KR102224677B1 - Thiazolopiperazine derivatives and composition for preventing or treating autoimmune diseases comprising the same - Google Patents

Abstract

The present invention provides thiazolo piperazine derivatives and pharmaceutical compositions and health functional food compositions for preventing or treating autoimmune diseases containing the same as an active ingredient. The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention can have an inhibitory effect on LPA1 (Lysophosphatidic acid 1) receptor activation, and thus is useful as a pharmaceutical composition for preventing or treating LPA1-related diseases and a health functional food composition. Can be used. In addition, the pharmaceutical composition and the health functional food composition can effectively prevent or treat not only autoimmune diseases, but also other immune-related diseases having similar mechanisms of development.

Description

Thiazolo piperazine derivatives and compositions for preventing or treating autoimmune diseases containing them as active ingredients {THIAZOLOPIPERAZINE DERIVATIVES AND COMPOSITION FOR PREVENTING OR TREATING AUTOIMMUNE DISEASES COMPRISING THE SAME}

The present invention relates to a thiazolo piperazine derivative and a composition for preventing or treating autoimmune diseases containing the same as an active ingredient.

Autoimmune diseases are diseases that cause abnormal immune responses by mistaken substances in the body as antigens, psoriasis, Sjogren syndrome, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, optic nerve myelitis, Guillain-Barre syndrome, Graves' disease, Behcet's disease. Etc.

The main cause of autoimmune diseases is believed to trigger abnormalities in the autoimmune system due to the transfer of lymphocytes to tissues, but the pathogenesis of each disease is not yet known.

Recently, with a focus on effective immunosuppression, research on the development of autoimmune disease treatments is underway, focusing on immunosuppression at the cellular level (suppression of activation of cell tumors responsible for immune responses in lymphocytes and diseased tissues) and molecular level.

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), represented by lysophospholipids, have long been considered as phospholipid metabolites of cell membrane components. coupled receptor (GPCR) is reported as an important extracellular signaling substance that regulates various biological functions through activation of lysophospholipid receptors.

Among them, LPA1 is the first receptor identified among lysophospholipid receptors (identified in 1996) and is a key factor regulating the development of the nervous system, and its importance in various diseases has been identified through recent studies. Immune response regulation is attracting attention. The signal transduction mechanism of LPA1 and the organic system with tissues in vivo revealed through various research data are not only autoimmune diseases such as Sjogren's syndrome, stroke, psoriasis, inflammatory bowel disease, diabetic nephropathy and fibrosis, and systemic sclerosis, but also the neuropsychiatric system. It is becoming important data for the treatment of a variety of diseases including disability, neurological pain, infertility, cardiovascular disease, and cancer. (Ref. Park et al, “Inhibition of lysophosphatidic acid receptor ameliorates Sjogren's syndrome in NOD mice” Oncotarget. 2017 , 8(16), 27240-27251, Yung et al, “LPA receptor signaling: pharmacology, physiology, and pathophysiology“ J Lipid Res. 2014, 55, 1192-1214, Choi et al. “LPA receptors: subtypes and biological actions “Annu Rev Pharmacol Toxicol. 2010;50:157-86. Debendra Pattanaik et al, “A Role for Lysophosphatidic Acid and Sphingosine 1-Phosphate in the Pathogenesis of Systemic Sclerosis” Discov Med 10(51):161-167, August 2010 .)

Currently, steroids, Cyclosporine, Rapamycin, Methotrexate, Cyclophosphamide, IV Immunoglobulin, Axathioprine, Infliximab, etc. Although it is treated with a combination therapy of various immunosuppressive drugs, most of them have persistent inflammation and frequent recurrence, and there are many systemic side effects following the treatment.

In particular, rare autoimmune diseases have a small number of patients, but the cost of the therapeutic agent to be applied is very high, so the economic burden of the patients is very large, and the cost burden is increasing because a long-term treatment is required. Although the number of patients with rare autoimmune diseases is increasing in Korea, there are no clear treatments and the cure rate is low, which is still an economic and social problem.

Korean Patent Registration No. 10-1020431 (registered on February 28, 2011)

In order to solve the above problems, the present invention provides a thiazole piperazine derivative.

The present invention provides a pharmaceutical composition for preventing or treating autoimmune diseases containing the thiazole piperazine derivative as an active ingredient.

The present invention provides a health functional food composition for improving or preventing autoimmune diseases containing the thiazolo piperazine derivative as an active ingredient.

The compound represented by the following formula 1 according to the present invention or a pharmaceutically acceptable salt thereof,

[Formula 1]

In the above formula, R ¹ and R ² may each be the same or different, and are selected from hydrogen, (C1 ~ C4) alkyl, (C1 ~ C4) alkoxy, halogen, nitro, or a substituent of the following formula (2),

[Formula 2]

At this time, R ³ and R ⁴ may be the same or different, respectively, and selected from hydrogen, (C1 ~ C4) alkyl, (C1 ~ C4) alkoxy, trifluoromethyl, phenoxy, halogen or nitro, or R ³ and R ⁴ may be connected to form a 5-cyclic heterocycle.

The pharmaceutical composition for preventing or treating LPA1-related diseases according to the present invention contains the compound or a pharmaceutically acceptable salt thereof as an active ingredient, and may have an effect of inhibiting LPA1 (Lysophosphatidic acid 1) receptor activation.

The health functional food composition for improving or preventing LPA1-related diseases according to the present invention contains the compound or a pharmaceutically acceptable salt thereof as an active ingredient, and may have an effect of inhibiting LPA1 (Lysophosphatidic acid 1) receptor activation.

Since thiazolo piperazine derivatives according to the present invention have an inhibitory effect on LPA1 receptor activation, pharmaceutical compositions and health functional foods for the prevention or treatment of LPA1-related diseases such as stroke, psoriasis, Sjogren's syndrome, inflammatory bowel disease, diabetic nephropathy and fibrosis It can be usefully used as a composition.

Autoimmune diseases can be effectively prevented and treated through the pharmaceutical composition and health functional food composition for preventing or treating LPA1-related diseases according to the present invention. In addition, it can be applied in various ways to the treatment of not only the autoimmune diseases, but also other immune-related diseases having a similar mechanism of development.

1 is a graph showing a calcium analysis result according to an experimental example of the present invention.

Hereinafter, the present invention will be described in detail.

The present invention is an animal model of autoimmune diseases such as sjogren's disease, psoriasis, multiple sclerosis, and abnormal immune response diseases such as diabetic nephropathy and cerebral ischemia (in vivo disease model). ) Through prior studies using LPA1 as a novel target molecule for the treatment of autoimmune diseases, and by discovering a compound with LPA1 antagonism, the present invention was completed.

The present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

[Formula 1]

In the above formula, R ¹ and R ² may each be the same or different, and may be any one selected from hydrogen, (C1 ~ C4) alkyl, (C1 ~ C4) alkoxy, halogen, nitro, or a substituent represented by the following formula (2).

[Formula 2]

At this time, R ³ and R ⁴ may each be the same or different, and hydrogen, (C1 ~ C4) alkyl, (C1 ~ C4) alkoxy, trifluoromethyl, phenoxy, halogen, or any one selected from nitro, or R ³ and R ⁴ may be connected to each other to form a 5-ring heterocycle.

In the compound, R ¹ and R ² may be the same or different, respectively, and may be any one selected from hydrogen, (C1 ~ C2) alkoxy, halogen, or nitro.

More specifically, the compound is 3-(5-(2-phenylacetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3- (5-(2-(2-chlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2 -(3-chlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4-chloro) Phenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(3,4-dichlorophenyl)acetyl )-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(3-fluorophenyl)acetyl)-4, 5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4-bromophenyl)acetyl-4,5,6,7 -Tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4-methoxyphenyl)acetyl)-4,5,6,7-tetrahydrothia Zolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(3-methoxyphenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5, It may be any one selected from the group consisting of 4-c]pyridin-2-yl)propanoic acid.

In addition, the compound may be a compound represented by the following formula (3) or a pharmaceutically acceptable salt thereof.

[Formula 3]

In Formula 3, R ¹ and R ² may each be the same or different, and hydrogen, (C1 ~ C4) alkyl, (C1 ~ C4) alkoxy, trifluoromethyl, phenoxy, halogen, or any one selected from nitro, or , R ¹ and R ² may be connected to form a 5-ring heterocycle.

In the compound represented by Formula 3, R ¹ and R ² may each be the same or different, and hydrogen, (C1 ~ C4) alkyl, (C1 ~ C2) alkoxy, trifluoromethyl, phenoxy, fluoro, or chloro Any one selected from, or R ¹ and R ² may be linked to form a 1,3-dioxole ring.

More specifically, the compound is 3-(5-(2-(4'-methoxy-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydro Thiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(3'-methoxy-[1,1'-biphenyl]-4-yl)acetyl)- 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4'-phenoxy-[1,1'-bi Phenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(3'-) Fluoro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3- (5-(2-(4'-fluoro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine -2-yl)propanoic acid, 3-(5-(2-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7 -Tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4'-(trifluoromethyl)-[1,1'-biphenyl]- 4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4'-methyl-[ 1,1'-Biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-( 2-(4-(benzo[d][1,3]dioxol-5-yl)phenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2- Yl)propanoic acid, 3-(5-(2-(4'-chloro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5 It may be any one selected from the group consisting of ,4-c]pyridin-2-yl)propanoic acid.

The present invention provides a pharmaceutical composition for preventing or treating LPA1-related diseases, characterized in that it contains the compound or any one of its pharmaceutically acceptable salts as an active ingredient and has an effect of inhibiting LPA1 (Lysophosphatidic acid 1) receptor activation. do.

The LPA1-related disease may be any one selected from the group consisting of stroke, psoriasis, Sjogren's syndrome, inflammatory bowel disease, diabetic nephropathy, and fibrosis, but is not limited thereto.

The pharmaceutical composition according to the present invention can be prepared further comprising a suitable pharmaceutically acceptable carrier, excipient, or diluent according to the above formulation. The "pharmaceutically acceptable" means exhibiting properties that are not toxic to cells or humans exposed to the pharmaceutical composition.

Carriers, excipients or diluents usable in the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, Methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil.

The pharmaceutical compositions according to the present invention can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injectable solutions, respectively, according to conventional methods. have.

When the pharmaceutical composition according to the present invention is formulated in the above form, it can be prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like. These solid preparations include at least one excipient, such as starch, calcium carbonate, and sucrose. ) Or lactose (lactose), gelatin, etc. can be mixed to prepare.

In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral use include suspensions, liquid solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweetening agents, fragrances, and preservatives may be included. .

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogelatin, and the like may be used.

In the pharmaceutical composition according to the present invention, the pharmaceutical composition may be administered in a pharmaceutically effective amount. The "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and does not cause side effects, and the effective dose level is the patient's health condition, It can be determined by the type, severity, activity of the drug, sensitivity to the drug, the method of administration, time of administration, route of administration and rate of excretion, duration of treatment, factors including drugs used in combination or concurrently, and other factors well known in the medical field. .

The amount of the compound, which is the active ingredient of the pharmaceutical composition according to the present invention, may vary depending on the patient's age, sex, weight, and disease, but is 0.001 to 100 mg/kg, preferably 0.01 to 10 mg/kg, once to several times a day. Can be administered. In addition, the dosage of the compound according to the present invention may be increased or decreased depending on the route of administration, the degree of disease, sex, weight, age, and the like. Therefore, the above dosage does not limit the scope of the present invention in any way.

The pharmaceutical composition may be administered to mammals such as rats, mice, livestock, and humans by various routes. All modes of administration can be expected, for example, oral, rectal or intravenous, intramuscular, subcutaneous, intrabronchial inhalation, intrauterine dura mater or by intracere-broventricular injection.

The present invention provides a health functional food composition for improving or preventing LPA1-related diseases, characterized in that it contains the compound or a pharmaceutically acceptable salt thereof as an active ingredient and has an effect of inhibiting LPA1 (Lysophosphatidic acid 1) receptor activation. .

The LPA1-related disease may be any one selected from the group consisting of stroke, psoriasis, Sjogren's syndrome, inflammatory bowel disease, diabetic nephropathy, and fibrosis, but is not limited thereto.

The health functional food according to the present invention may be provided in the form of powder, granule, tablet, capsule, syrup or beverage, and the health functional food is used with other foods or food additives in addition to the compound according to the present invention, which is an active ingredient, It can be suitably used according to a conventional method. The mixing amount of the active ingredient may be appropriately determined according to the purpose of use thereof, for example, prevention, health or therapeutic treatment.

The effective dose of the compound contained in the health functional food according to the present invention can be used according to the effective dose of the pharmaceutical composition, but in the case of long-term intake for the purpose of health and hygiene or for the purpose of health control, the above It may be less than the range, and since there is no problem in terms of safety, the active ingredient may be used in an amount greater than the range.

There is no particular limitation on the type of health functional food according to the present invention, and examples include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, Beverages, teas, drinks, alcoholic beverages, and vitamin complexes.

The compound according to the present invention may be used in the form of a pharmaceutically acceptable salt, and the salt may be used in the form of either a pharmaceutically acceptable basic salt or an acidic salt.

The basic salt can be used in the form of either an organic base salt or an inorganic base salt, and sodium salt, potassium salt, calcium salt, lithium salt, magnesium salt, cesium salt, aminium salt, ammonium salt, triethyl salt It may be selected from the group consisting of an aminium salt and a pyridinium salt, but is not limited thereto.

Acidic salts are useful acid addition salts formed by free acids. Inorganic acids and organic acids can be used as the free acid, hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid, etc. can be used as inorganic acids, and citric acid, acetic acid, maleic acid, fumaric acid, glucolic acid, and methanesulfonic acid can be used as organic acids. , Benzenesulfonic acid, camphorsulfonic acid, oxalic acid, malonic acid, glutaric acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid, aspartic acid Etc. can be used. Preferably, hydrochloric acid is used as the inorganic acid and methanesulfonic acid is used as the organic acid.

In addition, the compound according to the present invention may include all salts, hydrates, and solvates that can be prepared by conventional methods, as well as pharmaceutically acceptable salts.

The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound represented by Chemical Formula 1 to Chemical Formula 3 in a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile. It can be prepared by precipitating or crystallizing after adding an excessive amount of organic base or an aqueous base solution of an inorganic base. Alternatively, the mixture may be prepared by evaporating a solvent or an excess base and drying to obtain an addition salt, or by suction filtration of the precipitated salt.

Hereinafter, examples will be described in detail to aid understanding of the present invention. However, the following examples are merely illustrative of the contents of the present invention, and the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more completely describe the present invention to those of ordinary skill in the art.

<Synthesis method>

All reagents required for synthesis were purchased from TCI, Sigma Aldrich, and Alfa Aesar with a purity of 97% or higher. Before performing the synthesis, after sufficiently washing the glassware to be used for the reaction with acetone, it was dried in an oven at 60° C. and the synthesis was carried out under a stream of nitrogen. Dichloromethane, tetrahydrofuran, methanol, acetone, toluene, diethyl ether, ethyl acetate, and hexane are largely purified. It was purchased from gold, and in the case of anhydrous solvent, it was purchased from Sigma Aldrich. In TLC, the progress of the reaction was confirmed using a UV lamp and color developing reagents AA, CAM, potassium permanganate (KMnO _{4 ), and ninhydrin.} For H NMR and C NMR spectra, a BRUKER Ascend 600 spectrometer and Varian VnmrS-400 were used, and CDCl3 and DMSO-d6 were used as solvents for analysis. Chemical shift values are expressed in ppm, and coupling constants (J) are expressed in Hz.

<Example 1>

Synthesis of Dihydrothiazolopyridine

[Scheme 1]

Scheme 1 is a process for synthesizing dihydrothiazolopyridine, which is a core parent nucleus according to the present invention, in the same manner as in Scheme 1, methyl 4-amino-4-oxobutanoate ) As a starting material, the synthesis of dihydrothiazolopyridine was carried out according to the following method.

<Example 1-1> Methyl 4-amino-4-thioxobutanoate

Methyl-4-amino-4-oxobutanoate (5g, 0.038mol) and Lawesson's reagent (6.15g, 0.015mol) were added to tetrahydrofuran (200ml) and stirred at room temperature for 1 hour. I did. After that, the solvent was removed and separated and purified through column chromatography to obtain compound 1 (4.4g, 80%).

Compound 1: ¹ H NMR (600 MHz, Chloroform-d) δ 7.52 (d, J = 58.7 Hz, 2H), 3.71 (s, 3H), 2.93-2.90 (m, 2H), 2.88 (dd, J = 5.6 , 1.2 Hz, 2H); ¹³ C NMR (151 MHz, Chloroform-d) δ 208.8, 173.8, 52.1, 39.1, 32.7.

<Example 1-2> Tert-butyl 2-(3-methoxy-3-oxopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-carboxylate [Tert -butyl 2-(3-methoxy-3-oxopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate]

Compound 1 (2.28 g, 0.015 mol) and tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (4.3 g, 0.015 mol) ) Was added to isopropanol (38ml) and refluxed for 1 hour. After cooling the compound at room temperature, extraction was performed through ethyl acetate and water was removed through magnesium sulfate. The filtrate was concentrated under reduced pressure, and then separated and purified through column chromatography to obtain compound 2 (2.9g, 60%).

Compound 2: ¹ H NMR (600 MHz, Chloroform-d) δ 4.58 (s, 2H), 3.75-3.71 (m, 2H), 3.71 (s, 3H), 3.27 (s, 2H), 2.82 (s, 4H ), 1.48 (s, 9H).

<Example 1-3> Synthesis of Core Intermediate Compound 3

After compound 2 (1.1g, 3.37mmol) was added to dichloromethane (19ml), trifluoroacetic acid (TFA, 6.3ml) was slowly added dropwise at 0°C. Then, it was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and then separated and purified through column chromatography to obtain compound 3 (1g, 99%).

Compound 3: ¹ H NMR (600 MHz, Chloroform-d) δ 4.47 (s, 2H), 3.71 (d, J = 2.7 Hz, 3H), 3.62 (t, J = 5.9 Hz, 2H), 3.39 (t, J = 7.0 Hz, 2H), 3.21 (d, J = 6.1 Hz, 2H), 2.85 (t, J = 7.1 Hz, 2H).

<Example 1-4> Amide coupling reaction (4a to 4i)

A mixture was prepared by adding amine (Amine, 146mg, 0.56mmol), acid (113.6mg, 0.67mmol), and triethylamine (Triethylamine; TEA, 0.14ml, 1.11mmol) to chloroform (2ml). To the resulting mixture, 4-dimethylaminopyridine (6.8mg, 0.055mmol), N,N'-dicyclohexylcarbodiamide (N,N'-dicyclohexylcarbodiamide, 114.5mg, 0.55mmol) was added and It was stirred at room temperature for 12 hours. After completion of the reaction, the product was extracted through dichloromethane. After removing water by adding magnesium sulfate to the extracted product, the filtrate was concentrated under reduced pressure and the next reaction was carried out without separation.

<Example 1-5> Hydrolysis (5a-5i)

A mixture was produced by adding ester (Ester, 116 mg, 0.3 mmol) to tetrahydrofuran (0.4 ml). Then, sodium hydroxide (24mg, 0.6mmol) dissolved in water (0.8ml) was added and stirred at room temperature for 12 hours. After completion of the reaction, 1-normal hydrochloric acid was added to neutralize it, and the product was extracted through dichloromethane. After removing water by adding magnesium sulfate to the extracted product, the filtrate was concentrated under reduced pressure and separated and purified through column chromatography to obtain compounds 5a-5i (100mg, 91%).

[Compound 5a~5i]

1) Compound 5a: 3-(5-(2-phenylacetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid [3-(5- (2-phenylacetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.31 (t, J = 7.5 Hz, 1H), 7.26 (dd, J = 6.7, 2.1 Hz, 2H), 7.22 (t, J = 7.2 Hz, 2H) , 4.75 (s, 0.5H), 4.67 (s, 1.5H), 3.83 (s, 1.5H), 3.80 (s, 0.5H), 3.79-3.76 (m, 2H), 3.11 (t, J = 7.2 Hz , 2H), 2.69 (s, 0.5H), 2.67 (t, J = 7.1 Hz, 2H), 2.62-2.59 (m, 1.5H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 175.7, 170.3, 167.5, 147.4, 134.5, 129.4, 128.9, 128.7, 128.6, 127.3, 127.1, 41.3, 41.0, 40.4, 33.4, 27.9, 27.1.

2) Compound 5b: 3-(5-(2-(2-chlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid [ 3-(5-(2-(2-chlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.42 (ddd, J = 6.6, 5.7, 3.6 Hz, 1H), 7.40-7.36 (m, 1H), 7.32-7.29 (m, 1H), 7.26 (s , 1H), 4.82 (s, 0.5H), 4.67 (d, J = 1.9 Hz, 1.5H), 3.94 (s, 1.5H), 3.87 (s, 0.5H), 3.84 (s, 1.5H), 3.79 (s, 0.5H), 3.12 (d, J = 8.2 Hz, 2H), 2.80 (s, 1.5H), 2.71-2.69 (m, 0.5H), 2.67 (d, J = 6.8 Hz, 2H); ¹³ C NMR (151 MHz, DMSO) δ 173.6, 168.6, 167.4, 148.2, 134.2, 129.5, 129.4, 129.2, 128.9, 127.6, 127.5, 39.2, 38.4, 37.9, 33.4, 28.4, 27.6.

3) Compound 5c: 3-(5-(2-(3-chlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid [ 3-(5-(2-(3-chlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.34 (dd, J = 4.9, 2.7 Hz, 1H), 7.33-7.30 (m, 1H), 7.30-7.26 (m, 1H), 7.23-7.16 (m , 1H), 4.77 (s, 0.5H), 4.67 (d, J = 1.9 Hz, 1.5H), 3.87 (s, 1.5H), 3.81 (s, 0.5H), 3.83-3.77 (m, 2H), 3.12 (q, J = 7.0 Hz, 2H), 2.74-2.69 (m, 2H), 2.69-2.65 (m, 2H); ¹³ C NMR (151 MHz, DMSO) δ 173.6, 169.4, 167.4, 148.1, 138.8, 133.2, 130.5, 129.7, 128.5, 126.9, 125.1, 55.4, 43.4, 39.3, 33.4, 28.4, 27.6, 26.7.

4) Compound 5d: 3-(5-(2-(4-chlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid [ 3-(5-(2-(4-chlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

¹ H NMR (600 MHz, Chloroform-d) δ 7.31-7.24 (m, 2H), 7.21-7.12 (m, 2H), 4.76 (d, J = 2.0 Hz, 1.5H), 4.57 (s, 0.5H) , 3.92 (s, 0.5H), 3.79 (s, 1.5H), 3.73 (s, 1.5H), 3.25 (t, J = 7.2 Hz, 0.5H), 2.85 (t, J = 1.7 Hz, 0.5H) , 2.80 (t, J = 7.2 Hz, 2H), 2.71 (s, 1.5H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 174.9, 169.8, 167.8, 147.3, 133.0, 130.1, 130.1, 129.0, 129.0, 128.9, 125.1, 43.7, 40.5, 40.3, 33.5, 28.1, 27.2.

5) Compound 5e: 3-(5-(2-(3,4-dichlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propane Acid [3-(5-(2-(3,4-dichlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

¹ H NMR (600 MHz, Chloroform-d) δ 7.43-7.35 (m, 2H), 7.11 (dd, J = 8.3, 2.1 Hz, 1H), 4.78 (t, J = 1.8 Hz, 1.5H), 4.60 ( d, J = 1.9 Hz, 0.5H), 3.94 (s, 0.5H), 3.78 (s, 1.5H), 3.77-3.73 (m, 1.5H), 3.60 (s, 0.5H), 3.27 (t, J = 7.2 Hz, 2H), 2.89-2.86 (m, 0.5H), 2.84 (t, J = 7.2 Hz, 2H), 2.80 (s, 1.5H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 175.8, 169.2, 167.8, 147.2, 134.6, 132.8, 131.4, 130.9, 130.7, 128.3, 125.1, 43.7, 40.6, 39.8, 33.4, 27.9, 27.2.

6) Compound 5f: 3-(5-(2-(3-fluorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(3-fluorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

¹ H NMR (600 MHz, Chloroform-d) δ 7.30 (d, J = 6.0 Hz, 1H), 7.06-7.02 (m, 1H), 6.99 (td, J = 6.7, 6.1, 2.0 Hz, 1H), 6.96 -6.92 (m, 1H), 4.79 (d, J = 1.8 Hz, 1.5H), 4.59 (s, 0.5H), 3.94 (s, 0.5H), 3.83 (s, 1.5H), 3.79 (s, 0.5 H), 3.75 (s, 1.5H), 3.26 (s, 2H), 2.89-2.86 (m, 0.5H), 2.85 (d, J = 6.8 Hz, 2H), 2.72 (s, 1.5H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 169.6, 167.7, 163.8, 162.2, 147.2, 136.9, 130.4, 125.2, 124.4, 115.7, 114.1, 43.7, 40.8, 40.5, 33.4, 27.9, 27.2.

7) Compound 5g: 3-(5-(2-(4-bromophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(4-bromophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.48 (dd, J = 19.9, 8.2 Hz, 2H), 7.20 (dd, J = 26.0, 8.1 Hz, 2H), 4.75 (s, 0.5H), 4.66 (s, 1.5H), 3.83 (s, 1.5H), 3.81-3.78 (m, 2H), 3.77 (s, 0.5H), 3.12 (q, J = 7.4 Hz, 2H), 2.71-2.68 (m, 2H), 2.67 (d, J = 7.2 Hz, 2H); ¹³ C NMR (151 MHz, DMSO) δ 173.6, 169.5, 167.4, 148.1, 135.8, 132.0, 131.6, 131.6, 125.1, 124.8, 120.1, 43.4, 39.2, 33.4, 28.4, 27.6, 26.7.

8) Compound 5h: 3-(5-(2-(4-methoxyphenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(4-methoxyphenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

¹ H NMR (600 MHz, Chloroform-d) δ 7.14 (dd, J = 33.8, 8.5 Hz, 2H), 6.83 (dd, J = 20.8, 8.6 Hz, 2H), 4.77 (t, J = 1.8 Hz, 1.5 H), 4.57 (d, J = 1.9 Hz, 0.5H), 3.92 (s, 0.5H), 3.78 (s, 3H), 3.77 (s, 1.5H), 3.73 (s, 2H), 3.25 (s, 2H), 2.85 (d, J = 5.8 Hz, 1H), 2.81 (s, 2H), 2.66 (s, 1.5H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 175.4, 170.8, 167.8, 158.6, 147.4, 129.6, 129.6, 126.4, 125.2, 114.3, 114.3, 55.3, 43.7, 40.4, 40.4, 33.5, 28.0, 27.1.

9) Compound 5i: 3-(5-(2-(3-methoxyphenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(3-methoxyphenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

¹ H NMR (600 MHz, Chloroform-d) δ 7.26-7.17 (m, 1H), 6.84 (d, J = 7.7 Hz, 1H), 6.81 (d, J = 1.8 Hz, 1H), 6.80-6.73 (m , 1H), 4.78 (d, J = 2.0 Hz, 1.5H), 4.56 (s, 0.5H), 3.93 (s, 0.5H), 3.81 (s, 1.5H), 3.78 (s, 3H), 3.74 ( s, 2H), 3.25 (d, J = 7.2 Hz, 2H), 2.87 (s, 0.5H), 2.82 (s, 2H), 2.67 (s, 1.5H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 175.2, 170.2, 167.6, 156.0, 147.4, 136.0, 129.9, 125.2, 120.9, 114.3, 112.5, 55.3, 43.8, 41.3, 40.4, 33.5, 28.0, 27.1.

<Example 2> Synthesis of biphenylacetic acid derivative

<Example 2-1> Biphenylacetic acid synthesis (6a to 6j)

In order to synthesize a biphenylacetic acid derivative, biphenylacetic acid was first synthesized in the same manner as in Scheme 2 below.

[Scheme 2]

In methanol (2.5 ml), 4-Bromophenylacetic acid (4-Bromophenylacetic acid, 500 mg, 2.325 mmol), 4-methylphenylboronic acid (340 mg, 4.65 mmol), cesium carbonate (1.5 g, 4.6 mmol) was added to give a mixture. Thereafter, a palladium catalyst (2.5 mg) was added and refluxed for one day. After completion of the reaction, the temperature of the mixture was brought close to room temperature, neutralized with 1 normal hydrochloric acid, and the product was extracted through dichloromethane. After removing water by adding magnesium sulfate to the extracted product, the filtrate was concentrated under reduced pressure and separated and purified through column chromatography to obtain compounds 6a-6j (470mg, 95%).

[Compound 6a~6j]

1) Compound 6a: 2-(4'-methoxy-[1,1'-biphenyl]-4-yl)acetic acid [2-(4'-methoxy-[1,1'-biphenyl]-4-yl) )acetic acid]

¹ H NMR (600 MHz, Methanol-d4) δ 7.52 (m, 4H), 7.32 (m, 2H), 6.98 (m, 2H), 3.82 (s, 3H), 3.62 (s, 2H).

2) Compound 6b: 2-(3'-methoxy-[1,1'-biphenyl]-4-yl)acetic acid [2-(3'-methoxy-[1,1'-biphenyl]-4-yl) )acetic acid]

¹ H NMR (600 MHz, Methanol-d4) δ 7.54 (d, J = 8.1 Hz, 2H), 7.33 (dd, J = 17.4, 8.2 Hz, 3H), 7.16 (d, J = 7.0 Hz, 1H), 7.12 (m, 1H), 6.88 (ddd, J = 8.2, 2.5, 1.0 Hz, 1H), 3.82 (s, 3H), 3.63 (s, 2H).

3) Compound 6c: 2-(4'-phenoxy-[1,1'-biphenyl]-4-yl)acetic acid [2-(4'-phenoxy-[1,1'-biphenyl]-4-yl) )acetic acid]

¹ H NMR (600 MHz, Methanol-d4) δ 7.60 (m, 2H), 7.55 (m, 2H), 7.36 (m, 4H), 7.12 (m, 1H), 7.03 (m, 4H), 3.64 (s , 2H).

4) Compound 6d: 2-(3'-fluoro-[1,1'-biphenyl]-4-yl)acetic acid [2-(3'-fluoro-[1,1'-biphenyl]-4-yl) )acetic acid]

¹ H NMR (600 MHz, Methanol-d4) δ 7.57 (m, 2H), 7.42 (m, 2H), 7.35 (m, 4H), 3.65 (s, 2H).

5) Compound 6e: 2-(4'-fluoro-[1,1'-biphenyl]-4-yl)acetic acid [2-(4'-fluoro-[1,1'-biphenyl]-4-yl) )acetic acid]

¹ H NMR (600 MHz, Methanol-d4) δ 7.61 (m, 2H), 7.54 (m, 2H), 7.36 (m, 2H), 7.15 (m, 2H), 3.64 (s, 2H).

6) Compound 6f: 2-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)acetic acid [2-(4'-(tert-butyl)-[1,1') -biphenyl]-4-yl)acetic acid]

¹ H NMR (600 MHz, Methanol-d4) δ 7.54 (m, 4H), 7.45 (d, J = 8.6 Hz, 2H), 7.33 (m, 2H), 3.63 (s, 2H), 1.34 (s, 9H) ).

7) Compound 6g: 2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)acetic acid [2-(4'-(trifluoromethyl)-[1,1'-) biphenyl]-4-yl)acetic acid]

¹ H NMR (600 MHz, Methanol-d4) δ 7.80 (m, 2H), 7.72 (m, 2H), 7.64 (m, 2H), 7.41 (m, 2H), 3.67 (s, 2H).

8) Compound 6h: 2-(4'-(methyl)-[1,1'-biphenyl]-4-yl)acetic acid [2-(4'-methyl-[1,1'-biphenyl]-4- yl)acetic acid]

¹ H NMR (600 MHz, Methanol-d4) δ 7.54 (m, 2H), 7.48 (m, 2H), 7.33 (m, 2H), 7.23 (m, 2H), 3.63 (s, 2H), 2.36 (s , 3H).

9) Compound 6i: 2-(4-(benzo[d][1,3]dioxol-5-yl)phenyl)acetic acid [2-(4-(benzo[d][1,3]dioxol-5- yl)phenyl)acetic acid]

¹ H NMR (600 MHz, Methanol-d4) δ 7.49 (m, 2H), 7.32 (m, 2H), 7.08 (m, 2H), 6.87 (m, 1H), 5.97 (s, 2H), 3.62 (s , 2H).

10) Compound 6j: 2-(4'-chloro-[1,1'-biphenyl]-4-yl)acetic acid [2-(4'-chloro-[1,1'-biphenyl]-4-yl) acetic acid]

¹ H NMR (600 MHz, Methanol-d4) δ 7.57 (dd, J = 18.5, 8.4 Hz, 4H), 7.42 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 3.64 (s, 2H).

<Example 2-2> Synthesis of biphenylacetic acid derivative

[Scheme 3]

In the same manner as in Scheme 3, the core intermediate compound 3 synthesized in Example 1 and the synthesized compounds 6a to 6j were synthesized using the amide coupling reaction of Example 1-4, and compounds 7a to 7j were synthesized, Compounds 8a to 8j were synthesized using the hydrolysis of Example 1-5.

[Compound 8a~8j]

1) Compound 8a: 3-(5-(2-(4'-methoxy-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[ 5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(4'-methoxy-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6 ,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

¹ H NMR (600 MHz, Chloroform-d) δ 7.55 (d, J = 8.2 Hz, 2H), 7.36-7.31 (m, 2H), 7.28 (s, 1H), 7.18-7.13 (m, 1H), 7.10 (dd, J = 2.6, 1.7 Hz, 1H), 6.89 (dd, J = 8.2, 1.0 Hz, 1H), 4.80 (d, J = 1.8 Hz, 1.5H), 4.61 (s, 0.5H), 3.95 ( s, 0.5H), 3.87 (s, 1.5H), 3.86 (d, J = 2.6 Hz, 3H), 3.84 (s, 0.5H), 3.78 (s, 1.5H), 3.25 (d, J = 7.1 Hz , 2H), 2.88 (s, 0.5H), 2.82 (d, J = 7.0 Hz, 2H), 2.72 (s, 1.5H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 175.2, 170.2, 167.6, 159.9, 147.4, 142.1, 139.9, 133.7, 129.8, 129.0, 129.0, 127.6, 127.6, 125.3, 119.6, 112.8, 55.3, 43.8, 40.8, 40.4 , 33.4, 28.0, 27.2.

2) Compound 8b: 3-(5-(2-(3'-methoxy-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[ 5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(3'-methoxy-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6 ,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

¹ H NMR (600 MHz, Chloroform-d) δ 7.53-7.49 (m, 3H), 7.49-7.44 (m, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.26 (s, 1H), 7.04 -6.94 (m, 2H), 4.79 (s, 1.5H), 4.60 (s, 0.5H), 3.94 (s, 0.5H), 3.86 (s, 1.5H), 3.84 (d, J = 2.8 Hz, 3H ), 3.82 (s, 0.5H), 3.77 (t, J = 5.8 Hz, 1.5H), 3.24 (d, J = 7.2 Hz, 2H), 2.87 (s, 0.5H), 2.81 (t, J = 7.1 Hz, 2H), 2.71 (s, 1.5H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 175.2, 170.3, 167.7, 159.2, 147.4, 139.6, 133.1, 132.9, 129.0, 129.0, 128.0, 128.0, 127.3, 127.1, 127.1, 125.2, 114.2, 55.4, 43.8, 40.8 , 40.4, 33.5, 28.0, 27.2.

3) Compound 8c: 3-(5-(2-(4'-phenoxy-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[ 5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(4'-phenoxy-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6 ,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

¹ H NMR (600 MHz, Chloroform-d) δ 7.53 (dd, J = 6.5, 4.5 Hz, 2H), 7.52-7.49 (m, 1H), 7.39-7.31 (m, 3H), 7.27 (s, 3H) , 7.13 (s, 1H), 7.09-7.04 (m, 3H), 4.81 (s, 1.5H), 4.62 (s, 0.5H), 3.96 (s, 0.5H), 3.87 (s, 1.5H), 3.83 (s, 0.5H), 3.79 (s, 1.5H), 3.26 (s, 2H), 2.93 (d, J = 43.9 Hz, 2H), 2.84 (s, 1H), 2.72 (s, 1H);

4) Compound 8d: 3-(5-(2-(3'-fluoro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[ 5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(3'-fluoro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6 ,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

¹ H NMR (600 MHz, Chloroform-d) δ 7.56-7.49 (m, 2H), 7.41-7.37 (m, 1H), 7.36-7.33 (m, 2H), 7.32-7.25 (m, 2H), 7.05- 7.00 (m, 1H), 4.80 (t, J = 1.8 Hz, 1.5H), 4.61 (d, J = 1.8 Hz, 0.5H), 3.96 (s, 0.5H), 3.88 (s, 1.5H), 3.84 (s, 0.5H), 3.78 (t, J = 5.8 Hz, 1.5H), 3.25 (d, J = 7.1 Hz, 2H), 2.90-2.86 (m, 0.5H), 2.83 (s, 2H), 2.73 (s, 1.5H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 170.1, 167.7, 164.0, 162.4, 147.3, 138.7, 134.2, 130.3, 130.2, 129.2, 129.2, 127.5, 127.5, 125.2, 122.7, 122.7, 114.1, 43.8, 40.8, 40.5 , 33.5, 28.0, 27.2.

5) Compound 8e: 3-(5-(2-(4'-fluoro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[ 5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(4'-fluoro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6 ,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

¹ H NMR (600 MHz, Chloroform-d) δ 7.54-7.51 (m, 2H), 7.50 (s, 1.5H), 7.47 (d, J = 7.9 Hz, 0.5H), 7.33 (d, J = 8.1 Hz , 1.5H), 7.28 (s, 0.5H), 7.14-7.08 (m, 2H), 4.80 (d, J = 1.8 Hz, 1.5H), 4.62 (s, 0.5H), 3.96 (s, 0.5H) , 3.87 (s, 1.5H), 3.83 (s, 0.5H), 3.78 (s, 1.5H), 3.25 (d, J = 6.9 Hz, 2H), 2.90-2.87 (m, 0.5H), 2.82 (d , J = 6.9 Hz, 2H), 2.72 (s, 1.5H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 175.1, 170.1, 167.6, 163.3, 147.4, 139.1, 136.7, 133.6, 129.2, 129.1, 128.6, 128.6, 128.5, 127.5, 127.4, 115.7, 115.6, 43.8, 40.8, 40.4 , 33.5, 28.0, 27.2.

6) Compound 8f: 3-(5-(2-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydro Thiazolo[5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)acetyl )-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

¹ H NMR (600 MHz, Chloroform-d) δ 7.56 (d, J = 8.2 Hz, 2H), 7.51 (s, 2H), 7.48-7.44 (m, 2H), 7.32 (d, J = 8.1 Hz, 1.5 H), 7.27 (s, 0.5H), 4.80 (d, J = 1.8 Hz, 1.5H), 4.61 (s, 0.5H), 3.95 (s, 0.5H), 3.87 (s, 1.5H), 3.83 ( s,0.51H), 3.78 (s, 1.5H), 3.26 (s, 2H), 2.88 (s, 0.5H), 2.82 (d, J = 7.0 Hz, 2H), 2.72 (s, 1.5H), 1.36 (s, 9H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 175.4, 170.3, 167.7, 150.4, 147.4, 139.9, 137.7, 133.2, 129.0, 129.0, 129.0, 127.4, 127.4, 126.7, 126.6, 125.8, 125.2, 43.8, 40.8, 40.5 , 34.6, 33.5, 31.4, 28.0, 27.2.

7) Compound 8g: 3-(5-(2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetra Hydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)acetyl) -4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

¹ H NMR (600 MHz, Chloroform-d) δ 7.70-7.64 (m, 4H), 7.55 (dd, J = 21.9, 8.1 Hz, 2H), 7.35 (dd, J = 33.4, 8.0 Hz, 2H), 4.81 (d, J = 1.8 Hz, 1.5H), 4.63 (s, 0.5H), 3.96 (s, 0.5H), 3.89 (s, 1.5H), 3.85 (s, 0.5H), 3.79 (t, J = 5.8 Hz, 1.5H), 3.26 (t, J = 7.1 Hz, 2H), 2.88 (s, 0.5H), 2.83 (t, J = 7.0 Hz, 2H), 2.75 (s, 1.5H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 175.3, 170.0, 167.6, 147.3, 144.1, 138.5, 134.6, 129.4, 129.3, 127.7, 127.6, 127.3, 127.3, 125.8, 125.7, 125.7, 125.2, 125.2, 43.8, 40.7 , 40.5, 33.5, 28.0, 27.2.

8) Compound 8h: 3-(5-(2-(4'-methyl-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5 ,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(4'-methyl-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6, 7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

¹ H NMR (600 MHz, Chloroform-d) δ 7.54 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz, 1.5H), 7.26 (s, 0.5H), 7.23 (d, J = 8.0 Hz, 2H), 4.80 (d, J = 1.8 Hz, 1.5H), 4.60 (s, 0.5H), 3.95 (s, 0.5H), 3.86 ( s, 1.5H), 3.83 (s, 0.5H), 3.77 (t, J = 5.7 Hz, 1.5H), 3.24 (dt, J = 15.3, 7.1 Hz, 2H), 2.87 (s, 0.5H), 2.84 -2.78 (m, 2H), 2.74-2.69 (m, 1.5H), 2.39 (s, 3H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 175.2, 170.2, 170.1, 167.6, 147.4, 139.9, 137.7, 137.1, 133.2, 129.5, 129.0, 129.0, 127.4, 127.3, 126.9, 126.8, 125.2, 43.8, 40.8, 40.4 , 33.5, 28.0, 27.2, 21.1.

9) Compound 8i: 3-(5-(2-(4-(benzo[d][1,3]dioxol-5-yl)phenyl)acetyl)-4,5,6,7-tetrahydrothiazolo [5,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(4-(benzo[d][1,3]dioxol-5-yl)phenyl)acetyl)-4, 5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

¹ H NMR (600 MHz, Chloroform-d) δ 7.49-7.42 (m, 2H), 7.32-7.24 (m, 2H), 7.05-7.00 (m, 2H), 6.88-6.85 (m, 1H), 5.99 ( s, 2H), 4.80 (d, J = 1.8 Hz, 1.5H), 4.60 (s, 0.5H), 3.95 (s, 0.5H), 3.86 (s, 1.5H), 3.82 (s, 0.5H), 3.77 (t, J = 5.8 Hz, 1.5H), 3.25 (d, J = 6.9 Hz, 2H), 2.87 (s, 0.5H), 2.82 (t, J = 7.3 Hz, 2H), 2.72 (td, J = 5.6, 2.7 Hz, 1.5H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 175.2, 170.2, 167.6, 148.1, 147.4, 147.1, 139.7, 135.0, 133.2, 129.0, 129.0, 127.3, 127.2, 125.2, 120.5, 108.6, 107.5, 101.2, 43.8, 40.8 , 40.4, 33.5, 28.0, 27.2.

10) Compound 8j: 3-(5-(2-(4'-chloro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5 ,4-c]pyridin-2-yl)propanoic acid [3-(5-(2-(4'-chloro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6, 7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid]

¹ H NMR (600 MHz, Chloroform-d) δ 7.53? 7.49 (m, 2H), 7.48 (d, J = 9.5 Hz, 2H), 7.41-7.37 (m, 2H), 7.34 (d, J = 8.1 Hz, 1.5H), 7.28 (d, J = 8.1 Hz, 0.5H), 4.80 (d, J = 1.8 Hz, 1.5H), 4.61 (s, 0.5H), 3.95 (s, 0.5H), 3.87 (s, 1.5H), 3.83 (s, 0.5H), 3.78 (s, 1.5H), 3.25 (d, J = 7.1 Hz, 2H), 2.87 (s, 0.5H), 2.81 (d, J = 7.3 Hz, 2H), 2.73 (s, 1.5H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 175.4, 170.1, 167.7, 147.3, 139.0, 138.8, 134.0, 133.5, 129.2, 129.2, 129.0, 128.3, 128.2, 127.4, 127.4, 125.2, 43.8, 40.7, 40.5,

<Experimental Example 1> Calcium assay

The LPA1 overexpressing cell line (RH7777-human EDG1 cell) ^{was seeded at 1×10 5} /well in a 96 well black plate (clear bottom) and cultured for one day. Then, it was replaced with a serum-free culture solution containing 0.1% fatty acid-free BSA (fatty acid-free BSA) and cultured for an additional day.

Next, pretreatment with drugs (compounds 5a-5i, 6a-6j or AM152 (LPA1 antagonist), 1 μM) for 30 minutes, followed by treatment with Fluo-3AM (5 μM), a fluorescent dye for calcium measurement. After incubation for 60 minutes, the cells were treated with 10 μM LPA, and fluorescence intensity was measured (absorption: 506 nm) 1 minute later. (Fluorescence intensity: 3rd floor victor used)

1 is a graph showing a calcium analysis result according to an experimental example of the present invention. ^{The'Ca 2+} response' in the graph represents a fold increase compared to a vehicle.

Referring to FIG. 1, it was confirmed that compound 6c exhibited almost similar efficacy to AM152 (1 μM), and other compounds showed about 50% efficacy compared to AM152 (1 μM) efficacy.

<Experimental Example 2> Toxicity evaluation

To male Balb/c mice, compound 5a, compound 5g, and compound 5h were each suspended in 0.5% methylcellulose solution and orally administered once at a dose of 0.5g/kg, 1g/kg and 2g/kg. Survival rate and body weight were investigated.

After these administrations, mortality, clinical symptoms, and weight change were observed, hematologic and hematologic tests were performed, and abnormalities of the abdominal and thoracic organs were observed visually by autopsy.

As a result, there were no significant clinical symptoms or deceased animals in all animals, and no toxic changes were observed in weight change, blood test, blood biochemical test, and autopsy findings.

As a result of the above, the compounds of the present invention did not show a toxic change up to 2g/kg in mice, and therefore, the intermediate lethal dose (LD50) of oral administration was determined to be a safe substance with 2g/kg or more.

Hereinafter, an example of the preparation of the composition containing the compound 5h according to the present invention will be described, but the present invention is not intended to limit it, but is intended to be described in detail.

<Prescription Example 1> Formulation example of pharmaceutical composition

<Prescription Example 1-1> Preparation of powder

Compound 5h 20 mg, lactose 100 mg, and talc 10 mg were mixed and filled in an airtight bag to prepare a powder.

<Prescription Example 1-2> Preparation of tablets

After mixing 20 mg of compound 5h, 100 mg of corn starch, 100 mg of lactose, and 2 mg of magnesium stearate, tablets were prepared by tableting according to a conventional tablet preparation method.

<Prescription Example 1-3> Preparation of capsules

After mixing 10 mg of compound 5h, 100 mg of corn starch, 100 mg of lactose, and 2 mg of magnesium stearate, the above ingredients were mixed according to a conventional capsule preparation method, and then filled into a gelatin capsule to prepare a capsule.

<Prescription Example 1-4> Preparation of injection

After mixing 10 mg of compound 5h, an appropriate amount of sterile distilled water for injection, and an appropriate amount of a pH adjuster, it was prepared with the above component content per ampoule (2 ml) according to a conventional preparation method for injection.

<Prescription Example 1-5> Preparation of ointment

Compound 5h 10mg, PEG-4000 250mg, PEG-400 650mg, white petrolatum 10mg, paraoxybenzoate methyl 1.44mg, paraoxybenzoate 0.18mg and the remaining amount of purified water are mixed to prepare an ointment according to a conventional ointment preparation method. I did.

<Prescription Example 2> Health functional food

<Prescription Example 2-1> Preparation of health food

Compound 5h 1 mg, vitamin mixture appropriate amount (vitamin A acetate 70 μg, vitamin E 1.0 mg, vitamin B 1 0.13 mg, vitamin B 2 0.15 mg, vitamin B 6 0.5 mg, vitamin B 12 0.2 μg, vitamin C 10 mg, biotin 10 μg, nicotinic acid amide 1.7 mg, folic acid 50 μg, calcium pantothenate 0.5 mg) and an appropriate amount of inorganic mixture (ferrous sulfate 1.75 mg, zinc oxide 0.82 mg, magnesium carbonate 25.3 mg, potassium monophosphate 15 mg, dibasic calcium phosphate) 55 mg, potassium citrate 90 mg, calcium carbonate 100 mg, magnesium chloride 24.8 mg) were mixed, and then granules were prepared and health food was prepared according to a conventional method.

<Prescription Example 2-2> Preparation of health drink

Add 1 mg of compound 5h, 1000 mg of citric acid, 100 g of oligosaccharide, 2 g of plum concentrate, 1 g of taurine and purified water to make a total of 900 ml. After mixing the above ingredients according to the general health drink manufacturing method, about 1 After stirring and heating at 85° C. for an hour, the resulting solution was filtered and obtained in a sterilized 2 L container, sealed and sterilized, and then stored in a refrigerator.

As described above, a specific part of the present invention has been described in detail, and for those of ordinary skill in the art, it is obvious that this specific description is only a preferred embodiment, and the scope of the present invention is not limited thereby. Do. That is, the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims (10)

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

In the above formula, R ¹ and R ² may each be the same or different, and are selected from hydrogen, (C1 ~ C4) alkyl, (C1 ~ C4) alkoxy, halogen, nitro, or a substituent of the following formula (2),
[Formula 2]

At this time, R ³ and R ⁴ may be the same or different, respectively, and selected from hydrogen, (C1 ~ C4) alkyl, (C1 ~ C4) alkoxy, trifluoromethyl, phenoxy, halogen or nitro, or R ³ and R ⁴ is connected to form a 5-ring heterocycle. The method according to claim 1,
In the compound, R ¹ and R ² may be the same or different, respectively, and hydrogen, (C1 ~ C2) alkoxy, halogen, or nitro, a compound or a pharmaceutically acceptable salt thereof. The method according to claim 2,
The compound is 3-(5-(2-phenylacetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2 -(2-chlorophenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(3-chloro) Phenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4-chlorophenyl)acetyl)- 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(3,4-dichlorophenyl)acetyl)-4,5 ,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(3-fluorophenyl)acetyl)-4,5,6,7 -Tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4-bromophenyl)acetyl-4,5,6,7-tetrahydrothiazolo [5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4-methoxyphenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4 -c]pyridin-2-yl)propanoic acid, 3-(5-(2-(3-methoxyphenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine A compound or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of -2-yl) propanoic acid. The method according to claim 1,
The compound is characterized in that the compound represented by the following formula (3), a compound or a pharmaceutically acceptable salt thereof:
[Formula 3]

In the above formula, R ¹ and R ² may each be the same or different, and are selected from hydrogen, (C1 ~ C4) alkyl, (C1 ~ C4) alkoxy, trifluoromethyl, phenoxy, halogen or nitro, or R ¹ and R ² is connected to form a 5-ring heterocycle. The method of claim 4,
In the compound, R ¹ and R ² may be the same or different, respectively, and selected from hydrogen, (C1∼C4)alkyl, (C1∼C2)alkoxy, trifluoromethyl, phenoxy, fluoro, or chloro, or R ^A compound or a pharmaceutically acceptable salt thereof, characterized in that 1 and R ^{2 are linked to form a 1,3-dioxole ring.} The method of claim 4,
The compound is 3-(5-(2-(4'-methoxy-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5, 4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(3'-methoxy-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6 ,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4'-phenoxy-[1,1'-biphenyl]-4- Yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(3'-fluoro-[1) ,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2) -(4'-fluoro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl) Propanoic acid, 3-(5-(2-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo [5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)acetyl )-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4'-methyl-[1,1'-) Biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4- (Benzo[d][1,3]dioxol-5-yl)phenyl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)propanoic acid, 3-(5-(2-(4'-chloro-[1,1'-biphenyl]-4-yl)acetyl)-4,5,6,7-tetrahydrothiazolo[5,4-c] A compound or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of pyridin-2-yl) propanoic acid. A pharmaceutical for preventing or treating LPA1-related diseases, characterized in that it contains the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient, and has an effect of inhibiting LPA1 (Lysophosphatidic acid 1) receptor activation. As a composition,
The LPA1-related diseases are stroke, psoriasis, Sjogren's syndrome, inflammatory bowel disease, diabetic nephropathy and fibrosis, characterized in that selected from the group consisting of, LPA1-related disease prevention or treatment pharmaceutical composition. delete It contains the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient, and has an effect of inhibiting LPA1 (Lysophosphatidic acid 1) receptor activation, LPA1-related disease improvement or prevention health As a nutraceutical composition,
The LPA1-related diseases are stroke, psoriasis, Sjogren's syndrome, inflammatory bowel disease, diabetic nephropathy and fibrosis, characterized in that selected from the group consisting of, LPA1-related disease improvement or prevention health functional food composition. delete

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