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    • 专利摘要:
    The present invention relates to a group of novel 1H-imidazole derivatives, methods of making these compounds, and pharmaceutical compositions containing one or more of these compounds as active ingredients. These 1H-imidazole derivatives are potent cannabinoid-CB 1 receptor agonists, partial agonists or antagonists useful for treating psychiatric and neurological diseases as well as other diseases associated with cannabinoid neurotransmission. The compound has the structure of formula (I). Formula I Wherein R and R 1 to R 4 have the meanings defined in the specification.
    公开号:KR20040035847A
    申请号:KR10-2004-7004084
    申请日:2002-09-17
    公开日:2004-04-29
    发明作者:크루제코르넬리스지；란게요세푸스에이취엠；헤레만스아르놀두스에이취제이；반스투이벤베르그헤르만에이취
    申请人:솔베이 파마슈티칼스 비. 브이；
    IPC主号:
    专利说明:

    1H-Imidazole derivatives having CB1 agonistic, CB1 partial agonistic or CB1-antagonistic activity}
    [1] The present invention relates to a group of novel 1H-imidazole derivatives, methods of making these compounds, and pharmaceutical compositions containing one or more of these compounds as active ingredients. These 1H-imidazole derivatives are potent cannabinoid-CB 1 receptor agonists, partial agonists or antagonists useful for treating psychiatric and neurological diseases as well as other diseases associated with cannabinoid neurotransmission.
    [2] Cannabinoids are present in Indian hemp Cannabis sativa and have been used as therapeutics for centuries [Mechoulam, R. and Feigenbaum, JJ Prog. Med. Chem. 1987 , 24, 159]. However, research in the field of cannabinoids has only revealed important information regarding cannabinoid receptors and their (endogenous) agonists and antagonists in the last decade. This discovery and subsequent cloning of two different subtypes of cannabinoid receptors (CB 1 , CB 2 ) has facilitated the study of novel cannabinoid receptor antagonists [Munro, S. et al. , Nature 1993 , 365,61. Matsuda, LA and Bonner, TI Cannabinoid Receptors , Pertwee, RG Ed. 1995 , 117, Academic Press, London. In addition, pharmaceutical companies have been interested in the development of cannabinoid drugs for the treatment of diseases associated with disorders of the cannabinoid family [Consroe, P. Nuerobiology of Disease 1998 , 5, 534. Pop, E. Curr. . Opin. In CPNS Investigational Drugs 1999 , 1, 587. Greenberg, DA Drug News Perspect . 1999 , 12, 458. Pertwee, RG, Progress in Neurobiology 2001 , 63, 569]. To date, several CB 1 receptor antagonists have been known. Sanofi has identified their diarylpyrazole homologues as selective CB 1 receptor antagonists. Representative examples include SR-141716A [Dutta, AK et al. , Med. Chem. Res. 1994 , 5, 54. Lan, R. et al. , J. Med. Chem. 1999 , 42, 769. Nakamura-Palacios, EM et al. , CNS Drug Rev. 1999 , 5, 43]. CP-272871, like SR141716A, is a pyrazole derivative, but less potent than SR14176IA, and is not CB 1 receptor subtype-selective [Meschler, JP et al. , Biochem. Pharmacol. 2000 , 60, 1315]. Aminoalkylindoles have been identified as CB 1 receptor antagonists. A representative example is Rhodopravadoline (AM-630), introduced in 1995. AM-630 is a moderately active CB 1 receptor antagonist, but acts as a weak partial agonist in some assays . Hosohata, K. et al. , Life Sc. 1997 , 61, PL 115]. Eli Lilly researchers described aryl-aroyl substituted benzofuran (eg, LY-320135) as a selective CB 1 receptor antagonist (Felder, CC et al. , J. Pharmacol. Exp. Ther. 1998 , 284, 291]. 3-alkyl-5,5'-diphenylimidazolidine-dione has been described as a cannabinoid receptor ligand, which has been pointed out as a cannabinoid antagonist . Kanyonyo, M. et al. , Biorg. Med. Chem. Lett. 1999 , 9, 2233]. Aentis Pharma has claimed a diarylmethyleneazetidine analog as a CB 1 receptor antagonist [Mignani, S. et al. , Patent FR 2783246, 2000; Chem. Abstr. 2000 , 132, 236982. Tricyclic pyrazole has been patented as a CB 1 antagonist by Sanofi-Synthelabo . Barth, F. et al. , Patent WO 0132663, 2001; Chem. Abstr. 2001 , 134, 340 504]. Interestingly, many CB 1 receptor antagonists have been reported to act as inverse agonists in vitro [Landsman, RS et al. , Eur. J. Pharmacol. 1997 , 334, R 1]. In addition, cannabinoids have been reported as CB 1 receptor partial agonists that exhibit cannabimimetic effects in vivo. Wiley, JL et al., J. Pharmacol. Exp. Ther . 2001 , 296, 1013. For example, numerous classes of CB 1 receptor agonists are known, such as typical cannabinoids (e.g. Δ 9 -THC), non-traditional cannabinoids, aminoalkylindoles and eicosanoids (e.g. anandamides). . A review of the literature provides a detailed overview of the field of cannabinoid research. See Mechoulam, R. et al. , Prog. Med. Chem. 1998 , 35, 199. Lambert, DM Curr. Med. Chem. 1999 , 6, 635. Mechoulam, R. et al. , Eur.J. Pharmacol. 1998 , 359, 1. Williamson, EM and Evans, FJ Drug 2000 , 60, 1303. Pertwee, RG Addiction Biology 2000 , 5, 37. Robson, P. Br. J. Psychiatry 2001 , 178, 107. Pertwee, RG Prog. Neurobiol. 2001 , 63, 569. Goya, P and Jagerovic, N. Exp. Opin. Ther. Patents 2000 , 10, 1529. Pertwee, RG Gut 2001, 48, 859.
    [3] Surprisingly, it has now been found that the novel 1H-imidazole derivatives of formula I, their prodrugs and salts thereof are potent agonists, partial agonists or antagonists for cannabinoid-CB 1 receptors.
    [4]
    [5] In the above formula,
    [6] R is phenyl, thienyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl which may be substituted with 1, 2, 3 or 4 substituents Y Group, wherein Y may be the same or different and group C 1-3 alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or Dialkyl (C 1-2 ) -amino, mono- or dialkyl (C 1-2 ) -amido, (C 1-3 ) -alkoxycarbonyl, carboxyl, cyano, carbamoyl and acetyl Or R is naphthyl provided that when R is 4-pyridinyl R 4 is a halogen atom or cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methane sulfonyl, and methylsulfanyl or branched or unbranched C 1-4 alkyl group, wherein the C 1-4 alkyl group is from 1 to 3 Substituted with a fluoro atom, or bromo, chloro, iodo, cyano or may be substituted with a hydroxyl group, and;
    [7] R 1 is a phenyl or pyridinyl group which may be substituted with 1 to 4 identical or different and substituents having the above meaning, or R 1 may be substituted with 1 to 2 identical or different substituents Y Pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, or R 1 is a 5-membered aromatic heterocyclic having 1 or 2 identical or different heteroatoms in the group (N, O, S) As a ring, it may be substituted with 1 to 2 same or different substituents Y, or R 1 is naphthyl;
    [8] R 2 is H, or a branched or unbranched C 1-8 alkyl, C 3-8 cycloalkyl, C 3-8 alkenyl, C 5-8 cycloalkenyl group which may contain sulfur, oxygen or nitrogen atoms ego;
    [9] R 3 is branched or unbranched C 2-8 alkyl, C 1-8 alkoxy, C 5-8 cycloalkoxy, C 3-8 cycloalkyl, C 5-10 bicycloalkyl, C 6-10 tricycloalkyl, C 3-8 alkenyl, C 5-8 cycloalkenyl groups, which groups may optionally contain one or more heteroatoms of groups (O, N, S) and are hydroxy groups or 1 to 2 C 1-3 May be substituted with an alkyl group or with 1 to 3 fluoro atoms, or
    [10] R 3 represents benzyl or phenethyl group, wherein the aromatic ring is C 1-3 alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or Dialkyl (C 1-2 ) -amino, mono- or dialkyl (C 1-2 ) -amido, (C 1-3 ) -alkylsulfonyl, dimethyl-sulfamido, C 1-3 -alkoxycarbonyl May be substituted with 1 to 5 identical or different substituents Z selected from the group consisting of carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R 3 is A phenyl or pyridinyl group substituted with 1 to 4 substituents Z having the meaning as defined above, or
    [11] R 3 is a pyridinyl group, or R 3 is a phenyl group, provided that R 4 is a halogen atom or cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methanesul Phonyl, methylsulfanyl or C 1-4 alkyl group, wherein the C 1-4 alkyl group may be substituted with 1 to 3 fluoro atoms or bromo, chloro, iodo, cyano or hydroxy groups, or Or R 3 represents a group NR 5 R 6 , provided that R 2 is a hydrogen atom or a methyl group,
    [12] R 5 and R 6 are the same or different, branched or unbranched C 1-4 alkyl, or R 5 and R 6 have 4 to 10 ring atoms, saturated or unsaturated with a nitrogen atom bonded thereto; To form a monocyclic or bicyclic heterocyclic group, wherein the heterocyclic group contains one or two identical or different heteroatoms in the group (N, O, S) and may also be C 1-3 alkyl May be substituted with a group or a hydroxy group; or
    [13] R 2 and R 3 together with the nitrogen atom bonded to them form a heterocyclic group having 4 to 10 ring atoms, saturated or unsaturated, wherein the heterocyclic group is selected from the group (N, O, S) Contains 1 or 2 identical or different heteroatoms and may also be substituted with a C 1-3 alkyl group or a hydroxy group;
    [14] R 4 is hydrogen or a halogen atom, cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methanesulfonyl, methylsulfanyl or branched or unbranched C 1- 4 alkyl group, wherein C 1-4 alkyl group may be substituted with 1 to 3 fluoro atoms or bromo, chloro, iodo, cyano or hydroxy groups.
    [15] Because of the potent CB 1 agonistic, partial efficacy or antagonistic activity, the compounds according to the invention can be used for psychosis, anxiety, depression, attention deficit, memory disorder, cognitive impairment, appetite disorder, obesity, addiction, desire, drug Psychiatric diseases such as dependence and neurodegenerative diseases, dementia, dystonia, muscle stiffness, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette syndrome, cerebral ischemia, stroke Treatment of psychiatric diseases such as brain trauma, stroke, spinal cord injury, neuroinflammatory diseases, plaque sclerosis, viral encephalitis, demyelinisation-related diseases, as well as pain diseases including neuropathic pain diseases, and plaque Cannabinoid neurotransmission-tubule, including bloody shock, glaucoma, cancer, diabetes, vomiting, nausea, asthma, respiratory disease, gastrointestinal disorders, gastric ulcer, diarrhea and cardiovascular disease It is suitable for use in the treatment of other diseases.
    [16] Cannabinoid CB 1 of the affinity of the compounds of the present invention for a receptor, the human cannabinoid CB 1 receptor is a radioactive ligand [3 H] stably transfected in conjunction with the CP-55,940-infected Chinese hamster ovary (CHO) cells Was measured using a membrane preparation. After incubation of freshly prepared cell membrane preparations with [ 3 H] -ligand, with or without addition of the compounds of the invention, separation of bound ligand and free ligand was performed by filtration through a glass fiber filter. Radioactivity on the filter was measured with a liquid scintillation counter.
    [17] The cannabinoid CB 1 antagonist activity of the compound of the present invention was measured by a functional study using CHO cells in which human cannabinoid CB 1 receptor was stably expressed. Adenylyl cyclase was measured by stimulating with forskolin and quantifying the amount of accumulated cyclic AMP. Activation of ancillary CB1 receptors by agonists of CB 1 receptors (eg CP-55,940 or (R) -WIN-55,212-2) may reduce forskolin-induced accumulation of cAMP in a concentration-dependent manner. have. Such CB 1 receptor-mediated responses may be antagonized by CB 1 receptor antagonists such as the compounds of the invention.
    [18] The efficacy of cannabinoids with partial potency activity of the compounds of the present invention can be measured according to published methods such as the evaluation of cannabimimetic effects in vivo. Wiley, JL et al., J. Pharmacol. Exp. Ther. 2001, 296, 1013.
    [19] The present invention relates to both racemates and individual stereoisomers which are diastereomeric mixtures of compounds of formula (I).
    [20] The compounds of the present invention may be prepared in a form suitable for administration by conventional methods using auxiliary materials and / or liquid or solid carrier materials.
    [21] Suitable synthetic routes of the compounds of the present invention are as follows:
    [22] Synthetic Path A
    [23] Step 1 : ester hydrolysis of the compound of formula II
    [24]
    [25] Wherein R 7 is a branched or unbranched alkyl group (C 1-4 ) or benzyl group.
    [26] This reaction produces a compound of formula III.
    [27]
    [28] Wherein R, R 1 and R 4 have the same meaning as described above.
    [29] Intermediates of formula II, wherein R 7 is a branched or unbranched alkyl group (C 1-4 ) or benzyl group can be obtained, for example, according to methods known in the following literature:
    [30] a) I.K. Khanna et al., J. Med. Chem. 2000, 43, 3168-3185
    [31] b) N. Kudo et al L., Chem. Pharm. Bull. 1999, 47, 857-868
    [32] c) K. Tsuji et al L., Chem. Pharm. Bull. 1997, 45, 987-995
    [33] d) I.K. Khanna et al., J. Med. Chem. 1997, 40, 1634-1647
    [34] e) M. Guillemet et al., Tetrahedron Lett. 1995,36, 547-548
    [35] Step 2 : Through the activation and coupling method such as formation of the active ester, or in the presence of a coupling reagent such as DCC, HBTU, BOP or similar reagent, the compound of formula III and formula R 2 R 3 NH ( Wherein R 2 and R 3 have the same meanings as described above).
    [36] This reaction gives the desired 1H-imidazole derivative of formula (I).
    [37] (For more information on the activation and coupling method, see M. Bodanszky and A. Bodanszky: The Practice of Peptide Synthesis, Springer-Verlag, New York, 1994; ISBN: 0-387-57505-7 ).
    [38] Alternatively, the compound of formula III is reacted with a halogenating agent, for example thionyl chloride (SOCl 2 ). This reaction produces the corresponding carbonyl chloride of formula IV.
    [39]
    [40] Reacting the compound of formula IV with a compound of formula R 2 R 3 NH, wherein R 2 and R 3 have the meanings as described above, yields a 1H-imidazole derivative of formula I. This reaction is preferably carried out in the presence of an organic base such as diisopropylethylamine (DIPEA) or triethylamine.
    [41] Alternatively, the compound of formula II is reacted with formula R 2 R 3 NH, wherein R 2 and R 3 have the meaning as described above, in an amidation reaction to give the 1H-imidazole derivative of formula I.
    [42] Synthetic Path B
    [43] A compound of formula II wherein R 4 is hydrogen and R, R 1 and R 7 have the same meanings as described above in formula II and a compound of formula R 4 '-X wherein X is a leaving group , R 4 ′ is a C 1-4 alkyl group which may be substituted by 1 to 3 fluoro atoms, or R 4 ′ is cyano, formyl, acetyl, trifluoroacetyl, fluoroacetyl, methylsulfanyl or Reactions with propionyl residues, or halogen atoms).
    [44] The reaction is carried out in an inert organic solvent such as tetrahydrofuran in the presence of a strong non-nucleophilic base such as lithium diisopropylamide (LDA), preferably under anhydrous conditions, whereby Compounds of are obtained.
    [45] Formula II
    [46]
    [47] In the above formula,
    [48] R, R 1 and R 7 have the same meaning as described above,
    [49] R 4 is a C 1-4 alkyl group which may be substituted with 1 to 3 fluoro atoms, or R 4 is a cyano, formyl, acetyl, trifluoroacetyl, fluoroacetyl, methylsulfanyl or propionyl group, Or a halogen atom.
    [50] Compounds of formula (II) obtained according to synthetic route B can be converted to compounds of formula (I), similar to the process described in step 1 or step 2 of synthetic route A (see above).
    [51] Synthetic Path C
    [52] Compounds of formula (V) or tautomers thereof can be reacted with compounds of formula (VI) to synthesize compounds of formula (II).
    [53] Formula II
    [54]
    [55]
    [56]
    [57] In the above formula,
    [58] R 4 is a C 1-4 alkyl group which may be substituted with one to three fluoro substituents;
    [59] R 7 is a branched or unbranched alkyl group (C 1-4 ) or benzyl group;
    [60] R 8 is a leaving group, eg a bromo substituent;
    [61] R and R 1 have the same meaning as described above.
    [62] The reaction is preferably carried out in an organic solvent, for example 2-propanol or N-methyl-2-pyrrolidinone (NMP). The addition of an acid such as trifluoroacetic acid (TFA) during the reaction can increase the formation of the compound of formula II.
    [63] (For more information on the concept of exit groups, see MB Smith and J. March: Advanced Organic Chemistry, P. 275, 5th ed., (2001) John Wiley & Sons, New York, ISBN: 0- 471-58589-O).
    [64] Compounds of formula (II) obtained according to synthetic route C can be converted to compounds of formula (I), similar to the process described in step 1 or step 2 of synthetic route A (see above).
    [65] Compounds of formula VI are described, for example, in P. Seifert et al., Helv. Chim. Acta, 1950, 33, 725].
    [66] Composite path D
    [67] Compounds of formula (II) are regioselective brominated compounds, such as N-bromo-succinimide (NBS), in an organic solvent (eg CCl 4 ) in the presence of a free-radical initiator such as dibenzoyl peroxide. Reaction with gives a compound of formula (VII).
    [68] Formula II
    [69]
    [70]
    [71] In the above formula,
    [72] R 4 is a methyl group;
    [73] R and R 1 have the same meaning as described above;
    [74] R 7 is a branched or unbranched alkyl group (C 1-4 ) or benzyl group.
    [75] Reacting a compound of formula (VII) with, for example, KCl, KI, KF or KCN (similar to the method described in Mathews, WB et al., J. Label. Compds. Radiopharm., 1999, 42, 589) Obtain the compound of formula VIII.
    [76]
    [77] In the above formula,
    [78] R, R 1 and R 7 have the same meanings as described above;
    [79] Nu is a chloro, iodo, fluoro or cyano group.
    [80] The reaction is preferably carried out in the presence of a weak base (eg NaHCO 3 ) or in the presence of crown ethers or cryptands. (For more information on crown ethers and pocket ligands, see MB Smith and J. March: Advanced Organic Chemistry, P. 105, 5th ed., (2001) John Wiley & Sons, New York, ISBN: 0-471-58589-O).
    [81] Compounds of formula (VII) or (VIII) obtained according to synthetic route D can be converted to compounds of formula (I), similar to the process described in step 1 or step 2 of synthetic route A (see above).
    [82] Example 1
    [83] A: To a 1M solution of sodium bis (trimethylsilyl) amide in THF (70 mL) was added dropwise 4-chloroaniline (8.86 g, 69.5 mmol) in dry THF under nitrogen atmosphere. The mixture is mixed for 20 minutes and then 2,4-dichlorobenzonitrile (12 g, 70 mmol) in THF is added. The resulting mixture is stirred overnight, poured into ice water (400 mL), extracted with dichloromethane, dried over Na 2 SO 4 and concentrated in vacuo to give a yellow oil (15.7 g). Crystallize from dichloromethane / heptane mixture, then wash with methyl-t-butyl ether, N- (4-chlorophenyl) -2,4-dichlorobenzenecarboxamidine (8.66 g, 42% yield) Is obtained as a yellow oil. Melting point (MP): 93-95 ° C.
    [84] Similarly, N- (4-bromophenyl) -2,4-dichlorobenzenecarboxamidine (MP: 117-119 ° C.) was prepared.
    [85] B: N- (4-chlorophenyl) -2,4-dichlorobenzenecarboxamidine (2.00 g, 6.68 mmol) in 2-propanol, ethyl 3-bromo-2-oxopropanoate (2.65 g, 13.6 mmol) and NaHCO 3 (1.12 g, 13.3 mmol) are stirred at reflux for 20 h. After cooling to room temperature, the mixture is concentrated in vacuo and the residue is suspended in dichloromethane and washed with water (3 x 50 mL) and brine (3 x 50 mL). The aqueous layer is extracted with dichloromethane. The combined organic layers are dried over Na 2 S0 4 and concentrated in vacuo to afford a brown crude product (2.0 g). The product was further purified by column chromatography (silica gel, heptane / EtOAc = 90/10 (v / v)) to give ethyl 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl)- 1H-imidazole-4-carboxylate (0.759 g, 29% yield) is obtained as a yellow oil, which is slowly solidified under standing. Melting point: 150-152 ° C .; MS: 395 (MH + ). 1 H-NMR (400 MHz, CDCl 3 ): δ 7.91 (s, 1 H), 7.49 (dd, J = 8 Hz, J = 2 Hz, 1 H), 7.29-7.36 (m, 4H), 7.07 (dt, J = 8 Hz, J = 2 Hz, 2H), 4.44 (q, J = 7 Hz, 2H), 1.42 (t, J = 7 Hz, 3H).
    [86] C: ethyl 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxylate (0.810 g, 2.06 mmol) and LiOH (0.173 g, 7.20 mmol) Dissolve in 2 O / THF (20 mL / 20 mL) mixture and stir at 50 ° C. for 16 h. The mixture is concentrated in vacuo to afford 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxylic acid. Thionyl chloride (60 mL) is added and the mixture is heated at reflux for 1 h and concentrated in vacuo to afford crude 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -1H-imidazole Obtain 4-carbamoyl chloride.
    [87] D: crude 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -1H-imidazole-4-carbonyl chloride (919 mg, ˜2.39 mmol), 1-aminopiperidine (0.469 g , 4.69 mmol) and triethylamine (0.363 g, 3.59 mmol) are dissolved in dichloromethane and stirred at room temperature for 1 hour. The mixture was washed with saturated aqueous NaHCO 3 (3 × 20 mL), dried over Na 2 SO 4 , concentrated in vacuo, and further purified by column chromatography (ethyl acetate, silica gel) to give 1- ( 4-chlorophenyl) -2- (2,4-dichlorophenyl) -N- (piperidin-1-yl) -1H-imidazole-4-carboxamide [356 mg, 26% yield (ethyl 1- ( 4-chlorophenyl) -2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxamide)] is obtained. Mass spectroscopy (MS): 449.
    [88] Similarly, the following compounds were prepared:
    [89] 2. 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -N- (pyrrolidin-1-yl) -1H-imidazole-4-carboxamide; MS: 435.
    [90] 3. N- (t-butoxy) -1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxamide; MS: 438.
    [91] 4. 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -N-phenyl-1H-imidazole-4-carboxamide; MS: 442.
    [92] 5. 1- (4-chlorophenyl) -N-cyclohexyl-2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxamide; MS: 448.
    [93] 6. N- (benzyl) -1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -N-methyl-1H-imidazole-4-carboxamide; MS: 470.
    [94] 7. 1-1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -4- (1H-imidazolyl) carbonyl] hexahydro-1H-azepine; MS: 448.
    [95] 8. 2- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -N- (piperidin-1-yl) -1H-imidazole-4-carboxamide (2,4-dichloro Prepared from aniline and 4-chlorobenzo-nitrile); MS: 449.
    [96] 9.N- (t-butoxy) -2- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -1H-imidazole-4-carboxamide (2,4-dichloroaniline and 4 Prepared from -chlorobenzo-nitrile); MS: 438.
    [97] Example 10
    [98] A: Diisopropylamine (2.30 g, 22.8 mmol) is dripped at dry THF (100 mL) at 0 degreeC under nitrogen atmosphere. n-BuLi is added dropwise (7.34 mL, 2.5 M solution in hexane, 18.4 mmol). The resulting solution is cooled to -78 ° C. A solution of ethyl 2- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -1H-imidazole-4-carboxylate (6.0 g, 15.2 mmol) in anhydrous THF is added dropwise. The color of the mixture changes from yellow to purplish brown. The stirred mixture is warmed to −40 ° C. and cooled to −78 ° C. and then left to stand for 30 minutes. Methyl iodide (6.44 g, 45.4 mmol) is added dropwise, and the resulting solution is stirred at −78 ° C. for 30 minutes and then allowed to come to room temperature. The resulting solution was quenched with aqueous NH 4 Cl solution, diethyl ether was added, the organic layer was dried over MgSO 4 , filtered and concentrated in vacuo to give an oil (6.4 g). This oil was purified by column chromatography (toluene / EtOAc = 10/2 (V / V), silica gel) to give pure ethyl 2- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -5- Methyl-1H-imidazole-4-carboxylate (5.3 g, 85% yield) is obtained as a yellow oil.
    [99] B: ethyl 2- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -5-methyl-1H-imidazole-4-carboxylate (0.250 g, 0.61 mmol) and LiOH (0.052 g, 2.17 mmol) is dissolved in H 2 O / THF (1: 1 (v / v); 50 mL) and stirred at 50 ° C. for 1 h. The mixture is concentrated to give crude 2- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -5-methyl-1H-imidazole-4-carboxylic acid. SOCl 2 (50 mL) is added to this mixture and the resulting mixture is heated at reflux for 1 h. The mixture is concentrated to give 2- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -5-methyl-1H-imidazole-4-carbonyl chloride.
    [100] C: 2- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -5-methyl-1H-imidazole-4-carbonyl chloride (1.5 g, 3.75 mmol), 1-aminopyriridine (0.725 g, 7.25 mmol) and triethylamine (0.549 g, 5.44 mmol) are dissolved in dichloromethane and stirred at room temperature for 1 hour. The mixture was washed with saturated aqueous NaHCO 3 , dried over Na 2 SO 4 , concentrated in vacuo, and further purified by column chromatography (heptane / ethyl acetate = 1/1 (v / v), silica gel). , 2- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -5-methyl-N- (piperidin-1-yl) -1H-imidazole-4-carboxamide (0.220 g , 13% yield) is obtained as a white foam. MS: 463.
    [101] Similarly the following compounds were prepared:
    [102] 11. N- (t-butoxy) -2- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -5-methyl-1H-imidazole-4-carboxamide: MS: 452.
    [103] 12. 1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -5-methyl-N- (piperidin-1-yl) -1H-imidazole-4-carboxamide: MS : 463; Melting point: 165 to 167 ° C.
    [104] 13. N- (t-butoxy) -2- (2,4-dichlorophenyl) -1- (4-chlorophenyl) -5-methyl-1H-imidazole-4-carboxamide: MS: 452.
    [105] 14. N- (t-butoxy) -1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-ethyl-1H-imidazole-4-carboxamide: anhydrous. MS: 468.
    [106] 15. 1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -5-ethyl-N- (piperidin-1-yl) -1 H-imidazole-4-carboxamide: MS: 477.
    [107] 16. 1- (4-Bromophenyl) -N- (t-butoxy) -2- (2,4-dichlorophenyl) -5-methyl-1H-imidazole-4-] carboxamide: anhydrous .
    [108] 17. 1- (4-Bromophenyl) -2- (2,4-dichlorophenyl) -5-methyl-N- (piperidin-1-yl) -1H-imidazole-4-carboxamide: MP:> 204 ° C. TLC (silica gel, EtOAc) R f = 0.3.
    [109] 18. 1- (4-Bromophenyl) -N- (t-butoxy) -2- (2,4-dichlorophenyl) -5-ethyl-1H-imidazole-4-carboxamide: anhydrous. TLC (silica gel, CH 2 Cl 2 / acetone = 9/1 (V / V)) R f = 0.45.
    [110] 19. 1- (4-Bromophenyl) -2- (2,4-dichlorophenyl) -5-ethyl-N- (piperidin-1-yl) -1 H-imidazole-4-carboxamide : MP:> 140 ° C. TLC (silica gel, EtOAc) R f = 0.4.
    [111] 20. 1- (4-Bromophenyl) -N-cyclohexyl-2- (2,4-dichlorophenyl) -5-ethyl-1H-imidazole-4-carboxamide: Melting point> 135 to 140 ° C.
    [112] 21.1- (4-Bromophenyl) -2- (2,4-dichlorophenyl) -5-ethyl-N- (N-pentyl) -1H-imidazole-4-carboxamide: syrupy. TLC (silica gel, CH 2 Cl 2 / acetone = 19/1 (V / V) R f = 0.4.
    [113] Example 22
    [114] A: LiOH in a stirred solution of ethyl 1- (4-bromophenyl) -2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxylate (6.10 g, 0.0139 mol) in THF (70 mL) (0.67 g, 0.0278 mol) and water (70 mL) are added. The resulting mixture is stirred at 50 ° C. for 16 hours to give a clear solution. After cooling to room temperature, HCl (IN solution, 28 mL) is added to give an oily precipitate which is completely solidified by continued stirring and addition of water (70 mL). The precipitate was collected by filtration, washed with water and dried in vacuo to give 1- (4-bromophenyl) -2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxyxin (4.92 g, 86% yield). Melting point: 138 to 142 ° C.
    [115] B: To a stirred suspension of 1- (4-bromophenyl) -2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxylic acid (1.23 g, 2.99 mmol) in anhydrous acetonitrile (40 mL). Successively diisopropylethylamine (DIPEA) (1.15 mL, 6.6 mmol), O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU) ( 1.36 g, 3.6 mmol) and 1-aminopiperidine (0.39 mL, 3.6 mmol) are added. After stirring for 16 hours, the resulting mixture is concentrated in vacuo. The residue is dissolved in ethyl acetate and aqueous NaHCO 3 solution is added. The ethyl acetate layer was collected, washed with water and brine, then dried over Na 2 SO 4 , filtered and concentrated to give a crude solid. The solid was further purified by recrystallization from acetonitrile to further purified 1- (4-bromophenyl) -2- (2,4-dichlorophenyl) -N- (piperidin-1-yl) -1H-imid Obtained dazole-4-carboxamide (830 mg, 56% yield). Melting point: 219-221 degreeC.
    [116] Similarly the following compounds were prepared:
    [117] 23. N- (t-butoxy) -1- (4-bromophenyl) -2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxamide. Anhydrous. TLC (silica gel, Et 2 0) R f = 0.3.
    [118] 24. 1- (4-Bromophenyl) -2- (2,4-dichlorophenyl) -N- (pyrrolidin-1-yl) -1H-imidazole-4-carboxamide. Melting point: 238 to 240 ° C.
    [119] 25. N- (Azepan-1-yl) -1- (4-bromophenyl) -2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxamide. Melting point: 201 to 204 ° C.
    [120] 26. 1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -N- (hexahydrocyclopenta [c] pyrrole 2 (1H) -yl) -1H-imidazole-4-carbox amides. MS: 475.
    [121] 27. 1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -N- (4-fluorobenzyl) -1H-imidazole-4-carboxamide. MS: 474.
    [122] 28. 1- (4-Chlorophenyl) -2- (2-methoxy-4-chlorophenyl) -N- (piperidin-1-yl) -1H-imidazole-4-carboxamide. Melting point: 220 ° C.
    [123] 29. 1- (4-Chlorophenyl) -N-cyclohexyl-2- (2-methoxy-4-chlorophenyl) -1H-imidazole-4-carboxamide. Melting point: 177 to 179 ° C.
    [124] 30. 1- (4-Chlorophenyl) -2- (2-fluoro-4-chlorophenyl) -N- (piperidin-1-yl) -1H-imidazole-4-carboxamide. Melting point: 217 to 218 ° C.
    [125] 31. 2- (2,4-Dichlorophenyl) -1- (4-fluorophenyl) -N- (piperidin-1-yl) -1H-imidazole-4-carboxamide. Melting point: 175 to 176 ° C.
    [126] 32. N-cyclohexyl-2- (2,4-dichlorophenyl) -1- (4-fluorophenyl) -1H-imidazole-4-carboxamide. Melting point: 184 to 185 ° C.
    [127] 33. N-cyclohexyl-2- (2-fluoro-4-chlorophenyl) -1- (4-chlorophenyl) -1H-imidazole-4-carboxamide. Melting point: 157-159 ° C.
    [128] 34. 1- (4-Chlorophenyl) -2- (2-methoxy-4-chlorophenyl) -N- (n-pentyl) -1 H-imidazole-4-carboxamide. Melting point: 115 ° C.
    [129] 35. 2- (2,4-dichlorophenyl) -1- (4-methoxyphenyl) -N- (piperidin-1-yl) -1H-imidazole-4-carboxamide. Melting point: 178 to 179 ° C.
    [130] 36. N-cyclohexyl-2- (2,4-dichlorophenyl) -1- (4-methoxyphenyl) -1H-imidazole-4-carboxamide. Melting point: 175 to 176 ° C.
    [131] 37. 1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -N, N-diethyl-1 H-imidazole-4-carboxamide. Melting point: 177 to 179 ° C.
    [132] 38. 1- (4-Chlorophenyl) -N-cyclohexyl-2- (2-trifluoromethyl-4-chlorophenyl) -1H-imidazole-4-carboxamide. Melting point: 172 ° C.
    [133] 39. 1- (4-Chlorophenyl) -N- (piperidin-1-yl) -2- (2-trifluoromethyl-4-chlorophenyl) -1H-imidazole-4-carboxamide. Melting point: 219 ° C.
    [134] 40. N- (1-adamantyl) -1- (4-chlorophenyl) -2- (2-trifluoromethyl-4-chlorophenyl) -1H-imidazole-4-carboxamide. Melting point: 288 ° C.
    [135] 41. 1- (4-Chlorophenyl) -N- (2,2,2-trifluoroethyl) -2- (2-trifluoromethyl-4-chlorophenyl) -1 H-imidazole-4-car Voxamide. Melting point: 149 ° C.
    [136] 42. 2- (2,4-dichlorophenyl) -1- (pyridin-3-yl) -N- (piperidin-1-yl) -1H-imidazole-4-carboxamide. Melting point: 165 to 170 ° C.
    [137] 43. N-cyclohexyl-2- (2,4-dichlorophenyl) -1- (pyridin-3-yl) -1H-imidazole-4-carboxamide. Melting point: 195 ° C.
    [138] 44. 2- (2,4-dichlorophenyl) -1- (pyridin-3-yl) -N- (n-pentyl) -1H-imidazole-4-carboxamide. Melting point: 117 ° C.
    [139] Example 45
    [140] A: 2,4-dichlorobenzoyl chloride (40.0 g, 0.19 mol) is dissolved in tetrahydrofuran (1 L). To the resulting stirred solution is successively added diisopropylethylamine (DIPEA) (73.4 mL, 2.2 molar equivalents) and 4- (trifluomethyl) phenylamine (30.7 g, 0.19 mol). After 1 hour the mixture is concentrated in vacuo to give an oil. This oil is crystallized from ethanol to give pure 2,4-dichloro-N-4-trifluoromethyl) phenyl) benzamide (53.2 g, 83% yield). 1 H-NMR (200 MHz, DMSO-δ 6 ): δ 10.90 (br s, 1 H), 7.91 (br d, J = 8 Hz, 2H), 7.63-7.77 (m, 4H), 7.57 (dt, J = 8 Hz, J = 2 Hz, 1H).
    [141] B: 2,4-dichloro-N- (4- (trifluoromethyl) phenyl) benzamide (19.0 g, 0.057 mol) was dissolved in benzene (150 mL) and PCl 5 (13.0 g, 1.1 molar equivalents) was dissolved. Add. The resulting mixture is heated at reflux for 2 hours, brought to room temperature and concentrated in vacuo to afford a residue. The residue is dissolved in anhydrous THF, cooled to 0 ° C. and then transferred to an autoclave. Excess NH 3 is quickly added from the lesson bottle and the mixture is stirred for 50 h at room temperature. A mixture of ethyl acetate and aqueous NaHCO 3 is added. The ethyl acetate layer was collected, dried over Na 2 SO 4 , filtered and dried under vacuum. The resulting oil was purified by column chromatography (diethyl ether / petroleum ether = 1/1 (v / v), silica gel) to give pure 2,4-dichloro-N- (4- (trifluoromethyl) phenyl) Benzene-carboxamidine (16.9 g, 89% yield) is obtained. Melting point: 108-109 ° C.
    [142] C: 2,4-dichloro-N- (4- (trifluoroomethyl) phenyl) benzenecarboxamidine (15.0 g, 0.0450 mol) was dissolved in 2-propanol and ethyl 3-bromo-2-oxo Butanoate (20.8 g, 2 molar equivalents) and NaHCO 3 are added sequentially. The resulting mixture is heated at reflux for 40 h and brought to room temperature. 2-propanol is removed under vacuum, ethyl acetate is added to the residue, and the resulting organic layer is washed with NaHCO 3 (5% aqueous solution). The ethyl acetate layer was collected, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The resulting oil was purified by column chromatography (diethyl ether / petroleum ether = 1/3 (v / v), silica gel) and then further purified by crystallization with cyclohexane to give ethyl 2- (2,4-dichloro Phenyl) -5-methyl-1- (4- (trifluoromethyl) phenyl) -1H-imidazole-4-carboxylate (10.45 g, 52% yield) is obtained as a yellow oil. Melting point: 160-162 ° C.
    [143] D: ethyl 2- (2,4-dichlorophenyl) -5-methyl-1- (4- (trifluoromethyl) phenyl) -1H-imidazole-4 formed according to the method described in Example 22 above -Carboxylate to 2- (2,4-dichlorophenyl) -5-methyl-1- (4- (trifluoromethyl) phenyl) -1H-imidazole-4-carboxylic acid (melting point: 224-226 ° C.) Convert this carboxylic acid to 2- (2,4-dichlorophenyl) -5-methyl-N- (piperidin-1-yl) -1- (4- (trifluoromethyl) phenyl) -1H- Conversion to dozol-4-carboxamide (melting point: 173-174 ° C.).
    [144] Similarly the following compounds were prepared:
    [145] 46. 2- (2,4-dichlorophenyl) -N- (piperidin-1-yl) -1- (4- (trifluoromethyl) phenyl) -1H-imidazole-4-carboxamide. Melting point:> 200 ° C. (decomposition).
    [146] 47. N-cyclohexyl-2- (2,4-dichlorophenyl) -5-methyl-1- (4- (trifluoromethyl) phenyl) -1H-imidazole-4-carboxamide. Melting point: 178 to 179 ° C.
    [147] 48. N-cyclohexyl-2- (2,4-dichlorophenyl) -1- (4- (trifluoromethyl) phenyl) -1H-imidazole-4-carboxamide. Melting point: 199 to 200 ° C.
    [148] Example 49
    [149] A: N- (4-methoxyphenyl) -2,4-dichlorobenzenecarboxamidine (15.0 g, 50.8 mmol) was dissolved in 2-propanol and ethyl 3-bromo-2-oxobutanoate ( 23.5 g, 2 molar equivalents) and NaHCO 3 (8.5 g, 2 molar equivalents) are added sequentially. The resulting mixture is heated at reflux for 40 hours to room temperature. The 2-propanol is removed under vacuum, ethyl acetate is added to the residue and the resulting organic layer is washed with NaHCO 3 (5% aqueous solution). The ethyl acetate layer was collected, dried over Na 2 SO 4 , filtered and concentrated. The resulting oil was purified by column chromatography (diethyl ether / petroleum ether = 1/3 (V / V), silica gel) to give ethyl 2- (2,4-dichlorophenyl) -5-methyl-1- (4 -Methoxy-phenyl) -1H-imidazole-4-carboxylate (8.61 g, 42% yield) is obtained as a solid. 1 H-NMR (200 MHz, CDCl 3 ): δ 7.33 (d, J = 8 Hz, 1H), 7.27 (d, J = 2 Hz, 1H), 7.18 (dd, J = 8 Hz, J = 2 Hz, 1H), 7.03 (dt, J = 8 Hz, J = 2 Hz, 2H), 6.85 (dt, J = 8 Hz, J = 2 Hz, 2H), 4.42 (q, J = 7 Hz, 2H), 3.80 (s, 3H), 2.43 ( s, 3H), 1.43 (t, J = 7 Hz, 3H).
    [150] B: of ethyl 2- (2,4-dichlorophenyl) -5-methyl-1- (4-methoxyphenyl) -1H-imidazole-4-carboxylate (8.00 g, 0.0198 mol) in THF (80 mL) To the stirred solution is added LiOH (0.59 g, 2 molar equivalents) and water (80 mL). The resulting mixture is stirred at 80 ° C. for 16 hours. After cooling to room temperature, HCl (2N solution, 12.3 mL) is added to give an oily precipitate. After addition of water and extraction with ethyl acetate, the ethyl acetate layer was collected, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was crystallized from diisopropyl ether and dried to give 2- (2,4-dichlorophenyl) -5-methyl-1- (4-methoxyphenyl) -1H-imidazole-4-carboxylic acid (4.04 g, 87% yield) as a light gray solid. Melting point: 189-191 ° C.
    [151] C: To 2- (2,4-dichlorophenyl) -5-methyl-1- (4-methoxyphenyl) -1H-imidazole-4-carboxylic acid (1.00 g, 2.65 mmol) in anhydrous acetonitrile (25 mL). Diisopropylethylamine (DIPEA) (1.02 mL, 2.2 molar equivalents), O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluoro-phosphate (HBTU) ( 1.21 g, 1.2 molar equivalents) is added continuously and the resulting solution is stirred for 15 minutes. Add cyclohexylamine (0.36 mL, 1.2 molar equivalents). After stirring for 50 hours, the resulting mixture is concentrated in vacuo. The residue is dissolved in dichloromethane and aqueous NaHCO 3 solution is added. The dichloromethane layer is collected, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was further purified by column chromatography (gradient: dichloromethane => dichloromethane / methanol = 99/1 (v / v), silica gel) to give N- (1-cyclohexyl) -2- (2,4 -Dichlorophenyl) -5-methyl-1- (4-methoxyphenyl) -1H-imidazole-4-carboxamidine (1.03 g, 85% yield) is obtained. Melting point: 160-161 degreeC.
    [152] Similarly the following compounds were prepared:
    [153] 50. 1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -N, N, 5-trimethyl-1H-imidazole-4-carboxamide. Melting point: 101-104 ° C.
    [154] 51. 1- (4-Chloropyridin-2-yl) -2- (2,4-dichlorophenyl) -5-methyl-N- (piperidin-1-yl) -1H-imidazole-4-car Voxamide. MS: 464 (MH + ).
    [155] 52. 1- (4-Chloropyridin-2-yl) -2- (2,4-dichlorophenyl) -5-methyl-N- (4-morpholinyl) -1 H-imidazole-4-carboxamide . MS: 466 (MH + ).
    [156] 53. N- (1-Azepanyl) -1- (4-chloropyridin-2-yl) -2- (2,4-dichlorophenyl) -5-methyl-1H-imidazole-4-carboxamide. MS: 478 (MH + ).
    [157] 54. 1- (4-Chloropyridin-2-yl) -N-cyclohexyl-2- (2,4-dichlorophenyl) -5-methyl-1H-imidazole-4-carboxamide. MS: 463.
    [158] 55. 1- (4-Chloropyridin-2-yl) -2- (2,4-dichlorophenyl) -5-methyl-N- (N-pentyl) -1 H-imidazole-4-carboxamide. MS: 451.
    [159] 56. 1- (4-Chloropyridin-2-yl) -2- (2,4-dichlorophenyl) -N- (4-fluorobenzyl) -5-methyl-1H-imidazole-4-carboxamide . MS: 489. Melting point: 123 to 126 ° C.
    [160] 57. 1- (4-Chlorophenyl) -N-cyclohexyl-5-methyl-2- (2-trifluoromethyl-4-chlorophenyl) -1 H-imidazole-4-carboxamide. Melting point: 212 ° C.
    [161] 58. 1- (4-Chlorophenyl) -5-methyl-N- (piperidin-1-yl) -2- (2-trifluoromethyl-4-chlorophenyl) -1H-imidazole-4- Carboxamide. Melting point: 165 ° C.
    [162] 59. 1- (4-Chlorophenyl) -2- (2-methoxy-4-chlorophenyl) -5-methyl-N- (N-pentyl) -1 H-] imidazole-4-carboxamide. Melting point: 131 ° C.
    [163] 60. 1- (4-Chlorophenyl) -2- (2-methoxy-4-chlorophenyl) -5-methyl-N- (piperidin-1-yl) -1H-imidazole-4-carbox amides. Melting Point:> 256 ° C.
    [164] 61. N-cyclohexyl-1- (4-chlorophenyl) -2- (2-methoxy-4-chlorophenyl) -5-methyl-1H-imidazole-4-carboxamide. Melting point: 201 ° C.
    [165] 62. 2- (2,4-dichlorophenyl) -1- (4-fluorophenyl) -5-methyl-N- (piperidin-1-yl) -1H-imidazole-4-carboxamide. Melting point: 223 to 224 ° C.
    [166] 63. 2- (2,4-Dichlorophenyl) -5-methyl-1- (4-methoxyphenyl) -N- (piperidin-1-yl) -1 H-imidazole-4-carboxamide . Melting point:> 90 ° C. (decomposition).
    [167] 64. N-cyclohexyl-1- (4-fluorophenyl) -2- (2,4-dichlorophenyl) -5-methyl-1H-imidazole-4-carboxamide. Melting point: 229 to 230 ° C.
    [168] 65. 1- (4-Chlorophenyl) -5-methyl-N- (N-pentyl) -2- (2-trifluoromethyl-4-chlorophenyl) -1 H-imidazole-4-carboxamide. Anhydrous.
    [169] 66. 1- (4-Chlorophenyl) -2- (2-fluoro-4-chlorophenyl) -5-methyl-N- (piperidin-1-yl) -1H-imidazole-4-carbox amides. Melting point: 195 ° C.
    [170] 67. 1- (4-Chlorophenyl) -2- (2-fluoro-4-chlorophenyl) -5-methyl-N- (N-pentyl) -1 H-imidazole-4-carboxamide. Melting point: 115 ° C.
    [171] 68. 1- (4-Chlorophenyl) -N- (cyclohexyl) -2- (2-fluoro-4-chlorophenyl) -5-methyl-1H-imidazole-4-carboxamide. Melting point: 188 ° C.
    [172] 69. 1- (4-Chlorophenyl) -N- (cyclohexyl) -2- (1,5-dimethyl-1H-pyrrol-2-yl) -5-methyl-1H-imidazole-4-carboxamide . Melting point: 188-189 ° C.
    [173] 70. 1- (4-Chlorophenyl) -2- (1,5-dimethyl-1H-pyrrole-2-yl) -5-methyl-N- (piperidin-1-yl) -1H-imidazole- 4-carboxamide. Melting point: 208 to 210 ° C.
    [174] 71. 2- (2-Chlorophenyl) -1- (3-fluorophenyl) -5-methyl-N- (piperidin-1-yl) -1H-imidazole-4-carboxamide. Melting point: 236 to 238 ° C.
    [175] 72. 2- (2-Chlorophenyl) -1- (3-fluorophenyl) -5-methyl-N- (N-pentyl) -1H-imidazole-4-carboxamide. Melting point: 97-102 ° C.
    [176] 73. 2- (2-Chlorophenyl) -N-cyclohexyl-1- (3-fluorophenyl) -5-methyl-1H-imidazole-4-carboxamide. Melting point: 180-182.5 ° C.
    [177] 74. 2- (2-Chlorophenyl) -1- (3-fluorophenyl) -N- (2- (4-fluorophenyl) ethyl) -5-methyl-1H-imidazole-4-carboxamide . Melting point: 123.5-126 ° C.
    [178] 75. 1- (4-Chloropyridin-2-yl) -2- (2,4-dichlorophenyl) -5-ethyl-N- (piperidin-1-yl) -1 H-imidazole-4- Carboxamide. Melting point: 146 ° C.
    [179] 76. 1- (4-Chloropyridin-2-yl) -2- (2,4-dichlorophenyl) -5-ethyl-N- (4-morpholinyl) -1H-imidazole-4-carboxamide . Melting point: 223 ° C.
    [180] 77. N- (1-azpanyl) -1- (4-chloropyridin-2-yl) -2- (2,4-dichlorophenyl) -5-ethyl-1H-imidazole-4-carboxamide. Melting point: 177 ° C.
    [181] 78. 1- (4-Chloropyridin-2-yl) -N-cyclohexyl-2- (2,4-dichlorophenyl) -5-ethyl-1H-imidazole-4-carboxamide. Melting point: 149 ° C.
    [182] 79. 1- (4-Chloropyridin-2-yl) -2- (2,4-dichlorophenyl) -5-ethyl-N- (n-pentyl) -1 H-imidazole-4-carboxamide. Melting Point: Oil.
    [183] 80. 1- (4-Chloropyridin-2-yl) -2- (2,4-dichlorophenyl) -5-ethyl-N- (4-fluorophenylmethyl) -1H-imidazole-4-carbox amides. MP: anhydrous.
    [184] 81. 1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -N- (hexahydrocyclopenta- [c] pyrrole-2 (1H) -yl) -5-methyl-1H-already Dozol-4-carboxamide. MP: 143-146 degreeC.
    [185] 82. 1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -5-methyl-N-phenyl-1H-imidazole-4-carboxamide. Melting point: 91-95 ° C.
    [186] 83. 1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -5-methyl-N- (tetrahydro-2H-pyran-2-yloxy) -1H-imidazole-4-car Voxamide. Melting point: 128-133 ° C.
    [187] 84.N- (Exo-Bicyclo [2.2.1] hept-2-yl) -1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methyl-1H-imidazole- 4-carboxamide. Melting point: 194-195 ° C.
    [188] 85. 1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -N- (2-fluoroethyl) -5-methyl-1H-imidazole-4-carboxamide. Melting point: 128-133 ° C.
    [189] 86. 1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -N- (trans-4-hydroxycyclohexyl) -5-methyl-1H-imidazole-4-carboxamide. Melting point: 160 ° C. (decomposition).
    [190] 87. 1-{[1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -5-methyl-1H-imidazol-4-yl] carbonyl} -4-hydroxypiperidine . Melting Point: Anhydrous.
    [191] 88. 1-{[1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -5-methyl-1H-imidazol-4-yl] carbonyl} -1,2,3,4 Tetrahydroisoquinoline. Melting point: 143 to 146 ° C.
    [192] 89. N- (endo-bicyclo [2.2.1] hept-2-yl) -1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methyl-1H-imidazole- 4-carboxamide. Melting point: 194-195 ° C.
    [193] 90. 1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -N- (4-fluorobenzyl) -5-methyl-1H-imidazole-4-carboxamide. Melting point: 165 to 166 ° C.
    [194] 91. 1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -5-methyl-N- (N-pentyl) -1H-imidazole-4-carboxamide. oil.
    [195] 92. N- (Azepan-1-yl) -1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methyl-1H-imidazole-4-carboxamide. Melting point: 147 to 149 ° C.
    [196] 93. 1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -5-methyl-N- (pyrrolidin-1-yl) -1H-imidazole-4-carboxamide. Melting point: 205-206 degreeC.
    [197] 94. 1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -5-methyl-N- (morpholin-4-yl) -1H-imidazole-4-carboxamide. Melting point: 225 ° C. (decomposition).
    [198] 95. 2- (2,5-dichlorophenyl) -5-methyl-1-phenyl-N- (piperidin-1-yl) -1H-imidazole-4-carboxamide. Melting point: 227 ° C.
    [199] 96. N-cyclohexyl-2- (2,5-dichlorophenyl) -5-methyl-1-phenyl-1H-imidazole-4-carboxamide. Melting point: 236 ° C.
    [200] 97. N-cyclohexyl-2- (2,4-dichlorophenyl) -1- (2,5-difluorophenyl) -5-ethyl-1H-imidazole-4-carboxamide. Melting point: 144 to 146 ° C.
    [201] 98. N-cyclohexyl-2- (2,4-dichlorophenyl) -1- (2,5-difluorophenyl) -5-methyl-1H-imidazole-4-carboxamide. Melting point: 206 to 208 ° C.
    [202] 99. N-cyclohexyl-2- (1,5-dimethyl-1H-pyrrol-2-yl) -5-ethyl-1-phenyl-1H-imidazole-4-carboxamide. Melting point: 195-196 ° C.
    [203] 100. N-cyclohexyl-2- (2,5-dichlorophenyl) -5-ethyl-1-phenyl-1H-imidazole-4-carboxamide. Melting point: 198-199 ° C.
    [204] 101. 2- (2,5-dichlorophenyl) -5-ethyl-1-phenyl-N- (piperidin-1-yl) -1H-imidazole-4-carboxamide. Melting point: 207-208 degreeC.
    [205] 102. 1- (4-Chlorophenyl) -5-methyl-2- (3-methylpyridin-2-yl) -N- (piperidin-1-yl) -1H-imidazole-4-carboxamide . Melting point: 211 to 213 ° C.
    [206] 103. 1- (4-Chlorophenyl) -N-cyclohexyl-5-methyl-2- (3-methylpyridin-2-yl) -1H-imidazole-4-carboxamide. Melting point: 188 to 190 ° C.
    [207] 104. 1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -5-methyl-N- (3- (trifluoromethyl) phenyl) -1H-imidazole-4-carboxamide . Melting point: 177 ° C.
    [208] 105. 1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -5-methyl-N- (3- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxamide . Melting point: 138 to 140 ° C.
    [209] 106. 1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -5-methyl-N- (4- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxamide . Melting point: 232 ° C.
    [210] 107. 1- (4-Chlorophenyl) -N-cyclopentyl-2- (2,4-dichlorophenyl) -5-methyl-1H-imidazole-4-carboxamide. Melting point: 172 ° C.
    [211] 108. 1- (4-Chlorophenyl) -N-cycloheptyl-2- (2,4-dichlorophenyl) -5-methyl-1H-imidazole-4-carboxamide. Melting point: 154 to 156 ° C.
    [212] Example 109
    [213] A: Published method using excess S0 2 Cl 2 in dichloroethane at reflux temperature for 50 hours [N. Kudo et al., Chem. Pharm. Bull. 1999, 47, 857-868, ethyl 1- (4-bromophenyl) -2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxylate is converted to ethyl 1- (4 -Bromophenyl) -5-chloro-2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxylate.
    [214] B: Similar to the method described in Example 22 above, ethyl 1- (4-bromophenyl) -5-chloro-2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxylate 1- (4-Bromophenyl) -5-chloro-2- (2,4-dichloro-phenyl) -N- (piperidin-1-yl) -1H-imidazole-4-carboxamide (melting point :> 150 ° C .; R f (silica gel, EtoAc) ˜0.35). 1 H-NMR (400 MHz, CDCl 3 ): δ 7.85 (br s, 1 H), 7.52 (dt, J = 8 Hz, J = 2 Hz, 2H), 7.26-7.36 (m, 3H), 7.01 (dt, J = 8 Hz, J = 2 Hz, 2H), 2.85-2.92 (m, 4H), 1.72-1.80 (m, 4H), 1.40-1.44 (m, 2H).
    [215] Example 110
    [216] A: N, N-dimethyl in a stirred solution of 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxylic acid (18.38 g, 50 mmol) in toluene (200 mL) Formamide di-tert-butyl acetal (50 mL) is added under a nitrogen atmosphere and the resulting mixture is heated at 80 ° C. for 4 hours. After cooling to room temperature, the reaction mixture is concentrated and diethyl ether is added. The resulting solution is washed twice with water, dried over MgSO 4 , filtered and concentrated in vacuo. The residue was crystallized from diisopropyl ether to give pure tert-butyl 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxylate (10.35 g, 49 % Yield). Melting point: 179 to 181 ° C.
    [217] B: Lithium diisopropyl amide (LDA) (5.25 mL of 2M solution in THF, 0.0105 mol) was tert-butyl1- (4-chlorophenyl) -2- (2,4-dichloro in anhydrous THF (80 mL). To a cooled solution (-70 ° C.) of phenyl) -1H-imidazole-4-carboxylate (4.24 g, 0.010 mol) was added dropwise under nitrogen atmosphere and the resulting mixture was stirred for 1 hour. P-toluenesulfonyl cyanide (1.88 g, 0.011 mol) in anhydrous THF (20 mL) is added dropwise, and the resulting red solution is stirred at −70 ° C. for 1 hour and then allowed to come to room temperature. Diethyl ether is added and the resulting solution is quenched with water and filtered through hyflo. The organic layer is collected, washed with water, dried over MgSO 4 and concentrated in vacuo to give an oil. This oil was purified by column chromatography (dichloromethane, silica gel) to give tert-butyl 1- (4-chlorophenyl) -5-cyano-2- (2,4-dichlorophenyl) -1H-imidazole- 3.4 g of 4-carboxylate are obtained. Recrystallization from diisopropyl ether, crystalline tert-butyl 1- (4-chlorophenyl) -5-cyano-2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxylate (2.57 g, 57% yield) is obtained. Melting point: 210 to 212 ° C.
    [218] Similarly the following compounds were prepared:
    [219] Tert-butyl 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methyl-1H-imidazole-4-carboxylate. 1 H-NMR (400 MHz, CDCl 3 ): 87.38 (d, J = 8 Hz, 1 H), 7.34 (dt, J = 8 Hz, J = 2 Hz, 2H), 7.27 (d, J = 2 Hz, 1H), 7.22 ( dd, J = 8 Hz, J = 2 Hz, 1 H), 7.03 (dt, J = 8 Hz, J = 2 Hz, 2H), 2.40 (s, 3H), 1.63 (s, 9H).
    [220] C: tert-butyl 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-cyano-1H-imidazole-4-carboxylate (2.57 g, in dichloromethane (40 mL) 5.73 mmol) trifluoroacetic acid is added and the resulting solution is stirred at room temperature for 20 hours and concentrated in vacuo. The residue was crystallized from diisopropyl ether to give pure 1-4-chlorophenyl) -5-cyano-2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxylic acid (1.95 g, 87% yield) ). Melting point: 200-202 ° C. (decomposition).
    [221] D: 1- (4-chlorophenyl) -5-cyano-2- (2,4-dichlorophenyl) -1H-imidazole-4- in a similar manner to that described in Example 22, Part B above. Carboxylic Acid in 60% Yield 1- (4-Chlorophenyl) -5-cyano-2- (2,4-dichlorophenyl) -N- (piperidin-1-yl) -1H-imidazole-4- Convert to carboxamide. Melting point: 231 to 233.5 ° C.
    [222] Similarly the following compounds were prepared:
    [223] 111. 1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -5-urido-N- (piperidin-1-yl) -1H-imidazole-4-carboxamide. Melting point: 196 to 201 ° C.
    [224] 112. 1- (4-Chlorophenyl) -N-cyclohexyl-2- (2,4-dichlorophenyl) -5-urido-1H-imidazole-4-carboxamide. Melting point: 226 to 230 ° C.
    [225] 113. 1- (4-Chlorophenyl) -5-cyano-N-cyclohexyl-2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxamide. Melting point: 157 to 158 ° C.
    权利要求:
    Claims (10)
    [1" claim-type="Currently amended] Compounds of formula (I).
    Formula I

    In the above formula,
    R is phenyl, thienyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl which may be substituted with 1, 2, 3 or 4 substituents Y Group, wherein Y may be the same or different and group C 1-3 alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or Dialkyl (C 1-2 ) -amino, mono- or dialkyl (C 1-2 ) -amido, (C 1-3 ) -alkoxycarbonyl, carboxyl, cyano, carbamoyl and acetyl Or R is naphthyl provided that when R is 4-pyridinyl R 4 is a halogen atom or cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methane sulfonyl, and methylsulfanyl or branched or unbranched C 1-4 alkyl group, wherein the C 1-4 alkyl group is from 1 to 3 Substituted with a fluoro atom, or bromo, chloro, iodo, cyano or may be substituted with a hydroxyl group, and;
    R 1 is a phenyl or pyridinyl group which may be substituted with 1 to 4 identical or different and substituents having the above meaning, or R 1 may be substituted with 1 to 2 identical or different substituents Y Pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, or R 1 is a 5-membered aromatic heterocyclic having 1 or 2 identical or different heteroatoms in the group (N, O, S) As a ring, it may be substituted with 1 to 2 same or different substituents Y, or R 1 is naphthyl;
    R 2 is H, or a branched or unbranched C 1-8 alkyl, C 3-8 cycloalkyl, C 3-8 alkenyl, C 5-8 cycloalkenyl group which may contain sulfur, oxygen or nitrogen atoms ego;
    R 3 is branched or unbranched C 2-8 alkyl, C 1-8 alkoxy, C 5-8 cycloalkoxy, C 3-8 cycloalkyl, C 5-10 bicycloalkyl, C 6-10 tricycloalkyl, C 3-8 alkenyl, C 5-8 cycloalkenyl groups, which groups may optionally contain one or more heteroatoms of groups (O, N, S) and are hydroxy groups or 1 to 2 C 1-3 May be substituted with an alkyl group or with 1 to 3 fluoro atoms, or
    R 3 represents benzyl or phenethyl group, wherein the aromatic ring is C 1-3 alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or Dialkyl (C 1-2 ) -amino, mono- or dialkyl (C 1-2 ) -amido, (C 1-3 ) -alkylsulfonyl, dimethyl-sulfamido, C 1-3 -alkoxycarbonyl May be substituted with 1 to 5 identical or different substituents Z selected from the group consisting of carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R 3 is A phenyl or pyridinyl group substituted with 1 to 4 substituents Z having the meaning as defined above, or
    R 3 is a pyridinyl group, or R 3 is a phenyl group, provided that R 4 is a halogen atom or cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methanesul Phonyl, methylsulfanyl or C 1-4 alkyl group, wherein the C 1-4 alkyl group may be substituted with 1 to 3 fluoro atoms or bromo, chloro, iodo, cyano or hydroxy groups, or Or R 3 represents a group NR 5 R 6 , provided that R 2 is a hydrogen atom or a methyl group,
    R 5 and R 6 are the same or different, branched or unbranched C 1-4 alkyl, or R 5 and R 6 have 4 to 10 ring atoms, saturated or unsaturated with a nitrogen atom bonded thereto; To form a monocyclic or bicyclic heterocyclic group, wherein the heterocyclic group contains one or two identical or different heteroatoms in the group (N, O, S) and may also be C 1-3 alkyl May be substituted with a group or a hydroxy group; or
    R 2 and R 3 together with the nitrogen atom bonded to them form a heterocyclic group having 4 to 10 ring atoms, saturated or unsaturated, wherein the heterocyclic group is selected from the group (N, O, S) Contains 1 or 2 identical or different heteroatoms and may also be substituted with a C 1-3 alkyl group or a hydroxy group;
    R 4 is hydrogen or a halogen atom, cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methanesulfonyl, methylsulfanyl or branched or unbranched C 1- 4 alkyl group, wherein C 1-4 alkyl group may be substituted with 1 to 3 fluoro atoms or bromo, chloro, iodo, cyano or hydroxy groups.
    [2" claim-type="Currently amended] A pharmaceutical composition containing, as active ingredient, at least one pharmaceutically active amount of the compound of claim 1.
    [3" claim-type="Currently amended] A method for preparing the composition of claim 2, wherein the compound of claim 1 is prepared in a form suitable for administration.
    [4" claim-type="Currently amended] Reacting a compound of Formula (II), (III) or (IV) with a compound of Formula (R 2 R 3 NH), R, R 1 to R 3 have the meanings defined in claim 1, and R 4 is hydrogen or a halogen atom Or a C 1-4 alkyl group which may be substituted with cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, propionyl, sulfamoyl, methanesulfonyl, methylsulfanyl group, or 1 to 3 fluoro atoms A process for preparing a compound of formula (I).
    [5" claim-type="Currently amended] In the presence of a strong non-nucleophilic base, the compound of formula II wherein R 4 is a hydrogen atom and the formula R 4 '-X wherein X is a leaving group and R 4 ' is substituted with 1 to 3 fluoro substituents Or a C 1-4 alkyl group, or R 4 ′ is a halogen atom or a compound of cyano, formyl, acetyl, trifluoroacetyl, fluoroacetyl, methylsulfanyl or propionyl group). To prepare a compound of formula (II).
    Formula II

    In the above formula,
    R 4 is a C 1-4 alkyl group which may be substituted with 1 to 3 fluoro substituents, or R 4 is a halogen atom or cyano, formyl, acetyl, trifluoroacetyl, fluoroacetyl, methylsulfanyl Or propionyl group,
    R and R 1 have the meaning defined in claim 1,
    R 7 is a branched or unbranched alkyl group (C 1-4 ) or benzyl group.
    [6" claim-type="Currently amended] A process for preparing a compound of formula II, characterized by reacting a compound of formula V or a tautomer thereof with a compound of formula VI.
    Formula II

    Formula V

    Formula VI

    In the above formula,
    R 4 is a branched or unbranched C 1-4 alkyl group which may be substituted with one to three fluoro substituents;
    R 7 is a branched or unbranched alkyl group (C 1-4 ) or benzyl group;
    R 8 is a leaving group;
    R and R 1 have the meanings defined in claim 1.
    [7" claim-type="Currently amended] Compound of Formula IX.

    In the above formula,
    R and R 4 have the meanings defined in claim 1;
    R 1 is a phenyl or pyridinyl group which may be substituted with 1 to 4 identical or different substituents Y, or R 1 may be substituted with 1 to 2 identical or different substituents Y pyrimidy A silyl, pyrazinyl, pyridazinyl or triazinyl group, or R 1 is a 5-membered aromatic heterocyclic moiety having 1 or 2 identical or different heteroatoms in the group (N, O, S), May be substituted with 1 to 2 same or different substituents Y, or R 1 is naphthyl;
    R 9 is a hydroxy group, a branched or unbranched alkoxy (C 1-4 ) group, benzyloxy group or chloro substituent.
    [8" claim-type="Currently amended] Compounds of Formula X and tautomers thereof.

    In the above formula,
    R is a 4-chlorophenyl group, a 4-bromophenyl group or a 4- (trifluoromethyl) phenyl group.
    [9" claim-type="Currently amended] Use of the compound of claim 1 in the manufacture of a pharmaceutical composition for treating a disease associated with cannabinoid neurotransmission.
    [10" claim-type="Currently amended] 10. The method of claim 9, wherein the disorder comprises psychosis, anxiety, depression, attention deficit, memory disorder, cognitive impairment, appetite disorders, obesity, addiction, desire, psychiatric disorders including drug dependence, and neurodegenerative diseases, dementia, dystonia, Muscle stiffness, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette syndrome, cerebral ischemia, stroke, brain trauma, stroke, spinal cord injury, neuroinflammatory disease, valve sclerosis, Neurological diseases including viral encephalitis, demyelinization-related diseases, as well as pain diseases including neuropathic pain diseases, and septic shock, glaucoma, cancer, diabetes, vomiting, nausea, asthma, respiratory diseases, gastrointestinal disorders, And other diseases related to cannabinoid neurotransmission, including gastric ulcer, diarrhea and cardiovascular disease.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2001-09-21|Priority to EP01203851.9
    2001-09-21|Priority to EP01203851
    2002-09-17|Application filed by 솔베이 파마슈티칼스 비. 브이
    2002-09-17|Priority to PCT/EP2002/010434
    2004-04-29|Publication of KR20040035847A
    2010-04-02|Application granted
    2010-04-02|Publication of KR100950431B1
    优先权:
    申请号 | 申请日 | 专利标题
    EP01203851.9|2001-09-21|
    EP01203851|2001-09-21|
    PCT/EP2002/010434|WO2003027076A2|2001-09-21|2002-09-17|1h-imidazole derivatives having cb1 agonistic, cb1 partial agonistic or cb1- antagonistic activity|
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