MXPA06009508A - Imidazoline derivatives having cb1 - Google Patents

Abstract

The present invention relates to 1,2,4-tri-substituted imidazoline derivatives, to methods for the preparation of these compounds, to novel intermediates useful for the synthesis of said imidazoline derivatives, to methods for the preparation of these intermediates, to pharmaceutical compositions containing one or more of these imidazoline derivatives as active ingredient, as well as to the use of these pharmaceutical compositions for the treatment of psychiatric and neurological disorders. The compounds have the general formula (I) wherein the symbols have the meanings given in the specification.

Description

DERIVATIVES OF IM1DAZOLINA THAT HAVE ANTAGONIST ACTIVITY DESCRIPTIVE MEMORY The present invention relates to 1, 2,4-trisubstituted imidazoline derivatives as CB-? Antagonists to methods for the preparation of these compounds and to novel intermediates useful for the synthesis of said imidazoline derivatives. The invention also relates to the use of a compound disclosed therein for the manufacture of a medicament that provides a beneficial effect. A beneficial effect is revealed in this or is apparent to a person skilled in the art from the descriptive memory and general knowledge of the art. The invention also relates to the use of a compound of the invention for the manufacture of a medicament for treating or preventing a disease or condition. More particularly, the invention relates to a new use for the treatment of a disease or condition disclosed therein or apparent to a person skilled in the art from the specification and general knowledge of the art. In embodiments of the invention, specific compounds disclosed therein are used for the manufacture of a medicament useful in the treatment of disorders in which cannabinoid receptors are involved or which can be treated by manipulation of these receptors.

Multisubstituted imidazoline derivatives are known from WO 03/101954 and WO 03/101969. The compounds described in these applications are potent inhibitors of the transcription factor NF-KB, making them useful in the treatment of certain types of tumors. Said imidazoline derivatives also have potent activities as anti-inflammatory agents and antibiotics, which leads to an additional set of indications in which said derivatives are likely of therapeutic interest, including inflammatory and infectious diseases. It was not shown that the compounds described in the above-mentioned patent applications have any affinity for cannabinoid receptors, and therefore are unlikely to have therapeutic value in disorders in which these cannabinoid receptors are involved. It was the object of the present invention to identify imidazoline derivatives with potent modulating activity of the CB-β cannabinoid receptor essentially maintaining the physico-chemical properties that make some imidazoline derivatives useful therapeutic agents. It has now been surprisingly found that a potent antagonism or inverse agonism of CB-i cannabinoid receptors is present in the novel 4,5-dihydro-1 H-imidazole derivatives of formula (I): ' (I where: Ri and R2 independently represent phenyl, thienyl or pyridyl, groups which may be substituted with 1, 2 or 3 substituents Y, which may be the same or different, from the group consisting of C1-3 alkyl or branched C-? -3 alkoxy or linear, phenyl, hydroxy, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or Ri and / or R2 represent naphthyl, X represents one of the subgroups (i ) or (ii), wherein: R3 represents a hydrogen atom or a branched or linear C-? -3 alkyl group, - R represents an alkyl group of C? -8 or C3-8 cycloalkyl-C? -2 branched or linear alkyl, branched or linear C-? - 8 alkoxy, C3-8 cycloalkyl, C5-? 0 bicycloalkyl, C6-? tricycloalkyl, or groups which may contain one or more heteroatoms of the group (O, N, S) and which they may be substituted with a hydroxy group, 1-3 methyl groups, an ethyl group or 1-3 fluorine atoms, or R represents a phenyl, phenoxy, benzyl, phenethyl or phenylpropyl group, optionally substituted on its phenyl ring with 1-3 substituents Y, where Y has the above-mentioned meaning, or R4 represents a pyridyl or thienyl group, or R4 represents a group NR5R6 where Rs and - together with the nitrogen atom to which they are attached - form a heterocyclic, monocyclic or bicyclic, saturated or unsaturated group having 4 to 10 ring atoms, heterocyclic group containing one or two heteroatoms of the group (O, N, S) and which may be substituted with a branched or linear C1-3 alkyl group, phenyl, hydroxy or trifluoromethyl or a fluorine atom, or R3 and R - together with the nitrogen atom to which they are attached - form a heterocyclic group , monocyclic or bicyclic, saturated or unsaturated having 4 to 10 ring atoms, heterocyclic group containing one or two heteroatoms of the group (O, N, S) and which may be substituted with a branched C? -3 alkyl group or linear, phenyl, amino, hydroxy or trifluoromethyl or a fluoro atom, R7 represents a benzyl, phenyl, thienyl or pyridyl group, which groups can be substituted on their aromatic ring with 1, 2, 3 or 4 Y substituents, where Y has and The meaning indicated above, which may be the same or different, or R7 represents branched or linear C1-8 alkyl, C3-8 alkenyl, C3-? 0 cycloalkyl, C5-10 bicycloalkyl, C6-? oo tricycloalkyl C5-8 cycloalkenyl or R7 represents naphthyl or R7 represents an amino group or R7 represents a dialkylamino group of C 1-8, a monoalkylamino group of C? -8 or a heterocyclic, monocyclic or bicyclic group, saturated or unsaturated having 4 to 10 ring atoms, a heterocyclic group containing one or two nitrogen atoms and which may contain a heteroatom of the group (O, S) and which may be substituted with a group C1-3 branched or linear alkyl, phenyl, hydroxy or trifluoromethyl or a fluoro atom, R8 represents a hydrogen atom or a methyl group, Rg represents a hydrogen atom or a methyl, ethyl or methoxy group, and tautomers, stereoisomers , prodrugs and salts thereof. In the compounds of formula (I), at least one chiral counter-ion is present (at the C-position of the imidazoline functional group). The invention relates to both racemates, mixtures of diastereomers as well as individual stereoisomers of the compounds of formula (I). The invention also relates to the E isomer, Z isomer and the E / Z mixtures of the compounds of formula (I). Prodrugs are therapeutic agents that are inactive per se, but that are transformed into one or more active metabolites. Prodrugs are bioreversible derivatives of drug molecules, used to overcome some barriers that limit the utility of the parent drug molecule. These barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism, and target limitations (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 research prodrugs", J. Med. Chem., 47, 2393-2404, 2004). The prodrugs, ie the compounds that when administered to humans by any known route are metabolized to compounds having the formula (I), belong to the invention. This relates in particular to compounds with primary or secondary amino groups or hydroxy. Such compounds can be reacted with organic acids to provide compounds of formula (I) which have an additional group which can be easily separated after administration, for example, but not being limited to, an amidino, enamino, a Mannich base. , a hydroxyl-methylene derivative, an O- (acyloxymethylenecarbamate) derivative, carbamate, ester, amide or enaminone. The invention relates particularly to compounds of formula where Ri and R2 independently represent phenyl, phenyl group which may be substituted with 1, 2 or 3 Y substituents, which may be the same or different, from the group consisting of C1-3 alkyl or branched or linear C? -3-alkoxy, phenyl, hydroxy, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R-i and / or R2 represent naphthyl, thienyl or pyridyl, X represents one of subgroups (i) or (ii), wherein R3 represents a hydrogen atom, - R4 represents a branched or linear C1-8 alkyl group, branched or linear C? -8 alkoxy or C3-8 cycloalkyl, groups which may be substituted with a hydroxy group, 1- 3 methyl groups, an ethyl group or 1-3 fluorine atoms, or R represents a phenyl, phenoxy, pyridyl or thienyl group, or R represents a group NR5R6 where R5 and R6 - together with the nitrogen atom to which they are attached - they form a heterocyclic, monocyclic or bicyclic, saturated or unsaturated group having 4 to 10 ring atoms, heterocyclic group containing one or two heteroatoms of the group (O, N, S) or R3 and R - together with the nitrogen atom at which are joined - form a heterocyclic, monocyclic or bicyclic, saturated or unsaturated group having 4 to 10 ring atoms, heterocyclic group containing one or two heteroatoms of the group (O, N, S) and which may be substituted with a group methyl, hydroxy or trifluoromet ilo or a fluoro atom, R7 represents a phenyl group, phenyl group which may be substituted on its aromatic ring with 1, 2, 3 or 4 substituents Y, where Y has the meaning indicated above, which may be the same or different, or R7 represents C? Branched or linear, C3-? Oo cycloalkyl or C5-? Or bicycloalkyl, or R7 represents naphthyl or R7 represents an amino group or R7 represents a dialkylamino group of C -8, a monoalkylamino group of C1-8 or a heterocyclic group , monocyclic or bicyclic, saturated or unsaturated having 4 to 10 ring atoms, heterocyclic group containing one or two nitrogen atoms and which may contain a heteroatom of the group (O, S) and which may be substituted with an alkyl group of C? -3 branched or linear or hydroxy, R8 represents a hydrogen atom, R9 represents a hydrogen atom and tautomers, stereoisomers, prodrugs and salts thereof. Due to the potent CBi antagonist activity, the compounds according to the invention are suitable for use in the treatment of psychiatric disorders such as psychosis, anxiety, depression, attention deficit, memory disorders, cognitive disorders, appetite disorders, obesity, in particular juvenile obesity and drug-induced obesity, addiction, impulse control disorders, appetite, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, sclerosis multiple, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischemia, cerebral stroke, craniocerebral trauma, syncope, spinal cord damage, neuroinflammatory disorders, sclerosis in plaque, viral encephalitis, disorders related to demyelination, as well as for the treatment of painful disorders, including disorders with neuropathic pain, and other diseases involving cannabinoid neurotransmission, including the treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea , asthma, respiratory diseases, gastrointestinal disorders, gastric ulcers, diarrhea, cardiovascular disorders, atherosclerosis, cirrhosis of the liver and sexual disorders. The cannabinoid receptor modulating activity of the compounds of the invention makes them particularly useful in the treatment of obesity, juvenile obesity and drug-induced obesity, when used in combination with lipase inhibitors. Specific examples of compounds that can be used in such combination preparations are (but are not restricted to) the synthetic lipase inhibitor orlistat, lipase inhibitors isolated from microorganisms such as lipstatin (from Streptomyces toxytricini), ebelactone B ( from Streptomyces aburaviensis), synthetic derivatives of these compounds, as well as plant extracts known to possess inhibitory activity of lipase, for example extracts of Alpinia officinarum or compounds isolated from such extracts, such as 3-methyletergalangin (from A. officinarum).

General aspects of synthesis Scheme 1 summarizes the synthesis of compounds that have the formula (I) where X represents subgroup (i). Intermediates having the general formula (II) can be obtained according to known methods, see for example: I.K. Khanna et al., J. Med. Chem. 2000, 43, 3168-3185; I. K. Khanna et al., J. Med. Chem. 1997, 40, 1634-1647; WO 03/027076 or WO 03/040107. Intermediates having the general formula (IV) can be obtained according to known methods, see for example: I. Khanna et al., J. Med. Chem. 2000, 43, 3168-3185. The carboxamidine derivatives of general formula (II) can be reacted with 2-chloroacrylonitrile (III) to provide a 4,5-dihydro-1H-α-dimdazole derivative of general formula (IV). This reaction is preferably carried out in the presence of a base such as N, N-diisopropylethylamine. The obtained derivatives of general formula (IV) can be esterified with an alcohol R 10 -OH to provide a 4,5-dihydro-1 H-imidazole derivative of general formula (V), wherein R 10 represents an alkyl group of C? -5 branched or linear or a benzyl group. This reaction is preferably carried out under acidic conditions. A compound of general formula (V) can be reacted with an amine R3R NH, preferably in the presence of trimethylaluminum (Me3AI) to provide a compound of formula (I), where X represents subgroup (i) and R3 and R have the meaning given above on page 3. Additional information on amidation reactions of esters catalyzed by trimethylaluminum AI (CH3) 3 can be found in: J.l. Levin, E. Turos, S.M. Weinreb, Synth Commun. (1982), 12, 989-993. Alternatively, a compound of general formula (V) can be hydrolyzed to form the corresponding carboxylic acid derivative of general formula (VI), where R n represents H or an alkaline earth metal, in particular Li, Na or K. Alternatively, the compound of general formula (VI) can be reacted with a chlorinating agent such as thionyl chloride to provide the corresponding acid chloride. The compound of general formula (VI) can be reacted with an amine R3R4NH to provide a compound of formula (I), where X represents subgroup (i) and R3 and R have the meaning given above on page 3, via methods of activation and coupling such as the formation of an active ester, or in the presence of a so-called coupling agent, such as, for example, DCC, HBTU, BOP (benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate) and the like . Additional information on methods of activation and coupling of amines to carboxylic acids can be found in: a) M. Bodanszky and A. Bodanszky: The Practice of Peptide Synthesis, Springer-Verlag, New York, 1994; ISBN: 0-387-57505-7; b) K. Akaji et al., Tetrahedron Lett., 1994, 35, 3315-3318); c) F. Aibericio ef al., Tetrahedron Lett., 1997, 38, 4853-4856).

SCHEME 1 (ll) (ül) (IV) (V) The synthesis of compounds having the formula (I) wherein X represents subgroup (ii) is summarized in Scheme 2. An intermediate of general formula R SO2NH2 either is commercially available or can be prepared via standard synthesis methodology, for example from the corresponding compound R7SO2CI (see for example, McManus et al., J. Med. Chem. 1965, 8, 766). A compound of general formula (IV) can be reacted with a compound of general formula R7SO2NH2 in the presence of a Lewis acid such as for example AIMe3 in an inert organic solvent such as benzene to provide a compound of general formula (I) wherein X represents the subgroup (ii) and Ri, R2 and R7 have the meaning given above on pages 3 and 4 and where R8 and Rg represent a hydrogen atom. A compound of general formula (V) can be reacted with a compound of general formula R7SO2NH2 to provide a compound of general formula (VII). This reaction is preferably carried out in the presence of a strong non-nucleophilic base. A compound of general formula (VII) can be reacted with a chlorinating agent in a chloroimidation reaction and subsequently treated with an amine R8RgNH to provide a compound of formula (I), where X represents the subgroup (ii).

SCHEME 2 '' d (lo) nde X represents the subgroup (ii) where R8 and R9 represent H presents the subgroup (ii) The selection of a particular synthesis method depends on factors such as the compatibility of the functional groups with the reagents used, the possibility of using protection groups, catalysts, activation and coupling reagents and the final structural characteristics present in the final compound prepared. According to these procedures, the following compounds can be prepared. The purpose of said compounds is to illustrate the invention further in greater detail and, therefore, the compounds do not restrict the scope of the invention in any way.

Pharmaceutical Preparations The compounds of the invention can be brought into forms suitable for administration by usual processes, using auxiliary substances such as liquid or solid excipient materials. The pharmaceutical compositions of the invention can be administered enterally, orally, parenterally (intramuscularly or intravenously), rectally or locally (topically). They can be administered in the form of solutions, powders, tablets, capsules (including microcapsules), ointments (creams or gels) or suppositories. Suitable excipients for such formulations are the liquid or solid fillers and solvents, solvents, emulsifiers, lubricants, flavors, colorants and / or pharmaceutically customary pH regulating substances. Frequently used auxiliary substances which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactoprotein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as fish liver oil, oil of sunflower, peanut or sesame, polyethylene glycol and solvents such as, for example, sterile water and mono- and polyhydric alcohols such as glycerol. The compounds of the present invention are generally administered as pharmaceutical compositions which are important and novel embodiments of the invention due to the presence of the compounds, more particularly the specific compounds disclosed therein. Types of pharmaceutical compositions that can be used include, but are not limited to, tablets, chewable tablets, capsules, solutions, parenteral solutions, suppositories, suspensions and other types disclosed therein or apparent to a person skilled in the art from the memory. descriptive and general knowledge of the technique. In embodiments of the invention, a pharmaceutical package or equipment is provided comprising one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention. With such a container (such containers) may be associated various written materials, such as instructions for use or a note in the form required by a government agency that regulates the manufacture, use or sale of pharmaceutical products, note that reflects approval by the agency of manufacture, use or sale for human or veterinary administration.

Pharmacological methods In vitro affinity for CB cannabinoid receptors The affinity of the compounds of the invention for cannabinoid CBi receptors can be determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabinoid receptor CBi is found Stably transfected, together with [3 H] CP-55,940 as radioligand. After incubation of a cell membrane preparation recently prepared with the [3H] -ligand, with or without the addition of compounds of the invention, the separation of the ligand-free ligand ligand is performed by filtration through glass fiber filters . The radioactivity on the filter is measured by liquid scintillation counting.

In vitro Antagonism of the CB cannabinoid receptor ^ In vitro antagonism of the CBT receptor can be evaluated with the human CBi receptor cloned in Chinese hamster ovary (CHO) cells. CHO cells are cultured in Dulbecco's modified Eagle culture medium (DMEM), supplemented with 10% heat inactivated fetal calf serum. The medium is aspirated and replaced by DMEM without fetal calf serum, but containing [3H] -arachidonic acid, and incubated overnight in a cell culture oven (5% CO2 / 95% air).; 37 ° C; atmosphere saturated with water). During this period, [3H] -arachidonic acid is incorporated into the phospholipids of the membrane. The day of the rehearsal, the is aspirated and the cells are washed three times using 0.5 mL of DMEM containing 0.2% bovine serum albumin (BSA). Stimulation of the CB-i receptor by WIN 55,212-2 leads to the activation of phospholipase A2 (PLA2), followed by the release of [3H] -arachidonic acid in the medium. This release induced by WIN 55,212-2 is antagonized by CBI receptor antagonists depending on their concentration.

The in vivo antagonism of CB-i can be evaluated with the rat hypotension test induced by CP-55,940. Male rats with normal tension (225-300 g; Harian, Horst, The Netherlands) are anesthetized with pentobarbital (80 mg / kg ip). The blood pressure is measured, via a cannula inserted into the left carotid artery, by means of a Spectramed DTX-plus pressure transducer (Spectramed B.V., Bilthoven, The Netherlands). After amplification using a Carrier Nihon Kohden amplifier (type AP-621 G, Nihon Kohden BV, Amsterdam, The Netherlands), the blood pressure signal is recorded on a personal computer (Compaq Deskpro 386s), through an acquisition program of Po-Ne-Mah data (Po-Ne-Mah Inc., Storrs, USA). The heart rate is derived from the pulsatile pressure signal. All compounds are administered orally in the form of a microsuspension in 1% methylcellulose 30 minutes before the induction of anesthesia, ie 60 minutes before the administration of the CBi receptor agonist CP-55,940. The injection volume is 10 ml / kg.

After hemodynamic stabilization, the CB- receptor agonist is administered. CP-55,940 (0.1 mg / kg i.v.) and the hypotensive effect is established. (Wagner, J.A., Jarai, Z., Batkai, S., Kunos, G. Hemodynamic effects of cannabinoids: coronary and cerebral vasodilation mediated by cannabinoid CB1 receptors, Eur. J. Pharmacol., 2001, 423, 203-210). Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable acid, for example an inorganic acid such as hydrochloric acid, or with an organic acid.

Dosage The affinity of the compounds of the invention for cannabinoid receptors was determined according to (or described above) From the binding affinity measured for a given compound of formula (I), it is possible to estimate a theoretical minimum effective dose. of the compound equal to twice the K value measured, probably 100% of the cannabinoid receptors will be occupied by the compound.The conversion of this concentration to mg of compound per kg of body weight of the patient provides a theoretical minimum effective dose, assuming a ideal bioavailability Pharmacokinetic, pharmacodynamic, and other considerations can change the dose actually administered to a higher or lower value The dose conveniently administered is 0.001 -1000 mg / kg, preferably 0.1-100 mg / kg of the patient's body weight.

EXAMPLE 1 Synthesis of specific compounds Compounds 1-2 Part A A magnetically stirred mixture of N- (4-chlorophenyl) -2,4-dichlorobenzenecarboxamidine (10.0 grams, 0.033 moles), 2-chloroacrylonitrile (5.7 grams, 0.065 moles) and N, N-diisopropylethylamine (DIPEA) (12.5 ml) , 0.069 moles) in tetrahydrofuran (150 ml) is heated at reflux temperature for 40 hours (N2 atmosphere). After cooling to room temperature, the mixture is concentrated in vacuo. The residue is dissolved in a mixture of dichloromethane and water (200 ml / 200 ml). The dichloromethane layer is collected, dried over MgSO 4, filtered and concentrated in vacuo. The residue is recrystallized from ethanol / water to give 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -4,5-dihydro-1 H-imidazole-4-carbonitrile (11.23 grams, yield 97 %). 1 H-NMR (400 MHz, CDCl 3): d 4.28 (dd, J = 10 and 8 Hz, 1H), 4.36 (t, J = 10 Hz, 1 H), 5.07 (dd, J = 10 and 8 Hz, 1 H), 6.68 (br d, J = 8 Hz, 2H), 7.16 (br d, J = 8 Hz, 2H), 7.32-7.36 (m, 2H), 7.45 (d, J = 8 Hz, 1 H) .

Part B Acetyl chloride (17.76 ml, 0.25 moles) is added slowly to ethanol (1 l) to give solution A. 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -4,5-dihydro -1 H-imidazole-4-carbonitrile (17.52 grams, 0.05 moles) is added in one portion to solution A. After cooling to room temperature, the mixture is stirred for another 40 hours and concentrated in vacuo. The residue is dissolved in dichloromethane and washed (3 x) with 5% aqueous solution of NaHCO 3. The dichloromethane layer is separated, dried over MgSO, filtered and concentrated in vacuo to provide 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -4,5-dihydro-1 H-imidazole- 4-ethyl carboxylate (18.0 grams, yield 90%) in the form of a brown oil which slowly solidifies with rest. ^ -NMR (400 MHz, CDCI3): d 1.34 (t, J = 7 Hz, 3H), 4.15 (dd, J = 10 and 8 Hz, 1 H), 4.22-4.41 (m, 3H), 4.91 (dd) , J = 10 and 8 Hz, 1 H), 6.66 (br d, J = 8 Hz, 2 H), 7.11 (br d, J = 8 Hz, 2 H), 7.30 (dd, J = 8 and 2 Hz, 1 H), 7.33 (d, J = 2 Hz, 1 H), 7.46 (dd, J = 8 Hz, 1 H).

Part CA a magnetically stirred solution of exo-2-aminobicyclo [2.2.1] heptane (0.67 ml, 0.009 mol) in anhydrous dichloromethane (10 ml) is added trimethylaluminum (5.4 ml of a 2 N solution in hexane, 0.0108 mol) and The resulting solution is stirred for 20 minutes at room temperature. 1- (4-Chlorophenyl) -2- (2,4-dichlorophenyl) -4,5-dihydro-1 H-imidazole-4-carboxylate (2.385 g, 0.006 mole) is slowly added in anhydrous dichloromethane (10 ml) and the resulting mixture is reacted at 40 ° C for 40 hours (N2 atmosphere). After cooling to room temperature, the mixture is quenched with 5% aqueous NaHCO 3 solution and extracted with dichloromethane. The dichloromethane layer is separated, dried over MgSO, filtered and concentrated in vacuo to give a crude yellow syrup (2.58 grams) which is further purified with ultrafast chromatography (silica gel, ethyl acetate / petroleum ether = 8/2 (v / v)) to provide 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -N- (exo-2-bicyclo [2.2.1] heptyl) -4,5-dihydro-1 H-imidazole-4-carboxamide that moves faster (diastereomer A) (0.70 grams, 25% yield) and 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -N- (exo-2) -bicyclo [2.2.1] heptyl) -4,5-dihydro-1H-imidazole-4-carboxamide which moves more slowly (diastereomer B) (0.69 grams, yield 25%). Diastereomer A: 1 H-NMR (400 MHz, CDCl 3): d 1.10-1.58 (m, 7H), 1.76-1.84 (m, 1 H), 2.26-2.30 (m, 2H), 3.74-3.82 (m, 1 H), 4.27 (d, J ~ 10 Hz, 2H), 4.78 (t, J ~ 10 Hz, 1 H), 6.65 (br d, J = 8 Hz, 2H), 6.70-6.78 (m, 1 H) , 7.12 (br d, J = 8 Hz, 2 H), 7.29 (br s, 2 H), 7.40 (br s, 1 H). Diastereomer B: H-NMR (400 MHz, CDCl 3): d 1.10-1.56 (m, 7H), 1.78-1.85 (m, 1 H), 2.17-2.20 (m, 1 H), 2.26-2.30 (m, 1 H), 3.76-3.82 (m, 1 H), 4.25-4.30 (m, 2H), 4.78 (dd, J = 10 and 8 Hz, 1 H), 6.66 (br d, J = 8 Hz, 2H), 6.80 (br d, J ~ 7 Hz, 1 H), 7.11 (br d, J = 8 Hz, 2 H), 7.30 (br s, 2 H), 7.41 (br s, 1 H).

Compounds 3 and 4 Part A A mixture of ethyl 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -4,5-dihydro-1 H-imidazole-4-carboxylate (3.97 g, 0.01 mol) in methanol / water it is reacted with LiOH (1.3 grams, 0.054 moles) at room temperature for 16 hours. The resulting mixture is concentrated in vacuo to provide crude lithium 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -4,5-dihydro-1 H-imidazole-4-carboxylate (4.7 grams).

Part B A mixture of crude lithium 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -4,5-dihydro-1 H-imidazole-4-carboxylate (1.0 gram, ~0.0027 mol), hexafluorophosphate of benzotriazole-1-yloxytris (dimethylamino) phosphono (BOP) (1.2 grams, 0.0027 moles), 1-aminopiperidine (0.3 grams, 0.003 moles) and triethylamine (1 ml) in DMF (30 ml) is stirred at room temperature for 16 hours. After concentration in vacuo, water is added and the resulting mixture is extracted (2 x) with dichloromethane. The dichloromethane layers are collected, dried over MgSO, filtered and concentrated in vacuo to provide a residue which is further purified by ultrafast chromatography (silica gel, dichloromethane / methanol = 95/5 (v / v)) to provide 1 - (4-chlorophenyl) -2- (2,4-dichlorophenyl) -N- (piperidin-1-yl) -4,5-dihydro-1 H-imidazole-4-carboxamide (380 mg, 31% yield). Melting point: 113-116 ° C 1 H-NMR (200 MHz, CDCl 3): d 1.33-1.48 (m, 2H), 1.60-1.80 (m, 4H), 2.68-2.82 (m, 4H), 4.28-4.35 (m, 2H), 4.84 (dd, J = 11 and 9 Hz, 1 H), 6.65 (br d, J = 8 Hz, 2H), 7.11 (br d, J = 8 Hz, 2H), 7.23-7.33 (m, 2H), 7.41 (d, J = 2 Hz, 1 H), 7.57 (br s, 1 H).

In an analogous way compound 4 was prepared: Compound 4 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -N-cyclohexyl-4,5-dihydro-1H-imidazole-4-carboxamide. Melting point: 127-129 ° C 1 H-NMR (200 MHz, CDCl 3): d 1.04-2.03 (m, 10H), 3.73-3.92 (m, 1 H), 4.23-4.33 (m, 2H), 4.81 ( t, J ~ 10 Hz, 1 H), 6.66 (br d, J = 8 Hz, 2 H), 6.79 (br d, J ~ 7 Hz, 1 H), 7.12 (br d, J = Hz, 2 H), 7.25-7.32 (m, 2H), 7.41 (br s, 1 H).

Compounds 5-8 Part AA a suspension of 4-chlorobenzenesulfonamide (0.45 grams, 0.00236 moles) in benzene (5 ml) is added dropwise to trimethylaluminium (1.2 ml of a 2 N solution in toluene, 0.0024 moles) to provide a clear solution which is stirred at room temperature for 1 hour. Add 1- (4-chlorophenyl) -2- (2,4-dichlorophenii) -4,5-dihydro-1H-imidazole-4-carbonitrile (0.55 grams, 0.00157 moles) and the resulting mixture is heated to 90 ° C. for 16 hours. After cooling to room temperature, a mixture of methanol / water (8/2 (v / v)) is added slowly, the solids are separated by filtration and washed with chloroform (50 ml). The filtrate is concentrated in vacuo. The residue is triturated with N-pentane and recrystallized twice from methanol to provide 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -N - [(4-chlorophenyl) sulfonyl] -4, 5-dihydro-1 H-imidazole-4-carboxamidine (0.435 grams, 51% yield). Melting point: 165-166 ° C 1 H-NMR (200 MHz, CDCl 3): d 4.11-4.35 (m, 2H), 4.94 (dd, J = 12 and 10 Hz, 1 H), 6.63 (br d, J = 8 Hz, 2H), 7.12 (br d, J = 8 Hz, 2H), 7.22-7.52 (m, 6H), 7.90 (br d, J = 8 Hz, 2H), 8.10-8.20 (m, 1 H ).

In an analogous manner, the compounds of formula I) listed below were prepared: Compound 6 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -N - [(4-fluorophenyl) sulfonyl] -4,5-dihydro-1 H-imidazole-4-carboxamidine. Melting point: 172-175 ° C. 1 H-NMR (200 MHz, CDCl 3): d 4.12-4.35 (m, 2H), 4.93 (dd, J = 12 and 10 Hz, 1 H), 6.63 (br d, J = 8 Hz, 2H), 7.08- 7.43 (m, 8 Hz), 7.90-8.02 (m, 2H), Compound 7 2- (4-chlorophenyl) -N- (dimethylaminosulfonyl) -1-phenyl-4,5-dihydro-1 H-imidazole-4-carboxamidine. Melting point: 136-139 ° C 1 H-NMR (200 MHz, CDCl 3): d 2.79 (s, 6H), 4.20-4.40 (m, 2H), 4.97 (t, J ~ 10 Hz, 1 H), 6.83 (br d, J = 8 Hz, 2H), 7.05-7.50 (m, 8H), 7.80-7.90 (m, 1 H). compound 7 Compound 8 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -N- (dimethylaminosulfonyl) -4,5-dihydro-1 H-imidazole-4-carboxamidine. Melting point: 146-147 ° C.

EXAMPLE 2 Formulations used in animal studies Formulation of compound 1 For oral administration (po) To the desired amount (0.5-15 mg) of the above compound as "compound 1" in a glass tube, some glass beads were added and the substance was triturated by vortexing for 2 hours. minutes After the addition of 1 ml of a 1% solution of methylcellulose in water, the compound was suspended by vortexing for 10 minutes. For concentrations up to and greater than 1 mg / ml, the remaining particles in the suspension were further suspended by an ultrasonic bath.

EXAMPLE 3 Results of pharmacological tests The in vitro affinity and functional data of the cannabinoid receptor obtained according to the protocols mentioned above are shown in the following table.

TABLE 1 Pharmacological data

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. - Compounds of the general formula (I) (I) • wherein: Ri and R 2 independently represent phenyl, thienyl or pyridyl, groups which may be substituted with 1, 2 or 3 Y substituents, which may be the same or different, from the group consisting of C 1-3 alkyl or alkoxy C1-3 branched or linear, phenyl, hydroxy, chloro, bromo, fluoro, iodo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R < And / or R2 represent naphthyl, - X represents one of the subgroups (i) or (ii), wherein: - R3 represents a hydrogen atom or a branched or linear C1-3 alkyl group, - R represents a C1-8 alkyl or C3-8 cycloalkyl-branched or linear C2-2 alkyl, alkoxy group, Branched or linear C? -8, C3-8 cycloalkyl, C5-? 0 bicycloalkyl, C6-? Tricycloalkyl or > groups that can containing one or more heteroatoms of the group (O, N, S) and which may be substituted with a hydroxy group, 1-3 methyl groups, an ethyl group or 1-3 fluorine atoms, or R4 represents a phenoxy, benzyl group, phenethyl or phenylpropyl, optionally substituted on its phenyl ring with 1-3 substituents Y, where Y has the above-mentioned meaning, or R represents a pyridyl or thienyl group, or R4 represents a group NR5R6 where Rs and Re- together with the atom of nitrogen to which they are attached - they form a heterocyclic, monocyclic or bicyclic, saturated or unsaturated group having 4 to 10 ring atoms, a heterocyclic group containing one or two heteroatoms of the group (O, N, S) and which may be substituted with a branched or linear C-? -3 alkyl group, phenyl, hydroxy or trifluoromethyl or a fluorine atom, or R3 and R4 - together with the nitrogen atom to which they are attached - form a heterocyclic, monocyclic or bicyclic, saturated group or not sat ured having 4 to 10 ring atoms, heterocyclic group containing one or two heteroatoms of the group (O, N, S) and which may be substituted with a branched or linear C? -3 alkyl group, phenyl, amino, hydroxy or trifluoromethyl or a fluorine atom, - R7 represents a benzyl, phenyl, thienyl or pyridyl group, which groups can be substituted on their aromatic ring with 1, 2, 3 or 4 Y substituents, where Y has the meaning indicated above, which can be be the same or different, or R7 represents branched or linear C? -8 alkyl, C3-8 alkenyl, C3-? 0 cycloalkyl, C5-10 bicycloalkyl, C6-? oo or cycloalkenyl tricycloalkyl of C8 or R7 represents naphthyl or R7 represents an amino group or R7 represents a dialkylamino group of C1-8, a monoalkylamino group of C-? -8 or a heterocyclic, monocyclic or bicyclic, saturated or unsaturated group having 4 to 10 ring atoms, heterocyclic group containing one or two nitrogen atoms and which may contain a heteroatom of the group (O, S) and whose heterocyclic group can be substituted with a branched or linear C?-3 alkyl group, phenyl, hydroxy or trifluoromethyl or a fluorine atom, - R 8 represents a hydrogen atom or a methyl group, - Rg represents an atom of hydrogen or a methyl, ethyl or methoxy group, and tautomers, stereoisomers, prodrugs and salts thereof.

2. The compounds according to claim 1, further characterized by the general formula (I) (I) where - Ri and R2 independently represent phenyl, phenyl group which may be substituted with 1, 2 or 3 substituents Y, which may have the meanings given in claim 1, or Ri and / or R2 represent naphthyl, thienyl or pyridyl, - X represents one of the subgroups (i) or (¡i), where - R3 represents a hydrogen atom, - R represents a branched or linear C-? 8 alkyl group, branched or linear C1-8 alkoxy or C3-8 cycloalkyl, groups which may be substituted with a hydroxy group, 1-3 methyl groups, an ethyl group or 1-3 fluorine atomsor R4 represents a phenoxy, pyridyl or thienyl group, or R4 represents a group NR5R6 where R5 and R6 - together with the nitrogen atom to which they are attached - form a heterocyclic, monocyclic or bicyclic, saturated or unsaturated group having 4 to 10 ring atoms, heterocyclic group containing one or two heteroatoms of the group (O, N, S) or R3 and R4 - together with the nitrogen atom to which they are attached - form a heterocyclic, monocyclic or bicyclic group, saturated or not saturated having 4 to 10 ring atoms, heterocyclic group containing one or two heteroatoms of the group (O, N, S) and whose heterocyclic group can be substituted with a methyl, hydroxy or trifluoromethyl group or a fluorine atom, - R represents a phenyl group, phenyl group which may be substituted on its aromatic ring with 1, 2, 3 or 4 substituents Y, where Y has the meaning indicated above, which may be identical or different, or R7 represents alkyl of branched or linear C? -8, C3-10 cycloalkyl or C5-10 bicycloalkyl, or R7 represents naphthyl or R7 represents an amino group or R7 represents a dialkylamino group of C1-8, a monoalkylamino group of C? -8 or a heterocyclic, monocyclic or bicyclic, saturated or unsaturated group having 4 to 10 ring atoms, heterocyclic group containing one or two nitrogen atoms and which may contain a heteroatom of the group (O, S) and whose heterocyclic group may to be substituted with a branched or linear C1-3 alkyl group or hydroxy, - R8 represents a hydrogen atom, - Rg represents a hydrogen atom and to tautomers, stereoisomers, prodrugs and salts thereof.

3. The compound according to claim 1, further characterized in that it is: 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -N- (exo-2-bicyclo [2.2.1] heptyl) -4,5-dihydro-1 H-imidazole-4-carboxamide (diastereomer A); 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -N- (exo-2-bicyclo [2.2.1] heptyl) -4,5-dihydro-1 H-imidazole-4-carboxamide (diastereoisomer B); 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -N- (piperidin-1-yl) -4,5-dihydro-1 H-imidazole-4-carboxamide; 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -N-cyclohexyl-4,5-dihydro-1 H-imidazole-4-carboxamide; 1- (4-chlorophenol) -2- (2,4-dichlorophenyl) -N - [(4-chlorophenyl) sulfonyl] -4,5-dihydro-1 H-imidazole-4-carboxamidine; 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -N - [(4-fluorophenyl) sulfonyl] -4,5-dihydro-1 H -medazole-4-carboxamidine; 2- (4-chlorophenyl) -N- (dimethylaminosulfonyl) -l-phenyl-4,5-dihydro-1 H-imidazole-4-carboxamidine; 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -N- (d -methalylamine-sulfonyl) -4,5-dihydro-1H-imidazole-4-carboxamidine.

4. Pharmaceutical compositions comprising, in addition to a pharmaceutically acceptable excipient and / or at least one pharmaceutically acceptable auxiliary substance, as active ingredient a pharmacologically active amount of at least one compound according to any of claims 1-3, or a come out of it

5. Use of a compound as claimed in any of claims 1-3, for the preparation of a pharmaceutical composition for the treatment of psychosis, anxiety, depression, attention deficit, memory disorders, cognitive disorders, appetite disorders, obesity, in particular juvenile obesity and drug-induced obesity, addiction, impulse control disorders, appetite, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischemia cerebral apoplexy, craniocerebral trauma, syncope, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, disorders related to demyelination, as well as for the treatment of painful disorders, including disorders with neuropathic pain, and other diseases that they involve neuro cannabinoid transmission, including the treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases, gastrointestinal disorders, gastric ulcers, diarrhea, cardiovascular disorders, atherosclerosis, cirrhosis of the liver and sexual disorders.

6. The use of a compound of formula (I) (" where: - Ri and R2 have the meanings given in claim 1, but can also independently represent methylsulfonyl, - X represents subgroup (i), --.-'- oj; . wherein: - R3 and R4 have the same meaning given in claim 1, but wherein R may also represent a phenyl group, optionally substituted with 1-3 Y substituents, wherein Y has the meaning given in claim 1, for the preparation of a pharmaceutical composition for the treatment of psychosis, anxiety, depression, attention deficit, memory disorders, cognitive disorders, appetite disorders, obesity, in particular juvenile obesity and drug-induced obesity, addiction, impulse control disorders, Appetite, dependence on drugs and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, syndrome de Tourette, cerebral ischemia, cerebral apoplexy, craniocerebral trauma, sin cope, spine damage, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, disorders related to demyelination, as well as for the treatment of disorders painful, including disorders with neuropathic pain, and other diseases involving cannabinoid neurotransmission, including the treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases, gastrointestinal disorders, gastric ulcers, diarrhea, cardiovascular disorders, atherosclerosis , cirrhosis of the liver and sexual disorders.

7. The use as claimed in claim 5, wherein said disorders are eating disorders, in particular obesity, juvenile obesity and drug-induced obesity.

8. The use of a compound as claimed in any of claims 1-3 for the preparation of a pharmaceutical composition for the treatment of eating disorders, in particular obesity, juvenile obesity and drug-induced obesity, wherein said pharmaceutical composition also contains at least one lipase inhibitor.

9. The use as claimed in claim 8, wherein said lipase inhibitor is orlistat or lisptatin.