WO2014208939A1 - 1,5-diaryl-4,5-dihydro-1h-pyrazole-3-carboxamidine derivatives as cannabinoid cb1 receptor antagonist, method for preparing same, and pharmaceutical composition comprising same - Google Patents

1,5-diaryl-4,5-dihydro-1h-pyrazole-3-carboxamidine derivatives as cannabinoid cb1 receptor antagonist, method for preparing same, and pharmaceutical composition comprising same Download PDF

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Publication number
WO2014208939A1
WO2014208939A1 PCT/KR2014/005479 KR2014005479W WO2014208939A1 WO 2014208939 A1 WO2014208939 A1 WO 2014208939A1 KR 2014005479 W KR2014005479 W KR 2014005479W WO 2014208939 A1 WO2014208939 A1 WO 2014208939A1
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Prior art keywords
chlorophenyl
dihydro
pyrazole
carboximidamido
sulfonyl
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PCT/KR2014/005479
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French (fr)
Inventor
Moon Sub Lee
Dong Jin Hong
Hee Sook Oh
Jong Ouk Baek
Young Hee Jung
Nam Du Kim
Tae Hee Ha
Kwee Hyun Suh
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Hanmi Pharm. Co., Ltd.
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Publication of WO2014208939A1 publication Critical patent/WO2014208939A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D231/08—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen or sulfur atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel l,5-diaryl-4,5-dihydro-lH- pyrazole-3-carboxamidine compound or a pharmaceutically acceptable salt thereof having inverse agonist activity or antagonistic activity against a cannabinoid CB 1 receptor, a method for preparing the same, and a pharmaceutical composition comprising the same.
  • rimonabant SR141716A, Pfizer
  • CB 1 receptor antagonist a selective CB 1 receptor antagonist
  • CB 1 receptors including otenabant (CP-945598, Pfizer), surinabant (Sanofi-Aventis), ibipinabant (SLV 319, Solvay Pharmaceuticals), Taranabant (MK-0364, Merck), drinabant (AVE 1625, Aventis Pharmaceuticals), and the like were tested on clinical trials or available on the market.
  • these drugs were accompanied by CNS-related adverse side effects such as depression, anxiety, dizziness, insomnia, and the l like, as well as other adverse effects related to gastrointestinal disorders including nausea, diarrhea, and the like, and thus, these drugs were withdrawn from the market and their development have been discontinued.
  • the main cause for such psychiatric side effects caused by the administration of the conventional CB1 receptor antagonists is due to the fact that these drugs are distributed largely in the brain tissue.
  • the present inventors have endeavored to manufacture a CB 1 receptor antagonist which are selective for the peripheral tissues, rather than the brain tissue, so as to reduce the adverse side effects of conventional drugs, and have accomplished the present invention by discovering a novel 1,5- diaryl-4,5-dihydro-lH-pyrazole-3-carboxamidine derivative having antagonistic activity against a CB1 receptor with a high selectivity for the peripheral tissues.
  • R' and R" are each independently linear or branched Ci -6 alkyl
  • Ri and R 2 are each independently hydrogen or C 1-6 alkyl, and optionally, each of which is independently substituted with at least one substituent selected from the group consisting of hydrogen, linear or branched Ci -6 alkyl, linear or branched Ci -6 alkoxy, halo, CN, OH, NO 2 , and SH.
  • a pharmaceutical composition for the prevention or treatment of obesity or an obesity-related metabolic disease comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound in accordance with the present invention having inverse agonist activity or antagonistic activity against a cannabinoid CB 1 receptor with a high selectivity for the peripheral tissues exhibits anti-obesity effects, and thus can be useful in the prevention or treatment of obesity or obesity-related metabolic diseases.
  • Fig. 1 is a graph showing a weight reduction effect resulting from administration of the compounds prepared in Examples 13 and 31 of the present invention in diet-induced obesity (DIO) mice.
  • Fig. 2 is a graph showing a food intake suppression effect resulting from administration of the compounds prepared in Examples 13 and 31 of the present invention in DIO mice.
  • Fig. 3 is a graph demonstrating improved insulin and leptin resistance resulting from administration of the compounds prepared in Examples 13 and 31 of the present invention.
  • Fig. 4 is a graph showing reduced translocation of the drug into the brain tissue resulting from administration of the compounds prepared in Examples 13 and 31 of the present invention.
  • Fig. 5 is a graph showing the time spent at open arms and the total distance travelled resulting from administration of the compounds prepared in Examples 13 and 31 of the present invention.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
  • R' and R" are each independently linear or branched C 1 -6 alkyl
  • Ri and R 2 are each independently hydrogen or C 1-6 alkyl, and optionally, each of which is independently substituted with at least one substituent selected from the group consisting of hydrogen, linear or branched C 1-6 alkyl, linear or branched C 1-6 alkoxy, halo, CN, OH, NO 2 , and SH.
  • A is C 6-10 aryl or C4 -1 oheteroaryl, each of which is independently substituted with at least one substituent selected from the group consisting of hydrogen, halo, dihalo, and C 1-6 alkyl;
  • B is C 6- i 0 aryl or C 4- 10 heteroaryl, each of which is independently substituted with at least one substituent selected from the group consisting of hydrogen and CN;
  • C is C 6- i 0 aryl which is optionally substituted with halo;
  • Ri and R 2 are each independently hydrogen, linear or branched Ci -6 alkyl, or linear or branched Q. 6 alkyl substituted with OH.
  • the C 6-10 aryl and C 4-10 heteroaryl is selected from the group consisting of phenyl, furanyl, benzofuranyl, thienyl, benzothienyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridizinyl.
  • A is 4-chlorophenyl, 4,4-difluoropiperidinyl or 4- methylpiperazinyl
  • B is phenyl, 4-cyanophenyl or 2-thiophenyl
  • C is 4- chlorophenyl
  • R] is hydrogen or methyl
  • R 2 is methyl, hydroxymethyl, isopropyl or isobutyl.
  • halo refers to fluoro, bromo, chloro or iodo.
  • alkyl 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, ⁇ -propyl, isopropyl, n- butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and hexyl.
  • alkoxy refers to -ORa groups, wherein Ra is an alkyl as defined above. Particular examples thereof may include, but not limited to, methoxy, ethoxy, rc-propoxy, isopropoxy, rc-butoxy, and t-butoxy.
  • aryl refers not only to fused groups such as naphthyl and phenanthrenyl, but also to monocyclic or bicyclic aromatic rings such as phenyl, substituted phenyl, etc.
  • heteroaryl refers to 5- to 10-membered monocyclic heteroaryl groups 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,
  • a "pharmaceutically acceptable salt" of the compound of formula (I) may be prepared by conventional methods well-known in the art, for example, an acid-addition salt of inorganic acid such as hydrochloric acid, bromic acid, sulfuric acid, sodium bisulfate, phosphoric acid, nitric acid, carbonic acid, and the like; 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; amino acid such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline, and the like;
  • the compound of formula (I) may be prepared by a method comprising the steps of: 1) allowing a compound of formula (II) to react with phosphorus pentasulfide (P 2 S 5 ) 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); 2) 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 such as triethylamine to obtain a compound of formula (IV); and 3) 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, tetra
  • the compound of formula (I) according to the present invention may be prepared by a method comprising the steps of: a step of allowing the compound of formula (II) to react with chloride such as phosphorus pentachloride (PC1 5 ) in a solvent selected from toluene, xylene, benzene, chlorobenzene, and a mixture thereof to obtain a compound of formula (V); and a step of allowing the compound of formula (V) thus obtained 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 to obtain the compound of formula (I).
  • chloride such as phosphorus pentachloride (PC1 5 )
  • 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 References [J. Med. Chem. 2007, 50, p5951-5966; Bioorganic & Medicinal Chemistry Letters, 2010, 20(5), pi 752- 1757; and WO 2005074920] or any similar method thereof.
  • the sulfonamide compound is, for example, 4- chlorobenzenesulfonamide, 4,4-difluoropiperidin- 1 -sulfonamide, 4- methylpiperazine- 1 -sulfonamide, and the like.
  • step 1) the compound of formula (III) is obtained by introducing sulfur to the compound of formula (II).
  • the compound of formula (II) is subjected to a reaction with P 2 S 5 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.
  • step 2) the 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.
  • step 3 the compound of formula (I) is obtained by allowing the compound of formula (IV) with an amide derivative such as the 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.
  • an organic solvent for example, such as tetrahydrofuran
  • a base such as triethylamine or potassium carbonate
  • the compound of formula (II) is subjected to a reaction in an organic solvent, for example, such as chlorobenzene in the presence of PC1 5 by heating or heating under reflux conditions for 1 to 3 hours to obtain the compound of formula (V), changing the reaction temperature to a lower or room temperature, and then subjecting the compound thus formed to a reaction with an amide derivative such as the 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.
  • an organic solvent for example, such as chlorobenzene in the presence of PC1 5 by heating or heating under reflux conditions for 1 to 3 hours to obtain the compound of formula (V), changing the reaction temperature to a lower or room temperature, and then subjecting the compound thus formed to a reaction with an amide derivative such as the compound of formula (VI) in an organic solvent, for example, such as dichloromethane in the presence of a base such as triethy
  • the present invention also provides a pharmaceutical composition for the prevention or treatment of obesity and an obesity-related metabolic disease, comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the obesity-related metabolic disease may be selected from the group consisting of Type 2 Diabetes, chronic hepatic diseases, angina, hypertension, congestive heart failure, and hyperlipidemia, but not limited thereto.
  • the pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof may be formulated in the form of oral or parenteral formulations according to conventional methods, and may contain a filler, an extender, a binder, a wetting agent, a disintegrant, a diluent such as a surfactant, or an excipient.
  • 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 or gelatin. Also, besides a simple excipient, a lubricant such as magnesium stearate or talc may be used.
  • excipient for example, starch, calcium carbonate, sucrose, lactose or gelatin.
  • 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 or a preservative, may be employed.
  • 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.
  • a base material may include Witepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerol or gelatin.
  • a proposed daily dose of the pharmaceutical composition of the present invention to a human 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 disease severity.
  • the present invention provides a use of the compound of formula (I) for the manufacture of a medicament for preventing or treating obesity or an obesity-related metabolic disease.
  • the present invention provides a method for preventing or treating obesity or an obesity-related metabolic disease, comprising administering to a mammal an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • Step 1) Preparation of l-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)- 5-phenyl-4,5-dihvdro-lH-pyrazole-3-carbothioamide
  • Step 2) Preparation of methyl l-(4-chlorophenyl)-N-((4- chlorophenyl)sulfonyl)-5-phenyl-4,5-dihydro-lH-pyrazole-3-carbimidothiolate
  • Step 1 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 ⁇ aqueous hydrochloric acid solution and brine. The solid residue thus obtained was crystallized by using methanol to obtain the title compound (150 mg).
  • Step 3) Preparation of (2S)-2-n-(4-chlorophenyl -N f -((4- chlorophenyl)sulfonyl)-5-phenyl-4,5-dihydro-lH-pyrazole-3- carboximidamido)-3-methylbutanamide
  • the concentrated compound was added with a solvent, dichloromethane, and then cooled down to 0°C under an atmosphere of nitrogen. Subsequently, L-valinamide (62.9 mg, 0.54 mmol) and triethylamine (114 mg, 1.13 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 layer chromatography (silica gel 60 F 254 , 1mm) to obtain the title compound as a yellow compound (18 mg).
  • Step 1) Preparation of l-(4-chlorophenyl)-N-((4-methylpiperazin-l- yl)sulfonyl)-5-phenyl-4,5-dihydro-lH-pyrazole-3-carboxamide l-(4-chlorophenyl)-5-phenyl-4,5-dihydro-lH-pyrazole-3-carboxylic acid was prepared according to the method disclosed in References [J. Med. Chem. 2007, 50, p5951-5966; Bioorganic & Medicinal Chemistry Letters, 2010, 20(5), pi 752- 1757; and WO 2005/074920] or a similar method thereto.
  • Step 1 The compound obtained in Step 1) (0.52 g, 1.1 mmol) and phosphorus pentachloride (0.46 g) were added to chlorobenzene (5.0 mL) and stirred at 130°C for 1 hour. Upon completion of the reaction, the reaction solution was concentrated. The concentrated compound was added with dichloromethane (5.0 mL), and then cooled down to 0°C under an atmosphere of nitrogen.
  • Example 2 The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (60 mg).
  • Example 2 The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (4.4 mg).
  • Example 2 The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (24 mg).
  • Example 2 The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (50 mg).
  • Example 2 The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (80 mg).
  • Example 2 The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (34 mg).
  • Example 2 The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (36 mg).
  • Example 2 The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (24 mg).
  • Example 2 The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (54 mg).
  • Example 2 The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (25 mg).
  • Example 2 The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (816 mg).
  • Example 14 Preparation of (5)-2-(( ?, )-l-(4-chIorophenyl)-7V'-((4- chlorophenyl)sulfonyl)-5-phenyl-4,5-dihydro-l /-pyrazole-3- carboximidamido)-3,3-dimethylbutanamide
  • Example 2 The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (66 mg).
  • Example IB The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (66 mg).
  • Example 16 Preparation of (5 -2-((i?,Z)-l-(4-chlorophenyl)- J ?V'-((6- chIoropyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-4,5-dihydro-l J i/-pyrazole-3- carboximidamido -3-methyIbutanamide
  • Example IB The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (124 mg).
  • Example IB The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (46.7 mg).
  • Example IB The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (42.3 mg).
  • Example IB The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (46.5 mg).
  • Example IB The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (198 mg).
  • Example IB The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (80 mg).
  • Example IB 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).
  • Example IB 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).
  • Example IB The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (40 mg).
  • Example 25 Preparation of (25 -2-(l-(4-chlorophenyl)- V'-((4- chlorophenyl)sulfonyl)-5-(5-methyl-2-thiophenyl)-4,5-dihydro-l ⁇ T-pyrazole- 3-carboximidamido)-3-methylbutanamide
  • Example 26 Preparation of (2- )-2-(l-(4-chlorophenyl)- V'-((4- chlorophenyl)sulfonyl)-5-(2-pyridinyl)-4,5-dihydro-l J H r -pyrazole-3- carboximidamido)-3-methylbutanamide
  • Example IB The same method as that in Example IB or a similar method thereof was conducted to obtain the title compound as a yellow compound (30 mg).
  • Example IB The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (250
  • Example IB The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (68 mg).
  • Example 29 Preparation of (5 -2-((7?,Z)-l-(4-chlorophenyl)-A ⁇ '-((4- chlorophenyl)sulfonyl)-5-(furan-2-yl)-4,5-dihydro-l J i- r -pyrazole-3- carboximidamido)-3,3-dimethylbutanamide
  • Example IB 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).
  • Example IB The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (26 mg).
  • Example IB The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (20 mg).
  • Example IB The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (150 mg).
  • Example 33 Preparation of (5)-2-((Z)-l-(4-chlorophenyl)-/Y'-((6- chloropyridin-3-yl)suIfonyl)-5-(pyridin-2-yl)-4,5-dihydro-l - r -pyrazole-3- carboximidamido)-3-methylbutanamide
  • Example IB The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (150 mg).
  • a binding assay was conducted to evaluate the antagonistic activity of Gi protein-coupled receptor, i.e., cannabinoid receptor 1, as follows.
  • the assay is based upon the principle that agonists bind to G-protein coupled receptors to stimulate GDP-GTP exchange at the G-protein.
  • a non- hydrolyzable form of GTP i.e. , GTPyS, a radiochemical [ 35 S]- 1250Ci/mmol, 12.5mCi/mmol, 1 mCi (Perkin Elmer, cat. NEG030H001MC), and WGA-coated SPA beads (Cat. RPNQ0210) were used for the assay.
  • Each of the compounds prepared in Examples 1 to 5 was placed in an lx assay buffer (20 mM HEPES, 100 mM NaCl, 25 mM MgCl 2 , 1 mM EDTA, pH 7.4), and diluted to produce samples with various concentrations including 10 ⁇ , 1 ⁇ , 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 ⁇ GDP at the ratio of 1 : 1 (v/v) to form a mixture.
  • the mixture of the CB1 receptor membrane and GDP thus prepared (100 ⁇ ) was added with diluted samples, further added with a mixture prepared by adding WGA-coated SPA beads and the [ 35 S]GTPyS mixture at the ratio of 1 : 1 (v/v).
  • the reaction mixture was allowed to react for 50 minutes at room temperature, and then [ 35 S]GTPyS activity was measured by using a ⁇ - 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.
  • IC 50 values were calculated for each compound by using GraphPad Prism 4.0 software.
  • Diet induced obesity (DIO) mice were used to evaluate the suppressive effect of the inventive compounds on feeding amount and body weight gain.
  • mice 5-week-old C57BL/6 mice (OrientBio, Korea) 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 ligh dark cycle room (11 :00 light-out, 23:00 light-on) with controlled conditions of temperature and humidity, and had free access to food and water. One week before each test, each mouse was individually housed, and a baseline of its feeding amount and body weight was determined by conducting a habituation to a treatment. Mice were randomly grouped into treatment groups, based on their initial body weights and feeding amounts.
  • DIO mice were treated with the test compound at 3 mg/kg.
  • the body weight and feeding amount were measured every 24 hours from day 0 (before the treatment) until day 28 using an electronic scale.
  • the effectiveness of the test compounds was evaluated by comparing the data (changes in body weight and feeding amount) obtained from the vehicle-treated group, the standard positive control-treated group, and the test compound- treated groups.
  • feeding amount was decreased owing to the administration of the inventive compounds.
  • the feeding amount slowly returned to the normal level, and was maintained constantly at the normal level after the body weight had been reduced.
  • ELISA Enzyme linked immunosorbent assay
  • the compounds of Examples 13 and 31 according to the present invention effectively reduced the levels of insulin and leptin that are closely related to obesity-related metabolic diseases and obesity.
  • Brain exposure rates of the compounds of the present invention were examined after oral administration of the compounds to the DIO mice and normal ICR mice.
  • mice were orally administered to the mice at a dose of 3 mg/kg body weight.
  • blood and brain tissue samples were taken from the mice.
  • the blood samples were placed in heparin-treated eppendorf tubes (1000 IU/mL, heparin, 3 ⁇ ,), and immediately centrifuged (12,000 rpm, 2 minutes) to separate the plasma.
  • Brain samples were diluted 10 times using a 4% bovine serum albumin (BSA) solution, and pulverized.
  • BSA bovine serum albumin
  • the concentrations of the test compounds in the blood and brain tissue samples were analyzed by (LC-MS/MS), and the results are shown in Fig. 4.
  • the brain exposure rates of the compounds of Examples 13 and 31 according to the present invention (about 7%, and 9%, respectively) was superior to that of rimonabant (about 59%) in DIO mice.
  • the brain exposure rates of the compounds of Examples 13 and 31 according to the present invention (about 3% and 0.4%, respectively) was also superior to that of rimonabant (about 42%).
  • EPM elevated plus maze
  • mice 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 ICR mice administered with a vehicle only (vehicle group). The result is shown in Fig. 5.
  • mice administered with the compounds of Examples 13 and 31 showed movements in both the open and closed arms, whereas the mice treated with rimonabant exhibited movements in the closed arms only.

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Abstract

The present invention relates to a novel 1,5-diaryl-4,5-dihydro-1H-pyrazole-3-carboxamidine compound or a pharmaceutically acceptable salt thereof having inverse agonist activity or antagonistic activity against a cannabinoid CB1 receptor, a method for preparing the same, and a pharmaceutical composition comprising the 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 l,5-DIARYL-4,5-DIHYDRO-l//-PYRAZOLE-3-CARBOXAMIDINE DERIVATIVES AS CANNABINOID CB1 RECEPTOR
ANTAGONIST, METHOD FOR PREPARING SAME, AND PHARMACEUTICAL COMPOSITION COMPRISING SAME
FIELD OF THE INVENTION
The present invention relates to a novel l,5-diaryl-4,5-dihydro-lH- pyrazole-3-carboxamidine compound or a pharmaceutically acceptable salt thereof having inverse agonist activity or antagonistic activity against a cannabinoid CB 1 receptor, a method for preparing the same, and a pharmaceutical composition comprising the 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 CB 1 receptor can affect energy homeostasis via central and peripheral mechanisms of action.
Based on clinical trials, it was proven that rimonabant (SR141716A, Pfizer), a selective CB 1 receptor antagonist, was effectively in reducing the weights of obese patients and thereby alleviating conditions such as metabolic syndromes including obesity-related cardiovascular disorders, diabetes, etc. Since then CB 1 receptors have become a topic of interest for the treatment of obesity and obesity-related metabolic diseases.
Besides rimonabant, a number of CB 1 receptors including otenabant (CP-945598, Pfizer), surinabant (Sanofi-Aventis), ibipinabant (SLV 319, Solvay Pharmaceuticals), Taranabant (MK-0364, Merck), drinabant (AVE 1625, Aventis Pharmaceuticals), and the like were tested on clinical trials or available on the market. However, these drugs were accompanied by CNS-related adverse side effects such as depression, anxiety, dizziness, insomnia, and the l like, as well as other adverse effects related to gastrointestinal disorders including nausea, diarrhea, and the like, and thus, these drugs were withdrawn from the market and their development have been discontinued. The main cause for such psychiatric side effects caused by the administration of the conventional CB1 receptor antagonists is due to the fact that these drugs are distributed largely in the brain tissue.
Considering the fact that there is a lack of effective drugs for the treatment of obesity as for its severity, a development of an effective CB 1 receptor antagonist having its preexisting problems fixed has become a topic of interest.
Accordingly, the present inventors have endeavored to manufacture a CB 1 receptor antagonist which are selective for the peripheral tissues, rather than the brain tissue, so as to reduce the adverse side effects of conventional drugs, and have accomplished the present invention by discovering a novel 1,5- diaryl-4,5-dihydro-lH-pyrazole-3-carboxamidine derivative having antagonistic activity against a CB1 receptor with a high selectivity for the peripheral tissues.
SUMMARY OF THE INVENTION
Therefore, it is an object of the present invention to provide a novel 1,5- diaryl-4,5-dihydro-lH-pyrazole-3-carboxamidine derivative compound having cannabinoid receptor antagonistic activity with a high selectivity for the peripheral tissues.
It is another object of the present invention to provide a method for preparing the compound.
It is another object of the present invention to provide a pharmaceutical composition comprising the compound.
In accordance with one object of the present invention, there is provided a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000004_0001
wherein A is selected from the group consisting of Ci-7alkyl, C6-ioaryl, C4-10heteroaryl, C3-6cycloalkyl, and C3-6heterocycloalkyl, and optionally, each of which is independently substituted with at least one substituent selected from the group consisting of hydrogen, linear or branched C^alkyl, linear or branched C1-6alkoxy, halo, CN, OH, NO2, -(C=O)-R', SH, SR', SOR', SO2R', NH2, NHR', NR'R", -(C=O)-NH2, -(C=O)-NHR\ and -(C=O)-NR'R";
B and C are each independently C6-1oaryl or C4-10heteroaryl, and optionally, each of which is independently substituted with at least one substituent selected from the group consisting of hydrogen, linear or branched Ci-6alkyl, linear or branched Ci-6alkoxy, halo, dihalo, trihalo, CN, OH, NO2, - (CO)-R', SH, SR', SOR', SO2R', NH2, NHR', NR'R", -(C=O)-NH2, -(C=O)- NHR', and -(C=O)-NR'R";
R' and R" are each independently linear or branched Ci-6alkyl; and
Ri and R2 are each independently hydrogen or C1-6alkyl, and optionally, each of which is independently substituted with at least one substituent selected from the group consisting of hydrogen, linear or branched Ci-6alkyl, linear or branched Ci-6alkoxy, halo, CN, OH, NO2, and SH.
In accordance with another object of the present invention, there is provided a method for preparing the compound or a pharmaceutically acceptable salt thereof.
In accordance with another object of the present invention, there is provided a pharmaceutical composition for the prevention or treatment of obesity or an obesity-related metabolic disease, comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient. The compound in accordance with the present invention having inverse agonist activity or antagonistic activity against a cannabinoid CB 1 receptor with a high selectivity for the peripheral tissues exhibits anti-obesity effects, and thus can be useful in the prevention or treatment of obesity or obesity-related metabolic diseases.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a graph showing a weight reduction effect resulting from administration of the compounds prepared in Examples 13 and 31 of the present invention in diet-induced obesity (DIO) mice.
Fig. 2 is a graph showing a food intake suppression effect resulting from administration of the compounds prepared in Examples 13 and 31 of the present invention in DIO mice.
Fig. 3 is a graph demonstrating improved insulin and leptin resistance resulting from administration of the compounds prepared in Examples 13 and 31 of the present invention.
Fig. 4 is a graph showing reduced translocation of the drug into the brain tissue resulting from administration of the compounds prepared in Examples 13 and 31 of the present invention.
Fig. 5 is a graph showing the time spent at open arms and the total distance travelled resulting from administration of the compounds prepared in Examples 13 and 31 of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000006_0001
wherein A is selected from the group consisting of Ci- alkyl, C6-i0aryl, C4-10heteroaryl, C3-6cycloalkyl, and C3-6heterocycloalkyl, and optionally, each of which is independently substituted with at least one substituent selected from the group consisting of hydrogen, linear or branched C1-6alkyl, linear or branched C1-6alkoxy, halo, CN, OH, NO2, -(C=O)-R', SH, SR', SOR', SO2R', NH2, NHR', NR'R", -(C=O)-NH2, -(C=O)-NHR', and -(C=O)-NR'R";
B and C are each independently C6-10aryl or C4-10heteroaryl, and optionally, each of which is independently substituted with at least one substituent selected from the group consisting of hydrogen, linear or branched C1-6alkyl, linear or branched C1-6alkoxy, halo, dihalo, trihalo, CN, OH, NO2, - (C=O)-R', SH, SR', SOR', SO2R', NH2, NHR', NR'R", -(C=O)-NH2, -(C=O)- NHR', and -(C=O)-NR'R";
R' and R" are each independently linear or branched C1 -6alkyl; and
Ri and R2 are each independently hydrogen or C1-6alkyl, and optionally, each of which is independently substituted with at least one substituent selected from the group consisting of hydrogen, linear or branched C1-6alkyl, linear or branched C1-6alkoxy, halo, CN, OH, NO2, and SH.
Preferably, A is C6-10aryl or C4-1oheteroaryl, each of which is independently substituted with at least one substituent selected from the group consisting of hydrogen, halo, dihalo, and C1-6alkyl; B is C6-i0aryl or C4- 10heteroaryl, each of which is independently substituted with at least one substituent selected from the group consisting of hydrogen and CN; C is C6- i0aryl which is optionally substituted with halo; and Ri and R2 are each independently hydrogen, linear or branched Ci-6alkyl, or linear or branched Q. 6alkyl substituted with OH. In substituents A to C, the C6-10aryl and C4-10heteroaryl is selected from the group consisting of phenyl, furanyl, benzofuranyl, thienyl, benzothienyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridizinyl.
More preferably, A is 4-chlorophenyl, 4,4-difluoropiperidinyl or 4- methylpiperazinyl; B is phenyl, 4-cyanophenyl or 2-thiophenyl; C is 4- chlorophenyl; R] is hydrogen or methyl; R2 is methyl, hydroxymethyl, isopropyl or isobutyl.
More preferable compounds according to the compound of formula (I) of the present invention are listed below:
1) (2S)-2-(l -(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-phenyl- 4,5-dihydro- lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
2) (2S)-2-( 1 -(4-chlorophenyl)-N'-((4-methy lpiperazin- 1 -yl)sulfony l)-5- phenyl-4,5-dihydro- lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
3) (2S)-2-(N'-((4-chlorophenyl)-l-(4-methoxyphenyl)sulfonyl)-5- phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
4) (2S)-2-( 1 -(4-chloropheny l)-N'-((4,4-difluoropiperidin- 1 -y l)sulfonyl)- 5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
5) ' (2S)-2-(l-(4-chlorophenyl)-N'-((4-cyanophenyl)sulfonyl)-5-phenyl- 4,5-dihydro-lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
6) (2S)-2-(l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-(4- cyanophenyl)-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3- methylbutanamide;
7) (2S)-( 1 -(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-(2- thiophenyl)-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3- methy lbutanamide ;
8) (2S)-2-(l -(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-phenyl- 4,5-dihydro-lH-pyrazole-3-carboximidamido)acetamide;
9) (2S)-2-( 1 -(4-chloropheny l)-N'-((4-chloropheny l)sulfonyl)-5 -phenyl- 4,5-dihydro- lH-pyrazole-3-carboximidamido)propanamide;
10) (R,Z)-2-( 1 -(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5- phenyl-4,5-dihydro- lH-pyrazole-3-carboximidamido)-2-methylpropanamide; 11 ) (2S)-2-( 1 -(4-chlorophenyl)-N'-((4-chlorophenyl)sulfony l)-5-phenyl- 4,5-dihydro- lH-pyrazole-3-carboximidamido)-4-methylpentanamide;
12) (2S)-2-(l-(4-chlorophenyl)-N -((4-chlorophenyl)sulfonyl)-5-phenyl- 4,5-dihydro-lH-pyrazole-3-carboximidamido)-3-hydroxypropanamide;
13) (S)-2-((R,Z)- l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5- phenyl-4,5-dihydro- lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
14) (S)-2-((R,Z)-lK4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5- phenyl-4,5-dihydro- lH-pyrazole-3-carboximidamido)-3,3-dimethylbutanamide;
15) (2S)-2-((Z)-N'-((4-chlorophenyl)sulfonyl)- 1 -(2,4-difluorophenyl)-5- phenyl-4,5-dihydro- lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
16) (S)-2-((R,Z)- l-(4-chlorophenyl)-N'-((6-chloropyridin-3-yl)sulfonyl)- 5 -(2-fluorophenyl)-4, 5 -dihy dro- 1 H-pyrazole-3-carboximidamido)-3- methy lbutanami de ;
17) (S)-2-((R,Z)-N'-((4-chlorophenyl)sulfonyl)-l-(2,4-difluorophenyl)-5- phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
18) (S)-2-((R,Z)-N'-((4-chlorophenyl)sulfonyl)-l-(4-fluorophenyl)-5- phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
19) (S)-2-((R,Z)- l-(4-chlorophenyl)-N'-((4-fluorophenyl)sulfonyl)-5- phenyl-4,5-dihydro- lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
20) (S)-2-((R,Z)- l-(4-chlorophenyl)-N'-((6-chloropyridin-3-yl)sulfonyl)- 5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
21 ) (2S)-2-( 1 -(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-(2- furanyl)-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
22) 2-(R,Z)-(l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-(2- thiophenyl)-4,5-dihydro- lH-pyrazole-3-carboximidamido)-3- methy lbutanamide ;
23) (2S)-2-(l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-(5- methyl-2-furanyl)-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3- methylbutanamide;
24) (2S)-2-(l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-(5- methyl-2-furanyl)-4,5-dihydro- lH-pyrazole-3-carboximidamido)-3- methy lbutanamide;
25) (2S)-2-(l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-(5- methyl-2-thiophenyl)-4,5-dihydro- lH-pyrazole-3-carboximidamido)-3- methylbutanamide
26) (2S)-2-(l -(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-(2- pyridinyl)-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
27) 2-(R,Z)-(l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-(2- fluorophenyl)-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3- methylbutanamide;
28) (S)-2-((R,Z)- l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl-5- (pyridin-2-yl)-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3- methylbutanamide;
29) (S)-2-((R,Z)-l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5- (furan-2-yl)-4,5-dihydro- lH-pyrazole-3-carboximidamido)-3,3- dimethy lbutanami de ;
30) (2S)-2-((Z)-N'-((4-chlorophenyl)sulfonyl)- l-(2,4-dichlorophenyl)-5- phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
31) (S)-2-((R,Z l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-(2- fluorophenyl)-4,5-dihydro- lH-pyrazole-3-carboximidamido)-3- methylbutanamide;
32) (S)-2-((R,2)-5-(2-chlorophenyl)- l-(4-chlorophenyl)-N'-((4- chlorophenyl)sulfonyl)-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3- methylbutanamide; and
33) (S)-2-((Z)-l-(4-chlorophenyl)-N'-((6-chloropyridin-3-yl)sulfonyl)-5- (pyridin-2-yl)-4,5-dihydro- lH-pyrazole-3-carboximidamido)-3- methy lbutanamide .
The term "halo," as used herein, refers to fluoro, bromo, chloro or 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, ^-propyl, isopropyl, n- butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and hexyl.
The term "alkoxy," as used herein, refers to -ORa groups, wherein Ra is an alkyl as defined above. Particular examples thereof may include, but not limited to, methoxy, ethoxy, rc-propoxy, isopropoxy, rc-butoxy, and t-butoxy. The term "aryl," as used herein, refers not only to fused groups such as naphthyl and phenanthrenyl, but also to monocyclic or bicyclic aromatic rings such as phenyl, substituted phenyl, etc. The said aryl group is optionally substituted with one or more substituents, i.e., halogen, alkyl, alkoxy, hydroxy 1, carboxy, carbamoyl, alkyloxycarbonyl, nitro, trifluoromethyl, amino, cycloalkyl, cyano, alkyl S(O)n (n = 1, 2, 3) or thiol, but not limited thereto.
The term "heteroaryl," as used herein, refers to 5- to 10-membered monocyclic heteroaryl groups 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, and 6,7-dihydro-5H-[l]pyridinyl; or bicyclic heteroaryl groups such as 5,6,7,8- tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzo[b]thiophenyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofurayl, isobenzofuranyl, isoindolyl, indolyl, indolyzinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, pyrazolo[3,4-b]pyridinyl, and benzoxazinyl.
A "pharmaceutically acceptable salt" of the compound of formula (I) may be prepared by conventional methods well-known in the art, for example, an acid-addition salt of inorganic acid such as hydrochloric acid, bromic acid, sulfuric acid, sodium bisulfate, phosphoric acid, nitric acid, carbonic acid, and the like; 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; amino acid such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline, and the like; and sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and the like; or a metallic salt formed by the reaction with an alkali metal such as sodium, potassium, and the like; or a salt formed with an ammonium ion. Further, the present invention provides a method for preparing the compound of formula (I).
The compound of formula (I) according to the present invention may be prepared by a method comprising the steps of: 1) 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); 2) 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 such as triethylamine to obtain a compound of formula (IV); and 3) 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 to obtain the compound of formula (I).
Alternatively, the compound of formula (I) according to the present invention may be prepared by a method comprising the steps of: a step of allowing the compound of formula (II) to react with chloride such as phosphorus pentachloride (PC15) in a solvent selected from toluene, xylene, benzene, chlorobenzene, and a mixture thereof to obtain a compound of formula (V); and a step of allowing the compound of formula (V) thus obtained 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 to obtain the compound of formula (I).
Figure imgf000011_0001
Figure imgf000012_0001
wherein A, B, C, Ri and R2 have the same meanings as defined in the compound of formula (I) above.
The method for preparing the compound of formula (I) may be prepared according to the procedure shown in Reaction Scheme 1 below:
[Reaction Scheme 1]
Figure imgf000013_0001
wherein A, B, C, R] and R2 have the same meanings as defined in the compound of formula (I) above.
In accordance with an embodiment of the present invention, the above reaction processes are exemplified as below.
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 References [J. Med. Chem. 2007, 50, p5951-5966; Bioorganic & Medicinal Chemistry Letters, 2010, 20(5), pi 752- 1757; and WO 2005074920] or any similar method thereof. According to one embodiment of the present invention, the sulfonamide compound is, for example, 4- chlorobenzenesulfonamide, 4,4-difluoropiperidin- 1 -sulfonamide, 4- methylpiperazine- 1 -sulfonamide, and the like.
The reaction processes are explained in more detail with reference to Reaction Scheme 1. In step 1), the compound of formula (III) is obtained by introducing sulfur to the 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 2), the 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 3), the compound of formula (I) is obtained by allowing the compound of formula (IV) with an amide derivative such as the 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. Alternatively, the compound of formula (I) may be prepared by the following method. The compound of formula (II) is subjected to a reaction in an organic solvent, for example, such as chlorobenzene in the presence of PC15 by heating or heating under reflux conditions for 1 to 3 hours to obtain the compound of formula (V), changing the reaction temperature to a lower or room temperature, and then subjecting the compound thus formed to a reaction with an amide derivative such as the 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.
Meanwhile, the present invention also provides a pharmaceutical composition for the prevention or treatment of obesity and an obesity-related metabolic disease, comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
The obesity-related metabolic disease may be selected from the group consisting of Type 2 Diabetes, chronic hepatic diseases, angina, hypertension, congestive heart failure, and hyperlipidemia, but not limited thereto.
The pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof may be formulated in the form of oral or parenteral formulations according to conventional methods, and may contain a filler, an extender, a binder, a wetting agent, a disintegrant, a diluent such as a surfactant, or an excipient.
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 or gelatin. 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 or a preservative, may be employed.
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 or gelatin.
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 disease severity.
Further, the present invention provides a use of the compound of formula (I) for the manufacture of a medicament for preventing or treating obesity or an obesity-related metabolic disease.
Furthermore, the present invention provides a method for preventing or treating obesity or an obesity-related metabolic disease, comprising administering to a mammal an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
[Examples]
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 (2.S)-2-(l-(4-chlorophenyl)-A^ -((4- chlorophenyl)sulfonyl)-5-phenyl-4,5-dihydro-lH-pyrazole-3- carboximidamido)-3-methylbutanamide
<Example 1A>
Step 1) Preparation of l-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)- 5-phenyl-4,5-dihvdro-lH-pyrazole-3-carbothioamide
Figure imgf000016_0001
The compound of formula (II), 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), pi 752- 1757; and WO 2005/074920] or a similar method thereto. The compound of formula (II) (1.0 g, 2.1 mmol) and phosphorus pentasulfide (P2S5, 0.94 g, 4.2 mmol) were added to toluene (20 mL), and stirred at 120°C for 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).
Ή-NMR (300 MHz, CDC13) 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, 1H), 3.24 (dd, 1H).
MS (ESI+): m/z = 490.0 [M+H]+.
Step 2): Preparation of methyl l-(4-chlorophenyl)-N-((4- chlorophenyl)sulfonyl)-5-phenyl-4,5-dihydro-lH-pyrazole-3-carbimidothiolate
Figure imgf000017_0001
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 Ν aqueous hydrochloric acid solution and brine. The solid residue thus obtained was crystallized by using methanol to obtain the title compound (150 mg).
Ή-NMR (300 MHz, CDC13) 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, 1H), 3.44 (dd, 1H), 2.38 (s, 3H).
Step 3): Preparation of (2S)-2-n-(4-chlorophenyl -Nf-((4- chlorophenyl)sulfonyl)-5-phenyl-4,5-dihydro-lH-pyrazole-3- carboximidamido)-3-methylbutanamide
Figure imgf000017_0002
The compound obtained in Step 2) (100 mg, 0.2 mmol) was dissolved in tetrahydrofuran (2 mL), and then L-valinamide (34 mg, 0.22 mmol) and triethylamine (44 mg, 0.44 mmol) were sequentially added thereto. The reaction mixture was heated to 80°C and stirred for 6 hours. The organic layer thus formed was washed with water, 1 N aqueous hydrochloric acid solution and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue thus obtained was purified by preparative layer chromatography (silica gel 60 F254, 1mm) to obtain the title compound as a yellow compound (30 mg).
1H-NMR (300 MHz, DMSO-d6) δ 9.10 (d, 1H), 7.85 (d, 2H), 7.77 (d, 2H), 7.4-7.1 (m, 7H) 6.86 (d, 1H), 5.44 (dd, 1H), 4.33 (m, 1H). 4.0 (dd, 1H), 3.13 (dd, 1H), 2.09 (m, 1H), 1.04-0.88 (m, 6H).
MS (ESI+): m/z = 572.1 [M+H]+.
<Example 1B>
(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 (189 mg, 0.4 mmol) and phosphorus pentachloride (214 mg, 0.45 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, L-valinamide (62.9 mg, 0.54 mmol) and triethylamine (114 mg, 1.13 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 layer chromatography (silica gel 60 F254, 1mm) to obtain the title compound as a yellow compound (18 mg).
Example 2: Preparation of (2.S -2-(l-(4-chlorophenyl)-A^'-((4- methylpiperazin-l-yl)sulfonyl)-5-phenyl-4,5-dihydro-lJy-pyrazole-3- carboximidamido)-3-methylbutanamide
Step 1) Preparation of l-(4-chlorophenyl)-N-((4-methylpiperazin-l- yl)sulfonyl)-5-phenyl-4,5-dihydro-lH-pyrazole-3-carboxamide
Figure imgf000019_0001
l-(4-chlorophenyl)-5-phenyl-4,5-dihydro-lH-pyrazole-3-carboxylic acid was prepared according to the method disclosed in References [J. Med. Chem. 2007, 50, p5951-5966; Bioorganic & Medicinal Chemistry Letters, 2010, 20(5), pi 752- 1757; and WO 2005/074920] or a similar method thereto. The compound thus prepared (1.0 g, 3.3 mmol) was added to toluene (20 mL) and added with thionyl chloride (1.6 g, 13.3 mmol). The mixture was heated to 120°C and it was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue thus obtained was dissolved in acetonitrile (20 mL) to obtain a solution (Solution A).
Sodium hydroxide (0.33 g, 8.3 mmol) was dissolved in water (0.33 mL), which was added to acetonitrile (20 mL). Then 4-methylpiperazine sulfonamide (0.71 g, 4.0 mmol) was added thereto. The mixture thus obtained was slowly added with Solution A (20 mL), followed by stirring for 1 hour. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure. The concentrated residue thus obtained was added with ethyl acetate, and then washed with 1 Ν aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate, and brine. The solid residue thus obtained was crystallized by using ethanol to obtain the title compound
(0.52 g).
Ή-NMR (300 MHz, CDC13) 5 7.4-7.3 (m, 4H), 7.20-7.16 (m, 3H), 7.01 (d, 2H), 5.41 (dd, 1H), 3.73 (dd, 1H), 3.1 (m, 9H), 2.86 (s, 3H).
MS (ESI+): m/z = 462.1 [M+H]+.
Step 2) Preparation of (2S)-2-( 1 -(4-chlorophenvn-N'-((4- methylpiperazin-l-vnsulfonyl)-5-phenyl-4,5-dihydro-lH-pyrazole-3- carboximidamido -3-methylbutanamide
Figure imgf000020_0001
The compound obtained in Step 1) (0.52 g, 1.1 mmol) and phosphorus pentachloride (0.46 g) were added to chlorobenzene (5.0 mL) and stirred at 130°C for 1 hour. Upon completion of the reaction, the reaction solution was concentrated. The concentrated compound was added with dichloromethane (5.0 mL), and then cooled down to 0°C under an atmosphere of nitrogen.
Subsequently, L-valinamide (0.15 g, 1.1 mmol) and triethylamine (0.16 g, 1.65 mmol) were sequentially added thereto. The reaction mixture was slowly heated to room temperature while stirring for 1.5 hours. The organic layer was washed with water, 1 N aqueous hydrochloric acid solution and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue thus obtained was purified by preparative layer chromatography (silica gel 60 F254, 1mm) to obtain the title compound as a yellow compound (56 mg).
1H-NMR (300 MHz, DMSO-d6) 5 8.49 (dd, 1H), 7.56 (m, 1H), 7.4-7.1
(m, 9H) 6.90 (d, 1H), 5.48 (dd, 1H), 4.37 (m, 1H), 4.0 (dd, 1H), 4.0-3.6 (m, 1H), 3.07 (m, 4H), 2.36 (m, 4H), 0.96-0.93 (m, 6H).
MS (ESI+): m/z = 560.2 [M+H]+. Example 3: Preparation of (25 -2-(A^'-((4-chIorophenyl)suLfonyl)-l-(4- methoxyphenyl)-5-phenyl-4,5-dihydro-lii-pyrazole-3-carboximidainido)-3- meth lbutanamide
Figure imgf000020_0002
The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (60 mg).
Ή-NMR (300 MHz, DMSO-d6) δ 8.6 (m, 1H), 7.85-7.78 (m, 2H), 7.75-7.54 (m, 2H) 7.41-7.21 (m, 5H), 6.85-6.7 (m, 3H), 5.48 (dd, 1H), 4.27 (m, 1H), 4.0 (dd, 1H), 3.65 (s, 3H), 3.13 (dd, 1H), 2.07 (m, 1H), 0.95-0.85 (m, 6H).
MS (ESI+): m/z = 568.2 [M+H]+.
Example 4: Preparation of (2^-2-(l-(4-chlorophenyl)-A^'-((4,4- difluoropiperidin-l-yl)sulfonyl)-5-phenyl-4,5-dihydro-lj^-pyrazole-3- carboximidamido)-3-methylbutanamide
Figure imgf000021_0001
The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (4.4 mg).
1H-NMR (300 MHz, DMSO-d6) δ 8.49 (dd, 1H), 7.56 (m, 1H), 7.4-7.1 (m, 9H), 6.90 (d, 1H), 5.48 (dd, 1H), 4.37 (m, 1H), 4.0 (dd, 1H), 4.0-3.6 (m, 1H), 3.8-3.6 (m, 4H), 3.1-3.0 (m, 4H), 0.96-0.93 (m, 6H).
MS (ESf): m/z = 581.2 [M+H]+.
Example 5: Preparation of (IS^- l-^-chloropheny -iV'-^- cyanophenyl)sulfonyl)-5-phenyl-4,5-dihydro-177-pyrazole-3- carboximidamido)-3-methylbutanamide
Figure imgf000021_0002
The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (24 mg).
Ή-NMR (300 MHz, DMSO-d6) 6 9.10 (m, 1H), 7.91-7.7 (m, 4H), 7.4-7.1 (m, 9H), 6.8 (m, 2H), 5.5 (dd, 1H), 4.4 (m, 1H), 4.1 (dd, 1H), 3.2 (dd, 1H), 2.1 (m, 1H), 1.0-0.9(m, 6H).
MS (ESf): m/z = 563.2[M+H]+. Example 6: Preparation of (2£)-2-(l-(4-chlorophenyi)-.V chIorophenyl)sulfonyl)-5-(4-cyanophenyl)-4,5-dihydro-l^T-pyrazole-3- carboximidamido)-3-methyIbutanamide
Figure imgf000022_0001
The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (50 mg).
Ή-NMR (300 MHz, DMSO-d6) δ 9.16 (d, 1H), 7.85 (d, 2H), 7.95 (m, 2H), 7.80 (m, 3H), 7.21 (m, 2H), 6.77 (d, 2H), 5.56 (dd, 1H), 4.28 (m, 1H), 4.0-3.8 (m, 1H), 3.2-3.1 (m, 1H), 2.0 (m, 1H), 0.9-0.8 (m, 6H).
MS (ESf ): m/z = 597.1 [M+H]+.
Example 7: Preparation of (25)-(l-(4-chlorophenyl)-7V'-((4- chlorophenyl)sulfonyl)-5-(2-thiophenyl)-4,5-dihydro-l -r-pyrazole-3- carboximidamido)-3-methylbutanamide
Figure imgf000022_0002
The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (80 mg).
Ή-NMR (300 MHz, CDC13) δ 8.63 (s, 1H), 7.85-7.90 (m, 2H), 7.45-7.48 (m, 2H), 7.17-7.20 (m, 3H), 6.98-7.04 (m, 2H), 6.89-6.91 (m, 2H), 6.11 (s, 1H), 5.90 (s, 1H), 5.73 (m, 1H), 5.55-5.61 (m, 2H), 4.85-4.89 (m, 1H), 4.40 (m,lH), 4.10-4.13 (m, 1H), 3.49-3.79 (m, 2H), 3.17-3.30 (m, 1H), 2.52 (s, 1H), 2.15 (s, 1H), 1.12-1.14 (d, 6H).
MS (ESf): m/z = 578.1 [M+H]+. Example 8: Preparation of (25 -2-(l-(4-chIorophenyl)-A^'-((4- chloropheny^sulfony^-S-pheny jS-dihydro-l ^-pyrazoIe-S- carboximidamido)acetamide
Figure imgf000023_0001
The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (34 mg).
1 H-NMR (300MHz, CDC13) δ 7.87 (d, 2H), 7.44 (d, 2H), 7.41-7.12 (m, 7H), 6.96 (d, 2H), 5.84 (m, 1H), 5.57 (m, 1H) 5.35 (m, 1H), 4.42 (m, 2H), 3.87 (m, 1H), 3.20 (m, 1H).
MS (ESf): m z = 530.1 [M+H]+.
Example 9: Preparation of (2S)-2-(l-(4-chlorophenyl)-W-((4- chlorophenyl)suIfonyl)-5-phenyl-4,5-dihydro-l/f-pyrazole-3- carboximidamido ropanamide
Figure imgf000023_0002
The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (36 mg).
1H-NMR (300 MHz, DMSO-d6) δ 9.10 (m, 1H), 7.8-7.77 (m, 4H), 7.4-7.1 (m, 9H), 6.75 (m, 2H), 5.44 (dd, 1H), 4.33 (m, 1H), 4.0 (dd, 1H), 3.13 (dd, 1H), 1.4 (m, 3H).
MS (ESf): m/z = 544.1 [M+H]+.
Example 10: Preparation of (/?,Z)-2-(l-(4-chlorophenyl)-yV'-((4- chlorophenyl)sulfonyl)-5-phenyl-4,5-dihydro-l /-pyrazoIe-3- carboximidamido)-2-methylpropanamide
Figure imgf000023_0003
The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (24 mg).
Ή-NMR (300 MHz, DMSO-d6) 5 9.10 (m, IH), 7.8-7.77 (m, 4H), 7.4-7.1 (m, 9H), 6.75 (m, 2H), 5.44 (dd, IH), 4.33 (m, IH), 4.0 (dd, IH), 3.13 (dd, IH), 1.3 (m, 6H).
MS (ESI+): m/z = 558.1 [M+H]+.
Example 11: Preparation of (2£)-2-(l-(4-chlorophenyl)-yV'-((4- chIorophenyI)sulfonyl)-5-phenyl-4,5-dihydro-l /-pyrazole-3- carboximidamido)-4-methylpentanamide
Figure imgf000024_0001
The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (54 mg).
1H-NMR (300 MHz, DMSO-d6) δ 9.15 (m, IH), 7.83 (m, 2H), 7.58 (m, 2H), 7.4-7.1 (m, 9H), 6.86 (m, 2H), 5.54 (m, IH), 4.4 (m, IH), 4.0 (m, IH), 3.2 (m, IH), 2.3(m, IH), 1.68 (m, IH), 0.9-0.7 (m, 6H).
MS (ESI+): m/z = 586.1 [M+H]+.
Example 12: Preparation of (2S)-2-(l-(4-chIorophenyl)-7V'-((4- chlorophenyl)sulfonyl)-5-pheny.-4,5-dihydro-li/-pyrazole-3- carboximidamido)-3-hydroxypropanamide
Figure imgf000024_0002
The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (25 mg).
Ή-NMR (300 MHz, DMSO-d6) 5 8.9 (m, IH), 8.06 (m, 2H), 7.85 (m, 2H), 7.77 (m, 2H), 7.4-7.1 (m, 7H), 6.86 (m, 2H), 5.6 (dd, IH), 4.3 (m, IH), 4.0 (dd, IH), 3.7 (m, 2H), 3.13 (dd, IH).
MS (ESI+): m/z = 560.1 [M+H]+.
Example 13: Preparation of (5)-2-(( ?,^)-l-(4-chlorophenyI)-yV'-((4- chlorophenyl)sulfonyl)-5-phenyl-4,5-dihydro-li -pyrazole-3- carboximidamido)-3-methylbutanamide
Figure imgf000025_0001
The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (816 mg).
1H-NMR (300MHz, DMSO-d6) δ 9.05 (d, H), 7.77 (d, 2H), 7.56 (d, 2H), 7.43-7.18 (m, 7H), 6.85 (d, IH), 5.47 (dd, IH), 4.30 (t, IH), 3.90 (dd, IH), 3.23 (dd, IH), 2.12-2.05 (m, IH), 0.95-0.88 (m, 6H).
MS (ESf ): m/z = 572.1 [M+H]+.
Example 14: Preparation of (5)-2-(( ?, )-l-(4-chIorophenyl)-7V'-((4- chlorophenyl)sulfonyl)-5-phenyl-4,5-dihydro-l /-pyrazole-3- carboximidamido)-3,3-dimethylbutanamide
Figure imgf000025_0002
The same method as that in Example 1 or a similar method thereto was conducted to obtain the title compound as a yellow compound (66 mg).
Ή-NMR (300MHz, DMSO-d6) δ 8.98 (d, IH), 7.76 (d, 2H), 7.55 (d, 2H), 7.47-7.18 (m,7H), 6.80 (d, 2H), 5.40 (dd, IH), 4.44 (d, IH), 3.86 (dd, IH), 3.21 (dd, IH), 0.94 (s, 9H).
MS(ESI+): m/z = 586.1 [M+H]+. Example 15: Preparation of (2i_f)-2-((Z)-^V'-((4-chlorophenyl)sulfonyl)-l-
(2,4-difluorophenyl)-5-phenyl-4,5-dihydro-l /-pyrazole-3- carboximidamido -3-methylbutanamide
Figure imgf000026_0001
The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (66 mg).
1H-NMR (300MHz, DMSO-d6) δ 9.06 (bs, H), 7.92-6.88 (m, 12H), 5.53 (dd, IH), 4.28 (t, IH), 3.94 (dd, IH), 3.23 (dd, IH), 2.18-1.99 (m, IH), 0.93-0.72 (m, 6H).
MS (ESI+): m/z = 574.1 [M+H]+.
Example 16: Preparation of (5 -2-((i?,Z)-l-(4-chlorophenyl)-J?V'-((6- chIoropyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-4,5-dihydro-lJi/-pyrazole-3- carboximidamido -3-methyIbutanamide
Figure imgf000026_0002
The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (124 mg).
Ή-NMR (300MHz, DMSO-d6) 5 9.13 (d, IH), 8.76 (bs, IH), 8.16 (dd, IH), 7.71 (d, IH), 7.43-7.05 (m, 7H), 6.85 (d, 2H) 5.74 (dd, IH), 4.27 (t, IH), 3.94 (dd, IH), 3.25 (dd, IH), 2.17-2.00 (m, IH), 0.95-0.76 (m, 6H).
MS(ESI+): m/z = 591.1 [M+H]+.
Example 17: Preparation of (S)-2 (tf,Z)-NH(4-chlorophenyl)sulfonyl)-l-
(2,4-difluorophenyl)-5-phenyl-4,5-dihydro-l//-pyrazole-3- carboximidamido)-3-methylbutanamide
Figure imgf000027_0001
The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (46.7 mg).
Ή-NMR (300MHz, DMSO-d6) δ 9.06 (d, H), 7.92-6.88 (m, 12H), 5.53
(dd, IH), 4.28 (t, IH), 3.94 (dd, IH), 3,23 (dd, IH), 2.18-1.99 (m, IH), 0.93-0.72 (m, 6H).
MS (ESf ): m/z = 574.1 [M+H]+. Example 18: Preparation of (5 -2-((/?,Z)- V'-((4-chlorophenyl)sulfonyl)-l-(4- fluorophenyl)-5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3- methylbutanamide
Figure imgf000027_0002
The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (42.3 mg).
Ή-NMR (300MHz, DMSO-d6) δ 8.99 (d, IH), 7.77 (d, 2H), 7.56 (d, 2H), 7.51-6.95 (d, 7H), 6.93-6.80 (m, 2H), 5.45 (dd, IH), 4.29 (t, IH), 3.88 (dd, IH), 3.25 (dd, IH), 0.99-0.78 (m, 6H).
MS(ESI+): m/z = 556.2 [M+H]+.
Example 19: Preparation of (S)-2-(( ,Z)-l-(4-chlorophenyl)-7V'-((4- fluoropheny^sulfony -S-pheny jS-dihydro-l i-pyrazole-S- carboximidamido -3-methylbutanamide
Figure imgf000027_0003
The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (46.5 mg).
Ή-NMR (300MHz, DMSO-d6) δ 8.99 (d, IH), 7.82 (d, 2H), 7.49-7.16 (m, 9H), 6.87 (d, 2H), 6.91-6.88 (d, 2H), 5.47 (dd, IH), 4.30 (t, IH), 3.90 (dd, 5 IH), 3.23 (dd, IH), 2.18-2.01 (m, IH), 0.95-0.79 (m, 6H).
MS(ESI+): m/z = 556.2 [M+H]+.
Example 20: Preparation of (S)-2-((R,Z)-l-(4-chloropheny\)-N'-((6- chloropyridin-S-y sulfony -S-pheny jS-dihydro-l T-pyrazoIe-S- i o carboximidamido)-3-methylbutanamide
Figure imgf000028_0001
The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (198 mg).
Ή-NMR (300MHz, DMSO-d6) δ 9.14 (bs, IH), 8.75 (bs, IH), 8.15 (dd, IH), 7.66 (d, IH), 7.45-7.03 (m, 7H), 6.84 (d, 2H), 5.54 (dd, IH), 4.26 (t, IH), 3.90 (dd, IH), 3.24 (dd, IH), 2.15-1.98 (m, IH), 0.97-0.73 (m, 6H).
MS(ESI+): m/z = 573.1 [M+H]+.
Example 21: Preparation of (2-S)-2-(l-(4-chlorophenyl)-/V,-((4- chlorophenyl)sulfonyl)-5-(2-furanyl)-4,5-dihydro-lJ-7-pyrazole-3- carboximidamido)-3-methylbutanamide
Figure imgf000028_0002
5 The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (80 mg).
Ή-NMR (300MHz, CDC13) δ 8.63 (s, IH), 7.87-7.92 (m, 2H), 7.46-7.48 (m, 1H), 7.32-7.35 (m, 2H), 7.19-7.22 (m, 2H), 7.03-7.08 (m, 2H), 6.15 (s, 1H), 5.85 (s, 1H), 5.45 (m, 1H), 5.29 (m, 2H), 4.84 (m, 1H), 4.40 (m, 1H), 4.10-4.15 (m, 1H), 3.49-3.79 (m, 2H), 3.17-3.30 (m, 1H), 2.23 (s, 1H), 2.17 (s, 3H), 2.15 (s, 1H), 1.12-1.14 (d, 6H).
MS (ESI+): m/z = 562.1 [M+H]+.
Example 22: Preparation of 2-(J?,Z)-(l-(4-chlorophenyl)-/y'-((4- chlorophenylJsulfony^-S^-thiopheny ^jS-dihydro-l T-pyrazoIe-S- carboximidamido)-3-methylbutanamide
Figure imgf000029_0001
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 8.65 (s, 1H), 7.85-7.90 (m, 2H), 7.44-7.47 (m, 1H), 7.26-7.33 (m, 2H), 7.17-7.19 (m, 2H), 6.98-7.05 (m, 1 H), 6.85-6.90 (m, 2H), 6.15 (s, 1H), 5.85 (s, 1H), 5.45 (m, 1H), 5.29 (m, 2H), 4.84 (m, 1H), 4.40 (m, 1H), 4.10-4.15 (m, 1H), 3.49-3.79 (m, 2H), 3.17-3.30 (m, 1H), 2.23 (s, 1H), 2.17 (s, 3H), 2.15 (s, 1H), 1.12-1.14 (d, 6H).
MS (ESI+): m/z = 578.1 [M+H]+.
Example 23: Preparation of (2.S)-2-(l-(4-chlorophenyl)-7Vr-((4- chlorophenyl)sulfonyl)-5-(5-methyl-2-furanyI)-4,5-dihydro-l^T-pyrazole-3- carboximidamido)-3-methyIbutanamide
Figure imgf000029_0002
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 8.61 (s, 1H), 7.89-7.92 (m, 2H), 7.45-7.48 (m, IH), 7.26-7.32 (m, 2H), 7.20-7.22 (m, 2H), 7.08 (m, 2H), 6.15 (s, IH), 5.85 (s, IH), 5.45 (m, IH), 5.29 (m, 2H), 4.84 (m, IH), 4.40 (m, IH), 4.10-4.15 (m, IH), 3.49-3.79 (m, 2H), 3.17-3.30 (m, IH), 2.23 (s, IH), 2.17 (s, 3H), 2.15 (s, IH), 1.12-1.14 (d, 6H).
MS (ESI+): m/z = 576.1 [M+H]+.
Example 24: Preparation of (25)-2-(l-(4-chlorophenyI)-A^'-((4- chloropheny sulfony^-S^-fluorophenyl^jS-dihydro-l^fiT-pyrazole-S- carboximidamido)-3-methylbutanamide
Figure imgf000030_0001
The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (40 mg).
1H-NMR (300MHz, CDC13) 6 8.61 (s, IH), 7.85-7.88 (m, 2H), 7.42-7.45 (m, 3H), 7.14-7.17 (m, 2H), 7.08 (m, 2H), 6.92-6.95 (m, 2H), 6.32 (s, IH), 6.15 (s, IH), 5.85 (m, IH), 5.55 (m, 2H), 4.84 (m, IH), 4.40 (m, IH), 4.10-4.15 (m, IH), 3.49-3.79 (m, 2H), 3.17-3.30 (m, IH), 2.53 (s, IH), 2.23 (s, IH), 1.12-1.14 (d, 6H).
MS (ESI+): m/z = 590.1 [M+H]+.
Example 25: Preparation of (25 -2-(l-(4-chlorophenyl)- V'-((4- chlorophenyl)sulfonyl)-5-(5-methyl-2-thiophenyl)-4,5-dihydro-l^T-pyrazole- 3-carboximidamido)-3-methylbutanamide
Figure imgf000030_0002
The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (40 mg). Example 26: Preparation of (2- )-2-(l-(4-chlorophenyl)- V'-((4- chlorophenyl)sulfonyl)-5-(2-pyridinyl)-4,5-dihydro-lJHr-pyrazole-3- carboximidamido)-3-methylbutanamide
Figure imgf000031_0001
The same method as that in Example IB or a similar method thereof was conducted to obtain the title compound as a yellow compound (30 mg).
1H-NMR (300MHz, CDC13) δ 8.67 (s, IH), 7.85-7.90 (m, 2H), 7.62-7.65 (m, IH), 7.45-7.48 (m, 2H), 7.19-7.22 (m, 2H), 7.16 (m, 2H), 7.05-7.09 (m, 2H), 6.08-6.15 (m, IH), 5.60 (m, IH), 5.55 (m, 2H), 4.90 (m, IH), 4.43 (m, IH), 4.10-4.29 (m, IH), 3.67-3.81 (m, 2H), 3.22-3.31 (m, 2H), 2.53 (s, IH), 2.23 (s, IH), 1.12-1.14 (d, 6H).
MS (ESI+): m/z = 573.1 [M+H]+.
Example 27: Preparation of 2-(JR,Z)-(l-(4-chlorophenyl)-J?V,-((4- chloropheny sulfony^-S^-fluoropheny^^.S-dihydro-l T-pyrazole-S- carboximidamido)-3-methylbutanamide
Figure imgf000031_0002
The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (250
Ή-NMR (300MHz, CDC13) 6 8.61 (s, IH), 7.85-7.88 (m, 2H), 7.42-7.45 (m, 3H), 7.14-7.17 (m, 2H), 7.08 (m, 2H), 6.92-6.95 (m, 2H), 6.32 (s, IH), 6.15 (s, IH), 5.85 (m, IH), 5.55 (m, 2H), 4.84 (m, IH), 4.40 (m, IH), 4.10-4.15 (m, IH), 3.49-3.79 (m, 2H), 3.17-3.30 (m, IH), 2.53 (s, IH), 2.23 (s, IH), 1.12-1.14 (d, 6H).
MS (ESf ): m/z = 590.1 [M+H]+. Example 28: Preparation of (5)-2-(( ?,Z)-l-(4-chIorophenyl)-^r-((4- chlorophenyI)su!fonyl-5-(pyridin-2-yl)-4,5-dihydro-l -r-pyrazole-3- carboximidamido)-3-methylbutanamide
Figure imgf000032_0001
The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (68 mg).
1H-NMR (300 MHz, DMSO-d6) δ 9.02(d, IH), 8.56-8.52 (m, IH), 7.88-7.12 (m, 9H), 6.86-6.83 (d,2H), 5.54-5.50 (dd, IH), 4.30 (t, IH), 3.97-3.88 (dd, IH), 3.28-3.07 (m, IH), 2.12-2.05 (m, IH) 0.89-0.83 (m, 6H).
MS (ESI+): m/z = 572.1 [M+H]+.
Example 29: Preparation of (5 -2-((7?,Z)-l-(4-chlorophenyl)-A^'-((4- chlorophenyl)sulfonyl)-5-(furan-2-yl)-4,5-dihydro-lJi-r-pyrazole-3- carboximidamido)-3,3-dimethylbutanamide
Figure imgf000032_0002
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 8.97 (d, H), 7.77 (d, 2H), 7.58 (d, 2H), 7.45-7.18 (m, 7H), 6.84 (d, IH), 5.49 (dd, IH), 4.80 (t, IH), 3.88 (dd, IH), 3.77 (bs, IH), 3.59-3.42 (m, 2H), 3.23 (dd, IH), 1.98-1.80 (m, IH), 0.90-0.74 (m, 6H).
MS (ESI+): m/z = 561.1 [M+H]+.
Example 30: Preparation of (25)-2-((Z)- V'-((4-chIorophenyl)sulfonyl)-l- (2,4-dichlorophenyl)-5-phenyl-4,5-dihydro-l//-pyrazole-3- carboximidamido)-3-methylbutanamide
Figure imgf000033_0001
The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (26 mg).
Ή-NMR (300 MHz, DMSO-d6) δ 9.22-9.08 (m, IH), 7.89-7.79 (m,
2H), 7.62-7.55 (m, 2H), 7.49-7.21 (m,8H), 5.82-5.80 (m, IH), 4.29 (t, IH), 3.63-3.58 (m, IH), 3.32-3.28 (m, IH), 2.09-2.07 (m, IH), 0.89-0.83 (m, 6H).
MS(ESI+): m/z = 605.1 [M+H]+.
Example 31: Preparation of (5)-2-((i?,Z)-l-(4-chlorophenyl)-yV chlorophenyl)sulfonyI)-5-(2-fluorophenyl)-4,5-dihydro-l^?-pyrazole-3- carboximidamido)-3-methylbutanamide
Figure imgf000033_0002
The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (20 mg).
Ή-NMR (300MHz, CDC13) δ 8.61 (s, IH), 7.85-7.88 (m, 2H), 7.42-7.45 (m, 3H), 7.14-7.17 (m, 2H), 7.08 (m, 2H), 6.92-6.95 (m, 2H), 6.32 (s, IH), 6.15 (s, IH), 5.85 (m, IH), 5.55 (m, 2H), 4.84 (m, IH), 4.40 (m, IH), 4.10-4.15 (m, IH), 3.49-3.79 (m, 2H), 3.17-3.30 (m, IH), 2.53 (s, IH), 2.23 (s, IH), 1.12-1.14 (d, 6H).
MS (ESf ): m/z = 574.1 [M+H]+.
Example 32: Preparation of (^-((^^-S^-chloropheny -l^- chlorophenyl)- V -((4-chlorophenyl)sulfonyl)-4,5-dihydro-l/T-pyrazoIe-3- carboximidamido)-3-methylbutanamide
Figure imgf000034_0001
The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (150 mg).
1H-NMR (300 MHz, DMSO-d6) δ 9.06 (br, 1H), 7.88-7.02 (m, 10H), 6.76-6.73 (d, 2H), 5.66-5.59 (m, 1H), 4.32 (t, 1H), 4.01-3.91 (m, 1H), 3.31-3.11 (m, 1H), 2.10-2.04 (m, 1H), 0.89-0.83 (m, 6H).
MS(ESI+): m/z = 605.1 [M+H]+.
Example 33: Preparation of (5)-2-((Z)-l-(4-chlorophenyl)-/Y'-((6- chloropyridin-3-yl)suIfonyl)-5-(pyridin-2-yl)-4,5-dihydro-l -r-pyrazole-3- carboximidamido)-3-methylbutanamide
Figure imgf000034_0002
The same method as that in Example IB or a similar method thereto was conducted to obtain the title compound as a yellow compound (150 mg).
1H-NMR (300 MHz, DMSO-d6) 5 9.26-9.11 (br, 1H), 8.79-8.76 (dd, 1H), 8.58-8.57 (dd, 1H), 8.17-8.16 (dd, 1H) 7.82-7.10 (m, 6H), 6.87-6.85 (d, 2H), 5.60-5.54 (m, 1H), 4.27 (t, 1H), 4.03-3.92 (m, 1H), 3.31-3.13 (m, 1H), 2.13-2.06 (m, 1H), 0.88-0.85 (m, 6H).
MS(ESf): m/z = 573.1 [M+H]+.
The chemical structures of the compounds according to Examples 1 to 33 are shown in Table 1 below.
[Table 1]
Ex. Chemical name
Figure imgf000035_0001
methylbutanamide
Figure imgf000036_0001
dimethylbutanamide
Figure imgf000037_0001
methylbutanamide
Figure imgf000038_0001
methylbutanamide
Figure imgf000039_0001
Experimental Example 1: ["SJGTPyS Binding Assay
A binding assay was conducted to evaluate the antagonistic activity of Gi protein-coupled receptor, i.e., cannabinoid receptor 1, as follows.
The assay is based upon the principle that agonists bind to G-protein coupled receptors to stimulate GDP-GTP exchange at the G-protein. A non- hydrolyzable form of GTP, i.e. , GTPyS, a radiochemical [35S]- 1250Ci/mmol, 12.5mCi/mmol, 1 mCi (Perkin Elmer, cat. NEG030H001MC), and WGA-coated SPA beads (Cat. RPNQ0210) were used for the assay. Each of the compounds prepared in Examples 1 to 5 was placed in an lx 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 (v/v) to form a mixture.
The mixture of the CB1 receptor membrane and GDP thus prepared (100 μΕ) 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 (v/v). The reaction mixture was allowed to react for 50 minutes at room temperature, 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, compounds of Examples 1, 2, 3, 4, 5, 7, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 24, 25, 26, 27, 28, 29, 30, 31, 32, and 33 exhibited IC50 values of 10 nM, 8 nM, 14 nM, 16 nM, 10 nM, 3 nM, 4 nM, 10 nM, 13 nM, 5 nM, 11 nM, 7 nM, 9 nM, 6 nM, 10 nM, 5 nM, 7 nM, 17 nM, 8 nM, 5 nM, 8 nM, 6 nM, 17 nM, 10 nM, 16 nM, and 16 nM, respectively. These values indicate that the compounds according to the Examples of the present invention show excellent antagonistic activity against the CB 1 receptors.
Experimental Example 2: Assay for Anti-Obesity Effects (in vivo)
2-1 : Change in Feeding Amount and Body Weight
Diet induced obesity (DIO) mice were used to evaluate the suppressive effect of the inventive compounds on feeding amount and body weight gain.
5-week-old C57BL/6 mice (OrientBio, Korea) 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 ligh dark cycle room (11 :00 light-out, 23:00 light-on) with controlled conditions of temperature and humidity, and had free access to food and water. One week before each test, each mouse was individually housed, and a baseline of its feeding amount and body weight was determined by conducting a habituation to a treatment. Mice were randomly grouped into treatment groups, based on their initial body weights and feeding amounts. A vehicle 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 compounds of Examples 13 and 31 according to the present invention on feeding amount. One hour before the start of dark cycle, DIO mice were treated with the test compound at 3 mg/kg. The body weight and feeding amount were measured every 24 hours from day 0 (before the treatment) until day 28 using an electronic scale. The effectiveness of the test compounds was evaluated by comparing the data (changes in body weight and feeding amount) obtained from the vehicle-treated group, the standard positive control-treated group, and the test compound- treated groups.
As shown in Fig. 1, body weights were gradually reduced in mice which were treated with the compounds of Examples 13 and 31 according to the present invention, and this weight reduction effect was observed during the 4- week treatment period, and lasted for a certain period of time even after the treatment.
Additionally, as shown in Fig. 2, feeding amount was decreased owing to the administration of the inventive compounds. The feeding amount slowly returned to the normal level, and was maintained constantly at the normal level after the body weight had been reduced. Thus, it can be concluded that the compounds of Examples 13 and 31 according to the present invention exhibit anti-obesity effects.
2-2: Changes in Leptin and Insulin levels
Blood samples were taken from the DIO mice used in Experimental Example 2- 1 , and changes in leptin and insulin levels were measured.
Plasma was separated from the blood sampled from the DIO mice when Experimental Example 2-1 was completed, and plasma leptin and insulin levels were measured using an ELISA (Enzyme linked immunosorbent assay) kit (insulin: Crystal Chem, cat #90060, leptin: ALPCO), and quantified so as to evaluate the changes due to the administration of the test compounds.
As shown in Fig. 3, the compounds of Examples 13 and 31 according to the present invention effectively reduced the levels of insulin and leptin that are closely related to obesity-related metabolic diseases and obesity.
2-3 : Brain-to-Plasma Exposure ratio
Brain exposure rates of the compounds of the present invention were examined after oral administration of the compounds to the DIO mice and normal ICR mice.
The compounds of Examples 13 and 31 according to the present invention and rimonabant, a comparative compound, were orally administered to the mice at a dose of 3 mg/kg body weight. At 0.5 hour after the administration, which is expected to be the Tmax of the compounds, blood and brain tissue samples were taken from the mice. The blood samples were placed in heparin-treated eppendorf tubes (1000 IU/mL, heparin, 3 μΐ,), and immediately centrifuged (12,000 rpm, 2 minutes) to separate the plasma. Brain samples were diluted 10 times using a 4% bovine serum albumin (BSA) solution, and pulverized.
The concentrations of the test compounds in the blood and brain tissue samples were analyzed by (LC-MS/MS), and the results are shown in Fig. 4.
As can be seen in Fig. 4, the brain exposure rates of the compounds of Examples 13 and 31 according to the present invention (about 7%, and 9%, respectively) was superior to that of rimonabant (about 59%) in DIO mice. In normal ICR mice, the brain exposure rates of the compounds of Examples 13 and 31 according to the present invention (about 3% and 0.4%, respectively) was also superior to that of rimonabant (about 42%).
Considering the close relationship between the brain exposure rate and adverse side effects, this result demonstrates that the compounds according to the present invention are excellent drugs which have the possibilities of overcoming preexisting problems of conventional drugs.
Experimental Example 3: Evaluation of Depression and Anxiety via Behavioral Test The incidence of central nervous system adverse effects, i.e., depression and anxiety caused by the compounds of the present invention was evaluated as follows.
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 compounds of Examples 13 and 31 , and rimonabant, as a positive control, were each orally administered to ICR mice at 3 mg/kg, 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 ICR mice administered with a vehicle only (vehicle group). The result is shown in Fig. 5.
After measuring the behavior of the animals, it was discovered that, like the vehicle group, the mice administered with the compounds of Examples 13 and 31 showed movements in both the open and closed arms, whereas the mice treated with rimonabant exhibited movements in the closed arms only.

Claims

What is claimed is:
1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000044_0001
wherein A is selected from the group consisting of C1-7alkyl, C6-i0aryl, C4-i0heteroaryl, C3-6cycloalkyl, and C3.6heterocycloalkyl, and optionally, each of which is independently substituted with at least one substituent selected from the group consisting of hydrogen, linear or branched Ci. alkyl, linear or branched C^alkoxy, halo, CN, OH, NO2, -(CO)-R', SH, SR', SOR', SO2R', NH2, NHR', NR'R", -(C=O)-NH2, -(C=O>NHR', and -(C=O)-NR'R";
B and C are each independently C6-ioaryl or C4.i0heteroaryl, and optionally, each of which is independently substituted with at least one substituent selected from the group consisting of hydrogen, linear or branched Ci-6alkyl, linear or branched Ci-6alkoxy, halo, dihalo, trihalo, CN, OH, NO2, - (C=O)-R', SH, SR', SOR', SO2R', NH2, NHR', NR'R", -(C=O)-NH2, -(C=O)- NHR', and -(C=O)-NR'R";
R' and R" are each independently linear or branched C1-6alkyl; and
R\ and R2 are each independently hydrogen or C].6alkyl, and optionally, each of which is independently substituted with at least one substituent selected from the group consisting of hydrogen, linear or branched C|.6alkyl, linear or branched C1-6alkoxy, halo, CN, OH, NO2, and SH.
2. The compound of claim 1, wherein
A is C6-i0aryl or C4- 10heteroaryl, each of which is independently substituted with at least one substituent selected from the group consisting of hydrogen, halo, dihalo, and Ci- alkyl; B is C6-ioaryl or C4-i0heteroaryl, each of which is independently substituted with at least one substituent selected from the group consisting of hydrogen and CN;
C is C6-10aryl which is optionally substituted with halo; and
Ri and R2 are each independently hydrogen, linear or branched Ci-6alkyl, or linear or branched Ci-6alkyl substituted with OH.
3. The compound of claim 1, wherein the compound is selected from the group consisting of:
1 ) (2S)-2-( 1 -(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-phenyl- 4,5-dihydro-lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
2) (2S)-2-( 1 -(4-chlorophenyl)-N'-((4-methylpiperazin- 1 -yl)sulfonyl)-5- phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
3) (2S)-2-(N'-((4-chlorophenyl)- 1 -(4-methoxyphenyl)sulfonyl)-5- phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
4) (25)-2-( 1 -(4-chloropheny l)-N'-((4,4-difluoropiperidin- 1 -yl)sulfony 1)- 5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
5) (2S)-2-(l -(4-chloropheny l)-N'-((4-cyanopheny l)sulfonyl)-5 -phenyl- 4,5-dihydro-lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
6) (2S)-2-(l -(4-chloropheny l)-N'-((4-chlorophenyl)sulfonyl)-5-(4- cyanophenyl)-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3- methylbutanamide;
7) (2S)-(l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-(2- thiophenyl)-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3- methylbutanamide;
8) (2S)-2-(l -(4-chloropheny l)-N'-((4-chloropheny l)sulfonyl)-5 -phenyl- 4,5-dihydro-lH-pyrazole-3-carboximidamido)acetamide;
9) (2S)-2-(l -(4-chloropheny l)-N'-((4-chlorophenyl)sulfonyl)-5-phenyl- 4,5-dihydro-lH-pyrazole-3-carboximidamido)propanamide;
10) (R,Z)-2-( 1 -(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5- phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamido)-2-methylpropanamide;
11 ) (2S)-2-( 1 -(4-chloropheny l)-N'-((4-chloropheny l)sulfonyl)-5 -phenyl- 4,5-dihydro-lH-pyrazole-3-carboximidamido)-4-methylpentanamide; 12) (2S)-2-(l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-phenyl- 4,5-dihydro-lH-pyrazole-3-carboximidamido)-3-hydroxypropanamide;
13) (S)-2-((R,Z)-l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5- phenyl-4,5-dihydro- lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
14) (S)-2-((R,Z)- l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5- phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3,3-dimethylbutanamide;
15) (2S)-2-((Z)-N'-((4-chlorophenyl)sulfonyl)-l-(2,4-difluorophenyl)-5- phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
16) (S)-2-((R,Z)-l-(4-chlorophenyl)-N'-((6-chloropyridin-3-yl)sulfonyl)- 5-(2-fluorophenyl)-4,5-dihydro- lH-pyrazole-3-carboximidamido)-3- methylbutanamide;
17) (S)-2-((R, Z)-N'-((4-chlorophenyl)sulfonyl)- 1 -(2,4-difluorophenyl)-5- phenyl-4,5-dihydro- lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
18) (S)-2-((R,2)-N'-((4-chlorophenyl)sulfonyl)- l-(4-fluorophenyl)-5- phenyl-4,5-dihydro- lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
19) (S)-2-((R,Z)- 1 -(4-chlorophenyl)-N'-((4-fluorophenyl)sulfonyl)-5- phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
20) (S)-2-((R,Z)-l-(4-chlorophenyl)-N'-((6-chloropyridin-3-yl)sulfonyl)- 5-phenyl-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
21) (2S)-2-(l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-(2- furanyl)-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3-methylbutanamide;
22) 2-(R,Z)-(l -(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-(2- thiophenyl)-4,5-dihydro- lH-pyrazole-3-carboximidamido)-3- methylbutanamide;
23) (2S)-2-(l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-(5- methyl-2-furanyl)-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3- methylbutanamide;
24) (2S)-2-( 1 -(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-(5- methyl-2-furanyl)-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3- methylbutanamide;
25) (2S)-2-(l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-(5- methyl-2-thiophenyl)-4,5-dihydro- lH-pyrazole-3-carboximidamido)-3- methylbutanamide 26) (2S)-2-(l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-(2- pyridinyl)-4,5-dihydro- lH-pyrazole-3-carboximidamido)-3-methylbutanam
27) 2-(R,Z)-(l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-(2- fluorophenyl)-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3- methylbutanamide;
28) (S)-2-((R,Z)- l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl-5- (pyridin-2-yl)-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3- methylbutanamide;
29) (S)-2-((R)2)- l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5- (furan-2-yl)-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3,3- dimethylbutanamide;
30) (2S)-2-((Z)-N'-((4-chlorophenyl)sulfonyl)- l-(2,4-dichlorophenyl)-5- phenyl-4,5-dihydro- lH-pyrazoIe-3-carboximidamido)-3-methylbutanamide;
31) (S)-2-((R,Z)-l-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-5-(2- fiuorophenyl)-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3- methylbutanamide;
32) (S)-2-((R)Z)-5-(2-chlorophenyl)- l-(4-chlorophenyl)-N'-((4- chlorophenyl)sulfonyl)-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3- methylbutanamide; and
33) (S)-2-((Z)- l-(4-chlorophenyl)-N'-((6-chloropyridin-3-yl)sulfonyl)-5- (pyridin-2-yl)-4,5-dihydro-lH-pyrazole-3-carboximidamido)-3- methylbutanamide.
4. A method for preparing a compound of formula (I), which comprises the steps of:
1) 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);
2) 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 under a basic condition to obtain a compound of formula (IV); and 3) 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 resence of a base to obtain the compound of formula (I):
Figure imgf000048_0001
wherein A, B, C, R( and R2 have the same meanings as defined in claim
1.
5. A method for preparing a compound of formula (I), which comprises the steps of:
1) allowing the compound of formula (II) to react with chloride in a solvent selected from toluene, xylene, benzene, chlorobenzene, and a mixture thereof to obtain a compound of formula (V); and 2) allowing the compound of formula (V) thus obtained 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 to obtain the compound of formula (I):
Figure imgf000049_0001
Figure imgf000049_0002
wherein A, B, C, K\ and R2 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 or a pharmaceutically acceptable salt thereof as an active ingredient.
7. The pharmaceutical composition of claim 6, wherein the obesity- related metabolic disease is Type 2 Diabetes, chronic hepatic diseases, angina, hypertension, congestive heart failure or hyperlipidemia.
8. A use of the compound of claim 1 for the manufacture of a medicament for preventing or treating obesity or an obesity-related metabolic disease.
9. A method for preventing or treating obesity or an obesity-related metabolic disease, comprising administering to a mammal the compound of formula (I) of claim 1 or a pharmaceutically acceptable salt thereof.
PCT/KR2014/005479 2013-06-28 2014-06-20 1,5-diaryl-4,5-dihydro-1h-pyrazole-3-carboxamidine derivatives as cannabinoid cb1 receptor antagonist, method for preparing same, and pharmaceutical composition comprising same WO2014208939A1 (en)

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Citations (4)

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