ZA200603124B - 1H-imidazole derivatives as cannabinoid receptor modulators - Google Patents

Description

1H-IMIDAZOLE DERIVATIVES AS CANNABINOID RECEPTOR

MODULATORS

The present 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 1H-imidazole derivatives as active ingredient, as well as to the use of these pharmaceutical compositions for the treatment of psychiatric and neurological disorders in which cannabinoid receptors are involved.

The invention also relates to the use of a compound disclosed herein for the manufacture of a medicament giving a beneficial effect. A beneficial effect is disclosed herein or apparent to a person skilled in the art 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 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 herein or apparent to a person skilled in the art from the specification and general knowledge in the art. In embodiments of the invention specific compounds disclosed herein are used for the manufacture of a medicament. 1H-Imidazole derivatives as CB receptor modulators are already known from WO 03/027076. However, the compounds described in WO 03/027076 are characterized by a relatively poor aqueous solubility. The goal of the present invention was to improve the aqueous solubility of 1H-imidazole derivatives whilst maintaining their cannabinoid receptor modulating activity. From the prior art it is not obvious how this goal should be achieved.

Surprisingly, it has now been found that the introduction of a 5-aminomethy! moiety in the 1H-imidazole core results in an enhanced aqueous solubility. Moreover, the derivatives containing said 5-aminomethyl moiety retain their cannabinoid receptor modulating activity, such as receptor antagonism, receptor inverse agonism or receptor (partial) agonism.

The invention relates to compounds of the general formula (1)

NV] '

AX _~R, 0)

R NR,

R, wherein: - Rand Ry are the same or different and represent phenyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, which groups may be substituted with 1, 2, 3 or 4 substituents Y, which can be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, hydroxymethyl, hydroxyethyl, chloro, iodo, bromo, fluoro, trifluoromethyl, trifluoromethoxy, methyisulfonyl, phenyl and cyano, or R represents naphtyl, or R represents a C1 branched or linear alkyl group, a C1; cycloalkyl group, C7 cycloalkyl-C,., alkyl group, a Csgbranche d or linear heteroalkyl group, a Cs; heterocycloalky! group or a C.; heterocycioalkyl -Cs.; alkyl group which groups may be substituted with a fluoro atom or a CF; or OH group, - Ryand R; are the same or different and represent H, a Cys branched or linear alkyl group which alkyl group may be substituted with a hydroxy group, or 1-3 fluoro atoms or,

R. represents a branched or linear C 13 alkoxy group, with the proviso that Rs; represents H or a methyl group - Rp and R; - together with the nitrogen atom to which they are bonded - form a saturated or unsaturated non-aromatic, monocyclic or bicyclic, heterocyclic group having 5 to 10 ring atoms which heterocyclic group contains one or two ring heteroatoms from the group (N, O, S), which heteroatoms can be the same or different, which heterocyclic group may be substituted with a C+.; alkyl group, a hydroxy group, or a fluoro atom, - Ry represents H or a methyl, ethyl, propyl, isopropyl or n-butyl group, - Xrepresents one of the subgroups (i), or (ii),

0 0

LL, Loe \ R, 0) (ii) wherein: - Rs represents a hydrogen atom, or a Ca.5 branched or linear alkyl group, C1.- alkyl-SO,-C1.4- alkyl group, Cs cycloalkyl group, Csz-cycloalkyl-Cy.-alkyl group,

Cs7-heterocycloalkyl-Cy.2-alkyl group which groups may be substituted with a hydroxy, methyl or trifluoromethyl group or a fluoro atom and which Cs heterocycloalkyl-C.-alkyl group contains one or two heteroatoms from the group (O, N, S), or Rs represents a phenyl, benzyl, phenethyl or phenylpropy! group which may be substituted on their phenyl ring with 1-3 substituents Y, wherein Y has the abovementioned meaning, or Rs represents a pyridyl or thienyl group, - Re represents a hydrogen atom or a branched or linear C+.; alkyl group, - R; represents hydrogen, a branched or linear C 14 alkyl or Cy g-cycloalkyl-C;.o- alkyl group, branched or linear Cg alkoxy, Cs cycloalkyl, Cs 1 bicycloalkyl, Cs. bicycloalkyl-C1.; alkyl, Cs. tricycloal kyl, C 4 tricycloalkyimethyl, which groups may contain one or more heteroatoms from the group (O, N, S) and which groups may be substituted with a hydroxy group, 1-3 methyl groups, an ethyl group or 1- 3 fluoro atoms, or R; represents a phenyl, phenylamino, phenoxy, benzyl, phenethy! or phenylpropyl group, optionally substituted on their phenyl ring with 1-3 substituents Y, wherein Y has the abovementioned meaning, or R; represents a pyridyl or thienyl group, or Ry represents a group NRgRg wherein

Rs and Ry - together with the nitrogen atom to which they are attached -form a saturated or unsaturated, monocyclic or bicyclic, heterocyclic group having 4 to 10 ring atoms, which heterocyclic group contains one or more heteroatoms from the group (O, N, S) and which heterocyclic group may be substituted with a branched or linear C13 alkyl, phenyl, hydroxy or trifluoromethyt group or a fluoro atom, or

Rs and R; — together with the nitrogen atom to which they are attached - form a saturated or unsaturated, monocyclic or bicyclic, heterocyclic group having 4 to 10 ring atoms, which heterocyclic group contains one or more heteroatoms from the group (O, N, S) and which heterocyclic group may be substituted with a branched or linear Cy alkyl, phenyl, amino, hydroxy or trifluoromethyl group or a fluoro atom, and pharmacologically acceptable salts and prodrugs thereof.

To the invention belong all compounds having formula (I), racemates, mixtures of diastereomers and the individual stereoisomers. Thus compounds in which the substituents on potentially asymmetrical carbon atoms are in either the R- configuration or the S-configuration belong to the invention.

Prodrugs are therapeutic agents which are inactive per se but are transformed into one or more active metabolites. Prodrugs are bioreversible derivatives of drug molecules used to overcome some barriers to the utility of the parent drug molecule.

These barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism and targeting limitations (Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed. F. D. King, p. 215; J. Stella, “ Prodrugs as therapeutics”, Expert Opin. Ther. Patents, 14(3), 277-280, 2004; P. Ettmayer et al., “Lessons leamed from marketed and investigational prodrugs”, J.Med.Chem., 47, 2393-2404, 2004). Pro-drugs, i.e. compounds which when administered to humans by any known route, are metabolised to compounds having formula (1), belong to the invention. In particular this relates to compounds with primary or secondary amino or hydroxy groups. Such compounds can be reacted with organic acids to yield compounds having formula (1) wherein an additional group is present which is easily removed after administration, for instance, but not limited to amidine, enamine, a

Mannich base, a hydroxyl-methylene derivative, an O-(acyloxy-methylene carbamate) derivative, carbamate, ester, amide or enaminone.

The invention particularly relates to compounds having formula (I) wherein X represents the subgroup (ii), and all other symbols have the meanings as described above.

More particular the invention relates to compounds of formula (1) wherein X represents the subgroup (ii), and R represents phenyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, which groups may be substituted with 1, 2, 3 or 4 substituents Y, which can be the same or different, from the group methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, hydroxymethyl, hydroxyethyl, chloro, iodo, bromo, fluoro, trifluoromethyl, trifluoromethoxy, methylsulfonyl, phenyl or cyano, or R represents naphtyl, and all other symbols have the meanings as described above.

GENERAL ASPECTS OF SYNTHESES

Compounds of formula (I) and the synthetic intermediates of formula (il) and (Vh respectively may be prepared by a variety of methodologies. The synthesis of 5 structurally related imidazoles as cannabinoid receptor modulators has been described in WO 03/027076 and WO 03/063781. The synthesis of structurally related imidazoles as anti-obesity compounds has also been described in WO 03/040107.

The selection of the particular method depends on factors such as the compatibility of functional groups with the reagents used, the possibility to use protecting groups, catalysts, activating and coupling reagents and the ultimate structural features present in the final compound being prepared. More information on activating and coupling methods of amines to carboxylic acids can be found in: a) M.Bodanszky and A. Bodanszky: The Practice of Peptide Synthesis, 16 Springer-Verlag, New York, 1994; ISBN: 0-387-57505-7: b) K.Akaji etal., Tetrahedron Lett, 1994, 35, 3315-3318); c) F.Albericio et al., Tetrahedron Lett.,1997, 38, 4853-4856).

More information on trimethylaluminum AI(CH3); promoted amidation reactions of esters can be found in: J. I. Levin, E. Turos, S. M. Weinreb, Synth Commun. 1982, 12, 989-993.). For more information on nucleophiles, electrophiles and the leaving group concept see: M. B. Smith and J. March: Advanced organic chemistry, p. 275, 5" ed., (2001) John Wiley & Sons, New York, ISBN: 0-471-58589-0). More information on addition and subsequent removal of protective groups in organic synthesis can be found in: T.W. Greene and P.G.M. Wuts, “Protective Groups in

Organic Synthesis”, third edition, John Wiley & Sons, Inc., New York, 1999.

A suitable synthesis for the compounds of the invention is the following:

Synthesis route A

Reaction of a compound having formula (If) 0

OR a ’ 0 red (

R Rq wherein R, Ry, R4 have the meanings given above and Ry represents a branched or linear alkyl group (C4) or benzyl group with a regioselective brominating compound such as N-bromosuccinimide (NBS) in an organic solvent such as CCl, in the presence of a free-radical initiator such as dibenzoyl peroxide can give a compound of formula (1) 0]

OR,,

P \ 1)

RN Br (

RR, wherein R, R;, R4 and Ryo have the meanings given above. Reaction of a compound having formula (Ill) with an amine of general formula R,R3NH can give a compound of general formula (IV) oO

OR

Ny j Vv rR, NR,R, (Vv)

RR, wherein R, Ry, R2, R3, Ry and Ryo have the meanings given above.

Compounds of general formula (I'V) which have been obtained according to synthesis route A can be converted to compounds of general formula (I) wherein X represents subgroup (ii), analogously to the procedures described in WO 03/027076.

Synthesis route B

Reaction of a compound having formula (IV) wherein R, R4, Ry, Rs and R4 have the meanings given above and Ry, represents a hydrogen atom

0

ORy,

A (IV rR, NR,R, ) with N-methoxy-N-methylamine can give a compound of formula (V), 0 N y,

Ty o- Vv)

Ry NRR,

R Ry wherein R, Ry, Ry, Ry; and R, have the meanings given above. Reaction of a compound having formula (V) with an organometallic compound of general formula

Re-MgBr (a Grignard reagent) or Rs-Li (an organo lithium reagent) can give a compound of general formula (1), wherein X represents subgroup (i). Such a reaction is preferably carried out under N, in an anhydrous inert organic solvent.

Synthesis route C 2-Aryl-(1H}imidazole-4-carboxylates can be obtained according to the procedure described in Tetrahedron Lett. (1971), 18, 1439-1440 (Heindel and Chun).

Subsequent derivatisation (for example, an N-arylation or N-alkylation reaction) of the proper imidazole N-atom can produce compounds having formula (V1). Reaction of a compound having formula (V1) 0]

OR

, { ;

Ry (v1)

R wherein R and Ry have the meanings given above and Ry, represents a branched or linear alky! group (C1.4) or benzyl group, with a non-nucleophilic base such as lithium diisopropylamide (LDA), followed by an electrophile such as formic acid ethyl ester in an inert anhydrous organic solvent such as THF can give a compound of general formula (VII)

0]

N OR, ro \ vi)

Ry Y

R R, wherein R, Ry, R4 and Ry, have the meanings given above in this synthetic route.

Reductive amination of a compound having general formula (VII) with an amine of general formula R;R3NH in the presence of a reducing agent such as NaCNBH 3 can give a compound of general formula (IV) 0]

OR i \% rR, NR,R, (iv)

R R, wherein R, Ry, Raz, Rs, Rs and Ry have the meanings given above in this synthetic route.

Compounds of general formula (IV) which have been obtained according to synthesis route C can be converted to compounds of general formula (I) wherein X represents subgroup (ii), analogously to the procedures described in WO 03/027076.

Pharmaceutically acceptable salts may 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 instance an inorganic acid such as hydrochloric acid, or with an organic acid.

Due to their cannabinoid receptor modulating activity the compounds according to the invention are suitable for use in the treatment of psychiatric disorders such as psychosis, anxiety, depression, attention deficits, memory disorders, cognitive disorders, appetite disorders, obesity, in particular juvenile obesity and drug induced obesity, addiction, appetence, 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 ischaemia, cerebral apoplexy, craniocerebral frauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelinisation related disorders, as well as for the treatment of pain disorders, including neuropathic 9 pain disorders, and other diseases involving cannabinoid neurotransmission, including the treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases, gastrointestinal disorders, sexual disorders, liver cirrhosis, gastric ulcers, diarrhoea and cardiovascular 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 lip ase inhibitors. Specific examples of compounds which can be used in such combination preparations are (but not restricted to) the synthetic lipase inhibitor orlistat, lipase inhibitors isolated from micro organisms such as lipstatin (from Streptomyces toxytricini), ebelactone B 16 (from Streptomyces aburaviensis), synthetic derivatives of these compounds, as well as extracts of plants known to possess lipase inhibitory activity, for instance extracts of Alpinia officinarum or compounds isolated from such extracts like 3- methylethergalangin (from A. officinarum).

The compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances and/or liquid or solid carrier materials.

Compounds of the invention are generally administered as pharmaceutical compositions which are important and novel embodiments of the invention because of the presence of the compounds, more particularly specific compounds disclosed herein. Types of pharmaceutical compositions that may be used include but are not limited to tablets, chewable tablets, capsules, solutions, parenteral solutions, suppositories, suspensions, and other types disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art. In embodiments of the invention, a pharmaceutical pack or kit is provided comprising one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention. Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals products, which notice reflects approval by the agency of manufacture, use, or sale for human or veterinary administration.

PHARMACOLOGICAL METHODS

In vitro affinity for cannabinoid-CB; receptors

The affinity of the compounds of the invention for cannabinoid CB ; receptors can be determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabinoid CB; receptor is stably transfected in conjunction with [PHICP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [*HJHigand, with or without addition of compounds of the invention, separation of bound and free ligand is performed by filtration over glassfiber filters. Radioactivity on the fitter is measured by liquid scintillation counting.

In vitro affinity for cannabinoid-CB; receptors

The affinity of the compounds of the invention for cannabinoid CB , receptors can be determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabinoid CB, receptor is stably transfected in conjunction with [PHICP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [*HJHigand, with or without addition of compounds of the invention, separation of bound and free ligand is performed by filtration over glassfiber filters. Radioactivity on the filter is measured by liquid scintillation counting.

In vitro cannabinoid-CB, receptor antagonism

In vitro CB; receptor antagonism can be assessed with the human CB, receptor cloned in Chinese hamster ovary (CHO) cells. CHO cells are grown in a Dulbecco's

Modified Eagle's medium (DMEM) culture medium, supplemented with 10% heat- inactivated fetal calf serum. Medium is aspirated and replaced by DMEM, without fetal calf serum, but containing [*H]-arachidonic acid and incubated overnight in a cell culture stove (5% CO./95% air; 37 °C; water-saturated atmosphere). During this period [*H]-arachidonic acid is incorporated in membrane phospholipids. On the test day, medium is aspirated and cells are washed three times using 0.5 mL DMEM, containing 0.2% bovine serum albumin (BSA). Stimulation of the CB receptor by

WIN 55,212-2 leads to activation of PLA followed by release of [*H]-arachidonic acid into the medium. This WIN 55,212-2-induced release is concentration -dependently antagonized by CB, receptor antagonists.

In vivo cannabinoid-CB receptor antagonism

In vivo CB4 antagonism can be assessed with the CP-55,940-induced hypotension test in rat. Male normotensive rats (225-300 g; Harlan, Horst, The Netherlands) are anaesthetized with pentobarbital (80 mg/kg ip). 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 by a Nihon Kohden Carrier Amplifier (Type AP-621G; Nihon Kohden

B.V., Amsterdam, The Netherlands), the blood pressure signal is registered on a personal computer (Compaq Deskpro 386s), by means of a Po-Ne-Mah data- acquisition program (Po-Ne-Mah Inc., Storrs, USA). Heart rate is derived from the pulsatile pressure signal. All compounds are administered orally as a microsuspension in 1% methylcellulose 30 minutes before induction of the anesthesia which is 60 minutes prior to administration of the CB receptor agonist

CP-55,940. The injection volume is 10 mig. After haemodynamic stabilization the

CB; receptor agonist CP-55,940 (0.1 mg/kg i.v.) is administered and the hypotensive effect 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); Lange, J. H. M. et al., J.

Med. Chem. 2004, 47, 627-643.

In vivo cannabinoid-CB, receptor (partial) agonistic activity

Cannabinoid receptor agonistic or partial agonistic activity of compounds of the invention can be determined according to published methods, such as assessment of in vivo cannabimimetic effects (Wiley, J. L. et al,, J. Pharmacol. Exp. Ther. 2001, 296, 1013).

DETERMINATION OF AQUEOUS SOLUBILITY

The compounds are dissolved in DMSO to give 10 mg/mi stock solutions. These stock solutions are divided over several plates. Several diluted concentrations are made with DMSO to 5, 2.5, 1.25, 0.625 and 0.3125 mg/ml, respectively. The stock solution and each derived concentration from this stock solution is taken and diluted 100 fold with water or with water containing a buffer. In every case this gives an aqueous solution which contains 1 % DMSO (v/v) and 100, 50, 25, 12.5 and 6.25 and

3.125 ug compound /ml, respectively. The formation of a precipitate is determined in each plate. The measurements were performed at pH= 7, applying a HEPES buffer and at pH= 2, applying hydrochloric acid. Aqueous solubility is expressed in ug/ml in the table below.

The specific compounds of which the synthesis is described below are intended to further illustrate the invention in more detail, and therefore are not deemed to restrict the scope of the invention in any way.

EXAMPLE 1: SYNTHESES OF SPECIFIC COMPOUNDS

Synthesis of compound 1

Part A: Ethyl S-bromomethyl-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H- 16 imidazole-d-carboxylate. To a magnetically stired mixture of ethyl 1-(4- chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyi-1H-imidazole-4-carboxylate (2.05 g, 5.00 mmol) in CCl4 (25 mL) was added N-bromosuccinimide (NBS) (1.34 g, 7.53 mmol) and dibenzoy! peroxide (10.0 mg, assay 75%, 0.0310 mmol) and the resulting mixture was refluxed for 38 h. The formed precipitate was removed by filtration. The filtrate was successively washed with brine and water, dried over MgSO, filtered and concentrated in vacuo. The residue was purified by flash chromatography (CHCl /acetone = 98/2 (viv) to give ethyl 5-bromomethyi-1-(4-chloropheny!)-2-(2,4- dichlorophenyl)-1H-imidazole-4-carboxylate (1.29 g, 53 % yield) as an amorphous solid, "H-NMR (200 MHz, CDCl3): § 1.45{ J =7 Hz, 3H), 4.48 (q, J = 7 Hz, 2H), 4.72 (s,2H),7.18-7.43 (m, 7TH).

Part B: To a magnetically stirred solution of ethyl 5-bromomethyi-1-(4-chlorophenyl}- 2-(2,4-dichlorophenyl}-1H-imidazole-4-carboxylate (11.69 g, 23.9 mmol) in acetonitrile (40 ml) is added diisopropylethylamine (DIPEA) (5.2 ml, 30 mmol) and pyrrolidine (1.7 g, 23.9 mmol) and the resulting solution is reacted at room temperature for 2 hours. Water (250 ml) is added and the resulting mixture is extracted three times with dichloromethane. The collected dichloromethane layers are dried over Na ;SQ,, filtered and concentrated in vacuo. Subsequent purification with flash chromatography (petroleum ether/EtOAc = 20/80 (viv)) gives ethyl 1-(4- chlorophenyl)-2-(2,4-dichloro-phenyl)-5-{pyrrolidin-1-ylmethyl)-1H-imidazole4- carboxylate (3.7 gram, 32 % vield). "H-NMR (200 MHz, CDCl): §1.42 (t, J = 7 Hz,

3H), 1.62-1.72 (m, 4H), 2.42-2.50 (m, 4H), 3.83 (s, 2H), 4.43 (q, J = 7 Hz, 2H), 7.17- 7.40 (m, TH).

Part C: Cyclohexylamine (0.91 mi, 8 mmol) is dissolved in dichloromethane (20 mi) 9 and (CHskAl (4 ml of a 2 M solution in heptane, 8 mmol) is added. The resulting mixture is stirred for 10 minutes at room temperature and ethyl 1-(4-chlorophenyl)-2- (2,4-dichlorophenyl)-5-(pyrrolidin-1-ylmethyl)-1H-imidazole-4-carboxylate (1.8 gram , 3.8 mmol) is added. The resulting mixture is stirred at room temperature for 16 hours, poured into an aqueous NaHCO; solution, stirred for 30 minutes and filtered over hyflo. The filtrated is twice extracted with dichloromethane. The organic layers are dried over Na,SO,, filtered and concentrated in vacuo. Subsequent purification with flash chromatography (dichloromethane/methanol = 98/2 (v/v) gives N-cyclohexyi-1- (4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-(pyrrolidin-1-yimethyl)-1H-imidazole-4- carboxamide, compound 1 (1.06 gram, 53 % yield). Melting point: 155-157 °C. 16 lo] rr

Naa N ole

Cl

Analogously, the following compounds 2 — 6 were prepared : 2 2 N-cyclohexyi-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-(N-ethyl,N- methylaminomethyl)-1H-imidazole-4-carboxamide. Melting point: 135-136 °C. 0] cl -

Saf a N \

Cl 3. N-(piperidin-1-yi}-1-{4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-(N,N- dimethylaminomethyl)-1H-imidazole-4-carboxamide. Melting point: 163-166 []

C.

» 0 cl N+) if a N cl 4. N-cyclohexyl-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-(N,N- dimethylaminomethyl)-1H-imidazole-4-carboxamide. "H-NMR (400 MHz,

CDCl3): $1.12-1.68 (m, 6H), 1.72-1.80 (m, 2H), 1.99-2.06 (m, 2H), 2.18 (s, 6H), 3.65 (s, 2H), 3.88-4.00 (m, 1H), 7.22-7.37 (m, 8H). 0

RET

7 \ c N

Cl 5. N-(piperidin-1-yl)-1-(4~chlorophenyl)-2-(2,4-dichlorophenyl)-5-(pyrrolidin-1- ylmethy)-1H-imidazole-4-carboxamide. 2 HCI. "H-NMR (400 MHz, DMSO-d): § 1.46-1.56 (m, 2H), 1.79-1.96 (m, 8H), 2.90-3.00 (m, 2H), 3.26-3.50 (m, 6H), 4.57 (br s, 2H), 7.45-7.60 (m, 6H), 7.70 (d, J = 8 Hz, 1H), 10.95 (br s, 2H). 0 a {0

Oy

N c 0 & 2HCI cl 6. N-(piperidin-1-yl)-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-(N-ethyl,N- methylaminomethyl)-1H-imidazole-4-carboxamide. "H-NMR (400 MHz,

CDCl3): § 0.86 (t, J = 7 Hz, 3H), 1.38-1.46 (m, 2H), 1.72-1.78 (m, 4H), 2.14 (s, 3H), 2.36 (q, J = 7 Hz, 2H), 2.82-2.86 (m, 4H), 3.72 (s, 2H), 7.21-7.31 (m, 6H), 7.34 (d, J = 2 Hz, 1H), 8.16 (br s, 1H).

0) of N {3 0 N \ cl

EXAMPLE 2: DETERMINATION OF AQUEOUS SOLUBILITIES 9 Aqueous solubilities of two of the compounds of general formula (1), the compounds 1 and 4, and the compound 1-(4-chlorophenyl)-2-(2,4~dichloro-phenyl)-N-cyclohexyl- 1H-imidazole-4-carboxamide ( compound 3 from WO 03/063781) were determined according to the procedure described above. The results are shown in Table 1.

Table 1: aqueous solubility (expressed in pg/ml)

Compound name Aqueous solubility in pg/ml at:

TT ToH=2 JpH=7

EE FO EN

N-cyclohexyl-1-(4-chlorophenyi)-2-(2,4-dichloropheny!)- 5-(pyrrolidin-1-ylmethyl)-1H-imidazole-4-carboxamide compound 1

N-cyclohexyl-1-(4-chlorophenyi)-2-(2,4-dichlorophenyl)- 5-(N,N-dimethylaminomethyl)-1H-imidazole-4- carboxamide (compound 4

N-cyclohexyl-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)- 1H-imidazole-4-carboxamide (WO 03/063781

EXAMPLE 3: PHARMACOLOGICAL DATA

Pharmacological test results of a subset of the compounds of the invention, obtained with the assay described above, are given in table 2 below:

Table 2: pharmacological data

T Human cannabinoid-CB; receptor vitro affinity . pK value (Compound | ~~ rr

Compound? | ~~ 81 (Compound2 | ~~ 82

Compoundd | ~~ 70

Compound 4 [Compounds | 63 (Compound6 [68

Claims (26)

Claims

1. Compounds of the general formula (1) 1 ’ AK on (0) R NR Ry ’ wherein: - Rand R, are the same or different and represent phenyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridaziny! or triazinyt, which groups may be substituted with 1, 2, 3 or 4 substituents Y, which can be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, hydroxymethyl, hydroxyethyl, chloro, iodo, bromo, fluoro, trifluoromethyl, trifluoromethoxy, methylsulfonyl, phenyl and cyano, or R represents naphtyl, or R represents a C1. branched or linear alkyl group, a C3 cycloalkyl group, Cs cycloalkyl-C.2 alkyl group, a Cs branched or linear heteroalkyl group, a Cs heterocycloalkyl group or a Cs heterocycloalkyl -C,., alkyl group which groups may be substituted with a fluoro atom or a CF 3 or OH group, - Roand R; are the same or different and represent H, a Cbranched or linear alkyl group which alkyl group may be substituted with a hydroxy group, or 1-3 fluoro atoms or, R, represents a branched or linear C1.; alkoxy group, with the proviso that R; represents H or a methyl group, or R; and R; - together with the nitrogen atom to which they are bonded - form a saturated or unsaturated non-aromatic, monocyclic or bicyclic, heterocyclic group having 5 to 10 ring atoms which heterocyclic group contains one or two "ring heteroatoms from the group (N, O, S), which heteroatoms can be the same or different, which heterocyclic group may be substituted with a C3 alkyl group, a hydroxy group, or a fluoro atom, - Ry represents H or a methyl, ethyl, propyl, isopropyl or n-butyl group, - Xrepresents one of the subgroups (i), or (ii),

0 0 EE “R, (i) (ii) wherein:

5 - Rs represents a hydrogen atom, or a Cy. branched or linear alkyl group, C1.> alkyl-SO2-C1.4- alkyl group, Caz cycloalkyl group, Cs;-cycloalkyl-Cs.-alkyl group, Csr-heterocycloalkyl-C+.o-alkyl group which groups may be substituted with a hydroxy, methyl or trifluoromethyl group or a fluoro atom and which Cs. rheterocycloalkyl-Cy.o-alky! group contains one or two heteroatoms from the group (O, N, S), or Rs represents a phenyl, benzyl, phenethyl or phenyipropyl group which may be substituted on their phenyl ring with 1-3 substituents Y, wherein Y has the abovementioned meaning, or Rs represents a pyridyl or thienyl group,

- Rs represents a hydrogen atom or a branched or linear C 4.3 alkyl group,

- Ry represents hydrogen, a branched or linear C4 alkyl or Cg-cycloalkyl-Cyo- alkyl group, branched or linear C4 alkoxy, Ca cycloalkyl, Cs. bicycloalkyi, Cs-10 bicycloalkyl -C,., alkyl, Cg.19 tricycloalkyl, Ceo tricycioalkylmethyl, which groups may contain one or more heteroatoms from the group (O, N, S) and which groups may be substituted with a hydroxy group, 1-3 methyl groups, an ethyl group or 1-3 fluoro atoms, or R; represents a phenyl, phenylamino, phenoxy, benzyl, phenethyl or phenylpropyl group, optionally substituted on their phenyl ring with 1-3 substituents Y, wherein Y has the abovementioned meaning, or Rr represents a pyridyl or thienyl group, or R; represents a group NRgRg wherein

- Rg and Ry - together with the nitrogen atom to which they are attached -form a saturated or unsaturated, monocyclic or bicyclic, heterocyclic group having 4 to 10 ring atoms, which heterocyclic group contains one or more heteroatoms from the group (O, N, S) and which heterocyclic group may be substituted with a branched or finear C3 alkyl, phenyl, hydroxy or trifluoromethyl group or a fluoro atom, or - Re and R; — together with the nitrogen atom to which they are attached - form a saturated or unsaturated, monocyclic or bicyclic, heterocyclic group having 4 to 10 ring atoms, which heterocyclic group contains one or more heteroatoms from the group (O, N, S) and which heterocyclic group may be substituted with a branched or linear C3 alkyl, phenyl, amino, hydroxy or trifluoromethyl group or a fluoro atom, and all stereoisomers, as well as pharmacologically acceptable salts and prodrugs thereof.

2. Compounds as claimed in claim 1 having general formula (I) wherein X represents the subgroup (ii), and all other symbols have the meanings as given in claim 1.

3. Compounds as claimed in claim 1 having formula (1) wherein X represents the subgroup (ii), R represents phenyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, which groups may be substituted with 1, 2, 3 or 4 substituents Y, which can be the same or different, from the group methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, hydroxymethyl, hydroxyethyl, chloro, iodo, bromo, fluoro, trifluoromethyl, trifluoromethoxy, methyisulfonyl, phenyl or cyano, or R represents naphtyl, and all other symbols have the meanings as given in claim 1,

4. Compounds of the general formula (IV) 0 OR N { 10 rR, NRR, (v) RR, wherein R, Ry, Ry, R; and Ry have the meanings given in claim 1 and Ry represents a hydrogen atom, a linear or branched C4 alkyl group or a benzyl group, such compounds being useful in the synthesis of compounds of the general formula (1).

5. Compounds of the general formula (VI) 0} OR NT J Rel ong RR, wherein Ry and R4 have the meanings given above in claim 1 and R represents a Cie branched or linear alkyl group, a C,; cycloalkyl group, Cs; cycloalkyl -Cy., alkyl group, a C34 branched or linear heteroalkyl group, a Cs heterocycloalkyl group or a Cs heterocycloalkyl-C,, alkyl group which groups may be substituted with a fluoro atom or a CF; or OH group, and Ry, represents a branched or linear alkyl group (C+.) or benzyl group.

6. Pharmaceutical compositions containing at least one compound as claimed in any one of the claims 1-3 as an active component.

7. A compound as claimed in any of the claims 1-3, or a salt thereof, for use as a medicament

8. Use of a compound as claimed in any one of the claims 1-3 for the preparation of a pharmaceutical composition for the treatment of disorders involving cannabinoid neurotransmission.

9. Use as claimed in claim 8, characterized in that said disorders are psychosis, anxiety, depression, attention deficits, memory disorders, cognitive disorders, appetite disorders, obesity, in particular juvenile obesity and drug induced obesity, addiction, appetence, 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 ischaemia, cerebral apoplexy, craniocerebral trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelinisation related disorders, as well as for the treatment of pain disorders, including neuropathic pain disorders, and other diseases involving cannabinoid

PCT/EP2004/052575 ” neurotransmission, including the treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases, gastrointestinal disorders, sexual disorders, liver cirrhosis, gastric ulcers, diarrhoea and cardiovascular disorders.

10. Use as claimed in claim 8, characterized in that said disorders are eating disorders, in particular obesity, juvenile obesity and drug induced obesity.

11. Use of a compound as claimed in claim 1 and at least one lipase inhibitor for the preparation of a pharmaceutical composition for the treatment of eating disorders, in particular obesity, juvenile obesity and drug induced obesity.

12. Use of a compound as claimed in claim 1 in the manufacture of a medicament for use with at least one lipase inhibitor, for the treatment of eating disorders, in particular obesity, juvenile obesity and drug induced obesity.

13. Use as claimed in claim 11, or claim 12 characterized in that said lipase inhibitor is orlistat or lipstatin.

14. Use of a compound as claimed in any of the claims 1-3, or a salt thereof, in the manufacture of a medicament for treating a disease, illness, disorder or condition.

15. A substance or composition for use in a method of treatment, said substance or compasition comprising a compound as claimed in any one of the claims 1-3, or a salt thereof, and said method comprising administering said substance or composition.

16. A substance or composition for use in a method for the treatment of disorders involving cannabinoid neurotransmission, said substance or composition comprising a compound as claimed in any of the claims 1-3, and said method comprising administering said substance or composition.

17. A substance or composition for use in a method of treatment as claimed in claim 16, characterized in that said disorders are psychosis, anxiety, depression, attention deficits, memory disorders, cognitive disorders, appetite disorders, obesity, in particular juvenile obesity and drug induced obesity, AMENDED SHEET

PCT/EP2004/052575 ® 2 addiction, appetence, 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 ischaemia, cerebral apoplexy, craniocerebral trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelinisation related disorders, as well as for the treatment of pain disorders, including neuropathic pain disorders, and other diseases involving cannabinoid neurotransmission, including the treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases, gastrointestinal disorders, sexual disorders, liver cirrhosis, gastric ulcers, diarrhoea and cardiovascular disorders.

18. A substance or composition for use in a method of treatment as claimed in claim 16, characterized in that said disorders are eating disorders, in particular obesity, juvenile obesity and drug induced obesity.

19. A substance or composition for use in a method for the treatment of eating disorders, in particular obesity, juvenile obesity and drug induced obesity, said substance or composition comprising a compound as claimed in claim 1 and at least one lipase inhibitor, and said method comprising administering said substance or composition.

20. A substance or composition for use with at least one lipase inhibitor in a method for the treatment of eating disorders, in particular obesity, juvenile obesity and drug induced obesity, said substance or composition comprising a compound as claimed in claim 1, and said method comprising administering said substance or composition and said lipase inhibitor.

21. A substance or composition for use in a method of treatment as claimed in claim 19 or claim 20, characterized in that said lipase inhibitor is orlistat or lipstatin.

22. A compound as claimed in any one of claims 1 to 5 or 7, substantially as herein described and illustrated. AMENDED SHEET

PCT/EP2004/052575 ’s

23. A composition as claimed in claim 6, substantially as herein described and illustrated.

24. Use as claimed in any one of claims 8 to 14, substantially as herein described and illustrated.

25. A substance or composition for use in a method of treatment as claimed in any one of claims 15 to 21, substantially as herein described and illustrated.

26. A new compound, a new composition, a new use of a compound as claimed in any one of claims 1 to 3, a new use of a compound as claimed in claim 1 and at least one lipase inhibitor, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET