TW200530191A - Imidazoline derivatives having CB1-antagonistic activity - Google Patents

Abstract

The present invention relates to 1,2,4-tri-substituted imidazoline derivatives, to methods for the preparation of these compounds, to novel intermediates useful for the synthesis of said imidazoline derivatives, to methods for the preparation of these intermediates, to pharmaceutical compositions containing one or more of these imidazoline derivatives as active ingredient, as well as to the use of these pharmaceutical compositions for the treatment of psychiatric and neurological disorders. The compounds have the general formula (I), wherein the symbols have the meanings given in the specification.

Description

200530191 IX. Description of the invention: L is a well-known member of the genus Liaowuming] The present invention relates to 1,2,4-trisubstituted imidazoline derivatives as CBj # antagonists, methods for preparing these compounds, and applications A novel intermediate for synthesizing the imidazoline derivative. 5 The present 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 field. 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 the treatment of diseases or conditions disclosed herein or apparent to those skilled in the art from this specification and general knowledge in the art. In an embodiment of the invention, the specific compounds disclosed herein are used to produce a medicament that is suitable for treating disorders involving cannabinoids ((^ nnabmoid) :), or which can be treated by controlling these receptors Obstacles. L ·] | Multi-substituted imidazoline derivatives are known from WO 03/101954 and WO 03/101969. 15 The compounds described herein are potent inhibitors of the transcription factor NF-KB, making them suitable for treating certain diseases Examination of the tumor. Therefore, "Nana-derived contact has effective anti-inflammatory agents and antibiotics, leading to another indication. Among them, they may have therapeutic significance, including inflammation and transmission. Diseases. The compound described has any affinity for cannabinoids, so it is unlikely that the disorders involving these cannabinoid receptors have a therapeutic value of 20. The object of the present invention is to have such a cardiac derivative, that is, to have as a cannabinoid -CB] receptor-modulated effective activity, while basically maintaining the physicochemical properties of some pure heart derivatives suitable for use as therapeutic agents. C SUMMARY 3 5 200530191 It has now been unexpectedly discovered that cannabis, _CBi accepts Effective antagonism of the body 体 Ni Xingba The effect exists in the novel 4,5_dihydroimidium derivatives of formula (I) and their tautomeric isomers, prodrugs and salts

X

r2 5 wherein: -R ^ R2 independently represents a radical, π-phenenyl or. These groups may be substituted by 1, 2 or 3 substituents Υ which may be the same or different, and the substituent γ is selected from the group consisting of a branched or linear Qr alkyl group or a C3 · alkoxy group, Phenyl, hydroxyl, chlorine, bromine, fluorine, iodine, trimethyl, trifluoromethylthio, trifluoromethoxy, carboxyl, trifluoromethanesulfonium, cyano, methylaminosulfonium, 10 fluorene and acetamidine Group 'or Ri and / or R2 represents naphthyl, -X represents one of subgroups ⑴ or (ii),

VR3

(ί)

IIVR7 where: -R3 represents a hydrogen atom or a branched or linear Ci3 alkyl group, 15 -1 ^ 4 represents a branched or linear ^^ 8 alkyl group or C3 · 8-cycloalkyl group-C] _r alkyl group, branched Or linear c & alkoxy '& cycloalkyl, C5_] G bicycloalkyl, (^ tricycloalkyl, these groups may contain one or more hetero groups selected from the group (0, N, S) Atoms, and these groups may be substituted by a hydroxyl group, a methyl group, an ethyl group, or 1-3 fluorine atoms, or ^ represents a phenyl group, a phenoxy group, or a benzyl group 200530191 ^ this ethyl group or this propyl group, The benzylic ring is optionally substituted by _ substituent Y, where Υ has the above meaning, or _ _, y, _ _ _ _, or 执 represents a radical, a sub-㈣ 彡-㈣ has ㈣ ring atoms Or unsaturated, monocyclic or bicyclic heterocyclic group, the heterocyclic group contains-one or two options .: _N, Wuxuan, and the complex tender 43 silk, phenyl, hydroxyl earth or difluoromethyl Group or fluorine atom substitution, or the nitrogen atom to which they are attached _ form _ a 10 15 20 saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4__ ring atoms, the heterocyclic group containing -One or two Self-organized (0 _ 轩, and _ can be substituted by branched or linear ^ silk, phenyl, amino, hydroxyl or trifluoromethyl or fluorine atom, such as «, phenyl, methylphenyl or ahyl, These groups can be substituted by 1, 2, and 4 domains on their aromatic rings. Among them, γ has the meaning of reading. They can be the same or different. Weave 7 represents Cl_8 branched or linear alkyl group, and C3 8 alkenyl group. , C31. Cyclopentyl, 'Shuangchengji, (: ㈣Sankenyl is like 8-cycloalkenyl, or & represents naphthyl, or exemplified represents amino, or _ Zhu, .8 digreen amino, c18 monofilament amino Or a saturated or unsaturated, monocyclic or bicyclic heterocyclic group with a ring shoulder, the heterocyclic group containing a positive nitrogen atom 'and the heterocyclic group may contain a heteroatom selected from the group ( And the heterocyclic group may be substituted by branched or linear C1_3 silk, benzyl, woven or trifluoro? Group or fluorine atom, -¾ represents a hydrogen atom or a fluorenyl group, -R9 represents a hydrogen atom or a methyl group, an ethyl group or a methyl group There is at least one chiral center in the compound of formula (I) (the ^ position at the Lynn part). The present invention relates to the external complementation of compounds of formula The compound also relates to a single stereoisomer of the compound of formula _. The present invention also relates to the isomer of the compound of formula VII 200530191, the Z isomer, and the E / z mixture. Prodrugs are themselves inactive but are not Therapeutic agents that are converted into one or more active metabolites. Prodrugs are bioreversible derivatives of drug molecules that overcome certain obstacles in the use of the parent drug molecule. These obstacles include, but are not limited to, solubility, permeability, 5 Stability, presystemic metabolism and restriction of targeting (Medicinal Chemistry: Principles and Practice, 1994JSBN 0-85186-494-5? Ed .: FD King? P. 215; J. Stella, uProdrugs as therapeutics ', Expert Opin. Ther. Patents 4 (3) »277-280,2004; P. Ettmayer et al.? &Quot; Lessons learned from marketed and investigational prodrugs'' 10 J. Med. Chem., 47, 2393-2404, 2004 ). Prodrugs, i.e. compounds that are metabolized to a compound of formula (I) when administered to a human by any known route, belong to the present invention. In particular, this relates to compounds having primary or secondary amino groups or vias. Such a compound can react with an organic acid to form a compound of formula (I), in which there are additional groups that can be easily removed after administration, such as, but not limited to, amidine, enamine, Mannich domain, hydroxy-methylene derivative 0- (acid 15 methylene carbamate) derivatives, carbamates, esters, amidines or enaminones. The invention relates in particular to compounds of formula (I)

r2 (|) where: R and independently represent a phenyl group, which may be substituted by 1, 2 or 3 substituents Y which may be the same or different from 20, and the substituent Y is selected from the group consisting of: branched or Linear alkyl or C! -3-alkoxy 'benzyl, hydroxyl, chlorine, bromine, fluorine, iodine, trifluoromethyl, trifluorosulfanylthio, trifluoro200530191 fluorenyloxy, carboxyl, trifluorosulfanyl Fluorene, cyano, methylaminosulfonium, sulfamidine, and ethynyl, or R] and / or R] represents a naphthyl group, a phenoxy group, or a sulfonyl group,

-X represents one of subgroups (i) or ⑻ X / R3 (i)

5 Among them: -R3 represents a hydrogen atom, -¾ represents a branched or linear Cm alkyl group, a branched or linear C " oxyl group or a Cw cycloalkyl group, and these groups can be substituted by a methyl group, W methyl groups, and Ethyl or μ3 gas atoms are substituted, or R4 represents phenyl, benzyloxy, cyno or phenphenyl, or 仏 represents a line, 10 where R5 and the heart are together with the nitrogen atom to which they are attached-forming one A saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms, the heterocyclic group containing one or two heteroatoms selected from the group (0, N, S), or 15 3 and the nitrogen atom to which they are attached form a saturated or unsaturated, monocyclic or bicyclic cyclic group with a simple ring atom, the cyclic group contains _ or two selected from the group (0, N, S) A heteroatom, and the heterocyclic group may be substituted by a methyl group, a group or a trifluoro atom, /, and represents a phenyl group. The phenyl group is pasted on its aromatic ring. Two, three or four substituents are selected. Meaning 'they may be the same or different' or ~ means Ci-8 branched or-'M group or k. Bisweilyl, or R7 silk naphthyl, or the chemical formula is not diminished, or R7 means, · 8: eryl, ^ aryl amino or a saturated or unsaturated, single, ... ^ Also cyclyl, _x contains two or two lice atoms, and the heterocyclyl may contain a solid atom of the solid group (0, S), and the heteroacyl group may be branched or linear c Formed or substituted by a group, heterodrug -¾ represents a hydrogen atom, 5 10 15 -¾ represents a hydrogen atom, and tautomers, stereoisomers, precursors and salts thereof. 'Relying on anti-miscellaneous, this issue _ compound _ Yu silk psychiatry _' such as psychosis, anxiety, attention deficit, ^ anxiety disorder 'transition, _ is an anti-obesity and drug-induced obesity, addiction, Impulse control disorders' carnal, drug-dependent and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle rigidity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, _, Huntington's disease, Tourette Syndrome, Cerebral ischemia, 'Cerebrostroke, Craniocerebral trauma, Stroke, Spinal cord injury, Neurokinetic disorders' " Variation of plaques, Viral function, Disorders and disorders, and treatment of pain disorders , Including neuropathic pain, and other diseases involving neurotransmission of Amaxin, including the treatment of the following diseases: septic shock, glaucoma, cancer, diabetes, vomiting, chewing heart 'asthma, respiratory disease, gastrointestinal disorders' Gastric ulcers, abdominal wetness, cardiovascular disorders, atherosclerosis, cirrhosis and sexual disorders. The compounds of the present invention have a cannabinoid receptor-modulating activity so that they can be combined with lipase inhibitory agents to suppress the treatment of obesity, juvenile obesity, and drug-induced obesity. Specific examples of compounds that can be used in such combination preparations are, but are not limited to, synthetic lipase inhibitors orlistat, lipase inhibitors isolated from microorganisms, such as lipstatin [available From # 三 面 / 新 级 immunity® 1 B (ebelact〇ne B) [obtained from Ye Ye in Streptomyces moganin 10 200530191, synthetic derivatives of these compounds, and plant extracts known to have lipase inhibitory activity A substance such as an extract of Alpinia officinarum or a compound isolated from such an extract, such as 3-methyl ether galangal extract (obtained from Alpinia officinalis). General aspects of synthesis 5 The synthesis of compounds of formula (I) where X represents subgroup (i) is outlined in Scheme 1. Intermediates of general formula (Π) can be obtained according to known methods, see for example: I. K. Khanna et al. 5J. Med.

Chem. 2000, 43, 3168-3185; I. K. Khanna et al "J. Med. Chem. 1997, 40, 1634 · 1647; WO 03/027076 or WO 03/040107. Intermediates of general formula (IV) Available according to known methods' See, for example: I. K. Khanna et al., J. Med. Chem. 10 2000, 43, 3168-3185. Formamidine compounds of general formula (Π) can be combined with 2.chloropropene The nitrile reaction gives a 4,5-dihydro-1H-imidazole derivative of the general formula (IV). The reaction is preferably carried out in the presence of a domain such as n, N_: isopropylethylamine. The alcohol R1 (r. The derivative of the general formula (iv) obtained by H esterification gives a 4,5-dihydro-1H-imidazole derivative of the general formula (v), wherein R10 represents a branched or linear alkyl group or a benzyl 15 group The reaction is preferably performed under acidic conditions. The compound of general formula (v) can be reacted with the amine R3R4NH, preferably in the presence of trimethylaluminum (MαA1), to give a compound of formula (j), where X represents a subgroup ⑴, and ^ and ^ have the meanings given above on page 2. More information on the hydrazone amination reaction of esters promoted by trisaluminum aluminum A1 (CHS) 3 can be found in: J; [丄 evin, E.

Turos, S.M. Weinreb, 5 > —C Leakage and Chaos (1982), 72,989-993. 20 In a remote place, a compound of the general formula (V) can be hydrolyzed to the corresponding carboxylic acid derivative of the general formula (VI) 'wherein': ^ Table Lee or alkaline earth metals, especially Li, Na ^. It is also possible to react a chemical substance of the general formula ㈤ with a gasification test such as thionyl chloride to give the corresponding secret chlorine. A compound of formula (VI) can be reacted with an amine RshNH to give a compound of formula (1), where χ represents the subgroup ⑴, and Rs and ratio have the meanings given on page 2 above, that is, by activation And coupling 200530191 methods, such as the formation of active esters, or in the presence of so-called coupling agents such as DCC, HBTU, BOP (benzotriazol-1-yloxytris (dimethylamino) hexafluorophosphate scale) and the like . More information on the activation and coupling methods of amines and carboxylic acids can be found in a) M. Bodanszky and A. Bodanszky: The Practice of Peptide 5, Springer-Verlag, New York, 1994; ISBN: 0- 387-57505-7; b) K. AkdL] i et aL, Tetrahedron Lett. (\ 99A) »35,3315-3318); c) F.Albericioeia /., 7 > ira / ze (iiFW2Z ^ ". (1997), 38,4853-4856).

(CH3) aAI / R3R4NH

(V)

Where X represents the subgroup (i)

Scheme 1 10 Scheme 2 outlines the synthesis of compounds of formula (I) where X represents the subgroup VII. Intermediates of the general formula R7SO2NH2 are commercially available or can be prepared by standard synthetic methods, for example from the corresponding compound R7SO2Cl (see, for example, McMmius et al., J. Med. Chem. 1965, 8/766). A compound of the general formula (IV) can be reacted with a compound of the general formula 0022 in the presence of a Lewis acid such as AlMes in an inert organic solvent such as benzene to give a compound of formula (1), where X Represents a subgroup ⑴), and 1 ^, 112, and 117 have the meanings given on pages 1 to 3 above, and wherein R8 and A represent a hydrogen atom. A compound of the general formula (v) can be reacted with a compound of the general formula RySC ^ NH2 to give a compound of the general formula (V [[). The reaction was excellent. 12 200530191 Election was performed under strong non-parent test. Compounds that can be refined) are reacted with a gasification agent in an awake imidization reaction, and then tested by cis-treatment to give compounds of the formula (I), where X represents a subgroup (U).

(I) where X represents a subgroup (ii) where 1¾ and R9 represent} 1

υ gas imidization. 2) R8RbNH

(I) where X represents a subgroup. Scheme 2 The choice of the formation method depends on such factors as the functional group and the application. Phase Valley of Formula J 'The possibility of applying protecting groups, catalysts, activation and coupling agents, and the final structural features present in the final compounds prepared. According to these methods, the following compounds can be prepared. They are intended to further elaborate the invention ' so they should not be seen as limiting the scope of the invention in any way. Pharmaceutical formulations The compounds of the present invention can be made into a form suitable for administration using auxiliary substances such as liquid or solid carrier substances by conventional methods. The pharmaceutical composition of the present invention can be administered enterally, orally, parenterally (intramuscularly or intravenously), or transrectally. They can be administered in the form of solutions, powders, tablets, 15 capsules (including microcapsules), ointments (creams or gels) or test agents. Suitable excipients for such formulations are conventional liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavoring agents, coloring agents and / or buffering substances for pharmaceutical use. Common auxiliary substances that can be mentioned are carbonates, titanium dioxide, lactose, mannitol and other sugars, slip 13 200530191 stone, milk protein, cellulose, cellulose and its derivatives, animal and vegetable oils, such as cod liver oil, sunflower oil, Peanut or sesame oil, polyethylene glycol and solvents such as sterile water and mono- or polyhydric alcohols such as glycerol. The compounds of the present invention are generally administered as pharmaceutical compositions, which are important 5 and new embodiments of the present invention due to the presence of said compounds, and more particularly the specific compounds 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, and those disclosed herein or in the art. It will be apparent to those skilled in the art from this description and general knowledge in the art Other types. In an embodiment of the present invention, a pharmaceutical pack or kit comprising one or more containers is provided, said container being filled with one or more of the components of the pharmaceutical composition of the present invention. Associated with such a state may 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 regarding human or veterinary administration License to produce, use or sell. Pharmacological method 15 In vitro affinity for cannabinoid-CB! Receptor _ The affinity of the compound of the present invention for the cannabinoid CB receptor can be determined using a membrane product of Chinese hamster ovary (CHO) cells, in said cells The human cannabinoid CBi receptor was stably transfected with [3H] CP_55,94. After the freshly prepared cell membrane preparation was incubated with [3H] ligand with or without the compound of the present invention, 20 the bound and free ligands were separated by filtration on a glass fiber filter. Radioactivity on the filter was determined by a liquid flicker count. Cannabinoid-CB! Receptor antagonism in vitro Human CB] receptors cloned in Chinese hamster ovary (CH0) cells can be used to estimate CB] receptor antagonism in vitro. CH 0 cells were incubated with 10% heat-inactivated fetal calf serum 14 200530191

It was grown in Dulbecco's Modified Eagle's medium (DMEM) medium. The culture medium was drawn out and replaced with DMEM without fetal bovine serum but containing [3H] -arachidonic acid, and cultured overnight in a cell culture greenhouse (5% CCV 95% air; 37 ° C; water-saturated atmosphere). During this time, [3H] -arachidonic acid was incorporated into the membrane phospholipid. On the test day, the medium was withdrawn and the cells were washed three times with 0-5 ml of DMEM containing 0.2% bovine serum albumin (BSA). Stimulation of the CBA body with WIN 55,212-2 resulted in the activation of PLA2 followed by the release of [3H] _arachidonic acid into the culture medium. This WIN 55,212-2-induced release is antagonized by the CB receptor antagonist in a concentration-dependent manner.

Cannabinoid-CB! Receptor Antagonism in vivo 10 CB! Antagonism in vivo can be estimated using a CP-55,940-induced hypotension test in rats. Normally blood pressure male rats (225-300 g; Harlan, Horst, The Netherlands) were anesthetized with pentobarbital (80 mg / kg). Blood pressure was measured by a Spectramed DTX-plus pressure sensor (Spectramed B.V., Bilthoven, The Netherlands) via a cannula inserted into the left carotid artery. After zooming in by Nihon Kohden Carrier Amplifier (Type 15 AP-621G; Mhon Kohden BV ·, Amsterdam, The Netherlands), use the Po-Ne-Mah information-acquisition program (P〇-Ne-Mah Inc ·, Storrs, USA) in Blood pressure signals were recorded on a personal computer (Compaq Deskpro 386s). Heart rate is derived from the pulsating pressure signal. All compounds were administered orally 30 minutes before inducing anesthesia in the form of a microsuspension in 1% amidine cellulose, which was 60 minutes earlier than the administration of CB receptor stimulant CP-55,940. The injection volume was 10 ml / kg. After hemodynamic stabilization, the CB 丨 receptor stimulant CP-55,940 (0.1 mg / kg # inexpensive cold) was administered to produce a hypotensive effect. (Wagner, J. A .; Jarai, Z .; Batkai, S .; Kunos, G. Hemodynamic effects of cannabinoids xoronary and cerebral vasodilation mediated by cannabinoid CB] receptors. Eur. J. Pharmacol 2001 203-10). 15 200530191 Pharmaceutically acceptable salts can be obtained using standard methods well known in the art, for example, by mixing a compound of the invention with a suitable, such as non-mineral, such as, or with an organic acid. Dose 5 The affinity of the compound of the invention for the cannabinoid receptor was determined as described above. From the binding affinity determined for a given compound of formula (1), one can estimate the theoretically least effective agent to buy. At a compound concentration equal to twice the measured κΓ value, a 100% cannabinoid receptor is likely to be occupied by the compound. Assuming ideal bioavailability, converting this concentration to a compound / kg patient results in a theoretically lowest effective dose. Pharmacokinetic, pharmacodynamic, and other considerations can change the actual dose administered to higher or lower values. A suitable dose is 0.001 to 1000 mg / kg, preferably 0.1 to 100 mg / kg of the patient's body weight.

[U U Example 1: Synthesis of Specific Compounds Compounds 1-2 15 Some points: will be called 4-gas phenyl) _2,4-digas phenylhydrazone (10.0 g, 0.033 mol), 2- The magnetically stirred mixture of gas acrylonitrile (5.7 g, 0.065 mol) and N, N-diisopropylethylamine (DIPEA) (12.5 ml, 0.069 mol) in tetrahydrofuran (150 ml) was heated at reflux temperature for 40 hours. (N2 atmosphere). After cooling to room temperature, the mixture was concentrated in vacuo. The residue was dissolved in a mixture of dioxane and water (200 ml / 200 ml). The dioxane layer was collected, dried over MgS04, filtered, and concentrated in vacuo. The residue was recrystallized from ethanol / water to give 1- (4-fluorophenyl) -2- (2,4-difluorophenyl) -4,5 · dihydro-1H-amidazole melamine nitrile ( 11.23 g, 97% yield). WNMRGOO MHz, CDC13): δ 4.28 (dd, J = 10 and 8 Hz, 1H), 4.36 (t, J = 1〇Ηζ, 1Η), 5.07 (dd, J = 10 and 8 Ηζ, 1Η), 6.68 ( br d, J = 8 Hz, 2H), 7.16 (br d, Bu 8Hz, 2H), 7.32-7.36 (m, 2H), 7.45 (d, J = 8Hz, 1H). 16 200530191 Kyoto · Slowly add ethyl alcohol gas (n · 76 ml, 0.25 mol) to ethanol (1 D to give solution A. Add 1- (4'air-benzyl group> 2_ (2, 4-Diphenylphenylmethyl methotine (17.52 g '0.05 md)-added once to solution a. After cooling to room temperature, the mixture was stirred for another 40 hours and concentrated in vacuo. The residue was dissolved in Wash (3x) with dichloromethane in water (5%) NaHC03 5. Cut off the sintered layer, dry over MgS04, and concentrate under vacuum to give 1- (4-chlorophenyl). -2- (2,4-Difluorophenyl tartaric acid ethyl ester (180 g, 90% yield)) is a brown oil, which solidifies slowly upon standing. 1h_nmr (400 MHz, CDC13) : δ 1.34 (U = 7 Hz, 3H), 4.15 (dcU = 10 and 8 Ηζ, ΙΗ), 4.22 · 4 · 41 (ιή, 3Η) '4.91 (dd, J = 10 and 8 Ηζ, ΙΗ) , Secret button d, J = 8 Hz, 2H), 10 7.11 (brd, J = 8Hz, 2H), 7.30 (d (U = 8 and 2Hz, lH), 7.33 (d, J = 2Hz, lH), 7.46 (dd, J = 8 Hz, lH). — ^ • Magnetic stirring solution of outward aminobicyclo [2 · 2 · 1] heptane (0.67 ml, 0.009 mol) in anhydrous dioxane (10 ml) Add trimethyl aluminum (54 ml of 2N hexane Solution, 0.0108 mol) 'Stir the resulting solution for 20 minutes at room temperature. Slowly add 15-phenyl) -2- (2,4-diphenylphenyl) -4,5-dihydro] A solution of Ethyl sialo-4-weilate (2.385 g, 0.006 mol) in anhydrous dichloromethane (10 mi), the resulting mixture was reacted at 400 c for 40 hours (N 2 atmosphere). After cooling to room temperature, the mixture was quenched with aqueous (5%) NaHC03 and extracted with a gas burner. The dichloromethane layer was separated, dried over MgS04, filtered and concentrated in vacuo to give a crude yellow slurry ( 2.58 g), which was further purified by flash chromatography (silica gel, ethyl acetate / petroleum 20 ether = 8/2 (v / v)) to give a more rapidly moving chlorochlorophenyl) _2 · (2, 4-diphenylphenyl) -N- (exo-2-bicyclo [2 · 2 · 1] heptyl) -4,5_dihydro_1fanweizol · 4 · amine (diastereomer A ) (0.70 g, 25% yield) and slower moving Benzenebenzyl) winter (2,4-dioxophenyl) -N- (exo-2-bicyclo [2.2.1] heptyl> ; 4,5-dihydro-1fluorene-amidazole * 4-formamidine (diastereomer B) (0.69 g, 25% yield). 17 200530191 Diastereomer A: W-NMRGOO MHz, CDC13): δ ll (M.58 (m, 7H), 1.76- 1.84 (m, lH), 2.26-2.30 (ιή 52Η), 3.74-3.82 (m, lH), 4.27 (d, J ~ 10 Hz, 2H), 4.78 (tJ ~ 10Hz, 1H), 6.65 (br dj = 8 Hz, 2H), 6.70-6.78 (m, lH), 7.12 (br d, J = 8 Hz, 2H), 7.29 (br s, 2H), 7.40 (br s, lH). Diastereomer B: h-NMRGOO MHz, CDC13): δ U0-1.56 (m, 7H), 1.78-1.85 (m, lH) '2.17-2.20 (m, lH)' 2.26-2.30 (m, lH) , 3.76-3.82 (m, lH), 4.25- 4.30 (m, 2H) '4.78 (dd, J = 10 and 8 Hz, lH), 6.66 (br d, J = 8 Hz, 2H), 6.80 (br d , J ~ 7 Hz, lH), 7.11 (br d, J = 8 Hz, 2H), 7.30 (br s, 2H), 7.41 (br s, lH).

Compounds 3 and 4: K4-Gaphenyl) -2- (2,4-difluorophenyl) -4,5-dihydro-1H-imidazole-4-carboxylic acid ethyl ester (3.97 g, 0.01 mol) in a methanol / water mixture was reacted with LiOH (13 g, 0.054 mol) for 16 hours. The resulting mixture was concentrated in vacuo to give the crude acetone (I5abenzyl) -2 · (2,4-dichlorophenyl) -4,5_dihydro-1HH4-weiric acid (4 · 7 g). Breaking the points •• Crude K4-chlorophenyl) -2 · (2,4-dichlorophenyl) -4,5-dihydro-1Η- ^ at room temperature. Zy-4-weiric acid (1.0 g '~ 0.0027 mol), benzotrifluorene bis (small group) oxytri (dimethylamino) fluorene hexaphosphate (BOP) (1.2 g, 0.0027 mol), 1-amino A mixture of bite (03 g, 2003 mol) and triethylamine (1 ml) in DMF (30 ml) was stirred for 16 hours. After concentration in vacuo, 18 200530191 water was added and the resulting mixture was extracted (2x) with dichloromethane. The dichloromethane layer was collected, dried over MgS04, filtered and concentrated in vacuo to give a residue, which was further purified by flash chromatography (silica gel 'dichloromethane / methanol = 95/5 (v / v)) Gives i_ (4-aminophenyl) -2 · (2,4-dichlorophenyl) -N- (foxidinyl) -4,5-dihydro-1H-imidazole-4-carboxamide ( 3 80 5 mg, 31% yield). Hyun point: 113-116 ° C. h-NMRQOO MHz, CDC13): δ 1.33-1.48 (m, 2H), 1.60-1.80 (m, 4H), 2.68-2.82 (m, 4H), 4.28-4.35 (m, 2H), 4.84 (dd, J = 11 and 9 Hz, lH), 6.65 (br d, J = 8 Hz, 2H), 7.11 (br d, J = 8 Hz, 2H), 7.23-7.33 (m, 2H), 7.41 (d, J = 2Hz, 1H), 7.57 (brs, 1H).

10 Compound 4 was prepared in a similar manner: Compound 4 1- (4-Gaphenyl) _2- (2,4-dichlorophenyl) -N-cyclohexyl-4,5-diaza-1H-imidazole- 4-Amine. Melting point: 127-129 ° C. iH-NMRGOO MHz, CDC13): δ 1.04 · 2 · 03 (m, 10H), 3.73-3.92 (m, 1H), 4.23-4.33 (m, 2H), 4.81 (t, J ~ 10 Ηζ, 1Η ), 6.66 (br d, J = 8 Hz, 2H), 6.79 (br d, J ~ 7 Ηζ, 1Η), 7.12 (br d, J = 8 15 Hz, 2H), 7.25-7.32 (m, 2H) , 7.41 (brs, lH). 19 200530191

Compound 5-8

: Trimethylammonium (1.2 ml of 2N toluene solution, 0.0024 mol) was added dropwise to a suspension of 4-gas besysulfame (0.45 g, 0.00236 mol) in benzene (5 ml) to give a clear solution. 'Stir it at room temperature for 1 hour. Add 1- (4-chlorophenyl) -2- (2,4-difluorophenyl) -4,5-dihydro-1 tomidazol-4-carbonitrile (0.55 g, 0.00157 mol) at The resulting mixture was heated at 90 ° C for 16 hours. After cooling to room temperature, a methanol / water (8/2 (v / v)) mixture was slowly added, and the solid matter was removed by filtration and washed with chloroform (50 ml). The filtrate was concentrated in vacuo. The residue was triturated with n-pentane and recrystallized twice from methanol to give 1- (4-chlorophenyl) -2- (2,4-difluorophenyl) · N-[(4-gas Phenyl) sulfofluorene] -4,5_dihydro-1H-midol-4-methyl vein (0.435 g, 51% yield). Melting point: 165-166 ° C. ^ -NMRQOO MHz, CDC13): δ 4 · 11-4 · 35 (γπ, 2Η), 4.94 (dd, J = 12 and 10 Ηζ, 1Η), 6.63 (bi * d, J = 8 Ηζ, 2Η), 7.12 (br d, J = 8 Hz, 2H), 7.22-7.52 (m, 6H), 7.90 (brd, J = 8 Hz, 2H), 8.10-8.20 (m, lH). 20 200530191

A compound of formula (I) given below was prepared in a similar manner:

Compound 6: 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -N-[(4-fluorophenyl) -sulfofluorene] -4,5-dihydro-1H- Imidazole-4- 曱 脒. Melting point: 172-175 ° C. iH-NMRQOOMHzfDCb): δ4 · 12-4.35 (Γα, 2Η), 4.93 (dd, J = 12 and 10Hz, 1H), 6.63 (brd, J = 8Hz, 2H), 7.08-7_43 (m, 8H), 7.90 -8.02 (m, 2H), 8.10-8.20 (m, 1H).

Compound 7: 2- (4-Gaphenyl) -N- (dimethylaminosulfonium) -1-phenyl-4,5-dihydro-1H-imidazole-4-carboxamidine. Melting point: 136-139 ° C. W-NMRQOO MHz, CDC13): δ 2.79 (s, 6H), 4.20-4.40 (m, 2H), 4.97 (t, J ~ 10 Ηζ, ΙΗ), 6.83 (br d, J = 8 Hz, 2H), 7.05-7.50 (m, 8H), 7.80-7.90 (m, 1H). 21 10 200530191

= 〇

Cl

nh2

5 Example 2: Formulations used in animal studies

Formulation of Compound 1: Oral administration: Add some glass beads to the required compound ("Compound Γ ') given above in a glass tube (05 ~ 15 he), and grind the substance by vortexing for 2 minutes After adding 1 ml of methyl methylcellulose aqueous solution, the compound was suspended for 10 to 10 minutes. In order to achieve a concentration higher than and equal to mg mg, the remaining particles were further suspended in the suspension by using an ultrasonic bath. Example 3: Pharmacological test results The table below shows the in vitro cannabinoid receptor affinity and functional data obtained according to the protocol given above. 22 200530191 Table 1: Pharmacological data of human cannabinoid-CB1 receptor Antagonistic effect Compound number pKi value pA2-value (arachidic acid release) Compound 1 7.7-Compound 2 7.0-Compound 4 7.0 7.7 Compound 8 6.8-L Scheme Simple Description] (None) 5 [Description of Main Component Symbols] ( no)

twenty three

Claims (1)

200530191 10. Scope of patent application: 1. A compound of general formula (I): (I) where: -RjnR2 independently represents a phenyl group, a thienyl group or a sigma stilbyl group, these groups may be substituted by 1, 2 or 3 substituents which may be the same or different, 'substituents' are selected from the group consisting of: branched or linear alkyl Or Cl_r alkoxy, phenyl, hydroxyl, gas, bromine, fluorine, iodine, trifluoromethyl, trifluorofluorenylthio, trifluoromethoxy, carboxyl, trifluorosulfonylsulfonium, cyano, methylaminosulfonyl , Sulfasalazine and acetamidine, or oxo and / or R2 represents naphthyl, 10 -X represents one of subgroups (i) or ⑼, η -¾ represents a hydrogen atom or a branched or linear Ci3 alkyl group, -R4 represents a branched or linear C, -8 alkyl group or c3-r cycloalkyl々2-alkyl, branched or linear c, to form an oxygen group ' C3_8 ring filaments, C5] g bicyclic filaments, ^ Sanguanyl radicals, these radicals may contain one or more heteroatoms selected from the group (0, N, s), these radicals may be 3 Methyl 'one ethyl or W said atom substitution, or phenyl lactyl 1 group' red radical squamyl group, which serves on its phenyl ring 丨 3 take 24 15 200530191 substituted Y Y has the above meaning, or h represents a donating group or a phenenyl group, or R4 represents a group nr ^ r ^, wherein R5 and IV are connected to the nitrogen atom of the dagger to form a saturation with 4-10 ring atoms. Or unsaturated, monocyclic or bicyclic ring group, the heterocyclic group contains one or two heteroatoms selected from the group (0, N, S), and the heterocyclic group may be branched or linear Cw , Phenyl, or triyl or fluorine atom substitution, or • Heart and ^ together with the nitrogen atom to which they are attached, into a single-country double-heterocountry with 4-10 cyclic protons , _ County contains one or A heteroatom selected from the group (0 class), and the heterocyclic group may be substituted by a branched or linear Ci 3 10 silk, phenyl, amino, substituted by a group or a trifluoromethyl or ll atom, R > 7 represents > Benzyl 'σ sedynyl or stilbyl, these groups may be substituted on their aromatic ring by 2, 3 or 4 substituents γ, wherein γ has the aforementioned meaning, they may be the same or different, or 仏Represents Cl.8 branched or linear alkyl group, ~ bond dilute group,% cycloalkyl group, C · bicyclic alkyl group,% tricyclic alkyl group or Q · 8 cycloalkenyl group, or the heart represents 15 Czeki, or R7 represents Amino group, or & represents h-dialkylamino group, Cl.8 mono-aeroyl group, amino group—has a 4] _ring atom_ and a saturated, monocyclic or bicyclic heterocyclic group including heterocyclic group containing one or two Nitrogen atoms, and the heterocyclic group may include a heteroatom selected from the group (o, s), and the heterocyclic group may be branched or linear c to form a group, a benzyl group, a hydroxyl group or a trifluoromethyl group or Fluorine atom substitution, 20 • -¾ represents a hydrogen atom or a methyl group, represents a hydrogen atom or a methyl group, an ethyl group or a methoxy group, and tautomers, stereoisomers, and prodrugs thereof And salts. 2 · —Compounds of general formula (I) 25 X 200530191 r2 (i) wherein: -1 ^ and Xin independently represent a phenyl group, and the phenyl group may be substituted by 丨, 2 or 3 substituents Y which may be the same or different, and the substituent γ is selected from the group consisting of branched or Linear Civ alkyl or ^ · 3-alkyloxy, phenyl, hydroxy, chloro, bromo, fluoro, hard, trifluoromethyl, difluorosulfanyl, diImethoxy, methyl, trimethylmethoxide Since, cyano, methylamine, ammonia and fluorenyl, or fluorenyl and / or R2 represent naphthyl, thienyl or pyridyl, -X represents one of subgroup (i) or hydrazone, 10 Among them: -R3 represents a gas atom, -R4 represents a branched or linear C]. 8 alkyl group, a branched or linear Q • ethoxy group, or a Cw ring alkyl group, these groups can be replaced by a warp group ,: 1-3 fluorenyl groups, substituted by one ethyl group or ^ gas atoms, or R4 represents a benzyloxy group, such as an amidyl group or a fluorenyl group, or a fluorinated group of 15 NRjR ^, where R5g- a nitrogen atom attached to them -From. To form a saturated or unsaturated, monocyclic or bicyclic heterocycle having a rigid ring atom of 4. The ring radical contains one or two heteroatoms selected from the group (0; N, S), Or 26 200530191 The nitrogen atoms connected to them carefully—form · form · a monocyclic or bicyclic heterocycle with a co-or complement of 4 · ω ring atoms, the heterocyclic group contains one or two selected from A heteroatom of group (0, N, S), and the heterocyclic group may be substituted by a fluorenyl group, a group or a dimuryl group or a fluorine atom, 5% represents a phenyl group, and the phenyl group may be on its aromatic ring Substituted by 2, 3 or 4 substituents Y, where Y has the aforementioned meaning, they may be the same or different, or the machine represents C " branched or linear courtyard, 'ring courtyard or' bicyclic alkyl group , Or R? Represents Zeki, or heart represents amino, or R7 represents C, P, phenylamino, h single alkylamino, or saturated or unsaturated, monocyclic or bicyclic heterocyclic having 4 to 10 ring atoms Ring group, the hetero 10 ring group contains one or two nitrogen atoms, and the heterocyclic group may contain one hetero atom selected from group (0, s), and the heterocyclic group may be branched or linear Ci_3 Alkenyl or substituted by a group, -¾ represents a hydrogen atom, -R9 represents a hydrogen atom, 15 and tautomers, stereoisomers, prodrugs, and salts thereof. 3. · A pharmaceutical composition, in addition to a pharmaceutically acceptable carrier and / or at least one pharmaceutically acceptable substance, it also contains at least an active amount of-as in the patent application scope No. 1-2 One of the compounds or a salt thereof is used as an active ingredient. 4. If the compound of the second domain of the patent application, or a salt thereof, is used for medicine. 20 5 · A compound of general formula (IV) CN R2 (IV) Among them, RjnR2 has the meaning given in item 丨 of the patent application scope, and these compounds are suitable for the synthesis of compounds of general formula (i). 6. — A compound of general formula (V) Ri Among them, R4〇R2 has the meaning given in item 丨 of the scope of patent application, and Rio represents a branched or linear (^ · 5 alkyl or benzyl group, such compounds are suitable for the synthesis of compounds of general formula (I). 7 . — Compounds of general formula (VI) Among them, RAR2 has the meaning given in item 1 of the scope of patent application, and Rn represents rhenium or soil test metal. Such compounds are compounds of the general formula ⑴ 0 δ The use of compounds, which are for the preparation-pharmaceutical compositions for the treatment of diarrhea: psychosis, anxiety, depression, attention deficits, miscellaneous' cognitive disorders, appetite disorders, obesity, especially juvenile obesity and drugs Caused by obesity, addiction, impulse control, sensuality, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle rigidity, tremors, tumor pain, multiple sclerosis, traumatic injury, stroke, Parkinson's disease 'Alzheimer's' epilepsy 'f Tinton's disease, Tourette syndrome, cerebral ischemia, cerebral stroke, 28 15 200530191' plaque sclerosis, viral diseases including neuropathic pain, craniocerebral trauma, stroke, Spinal cord injury, neuritis, encephalitis, demyelination-related disorders, and pain disorders, disorders, and other diseases involving cannabinoid neurotransmission, including Septic shock, glaucoma, cancer, diabetes "area vomiting" nausea, asthma, respiratory disease, gastrointestinal disorders, gastric ulcers' abdominal fillings, cardiovascular disorders, atherosclerosis, cirrhosis and sexual disorders.-The following treatments Methods of disorders: psychiatry, anxiety, depression #, attention deficit, memory impairment, cognitive impairment, appetite disorder, obesity, addiction, impulse control disorder, drug 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, cerebral ischemia, cerebral stroke, brain trauma and neuropathic pain disorders, and Other diseases involving cannabinoid neurotransmission 'include glaucoma, cancer, sigma vomiting, noisy heart, asthma, respiratory disease, gastrointestinal disorders, gastric ulcers, diarrhea, cardiovascular disorders, atherosclerosis, cirrhosis and sexual disorders, 15 Λ is characterized by applying a compound of formula (I) Where: • 1 ^ and 112 independently represent phenyl, thienyl, or pyridyl, and these groups may be substituted with 1, 2, or 3 substituents Υ which may be the same or different, and the substituent Υ is selected from the group consisting of: alkyl Or (^ 3-alkoxy, phenyl, hydroxyl, chlorine, bromine, fluorine, iodine, trifluorofluorenyl, trifluoromethylthio, trifluoromethoxy, methanesulfonyl, carboxyl, trifluorosulfonylsulfonium , Cyano, 29 200530191 曱 amino 醯 'NH 绩 · ethyl 醯' or Ri # l ^ R2 represents Cai Ji, -X represents one of subgroups (i) or (ii), 0 X / R3 (0 where: -Rs represents a hydrogen atom or a branched or linear alkyl group, -R4 represents a branched or linear ^ · 8 alkyl group or a C3-r cycloalkyl_c_2 alkyl group, branched Or a linear C, 8-alkoxy group, a C3 · 8 ring group, a 'bicyclic group, a% tricyclic group, these groups may contain one or more heteroatoms selected from the group (0, N, S), And these groups can be substituted by a group of "I · 3 methyl groups, an ethyl group or a μ3 group, or 仏 represents a phenyl group, a phenyloxy H phenethyl group, or a phenylpropyl group" on their benzene filament. Optionally substituted with 1 to 3 substituents 其 whose γ has the above meaning, or < silanyl or phenphenyl, or R4 represents the group NR5R6, wherein Ι ^ ιν is formed together with the nitrogen atom to which they are attached A saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms, the heterocyclic group containing one or two heteroatoms selected from the group (0, N, S), and the heterocyclic ring The radical may be substituted by a branched or linear c "3 alkyl, phenyl, hydroxy or trifluoromethyl or fluorine atom, or R3 and the nitrogen atom to which they are attached-form a saturation with 4 to 10 ring atoms Unsaturated, monocyclic or bicyclic heterocyclyl, a cyclyl contains one or more heteroatoms selected from the group (o, n, s) and the heterocyclyl may be branched or linear A. Hyunyl 'Phenyl, amino' or triphenylene atom substitution,% represents benzyl, phenyl, phenenyl or back group, these groups can be 1, 2, 3 or 4 on their aromatic ring 30 200530191 Y substituents, wherein γ has the aforementioned meaning, they may be the same or different, or R? Represents Cl · 8 branched or linear alkyl, C3_8 alkenyl, C3 i0 cycloalkyl, C5_] G bicycloalkyl , Q is a tricycloalkyl or Q_8 cycloalkenyl, or is a naphthyl, or R7 is an amino, or is a Q · 8 dialkylamino, a monoalkylamino or a saturated or An unsaturated, monocyclic or bicyclic heterocyclic group, the heterocyclic group containing 1 or 2 nitrogen atoms, and the heterocyclic group may include a hetero atom selected from the group (0, S), and the heterocyclic group Can be branched or linear & alkyi, benzyl, substituted by a radical or trifluorofluorenyl or fluorine atom, -¾ represents a hydrogen atom or methyl, • R9 represents a hydrogen atom or fluorenyl Ethyl or methoxy, and tautomers' stereoisomers, precursors and salts thereof. Ο. The use according to the scope of patent application No. 8 is characterized in that the disorder is an eating disorder, especially Obesity, juvenile obesity, and obesity caused by drugs. Η · A kind of low-quality compound, such as an application for supplementation, which is prepared for the treatment of eating disorders, and is made of obesity, obesity, and obesity caused by drugs. The pharmaceutical-pharmaceutical domain is characterized in that the drunk domain further comprises at least a lipase inhibitor. U. If the application in the scope of application of the patent application item u is orlistat or ribasstatin. /, Characterized in that the lipase inhibitor 31 200530191 VII. Designated representative map: (1) The designated representative map in this case is: (). (2) Brief description of the component symbols in this representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: