WO2006087355A1

WO2006087355A1 - 1h-imidiazole derivatives as cannabinoid cb2 receptor modulators

Info

Publication number: WO2006087355A1
Application number: PCT/EP2006/060009
Authority: WO
Inventors: Josephus H. M. Lange; Herman H. Stuivenberg; Bernard J. Van Vliet
Original assignee: Solvay Pharmaceuticals B.V.
Priority date: 2005-02-16
Filing date: 2006-02-16
Publication date: 2006-08-24
Also published as: JP2008530179A; AU2006215567A1; RU2410377C2; BRPI0607439A2; NO20074710L; RU2007134428A; AU2006215567B2; IL184006A0; CA2597896A1; EP1874734A1

Abstract

The invention relates to a group of 1 H-imidazole derivatives which are modulators of cannabinoid CB2 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 1 H-imidazole derivatives as active ingredient, as well as to the use of these pharmaceutical compositions for the treatment of disorders in which cannabinoid CB2 receptors are involved. The compounds have the general formula (I) wherein R1-R4 have the meanings given in the specification.

Description

1 H-IMIDAZOLE DERIVATIVES AS CANNABINOID CB₂ RECEPTOR MODULATORS

The present invention relates to a group of 1 H-imidazole derivatives which are modulators of cannabinoid CB₂ receptors, to methods for the preparation of these compounds, to novel intermediates useful for the synthesis of said imidazole derivatives. 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 useful in the treatment of disorders in which cannabinoid CB₂ receptors are involved, or that can be treated via manipulation of those receptors.

1 H-lmidazole derivatives as CB₁ receptor modulators are known from WO 03/027076, WO 03/063781 , WO 03/040107 and WO 03/007887. (Morpholin-4-yl)alkyl-(1H)-imidazole derivatives have been claimed as CB₂ receptor modulators in WO 01/58869 disclosing three specific imidazoles (examples 64, 65 and 66) all containing a n L -phenylalanine derived carboxamide group at the 4-position of their (IH)-imidazole moiety. 1 -Aryl-(1H)-imidazole derivatives have been claimed in US 4,952,698 as CNS active compounds. Recent advances in the field of CB₂ receptor selective ligands have been reviewed by K.H. Raitio et al. (Curr. Med. Chem. 2005, 12, 1217-1237).

Surprisingly, novel 1 H-imidazole derivatives have been found which bind to the CB ₂ receptor, including compounds having approximately hundred-fold higher CB₂ receptor affinities as compared to the prior art compounds which were exemplified in WO 01/58869. Moreover, many of the compounds within this invention are highly CB ₂ receptor subtype selective which means that they bind with a much higher affinity to the CB₂ receptor than to the CB₁ receptor. The compounds within this invention are either CB₂ receptor agonists, CB₂ receptor partial agonists, CB₂ receptor antagonists or CB₂ receptor inverse agonists. The invention relates to compounds of the general formula (I)

wherein:

- Ri represents a hydrogen or halogen atom or a Ci_-3-alkyl group, which d_-3-alkyl group may contain 1-3 fluoro atoms or a hydroxy or amino group, or R₁ represents a C_2-3- alkynyl group, a C_2-3-alkenyl group, which C_2-3-alkynyl group or C_2-3-alkenyl group may contain 1-3 fluoro atoms, or R₁ represents an acetyl, cyclopropyl, cyano, methylsulfonyl, ethylsulfonyl, methylsulfinyl, ethylsulfinyl trifluoromethylsulfanyl, methylsulfanyl, ethylsulfanyl group, formyl group or a C_2-4-heteroalkyl group,

- R₂ represents a phenyl group which may be substituted with 1 , 2, 3, 4 or 5 substituents Y, which can be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chloro, iodo, bromo, fluoro, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano, or R₂ represents a heteroaryl group which heteroaryl group may be substituted with 1, 2 or 3 substituents Y, wherein Y has the meaning as defined above, with the proviso that R₂ is not a 6-methyl- 2-pyridyl group, or R₂ represents a mono-unsaturated or fully saturated 4-10 membered monocyclic, fused bicyclic or fused tricyclic carbocyclic ring system, or

R₂ represents a mono-unsaturated or fully saturated 4-10 membered monocyclic, fused bicyclic or fused tricyclic heterocyclic ring system which carbocyclic or heterocyclic ring system may be substituted with 1-5 substituents selected from methyl, ethyl, amino, hydroxy or fluoro, or R₂ represents a group of general formula CH₂-R₅ wherein R₅ represents a phenyl group which is substituted with 1 , 2, 3, 4 or 5 substituents Y as defined above, or R₅ represents a heteroaryl group or a 1 ,2,3,4-tetrahydronaphtyl or indanyl group, which heteroaryl group or 1 ,2,3,4-tetrahydronaphtyl or indanyl group may be substituted with 1 , 2 or 3 substituents Y as defined above or R₅ represents a mono-unsaturated or fully saturated monocyclic, fused bicyclic or fused tricyclic 4-10 membered carbocyclic ring system, or

R₅ represents a mono-unsaturated or fully saturated 4-10 membered monocyclic, fused bicyclic or fused tricyclic heterocyclic ring system, which carbocyclic or heterocyclic ring systems are optionally substituted with 1 -5 substituents selected from the group consisting of methyl, ethyl, amino, hydroxy or fluoro, or

R₂ represents a methylsulfonylaminoalkyl group, methylsulfonylalkyl or a acetamidoalkyl group, - R₃ represents a hydrogen or halogen atom or a formyl, Ci_-6-alkylsulfonyl, Ci_-6- alkylsulfinyl, Ci_-6-alkylsulfanyl, trifluoromethylsulfanyl, benzylsulfanyl or cyano group , or R₃ represents Ci_-8-alkyl group, which d_-8-alkyl group may be substituted with 1-5 substituents selected from the group consisting of fluoro, hydroxy or amino, or R₃ represents a C_2-6-alkynyl, C_2-6-alkenyl, Ci_-6-alkanoyl, C_3-8-cycloalkyl, C_5-8-heterocycloalkyl or a C_2-6-heteroalkyl group, which groups are optionally substituted with 1-3 methyl groups, an ethyl, amino or hydroxy group or with 1-3 fluoro atoms, or R₃ represents a phenyl group which is substituted with 1-5 substituents Y, wherein Y has the meaning as defined above, or R ₃ represents a heteroaryl group which heteroaryl group may be substituted with 1 , 2 or 3 substituents Y, wherein Y has the meaning as defined above or R₃ represents a benzyl or heteroaryl methyl group which benzyl or heteroaryl methyl group may be substituted with 1, 2 or 3 substituents Y - R₄ represents one of the subgroups (i) or (ii)

0) Oi)

wherein R₆ represents a C_4-8 branched or linear alkyl group, C_3-8 cycloalkyl group, C_3-8- cycloalkyl-Ci_-2-alkyl group, C_5-7-heterocycloalkyl-Ci_-2-alkyl group, C_5-I0 bicycloalkyl group, C_5-io-bicycloalkyl-Ci_-2-alkyl group, C_5-i₀-heterobicycloalkyl-Ci_-2-alkyl group, C_6-Io tricycloalkyl group, C_6-i₀-tricycloalkyl-Ci_-2-alkyl group, C_6-i₀-heterotricycloalkyl-Ci_-2-alkyl group which groups may be substituted with 1-5 substituents selected from methyl, hydroxy, ethyl, trifluoromethyl or fluoro, or R₆ represents a phenyl, benzyl, napthyl or phenethyl group which groups may be substituted on their aromatic ringsystem with 1-3 substituents Y as defined above, with the proviso that R₆ is not a 2-methylphenyl group, or R₆ represents a pyridyl or thienyl group, - R₇ represents a hydrogen atom or a Ci_-6 linear alkyl group which Ci_-6 linear alkyl group may be substituted with 1-3 fluoro atoms or R₇ represents an isopropyl group, R₈ represents a C_2-6 alkyl group which group is substituted with a hydroxy or amino group or with 1-3 fluoro atoms, or R₈ represents a C_7-I0 branched alkyl group, C_3-8 cycloalkyl group, C_5-8 heterocycloalkyl group, C_3-8-cycloalkyl-Ci_-2-alkyl group, C_5-7- heterocycloalkyl-d-₂-alkyl group, C_5-I0 bicycloalkyl group,

group, C_δ-io-heterobicycloalkyl-Ci^-alkyl group, C_6-Io tricycloalkyl group, C_6-I0- tricycloalkyl-Ci-₂-alkyl group, Ce-iQ-heterotricycloalkyl-Ci^-alkyl group which groups may be substituted with 1-5 substituents selected from methyl, hydroxy, ethyl, amino, hydroxymethyl, trifluoromethyl or fluoro, or R₈ represents a phenyl group which group is substituted with 1-5 substituents Y as defined above, or R₈ represents a naphtyl, 1 ,2,3,4- tetrahydronaphtyl or indanyl group which naphtyl, 1 ,2,3,4-tetrahydronaphtyl or indanyl groups may be substituted with 1-3 substituents Y, or R₈ represents a phenyl -Ci_-3-alkyl group, a diphenyl-Ci_-3-alkyl group, which groups may be substituted on their phenyl ring with 1-5 substituents Y, wherein Y has the above mentioned meaning, or R₈ represents a benzyl group, which benzyl group is substituted with 1-5 substituents Y, or R₈ represents a heteroaryl, heteroaryl methyl, napthylmethyl or heteroarylethyl group, which heteroaryl, heteroaryl methyl, naphtyl methyl or heteroarylethyl group may be substituted with 1-3 substituents Y, wherein Y has the abovementioned meaning, or R₈ represents a piperidinyl, azepanyl, morpholinyl, azabicyclo[3.3.0]octanyl, 4-hydroxypiperidinyl or pyrrolidinyl group, with the proviso that R₈ is neither a 6-methoxy-benzothiazol-2-yl group nor a [3-chloro-5-(trifluoromethyl)pyrid-2-yl]methyl group, or R₇ and R₈ - together with the nitrogen atom to which they are bonded - form a saturated or unsaturated, non-aromatic or partly aromatic, monocyclic, bicyclic or tricyclic heterocyclic group having 7 to 10 ring atoms, which saturated or unsaturated, non- aromatic or partly aromatic, monocyclic, bicyclic or tricyclic heterocyclic group may be substituted with 1-5 substituents selected from the group consisting of Ci_-3 alkyl, hydroxy, methoxy, cyano, phenyl, trifluoromethyl or halogen, or R₇ and R₈ - t ogether with the nitrogen atom to which they are bonded - form a saturated monocyclic heterocyclic group, optionally containing another heteroatom (selected from N, O, S), having 5 to 6 ring atoms, which heterocyclic group is substituted with 1-5 substituents selected from the group consisting of Ci_-3 alkyl, hydroxy, amino, phenyl, benzyl, or fluoro, with the proviso that R₇ and R₈ - together with the nitrogen atom to which they are bonded - do not form a trimethyl-substituted aza-bicyclo[3.2.1]octanylgroup, and tautomers, stereoisomers and N-oxides thereof, as well as pharmaco-logically acceptable salts, hydrates and solvates of said compounds of formula (1) and its tautomers, stereoisomers and N-oxides.

The invention relates to racemates, mixtures of diastereomers as well as the individual stereoisomers of the compounds having formula (I).

In the description of the substituents the abbreviation 'alkyl' means a linear or branched alkyl group. For example, C i_-3-alkyl m eans methyl, ethyl, n-propyl or isopropyl. The abbreviation 'heteroaryl' means monocyclic or fused bicyclic heteroaromatic groups, including but not limited to furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, indazolyl, indolyl, indolizinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, 1 ,3-benzodioxolyl, 2,3- dihydro-1,4-benzodioxinyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isochinolyl, 1,2,3,4-tetrahydroquinolinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, chinolyl, phtalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, with the exclusion of the quinolin-2-one group. The abbreviation 'halogen' means chloro, fluoro, bromo or iodo. The abbreviation 'C₃.₈- cycloalkyl' means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. The abbreviation 'C₅.₈ heterocycloalkyl' refers to (N, O, S) heteroatom containing rings, including but not limited to piperidinyl, morpholinyl , azepanyl, pyrrolidinyl, thiomorpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl. The abbreviation 'C₅.i₀ bicycloalkyl group' refers to carbo-bicyclic ring systems, including but not limited to bicyclo[2.2.1]heptanyl, bicyclo[3.3.0]octanyl or the bicyclo[3.1.1]heptanyl group. The abbreviation 'C₆-io tricycloalkyl group' refers to carbo-tricyclic ring systems such as the 1-adamantyl, noradamantyl or the 2-adamantyl group. The abbreviation 'C_2-4 heteroalkyl' refers to (N, O, S) heteroatom containing linear or branched C₂^-alkyl groups, including but not limited to methoxy methyl, dimethylaminomethyl and ethylsulfanylmethyl.

Prodrugs of the compounds mentioned above are in the scope of the present 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 learned from marketed and investigational prodrugs", J. Med. Chenn., 47, 2393-2404, 2004). Pro-drugs, i.e. compounds which when administered to humans by any known route, are metabolised to compounds having formula (I), 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 (I) 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-(acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone.

N-oxides of the compounds mentioned above are in the scope of the present invention. Tertiary amines may or may not give rise to N-oxide metabolites. The extend to what N- oxidation takes place varies from trace amounts to a near quantitative conversion. N-oxides may be more active than their corresponding tertiary amines or less active. Whilst N-oxides are easily reduced to their corresponding tertiary amines by chemical means, in the human body this happens to varying degrees. Some N-oxides undergo nearly quantitative reductive conversion to the corresponding tertiary amines, in other cases the conversion is a mere trace reaction or even completely absent. (M. H. Bickel: "The pharmacology and Biochemistry of N-oxides", Pharmacological Reviews, 21.(4), 325 - 355, 1969).

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

wherein:

- Ri represents a halogen atom or a d_-3-alkyl group, which Ci_-3-alkyl group may contain 1-3 fluoro atoms or a hydroxy or amino group, or R₁ represents a C_2-3-alkynyl group, a C_2-3-alkenyl group, which C_2-3-alkynyl group or C_2-3-alkenyl group may contain 1-3 fluoro atoms, or R₁ represents an acetyl, cyclopropyl, cyano, methylsulfonyl, ethylsulfonyl, methylsulfinyl, ethylsulfinyl trifluoromethylsulfanyl, methylsulfanyl, ethylsulfanyl group, formyl group or a C_2-4-heteroalkyl group, and R₂, R₃ and R₄ have the meanings as given above. More in particular, the invention relates to compounds of formula (I):

R,

wherein:

- R₃ represents a hydrogen or halogen atom or a formyl, methylsulfonyl, ethylsulfonyl, methylsulfinyl, ethylsulfinyl, trifluoromethylsulfanyl, methylsulfanyl, ethylsulfanyl or cyano group, or R₃ represents Ci_-6-alkyl group, which d_-6-alkyl group may contain 1 -3 fluoro atoms or a hydroxy or amino group, or R₃ represents a C_2-6-alkynyl, C_2-6-alkenyl, Ci_-6- alkanoyl, C_3-8-cycloalkyl, C_5-8-heterocycloalkyl or a C_2-6-heteroalkyl group, which groups are optionally substituted with 1-3 methyl groups, an ethyl, amino or hydroxy group or with 1-3 fluoro atoms, or R₃ represents a phenyl group which is substituted with 1-5 substituents Y, wherein Y has the meaning as defined above, or R₃ represents a heteroaryl group which heteroaryl group may be substituted with 1 , 2 or 3 substituents Y, wherein Y has the meaning as defined above or R₃ represents a benzyl or heteroaryl methyl group which benzyl or heteroaryl methyl group may be substituted with 1 , 2 or 3 substituents Y

- R₄ represents subgroup (ii)

(ϋ) wherein

R₇ represents a hydrogen atom or a Ci_-6 linear alkyl group or an isopropyl group,

- R₈ represents a C_2-6 alkyl group which group is substituted with a hydroxy or amino group or with 1-3 fluoro atoms, or R₈ represents a C_7-I0 branched alkyl group, C_3-8 cycloalkyl group, C_5-8 heterocycloalkyl group, C_3-8-cycloalkyl-Ci_-2-alkyl group, C_5-7- heterocycloalkyl-Ci_-2-alkyl group, C_5-I0 bicycloalkyl group, C_5-i₀-bicycloalkyl-Ci_-2-alkyl group, C_5-io-heterobicycloalkyl-Ci_-2-alkyl group, C_6-I0 tricycloalkyl group, C_6-I0- tricycloalkyl-Ci_-2-alkyl group, C_6-i₀-heterotricycloalkyl-Ci_-2-alkyl group which groups may be substituted with 1-5 substituents selected from methyl, hydroxy, ethyl, amino, hydroxy methyl, trifluoromethyl, or fluoro, or R₈ represents a phenyl group which group is substituted with 1 -5 substituents Y as defined above, or R₈ represents a naphtyl or a 1 ,2,3,4-tetrahydronaphtyl or indanyl group which groups may be substituted with 1-3 substituents Y, or R₈ represents a phenyl-Ci_-3-alkyl group, a diphenyl-Ci_-3-alkyl group, which groups may be substituted on their phenyl ring with 1 -5 substituents Y, wherein Y has the abovementioned meaning, or R₈ represents a benzyl group, which benzyl group is substituted with 1-5 substituents Y, or R₈ represents a heteroaryl, heteroaryl methyl or heteroarylethyl group, which heteroaryl, heteroaryl methyl or heteroarylethyl group may be substituted with 1-3 substituents Y, as defined above, or R₈ represents a piperidinyl, azepanyl, morpholinyl, azabicyclo[3.3.0]octanyl, 4-hydroxypiperidinyl or pyrrolidinyl group, with the proviso that R₈ is neither a 6-methoxy-benzothiazol-2-yl group nor a [3- chloro-5-(trifluoromethyl)pyrid-2-yl]methyl group, or R₇ and R₈ - together with the nitrogen atom to which they are bonded - form a saturated or unsaturated, non-aromatic or partly aromatic, monocyclic, bicyclic or tricyclic heterocyclic group having 7 to 10 ring atoms, which heterocyclic group may be substituted with one or two Ci_-3 alkyl groups, a hydroxy group, a phenyl group, a trimethylfluoromethyl group, a benzyl group, a diphenyl methyl group or a halogen atom, or R₇ and R₈ - together with the nitrogen atom to which they are bonded - form a saturated monocyclic heterocyclic group, optionally containing another heteroatom

(selected from N, O, S), having 5 to 6 ring atoms, which heterocyclic group is substituted with 1-3 Ci_-3 alkyl groups, a hydroxy group or 1-2 fluoro atoms, with the proviso that R₇ and R₈ - together with the nitrogen atom to which they are bonded - do not form a trimethyl-substituted aza-bicyclo[3.2.1]octanylgroup, and Ri and R₂ have the meanings as given above.

Also more in particular the invention relates to compounds of formula (I)

(I)

wherein:

- Ri represents a halogen atom or a Ci_-3-alkyl group, which d_-3-alkyl group may contain 1- 3 fluoro atoms or a hydroxy group, or R₁ represents a C_2-3-alkynyl group, a C_2-3-alkenyl group, acetyl, cyclopropyl, cyano, methylsulfonyl, methylsulfinyl, methylsulfanyl or a C_2-4- heteroalkyl group,

- R₂ represents a phenyl group which may be substituted with 1 , 2, 3, 4 or 5 substituents Y, which can be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chloro, iodo, bromo, fluoro, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano, or R₂ represents a monocyclic heteroaryl group which heteroaryl group may be substituted with 1 , 2 or 3 substituents Y, wherein Y has the meaning as defined above, with the proviso that R₂ is not a 6-methyl-2-pyridyl group, or R₂ represents a mono -unsaturated or fully saturated 4-10 membered monocyclic, fused bicyclic or fused tricyclic carbocyclic ring system, or

R₅ represents a mono-unsaturated or fully saturated 4-10 membered monocyclic, fused bicyclic or fused tricyclic heterocyclic ring system, which carbocyclic or heterocyclic rings systems are optionally substituted with 1-3 methyl groups, an ethyl, amino or hydroxy group or with a fluoro atom, - R₃ represents a hydrogen or halogen atom or a methylsulfanyl or cyano group, or R₃ represents Ci_-6-alkyl group, which Ci_-6-alkyl group may contain 1-3 fluoro atoms or a hydroxy or amino group, or R₃ represents a C_2-6-alkynyl or C_2-6-alkenyl group, which groups are optionally substituted with 1-3 fluoro atoms, R₄ represents subgroup (ii)

(ϋ) wherein

R₇ represents a hydrogen atom or a Ci_-3 linear alkyl group, - R₈ represents a C_2-6 alkyl group which group is substituted with a hydroxy or amino group or with 1-3 fluoro atoms, or R₈ represents a C_7-I0 branched alkyl group, C_3-8 cycloalkyl group, C_5-8 heterocycloalkyl group, C_3-8-cycloalkyl-Ci_-2-alkyl group, C_5-7- heterocycloalkyl-d-₂-alkyl group, C_5-I0 bicycloalkyl group,

group, Ce-io-heterobicycloalkyl-Ci^-alkyl group, C_6-io tricycloalkyl group, C_6-io- tricycloalkyl-Ci-₂-alkyl group, Ce-io-heterotricycloalkyl-Ci^-alkyl group which groups may be substituted with 1-5 substituents selected from methyl, hydroxy, ethyl, amino, hydroxymethyl, trifluoromethyl or fluoro, or R₈ represents a phenyl group which group is substituted with 1-5 substituents Y as defined above, or R₈ represents a naphtyl or a 1 ,2,3,4-tetrahydronaphtyl or indanyl group which groups may be substituted with 1-3 substituents Y, or R₈ represents a phenyl-Ci_-3-alkyl group, a diphenyl-Ci_-3-alkyl group, which groups may be substituted on their phenyl ring with 1 -5 substituents Y, wherein Y has the abovementioned meaning, or R₈ represents a benzyl group, which benzyl group is substituted with 1-5 substituents Y, or R₈ represents a heteroaryl, heteroaryl methyl or heteroarylethyl group, which heteroaryl, heteroaryl methyl or heteroarylethyl group may be substituted with 1-3 substituents Y, as defined above, or R₈ represents a piperidinyl, azepanyl, morpholinyl, azabicyclo[3.3.0]octanyl, 4-hydroxypiperidinyl or pyrrolidinyl group, with the proviso that R₈ is neither a 6-methoxy-benzothiazol-2-yl group nor a [3- chloro-5-(trifluoromethyl)pyrid-2-yl]methyl group,

Even more particular the invention relates to compounds of formula (I)

(I)

wherein:

- Ri represents a halogen atom or a d_-3-alkyl group, which Ci_-3-alkyl group may contain 1- 3 fluoro atoms or a hydroxy group, or R₁ represents a cyano, or methylsulfanyl group,

- R₂ represents a mono-unsaturated or fully saturated 5-7 membered monocyclic carbocyclic ring system which may be substituted with 1-5 substituents selected from methyl, ethyl, amino, hydroxy or fluoro or R₂ represents a phenyl group which may be substituted with 1 , 2, 3, 4 or 5 substituents Y, which can be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chloro, iodo, bromo, fluoro, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano,

- R₃ represents a hydrogen or halogen atom or a methylsulfanyl or cyano group, or R₃ represents Ci_-6-alkyl group, which Ci_-6-alkyl group may contain 1-3 fluoro atoms or a hydroxy or amino group,

- R₄ represents subgroup (ii)

(ϋ)

wherein

R₇ represents a hydrogen atom or a methyl group, - R₈ represents a C_2-6 alkyl group which group is substituted with 1-3 fluoro atoms, or R₈ represents a C_7-io branched alkyl group, C_3-8 cycloalkyl group, C_5-8 heterocycloalkyl group, C_3-8-cycloalkyl-Ci_-2-alkyl group, C_5-7-heterocycloalkyl-Ci_-2-alkyl group, C_5-I0 bicycloalkyl group, C_5-i₀-bicycloalkyl-Ci_-2-alkyl group, C_5-i₀-heterobicycloalkyl-Ci_-2-alkyl group, C_6-io tricycloalkyl group, C_6-i₀-tricycloalkyl-Ci_-2-alkyl group, C_6-I0-

group which groups may be substituted with 1 -5 substituents selected from methyl, hydroxy, ethyl, amino, hydroxymethyl, trifluoromethyl or fluoro, or R₈ represents a phenyl group which group is substituted with 1 -5 substituents Y as defined above, or R₈ represents a naphtyl or 1 ,2,3,4-tetrahydronaphtyl or indanyl group which groups may be substituted with 1-3 substituents Y, or R₈ represents a phenyl-Ci_-3- alkyl group, a diphenyl-Ci_-3-alkyl group, which groups may be substituted on their phenyl ring with 1-5 substituents Y, wherein Y has the abovementioned meaning, or R₈ represents a substituted benzyl group, which benzyl group is substituted with 1-5 substituents Y, or R₈ represents a heteroaryl, heteroaryl methyl or heteroarylethyl group, which heteroaryl, heteroaryl methyl or heteroarylethyl group may be substituted with 1-3 substituents Y, as defined above, with the proviso that R₈ is neither a 6-methoxy- benzothiazol-2-yl group nor a [3-chloro-5-(trifluoromethyl)pyrid-2-yl]methyl group,

Most particular, the invention relates to compounds of formula (I)

wherein: - Ri represents a halogen atom or a Ci_-3-alkyl group, which d_-3-alkyl group may contain 1- 3 fluoro atoms, or R₁ represents a cyano, or methylsulfanyl group,

- R₂ represents a saturated six-membered monocyclic carbocyclic ring or R₂ represents a phenyl group which may be substituted with 1, 2 or 3 substituents Y, which can be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chloro, iodo, bromo, fluoro, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano,

- R₃ represents a hydrogen or halogen atom or a methylsulfanyl or cyano group, or R₃ represents Ci_-4-alkyl group, which Ci_-4-alkyl group may contain 1-3 fluoro atoms,

- R₄ represents subgroup (ii)

(ϋ)

wherein

R₇ represents a hydrogen atom or a methyl group, - R₈ represents a C_2-6 alkyl group which group is substituted with 1-3 fluoro atoms, or R₈ represents a C_7-I0 branched alkyl group, C_3-8 cycloalkyl group, C_5-8 heterocycloalkyl group, C_3-8-cycloalkyl-Ci_-2-alkyl group, C_5-7-heterocycloalkyl-Ci_-2-alkyl group, C_5-I0 bicycloalkyl group, C_5-i₀-bicycloalkyl-Ci_-2-alkyl group, C_5-i₀-heterobicycloalkyl-Ci_-2-alkyl group, C_6-io tricycloalkyl group, Ce-^-tricycloalkyl-C^-alkyl group, C_6-I0- heterotricycloalkyl-Ci_-2-alkyl group, which groups may be substituted with 1-5 substituents selected from methyl, hydroxy, ethyl, amino, hydroxymethyl, trifluoromethyl or fluoro, or R₈ represents a phenyl group which group is substituted with 1-3 substituents Y, wherein Y has the meaning as defined above, or R₈ represents a naphtyl group which group may be substituted with 1 -3 substituents Y, or R₈ represent s a phenyl-Ci_-2-alkyl group, which group may be substituted on the phenyl ring with 1-3 substituents Y, wherein Y has the abovementioned meaning, or R₈ represents a substituted benzyl group, which benzyl group is substituted with 1-5 substituents Y

Finally, the invention also specifically relates to compounds having formula (I) wherein R₂ represents a saturated six-membered monocyclic carbocyclic ring or R₂ represents a phenyl group which may be substituted with 1 , 2, 3, 4 or 5 substituents Y, which can be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chloro, iodo, bromo, fluoro, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano, and all other symbols have the meanings as described above.

In a further embodiment, the invention relates to compounds of the general formula (XIV)

(XIV) wherein:

- Ri represents a halogen atom or a Ci_-3-alkyl group, which d_-3-alkyl group may contain 1- 3 fluoro atoms or a hydroxy or amino group, or R₁ represents a C_2-3-alkynyl group, a C_2- ₃-alkenyl group, which C_2-3-alkynyl group or C_2-3-alkenyl group may contain 1-3 fluoro atoms, or R₁ represents an acetyl, cyclopropyl, cyano, methylsulfonyl, ethylsulfonyl, methylsulfinyl, ethylsulfinyl trifluoromethylsulfanyl, methylsulfanyl, ethylsulfanyl group, formyl group or a C_2-4-heteroalkyl group,

- R₂ represents a phenyl group which may be substituted with 1 , 2, 3, 4 or 5 substituents Y, which can be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chloro, iodo, bronrio, fluoro, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano, or R₂ represents a heteroaryl group which heteroaryl group may be substituted with 1 , 2 or 3 substituents Y, wherein Y has the meaning as defined above, with the proviso that R₂ is not a 6-methyl- 2-pyridyl group, or

R₂ represents a mono -unsaturated or fully saturated 4-10 membered monocyclic, fused bicyclic or fused tricyclic carbocyclic ring system, or

R₂ represents a mono-unsaturated or fully saturated 4-10 membered monocyclic, fused bicyclic or fused tricyclic heterocyclic ring system which carbocyclic or heterocyclic ring system may be substituted with 1-5 substituents selected from methyl, ethyl, amino, hydroxy or fluoro, or

R₂ represents a group of general formula CH₂-R₅ wherein R₅ represents a phenyl group which is substituted with 1 , 2, 3, 4 or 5 substituents Y as defined above, or R₅ represents a heteroaryl group or a 1 ,2,3,4-tetrahydronaphtyl or indanyl group, which heteroaryl group or 1 ,2,3,4-tetrahydronaphtyl or indanyl group may be substituted with 1 , 2 or 3 substituents Y as defined above or R₅ represents a mono-unsaturated or fully saturated monocyclic, fused bicyclic or fused tricyclic 4-10 membered carbocyclic ring system, or R₅ represents a mono-unsaturated or fully saturated 4-10 membered monocyclic, fused bicyclic or fused tricyclic heterocyclic ring system, which carbocyclic or heterocyclic ring systems are optionally substituted with 1-5 substituents selected from the group consisting of methyl, ethyl, amino, hydroxy or fluoro, or

R₂ represents a methylsulfonylaminoalkyl group, methylsulfonylalkyl or a acetamidoalkyl group, With the proviso that R₂ re presents not a phenyl, 4-methylphenyl or 4-methoxyphenyl group, R₃ represents a hydrogen or halogen atom or a formyl, d_-6-alkylsulfonyl, Ci_-6- alkylsulfinyl, Ci_-6-alkylsulfanyl, trifluoromethylsulfanyl, benzylsulfanyl or cyano group, or R₃ represents Ci_-8-alkyl group, which Ci_-8-alkyl group may be substituted with 1-5 substituents selected from the group consisting of fluoro, hydroxy or amino, or R₃ represents a C_2-6-alkynyl, C_2-6-alkenyl, Ci_-6-alkanoyl, C_3-8-cycloalkyl, C_5-8-heterocycloalkyl or a C_2-6-heteroalkyl group, which groups are optionally substituted with 1-3 methyl groups, an ethyl, amino or hydroxy group or with 1-3 fluoro atoms, or R₃ represents a phenyl group which is substituted with 1-5 substituents Y, wherein Y has the meaning as defined above, or R₃ represents a heteroaryl group which heteroaryl group may be substituted with 1 , 2 or 3 substituents Y, wherein Y has the meaning as defined above or R₃ represents a benzyl or heteroaryl methyl group which benzyl or heteroaryl methyl group may be substituted with 1, 2 or 3 substituents Y,

- Z represents a chloro atom or a Ci_₃ alkyl group, a hydroxy group, or a -O-Na, -O-K, -O- Li, or -O-Cs group, or Z represents a N-methoxy-N-methyl-amino group, such compounds being useful in the synthesis of compounds of general formula (I) wherein:

- Ri represents a halogen atom or a d_-3-alkyl group, which Ci_-3-alkyl group may contain 1-3 fluoro atoms or a hydroxy or amino group, or R₁ represents a C_2-3-alkynyl group, a C_2-3-alkenyl group, which C_2-3-alkynyl group or C_2-3-alkenyl group may contain 1-3 fluoro atoms, or R₁ represents an acetyl, cyclopropyl, cyano, methylsulfonyl, ethylsulfonyl, methylsulfinyl, ethylsulfinyl trifluoromethylsulfanyl, methylsulfanyl, ethylsulfanyl group, formyl group or a C_2-4-heteroalkyl group,

- R₂ represents a phenyl group which may be substituted with 1 , 2, 3, 4 or 5 substituents Y, which can be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chloro, iodo, bromo, fluoro, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano, or R₂ represents a heteroaryl group which heteroaryl group may be substituted with 1 , 2 or 3 substituents Y, wherein Y has the meaning as defined above, with the proviso that R₂ is not a 6-methyl- 2-pyridyl group, or R₂ represents a mono -unsaturated or fully saturated 4-10 membered monocyclic, fused bicyclic or fused tricyclic carbocyclic ring system, or

R₂ represents a group of general formula CH₂-R₅ wherein R₅ represents a phenyl group which is substituted with 1 , 2, 3, 4 or 5 substituents Y as defined above, or R₅ represents a heteroaryl group or a 1 ,2,3,4-tetrahydronaphtyl or indanyl group, which heteroaryl group or 1 ,2,3,4-tetrahydronaphtyl or indanyl group may be substituted with 1 , 2 or 3 substituents Y as defined above or R₅ represents a mono-unsaturated or fully saturated monocyclic, fused bicyclic or fused tricyclic 4-10 membered carbocyclic ring system, or R₅ represents a mono-unsaturated or fully saturated 4-10 membered monocyclic, fused bicyclic or fused tricyclic heterocyclic ring system, which carbocyclic or heterocyclic ring systems are optionally substituted with 1-5 substituents selected from the group consisting of methyl, ethyl, amino, hydroxy or fluoro, or R₂ represents a methylsulfonylaminoalkyl group, methylsulfonylalkyl or a acetamidoalkyl group,

- R₃ represents a hydrogen or halogen atom or a formyl, d_-6-alkylsulfonyl, Ci_-6- alkylsulfinyl, Ci_-6-alkylsulfanyl, trifluoromethylsulfanyl, benzylsulfanyl or cyano group, or R₃ represents Ci_-8-alkyl group, which Ci_-8-alkyl group may be substituted with 1-5 substituents selected from the group consisting of fluoro, hydroxy or amino, or R₃ represents a C_2-6-alkynyl, C_2-6-alkenyl, Ci_-6-alkanoyl, C_3-8-cycloalkyl, Cs-s-heterocycloalkyl or a C_2-6-heteroalkyl group, which groups are optionally substituted with 1-3 methyl groups, an ethyl, amino or hydroxy group or with 1-3 fluoro atoms, or R₃ represents a phenyl group which is substituted with 1-5 substituents Y, wherein Y has the meaning as defined above, or R₃ represents a heteroaryl group which heteroaryl group may be substituted with 1 , 2 or 3 substituents Y, wherein Y has the meaning as defined above or R₃ represents a benzyl or heteroaryl methyl group which benzyl or heteroaryl methyl group may be substituted with 1, 2 or 3 substituents Y

GENERAL ASPECTS OF SYNTHESES

Compounds of formula (I) may be prepared by different methodologies. 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.

Imidazole derivatives can be obtained according to methods known. Relevant articles are:

a) Gomez-Sanchez et al., J. Heterocyclic Chem. (1987), 24, 1757-1763. b) Matsuura et al., J. Chem. Soc. Perkin Trans. I (1991), 11, 2821-2826 c) Ueda et al., Tetrahedron Lett. (1988), 29, 4607-4610 d) Gupta et al., Eur. J. Med. Chem. (2004), 39, 805-814 e) Van Berkel et al. Tetrahedron Lett. (2004), 45, 7659-7662 f) Haberhauer and Rominger, Tetrahedron Lett. (2002), 43, 6335-6338 g) Dell'Erba et al., Tetrahedron (1997), 53, 2125-2136 h) Lipshutz et al., Tetrahedron Lett. (1992), 33, 5865-5868 Compounds of general formula (I) can be obtained according to the procedures outlined in Schemes 1 - 6.

HNMe(OMe) coupling reagent

(I) wherein X represents subgroup (i)

Scheme 1 : The symbols Ri - R₈ have the meanings as given above on pages 2-5, R₉ and Rio represent alkyl(d_-3)

Nitroenamine derivatives of general formula (II) can be prepared according to the procedure published by Gomez-Sanchez et al., J. Heterocyclic Chem. (1987), 24, 1757-1763. Nitroenamine derivatives of general formula (II) can be reacted with ortho-esters of general formula (III) to give imidazole derivatives of general formula (IV) (Scheme 1). Subsequent basic ester hydrolysis, for example using lithium hydroxide (LiOH), NaOH, KOH or CsOH can provide intermediate imidazolecarboxylic acid alkali salts, which can be acidified by an acid such as aqueous hydrochloride (HCI) to give imidazolecarboxylic acid derivatives of general formula (V). Compounds of general formula (IV) can be amidated with an amine of general formula R₇R₈NH into a compound of general formula (I) wherein X represents subgroup (ii) as defined above. Such amidations can be catalyzed by trimethylaluminum (CHs)₃AI. (For more information on aluminum-mediated conversion of esters to amides, see: J. I. Levin, E. Turos, S. M. Weinreb, Synth. Commun. (1982), 12, 989-993.). Imidazolecarboxylic acid derivatives of general formula (V) or their corresponding alkali salts can be reacted with an amine of general formula R₇R₈NH into a compound of general formula (I) wherein X represents subgroup (ii) as defined above. This particular reaction preferably proceeds via activating and coupling methods such as formation of an active ester, or in the presence of a so-called coupling reagent, such as for example, DCC, HBTU (O-benzotriazol-1-yl-N, N, N', N'-tetramethyluronium hexafluorophosphate), TBTU, HOAt (N- hydroxy-7-azabenzotriazole), PyBOP (benzotriazol-1 -yloxytris(pyrrolidino)-phosphonium hexafluorophosphate), BOP, CIP (2-chloro-1,3-dimethylimidazolinium hexafluorophosphate), 2-chloro-1,3-dimethylimidazolinium chloride, PyAOP (7-azabenzotriazol-1- yloxytris(pyrrolidino)-phosphonium hexafluoro-phosphate) and the like. (For more information on activating and coupling methods see a) M. Bodanszky, A. Bodanszky: The Practice of Peptide Synthesis, Springer-Verlag, New York, 1994; ISBN: 0-387-57505-7; b) K. Akaji et al., Tetrahedron Lett. (1994), 35, 3315-3318; c) F. Albericio et al., Tetrahedron Lett. (1997), 38, 4853-4856); d) C. Montalbetti and V. Falque, Tetrahedron (2005), 61, 10827- 10852).

Alternatively, a compound having general formula (V) or the corresponding alkali salts can be reacted with a so-called halogenating agent such as for example thionyl chloride (SOCI₂) or oxalyl chloride. This reaction gives the corresponding carbonyl chloride (acid chloride)

(Va) which can subsequently be reacted with a compound having formula R₇R₈NH wherein

R₇ and R₈ have the meanings as described above, to give a compound of general formula (I) wherein X represents subgroup (ii) as defined above. Such reactions can be catalyzed by pyridine or 4-dimethylaminopyridine (DMAP).

A compound having general formula (V) can be reacted with N-methoxy-N-methylamine in the presence of a coupling reagent to yield the corresponding N-methoxy-N-methylamide of general formula (Vl) and subsequently reacted with a lithium reagent of general formula Re- Li or a Grignard reagent to give a compound of general formula (I), wherein X represents subgroup (i) as defined above.

(VII) (VIII) (IV) wherein R₂ represents -CH₂R₅

₂

(IV)

Scheme 2: The symbols Ri - R₅ have the meanings as given above as given above on pages 2-5, R₉ represents alkyl(d_-3). In the compounds of general formula R₂-B(OH)₂, R₂ represents an optionally substituted phenyl or heteroaryl group, a so-called Suzuki reagent.

Alternatively, a compound having general formula (VII) can be reacted with a compound of general formula (VIII), wherein L represents a so-called leaving group, such as chloro, bromo, iodo or mesyloxy (Scheme 2). A compound having general formula (VII) can also be reacted with a methylsulfonylaminoalkyl halogenide or methylsulfonylalkyl halogenide to add a methylsulfonylaminoalkyl group or methylsulfonylalkyl group to the 1 -position of the imidazole nucleus. Such reactions are preferably carried out in the presence of a base, such as sodium hydride or potassium carbonate to facilitate the nucleophilic attack of compound (VII) to produce a compound of formula (IV), wherein R₂ represents a group -CH₂R₅ and R₅ has the abovementioned meaning.

Alternatively, a compound having general formula (VII) can be reacted with compound of general formula R₂-B(OH)₂ wherein R₂ represents an optionally substituted phenyl or heteroaryl group, a so-called Suzuki reagent, to produce a compound of general formula (IV). Compounds of general formula (IV) can be converted to compounds of general formula (I) according to Scheme 1. Such reactions may be metal -catalyzed.

Scheme 3: The symbols R₁ - R₃ have the meanings as given above as given above on pages 2-5, R₉ represents alkyl(d_-3)

A compoun d having general formula (IX) can be reacted with a nitrite derivative such as sodium nitrite (NaNO₂) to give a compound of general formula (X). (Scheme 3). A compound having general formula (X) can be reacted with an anhydride of general formula (RiCO)₂O in the presence of a reducing agent such as hydrogen and a catalyst such as Pd on carbon (Pd/C) and the like, in an inert organic solvent such as ethanol to give a compound of general formula (Xl). A compound having general formula (Xl) can be reacted with an amine of general formula R₂NH₂ in an inert solvent such as butyronitrile, to give a compound of general formula (IV). Compounds of general formula (IV) can be converted to compounds of general formula (I) according to Scheme 1. Alternatively, a compound of general formula (Xl) can be obtained in a two-pot reaction from a compound of general formula (XII). A compound of general formula (XII) can be deprotonated with a strong base such as potassium tert-butoxide (KO-t-Bu) and subsequently reacted with an acylating compound of general formula R₃COL, wherein L represents a leaving group such as chloride, followed by treatment with an acid such as hydrochloric acid and the like. The resulting compound of general formula (XIII) can be reacted with an anhydride of general formula (RiCO)₂O to give a compound of formula (Xl). Alternatively, a compound having general formula (X) can be reacted with a reducing agent such as hydrogen and a catalyst such as Pd on carbon (Pd/C) and the like, in an inert organic solvent such as ethanol in the presence of an acid such as hydrochloric acid to give a compound of general formula (XIII).

(I) (I) wherein X represent subgroup (ιι) wherein X represent subgroup (ιι)

Scheme 4: The symbols R₁ - R₃ have the meanings as given above as given above on pages 2-5, X represents subgroup (ii).

A compound having general formula (I) wherein X represents subgroup (ii) and wherein the 5-position of the imidazole moiety contains a hydrogen atom can be deprotonated with a strong non-nucleophilic base such as lithium diisopropylamide (LDA), followed by treatment with a group R₃-L wherein L represents a leaving group to give a compound of general formula (I) wherein X represents subgroup (ii) and wherein the 5-position of the imidazole moiety contains a substituent R₃ (Scheme 4).

(IV) wherein R₁ and

(V) wherein R₁ and (I) wherein R₁ and R₃ represent H R, represent H R₃ represent H

(I) wherein R₁ and (I) wherein R₁ = H and (I) wherein R₁ = H and (I) wherein R₁ and R₃ represent H R₃ represents E R₃ represents E R₃ represent E

Scheme 5: The symbols R₂, R₇, Re and R₉ have the meanings as given above as given above on pages 2-5, E is derived from an electrophilic moiety, L represents a leaving group.

An imidazole derivative of general formula (IV) wherein R₁ and R₃ re present hydrogen and wherein R₉ has the abovementioned meaning can be converted via ester hydrolysis, for example by using lithium hydroxide (LiOH), NaOH, KOH or CsOH to provide intermediate imidazolecarboxylic acid alkali salts, which salts can be acidified by an acid such as aqueous hydrochloride (HCI) to give imidazolecarboxylic acid derivatives of general formula (V). Imidazolecarboxylic acid derivatives of general formula (V) can be amidated to give a compound of general formula (I) wherein R₁ and R₃ represent hydrogen and R₂, R₇ and R₈ have the abovementioned meaning. This compound of general formula (I) wherein R₁ and R₃ represent hydrogen and R ₂, R ₇ and R₈ have the abovementioned meaning can be deprotonated with a strong non-nucleophilic base such as lithium diisopropylamide (LDA) or n-Buli, followed by treatment with a group E-L wherein L represents a leaving group, such as iodide, bromide, or S-alkyl and E represents an electrophilic group, including but not limited to -S-alkyl, primary alkyl, chloro, bromo, iodo or cyano to give a compound of general formula (I) wherein X represents subgroup (ii) and wherein the 2/5-position of the imidazole moiety represent a substituent E and/or a hydrogen atom, depending on the type of group E- L applied in this reaction (Scheme 5). The definition of the group E is part of the definition of R₁ and R₃ and does not exceed the definitions of R₁ and R₃ given above. The mixtures of compounds that may be formed in the last reaction step in Scheme 5 can be separated and purified, for example by chromatographic methods or by crystallisation techniques.

(I) wherein R₁ and (I) wherein R₁ = H and (I) wherein R₁ = Cl or Br and R₃ represent H R₃ represents Cl or Br R₃ represents Cl or Br

Scheme 6: The symbols R₂, R₇, and R₈ have the meanings as given above as given above on pages 2-5.

A compound of general formula (I) wherein R₁ and R₃ represent hydrogen and R₂, R₇ and R₈ have the abovementioned meaning can be reacted with a halogenating agent such as N- chlorosuccinimide (NCS) or bromine (Br₂) in an inert organic solvent such as dichloromethane to give a compound of general formula (I) wherein R₃ represents Cl or Br and Ri represents a hydrogen atom. A compound of general formula (I) wherein R₃ represents Cl or Br and Ri represents a hydrogen atom can be reacted with a halogenating agent such as NCS or Br₂ in an inert organic solvent such as dichloromethane to give a compound of general formula (I) wherein R₃ represents Cl or Br and Ri represents Cl or Br (Scheme 6).

For more detailed information on nucleophiles, electrophiles and the leaving group concept see: M. B. Smith and J. March: Advanced organic chemistry, p. 275, 5^th 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.

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 such as fumaric acid. PHARMACEUTICAL PREPARATIONS

The compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances such as liquid or solid carrier material. The pharmaceutical compositions of the invention may be administered enterally, orally, parenterally (intramuscularly or intravenously), rectally or locally (topically). They can be administered in the form of solutions, powders, tablets, capsules (including microcapsules), ointments (creams or gel) or suppositories. Suitable excipients for such formulations are the pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances. Frequently used auxiliary substances which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars or sugar alcohols, talc, lactoprotein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as fish liver oil, sunflower, groundnut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol.

Compounds of the present 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 vivo and in vitro pharmacological assays related to cannabinoid CB₂ receptor neurotransmission have been described in the literature. Some examples are: • Ibrahim, M.M. et al. (2003) Proc. Natl. Acad. Sci. USA 100, 10529-10533 • Hanus, L. et al. (1999) Proc. Natl. Acad. ScL USA 96, 14228-14233

• Zhang, J. et al. (2003) Eur. J. Neuroscience 17, 2750-2754.

• Klein, T.W. et al. (2003) J. Leukoc. Biol. 74, 486-496

• Shoemaker, J. L. et al. (2005), J. Pharmacol. Exp. Ther. 315, 828-838 • Iwamura, H. et al. (2001), J. Pharmacol. Exp. Ther. 296, 420-425.

In vitro affinity for cannabinoid-CBi receptors

The affinity of the compounds of the invention for cannabinoid CB₁ receptors can be determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabinoid CB₁ receptor is stably transfected in conjunction with [³H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the

[³H]-ligand, 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 affinity for cannabinoid-CB₂ receptors

The affinity of the compounds of the invention for cannabinoid CB₂ receptors can be determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabinoid CB₂ receptor is stably transfected in conjunction with [³H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the

Due to their cannabinoid CB₂ receptor modulating activity the compounds according to the invention are suitable for use in the treatment of immune system disorders, inflammatory disorders, allergies, pain, neuropathic pain, multiple sclerosis, neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, cerebral ischaemia, cerebral apoplexy, craniocerebral trauma, spinal cord injury, neuroinflammatory disorders, brainstem neurodegeneration, plaque sclerosis, viral encephalitis, demyelinisation related disorders, and other neurological disorders as well as in the treatment of cancers, diabetes, gastric diseases, lung diseases, asthma and cardiovascular diseases as well as other diseases wherein CB₂ receptor neurotransmission is involved.

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.

DOSE

The affinity of the compounds of the invention for cannabinoid CB₂ receptors was determined as described above. From the binding affinity measured for a given compound of formula (I), one can estimate a theoretical lowest effective dose. At a concentration of the compound equal to twice the measured Kj-value, 100% of the cannabinoid CB₂ receptors likely will be occupied by the compound. Converting that concentration to mg of compound per kg of patient yields a theoretical lowest effective dose, assuming ideal bioavailability. Pharmacokinetic, pharmacodynamic, and other considerations may alter the dose actually administered to a higher or lower value. The dosage expediently administered is 0.001 -

1000 mg/kg, preferably 0.1-100 mg/kg of patient's bodyweight.

TREATMENT

The term "treatment" as used herein refers to any treatment of a mammalian, preferably human condition or disease, and includes: (1) preventing the disease or condition from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it, (2) inhibiting the disease or condition, i.e., arresting its development, (3) relieving the disease or condition, i.e., causing regression of the condition, or (4) relieving the conditions caused by the disease, i.e., stopping the symptoms of the disease.

EXAMPLES

EXAMPLE 1 : MATERIALS AND METHODS

All reactions involving moisture sensitive compounds or conditions were carried out under an anhydrous nitrogen atmosphere. Reactions were monitored by using thin-layer chromatography (TLC) on silica coated plastic sheets (Merck precoated silica gel 60 F254) with the indicated eluent. Spots were visualised by UV light (254 nm) or I₂. Flash chromatography refers to purification using the indicated eluent and Acros silica gel (0.030- 0.075 mm). Petroleum ether means petroleum ether 40-60. Nuclear magnetic resonance spectra (¹H NMR and ¹³C NMR) were determined in the indicated solvent with tetramethylsilane as an internal standard. Chemical shifts are given in ppm (δ scale) downfield from tetra-methylsilane. Coupling constants J are given in hertz (Hz). Peakshapes in the NMR spectra are indicated with the symbols 'q' (quartet), 'dq' (double quartet), 't' (triplet), 'dt' (double triplet), 'd' (doublet), 'dd' (double doublet), 's' (singlet), 'br s' (broad singlet) and 'πϊ (multiplet). Melting points were recorded on a Bϋchi B-545 melting point apparatus or determined by a differential scanning calorimetry (DSC) method. Yields refer to isolated pure products.

Preparative LC/MS instrumentation and procedure

Sciex API 150 EX masspectrometer with electron spray, 2 Shimadzu LC8A LC pump,

Shimadzu SCL-10A VP system controller, Shimadzu SPD-10A VP UV meter, Gilson 215 injector/collector,

Column Phenomenex Luna C18 (2) 150 x 21.2 x 5 μ

Eluant A 100% Water + 0.1% Formic acid on pH=3 B 100% Acetonitrile + 0.1% Formic acid

Injection 2.5 ml Splitter 1 to 50,000 with a make-up flow of 0.2 ml/min (25% H₂O/75% ACN met 0.25% HCOOH)

MS scan : from 100 - 900 amu step 1 amu scan time 1 sec.

Method : Flow rates and gradient profiles.

EXAMPLE 2: SYNTHESES OF SPECIFIC COMPOUNDS

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. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is thus intended that the specification and compounds be considered as exemplary only, with a true scope and spirit of the invention being indicated by the claims.

Synthesis of compound 1

Part A: A magnetically stirred mixture of ethyl 5-methyl-1 H-imidazole-4-carboxylate (13.875 g, 0.090 mol), phenylboronic acid (13.16 g, 0.108 mol) and CuI (0.85 g, 0.0045 mol) in ethanol/water (900 ml, 1/1 (v/v)) was divided in 12 equal portions and reacted in parallel at 85 ⁰C for 60 hours. After cooling to room temperature the 12 portions were combined and concentrated in vacuo. The residue was purified by flash chromatography (Ethylacetate/petroleum ether 40-65 = 1/1 (v/v)) to give ethyl 5-methyl-1-phenyl-1 H- imidazole-4-carboxylate (5.88 g, 26 % yield). ¹H-NMR (400 MHz, CDCI₃): δ 1.42 (t, J = 7 Hz, 3H), 2.47 (s, 3H), 4.40 (q, J = 7 Hz, 2H), 7.26-7.31 (m, 2H), 7.48-7.56 (m, 3H), 7.59 (s, 1 H). Part B: (-)-Cis-myrtanylamine (CAS 38235-68-6) (0.95 ml, 5.7 mmol) was dissolved in anhydrous dichloromethane (15 ml) and (CHs)₃AI (2.9 ml of a 2 M solution in heptane, 5.8 mmol) was added. The resulting mixture was magnetically stirred for 10 minutes at room temperature and ethyl 5-methyl-1-phenyl-1 H-imidazole-4-carboxylate (1.1 gram, 4.8 mmol) was added. The resulting mixture was stirred at 35 ⁰C for 16 hours, poured into an aqueous NaHCO₃ solution, stirred for 30 minutes and filtered over hyflo. The filtrate was twice extracted with dichloromethane. The organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo. Subsequent purification with flash chromatography (ethyl acetate/petroleum ether 40-65 = 1/2 (v/v)) gave N-[(1R,2S,5R)-rel-6,6- dimethylbicyclop.i .ilheptan^-methylJ-S-methyl-i-phenyl-I H-imidazole^-carboxamide, compound 1 (1.05 gram, 65 % yield). Melting point: 85-89 ⁰C.

Analogously, the following compounds 2 - 7 were prepared

Compound 2: Melting point: 214-219 ⁰C.

Compound 3: Melting point: 167-169 ⁰C.

Compound 4: from R-(+)-bomylamine (CAS 32511-34-5). Melting point: 209-212 ⁰C.

Compound 5: from endo-(1 R)-1 ,3,3-trimethylbicyclo[2.2.1]heptan-2-amine. Melting point: 149-152 ⁰C.

Compound 6: Melting point: 198-200 ⁰C.

Compound 7: Melting point: 232-234 ⁰C.

Compound 8

Synthesis of compound 8

Part A: Ethyl 2-methyl-1-phenyl-1 H-imidazole-4-carboxylate (4.8 gram, 21 % yield) was prepared according to the procedure described (in J. Heterocyclic Chem. 1987, 24, 1757- 1763) from ethyl 3-anilino-2-nitro-acrylate (23.6 gram, 0.01 mol) and triethylorthoacetate (150 ml). The initially formed crude product was purified by flash chromatography (eluent: diethyl ether). Rf (diethylether ~ 0.15) to give pure ethyl 2-methyl-1-phenyl-1 H-imidazole-4- carboxylate as an oil.

Part B: Ethyl 2-methyl-1-phenyl-1 H-imidazole-4-carboxylate (2.25 gram, 0.012 mol) was reacted (analogously to the procedure described hereinabove for compound 1) with AIMe₃ (7.2 ml of a 2M solution in hexane, 0.0144 mol) and 1-adamantane amine. HCI (2.25 g, 0.012 mol). The initially formed crude product was purified by flash chromatography (eluent: diethyl ether) to give N-adamantyl-2-methyl-1-phenyl-1 H-imidazole-4-carboxamide (2.2 gram, 55 % yield). Melting point: 207-210 ⁰C.

Compound 9 was prepared analogously to compound 6 from (-)-cis-myrtanylamine (CAS 38235-68-6). Melting point: 124-127 ⁰C.

Compound 10

Compound 10 : N-Adamantyl^-methyl-i-phenyl-I H-imidazole^-carboxamide (0.33 gram, 0.001 mol) was dissolved in anhydrous tetrahydrofuran (25 ml). The resulting solution was slowly added to a solution of lithium diisopropylamide (1.25 ml of a 2 M solution in heptane/THF, 0.0025 mol LDA) under N₂ at -70 ⁰C. A solution of methyl iodide (0.14 gram, 0.001 mol) in anhydrous THF was added and the resulting solution was stirred for 1 hour at - 70 ⁰C. The solution was allowed to attain room temperature and stirred for another 2 hours and subsequently quenched with aqueous acetic acid. After concentration in vacuo the resulting residue was purified by flash chromatography (diethyl ether/petroleum ether (40-60) = 3/1 (v/v)) to give compound 10 and compound 11 , respectively. Melting point compound 10: 180-183 ⁰C.

Compound 11

Compound 11 : Compound 11 was prepared more efficiently by reacting ethyl 2,5-dimethyl-i- phenyl-1 H-imidazole-4-carboxylate (Cf. the corresponding methyl ester 3j in J. Heterocyclic Chem. 1987, 24, 1757-1763) with AIMe₃ and 1-adamantane-amine.HCI, according to the Weinreb amidation procedure described hereinabove for compound 1 , Part B. Melting point: 201-204 ⁰C.

Synthesis of compound 12

Part A: Ethyl 2,5-dimethyl-1-(3-methoxyphenyl)-1 H-imidazole-4-carboxylate was prepared analogously to the procedure described (in J. Heterocyclic Chem. 1987, 24, 1757-1763) from ethyl 3-(3-methoxyphenylamino)-3-methyl-2-nitro-acrylate and triethylorthoacetate.

Part B: Ethyl 2,5-dimethyl-1-(3-methoxyphenyl)-1 H-imidazole-4-carboxylate was amidated

(analogously to the procedure described hereinabove for compound 1) (stirred at 70 ⁰C for

16 hours) with AIMe₃ and (-)-cis-myrtanylamine (CAS 38235-68-6) to give compound 12.

Melting point: 153-155 ⁰C.

Compound 12

Analogously were prepared compounds 13-20.

m.p.: 156-158 ⁰C. m.p.: 214-216 ⁰C. m.p.: 190-193 ⁰C.

m.p.: 217-223 ⁰C m.p.: 216-218 ⁰C m.p.: 137-140 ⁰C.

Compound 19

m.p.: 119-121 ⁰C. m.p.: 186-188 ⁰C.

Synthesis of compound 21

Part A: To a magnetically stirred suspension of ethyl 4-methyl-1 H-imidazole-5-carboxylate

(15.42 gram, 0.100 mol) in anhydrous THF was slowly added sodium hydride (NaH) (4.88 g of a 60 % suspension, 0.120 mol) and the resulting mixture was stirred at room temperature for 30 minutes. Benzyl bromide (13.8 ml, 0.120 mol) was slowly added and the resulting mixture was reacted for 16 hours. Water was added to the mixture. The organic layer was separated from the water layer. The water layer was extracted 3 times with ethylacetate. The organic layer was dried over MgSO₄, filtered and thoroughly concentrated to give an oil. The resulting residue was purified (in order to separate the two formed regioisomers) by flash chromatography (diethyl ether/ethyl acetate gradient) to give ethyl N-benzyl-5-methyl-1 H- imidazole-4-carboxylate (11.4 gram, 47 % yield). ¹H-NMR (400 MHz, CDCI₃): δ 1.40 (t, J = 7, 3H), 2.45 (S, 3H), 4.37 (q, J = 7, 2H), 5.10 (s, 2H), 7.03-7.08 (m, 2H), 7.28-7.38 (m, 3H), 7.48 (s, 1 H).

Part B: Ethyl N-benzyl-δ-methyl-I H-imidazole^-carboxylate (1.5 gram, 0.0061 mol) was reacted with adamantyl-1-amine.HCI (1.72 g, 0.0092 mol) and AI(CH₃)₃ (4.6 ml. 2M in hexane, 0.0092 mol) in 1,2-dichloroethane (20 ml) at 70 ⁰C for 40 hours according to the procedure described for compound 1 , part B. Purification by flash chromatography (ethyl acetate/petroleum ether = 1/1 (v/v)) gave compound 21 (1.24 gram, 58 %). Melting point: 182-184 ⁰C.

Analogously were prepared compounds 22, 23 and 23A:

Synthesis of compound 22

Compound 22 was prepared via the coupling of 3-(methylsulfonylamino)propyl chloride with ethyl 4-methyl-1 H-imidazole-5-carboxylate using K₂CO₃ as the base in DMF at 90 ⁰C for 20 hours, subsequent separation of the two formed regioisomers by flash chromatography

(ethyl acetate/methanol = 9/1 (v/v)), followed by the AI(CH₃)₃ catalyzed amidation with (-)-cis- myrtanylamine.

Compound 22. Melting point: 84-108 ⁰C. R_f 0.35 (EtOAc/MeOH = 4/1 (v/v)).

Compound 23. (from endo-(1 R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-amine) Melting point: 149-156 ⁰C. R_f 0.4 (EtOAc/MeOH = 4/1 (v/v)).

Compound 23A Synthesis of compound 23A

Compound 23A was prepared via the coupling of methanesulfonic acid 1-methyl-piperidin-2- ylmethyl ester .HCI with ethyl 4-methyl-1 H-imidazole-5-carboxylate using KOH as the base in DMSO at 60 ⁰C for 40 hours, subsequent separation of the formed regioisomers by flash chromatography (dichloromethane/methanol = 95/5 (v/v)) , followed by conversion of the resulting ester to the corresponding carboxylic acid (lithium hydroxidefTHF/water; at 60 ⁰C for 20 hours) and coupling of the formed carboxylic acid with (-)-cis-myrtanylamine using PyBOP (benzotriazol-i-yloxytris(pyrrolidino)-phosphonium hexafluorophosphate) as the coupling reagent in the presence of diisopropylethylamine in dichloromethane. The crude compound 23A was further purified by flash chromatography (dichloromethane/methanol = 95/5 (v/v)), followed by conversion of the isolated free base to the dihydrochloride salt. Compound 23A. Melting point: 148-153 ⁰C.

Synthesis of compound 24

Part A: To a magnetically stirred solution of ethyl N-benzyl-5-methyl-1 H-imidazole-4- carboxylate (8.4 gram, 0.0345 mol) in methanol (200 ml) was slowly added a solution of KOH (7.3 gram, 85 % grade, 0.110 mol) and the resulting mixture was heated at 80 ⁰C for 2 hours. The solution was cooled to room temperature and concentrated HCI (9.2 ml) was subsequently added. The formed precipitate was collected by filtration to give N-benzyl-5- methyl-1 H-imidazole-4-carboxylic acid (6.77 gram, 91 % yield). Melting point: 292 ⁰C (decomposition).

Part B: To a magnetically stirred solution of N-benzyl-5-methyl-1 H-imidazole-4-carboxylic acid (6.77 gram, 0.031 mol) in anhydrous acetonitrile (35 ml) was successively added diisopropylethylamine (DIPEΞA) (17.2 ml, 0.0992 mol), HBTU (14.098 gram, 0.0372 mol) and methoxy-methylamine (3.63 gram, 0.0372 mol). The resulting mixture was reacted at 20 ⁰C for 16 hours and subsequently concentrated in vacuo. The resulting residue was taken up in ethylacetate and successively washed with 5 % aqueous NaHCO₃ solution and water. The organic layer was dried over MgSO₄, filtered and concentrated in vacuo. The resulting oily residue (18.45 gram) was purified by flash chromatography (ethyl acetate/acetone = 7/3 (v/v)) to give N-methoxy-N-methyl-S-methyl-i-benzyl-I H-imidazole^-carboxamide (10.77 gram, 82 % yield). MH⁺ = 260. ¹H-NMR (400 MHz, CDCI₃): δ 2.34 (s, 3H), 3.47 (s, 3H), 3.77 (s, 3H), 5.09 (s, 2H), 7.05-7.10 (m, 2H), 7.18-7.28 (m, 3H), 7.48 (s, 1H). Part C: To a magnetically stirred solution of 1-naphtylmagnesium bromide (49 ml, 0.25 M in THF, 0.00123 mol) was added a solution of N-methoxy-N-methyl-5-methyl-1-benzyl-1 H- imidazole-4-carboxamide (2.69 gram, 0.0104 mol) in anhydrous THF (10 ml) and the resulting solution was stirred for 1 hour. The reaction mixture was quenched in 1N HCI (21 ml) and subsequently extracted with ethyl acetate (EtOAc). The EtOAc layer was twice washed with water, dried over MgSO₄, filtered and concentrated in vacuo. The resulting crude residue was purified by flash chromatography (ethyl acetate/petroleum ether = 1/1 (v/v)), followed by another flash chromatographic purification (dichloromethane/methanol = 99/1 (v/v)) to give pure compound 24 (1.35 gram, 66 % yield) as an oil. ¹H-NMR (400 MHz, CDCI₃): δ 2.58 (s, 3H), 5.12 (s, 2H), 7.08-7.13 (m, 2H), 7.31-7.40 (m, 3H), 7.44-7.56 (m, 4H), 7.78-7.82 (m, 1 H), 7.84-7.89 (m, 1H), 7.92-7.96 (m, 1 H), 8.16-8.22 (m, 1H).

Synthesis of compound 25

Analogously was prepared compound 25 (from N-methoxy-N-methyl-5-methyl-1-phenyl-1 H- imidazole-4-carboxamide and n-hexyllithium in anhydrous diethyl ether). Flash chromatographic purification (methyl-tert-butyl ether/petroleum ether = 1/3 (v/v)) of the initially isolated crude product gave compound 25 (24 % yield) as a pale yellow oil.

Compound 25. ¹H-NMR (400 MHz, CDCI₃): δ 0.86-0.94 (m, 3H), 1.25-1.47 (m, 6H), 1.70- 1.80 (m, 2H), 2.50 (s, 3H), 3.04-3.11 (m, 2H), 7.26-7.32 (m, 2H), 7.50-7.59 (m, 4H).

Analogously was prepared compound 26 ;

Compound 26

Compound 26; R_f (methanol/dichloromethane = 3/97 (v/v), silica gel) = 0.65.

Synthesis of compound 27

To a magnetically stirred solution of N-(adamant-1-yl)-1-phenyl-1 H-imidazole-4-carboxylate (1.61 gram, 0.005 mol) in dichloromethane (20 ml) was added a solution of Br₂ (0.52 ml, 0.010 mmol) in dichloromethane (5 ml). The resulting mixture was reacted at room temperature for 4 hours. Dichloromethane and 5 % aqueous NaHCO₃ solution was added to the reaction mixture. The separated organic layer was dried over MgSO₄, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (dichloromethane/acetone = 19/1 (v/v)). Subsequent recrystallisation from acetonitrile gave N-(adamant-1-yl)-5-bromo-1-phenyl-1 H-imidazole-4-carboxamide (0.51 gram, 26 % yield). Melting point: 229-232 ⁰C.

Compound 27

Analogously was prepared compound 28 in 17 % yield using N-chlorosuccinimide (NCS) as the chlorinating agent for 40 hours at room temperature. Flash chromatography (dichloromethane/acetone = 19/1 (v/v)). Melting point: 209-213 ⁰C.

Synthesis of compound 29

To a magnetically stirred solution of N-(adamant-1-yl)-5-bromo-1-phenyl-1 H-imidazole-4- carboxylate (0.60 gram) in dichloromethane (20 ml) was added a solution of Br₂ (0.30 ml) in dichloromethane (5 ml) and triethylamine (0.21 ml). The resulting mixture was reacted at room temperature for 50 hours. Dichloromethane and 5 % aqueous NaHCO₃ solution was added to the reaction mixture. The separated organic layer was dried over MgSO₄, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (dichloromethane). Subsequent stirring in diethyl ether followed by filtration gave N- (adamant-1-yl)-2,5-dibromo-1-phenyl-1 H-imidazole-4-carboxamide (0.29 gram). Melting point: 228-231 ⁰C.

Compound 29

Analogously was prepared compound 30 in 32 % yield from N-(adamant-1-yl)-5-chloro-1- phenyl-1 H-imidazole-4-carboxylate using N-chlorosuccinimide (NCS) as the chlorinating agent. Melting point: 193-195 ⁰C.

Compound 30

Synthesis of compound 31

To a magnetically stirred suspension of N-(adamant-1-yl)-2-methyl-1-phenyl-1 H-imidazole-4- carboxylate (2.01 gram, 0.006 mol) in anhydrous THF (20 ml) under N₂ at -70 ⁰C was slowly added a solution of lithium diisopropylamide (LDA) (9.0 ml of a 2 M solution in heptane/THF, 0.018 mol LDA) under N₂ at -70 ⁰C and the resulting solution was stirred for 1 hour. A solution of para-tolylsulfonyl cyanide (1.63 gram, 0.009 mol) in anhydrous THF (10 ml) was added and the resulting solution was stirred for 1 hour at -70 ⁰C. The solution was allowed to attain room temperature and stirred for another 12 hours and subsequently quenched with water. The mixture was extracted with diethyl ether. The organic layer is dried over MgSO₄, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (dichloromethane/acetone = 19/1 (v/v)) and subsequently recrystallized from acetonitrile to give compound 31 (0.23 gram, 11 % yield). Melting point compound 30: 246-248 ⁰C.

Compound 31

Analogously was prepared compound 32 in 31 % yield from N-(adamant-1-yl)-2-methyl-1- phenyl-1 H-imidazole-4-carboxylate using dimethyldisulfide (CH₃SSCH₃). Melting point: 172- 173 ⁰C.

Compound 32

Analogously was prepared compound 33 in 28 % yield from N-(adamant-1-yl)-2-methyl-1- phenyl-1 H-imidazole-4-carboxylate using para-tolylsulfonyl chloride. Melting point: 216-218 ⁰C.

Analogously was prepared compound 33A from N-(adamant-1-yl)-2-methyl-1-phenyl-1 H- imidazole-4-carboxylate using para-tolylsulfonyl bromide. Melting point: 242-244 ⁰C.

Compound 33A

Analogously was prepared compound 34 in 7 % yield from N-(adamant-1-yl)-1-phenyl-1 H- imidazole-4-carboxylate using para-tolylsulfonyl cyanide. Melting point: 237-239 ⁰C.

Compound 34

Analogously was prepared compound 35 in 12 % yield from N-(adamant-1-yl)-1-phenyl-1 H- imidazole-4-carboxylate using dimethyldisulfide (CH₃SSCH₃). Melting point: 166-168 ⁰C.

General: Compounds 36 - 114 were all prepared according to the general method outlined in Scheme 3 hereinabove. The obtained compounds of general formula (IV) were converted (see Scheme 1 hereinabove) via the corresponding carboxylic acids of general structure (V) to the compounds of general formula (I) wherein X represents subgroup (ii) Synthesis of compound 36

Part A: NaNO₂ (13.8 gram) was dissolved in water (48 ml) at 4 ⁰C. The resulting solution was slowly added to a magnetically stirred solution of 3-oxo-butyric acid methyl ester (17.4 gram, 0.15 mol) while keeping the temperature < 5 ⁰C. After stirring the mixture for two hours water (120 ml) was added and the resulting mixture was extracted twice with diethyl ether. The combined organic layers were successively washed with water and a 5 % aqueous NaHCO₃ solution. The organic layer was dried over MgSO₄, filtered and thoroughly concentrated to give crude 2-hydroxyimino-3-oxo-butyric acid methyl ester (24 gram) as a colorless oil which was not further purified. ¹H-NMR (400 MHz, CDCI₃): δ 2.42 (s, 3H), 3.91 (s, 3H), 9.90 (br s, 1H). Part B: Crude 2-hydroxyimino-3-oxo-butyric acid methyl ester (24 gram, - 0.15 mol) dissolved in a magnetically stirred mixture of acetic acid (293 ml), acetic acid anhydride (110 ml) and Pd/C (4 gram) was hydrogenated for 20 hours at room temperature at 1 atmosphere H₂ pressure. After filtration over hyflo, the acetic acid and acetic acid anhydride were removed by concentration in vacuo. The resulting crude mixture was purified by flash chromatography (dichloromethane/methanol = 95/5 (v/v)) to give 2-acetylamino-3-oxo- butyric acid methyl ester (16.7 gram, 60 % yield) as a white solid. R_f (dichloromethane/methanol = 95/5 (v/v)) = 0.4. ¹H-NMR (400 MHz, CDCI₃): δ 2.08 (s, 3H), 2.40 (s, 3H), 3.83 (s, 3H), 5.29 (d, J ~ 7, 1 H), 6.71 (br s, 1H). Part C: To a magnetically stirred solution of 2-acetylamino-3-oxo-butyric acid methyl ester (5 gram, 28.9 mmol) in butyronitrile was added aniline (3.42 ml) and trifluoroacetic acid (2.89 ml) and the resulting mixture was heated at reflux for 45 minutes. The butyronitrile was removed in vacuo at room temperature and the resulting residues was taken up dichloromethane and washed twice with an aqueous potassium carbonate solution. The organic layer was dried over MgSO₄, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (diethyl ether/acetone = 4/1 (v/v)) to give methyl 2,5-dimethyl-1-phenyl-1 H-imidazole-4-carboxylate (3.0 gram, 46 % yield). ¹H-NMR (400 MHz, CDCI₃): δ 2.22 (s, 3H), 2.33 (s, 3H), 3.91 (s, 3H), 7.18-7.22 (m, 2H), 7.51-7.59 (m, 3H). Part D: To a magnetically stirred solution of methyl 2,5-dimethyl-1-phenyl-1 H-imidazole-4- carboxylate (8.0 gram, 0.035 mol) in THF (100 ml) was added a solution of LiOH (1.68 gram) in water (100 ml). The resulting mixture was heated at 70 ⁰C for 16 hours, allowed to attain room temperature and acidified with 2 molar equivalents of a 1 N HCI solution. The formed precipitate was collected to give crude 2,5-dimethyl-1-phenyl-1 H-imidazole-4-carboxylic acid (7.0 gram, 93 % yield). ¹H-NMR (400 MHz, DMSO-d₆): δ 2.31 (s, 3H), 2.43 (s, 3H), 7.56-7.61 (m, 2H), 7.66-7.71 (m, 3H).

Part D: To a magnetically stirred solution of 2,5-dimethyl-1-phenyl-1 H-imidazole-4-carboxylic acid (0.6 gram, 0.0028 mol) in acetonitrile (35 ml) was successively added diisopropylethylamine (DIPEΞA, Hϋnig's base) (1.27 gram), O-benzotriazol-1-yl-N, N, N', N'- tetramethyluronium hexafluorophosphate (HBTU) (1.27 gram) and (-)-cis-myrtanylamine (1.05 ml, 0.0028 mol). The resulting mixture was reacted at 20 ⁰C for 16 hours and subsequently concentrated in vacuo. The resulting residue was taken up in dichloromethane and washed with 5 % aqueous NaHCO₃ solution. The organic layer was dried over MgSO₄, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (dichoromethane/methanol = 95/5 (v/v)) to give N-[(1R,2S,5R)-rel-6,6- dimethylbicyclop.i .iJheptan^-methylJ^.S-dimethyl-i-phenyl-I H-imidazole^-carboxamide (compound 36) (0.70 gram, 72 % yield). R_f (silica gel/ dichoromethane/methanol = 95/5 (v/v)) - 0.6.

Analogously were prepared compounds 37 -47:

Compound 37: ¹H-NMR (400 MHz, CDCI₃): δ 1.26 (t, J = 7, 3H), 2.41 (s, 3H), 2.56 (q, J = 7, 2H), 7.23-7.28 (m, 2H), 7.49-7.60 (m, 6H), 7.66 (d, J = 8, 1 H), 7.88 (d, J = 8, 1 H), 8.11 (d, J = 8, 1 H), 8.28 (d, J = 8, 1 H), 9.85 (s, 1 H).

Compound 38: Melting point: 177-179 ⁰C.

Compound 39: from endo-(1S)-1 ,3,3-trimethylbicyclo[2.2.1]heptan-2-amine. Melting point: 130-132 ⁰C (DSC).

Compound 40: from endo-(1S)-1 ,3,3-trimethylbicyclo[2.2.1]heptan-2-amine. ¹H-NMR (300 MHz, CDCI₃): δ 0.89 (s, 3H), 0.96 (t, J = 7, 3H), 1.12 (s, 3H), 1.17-1.27 (m, 5H), 1.40-1.60 (m, 2H), 1.67-1.81 (m, 3H), 2.15 (s, 3H), 2.70-2.95 (m, 2H), 3.78 (dd, J -10 and 2, 1 H), 7.18-7.23 (m, 2H), 7.34 (br d, J ~ 10, 1 H), 7.48-7.57 (m, 3H).

Compound 41 : Melting point: 117.5-120 ⁰C (DSC).

Compound 42: Melting point: 193-196 ⁰C (DSC).

Compound 43: Melting point: 157-159 ⁰C (DSC).

Compound 44: Melting point: 76-79 ⁰C (DSC).

Compound 45: From R-(+)-phenethylamine. ¹H-NMR (300 MHz, CDCI₃): δ 1.58-1.61 (m, 3H), 2.17 (s, 3H), 2.33 (s, 3H), 5.25-5.35 (m, 1 H), 7.15-7.54 (m, 11 H).

Compound 46

Compound 46: Melting point: 139-141 ⁰C (DSC).

Compound 47: ¹H-NMR (400 MHz, CDCI₃): δ 1.10 (s, 9H), 1.69 (s, 3H), 2.24 (s, 3H), 7.00- 7.06 (m, 2H), 7.46-7.55 (m, 3H), the NH peak is invisible and probably merged with the H₂O peak at δ 1.60.

Synthesis of compound 48

To a magnetically stirred solution of 2,5-dimethyl-1-phenyl-1 H-imidazole-4-carboxylic acid (0.66 gram, 0.00306 mol) in dichloromethane (35 ml) was successively added diisopropylethylamine (DIPEA) (3.1 ml), CIP (2-chloro-1 ,3-dimethylimidazolinium hexafluorophosphate) (2.55 gram) and 3-hydroxyadamantane amine (0.612 gram, 0.00366 mol). The resulting mixture was reacted at 20 ⁰C for 16 hours and subsequently concentrated in vacuo. The resulting residue was taken up in dichloromethane and washed with 5 % aqueous NaHCO₃ solution. The organic layer was dried over MgSO₄, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (dichoromethane/methanol = 98/2 (v/v)) to give N-(3-hydroxyadamant-1-yl)-2,5-dimethyl-1- phenyl-1 H-imidazole-4-carboxamide (0.75 gram, 67 % yield). R_f (silica gel/ dichoromethane/methanol = 98/2 (v/v)) ~ 0.6. Melting point: 215-220 ⁰C.

Analogously were prepared compounds 49-85:

Compound 49: Melting point: 245-247 ⁰C.

Compound 50: Melting point: 251-253 ⁰C.

Compound 51

Compound 51 : (from racemic endo-2-amino-bicyclo[2.2.1]heptane: ¹H-NMR (400 MHz, DMSO-d₆): δ 0.85-1.64 (m, 8H), 2.13 (s, 3H), 2.21 (br s, 1 H), 2.24 (s, 3H), 2.40 (br s, 1 H), 4.07-4.16 (m, 1H), 7.34 (br d, J ~ 8, 2H), 7.40 (br d, J ~ 7, 1H), 7.52-7.61 (m, 3H).

Compound 52: (from noradamantylamine): Melting point: 147-150 ⁰C.

Compound 53: Melting point: 111-113 ⁰C.

Compound 54

Compound 54: Melting point: 204-207 ⁰C.

Compound 55 Compound 55: Melting point: 115-117 ⁰C.

Compound 56: Melting point: 208-210 ⁰C.

Compound 57: Melting point: 243-245 ⁰C.

N H V^

Ji

N

F Compound 58

Compound 58: Melting point: 178-181 ⁰C.

Compound 59: ¹H-NMR (300 MHz, CDCI₃): .5 2.28 (s, 3H), 2.43 (s, 3H), 7.23-7.27 (m, 2H), 7.55-7.60 (m, 3H), 7.79 (dd, J = 9 and 2 Hz, 1 H), 8.22 (d, J = 9 Hz, 1H), 8.42 (s, 1 H), 8.62 (d, J ~ 5 Hz, 1 H), 8.94 (d, J = 5 Hz, 1H), 10.25 (br s, 1 H). Melting point: 198.5 ⁰C (DSC).

Compound 60: ¹H-NMR (300 MHz, CDCI₃): .5 2.29 (s, 3H), 2.43 (s, 3H), 7.23-7.27 (m, 2H), 7.54-7.60 (m, 3H), 7.70-7.76 (m, 2H), 7.95 (d, J = 8 Hz, 1H), 8.17-8.21 (m, 1H), 8.27-8.29 (m, 1H), 8.63 (d, J = 8 Hz, 1 H), 10.20 (br s, 1H). Melting point: 241.5 ⁰C (DSC).

Compound 61 : Melting point: 171-172 ⁰C.

Compound 62: Melting point: -113 ⁰C. R_f (diethyl ether/petroleum ether = 1/1 (v/v) ~ 0.15. ¹H-NMR (400 MHz, CDCI₃): .5 1.66-1.78 (m, 6H), 2.08-2.18 (m, 9H), 2.19 (s, 3H), 3.22 (s, 3H), 4.59 (s, 3H), 7.06 (br s, 1 H), 7.25-7.30 (m, 2H), 7.47-7.55 (m, 3H).

Compound 63: Melting point: 221-223 ⁰C.

Compound 64

Compound 64: Melting point: 170-172 ⁰C.

Compound 65

Compound 65: Melting point: 168-170 ⁰C.

Compound 66: (from endo-(1S)-1 ,3,3-trimethylbicyclo[2.2.1]heptan-2-amine). Melting point: 102-107 ⁰C.

^ N ^

.HCI Compound 67 Compound 67: Melting point: 166-168 ⁰C.

Compound 68: Melting point: 208-210 ⁰C.

Compound 69

Compound 69: Melting point: 154-156 ⁰C.

Compound 70 Compound 70: (from racemic endo-2-amino-bicyclo[2.2.1]heptane. Melting point: 165-167 ⁰C.

Compound 71 : Melting point: 69-72 ⁰C.

Compound 72: ¹H-NMR (400 MHz, CDCI₃): δ 1.66-1.78 (m, 6H), 2.08-2.17 (m, 9H), 2.32 (s, 3H), 2.51 (s, 3H), 6.95 (br s, 1 H), 7.51 (d, J = 4, 1H), 7.83 (d, J = 4, 1 H). Melting point: 130- 133 ⁰C.

Compound 73: (from endo-(1S)-1 ,3,3-trimethylbicyclo[2.2.1]heptan-2-amine). Melting point: 146-148 ⁰C.

74

Compound 74: ¹H-NMR (400 MHz, CDCI₃): δ 1.65-1.78 (m, 6H), 2.08-2.19 (m, 12H), 2.27 (s, 3H), 3.78 (s, 3H), 6.97 (br s, 1 H), 7.03-7.12 (m, 3H), 7.43-7.49 (m, 1H).

75

Compound 75: ¹H-NMR (400 MHz, CDCI₃): δ 2.21 (s, 3H), 2.37 (s, 3H), 3.82 (s, 3H), 7.07- 7.13 (m, 2H), 7.16-7.21 (m, 1H), 7.46-7.59 (m, 4H), 7.66 (d, J = 8, 1H), 7.87 (d, J = 8, 1H), 8.13 (d, J = 8, 1 H), 8.28 (d, J = 8, 1 H), 9.70 (br s, 1 H).

Compound 76: Melting point: 217-219 ⁰C.

Compound 77: Melting point: 217-218 ⁰C. In the synthesis of this particular compound 2- Chloro-1,3-dimethylimidazolinium chloride was used in the last reaction step as the coupling reagent instead of CIP.

Compound 78: Melting point: 186-187 ⁰C. In the synthesis of this particular compound 2- Chloro-1,3-dimethylimidazolinium chloride was used in the last reaction step as the coupling reagent instead of CIP.

Compound 79: Melting point: 123-125 ⁰C.

Compound 80

Compound 80: Melting point: 214-217 ⁰C.

Compound 81 : Melting point: 149-150 ⁰C.

Compound 82: ¹H-NMR (400 MHz, CDCI₃): δ 0.75-0.80 (m, 2H), 0.97-1.03 (m, 2H), 1.45- 1.52 (m, 1 H), 1.65-1.78 (m, 6H), 2.08-2.18 (m, 9H), 2.34 (s, 3H), 6.98 (br s, 1H), 7.23-7.28 (m, 2H), 7.45-7.56 (m, 3H). In the synthesis of this particular compound 2-chloro-1,3- dimethylimidazolinium chloride was used in the last reaction step as the coupling reagent instead of CIP.

Compound 83

Compound 83: ¹H-NMR (400 MHz, CDCI₃): δ 0.75-0.80 (m, 2H), 0.97-1.02 (m, 2H), 1.45- 1.52 (m, 1H), 2.38 (s, 3H), 4.80 (br d, J = 7, 2H), 7.25-7.30 (m, 2H), 7.35 (br t, J = 7, 1H), 7.47-7.68 (m, 7H).

Compound 84: Melting point: 136-137 ⁰C.

85

Compound 85: R_f (di<

Compound 86

Compound 86: Melting point: 242-244 ⁰C. MH⁺ (free base) = 368. Compound 86 was derived from racemic exo-2-aminobicyclo[2.2.1]heptane and 2-acetylamino-3-oxo-butyric acid methyl ester analogously to the synthesis as described herein above for compound 36 , part C.

Compound 87: Melting point: 181-183 ⁰C. MH⁺ = 410. Compound 87 was derived from (-)- cis-myrtanylamine (CAS 38235-68-6) and 2-acetylamino-3-oxo-butyric acid methyl ester analogously to the synthesis as described herein above for compound 36, part C.

Compound 88: R_f (dichloromethane / methanol = 97/3 (v/v)) = 0.2. In the synthesis of this particular compound 2-chloro-1,3-dimethylimidazolinium chloride was used in the last reaction step as the coupling reagent instead of CIP. Synthesis of compound 89

Part A: To a magnetically stirred suspension of 2,5-dimethyl-1-phenyl-1 H-imidazole-4- carboxylic acid (0.4 gram, 1.85 mmol) in CHCI₃ (4 ml) was added oxalyl chloride (0.34 gram, 2.685 mmol) and the resulting mixture was reacted at 58 ⁰C for 2 hours and subsequently concentrated in vacuo. The resulting residue was taken up in dichloromethane and diisopropylethylamine (0.28 gram, 2.148 mmol) was subsequently added. A solution of 2,3- dichloroaniline (0.35 gram, 2.146 mmol) in dichloromethane (5 ml) was slowly added to the resulting mixture and the resulting mixture was reacted for 2 hours at room temperature and subsequently concentrated in vacuo. The resulting residue was purified by flash chromatography (dichloromethane) to give N-(2,3-dichlorophenyl)-2,5-dimethyl-1-phenyl-1 H- imidazole-4-carboxamide (compound 89) (0.24 gram, 36 % yield). Melting point: 127-129 ⁰C.

Analogously were prepared compounds 90-114:

Compound 90: ¹H-NMR (400 MHz, CDCI₃): δ 1.50-1.78 (m, 12H), 1.88-1.98 (m, 2H), 2.18 (s, 3H), 2.34 (s, 3H), 4.12-4.23 (m, 1 H), 7.10-7.20 (m, 3H), 7.48-7.57 (m, 3H). LC/MS: retention time: 2.88 minutes; MH⁺ = 326.

Compound 91 : ¹H-NMR (400 MHz, CDCI₃): δ 1.65-2.07 (m, 9H), 2.17 (s, 3H), 2.32 (s, 3H), 3.73 (S, 2H), 7.16-7.20 (m, 2H), 7.41 (br s, 1H), 7.49-7.57 (m, 3H). LC/MS: retention time: 2.22 minutes; MH⁺ = 314.

Compound 92: ¹H-NMR (400 MHz, CDCI₃): δ 1.56-1.66 (m, 4H), 1.73-1.87 (m, 4H), 2.18 (br s, 6H), 3.65 (t, J = 7, 2H), 3.91 (t, J = 7, 2H), 7.19-7.23 (m, 2H), 7.47-7.56 (m, 3H). LC/MS: retention time: 2.12 minutes; MH⁺ = 297.

Compound 93

Compound 93: R_f (dichloromethane/methanol = 95/5 (v/v)) = 0.65.

Compound 94: LC/MS: retention time: 1.88 minutes; MH = 307

Compound 95: Melting point: 134-135 ⁰C.

Compound 96

Compound 96: Melting point: 119-121 ⁰C.

Compound 97 Compound 97: R_f (dichloromethane/methanol = 97/3 (v/v)) = 0.6.

98

Compound 98: Melting point: 125-127 ⁰C.

Compound 99: ¹H-NMR (400 MHz, CDCI₃): δ 1.60 (d, J = 7, 3H), 2.17 (s, 3H), 2.33 (s, 3H), 5.30 (quintet, J = 7, 1 H), 7.15-7.54 (m, 11 H). LC/MS: retention time: 2.60 minutes; MH⁺ = 320.

Compound 100: ¹H-NMR (400 MHz, CDCI₃): .5 2.15 (s, 3H), 2.36 (s, 3H), 2.97 (dd, J ~ 15 and 6, 2H), 3.40 (dd, J ~ 15 and 8, 2H), 4.88-4.98 (m, 1 H), 7.16-7.27 (m, 6H), 7.37 (br d, J ~ 8, 1 H), 7.48-7.57 (m, 3H). LC/MS: retention time: 2.63 minutes; MH⁺ = 332.

Compound 101 : ¹H-NMR (400 MHz, CDCI₃): δ 2.18 (s, 3H), 2.34 (s, 3H), 6.44 (d, J = 8, 1 H), 7.15-7.38 (m, 12H), 7.48-7.57 (m, 3H), 7.92 (br d, J ~ 8, 1 H). LC/MS: retention time: 3.59 minutes; MH⁺ = 382.

Compound 102: LC/MS: retention time: 1.30 minutes; MH⁺ = 338.

Compound 103: LC/MS: retention time: 2.81 minutes; MH⁺ = 356.

104

Compound 104: LC/MS: retention time: 2.98 minutes; MH⁺ = 396.

Compound 105: LC/MS: retention time: 2.17 minutes; MH = 300

106 Compound 106: LC/MS: retention time: 2.08 minutes; MH⁺ = 346

Compound 107

Compound 107: Melting point: 117-118 ⁰C.

Compound 108

Compound 108: Melting point: 123-125 ⁰C.

Compound 109: Melting point: 130-132 ⁰C. Compound 110

Compound 110: ¹H-NMR (400 MHz, CDCI₃): δ 2.17 (s, 3H), 2.37 (s, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 4.55 (d, J ~ 6, 2H), 6.82 (d, J = 8, 1 H), 6.90-6.95 (m, 2H), 7.17-7.21 (m, 2H), 7.45 (br s, 1H), 7.50-7.57 (m, 3H).

Compound 111 : R_f (dichloromethane / methanol = 95/5 (v/v)) = 0.65.

Compound 112: ¹H-NMR (400 MHz, CDCI₃): δ 2.16 (s, 3H), 2.35 (s, 3H), 2.93 (t, J = 7, 2H), 3.66 (q, J ~ 7, 2H), 7.16-7.34 (m, 8H), 7.48-7.56 (m, 3H). LC/MS: retention time: 3.13 minutes; MH⁺ = 320.

Compound 113: LC/MS: retention time: 2.67 minutes; MH⁺ = 352.

Compound 114: ¹H-NMR (400 MHz, CDCI₃): δ 0.94-1.05 (m, 2H), 1.11-1.31 (m, 3H), 1.52- 1.87 (m, 6H), 2.18 (s, 3H), 2.35 (s, 3H), 3.25 (t, J = 7, 2H), 7.16-7.21 (m, 2H), 7.22-7.29 (m, 1H), 7.48-7.57 (m, 3H). LC/MS: retention time: 2.76 minutes; MH⁺ = 312.

EXAMPLE 3: FORMULATION OF COMPOUND 1

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

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

EXAMPLE 4: PHARMACOLOGICAL TEST RESULTS

Cannabinoid receptor affinity data obtained according to the protocols given above are shown in the table below. BMS-1, BMS-II and BMS-III are the three exemplified imidazoles in WO 01/58869 (examples 64, 65 and 66 therein, respectively). These three specific imidazole derivatives all contain a L-phenylalanine derived carboxamide moiety at the 4- position of their (I H)-imidazole moiety as shown below. Our invention includes novel 1H- imidazole derivatives which lack such a L-phenylalanine derived carboxamide moiety but have approximately hundred-fold higher CB₂ receptor affinities as compared to the prior art compounds exemplified in WO 01/58869 as becomes clear from the data depicted in Table 1.

BMS-I BMS-II BMS-III

Table 1

- = not determined

Claims

1. Compounds of the general formula (I)

R₂

wherein:

- Ri represents a hydrogen or halogen atom or a d_-3-alkyl group, which Ci_-3-alkyl group may contain 1-3 fluoro atoms or a hydroxy or amino group, or R₁ represents a C_2-3- alkynyl group, a C_2-3-alkenyl group, which C_2-3-alkynyl group or C_2-3-alkenyl group may contain 1-3 fluoro atoms, or R₁ represents an acetyl, cyclopropyl, cyano, methylsulfonyl, ethylsulfonyl, methylsulfinyl, ethylsulfinyl trifluoromethylsulfanyl, methylsulfanyl, ethylsulfanyl group, formyl group or a C_2-4-heteroalkyl group,

- R₂ represents a phenyl group which may be substituted with 1 , 2, 3, 4 or 5 substituents Y, which can be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chloro, iodo, bromo, fluoro, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano, or R₂ represents a heteroaryl group which heteroaryl group may be substituted with 1 , 2 or 3 substituents Y, wherein Y has the meaning as defined above, with the proviso that R₂ is not a 6-methyl- 2-pyridyl group, or R₂ represents a mono-unsaturated or fully saturated 4-10 membered monocyclic, fused bicyclic or fused tricyclic carbocyclic ring system, or

R₅ represents a mono-unsaturated or fully saturated 4-10 membered monocyclic, fused bicyclic or fused tricyclic heterocyclic ring system, which carbocyclic or heterocyclic ring systems are optionally substituted with 1-5 substituents selected from the group consisting of methyl, ethyl, amino, hydroxy or fluoro, or

R₂ represents a methylsulfonylaminoalkyl group, methylsulfonylalkyl or a acetamidoalkyl group,

- R₃ represents a hydrogen or halogen atom or a formyl, Ci_-6-alkylsulfonyl, Ci_-6- alkylsulfinyl, d_-6-alkylsulfanyl, trifluoromethylsulfanyl, benzylsulfanyl or cyano group, or R₃ represents Ci_-8-alkyl group, which Ci_-8-alkyl group may be substituted with 1-5 substituents selected from the group consisting of fluoro, hydroxy or amino, or R₃ represents a C_2-6-alkynyl, C_2-6-alkenyl, Ci_-6-alkanoyl, C_3-8-cycloalkyl, Cs-β-heterocycloalkyl or a C_2-6-heteroalkyl group, which groups are optionally substituted with 1-3 methyl groups, an ethyl, amino or hydroxy group or with 1-3 fluoro atoms, or R₃ represents a phenyl group which is substituted with 1-5 substituents Y, wherein Y has the meaning as defined above, or R₃ represents a heteroaryl group which heteroaryl group may be substituted with 1 , 2 or 3 substituents Y, wherein Y has the meaning as defined above or

R₃ represents a benzyl or heteroaryl methyl group which benzyl or heteroaryl methyl group may be substituted with 1, 2 or 3 substituents Y

- R₄ represents one of the subgroups (i) or (ii)

O) 00

wherein R₆ represents a C_4-8 branched or linear alkyl group, C_3-8 cycloalkyl group, C_3-8- cycloalkyl-Ci_-2-alkyl group, C_5-7-heterocycloalkyl-Ci_-2-alkyl group, C_5-I0 bicycloalkyl group, C_5-i₀-bicycloalkyl-Ci_-2-alkyl group, C_5-i₀-heterobicycloalkyl-Ci_-2-alkyl group, C_6-I0 tricycloalkyl group, C_6-i₀-tricycloalkyl-Ci_-2-alkyl group, C_6-i₀-heterotricycloalkyl-Ci_-2-alkyl group which groups may be substituted with 1-5 substituents selected from methyl, hydroxy, ethyl, trifluoromethyl or fluoro, or R₆ represents a phenyl, benzyl, napthyl or phenethyl group which groups may be substituted on their aromatic ringsystem with 1-3 substituents Y as defined above, with the proviso that R₆ is not a 2-methylphenyl group, or R₆ represents a pyridyl or thienyl group, - R₇ represents a hydrogen atom or a Ci_-6 linear alkyl group which Ci_-6 linear alkyl group may be substituted with 1 -3 fluoro atoms or R₇ represents an isopropyl group,

- R₈ represents a C_2-6 alkyl group which group is substituted with a hydroxy or amino group or with 1-3 fluoro atoms, or R₈ represents a C_7-I0 branched alkyl group, C_3-8 cycloalkyl group, C_5-8 heterocycloalkyl group, C_3-8-cycloalkyl-Ci_-2-alkyl group, C_5-7- heterocycloalkyl-d-₂-alkyl group, C_5-I0 bicycloalkyl group,

group, C_δ-io-heterobicycloalkyl-Ci^-alkyl group, C_6-Io tricycloalkyl group, C_6-I0- tricycloalkyl-Ci-₂-alkyl group, Ce-io-heterotricycloalkyl-d^-alkyl group which groups may be substituted with 1-5 substituents selected from methyl, hydroxy, ethyl, amino, hydroxymethyl, trifluoromethyl or fluoro, or R₈ represents a phenyl group which group is substituted with 1-5 substituents Y as defined above, or R₈ represents a naphtyl, 1,2,3,4- tetrahydronaphtyl or indanyl group which naphtyl, 1 ,2,3,4-tetrahydronaphtyl or indanyl groups may be substituted with 1-3 substituents Y, or R₈ represents a phenyl-Ci_-3-alkyl group, a diphenyl-Ci_-3-alkyl group, which groups may be substituted on their phenyl ring with 1-5 substituents Y, wherein Y has the abovementioned meaning, or R₈ represents a benzyl group, which benzyl group is substituted with 1-5 substituents Y, or R₈ represents a heteroaryl, heteroaryl methyl, napthylmethyl or heteroarylethyl group, which heteroaryl, heteroaryl methyl, naphtylmethyl or heteroarylethyl group may be substituted with 1 -3 substituents Y, wherein Y has the abovementioned meaning, or R₈ represents a piperidinyl, azepanyl, morpholinyl, azabicyclo[3.3.0]octanyl, 4-hydroxypiperidinyl or pyrrolidinyl group, with the proviso that R₈ is neither a 6-methoxy-benzothiazol-2-yl group nor a [3-chloro-5-(trifluoromethyl)pyrid-2-yl]methyl group, or R₇ and R₈ - together with the nitrogen atom to which they are bonded - form a saturated or unsaturated, non-aromatic or partly aromatic, monocyclic, bicyclic or tricyclic heterocyclic group having 7 to 10 ring atoms, which saturated or unsaturated, non- aromatic or partly aromatic, monocyclic, bicyclic or tricyclic heterocyclic group may be substituted with 1-5 substituents selected from the group consisting of Ci_-3 alkyl, hydroxy, methoxy, cyano, phenyl, trifluoromethyl or halogen, or R₇ and R₈ - together with the nitrogen atom to which they are bonded - form a saturated monocyclic heterocyclic group, optionally containing another heteroatom

(selected from N, O, S), having 5 to 6 ring atoms, which heterocyclic group is substituted with 1-5 substituents selected from the group consisting of C i_-3 alkyl, hydroxy, amino, phenyl, benzyl, or fluoro, with the proviso that R₇ and R₈ - together with the nitrogen atom to which they are bonded - do not form a trimethyl-substituted aza-bicyclo[3.2.1]octanylgroup, and tautomers, stereoisomers and N-oxides thereof, as well as pharmaco-logically acceptable salts, hydrates and solvates of said compounds of formula (1) and its tautomers, stereoisomers and N-oxides.

2. Compounds as claimed in claim 1 of the general formula (I):

R₂

wherein: - Ri represents a halogen atom or a Ci_-3-alkyl group, which d_-3-alkyl group may contain 1-3 fluoro atoms or a hydroxy or amino group, or R₁ represents a C_2-3-alkynyl group, a C_2-3-alkenyl group, which C_2-3-alkynyl group or C_2-3-alkenyl group may contain 1-3 fluoro atoms, or R₁ represents an acetyl, cyclopropyl, cyano, methylsulfonyl, ethylsulfonyl, methylsulfinyl, ethylsulfinyl trifluoromethylsulfanyl, methylsulfanyl, ethylsulfanyl group, formyl group or a C_2-4-heteroalkyl group, and R₂, R₃ and R₄ have the meanings as given in claim 1

3. Compounds as claimed in claim 2 of the general formula (I):

R₂

wherein:

- R₃ represents a hydrogen or halogen atom or a formyl, methylsulfonyl, ethylsulfonyl, methylsulfinyl, ethylsulfinyl, trifluoromethylsulfanyl, methylsulfanyl, ethylsulfanyl or cyano group, or R₃ represents C_1-6-alkyl group, which C_1-6-alkyl group may contain 1 -3 fluoro atoms or a hydroxy or amino group, or R₃ represents a C_2-6-alkynyl, C_2-6-alkenyl, C_1-6- alkanoyl, C_3-8-cycloalkyl, C_5-8-heterocycloalkyl or a C_2-6-heteroalkyl group, which groups are optionally substituted with 1-3 methyl groups, an ethyl, amino or hydroxy group or with 1-3 fluoro atoms, or R₃ represents a phenyl group which is substituted with 1-5 substituents Y, wherein Y has the meaning as defined above, or R₃ represents a heteroaryl group which heteroaryl group may be substituted with 1 , 2 or 3 substituents Y, wherein Y has the meaning as defined above or R₃ represents a benzyl or heteroaryl methyl group which benzyl or heteroaryl methyl group may be substituted with 1 , 2 or 3 substituents Y

- R₄ represents subgroup (ii)

(ϋ) wherein R₇ represents a hydrogen atom or a Ci_-6 linear alkyl group or an isopropyl group,

- R₈ represents a C_2-6 alkyl group which group is substituted with a hydroxy or amino group or with 1-3 fluoro atoms, or R₈ represents a C_7-I0 branched alkyl group, C_3-8 cycloalkyl group, C_5-8 heterocycloalkyl group, C_3-8-cycloalkyl-Ci_-2-alkyl group, C_5-7- heterocycloalkyl-Ci-₂-alkyl group, C_5-I0 bicycloalkyl group, C_5-i₀-bicycloalkyl-Ci_-2-alkyl group, Cs-io-heterobicycloalkyl-d^-alkyl group, C_6-Io tricycloalkyl group, C_6-I0- tricycloalkyl-Ci-₂-alkyl group, C_6-i₀-heterotricycloalkyl-Ci_-2-alkyl group which groups may be substituted with 1-5 substituents selected from methyl, hydroxy , ethyl, amino, hydroxy methyl, trifluoromethyl, or fluoro, or R₈ represents a phenyl group which group is substituted with 1-5 substituents Y as defined above, or R₈ represents a naphtyl or a 1 ,2,3,4-tetrahydronaphtyl or indanyl group which groups may be substituted with 1-3 substituents Y, or R₈ represents a phenyl-Ci_-3-alkyl group, a diphenyl-Ci_-3-alkyl group, which groups may be substituted on their phenyl ring with 1-5 substituents Y, wherein Y has the abovementioned meaning, or R₈ represents a benzyl group, which benzyl group is substituted with 1-5 substituents Y, or R₈ represents a heteroaryl, heteroaryl methyl or heteroarylethyl group, which heteroaryl, heteroaryl methyl or heteroarylethyl group may be substituted with 1-3 substituents Y, as defined above, or R₈ represents a piperidinyl, azepanyl, morpholinyl, azabicyclo[3.3.0]octanyl, 4-hydroxypiperidinyl or pyrrolidinyl group, with the proviso that R₈ is neither a 6-methoxy-benzothiazol-2-yl group nor a [3- chloro-5-(trifluoromethyl)pyrid-2-yl]methyl group, or R₇ and R₈ - together with the nitrogen atom to which they are bonded - form a saturated or unsaturated, non-aromatic or partly aromatic, monocyclic, bicyclic or tricyclic heterocyclic group having 7 to 10 ring atoms, which heterocyclic group may be substituted with one or two Ci_-3 alkyl groups, a hydroxy group, a phenyl group, a trimethylfluoromethyl group, a benzyl group, a diphenylmethyl group or a halogen atom, or R₇ and R₈ - together with the nitrogen atom to which they are bonded - form a saturated monocyclic heterocyclic group, optionally containing another heteroatom (selected from N, O, S), having 5 to 6 ring atoms, which heterocyclic group is substituted with 1-3 Ci_-3 alkyl groups, a hydroxy group or 1-2 fluoro atoms, with the proviso that R₇ and R₈ - together with the nitrogen atom to which they are bonded - do not form a trimethyl-substituted aza-bicyclo[3.2.1]octanylgroup, and Ri and R₂ have the meanings as given in claim 2

4. Compounds as claimed in claim 3 of the general formula (I)

wherein:

- R₂ represents a phenyl group which may be substituted with 1 , 2, 3, 4 or 5 substituents Y, which can be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chloro, iodo, bromo, fluoro, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano, or R₂ represents a monocyclic heteroaryl group which heteroaryl group may be substituted with 1 , 2 or 3 substituents Y, wherein Y has the meaning as defined above, with the proviso that R₂ is not a 6-methyl-2-pyridyl group, or R₂ represents a mono-unsaturated or fully saturated 4-10 membered monocyclic, fused bicyclic or fused tricyclic carbocyclic ring system, or

R₂ represents a mono-unsaturated or fully saturated 4-10 membered monocyclic, fused bicyclic or fused tricyclic heterocyclic ring system which carbocyclic or heterocyclic ring system may be substituted with 1-5 substituents selected from methyl, ethyl, amino, hydroxy or fluoro, or R₂ represents a group of general formula CH₂-R₅ wherein R₅ represents a phenyl group which is substituted with 1 , 2, 3, 4 or 5 substituents Y as defined above, or R₅ represents a heteroaryl group or a 1 ,2,3,4-tetrahydronaphtyl or indanyl group, which heteroaryl group or 1 ,2,3,4-tetrahydronaphtyl or indanyl group may be substituted with 1 , 2 or 3 substituents Y as defined above or R₅ represents a mono-unsaturated or fully saturated monocyclic, fused bicyclic or fused tricyclic 4-10 membered carbocyclic ring system, or R₅ represents a mono-unsaturated or fully saturated 4-10 membered monocyclic, fused bicyclic or fused tricyclic heterocyclic ring system, which carbocyclic or heterocyclic rings systems are optionally substituted with 1-3 methyl groups, an ethyl, amino or hydroxy group or with a fluoro atom,

- R₃ represents a hydrogen or halogen atom or a methylsulfanyl or cyano group, or R₃ represents Ci_-6-alkyl group, which d_-6-alkyl group may contain 1-3 fluoro atoms or a hydroxy or amino group, or R₃ represents a C_2-6-alkynyl or C_2-6-alkenyl group, which groups are optionally substituted with 1-3 fluoro atoms, - R₄ represents subgroup (ii)

(ϋ)

wherein - R₇ represents a hydrogen atom or a Ci_-3 linear alkyl group,

R₈ represents a C_2-6 alkyl group which group is substituted with a hydroxy or amino group or with 1-3 fluoro atoms, or R₈ represents a C_7-io branched alkyl group, C_3-8 cycloalkyl group, C_5-8 heterocycloalkyl group, C_3-8-cycloalkyl-Ci_-2-alkyl group, C_5-7- heterocycloalkyl-Ci_-2-alkyl group, C_5-I0 bicycloalkyl group, C_5-i₀-bicycloalkyl-Ci_-2-alkyl group, Cs-io-heterobicycloalkyl-Ci^-alkyl group, C_6-Io tricycloalkyl group, C_6-I0- tricycloalkyl-Ci_-2-alkyl group, C_6-iQ-heterotricycloalkyl-Ci_-2-alkyl group which groups may be substituted with 1-5 substituents selected from methyl, hydroxy , ethyl, amino, hydroxymethyl, trifluoromethyl or fluoro, or R₈ represents a phenyl group which group is substituted with 1-5 substituents Y as defined above, or R₈ represents a naphtyl or a 1 ,2,3,4-tetrahydronaphtyl or indanyl group which groups may be substituted with 1-3 substituents Y, or R₈ represents a phenyl-Ci_-3-alkyl group, a diphenyl-Ci_-3-alkyl group, which groups may be substituted on their phenyl ring with 1 -5 substituents Y, wherein Y has the abovementioned meaning, or R₈ represents a benzyl group, which benzyl group is substituted with 1-5 substituents Y, or R₈ represents a heteroaryl, heteroary I methyl or heteroarylethyl group, which heteroaryl, heteroaryl methyl or heteroarylethyl group may be substituted with 1-3 substituents Y, as defined above, or R₈ represents a piperidinyl, azepanyl, morpholinyl, azabicyclo[3.3.0]octanyl, 4-hydroxypiperidinyl or pyrrolidinyl group, with the proviso that R₈ is neither a 6-methoxy-benzothiazol-2-yl group nor a [3- chloro-5-(trifluoromethyl)pyrid-2-yl]methyl group,

5. Compounds as claimed in claim 4 of the general formula (I)

wherein:

- R₄ represents subgroup (ii)

(ϋ) wherein

R₇ represents a hydrogen atom or a methyl group,

- R₈ represents a C_2-6 alkyl group which group is substituted with 1-3 fluoro atoms, or R₈ represents a C_7-I0 branched alkyl group, C_3-8 cycloalkyl group, C_5-8 heterocycloalkyl group, C_3-8-cycloalkyl-Ci_-2-alkyl group, C_5-7-heterocycloalkyl-Ci_-2-alkyl group, C_5-I0 bicycloalkyl group,

group, C_6-I0 tricycloalkyl group, C_6-iQ-tricycloalkyl-Ci_-2-alkyl group, C_6-I0- heterotricycloalkyl-Ci-₂-alkyl group which groups may be substituted with 1 -5 substituents selected from methyl, hydroxy, ethyl, amino, hydroxymethyl, trifluoromethyl or fluoro, or R₈ represents a phenyl group which group is substituted with 1 -5 substituents Y as defined above, or R₈ represents a naphtyl or 1, 2,3,4 -tetrahydronaphtyl or indanyl group which groups may be substituted with 1-3 substituents Y, or R₈ represents a phenyl-d_-3- alkyl group, a diphenyl-d_-3-alkyl group, which groups may be substituted on their phenyl ring with 1-5 substituents Y, wherein Y has the abovementioned meaning, or R₈ represents a substituted benzyl group, which benzyl group is substituted with 1-5 substituents Y, or R₈ represents a heteroaryl, heteroaryl methyl or heteroarylethyl group, which heteroaryl, heteroaryl methyl or heteroarylethyl group may be substituted with 1-3 substituents Y, as defined above, with the proviso that R₈ is neither a 6-methoxy- benzothiazol-2-yl group nor a [3-chloro-5-(trifluoromethyl)pyrid-2-yl]methyl group,

6. Compounds as claimed in claim 5 of the general formula (I)

wherein:

- Ri represents a halogen atom or a Ci_-3-alkyl group, which Ci_-3-alkyl group may contain 1- 3 fluoro atoms, or R₁ represents a cyano, or methylsulfanyl group,

- R₂ represents a saturated six-membered monocyclic carbocyclic ring or R₂ represents a phenyl group which may be substituted with 1 , 2 or 3 substituents Y, which can be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chloro, iodo, bromo, fluoro, trifluoromethyl, trifluoromethoxy, methylsulfonyl, carbamoyl, phenyl and cyano, - R₃ represents a hydrogen or halogen atom or a methylsulfanyl or cyano group, or R₃ represents d_-4-alkyl group, which Ci_-4-alkyl group may contain 1-3 fluoro atoms,

- R₄ represents subgroup (ii)

(ii)

wherein - R₇ represents a hydrogen atom or a methyl group,

R₈ represents a C_2-6 alkyl group which group is substituted with 1-3 fluoro atoms, or R₈ represents a C _7-i₀ branched alkyl group, C_3-8 cycloalkyl group, C_5-8 heterocycloalkyl group, C_3-8-cycloalkyl-Ci_-2-alkyl group, C_5-7-heterocycloalkyl-Ci_-2-alkyl group, C_5-I0 bicycloalkyl group,

group, C_6-io tricycloalkyl group,

group, C_6-io- heterotricycloalkyl-Ci_-2-alkyl group, which groups may be substituted with 1-5 substituents selected from methyl, hydroxy, ethyl, amino, hydroxymethyl, trifluoromethyl or fluoro, or R₈ represents a phenyl group which group is substituted with 1-3 substituents Y, wherein Y has the meaning as defined above, or R₈ represents a naphtyl group which group may be substituted with 1 -3 substituents Y, or R₈ represents a phenyl-Ci_-2-alkyl group, which group may be substituted on the phenyl ring with 1-3 substituents Y, wherein Y has the abovementioned meaning, or R₈ repres ents a substituted benzyl group, which benzyl group is substituted with 1-5 substituents Y

7. A compound of the general formula (XIV)

(XIV) wherein:

- Ri represents a halogen atom or a d_-3-alkyl group, which Ci_-3-alkyl group may contain 1- 3 fluoro atoms or a hydroxy or amino group, or R₁ represents a C_2-3-alkynyl group, a C_2- ₃-alkenyl group, which C_2-3-alkynyl group or C_2-3-alkenyl group may contain 1-3 fluoro atoms, or R₁ represents an acetyl, cyclopropyl, cyano, methylsulfonyl, ethylsulfonyl, methylsulfinyl, ethylsulfinyl trifluoromethylsulfanyl, methylsulfanyl, ethylsulfanyl group, formyl group or a C_2-4-heteroalkyl group,

With the proviso that R₂ represents not a phenyl, 4-methylphenyl or 4-methoxyphenyl group, - R₃ represents a hydrogen or halogen atom or a formyl, d_-6-alkylsulfonyl, Ci_-6- alkylsulfinyl, Ci_-6-alkylsulfanyl, trifluoromethylsulfanyl, benzylsulfanyl or cyano group, or R₃ represents Ci_-8-alkyl group, which Ci_-8-alkyl group may be substituted with 1-5 substituents selected from the group consisting of fluoro, hydroxy or amino, or R₃ represents a C_2-6-alkynyl, C_2-6-alkenyl, Ci_-6-alkanoyl, C_3-8-cycloalkyl, Cs-s-heterocycloalkyl or a C_2-6-heteroalkyl group, which groups are optionally substituted with 1-3 methyl groups, an ethyl, amino or hydroxy group or with 1-3 fluoro atoms, or R₃ represents a phenyl group which is substituted with 1-5 substituents Y, wherein Y has the meaning as defined above, or R₃ represents a heteroaryl group which heteroaryl group may be substituted with 1 , 2 or 3 substituents Y, wherein Y has the meaning as defined above or

R₃ represents a benzyl or heteroaryl methyl group which benzyl or heteroaryl methyl group may be substituted with 1, 2 or 3 substituents Y,

- Z represents a chloro atom or a Ci_₃ alkyl group, a hydroxy group, or a -O-Na, -O-K, -O- Li, or -O-Cs group, or Z represents a N-methoxy-N-methyl-amino group, such compounds being useful in the synthesis of compounds of general formula (I) wherein R₁, R₂, and R₃ have the meanings as given in claim 2.

8. A pharmaceutical composition comprising, in addition to a pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable auxiliary substance, a pharmacologically active amount of at least one compound of one of the claims 1 -6, or a salt thereof, as an active ingredient.

9. A method of preparing pharmaceutical compositions as claimed in claim 8, characterized in that a compound of one of the claims 1-6 is brought into a form suitable for administration.

10. Compound as claimed in any of the claims 1-6, or a salt thereof, for use as a medicament

11. Use of a compound as claimed in claims 1-6 for the preparation of a pharmaceutical composition for the treatment of disorders involving cannabinoid CB₂ receptor neurotransmission.

12. Use as claimed in claim 11, characterized in that said disorders in which cannabinoid CB₂ receptors are involved, or that can be treated via manipulation of those receptors are immune system disorders, inflammatory disorders, Huntington's disease, multiple sclerosis, allergies, cancer and pain, including neuropathic pain.