HK1101275A - Novel medical uses of compounds showing cb1-antagonistic activity and combination treatment involving said compounds - Google Patents

Description

Display CB1New medical use of compounds with antagonistic activity and combination therapy comprising said compounds

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The invention relates to a display CB₁New therapeutic and/or prophylactic uses of compounds with antagonistic activity, and also pharmaceutical compositions comprising one or more of these compounds as active ingredients for new uses. The compounds proposed by the present invention show cannabis-1 (CB)₁) Receptor antagonistic activity, may provide significant utility for the novel medical uses provided by the present invention. Further, according to an embodiment of the present invention, the capacitor has a CB₁The compounds of antagonistic activity can be used in combination with other active ingredients, and also relates to compositions comprising at least one of said CBs₁-a pharmaceutical composition for the treatment and/or prevention of obesity in combination with said other active ingredients. The hemp-1 (CB) provided by the invention₁) The combined administration of the compounds with receptor antagonistic activity and the further active ingredients is particularly useful for the treatment of obesity.

Cannabinoids are present in the Indian hemp Cannabis Sativa L. and have been used as medicaments for centuries (Mechoulam, R.; Feigenbaum, J.J.prog.Med.chem.1987, 24, 159). However, only over the past decade, research in the cannabinoid field has revealed key information about cannabinoid receptors and their (endogenous) agonists and antagonists. Two distinct subtypes (CB) of cannabinoid receptors₁And CB₂) The discovery and subsequent cloning of (a) stimulated the study of new cannabinoid receptor antagonists (Munro, s.; thomas, k.l.; Abu-Shaar, m.nature 1993, 365, 61.Matsuda, l.a.; bonner, t.i.cannabiniodreceptors, Pertwee, r.g.ed.1995, 117, Academic Press, London). In addition, pharmaceutical companies are interested in the development of cannabinoid drugs for use in the treatment of diseases associated with disturbances of the cannabinoid system. CB (CB)₁Broad distribution of receptors in the brain plus CB₂Very strict peripheral localization of the receptor, such that CB₁Receptors have become very interesting molecular targets for CNS-directed drug discovery in several fields of medical indications, for example, interesting psychiatric and neurological diseases are described in the prior art (consiroe, p. neurobiology of diseases 1998, 5, 534.Pop, e.curr. opin. inpns. innovative therapeutic Drugs 1999, 1, 587.Greenberg, d.a. drug news perspective 1999, 12, 458).

From the international patent applications WO 03/026647, WO 03/027076, WO03/078413, WO03/078413, and the more recently filed international patent application, which will be published in 2004 at 3/4 and which is proposed on the basis of the european prior application EP02078966.5 with a priority date of 2002 at 9/19, compounds for the treatment of diseases associated with disturbances of the cannabinoid system are known. Accordingly, theseCompounds cannabinoid CB₁The receptor is active, exhibiting, for example, CB₁Antagonistic activity, which have the structure of formula (I), (II), (III), (IV) or (V) as defined below in the description. In particular, said has CB₁Compounds with receptor activity have been suggested for the treatment of psychiatric disorders such as psychosis, anxiety disorders, depression, attention deficit, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, desire (apetence), drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral stroke, craniocerebral trauma, stroke, spinal cord injury, neuroinflammatory disorders (neuroinflata ydoreders), plaque sclerosis, viral encephalitis, disorders associated with demyelination, and for the treatment of pain disorders, including neuropathic pain disorders, and other diseases involving cannabinoid neurotransmission, including the treatment of septic shock, anxiety, depression, attention deficit, memory disorders, cognitive disorders, appetite disorders, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral stroke, spinal cord injury, neuroinflammatory disorders, and conditions associated with demyelination, 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 having the structure of formula (I) as defined below. These 4, 5-dihydro-1H-pyrazole derivatives are potent Cannabinoids (CB)₁) Receptor antagonists for the treatment of diseases associated with disturbances of the cannabinoid system. These compounds have the general formula (I) wherein the symbols have the meanings given below in the description, show particularly effective CB₁Antagonistic activity.

International patent application WO 03/027076 describes a group of novel compounds which are 1H-imidazole derivatives having the structure of formula (II) defined below. These 1H-imidazole derivatives are potent Cannabinoids (CB)₁) Receptor agonists, partial agonists or antagonists, for the treatment of psychiatric and neurological disorders, and other diseases involving cannabinoid neurotransmission. TheseThe compounds have the general formula (II) wherein the symbols have the meanings given below in the description.

International patent application WO 03/026648 describes a group of novel compounds which are also 4, 5-dihydro-1H-pyrazole derivatives having a structure of formula (III) as defined below. These 4, 5-dihydro-1H-pyrazole derivatives are also potent Cannabinoid (CB)₁) Receptor antagonists for the treatment of diseases associated with disturbances of the cannabinoid system. In particular, these compounds have the general formula (IIIa) or (IIIb), wherein the symbols have the meanings given below in the description.

International patent application WO03/078413 describes a group of novel compounds which are thiazole derivatives having the structure of formula (IV) defined below. These thiazole derivatives are potent antagonists, agonists or partial agonists of the cannabinoid CB 1-receptor and are useful in the treatment of diseases related to disorders of the cannabinoid system. These compounds have the general formula (IV) wherein the symbols have the meanings given below in the description.

A recently filed international patent application, which was published at 2004, 3/4 and which was based on the european prior application EP02078966.5, with a priority date of 2002, 9, 19, describes a group of novel compounds which are 1, 5-diaryl-1H-1, 2, 4-triazole-3-carboxamide derivatives having the structure of formula (V) as defined below. These 1, 5-diaryl-1H-1, 2, 4-triazole-3-carboxamide derivatives are cannabinoid CB₁Effective antagonists, agonists, inverse agonists or partial agonists of the receptor for the treatment of diseases associated with disorders of the cannabinoid system. These compounds have the general formula (V) wherein the symbols have the meanings given below in the description.

The object of the present invention is to provide improved methods of treatment and/or prevention, especially suitable for patients with a higher need for safety and tolerability, such as for the treatment of obese patients, especially for example juvenile obese patients, and/or for patients undergoing long term treatment, such as for example juvenile or adolescent patient drug induced obesity. A further object is to provide a particularly advantageous combination therapy and medicaments thereof,to treat and/or prevent obesity in patients of any age, e.g. juvenile and adolescent patients, wherein the present invention uses a compound having CB₁The antagonistic compound is combined with another active ingredient for the treatment of obesity.

It has now surprisingly been found that due to the selectivity CB₁Outstanding and unique pharmacological properties of antagonistic compounds, including a particularly high safety and tolerability, are particularly suitable for the treatment and/or prevention of diseases associated with disorders of the cannabinoid system, especially in patients with a higher need for safety and tolerability, especially for patients such as juvenile patients and/or patients undergoing long-term therapy, for example drug-induced obesity.

The invention therefore relates to a compound having one of the structures of the formulae (I), (II), (III), (IV) or (V) defined below, having CB₁-a receptor active compound, or a prodrug, tautomer or salt thereof, preferably CB₁A receptor antagonist compound, or a prodrug, tautomer, or salt thereof, in combination with at least one lipase inhibiting compound. In one variant embodiment of the invention, one of the structures of the formulae (I), (II), (III), (IV) or (V) defined below has CB₁-a receptor active compound, or a prodrug, tautomer or salt thereof, preferably CB₁A receptor antagonist compound, or a prodrug, tautomer, or salt thereof, is combined with at least one lipase inhibiting compound selected from the group consisting of lipase inhibiting polymers, orlistat, panclicins, ATL-962, and lipstatin.

In particular, it has surprisingly been found that the formulae (I), (II), (III), (IV) and/or (V) CB₁Antagonists, prodrugs thereof, tautomers thereof and salts thereof, exhibit unique pharmacological properties and are therefore particularly suitable for the preparation of a medicament for the treatment and/or prevention of obesity in obese patients, in particular in juvenile patients and/or obesity caused by juvenile or adolescent patients. In this connection, CB of the formulae (I), (II), (III), (IV) and/or (V)₁Antagonistic compounds, their prodrugs, their tautomers and their salts, in one aspect for providing pediatric useDrugs, and drugs for general use in drug induced obesity are of great value.

Due to their cannabinoid CB₁The activity of the receptor, the compounds used according to the invention are also suitable for the treatment and/or prevention of other disorders in paediatrics, in addition to juvenile obesity and drug induced obesity in juvenile patients. These other conditions include those known from the literature for cannabinoid CB₁Conditions for which a compound with active receptor is indicated, for example in young patients, pediatric treatment and/or prevention may also involve psychiatric disorders, for example psychosis, anxiety disorders, depression, attention deficit, memory disorders, cognitive disorders, obesity, disorders, addiction, desire, drug dependence and neurological disorders, for example neurodegenerative disorders, dementia, dystonia, myospasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral stroke, craniocerebral trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, disorders associated with demyelination, and for the treatment of pediatric pain disorders, including neuropathic pain disorders, and other diseases involving cannabinoid neurotransmission including pediatric treatment for septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases, gastrointestinal disorders, gastric ulcers, diarrhea, and cardiovascular disorders.

The documents mentioned in the present description are incorporated in their entirety by reference into the present application.

CB for use in the invention₁The antagonistic compound can be obtained according to known methods. Suitable synthetic methods for the compounds used in the present invention are described in the prior art, for example, in the documents cited and incorporated by reference in the present application.

Furthermore, it has surprisingly been found that the formulae (I), (II), (III), (IV) and/or (V) CB₁Antagonistic Compound (CB)₁Antagonists) and prodrugs and conjugates thereofThe mutants and salts, due to their unique pharmacological properties, are particularly suitable for use in combination with at least one lipase inhibiting compound (lipase inhibitor) for the preparation of a medicament for the treatment and/or prevention of obesity, including in particular the treatment and/or prevention of obesity in juvenile patients and/or obesity caused by medicaments in juvenile patients and adolescent patients. In this regard, at least one CB as defined herein₁The combination of an antagonistic compound with at least one lipase inhibiting compound is very useful in providing a medicament for the treatment and/or prevention of obesity in general, such as obesity in juvenile patients of any age, and especially pediatric or juvenile obesity, and drug induced obesity in juvenile and adolescent patients.

In particular, the invention is based on the surprising discovery that this is the CB of the formula (I)₁The antagonistic compound is a 4, 5-dihydro-1H-pyrazole derivative, (II) is a 1H-imidazole derivative, (III) is a 4, 5-dihydro-1H-pyrazole derivative, (IV) is a thiazole derivative, or (V) is a 1H-1, 2, 4-triazole-3-carboxamide derivative, which are all cannabinoid CB₁-receptor antagonists, prodrugs thereof, tautomers thereof and salts thereof, which, due to their unique pharmacological properties, are particularly suitable for use in combination with at least one lipase inhibiting compound for the preparation of a medicament for the treatment and/or prevention of obesity in general, such as in adolescent patients of any age, and in particular for the treatment and/or prevention of obesity in juvenile patients, and/or drug induced obesity in juvenile and adolescent patients. In this regard, each compound having formula (I), (II), (III), (IV) or (V), together with a lipase inhibiting compound, is of great value in providing a medicament for the treatment and/or prevention of obesity in general, e.g. in adolescent patients of any age, and in particular in pediatric or juvenile obesity, and drug induced obesity.

The compounds of formula (I), (II), (III), (IV) or (V) used according to the invention can be obtained according to known methods. Suitable synthetic methods for the compounds of the formulae (I), (II), (III), (IV) to be used according to the invention are described in the international patent applications WO 03/026647, WO 03/027076, WO03/078413 or WO03/078413, which are incorporated herein by reference. The compounds of formula (V) may be prepared according to the most recently filed international patent application, which will be published at 3/4 in 2004 and which was filed on the basis of the european prior application EP02078966.5 with a priority date of 9/19 in 2002, which is also incorporated herein by reference. The preparation of the compounds of formula (V) is also described at the end of the present description.

In the following, embodiments of the present invention are described in more detail with respect to compounds of formula (I), (II), (III), (IV) or (V), exemplarily especially with respect to obesity.

A compound of formula (I)

In a first embodiment, the present invention is based on the surprising discovery that are 4, 5-dihydro-1H-pyrazole derivatives of formula (I) which are potent and selective cannabinoid CB₁-receptor antagonists, prodrugs thereof, tautomers thereof and salts thereof:

wherein

-R and R₁Independently represents phenyl, thienyl or pyridyl, which groups may be substituted by 1, 2, 3 or 4 identical or different substituents Y, Y being selected from C_1-3-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono-or dialkyl (C)_1-2) -amino, mono-or dialkyl (C)_1-2) -acylamino group, (C)_1-3) -alkylsulfonyl, dimethylsulfonamido, C_1-3Alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, aminosulfonyl and acetyl, or R and/or R₁Represents a naphthyl group, and the naphthyl group,

-R₂represents hydrogen, hydroxy, C_1-3-alkoxy, acetoxy or propionyloxy,

-R₃represents a hydrogen atom, or C which is branched or unbranched_1-8Alkyl, or C_3-7Cycloalkyl, wherein alkyl or cycloalkyl may be substituted by hydroxy,

-R₄represents C_2-10Branched or unbranched heteroalkyl, C_3-8Non-aromatic heterocycloalkyl or C_4-10Non-aromatic heterocycloalkyl-alkyl radicals containing one or more heteroatoms selected from O, N, S or-SO₂A group in which C_2-10Branched or unbranched heteroalkyl, C_3-8Non-aromatic heterocycloalkyl or C_4-10Non-aromatic heterocycloalkyl-alkyl groups may be substituted by keto, trifluoromethyl, C_1-3Alkyl, hydroxy, amino, monoalkylamino, or dialkylamino groups or fluorine atom substitution; or R₄Represents amino, hydroxy, phenoxy or benzyloxy; or R₄Represents C_1-8Alkoxy radical, C_3-8Alkenyl radical, C_5-8Cycloalkenyl or C_6-9Cycloalkenylalkyl, which may contain a sulfur, nitrogen or oxygen atom, a keto group or-SO₂-groups in which alkoxy, alkenyl and cycloalkenyl groups can be substituted by hydroxy, trifluoromethyl, amino, monoalkylamino or dialkylamino groups or by fluorine atoms; or R₄Represents C_2-5An alkyl group, wherein the alkyl group contains a fluorine atom; or R₄Represents imidazolylalkyl, benzyl, pyridylmethyl, phenethyl or thienyl; or R₄Represents substituted phenyl, benzyl, pyridyl, thienyl, pyridylmethyl or phenethyl, in which the aromatic rings are substituted by 1, 2 or 3 substituents Y, in which Y has the meaning indicated above,

or when R is₃When it is hydrogen or methyl, R₄May be a group NR₆R₇Wherein

-R₆And R₇Identical or different, represents C_2-4Alkyl radical, C_2-4Trifluoroalkyl, or R₆Represents methyl, provided that R₇Represents C_2-4Alkyl, or R₆And R₇Together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic moiety having from 4 to 8 ring atoms, in which the heterocyclic moiety may contain an oxygen or sulfur atom or a keto group or-SO₂A group or other nitrogen atom, in which the saturated or unsaturated heterocyclic moiety may be replaced by C_1-4Alkyl is substituted, or

-R₃And R₄Together 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, wherein the heterocyclic moiety may contain one or more atoms selected from O, N, S or a keto group or-SO₂A group, which moiety may be substituted by C_1-4Alkyl, hydroxyalkyl, phenyl, thienyl, pyridyl, amino, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylamino, dialkylamino, aminoalkyl, azetidinyl, pyrrolidinyl, piperidinyl, or hexahydro-1H-aza * -yl,

-R₅represents benzyl, phenyl, thienyl or pyridyl, which may be substituted by 1, 2, 3 or 4 substituents Y, wherein Y has the meaning indicated above, which may be identical or different; or R₅Represents C_1-8Branched or unbranched alkyl, C_3-8Alkenyl radical, C_3-10 cycloalkyl group, C_5-10Bicycloalkyl radical, C_6-10Tricycloalkyl or C_5-8A cycloalkenyl group; or R₅Represents a naphthyl group, and the naphthyl group,

due to their unique pharmacological profile they are particularly suitable for use in combination with at least one lipase inhibiting compound for the preparation of a medicament for the treatment and/or prevention of obesity in general, such as obesity in juvenile patients of any age, and in particular also for the treatment and/or prevention of obesity in juvenile patients, and/or drug induced obesity in juvenile and adolescent patients. In this respect, the combination of a compound of formula (I) with a lipase inhibiting compound is of great value in providing a medicament for the treatment and/or prevention of obesity in general, such as obesity in juvenile patients of any age, in particular pediatric or juvenile obesity, and drug induced obesity.

The presence of at least one chiral centre (C at the 4, 5-dihydro-1H-pyrazole moiety) in the compounds of formula (I)₄Location). The invention relates to racemates, diastereomers and mixtures of the individual stereoisomers of the compounds of formula (I). In particularInteresting compounds of formula (I) C in the 4, 5-dihydro-1H-pyrazole moiety₄Positionally possessing an absolute spatial configuration, as in formula (1)^a) The method comprises the following steps:

the invention also relates to the E isomer, the Z isomer and the mixture of the E/Z forms of the compound of formula (I).

A compound of formula (II)

In a second embodiment, the invention is based on the surprising finding that compounds of the formula (II) having CB₁1H-imidazole derivatives, prodrugs and salts thereof having antagonistic activity are potent cannabinoid-CB₁Receptor antagonists:

wherein

R represents phenyl, thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, which may be substituted by 1, 2, 3 or 4 identical or different substituents Y, Y being selected from C_1-3-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono-or dialkyl (C)_1-2) -amino, mono-or dialkyl (C)_1-2) -acylamino group, (C)_1-3) -alkoxycarbonyl, carboxyl, cyano, carbamoyl and acetyl; or R represents naphthyl, with the proviso that when R is 4-pyridyl, R₄Represents a halogen atom or a cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, aminosulfonyl, methanesulfonyl, methylthioalkyl or branched or unbranched C_1-4Alkyl radical, wherein C_1-4Alkyl may be substituted by 1 to 3 fluorine atoms or by bromine, chlorine, iodine, cyano or hydroxy,

-R₁represents phenyl or pyridyl, which radicals can be substituted by 1 to 4 identical or different substituents Y, where Y has the abovementioned meaning; or R₁Represents pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, which radicals may be substituted by 1 to 2 identical or different substituents Y; or R₁Represents a 5-membered heteroaromatic ring having 1 or 2 heteroatoms selected from N, O, S, wherein the heteroatoms may be the same or different, and the 5-membered heteroaromatic ring may be substituted with 1 to 2 substituents Y which may be the same or different; or R₁Represents a naphthyl group, and the naphthyl group,

-R₂represents hydrogen, branched or unbranched C_1-8Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Alkenyl radical, C_5-8Cycloalkenyl radicals, which may contain sulfur, oxygen or nitrogen atoms,

-R₃represents branched or unbranched C_2-8Alkyl radical, C_1-8Alkoxy radical, C_5-8Cycloalkoxy, C_3-8Cycloalkyl radical, C_5-10Bicycloalkyl radical, C_6-10Tricycloalkyl radical, C_3-8Alkenyl radical, C_5-8Cycloalkenyl radicals, which may optionally contain one or more heteroatoms selected from O, N, S, which may be substituted by hydroxyl or 1-2C_1-3Alkyl or 1-3 fluorine atoms; or R₃Represents benzyl or phenethyl, wherein the aromatic rings may be substituted by 1 to 5 identical or different substituents Z, Z being selected from C_1-3-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono-or dialkyl (C)_1-2) -amino, mono-or dialkyl (C)_1-2) -acylamino group, (C)_1-3) -alkylsulfonyl, dimethyl-sulfamino, C_1-3-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, aminosulfonyl and acetyl; or R₃Represents phenyl or pyridyl, which groups may be substituted by 1 to 4 substituents Z, wherein Z has the meaning indicated above,

or R₃Represents a pyridyl group; or R₃Represents phenyl, provided that R₄Represents a halogen atom or a cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, aminosulfonyl, methanesulfonyl, methylthioalkyl or C group_1-4Alkyl radical, wherein C_1-4Alkyl may be substituted with 1 to 3 fluorine atoms or with bromine, chlorine, iodine, cyano or hydroxy;

or R₃Represents a group NR₅R₆Provided that R is₂Represents a hydrogen atom or a methyl group, wherein

-R₅And R₆Identical or different and represents branched or unbranched C_1-4An alkyl group; or R₅And R₆Together with the nitrogen atom to which they are attached form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms, wherein the heterocyclic group contains one or two heteroatoms selected from N, O, S, which may be the same or different, wherein the heterocyclic group may be substituted with C_1-3Alkyl or hydroxy substituted, or R₂And R₃Together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic group having from 4 to 10 ring atoms, wherein the heterocyclic group contains one or two heteroatoms selected from N, O, S, wherein the heteroatoms may be the same or different, wherein the heterocyclic group may be substituted by C_1-3Alkyl or hydroxyl is substituted, and the alkyl or the hydroxyl is substituted,

-R₄represents a hydrogen or halogen atom or a cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, aminosulfonyl, methanesulfonyl, methylthioalkyl or branched or unbranched C_1-4Alkyl radical, wherein C_1-4Alkyl may be substituted by 1 to 3 fluorine atoms or by bromine, chlorine, iodine, cyano or hydroxy,

due to their unique pharmacological profile it is particularly suitable for use in combination with at least one lipase inhibiting compound for the preparation of a medicament for the treatment and/or prevention of obesity in general, e.g. in adolescent patients of any age, in particular for the treatment and/or prevention of obesity in adolescent patients, and/or drug induced obesity in adolescent and adolescent patients. In this respect, the combination of a compound of formula (II) with a lipase inhibiting compound is of great value in providing a medicament for the treatment and/or prevention of obesity in general, such as obesity in juvenile patients of any age, in particular pediatric or juvenile obesity, and drug induced obesity.

A compound of formula (III)

In a third embodiment, the present invention is based on the surprising discovery that cannabinoid-CB, which is an effective and selective presence of 4, 5-dihydro-1H-pyrazole derivatives of formula (IIIa) or (IIIb), prodrugs thereof, tautomers thereof and salts thereof, is useful and selective₁Receptor antagonism:

wherein

-R and R₂Independently represents phenyl, thienyl or pyridyl, which groups may be substituted by 1, 2 or 3 identical or different substituents Y, Y being selected from C_1-3-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono-or dialkyl (C)_1-2) -amino, mono-or dialkyl (C)_1-2) -acylamino group, (C)_1-3) Alkylsulfonyl, methylsulfonylamino, C_1-3-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, aminosulfonyl and acetyl; or R and/or R₁Represents a naphthyl group, and the naphthyl group,

-R₂represents hydrogen, hydroxy, C_1-3-alkoxy, acetoxy or propionyloxy,

-R₃represents a hydrogen atom or a branched or unbranched C_1-8Alkyl or C_3-7Cycloalkyl, wherein alkyl or cycloalkyl may be substituted by hydroxy,

-R₄represents a hydrogen atom or a branched or unbranched C_1-8Alkyl radical, C_3-8Cycloalkyl radical, C_2-10Heteroalkyl group, C_3-8Non-aromatic heterocycloalkyl or C_4-10Non-heteroaromatic alkyl moieties wherein these moieties may contain one or more heteroatoms selected from O, N, S, which moieties may be substituted by keto, trifluoromethyl, C_1-3Alkyl, hydroxy, amino, monoalkylamino, or dialkylamino groups or fluorine atom substitution; or R₄Represents amino, hydroxy, phenoxy or benzyloxy; or R₄Represents branched or unbranched C_1-8Alkoxy radical, C_3-8Alkenyl radical, C_5-8Cycloalkenyl or C_6-9Cycloalkenylalkyl, which may contain a sulfur, nitrogen or oxygen atom, a keto group or-SO₂A group in which C_1-8Alkoxy radical, C_3-8Alkenyl radical, C_5-8Cycloalkenyl or C_6-9Cycloalkenylalkyl may be substituted by hydroxy, trifluoromethyl, amino, monoalkylamino or dialkylamino groups or by fluorine atoms; or R₄Represents phenyl, benzyl, pyridyl, thienyl, pyridylmethyl or phenethyl, wherein the aromatic rings may be substituted by 1, 2 or 3 substituents Y, wherein Y has the meaning indicated above; or

R₄Represents a group NR₈R₉Provided that R is₃Represents a hydrogen atom or a methyl group, wherein R₈And R₉Identical or different, represents C_1-4Alkyl or C_2-4A trifluoroalkyl group; or R₈And R₉Together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic moiety having from 4 to 8 ring atoms, in which the heterocyclic moiety may contain an oxygen or sulfur atom or a keto group or-SO₂A group or other nitrogen atom, in which the saturated or unsaturated heterocyclic moiety may be replaced by C_1-4Alkyl is substituted or

R₃And R₄Together 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, wherein the heterocyclic moiety may contain one or more atoms selected from O, N, S or a keto group or-SO₂A group, which moiety may be substituted by C_1-4Alkyl, hydroxyalkyl, phenyl, thienyl, pyridyl, amino, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylamino, or dialkyl aminoAlkylamino, aminoalkyl, azetidinyl, pyrrolidinyl, piperidinyl, or hexahydro-1H-aza * yl,

-R₅and R₆Each independently represents a hydrogen atom or a branched or unbranched C_1-8Alkyl or alkenyl, which groups may contain one or more heteroatoms selected from O, N, S, keto or-SO₂-groups, which may be substituted by hydroxyl or amino groups; or R₅And R₆Each independently represents C_3-8-cycloalkyl or C_3-8Cycloalkenyl which may contain one or more ring heteroatoms selected from O, N, S or-SO₂Groups, which may be substituted by hydroxy, alkyl (C)_1-3)、-SO₂A radical, a keto radical, an amino radical, a monoalkylamino radical (C)_1-3) Or dialkylamino (C)_1-3) Is substituted, or

R₅Represents naphthyl or phenyl, wherein the phenyl group may be substituted by 1, 2 or 3 substituents Y, wherein Y has the meaning described herein above, with the proviso that R₆Represents a hydrogen atom, or a branched or unbranched alkyl group (C)_1-5) Wherein the alkyl group may contain one or more heteroatoms selected from O, N, S or-SO₂-a group wherein alkyl may be substituted by hydroxy, keto or amino; or

R₅And R₆Together with the nitrogen atom to which they are attached form a monocyclic, bicyclic or tricyclic alkyl or alkenyl group which may contain a ring heteroatom selected from O, N, S, a keto group or SO₂Groups in which the monocyclic, bicyclic or tricyclic alkyl or alkenyl groups may be substituted by hydroxy, alkyl (C)_1-3)、SO₂Radical, keto group, amino group, monoalkylamino group (C)_1-3) Dialkylamino (C)_1-3) Pyrrolidinyl or piperidinyl, wherein the monocyclic, bicyclic or tricyclic alkyl or alkenyl group may comprise an annelated phenyl group, wherein the annelated phenyl group may be substituted with 1 or 2 substituents Y, wherein Y has the meaning described herein above,

-R₇represents branched or unbranched C_1-3An alkyl group, a carboxyl group,

due to their unique pharmacological profile it is particularly suitable for use in combination with at least one lipase inhibiting compound for the preparation of a medicament for the treatment and/or prevention of obesity in general, e.g. in adolescent patients of any age, in particular for the treatment and/or prevention of obesity in adolescent patients, and/or drug induced obesity in adolescent and adolescent patients. In this regard, the combination of a compound of formula (IIIa) and/or (IIIb) with a lipase inhibiting compound is of great value in providing a medicament for the treatment and/or prevention of obesity in general, such as obesity in adolescent patients of any age, in particular pediatric or juvenile obesity, and drug induced obesity.

The presence of at least one chiral centre (C at the 4, 5-dihydro-1H-pyrazole moiety) in the compounds of formulae (IIIa) and (IIIb)₄Location). The invention relates to racemates, diastereomers and mixtures of the individual stereoisomers of compounds of formula (IIIa) or (IIIb). Of particular interest are compounds of formula (IIIa) or (IIIb) at C of the 4, 5-dihydro-1H-pyrazole moiety₄Positionally possessing an absolute spatial configuration, as in formula (IIIa)^*) And (IIIb)^*) The method comprises the following steps:

the invention also relates to the E isomer, Z isomer and E/Z mixture of the compound of formula (IIIa) or (IIIb).

A compound of formula (IV)

In a fourth embodiment, the invention is based on the surprising finding that of formula (IV) having CB₁Antagonistic 4, 5-diarylthiazole derivatives, prodrugs thereof, and salts thereof

Wherein

R represents a hydrogen atom or a substituent X chosen from branched or unbranched C_1-3-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono-or dialkyl (C)_1-2) -amino, mono-or dialkyl (C)_1-2) Acylamino, branched or unbranched (C)_1-3) Alkoxycarbonyl, trifluoromethylsulfonyl, aminosulfonyl, branched or unbranched alkyl (C)_1-3) Sulfonyl, carboxyl, cyano, carbamoyl, branched or unbranched dialkyl (C)_1-3) Aminosulfonyl, branched or unbranched monoalkyl (C)_1-3) -an aminosulfonyl group and an acetyl group,

-R₁is a hydrogen atom or represents 1 to 4 substituents X, where X has the abovementioned meaning,

-R₂represents phenyl, thienyl, pyridyl or pyrimidinyl, which radicals can be substituted by 1 to 4 substituents X, wherein X has the abovementioned meaning; or R₂Represents a naphthyl group, and the naphthyl group,

-R₃represents a hydrogen atom or a branched or unbranched C_1-10Alkyl or cycloalkyl-alkyl or phenyl, benzyl or phenethyl, in which the aromatic rings may be substituted by 1 to 5 identical or different substituents Z, Z being selected from branched or unbranched C_1-3-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono-or dialkyl (C)_1-2) -amino, mono-or dialkyl (C)_1-2) Acylamino, branched or unbranched (C)_1-3) Alkylsulfonyl, dimethylsulfonamido, branched or unbranched C_1-3-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, aminosulfonyl and acetyl; or R₃Represents a pyridyl group or a thienyl group,

-R₄represents branched or unbranched C_1-10Alkyl or cycloalkyl-alkyl, branched or unbranched C1_-10Alkoxy radical, C_3-8Cycloalkyl radical, C_5-10Bicycloalkyl radical, C_6-10Tricyclic alkanesRadical, branched or unbranched C_3-10Alkenyl radical, C_5-8Cycloalkenyl, which may contain one or more heteroatoms selected from O, N, S, which groups may be substituted by hydroxy, 1-3 methyl, 1 ethyl or 1-3 fluorine atoms; or R₄Represents phenyl, benzyl or phenethyl, in which the aromatic rings may be substituted by 1 to 5 substituents Z, where Z has the abovementioned meaning; or R₄Represents pyridyl or thienyl; or R₄Represents a group NR₅R₆Wherein

R₅And R₆Together with the nitrogen atom to which they are attached form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms, wherein the heterocyclic group contains one or more heteroatoms selected from O, N, S, wherein the heterocyclic group may be branched or unbranched C_1-3Alkyl, hydroxy or trifluoromethyl or fluorine atom, or

-R₃And R₄Together with the nitrogen atom to which they are attached form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms, wherein the heterocyclic group contains one or more heteroatoms selected from O, N, S, wherein the heterocyclic group may be branched or unbranched C_1-3Alkyl, hydroxy or trifluoromethyl or fluorine atom,

due to their unique pharmacological profile it is particularly suitable for use in combination with at least one lipase inhibiting compound for the preparation of a medicament for the treatment and/or prevention of obesity in general, e.g. in adolescent patients of any age, in particular for the treatment and/or prevention of obesity in adolescent patients, and/or drug induced obesity in adolescent and adolescent patients. In this respect, the combination of a compound of formula (IV) with a lipase inhibiting compound is of great value in providing a medicament for the treatment and/or prevention of obesity in general, such as obesity in juvenile patients of any age, in particular pediatric or juvenile obesity, and drug induced obesity.

A compound of formula (V)

In a fifth embodiment, the invention is based on the surprising discovery that CB of formula (V)₁1, 5-diaryl-1H-1, 2, 4-triazole-3-carboxamide derivatives having antagonistic activity, prodrugs and salts thereof, are cannabinoid CB₁Potent antagonists, agonists, inverse agonists or partial agonists of the receptor:

wherein

-R and R₁Independently represents phenyl, naphthyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, which groups may be substituted by 1 to 4 identical or different substituents X, selected from branched or unbranched (C)_1-3) -alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono-or dialkyl (C)_1-2) -amino, mono-or dialkyl (C)_1-2) -acylamino group, (C)_1-3) Alkoxycarbonyl, trifluoromethylsulfonyl, aminosulfonyl, (C)_1-3) Alkylsulfonyl, carboxy, cyano, carbamoyl, (C)_1-3) -dialkylaminosulfonyl, (C)_1-3) -monoalkylamino-sulfonyl and acetyl groups,

-R₂represents a hydrogen atom or a branched or unbranched C_1-8Alkyl or C_1-4Cycloalkyl-alkyl or phenyl, benzyl or phenethyl, in which the aromatic rings may be substituted by 1 to 4 substituents X, in which X has the meaning indicated above; or R₂Represents a pyridyl group or a thienyl group,

-R₃represents branched or unbranched C_1-8Alkyl radical, C_1-8Alkoxy radical, C_3-8Cycloalkyl radical, C_5-10Bicycloalkyl radical, C_6-10Tricycloalkyl radical, C_3-8Alkenyl radical, C_5-8Cycloalkenyl, these groups optionally containing one or more heteroatoms selected from O, N, S, these groups being possibly substituted by hydroxyl, ethynyl or 1-3 fluorine atoms;or R₃Represents phenyl, benzyl or phenethyl, in which the aromatic rings may be substituted by 1 to 4 substituents X, in which X has the meaning indicated above; or R₃Represents pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl or thienyl, wherein the heteroaromatic rings may be substituted by 1 to 2 substituents X, wherein X has the meaning indicated above; or R₃Represents a group NR₄R₅Wherein

R₄And R₅Together 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, wherein the heterocyclic moiety contains one or two heteroatoms selected from N, O or S, wherein the heteroatoms may be the same or different, and wherein the heterocyclic moiety may be branched or unbranched C_1-3Alkyl, hydroxy or trifluoromethyl or fluorine atom; or

-R₂And R₃Together 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, wherein the heterocyclic moiety contains one or two heteroatoms selected from N, O or S, wherein the heteroatoms may be the same or different, and wherein the heterocyclic moiety may be branched or unbranched C_1-3Alkyl, hydroxy, piperidinyl or trifluoromethyl or fluorine atom,

due to their unique pharmacological profile it is particularly suitable for use in combination with at least one lipase inhibiting compound for the preparation of a medicament for the treatment and/or prevention of obesity in general, e.g. in adolescent patients of any age, in particular for the treatment and/or prevention of obesity in adolescent patients, and/or drug induced obesity in adolescent and adolescent patients. In this respect, the combination of a compound of formula (V) with a lipase inhibiting compound is of great value in the manufacture of a medicament for the treatment and/or prevention of obesity in general, such as obesity in juvenile patients of any age, in particular pediatric or juvenile obesity, and drug induced obesity.

In the following, embodiments of the present invention will be described in more detail with respect to the medical and pharmaceutical use of the compounds of formula (I), (II), (III), (IV) or (V).

Medical and pharmaceutical use

Due to their cannabinoid CB₁-beneficial activity of the receptor, the compounds of formula (I), (II), (III), (IV) and/or (V) used according to the invention are suitable for general use in the pediatric treatment and/or prevention of other disorders, in addition to juvenile obesity and drug induced obesity in juvenile patients. These other conditions include those known in the literature to be cannabinoid CB₁-those which can be treated by related compounds for which the receptor is active, for example in young patients, pediatric treatment and/or prevention may also relate to psychiatric disorders such as psychosis, anxiety disorders, depression, attention deficit, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, desire, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral stroke, craniocerebral trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelination-related disorders, and for pediatric treatment of pain disorders including neuropathic pain disorders, and other diseases involving cannabinoid neurotransmission including pediatric treatment for septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases, gastrointestinal disorders, gastric ulcers, diarrhea, and cardiovascular disorders.

The compounds of formula (I), (II), (III), (IV) or (V) are cannabinoid CB₁The affinity of the receptor may be determined as described in WO 03/026647, WO 03/027076, WO 03/026648 or WO03/078413, for example using a Chinese Hamster Ovary (CHO) cell membrane specimen, of which human cannabis CB₁Receptors and [3H as radioligand]CP-55,940 binds and is stably transfected. With [3H ]]After incubation of freshly prepared cell membrane specimens of the ligands, with or without addition of the compounds according to the inventionThe bound and free ligands were separated by filtration through a glass fiber filter. Radioactivity on the filters was measured by liquid scintillation counting.

Cannabinoid CB for Compounds of formula (I), (II), (III), (IV) or (V)₁Antagonistic activity is also described in WO 03/026647, WO 03/027076, WO 03/026648 or WO03/078413 by using the human cannabinoid CB₁The receptor was determined by functional studies of stably expressed CHO cells. Stimulation of adenylate cyclase with forskolin was measured by quantifying the amount of accumulated cyclic adenylate. Concomitant CB₁Receptor agonists (e.g. CP-55,940 or (R) -WIN-55,212-2) for CB₁Activation of the receptor may attenuate forskolin-induced cAMP accumulation in a concentration-dependent manner. Such a CB₁The receptor-mediated response may be CB₁Receptor antagonists such as the compounds used in the present invention antagonize.

Cannabinoid CB, such as the inventive compound of formula (V)₁Receptor antagonistic, agonistic or partial agonistic activity human CB cloned in Chinese Hamster Ovary (CHO) cells may also be used according to the following protocol₁Receptors, determined by functional studies. CHO cells were cultured in DMEM medium supplemented with 10% heat-inactivated fetal bovine serum. Aspirating the culture medium with a medium containing no fetal bovine serum but containing [2 ]³H]DMEM replacement of arachidonic acid, in cell culture chambers (5% CO)₂95% of air; 37 ℃; water saturated atmosphere) overnight. During this time, the³H]-incorporation of arachidonic acid into membrane phospholipids. On the day of testing, the medium was aspirated and the cells were washed 3 times with 0.5ml of phosphate buffered saline containing 0.2% bovine serum albumin. Stimulation of CB with WIN 55,212-2₁Receptor induced PLA₂Is then [2 ]³H]-release of arachidonic acid into the culture medium. The WIN 55,212-2-induced release is CB₁The receptor antagonist antagonizes concentration-dependently.

Cannabinoid receptor agonistic or partial agonistic activity of the compounds of the invention can be determined according to published methods, such as the assessment of in vivo cannabimimetic effects (Wiley, j.l.jeffersonet al., j.pharmacol.exp.ther.2001, 296, 1013).

Cannabinoid receptor antagonists are useful as inverse agonists (Landsman, r.s.et al., eur.j.pharmacol.1997, 334, R1-R2).

The entire contents of the international patent applications WO 03/026647, WO 03/027076, WO 03/026648 and WO03/078413 are incorporated into the CB of the formula (I), (II), (III), (IV) or (V) used in the present application in relation to the invention₁The disclosure of combinations of antagonistic compounds with lipase inhibitors is incorporated in part by reference.

With CB₁-receptor activity and a compound of formula (I), (II), (III), (IV) or (V) (which is cannabis CB)₁Receptor antagonists) and prodrugs, tautomers and salts thereof, including particularly high safety and tolerability, in combination with other drugs, and in particular in combination with the lipase inhibiting compounds of the invention. Thus CB of the formula (I), (II), (III), (IV) or (V)₁The combination of an antagonistic compound with a lipase inhibiting compound is also particularly suitable for patients with a higher need for safety and tolerability, especially for example juvenile patients and/or patients undergoing long-term treatment, for example drug induced obesity.

CB of formula (I), (II), (III), (IV) or (V)₁The safety and tolerability of the combination of an antagonistic compound and a lipase inhibiting compound is beneficial in the treatment and/or prevention of obesity in patients who are not sufficiently effective for monotherapy, are expected to, or require combination therapy and/or prevention involving different medical or metabolic mechanisms to achieve and stabilize a defined degree of weight loss.

Thus, it is desirable that the formula (I), (II), (III), (IV) or (V) CB of the present invention₁The combination of an antagonistic compound with a lipase inhibiting compound is very beneficial in the treatment and/or prevention of obesity in general, such as obesity in adolescent patients of any age, especially pediatric or juvenile obesity, and drug induced obesity.

C of the inventive compounds of the formula (I), (II), (III), (IV) or (V)B₁The receptor modulating activity makes them particularly useful for the treatment of obesity, juvenile obesity and drug induced obesity when used in combination with lipase inhibitors. Specific examples of lipase inhibiting compounds that may be used in the combined preparation are, but are not limited to, the synthetic lipase inhibitors orlistat, panclicins, lipase inhibitors isolated from microorganisms, such as lipstatin (from Streptomyces toxytricini), ebelactone B (from Streptomyces abruvaginis), synthetic derivatives of these compounds, 2-oxo-4H-3, 1-benzoxazin-4-one derivatives such as ATL-962, and structurally related compounds, 2-amino-4H-3, 1-benzoxazin-4-one derivatives, and plant extracts known to have lipase inhibitor activity, such as galangal extract, or a compound isolated from the extract, such as 3-methyl ethyl ether galangin (from a. officinalis). The lipase inhibiting compound may also be a lipase inhibiting polymer. These lipase inhibiting compounds and their preparation are well known in the art.

The lipase inhibiting compounds used in the combination of the invention may be any lipase inhibiting compound suitable for pharmaceutical use, for example, in particular pancreatic lipase inhibitors. Lipases are key enzymes in the digestive system, which cleave triglycerides and diglycerides, which are too large to be absorbed by the small intestine, into fatty acids that can be absorbed. Since lipases are responsible for fat hydrolysis, the result of inhibiting them is a reduction in fat hydrolysis and absorption. Thus, inhibition of lipase results in decreased fat absorption. Preferred lipase inhibiting compounds are the synthetic lipase inhibitors orlistat and structurally related compounds, 2-oxo-4H-3, 1-benzoxazin-4-one derivatives such as ATL-962 and structurally related compounds, 2-amino-4H-3, 1-benzoxazin-4-one derivatives, lipase inhibitors isolated from microorganisms such as lipstatin, ebelactone B, or synthetic derivatives of these compounds, however, lipase inhibiting polymers are also possible. Most preferred are orlistat, panclicins, ATL-962 and lipstatin.

Orlistat (tetrahydrolipstatin) and lipstatin are described in U.S. Pat. No. 4,598,089, and in more detail in its european counterpart EP 0129748B 1. The compounds are 2-hexyl-3-hydroxy-hexadecanolide derivatives with the chemical names (2S, 3S, 5S, 7Z, 10Z) -5- ((S) -2-carboxamido-4-methylpentanoyloxy) -2-hexyl-3-hydroxy-7, 10-hexadecadienoic acid lactone (lipstatin) and (2S, 3S, 5S) -5- ((S) -2-4-methylpentanoyloxy) -2-hexyl-3-hydroxy-hexadecanolide (tetrahydrolipstatin). The compounds are known as pancreatic lipase inhibitors which can be used for the prophylaxis or treatment of obesity and hyperlipidemia, for which purpose they can be formulated into medicaments or incorporated into industrially prepared foods. Inhibition of pancreatic lipase prevents the hydrolysis of food fat to absorbable free fatty acids and monoglycerides, allowing the unchanged excretion of fat. The IC50 for lipstatin and tetrahydrolipstatin to inhibit the hydrolysis of triolein by porcine pancreatic lipase was 0.07 and 0.18mcg/ml, respectively.

Furthermore, there are suitable lipase inhibitors structurally related to orlistat and/or lipstatin, which are known as panclicins. These panclicines are derived from orlistat and comprise 4-cyclic lactones (Mutoh M; Nakada N; Matsukima S; Ohshima S; Yoshinarik; Watanabe J Location: Kanagawa, Japan Issue Date: 19-JAN-1995 Journal: J.Antibiot., 47, No.12, 1369-75, 1994). The biological data for these panclicins can be summarized as follows: panlicins A, B, C, D and E are structural analogs of Tetrahydrolipstatin (THL) that dose-dependently inhibit the hydrolysis of fatty acid glycerol trioleate by porcine pancreatic lipase, with IC50 values of 2.9, 2.6, 0.62, 0.66 and 0.89. mu.M, respectively. panclicins A and B (alanine partial replacement of leucine in THL) were 2-3 times less inhibitory than THL; in contrast, panclicins C, D and E (glycine partially substituted for leucine in THL) were 2-fold more potent in inhibitory activity than THL. Panclicins a, B, C, D and E were also effective in inhibiting plasma lipases at IC50 values of 1.0, 1.2, 0.29, 0.25 and 0.15 μ M, respectively. Panlicins A and B inhibited plasma lipase with the same potency as THL, while Panclicins C, D and E were 3-6 times more active than THL in inhibition. Panlicins A, B, C, D, and E inhibited bacterial and fungal lipase in a manner similar to that of porcine pancreatic lipase. Panclicins irreversibly inhibit pancreatic lipase, but are less irreversible than THL. Panclicins a, B, C, D and E irreversibly inhibit pancreatic lipase.

Ebelactone B is described in US patent US 4,358,602 and its german counterpart DE 3109335C 1. Ebelactone a and Ebelactone B belong to a group of compounds having activity of enhancing cell-mediated immune response in living animals, and they also inhibit inflammation in living animals. They are therefore useful in the immunotherapy of tumors, and in the enhancement of antineoplastic agents such as bleomycin. The compounds have anti-esterase activity and anti-formylmethionine aminopeptidase activity. Administration of these compounds to mice at a dose of 0.781-50mg/kg (i.p.) or 0.5mg/kg (i.p.) enhances the development of DTH responses, and the compounds show a synergistic effect on cell-mediated immunity. Ebelactone B attenuated carrageenan-induced swelling in mice.

In the context of the present invention, with CB₁The lipase inhibitor which is administered to a patient in combination with an antagonist compound to treat obesity can also be a polymer which has been substituted with or contains one or more groups which inhibit lipase. Such lipase inhibiting polymers are described in US 6572850, US 6558657, US 6352692, US 6267952 and in international patent application WO 99/34786. In one embodiment, the lipase inhibiting group can be a "suicide substrate" which inhibits lipase activity by forming a covalent bond with the active site or other sites of the enzyme. In another embodiment, the lipase inhibitory group is an isospecific (isospecific) inhibitor of an enzyme.

In the first aspect of the present invention, when a material other than CB is used₁Lipase inhibiting groups inactivate lipases, such as gastric, pancreatic and lingual lipases, when antagonizing lipase inhibiting polymers other than the compound. Inactivation may result in enzyme inactivity through the formation of covalent bonds. Either at or near the active site of the enzyme, or at residues remote from the active site, as long as the formation of covalent bonds results in inhibition of the enzyme activityForm a covalent bond with an amino acid residue. Lipases contain a catalytic triad, which is responsible for the hydrolysis of lipids to fatty acids. The catalytic triad consists of serine, aspartate, and histidine amino acid residues. This triad is also responsible for the hydrolysis of amide bonds in serine proteases, and it is expected that serine protease inhibitor compounds will also inhibit lipases. Thus, serine protease inhibitors which may be covalently linked to the polymer are preferably lipase inhibiting groups. For example, a covalent bond may be formed between a lipase inhibitory group and a hydroxyl group at the enzyme catalytic site. For example, a covalent bond may be formed with serine. Inactivation may also be caused by the formation of a covalent bond of the lipase inhibiting group with an amino acid, e.g. cysteine, located at a distance from the active site. In the second aspect of the present invention, when a material other than CB is used₁Non-covalent interactions between the lipase inhibiting group and the enzyme may also result in enzyme inactivation when antagonizing lipase inhibiting polymers other than the compound. For example, the lipase inhibiting group can be a homosteric ligand for a fatty acid, which can interact non-covalently with the catalytic site of the lipase. In addition, the lipase inhibiting group can compete with native triglycerides for lipase hydrolysis.

A variety of polymers may be used in the invention described herein. The polymers may be aliphatic, cycloaliphatic, or aromatic, or synthetic, or naturally occurring. However, aliphatic and cycloaliphatic synthetic polymers are preferred. Furthermore, the polymer may be hydrophobic, hydrophilic or a copolymer of hydrophobic and/or hydrophilic monomers. All or a portion of the polymer may be nonionic (e.g., neutral), anionic, or cationic. In addition, the polymers may be prepared from olefinic or vinylic monomers (e.g., vinyl alcohol), or condensation polymers. For example, the polymer may be polyvinyl alcohol, polyvinylamine, poly-N-alkylvinylamine, polyallylamine, poly-N-alkylallylamine, polyalkyleneimine, polyethylene, polypropylene, polyether, polyethylene oxide, polyamide, polyacrylic acid, polyalkyl acrylate, polyacrylamide, polymethacrylic acid, polyalkyl methacrylate, polymethacrylamide, poly-N-alkylacrylamides, poly-N-alkylmethacrylamides, polystyrenes, vinylnaphthalenes, ethylvinylbenzenes, aminostyrenes, vinyldiphenyls, vinylanisoles, vinylimidazoles, vinylpyridines, dimethylaminomethylstyrenes, trimethylammonium ethyl methacrylate, trimethylammonium ethyl acrylate, carbohydrates, proteins and substituted derivatives of the above (e.g., their fluorinated monomers) and copolymers thereof. Preferred polymers include polyethers, such as polyalkylene glycols.

The polymers employed in the processes described herein, as well as intermediates and processes for preparing the polymers, are described in detail in U.S. patents US 6572850, US 6558657, US 6352692, US 6267952 and international patent application WO 99/34786, which are all incorporated herein by reference.

Recently, in international patent application WO 03/072555, novel 5-hydrocarbyloxy-3-phenyl-1, 3, 4-oxadiazol-2-ones of formula (A) have been described as pancreatic lipase inhibitors for the treatment of metabolic diseases, cardiovascular diseases or especially obesity.

Oxadiazolones of the formula (A) and their salts and acid addition salts are also suitable for use with CB for use in the present invention₁Combinations of antagonistic compounds. In formula (a), the substituents may be as follows:

r1 can be 7-22C alkyl; 2-4C alkyl substituted with 4-20C alkoxy, 6-10C aryl, 6-10C aryloxy or (4-12C) alkoxy- (2-4C) alkoxy wherein the aryl may be substituted with one or more halogen, 1-4C alkyl, 1-4C alkoxy, NO2 or CF 3; 7-20C alkenyl; or phenyl substituted by 6-12C alkyl or phenoxy; and

r2 to R5 each may be H, halogen, NO2, 1-4C alkyl, 1-4C alkoxy, CF3 or OCF 3; or (6-10C) aryl- (1-4C) alkoxy, 6-10C aryloxy, 6-10C aryl, 3-8C cycloalkyl or 3-8C cycloalkoxy (optionally substituted with halogen, CF3, 1-4C alkoxy or 1-4C alkyl).

These 5-hydrocarbyloxy-3-phenyl-1, 3, 4-oxadiazol-2-ones are described as having pharmacological properties such as anorexia, antidiabetic, blood pressure lowering or cardiac excitability, the mechanism of action being as pancreatic lipase inhibitors. For example, 5-dodecyloxy-3- (4-trifluoromethoxy-phenyl) -3H- (1, 3, 4) -oxadiazol-2-one has an IC50 of 0.03. mu.M for inhibiting porcine pancreatic lipase. These 5-hydrocarbyloxy-3-phenyl-1, 3, 4-oxadiazol-2-ones are therefore useful as medicaments, especially for the treatment of obesity. As pancreatic lipase inhibitors, 5-hydrocarbyloxy-3-phenyl-1, 3, 4-oxadiazol-2-one inhibits the reabsorption of dietary fat, thereby reducing fat absorption and reducing body weight (or preventing weight gain). Furthermore, 5-hydrocarbyloxy-3-phenyl-1, 3, 4-oxadiazol-2-one has also been reported to have beneficial effects in the treatment of metabolic disorders (e.g., diabetes) or cardiovascular disorders (e.g., hypertension and myocardial infarction). The lipase-inhibiting compounds of formula (a) are described in more detail in WO 03/072555 and can be obtained according to known methods. Suitable syntheses of lipase-inhibiting compounds of formula (A) are also described in International patent application WO 03/072555. The entire content of international patent application WO 03/072555 is incorporated by reference into the present application for the disclosure of lipase inhibitors of formula (a).

Furthermore, 5-hydrocarbyloxy-3-phenyl-1, 3, 4-oxadiazol-2-one of formula (A) is further described in International patent application WO 03/072098 as a pancreatic lipase inhibitor for the treatment of obesity or type I and type II diabetes. The oxadiazolones of formula (A) and their salts and acid addition salts described in WO 03/072098 are also suitable for use with CB's for use in the present invention₁Combinations of antagonistic compounds. In formula (a), the substituents may be as follows:

r1 can be 1-6C alkyl; 3-9C-cycloalkyl, which two radicals may optionally be substituted by phenyl, 1-4C-alkoxy, S-1-4C-alkyl, N (1-4C-alkyl) 2; and phenyl optionally substituted by halogen, 1-4C alkyl, 1-4C-alkoxy, nitro or CF 3; and

r2 to R5 may each independently be H, halogen, NO2, 1-4C alkyl, 1-9C alkoxy substituted by F, 6-10C-aryl, amino or 1-4C alkylamino; 6-10C-aryl-1-4C-alkoxy, 6-10C-aryloxy, 6-10C-aryl, 6-10C-aryloxy-1-4C-alkyl, 3-8C-cycloalkyl or 0(3-8 cycloalkyl), which may optionally be substituted by halogen, CF3, 1-4 alkoxy or 1-4C-alkyl; SO2-NH- (1-6C alkyl) 2 optionally substituted with N (1-6C alkyl) 2, SO2-NH- (2, 2, 6, 6-tetramethylpiperidin-4-yl), SO2-NH- (3-8C cycloalkyl) optionally substituted with 1-4C alkyl, SO2-N (1-6C alkyl) 2 or COX; 2-oxo-pyrrolidin-1-yl, 2, 5-dimethylpyrrol-1-yl or NR 6-a-R7;

with the proviso that R2, R3, R4 and R5 are not simultaneously H when:

x is 0(1-6C alkyl), NH (3-8C cycloalkyl) or N (1-6C alkyl) 2, N (1-6C alkyl) 2 is also pyrrolidine, piperidine, morpholine, thiomorpholine or piperazine, optionally substituted with 1-4C alkyl, benzyl, 6-10C aryl, CO- (1-4 alkyl), CO- (6-10 aryl), CO-O- (1-4C alkyl), SO2- (1-4C alkyl) or SO2- (6-10C aryl);

r6 is H, 1-4C alkyl or 6-10C-aryl-1-4C-alkyl, wherein aryl may be substituted by halogen, CF3, 1-8C alkoxy or 1-4C alkyl;

a is a single bond, COn, SOn or CONH;

n is 1 or 2;

r7 is H; 1-18C alkyl or 2-18C alkenyl which may be substituted up to three times by 1-4C alkyl, halogen, CF3, 1-4C alkoxy, N (1-4C alkyl) 2, -COOH, 1-4C alkoxycarbonyl, 6-12C aryl, 6-12C aryloxy, 6-12C arylcarbonyl, 6-10-aryl-1-4C alkoxy or oxygen, where the aryl radical may itself be optionally substituted by halogen, 1-4C alkyl, aminosulfonyl or methylthio;

6-10C-aryl-1-4C-alkyl, 5-8C-cycloalkyl, 6-10-aryl-2-6C-alkenyl, 6-10C-aryl, diphenyl- (1-4 alkyl), indanyl which may be substituted by 1-18C-alkyl, 1-18C-alkoxy, 3-8C-cycloalkyl, COOH, hydroxy, 1-4C-alkylcarbonyl, 6-10C-aryl-1-4C-alkyl, 6-10C-aryl-1-4C-alkoxy, 6-10C-aryloxy, nitro, cyano, 6-10C-aryl, fluorosulfonyl, 1-6C-alkoxycarbonyl, indanyl, 6-10 arylsulfonyloxy, pyridinyl, NHSO2- (6-10 aryl), halogen, CF3 or OCF3 optionally substituted, wherein alkyl may also be substituted by 1-4C alkoxycarbonyl, CF3 or carboxy and aryl may also be substituted by halogen, CF3 or 1-4C alkoxy;

or is a group Het- (CH2) r-, wherein r is 0, 1, 2 or 3 and Het is a saturated or unsaturated 5-7-membered heterocyclic ring which may be benzo, optionally annelated or substituted by 1-4C alkyl, 6-10C aryl, halogen, 1-4C alkoxy, 1-4C alkoxycarbonyl, 6-10C-aryl-1-4C alkyl, 6-10C-aryl-1-4C-alkylthio or nitro, wherein the benzo annelated by aryl may be substituted by halogen, 1-4C alkoxy or CF3, and the alkyl in the aralkyl may be substituted by methoxy and CF 3.

The lipase-inhibiting compounds of formula (a) are described in more detail in WO 03/072098 and can be obtained according to known methods. Suitable syntheses of lipase-inhibiting compounds of formula (A) are also described in International patent application WO 03/072098. The entire content of international patent application WO 03/072098 is incorporated by reference into the present disclosure for lipase inhibitors of formula (a).

In addition, lipase inhibiting compounds are further described in US patent US 6,624,161 and its corresponding international patent applications WO00/040569 and WO 00/40247, which are also suitable in the context of the present invention in combination with the CB1 antagonist compounds described herein. These patent documents US 6,624,161 and WO00/040569 describe a series of compounds which are 2-oxo-4H-3, 1-benzoxazin-4-one derivatives, including ATL-962, and their use in obesity and obesity related diseases, including type II diabetes. The 2-oxy-4H-3, 1-benzoxazin-4-one derivative has the structure of formula (B), or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof:

wherein:

r1a is

(i) C10-30 branched OR unbranched alkyl optionally substituted by one OR more C3-6 cycloalkyl, C3-6 cycloalkenyl, aryl, heteroaryl, reduced heteroaryl, -C (O) R13, -CO2R13, -SOR13, -SO2R13, -NR13R14, -OR13 independently,

-SR13, -c (O) NR13R14, -NR14C (O) R13, halogen, cyano and nitro, and/or optionally interrupted by one or more oxygen atoms, with the proviso that any heteroatom in R1a must be separated from the exocyclic oxygen atom (or from any other heteroatom) by at least two carbon atoms;

(ii) c2-25 alkenyl, C2-25 alkynyl, C3-6 cycloalkenyl, aryl-C2-25 alkenyl, heteroaryl-C2-25 alkenyl, reduced heteroaryl-C1-25 alkyl, OR substituted derivatives of any of the foregoing, wherein the substituents are independently one OR more C1-6 alkyl, halogen-substituted C1-6 alkyl, aryl-C1-6 alkyl, heteroaryl, reduced heteroaryl-C1-6 alkyl, C1-6 alkoxy, aryl-C1-6 alkoxy, -C (O) R13, -CO2R13, -SOR13, -SO2R13, -NR13R14, -OR13, -SR13, -C (O) NR13R14, -NR14C (O) R13, halogen, Cyano and nitro, provided that any heteroatom in R1a must be separated from the exocyclic oxygen atom (or from any other heteroatom) by at least two carbon atoms;

(iii) c2-9 alkyl interrupted by one OR more oxygen atoms, optionally independently substituted by one OR more C3-6 cycloalkyl, C3-6 cycloalkenyl, aryl, heteroaryl, reduced heteroaryl, -C (O) R13, -CO2R13, -SOR13, -SO2R13, NR13R14, OR13, SR13, -C (O) NR13R14, -NR14C (O) R13, halogen, cyano and nitro, provided that any heteroatom in R1a must be separated from the exocyclic oxygen atom (OR from any other heteroatom) by at least two carbon atoms; or

(iv) C1-9 alkyl substituted with a group selected from: -c (O) R13, -CO2R13, SOR13, SO2R13, NR13R14, OR13, SR13, c (O) NR13R14, NR14C (O) R13; tetrahydronaphthyl, pyridyl, pyrrolyl, piperidinyl, halo, cyano, nitro, bicyclic aryl, bicyclic heteroaryl, monocyclic or bicyclic reduced heteroaryl, monocyclic heteroaryl excluding imidazolyl;

(v) phenyl substituted with a group selected from: OR17, -COR13, -CO2R13, SOR13, SO2R13, CONR13R14, NR14C (O) R13; halogen-substituted C1-6 alkyl, aryl C1-6 alkyl, heteroaryl, and heteroaryl C1-6 alkyl; or

(vi) Bicyclic aryl, bicyclic heteroaryl, monocyclic OR bicyclic reduced heteroaryl, OR monocyclic heteroaryl other than imidazolyl, optionally substituted with OR17, -COR13, -CO2R13, SOR13, SO2R13, CONR13R14, NR14C (O) R13; halogen-substituted C1-6 alkyl, aryl C1-6 alkyl, heteroaryl, and heteroaryl C1-6 alkyl;

wherein R13 and R14 each independently represent hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, aryl C1-10 alkyl, heteroaryl C1-10 alkyl, reduced heteroaryl or reduced heteroaryl, C1-10 alkyl, R17 represents hydrogen or C2-10 alkenyl, C2-10 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, aryl C1-10 alkyl, heteroaryl C1-10 alkyl, reduced heteroaryl or reduced heteroaryl C1-10 alkyl,

and R8a, R9a, R10a and R11a,

each independently is hydrogen, halogen, hydroxy, amino, nitro, cyano, mercapto, C1-10 alkyl, C1-10 alkoxy, C1-10 cycloalkyl, C1-10 cycloalkoxy, C (O) R15, C (O) NR15R16, S (O) R15 or halo C1-10 alkyl;

wherein R15 and R16 each independently represent hydrogen or C1-10 alkyl, with the proviso that when R8a, R9a, R10a and R11a are H, R1a is not CH2CH2C1 or C3 alkenyl.

Furthermore, in international patent application WO 00/40247, 2-amino-4H-3, 1-benzoxazin-4-one derivatives are mentioned as lipase inhibiting compounds for the treatment of obesity. In formula (B) the-OR 1a substituent is replaced by a-NR 1R2 group, the definitions of R1 and R2 being given in WO 00/40247.

The above structurally related compounds, including ATL-962, an oral non-absorbable synthetic lipase inhibitor, are being developed from the Alizyme's pancreatic lipase inhibitor research project for the effective treatment of obesity and for the effective treatment of type II diabetes. ATL-962 is chemically 2-hexadecyloxy-6-methyl-4H-3, 1-benzoxazin-4-one. Preclinical studies showed that ATL-962 has similar potency to orlistat and no toxicity was observed. Clinical data for these compounds are also available in the public domain, for example from ATL-962 in clinical studies of obesity.

Thus, the results obtained with the phase Ib program performed with ATL-962 were published in the International conference on Saint Paul obesity in Brazil. The three phase Ib trials included 99 healthy male volunteers in total, divided into 7 or 9 groups, given one of several doses of ATL-962 (66 subjects) or placebo (24 subjects), three times a day, taken with food for 5 days. In one group, 9 patients were given orlistat (qv)120mg three times a day. Overall, ATL-962 is safe and well tolerated, and increased excretion of fat in the diet indicates efficacy. Patients given doses of 50mg to 300mg of ATL-962 twice daily with food excrete an average amount of fat of 4.9(+/-4.3) to 11.2(+/-6.9) g/day, 1.4(+/-1.0) g/day relative to placebo, and 5.6(+/-3.8) g/day for orlistat. 55% of patients receiving ATL-962(50mg to 300mg) showed a 3-fold or more increase in fat excretion and 27% showed a 7-fold or more increase compared to placebo. There is evidence of dose dependence. Side effects and their frequency were similar, between ATL-962 and placebo, with a major gastrointestinal side effect, and a more major side effect being oily stools.

The results of a multicenter, randomized, double-blind, parallel group trial (phase IIb study) comprising 370 patients with clinical obesity were performed in 5 european national specialist clinics, with preliminary results reported in 9 months of 2003. All dose levels of ATL-962 (60, 120 and 240mg) showed significant weight loss relative to placebo for all treatment groups. There was no difference in the degree of weight loss between the treatment groups. LDL-cholesterol was reduced in the treatment group, but not in the placebo group. HDL-cholesterol levels did not differ between treatment groups, however they increased in the placebo treated group. The total cholesterol was reduced in the treatment group, whereas the placebo group showed an increase. ATL-962 is safe and universally well tolerated.

Lipase inhibiting compounds of formula (B) such as ATL-962 and structurally related compounds are described in more detail in US 6,624,161 and its corresponding International patent application WO00/040569 and can be obtained according to known methods. Suitable syntheses of lipase-inhibiting compounds of formula (B) are also described in US 6,624,161 and international patent application WO 00/040569. The entire contents of US 6,624,161 and international patent application WO00/040569 are incorporated in the present application for reference in the disclosure of lipase inhibitors of formula (B). The entire content of International patent application WO00/040247 is also incorporated herein by reference in its entirety for the disclosure of lipase inhibitors having the structure of the related 2-amino-4H-3, 1-benzoxazin-4-one compounds described therein.

Pharmaceutically acceptable salts, hydrates, solvates and prodrugs of all of the lipase inhibiting compounds described above may also be used in the context of the present invention.

CB of the formula (I), (II), (III), (IV) or (V) by using pharmaceutical adjuvants, auxiliary substances and/or liquid or solid carrier substances, using customary methods₁The antagonistic compound or a prodrug, tautomer or salt thereof and the lipase inhibitory compound used in the present invention may be formulated into a dosage form suitable for the treatment and/or prevention of the above-mentioned diseases, particularly obesity, for example for administration to adolescents or children and for administration to treat drug-induced obesity. As therapeutic agents, selective CB₁The antagonistic compound and/or the lipase inhibiting compound may be included in a pharmaceutical preparation such as a tablet, capsule, suppository or solution together with (conventional) pharmaceutical adjuvants, adjuvants and/or adjuvants. These pharmaceutical preparations can be prepared according to known methods using conventional solid or liquid excipients, for example lactose, starch or talc, or liquid paraffin, and/orAre prepared with (conventional) pharmaceutical adjuvants, adjuvants and/or adjuvants such as tablet disintegrating agents, solubilizers and preservatives.

Thus, in a further aspect the invention also relates to a composition having CB comprising at least one compound of formula (I), (II), (III), (IV) or (V)₁-a receptor active compound, or a prodrug, tautomer or salt thereof, in combination with at least one lipase inhibiting compound. Preferred pharmaceutical compositions comprise at least one compound of formula (I), (II), (III), (IV) or (V) as defined above, in combination with at least one lipase-inhibiting compound as a combined active ingredient. Another preferred pharmaceutical composition of the invention comprises as active ingredient at least one compound of formula (I), (II), (III), (IV) or (V) having CB₁-a receptor-active compound, preferably CB₁The antagonistic compound, or a prodrug, tautomer or salt thereof, and the at least one lipase inhibiting compound are useful for the treatment and/or prevention of obesity in juvenile or adolescent patients, and/or for the treatment and/or prevention of drug induced obesity in juvenile and adolescent patients. Particular pharmaceutical compositions of the invention are characterized in that at least one compound of formula (I), (II), (III), (IV) or (V) as defined above has CB₁-a receptor-active compound, preferably CB₁The antagonist, or a prodrug, tautomer or salt thereof, and the at least one lipase inhibiting compound, are each present in an effective amount suitable for the treatment and/or prevention of obesity in a juvenile patient in need of such treatment. In another embodiment of the present invention, CB₁Antagonistic compounds, in particular CB's of formula (I), (II), (III), (IV) or (V)₁The antagonist compound, and the lipase inhibiting compound are present in the pharmaceutical composition in amounts effective for the treatment and/or prevention of drug induced obesity in juvenile and adolescent patients, respectively, in need of such treatment. In the pharmaceutical composition of the present invention, CB₁Antagonistic compounds, preferably CB of formula (I), (II), (III), (IV) or (V)₁Antagonistic compounds, or prodrugs, tautomers or salts thereof, preferably in combination with at least one lipase inhibiting compound selected from the group consisting of lipase inhibiting polymers, orlistat, panclicins, ATL-962 and lipstatinCan be used together.

The invention also relates to a pharmaceutical product comprising CB as a medicament₁Antagonistic compounds, preferably CB having one of the formulae (I), (II), (III), (IV) or (V) as defined above₁Antagonistic compounds, or prodrugs, tautomers or salts thereof, and instructions for said CB₁The antagonistic compound may be administered in combination with the lipase inhibiting compound simultaneously, separately or in steps for the treatment and/or prevention of obesity.

Finally, the invention also encompasses a method for the treatment and/or prevention of obesity, for example in adolescent or in juvenile patients, and/or for the treatment and/or prevention of drug induced obesity in juvenile and in adolescent patients, characterized by CB₁Antagonistic compounds, in particular compounds of formula (I), (II), (III), (IV) or (V), which are cannabis CB₁-administering a receptor antagonist, or a prodrug, tautomer or salt thereof, in combination with at least one lipase inhibiting compound to a patient in need of such treatment. In a preferred method of the invention for the treatment and/or prevention of obesity, CB₁An antagonistic compound, which is one of the compounds of formula (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 inhibiting compound. The methods of the present invention for treating and/or preventing obesity are useful for obesity in juvenile or adolescent patients, and/or for drug induced obesity in juvenile and adolescent patients. In a variant embodiment of the invention, the method of treatment and/or prevention is characterized in that the treatment is directed to obesity in a juvenile patient. In another variant embodiment of the invention, the method of treatment and/or prevention is characterized in that the treatment is directed to drug induced obesity in a juvenile or adolescent patient. In the therapeutic and/or prophylactic methods of the present invention, CB₁Antagonistic compounds, preferably CB having one of the formulae (I), (II), (III), (IV) or (V) as defined above₁Antagonistic compounds, or prodrugs, tautomers or salts thereof, preferably with at least one lipase selected from the group consisting of lipase-inhibiting polymers, orlistat, panclicins, ATL-962 and lipstatinThe inhibitory compounds are administered in combination.

According to the invention, CB₁Antagonistic compounds, preferably CB having one of the formulae (I), (II), (III), (IV) or (V) as defined above₁The antagonist compound, or a prodrug, tautomer, or salt thereof, is administered in combination with the lipase inhibiting compound by a simultaneous, separate, or step-wise route of administration.

The compounds for use in the combination or composition of the invention are each preferably administered to a patient in need of treatment in an amount sufficient to prevent and/or treat the condition, disorder or disease symptom, e.g., obesity. For all aspects of the invention, especially for medical use, there is a dosage regimen for the administration of the compound or composition which will be ultimately determined by the attending physician, taking into account such factors as the compound employed, the type of animal, the age, body weight, severity of symptoms, method of administration, side effects and/or other contraindications. The specifically defined dose range can be determined by standard design clinical trials, monitoring the course of the patient's disease and recovery over time. The trial may use a escalating dose schedule using a low percentage of the maximum tolerated dose in the animal as the starting dose in humans.

The physiologically acceptable compounds for use in the combination or composition of the invention will generally each be administered in a daily dosage regimen (for adult patients), for example an oral dose of 1mg to 2000mg, preferably 30mg to 1000mg, for example 10 to 250mg, or an intravenous, subcutaneous or intramuscular dose of 0.1mg to 100mg, preferably 0.1mg to 50mg, for example 1 to 25mg, of a compound of formula (I) or a physiologically acceptable salt thereof, which compound is administered 1 to 4 times per day, calculated as the free base. Suitable compounds will be administered for a period of continuous therapy, for example for a week or more. For juvenile patients, a portion of the oral dose is typically administered to an adult patient, for example one fifth or one half of the aforementioned oral dose in an adult patient.

Preferably, in one embodiment of the present invention, the method of treatment and/or prevention is for the treatment of obesity in a juvenile patient. In another preferred embodiment of the present invention, the method of treatment and/or prevention is for the treatment of drug induced obesity in a juvenile or adolescent patient. Obesity caused by the drug may be particularly caused by drugs such as atypical antipsychotics.

In one embodiment of the invention, the method of treatment and/or prevention is for the treatment of obesity in a juvenile patient. Thus, it would be beneficial if cannabinoid antagonists in combination with lipase inhibitors were particularly suitable for the treatment of childhood obesity and related comorbidities, such as type II diabetes. There is a clear medical need for improved treatment, as obesity has become an increasingly important medical problem not only in the adult population, but also in children and adolescents (younger and older). From the 60 s to the 90 s of the nineteenth century, the prevalence of overweight in children increased from 5% to 11% in a national survey of the united states (soruf and Daniels 2002). As another example, canadian childhood obesity has increased 3-fold over the past 20 years (Spurgeon 2002). Childhood obesity causes a wide range of serious complications, increasing the risk of premature illness and death in the future, and increasing public health concerns (Ebbeling, Pawlak et al 2002). A large increase in cases of type II diabetes has been observed in the last decade, especially in children. This prevalence trend clearly reflects an increased rate of obesity. Type II diabetes has been considered in the past as a disease in adults and elderly patients, rather than as a pediatric condition (Arslanian 2002). One of the major risk factors for pediatric type II diabetes is obesity.

Childhood type II diabetes (as with adults) is part of the insulin resistance syndrome (rosenbom 2002), which includes hypertension, dyslipidemia, and other risk factors for atherosclerosis, and hyperandrogenism such as premature adrenal function onset and polycystic ovary syndrome. Other consequences associated with childhood obesity include left ventricular hypertrophy, non-alcoholic fatty liver, obstructive sleep apnea, orthopedic problems, and serious psychological problems.

In addition, essential hypertension is becoming increasingly common in children, and associated obesity is again a major independent risk factor. Obese children are at approximately 3 times higher risk of developing hypertension than non-obese children (soraf and Daniels 2002). The benefits of weight loss in children on blood pressure reduction have been demonstrated in both observational and interventional studies.

Public concern has increased due to the rapid development of childhood obesity epidemics among genetically immobilized populations. Given that the driving factors are primarily adverse environmental factors, there is a direct suggestion for lifestyle changes. Obesity and its associated comorbidities are very serious medical conditions and the prior art measures and treatments for obesity, especially childhood obesity, are still largely ineffective (Ebbeling, Pawlak et al 2002). Treatment of type II diabetes is also particularly difficult in the child and adolescent age groups (Silink 2002). The craving and overeating of palatable foods is an important factor in lifestyle-related obesity in humans, particularly in children and adolescents. Treatment of type II diabetes and other comorbidities depending on the extent of metabolic disorders and symptoms: the only data for children with type II diabetes using oral hypoglycemic agents is the use of metformin (rosenbom 2002).

Thus, the CB used in the present invention₁The combination of antagonists with lipase inhibitors offers a unique possibility to treat obesity by influencing these "driving forces". They are superior to current medical treatment methods, especially suitable for adolescent and pediatric treatment, because of their remarkable safety profile and/or tolerability and surprising beneficial combined effect. In addition to being effective, the treatment of obesity, especially childhood obesity, requires safety.

Childhood obesity is a medical condition that may require long-term treatment. CB for use in the invention₁The safety performance of the combination of the antagonist and the lipase inhibitor is better than that of the current standard drug treatment, and the CB is₁The combination of antagonist and lipase inhibitor would be particularly suitable for the treatment and prevention of juvenile obesity and childhood obesity and related co-morbidities.

The literature:

Arslanian，S.(2002).″Type 2 diabetes in childreh：clinicalaspects and risk factors.″ Horm Res 57 Suppl 1：19-28.

ebbeling, C.B., D.B. Pawlak, et al (2002). "childodob: public-health crisis, common sense cureLancet360(9331)：473-82.

Rosenbloom，A.L.(2002).″Increasing incidence of type 2diabetes in children and adolescents：treatmentconsiderations.″ Paediatr Drugs 4(4)：209-21.

Silink，M.(2002).″Childhood diabetes：a globalperspective.″ Horm Res 57 Suppl 1：1-5.

Sorof，J.and S.Daniels(2002).″Obesity hypertension inchildreh：a problem of epidemic proportions.″ Hypertension40(4)：441-7.

Spurgeon，D.(2002).″Childhood obesity in Canada hastripled in past 20 years.″ Bmj 324(7351)：1416.

In another embodiment of the present invention, the method of treatment and/or prevention is for the treatment of drug induced obesity in a juvenile or adolescent patient. Weight gain by drugs is also a major concern and there is a high medical need for improved treatment. Further, the invention CB herein₁Combinations of antagonists with lipase inhibitors are suggested to be superior to current standard drug therapy, these CB' s₁The combination of the antagonist with a lipase inhibitor is particularly suitable for the treatment and prevention of drug induced obesity in juvenile and adolescent patients.

With respect to drug-induced weight gain, it has been reported by Zimmermann, U.S., T.Kraus et al (2003, "Epidemiology, immunology and mechanics undersiding drug-induced weight gain in psychiatric patients," J Psychiatr Res 37 (3): 193-220), that body weight gain often occurs during psychiatric treatment and is often accompanied by increased appetite or increased desire for food. However, the occurrence and time course of such side effects is difficult to predict, which in most patients ultimately leads to obesity and its associated morbidity, often causing them to discontinue therapy, even if such therapy is effective. In patients treated with some second generation antipsychotic drugs and some mood stabilizers, weight gain showed the most prominence. Significant weight gain also often occurs during the course of treatment for most tricyclic antidepressants.

The enormous weight gain is associated with drugs like e.g. the atypical antipsychotics clozapine and olanzapine. However, some atypical antipsychotics tend to cause significant weight gain, which may lead to poor compliance and other adverse health effects (Nasrallah, H. (2003), "A review of the effect of the nutritional antipsychotics on weight." Psychoneuroendocrinology 28 Suppl 1: 83-96.). Although serotoninergic, histamine and adrenergic affinities have been implicated in other metabolic mechanisms, the mechanism of antipsychotic-associated weight gain remains uncertain. Atypical antipsychotics have an altered tendency to cause weight changes during long-term treatment. Follow-up studies showed that the greatest weight gain was associated with clozapine and olanzapine, with quetiapine and ziprasidone being the smallest. Risperidone was accompanied by moderate weight changes, which were not dose-related. Weight gain performance is a factor that should be considered when constructing a method for treating obesity due to severe drugs, assuming equal efficacy of atypical antipsychotics. In this regard, the CB of the present invention₁Combinations of antagonists with lipase inhibitors are effective.

Study of CB₁Experimental protocols for antagonizing the Effect of Compounds plus Lipase inhibitors on obesity

By measuring CB₁Combination of antagonist and lipase inhibitor for the treatment of obesity-related drive and performance parametersCan be shown by standard experimental animal models₁Beneficial pharmacological effects of the combination of antagonist and lipase inhibitor.

To study CB₁The effect of the combination of antagonist and lipase inhibitor on obesity, the body weight gain of rats can be measured as pharmacological index. Thus, the following experimental protocol for rats can be employed:

during the reversed dark period of 12h/12h photoperiod, e.g. 21:15 h light on, 09:15h light off, the rats had unrestricted access to food, 2 per day for 2.5 hours. Rats will be provided with a high fat, high sugar diet (western diet). The lipase inhibitor was administered at the very beginning of feeding the rats. Administration of CB1 hour before administration of Lipase inhibitor₁An antagonist.

For example, the following daily dosing regimen may be applied over a given period of time, e.g., days, weeks, or months:

CB₁antagonists, in particular CB of formula (I) as defined above₁The antagonist compound, or vehicle, is administered orally at about 07:45 to 08:00 hours in the morning. The lipase inhibitor, such as orlistat in particular, or the excipient is administered orally at about 08:45 to 09:00 h. After administration, the rats had free access to food from 09:15 to 11:45h, after which time the food was removed approximately 11:45 to 14:45 h. Another lipase inhibitor dose, such as orlistat in particular, or vehicle (Labrasol) is administered orally at approximately 14:15 to 14:30h in the afternoon, followed by free access to food from 14:45 to 17:15 h. Subsequently, the food was taken from 17:15-09:15 h.

The results of this protocol will be compared to daily food intake and weight gain as an indicator of the efficacy of the combination treatment for obesity during the experimental period. In addition to the parameters given above, feces may also be collected for evaluation of fat digestibility. And finally, animal carcass analysis can also be carried out.

In addition, biochemical parameters can be measured at the time of slaughtering the rats after completion of the experimental feeding and administration phase.

To study the effect, the total number of rats subjected to the experimental protocol was divided into the following groups, the number of rats in each group being approximately the same:

1) control group: according to the design, rats received vehicle alone for simulated administration (placebo group).

2)CB₁Group (2): rats received CB in vehicle₁An antagonist.

3) And (3) LI group: rats receive a lipase inhibitor ("LI") in a vehicle, such as the compound orlistat.

4)CB₁+ LI group (combo group): rats received CB in vehicle₁A lipase inhibitor ("LI") in an antagonist and an excipient, for example the compound orlistat.

The results of this design and respective studies show CB as defined above₁A beneficial suitability of a combination of an antagonist and a lipase inhibitor in the treatment and/or prevention of obesity.

Preparation of the Compound of formula (V)

1H-1, 2, 4-triazole-carboxamide derivatives of formula (V) are potent cannabinoid-CB₁Receptor agonists, partial agonists, inverse agonists or antagonists, for the treatment of psychiatric and neurological disorders, and others involving cannabinoid-CB₁A neurotransmission disorder, as defined above in the specification.

1, 5-diaryl-1H-1, 2, 4-triazole-3-carboxamide derivatives have been described as herbicides in EP 0346620 and GB 2120665. More recently, 1, 2, 4-triazole has been described as cannabinoid-CB₁and-CB₂Potent agonists and antagonists of the receptor (Jagerovic, N.et. al., Drugs fut.2002, 27 (suppl.A): XVIII int.Symp.on Medicinal Chemistry, P284).

Four 1, 5-diaryl-1H-1, 2, 4-triazole-3-carboxamide derivatives are described by Clerin and J.P.Fleury in Bull.Soc.Chim.Fr., 1974, 1-2, Pt.2, 211-217, in which the amide N-atom is part of an unsubstituted piperidinyl or morpholinyl group.

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-.

Four 1, 5-diaryl-N- (2-pyridyl) -1H-1, 2, 4-triazole-3-carboxamides are described in Indian J.Chem., 1976, 14B, 268-Ampere 272.

Suitable synthetic routes for the compounds of formula (V) for use in the present invention are as follows:

synthesis scheme A

Step 1: esterification of a compound of formula (S-II), wherein R₆Represents branched or unbranched (C)_1-4) -an alkyl group or a benzyl group,

to produce a compound of formula (S-III)

Wherein R and R₁Have the meaning as described above.

The compounds of the formula (S-II) according to the invention, in which R₆Represents a branched or unbranched alkyl radical (C)_1-4) Or benzyl, obtainable according to known methods, for example:

a)Sawdey，G.W.J.Am.Chem.Soc.1957，79，1955

b)Czollner，L.et al.，Arch.Pharm.(Weinheim)1990，323，225

c)Eicher，T. and Hauptmann，S.The Chemistry ofHeterocycles，Thieme Verlag，Stuttgart，1995(ISBN 313 1005114)，p.208-212.

step 2: compounds of formula (S-III) and formula R₂R₃NH compounds, wherein R₂And R₃Having the meaning as described above, by activation or coupling reactions, for example forming active esters, or in the presence of coupling reagents such as DCC, HBTU, BOP, CIP (2-chloro-1, 3-dimethylimidazolinium hexafluorophosphate) or PyAOP (7-azabenzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate). Activation and coupling methods are described in

a)M.Bodanszky and A.Bodanszky：The Practice of PeptideSynthesis，Springer-Verlag，New York，1994；ISBN：0-387-57505-7；

b)K.Akaji et al.，Tetrahedron Lett.(1994)，35，3315-3318)；

c)F.Albericio et al.，Tetrahedron Lett.(1997)，38，4853-4856)。

This reaction gives the 1H-1, 2, 4-triazole derivative of formula (V).

Synthesis scheme B

The compound of formula (S-III) is reacted with a halogenating agent such as thionyl chloride (SOCl)₂) Or oxalyl chloride. This reaction produces the corresponding carbonyl chloride (acid chloride) (S-IV).

Compounds of formula (S-IV) and formula R₂R₃Reaction of NH compound, wherein R₂And R₃Having the meanings described above, to give 1H-1, 2, 4-triazole derivatives of the formula (V).

Synthesis scheme C

A compound of formula (S-II) and formula R₂R₃Amidation of the NH compound, in which R₂And R₃Having the meaning as described herein above, to give 1H-1, 2, 4-triazole derivatives of formula (V). The amidation reaction may be carried out using trimethylaluminum Al (CH)₃)₃Catalysis (for more information on aluminum-mediated conversion of esters to amides, see J.I.Levin, E.Turos, S.M.Weinreb, Synth Commun, (1982), 12, 989-.

Example I

Part A: to a stirred solution of aminomalonic acid dimethyl ester hydrochloride (25 g, 0.136mol) in dichloromethane (200mL) at 0 deg.C was added triethylamine (41.4 mL, 2.2 molar equivalents). 4-chlorobenzoyl chloride (23.8 g, 0.136mol) was added slowly and the resulting solution was left overnight at room temperature. Water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The collected organic layer was washed with water and MgSO₄Dried, filtered under vacuum and concentrated. The residue was recrystallized from methanol (400mL) to give dimethyl 2- (4-chlorobenzoylamino) malonate (30.5 g, 79% yield). Melting point: 146 ℃ and 148 ℃.¹H-NMR(200MHz，CDCl₃)：3.86(s，6H)，5.38(d，J＝6Hz，1H)，7.15(br d，J～6Hz，1H)，7.43(d，J＝8Hz，2H)，7.79(d，J＝8Hz，2H)。

And part B: to a stirred suspension of 2, 4-dichloroaniline (19.44 g, 0.12mol) in concentrated HCl (25mL) and acetic acid (75mL) at 0 deg.C was added NaNO₂(9.0 g, 0.13mol) in water (50mL) and the resulting solution was stirred for 15 minutes. A solution of 2- (4-chlorobenzoylamino) -malonic acid dimethyl ester (28.55 g, 0.10mol) in acetone (200mL) was added slowly while maintaining the temperature below 0 ℃. Slowly adding K₂CO₃(120 g) in water (200mL) and the resulting black mixture was stirred at 0 ℃ for 30 min. The mixture was extracted three times with EtOAc. The collected organic phase is treated with water and NaHCO₃The aqueous solution and water were washed with MgSO 4₄Dried, filtered under vacuum and concentrated. The residue was dissolved in methanol (500mL), and a solution of sodium (1 g) in methanol (75mL) was added. The resulting stirred mixture was left overnight at room temperature and then cooled in a refrigerator. The precipitate formed was 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℃。¹H-NMR(200MHz，CDCl₃)：4.07(s，3H)，7.28-7.60(m，7H)。

Part C: to a stirred suspension of methyl 5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -1H-1, 2, 4-triazole-3-carboxylate (11.3 g, 0.0295mol) in methanol (100mL) was added KOH (45% aq., 7.5mL) and the resulting mixture was heated at reflux for 4 hours. The mixture was concentrated in vacuo, and water (150mL) and concentrated HCl were added. The yellow precipitate was collected by filtration, washed with water and dried under vacuum to give 5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -1H-1, 2, 4-triazole-3-carboxylic acid (10.0 g, 92% yield). Melting point: 141 and 144 deg.C (decomposition).

And part D: to a stirred solution of 5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -1H-1, 2, 4-triazole-3-carboxylic acid (1.48 g, 4.0mmol) in acetonitrile (20mL) were added successively Diisopropylethylamine (DIPEA) (1.5mL, 2.1 molar equivalents), O-benzotriazol-1-yl-N, N' -tetramethyluronium Hexafluorophosphate (HBTU) (1.66 g, 1.1 molar equivalents) and 1-aminopiperidine (0.44 g, 1.1 molar equivalents). After stirring overnight, NaHCO was added₃An aqueous solution. The resulting mixture was extracted three times with dichloromethane. The combined organic layers were washed with water and Na₂SO₄Dried, filtered under vacuum and concentrated to give a crude oil (3.6 g). The oil was purified by flash chromatography (silica gel; EtOAc/petroleum ether (40-60 ℃) ═ 7/3 (v/v)). The purified material was treated with ethanolic HCl (1M solution) to give 5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (piperidin-1-yl) -1H-1, 2, 4-triazole-3-carboxamide hydrochloride (1.50 g, 77% yield). Melting point: 238 deg.C and 240 deg.C (decomposition).¹H-NMR(400MHz，DMSO-d₆): 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 2Hz, 1H), 7.85-7.87(m, 1H), 7.91(d, J ═ 8Hz, 1H), (NH not observed).

Examples 2-18 were prepared similarly:

2.5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (pyrrolidin-1-yl) -1H-1, 2, 4-triazole-3-carboxamide hydrochloride. Melting point: 248-.

3.5- (4-chlorophenyl) -N-cyclohexyl-1- (2, 4-dichlorophenyl) -1H-1, 2, 4-triazole-3-carboxamide. Melting point: 186 ℃ and 188 ℃.

N-tert-butoxy-5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -1H-1, 2, 4-triazole-3-carboxamide. Melting point: 150 ℃ and 152 ℃.

5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (N-pentyl) -1H-1, 2, 4-triazole-3-carboxamide.¹H-NMR(400MHz，CDCl₃): 0.92(t, J ═ 7Hz, 3H), 1.35-1.44(m, 4H), 1.62-1.70(m, 2H), 3.48-3.56(m, 2H), 7.20-7.25(m, 1H), 7.34(dt, J ═ 8 and 2Hz, 2H), 7.42-7.50(m, 4H), 7.54(d, J ═ 2Hz, 1H).

5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -N- (morpholin-4-yl) -1H-1, 2, 4-triazole-3-carboxamide. Melting point: 184-186 ℃.

1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -N- (piperidin-1-yl) -1H-1, 2, 4-triazole-3-carboxamide hydrochloride. Melting point: 234 ℃ and 237 ℃ (decomposition).

1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -N- (pyrrolidin-1-yl) -1H-1, 2, 4-triazole-3-carboxamide hydrochloride. Melting point: 234 ℃ and 236 ℃ (decomposition).

1- (4-chlorophenyl) -N-cyclohexyl-5- (2, 4-dichlorophenyl) -1H-1, 2, 4-triazole-3-carboxamide.¹H-NMR(400MHz，CDCl₃): 1.14-1.81(m, 8H), 2.02-2.10(m, 2H), 4.00-4.11(m, 1H), 7.08(br d, J-7 Hz, 1H), 7.26(br d, J-8 Hz, 2H), 7.34(br d, J-8 Hz, 2H), 7.40(dd, J ═ 8 and 2Hz, 1H), 7.44-7.48(m, 2H).

N-tert-butoxy-1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -1H-1, 2, 4-triazole-3-carboxamide.¹H-NMR(400MHz，CDCl₃): 1.38(s, 9H), 7.25(brd, J-8 Hz, 2H), 7.35(br d, J-8 Hz, 2H), 7.41(dd, J ═ 8 and 2Hz, 1H), 7.44-7.48(m, 2H), 9.18, br s, 1H).

11.1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -N-(n-pentyl) -1H-1, 2, 4-triazole-3-carboxamide.¹H-NMR(400MHz，CDCl₃): 0.91(t, J ═ 7Hz, 3H), 1.35-1.41(m, 4H), 1.60-1.70(m, 2H), 3.48-3.56(m, 2H), 7.21(br t, J-7 Hz, 1H), 7.26(br d, J-8 Hz, 2H), 7.34(br d, J-8 Hz, 2H), 7.40(dd, J ═ 8 and 2Hz, 1H), 7.44-7.48(m, 2H).

1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -N- (morpholin-4-yl) -1H-1, 2, 4-triazole-3-carboxamide hydrochloride. Melting point: 224 ℃ and 226 ℃.

1- (2, 4-dichlorophenyl) -5- (pyridin-2-yl) -N- (piperidin-1-yl) -1H-1, 2, 4-triazole-3-carboxamide. Melting point: 191-193 ℃.

5- (2, 4-dichlorophenyl) -N- (piperidin-1-yl) -1- (4- (trifluoromethyl) phenyl) -1H-1, 2, 4-triazole-3-carboxamide. Melting point: 159 ℃ and 161 ℃.

15.1' - [5- (2, 4-dichlorophenyl) -1- (4- (trifluoromethyl) phenyl) -1H-1, 2, 4-triazol-3-yl) carbonyl ] piperidine. Melting point: 155 ℃ and 156 ℃.

1- (2, 4-dichlorophenyl) -N- (piperidin-1-yl) -5- (pyridin-3-yl) -1H-1, 2, 4-triazole-3-carboxamide. Melting point: 219 ℃ C.

1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -N- (5, 5, 5-trifluoropentyl) -1H-1, 2, 4-triazole-3-carboxamide.¹H-NMR(400MHz，CDCl₃): 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(br d, J-8 Hz, 2H), 7.40(dd, J ═ 8 and 2Hz, 1H), 7.44-7.48(m, 2H).

1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -N- (5-fluoropentyl) -1H-1, 2, 4-triazole-3-carboxamide.¹H-NMR(400MHz，CDCl₃): 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(br d, J-8 Hz, 2H), 7.40(dd, J ═ 8 and 2Hz, 1H), 7.44-7.48(m, 2H).

Example 19

Part A: 1- (chlorophenyl) -5- (2, 4-dichlorophenyl) -1H-1, 2, 4-triazole-3-carboxylic acid was prepared analogously to the method described in example 1, with the starting materials in each of part A-C being aminomalonic acid dimethyl ester hydrochloride, 2, 4-dichlorobenzoyl chloride and 4-chloroaniline. Melting point: 102-104 ℃.¹H-NMR(400MHz，DMSO-d₆): 7.36(br d, J-8 Hz, 2H), 7.50(br d, J-8 Hz, 2H), 7.59(dd, J ═ 8 and 2Hz, 1H), 7.70(d, J ═ 2Hz, 1H), 7.75(d, J ═ 8Hz, 1H), OH protons are part of the water peak at 3.4.

1- (chlorophenyl) -5- (2, 5-dichlorophenyl) -1H-1, 2, 4-triazole-3-carboxylic acid was prepared analogously, starting with dimethylaminomalonate hydrochloride, 2, 5-dichlorobenzoyl chloride and 4-chloroaniline, respectively. Melting point: 183-188 ℃.¹H-NMR(400MHz，DMSO-d₆): 7.41(br d, J-8 Hz, 2H), 7.52(br d, J-8 Hz, 2H), 7.56(d, J ═ 8Hz, 1H), 7.65(dd, J ═ 8 and 2Hz, 1H), 7.88(d, J ═ 2Hz, 1H), OH protons are part of the water peak at 3.5.

And part B: to a stirred solution of 1- (chlorophenyl) -5- (2, 4-dichlorophenyl) -1H-1, 2, 4-triazole-3-carboxylic acid (0.37g, 1.00mmol) in dichloromethane (10mL) was added oxalyl chloride (0.254g, 2.00 mmol). The resulting mixture was concentrated in vacuo to give crude 1- (chlorophenyl) -5- (2, 4-dichlorophenyl) -1H-1, 2, 4-triazole-3-carbonyl chloride.

Part C: crude 1- (chlorophenyl) -5- (2, 4-dichlorophenyl) -1H-1, 2, 4-triazole-3-carbonyl chloride was dissolved in Tetrahydrofuran (THF) (10 mL). 2, 3-dihydro-1H-inden-2-ylamine (0.40g, 3.00mmol) was added and the resulting solution was stirred at 25 ℃ for 42H. The mixture was concentrated in vacuo and the residue was purified by preparative liquid chromatography to give pure 1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -N- (2, 3-dihydro-1H-inden-2-yl) -1H-1, 2, 4-triazole-3-carboxamide (393mg, 81% yield). MS (ESI)⁺)485.6。¹H-NMR(400MHz，DMSO-d₆): 3.06(dd, J ═ 16 and 8Hz, 2H), 3.21(dd, J ═ 16 and 8Hz, 2H), 4.71-4.82(m, 1H), 7.12-7.16(m, 2H), 7.19-7.24(m.2h), 7.39(br d, J-8 Hz, 2H), 7.52(br d, J &)8Hz, 2H), 7.60(dd, J ═ 8 and 2Hz, 1H), 7.71(d, J ═ 2Hz, 1H), 7.79(d, J ═ 8Hz, 1H), 8.93-8.97(m, 1H, NH).

Examples 20-43 were prepared similarly:

1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -N- (1-ethynylcyclohexyl) -1H-1, 2, 4-triazole-3-carboxamide. MS (ESI)⁺)473.3。

1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -N- (2-methylcyclohexyl) -1H-1, 2, 4-triazole-3-carboxamide. MS (ESI)⁺)465.5。

1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -N- (4-methylcyclohexyl) -1H-1, 2, 4-triazole-3-carboxamide. MS (ESI)⁺)465.5。

1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -N-cyclooctyl-1H-1, 2, 4-triazole-3-carboxamide. MS (ESI)⁺)477.3。

1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -N- (azepan-1-yl) -1H-1, 2, 4-triazole-3-carboxamide. MS (ESI)⁺)466.4。

1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -N-cycloheptyl-1H-1, 2, 4-triazole-3-carboxamide. MS (ESI)⁺)465.5。

N-tert-butyl-1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -1H-1, 2, 4-triazole-3-carboxamide. MS (ESI)⁺)425.4。

1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -N- (1, 1-diethylprop-2-yn-1-yl) -1H-1, 2, 4-triazole-3-carboxamide. MS (ESI)⁺)461.5。

1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -N- (2, 2, 2-trifluoroethyl) -1H-1, 2, 4-triazole-3-carboxamide. MS (ESI)⁺)451.3。

29.1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -N- (exo-bicyclo [2.2.1]Hept-2-yl) -1H-1, 2, 4-triazole-3-carboxamide. MS (ESI)⁺)461.5。

1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -N- (4- (2-propyl) piperazin-1-yl) -1H-1, 2, 4-triazole-3-carboxamide. MS (ESI)⁺)480.3。¹H-NMR(400MHz，DMSO-d₆): 1.00(d, J ═ 7Hz, 6H), 2.46-2.56(m, 4H), 2.72(septet, J ═ 7Hz, 1H), 3.66-3.74(m, 4H), 7.36(br d, J ═ 8Hz, 2H), 7.51(br d, J ═ 8Hz, 2H), 7.59(dd, J ═ 8 and 2Hz, 1H), 7.72(d, J ═ 2Hz, 1H), 7.75(d, J ═ 8Hz, 1H).

31.1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -N- (hexahydrocyclopenta [ c ] group]Pyrrol-2 (1H) -yl) -1H-1, 2, 4-triazole-3-carboxamide. MS (ESI)⁺)476.4。

1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -N-pentyl-1H-1, 2, 4-triazole-3-carboxamide. MS (ESI)⁺)435.5。

1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -N- (2, 2-dimethylpropyl) -1H-1, 2, 4-triazole-3-carboxamide. MS (ESI)⁺)439.6。

1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -N- (3- (trifluoromethyl) phenyl) -1H-1, 2, 4-triazole-3-carboxamide. MS (ESI)⁺)511.7。

35.1' - [1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -1H-1, 2, 4-triazol-3-yl) carbonyl]-1, 4' -dipiperidine. MS (ESI)⁺)520.5。

1- (4-chlorophenyl) -N- (4-chlorophenyl) -5- (2, 5-dichlorophenyl) -N-methyl-1H-1, 2, 4-triazole-3-carboxamide. MS (ESI)⁺)491.4。

1- (4-chlorophenyl) -5- (2, 5-dichlorophenyl) -N- (1-ethynylcyclohexyl) -1H-1, 2, 4-triazole-3-carboxamide. MS (ESI)⁺)473.4。

1- (4-chlorophenyl) -5- (2, 5-dichlorophenyl) -N- (2-methylcyclohexyl) -1H-1, 2, 4-triazole-3-carboxamide. MS (ESI)⁺)465.5。

1- (4-chlorophenyl) -5- (2, 5-dichlorophenyl) -N- (4-methylcyclohexyl) -1H-1, 2, 4-triazole-3-carboxamide. MS (ESI)⁺)465.6。

1- (4-chlorophenyl) -5- (2, 5-dichlorophenyl) -N-cyclooctyl-1H-1, 2, 4-triazole-3-carboxamide. MS (ESI)⁺)477.3。

1- (4-chlorophenyl) -5- (2, 5-dichlorophenyl) -N-cycloheptyl-1H-1, 2, 4-triazole-3-carboxamide. MS (ESI)⁺)465.6。

1- (4-chlorophenyl) -5- (2, 5-dichlorophenyl) -N-cyclopentyl-1H-1, 2, 4-triazole-3-carboxamide. MS (ESI)⁺)435.5。

1- (4-chlorophenyl) -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 according to the invention obtained with the above-mentioned determination methods are given in the following table:

	human cannabinoid-CB1Receptors
				Affinity in vitro	In vitro antagonism
Examples	pKiValue of	pA2Value of
			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 (26)

1. Having CB of the formula (I), (II), (III), (IV) and/or (V)₁-compounds active at the receptor, prodrugs thereof, tautomers thereof or salts thereof for the preparation of a medicament for the treatment and/or prophylaxis of juvenile patients with CB₁Receptor-related diseases and/or for the treatment and/or prevention of drug induced obesity in juvenile and adolescent patients.

2. According to claim 1, having CB₁Use of a compound having receptor activity, wherein, has CB₁Activation of the receptorThe sex compound is selected from: 4, 5-dihydro-1H-pyrazole derivatives of formula (I) and/or (III), 1H-imidazole derivatives 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 compound of formula (I) is

Wherein

-R and R₁Independently represents phenyl, thienyl or pyridyl, which groups may be substituted by 1, 2, 3 or 4 identical or different substituents Y, Y being selected from C_1-3-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono-or dialkyl (C)_1-2) -amino, mono-or dialkyl (C)_1-2) -acylamino group, (C)_1-3) Alkylsulfonyl, methylsulfonylamino, C_1-3Alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl groups, or R and/or R₁Represents a naphthyl group, and the naphthyl group,

-R₂represents hydrogen, hydroxy, C_1-3-alkoxy, acetoxy or propionyloxy,

-R₃represents a hydrogen atom, or C which is branched or unbranched_1-8Alkyl, or C_3-7Cycloalkyl, wherein alkyl or cycloalkyl may be substituted by hydroxy,

-R₄represents C_2-10Branched or unbranched heteroalkyl, C_3-8Non-aromatic heterocycloalkyl or C_4-10Non-aromatic heterocycloalkyl-alkyl radicals containing one or more heteroatoms selected from O, N, S or-SO₂A group in which C_2-10Branched or unbranched heteroalkyl, C_3-8Non-aromatic heterocycloalkyl or C_4-10Non-aromatic heterocycloalkyl-alkyl groups may be substituted by keto, trifluoromethyl, C_1-3Alkyl, hydroxy, amino, monoalkylamino, or dialkylamino groups or fluorine atom substitution; or R₄Represents amino, hydroxy, phenoxy or benzyloxy; or R₄Represents C_1-8Alkoxy radical, C_3-8Alkenyl radical, C_5-8Cycloalkenyl or C_6-9Cycloalkenylalkyl, which may contain a sulfur, nitrogen or oxygen atom, a keto group or-SO₂-groups in which alkoxy, alkenyl and cycloalkenyl groups can be substituted by hydroxy, trifluoromethyl, amino, monoalkylamino or dialkylamino groups or by fluorine atoms; or R₄Represents C_2-5An alkyl group, wherein the alkyl group contains a fluorine atom; or R₄Represents imidazolylalkyl, benzyl, pyridylmethyl, phenethyl or thienyl; or R₄Represents substituted phenyl, benzyl, pyridyl, thienyl, pyridylmethyl or phenethyl, in which the aromatic rings are substituted by 1, 2 or 3 substituents Y, in which Y has the meaning indicated above,

or when R is₃When it is hydrogen or methyl, R₄May be a group NR₆R₇Wherein

-R₆And R₇Identical or different, represents C_2-4Alkyl radical, C_2-4A trifluoroalkyl group, a cycloalkyl group,

or R₆Represents methyl, provided that R₇Represents C_2-4Alkyl, or R₆And R₇Together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic moiety having from 4 to 8 ring atoms, in which the heterocyclic moiety may contain an oxygen or sulfur atom or a keto group or-SO₂A group or other nitrogen atom, in which the saturated or unsaturated heterocyclic moiety may be replaced by C_1-4Alkyl is substituted, or

-R₃And R₄Together 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, wherein the heterocyclic moiety may contain one or more atoms selected from O, N, S or a keto group or-SO₂A group, which moiety may be substituted by C_1-4Alkyl, hydroxyalkyl, phenyl, thienyl, pyridyl, amino, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylamino, dialkylamino, aminoalkyl, azetidinyl, pyrrolidinyl, piperidinyl, or hexahydro-1H-aza * -yl,

-R₅represents benzyl, phenyl, thienyl or pyridyl, which may be substituted by 1, 2, 3 or 4 substituents Y, which areWherein Y has the meaning as indicated above, which may be the same or different; or R₅Represents C_1-8Branched or unbranched alkyl, C_3-8Alkenyl radical, C_3-10Cycloalkyl radical, C_5-10Bicycloalkyl radical, C_6-10Tricycloalkyl or C_5-8A cycloalkenyl group; or R₅Represents a naphthyl group, and the naphthyl group,

b) the compound of formula (II) is

Wherein

R represents phenyl, thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, which may be substituted by 1, 2, 3 or 4 identical or different substituents Y, Y being selected from C_1-3-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono-or dialkyl (C)_1-2) -amino, mono-or dialkyl (C)_1-2) -acylamino group, (C)_1-3) -alkoxycarbonyl, carboxyl, cyano, carbamoyl and acetyl; or R represents naphthyl, with the proviso that when R is 4-pyridyl, R₄Represents a halogen atom or a cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methanesulfonyl, methylthioalkyl or branched or unbranched C_1-4Alkyl radical, wherein C_1-4Alkyl may be substituted by 1 to 3 fluorine atoms or by bromine, chlorine, iodine, cyano or hydroxy,

-R₁represents phenyl or pyridyl, which radicals can be substituted by 1 to 4 identical or different substituents Y, where Y has the abovementioned meaning; or R₁Represents pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, which radicals may be substituted by 1 to 2 identical or different substituents Y; or R₁Represents a 5-membered heteroaromatic ring having 1 or 2 heteroatoms selected from N, O, S, wherein the heteroatoms may be the same or different, and the 5-membered heteroaromatic ring may be substituted with 1 to 2 substituents Y which may be the same or different; or R₁Represents a naphthyl group, and the naphthyl group,

-R₂represents hydrogen, branched or unbranched C_1-8Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Alkenyl radical, C_5-8Cycloalkenyl radicals, which may contain sulfur, oxygen or nitrogen atoms,

-R₃represents branched or unbranched C_2-8Alkyl radical, C_1-8Alkoxy radical, C_5-8Cycloalkoxy, C_3-8Cycloalkyl radical, C_5-10Bicycloalkyl radical, C_6-10Tricycloalkyl radical, C_3-8Alkenyl radical, C_5-8Cycloalkenyl radicals, which may optionally contain one or more heteroatoms selected from O, N, S, which may be substituted by hydroxyl or 1-2C_1-3Alkyl or 1-3 fluorine atoms; or R₃Represents benzyl or phenethyl, wherein the aromatic rings may be substituted by 1 to 5 identical or different substituents Z, Z being selected from C_1-3-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono-or dialkyl (C)_1-2) -amino, mono-or dialkyl (C)_1-2) -acylamino group, (C)_1-3) -alkylsulfonyl, dimethyl-sulfamino, C_1-3-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl; or R₃Represents phenyl or pyridyl, which are substituted by 1 to 4 substituents Z, wherein Z has the meaning indicated above,

or R₃Represents a pyridyl group; or R₃Represents phenyl, provided that R₄Represents a halogen atom or a cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methanesulfonyl, methylthioalkyl or C group_1-4Alkyl radical, wherein C_1-4Alkyl may be substituted with 1 to 3 fluorine atoms or with bromine, chlorine, iodine, cyano or hydroxy;

or R₃Represents a group NR₅R₆Provided that R is₂Represents a hydrogen atom or a methyl group, wherein

-R₅And R₆Identical or different and represents branched or unbranched C_1-4An alkyl group; or R₅And R₆Together with the nitrogen atom to which they are attachedInto a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms, wherein the heterocyclic group contains one or two heteroatoms selected from N, O, S, which may be the same or different, and wherein the heterocyclic group may be substituted with C_1-3Alkyl or hydroxy substituted, or R₂And R₃Together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic group having from 4 to 10 ring atoms, wherein the heterocyclic group contains one or two heteroatoms selected from N, O, S, wherein the heteroatoms may be the same or different, wherein the heterocyclic group may be substituted by C_1-3Alkyl or hydroxyl is substituted, and the alkyl or the hydroxyl is substituted,

-R₄represents a hydrogen or halogen atom or a cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methanesulfonyl, methylthioalkyl or branched or unbranched C_1-4Alkyl radical, wherein C_1-4Alkyl may be substituted by 1 to 3 fluorine atoms or by bromine, chlorine, iodine, cyano or hydroxy,

c) the compound of the formula (III) is

Wherein

-R and R₁Independently represents phenyl, thienyl or pyridyl, which groups may be substituted by 1, 2 or 3 identical or different substituents Y, Y being selected from C_1-3-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono-or dialkyl (C)_1-2) -amino, mono-or dialkyl (C)_1-2) -acylamino group, (C)_1-3) Alkylsulfonyl, methylsulfonylamino, C_1-3-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl; or R and/or R₁Represents a naphthyl group, and the naphthyl group,

-R₂represents hydrogen, hydroxy, C_1-3-alkoxy, acetoxy or propionyloxy,

-R₃represents a hydrogen atom or a branched or unbranched C_1-8Alkyl or C_3-7Cycloalkyl, wherein alkyl or cycloalkyl may be substituted by hydroxy,

-R₄represents a hydrogen atom or a branched or unbranched C_1-8Alkyl radical, C_3-8Cycloalkyl radical, C_2-10Heteroalkyl group, C_3-8Non-aromatic heterocycloalkyl or C_4-10Non-heteroaromatic alkyl moieties wherein these moieties may contain one or more heteroatoms selected from O, N, S, which moieties may be substituted by keto, trifluoromethyl, C_1-3Alkyl, hydroxy, amino, monoalkylamino, or dialkylamino groups or fluorine atom substitution; or R₄Represents amino, hydroxy, phenoxy or benzyloxy; or R₄Represents branched or unbranched C_1-8Alkoxy radical, C_3-8Alkenyl radical, C_5-8Cycloalkenyl or C_6-9Cycloalkenylalkyl, which may contain a sulfur, nitrogen or oxygen atom, a keto group or-SO₂A group in which C_1-8Alkoxy radical, C_3-8Alkenyl radical, C_5-8Cycloalkenyl or C_6-9Cycloalkenylalkyl may be substituted by hydroxy, trifluoromethyl, amino, monoalkylamino or dialkylamino groups or by fluorine atoms; or R₄Represents phenyl, benzyl, pyridyl, thienyl, pyridylmethyl or phenethyl, wherein the aromatic rings may be substituted by 1, 2 or 3 substituents Y, wherein Y has the meaning indicated above; or

R₄Represents a group NR₈R₉Provided that R is₃Represents a hydrogen atom or a methyl group, wherein R₈And R₉Identical or different, represents C_1-4Alkyl or C_2-4A trifluoroalkyl group; or R₈And R₉Together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic moiety having from 4 to 8 ring atoms, in which the heterocyclic moiety may contain an oxygen or sulfur atom or a keto group or-SO₂A group or other nitrogen atom, in which the saturated or unsaturated heterocyclic moiety may be replaced by C_1-4Alkyl is substituted or

R₃And R₄Together 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, wherein the heterocyclic moiety may contain one or more atoms selected from O, N, S or a keto group or-SO₂A group, which moiety may be substituted by C_1-4Alkyl, hydroxyalkyl, phenyl, thienyl, pyridyl, amino, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylamino, dialkylamino, aminoalkyl, azetidinyl, pyrrolidinyl, piperidinyl, or hexahydro-1H-aza * -yl,

-R₅and R₆Each independently represents a hydrogen atom or a branched or unbranched C_1-8Alkyl or alkenyl, which groups may contain one or more heteroatoms selected from O, N, S, keto or-SO₂-groups, which may be substituted by hydroxyl or amino groups; or R₅And R₆Each independently represents C_3-8-cycloalkyl or C_3-8Cycloalkenyl which may contain one or more ring heteroatoms selected from O, N, S or-SO₂Groups, which may be substituted by hydroxy, alkyl (C)_1-3)、-SO₂A radical, a keto radical, an amino radical, a monoalkylamino radical (C)_1-3) Or dialkylamino (C)_1-3) Is substituted, or

R₅Represents naphthyl or phenyl, wherein the phenyl group may be substituted by 1, 2 or 3 substituents Y, wherein Y has the meaning described herein above, with the proviso that R₆Represents a hydrogen atom, or a branched or unbranched alkyl group (C)_1-5) Wherein the alkyl group may contain one or more heteroatoms selected from O, N, S or-SO₂-a group wherein alkyl may be substituted by hydroxy, keto or amino; or

R₅And R₆Together with the nitrogen atom to which they are attached form a monocyclic, bicyclic or tricyclic alkyl or alkenyl group which may contain a ring heteroatom selected from O, N, S, a keto group or SO₂Groups in which the monocyclic, bicyclic or tricyclic alkyl or alkenyl groups may be substituted by hydroxy, alkyl (C)_1-3)、SO₂Radical, keto group, amino group, monoalkylamino group (C)_1-3) Dialkylamino (C)_1-3) Pyrrolidinyl or piperidinyl, wherein the monocyclic, bicyclic or tricyclic alkyl or alkenyl group may contain an annelated phenyl group, wherein the annelated phenyl group may be substituted with 1 or 2 substituents Y, wherein Y has the meaning described herein above,

-R₇represents branched or unbranchedC of a branched chain_1-3An alkyl group, a carboxyl group,

d) the compound of formula (IV) is

Wherein

R represents a hydrogen atom or a substituent X chosen from branched or unbranched C_1-3-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono-or dialkyl (C)_1-2) -amino, mono-or dialkyl (C)_1-2) Acylamino, branched or unbranched (C)_1-3) Alkoxycarbonyl, trifluoromethylsulfonyl, sulfamoyl, branched or unbranched alkyl (C)_1-3) Sulfonyl, carboxyl, cyano, carbamoyl, branched or unbranched dialkyl (C)_1-3) Aminosulfonyl, branched or unbranched monoalkyl (C)_1-3) -an aminosulfonyl group and an acetyl group,

-R₁is a hydrogen atom or represents 1 to 4 substituents X, where X has the abovementioned meaning,

-R₂represents phenyl, thienyl, pyridyl or pyrimidinyl, which radicals can be substituted by 1 to 4 substituents X, wherein X has the abovementioned meaning; or R₂Represents a naphthyl group, and the naphthyl group,

-R₃represents a hydrogen atom or a branched or unbranched C_1-10Alkyl or cycloalkyl-alkyl or phenyl, benzyl or phenethyl, in which the aromatic rings may be substituted by 1 to 5 identical or different substituents Z, Z being selected from branched or unbranched C_1-3-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono-or dialkyl (C)_1-2) -amino, mono-or dialkyl (C)_1-2) Acylamino, branched or unbranched (C)_1-3) Alkylsulfonyl, methylsulfonylamino, branched or unbranched C_1-3-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl; or R₃Represents a pyridyl group or a thienyl group,

-R₄represents branched or unbranched C_1-10Alkyl or cycloalkyl-alkyl, branched or unbranched C_1-10Alkoxy radical, C_3-8Cycloalkyl radical, C_5-10Bicycloalkyl radical, C_6-10Tricycloalkyl, branched or unbranched C_3-10Alkenyl radical, C_5-8Cycloalkenyl, which may contain one or more heteroatoms selected from O, N, S, which groups may be substituted by hydroxy, 1-3 methyl, ethyl or 1-3 fluorine atoms; or R₄Represents phenyl, benzyl or phenethyl, in which the aromatic rings may be substituted by 1 to 5 substituents Z, where Z has the abovementioned meaning; or R₄Represents pyridyl or thienyl; or R₄Represents a group NR₅R₆Wherein

R₅And R₆Together with the nitrogen atom to which they are attached form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms, wherein the heterocyclic group contains one or more heteroatoms selected from O, N, S, wherein the heterocyclic group may be branched or unbranched C_1-3Alkyl, hydroxy or trifluoromethyl or fluorine atom, or

-R₃And R₄Together with the nitrogen atom to which they are attached form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms, wherein the heterocyclic group contains one or more heteroatoms selected from O, N, S, wherein the heterocyclic group may be branched or unbranched C_1-3Alkyl, hydroxy or trifluoromethyl or fluorine atom,

e) the compound of formula (V) is

Wherein

-R and R₁Independently represents phenyl, naphthyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, which groups may be substituted by 1 to 4 identical or different substituents X, selected from branched or unbranched (C)_1-3) Alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthioAlkyl, trifluoromethoxy, nitro, amino, mono-or dialkyl (C)_1-2) -amino, mono-or dialkyl (C)_1-2) -acylamino group, (C)_1-3) Alkoxycarbonyl, trifluoromethylsulfonyl, sulfamoyl, (C)_1-3) Alkylsulfonyl, carboxy, cyano, carbamoyl, (C)_1-3) -dialkylaminosulfonyl, (C)_1-3) -monoalkylamino-sulfonyl and acetyl groups,

-R₂represents a hydrogen atom or a branched or unbranched C_1-8Alkyl or C_1-8Cycloalkyl-alkyl or phenyl, benzyl or phenethyl, in which the aromatic rings may be substituted by 1 to 4 substituents X, in which X has the meaning indicated above; or R₂Represents a pyridyl group or a thienyl group,

-R₃represents branched or unbranched C_1-8Alkyl radical, C_1-8Alkoxy radical, C_3-8Cycloalkyl radical, C_5-10Bicycloalkyl radical, C_6-10Tricycloalkyl radical, C_3-8Alkenyl radical, C_5-8Cycloalkenyl, these groups optionally containing one or more heteroatoms selected from O, N, S, these groups being possibly substituted by hydroxyl, ethynyl or 1-3 fluorine atoms; or R₃Represents phenyl, benzyl or phenethyl, in which the aromatic rings may be substituted by 1 to 4 substituents X, in which X has the meaning indicated above; or R₃Represents pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl or thienyl, wherein the heteroaromatic rings may be substituted by 1 to 2 substituents X, wherein X has the meaning indicated above; or R₃Represents a group NR₄R₅Wherein

R₄And R₅Together 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, wherein the heterocyclic moiety contains one or two heteroatoms selected from N, O or S, wherein the heteroatoms may be the same or different, and wherein the heterocyclic moiety may be branched or unbranched C_1-3Alkyl, hydroxy or trifluoromethyl or fluorine atom; or

-R₂And R₃Together with the nitrogen atom to which they are attached form a saturated or unsaturated, or saturated or unsaturated compound having 4 to 10 ring atoms,Monocyclic or bicyclic heterocyclic moiety, wherein the heterocyclic group contains one or two heteroatoms selected from N, O or S, which may be the same or different, and wherein the heterocyclic moiety may be branched or unbranched C_1-3Alkyl, hydroxy, piperidinyl or trifluoromethyl or a fluorine atom.

3. According to claim 1 or 2, having CB₁-use of a receptor active compound, a prodrug, a tautomer or a salt thereof, wherein the use is in the preparation of a medicament: for pediatric treatment and/or prevention of psychiatric disorders such as psychosis, anxiety disorders, depression, attention deficit, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, desire, drug dependence, and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral stroke, craniocerebral trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelination-related disorders, and for pediatric treatment of pain disorders, including neuropathic pain disorders, and other diseases involving cannabinoid neurotransmission, including pediatric treatment of septic shock, glaucoma, attention deficit, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, urge, drug dependence, and neurological disorders, Cancer, diabetes, emesis, nausea, asthma, respiratory diseases, gastrointestinal disorders, gastric ulcers, diarrhea, and cardiovascular disorders.

4. Having CB according to any one of claims 1 to 3₁-a receptor active compound, or a prodrug, tautomer or salt thereof, preferably CB₁Use of a receptor antagonist compound or a prodrug, tautomer or salt thereof for the manufacture of a medicament for the treatment and/or prevention of obesity in juvenile patients and/or drug induced obesity in juvenile and adolescent patients.

5. Has CB as defined in claim 2₁-a receptor active compound, or a prodrug, tautomer or salt thereof, preferably CB₁Use of a receptor antagonist compound, or a prodrug, tautomer or salt thereof, in combination with at least one lipase inhibiting compound, for the manufacture of a medicament for the treatment and/or prevention of obesity in juvenile or adolescent patients, and/or drug induced obesity in juvenile and adolescent patients.

6. Has CB according to claim 5₁Use of a compound having receptor activity, wherein, has CB₁-a receptor active compound or a prodrug, tautomer or salt thereof, preferably CB₁A receptor antagonist compound, or a prodrug, tautomer, or salt thereof, for use in combination with at least one lipase inhibiting compound selected from the group consisting of lipase inhibiting polymers, orlistat, panclicins, ATL-962, and lipstatin.

7. Pharmaceutical composition comprising at least one compound having CB₁-receptor-active compounds of formulae (I), (II), (III), (IV) and/or (V), or prodrugs, tautomers or salts thereof, as active ingredients suitable for the treatment and/or prophylaxis of juvenile patients with CB₁A receptor related disease, and/or is useful in the treatment and/or prevention of drug induced obesity in juvenile and adolescent patients.

8. The pharmaceutical composition according to claim 7, wherein, has CB₁-the receptor-active compound is selected from the group consisting of 4, 5-dihydro-1H-pyrazole derivatives of formula (I) and/or (III), 1H-imidazole derivatives of formula (II), thiazole derivatives of formula (IV) and/or 1H-1, 2, 4-triazole-3-carboxamide derivatives of formula (V), each as defined in claim 1 or 2.

9. Pharmaceutical composition according to claim 7 or 8, wherein at least one has CB₁-a receptor active compound of formula (I), (II), (III), (IV) and/or (V), or a prodrug, tautomer or salt thereof, in an effective amount suitable for the following use: pediatric treatment andand/or for the prevention of psychiatric disorders such as psychosis, anxiety disorders, depression, attention deficit, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, desire, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, myospasm, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral stroke, craniocerebral trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, disorders associated with demyelination, and for the treatment of pain disorders in pediatrics, including neuropathic pain disorders, and other diseases involving cannabinoid neurotransmission, including the treatment of septic shock, glaucoma, cancer, diabetes, septic shock, anxiety, depression, attention deficit disorder, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, urge, drug dependence and neurological disorders, Emesis, nausea, asthma, respiratory diseases, gastrointestinal disorders, gastric ulcers, diarrhea, and cardiovascular disorders in juvenile patients in need of treatment.

10. The pharmaceutical composition according to any of claims 7 to 9, wherein at least one compound of formula (I), (II), (III), (IV) and/or (V) has CB₁-a receptor active compound, or a prodrug, tautomer or salt thereof, preferably CB₁A receptor antagonist compound, or a prodrug, tautomer, or salt thereof, in an amount effective for the treatment and/or prevention of obesity in juvenile patients, and/or drug induced obesity in juvenile and adolescent patients.

11. Pharmaceutical composition comprising, as active ingredient, at least one compound having CB as defined in claim 2₁-a receptor active compound, or a prodrug, tautomer or salt thereof, preferably CB₁A receptor antagonist compound, or a prodrug, tautomer, or salt thereof, and at least one lipase inhibiting compound, for use in the treatment and/or prevention of obesity in juvenile or adolescent patients, and/or drug induced obesity in juvenile and adolescent patients.

12. Pharmaceutical composition according to claim 11, comprising at least one compound having CB₁-a receptor active compound or a prodrug, tautomer or salt thereof, preferably CB₁A receptor antagonist compound or a prodrug, tautomer or salt thereof, in combination with at least one lipase inhibiting compound selected from the group consisting of lipase inhibiting polymers, orlistat, panclicins, ATL-962 and lipstatin.

13. The pharmaceutical composition according to any one of claims 10 to 12, wherein at least one of the structures of formula (I), (II), (III), (IV) or (V) as defined in claim 2 has CB₁-a receptor active compound, or a prodrug, tautomer or salt thereof, preferably CB₁The antagonist compound, or a prodrug, tautomer, or salt thereof, and the at least one lipase inhibiting compound are each present in an amount effective for the treatment and/or prevention of obesity in a juvenile patient in need of treatment.

14. The pharmaceutical composition according to any one of claims 10 to 12, wherein at least one of the structures of formula (I), (II), (III), (IV) or (V) as defined in claim 2 has CB₁-a receptor active compound, or a prodrug, tautomer or salt thereof, preferably CB₁The antagonist compound, or a prodrug, tautomer, or salt thereof, and the at least one lipase inhibiting compound are each present in an amount effective for the treatment and/or prevention of drug induced obesity in juvenile and adolescent patients in need of such treatment.

15. Treatment and/or prevention of juvenile patients with CB₁Receptor-related disease and/or method for the treatment and/or prevention of drug induced obesity in juvenile and adolescent patients, characterized in that at least one compound having CB as defined in claim 2₁-a receptor-active compound of formula (I), (II), (III), (IV) and/or (V), or a prodrug, tautomer or salt thereof, for administration to a patient in need of treatment.

16. A method of treatment and/or prevention according to claim 15, wherein the treatment and/or prevention is for pediatric treatment and/or prevention of psychiatric disorders such as psychosis, anxiety, depression, attention deficit, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, desire, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral stroke, craniocerebral trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelination-related disorders, and for pediatric treatment of pain disorders including neuropathic pain disorders, and other diseases involving cannabinoid neurotransmission including pediatric treatment for septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases, gastrointestinal disorders, gastric ulcers, diarrhea, and cardiovascular disorders.

17. A method of treatment and/or prophylaxis according to any of claims 15 or 16, wherein the treatment and/or prophylaxis is for obesity in juvenile patients and/or drug induced obesity in juvenile and adolescent patients.

18. Method for the treatment and/or prevention of obesity in juvenile or adolescent patients, and/or drug induced obesity in juvenile and adolescent patients, characterized in that at least one compound having CB as defined in claim 2 is administered₁-a receptor active compound, or a prodrug, tautomer or salt thereof, preferably CB₁A receptor antagonist compound, or a prodrug, tautomer, or salt thereof, in combination with at least one lipase inhibiting compound, is administered to a patient in need of treatment.

19. The therapeutic and/or prophylactic method according to claim 18, characterized in that at least one has CB₁-a receptor active compound or a prodrug, tautomer or salt thereof, preferably CB₁The receptor antagonist compound, or a prodrug, tautomer, or salt thereof, is administered in combination with at least one lipase inhibiting compound selected from the group consisting of lipase inhibiting polymers, orlistat, panclicins, ATL-962, and lipstatin.

20. A method of treatment and/or prevention according to any of claims 15 to 19, characterized in that it is for the treatment of obesity in juvenile patients.

21. A method of treatment and/or prophylaxis according to any of claims 15 to 19, characterized in that it is a medicament for the treatment of obesity in juvenile or adolescent patients.

22. Method of treatment and/or prevention according to any of claims 15 to 21, characterized in that it has CB₁-a receptor active compound or a prodrug, tautomer or salt thereof, preferably CB₁The receptor antagonist compound, or a prodrug, tautomer, or salt thereof, is administered in combination with the lipase inhibiting compound by a simultaneous, separate, or step-wise route of administration.

23. A pharmaceutical product comprising as a medicament at least one compound of formula (I), (II), (III), (IV) or (V) as defined in claim 2 having CB₁-a receptor active compound, or a prodrug, tautomer or salt thereof, preferably CB₁A receptor antagonist compound or a prodrug, tautomer or salt thereof, as a combined preparation with at least one lipase inhibiting compound for simultaneous, separate or sequential use in the treatment and/or prevention of obesity.

24. A pharmaceutical product comprising as a medicament at least one compound of formula (I), (II), (III), (IV) or (V) as defined in claim 2 having CB₁-compounds of receptor activityOr a prodrug, tautomer or salt thereof, preferably CB₁A receptor antagonistic compound or a prodrug, tautomer or salt thereof, and instructions indicating that said compound has CB₁-a receptor-active compound, preferably CB₁A receptor antagonist compound for simultaneous, separate or step-wise administration in combination with a lipase inhibiting compound for the treatment and/or prevention of obesity.

25. Has CB as defined in claim 2₁-a compound having one of the formulae (I), (II), (III), (IV) or (V) with receptor activity, or a prodrug, tautomer or salt thereof, preferably CB₁A receptor antagonist compound, or a prodrug, tautomer, or salt thereof, in combination with at least one lipase inhibiting compound.

26. According to claim 26 having CB as defined in claim 2₁Combinations of compounds having one of the formulae (I), (II), (III), (IV) or (V) with receptor activity, where CB is present₁-a receptor active compound, or a prodrug, tautomer or salt thereof, preferably CB₁A receptor antagonist compound or a prodrug, tautomer or salt thereof, in combination with at least one lipase inhibiting compound selected from the group consisting of lipase inhibiting polymers, orlistat, panclicins, ATL-962 and lipstatin.