HK1119398A

HK1119398A - Benzotriazole derivatives as cannabinoid receptor antagonists

Info

Publication number: HK1119398A
Application number: HK08111249.8A
Authority: HK
Inventors: Monique Jenny Marie Berwaer; Joannes Theodorus Maria Linders; Peter John King; Geert Maria Robert Van Hecke
Original assignee: Janssen Pharmaceutica N.V.
Priority date: 2005-04-29
Filing date: 2006-04-24
Publication date: 2009-03-06

Description

Benzotriazole derivatives as cannabinoid receptor antagonists

Background

The present invention relates to a group of benzotriazole derivatives, to a process for the preparation of these compounds and to pharmaceutical compositions containing one or more of said compounds as active ingredient.

EP 293978; venet M. et al, actualites de chimie terreutique (1997) volume 23, pages 239-246 andp. et al, Nuclear Medicine&(1H-pyrrol-1-ylmethyl) substituted benzotriazole derivatives are described as aromatase inhibitors for the treatment of estrogen dependent diseases in Biology (1998) volume 25, page 497-501. Fused tricyclic and fused tetracyclic pyrazole derivatives have also recently been introduced as potential CB₁Antagonist (Current Opinion in Drug Discovery)& Development 20047(4)：498-506)。

It has been unexpectedly found that known and novel benzotriazole derivatives of formula (I) and pharmaceutically acceptable addition salts and stereoisomers thereof are potent cannabinoid CB₁Receptor modulators (also known as antagonists or inverse agonists) and are therefore useful in the treatment of obesity, psychiatric and neurological disorders, and other cannabinoid-CB₁Neurotransmission-associated diseases (Current Opinion in drug discovery)& Development 20047(4)：498-506)。

Detailed Description

The present invention relates to benzotriazole derivatives of the formula:

wherein

R¹Is hydrogen, halogen, hydroxy, hydroxymethyl, trifluoromethyl, C_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkoxycarbonyl-, carboxy, formyl, (hydroxyimino) methyl, cyano, amino, mono-and di- (C)_1-6Alkyl) amino or nitro;

R²is hydrogen; optionally substituted with Ar¹、C_3-7Cycloalkyl, hydroxy or C_1-6Alkoxy-substituted C_1- ₁₀An alkyl group; ar (Ar)¹；C_2-6An alkenyl group; c_2-6An alkynyl group; c_3-7A cycloalkyl group; bicyclo [2.2.1]Hept-2-yl; 2, 3-dihydro-1H-indenyl; 1, 2, 3, 4-tetrahydronaphthyl; a hydroxyl group; optionally substituted with Ar²Substituted C_2-6An alkenyloxy group; c_2-6An alkynyloxy group; a pyrimidinyloxy group; bis (Ar)²) A methoxy group; (1-C)_1-4Alkyl-4-piperidinyl) oxy; or R²Is C optionally substituted by halogen_1-10An alkoxy group; a hydroxyl group; c_1-6An alkoxy group; ammoniaA group; mono-and di (C)_1-6Alkyl) amino; a trifluoromethyl group; a carboxyl group; c_1-6An alkoxycarbonyl group; ar (Ar)¹；Ar²-O-；Ar²-S-；C_3-7A cycloalkyl group; 2, 3-dihydro-1, 4-benzodioxinyl; 1H-benzimidazolyl; c_1-4Alkyl substituted 1H-benzimidazolyl; (1, 1' -biphenyl) -4-yl or 2, 3-dihydro-2-oxo-1H-benzimidazolyl;

R³is hydrogen, hydroxy or C_1-6An alkyl group;

Ar¹is phenyl, naphthyl, pyridyl, aminopyridyl, imidazolyl, triazolyl, thienyl, halothienyl, furyl, C_1-6An alkyl furyl, halo furyl, thiazolyl or phenyl substituted with up to 3 substituents each independently selected from the group consisting of halogen, hydroxy, hydroxymethyl, trifluoromethyl, C_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkoxycarbonyl-, carboxy, formyl, (hydroxyimino) methyl, cyano, amino, nitro or mono-and di- (C)_1-6Alkyl) amino;

Ar²is phenyl, pyridyl or phenyl substituted with up to 3 substituents, each substituent being independently selected from halogen, hydroxy, hydroxymethyl, trifluoromethyl, C_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkoxycarbonyl-, carboxy, formyl, (hydroxyimino) methyl, cyano, amino, mono-and di- (C)_1-6Alkyl) amino or nitro;

het represents a5 or 6 membered partially saturated monocyclic heterocycle or monocyclic aromatic heterocycle selected from furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyrimidinyl, pyridinyl, pyrazinyl, triazinyl, pyridazinyl, 2H-pyranyl or 4H-pyranyl, wherein the heterocycle is optionally substituted with up to 3 substituents each independently selected from halo, hydroxy, hydroxymethyl, trifluoromethyl, C_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkoxycarbonyl-, carboxy, formyl, (hydroxyimino) methyl, cyano, amino, mono-and di- (C)_1-6Alkyl) amino or nitro; in a particular embodiment, said Het is optionally substituted with C_1-6Alkyl substitution.

In particular, the invention relates to compounds of formula (I) as CB₁Use of a receptor modulator for the manufacture of a medicament for the treatment of: obesity, psychiatric and neurological disorders and other cannabinoid-CB₁Neurotransmission-related diseases. CB (CB)₁Receptor antagonists have potential in the treatment of a variety of diseases such as neuroinflammatory disorders, cognitive and memory disorders, obesity, psychosis, gastrointestinal disorders, and addiction (e.g., to help quit smoking). Pre-synaptic CB in the lung of guinea pig₁Following receptor-mediated inhibition of norepinephrine release, CB has been proposed₁The receptor antagonists are useful in the treatment of asthma. Another disease where the compound may have therapeutic potential is cirrhosis of the liver. This is based on the presence of CCl₄Reversal of hypotension was observed in rats induced cirrhosis, with concomitant decrease in mesenteric blood flow and portal vein pressure. It is therefore an object of the present invention to provide compounds of the formula (I) as CB₁Use of a receptor modulator for the manufacture of a medicament for the treatment of: obesity, psychiatric and neurological disorders and other cannabinoid-CB₁Neurotransmission-related diseases, in particular, the treatment of neuroinflammatory diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, dementia of HIV-1 type, frontotemporal dementia and various prion diseases; cognitive and memory disorders such as dementia and schizophrenia; obesity; psychosis; addiction, e.g. to help quit smoking; gastrointestinal disorders such as nausea and vomiting, gastric ulcers, irritable bowel syndrome, Chron's disease, secretory diarrhoea, paralytic ileus and gastro-oesophageal reflux.

The term halogen as used in the foregoing definitions generally refers to fluorine, chlorine, bromine and iodine; the term "C_1-4Alkyl is meant to include straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atomsSuch as methyl, ethyl, 1-methylethyl, 1-dimethylethyl, propyl, and the like; "C_1-6Alkyl "is meant to include C as defined above_1-4Alkyl groups and their higher homologs having 5 to 6 carbon atoms such as 2-methylpropyl, butyl, pentyl, hexyl, and the like; "C_1-10Alkyl "is meant to include C as defined above_1-6Alkyl and its higher homologues having 7 to 10 carbon atoms; the term "C_3-7Cycloalkyl "is typically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; "C_2-6Alkenyl "is defined as straight and branched chain hydrocarbon groups containing one double bond and having 2 to 6 carbon atoms, such as vinyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-methyl-2-butenyl, and the like; "C_2-6Alkynyl "is defined as straight and branched chain hydrocarbon radicals containing one triple bond and having 2 to 6 carbon atoms, such as 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, and the like; if C is present_2-6Alkenyl or C_2-6Alkynyl is substituted by a heteroatom, then said C attached to said heteroatom_2-6Alkenyl or said C_2-6The carbon atoms of the alkynyl group are preferably saturated.

The above definitions and the references hereinafter to heterocycles are meant to include all possible isomers thereof, for example triazolyl also includes 1, 2, 4-triazolyl and 1, 3, 4-triazolyl; oxadiazolyl groups include 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl and 1, 3, 4-oxadiazolyl; the thiadiazolyl group includes 1, 2, 3-thiadiazolyl group, 1, 2, 4-thiadiazolyl group, 1, 2, 5-thiadiazolyl group and 1, 3, 4-thiadiazolyl group.

Furthermore, the above definitions and the heterocycles mentioned hereinafter may be attached to the rest of the molecule of formula (I) via any suitable ring carbon or ring heteroatom. Thus, for example, when the heterocycle is imidazolyl, it can be 1-imidazolyl, 2-imidazolyl, 3-imidazolyl, 4-imidazolyl and 5-imidazolyl; when the heterocyclic ring is thiazolyl, it may be 2-thiazolyl, 4-thiazolyl or 5-thiazolyl.

The compounds of interest according to the invention are the compounds defined below: wherein the 1-Het-1-ylmethyl moiety is substituted at position 5 or 6 of the benzotriazole heterocycle and wherein Het is a5 membered partially saturated monocyclic heterocycle or monocyclic aromatic heterocycle selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl.

Further valuable compounds of the invention are valuable compounds of the formula (I) wherein Het is imidazolyl or 1, 2, 4-triazolyl; r¹Is halogen, C_1-4Alkyl radical, C_1-4Alkoxy or trifluoromethyl; r²Is phenyl, C_3-7Cycloalkyl or optionally substituted by Ar¹Substituted C_1-6An alkyl group.

Also of interest are compounds defined below, wherein R²Is hydrogen; c_1-6Alkyl (optionally substituted by phenyl, naphthyl, thienyl, furyl, C_1-4Alkyl furyl group, C_3-7Cycloalkyl, hydroxy or C_1-4Alkoxy substituted); a phenyl group; c_2-6An alkenyl group; c_2-6An alkynyl group; c_3-7A cycloalkyl group; bicyclo [2.2.1]Hept-2-yl; 2, 3-dihydro-1H-indenyl; 1, 2, 3, 4-tetrahydronaphthyl; a hydroxyl group; c_2-6Alkenyloxy (optionally substituted with phenyl); c_2-6An alkynyloxy group; a pyrimidinyloxy group; di (phenyl) methoxy; (1-C)_1-4Alkyl-4-piperidinyl) oxy; or C_1-6Alkoxy, optionally substituted with: halogen, hydroxy, amino, mono-and di (C)_1-4Alkyl) amino, trifluoromethyl, carboxyl, C_1-6Alkoxycarbonyl, phenyl, thienyl, furyl, pyridyl, phenoxy, phenylthio, C_3-7Cycloalkyl, 2, 3-dihydro-1, 4-benzodioxinyl, 1H-benzimidazolyl, C_1-4Alkyl-substituted 1H-benzimidazolyl, (1, 1-biphenyl) -4-yl or 2, 3-dihydro-2-oxo-1H-benzimidazolyl.

A particular group of compounds are compounds of formula (I) wherein one or more of the following limitations apply:

-R¹is hydrogenHalogen, trifluoromethyl, C_1-4Alkyl radical, C_1-4Alkoxy or C_1-4Alkoxycarbonyl-; in particular, R¹Is halogen, C_1-4Alkyl radical, C_1-4Alkoxy or trifluoromethyl;

-R²is phenyl, C_3-7Cycloalkyl or optionally substituted by Ar¹Substituted C_1-6An alkyl group; in particular, R²Is phenyl, cyclohexyl or optionally substituted by Ar¹Substituted C_1-6An alkyl group;

-Ar¹is phenyl or phenyl substituted with up to 3 halogen substituents; more specifically, Ar¹Is phenyl or chloro-phenyl, wherein the chloro substituent is located in the para position relative to the attachment of the phenyl ring to the remainder of the molecule;

-Het represents a5 or 6 membered partially saturated monocyclic heterocycle or monocyclic aromatic heterocycle selected from thiazolyl, imidazolyl, triazolyl, pyrimidinyl or pyridinyl, wherein said heterocycle is optionally substituted by C_1-4Alkyl substitution; in a particular embodiment Het represents a5 membered partially saturated monocyclic heterocycle or monocyclic aromatic heterocycle selected from thiazolyl, imidazolyl or triazolyl; in a more particular embodiment, Het represents imidazolyl or 1, 2, 4-triazolyl.

Furthermore, a further group of compounds of the formula (I) (hereinafter also referred to as compounds of the formula (Ia)) differs from EP 293978 andand the like (supra) except that Het' does not represent imidazolyl, 1, 2, 4-triazolyl or 1, 3, 4-triazolyl. Venet M. et al (supra) disclose two compounds, 6- [ (4-chloro-phenyl) -pyridin-3-yl-methyl]-1-methyl-1H-benzotriazole and 6- [ (4-chloro-phenyl) -pyrimidin-5-yl-methyl]-1-methyl-1H-benzotriazole, wherein Het' represents pyridinyl and pyrimidinyl, respectively, but the above article is totally silent about the potential use of these compounds as CB-1 antagonists.

It is therefore an object of the present invention to provide compounds of the formula:

wherein

R²is hydrogen; optionally substituted with Ar¹、C_3-7Cycloalkyl, hydroxy or C_1-6Alkoxy-substituted C_1- ₁₀An alkyl group; ar (Ar)¹；C_2-6An alkenyl group; c_2-6An alkynyl group; c_3-7A cycloalkyl group; bicyclo [2.2.1]Hept-2-yl; 2, 3-dihydro-1H-indenyl; 1, 2, 3, 4-tetrahydronaphthyl; a hydroxyl group; optionally substituted with Ar²Substituted C_2-6An alkenyloxy group; c_2-6An alkynyloxy group; a pyrimidinyloxy group; bis (Ar)²) A methoxy group; (1-C)_1-4Alkyl-4-piperidinyl) oxy; or R²Is C optionally substituted by halogen_1-10An alkoxy group; a hydroxyl group; c_1-6An alkoxy group; an amino group; mono-and di (C)_1-6Alkyl) amino; a trifluoromethyl group; a carboxyl group; c_1-6An alkoxycarbonyl group; ar (Ar)¹；Ar²-O-；Ar²-S-；C_3-7A cycloalkyl group; 2, 3-dihydro-1, 4-benzodioxinyl; 1H-benzimidazolyl; c_1-4Alkyl substituted 1H-benzimidazolyl; (1, 1' -biphenyl) -4-yl or 2, 3-dihydro-2-oxo-1H-benzimidazolyl;

R³is hydrogen, hydroxy or C_1-6An alkyl group;

Ar¹is phenyl, naphthyl, pyridyl, aminopyridyl, imidazolyl, trisAzolyl, thienyl, halothienyl, furyl, C_1-6An alkyl furyl, halo furyl, thiazolyl or phenyl substituted with up to 3 substituents each independently selected from the group consisting of halogen, hydroxy, hydroxymethyl, trifluoromethyl, C_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkoxycarbonyl-, carboxy, formyl, (hydroxyimino) methyl, cyano, amino, nitro or mono-and di- (C)_1-6Alkyl) amino;

het' represents a5 or 6 membered partially saturated monocyclic heterocycle or monocyclic aromatic heterocycle selected from furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrimidinyl, pyridyl, pyrazinyl, triazinyl, pyridazinyl, 2H-pyranyl or 4H-pyranyl, wherein the heterocycle is optionally substituted with up to 3 substituents each independently selected from halo, hydroxy, hydroxymethyl, trifluoromethyl, C_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkoxycarbonyl-, carboxy, formyl, (hydroxyimino) methyl, cyano, amino, mono-and di- (C)_1-6Alkyl) amino or nitro; in a particular embodiment, said Het' is optionally substituted by C_1-6Alkyl substitution;

with the proviso that the compound of formula (Ia) is not represented

6- [ (4-chloro-phenyl) -pyridin-3-yl-methyl ] -1-methyl-1H-benzotriazole or

6- [ (4-chloro-phenyl) -pyrimidin-5-yl-methyl ] -1-methyl-1H-benzotriazole.

A particular group of compounds are compounds of formula (Ia) wherein one or more of the following limitations apply:

-R¹is hydrogen, halogen, trifluoromethyl, C_1-4Alkyl radical, C_1-4Alkoxy or C_1-4Alkoxycarbonyl-; in particular, R¹Is halogen, C_1-4Alkyl radical, C_1-4Alkoxy or trifluoromethyl;

-Het' represents a5 or 6 membered partially saturated monocyclic heterocycle or monocyclic aromatic heterocycle selected from thiazolyl, pyrimidinyl or pyridinyl, wherein said heterocycle is optionally substituted by C_1-4Alkyl substitution; in a particular embodiment, Het' represents thiazolyl;

the present invention therefore relates to compounds of formula (Ia) for use as medicaments, in particular to the use of compounds of formula (Ia) for the manufacture of medicaments for the treatment of the following diseases: obesity, psychiatric and neurological disorders and other cannabinoid-CB₁Neurotransmission-related diseases. In particular, treatment of neuroinflammatory diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, dementia of HIV-1 type, frontotemporal dementia and various prion diseases; cognitive and memory disorders such as dementia and schizophrenia; obesity; psychosis; addiction, e.g. to help quit smoking; gastrointestinal disorders such as nausea and vomiting, gastric ulcers, irritable bowel syndrome, Chron's disease, secretory diarrhoea, paralytic ileus and gastro-oesophageal reflux.

Wherein Het represents a5 or 6 membered partially saturated N-containing monocyclic heterocycleCompounds of formula (I) having a cyclic or N-containing monocyclic aromatic heterocycle may generally be prepared as described in EP 293978 by reacting said heterocycle of formula (III) or its alkali metal salt with said benzotriazole of formula (II)N-alkylation.

W used for the reaction of (II) with (III) is a suitable leaving group such as halogen (e.g. chloro), sulfonyloxy (e.g. 4-methylbenzenesulfonyloxy).

As described aboveNThe alkylation is conveniently carried out by stirring the reactants in the presence of a suitable organic solvent: such as aromatic hydrocarbons (e.g., toluene); ketones (e.g., 4-methyl-2-pentanone); ethers (e.g., tetrahydrofuran); polar aprotic solvents (e.g., N-dimethylformamide) and mixtures of these solvents. Slight heating can suitably increase the reaction rate.

The addition of a suitable base, such as an alkali or alkaline earth metal carbonate, bicarbonate, hydroxide, amide or hydride (e.g., sodium hydroxide, sodium hydride) or an organic base (e.g., pyridine or N, N-diethylethylamine) may be employed.

Alternatively, compounds of formula (I) wherein Het represents a5 or 6 membered partially saturated N-containing monocyclic heterocycle or N-containing monocyclic aromatic heterocycle may be prepared by:

i) reacting said heterocycle of formula (III) or its alkali metal salt with an arylamine of formula (IV)N-alkylation;

ii) N-alkylating a secondary amine of formula (VI) with a compound of formula (V) to give a nitroarylamine of formula (VII);

iii) followed by reduction and N-nitrosation to give the compound of formula (I).

The use of W in step i) and step ii) above refers to suitable leaving groups such as halogen (e.g. chloro), sulfonyloxy (e.g. 4-methylbenzenesulfonyloxy). The N-alkylation in steps i) and ii) above is conveniently carried out as described hereinbefore.

The reduction of the aromatic nitro compound (VII) is conveniently carried out with reducing agents known in the art, see for example Advanced Organic Chemistry-Jerry March-third edition, sections 9-48. Many reducing agents have been used to reduce aromatic nitro compounds, among which Zn, Sn or Fe and acids; catalytic hydrogenation such as 5% Pt/C; AlH₃-AlCl₃(ii) a Hydrazine and a catalyst; dodecacarbonyl iron [ Fe ]₃(CO)₁₂]-methanol; TiCl (titanium dioxide)₃(ii) a Hot liquid paraffin; formic acid and Pd/C; sulfides such as NaHS, (NH)₄)₂S or polysulfides. As described in the examples below, the preferred reduction reaction is catalytic hydrogenation using 5% Pt/C.

The N-nitrosation reaction is carried out using methods known in the art, see, for example, advanced organic Chemistry-Jerry March-third edition, sections 2-50. The reaction is typically carried out in aqueous hydrochloric acid or acetic acid with nitrous acid generated in situ from sodium nitrite.

Compounds of formula (I) wherein the 5-or 6-membered partially saturated N-containing monocyclic heterocycle or N-containing monocyclic aromatic heterocycle (Het) is not linked to the remainder via an N-atom, hereinafter also referred to as compounds of formula (Ib), can generally be prepared by alkylation of a benzotriazole of formula (VIII) below, using said heterocycle of formula (III) as organometallic reagent, at low temperatures:

the alkylation described above is conveniently carried out under the following conditions: the heterocyclic ring is converted to the aryllithium reagent by adding butyllithium to the heterocyclic ring in a first step at low temperature (typically-70 ℃) in the presence of a suitable organic solvent such as an ether (e.g. tetrahydrofuran). In a subsequent step, the organometallic reagent thus obtained is stirred at low temperature (generally-70 ℃) for 1-6 hours, generally 2 hours, with the benzotriazole of formula (VIII) in the same suitable organic solvent.

The triarylcarbonols thus obtained can be easily reduced with hydrogenation reagents, such as LiAlH₄-AlCl₃；NaBH₄/F₃CCOOH; diiodomethylsilane (Me)₂SiI₂)；Fe(CO)₅；P₂I₄Or tin and hydrochloric acid. The triarylcarbonol is typically SnCl as described in the examples below₂And HCl (12N) reduction.

EP 293978 also provides the preparation, dosage form and pharmaceutical properties of aromatase inhibitors of the compound of formula (Ic) for the treatment of estrogen dependent diseases. The structure of the compounds of formula (Ic) and the pharmaceutically acceptable acid addition salts or stereochemically isomeric forms thereof is represented by:

wherein A is¹＝A²-A³＝A⁴Is a divalent group having the formula:

-CH＝N-CH＝CH-(a-1)，

-CH-N- (a2), or

-CH＝N-N＝CH-(a3)；

R is hydrogen or C_1-6An alkyl group;

R¹is hydrogen, C_1-10Alkyl radical, C_3-7Cycloalkyl radical, Ar¹、Ar²-C_1-6Alkyl radical, C_2-6Alkenyl or C_2-6An alkynyl group;

R²is hydrogen; optionally substituted with Ar₁、C_3-7Cycloalkyl, hydroxy or C_1-6Alkoxy-substituted C_1- ₁₀An alkyl group; ar (Ar)¹；C_2-6An alkenyl group; c_2-6An alkynyl group; c_3-7A cycloalkyl group; bicyclo [2.2.1]Hept-2-yl; 2, 3-dihydro-1H-indenyl; 1, 2, 3, 4-tetrahydronaphthyl; a hydroxyl group; optionally substituted with Ar²Substituted C_2-6An alkenyloxy group; c_2-6An alkynyloxy group; a pyrimidinyloxy group; bis (Ar)²) A methoxy group; (1-C)_1-4Alkyl-4-piperidinyl) oxy; or R²Is C optionally substituted by halogen_1-10An alkoxy group; a hydroxyl group; c_1-6An alkoxy group; an amino group; mono-and di (C)_1-6Alkyl) amino; a trifluoromethyl group; a carboxyl group; c_1-6An alkoxycarbonyl group; ar (Ar)¹；Ar²-O-；Ar²-S-；C_3-7A cycloalkyl group; 2, 3-dihydro-1, 4-benzodioxinyl; 1H-benzimidazolyl; c_1-4Alkyl substituted 1H-benzimidazolyl; (1, 1-biphenyl) -4-yl or 2, 3-dihydro-2-oxo-1H-benzimidazolyl;

R³is hydrogen, nitro, amino, mono-and di (C)_1-6Alkyl) amino, halogen, C_1-6Alkyl, hydroxy or C_1-6An alkoxy group;

Ar¹is phenyl, substituted phenyl, naphthyl, pyridyl, aminopyridyl, imidazolyl, triazolyl, thienyl, halothienyl, furyl, C_1-6An alkyl furyl, halo furyl, or thiazolyl group;

Ar²is phenyl, pyridyl or phenyl substituted with up to 3 substituents, each substituent being independently selected fromHalogen, hydroxy, hydroxymethyl, trifluoromethyl, C_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkoxycarbonyl-, carboxy, formyl, (hydroxyimino) methyl, cyano, amino, nitro or mono-and di- (C)_1-6Alkyl) amino.

Unexpectedly, we have found that aromatase inhibitors, hereinafter also referred to as (compounds of) the invention, as identified above, are potent cannabinoid-CB₁Modulators (also known as antagonists or inverse agonists) useful for the treatment of obesity, psychiatric and neurological disorders and other cannabinoid-CB₁Neurotransmission-related diseases. In particular, for the treatment of neuroinflammatory diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, dementia of HIV-1 type, frontotemporal dementia and various prion diseases; cognitive and memory disorders such as dementia and schizophrenia; obesity; psychosis; addiction, e.g. to help quit smoking; gastrointestinal disorders such as nausea and vomiting, gastric ulcers, irritable bowel syndrome, Chron's disease, secretory diarrhoea, paralytic ileus and gastro-oesophageal reflux.

As for EP 293978, a compound is disclosed, namely racemic 6- [ (4-chlorophenyl) -1H-1, 2, 4-triazol-1-ylmethyl]-1-cyclohexyl-1H-benzotriazole, which we have unexpectedly found that there is only one enantiomer, namely (-) -6- [ (4-chlorophenyl) -1H-1, 2, 4-triazol-1-ylmethyl]-1-cyclohexyl-1H-benzotriazoles having CB₁Modulating the activity of the agent. It is therefore an object of the present invention to provide compounds of formula (Ic) wherein said compounds consist of the enantiomer (-) -6- [ (4-chlorophenyl) -1H-1, 2, 4-triazol-1-ylmethyl]-1-cyclohexyl-1H-benzotriazole; in particular, the compounds are useful as medicaments, more particularly for the manufacture of medicaments for the treatment of obesity, psychiatric and neurological disorders and other cannabinoid-CB₁A medicament for neurotransmission-related diseases. The present invention therefore relates to the use of compounds of formula (I), formula (Ia), formula (Ib), formula (Ic) for the preparation of a medicament for the treatment of obesity, psychiatric and neurological disorders and other cannabinoid-CB as described hereinbefore₁Use in the preparation of a medicament for the treatment of a disorder associated with neurotransmission.

The invention also includes the treatment of obesity, psychiatric and neurological disorders and other cannabinoid-CB in mammals, including humans, by administering a therapeutically effective amount of a compound of the invention₁Methods of neurotransmission-related disorders.

The invention also includes the prevention of obesity, psychiatric and neurological disorders and other cannabinoid-CB in mammals, including humans, by the administration of a therapeutically effective amount of a compound of the invention₁Methods of neurotransmission-related disorders.

In particular, the present invention relates to the use of an aromatase inhibitor, which is a (1H-pyrrol-1-ylmethyl) substituted benzotriazole derivative of formula (I), for the preparation of a pharmaceutical composition for the treatment of inflammatory bowel disease.

The compounds of formula (I) and certain intermediates of the invention may have asymmetric carbon atoms in their structure. The chiral centers may exist in both the R-configuration and the S-configuration.

Pure stereochemical isomers of the compounds of the present invention may be obtained by applying methods known in the art. Diastereoisomers may be separated by physical separation methods, for example selective crystallisation and chromatographic techniques (e.g. counter-current distribution), and enantiomers may be separated from one another by selective crystallisation of their diastereoisomeric salts with optically active acids. They may also be obtained from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction proceeds stereospecifically.

The compounds of formula (I), their pharmaceutically acceptable acid addition salts and possible stereochemically isomeric forms possess valuable pharmacological properties. They modulate cannabinoid-CB₁The action of the receptor.

Cannabinoid receptors belong to the class of G protein-coupled receptors, CB₁By activating G_i/0Proteins) trigger activation of intracellular signal transduction normally associated with these G protein-coupled receptors (GPCRs), namely:

(i) inhibition of stimulus-induced adenylate cyclase, which in turn impairs short-term and long-term cAMP/protein kinase a-mediated effects;

(ii) stimulating mitogen-activated protein kinase signal transduction;

(iii) inhibition of voltage-gated P, Q and N-type Ca²⁺Channel, stimulating inward-rectifying G-protein coupled K⁺A channel, and

(iv) stimulation of phosphatidylinositol 3-kinase and intracellular Ca²⁺Mobilization, possibly by G_i/oProtein beta_γSubunit, activating PLC- γ.

CB can be evaluated in vitro on the basis of these intracellular signal transduction effects₁Modulation of receptors, e.g. by measuring CB expression₁Intracellular cAMP production at the receptor, e.g. using a time-resolved fluorescence assay, in which free cAMP contained in the sample competes with the anti-cAMP cryptate/cAMP-XL 665 conjugate system. Alternatively, possible CB's may be identified using receptor binding assays on membrane preparations or in situ brain sections of laboratory animals, e.g., as described in the examples below₁-a receptor modulator. For example, CB₁The in vivo effect of receptor modulators could be demonstrated by measuring the acute dose response of compounds to food intake in male Sprague Dawley rats. In vitro cAMP assay and CB₁The compounds of formula (I) modulate CB, illustrated by a combination of assays and in vivo feeding experiments described in the examples below₁The potency of the receptor activity.

In view of the beneficial pharmacological properties, the subject compounds may be prepared in different pharmaceutical forms for administration purposes.

To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in the form of an acid addition salt, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in single dosage form, preferably suitable for oral, rectal, transdermal administration, or parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as water, glycols, oils, alcohols and the like in the case of oral liquid preparations (e.g., suspensions, syrups, elixirs and solutions), and solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. With regard to parenteral compositions, the carrier will typically comprise sterile water, at least in large part, although other ingredients, such as those which aid solubility, may also be included. For example, injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Suspensions for injection may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.

The following examples are given for illustration and are not intended to limit the scope of the invention. All ingredients are by weight unless otherwise indicated.

Experimental part

Hereinafter the term "MP" refers to the melting point, "THF" refers to tetrahydrofuran, "EtOAc" refers to ethyl acetate, "DIPE" refers to diisopropyl ether, "MgSO₄"means magnesium sulfate," CH₂Cl₂"refers to methylene chloride," DMA "refers to dimethylacetamide," DMSO "refers to dimethyl sulfoxide," NaBH₄"refers to sodium borohydride (-1).

A. Preparation of intermediates

Example A1

a) Preparation of intermediate 1

5-chloro-N-cyclohexyl-2-nitroaniline (0.244mol) was stirred in THF (400 ml). Then, 4-chlorobenzonitrile (0.244mol), 10N sodium hydroxide solution (78.8ml) and N, N, N-triethylbenzalkonium chloride (6.4g) were added. The reaction mixture was stirred at 50 ℃ for 48 hours. The reaction mixture was poured into water and then diluted with CH₂Cl₂And (4) extracting. The separated organic layer was dried (MgSO)₄) Filtered and the solvent evaporated. The residue was purified by silica gel column chromatography (eluent: CH)₂Cl₂). The desired fractions were collected and the solvent was evaporated to yield 45g (49.9%) of intermediate 1.

b) Preparation of intermediate 2

Intermediate 1(0.07mol) was stirred in DMA (250 ml). N, N, N-triethylbenzalkonium chloride (1.3g) was added, followed by potassium carbonate (13 g). Compressed air was introduced at room temperature over a period of 48 hours. The reaction mixture was poured into water. The resulting gum is filtered off, washed with water and then recrystallized from methanol. The precipitate was filtered off and dried to yield 20.5g (81.3%) of intermediate 2.

c) Preparation of intermediate 3

A mixture of intermediate 2(0.07mol) in methanol (250ml) was hydrogenated at room temperature using Raney Nickel (25g) as a catalyst. Inhalation H₂After (3 eq, pressure: 3 bar), the catalyst was filtered off over celite and the filtrate was evaporated to give 23g of intermediate 3.

d) Preparation of intermediate 4

Intermediate 3(0.07mol) was stirred in 6N HCl solution (250ml) and cooled to 0 ℃. A solution of sodium nitrite (0.104mol) in water (20ml) was added dropwise (0 ℃ C.) and the resulting reaction mixture was stirred at 0 ℃ C. for 2 hours. The mixture was basified with concentrated ammonia and then with CH₂Cl₂And (4) extracting. The separated organic layer was washed with water and dried (MgSO)₄) Filtration and evaporation of the solvent gave 20g (84%, oil) of intermediate 4.

e) Preparation of intermediate 5

A solution of intermediate 4(0.059mol) in methanol (200ml) was stirred at 0 ℃. Adding NaBH₄(0.06mol) in water (20ml) and the resulting reaction mixture was stirred at 10 ℃ for 1 hour. Pouring the mixture into water with CH₂Cl₂And (4) extracting. The separated organic layer was dried, filtered and the solvent was evaporated. The residue (13g of oil) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂Methanol 98/2). The product fractions were collected and the solvent was evaporated to yield 8g (40%) of intermediate 5.

f) Preparation of intermediate 6

Thionyl chloride (8ml) was added to CH of intermediate 5(0.023mol) stirred at 0 deg.C₂CH₂(100ml) in solution. The reaction mixture was stirred at room temperature for 12 hours. Evaporating the solvent to obtainTo 8.5g of intermediate 6.

g) Preparation of intermediate 7

A mixture of intermediate 6(0.023mol), 1H-1, 2, 4-triazole (0.117mol), potassium carbonate (0.117mol) and acetonitrile (200ml) was stirred and refluxed for 12 hours. The solvent was evaporated to dryness. The residue was dissolved in water and then treated with CH₂Cl₂And (4) extracting. The separated organic layer was washed with water and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (10g, oil) was purified by high performance liquid chromatography on silica gel (eluent: CH)₂Cl₂Methanol 98/2). Several product fractions were collected and the solvent was evaporated. One fraction gave 2.4g, which was recrystallized from ether, filtered off and dried to give 1.8g (20%; MP: 154 ℃ C.) of intermediate 7.

Example A2

a) Preparation of intermediate 8

Potassium hydroxide (300g) was stirred in methanol (1500ml) (exotherm temperature raised to 70 ℃). The mixture was cooled to 55 ℃. 4-Chlorobenzeneacetonitrile (1.38mol) was added and the mixture was stirred for 15 minutes. A solution of 1-chloro-2-nitrobenzene (1.25mol) in methanol (250ml) was added (the exothermic temperature rose to 50 ℃ C.). Water (2000ml) was added and the mixture was stirred until it became a homogeneous suspension. The suspension was poured into a mixture of ice (1250g) and glacial acetic acid (545 ml). The mixture was stirred overnight. The resulting precipitate is filtered off and crystallized from 2-propanol. The precipitate was filtered off, then stirred in DIPE, filtered off and dried, yielding 80.5g (22.0%, MP: 181.6 ℃; (E + Z)) of intermediate 8.

b) Preparation of intermediate 9

A mixture of intermediate 8(0.172mol), potassium hydroxide (120g), methanol (400ml) and water (1200ml) was stirred until a homogeneous red suspension formed. A30% hydrogen peroxide solution (240g) was added and the reaction mixture was stirred at 30-35 ℃ for 4 hours. The yellow precipitate is filtered off, washed with water and then crystallized from ethanol. The precipitate is filtered off and dried to yield 22g (43.2%; MP: 120 ℃) of intermediate 9.

c) Preparation of intermediate 10

A mixture of intermediate 9(0.1mol) in methanol (250ml) was stirred at 10 ℃. Adding NaBH in portions₄(0.05 mol). The mixture was stirred at 10 ℃ for 1 hour, allowed to warm to room temperature, and a solution of acetic acid (3ml) in water (20ml) was added dropwise. The mixture was evaporated, water (50ml) was added and the product extracted with DIPE. The organic layer was dried (MgSO)₄) And evaporated to yield 27g (90%) of intermediate 10.

d) Preparation of intermediate 11

48% aqueous HBr (250ml) was stirred and intermediate 10(0.1mol) was added portionwise. The mixture was refluxed for 2 hours and then cooled. The product was extracted with toluene and washed with water. The organic layer was dried (MgSO)₄) And evaporated to give 24g (70%) of intermediate 11.

e) Preparation of intermediate 12

A mixture of intermediate 11(0.0735mol), 1H-imidazole (0.397mol) and acetonitrile (250ml) was stirred and refluxed for 8 hours. The mixture was evaporated, water (200ml) was added and CH was used₂Cl₂And (4) extracting. The organic layer was extracted twice with 1N HCl. The aqueous layer was basified with ammonium hydroxide while cooling. Product is with CH₂Cl₂And (4) extracting. The organic layer was dried (MgSO)₄) And evaporation. The free base residue was transferred to a solution of the ethanedioic acid salt (1: 1) in 2-propanone. The precipitate is filtered off and dried to yield 15g (58%; C)₂H₂O₄(1: 1)) intermediate 12.

f) Preparation of intermediate 13

A mixture of intermediate 12 free base (0.047mol), cyclohexylamine (0.25mol) and DMSO (62.5ml) was stirred at 80 ℃ for 24 h. Adding water, using CH₂Cl₂And (4) extracting. The organic layer was dried (MgSO)₄) And evaporation. The residue (28.8g) was purified by chromatography on silica gel using a glass filter and silica gel column (eluent: methanol/chloroform 2/98). The pure fractions were collected and evaporated. The residue was evaporated again with toluene. The residue obtained (2.0g) was transferred into 2-propanol with the oxalate salt (1: 1). The product was precipitated with DIPE and decanted. The residue was crystallized from 2-propanone. The precipitate is filtered off, washed with 2-propanone and dried at 50 ℃ in vacuo to give 0.2g (MP: 114.4 ℃ C.; C)₂H₂O₄(1: 1)) intermediate 13.

g) Preparation of intermediate 14

A4% thiophene solution (2ml) mixture of intermediate 13 in free base (0.026mol) was hydrogenated with methanol (250ml) at room temperature using Pt/C (5%) (2g) as a catalyst. Inhalation H₂After (3 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was evaporated again with toluene to give 7.9g (77%) of intermediate 14.

Example A3

a) Preparation of intermediate 15

A mixture of intermediate 12 free base (0.047mol), 3-methyl-1-butylamine (0.24mol) and DMSO (62.5ml) was stirred at 80 ℃ for 24 h. Adding water, using CH₂Cl₂And (4) extracting. The organic layer was dried (MgSO)₄) And evaporation. The residue (25.5g) was purified over silica gel using a glass filter (eluent: chloroform). The pure fractions were collected and evaporated. The residue (15.9g) was purified by column chromatography over silica gel (eluent: methanol/chloroform 2/98). The pure fractions were collected and evaporated. The resulting residue (2.8g) was transferred to a solution of nitrate (1: 1) in EtOAc (10 mL). The product was precipitated with DIPE and decanted. The residue was crystallized from EtOAc (15 mL). The precipitate was filtered off, washed with EtOAc and DIPE and dried at 60 ℃ in vacuo to give 2.1g (69%; MP: 150.5 ℃; HNO)₃(1: 1)) intermediate 15.

b) Preparation of intermediate 16

The intermediate was reacted at room temperature using Pt/C (5%) (1g) as a catalyst15 free base (0.015mol) 4% thiophene solution (1ml), methanol (200ml) and NH₃A mixture of methanol (50ml) was hydrogenated. Inhalation H₂After (3 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was evaporated again with toluene to give 9.6g (100%) of intermediate 16.

Example A4

a) Preparation of intermediate 17

A mixture of the free base of intermediate 12 (0.047mol), 4-chlorobenzylamine (0.2lmol) and DMSO (62.5ml) was stirred at 80 ℃ for 24 h. Adding water, using CH₂Cl₂And (4) extracting. The organic layer was dried (MgSO)₄) And evaporation. The residue was purified over silica gel using a glass filter (eluent 1: chloroform) (eluent 2 (methanol/NH)₃) Trichloromethane 2.5/97.5). The pure fractions were collected and evaporated. The residue was purified by column chromatography over silica gel (eluent: (methanol/NH)₃) /trichloromethane 1/99). The pure fractions were collected and evaporated, yielding 16.5g (78%) of intermediate 17.

b) Preparation of intermediate 18

An aqueous solution (250ml) of sodium dithionite (0.18mol) was added to a stirred mixture of intermediate 17(0.036mol) in ethanol (600ml) at room temperature. The mixture was stirred for 2 hours and evaporated. The residue was stirred with water and basified with sodium carbonate. Product is with CH₂Cl₂And (4) extracting. The organic layer was dried (MgSO)₄) And evaporated to give 7.8g (50%) of intermediate 18.

Example A5

a) Preparation of intermediate 19

4-Chlorobenzeneacetonitrile (0.562mol) was added to a solution of 5-chloro-N-methyl-2-nitroaniline (0.536mol) in THF (620 ml). N, N, N-triethylbenzalkonium chloride (14g) was added. 10N sodium hydroxide (173.2ml) was added and the resulting reaction mixture was stirred at 50 ℃ for 48 hours. The mixture was poured into water, acidified with concentrated hydrochloric acid and extracted with EtOAc. The separated organic layer was washed with water and dried (MgSO)₄) Filtered and the solvent evaporated. The residue was stirred in DIPE, filtered off, washed with DIPE and then dried, yielding 108g (66.8%) of intermediate 19.

b) Preparation of intermediate 20

Intermediate 19(0.358mol) was stirred in DMA (800 ml). Potassium carbonate (54g) and N, N, N-triethylbenzalkonium chloride (5.4g) were added. Making compressed air (O) at room temperature₂) The mixture was passed through for 48 hours. The mixture was poured into water. All were filtered off and the filter residue was washed with water and then dissolved in DIPE (3 times), filtered off and dried to yield 100g (97%) of intermediate 20.

c) Preparation of intermediate 21

A mixture of intermediate 20(0.206mol) in methanol (500ml) was hydrogenated over Raney nickel (50g) as a catalyst for 2 hours. Inhalation H₂(3 eq.) after filtrationThe catalyst was removed and the filtrate was evaporated to yield 38g (70.6%) of intermediate 21.

d) Preparation of intermediate 22

Intermediate 21(0.146mol) was stirred in 6N HCl (400ml) and cooled to 5 ℃. A solution of sodium nitrite (0.218mol) in water (approx.) was added while maintaining the temperature at 5 ℃. Then, the reaction mixture was stirred at room temperature for 6 hours. The precipitate is filtered off and dried to yield 32g (80.8%; MP: 169.9 ℃) of intermediate 22.

e) Preparation of intermediate 23

-70℃、N₂N-butyllithium (29.3ml) was added dropwise to a THF solution of thiazole (0.0375mol) under an atmosphere, and the mixture was stirred at-70 ℃ for 1 hour. A THF solution of intermediate 22(0.0312mol) was added dropwise and the mixture was stirred at-70 ℃ for 2 hours. The mixture was quenched with water and extracted with ether. The organic layer was dried (MgSO)₄) Filtered off and evaporated. The residue (11.3g) was taken up with CH₂Cl₂Crystallization gave 10.88g (98%; MP: 162.1 ℃) of intermediate 23.

B. Preparation of the Compounds

Example B1

Preparation of Compound 1 and Compound 2

Compound 1 Compound 2

Intermediate 7(0.350g, 0.00089mol) was isolated and purified by chiral column chromatography over ChiralPak AD (500g, eluent: 100% ethanol; flow rate: 110 ml/min). Two product fractions were collected and the solvent was evaporated to give 0.120g of (C(c: 1mg/ml, methanol)) Compound 1 and 0.120g of (C: 1mg/ml, methanol)) ((c: 1mg/ml, methanol)) Compound 2.

The following compounds were prepared accordingly:

example B2

Preparation of Compound 3

A solution of intermediate 14(0.021mol) in 5N HCl (100ml) was stirred at 0-5 ℃. A solution of sodium nitrite (0.105mol) in water (20ml) was added dropwise, and the mixture was stirred at room temperature for 3 hours. The mixture was poured into ice and basified with sodium carbonate. Product is with CH₂Cl₂And (4) extracting. The organic layer was dried (MgSO)₄) And evaporated. The residue (8.9g) was purified twice over silica gel using a glass filter (eluent 1: methanol/chloroform 2/98) (eluent 2): (methanol-NH)₃) /trichloromethane 1/99). The pure fractions were collected and evaporated. The residue (7.2g) was crystallized from EtOAc (40 mL). The precipitate was filtered off, washed with EtOAc, DIPE and dried at 50 ℃ in vacuo to yield 4.8g (59%; MP: 162.0 ℃) of compound 3.

The following compounds were prepared accordingly:

example B3

Preparation of Compound 4

A solution of intermediate 16(0.026mol) in 5N HCl (100ml) was stirred at 0-5 ℃. A solution of sodium nitrite (0.13mol) in water (20ml) was added dropwise, and the mixture was stirred at room temperature overnight. The mixture was poured into ice and basified with sodium carbonate. Product is with CH₂Cl₂And (4) extracting. The organic layer was dried (MgSO)₄) And evaporated. The residue (8.4g) was purified over silica gel using a glass filter (eluent: methanol/chloroform 2/98). The pure fractions were collected and evaporated. The residue (7.4g) was transferred to a solution of the hydrochloride salt (1: 1) in EtOAc (20 mL). The product was precipitated with DIPE and decanted. The residue was crystallized from 2-propanone (15 ml). The precipitate was filtered off, washed with 2-propanone, DIPE and dried under vacuum at 50 ℃ to give 4.5g (41.5%; MP: 163.8 ℃; HCl (1: 1)) of compound 4.

Example B4

Preparation of Compound 5

A solution of intermediate 18(0.0185mol) in 5N HCl (100ml) and acetic acid (35ml) was stirred at 0-5 ℃. A solution of sodium nitrite (0.0204mol) in water (20ml) was added dropwise and the mixture was stirred at room temperature for 2 hours. The mixture was poured into ice and basified with sodium carbonate. Product is with CH₂Cl₂And (4) extracting. The organic layer was dried (MgSO)₄) And evaporated. The residue (7.2g) was purified twice by column chromatography on silica gel (eluent 1: methanol/CH)₂Cl₂5/95) (eluent 2: (methanol/NH)₃) EtOAc2.5/97.5). The pure fractions were collected and evaporated. The residue (4.5g) was purified over silica gel using a glass filter (eluent: (methanol/NH)₃) EtOAc 2.5/97.5). The pure fractions were collected and evaporated. The residue (4g) was transferred to a solution of nitrate (1: 1) in EtOAc (20 mL). The product was precipitated with DIPE and decanted. The residue was crystallized from 2-propanone (25 ml). The precipitate was filtered off, washed with DIPE and dried under vacuum at 60 ℃ to give 3.5g (38%; MP: 185.9;. HNO)₃(1: 1)) Compound 5.

Example B5

Preparation of Compound 6

A mixture of intermediate 23(0.0248mol), tin chloride (28.25g) and acetic acid (40ml) was stirred with 12N HCl (40ml) and refluxed overnight. The mixture was allowed to cool, poured into ice water and basified with ammonium hydroxide. The mixture was filtered through celite, using CH₂Cl₂And (4) extracting. The organic layer was washed with 10% potassium carbonate solution and water, and dried (MgSO)₄) Filtered off and evaporated. The residue (6.45g) was purified by silica gel column chromatography (eluent: CH)₂Cl₂Methanol/ammonium hydroxide 99.25/0.75/0.1) (15-40 μm). The pure fractions were collected and evaporated. The residue (4.21g) was transferred to nitrate (1: 1) and recrystallized from methanol/ether to give 2.54g (50%; MP:113.3℃；.HNO₃(1: 1)) Compound 6.

C. Pharmacological examples

The following test procedures can be used to demonstrate that the compounds of the present invention modulate CB₁The potency of the receptor activity.

Reagent

CP-55, 940[ side chain 2, 3, 4(N) -³H]- (168Ci/mmol) and³H]microscales were purchased from Perkin Elmer Life Sciences, Inc. (Boston, MA, USA) and Amersham biosciences Europe GmbH (Benelux, Roosendaal, Nederland), respectively.

CP55, 940, JWH133, arachidonic acid ethanolamide, was purchased from Tocris Cookson (Bristol, UK).

The Sanofi rimonabant and JNJ compounds were obtained from an "internal" central pharmacy. All other reagents were of high purity, obtained from Merck (Darmstadt, Germany) or Sigma-Aldrich NV/SA (Bormem, Belgium).

Cells

Human Cb-1 transfected CHO-K1 cells (Euroscreen; Cat # ES-110-C; hCB₁-D1; accession number Swissprot X54937) was maintained as described previously (Felder et al, 1995)&1998). For membrane preparation, at 5% CO₂Cells were cultured at 37 ℃ in roller bottles containing DMEM/Ham F12 medium containing 10% (v/v) heat-inactivated FCS, 100U/ml penicillin and 100. mu.g/ml streptomycin, 100. mu.g/ml pyruvate and 292. mu.g/ml L-glutamine, the medium being changed 3 times per week. When 90% were confluent, cells were harvested by trypsinization, diluted 1: 10 or 1: 20 and reseeded in clean fresh roller bottles. For measurement of cAMP formation, cells were cultured to 90% confluence in Falcon T175 flasks.

Preparation of the film

Confluent cells were treated with 5mM butyric acid for 24 hours prior to membrane preparation. Aspirate the medium, scrape the cells from the flask with 50ml homogenization buffer, homogenize the bufferThe flushing liquid is prepared from the mixture containing 2mM MgCl₂0.3mM EDTA and 1mM EGTA in 15mM Tris-HCl (pH 7.4). Then, the cells were centrifuged for 10 minutes (1700 Xg, 4 ℃), and the cells were homogenized in 20ml of the same buffer using an Ultra Turrax. The crude membrane pellet was collected by two successive centrifugation steps of 20,000 Xg for 10 minutes and 25,000 Xg for 20 minutes, respectively, and separated by a 10ml homogenization buffer wash/homogenization step. Resuspending the final cell pellet in 6 ml/roller bottle of storage buffer consisting of 12.5mM MgCl₂0.3mM EDTA, 1mM EGTA and 250mM sucrose in 7.5mM Tris-HCl (pH 7.4). The protein content was determined by the BioRad method (Bradford, 1976).

Animal(s) production

Male Sprague Dawley rats (250-g heavy at the time of the experiment) were obtained from Charles River (Sulzfeld, Kisslegg, Germany). Male C57B1/6J Rj mice (weighing 25-30g at the time of the experiment) were obtained from Janvier (Le Genest-St-Isle, France). All animals were free to drink and housed individually in Techniplast IVC cages suitable for external food hoppers at 12 hours light-dark cycle (22:00 with light on), temperature 19-22 ℃ and humidity 35-40%. Rats and mice were fed with standard purified chow containing 10% kcal fat (Dyets, inc. bethlehem, USA; or Research diets, New Brunswick, NJ, USA). All experiments were performed according to the European Committee guidelines (European Committee Council Directives (86/609/EEC)) and approved by the local ethical Committee.

Example C1：Competitive receptor binding of cell membrane Cb-1

50. mu.l of incubation buffer (50mM Tris-HCl, pH7.4, containing 2.5mM EDTA and 0.5% (w/v) BSA) in a final volume of 0.5ml in the presence or absence of test compound³H-CP55, 940 (final 0.5nM), 0.4ml of a CHO-K1 membrane protein (60. mu.g/ml) transfected sample, were tested for competitive binding in triplicate. Nonspecific binding was determined with 1 μ M CP55, 940. The samples were incubated at 25 ℃ for 1 hour using a Unifilter-96Harvester (Perkinelmer N.V./S.A.Belgium),the incubation was terminated by rapid filtration through GF/C filter plates pre-soaked with 0.1% polyethyleneimine. The filter plates were washed 6 times with cold wash buffer (50mM Tris-HCl containing 0.1% BSA, pH7.4), each plate air dried overnight, and bound [ deg. ] was determined by liquid scintillation counting using a TopCount NXT microplate scintillation counter (Packard Bioscience/PerkinElmer N.V./S.A.Belgium)³H]CP55, 940. IC was determined using a single-site binding equation (GraphPad Prism, San Diego, Calif., U.S.A.)₅₀The value is obtained.

Example C2：Cyclic AMP accumulation

cAMP assays were performed in CHO-K1 cells stably expressing Cb-1 receptors using a commercially available dynamic homogeneous time-resolved fluorescence cAMP assay. Cells were detached from the flask with 3ml EDTA (0.04% (weight/volume) PBS solution) and resuspended in PBS (Ca-free)²⁺And Mg²⁺) In (5), centrifuge at 500 Xg for 5 minutes. Resuspend the cell pellet in stimulation buffer (containing 1mM IBMX, 5mM Hepes, 10mM MgCl₂And 0.1% (w/v) BSA in HBSS medium) and distributed at a cell density of 20000 cells/well onto black 96-well plates. After 30 minutes at 25 deg.C, an equal volume of stimulation buffer containing forskolin and CP55940 (agonist) and/or Cb-1 antagonist is added to the cells. After incubation at 25 ℃ for 30 min, equal volumes of cAMP-XL665 and anti-cAMP-cryptate conjugate were added for cAMP detection. The plates were incubated at 25 ℃ for a further 60 minutes and then assayed with Discovery (PerkinElmer n.v./s.a.belgium).

Example C3：Feeding experiment

Acute dose-response analysis was performed on each compound. All rats and mice were randomized and vehicle (10% cyclodextrin with 0.9% (weight/volume) saline) or vehicle with a single concentration of compound (0.16mg/kg, 0.63mg/kg, 2.50mg/kg, 10.0mg/kg, 40.0mg/kg, as 10ml/kg) was administered orally such that the mean latency from administration and light shut-off was 45 minutes for 6 animals per group. Food intake was measured at 1 hour, 2 hours, 4 hours, 6 hours and 24 hours after the illumination was turned off.

Example C4：Receptor occupancy assay

In a supplementary experiment, rats and mice were treated with 5 doses ranging from 0.6 to 40mg/kg under the same conditions as described above in order to determine the Cb-1 receptor occupancy by different compounds in different brain regions. Animals were sacrificed by decapitation 1 or 2 hours after turning off the illumination. The brains were removed quickly and frozen with 2-methylbutane cooled on dry ice (-between-30 ℃ and-40 ℃). Coronal sections (10 μm thick) were cut with a Reichert Jung2800R cryostat (Cambridge Instruments, Cambridge, UK) and dissected with reference to stereograms (Paxinos)&Watson, 1998), sections at the level of the striatum/nucleus accumbens (nucleus accumbens), anterior hypothalamus (anterior hypothalamus) and mid-hypothalamus (mid-hypothalamus) (0.70mm, -1.80mm, 3.30mm limbus to forechimney, respectively), thawed and mounted on polylysine coated microscope slides (StarFrost, Knittel)Germany). The sections were stored at-80 ℃ until use.

In vitro receptor binding

This method has been described for a long time (Glass et al, 1997; Adams et al, 1998; Harrold et al, 2002). A Saturation and association experiment (Saturation and association experiment) was first conducted to determine [2 ]³H]K of CP55, 940_d. Scatchard analysis was performed on coronal sections of untreated animals containing nucleus accumbens and caudate putamen (0.70mm from forechimney). Briefly, the slides were allowed to warm to room temperature and 200. mu.l of slide containing several concentrations of [ lambda ] without CP55, 940 (total binding) or 10. mu.M CP55, 940 (non-specific binding)³H]CP55, 940(0.01nM, 0.1nM, 1nM, 10nM, 100nM) in binding buffer (50mM Tris-HCl containing 50. mu.M PMSF, 5% (w/v) BSA, pH7.4) was incubated at room temperature for 120 min. After incubation, wash buffer (50mM Tris-HCl, 1)% w/v BSA, pH7.4) was rinsed twice at 4 ℃ for 10 minutes each to remove unbound ligand, followed by rapid immersion in cold (4 ℃ C.) deionized water to remove salts. Sections were then either scraped from the slides using whatmann gf/C filter plates, placed into scintillation vials containing 3ml of scintillation fluid (UltraGold, PerkinElmer n.v./s.a.belgium), and counted by liquid scintillation (Tri-Carb 1900CA liquid scintillation analyzer, Packard/PerkinElmer n.v./s.a.belgium). Alternatively, the slice is used for [2 ]³H]CP55, 940 autoradiography (see below). Transformation data and K were obtained by a single site binding equation (GraphPad Prism, San Diego, Calif., U.S.SA.)_dThe values are calculated.

Example C5：Cb-1 competitive receptor binding of brain slices

For the competitive binding experiments, reaction buffer and incubation and washing times/temperatures were as described above for the in situ binding assays. Coronal sections of untreated animals containing nucleus accumbens and caudate putamen (0.70mm from forechimney) were used. Several concentrations of each compound ranging from 10pM to 10. mu.M were tested, and nonspecific binding was determined using 10. mu.M CP55, 940, using 10nM [2 ]³H]CP55, 940 determines total binding. Each experiment was repeated 3 times. IC (integrated circuit)₅₀Values were determined using grapgppad Prism software (San Diego, CA, u.s.a.).

Ex vivo receptor binding of brain sections

Three adjacent brain sections of the same treated animal were collected from each slide through 3 different planes (0.70mm, -1.80mm, 3.30mm limbus to chimney) (see feeding and receptor occupancy experiments). Reaction buffer and wash temperature/times as before for the in situ binding assay. Incubation was limited to 20 minutes at room temperature to minimize drug dissociation at the receptor. Ex vivo receptor labeling is expressed as the percentage of receptor labeling relative to the brain region of saline-treated animals. Since only unoccupied receptors can utilize radioligands, ex vivo receptor labeling is inversely proportional to receptor occupancy by drugs administered in vivo. The percent occupancy of the receptor by the drug administered to the animal corresponds to 100% minus the percent of receptor labeling in the treated animal. The percent receptor occupancy is plotted against dose, and the best-fit curve for sigmoidal log dose-effect is calculated using GraphPad Prism software (San Diego, CA, u.s.a.) and using non-linear regression analysis.

[³H]CP55, 940 autoradiography

After the sections were washed, they were quickly dried under a stream of hot air, and then placed in an X-ray box containing slides (RPA 501 and RPA 505; Amersham) set with tritium micro-scale standards (tritium-Hyperfilm) (RPN 535B) and the sections were exposed for 10 weeks to tritium-Hyperfilm (RPN 535B). The film was then developed in Kodak D19 for 3 minutes, developed and fixed at room temperature. All autoradiograms were analyzed by computer densitometry (AIS system, Imaging Research inc., Brock University, st. catherises, Ontario, Canada). Converting optical density of target anatomical region into³The level of bound radioactivity produced by H-microscales (fmol/mg tissue equivalent).

The above CB₁pIC50 for the competitive receptor binding assay and the cAMP assay are shown in Table I. The results in table I are not intended to limit the present invention, but merely to illustrate the useful pharmacological properties of all compounds within the scope of formula (I).

TABLE I

The claims (modification according to treaty clause 19)

1. Use of compounds of formula (I) or pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof for the manufacture of a medicament for the treatment of obesity, psychiatric and neurological disorders and other cannabinoid-CB₁Use in medicine of neurotransmission-related diseases:

wherein

R²is hydrogen; optionally substituted with Ar¹、C_3-7Cycloalkyl, hydroxy or C_1-6Alkoxy-substituted C_1- ₁₀An alkyl group; ar (Ar)¹；C_2-6An alkenyl group; c_2-6An alkynyl group; c_3-7A cycloalkyl group; bicyclo [2.2.1]Hept-2-yl; 2, 3-dihydro-1H-indenyl; 1, 2, 3, 4-tetrahydronaphthyl; a hydroxyl group; optionally substituted with Ar²Substituted C_2-6An alkenyloxy group; c_2-6An alkynyloxy group; a pyrimidinyloxy group; bis (Ar)²) A methoxy group; (1-C)_1-4Alkyl-4-piperidinyl) oxy; or R²Is C optionally substituted by halogen_1-10An alkoxy group; a hydroxyl group; c_1-6An alkoxy group; an amino group; mono-and di (C)_1-6Alkyl) amino; a trifluoromethyl group; a carboxyl group; c_1-6An alkoxycarbonyl group; ar (Ar)¹；Ar²-O-；Ar²-S-；C_3-7A cycloalkyl group; 2, 3-dihydro-1, 4-benzodioxinyl; 1H-benzimidazolyl; c_1-4Alkyl substituted 1H-benzimidazolyl; (1, 1-biphenyl) -4-yl or 2, 3-dihydro-2-oxo-1H-benzimidazolyl;

R³is hydrogen, hydroxy or C_1-6An alkyl group;

Ar¹is phenyl, naphthyl, pyridyl, aminopyridyl, imidazolyl, triazolyl, thienyl, halothienyl, furyl, C_1-6An alkyl furyl group, a halogenated furyl group, a thiazolyl group or a phenyl group substituted with up to 3 substituents, each substituent independently selected from the group consisting of halogen, a,Hydroxy, hydroxymethyl, trifluoromethyl, C_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkoxycarbonyl-, carboxy, formyl, (hydroxyimino) methyl, cyano, amino, nitro or mono-and di- (C)_1-6Alkyl) amino;

het represents a5 or 6 membered partially saturated monocyclic heterocycle or monocyclic aromatic heterocycle selected from furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyrimidinyl, pyridinyl, pyrazinyl, triazinyl, pyridazinyl, 2H-pyranyl or 4H-pyranyl, wherein the heterocycle is optionally substituted with up to 3 substituents each independently selected from halo, hydroxy, hydroxymethyl, trifluoromethyl, C_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkoxycarbonyl-, carboxy, formyl, (hydroxyimino) methyl, cyano, amino, mono-and di- (C)_1-6Alkyl) amino or nitro.

2. The use of claim 1, wherein for the compound of formula (I):

R¹is hydrogen, halogen, trifluoromethyl, C_1-4Alkyl radical, C_1-4Alkoxy-or C_1-4Alkoxycarbonyl-;

R²is phenyl, C_3-7Cycloalkyl or optionally substituted by Ar¹Substituted C_1-6An alkyl group;

Ar¹is phenyl or phenyl substituted with up to 3 halogen substituents;

het represents 5 or 6 membered partially saturatedAnd a monocyclic heterocycle or monocyclic aromatic heterocycle selected from thiazolyl, imidazolyl, triazolyl, pyrimidinyl or pyridinyl, wherein said heterocycle is optionally substituted by C_1-4Alkyl substitution.

3. Use according to claim 1 or 2, wherein for the compound of formula (I)

Het is imidazolyl or 1, 2, 4-triazolyl;

R¹is halogen, C_1-4Alkyl radical, C_1-4Alkoxy-or trifluoromethyl;

R²is phenyl, C_3-7Cycloalkyl or optionally substituted by Ar¹Substituted C_1-6An alkyl group.

4. The use according to claim 1, wherein the compound is selected from the following compounds or stereoisomers or pharmaceutically acceptable acid or base addition salts thereof:

(1) (-) -6- [ (4-chlorophenyl) -1H-1, 2, 4-triazol-1-ylmethyl ] -1-cyclohexyl-1H-benzotriazole;

(2)6- [ (4-chlorophenyl) -1H-imidazol-1-ylmethyl ] -1-cyclohexyl-1H-benzotriazole;

(3)6- [ (4-chlorophenyl) -1H-1, 2, 4-triazol-1-ylmethyl ] -1- (1-methylethyl) -1H-benzotriazole;

(4)6- [ (4-chlorophenyl) -1H-1, 2, 4-triazol-1-ylmethyl ] -1-cyclohexyl-1H-benzotriazole;

(5) 1-butyl-6- [ (4-chlorophenyl) -1H-1, 2, 4-triazol-1-ylmethyl ] -1H-benzotriazole;

(6)6- [ (4-chlorophenyl) -1H-imidazol-1-ylmethyl ] -1-phenyl-1H-benzotriazole;

(7)6- [ (4-chlorophenyl) -1H-1, 2, 4-triazol-1-ylmethyl ] -1- ((4-chlorophenyl) methyl) -1H-benzotriazole;

(8)6- [ phenyl-1H-imidazol-1-ylmethyl ] -1-cyclohexyl-1H-benzotriazole;

(9)6- [ (4-chlorophenyl) -1H-imidazol-1-ylmethyl ] -1- (3-methylbutyl) -1H-benzotriazole;

(10)6- [ (4-chlorophenyl) -1H-1, 2, 4-triazol-1-ylmethyl ] -1- (phenylethyl) -1H-benzotriazole;

(11)6- [ (4-chlorophenyl) -1H-1, 2, 4-triazol-1-ylmethyl ] -1- (phenylmethyl) -1H-benzotriazole;

(12)6- [ (4-chlorophenyl) -1H-imidazol-1-ylmethyl ] -1- (1-methylethyl) -1H-benzotriazole; and

(13)6- [ (4-chlorophenyl) -2-thiazolylmethyl ] -1-methyl-1H-benzotriazole.

5. cannabinoid-CB for the treatment of mammals₁A method of neurotransmission-related disorders, the method comprising administering to the mammal a therapeutically effective amount of the CB of any of claims 1 to 4₁A receptor modulator.

6. cannabinoid-CB for the prophylaxis of mammals₁A method of neurotransmission-related disorders, the method comprising administering to the mammal a therapeutically effective amount of the CB of any of claims 1 to 4₁A receptor modulator.

7. A compound of the following formula (Ia) or pharmaceutically acceptable acid addition salts and stereoisomers thereof:

wherein

R³is hydrogen, hydroxy or C_1-6An alkyl group;

Ar²is phenyl, pyridyl or phenyl substituted with up to 3 substituents, each substituent being independently selected from halogen, hydroxy, hydroxymethyl, trifluoromethyl, C_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkoxycarbonyl-, carboxy, formyl, (hydroxyimino) methyl, cyano,Amino, mono-and di- (C)_1-6Alkyl) amino or nitro;

het' represents a5 or 6 membered partially saturated monocyclic heterocycle or monocyclic aromatic heterocycle selected from thiazolyl, pyrimidinyl or pyridinyl, wherein said heterocycle is optionally substituted by C_1-4Alkyl substitution;

with the proviso that the compound of formula (Ia) is not represented

6- [ (4-chloro-phenyl) -pyridin-3-yl-methyl ] -1-methyl-1H-benzotriazole or

6- [ (4-chloro-phenyl) -pyrimidin-5-yl-methyl ] -1-methyl-1H-benzotriazole.

8. The compound of claim 7, wherein:

R¹is hydrogen, halogen, trifluoromethyl, C_1-4Alkyl radical, C_1-4Alkoxy-or C_1-4An alkoxycarbonyl group;

Ar¹is phenyl or phenyl substituted with up to 3 halogen substituents.

9. The compound of claim 7 or 8, wherein:

het is thiazolyl;

R¹is halogen, C_1-4Alkyl radical, C_1-4Alkoxy-or trifluoromethyl;

10. A compound according to any one of claims 7 to 9 for use as a medicament.

11. Use of a compound according to any one of claims 7-9 for the manufacture of a medicament for the treatment of obesity, psychiatric and neurological disorders and other cannabinoid-CB₁Phase of neurotransmissionThe application in the medicines for treating diseases.

12. cannabinoid-CB for the treatment of mammals₁A method of neurotransmission-related disorders, the method comprising administering to the mammal a therapeutically effective amount of the CB of any of claims 7 to 9₁A receptor modulator.

13. cannabinoid-CB for the prophylaxis of mammals₁A method of neurotransmission-related disorders, the method comprising administering to the mammal a therapeutically effective amount of the CB of any of claims 7 to 9₁A receptor modulator.

14. Use of a compound of formula (Ic) or a pharmaceutically acceptable acid addition salt or a stereoisomer thereof for the manufacture of a medicament for the treatment of obesity, psychiatric and neurological disorders and other cannabinoid-CB₁Use in medicine of neurotransmission-related diseases:

wherein A is¹＝A²-A³＝A⁴Is a divalent group having the formula:

-CH＝N-CH＝CH-(a-1)，

-CH-N- (a2), or

-CH＝N-N＝CH-(a3)；

R is hydrogen or C_1-6An alkyl group;

R²is hydrogen; optionally substituted with Ar₁、C_3-7Cycloalkyl, hydroxy or C_1-6Alkoxy-substituted C_1- ₁₀An alkyl group; ar (Ar)¹；C_2-6An alkenyl group; c_2-6An alkynyl group; c_3-7A cycloalkyl group; bicyclo [2.2.1]Hept-2-yl; 2, 3-dihydro-1H-indenyl; 1, 2, 3, 4-tetrahydronaphthyl; a hydroxyl group; optionally substituted with Ar²Substituted C_2-6An alkenyloxy group; c_2-6An alkynyloxy group; a pyrimidinyloxy group; bis (Ar)²) A methoxy group; (1-C)_1-4Alkyl-4-piperidinyl) oxy; or R²Is C optionally substituted by halogen_1-10An alkoxy group; a hydroxyl group; c_1-6An alkoxy group; an amino group; mono-and di (C)_1-6Alkyl) amino; a trifluoromethyl group; a carboxyl group; c_1-6An alkoxycarbonyl group; ar (Ar)¹；Ar²-O-；Ar²-S-；C_3-7A cycloalkyl group; 2, 3-dihydro-1, 4-benzodioxinyl; 1H-benzimidazolyl; c_1-4Alkyl substituted 1H-benzimidazolyl; (1, 1' -biphenyl) -4-yl or 2, 3-dihydro-2-oxo-1H-benzimidazolyl;

Ar²is phenyl, pyridyl or phenyl substituted with up to 3 substituents, each substituent being independently selected from halogen, hydroxy, hydroxymethyl, trifluoromethyl, C_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkoxycarbonyl-, carboxy, formyl, (hydroxyimino) methyl, cyano, amino, nitro or mono-and di- (C)_1-6Alkyl) amino.

(-) -6- [ (4-chlorophenyl) -1H-1, 2, 4-triazol-1-ylmethyl]Use of (E) -1-cyclohexyl-1H-benzotriazole for the treatment of obesity, psychiatric and neurological disorders and other cannabinoid-CB₁Use in the preparation of a medicament for the treatment of a disorder associated with neurotransmission.

Claims

wherein

R¹Is hydrogen,Halogen, hydroxy, hydroxymethyl, trifluoromethyl, C_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkoxycarbonyl-, carboxy, formyl, (hydroxyimino) methyl, cyano, amino, mono-and di- (C)_1-6Alkyl) amino or nitro;

R²is hydrogen; optionally substituted with Ar¹、C_3-7Cycloalkyl, hydroxy or C_1-6Alkoxy-substituted C_1-10An alkyl group; ar (Ar)¹；C_2-6An alkenyl group; c_2-6An alkynyl group; c_3-7A cycloalkyl group; bicyclo [2.2.1]Hept-2-yl; 2, 3-dihydro-1H-indenyl; 1, 2, 3, 4-tetrahydronaphthyl; a hydroxyl group; optionally substituted with Ar²Substituted C_2-6An alkenyloxy group; c_2-6An alkynyloxy group; a pyrimidinyloxy group; bis (Ar)²) A methoxy group; (1-C)_1-4Alkyl-4-piperidinyl) oxy; or R²Is C optionally substituted by halogen_1-10An alkoxy group; a hydroxyl group; c_1-6An alkoxy group; an amino group; mono-and di (C)_1-6Alkyl) amino; a trifluoromethyl group; a carboxyl group; c_1-6An alkoxycarbonyl group; ar (Ar)¹；Ar²-O-；Ar²-S-；C_3-7A cycloalkyl group; 2, 3-dihydro-1, 4-benzodioxinyl; 1H-benzimidazolyl; c_1-4Alkyl substituted 1H-benzimidazolyl; (1, 1-biphenyl) -4-yl or 2, 3-dihydro-2-oxo-1H-benzimidazolyl;

R³is hydrogen, hydroxy or C_1-6An alkyl group;

Ar²is phenyl, pyridyl or phenyl substituted with up to 3 substituents, each substituent independently selected from the group consisting of halogen, C,Hydroxy, hydroxymethyl, trifluoromethyl, C_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkoxycarbonyl-, carboxy, formyl, (hydroxyimino) methyl, cyano, amino, mono-and di- (C)_1-6Alkyl) amino or nitro;

het represents a 5-or 6-membered partially saturated monocyclic heterocycle or monocyclic aromatic heterocycle selected from furyl, thienyl, pyrrolyl,Azolyl, thiazolyl, imidazolyl, pyrazolyl, isopyrazolylAzolyl, isothiazolyl, thiazolyl,Oxadiazolyl, triazolyl, thiadiazolyl, pyrimidinyl, pyridinyl, pyrazinyl, triazinyl, pyridazinyl, 2H-pyranyl or 4H-pyranyl, wherein the heterocycle is optionally substituted with up to 3 substituents, each substituent being independently selected from halo, hydroxy, hydroxymethyl, trifluoromethyl, C_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkoxycarbonyl-, carboxy, formyl, (hydroxyimino) methyl, cyano, amino, mono-and di- (C)_1-6Alkyl) amino or nitro.

2. The use of claim 1, wherein for the compound of formula (I):

Ar¹is phenyl or phenyl substituted with up to 3 halogen substituents;

het represents a 5-or 6-membered partially saturated monocyclic heterocycle or monocyclic aromatic heterocycle selected from thiazolyl, imidazolyl, tricyclohetarylOxazolyl, pyrimidinyl or pyridinyl, wherein the heterocycle is optionally substituted by C_1-4Alkyl substitution.

3. Use according to claim 1 or 2, wherein for the compound of formula (I)

Het is imidazolyl or 1, 2, 4-triazolyl;

R¹is halogen, C_1-4Alkyl radical, C_1-4Alkoxy-or trifluoromethyl;

(6)6- [ (4-chlorophenyl) -1H-imidazol-1-ylmethyl ] -1-phenyl-1H-benzotriazole;

(8)6- [ phenyl-1H-imidazol-1-ylmethyl ] -1-cyclohexyl-1H-benzotriazole;

(13)6- [ (4-chlorophenyl) -2-thiazolylmethyl ] -1-methyl-1H-benzotriazole.

wherein

R³is hydrogen, hydroxy or C_1-6An alkyl group;

het' represents a 5-or 6-membered partially saturated monocyclic heterocycle or monocyclic aromatic heterocycle selected from furyl, thienyl, pyrrolyl,Azolyl, thiazolyl, pyrazolyl, isoAzolyl, isothiazolyl, thiazolyl,Oxadiazolyl, thiadiazolyl, pyrimidinyl, pyridinyl, pyrazinyl, triazinyl, pyridazinyl, 2H-pyranyl or 4H-pyranyl, wherein the heterocycle is optionally substituted with up to 3 substituents, each substituent being independently selected from halogen, hydroxy, hydroxymethyl, trifluoromethyl, C_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkoxycarbonyl-, carboxy, formyl, (hydroxyimino) methyl, cyano, amino, mono-and di- (C)_1-6Alkyl) amino or nitro;

with the proviso that the compound of formula (Ia) is not represented

6- [ (4-chloro-phenyl) -pyridin-3-yl-methyl ] -1-methyl-1H-benzotriazole or

6- [ (4-chloro-phenyl) -pyrimidin-5-yl-methyl ] -1-methyl-1H-benzotriazole.

8. The compound of claim 7, wherein:

R¹is hydrogen, halogen, trifluoromethyl, C₁-4 alkyl, C_1-4Alkoxy-or C_1-4An alkoxycarbonyl group;

Ar¹is phenyl or phenyl substituted with up to 3 halogen substituents;

het' represents a5 or 6 membered partially saturated monocyclic heterocycle or monocyclic aromatic heterocycle selected from thiazolyl, pyrimidinyl or pyridinyl, wherein said heterocycle is optionally substituted by C_1-4Alkyl substitution.

9. The compound of claim 7 or 8, wherein:

het is thiazolyl;

R¹is halogen, C_1-4Alkyl radical, C_1-4Alkoxy-or trifluoromethyl;

10. A compound according to any one of claims 7 to 9 for use as a medicament.

11. Use of a compound according to any one of claims 7-9 for the manufacture of a medicament for the treatment of obesity, psychiatric and neurological disorders and other cannabinoid-CB₁Use in the preparation of a medicament for the treatment of a disorder associated with neurotransmission.

wherein A is¹＝A²-A³＝A⁴Is a divalent group having the formula:

-CH＝N-CH＝CH-(a-1)，

-CH-N- (a2), or

-CH＝N-N＝CH-(a3)；

R is hydrogen or C_1-6An alkyl group;

R²is hydrogen; optionally substituted with Ar₁、C_3-7Cycloalkyl, hydroxy or C_1-6Alkoxy-substituted C_1-10An alkyl group; ar (Ar)¹；C_2-6An alkenyl group; c_2-6An alkynyl group; c_3-7A cycloalkyl group; bicyclo [2.2.1]Hept-2-yl; 2, 3-dihydro-1H-indenyl; 1, 2, 3, 4-tetrahydronaphthyl; a hydroxyl group; optionally substituted with Ar²Substituted C_2-6An alkenyloxy group; c_2-6An alkynyloxy group; a pyrimidinyloxy group; bis (Ar)²) A methoxy group; (1-C)_1-4Alkyl-4-piperidinyl) oxy; or R²Is C optionally substituted by halogen_1-10An alkoxy group; a hydroxyl group; c_1-6An alkoxy group; an amino group; mono-and di (C)_1-6Alkyl) amino; a trifluoromethyl group; a carboxyl group; c_1-6An alkoxycarbonyl group; ar (Ar)¹；Ar²-O-；Ar²-S-；C_3-7A cycloalkyl group; 2, 3-dihydro-1, 4-benzodioxinyl; 1H-benzimidazolyl; c_1-4Alkyl substituted 1H-benzimidazolyl; (1, 1' -biphenyl) -4-yl or 2, 3-dihydro-2-oxo-1H-benzimidazolyl;

15. A compound of formula (Ic) wherein said compound consists of enantiomer (-) -6- [ (4-chlorophenyl) -1H-1, 2, 4-triazol-1-ylmethyl ] -1-cyclohexyl-1H-benzotriazole.

(-) -6- [ (4-chlorophenyl) -1H-1, 2, 4-triazol-1-ylmethyl ] -1-cyclohexyl-1H-benzotriazole for use as a medicament.