TWI335321B - Imidazoline derivatives having cb1-antagonistic activity - Google Patents

Description

IX. INSTRUCTIONS: [Technical Field] The present invention relates to a 1,2,4-disubstituted rice guillotine derivative as a CBi antagonist, a method for preparing the same, and a method for synthesizing the imipenem A novel intermediate for derivatives. 5 The invention also relates to the use of a compound disclosed herein in the manufacture of a medicament which gives a beneficial effect. Advantageous effects are disclosed herein or will be apparent to those skilled in the art from this disclosure and the general knowledge in the field. The invention further 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 particularly, the present invention relates to the novel use of treating a disease or condition disclosed herein or apparent to those skilled in the art from this disclosure and the general knowledge of the art. In an embodiment of the invention, the particular compounds disclosed herein are used to produce a drug, i.e., a disorder suitable for treating a cannabinoid receptor, or a disorder that can be treated by controlling these receptors. 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 the treatment of certain types of tumors. The imipenem derivatives also have potent activity as anti-inflammatory agents and antibiotics, leading to another series of indications in which they may have therapeutic implications including inflammatory and infectious diseases. It is not clear that the compounds described in the above patent applications have any affinity for cannabinoids, so they are unlikely to have a therapeutic value for a disorder involving these cannabinoid receptors. The object of the present invention is to identify such imidazolium derivatives, i.e., having an effective activity as a cannabinoid-匸8| receptor modulator while substantially maintaining the physicochemical properties of the imidazole derivatives as therapeutic agents.丄) is 321 It has been unexpectedly discovered that the effective antagonism or reverse action of the cannabinoid <31 receptor exists in the novel 4,5-dihydro-1H-isoxazole derivative of formula (I) and Its tautomers, Lie isomers, prodrugs and salts

R2 (I) 5 wherein: - 艮 and 尺 2 independently represent phenyl, thienyl or pyridyl, these groups may be substituted by 3 substituents Y which may be the same or different, and substituent Y is selected from the group consisting of Base: Branch or line hard Cw base or Ci-r house oxy 'phenyl, via base, gas, bromine, fluorine, hydrazine, trioxo, two #1 methylthio, difluoroantimony, Rebel, trifluoromethane, cyano, methylamine, ampicillin 10 and ethyl, or Ri and / or R2 for Cai Ke, -X for one of subgroups (i) or (ii) ,

Wherein: -3⁄4 represents a hydrogen atom or a branched or linear Ci3 alkyl group, and 15-R4 represents a branched or linear 0^-8 alkyl group or a C3·8. cycloalkyl-Q.2-alkyl group, branched or linear C,·8·alkoxy, C 3-8 il alkyl, C 5 —IG bicycloalkyl, c 61 Gi cycloalkyl, these groups may contain one or more heteroatoms selected from the group (〇, N, S), and These groups may be substituted by a hydroxy group, a _3 methyl group, an ethyl group or an I.3 atom, or a heart, a phenoxy group, a phenoxy group, a hexyl group or a propyl group. The stupid base ring is optionally substituted with 13 substituents, wherein γ has the above meaning 'or 1^ represents a thiol or porphinyl group, or & represents a group NR5R6, wherein, as in the nitrogen atom to which they are attached Forming together a '5-saturated or unsaturated, monocyclic or bis-heterocyclic group having 4 to 10 ring atoms, the heterocyclic group containing - or two selected groups (the hetero atom of the flood season, Further, the heterocyclic group may be branched or substituted by a linear C,·3 alkyl group, a phenyl group, a fluorenyl group or a trifluoromethyl group or a fluorine atom, or a nitrogen atom to which R3 and R4 are bonded to form a Have a bribe A saturated or unsaturated, monocyclic or bicyclic heterocyclic group of a ring atom, the heterocyclic group comprising one or two selected H) self groups (0, N, __ sub' and the transrading group may be supported a domain _Ci·alkyl, a styl group, an amino group, a hydroxy or a trifluoromethyl group or a fluorine atom substituted, also denotes a benzyl group, a stupid group, an anthranyl group or a donor group, which groups may be i on their aromatic rings, 2 '3 or 4 substituents Y substituted, wherein γ has the aforementioned meaning, they may be the same or different 'or R7 represents Cl_8 branching or linear group, Q marriage group, ^cyclofilament, A ·]. , % tricycloalkyl or & ring, or & represents naphthyl, or exemplified by • gas-based or R-n. -8 dialkylamino, ~monoalkylamino or 4-islet a saturated or unsaturated, monocyclic or bicyclic heterocyclic group of an atom, the heterocyclic group containing a cation of a chaotic atom, and the heterocyclic group may contain one selected from the group (〇s)_ atom, and the heterocyclic ring The group may be substituted by a branched scaly W group, a phenyl group, a woven group or a _ group, 20-R8 represents a hydrogen atom or a fluorenyl group, and -R9 represents a hydrogen atom or a fluorenyl group, an ethyl group or a decyloxy group. Combination There is at least one chiral core (C4 position of the entangled portion). The present invention relates to both a formula, a mixture of hybrids and a single stereoisomer of a compound of formula (1). Also contemplated is a compound of the formula 7 1335321, a Z isomer and an E/Z mixture. A prodrug is a therapeutic agent that is itself inactive but is converted to one or more active metabolites. The prodrug is used A bioreversible derivative of a drug molecule that overcomes certain obstacles in the use of a parent drug molecule, including but not limited to, solubility, permeability, 5 stability, presystemic metabolism, and targeting limitations (Medicinal)

Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed·: F D

King, p. 215; J. Stella, uProdrugs as therapeutics', Expert Opin. Ther Patents, 14(3) > 277-280, 2004; P. Ettmayer et al., uLessons learned from marketed and investigational prodrugs 10 J. Med. Chem., 47, 2393-2404, 2004). Prodrugs, i.e., compounds which are metabolized to a compound of formula (I) when administered to a human by any known route, are within the scope of the invention. In particular this relates to compounds having a primary or secondary amino group or a trans group. Such compounds can be reacted with an organic acid to form a compound of formula (I) wherein 'there are additional groups which are readily removed after administration, such as, but not limited to, hydrazine, enamine, Mannich, hydroxy-methylene Derivatives, hydrazine (acid 15 fluorenyl amino phthalate) derivatives, amino phthalates, esters, g! amines or dilute ketones. The invention particularly relates to compounds of formula (I)

R2 (|) wherein: - heart and rule 2 independently represent phenyl 'the phenyl group may be substituted by 2 or 3 substituents Y which may be the same or different 20, and the substituent Y is selected from the group consisting of: branching or Linear c]_3-alkyl or Cw-alkoxy, phenyl 'trans group, It 'bromo, fluoro, argon, trifluoromethyl, trifluorosulfonyl, trifluoro 8 1335321 methoxy, carboxyl, tri Fluoromethylsulfonium, cyano, methotrexate, amsulfoxane and ethenyl, or R and/or R2 represent naphthyl, anthracenyl or. Than the bite base, -X indicates one of the subgroups (i) or (H), 5

10

N (0 / latch 3

R where: • R3 is not a wind atom, -R4 is unbranched or linear. 8 alkyl, branched or linear Ci 8 methoxy or 8-ring valence ' these groups can be - a warp group, W 曱a group, an ethyl or 13 money atom substituted, or R4 table * phenyl 'stupoxy' gift group or phenyl group, or &silk;

Rs and IV with the nitrogen atom to which they are attached form a saturated or unsaturated, monocyclic or bicyclic ring group having 4 to 1 ring atoms, and the face ring group contains one or two selected from the group (0, N, S) heteroatoms, or

15 & and R4 together with the nitrogen atom to which they are attached form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 1 ring atom, the heterocyclic group containing one or two selected from a hetero atom of the group (0, N, S), and the hetero group can be substituted by a fluorenyl group, a trifluoroindenyl group or a gas atom, and -R7 represents a phenyl group, which can be deuterated on its anthracene ring, 2 , 3 or a substituent Y substituted, wherein Y has the aforementioned meaning, which may be singular or different, or R? represents a branched or 20-line alkyl group 'C3.10 cycloalkyl or 'bicyclic alkyl, or & represents The base or chemical represents an amino group, or r7 represents (^ dialkylamino group, Ci 8 monoalkylamino group or saturated or unsaturated (4) having a 4-position ring 9 atom, a single county double-ring county, n K v α °^ The hetero group contains 1 or 2", the ring group may contain - a hetero atom selected from the group (〇, S), and the group may be debranched or linear C|3 alkyl or hydroxy substituted, -Rs represents a hydrogen atom, -R9 represents a hydrogen atom, and its tautomers, stereoisomers' prodrugs and salts. The compounds of the invention are suitable for use due to potent CB^ anti-activity Psychiatry = obstruction 'such as mental illness, anxiety, hip, attention deficit, memory disorder, cognitive impairment, dysentery disorder, transfusion' system is to solve obesity (four) set off obesity, paralyzed, impulsive control disorder, meat Punishment 'drug dependence and neurological disorders such as neurodegenerative disorders, dystonia's dystonia's muscle rigidity, tremor, pain, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease , Tourette syndrome, cerebral ischemia, cerebral apoplexy 'cranial trauma, stroke, spinal cord injury, neuroinflammatory disorder, plaque sclerosis, malignant encephalitis, dislocation phase _ disorder, in order to treat pain disorders, including Neuropathic pain disorders, as well as other diseases involving cannabinoid neurotransmission, including treatment of septic shock, glaucoma, cancer, diabetes, vomiting, nausea, asthma, respiratory disease, gastrointestinal disorders, gastric ulcer, diarrhea, cardiovascular Barriers, atherosclerosis, cirrhosis and sexual disorders. The cannabinoid receptor modulating activity of the compounds of the invention allows them to It is particularly suitable for the treatment of obesity, juvenile obesity and drug-induced obesity when used in combination with a lipase inhibitor. Specific examples of compounds which can be used in such a combination preparation are, but not limited to, synthetic lipase inhibitor Orlistis He (orlistat), a lipase inhibitor isolated from microorganisms, such as lipstatin (from the table 爹 泼 泼 泼 冲 冲 冲 . . . . . 7 7 7 7 7 7 7 7 7 7 7 7 7 7 、 、 、 、 、 、 、 、 、 、 、 、 、 (ebelactone B) [derived from Strupa 1333321, synthetic derivatives of these compounds, and plant extracts known to have lipase inhibitory activity, such as extracts of Alpinia officinarum or extracts from such An isolated compound, such as 3-mercaptoether galangin (from galangal). General Aspects of Synthesis 5 The synthesis of compounds of formula (I) wherein X represents subgroup (i) is outlined in Scheme 1. Intermediates of the formula (π) can be obtained according to known methods, see for example: IK Khanna et al., J. Med. Chem. 2000, 43, 3168-3185; IK Khanna et al., J. Med. Chem. l"7,4〇,l634-l647; WO 〇3/〇27〇76 or wo 〇3/〇4〇l〇7. The intermediate of the formula (IV) can be obtained according to known methods, see for example: I. K. Khanna et al., J. Med. Chem. 10 2000, 43, 3168-3185. The formazan compound of the formula (Π) can be reacted with 2-propene propylene (m) to give a 4,5-dihydro-1H-imidazole derivative of the formula (iv). This reaction is preferably carried out in the presence of a domain such as n,N-diisopropylethylamine. The derivative of the formula (W) obtained by the alcohol 1110-〇118 can be used to give a 4,5-dihydro-1H-imidazole derivative of the formula (v) wherein 'R, 〇 represents branching or linear (^5 alkyl or benzyl 15 group. The reaction is preferably carried out under acidic conditions. The compound of formula (V) can be reacted with an amine R&NH, preferably in the presence of trimethylaluminum, to give formula (j) a compound wherein 'X represents a subgroup (i), and the scales 3 and 1^ have the meanings given on page 2 above. More on the amidation reaction of the ester promoted by the tridecyl chain A1(CH3)3 Information can be found at: JI Levin, E. Turos, SM Weinreb, 5y «i/z Commun. (\9%2) > 72.989-993 ° 20 Alternatively, the compound of formula (V) can be hydrolyzed to the corresponding A carboxylic acid derivative of the formula (VI) wherein 'R' represents a ruthenium or a soil tester 'in particular Li, Ma or K. The compound of the formula (VI) can also be chlorinated with a chlorinating agent such as sulphur. The gas reacts to give the corresponding ruthenium chloride. The compound of the formula (VI) can be reacted with an amine to give a compound of the formula (j), wherein χ represents a subgroup (1), and the rulers 3 and 1 have the former The meaning given on page 2, ie by activation And coupling 11 1335321 methods, such as the formation of active esters, or in the presence of so-called coupling agents such as DCC, HBTU, BOP (benzotris-l-yloxy-tris(diamino) hexafluorophosphate) 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 ,S>;«/A^/i,Springer-Verlag, New York, 1994; ISBN: 0-387-57505-7; b) K. Akai\ et al., Tetrahedron Lett. (\994), 35, 3315-3318);

NH =<

CN

Cl R2 (il) (HI) DIPEA reflow

, 38, 4853-4856).

(V)

(CH^aAI/RjR^NH

(V) (VI) (I) where X represents subgroup (i) diagram 1

Scheme 2 summarizes the synthesis of compounds of formula (I) wherein X represents subgroup (ii). Intermediates of the formula R7S02NH2 are commercially available or can be prepared by standard synthetic methods, for example from the corresponding compounds (see, for example, McManus et al., J. Med. Chem. 1965, 8, 766). A compound of the formula (I) can be obtained by reacting a compound of the formula (IV) with a compound of the formula R7s〇2NH2 in the presence of a Lewis acid such as AlMe3 in an inert organic solvent such as stupid, wherein 'X represents a subgroup (9), and R1; R々R7 have the meanings given on pages 1 to 3 above and wherein R8 and R9 represent a hydrogen atom. The compound of the formula (v) can be reacted with a compound of the formula R7S〇2NH2 to give a compound of the formula (10)). The reaction is preferably carried out in the presence of a strong non-nucleophilic domain. The compound of the formula (νπ) can be reacted with a gasifying agent in a gas imidization reaction, followed by treatment with an amine RsI^NH to give a character of the formula (1), wherein X represents a subgroup (ii) .

X I (0 where X represents subgroup (ii) where fe and R9 represent Η

Xenon fe imidization 2) ReReNH

4

I 〇) where X represents subgroup (ii) Scheme 2 The choice of synthetic method depends on such factors as the phase of the functional group with the deer reagent, the application of protecting groups, catalysts, activation and coupling agents. The possibility, as well as the final structural characteristics present in the final compound produced. According to these methods, the following compounds can be prepared. They are intended to further illustrate the invention in further detail and are not to be considered as limiting the scope of the invention in any way. Pharmaceutical Formulations The compounds of the present invention can be formulated into a form suitable for administration by a conventional method using an auxiliary substance such as a liquid or solid carrier. The pharmaceutical composition of the present invention can be administered enterally, orally, parenterally (intramuscularly or intravenously), rectally or topically. They may be administered in the form of a solution, a powder, a tablet, an I5 sac (package minus M), an ointment (cream gel) or a suppository. Suitable excipients for use in such formulations are conventional liquid or solid fillers and extenders, colds, emulsifiers, lubricants, flavoring agents, coloring agents and/or buffering substances. Common auxiliary substances that may be mentioned are magnesium carbonate 'dioxide, lactose, mannitol and other sugars, slip 13 stone, milk protein, gelatin, hard, cellulose and its derivatives, animal and vegetable oils, such as cod liver oil, coleus Oil, peanut oil, sesame oil, polyethylene glycol and a solvent such as sterile water and a monohydric or polyhydric alcohol such as glycerin. The compounds of the invention are typically administered as pharmaceutical compositions which are important and novel embodiments of the invention due to the presence of the compounds, more specifically the particular compounds disclosed herein. Types of pharmaceutical compositions that may be used include, but are not limited to, tablets, chewable tablets, capsules, solutions, parenteral solutions, suppositories, suspensions, and others disclosed herein or apparent to those skilled in the art from this disclosure and the general knowledge in the art. Types of. In an embodiment of the invention, a package or kit comprising or a spicy container is provided, the barn being filled with one or more of the components of the pharmaceutical composition of the invention. Related to such containers may be various written materials, such as instructions for use, or precautions in the form prescribed by a government agency that regulates the manufacture, use, or sale of pharmaceutical products, which reflect the government agency's administration of human or veterinary medicine. A license to produce, use or sell. In vitro affinity of the pharmacological method for the cannabinoid-CB1 receptor The affinity of the compound of the present invention for cannabinoid CB, receptor can be determined using a membrane preparation of Chinese hamster ovary (CHO) cells. The human cannabinoid CBi receptor was transfected together with [3H]CP_55, 94〇 as a radioligand. Freshly prepared cell membrane preparations were incubated with [3H] ligands with or without the addition of the compounds of the invention, and the bound and free ligands were separated by filtration on a glass fiber filter. The radioactivity on the filter was determined by liquid scintillation counting. In vitro cannabinoid-CB, receptor antagonism CB receptor antagonism in vitro can be estimated using human CB丨 receptors cloned in Chinese hamster ovary (CHO) cells. CH〇 cells were added to 1〇% heat-inactivated fetal bovine serum 1335321

Growth in Dulbecco's Modified Eagle's medium (DMEM) medium. The medium was extracted and replaced with DMEM containing no fetal bovine serum but containing [3H]-arachidonic acid, and cultured overnight in a cell culture greenhouse (5% CO 2 /95% air; 37 ° C; water-saturated atmosphere). During this time, [3H]-arachidonic acid was incorporated into the membrane phospholipid. On the day of the experiment, the medium was withdrawn, and the cells were washed three times with 5 ml of DMEM containing 0.2% bovine serum albumin (BSA). Stimulation of the CB 丨 receptor with WIN 55,212-2 resulted in activation of PLA2, followed by release of [3H]-arachidonic acid into the medium. The WIN 55,212-2-induced release is antagonized by CB! receptor antagonists depending on the concentration. Cannabinoid-CBi receptor nociceptive effects in vivo 10 In vivo CB! antagonism can be estimated using CP-55,940-induced hypotension test in rats. Male normotensive rats (225-300 g; Harlan, Horst, The Netherlands) were anesthetized with pentobarbital (80 mg/kg guanglan). Blood pressure was measured via a cannula inserted into the left carotid artery by a Spectramed DTX-plus pressure sensor (Spectramed B.V., Bilthoven, The Netherlands). After zooming in, Nihon Kohden Carrier Amplifier (Type 15 AP-621G; Nihon Kohden B.V., Amsterdam, The Netherlands)

Blood pressure signals were recorded on a personal computer (Comp called Deskpro 386s) using the Po-Ne-Mah information-acquisition program (Po-Ne-Mah Inc., Storrs, USA). The heart rate is derived from the pulsating pressure signal. All compounds were administered orally in the form of a microsuspension in 1% thiol cellulose 30 minutes prior to anesthesia, which was 60 minutes earlier than administration of CB, the receptor agonist CP-55, 940. The amount of 20 injected is 10 ml/kg. After hemodynamic stabilization, CB 丨 receptor stimulant CP-55, 940 (0.11 mg/kg #靡巧) was administered to produce hypotensive effects. (Wagner, JA; Jarai, Z.; Batkai, S.; Kunos, G. Hemodynamic effects of cannabinoidsxoronary and cerebral vasodilation mediated by cannabinoid CB] receptors. Eur.J.Pharmacol. 2001,423, 203-10) « 15 1335321 The pharmaceutically acceptable salts can be obtained, for example, by mixing the compounds of the invention with a suitable acid, such as a mineral acid, such as hydrochloric acid, or with an organic acid, using standard methods well known in the art. Dosage 5 The affinity of the compounds of the invention for cannabinoid receptors was determined as described above. From the binding affinity determined for a given compound of formula (1), one can estimate the theoretical minimum effective dose. At a compound concentration equal to twice the measured κ Γ value, the 100% cannabinoid receptor is likely to be occupied by the compound. Assuming the desired bioavailability, converting this concentration to mg compound/kg patient yields the theoretical minimum effective dose. Pharmacokinetic, pharmacodynamic, and other factors may change the actual administered dose to a higher or lower value. The appropriate dose to be administered is 0.001-1000 mg/kg, preferably 0.1-100 mg. /kg patient weight. C. Embodiment 3 Example 1: Synthesis of a specific compound Compound 1-2 15 Four points: a team (4~chlorophenyl)-2,4-digastric a formazan (1〇.〇克,〇.〇 Magnetic stirring of 23 mol), 2-chloroacrylonitrile (5.7 g '〇.〇65 mol) and N,N-diisopropylethylamine (DIPEA) (12.5 ml, 0.069 mol) in tetrahydrofuran (150 ml) The mixture was heated at reflux temperature for 4 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 20 mL of MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from ethanol/water to give 1-(4-carboyl)-2-(2,4-dioxaphenyl)·4,5-dihydro-1 Η-[Mazole-4- Nitrile (11_23 g, 97% yield). 'H-NMR (400 MHz 5 CDC13): δ 4.28 (ddJ = 10#〇8 Ηζ, ΙΗ) >4.36(t; J = l〇Hz51H), 5.07 (dd, J = i〇 and 8 Hz; lH), 6.68 (br ty = 8 Hz, 2H), 7.16 (br d, J = 8 Hz, 2H), 7.32 - 7.36 (m, 2H), 7.45 (d, J = 8 Hz, lH). 16 1335321 Hoof: Ethanol (17.76 m1, 0·25 mol) was slowly added to ethanol (1 Torr) to give solution A. 1-(4-Phenylphenyl)-2-(2,4-dioxaphenyl)_4,5-dihydro-out-imidazole-indole nitrile (17.52 g '〇.〇5 mol) - sub-additive Go to solution A. After cooling to room temperature, the mixture was stirred for additional 40 hours and concentrated in vacuo. The residue was dissolved in dichloromethane and washed (3×) with aqueous (5%) NaHC. The dioxane layer was separated, dried over MgS(R) 4, filtered and concentrated in vacuo to give <RTI ID=0.0>> -1H- glutinous rice salicylic acid ethyl ester (18 · 0 g, 90% yield) 'as a color oil' which slowly solidifies at rest, MHz, CDC13): δ 1.34 (t, J = 7 Hz, 3H) ' 4.15 (dd, J = 1 〇 and 8 Ηζ, ΙΗ), 4.22-4.41 (m, 3H), 4.91 (dd, J = 10 and 8 Ηζ, 1 Η), 6.66 (br d, J = 8 Hz, 2H), 10 7.11 (br d, J = 8 Hz, 2H), 7.30 (dd, J = 8 and 2 Hz, lH), 7.33 (d, J = 2 Hz, lH), 7.46 (dd , J = 8 Hz, lH). Part: The external type-2_aminobicycloindole·2·1]heptane (〇·67 ml, 0.009 mol) was added to the magnetic search solution in a water-free gas pit (10 ml). 4 m 丨 2n hexane solution '0.0108 mol) 'The resulting solution was stirred at room temperature for 20 minutes. Slowly add 1(4_ 15 lactyl)-2-(2,4-diphenyl)-4,5-dihydro-1H-0 m. -4-butyric acid vinegar (2.385 g, 0.006) Mol) Solution in a water-free broth (10 ml) 'The resulting mixture was reacted at 4 ° C for 40 hours (N 2 gas). After cooling to room temperature, the mixture was quenched with aqueous (5%) NaHC03 and extracted with a gas. Separation of the second gas enthalpy layer 'dry on MgS 〇 4, after the transition, the vacuum is concentrated. 1⁄2 to give a crude yellow stimulating material (2.58 g)' by flash chromatography (Shi Xijiao, acetic acid vinegar / petroleum 20 test = 8/2(v/v)) further purified to give a more rapidly moving 丨_(4·gasphenyl)·2_(2 4_一乳本基)_Ν-(exotype-2-double%[ 2.2.1] heptyl)-4,5-dihydro-1 Η-° 〇 -4--4-methylamide (diastereomer oxime) (0·70 g '25% yield) and more slowly moving Ϊ́-(4·chlorophenyl)_2_(2,4-diphenyl)-N-(exo-2-bicyclo[2.2.1]heptyl)-4;5-dihydro-1H-imidazole- 4-decylamine (diastereomer oxime) (0·69 g, 25% yield). 17 1335321

Diastereomer A : b-NMRGOO MHz, CDC13) : δ ll〇-l.58 (m7H), 1.76-1.84 (m, lH), 2.26-2.30 (m, 2H), 3.74-3.82 (m, lH ), 4.27 (d, J ~ 10 Hz, 2H) ' 4.78 (t, J ~ i 〇Ηζ, ΙΗ), 6_65 (br d, J = 8 Hz, 2H) ' 6.70-6.78(m, lH), 7.12 (brd, J = 8 Hz, 2H), 7.29 (brs, 2H), 7.40 (brs, lH). Diastereomer B : Α-ΝΜΙ^ΟΟ MHz, CDC13) : δ ll〇-i.56(m7H), 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), 0.66 (br d, J = 8 Hz 2H), 6.80 (br d, J ~ 7 Ηζ, ΙΗ) ' 7.11 (br d, J = 8 Hz, 2H), 7.30 (br S, 2H), 7.4l (br s, lH).

Compound 3 and 4 A: 1-(4-Phenylphenyl)-2-(2,4-diphenyl)-4,5-diaza_1H-imidazole-4-carboxylic acid B at room temperature A mixture of ester (3.97 g, 0.1 mol) in methanol/water was reacted with Li〇H (13 g, 0.054 mol) for 16 h. The resulting mixture was concentrated in vacuo to give crude </RTI> <RTI ID=0.0>(4 </RTI> phenyl)-2-(2,4-dichlorophenyl)-4,5-dihydro-1 oxime- carbazole-4-carboxylate Acid by (4.7 g). Part B: Crude 1-(4-Phenylphenyl)-2-(2,4-diphenyl)-4,5-dihydro-1H-m-O--4-indolic acid at room temperature Li (1·〇克'~0.0027 mol), stupid and three-seat _ι·yloxytris(dimethoxy)phosphonium hexaphosphate (Β〇Ρ) (1·2 g ' 0.0027 mol), 1-amino A mixture of bite (0 3 g, 0.003 mol) and triethylamine (1 ml) in DMF (30 ml) was stirred for 16 h. After concentration in vacuo, water was added at 18 1335321, and the resulting mixture was extracted with dioxane (2 χ). The dioxane layer was collected, dried over MgSO4, filtered and concentrated in vacuo to give a residue which was further purified by flash chromatography (eluent, hexane, decane = 95/5 (v/v)) 1-(4-Phenylphenyl)-2-(2,4-dichlorophenyl)-N-(acridin-1-yl)-4,5-dihydro-1H-imidazole-4- Indoleamine (3 80 5 mg, 31% yield). Melting point: 113-116 ° C. W-NMRPOO MHz, CDC13): δ 1.33-1.48 (m, 2H) &gt; 1.60-1.80 (m, 4H) &gt; 2.68-2.82 (m, 4H) &gt; 4.28-4.35 (m, 2H) &gt; 4.84 (dd, J = 11 and 9 Ηζ, ΙΗ), 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 = 2 Hz, lH), 7.57 (brs, lH).

10 Compound 4 was prepared in a similar manner: Compound 4: 1-(4-Phenylphenyl)-2-(2,4-diphenyl)-N-cyclohexyl-4,5-dihydro-1H-imidazole -4-decylamine. Melting point: 127-129 ° C. W-NMRPOO MHz, CDC13): δ 1.04-2.03 (m, 10H), 3_73-3.92 (m, lH), 4.23-4.33 (m, 2H), 4.81 (t, J 〜10 Ηζ, ΙΗ), 6.66 ( Br d5J = 8 Hz, 2H), 6.79 (br d, J ~ 7 Hz, lH), 7.12 (br d, J = 8 15 Hz, 2H), 7.25-7_32 (m, 2H), 7.41 (br s, lH). 19 Compound 4 Compound 5-8: Add trimethylaluminum (1.2 ml of 2N toluene solution, 0.0024) to the suspension of 4-oxophthalamide (0.45 g, 0.00236 mol) in benzene (5 ml). Mol) gives a clear "Valley" which is stirred for 1 hour at room temperature. Add 1-(4-Phenylphenyl)-2-(2,4-diphenyl)-4,5-—gas-1H-°mwa-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 mixture of methanol/water (8/2 (v/v)) was slowly added, and the solid was removed by filtration and washed with chloroform (50 ml). The filtrate was concentrated in vacuo. The residue was triturated with hydrazine and recrystallized twice from methanol to give 1-(4-phenylphenyl)-2-(2,4-dis. Chlorophenyl base) Continued brewing] 4,5-dihydro-1 private microphone sitting 4-mercapto (0.435 g, yield). Melting point: 165 ~ 166 ° C. , H-NMR (200 MHZ, CDC13): δ 4.11-4.35 (m, 2H), (94 (dd, J = 12 and i 〇 Hz, 1H), 6 63 (br d J = 8 Hz, 2H), 7 12 buckle d J = 8

Hz, 2H) &gt; 7.22-7.52 (m, 6H) &gt; 7.90 (br d, J = 8 Hz, 2H) » 8.10-8.20 (m, lH). 20 1335321

=〇

The compound of formula (i) given below was prepared in a similar manner: Compound 6: 1-(4-Phenylphenyl)-2-(2,4-dichlorophenyl)-N-[(4-fluorobenzene) Base)-sulfonyl]-4,5-dihydro-1H-imidazole-4-indole. Melting point: 172-175 ° C. W-NMRpOOMHzfDCb): 5 δ 4.12-4.35 (m, 2H), 4.93 (dd, J=12 and 10 Ηζ, ΙΗ), 6.63 (br d, J = 8 Hz, 2H), 7.08-7.43 (m, 8H) ), 7.90-8.02 (m, 2H), 8.10-8.20 (m, lH).

Compound 7: 2-(4-Phenylphenyl)-N-(diazepinesulfonyl)-1-phenyl-4,5-dihydro-1H-imidazol-4-indole. Melting point: 136-139 ° C. W-NMRPOO MHz, CDC13): δ 2.79 (s, 6H), 4_20-4.40 (m; 2H), 4.97 (t, J 〜10 Ηζ, 1 Η), 6.83 (br d, J = 8 Hz, 2H), 7.05-7_50 (m, 8H), 7_80-7.90 (m, lH). 21 丄州5321

S species 8. 1_(4_qiqiji)_2 "2,4_di-phenylene" ice (dioxasulfonamide) _4 5_ dihydro-1H-mi 唆.4_曱肼'. Melting point: i46_i4rc.

Example 2: Formulations for use in animal studies Formulation of Compound 1 : Oral (iv) administration: To the required amount (05 to 15 mg) in a glass tube, some glass beads were added as a "compound given in compound 1" by vortexing The material was ground for 2 minutes. After adding 1 ml of 1% methylcellulose aqueous solution, the compound was suspended by vortexing for 〇min. To achieve a concentration of 1 mg/mi or higher, the remaining particles were made by ultrasonic bath. Further suspension in suspension.Example 3: Pharmacological test results The in vitro cannabinoid receptor affinity and function data obtained according to the protocol given above are shown in the table below. 22 1335321 Table 1: Pharmacological data Human cannabinoids - CB! Receptor Affinity Affinity Incentive Compound Number pKi value pA2-value (arachidonic acid release) Compound 1 7.7 - Compound 2 7.0 - Compound 4 7.0 7.7 Compound 8 6.8 - I: Simple description of the figure 3 (none) 5 [Description of main component symbols] (none)

twenty three

Claims (1)

1335321 Patent application No. 94104182 Application for amendment of patent scope This revision period: September 10, 1999, the scope of application for patent: 1. A compound of the formula (I): Double-sided photocopying I If! Μ r2 (I) where: 5 10 -Rj〇R2 independently represents a stupid, thienyl or pyridyl group which may be substituted by 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 ( ^-3-Alkyl or CK3-alkoxy, phenyl, hydroxy, qi, bromo, fluoro, iodo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, carboxy, trifluorosulfonium sulfonate , cyano, methotrexate, amsulfoxane and ethenyl, or Rja/ or R2 represents naphthyl, and -X represents one of subgroups (1) or (ii), Of which: ΙΑ (0 -R3 represents a hydrogen atom or a branched or linear cN3 group, -R4 represents a branched or linear CN8 alkyl group or a C3_8-cycloalkyl-Cw alkyl group, a branched or linear Cm alkoxy group, &lt;:3_8 naphthenic acid a group, c5-1G bicycloalkyl, CV1Q tricycloalkyl, these groups may contain one or more heteroatoms selected from the group (〇, N, S), and these groups may be a hydroxyl group, 1-3 Substituent, one ethyl or 丨_3 fluorine atom substituted, or ^ represents phenoxy 'benzyl' phenethyl or phenylpropyl 'optionally on their phenyl ring 丨 _ 3 take 24 15 1335321 Patent Application No. 94104182, the scope of the patent application is amended. The term of the amendment is: September 5, 10 10 15 Substituted by Y, wherein Y has the above meaning, or R4 represents pyridyl or thienyl, or R4 represents NR5R6, wherein ^ and !^- together with the nitrogen atom to which they are attached - form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4-1 turns of a ring atom, the heterocyclic group comprising one or two selected from a hetero atom of the group (〇, N, S), and the heterocyclic group may be branched or linear c13 alkyl, phenyl, hydroxy or trifluoromethyl or fluorocarbon Substituting, or &amp; and Rr together with the nitrogen atom to which they are attached - form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4-1 ring atoms containing one or two a hetero atom selected from the group (0, N, S), and the heterocyclic group may be substituted by a branched or linear Cl 3 alkyl group, a strepyl group, an amino group, a hydroxyl group or a trifluoromethyl group or a fluoroquinone, -R7 Representing a thiol group, a phenyl group, a porphinyl group or an η ratio octyl group, these groups being substituted on their aromatic rings by 2, 3 or 4 substituents γ, wherein γ has the aforementioned meanings, which may be the same or different, Or the heart represents a Cm branched or linear alkyl group, a C3 8 alkenyl group, a cycloalkyl group, a Q.-cycloalkyl group, a tricycloalkyl group or a Q8 cycloalkenyl group, or &amp; represents a naphthyl group, or R7 represents an amino group, Or R? represents a Cl 8 dialkylamino group, a Ci 8 monoalkylamino group or a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms, the heterocyclic group comprising one or two a nitrogen atom, and the heterocyclic group may contain a hetero atom selected from the group (0, S), and the heterocyclic group may be branched or linear Substituted with a fluorine atom or a trifluoromethyl group, -Rs represents a hydrogen atom or a methyl group, • Fo represents a hydrogen atom or a methyl, ethyl or methoxy, and tautomers, stereoisomers and salts thereof. 2. A compound of the formula (I) as described in claim 1 of the patent scope 25 1335321 Revision period: September 1999, 94th reading of patent application No. 82, please fix the patent scope (I) X of which: 5 R! and &amp; independently represent a phenyl group which may be substituted by 2 or 3 substituents Y which may be the same or different, and the substituent γ has the meaning of the item of the patent, or R1 and / Or ruler 2 represents a naphthyl group, a thienyl group or a pyridyl group, and -X represents one of the subgroups (i) or (ii), JL /R3 \ \r4 (0 where: -R3 represents a chlorine atom, -R4 represents a branched or linear alkyl group, a branched or linear CN8 alkoxy group, or a c3.8 cycloalkyl group, which may be a hydroxyl group , 1-3 methyl, one ethyl or 1-3 fluorine atoms substituted 'or R 4 represents a phenoxy group, D is a bite or a thiophene group, or R 4 represents a base, wherein R 5 and R 6 — The nitrogen atoms to which they are attached together form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms, the heterocyclic group containing one or two selected from the group (〇, N a hetero atom of S, or r3 and I- together with the nitrogen atom to which they are attached - form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms, the heterocyclic group comprising A 26 1335321 Patent Application No. 9410 Applicable Patent Revision Amendment Date: September 1999 or two heteroatoms selected from the group (〇, N, S), and the heterocyclic group may be methyl, Substituted by a trifluoromethyl or a fluorine atom, -r7 represents a phenyl group which may be substituted on its aromatic ring by i, 2, 3 or 4 substituents Y. In the above sense, they may be the same or different, or the heart represents a fluorene or a hydrazone 'C3.1G cyclofilament or Q-U) bis-guanidinyl, or r7 represents a naphthyl group, or R7 represents an amino group, or r7 represents a Q 8 dimethylamino group, a Ci 8 monoalkyloxy group or a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms, the heterocyclic group containing one or two nitrogen atoms, Further, the heterocyclic group may contain a hetero atom selected from the group (o, s), and the heterocyclic group may be branched or linear & 3 alkyl or via a group for 10 generations, - Κ · 8 represents a hydrogen atom , -Κ·9 represents a hydrogen atom, and its tautomers, stereoisomers and salts. 3. The compound according to claim 1, wherein the compound is 15 1_(4_ oxaphenyl)-1 2·(2,4-diphenyl)-indole- (exo-2-bicyclo[2.2 .1]heptyl hydrazine, 5·dihydro-1 Η-imidazole ice methamine (diastereomer Α), Η4-chlorophenyl phenyl & ( (exo: bicyclo [2 2 η heptyl) 4 5_Dihydro·1Η-imidazole· 4-decylamine (diastereomer Β), Η4-qi phenyl)_2-(2,4-diphenyl)-Ν-(» guanidine-1 -yl)_4,5-dihydro-exe_imidazole·4·2 anthraquinone, 27 1 (4 gas table)_2_(2,4_diphenyl)-indole-cyclohexyl-4,5 - Dihydro-1-hearted rice. Sit _4-carbamamine, 2 Η4-gas base)-2_(2,4_di-phenylphenyl&gt; Ν-[(4_chlorophenyl broth)#二氮]Η-imidazole•4*曱脒, [£] 1335321 Patent Application No. 94104182 Patent Application Revision Amendment Date: September 1999 H4-Phenylphenyl)-2-(2,4-diqi-based)-N-[(4 -Fluoroyl)-continuation]_45_Dinitrogen-1H_imidazole-4-indole, 2_(4_chlorophenyl)Nan (dioxasulfonyl-stiryl-4,5-dihydro-1H -Mi. Sitting _4_甲脒, and 5 10 15 20 ^(4-Phenylphenyl)-2-(2,4-diphenyl) with (dimethylaminosulfonamide)-4,5-dihydro·1H_flavor Sal-4-carboxamidine. 4. A pharmaceutical composition comprising, in addition to a pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable auxiliary substance, a pharmaceutically active amount, as in any one of claims 1 to 3 of the patent application. At least one of the compounds or a salt thereof is used as an active ingredient. 5. A compound according to any one of claims 3 to 3, or a salt thereof, for use in medicine. 6. The use of a compound according to any one of claims 3 to 3 for the preparation of a pharmaceutical composition for the treatment of psychosis, anxiety, camp, attention deficit, memory impairment , cognitive impairment, appetite disorders, obesity, especially childhood obesity and drug-induced obesity, paralysis, impulsive control disorders, meat punishment, drug dependence 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, epileptic pain' Huntington's disease, Tourette syndrome (Tourette's syndrome), cerebral ischemia, cerebral apoplexy, traumatic brain injury, stroke, spinal cord injury, neuroinflammatory disorder, plaque sclerosis, viral encephalitis, demyelination-related disorders, and pain disorders including neuropathic pain Barriers, and other diseases involving cannabinoid neurotransmission' including septic shock, glaucoma, cancer, diabetes Vomiting, Evil 28 1335321 Patent Application No. 94104182 Patent Application Amendment Revision Date: September 1999 Heart 'Asthma, respiratory disease, gastrointestinal disorders, gastric ulcer, diarrhea, cardiovascular disorders, atherosclerosis, cirrhosis A disability disorder. 7. The use of a compound of the following formula (1), which is a pharmaceutical composition for treating the following disorders: psychosis, domain depression, attention deficit, memory impairment, cognitive impairment, eating disorders, obesity , especially childhood obesity and medicine (4) obesity, paralysis, impulsive control disorders, meat, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle rigidity, tremor, epilepsy, multiple Hardening 'traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, tumor pain, Huntington's disease' Tourette syndrome' cerebral ischemia, cerebral apoplexy, craniocerebral trauma, mid 10 wind, spinal cord injury, Neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelination-related disorders, and neurological damage, and other diseases involving cannabinoid neurotransmission, including septic shock, glaucoma, cancer, diabetes, vomiting , nausea, asthma, respiratory disease, gastrointestinal disorders, gastric ulcer, diarrhea, cardiovascular disorders, atherosclerosis, cirrhosis and sexual disorders, 15 X R2 (I) where: - ruler and ruler 2 have the meaning as defined in the scope of the patent application, but can also independently represent methanesulfonyl, 2〇-X represents subgroup (1), [S] 29 1335321 94104182 Patent application for the scope of patent application amendments to this revision period: September 1999 X / 3⁄4 N, 0) where: % and R4 have the meaning of a full-time 丨 丨 item, but where ~ can also mean phenyl, Optionally, 3 substituents Y are substituted, wherein Y has the scope as claimed in the patent! The meaning of item 5. 8. The method of claim 6 is characterized in that the disorder is an eating disorder, particularly obesity, juvenile obesity, and drug-induced obesity. 9. The use of a compound according to any one of claims 1 to 1 for the preparation of a pharmaceutical composition for the treatment of eating disorders, obesity, juvenile obesity and drug-induced obesity, Characterized in that the pharmaceutical composition further comprises at least one lipase inhibitor. 10. The use of claim 9 wherein the lipase inhibitor is orlistat or iipstatin. 30