KR20100095277A - A new 3,4-diphenyl-4,5-dihydro-pyrazole-1-carboxylic acid hydrazide compound - Google Patents

Abstract

PURPOSE: A novel compound of 3,4-diphenyl-4,5-dihydro-pyrazole-1-carboxylic acid hydrazide is provided to act as a cannabinoid 1 regulator and to use in treating obesity and central nervous system. CONSTITUTION: An optical isomer compound or pharmaceutically acceptable salt thereof is denoted by chemical formula I. A racemic body compound or pharmaceutically acceptable salt is denoted by chemical formula I. A pharmaceutical composition contains pharmaceutically effective amount of the compound of chemical formula I. The pharmaceutical composition further contains the pharmaceutically acceptable adjuvant, diluents, or carrier. The pharmaceutical composition is used in preventing or treating diseases relating neurotransmission.

Description

Novel 3,4-diphenyl-4,5-dihydro-pyrazole-1-carboxylic acid hydrazide compound {A NEW 3,4-DIPHENYL-4,5-DIHYDRO-PYRAZOLE-1-CARBOXYLIC ACID HYDRAZIDE COMPOUND}

The present invention relates to a novel 3,4-diphenyl-4,5-dihydro-pyrazole-1-carboxylic acid hydrazide family of compounds that acts as an effective cannabinoid 1 (CB1) modulator for obesity and central nervous system diseases. It is about.

Cannabinoids (CannaBinoid, CB) are components of hemp (Indian hemp, Cannabis sativa) have been used as a medicine for centuries. Cannabinoids bind to cannabinoid receptors present in the human body and cause various physiological activities. To date, there are two different subtypes of cannabinoid receptors present in the human body: CB1 and CB2. Among them, CB1 receptors are widely present in the cerebral cortex, hippocampus, hypothalamus, cerebellum, basal ganglia, brain stem, and spinal cord, and central nervous system diseases related to obesity, cannabinoid neurotransmission (e.g. schizophrenia, bipolar disorder, anxiety, depression, Cognitive and memory disorders, OCD, attention disorders, epilepsy, dementia, Parkinson's disease, Huntington's chorea and Alzheimer's disease, drug addiction and abuse), immunity, cardiovascular, reproductive and endocrine diseases, septic shock, respiratory and gastrointestinal systems It was found to be closely related to the diseases involved.

The following papers detail the association between CB1 receptors and specific diseases.

Anorexia, bulimia, schizophrenia, schizophrenia, bipolar disorder, anxiety, anxiety, obsessive-compulsive disorder, Parkinson's disease, Huntington's chorea, drug addiction: The endocannabinoid system in the basal ganglia and in the mesolimbic reward system: implications for neurological and psychiatric disorders, Mario van der Stelt et al., Eur. J. Pharmacology, 2003, 480, 133-150

Depression: A therapeutic tole for cannabinoid CB1 receptor antagonists in major depressive disorders, Jeffrey M. Witkin et al., 4, TRENDS in Pharmacological Sciences, 2005, 26, 609-617

-Cognitive disorders, memory disorders, attention disorders, drug addiction: Endocannabinoids in cognition and dependence, A.H. Lichtman et al., Prostaglandins, Leukotrienes and Essential Fatty Acids 2002, 66, 269-285

Parkinson's disease, Huntington's chorea, schizophrenia, convulsions: The role of cannabinoids in neurodegeberative diseases, Michelle Glass, Prog. Neuro-Psychopharmacology & Psychiat 2001, 25, 743-765

Diseases related to the gastrointestinal system, cardiovascular, stress, anxiety: Cannabis and endocannabinoid modulators: Therapeutic promises and challenges, Igor Grant et al., Clinical Neuroscience Research, 2005, 5, 185-199

Nicotine addiction: CB1 receptor antagonists for the treatment of nicotine addiction, Caroline Cohen et al., Pharmacology, Biochemistry and Behavior, 2005, 81, 387-395

Drug addiction: Cannabnoid CB1 receptor antagonists as promising new medications for drug dependence, Le Poll, B. et al., J. Pharmacol. Exp. Ther. 2005, 312, 875-883

In addition, WO 01/70700 and EP 656354 show that certain CB1 modulators that antagonize or counteract the CB1 receptor are effective in treating obesity and central nervous system disease. Accordingly, research and development of various CB1 modulator compounds for the treatment of obesity and central nervous system diseases have been made.

CB1 modulators identified to date include diaryl pyrazole equivalents, amino alkylindoles, aryl-aroyl benzofurans, and the like. Representative examples of the diaryl pyrazole analogs include Acompila (Rimonabant), which is currently sold in Europe, and a representative example of amino alkylindole is Rhodopravadoline (AM-630), introduced in 1995. .

In addition, various CB1 modulators have been developed so far, but efforts to develop new structures of CB1 modulators that can improve toxicity, physicochemical properties, or pharmacokinetic properties are still ongoing.

As part of this effort, the present invention aims to provide a novel compound that performs selective and effective antagonistic action on cannabinoid receptors and a pharmaceutical composition comprising the compound.

To this end, the present invention provides an optical isomer compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[Formula I]

In Formula I, R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halide, alkyl halide, alkyl group, alkoxy group, hydroxyl group, benzyloxyl group, nitro group, aminoalkyl group, cyano group 1 to 3 substituents, R ₃ is hydrogen or C _1-3 alkyl, R ₄ and R ₅ are each independently selected from hydrogen, C _1-3 alkyl group or carboxyl group, or R ₄ and R ₅ are bonded to Saturated 5 to 7 membered heterocyclic groups containing 1 or 2 elements selected from nitrogen or oxygen atoms to be formed or 5 to 8 membered heterocyclic groups saturated with the nitrogen atoms to which they are attached.

Specific examples of the optical isomer compound represented by the formula (I) include

(+)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(+)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

(+)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid (4-methylpiperazin-1-yl) -amide,

(+)-3- (3-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(+)-3- (4-bromo-phenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(+)-4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(+)-3- (4-cyano-phenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(+)-3,4-bis- (4-chlorophenyl) -4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(+)-3- (4-methylphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(+)-N '-[3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carbonyl] -hydrazine carboxylic acid ethyl ester,

(+)-N '-[3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carbonyl] -hydrazine carboxylic acid thi-butylester,

(+)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid (hexahydro cyclopenta [C] pyrrol-2-yl) -amide,

(+)-4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

(+)-4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid (hexahydrocyclopenta [C] pyrrol-2-yl)- Amide,

(+)-4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide,

(+)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide,

(+)-3- (4-cyanophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide,

(+)-3- (4-bromophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide,

(+)-3- (4-fluorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide,

(+)-4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid N ', N'-dimethylhydrazide,

(+)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid N ', N'-dimethylhydrazide,

(+)-3- (4-fluorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(+)-3- (3,4-dichlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(+)-4- (4-fluorophenyl) -3-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(+)-3- (4-hydroxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(+)-4-phenyl-3- (3-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(+)-3- (4-benzyloxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(+)-3- (4-dimethylaminophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(+)-3- (4-fluorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

(+)-3- (4-bromophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

(+)-3- (4-hydroxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

(+)-3- (4-cyanophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

(+)-4- (4-chlorophenyl) -3-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

(+)-3- (4-benzyloxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

(+)-3- (4-methoxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

(+)-3- (4-methoxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(+)-3- (4-nitrophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(+)-3- (4-nitrophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

(+)-3- (4-nitrophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid morpholine-4-1-ylamide,

(+)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid hydrazide,

(+)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid N'-ethylhydrazide,

(+)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid N'-propylhydrazide,

(-)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(-)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

(-)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid (4-methylpiperazin-1-yl) -amide,

(-)-3- (3-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(-)-3- (4-bromo-phenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(-)-4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(-)-3- (4-cyano-phenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(-)-3,4-bis- (4-chlorophenyl) -4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(-)-3- (4-methylphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(-)-N '-[3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carbonyl] -hydrazine carboxylic acid ethyl ester,

(-)-N '-[3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carbonyl] -hydrazine carboxylic acid thi-butylester,

(-)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid (hexahydro cyclopenta [C] pyrrol-2-yl) -amide,

(-)-4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

(-)-4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid (hexahydrocyclopenta [C] pyrrol-2-yl)- Amide,

(-)-4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide,

(-)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide,

(-)-3- (4-cyanophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide,

(-)-3- (4-bromophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide,

(-)-3- (4-fluorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide,

(-)-4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid N ', N'-dimethylhydrazide,

(-)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid N ', N'-dimethylhydrazide,

(-)-3- (4-fluorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(-)-3- (3,4-dichlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(-)-4- (4-fluorophenyl) -3-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(-)-3- (4-hydroxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(-)-4-phenyl-3- (3-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(-)-3- (4-benzyloxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(-)-3- (4-dimethylaminophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(-)-3- (4-fluorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

(-)-3- (4-bromophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

(-)-3- (4-hydroxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

(-)-3- (4-cyanophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

(-)-4- (4-chlorophenyl) -3-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

(-)-3- (4-benzyloxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

(-)-3- (4-methoxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

(-)-3- (4-methoxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(-)-3- (4-nitrophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(-)-3- (4-nitrophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

(-)-3- (4-nitrophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid morpholine-4-1-ylamide,

(-)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid hydrazide,

(-)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid N'-ethylhydrazide,

(-)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid N'-propylhydrazide,

(R, R) -3- (4-chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(R, S) -3- (4-chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(S, S) -3- (4-chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(S, R) -3- (4-chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

(R, R) -3- (4-chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

(R, S) -3- (4-chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

(S, S) -3- (4-chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide and

(S, R) -3- (4-chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide and the like. .

The present invention also provides a racemate compound represented by the formula (I) or a pharmaceutically acceptable salt thereof. In this case, in Formula I, R ₁ and R ₂ are each independently from the group consisting of hydrogen, halide, alkyl halide, alkyl group, alkoxy group, hydroxyl group, benzyloxyl group, nitro group, aminoalkyl group and cyano group 1 to 3 substituents selected, R ₃ is hydrogen or C _1-3 alkyl, R ₄ and R ₅ are each independently selected from hydrogen, C _1-3 alkyl group or carboxyl group, or R ₄ and R ₅ are Saturated 5 to 7 membered heterocyclic groups comprising one or two elements selected from nitrogen or oxygen atoms formed by bonding, or 5 to 8 membered heterocyclic groups saturated with nitrogen atoms to which they are attached, provided NR ₄ R ₅ Is piperidine).

Specific examples of the racemate compound represented by the above formula (I) of the present invention,

3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid (4-methylpiperazin-1-yl) -amide,

N '-[3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carbonyl] -hydrazine carboxylic acid ethyl ester,

N '-[3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carbonyl] -hydrazine carboxylic acid thi-butylester,

3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid (hexahydrocyclopenta [C] pyrrol-2-yl) -amide,

4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid (hexahydrocyclopenta [C] pyrrol-2-yl) -amide,

4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide,

3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide,

3- (4-cyanophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide,

3- (4-bromophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide,

3- (4-fluorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide,

4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid N ', N'-dimethylhydrazide,

3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid N ', N'-dimethylhydrazide,

 3- (4-fluorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

3- (4-bromophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

3- (4-hydroxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

3- (4-cyanophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

4- (4-chlorophenyl) -3-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

3- (4-benzyloxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

3- (4-methoxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

3- (4-nitrophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

3- (4-nitrophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid morpholin-4-1-ylamide,

3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid hydrazide,

3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid N'-ethylhydrazide,

3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid N'-propylhydrazide,

3- (4-chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide or

3- (4-chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide and the like.

In addition, the present invention provides a pharmaceutical composition comprising a pharmaceutically effective amount of the compound of Formula I, wherein the pharmaceutical composition may further include a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical composition may be used for treating or preventing obesity, and may also be used for treating or preventing diseases related to cannabinoid neurotransmission. At this time, the diseases related to the canonoid neurotransmission are schizophrenia, bipolar disorder, anxiety, depression, cognitive and memory disorders, OCD, attention disorders, epilepsy, dementia, Parkinson's disease, Huntington's chorea, Alzheimer's disease, drug addiction and drug abuse It is a disease selected from the group consisting of.

The novel compounds of the invention act as cannabinoid 1 modulators and can be used to treat obesity and central nervous system diseases associated with cannabinoid receptors.

The inventors of the present invention have repeatedly studied to achieve the above object, and as a cannabinoid 1 regulator, 3,4-diphenyl-4,5-dihydro- that selectively and effectively antagonizes the CB1 receptor We have succeeded in synthesizing novel compounds of the pyrazole-1-carboxylic acid hydrazide family.

The novel compound of the present invention is a compound of the 3,4-diphenyl-4,5-di hydro-pyrazole-1-carboxylic acid hydrazide family defined by the following formula (I), and is defined by the formula (I) of the present invention. Compounds to be included include all types of isomers, isomer mixtures, racemates, pharmaceutically acceptable salts and solvates.

[Formula 1]

In Formula [I], R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halide, alkyl halide, alkyl group, alkoxy group, hydroxyl group, benzyloxyl group, nitro group, aminoalkyl group and cyano group 1 to 3 substituents selected,

R ₃ is hydrogen or C _1-3 alkyl,

R ₄ and R ₅ is hydrogen, C _{1 ~ 3} are each selected independently from alkyl group or carboxy group, R ₄ and R ₅ is a saturated 5 comprising one or two elements selected from nitrogen or oxygen atoms that is formed by combining To 7-membered heterocyclic group or a 5-8 membered heterocyclic group saturated with the nitrogen atom to which they are attached.

However, when the compound defined by the formula (I) is a racemate, except when NR ₄ R ₅ is piperidine.

On the other hand, pharmaceutically acceptable salts of the chemicals of the present invention include pharmaceutically acceptable acid addition salts. Suitable pharmaceutically acceptable salts for the compounds of formula (I) include, for example, inorganic acids or organic acids selected from the group consisting of hydrochloric acid, bromic acid, sulfuric acid, trifluoroacetic acid, citric acid, maleic acid in a sufficiently basic compound of formula (I). Acid addition salts to include.

The present invention also provides a pharmaceutical composition comprising a pharmaceutically effective amount of the compound or the pharmaceutically acceptable salt of the compound (I). In this case, if necessary, a pharmaceutically acceptable adjuvant, diluent, or carrier may be added to the pharmaceutical composition.

The pharmaceutical composition is a cannabinoid 1 modulator and can be used for the treatment and prevention of central nervous system (CNS) diseases associated with obesity or cannabinoid neurotransmission by selectively and effectively antagonizing the cannabinoid CB1 receptor. In this case, the central nervous system diseases include schizophrenia, bipolar disorder, anxiety, depression, cognitive and memory disorders, obsessive compulsive disorder, attention disorder, epilepsy, dementia, Parkinson's disease, Huntington's chorea and Alzheimer's disease, drug addiction and abuse.

compound

Hereinafter, the compound of the present invention will be described in detail. The compounds of the present invention are compounds of the 3,4-diphenyl-4,5-dihydro-pyrazole-1-carboxylic acid hydrazide family defined by the following formula (I). Compounds of the present invention include all isomers, isomeric mixtures and racemate compounds of the compounds defined by Formula I below and their pharmaceutically acceptable salts.

[Formula 1]

In this case, in Formula I, R ₁ and R ₂ are each independently from the group consisting of hydrogen, halide, alkyl halide, alkyl group, alkoxy group, hydroxyl group, benzyloxyl group, nitro group, aminoalkyl group and cyano group 1 to 3 substituents selected,

R ₃ is hydrogen or C _1-3 alkyl,

R ₄ and R ₅ is hydrogen, C _{1 ~ 3} alkyl group, or are each selected independently from carboxyl group, R ₄ and R ₅ are bonded a saturated containing one or two elements selected from a nitrogen or oxygen atom a 5 to 7 A heterocyclic group or a 5-8 membered heterocyclic group saturated with the nitrogen atom to which they are attached.

Specific examples of the compound defined by Chemical Formula I of the present invention include the following compounds.

1) 3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

2) 3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

3) 3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid (4-methylpiperazin-1-yl) -amide,

4) 3- (3-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

5) 3- (4-bromo-phenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

6) 4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

7) 3- (4-cyano-phenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

8) 3,4-bis- (4-chlorophenyl) -4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

9) 3- (4-methylphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

10) N '-[3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carbonyl] -hydrazine carboxylic acid ethyl ester,

11) N '-[3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carbonyl] -hydrazine carboxylic acid thi-butylester,

12) 3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid (hexahydro cyclopenta [C] pyrrol-2-yl) -amide,

13) 4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

14) 4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid (hexahydrocyclopenta [C] pyrrol-2-yl) -amide,

15) 4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide,

16) 3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide,

17) 3- (4-cyanophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide,

18) 3- (4-bromophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide,

19) 3- (4-fluorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide,

20) 4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid-N ', N'-dimethylhydrazide,

21) 3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid-N ', N'-dimethylhydrazide,

22) 3- (4-fluorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

23) 3- (3,4-dichlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

24) 4- (4-fluorophenyl) -3-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

25) 3- (4-hydroxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

26) 4-phenyl-3- (3-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

27) 3- (4-benzyloxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

28) 3- (4-dimethylaminophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

29) 3- (4-fluorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

30) 3- (4-bromophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

31) 3- (4-hydroxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

32) 3- (4-cyanophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

33) 4- (4-chlorophenyl) -3-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

34) 3- (4-benzyloxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

35) 3- (4-methoxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

36) 3- (4-methoxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

37) 3- (4-nitrophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

38) 3- (4-nitrophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide,

39) 3- (4-nitrophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid morpholin-4-1-ylamide,

40) 3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid hydrazide,

41) 3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid N'-ethylhydrazide,

42) 3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid N'-propylhydrazide,

43) 3- (4-chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide,

44) 3- (4-Chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide.

In addition, the present invention includes all the isomers, enantiomers, optical isomers, diastereomers of the individual compounds described above, and includes racemates of the compounds and mixtures of enantiomers mixed in different proportions.

Compound Synthesis Method

Hereinafter, a method of synthesizing the compound of Formula I of the present invention will be described.

Synthesis Process A

Dissolve 1.2 to 2 equivalents of the amine in tetrahydrofuran or dichloromethane with hydrazine amine and 1,1-carbonyldiimidazole or trichlorophosgene, and then stir at room temperature for 30 minutes to 3 hours. To obtain a compound. Wherein R ₄ and R ₅ are the same as above and R ₆ is imidazole or chloride.

Scheme 1

[Formula II]

Synthesis Process B

(1) step 1

The compound of formula III and 4.2 equivalents of formaldehyde are dissolved in methanol, a catalytic amount of acetic acid and piperidine are added, followed by stirring at reflux for 3 hours to obtain a compound of formula IV. At this time, R ₁ and R ₂ are the same as above.

Scheme 2

[Formula III]

[Formula IV]

(2) step 2

After dissolving the compound of Formula IV obtained in step 1 in ethanol, 5 mL of an aqueous solution of hydrazine per mol is added and stirred under reflux to obtain a compound of Formula V.

Scheme 3

[Formula V]

Synthesis Process B '

(1) step 1

After dissolving 1 equivalent of benzyl-4-chlorophenyl ketone in a tetrahydrofuran solvent, 1 equivalent of lithium diisopropylamine and 2 equivalents of chlorotrimethylsilane were added at 0 ° C. and stirred for 1 hour. The oil obtained by the above reaction and 3 equivalents of acetaldehyde are added to a dichloromethane solvent, and the solution is slowly added to a vessel in which titanium tetrachloride is dissolved at a temperature of −78 ° C. to obtain a compound of Compound VI.

Scheme 4

[Formula VI]

(2) step 2

After dissolving one equivalent of the compound of formula VI in a dichloromethane solvent, 1.2 equivalents of methanesulfonyl chloride and 2 equivalents of triethylamine were added and stirred at room temperature to obtain a compound of formula VII.

Scheme 5

[Formula VII]

(3) 3 levels

One equivalent of the compound of formula VII is dissolved in an ethanol solvent, and then 10 equivalents of hydrazine monohydrate is added, followed by stirring under reflux to obtain a compound of formula VIII.

Scheme 6

(VIII)

Synthesis Process C

One equivalent of the compound of formula V or formula VIII is dissolved in a tetrahydrofuran solvent together with 1-2 equivalents of compound of formula II, respectively, and then stirred at room temperature to obtain a compound of formula IX or formula X.

Scheme 7

Scheme 8

(IX)

[Formula X]

Synthesis Process D

One equivalent of the compound of formula IX or X is dissolved in dichloromethane, supersaturated etheric HCl is added and stirred at room temperature to obtain a compound of formula XI or XII, respectively.

Scheme 9

Scheme 10

(XI)

(XII)

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are merely examples of the present invention, and the present invention is not limited by the following examples.

Example 1

Synthesis Process A

To a tetrahydrofuran solvent in which 1-aminopiperidine (1 g, 9.98 mmol) is dissolved, slowly add 1,1'-carbonyldiimidazole (2.43 g, 14.97 mmol) and stir for 2 hours. After completion of the reaction by TLC, water was added and the organic layer was separated. The aqueous layer is extracted twice with ethyl acetate. The collected organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give an oil. The crude oil, imidazole-1-carboxylic acid piperidin-1-ylamide (1.45 g, 74% yield) was obtained and used in the reaction of C part without further purification.

Synthesis Process B

(1) step 1

Benzyl-4-chlorophenyl ketone (10 g, 43.3 mmol) was dissolved in methanol, followed by addition of formaldehyde (13.6 mL, 1.82 mol), acetic acid (0.5 mL, 8.6 mmol) and piperidine (0.43 mL, 6.9 mmol). After stirring for 7 hours at reflux temperature. After confirming that all benzyl-4-chlorophenyl ketone disappeared by TLC, water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane and the collected organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum to afford 1- (4-chloro-phenyl) -2-phenyl-propenone. The reaction proceeds in two steps without further purification.

1 H-NMR (200 MHz, CDCl ₃ ): δ 9.92 (m, 2H), 7.31-7.53 (m, 7H), 6.14 (s, 1H), 5.62 (s, 1H)

(2) step 2

1- (4-Chloro-phenyl) -2-phenyl-propenone (9.8 g, 40.4 mmol) obtained in step 1 was dissolved in ethanol, and an aqueous hydrazine solution (15 mL) was added thereto, followed by stirring at reflux for 5 hours. After confirming that 1- (4-chloro-phenyl) -2-phenyl-propenone disappeared, ethanol is concentrated in vacuo. The resulting residue was collected by filtration and washed with a solution of normal hexane / ethyl acetate = 5/1 to give a white powder of 3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-1H. Obtain pyrazole (7.2 g, 69% yield).

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.52 (m, 2H), 7.20-7.31 (m, 7H), 4.49 (m, 1H), 3.99 (t, 1H), 3.55 (m, 1H)

Synthesis Process C

3- (4-chlorophenyl) -4-phenyl-4,5-dihydro in a solution of imidazole-1-carboxylic acid piperidin-1-ylamide (1 g, 5.1 mmol) dissolved in a tetrahydrofuran solvent. -1H-pyrazole (1.32 g, 5.1 mmol) was added, followed by stirring at room temperature for 2 hours, then water was added and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate, and the collected organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-. 1-carboxylic acid piperidin-1-yl amide (1.5 g, 76% yield) is obtained.

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.57 (d, 2H), 7.16-7.38 (m, 7H), 7.02 (s, 1H), 4.64 (m, 1H), 4.39 (t, 1H), 4.03 ( m, 1H), 2.92 (m, 4H), 1.81 (m, 4H), 1.47 (m, 2H)

Synthesis Process D

3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide (1 g, 2.6 mmol) was dissolved in dichloromethane and supersaturated. Added ethereal HCl (5 mL) and stirred at room temperature for 5 hours. The resulting precipitate was collected by filtration and washed with diethyl ether to give a white powder of 3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidine- 1-ylamide hydrochloride (1.0 g, 92% sudule) is obtained.

In a similar manner, the compounds of Examples 2 to 39 were prepared as described below.

Example 2

3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.56 (m, 2H), 7.17-7.39 (m, 7H), 4.62 (m, 1H), 4.39 (t, 1H), 4.02 (m, 1H), 3.21 ( m, 4H), 1.72 (m, 8H)

Example  3

3- (4-Chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid (4-methylpiperazin-1-yl) -amide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.56 (m, 2H), 7.17-7.39 (m, 7H), 4.62 (m, 1H), 4.39 (t, 1H), 4.02 (m, 1H), 3.02 ( m, 4H), 2.71 (m, 4H), 2.38 (m, 3H)

Example 4

3- (3-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.66 (m, 1H), 7.06-7.42 (m, 8H), 4.64 (m, 1H), 4.40 (t, 1H), 4.03 (m, 1H), 2.92 ( m, 4H), 1.81 (m, 4H), 1.47 (m, 2H)

Example 5

3- (4-Bromo-phenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.16-7.56 (m, 9H), 7.01 (s, 1H), 4.64 (m, 1H), 4.39 (t, 1H), 4.10 (m, 1H), 2.92 ( m, 4H), 1.81 (m, 4H), 1.47 (m, 2H)

Example 6

4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.71 (m, 2H), 7.57 (m, 2H), 7.16-7.38 (m, 5H), 4.64 (m, 1H), 4.41 (t, 1H), 4.10 ( m, 1H), 3.01 (m, 4H), 1.81 (m, 4H), 1.47 (m, 2H)

Example 7

3- (4-cyano-phenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.71 (m, 2H), 7.57 (m, 2H), 7.16-7.38 (m, 5H), 4.64 (m, 1H), 4.41 (t, 1H), 4.10 ( m, 1H), 3.01 (m, 4H), 1.81 (m, 4H), 1.47 (m, 2H)

Example 8

3,4-bis- (4-chlorophenyl) -4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.56 (d, 2H), 7.31 (m, 4H), 7.16 (m, 3H), 4.61 (m, 1H), 4.38 (t, 1H), 3.98 (m, 1H), 2.96 (m, 4H), 1.81 (m, 4H), 1.47 (m, 2H)

Example  9

3- (4-methylphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.71 (m, 2H), 7.57 (m, 2H), 7.16-7.38 (m, 5H), 4.64 (m, 1H), 4.41 (t, 1H), 4.10 ( m, 1H), 3.01 (m, 4H), 1.81 (m, 4H), 1.47 (m, 2H)

Example 10

N '-[3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carbonyl] -hydrazinecarboxylic acid ethyl ester

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.80 (m, 1H), 7.57 (d, 2H), 7.16-7.36 (m, 6H), 6.82 (s, 1H), 4.64 (m, 1H), 4.41 ( t, 1H), 4.22 (m, 2H), 4.10 (m, 1H), 1.34 (m, 3H),

Example 11

N '-[3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carbonyl]-hydrazinecarboxylic acid thi-butyl ester

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.80 (m, 1H), 7.19 (d, 2H), 6.78-6.94 (m, 7H), 4.36 (m, 1H), 3.96 (t, 1H), 3.52 ( m, 1H), 1.04 (s, 9H),

Example  12

3- (4-Chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid (hexahydrocyclopenta [C] pyrrol-2-yl) -amide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.56 (d, 2H), 7.14-7.37 (m, 7H), 6.79 (s, 1H), 4.62 (m, 1H), 4.37 (t, 1H), 4.01 ( m, 1H), 3.37 (m, 2H), 2.71 (m, 2H), 2.42 (m, 2H), 1.43-1.78 (m, 6H)

Example  13

4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.64 (d, 2H), 7.46 (d, 2H), 7.14-7.36 (m, 5H), 4.62 (m, 1H), 4.39 (t, 1H), 4.01 ( m, 1H), 3.17 (m, 4H), 1.69 (m, 8H)

Example 14

4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid (hexahydrocyclopenta [C] pyrrol-2-yl) -amide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.64 (d, 2H), 7.46 (d, 2H), 7.17-7.38 (m, 5H), 6.81 (s, 1H), 4.64 (m, 1H), 4.39 ( t, 1H), 4.01 (m, 1H), 3.38 (m, 2H), 2.72 (m, 2H), 2.46 (m, 2H), 1.43-1.78 (m, 6H)

Example 15

4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.64 (d, 2H), 7.46 (d, 2H), 7.17-7.38 (m, 5H), 6.86 (s, 1H), 4.63 (m, 1H), 4.38 ( t, 1H), 4.02 (m, 1H), 3.02 (m, 4H), 1.86 (m, 4H)

Example 16

3- (4-Chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.57 (d, 2H), 7.16-7.38 (m, 7H), 6.91 (s, 1H), 4.60 (m, 1H), 4.37 (t, 1H), 4.03 ( m, 1H), 3.01 (m, 4H), 1.86 (m, 4H)

Example 17

3- (4-cyanophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.68 (d, 2H), 7.52 (d, 2H), 7.16-7.38 (m, 5H), 6.97 (s, 1H), 4.62 (m, 1H), 4.42 ( t, 1H), 4.03 (m, 1H), 3.01 (m, 4H), 1.87 (m, 4H)

Example 18

3- (4-Bromophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.16-7.58 (m, 9H), 6.94 (s, 1H), 4.64 (m, 1H), 4.38 (t, 1H), 4.03 (m, 1H), 3.03 ( m, 4H), 1.87 (m, 4H)

Example 19

3- (4-fluorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.63 (m, 1H), 7.20-7.39 (m, 5H), 6.89-7.09 (m, 3H) 4.62 (m, 1H), 4.41 (t, 1H), 4.05 (m, 1H), 3.02 (m, 4H), 1.92 (m, 4H)

Example 20

4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid N ', N'-dimethylhydrazide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.68 (d, 2H), 7.57 (d, 2H), 7.18-7.42 (m, 5H), 6.90 (s, 1H), 4.65 (m, 1H), 4.41 ( t, 1H), 4.09 (m, 1H), 2.73 (s, 6H)

Example 21

3- (4-Chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid N ', N'-dimethylhydrazide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.58 (d, 2H), 7.16-7.37 (m, 7H), 6.92 (s, 1H), 4.62 (m, 1H), 4.38 (t, 1H), 4.03 ( m, 1H), 2.72 (s, 6H)

Example 22

3- (4-fluorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.59 (m, 1H), 7.18-7.36 (m, 5H), 6.92 (m, 3H), 4.63 (m, 1H), 4.38 (t, 1H), 4.01 ( m, 1H), 2.97 (m, 4H), 1.80 (m, 4H), 1.48 (m, 2H)

Example 23

3- (3,4-Dichlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.80 (s, 1 H), 7.38 (m, 5 H), 7.19 (m, 3 H), 6.92 (s, 1 H), 4.62 (m, 1 H), 4.42 (t, 1H), 4.08 (m, 1H), 2.98 (m, 4H), 1.79 (m, 4H), 1.47 (m, 2H)

Example 24

4- (4-fluorophenyl) -3-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.61 (m, 2H), 7.31 (m, 5H), 7.18 (d, 2H), 7.01 (s, 1H), 4.63 (m, 1H), 4.39 (t, 1H), 4.01 (m, 1H), 2.96 (m, 4H), 1.81 (m, 4H), 1.46 (m, 2H)

Example  25

3- (4-hydroxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.51 (d, 2H), 7.17-7.34 (m, 5H), 7.12 (s, 1H), 6.81 (d, 2H), 4.61 (m, 1H), 4.38 ( t, 1H), 3.99 (m, 1H), 2.97 (m, 4H), 1.78 (m, 4H), 1.43 (m, 2H)

Example 26

4-phenyl-3- (3-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.90 (s, 1H), 7.61 (d, 1H), 747 (d, 1H), 7.16-7.39 (m, 6H), 6.99 (s, 1H), 4.63 ( m, 1H), 4.39 (t, 1H), 4.02 (m, 1H), 2.92 (m, 4H), 1.76 (m, 4H), 1.43 (m, 2H)

Example 27

3- (4-benzyloxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.58 (d, 2H), 7.18-7.40 (m, 9H), 7.00 (s, 1H), 6.89 (d, 2H), 5.01 (s, 2H), 4.62 ( m, 1H), 4.38 (t, 1H), 4.00 (m, 1H), 2.96 (m, 4H), 1.79 (m, 4H), 1.46 (m, 2H)

Example 28

3- (4-dimethylaminophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.51 (d, 2H), 7.34 (m, 5H), 7.02 (s, 1H), 6.61 (d, 2H), 4.61 (m, 1H), 4.36 (t, 1H), 3.99 (m, 1H), 3.00 (s, 6H), 2.97 (m, 4H), 1.80 (m, 4H), 1.42 (m, 2H)

Example 29

3- (4-fluorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.63 (m, 2H), 7.51 (s, 1H), 7.17-7.39 (m, 5H), 7.02 (t, 2H), 4.62 (m, 1H), 4.39 ( t, 1H), 4.02 (m, 1H), 3.21 (m, 4H), 1.72 (m, 8H)

Example 30

3- (4-Bromophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.48 (m, 5H), 7.31 (m, 2H), 7.18 (m, 2H), 4.62 (m, 1H), 4.37 (t, 1H), 4.01 (m, 1H), 3.20 (m, 4H), 1.72 (m, 8H)

Example 31

3- (4-hydroxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.48 (d, 2H), 7.17-7.37 (m, 5H), 6.81 (d, 2H), 4.60 (m, 1H), 4.34 (t, 1H), 3.95 ( m, 1H), 3.18 (m, 4H), 1.68 (m, 8H)

Example 32

3- (4-cyanophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.72 (d, 2H), 7.59 (d, 2H), 7.51 (s, 1H), 7.31 (m, 3H), 7.19 (m, 2H), 4.62 (m, 1H), 4.41 (t, 1H), 4.02 (m, 1H), 3.21 (m, 4H), 1.69 (m, 8H)

Example 33

4- (4-Chlorophenyl) -3-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.59 (m, 2H), 7.47 (s, 1H), 7.31 (m, 5H), 7.14 (d, 2H), 4.62 (m, 1H), 4.37 (t, 1H), 4.01 (m, 1H), 3.18 (m, 4H), 1.72 (m, 8H)

Example 34

3- (4-benzyloxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.57 (d, 2H), 7.51 (s, 1H), 7.18-7.38 (m, 10H), 6.87 (d, 2H), 5.02 (s, 2H), 4.61 ( m, 1H), 4.39 (t, 1H), 4.02 (m, 1H), 3.21 (m, 4H), 1.69 (m, 8H)

Example 35

3- (4-methoxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.59 (d, 2H), 7.11-7.37 (m, 5H), 6.79 (d, 2H), 4.72 (m, 1H), 4.38 (t, 1H), 3.94 ( m, 1H), 3.78 (s, 3H), 3.20 (m, 4H), 1.72 (m, 8H)

Example 36

3- (4-methoxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.59 (d, 2H), 7.35 (m, 5H), 7.01 (s, 1H), 6.80 (d, 2H), 4.62 (m, 1H), 4.38 (t, 1H), 4.01 (m, 1H), 3.80 (s, 3H), 2.96 (t, 4H), 1.78 (m, 4H), 1.42 (m, 2H)

Example 37

3- (4-nitrophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 8.17 (d, 2H), 7.78 (d, 2H), 7.18-7.36 (m, 5H), 7.02 (s, 1H), 4.71 (m, 1H), 4.42 ( t, 1H), 4.07 (m, 1H), 2.87 (m, 4H), 1.80 (m, 4H), 1.42 (m, 2H)

Example 38

3- (4-nitrophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 8.13 (d, 2H), 7.78 (d, 2H), 7.51 (s, 1H), 7.11-7.34 (m, 5H), 4.78 (m, 1H), 4.43 ( t, 1H), 4.11 (m, 1H), 3.24 (m, 4H), 1.77 (m, 8H)

Example 39

3- (4-nitrophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid morpholine-4-1-ylamide hydrochloride

1 H-NMR (200 MHz, CDCl ₃ ): δ 8.14 (d, 2H), 7.76 (d, 2H), 7.11-7.34 (m, 5H), 4.74 (m, 1H), 4.42 (t, 1H), 4.10 ( m, 1H), 3.74 (m, 4H), 2.51 (m, 4H)

Example 40

N '-[3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxyl] -hydrazinecarboxylic acid tertiary synthesized in a similar manner to Example 1 Butyl ester (1 g, 2.4 mmol) was dissolved in methanol, methanolic HCl (1 M, 30 mL) was added and stirred at room temperature for 10 hours. The methanol was concentrated in vacuo and the resulting residue was collected by filtration and washed with a solution of normal hexane / ethyl acetate = 5/1 to give a white powder of 3- (4-chlorophenyl) -4-phenyl-4,5- Dihydropyrazole-1-carboxylic acid hydrazide hydrochloride (0.81 g, 90% yield) is obtained.

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.81 (s, 1H), 7.57 (d, 2H), 7.11-7.38 (m, 7H), 5.41 (s, 2H), 4.68 (m, 1H), 4.39 ( t, 1H), 4.01 (m, 1H)

Example 41

3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid hydrazide hydrochloride (0.1 g, 0.26 mmol) synthesized by the method of Example 39 was prepared. After dissolving in dichloromethane, acetaldehyde (0.03 mL, 0.52 mmol) and triethylamine (1 mL) were added, followed by stirring at room temperature for 3 hours. Water is added and the organic layer is separated. The aqueous layer was extracted twice with dichloromethane and the collected organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to dissolve the crude oil obtained in methanol, followed by sodium borohydride (0.3 g, 0.78 mmol). Put it slowly. After stirring for 5 hours at room temperature, water is slowly added and the organic layer is separated. The aqueous layer was extracted twice with dichloromethane, and the collected organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The collected product was purified by chromatography (silica gel: ethyl acetate / normal hexane = 7/3), (4-Chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid N'-ethylhydrazide hydrochloride (62 mg, 69% yield) is obtained.

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.78 (m, 3H), 7.15-7.37 (m, 7H), 4.67 (m, 1H), 4.38 (t, 1H), 4.00 (m, 1H), 3.12 ( m, 2H), 1.19 (t, 3H)

Example 42

3- (4-Chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid N 'using propioaldehyde (0.03 mL, 0.52 mmol) by the method described in Example 40. Obtain propylhydrazide hydrochloride (67 mg, 73% yield).

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.77 (m, 3H), 7.18-7.36 (m, 7H), 4.69 (m, 1H), 4.39 (t, 1H), 4.01 (m, 1H), 2.99 ( t, 2H), 1.63 (m, 2H), 1.09 (t, 3H)

Example 43

Benzyl-4-chlorophenyl ketone (900 mg, 3.9 mmol) was dissolved in tetrahydrofuran solvent, and 2 M lithium diisopropylamine (7.8 mL, 3.9 mmol) and chlorotrimethylsilane (0.99 mL, 7.8 mmol) at 0 ° C. ) And stir at the same temperature for one hour. After adding water, dichloromethane solvent was added, the organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Acetaldehyde (0.66 mL, 11.7 mmol) is added to a dichloromethane solvent and titanium tetrachloride (0.87 mL, 7.8 mmol) is slowly added at -78 ° C. After 10 minutes, the concentrated oil obtained in the above procedure is dissolved in dichloromethane solution and slowly added to the stirring solution. Stir at -78 ° C. After confirming the reaction, water was added, the organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The oil was purified by chromatography (silica gel: ethyl acetate / normal hexane = 1/4) to give 1- (4-chlorophenyl) -3-hydroxy-2-phenyl-butan-1-one (660 mg, 61.6% Yield).

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.85 (m, 2H), 7.20-7.48 (m, 7H), 4.55 (m, 1H), 4.44 (d, 1H), 2.70 (br, 1H), 1.20 ( d, 3H)

Dissolve 1- (4-chlorophenyl) -3-hydroxy-2-phenyl-butan-1-one (660 mg, 2.4 mmol) in dichloromethane solvent, then dissolve with methanesulfonyl chloride (0.22 mL, 2.9 mmol). Ethylamine (0.67 mL, 4.8 mmol) was added and stirred at room temperature. After confirming the reaction, water was added, the organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The oil was purified by chromatography (silica gel: ethyl acetate / normal hexane = 1/4) to give methanesulfonyl acid 3- (4-chlorophenyl) -1-methyl-3-oxo-2-phenyl-propyl ester ( 630 mg, 74.5% yield).

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.89 (m, 2H), 7.20-7.48 (m, 7H), 5.35 (m, 1H) 4.71 (d, 1H), 2.18 (s, 3H), 1.58 (m , 3H)

Methanesulfonyl acid 3- (4-chlorophenyl) -1-methyl-3-oxo-2-phenyl-propyl ester (600 mg, 1.70 mmol) was dissolved in ethanol solvent and hydrazine monohydrate (0.83 mL, 17.0 mmol) was dissolved. Put and stirred under reflux. After confirming the reaction, the reaction is concentrated. Add ethyl acetate solvent and wash with water. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to afford 3- (4-chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole (460 mg, 52% yield). To obtain. Proceed to the next step without further purification

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.58 (m, 2H), 7.15-7.48 (m, 7H), 4.05 (d, 1H) 3.82 (m, 1H), 1.36 (d, 3H)

3- (4-chlorophenyl) -5-methyl-4-phenyl-4 in a solution of imidazole-1-carboxylic acid piperidin-1-ylamide (0.1 g, 0.51 mmol) dissolved in TF 5-dihydro-1H-pyrazole (0.20 g, 0.51 mmol) was added, followed by stirring at room temperature for 2 hours, then water was added and the organic layer was separated. The aqueous layer, which was extracted twice with ethyl acetate, was collected, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3- (4-chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyra. The sol-1-carboxylic acid piperidin-1-ylamide hydrochloride (0.15 g, 76% yield) is obtained.

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.58 (m, 2H), 7.05-7.40 (m, 7H), 4.72 (m, 1H) 4.48 (m, 1H), 4.14 (m, 1H), 3.02 (m , 4H), 1.82 (m, 4H) 1.36-1.53 (m, 5H)

Example 44

3- (4-Chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide hydrochloride by the method described in Example 43. To obtain.

1 H-NMR (200 MHz, CDCl ₃ ): δ 7.58 (m, 2H), 7.25-7.40 (m, 5H), 7.09 (m, 2H), 4.72 (m, 1H) 4.40 (m, 1H), 4.11 (d , 1H), 3.22 (m, 4H), 1.60-1.89 (m, 8H), 1.13 (d, 2H)

Example 45

By separating the racemate compound of formula (I) prepared by the method of Examples 1 to 43 by using prefractional chromatography (Chiralcell OD, 5 cm x 0 cm IDxL: acetonitrile / isopropyl alcohol = 80/20), The optical isomer of each compound is obtained.

On the other hand, the pharmaceutical composition comprising a pharmaceutically effective amount of the compound of formula (I) can be used for the treatment and prevention of central nervous system (CNS) diseases associated with obesity and cannabinoid neurotransmission. In this case, the central nervous system diseases include schizophrenia, bipolar disorder, anxiety, depression, cognitive and memory disorders, obsessive compulsive disorder, attention disorder, epilepsy, dementia, Parkinson's disease, Huntington's chorea and Alzheimer's disease, drug addiction and abuse.

On the other hand, to patients in need of treatment of obesity and central nervous system diseases, when administering the pharmaceutical composition of the present invention, the preferred dosage is in the range of about 0.01 mg to about 200 mg / kg body weight (kg), preferably 0.1 mg to about 100 mg per kg body weight, most preferably about 1 mg to about 50 mg per kg body weight. However, the dosage depends on the condition of the patient, the severity of the patient's condition and the activity of the compound, and the determination of the optimal dosage for a particular condition must be determined clinically. Therefore, the dosage referred to herein is only one example of the present invention, and does not limit the scope of the present invention.

The pharmaceutical compositions of the present invention can be administered to patients in a variety of ways for the treatment of obesity or central nervous system disease.

For example, the pharmaceutical composition of the present invention may be prepared orally administered in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing combs and the like. While these formulations preferably contain at least 10% or more of the compounds of the present invention, the content of the compounds of the present invention may vary depending on the particular formulation. Preferred compositions and formulations according to the present invention are prepared to contain from about 0.1 mg to about 100 mg of a compound of the present invention in oral dosage unit form.

Meanwhile, the pills, capsules, troches, and the like may be used as binders such as microcrystalline cellulose, tragaganth gum or gelatin, excipients such as starch or lactose, disintegrants such as alganic acid or corn starch, magnesium stearate, and the like. It can be prepared by mixing lubricants, lubricants such as colloidal silicon dioxide, sweeteners such as sucrose or saccharin and flavoring agents such as peppermint, methyl salicylate, orange flavor. On the other hand, in the case of capsules may contain a liquid carrier such as fatty oil in addition to the above kinds of substances. Other dosage unit forms may contain various other materials necessary to modify the physical form of the dosage unit. Thus, tablets or pills may be avoided with sugars, shellac or other enteric coatings. Syrups may contain sucrose, certain preservatives, dyes, colorants and flavoring agents as sweetening agents in addition to the active ingredient. In preparing these various pharmaceutical compositions, the materials used must be pharmaceutically pure and nontoxic in use.

In addition, the pharmaceutical compositions of the present invention may be administered parenterally in the form of a solution or suspension. These formulations preferably contain at least 10% or more of the compounds of the present invention. The compositions and formulations are preferably prepared to contain from about 0.1 mg to about 100 mg of a compound of the present invention in parenteral dosage dosage unit form.

In addition, the solutions and suspensions may be prepared by injection, physiological saline, non-volatile oils, polyethylene glycol, sterile diluents such as glycerin or propylene glycol, antibacterial agents such as benzyl alcohol or methylparaben, antioxidants such as ascorbic acid or sodium bisulfite, ethylene Chelating agents such as diaminetetraacetic acid, buffers such as acetate, citrate or phosphate, and isotonic constituents such as sodium chloride or dextrose and the like. The parenteral formulation can be used by filling in ampoules, disposable syringes or multiple vials of glass or plastic material.

Pharmacological activity measurement

To determine whether the compound of the present invention is related to cannabinoid neurotransmission and whether it is effective in obesity diseases, pharmacological activity was measured by the following method. The measured pharmacological test results are shown in the tables below.

Affinity for the Human Cananoid CB1 Receptor (CB1 RBA)

The affinity of the compounds of the invention to the CB1 receptor was determined using membrane preparations of cell lines (HEK-293) stably transfected with human cananoid CB1 receptors bound to [3H] CP-55,940 as radioligands. After adding the compound of the present invention (test concentration of 3 μM) or incubating the cell membrane preparation prepared immediately without addition with [3H] -ligand, the binding ligand and the free ligand were separated by filtration through a glass fiber filter. . Radioactivity on the filter was measured by liquid scintillation counting. (Note: Compton DR, Rice KC, De Costa BR, Razdan RK, Melvin LS, Johnson MR, Martin BR, J. Pharmaceutical Exp Ther., 1993, 265, 218)

The measurement results are as shown in Table 1 below.

<Table 1>

compound CB1 affinity (%) compound CB1 affinity (%) Example 2 85 Example 18 63 Example 6 92 Example 20 49 Example 7 61 Example 28 66 Example 8 66 Example 38 87 Example 12 81 Example 44 97

Hypothermia test by CB1 receptor activation

The antagonistic action of the compound of the present invention on the cannabinoid receptor was confirmed through animal experiments using male rats (ICR, 4 weeks old, mouse). After administration of WIN55,212-2, 5 mg / kg of agonist specific for cannabinoid receptors subcutaneously, induces a decrease in body temperature by CB1 receptor activation, an effective amount of 10 mg of the compound of the present invention 30 minutes later / kg was administered by intraperitoneal injection to the rat's abdomen. The degree of antagonism was confirmed by the recovery of body temperature through measurement of anal temperature 30 minutes after administration of the compound of the present invention. (Reference: Lange JH, Coolen HK, Stuivenberg HH, Dijksman JA, Hervemens AH, Ronken HE et al., 12, J. Med. Chem., 2004, 47, 627)

The measurement results are as shown in Table 2 below.

TABLE 2

compound Body temperature recovery (%) compound Body temperature recovery (%) Example 1 66.6 Example 22 58.0 Example 2 59.8 Example 28 40.4 Example 5 73.9 Example 29 45.1 Example 6 65.5 Example 32 39.6 Example 7 80.7 Example 35 45.9 Example 9 70.9 Example 36 55.5 Example 12 72.0 Example 37 50.9 Example 13 75.1 Example 43 52.9 Example 14 42.2 Example 44 54.9 Example 20 35.7

On the other hand, the difference in the effect between the racemate compound and the optical isomer compound of the compound of the present invention was examined through hypothermia induction experiment. Experimental method was the same as the above method, and oral administration was performed at various concentrations instead of the intraperitoneal administration.

The measurement results are as shown in Table 3 below.

TABLE 3

compound Dosage Body temperature recovery (%) Example 6 0.3 20.6 One 37.4 3 78.7 5 94.0 Example 6
(-) Optical isomer 0.3 45.1 One 90.8 3 103.1 5 105.0 Example 6
(+) Optical isomer 3 6.1 5 2.4 10 3.1

Test to reduce appetite (Acute FI test)

In order to confirm the anti-obesity effect of the present invention, the test of the degree of appetite reduction using male rats (ICR, 4 weeks old mouse) was performed. After the rats were artificially fasted for 24 hours, the compound of the present invention was orally administered at an effective amount of 30 mg / kg. Food was provided 1 hour after administration of the compound of the present invention, and then the food intake for 1 hour was measured. The degree of loss of appetite was confirmed by comparing food intake with the subject not administered the compound of the present invention. (Note: Blavet N, DeFeudis FV, Clostre F, Gen Pharmacol, 1982, 13, 173)

The experimental results are as shown in Table 4 below.

TABLE 4

compound Appetite Reduction (%) compound Appetite Reduction (%) Example 1 65.6 Example 15 33.3 Example 2 23.0 Example 36 29.0 Example 6 40.2 Example 37 25.2 Example 12 30.7 Example 43 18.8 Example 13 17.9

Claims (9)

The optical isomer compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof. [Formula I]

In Formula I, R 1 and R 2 are each independently selected from the group consisting of hydrogen, halide, alkyl halide, alkyl group, alkoxy group, hydroxyl group, benzyloxyl group, nitro group, aminoalkyl group, cyano group Three substituents, R3 is hydrogen or C1-3 alkyl, R4 and R5 are each independently selected from hydrogen, a C1-3 alkyl group, a carboxy group, A saturated 5 to 7 membered heterocyclic group, wherein R 4 and R 5 are bonded to contain 1 or 2 elements selected from nitrogen or oxygen atoms, or a 5 to 8 membered heterocyclic group saturated with the nitrogen atom to which they are attached. The racemate compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof. [Formula I]

In Formula I, R 1 and R 2 are each independently selected from the group consisting of hydrogen, halide, alkyl halide, alkyl group, alkoxy group, hydroxyl group, benzyloxyl group, nitro group, aminoalkyl group, cyano group Three substituents, R3 is hydrogen or C1-3 alkyl, R4 and R5 are each independently selected from hydrogen, a C1-3 alkyl group, a carboxy group, A saturated 5 to 7 membered heterocyclic group, wherein R 4 and R 5 are bonded to contain 1 or 2 elements selected from nitrogen or oxygen atoms, or a 5 to 8 membered heterocyclic group saturated with the nitrogen atom to which they are attached. Except where NR4R5 is piperidine. The method of claim 1, The optical isomer compound, (+)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (+)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, (+)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid (4-methylpiperazin-1-yl) -amide, (+)-3- (3-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (+)-3- (4-bromo-phenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (+)-4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (+)-3- (4-cyano-phenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (+)-3,4-bis- (4-chlorophenyl) -4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (+)-3- (4-methylphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (+)-N '-[3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carbonyl] -hydrazine carboxylic acid ethyl ester, (+)-N '-[3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carbonyl] -hydrazine carboxylic acid thi-butylester, (+)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid (hexahydro cyclopenta [C] pyrrol-2-yl) -amide, (+)-4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, (+)-4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid (hexahydrocyclopenta [C] pyrrol-2-yl)- Amide, (+)-4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide, (+)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide, (+)-3- (4-cyanophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide, (+)-3- (4-bromophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide, (+)-3- (4-fluorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide, (+)-4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid N ', N'-dimethylhydrazide, (+)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid N ', N'-dimethylhydrazide, (+)-3- (4-fluorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (+)-3- (3,4-dichlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (+)-4- (4-fluorophenyl) -3-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (+)-3- (4-hydroxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (+)-4-phenyl-3- (3-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (+)-3- (4-benzyloxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (+)-3- (4-dimethylaminophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (+)-3- (4-fluorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, (+)-3- (4-bromophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, (+)-3- (4-hydroxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, (+)-3- (4-cyanophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, (+)-4- (4-chlorophenyl) -3-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, (+)-3- (4-benzyloxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, (+)-3- (4-methoxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, (+)-3- (4-methoxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (+)-3- (4-nitrophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (+)-3- (4-nitrophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, (+)-3- (4-nitrophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid morpholine-4-1-ylamide, (+)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid hydrazide, (+)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid N'-ethylhydrazide, (+)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid N'-propylhydrazide, (-)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (-)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, (-)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid (4-methylpiperazin-1-yl) -amide, (-)-3- (3-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (-)-3- (4-bromo-phenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (-)-4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (-)-3- (4-cyano-phenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (-)-3,4-bis- (4-chlorophenyl) -4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (-)-3- (4-methylphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (-)-N '-[3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carbonyl] -hydrazine carboxylic acid ethyl ester, (-)-N '-[3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carbonyl] -hydrazine carboxylic acid thi-butylester, (-)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid (hexahydro cyclopenta [C] pyrrol-2-yl) -amide, (-)-4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, (-)-4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid (hexahydrocyclopenta [C] pyrrol-2-yl)- Amide, (-)-4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide, (-)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide, (-)-3- (4-cyanophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide, (-)-3- (4-bromophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide, (-)-3- (4-fluorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic excid pyrrolidin-1-ylamide, (-)-4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid N ', N'-dimethylhydrazide, (-)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid N ', N'-dimethylhydrazide, (-)-3- (4-fluorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (-)-3- (3,4-dichlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (-)-4- (4-fluorophenyl) -3-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (-)-3- (4-hydroxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (-)-4-phenyl-3- (3-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (-)-3- (4-benzyloxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (-)-3- (4-dimethylaminophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (-)-3- (4-fluorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, (-)-3- (4-bromophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, (-)-3- (4-hydroxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, (-)-3- (4-cyanophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, (-)-4- (4-chlorophenyl) -3-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, (-)-3- (4-benzyloxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, (-)-3- (4-methoxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, (-)-3- (4-methoxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (-)-3- (4-nitrophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (-)-3- (4-nitrophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, (-)-3- (4-nitrophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid morpholine-4-1-ylamide, (-)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid hydrazide, (-)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid N'-ethylhydrazide, (-)-3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid N'-propylhydrazide, (R, R) -3- (4-chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (R, S) -3- (4-chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (S, S) -3- (4-chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (S, R) -3- (4-chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide, (R, R) -3- (4-chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, (R, S) -3- (4-chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, (S, S) -3- (4-chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide or (S, R) -3- (4-chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide Compound or a pharmaceutically acceptable salt thereof. The method of claim 2, The racemate compound, 3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, 3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid (4-methylpiperazin-1-yl) -amide, N '-[3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carbonyl] -hydrazine carboxylic acid ethyl ester, N '-[3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carbonyl] -hydrazine carboxylic acid thi-butylester, 3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid (hexahydrocyclopenta [C] pyrrol-2-yl) -amide, 4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, 4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid (hexahydrocyclopenta [C] pyrrol-2-yl) -amide, 4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide, 3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide, 3- (4-cyanophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide, 3- (4-bromophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide, 3- (4-fluorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid pyrrolidin-1-ylamide, 4-phenyl-3- (4-trifluoromethylphenyl) -4,5-dihydro-pyrazole-1-carboxylic acid N ', N'-dimethylhydrazide, 3- (4-chlorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid N ', N'-dimethylhydrazide,  3- (4-fluorophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, 3- (4-bromophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, 3- (4-hydroxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, 3- (4-cyanophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, 4- (4-chlorophenyl) -3-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, 3- (4-benzyloxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, 3- (4-methoxyphenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, 3- (4-nitrophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, 3- (4-nitrophenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid morpholin-4-1-ylamide, 3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid hydrazide, 3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid N'-ethylhydrazide, 3- (4-chlorophenyl) -4-phenyl-4,5-dihydropyrazole-1-carboxylic acid N'-propylhydrazide, 3- (4-chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid piperidin-1-ylamide or 3- (4-Chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-pyrazole-1-carboxylic acid azepan-1-ylamide, or a pharmaceutical thereof Permissible salts. A pharmaceutical composition comprising a compound of formula (I) as defined by any one of claims 1 to 4 in a pharmaceutically effective amount. The method of claim 5, The pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant, diluent or carrier. The method of claim 5, The pharmaceutical composition is a pharmaceutical composition, characterized in that used for the treatment or prevention of obesity. The method of claim 5, The pharmaceutical composition is a pharmaceutical composition, characterized in that used for the treatment or prevention of diseases related to cannabinoid neurotransmission. The method of claim 8, Diseases related to canonoid neurotransmission include schizophrenia, bipolar disorder, anxiety, depression, cognitive and memory disorders, OCD, attention disorders, epilepsy, dementia, Parkinson's disease, Huntington's chorea, Alzheimer's disease, drug addiction and drug abuse A pharmaceutical composition, characterized in that the disease is selected from the group.