Abstract:
The present invention relates to 1,2,3-triazole derivatives which can be used as cannabinoid CB1 receptor antagonists. In addition, the compound of the 1,2,3-triazole derivatives in the present invention can be formulated into a pharmaceutical composition for treating indications relative to signal transduction of CB1 receptors.

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The present invention relates to 1,2,3-triazole derivatives and, more particularly, to those capable of being used as cannabinoid CB1 receptor antagonists. 
     2. Description of Related Art 
     Obesity caused by an imbalance between food intake and energy expenditure, is a significant risk factor for cardiovascular disease and diabetes, and associated with significantly reduced life longevity. The World Health Organization (WHO) declared that obesity has become a global epidemic posing a serious threat to public health. The short-term diet or exercise is not effective as most obese patients readily regain their lost weight thereafter. Therefore, the medical treatment of obesity is an attractive approach. 
     In this respect, cannabinoid-1 receptor (CB1R) and its endogenous ligands (agonists), the endocannabinoids, have been found to be involved in the control of weight via a dual mechanism of food intake modification and the regulation of energy homeostasis. Indeed, the biological effects of the CB1 receptors, which are mainly located within the central nervous system, can be mediated through exposure to agonists or antagonists (inverse agonists). Blocking the effects of the endogenous cannabinoids has become a therapeutic avenue to treat obesity. 
     The other known cannabinoid receptor (CB2R), is predominantly found in the immune system and related to immune regulation. Therefore, good CB1/CB2 selectivity is a desired feature for the development of new anti-obesity drug. The most clinically advanced CB1 receptor antagonist, Rimonabant (SR141716A) launched by Sanofi-Aventis, binds to the human CB1 receptor with 5.6±0.5 nM (K i ) affinity (formula A). Since that development, many small molecule CB1 antagonists with diverse chemical structures have been prepared and reviewed. For example, Ibipinabant (SLV319), Otenabant (CP-945,598) and Taranabant (MK-0364) have been reported to be in various phases of clinical trials. 
                                
In addition to the pyrazole core of SR141716A, derivatives of other five-membered heterocycles, such as pyrrole, thiophene, thiazole, imidazole, oxazole, and 1,2,4-triazole are also known as the CB1 receptor antagonists. However, whether the derivatives of 1,2,3-triazole serve as CB1 receptor antagonists has not been explored yet.
 
     SUMMARY OF THE INVENTION 
     The object of the present invention is to provide the derivatives of 1,2,3-triazole which can function as cannabinoid-1 (CB1) receptor antagonists. 
     To achieve the object, the present invention provides a compound of formula I and pharmaceutically acceptable salts, prodrugs and solvates thereof,
 
Ar—X—Y—Z  formula I
 
     wherein Ar is 
                                
in which R 1  and R 2  each independently represent H, phenyl, thienyl or pyridyl, unsubstituted or substituted by halo, hydroxy, cyano, nitro, thiohydroxy, amino, carbonyl, carbamoyl, sulfamoyl, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  alkoxy, C 1-4  alkyl alcohol, C 1-4  haloalkyl, C 1-4  haloalkylthio, C 1-4  alkylamino, C 1-4  alkylamido, C 1-4  alkylsulfonyl, C 1-4  haloalkylsulfonyl, C 1-4  alkoxycarbonyl or C 1-4  alkylcarbamoyl, with a proviso that one of R 1  and R 2  is not H;
 
     X is —(CH 2 ) b — in which b is 0, 1, 2, 3 or 4; 
     Y is —C(O)— or —S(O 2 )—; and 
     Z is —(CH 2 ) r (Ph) s  in which s is 1 or 2 and r is 0, 1, 2, 3 or 4, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 5-9  aryl, C 4-9  cycloalkyl, naphthyl, anthracenyl, OR 3 , NR 4 R 5 , or C 4-9  heteroaryl or C 3-10  heterocycloalkyl comprising one to three heteroatoms which each independently are N, O or S; 
     R 3  is C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, —(CH 2 ) r (Ph) s , C 5-9  aryl, C 4-9  cycloalkyl, naphthyl, anthracenyl, or C 4-9  heteroaryl or C 3-10  heterocycloalkyl comprising one to three heteroatoms which each independently are N, O, or S; 
     R 4  and R 5  each independently are H, 
                                
—(CH 2 ) r (Ph) s , C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 5-9  aryl, C 4-9  cycloalkyl, carbamoyl, ureido, adamantyl, —CHR 6 R 7 , or C 4-9  heteroaryl or C 3-10  heterocycloalkyl comprising one to three heteroatoms which each independently are N, O, or S, in which R 6  and R 7  each independently are C 1-4  alkyl alcohol, C 1-4  alkyl or benzyl, with a proviso that one of R 4  and R 5  is not H and one of R 6  and R 7  is not H,
 
     wherein R 6  and R 7  are unsubstituted or optionally substituted by thiohydroxy, hydroxy, phenyl, nitro, or C 1-4  alkoxy; and 
     R 3 , R 4 , R 5 , ph, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 5-9  aryl, C 4-9  cycloalkyl, C 4-9  heteroaryl, C 3-10  heterocycloalkyl, naphthyl, anthracenyl are unsubstituted or optionally substituted by halo, hydroxy, cyano, nitro, thiohydroxy, amino, carbonyl, carbamoyl, sulfamoyl, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  alkoxy, C 1-4  alkyl alcohol, C 1-4  haloalkyl, C 1-4  haloalkylthio, C 1-4  alkylamino, C 1-4  alkylamido, C 1-4  alkylsulfonyl, C 1-4  haloalkylsulfonyl, C 1-4  alkoxycarbonyl, C 1-4  alkylcarbamoyl, phenyl or benzyl. 
     In one aspect of the present invention, Ar is 
                                
Meanwhile, R 1  and R 2  each independently are H, phenyl or thienyl, and Y is —C(O)—. Z is —(CH 2 ) r (Ph) s  in which s is 1 or 2 and r is 0, 1, 2, 3 or 4, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 5-9  aryl, C 4-9  cycloalkyl, naphthyl, anthracenyl, OR 3 , NR 4 R 5 , or C 4-9  heteroaryl or C 3-10  heterocycloalkyl comprising one to three heteroatoms which each independently are N, O or S. Particularly, R 1  and R 2  are phenyl; R 3  is C 4-8  alkyl or benzyl; and R 4  and R 5  each independently are H, C 1-8  alkyl, C 2-8  alkenyl, six-membered heterocycloalkyl comprising a heteroatom of N, C 4-8  alkylcarbamoyl or C 4-8  alkylureido. Besides, R 1  and R 2  can be optionally substituted by halo, methoxy, methyl, halomethyl, methoxycarbonyl, nitro, or cyano, wherein halo can be F, Cl, or Br.
 
     In another aspect of the present invention, Ar is 
                                
In addition, R 1  and R 2  are phenyl. Y is —C(O)— and Z is phenyl, halophenyl, C 4-8  alkyl, OR 3 , NR 4 R 5 , or C 4-5  heterocycloalkyl comprising one to two heteroatoms selected from N and O. Particularly, R 3  is C 2-8  alkyl, or phenyl, and R 4  and R 5  each independently are H, C 4-8  alkyl, phenyl, benzyl, phenylethyl, phenylpropyl, cyclohexyl, propinylcyclohexyl, C 2-4  alkoxycarbonylmethyl, adamantyl, six-membered heterocycloalkyl comprising one to two heteroatoms which each independently are N or O. Alternatively, R 4  and R 5  each independently are
 
                                
R 1  and R 2  can be optionally substituted by halo, and halo can be Cl, and C 4-8  alkyl, phenyl, benzyl, phenylethyl, phenylpropyl, cyclohexyl, propinylcyclohexyl, C 2-4  alkoxycarbonylmethyl, adamantyl, and six-membered heterocycloalkyl can be substituted by methoxy, methyl, halomethyl or halo.
 
     Pharmaceutically acceptable salts and prodrugs of compounds disclosed herein are within the scope of this disclosure. The term “pharmaceutically acceptable salt” as used herein and in the claims is intended to include nontoxic base addition salts. Suitable salts include those derived from organic and inorganic acids such as, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, sulfinic acid, citric acid, maleic acid, fumaric acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, and the like. The term “pharmaceutically acceptable salt” as used herein is also intended to include salts of acidic groups, such as a carboxylate, with such counterions as ammonium, alkali metal salts, particularly sodium or potassium, alkaline earth metal salts, particularly calcium or magnesium, and salts with suitable organic bases such as lower alkylamines (methylamine, ethylamine, cyclohexylamine, and the like) or with substituted lower alkylamines (e.g. hydroxy-substituted alkylamines such as diethanolamine, triethanolamine or tris(hydroxymethyl)-aminomethane), or with bases such as piperidine or morpholine. 
     Another object of the present invention is to provide a pharmaceutical composition comprising an effective amount of any one compound of the present invention and a pharmaceutical acceptable carrier or diluent. Such a pharmaceutical composition can be used to treat obesity, psychiatric disorders, psychotic disorders, schizophrenia, bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders, epilepsy, neurological disorders, dementia, Parkinson&#39;s Disease, Huntington&#39;s Chorea, Alzheimer&#39;s Disease, immune disorders, cardiovascular disorders, reproductive disorders, endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems, and extended abuse, addiction and/or relapse indications. 
     Also within the scope of this invention is a method for treating the foregoing indications by administering an effective amount of the abovementioned pharmaceutical composition to a subject in need. 
     The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances. 
     The term “C 1-10  alkyl” as used herein and in the claims (unless specified otherwise) means a saturated aliphatic hydrocarbon including straight chain and branched chain groups, and such a hydrocarbon with 1 to 10 carbon atoms (whenever a numerical range; e.g., “1-10”, is stated herein, it means that the group, in this case the alkyl group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 10 carbon atoms). More preferably, it is a lower alkyl having 1 to 4 carbon atoms. For example, C 1-4  alkyl represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and the like 
     The term “C 2-10  alkenyl” as used herein and in the claims (unless specified otherwise) means an alkyl group, as defined herein, having at least one carbon-carbon double bond, for example ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, t-butenyl and the like. 
     The term “C 2-10  alkynyl” as used herein and in the claims (unless specified otherwise) means an alkyl group, as defined herein, having at least one carbon-carbon triple bond, for example ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, t-butynyl and the like. 
     The term “C 5-9  aryl” as used herein and in the claims (unless specified otherwise) means an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having 5 to 9 carbon atoms and a completely conjugated pi-electron system. 
     The term “C 4-9  cycloalkyl” as used herein and in the claims (unless specified otherwise) means an all-carbon monocyclic or fused ring (i.e., rings which share and adjacent pair of carbon atoms) group with 4 to 9 carbon atoms, wherein one or more rings do not have a completely conjugated pi-electron system. Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, cycloheptane, and cycloheptatriene. 
     The term “C 4-9  heteroaryl” as used herein and in the claims (unless specified otherwise) means a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having 4 to 9 carbon atoms and in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system. 
     The term “C 3-10  heterocycloalkyl” as used herein and in the claims (unless specified otherwise) means a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having 3 to 10 carbon atoms and in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur wherein one or more rings do not have a completely conjugated pi-electron system. 
     The term “Ph” refers to phenyl or phenylene. 
     The term “C 2-4  alkoxy” refers to an —O—C 1-4  alkyl as defined herein. 
     The term “C 1-4  alkyl alcohol” refers to an —ROH group in which R is C 1-4  alkyl as defined herein. 
     The term “hydroxy” refers to an —OH group. 
     The term “halo” refers to chlorine, bromine, iodine or fluorine. 
     The term “cyano” refers to a —CN group. 
     The term “thiohydroxy” refers to an —SH group. 
     The term “amino” refers to an —NH 2  group. 
     The term “carbonyl” refers to a —C(═O)—R group, where R is selected from the group consisting of hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-6  cycloalkyl, C 4-6  aryl, and C 3-6  heteroaryl (bonded through a ring carbon). 
     The term “sulfonyl” refers to an —S(═O) 2 R″ group with R being C 1-6  alkyl. 
     The term “sulfamoyl” refers to an —S(═O) 2 —NR x R y  group or a R y S(O 2 )—NR x — group or, where R x  and R y  are selected from the group consisting of hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-6  cycloalkyl, C 4-6  aryl, and C 3-6  heteroaryl (bonded through a ring carbon). 
     The term “carbamoyl” refers to an —OC(═O)NR x R y  group or 
     R x OC(═O)NR y — group, with R x  and R y  independently being H or C 1-6  alkyl. 
     The term “C 1-4  haloalkyl” refers to a C 1-4  alkyl group substituted by at least one halogen atom. 
     The term “C 1-4  haloalkylthio” refers to an —SR group where R is C 1-4  alkyl substituted by at least one halogen atom. 
     The term “C 1-4  alkylamino” refers to an —RNH 2  group where R is C 1-4  alkyl. 
     The term “C 1-4  alkylsulfonyl” refers to an —S(═O) 2 R group where R is C 1-4  alkyl. 
     The term “C 1-4  haloalkylsulfonyl” refers to an —S(═O) 2 R group where R is C 1-4  alkyl substituted by at least one halogen atom. 
     The term “C 1-4  alkoxycarbonyl” refers to a —C(═O)OR group where R is C 1-4  alkoxy. 
     The term “C 1-4  alkxylcarbamoyl” refers to an —OC(═O)NR x R y  group or R x OC(═O)NR y — group, group where R x  is C 1-4  alkyl. 
     The term “C 1-4  alkxylcarbamoyl” refers to an —OC(═O)NR x R y  group or R x OC(═O)NR y — group, group where R x  is C 1-4  alkyl. 
     The term “ureido” refers to an —NR x C(═O)NR y R z  group, with R x , R y , and R z  independently being H or C 1-6  alkyl. 
     The term “amido” refers to a —C(═O)NR x R y  or —R x C(═O)NR y — group, with R x  and R y  independently being H or C 1-6  alkyl. The term “C 1-4  alkylamido” refers to amido as defined herein wherein R x  is C 1-4  alkyl. 
     Other objects, advantages, and novel features of the invention will become more apparent from the following detailed description when taken in conjunction with the accompanying drawings. 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 
     The carrier in the pharmaceutical composition must be “acceptable” in the sense that it is compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and not deleterious to the subject to be treated. One or more solubilizing agents can be utilized as pharmaceutical excipients for delivery of active 1,2,3-triazole derivatives or an analogue thereof. Examples of other carriers include colloidal silicon oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&amp;C Yellow # 10. 
     To practice the method of the present invention, a composition having one or more of the above-described 1,2,3-triazole derivatives and their analogues can be administered parenterally, orally, nasally, rectally, topically, or buccally. The term “parenteral” as used herein refers to subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial injection, as well as any suitable infusion technique. 
     A sterile injectable composition can be a solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol and water. In addition, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or diglycerides). Fatty acid, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long chain alcohol diluent or dispersant, carboxymethyl cellulose, or similar dispersing agents. Other commonly used surfactants such as Tweens or Spans or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purpose of formulation. 
     A composition for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions. In the case of tablets, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added. 
     A nasal aerosol or inhalation composition can be prepared according to techniques well known in the art of pharmaceutical formulation. For example, such a composition can be prepared as a solution in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. A composition having one or more active 1,2,3-triazole derivatives or their analogues can also be administered in the form of suppositories for rectal administration. 
     The following exemplifies the synthesis of 1,2,3-triazoles derivatives of the present invention. 
     EXAMPLE 1 
     The synthesis of 4,5-diaryl-N1-substituted-1,2,3-triazoles 
     
       
                 
         
             
             
         
      
     
     First, as shown in Scheme 1, diaryl acetylenes (such as di-4-chlorophenyl acetylenes) and azides (such as N 3 CH 2 COO n Bu and N 3 CH 2 CON(CH 2 ) 5 ) were added to benzene in the presence of RuCpCl(PPh 3 ) 3 , and refluxed to synthesize 4,5-diaryl-N1-substituted-1,2,3-triazoles under Ru-catalyzed cyclization reaction. The yield of the reaction was about from 75% to 80%. Table 1 lists derivatives of 4,5-diaryl-N1-substituted-1,2,3-triazoles, synthesized from different starting materials according to Scheme 1. 
     In addition, the affinity of test compounds of this invention toward CB1 and CB2 receptors was determined by competitive radioligand binding assays in vitro. This method differentiates the binding strength between compounds by their abilities in displacing a receptor-specific radioactive ligand. Compounds with higher affinity than the radioactive ligand displace the specific radioactive ligand and bind to the receptors, while compounds with no affinity or lower affinity than the radioactive ligand do not. The readings of the radioactivity retained allow further analysis of receptor binding, and assist in predictions of the pharmacological activities of the test compounds. 
     In the assays, CB1 receptors are from human CB1 stably expressed cell lines, and CB2 receptors are from human CB2 stably expressed cell lines. For purification of membrane-enriched fractions, cells were scraped off from the culture dishes in ice-cold buffer A (50 mM Tris, 5 mM MgCl 2 , 2.5 mM EDTA, pH 7.4, 10% sucrose) with 1 mM PMSF. After sonication, the membrane-enriched fractions were centrifuged for 15 minutes at 2,000×g at 4° C. The supernatant was centrifuged again for 30 minutes at 43,000×g at 4° C. The final pellet was re-suspended in buffer A and stored at −80° C. The protein concentration of the purified membrane was determined by the Bradford method as described by the manual provided by Bio-Rad Laboratories, Inc., Hercules, Calif. 
     During the receptor binding experiments, 0.2˜8 μg of membrane fractions were incubated with 0.75 nM [ 3 H]CP55,940 and a test compound in the incubation buffer of 50 mM Tris-HCl, 5 mM MgCl 2 , 1 mM EDTA, 0.3% BSA, pH 7.4. The non-specific binding was determined by using 1 μM of CP55,940. The mixture was incubated for 1.5 hours at 30° C. in Multiscreen microplates (Millipore, Billerica, Mass.). At the completion of the incubation, the reaction was terminated by Manifold filtration and washed with ice-cold wash buffer (50 mM Tris, pH 7.4, 0.25% BSA) four times. The radioactivity bound to the filters was measured by Topcount (Perkin Elmer Inc.). IC 50  values were calculated based on the concentration of the compounds required to inhibit 50% of the binding of [ 3 H]CP55,940. 
     The activities of the compounds were determined by DELFIA GTP-binding kit (Perkin Elmer Inc., Boston, Mass.). The DELFIA GTP-binding assay is a time-resolved fluorometric assay based on GDP-GTP exchange on G-protein subunits followed by activation of a G protein-coupled receptor by its agonists. Eu-GTP was used to monitor agonist-dependent activation of G protein. Note that stimulation of CB1 receptors by CP55,940 leads to the replacement of GDP by GTP on the α-subunit of G protein. The resultant GTP-Gα complex represents the activated form of G protein. Eu-GTP, a non-hydrolysable analogue of GTP, is used to quantify the amount of activated G protein (Peltonen et al., Eur. J. Pharmacol. (1998) 355:275). 
     CB1 containing membrane fraction as described above was diluted in the assay buffer (50 mM HEPES, pH 7.4, 100 mM NaCl, 100 μg/mL saponin, 5 mM MgCl 2 , 2 μM GDP, 0.5% BSA) and added to the wells of AcroPlates (Pall Life Sciences, Ann Arbor, Mich.). After addition of a test compound (various concentrations in 0.1% DMSO) and CP55,940 (20 nM in the assay buffer), the assay plate was incubated in the dark at 30° C. with slow shaking for 60 minutes. Eu-GTP was added to each well and the plate was incubated for another 35 minutes at 30° C. in the dark. The assay was terminated by washing the plate four times with a wash solution provided in the assay kit. Binding of the Eu-GTP was determined based on the fluorescence signal from a Victor 2 multi-label reader. The IC 50  value (i.e., 50% inhibition of CP55,940-stimulated Eu-GTP binding) for each test compound was determined by a concentration-response curve using nonlinear regression (Prism; GraphPad, San Diego, Calif.). 
     The results of the above-mentioned assay are summarized in Table 1. 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                   
                   
                   
                 CB1 
               
               
                   
                   
                   
                 Inhibition (%) 
               
               
                 No. 
                 Compound 
                 M.w. 
                 (10 μM) b   
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 335.40 
                 40.8% 
               
               
                   
               
               
                 2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 334.41 
                 22.6% 
               
               
                   
               
               
                 3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 346.43 
                 26.6% 
               
               
                   
               
               
                 4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 259.30 
                  9.6% 
               
               
                   
               
               
                 5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 362.47 
                 18.0% 
               
               
                   
               
               
                 6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 473.18 
                 50.5% 
               
               
                   
               
               
                 7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 318.37 
                 15.4% 
               
               
                   
               
               
                 8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 361.44 
                 12.3% 
               
               
                   
               
               
                 9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 292.34 
                 21.1% 
               
               
                   
               
               
                 10 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 482.02 
                 20.3% 
               
               
                   
               
               
                 11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 414.10 
                 20.4% 
               
               
                   
               
               
                 12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 450.08 
                 30.7% 
               
               
                   
               
               
                 13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 259.30 
                 22.0% 
               
               
                   
               
               
                 14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 404.29 
                 64.1% 
               
               
                   
               
               
                 15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 369.42 
                 35.4% 
               
               
                   
               
               
                 16 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 415.32 
                 33.0% 
               
               
                   
               
               
                 17 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 484.21 
                 25.9% 
               
               
                   
               
               
                 18 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 382.41 
                 19.7% 
               
               
                   
               
               
                 19 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 404.29 
                 36.7% 
               
               
                   
               
               
                 20 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 418.32 
                 51.2% 
               
               
                   
               
               
                 21 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 440.27 
                 15.7% 
               
               
                   
               
               
                 22 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 371.38 
                 27.1% 
               
               
                   
               
               
                 23 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 473.17 
                 29.9% 
               
               
                   
               
               
                 24 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 349.40 
                 31.6% 
               
               
                   
               
               
                 25 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 446.40 
                 53.6% 
               
               
                   
               
               
                 26 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 460.40 
                 51.2% 
               
               
                   
               
               
                 27 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 363.60 
                 46.0% 
               
               
                   
               
               
                 28 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 432.34 
                 36.5% 
               
               
                   
               
               
                 29 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 393.44 
                 31.9% 
               
               
                   
               
               
                 30 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 365.43 
                 40.0% 
               
               
                   
               
               
                 31 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 360.41 
                 18.9% 
               
               
                   
               
               
                 32 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390.26 
                 28.3% 
               
               
                   
               
               
                 33 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 418.32 
                 24.6% 
               
               
                   
               
               
                 34 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 395.45 
                 45.9% 
               
               
                   
               
               
                 35 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 471.40 
                  46.00% 
               
               
                   
               
               
                 36 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 369.84 
                  35.20% 
               
               
                   
               
               
                 37 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 349.43 
                  26.50% 
               
               
                   
               
               
                 38 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390.52 
                  23.80% 
               
               
                   
               
               
                 39 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 502.73 
                  4.10% 
               
               
                   
               
               
                 40 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 403.40 
                  16.30% 
               
               
                   
               
               
                 41 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 380.40 
                  14.70% 
               
               
                   
               
               
                 42 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 341.43 
                  35.60% 
               
               
                   
               
               
                 43 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 360.45 
                  34.40% 
               
               
                   
               
               
                 44 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 393.44 
                  14.10% 
               
               
                   
               
               
                 45 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 489.40 
                  9.80% 
               
               
                   
               
               
                 46 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 438.70 
                  50.80% 
               
               
                   
               
               
                 47 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 449.80 
                  61.80% 
               
               
                   
               
               
                 48 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 353.40 
                  36.10% 
               
               
                   
               
               
                 49 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 517.50 
                  30.30% 
               
               
                   
               
               
                 50 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 503.40 
                  27.50% 
               
               
                   
               
               
                 51 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 475.40 
                  18.60% 
               
               
                   
               
               
                 52 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 364.40 
                  11.00% 
               
               
                   
               
               
                 53 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 493.19 
                  68.70% 
               
               
                   
               
               
                 54 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 473.18 
                 71.7% (&gt;10 uM) 
               
               
                   
               
               
                 55 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 466.79 
                  45.70% 
               
               
                   
               
               
                 56 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 466.79 
                  47.70% 
               
               
                   
               
               
                 57 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 501.23 
                  55.70% 
               
               
                   
               
               
                 58 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 487.21 
                  58.30% 
               
               
                   
               
               
                 59 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 515.26 
                  30.10% 
               
               
                   
               
               
                 60 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 484.21 
                  55.70% 
               
               
                   
               
               
                 61 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 451.47 
                  46.10% 
               
               
                   
               
               
                 62 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 493.19 
                  18.30% 
               
               
                   
               
               
                 63 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 363.45 
                  9.90% 
               
               
                   
               
               
                 64 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 486.18 
                  26.00% 
               
               
                   
               
               
                   a Displacement of specific [ 3 H]-CP55940 binding in HEK 293 cells stably transfected with human CB1 receptor. 
               
               
                   b Percent inhibition at 10 μM. 
               
             
          
         
       
     
     EXAMPLE 2 
     The synthesis of 4,5-diaryl-N2-substituted-1,2,3-triazoles 
     
       
                 
         
             
             
         
      
     
     First, as shown in the following Scheme 2, diarylacetylenes were reacted with sodium azide (a) in DMF at 170° C. for 3 to 4 hours to perform 1,3-dipolar cycloaddition reactions. The yield of the reaction was approximately from 75% to 88%. Subsequently, the resultant products, 4,5-diaryl-1,2,3-triazoles, of the abovementioned reaction and various isocyanates (b) (generating ureas) were added in THF in the presence of DMAP, and then refluxed for 1 to 2 hours to perform coupling reactions. The yield of the reaction was around from 20% to 90%. 
     
       
                 
         
             
             
         
      
     
     Alternatively, 4,5-diaryl-1,2,3-triazoles (for example 4,5-di-2,4-dichlorophenyl-1,2,3-triazole) were reacted with bromoacetate (such as BrCH 2 CO 2   n Bu) or bromoacetamide (such as BrCH 2 CON(CH 2 ) 5 ) by alkylation in THF in the presence of NaH and Bu 4 NI at room temperature for 1 hour, resulting in the mixture of 1-substituted and 2-substituted triazoles as shown in Scheme 3. Subsequently, 1- and 2-substituted triazoles were separated by column chromatography and then unmistakably identified by  1 H and  13 C NMR spectroscopy. The results showed that the ratio of 1- and 2-substituted triazoles was about 1/4 to 1/5, and the yield thereof was around from 63% to 66%. 
     Then, such 2-substituted triazoles (for example 2-(phenoxycarbonyl)methyl triazoles) as convenient precursors were further reacted with amines in toluene, and refluxed for 4 to 12 hours to synthesize amide derivatives of 2-substituted triazoles. The yield of the resulting products was approximately from 65% to 98%. 
     Table 2 lists derivatives of 4,5-diaryl-N2-substituted-1,2,3-triazoles, synthesized from different starting materials according to Schemes 2 and 3. Besides, the compounds listed in Table 2 were tested under the displacement ligand binding assay as described in Example 1, in comparison with SR141716A. The results of the assay are also summarized in Table 2. 
     
       
         
               
               
             
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
             
             
               
                 No. 
                 Compound 
               
               
                   
               
             
          
           
               
                 65 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 66 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 67 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 68 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 69 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 70 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 71 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 72 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 73 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 74 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 75 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 76 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 77 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 78 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 79 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 80 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 81 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 82 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 83 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 84 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 85 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 86 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 87 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 88 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 89 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 90 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 91 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 92 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 93 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 94 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 95 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 96 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 97 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 98 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 99 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 100 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 101 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 102 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 103 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 104 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 105 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 106 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 107 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 108 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 109 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 110 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 111 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 112 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 113 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 114 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 115 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 116 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 117 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 118 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 119 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 120 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 121 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 122 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 123 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 124 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 125 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 126 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 127 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 128 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 129 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 130 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 131 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 132 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 133 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 134 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 135 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 136 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 137 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 138 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 139 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 140 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 141 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 142 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 143 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 144 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 145 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 146 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 147 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 148 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 149 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 150 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 151 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 152 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 153 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 154 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 155 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 156 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 157 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 158 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 159 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 160 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 161 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 162 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 163 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 164 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 165 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 166 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 167 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 168 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 169 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 170 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 171 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 172 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 173 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 174 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 175 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 176 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 177 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 178 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 179 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 180 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 181 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 182 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 183 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 184 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 185 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 186 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 187 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 188 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 189 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 190 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 191 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 192 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 193 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 194 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 195 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 196 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 197 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 198 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 199 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 200 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 201 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 202 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 203 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 204 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 205 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 206 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 207 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 208 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                 SR141716A 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 CB1 
                   
                   
                   
               
               
                   
                   
                   
                 Inhibition 
                 CB1 
                 CB1 
                 CB2 
               
               
                   
                   
                   
                 (%) 
                 IC50 
                 EC50 
                 IC50 
               
               
                   
                 No. 
                 M.w. 
                 (10 μM) b   
                 (nM) a   
                 (nM) c   
                 (nM) 
               
               
                   
                   
               
             
          
           
               
                   
                 65 
                 325.36 
                 11.4 
               
               
                   
                 66 
                 305.37 
                 32.1 
               
               
                   
                 67 
                 359.81 
                 13.1 
               
               
                   
                 68 
                 443.20 
                 24.2 
               
               
                   
                 69 
                 439.30 
                 9.9 
               
               
                   
                 70 
                 394.25 
                 16.2 
               
               
                   
                 71 
                 437.32 
                 3.6 
               
               
                   
                 72 
                 423.30 
               
               
                   
                 73 
                 492.18 
                 23.80 
               
               
                   
                 74 
                 484.21 
                 50.80 
               
               
                   
                 75 
                 514.28 
                 3.30 
               
               
                   
                 76 
                 506.21 
                 12.70 
               
               
                   
                 77 
                 486.22 
                 27.50 
               
               
                   
                 78 
                 508.18 
                 6.40 
               
               
                   
                 79 
                 443.71 
                 1.50 
               
               
                   
                 80 
                 415.32 
                 29.90 
               
               
                   
                 81 
                 417.33 
                 41.50 
               
               
                   
                 82 
                 445.38 
                 26.90 
               
               
                   
                 83 
                 374.26 
                 11.80 
               
               
                   
                 84 
                 416.34 
                 21.20 
               
               
                   
                 85 
                 430.37 
                 18.30 
               
               
                   
                 86 
                 403.31 
                 8.40 
               
               
                   
                 87 
                 431.36 
                 12.90 
               
               
                   
                 88 
                 472.20 
                 7.00 
               
               
                   
                 89 
                 500.25 
                 12.90 
               
               
                   
                 90 
                 437.75 
                 14.40 
               
               
                   
                 91 
                 506.21 
                 11.20 
               
               
                   
                 92 
                 516.20 
                 22.30 
               
               
                   
                 93 
                 449.76 
                 30.50 
               
               
                   
                 94 
                 451.78 
                 10.90 
               
               
                   
                 95 
                 465.80 
                 14.90 
               
               
                   
                 96 
                 479.83 
                 17.70 
               
               
                   
                 97 
                 484.21 
                 29.20 
               
               
                   
                 98 
                 514.27 
                 19.40 
               
               
                   
                 99 
                 486.22 
                 6.60 
               
               
                   
                 100 
                 415.32 
                 19.90 
               
               
                   
                 101 
                 417.33 
               
               
                   
                 102 
                 445.38 
                 15.70 
               
               
                   
                 103 
                 471.77 
                 23.40 
               
               
                   
                 104 
                 481.76 
                 11.80 
               
               
                   
                 105 
                 457.74 
                 18.60 
               
               
                   
                 106 
                 398.50 
                 4.80 
               
               
                   
                 107 
                 467.39 
                 19.70 
               
               
                   
                 108 
                 501.84 
                 34.50 
               
               
                   
                 109 
                 447.31 
                 58.10 
               
               
                   
                 110 
                 307.35 
                 59.10 
               
               
                   
                 111 
                 473.18 
                 90.30 
                 1173.2 ± 263.4 
                  486.4 ± 101.6 
                 &gt;10 μM 
               
               
                   
                 112 
                 404.29 
                 82.10 
                 2806.3 ± 300.9 
               
               
                   
                 113 
                 536.28 
                 78.90 
                 4496.8 ± 871.1 
               
               
                   
                 114 
                 466.79 
                 39.10 
               
               
                   
                 115 
                 501.23 
                 72.70 
                 4456.3 ± 698.0 
               
               
                   
                 116 
                 487.21 
                 76.50 
                 2795.9 ± 544.4 
               
               
                   
                 117 
                 515.26 
                 47.50 
               
               
                   
                 118 
                 438.73 
                 67.40 
               
               
                   
                 119 
                 498.23 
                 74.20 
               
               
                   
                 120 
                 484.21 
                 93.70 
                  168.9 ± 32.2 
                  122.0 ± 32.1 
                 5903.4 ± 763.5 
               
               
                   
                 121 
                 499.22 
                 70.30 
               
               
                   
                 122 
                 506.21 
                 99.30 
                  66.9 ± 8.9 
                  87.0 ± 17.0 
                 &gt;10 μM 
               
               
                   
                 123 
                 360.45 
                 11.60 
               
               
                   
                 124 
                 493.17 
                 14.30 
               
               
                   
                 125 
                 498.23 
                 91.40 
                  144.4 ± 110.0 
                  203.6 ± 112.3 
                 &gt;10 μM 
               
               
                   
                 126 
                 522.25 
                 102.30 
                  86.8 ± 1.0 
                  210.1 ± 77.3 
               
               
                   
                 127 
                 548.25 
                 89.40 
                 1243.8 ± 697.3 
               
               
                   
                 128 
                 947.31 
                 13.60 
               
               
                   
                 129 
                 449.76 
                 76.50 
                  587.2 ± 139.2 
                  185.0 ± 44.5 
               
               
                   
                 130 
                 415.32 
                 48.60 
               
               
                   
                 131 
                 486.18 
                 84.20 
                  71.9 ± 16.5 
                  143.2 ± 26.8 
               
               
                   
                 132 
                 550.26 
                 88.20 
                  294.9 ± 111.8 
                  753.7 ± 130.6 
               
               
                   
                 133 
                 626.36 
                 75.70 
                  759.6 ± 273.3 
               
               
                   
                 134 
                 580.29 
                 95.90 
                  806.2 ± 346.3 
                  223.1 ± 56.4 
               
               
                   
                 135 
                 611.26 
                 60.10 
               
               
                   
                 136 
                 612.35 
                 66.30 
               
               
                   
                 137 
                 566.26 
                 59.30 
               
               
                   
                 138 
                 463.79 
                   
                 1704.9 ± 424.8 
               
               
                   
                 139 
                 577.91 
               
               
                   
                 140 
                 545.84 
                   
                 1045.5 ± 256.3 
               
               
                   
                 141 
                 487.81 
                   
                   
                  365.5 ± 9.6 
               
               
                   
                 142 
                 464.78 
                 76.10 
                 1847.6 ± 1380.1 
               
               
                   
                 143 
                 591.91 
                 80.00 
                  788.5 ± 202.3 
                  952.8 ± 511.9 
               
               
                   
                 144 
                 619.97 
                 89.50 
                  140.1 ± 63.1 
                  440.6 ± 72.3 
               
               
                   
                 145 
                 520.24 
                 95.00 
                  251.6 ± 75.1 
                  157.0 ± 43.9 
               
               
                   
                 146 
                 536.24 
                 94.80 
                  81.9 ± 44.2 
                  56.2 ± 8.1 
                 &gt;10 μM 
               
               
                   
                 147 
                 492.18 
                 99.50 
                  251.1 ± 88.1 
                  136.2 ± 17.6 
                 &gt;10 μM 
               
               
                   
                 148 
                 485.79 
                 94.50 
                  591.6 ± 302.3 
                  48.2 ± 3.5 
               
               
                   
                 149 
                 501.79 
                 78.20 
                  684.5 ± 428.1 
                  331.8 ± 132.7 
               
               
                   
                 150 
                 506.21 
                 91.40 
                  703.7 ± 282.5 
                  277.4 ± 34.0 
               
               
                   
                 151 
                 515.78 
                 61.80 
                 5969.0 ± 2597.0 
               
               
                   
                 152 
                 540.66 
                 90.50 
                  711.0 ± 174.8 
                  244.2 ± 49.5 
               
               
                   
                 153 
                 540.66 
                 87.00 
                 1056.2 ± 655.8 
                  982.9 ± 140.2 
               
               
                   
                 154 
                 485.79 
                 95.20 
                  772.4 ± 446.3 
                  204.2 ± 60.7 
               
               
                   
                 155 
                 485.79 
                 85.00 
                  473.3 ± 299.7 
                  983.2 ± 19.4 
               
               
                   
                 156 
                 501.79 
                 69.50 
               
               
                   
                 157 
                 507.75 
                 95.20 
                  217.1 ± 86.6 
                  122.7 ± 42.8 
               
               
                   
                 158 
                 539.76 
                 92.50 
                  302.4 ± 132.5 
                  237.0 ± 70.4 
               
               
                   
                 159 
                 506.2113 
                 87.30 
                  364.8 ± 160.2 
                  132.8 ± 52.7 
               
               
                   
                 160 
                 489.76 
                 88.20 
                  262.2 ± 183.7 
                  256.1 ± 98.7 
                 &gt;10 μM 
               
               
                   
                 161 
                 489.76 
                 87.70 
                  529.5 ± 143.9 
                  346.7 ± 45.6 
               
               
                   
                 162 
                 489.76 
                 90.50 
                  449.2 ± 67.9 
                  235.2 ± 28.8 
                 &gt;10 μM 
               
               
                   
                 163 
                 497.80 
                 76.60 
                 2072.5 ± 186.0 
                  501.9 ± 182.6 
               
               
                   
                 164 
                 531.82 
                 82.10 
                 2831.0 ± 377.8 
                 4031.8 ± 397.3 
               
               
                   
                 165 
                 507.75 
                 89.80 
                  151.5 ± 71.0 
                  70.3 ± 0.5 
                 &gt;10 μM 
               
               
                   
                 166 
                 507.75 
                 88.30 
                   
                  265.2 ± 53.6 
               
               
                   
                 167 
                 477.81 
                 92.10 
                   
                  431.9 ± 184.5 
               
               
                   
                 168 
                 471.77 
                 93.90 
                  203.5 ± 78.1 
                  216.3 ± 60.7 
                 &gt;10 μM 
               
               
                   
                 169 
                 503.78 
                   
                   
                  357.0 ± 81.1 
               
               
                   
                 170 
                 524.20 
                   
                  25.7 ± 2.9 
                  35.1 ± 22.2 
                 &gt;10 μM 
               
               
                   
                 171 
                 524.20 
                   
                  11.6 ± 3.4 
                  50.7 ± 11.8 
                 &gt;10 μM 
               
               
                   
                 172 
                 844.40 
                   
                   
                 &gt;10 μM 
               
               
                   
                 173 
                 524.20 
                   
                  19.3 ± 3.5 
                  23.5 ± 11.2 
               
               
                   
                 174 
                 501.79 
                   
                   
                  947.3 ± 207.4 
               
               
                   
                 175 
                 539.76 
                   
                   
                  549.2 ± 90.8 
               
               
                   
                 176 
                 477.81 
                   
                   
                  126.7 ± 49.6 
               
               
                   
                 177 
                 511.83 
                   
                   
                 1190.3 ± 275.2 
               
               
                   
                 178 
                 554.90 
                   
                   
                 1079.4 ± 157.2 
               
               
                   
                 179 
                 539.76 
                   
                   
                 1013.6 ± 118.8 
               
               
                   
                 180 
                 479.79 
                   
                   
                 6822.8 ± 1254.3 
               
               
                   
                 181 
                 574.21 
                   
                   
                  55.3 ± 24.1 
               
               
                   
                 182 
                 574.21 
                   
                   
                  37.0 ± 17.1 
               
               
                   
                 183 
                 574.21 
                   
                   
                  67.5 ± 6.1 
               
               
                   
                 184 
                 542.19 
                   
                  22.0 ± 6.1 
                  22.0 ± 6.1 
                 &gt;10 μM 
               
               
                   
                 185 
                 542.19 
                   
                   
                  15.6 ± 3.4 
               
               
                   
                 186 
                 540.66 
                   
                   
                  12.2 ± 5.4 
               
               
                   
                 187 
                 540.66 
                   
                   
                  17.8 ± 6.7 
               
               
                   
                 188 
                 520.24 
                   
                  51.7 ± 15.5 
                  27.6 ± 18.7 
                 &gt;10 μM 
               
               
                   
                 189 
                 487.77 
                   
                   
                 3967.5 ± 1521.4 
               
               
                   
                 190 
                 542.19 
                   
                  45.9 ± 18.4 
                  15.6 ± 3.4 
                 &gt;10 μM 
               
               
                   
                 191 
                 540.66 
                   
                  48.9 ± 12.0 
                  12.2 ± 5.4 
                 &gt;10 μM 
               
               
                   
                 192 
                 540.66 
                   
                  64.8 ± 10.5 
                  17.8 ± 6.7 
                 &gt;10 μM 
               
               
                   
                 193 
                 520.24 
                   
                  51.7 ± 15.5 
                  27.6 ± 18.7 
                 &gt;10 μM 
               
               
                   
                 194 
                 536.01 
                   
                   
                  126.5 ± 18.5 
               
               
                   
                 195 
                 571.93 
                   
                   
                  119.6 ± 1.6 
               
               
                   
                 196 
                 534.02 
                   
                  124.7 ± 23.1 
                   
                 &gt;10 μM 
               
               
                   
                 197 
                 564.03 
                   
                   
                  212.8 ± 79.0 
               
               
                   
                 198 
                 542.19 
                   
                  82.9 ± 7.0 
                  80.3 ± 24.6 
                 &gt;10 μM 
               
               
                   
                 199 
                 536.24 
                   
                   
                  258.5 ± 52.9 
               
               
                   
                 200 
                 575.10 
                   
                   
                  209.2 ± 78.7 
               
               
                   
                 201 
                 520.24 
                   
                   
                  141.6 ± 13.0 
               
               
                   
                 202 
                 520.24 
                   
                  48.0 ± 11.1 
                  34.9 ± 13.9 
                 &gt;10 μM 
               
               
                   
                 203 
                 512.26 
                   
                   
                  301.9 ± 66.8 
               
               
                   
                 204 
                 512.26 
                   
                   
                  111.3 ± 27.9 
               
               
                   
                 205 
                 520.24 
                   
                   
                   5.8 ± 1.5 
               
               
                   
                 206 
                 534.26 
                   
                   
                  99.9 ± 6.9 
               
               
                   
                 207 
                 485.79 
                   
                   
                  29.5 ± 5.6 
               
               
                   
                 208 
                 499.82 
               
               
                   
                   
                   
                   
                  15.0 ± 1.8 
                  18.2 ± 9.5 
                   1.9 ± 0.1 μM 
               
               
                   
                   
               
               
                   
                   a Displacement of specific [ 3 H]-CP55940 binding in HEK 293 cells stably transfected with human CB1 receptor. 
               
               
                   
                   b Percent inhibition at 10 μM. 
               
               
                   
                   c Fuctional activity (EC 50 ) determined by inhibition of Eu-GTP binding to hCB1 transfected HEK 293 membrane. 
               
             
          
         
       
     
     As shown in Tables 1 and 2, the compounds with an additional methylene group between the triazole and the carbonyl moiety have good antagonist efficacy to the CB1 receptor. Particularly, insertion of a methylene group can change the distance, disrupt the conjugation between the carbonyl group and the 1,2,3-triazole of ureas, and then make the orientation of the carbonyl group more flexible for interaction with Lys192-Asp366 residues of the CB1 receptor. Hence, the compounds inserted with a methylene group have good affinity to the CB1 receptor and can serve as CB1 antagonists. 
     In addition, the compounds, which are halogenated benzyl amides, exhibit excellent antagonist efficacy. These amide compounds were further tested in the affinity to the CB2 receptor, and the results showed that they have very low affinity to CB2 receptor. Such very low affinity means these amide compounds possess great selectivity between CB1 and CB2 receptors, and such a characteristic of CB1/CB2 selectivity is quite unusual among conventionally reported antagonists. 
     In conclusion, the 1,2,3-triazole derivatives of the present invention can be used as effective CB1 antagonists and have good selectivity of CB1 receptors over CB2 receptors. 
     Although the present invention has been explained in relation to its preferred embodiment, it is to be understood that many other possible modifications and variations can be made without departing from the scope of the invention as hereinafter claimed.