TW200530219A - Novel medical uses of compounds showing CB1-antagonistic activity and combination treatment involving said compounds - Google Patents

Abstract

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

Description

200530219 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to the brand-new use of compounds exhibiting CBr antagonistic activity in the treatment and / or prevention, and relates to pharmaceutical compositions that contain one or more of these The compound is the active ingredient for this new use. The compounds expressed in the present invention show marijuana-1 (CBO receptor antagonistic activity), and can exhibit significant effects on the novel use provided by the present invention. Furthermore, according to one embodiment of the present invention, all It can be said that a compound having CBi-antagonistic activity can be used in combination with another active ingredient, and a pharmaceutical composition containing at least one of these CB ^ antagonistic compounds can be used in combination with the other active ingredient as an obesity Treatment and / or prevention. The combination of the compound having marijuana-1 (CBl) receptor antagonistic activity and the other active ingredient provided by the present invention is particularly useful for the treatment of obesity. [Previous Technology] Cannabinoids ) Exists in the Indian cannabis Cannabis Sativa L. 'and has been used as a medicament for centuries (Mechoulam, R .; Feigenbaum, JJ Prog. Med. Chem. 1987, 24, 159). But only in the past Within ten years, research in the field of cannabinoids has revealed cannabinoid receptors and their (endogenous) agonists and antagonists (antagon ist) important message. The discovery and subsequent colonization of two cannabinoid receptors (CB! and CB2) stimulated the search for new cannabinoid receptor antagonists (Munro, S .; Thomas, K. · Abu-Shaar, M. Nature 1993, 365, 61. Matsuda, LA; Bonner, T.I. Cannabinoid Receptors, Pertwee, RG Ed. 1995, 117, Academic Press, London). In addition, pharmaceutical companies are developing cannabinoids. Drugs are interested in treating 200530219 diseases related to cannabinoid system disorders. The widespread distribution of CB! Receptors in the brain, plus the fact that CB receptors are located at the nerve endings, makes CBl receptors a very interesting one The molecular target is used in many medical instructions as: present; for example, psychiatric and neurological disorders, which become life in technical conditions ^ (Consroe, P · Neurobiology of Disease 1998, 5, 534 · P〇p £ Curr · Opin · In CPNS Investigational Drugs 1999, i 587 Greenberg, D · A · Drug News Perspect · 1999, 12, 458). International patent applications WO 03/026647, WO 03 / 〇27〇76, W 〇03 / 078413, W0 03 / 078413 and the most recently filed international patent application, which will be announced in March / April 2004, and it is based on the European priority application EP 02078966.5 priority date September 19, 2002, and learned that the compound, which The purpose is to treat diseases related to disorders of the cannabinoid system. Therefore, these compounds exhibit activity at the cannabis CBr receptor, exhibiting, for example, CB! Antagonist activity, and they have the general formula (I), (II), (m), (IV) as defined below in this description. ) Or (V). In particular, compounds with a cannabis CBr receptor complex have been proposed for the treatment of psychiatric diseases, such as psychosis, anxiety, anxiety, inadequate attention, memory disorders, cognitive disorders, appetite disorders, obesity, health Cancerous, thirsty, drug dependence 'and neurological diseases such as neurodegeneration, dementia, abnormal muscle tone, muscle cramps, tremor, epilepsy, multiple sclerosis, traumatic brain injury, wind , Parkinson ’s disease, Attmer ’s disease, pain tumors, Huntington ’s disease, Trollett syndrome, cerebral ischemia, cerebral stroke, Gu Shao's traumatic brain injury, looking for, spinal cord injury, Shenqianfangsha disease , Spot sclerosis, viral encephalitis, conditions related to loss, and use as a cure, including neuropathic diseases, and other diseases of the central nervous system related to Dahe nerve material, including Treatment of sepsis 200530219 sick shock, glaucoma, cancer, diabetes, vomiting, nausea, asthma, respiratory disorders, gastrointestinal disorders, gastric ulcers, diarrhea and cardiovascular diseases. International patent application wo 03/026647 describes a new group of compounds' which are derivatives of 4,5-dihydro-iH-u and have the structure of the general formula (I) as defined below. These 4,5_dihydro · 1H_oxazole derivatives are potent antagonists of cannabinoids (CBD receptors), and their use is to treat diseases related to disorders of the cannabinoid system. These compounds have the general formula (1) The structure in which the symbols have the representativeness stated in the rest of this description, and particularly show their strong CBi antagonistic activity. International patent application WO 03/027076 describes a whole new group of compounds, which are 1H- Derivatives of imidazole and having the structure of the general formula (11) 1 as defined below. Children's derivatives of imidazole are potent agonists, potent agonists or antagonists of the cannabinoid (CBi) receptor. It is used for the treatment of psychiatric and neurological conditions, and other diseases related to cannabinoid nerve conduction. These compounds have the structure of general formula (11), and the symbols in them have the representative stated in the following of this description International patent application WO 03/026648 describes a whole new group of compounds, which are also derivatives of 4, 5-dihydro-fluorene-α-pyrazole and have the general formula (III) defined below- The structure of the species. Such + 5_ dihydro. _ 'Sit The organism is once again a potent antagonist of the cannabinoid (CB!) Receptor, and its purpose is to treat diseases related to disorders of the cannabinoid system. In particular, the compound has the general formula (Ilia) or (Illb). Representativeness is set out in the rest of this description. International patent application WO 03/078413 describes a whole new group of compounds which are derivatives of pyrazole and have a structure of the general formula (ιν) defined below. The derivatives of these pyrazoles are potent antagonists of the cannabinoid (CBi) receptor 200530219 T, agonists, or partial agonists, and are used to treat diseases related to disorders of the cannabinoid system. These compounds It has the structure of general formula (IV), in which (there is a representative of the following statements in this description. The recently filed international patent application will be filed in March / April, 2004, and Based on the European priority application EP 02078966.5 priority date: September 19, 2002, it describes that a group of brand-new compounds,… is 1,5-_ aromatic tobacco base heart with ^ 三座 _3 ^ 炭Derivatives of amidine, The structure of the general formula (V) as defined in the above. The derivatives of i, 5 diaryl 2, tri 'carbon amines are cannabinoids CBl. Agents or partial agonists whose purpose is to treat diseases related to disorders of the cannabinoid system. These compounds have the structure of the general formula (V), and the symbols in them have the representations stated in the rest of this description [Summary of the Invention] Another object of the present invention is to provide an improved method for treatment and / or prevention, which is particularly suitable for a population of patients with increased safety and tolerance requirements, such as for treating obesity. Suffering from, especially, obese patients such as infants and / or patients undergoing long-term treatment, such as juvenile and adolescent patients, as a result of drugs causing obesity. In addition—the project aims to provide a particularly useful combination therapy and its medicines for the treatment and / or prevention of obesity in patients of any age, such as juvenile and adolescents, whose towels use compounds having CBl • antagonistic activity according to the present invention and In addition, a combination of active ingredients ^ is used for the treatment of obesity. It has now surprisingly been discovered that due to the excellent and unique pharmacological properties of the selective CB1_ antagonist compounds, which include particularly high levels of safety and tolerability, 'these compounds are turning towards treatment and / or Preventing aspects related to 200530219 leprosy disorders, especially those with increased safety and tolerance needs _ 'From fat female patients who are as expected and / or long-term transfer to H such as juvenile and adolescent patients Obesity caused by drugs. Therefore, the present invention relates to a compound having a wide receptor activity, which has the general formula ⑴, ⑻, (III), (IV) or (V) as one of the following meanings, or the like -A prodrug, tautomers, or Lai, preferring a CB1 cutting resistance to chemo, or tautomers, etc., a kind of prodrugs, tautomers, or salts , Combined with at least one compound that inhibits lipase activity. In one aspect of the present invention, the compound having CBi receptor activity has the general formula ⑴, (π), or one of the structures, or one of the prodrugs, intermutation, etc. as defined below. Tautomers or salts are more preferred as a compound that antagonizes the CBi receptor, or as a prodrug, tautomers or salt, and at least one fat-inhibiting compound. Enzyme-active compounds are used in combination and are selected from the group consisting of lipase inhibitor polymers, orlistat, panciicin, αχχ962, and lipstatin. In particular, 'CBi antagonists with the general structure ⑴, (Η), (III), (IV) and / or (V) have been found surprisingly, their precursors, their interactions The isomers and their salts exhibit a unique pharmacological property, and are therefore particularly suitable for the manufacture of a drug for the treatment and / or prevention of obesity, especially in obese patients and / or during childhood and Drug-induced obesity in adolescent patients. In this regard, CBi antagonists having the general structure ⑴, (II), (III), (IV) and / or (V) structures, their precursors, their tautomers and their salts On the one hand, it is very valuable to mention 200530219 as a pediatric medicine, and on the other hand, it is very valuable for general use in obesity caused by drugs. Since they are active at the cannabinoid CBr receptor, the compounds used in accordance with the present invention are also suitable for use in the treatment and / or treatment of pediatric disorders other than juvenile obesity and obesity caused by drugs in juvenile patients. prevention. Such other conditions include those known from the literature directed at compounds that are active at the cannabinoid CBr receptor, such as pediatric treatment and / or prevention may also be related to psychiatric diseases in young patients, Such as mental illness, anxiety, depression, lack of attention, memory impairment, cognitive impairment, appetite disorder, obesity, addiction, hunger, drug dependence, and neurological diseases such as neurodegenerative 'dementia, Abnormal muscle tone, muscle cramps, tremors, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Draught's syndrome, brain Ischemic disease, cerebral stroke, cranial and brain trauma, stroke, spinal cord injury, neuritis, sclerosis, viral encephalitis, conditions related to demyelination, and use as a treatment for pain , Including pain disorders with a neurological cause, and other central nervous system diseases related to cannabinoid nerve conduction, including treatment of septic shock, glaucoma Eyes, cancer, diabetes, vomiting, nausea, asthma, respiratory disorders, gastrointestinal disorders, gastric ulcers, diarrhea, and cardiovascular diseases. The full text of the documents referred to in the description of the present invention is incorporated into this application by reference. The CBi antagonist compound used in the present invention can be prepared according to a known method. The applicable methods of the compounds used according to the present invention are detailed in the references cited in the present application and incorporated into the text of 200530219 according to the current state of the art. Furthermore, it has been surprisingly discovered that CBi antagonists (CBl antagonists) having the general structure (I), (II), (in), (IV) and / or (V), and the like Prodrugs, tautomers, and salts, because of their unique pharmacological properties, are 'especially suitable for use in combination with at least one lipase-inhibiting compound (lipase inhibitor) as a drug for the treatment and And / or prevention of obesity, including, in particular, treatment and / or prevention of obesity in young patients and / or obesity due to drugs in young and adolescent patients. In this regard, the use of at least one CBi antagonist compound as defined herein in combination with at least one compound that inhibits lipase activity is provided in medicines for the treatment and / or prevention of general, such as obesity in adolescents of any age It is especially valuable in pediatric or juvenile obesity, as well as obesity caused by drugs in juvenile and adolescent patients. In particular, the present invention is based on the surprising discovery that a CBi antagonist compound having a structure of general formula (I) is a derivative of 4,5-dihydro_1H_pyrazole and has a structure of general formula (π) Derivatives of 1H-imidazole, those having the structure of general formula (ΠΙ) are also derivatives of 4, 5-dihydro-1Η-pyrazole, those having the structure of general formula (IV) are derivatives of pyrazole or have Those with the general formula (ν) are 丨 乩 丨, derivatives of 2, triazol-3-carboxamide, which are all antagonists of the cannabinoid CBi receptor, and their precursor drugs, etc. Tautomers and their salts ^ Due to their heterogeneous pharmacological properties, they are particularly suitable for use in combination with at least one compound that inhibits lipase activity for manufacturing-transgenics for the treatment and / or management of obesity In particular, it treats and / or treats obesity in young patients and / or obesity caused by drugs in young and adolescent patients. Hereby, each compound having the general formula (I), (π), (ΙΠ), (ιν) or (v) structure and a lipase inhibitory compound is used in combination with the drug provided on 13 200530219 As a treatment and / or prevention of obesity in general, such as the voice of young people of any age, especially in pediatric or juvenile obesity, it is extremely valuable for obesity caused by drugs. 2. The compound having the general structure IX, (II), (III), (IV) or (V) used in the present invention can be prepared according to a known method. Suitable methods for compounds having the general formulae (1), (11), (III), (IV) used in accordance with the present invention are described in international patent applications WO 03/026647, WO 03/027076, W03 / 078413 or WO 03 contact 413, etc., which are incorporated into this description by reference. The preparation of compounds with the general structure (V) can be based on the international patent application that has only recently been published. It will be published in March / April 2004, and its priority application is European Priority Application EP 02078966 · 5. 2002 September 19, 2014, which is also incorporated into this description by reference. The preparation of compounds having the general structure (V) is also described at the end of this description. [Embodiments] In the following examples of the present invention, compounds with the general formula (I), (II), (III), (IV) or (V) are described in more detail, especially for obesity The symptoms are explained by examples. Compounds having the structure of general formula α) In the first embodiment, the present invention is based on this amazing discovery, that is, 4,5_bispyrazole with the structure of general formula (1) Derivatives' which are potent and selective insertion inhibitors of cannabinoid CBr · receptors, their precursors, their tautomers or their salts: -200530219 of which

One R and the other independently represent phenyl, thienyl or bipyridyl, these functional groups can be one, two, three or four which can be the same or different , Derived from containing 1 to 3 carbon atoms-alkyl or alkoxy, hydroxy, functional, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, pinyl, amino , Mono or dialkyl (containing 1 to 2 carbon atoms) -amino, mono or dialkyl (containing 1 to 2 carbon atoms) -fluorenylamino, (containing 1 to 3 carbon atoms) alkyl-sulfonyl Group, dimethylsulfonylamino group, alkoxy-carbamyl group containing 1 to 3 carbon atoms, carboxyl group, trifluoromethylsulfonyl group, cyano group, carbamoyl group, ammonia group Sulfamoyl and acetate groups are substituted by substituent Y in this group, or R and / or Ri represent naphthyl, R2 represents hydrogen atom, hydroxyl group, (containing 1 to 3 carbon atoms) alkoxy group, ethyl group Ethoxy or propionyloxy, R3 represents a hydrogen atom, or a branched or unbranched alkyl group containing 1 to 8 carbon atoms, or a ring containing 3 to 7 carbon atoms Burning base ' Alkyl with or cycloalkyl group may be substituted with burning a few groups,

-R4 represents a bifurcated or unbranched heteroalkyl group containing 2 to 10 carbon atoms, 'represents a heterocycloalkyl group of non-aromatic hydrocarbons containing 3 to 8 carbon atoms, or represents a heteroalkyl group containing 4 to 1 Non-aromatic hydrocarbon heterocyclic alkyl group of 0 carbon atoms, the functional group contains one or more heteroatoms selected from the group (oxygen, nitrogen, sulfur), or a -S02- group containing 2 Forked or unbranched heteroalkyl groups of up to 10 broken atoms, heteroaromatic alkyl groups of non-aromatic hydrocarbons containing 3 to 8 carbon atoms, or non-aromatic smoked heterocyclic rings containing 4 to 10 carbon atoms Alkyl-alkynyl can be keto, trifluoromethyl, alkynyl containing 1 to 3 carbon atoms, carboxyl, amino, mono-alkynyl, or double-alkoxy 15 200530219

Substituted by an amino group, or by a fluorine atom, or by a rule of 4 representing an amino group, a mesityl group, a phenoxy group, or a tolyloxy group; A fluorenyl group of one carbon atom represents an allyl group containing 5 to 8 atoms, or a cyclic alkyl group of 6 to 9 carbon atoms, and its functional group contains a sulfur, nitrogen, or oxygen atom. A keto group or -S02- group, in which the alkoxy group, the alkyl group and the cycloalkylene group may be substituted by a hydroxyl group, a trifluoromethyl group, an amino group, a monoalkylamino group or a dialkylamino group, or a fluorine atom Substitution; or 1 ^ 4 represents an alkyl group containing 2 to 5 carbon atoms, the alkyl group of which contains a fluorine atom; or R4 represents an imidazolidinyl group, benzyl group, oripidylmethyl group, phenethyl group, or p-synyl; or R4 represents a substituted phenyl, benzyl, this yl, p-syl, u-pyridylmethyl, or phenethyl, in which the aromatic smoke ring is One or three substituents Y, wherein Y has the meaning as mentioned above; or when R3 is a hydrogen atom or a methyl group, R4 may represent a functional group, in which

Where 6 and R? Are the same or different, and represent an alkyl group containing 2 to 4 carbon atoms, a trifluoroalkyl group containing 2 to 4 carbon atoms, or R6 represents a methyl group, but the prerequisites are Yes, 117 represents an alkyl group containing 2 to 4 carbon atoms, or R6 and R?-Together with the nitrogen atom to which they are attached-form a saturated or unsaturated heterocyclic moiety containing 4 to 8 ring atoms Where the heterocyclic part may contain an oxygen atom or a sulfur atom, 'or a steel or 疋 -S〇2_ group' or another nitrogen atom, and the saturated or unsaturated heterocyclic part may be Substituted by an alkyl group containing 1 to 4 carbon atoms, or hydrazone and hydrazone together with the nitrogen atom to which they are attached form a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing 4 to 10 ring atoms , 16 200530219 wherein the heterocyclic group may contain one or more atoms selected from the group (oxygen, nitrogen, sulfur), or a keto group or a -S02- group, wherein the functional group may contain 1 Alkyl, hydroxide, phenyl, pyrimyl, pyrimidine, amino, monoalkylaminoalkyl, dioxane to 4 carbon atoms Substituted by aminoalkyl,, monoalkylamino, dialkylamino, aminoalkyl, cycloaziridinyl, pyrrolidinyl, aziridinyl, or hexahydro · 1Η-cycloaziridinyl, —R5 Represents benzyl, phenyl, pyrimyl, or orbipyridyl, which can be substituted by one, two, three, or four substituents γ, where γ has the meaning as described above, and it can Are the same or different; or _ Rs represents a bifurcated or unbranched group containing 1 to 8 carbon atoms, represents an alkenyl group containing 3 to 8 carbon atoms, and represents 3 to 10 carbon atoms A cycloalkyl group of carbon atoms represents a bicycloalkyl group containing 5 to 10 carbon atoms, a tricycloalkyl group containing 6 to 10 carbon atoms, or a ring containing 5 to 8 carbon atoms Alkyl; or & represents naphthyl, because of its unique pharmacological properties, it is particularly suitable for use in combination with at least one compound that inhibits lipase activity for manufacturing-a drug for treating and / or preventing general Obesity, such as the treatment of obesity in adolescents of any age // Prevent obesity in young patients and / or obesity due to drugs in young and adolescent patients. In this regard, a compound having the structure of general formula (I) is used in combination with a lipase inhibitory compound to provide medicines for the treatment and / or prevention of general obesity, such as the treatment of obesity in adolescent patients of any age, It is especially valuable in pediatric or juvenile obesity, and drug-induced obesity. In the compound having the structure of the general formula (I) (at the _ carbon atom of the 4,5-dihydro_H_pyrazole moiety), at least the epicenter is present. The present invention relates to a compound having the structure of the general formula (i) and its racemic isomer, that is, a mixture of cis-trans isomers and individual stereoisomers thereof. In particular, the compound of interest having the general formula (I) has an absolute stereo configuration on the fourth carbon atom of the 4,5-dihydro-lH-u-pyrazole moiety, as shown by the general formula (la) representative.

The present invention also relates to compounds having the structure of the general formula (I), its E isomer, Z isomer, and E / Z mixture. Compounds of general structure (Π)

In the second embodiment, the present invention is based on this amazing discovery, that is, a 1-imide derivative having the structure of general formula (II) and having CBi antagonistic activity. Drugs and their salts, which are potent antagonists of the cannabinoid CBr receptor:

Ri

(II) 18 200530219 of which

—R represents phenyl, 4-umyl, or 2-upyridyl, 3 < pyridyl, 4-αpyridyl, pyrimidinyl, this azinyl, Pyridaziny1, or triazinyl , Its functional group can be one, two, two or 疋 four can be the same or different, derived from an alkyl group containing 1 to 3 carbon atoms or an alkoxy group, a hydroxyl group, a functional group, a trifluoro group Methyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono or dialkyl (containing 1 to 2 carbon atoms)-amino, mono or dialkyl (containing 1 to 2 (Carbon atom)-fluorenylamino, (containing 1 to 3 carbon atoms)-alkoxycarbamyl, carboxyl, chloro, carbamoyl, and ethynyl substituents of this group are substituted by Y, or R represents Naphthyl, but the prerequisite is that when R is 4-σ than yodo, R4 represents a halogen atom or a cyano, carbamoyl, formamyl, acetamyl, trifluoroacetamyl, fluorine Acetyl, propanoic acid, calcidic acid, methylcarbamate, methylsulfanyl or a branched or unbranched alkyl group containing 1 to 4 carbon atoms, which contains An alkyl group of 1 to 4 carbon atoms can be One to three fluorine atoms are replaced by one atom such as bromine, chlorine, iodine, cyano or hydroxy. One Ri stands for phenyl or π-pyridyl. Its functional group can be one to four. It can be the same or The different substituents Y are substituted, wherein Y has the meaning as mentioned above; or Ri represents a hydroxy group, a u group, a p- group or a triazine, and the functional groups may be one to two and may be the same Or it is replaced by a different substituent Y; or Ri represents a heterocyclic ring of a pentacyclic aromatic hydrocarbon, which contains one or more heteroatoms derived from the group (nitrogen, oxygen, sulfur), wherein the heteroatom may be The same or different, the heterocyclic ring of its five-ring aromatic smoke can be replaced by one or two substituents which can be the same or different γ 19 200530219; or R1 represents naphthyl '-R2 represents a hydrogen atom, which contains A bifurcated or unbranched alkyl group of 1 to 8 carbon atoms, representing a cycloalkyl group containing 3 to 8 carbon atoms, representing an alkenyl group containing 3 to 8 carbon atoms, representing 5 to 8 carbon atoms Cycloalkenyl, in which the functional group contains a sulfur, oxygen or nitrogen atom,

—Private represents a bifurcated or unbranched alkyl group containing 2 to 8 carbon atoms, represents an alkoxy group containing 1 to 8 carbon atoms' represents a cycloalkoxy group containing 5 to 8 carbon atoms, represents containing A cycloalkyl group of 3 to 8 carbon atoms represents a bicycloalkyl group of 5 to 10 carbon atoms' represents a tricycloalkyl group of 6 to 10 carbon atoms and an alkenyl group of 3 to 8 carbon atoms , Represents a cycloalkenyl group containing 5 to 8 carbon atoms, wherein the functional group may contain one or two heteroatoms derived from the group (nitrogen, oxygen, sulfur), and the functional group may be a hydroxyl group, or one to Two alkyl groups containing 1 to 3 carbon atoms, or one to three fluorine atoms substituted; or R3 represents a benzyl or phenethyl group, wherein the aromatic hydrocarbon ring may be the same or Is different, derived from an alkyl or alkoxy group, hydroxy group, hydroxy group, trifluoromethyl group, trifluoromethylthio group, trifluoromethoxy group, nitro group, amino group containing 1 to 3 carbon atoms , Mono or dialkyl contains 1 to 2 carbon atoms-amino, mono or dialkyl contains 1 to 2 carbon atoms-fluorenylamino, (containing 1 to 3 Atoms) alkyl_sulfonyl, dimethylsulfonamido, alkoxy-carbofluorenyl containing 1 to 3 carbon atoms, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl Sulfamoyl and ethynyl are substituted by the substituent Z of this group; or R3 represents a phenyl group or a π specific group, and its functional group may be substituted by one to four substituents Z, where z has the above What it means; 20 200530219 Either R3 represents one such group or one represents phenyl, but the prerequisite is that R4 represents a halogen atom or a cyano group, carbamate group, methyl alcohol group, ethyl group Fluorenyl, trifluoroethylfluorenyl, fluoroethylfluorenyl, propionate, sulfamoyl, methanesulfonyl, methylsulfamoyl, or an alkyl group containing 1 to 4 carbon atoms, which contains 1 An alkyl group of 4 to 4 carbon atoms may be substituted by one to three fluorine atoms or by an atom such as bromine, chlorine, moth, cyano or hydroxyl; or R3 represents a functional group NR5R6, but the prerequisite is that R2 Represents a hydrogen atom or an alkyl group, where

-R5 and R6 are the same or different 'and represent a forked or unforked alkyl group containing 1 to 4 broken atoms, or R5 and R6- together with the nitrogen atom to which they are attached-form a saturated or Is an unsaturated monocyclic or bicyclic heterocyclic group containing 4 to 10 ring atoms, where the heterocyclic group may contain one or two may be the same or different, derived from (nitrogen, oxygen, sulfur) from this group Heteroatoms in which the heterocyclic group may be substituted by an alkyl group containing 1 to 3 carbon atoms or a hydroxyl group, or 112 and R3- together with the nitrogen atom to which they are attached-form a saturated or unsaturated A heterocyclic group containing 4 to 10 ring atoms, where the heterocyclic group may contain one or two of the same or different and derived from (nitrogen, oxygen, sulfur) heteroatoms of this group, where the heterocyclic group may be An alkyl group containing 1 to 3 carbon atoms or substituted by a radical '-R4 represents a hydrogen or halogen atom or a cyano, carbamoyl, formamidin, ethenyl, trifluoroethenyl , Fluoroethenyl, propionyl, sulfamoyl, methanesulfino, methylsulfamoyl, or contain 1 to 4 carbon atoms The bifurcation of the bifurcated or burned group, an alkyl group containing from 1 to 4 carbon atoms may be substituted with one to three fluorine atoms or with one bromine, chlorine or iodine atom, a cyano group or a hydroxyl group. 21 200530219 Due to its unique pharmacological properties, it is particularly suitable for use in combination with at least one lipase-inhibiting compound as a pharmaceutical for the treatment and / or prevention of melon obesity, such as the treatment of adolescents of any age Obesity in patients, especially for the treatment and / or prevention of juveniles

Obesity and / or drugs in early childhood and adolescent patients: obesity. In this regard, a compound having the structure of general formula (11) and a compound that inhibits lipase activity are used in combination to provide medicines for the treatment and / or prevention of general obesity, such as the treatment of obesity in adolescent patients of any age, especially It is also extremely valuable in pediatric or juvenile obesity, as well as obesity caused by drugs. Compounds of general formula (IAπ) structure In the third embodiment, the present invention is based on this amazing discovery, that is, 4,5- Dihydro-1H-pyrazole derivatives, their precursors, their tautomers, and their salts have strong and selective anti-cannabinoid CB! -Receptors:

(IHa) (Illb) where R and R! Independently of each other represent a phenyl group, a fluorenyl group, or a sigma group, 22 200530219

These functional groups can be one, two, or three of which can be the same or different, derived from an alkyl or alkoxy group containing 1 to 3 carbon atoms, a hydroxy group, a hydroxyl group, a trifluoromethyl group , Trifluoromethylthio, trifluoromethoxy, nitro, amino, mono or dialkyl (containing 1 to 2 carbon atoms)-amino, mono or dialkyl (containing 1 to 2 carbon atoms) ) -Amino, (containing 1 to 3 carbon atoms) alkyl-sulfonamido, dimethylsulfonamido, alkoxy-carbohydrazone containing 1 to 3 carbon atoms, carboxyl, trifluorofluorene Sulfosulfanyl, cyano, carbamoyl, sulfamoyl and ethynyl are substituted by the substituent γ in this group, or R and / or K represents naphthyl, -R2 represents a hydrogen atom, a hydroxyl group, Alkoxy, ethoxy, or propionyloxy of 1 to 3 carbon atoms,-R3 represents a hydrogen atom 'or a branched or unbranched alkyl group containing 1 to 8 carbon atoms, or Represents a cycloalkyl group containing 3 to 7 carbon atoms, and the alkyl group or cycloalkyl group may be substituted by a few groups,

—R4 represents a hydrogen atom, or a bifurcated or unbranched alkyl group containing 1 to 8 carbon atoms, a cycloalkyl group containing 3 to 8 carbon atoms, and a 2 to 10 carbon group Atomylheterosyl, represents a non-aromatic hydrocarbon heterocycloalkyl group containing 3 to 8 carbon atoms, or represents a non-aromatic hydrocarbon heterocycloalkyl group containing 4 to 10 carbon atoms, its functional group Contains one or more heteroatoms selected from the group (oxygen, nitrogen, sulfur). Its functional group can be keto, trifluoromethyl, alkyl containing 1 to 3 carbon atoms, hydroxyl, amino, Substituted by amino or dialkylamino, or fluorine atom; or R4 represents amino, hydroxyl, phenoxy, or tolyloxy; or R4 represents a branched or undivided group containing 1 to 8 carbon atoms Fork alkoxy group, which represents 3 to 8 carbon atoms) \ woyl, which represents a cycloalkyl group containing 5 to 8 carbon atoms, or a cycloalkene group containing 6 to 9 carbon atoms. 23 200530219 , Its functional group can contain a sulfur, nitrogen or oxygen atom, a keto group or -S〇2- group, which contains 1 to 8 carbon atoms of the alkoxy group , A fluorenyl group containing 3 to 8 carbon atoms, a cycloalkenyl group containing 5 to 8 carbon atoms, or a cycloalkenyl group containing 6 to 9 carbon atoms can be substituted by trimethyl, trifluoromethyl, gas, Benzyl radical or dialkyl radical, or a fluorine atom, or 4R · 4 represents Fengji, benzyl, σ-pyridyl, faryl, aziridylmethyl, or phenylethyl Group, in which the aromatic tobacco ring is replaced by one, three or three substituents ，, wherein γ has the meaning mentioned above; or R4 represents a functional group NRSR9, but the prerequisite is that when Rs represents a A hydrogen atom is a methyl group, and the center and ^ are the same or different, and represents an alkyl group containing 1 to 4 carbon atoms, or a difluoroalkyl group containing 2 to 4 carbon atoms, or 8 and r9-together with the nitrogen atom to which they are attached-form a saturated or unsaturated heterocyclic group containing 4 to 8 ring atoms, wherein the heterocyclic group may contain an oxygen or sulfur atom, or a keto group , Or a _S〇2_ group, or another nitrogen atom, in which a saturated or unsaturated heterocyclic group can be contained from one to four A3 is substituted by an alkyl group of the atom; or R3 and 114_ and the nitrogen atom to which they are attached form the same as a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing 4 to 10 ring atoms, in which hetero A cyclic group can contain one or more atoms from the group (nitrogen, oxygen, sulfur), or a keto group, or a alkoxy group, where the functional group can be-contains 1 ^ 4 carbons Atomic County 'Silk Silk, Phenyl', Senyl, Hexamin, Monofilament Amino Silk, Dimethylamino, Alkyl, Amino, Amino, Amino, Cyclonitrogen, Oral , _ Or hexahydro. Substituted by cyclohexyltrimethyl, 24 200530219

R5 and R_6 independently of each other represent a hydrogen atom, or represent a branched or unbranched alkyl or fluorenyl group having 1 to 8 carbon atoms, wherein the functional group may contain one or more A heteroatom derived from the group (nitrogen, oxygen, sulfur) is either a keto group or a -S02- group, where the functional group may be substituted with a hydroxyl or amino group; or & and R6 independently of each other represents a cycloalkyl group (containing 3 to 8 carbon atoms), or a cycloalkenyl group (containing 3 to 8 carbon atoms), which may contain one or more derived from (nitrogen , Oxygen, sulfur) ring heteroatom in this group, or a keto group, or a-^ 〇2_ group, where the functional group can be a few groups, (containing 1 to 3 carbon atoms), -S〇2- group, keto group, amino group, (containing 1 to 3 carbon atoms) monoalkylamino group (containing 1 to 3 carbon atoms) dialkylamino group; or

Rs represents a naphthyl group or a phenyl group, and the phenyl group may be substituted by one, two or three substituents Y, wherein γ has the meaning as mentioned above, but the prerequisite is that R6 represents A tritium atom, or a branched or undivided alkyl group (containing 1 to 5 carbon atoms) whose alkyl group may contain one or more impurities derived from the group (nitrogen, oxygen, sulfur) Atom, or -S02- group, and the alkynyl group can be replaced by a #triyl, keto, or amino group, or R5 and R6- together with the gas atom to which they are attached-form a single ring, * Mono- or tricyclic alkyl or alkenyl groups, which may contain ring heteroatoms, keto groups, or -S02_ groups derived from (nitrogen, oxygen, sulfur), of which mono- and bicyclic Either a tricyclic alkyl group or an alkenyl group can be a hydroxyl group (containing 1 to 3 broken atoms), a thiol group, -S02-yl, keto, amino, (containing 1 to 3 carbon atoms) ) Monoalkylamino (or containing 1 to 3 carbon atoms) monoalkylamino, pyrrolidinyl, or piperidinyl, of which monocyclic, difluorinated, or trialkyl 25 200530219 ring alkyl or olefin It may contain a chained phenyl group, wherein the chained phenyl group may be substituted with one or two substituents Y, where γ has the meaning as described above, R7 represents a group containing 1 to 3 isthmus atoms The bifurcated or unbranched burned base is particularly suitable for use in combination with at least one lipase-inhibiting compound as a pharmaceutical for the treatment and / or prevention of general obesity due to its unique pharmacological properties. Disorders, such as the treatment of obesity in adolescents of any age, are particularly useful for the treatment and / or prevention of obesity in young patients and / or obesity due to drugs in young and adolescent patients. In this regard, combining compounds having the general structure (IIIa) and / or (mb) with compounds that inhibit lipase activity is used to provide medicines for the treatment and / or prevention of general obesity, such as the treatment of adolescents of any age Obesity of patients, especially in pediatric or juvenile obesity, and obesity caused by drugs are extremely valuable. In the general formula mTa ,; 5 rmh, a few people 纴 媸 /.

heart. The present invention relates to steric isomers of compounds having the structures of the general formulae (iIIa) and (IIIb), that is, mixtures of cis-trans isomers and individual stereostructures thereof. In particular, the compounds with the general structure _ *) and _ *) are of interest ^ 4,5-dihydro_ 丨 h—The fourth carbon atom of the biazole moiety has an absolute three-dimensional configuration, such as Represented by (Ilia *) and (Illb *) ·

(Ilia *) (Illb *) 26 200530219 The present invention also relates to compounds having the general structure (Ilia) or (Illb), the E isomers, Z isomers, and E / Z mixtures. A compound of general formula αν) In the fourth embodiment, the present invention is based on this surprising discovery, that is, it has the general formula (IV) structure and has CB! Antagonistic activity 4, 5 -Derivatives of diaromatic hydrocarbon pyrazoles, their precursors or their salts:

Wherein one R represents a hydrogen atom, or one substituent X, which is derived from a branched or unbranched alkyl or alkoxy group, an alkoxy group, a hydroxyl group, a trifluoro group, and a trifluoro group containing i to 3 carbon atoms. Methyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono or dialkyl (containing 1 to 2 carbon atoms)-amino, mono or dialkyl (containing 1 to 2 (Carbon atom)-fluorenylamino, branched or unbranched (containing 1 to 3 carbon atoms) alkoxy-carbofluorenyl, trifluoromethyl continuous, ammonia continuous, branched or not Bifurcated (containing 1 to 3 carbon atoms) alkyl-sulfofluorenyl, carboxyl, cyano, carbamoyl, branched or unbranched (containing 1 to 3 carbon atoms) dialkylamino Sulfofluorenyl, bifurcated or unbranched (containing 1 to 3 carbon atoms) monoalkylaminocontinyl or ethenyl,

—Ri represents a hydrogen atom, or one to four substituents X, wherein X 27 200530219 has the meaning mentioned above, and -R2 represents a phenyl group “synyl” or a heterocyclic group, among which ^^ Can be replaced by-to four substituents x, where x has the meaning of ^; or R2 represents naphthyl 'γ -R3 represents a hydrogen atom, or represents (containing u1G, original forest fork or not branched The alkyl group is either a cycloalkyl group or a phenyl group, a benzyl group, or a phenethyl group, where the aromatic group can be one or five and can be the same or different, derived from containing 1 S3 carbons. Forked or unbranched alkyl radicals, or alkoxy radicals, minus, halogen, trispinyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono or di ^ (Containing 1 to 2 broken atoms)-amino, mono- or di-alkyl (containing 1 f 2 carbon atoms)-amino, branched or unbranched alkyl-sulfonic acid containing 1 to 3 plate atoms Fluorenyl, dimethylsulfonamido, branched or unfked (containing 1 to 3 carbon atoms) alkoxy-carbofluorenyl, carboxyl, difluoromethylsulfonyl, cyano, amino Formamyl, sulfamoyl, or Is ethanoyl, or R3 represents a CT ratio or an alkyl group.-R4 represents a branched or unbranched alkyl or cycloalkyl-alkyl group containing 1 to 10 carbon atoms. An alkoxy group containing 1 to 10 carbon atoms, a cycloalkyl group containing 3 to 8 carbon atoms, a bicycloalkyl group containing 5 to 10 carbon atoms, and a tricyclic group containing 6 to 10 carbon atoms Alkyl, which represents a branched or unbranched alkenyl group containing 3 to 10 carbon atoms, represents a cycloalkenyl group containing 5 to 8 carbon atoms, and whose functional group contains one or more members selected from (oxygen, nitrogen , He) heteroatoms of this group 'and its functional group can be substituted by one hydroxyl group, one to three methyl groups, one ethyl group or one to three gas atoms; Group, in which the aromatic hydrocarbon ring may be substituted by one to five substituents Z 28 200530219 'wherein z has the meaning as mentioned above, a bisyl group or a vinyl group, or | ^ represents one ^ in it T? _ 艿 T ?, Ming Gan Xiao Shen 1;

1 .; or R4 represents a functional group NR5R6, the atom is substituted, or-Rs and R4 and the nitrogen atom to which they are attached-together with _ form a saturated or not% saturated monocyclic ring containing 4 to 10 atoms or Is a bicyclic heterocyclic group, wherein the heterocyclic group may contain one or more heteroatoms selected from the group (oxygen, nitrogen, sulfur), and the heterocyclic group may be-containing 至 to 3 carbon ^ It is substituted by a forked or unbranched alkyl group, a few groups or a tri | methyl group or a fluorine atom. Due to its unique pharmacological properties, it is particularly suitable for use in combination with at least one compound that inhibits lipase activity. For the manufacture of a medicine for the treatment and / or prevention of general obesity, such as the treatment of obesity in young and old patients of any age, and especially for the treatment and / or prevention of obesity in young patients and / or in childhood Drug-induced obesity in patients in the onset and onset. In this regard, a compound having the structure of general formula (IV) and a compound that inhibits lipase activity are used in combination to provide medicines for the treatment and / or prevention of general obesity, such as the treatment of obesity in adolescent patients of any age, It is especially valuable in pediatric or juvenile obesity, as well as obesity caused by drugs. A Compound of general formula (V) structure 29 200530219 In the fifth embodiment, the present invention is based on this surprising discovery, that is, a compound of general formula (V) structure and CB! Antagonistic activity. Derivatives of ^ diaromatic hydrocarbyl-1,1,2,4-triazole-3-carboxamide, their precursors, salts and stereoisomers are antagonistic to the potency of cannabinoid CBr receptor Agent, agonist, reverse agonist or partial agonist:

among them

— Ruler! ^ Represents phenyl, naphthyl, pyrimyl, fluorenyl, pyrimidyl, σ-pyrazinyl, pyridinyl, or trisyl, independently of each other. Their functional groups may be one to four and may be the same or Is different and originates from a branched or unbranched alkyl (containing 1 to 3 carbon atoms) or an alkoxy, hydroxyl, halogen, trifluoromethyl, trifluoromethylthio, trifluoro Methoxy, nitro, amino, mono or dialkyl (containing 1 to 2 carbon atoms)-amino, mono or dialkyl (containing 1 to 2 carbon atoms)-fluorene amino, containing 1 to 3 carbons Atomic alkoxy-carbamyl, trifluoromethylsulfonyl, sulfamoyl, (containing 1 to 3 carbon atoms)-alkylsulfonyl, carboxyl, chloro, carbamoyl, ( Contains 1 to 3 carbon atoms) -dialkylaminosulfonyl, (containing 1 to 3 complete atoms) -early-burned gas-base-continuous group and ethyl group, which are substituted by the group X, —R2 represents a fluorene atom, or represents a radical containing 1 to 8 carbon atoms. 30 200530219 Forked or unbranched alkyl group, or represents a k-alkyl group containing 1 to 8 carbon atoms, or Phenyl, benzyl or phenethyl , Its aromatic ring can be substituted by one to four substituents X, where X has the meaning as mentioned above; or R2 represents a sigma group or a farinyl group, — & represents 1 to 8 A bifurcated or unbranched alkyl group of carbon atoms represents an alkoxy group containing 1 to 8 carbon atoms, a cycloalkyl group containing 3 to 8 carbon atoms, and a bicyclic ring containing 5 to 10 carbon atoms. An alkyl group represents a tricycloalkyl group containing 6 to 10 carbon atoms, represents a feminine group containing 3 to 8 carbon atoms, and represents a cyclofluorenyl group containing 5 to 8 carbon atoms. Its functional group may contain one or more The functional group of a heteroatom selected from (oxygen, nitrogen, sulfur) may be substituted by a few groups, an ethynyl group, or one to three fluorine atoms; or R3 represents a phenyl group, a benzyl group, or Phenethyl, whose aromatic smoke ring can be replaced by one to four substituents X, where X has the meaning as mentioned above; or R3 represents an ortho group, an oxo group, an alpha group, or a Group, trisyl group, or thionyl group, the heteroaromatic ring may be substituted by one or two substituents X, where X has As previously mentioned; or R3 represents a functional group NR4R5, in which R4 and R5 together with the nitrogen atom to which they are attached form a saturated or unsaturated monocyclic or bicyclic ring containing 4 to 10 ring atoms Heterocyclyl, where the heterocyclyl contains one or two heteroatoms selected from the group (oxy, nitrogen, sulfur), and where the heterocyclyl may contain 1 to 3 carbons A bifurcated or unbranched alkyl, hydroxy or trifluoromethyl or a fluorine atom is substituted, or-R2AR3 together with the nitrogen atom to which it is attached forms a saturated or unsaturated containing 4 to 10 A monocyclic or bicyclic heterocyclic group of each ring atom, its 31 200530219 heterocyclic group contains one or two heteroatoms which can be the same or different, selected from the group (oxygen, nitrogen, sulfur), And the heterocyclic group may be substituted by a branched or unbranched alkyl group containing 1 to 3 carbon atoms, a few groups, a fenidyl group or a trifluoromethyl group or a fluorine atom,

Due to their unique pharmacological properties, it is particularly suitable for use in combination with at least one compound that inhibits lipase activity as a pharmaceutical for the treatment and / or prevention of general obesity, such as the treatment of obesity in adolescent patients of any age It can also be used to treat and / or prevent obesity in young patients and / or obesity caused by drugs in young and adolescent patients. In this regard, the combination of a compound having the general structure (V) and a compound that inhibits lipase activity is used to provide medicines for the treatment and / or prevention of general obesity, such as the treatment of obesity in adolescents of any age, especially It is also extremely valuable in pediatric or juvenile obesity, as well as obesity caused by drugs. In the following examples of the present invention, there is a more detailed description of compounds of the formula (I), (II), (III), (IV) or (V) in medical treatment and preparation.

Therefore, the use of the cannabinoid CBl_ receptor has a beneficial effect. The treatment of the disease is not controlled by the department, and the patient is also suffering from distress, anxiety, 32 200530219 and lack of attention. , Memory disorders, cognitive disorders, appetite disorders, obesity, addiction, hunger, drug dependence, and neurological diseases such as neurodegeneration, dementia, abnormal muscle tone, muscle spasms, tremors, epilepsy, multiple Sclerosis, Traumatic Brain Injury, Stroke, Parkinson's Disease, Alzheimer's Disease, Epilepsy, Huntington's Disease, Trollett's Syndrome, Cerebral Ischemia, Stroke, Skull and Brain Trauma, Stroke, Spinal Cord Injury, Neuritis, Sclerosis, Viral Encephalitis, Demyelination-Related Disorders, and Uses for the Treatment of Pain, including Nerve Caused Pain, among others Central nervous system diseases related to cannabinoid nerve conduction, including treatment of septic shock, glaucoma, cancer, diabetes, vomiting, nausea, asthma, respiratory disorders, gastrointestinal disorders Gastric ulcer, abdomen, heart and blood vessel disease post. The affinity of a compound having the general formula (I), (II), (III), (IV) or (V) for the cannabinoid CBr receptor can be determined by the following texts: WO 03/026647, WO 03/027076, WO 03/026648 or the method described in WO 03/078413, for example, it can be measured using a cell membrane preparation of Chinese hamster egg cells (Ch0) in which the human cannabinoid CB! Receptor is stably transferred Infected and combined with [3H] CP-55,940 as a radiation complex. After the freshly prepared cell membrane product and the [3H] -complex are added with or without the compound of the present invention, after incubation, the binding and non-binding complexes are separated by filtration through glass fiber filter paper. The radioactivity on the filter paper is measured with a liquid flash counter. The antagonistic activity of compounds having the general structure ⑴, (II), (III), (IV) or (V) on cannabinoids CB is described in the texts WO 03/026647, WO 03/027076, WO 03/026648 or It is also described in WO 03/078413 ', and its measurement is performed using a functional research method, which uses China Cang 33 200530219 mouse egg cells in which the human cannabinoid CBi receptor is stably expressed. Adenylate cyclase was stimulated with forskolin and determined by quantifying the amount of cyclic adenosine monophosphate accumulated. Co-activation of the CB1 receptor with a CBi receptor agonist (such as CP-55,940 or (R) -WIN-55,212-2) can attenuate the cyclic adenosine mononucleotide stigmatized by forskolin in a concentration-dependent manner Phosphoric acid accumulation. Such a reaction transmitted by the CBi receptor can be antagonized by an antagonist of the CBi receptor, such as a compound used in the present invention.

For example, the compounds of the present invention having the structure of the general formula (V) which have an antagonistic, potent or partial potent activity on the cannabinoid CBi receptor can also be measured by a functional research method, which is selected using the following method Human CBr receptors colonized into Chinese hamster egg cells (CHO). CH0 cells were grown in DMEM medium and supplemented with 10% to heat deactivated fetal calf serum. Aspirate the culture solution, and then replace the DMEM culture solution containing no fetal calf serum, but containing [3H] -arachidonic acid, and place it in a cell culture incubator (5% C02 / 95% air; 37 ° C; moisture-saturated air). During this time, [3H] -arachidonic acid was added to the phosphorus lipids of the cell membrane. On the day of the test, the culture solution was aspirated, and the cells were washed with 0.5 ml of a phosphate-buffered saline solution containing 0.2% bovine serum albumin for three times. The stimulation of the CBi receptor with WIN 55,212-2 caused PLA2 to be activated, and then [3H] -arachidonic acid was released into the culture medium. The release effect stigmatized by WIN-55,212-2 can be antagonized by CBi receptor antagonists in a concentration-dependent manner. The agonist or partial agonist activity of the compounds of the present invention on the cannabinoid receptor can be according to published methods, such as assessment of in vivo cannabinoid effects (Wiley, J. L. Jefferson et al., J. • Five χ / λ 77 ^, · 2001, 296, 1013). 34 200530219 Antagonists of cannabinoid receptors can exhibit inverse agonist behavior (Landsman, R.S. et al. 'Eur. J. Pharmacol. \ 99', 334, R1-R2). The international patent application WO 03/026647, WO 03/027076, WO 03/026648, or wo 03/078413 are incorporated by reference in this application for the purpose of disclosing the general formula ⑴, (II ), (III), (IV) or (V) structure and compounds having an antagonistic effect on CBl are combined with a part of a lipase inhibitor.

Compounds with CBir receptor activity and the general structure ⑴, (Π), (m), (IV), or (v) are antagonists of the cannabinoid CBl_ receptor, as well as other previous drugs, Its unique pharmacological properties, such as tautomers and salts, also include a particularly high degree of safety when used in combination with other drugs, especially when combined with compounds that inhibit lipase activity according to the present invention. Tolerance. Therefore, the combination of a CBi antagonist compound having the general structure ⑺, (11), (m), (IV) or (V) with a compound that inhibits lipase activity is particularly suitable for increasing safety and tolerance requirements. Patient populations, especially patients such as infants and / or patients receiving long-term treatment, such as obesity due to drugs. Safety and financial benefits of CBi antagonist compounds having the general formula (I), (II), (III), (IV) or (V) when combined with compounds that inhibit lipase activity Or preventing obesity in this group of patients is advantageous. 'The single treatment is not effective enough, and combined treatment and / or prevention involving several different medicines and metabolic mechanisms are required or required to be achieved and stabilized. I know the degree of weight loss. Therefore, a combination of a CBi antagonist compound having the general formula (I), (11), (111), (IV) or (V) and a compound for inhibiting lipase activity according to the present invention 35 200530219 is expected to be used in Treatment and / or prevention of general obesity, such as the treatment of obesity in adolescents of any age, especially in pediatric or juvenile obesity, as well as drug-induced obesity has great advantages. The compounds of the present invention having the general formula (I), (II), (m), (IV) or (V) have the ability to regulate the activity of the CBi receptor. When used in combination with a lipase inhibitor, they are allowed to wait It is particularly useful in treating obesity, juvenile obesity, and drug-induced obesity. Special examples of lipase-inhibiting compounds that can be used in this combined preparation are, but are not limited to, synthetic lipase inhibitors orlistat, panclicins; lipase inhibitors isolated from microorganisms such as lipstatin ( From such as: shengcaru), ebelactone B (from fenre; plus —ca ahraW⑼ this), synthetic derivatives of these compounds, 2-oxo-4Η · 3,1-benzoxazinone ATL-962 and structurally related compounds 2-amino-4Η-3,1-benzoxazin-4-one derivatives, and extracts of plants known to have lipase inhibitory activity, such as "Hance" Extract, or compounds such as 3-methylethergalangin (3-methylethergalangin) (extracted from A. extract). The compound that inhibits lipase activity can also be a polymer that inhibits lipase activity. These lipase-inhibiting compounds and their production methods are well known in the current state of the art. The lipase-inhibiting compounds used in combination according to the present invention may be any lipase-inhibiting compounds It is suitable for use in pharmaceuticals, such as, in particular, inhibitors of pancreatic lipase. Lipase is the main enzyme in the digestive system, and it can cut triglycerides and diglycerides that are too large to be absorbed by the small intestine. Absorbed fatty acids. Since the lipase hydrolyzes fats at 36 200530219, the result of inhibiting lipases is a reduction in the hydrolysis and absorption of fats. Therefore, inhibition of lipases results in reduced fat absorption. Inhibition of fats Active compounds prefer synthetic lipase inhibitor orlistat and structurally related compounds, and derivatives of 2_oxy_4qin3, 丨 _benzoxazinone such as ATL-962 and structurally related Compounds, 2-amino-4 氨基 -3, 1-benzopyridine 4-one derivatives, lipase inhibitors isolated from microorganisms such as lipstatin, ebelactone B, or synthetic derivatives of these compounds, But it can also be a polymer that inhibits lipase activity. The most preferred are orlistat 'panclicins, ATL-962 and lipstatin.

Orlistat (tetrahydrolipstatin) and lipstatin are described in more detail in U.S. Patent No. 4,598,089 and European Patent EP 0 129 748 B1. This compound is a derivative of 2 · hexyl_3_ meridyl-hexadecanoic acid lactone, and its chemical name is (2S, 3S, 5S, 7Z, 10Z) -5-((S) -2-A (Aminomethyl dungylpentyloxy) -2-hexyl-3-hydroxy-7, 10 · hexadecane lactone (lipstatin) and (2S, 3S, 5S) -5-((S) -2-4-methylpentyloxy) _2-hexyl · 3-tris (hexadecyl) tetrahydrolipstatin. These compounds have been known to be inhibitors of pancreatic lipase, which can be used as prevention or treatment of obesity and hyperlipidemia. For this purpose, they can be made into medicines according to prescriptions or infused. Among food nutrients prepared by industrial methods. Inhibiting pancreatic lipase activity prevents dietary fats from being hydrolyzed to produce free fatty acids and monoglycerides', so fat is excreted intact. The IC50 values of lipstatin and tetrahydrolipstatin for inhibiting the hydrolysis of glycerol triolein by porcine pancreatic lipase were 0.07 and 0.018 μg / ml, respectively. Furthermore, some suitable pancreatic lipase inhibitors are structurally related to odistat and / or lipstatin, and they are already known as pancHcins. The 37 200530219 and other panclicins are derived from orlistat and contain a tetracyclic inner vinegar (Mutoh M; Nakada N; Matsukima S; Ohshima S; Yoshinari K. Watanabe J Location: Kanagawa? Japan Issue Date · 19-JAN-1995 Journal: J. Antibiot., 47, No. 12 1369 75 1994). The biological data of these pandidns can be summarized as follows: ’

Panclicins A, B, C, D and E 'are structural analogs of tetrahydrolipstatin (THL), which inhibits the hydrolysis of glycerol trioleate by porcine pancreatic lipase in a dose-dependent manner, with IC50 values of 2 9, 2 6, 〇62,

0.66, 0.89 microM. The inhibitory activity of Panclicins A and B (the leucine in THL is replaced by alanine) is two to three times weaker than the inhibitory activity of THL; in contrast, panclicins C, D, and E (the leucine in THL is replaced by glycine) The inhibitory activity of the amino acid substituted) is two times stronger than that of THL. Pandicins A, B, C, D, and E can also strongly inhibit the activity of blood polylipase, with π% values of 1.0, 1.2, 0.29, 0.25, and 0.15 microM, respectively. Panclicins

A and B have the same level of inhibition of plasma lipase as THL, while pandidnsC, D, and E are three to six times stronger than THL. pandidns A, B, C, D, and E inhibit lipase activity of bacteria and molds, and their properties are similar to their inhibitory effects on porcine pancreatic lipase. Panclidns inhibits membrane lipase activity in an irreversible manner, but its irreversibility is lower than THL. pandidns A, B, C, D, and E inhibit pancreatic lipase activity in an irreversible manner.

Ebelactone B is described in U.S. Patent US Seven States and German Patent DE 3109 335 C1. Ebelactone and Huajialu B belong to a group of compounds, which show an activity to increase the immune response transmitted by cells in the animal's living body, and they can also suppress the inflammation in the animal's living body. Therefore, they can be used as immunological tumor treatments and as antitumor enhancers such as bleomycins. These compounds have activity against ester hydrolase and resistance to formamidinemethionine aminopeptidase. These compounds were administered to mice at a dose of 0.7781-50 mg / kg (intravenous injection) or 0.5 mg / kg (oral). As a result, the occurrence of DTH response was enhanced, and the compounds showed a cellular effect. Da's immunity has the effect of enhancing. Ebelactone B reduces the swelling induced by carragheenin in mice.

For the purposes of the present invention, a lipase inhibitor administered to a patient in combination with a CBi antagonist compound as a treatment for obesity can also be a polymer that has been substituted with one or more functional groups or contains one or more Each functional group is capable of inhibiting a lipase. Such polymers that inhibit lipase activity are described in U.S. patents US 6572850, US 6558657, US 6352692, US 6267952 and international patent application WO 99/34786.

Described. In one embodiment, the lipase-inhibiting functional group may be a "suicide-accepting enzyme, which inhibits the enzyme by forming a covalent bond with the active site or other positions of the lipase. Activity. In another /, Example S, the functional group that inhibits lipase activity is an isosteric inhibitor of the enzyme. In the first aspect of the present invention, when a CBl antagonist compound is used, When using a polymer that inhibits lipase activity, the lipase inhibiting activity ^ ^ makes a lipase such as gastric lipase, lipase and tongue lipase = loss; tongue. Deactivation can be caused by the formation of covalent bonds Reaction, so that the enzyme appears inactive state, and the covalent bond can be formed with an amino acid residue located at or near the $ prime / tongue position, or separated from a residue from the active position Group formation, but the prerequisite is that the activity of the formed covalent enzyme is inhibited. Lipase contains a catalytic second 39 200530219 ::: Amino acid in the ammonia. The hydrolysis of the _ bond in the triammine, so The expected compound, which is a serine / hydrolase inhibitor, will also reduce the activity of lipases. Therefore, a serine protein preparation that can be linked to a polymer by a covalent bond is preferred. Functional groups that are preferred for lipase inhibitory activity. For example, it can be used to inhibit the axis-covalent bond between a lipase-active functional group and a county near the enzyme's position where the enzyme has a gamma action. For example, it can form with serine A covalent bond. The deactivation reaction can also be promoted by a covalent bond between a functional group that inhibits the activity of a lipase and an amino acid, such as cysteine that is at a distance from the active site. In the second aspect of the present invention, When a polymer that inhibits lipase activity is used in addition to the CBi compound, the non-covalent bond interaction between the lipase-reactive functional group and the enzyme will also cause the enzyme to lose its activity. For example, The lipase-inhibiting functional group may be a kind of fatty acid isostere, which can interact with the lipase catalytic position in a non-covalent manner. In addition, the lipase-inhibiting activity The energy base can compete with the natural triglyceride to hydrolyze lipid anti-enzyme. Many kinds of polymers can be used in the invention described here. These polymers can be fatty linear, fatty cyclic or aromatic Hydrocarbons are either synthetic or naturally occurring. However, the preferred ones are synthetic fatty linear or cyclic polymers. Furthermore, the polymers can be water-repellent, hydrophilic, or Heteroplastic polymers of water-repellent and / or hydrophilic monomers. The polymers may be wholly or partly non-isotropic (such as neutral), anionic or cationic. Furthermore, these polymers may be made from 200530219

It is made from vinyl monomers (such as vinyl alcohol) or condensation polymers. For example, the polymers may be a polyethylene glycol, polyethylene amine, polyethylene vinylamine, polyisopropenylamine, polyisopropenylamine, polyalkylenimine, polyethylene, Polypropylene, polyethers, polyethylene oxide, polycarcinamide, polyacrylic acid, polyacrylic acid, polyacrylamide, polymethacrylic acid, polyalkylmethacrylic acid, polymethylpropane Amine, polyalkylprofenamine, polyalkylmethacrylamidine, polystyrene, acetone, ethyl ethyl benzene, acetophenone, ethyl lianfeng, ethyl benzoic acid, Vinyl imidazole, ethylene alpha-pyridine, dimethylaminomethylacetophenone, trimethylammonium ethylmethacrylic acid, trimethylammonium ethylpropionic acid, carbohydrates, proteins, and substituted derivatives thereof (E.g., their fluorinated monomers) and their heteropolymers. Preferred polymers include polyethers, such as polyalkylene glycols. The polymers and intermediates used in the methods described herein, as well as methods for preparing these complexes, are in US patents US 6572850, US 6558657, US 6352692, US 6267952 and international patent applications

A detailed description is provided in WO 99/34786, all of which are incorporated in the present invention by reference. Recently, in International Patent Application WO 03/072555, a new 5-hydrocarbyloxyphenyl group having the structure of the general formula (A) has been described. It is an inhibitor of pancreatic lipase and is effective for the treatment of metabolic diseases, cardiovascular diseases or especially obesity.

41 200530219 These oxadiazolones having the structure of the general formula (A), their salts and acid addition salts are also suitable for use with the CBj # anti-compounds used according to the present invention. Combined use. In the structure of the general formula (A), the substituent may be as follows: R1 may be an alkyl group (containing 7 to 22 carbon atoms); an alkyl group (containing 2 to 4 broken atoms) which is contained 4 to 20 An alkoxy group having 6 carbon atoms, an aromatic nicotyl group having 6 to 10 carbon atoms, an aromatic hydrocarbon group having 6 to 10 carbon atoms, or an alkoxy group (containing 4 to 12 carbon atoms)- (Containing 2 to 4 broken atoms) substituted by alkoxy (wherein the aromatic group may be substituted by one or more halogen atoms, a phenyl group containing 1 to 4 carbon atoms, a phenyl group containing 1 to 4 carbon atoms Oxygen, No2 or CF3)); alkenyl containing 7 to 20 carbon atoms; or phenyl substituted by alkyl having 6 to 12 carbon atoms or phenoxy And each of R2 to R5 may be a hydrogen atom, a southern atom, a NO2 group, an alkyl group containing 1 to 4 carbon atoms, an alkoxy group containing 1 to 4 broken atoms, a CF3 group, or 0CF3 group; or (containing 6 to 10 carbon atoms) aromatic hydrocarbon group ((containing 1 to 4 carbon atoms) fluorenyl group, aromatic hydrocarbon group containing 6 to 10 carbon atoms, containing 6 to 10 carbon atoms Aromatic hydrocarbon group, cycloalkyl group containing 3 to 8 carbon atoms or cycloalkoxy group containing 3 to 8 carbon atoms (can be halogen, CF3 group, alkoxy group containing 1 to 4 carbon atoms, containing 1 Straight 4 carbon atoms are substituted). These 5-hydrocarbyloxy) phenyl-1,3,4-oxodiazepine-2-ones have been described as having pharmacological properties such as appetite reduction, anti-diabetes, hypotension, or cardiotonics. The mechanism is a pancreatic lipase inhibitor. For example 5-dodecane 42 200530219 oxy-3- (4-trifluoromethoxy-phenyl) _3H- (1,3, 4) -oxodiazepine_2_one is used to inhibit porcine pancreatic lipase The IC50 value was 0.03 mieroM. Therefore, these 5-hydrocarbyloxy-3-phenyl-1,3,4-oxodiazepine-2-ones can be used as medicines especially for treating obesity. As a pancreatic lipase inhibitor, 5-hydrocarbyloxy-3-phenyl-1,3,4-oxodiazepine-2-ones inhibit the reabsorption of fat components in foods, so fat intake and Weight loss (or suppression of weight gain). Furthermore, 5-hydrogenyloxy-3_phenyl-1,3,4-oxodiazepine_2_ones have been reported for metabolic diseases (such as diabetes) or cardiovascular diseases (such as hypertension). : And myocardial embolism) and other treatments have good results. Compounds having the structure (A) that inhibit lipase activity are described in detail in WO 03/072555, and can be prepared according to known methods. A suitable method for synthesizing a lipase-active compound having a structure of the general formula (A) is also described in International Patent Application WO 03/072555. The entire content of the international patent application WO 03/072555 is incorporated by reference in the present invention for the disclosure of a lipase inhibitor having the structure of the general formula (A). In addition, the international patent application WO 03/072098 further describes 5-hydrocarbyloxy-3-phenyl-1,3,4-oxodiazepine-2-ones having the structure of the general formula (A) It is a pancreatic lipase inhibitor, which is effective for the treatment of obesity or type 1 and type 2 diabetes. As described in the document WO 03/072098, the oxydiazepines having the structure of the general formula (A), their salts and acid addition salts are also suitable as the CB used in accordance with the present invention! Combination of antagonist compounds. In the structure of the general formula (A), the substituent may be as follows: R1 may be an alkyl group (containing 1 to 6 carbon atoms); a ring pit group containing 3 to 9 carbon atoms, and both functional groups may be benzene Group, substituted with alkoxy having 1 to 4 carbon atoms, S-alkyl having 1 to 4 carbon atoms, N (alkyl having 1 to 4 carbon atoms) 2; and phenyl, which is 43 200530219 can also be replaced by a commercial atom, an alkyl group containing 1 to 4 carbon atoms, an alkoxy group containing 1 to 4 carbon atoms, a nitro group, or a CF3 group; and

Each of R2 to R5 may independently represent a hydrogen atom, a halogen atom, a N02 group, an alkyl group containing 1 to 4 carbon atoms, a alkoxy group containing 1 to 9 carbon atoms, which is represented by an ll atom, Substituted by aromatic hydrocarbon groups, amino groups containing 6 to 10 carbon atoms, or alkylamino groups containing 1 to 4 carbon atoms; aromatic hydrocarbon groups containing 6 to 10 carbon atoms-alkoxy groups containing 1 to 4 carbon atoms , Aromatic hydrocarbonoxy groups containing 6 to 10 carbon atoms, aromatic hydrocarbon groups containing 6 to 10 carbon atoms, aromatic nicotinyloxy groups containing 6 to 10 carbon atoms-alkyl groups containing 1 to 4 interfering atoms, containing A cycloalkyl group of 3 to 8 carbon atoms or 0 (a cycloalkyl group containing 3 to 8 broken atoms), which may be a halogen atom, a CF3 group, an alkoxy group containing 1 to 4 carbon atoms, or Substituted by alkyl groups of 1 to 4 carbon atoms;

S〇2-NH- (alkyl group containing 1 to 6 carbon atoms), which can be replaced by N (alkyl group containing 1 to 6 carbon atoms) 2; S02_NH- (2, 2, 6, 6_tetramethyl Piperidine_4_yl); S02_NH- (cycloalkyl containing 3 to 8 carbon atoms), which can be an alkyl group containing 1 to 4 carbon atoms, S02-NH- (containing 1 to 6 Alkyl group with 2 carbon atoms) 2 or COX; 2-oxobihalan-1-yl; 2,5-dimethyl0 pyrrolyl or NR6-A-R7, the prerequisite is that R2 , R3, R4, and R5 are not hydrogen atoms at the same time, when X represents 0 (alkyl group containing 1 to 6 carbon atoms), NH (alkyl group containing} to 6 carbon atoms), NH (containing 3 to 8 carbon atoms) Carbon cycloalkyl) or N (carbon containing 1 to 6 carbon atoms) 2 and 44 200530219 N (alkyl containing 1 to 6 carbon atoms) 2 can also represent α-pyrrolyl, Brididyl, molyddenyl, thiomolydyl, or molybdenyl, which can be pitted with 1 to 4 broken atoms, benzyl, aromatic hydrocarbon containing 6 to 10 carbon atoms, CO- (Alkyl group containing 1 to 4 carbon atoms), CO- (aromatic hydrocarbon group containing 6 to 10 carbon atoms), C0-0- (alkyl group containing 1 to 4 carbon atoms) , S〇2_ (alkyl group containing 1 to 4 carbon atoms) or S02- (aromatic hydrocarbon group containing 6 to 10 carbon atoms); R6 represents a hydrogen atom, containing 1 to 4 broken atoms Or an aromatic hydrocarbon group containing 6 to 10 carbon atoms-an alkyl group containing 1 to 4 carbon atoms in which the aromatic nicotyl group may be a halogen atom, a CF3 group, an alkoxy group containing 1 to 8 carbon atoms, or Is substituted by an alkyl group containing 1 to 4 carbon atoms; A represents a single bond, COn, SOn, or CONH; η represents 1 or 2 · R7 represents a hydrogen atom; an alkyl group containing 1 to 18 carbon atoms or A feminine group containing two to eighteen carbon atoms can be substituted by a carbonyl group containing 1 to 4 carbon atoms, a halogen atom, a CF3 group, an alkyloxy group containing 1 to 4 carbon atoms, and N (containing 1 to 4 carbon atoms). Carbonyl group) 2, -COOH group, alkoxycarbamyl group containing 1 to 4 carbon atoms, aromatic hydrocarbon group containing 6 to 12 carbon atoms, aromatic hydrocarbon group containing 6 to 12 carbon atoms Aromatic hydrocarbons containing 6 to 12 carbon atoms, aromatic hydrocarbons containing 6 to 10 carbon atoms-fluorenyl or oxo groups containing 1 to 4 carbon atoms Second, the aromatic hydrocarbon itself can be replaced by a halogen atom, an alkyl group containing 1 to 4 carbon atoms, an aminosulfonyl group, or a methylhydrofluorenyl group; 45 200530219 represents an aromatic hydrocarbon group containing 6 to 10 carbon atoms -An alkyl group containing 1 to 4 broken atoms, representing a cycloalkyl group containing 5 to 8 carbon atoms_an alkyl group containing 1 to 4 carbon atoms, representing a cycloalkyl group containing 5 to 8 carbon atoms, representative Aromatic nicotyl groups containing 6 to 10 carbon atoms-alkenyl groups containing 2 to 6 carbon atoms, representing (aromatic hydrocarbon groups containing 6 to 10 carbon atoms), representing diphenyl groups, representing diphenyl groups-containing 1 to An alkyl group of 4 carbon atoms, representing an indanyl group, which can be an alkyl group containing 1 to 18 carbon atoms, an alkoxy group containing 1 to 18 carbon atoms, a cycloalkyl group containing 3 to 8 carbon atoms , COOH group, hydroxyl group, alkyl carbofluorenyl group containing 1 to 4 carbon atoms, aromatic hydrocarbon group containing 6 to 10 carbon atoms-an alkyl group containing 1 to 4 carbon atoms, containing 6 to 10 carbon atoms Aromatic nicotinyl group-alkoxy group containing 1 to 4 carbon atoms, aromatic nicotyl group containing 6 to 10 carbon atoms, nitro, cyano, containing 6 Aromatic nicotinylfluorosulfonyl group of 10 carbon atoms, alkoxycarbenyl group of 1 to 6 carbon atoms, aromatic hydrocarbon sulfonyloxy group of 6 to 10 carbon atoms, n-pyridyl group, NHSOH: Contained An aromatic hydrocarbon group of 6 to 10 carbon atoms), a halogen atom, a CF3 group, or an OCF3 group, wherein the alkyl group may also be substituted with an alkoxycarbamyl group, a CF3 group, or a carboxyl group containing 1 to 4 carbon atoms, and The aromatic hydrocarbon group may be substituted by a halogen atom, a CF3 group, or an alkoxy group containing 1 to 4 carbon atoms; or it may represent a functional group Het_ (CH2) r, where r is equal to 0, 1, 2, or 3 and Het is Saturated or unsaturated five to seven ring heterocyclic compounds' which can be formed into a benzo anellated and can be substituted by an alkyl group containing 1 to 4 carbon atoms and an aromatic group containing 6 to 10 carbon atoms 46 200530219 Hyunyl, _ prime atom, alkoxy group containing 1 to 4 carbon atoms, alkoxy carbofluorenyl group containing 1 to 4 carbon atoms, aromatic hydrocarbon group containing 6 to 10 broken atoms-containing 1 to 4 Carbon atom moieties, aromatic hydrocarbon radicals containing 6 to 10 carbon atoms-thiol radicals containing 1 to 4 carbon atoms, or nitro radicals Substituted, in which a cigarette ring is formed by a halogen atom, an alkoxy group containing 1 to 4 carbon atoms, or a CF3 group, and the alkyl group in an aromatic nicotinyl alkyl group may be methoxy or It is substituted by CF3 group.

Compounds having the general formula (A) for inhibiting lipase activity are described in more detail in WO 03/072098, and can be prepared according to known methods. A suitable method for synthesizing a lipase-active compound having the structure of the general formula (A) is also described in the international patent application WO 03/072098. The entire content of the international patent application WO 03/072098 is incorporated herein by reference for the disclosure of a lipase inhibitor having the structure of the general formula (A).

In addition, US Pat. No. 6,624,161 and its corresponding international patent applications WO 00/040569 and WO 00/40247 further describe compounds that inhibit lipase activity, which are also suitable for use in connection with the present invention. Combinations of the CBi antagonist compounds described herein. These patents US 6,624,161 and WO 00/040569 describe a series of compounds, which are derivatives of 2-oxo-4H-3, 1-benzopoxan-4-one, including atl-962 , And its use in obesity and obesity-related diseases, including type 2 diabetes. Derivatives of 2-oxo_4H-3, 1-benzoxazin-4-one have the structure of general formula (b), or should they be salts, cools, and amines which are acceptable for pharmaceutical use Or prodrug: 47 200530219

among them

Rla representative

⑴A bifurcated or unbranched alkyl group containing 10 to 30 carbon atoms, which can be replaced by one or more cycloalkyl groups containing 3 to 6 carbon atoms that are unrelated to each other, containing 3 to 6 Carbon atom ring ring group, aromatic nicotyl group, heteroaromatic nicotyl group, reduced heteroaromatic nicotyl group, —C (0) R13, —C02R13, —S0R13, —s〇2R13, —NR13R14, —OR13, —SR13 , —C (0) NR13R14, -_NR14C (0) R13, halogen atom, cyano and nitro group, and / or can be inserted by one or more oxygen atoms, but its prerequisite is that any of them in Rla The heteroatom must be with the oxygen atom outside the ring

(Or with any other heteroatom) separating at least two carbon atoms; (ii) an alkenyl group containing 2 to 25 carbon atoms, a bulk group containing 2 to 25 carbon atoms, containing 3 to 6 carbon atoms Cycloalkenyl, Aromatic Hydrocarbyl_ Women's Group Containing 2 to 25 Former Atoms, Heteroarylxyl-Alkenyl With 2 to 25 Carbon Atoms, Reduced Heteroaromatic Hydrocarbyl, Reduced Heteroaromatic Hydrocarbyl-Containing丨 Alkyl to 25 carbon atoms or any of the above-mentioned functional group substituted derivatives, wherein the substituents are one or more alkyl groups containing 1 to 6 carbon atoms which are not related to each other, The fungin replaces an alkyl group containing 1 to 6 carbon atoms, an aromatic nicotyl group, an aromatic nicotinyl group-an alkyl group containing 1 to 6 carbon atoms, a heteroaromatic hydrocarbon group, a reduced heteroaromatic nicotyl group, a reduced heteroaromatic group Nicotinyl contains an alkyl group having 1 to 6 carbon atoms, alkoxy group containing 1 to 6 carbon atoms, aromatic hydrocarbon group-alkoxy group containing 1 to 6 carbon atoms, _C (〇) R13, --C02R13,- -SOR13, --S02R13, --NR13R14, --OR13, SR13, --C (0) NR13R14, --NR14C (0) R13, halogen atom, cyano And nitro, but the prerequisite is that any heteroatom in Rla must be separated from the oxygen atom (or any other heteroatom) outside the ring by at least two carbon atoms; (iii) one containing 2 to 9 atom-breaking entertainments: radicals that are inserted by one or more oxygen atoms, and can be one or more cycloalkyl groups containing 3 to 6 carbon atoms, containing 3 to 6 carbon atoms, which are unrelated to each other Cycloalkenyl, aromatic hydrocarbon group, heteroaromatic hydrocarbon group, reduced heteroaromatic hydrocarbon group, -C (0) R13, -C02R13, -SOR13, -S02R13, --NR13R14, --OR13, -SR13, -C (0 ) NR13R14, --NR14C (0) R13, substituted by a prime atom, cyano and nitro, but the prerequisite is that any heteroatom in Rla must be an oxygen atom outside the ring (or with any other heteroatom Atoms) separate at least two carbon atoms; or (iv) an alkyl group containing 1 to 9 carbon atoms, which is selected from the group consisting of C (0) R13, -C02R13, -SOR13, -S02R13, -NR13R14, -OR13, -SR13, -C (0) NR13R14, -NR14C (0) R13 substituted by this group; tetrahydronaphthyl, pyridyl, pyrrolyl, piperidinyl, Elementary atom, cyano, nitro, bicyclic aromatic hydrocarbon group, bicyclic heteroaromatic, monocyclic or tricyclic quilt cigarette base, 49 200530219 monocyclic heteroaromatic hydrocarbon group other than imidyl group; (V) — Phenyl 'which is one selected from -〇R17, -coR13, C02R13, -SOR13, -S02R13, -C (0) NR13R14, --NR14C (0) R13, substituted with halogen containing 1 to $ carbons Atomic alkyl, aromatic nicotyl, aromatic nicotyl-(containing 1 to 6 carbon atoms) alkyl, heteroaromatic hydrocarbon and heteroaromatic hydrocarbon-alkyl groups containing 1 to 6 carbon atoms are replaced by this group; or Is (vi) a bicyclic aromatic hydrocarbon group, a bicyclic heteroaromatic hydrocarbon group, a monocyclic or bicyclic reduced heteroaromatic hydrocarbon group, or a monocyclic heteroaromatic nicotyl group other than imidyl, which can be selected Since __〇R17, --COR13, --C02R13, --SOR13, --S02R13, --CONR13R14, --NR14 C (0) R13, halogen-substituted alkynyl, aromatic nicotyl, aromatic containing 1 to 6 carbon atoms Nicotinyl-an alkyl group containing 1 to 6 complex atoms, heteroaromatic nicotinyl group and heteroaromatic nicotinyl group-alkyl groups containing 1 to 6 broken atoms are substituted by this group; each of R13 and R14 Independently of one another, it represents a hydrogen atom, an alkyl group containing 1 to 10 carbon atoms, an alkenyl group containing 2 to 10 broken atoms, an alkynyl group containing 2 to 10 carbon atoms, and 3 to 6 carbon atoms Cycloalkyl, cycloalkenyl containing 3 to 6 carbon atoms, aromatic nicotinyl, aromatic nicotinyl-alkyl containing 1 to 10 carbon atoms, heteroaromatic nicotinyl, heteroaromatic hydrocarbon group-containing 1 to 10 An alkyl group of carbon atom, a reduced aromatic nicotyl group or a reduced aromatic hydrocarbon group, an alkyl group containing 1 to 10 carbon atoms, and R17 represents a hydrogen atom or an alkenyl group containing 2 to 10 carbon atoms, Fast radicals containing 2 to 10 carbon atoms, cycloalkyls containing 3 to 6 carbon atoms, cycloalkenyls containing 3 to 6 carbon atoms, aromatic hydrocarbon groups, aromatic hydrocarbon groups-containing 1 to 50 200530219 ί carbons Atomic alkyl groups, heteroaromatic hydrocarbon groups, heteroaromatic hydrocarbon groups (alkyl groups containing 1 to 10 carbon atoms), reduced aromatic hydrocarbon groups or reduced aromatic hydrocarbon groups-alkyl groups containing 1 to 10 carbon atoms, and R8a, R9a, R10a, and Rlla

Each of them independently represents a hydrogen atom, a commercial atom, a hydroxyl group, an amino group, a nitro group, a cyano group, a hydrogen thio group, an alkyl group containing 1 to 10 carbon atoms, a ring containing 1 to 10 carbon atoms Alkyl, alkoxy with 1 to 10 carbon atoms, cycloalkoxy (with 1 to 10 carbon atoms), C (〇) R15, C (0) NR15R16, S (0) R15 or halogen -A radical containing 1 to 10 carbon atoms; wherein each of R15 and R16 represents a hydrogen atom independently of each other, or represents an alkyl group containing 1 to 10 carbon atoms, but its prerequisite is that when When R8a, R9a, R10a, and R1la are hydrogen atoms, and Ria is not ch2CH2C1 or a bromine γ group containing three carbon atoms. Furthermore, in the international patent application WO 00/40247, the related 2-aminopyrene-4H-3, 1-benzoxazin-4-one derivative is described as a compound that acts as an inhibitor of lipase activity. To treat obesity. In the general formula (B),

The substituent is substituted by a functional group -NR1R2, and the definitions of R1 and R2 are as described in WO 00/40247. The above structurally related compounds in this group include atl_% 2, which is a synthetic lipase inhibitor that is not absorbed orally and is derived from

The research plan of Alizyme ’s pancreatic lipase inhibitors is currently developing potential treatments for obesity and potential treatments for diuretic disease. ATL.962 has the same chemical name as 2 • tetra-4 --benzofluorene-4-fluorene. Preclinical studies have pointed out that Ατ ^ 2 ^ orlistat has similar efficacy, and there is no tumbling life or toxicity. The clinical data of these chemical compounds can also be obtained in the state of invalidation of patent rights. ATL-962 clinical studies on obesity were obtained. As a result, these fruits obtained during the day-to-day period of the ATL-962 research report were reported at the International Conference on Obesity in São Paulo, Brazil. The three phase 1 trials consisted of a total of 99 healthy male volunteers divided into seven or domain groups, (66 * study subjects) received one of several ATL-962 study doses, or: (24 study% subjects) accepted Placebo was administered three times daily with a meal-for-five for five days. In one of the groups, nine subjects were administered 120 mg of statin (qv) three times a day. The results of the trial as a whole, atl_962 is safe and well tolerated, and shows evidence of a% efficacy as indicated, ie the elimination of increased fat from the diet. Study subjects who were administered twice daily with a dose between 50 mg and 300 mg atl_962, with an average fat excretion between 4.9 (+ M + and 112 (+ / _ 6 9) g / day , Compared with 14 (+ /] 〇) g / day in the control group receiving placebo and 5.6 (+ / _ 3 · 8) g / day in the test group receiving orlistat. Compared with placebo, 50 mg And 55% of the 300 mg ATL-962 subjects showed a three-fold or higher increase in fat excretion, and 27% of them studied a seven-fold or higher increase in fat excretion. This result is evidence of dose dependence. The frequency of adverse reactions and their occurrence was similar between the ATL-962 and placebo groups, and the most obvious symptom was gastrointestinal. A multi-center, randomized, double-blind, parallel-grouped trial (% of Phase IIb studies), which included 370 clinically obese patients, was performed in five European and national specialist hospitals and was performed in 2003 Preliminary results and results were published in September. For all treatment groups, all ATL-962 The dose levels (60, 120 and 240 g) all showed a significant reduction in body weight compared to the placebo 52 200530219 dose. There was no difference in the degree of 'fS weight reduction between the treatment groups. There was no difference between the treatment groups. There was a decrease in LDL · cholesterol in the placebo group, but not in the placebo group. There was no difference in HDL_cholestanol in each treatment group, but it was in the group of patients treated with placebo. Increasing phenomenon. In each treatment group, total bile domains showed a decrease in silk, while comfort maggots showed an increase. Therefore, 'ATL ·% 2 is full-bodied and generally accepts well. It has the general formula ( B) Compounds that are structurally and inhibit lipase activity, such as ATL-962 and structurally related compounds, are described in more detail in U.S. Patent 6,624,161 and its corresponding international patent application WO00 / 04504569. It can be prepared according to known methods. Suitable methods for synthesizing lipase inhibitory compounds having the structure of the general formula (B) are also described in 6,624,161 and the international patent application WO00 / 04004569. Described to. The US 6,624,16 1 and the entire international patent application WO00 / 04504569 are incorporated by reference in the present invention for the purpose of disclosing a lipase inhibitor having the general formula (B). International patent application WO00 / 〇〇〇〇〇〇〇〇〇〇〇〇〇〇２〇247 The content of the full text is incorporated by reference in the present invention is related to the disclosure of compounds described herein inhibiting lipase activity, which has a 2-amino-4η_3 ,; Relevant Structures. All the pharmaceutically acceptable salts, hydrates, and solvents, and prodrugs of the lipase-inhibiting compounds described above can be used in the present invention. CB! Antagonist compounds having the general formula (I), (II), (III), (IV), or (V) structure, or their previous drugs, tautomers or salts, and according to The lipase-inhibiting compound used in the present invention can be made into various dosage forms, which are suitable for treating and / or preventing the above diseases in pediatrics. 200530219

The treatment and / or prevention of obesity, especially obesity, for example, as adolescent or pediatric medicine, and as a medicine for obesity caused by drugs, the method is a common process using pharmaceutical excipients, Auxiliary substances and / or liquid or solid carrier materials. As therapeutic agents, c-type antagonist compounds and / or lipase-inhibiting compounds may be included in (traditionally) pharmaceutical excipients, adjuvants and / or adjuvants such as tablets, capsules, Suppositories or elixir medicines. These medicines can be prepared according to known methods, using traditional solid or liquid excipients such as lactose, starch or talc, or liquid stone sacrificial and / or using (traditional) pharmaceutical excipients. Preservatives, adjuvants and / or supplements, such as lozenge disintegrating agents, solubilizers and preservatives.

Therefore, in another aspect, the present invention also relates to a pharmaceutical composition containing at least one compound having the general structure ⑴, (H), (m), (IV) or (V) and having CBi receptor activity. The compound, or its preexisting drug, tautomer or salt, is used in combination with at least one lipase-inhibiting compound. A more preferred pharmaceutical composition contains at least one compound having the general formula (I), (Π), (ΠI), (IV) or (v) structure as defined above, and at least one compound that inhibits lipase activity Combined use as the active ingredient of the compound. Another pharmaceutical composition according to the present invention is an active ingredient containing at least one compound having the general formula (i), (π), or (V) structure as defined above and having a CBi receptor activity, preferably CBi antagonisticity. A compound, or a pre-drug, tautomer or salt thereof 'and at least one lipase-inhibiting compound for the treatment and / or prevention of obesity in adolescent or juvenile patients, and / Or for the treatment and / or prevention of obesity caused by drugs in young and adolescent patients. The special medicinal composition according to the present invention is characterized in that at least one of the compounds having the general formula (I), (π), (III), (IV) or (V) structure as defined above has a CBi receptor. Active compounds are more likely to be CBi antagonistic compounds, or one of their predecessors, tautomers, or salts, and at least one lipase-inhibiting compound, each of which is present at a dose, which has It is effective and suitable for the treatment and / or prevention of obesity in young patients who need such treatment. In another embodiment of the present invention, eh antagonistic compounds, especially CBi antagonistic compounds having the general formula (I), (II), (H), (IV) or (v) structure and inhibition Each of the lipase active compounds is present in the medicinal composition in a dose, which is effective and suitable for the treatment and / or prevention of drug-induced obesity in young and adolescent patients in need of such treatment. In the pharmaceutical composition according to the present invention, a cBi antagonistic compound, particularly a CBi antagonistic compound having a general formula (I), (II), (〗 〖1), (IV) or (v) structure, These previous drugs, tautomers or salts are preferred to be used in combination with a lipase-inhibiting compound selected from the group consisting of polymers that inhibit lipase activity, orlistat, panclicins, ATL-962, and lipstatin. The present invention also relates to a pharmaceutical product containing a CB! Antagonist compound, especially one having the general formula (I), (II), (III), (IV) or (V) structure as defined above. CBi antagonistic compound, or one of its tendon drugs, tautomers or salts, and a description, indicating that the CBi antagonistic compound can be simultaneously and separately from a lipase inhibitory compound Or they can be administered together in a phased manner for the treatment and / or prevention of obesity. Finally, the present invention also includes a method for treating and / or preventing obesity in, for example, adolescent or juvenile patients and / or for treating and / or preventing adolescent and juvenile patients due to drugs. Obesity is characterized by a CBi antagonistic compound, especially a compound having the general structure ⑴, 200530219 (II), (III), (IV) or (V) structure, which is a cannabinoid CB i- Receptor antagonists, or prodrugs, tautomers and salts thereof, are administered in combination with at least one lipase-inhibiting compound to a patient in need of such treatment. In a method for treating and / or preventing obesity according to the present invention, a CBicum anti-1 compound is a compound having the general formula ⑴, () j),

One of the structures (III), (IV) or (V), or a prodrug, tautomer and salt thereof, is combined with and administered with at least one lipase-inhibiting compound. The method for treating and / or preventing obesity according to the present invention can be aimed at obesity in adolescent or juvenile patients and / or obesity caused by drugs in adolescent and juvenile patients. In one aspect of the present invention, the method for treatment and / or prevention is characterized in that the treatment is directed toward obesity in a juvenile patient. In another aspect of the present invention, the method for treating and / or preventing is characterized in that the treatment is aimed at obesity caused by drugs in infants or adolescents. In the method for treating and / or preventing according to the present invention, the CBi antagonistic compound preferably has one of the general formula ⑴, (11), (m), (IV) or (v) structure as defined above. CBi antagonistic compound, or one of its predecessor drugs, tautomers or salts and a lipase inhibitory compound selected from the group consisting of lipase inhibitory polymers, orlistat, panciieins, atL_962 and lipstatin Combined use. According to the present invention, the CBi antagonistic compound is preferably a CB1 antagonistic compound having one of the general formula (I), (II), (III), (IV) or (V) structure as defined above, or It is a kind of predecessor drug, tautomer or salt and a lipase-inhibiting compound are combined and administered simultaneously, separately, or in a step of 1¾. Each of the chemical compounds used in combination or composition according to the present invention is a 200530219 compound, each of which prefers to be administered to a patient in need, and more preferably to a dose sufficient to prevent and / or treat The problem, condition or disease, such as the symptoms of obesity. For all viewpoints of the present invention, especially with regard to pharmaceuticals, the administration of a compound or composition in terms of its dosage will ultimately be determined by the treating physician, taking into account the following factors such as the compound used , Animal type, age, weight, severity of symptoms, method of administration, adverse reactions and / or other / or contraindicated symptoms. The specially defined dose range can be determined by standard designed clinical trials, and the patient's progress and rehabilitation are fully monitored. These trials can use a escalating dose design that uses a low percentage of the maximum zero tolerated dose in animals as the starting dose in humans. Each of the physiologically acceptable compounds used in the combined or constituent drugs according to the present invention will normally be administered in a daily regimen (for adult patients), for example A single oral dose is between 1 mg and 2000 mg, preferably between 30 mg and 1000 mg, such as between 10 mg and 250 mg, or intravenous, subcutaneous or muscle A single dose for internal injection is between 0.01 mg and 100 mg, preferably between 0.1 mg and 50 mg, such as between 丨 mg · and 25 mg, which has the general formula (A) A structural compound or one of its physiologically acceptable salts (calculated on a free base) is administered one to four times per compound. It is more appropriate to administer the compound for a continuous period of time, such as one week or longer. In the case of juvenile =. One oral dose is usually administered to an adult patient. ≪ Knife ', for example, administered to an adult patient-one-fifth of the oral dose-to two points "-0 is preferred, in one embodiment of the invention, The treatment and / or 57 200530219 prevention method is aimed at treating obesity in young patients. In another preferred embodiment of the present invention, the treatment and / or prevention method is aimed at treating obesity caused by drugs in infants or adolescents. This drug-induced obesity may be caused in particular by atypical antipsychotic drugs.

In one embodiment of the present invention, the method of treating and / or preventing is aimed at treating obesity in a juvenile patient. Therefore, its advantage is that the combination of cannabinoid antagonists and lipase inhibitors is particularly suitable for the treatment of obesity in children and related common diseases, such as type 2 diabetes. There is a clear need for improved medical treatment because obesity has become an increasingly important medical treatment not only in the adult population, but also in children and (young or older) adolescents. problem. In the nationwide survey of the United States from the 1960s to the 1990s, the prevalence of weight lifting in children increased from 5% to η% (solof and Daniels 2002). As another example, obesity among children in Canada has tripled in the past two decades (Spurgeon 2002). Obesity in childhood can cause a wide range of serious complications and increase the risk of early onset of disease and death in the middle and later stages of life, which has drawn public health attention (Ebbeling, Pawlak et al. 2002). Over the past few decades, a significant increase in cases of type 2 diabetes has been observed, especially in children. This epidemiological trend clearly reflects the increasing obesity rate. Type 1 diabetes was previously considered an adult or older disease rather than a pediatric disorder (Arslanian2. 〇2). One of the major risk factors for type 2 diabetes in children is obesity. Partial type 2 diabetes (as in adults) is part of the insulin resistance syndrome (R0senblom 2000), which includes hypertension, abnormal lipids 58 200530219 and other risk factors for arteriosclerosis, and It is regarded as precocious adrenocortical function with rising androgen and polycystic ovary syndrome. Other consequences associated with childhood obesity include left ventricular hypertrophy, non-alcoholic fatty liver, hindered sleep apnea, orthopedic problems, and serious mental and social problems. In addition, primary hypertension has become more common in children, and once again it has obesity as the main independent risk factor associated with it. Obese children are about three times more likely to develop high blood pressure than non-obese children (sorf and Daniel 2002). Weight loss is beneficial for lowering blood pressure in children, and has been shown in both observational and interventional studies. The rapid development of childhood obesity in genetically stable ethnic groups is causing concern. The driving factors are assumed to be mainly negative environmental factors, and there are direct suggestions for lifestyle changes. Obesity and related common diseases are very serious medical problems, and the latest measures and treatments for obesity, especially childhood obesity, are not effective for a large I5 point (Ebbeling, Pawlak et al. 2002). Managing type 2 diabetes is also particularly difficult in children and adolescents (Silink 2002). Craving for food is one of the most important factors in humans, especially children, and adolescents and lifestyle-related obesity. Treating Type 2 Diabetes and Other Common Disorders by the Level of Metabolic Disorders and Symptoms • The only data on the use of oral hypoglycemic agents in children with type 1 diabetes has been metformin (Rosenbloom 2002). Therefore, the CBl antagonists and lipase inhibitors used in accordance with the present invention provide a unique opportunity to treat obesity by interacting with these "driving forces." These are superior to current medical treatments, and are particularly suitable for adolescent and pediatric treatments because of their excellent safety properties and the surprisingly good combined effects. Treatment of obesity, especially childhood obesity, requires safety in addition to its efficacy. Obesity in children is a medical problem that may require long-term management. The safety characteristics of CBi insertion inhibitors and lipase inhibitors according to the present invention are considered to be better than the current standard drugs, and these CBi antagonists and lipase inhibitors are particularly suitable for adolescents and children with obesity and related Treatment and prevention of common diseases. literature:

Arslanian, S. (2002). UType 2 diabetes in children: clinical aspects and risk factors ·, Horm Res 57 Suppl 1: 19-28.

Ebbeling, C. B. D. B. Pawlak, et al. (2002). "Childhood obesity: public-health crisis, common sense cure.", Lancet 360 (9331): 473-82.

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

Silink, M. (2002). "Childhood diabetes: a global perspective.", Horm Res 57 Suppl 1: 1-5.

Sorof, J. and S. Daniels (2002). &Quot; Obesity hypertension in children: a problem of epidemic proportions " Hypertension 40 (4): 441-7.

Spurgeon, D. (2002). "Childhood obesity in Canada has tripled in past 20 years.", Bmi 324 (7351): 1416. In another embodiment of the invention, the method of treatment and / or prevention is It is aimed at treating obesity caused by drugs in juvenile or adolescent patients. Weight gain caused by drugs is also the main focus of attention, and 200530219 has a high demand for medical treatment to improve. In this connection, CB! Antagonists combined with lipase inhibitors according to the present invention are considered to be superior to standard medications, and these CBi antagonists plus lipase inhibitors are particularly suitable for use in young or adolescent patients Treatment and prevention of obesity caused by drugs. Zimmermann, U., T. on weight gain caused by drugs

Kraus, et al. (2003, "Epidemiology, implications and mechanisms underlying drug-induced weight gain in psychiatric patients." During the treatment of sexual disorders, and often accompanied by increased appetite or food cravings. Because the occurrence of such side effects and the time course are difficult to predict, it will eventually lead to obesity and related diseases in a considerable proportion of patients. Disease, so often they do not continue to receive treatment, even if the treatment is effective. Weight gain seems to be the most prominent phenomenon in patients receiving some second-generation neuroleptic drugs and some mood-stabilizing drugs. Significant weight gain often occurs during the treatment of ring-shaped antidepressants. Very large weight gains are related to drugs such as the atypical antipsychotic drugs clozapine and olanzapine. However, some atypical

Neurosuppressive drugs tend to cause significant weight gain, which may lead to poor compliance and other adverse health effects (Nasranah, H. (2003) "A review of the effect of atypical antipsychotics on weight ·, Psychoneuroendocrinology 28 SuppLl : 83-96 ·). Although their affinity for serotoninergic, histamine, and adrenergic all point to other metabolic mechanisms, weight gain related to neuroleptic drugs The mechanism involved is not clear until now 61 200530219. Under long-term treatment, atypical neuroleptics change their habits and cause weight changes. Tracking studies indicate that the largest increase in weight is related to clozapine and olanzapine And the smallest increase is related to quetiapine and zipmsidone. Risperidone is and

There is a slight change in body weight that is independent of the dose. If atypical antipsychotics have the same effect, then when establishing a therapeutic algorithm for the medical consequence of obesity, the characteristics of weight gain are a factor that is justified. In this connection, the simultaneous administration of a cBi antagonist according to the present invention plus a lipase inhibitor is considered to be beneficial for the effect.

The experimental report of the study of the effect of Cl antagonist compound plus lipase inhibitor on obesity combines the use of CBi antagonist and the lipase inhibitor according to the present invention, and its beneficial pharmacological effects can be shown by standard experimental animal models. It is by measuring the effect of coadministration of CBi antagonists and lipase inhibitors on driving and characteristic parameters associated with obesity. In order to study the effect of combined use of CBi antagonists and lipase inhibitors according to the present invention on obesity, the weight gain of rats was measured as a medicine

Physical indicators. Therefore, it can be applied to the following experimental methods for rats: Rats have unrestricted access to feed for 2.5 hours twice a day, during a dark period of upside down 12 hours / 12 hours light cycle, For example, the light is turned on at 21:15 and turned off at 09:15. These rats were provided with high-fat, high-sucrose food (Western diet). A certain amount of lipase inhibitor was administered immediately before the rats began to be fed. A certain amount of CBi antagonist is administered one hour before the lipase inhibitor is administered. 62 200530219 For example, the following daily dosage tables can be applied at specific times, such as days, weeks, or months: CBi antagonists, especially those with CB1 antagonists as defined above, P 弋 (1) ~ constitution The sex compound, or an excipient in a dose of three, is administered in the morning from about 7.45 to the g-qq. And lipase inhibitors, such as orlistat in particular, or an excipient are administered orally from about 8.45 to 9:00 =. Between 15 and 11:45, food was left unchecked and food was removed from approximately 11:45 to 14:45. _ Sub-dose of the linguistic side, for example, orlistat 'or an excipient (the dosage of ethalamine ^ is administered orally from about 14:15 to 14:30 in the afternoon, Immediately afterwards, the rats were eaten freely from 14:45 to 17:15. Then rats were fasted from 17:15 to 09:15. The results reported will compare the daily food intake. The increase in intake and weight is used as an indicator of the efficacy of combined therapy for obesity during the experiment. In addition to the parameters already stated, 'excretion can also be collected to assess the digestibility of lipid control. Finally, it can also be done in rats The analysis of the corpse. In addition, after the feeding and administration period of the experiment is completed, the biochemical parameters can be measured after the rats are killed. In terms of the percent effect of the study, the rats are used as experimental reports. The numbers were divided into the following arrays, each group had approximately the same number of rats ... 1) Control group ... The large M received the excipients transferred to this experiment report for the purpose of mock administration (placebo group). 2) CB! Group: Daizo received-a C Bi antagonist in one form]. 3) LI group. Rats receive a message such as Compound 0 as a lipase inhibitor ("LI") in an excipient. 63 200530219 4) CB # LI group (combined use group): rats receive a CB1 antagonist in an excipient, and also receive, for example, the compound orlistat as a lipase inhibitor ("LI") in an excipient. The report and the results of individual studies show that the combined use of a CBi antagonist and a lipase inhibitor has excellent applicability in the treatment and / or prevention of obesity. The compound having the structure of the general formula (V) is a 1H-1,2,4-triazole-carboxamide derivative having the structure of the general formula (V), which is a potent agonist for the cannabinoid CBr receptor, Some agonists, inverse agonists or antagonists, which are effective for the treatment of psychiatric and neurological disorders and other cannabinoid-CB! Neurotransmission-related disorders. definition. The 1,5 · diaromatic hydrocarbyl-1H-1,2,4-triazol-3-carboxamide derivative has been described as a herbicide in EP 0346620 and GB 2120665. Recently, 1,2,4-triazole has been described as a potent agonist and antagonist of the cannabinoid CBr receptor and CB2-receptor (Jagerovic, N. d α /., 2 > Feed Αί. 2002, 27 ( Suppl. A): XVIIth Int. Symp. On Medicinal Chemistry, P284) o D. Clerin and J. P. Fleury, such as // C7? / W · Fr ·, 1974, 1-2,

Pt.2, 211-217 describes a group of derivatives containing four 1,5-diaromatic hydrocarbyl-1H-1, 2, 4-triazole-3-carboxamides, among which The nitrogen atom is an unsubstituted part of Ludian or Morinyl. MH Elnagdi et al. Described 1- (4-tolyl) -5 • phenyl-N- (1) in (if you plant (9 oil) /? 7 CT?), 1995, 6, 589-592. 2-Hydroxypyridyl:)-1H-1,2,4-triazol-3-carboxamide. Α · Η · Harhash et al. And m J · CAew ·, 1976, 14B, 64 200530219 268-272 describe a group containing four ) -1,1,2,4-triazol-3-carboxamide derivative. The following are suitable synthetic routes for compounds of the general formula (V) used in the present invention:

Synthetic route A 1 · @ Purpose hydrolyzes a compound having the structure of general formula (S-II), wherein R 6 represents a branched or unbranched alkyl group (containing 1 to 4 carbon atoms) or a phenyl group

Produces a compound with the general structure (S-III)

In which R and & have the meanings as mentioned above. The compound of the present invention having the general structure (S-II), in which 仏 represents a branched or unbranched alkyl group (containing 1 to 4 carbon atoms) or a phenyl group, which can be prepared according to known methods Obtain, for example: a) Sawdey, GWJ Am. Chem. S〇c. X957? 79 1955 65 200530219 b) Czollner, L. et al.? Arch. Pharm. {Weinheim) 1990? 323? 225 c) Eicher, T and Hauptmann, S. The Chemistry of Heterocycles, Thieme Verlag, Stuttgart, 1995 (ISBN 313 100511 4)? p. 208-212.

Step 2 • A compound having the structure of the general formula (S-III) and a compound having the structure of the general formula R2R3NH, in which r2 and r3 have the meanings as mentioned above, react with each other, and pass through activation and coupling methods Such as forming an active ester, or in a coupling agent such as DCC, HBTU, BOP, CIP (2-chloro-1,3-dimethylimidazofluorene hexafluorophosphate) or PyAOP (7-aza In the presence of benzotrien-1-yloxytriazolyl alkyl) hexafluorophosphorylic acid). Methods of this type of activation and coupling are described in a) M. Bodanszky and A. Bodanszky: The Practice of Peptide Synthesis, Springer-Verlag, New York, 1994; ISBN: 0-387-57505-7; b) K. Akaji et al, Tetrahedron Lett (1994), 35, 3315-3318; c) F. Albericio et al., Tetrahedron Lett. (1997), 38, 4853-4856 ·

This reaction produces a derivative of 1H-1,2,4-triazole having the general formula (V).

Synthetic route B: A compound having the structure of the general formula (S-III) is reacted with a chemical agent such as thionyl chloride (SOC12) or chloramphenicol. This reaction produces the corresponding carbochloride (acid chloride) (S-IV)

R R \ / 1

66 200530219 A compound having the structure of general formula (S-IV) and a compound having the structure of general formula R2R3NH, wherein R2 and rs have the meanings mentioned above and react with each other, resulting in a compound having the structure of general formula (V) 1H-1,2 4-Sanjun's derivative.

Synthetic route C

A compound having the general structure (s-π) structure and a compound having the general structure RzRsNH, in which I and R3 have the meanings mentioned above, are subjected to amidation reaction, resulting in a structure having the general formula (V) Zhiqin 丨, 2, 4-Sanjun's derivative. This kind of ammonium amination reaction can be achieved by using trimethylamine A1 (CH: 3) 3 (For more information about the conversion of melamine to melamine by the library media, please refer to: J. I. Levin, E. Turos S. Weinreb, Synth Commun. (1982), 12, 989-993). Example 1

Part A: Add triethylamine (41.4 ml, 2.2 mole equivalents) to a solution of dimethylaminomalonate hydrogen chloride (25 g, 0.136 mole) at 0 ° C with stirring It was then dissolved in a solution consisting of dichloromethane (200 ml). Then, 4-chlorobenzidine chloride (23.8 g, 0.136 mol) was slowly added, and the resulting solution was allowed to stand overnight at room temperature. Water was then added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The collected organic layer was washed with water ', then dried over magnesium sulfate, then filtered, and finally concentrated to dryness under vacuum. The residue was recrystallized from methanol (400 ml), and as a result, dimethyl 2- (4-chlorobenzylamino) malonate (30.5 g, yield 79%) was obtained. Melting point: 146-148 ° C. b-NMR: (200 MHz, CDC13): 3.86 (s, 6H), 5.38 (d, J = 6 Hz, 1H), 7.15 (brd, J ~ 6 Hz, 1H), 7.43 (d, J = 8 Hertz, 2H), 7.79 (d, J = 8 Hertz, 2H). Part B: Add a solution consisting of NaNO2 (9.0 g, 0.13 mole) 67 200530219> Gu Yu water (50 liters) at 0 ° C to a solution of 2,4-digas aniline (19.44 g (0.12 mol), after stirring, was dissolved in a solution consisting of concentrated hydrochloric acid (25 ml) and acetic acid (75 ml), and then the resulting solution was stirred for fifteen minutes. Then, while maintaining the temperature below 0 ° C, a solution of monomethyl 2- (4-chlorobenzylamino) -malonate (28.55 g, 0.10 mole) was slowly added. In acetone (200 ml). Then slowly add a solution consisting of K2CO3 (120g) in water (200ml), and the resulting black mixture was dropped at 0 ° C for 30 minutes. The mixture was extracted three times with ethyl acetate. The collected organic layers were washed with water, aqueous bicarbonate solution and water, respectively, then dried over magnesium sulfate, then reduced, and finally concentrated and dried under vacuum. The residue was dissolved in methanol (5QQ ml) and a solution consisting of sodium metal (1 g) in methanol (75 ml) was added. The resulting stirred mixture was left at room temperature overnight, and then cooled in a refrigerator. The resulting precipitate was collected by the hydrazone method and washed with methanol. As a result, methyl 5- (4-chlorophenyl) _1_ (2,4-dichlorophenyl) -1Η-1,2,4-di p--3-carboxylic acid salt (4 g, 30% yield). Melting point: 153_154 ° C. NMR: (200 MHz, CDC13): 4.07 (s, 3H), 7.28 · 7 · 60 (m, 7H). Part C: Potassium hydroxide (45% aqueous solution, 7.5 ml) was added to a methyl 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) _1H-1,2, 4-Triki-3-benzyl acid salt (11.3 g, 0.0295 mole) was stirred and dissolved in a solution of methanol (100 liters), and the resulting mixture was heated at reflux temperature Four hours. The mixture was concentrated to dryness under vacuum, and then water (15.0 liters) and concentrated hydrochloric acid were added. The resulting yellow precipitate was collected by filtration, washed with water, and dried under vacuum. As a result, 5_ (φ_aerophenyl) 4- (2, 4_diaerophenyl) -1Η-1,2, 4-triazole · 3-carboxylic acid (1.0 g, yield 68 200530219 92%). Melting point: 141-144 ° C (decomposed). Part D ... Diisopropylethylamine (DIPEA) (1.5 ml, 2.1 moles), 0-benzotriπ--1-yl _] ^, N, N ', N'_tetramethyluronium 6 Fluorophosphate (HBTU) (1.66 g, 1.1 mol equivalent), and 1-aminopiperidine (0.44 g, 1.1 mol equivalent) were successively added to a 5- (4-chlorophenyl) small (2 , 4-difluorophenyl) -1H-1,2,4-triazole-3-carboxylic acid (1.48 g, 4.0 mmol) was stirred and dissolved in a solution of acetonitrile (20 ml). After stirring overnight, an aqueous solution of steel bicarbonate was added. The resulting mixture was extracted three times with dichloromethane. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and finally concentrated to dryness under vacuum, resulting in a crude oil (3.6 g). This oil was further purified using rapid chromatography (silica gel; ethyl acetate / petroleum ether (40-60 ° C) = 7/3 (ν / ν)). The result obtained by treating the purified substance with a solution of hydrochloric acid in ethanol (1M solution) was transmitted to 5_ (4_chlorophenyl) _1_ (2,4_dichlorophenyl) -N · (σ 比 症 -1-yl) · 1Η-1,2,4 · triazole-3-carboxamide hydrogenated gas (1.50 g, 77% yield). Melting point: 238-240 ° C (decomposed). ^ -NMR: (400 MHz, 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 2 Hz, 1H), 7.85-7.87 (m, 1Η), 7.91 (d, J = 8 Hz, 1Η), (NΗ cannot see). Example 2-18 was prepared according to a similar method: 2.5- (4-chlorophenyl) small (2,4-dichlorophenyl) -N_〇 than pyrrolidine small group WH-1, 2, 4-tri ♦ -3-Carbonamine hydrogen chloride. Melting point: 248-255 ° C (decomposed). 3 · 5_ (4_chlorophenyl) _N-cyclohexyl q_ (2, 4_dichlorophenyl) -1Η-1,2,4_ 2 mouth -3-carbon test donkey amine. Melting point: 186-188 ° C. 4 · N-tertiary_butoxy_5- (4-chlorophenyl) small (2, 4-dichlorophenyl) -1Η-1, 200530219 2, 4-triazole-3-carboxamide . Melting point: 150-152 ° C. 5. 5- (4-chlorophenyl) _1- (2, 4-dichlorophenyl) -N_ (n-pentyl) -1) 1,2,4-triazole · 3 · carbamidine. 1H-NMR: (400 MHz, CDC13): 0.92 (t, J = 7 Hz, 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 2 Hz, 2H), 7.42-7.50 (m, 4H), 7.54 (d, J = 2 Hertz, 1H). 6. 5- (4-chlorophenyl) small (2,4-dichlorophenyl) -N- (morpholin-4-yl) -1Η-1,2,4-trisamino-3-fluorenamine . Melting point: 184-186 ° C. 7. 1_ (4_chlorobenzyl) _5_ (2,4-Nizobenzobenjido-1 · yl) -1Η · 1,2,4-triazole_3_carbamidine hydrogen chloride. Melting point: 234-237 ° C (decomposed). 8. 1 · (4-chlorobenzyl) _5- (2,4-dilactide) · N- (σBiharan-1 -yl) -1H-1, 2, 4-triazole_3_ Carbamine hydrogen chloride. Melting point: 234-236 ° C (decomposed). 9. 1_ (4 · Chlorinyl) _N · ί ^ Hexyl-5- (2,4-Diτ random base) · 1Η-1,2,4_ Three-mouthed -3_carbamidine. 1H-NMR: (400 MHz, CDC13) 1.14-1.81 (m, 8Η), 2.02-2 · 10 (ιη, 2Η), 4.00-4.11 (m, 1Η), 7.08 (br d, J ~ 7 Hertz, 1Η), 7.26 (br d, J ~ 8 Hz, 2H), 7.34 (br d ,: [~ 8 Hertz, 2H), 7.40 (dd, J = 8 and 2 Hertz, 1H), 7.44-7.48 (m, 2H). 10. N-tertiary-butoxy-1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -1H-1, 2, 4-triazole-3_carbohydrazone amine. 1H-NMR (400 MHz, CDC13): 1.38 (m, 9H), 7.25 (br d, J ~ 8 Hz, 2H), 7.35 (br d, J ~ 8 Hz, 2H), 7.41 (dd, J = 8 and 2 Hz, 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- 200530219 triazole_3_carboxamide. 1H -NMR (400 MHz, CDC13) · 0.91 (t, J = 7 Hz, 3H), 1.35 · 1 · 41 (m, 4H), 1.60-1 · 70 (m, 2H), 3.48-3.56 (m, 2H), 7.21 (br t, J to 7 Hz, 1H), 7.26 (br d, J to 8 Hz, 2H), 7.34 (br d, J to 8 Hertz, 2H), 7.40 (dd, J = 8 and 2 Hertz, 1Η), 7.44_7 · 48 (m, 2H). 12 · 1 · (4_chlorophenyl) _5_ (2, 4-dichlorobenzene ) _N- (morpholin-4_yl) _1H_1,2,4-triye-3-carboxamide hydrogen chloride. Melting point: 224-226 ° C. 13 · 1 " " (2,4-a Ranfengji) _5- (π 比 路 -2-yl) -N-(-1 -yl) -1Η-1, 2, 4-triazole_3-carboxamide. Melting point: 191-193 ° C 14.5- (2,4-dichlorophenyl) · N- (piperidin-1-yl) _1_ (4- (trifluoromethyl) phenyl) -1Η1,2,4-triya-3 _Carbaminamine. Melting point: 159-161 T: 15 · 1 '-[5_ (2, 4-dichlorophenyl) -1- (4- (trifluorofluorenyl) phenyl) _1Η_1,2, 4. Triazol-3-yl) carbamidine] pyridine. Melting point: 155_156 ° C. 16. 1- (2,4 ·-"Lactidyl) yl) -5 · (υ 比比 -3-yl) -1H-1,2,4-tri-p--3-carboxamide. Melting point: 219 ° C. 17 · (4-chlorophenyl) -5_ (2,4-dichlorophenyl) · N · (5,5,5-trifluoropentyl) -1Η-1,2,4_triazole_ 3. Carbamine. 々-NMRGOO megahertz, CDC13) · 1.63-1.80 (m, 4H), 2.06-2.22 (m, 2H), 3.54 (q, J ~ 7 Hz, 2Η), 7.26 (m, 3Η) , 7.34 (br d, J to 8 Hz, 2H), 7.40 (dd, J = 8 and 2 Hz, 1H), 7.44 to 7.48 (m, 2H). 18. 1- (4-chlorophenyl) -5_ (2,4-dichlorophenyl) _N- (5-fluoropentyl) _1H_1,2,4-triazole-3-carboxamide. 1H-NMR (400 MHz, 0 (: 13): 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 to 8 Hz, 2H), 7.40 (dd, J = 8 and 2 Hz, 1H), 7.44 to 7.48 (m, 2H). Example 19 71 200530219 Part A: With reference to the examples, the preparation of 1- (chlorophenyl) -5- (2, 4 · dichlorophenyl) was performed as described in Part A to Part C. Purchase, 2, 4 In the tenth day, the base acids, among which 4-based aminomalonate hydrogen chloride, U dichlorobenzene, and 4-chloroaniline were used as starting materials. Wei: Removal. C gas 1H-NMR (400 > DMSO-d6): 7.36 (br d, J ~ 8 2H), 7.50 (br d, J ~ 8 Hz, 2H), 7 59 ⑽, ^ = 8 and 2 Hz ^, JH) '7.70 (d, Bu 2 Hertz, 1H), 7 75 (d, j = 8 Hertz, m 'oxygen protons are part of the water wave peak, the position is 3.4. It is enough to prepare K gas phenyl according to a similar method) _5_ (2, k gas phenyl) _ 2,4-trilateral acid, of which dimethylaminomalonate chloride chloride, 2, ^ dichlorobenzene T 醯 chloride and 4-chloroaniline are used as starting materials. ’Point: ⑻ · 188 t. Also NMR (400 MHz, DMs0_d6): 7 1 d, ^ ~ 8 Hz, 2H), 7.52 (brd, J ~ 8 Hz, 2H), 7.56 (d, J = 8r, Hz, 1H ), 7.65 (dd, J = 8 and 2 Hz, 1H), 7 88 (d, Bu 2 Hz, 1H), wind oxygen protons are part of water wave science, and their positions are at 3 5. … Part B: Add chlorammonium chloride (0.254 g, 2.00 mol) to a kind of chlorophenyl) -5- (2, 4_dichlorophenyl), delete, 2,4 _ 三座 _ 3-side acid (0.37 g, 1.00 mmol) is stirred and dissolved in dichloromethane (min.). The resulting mixture is concentrated and dried under vacuum, resulting in a rough i · (Chlorophenyl) _5_ (2, 4_dichlorobenzene-Jun-3-carbon shout. 1,2 > —c part ^ crude 敎 __ (chlorophenyl) _5_ (2,4_dichlorobenzene) Glyphosate was dissolved in tetrahydrofuran (THF) (10 liters) with 4-diazole-3-carbamyl chloride. To this was added 2, 3 · dihydrazine-1H | 2-ylamine (〇4 Gram, 300 millimolar), and then the resulting solution was forty-two hours at 25. The mixture was concentrated to dryness under vacuum, and the residue was purified by preparative Wei chromatography chromatography 72 200530219 As a result, pure 1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -N- (2, 3-dihydro_1-inden-2-yl) -1Η is produced. 1,2,4-triazole-3-carboxamide (393 mg, yield 81%). MS (ESI +) 485 · 6. H-NMRGOO megahertz, DMSO-d6): 3.06 (dd, J = 16 and 8 Hz, 2H), 3.21 (dd, J = 16 and 8 Hz 2H), 4.71-4.82 (m, 1H), 7.12_7 · 16 (m, 2H), 7.19-7.24 (m, 2H), 7.39 (brd, J ~ 8 Hz, 2H), 7.52 (brd, J ~ 8 Hz, 2H), 7.60 (dd, J = 8 and 2 Hz, 1H), 7.71 (d, J = 2 Hz, 1H), 7.79 (d, J = 8 Hz, 1H), 8.93 · 8.97 (m, 1H, NH).

Example 20-43 was prepared according to a similar method: 20 · 1- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) _N- (1-ethylcyclohexyl) -1H-1,2 , 4-Tris-3-carboxamide. MS (ESI +) 473.3. 21. l- (4-Rhamnyl) -5- (2,4-dichlorophenyl) _N- (2 • methylcyclohexyl) -1Η · 1,2,4-three-mouthed_3_carbon 醯Lamine. MS (ESI +) 465.5 〇22 · 1 · (4-Geosyl) _5- (2,4-dioxophenyl) _N- (4-methylcyclohexyl) -1Η-1,2,4-triazole -3_ Carbamide. MS (ESI +) 465.5.

23.1- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -N-cyclooctyl_1Η · 1,2,4-triazole-3-carboxamide. MS (ESI +) 477.3. 24 · 1- (4-chlorophenyl) _5- (2, 4-dichlorophenyl) _N- (cycloazahexatriene small group) -1Η-1,2,4 · triazole-3-carbohydrazone Lamine. MS (ESI +) 466.4. 25 · 1- (4-chlorophenyl) -5- (2,4-dichlorophenyl) · N-cycloheptyl-1H-1,2,4-triazole-3-carboxamide. MS (ESI +) 465.5. 26 · N-tertiary-butyl · 1 · (4 · chlorophenyl) -5- (2,4-dichlorophenyl) _1H_1,2,4-triazole_3_carbamidine. MS (ESI +) 425.4. 27 · Η4 · chlorophenyl) _5_ (2,4_dichlorophenyl) -N_ (1,1_diethylpropyl_2-alkyn-1-yl) _1H_1,2,4 · triazole Lamine. MS (ESI +) 461.5. 28 · 1_ (4_chlorophenyl) _5_ (2,4_dichlorophenyl) (2,2,2-trifluoroethyl 73 200530219 group) -1Η-1,2,4-triazole-3- Carbamine. MS (ESI +) 451.3. 29. 1- (4-Chlorophenyl) -5_ (2,4-dichlorophenyl) -N_ (Xiebibicyclo [2.2.1] heptyl) -1Η1,2,4, triazole-3 -Carbamine. MS (ESI +) 461.5.

30. 1- (4 · chlorophenyl) -5- (2,4-dichlorophenyl) _N- (4- (2-propyl) piperazine · 1-yl) -1Η-1, 2, 4 _Triazole_3_carboxamide. MS (ESI +) 480.3. iH-NMRGOO megahertz, DMSO-d6): 1.00 (d, J = 7 Hz, 6H), 2.46_2.56 (m, 4H), 2.72 (septet, J = 7 Hz, 1H), 3. · 66 · 3 · 74 (m, 4H), 7.36 (br d, J = 8 Hz, 2H), 7.51 (br d, J = 8 Hz, 2H), 7.59 (dd, J = 8 and 2 Hz, 1H), 7.72 (d, J = 2 Hz, 1H), 7.75 (d, J = 8 Hz, 1H). 31. 1- (4-Chlorophenyl) -5- (2, 4-dichlorophenyl) -N- (hexahydrocyclopentane [c] alpha ratio_2 (1H) _yl) -1Η- 1,2,4-triazole-3-carboxamide. MS (ESI +) 476.4. 32. 1- (4-Gasyl) -5- (2,4-dimuryl) -N-pentyl_1H_1,2,4-diazole-3-carboxamide. MS (ESI +) 435.5. 33. 1- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -N- (2,2-dimethylpropyl) -1Η-1,2,4-triazole- 3. Carbamine. MS (ESI +) 439.6.

34. 1-(4-chlorophenyl) -5_ (2,4-dichlorophenyl) -N- (3- (difluoromethyl) phenyl) -1Η-1,2,4 · triazole- 3-carboxamide. MS (ESI +) 511.7. 35. l,-[l- (4-chlorophenyl) _5- (2, 4-dichlorophenyl) _1H_1,2,4_triazol-3-yl] carbohydrazine] _1,4'-two Pyridine. MS (ESI +) 520.5. 36. 1- (4-muryl) -N_ (4-chlorobenzyl) -5- (2,5-dilactyl) -N_methyl-1H-1, 2, 4, 3 3. Carbamine. MS (ESI +) 491.4. 37. 1- (4-chlorophenyl) _5_ (2,5-dichlorophenyl) -N- (l-acetylenecyclohexyl) -1Η-1,2,4 · triazole-3-carboxamide . MS (ESI +) 473.4. 38. 1- (4-chlorophenyl) -5- (2,5-dichlorophenyl) -N- (2-methylcyclohexyl 74 200530219) -1Η1,2,4-triazole- 3-carboxamide. MS (ESI +) 465.5. 39. 1- (4-chlorophenyl) -5- (2, 5-dichlorophenyl) -N- (4-methylcyclohexyl) -1Η · 1,2,4-triazole_3 · carbon Lamine. MS (ESI +) 465.6 0-40. 1- (4-chlorophenyl) -5_ (2,5-dichlorophenyl) N_cyclooctyl-1H-1,2,4, triazole-3- Carbamine. MS (ESI +) 477.3. 41. 1- (4-chlorophenyl) -5- (2,5-dichlorophenyl) _N · cycloheptyl_1H_1,2,4-triazole-3-carboxamide. MS (ESI +) 465.6.

42. 1- (4-chlorophenyl) -5- (2, 5-dichlorophenyl) -N-l-pentyl-1H-1,2,4-diazole_3-carboxamide. MS (ESI +) 435.5. 43. 1_ (4_chlorophenyl) -5- (2,5-dioxanyl) -N- (2,2-dimethylpropyl) _1Η · 1,2,4-triazole-3-carbon Lamine. MS (ESI +) 439.6. The following table states several compounds of the invention and their drugs obtained from the above experiments.

Physical test results: Human cannabinoid hepta 61 receptor in vitro affinity in vitro antagonism Example pKi value pA2 value 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 75

Claims (1)

200530219 X. Scope of patent application: 1. A compound having the general formula (I), (II), (in), (IV) and / or (V) structure and having CBr receptor activity, a drug of its kind , A tautomer thereof, or a salt thereof, for use in the manufacture of medicine to treat and / or prevent disorders related to the CBi receptor in young patients, and / or for treatment and / Or prevent obesity caused by drugs in young and adolescent patients. 2. Use of a compound having CBr receptor activity according to item 1 of the scope of the patent application, wherein the compound having CBr receptor activity is selected from 4 having the structure of general formula (I) and / or (III) , 5_Diargon_111 · ^ Specific derivatives of pr, derivatives of 1H-imide having the structure of general formula (II), derivatives with mouth edges of the structure of general formula (IV), and / or Derivatives of m-1,2,4_triazole carbohydrazones of the general formula (V) This group is characterized by: a) Compounds with the general structure ⑴ are K⑴ o = s = o where- R and Ri independently of each other represent phenyl, p-thienyl, or orbipyridyl. These functional groups may be one, two, three, or four may be the same or different. , Derived from (containing 1 to 3 carbon atoms) alkyl or alkoxy, meridian, halide, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitrate Radical, ammonia, radical, mono- or dialkyl (containing 1 to 2 carbon atoms)-amino, mono- or dialkyl (containing 1 to 2 carbon atoms)-amido, (containing 1 to 3 carbons 76 200530219 Atom) alkyl-sulfonyl Dimethylsulfonylamino, alkoxy-carbamyl containing 1 to 3 carbon atoms, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl ( sulfamoyl) and ethanoyl are substituted by substituent Y in this group, or R and / or Ri represent naphthyl, -R2 represents hydrogen atom, hydroxyl group, (containing 1 to 3 carbon atoms) alkoxy group, acetamidine Oxy or propionyloxy, R3 represents a hydrogen atom, or a branched or unbranched alkyl group containing 1 to 8 carbon atoms, or a cycloalkyl group containing 3 to 7 carbon atoms , Its alkyl or cycloalkyl group may be substituted by a hydroxyl group ' —R4 represents a bifurcated or unbranched heteroalkyl group containing 2 to 10 carbon atoms, a heterocyclic alkyl group containing non-aromatic hydrocarbons containing 3 to 8 carbon atoms, or a heterocyclic group containing 4 to 10 carbon atoms A non-aromatic hydrocarbon heterocycloalkyl-alkyl group of one carbon atom whose functional group contains one or more heteroatoms selected from the group (oxygen, nitrogen, sulfur), or a -S02- group, which contains 2 to A forked or unforked heteroalkyl group of 10 carbon atoms, a heterocyclic alkyl group of a non-aromatic hydrocarbon containing 3 to 8 carbon atoms, or a non-aromatic hydrocarbon heteroalkyl group of 4 to 10 carbon atoms · The alkyl group may be substituted by a keto group, a trifluoromethyl group, an alkyl group containing 1 to 3 carbon atoms, a carboxyl group, an amino group, a monosulphenylamino group, or a dialkylamino group or a fluorine atom; or R4 represents an amino group, Hydroxy, phenoxy, or tolyloxy; or R4 represents an alkoxy group containing 1 to 8 carbon atoms, represents a feminine group containing 3 to 8 carbon atoms, 'represents a cyclic group containing 5 to 8 carbon atoms Group, or a cycloalkylene group containing 6 to 9 carbon atoms, its functional group contains a sulfur, nitrogen or oxygen atom, a keto group or -S02- group, which The alkoxy, alkenyl, and cycloalkylene groups may be substituted with a hydroxyl group, a trifluoromethyl group, an amino group, a monoalkylamino group or a dialkylamino group, or a fluorine atom; or R4 represents a group containing 2 to 5 carbon atoms Alkyl group, the alkyl group of which contains a fluorine atom; or R4 represents a π-pyridyl group, a benzyl group, a σ-methyl group, a phenethyl group, or a pyrimyl group; or R4 represents a substituted benzene Group, benzene 77 200530219 methyl group, σbityl group, psynyl group, αbityl methyl group or phenethyl group, in which the aromatic tobacco ring is replaced by one, two or three substituents fluorene, Wherein Υ has the meaning as mentioned above; or when R3 is a hydrogen atom or a methyl group, R4 may represent a functional group NR6R7, wherein one of R6 and R7 is the same or different, and represents that it contains 2 to 4 carbon atoms The alkyl group represents a trifluoroalkyl group containing 2 to 4 carbon atoms, or R6 represents a methyl group, but the prerequisite is that R7 represents an alkyl group containing 2 to 4 carbon atoms, or R6 and R7- Together with the nitrogen atom to which it is attached-to form a saturated or unsaturated heterocyclic group containing 4 to 8 ring atoms, wherein the heterocyclic group may Contains an oxygen atom or a sulfur atom, or a keto group or a -S02- group, or another nitrogen atom, in which a saturated or unsaturated heterocyclic group may be containing 1 to 4 carbon atoms. Substituted with alkyl, or R3 and R4 together with the nitrogen atom to which they are attached form a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing 4 to 10 ring atoms, wherein the heterocyclic group may contain one or more selected from ( (Oxygen, nitrogen, sulfur) The atom of this group is either a keto group or -S02- group, where the functional group can be an alkyl group, a hydroalkyl group, a phenyl group, and a plate containing 1 to 4 carbon atoms. Base, amino, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylamino, dialkylamino, aminoalkyl, cycloaziridinyl, rtbalkyl, tripodyl, or It is substituted by hexahydro-1H-cycloazepine, one R5 represents benzyl, phenyl, pyrimyl or α-pyridylmethyl, which can be substituted by one, two, three or four Substituted by Υ, where Υ has the meaning as mentioned above, which may be the same or different; or R5 represents a branched or undivided dry group containing 1 to 8 carbon atoms, and contains 3 A radical of 8 to 8 carbon atoms' represents a cycloalkyl radical containing 3 to 10 carbon atoms, and a radical of 5 to 4 atomic radicals represents a radical containing There are 6 to 10 diatomic dry bases, 78 200530219, or a cycloalkenyl group containing 5 to 8 carbon atoms; or R5 represents a naphthyl group, b) a compound having the structure of the general formula (Π) is among them —R represents a phenyl group, a pyrimyl group, a 2-rtt pyridyl group, a 3-α-pyridyl group, a 4 < pyridyl group, an orallydronyl group, a u-based group, a pyridazinyl group, or an orallyn group ( triazinyl), the functional group of which can be one, two, three, or four can be the same or different, derived from an alkyl or alkoxy group containing 1 to 3 carbon atoms, a hydroxyl group, a halide, Trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono or dialkyl (containing 1 to 2 carbon atoms)-amino, mono or dialkyl (containing 1 to 2 carbon atoms)-fluorenylamino, (containing 1 to 3 carbon atoms)-alkoxycarbamyl, carboxyl, cyano, carbamoyl, and ethynyl substituted by the substituent Y of this group, or R represents naphthyl, but the prerequisite is that when R is a 4-methylpyridyl group, R4 represents a self atom or a cyano group, a carbamoyl group, a methylamino group, an ethylfluorenyl group, and a trifluoroacetamidine Base, fluoroethenyl, propionyl, phytonic acid, methylamine, methylsulfanyl, or a branched or unbranched alkyl group containing 1 to 4 carbon atoms , An alkyl group containing 1 to 4 carbon atoms It is substituted by one to three fluorine atoms or by one atom such as bromine, chlorine, iodine, cyano or hydroxy. One Ri represents the main group or the bisphenol group. Its functional group can be one to four and can be the same. Or it is replaced by a different substituent Y, wherein Y has the meaning as indicated in 79 200530219; or Gen represents pyrimidinyl, ubiazinyl, pyridazine, or triazine, and its functional group can be one to two May be replaced by the same or different substituent Y; or Ri represents a heterocyclic ring of a pentacyclic aromatic hydrocarbon, which contains one or two heteroatoms derived from the group (nitrogen, oxygen, sulfur), where Heteroatoms may be the same or different, and the heterocyclic ring of its pentacyclic aromatic hydrocarbon may be substituted by one or two substituents Y which may be the same or different; or Gen represents naphthyl, and R2 represents a hydrogen atom, Represents a branched or unbranched alkyl group containing 1 to 8 carbon atoms, represents a cycloalkyl group containing 3 to 8 carbon atoms, represents a bromo group containing 3 to 8 carbon atoms, and represents 5 to 8 A carbon atom of a feminine group, in which the functional group contains a sulfur, oxygen or nitrogen atom, -R3 represents a branched or unbranched alkyl group containing 2 to 8 carbon atoms, represents a alkoxy group containing 1 to 8 carbon atoms, represents a cycloalkyl group containing 5 to 8 carbon atoms, represents containing A cycloalkyl group of 3 to 8 carbon atoms represents a bicyclic alkyl group containing 5 to 10 carbon atoms, a tricyclic alkyl group containing 6 to 10 carbon atoms, and an alkenyl group containing 3 to 8 broken atoms , Represents a cycloalkenyl group containing 5 to 8 carbon atoms, where the functional group can optionally contain one or two heteroatoms derived from the group (nitrogen, oxygen, sulfur) and its functional group can be a few groups, Either one or two alkyl groups containing one to three carbon atoms, or one to three fluorine atoms being substituted; or R3 represents a benzyl or phenethyl group, where the aromatic ring can be one to five Can be the same or different 'derived from a thiol or thiol group containing 1 to 3 carbon atoms, a few bases, an autogen, a difluoromethyl group, a trifluoromethylthio group, a trifluoromethoxy group , Nitro, amino, mono or dialkyl (containing 1 to 2 carbon atoms) _amino, mono or dialkyl (containing 1 to 2 carbon atoms) -fluorenylamino, ( (Working to 3 carbon atoms) alkyl_sulfofluorenyl group, dimethylsulfonamido group, dry oxy-carbofluorenyl group containing fluorene to 3 carbon atoms, cumyl group, trifluoromethyl fluorenyl group, 80 200530219 Cyanocarbamoyl, ammonium and ethyl groups The substituents in this group are ^^ 'or & represents a phenyl group or this pyridyl group, the functional group of which is 12 to 4 Substituted by a substituent Z, where Z has as above t Ϊ 'or & represents a σ ratio lake, or H 3 represents a benzene ^ ^ ^ The prerequisite is that R4 represents a halogen atom or a cyanide. i Carboxyl, formamyl, ethenyl, trifluoroethenyl, fluoroethenyl, propionyl, sulfamoyl, methanesulfonyl, methylsulfamoyl or contain 1 to An alkyl group of 4 carbon atoms, which contains from 1 to 4 carbon atoms, and the alkyl group of the child may be substituted by one to three fluorine atoms or by one of: a gas, iodine and other atoms, a cyano group or a hydroxyl group; or R3, Table 1 functional group NRSR6, but the prerequisite is that R2 represents a fluorene atom or a calcined group, where I and Re are the same or different, and represents a branch containing 1 to 4 carbon atoms Or an unbranched alkyl group, or Y5 and R6_ together with the nitrogen atom to which they are attached-to form a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing 4 to 10 ring atoms, The heterocyclic group may contain one or two heteroatoms which may be the same or different and originate from (nitrogen, oxygen, sulfur). The heterocyclic group may be an alkyl group containing 1 to 3 carbon atoms or Is substituted by a hydroxyl group, or & and Rs_ together with the nitrogen atom to which they are attached-form a saturated or unsaturated heterocyclic group containing 4 / to 10 ring atoms, wherein the heterocyclic group may contain one or Rain can be the same or different, derived from (nitrogen, oxygen, sulfur) of the group of heterogenes, wherein the heterocyclic group can be replaced by an alkyl group containing 1 to 3 carbon atoms or a hydroxyl group, represents A hydrogen or halogen atom, or a cyano group, a carbamoyl group, a carbamoyl group, a stilbyl group, a trifluoroethylsulfonyl group, a fluoroethylsulfonyl group, a propylsulfonyl group, a fluorenylsulfonyl group, Methylsulfamoyl is a bifurcated or unbranched alkyl group containing 1 to 4 carbon atoms, which contains 1 to 4 carbon atoms. The group can be replaced by one or two fluorine atoms or by a single atom, 81 200530219 gas, iodine and other atoms, cyano or hydroxyl. C) The compound having the structure of general formula (III) is (Ilia) (Illb) where 1, —R and Gen represent phenyl, pyrimyl or fluorenyl unrelated to each other, and these functional groups may be one, two, or three may be the same Or different, derived from a radical containing 1 to 3 carbon atoms or an alkoxy group, a hydroxyl group, an autogen, a trifluoromethyl group, a trifluoromethylthio group, a trifluoromethoxy group, a nitro group, Amino, mono or dialkyl (containing 1 to 2 carbon atoms)-amino, mono or dialkyl (containing 1 to 2 broken atoms) 醯 amino, (containing 1 to 3 carbon atoms) alkyl- Fluorenyl, dimethylcontinylamino, alkoxy-carbofluorenyl containing 1 to 3 carbon atoms, carboxyl, dimurinomethyl, chloro, methylamino, methylamino And ethanoyl are substituted by substituent Y in this group, or R and / or R1 represents naphthyl, -R2 represents hydrogen atom, hydroxyl group, alkoxy group containing 1 to 3 carbon atoms, ethoxyl group, or Propionyloxy represents a hydrogen atom, or a bifurcated, unbranched alkyl group containing 1 to 8 carbon atoms, or a morning ^ 〇 group containing 3 to 7 carbon atoms, which is a very strong group. Or the cycloalkyl group can be replaced by Substituted by a group, represents a hydrogen atom, or represents a branch containing 丨 to 8 carbon atoms = or an unbranched alkyl group, represents a cyclofluorenyl group containing 3 to 8 carbon atoms, represents a group containing 2 to A heterocarbon group of 10 carbon atoms represents a 82 200530219 non-aromatic hydrocarbon heterocycloalkyl group containing 3 to 8 carbon atoms, or a non-aromatic hydrocarbon heterocycloalkyl group containing 4 to 10 carbon atoms. Alkenyl 'whose functional group contains one or more heteroatoms selected from the group (oxygen, nitrogen, sulfur). Its functional group can be keto, trifluoromethyl, alkyl containing 1 to 3. carbon atoms , Hydroxy, amino, monoalkylamino or dialkylamino, or a fluorine atom; or R4 represents an amino, mesityl, phenoxy, or tolyloxy; or R4 represents 1 to 8 carbons A branched or unbranched alkoxy group represents an alkenyl group containing 3 to 8 carbon atoms, a cycloalkenyl group containing 5 to 8 carbon atoms, or an alkenyl group containing 6 to 9 carbon atoms Cycloalkyl, its functional group can contain a sulfur, nitrogen or oxygen atom, a keto group or a ^ group, which contains 1 to 8 carbons Alkoxy, fluorenyl containing 3 to 8 carbon atoms, cycloalkenyl containing 5 to 8 carbon atoms, or cycloalkenyl containing 6 to 9 carbon atoms may be hydroxyl, trifluoromethyl , Amino, monoalkylamino or dialkylamino, or a fluorine atom; or R4 represents phenyl, benzyl, σ-pyridyl, pyrimyl, α-pyridylmethyl, or phenethyl In which the aromatic hydrocarbon ring is replaced by one, two or three substituents Υ, wherein Υ has the meaning as mentioned above; or R4 represents a functional group NR8 R9, but the prerequisite is that when I represents & amp A hydrogen atom or a methyl group, and R8 and R9 are the same or different, and represent an alkyl group containing 1 to 4 carbon atoms, or a trifluoroalkyl group containing 2 to 4 carbon atoms, Or Rs and Ry together with the nitrogen atom to which they are attached-form a saturated or unsaturated heterocyclic group containing 4 to 8 ring atoms, wherein the heterocyclic group may contain an oxygen or sulfur atom, or a keto group , Or a -SOr · group, or another 'other nitrogen atom, in which a saturated or unsaturated heterocyclic group may be Is replaced by an alkyl group containing 1 to 4 carbon atoms; or R3 and R4- together with the nitrogen atom to which they are attached-form a saturated or 83 200530219 unsaturated monomer containing 4 to 10 rings Ring or bicyclic heterocyclic group, wherein the heterocyclic group may contain one or more atoms (nitrogen, oxygen, sulfur) from the group, or a _ group, or a -802_ group, where the functional group Can be mono (containing 1 to 4 carbon atoms) alkyl, hydroxide alkyl, phenyl, methylamine, amino, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylamino, Substituted by dialkylamino, aminoalkyl, cycloaziridinyl, 0-pyrrolidinyl, pyridinyl, or hexahydro-1H-cycloazahexatrienyl '-R5 and R6 represent one independently of each other A hydrogen atom, either representing an alkyl or alkenyl group containing 1 to 8 carbon atoms, or an unbranched group, where the functional group may contain one or more groups derived from (nitrogen, oxygen, sulfur) A heteroatom is either a keto group or a 02-group, where the functional group may be substituted by a hydroxyl or amino group; or r5 and R6 are This independently represents a cycloalkyl group containing 3 to 8 carbon atoms, or a cycloalkenyl group (containing 3 to 8 carbon atoms), which may contain one or more sources (nitrogen, oxygen, Sulfur) ring heteroatom in this group, or a keto group, or a -S02- group, in which the functional group can be a hydroxyl group, (containing 1 to 3 carbon atoms) alkyl, -S02- group, ketone Group, amino, monoalkylamino (containing 1 to 3 carbon atoms) or dialkylamino (containing 1 to 3 carbon atoms); or Rs represents a naphthyl group, or represents a phenyl group, The phenyl group may be substituted by one, two or three substituents Y, in which Y has the meaning as mentioned above, but the prerequisite is that R6 represents a hydrogen atom, or fluorene represents one (containing 1 to 5 Carbon atoms) of a bifurcated or unbranched alkyl group, its alkyl group may contain one or more heteroatoms derived from the group (nitrogen, oxygen, sulfur), or a -S02- group, and the alkyl group May be substituted by a keto group or an amino group; or ^ and Rr together with the nitrogen atom to which they are attached-to form a monocyclic, di or tricyclic alkyl or Alkenyl, which can contain ring heteroatoms, keto groups, or -S02_ groups derived from (nitrogen, 200530219 oxygen, sulfur), of which monocyclic, bicyclic, or tricyclic alkyl groups or Women's bases can be used as bases, (containing 1 to 3 carbon atoms) alkyl, (40-yl, keto, gas), (containing 1 to 3 carbon atoms) early-burning carbon or ( (Containing 1 to 3 carbon atoms) a dialkylamino group, a σ-pyrrolidinyl group or a pyridyl group, in which a monocyclic, bicyclic or tricyclic alkyl or alkenyl group may contain a chained benzene Group, in which the chained phenyl group may be substituted by one or two substituents Υ, in which Υ has the meaning as described above, ―know represents a branched or unbranched group containing 1 to 3 carbon atoms D), the compound having the structure of general formula (IV) is Where -R represents a hydrogen atom or a substituent X, which is derived from (containing 5 Φ 1 to 3 carbon atoms) or an unbranched alkyl group, or an oxy group, a hydroxyl group, or a fluorene group. Element, trifluoromethyl, tris-methylthio, dimethoxy, nitro, amino, mono- or dialkyl (containing 1 or 2 broken atoms)-amino, mono- or dialkyl (containing 1 to 2 carbon atoms)-total gas radicals: bifurcated or unbranched (containing 1 to 3 interfering atoms) alkoxy group-phenol group, trifluoromethylsulfonyl group, amino fluorenyl group, Forked or unbranched (groups with 1 to 3 carbon atoms-sulfanyl, carboxyl, cyano, carbamoyl, branched or unbranched (containing 1 to 3 carbon atoms乂 ^ dialkylaminosulfonyl, bifurcated or unbranched (containing 1 to 3 atoms) monoalkylaminosulfonyl or ethylfluorenyl, 85 200530219-R1 represents a hydrogen atom, or Represents one to four substituents χ, where X has the meaning previously referred to, and you—R2 represents phenyl, disconyl, u-pyridyl, or pyrimidinyl, where the official criminal group can be substituted by one to four Replaced by X, where χ has What is meant by the text; either r2 represents naphthyl, B, -¾ represents a hydrogen atom, or a ^-or unbranched alkyl or cycloalkyl-alkyl group containing 1 to 10 carbon atoms, Or represents / phenyl, benzyl, or phenethyl, where the aromatic hydrocarbon ring can be / to five can be the same or different, derived from containing 1 to 3 carbon atoms $ forked or unforked Alkyl or alkoxy, hydroxy, halogen, trimethyl, trifluoromethylthio, trifluorofoxy, nitro, amino, mono or dialkyl (containing 1 to 2 carbon atoms ) -Amino, mono- or bis-pyridyl (containing 1 to 2 carbon atoms)-fluorenylamino, branched or unbranched (containing 1 to 3 carbon atoms) alkyl-sulfonyl, dimethylsulfonyl Sulfonyl, bifurcated or unbranched alkoxy-carbonates containing 1 to 3 carbon atoms, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, amidoacid or Acetyl; either R3 represents a pyrimidinyl or a farinyl group '— IU represents a branched or unbranched alkyl group containing 1 to 10 carbon atoms or a cycloalkyl-alkyl group, containing 1 Carbonyl oxy, represents A cycloalkyl group containing 3 to 8 carbon atoms represents a bicycloalkyl group containing 5 to 10 carbon atoms, a tricycloalkyl group containing 6 to 10 carbon atoms, and a cycloalkyl group containing 3 to 10 carbon atoms. A bifurcated or unbranched alkenyl group represents a cycloalkenyl group containing 5 to 8 carbon atoms, its functional group contains one or more heteroatoms selected from the group (oxygen, nitrogen, sulfur), and its functional group It may be substituted by one hydroxyl group, one to three methyl groups, one ethyl group, or one to three fluorine atoms; or R4 represents a benzyl group, a benzyl group, or a phenethyl group, wherein the aromatic hydrocarbon ring may be one to five Substituted by Z, in which Z has the meaning as mentioned above; or R4 represents a σ-pyridyl or pyrimyl, or R4 represents 86 200530219 a functional group nr5r6, in which R5 and R6 and the like The linked nitrogen atoms together form a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing 4 to 10 ring atoms, wherein the heterocyclic group may contain one or more members selected from (oxygen, nitrogen, sulfur ) Heteroatoms of this group, and the heterocyclyl may be branched by one (containing 1 to 3 carbon atoms) or Bifurcated alkyl, hydroxy or trifluoromethyl or a fluorine atom is substituted, or-R3 and R4 together with the nitrogen atom to which they are attached form a saturated or unsaturated group containing 4 to 10 ring atoms A monocyclic or bicyclic heterocyclic group, wherein the heterocyclic group may contain one or more heteroatoms selected from the group (oxy, nitrogen, sulfur), and the heterocyclic group may be one (containing 1 to 3 (A carbon atom) is substituted by a branched or unbranched alkyl group, a hydroxyl group or a trifluoromethyl group or a fluorine atom, e) the compound having the structure of the general formula (V) is Among them, RARi represents phenyl, naphthyl, pyrimyl, orthopyridyl, oxidyl, σ ratio of 1: 7, Qinyl, sulphone, or trisyl, independently of each other. The functional groups can be One to four can be the same or different, derived from a branched or unbranched alkyl group (containing 1 to 3 carbon atoms) or an alkoxy group, hydroxy group, functional group, trifluoromethyl group, trifluoro group Methylthio, trifluoromethoxy, nitro, amino, mono or dialkyl (containing 1 to 2 carbon atoms)-amino, mono or dialkyl (containing 1 to 2 carbon atoms)-醯Amino group, alkoxy-carbofluorenyl group containing 1 to 87 200530219 3 carbon atoms, trifluorof-carboxylic acid group, amino fluorenyl group, (containing 1 to 3 carbon atoms) -alkylsulfonic acid group, Benzyl, cyano, carbamoyl, (containing 1 to 3 carbon atoms) _ disulfonyl ^ aminosulfonyl, (containing 1 to 3 carbon atoms) _ monocarbylamino sulfonyl and ethyl Substituted by substituent X in this group -R2 represents a hydrogen atom, or a branched or unbranched alkyl group containing 1 to 8 ytterbium atoms, or an alkyl group-alkyl group containing 1 to 8 carbon atoms, or Phenyl, benzyl, or phenethyl 'can be substituted by one to four substituents X, where X has the meaning as mentioned above; or R2 represents a 17-amino group or 疋 1 " Um, —R3 represents a branched or unbranched alkyl group containing 1 to 8 carbon atoms, represents an alkoxy group containing 1 to 8 carbon atoms, represents a cycloalkyl group containing 3 to 8 carbon atoms, and represents (containing 5 (From 10 to 10 carbon atoms) bicyclic alkyl group (representing 6 to 10 carbon atoms) trisorcinyl group (representing 3 to 8 carbon atoms) alkenyl group (representing 5 to 8 carbon atoms) Atomic) cycloalkenyl, whose functional group may contain one or more heteroatoms selected from the group / (oxygen, nitrogen, sulfur), whose functional group may be a light group, an ethylene group, or one to three fluorines Substituted by an atom; or R3 represents a phenyl group, a phenylmethyl group or a phenethyl group, and the aromatic hydrocarbon ring thereof is substituted by one to four substituents X, wherein X has the meaning as mentioned above; or R3 represents a The aryl group, pyrimidine group, α ratio # group, pyridazinyl group, triazinyl group, or sulfonyl group, and the heteroaromatic hydrocarbon ring thereof may be substituted by fluorene to two substituents X, wherein X has the same meaning as mentioned above. Meaning; or Rs represents a functional group NR4R5, in which ^^ and rule 5 together with the nitrogen atom to which they form a saturated or unsaturated containing 4 to 1 A monocyclic or bicyclic heterocyclic group of 0 ring atoms, wherein the heterocyclic group contains one or two heteroatoms selected from the group of nitrogen, oxygen, sulfur, and the same or different, and wherein the heterocyclic group Can be replaced by a bifurcated or unsubstituted radical containing 1 几 88 200530219 3 carbon atoms, a few radicals or a trimethyl radical or a fluorine atom, or the nitrogen to which R2 and Rs are attached The atoms together form a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing 4 to 10 ring atoms, wherein the heterocyclic group contains one or two of which can be the same or different. Choose from mouse, milk Or a sulfur atom of this group 'and in which the heterocyclic group can be two or one or three carbon atoms containing 1 to 3 carbon atoms, several groups, triphenyl, or trifluoromethyl or one Replaced by a fluorine atom. 3. Use of a compound having CBr receptor activity, one of its pre-drugs, tautomers, or salts according to any one of claims 1 to 2 of the scope of the patent application, wherein Manufacture of medicines for the treatment and / or prevention of psychiatric disorders such as mental illness, anxiety, depression, lack of attention, memory impairment, cognitive impairment, eating disorders, obesity, health Addiction, hunger, drug dependence, and neurological diseases such as neurodegeneration, dementia, abnormal muscle tone, muscle spasms, tremors, epilepsy, multiple sclerosis, traumatic brain injury, 'Stroke, Parkinson's Symptoms of Alzheimer's disease, Alzheimer's disease, epilepsy, Huntington's disease, group disease, cerebral ischemia, cerebral stroke, trauma to the skull and brain, stroke, spinal cord injury, neuritis , Lai sclerosis, viral encephalitis, conditions related to demyelination, and use as a treatment for pain, including pain caused by the U nerve, and other central nervous system diseases related to cannabinoid nerve conduction Including the treatment of septic shock, glaucoma, cancer, disease, sugar ^ "District spit" nausea, asthma, respiratory disease, gastrointestinal tract disorders ulcers, diarrhea and cardiovascular disorders. 4. i According to any one of the items 1 to 3 of the scope, it has two or more compounds, one of its predecessor drugs, tautomers. For the use of one compound, a CBr receptor antagonist compound is preferred. Or wait for the previous drugs, tautomers or other aspects, in its' clever use is to manufacture-turnaround, which is used to treat and / or obesity in children with 89 200530219 in childhood, and / or Drug-induced obesity in juvenile and adolescent patients. 5. Use a compound with CBr receptor activity as defined in item 2 of the scope of the patent application, a predecessor drug, tautomer or salt, prefer to use a CBr receptor antagonist compound or a Such as previous drugs, tautomers or salts, combined with at least one compound that inhibits lipase activity for use in the manufacture of a drug for the treatment and / or prevention of obesity in adolescent or juvenile patients, and / Or drug-induced obesity in juvenile and adolescent patients. 6. Utilizing the use of a compound having CBi-receptor activity as described in item 5 of the scope of the patent application, in which the compound having CBr-receptor activity or one of its predecessor drugs, tautomers, or Salts, preferably the CBi-receptor compound or one of its predecessor drugs, a tautomer, or a salt and at least one compound that inhibits lipase activity, which is selected from the group consisting of inhibitors of lipase activity polymerization Objects, orlistat, panclieins, ATL-962 and lipstatin. 7. A pharmaceutical composition containing at least one compound having the general formula (〗), (〖〗), (m), (IV) and / or (V) structure and having CBi-receptor activity, or Immediately prior drugs, tautomers or salts are effective ingredients, which are suitable for treating and / or preventing disorders related to CBi receptors in young patients, and / or for treating and / or preventing Drug-induced obesity in juvenile and adolescent patients. 8. The pharmaceutical composition according to item 7 of the scope of the patent application, wherein the compound having CBl · receptor activity is selected from 4, 5-dihydro_1H having the general structure ⑴ and / or ⑽ ^ structure _ Derivatives of pyrazole, 1H with the structure of general formula (π) _ Derivatives of imidazole, derivatives of pyrazole with the structure of general formula (IV) and / or structures with the general formula (V) "111_1, 2, 4 -Derivatives of sanjun-3-ammonium carbonate This group, each of which is as defined in item 丨 or item 2 of the scope of patent application. 9. According to the pharmaceutical group described in any one of items 7 to 8 of the patent application scope 200530219 ίϊ ^ > (ΐΐ) ^ (ΐπ) ^ (ΐν ^ /, κν) -Receptor active compound, a predecessor drug, a tautomer or a salt thereof, which is present in an amount, which has curative effect and is suitable for the treatment and / or prevention of pediatric diseases. , Such as mental illness, anxiety, anxiety, anxiety, memory deficits, cognitive impairment, appetite disorders, obesity, addiction, thirst, drug dependence, academic diseases, such as neurodegenerative disease, dementia, Normal muscle tone, muscle cramps, tremors, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, handyman's disease, Draught's syndrome, Cerebral ischemia, cerebral stroke, ward and brain trauma, stroke, sacral injury, neuritis, spot sclerosis, viral encephalitis, conditions related to demyelination, and use as a pediatrician Aspects to treat pain Diseases, including painful diseases with nerves as the etiology, and other central nervous system related to cannabinoid nerve conduction, pediatric shooting, hemorrhagic shock, blue silk, vomiting, heart palpitations, asthma, respiratory disorders, gastrointestinal disorders, Diarrhea and cardiovascular diseases are in young patients who need such treatment. 10. The pharmaceutical composition according to any one of items 7 to 9 of the scope of the patent application, wherein at least one of them has the general formula (1), (11), (111), (IV) & ^ 1 ( V) A compound with a structure and CBl-receptor activity, one of its predecessor drugs, tautomers, or salts, preferring the CBr receptor antagonist compound or one of its predecessor drugs, intermutation Structures or salts that exist as a form of I, which is effective and suitable for the treatment and / or prevention of obesity in young patients, and / or for the treatment and / or prevention of obesity caused by drugs in young and adolescents disease. ～ U · Pharmaceutical composition, the active ingredient of which contains at least one compound with CBr receptor activity as described in the patent application-item 2 or ^ such as previous drugs, tautomers or salts Type, prefer a CB1_receptor antagonist compound or one of its predecessor drugs, tautomers or salts, 91 200530219 and at least one compound that inhibits lipase activity for the treatment and / or prevention of adolescence And obesity in young patients, and / or as treatment and / or prevention of drug-induced obesity in young and adolescent patients. 12. The pharmaceutical composition according to item 11 of the scope of the patent application, which contains at least one compound having CB! Receptor activity, or one of its predecessor drugs, tautomers, or salts. The CB1 receptor antagonist compound or a predrug, tautomer or salt thereof is used in combination with a compound that inhibits lipase activity, which is selected from the group consisting of a polymer that inhibits lipase activity, orlistat, and panclicins. , ATL_962, and lipstatin. 13. The pharmaceutical fl composition according to any one of items 10 to 12 of the scope of the applied patent, wherein at least one compound having (: receptor activity or one of its predecessor drugs, intermutation Structure or salt, it is preferred that the CB! Receptor antagonist has the general formula ⑺, (II), (m), (Iv) and / or (V) structure as defined in item 2 of the scope of patent application The compound or one of its predecessor drugs, tautomers or salts, and at least one lipase-inhibiting compound, each present in an amount, which is curative and suitable for treatment and / or prevention. Obesity for treated juvenile patients. 14. The pharmaceutical composition according to any one of claims 1 to 12 of the scope of patent application, wherein at least one compound having CBr receptor activity or one species Tendency to drugs, tautomers or salts, it is preferred to have the general formula (I), (I), (hi), (iv) and / or ( V) Structure of the CB! Receptor antagonist compound or one of its previous drugs Tautomers or salts and at least one lipase-inhibiting compound, each present in an amount, which is effective and suitable for the treatment and / or prevention of childhood and adolescent patients who need such treatment Drug-induced obesity. 15 · — A kind of treatment and / or prevention of cBr receptor-related disorders in young patients and / or treatment and / or prevention of drug-induced diseases in young and adolescent patients 92 200530219 Method for obesity, characterized by at least one and (III), (IV), or (V) structure and having two CBi receptor active gamma compounds (,): etc. prodrugs, tautomers Or salt, as the meaning of item 2 of the scope of the patent application, is given to those who need this kind of treatment. 16. = Apply to the treatment described in item 15 and ;; The method, prevention is for pediatrics Aspects _ J Prevention, the myriad of symptoms, such as mental illness, distress, anxiety, lack of thought, memory impairment, cognitive impairment, anorexia, obesity, addiction, thirst, drug dependence, and Neurological diseases, degenerative diseases, dementia Symptoms: abnormal muscle tone, lean muscle, facial tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Trollett Syndrome, cerebral ischemia, cerebral stroke, cranial and brain trauma, stroke, spinal cord injury, neuritis, sclerosis, viral encephalitis, = related to myelin loss, and use As a pediatric treatment of pain, including neuropathic pain, there are other central nervous system diseases related to cannabinoid conduction, including pediatric treatment of sepsis = shock, glaucoma, cancer, diabetes, vomiting, nausea , Asthma, respiratory disorders, gastrointestinal disorders, gastric ulcers, diarrhea and cardiovascular diseases. 17. The method of home treatment and / or prevention according to any one of item 15 or 16 of the scope of the patent application, wherein the treatment and / or prevention is aimed at obesity and / Or drug-induced obesity in juvenile and adolescent patients. 18. A method for treating and / or preventing obesity in adolescent or juvenile patients, and / or treating and / or preventing drug-induced obesity in juvenile and adolescent patients, characterized in that at least one A compound having CBi receptor activity as defined in item 2 of the scope of patent application, a predecessor drug, tautomer or salt thereof, which is administered in combination with at least one compound that inhibits lipase activity and is required for the species Treated patients. 93 200530219 19. The method of treatment and / or prevention according to item 18 of the scope of the patent application, characterized in that at least one compound having CBl_receptor activity or one of its previous tautomeric drugs, tautomers or It is a salt, and it is preferred to be a CBi receptor antagonist compound or a predecessor drug, a tautomer or a salt thereof in combination with at least one compound that inhibits lipase activity, which is selected from-inhibition of lipase activity polymerization Objects, orlistat, panclicins, ATL_962 and • Hpstatin This group.方法 The method of treatment and / or prevention according to any one of the 15th or 19th of the scope of the patent application, characterized in that the treatment is aimed at obesity in infancy. "21. The method for treatment and / or prevention according to any one of the 15th or 19th in the scope of the patent application, characterized in that the treatment is directed to drugs caused by infants and adolescents due to drugs Obesity 22. The method for treatment and / or prevention according to item 15 or item 22 of the scope of the patent application, characterized in that the compound having 〇81_receptor activity or a kind thereof Pre-drugs, tautomers or salts, preferably; CBi receptor antagonists or one of their pre-drugs, tautomers or salts and at least one compound that inhibits lipase activity, Simultaneous, separate or combined administration in a phased manner. 23 · —A drug product containing at least one drug having the general formula (I), (π), (In), (IV) or (v) a compound with a structure and CBr receptor activity, or one of its predecessors, tautomers, or salts, preferring a CBi receptor antagonist compound or Is one of the most prevalent drugs Structures or salts with at least one lipase-inhibiting compound as a combined drug for simultaneous, separate, or phased administration for the treatment and / or prevention of obesity. · 24 · —A drug product containing The drug is at least one compound having the general formula (I), (Π), (III), (IV) or (v) structure and CBi-receptor activity as defined in item 2 of the scope of patent application, or Other previous drugs: Inter-94 200530219 isomers or salts, preferring a CBl receptor antagonist or one of its predecessors, tautomers or salts, and a description, It is indicated that the compound having CBl-receptor activity is preferred that a CBj # anti-compound may be administered in combination with a lipase-inhibiting compound for simultaneous, separate, or phased administration to treat and / or prevent obesity. r ^ 25 · 26. A compound having the general formula ⑴, (π), (III), (IV) or (V) structure and CBr receptor activity as defined in item 2 of the scope of patent application, or a compound Pre-drugs, tautomers It is a salt, and it is preferred that it is a CBr receptor antagonist compound or a predecessor drug, tautomer or salt thereof, and is used in combination with at least one lipase inhibitory compound. The combination uses a compound having the general formula ⑴, (positive, or structural, and CBi-receptor activity as defined in item 2 of the scope of the patent application, wherein the compound having CB1_receptor activity or one or the like Previously-adapted drugs, tautomers or salts are preferred as far CBi receptor antagonist compounds or one of their pre-adapted drugs, tautomers or salts, and used in combination with at least one lipase inhibitory compound , Which is selected from the group consisting of polymers inhibiting lipase activity, orlistat, panclicins, ATL-962 and lipstatin. 200530219 VII. Designated representative map (1) The designated representative map in this case is: (). (2) Brief description of the component symbols in this representative map: 8. If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: (IHa)