TWI330181B - Thiazole derivatives having cb1-antagonistic, agonistic or partial agonistic activity - Google Patents

Description

1330181 发明, DESCRIPTION OF THE INVENTION [Technical Field] The present invention relates to a group. A method of preparing these compounds, and a pharmaceutical combination comprising one or more of these compounds as an active ingredient. L· ^tr j

The above thiazole derivatives are potent cannabinoid (CB1) receptor antagonists, CB1 stunting agents or CB-receptor partial co-agents, and can be used for the treatment of psychoactive and neurological diseases and other diseases involving cannabinoid CB] neurotransmission . 10 Document EP 388909 and EP 377457 have described 4,5-diarylmethine

Oxazole derivatives are used as 5-lipoxygenase inhibitors for the treatment of thrombosis, high blood pressure, allergies and inflammation. All of the exemplary structures in both documents contain two stupid rings that are replaced by methoxy, fluoro, methylthio or methyl sulfinylene groups. Document WO 9603392 describes sulfonylaryl-arylthiazole compounds for use in the treatment of inflammation and inflammation, arthritis or fever associated with inflammation. Jp 05345772 relates to a 4,5-diarylfluorene sitting compound as an acetylcholinesterase inhibitor, and JP 04154773 describes a 4,5-diarylthiazole compound having an analgesic, anti-inflammatory and antipyretic effect. C invention content:! 20 It is now surprisingly found that the 4,5-diarylthiazole derivatives of the formula (1), their prodrugs and their salts

6 丄 330181 玖, invention description wherein R represents no hydrogen atom or substituent x, the substituent χ selected from branched or unbranched 13 carbon atoms of the alkyl or alkoxy group via the base, three said Mercapto, difluoromethylthio, trifluoromethoxy, nitro, amino, mono- or 5-(Cl-2)alkylamino, mono- or di-(Cl-2)alkylguanidino , branched or unbranched (q.3) alkoxy group, trimethylmethyl awakening group, amino-branched, branched or unbranched (Cw) alkylsulfonyl, carboxyl, Cyano, carbachol, branched or unbranched bis(C13)alkylaminosulfonyl, branched or unbranched mono-(C1-3)alkylsulfamoyl and acetamidine The group, 10 R is a hydrogen atom or a tetra substituent X, wherein X has the above-mentioned meaning, and R 2 represents a nonyl group, a thienyl group. With a pyridyl or pyrimidinyl group, these groups may be substituted by 1 to 4 substituents, wherein hydrazine has the above-mentioned meaning, or h represents a naphthyl group, 15 R3 represents a hydrogen atom, branched or unbranched An alkyl or cycloalkyl-alkyl group of 1 to 10 carbon atoms, a phenyl group, a benzyl group or a phenethyl group, the aromatic ring may be substituted by 15 substituents fluorene, and the fluorene may be the same or different and selected from the group consisting of branching Or unbranched alkyl or alkoxy of 1 to 3 carbon atoms, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono or di _(Ci2) 20 alkylamino, mono- or dialkylguanidino, branched or unbranched (Q-3) alkylsulfonyl, dimethylsulfonylamino, branched or unbranched (Ci alkoxycarbonyl, carboxyl, trifluoromethyl sulfhydryl, cyano, carbachiryl, azide and ethene, or R3 represents η than a dimethyl or porphinyl group, R4 represents branching Or an unbranched alkyl or cycloalkyl group of 1 to 10 carbon atoms _ 7 1330181 玖, the invention describes an alkyl group, a branched or unbranched alkoxy group of 1 〇 carbon atom, 3 8 a cycloalkyl group of carbon atoms, 5-10 carbon atoms a cycloalkyl group, a tricycloalkyl group of 61 碳 carbon atoms, a branched or unbranched alkenyl group of 31 碳 carbon atoms, a cycloalkenyl group of 5-8 carbon atoms, these groups may contain one or a plurality of heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, and may be substituted by a hydroxyl group, a methyl group, an ethyl group, or a 1-3 fluorine atom, or & represents a phenyl group, a benzyl group, or a phenethyl group. The aromatic ring may be substituted by 1 to 5 substituents z, z having the above-mentioned meaning, or R4 represents a pyridine group or a thienyl group, or 4 is a group NH, wherein R5 and R6 are bonded to the nitrogen to which they are attached The atoms together form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 1 ring atoms containing one or more heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, and Branched or unbranched 1-3 groups of carbon atoms, substituted by a radical, a triterpene or a fluorine atom, or R3 and R4 together with the nitrogen atom to which they are attached form a saturation of 4 to 1 ring atom Or an unsaturated, monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from the group consisting of oxygen 'nitrogen, sulfur and Branched or unbranched 1-3 groups of carbon atoms, substituted by a base group, a trifluoromethyl sulfonium atom, an effective anti-reagent, co-agent or part of the cannabinoid CB! receptor The compound of the present invention is suitable for the treatment of mental disorders such as psychosis, anxiety, depression, attention deficit disorder, memory disorder, cognitive disorder, appetite disorder, obesity, drug addiction, desire due to its potent CB! receptor activity. Symptoms, 8 玖, inventions indicate drug dependence, and neurological diseases such as neurodegenerative diseases, cancer, dystonia, muscle strength I, Yan Zhen, ovarian cancer, multiple sclerosis, traumatic brain injury, stroke Parkinson's disease, early Pure dementia, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral apoplexy, brain trauma, stroke, spinal cord injury, neuritis, platelet sclerosis, viral encephalitis, diseases associated with ecstasy And the treatment of secret pain, including neuropathic pain and other diseases involving cannabinoid neurotransmission 'including treatment of abdominal toxicity shock, glaucoma, cancer, diabetes, ° district soil... nausea, asthma, respiratory system Disease, gastrointestinal disorders, gastric ulcers, diarrhea and cardiovascular disease. 10 15 The affinity of the compounds of the invention for the cannabinoid CBi receptor is determined using a membrane preparation of Chinese hamster ovary (CHO) cells in which human cannabinoid CB, receptor together with radioligand [3h] Cp_55, 94〇 was stably transfected. After incubating the newly prepared cell membrane preparation containing [3h]-ligand, the bound ligand and the free ligand were separated by filtration with a glass fiber screening procedure with or without the addition of the compound of the present invention. The radioactivity on the screening program was measured by liquid scintillation counting. 20 The cannabinoid CB1 receptor antagonist, the same or a part of the same activity of the compound of the present invention is determined by a functional study using human cannabinoids (C81 cells in which 81 receptors are stably expressed). (forskohn) stimulates adenylate cyclase and determines adenylate cyclase by measuring the amount of accumulated cyclic adenosine monophosphate (AMP). In a concentration-dependent manner, 'passing through CB! receptors The CB of the agent (such as cp_55, 940 or (R)-WIN-55, 212-2), the receptor-associated activity can reduce the accumulation of cyclic AMP induced by forskolin. CB] receptor antagonist or partial co-agent, such as The present invention can be antagonized by the CB receptor-mediated reaction of the compound of the present invention. The canine receptors of the present invention can be determined by the method of A. Such as the in vivo cannabis simulation (cannabimimetic) effect of the flat (Wiley, JL et al. J. pharmacol. Exp. Ther. 5 2001, 296, 1013) 〇

Cannabinoid receptor antagonists can be expressed as anti-synergy agents (Landsnian, R S. et al. Eur. J. Pharmacol. 1997, 334, R1-R2). The invention also relates to racemates of the compounds of formula (1), Mixtures of diastereomers and individual stereoisomers. The compounds of the invention may be formulated for administration by means of conventional methods, using auxiliary substances and/or liquid or solid carrier materials. Suitable methods for the compounds are as follows:

An ester hydrolysis reaction of a compound of formula (II) of a boat ap 5 of Scheme A, wherein I represents a branched or unbranched alkyl or benzyl group of 1 to 4 carbon atoms.

(II) The reaction produces a compound of formula (III):

(Hi) 20 wherein R, Rj 〇 R2 have the meanings described above. 10 1330181 Inventively, the compound of the present invention of the formula (II), wherein r7 represents a branched or unbranched alkyl or benzyl group of 1 to 4 carbon atoms, can be produced by a known method such as: a) Organic Reactions, Vol. VI, (1951), p.367-409, Ed. 5 R. Adams, John Wiley and Sons Inc., New York b) JS Carter et al., Bioorg. Med. Chem. Lett. (1999 ), 9, 1167-1170 c) TT Sakai et al., Bioorg. Med. Chem. (1999), 7, 1559-1566 10 d) A. Tanaka et al., J. Med. Chem. (1994), 37, 1189-1199 e) JJ Talley et al., WO 9603392: Chem. Abstr. 125, 33628 f) V. Cecchetti et al., Bioorg. Med. Chem. (1994), 2, 799-806 Route A Step 2 15 by activation and coupling methods, such as formation of an active ester or in a so-called coupling reagent such as DCC, HBTU, BOP, CIP (2-a-1,3-dimercaptoimidazolium hexafluorophosphate), PyAOP Reaction of a compound of formula (III) with a compound of formula R3R4NH in the presence of (7-azabenzotriazol-1-yloxytris(pyrrolidinyl)anthracene hexafluorophosphate), and the like, wherein R3 and R4 Has the meaning of 20 described above. For more detailed information on activation and coupling methods see a) M. Bodanszky, 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), 11 1330181 玖, invention description 38, 4853-4856 ° A thiazole derivative of the formula (1) is required. Alternatively, the compound of formula (III) is reacted with a so-called halogenating agent such as a sulfurous gas test (soc 2) to give the corresponding carbon helium (IV).

The compound of formula (IV) is then reacted with a compound of formula r3r4nh to give the '•sniffing derivative' of formula (I) wherein R3*R4 has the meanings as described above. The reaction is preferably carried out in the presence of an organic domain such as diisopropylethylamine (DIPEA) or triethylamine. 10 or a compound of the formula (11) is reacted with a compound of the formula r3r4nh in a so-called amination reaction to give a thiazole derivative of the formula (1), wherein Rj〇R4 has the meanings as described above. Alternatively, a compound of the formula R3R4NH and a strong base such as lithium diisopropylamide (LDA), hexamethyl diazepine clock (UhMds), hexamethyl diazepine, potassium hexahydrate (KHMDS) or A reaction of hexamethyldiazepine nitrogen (NaHMDS) or the like to produce a compound of the formula R3R4NU, R3R4NK or R3R4NNa, respectively, which is then reacted with a compound of the formula (II) to give a thiazole derivative of the formula (1). C. Embodiment 3 Example 1 20 Part A: 3.04 g of magnesium (0.125 mol) was suspended in 500 ml of anhydrous diethyl ether under a nitrogen atmosphere, and then iodine crystals were added. 20.12 g (0.125 mol) of 4-chlorohexyl chloride dissolved in 100 ml of anhydrous diethyl ether, 12 Torr, invention note 5 10 was slowly added to maintain a gentle reflux. After the resulting mixture was cooled to room temperature, a solution of 2,4-di-n-nitro nitrile, 1 〇mol was dissolved in 1 ml of a solution. The mixture was warmed to 135 Torr, and the mixture was removed by steaming, and the mixture was again added to the mixture, and then the mixture was refluxed for 2 hr. After cooling to room temperature, 400 ml of a hydrochloric acid solution (1 N) was slowly added thereto under stirring and cooling. The mixture was extracted twice with diethyl ether and dried over EtOAc EtOAc. Using flash chromatography (monomethane), 19.96 g (yield: 67%) of 2-(4-chlorophenyl)-1-(2,4-diphenylphenyl)ethanone as a yellow oil was obtained. The oil was crystallized from Cycloheximide to give pure 2-(4-indolyl) gas. Melting point: 65-66 ° C. i-NMR (200 CDC13) (m,7H), 4.22 (s,2H) 〇B part: 2.82 g (9.42 mmol) of 2_(4·chlorophenyl)-b (2,4-dichlorophenyl) Ethyl ketone in a solution of 25 ml of benzene was added to a solution of 48 ml (149 15 g, 9.31 mmol) of bromine, and the mixture was stirred at room temperature for 2 hours. Then, dichloromethane was added thereto, and the resulting solution was washed with an aqueous sodium hydrogencarbonate solution, and the organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to remove solvent to afford 3.5 g (yield quantitatively) of 2-bromo A yellow oil of -2-(4-chlorophenyl)-1-(2,4-dioxaphenyl)ethanone (purity 20 to 95% as determined by HPLc analysis). W-NMR (200 MHz, CDC13): δ 7.00-7.50 (m, 7H), 6.16 (s, 1H). Prepared in a similar manner: 2-stained 1-(4-chlorophenyl)-2-(2,4-diphenyl)ethyl _. W-NMR (200 MHz, CDC13): δ 7.95 (d, J = 8 Hz, 2H), 7.23-7.62 (m, 13 丄 玖, invention description 5H), 6.77 (s, 1H). P knife will be 9.83 g (26.0 mmol) 2-di- 2-(4-chlorophenyl)·1·('-phenoxyphenyl)-B and 5,28 g (39 6 mmol) thio-lysine Ethyl acetate; trough solution in 50 ml of absolute ethanol, and the resulting red solution was heated at reflux temperature 5 for 4 hours. After removing the solvent by evaporation in vacuo, (10) red was crude. W. In a mixture of Qijiayuan and thiol tert-butyl, the liquid obtained by removing the S/H from the oxime is purified by column chromatography (eluent: two gas: Rf~) 〇.4), obtaining a yellow oil of 5 21 g (yield 48%) of 5 (4-phenylphenyl)_ 4-(2,4-dioxaphenyl) hydrazone_2-rebel vinegar Yellow 1 〇 oil slowly solidified. Melting point: 117-118 °C. H-NMR (200 MHz, CDC13) · δ 7.53, (d, J=2Hz, 1H), 7.40 (dt, J=8Hz, J=2Hz, 2H), 7.22-7.35 (m, 4H), 4.52 ( q, J=7 Hz, 2H), 1.45 (t, J=7 Hz, 3H). Prepared in a similar manner: 15 4-(4-indolyl)_5_(2,4-diphenyl)thiazole-2-carboxylic acid ethyl ester β D moiety: 1.00 g (2_42 mmol) 5-(( Ethyl 4-phenylphenyl)-4-(2,4-diphenyl)thiazole-2-carboxylate was added to 1 mL of hydrazine-aminopiperidine, and the resulting mixture was at 50. The mixture was heated and mixed for 4 hours. Dioxo methane was then added and the resulting solution was washed twice with water, dried over magnesium sulfate (2 hr), filtered and evaporated and evaporated. Then, diisopropyl ether was added thereto, and the formed precipitate was removed by filtration, and the filtrate was concentrated in vacuo and purified by flash chromatography (ethyl acetate: petroleum ether (40-60) = 1:3 (v/v)) , 330 mg (yield 29%) of white 5-(4-phenylphenyl)-4-(2,4-dichlorophenyl)-N-(piperidinyl)thiazole-2-carboxamide Foam 14 1330181 玖, invention description body. 1H-NMR (400 MHz, CDC13): δ 7.92 (s, 1H), 7.47 (t, J=2Hz, 1H), 7.24-7.32 (m, 4H), 7.13 (dt, J=8Hz, J=2Hz, 2H), 2.85-2.93 (m, 4H), 1.40-1.82 (m, 6H). Prepared in a similar manner: 5 4-(4-oxaphenyl)-5-(2,4-dioxaphenyl)-N-(l-piperidinyl)thiazole-2-carboxyguanamine 'M. -191 ° C. W-NMR (400 MHz, CDC13): δ 8.03 (s, 1H), 7.51 (d, J=2Hz, 1H), 7.22-7.38 (m, 6H), 2.90-2.97 (m, 4H), 1.75-1.84 (m, 4H), 1.44-1.52 (m, 2H). 5-(4-Chlorophenyl)-N-cycloheptyl-4-(2,4-diphenyl)thiazole-2-carboxyindole 10 amine, m.p.: 159-161. 5-(4-Chlorophenyl)-N-cyclopentyl-4-(2,4-dichlorophenyl)thiazole-2-carboxyindoleamine, m.p.: 111-113. 5-(4-Phenylphenyl)-4-(2,4-dichlorophenyl)-N-(trans-4-hydroxycyclohexyl)thiazole-2-carboxyguanamine, melting point: i 〇 9 ° C . 15 5-(4-Phenylphenyl)-4-(2,4-dichlorophenyl)-N-(2-mercaptocyclohexyl)thiazol-2-carboxyguanamine, m.p.: 134-147e. 5-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)-N-(4-fluorobenzyl)thiazole-2-carboxyguanamine, m.p.: 142-144. 5-(4-Phenylphenyl)-4-(2,4-dioxaphenyl)-N-(trans-4-indolylcyclohexyl 20)thiazole-2-carboxamide, m.p.: 165-166 °C. 5-(4-Phenylphenyl)-N-(cis-4-methylcyclohexyl)-4·(2,4·di-phenylphenyl)thiazole-2-carboxamide, m.p.: 72°C. Example 2 Part A: 4.10 g (9.93 mmol) of 5-(4-phenylphenyl)-heart (2,4_2 15 1330181 玖, inventive description chlorophenyl)thiazole-2-carboxylic acid ethyl ester suspension To 75 ml of methanol, a solution of potassium hydroxide solution (1.98 g (30 mmol) of potassium hydroxide dissolved in 75 ml of water) was added thereto, and the resulting mixture was heated at reflux temperature for 2 hours. The resulting yellow solution was then allowed to reach room temperature, poured into water and acidified with a 5 gu & water' solution to give a white sink. The chamber was collected by filtration and washed twice with water, and the precipitate was dried in vacuo to give 2 59 g (yield: 68%) of 5-(4-carbophenyl)_4_(2,4-diphenyl)thiazole. _2• White solid of carboxylic acid. iH-NMR (200 MHz, DMSO-d6): δ 9.25 (s, 1H), 7.65-7.72 (m, 1 Η), 7, 28-7.52 (m, 6 Η). 10 Prepared in a similar manner: 4-(4-Phenylphenyl)-5-(2,4-dichlorophenyl)thiazole·2·carboxylic acid hydrazine moiety: l.oo gram under nitrogen atmosphere and room temperature (2.6 mmol) 5-(4-oxaphenyl)-4-(2,4-dioxaphenyl)thiazole-2-carboxylic acid was suspended in 2 mL of dry acetonitrile. To this was added 丨36 ml (78 mmol) of diisopropyl15-ethylethylamine (1) (4)^ 克 克 别 毫 摩尔 摩尔 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Methyl uronium hexafluorophosphate (HBTU) and 0.35 g (25.1 mmol) of 0-succinylamine hydrochloride were stirred at room temperature overnight. The resulting mixture was concentrated in vacuo, then EtOAc (EtOAc) was evaporated. It was then purified by flash chromatography (ethyl acetate: petroleum ether (40-60) = 1:3 (v/v)) to give 0.6 g (yield: 51%) of N-(tert-butoxy)-5- ( White foam of 4-oxophenyl)-4-(2,4-diphenyl)thiazole-2-carboxylamine. 1H-NMR (400 MHz, CDC13): δ 9.20 (s, 1H), 7.47 (t, J = 2 Hz, 1H), 7.25-7.31 (m, 4H), 16 1330181 Rose, invention description 7.14 (dt, J= 8 Hz, J = 2 Hz, 2H), 1.36 (s, 9H). Prepared in a similar manner: N-(tert-butoxy)-4-(4-phenylphenyl)-5-(2,4-dichlorophenyl)hydrazine Carboxamide. 1H-NMR (400 MHz, CDC13): δ 9'23 (s,1Η) η ^ 5 (d, J=2Hz, 1Η), 7.35 (dt, J=8Hz, J=2Hz, 2Η) 7.23-7.31 ( m 4H), 1.40 (s, 9H). 5-(4-Phenylphenyl)-4-(2,4-dichlorophenyl)-N-(n-pentyl)pyrazine-2 decylamine. iH-NMR (400 MHz, CDC13): δ 7.46 (S, 1H), 7 21 7.32 (m, 5H), 7.14 (dt, J=8Hz, J=2Hz, 2H), 3.42-3.48 (m 10 2H) , 1.59-1.67 (m, 2H), 1.30-1.40 (m, 4H), 0.90 (t, j = 7Hz 3H). 5-(4-Gasyl)->1-1 hexyl-4-(2,4-dichlorophenyl)> Sit _2_ brewing amine. 1H-NMR (400 MHz, CDC13): δ7·46 (s, 1H), 7.24-7.35 (m, 4H), 7.05-7.17 (m, 3H), 3.90-4.00 (m, 1H), 1.98-2 07 15 (m, 2H), i·72·1·82 (m, 2H), 1.14-1.70 (m, 6H). Example 3 Part A: To 25 g (0.135 mol) of 4-bromobenzaldehyde, 27.7 g (〇.135 mol) of 2,4-dichlorophenylacetic acid, 1 ml of acetic anhydride and 19 ml (0.136) were added successively. Methyl)triethylamine, the resulting mixture was heated at reflux temperature for 9 Torr for 20 minutes. The reaction mixture was then cooled to 110 mil, and 100 ml of water was slowly added thereto, and the mixture was allowed to reach room temperature, then ethyl acetate was added thereto, and the ethyl acetate layer was washed twice with water and dried over magnesium sulfate. Filtration and concentration in vacuo, the obtained oil was crystallised from diisopropyl ether to give 26.55 g (yield: 53%) of 3-(4-bromophenyl)-2-(2 4-diphenyl). 17 1330181 玖 Inventive Description White solid of dilute acid. Part B. 26.55 g (71 Å:mol) of 3-(4-bromophenyl)_2_(2,4-dioxaphenyl)acrylic acid was dissolved in 130 ml of anhydrous methylbenzene, and the resulting solution was cooled to 0C. 7.40 g (73 mmol) of triethylamine and 198 g of 5 (72 mmol) of diphenylphosphonium azide were successively added thereto, and the resulting mixture was stirred at 〇 °c for 20 minutes, and then stirred at room temperature. 150 minutes. The reaction mixture was poured into water and extracted with EtOAc EtOAc. The resulting toluene layer was slowly added to 15 ml of refluxing hydrazine, and after 90 minutes, tert-butanol was added and heating was continued at reflux temperature for 1 hour, and then 5 ml of concentrated hydrochloric acid was slowly added. The resulting solution was at 90. (After stirring overnight, it was cooled to room temperature, washed twice with water and dried over magnesium sulfate, filtered and evaporated in vacuo to give crystals 72 g (yield 60%) 2-(4-/smoke base)-1-(2,4-one phenyl) E-same, melting point: 69_7 〇. 匚. 15 C part: to 5. 〇 〇 (15 mmol) 2-(4-bromo-bromodibubu 2-diphenyl) ethyl ketone in a solution of 50 ml of benzene, dropwise addition of 75 ml (15 mmol) of bromine, the resulting The solution was stirred at room temperature for 4 hours and concentrated in vacuo. Then dioxophane was added thereto, and the resulting solution was washed with brine and dried over magnesium sulfate, filtered and concentrated in vacuo to give 5.96.克(yield 94%) 2-'; odor · 2_(4_ desert phenyl) small (24 dichlorophenyl) ethyl I oil. Part D: will contain 5 96 g in 3G ml of ethanol ( a solution of 14 mmoles of 2_mo·2-(4-Bistyl)+(2,4-dichlorophenyl)ethyl and 28 g (21 mmol) of ethyl thiooxamate at reflux Heat at temperature for *hour. Cool it 18 1330181 玖, Invention instructions After room temperature, the precipitated crystal material was removed by filtration, and the filtrate was concentrated in vacuo to obtain 756 g of a color oily material. The oily material was purified by flash chromatography (ethyl acetate/oil) Ether = 1/3 (v/v)) was purified, followed by crystallization from diisopropyl ether solvent to give 2.11 g (yield: 33%) of 5-(4-bromophenyl)-5 4-(2,4 - Diphenylphenyl) Thiazole-2-carboxylic acid ethyl ester, melting point: 129_13 〇. [Part E: will contain 1.00 g (2·2 mmol) of 5_(4•bromophenyl) 4 (24_二气A mixture of ethyl thiazol-2-carboxylate and 1 〇ml of hydrazine-aminopiperidine was stirred with heating at 50 C overnight. Then, the resulting mixture was allowed to reach room temperature, and a gas broth was added thereto, and the resulting solution was washed with water. The reaction was carried out with MgSO4, EtOAc (EtOAc m.) Obtained 870 mg (yield 78%) of 5-(4.bromophenyl)_4_(24-dioxaphenyl)_n(i piperidinyl)thiazole-2-carboxamide, dazzling point: 171-1733⁄4. Party Preparation: 15 4_(2,4_di-phenylphenyl)-NU-piperidinyl)-5-(4-(trifluoromethyl)phenyl)thiazole-2-carboxyguanamine, melting point: i81-183 °C. N-Cyclohexyl-4-(2,4-dichlorophenyl)-5-(4.(trifluoromethyl)phenyl)thiazol-2-carboxamide, m.p.: 14 - 142. (: Example 4 Π) Part A: 1.80 g (3.94 mmol) of ethyl 5-(4-bromophenyl)-4-(24-diphenyl)thiazole-2-carboxylate was dissolved in 20 ml of hydrazine. To the alcohol, an aqueous solution of potassium hydroxide (a solution of 0.65 g (85%), 9.85 mmol of potassium oxynitride dissolved in 20 ml of water) was added thereto, and the resulting mixture was heated at reflux temperature for 1 hour, and then it was added. Pour into water and use a 1N hydrochloric acid solution 19 1330181 玖, invented instructions for deuteration. The resulting sink was collected by filtration and dried under vacuum at room temperature to obtain a quantitative yield of 5-(4-bromophenyl) 4(2,4-dichlorophenyl)thiazole-2-carboxylic acid. : 94-95. (: Part B. 0.50 g (1.17 mmol) of 5-(4-bromophenyl)4_(24-di-5-phenylphenyl)thiazolecarboxylic acid and 丨.02 ml (5.85 mmol) of diisopropyl The amine (DIPEA) was dissolved in 5 ml of dichloromethane and cooled to. To this was added 0.11 g (0.81 mmol) of 7-azahydroxybenzoindole (H〇At) and 0.50 g (1.76 mmol). 2· gas-i,3-dimethylimidazolium rust hexafluorophosphate (CIP), followed by the addition of 15 g (1.76 mmol) of n-pentylamine'. The resulting mixture 10 was stirred at room temperature overnight. Purification by flash chromatography (di-methane) gave 0.28 g (yield: 48%) of 5-(4-bromophenyl)-4-(2,4-diphenylphenyl)-1^-(n-decyl) An amorphous solid of serotonin-2- leucine. Prepared in a similar manner: 5-(4-bromophenyl)-4-(2,4-dichlorophenyl)_N_(hexahydro (1H) Azetidin-15 trien-1-yl)thiazole-2-salt amine, melting point: 2〇6-207 ° C. 5-(4-bromo-phenyl)-4-(2,4-digas Phenyl)_N_(imiline-4-yl)thiazole_2_carboxamide, amorphous solid 5-(4-chlorophenyl)-4_(2,4-diphenyl)_N_(pyrrolidine 4· Thiazole _ 2·carboxamide, Point: 179-181. 20 Part A: 0.50 g (1.30 mmol) of 5-(4·cyclophenyl)-4_(2,4-diphenyl)thiazole-2-carboxylic acid was dissolved in 10 ml of two In chlorodecane, 0.15 g (1.30 mmol) of iota-hexahydro(1Η)azetane and 0.18 g (1.30 mmol) of 7-aza-1-hydroxybenzotriazole were successively added thereto. 〇68g (1 3〇20 1330181 玖, invention description mmol) 7-aza-p-triazole-丨-yloxytri(pyrrolidinyl) squamous hexafluorophosphate (PyAOP) and 〇·34 ml (1. 95 mmol) of diisopropylethylamine, the resulting solution was stirred at room temperature for 1 hour, concentrated in vacuo to give a crude oil (2.01 g, The oil was purified by 5 = 1/3 (v/v) to give 〇·35 g (yield 56%) 5-(4-hydroxyphenyl)-4-(2,4-diphenyl) _1^-(hexahydro(111)azetidin-1-yl)0-pyrazole-2-carboxyguanamine 'M.p.: 185-186. 〇 (measured after recrystallization from diisopropyl ether). Prepared in a similar manner: 10 5-(4-indolyl)-4-(2,4·di-phenyl)-indole-(hexahydrocyclopenta[c] 0 ratio -2(1Η)-yl)thiazole-2-carboxyguanamine, melting point: 173-174 Χ: Ν-knot group-5-(4-gasstyyl)_4·(2,4-dichlorophenyl)- Ν·Methyl_嗟嗤_ 2-carboxyguanamine, melting point: 141-144. (: 5-(4-Phenylphenyl)-4-(2,4-diphenyl)-indole-(4-(trifluoromethyl)benzyl) 15 ° plug ° sit-2-slow Amine, melting point: i74-176 ° C. 5-(4-indolyl)-4-(2,4-dioxaphenyl)-indole-(exo-bicyclo[2.2.1]hept-2-yl)嗟° sit-2-slowing amine, refining point: i94-195 ° C. 5-(4-Phenylphenyl)-4-(2,4-diphenyl)-N-(endo-bicyclo[2.2 .1] Geng 2 - yl) ° Sewa-2-Rebelamine, Hyun Point: 181_183. (3. 20 5-(4-Chlorophenyl)-4-(2,5-diqi stupid) -N-(Exo-bicyclo[2.2.1]heptan-2-yl)° plug. Sit-2-enem-prepared amine, dazzling point: i70 ° C. 5-(4·Phenylphenyl)-N-(ring Hexyl)_4_(2 5_di-phenylphenyl)thiazole-2-carboxyguanamine, melting point: 75 ° C. 5-(4-chlorophenyl)-4-(2,4-diphenyl)_N_(four Hydrogen 2H_b is more than oxa-2-yl 21 1330181, the invention oxy) thiazol-2-carboxyguanamine, melting point: 85 ° C. Example 6 1.65 g (4_0 mmol) of 5-(4-chlorophenyl)- Ethyl 4-(2,4-diphenylphenyl)oxazole-2-carboxylate was dissolved in 25 ml of anhydrous tetrahydrofuran, and 0.37 ml (4.0 mmol) of aniline was added thereto. The resulting solution was cooled to 〇<;c, add 4.4 to it To a tetrahydrofuran solution (1M) of hexamethylenedisulfonium azide. The reaction mixture was stirred for 2 hours, then water was added and the mixture was extracted twice with ethyl acetate. The brine was washed with sodium sulphate and dried without hydration, and concentrated in vacuo. The residue was crystallized from diisopropyl ether to give I·42 g (yield 77%) 5-(4-phenylphenyl)_4 -(2,4-Dichlorophenyl)-N-phenyl-thiazolecarboxamide, refining point: 167-168. (:. [Simple description of the diagram] (none) [The main components of the diagram represent the symbol table 】 (none) 22

Claims (1)

1330181 Picking up, applying for a patent scope|The next year's revised sentence in the original year"' No. 921〇5655 Special money request case towel replacement patent scope replacement ^ Correction date: July 1999 1. Type (I) a compound, a stereoisomer or a salt thereof, 5 wherein R represents a substituent X which is selected from a branched or unbranched 1-3 carbon atom group or alkoxy group, a thiol group, a carbaryl group, a trimethyl group, a difluoro group. Methylthio, trifluoromethoxy, nitro 'amino, mono- or mono-(Q-2)alkylamino, mono- or di-(Ci 2)alkylguanidino, branched or unsubstituted Branched (Cl-3) alkoxycarbonyl, trifluoromethylsulfonyl, amsulfonyl 'branched or unbranched (Ci 3) alkylsulfonyl 'carboxy, cyano' Styrene, branched or unbranched bis(Ci_3)alkylaminosulfonyl, branched or unbranched mono-(Cl3)alkylaminosulfonyl and ethenyl, R1 is a chlorine atom or 1·4 substituents X, wherein X has the meaning of the above-mentioned reference 15, R·2 represents a non-preferable group. The group may be substituted by 1 to 4 substituents X, wherein X has the above-mentioned meaning, and R 3 represents hydrogen. Atom, branched or unbranched alkyl or cycloalkyl-alkyl group of 1 to 10 carbon atoms, phenyl, benzyl, phenethyl, aryl ring 20 may be substituted by 1 to 5 Z Substituting, Z may be the same or different, selected from branched or unbranched alkyl or alkane of 1 to 3 carbon atoms Base, hydroxyl, halogen, difluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, ammonia 1330181 pick up, patent-based base, mono- or di-(Cl.2) alkylamino, Single "Ge 2" 2) Amino, branched or unbranched (Cm) alkylsulfonyl, dimethylsulfonylamino, branched or unbranched (Cw) alkoxycarbonyl , a carboxyl group, a trifluorof group, a decyl group, a cyano group, a carbamic acid group, an amino sulfhydryl group, and an ethyl aryl group, and R 4 represents a branched or unbranched alkyl group or a cycloalkyl group of i_1 〇 carbon atoms - An alkyl group, a branched or unbranched alkoxy group of M carbon atoms, a cycloalkyl group of 3-8 carbon atoms '5_1〇 a carbon atom of a bicycloalkyl group 6 10 carbon atoms of two a cycloalkyl group, a branched or unbranched alkenyl group of carbon atoms, a cycloalkenyl group of 5 to 8 carbon atoms, these groups may contain one or more hetero atoms selected from the group consisting of hydrazine, nitrogen, and sulfur. And may be substituted by a radical, 1-3 methyl, ethyl or 1-3 atoms, or & represents phenyl, benzyl or phenethyl, these aromatic rings may be substituted by 15 substituents Z, Z has the meaning mentioned above, or the rule 4 a group Nn wherein I and I together with the nitrogen atom to which they are attached form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 41 ring atoms. The heterocyclic group contains one or more a hetero atom selected from oxygen, nitrogen, sulfur 'and may be substituted with a branched or unbranched alkyl group of 1 to 3 carbon atoms, a hydroxyl group, a diterpene group or a fluorine atom, or a ruler 3 and R·4 Together with the nitrogen atom to which they are attached, a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 41 ring atoms containing one or more selected from the group consisting of oxygen, nitrogen, and sulfur is formed. The hetero atom can be substituted by a branched or unbranched alkyl group of 3 to 3 carbon atoms, a dihydroxymethyl group or a fluorine atom. 2 1330181 • The following is a compound, a stereoisomer or a salt thereof, in which the X is selected from a branched or unbranched alkyl group of 3 to 3 carbon atoms. Or alkoxy, hydroxy, cyclin, trifluoromethyl, trifluoromethylthio, tris 5 fluoromethoxy, nitro, amino, mono- or di-(c^)alkylamino, mono- or a group consisting of a di-(Ci-2)alkylguanidino group, a branched or unbranched (C)3) alkoxycarbonyl group, a carboxyl group, a cyano group, an aminoguanidino group and an ethyl fluorenyl group, R2 represents Stupid, the group may be substituted by one or more substituents X where X has the meanings mentioned above, 10 R3 is a nitrogen atom, and R·4 represents a branched or unbranched alkyl group of 1 to 10 carbon atoms Or alkyl-cycloalkyl, branched or unbranched alkoxy group of U0 carbon atoms, cycloalkyl group of 3-8 carbon atoms, bicycloalkyl group of 5_1〇 carbon atoms, 6_ ίο carbon a tricycloalkyl group of an atom, a branched or unbranched 31-membered alkenyl group of 15 carbon atoms, a cycloalkenyl group of 5-8 carbon atoms, these groups may contain one or more selected from oxygen, Nitrogen, sulfur a hetero atom and optionally substituted by a hydroxy group, 1-3 methyl groups, ethyl groups, 1-3 fluorine atoms, or & represents a phenyl group, a benzyl group or a phenethyl group, and the aromatic ring may be substituted by one to five Substituent z, wherein Z has the meaning as mentioned above, or to denote a group Nn 20 , wherein R 5 and R 6 together with the nitrogen atom to which they are attached form a saturated or unsaturated monocyclic or bicyclic ring having 4 to 1 ring atoms Heterocyclic group, the heterocyclic group containing one or more heteroatoms selected from oxygen, nitrogen, sulfur and which may be branched or unbranched, alkyl, hydroxy, 3 1330181, application The patent range is substituted with a trifluoromethyl or a fluorine atom, and all other symbols have the same meaning as the scope of the patent application. & 3. For the compound of claim 2, its stereoisomer or sleep 5 wherein R represents a _ atom, all remaining symbols have the same definition as item 2 of the scope of the patent application. 4. A compound, a stereoisomer or a salt thereof, according to claim 3, wherein π, R4 represents a group NR5R6, wherein '10 and R·6 together with the nitrogen atom to which they are attached form 4 〇 ring a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing one or more heteroatoms selected from oxygen, nitrogen, sulfur and which may be branched or unbranched 1- Substituted by an alkyl group of 3 carbon atoms, a radical, a trifluoromethyl group or a fluorine atom, 15 all remaining symbols have the same definitions as in item 3 of the patent application. 5. A compound, a stereoisomer or a salt thereof, according to claim 4, wherein Ri represents one or more halogen atoms, and all remaining symbols have the same definitions as in item 4 of the scope of the patent application. 20. A compound, a stereoisomer or a salt thereof, according to claim 1, wherein the compound is 5-(4-phenylphenyl)-4-(2,4-dichlorophenyl)-N-( L-piperidinyl)thiazole-2-carboxylate 5-(4-chlorophenyl)_N_cycloheptyl_4_(2,4-dichlorophenyl)thiazole_2_ several brewed 4 1330181 Patent Range Amine 5-(4-chlorophenyl)-N-cyclopentyl-4-(2,4-dichlorophenyl)thiazole-2-carboxyguanamine 5-(4-chlorophenyl)-4- P,4-dichlorophenyl)-N-(trans-4-hydroxycyclohexyl5)thiazole-2-carboxyguanamine 5-(4-chlorophenyl)-4-(2,4-dichlorobenzene -N-(2-methylcyclohexyl)thiazole-2-carboxydecylamine 5-(4-chlorophenyl)-4-(2,4-diphenyl)-N-(4-fluorobenzyl) Thiazol-2-carboxyguanamine 10 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-N-(trans-4-indolylcyclohexyl)thiazole-2- Carboxylamamine 5-(4-chlorophenyl)-N-(cis-4-methylcyclohexyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxyguanamine N-(uncle Butoxy)-5-(4-chlorophenyl)-4-(2,4-diphenyl)thiazole-2-15 Carboxamide A 5-(4-chlorobenzyl)-4-(2, 4-dichlorophenyl)-N-(n-decyl) sold °-2-pyramine 5-(4-chlorophenyl)-N-cyclohexyl-4 -(2,4-dichlorophenyl)thiazole-2-carboxyguanamine 20 4-(2,4-dichlorophenyl)-N-(piperidinyl)-5-(4-(trifluoroanthracene) Phenyl) thiazole-2-carboxyguanamine 'N-cyclohexyl-4-(2,4-diphenyl)-5-(4-(trifluoromethyl)phenyl)thiazole-2-carboxylate Indole 4-(2,4-dichlorophenyl)(exo-bicyclo[2.2.1]hept-2-yl)-5-(4-(three 5 1330181 pick, patent pending 曱1 fluoroindolyl) Phenyl)thiazole-2-carboxyguanamine 4-(2,4-dichlorophenyl)-N-(4- morpholinyl)-5-(4-(trifluoromethyl)phenyl)thiazole-2 - Carboxylamamine 5-(4->odorophenyl)-4-(2,4-dichlorophenyl)-N-(n-pentyl-5 decylamine 5-(4-bromophenyl)-4- (2,4-dichlorophenyl)-N-(hexahydro(1H)azephen-1-yl)thiazole-2-carboxydecylamine 5-(4-phenylphenyl)-4-( 2,4-Dichlorophenyl)-N-(porphyrin-4-yl)thiazole-2-carboxyguanamine 10 5-(4-chlorophenyl)-4-(2,4-di-phenyl) -N- (σ 比洛烧-1 -基)°塞零坐_ 2-Carboxyguanamine 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-indole-(six Hydrogen (1Η) azepan-1-enyl)thiazole-2-carboxydecylamine 5-(4-milophenyl)-4-(2,4-dichlorophenyl)-N-(six Ring burned and [c] 0 to 15 -2(1H)-yl)thiazole-2-carboxyguanamine N-benzyl-5-(4-chlorophenyl)-4-(2,4-diphenyl)-N-indenyl-thiazole- 2-Carboxynonamide 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-N-(4-(trifluoromethyl)benzyl)thiazole-2-carboxyguanamine 20 5-(4-Phenylphenyl)-4-(2,4-dichlorophenyl)-N-(exo-bicyclo[2.2.1]hept-2-yl)thiazole-2-carboxydecylamine 5-( 4-oxophenyl)-4-(2,4-diphenyl)-indole-(endo-bicyclo[2.2.1]hept-2-yl)thiazole-2-carboxyguanamine 4-(2,5 -Dichlorophenyl)-N-(exo-bicyclo[2.2.1]heptan-2-yl)-5-(phenyl) 6 1330181 Pickup, Patent Range Thiazol-2-sulfonamide N-(cyclohexyl) )-4-(2,5-Dichlorophenyl)·5-(phenyl)anthracene. Sit _2· Atherosamine 5-(4-indolyl)_4-(2,4-dichlorophenyl)-N-(tetrahydro-2-indole-β-pyran-2-yloxy)thiazole-2- Carboxylamamine 5-(4-chlorophenyl)_4-(2,4-dichlorophenyl)-indole-(5,5,5-trifluoropentyl)thiazole-2-decylamine 5-(4 - gas unyl)-4-(2,4-dichlorophenyl)-indole-(2-fluoroethyl) sold salivary-2-rebelamine 5-(4-phenylphenyl)_4-(2, 4-diphenylphenyl)-indole-(5-fluoropentyl)-s-oxazol-2-destroy 10 decylamine 4-(2,5-diphenyl)-indol-4-(porphyrinyl)-5 -(stupyl)thiazole-2-carboxamide 5-(4-chlorophenyl)-4-(2,4-diphenyl)_N_phenyl_thiazole_2-carboxamide 5-(4 -Chlorophenyl)-4-(2,4-dichlorophenyl)_N_(4,4,4-trifluorobutyl)thia 15 °-sodium 2-carboxamide. 7. A compound, a stereoisomer or a salt thereof, as claimed in any one of claims 1 to 6, for use as a pharmaceutical product. 8. A pharmaceutical composition for treating a disease involving a cannabinoid receptor (CBi), which comprises at least one compound, a stereoisomer or a salt thereof as described in claims 1-6 to Active ingredient. 9. A compound of the formula (V); 7 (V) 1330181 Pick up, apply for a patent range where R2 is as defined in item 1 of the patent application, 118 represents a hydroxyl group, a branched or unbranched (C1-4) alkoxy group, a benzyloxy group, Or chlorine atoms.