WO2006060190A2

WO2006060190A2 - Imidazole derivatives

Info

Publication number: WO2006060190A2
Application number: PCT/US2005/041895
Authority: WO
Inventors: Zahra Fathi
Original assignee: Bayer Pharmaceuticals Corporation
Priority date: 2004-11-30
Filing date: 2005-11-18
Publication date: 2006-06-08
Also published as: WO2006060190A3

Abstract

This invention relates to imidazole derivatives which are useful in treating diseases linked to the modulation of the cannabinoid receptors.

Description

IMIDAZOLE DERIVATIVES

[001] This application claims benefit of U.S. Provisional Application Serial No. 60/632,012; filed on November 30, 2004, the contents of which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

[002] This invention relates to imidazole derivatives as cannabinoid receptor ligands which are useful in the treatment of diseases linked to the modulation of the cannabinoid receptors.

BACKGROUND OF THE INVENTION

[003] The pharmacological effects of cannabinoids pertain to a variety of areas such as the central nervous system, the cardiovascular system, the immune system and/or endocrine system. Thus, compounds possessing an affinity for the cannabinoid receptors are useful as agents acting on the central nervous system and as immunomodulators, in thymic disorders, myorelaxation, various types of neuropathy, memory disorders, dyskinesia, anticancer chemotherapy, ischemia and angor, orthostatic hypotension, and cardiac insufficiency.

[004] In particular, diseases, conditions, and/or disorders modulated by cannabinoid receptor antagonists include eating disorders (e.g., binge eating disorder, anorexia, and bulimia), weight loss or control (e.g., reduction in calorie or food intake, and/or appetite suppression), obesity, depression, atypical depression, bipolar disorders, psychoses, schizophrenia, behavioral addictions, suppression of reward-related behaviors (e.g., conditioned place avoidance, such as suppression of cocaine- and morphine- induced conditioned place preference), substance abuse, addictive disorders, impulsivity, alcoholism (e.g., alcohol abuse, addiction and/or dependence including treatment for abstinence, craving reduction and relapse prevention of alcohol intake), tobacco abuse (e.g., smoking addiction, cessation and/or dependence including treatment for craving reduction and relapse prevention of tobacco smoking), dementia (including memory loss, Alzheimer's disease, dementia of aging, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild neurocognitive disorder), sexual dysfunction in males (e.g., erectile difficulty), seizure disorders, epilepsy, inflammation, gastrointestinal disorders (e.g., dysfunction of gastrointestinal motility or intestinal propulsion), diarrhea, nausea, emesis, attention deficit disorder (ADD/ADHD), Parkinson's disease, Huntington's disease, Tourette's syndrome, type 2 diabetes, pain, migraine, and glaucoma.

[005] In addition, cannabinoid receptor antagonists may be used for the treatment of neuroinflammatory pathologies including conditions involving demyelinization such as multiple sclerosis or Guillain-Barre syndrome, and viral encephalitis, cerebrovascular accidents and cranial trauma. Cannabinoid receptor antagonists may also be used for the treatment of neurological disorders such as dystonia, muscle spasticity, tremor, traumatic brain injury, stroke, spinal cord injury, and neurodegenerative disorders.

[006] Cannabinoid receptor ligands may also be useful in treating conditions characterized by inflammation and immunomodulatory irregularities such as cutaneous T-cell lymphoma, rheumatoid arthritis, systemic lupus erythematosus, sepsis, shock, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal disease, scleroderma, osteoporosis, renal ischemia, myocardial infarction, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing aveolitis, psoriasis, transplant rejection, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, Crohn's disease, inflammatory bowel disease, reversible airway obstruction, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (COPD) or bronchitis.

[007] Accordingly, despite the presence of some pharmaceuticals that are used to treat these diseases, there remains a need for new pharmaceuticals that are both safe and effective agents for the treatment of disease, and for useful methods to prepare them.

[008] Thus, the imidazole derivatives of the present invention which act as cannabinoid receptor ligands, are useful in the treatment of diseases linked to the modulation of the cannabinoid receptors.

DETAILED DESCRIPTION OF THE INVENTION

[009] The invention relates to substituted imidazole derivatives that have utility in the treatment of diseases linked to the modulation of the cannabinoid receptors, said derivatives of the Formula (I), prodrugs thereof, tautomers thereof and salts thereof

( D

wherein

R¹ and R² are identical or different and are selected from a phenyl group optionally substituted with one or more halogen, (d-C₆)alkyl, (C₁- C₆)alkoxy, trifluoromethyl, cyano, nitro, (Ci-C₆)alkyl sulfonyl, (Q-C^alkyl sulfonyl- amino, (Ci-C₆)alkyl carbonyl-amino, (Ci-C6)alkyl amino-carbonyl-amino, or phenyl,

(C₂-C₆)alkyl,

cyclohexyl optionally substituted with (C₁-C₆)alkyl, (Ci-C₆)alkoxy, trifluoromethyl, cyano, or with one or more fluorine,

1-naphthyl or 2-naphthyl optionally substituted with halogen, (Ci-C₆)alkyl, (C₁- C6)alkoxy, trifluoromethyl, or cyano,

benzyl optionally substituted on the phenyl ring with one or more halogen, (Ci-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl, or cyano,

a 5- to 10-membered saturated or unsaturated heterocyclic radical optionally substituted with fluorine,

(Ci-C₆)alkoxy, trifluoromethyl, or cyano, and

a 5- to 10-membered aromatic monocyclic or bicyclic heterocyclic radical optionally substituted with one or more halogen, (Ci-C₆)alkyl,

trifluoromethyl, cyano, nitro, or phenyl;

R³ is hydrogen, (Ci-C₆)alkyl, benzyl, chloro, orbromo;

where R⁴ is hydrogen or (Q-C₆)alkyl;

R⁵ is selected from

(C₂-C₉)alkyl or (C₇-Cn)bicycloalkyl, each of which may optionally be substituted with one or more phenyl, hydroxy, benzyloxy, (Q-C^alkoxy, (Ci-C₆)alkyl- amino, bis[(C₁-C₃)alkyl]-amino, 1-piperidinyl, 1-pyrrolidinyl, 2,3-dihydro-l,4- benzodioxin-2-yl, hydroxy-substituted (Ci-C₆)allcyl, or fluorine,

benzyl, 2-phenyl-ethyl, benzocyclohexyl or benzocyclopentyl, each of which may optionally be substituted on one of the alkyl carbons with hydroxy, benzyloxy, or hydroxy (Q-C^alkyl, and optionally substituted on the phenyl ring with one or more halogen, (Ci-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl, cyano, hydroxy, benzyloxy, or nitro,

piperidin-4-yl, piperidin-3-yl, or pyrrolidin-3-yl, each of which may optionally be substituted on the nitrogen atom of the piperidine or pyrrolidine ring with (C₁- C₆)alkyl, hydroxy-substituted (Ci-C₆)alkyl, (Ci-C₃)alkoxy-substituted (C₁- C₃)alkyl, benzyl, or phenyl optionally substituted with one or more of (C₁- C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl, cyano, hydroxy, benzyloxy, nitro, or halogen,

-NR⁶R⁷ where R⁶ is hydrogen or

R⁷ is (Q-C^alkyl; or phenyl optionally substituted with one or more of (C₁-C₆)alkyl, hydroxy-substituted (Ci-C₆)alkyl, (C₁-C₃)alkoxy- substituted (C₁-C₃)alkyl, phenyl, hydroxy, benzyloxy, (Ci-C₆)alkoxy, trifluoromethyl, cyano, nitro, or a halogen atom, or

R⁶ and R⁷, taken together with the nitrogen atom to which they are attached, form a 5- to 10-membered saturated or unsaturated heterocyclic ring which is optionally substituted by one or more (Q-C^alkyl, (Q- C₆)alkoxy, hydroxy-substituted (C₁-C₃)alkyl, (C₁-C₃)alkoxy-substituted (C₁-C₃)alkyl, benzyl, phenyl, hydroxy, benzyloxy, or fluorine;

or

R⁴ and R⁵, taken together with the nitrogen atom to which they are attached, form a 5- to 10-membered saturated or unsaturated heterocyclic radical optionally substituted with one or more of fluorine, (Ci-C₆)alkyl, (C₁-Cβ)ahcoxy, (C₁- C₆)alkyl-amino, bis[(Q-C₃)alkyl]-amino, trifluoromethyl, hydroxy, hydroxy- substituted (C₁-C₆)alkyl, phenyl-substituted (Ci-C₆)alkyl, cyano, a 5- to 10- membered aromatic monocyclic or bicyclic heterocyclic radical, or phenyl optionally substituted with one or more (C₁-C₆)aU<yl, hydroxy, benzyloxy, (C₁- C₆)alkoxy, trifluoromethyl, cyano, nitro, or halogen;

where R¹⁰ is (Ci-C₉)alkyl optionally substituted with one or more phenyl, hydroxy, benzyloxy, (Ci-C₆)alkoxy, or a fluorine atom, or

phenyl, benzocyclohexyl or benzocyclopentyl optionally substituted on the phenyl ring with one or more of a phenyl, hydroxy, benzyloxy, (Ci-C₆)alkoxy, or halogen;

and pharmaceutical salts and esters thereof.

[010] Methods of synthesizing compounds of Formula (I) are described in WO 03/040107 (PCT/EP01/03247), which is incorporated herein in its entirety.

[011 ] Examples of compounds of Formula (I) include, but are not limited to:

1 - { [2-(2-chlorophenyl)- 1 -(4-chlorophenyl)- 1 H-imidazol-4-yl]carbonyl } -4-(4- fluorophenyl)-4-piperidinol;

1 - { [2-(2-chlorophenyl)- 1 -(4-chlorophenyl)- lH-imidazol-4-yl]carbonyl } -4-(4- chlorophenyl)-4-piperidinol;

1 - { [2-(2-chlorophenyl)- 1 -(4-chlorophenyl) - 1 H-imidazol-4-y 1] carbony 1 } -4- [3 -

(trifluromethyl)phenyl]-4-piperidinol;

1 - { [2-(2-chlorophenyl)- 1 -(4-chlorophenyl)- 1 H-imidazol-4-y l]carbonyl } -4-(4- trifluoromethoxyphenyl)-4-piperidinol;

1 - { [2-(2-chlorophenyl)- 1 -(4-chlorophenyl)- 1 H-imidazol-4-y l]carbonyl } -4-(3 - fluorophenyl)-4-piperidinol; l-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-5-ethyl-lH-imidazol-4- yl]carbonyl}-4-(3-chlorophenyl)-4-piperidinol; l-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yl]carbonyl}-4-(3- fluoro-4-chlorophenyl)-4-piperidinol; l-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yl]carbonyl}-4-[3-

(trifluoromethoxy)phenyl]-4-piperidinol;

2-(2-chlorophenyl)-l-(4-chlorophenyl)-N-[l-(2-pyridinyl)-4-piperidinyl]-lH- imidazole-4-carboxamide;

[2-(2-chlorophenyl)- 1 -(4-chlorophenyl)- lH-imidazol-4- yl](cyclohexyl)methanone; 2-(2-chlorophenyl)- l-(4-chlorophenyl)-N-(4-pyridinyl)- 1 H-imidazole-4- carboxamide;

2-(2-chlorophenyl)-l-(4-chlorophenyl)-N'-[2-(trifluoromethyl)phenyl]-lH- imidazole-4-carbohydrazide;

2-(2-chlorophenyl)-l-(4-chlorophenyl)-N'-[3-(trifluoromethyl)phenyl]-lH- imidazole-4-carbohydrazide;

N'-[2-chloro-4-(trifluoromethyl)phenyl]-2-(2-chlorophenyl)-l-(4- chlorophenyl)- 1 H-irnidazole-4-carbohydrazide;

2-(2-chlorophenyl)-l-(4-chlorophenyl)-N'-[4-chloro-2-

(trifluoromethyl)phenyl]-lH-imidazole-4-carbohydrazide;

N'-(4-chloro-2-methylphenyl)-2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH- imidazole-4-carbohydrazide;

N'-(2,4-dichlorophenyl)-2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH- imidazole-4-carbohydrazide;

N'-[2,4-bis(trifluoromethyl)phenyl]-2-(2-chlorophenyl)-l-(4-chlorophenyl)- lH-imidazole-4-carbohydrazide;

N'-(2-chloro-4-cyanophenyl)-2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH- imidazole-4-carbohydrazide ;

2-(2-chlorophenyl)-l-(4-chlorophenyl)-N'-(2,4-dichlorophenyl)-5-methyl- lH-imidazole-4-carbohydrazide; l-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(l-piperidinyl)-lH-imidazole-

4-carboxamide; l-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(l-piperidinyl)-lH-imidazole-4- carboxamide; l-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(l-piperidinyl)-5-butyl-lH- imidazole-4-carboxainide; l-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(l-piperidinyl)-5-ethyl-lH- imidazole-4-carboxamide; l-(4-bromophenyl)-2-(2-chlorophenyl)-N-(l-piperidinyl)-5-ethyl-lH- imidazole-4-carboxamide; l-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(l-piperidinyl)-5-methyl-lH- imidazole-4-carboxamide; l-(4-isopropylphenyl)-2-(2-chlorophenyl)-N-(l-piperidinyl)-5-ethyl-lH- imidazole-4-carboxamide;

2-(2-chlorophenyl)-l-(4-chlorophenyl)-N-hexahydrocyclopenta[c]pyrrol- 2(lH)-yl-lH-imidazole-4-carboxamide;

2-(2-chlorophenyl)-l-(4-chlorophenyl)-N'-[4-(trifluoromethyl)phenyl]-lH- imidazole-4-carbohydrazide;

2-(2-chlorophenyl)-l-(4-chlorophenyl)-N-[(lS,2S)-2-hydroxycyclohexyl]- lH-imidazole-4-carboxamide ;

2-(2-chloiOphenyl)-l-(4-chlorophenyl)-N-[(lS,2S)-2-hydroxycyclopentyl]- lH-imidazole-4-carboxamide;

2-(2-chlorophenyl)- l-(4-chlorophenyl)-5-ethyl-N-[( 1 S,2S)-2- hydroxycyclohexyl]-lH-imidazole-4-carboxamide;

2-(2-chlorophenyl)-l-(4-chlorophenyl)-5-propyl-N-[(lS,2S)-2- hydroxycyclohexyl]-lH-imidazole-4-carboxamide; l-(4-bromophenyl)-2-(2-chlorophenyl)-5-ethyl-N-[(lS,2S)-2- hydroxycyclohexylJ-lH-imidazole^-carboxamide; l-(4-bromophenyl)-2-(2-chlorophenyl)-5-ethyl-N-[(lR,2R)-2~ hydroxycyclohexyl]-lH-imidazole-4-carboxamide; l-(4-bromophenyl)-2-(2-chlorophenyl)-5-ethyl-N-[(cis)~2- hydroxycyclohexyl]-lH-imidazole-4-carboxamide;

4-(4- { [ 1 -(4-chlorophenyl)-2-(2,4-dichlorophenyl)- 1 H-imidazol-4- yl]carbonyl }-l-piperazinyl)benzonitrile; and

4-(4-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yl]carbonyl}-l- piperazinyl)benzonitrile.

[012] When any moiety is described as being substituted, it can have one or more of the indicated substituents that can be located at any available position on the moiety. When there are two or more substituents on any moiety, each term shall be defined independently of any other in each occurrence.

[013] Representative salts of the compounds of the present invention include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, and undecanoate.

[014] Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine salts and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.

[015] It will be appreciated that diastereomers and enantiomers of the exemplified structures will often be possible, and that pure isomers represent preferred embodiments. It is intended that pure stereoisomers, and mixtures thereof, are within the scope of the invention.

[016] The compounds of this invention may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers. Any isomer may be present in the (R)-, (S)-, or (R, S) configuration, preferably in the (R)- or (S)- configuration, whichever is most active.

[017] All isomers, whether separated, pure, partially pure, or in racemic mixture, of the compounds of this invention are encompassed within the scope of this invention. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art.

[018] Geometric isomers by nature of substituents about a double bond or a ring may be present in cis (= Z-) or trans (= E-) form, and both isomeric forms are encompassed within the scope of this invention.

[019] The particular process to be utilized in the preparation of the compounds of this invention depends upon the specific compound desired. Such factors as the selection of the specific moieties and the specific substituents on the various moieties, all play a role in the path to be followed in the preparation of the specific compounds of this invention. These factors are readily recognized by one of ordinary skill in the art.

[020] For synthesis of any particular compound, one skilled in the art will recognize that the use of protecting groups may be required for the synthesis of compounds containing certain substituents. A description of suitable protecting groups and appropriate methods of adding and removing such groups may be found in: Protective Groups in Organic Synthesis, Second Edition, T. W. Greene, John Wiley and Sons, New York, 1991.

[021] It is anticipated that prodrug forms of the compounds of this invention will prove useful in certain circumstances, and such compounds are also intended to fall within the scope of the invention. Prodrug forms may have advantages over the parent compounds exemplified herein, in that they are better absorbed, better distributed, more readily penetrate the central nervous system, are more slowly metabolized or cleared, etc. Prodrug forms may also have formulation advantages in terms of crystallinity or water solubility. For example, compounds of the invention having one or more hydroxyl groups may be converted to esters or carbonates bearing one or more carboxyl, hydroxyl or amino groups, which are hydrolyzed at physiological pH values or are cleaved by endogenous esterases or lipases in vivo. See for example U.S. Patent Nos. 4,942,184; 4,960,790; 5,817,840; and 5,824,701 (all of which are incorporated herein by reference in their entirety), and references therein.

Methods of Use

[022] As used herein, various terms are defined below.

[023] When introducing elements of the present invention or the preferred embodiment(s) thereof, the articles "a," "an," "the," and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "including," and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[024] The term "subject" as used herein includes mammals (e.g., humans and animals).

[025] The term "treatment" includes any process, action, application, therapy, or the like, wherein a subject, including a human being, is provided medical aid with the object of improving the subject's condition, directly or indirectly, or slowing the progression of a condition or disorder in the subject.

[026] The term "combination therapy" or "co-therapy" means the administration of two or more therapeutic agents to treat a disease condition and/or disorder. Such administration encompasses co-administration of two or more therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each inhibitor agent. In addition, such administration encompasses use of each type of therapeutic agent in a sequential manner.

[027] The phrase "therapeutically effective" means the amount of each agent administered that will achieve the goal of improvement in a disease condition or disorder severity, while avoiding or minimizing adverse side effects associated with the given therapeutic treatment.

[028] The term "pharmaceutically acceptable" means that the subject item is appropriate for use in a pharmaceutical product.

[029] The compounds of the present invention are useful in treating diseases linked to the modulation of the cannabinoid receptors. [030] The compounds of the present invention may be used alone or in combination with additional therapies and/or compounds known to those skilled in the art in the treatment of diseases linked to the modulation of the cannabinoid receptors. Alternatively, the methods and compounds described herein may be used, partially or completely, in combination therapy.

[031] Such co-therapies may be administered in any combination of two or more drugs (e.g., a compound of the invention in combination with nicotine replacement therapy and an anti-obesity drug). Such co-therapies may be administered in the form of pharmaceutical compositions, as described above.

[032] Based on well known assays used to determine the efficacy for treatment of conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient (e.g., compounds) to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.

[033] The total amount of the active ingredient to be administered may generally range from about 0.0001 mg/kg to about 200 mg/kg, and preferably from about 0.01 mg/kg to about 200 mg/kg body weight per day. A unit dosage may contain from about 0.05 mg to about 1500 mg of active ingredient, and may be administered one or more times per day. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous, and parenteral injections, and use of infusion techniques may be from about 0.01 to about 200 mg/kg. The daily rectal dosage regimen may be from 0.01 to 200 mg/kg of total body weight. The transdermal concentration may be that required to maintain a daily dose of from 0.01 to 200 mg/kg.

[034] Of course, the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age of the patient, the diet of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention may be ascertained by those skilled in the art using conventional treatment tests.

[035] The compounds of this invention may be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof in an appropriately formulated pharmaceutical composition. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for a particular condition or disease. Therefore, the present invention includes pharmaceutical compositions which are comprised of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound. A pharmaceutically acceptable carrier is any carrier which is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. A therapeutically effective amount of a compound is that amount which produces a result or exerts an influence on the particular condition being treated. The compounds described herein may be administered with a pharmaceutically- acceptable carrier using any effective conventional dosage unit forms, including, for example, immediate and timed release preparations, orally, parenterally, topically, or the like.

[036] For oral administration, the compounds may be formulated into solid or liquid preparations such as, for example, capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms may be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers.

[037] In another embodiment, the compounds of this invention may be tableted with conventional tablet bases in combination with binders, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, dyes, coloring agents, and flavoring agents intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include diluents either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.

[038] Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, those sweetening, flavoring and coloring agents described above, may also be present.

[039] The pharmaceutical compositions of this invention may also be in the form of oil-in- water emulsions. The emulsions may also contain sweetening and flavoring agents. [040] Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, and preservative, flavoring and coloring agents.

[041] The compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which may be a sterile liquid or mixture of liquids with or without the addition of a pharmaceutically acceptable surfactant or emulsifying agent and other pharmaceutical adjuvants.

[042] The parenteral compositions of this invention may typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant.

[043] The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents.

[044] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.

[045] A composition of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the drug (e.g., compound) with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.

[046] Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art {see, e.g., U.S. Patent No. 5,023,252, incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. [047] Another formulation employs the use of biodegradable microspheres that allow controlled, sustained release. Such formulations can be comprised of synthetic polymers or copolymers. Such formulations allow for injection, inhalation, nasal or oral administration. The construction and use of biodegradable microspheres for the delivery of pharmaceutical agents is well known in the art (e.g., U.S. Patent No. 6, 706,289, incorporated herein by reference).

[048] It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. For example, direct techniques for administering a drag directly to the brain usually involve placement of a drag delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in U.S. Patent No. 5,011,472, incorporated herein by reference.

[049] The compositions of the invention may also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Any of the compositions of this invention may be preserved by the addition of an antioxidant such as ascorbic acid or by other suitable preservatives. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized.

[050] Formulations suitable for subcutaneous, intravenous, intramuscular, and the like; suitable pharmaceutical carriers; and techniques for formulation and administration may be prepared by any of the methods well known in the art {see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 20^th edition, 2000).

[051] It should be apparent to one of ordinary skill in the art that changes and modifications can be made to this invention without departing from the spirit or scope of the invention as it is set forth herein.

Evaluation of Biological Activity

[052] In order that this invention may be better understood, the following examples are set forth. These examples are for the purpose of illustration only, and are not to be construed as limiting the scope of the invention in any manner. AU publications mentioned herein are incorporated by reference in their entirety.

[053] Demonstration of the activity of the compounds of the present invention may be accomplished through in vitro, ex vivo, and in vivo assays that are well known in the art. For example, to demonstrate the efficacy of a pharmaceutical agent for the treatment of diseases linked to the modulation of the cannabinoid receptors, the following assays may be used. In Vitro Biological Assays

[054] Bioassay systems for determining the CB-I and CB-2 binding properties and pharmacological activity of cannabinoid receptor ligands are described by Roger G. Pertwee (Current Medicinal Chem. 6:635-664, 1999) and in WO 92/02640, incorporated herein by reference).

[055] The following assays are designed to detect compounds that inhibit the binding of [ ³H] SR141716A (selective radiolabeled CB-I ligand) and [³H] 5-(l,l-dimethylheptyl)-2-[5- hydroxy- 2-(3-hydroxypropyl)- cyclohexyl]-phenol ([³H] CP-55940; radiolabeled CB-l/CB-2 ligand) to their respective receptors.

Rat CB-I Receptor Binding Protocol

[056] Brain samples (available from Pel Freeze Biologicals, Rogers, Arkansas) are dissected and placed in tissue preparation buffer (5 mM Tris HCl, pH=7. 4 and 2 mM EDTA), polytroned at high speed and kept on ice for 15 minutes. The homogenate is then spun at 1,00Ox g for 5 minutes at 4°C. The supernatant is recovered and centrifuged at 100, 00Ox G for 1 hour at 4°C. The pellet is then re-suspended in 25 ml of TME (25 nM Tris, pH=7.4, 5 mM MgCl ₂, and 1 mM EDTA) per brain used. A protein assay is performed and 200 μl of tissue totaling 20 μg is added to the assay.

[057] The test compounds are diluted in drug buffer (0.5% BSA, 10% DMSO and TME) and then 25 μl is added to a deep well polypropylene plate. [ ³H] SR141716A is diluted in a ligand buffer (0.5% BSA plus TME) and 25 μl is added to the plate. A BCA protein assay is used to determine the appropriate tissue concentration and then 200 μl of rat brain tissue at the appropriate concentration is added to the plate. The plates are covered and placed in an incubator at 20⁰C for 60 minutes. At the end of the incubation period, 250 μl of stop buffer (5% BSA plus TME) is added to the reaction plate. The plates are then harvested by Skatron onto GF/B filtermats presoaked in BSA (5 mg/ml) plus TME. Each filter is washed twice. The filters are dried overnight and then, the filters are counted on a Wallac Betaplate® counter (available from PerkinElmer Life Sciences®, Boston, Mass.).

Human CB-I Receptor Bindinq Protocol

[058] Human embryonic kidney 293 (HEK 293) cells transfected with the CB-I receptor cDNA are harvested in homogenization buffer (10 mM EDTA, 10 mM EGTA, 10 mM Na Bicarbonate, protease inhibitors; pH=7.4), and homogenized with a Dounce Homogenizer. The homogenate is then spun at 1, 00Ox g for 5 minutes at 4°C. The supernatant is recovered and centrifuged at 25,00Ox G for 20 minutes at 4⁰C. The pellet is then re-suspended in 10 ml homogenization buffer and re-spun at 25,00Ox G for 20 minutes at 4⁰C. The final pellet is re-suspended in 1 ml TME (25 mM Tris buffer (pH=7. 4) containing 5 mM MgCl ₂ and 1 mM EDTA). A protein assay is performed and 200 μl of tissue totaling 20 μg is added to the assay.

[059] The test compounds are diluted in drug buffer (0.5% BSA, 10% DMSO and TME) and then 25 μl is added to a deep well polypropylene plate. [3H] SR141716A is diluted in a ligand buffer (0.5% BSA plus TME) and 25 μl is added to the plate. The plates are covered and placed in an incubator at 30⁰C for 60 minutes. At the end of the incubation period, 250 μl stop buffer (5% BSA plus TME) is added to the reaction plate. The plates are then harvested by Skatron onto GF/B filtermats presoaked in BSA (5 mg/ml) plus TME. Each filter is washed twice. The filters are dried overnight, and the filters are counted on a Wallac Betaplate® counter (available from PerkinElmer Life Sciences®, Boston, Mass.).

CB-2 Receptor Binding Protocol

[060] Chinese hamster ovary-Kl (CHO-Kl) cells transfected with CB-2 cDNA are harvested in tissue preparation buffer (5 mM Tris-HCl buffer (pH=7.4) containing 2 mM EDTA), polytroned at high speed and kept on ice for 15 minutes. The homogenate is then spun at l,000x g for 5 minutes at 4°C. The supernatant is recovered and centrifuged at 100,000x G for 1 hour at 4°C. The pellet is then re-suspended in 25 ml of TME (25 mM Tris buffer (pH=7.4) containing 5 mM MgCl ₂ and 1 mM EDTA) per brain used. A protein assay is performed and 200 μl of tissue totaling 10 μg is added to the assay.

[061 ] The test compounds are diluted in drug buffer (0.5% BSA, 10% DMSO, and 80.5% TME) and then 25 μl is added to the deep well polypropylene plate. [3H] CP-55940 is diluted in ligand buffer (0.5% BSA and 99.5% TME) and then 25 μl is added to each well at a concentration of 1 nM. A BCA protein assay is used to determine the appropriate tissue concentration and 200 μl of the tissue at the appropriate concentration is added to the plate. The plates are covered and placed in an incubator at 30⁰C for 60 minutes. At the end of the incubation period, 250 μl stop buffer (5% BSA plus TME) is added to the reaction plate. The plates are then harvested by Skatron format onto GF/B filtermats presoaked in BSA (5 mg/ml) plus TME. Each filter is washed twice. The filters are dried overnight. The filters are then counted on the Wallac BetaplateTM counter.

CB-I GTPγ [³⁵S] Binding Assay

[062] Membranes are prepared from CHO-Kl cells stably transfected with the human CB-I receptor cDNA. Membranes are prepared from cells as described by Bass, et al., (MoI. Pharmacol. 50:709-715, 1996). GTPγ [³⁵S] binding assays are performed in a 96-well FlashPlate® format in duplicate using 100 pM GTPy[³⁵S] and 10 μg membrane per well in assay buffer composed of 50 mM Tris HCl, pH 7.4, 3 mM MgCl ₂, pH 7.4, 10 mM MgCl₂, 20 mM EGTA, 100 mM NaCl, 30 μM GDP, 0.1% bovine serum albumin and the following protease inhibitors: 100 μg/ml bacitracin, 100 μg/ml benzamidine, 5 μg/ml aprotinin, and 5 μg/ml leupeptin. The assay mix is then incubated with increasing concentrations of test compounds (10^'10M to 10^"5M) for 10 minutes and challenged with the cannabinoid agonist CP-55940 (10 μM). Assays are performed at 30⁰C for one hour. The FlashPlates® are then centrifuged at 200Ox g for 10 minutes. Stimulation of GTPγ[³⁵ S] binding is then quantified using a Wallac Microbeta.EC₅₀ calculations done using Prism® by Graphpad. Inverse agonism is measured in the absense of agonist.

In Vivo Biological Assays

[063] Cannabinoid agonists such as Δ ⁹- tetrahydrocannabinol (Δ⁹-THC) and CP-55940 have been shown to affect four characteristic behaviors in mice, collectively known as the Tetrad (Smith, et al., J. Pharmacol. Exp. Ther. 270(l):219-227, 1994; Wiley, et al., Eur. J. Pharmacol. 276(l-2):49-54, 1995). Reversal of these activities in the Locomotor Activity, Catalepsy, Hypothermia, and Hot Plate assays described below provides a screen for in vivo activity of CB-I antagonists.

Locomotor Activity

[064] Male ICR mice (n=6) (17-19 g, Charles River Laboratories, Inc., Wilmington, Mass.) are pre-treated with test compound (sc, po, ip, or icv). Fifteen minutes later, the mice are challenged with CP-55940 (sc). Twenty-five minutes after the agonist injection, the mice are placed in clear acrylic cages (431.8 cmx20.9 cmx20.3 cm) containing clean wood shavings. The subjects are allowed to explore surroundings for a total of about 5 minutes and the activity is recorded by infrared motion detectors (available from Coulbourn Instruments®, Allentown, Pa.) that are placed on top of the cages. The data is computer collected and expressed as "movement units."

Catalepsy

[065] Male ICR mice (n=6)(17-19 g upon arrival) are pre-treated with test compound (sc, po, ip or icv). Fifteen minutes later, the mice are challenged with CP-55940 (sc). Ninety minutes post injection, the mice are placed on a 6.5 cm steel ring attached to a ring stand at a height of about 12 inches. The ring is mounted in a horizontal orientation and the mouse is suspended in the gap of the ring with fore- and hind-paws gripping the perimeter. The duration that the mouse remained completely motionless (except for respiratory movements) is recorded over a 3- minute period.

[066] The data are presented as a percent immobility rating. The rating is calculated by dividing the number of seconds the mouse remains motionless by the total time of the observation period and multiplying the result by 100. A percent reversal from the agonist is then calculated. Hypothermia

[067] Male ICR mice (n=5) (17-19 g upon arrival) are pretreated with test compounds (sc, po, ip or icv). Fifteen minutes later, mice are challenged with the cannabinoid agonist CP-55940 (sc). Sixty-five minutes post agonist injection, rectal body temperatures are taken. This is done by inserting a small thermostat probe approximately 2-2.5 cm into the rectum. Temperatures are recorded to the nearest tenth of a degree

Hot Plate

[068] Male ICR mice (n=7) (17-19 g upon arrival) are pre-treated with test compounds (sc, po, ip or iv). Fifteen minutes later, mice are challenged with a cannabinoid agonist CP-55940 (sc). Forty-five minutes later, each mouse is tested for reversal of analgesia using a standard hot plate meter (Columbus Instruments). The hot plate is 10"xl0"x0.75" with a surrounding clear acrylic wall. Latency to kick, lick or flick hindpaw or jump from the platform is recorded to the nearest tenth of a second. The timer is experimenter activated and each test had a 40 second cut off. Data are presented as a percent reversal of the agonist induced analgesia.

Alcohol Intake

[069] The following protocol evaluates the effects of alcohol intake in alcohol preferring (P) female rats with an extensive drinking history. The following references provide detailed descriptions of P rats: Li ,T.-K., et al., "Indiana selection studies on alcohol related behaviors" in Development of Animal Models as Pharmacogenetic Tools (eds McClearn C. E., Deitrich R. A. and Erwin V. G.), Research Monograph 6, 171-192 (1981) NIAAA, ADAMHA, Rockville, Md.; Lumeng, L, et al., "New strains of rats with alcohol preference and nonpreference "Alcohol And Aldehyde Metabolizing Systems, 3, Academic Press, New York, 537-544 (1977); and Lumeng, et al., Pharmacol, Biochem Behav. 16:125-130, 1982.

[070] Female rats are given 2 hours of access to alcohol (10% v/v and water, 2- bottle choice) daily at the onset of the dark cycle. The rats are maintained on a reverse cycle to facilitate experimenter interactions. The animals are initially assigned to four groups equated for alcohol intakes: Group I—vehicle; Group 2~positive control; Group 3— low dose test compound; and Group 4— high dose of test compound. Test compounds are generally mixed into a vehicle of 30% (w/v) β-cyclodextrin in distilled water at a volume of 1-2 ml/kg. Vehicle injections are given to all groups for the first two days of the experiment. This is followed by 2 days of drug injections (to the appropriate groups) and a final day of vehicle injections. On the drag injection days, drugs are given sc 30 minutes prior to a 2-hour alcohol access period. Alcohol intake for all animals is measured during the test period and a comparison is made between drag and vehicle-treated animals to determine effects of the compounds on alcohol drinking behavior. [071] The structures, materials, compositions, and methods described herein are intended to be representative examples of the invention, and it will be understood that the scope of the invention is not limited by the scope of the examples. Those skilled in the art will recognize that the invention may be practiced with variations on the disclosed structures, materials, compositions and methods, and such variations are regarded as within the ambit of the invention.

Claims

ClaimsWhat is claimed:

1. A method for treating diseases linked to the modulation of the cannabinoid receptors comprising administering to a subject in need thereof an effective amount of a compound of Formula (I)

( D wherein

R¹ and R² are identical or different and are selected from a phenyl group optionally substituted with one or more halogen, (Ci-C₆)alkyl, (Q- C₆)alkoxy, trifluoromethyl, cyano, nitro, (Ci-C₆)alkyl sulfonyl, (Ci-C₆)alkyl sulfonyl- amino, (Ci-C₆)alkyl carbonyl-amino, (Ci-C₆)alkyl amino-carbonyl-amino, or phenyl,

(C₂-C₆)alkyl,

cyclohexyl optionally substituted with (Ci-C₆)alkyl, (Ci-Ce)alkoxy, trifluoromethyl, cyano, or with one or more fluorine,

1-naphthyl or 2-naphthyl optionally substituted with halogen, (Q-C^alkyl, (Q- C₆)alkoxy, trifluoromethyl, or cyano,

benzyl optionally substituted on the phenyl ring with one or more halogen, (Q-Cgjalkyl, (Q-C₆)alkoxy, trifluoromethyl, or cyano,

a 5- to 10-membered saturated or unsaturated heterocyclic radical optionally substituted with fluorine, (Q-Cgjalkyl, (Q-C₆)alkoxy, trifluoromethyl, or cyano, and

a 5- to 10-membered aromatic monocyclic or bicyclic heterocyclic radical optionally substituted with one or more halogen, (Ci-C₆)alkyl, (Q-C₆)alkoxy, trifluoromethyl, cyano, nitro, or phenyl;

R³ is hydrogen, (Ci-C₆)alkyl, benzyl, chloro, or bromo;

where R⁴ is hydrogen or (Q-C₆)alkyl;

R⁵ is selected from

(C₂-C₉)alkyl or (C₇-Ci Obicycloalkyl, each of which may optionally be substituted with one or more phenyl, hydroxy, benzyloxy, (Q-Q) alkoxy, (Q-Q)alkyl- amino, bis[(Q-Q)allcyl]-arnino, 1-piperidinyl, 1-pyrrolidinyl, 2,3-dihydro-l,4- benzodioxin-2-yl, hydroxy-substituted (Q-Q)alkyl, or fluorine,

benzyl, 2-phenyl-ethyl, benzocyclohexyl or benzocyclopentyl, each of which may optionally be substituted on one of the alkyl carbons with hydroxy, benzyloxy, or hydroxy (Ci-C₆)alkyl, and optionally substituted on the phenyl ring with one or more halogen, (Ci-C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl, cyano, hydroxy, benzyloxy, or nitro,

piperidin-4-yl, piperidin-3-yl, or pyrrolidin-3-yl, each of which may optionally be substituted on the nitrogen atom of the piperidine or pyrrolidine ring with (Q- C₆)alkyl, hydroxy-substituted (Q-C₆)alkyl, (Q-C₃)alkoxy-substituted (Q- Q)alkyl, benzyl, or phenyl optionally substituted with one or more of (Q- Q)alkyl, (Q-C₆)allcoxy, trifluoromethyl, cyano, hydroxy, benzyloxy, nitro, or halogen,

-NR⁶R⁷ where R⁶ is hydrogen or (Q-Q)alkyl;

R⁷ is (Ci-C₉)alkyl; or phenyl optionally substituted with one or more of (Q-C₆)alkyl, hydroxy-substituted (Q-C₆)alkyl, (Q-Q)alkoxy- substituted (Q-Q)alkyl, phenyl, hydroxy, benzyloxy, (Q-C₆)alk:oxy, trifluoromethyl, cyano, nitro, or a halogen atom, or

R⁶ and R⁷, taken together with the nitrogen atom to which they are attached, form a 5- to 10-membered saturated or unsaturated heterocyclic ring which is optionally substituted by one or more (Q-C₆)alkyl, (Q- Q)alkoxy, hydroxy-substituted (Q-Q)alkyl, (Q-C₃)alkoxy~substituted

(Q-C₃)alkyl, benzyl, phenyl, hydroxy, benzyloxy, or fluorine; or

R⁴ and R⁵, taken together with the nitrogen atom to which they are attached, form a 5- to 10-membered saturated or unsaturated heterocyclic radical optionally substituted with one or more of fluorine, (Q-C^alkyl, (C₁-C₆)OIkOXy, (C₁- C₆)alkyl-amino, bis[(Ci-C₃)alkyl]-amino, trifluoromethyl, hydroxy, hydroxy- substituted (Ci-C₆)alkyl, phenyl-substituted (Ci-C₆)alkyl, cyano, a 5- to 10- membered aromatic monocyclic or bicyclic heterocyclic radical, or phenyl optionally substituted with one or more (Ci-C₆)alkyl, hydroxy, benzyloxy, (C₁- C₆)alkoxy, trifluoromethyl, cyano, nitro, or halogen;

or

phenyl, benzocyclohexyl or benzocyclopentyl optionally substituted on the phenyl ring with one or more of a phenyl, hydroxy, benzyloxy, (C₁-C₆)alkoxy, or halogen;

and pharmaceutical salts and esters thereof.

2. The method of claim 1, wherein said compound of Formula (I) is selected from

l-{[2-(2-chloroρhenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yl]carbonyl}-4-(4- fluorophenyl)-4-piperidinol; l-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yl]carbonyl}-4-(4- chlorophenyl)-4-piperidinol; l-{ [2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yl]carbonyl}-4-[3-

(trifluromethyl)phenyl]-4-piρeridinol; l-{ [2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yl]carbonyl}-4-(4- trifluoromethoxyphenyl)-4-piperidinol; l-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yl]carbonyl}-4-(3- fluorophenyl)-4-piperidinol; l-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-5-ethyl-lH-imidazol-4- yl]carbonyl}-4-(3-chlorophenyl)-4-piperidinol; l-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yl]carbonyl}-4-(3- fluoro-4-chlorophenyl)-4-piperidinol; l-{[2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH-imidazol-4-yl]carbonyl}-4-[3-

(trifluoromethoxy)phenyl]-4-piperidinol;

[2-(2-chlorophenyl)- 1 -(4-chloroρhenyl)- lH-imidazol-4- yl](cyclohexyl)methanone;

2-(2-chlorophenyl)-l-(4-chlorophenyl)-N-(4-pyridinyl)-lH-imidazole-4- carboxamide;

N'-[2-chloro-4-(trifluoromethyl)phenyl]-2-(2-chlorophenyl)-l-(4- chlorophenyl)-lH-imidazole-4-carbohydrazide;

2-(2-chlorophenyl)-l-(4-chlorophenyl)-N'-[4-chloro-2-

(trifluoromethyl)phenyl]-lH-imidazole-4-carbohydrazide;

N'-(2-chloro-4-cyanophenyl)-2-(2-chlorophenyl)-l-(4-chlorophenyl)-lH- imidazole-4-carbohydrazide;

2-(2-chlorophenyl)-l-(4-chlorophenyl)-N'-(2,4-dichlorophenyl)-5-methyl- lH-imidazole-4-carbohydrazide;

1 -(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-( 1 -piperidinyl)- lH-imidazole-

4-carboxamide; l-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(l-piperidinyl)-lH-imidazole-4- carboxamide; l-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(l-piρeridinyl)-5-butyl-lH- imidazole-4-carboxamide; l-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(l-piperidinyl)-5-ethyl-lH- imidazole-4-carboxamide; l-(4-bromophenyl)-2-(2-chlorophenyl)-N-(l-piperidinyl)-5-ethyl-lH- imidazole-4-carboxamide; l-(4-chlorophenyl)-2-(2-chlorophenyl)-N-(l-piperidinyl)-5-methyl-lH- imidazole-4-carboxamide; l-(4-isopropylphenyl)-2-(2-chlorophenyl)-N-(l-piperidinyl)-5-ethyl-lH- imidazole-4-carboxamide;

2-(2-chlorophenyl)-l-(4-chlorophenyl)-N-hexahydrocyclopenta[c]pyrrol-

2( lH)-yl- lH-imidazole-4-carboxamide;

2-(2-chlorophenyl)-l-(4-chlorophenyl)-N-[(lS,2S)-2-hydroxycyclohexyl]- lH-imidazole-4-carboxamide;

2-(2-chlorophenyl)-l-(4-chlorophenyl)-N-[(lS,2S)-2-hydroxycyclopentyl]- lH-imidazole-4-carboxamide;

2-(2-chlorophenyl)-l-(4-chlorophenyl)-5-ethyl-N-[(lS,2S)-2- hydroxycyclohexyl]-lH-imidazole-4-carboxamide;

2-(2-chlorophenyl)-l-(4-chlorophenyl)-5-propyl-N-[(lS,2S)-2- hydroxycyclohexyl]-lH-imidazole-4-carboxamide; l-(4-bromophenyl)-2-(2-chlorophenyl)-5-ethyl-N-[(lS,2S)-2- hydroxycyclohexyl]-lH-imidazole-4-carboxamide; l-(4-bromophenyl)-2-(2-chlorophenyl)-5-ethyl-N-[(lR,2R)-2- hydroxycyclohexylj-lH-imidazole^-carboxamide; l-(4-bromophenyl)-2-(2-chlorophenyl)-5-ethyl-N-[(cis)-2- hydroxycyclohexylJ-lH-imidazole^-carboxamide;

4-(4- { [ 1 -(4-chlorophenyl)~2-(2,4-dichlorophenyl)- 1 H-imidazol-4- yl]carbonyl } - 1 -piperazinyl)benzonitrile; and

3. The method of claim 1 or 2, wherein said disease is selected from eating disorders, binge eating disorder, anorexia, bulimia, depression, atypical depression, bipolar disorders, psychoses, schizophrenia, behavioral addictions, suppression of reward-related behaviors, substance abuse, addictive disorders, impulsivity, alcoholism, tobacco abuse, dementia, memory loss, Alzheimer's disease, dementia of aging, vascular dementia, mild cognitive impairment, age-related cognitive decline, neurocognitive disorder, sexual dysfunction, erectile difficulty, seizure disorders, epilepsy, inflammation, gastrointestinal disorders, diarrhea, nausea, emesis, attention deficit disorder, Parkinson's disease, Huntington's disease, Tourette's syndrome, type 2 diabetes, pain, migraine, and glaucoma.

4. The method of claim 1 or 2, wherein said disease is neuroinflammatory disease.

5. The method of claim 4, wherein said neuroinflammatory disease is selected from multiple sclerosis, Guillain-Barre syndrome, viral encephalitis, cerebrovascular accidents, and cranial trauma.

6. The method of claim 1 or 2, wherein said disease is a neurological disorder.

7. The method of claim 6, wherein said neurological disorder is selected from dystonia, muscle spasticity, tremor, traumatic brain injury, stroke, spinal cord injury, and neurodegenerative disorders.

8. The method of claim 1 or 2, wherein said disease is an inflammation or immunomodulatory disorder.

9. The method of claim 8, wherein said inflammation or immunomodulatory disorder is selescted from cutaneous T-cell lymphoma, rheumatoid arthritis, systemic lupus erythematosus, sepsis, shock, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal disease, scleroderma, osteoporosis, renal ischemia, myocardial infarction, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing aveolitis, psoriasis, transplant rejection, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, Crohn's disease, inflammatory bowel disease, reversible airway obstruction, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, and bronchitis.

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) as defined in claim 1 or 2, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier and one or more pharmaceutical agents.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) as defined in claim 1 or 2, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier and one or more pharmaceutical agents for neuroinflammatory disease.

12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) as defined in claim 1 or 2, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier and one or more pharmaceutical agents for neurological disorder.

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) as defined in claim 1 or 2, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier and one or more pharmaceutical agents for inflammation or immunomodulatory disorder.