WO2015152550A1

WO2015152550A1 - 4,5-dihydro-1h-pyrazole-3-carboximidamide derivatives containing sulfur groups, method for preparing same, and pharmaceutical composition comprising same

Info

Publication number: WO2015152550A1
Application number: PCT/KR2015/002834
Authority: WO
Inventors: Dong Jin Hong; Jong Ouk Baek; Hee Sook Oh; Moon Sub Lee; Tae Hee Ha; Kwee Hyun Suh
Original assignee: Hanmi Pharm. Co., Ltd.
Priority date: 2014-03-31
Filing date: 2015-03-23
Publication date: 2015-10-08
Also published as: AR099870A1; KR20150113762A; TW201623244A

Abstract

The present invention relates to a 4,5-dihydro-1H-pyrazole-3-carboximidamide derivative containing sulfur groups or a pharmaceutically acceptable salt thereof having inverse agonist activity or antagonistic activity against a cannabinoid CB-1 receptor, a method for preparing same, and a pharmaceutical composition comprising same. The inventive compound shows cannabinoid CB1 receptor antagonistic activity with a high selectivity for the peripheral tissues, thereby exhibiting anti-obesity effects, and thus is useful in the prevention or treatment of obesity or obesity-related metabolic diseases.

Description

DESCRIPTION

4,5-DIHYDRO-l^-PYRAZOLE-3-CARBOXIMIDAMIDE

DERIVATIVES CONTAINING SULFUR GROUPS, METHOD FOR PREPARING SAME, AND PHARMACEUTICAL COMPOSITION

COMPRISING SAME

FIELD OF THE INVENTION The present invention relates to a novel 4,5-dihydro-lH-pyrazole-3- carboximidamide derivative containing sulfur groups or a pharmaceutically acceptable salt thereof having inverse agonist activity or antagonistic activity against a cannabinoid CB-1 receptor, a method for preparing same, and a pharmaceutical composition comprising same.

BACKGROUND OF THE INVENTION

Previous in vitro and in vivo studies have indicated that antagonists with inverse agonist activity or antagonist activity against a cannabinoid CBl receptor can affect energy homeostasis via central and peripheral nervous system. Based on clinical trials, it was proven that rimonabant (SR141716A, Pfizer), a selective CB 1 receptor antagonist, was effective in reducing the weights of obese patients and thereby alleviating conditions such as metabolic syndromes including obesity- related diabetes, cardiovascular disorders, etc. Since then, CB l receptors have become a promising target for the treatment of obesity and obesity-related metabolic diseases.

However, CNS-related side effects such as depression, anxiety, dizziness, insomnia, and the like, as well as other side effects related to gastrointestinal disorders including nausea, diarrhea, and the like were observed upon administration of rimonabant, as well as other CB1 receptor antagonists including otenabant (CP-945598, Pfizer), surinabant (Sanofi-Aventis), ibipinabant (SLV 319, Solvay Pharmaceuticals), taranabant (MK-0364, Merck), drinabant (AVE1625, Aventis Pharmaceuticals), and the like, and thus, these drugs were withdrawn from the market and their development have been discontinued.

Considering severity of obesity and a lack of effective drugs for the treatment of obesity, a development of an effective GB 1 receptor antagonist having the above problems fixed has become a topic of interest.

Accordingly, the present inventor have endeavored to develop a CB1 receptor antagonist which is selective for the peripheral tissues, rather than the brain tissue, so as to reduce the side effects of conventional drugs, and have accomplished the present invention by discovering a novel 4,5-dihydro-lH-pyrazole-3- carboximidamide derivative containing sulfur groups having antagonistic activity against a CB1 receptor which also exhibits reduced side effects owing to its high selectivity for the peripheral tissues.

SUMMARY OF THE INVENTION

Therefore, an object of the present invention is provided with a novel compound containing sulfur groups having antagonistic activity against a CB 1 receptor which also exhibits reduced side effects owing to its high selectivity for the peripheral tissues.

Also, another object of the present invention is provided with a method for preparing the compound and a pharmaceutical composition comprising the compound.

In accordance with one object, the present invention provides a novel compound selected from the group consisting of a 4,5-dihydro-lH-pyrazole-3- carboximidamide derivative containing sulfur groups and a pharmaceutically acceptable salt thereof.

In accordance with another object, the present invention provides a method for preparing the compound.

In accordance with still another object, the present invention provides a pharmaceutical composition for the prevention or treatment of obesity or an obesity- related metabolic disease, comprising the compound as an active ingredient.

The compound of present invention has reduced side effects owing to its high selectivity for the peripheral tissues. Further, since the compound has inverse agonist activity or antagonistic activity against a cannabinoid CB1 receptor, it exhibits excellent anti-obesity effects, and, thus, it is useful in the prevention or treatment of obesity or obesity-related diseases.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a graph showing a weight reduction effect resulting from administration of the compound of Example 1 in diet- induced obesity (DIO) mice.

Fig. 2 is a graph showing reduced translocation of the drug into the brain tissue resulting from administration of the compound of Example 1.

Fig. 3 is a graph showing reduced CNS-related side effects resulting from administration of the compound of Example 1 as measured by elevated plus maze (EPM) test.

Fig. 4 is a graph showing reduced CNS-related side effects resulting from administration of the compound of Example 1 as measured by forced swimming test (FST).

DETAILED DESCRIPTION OF THE INVENTION

Hereinafter, the present invention is described in detail.

The term "sulfur group," as used herein, refers to thio (-S-), sulfinyl (- S(=O)-) and sulfonyl (-S(=O)₂-), unless otherwise specified.

The term "halogen," as used herein, refers to fluoro, bromo, chloro and iodo.

The term "alkyl," as used herein, refers to linear or branched saturated hydrocarbon chain radicals having 1 to 7 carbon atoms. Particular examples thereof may include, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, /-butyl, «-pentyl, isopentyl and hexyl.

The term "alkoxy," as used herein, refers to -OR groups, wherein R is an alkyl as defined above. Particular examples thereof may include, but not limited to, methoxy, ethoxy, -propoxy, isopropoxy, n-butoxy and t-butoxy.

The term "cycloalkyl," as used herein, refers to monocyclic alkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, or bi- or multicyclic alkyl, unless otherwise specified.

The term "aryl," as used herein, refers not only to monocyclic aromatic rings such as phenyl, substituted phenyl, etc., but also to bi- or multicyclic aromatic rings such as naphthyl, phenanthrenyl and the like, unless otherwise specified. The said aryl group is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, nitro, trifluoromethyl, amino, cycloalkyl, cyano, alkyl- S(0)_n- (n= 1 ,2 ,3 ) and thiol, but not limited thereto .

The term "heteroaryl," as used herein, refers to monocyclic or bicyclic heteroaryl groups having at least one hetero atom selected from O, N and S, unless otherwise specified. Particular examples may include monocyclic heteroaryl such as furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isooxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3- oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, cinnolinyl, phtheridinyl, purinyl; or bicyclic heteroaryls such as 5,6,7,8-tetrahydro- quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzo[b]thienyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolyzinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, pyrazolo[3,4-b]pyridinyl, benzoxazinyl and the like.

The term "heterocycloalkyl," as used herein, refers to monocyclic or bi- or multicyclic alkyl having at least one hetero atom selected from O, N and S, unless otherwise specified. Particular examples of monocyclic heterocycloalkyl may include, but not limited to, piperidinyl, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperazinyl and the like.

The present invention provides a compound represented by formula (I) or a pharmaceuticall acceptable salt thereof:

wherein A¹ is C_1-7alkyl, C_6-10aryl, 5 to 10-membered heteroaryl, C_3- ₆cycloalkyl or 3 to 6-membered heterocycloalkyl;

A² and A³ are each independently C_6-10aryl or 5 to 10-membered heteroaryl;

X is -S-, -S(=O)- or -S(=O)₂-;

L is

R is C_1-6alkyl;

each of A¹, A², A³, L and R is optionally substituted with at least one substituent selected from the group consisting of hydrogen, C_1-6alkyl, C_1-6alkoxy, halogen, cyano, hydroxy, nitro, -C(=O)-R', -S-R, -S(=O)-R', -S(=O)₂-R', -NR'R" and -C(=O)-NR'R", and R' and R" are each independently hydrogen or C_1-6alkyl; and

each of said heteroaryl and heterocycloalkyl independently contains at least one heteroatom selected from N, O and S.

According to one embodiment of the compound of formula (I),

A¹ is C_6-10aryl or 5 to 10-membered heteroaryl, and A¹ is optionally substituted with at least one substituent selected from the group consisting of hydrogen, halogen and C_1-6alkyl; A² is C₆_i₀aryl or 5 to 10-membered heteroaryl, and A² is optionally substituted with at least one substituent selected from the group consisting of hydrogen and cyano;

A³ is C_6-i₀aryl, and A³ is optionally substituted with at least one halogen; X is -S-, -S(=0)- or -S(=O)₂-;

L is C_{1 -6}alkylene, R is Ci_-3alkyl, each of L and R is optionally substituted with at least one substituent selected from the group consisting of C_1-6alkyl, Cj. ₆alkoxy, halogen, cyano, hydroxy, nitro, -C(=O)-R', -S-R', -S(=O)-R', -S(=O)₂-R', - NR'R" and -C(=O)-NR'R", and R' and R" are each independently hydrogen or CV ₆alkyl; and

said heteroaryl contains at least one heteroatom selected from N, O and S.

According to another embodiment of the compound of formula (I), when each of A¹ to A³ is independently C_6-10aryl or 5 to 10-membered heteroaryl, A¹ to A³ are each independently selected from the group consisting of phenyl, furanyl, benzofuranyl, thienyl, benzothienyl, pyridyl, pyrimidyl, pyrazinyl and pyridazinyl; and

each of A¹ to A³ is optionally substituted with at least one substituent selected from the group consisting of hydrogen, halogen, cyano and C_1-6alkyl.

According to still another embodiment of the compound of formula (I), A¹ is chlorophenyl or chloropyridyl;

A² is phenyl, fluorophenyl or thienyl;

A³ is chlorophenyl, fluorophenyl or difluorophenyl;

X is -S-, -S(=O)- or -S(=O)₂-; and

L is C_1-6alkylene, R is C_1-3alkyl, each of L and R is optionally substituted with at least one C_1-3alkyl.

According to preferred embodiments, the 4,5-dihydro-lH-pyrazole-3- carboximidamide derivative of formula (I) is selected from the group consisting of 1) to 12) as listed below:

1 ) (R,Z - 1 -(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-N-(2- (me1hylsulfonyl)ethyl)-5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamide;

2) (S, Z)- 1 -(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-N-(2- (methylsulfonyl)ethyl)-5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamide;

3) (R₎2)-l-(4_:chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-(2- fluorophenyl)-N-(2-(methylsulfonyl)ethyl)-4,5-dihydro-lH-pyrazole-3- carboximidamide;

4) (R,Z)-l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-N-(2- (methylsulfonyl)ethyl)-5-(thien-2-yl)-4,5-dihydro-lH-pyrazole-3-carboximidamid^

5) (R_>Z)-N'-((4-chlorophenyl)sulfonyl)-l-(2,4-difluorophenyl)-N-(2- (methylsulfonyl)ethyl)-5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamide;

6) (R,Z)- 1 -(4-chlorophenyl)-N'-((6-chloropyridin-3 -yl)sulfonyl)-N-(2- methylsulfonyl)ethyl)-5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamide;

7) (R,Z)-l-(4-chlorophenyl)-N'-((6-chloropyridin-3-yl)sulfonyl)-5-(2- fluorophenyl)-N-(2-(methylsulfonyl)ethyl)-4,5-dihydro-lH-pyrazole-3- carboximidamide ;

8) (R,2)- 1 -(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-N-(2- (methylthio)e11iyl-5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamide;

9) (R,Z)-l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-N-(2- (methylsulfmyl)ethyl)-5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamide;

10) (R, )- 1 -(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-N-((S)-3- methyl- 1 -(methylsulfonyl)butan-2-yl)-5-phenyl-4,5-dihydro- lH-pyrazole-3 - carboximidamide ;

11) (R,Z)- 1 -(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-(2- fluorophenyl)-N-((S)-3 -methyl- 1 -(methylsulfonyl)butan-2-yl)-4,5-dihydro- 1H- pyrazole-3-carboximidamide; and

12) (R, Z)-N'-((4-chlorophenyl)sulfonyl)- 1 -(4-fluorophenyl)-N-((S)-3- methyl- 1 -(methylsulfonyl)butan-2-yl)-5-phenyl-4,5-dihydro- lH-pyrazole-3- carboximidamide. Besides 4,5-dihydro-lH-pyrazole-3-carboximidamide derivatives of formula (I) and pharmaceutically acceptable salts thereof, stereoisomers, solvates and hydrates thereof are also included within the scope of the present invention.

A pharmaceutically acceptable salt of the compound of formula (I) may be prepared by conventional methods well-known in the art, for example, a salt formed with an inorganic acid such as hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, and the like; a salt formed with an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestisic acid, fumaric acid, lactobionic acid, salicylic acid, acetylsalicylic acid (aspirin), and the like; a salt formed with an amino acid such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline, and the like; a salt formed with a sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and the like; a metallic salt formed by the reaction with an alkali metal such as sodium, potassium, and the like; and a salt formed with an ammonium ion.

Also, the compounds of the present invention may have asymmetric carbon atoms and, thus, may exist as R- or S- isomer, racemic mixtures, individual enantiomers or mixtures thereof, and individual diastereomers or mixtures thereof. Such stereoisomers and mixtures thereof are also included within the scope of the present invention.

Additionally, solvates and hydrates of the compound of formula (I) are also included within the scope of the present invention. Such solvates and hydrates may be prepared by conventional methods well-known in the art. Preferably, the solvates and hydrates are non-toxic and water-soluble, and form 1 to 5 bonds with water or alcohol-based solvent (particularly, ethanol and the like). Further, the present invention provides a method for preparing the compound of formula (I).

The method for preparing the compound of formula (I) is represented by the procedure shown in Reaction Scheme 1 below.

[Reaction Scheme 1]

1

wherein A , A , A , L, X and R have the same meanings as defined in formula (I).

The compound of formula (II) which is used as a starting material may be prepared by halogenating 4,5-dihydro-lH-pyrazole-3-carboxylate and then reacting with a sulfonamide compound in the presence of a base, using the method disclosed in Reference [J. Med. Chem, 2007, 50, p5951-5966; Bioorganic & Medicinal Chemistry Letters, 2010, 20(5), pi 752- 1757; and WO 2005/074920] or any similar method thereto. For example, the sulfonamide compound may be 4- chlorobenzenesulfonamide, 4,4-difluoropiperidine-l -sulfonamide, 4- methylpiperazinesulfonamide, and the like. According to one method for preparing the compound of formula (I) from the starting material, the reaction processes are explained with reference to Reaction Scheme 1.

In step (a), a compound of formula (III) is obtained by introducing sulfur to a compound of formula (II). The compound of formula (II) is subjected to a reaction with P₂S₅ or Lawesson's reagent in an organic solvent, for example, such as toluene by heating or heating under reflux conditions for 6 to 12 hours.

In step (b), a compound of formula (IV) is obtained by introducing methyl reaction group to the compound of formula (III). The compound of formula (III) is subjected to a reaction with methyl iodide in an organic solvent, for example, such as acetone in the presence of a base such as triethylamine or potassium carbonate under room temperature or heating conditions for 1 to 5 hours.

In step (c), a compound of formula (I) is obtained by allowing the compound of formula (IV) to react with an amide derivative such as a compound of formula (VI) in an organic solvent, for example, such as tetrahydrofuran in the presence of a base such as triethylamine or potassium carbonate under room temperature or heating conditions for 3 to 12 hours.

According to another method for preparing the compound of formula (I) from the starting material, the reaction processes are explained with reference to Reaction Scheme 1.

In step (a'), a compound of formula (V) is obtained by introducing a chlorine group to a compound of formula (II). The compound of formula (II) is subjected to a reaction in an organic solvent, for example, such as chlorobenzene in the presence of a chlorinated compound such as phosphorus pentachloride (PC1₅) by heating or heating under reflux conditions for 1 to 3 hours.

In step (b'), a compound of formula (I) is obtained by changing the reaction temperature to a lower or room temperature, and then subjecting the compound of formula (V) to a reaction with an amine derivative such as a compound of formula (VI) in an organic solvent, for example, such as dichloromethane in the presence of a base such as triethylamine or potassium carbonate at a room temperature or heating conditions for 1 to 3 hours.

Thus, in accordance with one embodiment of the present invention, a compound of formula (I) is prepared by a method comprising the steps of:

(a) allowing a compound of formula (II) to react with phosphorus pentasulfide (P2S5) or Lawesson's reagent in a solvent selected from the group consisting of toluene, xylene, benzene, chlorobenzene, and a mixture thereof to obtain a compound of formula (III);

(b) allowing the compound of formula (III) to react with methyl iodide in a solvent selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, and a mixture thereof in the presence of a base selected from the group consisting of triethylamine, potassium carbonate, and a mixture thereof to obtain a compound of formula (IV); and

(c) allowing the compound of formula (IV) to react with a compound of formula (VI) in a solvent selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, and a mixture thereof in the presence of a base selected from the group consisting of triethylamine, potassium carbonate, and a mixture thereof.

In accordance with another embodiment of the present invention, a compound of formula (I) is prepared by a method comprising the steps of:

(a) allowing a compound of formula (II) to react with phosphorus pentachloride (PC1₅) in a solvent selected from the group consisting of toluene, xylene, benzene, chlorobenzene and a mixture thereof to obtain a compound of formula (V); and

(b) allowing the compound of formula (V) to react with a compound of formula (VI) in a solvent selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, and a mixture thereof in the presence of a base selected from the group consisting of triethylamine, potassium carbonate, and a mixture thereof.

Meanwhile, the present invention also provides a pharmaceutical composition for the prevention or treatment of obesity or an obesity-related metabolic disease, comprising the compound of the present invention as an active ingredient.

The obesity-related metabolic disease may be selected from the group consisting of type 2 diabetes, chronic hepatic disease, angina, hypertension, congestive heart failure, and hyperlipidemia, but not limited thereto.

The active ingredient has antagonistic activity against a cannabinoid CB-1 receptor.

The pharmaceutical composition may be formulated in the form of oral or parenteral formulations well-known in the art, and may contain a filler, an extender, a binder, a wetting agent, a disintegrant, a diluent such as a surfactant, or an excipient that are well-known in the art.

A solid formulation for oral administration may be prepared by mixing at least one benzamide derivative of the present invention with at least one excipient, for example, starch, calcium carbonate, sucrose, lactose, gelatin, and the like. Also, besides a simple excipient, a lubricant such as magnesium stearate or talc may be used.

A liquid formulation for oral administration may be prepared in the form of a suspension, a liquid preparation, an emulsion or a syrup. A simple diluent such as water, liquid paraffin, and the like, as well as other excipients including a wetting agent, a sweetening agent, a flavoring agent, a preservative and the like, may be used.

A formulation for parenteral administration may be prepared in the form of a sterilized aqueous solution, a non-aqueous solvent, a solvent suspension, an emulsion, a lyophilized formulation or a suppository. The non-aqueous solvent or solvent suspension may contain propylene glycol, polyethylene glycol or vegetable oil such as olive oil, injectable ester such as ethylolate. In the suppository, a base material may include Witepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerol, gelatin, and the like.

Additionally, a proposed daily dose of the pharmaceutical composition of the present invention to a human (of approximately 70 kg body weight) may be in the range of 0.1 to 1,000 mg/day, preferably 1 to 500 mg/day, in a single dose or in divided doses per day. It is understood that the daily dose should be determined in light of various relevant factors including the condition, age, body weight and sex of the subject to be treated, administration route, and diseases severity. The present invention also provides a use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of obesity or an obesity-related metabolic disease.

The present invention also provides a method for preventing or treating obesity or an obesity-related metabolic disease in a mammal, which comprises administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to the mammal.

Particular examples of said obesity-related metabolic disease are same as defined above. The following Examples are provided to illustrate preferred embodiments of the present invention, and are not intended to limit the scope of the present invention.

Example 1: Preparation of (^,Z)-l-(4-chlorophenyl)-/V -((4- chlorophenyI)sulfonyI)-/V-(2-(methylsulfonyl)ethyl)-5-phenyl-4,5-dihydro-l -^r- pyrazole-3-carboximidamide

The title compound of Example 1 was prepared by the following two methods (i.e., Example 1 A or Example IB). Example (1A)

Step 1) Preparation of (R)-l-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)- 5-phen l-4,5-dihydro- lH-pyrazole-3-carbothioamide

(R)-l-(4-Chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-5-phenyl-4,5- dihydro-lH-pyrazole-3-carboxamide was prepared according to the method disclosed in References [J. Med. Chem, 2007, 50, p5951-5966; Bioorganic & Medicinal Chemistry Letters, 2010, 20(5), pl752-1757; and WO 2005/074920] or a similar method thereto. The compound thus prepared (1.0 g, 2.1 mmol) and phosphorus pentasulfide (P₂S₅, 0.94 g, 4.2 mmol) were added to toluene (20 niL), and stirred at 120°C for about 6 hours.

Substances which were undissolved in the organic solvent were filtered out using a Celite. The resulting filtrate was washed with ethyl acetate, and the organic layer was concentrated under reduced pressure. The concentrated residues were dissolved in ethyl acetate, and washed with a saturated aqueous solution of sodium hydrogen carbonate and brine. The solid residue thus obtained was crystallized by using ethanol to obtain the title compound (0.7 g).

H-NMR(300MHz, CDC1₃) δ 8.05(d, 2H), 7.50(d, 2H), 7.4-7.1(:

7.02(d, 2Η), 5.40(dd, 1Η), 3.77(dd, 1Η), 3.24(dd, 1Η).

MS(ESI⁺): m/z = 490.0 [M+H]⁺.

Step 2) Preparation of (R,Z)-methyl l-(4-chlorophenyl)-N-((4- chloroph nyl) sulf onyl) - 5 -phenyl-4 , 5 -dihydro- 1 H-pyrazole- 3 -carbimidothiolate

The compound obtained in Step 1) (240 mg, 0.5 mmol) was dissolved in acetone, and added with methyl iodide (70 mg, 0.5 mmol) and triethylamine (100 mg, 1.0 mmol). The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The concentrated residue thus obtained was dissolved in ethyl acetate, and washed with 1 N aqueous hydrochloric acid solution and brine. The solid residue thus obtained was crystallized by using methanol to obtain the title compound (150 mg).

1H-NMR(300MHz, CDC1₃) δ 7.93(d, 2H), 7.47(d, 2H), 7.4-7. l(m, 5H), 7.05(d, 2H), 5.50(dd, 1H), 4.16(dd, 1H), 3.44(dd, 1H), 2.38(s, 3H).

MS(ESf): m/z = 504.0 [M+H]⁺.

Step 3) Preparation of (R,Z)-l-(4-chlorophenyl)-N'-((4- chlorophenyl)sulfonyl)-N-(2-(methylsulfonyl)ethyl)-5-phenyl-4,5-dihydro-lH- pyrazol -3 -carboximidamide

The compound obtained in Step 2) (1.14 g, 2.26 mmol) was dissolved in tetrahydrofuran (5 mL), and then 2-aminoethyl methyl sulfone hydrochloride (613 mg, 3.84 mmol) and triethylamine (571 mg, 5.65 mmol) were sequentially added thereto. The reaction mixture was heated to 60°C and stirred for 4 hours. The organic layer thus formed was washed with water, 1 Ν aqueous hydrochloric acid solution and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue thus obtained was crystallized by using a mixed solution of chloromethane/diethyl ether to obtain the title compound as a yellow compound (1.35 g).

1H-NMR(300MHz, DMSO-d₆) δ 9.28(s, 1H), 7.86(d, 2H), 7.59(d, 2H), 7.40-7.27(m, 5H), 7.23(d, 2H), 6.96(d, 2H), 5.65(dd, 1H), 3.97(dd, 1H), 3.69(t, 2H), 3.39(t, 2H), 3.17(dd, 1H), 3.00(s, 3H). MS(ESf ): m/z = 579.1 [M+H]⁺.

Example (IB) (R)- 1 -(4-Chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-5-phenyl-4,5- dihydro-lH-pyrazole-3-carboxamide was prepared according to the method disclosed in References [J. Med. Chem, 2007, 50, p5951-5966; Bioorganic & Medicinal Chemistry Letters, 2010, 20(5), pl752-1757; and WO 2005/074920] or a similar method thereto. The compound thus prepared (189 mg, 0.4 mmol) and phosphorus pentachloride (83 mg, 0.8 mmol) were added to chlorobenzene, and stirred at 130°C for 1 hour. Upon completion of the reaction, the reaction solution was concentrated.

The concentrated compound was added with a solvent, dichloromethane, and then cooled down to 0°C under an atmosphere of nitrogen. Subsequently, 2- aminoethyl methyl sulfone hydrochloride (64 mg, 0.4 mmol) and triethylamine (60 mg, 0.6 mmol) were sequentially added thereto. The reaction mixture was slowly heated to room temperature while stirring for 1.5 hours. Upon completion of the reaction, the mixture was extracted using dichloromethane and water, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The compound thus obtained was purified by preparative liquid chromatography (PLC, silica gel 60 F₂₅₄, 1 mm) to obtain the title compound as a yellow compound (18 mg).

'H-NMR(300MHz, DMSO-d₆) δ 9.28(s, 1H), 7.86(d, 2H),^' 7.59(d, 2H), 7.40-7.27(m, 5H), 7.23(d, 2H), 6.96(d, 2H), 5.65(dd, 1H), 3.97(dd, 1H), 3.69(t, 2H), 3.39(t, 2H), 3.17(dd, lH), 3.00(s, 3H).

MS(ESI⁺): m/z = 579.1 [M+H]⁺.

Example 2: Preparation of (5',Z)-l-(4-chlorophenyl)-A^ -((4- chlorophenyl)sulfonyl)-A^-(2-(methylsulfonyl)ethyl)-5-phenyl-4,5-dihydro-lH- pyrazole-3-carboximidamide

The same method as that in Example (IB) or a similar method thereto was conducted to obtain the title compound as a yellow compound (38 mg).

1H-NMR(300MHz, DMSO-d₆) δ 9.29(s, 1H), 7.88-7.85(d, 2H), 7.60-7.57(d, 2H), 7.39-7.21(m, 7H), 6.97-6.94(d, 2H), 5.68-5.62(dd, 1H), 4.02-3.91(m, 1H), 3.68-3.66(m, 2H), 3.41-3.39(m, 2H), 3.00(s, 3H).

MS(ESI⁺): /z=579.1 [M+H]⁺

Example 3: Preparation of ( f,Z)-l-(4-chlorophenyl)-7V -((4- chlorophenyl)sulfonyl)-5-(2-fluorophenyl)- V-(2-(methylsuIfonyl)ethyl)-4,5- dihydr -l^-pyrazole-S-carboximidainide

The same method as that in Example (IB) or a similar method thereto was conducted to obtain the title compound as a yellow compound (50 mg).

1H-NMR(300MHz, CDC1₃) δ 7.9(d, 2H), 7.48-7.45(d, 2H), 7.28-7.17(m, 2H), 7.12-7.08(m, 3H), 6.95-6.92(m, 3H), 5.7(dd, 1H), 4.3(t, 1H), 4.0(m, 2H), 3.5- 3.3(m, 3H), 3.0(s, 3H).

MS(ESI⁺): m/z = 597.1 [M+H]⁺.

Example 4: Preparation of (7?,Z)-l-(4-chlorophenyl)- V'-((4- chlorophenyl)sulfonyl)-A^L(2-(methylsulfonyl)ethyl)-5-(thien-2-yl)-4,5-dihydro- l.iT-pyrazole-3-carboximidamide

The same method as that in Example (IB) or a similar method thereto was conducted to obtain the title compound as a yellow compound (30 mg).

1H-NMR(300MHz, CDC1₃) δ 7.9(d, 2H), 7.47-7.44(d, 2H), 7.25-7.18(m, 3H), 7.06(m, 2H), 6.95-6.92(m, 2H), 5.7(dd, IH), 4.5(t, IH), 4.0(m, 2H), 3.5-3.4(m, 3H), 3.0(s, 3H).

MS(ESI⁺): m/z = 585.0 [M+H]⁺.

Example 5: Preparation of (/i,Z)-A^ -((4-chIorophenyl)sulfonyl)-l-(2,4- difluorophenyl)-iV-(2-(methylsulfonyl)ethyl)-5-phenyl-4,5-dihydro-l -^r- pyrazole-3-carboximidamide

The same method as that in Example (IB) or a similar method thereto was conducted to obtain the title compound as a yellow compound (53.8 mg).

1H-NMR(300MHz, DMSO-de) δ 9.3 l(s, IH), 7.89(d, 2H), 7.59(d, 2H), 7.54-7.40(m, IH), 7.36-7.19(m, 5H), 7.18-7.07(m, IH), 7.05-6.90(m, IH), 5.74- 5.60(m, IH), 3.92(dd, IH), 3.68(t, 2H), 3.39(t, IH), 3.28(dd, IH), 3.00(s, 3H).

MS(ESf): m/z = 581.1 [M+H]V

Example 6: Preparation of (i?,Z)-l-(4-chlorophenyl)-A^ -((6- chloropyridin-3-yl)sulfonyl)-A^,-(2-methylsulfonyl)ethyl)-5-phenyl-4,5-dihydro- l f-pyrazole-3-carboximidamide

The same method as that in Example (IB) or a similar method thereto was conducted to obtain the title compound as a yellow compound (72 mg).

1H-NMR(300MHz, DMSO-d₆) δ 9.36(s, IH), 8.86(d, IH), 8.29(dd, IH), 7.69(d, IH), 7.41-7.15(m, 7H), 6.96(d, 2H), 5.69(dd, IH), 3.96(dd, IH), 3.69(t, IH), 3.41 (t, 1 H), 3.17(dd, IH), 3.02(s, 3H)

MS(ESI⁺): m/z = 580.1 [M+H]⁺.

Example 7: Preparation of ( ?,Z)-l-(4-chlorophenyl)-A^^f-((6- chloropyridin-3-yI)suIfonyI)-5-(2-fluorophenyl)-A^r-(2-(methylsulfonyl)ethyl)- 4,5-dih dro-li7-pyrazole-3-carboximidamide

1H-NMR(300MHz, CDC1₃) δ 8.9(s, IH), 8.2(d, IH), 7.8(d, IH), 7.47- 7.45(d, 2H), 7.20-7.17(m, 2H), 7.12-7.10(d, 2H), 6.99-6.92(d, 2H), 5.8(dd, IH), 4.2(t, IH), 4.0(m, 2H), 3.5-3.3(m, 3H), 3.0(s, 3H).

MS(ESI⁺): m/z = 598.1 [M+H]⁺.

Example 8: (7?,Z)-l-(4-chlorophenyl)-^^f-((4-clilorophenyl)sulfonyl)- V- (2-(methylthio)ethyl-5-phenyl-4,5-dihydro-l -^r-pyrazole-3-carboximidamide

The same method as that in Example (1A) or a similar method thereto was conducted to obtain the title compound as a yellow compound (25.2 mg).

^• 1H-NMR(300MHz, DMSO-d₆) δ 9.26(s, IH), 7.82(d, 2H), 7.59(d, 2H), 7.40-7.25(m, 5H), 7.22(d, 2H), 6.95(d, 2H), 5.62(dd, IH), 3.97(dd, IH), 3.46(t, 2H), 3.16(dd, IH), 2.62(t, 2H), 1.97(s, 3H).

MS(ESI⁺): m/z = 547.1 [M+H]⁺.

Example 9: Preparation of (i?,Z)-l-(4-chlorophenyl)-iV -((4- chlorophenyl)sulfonyl)-A-(2-(methylsulfinyl)ethyl)-5-phenyl-4,5-dihydro-l^- pyrazol -3-carboximidamide

The same method as that in Example (IB) or a similar method thereto was conducted to obtain the title compound as a yellow compound (22.9. mg).

1H-NMR(300MHz, DMSO-d₆) δ 9.38(s, IH), 7.85(d, 2H), 7.58(d, 2H), 7.41-7.25(m, 5H), 7.22(d, 2H), 6.93(d, 2H), 5.63(dd, IH), 3.96(dd, IH), 3.62(t, 2H), 3.16(dd, IH), 3.12-2.99(m, IH), 2.95-2.80(m, IH), 2.56(s, 3H).

MS(ESI⁺): m/z = 563.1 [M+H]⁺.

Example 10: Preparation of ( ?,Z)-l-(4-chlorophenyl)-^V^r-((4- chlorophenyl)sulfonyl)-A-((S)-3-methyl-l-(methylsulfonyl)butan-2-yl)-5- phenyl-4,5-diliydro-l -^r-pyrazole-3-carboximidamide

The same method as that in Example (IB) or a similar method thereto was conducted to obtain the title compound as a yellow compound (35 mg).

1H-NMR(300MHz, DMSO-d₆) δ 9.08-9.05(d, 1H), 7.81-7.78(d, 2H), 7.61- 7.58(d, 2H), 7.37-7.27(m, 5H), 7.23-7.20(d, 2H), 6.91-6.88(d, 2H), 5.60-5.54(dd, 1H), 4.37(m, 1H), 3.97-3.87(m, 1H), 3.41-3.39(d, 2H), 3.22-3.20(m, 1H), 2.99(s, 3H), 1.92-1.90(m, 1H), 0.86-0.83(d, 6H).

MS(ESI⁺): m/z = 621.1 [M+H]⁺.

Example 11: Preparation of (/?,Z)-l-(4-chlorophenyI)-A^ -((4- chlorophenyl)sulfonyl)-5-(2-fluorophenyl)-A^L((S)-3-methyl-l - (methylsulfon l)butan-2-yl)-4,5-dihydro-l/T-pyrazole-3-;carboximidaniide

1H-NMR(300MHz, DMSO-d₆) 5 9.07-9.05(d, 1H), 7.80-7.77(d, 2H), 7.60- 7.58(d, 2H), 7.38-7.17(m, 6H), 6.91-6.88(m, 2H), 5.78-5.76(dd, 1H), 4.36(m, 1H), 3.97-3.95(m, 1H), 3.41-3.39(d, 2H), 3.24-3.18(m, 1H), 3.01(s, 3H), 1.92-1.90(m, 1H), 0.86-0.83(d, 6H).

MS(ESI⁺): m/z = 639.1 [M+H]⁺.

Example 12: Preparation of (l?,Z)-N'-((4-chlorophenyl)sulfonyl)-l-(4- fluorophenyl)-A^r-((S)-3-methyl-l-(methylsulfonyl)butan-2-yl)-5-phenyl-4,5- dihydro-lH-pyrazole-3-carboximidamide

The same method as that in Example (IB) or a similar method thereto was conducted to obtain the title compound as a yellow compound (45 mg).

1H-NMR(300MHz, DMSO-d₆) δ 9.03-9.00(d, 1H), 7.82-7.79(d, 2H), 7.60- 7.58(d, 2H), 7.41-7.26(m, 6H), 7.09-6.89(m, 4H), 5.58-5.51(dd, lH), 4.36(m, 1H), 3.96-3.86(m, 1H), 3.41-3.39(d, 2H), 3.23-3.20(m, 1H), 3.01(s, 3H), 1.94-1.88(m, 1H), 0.86-0.83(d, 6H).

MS(ESI⁺): m/z = 605.1 [M+H]⁺. The chemical structures of the compounds prepared in the above Examples are shown in Table 1 below.

[Table 1]

(R,∑)- 1 -(4-chlorophenyl)-N'-((4- chlorophenyl)sulfonyl)-5-(2-

11 fluorophenyl)-N-((S)-3 -methyl- 1 - (methylsulfonyl)butan-2-yl)-4,5-dihydro- lH-pyrazole-3-carboximidamide

(R,Z)-N'-((4-chlorophenyl)sulfonyl)-l-(4- fluorophenyl)-N-((S)-3 -methyl- 1 -

12 (methylsulfonyl)butan-2-yl)-5-phenyl- 4,5 -dihydro- 1 H-pyrazole-3 - carboximidamide

■

Experimental Example 1 : fS] GTPyS Binding Assay The antagonistic activity of the compounds prepared in Examples against Gi protein coupled receptors, i.e. , cannabinoid receptor 1, was evaluated as follows.

The assay is based upon the GDP-GTP exchange principle. A non- hydrolyzable form of GTP, i. e. , GTPyS, a radiochemical [³⁵S]-1250Ci/mmol, 12.5mCi/mmol, lmCi (Perkin Elmer, cat. NEG030H001MC), and WGA-coated SPA beads (Cat. RPNQ0210) were used for the assay. Each of the compounds prepared was placed in an IX assay buffer (20 mM HEPES, 100 mM NaCl, 25 mM MgCl₂, 1 mM EDTA, pH 7.4), and diluted to produce samples with various concentrations including 10 μΜ, 1 μΜ, 100 nM, 10 nM, 1 nM and 0.1 nM. A CB1 receptor membrane (Cat. HTS019M, Millipore) was diluted with a saponin solution, and mixed with 3 μΜ GDP at the ratio of 1 : 1 to form a mixture.

The mixture of the CB1 receptor membrane and GDP thus prepared (100 μΐ,) was added with diluted samples, further added with a mixture prepared by adding WGA-coated SPA beads and the [³⁵S]GTPyS mixture at the ratio of 1 : 1. The reaction mixture was allowed to react at room temperature for 50 minutes, and then [³⁵S]GTPyS activity was measured by using a β-scintillation counter. In this test, a basal well excluded only the compounds, and a background well excluded the compounds, membrane and GDP for the reaction. IC₅₀ values were calculated for each compound by using GraphPad Prism 4.0 software.

As a result of CB 1 GTPyS binding assay, compounds of Examples 1, 3, 4, 6, 8, 10, 11 and 12 exhibited IC₅₀ values of 13 nM, 15 nM, 18 nM, 13 nM, 14 nM, 14 nM, 19 nM and 8 nM, respectively. These values indicate that the compounds according to the Examples of the present invention show excellent antagonistic activity against the CB1 receptors.

Experimental Example 2: Assay for Anti-Obesity Effects (in vivo) (2-1) Change in Body Weight

Diet induced obesity (DIO) mice were used to evaluate the suppressive effect of the inventive compounds. 5-week-old C57BL/6 mice (OrientBio) were fed with a high fat diet for 2 to 5 months to make DIO mice. All DIO mice were housed in a 12:12 hour lightdark cycle room (11 :00 light-out, 23:00 light-on) with controlled conditions of humidity and temperature, and had free access to food and water.

One week before each test, each mouse was individually housed, and a baseline of body weight was determined by conducting a habituation to a treatment. Mice were randomly groups into treatment groups, based on their initial body weights and feeding amounts. The compound prepared according to Example 1 and a commonly known antagonist (rimonabant), as a positive control, were each administered to DIO mice so as to evaluate the suppressive effect of the test compound on feeding amount. Also, as a vehicle-treated group, untreated mice were tested.

One hour before the start of dark cycle, DIO mice were treated with the test compound at 10 mg/kg. The body weight was measured every 24 hours from day 0 (before the treatment) until day 7 using an electronic scale. The data (the change in body weight) obtained from the vehicle-treated group, the standard positive control-treated group, and the test compound-treated groups are shown in Fig. 1.

As shown in Fig. 1, body weights were gradually reduced in mice which were treated with the compound of Example 1 according to the present invention, and this weight reduction effect was observed during the 1-week treatment period, and lasted for a certain period of time even after the treatment. Thus, it can be concluded that the compound of Example 1 according to the present invention exhibits anti-obesity effects.

(2-2) Brain-to-Plasma Exposure Ratio

Brain exposure rate of the compound of the present invention was measured by using tissues sampled from DIO mice used for evaluation of changes in feeding amount and body weight. Blood samples were taken from the mice at 0.5 hour after the oral administration.

The blood samples were placed in heparin-treated eppendorf tubes 1 ,000

IU/mL, heparin, 3 uL), and immediately centrifuged (12,000 rpm, 2 minutes) to separate the plasma. At 0.5 hour after the administration, which is expected to be the T_max of the compound, brain samples were taken from the mice, diluted 10 times using a 4% bovine serum albumin (BSA) solution, pulverized, and then analyzed.

The exposure levels of the test compound in the blood and brain tissue samples are shown in Fig. 2.

As can be seen in Fig. 2, the brain exposure rate (which is closely related with side effects) of the compound of Example 1 according to the present invention (about 1%) was superior to that of rimonabant (about 41%)

This result demonstrates that the subject compound is excellent drug which can reduce side effect of conventional drugs. In other words, it can be confirmed that the subject compound is a drug having good antagonistic activity against a CB 1 receptor, which exhibits a high selectivity for the peripheral tissues, rather than the brain tissue.

Experimental Example 3: Evaluation of Depression and Anxiety via Behavioral Test The incidence of central nervous system (CNS)-related side effects, i.e., depression and anxiety caused by the compound of the present invention was evaluated as follow. (3-1) Elevated Plus Maze (EPM) Test

In order to evaluate the incidence of anxiety due to the drug, an elevated plus maze (EPM) test was carried out as follows, wherein an elevated plus maze was installed 50 cm above the ground. The maze for EPM test consisted of two open arms and two closed arms which were crossed over. The compound of Example 1, and rimonabant, as a positive control, were each orally administered to mice, and the test was conducted at 30 minutes post-dose. The mice were placed on a center zone where the open arms and the closed arms were crossed, and their behavior was observed for 6 minutes. The behavior of mice was recorded using a camera installed on the ceiling, and the time spent at the open arms and the total distance travelled were analyzed using a tracking software Ethovision XT 7 program (Noldus). Also, the same test was conducted using mice administered with a vehicle only (vehicle group).

After measuring the behavior of the mice for 6 minutes, it was discovered that, like the vehicle group, the mice administered with the compounds of Example 1 showed movements in both the open and closed arms, whereas the mice treated with rimonabant exhibited movements in the closed arms only. The amount of time spent in the open arms is shown in Fig. 3.

(3-2) Forced Swimming Test (FST)

In order to evaluate the incidence of depression due to the drug, a forced swimming test (FST) was carried out as follows. A water tank having a diameter of 12 cm was filled with water at 23 to 25°C until the depth of the tank became 15 cm or more. Mice were placed in the water tank, and their behavior was observed for 6 minutes. The behavior of mice was recorded using a camera, and an immobile time was analyzed using a tracking software Ethovision XT 7 program (Noldus). The immobile time was measured by using the change in area of tracked individual subject (%), and the immobility threshold was set at about 5%. The immobility threshold was optimized through the experiment.

The compound of Example 1 , and rimonabant, as a positive control, were each administered to mice, and the test was conducted at 30 minutes post-dose. Also, the same test was conducted using mice administered with a vehicle only. From the 6 minutes of total experiment time, the results of last 2 to 6 minutes were analyzed and illustrated in Fig. 4. As shown in Fig. 4, the mice administered with rimonabant exhibited longer immobile time as compared to the vehicle group, whereas the mice administered with the compound of Example 1 showed immobile time which is similar to that of the vehicle group.

As can be seen in the results of Experimental Tests (3-1) and (3-2), it was confirmed that the compound of Example 1, unlike the positive control, did not cause central nervous system (CNS)-related side effects, i.e., depression and anxiety.

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

What is claimed is;

1. A compound of a 4,5-dihydro-lH-pyrazole-3-carboximidamide derivative represented b formula (I) or a pharmaceutically acceptable salt thereof:

wherein

A¹ is C_1-7alkyl, C_6-1oaryl, 5 to 10-membered heteroaryl, C_3-6cycloalkyl or 3 to 6-membered heterocycloalkyl;

A and A^J are each independently C_6-1oaryl or 5 to 10-membered heteroaryl; X is -S-, -S(=O)- or -S(=O)₂-;

L is Q.ioalkylene; R is C_1-6alkyl;

each of A¹, A², A³, L and R is optionally substituted with at least one substituent selected from the group consisting of hydrogen, C_1-6alkyl, C_1-6alkoxy, halogen, cyano, hydroxy, nitro, -C(=O)-R', -S-R', -S(=O)-R', -S(=O)₂-R', -NR'R" and - C(=O)-NR'R", and R' and R" are each independently hydrogen or C_1-6alkyl; and

2. The compound of claim 1, wherein

A¹ is C_6-10aryl or 5 to 10-membered heteroaryl, and A¹ is optionally substituted with at least one substituent selected from the group consisting of hydrogen, halogen and Ci_-6alkyl;

A² is C_6-10aryl or 5 to 10-membered heteroaryl, and A² is optionally substituted with at least one substituent selected from the group consisting of hydrogen and cyano;

A is C_6-10aryl, and A is optionally substituted with at least one halogen;

X is -S-, -S(=O)- or -S(=0) ; L is C_1-6alkylene, R is Ci_-3alkyl, each of L and R is optionally substituted with at least one substituent selected from the group consisting of C_1-6alkyl, C_1-6alkoxy, halogen, cyano, hydroxy, nitro, -C(=0)-R', -S-R', -S(=0)-R', -S(=O)₂-R', -NR'R" and - C(=O)-NR'R", and R' and R" are each independently hydrogen or C_1-6alkyl; and

said heteroaryl contains at least one heteroatom selected from N, O and S.

3. The compound of claim 1 , wherein the 4,5-dihydro-lH-pyrazole-3- carboximidamide derivative represented by formula (I) is selected from the group consisting of:

1) (R,Z)- l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-N-(2- (methylsulfonyl)ethyl)-5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamide;

2) (S,Z)- l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-N-(2- (methylsulfonyl)ethyl)-5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamide;

3) (R,Z)- 1 -(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-(2-fluorophenyl)- N-(2-(memylsulfonyl)emyl)-4,5-dihydro-lH-pyrazole-3-carboximidamide;

4) (R,Z)- l-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-N-(2- (methylsulfonyl)ethyl)-5-(thien-2-yl)-4,5-dihydro-lH-pyrazole-3-carboximidamide;

5) (R,Z)-N'-((4-chlorophenyl)sulfonyl)- 1 -(2,4-difluorophenyl)-N-(2- (methylsulfonyl)ethyl)-5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamide;

6) (R,Z)- 1 -(4-chlorophenyl)-N'-((6-chloropyridin-3-yl)sulfonyl)-N-(2- methylsulfonyl)emyl)-5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamide;

7) (R,Z)- 1 -(4-chlorophenyl)-N'-((6-chloropyridin-3-yl)sulfonyl)-5-(2- fluorophenyl)-N-(2-(methylsulfonyl)ethyl)-4,5-dihydro- lH-pyrazole-3- carboximidamide;

8) (R,Z)- l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-N-(2- (methylthio)ethyl-5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamide;

9) (R,Z)-l-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-N-(2- (methylsulfinyl)ethyl)-5-phenyl-4,5-dihydro- lH-pyrazole-3-carboximidamide;

10) (R,2)-l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-N-((S)-3-methyl- l-(methylsulfonyl)butan-2-yl)-5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamide; 11) (R,Z)- 1 -(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-(2- fluorophenyl)-N-((S)-3 -methyl- 1 -(methylsulfonyl)butan-2-yl)-4,5-dihydro- IH- pyrazole-3-carboximidamide; and

12) (R, Z)-N'-((4-chlorophenyl)sulfonyl)- 1 -(4-fluorophenyl)-N-((S)-3-methyl- 1 - (methylsulfonyl)butan-2-yl)-5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamide.

4. A method for preparing a compound of formula (I), which comprises the steps of:

(a) allowing a compound of formula (II) to react with phosphorus pentasulfide (P₂S₅) or Lawesson's reagent in a solvent selected from the group consisting of toluene, xylene, benzene, chlorobenzene, and a mixture thereof to obtain a compound of formula (III);

(b) allowing the compound of formula (III) to react with methyl iodide in a - solvent selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, and a mixture thereof in the presence of a base selected from the group consisting of triethylamine, potassium carbonate, and a mixture thereof to obtain a compound of formula (IV); and

(c) allowing the compound of formula (IV) to react with a compound of formula (VI) in a solvent selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, and a mixture thereof in the presence of a base selected from the group consisting of triethylamine, potassium carbonate, and a mixture thereof:

H₂N-L-X R (VI)

wherein A¹, A², A³, L, X and R have the same meanings as defined in claim 1.

5. A method for preparing a compound of formula (I), which comprises the steps of:

, (b) allowing the compound of formula (V) to react with a compound of formula (VI) in a solvent selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, and a mixture thereof in the presence of a base selected from the group consisting of triethylamine, potassium carbonate, and a mixture thereof:

H₂N-L-X-R _(VI)

wherein A¹, A², A³, L, X and R have the same meanings as defined in claim 1.

6. A pharmaceutical composition for the prevention or treatment of obesity or an obesity-related metabolic disease, comprising the compound of claim 1 as an active ingredient.

7. The pharmaceutical composition of claim 6, wherein the obesity-related metabolic disease is selected from the group consisting of type 2 diabetes, chronic hepatic disease, angina, hypertension, congestive heart failure, and hyperlipidemia.

8. The pharmaceutical composition of claim 6, wherein the active ingredient exhibits antagonistic activity against a cannabinoid CB-1 receptor.

9. A use of the compound of claim 1 for the manufacture of a medicament for the prevention or treatment of obesity or an obesity-related metabolic disease.

10. A method for. preventing or treating obesity or an obesity-related metabolic disease in a mammal, which comprises administering the compound of claim 1 to the mammal.