KR20070031960A - Tetrasubstituted imidazole derivatives as cannabinoid CB1 receptor modulators with a high CB1/CB2 receptor subtype selectivity - Google Patents

Abstract

The present invention relates to selective cannabinoid CB ₁ receptor modulators with high CB ₁ / CB ₂ receptor subtype selectivity, in particular 1,2,4,5- tetrasubstituted imidazole derivatives as CB ₁ receptor antagonists or inverse agonists, A method for preparing a compound and a novel intermediate useful for the synthesis of the imidazole derivatives. The invention also relates to the use of a compound described herein for the manufacture of a medicament that provides a beneficial effect. The beneficial effects are apparent to those skilled in the art described herein or from the specification and are known in the art. The invention also relates to the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition. More particularly, the present invention relates to novel uses for treating diseases or conditions described herein or apparent from the specification to those skilled in the art and known in the art. In embodiments of the invention, certain compounds herein are used in the manufacture of a medicament useful for the treatment of psychiatric and neurological diseases. The present invention relates to compounds of formula (I).

Formula I

In Formula I,

The radical has the meaning described in the specification.

High CB1 / CB2 receptor subtype selectivity, selective cannabinoid CB1 receptor modulators, 1,2,4,5- tetrasubstituted imidazole derivatives, psychiatric and neurological diseases

Description

Tetrasubstituted imidazole derivatives as cannabinoid CB1 receptor modulators with a high CB1 / CB2 receptor subtype selectivity}

The present invention provides selective cannabinoid CB ₁ receptor modulators with high CB ₁ / CB ₂ receptor subtype selectivity, in particular 1,2,4,5- tetrasubstituted imidazole derivatives as CB ₁ receptor antagonists or inverse agonists, Novel intermediates useful for the preparation of compounds and for the synthesis of imidazole derivatives. The invention also relates to the use of a compound described herein for the manufacture of a medicament that provides a beneficial effect. The beneficial effects are apparent to those skilled in the art, described herein or from the specification and general knowledge in the art. The invention also relates to the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition. More particularly, the present invention relates to novel uses for treating diseases or conditions described herein or that are apparent to those skilled in the art from the specification and general knowledge in the art. In embodiments of the invention, certain compounds herein are used in the manufacture of a medicament useful for the treatment of psychiatric and neurological diseases.

Polysubstituted imidazole derivatives with CB ₁ receptor affinity are known from WO 03/027076 and WO 03/063781. In addition, WO 03/040107 is known imidazole for the treatment of obesity. It has also been published in the literature that imidazoles have been described as CB ₁ receptor antagonists. Dyck et al., Bioorg. Med. Chem. Lett. 2004, 14, 1151-1154. The patent applications and documents mentioned do not show data for CB ₁ / CB ₂ receptor subtype selectivity of the compounds described herein.

CB ₁ receptor modulators include mental disorders, anxiety, depression, attention deficit, memory impairment, cognitive impairment, appetite disorders, obesity, addiction, desire, drug dependence, neurodegenerative disorders, dementia, dystonia, muscle stiffness, tremors, epilepsy, multiple Sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, Huntington's disease, Tourette syndrome, cerebral ischemia, head injury, spinal cord injury, seizures, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, myelopathy-related diseases, as well as neuropathy It is effectively applied as a medicament for treating pain disorders including pain disorders and pulmonary shock, glaucoma, diabetes, cancer, vomiting, nausea, gastrointestinal disorders, gastric ulcers, diarrhea, sexual disorders, impulse control disorders and cardiovascular disorders.

CB ₂ receptors occur mainly in the microglia and astrocytes as well as in the immune system (spleen, tonsil, immune cells) and are associated with the recognition of neuropathic pain. Potential CB ₁ receptor modulators with low CB ₂ receptor affinity (ie, compounds with high CB ₁ / CB ₂ receptor subtype selectivity) are advantageous compounds compared to non-selective or lower selective cannabinoid receptor modulators, This is because it can eliminate undesired potential CB ₂ receptor-mediated side effects such as immunological side effects or inflammation related side effects or neuropathic pain perception.

It is an object of the present invention to develop imidazole derivatives having high CB ₁ / CB ₂ receptor subtype selectivity.

Surprisingly, we have found in the prior art CB ₁ / CB ₂ receptor subtype selectivity in which modification of the original CH ₂ group X by residues containing sulfur atoms in the imidazole of Formula I is improved by ample factor 10. It has been found to produce new compounds having a, which results in a CB ₁ / CB ₂ affinity ratio of at least 100.

Compounds of formula (I) and their tautomers, stereoisomers, prodrugs and pharmaceutically acceptable salts thereof are novel, potential CB ₁ / CB ₂ selective CB ₁ receptor antagonists or inverse agonists.

In Formula I,

R ₁ is chloro, bromo, fluoro or hydrogen atom,

R ₂ is a chloro or bromo atom or a CF ₃ group,

A is a nitrogen atom or a CH group,

X is a sulfur atom or a sulfoxide (S═O) residue or a sulfone (SO ₂ ) residue,

Y is hydrogen atom or methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, trifluoromethyl, phenyl, benzyl or pyridyl group,

Z is a nitrogen atom or a CH group,

n is 1, 2 or 3.

All sulfoxides of the present invention comprise a chiral center. The present invention relates not only to racemates, mixtures of diastereomers of the compounds of formula (I), but also to individual stereoisomers. The invention also relates to the E isomers, Z isomers and / or E / Z mixtures of the compounds of formula (I).

Prodrugs of the foregoing compounds are within the scope of the present invention. Prodrugs are therapeutic agents that are inactive by themselves but are transformed into one or more active metabolites. Prodrugs are bioreversible derivatives of drug molecules used to overcome certain barriers to the utility of the parent drug molecule. Such barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism and targeting limits. Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed .: FD King, p. 215; J. Stella, "Prodrugs as therapeutics", Expert Opin. Ther. Patents, 14 (3), 277-280, 2004; P. Ettmayer et al., “Lessons learned from marketed and investigational prodrugs”, J. Med. Chem., 47, 2393-2404, 2004]. Prodrugs, ie compounds that are metabolized into compounds of formula (I) upon administration to the human body by known routes, also belong to the invention. In particular, this relates to compounds containing primary or secondary amino or hydroxy groups. The compound may react with an organic acid to produce a compound of formula I, which is readily removed after administration, for example, amidine, enamine, Mannich base, hydroxyl-methylene derivative, O- ( Additional groups such as, but not limited to, acyloxy-methylenecarbamate) derivatives, carbamate, esters, amides or enaminons.

In the present invention, in particular, R ₁ is a hydrogen atom or a chloro atom, R ₂ is a chloro atom, Y is a methyl or ethyl group, Z is CH, n is 1, 2 or 3, and A and X are as defined above. Compounds of Formula I having and tautomers, stereoisomers, prodrugs and pharmaceutically acceptable salts thereof.

More particularly, the present invention relates to compounds of formula (I), wherein R ₁ and R ₂ are chloro atoms, Y is a methyl group, Z is CH, n is 1, 2 or 3, A is a nitrogen atom, and X is a chemical formula having the above meanings A compound of I and its tautomers, stereoisomers, prodrugs and pharmaceutically acceptable salts thereof.

General Aspects of Synthesis

The synthesis of compounds of formula I is summarized in Scheme 1. The carboxylic acid of formula (II) can be converted to the corresponding tert-butyl ester (III). This ester (III) is treated with an inert anhydrous organic solvent with a strong non-nucleophilic base and subsequently sulfur-derived electrophile YSSY, wherein Y is methyl, ethyl, n-propyl, isopropyl, n-butyl , t-butyl, trifluoromethyl, phenyl, benzyl or pyridyl group) to give a compound of formula IV. The compound of formula IV can be oxidized with 1 mol equivalents of meta-chloroperbenzoic acid to afford the corresponding sulfoxide analogs. Alternatively, the compound of formula IV can be reacted with 2 mol equivalents of meta-chloroperbenzoic acid to convert the sulfur moiety to the corresponding sulfone moiety. The esters of formula IV-preferably under acidic conditions-can be hydrogenated to give the corresponding carboxylic acids (V). The obtained compound of formula V is coupled in the presence of an amine with an activating or coupling reagent to give a compound of formula I wherein R ₁ , R ₂ , A, X, Y, Z and n have the above meanings. Can be obtained.

Reagents and Conditions: (a) Boc ₂ O, DMAP, t-BuOH; (b) LDA, THF;

(C) YSSY; (d) TFA, CH ₂ Cl ₂ ; (e) amine derivatives, HBTU, DIPEA, CH ₃ CN, rt;

(f) 1 equivalent m-CPBA, CH ₂ Cl ₂ , rt; (g) 2 equivalents m-CPBA, CH ₂ Cl ₂ , rt

Alternatively, compounds of formula Vl, wherein R ₁ , R ₂ , A, Z and n have the above meanings, are reacted in a non-nucleophilic strong base such as LDA and an inert anhydrous organic solvent , Sulfur (S ₈ ) or sulfur-derived electrophile YSSY, wherein Y is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, trifluoromethyl, phenyl, benzyl or pyridyl group Is a compound of formula I wherein X is a sulfur atom, Y is a hydrogen atom or methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, trifluoromethyl, phenyl, benzyl Or a pyridyl group, wherein R ₁ , R ₂ , A, Z and n are as defined above (Scheme 2).

Reagents and Conditions: (a) LDA, Et ₂ O; (b) S ₈ or YSSY

More detailed information on how to activate and bind amines to carboxylic acids is found in:

In particular, the choice of synthetic procedure can be accomplished by those skilled in the art, such as miscibility of reagents used with functional groups, the availability of protecting groups, catalysts, activation or coupling reagents, and the final structural properties present in the final compounds produced. Depends on factors known to them.

Pharmaceutically acceptable salts can be obtained using standard procedures well known to those skilled in the art and can be prepared, for example, by mixing the compounds of the invention with a suitable acid, for example an inorganic acid such as hydrochloric acid, or an organic acid. have.

Pharmaceutical formulation

The compounds of the present invention may be made in a form suitable for administration by conventional methods using auxiliary substances, for example liquid or solid carrier materials. The pharmaceutical compositions of the present invention can be administered intestinal, oral, parenteral (muscular or intravenous), rectal or topical (local). They may be administered in the form of solvents, powders, tablets, capsules (including microcapsules), ointments (creams or gels) or suppositories. Suitable excipients for such formulations are pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavors, colorants and / or buffer materials. Often used auxiliary substances that may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars or sugar alcohols, talc, milk proteins, gelatin, starch, cellulose and derivatives thereof, animal and vegetable oils such as fish Cod liver oil, sunflower oil, peanut oil, sesame oil, polyethylene glycols and solvents such as sterile water and mono or polyhydric alcohols such as glycerol.

The compounds of the present invention are generally administered in pharmaceutical compositions, which are important and novel embodiments of the present invention, due to the presence of the compounds herein, more particularly the specific compounds described herein. Pharmaceutical composition types that can be used are tablets, chewable tablets, capsules, solutions, parenteral solutions, suppositories, suspensions, and other types described herein or apparent to those skilled in the art from the specification and general knowledge in the art. It includes, but is not limited to. The invention also encompasses the formulation and preparation of pharmaceutical compositions.

In one aspect of the invention, there is provided a pharmaceutical pack or kit comprising one or more containers filled with one or more components of the pharmaceutical composition of the invention. The container may involve a variety of substrate members, such as, for example, in the form defined by the instructions for use or by the competent authority regulating the manufacture, use, and sale of the pharmaceutical product, which may involve human or veterinary administration. Reflect the approval of the competent authority for the manufacture, use or sale of the product.

Due to the activity of potential CB ₁ antagonists or inverse agonists, the compounds of the present invention can lead to mental disorders, anxiety, depression, attention deficit, memory impairment, cognitive impairment, appetite disorder, obesity, especially juvenile obesity and drug obesity, addiction, desire Mental disorders, such as drug dependence, and neurodegenerative disorders, dementia, dystonia, muscle stiffness, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, Huntington's disease, Tourette syndrome, cerebral ischemia, Head injury, spinal cord injury, seizures, neuroinflammatory disorders, plague sclerosis, neurological disorders such as viral encephalitis, pain disorders including demyelination related disorders, neuropathic pain disorders and pulmonary shock, glaucoma, cancer, diabetes, vomiting, nausea, Cannabinoid neurotransmitters, including asthma, respiratory disorders, gastrointestinal disorders, sexual disorders, cirrhosis, gastric ulcers, diarrhea, sexual disorders, impulse control disorders and cardiovascular disorders It is suitable for the treatment of other diseases involved.

The cannabinoid receptor modulating activity of the compounds of the present invention is particularly useful in the treatment of obesity, juvenile obesity and drug obesity in combination with lipase inhibitors. Examples of specific compounds that can be used in the combination formulations include lipase inhibitors, Streptomyces aburaviensis , isolated from microorganisms such as synthetic lipase inhibitors orlistat, Streptomyces toxytricini lipstatin. ) A plant extract known to possess lipase inhibitory activity, such as Ebelactone B of origin, a synthetic derivative of the compound, an extract of Alpinia officinarum , or 3-methylethergallangin (A. oryrinarum Compounds, such as, but not limited to, extracts.

Pharmacological method

In vitro affinity for cannabinoid-CB ₁ receptor

The affinity of the compounds of the invention for cannabinoid CB ₁ receptors, one car cannabinoid CB ₁ receptor a radioactive labeling substance as a ^[3 H] stably combined to the CP-55,940 trans Defect cells of Chinese hamster ovary (CHO) film It can be measured using a formulation. After incubation of freshly prepared cell membrane preparations with [ ³ H] -ligand with or without addition of the compounds of the invention, the binding and free ligands were isolated by filtration with a glass fiber filter. The radioactivity of the filtrate was measured by liquid scintillation counting.

In vitro affinity for cannabinoid-CB ₂ receptor

The affinity of the compounds of the invention for cannabinoid CB ₂ receptor is human cannabinoid CB ₂ receptor is a cell membrane preparation of a radioactive labeling substance as a ^[3 H] stably bind to CP-55,940 trans defect Chinese hamster ovary (CHO) Can measure using. After incubation of freshly prepared cell membrane preparations with [ ³ H] -ligand with or without addition of the compounds of the invention, the binding and free ligands were isolated by filtration with a glass fiber filter. The radioactivity of the filtrate was measured by liquid scintillation counting.

In vitro cannabinoid-CB ₁ receptor antagonists

In vitro CB ₁ receptor antagonism can be measured by human CB ₁ receptor cloned in Chinese hamster ovary (CHO) cells. CHO cells were grown in culture medium of Dulbecco's Modified Eagle's medium (DMEM) supplemented with 10% heat inactivated fetal bovine serum. The medium was aspirated and replaced with DMEM containing [ ³ H] -arachidonic acid without fetal bovine serum and incubated overnight in a cell culture stove (5% CO ₂ /95% air; 37 ° C .; steam saturated atmosphere). . During this period, [ ³ H] -arachidonic acid was incorporated into the membrane phospholipid. On the day of the test, the medium was aspirated and the cells washed three times with 0.5 mL DMEM containing 0.2% bovine serum albumin (BSA). CB ₁ receptor stimulation by WIN 55,212-2 activates PLA ₂ , thereby releasing [ ³ H] -arachidonic acid into the medium. This WIN 55,212,2-induced release is concentration dependently antagonized by CB ₁ receptor antagonists.

Dosage

The affinity of the compounds of the invention for the CB ₁ receptor was measured as described above. From the binding affinity measured twice for the compound of formula (I) provided, one can theoretically estimate the lowest effective dose. At the same concentration of compound as the measured K-value, about 100% of the CB ₁ receptor may also be nearly occupied by the compound. Conversion to the concentration of compound (mg) per kilogram of patient yields the theoretically lowest effective dose estimated to be the ideal bioavailability. Pharmacokinetics, pharmacological and other considerations may actually alter the dosage to be administered at higher or lower values. Suitable dosages are 0.001-1000 mg / kg, preferably 0.1-100 mg / kg, per patient body weight.

Example 1 Materials and Methods

¹ H and ¹³ C NMR spectra were used as solvent and DMSO-d ₆ or CDCl ₃ in Bruker Avance DRX600 unit (600 MHz), Varian UN400 unit (400 MHz) or Varian VXR200 unit (200 MHz) and tetramethylsilane was Recorded as standard. Chemical changes are given in ppm (δ scale) downfield from tetramethylsilane. Coupling constants (J) are expressed in Hz. Flash chromatography is performed using silica gel 60 (0.040-0.063 mm, Merck). Column chromatography is performed using silica gel 60 (0.063-0.200 mm, Merck). Melting points were recorded with a Buchi B-545 melting point apparatus. Mass spectra were recorded for data acquisition and reconstruction using the MassLynx application software on a Micromass QTOF-2 device. Accurate mass measurement is performed with quasi-molecular ions [M + H] ⁺ .

Example 2: Synthesis of Specific Compounds

Compound 1 to 3

1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxylic acid

LiOH (self-stirred solution of ethyl 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxylate (18.44 g, 0.0466 mol) in THF (240 ml) 2.24 g, 0.0932 mol) and H ₂ O (240 ml) were added. The resulting mixture was stirred at 50 ° C. for 16 hours to give a clear solution. After cooling to room temperature, HCl (1N solution, 95 ml) and H ₂ O (240 ml) were added to give a precipitate which was collected by filtration, washed with water and dried under vacuum to give 1- (4-chlorophenyl)- 2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxylic acid (16.83 g, 98% yield) was obtained. mp 138-142 ° C. (decomposition);

Tert-butyl 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxylate

1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxylic acid (20.77 g, 0.0565 mol) and Boc ₂ O (24.63 g, in t-BuOH (275 ml) 0.113 mol) of self-stirred mixture was added DMAP (2.07 g, 0.017 mol), and the obtained mixture was stirred for 16 hours. After concentration in vacuo, toluene was added and the mixture was concentrated again. The residue was purified by column chromatography (CH ₂ Cl ₂ / acetone = 95/5 (v / v)) and recrystallized from diisopropyl ether to give tert-butyl-1- (4-chlorophenyl) -2- Obtain (2,4-dichlorophenyl) -1H-imidazole-4-carboxylate (15.75 g, 66% yield). mp 178-180 ° C .;

Tert-butyl 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methylsulfanyl-1H-imidazole-4-carboxylate

Cooled tert-butyl 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -1H-imidazole-4-carboxylate (10.59 g, 25.0 mmol) in dry THF (100 ml) ( LDA (15.0 ml, 2M solution in heptane / THF, 30.0 mmol) was added to the autostirred solution and the resulting mixture was stirred under N ₂ for 1 h. A solution of (CH ₃ S) ₂ (2.7 ml, 30.0 mmol) in THF (20 ml) was added and the resulting solution was continuously stirred at −40 ° C. for 1 h, brought to room temperature and stirred for a further 16 h It was. NH ₄ Cl saturated aqueous solution (250 ml) was added, and the resulting solution was extracted twice with ethyl acetate (EtOAc). The combined organic layers were washed with water, dried over MgSO ₄ , filtered and concentrated to tert-butyl 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methylsulfanyl-1H -Imidazole-4-carboxylate in 90% yield as an oil, which slowly solidifies;

Tert-butyl 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methylsulfonyl-1H-imidazole-4-carboxylate

Tert-butyl 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methylsulfanyl-1H-imidazole-4-carboxylate (6.00 g) in CH ₂ Cl ₂ (25 ml) , 12.8 mmol) of m-CPBA (6.90 g, 70% grade, 0.282 mol) in CH ₂ Cl ₂ was slowly added and the resulting mixture was stirred for 16 h. The reaction mixture was washed twice with 2N NaOH solution, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (Et ₂ O / petroleum ether = 2/1 (v / v)) to give tert-butyl 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl)- 5-Methylsulfonyl-1H-imidazole-4-carboxylate (4.76 g, 74% yield) was obtained as a white solid. mp 130 ° C .;

Similarly 1 mol equivalent of m instead of 2 mol equivalent of tert-butyl 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methylsulfinyl-1H-imidazole-4-carboxylate Prepared by reaction with -CPBA:

1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -5-methylsulfonyl-1H-imidazole-4-carboxylic acid

Tert-butyl 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methylsulfonyl-1H-imidazole-4-carboxylate (4.76 g) in CH ₂ Cl ₂ (60 ml) , 9.49 mmol) was added excess TFA (9.40 ml, 0.2124 mol) and Et ₃ SiH (3.8 ml, 0.0238 mol). The solution was reacted for 16 hours at room temperature and concentrated in vacuo. Water was added and the precipitate formed was collected by filtration and subsequently dried to give 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methylsulfonyl-1H-imidazole-4- Carboxylic acids are obtained in quantitative yield. mp = 13O < 0 > C (decomposition);

Similarly 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methyl-sulfinyl-1H-imidazole-4-carboxylic acid is prepared.

1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -5-methylsulfonyl-N- (piperidin-1-yl) -1H-imidazole-4-carboxamide (compound One)

Of 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methylsulfonyl-1H-imidazole-4-carboxylic acid (2.23 g, 5.01 mmol) in anhydrous CH ₃ CN (50 ml) N, N-diisopropylethylamine (Hunig's base) (1.90 ml, 11.0 mmol), O-benzotriazol-1-yl-N, N, N ', N'-tetramethyl in succession in a self-stirred suspension Uronium hexafluorophosphate (HBTU) (2.27 g, 5.99 mmol) and 1-aminopiperidine (0.65 ml, 6.03 mmol) were added. After stirring for 16 hours, the resulting mixture was concentrated in vacuo. The residue was dissolved in EtOAc and subsequently washed with aqueous NaHCO ₃ solution, water and brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a crude solid. This solid was further purified by flash chromatography (silica gel, EtOAc) and triturated with methyl tert-butyl ether to give 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5- Methylsulfonyl-N- (piperidin-1-yl) -1H-imidazole-4-carboxamide is obtained in 84% yield. mp 181-185 ° C. (decomposition);

Similarly the following was prepared: 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methyl sulfonyl-N- (cyclohexyl) -1H-imidazole-4-carboxamide (Compound 2) Melting Point: 191-192 ° C.

Similarly the following was prepared: 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methyl sulfinyl-N- (piperidin-1-yl) -1H-imidazole- 4-carboxamide (compound 3) Melting point: 218-221 ° C.

Compound 4 and 5

Racemate 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methylsulfinyl-N- (piperidin-1-yl) -1H-imidazole-4-carbox Amide (Compound 3, 3.86 gram, 0.0075 mol) was added to its enantiomer (-)-1- (4-chlorophenyl) -2- (2,4-dichloro-phenyl) -5-methylsulfinyl-N- ( Piperidin-1-yl) -1H-imidazole-4-carboxamide (Compound 4, 1.3 gram) ([a _D ²⁵ ] = -19 °, c = 0.94 (g / 100ml solvent), methanol; enan Thiomeric excess 97.2%: Melting point: 242-244 ° C.) and (+)-1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methylsulfinyl-N- (piperidine -1-yl) -1H-imidazole-4-carboxamide (Compound 5, 1.4 gram) ([a _D ²⁵ ] = + 23 °, c = 0.94 (g / 100ml solvent), methanol: enantiomeric excess 99.5%: melting point: 243-245 ° C.), respectively, using preparative HPLC and Chiralpak AD 20 μm chiral stationary phases. The mobile phase consists of a mixture of 25% ethanol / heptane (25/75 (v / v)).

Compound 6 to 11

1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -5-methylsulfanyl-1H-imidazole-4-carboxylic acid

Tert-butyl 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methylsulfanyl-1H-imidazole-4-carboxylate (4.00 g) in CH ₂ Cl ₂ (60 ml) , 8.53 mmol) of excess TFA (8.40 ml, 0.111 mol) was added. The solution was reacted for 16 hours at room temperature and subsequently concentrated in vacuo. Water was added and the precipitate formed was collected by filtration and subsequently dried to give 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methylsulfanyl-1H-imidazole-4- Carboxylic acid was obtained in 98% yield. mp = 100 ° C. (decomposition);

1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -5-methylsulfanyl-N- (piperidin-1-yl) -1H-imidazole-4-carboxamide (compound 6)

Of 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methylsulfanyl-1H-imidazole-4-carboxylic acid (1.72 g, 4.16 mmol) in anhydrous CH ₃ CN (45 ml) N, N-diisopropylethylamine (Hunig's base) (1.60 ml, 9.20 mmol), O-benzotriazol-1-yl-N, N, N ', N'-tetramethyl in succession in a self-stirred suspension Uronium hexafluorophosphate (HBTU) (1.89 g, 4.99 mmol) and 1-aminopiperidine (0.54 ml, 5.01 mmol) were added. After stirring for 40 hours, water was added and the resulting mixture was extracted with dichloromethane. The dichloromethane layer was successively washed twice with 1N HCl solution and water, dried over MgSO ₄ , filtered and concentrated to give crude oil. The oil was further purified by flash chromatography (silica gel, EtOAc), triturated with diethyl ether to give 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methylsulfanyl- N- (piperidin-1-yl) -1H-imidazole-4-carboxamide was obtained in 72% yield. mp 170 ° C. (decomposition);

Similarly the following was prepared: 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methylsulfanyl-N- (cyclohexyl) -1H-imidazole-4-carboxamide (Compound 7) Melting Point: 152-154 占 폚.

Similarly the following was prepared: 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-ethylsulfanyl-N- (piperidin-1-yl) -1H-imidazole- 4-carboxamide (Compound 8)

Similarly the following was prepared: 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methylsulfanyl-N- (pyrrolidin-1-yl) -1H-imidazole- 4-carboxamide (Compound 9) Melting point: 158 ° C.

Similarly the following was prepared: 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -5-methylsulfanyl-N- (azpan-1-yl) -1H-imidazole-4 Carboxamide (Compound 10)

Similarly the following was prepared: 1- (4-chlorophenyl) -2- (2-chlorophenyl) -5-methylsulfanyl-N- (piperidin-1-yl) -1H-imidazole-4- Carboxamide (Compound 11) Melting Point: 192- 193 ° C.

The specific compounds described in the above synthesis are intended to further illustrate the present invention in detail, and therefore are not intended to limit the scope of the present invention in any way. Other aspects of the invention will be apparent to those skilled in the art in view of the specification and examples of the invention described herein. Accordingly, the specification and examples are to be considered as illustrative only.

Example 4: Formulations Used in Animal Studies

For oral (p.o.) administration: In the desired amount (0.5-5 mg) of solid compound 1 in a glass tube, several glass beads were added and the solid was ground by vortexing for 2 minutes. After adding 1 ml of a solution of 1% methylcellulose and 2% (v / v) Poloxamer 188 (Lutrol F68) in water, the compound was suspended by vortexing for 10 minutes. The pH was adjusted to 7 with a few drops of aqueous NaOH (0.1 N). Particles remaining in the suspension were further suspended using an ultrasonic bath.

For intraperitoneal (i.p.) administration: To the desired amount (0.5-15 mg) of solid Compound 1 in a glass tube, several glass beads were added and the solid was ground by vortexing for 2 minutes. After adding 1 ml of a solution of 1% methylcellulose and 5% mannitol in water, the compound was suspended by vortexing for 10 minutes. Finally, the pH was adjusted to 7.

Example 5: Pharmacological Test Results

Some CB ₁ / CB ₂ receptor affinity data of the compounds of the prior art and representative compounds of the present invention (average results of three or more independent tests performed according to the above protocol) are listed in the table below. These data show the effect on the CB _1/2 receptor selectivity ratio achieved with the structural modifications that form the basis of the present invention: The novel compounds maintain a high affinity for cannabinoid-CB ₁ receptors, but with CB ₂ receptors Affinity for is substantially reduced.

The compound of Table 1 has the following general structural formula:

Claims (12)

Compounds of formula I and tautomers, stereoisomers and pharmaceutically acceptable salts thereof. Formula I

In Formula I, R ₁ is chloro, bromo, fluoro or hydrogen atom, R ₂ is a chloro or bromo atom or a CF ₃ group, A is a nitrogen atom or a CH group, X is a sulfur atom or sulfoxide (S═O) residue or sulfone (SO ₂ ) residue, Y is hydrogen atom or methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, trifluoromethyl, phenyl, benzyl or pyridyl group, Z is a nitrogen atom or a CH group, n is 1, 2 or 3. 2. A compound according to claim 1 wherein R ₁ is a hydrogen atom or a chloro atom, R ₂ is a chloro atom, Y is a methyl or ethyl group, Z is CH, n is 1, 2 or 3, and A and X are Compounds of formula (I) and their tautomers, stereoisomers and pharmaceutically acceptable salts, having the meanings as defined in claim 1. The compound of formula (I) and tautomers, stereoisomers and pharmaceutically acceptable salts thereof according to claim 2, wherein R ₁ is a chloro atom, Y is a methyl group and A is a nitrogen atom. A pharmaceutical composition comprising, as an active ingredient, a pharmaceutically active amount of one or more compounds of any one of claims 1 to 3 or salts thereof, in addition to a pharmaceutically acceptable carrier and / or one or more pharmaceutically acceptable auxiliary substances. . A process for preparing a pharmaceutical composition according to claim 4, characterized in that the compound of claim 1 is prepared in a form suitable for administration. A compound of any one of claims 1 to 3 or a salt thereof for use as a medicament. Compounds of formula IV useful for the synthesis of compounds of formula I. Formula IV

In Formula IV, Y is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, trifluoromethyl, phenyl, benzyl or pyridyl group, R ₁ , R ₂ , X and Z have the meaning described in claim 1. Compounds of formula (V) useful for the synthesis of compounds of formula (I). Formula V

In Formula V, Y is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, trifluoromethyl, phenyl, benzyl or pyridyl group, R ₁ , R ₂ , X and Z have the meaning described in claim 1. Neurodegenerative disorders such as mental disorders, anxiety, depression, attention deficit, memory disorders, cognitive impairment, appetite disorders, obesity, especially childhood obesity and drug-related obesity, addiction, desire, drug dependence and neurodegenerative diseases, dementia, Dystonia, muscle stiffness, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, Huntington's disease, Tourette syndrome, cerebral ischemia, head injury, spinal cord injury, seizures, neuroinflammatory disorders, plaque sclerosis, viral encephalitis And pain disorders including neuropathic pain disorders, as well as pneumoconitic shock, glaucoma, diabetes, cancer, vomiting, nausea, asthma, respiratory disorders, gastrointestinal disorders, gastric ulcers, diarrhea, sexual disorders and cardiovascular disorders. Claims according to any one of claims 1 to 3 for the manufacture of a pharmaceutical composition for treating other diseases involving cannabinoid neurotransmission, including Total water usage. Use of a compound as claimed in any one of claims 1 to 3 for the manufacture of a pharmaceutical composition for the treatment of appetite disorders, in particular obesity, childhood obesity and obesity by drugs. A compound as claimed in claim 1 for the preparation of a pharmaceutical composition comprising at least one lipase inhibitor for the treatment of appetite disorders, in particular obesity, childhood obesity and obesity by drugs. Use of Use according to claim 11, wherein the lipase inhibitor is orlistat or rifstatin.