KR20150113762A - 4,5-dihydro-1h-pyrazol-3-carboximidamide derivatives containing sulfur groups, method for preparing same, and pharmaceutical composition comprising same - Google Patents

Abstract

The present invention relates to a 4,5-dihydro-1H-pyrazole-1-carboximidamide derivative containing sulfur which exhibits an inverse agonist or antagonistic activity of a cannabinoid receptor (CB1) or a pharmaceutically acceptable salt thereof, a producing method thereof and a pharmaceutical composition comprising the same. The compound according to the present invention has fewer side effects due to having excellent peripheral tissue selectivity and exhibits antagonistic activity of a cannabinoid receptor and thus can be used for preventing or treating obesity or obesity-related metabolic diseases.

Description

4,5-dihydro-1H-pyrazole-3-carboximidamide derivative containing a sulfur functional group, a process for producing the same, and a pharmaceutical composition containing the same. BACKGROUND ART SULFUR GROUPS, METHOD FOR PREPARING SAME, AND PHARMACEUTICAL COMPOSITION COMPRISING SAME}

The present invention relates to a 4,5-dihydro-1H-pyrazole-3-carboximidamide derivative or a pharmaceutically acceptable salt thereof, comprising a novel sulfur functional group having an inverse or antagonistic activity to the cannabinoid CB1 receptor, And a pharmaceutical composition containing the same as an active ingredient.

Antagonists that exhibit inverse or antagonistic activity to cannabinoid CB1 receptors are known to be able to affect energy homeostasis through central and peripheral action mechanisms by in vitro and in vivo experiments. Since the selective CB1 receptor antagonist rimonabant (SR141716A, Pfizer) has been shown to effectively reduce body weight in obese patients in clinical trials and to alleviate metabolic syndrome such as diabetes or cardiovascular disease associated with obesity, And obesity-related metabolic syndrome diseases.

However, in addition to the above Rimonabant, otenabant (CP-945598, Pfizer), Surinabant (Sanofi-Aventis), ibipinabant (SLV 319, Solvay Pharmaceuticals), Taranabant (MK- A number of CB1 receptor antagonists such as Merck and Drinabant (AVE1625, Aventis Pharmaceuticals) have been shown to significantly reduce CNS related side effects such as depression, anxiety, dizziness and insomnia, Nausea and diarrhea, and have withdrawn from the market or have ceased development.

The development of an effective CB1 receptor antagonist that solves the above-mentioned side effect problems is very important in the development of a therapeutic agent for metabolic syndrome related to obesity and obesity, considering the situation that there is not enough effective medicine to treat the present at present compared to the severity of obesity.

In order to overcome the side effects of existing drugs, the present inventors have studied to develop selective antagonists of CB1 receptors distributed in peripheral tissues rather than brain tissue. As a result, Dihydro-1H-pyrazole-3-carboximidamide derivative containing a sulfur functional group that exhibits antagonistic activity to the receptor has been completed.

PCT Publication No. WO 2007/131219 (JENRIN DISCOVERY) Nov. 15, 2007.

Accordingly, the present invention is to provide a novel compound containing a sulfur functional group that is excellent in peripheral tissue selectivity, has few side effects, and exhibits antagonistic activity against cannabinoid receptors.

The present invention also provides a process for preparing the above compound and a pharmaceutical composition comprising the same as an active ingredient.

To this end, the present invention provides a novel 4,5-dihydro-1H-pyrazole-3-carboximidamide derivative comprising a sulfur functional group and a pharmaceutically acceptable salt thereof.

According to another aspect of the present invention, there is provided a process for preparing the above compound.

According to yet another object, the present invention provides a pharmaceutical composition for preventing or treating obesity or obesity-related metabolic diseases, which comprises the compound as an active ingredient.

The compound according to the present invention has excellent anti-obesity effect because it has excellent side chain selectivity, low side effects, and exhibits inverse or antagonistic activity against cannabinoid CB1 receptor. Therefore, a pharmaceutical composition comprising the compound as an active ingredient is useful for obesity and obesity-related Can be usefully used for preventing or treating diseases.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the weight loss effect of diet-induced obesity (DIO) mice by administration of the compound of Example 1. FIG.
Fig. 2 is a graph showing the reduction of the drug to brain tissue for administration of the compound of Example 1. Fig.
Figure 3 is a graph showing the reduction of adverse effects on the central nervous system (CNS) via an elevated plus maze test (EPM) upon administration of the compound of Example 1.
Figure 4 is a graph showing the reduction of adverse effects on the central nervous system (CNS) through a forced swimming test (FST) upon administration of the compound of Example 1.

Hereinafter, the present invention will be described more specifically.

As used herein, "sulfur functional groups" unless otherwise noted are thio (-S-), sulfinyl (-S (= O) -) and sulfonyl _{(-S (= O) 2 -} ) means a functional group do.

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

The term "alkyl" as used herein refers to a linear or branched, saturated C ₁ to C ₇ hydrocarbon radical chain. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl and hexyl.

The term "alkoxy" as used herein means an -OR group, wherein R is alkyl as defined above. Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and the like.

The term "cycloalkyl ", as used herein, unless otherwise indicated, refers to monocyclic or bicyclic or higher cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "aryl ", as used herein, unless otherwise indicated, refers to monocyclic aromatic rings such as phenyl, substituted phenyl, and the like, as well as aromatic rings above bicyclic such as naphthyl, phenanthrenyl, and the like. The 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 n = 1, 2, 3), and thiol, but is not limited thereto.

The term "heteroaryl ", as used herein, unless otherwise indicated, refers to a monocyclic heteroaryl containing one or more heteroatoms selected from O, N and S as furyl, thienyl, thiazolyl, Thiazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-oxadiazolyl, 3-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazine Yl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, cinnolinyl, pteridinyl, purine; Or bicyclic heteroaryl is 5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzo [b] thienyl, benzisothiazolyl, Isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, isoquinolyl, quinolyl, quinolyl, quinolyl, quinolyl, quinolyl, quinolyl, Quinazolinyl, pyrazolo [3,4-b] pyridinyl, benzoxazaphyl, and the like.

The term "heterocycloalkyl ", as used herein, unless otherwise indicated, means monocyclic or bicyclic or higher cyclic alkyl containing one or more heteroatoms selected from O, N and S. Examples of monocyclic heterocycloalkyl include, but are not limited to, piperidinyl, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperazinyl and similar groups. It is not.

The present invention provides a compound selected from a compound represented by the following formula 1 and a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

In this formula,

A ¹ Is C _1-7 alkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

A ² and A ³ Are each independently C _6-10 aryl or 5-10 membered heteroaryl;

X is -S-, -S (= O) -, or -S (= O) _2- ;

L is C _1-10 alkylene; R is C _1-6 alkyl;

Wherein each of A ¹ , A ² , A ³ , L and R is independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 alkoxy, halogen, cyano, -S (= O) -R ', -S (= O) ₂ -R', -NR'R "and -C Wherein R 'and R "are each independently hydrogen or C _1-6 alkyl;

The heteroaryl and heterocycloalkyl each independently contain one or more heteroatoms selected from N, O,

In one embodiment of Formula 1 above,

The A ¹ Is C _6-10 aryl or 5-10 membered heteroaryl, and A ¹ May be substituted with one or more substituents selected from the group consisting of hydrogen, halogen and C _1-6 alkyl;

Said A ² is C _6-10 aryl, or 5-10 membered heteroaryl, said A ² may be substituted with one or more substituents selected from the group consisting of hydrogen and cyano;

The A ³ Is C _6-10 aryl, and A ³ May be substituted with one or more halogens;

Wherein X is -S-, -S (= O) - or -S (= O) ₂ -;

_Wherein L is C _1-6 alkylene and R is And C _1-3 alkyl, wherein L and R are each independently selected from C _1-6 alkyl, C _1-6, alkoxy, nitro, halogen, cyano, hydroxy, -C (= O) -R ' , -S And at least one group selected from the group consisting of -R ', -S (═O) -R', -S (═O) ₂ -R ', -NR'R " , Wherein R 'and R "are each independently hydrogen or C _1-6 alkyl;

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

In another embodiment of Formula 1 above,

When each of A ¹ to A ³ is independently C _6-10 aryl or 5-10 membered heteroaryl, they are each independently phenyl, furanyl, benzofuranyl, thienyl, benzothienyl, pyridyl , Pyrimidyl, pyrazinyl, and pyridazinyl,

Here, A ¹ to A ³ each independently may be substituted with at least one substituent selected from the group consisting of hydrogen, halogen, cyano, and C _1-6 alkyl.

In another embodiment of Formula I,

Wherein A < ¹ > is chlorophenyl or chloropyridyl;

Wherein A < ^{2 &} gt; is phenyl, fluorophenyl or thienyl;

Wherein A ³ is chlorophenyl, fluorophenyl, or a difluorophenyl;

Wherein X is -S-, -S (= O) - or -S (= O) ₂ -;

_Wherein L is C _1-6 alkylene and R is C _1-3 alkyl, and L and R may each independently be substituted with one or more C _1-3 alkyl.

As a preferred example, the 4,5-dihydro-1H-pyrazole-3-carboximidamide derivative of the above formula (1) can be selected from the following 1) to 12)

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

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

3) Synthesis of (R, Z) -1- (4-chlorophenyl) -N '- (4-chlorophenyl) sulfonyl) -5- ) Ethyl) -4,5-dihydro-lH-pyrazole-3-carboximidamide;

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

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

6) (R, Z) -1- (4-chlorophenyl) -N '- (6-chloropyridin- -4,5-dihydro-lH-pyrazole-3-carboximidamide;

7) (R, Z) -1- (4-Chlorophenyl) -N '- (6-chloropyridin- (Methylsulfonyl) ethyl) -4,5-dihydro-lH-pyrazole-3-carboximidamide;

8) (R, Z) -1- (4-Chlorophenyl) -N '- (4-chlorophenyl) sulfonyl) -N- (2- (methylthio) ethyl- - dihydro-lH-pyrazole-3-carboximidamide;

9) (R, Z) -1- (4-Chlorophenyl) -N '- (4-chlorophenyl) sulfonyl) -N- (2- (methylsulfinyl) 5-dihydro-lH-pyrazole-3-carboximidamide;

10) Synthesis of (R, Z) -1- (4-chlorophenyl) -N '- (4-chlorophenyl) sulfonyl) -N - -2-yl) -5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamide;

11) (R, Z) -1- (4-Chlorophenyl) -N '- ((4-chlorophenyl) sulfonyl) Methyl-1- (methylsulfonyl) butan-2-yl) -4,5-dihydro-1H-pyrazole-3-carboximidamide; And

12) (S) -3-Methyl-1- (methylsulfonyl) -1- (4-fluorophenyl) -N - Butan-2-yl) -5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamide.

Also within the scope of the present invention are the 4,5-dihydro-1H-pyrazole-3-carboximidamide derivatives of formula 1 and their pharmaceutically acceptable salts, as well as their possible stereoisomers, solvates and hydrates .

The pharmaceutically acceptable salt of the compound of formula (1) may be prepared by a conventional method in the art and includes, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, Salts with inorganic acids; Such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, malonic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestic acid, fumaric acid, lactobionic acid, salicylic acid, acetylsalicylic acid Salts with organic acids; Salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, asparaginic acid, glutamine, lysine, arginine, tyrosine, proline and the like; Salts with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and the like; A metal salt by reaction with an alkali metal such as sodium or potassium; And salts with ammonium ions and the like.

In addition, the compounds according to the invention may have asymmetric carbon centers and therefore may exist as R or S isomers, racemic compounds, individual enantiomers or mixtures, individual diastereomers or mixtures thereof, All stereoisomers and mixtures are included within the scope of the present invention.

In addition, solvates and hydrate forms of the compounds of formula (1) are also included within the scope of the present invention. Such a hydrate or solvate may be prepared by a known method and is preferably non-toxic and water-soluble, and may be a hydrate or a solvate in which one to five molecules of water or an alcohol-based solvent (particularly, ethanol etc.) .

The present invention also provides a process for preparing the compound of formula (1).

An example of the method for preparing the compound of formula (1) is shown in the following reaction formula (1).

[Reaction Scheme 1]

Wherein A ¹ , A ² , A ³ , L, X and R are as defined in claim 1.

The compounds of formula (2) used as starting materials are described in J. Med. Chem , 2007, 50, p5951-5966; Bioorganic & Medicinal Chemistry Letters, 2010, 20 (5), p1752-1757; And WO 2005/074920, or a similar method, to give a compound of formula (I), which is prepared by reacting a 4,5-dihydro-1H-pyrazole-3-carboxylic acid compound with a sulfonamide compound after the halogenation reaction under the reaction conditions in the presence of a base . The sulfonamide compound may be 4-chlorobenzenesulfonamide, 4,4-difluoropiperidine-1-sulfonamide or 4-methylpiperazine-sulfonamide.

As a method for preparing the compound of the formula (1) from the starting material, the following reaction formula 1 will be described.

In step (a), the compound of formula (2) is reacted with phosphorus pentasulfide (P ₂ S ₅ ) or Lawesson reagent in an organic solvent such as toluene under heating or refluxing conditions, The reaction is carried out for 12 hours to introduce sulfur (S), thereby preparing the compound of formula (3).

In step (b), the compound of formula (3) is reacted with methyl iodide in an organic solvent such as, for example, acetone in the presence of a base such as triethylamine and potassium carbonate for 1 to 5 hours under normal or warm conditions The compound of formula (4) can be prepared by introducing a methyl functional group.

In step (c), the compound of formula (4) is reacted with an amine derivative of formula (6) in the presence of a base such as triethylamine and potassium carbonate in an organic solvent such as tetrahydrofuran for 3 to 12 hours The compound of Formula 1 may be prepared.

Another method for preparing the compound of formula (I) from the above starting material is described below with reference to Scheme 1.

In step (a '), the compound of formula (2) is first reacted with a chlorine compound such as phosphorus pentachloride (PCl ₅ ) in an organic solvent such as chlorobenzene under heating or reflux for 1 to 3 hours (Cl) may be introduced to prepare a compound of formula (5).

In step (b '), the reaction temperature is lowered to a low temperature or a normal temperature and, in an organic solvent such as dichloromethane, in the presence of a base such as triethylamine and potassium carbonate, an amine derivative represented by the formula (6) The compound of Formula 1 may be prepared by reacting the compound of Formula 1 for 3 hours.

Accordingly, in one embodiment of the present invention, the compound of formula (1) can be prepared according to the preparation method comprising the following steps:

(a) reacting the compound of formula 2 with phosphorus pentasulfide (P ₂ S ₅ ) or Lawesson reagent in a solvent selected from the group consisting of toluene, xylene, benzene, chlorobenzene, To prepare a compound of Formula 3;

(b) reacting the compound of formula (3) with a compound selected from the group consisting of triethylamine, potassium carbonate, and mixtures thereof in a solvent selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, Reacting the compound of formula 4 with methyl iodide in the presence of a base selected to produce the compound of formula 4; And

(c) reacting the compound of formula (4) with a compound selected from the group consisting of triethylamine, potassium carbonate, and mixtures thereof in a solvent selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, With a compound of formula (VI) in the presence of a selected base.

In another embodiment of the present invention, the compound of Formula 1 may be prepared according to the preparation method comprising the following steps:

(a) reacting the compound of Formula 2 with phosphorus pentachloride (PCl ₅ ) in a solvent selected from the group consisting of toluene, xylene, benzene, chlorobenzene, and mixtures thereof to prepare the compound of Formula 5 step; And

(b) reacting the compound of formula (5) with a compound selected from the group consisting of triethylamine, potassium carbonate, and mixtures thereof in a solvent selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, With a compound of formula (VI) in the presence of a selected base.

The present invention also provides a pharmaceutical composition for the prophylaxis or treatment of obesity or obesity-related metabolic diseases comprising the compound according to the present invention as an active ingredient.

The obesity-related metabolic diseases may be selected from the group consisting of Type 2 diabetes, chronic liver disease, angina pectoris, hypertension, congestive heart failure and hyperlipemia, but are not limited thereto.

The active ingredient exhibits antagonistic activity against the cannabinoid CB1 receptor.

The pharmaceutical composition can be administered orally or parenterally at the time of clinical administration and can be used in the form of a general pharmaceutical preparation. In the case of pharmaceutical preparation, the pharmaceutical composition can be used as a commonly used filler, extender, binder, wetting agent, disintegrant, Diluents or excipients.

Solid formulations for oral administration may be prepared by mixing at least one excipient, such as starch, calcium carbonate, sucrose, lactose or gelatin, with one or more benzamide derivatives according to the invention have. In addition to simple excipients, lubricating agents such as magnesium stearate or talc may also be used.

Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups. Various excipients such as wetting agents, sweetening agents, perfumes or preservatives can be used in addition to water and liquid paraffin, which are commonly used simple diluents. have.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. Examples of the non-aqueous solvent or suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, etc. Examples of the suppository include withexol, macrogol, tween 61, Cacao paper, laurin paper, glycerol paper, gelatin paper, and the like.

The human body dose (based on the active ingredient) of the pharmaceutical composition according to the present invention may vary depending on the patient's age, weight, sex, dosage form, health condition, and disease severity. Based on the adult patient weighing 70 kg , It is generally 0.1 to 1000 mg / day, preferably 1 to 500 mg / day, and may be dividedly administered once to several times a day at predetermined time intervals.

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

Example 1: Synthesis of (R, Z) -1- (4-chlorophenyl) -N '- (4-chlorophenyl) sulfonyl) -N- (2- (methylsulfonyl) Preparation of 4,5-dihydro-lH-pyrazole-3-carboximidamide

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

Example (1A)

Step 1) (R) -1- (4-Chlorophenyl) -N- (4-chlorophenyl) sulfonyl) -5-phenyl-4,5-dihydro-1H-pyrazole- Preparation of amide

J. Med. Chem , 2007, 50, p5951-5966; Bioorganic & Medicinal Chemistry Letters , 2010, 20 (5), p1752-1757; (R) -1- (4-chlorophenyl) -N - ((4-chlorophenyl) sulfonyl) -5-phenyl-4, (1.0 g, 2.1 mmol) and phosphorus pentasulfide (P ₂ S ₅ , 0.94 g, 4.2 mmol) were placed in toluene (20 mL) And stirred for 6 hours.

The material not soluble in organic solvent was removed using celite, washed with ethyl acetate, and the organic layer was concentrated under reduced pressure. The concentrated residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium hydrogencarbonate and brine. The organic solvent was concentrated under reduced pressure, and the resulting residue was crystallized with ethanol to give the title compound (0.7 g).

^{1 H-NMR (300MHz, CDCl} 3) δ 8.05 (d, 2H), 7.50 (d, 2H), 7.4-7.1 (m, 5H), 7.02 (d, 2H), 5.40 (dd, 1H), 3.77 ( dd, 1 H), 3.24 (dd, 1 H).

MS (ESI ⁺ ): m / z = 490.0 [M + H] < ⁺ >.

Step 2) (R, Z) -Methyl 1- (4-chlorophenyl) -N- (4-chlorophenyl) sulfonyl) -5-phenyl-4,5-dihydro- Preparation of carboximidothiolate

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

^{1 H-NMR (300MHz, CDCl} 3) δ 7.93 (d, 2H), 7.47 (d, 2H), 7.4-7.1 (m, 5H), 7.05 (d, 2H), 5.50 (dd, 1H), 4.16 ( dd, 1 H), 3.44 (dd, 1 H), 2.38 (s, 3 H).

MS (ESI ⁺ ): m / z = 504.0 [M + H] < ⁺ >.

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

The compound (1.14 g, 2.26 mmol) obtained in the above step 2) was dissolved in tetrahydrofuran (5 mL), followed by the addition of 2-aminoethyl methylsulfone hydrochloride (613 mg, 3.84 mmol) and triethylamine (571 mg, 5.65 mmol ) Were sequentially added, the temperature was raised to 60 占 폚, and the mixture was stirred for 4 hours. The organic layer was washed with water, 1N hydrochloric acid aqueous solution and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was crystallized in a mixed solvent of chloromethane / diethylether to obtain 1.35 g of yellow title compound.

^{1 H-NMR (300MHz, DMSO} -d 6) δ 9.28 (s, 1H), 7.86 (d, 2H), 7.59 (d, 2H), 7.40-7.27 (m, 5H), 7.23 (d, 2H), 2H), 3.96 (d, 2H), 3.96 (dd, 1H), 3.97 (dd,

MS (ESI ⁺ ): m / z = 579.1 [M + H] < ⁺ >.

Example (1B)

J. Med. Chem , 2007, 50, p5951-5966; Bioorganic & Medicinal Chemistry Letters , 2010, 20 (5), p1752-1757; (R) -1- (4-chlorophenyl) -N - ((4-chlorophenyl) sulfonyl) -5-phenyl-4, 3-carboxamide (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. After completion of the reaction, the reaction solution was concentrated.

Dichloromethane, the solvent, was added to the concentrated compound and cooled to 0 < 0 > C under nitrogen. Then, 2-aminoethyl methyl sulfone hydrochloride (64 mg, 0.4 mmol) and triethylamine (60 mg, 0.6 mmol) were successively added thereto, followed by stirring for 1.5 hours while gradually warming to room temperature. When the reaction was completed, the reaction mixture was extracted with dichloromethane and water, and the organic layer was dried over anhydrous sodium sulfate and the solvent was concentrated. The obtained compound was purified by preparative liquid chromatography (PLC, silica gel 60 F ₂₅₄ , 1 mm) to obtain 18 mg of the title compound as a yellow substance.

^{1 H-NMR (300MHz, DMSO} -d 6) δ 9.28 (s, 1H), 7.86 (d, 2H), 7.59 (d, 2H), 7.40-7.27 (m, 5H), 7.23 (d, 2H), 2H), 3.96 (d, 2H), 3.96 (dd, 1H), 3.97 (dd,

MS (ESI ⁺ ): m / z = 579.1 [M + H] < ⁺ >.

Example 2: Synthesis of (S, Z) -l- (4-chlorophenyl) -N '- ((4- chlorophenyl) sulfonyl) -N- (2- (methylsulfonyl) Preparation of 4,5-dihydro-lH-pyrazole-3-carboximidamide

By carrying out the same or similar procedure as in the above Example (1B), the yellow title compound (38 mg) was obtained.

^{1 H-NMR (300MHz, DMSO} -d 6) 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,

MS (ESI < ⁺ >): m / z = 579.1 [M + H] < ⁺

Example 3: (R, Z) -1- (4-Chlorophenyl) -N '- (4-chlorophenyl) sulfonyl) Sulfonyl) ethyl) -4,5-dihydro-1H-pyrazole-3-carboximidamide

By carrying out the same or similar procedure as in the above Example (1B), yellow title compound (50 mg) was obtained.

^{1 H-NMR (300MHz, CDCl} 3) 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 (M, 3H), 5.7 (dd, IH), 4.3 (t, IH), 4.0 (m, 2H), 3.5-3.3 (m, 3H), 3.0 (s, 3H).

MS (ESI ⁺ ): m / z = 597.1 [M + H] &lt; ⁺ &gt;.

Example 4: Preparation of (R, Z) -1- (4-chlorophenyl) -N '- (4-chlorophenyl) sulfonyl) -N- (2- (methylsulfonyl) En-2-yl) -4,5-dihydro-1H-pyrazole-3-carboximidamide

The title compound (30 mg) was obtained by carrying out the same or similar procedure as in the above Example (1B).

^{1 H-NMR (300MHz, CDCl} 3) 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] &lt; ⁺ &gt;.

Example 5: Synthesis of (R, Z) -N '- ((4-chlorophenyl) sulfonyl) -1- (2,4-difluorophenyl) Preparation of 5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamide

By carrying out the same or similar procedure as in the above Example (1B), the title compound (53.8 mg) was obtained in yellow.

^{1 H-NMR (300MHz, DMSO} -d 6) δ 9.31 (s, 1H), 7.89 (d, 2H), 7.59 (d, 2H), 7.54-7.40 (m, 1H), 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, 3.28 (dd, 1 H), 3.00 (s, 3 H).

MS (ESI ⁺ ): m / z = 581.1 [M + H] &lt; ⁺ &gt;.

Example 6: (R, Z) -1- (4-Chlorophenyl) -N '- (6-chloropyridin- -Phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamide

The title compound (72 mg) was obtained by carrying out the same or similar procedure as in the above Example (1B).

^{1 H-NMR (300MHz, DMSO} -d 6) δ 9.36 (s, 1H), 8.86 (d, 1H), 8.29 (dd, 1H), 7.69 (d, 1H), 7.41-7.15 (m, 7H), 1H), 3.96 (d, 2H), 5.69 (dd, 1H), 3.96 (dd,

MS (ESI ⁺ ): m / z = 580.1 [M + H] &lt; ⁺ &gt;.

Example 7: (R, Z) -1- (4-Chlorophenyl) -N '- (6-chloropyridin- Preparation of 2- (methylsulfonyl) ethyl) -4,5-dihydro-1H-pyrazole-3-carboximidamide

By carrying out the same or similar procedure as in the above Example (1B), yellow title compound (50 mg) was obtained.

^{1 H-NMR (300MHz, CDCl} 3) δ 8.9 (s, 1H), 8.2 (d, 1H), 7.8 (d, 1H), 7.47-7.45 (d, 2H), 7.20-7.17 (m, 2H), (D, 2H), 3.5 (m, 3H), 3.0 (m, 2H) s, 3H).

MS (ESI ⁺ ): m / z = 598.1 [M + H] &lt; ⁺ &gt;.

Example 8: (R, Z) -1- (4-Chlorophenyl) -N '- ((4-chlorophenyl) sulfonyl) -N- (2- (methylthio) ethyl- , 5-dihydro-lH-pyrazole-3-carboximidamide

By carrying out the same or similar procedure as in Example 1A above, the title compound (25.2 mg) was obtained in yellow.

^{1 H-NMR (300MHz, DMSO} -d 6) δ 9.26 (s, 1H), 7.82 (d, 2H), 7.59 (d, 2H), 7.40-7.25 (m, 5H), 7.22 (d, 2H), 2H), 3.97 (d, 2H), 3.96 (d, 2H), 3.96 (d, 2H).

MS (ESI ⁺ ): m / z = 547.1 [M + H] &lt; ⁺ &gt;.

Example 9: (R, Z) -l- (4-Chlorophenyl) -N '- (4- chlorophenyl) sulfonyl) -N- (2- (methylsulfinyl) Preparation of 4,5-dihydro-lH-pyrazole-3-carboximidamide

The title compound (22.9 mg) was obtained by carrying out the same or similar procedure as in the above Example (1B)

^{1 H-NMR (300MHz, DMSO} -d 6) δ 9.38 (s, 1H), 7.85 (d, 2H), 7.58 (d, 2H), 7.41-7.25 (m, 5H), 7.22 (d, 2H), 2H), 3.16 (d, 2H), 5.63 (dd, 1H), 3.96 (dd, 1H), 2.56 (s, 3H).

MS (ESI ⁺ ): m / z = 563.1 [M + H] &lt; ⁺ &gt;.

Example 10: Synthesis of (R, Z) -1- (4-chlorophenyl) -N '- (4-chlorophenyl) sulfonyl) -N - ) Butan-2-yl) -5-phenyl-4,5-dihydro-1H-pyrazole-3-carboximidamide

By carrying out the same or similar procedure as in the above example (1B), the title compound (35 mg) was obtained in the form of yellow

^{1 H-NMR (300MHz, DMSO} -d 6) 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 (D, 2H), 3.21 (d, 2H), 3.91-3.52 (m, (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] &lt; ⁺ &gt;.

Example 11: Preparation of (R, Z) -l- (4-chlorophenyl) -N '- (4-chlorophenyl) sulfonyl) Preparation of 3-methyl-1- (methylsulfonyl) butan-2-yl) -4,5-dihydro-1H-pyrazole-3-carboximidamide

By carrying out the same or similar procedure as in the above example (1B), the title compound (35 mg) was obtained in the form of yellow

^{1 H-NMR (300MHz, DMSO} -d 6) δ 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 (D, 2H), 3.24-3.18 (m, 1H), 3.01 (m, (s, 3H), 1.92-1.90 (m, 1H), 0.86-0.83 (d, 6H).

MS (ESI ⁺ ): m / z = 639.1 [M + H] &lt; ⁺ &gt;.

Example 12: (R, Z) -N '- ((4-chlorophenyl) sulfonyl) 2-yl) -5-phenyl-4,5-dihydro-1H-pyrazole-3-carboximidamide

By carrying out the same or similar procedure as in the above Example (1B), yellow title compound (45 mg) was obtained.

^{1 H-NMR (300MHz, DMSO} -d 6) 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 2H), 3.23-3.20 (m, 1H), 3.01 (d, 2H), 3.91-3.40 (m, (s, 3H), 1.94-1.88 (m, 1H), 0.86-0.83 (d, 6H).

MS (ESI < ⁺ >): m / z = 605.1 [M + H] <^+> .

The structures of the compounds prepared in the above Examples are shown in Table 1 below.

Example denomination rescue One (R, Z) -1- (4-chlorophenyl) -N '- (4-chlorophenyl) sulfonyl) -N- (2- (methylsulfonyl) Dihydro-lH-pyrazole-3-carboximidamide

2 (S, Z) -1- (4-chlorophenyl) -N '- (4-chlorophenyl) sulfonyl) -N- (2- (methylsulfonyl) ethyl) Dihydro-lH-pyrazole-3-carboximidamide

3 (R, Z) -1- (4-chlorophenyl) -N '- (4- (chlorophenyl) sulfonyl) ) -4,5-dihydro-lH-pyrazole-3-carboximidamide

4 (4-chlorophenyl) -N '- ((4-chlorophenyl) sulfonyl) -N- (2- (methylsulfonyl) ethyl) Yl) -4,5-dihydro-lH-pyrazole-3-carboximidamide

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

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

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

8 (R, Z) -1- (4-chlorophenyl) -N '- (4-chlorophenyl) sulfonyl) -N- (2- (methylthio) ethyl- Hydro-1H-pyrazole-3-carboximidamide

9 (R, Z) -1- (4-chlorophenyl) -N '- (4-chlorophenyl) sulfonyl) -N- (2- (methylsulfinyl) ethyl) Dihydro-lH-pyrazole-3-carboximidamide

10 (S) -3-methyl-1- (methylsulfonyl) butane-2 &lt; RTI ID = 0.0 & Yl) -5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamide

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

12 (R, Z) -N '- ((4-chlorophenyl) sulfonyl) 2-yl) -5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamide

Test Example 1: [ ³⁵ S] GTPγS binding assay (Binding Assay)

The antagonistic activity of cannabinoid receptor 1, a Gi protein-coupled receptor, was evaluated as follows.

Using GDP-GTP exchange principle of non-hydrolyzable (non-hydrolyzable) GTPγS form of GTP, ^[35 S] -1250Ci / mmol, 12.5mCi / mmol, 1mCi (Perkin Elmer Corporation, cat. NEG030H001MC) radioactive materials and WGA - coated SPA beads (Cat. RPNQ0210) were used. Each test compound was diluted with 1X assay buffer (20 mM HEPES, 100 mM NaCl, 25 mM MgCl ₂ , 1 mM EDTA, pH 7.4) at concentrations of 10 μM, 1 μM, 100 nM, 10 nM, 1 nM and 0.1 nM, respectively. The CB1 receptor membrane (Cat. HTS019M, Millipore) was diluted in a saponin solution and then made into a 1: 1 mixture with 3 μM GDP.

The compound of the present invention was added to 100 μL of a mixture of CB1 receptor membrane and GDP prepared above, and a 1: 1 mixture of WGA-coated SPA beads and [ ³⁵ S] GTPγS was added, followed by reaction at room temperature for 50 minutes. [ ³⁵ S] GTP? S activity was measured with a? -scintillation counter. At this point, the basal wells excluded only the compound, and the background wells were reacted except for compound, membrane and GDP. The IC ₅₀ values of each compound were calculated using analytical software (GraphPad Prism 4.0).

As a result, the IC ₅₀ values of the compounds of Examples 1, 3, 4, 6, 8, 10, 11 and 12 for CB1 GTPγS binding analysis were 13 nM, 15 nM, 18 nM, 13 nM, 14 nM, 14 nM, 19 nM and 8 nM, respectively . As a result, it was found that the antagonistic activity of the compounds of the Examples against the CB1 receptor was excellent.

Test Example 2: In vivo (&lt; RTI ID = 0.0 &gt; in vivo ) Effectiveness test

(2-1) Weight change evaluation

To assess the efficacy of compounds of the present invention in inhibiting weight gain, diet-induced obesity (DIO) mice were used as a model. Diets-induced bovine mice were produced by feeding high fat food to 5-week-old C57BL / 6 mice (Orient Bio) for 2-5 months. The mice were maintained in a 12 hour light / dark cycle (11:00 lights, 23:00 lights) in a humidity and temperature controlled environment with free access to food and water.

One week prior to the start of the study, mice were individually housed and habituation was performed to establish baseline of body weight. Animals were randomly divided into treatment groups based on initial body weight and food consumption. To evaluate the effect of test compounds on food consumption, the compounds prepared in Example 1 above or known antagonists (rimonabant) as positive controls were each treated with diuretic-induced obesity (DIO) mice. The test was also conducted on mice that did not undergo any treatment as a vehicle group.

Obese mice were treated with test compound 10 mg / kg 1 hour before the start of the cancer cycle. Body weights were measured using electronic scales before the test compound treatment and every 24 hours for 7 days after the test compound treatment. Body weight data for vehicle-treated mice, positive control-treated mice, and compound-treated mice of Example 1 are shown in FIG.

As shown in FIG. 1, the body weight was gradually reduced by the administration of the compound of Example 1 according to the present invention, and this effect was observed to be maintained for a period of one week and for a period of time after treatment. Thus, it can be seen that the compound of the present invention according to Example 1 has an effect of inhibiting obesity.

(2-2) Evaluation of plasma exposure to plasma

The tissues of diet-induced obesity (DIO) mice used for the above food intake and body weight change were collected and brain exposure was measured. Blood collection was performed 0.5 hours after oral administration.

Plasma samples were separated by centrifugation (12000 rpm, 2 minutes) in a heparinized eppendorf tube (1000 IU / mL, heparin, 3 μL). Brain samples were taken at 0.5 hours after administration, which was estimated to be the T _max of the oral administration group. After extraction, the brain samples were diluted 10 times with 4% bovine serum albumin (BSA) and pulverized and analyzed. The plasma and brain doses measured are shown graphically in FIG.

As shown in FIG. 2, the compound of Example 1 according to the present invention showed the brain dose of the compound of Example 1 in comparison with the brain dose (about 41%) of the positive control group, Rimonabant, (About 1%) showed very good results.

This indicates that the compound of the present invention is an excellent drug having the potential to overcome or overcome the side effects of the existing drug development, that is, an excellent CB1 receptor antagonist through the high selectivity of peripheral tissues, It can be confirmed that it is medicine.

Test Example 3: Confirmation of depression and anxiety through behavior test

The occurrence of depression and anxiety, which are side effects of the central nervous system (CNS) caused by the compounds of the present invention, were evaluated by the following methods.

(3-1) Elevated plus maze test (EPM)

An EPM test was used to assess elevation of anxiety caused by drugs by placing elevated plus maze at a height of 50 cm from the ground. The labyrinth was made in a cross shape with two open openings and two closed openings. The animal was placed in the center zone where the open channel and the closed channel were crossed, and the movement of the animal was observed for 6 minutes. Animal behavior was recorded using a ceiling camera and analyzed for time spent in open passages using video tracking software (Ethovision XT 7 program, Noldus). As a positive control or the compound of Example 1, rimonabant was administered to each animal, and the test was carried out after 30 minutes. In addition, the test was conducted on animals that were not administered anything as a vehicle group.

As a result of tracking the movement of the animal for 6 minutes, it was confirmed that the animals administered with the compound of Example 1 were all moved in the open channel and the closed channel similarly to the vehicle group. In the case of the rimonabant group, It was found that this method was limited to closed channels only. The time the animal stays in the open passageway is shown graphically in Fig.

(3-2) forced swimming test (FST)

In order to evaluate drug induced depression by FST, water of 23 ~ 25 ° C was injected into a 12cm diameter water tank at a depth of 15cm or more. After recording the animal behavior, immobile time was measured using video tracking software (Ethovision XT 7 program, Noldus). Fine time was measured using the change in the tracked area (%), and the immobile threshold was set at around 5%. Threshold values were optimized by experiments.

As a positive control or the compound of Example 1, rimonabant was administered to animals, behavioral tests were conducted 30 minutes later, and the test was also conducted on animals that were not administered anything as a vehicle group. The results of the last 2 to 6 minutes of the 6-minute test were analyzed, and the results are shown graphically in FIG. As shown in Fig. 4, the fasting time of the rimonabant-treated group was measured to be longer than that of the vehicle group, whereas the compound administered group of Example 1 showed similar fasting time to that of the vehicle group.

Through the tests of (3-1) and (3-2) above, it was confirmed that the compound of Example 1 did not induce anxiety and depression, which are side effects of drugs, unlike the rimonabant which is a positive control group.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is clearly understood that the same is by way of illustration and example only and is not to be taken by way of limitation, It is to be understood that the invention may be practiced within the scope of the appended claims.

Claims (8)

A compound selected from the group consisting of 4,5-dihydro-1H-pyrazole-3-carboximidamide derivatives of formula (I) and pharmaceutically acceptable salts thereof:
[Chemical Formula 1]

In this formula,
A ¹ Is C _1-7 alkyl, C _6-10 aryl, 5-10 membered heteroaryl, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl;
A ² and A ³ Are each independently C _6-10 aryl or 5-10 membered heteroaryl;
X is -S-, -S (= O) -, or -S (= O) _2- ;
L is C _1-10 alkylene; R is C _1-6 alkyl;
Wherein each of A ¹ , A ² , A ³ , L and R is independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 alkoxy, halogen, cyano, -S (= O) -R ', -S (= O) ₂ -R', -NR'R "and -C Wherein R 'and R "are each independently hydrogen or C _1-6 alkyl;
The heteroaryl and heterocycloalkyl each independently contain one or more heteroatoms selected from N, O,
The method according to claim 1,
The A ¹ Is C _6-10 aryl or 5-10 membered heteroaryl, and A ¹ May be substituted with one or more substituents selected from the group consisting of hydrogen, halogen and C _1-6 alkyl;
Said A ² is C _6-10 aryl, or 5-10 membered heteroaryl, said A ² may be substituted with one or more substituents selected from the group consisting of hydrogen and cyano;
The A ³ Is C _6-10 aryl, and A ³ May be substituted with one or more halogens;
Wherein X is -S-, -S (= O) - or -S (= O) ₂ -;
_Wherein L is C _1-6 alkylene and R is And C _1-3 alkyl, wherein L and R are each independently selected from C _1-6 alkyl, C _1-6, alkoxy, nitro, halogen, cyano, hydroxy, -C (= O) -R ' , -S And at least one group selected from the group consisting of -R ', -S (═O) -R', -S (═O) ₂ -R ', -NR'R " , Wherein R 'and R "are each independently hydrogen or C _1-6 alkyl;
Wherein said heteroaryl contains one or more heteroatoms selected from N, &lt; RTI ID = 0.0 &gt; O and S. &lt; / RTI &gt;
The method according to claim 1,
The 4,5-dihydro-1H-pyrazole-3-carboximidamide derivative of formula 1 is selected from the following compounds 1) to 12):
1) (R, Z) -1- (4-chlorophenyl) -N '- (4-chlorophenyl) sulfonyl) -N- (2- (methylsulfonyl) 5-dihydro-lH-pyrazole-3-carboximidamide;
2) Synthesis of (S, Z) -1- (4-chlorophenyl) -N '- (4-chlorophenyl) sulfonyl) -N- (2- (methylsulfonyl) 5-dihydro-lH-pyrazole-3-carboximidamide;
3) Synthesis of (R, Z) -1- (4-chlorophenyl) -N '- (4-chlorophenyl) sulfonyl) -5- ) Ethyl) -4,5-dihydro-lH-pyrazole-3-carboximidamide;
4) (R, Z) -1- (4-Chlorophenyl) -N '- (4-chlorophenyl) sulfonyl) -N- (2- (methylsulfonyl) 2-yl) -4,5-dihydro-lH-pyrazole-3-carboximidamide;
5) (R, Z) -N '- ((4-chlorophenyl) sulfonyl) -1- (2,4- difluorophenyl) Phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamide;
6) (R, Z) -1- (4-chlorophenyl) -N '- (6-chloropyridin- -4,5-dihydro-lH-pyrazole-3-carboximidamide;
7) (R, Z) -1- (4-Chlorophenyl) -N '- (6-chloropyridin- (Methylsulfonyl) ethyl) -4,5-dihydro-lH-pyrazole-3-carboximidamide;
8) (R, Z) -1- (4-Chlorophenyl) -N '- (4-chlorophenyl) sulfonyl) -N- (2- (methylthio) ethyl- - dihydro-lH-pyrazole-3-carboximidamide;
9) (R, Z) -1- (4-Chlorophenyl) -N '- (4-chlorophenyl) sulfonyl) -N- (2- (methylsulfinyl) 5-dihydro-lH-pyrazole-3-carboximidamide;
10) Synthesis of (R, Z) -1- (4-chlorophenyl) -N '- (4-chlorophenyl) sulfonyl) -N - -2-yl) -5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamide;
11) (R, Z) -1- (4-Chlorophenyl) -N '- ((4-chlorophenyl) sulfonyl) Methyl-1- (methylsulfonyl) butan-2-yl) -4,5-dihydro-1H-pyrazole-3-carboximidamide; And
12) (S) -3-Methyl-1- (methylsulfonyl) -1- (4-fluorophenyl) -N - Butan-2-yl) -5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamide.
(a) reacting a compound of formula 2 with phosphorus pentasulfide (P ₂ S ₅ ) or Lawesson reagent in a solvent selected from the group consisting of toluene, xylene, benzene, chlorobenzene, To give a compound of formula (3);
(b) reacting the compound of formula (3) with a compound selected from the group consisting of triethylamine, potassium carbonate, and mixtures thereof in a solvent selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, With methyl iodide in the presence of a base selected to produce a compound of formula 4; And
(c) reacting the compound of formula (4) with a compound selected from the group consisting of triethylamine, potassium carbonate, and mixtures thereof in a solvent selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, With a compound of formula (6) in the presence of a base selected from the group consisting of:
[Chemical Formula 1]

(2)

(3)

[Chemical Formula 4]

[Chemical Formula 6]

Wherein A ¹ , A ² , A ³ , L, X and R are as defined in claim 1.
(a) reacting a compound of formula (2) with phosphorus pentachloride (PCl ₅ ) in a solvent selected from the group consisting of toluene, xylene, benzene, chlorobenzene and mixtures thereof to prepare a compound of formula step; And
(b) reacting the compound of formula (5) with a compound selected from the group consisting of triethylamine, potassium carbonate, and mixtures thereof in a solvent selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, With a compound of formula (6) in the presence of a base selected from the group consisting of:
[Chemical Formula 1]

(2)

[Chemical Formula 5]

[Chemical Formula 6]

Wherein A ¹ , A ² , A ³ , L, X and R are as defined in claim 1.
A pharmaceutical composition for the prophylaxis or treatment of obesity or obesity-related metabolic diseases, comprising the compound according to claim 1 as an active ingredient.
The method according to claim 6,
Wherein said obesity-related metabolic disease is selected from the group consisting of Type 2 diabetes, chronic liver disease, angina pectoris, hypertension, congestive heart failure and hyperlipemia.
The method according to claim 6,
Wherein the active ingredient exhibits antagonistic activity against the cannabinoid CB1 receptor.

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