HK1132998A - Thiazole derivatives having cb1-antagonistic, agonistic or partial agonistic activity - Google Patents

Description

With CB1Thiazole derivatives having antagonistic, agonistic or partial agonistic activity

The application is filed on 3-17.2003, has the application number of 03801558.7(PCT/EP03/50063) and is named as' with CB₁Thiazole derivatives with antagonistic, agonistic or partial agonistic activity.

The present invention relates to a group of thiazole derivatives, to processes for preparing these compounds, and to pharmaceutical compositions comprising one or more of these compounds as active ingredients.

The thiazole derivatives are effective Cannabinoid (CB)₁) Receptor antagonist, CB₁Receptor agonists or CB₁Partial receptor agonists useful in the treatment of diseases involving cannabinoid CB₁Neurotransmission in mental and neurological disorders, and other diseases.

The documents EP 388909 and EP 377457 have described 4, 5-diarylthiazole derivatives as 5-lipoxygenase inhibitors for the treatment of thrombosis, hypertension, allergy and inflammation. All of the structures listed in both documents contain two phenyl rings substituted at the para position with methoxy, fluoro, methylthio or methylsulfinyl. Document WO 9603392 describes sulfonylaryl-arylthiazole compounds for the treatment of inflammation and pain, arthritis or fever associated with inflammation. JP05345772 relates to 4, 5-diarylthiazole compounds as acetylcholinesterase inhibitors, and JP04154773 describes 4, 5-diarylthiazole compounds having analgesic, anti-inflammatory and antipyretic effects.

It has now surprisingly been found that 4, 5-diarylthiazole derivatives of formula (I), their prodrugs and their salts

Wherein

-R represents a hydrogen atom or a substituent X chosen from branched or unbranched alkyl or alkoxy groups of 1 to 3 carbon atoms, hydroxyl, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono-or di- (C)_1-2) Alkylamino, mono-or di- (C)_1-2) Alkylamido, branched or unbranched (C)_1-3) Alkoxycarbonyl, trifluoromethylsulfonyl, sulfamoyl, branched or unbranched (C)_1-3) Alkylsulfonyl, carboxy, cyano, carbamoyl, branched or unbranched di- (C)_1-3) Alkylaminosulfonyl, branched or unbranched mono- (C)_1-3) An alkylaminosulfonyl group and an acetyl group,

-R₁is a hydrogen atom or 1 to 4 substituents X, where X has the meaning mentioned above,

-R₂represents phenyl, thienyl, pyridyl or pyrimidinyl, which radicals may be substituted by 1 to 4 substituents X, where X has the abovementioned meaning, or R₂Represents a naphthyl group, and represents a naphthyl group,

-R₃represents a hydrogen atom, a branched or unbranched alkyl or cycloalkyl-alkyl radical of 1 to 10 carbon atoms, or a phenyl, benzyl or phenethyl radical, the aromatic ring of which can be substituted by 1 to 5 substituents Z, which can be identical or different, selected from the group consisting of branched or unbranched alkyl or alkoxy radicals of 1 to 3 carbon atoms, hydroxyl, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono-or di- (C)_1-2) Alkylamino, mono-or di- (C)_1-2) Alkylamido, branched or unbranched (C)_1-3) Alkylsulfonyl, dimethylsulfonamide, branched or unbranched (C)_1-3) Alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R₃Represents a pyridyl group or a thienyl group,

-R₄represents a branched or unbranched alkyl or cycloalkyl-alkyl radical of 1 to 10 carbon atoms, a branched or unbranched alkoxy radical of 1 to 10 carbon atoms, a cycloalkyl radical of 3 to 8 carbon atoms, a bicycloalkyl radical of 5 to 10 carbon atoms, a tricycloalkyl radical of 6 to 10 carbon atoms, a branched or unbranched alkenyl radical of 3 to 10 carbon atoms, a cycloalkenyl radical of 5 to 8 carbon atoms, which may contain one or more heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur and which may be substituted by hydroxyl, 1 to 3 methyl, ethyl or 1 to 3 fluorine atoms, or R₄Represents phenyl, benzyl or phenethyl, which aromatic rings may be substituted by 1 to 5 substituents Z, Z having the abovementioned meaning, or R₄Represents pyridyl or thienyl, or R₄Represents a group NR₅R₆Wherein

R₅And R₆Together with the nitrogen atom to which they are attached form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms, which contains one or more heteroatoms selected from oxygen, nitrogen, sulfur, and which may be substituted by branched or unbranched alkyl groups of 1 to 3 carbon atoms, hydroxy, trifluoromethyl or fluorine atoms, or

-R₃And R₄Together with the nitrogen atom to which they are attached form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms, which contains one or more heteroatoms selected from oxygen, nitrogen, sulfur and may be substituted by branched or unbranched alkyl groups of 1 to 3 carbon atoms, hydroxy, trifluoromethyl or fluorine atoms,

is cannabinoid CB₁A potent antagonist, agonist or partial agonist of the receptor.

A prodrug is an inactive compound that is converted to the active form after absorption (Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186-.

Due to its effective CB₁Receptor activity, the compounds of the invention are suitable for the treatment of psychotic disorders such as psychosis, anxiety, depression, anxietyAttention deficit disorder, memory disorder, cognitive disorder, appetite disorder, obesity, addiction, craving, drug dependence, and neurological disorders such as neurodegenerative disorders, dementia, dystonia, myotonia, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, parkinson's disease, alzheimer's disease, epilepsy, huntington's disease, tourette's syndrome, cerebral ischemia, cerebral stroke, craniocerebral trauma, stroke, spinal cord injury, neuritis, platelet sclerosis, viral encephalitis, diseases associated with demyelination, and the treatment of pain, including neuropathic pain and other diseases involving cannabinoid neurotransmission, including the treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory disorders, gastrointestinal disorders, gastric ulcers, diarrhea, and cardiovascular disorders.

The compounds of the present invention are cannabinoid CB₁Receptor affinity was determined using membrane preparations of Chinese Hamster Ovary (CHO) cells in which human cannabinoid CB was present₁The receptor together with a radioactive ligand³H]CP-55,940 was stably transfected. In cultivation of a seed containing [, ]³H]-separation of bound and free ligands after the newly prepared cell membrane preparation of ligands by filtration with or without addition of the compounds of the invention with glass fiber filters. The radioactivity on the filters was measured by liquid scintillation counting.

Cannabinoid CB of Compounds of the invention₁Receptor antagonistic, agonistic or partial agonistic activity by employing human cannabinoid CB₁Functional studies of CHO cells in which the receptor is stably expressed were performed. Adenylyl cyclase was stimulated with forskolin (forskolin) and was measured by measuring the amount of accumulated cyclic Adenosine Monophosphate (AMP). In a concentration-dependent manner by CB₁CB of receptor agonists (e.g. CP-55,940 or (R) -WIN-55, 212-2)₁Receptor associated activity may reduce forskolin-induced accumulation of cyclic AMP. CB (CB)₁Receptor antagonists or partial agonists, such as the compounds of the invention, may antagonize such CB₁Mediated by receptorsAnd (6) responding.

Cannabinoid receptor agonistic or partial agonistic activity of the compounds of the invention can be measured according to published methods, such as the evaluation of cannabimimetic (cannabimimetic) effects in vivo (Wiley, j.l.et.j.pharmacol.exp.ther.2001, 296, 1013).

Cannabinoid receptor antagonists can be characterized as inverse agonists (Landsman, r.s.et al., eur.j.pharmacol.1997, 334, R1-R2).

The invention also relates to racemates, diastereomeric mixtures and individual stereoisomers of the compounds of the formula (I).

The compounds of the invention may be brought into a form suitable for administration by conventional methods using auxiliary substances and/or liquid or solid carrier materials.

One suitable method for synthesizing the compounds of the present invention is as follows:

synthesis scheme A

Step 1 of route A

Ester hydrolysis of a compound of formula (II) wherein R₇Represents a branched or unbranched alkyl group of 1 to 4 carbon atoms or a benzyl group.

The reaction produces a compound of formula (III):

wherein R, R₁And R₂Have the meaning described hereinbefore.

Of formula (II)Compounds of the invention, wherein R₇Alkyl or benzyl radicals representing 1 to 4 carbon atoms, branched or unbranched, can be prepared by known methods, such as:

a)Organic Reactions，Vol.VI，(1951)，p.367-409Ed.R.Adams，JohnWiley and Sons Inc.，New York

b)J.S.Carter et al.，Bioorg.Med.Chem.Lett.(1999)，9，1167-1170

c)T.T.Sakai et al.，Bioorg.Med.Chem.(1999)，7，1559-1566

d)A.Tanaka et al.，J.Med.Chem.(1994)，37，1189-1199

e)J.J.Talley et al.，WO 9603392：Chem.Abstr.125，33628

f)V.Cecchetti et al.，Bioorg.Med.Chem.(1994)，2，799-806

step 2 of route A

The compounds of the formula (III) are reacted with compounds of the formula R by activation and coupling methods, such as the formation of active esters or in the presence of so-called coupling reagents, for example DCC, HBTU, BOP, CIP (2-chloro-1, 3-dimethylimidazolinium hexafluorophosphate), PyAOP (7-azabenzotriazol-1-yloxytris (pyrrolidinyl) phosphonium hexafluorophosphate) and the like₃R₄Reaction of compounds of NH, wherein R₃And R₄Have the meaning described hereinbefore. (for more details on the activation and coupling methods see a) m.bodanszky, a.bodanszky: the Practice of Peptide Synthesis, Springer-Verlag, New York, 1994; ISBN: 0-387-; b) akaji et al, Tetrahedron Lett, (1994), 35, 3315-; c) albericio et al, Tetrahedron Lett. (1997), 38, 4853-

This reaction gives the desired thiazole derivative of formula (I).

Alternatively, the compounds of formula (III) are reacted with a so-called halogenating agent such as thionyl chloride (SOCl)₂) Reaction to obtain the corresponding carbonyl chloride (IV).

Then the compound of formula (IV) with formula R₃R₄Reaction of the compound of NH to give a thiazole derivative of the formula (I) in which R₃And R₄Have the meaning described hereinbefore. The reaction is preferably carried out in the presence of an organic base such as Diisopropylethylamine (DIPEA) or triethylamine.

Alternatively, the compound of the formula (II) is reacted with a compound of the formula R in a so-called amidation reaction₃R₄NH to give a thiazole derivative of the formula (I), wherein R₃And R₄Have the meaning described hereinbefore.

Or, formula R₃R₄Reacting the NH compound with a strong base such as Lithium Diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), potassium hexamethyldisilazide (KHMDS), or sodium hexamethyldisilazide (NaHMDS), respectively, to generate the formula R in situ₃R₄NLi、R₃R₄NK or R₃R₄NNa, and then reacting these compounds with a compound of formula (II) to give the thiazole derivative of formula (I).

Or, wherein R₃And R₄The compound of formula (I) representing a hydrogen atom may be reacted with a strong base such as LDA, LiHMDS, NaH or the like, followed by reaction with the compound L-R₄Reaction, wherein L represents a so-called leaving group such as Br, Cl, I, etc., and R₄Denotes branched or unbranched C_1-10Alkyl, cycloalkylalkyl, or branched or unbranched C_3-10Alkenyl, which may contain one or more heteroatoms selected from N, O, S and which may be substituted by 1 to 3 methyl, ethyl or 1 to 3 fluorine atoms.

Example 1

Part A: under a nitrogen atmosphere, 3.04 g of magnesium (0.125 mol) was suspended in 500 ml of anhydrous ether, followed by addition of iodine crystals. 20.12 g (0.125 mol) of 4-chlorobenzyl chloride dissolved in 100 ml of anhydrous ether are slowly added to maintain a gentle reflux. After the resulting mixture was cooled to room temperature, a solution of 2, 4-dichlorobenzonitrile (17.2 g, 0.10 mol) in 100 ml of toluene was slowly added thereto. The mixture was warmed to 135 ℃, ether was removed by distillation, toluene was added, and the resulting mixture was refluxed for another 2 hours. After cooling to room temperature, 400 ml of hydrochloric acid solution (1N) was slowly added thereto with stirring and cooling. The resulting mixture was extracted twice with ether and dried over magnesium sulfate, filtered and concentrated under vacuum. Flash chromatography (dichloromethane) gave 19.96 g (67% yield) of 2- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) ethanone as a yellow oil. The oil was crystallized from cyclohexane to give pure 2- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) ethanone. Melting point: 65-66 ℃.¹H-NMR(200MHz，CDCl₃)：δ7.02-7.45(m，7H)，4.22(s，2H)。

And part B: to a solution of 2.82 g (9.42 mmol) of 2- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) ethanone in 25 ml of benzene was added 0.48 ml (1.49 g, 9.31 mmol) of bromine, and the resulting solution was stirred at room temperature for 2 hours. Dichloromethane was then added and the resulting solution was washed with aqueous sodium bicarbonate, the organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give 3.55 g (quantitative yield) of 2-bromo-2- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) ethanone as a yellow oil (-95% purity by HPLC analysis).¹H-NMR(200MHz，CDCl₃)：δ7.00-7.50(m，7H)，6.16(s，1H)。

Prepared in a similar manner:

2-bromo-1- (4-chlorophenyl) -2- (2, 4-dichlorophenyl) ethanone.¹H-NMR(200MHz，CDCl₃)：δ7.95(d，J＝8Hz，2H)，7.23-7.62(m，5H)，6.77(s，1H)。

Part C: 9.83 g (26.0 mmol) of 2-bromo-2-, (4-chlorophenyl) -1- (2, 4-dichlorophenyl) ethanone and 5.28 g (39.6 mmol) of ethyl thioaluminate are dissolved in 50 ml of absolute ethanol and the resulting red solution is heated at reflux temperature for 4 hours. After evaporation in vacuo, 14 g of the crude red product are suspended in a mixture of dichloromethane and methyl tert-butyl ether, the solid formed is removed by filtration and the filtrate obtained is purified by column chromatography (eluent: dichloromethane: R)_fAbout 0.4) to yield 5.21 g (yield 48%) of ethyl 5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) thiazole-2-carboxylate as a yellow oil which solidified slowly. Melting point: 117 ℃ and 118 ℃.¹H-NMR(200MHz，CDCl₃)：δ7.53，(d，J＝2Hz，1H)，7.40(dt，J＝8Hz，J＝2Hz，2H)，7.22-7.35(m，4H)，4.52(q，J＝7Hz，2H)，1.45(t，J＝7Hz，3H)。

Prepared in a similar manner:

4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) thiazole-2-carboxylic acid ethyl ester.

And part D: 1.00 g (2.42 mmol) of ethyl 5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) thiazole-2-carboxylate was added to 10 ml of 1-aminopiperidine, and the resulting mixture was stirred with heating at 50 ℃ for 4 hours. Dichloromethane was then added and the resulting solution was washed twice with water, dried over magnesium sulfate, filtered and most of the dichloromethane was removed by evaporation in vacuo. Diisopropyl ether was then added, the precipitate formed 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)) to give 330 mg (yield 29%) of 5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (1-piperidinyl) thiazole-2-carboxamide as a white foam.¹H-NMR(400MHz，CDCl₃)：δ7.92(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:

4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) -N- (1-piperidinyl) thiazole-2-carboxamide,melting point: 190 ℃ and 191 ℃.¹H-NMR(400MHz，CDCl₃)：δ8.03(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-dichlorophenyl) thiazole-2-carboxamide, melting point: 159 ℃ and 161 ℃.

5- (4-chlorophenyl) -N-cyclopentyl-4- (2, 4-dichlorophenyl) thiazole-2-carboxamide, melting point: 111-113 ℃.

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (trans-4-hydroxycyclohexyl) thiazole-2-carboxamide, melting point: 109 ℃.

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (2-methylcyclohexyl) thiazole-2-carboxamide, melting point: 134 ℃ and 147 ℃.

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (4-fluorobenzyl) thiazole-2-carboxamide, melting point: 142 ℃ and 144 ℃.

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (trans-4-methylcyclohexyl) thiazole-2-carboxamide, melting point: 165-166 ℃.

5- (4-chlorophenyl) -N- (cis-4-methylcyclohexyl) -4- (2, 4-dichlorophenyl) thiazole-2-carboxamide, melting point: 72 ℃.

Example 2

Part A: 4.10 g (9.93 mmol) of ethyl 5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) thiazole-2-carboxylate are suspended in 75 ml of methanol, an aqueous potassium hydroxide solution (a solution of 1.98 g (30 mmol) of potassium hydroxide in 75 ml of water) is added, and the resulting mixture is heated at reflux temperature for 2 hours. The resulting yellow solution was then brought to room temperature, poured into water and acidified with 1N aqueous hydrochloric acid to give a white precipitate. The precipitate 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-chlorophenyl) -4- (2, 4-dichlorophenyl) thiazole-2-carboxylic acid as a white solid.¹H-NMR(200MHz，DMSO-d₆)：δ9.25(s，1H)，7.65-7.72(m，1H)，7.28-7.52(m，6H)。

Prepared in a similar manner:

4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) thiazole-2-carboxylic acid

And part B: 1.00 g (2.6 mmol) of 5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) thiazole-2-carboxylic acid are suspended in 20 ml of anhydrous acetonitrile under a nitrogen atmosphere at room temperature. 1.36 ml (7.8 mmol) of Diisopropylethylamine (DIPEA), 1.08 g (2.85 mmol) of O-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU) and 0.35 g (25.1 mmol) of O-tert-butylhydroxylamine hydrochloride were added successively, and the resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo, then dichloromethane was added, the resulting solution was washed with water, then brine and dried over magnesium sulfate, filtered and evaporated in vacuo. Purification by flash chromatography (ethyl acetate: petroleum ether (40-60): 1: 3(v/v)) gave 0.60 g (51% yield) of N- (tert-butoxy) -5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) thiazole-2-carboxamide as a white foam.¹H-NMR(400MHz，CDCl₃)：δ9.20(s，1H)，7.47(t，J＝2Hz，1H)，7.25-7.31(m，4H)，7.14(dt，J＝8Hz，J＝2Hz，2H)，1.36(s，9H)。

Prepared in a similar manner:

n- (tert-butoxy) -4- (4-chlorophenyl) -5- (2, 4-dichlorophenyl) thiazole-2-carboxamide.¹H-NMR(400MHz，CDCl₃)：δ9.23(s，1H)，7.52(d，J＝2Hz，1H)，7.35(dt，J＝8Hz，J＝2Hz，2H)7.23-7.31(m，4H)，1.40(s，9H)。

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (N-pentyl) thiazole-2-carboxamide.¹H-NMR(400MHz，CDCl₃)：δ7.46(s，1H)，7.21-7.32(m，5H)，7.14(dt，J＝8Hz，J＝2Hz，2H)，3.42-3.48(m，2H)，1.59-1.67(m，2H)，1.30-1.40(m，4H)，0.90(t，J＝7Hz，3H)。

5- (4-chlorophenyl) -N-cyclohexyl-4- (2, 4-dichlorophenyl) thiazole-2-carboxamide.¹H-NMR(400MHz，CDCl₃)：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(m，2H)，1.72-1.82(m，2H)，1.14-1.70(m，6H)。

Example 3

Part A: to 25 g (0.135 mol) of 4-bromobenzaldehyde were added 27.7 g (0.135 mol) of 2, 4-dichlorophenylacetic acid, 100 ml of acetic anhydride and 19 ml (0.136 mol) of triethylamine, successively, and the resulting mixture was heated at reflux temperature for 90 minutes. The reaction mixture was then cooled to 110 ℃, 100 ml of water was slowly added thereto, the resulting mixture was brought to room temperature, and then ethyl acetate was added. The ethyl acetate layer was washed twice with water, dried over magnesium sulfate, filtered and concentrated in vacuo, and the resulting oil was crystallized from diisopropyl ether to give 26.55 g (53% yield) of 3- (4-bromophenyl) -2- (2, 4-dichlorophenyl) acrylic acid as a white solid.

And part B: 26.55 g (71 mmol) of 3- (4-bromophenyl) -2- (2, 4-dichlorophenyl) acrylic acid were dissolved in 130 ml of anhydrous toluene, and the resulting solution was cooled to 0 ℃. 7.40 g (73 mmol) of triethylamine and 19.8 g (72 mmol) of diphenylphosphorylazide were added successively, and the resulting mixture was stirred at 0 ℃ for 20 minutes and then at room temperature for 150 minutes. The reaction mixture was poured into water and extracted three times with ether, the organic layers were collected and dried over magnesium sulfate, and the ether was removed in vacuo. The resulting toluene layer was slowly added to 150 ml of refluxing toluene, after 90 minutes t-butanol was added and heating was continued at reflux temperature for 1 hour, then 5 ml of concentrated hydrochloric acid was slowly added. After stirring the resulting solution at 90 ℃ overnight, it was cooled to room temperature, washed twice with water and dried over magnesium sulfate, filtered and evaporated in vacuo to give a yellow oil which was crystallized from n-hexane to give 14.72 g (60% yield) of 2- (4-bromophenyl) -1- (2, 4-dichlorophenyl) ethanone, m.p.: 69-70 ℃.

Part C: to a solution of 5.00 g (15 mmol) of 2- (4-bromophenyl) -1- (2, 4-dichlorophenyl) ethanone in 50 ml of benzene, 0.75 ml (15 mmol) of bromine was added dropwise, and the resulting solution was stirred at room temperature for 4 hours and concentrated in vacuo. Dichloromethane was then added and the resulting solution was washed with brine and dried over magnesium sulfate, filtered and concentrated in vacuo to give 5.96 g (94% yield) of 2-bromo-2- (4-bromophenyl) -1- (2, 4-dichlorophenyl) ethanone as an oil.

And part D: a solution of 5.96 g (14 mmol) of 2-bromo-2- (4-bromophenyl) -1- (2, 4-dichlorophenyl) ethanone and 2.80 g (21 mmol) of ethyl thioaluminate in 30 ml of ethanol was heated at reflux temperature for 4 hours. After cooling to room temperature, the crystalline material that settled out was removed by filtration, and the filtrate was concentrated in vacuo to give 7.56 g of an orange oily material, which was purified by flash chromatography (ethyl acetate/petroleum ether ═ 1/3(v/v)) followed by crystallization from diisopropyl ether to give 2.11 g (33% yield) of ethyl 5- (4-bromophenyl) -4- (2, 4-dichlorophenyl) thiazole-2-carboxylate, m.p.: 129 ℃ and 130 ℃.

Part E: a mixture of 1.00 g (2.2 mmol) of ethyl 5- (4-bromophenyl) -4- (2, 4-dichlorophenyl) thiazole-2-carboxylate and 10 ml of 1-aminopiperidine was stirred with heating at 50 ℃ overnight. The resulting mixture was then brought to room temperature, dichloromethane was added and the resulting solution was washed twice with water and dried over magnesium sulfate, filtered and concentrated in vacuo to give an oil which was purified by flash chromatography (ethyl acetate/petroleum ether ═ 1/3(v/v)) to give 870 mg (78% yield) of 5- (4-bromophenyl) -4- (2, 4-dichlorophenyl) -N- (1-piperidinyl) thiazole-2-carboxylic acid amine, m.p.: 171 ℃ and 173 ℃.

Prepared in a similar manner:

4- (2, 4-dichlorophenyl) -N- (1-piperidinyl) -5- (4- (trifluoromethyl) phenyl) thiazole-2-carboxylic acid amine, melting point: 181 ℃ and 183 ℃.

N-cyclohexyl-4- (2, 4-dichlorophenyl) -5- (4- (trifluoromethyl) phenyl) thiazole-2-carboxylic acid amine, melting point: 140 ℃ and 142 ℃.

4- (2, 4-dichlorophenyl) -N- (exo-bicyclo [2.2.1] hept-2-yl) -5- (4- (trifluoromethyl) phenyl) thiazole-2-carboxamide, melting point: 184 ℃ and 185 ℃.

4- (2, 4-dichlorophenyl) -N- (4-morpholinyl) -5- (4- (trifluoromethyl) phenyl) thiazole-2-carboxamide, melting point: 95 ℃.

Example 4

Part A: 1.80 g (3.94 mmol) of ethyl 5- (4-bromophenyl) -4- (2, 4-dichlorophenyl) thiazole-2-carboxylate was dissolved in 20 ml of methanol, an aqueous solution of potassium hydroxide (a solution of 0.65 g (85%), 9.85 mmol of potassium hydroxide in 20 ml of water) was added, and the resulting mixture was heated at reflux temperature for 1 hour, then poured into water and acidified with 1N hydrochloric acid solution. The resulting precipitate was collected by filtration and dried in vacuo at room temperature to give quantitative yield of 5- (4-bromophenyl) -4- (2, 4-dichlorophenyl) thiazole-2-carboxylic acid, m.p.: 94-95 ℃.

And part B: 0.50 g (1.17 mmol) of 5- (4-bromophenyl) -4- (2, 4-dichlorophenyl) thiazole-2-carboxylic acid and 1.02 ml (5.85 mmol) of Diisopropylethylamine (DIPEA) were dissolved in 5 ml of dichloromethane and cooled to 0 ℃. To this were added 0.11 g (0.81 mmol) of 7-aza-1-hydroxybenzotriazole (HOAt) and 0.50 g (1.76 mmol) of 2-chloro-1, 3-dimethylimidazolinium hexafluorophosphate (CIP), followed by 0.15 g (1.76 mmol) of n-pentylamine, and the resulting mixture was stirred at room temperature overnight. Purification by flash chromatography (dichloromethane) gave 0.28 g (48% yield) of 5- (4-bromophenyl) -4- (2, 4-dichlorophenyl) -N- (N-pentyl) thiazole-2-carboxamide as an amorphous solid.

Prepared in a similar manner:

5- (4-bromophenyl) -4- (2, 4-dichlorophenyl) -N- (hexahydro (1H) azepin-1-yl) thiazole-2-carboxamide, melting point: 206- & lt207 & gt.

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (morpholin-4-yl) thiazole-2-carboxamide, amorphous solid.

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (pyrrolidin-1-yl) thiazole-2-carboxamide, melting point: 179 ℃ and 181 ℃.

Example 5

Part A: to a solution of 0.50 g (1.30 mmol) of 5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) thiazole-2-carboxylic acid in 10 ml of dichloromethane were added 0.15 g (1.30 mmol) of 1-aminohexahydro (1H) azepane triene, 0.18 g (1.30 mmol) of 7-aza-1-hydroxybenzotriazole, 0.68 g (1.30 mmol) of 7-azabenzotriazol-1-yloxytris (pyrrolidinyl) phosphonium hexafluorophosphate (PyAOP) and 0.34 ml (1.95 mmol) of diisopropylethylamine, and the resulting solution was stirred at room temperature for 1 hour. Concentration in vacuo afforded 2.01 g of a crude oil which was purified by flash chromatography (ethyl acetate/petroleum ether ═ 1/3(v/v)) to afford 0.350 g (56% yield) of 5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (hexahydro (1H) azepin-1-yl) thiazole-2-carboxamide, m.p.: 185 ℃ at 186 ℃ (measured after recrystallization from diisopropyl ether).

Prepared in a similar manner:

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) thiazole-2-carboxamide, melting point: 173 ℃ and 174 ℃.

N-benzyl-5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N-methyl-thiazole-2-carboxamide, melting point: 141 and 144 ℃.

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (4- (trifluoromethyl) benzyl) thiazole-2-carboxamide, melting point: 174 ℃ and 176 ℃.

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (exo-bicyclo [2.2.1] hept-2-yl) thiazole-2-carboxamide, melting point: 194 ℃ and 195 ℃.

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (endo-bicyclo [2.2.1] hept-2-yl) thiazole-2-carboxamide, melting point: 181 ℃ and 183 ℃.

4- (2, 5-dichlorophenyl) -N- (exo-bicyclo [2.2.1] hept-2-yl) -5- (phenyl) thiazole-2-carboxamide, melting point: 170 deg.C.

N- (cyclohexyl) -4- (2, 5-dichlorophenyl) -5- (phenyl) thiazole-2-carboxamide, melting point: at 75 ℃.

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (tetrahydro-2H-pyran-2-yloxy) thiazole-2-carboxamide, melting point: 85 ℃.

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (5, 5, 5-trifluoropentyl) thiazole-2-carboxamide.¹H-NMR(400MHz，CDCl₃)：δ7.47(br s，1H)，7.24-7.31(m，5H)，7.14(dt，J＝8Hz，J＝2Hz，2H)，3.49(q，J＝7Hz，2H)，2.07-2.20(m，2H)，1.62-1.77(m，4H).

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (2-fluoroethyl) thiazole-2-carboxylic acid amine.

An amorphous solid.¹H-NMR(400MHz，CDCl₃)：δ7.52-7.58(m，1H)，7.47(br s，1H)，7.24-7.32(m，4H)，7.14(dt，J＝8Hz，J＝2Hz，2H)，4.61(dt，J＝47Hz，J＝5Hz，2H)，3.72-3.84(m，2H).

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (5-fluoropentyl) thiazole-2-carboxamide.¹H-NMR(400MHz，CDCl₃)：δ7.47(br s，1H)，7.24-7.30(m，5H)，7.14(dt，J＝8Hz，J＝2Hz，2H)，4.45(dt，J＝47Hz，J＝6Hz，2H)，3.45-3.51(m，2H)，1.64-1.82(m，4H)，1.48-1.56(m，2H).

4- (2, 5-dichlorophenyl) -N- (4-morpholinyl) -5- (pentyl) thiazole-2-carboxamide melting point: 155 ℃ and 157 ℃.

Example 6

1.65 g (4.0 mmol) of ethyl 5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) thiazole-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 0 ℃, and 4.4 ml of a tetrahydrofuran solution (1M) of sodium hexamethyldisilazide was added thereto. The reaction mixture was stirred for 2 hours. Water was then added and the mixture was extracted twice with ethyl acetate, the organic layers were combined and washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo, and the residue was crystallized from diisopropyl ether to give 1.42 g (77% yield) of 5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N-phenyl-thiazole-2-carboxamide, m.p.: 167 ℃ and 168 ℃.

Example 7

Part A: at room temperature, gaseous NH₃To a stirred solution of ethyl 5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) thiazole-2-carboxylate (1.65 g, 4.0 mmol) in methanol (25 ml) was introduced. A small piece of sodium metal was added. After stirring the resulting mixture for 3 hours, the precipitate was collected by filtration, washed with a small amount of methanol and dried to give 5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) thiazole-2-carboxamide (1.16 g, yield 76%), m.p. 195-.¹HNMR(200MHz，CDCl₃)：δ7.48(br s，1H)，7.22-7.35(m，4H)，7.05-7.20(m，3H)，5.55-5.65(m，1H)。

And part B: to a cooled (0 ℃) solution of 5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) thiazole-2-carboxamide (1.16 g, 3.02 mmol) in anhydrous DMF (20 ml) was added NaH (0.13 g of a 60% dispersion) with stirring under a nitrogen atmosphere. The resulting mixture was stirred for 1 hour and an excess of 4, 4, 4-trifluoro-1-bromobutane (0.7 ml) was added. The resulting solution was stirred at room temperature for 1 hour, poured into ice/water and extracted twice with ether. The collected ether layer was washed twice with water and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was further purified by column chromatography (silica gel, eluent dichloromethane) to give 5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (4, 4, 4-trifluorobutyl) thiazole-2-carboxamide. Melting point: 99-101 ℃.

Claims (7)

1. A compound of formula (I)

Wherein

-R represents a substituent X chosen from branched or unbranched alkyl or alkoxy of 1 to 3 carbon atoms, hydroxyl, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono-or di- (C)_1-2) An alkylamino group,Mono-or di- (C)_1-2) Alkylamido, branched or unbranched (C)_1-3) Alkoxycarbonyl, trifluoromethylsulfonyl, sulfamoyl, branched or unbranched (C)_1-3) Alkylsulfonyl, carboxy, cyano, carbamoyl, branched or unbranched di- (C)_1-3) Alkylaminosulfonyl, branched or unbranched mono- (C)_1-3) An alkylaminosulfonyl group and an acetyl group,

-R₁is a hydrogen atom or 1 to 4 substituents X, where X has the meaning mentioned above,

-R₂represents phenyl, which radical may be substituted by 1 to 4 substituents X, where X has the abovementioned meaning,

-R₃represents a hydrogen atom, a branched or unbranched alkyl or cycloalkyl-alkyl radical of 1 to 10 carbon atoms or a phenyl, benzyl or phenethyl radical, the aromatic ring being substituted by 1 to 5 substituents Z, which may be identical or different, selected from the group consisting of branched or unbranched alkyl or alkoxy radicals of 1 to 3 carbon atoms, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono-or di- (C)_1-2) Alkylamino, mono-or di- (C)_1-2) Alkylamido, branched or unbranched (C)_1-3) Alkylsulfonyl, dimethylsulfonamide, branched or unbranched (C)_1-3) Alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl groups,

-R₄represents a branched or unbranched alkyl or cycloalkyl-alkyl radical of 1 to 10 carbon atoms, a branched or unbranched alkoxy radical of 1 to 10 carbon atoms, a cycloalkyl radical of 3 to 8 carbon atoms, a bicycloalkyl radical of 5 to 10 carbon atoms, a tricycloalkyl radical of 6 to 10 carbon atoms, a branched or unbranched alkenyl radical of 3 to 10 carbon atoms, a cycloalkenyl radical of 5 to 8 carbon atoms, which may contain one or more heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur and which may be substituted by hydroxyl, 1 to 3 methyl, ethyl or 1 to 3 fluorine atoms, or R₄Represents phenyl, benzyl or phenethyl, which aromatic rings may be substituted by 1 to 5 substituents Z, Z having the abovementioned meaning, or R₄Represents a group NR₅R₆Wherein

R₅And R₆Together with the nitrogen atom to which they are attached form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms, which contains one or more heteroatoms selected from oxygen, nitrogen, sulfur, and which may be substituted by branched or unbranched alkyl groups of 1 to 3 carbon atoms, hydroxy, trifluoromethyl or fluorine atoms, or

-R₃And R₄Together with the nitrogen atom to which they are attached form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms, which contains one or more heteroatoms selected from oxygen, nitrogen, sulfur and may be substituted by branched or unbranched alkyl groups of 1 to 3 carbon atoms, hydroxy, trifluoromethyl or fluorine atoms,

or a stereoisomer or salt thereof.

2. A compound of formula (I) according to claim 1, wherein

R represents a substituent X chosen from branched or unbranched alkyl or alkoxy groups of 1 to 3 carbon atoms, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono-or di- (C)_1-2) Alkylamino, mono-or di- (C)_1-2) Alkylamido, branched or unbranched (C)_1-3) Alkoxycarbonyl, carboxyl, cyano, carbamoyl and acetyl,

-R₁represents a hydrogen atom or one or more substituents X, wherein X has the meaning mentioned above,

-R₂represents phenyl, which radical may be substituted by one or more substituents X, where X has the abovementioned meaning,

-R₃is a hydrogen atom, and is a hydrogen atom,

-R₄represents a branched or unbranched alkyl or cycloalkyl-alkyl group of 1 to 10 carbon atoms, a branched or unbranched alkoxy group of 1 to 10 carbon atoms, a cycloalkyl group of 3 to 8 carbon atoms, a bicycloalkyl group of 5 to 10 carbon atoms, a tricycloalkyl group of 6 to 10 carbon atoms, a branched or unbranched alkenyl group of 3 to 10 carbon atoms, a cycloalkenyl group of 5 to 8 carbon atoms, which groups may contain one or more substituents selected from the group consisting ofHeteroatoms selected from oxygen, nitrogen, sulfur and optionally substituted by hydroxy, 1-3 methyl, ethyl or 1-3 fluorine atoms, or R₄Represents phenyl, benzyl or phenethyl, the aromatic ring being substituted by 1 to 5 substituents Z, Z being as defined in claim 1, or R₄Represents a group NR₅R₆Wherein

R₅And R₆Together with the nitrogen atom to which they are attached form a saturated or unsaturated monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms, which contains one or more heteroatoms selected from oxygen, nitrogen, sulfur and may be substituted by branched or unbranched alkyl groups of 1 to 3 carbon atoms, hydroxy, trifluoromethyl or fluorine atoms,

or a stereoisomer or salt thereof.

3. A compound of formula (I) as claimed in claim 2 wherein R represents a halogen atom, or a stereoisomer or salt thereof.

4. A compound of formula (I) according to claim 3, wherein R₄Represents a group NR₅R₆Wherein R is₅And R₆Together with the nitrogen atom to which they are attached form a saturated or unsaturated monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms, which contains one or more heteroatoms selected from oxygen, nitrogen, sulfur and may be substituted by a branched or unbranched alkyl group of 1 to 3 carbon atoms, a hydroxyl group, a trifluoromethyl group or a fluorine atom, or a stereoisomer or a salt thereof.

5. A compound of formula (I) as claimed in claim 4 wherein R₁Represents one or more halogen atoms, or a stereoisomer or salt thereof.

6. The compound of formula (I) according to claim 1, which is

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (1-piperidinyl) thiazole-2-carboxamide;

5- (4-chlorophenyl) -N-cycloheptyl-4- (2, 4-dichlorophenyl) thiazole-2-carboxamide;

5- (4-chlorophenyl) -N-cyclopentyl-4- (2, 4-dichlorophenyl) thiazole-2-carboxamide;

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (trans-4-hydroxycyclohexyl) thiazole-2-carboxamide;

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (2-methylcyclohexyl) thiazole-2-carboxamide;

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (4-fluorobenzyl) thiazole-2-carboxamide;

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (trans-4-methylcyclohexyl) thiazole-2-carboxamide;

5- (4-chlorophenyl) -N- (cis-4-methylcyclohexyl) -4- (2, 4-dichlorophenyl) thiazole-2-carboxamide;

n- (tert-butoxy) -5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) thiazole-2-carboxamide;

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (N-pentyl) thiazole-2-carboxamide;

5- (4-chlorophenyl) -N-cyclohexyl-4- (2, 4-dichlorophenyl) thiazole-2-carboxamide;

5- (4-bromophenyl) -4- (2, 4-dichlorophenyl) -N- (1-piperidinyl) thiazole-2-carboxamide;

4- (2, 4-dichlorophenyl) -N- (1-piperidinyl) -5- (4- (trifluoromethyl) phenyl) thiazole-2-carboxamide;

n-cyclohexyl-4- (2, 4-dichlorophenyl) -5- (4- (trifluoromethyl) phenyl) thiazole-2-carboxamide;

4- (2, 4-dichlorophenyl) -N- (exo-bicyclo [2.2.1] hept-2-yl) -5- (4- (trifluoromethyl) phenyl) thiazole-2-carboxamide;

4- (2, 4-dichlorophenyl) -N- (4-morpholinyl) -5- (4- (trifluoromethyl) phenyl) thiazole-2-carboxamide;

5- (4-bromophenyl) -4- (2, 4-dichlorophenyl) -N- (N-pentyl) thiazole-2-carboxamide;

5- (4-bromophenyl) -4- (2, 4-dichlorophenyl) -N- (hexahydro (1H) azepin-1-yl) thiazole-2-carboxamide;

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (morpholin-4-yl) thiazole-2-carboxamide;

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (pyrrolidin-1-yl) thiazole-2-carboxamide;

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (hexahydro (1H) azepin-1-yl) thiazole-2-carboxamide;

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) thiazole-2-carboxamide;

n-benzyl-5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N-methyl-thiazole-2-carboxamide;

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (4- (trifluoromethyl) benzyl) thiazole-2-carboxamide;

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (exo-bicyclo [2.2.1] hept-2-yl) thiazole-2-carboxamide;

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (endo-bicyclo [2.2.1] hept-2-yl) thiazole-2-carboxamide;

4- (2, 5-dichlorophenyl) -N- (exo-bicyclo [2.2.1] hept-2-yl) -5- (phenyl) thiazole-2-carboxamide;

n- (cyclohexyl) -4- (2, 5-dichlorophenyl) -5- (phenyl) thiazole-2-carboxamide;

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (tetrahydro-2H-pyran-2-yloxy) thiazole-2-carboxamide;

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (5, 5, 5-trifluoropentyl) thiazole-2-carboxamide;

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (2-fluoroethyl) thiazole-2-carboxamide;

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (5-fluoropentyl) thiazole-2-carboxamide;

4- (2, 5-dichlorophenyl) -N- (4-morpholinyl) -5- (pentyl) thiazole-2-carboxamide;

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N-phenyl-thiazole-2-carboxamide; or

5- (4-chlorophenyl) -4- (2, 4-dichlorophenyl) -N- (4, 4, 4-trifluorobutyl) thiazole-2-carboxamide.

7. Use of a compound of claim 1 as a chemical standard compound in the synthesis, purification and analysis of 4, 5-diarylthiazole-2-carboxamide derivatives.