TWI285197B - 1H-1,2,4-triazole-3-carboxamide derivatives having cannabinoid-CB1 receptor agonistic, partial agonistic, inverse agonistic or antagonistic activity - Google Patents

Abstract

The present invention relates to a group of 1H-1,2,4-triazole-3-carboxamide derivatives, to methods for the preparation of these compounds, and to pharmaceutical compositions containing at least one of these compounds as an active ingredient. These 1H-1,2,4-triazole-3-carboxamide derivatives are potent cannabinoid-CB1 receptor agonists, partial agonists, inverse agonists or antagonists, useful for the treatment of disorders involving cannabinoid neurotransmission. The compounds have the general formula (I), wherein R and R1-R3 have the meanings given in the specification.

Description

^i?2^364 Revision period: February 1996

Patent application application patent revision page, invention description: TECHNICAL FIELD OF THE INVENTION The present invention relates to 1H-1,2 having cannabinoid <61 receptor agonism, partial agonism, anti-agonism or antagonistic activity, 4-triazole-3_decylamine derivative. The present invention relates to a group of 1H-1,2,4-triazole derivatives, a process for preparing these compounds, and a pharmaceutical composition containing one or more of these compounds as an active ingredient. These 1 Η-1,2,4-triazole-nonylamine derivatives are potent cannabinoid-CB1 receptor agonists, partial agonists, inverse agonists or antagonists for the treatment of psychosis and neurological diseases, among others. A disease involving cannabinoid-CBjt transmission. Prior art 3 EP 0346620 and GB 2120665 disclose 1,5-diaryl_1H-1,2,4-triazol-3-indolamine derivatives as herbicides. Recently, i, 2,4-triazole has been disclosed as a possible agonist and antagonist of the cannabinoid-CB i and -CB2 receptors (Jagerovic, N. et al.? Drugs Fut. 2002, 27 (Suppl. A) ): XVIIth Int. Symp. on Medicinal Chemistry, P284) 〇 Now, it is surprisingly found that the known and new 1,5-diaryl-1H-1,2,4-three of formula (I) Zyridin-3-indole derivatives, as well as prodrugs, salts and stereoisomers thereof, are potent antagonists, agonists, inverse agonists or partial agonists of the cannabinoid CB! receptor: 1285197

R and the heart independently represent a phenyl group, a naphthyl group, an anthranyl group, an alpha thiol group, a carcinoid group, a pyridazinyl group, a pyridazinyl group or a triazinyl group, and these groups may be the same 5 or different from 1 to 4 Substituted by a substituent X, the X substituent is selected from a branched or unbranched (Ci-3)-alkyl or alkoxy group, a hydroxyl group, a 素素, a trifluoromethyl group, a trifluoromethylthio group, a difluoromethyl group. Oxy, nitro, amino, mono or dialkyl (C12)-amino, mono or dialkyl (<^_2)-nonylamino, (c^3)-alkoxycarbonyl, trifluoromethanesulfonyl Amisulphol, (Cw)-alkylsulfonyl, carboxyl, cyano, carbachol, (c^)-10 dialkylaminosulfonyl, (C^3)-monoalkylamino Sulfhydryl and ethenyl, R 2 represents a hydrogen atom or a branched or unbranched Ci-8 alkyl or Ci 8 cycloalkylalkyl group, or a phenyl group or a benzyl group in which an aromatic ring may be substituted with 1 to 4 substituents X. Or phenethyl, wherein X has the above meaning, or R2 represents pyridyl or thienyl, and R3 represents branched or unbranched Ci.8 alkyl, Cis alkoxy, Cw cycloalkanyl, c5_10 bicyclofilament, C6 i〇tricycloalkyl, C3 8 alkenyl, & cyclohexane, these groups may optionally contain One or more heteroatoms selected from the group consisting of hydrazine, N, S, and these groups may be substituted by an ethynyl group or a (tetra) group, or I represents a phenyl group, an aromatic ring which may be substituted with 1-4 substituents fluorene. Or phenethyl, wherein X has the above meaning, or & represents a heteroaryl ring which is substituted with 1 or 2 minus groups X, a (tetra)yl group, a fluorenyl group, a building 1285197 or R3 a base group, a triazinyl group or a thienyl group, wherein X has the above-mentioned shy group NRd towel 3, which is said to be a radical or unsaturated, monocyclic or bicyclic ring having 4 〇 裱 a 裱 atom. a heterocyclic moiety having a heterocyclic moiety containing the same or different heteroatoms selected from N, oxime or S. The heterocyclic moiety may be branched or unbranched, Ci-based, via Or a trimethyl group or a fluorine atom, or a heart and R3 together with the nitrogen atom to which they are attached form a saturated or unsaturated, monocyclic or bicyclic heterocyclic moiety having '1 fluorene atom, the heterocyclic ring 10 The group contains 1 or 2 identical or different heteroatoms selected from N, oxime or S, and the heterocyclic moiety may be supported Or an unbranched alkyl, hydroxy, 呱σ-decyl or trifluoromethyl or fluorine atom. D. Clerin and JP Flcury in Bull. Soc. Chim. Fr., 1974, 1-2, Pt. 2, 211- A group of four 1,5-diaryl-1H-1,2,4-tri-15oxazolidine derivatives are disclosed in 217, wherein the indole n atom is an unsaturated acridinyl group or a morphine Part of the group. H. Elnagdi et al., Heteroatom Chem., 1995, 6, 589-592 discloses 1-(4-methylphenyl)-5-phenyl-N-(2-pyridyl) -111-1, 2, 4-three 1| sit -3-decylamine. 20 AH Harhash et al. in Indian J. Chem., 1976, 14B, 268-272 discloses a group of four 1,5-diaryl-N-(2-pyridyl)-1H-1,2, 4-triazole-3-decylamine. Due to potent cannabinoid <81 receptor agonism, partial agonism, anti-agonism or antagonistic activity, the compounds of the invention are suitable for the treatment of psychosis, anxiety, 1285197 depression, attention deficit, memory impairment, cognitive impairment, appetite disorder, obesity Symptoms, addiction, desire, drug dependence, neurodegenerative diseases, dementia, abnormal muscle tone, muscle rigidity, tremors, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy , Hen 5,, Tourette syndrome, cerebral ischemia, stroke, craniocerebral injury, stroke, spinal cord injury, neuroinflammatory disease, plaque scler〇sis, viral encephalitis, and Demyelinating-related diseases, as well as treatment of painful diseases, including neuropathic pain, septic shock, glaucoma, diabetes, cancer, vomiting, sputum nausea, ileal disease, gastric ulcer, abdominal and cardiovascular diseases. 10 SUMMARY OF THE INVENTION The affinity of the compounds of the present invention with the cannabinoid CB]l receptor is determined using a membrane preparation of Chinese hamster ovary (CHO) cells, in the membrane preparation of the Chinese hamster-printed cells, 'human cannabis The CB! receptor was stably transfected and bound to the radioligand [3H]CP-55, 94〇. After incubation of the freshly prepared cell membrane preparation containing [3Η]_ligand, the bound and free ligands were separated by filtration through a glass fiber filter with or without the addition of the compound of the invention. The radioactivity on the filter was measured by a liquid scintillation counter. The cannabinoid CBX receptor upregulated, agonistic or partially agonistic activity of the compounds of the invention was determined by functional studies using human CB1 receptors cloned in Chinese hamster ovary (CHO) cells. CHO cells were grown in DMEM culture medium supplemented with 1% heat-inactivated fetal calf serum. The medium was aspirated and replaced with DMEM containing no fetal calf serum but containing [3H]-arachidonic acid and in a cell culture incubator (5% C〇2/95% air; 37. (:; water-saturated atmosphere) Alcoholization was carried out overnight. During this period, [3H]-arachidonic acid was incorporated into the membrane phospholipid. On the day of the test 1285197, the medium was aspirated and washed with 〇.5 ml of disc salt buffered saline containing 0.2% bovine serum albumin. The cells were stimulated three times. The CB1 receptor was stimulated with WIN 55, 212-2, resulting in the activation of PLA2, and then [3H]-arachidonic acid was released into the medium. This WIN 55,212-2-induced release was antagonized by the CBi receptor antagonist. 5 Antagonism depends on the concentration of the antagonist. It can be estimated according to literature methods, such as the in vivo pseudo-cannabinoid effect (Wiley3 JL; Jefferson, R. G; Grier, MC; Mahadevan, A.; Razdan, RK; Martin, BRJ Pharmacol. Exp. Ther. 2001, 296, 1013) to determine the cannabinoid agonistic or partial agonistic 10 activity of the compounds of the invention. The invention relates to racemates, mixtures of diastereomers of the compounds of formula (I) And each stereoisomer. Moreover, the prodrug, that is, when Compounds which are metabolized to a compound of formula (I) after administration to any human body are also within the scope of the invention. In particular, the invention relates to compounds having a primary or secondary amino group 15 or a hydroxy group. Such compounds may be organic The acid reacts to form a compound of formula (1) in which there is an additional group which is readily removed after administration, such as, but not limited to, anthracene, enamine, Mannich, viamethylene derivative, 0-(oxygen) a methylene carbamate derivative, a carbamate, an ester, a decylamine or an enaminone. A prodrug is an inactive compound that is converted to an active form after absorption 20 (Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed·: F· D· King, ρ· 216). The compounds of the invention may be formulated for administration by conventional methods using auxiliary substances and/or liquid or solid carrier materials. Form 1285197 A suitable synthetic route for the compounds of the invention is as follows:

Scheme A Step 1: Hydrolysis of an ester of a compound of formula (II) wherein R6 represents a branched or unbranched group or benzyl group,

(HI)

Production of a compound of the formula (III) R R \ /1 ΝγΝ /=° Η—0 wherein R and heart have the above meanings. The compound of the formula (II) wherein R6 represents a branched or unbranched ((4)-alkyl or benzyl group) can be obtained according to known methods, for example, as follows:

a) Sawdey, GWJ Am. Chem. Soc. 1957, 79, 1955 b) Czollner, L. et al., Arch Pharm· (Weinheim) 1990, 323, 225 c) Eicher, T. and Hauptmann, S. The Chemistry of 15 Heterocycles, Thieme Verlag, Stuttgart, 1995 (ISBN 313 100511 4), p. 208-212. Step 2: by activation and coupling methods, for example to form active esters, or in coupling agents such as DCC, HBTU, BOP , CIP (2-gas-1,3-dimethylimidazoline rust 10 1285197 hexafluorophosphate) or PyA0P (7-azabenzotriazol-1-yloxytris(decyl)alkyl The compound of formula (III) is reacted with a compound of formula R2R3NH wherein R2 and 113 have the above meanings in the presence of fluorophosphate. Such activation and coupling methods are disclosed in: a) M. Bodanszky and A. Bodanszky: The Practice of

Peptide Synthesis, Springer-Verlag, New York, 1994; ISBN: 0-387-57505-7; b) K. Akaji et al., Tetrahedron Lett (1994), 35, 3315-3318); c) F. Albericio Et al., Tetrahedron Lett. (1997), 38, 4853-4856). This reaction produces a 1H-1,2,4-triazole derivative of formula (I).

Synthetic Route B The compound of formula (III) should be reacted with a halogenating agent such as sulfite gas (S0C12) or grasshopper gas. This reaction produces the corresponding hydrazine (IV).

The compound of the formula (IV) is reacted with a compound of the formula r2r3nh wherein R2 and R3 have the above-mentioned meanings to give a 1H-1,2,4-triazole derivative of the formula (1).

Synthetic Route C 2 化合物 The compound of the formula (II) is subjected to a guanidation reaction with a compound of the formula r2r3nh wherein R2 and R3 have the above-mentioned meanings to give 1H-1,2,4-triazole derivative 11 1285197 of the formula (1). Tridecyl aluminum A1(CH3)3 can be used to facilitate this guanylation reaction (for more information on the conversion of aluminum-involved esters to guanamines, see J. L Levin, Ε· Turos, SM Weinreb, Synth Commun. (1982), 12, 989-993) ° Example 3 5 Example IA: At 〇 ° C, to dimethyl aminomalonate hydrochloride (25 g, 〇136 mol) in dichloromethane ( To the solution in 200 mL), triethylamine (4 ΐ·4 mL, 2.2 eq.) was added with stirring. 4-Benzylbenzamide (23.8 g, 0.136 mol) was slowly added, 10 and the resulting solution was allowed to stand at room temperature overnight. Add water and separate the organic layer. The aqueous layer was extracted twice with di-methane. The combined organic layers were washed with EtOAc EtOAc m. The residue was recrystallized from toluene (4 mL) to give <RTI ID=0.0>> Melting point: 146-148 °C · iH-NMRQOO MHz, CDC13): 15 occupies 3.86 (s, 6H), 5·38 (d, J = 6 Hz, 1H), 7·15 (br d, J 〜 6 Hz, 1H), 7·43 (d, J = 8 Hz, 2Η), 7·79 (d, J = 8 Hz, 2H) · Part B: To 2,4-dianiline (19.44 g, 0 · 12 mol) In a stirred suspension of concentrated hydrochloric acid (25 mL) and acetic acid (75 mL), add NaN02 20 (9·〇g, 〇·13 mol) in water (50 mL) at 〇 °c The solution in ) and the resulting solution was stirred for 15 minutes. A solution of 2-(4-benzobenzylideneamino)malonate (28.55 g, 0.10 mol) in acetone (200 mL) was slowly added while maintaining the temperature below 0 °C. A solution of K2C03 (120 g) in water (200 mL) was slowly added and the obtained mixture was stirred at 0 °C for 30 min. The mixed 12 1285197 was extracted three times with EtOAc. The combined organic layers were washed with water, aq. The residue was dissolved in methylation (500 mL) and a solution of sodium (1 g) in methanol (75 mL) was added. The resulting mixture was stirred at room temperature overnight and cooled in a refrigerator. The formed precipitate was collected by filtration, and washed with methanol to give 5-(4-(s).sup.1 - (2,4-monopropenyl)-1^1,2,4-tri. Take methyl -3-decanoate (11.4 g, 30% yield). Melting point: 153-154 °C· iH-NMRpOO MHz, CDC13): δ 4.07 (s, 3Η), 7.28-7.60 (m, 7H). Part C: 10 to 5-(4-phenylphenyl)-1- a suspension of (2,4-diphenyl)-methyl-1,2,4-trimethyl-3-indoleate (11.3 g, 0.0295 mol) in methanol (loo mL) with stirring KOH (45% aqueous solution, 7.5 mL) was added, and the obtained mixture was stirred at reflux temperature for 4 hr. The mixture was concentrated in vacuo and water (150 mL) and concentrated hydrochloric. The yellow precipitate was collected by filtration, washed with water, 15 and dried in vacuo to give 5-(4-phenylphenyl)-1-(2,4-diphenylphenyl)-1 -1,2,4-triazole-3 - carboxylic acid (1 〇·〇克, 92% yield). Melting point: 141-144 ° C (decomposition). Part D: To 5-(4-phenylphenyl) small (2,4-dioxaphenyl)-1Η-1,2,4-triazole-3-carboxylic acid (1·48 g, 4·0 mmol In a solution of acetonitrile (20 mL), the mixture was stirred and then diisopropylethylamine (DIPEA) (1.5 mL, 2.1 eq.), hydrazine-benzene-triazol-1-yl-N, N, N', N'-tetramethyluronium hexafluorophosphate (HBTU) (1.66 g, 1.1 eq.) and 1-aminoacridine (0.44 g, 1.1 eq.). After stirring overnight, an aqueous solution of NaHC〇3 was added. The resulting mixture was extracted three times with a gas-fired product. The combined organic layers were washed with EtOAc EtOAc m. The oil was further purified by flash chromatography (EtOAc, EtOAc / petroleum ether (40-60 ° C) = 7/3 (v/v)). The purified material was treated with HCl in ethanol (1M solution) to give 5-(4-phenylphenyl)-1-(2,4-diphenyl)-N-(acridin-1-yl) -1Η-1,2,4-triazole-3-5 guanamine hydrochloride (1.50 g, 77% yield). Melting point: 238-240 ° C (decomposition). XH-NMR (400 MHz, DMS0-d6): 1.46-1.54 (m, 2H)? 1.78- 1.85 (m, 4H), 3.22-3.28 (m, 4H), 7.50 (s, 4H), 7.70 (dd, J = 8 and 2 Hz, 1H), 7.85-7.87 (m, 1H), 7.91 (d, J = 8 Hz, 1H), (NH not observed). 10 Examples 2-18 were prepared analogously: 2. 5-(4-Phenylphenyl)-1-(2,4-diphenyl)-indole-( σpyroxy-1_yl)-1Η-1 , 2,4-triazole-3-decylamine hydrochloride. Melting point·· 248-255 °C (decomposition). 3. 5-(4-Hydroxyphenyl)-N-cyclohexyl-1-(2,4-dichlorophenyl)_1H-1,2,4-triazole-3-decylamine. Melting point: 186-188 °C. 15 4. N-t- Butyryl-5-(4-phenylphenyl)-1-(2,4-diphenyl)-1Η_ 1,2,4-triazole-3-decylamine. Melting point: 150-152 °C. 5. 5-(4-Phenylphenyl)-1-(2,4-diphenyl)-N-(n-indenyl)-1Η_ 1,2,4-triazole-3-decylamine. W-NMR (400 MHz, CDC13): (5 0·92 (t, J = 7 Ηζ, 3 Η), 1.35-1.44 (m, 4 Η), 1.62-1.70 (m, 2 Η), 3.48-3.56 20 (m , 2Η), 7.20-7.25 (m, 1Η), 7.34 (dt, J = 8*2Ηζ, 2Η), 7·42- 7.50(m, 4H), 7·54 (d, J = 2 Hz, 1H) 6. 5-(4-Gasyl)-1-(2,4-dihydrocarbyl)-N-(morphin-4-yl)-1H_ 1,2,4-triazole-3-indole Amine. Melting point: 184-186 ° C. 7· 1-(4 -lactyl)-5-(2,4 -disordered base)-Ν-(orphan-1-yl)-1Η·* 14 1285197 1,2,4-Triazol-3-indolamine hydrochloride. Melting point: 234-237 ° C (decomposition) 8. 1-(4-Phenylphenyl)-5-(2,4-digas Phenyl)-N-(desrolidine small group)-1H-1,2,4-triazole-3-indolylamine hydrochloride. Melting point: 234-236 ° C (decomposition). 9· 1-(4 - gas phenyl)-N-cyclohexyl-5-(2,4-diphenyl)-1Η-5 1,2,4-triazole-3-decylamine. W-NMR (400 MHz, CDC13) : (51.14-1.81 (m,8H),2·02·2·10 (m,2H), 4.00-4.11 (m,1H),7·08 (br d,J ～7 Hz,1H), 7.26 ( Br d, J ~ 8 Hz, 2H), 7.34 (br d, J ~ 8 Hz, 2H), 7.40 (dd, J = 8 and 2 Hz, 1H), 7.44 - 7.48 (m, 2H) · 10· Nt - Butoxy-1-(4-phenylene) -5-(2,4-diphenyl)_1H_ 10 1,2,4-triazole-3-decylamine. W-NMR (400 MHz, CDC13): 5 1.38 (s, 9H), 7.25 (br d, J ~ 8 Hz, 2H), 7·35 (br d, J ~ 8 Hz, 2H), 7·41 (dd, J = 8 and 2 Hz, 1H), 7.44 - 7.48 (m, 2H ), 9.18, br s, 1H)· 11· 1-(4-Phenylphenyl)-5-(2,4-diphenyl)-N-(n- fluorenyl)-1Η· 1,2,4 - triazole-3-decylamine. h-NMR (400 MHz, CDC13): 5 0.91 (t, J 15 = 7 Hz, 3H), 1·35-1·41 (m, 4H), 1.60-1.70 ( m, 2H), 3.48-3.56 (m, 2H), 7·21 (br t, J ~ 7 Hz, 1H), 7.26 (br d, J ~ 8 Hz, 2H), 7.34 (br d, J ~ 8 Hz, 2H), 7.40 (dd, J = 8 and 2 Hz, 1H), 7.44-7.48 (m, 2H). 12· 1-(4-Phenylphenyl)-5-(2,4-dibenzene ))-N-(morpholine-4.yl)-iH-20 1,2,4-triazole-3-decylamine hydrochloride. Melting point: 224-226 °C. 13· 1-(2,4_Di-phenylphenyl)-5-(pyridin-2-yl)-N-(acridin-1-yl)-iH-1,2,4-triazole-3-decylamine . Melting point: 191-193 °C. 14· 5-(2,4-diphenyl)-((口瓜唆小基)-1-(4-(trimethyl)phenyl)·1Η-1,2,4-triazole- 3-decylamine. Melting point: 159-161 °C. 15 1285197 15· l'-[5-(2,4-Diphenyl)-1-(4-(dimethylmethyl)phenyl)-1Η-1,2,4-triazole-3-yl ]carbonyl] acridine. Melting point: 155-156 °C. 16· 1-(2,4-Diphenyl)-N-(acridin-1-yl)-5-(pyridin-3-yl)-1Η-1,2,4-triazole-3-indole amine. Melting point: 219 °C. 5 17· 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(5,5,5-trifluoropentyl)-1Η-1,2,4-tri Azole — 3-decylamine. W-NIVIR (400 MHz, CDC13): (5 1.63- 1.80 (m, 4H), 2.06-2.22 (m, 2H), 3.54 (q, J -7 Hz, 2H), 7·26 (m, 3H) , 7·34 (br d, J ~ 8 Hz, 2H), 7.40 (dd, J = 8 and 2 Hz, 1H), 7·44-7·48 (m, 2H)· 10 18_1-(4-gas Benzo)_5-(2,4-dioxaphenyl)-1^-(5-pentylpentyl)-11·!- 1,2,4-trisole-3-amine. W-NMR (400 MHz, CDC13): δ 1.63- 1.80 (m, 4H), 2.06-2.22 (m, 2H), 3.54 (q, J ~ 7 Hz, 2H), 7.22-7.28 (m, 3H), 7.34 (br d, J 〜8 Hz, 2H), 7.40 (dd, J = 8 and 2 Hz, 1H), 7·44·7·48 (m, 2H). 15 Embodiment 19 Part A: AC part similar to Embodiment 1 The method comprises the following steps: using dimethylaminomalonate hydrochloride, 2,4-dibenzoic fluorene gas and 4-air aniline as starting materials to prepare 1-(gas phenyl)-5-( 2,4-Diphenyl)-1Η-1,2,4-triazole-3-20carboxylic acid. Melting point·· 102-104 ° C. h-NMR (400 MHz, DMSO-d6): 5 7.36 (br d, J ~ 8 Hz, 2H), 7.50 (br d, J ~ 8 Hz, 2H), 7·59 (dd, J = 8 and 2 Hz, 1H), 7·70 (d, J = 2 Hz, 1H), 7.75 (d, J = 8 Hz, 1H), OH proton is at δ 3.4 Part of the water peak. Prepare (gas phenyl)-5_ (similarly using aminomalonic acid dimethyl ester hydrochloride, 2,5-dibenzophenone oxime and 4-chloroaniline as the starting material of 1285197, respectively) 2,5_di-phenylphenyl)-ltM, 2,4-triazole carboxylic acid. Melting point: 183-188 °C / H-NMR (400 MHz, DMSO-d6): accounted for ·4! (br d ,j ~s Hz,2h),7 52 (br d,]~ 8 HZ,2H),7 56 (d,]=8 Hz,1H),7·65 (dd, J = 8 and 2 Hz, 1H ), 5 7·88(9)J = 2 Hz, 1H), the OH proton is part of the water peak at 53. ΒPart: 1-(Phenylphenyl)-5-(2,4-diphenyl)-indole-1,2,4-trisocene tartrate (〇·37 g, 1.00 mmol) Grass 醯 gas (〇·254 g, 2.00 mmol) was added to the solution of dioxazole (10 mL). The resulting mixture was vacuumed/collapsed to give a crude product of 1-(gasphenyl)_5-(2,4-diphenyl)-1H-1,2,triazole-3-3. Part C: The crude 1-(p-phenyl)-5-(2,4-diphenyl)-1Η-1,2,4-triazole-3-carboxamidine 15 gas was dissolved in tetrahydrofuran (THF) ( 10 mL). 2,3-Dihydro-1H-segment 1 amine (〇·4〇 g, 3.000 mmol) was added, and the resulting solution was stirred at 25 ° C for 42 hours. The mixture was concentrated in vacuo and the residue was purified by preparative liquid chromatography to afford of <"&&&&&&&&&&&&&&&& Dihydro-1H-indole-2-yl)-1Η-1,2,4-triazole-3-decylamine (393 mg, 81% yield 20%). MS (ESI+) 485·6· W-NMR (400 MHz, DMSO-d6): 3·06 (dd, J = 16 and 8 Hz, 2H), 3.21. (dd, J = 16 and 8 Hz, 2H), 4·71_4·82 (m,1H),7·12-7·16 (m,2H), 7.19-7.24 (m·2H), 7·39 (br d,J -8 Hz, 2H), 7.52 ( Br d, J ~ 8 Hz, 2H), 7.60 (dd, J = 8 and 2 Hz, 1H), 7.71 (d, J = 2 Hz, 1H), 7.79 (d, J = 8 Hz, 17 1285197 1Η) , 8·93-8·97 (m, 1H, NH)· Example 20-43 was prepared analogously: 20· 1-(4-Phenylphenyl)-5-(2,4-diphenyl)- Ethylcyclohexyl)-1H-1,2,4-triazole-3-decylamine. MS (ESI+) 473.3. 5 21· 1_(4-Phenylphenyl)-5-(2,4-diphenyl)-N-(2-methylcyclohexyl)-1H-1,2,4-triazole-3-indole amine. MS (ESI+) 465.5. 22.1-(4-Phenylphenyl)-5-(2,4-diphenyl)-1^-(4-methylcyclohexyl)-1H-1,2,4-triazole-3-decylamine . MS (ESI+) 465.5. 23. 1-(4-Phenylphenyl)-5-(2,4-diphenyl)-N-cyclooctyl 10 -triazole-3-decylamine. MS (ESI+) 477.3. 24· 1-(4-Phenylphenyl)-5-(2,4-diphenyl)-N-(azepanic group)-1Η-1,2,4-triazole-3- Guanamine. MS (ESI+) 466.4. 25· 1-(4-Phenylphenyl)-5-(2,4-dichlorophenyl)cycloheptyl·1Η_ 1,2,4-triazole-3-decylamine. MS (ESI+) 465.5. 15 26· Ν-t-butyl-1-(4-phenylphenyl)-5-(2,4-diphenyl)-lH-l,2,4-triazole-3-decylamine. MS (ESI+) 425.4. 27· 1-(4-Phenylphenyl)-5-(2,4-diphenyl)-N-(l,l-diethylpropan-2-alkyn-1-yl)_1Η-1,2, 4. Triazole-3. decylamine. MS (ESI+) 461.5. 28· 1-(4-Chlorophenyl)-5-(2,4-diphenyl)_N_(2,2,2_trifluoroethyl 20-yl)-1Η-1,2,4-triazole-3 - guanamine. MS (ESI+) 451.3. 29· 1-(4-Phenylphenyl)-5-(2,4-diphenyl)-N-(exo-bicyclo[2.2.1]hept-2-yl)-1Η-1,2,4 - Triazole-3-decylamine. MS (ESI+) 461.5.

30· 1-(4-Phenylphenyl)-5-(2,4-diphenyl)-N-(4-(2-propyl)pyridazin-1-yl)-1Η-1,2, 4-triazole-3-decylamine. MS (ESI+) 480.3. W-NMR 18 1285197 (400 MHz, DMSO-d6): 1.00 (d, J = 7 Hz, 6H), 2.46-2.56 (m, 4H), 2.72 (seven peaks, J =: 7 Hz, 1H), 3.66 -3.74 (m,4H),7·36 (br d,J = 8 Hz, 2H), 7·51 (br d, J = 8 Hz, 2H), 7·59 (dd, J = 8 and 2 Hz , 1H), 7.72 (d, J = 2 Hz, 1H), 7.75 (d, J = 8 Hz, 1H)· 5 31· 1-(4-Phenylphenyl)-5-(2,4-diox Phenyl)-N-(hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1Η_1,2,4-trimethyl-3-amine. MS (ESI+) 476.4. 32· 1-(4-Phenylphenyl)-5-(2,4-diphenyl)-N-pentyl-1Η·1,2,4-triazole-3-decylamine. MS (ESI+) 435.5. 33. 1-(4-Phenylphenyl)-5-(2,4·di-phenyl)-N-(2,2-dimethylpropanyl-10-yl)-1Η-1,2,4-triazole -3-decylamine. MS (ESI+) 439.6. 34· 1-(4-Phenylphenyl)-5-(2,4-dichlorophenyl)-N-(3-(trifluoromethyl)phenyl)-1Η-1,2,4-triazole -3-decylamine. MS (ESI+) 511.7. 35· l'-[l-(4-Phenylphenyl)-5-(2,4-diphenyl)-111-1,2,4-triazol-3-yl]carbonyl]-1,4 '-Lichidine. MS (ESI+) 520.5. 15 36· 1-(4-Phenylphenyl)-N-(4-phenylphenyl)-5-(2,5-diphenyl)-N-methyl-1H-1,2,4-tri Azole-3_decylamine. MS (ESI+) 491.4. 37. 1-(4-Phenylphenyl)-5-(2,5-diphenyl)ethynylcyclohexyl)-1Η-1,2,4-triazole-3-decylamine. MS (ESI+) 473.4. 38· 1-(4-Phenylphenyl)-5-(2,5-diphenyl)-N-(2-methylcyclohexyl 20-yl)-1Η-1,2,4-triazole-3 - guanamine. MS (ESI+) 465.5. 39. 1-(4-Phenylphenyl)-5-(2,5-diphenyl)methylcyclohexyl)-1Η-1,2,4-triazole-3-decylamine. MS (ESI+) 465.6. 40. 1-(4-Chlorophenyl)-5-(2,5-diphenyl)-N-cyclooctyl-1H-1,2,4-trisani-3-amine. MS (ESI+) 477.3. 19 1285197 41. 1-(4-Phenylphenyl)-5-(2,5-dichlorophenyl)-N-cycloheptyl-1H-1,2,4-triazole-3-decylamine. MS (ESI+) 465·6. 42. 1-(4-Phenylphenyl)-5-(2,5-diphenyl)-indole- ί 戍 Η Η Η 1, 1, 1, 1, 。 。. MS (ESI+) 435.5. 5 43· 1-(4-Phenylphenyl)-5-(2,5-diphenyl)-indole-(2,2·dimethylpropyl)-1Η-1,2,4-triazole -3-decylamine. MS (ESI+) 439.6.

The pharmacological test results of the above-obtained and analyzed group of the compounds of the present invention are shown in the following table: Human Cannabinoid-CB! Receptor In Vitro Affinity In Vitro Antagonistic Example pKi Value pA2 Value Example 2 6.6 7.2 Example 3 6.9 8.7 Example 5 6.9 Example 9 7.4 8.2 Example 11 6.3

10 [Simple description of the diagram] (None) [The main components of the diagram represent the symbol table] (None) 20

Claims (1)

Amendment date: February 1996, 183⁄464 No. 177 application No. 7 ^ Fen patent scope revision announcement q Pick up, apply for patent scope: Year, repair (more) jade formula (I) compound, its prodrug, Stereoisomers and salts are prepared for the treatment of psychosis, anxiety, depression, attention deficit, memory disorders, appetite disorders, obesity, dementia, abnormal muscle tone, Parkinson's disease Alzheimer's disease, epilepsy, f Use of a pharmaceutical composition of Tinton's disease, Tourette's syndrome, cerebral ischemia, pain, gastrointestinal disease, and cardiovascular disease, R2 r3 wherein R and the heart independently represent a phenyl group, a naphthyl group, a thienyl group, a pyridyl group. a hydrazinyl group, a σ-pyrazine group, a pyridazinyl group or a triazinyl group, these groups may be substituted by one to four identical or different substituents X, which are selected from branched or unbranched (Ci· 3)-alkyl or alkoxy, trans, halogen, trifluoromethyl, difluoromethylthio, trifluoromethoxy, nitro, amino, mono or dialkyl (Ci 2) _ amino, single Or dialkyl (Cl 2 ) 醯 醯 amino, (Ci 3) · oxycarbonyl, trifluoromethane, sulfonamide, (Cl 3)-alkylsulfonyl, carboxyl, cyano, amino Stuffed base, (Cl-3)-dialkylaminosulfonyl, (Ci 3)-monoalkylamino sulphate and ethyl, R 2 represents a hydrogen atom or a branched or unbranched Cl 8 alkyl group or Cy cycloalkylalkyl group or phenyl, benzyl or phenethyl group wherein the aromatic ring may be substituted by 1 to 4 substituents X, wherein X has the above meaning, or R 2 represents an acridinyl group 21 1285197 or a thiophene group , R3 represents unbranched or unbranched Ci 8 alkyl, Ci 8 alkoxy, 8-cycloalkyl, C5-1G dicycloalkyl, C6_1G tricycloalkyl, C3-8 alkenyl, C5-8 cycloaliphatic These groups may optionally contain one or more impurities selected from the group consisting of 0, N, S An atom, and these groups may be substituted by a hydroxyl group, an ethynyl group or a trivalent fluorine atom ' or I represents a phenyl group, a benzyl group or a phenethyl group in which the aromatic ring may be substituted with 1 to 4 substituents X, wherein The above meaning, or Rs represents a pyridyl group, a cancer sigma group, an indoxazinyl group, a pyridazinyl group, a triazinyl group or a thienyl group which may be substituted with 1-2 substituents X, wherein hydrazine has the above meaning, Or Rs represents a group NR4R5, wherein R4 and Rs together with the nitrogen atom to which they are attached form a saturated or unsaturated, monocyclic or bicyclic heterocyclic moiety having 4 to 10 ring atoms, the fluorene group containing 1 Or two identical or different heteroatoms selected from the group consisting of: ^, oxime or 8, which may be substituted by a branched or unsupported fluorenyl group, a light or trifluoromethyl group or a fluorine atom, or a 2 and R3 together with the nitrogen atom to which they are attached form a saturated or unsaturated, monocyclic or bicyclic heterocyclic moiety having 1 〇 of a solid, the heterocyclic group containing i or 2 selected from N, C^S of the same or different miscellaneous = sub-(four) ring part readable branching surface branching c-based, trans-soil, bite base Trifluoromethyl, or a fluorine atom. a compound of the formula (1), a prodrug thereof, a stereoisomer and a salt thereof, 22 1285197 Wherein the ruler and the heart have the meaning given in item 1 of the scope of the patent application, R2 represents a hydrogen atom or a branched or unbranched Ci8 alkyl group, 5 R3 represents an unbranched or unbranched C2-8 alkoxy group, (: 3_8 cycloalkyl, C5_10 bicycloalkyl, 〇6_1()tricycloalkyl, 〇48 alkenyl, &cycloalkenyl, these groups may optionally contain one or more selected from hydrazine, N, S heteroatoms, and these groups may be optionally substituted by hydroxy or 丨_3 fluorine atoms, or 1 means C3_8 difluoroalkyl or Cm fluoroalkyl, or r3 means the aromatic ring may be 10 1-4 Substituent Y substituted benzyl or phenethyl, γ substituents may be the same or different and are selected from branched or unbranched (c13)-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl Base, trifluoromethylthio, trifluoromethoxy, schlossyl, mono or dialkyl (Ci-2) _ amino, (Ci·3)-oxynoxy, trifluoromethane, acryl , (Ci·3)-alkyl group, carboxy group, aryl group, 15 aminocarbamyl group, (C!-3)-dialkylaminosulfonyl group, ((:^^-monoalkylaminosulfonate) Base and acetyl group, or Rs means heteroaryl ring丨_2 substituents Y-substituted 3-indolyl 17-, 4-indenyl, sigma-based, 0-pyrazyl, pyridazinyl, triazinyl or thienyl, which gives γ the same Meaning 'or R3 denotes the group NR4R5, which, together with the nitrogen atom to which they are attached, forms a saturated or unsaturated, monocyclic or bicyclic, heterocyclic moiety having 4 to 1 ring atoms, 23 The cyclic group contains 1 or 2 identical or different heteroatoms selected from N, oxime or s, which may be branched or unbranched, /amp; or trifluoromethyl or fluoro Atom substitution, or I and R3, together with the nitrogen atom to which they are attached, form a saturated or unsaturated, monocyclic or bicyclic heterocyclic moiety having 4-1 ring atoms containing 1 or 2 The same or different heteroatoms selected from hydrazine, hydrazine or S. The heterocyclic moiety may be substituted by a branched or unbranched Cw alkyl group, a aryl group or a trifluoromethyl group or a fluorine atom, provided that Is the heterocyclic knife not an unsaturated fox bite or an unsaturated morphine or a 2,2,6,6-tetraalkyl base. A compound of the formula (I) , its prodrugs, stereoisomers and salts, Wherein R and the core independently represent a phenyl group, a naphthyl group, a thienyl group, a pyridyl group, a deuterated group, a σ-based group, a zirconyl group or a tripodyl group, and these groups may be substituted by a substituent X having a The meaning given in the third paragraph of the patent application scope, R2 and R3 have the meanings given in item 2 of the scope of the patent application. A compound of the formula (1), a prodrug thereof, a stereoisomer and a salt, 1285197 Wherein the ruthenium and ruthenium independently represent a phenyl-5 group substituted by one to four identical or different substituents selected from methyl, methoxy, halogen, trifluoromethyl or cyano, or R and ^ independently Represents a phenyl, thienyl or pyridyl group substituted by one to four identical or different substituents selected from methyl, methoxy, halogen, trifluoromethyl or cyano, R2 having the application The meaning given in item 2 of the patent scope, R3 represents a group NR4R5, wherein 10 R4 and R5 together with the nitrogen atom to which they are attached form a saturated or unsaturated, monocyclic or 4-10 ring atom a bicyclic heterocyclic moiety containing one or two identical or different heteroatoms selected from N, oxime or S, which may be branched or unbranched (^-3 alkyl, Substituted by hydroxy or trifluoromethyl or fluorine atom 15 5. For the treatment of psychosis, anxiety, depression, attention deficit, memory disorder, appetite disorder, obesity, dementia, abnormal muscle tone, Parkinson's disease, Al Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischemia, pain A pharmaceutical composition of a gastrointestinal disease and a cardiovascular disease, which comprises a pharmacologically active amount of at least one compound of any one of claims 1 to 4 as an active ingredient. 25 1285197 6. Patent application scope The compound according to any one of items 1 to 4, which is useful for the treatment of psychosis, anxiety, depression, attention deficit, memory disorder, appetite IL, obesity, dementia, abnormal muscle tone, Parkinson's disease, Al Uses in pharmaceutical compositions of Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischemia, pain, gastrointestinal and cardiovascular diseases.