TW200528442A - 1,3,5-trisubstituted 4,5-dihydro-1h-pyrazole derivatives having CB1-antagonistic activity - Google Patents

Abstract

The present invention relates to 1,3,5-trisubstituted 4,5-dihydro-1H-pyrazole derivatives as CB1 antagonists, to methods for the preparation of these compounds and to novel intermediates useful for the synthesis of said pyrazole derivatives. The invention also relates to the use of a compound disclosed herein for the manufacture of a medicament giving a beneficial effect. The compounds have the general formula (I), wherein the symbols have the meanings given in the specification.

Description

200528442 IX. Description of the invention: [Technical target field to which the invention belongs] Field of the invention The present invention relates to ι, 3,5-trisubstituted 4,5-dihydro 5 -1H-Hou as a CBj # resist. Derivatives, methods for preparing these compounds, and novel intermediates suitable for synthesizing said derivatives. The invention also relates to the use of a compound disclosed herein in the manufacture of a medicament giving a beneficial effect. The beneficial effects are disclosed herein or will be apparent to those skilled in the art from the present specification and general knowledge in the art. The invention also relates to the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of a disease or condition. More specifically, the present invention relates to new uses for treating diseases or conditions disclosed herein or apparent to those skilled in the art from this specification and general knowledge in the art. In embodiments of the invention, the specific compounds disclosed herein are used to produce drugs that are 'ie' suitable for treating disorders involving the cannabinoid (3in〇id) I5 receptor, or by controlling these receptors Treatment of disorders.

In WO 8805046, N-aryl-4,5-dihydro-1H-pyrazole-3-phosphonate derivatives have been described as insecticides but not described as cannabinoid receptor antagonists. The 3,4-adenyl-4,5-dihydrosalane-1-methyl lung derivative is called a CB! Receptor antagonist (see WO 0170700, WO 0276949, WO 0326647 20, and wo 026648). However, the 4,5-dihydropyrazole derivatives described in the present invention have significantly different 1,3,5-substitution patterns, so they must be prepared by completely different synthetic routes.

JL Background of the Invention 200528442 It has now been unexpectedly discovered that potent and selective antagonistic or counter-excitatory effects of cannabinoid-CB! Receptors exist in the novel 1,3,5-trisubstituted 4, of formula (I), 5-dihydro-1H-pyrazole derivatives, their tautomers and their salts

among them:

-R4aR2 independently represents phenyl, thienyl or pyridyl, these groups may be substituted with 1, 2 or 3 substituents Y which may be the same or different, and the substituent Y is selected from the group consisting of branched or linear alkyl or Alkoxy, phenyl, hydroxy, chlorine, bromine, fluorine, iodine, trifluorofluorenyl, trifluoromethylsulfanyl, trifluorofluorenyloxy, methanesulfonyl, carboxyl, trifluoromethanesulfonyl, cyano, methyl Aminoamidine, sulfasalazine, and acetamidine, or Ri and / or R2 represents naphtyl, -X represents one of the subgroups ⑴ or (ii),

Among them: -R3 represents a hydrogen atom or a branched or linear C! _3 alkyl group, -R4 represents a branched or linear Ci_8 alkyl group or a C3-8-cycloalkyl group-Ci_2-alkyl group, a branched or linear CN8 alkoxy group , (: 3_8 cycloalkyl, C5_1G bicycloalkyl, c6_10 tricycloalkyl, these groups may contain one or more heterogens 200528442 selected from the group (0, N, S), and these groups may be substituted by a hydroxyl group , 1-3 methyl, one ethyl or 1 fluorine atom substitution, or ~ Table ^ phenyl, phenoxy, benzyl, benzene 3 ethyl or phenylpropyl, optional on their phenyl ring 5 10 15 20 is substituted by 1 to 3 substituents γ, wherein Y has the above meaning, or is represented by r4. The ratio is radical or stilphenyl R4 represents the group NR5R6, of which three R5 and R6-the nitrogen to which they are attached Atom-start-form-a saturated or non-saturated m-bicyclic heterocyclic group having: 1 ring atom, the heterocyclic group containing-one or two heteroatoms selected from the group (0, N, S), ^ Heterocyclyl can be branched or linear, radical, benzyl, minus or: fluorine atom substitution, or radical or the nitrogen atom to which R3 and R4 are connected—from the formation of a ~ _ ring atom saturation Or unsaturated, monocyclic or bicyclic heterocyclyl, the heterocyclyl contains one or two heteroatoms selected from the group (0, N, s), the heterocyclyl may be branched or the Cl3 filament, phenyl, amino, or domains:, methyl or fluorine atom, - the gas, represents an optionally substituted Bu, three or four substituents on the aromatic ring section ¥ group, stupid group, any group, or (iv) group, wherein — =: Back to the meaning, they can be the same or different, or R7 represents Ci 8 branch or line: alkyl, C3.8 chain dialkyl, c⑽cycloalkyl, c 烧 bicycloalkyl, c 乂 cycloalkyl or c5_8 ring Dilute base, or ~ Table: 10 戋 者 矣 矣 -Factory shows helium, or teaches 7 shows Cl.8 dialkylamino, Cm monoalkylamino or has = atomic and or Ring or Wei_ring group, containing 1 or 2 nitrogen atoms, and the heterocyclic group may include W selected from: two

) 'And the heterocyclic group can be branched or linear c into J 200528442' hydroxy or trifluorofluorenyl or fluorine atom, -R8 represents a hydrogen atom or a branched or linear ci3 alkyl group, -R9 represents hydrogen Atoms or branched or linear alkyl, C3 8 cycloalkyl or C2_1G heteroalkyl, these groups may be substituted by keto, trifluoromethyl or fluorine atoms, or r9 epicyl, minus, phenoxy or m or The machine represents a branched or linear < ^ 8 silk group 'which may be substituted by a g group, a trimethyl group or a fluorine atom, or R9 represents a phenyl group, a benzyl group, or the like. Bipyridyl, 嗟 & Me A ^ Bipyridylpyridyl or benzyl, wherein the aromatic ring may be substituted by ¥, 1, and ′, and ′ Y has the aforementioned meaning, or 10 15 20 R9 represents the group NR ^ Ru, but it must represent a hydrogen atom or a meaning, in which Rio and Rn are the same or different and represent Cw alkyl or C soil and it, or R1G and Rn-together with the nitrogen atom to which they are fluorinated A saturated or unsaturated heterocyclic moiety having 4 to 8 ring atoms in the radical has 80% of one or two atoms selected from the group (0, N, S): Substituted with Cl_2 alkyl, or 4 unsaturated

Rs and IV together with the nitrogen atom to which they are connected form a saturated or unsaturated, monocyclic or bicyclic ring atom with 4 to 10 heterocyclic moieties containing one or two selected from the group (0, N, S ) / Long ", the -S02- group 'This part can be ^ alkynyl, minus, phenyl group atom or i homo or methylamino' IUI cyclobutanyl group, ^ find group, π cumylamino 'Diheteropyridyl substitution. Soil or Hexanitrogen Compounds of formula (I) have at least one chiral center (-1H- ° than the c5 position of the salivary moiety). The present invention relates both to the mixture of enantiomers of the formula (in 4,5-dihydropyrene's rotator ', and X relates to a single 200528442 stereoisomer of the compound of the formula (1). The present invention also relates to the formula (I ) E isomers, Z isomers, and E / Z mixtures of the compounds. [Summary of the Invention within the month 5 Prodrugs are therapeutic agents that are inactive by themselves but are converted into one or more active metabolites. Prodrugs are bioreversible derivatives of drug molecules used to overcome certain obstacles in the use of the parent drug molecule. These obstacles include, but are not limited to, solubility, permeability, stability, presystemic metabolism, and dermatology Bar restrictions (Medicinal Chemistry 10: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed .: FD

King, p. 215; J. Stella, "Prodrugs as therapeutics", Expert Opin. Ther. Patents, M (3), 277-280, 2004; P. Ettmayer et al., Lessons learned from marketed and investigational prodrugs ", J. Med. Chem., 47, 2393-2404, 2004). Prodrugs, 15 That is, compounds that are metabolized to compounds of formula (1) when administered to a human by any known route, belong to the present invention. In particular This is a compound having a primary or secondary amino group or a hydroxyl group. Such a compound can be reacted with an organic acid to produce a compound of formula (1), in which there is another group that can be easily removed after administration, such as, but not limited to, a pulse , Enamine, Mannich domain, hydroxy-methylene derivative 20, 0- (acid fluorenylaminophosphonate) derivative, aminophosphonate, ester, fluorenamine or enamine fluorene I. present The invention relates in particular to compounds of formula VII 200528442 R1_

(I) wherein:-RjuR2 independently represents a phenyl group, and the phenyl group may be substituted with 1, 2 or 3 substituents Y which may be the same or different, and the substituent Y is selected from the group consisting of a branched or a linear alkyl group Or alkoxy, phenyl, mesityl, bromo, fluoro, andro, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, methanesulfonyl, carboxy, trifluoromethanesulfonyl, cyano , Methylaminosulfonium, sulfasalazine, and acetamidine, or the heart and / or R2 represents a phenylene group, σsedenyl or 0 to σ, and -X represents one of the subgroups ⑴ or (ii), 10

15 Among them:-R3 represents a hydrogen atom, -R4 represents a branched or linear Cm alkyl group, a branched or linear Ci_8 alkoxy group, or a C3_8 cycloalkyl group, and these groups may be one hydroxyl group, 1-3 fluorenyl groups, one Ethyl or 1-3 fluorine atoms are substituted, or R4 represents a phenoxy group, π is more than σ or thiophene, or R4 represents a group NR5R6, wherein R5 and R6-together with the nitrogen atom to which they are attached-form one A saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms, 10 20 200528442 hetero% group contains one or two heteroatoms selected from the group (0, N, S), or 4 together with the nitrogen atom attached to the daggers-to form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 ~ 1〇 &quot; ίsolid / 5, ^ <5 One or two heteroatoms selected from the group (0, N, S), and the 5 heterocyclic group may be substituted by fluorene, pen-glycosyl, or trifluoromethyl or fluorine atom, R7 represents a benzyl group The phenyl group may be substituted on its aromatic ring by a 1,2,3 or 4 ^ substituent Y, wherein γ has the aforementioned meaning, they may be the same or not, or the Cl · 8 branched or Shaped alkyl group, C3_n) cycloalkyl group or C5_10 bis 10% alkyl group 'or R? Represents naphthyl group, or R7 represents amino group, or R7 represents Cw monoalkyl group, Ci 8 monoalkyl group or having 4 ~ Saturated or unsaturated, monocyclic or bicyclic heterofilaments of difficult-to-ring atoms, the heterocyclyl group contains two or more nitrogen atoms, and the heterocyclyl group may contain 丨 heteroatoms selected from group (0, 8) 'And the heterocyclic group may be branched or linear Ci_ formed or substituted, -R8 represents a hydrogen atom or a branched or linear alkyl group, 15 R9 represents a hydrogen atom or a branched or linear C group. c3.8 Cycloalkyl radicals 'These radicals may be substituted by trifluoromethyl or fluorine atoms, or R9 represents a number radical, via a radical, a phenoxy group, or R9 represents a branched or oxo group' or R9 represents benzene Group, wherein the aromatic ring may be substituted by i, 2 or 3 in the substituent γ, wherein., Y has the aforementioned meaning, or 20 R9 represents the group Hi, but the &amp; represents a hydrogen atom or a methyl group 'and Among them, R, 〇 and R &quot; are the same or different and represent c] 4. Sandunyl, or R10 and ~-together with the nitrogen atom to which they are attached form a residual and unsaturated heterocyclic moiety having 4 to 8 ring atoms, the heterocyclic moiety containing one or two selected from Atoms of group (0, N, S), or 200528442 R8 * R9-together with the nitrogen atom to which they are attached-form a saturated or unsaturated, monocyclic or bicyclic heterocyclic moiety having 4 to 10 ring atoms, The heterocyclic moiety contains one or two atoms or keto groups or -S02- groups, 5 and tautomers, stereoisomers, prodrugs and salts selected from the group (0, N, S). ‘A compound of general formula (I) in which R4 is phenyl, that is, a compound described in WO 8805046, has been found to be active as a CB! Receptor antagonist. Φ Due to effective CBj # anti-activity, the compounds of the present invention are suitable for the treatment of 10 psychiatric disorders such as psychosis, anxiety, depression, attention deficit, memory disorders, cognitive disorders, appetite disorders, obesity, especially juvenile obesity and drugs Caused by obesity, addiction, impulse control disorders, sensuality, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle rigidity, tremors, epilepsy, multiple sclerosis, traumatic brain injury, 15 strokes, par Kingson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral palsy, craniocerebral trauma, stroke, spinal cord® injury, neuroinflammatory disorder, plaque sclerosis, viral encephalitis , Demyelination-related disorders, and treatments for the treatment of pain disorders, including neuropathic pain disorders, as well as other disorders involving cannabinoid neurotransmission, including the following 20 treatments: septic shock, glaucoma, cancer, diabetes, sigma Vomiting, nausea, asthma, respiratory disease, gastrointestinal disorders, gastric ulcers, diarrhea, cardiovascular Disorders, atherosclerosis, cirrhosis and sexual disorders. The cannabinoid receptor-modulating activities of the compounds of the present invention make them particularly suitable for treating obesity, juvenile obesity, and drug-induced obesity when used in combination with lipase inhibitors. A specific example of a compound that can be used in this combination formulation is (but is not limited to) the synthetic lipase inhibitor orlistat, a lipase inhibitor isolated from microorganisms, such as lipstatin [Obtained from Streptomyces tomoxytridni)], 5 elipactone B (derived from Streptomyces aburaviensis), synthetic derivatives of these compounds And plant extracts known to have lipase inhibitory activity, such as the extract of Alpinia officinarum or compounds isolated from such extracts, such as 3-fluorenyl ether galangal extract (obtained from the ginger). 10 General aspects of synthesis The synthesis of compounds of formula where X represents subgroup (i) is outlined in Scheme 1. Intermediates having the general formula (VII) can be obtained according to known methods, see for example: WO 88/05046 and the references cited therein. Compounds of formula (V) can be obtained according to known methods, for example: Shawali et al., J. Heterocyclic Chem. 15 2003, 4 (2), 207 and the references cited therein. The diazotization of the compound of formula (II) by treatment with NaN02 under acidic conditions (HC1) gives the diazonium chloride of formula (III). (III) Coupling with a 2-chloro-3-oxobutanoic acid alkyl ester derivative, such as ethyl 2-chloro-3-oxobutanoic acid ethyl ester (IV) can give a 2-gas of the general formula (V) (Hydrazinyl) acetate derivatives. (V) The reaction with an olefin derivative 20 of formula (VI) gives a 1,5-disubstituted-4,5-dihydro-1H-pyrazole-3-phosphonate analog of formula (VII) . Compounds of general formula (VII) can be reacted with amines R3R4NH, preferably in the presence of trimethylaluminum (Me3Al), to give compounds of formula (I), where X represents the subgroup ⑴ and r3 * r4 has the previous page The meaning given above. Further information on the amidation reaction of esters promoted by trisaluminum aluminum A1 (CH3) 3 13 200528442 Available at: J.I. Levin, E. Turos, S. M. Weinreb, Synth

Commun. (1982), 12, 989-993.

Scheme 1 Alternatively, a compound of general formula (VII) can be hydrolyzed to the corresponding carboxylic acid (view). The carboxylic acid (M) formed can be reacted with the amine R3R4NH to give a compound of formula ⑴, where X represents a subgroup ⑴, and Xin and 仏 have the meanings given in 10 on page 2 above, through activation and coupling Methods, such as the formation of active esters, or in so-called coupling agents such as DCC, HBTU, BOP, CIP (2-gas-1,3-diamidino hexafluorophosphate imidazoline rust), PyAOP (7-azabenzene Benzotriazole small base oxygen 14 200528442 Glycidine (σ bilo burn) hexafluoroscale acid scale) and the like. More information on the activation and coupling methods of amines and weilic acids can be found in: a) M. Bodanszky and A. Bodanszky: The Practice of Peptide Synthesis, Springer-Verlag, New York, 1994; ISBN: 50-387- 57505-7; b) K. Akaji et al., Tetrahedron Lett. (1994), 35, 3315-3318); c) F. Albericio et al. 5 Tetrahedron Lett. (1997), 38? 4853-4856) O • Alternatively, the carboxylic acid (VIII) can be reacted with a halogenating reagent such as thionyl chloride 10 (SOC12) to give the corresponding carbochlorine (IX). Compound (IX) can be reacted with amine R3R4NH to give a compound of formula (I), wherein X represents a subgroup (i), and Ri 'R2, R3 and R4 have the meanings given on page 2 above. Scheme 2 outlines the synthesis of compounds of formula VII where X represents subgroup (ii). For example, a compound of the general formula (VII) can be converted into the corresponding formazan derivative (X) by applying trisalyl aluminum (MesAl) and NHUC1, followed by treatment with an aqueous solution of a domain. Information on this conversion of esters into pyrene can be found at

Tetrahedron. Lett. 2002, 43, 419 (Gielen et al.). A compound of the general formula (χ) whose center and! ^ Have the meanings given on page 2 above is a new compound. Compounds of formula (X) can be given by reacting a compound of general formula (X) with dichloromethane R7SO2Cl in the presence of a domain such as N-diisopropylethylamine (DIPEA), where X represents a subgroup (ii ) 'And R !, R2, and R? Have the meanings given on page 2 above, and Rs and R9 each represent a hydrogen atom. Intermediates of the general formula R ^ SC ^ NH2 can be prepared from the corresponding compound r7s〇2q 15 200528442 or by a synthetically relevant scheme (see for example) \ ^ 1 ^ &amp; 111 ^ 6131 ·,] ·

Med. Chem. 1965, 8, 766). A compound of the general formula (XI) can be given by reacting a carbon of the general formula (IX) with a compound of the general formula r7s02nh2 in the presence of a domain such as NaH, wherein R1, r2, and r7 have the second and The meaning given by 5 on 3 pages. Compounds of general formula (XI) in which Ri, R2 and R? Have the meanings given on pages 2 and 3 above are novel compounds. The compound of formula (XII) can be reacted with a halogenating agent ', such as a gasifying agent such as PC15, to give a compound of formula (XII)' wherein Z represents a chlorine or bromine atom. Among them, Ri, &amp; and compounds of the general formula (χπ) having the meanings given on page 2 above are new compounds. The compound (XII) can be reacted with an amine of the general formula R8R9NH to give a compound of the general formula ⑴, where X represents a subgroup (π), and R1, R2, r7, ^, and ^ have the values on pages 1 to 3 The meaning given.

Among them, λ represents a group (η), where ′ 1¾ and Rg represent Η

«3 r2 (0 where X represents a union (ii) Scheme 2 The choice of a specific synthesis method depends on factors such as the compatibility of functional groups with the reagents used, the use of protective groups, catalysts, activation, and 16 15 200528442 The possibility of coupling agents, and the final structural characteristics present in the final compounds prepared. According to these methods, the following compounds can be prepared. They are intended to further elaborate the present invention and should not be considered as limiting the present invention in any way. 5 The scope of the invention. Pharmaceutical preparations can be prepared by conventional methods using auxiliary substances, such as liquid or solid carrier substances, to form the compounds of the present invention in a form suitable for administration. They can be enterally, orally, parenterally (intramuscularly or intravenously), The pharmaceutical composition of the present invention is administered rectally or topically. They can be administered in the form of solutions, powders, tablets, capsules (including microcapsules), ointments (creams or gels) or suppositories. For such preparations Suitable excipients are conventional liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavors, colorants and Commonly used auxiliary substances that can be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, such as cod liver oil, Flower oil, peanut oil or sesame oil, polyethylene glycol and solvents such as sterile water and mono- or polyhydric alcohols such as glycerin. The compounds of the present invention are usually administered as pharmaceutical compositions, which are important and new implementations of the present invention. Protocol, which is due to the presence of the compound, and more specifically the specific compound disclosed herein. The types of pharmaceutical compositions that can be applied include, but are not limited to: tablets, chewable tablets, capsules, solutions, parenteral solutions, suppositories, suspensions Liquid and other types disclosed herein or apparent to those skilled in the art from this specification and general knowledge in the art. In this embodiment of the invention, 200528442, there is provided a drug pack or reagent that includes one or more containers, household catties The container is filled with one or more of the components of the pharmaceutical composition of the present invention. Related to the container can be various written materials such as instructions for use, or precautions in the form prescribed by government agencies that regulate the production, use, or sale of pharmaceuticals, and these precautions reflect government agencies' requirements for human or veterinary administration. Licensing for production, use, or sale. Pharmacological methods The in vitro affinity of cannabinoid-CB receptors can be determined using the membrane products of Chinese warehouse (CHQ) cells. Affinity of the body, stably transfected the human cannabinoid CB receptor in the cells together with [H] CP-55,94 as a radioligand. The freshly prepared cell membrane product was mixed with [3 印 配After incubating the body together with + force or adding the compound of the present invention for a long time, the bound and free ligands are separated by filtration on the filter, and the bound and free ligands are separated. The filter is just fixed on the filter by 15 liquid flashing counts. Of radioactivity. Cannabinoid-CB! Receptor Antagonism in vitro Human CBi receptors cloned in Chinese hamster ovary (CH0) cells can be used to estimate receptor antagonism in vitro. CHO cells were grown in Duibecc0, s Modified Eagle, s medium 20 (DMEM) medium towels, which were inactivated by 10% heat-inactivated Yuekou cattle ash. The medium was withdrawn and replaced with DMEM without fetal bovine serum but containing [H] -arachidonic acid, in a cell culture greenhouse (5% CO2 / 95% air; 37. (:; water-saturated atmosphere). Incubate overnight. During this period 'incorporate [H] -arachidonic acid into membrane phospholipids. On the test day, remove the culture medium' with 0.5 ml of DMEM containing 0.2% bovine serum albumin (BSA). 18 200528442 Cells were washed three times. Stimulation of the CB receptor with WIN 5 5,212-2 resulted in activation of PLA2, followed by the release of [3H] -arachidonic acid into the culture medium. This WIN 55,212-2-induced release was antagonized by the CBi receptor Antagonism depends on concentration. Cannabinoid-CB! Receptor antagonism in vivo CBi antagonism in vivo can be estimated using a CP-55,940-induced hypotension test in rats. Pentobarbital (80 mg / kg intraperitoneally) anesthetize male normotensive rats (225-300 g; Harlan, Horst, The Netherlands)

〇 Blood pressure was measured with a Spectramed DTX-plus pressure sensor (Spectramed B.V., Bilthoven, The Netherlands) via a cannula inserted into the left carotid artery. Enlarged by Nihon Kohden Carrier Amplifier (Type AP-621G; Nihon Kohden BV, Amsterdam, The Netherlands), using the Po-Ne-Mah information-acquisition program (P〇-Ne-Mah Inc ·, 8 仂 still, 118 八) Blood pressure signals were recorded on a personal computer ((: 〇1 ^ &amp; 9〇631 ^ 1 * 〇3863). Heart rate was derived from the pulsating pressure signal. All compounds were given 1% methylated 30 minutes before 15 anesthesia episodes. It is administered orally in the form of a microsuspension in cellulose, which is 60 minutes earlier than the administration of the CB] receptor stimulant CP-55,940. The injection volume is 10 ml / kg. After hemodynamic stabilization, the cb receptor is excited Agent CP-55,940 (0.1 mg / kg intravenously) and produces hypotensive effects. (Wagner, JA &gt; Jarai, Z., Batkai, S.! Kunos, G. Hemodynaniic 20 effects of cannabinoids: coronary and cerebral vasodilation mediated by cannabinoid CB] receptors. Eur. J. Pharmacol. 2001, 423, 203-10) pharmaceutically acceptable salts can be obtained using standard methods well known in the art, for example, by combining a compound of the invention with a suitable acid, such as an inorganic acid , 19 200528442 such as hydrochloric acid, or Mixed with an organic acid. The dosages determined the affinity of the compounds of the present invention for the cannabinoid receptor as described above. From the binding affinity determined for a given compound of formula ⑴, humans can estimate that the theory is the least effective Dose. At a compound concentration equal to twice the measured &amp; value, '100% cannabinoid failure may be occupied by the compound. Assuming ideal bioavailability', converting this concentration to mg compound / kg produces a theoretical minimum effective dose Pharmacokinetic, pharmacodynamic, and other considerations can change the actual administered dose to higher or lower values. The appropriate dose for administration of 10 is 0.001 to 1000 mg / kg, preferably (U ~ 10 0 mg / kg patient weight.

Solution I Example Example 1: Synthesis of Specific Compounds 15 Compounds 1 to 4 Part A.-Slowly add a solution of NaNO2 (9.0 g, 0.13 mol) in water (16 ml) to 4-gas Styrylamine (15.68 g, 0.123 mol) in a stirred solution of ice (30 ml) and concentrated hydrochloric acid (30 ml), the resulting solution was stirred at 0 to 5 QC for 1 hour, and then added to the cold &gt; ^ 0.8 (: (32 g, 0.39 111〇1), ethanol (52〇1111) 20 and ethyl 2-chloro-3-oxobutanoate (16.6 ml, 0.12 mol). The resulting mixture was stirred After 1 hour, the resulting precipitate was collected by filtration, washed with ethanol, and dried under vacuum to give 2-chloro [(4-fluorobenzyl) hydrazino] ethyl acetate (22.99 g, 73% yield). Melting point: 147.5 to 149.5 ° C. B-NNIR (200 MHz, CDC13): (1.40 (t, J = 7 Hz, 3H), 4.39 (q, J = 7 Hz, 20 200528442 2H), 7.l6 (br d, J = 8 HZ, 2H), 7.30 (br d, J = 8 Hz, 2H), 8.31 (br s, 1H). Boiled 2-gas [(4-gasbenzyl) hydrazinyl group) once stirred in two directions. ] To a solution of ethyl acetate (22.95 g, 0.088 mol) and styrene (30.3 ml, 0.264 mol) in benzene 5 (140 ml) was added Triethylamine (34.3 ml, 0.247 mol), the resulting solution was heated at reflux temperature for 1 hour. The formed solution was cooled to room temperature, the resulting precipitate was removed by filtration and washed with toluene. The filtrate was concentrated in vacuo and passed through Purification by flash chromatography (silica gel, dichloromethane) to give 1- (4-chlorophenylphenyldihydro- (1Η) -σ than sialyl-3-pivalate ethyl acetate (27.2 10 g, 94 % Yield), it solidifies slowly upon standing. 1H-NMR (200 MZ, CDC13): δ (1.38 (ί, J = 7 Ηζ, 3Η), 3.06 (dd, J = 18 and 7 Hz, lH), 3.73 (dd, J = 18 and 13 Hz, 1Η), 4.33 (q, J = 7 Ηζ, 2H), 5.38 (dd, J = 13 and 7 Hz, 1H), 7.02 (br d, J = 8 Hz, 2H), 7.08-7.40 (m, 7H). 15: Benzene chlorophenyl) -5-phenyl-4,5-dihydro- (1H) "bizole-3 monoweilic acid To a stirred suspension of ethyl acetate (23.0 g, 0.07 mol) in methanol (200 ml) was added water (15 ml) and concentrated NaOH (10 ml), and the resulting solution was heated at reflux temperature for 2 hours. The methanol was partially removed by evaporation and the residue was dissolved in a mixture of water and ethyl acetate. Ice, concentrated HC1 (20 20 and ethyl acetate were added sequentially, and the ethyl acetate layer was collected, dried over MgSCU, filtered, and concentrated in vacuo. The resulting residue was washed with diethyl ether (100 ml) and diisopropyl ether, respectively, to give 1- (4-chlorobenzyl) -5-phenyl-4,5-dihydro- (1H) -oxazole slow acid (16.46 g, 78% yield). Melting point: 177 ~ 179 ° C. Pan |! 1 ^ Di-directional 1- (4-Gasphenyl) -5-phenyl-4,5-dihydro- (1HP Biazole: 21 200528442 Meta-acid (1.50 g, 5 mmol) in anhydrous acetonitrile (40 ml To the stirred suspension in), N-diisopropylethylamine (DIPEA) (1.992nll, 11mmol), 0, and 3 were added in this order. Sitting group -N, N, N ,, N, -tetramethyl The silver hexafluorophosphate (HBTU) (2.08 g, 5.5 mmol) and 1-amino ° melon bite (0.59 ml, 5.5 ') were reacted in a 5 A gas at room temperature for 16 hours. The mixture was added to a mixture of ethyl acetate and an aqueous solution of NaHC0. The ethyl acetate layer was collected, dried over MgS04, filtered, and concentrated in vacuo. The resulting residue was recrystallized from acetonitrile N_ (pyridine_ 丨 _ylchlorophenyl) _5, benzyl-4,5-dihydro- It was square, 1J4 g, 10% yield 7〇 yield). Melting point ·· 189 ~192 ° c.

Compound] Compounds of formula (I) listed below were prepared in a similar manner, namely compounds 2, 3, and 4: compounds 2, 3, and 4: 15 compound 2: N- (pyridinyl 4 • yl) _5_ ( 4-Chlorophenyl) Small (2,4-dichlorobenzyl) -4,5-dihydro- (1Η) _Π is more than sialo_3_ formamidine. Dazzling point: i85_l87〇c.

Compound 22 200528442 Compound 3 · N- (fox.amidin-1 -yl) -1- (2,4-difluorophenyl) -5 -benzyl-4,5-dihydro- (1H) -imidazole- 3-formamidine. Melting point: 163 ~ 165 ° C.

Compound 4.N-badhexyl) -1- (2,4-dioxophenyl) -5-phenyl-4,5-dimur- (1H) -pyrazole-3-carboxamide. Melting point: 160 ~ 163.5 ° C.

10 Compounds 5 and 6 Part A: The stirred suspension of NH4C1 (2.68 g, 0.05 mol) in toluene (25 ml) was cooled to VC in an atmosphere. A solution of Me3Al in toluene (25 ml of a 2 M solution) was slowly added to allow the mixture to reach room temperature. Slowly add 1- (4-chlorobenzyl) -5-phenyl-4,5-dihydro- (1Η) -pyrazole-3-carboxylic acid ethyl ester 15 (3.29 g, 10 mmol) in toluene (25 ml) solution, and the reaction mixture was stirred at 80 ° C for 16 hours. After cooling to 0 ° C, methanol was slowly added and the formed precipitate was removed by filtration through 23 200528442. The filtrate was concentrated, and the residue was dissolved in a mixture of hexane and methanol. The formed envy was removed by filtration. / ', &Quot; X. The filtrate was condensed, and the remaining residue was crystallized from dichloromethane to give 1 #yl) -5-benzyl-4,5-monohydro- (1Η) -σΛϋϋ-3 · 甲 脉 Ή (ϋ1 (2.7 ° c, square, 18'73% yield 5). H-NMR (200 MHz, DMSO-d6): 33.08 (dd J δ '丄 8 and 7 Hz, lH), 3.82 (dd, J = 18 and 13 Hz, lH), 5_84 (dd, J = ~ 丄 ^ and 7 Hz, lH), 7.15_7.46 (m, 9H), 8.85 (br s, 2H), 9.0G (br s, 2H) 1 &lt; 2,4-dichlorophenyl) -5-phenyl-4,5, -pyrazole i-mesa · 脉 α was similarly prepared. tNMRpOO MHz, DMSO-d ^ w (10 difluoroacetic acid): δ 3.32 (^, J = 18 and 7 Hz, 1H), 3.82 (dd, J = 18 and 13 HZ, 1H), 6.08 ( dd, J are 3 and 7 HZ, 1H), 7.13-7.3l (m, 6H) 7.42 (d, Bu 2 Hz, 1H), 7.52 (d, Bu 8 Hz, 1H), 8.95 (br s 2Fn 9.05 ( br s, 2H).,, to H4 'gas phenyl) -5-phenyl-4,5-dihydrofluorene H) m 15 Mizuki mouth ~ hC1 (1.87 g, 5 4-fluorophenylsulfonium To the stirred solution of anhydrous gas (〇97 匕 mm mm〇1) in anhydrous acetonitrile (20ml) was added triethylamine (2 "still 1'15mm〇1), and the resulting mixture was stirred at room temperature" empty: The residue was dissolved in a mixture of ethyl acetate and water. The 20 'ethyl acetate layer was collected, dried on MSS04, and filtered and concentrated in vacuo. The resulting residue was removed from the base. After recrystallization from tert-butyl silk, N _ [(4iphenyl) stone yellow, pore 4, chlorophenyl) -5-phenyl-4,5-dihydro- (1H) -nizole-3-carboxamidine (1.22 g '54% yield). Melting point: 200 ~ 23.50c. 24 200528442

化 ， 口 w:

Compound 6 was prepared in a similar manner: Compound 6: N-[(4-fluorophenyl) sulfonium] -l- (2,4-dichlorophenyl) -5-phenyl-4,5-dihydro- (1H) -pyrazole-3-carboxamidine. Melting point: 167 to 169.5 ° C.

Compounds 7 to 9 Part A: To 1- (4-chlorophenyl) -5-phenyl-4,5-dihydro- (1H) -oxazole-3-carboxylic acid (3.01 g, 10 mmol) in toluene To a stirred solution in (30 ml) was added thionine (S0C12) (2.9 ml, 40 mmol), and the resulting mixture was heated at 80 QC for 1 hour. After sufficient concentration in vacuo, the residue was dissolved in anhydrous 25 200528442 ethidium (50%) to give solution A. To a stirred solution of 4-chlorophenylpyridamine (1.92 g, 10-1) in ethidium (50 ml) was added concentrated NaCl. 3 ml, 25 mm. !). To the resulting mixture was slowly added solution a. A mixture of 5 10 15 20 was formed at room temperature for 16 hours. Add the ship (5Qmi's solution) and leeches _ ° to collect the sunk through the material, water secret, dissolved in two gas Jiaxuan, in

It was filtered over MgS04 and concentrated in vacuo. The obtained residue was weighed from ethanol, and said. '. The meaning of [(4-benzyl) item] small (4-benzyl) _5_phenyl_4 ^ dihydro-named M 3-formamidine (425g, 79% yield). Melting point: 2290C.

"Similarly prepared N. chlorobenzyl) Gang Xiao (2,4 diaminophenyl A Benzo-4,5_ dihydro- (1H)" than sialic acid methylamine (Hyun point: 178 ~ 181). 〇and

Then [4- (tri1methyl) phenyl] gallium]] pedichlorophenyl) _5_phenyl I diazine- (1H &gt; ° than sialoline_ (refining point: 175 ~ 177 ". Part B ： Call N-[(4- 匍 poor hair, Ί milk base) Shuo l · M4-Gaphenyl) -5-phenyl_4,5 · dihydro-call. Compare. Sit-3-Jiajiu 6 g of amine amidine, 5 mmol), PC1550 g 5.5 legs. 1) and a mixture of benzene (5G ml) was heated for 90 minutes at 14th generation. After the mixture was cooled to room temperature, the residue was dissolved in two Qijiayuan, according to the ice plus amine HC1 (0.34 g, 5 mm. 丨) and DIpEA 〇% m! 1 〇 at room temperature will form the mixture _i6 hours, washed twice with water 'in MgS 〇4 was dried, and concentrated in vacuo after use. The resulting residue was purified by flash chromatography, dimethanone = 99/1 (ww), and then crystallized from diisopropyl to give N. chlorophenyl) Butterfly-methyl-H4-phenyl) -5 · benzyl_4,5_dihydro_called potential 3_formyl, 15 said. Dazzling point: 134 ~ 144. 〇: Shi Xijiao, B_ = 〇_4). 26 200528442 ci

Compounds of formula (I) are prepared in a similar manner as follows: • Compound 8: N-[(4-chlorophenyl) ruthenium] -N'-fluorenyl-: 1- (2,4-di Gasoline

5) -5-phenyl-4,5-dihydro- (1Η) -σ is more than sial-3- 曱 vein. Dazzling point: 128 ~ 130.5oC. Rf (silicone, ether = 0.4).

CI

0 = S = 0

Compound 9 ·· N-{[(4-trifluoromethyl) phenyl] ruthenium methyl-l- (2,4-l0 diphenylphenyl) -5-phenyl-4,5-dihydro -(111)-° than 0 sits 3-formamidine. Melting point: 157 ~ 159 ° C. Rf (silicone, ether = 0.5). 27 200528442

Compounds 10 and 11 Part A · 1-(4-Gaphenyl) -5 -phenyl-4,5-diaza- (1 H)-° tb hydrazone- 3-5 carboxylic acid (3.01 g, 10 mmol ) To a stirred solution in toluene (30 ml) was added thionyl chloride (SOC12) (2.9 ml, 40 mmol), and the resulting mixture was heated at 80 QC for 1 hour. After sufficient concentration in vacuo, the residue was dissolved in anhydrous acetonitrile (50 ml) to give solution B. To an ice-cold, stirred solution of pyridin-1-sulfamethoxamine (3.28 g, 20 mmol) in anhydrous acetonitrile (50 ml) was added NaH (60% 10 dispersion, 0.80 g, 20 mmol). The resulting mixture was stirred for 1 hour. To the formed suspension was slowly added solution B. The resulting mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. To the residue were added hydrochloric acid (1N solution) and digas methane. The dichloromethane layer was collected, washed with water, dried over MgS04, filtered and concentrated in vacuo. The resulting residue was recrystallized from 15 in ethanol to give N-[(^. De-1-yl) contanoic acid] -1- (4-aminophenyl) -5 -benzyl-4,5-dihydro -(111) -pyrazole-3-carboxamide (3.68 g, 82% yield). Melting point: 239.5 to 241.50C. N-[(morpholin-4-yl) sulfonaminium] -l- (2,4-difluorophenyl) -5- 28 200528442 phenyl-4,5-monohydro- (1Η) was similarly prepared Than saliva! Methamine. Melting point: 176 ~ 179 ° c. This ugly II-willing team melonidine] -based) 醯 H- (4-chlorophenyl) -5-phenyl5. 5B1) and chlorobenzene (50% of the blended mixture in MOT Heating for 90 minutes. The mixture was cooled to room temperature, si / m, and then concentrated in vacuo. The residue was dissolved in milk crust, and methylamine DIPEA (1.74ml, 10%) was added in sequence. , 〇〇1) and d, Niche, Tian k, Shi to "the dish will stir the formed mixture 1 Xiao Nishou 'wash your knees twice with water, call in%. The obtained residue was added to the step- * * U after the real concentration of 10 dichloropyrene), and then from the diiso: two through the rapid-side-by-side methyl group called rhyme ^: 'gives Liaogua ~ -based) A Hydrazine (119 ancient soil 4,5-dihydro-GH) "Bizole methyl veins, 49% butterfly, 14% ether = 0.2). Μ4 ϋ Rf (Shi Xijiao,

15

— Jtsr, lice: 165C The compound of the formula ⑴ given below: 11 物 11 · N-[(MORINE Bingjimei, m 1 '] · N, · methyl with 2,4' soil)-Ben The base gas is 5_dihydro_ (1Η) 匕 〇R m ϋ 甲 脒. Melting point: 161 ~

Ri {石 夕 ¥, digas methane / propyl y8 / 2 (v / v) = 〇 15). 29 200528442

Example 2: The preparation used in animal research was administered orally (P · 0 ·): some glass beads were added to the required amount (0.5-5 mg) of solid 5 compound 3 in a glass tube, and all the beads were vortexed. The solid was ground for 2 minutes. After adding 1% methyl cellulose and 2% (v / v) 1 ml of an aqueous solution of poxamer 188 (Lutrol F68), the compound was suspended by vortexing for 10 minutes. The pH was adjusted to 7 with a few drops of aqueous NaOH (0.1N). The remaining particles were further suspended in the suspension using an ultrasonic bath. 0 Intraperitoneal (1.13.) Administration: Add some glass beads to the required amount (0.5 ~ 15 mg) of solid compound 3 in the sloped glass tube, and grind the solid for 2 minutes by vortexing. After adding a 1% methyl cellulose and 5% mannitol aqueous solution, the compound was suspended by vortexing for 10 minutes. Will it last? 11 is adjusted to 7. Example 3 · Results of pharmacological test 5 The following table does not show the in vitro cannabinoid receptor affinity and functional data obtained according to the protocol given above. 30 200528442 Table 1: Pharmacological data Human cannabinoid-CBi receptor in vitro affinity In vitro antagonism Compound number P &amp;% inhibitory compound at 1 (T6M 3% 7.6 98% Compound 10 7.1 79% I: Simple illustration 3 (none) 5 [Description of main component symbols] (none) 31

Claims (1)

X 200528442 10. Scope of patent application: 1. A compound of general formula ⑴ r2 (Ο where: 10 -IMnR2 independently represents phenyl, thienyl or pyridyl, these groups may be substituted by 1, 2 or 3 substituents Y which may be the same or different, and the substituent Y is selected from the group consisting of branched or linear C ^ -Alkyl or alkoxy, phenyl, mesityl, gas, bromine, fluorine, carbon, trifluorofluorenyl, trifluoromethylthio, trifluoromethoxy, methanesulfonyl, carboxyl, trifluoromethanesulfonyl , Cyano, methotrexate, ammonite yellow and ethylenyl, or Ri and / or R2 represents naphtyl, -X represents one of the subgroups ⑴ or (ii), 15 Among them: -R3 represents a hydrogen atom or a branched or linear Cm alkyl group, -R4 represents a branched or linear alkyl group or C3_8-cycloalkyl-C ^ -alkyl group, a branched or linear CN8 alkoxy group, and 03_8 cycloalkane Group, C5_1G bicycloalkyl group, C6_1 () tricycloalkyl group, these groups may contain one or more heteroatoms selected from the group (0, N, S), and these groups may be substituted by one hydroxyl group, 1-3 methyl groups 32 20 200528442, substituted by one ethyl or 1-3 fluorine atoms, or R4 represents phenoxy, benzyl, phenethyl or phenylpropyl, optionally substituted by 3 'on their phenyl ring Y substituted, where Y has the above meaning, or R4 represents pyridyl or thienyl, or R4 represents kevinyl, where, • 5 and the nitrogen atom to which they are attached together-to form one with 4 to 10 A saturated or unsaturated, monocyclic or bicyclic heterocyclic group of a ring atom, the heterocyclic group containing one or two heteroatoms φ selected from the group (0, N, s), and the heterocyclic group may be branched Or linear alkyl, phenyl, hydroxy, or trifluoromethyl or fluorine atom substitution, or 10R3 * R4- together with the nitrogen atom to which they are attached-to form A saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms, the heterocyclic group contains one or two heteroatoms selected from the group (0, N, S), and the Heterocyclic groups can be substituted by branched or linear BCI3 alkyl, phenyl, amino, secondary or dioxanyl or fluorine atom, ^ -r7 represents a 'phenyl' methylphenyl or a base, these groups are in • Their aromatic rings may be substituted by 2, 3, or 4 substituents Y, wherein γ has the aforementioned meaning, they may be the same or different, or R7 represents 亍 C 'branched or linear alkyl, C3-8 alkenes Base, CW decaying base, c5] 〇_8 2〇 = base, c㈣ tricyclic alkyl group or ^ ring dilute base, or Han 7 means extracting two = table money base, material R7 table is called .8 di green amino, ^ 8 monobasic amino group or a saturated or unsaturated, mono- or bicyclic heterocyclic group having 4 ~ _ ring atoms, the heterocyclic group containing-or-nitrogen atoms, and the heterocyclic group may include- A heterocyclic group selected from _, S) _, and a heterocyclic group may be substituted with a branched or linear C alkyl group, a phenyl group, or a ^ 33 200528442 group or an ii atom, representing a hydrogen atom or a branched or linear Cw alkyl group, • I table Shows a hydrogen atom or a branched or linear Cm alkyl group, a c3-8 cycloalkyl group, or a ^ 2 · 1 () heteroalkyl group, these groups may be substituted by a keto group, a trifluorofluorenyl group or a fluorine atom 5, or R9 represents an amino group , Hydroxy, phenoxy or benzyloxy, or R9 represents a branched or linear heart · 8 · alkoxy group, which may be substituted by a hydroxyl group, a trifluoromethyl group or a fluorine atom, or R9 represents a phenyl group, a benzyl group, or the like. ratio. Aryl, fluorenyl, pyridylmethyl, or phenethyl, wherein the aromatic ring may be substituted by 1, 2, or 3 of substituent Y, wherein γ has the foregoing meaning, or [0 R9 represents not * NRi〇Rn, provided that R8 represents a hydrogen atom or a methyl group, and wherein R10 and Rn are the same or different and represent a Cl · 4 alkyl group or a Cw trifluoroalkyl group, or R1G and Ru-together with the nitrogen atom to which they are attached -Forming a saturated or unsaturated heterocyclic moiety having 4 to 8 ring atoms, the heterocyclic moiety containing one or two atoms selected from the group (0, N, s), 15 the saturated or unsaturated heterocyclic The ring moiety may be substituted by Cm alkyl, or Rs and R9-together with the nitrogen atom to which they are attached-form a saturated or unsaturated, monocyclic or bicyclic heterocyclic moiety having 4 to 10 ring atoms, the heterocyclic ring The part contains one or two atoms selected from the group (0, N, s) or a keto group or a -SCV group. This part may be Cinyl, benzene20, methylamino, dimethylamino, azetidine Alkyl, pyrrolidinyl, 呱 σdenyl or hexahydro-1H-azaπ ratio substitution, as well as all stereoisomers, and their salts and precursors Thereof. 2 · —Compounds of general formula (I) 34 X 200528442 r2 (〇 where: -R4aR2 independently represents a phenyl group, and the phenyl group may be substituted with 1, 2, or 3 substituents Y which may be the same or different, and the substituent Y is selected from the group consisting of branched or linear Ci_3-benzene Or alkoxy group 'phenyl' via group 'chlorine' &gt; odor, fluorine, iodine, trifluorofluorenyl, trifluorofluorenylthio, trifluorofluorenyloxy, mesylsulfonium, weyl, trimethymethine Scutellaria baicalensis, cyano, methotrexate, ammonium scutellaria and acetic acid, or 1 and / or 2 represents naphthyl, thienyl or carbamoyl, 10 -X represents one of subgroups ⑴ or (ii), Among them: 15 -R3 represents a hydrogen atom, -R4 represents a branched or linear Cm alkyl group, a branched or linear Cw alkoxy group or a C3_8 cycloalkyl group, and these groups may be substituted by one hydroxyl group, 1-3 methyl groups, and one ethyl group. Or 1-3 fluorine atoms, or R4 represents phenoxy, pyridyl or thienyl, or R4 represents the group NR5R6, where 5 and R6- together with the nitrogen atom to which they are attached-form one with 4 to 10 Saturated or unsaturated, monocyclic or bicyclic heterocyclyl of each ring atom 35 20 200528442 'The heterocyclyl contains one or two heterogens selected from the group (0, N, s) or ", R3 and R4 -The nitrogen atoms attached to them form together-a saturated or unsaturated, monocyclic or bicyclic heterocyclic ring having 4 to 10 ring atoms, the heterocyclic group comprising one or two selected from the group (0, N, S) heteroatom and the heterocyclic group may be substituted by f group, minus or trifluoro? 10 15 20 represents a phenyl group, and the phenyl group may be substituted by 丨, 2, 3 or 4 substituents Y on the aromatic ring, wherein γ has the foregoing meaning, and they may be different or different, or R7 represents C〗 8 Branched or linear alkyl, Cm cycloalkyl or h. Bicyclic filament, or &amp; represents naphthyl, or &amp; represents ammonia ^ or R7 represents Q · 8 dialkylamino, Cl_8 monoalkylamino or a saturated or unsaturated, monocyclic ring having 4 to 10 ring atoms Or a bicyclic heterocyclic group, a heterocyclic group containing 1 or 2 nitrogen atoms, and the heterocyclic group may include a heteroatom selected from the group (0, S), and the heterocyclic group may be branched Or linear Cw alkyl or hydroxyl substitution, -R8 represents a hydrogen atom or a branched or linear Cw alkyl group, -R9 represents a hydrogen atom or a branched or linear Ci · 8 alkyl group or Cm cycloalkyl group, these groups may be trifluoro The methyl or fluorine atom is substituted, or the heart represents an amino group, the alkyl group, the benzyloxy group or the benzyloxy group, or the branched or linear alkoxy group is represented by 9, or R9 represents a phenyl group, wherein the aromatic ring may be substituted 1, 2 or 3 substitutions in the group Y, wherein γ has the foregoing meaning, or R9 represents the group NR] 〇Rn, but R8 represents a hydrogen atom or a methyl group, and wherein 'Rio and Rn are the same or different and represent C ] -4 alkyl or c2.4 trifluoroalkyl, or RIG and Rn-together with the nitrogen atom to which they are attached-form 36 200528442 〃, there are 4 A saturated or unsaturated heterocyclic moiety of 8 ring atoms. The heterocyclic moiety contains one or two atoms selected from the group (0, N, s), or the heart and the nitrogen atom connected to them form a A saturated or unsaturated, monocyclic or bicyclic heterocyclic moiety of 4 to 10 ring atoms, the heterocyclic moiety containing one or two atoms selected from the group (0, N, S) or a keto group or -S02- Groups, as well as all stereoisomers, and their salts and prodrugs. 3. A pharmaceutical composition, in addition to a pharmaceutically acceptable carrier and / or at least one pharmaceutically acceptable auxiliary substance, they also contain at least a pharmaceutically active amount of a compound or a compound in the scope or Salt as active ingredient. 4. A compound of general formula (X), its tautomers and their salts r2 ㈧, where 仏 and! ^ have the meanings as given in item} of the patent application scope, and the compound is suitable for synthesizing a compound of general formula ⑴. 5 · —A compound of general formula (XI) R7 〇 = r: s = 0 I NH R2 37 (XI) 200528442 Among them, R1, R2 and has the meaning as given in item 1 of the scope of patent application, and the compound is suitable for synthesizing the compound of general formula (I). 6 · —Compounds of general formula (XII) o = s = 〇 I r2 (XU) Among them, 'R1, R2 and R7 have the meanings given in item 1 of the scope of patent application, and wherein z represents a ci-level atom, and the compound is suitable for synthesizing a compound of the general formula (I). Shishenkouyue Patent | Compound No. W2 or its salt for use in medicine 10 15 The use of a compound such as the positive item in the patent scope is for the preparation of a composition for the treatment of the following disorders Substances: disorders involving neurotransmission of cannabinoids, such as psychosis, anxiety, depression, attention deficits, memory disorders, cognitive impairment, dysphagia, obesity, especially juvenile obesity and drug-induced obesity, shooting, impulse Controlling obstacles, carnal = physical dependence and mental disturbances such as neurodegeneration, cancer, dystonia, 'muscle stiffness, tremor®, _, multiple sclerosis, traumatic: injury' stroke 'Parkinson's disease, premature senility Dementia, epilepsy, Huntington's disease: disease 'Touret syndrome' cerebral ischemia, cerebral palsy, craniocerebral trauma, 'stroke', spinal cord injury ', neuritic disorder 1 plaquesclerosis, viral meningitis' demyelination Related disorders, as well as pain disorders, including diabetic 38 20 200528442 sexual pain disorders, and other diseases involving cannabinoid neurotransmission, including septic shock, glaucoma, cancer, diabetes, vomiting, Heart, asthma, respiratory diseases 'gastrointestinal disorders, gastric ulcers' diarrhea, cardiovascular disorders, atherosclerosis, liver cirrhosis and sexual disorders. 9 · -Treatment methods: disorders involving neurotransmission of cannabinoids, such as psychosis, anxiety, depression, attention deficit, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, impulse control disorders, drugs Dependence and neurological disorders such as dementia, dystonia, muscle rigidity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette syndrome, brain Ischemia, cerebral palsy, craniocerebral trauma, and neuropathic pain disorders, and other diseases involving cannabinoid neurotransmission, including glaucoma, cancer, vomiting, nausea, asthma, respiratory diseases, gastrointestinal disorders, gastric ulcers, diarrhea, cardiovascular Disorders, atherosclerosis, cirrhosis and sexual disorders characterized by the use of a compound of the formula ⑴ R2 (〇 where: -Ri and R2 independently represent a benzyl group, a sigme group, or a °°° group. This group may be substituted by 1, 2 or 3 substituents γ which may be the same or different. From the following groups: Cu-alkyl or alkoxy, phenyl, hydroxyl, gas, bromine, fluorine, iodine, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, 39 200528442 , County, trifluoromethane, cyano, formamidine, ammonia and ethyl, or R] and / or R2 represents naphthyl, -X represents one of subgroups (i) or (ii), 〇X / R3, r4 (i) R8, / R9 丄 N ~~ i (ϋ) where: 10 15 20 _R3 represents a hydrogen atom or a branched or linear CM alkyl group, -I represents a branched or linear 〇1_8 alkyl group or a C38_cycloalkyl group &lt; 12_force group 'branched or linear Cl-8 functional group, C3 8-ring radicals, C and r _ 5 * 1〇 double bad yuki '' ο tricyclic fluorenyl radicals, these radicals may contain one or more heteroatoms selected from the group ([N, S), and these radicals May be substituted by a mesityl group, u a methyl group, an ethyl group or 1.3 fluorine atoms, or &amp; represents a benzyl group, a ^ oxy group, a benzyl group, a phenethyl group or a phenylpropyl group, Rings are substituted by 1 to 3 substitutions, in which γ has the above meaning, or a seal represents a daggeryl group or a π sephenyl group, or &amp; represents a group in which I is together with the nitrogen atom to which they are attached -Forming a heterocyclic ring having 4 to 10% atoms saturated or unsaturated, monocyclic or bicyclic, the heterocyclic group comprising one or more heterogens selected from the group (0, N, s) and the Heterocyclic groups may be substituted by branched or linear ^ · 3 alkyl, phenyl, hydroxytrifluoromethyl or fluorine atoms, or together with the soil, I and the nitrogen atom to which they are attached-formed with: 4 10 Atom saturated or unsaturated, monocyclic or bicyclic heterocyclic 40 200528442, the heterocyclic group contains one or more selected from the group (0, N, S) and the heterofilament can be branched into Phenyl group; phenyl group; aryl group is substituted by a group or a trifluoromethyl group or a fluorine atom; 10 -R? Represents a benzyl group, a phenyl group, a D-sphenyl group or. Bis, these f rings can be substituted by 2, 3 or 4 substituents ^, Υ, Υ has the aforementioned meaning 'they may be the same or different branched or linear frequency radical, &amp; chain silk, said radical, Yuanji, C6_1G tribenzyl or ^ phenyl group, or Cai group, or R? Represents amino group, or rule 7 represents Cl-8 dialkylamino group, Cu monoalkylamino group or a group with 4 to 10 ring atoms Saturated or unsaturated, monocyclic or bicyclic heterocyclic group, the heterocyclic group contains 丨 or 2 nitrogen atoms, and the heterocyclic group may contain 1 heteroatom selected from the group (0, S), and the The heterocyclic group may be substituted by a branched or linear heart · 3 alkyl, phenyl, hydroxy, or trifluoromethyl or fluorine atom, 15 20 -R8 represents a hydrogen atom or a branched or linear Cl_3 alkyl group, and -R9 represents a hydrogen atom Or branched or linear Cm alkyl, c3-8 cycloalkyl or C ^ o heteroalkyl, these groups may be substituted by keto, trifluoromethyl or fluorine atoms, or R9 represents amino, hydroxyl, phenoxy or benzyloxy Or R9 represents a branched or linear C] _8 alkoxy group, which may be substituted by a hydroxyl group, a trifluorofluorenyl group or a fluorine atom, or R9 represents a phenyl group, benzyl , Σ is more than sulfonyl, fluorenyl '. Compared to pyridinyl fluorenyl or phenethyl, wherein the aromatic ring may be substituted by 1, 2, or 3 of the substituent Υ, wherein Υ has the aforementioned meaning, or Represents a group NR ^ Rn, but R8 represents a hydrogen atom or a methyl group, and among them, UnRn is the same or different and represents C] _4 alkyl group or C2-4 three 41 200528442 fluorocarbon group, or Rio and Rii- connected to them Nitrogen atoms together-forming a saturated or unsaturated heterocyclic moiety having 4 to 8 ring atoms, the heterocyclic moiety containing one or two atoms selected from the group (0, N, S), the saturated or unsaturated The heterocyclic part of the may be substituted by Ci_2 alkyl, or 5 Rs and R9-together with the nitrogen atom to which they are attached-form a saturated or unsaturated, monocyclic or bicyclic heterocyclic part having 4 to 10 ring atoms, The heterocyclic moiety contains one or two atoms selected from the group (0, N, S) or a keto group or a -so2- group. The moiety may be C! _2 alkyl, hydroxyl, phenyl, methylamino, dimethyl Amino, azetidinyl, aralkyl, pyridinyl 10 or hexahydro-1H-azapyridyl substitution, and tautomers thereof, Isomers, prodrugs and salts. 10. The use according to item 8 of the scope of patent application, characterized in that the disorder is an eating disorder, especially obesity, juvenile obesity and obesity caused by drugs. 15 11. Use of a compound according to item 1 or 2 of the scope of patent application for preparing a pharmaceutical composition for treating eating disorders, especially obesity, juvenile obesity, and drug-induced obesity, characterized in that The pharmaceutical composition further comprises at least one lipase inhibitor. 12. The use according to item 11 of the scope of patent application, characterized in that the lipase 20 inhibitor is orlistat or ritstatin. 42 200528442 VII. Designated Representative Map: (1) The designated representative map in this case is: (). (None) (b) 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 best shows the characteristics of the invention: