the priority date 19.09 2002, describes a group of new compounds which are derivatives of 1,5-diaryl-lH-l, 2,4-triazole-3-carboxamide and have the formula (V) defined later. These derivatives of 1,5-diaryl-lH-1,2,4-triazole-3-carboxamide are potent antagonists, agonists, inverse agonists or potent partial agonists of the cannabinoid receptor CBi, with utility in the treatment of diseases connected with disorders of the cannabinoid system. The compounds have the general formula (V) wherein the symbols have the meaning given later in the description. It is an object of the invention to provide improved methods for treatment and / or prophylaxis that are particularly suitable in groups of patients with greater need for safety and tolerability, for example in the treatment of patients with obesity, in particular such as young patients with obesity subjected to long treatments, for example with drug-induced obesity in young or adolescent patients. An additional objective is to provide combination treatments of particular benefit and drugs therefore for the treatment and / or prophylaxis of obesity in patients of any age, for example in adolescents as well as in young patients, wherein the compounds with antagonistic activity to the CBi used according to the present invention are combined with an additional active ingredient in the treatment of obesity. It has now surprisingly been found that due to the unique unique pharmacological profile of selective CBi antagonist compounds which includes particularly tolerability and high safety the compounds are particularly suitable for the treatment and / or prophylaxis of diseases connected with disorders of the cannabinoid system, in particular in groups of patients with greater need for safety and tolerability, in particular such as young patients and / or patients subject to long treatments, for example in drug-induced obesity. Therefore, the invention relates to a combination of a compound with activity at the CBi receptor, having one of the formulas (I), (II), (III), (IV) or (V) as defined later , or a prodrug, tautomer or salt thereof, preferably of a CBi receptor antagonist compound or a prodrug, tautomer or salt thereof, with at least one lipase inhibitor compound. In a variant of the invention, the compound with activity in the CBi receptor having one of the formulas (I), (II), (III), (IV) or (V) as defined later, or a prodrug, tautomer or salt thereof preferably the CBi receptor antagonist compound or a prodrug, tautomer or salt thereof, is in combination with at least one lipase inhibitor compound selected from the group of polymers inhibitors of lipase, orlistat, panclicins, ATL-962 and lipstatin. In particular, it has surprisingly been found that the CBi antagonists of the formulas (I), (II), (III), (IV) and / or (V), prodrugs, tautomers and salts thereof show a unique pharmacological profile and therefore are particularly suitable for use in the production of medicaments for the treatment and / or prophylaxis of obese patients, in particular of obesity in young patients and / or drug-induced obesity in particular in young patients as well as adolescent patients. In this regard, the CBi antagonist compounds of the formulas (I), (II), (III), (IV) and / or (V), prodrugs, tautomers and salts thereof, are very valuable in providing medicaments for use pediatric on the one hand, and for general use in drug-induced obesity. Due to its activity in the cannabis receptor CBi the compounds used according to the invention are also suitable for use in pediatric treatment and / or prophylaxis of other disorders other than juvenile obesity and drug-induced obesity in young patients. The other disorders include those known from the literature for the compounds concerned with activity in the cannabis receptor CBi, and for example the treatment and / or pediatric prophylaxis may also refer to psychiatric disorders such as psychosis, anxiety, depression, attention deficit, memory disorders, cognitive disorders, obesity, disorders, addiction, appetite, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremors, epilepsy, multiple sclerosis, traumatic brain injury, cardiovascular accident, Parkinson's disease , Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral apoplexy, cranioencephalic trauma, cardiovascular accident, spinal cord damage, neuroinflammatory alterations, plaque sclerosis, viral encephalitis, disorders related to demyelination, as well as for the pediatric treatment of pain disorders, including neuropathic pain disorders, and other diseases involving cannabinoid neurotransmission, which includes the pediatric treatment of septic shock , glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases, gastrointestinal disorders, gastric ulcers, diarrhea and cardiovascular disorders, in young patients. All the content of the literature mentioned in the description of the present invention is incorporated by reference in the present application. The CBi antagonist compounds used in the present invention can be obtained according to known methods. Suitable routes of synthesis for the compounds used in accordance with the present invention are described in the art for example in the documents cited in the present application, and incorporated for reference. In addition, it has surprisingly been found that the CBi antagonist compounds (CBi antagonists), of the formulas (I), (II), (III), (IV) and / or (V), as well as prodrugs, tautomers and salts of them, due to their unique pharmacological profile, are particularly suitable in combination with at least one lipase inhibitor compound (lipase inhibitor) for use in the manufacture of a medicament for the treatment and / or prophylaxis of obesity, which includes in particular the treatment and / or prophylaxis of obesity in young patients and / or drug-induced obesity in young patients as well as in adolescent patients. ? in this respect combinations of at least one CBi antagonist compound as defined herein with at least one lipase inhibitor compound are very valuable in providing medicaments for the treatment and / or prophylaxis of obesity in general, for example in adolescent patients of any age , and particularly also in pediatric or juvenile obesity, and also in drug-induced obesity in adolescent patients and young patients. In particular the present invention is based on the surprising fact that the CBi antagonist compounds of the formulas (I) which are derivatives of 5-dihydro-1H-pyrazole, (II) which are lH-imidazole derivatives, (III) ) which are also derivatives of 4,5-dihydro-1H-pyrazole, (IV) which are thiazole derivatives or (V) which are derivatives of 1H-1,2,4-triazole-3-carboxamide, which are antagonists of the cannabis receptor CBi, prodrugs thereof, tautomers thereof and salts thereof, due to their unique pharmacological profile are particularly suitable in combination with at least one lipase inhibitor compound for use in the production of a medicament for the treatment or prophylaxis of obesity in general, for example of obesity in adolescent patients of any age, and particularly also for the treatment and / or prophylaxis of obesity in young patients and / or drug-induced obesity in young patients as in paci adolescent entities. In this regard each of the combinations of the compounds with the formulas (I), (II), (III), (IV) or (V), together with the lipase inhibitor compounds are highly valuable to provide medicaments for the treatment and / or prophylaxis of obesity in general, for example obesity in adolescent patients of any age, and particularly also in pediatric or juvenile obesity, and in drug-induced obesity. The compounds of formulas (I), (II), (III), (IV) or (V) used in the present invention can be obtained according to known methods. A suitable synthesis for the compounds of formulas (I), (II), (III), (IV) used in accordance with the present invention is described in international patent applications WO 03/026647, WO 03/027076, WO 03 / 078413 or WO 03/078413, which are incorporated for reference in this application. The compounds of formula (V) can be prepared according to a recently filed international patent application document, which is going to be published in March / April 2004 and is based on the priority application of European patent document EP 02078966.5 dated of priority 19.09.2002, which is also incorporated by reference in the present application. The preparation of the compounds of formula (V) is also described at the end of this document. In the following the embodiments of the invention are described in more detail with reference to the compounds with the formulas (I), (II), (III), (IV) or (V) and are used in particular in the context of obesity.

Compounds of formula (I) In a first embodiment the present invention is based on the surprising discovery that the 4,5-dihydro-1H-pyrazole derivatives of the formula (I) which are potent and selective antagonists of the CBi cannabis receptor, prodrugs, tautomers and salts thereof: wherein R and Ri independently represent phenyl, thienyl or pyridyl whose groups may be substituted with 1, 2, 3 or 4 substituents and, which may be the same or different, from the alkyl or alkoxy group. -3, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono or dialkyl (Ci_2) amino, mono or dialkyl (C1-2) amido, alkyl (Ci-3) sulfonyl, dimethylsulfamido, alkoxy Ci_3 carbonyl, carboxyl , trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R and / or Ri represents naphthyl, -R2 represents hydrogen, hydroxy, Ci_3 alkoxy, acetyloxy or propionyloxy, -R3 represents a hydrogen atom or a linear C1-8 alkyl group or branched or a gru C3_7 cycloalkyl group whose alkyl or cycloalkyl group may be substituted with a hydroxy group, -R4 represents a linear or branched C2-10 heteroalkyl group, a non-aromatic group C3-heterocycloalkyl or a non-aromatic heterocycloalkyl group C4_i0-alkyl whose groups contain one or more heteroatoms of the group (0, N, S) or a group - S02-, whose linear or branched C2-10 heteroalkyl groups, non-aromatic group C3-8 heterocycloalkyl or non-aromatic group heterocycloalkyl C4-i0-alkyl, may be substituted with a keto group, trifluoromethyl, C1-3 alkyl, hydroxy, amino, monoalkylamino, or dialkylamino or a fluoro atom, or R4 represents an amino, hydroxy, phenoxy or benzyloxy group, or R4 represents an alkoxy Ci-e, C3-alkenyl 8, C5-C8 cycloalkenyl or cycloalkenylalkyl C6-g whose groups may contain a sulfur, nitrogen or oxygen atom, a keto group or a -SO2- group, whose alkoxy, alkenyl and cycloalkenyl groups may be substituted with a hydroxy group, a g trifluoromethyl, an amino group, a monoalkylamino group or a dialkylamino group, or a fluoro atom, or R 4 represents a C 2-5 alkyl group whose alkyl group contains a fluoro atom, or R 4 represents an imidazolylalkyl, benzyl, pyridylmethyl group, phenethyl or thienyl, or R4 represents a phenyl, benzyl, pyridyl, thienyl, pyridylmethyl or phenethyl substituted wherein the aromatic rings are substituted with 1, 2 or 3 of the substituents Y, wherein Y has the meaning indicated above, or when R3 is H or methyl, R4 may represent a group NR6R7 where RQ and R7 are the same or different and represent C2-4 alkyl, C2-4 trifluoroalkyl or R6 represents a methyl group with the proviso that R7 represents a C2- alkyl group, or R6 and R7 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic moiety having from 4 to 8 ring atoms whose heterocyclic moiety may contain an oxygen or sulfur atom or a keto group or a -S02- group or an additional nitrogen atom, whose saturated or unsaturated heterocyclic moiety may be substituted with a Ci_4 alkyl group, or - R3 and R together with the nitrogen atom to which they are attached form a saturated or unsaturated, monocyclic or bicyclic heterocyclic moiety having from 4 to 10 ring atoms, the heterocyclic portion of which may contain one or more atoms of the group (0, N , S) or a keto group or an -SO2 group, the moiety of which may be substituted with a Ci_4 alkyl, hydroxyalkyl, phenyl, thienyl, pyridyl, amino, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylamino, dialkyl group lamino, aminoalkyl, azetidinyl, pyrrolidinyl, piperidinyl or hexahydro-1H-azepinyl, -R 5 represents benzyl, phenyl, thienyl or pyridyl which can be substituted with 1, 2, 3 or 4 substituents Y wherein Y has the meaning indicated above, which they may be the same or different, or R 5 represents linear or branched C 1-8 alkyl, C 3-8 alkenyl, C 3-10 cycloalkyl, C 5-10 bicycloalkyl, tricycloalkyl e-10 or C 5-8 cycloalkenyl or R 5 represents naphthyl. Due to their unique pharmacological profile they are particularly suitable in combination with at least one lipase inhibitor compound for use in manufacturing. of a medicament for the treatment and / or prophylaxis of obesity in general, for example of obesity in adolescent patients of any age, and particularly also for the treatment and / or prophylaxis of obesity in young patients of any age, and particularly also for the treatment and / or prophylaxis of obesity in young patients and / or drug-induced obesity in young patients as well as adolescent patients. In this connection combinations of the compounds of formula (I) together with the lipase inhibitor compounds are highly valued to provide medicaments for the treatment and / or prophylaxis of obesity in general, for example of obesity in adolescent patients of any age, and particularly also in pediatric or juvenile obesity, and in drug-induced obesity. At least one center of chirality (at the C4 position of the 4,5-dihydro-1H-pyrazole portion) is present in the compounds of formula (I). The invention relates to racemates, mixtures of diastereomers and to the individual stereoisomers of the compounds of formula (I). Particular compounds of interest of formula (I) have absolute stereoconfiguration at the C4 position of the 4,5-dihydro-1H-pyrazole portion as represented by formula (Ia).

The invention also relates to the E-isomer, Z-isomer and E / Z mixture of the compounds having the formula (I).

Compounds of formula (II) In a second embodiment, the present invention is based on the surprising discovery that the IH-imidazole derivatives of formula (II) with CBi antagonist activity, prodrugs thereof and salts thereof, which are antagonists potent of cannabinoid CBi receptors R R wherein R represents phenyl, thienyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, whose groups may be substituted with 1, 2, 3 or 4 substituents Y, which may be the same or different, from the group alkyl or C1-3 alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono or dialkyl (Ci_2) amino, mono or dialkyl (Ci_2) amido, alkoxy (Ci_3) carbonyl, carboxyl, cyano, carbamoyl and acetyl, or R represents naphthyl, with the proviso that when R is 4-pyridinyl, R4 represents a halogen atom or a cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methanesulfonyl, methylsulphanyl or linear or branched Ci_4 alkyl group, whose C1-4 alkyl group may be substituted with 1-3 fluoro atoms or with a bromo, chloro, iodo, cyano or hydroxy group. Ri represents phenyl or pyrimidyl, which groups may be substituted with 1-4 Y substituents, which may be the same or different, wherein Y has the meaning mentioned above, or Ri represents pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, whose groups may be substituted with 1-2 substituents Y, which may be the same or different or Ri represents a five-membered aromatic heterocyclic ring having one or two heteroatoms of the group (N, 0, S), whose heteroatoms may be the same or different, whose ring Five-membered aromatic heterocyclic may be substituted with 1-2 substituents Y, which may be the same or different or Ri represents naphthyl, -R 2 represents H, straight or branched alkyl Ci-s, C 3-8 cycloalkyl, C 3 alkenyl, C 5- cycloalkenyl 8 whose groups may contain a sulfur, oxygen or nitrogen atom, - R3 represents straight or branched C2-8 alkyl, C] _8 alkoxy, C5-8 cycloalkyloxy, C3_8 cycloalkyl, C5_10 bicycloalkyl, t alkylcycloalkyl Ce-C3-3 alkenyl, C5-8 cycloalkenyl, whose groups may optionally contain one or more heteroatoms of the group (0, N, S) and whose groups may be substituted with a hydroxy group or 1-2 C1_3 alkyl groups or 1-3 fluoro atoms, or R3 represents a benzyl or phenethyl group whose aromatic rings may be substituted with 1-5 substituents Z, which may be the same or different, from the group alkyl or C1_3 alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio , trifluoromethoxy, nitro, amino, mono- or dialkyl (Ci_2) amino, mono- or dialkyl (C1-2) amido, alkyl (Ci_3) sulfonyl, dimethylsulfamido, C1_3 alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R3 represents a phenyl or pyridinyl group, whose groups are substituted with 1-4 Z substituents, wherein Z has the meaning indicated above, or R3 represents a pyridinyl group, or R3 represents a phenyl group, with the condition that R represents an ato halogen or a cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methanesulfonyl, methylsulfa il or the Ci_4 alkyl group, whose alkyl group CJL-4 may be substituted with 1-3 fluoro atoms or with a group of bromine, chlorine, iodine, cyano or hydroxy, or R3 represents a group NR5R6 with the proviso that R2 represents a hydrogen atom or a methyl group in which -R5 and R6 are the same or different and represent linear C1-4 alkyl or branched, or R5 and R6 together with the nitrogen atom to which they are attached form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having from 4 to 10 ring atoms whose heterocyclic group contains one or two heteroatoms of the group (N, 0, S), whose heteroatoms may be the same or different, the heterocyclic group of which may be substituted with a Ci_3 alkyl group or a hydroxy group, or R2 and R3, together with the nitrogen atom to which they are attached, form a saturated heterocyclic group or unsaturated having 4 to 10 ring atoms whose heterocyclic group contains one or two heteroatoms of the group (N, 0, S), whose heteroatoms may be the same or different, the heterocyclic group of which may be substituted with an alkyl group Ci_3 or a hydroxy group, - R represents a hydrogen or halogen atom or a cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methanesulfonyl, methylsulphanyl group or a linear or branched Ci_4 alkyl group, whose C1-4 alkyl group can be substituted with 1-3 fluorine atoms or with a bromine, chlorine, iodine, cyano or hydroxy group, because of their unique pharmacological profile they are particularly suitable in combination with at least one this lipase inhibitor for use in the manufacture of a medicament for the treatment and / or prophylaxis of obesity in general, for example of obesity in adolescent patients of any age and particularly also for the treatment or prophylaxis of obesity in young patients and / or drug-induced obesity in young patients as well as in adolescent patients. ? In this respect combinations of the compounds of formula (II) together with lipase inhibitor compounds are highly valuable to provide medicaments for the treatment and / or prophylaxis of obesity in general, for example of obesity in adolescent patients of any age, and particularly also of the pediatric or juvenile obesity, and of the obesity induced by drugs. Compounds of formula (III) In a third embodiment, the present invention is based on the surprising fact that a potent and selective antagonism to cannabinoid-CBi receptors is present in the 4,5-dihydro-1H-pyrazole derivatives of the formula ( Illa) or (Illb), prodrugs, tautomers and salts thereof.

(Illa) (illb) wherein R and Ri independently represent phenyl, thienyl or pyridyl whose groups may be substituted with 1, 2 or 3 Y substituents, which may be the same or different, from the group alkyl or C1-3 alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or diakyl (Ci_2) amino, mono- or dialkyl (Ci_2) amido, alkyl (Ci-3) sulfonyl, dimethylsulfamido, C1-3 alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R and / or Ri represents naphthyl, R 2 represents hydrogen, hydroxy, C 1-3 alkoxy, acetyloxy or propionyloxy, R 3 represents a hydrogen atom or a linear or branched C 1-6 alkyl group or a cycloalkyl group C3_7 whose alkyl or cycloalkyl group can be substituted with a hydroxy group, R4 represents a hydrogen atom or a linear or branched Ci_8 alkyl portion, C3-8 cycloalkyl, heteroalkyl C2-ior non-aromatic C3-.8 heterocyclealkyl or C4-10 heterocycloalkyl - alkyl not to which portions may contain one or more heteroatoms of the group (0, N, S), the portions of which may be substituted with a keto group, trifluoromethyl group, CX-3 alkyl / hydroxy, amino, monoalkylamino, or dialkylamino or a fluoro atom or R4 represents an amino, hydroxy, phenoxy or benzyloxy group or R4 represents a linear or branched Ci-g alkoxy group C3_8 alkenyl, C5_8 cycloalkenyl or C6_9 cycloalkenylalkyl, whose groups may contain a sulfur, nitrogen or oxygen atom, a group keto or -S02- whose Ci_8 alkoxy, C3_8 alkenyl, C5_8 cycloalkenyl, or cycloalkenylalkyl C6_g groups may be substituted with a hydroxy, trifluoromethyl, amino, monoalkylamino or dialkylamino group or a fluoro atom, or R4 represents a phenyl, benzyl or pyridyl group , thienyl, pyridylmethyl or phenethyl wherein the aromatic rings may be substituted with 1, 2 or 3 of the substituents Y, wherein Y has the meaning as indicated above, or R4 represents a NR8R9 group with the proviso that R3 represents a hydrogen atom or a methyl group and wherein R8 and R9 are the same or different and represent C1-4 alkyl, or C2- trifluoroalkyl, or R8 and Rg, together with the nitrogen atom to which they are attached, they form a saturated or unsaturated heterocyclic moiety having from 4 to 8 ring atoms whose heterocyclic moiety may contain an oxygen or sulfur atom or a keto group or a -SO2- group or an additional nitrogen atom whose saturated or unsaturated heterocyclic moiety may be substituted with a Ci_4 alkyl group or ¾ and ¾ together with the nitrogen atom to which they are attached form a monocyclic or bicyclic saturated or unsaturated heterocyclic moiety having from 4 to 10 ring atoms, whose moiety heterocyclic may contain one or more atoms of the group (0, N, S) or a keto group or a -S02- group, the portion of which may be substituted with a Ci_4 alkyl, hydroxialguil, phenyl, thienyl, pyro group idyl, amino, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylamino, dialkylamino, aminoalkyl, azetidinyl, pyrrolidinyl, piperidinyl or hexahydro-1H-azepinyl, R5 and Re independently of each other represent a hydrogen atom or a straight or branched Ci_8 alkyl or alkenyl group whose groups they may contain one or more heteroatoms of the group (0, N, S), a keto group or a -SC½- group and whose groups may be substituted with a hydroxy or amino group, or R5 and R6 independently of one another represent a cycloalkyl group C3-ao C3_8 cycloalkenyl which may contain one or more heteroatoms in the ring of the group (0, N, S) or the group -SO2- and whose groups may be substituted with a hydroxy group, alkyl (Ci_3), the group -SO2 - the keto amino monoalkyl (Ci_3) amino or dialkyl (1-3C) amino group, or R5 represents a naphthyl group or a phenyl group whose phenyl group can be substituted with 1, 2 or 3 Y substituents where Y has the meaning described anterio with the proviso that R6 represents a hydrogen atom, or a straight or branched alkyl group (C1-.5) whose alkyl group may contain one or more heteroatoms of the group (0, N, S) or the group -SO2- and whose alkyl group may be substituted with a hydroxy group, keto or amino, or Rs and R6A together with the nitrogen atom to which they are attached, form a monocyclic, bicyclic or tricyclic alkyl or alkenyl group or the alkenyl group which may contain heteroatoms in the ring of the group (O, N, S) , keto or S02 and whose monocyclic, bicyclic, tricyclic alkyl or alkenyl group can be substituted with a hydroxy group, (1-3C) alkyl, S02, keto, amino, mono (C3) amino, dialkyl (Ci_3) amino, pyrrolidinyl or piperidinyl, which monocyclic, bicyclic or tricyclic alkyl or alkenyl group can contain a phenyl group in the ring whose phenyl ring group can be substituted with 1 or 2 Y substituents, wherein Y has the meaning as described above, R7 represents alkyl Ci_3, linear or branched, due to its Unique pharmacological profile are particularly suitable in combination with at least one lipase inhibitor compound for use in the manufacture of a medicament for the treatment and / or prophylaxis of obesity in general, for example of obesity in adolescent patients of any age, and particularly also for the treatment and / or prophylaxis of obesity in young patients and / or drug-induced obesity in young patients as well as adolescent patients. In this regard combinations of the compounds of formula (Illa) and / or (Illb) together with the lipase inhibitor compounds are highly valued to provide medicaments for the treatment and / or prophylaxis of obesity in general, for example of obesity in adolescent patients of any age, and particularly also in pediatric or juvenile obesity, and in drug-induced obesity. At least one center of chirality (at the C4 position of the 4, 5-dihydro-1H-pyrazole portion) is present in the compounds of formula (Illa) and (Illb). The invention relates to racemates, mixtures of diastereomers and to the individual stereoisomers of the compounds having the formula (Illa) or (Illb). The particular compounds of interest of formula (Illa) or (Illb) have the absolute stereoconfiguration at the C position of the 4,5-dihydro-1H-pyrazole portion as represented in the formulas (Illa *) and (Illb *): (Illa *) (Illb *) The invention also relates to the E-isomer, the Z-isomer and the E / Z mixtures of the compounds having the formula (Illa) or (Illb).

Compounds of formula (IV) In a fourth embodiment, the present invention is based on the surprising discovery that 4,5-diarylthiazole derivatives with CBi antagonist activity of formula (IV), prodrugs thereof and salts thereof wherein R represents a hydrogen atom or a substituent X of the alkyl or linear or branched C1-3 alkoxy group, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C1-2) amino, mono - or dialkyl (Ci- 2) amido, linear or branched alkoxy (C ^) carbonyl, trifluoromethylsulfonyl, sulfamoyl, linear or branched alkyl (C1-3) alkylsulfonyl, carboxyl, cyano, carbamoyl, dialkyl (Ci_) 3) linear or branched aminosulfonyl, aminosulfonyl, straight or branched monoalkyl (Ci_3) aminosulfonyl and acetyl, Ri is a hydrogen atom or represents 1-4 substituents X, where X has the meaning mentioned above, R2 represents a phenyl group, thienyl, pyridyl or pyrimidinyl, which groups can be substituted with 1-4 substituents X, wherein X has the above-mentioned meaning or R 2 represents a naphthyl, R 3 represents a hydrogen atom or a linear or branched alkyl or cycloalkyl Ci-1 group or a phenyl, benzyl or phenethyl group whose aromatic rings may be substituted with 1-5 substituents Z, which may be the same or different, from the linear or branched alkyl or alkoxy group, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (Ci_2) amino, linear or branched mono- or dialkyl (Ca-2) amide alkyl (C1-3) alkylsulfonyl, dimethylsulfamido, linear or branched (C1-3) alkoxycarbonyl, ca rboxi, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R3 represents a pyridyl or thienyl group, R4 represents a linear or branched alkyl or cycloalkyl-alkyl group, a linear or branched Ci_i0 alkoxy, C3-8 cycloalkyl, bicycloalkyl C5-10, linear or branched C6-10 alkenyl C6-alkenyl tricycloalkyl, C5-8 cycloalkenyl, whose groups may contain one or more heteroatoms of the group (O, N, S) and whose groups may be substituted with a hydroxy group, -3 methyl groups, an ethyl group or 1-3 fluoro atoms, or R4 represents a phenyl, benzyl or phenethyl group whose aromatic rings can be substituted with 1-5 substituents Z, wherein Z has the meaning mentioned above, or R4 represents a pyridyl or thienyl group, or R4 represents a group R5R6 wherein ¾ Y 6r together with the nitrogen atom to which they are attached, form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having from 4 to 10 ring atoms whose group or heterocyclic contains one or more heteroatoms of the group (0, N, S) and whose heterocyclic group can be substituted with a linear or branched Ci_3 alkyl group, hydroxy or trifluoromethyl or a fluoro atom or R3 and R4, together with the nitrogen to which they are attached, form a monocyclic or bicyclic saturated or unsaturated heterocyclic portion having from 4 to 10 ring atoms, whose heterocyclic group contains one or more heteroatoms of the group (0, N, S) and whose heterocyclic group may be substituted with a C 1 -C 3 alkyl group, linear or branched, hydroxy or trifluoromethyl or a fluorine atom, due to its unique pharmacological profile are particularly suitable in combination with at least one lipase inhibitor compound for use in the manufacture of a medicament for the treatment and / or prophylaxis of obesity in general, for example of obesity in adolescent patients of any age, and particularly also for the treatment and / or prophylaxis xis of obesity in young patients and / or drug-induced obesity in young patients as well as adolescent patients. In this regard the combinations of the compounds of formula (IV) together with the lipase inhibitor compounds are highly valued to provide medicaments for the treatment and / or prophylaxis of obesity in general, for example of obesity in adolescent patients of any age , and particularly also in pediatric or juvenile obesity, and in drug-induced obesity.

Compounds of formula (V) In a fifth embodiment the present invention is based on the surprising fact that the 1,5-diaryl-lH-1,2,4-triazole-3-carboxamide derivatives of formula (V) with activity CBi antagonist, as well as the prodrugs, salts, and stereoisomers thereof, are potent antagonists, potent agonists, potent inverse agonists or potent partial agonists of the cannabinoid CBi receptor: (V) wherein R and Ri independently represent a phenyl naphthyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl triazinyl group, which groups may be substituted with 1-substituents X, which may be the same or different from the alkyl or alkoxy groups ( Ci_3) linear or branched, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C 1.-2) amino, mono- or dialkyl (Ci_2) amido, (C1-3) alkoxycarbonyl , trifluoromethylsulfonyl, sulfamoyl, (1-3C) alkylsulfonyl, carboxyl, cyano, carbamoyl, dialkyl (1-3C) aminosulfonyl, monoalkyl (Ci_3) aminosulfonyl and acetyl, R2 represents a hydrogen atom or a Ci_8 alkyl or cycloalkyl Ci_8- group linear or branched alkyl or a phenyl, benzyl or phenethyl group whose aromatic rings may be substituted with 1-4 substituents X, wherein X has the meaning indicated above, or R 2 represents a pyridyl or thienyl group, R 3 represents alkyl Ci- s linear or branched, Ci_8 alkoxy, C3_8 cycloalkyl, C5-10 bicycloalkyl, C6_io tricycloalkyl, C3-8 alkenyl, C5_8 cycloalkenyl, whose groups may optionally contain one or more heteroatoms of the group (O, N, S), groups may be substituted with a hydroxy group, an ethynyl group or 1-3 fluoro atoms, or R3 represents a phenyl, benzyl or phenethyl group whose aromatic rings may be substituted with 1-4 substituents X, wherein X has the meaning that as indicated above, or R3 represents a pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl or thienyl group whose heteroaromatic rings may be substituted with 1-2 substituents X, wherein X has the meaning indicated above, or R3 represents a group NR4R5 wherein R4 and together with the nitrogen atom to which they are attached form a saturated or unsaturated, monocyclic or bicyclic heterocyclic moiety having from 4 to 10 ring atoms, the heterocyclic group of which contains one or two hetero atoms of the group N, 0 or S, whose heteroatoms may be the same or different, the heterocyclic portion of which may be substituted with a linear or branched alkyl group, hydroxy or trifluoromethyl or a fluoro atom, or R2 and R3 together with the The nitrogen atom to which they are attached form a saturated or unsaturated, monocyclic or bicyclic heterocyclic moiety having 4 to 10 ring atoms, the heterocyclic group of which contains one or two heteroatoms of the group N, 0 or S, the heteroatoms of which may be same or different, the heterocyclic portion of which may be substituted with a linear or branched Ci_3 alkyl group, hydroxy, piperidinyl or trifluoromethyl or a fluoro atom, due to its unique pharmacological profile are particularly suitable in combination with at least one lipase inhibitor compound for use in the manufacture of a medicament for the treatment and / or prophylaxis of obesity in general, for example of obesity in adolescent patients is of any age, and particularly also for the treatment and / or prophylaxis of obesity in young patients and / or drug-induced obesity in young patients as well as adolescent patients. In this regard the combinations of the compounds of formula (V) together with the lipase inhibitor compounds are highly valued to provide medicaments for the treatment and / or prophylaxis of obesity in general, for example of obesity in adolescent patients of any age , and particularly also in pediatric or juvenile obesity, and in drug-induced obesity. The embodiments of the invention are described in more detail below with reference to the medical and pharmaceutical usefulness of the compounds of formula (I), (II), (III), (IV) or (V).

Medical and pharmaceutical utility Due to its beneficial activity on the CBi cannabis receptor the compounds of formula (I), (II), (III), [IV) and / or (V) used according to the invention are also suitable for general use in the pediatric treatment and / or prophylaxis of other disorders in addition to juvenile obesity and drug-induced obesity in young patients. The other disorders include those known from the literature for the compounds concerned with activity in the cannabis receptor CBi, and for example pediatric treatment and / or prophylaxis may also refer to psychiatric disorders such as psychosis, anxiety, depression, attention deficit , memory disorders, cognitive disorders, appetite disorders, obesity, addiction, appetite, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremors, epilepsy, multiple sclerosis, traumatic brain injury, cardiovascular accident, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral apoplexy, craniocerebral trauma, cardiovascular acider, spinal cord damage, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, disorders related to desmieli as well as for the pediatric treatment of pain disorders, including neuropathic pain disorders and other diseases involving cannabinoid neurotransmission including pediatric treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases, disorders gastrointestinal, gastric ulcers, diarrhea and cardiovascular disorders, in young patients. The affinity of the compounds of formula (I), (II), (III), (IV) or (V) for the cannabinoid receptors CBi can be determined as described in the international patent documents WO 03/026647, O 03 / 027076, WO 03/02648 or WO 03/078413, for example, can be determined using cells from Chinese hamster ovary (CHO) membrane preparations to which the human cannabis receptor CBi is transfected stably together with [3H] CP -55.940 as radioligand. After incubation of a fresh prepared preparation of membrane cells with the ligand [3H], with or without the addition of the compounds of the invention, separation of the free ligand was carried out and joined by filtration on glass fiber filters. The radioactivity of the filter was measured by liquid scintillation counting. The CBX cannabinoid antagonist activity of the compounds of formula (I), (II), (III), (IV) or (V) is also described in international patent documents WO 03/026647, WO 03/027076, WO 03/026648 or WO 03/078413, and was determined in functionality studies using CHO cells in which human cannabinoid CBi receptors have been stably expressed. The adenylyl cyclase was stimulated using forskolin and measured by quantifying the amount of accumulated cyclic AMP. Concomitant activation of CBi receptors by CBi receptor agonists (eg CP-55.940 or (R) -WIN-55.212-2) can attenuate the accumulation of cyclic AMP induced by forskolin in a concentration-dependent manner. This response mediated by the CBi receptor can be antagonized by the CBi receptor antagonists such as the compounds used in the present invention.

The activity of cannabinoid CBi antagonist, agonist or partially agonist of the compounds for example of formula (V) of the invention can also be determined by studies of functionality using the human CBi receptor cloned in Chinese hamster ovary (CHO) cells according to The following protocol. The CHO cells were cultured in a DMEM culture medium supplemented with 10% fetal calf serum inactivated by heat. The medium was aspirated and replaced with DMEM, without fetal calf serum, but containing [3H] -arachidonic acid and incubated overnight in a cell culture chamber (5% C02 / 95% air).; 37 ° C; atmosphere saturated with water). During this period, [3H] -arachidonic acid was incorporated into the phospholipids of the membranes. On the day of the test, the medium was aspirated and the cells were washed three times using 0.5 ml of phosphate buffered saline, containing 0.2% bovine serum albumin. The stimulation of the receptor with WIN 55.212-2 caused the activation of PLA2 followed by the release of [3H] -arachidonic acid in the medium. This release induced by WIN 55,212-2 was antagonized by the CBi receptor antagonists in a concentration dependent manner. The agonist or partially agonist activity to the cannabinoid receptor of the compounds of the invention can be determined according to published methods, such as the evaluation of cannabimimetic effects in vivo (Wiley, J.

L. Jefferson et al., J. Pharmacol. Exp. Ther. 2001, 296, 1013). Antagonists of the cannabinoid receptor can behave as inverse agonists (Landsman, R. S. et al., Eur. J. Pharmacol. 1997, 334, R1-R2). The entire contents of international patent applications O 03/026647, WO 03/027076, WO 03/026648 and WO 03/078413 are incorporated by reference in the present application in relation to the description of CBi antagonist compounds of formula (I ), (II), (III), (IV) or (V) used according to the present invention in combination with lipase inhibitors. The unique and outstanding pharmacological profile of the compounds with CBi antagonist activity of formula (I), (II), (III), (IV) or (V) which are antagonists of the cannabis receptor CBi, as well as the prodrugs, tautomers and salts thereof include a particularly high safety and tolerability also in combination with other drugs, particularly in combination with the lipase inhibitor compounds according to the present invention. Thus the CBi antagonist compounds of formula (I), (II), (III), (IV) or (V) in combination with the lipase inhibitor compounds are particularly suitable also in groups of patients with a greater need for safety and tolerability, such as in particular young patients and / or patients subject to long-term treatment, for example in drug-induced obesity.

This safety and tolerability of the CBX antagonist compounds of formula (I), (II), (III), (IV) or (V) in combination with the lipase inhibitor compounds is advantageous in the treatment and / or prophylaxis of obesity in those patient populations where a single treatment is not sufficiently effective and is desired or required to achieve and stabilize a defined degree of weight loss; a combination treatment and / or prophylaxis involving various medical or metabolic mechanisms. Hence, it is expected that the combination of the CBi antagonist compounds of formulas (I), (II), (III), (IV) or (V) in combination with the lipase inhibitor compounds according to the present invention will be very advantageous in the treatment and / or prophylaxis of obesity in general, for example of obesity in adolescent patients of any age, and particularly also of pediatric or juvenile obesity, and of drug-induced obesity. The modulating activity of the CBi receptor of the compounds of formulas (I), (II), (III), (IV) or (V) of the invention makes them particularly useful in the treatment of obesity, juvenile obesity and obesity induced by drugs, when used in combination with lipase inhibitors. Specific examples of lipase inhibitor compounds that can be used in said combination preparations are (but are not restricted to) the synthetic lipase inhibitor orlistat, the panclicins, lipase inhibitors isolated from microorganisms such as lipstatin (from Streptomyces toxytricini), ebelactone. B (from Streptomyces aburaviensis), synthetic derivatives of these compounds, derivatives of 2-oxy-4H-3, l-benzoxacin-4-one such as ATL-962 and structurally related compounds, 2-amino-4H derivatives -3, l-benzoxacin-4-one, as well as plant extracts known to possess lipase inhibitory activity, for example extracts of Alpinia officinazum Hance or compounds isolated from said extracts such as 3-methyltetragalangin (from A. officinarum) . The lipase inhibitor compounds can also be a lipase inhibiting polymer. These lipase inhibitor compounds and their manufacture are well known in the state of the art. The lipase inhibitor compounds used in the combinations according to the present invention can be any lipase inhibitor compound suitable for pharmaceutical use, for example in particular pancreatic lipase inhibitors. Lipases are key enzymes in the digestive system that break down tri- and di-glycerides, which are too large to be absorbed by the small intestine to fatty acids that can be absorbed. Since lipases are responsible for the hydrolysis of fats, a consequence of their inhibition is a reduction in the hydrolysis of fats and their absorption. Therefore, the inhibition of lipases causes a reduction in the absorption of fat. The lipase inhibitor compound is preferably the synthetic inhibitor of lipase orlistat and the structurally related compounds derived from 2-oxy-4H-3, l-benzoxacin-4-one such as ATL-962 and structurally related compounds, derivatives of the compound. -amino-4H-3, l-benzoxacin-4-one lipase inhibitors isolated from microorganisms such as lipstatin, ebelactone B, or synthetic derivatives of these compounds, however they can also be a lipase inhibiting polymer. Most preferred are orlistat, panclicines, ATL-962 and lipstatin. Orlistat (tetrahydrolipstatin) and lipstatin are described in U.S. Pat. No. 4,598,089 and its European equivalent EP 0 129 748 Bl in more detail. The compounds are derivatives of the lactone of 2-hexyl-3-hydroxy-hexadecanoic acid with the chemical names of acid lactone (2S, 3S, 5S, 7Z, 10Z) -5- ((S) -2-formamide-4 -methylvaleryloxy) -2-hexyl-3-hydroxy-7, 10-hexade-cadienoic (lipstatin) and lactone (2S, 3S, 5S) -5- ((S) -2-4-methylvaleryloxy) -2- hexyl-3-hydroxy-hexadecanoic (tetrahydrolipstatin). The compounds are known to be pancreatic lipase inhibitors that can be used in the prevention or treatment of obesity and hyperlipidemia for which purpose they can be formulated as drugs or incorporated into industrially prepared food products. The inhibition of pancreatic lipase prevents hydrolysis of dietary fats to produce free fatty acids that are absorbed, and monoglycerides, so that fats are excreted as such. The IC 50 of lipstatin and tetrahydrolipstatin for the inhibition of triolein hydrolysis by porcine pancreatic lipase is 0.07 and 0.18 μg / ml, respectively. In addition, there are suitable lipase inhibitors which are structurally related to orlistat and / or lipstatin and which are known as panclicins. These panclicins are derived from orlistat and contain a 4-membered lactone ring (Mutoh M; Nakada N Matsukima S; Ohshima S; Yoshinari K; Watanabe J Place: Kanaga a, Japan Publication date: January 19, 1995 Journal: J. Antibiot., 47, No. 12, 1369-75, 1994). The biological data of these panclicins can be summarized as follows: panclicins A, B, C, D and E, structural analogs of tetrahydrolipstatin (THL), inhibit in a dose-dependent manner the hydrolysis of the triolein of the fatty acids by the porcine pancreatic lipase, with IC50 values of 2.9, 2.6, 0.62, 0.66 and 0.89 μ ?, respectively. The inhibitory activity of panclicins A and B (portion of alanine instead of leucine in THL) was 2-3 times weaker than that of THL; On the contrary, the inhibitory activity of panclicines C, D and E (glycine portion instead of leucine in THL) was 2 times higher than that of THL. Panclicins A, B, C, D and E also potently inhibited plasma lipases with IC50 values of 1.0, 1.2, 0.29, 0.25 and 0.15 μ ?, respectively. Panclicins A and B inhibited plasma lipases with the same potency as THL, whereas panclicins C, D and E had a 3-6 times greater inhibitory activity than THL. Panclicins A, B, C, D and E inhibited bacterial and fungal lipases with profiles similar to porcine pancreatic lipase. Panclicins inhibited pancreatic lipase irreversibly, but less irreversibly than THL. Panclicins A, B, C, D and E irreversibly inhibit pancreatic lipase. Ebelactone B is described in US Pat. No. 4,358,602 and its German equivalent DE 3 109 335 Cl. Ebelactone A and ebelactone B belong to a group of compounds that show activity to increase the immune response mediated by cells in living animals and also inhibit inflammation in live animals. In this way they can be used in the immunological treatment of tumors and to improve anti-tumor agents such as bleomycins. The compounds possess antiesterase activity and antiformylmethionineaminopeptidase activity. The administration of these compounds to mice at a dose of 0.781-50 mg / kg (ip) or 0.5 mg / kg orally (per os) increases the development of the DTH response and the compounds show an enhanced effect of mediated immunity for the cells. Ebelactone B reduces inflammation induced by carrageenin in mice. In the context of the present invention the lipase inhibitors administered to a patient in combination with the CBi antagonist compounds for treating obesity can also be a polymer that has been substituted with or comprises one or more groups that can inhibit a lipase. Said lipase inhibiting polymers are described in U.S. Patent Nos. 6572850, 6558657, 6352692, 6267952 and in WO 99/34786. In one embodiment, the lipase inhibitor group can be a "suicide substrate" that inhibits lipase activity by forming a covalent bond with the enzyme either in the active site or elsewhere. In one embodiment, the lipase inhibitor group may be a "suicide substrate" that inhibits lipase activity mediating the formation of a covalent bond with the enzyme either in the active site or elsewhere. In another embodiment, the lipase inhibitor group is an isosteric inhibitor of the enzyme. In a first aspect of the present invention when lipase inhibitor polymers are used in addition to the CBi antagonist compounds, the lipase inhibitor group inactivates a lipase such as gastric, pancreatic and lingual lipases. The deactivation can be done by forming a covalent bond so that the enzyme is inactivated. The covalent bond can be formed with an amino acid residue in or near the active site of the enzyme, or in a residue that is distant from the active site as long as the formation of the covalent bond causes the inhibition of the enzymatic activity. Lipases contain a catalytic triad that is responsible for the hydrolysis of lipids to fatty acids. The catalytic triad consists of amino acid residues of a serine, aspartate and histidine. This triad is also responsible for the hydrolysis of the amide bonds of serine proteases, and it is expected that compounds that are inhibitors of serine proteases will also inhibit lipases. Therefore, inhibitors of serine proteases that can be covalently bound to a polymer are preferred lipase inhibitor groups. For example, a covalent bond can be formed between the lipase inhibitor group and a hydroxyl at the catalytic site of the enzyme. For example, a covalent bond with serine can be formed. Inactivation can also be carried out through the formation of a covalent bond. of a lipase inhibitor group with an amino acid, for example cysteine, which is some distance from the active site. In a second aspect of the present invention when lipase inhibiting polymers are used in addition to the CBi antagonist compounds, the non-covalent interaction between the lipase inhibitor group and the enzyme can also cause inactivation of the enzyme.

For example, the lipase inhibitor group can be an isostere of a fatty acid, which can interact non-covalently with the catalytic site of the lipase. In addition, the lipase inhibitor group can compete with natural triglycerides with the hydrolysis of the lipase. A variety of polymers can be employed in the invention described herein. The polymers can be aliphatic, alicyclic or aromatic or synthetic or natural. However, synthetic aliphatic and alicyclic polymers are preferred. In addition, the polymer can be hydrophobic, hydrophilic or copolymers of hydrophobic and / or hydrophilic monomers. The polymer can be non-ionic (for example neutral), anionic or cationic, in whole or in part. In addition, the polymers can be manufactured with olefinic or ethylenic monomers (such as vinyl alcohol) or condensation polymers. For example, the polymers can be a polyvinyl alcohol, polyvinyl amine, poly-N-alkylvinylamine, polyallylamine, poly-N-alkylallylamine, polyalkyleneimine, polyethylene, polypropylene, polyether, polyethylene oxide, polyamide, polyacrylic acid, polyalkyl acrylate, polyacrylamide, acid polymethacrylic, polyalkylmethacrylate, polymethacrylamide, poly-N-alkylacrylamide, poly-N-alkylmethacrylamide, polystyrene, vinylnaphthalene, ethylvinylbenzene, aminostyrene, vinylbiphenyl, vinylanisole, vinylimidazolyl, vinylpyridinyl, dimethylaminomethylstyrene, trimethylammonium methylmethacrylate, trimethylammonium methylacrylate, carbohydrates, proteins and substituted derivatives of the above (for example, fluorinated monomers thereof) and copolymers thereof. Preferred polymers include polyethers, such as polyalkylene glycols. The polymers employed in the methods described herein as well as the intermediates and methods for preparing the polymers are described in detail in U.S. patent documents US 6572850, US 6558657, US 6352692, US 6267952 and in the WO international patent document. 99/34786, all of which are incorporated by reference in the present invention. Recently, new 5-hydroxyloxy-3-phenyl-1,3,4-oxadiazol-2-ones of fla (A) as pancreatic lipase inhibitors useful for treating diseases are described in the application of the international patent document WO 03/072555. metabolic, cardiovascular diseases or especially obesity.

(A) Said oxadiazolones of fla (A) and their salts and acid addition salts are also suitable in combination with the CBi antagonist compounds used according to the present invention. In the fla (A) the substituents can be as follows: R1 can be C7_22 alkyl C2-4 alkyl substituted by C4-20 alkoxy, C6_i aryl, C6_io aryloxy or (C4_12) alkoxy-alkoxy (C2-) 4) (where the aryl may be substituted by one or more halogens, Ci_4 alkyl, Ci_4 alkoxy, N02 or CF3); C7_2o alkenyl or phenyl substituted by C6-I2 alkyl or by phenoxy; and Ri to R5 can each be H, halogen, N02, alkyl C1-4, Ci_4 alkoxy, CF3 or OCF3; or aryl (Ce-io) -alkoxy (C1-.4), aryloxy Ce-io, aryl C6-io, cycloalkyl C3-8 or cycloalkoxy C3-8 (optionally substituted by halogen, CF3, Ci_4 alkoxy or C1-4 alkyl). It is described that these 5-hydrocarbyloxy-3-phenyl-1,3,4-oxadiazol-2-ones possess pharmacological properties such as anorexic, antidiabetic, hypotensive or cardiotonic properties, with the mechanism of action which is as inhibitors of pancreatic lipase. . For example, 5-dodecyloxy-3- (4-trifluoromethoxy-phenyl) -3H- (1,3,4) -oxadiazol-2-one had an IC50 of 0.03 μ? in the inhibition of porcine pancreatic lipase. Thus, these 5-hydrocarbyloxy-3-phenyl-1,3,4-oxadiazol-2-ones can be used as medicaments, especially to treat obesity. As inhibitors of pancreatic lipase, 5-hydrocarbyloxy-3-phenyl-1,3,4-oxadiazol-2-ones inhibit the resorption of the fat content of food and thus reduce fat intake and body weight ( or prevent increases in body weight). furtherIt has been described that 5-hydrocarbyloxy-3-phenyl-1,3,4-oxadiazol-2-ones also have a beneficial effect in the treatment of metabolic disorders (eg diabetes) or cardiovascular disorders (eg hypertension). and cardiac infarction). The lipase inhibitor compounds of formula (A) are described in more detail in the international patent document WO 03/072555 and can be obtained according to known methods. A suitable synthesis for the lipase inhibitor compounds of formula (A) is also described in the document of the international patent application WO 03/072555. The entire contents of the document of the international patent application WO 03/072555 is incorporated by reference in the present application with regard to the description of the lipase inhibitors of formula (A). In addition, in the document of the international patent application WO 03/072098 further 5-hydrocarbyloxy-3-phenyl-1,3,4-oxadiazol-2-ones are described. of formula (A) as pancreatic lipase inhibitors useful for treating obesity or diabetes mellitus type 1 and 2. Said oxadiazolones of formula (A) are described in WO 03/072098 and their salts and salts thereof. Acid addition are also suitable for combinations with the CBi antagonist compounds used in accordance with the present invention. In the formula (A) the substituents can be as follows: Ri can be alkyl Ca_6; cycloalkyl C3_9, both groups may be optionally substituted with phenyl, alkoxy 0-4, alkyl S-C1-4, N (alkyl Ci-4) 2; and phenyl optionally may also be substituted with halogen, CX-4 alkyl, Ci_4 alkyloxy, nitro or CF3; and R2 to R5 may each independently be H, halogen, N02, Ci_alkyl, Ci-g alkoxy which is substituted by F, aryl C6-IOI amino or Ci_4 alkylamino, aryl C6_i0-alkyloxy Ci_4r aryloxy C6-i0, aryl C6_i0- C6_10 aryloxy-C1-4alkyl, C3-8 cycloalkyl or 0 (cycloalkyl 3-8), which may be optionally substituted by halogen, CF3, Ci_4alkyloxy or Ci_4alkyloxy; S02-NH- (Ci_6 alkyl), optionally substituted with N (Ci_6 alkyl) 2r S02-NH- (2, 2, 6, 6-tetrametillpiperidin-4-yl), S02-NH- (C3_g cycloalkyl), optionally substituted with C1-.4 alkyl, S02-N (Ci_6 alkyl) 2 or COX; 2-oxo-pyrrolidin-1-yl, 2, 5-dimethylpyrrol-1-yl or R6 ~ A ~ R7 With the proviso that R2, R3, R4 and R5 are not H at the same time when X is 0 (Ci_6 alkyl), NH (Ci_6 alkyl), NH (C3_8 cycloalkyl or N (Ci_6 alkyl) 2 and N ( alkyl Cxs) 2 can also be pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino, which is optionally substituted with C 1-4 alkyl, benzyl, aryl Ce-io, CO- (alkyl! _4), CO- (aryl 6-io) , CO-O- (Ci_4 alkyl), S02- (Ci_4 alkyl) or S02- (aryl C6-io) R6 is H, C1_4 alkyl or aryl C6_i0-C1-4 alkyl, where the aryl may to be substituted with halogen, CF3, C1_4alkyloxy or Ci_4alkyl; A is a single bond, COn, SOn or CONH; n is 1 or 2: R7 is H; alkyl Ci_ie or alkenyl C2_i8, which may be up to three times substituted with alkyl Ci_4, halogen, CF3, C1-4 alkyloxy, N (alkyl 01-4) 2, -COOH, alkyloxycarbonyl Ci_4, aryl Cg-i2f aryloxy C6-i2 arylcarbonyl C5-12, aryl 6-io-alkyloxy Ci_4 or oxo, where the aryl itself can be optionally substituted with halogen, Ci_4 alkyl, aminosulfonyl or methyl mercapto; aryl C6-io_alkyl Ca_4, C5-cycloalkyl-alkylalkyl C5-8 cycloalkyl, aryl 6_i0-C2-6 alkenyl, aryl C6-biphenylyl, diphenyl- (alkyl 1-4), indanyl, which may optionally be substituted with alkyl Ci_is, alkyloxy Ci-is, C3_8 cycloalkyl, COOH, hydroxy, C3-4 alkylcarbon, aryl C6-io-C1_4alkyl, aryl C6-io-al < 3 Ci-4-alkoxy, C6-io-aryloxy, nitro, cyano, aryl-??-,, fluorosulfonyl, Ci_6 alkyloxycarbonyl, arylsulfonyloxy 6-10, pyridyl, NHS02- (aryl 6-10) / halogen, CF3 or OCF3, where the alkyl can further substituted with alkyloxycarbonyl Ci-4, CF3 or carboxy and the aryl with halogen, CF3 or Ci_4alkyloxy; or the group Het- (CH2) r- where r = 0, 1, 2 or 3 and Het = a 5-7-membered saturated or unsaturated heterocycle, which may be optionally forming a benzene ring and substituted with Ci_4 alkyl, aryl Cz-W, halogen, Ci_4alkyloxy, C1-4alkyloxycarbonyl, aryl CVio-C1-4alkyl, aryl C6-io-alkylmercapto Ci_ or nitro, wherein the aryl fused with the benzene ring may be substituted by halogen, C1- alkyloxy 4 or CF3 and the alkyl in the arylalkyl may be substituted with methoxy and CF3. The lipase inhibitor compounds of formula (A) are described in more detail in the international patent document WO 03/072098 and can be obtained by known methods. An adequate synthesis of the lipase inhibitor compounds of formula (A) is also described in the document of the international patent application WO 03/072098. The complete contents of the document of the international patent application WO 03/072098 is incorporated by reference in the present application with regard to the description of the lipase inhibitors of formula (A). Furthermore, in the United States patent document US 6624161 and its corresponding international patent application documents WO 00/040569 and WO 00/040247 more lipase inhibitor compounds are described which are also suitable in the context of the present invention for their combination with CBi antagonist compounds described herein. These patent documents US 6624161 and WO 00/040569 describe a series of compounds that are derivatives of 2-oxy-4H-3, l-benzoxacin-4-one, including ATL-962, and its use in obesity and disorders related to obesity, including type 2 diabetes. Derivatives of 2-oxy-4H-3, l-benzoxacin-4-one have the formula (B) or are a pharmaceutically acceptable salt, ester, amide or prodrug of it: wherein: RIA is (i) A linear or branched C10-30 alkyl, optionally independently substituted with one or more C3_6 cycloalkyl, C3-6 cycloalkenyl, aryl, heteroaryl, reduced heteroaryl, -C (0) Ri3, -C02Ri3, - S0R13, -S02Ri3, -NR13R14, -OR13, -SR13, -C (0) NR13Ri4, -NR14C (0) R13, halogen, cyano, and nitro and / or optionally interrupted with one or more oxygen atoms with the proviso that any heteroatom in Ria must be separated from the exocyclic oxygen atom (or any other heteroatom) by at least two carbon atoms; (ii) 2-25 alkenyl C2-25 alkynyl / C3_6 cycloalkenyl, aryl-alkenyl 02-25 / · C2-25 heteroaryl-alkenyl, reduced heteroaryl, heteroaryl reduced -C1-25 alkyl or a substituted derivative of any of the above groups wherein the substituents are one or more independently of Ci_6 alkyl, halosubstituted alkyl Ci_6, aryl, aryl-Ci_6 alkyl, heteroaryl, reduced heteroaryl, heteroaryl reduced-alkyl Cl-6alkoxy Ci_6, aryl-alkoxy Ci_6, -C (0) Ri3, -C02Ri3, -SORi3, -S02Ri3, - Ri3Ri, -0Ri3, -SR13, -C (0) NRi3Ri4, - Ri4C (0) Ri3, halogen, cyano, and nitro, with the proviso that any heteroatom in Ria it must be separated from the exocyclic oxygen atom (or any other heteroatom) by at least two carbon atoms; (iii) a C2-9 alkyl group interrupted by one or more oxygen atoms and optionally substituted with one or more independently C3_6 cycloalkyl, C3-6 cycloalkenyl, aryl, heteroaryl, reduced heteroaryl, -C (0) Ri3, -C02Ri3, -OR13, -SO2R13, Ri3Ri4, OR13, SR13, -C (0) NRi3Ri4, -NRi4C (0) R13, halogen, cyano and nitro with the proviso that any heteroatom in Ria must be separated from the exocyclic oxygen atom (or any other heteroatom) by at least two carbon atoms; or (iv) a Ci_g alkyl group substituted with a group selected from -C (0) Ri3, -C02R13, S0R13, S02Ri3, NR13R14, 0Ri3, SR13, C (0) NRi3R14, NR14C (0) R13; tetrahydronaphthyl, pyridyl, pyrrolyl, piperidinyl, halogen, cyano, nitro, bicyclic aryl, bicyclic heteroaryl, monocyclic or reduced bicyclic heteroaryl, heteroaryl, monocyclic heteroaryl other than imidazolyl; (v) a phenyl group substituted with a group selected from ORi7, -COR13, - -CO2R13, SOR13, S02Ri3, CONR13Ri4, NRi4C (O) Ri3; SiO-substituted Ci_6 alkyl, aryl, aryl-alkyl-6, heteroaryl and heteroaryl Ci_6 alkyl; or (vi) a bicyclic aryl, bicyclic heteroaryl, monocyclic or reduced bicyclic heteroaryl, or a monocyclic heteroaryl group other than imidazolyl, optionally substituted with a group selected from ORi 7 -COR 13, -CO 2 R 13, SOR 13, SO 2 R 13, CONR 13 R 14, R 4 C (0) ) Ri3 alkyl-6-halo substituted, aryl, arylCi-6alkyl, heteroaryl and heteroaryl Ci_6alkyl; where R <3> and R <14> each independently represents hydrogen, C 1-10 alkyl, C 2 -io alkenyl, C 2-6 alkynyl C 3-6 cycloalkyl, C 3-6 cycloalkenyl, aryl, C 1-10 arylalkyl, heteroaryl, heteroarylalkyl? - ?? , reduced heteroaryl or reduced heteroaryl, Cx-10 alkyl and Ri7 represents hydrogen or C2-io alkenyl, C2-10 alkynyl / C3-6 cycloalkyl, C3_6 cycloalkenyl, aryl, C1-10 arylalkyl, heteroaryl, heteroaryl C1-10 alkyl, heteroaryl reduced or heteroaryl reduced C 1-10 alkyl and R 8a, R 9a, Ri 0a and Rna are each independently hydrogen, halogen, hydroxy, amino, nitro, cyano, thiol, Ci-alkyl, C 1-10 alkoxy, cycloalkyl Cj -io , C1-10 cycloalkoxy, C (0) Ri5, C (0) NRa5Ri6, S (0) Ri5 or haloalkyl Ca-i0; where R15 and Rie each independently represents hydrogen, or alkylCaOH with the proviso that when R8a, Rga Rioa and Rila are H, Rla is not CH2CH2C1 or C3 alkenyl.

Furthermore, in the document of the international patent application WO 00/40247 related compounds are described as lipase inhibitors derived from 2-amino-4H-3, 1-benzoxazin-4-one as compounds for treating obesity. Then in the formula (B) the substituent -ORla is replaced with a group -R1R2 with the definitions for Ri and R2 as described in the international patent document WO 00/40247. The previous group of structurally related compounds includes ATL-962, a synthetic lipase inhibitor that is not orally absorbed derived from Alizyme's pancreatic lipase inhibitor research program, which is under development for the potential treatment of obesity and obesity. potential management of type 2 diabetes. ATL-962 has the chemical name 2-hexadecyloxy-6-methyl-4H-3, 1-benzoxacin-4-one. Preclinical studies showed that ATL-962 had efficacy similar to orlistat and no toxicity was observed. Clinical data for these compounds are also available for public domain, for example those resulting from clinical studies with ATL-962 in obesity. Thus, the results of a phase Ib program with ATL-962 were presented at the international obesity congress in Sao Paulo, Brazil. Three phase Ib trials involved a total of 99 healthy volunteer men in groups of seven or nine, given one of several doses of ATL-962 (66 subjects) or placebo (24 subjects), three times a day with food For 5 days. A group of nine subjects were given orlistat (qv) 120 mg three times a day. Overall, ATL-962 was safe and well tolerated and showed evidence of efficacy as indicated by an increase in dietary fat excretion. Subjects given doses between 50 mg and 300 mg of ATL-962 with meals twice a day excreted fat at a mean of between 4.9 (+/- 4.3) and 11.2 (+/- 6.9) g / day compared with 1.4 (+/- 1.0) g / day of placebo and 5.6 (+/- 3.8) g / day of orlistat. Compared with placebo, 55% of subjects who received ATL-962 (50 mg to 300 mg) demonstrated a 3-fold increase in fat excretion and 27% of subjects showed a 7-fold or greater increase. There was evidence of dose dependence. Adverse effects and their frequency were similar between ATL-962 and placebo and were mainly gastrointestinal, with the predominant event being oily stools. The results of a randomized double-blind multicenter parallel-phase study (Ilb) study, involving 370 clinically obese patients, was being carried out in specialized clinics in 5 European countries, and in September 2003 the preliminary results were described. . All dose levels of ATL-962 (60, 120 and 240 mg) demonstrated a significant reduction in weight, compared with placebo, in all treatment groups. There were no differences in the extent of weight loss among the treated groups. LDL cholesterol decreased in the treatment groups but not in the placebo group. There were no differences in HDL cholesterol levels in the treatment groups, whereas it increased in patients treated with placebo. Total cholesterol decreased in the treated groups, while in the placebo group it showed an increase. ATL-962 was safe and generally well tolerated. The lipase inhibitor compounds of formula (B) such as ATL-962 and structurally related compounds are described in more detail in U.S. Patent No. 6,624,161 and its corresponding international patent application WO 00/040569, and they can be obtained according to known methods. A suitable synthesis for the lipase inhibitor compounds of formula (B) is also described in U.S. patent document US 6,624,161 and international patent application document WO 00/040569. The complete content of the United States patent document US 6,624, 161 and from the document of the international patent WO 00/040569 is incorporated by reference in the present application related to the description of the lipase inhibitors of formula (B). The entire contents of the international patent application document WO 00/040247 is also incorporated by reference in the present application related to the description of the lipase inhibitors described herein, with reference to the structure of the 2-amino-4H-3 compound , l-benzoxazin-4-one. The pharmaceutically acceptable salts, hydrates and solvates, and the prodrugs of all lipase inhibitor compounds previously described can also be used in the context of the present invention. The CBi antagonist compound, of formulas (I), (II), (III), (IV) or (V), or a prodrug, tautomer or salt thereof, and the lipase inhibitor compound used according to the invention can be prepared in suitable forms for the pediatric treatment and / or prophylaxis of the diseases indicated above, and in particular obesity, for example for administration to adolescents or pediatric, as well as for administration to treat drug-induced obesity by means of usual processes using pharmaceutical excipients, auxiliary substances and / or liquid or solid carriers. As therapeutic agents, the CBi antagonist compound and / or the lipase inhibitor compounds may be contained together with the pharmaceutical excipients (conventional), adjuvants and / or auxiliaries in pharmaceutical preparations such as tablets, capsules, suppositories or solutions. These pharmaceutical preparations can be prepared according to known methods, using conventional solid or liquid carriers such as lactose, starch or talc, or liquid paraffins and / or using (conventional) pharmaceutical excipients, adjuvants and / or auxiliaries, such as tablet disintegrating agents. , solubilizers or preservatives. Hence in a further aspect the invention also relates to a pharmaceutical composition containing at least one compound with CBi receptor antagonist activity of formula (I), (II), (III), (IV) or (V), or a prodrug, tautomer or salt thereof, in combination with at least one lipase inhibitor compound. A preferred pharmaceutical composition contains at least one compound of formula (I), (II), (III), (IV) or (V), as defined above in combination with at least one lipase inhibitor compound as combined active components. An additional pharmaceutical composition according to the invention contains as active components at least one compound with antagonist activity at the CBi receptor of formula (I), (II), (III), (IV) or (V) as defined above, preferably the CBX antagonist compound, or a prodrug, tautomer or salt thereof, and at least one lipase inhibitor compound for the treatment and / or prophylaxis of obesity in adolescent patients or in young patients, and / or for the treatment and / or prophylaxis of drug-induced obesity in young patients as well as in adolescent patients. Particular pharmaceutical compositions according to the invention are characterized in that the at least one compound with antagonist activity in the CBi receptor of formula (I), (II), (III), (IV) or (V) as defined above, preferably the CBi antagonist compound or the prodrug, tautomer or salt thereof, and the at least one lipase inhibitor compound are each present in an amount effectively suitable for the treatment and / or prophylaxis of obesity in a young patient in need of said treatment. In a further embodiment of the invention the CBi antagonist compound, in particular the CBi antagonist compound of formula (I), (II), (III), (IV) or (V), and the lipase inhibitor compound are each one present in the pharmaceutical composition in an amount effectively suitable for the treatment and / or prophylaxis of drug-induced obesity in young patients as well as in adolescent patients in need of such treatment. In the pharmaceutical compositions according to the invention the CBi antagonist compound, which formula has the CBi antagonist of formula (I), (II), (III), (IV) or (V), or the prodrug, tautomer or salt thereof, is preferably used in combination with at least a lipase inhibitor compound selected from the group of polymers inhibitors of lipase, orlistat, panclicins, ATL-962 and lipstatin. The invention also relates to the pharmaceutical product containing as a medicament a CBi antagonist compound, preferably the CBi antagonist compound having a formula (I), (II), (III), | (IV) or (V) as it was defined above, or a prodrug, tautomer or salt thereof, and a package insert indicating that said CBi antagonist compound can be administered in combination with a lipase inhibitor compound by route of simultaneous, separate or sequential administration in the treatment and / or prophylaxis of obesity. Finally, the invention also includes a method of treatment and / or prophylaxis of obesity, for example in adolescent patients or in young patients and / or treatment and / or prophylaxis of drug-induced obesity in young patients as well as in adolescent patients, characterized in that a CBi antagonist compound, in particular a compound of formula (I), (II), (III), (IV) or (V) which is an antagonist of the CBi cannabis receptor, or a prodrug, tautomer or salt thereof, it is administered in combination with at least one lipase inhibitor compound to a patient in need of such treatment. In a preferred method of treatment and / or prophylaxis of obesity according to the invention, a CBi antagonist compound which is a compound of one of formulas (I), (II), (III), (IV) or (V) ) as defined above, or a prodrug, tautomer or salt thereof, is administered in combination with at least one lipase inhibitor compound. The method of treatment and / or prophylaxis of obesity according to the present invention can be directed to obesity in adolescent patients or in young patients and / or drug-induced obesity in young patients as well as in adolescent patients. In a variant of the invention, the method of treatment and / or prophylaxis is characterized in that the treatment is aimed at obesity in young patients. In a further variant of the invention, the method of treatment and / or prophylaxis is characterized in that the treatment is directed to drug-induced obesity in young or adolescent patients. In the method of treatment and / or prophylaxis according to the invention, the CBi antagonist compound, preferably the CBi antagonist compound having one of the formulas (I), (II), (III), (IV) or (V) ) as defined above, or a prodrug, tautomer or salt thereof, is preferably administered in combination with at least one lipase inhibitor compound selected from the group of lipase inhibitor polymers, orlistat, panclicins, ATL-962 and lipstatin. According to the invention, the CBi antagonist compound, preferably the CBi antagonist compound having one of the formulas (I), (II), (III), (IV) or (V) as defined above, or a prodrug , tautomer or salt thereof, is administered in combination with the lipase inhibitor compound by route of simultaneous, separate or successive administration. The compounds used in the combinations or compositions according to the present invention are each preferably administered to a patient in need thereof and in an amount sufficient to prevent and / or treat the symptoms of the condition, disorder or disease, for example the obesity. For all aspects of the invention, particularly physicians, the administration of a compound or composition has a dosage regimen that will ultimately be determined by the attending physician and will take into consideration such factors as the compound being used, the type of animal , age, weight, severity of symptoms, method of administration, adverse reactions and / or other contraindications. Defined specific dose ranges can be determined by standard clinical tests designed to fully monitor the progress and recovery of the patient. Such tests should use a dose escalation design using a low percentage of the maximum tolerated dose in animals as the initial dose in man. The physiologically acceptable compounds used in the combinations or compositions according to the present invention will each be normally administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 2000 mg, preferably between 30 mg and 1000 mg, for example between 10 mg and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg preferably between 0.1 mg and 50 mg for example between 1 mg and 25 mg of the compound of formula (I) or a physiologically acceptable salt thereof calculated as a free base, the compound is administered 1 to 4 times per day. Suitably the compounds will be administered during a period of continuous therapy, for example for a week or more. For a young patient, a part of the oral dose is usually administered to an adult patient, for example from one-fifth to one-half of the oral dose described above for an adult patient. Preferably, in one embodiment of the invention, the method of treatment and / or prophylaxis is directed to the treatment of obesity in young patients. In another preferred embodiment of the invention, the method of treatment and / or prophylaxis is directed to the treatment of drug-induced obesity in young patients or adolescent patients. This drug-induced obesity can be caused in particular by drugs such as atypical antipsychotics. In one embodiment of the invention, the method of treatment and / or prophylaxis is directed to the treatment of obesity in young patients. Thus, it is advantageous that cannabinoid antagonists in combination with lipase inhibitors are particularly suitable for the treatment of childhood obesity and related comorbidities such as type 2 diabetes. There is a clear medical need for improved therapy since obesity has been transformed into a medical problem of growing importance not only in the adult pation but increasingly in children and (young and less young) adolescents. In national surveys from the 1960s to the 1990s in the United States, the prevalence of overweight children increased from 5% to 11% (Sorof and Daniels 2002). In Canada as another example, childhood obesity has tripled in the last 20 years (Spurgeon 2002). Obesity in childhood causes a wide range of serious complications, and increases the risk of premature diseases and death later in life, increasing public health concerns (Ebbeling, Pawlak et al., 2002). In recent decades there has been a tremendous increase in cases of type 2 diabetes, especially in children. This epidemic trend is clearly reflecting the increasing rates of obesity. Type 2 diabetes was considered in the past a disease of adults and older individuals, not a pediatric condition (Arslanian 2002). One of the main risk factors of pediatric type 2 diabetes is obesity. Type 2 diabetes in children (as it is in adults) is part of the insulin resistance syndrome (Rosenbloon 2002) that includes hypertension, dyslipidemia and other risk factors for atherosclerosis, and hyperandroginism seen as premature adrenarche and polycystic ovary syndrome. . Other consequences related to obesity in childhood include left ventricular hypertrophy, nonalcoholic steatohepatitis, obstructive sleep apnea, orthopedic problems, and severe psychosocial problems. In addition, primary hypertension is each more common in children again associated with obesity as the largest independent risk factor. Obese children have an approximately three times higher risk of hypertension than non-obese children (Sorof and Daniels 2002). The benefits of weight loss for lowering blood pressure in children have been demonstrated in observational and intervention studies. Public concern increases due to the rapid development of the childhood obesity epidemic in genetically stable populations. The determining factors are assumed to be mainly adverse environmental factors for which there are simple recommendations for lifestyle modifications. Obesity and its related comorbid states are very serious medical conditions and the current measures and treatment of obesity and especially childhood obesity remain largely ineffective at the moment (Ebbeling, Pawlak et al. 2002). The management of type 2 diabetes is also especially difficult in children and the adolescent age group (Silink 2002). The desire and excessive consumption of palatable food is one of the important factors of lifestyle related to obesity in humans and especially in children and adolescents. Treatment of type 2 diabetes and other comorbid conditions due to the degree of metabolic derangement and symptoms: the only data on the use of oral hypoglycemic agents in children with type 2 diabetes has been metformin (Rosenbloom 2002). Thus, CBi antagonists used in accordance with the present invention in combination with lipase inhibitors offer a unique opportunity for the treatment of obesity through interaction with these "driving forces." They are superior to current medical treatments. and especially suitable for adolescent as well as pediatric treatment due to its outstanding safety and / or tolerability profile and the surprising beneficial effects of the combination.The treatment of obesity especially in childhood obesity is dictated besides by efficacy for safety Obesity in childhood is a medical condition that will probably require long-term treatment.The safety profile of CBi antagonists according to the present invention in combination with lipase inhibitors is suggested to be superior to current standard medications. , and these CBi antagonists in combination with inhibitors lipase inhibitors will be especially suitable for the treatment and prevention of obesity in adolescents and childhood obesity and related comorbidities.

Bibliography Arslanian, S. (2002). "Type 2 diabetes in children: clinical aspects and risk factors." Horm Res 57 Suppl 1: 19-28. Ebbeling, C. B., D. B. Pawlak, et al. (2002). "Childhood obesity: public-health crisis, common sense cure". Lancet 360 (9331): 473-82. Rosenbloom, A .. L. (2002). "Increasing incidence of type 2 diabetes in children and adolescents: treatement considerations". Paediatr Drugs 4 (4): 209-21. Silink, M. (2002). "Childhood diabetes: a global perspective". Horm Res 57 Suppl 1: 1-5. Sorof, J. and S. Daniels (2002). "Obesity hypertension in children: a problem of epidemic proportions". Hypertension 40 (4): 441-7. Spurgeon, D. (2002). "Childhood obesity in Canada has tripled in past 20 years". Bmj 324 (7351): 1416. In another embodiment of the invention, the method of treatment and / or prophylaxis is directed to the treatment of drug-induced obesity in young patients or adolescent patients. Drug-induced weight gain is also a major concern and a cause of an important medical need for improved treatments. Again, in this context it is suggested that the CBi antagonists in combination with the lipase inhibitors according to the present invention are suggested to be superior to the current standard medications, and that these CBi antagonists in combination with the lipase inhibitors they will be especially suitable for the treatment and prevention of drug-induced obesity in young patients as well as in adolescent patients. In relation to drug-induced weight gain, it is published by Zimmermann, U., T. Graus, et al. (2003, "Psychiatry Res 37 (3): 193-220) that during the treatment of psychiatric disorders an increase in body weight frequently occurs and is often accompanied of increased appetite or craving for food. While the incidence and time course of this side effect is difficult to predict, it eventually produces the obesity and morbidity associated with it in a substantial part of the patients, often causing the abandonment of treatment even if it is effective. Weight gain seems to be more prominent in patients treated with some of the second generation antipsychotic drugs and with some mood stabilizers. A marked weight gain also frequently occurs during treatment with most tricyclic antidepressants.

Very large weight increases are associated with drugs such as atypical antipsychotics such as clozapine and olanzapine. Some atypical antipsychotics, however, tend to cause significant weight gain, which can lead to low adherence and other adverse health effects (Nasrallah, H. (2003). "A review of the effect of atypical antipsychotics on weight" Psychoneuroendocrinology 28 Suppl 1: 83-96). The mechanisms involved in weight gain related to antipsychotic drugs are still uncertain, although serotonergic, histamine and adrenergic affinities have been implicated along with other metabolic mechanisms. Atypical antipsychotics vary in their propensity to cause weight changes with long-term treatments. Follow-up studies show that the greatest increases in weight are associated with clozapine and olanzapine, and the smaller ones with quetiapine and ziprasidone. Risperidone is associated with modest weight changes that are not dose related. Given the equivalent efficacy of atypical antipsychotics, the weight gain profile is a legitimate factor to consider when constructing a regimen for treatment due to the serious medical consequences of obesity. In this regard it is suggested that the co-administration of CBi antagonists in combination with the lipase inhibitors according to the invention is suggested to work well.

Experimental protocol for the study of the effects of a CBi antagonist compound plus the lipase inhibitor in obesity The pharmacological beneficial effects of the combination of a CBi antagonist with a lipase inhibitor according to the invention can be shown in standard experimental models in animals by measuring the influence of the administered combination of a CBX antagonist with a lipase inhibitor on the conductive and characteristic parameters associated with obesity. For the investigation of the influence of the combination of a CBi antagonist with a lipase inhibitor in obesity the body weight gain in rats can be measured as a pharmacological indicator. Previously, the following experimental protocol for rats should be applied: Rats will have unlimited access to the food during periods of 2.5 hours per day, during the dark phase of a 12h / 12h light cycle reversed, that is, the lights are connected to the 9:15 p.m. and off at 9:15 p.m. Rats will be offered a high-fat, high-sucrose diet (Western diet). The lipase inhibitor will be dosed immediately before the rats are fed. The CBi antagonist will be dosed 1 hour before the lipase inhibitor is administered.

As an example, the following daily dosage regimen is applicable for a given period of for example days, weeks or months. The CBi antagonist, in particular the CBi antagonist compound of formula (I) as defined above, or a vehicle dose was administered (po) in the morning between 7.45 and 8.00 h. The lipase inhibitor, for example in particular orlistat, or a vehicle dose was administered (po) between 8.45 and 9.00 h. After the medication, the rats are given unlimited access to food from 9.15 am to 11:45 am, then the food is removed from 11.45 am to 2.45 pm. Another dose of the lipase inhibitor, for example, orlistat, or the vehicle dose (Labrasol) is administered in the evening around 2:15 p.m. to 2:30 p.m., followed by unlimited access to the food from 2: 45-5: 15 p.m. h. Next, rats are deprived of access to food from 5:15 - 9:15. The results of the experimental protocol compare daily the 'food intake and body weight gain as indicators of the effects of the combination treatment on obesity during the experimentation phase. In addition to the parameters given above, stool collection may also be desired to estimate fat digestion. Finally, it may also be desired to carry out an analysis of the dead animal.

In addition, after the end of the experimental feeding and the administration phase, the biochemical parameters can be measured when the rats are killed. To investigate the effects the total number of rats subject to the experimental protocol are divided into the following groups with approximately the same number of rats in each group: 1) Control group: the rats receive only the vehicle according to the protocol for the sham administration (placebo group). 2) CBi Group: the rats receive the CBi antagonist in a vehicle. 3) Group LI: the rats receive as a lipase inhibitor ("LI") for example the compound orlistat in a vehicle. 4) Group CBi + LI (combination group): The rats receive a CBi antagonist in a vehicle and as a lipase inhibitor ("LI") for example the compound orlistat in a vehicle. The results of this protocol and the respective investigations show the beneficial convenience of the combination of the CBi antagonist and the lipase inhibitor in the treatment and / or prophylaxis of obesity. Preparation of the compounds of formula (V) The 1H-1,2-triazolecarboxamide derivatives of formula (V), which are potent antagonists of the CBN cannabinoid receptor partial agonists, inverse agonists or antagonists, useful for treating psychiatric and neurological disorders, as well as other diseases involving the neurotransmission of cannabinoid CBi, are defined above in the application. Derivatives of 1,5-diaryl-lH-1,2,4-triazole carboxamide have been described as herbicides in European Patent Document EP 0346620 and GB Patent Document 2120665. 1, 2 were recently described. , -triazoles as potential agonists and antagonists of the cannabinoid receptors CBX and CB2 (Jagerovic, N. et al., Drugs Fut, 2002, 27 (Suppl A): XVII Int. Symp. on Medicinal Chemistry, page 284). A group of four derivatives of 1,5-diaryl-lH-1,2,4-triazole-3-carboxamide in which the N-atom of the amide is part of an unsubstituted piperidinyl or morpholinyl group is described by D Clerin and JP Fleury in Bull. Soc. Chim. Br. 19 4, 1-2, part 2, 211-217. 1- (4-Methylphenyl) -5-phenyl-N- (2-pyridyl) -1H-1,2,4-triazole-3-carboxamide is described by M. H. Elnagdi et al. in Heteroatom. Chem., 1995, 6, 589-592. A group of four derivatives of 1,5-diaryl-N- (2-pyridyl) -1H-1,2,4-triazole-3-carboxamide is described by A. H. Harhash et al. in Indian J. Chem., 1976, 14B, 268-272.

Suitable synthetic routes for the compounds of formula (V) used in the invention are the following: Synthetic ru-ba? Step 1: hydrolysis of the ester of a compound of formula (S-II) wherein Re represents a linear or branched alkyl (Ci-4) group or a benzyl group, which provides a compound of formula (S-III) where R and Ri have the meanings described above. The compounds of the invention having the formula (S-II) wherein Rs represents a linear or branched (C1-4) alkyl group or a benzyl group can be obtained according to known methods, for example: a) Sawdey, G.W. J. Am. Chem. Soc. 1957, 79, 1955 b) Czoliner, L. et al. , Arch. Pharm. (Weinheim) 1990, 323, 225 c) Eicher, T. and Hauptmann, S. The Chemistry of Heterocycles, Thieme Verlag, Stuttgart, 1995 (ISBN 313 1005114), pages 208-212. Step 2: reaction of a compound of formula (S-III) with a compound having the formula R2R3NH wherein R2 and R3 have the meaning described above by means of activation and coupling methods such as the formation of an active ester, or in the presence of a coupling reagent such as DCC, HBTU, BOP, CIP (2-chloro-1,3-dimethylimidazolinium hexafluorophosphate) or PyAOP (7-azabenzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate). Methods of activation and coupling of this type are described in a) M. Bodanszky and A. Bodanszky: The Practice of Peptide Synthesis. Springer-Verlag, New York, 1994; ISBN: 0-387-57505-7; b) K. Akaji et al., Tetrahendron Lett (1994), 35, 3315-3318; c) F. Albericio et al., Tetrahendron Lett (1997), 38, 4853-4856. This reaction provides a 1H-1,2,4-triazole derivative having the formula (V).

Synthetic Route B A compound of formula (S-III) is reacted with a halogenating agent such as thionyl chloride (SOCI2) or oxalyl chloride. This reaction gives the corresponding carbonyl chloride (acid chloride) (S-IV).

The reaction of a compound of formula (S-IV) with a compound of formula R2R3NH wherein R2 and R3 have the meaning described above provides a derivative of 1H-1,2-triazole having the formula (V).

Synthetic Route C A compound of formula (S-II) is reacted in an amidation reaction with a compound of formula R2R3NH wherein R2 and R3 have the meaning described hereinbefore to provide a derivative of 1H-1, 2, 4- triazole of formula (V). Said amidation reactions can be carried out using trimethylaluminum A1 (CH3) 3 (for more information on the conversion of asters to amides mediated by aluminum, see: JI Levin, E. Turos, SM Weinreb, Synth Común. (1982), 12, 989-993.

Example I Part A: is added to a stirred solution of dimethylaminomalonate hydrochloride (25 g, 0.136 mol) in dichloromethane (200 ml) triethylamine (41.4 ml, 2.2 molar equivalent) at 0 ° C. chlorobenzoyl (23.8 g, 0.136 mol) and the resulting solution is allowed to stand at room temperature overnight. Water is added and the organic layer is separated. The aqueous layer is extracted twice with dichloromethane. The combined organic layers are washed with water, dried over MgSO 4, filtered and concentrated in vacuo. The residue is recrystallized from methanol (400 ml) to give dimethyl 2- (4-chlorobenzoylamino) malonate (30.5 g, 79% yield). Melting point: 146-148 ° C. IH-NMR (200 MHz, CDC13): d 3.86 (s, 6H), 5.38 (d, J = 6 Hz, 1H), 7.15 (broad d, J ~ 6 Hz, 1H), 7.43 (d, J = 8 Hz, 2H), 7.79 (d, J = 8 Hz, 2H). Part B: To a stirred solution of 2,4-dichloroaniline (19.44 g, 0.12 mol) in concentrated HC1 (25 ml) and acetic acid (75 ml) at 0 ° C is added a solution of NaN02 (9.0 g, 0.13 mol) in water (50 ml) and the resulting solution is stirred for 15 minutes. A solution of dimethyl 2- (4-chlorobenzoylamino) -malonate (28.55 g, 0.10 mol) in acetone (200 ml) is added slowly while keeping the temperature below 0 ° C. A solution of K2C03 (120 g. g) in water (200 ml) and the resulting black mixture is stirred for 30 minutes at 0 ° C. The mixture is extracted three times with ethyl acetate. The combined organic layers are washed with water, Aqueous NaHC03 and water, respectively, are dried over gS04, filtered and concentrated in vacuo. The residue is dissolved in methanol (500 ml) and a solution of sodium (1 g) in methanol (75 ml) is added. The resulting stirred mixture is allowed to stand overnight at room temperature and is cooled in a refrigerator. The formed precipitate is collected by filtration and washed with methanol to give methyl 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -1H-1,2,4-triazole-3-carboxylate (11.4 g, 30% yield). Melting point 153-154 ° C. 1 H-NMR (200 MHz, CDC13): d 4.07 (s, 3H), 7.28-7, 60 (m, 7H). Part C: is added to a stirred suspension of methyl 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -1H-1,2,4-triazole-3-carboxylate (11.3 g, 0.0295 mol ) in methanol (100 ml) KOH (45% aqueous solution, 7.5 ml) and the resulting mixture is refluxed for 4 hours. The mixture is concentrated in vacuo and water (150 ml) and concentrated HC1 are added. Collect the yellow precipitate by filtration, wash with water and dry in vacuo to give the acid 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -1H-1,2,4-triazole-3. -carboxylic (10.0 g, 92% yield). Melting point: 141-144 ° C (with decomposition). Part D: is added successively to a stirred solution of 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -1H- 1,2,4-triazole-3-carboxylic acid (1.48 g, 4.0 mmol) in acetonitrile (20 ml) diisopropylethylamine (DIPEA) (1.5 ml, 2.1 molar equivalents), O-benzotriazol-1-yl-N,, ',' - tetramethyluronium hexafluorophosphate (HTB) (1.66 g, 1.1 molar equivalents) and 1- aminopipine (0.44 g, 1.1 molar equivalents). After stirring overnight an aqueous solution of NaHCC >is added;3 . The resulting mixture is extracted three times with dichloromethane. The combined organic layers are washed with water, dried over Na 2 SO 4, filtered and concentrated in vacuo to give an unpurified oil (3.6 g). This oil is further purified by silica gel flash chromatography; ethyl acetate / petroleum ether '(40-60 ° C) = 7/3 (v / v). The purified material is treated with ethanolic HC1 (1M solution) to provide 5- (4-chlorophenyl) -1- (2, -dichlorophenyl) -N- (piperidin-1-yl) 1H-1, 2, 4- hydrochloride triazole-3-carboxamide (1.50 g, 77% yield). Melting point: 238-240 ° C (with decomposition). XH-NMR (400 MHz, DMSO-d6): d 1.46-1.54 (m, 2H), 1.78-1.85 (m, 4H), 3.22-3.28 (m, 4H), 7.50 (s, 4H), 7.70 (dd, J = 8 and 2 Hz, 1H), 7.85-7.87 (m, 1H), 7.91 (d, J = 8 Hz, 1H), (NH is not visible). Examples 2-18 were prepared analogously: 2. 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -N-pyrrolidin-1-yl) -1 H-1, 2, 4- hydrochloride triazole-3-carboxamide. Melting point: 248-255 ° C (with decomposition). 3. 5- (4-chlorophenyl) -N-cyclohexyl-1- (2,4-dichlorophenyl) -1H-1,2,4-triazole-3-carboxamide. Melting point: 186-188 ° C. 4. N-t-Butoxy-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -1H-1,2,4-triazole-3-carboxamide. Melting point: 150-152 ° C. 5. 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -N- (n-pentyl) -1H-1,2,4-triazole-3-carboxamide. 1 H-NMR (400 Hz, CDCl 3): d 0.92 (t, J = 7 Hz, 3 H), 1.35-1.44 (m, 4 H), 1.62-1.70 (m, 2 H), 3.48-3.56 (m, 2 H), 7.20-7.25 (m, 1H), 7.34 (dt, J = 8 and 2 Hz, 2H), 7.42-7.50 (m, 4H), 7.54 (d, J = 2 Hz, 1H). 6. 5- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -N- (morpholin-4-yl) -1H-1,2, -triazole-3-carboxamide. Melting point: 184-186 ° C. 7. 1- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -N- (piperidin-1-yl) -1H-1,2,4-triazole-3-carboxamide hydrochloride. Melting point: 234-237 ° C (with decomposition). 8. 1- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -N- (pyrrolidin-1-yl) -1H-1,2,4-triazole-3-carboxamide hydrochloride. Melting point: 234-236 ° C (with decomposition). 9. 1- (4-chlorophenyl) -N-cyclohexyl-5- (2,4-dichlorophenyl) -1H-1,2, -triazole-3-carboxamide. 1 H-NMR (400 MHz, CDCl 3): d 1.14-1.81 (m, 8H), 2.02-2.10 (m, 2H), 4.00-4.11 (m, 1H), 7.08 (broad d, J ~ 7 Hz, 1H) , 7.26 (broad d, J ~ 8 Hz, 2H), 7.34 (broad d, J ~ 8 Hz, 2H), 7.40 (dd, J = 8 and 2 Hz, 1H), 7.44-7.48 (m, 2H). 10. N-t-Butoxy-1- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -1H-1,2,4-triazole-3-carboxamide. 1 H-NMR (400 MHz, CDC13): d 1.38 (s, 9H), 7.25 (broad d, J ~ 8 Hz, 2H), 7.35 (broad d, J ~ 8 Hz, 2H), 7.41 (dd, J = 8 and 2 Hz, 1H), 7.44-7.48 (m, 2H), 9.18, broad s, 1H). 11. 1- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -N- (n-pentyl) -1H-1,2, -triazole-3-carboxamide. 1H-R N (400 MHz, CDC13): d. 0.91 (t, J = 7 Hz, 3H), 1.35-1.41 (m, 4H), 1.60-1.70 (m, 2H), 3.48-3.56 (m, 2H), 7.21 (broad t, J ~ 7 Hz, 1H ), 7.26 (broad d, J ~ 8 Hz, 2H), 7.34 (broad d, J ~ 8 Hz, 2H), 7.40 (dd, J = 8 and 2 Hz, 1H), 7.44-7.48 (1, 2H) . 12. 1- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -N- (morpholin-4-yl) -1H-1,2,4-triazole-3-carboxamide hydrochloride. Melting point: 224-226 ° C. 13. 1- (2,4-Dichlorophenyl) -5- (pyridin-2-yl) -N- (piperidin-1-yl) -1H-1,2,4-triazole-3-carboxamide. Melting point: 191-193 ° C. 14. 5- (2, -Dichlorophenyl) -N- (piperidin-1-yl) -1- (4- (trifluoromethyl) phenyl) -1H-1,2, -triazole-3-carboxamide. Melting point: 159-161 ° C. 15. 1 '- [5- (2,4-dichlorophenyl) -1- (4- (trifluoromethyl) phenyl) -1H-1,2, -triazol-3-yl) carbonyl] piperidine. Melting point: 155-156 ° C. 16. 1- (2, -Dichlorophenyl) -N- (piperidin-1-yl) -5- (pyridin-3-yl) -1H-1,2,4-triazole-3-carboxamide. Melting point: 219 ° C. 17. 1- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -N- (5,5,5-trifluoropentyl) -1H-1,2, -triazole-3-carboxamide. 1 H-NMR (400 MHz, CDC13): d .1.63-1.80 (m, 4H), 2.06-2.22 (m, 2H), 3.54 (q, J ~ 7 Hz, 2H), 7.26 (m, 3H), 7.34 (broad d, J ~ 8 Hz, 2H), 7.40 (dd, J = 8 and 2 Hz, 1H), 7.44-7.48 (m, 2H). 18. 1- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -N- (5-fluoropentyl) -1H-1,2,4-triazole-3-carboxamide. XH-NMR (400 MHz, CDCl 3): d .1.63-1.80 (m, 4H), 2.06-2.22 (m, 2H), 3.54 (q, J ~ 7 Hz, 2H), 7.22-7.28 (m, 3H) , 7.34 (broad d, J ~ 8 Hz, 2H), 7.40 (dd, J = 8 and 2 Hz, 1H), 7.44-7.48 (m, 2H).

Example 19 Part A: 1- (Chlorophenyl) -5- (2,4-dichlorophenyl) -1H-1,2, -triazole-3-carboxylic acid was prepared analogously to the procedure described in Example 1, parts AC using dimethylaminomalonate hydrochloride, 2,4-dichlorobenzoyl chloride and 4-chloroaniline as starting products, respectively. Melting point: 102-104 ° C. 1 H-NMR (400 MHz, DMSO-d 6): d. 7.36 (broad d, J ~ 8 Hz, 2H), 7.50 (broad d, J ~ 8 Hz, 2H), 7.59 (dd, J = 8 and 2 Hz, 1H), 7.70 (d, J = 2 Hz, 1H ), 7.75 (d, J = 8 Hz, 1H), the OH proton is part of the water maximum ad 3.4.

Similarly, 1- (chlorophenyl) -5- (2, 5-dichlorophenyl) -1H-1,2,4-triazole-3-carboxylic acid prepared using dimethylaminomalonate hydrochloride, 2,4-dichlorobenzoyl chloride and 4-chloroaniline as starting products, respectively. Melting point: 183-188 ° C. 1 H-NMR (400 MHz, D SO-ds): d. 7.41 (broad d, J ~ 8 Hz, 2H), 7.52 (broad d, J ~ 8 Hz, 2H), 7.56 (d, J = 8 Hz, 1H), 7.65 (dd, J = 8 and 2 Hz, 1H ), 7.88 (d, 3 = 2 Hz, 1H), the OH proton is part of the water maximum ad 3.5. Part B: Add to a stirred solution of 1- (chlorophenyl) -5- (2,4-dichlorophenyl) -1H-1,2,4-triazole-3-carboxylic acid (0.37 g, 1.00 mmol) in dichloromethane ( 10 ml) oxalyl chloride (0.254 g, 2.00 mmol). The resulting mixture is concentrated in vacuo to provide the chloride of crude 1- (chlorophenyl) -5- (2, -dichlorophenyl) -1H-1,2,4-triazole-3-carbonyl chloride. Par-be C: The chloride is dissolved without purifying 1- (chlorophenyl) -5- (2, -dichlorophenyl) -1H-1,2,4-triazole-3-carbonyl in tetrahydrofuran (THF) (10 ml). 2,3-Dihydro-lH-inden-2-ylamine (0.40 g, 3.00 mmol) is added and the resulting solution is stirred for 42 hours at 25 ° C. The mixture is concentrated in vacuo and the residue is purified with liquid chromatography. Preparation to give 1- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -N- (2,3-dihydro-lH-inden-2-yl) -1H-1, 2,4-triazole-3 -carboxamide pure (393 mg, 81% yield). MS (ESI +) 485.6. 1 H-NMR (400 MHz, DMSO-de): 3.06 (dd, J = 16 and 8 Hz, 2H), 3.21 (dd, J = 16 and 8 Hz, 2H), 4.71-4.82 (m, 1H), 7.12 -7.16 (m, 2H), 7.19-7.24 (m.2H), 7.39 (broad d, J ~ 8 Hz, 2H), 7.52 (broad d, J ~ 8 Hz, 2H), 7.60 (dd, J = 8 and 2 Hz, 1H), 7.71 (d, J = 2 Hz, 1H), 7.79 (d, J = 8 Hz, 1H), 8.93-8.97 (m, 1H, NH). Examples 20-43 were prepared analogously: 20. 1- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -N- (1-ethynylcyclohexyl) -1H-1,2,4-triazole-3 -carboxamide. MS (ESI +) 473.3. 21. 1- (4-Chlorophenyl) -5- (2, -dichlorophenyl) -N- (2-methylcyclohexyl) -1H-1,2,4-triazole-3-carboxamide. MS (ESI +) 465.5. 22. 1- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -N- (4-methylcyclohexyl) -1H-1,2, -triazole-3-carboxamide. MS (ESI +) 465.5. 23. 1- (4-Chlorophenyl) -5- (2, -dichlorophenyl) -N-cyclooctyl-111-1,2,4-triazole-3-carboxamide. MS (ESI +) 477.3. 24. 1- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -N- (azepan-1-yl) -lH-1, 2,4-triazole-3-carboxamide. MS (ESI +) 466.4. 25. 1- (4-Chlorophenyl) -5- (2, -dichlorophenyl) -N-cycloheptyl-lH-1,2,4-triazole-3-carboxamide. MS (ESI +) 465.5. 26. N-t-Butyl-1- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -lH-1, 2,4-triazole-3-carboxamide. MS (ESI +) 425.4. 27. 1- (4-Chlorophenyl) -5- (2, -dichlorophenyl) -N- (1,1-diethylprop-2-yn-1-yl) -1H-1, 2,4-triazole-3-carboxamide. MS (ESI +) 461.5. 28. 1- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -N- (2,2,2-trifluoroethyl) -IH-1,2,4-triazole-3-carboxamide. MS (ESI +) 451.3. 29. 1- (4-Chlorophenyl) -5- (2, -dichlorophenyl) -N- (exo-bicyclo [2.2.1] hept-2-yl) -1H-1,2,4-triazole-3-carboxamide . MS (ESI4) 461.5. 30. 1- (4-Chlorophenyl) -5- (2,4-dichlorophenol) -N- (4- (2-propyl) iperazin-1-yl) -1H-1,2,4-triazole-3-carboxamide . MS (ESI +) 480.3. ^ -RM (400 MHz, DMSO-d6): 1.00 (d, J = 7 Hz, 6H), 2.46-2.56 (m, 4H), 2.72 (septuplet, J = 7 Hz, 1H), 3.66-3.74 (m , 4H), 7.36 (broad d, J = 8 Hz, 2H), 7.51 (broad d, J = 8 Hz, 2H), 7.59 (dd, J = 8 and 2 Hz, 1H), 7.72 (d, J = 2 Hz, 1H), 7.75 (d, J = 8 Hz, 1H). 31. 1- (4-Chlorophenyl) -5- (2, -dichlorophenyl) -N- (hexahydrocyclopenta [c] pyrrol-2 (1H) -yl) -1H-1,2,4-triazole-3-carboxamide. MS (ESI +) 476.4. 32. 1- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -N-pentyl-1H-1,2,4-triazole-3-carboxamide. MS (ESI +) 435.5. 33. 1- (4-Cloxophenyl) -5- (2,4-dichlorophenyl) -N- (2,2-dimethylpropyl) -lH-1, 2,4-triazole-3-carboxamide. MS (ESI +) 439.6. 34. 1- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -N- (3- (trifluoromethyl) phenyl) -1H-1,2,4-triazole-3-carboxamide. MS (ESI +) 511.7. 35. V - [1- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -1H-1,2,4-triazol-3-yl) carbonyl] -1, '-bipiperidine. MS (ESI +) 520.5. 36. 1- (4-Chlorophenyl) -N- (4-chlorophenyl) -5- (2,5-dichlorophenyl) -N-methyl-lH-1,2,4-triazole-3-carboxamide. S (ESI +) 491.4. 37. 1- (4-Chlorophenyl) -5- (2, 5-dichlorophenyl) -N- (1-ethynylcyclohexyl) -1H-1,2,4-triazole-3-carboxamide. MS (ESI +) 473.4. 38. 1- (4-Chlorophenyl) -5- (2, 5-dichlorophenyl) -N- (2-methylcyclohexyl) -1H-1,, 4-triazole-3-carboxamide. MS (ESI +) 465.5. 39. 1- (4-Chlorophenyl) -5- (2, 5-dichlorophenyl) -N- (4-methylcyclohexyl) -IH-1,, 4-triazole-3-carboxamide. MS (ESI +) 465.6. 40. 1- (4-Chlorophenyl) -5- (2, 5-dichlorophenyl) -N-cyclooctyl-lH-1,2,4-triazole-3-carboxamide. MS (ESI +) 477.3. 41. 1- (4-Chlorophenyl) -5- (2, 5-dichlorophenyl) -N-cycloheptyl-lH-1,2,4-triazole-3-carboxamide. MS (ESI +) 465.6. 42. 1- (4-Chlorophenyl) -5- (2,5-dichlorophenyl) -N-cyclopentyl-lH-1,2,4-triazole-3-carboxamide. MS (ESI +) 435.5. 43. 1- (4- Chloro-phenyl) -5- (2,5-dichlorophenyl) -N- (2,2-dimethylpropyl) -1H-1,2,4-triazole-3-carboxamide. MS (ESI +) 439. 6. The results of the pharmacological tests of a subgroup of compounds of the invention, obtained with the tests described above, are shown in the table below: Human cannabinoid CBi receptors Affinity in vltro Antagonism in vltro Example Value of K Value of pA2 Example 2 6.6 7.2 Example 3 6.9 8.7 Example 5 6.9 Example 9 7.4 8.2 Example 11 6.3

Claims

CLAIMS 1. Use of a compound with activity in the receptor CB.,. of formula (I), (II), (III), (IV), and / or (V), a prodrug thereof, tautomer thereof or a salt thereof, characterized in that it is used in the manufacture of medicaments for the treatment and / or prophylaxis of diseases related to the CBX receptor in young patients and / or for the treatment and / or prophylaxis of drug-induced obesity in young patients, as well as in adolescent patients.
2. Use of a compound with activity in the receptor CB1 according to claim 1, wherein the compound with activity in the CBir receptor is selected from the group of 4,5-dihydro-1H-pyrazole derivatives of formula (I) and / or (III), derivatives of lH- imidazole of formula (II), thiazole derivatives of formula (IV) and / or 1H-1,2,4-triazole-3-carboxamide derivatives of formula (V), characterized in that: a) the compounds of the formula ( I) are wherein -R and ¾ independently represent phenyl, thienyl or pyridyl whose groups may be substituted with 1, 2, 3 or 4 Y substituents, which may be the same or different, from the group C 1 alkoxy or hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C ^) amino, mono- or dialkyl (C ^.,) amido, alkyl (Cj_. 3) sulfonyl, dimethylsulfamido, alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R and / or RL represents naphthyl, -R2 represents hydrogen, hydroxy, C-, ^, acetyloxy or propyloxy alkoxy, -R3 represents a hydrogen atom or a linear or branched alkyl ^ B group or a C3_7 cycloalkyl group whose alkyl or cycloalkyl group can be substituted by a hydroxy group, -R4 represents a straight or branched C2_1D heteroalkyl group, a non-aromatic C3_8 heterocycloalkyl group or a non-aromatic C4.10 alkyl heterocyclealkyl group whose groups contain one or more heteroatoms of the upo (0, N, S) or a group -S02-, whose linear or branched heteroalkyl group C2"10, non-aromatic group heterocycloalkyl C3_a or non-aromatic group heterocycloalkyl C4.10 alkyl, may be substituted with a keto group, trifluoromethyl group , alkyl group C, _3, hydroxy, amino, monoalkylamino, or dialkylamino or a fluorine atom, or R4 represents an amino, hydroxy, phenoxy or benzyloxy group, or R4 represents an alkoxy, C3.8 alkenyl, C5.8 cycloalkenyl or C6_g cycloalkenylalkyl whose groups may contain a sulfur, nitrogen or oxygen atom, a keto group or a -S02- group, the alkoxy, alkenyl and cycloalkenyl groups of which may be substituted with a hydroxy group, a trifluoromethyl group, an amino group, a group monoalkylamino or a dialkylamino group, or a fluoro atom, or R4 represents a C2_s alkyl group whose alkyl group contains a fluoro atom, or R4 represents an imidazolylalkyl, benzyl, pyridylmethyl, phenethyl or thienyl group, or R4 represents a phenyl, ben cyl, pyridyl, thienyl, pyridylmethyl or phenethyl substituted wherein the aromatic rings are substituted with 1, 2 or 3 of the substituents Y, characterized in that Y has the meaning indicated above, or when R3 is H or methyl, R4 may represent a group NR6R7 wherein - R6 and R7 are the same or different and represent a C2_4 alkyl group, C2_4 trifluoroalkyl or R6 represents a methyl group with the proviso that R7 represents a C2_4 alkyl group, or R6 and R7, together with the nitrogen atom at which are attached, forms a saturated or unsaturated heterocyclic moiety having from 4 to 8 ring atoms whose heterocyclic moiety may contain an oxygen or sulfur atom or a keto group or a -S02- group or an additional nitrogen atom, whose saturated or unsaturated heterocyclic portion may be substituted with a C1-4 alkyl group, or -R3 and R4 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic moiety, monocyclic or bicyclic having 4 to 10 atoms in the ring, the heterocyclic portion of which may contain one or more atoms of the group (O, N, S) or a keto group or a -S02- group, which portion may be substituted with an alkyl 0-4 group, hydroxyalkyl, phenyl, thienyl, pyridyl, amine, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylamino, dialkylamino, aminoalkyl, azetidinyl , pyrrolidinyl, piperidinyl or hexahydro-1H-azepinyl, -Rs represents benzyl, phenyl, thienyl or pyridyl which may be substituted with 1, 2, 3 or 4 substituents Y wherein Y has the meaning indicated above, which may be the same or different, or R5 represents linear or branched alkyl, C3.B alkenyl, C3.10 cycloalkyl, Cs_10 bicycloalkyl, C6.10 tricycloalkyl or C5_8 cycloalkenyl or Rs represents naphthyl. b) the compounds of formula (II) are R wherein - R · represents phenyl, thienyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, whose groups may be substituted with 1, 2, 3 or 4 Y substituents, which may be same or different, from the group alkyl or Ci_3 alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono or dialkyl (Ci-2) amino, mono or dialkyl (Ci_2) amido, alkoxy (Ci-3) carbonyl , carboxyl, cyano, carbamoyl and acetyl, or R represents naphthyl, with the proviso that when R is 4-pyridinyl, R4 represents a halogen atom or a cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methanesulfonyl, methylsulphanyl or linear or branched Cx-4 alkyl group, whose Ci_4 alkyl group may be substituted with 1-3 fluoro atoms or with a bromo, chloro, iodo, cyano or hydroxy group. Ri represents phenyl or pyrimidyl, which groups can be substituted with 1-4 Y substituents, which can be the same or different, characterized in that Y has the meaning mentioned above, or Ri represents pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, whose groups can be substituted with 1-2 substituents Y, which may be the same or different or Ri represents a five-membered aromatic heterocyclic ring having one or two heteroatoms of the group (N, 0, S), whose heteroatoms may be the same or different, whose ring five-membered aromatic heterocyclic may be substituted with 1-2 Y substituents, which may be the same or different or Ri represents naphthyl, - R 2 represents H, linear or branched C 1 -C 8 alkyl, C 3-8 cycloalkyl, C 3-8 alkenyl, C 5-8 cycloalkenyl whose groups may contain a sulfur, oxygen or nitrogen atom, - R3 represents linear or branched C2-8 alkyl, Ci_a alkoxy, Cs-a cycloalkyloxy, C3-8 cycloalkyl bicycloalkyl il C5-10, C6-10 tricycloalkyl, C3_8 alkenyl, C5_8 cycloalkenyl, whose groups may optionally contain one or more heteroatoms of the group (0, N, S) and whose groups may be substituted with a hydroxy group or 1-2 alkyl groups Ci_3 or 1-3 fluoro atoms, or R3 represents a benzyl or phenethyl group whose aromatic rings may be substituted with 1-5 substituents Z, which may be the same or different, from the group alkyl or C1_3 alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (Ci_2) amino, mono- or dialkyl (Ci_2) amido, alkyl (Cx-3) sulfonyl, dimethylsulfamido, alkoxyC3 carbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R3 represents a phenyl or pyridinyl group, which groups are substituted with 1-4 Z substituents, wherein Z has the meaning indicated above, or R3 represents a pyridinyl group, or R3 represents a phenyl group, with the proviso of which R4 represe is a halogen atom or a cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methanesulfonyl, methylsulphanyl group or the Ci_ alkyl group, whose C1-4 alkyl group may be substituted by 1-3 fluoro atoms or with a group of bromine, chlorine, iodine, cyano or hydroxy, or R3 represents a group NR5R6 with the proviso that R2 represents a hydrogen atom or a methyl group in which -R5 and R6 are the same or different and represent C1-4 alkyl linear or branched, or R5 and R, together with the nitrogen atom to which they are attached, form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having from 4 to 10 ring atoms whose heterocyclic group contains one or two heteroatoms of the group (N, 0, S), whose heteroatoms may be the same or different, the heterocyclic group of which may be substituted with an alkyl group Ci_3 or a hydroxy group, or R2 and R3, together with the nitrogen atom to which they are attached, form a grup or saturated or unsaturated heterocyclic having from 4 to 10 ring atoms whose heterocyclic group contains one or two heteroatoms of the group (N, 0, S), whose heteroatoms may be the same or different, the heterocyclic group of which may be substituted by a C1-3 alkyl group or a hydroxy group, - R4 represents a hydrogen or halogen atom or a cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methanesulfonyl, methylsulphane group or a linear or branched C1-4 alkyl group, whose C1-4 alkyl group may be substituted with 1-3 fluoro atoms or with a bromo, chloro, iodo, cyano or hydroxy group, c) the compounds of formula (III) They are (lila) (lllb) wherein R and Rx independently represent phenyl, thienyl or pyridyl whose groups may be substituted with 1, 2 or 3 Y substituents, which may be the same or different, from the group alkyl or alkoxy C, hydroxy, halogen , trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or diakyl (G ^) amino, mono- or dialkyl (C ^) amido, alkyl (C ^ 3) sulfonyl, dimethylsulfamido, C1-3 alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R and / or -L represents naphthyl, R2 represents hydrogen, hydroxy, alkoxy ^ 3, acetyloxy or propionyl i, R3 represents a hydrogen atom or a linear C 8, alkyl group or branched or a C3_7 cycloalkyl group whose alkyl or cycloalkyl group may be substituted with a hydroxy group, R4 represents a hydrogen atom or a linear or branched alkylCB portion, C3_B cycloalkyl, C2_10 heteroalkyl, non-aromatic C3_a heterocycloalkyl or C4_10-alkyl heterocyclic alkyl aromatic c those portions may contain one or more heteroatoms of the group (O, N, S), the portions of which may be substituted with a keto group, trifluoromethyl group, C1-3i alkyl hydroxy, amino, monoalkylamino, or dialkylamino or a fluoro atom or R4 represents an amino, hydroxy, phenoxy or benzyloxy group or R4 represents a linear or branched C3_8 alkenyl, Cs_8 cycloalkenyl or C3_3 cycloalkenylalkyl group, which groups may contain a sulfur, nitrogen or oxygen atom, a keto group or - S02- whose C1_8 alkoxy C3_ alkenyl, Cs_8_ cycloalkenyl or C6.9 cycloalkenylalkyl groups may be substituted with a hydroxy, trifluoromethyl, amino, monoalkylamino or dialkylamino group or a fluoro atom, or R4 represents a phenyl, benzyl, pyridyl group , thienyl, pyridylmethyl or phenethyl wherein the aromatic rings may be substituted with 1, 2 or 3 of the Y substituents, wherein Y has the above meaning, or R4 represents a group NR8R9 with the condition d e that R3 represents a hydrogen atom or a methyl group and wherein R8 and Rg are the same or different and represent C1_i_alkyl or trifluoroalkylC2"4 < or Rs and R9, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic moiety having from 4 to 8 ring atoms whose heterocyclic moiety may contain an oxygen or sulfur atom or a keto group or an group -S02- or an additional nitrogen atom whose saturated or unsaturated heterocyclic portion can be substituted with an alkyl group or R3 and R4 together with the nitrogen atom to which they are attached form a monocyclic or bicyclic saturated or unsaturated heterocyclic portion having 4 to 10 atoms in the ring, whose heterocyclic portion may contain one or more atoms of the group (O, N, S) or a keto group or a -S02- group, the portion of which may be substituted with an alkyl group C, hydroxyalkyl phenyl, thienyl, pyridyl, amino, monoalkylaminoalkyl, dialkylaminoalguyl, monoalkylamino, dialkylamino, aminoalkyl, azetidinyl, pyrrolidinyl, piperidinyl or hexahydro-1H-azepinyl, Rs and R6 independently not otherwise represent a hydrogen atom or a linear or branched alkyl or alkenyl group Ca.B whose groups may contain one or more heteroatoms of the group (O, N, S), a keto group or a group -S02- and whose groups they may be substituted with a hydroxy or amino group, or Rs and R6 independently of each other represent a C3.8 cycloalkyl or C3_8 cycloalkenyl group which may contain one or more heteroatoms in the ring of the group (O, N, S) or the group -S02- and whose groups can be substituted with a hydroxy group, alkyl (C ^), the group -S02-, the keto group, amino monoalkylamino (C ^) or dialkylamino [Cx_3), or Rs represents a naphthyl group or a phenyl group whose phenyl group can be substituted with 1, 2 or 3 substituents Y wherein Y has the meaning described above with the proviso that Rs represents a hydrogen atom, or a linear or branched alkyl group (^ _5) whose group alkyl may contain one or more heteroatoms of the group (0, N, S) or the group -S02- and whose alkyl group can be substituted with a hydroxy, keto or amino group, or Rs and Rs, together with the nitrogen atom to which they are attached, form a monocyclic alkyl or alkenyl group , bicyclic or tricyclic, which may contain heteroatoms in the ring of the group (O, N, S), keto or S02 and whose monocyclic, bicyclic or tricyclic alkyl or alkenyl group may be substituted with a hydroxy group, alkyl (Ca_3), S02, keto, amino, (1-3C) aminoalkyl, dialkyl (C-3) amino, pyrrolidinyl or piperidinyl, whose monocyclic, bicyclic or tricyclic alkyl or alkenyl group may contain a phenyl group on the ring whose phenyl ring group may be substituted with 1 or 2 substituents Y, characterized in that Y has the meaning as described above, R7 represents C 1 alkyl, straight or branched, d) the compounds of formula (IV) are wherein R represents a hydrogen atom or a substituent X of the linear or branched C 1-3 alkyl or alkoxy group, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C 1-2) amino, mono- or dialkyl (Ci_2) amido, straight or branched alkoxy (Ci_3) carbonyl, trifluoromethylsulfonyl, sulfamoyl, linear or branched alkyl (C1-3) alkylsulfonyl, carboxyl, cyano, carbamoyl, dialkyl (Ci_3) straight or branched aminosulfonyl, aminosulfonyl, straight or branched monoalkyl (Ca-3) aminosulfonyl and acetyl, Ri is a hydrogen atom or represents 1-4 substituents X, where X has the meaning mentioned above, R2 represents a group phenyl, thienyl, pyridyl or pyrimidinyl, whose groups can be substituted with 1-4. X substituents, characterized in that X has the aforementioned meaning or R 2 represents a naphthyl, R 3 represents a hydrogen atom or a linear or branched alkyl or cycloalkyl-C 1-6 alkyl group or a phenyl, benzyl or phenethyl group whose aromatic rings may be substituted with 1-5 substituents Z, which may be the same or different, from the linear or branched C ^ 3 alkyl or alkoxy group, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C1-2) amino, mono- or dialkyl (Ci_2) amido, straight or branched alkyl ('Ci-3) sulfonyl, dimethylsulfamido, straight or branched alkoxy (Ci_3) carbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R3 represents a group pyridyl or thienyl, R 4 represents a linear or branched alkyl or cycloalkyl-C 1-10 alkyl group, a straight or branched C 1 -10 alkoxy, C 3 cycloalkyl, C 5-10 bicycloalkyl, C 6 -io tricycloalkyl, straight or branched C 3-10 alkenyl, ci Cs-s cloalkenyl, whose groups may contain one or more heteroatoms of the group (O, N, S) and whose groups may be substituted with a hydroxy group, 1-3 methyl groups, an ethyl group or 1-3 fluoro atoms, or R4 represents a phenyl, benzyl or phenethyl group whose aromatic rings can be substituted with 1-5 substituents Z, characterized in that Z has the meaning mentioned above, or R4 represents a pyridyl or thienyl group, or R4 represents a group NR5R6 where Rs and Rs, together with the nitrogen atom to which they are attached, form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having from 4 to 10 atoms in the ring, the heterocycle group containing one or more heteroatoms of the group (O, N , S) and whose heterocyclic group can be substituted with a linear or branched Cx_3 alkyl group, hydroxy or trifluoromethyl or a fluoro atom or R3 and R4, together with the nitrogen atom to which they are attached, form a heterocyclic group saturated monocyclic or bicyclic unsaturated having 4 to 10 atoms in the ring, whose heterocyclic group contains one or more heteroatoms of the group (O, N, S) and whose heterocyclic group may be substituted with a linear or C 1 alkyl group; branched, hydroxy or trifluoromethyl or a fluoro atom, e) the compounds of formula (V) are (V) wherein R and ¾ independently represent a phenyl, naphthyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or triazinyl group, which groups may be substituted with 1-4 substituents X, which may be the same or different from the alkyl groups or linear or branched alkoxy (Ci_3), hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (Ci_2) amino, mono- or dialkyl (Ci_ 2) amido, (C: -3) alkoxycarbonyl , trifluoromethylsulfonyl, sulfamoyl, alkyl (Cx-3) sulfonyl, carboxyl, cyano, carbamoyl, dialkyl (C ± -3) aminosulfonyl, monoalkyl (Ci_3) aminosulfonyl and acetyl, R2 represents a hydrogen atom or an alkyl group Ci-8 or linear or branched Ci-8-alkylcycloalkyl or a phenyl, benzyl or phenethyl group whose aromatic rings can be substituted by 1-4 substituents X, where X has the meaning indicated above, or] represents a pyridyl or thienyl groupR3 represents linear or branched Ci-g alkyl, Ci_8 alkoxy, C3_8 cycloalkyl, C5.10 bicycloalkyl, C6_10 tricycloalkyl, C3_8 alkenyl, cycloalkenyl Cs_g, whose groups may optionally contain one or more heteroatoms of the group (O, N, S), whose groups can be substituted with a hydroxy group, an ethynyl group or 1-3 fluoro atoms, or R3 represents a phenyl, benzyl or phenethyl group whose aromatic rings can be substituted with 1-4 substituents X, where X has the meaning as indicated above, or R3 represents a pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl or thienyl group whose eteroaromatic rings may be substituted with 1-2 substituents X, wherein X has the meaning indicated above, or R3 represents a group NR4RS wherein R4 and R5, together with the nitrogen atom to which they are attached, form a saturated or unsaturated, monocyclic or bicyclic heterocyclic moiety having from 4 to 10 atoms in the ring, which I heterocyclic group contains one or two heteroatoms of the group N, O or S, whose heteroatoms may be the same or different, whose heterocyclic portion may be substituted with a linear or branched alkyl group, hydroxy or trifluoromethyl or a fluoro atom, or R2 and R3, together with the nitrogen atom to which they are attached, form a saturated or unsaturated, monocyclic or bicyclic heterocyclic moiety having from 4 to 10 ring atoms, whose heterocyclic group contains one or two heteroatoms of the N, O or S group , whose heteroatoms may be the same or different, the heterocyclic portion of which may be substituted with a linear or branched C 3 alkyl group, hydroxy, piperidinyl or trifluoromethyl or a fluoro atom.
3. Use of a compound with activity in the receptor CBX according to any one of claims 1 or 2, or a prodrug, tautomer or salt thereof, wherein the use is in the manufacture of a medicament for pediatric treatment and / or prophylaxis that relates to psychiatric disorders such as psychosis , anxiety, depression, attention deficit, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, appetite, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremors, epilepsy, multiple sclerosis , traumatic brain injury, cardiovascular accident, Parkinson's disease, Alzheime disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral apoplexy, craniocerebral trauma, cardiovascular accident, spinal cord damage, neuroinflammatory disorders, plaque sclerosis , viral encephalitis, disorders related to demyelin as well as for the pediatric treatment of pain disorders, including neuropathic pain disorders and other diseases involving cannabinoid neurotransmission that includes the pediatric treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases, disorders gastrointestinal, gastric ulcers, diarrhea and cardiovascular disorders.
4. Use of a compound with activity in the CBj receptor. according to any of claims 1 to 3, or a prodrug, tautomer or salt thereof, preferably of a CB1 receptor antagonist compound or a prodrug, tautomer or salt thereof, characterized in that Use is in the manufacture of a medicament for the treatment and / or prophylaxis of obesity in young patients and / or drug-induced obesity in young patients, as well as in adolescent patients.
5. Use of a compound with activity in the CBX receptor according to claim 2, or a prodrug, tautomer or salt thereof, preferably of a CB1 receptor antagonist compound or a prodrug, tautomer or salt thereof, in combination with at least one lipase inhibitor compound characterized in that it is used in the manufacture of a medicament for the treatment and / or prophylaxis of obesity in adolescent patients or in young patients and / or drug-induced obesity in young patients, as well as in patients teenagers .
6. Use of a compound with activity in the CB-L receptor according to claim 5, characterized in that the compound with activity in the CB1 # receptor or a prodrug, tautomer or salt thereof, preferably the B receptor antagonist compound or a prodrug, tautomer or salt thereof, is used in combination with at least one lipase inhibitor compound selected from the group of lipase inhibitor polymers, orlistat, panclicins, ATL-962 and lipstatin.
7. Pharmaceutical composition that contains at least one compound with activity in the receptor ??? of formula (I), (II), (III), (IV) and / or (V), or a prodrug, tautomer or salt thereof, as an active component suitable for the treatment and / or prophylaxis of diseases related to the CB-L receptor in young patients and / or for the treatment and / or prophylaxis of drug-induced obesity in young patients, as well as in adolescent patients.
8. Pharmaceutical composition according to claim 7, characterized in that the compound with activity in the CB I receptor is selected from the group of 4,5-dihydro-1H-pyrazole derivatives of the formula (I) and / or (III) , lH-imidazole derivatives of the formula (II), thiazole derivatives of the formula (IV) and / or 1H-1, 2,4-triazole-3-carboxamide derivatives of the formula (V), as each is defined in claim 1 or 2.
9. Pharmaceutical composition according to any of claims 7 to 8, characterized in that the at least one compound with activity in the CB ^ receptor of formula (I), (II), (III), (IV) and / or (V), or a prodrug, tautomer or salt thereof, is present in an amount effectively suitable for pediatric treatment and / or prophylaxis related to psychiatric disorders such as psychosis, anxiety, depression, attention deficit, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, appetite, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremors, epilepsy, sclerosis multiple, traumatic brain injury, cardiovascular accident, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral stroke, cranioencephalic trauma, cardiovascular accident, spinal cord damage, neuroinflammatory disorders, sclerosis in plaque, viral encephalitis, alterations related to demyelination, as well as for the treatment or pediatric of pain disorders, which include neuropathic pain disorders, and other diseases involving cannabinoid neurotransmission, which includes the pediatric treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases, gastrointestinal disorders , gastric ulcers, diarrhea and cardiovascular disorders, in a young patient in need of such treatment.
10. Pharmaceutical composition according to any of claims 7 to 9, characterized in that the at least one compound with activity in the CB-L receptor of formula (I), (II), (III), (IV) and / or (V), or a prodrug, tautomer or salt thereof, preferably the CB1 receptor antagonist compound or a prodrug, tautomer or salt thereof, is present in an amount effectively suitable for the treatment and / or prophylaxis of obesity in patients Young people and / or drug-induced obesity in young patients, as well as in adolescent patients.
11. Pharmaceutical composition containing as active components at least one compound with activity in the receptor B ^ according to claim 2, characterized in that a prodrug, tautomer or salt thereof, preferably a CBX receptor antagonist compound or a prodrug, tautomer or salt thereof, and at least one lipase inhibitor compound for the treatment and / or prophylaxis of obesity in adolescent patients or in young patients and / or drug-induced obesity in young patients, as well as in adolescent patients.
12. Pharmaceutical composition according to claim 11, characterized in that it contains at least one compound with activity at the 0 receptor? or a prodrug, tautomer or salt thereof, preferably the CB1 receptor antagonist compound or a prodrug, tautomer or salt thereof, in combination. with at least one lipase inhibitor compound selected from the group of polymers inhibitors of lipase, orlistat, panclicins, ATL-962 and lipstatin.
13. Pharmaceutical composition according to any of claims 10 to 12, characterized in that the at least one compound with activity in the CBlt receptor or a prodrug, tautomer or salt thereof, preferably the B1 receptor antagonist compound having the formula ( I), (II), (III), (IV) or (V) as defined in claim 2, or the prodrug, tautomer or salt thereof, and the at least one lipase inhibitor compound are each present in an amount effectively suitable for the treatment and / or prophylaxis of obesity in a young patient in need of such treatment.
14. Pharmaceutical composition according to any of claims 10 to 12, characterized in that the at least one compound with activity in the Blt receptor or a prodrug, tautomer or salt thereof, preferably the CB antagonist compound having the formula (I) ), (II), (III), (IV) or (V) as defined in claim 2, or the prodrug, tautomer or salt thereof, and the at least one lipase inhibitor compound are each present in an amount effectively suitable for the treatment and / or prophylaxis of drug-induced obesity in young patients as well as in adolescent patients in need of such treatment.
15. Method for the treatment and / or prophylaxis of diseases related to the CBI receptor in young patients and / or for the treatment and / or prophylaxis of drug-induced obesity in young patients as well as in adolescent patients, characterized because at least a compound with activity in the CBa receptor of formula (I), (II), (III), (IV) and / or (V), a prodrug thereof, a tautomer thereof or salt thereof, in accordance with Claim 2, is administered to a patient in need of such treatment.
Method for the treatment or prophylaxis according to claim 15, characterized in that the treatment and / or prophylaxis is directed to a pediatric treatment and / or prophylaxis that refers to psychiatric disorders such as psychosis, anxiety, depression, attention deficit, disorders of memory, cognitive disorders, appetite disorders, obesity, addiction, appetite, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremors, epilepsy, multiple sclerosis, traumatic brain injury, cardiovascular accident, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral apoplexy, craniocerebral trauma, cardiovascular accident, spinal cord damage, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, disorders related to demyelination, as well as pair to the pediatric treatment of pain disorders, including neuropathic pain disorders and other diseases involving cannabinoid neurotransmission including pediatric treatment of septic snock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases, gastrointestinal disorders, gastric ulcers, diarrhea and cardiovascular disorders.
17. Method of treatment and / or prophylaxis according to any of claims 15 or 16, characterized in that the treatment and / or prophylaxis is directed to obesity in young patients and / or drug-induced obesity in young patients as well as in adolescent patients.
18. Method of treatment and / or prophylaxis of obesity in adolescent patients or in young patients and / or of drug-induced obesity in young patients, as well as in adolescent patients, characterized in that at least one compound with CB1 receptor activity in accordance with with claim 2, characterized in that a prodrug, tautomer or salt thereof, preferably a B1 receptor antagonist compound or a prodrug, tautomer or salt thereof, is administered in combination with at least one lipase inhibitor compound to a patient in need. of said treatment.
19. Method of treatment and / or prophylaxis according to claim 18, characterized in that the at least one compound with activity in the CBX receptor or a prodrug, tautomer or salt thereof, preferably a CB-L receptor antagonist compound or a The prodrug, tautomer or salt thereof is administered in combination with at least one lipase inhibitor compound selected from the group of lipase inhibitor polymers, orlistat, panclicins, ATL-962 and lipstatin.
20. Method of treatment and / or prophylaxis according to any of claims 15 to 19, characterized in that the treatment is directed to obesity in young patients.
21. Method of treatment and / or prophylaxis according to any of claims 15 to 19, characterized in that the treatment is directed to drug-induced obesity in young patients or adolescent patients.
22 Method of treatment and / or prophylaxis according to any of claims 15 to 21, characterized in that the compound with activity in the CB-L receptor or a prodrug, tautomer or salt thereof, preferably the receptor antagonist compound CB ^^ or a prodrug, tautomer or salt thereof, is administered in combination with the lipase inhibitor compound by simultaneous, separate or successive route of administration. 2. 3 .
A pharmaceutical product containing as a medicament at least one compound with activity in the CBi receptor having the formula (I), (II), (III), (IV), or (V) according to claim 2, characterized in that a prodrug, tautomer or salt thereof, preferably a CB-L receptor antagonist compound OR a prodrug, tautomer or salt thereof, as a combination preparation with at least one lipase inhibitor compound for simultaneous, separate or sequential administration in the treatment and / or obesity prophylaxis.
24 Pharmaceutical product containing as a medicament at least one compound with activity in the CB- receptor. having the formula (I), (II), (III), (IV), or (V) according to claim 2, characterized in that a prodrug, tautomer or salt thereof, preferably an antagonist compound of the CB1 receptor or a prodrug, tautomer or salt thereof, and a package insert indicating that said compound with activity in the CBlf receptor preferably · the CB1 antagonist compound, can be administered in combination with a lipase inhibitor compound for simultaneous, separate or sequential administration in the treatment and / or obesity prophylaxis.
25. Compound with activity in the CE ^ receptor having one of the formulas (I), (II), (III), (IV), or (V) according to claim 2, characterized in that a prodrug, tautomer or salt thereof, preferably CB1 receptor antagonist compound or a prodrug, tautomer or salt thereof, in combination with at least lipase inhibitor compound.
26. Combination according to claim 26 of Compound with activity at the CBX receptor having one of formulas (I), (II), (III), (IV), or (V) in accordance with claim 2, characterized in that the compound with activity at the CB1 receptor or a prodrug, tautomer or salt thereof, preferably CB1 receptor antagonist compound or a prodrug, tautomer or salt thereof, is in combination with at least one lipase inhibitor compound selected from the group of polymers inhibitors of lipase, orlistat, paneliciñas, ATL-962 and lipstatin.