UA82908C2 - 1h-imidazole derivatives as cannabinoid receptor modulators - Google Patents

Abstract

The invention relates to a group of 1H-imidazole derivatives which are modulators of cannabinoid receptors, to methods for the preparation of these compounds, to novel intermediates useful for the synthesis of said imidazole derivatives, to methods for the preparation of these intermediates, to pharmaceutical compositions containing one or more of these III-imidazole derivatives as active ingredient, as well as to the use of these pharmaceutical compositions for the treatraent of psychiatric and neurological disorders in which cannabinoid receptors are involved. The compounds have the general formula (I) wherein R, R1-R4 and X have the meanings given in the specification.

Description

Description of the invention

The invention relates to a group of 1H-imidazole derivatives that are cannabinoid receptor modulators, methods 2 of obtaining such compounds, new intermediate compounds suitable for the synthesis of the specified imidazole derivatives, methods of obtaining such intermediate compounds, pharmaceutical compositions containing one or more of these derivatives

N-imidazole as active substances, as well as the use of these pharmaceutical compositions for the treatment of mental and nervous disorders in which cannabinoid receptors are involved.

The invention also relates to the use of the compound described here for the manufacture of a medicinal product that provides a healing effect. This effect is described in this application or is obvious to a person skilled in the art after reading the description and on the basis of general professional knowledge. In particular, the invention relates to a new application for the treatment of a disease or disease state that is described in this application or is obvious to a person skilled in the art after reading the description and on the basis of general professional knowledge. In various embodiments of the invention, the individual compounds described herein are used for the manufacture of a medicinal product.

Derivatives of 1H-imidazole as cannabinoid receptor modulators are known from MO 03/027076. However, the compounds described in (MUO 03/027076) dissolve rather poorly in water. The task of the present invention is to improve the solubility of 1H-imidazole derivatives while maintaining their ability to modulate cannabinoid receptors. The prior art does not indicate how this goal can be achieved.

We unexpectedly found that the introduction of the 5-aminomethyl part to the nucleus of IN-imidazole leads to an increase in its solubility. Moreover, compounds containing a 5-aminomethyl moiety retain their ability to modulate cannabinoid receptors as receptor antagonists, inverse agonists, or partial agonists.

The invention relates to compounds of the general formula (I).

Etc

And a

Kk, M paradise in; (I) so | M o

Kk vch v t. F 4 s where: (ee) - K and K. are the same or different and represent phenyl, thienyl. pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, and these groups may be substituted 1, 2, C or 4 with the same or different substituents Y selected from metallic, ethyl, propyl, methoxy, ethoxy, hydroxy, hydroxymethyl, "hydroxyethyl, chlorine, iodine, bromine, fluorine, trifluoromethyl, trifluoromethoxy, methylsulfonyl, phenyl or cyano groups, or K represents naphthyl, or K represents C 4.8 branched or linear alkyl t c group, Cz.; cycloalkyl group, C3, cycloalkyl-C10 alkyl group, C1 branched or linear C1 heteroalkyl group, C17 heterocycloalkyl group or C1 heterocycloalkyl-C. o an alkyl group, and these groups can be replaced by a fluorine atom or groups of SE3 or OH,.- K2 and KZ are the same or different and represent a C..5 branched or linear alkyl group that can be replaced by a hydroxy group or 1-3 49 atoms fluorine, or Co" represents a C..3 branched or linear alkoxy group, provided that Kz represents H co or a methyl group, c - Co and Kz, together with the nitrogen atom to which they are attached, form a saturated or unsaturated non-aromatic, monocyclic or bicyclic , a heterocyclic group with 5-10 atoms in the ring, and this heterocyclic group contains in the ring one or two identical or different heteroatoms from the group (M, O, 5) and can be substituted by C.. with an alkyl group, a hydroxy group or a fluorine atom, - K. represents H or a methyl, ethyl, propyl, isopropyl or p-butyl group, so - X represents one of the subgroups (i) or (ii), 7 o o i r Dol z Kk M z o i che 7 - () (i) b5 where: - K5 represents a hydrogen atom, or C. 8 a branched or linear alkyl group, C.4.z -alkyl-5O5- Si. alkyl group, C3.7 cycloalkyl group, C3.; a cycloalkyl-C.»2alkyl group, a heterocycloalkyl-C.»2alkyl group, and these groups can be replaced by a hydroxy, methyl or trifluoromethyl group or a fluorine atom, and

Св -heterocycloalkyl- This alkyl group contains one or two heteroatoms from the group (0, M, 5), or K5 represents a phenyl, benzyl, phenethyl or phenylpropyl group, which can be substituted in the phenyl ring by 1-3 substituents U, where ХУ has the above values, or K85 represents a pyridyl or thienyl group, 70 - K6 represents a hydrogen or C atom). from a branched or linear alkyl group, - KE; represents a hydrogen atom, C..8 a branched or linear alkyl group or C3. a cycloalkyl-C..»-alkyl group, a C 1 branched or linear alkoxy group, a C 3.cycloalkyl group, a C.bicycloalkyl group,

C. obicycloalkyl-Ce oralalkyl group, Svotricycloalkyl group, Cb-th tricycloalkylmethyl group, which may contain one or more heteroatoms from the group (0, M, 5) and may be substituted by a hydroxy group, 1-3/5 methyl groups, an ethyl group or 1-3 fluorine atoms, or K, represents a phenyl, phenylamine, phenoxy, benzyl, phenethyl or phenylpropyl group, which can be arbitrarily substituted in the phenyl ring by 1-3 substituents Y, where Y has the above values, or K7 represents a pyridyl or thienyl group , or K, represents the group MKaCoe, where Ka and Co, together with the nitrogen atom to which they are attached, form a saturated or unsaturated monocyclic or bicyclic, heterocyclic group with 4-10 atoms in the ring, and this 2o Heterocyclic group contains in the ring one or more heteroatoms from the group (0, M, 5) and C..3 can be replaced by a branched or linear alkyl group, a phenyl group, a hydroxy group, a trifluoromethyl group or a fluorine atom, or

Kv and K; together with the nitrogen atom to which they are attached, form a saturated or unsaturated monocyclic or bicyclic, heterocyclic group with 4-10 atoms in the ring, and this heterocyclic group contains in the rings one or more identical or different heteroatoms from the group (0, M , 5) and can be replaced by C..3 alkyl phenyl, amino group, hydroxy group, trifluoromethyl group or a fluorine atom, and their pharmaceutically (8) acceptable salts and prodrugs.

The invention covers all compounds of formula (1), racemates, mixtures of diastereomers and individual stereoisomers. Therefore, compounds in which the substituents of potentially asymmetric carbon atoms are in the K-configuration or in the C-configuration belong to the scope of the invention.

Prodrugs are drugs that do not act by themselves, but are converted into one or more active metabolites. Prodrugs are biodegradable derivatives of molecules of medicinal substances, which are used to overcome some obstacles in favor of the molecule of the original medicinal substance. These barriers include, in particular, solubility, permeability, stability, presystemic metabolism, and targeting limitations (|Meaisipa| s

Spetivigu: Rgipsirievie and Rgasiiise 1994, I5VM 0-85186-494-5, Ba: R. O. Kipo, p. 215; 9. 5ieia, "Rgodgydz az so

Ipegareshiisv", Ekhrep Orip. Tag. Raiepiv, 14(3), 277-280, 2004; R. ENtaueg ei ai., "Pevzvopv Ievagpei yiut tagkebgei apa ipmeziidayopa! rgodgidve", U.Meya.Spet., 47, 2393-2404, 2004). Prodrugs, that is, compounds that, when administered to humans by any known route, are metabolized into compounds of formula (1), are part of this invention. In particular, this refers to compounds with primary or secondary amine or hydroxy groups. Such "compounds are capable of reacting with organic acids to give compounds of formula (1) where an additional group - c is present, which is easily cleaved after introduction into the body, for example, such as amidine, enamine , Mannich base, hydroxylmethylene derivative, O-(acyloxymethylenecarbamate), carbamate, ether, amide or enaminone derivative. In particular, the invention relates to compounds of formula (I), where X represents subgroup (ii) and all other symbols have the meanings given above .

Thus, the invention relates to compounds of the formula (I), where X represents subgroup (ii) and K represents phenyl, co-thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, and these groups can be substituted by 1, 2, 3 or 4 identical or various substituents on Y selected from metal, ethyl, propyl, methoxy, co ethoxy, hydroxy, hydroxymethyl, hydroxyethyl, chlorine, iodine, bromine, fluoro, trifluoromethyl, trifluoromethoxy, methylsulfonyl, phenyl or cyano groups, or K is naphthyl , and all other marks

Have the values given above. o General description of the synthesis. Compounds of formula (I) and synthetic intermediates of formulas (II) and (MI), respectively, can be obtained in various ways. Synthesis of structurally similar imidazoles as cannabinoid receptor modulators is described in MUO 03/027076 and MO 03/063781|. The synthesis of structurally similar imidazoles as anti-anxiety drugs is described in MO 03/0401071. The choice of a specific method depends on such factors as the compatibility of functional groups with the reagents used, the possibility of using protective groups, catalysts, activators and

HF) of binding reagents and features of the structure of the target compounds. Learn more about activation methods and

For linking amines with carboxylic acids, see: a) M. Vodapz2Kku, A. Vodapz2aKu: Te Rgasiise oi Reriiide Zupipevziv. Zrhipgeg-Megiag, Mem MogK, 1994; IZVM: bo /9-387-57505-7;

B) K. Akaiyi ei a, Tegganedhop G ekK. (1994), 35. 3315-3318; c) R. AIbegisio ei a!., Tehgapedgop I! Hey. (1997), 38, 4853-4856).

For more information about trimethylaluminum-activated AT(CH3) from the amidation reaction of ethers, see 9. I.Yi emip, E. Tygov,

Z.M. Mueipger, Zupii Sotyutip. 1982, 12, 989-993. Regarding nucleophiles, electrophiles and leaving groups, see: 65 IM.V.Ztyi apa 9. Magsp: Admapsedy ogdapis spetivigu, r.275, 5" ed., doyp Uuypyeu b Bop5, Mem MogKk, IZVM: 0-471-58589- 0. For detailed information on the addition and subsequent removal of protective groups during organic synthesis, see TMM.OSgeepe apa R.O.M.Mutsiv, "Rgoiesiime OSgotsirz ip Ogdapis Zupipeviv", with eaiiop, dop UMPeu b Bopvz Ips.,

Mem HogkK, 1999).

An acceptable way of synthesizing compounds according to the invention is as follows:

The path of synthesis of A

The reaction of the compound of formula (II) d

M OK, vyk

Kk, where K, Ku, Ka have the values given above, and Ko represents a C..4 branched or linear alkyl group or a benzyl group with a regioselective brominating compound, for example, M-bromosuccinimide (MV5), in an organic solvent, for example, CCi /,, in the presence of an initiator - a free radical, for example, dibenzoyl peroxide, can give a compound of the formula (II), c o (o)

M OK,

A and her 1 and F p

Kk K, so where K, Ku, Ku, Ko have the meanings given above. The reaction of the compound of the formula (II) with the amine of the general formula

K2ZMN, can give a compound of the general formula (IM), « o - s ' M i in MA (M) (se) 1 M 2 t

Fo H vk 4 o (Che where K, Ku, K2, Kz, K,, K/o have the values given above.

Compounds of the general formula (IM), obtained by the synthesis of A, can be converted into compounds of the general formula (I), where X represents the subgroup (ii), by the techniques described in (MO 03/0270761. 22 Path of synthesis B

The reaction of the compound of the formula (IM), where K, Ku, Ko, Kz, K. have the values given above, and Ko represents the i) hydrogen atom, ko 60 b5

95 M 10 you CC,

Kk, with M-methoxy-M-methylamine can give a compound of the formula (M)

M. 7 M O-

K; MA.

M 2773 s | (o) c, where K, Ku, Ko, Kz and K. have the values given above. The reaction of a compound of the formula (M) with an organometallic compound of the general formula K5-MoVg (Grignard reagent) or B5-Ii (organolithium reagent) can give a compound of the general formula (I), where X represents subgroup (i). Such a reaction is preferably carried out in an M2 atmosphere in an anhydrous inert organic solvent. (22)

The synthesis path of C with 2-aryl-(1H)-imidazole-4-carboxylate can be obtained according to the method described in Teigapeadgop Hek. (1971)|,

Zo 18, 1339-1440 (Neiipaei apa Spip). Subsequent derivatization (e.g., M-arylation or M-alkylation) of atom 89

M belonging to imidazole itself can give compounds of the formula (MI). The reaction of the compound of the formula (MI) - p ok i 19 g» M a i v (mu i x. schi t v (Se) ish where K and K. have the values given above, and K./o represents C.4.4 branched or a linear alkyl group

Ge) or a benzyl group, with a non-nucleophilic base, for example, lithium isopropylamide (ILA), and then with an electrophile, for example, formic acid ethyl ether, in an inert anhydrous organic solvent such as TNE can give a compound of the general formula (MII)

F) ko 60 b5 o, and OK,

M

EX (MI) 1

Кк в 4 where К, Ку, Ку, Ко have the values given above in this path of synthesis. Reductive amination of a compound of the general formula (MII) with an amine of the general formula K2KZMN in the presence of a reducing agent, for example, MaSMVNZ, can give a compound of the general formula (IM) about

About 10

M

M) 1 M o iach

Кк, о зо where К, Ку, Ко, Кз, Ку, Кио have the values given above in this path of synthesis.

Compounds of the general formula (IM), obtained by the synthesis of C, can be converted into compounds of the general formula (I), where X represents the subgroup (ii), by the methods described in (MO 03/0270761. b

Pharmaceutically acceptable salts can be obtained by methods known to those skilled in the art, for example, by mixing the compound of the invention with a suitable acid, for example, an inorganic acid such as hydrochloric acid or an organic acid. co

Due to their ability to modulate cannabinoid receptors, the compounds of the invention can be used in the treatment of mental disorders such as psychosis, confusion, depression, attention deficit, memory disorders, perception disorders, lack of appetite, fear, in particular, adolescent fear and fear of drug origin, alcoholism , hypersexuality, drug addiction, neurological disorders, such as "neurodegenerative disorders, dementia, dystonia, muscle spasms, tremors, epilepsy, multiple sclerosis, - with traumatic brain damage, stroke, Parkinson's disease, Alzheimer's disease, Huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral apoplexy, traumatic brain injury, stroke, spinal cord injuries, neuroinflammatory disorders, multiple sclerosis, viral encephalitis, muscle disorders, as well as pain syndromes, including neuropathic pain, and other diseases of the central nervous system associated with with cannabinoid neurotransmission, including the treatment of septic shock, ch aucoma, cancer, diabetes, vomiting, nausea, asthma, respiratory diseases, gastrointestinal diseases, sexual disorders, liver cirrhosis, stomach ulcers, diarrhea and cardiovascular diseases. The ability of the compounds according to the invention to modulate cannabinoid receptors makes them particularly useful in the treatment of anxiety, adolescent anxiety, and anxiety of drug origin, in combination with lipase inhibitors. Among the compounds that can be included in such a combination, we can cite, for example, (orlistat is a synthetic lipase inhibitor, lipase inhibitors isolated from microorganisms, for example, lipstatin so (from Zigeriotuses (ohuigisipi), ebelaston B (from Bigeriotuses arigamiepsiv), synthetic derivatives of these compounds, as well as extracts of plants known to inhibit lipase, such as extracts of Airipia oipsipagat, or compounds isolated from these extracts, for example, 3-methylethergalantin (from A. oiPisipagat). 5B The compounds of the invention can be administered in forms suitable for assimilation, by known methods with the participation of excipients and/or liquid or solid carriers.(F) The compounds of the invention are usually administered as part of pharmaceutical compositions that constitute an important part of the invention and have novelty due to the presence of compounds, in particular, individual compounds of the present invention Among the types of pharmaceutical compositions, one can list, in particular, tablets, chewable tablets, capsules, solutions, parenteral solutions, suppositories, suspensions, etc. and others described herein or apparent to one skilled in the art upon reading the description based on general professional knowledge. In the embodiments of the invention, a pharmaceutical kit is provided in one or more containers filled with one or more components of the pharmaceutical composition according to the invention. Such containers may be accompanied by a variety of printed materials, such as instructions for use, or notices in a form prescribed by the government body that regulates the production, 65 Use or sale of pharmaceutical products containing the authorization of this body for the manufacture, use or sale of the drug for human consumption or animals.

Pharmacological methods

Affinity for CB cannabinoid receptors. ip migo

Affinity of compounds according to the invention to receptors of CB| cannabinoids can be determined using preparations from the membranes of Chinese hamster ovary cells (HOC) in which the human cannabinoid receptor SVi is stably transfected in association with | ZNISR-55,940 as a radioligand. After incubation of freshly prepared preparations of cell membranes with the I"NiI-ligand, with or without the addition of compounds according to the invention, the bound and free ligands are separated by filtration through glass fiber filters. The radioactivity of the filter is measured with a liquid scintillation counter. 70 Affinity for CB" cannabinoid receptors ip migo

The affinity of the compounds of the invention for the cannabinoid receptor SVg can be determined using preparations from Chinese hamster ovary (HOC) cell membranes in which the human cannabinoid receptor SVg is stably transfected in association with | ZNISR-55,940 as a radioligand. After incubation of freshly prepared preparations of cell membranes with IZNiI-ligand, with or without the addition of compounds according to the invention, the bound and free 72 ligands are separated by filtration through glass fiber filters. The radioactivity of the filter is measured with a liquid scintillation counter.

Antagonism to CB cannabinoid receptors. ip mygo

Antagonism to SV receptors. ip migo is determined on the human SV receptor cloned in Chinese hamster ovary (HCH) cells. YAC cells are grown in Dulbecco's modified Eagle's medium (OMEM) with the addition of 1095 heat-inactivated fetal calf serum. The medium is aspirated and replaced with OMEM, to which, instead of fetal calf serum, | ZNI-arachidonic acid, and incubated all night in an oven with cell culture (595 COg/9595 air; 37 9С; atmosphere saturated with water). During this time

I"NI-arachidonic acid is rooted to the phospholipids of the membranes. On the day of the test, the medium is aspirated and the cells are washed three times with 0.5 ml of OMEM containing 0.295 bovine serum albumin (B5A).

Stimulation of CB 4 MM 55,212-2 receptors leads to activation of RiIA" with subsequent release (8)

IZNI-arachidonic acid to the environment. This UMIM 55,212-2-induced release is counteracted by CB receptor antagonists. depending on its concentration.

Antagonism to SV receptors. ip mimo so

Antagonism to SV. ip mimo is determined by CP-5 5,940 induced hypotension in rats. Male rats with normal blood pressure (225-300 g; Nagiap company, Horst, the Netherlands) are anesthetized with pentobarbital (vOmg/kg subcutaneously). Blood pressure is measured through a cannula inserted into the left carotid artery with the Teh!

Zresigatea OTH-riiz (Zresigatea V.M., Bilthoven, the Netherlands). After amplification in the Mipop Kopadep amplifier (type AR-6210; Mipop Kopadep V.M., Amsterdam, the Netherlands), the blood pressure signal is recorded on a personal computer (Sotrad UOezkrgo 3865), using the data collection program Ro- Me-May (Ro-Me-Man so

Ips., Storrs, USA). The pulse is calculated from the pulsating pressure signal. All compounds are administered orally in the form of a microsuspension in 195 methylcellulose 30 minutes before anesthesia, that is, 60 minutes before the administration of the CB receptor agonist. SR-55,940. The injection volume is 10 ml kg. After hemodynamic stabilization, the agonist of the SVi receptor SR-55,940 (0.1 mg kg" intravenously) is administered and the hypotensive effect is determined. sogopagu and segerga | mazodiiayop tepyiayeea Bu - s sappabipoii SVI geserioge. Eitsg. U. Rpagtasoi. 2001, 423, 203-210; Iapde, 9. N.M. egvaiYi, ). Meyd. Spet. 2004, 47, h 627- 643). (Partial) agonism to cannabinoid receptors SV. ip mimo. -" Agonistic or partially agonistic activity of compounds according to the invention on cannabinoid receptors can be determined by published methods, for example, the study of cannabimimetic effects of ip mimo (MMiIeu, u. |. egai. ,). Rpagtasoi. Ehr. TNeg. 2001, 296, 1013). o Determination of solubility in water The compound is dissolved in DMSO, obtaining initial solutions of 1Omg/ml. They are distributed on several plates.

Perform several DMSO dilutions to 5, 2.5, 1.25, 0.625, and 0.3125 mg/ml, respectively. The original and each of the (se) diluted solutions are diluted 100 times with water or water with a buffer content. In each case, an aqueous solution containing 106.95 DMSO and 100, 50, 25, 12.5, 6.25 and 3.125 μg of the compound/ml is obtained, respectively. The amount of sediment is determined on each plate. Measurements are carried out at pH-7 with NEREZ buffer and at pH-2 with hydrochloric acid. Solubility in water is expressed in µg/ml in the table below.

Individual compounds, the synthesis of which is described below, illustrate the invention in more detail, but in no way limit its scope. 22 Example 1: Synthesis of individual compounds

Synthesis of compound 1 o Part A: Ethyl 5-bromomethyl-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate. To the mixture 2.05

Kkz g (5.00 mmol) of ethyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylate in 25 ml of CC is added with magnetic stirring to 1.34 g ( 7.53 mmol) of M-bromosuccinimide (MV5) and 10.0 mg (0.0310 mmol) of 7590 60 dibenzoyl peroxide and heat the resulting mixture under reflux for 38 hours. The precipitate obtained is filtered. The filtrate is successively washed with brine and water, dried over M950O, filtered and concentrated in a vacuum. The precipitate is purified by evaporative chromatography (CH2Cl2/acetone - 98:2 vol.), obtaining 1.29 g (yield 5395) of ethyl-5-bromomethyl-1-( 4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate in the form of an amorphous solid mass. "H-NMR (200 MHz, SOSIv): 5 1.45 (6.9 - 7 Hz, ZH), 4.48 (d, U - 7 Hz, 2H), bo 4.72 (v, 2H), 7, 18-7.43 (t, 7H).

Part B: To a solution of 11.69 g (23.Omol) of ethyl 5-bromomethyl-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate in 40 ml of acetonitrile is added with 5.2 ml (30 mmol) of diisopropylethylamine (OIREA) and 1.7 g (23.9 mmol) of pyrrolidine were added with magnetic stirring and the resulting solution was kept at room temperature for 2 hours. Add 250 g of water and extract the resulting mixture three times with dichloromethane. The dichloromethane phases were combined, dried over vacuum, filtered and concentrated in vacuo. After purification by evaporative chromatography (petroleum ether/EuAc 20:80 vol.), 3.7 g (yield 3290) of ethyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-(pyrrolidine-1- ylmethyl)-1H-imidazole-4-carboxylate. "H-NMR (200 MHz, 70 SOCIz): 5 1.42 (5 9-7 Hz, ZN), 1.62-1.72 (t, ZN), 2.42-2.50 (t, 4H ), 3.83 (v, 2H), 443 (a,.9U - 7 Hz, 2H), 7.17-7.40 (t, 7H).

Part C: 0.91 ml (8 mmol) of cyclohexylamine is dissolved in 20 ml of dichloromethane and 4 ml (8 mmol) of a 2 M solution of (CH3)zA! in heptane. The mixture is stirred for 10 minutes. at room temperature and add 1.8 g (3.8 mmol) ethyl-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-(pyrrolidin-1-ylmethyl)-1H-imidazol-4 -carboxylate. The resulting 75 mixture is stirred at room temperature for 16 hours, poured into an aqueous solution of MansSoOz, stirred

REFERENCE and filtered through Nuyo filter. The filtrate was extracted twice with dichloromethane. The organic phases were dried over NaCl, filtered and concentrated in vacuo. After purification by evaporative chromatography (petroleum ether/20:80 vol.), 1.06 g are obtained (yield 5390)

M-cyclohexyl-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-(pyrrolidin-1-ylmethyl)-1H-imidazole-4-carboxamide - compounds 1. Melting point 155-1579C. with

I N o) ih si t so o (2) si her so

In a similar way, compounds 2-6 are obtained: 2. M-cyclohexyl-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-(M-ethyl,

M-methylaminemethyl)-1H-imidazole-4-carboxamide. Melting point 135-136. « 8 s and o ; x shchi m z SI s r 2 V ii") 3.

GF! MI-(piperidin-1-yl)-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-M,M-dimethylaminomethyl)-1H-imidazole-4-carboxamide.

Melting point 163-1660C. ko 60 b5 and m-M ich

SI M

With and 4.

K-cyclohexyl-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-(M,M-dimethylaminomethyl)-1H-imidazole-4-carboxamide. "H-NMR (400 MHz, SOSIv): 5 1.12-1.68 (t, 6H), 1.72-1.80 (t, 2H), 1.99-2.06 (t, 2H) , 2.18 (v, 6H), 3.65 (v, 2H), 3.88-4.00 (t. IN), 7.22-7.37 (t, 8H).

M (ge)

SI o b o s so

B. « 20 M-(piperidin-1-yl)-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-(pyrrolidin-1-ylmethyl)-1H-imidazole-4-carboxamide. 2 Z7Z s NOI. "n-NMR (400 MHz, OM5Odv): 5 1.46-1.56 (t, 2H), 1.79-1.96 (t, 8H), 2.90-3.00 (t, 2H) , 3.36-3.50 (t, 6H), 4.57 (Bg 8, 2H), 7.45-7.60 (t, 6H), 7.70 (a, 9-8 Hz, IN) , 10.95 (rg in, 2H). ;" what about

SI sh-M, oh M kh n o! m che SI

М 2 Not 60 6. M-(piperidin-1-yl)-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-(M-ethyl,

M-methylaminemethyl)-1H-imidazole-4-carboxamide. TN-nMR (400 MHz, SOSI): δ 0.86 (, 9-7 Hz, ЗН), 1.38-1.46 (t, 2Н), В, 72-1.78 (t, 4Н), 2.14 (in, ЗН), 2.36 (a, 9-7 Hz, 2Н), 2.82-2.86 (t, 4Н), 3.72 (in, 2Н), 7.21-7 .31 (t, 6H), 7.34 (9, 9-2 Hz, IN), 8.16 (rg in, IN). b5 o

M-M; I'm an M.Sc.

M si 70 ts Y Z

SI

Example 2: Determination of solubility in water

The solubility in water of two of the compounds of the general formula (I), namely compounds 1 and 4, and compound 1 -(4-chlorophenyl)-2-(2,4-dichlorophenyl)-M-cyclohexyl-1H-imidazole-4- carboxamide (compound C according to (MO 03/0637811) is determined by the above method. The results are presented in Table 1.

Table 1: solubility in water (μg/ml

Name of the compound Solubility in water, μg/ml at: nn I MO: NI Uh s; LOOK AT

M-cyclohexyl-1-(4-chlorophenyl)-2-2,4-dichlorophenyl)-5-2100 (pyrrolidin-1-ylmethyl)- I H-imidazole-4-carboxamide (compound 1 o

M-cyclohexyl-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-(M,M-2100 dimethylaminomethyl)- I H-imidazole-4-carboxamide (compound 4)

M-cyclohexyl-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H- 25 25 so imylazole-4-carboxamide (according to UMO 03/0637813 o

Example 3: Pharmacological data (22)

The results of pharmacological tests of a subset of compounds according to the invention, obtained by the above method, are presented in Table 2. co

Claims (12)

The formula of the invention 1. Compounds of the general formula (I) « 40 х ,( - - 1 h Ж я и? в. MM в х 45 в, Ra so . where: КкЗз К and Ки are the same or different and represent phenyl, thienyl, pyridinyl . hydroxyethyl, chlorine, iodine, bromine, fluorine, trifluoromethyl, trifluoromethoxy, methylsulfonyl, phenyl or cyano groups, or K represents naphthyl, or K represents C..8 branched (o or linear alkyl group, C3-cycloalkyl group, C3-7-cycloalkyl -C..»-alkyl group, C.sub.3 branched or linear heteroalkyl group, C.U.-heterocycloalkyl group or C.sub.-heterocycloalkyl-C.4 o-alkyl group, and these groups can be replaced by a fluorine atom or CE" or OH groups , E" and K" are the same or different and represent H, C..5 a branched or linear alkyl group, which m i.e., HF) is substituted by a hydroxy group or 1-3 fluorine atoms, or if Co represents a C.4.3-branched or linear alkoxy group, provided that Kz represents H or methyl in the GROUP, or E" and Kz together with a nitrogen atom, to to which they are attached, form a saturated or unsaturated non-aromatic, monocyclic or bicyclic, heterocyclic group with 5-10 atoms in the ring, and this heterocyclic group contains in the ring one or two identical or different heteroatoms from the group (M, O, 5) and can be replaced C.. with an alkyl group, a hydroxy group or a fluorine atom, in5 KE. represents H or a methyl, ethyl, propyl, isopropyl or n-butyl group, X represents one of the subgroups (i) or (ii) o (), o , (her) And dov i - Kk, where: K5 represents a hydrogen atom or C).4.8 branched or linear alkyl group, C.4.z-alkyl-505-C4.-alkyl group, Cz. ;-cycloalkyl group, C3-cycloalkyl-C.4 o-alkyl group, Sv 7-heterocycloalkyl-C 4 5-alkyl group, and these groups can be substituted by a hydroxy, methyl or trifluoromethyl group or a fluorine atom, and Sv -heterocycloalkyl -C..u-alkyl group contains one or two heteroatoms from the group (0, M, 5), or Ke represents a phenyl, benzyl, phenethyl or phenylpropyl group, which can be substituted in the phenyl ring by 1-3 substituents U, where U has the above values, or K5 represents a pyridyl or thienyl group, Ke represents a hydrogen atom or C..3 a branched or linear alkyl group, K represents a hydrogen atom, C 48 a branched or linear alkyl group or 19 C3.v-cycloalkyl-C. 4.o-alkyl group, C.i.8 branched or linear alkoxy group, C.sub.3-cycloalkyl group, C.sub.10-bicycloalkyl group, C.sub.10-bicycloalkyl-C.sub.4-2-alkyl to the group, C10-tricycloalkyl group, Sv.1o-tricycloalkylmethyl group, which can contain one or more heteroatoms from the group (0, M, 5) and can be substituted by a hydroxy group, 1-3 methyl groups, an ethyl group or 1-3 fluorine atoms, or Kk. represents a phenyl, phenylamine, phenoxy, benzyl, phenethyl, or phenylpropyl group, which may be arbitrarily substituted in the phenyl ring by 1-3 substituents U, where U has the above values, or K7 represents a pyridyl or thienyl group, or K represents a MKaKao group, where Ka and Ka, together with the nitrogen atom to which they are attached, form a saturated or unsaturated monocyclic or bicyclic, heterocyclic group with 4-10 atoms in the ring, and this heterocyclic group contains in the ring one or more heteroatoms from the group (0, M, 5 ) and C.4.3 can be replaced by a branched or linear C 29 alkyl group, a phenyl group, a hydroxy group, or a trifluoromethyl group or a fluorine atom, or He) Kv and K; together with the nitrogen atom to which they are attached, form a saturated or unsaturated monocyclic or bicyclic, heterocyclic group with 4-10 atoms in the ring, and this heterocyclic group contains one or more heteroatoms from the group (0, M, 5) in the ring and can be substituted by a branched or linear Si with alkyl, phenyl, amino group, hydroxy group, trifluoromethyl group or a fluorine atom, co and all their stereoisomers, as well as pharmaceutically acceptable salts and prodrugs. at 2. Compounds according to claim 1 of the general formula (I), where X represents the subgroup (ii), and all other symbols have the values given in claim 1. (22 C. Compounds according to claim 1 of the formula (I), where X represents subgroup (i) and K represents phenyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, and these groups can be substituted by 1, 2, З or 4 by the same or different substituents Y selected from methyl, ethyl, propyl, methoxy, ethoxy, co hydroxy, hydroxymethyl, hydroxyethyl, chlorine, iodine, bromine, fluorine, trifluoromethyl, trifluoromethoxy, methylsulfonyl, phenyl or cyano groups, or K represents naphthyl, and all other marks have the meaning given in claim 1. " 4. Compounds of the general formula (IM) o SCHO o, s OK z M ra MOR KE, Y so e В, ki de K, Ku, K», Kz, Ka have the values given in claim 1, and Ko represents a hydrogen atom , C. a branched or He linear alkyl group or a benzyl group, suitable for the synthesis of compounds of the general formula (1). 5. Compounds of the general formula (MII) and a) (M) 12; OR M ra v. KE. Ф) in c, where Ku and K. have the values given in claim 1, and K represents C.8 a branched or linear alkyl group, in C3.--cycloalkyl group, C3.-cycloalkyl-C.4. o-alkyl group, C-branched or linear heteroalkyl group, C-heterocycloalkyl group or C-heterocycloalkyl-C 4 5-alkyl group, and these groups can be replaced by a fluorine atom or CE" or OH groups, and K.o represents C ..4 a branched or linear alkyl group or a benzyl group. 6. A pharmaceutical composition containing at least one compound specified in any of claims 1-3 as an active ingredient. 7. The compound according to any of claims 1-3 or its salt for use as a medicinal product. 8. Use of the compound specified in any of claims 1-3 for the preparation of a pharmaceutical composition for the treatment of disorders associated with cannabinoid neurotransmission. 9. Application according to claim 8, which differs in that the specified disorders are psychosis, confusion, depression, attention deficit, memory disorders, perception disorders, lack of appetite, fearlessness, in particular adolescent fearlessness and fearlessness of drug origin, bad habits, alcoholism, hypersexuality, drug addiction, neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasms, tremors, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, Huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral apoplexy, 7/0 Craniocerebral trauma, stroke, spinal cord injuries, neuroinflammatory disorders, multiple sclerosis, viral encephalitis, muscle disorders, as well as for the treatment of pain syndromes, including neuropathic pain, and other diseases of the central nervous system, including related to cannabinoid neurotransmission, including treatment of septic shock, glaucoma, cancer, diabetes, vomiting, nausea, asthma and, respiratory diseases, gastrointestinal diseases, sexual disorders, liver cirrhosis, stomach ulcers, diarrhea and 7/5 cardiovascular diseases. 10. The application according to claim 8, which is characterized by the fact that the specified disorders are eating disorders, in particular anxiety, adolescent anxiety and drug-induced anxiety. 11. The use of the compound specified in claim 1 for the preparation of a pharmaceutical composition for the treatment of eating disorders, in particular anxiety, adolescent anxiety and anxiety of medical origin, which is characterized by the fact that the specified pharmaceutical composition also contains at least one lipase inhibitor. 12. Application according to claim 11, which differs in that the specified lipase inhibitor is orlistat or lipstatin. с шчи о со (ав) b» с Зо (ге) - a o io) (se) (av) 12; io) because b5