WO2012134231A2 - Dérivé de benzamide utilisable en tant qu'antagoniste du récepteur des cannabinoïdes (cb1) - Google Patents

Dérivé de benzamide utilisable en tant qu'antagoniste du récepteur des cannabinoïdes (cb1) Download PDF

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WO2012134231A2
WO2012134231A2 PCT/KR2012/002405 KR2012002405W WO2012134231A2 WO 2012134231 A2 WO2012134231 A2 WO 2012134231A2 KR 2012002405 W KR2012002405 W KR 2012002405W WO 2012134231 A2 WO2012134231 A2 WO 2012134231A2
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phenyl
chloro
methoxy
fluoro
dichloro
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PCT/KR2012/002405
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Korean (ko)
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WO2012134231A3 (fr
WO2012134231A9 (fr
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이현규
최은복
양희철
김광록
장택수
오정택
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한국화학연구원
주식회사종근당
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Publication of WO2012134231A2 publication Critical patent/WO2012134231A2/fr
Publication of WO2012134231A9 publication Critical patent/WO2012134231A9/fr
Publication of WO2012134231A3 publication Critical patent/WO2012134231A3/fr

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    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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Definitions

  • the present invention relates to novel benzamide compounds that act as inverse agonists or antagonists of cannabinoid CB1 receptors.
  • Obesity refers to a condition in which fat, especially abdominal fat, is excessively accumulated in the human body and is medically defined as a body mass index (BMI) of 30 or more.
  • BMI body mass index
  • WHO World Health Organization
  • Obesity is caused by a number of causes, but commonly causes various adult diseases such as hypertension, diabetes, hyperlipidemia, arteriosclerosis, fatty liver, gallstones, arthritis, pulmonary dysfunction, women's disease, breast cancer, endometritis, and the like.
  • Obesity is one of the biggest causes of metabolic syndrome, including vascular diseases such as diabetes, hypertension, hyperlipidemia, and atherosclerosis. It is one of the biggest problems in modern medicine [Ref: al et al, 1999 , JAMA, 282: 1523-1529, Calle et al, 1999, N. Engl. J. Med. 341: 1097-1105.
  • Obesity is a chronic disease that is difficult to cure with short-term diet or exercise alone and requires additional medication.
  • CB1 and CB2 Two different subtypes of cannabinoid receptors (CB1 and CB2) have been isolated, all of which belong to the G protein binding receptor superfamily.
  • the cannabinoid receptor CB1R together with the CB2R and endocannabinoid ligands (endocanabinoid: ex. Anandamide, 2-AG, etc.), constitutes an endocannabinoid system that plays an important role in maintaining energy homeostasis.
  • CB1R is mainly distributed in the central nervous system, including the brain of mammals including humans, and is known to be involved in energy metabolism and appetite control.
  • CB2R is mainly distributed in peripheral tissues, especially immune cells, and is involved in various inflammation expressions including pain. [Ref .: Marzo, Nat. Rev.
  • An object of the present invention is to provide a novel benzamide compound or a pharmaceutically acceptable salt thereof, which can act as an agonist or antagonist of the cannabinoid CB1 receptor, which can be usefully used for the prevention or treatment of obesity and obesity-related metabolic diseases. will be.
  • Another object of the present invention is to provide a method for preparing the compound.
  • Another object of the present invention to provide a composition for the prevention or treatment of obesity and obesity-related metabolic diseases containing the compound as an active ingredient.
  • the present invention provides a benzamide derivative compound of Formula 1 or a pharmaceutically acceptable salt thereof and a method of preparing the same.
  • a and B are each independently hydrogen, halogen, (C1-C20) alkyl, (C3-C20) cycloalkyl, -CH 2 -triazole, -CH 2 -imidazole, OR 6 , CO 2 R 7 , CF 3 , OCF 3 , cyano or nitro group;
  • X is -O- or -S-;
  • R 1 and R 2 are each independently hydrogen, (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl, (C 2 -C 20) alkenyl, (C 2 -C 20) alkynyl,-(CH 2 ) a -Ar ,-(CH 2 ) b -HetAr, -SO 2 -R 8 , , , , or ego;
  • R One and R 2 Can form the following ring structure with N;
  • D is OR 11, SR 12 , NR 13 R 14 , CO 2 R 15 , or CN;
  • E is CH 2 , O, S, SO, SO 2 , or NR 16 ;
  • J, K are each independently hydrogen, halogen, (C1-C20) alkyl, (C3-C20) cycloalkyl,-(CH 2 ) g -OR 21 , CO 2 R 22 , NR 23 R 24 , CONR 25 R 26 , CN, NO 2 , CF 3 , or OCF 3 ;
  • R A , R B , R C , R D are independently hydrogen, halogen, (C1-C20) alkyl, (C3-C20) cycloalkyl,-(CH 2 ) h -Ar,-(CH 2 ) i -OR 27 , CO 2 R 28 , CN, NO 2 , CF 3 , or OCF 3 ;
  • R 3 is hydrogen, halogen or (C 1 -C 5) alkyl
  • R 4 , R 5 are each independently (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl,-(CH 2 ) j -Ar or-(CH 2 ) k -HetAr;
  • R 6 , R 7 are each independently hydrogen, (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl;
  • R 8 is (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl, or — (CH 2 ) 1 -Ar;
  • Ar is ego
  • HetAr is selected from the following structures
  • P and Q are each independently hydrogen, halogen, (C1-C20) alkyl, (C3-C20) cycloalkyl, -CH 2 -triazole, -CH 2 -imidazole, OR 31 , CO 2 R 32 , CF 3 , OCF 3 , cyano or nitro group;
  • R 11 to R 17 , R 21 to R 28 , R 31 and R 32 are each independently hydrogen, (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl;
  • a to d, g to l are each an integer of 0 to 2;
  • e and f are each an integer of 0-5.
  • the substituents that may be substituted for R 1 to R 8 , R 11 to R 17 , R 21 to R 28 , R 31, and R 32 may be each independently hydrogen, halogen, (C 1 -C 10) alkyl, or halogen substituted ( C1-C10) alkyl, (C6-C30) aryl, (C3-C30) cycloalkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, cyano, carbazolyl, carboxyl, nitro or hydroxy It is characterized in that at least one selected from the group consisting of.
  • Substituents comprising the "alkyl” and “alkyl” moieties described in this invention include both straight and pulverized forms, and "cycloalkyl” is not only a monocyclic system, but also like adamantyl or (C7-C30) bicycloalkyl It also includes several ring hydrocarbons.
  • the invention should also be understood to include pharmaceutically acceptable salts of compounds according to the invention, and addition salts such as hydrochloride, hydrobromide or trifluoroacetic acid salts, and sodium, potassium and magnesium salts.
  • the invention should also be understood to include pharmaceutically acceptable salts of compounds according to the invention, and addition salts such as hydrochloride, hydrobromide or trifluoroacetic acid salts, and sodium, potassium and magnesium salts.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemate and optically active forms. All such compounds and enantiomers are included within the scope of the present invention.
  • compositions comprising a compound as defined above and a pharmaceutically acceptable carrier or adjuvant.
  • composition is derived from or in combination with, or in combination with, any two or more components of a product as well as a product comprising the active ingredient and an inert ingredient (pharmaceutically acceptable excipient) which constitutes the carrier. Any product resulting from dissociation of the above components or from other types of reactions or interactions of one or more components.
  • pharmaceutical compositions of the present invention include all compositions prepared by admixing a compound of formula 1, an additional active ingredient, with a pharmaceutically acceptable carrier.
  • obesity-related metabolic disease refers to a chronic disease that requires treatment to reduce excessive health risk factors associated with obesity, such as type 2 diabetes, angina, hypertension and congestive heart failure.
  • Cardiovascular diseases such as hyperlipidemia, thrombolytic disorders.
  • disease associated with the regulation of CB1 receptors refers to diseases that can be treated and prevented by the regulation of CB1 receptors. These diseases include anxiety disorders, psychosis, schizophrenia, mental disorders including depression, substance abuse disorders such as abuse or dependence of substances including alcohol dependence and nicotine dependence, memory and cognitive disorders, senile dementia, Alzheimer's disease, eating disorders , Cardiovascular diseases such as obesity, type II diabetes or non-insulin dependent diabetes mellitus (NIDD), angina pectoris, hypertension and congestive heart failure, hyperlipidemia, thrombolytic disorders.
  • NIDD non-insulin dependent diabetes mellitus
  • 'diseases associated with the modulation of CB1 receptors' are associated with abuse or dependence of substances including eating disorders, obesity, type II diabetes or non-insulin dependent diabetes mellitus (NIDD), neuroinflammation, diarrhea, alcohol dependence and nicotine dependence. It is about.
  • NIDD non-insulin dependent diabetes mellitus
  • the 'disease associated with the modulation of the CB1 receptor' relates to abuse or dependence of substances including eating disorders, obesity, type II diabetes or non-insulin dependent diabetes mellitus (NIDD), alcohol dependence and nicotine dependence, In particular obesity is most preferred.
  • substances including eating disorders, obesity, type II diabetes or non-insulin dependent diabetes mellitus (NIDD), alcohol dependence and nicotine dependence, In particular obesity is most preferred.
  • NIDD non-insulin dependent diabetes mellitus
  • compositions of the invention can be administered orally, intramuscularly and subcutaneously.
  • Formulations for oral administration can be prepared in various forms such as syrups, tablets, capsules, creams and lozenges.
  • the syrup formulation may contain any sweetening or coloring agent, together with one or more liquid carriers selected from ethanol, peanut oil, olive oil, glycerin or water and the compounds according to the invention or salts thereof.
  • any of the pharmaceutical carriers generally used for the preparation of solid dosage forms can be used. Examples of such carriers include magnesium stearate, calcium sulfate, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose.
  • any of the general encapsulation processes may be used, for example incorporating the aforementioned carriers into the hard gelazine capsule shell.
  • any of the pharmaceutical carriers commonly used in the preparation of dispersions or suspensions may be used, such as aqueous gums, celluloses, silicates or oils. have.
  • Formulations for intramuscular or subcutaneous administration are in the form of solutions, suspensions and emulsions comprising aqueous solvents such as water, saline and Ringer's solution and lipophilic solvents such as fatty oils, sesame oil, corn oil and synthetic fatty acid esters. Can be prepared.
  • aqueous solvents such as water, saline and Ringer's solution
  • lipophilic solvents such as fatty oils, sesame oil, corn oil and synthetic fatty acid esters.
  • the pharmaceutical composition is preferably formulated in a form suitable for the patient.
  • Each unit dose of the formulation for oral administration suitably contains 0.1 to 500 mg / kg, preferably 1 to 100 mg / kg of the compound of formula 1 or a pharmaceutically acceptable salt thereof.
  • the compound of formula 1 or a pharmaceutically acceptable salt thereof, as an active ingredient may be administered 1 to 6 times in an amount of 0.01 to 40 mg / kg body weight per day, depending on the condition of the patient.
  • the compounds of formula 1 and their pharmaceutically acceptable salts can be used as medicaments, such as medicaments in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They are for example orally such as in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions, rectally for example in the form of suppositories, parenterally such as in the form of injection solutions or infusion solutions, or topically. In the form of ointments, creams or oils, for example. Oral administration is preferred.
  • the preparation of pharmaceutical preparations may be carried out by combining the compound of Formula 1 or a pharmaceutically acceptable salt thereof, optionally with other therapeutically important substances, in a preferred nontoxic inert pharmaceutically compatible solid or liquid carrier. It can be carried out in a manner familiar to those skilled in the art by formulating a galenose formulation dosage form with the substance and, if desired, conventional pharmaceutical auxiliaries.
  • the carrier material is acceptable as well as inorganic carrier material. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatin capsules.
  • Suitable carrier materials for soft gelatin capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (which are necessary for soft capsules, although the carrier may not be necessary depending on the nature of the active ingredient).
  • Preferred carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like.
  • Preferred carriers for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils.
  • Suitable carrier materials for suppositories are, for example, natural or light oils, waxes, fats and semi-liquid or liquid polyols.
  • Preferred carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
  • Conventional stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavor-improving agents, salts for osmotic pressure changes, buffer materials, solubilizers, coloring and masking agents, and antioxidants are contemplated as pharmaceutical auxiliaries.
  • the dosage of the compound of formula 1 may vary within wide ranges depending on the disease, age and patient's individual condition and mode of administration, and will naturally be adjusted to the individual requirements in each particular case. For adults, a daily dosage of about 0.1 to 500 mg / kg, especially about 1 to 100 mg / kg, is contemplated. Depending on the severity of the disease and the exact pharmacokinetic profile, the compounds may be administered in one daily dosage unit or in several daily dosage units, such as one to three dosage units.
  • the pharmaceutical preparations conveniently contain about 0.1 to 500 mg / kg, preferably 1 to 100 mg / kg of the compound of formula (1).
  • Benzamide derivative (4) according to the present invention can be prepared as shown in the following scheme.
  • Compound 2 is hydrolyzed to synthesize carboxylic acid (3).
  • Carboxylic acid 3 is activated with acid chloride, active easter or mixed anhydride in a conventional manner and then reacted with HNR 1 R 2 to synthesize 4.
  • Compound 4 can also be synthesized by reacting carboxylic acid (3) with HNR 1 R 2 in the presence of binding reagents (DCC, EDC, BOP, HMPU).
  • Amide derivatives 8 according to the invention can be prepared as shown in Scheme 2 below.
  • the aniline compound (10) can be obtained by reducing the nitro compound (9) by a conventional method.
  • the amide compound (8) can be synthesized using aniline compound (10) and carboxylic acid (11) using binding reagents (DCC, EDC, BOP, HMPU).
  • the aryl urea derivative 12 according to the present invention can be prepared as shown in Scheme 3 below.
  • Isocyanate compound (13) can be synthesized from benzoic acid (3) via Curtius rearrangement. That is, compound (3) can be converted to an acid azide compound by a conventional method, and then heated to synthesize an isocyanate compound (13), which can be reacted with an amine (R 1 R 2 NH) to synthesize urea compound (12). have.
  • the urea compound (12) can also be synthesized by condensing aniline compound 10 and carbamoyl chloride compound 14 in the presence of a base, as shown in Scheme 4 below.
  • L is Cl, Br, I, OTs or OMs
  • R 1 , R 2 , R 3 , R 4 , and R 5 are the same as above, and R 'is a (C1-C20) alkyl or (C3-C20) cycloalkyl group.
  • the benzamide compound of formula 1 or a pharmaceutically acceptable salt thereof according to the present invention has an excellent inhibitory effect on cannabinoid receptor 1 (CB1). Therefore, the pharmaceutical composition comprising as an active ingredient a benzamide compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention is expected to have an excellent effect in the prevention or treatment of obesity or obesity-related metabolic diseases.
  • 1 shows a screening system of CHO-CB1- # 37 cells.
  • FIG. 2 is a diagram illustrating a 96well plate screening system.
  • 3 is a graph of the IC 50 value of the compound rimonabant used as a control agent.
  • HBTU O-benzotriazol-1-yl-N, N, N, N-tetramethyluronium hexafluorophosphate
  • NMM N-methyl morpholine
  • ether diethyl ether
  • brine means saturated aqueous NaCl solution.
  • temperatures are all in degrees Celsius. All reactions were carried out under inert atmosphere at room temperature unless otherwise noted, and all solvents were used with the highest purity unless otherwise noted.
  • Mass spectra were obtained using one of the following instruments [Micromass, Quattro LC Triple Quadruple Tandem Mass Spectometer, ESI or Agilent, 1100LC / MSD, ESI].
  • Flash column chromatography analysis was performed using Merck silica gel 60 (230-400 mesh). Most reactions are thin layer chromatography using E. Merck 0.25 mm silica gel plates (60F-254) and UV detection using 5% ethanolic phosphomolybdic acid or p-anisaldehyde solution. Monitoring by graphy.
  • Step 1 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid methyl ester
  • Step 2 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid
  • step 3 It was synthesized according to Example 1 (step 3, method 2) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and cyclohexyl amine. .
  • Example 1 (Step 3, Method 2 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and N-ethyl-N-propyl amine )
  • Example 1 (Step 3, Method 2) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 1-amino adamantane Thus synthesized.
  • step 3 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and N-amino morpholine Synthesized.
  • step 3 It was synthesized according to Example 1 (step 3, method 2) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and isobutyl amine. .
  • Example 1 (step 3, method from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-trifluoromethyl-benzyl amine It synthesize
  • Example 1 (Step 3, Method 2) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and N-amino piperidine Thus synthesized.
  • Example 1 (Step 3, Method 2 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-hydroxy-cyclohexyl amine )
  • Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 1-hydroxymethyl-2-methyl-propyl amine 3, method 2).
  • Example 1 (Step 3, Method 2) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and N-sec-butyl amine Thus synthesized.
  • Example 1 (Step from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-dimethylamino-1-methyl-ethyl amine 3, method 2).
  • step 3 It was synthesized according to Example 1 (step 3, method 2) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and thiomorpholine. .
  • Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-2-methyl-propanoic acid methylester 3, method 2).
  • Example 1 (Step 3, Method 2) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-methyl-piperazine Thus synthesized.
  • Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-hydroxy-1,1-dimethyl-ethyl amine It synthesize
  • step 3 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-aminomethyl pyridine Synthesized.
  • step 3 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 3-aminomethyl pyridine Synthesized.
  • step 3 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-aminomethyl pyridine Synthesized.
  • Example 1 (Step 3, Method 2 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-hydroxy-piperidine )
  • Example 1 (Step 3, Method 2 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 3-hydroxy-piperidine )
  • Example 25 1- ⁇ 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -piperidin-4-one
  • Example 1 (Step 3, Method 2) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-oxo-piperidine According to the synthesis.
  • Example 26 1- ⁇ 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -piperidine-4-carboxylic acid methyl ester
  • Example 1 (Step 3, from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-methoxycarbonyl-piperidine It synthesize
  • Example 27 ⁇ 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl ⁇ -(1,1-dioxo-thiomorpholine- 4-day) -methanone
  • Example 1 (Step 3, Method 2 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-dioxo-thiomorpholine )
  • Example 28 1- ⁇ 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -piperidine-3-carboxylic acid ethyl ester
  • Example 1 (Step 3, from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 3-ethoxycarbonyl-piperidine It synthesize
  • Example 29 1- ⁇ 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -piperidine-2-carboxylic acid ethyl ester
  • Example 1 (Step 3, from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-ethoxycarbonyl-piperidine It synthesize
  • Example 30 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N- (2-hydroxy-1, 1-bis-hydro Oxymethyl-ethyl) -benzamide
  • Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and tris (hydroxymethyl) methyl amine )
  • Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-4-methyl-pentanoic acid tert-butyl ester It synthesize
  • Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-3-methyl-butanoic acid ethyl ester 3, method 2).
  • Example 1 (step 3, method from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-acetic acid tert-butyl ester It synthesize
  • Example 36 1- ⁇ 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -pyrrolidine-2-carboxylic acid methyl ester
  • Example 1 (Step 3, from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and pyrrolidine-2-carboxylic acid methyl ester Synthesis was carried out according to method 4).
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-propionic acid benzyl ester According to the synthesis.
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-acetic acid ethyl ester According to the synthesis.
  • Example 1 (Step 3 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-succinic acid 1-tert-butyl ester , According to Method 4).
  • Example 1 (Step 3, from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-pentanedioic acid diethyl ester Synthesis was carried out according to method 4).
  • Example 1 (Step 3 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-3-phenyl-propionic acid methyl ester , According to Method 4).
  • Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-3-phenyl-propionic acid tert-butyl ester Synthesis was carried out according to step 3, method 4).
  • Example 1 (Step from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-3-hydroxy-propionic acid methylester 3, method 4).
  • Example 45 1- ⁇ 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -pyrrolidine-2-carboxylic acid tert- Butyl ester
  • Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-3-hydroxy-butyl acid methyl ester Synthesis was carried out according to step 3, method 4).
  • Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 3-hydroxy-pyrrolidine )
  • Example 1 (Step 3, Method) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-hydroxymethyl-pyrrolidine It synthesize
  • Example 1 (Step 3, Method 4 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and pyrrolidine-2-carboxylic acid )
  • Example 1 (Step 3, from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-3-methyl-butanoic acid Synthesis was carried out according to method 4).
  • Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and thiazolidine-2-carboxylic acid )
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and thiazolidine-4-carboxylic acid )
  • Example 56 1- ⁇ 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -pyrrolidine-2-carboxylic acid sodium salt
  • Example 57 (step 2) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and tert-butyl amine )
  • Example 57 (step from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and N-propazyl amine It synthesize
  • Example 57 (step 2) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and morpholine Thus synthesized.
  • Example 65 ⁇ 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoylamino ⁇ -acetic acid tert-butyl ester
  • Example 57 (step from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and 3-hydroxy proline It synthesize
  • Example 70 1- ⁇ 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -pyrrolidine-2-carboxylic acid amide
  • Example 72 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N- (2-hydroxy-1, 1-dimethyl-ethyl)- Benzamide
  • Example 74 1- ⁇ 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -pyrrolidine-2-carboxylic acid ethyl ester
  • Example 75 1- ⁇ 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -pyrrolidine-2-carboxylic acid isopropyl ester
  • Example 80 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N, N-bis- (2-hydroxy-ethyl) -benzamide
  • Example 81 1- ⁇ 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -piperidine-3-carboxylic acid ethyl ester
  • Example 82 1- ⁇ 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -piperidine-2-carboxylic acid ethyl ester
  • Example 84 1- ⁇ 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ pyrrolidine-2-carboxylic acid dimethylamide
  • Example 57 (Step 2 from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and N-allyl amine )
  • Example 57 from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and 4-chloro-benzenesulfonamide It synthesize
  • Example 57 (step 2) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and methanesulfonamide According to the synthesis.
  • Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-chloro-benzoic acid and N- (4-trifluoromethyl-benzyl) amine Synthesis was carried out according to step 3, method 4).
  • Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-chloro-benzoic acid and N-amino-piperidine According to the synthesis.
  • Example 100 1- ⁇ 3-Chloro-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -benzoyl ⁇ -pyrrolidine-2-carboxylic acid methyl ester
  • Example 1 (Step 3, from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-chloro-benzoic acid and pyrrolidine-2-carboxylic acid methyl ester Synthesis was carried out according to method 4).
  • Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-chloro-benzoic acid and 3-hydroxy-pyrrolidine )
  • Example 1 (Step 3, Method) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-chloro-benzoic acid and 2-hydroxymethyl-pyrrolidine It synthesize
  • Example 104 1- ⁇ 3-Chloro-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] benzoyl ⁇ -pyrrolidine-2-carboxylic acid methyl ester
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-chloro-benzoic acid and pyrrolidine-2-carboxylic acid methyl ester According to the synthesis.
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-chloro-benzoic acid and 3-hydroxy-pyrrolidine Synthesized.
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-chloro-benzoic acid and 2-hydroxymethyl-pyrrolidine Thus synthesized.
  • Example 1 (Step 3, Method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-chloro-benzoic acid and thiazolidine-4-carboxylic acid methyl ester According to the synthesis.
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-chloro-benzoic acid and 2-hydroxy-cyclohexylamine Synthesized.
  • Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoic acid and 4-trifluoromethyl-benzylamine )
  • step 3 It was synthesized according to example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoic acid and isobutyl amine.
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoic acid and N-aminopiperidine Synthesized.
  • Example 1 (step 3, method from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoic acid and pyrrolidine-2-carboxylic acid methyl ester It synthesize
  • Example 120 ⁇ 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-phenyl ⁇ -(3-hydroxy-pyrrolidin-1-yl ) -Methanone
  • Example 1 (Step 3, Method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoic acid and 3-hydroxy-pyrrolidine According to the synthesis.
  • Example 1 (Step 3, Method 4 from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoic acid and 2-hydroxymethyl-pyrrolidine )
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-benzoic acid and 3-hydroxy-pyrrolidine Synthesized.
  • Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-benzoic acid and 2-hydroxymethyl-pyrrolidine Thus synthesized.
  • Example 1 (Step 3, Method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-benzoic acid and thiazolidine-4-carboxylic acid methyl ester According to the synthesis.
  • Example 126 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-N-piperidin-1-yl-benzamide
  • Example 1 (Step 3, Method) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-benzoic acid and N- (2-hydroxycyclohexyl) amine It synthesize
  • Example 128 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-N-p-tolyl-benzamide
  • Example 130 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N-isobutyl-3-methoxy-benzamide
  • Example 1 (Step 3, Method) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-benzoic acid and 4-trifulormethyl-benzylamine It synthesize
  • Example 132 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-N-piperidin-1-yl-benzamide
  • Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-benzoic acid and N-amino-piperidine According to the synthesis.
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyl-benzoic acid and tert-butyl amine Thus synthesized.
  • Example 136 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyll-N- (4-trifluoromethyl-benzyl) -benzamide
  • Example 1 (Step 3 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyl-benzoic acid and 4-trifluoromethyl-benzylamine , According to Method 4).
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyl-benzoic acid and isobutyl amine Synthesized.
  • Example 138 1- ⁇ 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyl-benzoyl ⁇ -pyrrolidine-2-carboxylic acid Methyl ester
  • Example 1 (step from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyl-benzoic acid and pyrrolidine-2-carboxylic acid methyl ester 3, method 4).
  • Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyl-benzoic acid and N- (2-hydroxy-cyclohexyl) amine It synthesize
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2,3-difluoro-benzoic acid and tert-butyl amine According to the synthesis.
  • Example 141 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2,3-difluoro-N- (4-trifluoromethyl-benzyl)- Benzamide
  • Example 1 (step from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2,3-difluoro-benzoic acid and 4-trifluoromethyl-benzyl amine 3, method 4).
  • Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2,3-difluoro-benzoic acid and pyrrolidine-2-carboxylic acid methyl ester Synthesis was carried out according to step 3, method 4).
  • Example 145 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N- (4-trifluoromethyl-benzyl) -benzamide
  • Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2-fluoro-benzoic acid and 4-trifluoromethyl-benzyl amine According to the synthesis.
  • Example 150 4- [bis- (4-fluoro-phenyl) -methoxy] -3-fluoro-N- (4-trifluoromethyl-benzyl) -benzamide
  • Example 152 4- [bis- (4-fluorophenyl) -methoxy] -3-fluoro-N- (piperidin-1-yl) benzamide
  • Example 156 4- [bis- (4-fluoro-phenyl) -methoxy] -3-fluoro-N-ethyl-N-propyl-benzamide
  • Step 3 4-[(2-Chloro-phenyl)-(5-chloro-pyridin-2-yl) -methoxy] -3-fluoro-benzoic acid methyl ester
  • Step 4 4-[(2-Chloro-phenyl)-(5-chloro-pyridin-2-yl) -methoxy] -3-fluoro-benzoic acid
  • Example 158 (step 5) from 4-[(2-chloro-phenyl)-(5-chloro-pyridin-3-yl) -methoxy] -3-fluoro-benzoic acid and methyl (S) -proline Synthesized.
  • Example 160 1- ⁇ 4-[(5-Chloro-pyridin-2-yl)-(3-chloro-pyridin-2-yl) -methoxy] -3-fluoro-benzoyl ⁇ -pyrrolidine- 2-carboxylic acid methyl ester
  • Step 3 4-[(5-Chloro-pyridin-2-yl)-(3-chloro-pyridin-2-yl) -methoxy] -3-fluoro-benzoic acid methyl ester
  • Step 4 4-[(5-Chloro-pyridin-2-yl)-(3-chloro-pyridin-2-yl) -methoxy] -3-fluoro-benzoic acid
  • Example 16 1- ⁇ 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3- (1,2,4-triazol-1-yl) methyl-benzoyl ⁇ -Pyrrolidine-2-carboxylic acid methyl ester
  • Step 2 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3- [1,2,4] triazol-1-ylmethyl-benzoic acid methyl ester
  • Step 3 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3- [1,2,4] triazol-1-ylmethyl-benzoic acid
  • Example 1 (step 3, method 4) using 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-fluoro-benzoic acid and tert-butylamine Synthesis was carried out in the same process.
  • Example 1 (Step 3, Method 4) using 3-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-benzoic acid and N-amino-pyridine Synthesis was carried out in the same process as).
  • Example 1 (step 3, using 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-benzoic acid and 4-trifluoromethyl-benzylamine Synthesis was carried out in the same manner as in Method 4).
  • Example 1 (step 3, method 4) using 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methoxy-benzoic acid and tert-butylamine Synthesis was carried out in the same process.
  • Example 1 (step 3, using 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methoxy-benzoic acid and 4-trifluoromethyl-benzyl Synthesis was carried out in the same manner as in Method 4).
  • Example 1 (step 3, method using 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methoxy-benzoic acid and N-amino-piperidine It synthesize
  • Step 1 1-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2-fluoro-4-nitro-benzene
  • Example 176 Process of Example 176 (step 3) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-aniline and 4-trifluoromethyl benzoyl chloride Synthesized.
  • Example 176 (step 3) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-aniline and 2,2-dimethyl-propionic acid chloride Synthesized.
  • Example 180 1- ⁇ 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl ⁇ -3- (4-trifluoromethyl-benzyl ) -Urea
  • Example 180 It was synthesized according to the process of Example 180 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and t-butylamine.
  • Example 176 In the process of Example 176 (step 3) from 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-aniline and 2,2-dimethyl-propionic acid chloride Synthesized.
  • Example 184 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid N '-(2,2-dimethyl-propionyl) -hydride Zayed
  • Human CNR1 (NM016083) was cloned in human brain tumor cells (SNB-19).
  • the cloning method is briefly described by treating the human brain tumor cells with Trizol (Invitorgen) and chloroform, separating the layers by centrifugation, taking the supernatant, and then mixing the isopropyl alcohol to precipitate the mRNA.
  • the isolated mRNA is synthesized by RT-PCR (reverse transcriptional polymerase chain reaction) kit (Bioneer), amplified by PCR (polymerase chain reaction) using specific primers of cannabinoid receptor 1 (CNR1), and recombined into pTarget (Invitrogen). .
  • CNR1 recombined with pTarget is introduced into CHO-K1 (ATCC) with a pCRE (Takara) vector and treated with 500 ug / ml G418 (Gibco) for 2 weeks to select cells into which the vector is introduced.
  • CHO-CB1- # 37 cells were selected as an experiment to confirm whether luciferase increased by forskolin was inhibited by CP55940 and increased by Rimonabant (self-synthesis) by simultaneously treating 2uM forskolin, 20nM CP55940 and 200nM Rimonabant.
  • the screening system of cells is shown in FIG. 1 below.
  • Selected CHO-CB1- # 37 cells were cultured in DMEM (Dulbecco's Modified Eagle Medium; Gibco), 10% FBS (fetal bovine serum; Gibco), 50 ug / ml G418 medium.
  • DMEM Dulbecco's Modified Eagle Medium
  • FBS fetal bovine serum
  • cultured CHO-CB1- # 37 cells were separated into individual cells with 0.05% trypsin EDTA (Gibco) solution, and then treated with DMEM culture medium, 20,000 cells per well were put into a 96-well plate (Corning). Incubate for 24 hours at 37 degrees in a 5% CO 2 incubator (Thermo).
  • Luminoskan (Thermo) was used to treat 50ul luciferase assay solution and measure luciferase activity for 10 seconds per well.
  • the activity of Rimonabant was measured by calculating 100% of samples treated with 2uM forkolin and 0% of wells treated with 2uM forskolin and 20nM CP55940 simultaneously. Rimonabant is used as a control antagonist for CNR1.
  • IC 50 of Rimonabant is shown in FIG. 3.
  • Human CNR2 (NM001841) was cloned in HepG2 cells.
  • CDNA is synthesized by RT-PCR (reverse transcriptional polymerase chain reaction) kit (Bioneer), amplified by PCR (polymerase chain reaction) using specific primers of CNR2 and recombined into pTarget (Invitrogen).
  • RT-PCR reverse transcriptional polymerase chain reaction
  • CNR1 recombined with pTarget is introduced into CHO-K1 (ATCC) with a pCRE (Takara) vector and treated with 500 ug / ml G418 (Gibco) for 2 weeks to select cells into which the vector is introduced.
  • CHO-CB2- # 59 cells were selected.
  • Compound screening methods are the same as for CHO-CB1- # 37 cells. Only CHO-CB2- # 57 cells did not increase the activity of luciferase inhibited by CP55940 by 200 nM Rimonabant.

Abstract

La présente invention concerne un composé benzamide inédit agissant en tant qu'agoniste inverse ou antagoniste d'un récepteur des cannabinoïdes (CB1), ou des sels pharmaceutiquement acceptables de celui-ci. Le composé selon la présente invention peut être utilisé en vue de la prévention ou du traitement de l'obésité et des maladies métaboliques liées à l'obésité. De plus, l'invention concerne un procédé de préparation du composé benzamide, un composé pharmaceutique comprenant celui-ci et une méthode de prévention ou de traitement de l'obésité et des maladies métaboliques liées à l'obésité.
PCT/KR2012/002405 2011-03-31 2012-03-30 Dérivé de benzamide utilisable en tant qu'antagoniste du récepteur des cannabinoïdes (cb1) WO2012134231A2 (fr)

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WO2006047516A2 (fr) * 2004-10-26 2006-05-04 Irm Llc Composes et compositions servant d'inhibiteurs d'activite de recepteur cannabinoide de type 1
WO2007058960A1 (fr) * 2005-11-10 2007-05-24 Adolor Corporation Sulfamoyle benzamides et procedes d’utilisation
WO2007096764A2 (fr) * 2006-02-27 2007-08-30 Glenmark Pharmaceuticals S.A. Dérivés d'hétéroaryles bicycliques en tant que modulateurs des récepteurs cannabinoïdes
WO2008094476A1 (fr) * 2007-01-31 2008-08-07 Merck & Co., Inc. Dérivés de pyrano[2,3-b]pyridine substituée en tant que modulateurs du récepteur du cannabinoïde 1

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006047516A2 (fr) * 2004-10-26 2006-05-04 Irm Llc Composes et compositions servant d'inhibiteurs d'activite de recepteur cannabinoide de type 1
WO2007058960A1 (fr) * 2005-11-10 2007-05-24 Adolor Corporation Sulfamoyle benzamides et procedes d’utilisation
WO2007096764A2 (fr) * 2006-02-27 2007-08-30 Glenmark Pharmaceuticals S.A. Dérivés d'hétéroaryles bicycliques en tant que modulateurs des récepteurs cannabinoïdes
WO2008094476A1 (fr) * 2007-01-31 2008-08-07 Merck & Co., Inc. Dérivés de pyrano[2,3-b]pyridine substituée en tant que modulateurs du récepteur du cannabinoïde 1

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