KR20220146000A - Biphenylsulfonamide derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating glucagon Receptor activity related diseases containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a biphenylsulfonamide derivative, a preparation method thereof, and a pharmaceutical composition containing the same as an active ingredient for preventing or treating a glucagon receptor activity-related disease. The biphenylsulfonamide derivative of the present invention has not only excellent effects of inhibiting the activity of a glucagon receptor, but also effectively suppresses the generation of glucagon-induced cAMP and the generation of glucagon-induced glucose and has outstanding effects of reducing a blood sugar level in an animal model for diabetes. Therefore, the biphenylsulfonamide derivative can be useful in providing a pharmaceutical composition for preventing or treating glucagon receptor activity-related diseases such as diabetes.

Description

Biphenylsulfonamide derivative, preparation method thereof, and pharmaceutical composition for preventing or treating glucagon receptor activity-related diseases containing the same as an active ingredient TECHNICAL FIELD [0002] diseases containing the same as an active ingredient}

The present invention relates to a biphenylsulfonamide derivative, a method for preparing the same, and a pharmaceutical composition for preventing or treating glucagon receptor activity-related diseases containing the same as an active ingredient.

Glucagon is an endocrine hormone secreted by the alpha cells of the islet of Langerhans in the pancreas. It increases blood glucose by increasing glycogenolysis and gluconeogenesis in the liver. It is well known.

Glucagon acts on target tissues through the glucagon receptor (GCGR, Glucagon Receptor), which is one of the seven-transmembrane G-protein coupled receptor superfamily. Glucagon binding to GCGR activates adenylyl cyclase and induces biological effects by increasing intracellular cyclic adenosine monophosphate (cAMP). Inhibition of GCGR by GCGR neutralizing antibodies, anti-sense oligonucleotides and/or peptides and small molecule GCGR antagonists has been shown to reduce hepatic glucose production and improve glucose tolerance in various diabetes models. appear.

In type 2 diabetes, hyperglucagonemia is associated with hyperglycemia, and elevated glucagon levels exacerbate the hyperglycemic condition by increasing hepatic glucose production. Accordingly, the development of glucagon receptor antagonists targeting the glucagon receptor is being made by leading pharmaceutical companies. Glucagon receptor antagonists have been found to significantly reduce blood sugar in an animal model of type 2 diabetes, and since they also show a reduction effect in blood sugar in clinical trials, an improvement in blood sugar can be expected in patients with type 2 diabetes.

The glucagon receptor antagonist drugs developed so far include Bayer's Bay 27-9955, Merck's MK-0893/MK-3577, Pfizer's PF-06291874, Eli Lily's LY-2409021, Ligand's LGD-6972, etc. have been developed, Development of most drugs except LGD-6972 was stopped due to various side effects in clinical trials, and among them, no drug has been developed as a treatment for diabetes yet, so attempts to develop drugs targeting the glucagon receptor are continuously made. have.

Under the above background, the present inventors have endeavored to develop novel inhibitors targeting the glucagon receptor, and as a result, the biphenylsulfonamide derivative according to the present invention not only exhibits an excellent activity inhibitory effect on the glucagon receptor, but also glucagon-inducing A pharmaceutical for preventing or treating diabetes containing the biphenylsulfonamide derivative of the present invention as an active ingredient, as it was revealed that it effectively inhibits cAMP production and glucagon-induced glucose production and has an excellent effect in lowering blood sugar levels in an animal model of diabetic disease. By confirming that a composition can be provided, the present invention has been completed.

An object of the present invention is to provide a novel inhibitor compound targeting the glucagon receptor, and to provide a pharmaceutical composition for preventing or treating diabetes from its excellent hypoglycemic effect.

In order to achieve the above object,

One aspect of the present invention provides a compound represented by the following formula (1), a stereoisomer or a pharmaceutically acceptable salt thereof:

[Formula 1]

(In Formula 1,

R ¹ is hydrogen or substituted or unsubstituted C 1-10 straight or branched chain alkyl;

R ² is each independently hydrogen or substituted or unsubstituted C1-10 straight-chain or branched alkyl;

R ³ is each independently hydrogen, halogen, substituted or unsubstituted C1-10 straight or branched chain alkyl, or substituted or unsubstituted C1-10 straight or branched chain alkoxy;

R ⁴ is -COOR ⁵ or -SO ₂ -OR ⁵ ,

wherein R ⁵ is hydrogen or substituted or unsubstituted C1-10 straight-chain or branched alkyl;

n is an integer from 1 to 5; and

wherein said substituted alkyl and substituted alkoxy are substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, nitro and amino).

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating a disease related to glucagon receptor activity, comprising the compound represented by Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient.

Another aspect of the present invention provides a health functional food composition for preventing or improving glucagon receptor activity-related diseases, comprising the compound represented by Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient. .

Another aspect of the present invention is a method of treating a disease related to glucagon receptor activity, comprising administering to a subject in need thereof a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof provides

Another aspect of the present invention provides the use of a compound represented by Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof, in the manufacture of a drug for use in the prevention or treatment of a glucagon receptor activity-related disease. .

The biphenylsulfonamide derivative of the present invention not only exhibits an excellent activity inhibitory effect on the glucagon receptor, but also effectively inhibits glucagon-induced cAMP production and glucagon-induced glucose production, and has an excellent effect of lowering blood sugar levels in an animal model of diabetic disease. As a result, there is a useful effect of providing a pharmaceutical composition for preventing or treating glucagon receptor activity-related diseases, for example, diabetes.

1 is a graph showing the measurement of cytotoxicity changes according to the treatment of the compound of the present invention in a GCGR (Glucagon Receptor)-expressing cell line.
2 is a graph showing the change in the glucagon-induced cAMP production rate according to the treatment of the compound of the present invention in a GCGR (Glucagon Receptor)-expressing cell line.
3 is a graph showing the change in glucagon-induced cAMP production rate according to the treatment dose of the compound of the present invention in a GCGR-expressing cell line.
Figure 4 is a graph observing the change in the glucagon-induced cAMP production rate according to the treatment dose of the present invention compound for the GCGR-expressing cell line in order to calculate the IC ₅₀ value.
5 is a graph showing changes in the glucagon-induced glucose production rate according to treatment with the compound of the present invention in a mouse liver cell line.
6 is a graph showing the change in glucagon-induced cAMP production rate according to the treatment dose of the compound of the present invention in a mouse liver cell line.
7 is a graph showing changes in blood glucagon-induced glucose production rate according to administration of the compound of the present invention or a positive control (LGD-6972) after fasting for 5 hours on the first day of experiment in obese mice induced by a high-fat diet.
8 is a graph showing the measurement of AUC (Area Under the Curve) of the glucagon-induced glucose fluctuation range test according to the administration of the compound of the present invention or a positive control (LGD-6972) in a high-fat diet-induced obese mouse.
9 is a graph showing the measurement of body weight at the start of the experiment (week 0) and the last week (week 6) according to administration of the compound of the present invention or a positive control (LGD-6972) in obese mice induced by a high fat diet.
10 is a graph showing the average value calculated after daily food intake of obese mice induced on a high fat diet according to administration of the compound of the present invention or a positive control (LGD-6972) administration.
11 is a graph showing the measurement of non-fasting blood glucose levels at 0, 3 and 4 weeks according to administration of the compound of the present invention or a positive control (LGD-6972) in obese mice induced by a high fat diet.
12 is a high-fat diet-induced obese mouse fasted for 14 hours at the 6th week of the experiment, and after intraperitoneal injection of 2 g/kg of glucose, the time after glucose injection of each of the present invention compound treatment experimental group or positive control group (LGD-6972) It is a graph showing changes in blood glucose levels according to the progress.
13 is a graph showing the plasma concentration of the compound of the present invention over time after administration in order to investigate the pharmacokinetic profile after intravenous (IV) administration of the compound of the present invention to rats.

Hereinafter, the present invention will be described in detail.

One aspect of the present invention provides a compound represented by the following formula (1), a stereoisomer or a pharmaceutically acceptable salt thereof:

[Formula 1]

(In Formula 1,

R ¹ is hydrogen or substituted or unsubstituted C 1-10 straight or branched chain alkyl;

R ² is each independently hydrogen or substituted or unsubstituted C1-10 straight-chain or branched alkyl;

R ³ is each independently hydrogen, halogen, substituted or unsubstituted C1-10 straight or branched chain alkyl, or substituted or unsubstituted C1-10 straight or branched chain alkoxy;

R ⁴ is -COOR ⁵ or -SO ₂ -OR ⁵ ,

wherein R ⁵ is hydrogen or substituted or unsubstituted C1-10 straight-chain or branched alkyl;

n is an integer from 1 to 5; and

wherein said substituted alkyl and substituted alkoxy are substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, nitro and amino).

In one embodiment of the present invention, R ¹ is C1-5 straight-chain or branched alkyl substituted or unsubstituted with halogen;

wherein R ² is each independently hydrogen or C1-3 straight-chain or branched alkyl;

wherein R ³ is each independently hydrogen, halogen, or C1-5 straight or branched chain alkyl substituted or unsubstituted with halogen; and

The R ⁴ is -COOH.

In another embodiment of the present invention, R ¹ is C3-4 straight or branched chain alkyl substituted or unsubstituted with halogen;

wherein R ² is each independently hydrogen or methyl;

wherein R ³ is each independently hydrogen, halogen, or C1-5 straight or branched chain alkyl substituted or unsubstituted with halogen; and

The R ⁴ is -COOH.

In another embodiment of the present invention, R ¹ is n-propyl, n-butyl or —CH ₂ CH ₂ CF ₃ ;

wherein R ² is hydrogen or methyl;

wherein R ³ is each independently hydrogen, F, Cl, tert-butyl or —CF ₃ ; and

The R ⁴ is -COOH.

In one embodiment of the present invention, the compound represented by Formula 1 is a compound, characterized in that any one selected from the following compound group, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

(1) 3-(4-(N-propyl-[1,1′-biphenyl]-4-sulfonamido)benzamido)propanoic acid;

(2) 3-(4-((4′-chloro-N-propyl-[1,1′-biphenyl])-4-sulfonamido)benzamido)propanoic acid;

(3) 3-(4-((N-propyl-4′-(trifluoromethyl)-[1,1′-biphenyl])-4-sulfonamido)benzamido)propanoic acid;

(4) 3-(4-((4′-(tert-butyl)-N-propyl-[1,1′-biphenyl])-4-sulfonamido)benzamido)propanoic acid;

(5) 3-(4-((3′,5′-dichloro-N-propyl-[1,1′-biphenyl])-4-sulfonamido)benzamido)propanoic acid;

(6) 3-(4-((2′-fluoro-N-propyl-5′-(trifluoromethyl)-[1,1′-biphenyl])-4-sulfonamido)benzamido ) propanoic acid;

(7) 3-(4-((4'-chloro-N-(3,3,3-trifluoropropyl)-[1,1'-biphenyl])-4-sulfonamido)benzamido ) propanoic acid;

(8) 3-(4-((4′-(trifluoromethyl)-N-(3,3,3-trifluoropropyl)-[1,1′-biphenyl])-4-sulfonami Figure) benzamido) propanoic acid;

(9) 3-(4-((4′-(tert-butyl)-N-(3,3,3-trifluoropropyl)-[1,1′-biphenyl])-4-sulfonamido )benzamido)propanoic acid;

(10) 3-(4-((4′-chloro-2,6-dimethyl-N-propyl-[1,1′-biphenyl])-4-sulfonamido)benzamido)propanoic acid;

(11) 3-(4-((2,6-dimethyl-N-propyl-4′-(trifluoromethyl)-[1,1′-biphenyl])-4-sulfonamido)benzamido ) propanoic acid;

(12) 3-(4-((4′-(tert-butyl)-2,6-dimethyl-N-propyl-[1,1′-biphenyl])-4-sulfonamido)benzamido) propanoic acid;

(13) 3-(4-((N-Butyl-4′-chloro-2,6-dimethyl-[1,1′-biphenyl])-4-sulfonamido)benzamido)propanoic acid;

(14) 3-(4-((N-butyl-2,6-dimethyl-4′-(trifluoromethyl)-[1,1′-biphenyl])-4-sulfonamido)benzamido ) propanoic acid;

(15) 3-(4-((4′-(tert-butyl)-N-butyl-2,6-dimethyl-[1,1′-biphenyl])-4-sulfonamido)benzamido) propanoic acid;

(16) 3-(4-((4′-chloro-2,6-dimethyl-N-(3,3,3-trifluoropropyl)-[1,1′-biphenyl])-4-sulfone amido)benzamido)propanoic acid;

(17) 3-(4-((2,6-dimethyl-4′-(trifluoromethyl)-N-(3,3,3-trifluoropropyl)-[1,1′-biphenyl] )-4-sulfonamido)benzamido)propanoic acid; and

(18) 3-(4-((4′-(tert-butyl)-2,6-dimethyl-N-(3,3,3-trifluoropropyl)-[1,1′-biphenyl]) -4-sulfonamido)benzamido)propanoic acid.

The compound represented by Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc., organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. get it from Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube Late, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, βhydroxybutyrate, glycol late, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate formed by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic or inorganic acid It can be prepared by filtration and drying, or by distilling the solvent and excess acid under reduced pressure, followed by drying and crystallization in an organic solvent.

In addition, a pharmaceutically acceptable metal salt may be prepared using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. The corresponding salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg silver nitrate).

Furthermore, the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, optical isomers, hydrates, and the like that can be prepared therefrom.

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating a disease related to glucagon receptor activity, comprising the compound represented by Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient.

Here, the glucagon receptor activity-related disease can be understood as a disease that can be prevented or treated by inhibiting glucagon receptor activity, for example, by inhibiting glucagon-induced cAMP production or glucose production, which can be prevented or treated It can be understood as a disease and a disease that can be prevented or treated by lowering blood glucose levels. The disease associated with glucagon receptor activity is, for example, a metabolic disease.

The metabolic disease may be any one or more selected from the group consisting of diabetes, obesity, hyperlipidemia, hypertension, hyperinsulinemia, fatty liver, hyperuricemia, hypercholesterolemia, hypertriglyceridemia, metabolic syndrome (Syndrome X) and dyslipidemia. have.

The compound represented by Formula 1 inhibits GCGR (Glucagon Receptor) activity, inhibits glucagon-induced cAMP production or glucose production, and lowers blood glucose levels to prevent or treat diseases related to glucagon receptor activity. can

In one embodiment of the present invention, as a result of treatment with the compound of the present invention in a GCGR-expressing cell line that did not show toxicity, it was confirmed that cAMP production induced by glucagon was inhibited in a dose-dependent manner (Fig. 1, Fig. 2, Fig. 3). and Fig. 4), it was confirmed that glucose production induced by glucagon was also inhibited in a treatment dose-dependent manner (see Figs. 5 and 6).

In addition, as a result of treatment with the compound of the present invention in high-fat diet-induced obese mice, blood glucagon-induced glucose levels were significantly reduced (see FIG. 7), area under the curve (AUC) decreased (see FIG. 8), and fasting The blood glucose level decreased (see FIG. 11 ), and the effect of reducing the blood glucose level in a hyperglycemia state was confirmed (see FIG. 12 ). Furthermore, an excellent pharmacokinetic profile was confirmed when the compound of the present invention was administered intravenously (see FIG. 13 ).

Accordingly, the biphenylsulfonamide derivative of the present invention can be usefully used as a pharmaceutical composition for preventing or treating diseases related to glucagon receptor activity, for example, diabetes.

The compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral formulations during clinical administration. In the case of formulation, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include one or more compounds and at least one excipient, for example, starch, calcium carbonate, sucrose or lactose ( lactose), gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral administration include suspensions, internal solutions, emulsions, syrups, etc. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, and emulsions. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

A pharmaceutical composition comprising the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration is subcutaneous injection, intravenous injection, intramuscular injection, or thoracic injection. Depends on how I inject my injection.

At this time, in order to formulate a formulation for parenteral administration, the compound represented by Formula 1, its optical isomer, or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or buffer to prepare a solution or suspension, which is then prepared in an ampoule or It may be prepared in vial unit dosage form. The composition may be sterilized and/or contain adjuvants such as preservatives, stabilizers, wetting agents or emulsification accelerators, salts and/or buffers for regulating osmotic pressure, and other therapeutically useful substances, and mixing, granulation, in a conventional manner. It can be formulated according to the method of formulation or coating.

Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (eg silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine and the like, and optionally boron such as starch, agar, alginic acid or its sodium salt, etc. It may contain releasing or boiling mixtures and/or absorbents, colorants, flavoring agents, and sweetening agents.

Another aspect of the present invention provides a health functional food composition for preventing or improving glucagon receptor activity-related diseases, comprising the compound represented by Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient. .

Here, the glucagon receptor activity-related disease can be understood as a disease that can be prevented or ameliorated by inhibiting glucagon receptor activity, for example, can be prevented or improved by inhibiting glucagon-induced cAMP production or glucose production It can be understood as a disease and a disease that can be prevented or ameliorated by lowering blood glucose levels. The disease associated with glucagon receptor activity is, for example, a metabolic disease.

The metabolic disease may be any one or more selected from the group consisting of diabetes, obesity, hyperlipidemia, hypertension, hyperinsulinemia, fatty liver, hyperuricemia, hypercholesterolemia, hypertriglyceridemia, metabolic syndrome (Syndrome X) and dyslipidemia. have.

The compound represented by Formula 1 inhibits GCGR (Glucagon Receptor) activity, inhibits glucagon-induced cAMP production or glucose production, and prevents or improves glucagon receptor activity-related diseases from lowering blood glucose levels can do.

Therefore, the biphenylsulfonamide derivative of the present invention can be usefully used as a health functional food composition for preventing or improving glucagon receptor activity-related diseases, for example, diabetes.

Hereinafter, the present invention will be described in detail by way of Examples and Experimental Examples.

However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following Examples and Experimental Examples.

<Example 1> Preparation of 3-(4-(N-propyl-[1,1'-biphenyl]-4-sulfonamido)benzamido)propanoic acid

Step 1: Preparation of ethyl 3-(4-nitrobenzamido)propanoate

4-Nitrobenzoyl chloride (5g, 26.9mmol) in a stirred solution of β-alanine ethyl ester hydrochloride (4.1g, 26.9mmol) and TEA (8.3mL, 59.3mmol) in CHCl ₃ (135 mL) at 0 ° C. was added continuously and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc. The organic layer was washed with H ₂ O and brine, then dried over MgSO ₄ . After filtration, the solvent was removed under reduced pressure, and the residue was purified by SiO ₂ flash column chromatography to obtain the title compound.

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.26 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.37 (s, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.75 (q, J = 5.4 Hz, 2H), 2.68 (t, J = 6 Hz, 2H), 1.28 (t, J = 6.6 Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ (ppm): 172.8, 165.4, 149.5, 139.9, 128.2, 123.7, 61.0, 35.7, 33.6, 14.1; HRMS (ESI-TOF) m/z [M + H] ⁺ calculated for C ₁₂ H ₁₅ N ₂ O ₅ ⁺ 267.0903, found 267.0913.

Step 2: Preparation of ethyl 3-(4-aminobenzamido)propanoate

To a stirred solution of the compound of step 1 above (6.15 g, 23.1 mmol) in MeOH (75 mL) was added palladium (10% on carbon, 250 mg, 0.231 mmol) and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 h. The reaction mixture was filtered and washed with MeOH. After filtration, the solvent was removed under reduced pressure, and the residue was purified by SiO ₂ flash column chromatography to obtain the title compound.

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 7.59 (d, J = 8.4 Hz, 2H), 6.72 (s, 1H), 6.64 (d, J = 8.4 Hz, 2H), 4.15 (q, J = 7.2 Hz, 2H), 3.99 (bs, 2H), 3.68 (q, J = 6.6 Hz, 2H), 2.61 (t, J = 6 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H) ; ¹³ C NMR (150 MHz, CDCl ₃ ) δ (ppm): 173.1, 167.1, 149.6, 128.7, 123.9, 114.1, 60.7, 35.2, 34.1, 14.2; HRMS (ESI-TOF) m/z [M + H] ⁺ calculated for C ₁₂ H ₁₇ N ₂ O ₃ ⁺ 237.1161, found 237.1153.

Step 3: Preparation of ethyl 3-(4-(propylamino)benzamido)propanoate

To a stirred solution of the compound of step 2 above (2 g, 8.46 mmol) in MeOH (42 mL) was added palladium (10% on carbon, 450 mg, 0.846 mmol) and propanal (0.909 mL, 12.7 mmol) and the mixture was stirred Stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered and washed with MeOH. After filtration, the solvent was removed under reduced pressure, and the residue was purified by SiO ₂ flash column chromatography to obtain the title compound.

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 7.61 (d, J = 9 Hz, 2H), 6.71 (bs, 1H), 6.54 (d, J = 9 Hz, 2H), 4.16 (q, J = 7.2 Hz, 2H), 4.11 (bs, 1H), 3.69 (q, J = 6 Hz, 2H), 3.10 (t, J = 7.2 Hz, 2H), 2.62 (t, J = 6 Hz, 2H) , 1.67-1.61 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ (ppm): 173.0, 167.2, 151.1, 128.6, 122.1, 111.6, 60.7, 45.2, 35.1, 34.2, 22.5, 14.2, 11.6; HRMS (ESI-TOF) m/z [M + H] ⁺ calculated for C ₁₅ H ₂₃ N ₂ O ₃ ⁺ 279.1530, found 279.1541.

Step 4: Preparation of ethyl 3-(4-((4-iodo-N-propylphenyl)sulfonamido)benzamido)propanoate

4-Io in a stirred solution of the compound of step 3 above (750 mg, 2.69 mmol) in CH ₂ Cl ₃ (15 mL) and TEA (0.6 mL, 4.04 mmol) in CH ₂ Cl ₃ (15 mL) at 0 °C Dobenzenesulfonylchloride (978 mg, 3.23 mmol) was added successively and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc. The organic layer was washed with H ₂ O and brine, then dried over MgSO ₄ . After filtration, the solvent was removed under reduced pressure, and the residue was purified by SiO ₂ flash column chromatography to obtain the title compound.

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 7.81 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 9 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H) , 7.13 (d, J = 9 Hz, 2H), 7.00 (t, J = 6 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.72 (q, J = 6 Hz, 2H), 3.51 (t, J = 6.6 Hz, 2H), 2.65 (t, J = 6 Hz, 2H), 1.45-1.69 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H), 0.89 (t, J = 7.2 Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ (ppm): 172.8, 166.4, 141.6, 138.2, 137.6, 133.8, 128.9, 128.5, 127.6, 100.3, 60.8, 60.4, 52.0, 35.4, 33.8, 21.4, 21.1, 14.2 , 10.9; HRMS (ESI-TOF) m/z [M + H] ⁺ calculated for C ₂₁ H ₂₆ IN ₂ O ₅ S ⁺ 545.0529, found 545.0512.

Step 5: Preparation of ethyl 3-(4-(N-propyl-[1,1'-biphenyl]-4-sulfonamido)benzamido)propanoate

The compound of step 4 above (50mg, 0.092mmol), phenylboronic acid (17mg, 0.138mmol) and 20% K ₂ CO ₃ (2.2mL) were dissolved in anhydrous THF (2.2mL). The mixture was purged with nitrogen for 5 min. Pd(PPh ₃ ) ₄ (5 mg, 4.6 μmol) was added and the mixture was stirred at 80 °C overnight. The mixture was partitioned between EtOAc and water and the aqueous layer was extracted with EtOAc. The pooled organic layer was washed with H ₂ O and brine, then dried over MgSO ₄ . After filtration, the solvent was removed under reduced pressure, and the residue was purified by SiO ₂ flash column chromatography to obtain the title compound.

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 7.73 (d, J = 8.4, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.63-7.61 (m, 4H), 7.48 (t) , J = 7.4 Hz, 2H), 7.42 (t, J = 7.4 1H), 7.18 (d, J = 8.4 Hz, 2H), 6.87 (t, J = 5.4 Hz, 1H), 4.18 (q, J = 7.2) Hz, 2H), 3.73 (q, J = 6 Hz, 2H), 3.56 (t, J = 7.2 Hz, 2H), 2.65 (t, J = 6 Hz, 2H), 1.48-1.42 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ (ppm): 173.0, 166.4, 141.9, 139.6, 136.2, 133.7, 132.9, 128.6, 127.7, 126.6, 60.9, 52.0, 35.4, 33.8, 24.0, 21.4, 14.2, 10.9 ; HRMS (ESI-TOF) m/z [M + H] ⁺ calculated for C ₂₇ H ₃₁ N ₂ O ₅ S ⁺ 495.1875, found 495.1887.

Step 6: Preparation of 3-(4-(N-propyl-[1,1'-biphenyl]-4-sulfonamido)benzamido)propanoic acid

LiOH·H ₂ O (6.0 mg, 0.135 mmol) was added to a THF/H ₂ O (0.3 mL/0.2 mL) solution of the compound obtained in the above step (33 mg, 0.068 mmol). The reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was diluted with H ₂ O and acidified to pH 2 with 1N HCl. The mixture was diluted with EtOAc and the organic layer was washed with H ₂ O and brine, then dried over MgSO ₄ . After filtration, the solvent was removed under reduced pressure and the residue was purified by SiO ₂ flash column chromatography.

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 7.72 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.6 Hz, 2H), 7.62-7.60 (m, 3H), 7.48 ( t, J = 7.5 Hz, 2H), 7.43-7.41 (m, 1H), 7.19 (d, J = 8.6 Hz, 2H), 6.77 (t, J = 6 Hz, 1H), 3.75 (q, J = 5.9) Hz, 2H), 3.56 (t, J = 7.1 Hz, 2H), 2.74 (t, J = 5.8 Hz, 2H), 1.48-1.42 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ (ppm): 129.1, 128.6, 128.1, 127.8, 127.5, 127.3, 51.9, 35.2, 33.3, 21.4, 11.0; HRMS (ESI-TOF) m/z [M + H] ⁺ calculated for C ₃₃ H ₄₀ F ₃ N ₂ O ₅ S ⁺ 467.1562, found 467.1506.

<Example 2> Preparation of 3-(4-((4'-chloro-N-propyl-[1,1'-biphenyl])-4-sulfonamido)benzamido)propanoic acid

The title compound was prepared in the same manner as in Example 1, except that (4-chlorophenyl)boronic acid was used instead of phenylboronic acid in step 5 of Example 1.

<Example 3> 3-(4-((N-propyl-4'-(trifluoromethyl)-[1,1'-biphenyl])-4-sulfonamido)benzamido)propanoic acid Produce

The title compound was prepared in the same manner as in Example 1, except that (4-(trifluoromethyl)phenyl)boronic acid was used instead of phenylboronic acid in step 5 of Example 1.

<Example 4> Preparation of 3-(4-((4'-(tert-butyl)-N-propyl-[1,1'-biphenyl])-4-sulfonamido)benzamido)propanoic acid

The title compound was prepared in the same manner as in Example 1, except that (4-(tert-butyl)phenyl)boronic acid was used instead of phenylboronic acid in step 5 of Example 1 above.

<Example 5> Preparation of 3-(4-((3',5'-dichloro-N-propyl-[1,1'-biphenyl])-4-sulfonamido)benzamido)propanoic acid

The title compound was prepared in the same manner as in Example 1, except that (3,5-dichlorophenyl)boronic acid was used instead of phenylboronic acid in step 5 of Example 1 above.

<Example 6> 3-(4-((2'-fluoro-N-propyl-5'-(trifluoromethyl)-[1,1'-biphenyl])-4-sulfonamido)benz Preparation of amido) propanoic acid

The title compound was obtained in the same manner as in Example 1, except that (2-fluoro-5-(trifluoromethyl)phenyl)boronic acid was used instead of phenylboronic acid in step 5 of Example 1 prepared.

<Example 7> 3-(4-((4'-chloro-N-(3,3,3-trifluoropropyl)-[1,1'-biphenyl])-4-sulfonamido)benz Preparation of amido) propanoic acid

3,3,3-trifluoropropanal was used instead of propanal in step 3 of Example 1, and (4-chlorophenyl)boronic acid was used instead of phenylboronic acid in step 5 of Example 1 The title compound was prepared in the same manner as in Example 1, except that .

<Example 8> 3-(4-((4'-(trifluoromethyl)-N-(3,3,3-trifluoropropyl)-[1,1'-biphenyl])-4- Preparation of sulfonamido)benzamido)propanoic acid

3,3,3-trifluoropropanal was used instead of propanal in step 3 of Example 1, and (4-(trifluoromethyl) was used instead of phenylboronic acid in step 5 of Example 1 ) The title compound was prepared in the same manner as in Example 1, except that phenylboronic acid was used.

<Example 9> 3-(4-((4'-(tert-butyl)-N-(3,3,3-trifluoropropyl)-[1,1'-biphenyl])-4-sulfone Preparation of amido)benzamido)propanoic acid

In step 3 of Example 1, 3,3,3-trifluoropropanal was used instead of propanal, and in step 5 of Example 1, (4-(tert-butyl) was used instead of phenylboronic acid. The title compound was prepared in the same manner as in Example 1, except that phenyl) boronic acid was used.

<Example 10> 3-(4-((4'-chloro-2,6-dimethyl-N-propyl-[1,1'-biphenyl])-4-sulfonamido)benzamido)propanoic acid manufacture of

In step 4 of Example 1, 4-bromo-3,5-dimethylbenzenesulfonyl chloride was used instead of 4-iodobenzenesulfonyl chloride, and in step 5 of Example 1, phenylboronic acid was replaced The title compound was prepared in the same manner as in Example 1, except that (4-chlorophenyl)boronic acid was used.

<Example 11> 3-(4-((2,6-dimethyl-N-propyl-4'-(trifluoromethyl)-[1,1'-biphenyl])-4-sulfonamido)benz Preparation of amido) propanoic acid

In step 4 of Example 1, 4-bromo-3,5-dimethylbenzenesulfonyl chloride was used instead of 4-iodobenzenesulfonyl chloride, and in step 5 of Example 1, phenylboronic acid was replaced The title compound was prepared in the same manner as in Example 1, except that (4-(trifluoromethyl)phenyl)boronic acid was used.

<Example 12> 3-(4-((4'-(tert-butyl)-2,6-dimethyl-N-propyl-[1,1'-biphenyl])-4-sulfonamido)benzami Figure) Preparation of propanoic acid

In step 4 of Example 1, 4-bromo-3,5-dimethylbenzenesulfonyl chloride was used instead of 4-iodobenzenesulfonyl chloride, and in step 5 of Example 1, phenylboronic acid was replaced The title compound was prepared in the same manner as in Example 1, except that (4-(tert-butyl)phenyl)boronic acid was used.

<Example 13> 3-(4-((N-butyl-4'-chloro-2,6-dimethyl-[1,1'-biphenyl])-4-sulfonamido)benzamido)propanoic acid manufacture of

In step 3 of Example 1, butanal was used instead of propanal, and in step 4 of Example 1, 4-bromo-3,5-dimethylbenzenesulfonyl was used instead of 4-iodobenzenesulfonyl chloride. The title compound was prepared in the same manner as in Example 1, except that phonyl chloride was used and (4-chlorophenyl)boronic acid was used instead of phenylboronic acid in step 5 of Example 1.

<Example 14> 3-(4-((N-butyl-2,6-dimethyl-4'-(trifluoromethyl)-[1,1'-biphenyl])-4-sulfonamido)benz Preparation of amido) propanoic acid

In step 3 of Example 1, butanal was used instead of propanal, and in step 4 of Example 1, 4-bromo-3,5-dimethylbenzenesulfonyl was used instead of 4-iodobenzenesulfonyl chloride. In the same manner as in Example 1, except that phonyl chloride was used and (4-(trifluoromethyl)phenyl)boronic acid was used in place of phenylboronic acid in step 5 of Example 1, the title compound was was prepared.

<Example 15> 3-(4-((4'-(tert-butyl)-N-butyl-2,6-dimethyl-[1,1'-biphenyl])-4-sulfonamido)benzami Figure) Preparation of propanoic acid

In step 3 of Example 1, butanal was used instead of propanal, and in step 4 of Example 1, 4-bromo-3,5-dimethylbenzenesulfonyl was used instead of 4-iodobenzenesulfonyl chloride. The title compound was obtained in the same manner as in Example 1, except that phonyl chloride was used and (4-(tert-butyl)phenyl)boronic acid was used instead of phenylboronic acid in step 5 of Example 1 prepared.

<Example 16> 3-(4-((4'-chloro-2,6-dimethyl-N-(3,3,3-trifluoropropyl)-[1,1'-biphenyl])-4 -Preparation of sulfonamido)benzamido)propanoic acid

3,3,3-trifluoropropanal was used instead of propanal in step 3 of Example 1, and 4-bromine was used instead of 4-iodobenzenesulfonylchloride in step 4 of Example 1 Same procedure as in Example 1, except that parent-3,5-dimethylbenzenesulfonylchloride was used and (4-chlorophenyl)boronic acid was used instead of phenylboronic acid in step 5 of Example 1 Thus, the title compound was prepared.

<Example 17> 3-(4-((2,6-dimethyl-4'-(trifluoromethyl)-N-(3,3,3-trifluoropropyl)-[1,1'-bi Preparation of phenyl])-4-sulfonamido)benzamido)propanoic acid

In step 3 of Example 1, 3,3,3-trifluoropropanal was used instead of propanal, and in step 4 of Example 1, 4-bromine was used instead of 4-iodobenzenesulfonyl chloride. The above procedure was carried out, except that parent-3,5-dimethylbenzenesulfonylchloride was used and (4-(trifluoromethyl)phenyl)boronic acid was used instead of phenylboronic acid in step 5 of Example 1 above. Performed as in Example 1 to prepare the title compound.

<Example 18> 3-(4-((4'-(tert-butyl)-2,6-dimethyl-N-(3,3,3-trifluoropropyl)-[1,1'-biphenyl) ]) -4-sulfonamido) benzamido) preparation of propanoic acid

3,3,3-trifluoropropanal was used instead of propanal in step 3 of Example 1, and 4-bromine was used instead of 4-iodobenzenesulfonylchloride in step 4 of Example 1 Except that parent-3,5-dimethylbenzenesulfonyl chloride was used and (4-(tert-butyl)phenyl)boronic acid was used instead of phenylboronic acid in step 5 of Example 1, above Performed as in 1 to prepare the title compound.

The chemical structures of the compounds prepared in Examples 1-18 are shown in Table 1 below.

Example chemical structure Example chemical structure One

10

2

11

3

12

4

13

5

14

6

15

7

16

8

17

9

18

<Experimental Example 1> Evaluation of glucagon-induced cAMP production inhibitory activity in GCGR-expressing cell lines

In order to evaluate the inhibitory activity of the compounds of the present invention on glucagon-induced cAMP production in GCGR (Glucagon Receptor)-expressing cell lines, an experiment was performed as follows.

<1-1> Cytotoxicity evaluation

In order to evaluate the cytotoxicity of the synthesized compound of the present invention, 20 μM of each of the compounds of Examples 1-18 of the present invention was treated in the CHO-K1 GCGR Gs cell line, and the degree of apoptosis was evaluated, and the results are shown in FIG. 1 .

<1-2> Evaluation of inhibitory activity on glucagon-induced cAMP production

Based on the fact that when GCGR is activated by glucagon, it stimulates adenylate cyclase to increase intracellular cAMP levels and activates the cAMP-dependent protein kinase (PKA) pathway, specifically, After treating the CHO-K1 GCGR Gs cell line with 10 μM of the compounds of the present invention in the presence of 0.1 nM glucagon, the cAMP production rate was measured to evaluate the glucagon-induced cAMP production inhibitory activity of the compound of the present invention, and the results are shown in FIG. 2 indicated.

As can be seen in FIG. 2 , it is confirmed that the biphenylsulfonamide derivative of the present invention effectively inhibits glucagon-induced cAMP production, and in particular, the R ¹ position of Formula 1 is n-propyl or 3,3,3-trifluoropropyl In the case of the compound substituted with , a better inhibitory effect on glucagon-induced cAMP production was confirmed. In addition, when R ³ positioned at para of phenyl is t-butyl (4-t-Bu), or in the case of a compound having a methyl substituent at the R ² position, a better inhibitory effect on glucagon-induced cAMP production was confirmed.

<1-3> Evaluation of dose-dependent inhibitory activity on glucagon-induced cAMP production

To investigate the dose-dependent effect on glucagon-induced cAMP production, various concentrations (5, 10 or 20 μM) of the compounds of Examples 9, 12 and 18 of the present invention were administered to CHO-K1 GCGR Gs cells in the presence of 0.1 nM of glucagon. treatment, and the results are shown in FIG. 3 .

As can be seen in FIG. 3 , all of the biphenylsulfonamide derivatives of the present invention exhibited dose-dependent inhibitory activity on glucagon-induced cAMP production.

<1-4> IC of glucagon-induced cAMP production inhibitory activity ₅₀

IC ₅₀ of the glucagon-induced cAMP production inhibitory activity of Example 12 of the present invention was calculated for CHO-K1 GCGR Gs cells in the presence of 0.1 nM of glucagon, and the results are shown in FIG. 4 .

As confirmed in FIG. 4 , the IC ₅₀ value of the glucagon-induced cAMP generation inhibitory activity of Example 12 of the present invention was confirmed to be 8.4 μM.

<Experimental Example 2> Evaluation of glucagon-induced glucose production inhibitory activity in liver cell lines

In order to evaluate the inhibitory activity of the compounds of the present invention on glucagon-induced glucose production in liver cell lines (primary hepatocytes), the experiment was performed as follows.

<2-1> Evaluation of inhibitory activity on glucagon-induced glucose production

Based on the fact that activation of GCGR by glucagon induces gluconeogenesis in the liver and glycogenolysis, which converts glycogen to glucose-6 phosate, thereby promoting glucose production, mouse primary hepatocytes ), the inhibitory activity of the compounds of the examples of the present invention on glucagon-induced glucose production was evaluated. Specifically, a mouse liver cell line was treated with 20 μM of the compounds of the present invention (Examples 9, 12 and 18) in the presence of 10 nM glucagon and gluconeogenic substrates (2 mM sodium pyruvate and 20 mM sodium lactate). After 30 minutes of glucagon treatment, the glucagon-induced glucose production rate was measured, and the results are shown in FIG. 5 .

As can be seen in FIG. 5 , all of the biphenylsulfonamide derivatives of the present invention exhibited excellent inhibitory activity of 70% or more against glucagon-induced glucose production.

<2-2> Evaluation of dose-dependent inhibitory activity on glucagon-induced glucose production

To investigate the dose-dependent effect on glucagon-induced glucose production, various concentrations (1, 5, 10 or 20 μM) of the compounds of Examples 9, 12 and 18 of the present invention were treated, and the glucagon-induced glucose production rate was measured after 30 minutes of glucagon treatment, and the results are shown in FIG. 6 .

As can be seen in FIG. 6 , all of the biphenylsulfonamide derivatives of the present invention exhibited dose-dependent inhibitory activity on glucagon-induced glucose production.

<Experimental Example 3> In vivo glucose lowering effect evaluation

In order to evaluate the blood glucose concentration lowering effect of the compound of the present invention in vivo, the experiment was conducted as follows.

Specifically, the compound of Example 12 of the present invention or LGD-6972 (positive control) was orally administered to high-fat diet-induced obese mice once daily for 6 weeks at 50 mg/kg. In addition, a glucagon challenge test was performed to investigate whether the effect of the compound of the present invention on blood glucose control is mediated by the inhibition of GCGR, the results are shown in FIG. 7 , and the area under the curve (AUC) is shown in FIG. The body weight and daily food intake were measured and shown in FIGS. 9 and 10, the non-fasting blood glucose level was monitored at the 3rd and 4th weeks of the experiment and shown in FIG. 11, and the hyperglycemia at the 6th week A glucose tolerance test was performed to confirm the improvement effect of the compounds of Examples of the present invention, and the results are shown in FIG. 12 .

7, it was confirmed that the treatment with the compound of Example 12 of the present invention significantly reduced glucagon-induced glucose levels at all time points measured in high-fat diet-induced obese mice.

In addition, as confirmed in FIG. 8 , it was confirmed that the area under the curve (AUC) was also significantly reduced according to the treatment with the compound of Example 12 of the present invention.

Meanwhile, as can be seen in FIGS. 9 and 10 , body weight and daily food intake did not change, and there was no specific change between all groups.

11 , it was confirmed that the fasting blood glucose level was decreased in the experimental group treated with the compound of Example 12 of the present invention.

12, it was confirmed that the treatment with the compound of Example 12 of the present invention reduced blood glucose levels in high-fat diet-induced obese mice administered with glucose 2 g/kg.

<Experimental Example 4> In vivo pharmacokinetic profile and characteristics analysis

For the in vivo pharmacokinetic profile and characterization of the compound of the present invention, the experiment was performed as follows.

Specifically, plasma concentration-time profiling was performed after intravenous administration (IV) of the compound of Example 12 of the present invention to rats, and plasma concentration was measured up to 480 minutes after administration, and the measured pharmacokinetic parameters are shown in Table 2. and the graph is shown in FIG. 13 .

Pharmacokinetic parameters Example 12 IV (2 mg/kg) AUC _0→∞ (μg min/mL) 86.3 ± 13.7 Terminal t _1/2 (min) 90.0 ± 15.6 MRT (min) 15.8 ± 2.0 V _ss (mL/kg) 371.4 ± 67.1 CL (mL/min/kg) 23.6 ± 3.3

13 , the CL (clearance rate) value after intravenous administration was confirmed to be 23.6 mL/min/kg, and the elimination half-life was confirmed to be 90 minutes.

As confirmed from the results of the in vitro and in vivo experimental examples conducted in the present invention, the biphenylsulfonamide derivative compound of the present invention is used as a pharmaceutical composition for the prevention or treatment of glucagon receptor activity-related diseases. It can be seen that it can be usefully used, and in particular, it can be seen that it can be provided as an effective therapeutic agent for diabetes, for example, type 2 diabetes.

Claims (12)

A compound represented by the following formula (1), a stereoisomer or a pharmaceutically acceptable salt thereof:
[Formula 1]

(In Formula 1,
R ¹ is hydrogen or substituted or unsubstituted C 1-10 straight or branched chain alkyl;
R ² is each independently hydrogen or substituted or unsubstituted C1-10 straight-chain or branched alkyl;
R ³ is each independently hydrogen, halogen, substituted or unsubstituted C1-10 straight or branched chain alkyl, or substituted or unsubstituted C1-10 straight or branched chain alkoxy;
R ⁴ is -COOR ⁵ or -SO ₂ -OR ⁵ ,
wherein R ⁵ is hydrogen or substituted or unsubstituted C1-10 straight-chain or branched alkyl;
n is an integer from 1 to 5; and
wherein said substituted alkyl and substituted alkoxy are substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, nitro and amino).
According to claim 1,
R ¹ is C1-5 straight-chain or branched alkyl substituted or unsubstituted with halogen;
each R ² is independently hydrogen or C1-3 straight-chain or branched alkyl;
R ³ is each independently hydrogen, halogen, or C1-5 straight or branched chain alkyl substituted or unsubstituted with halogen; and
R ⁴ is -COOH, characterized in that the compound, a stereoisomer or a pharmaceutically acceptable salt thereof.
According to claim 1,
R ¹ is C3-4 straight-chain or branched alkyl substituted or unsubstituted with halogen;
each R ² is independently hydrogen or methyl;
R ³ is each independently hydrogen, halogen, or C1-5 straight or branched chain alkyl substituted or unsubstituted with halogen; and
R ⁴ is -COOH, characterized in that the compound, a stereoisomer or a pharmaceutically acceptable salt thereof.
According to claim 1,
R ¹ is n-propyl, n-butyl or —CH ₂ CH ₂ CF ₃ ;
R ² is hydrogen or methyl;
each R ³ is independently hydrogen, F, Cl, tert-butyl or —CF ₃ ; and
R ⁴ is -COOH, characterized in that the compound, a stereoisomer or a pharmaceutically acceptable salt thereof.
According to claim 1,
The compound represented by Formula 1 is,
A compound, characterized in that any one selected from the group of compounds, a stereoisomer or a pharmaceutically acceptable salt thereof:
(1) 3-(4-(N-propyl-[1,1′-biphenyl]-4-sulfonamido)benzamido)propanoic acid;
(2) 3-(4-((4′-chloro-N-propyl-[1,1′-biphenyl])-4-sulfonamido)benzamido)propanoic acid;
(3) 3-(4-((N-propyl-4′-(trifluoromethyl)-[1,1′-biphenyl])-4-sulfonamido)benzamido)propanoic acid;
(4) 3-(4-((4′-(tert-butyl)-N-propyl-[1,1′-biphenyl])-4-sulfonamido)benzamido)propanoic acid;
(5) 3-(4-((3′,5′-dichloro-N-propyl-[1,1′-biphenyl])-4-sulfonamido)benzamido)propanoic acid;
(6) 3-(4-((2′-fluoro-N-propyl-5′-(trifluoromethyl)-[1,1′-biphenyl])-4-sulfonamido)benzamido ) propanoic acid;
(7) 3-(4-((4'-chloro-N-(3,3,3-trifluoropropyl)-[1,1'-biphenyl])-4-sulfonamido)benzamido ) propanoic acid;
(8) 3-(4-((4′-(trifluoromethyl)-N-(3,3,3-trifluoropropyl)-[1,1′-biphenyl])-4-sulfonami Figure) benzamido) propanoic acid;
(9) 3-(4-((4′-(tert-butyl)-N-(3,3,3-trifluoropropyl)-[1,1′-biphenyl])-4-sulfonamido )benzamido)propanoic acid;
(10) 3-(4-((4′-chloro-2,6-dimethyl-N-propyl-[1,1′-biphenyl])-4-sulfonamido)benzamido)propanoic acid;
(11) 3-(4-((2,6-dimethyl-N-propyl-4′-(trifluoromethyl)-[1,1′-biphenyl])-4-sulfonamido)benzamido ) propanoic acid;
(12) 3-(4-((4′-(tert-butyl)-2,6-dimethyl-N-propyl-[1,1′-biphenyl])-4-sulfonamido)benzamido) propanoic acid;
(13) 3-(4-((N-Butyl-4′-chloro-2,6-dimethyl-[1,1′-biphenyl])-4-sulfonamido)benzamido)propanoic acid;
(14) 3-(4-((N-butyl-2,6-dimethyl-4′-(trifluoromethyl)-[1,1′-biphenyl])-4-sulfonamido)benzamido ) propanoic acid;
(15) 3-(4-((4′-(tert-butyl)-N-butyl-2,6-dimethyl-[1,1′-biphenyl])-4-sulfonamido)benzamido) propanoic acid;
(16) 3-(4-((4′-chloro-2,6-dimethyl-N-(3,3,3-trifluoropropyl)-[1,1′-biphenyl])-4-sulfone amido)benzamido)propanoic acid;
(17) 3-(4-((2,6-dimethyl-4′-(trifluoromethyl)-N-(3,3,3-trifluoropropyl)-[1,1′-biphenyl] )-4-sulfonamido)benzamido)propanoic acid; and
(18) 3-(4-((4′-(tert-butyl)-2,6-dimethyl-N-(3,3,3-trifluoropropyl)-[1,1′-biphenyl]) -4-sulfonamido)benzamido)propanoic acid.
A pharmaceutical composition for preventing or treating a disease related to glucagon receptor activity, comprising the compound represented by Formula 1 of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
7. The method of claim 6,
The glucagon receptor activity-related disease is a pharmaceutical composition, characterized in that the metabolic disease.
7. The method of claim 6,
The glucagon receptor activity-related disease is any one selected from the group consisting of diabetes, obesity, hyperlipidemia, hypertension, hyperinsulinemia, fatty liver, hyperuricemia, hypercholesterolemia, hypertriglyceridemia, metabolic syndrome (Syndrome X) and dyslipidemia A pharmaceutical composition, characterized in that one.
7. The method of claim 6,
The glucagon receptor activity-related disease is a pharmaceutical composition, characterized in that type 2 diabetes.
7. The method of claim 6,
The pharmaceutical composition is a pharmaceutical composition, characterized in that inhibiting the cAMP production or glucose production induced by glucagon.
7. The method of claim 6,
The pharmaceutical composition is a pharmaceutical composition, characterized in that it exhibits a blood glucose lowering effect.
A health functional food composition for preventing or improving glucagon receptor activity-related diseases, comprising the compound represented by Formula 1 of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

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