阅读说明：本技术 代谢性疾病的预防或治疗用复合制剂 (Compound preparation for preventing or treating metabolic diseases ) 是由 梁镇 金镇雄 李汉奎 金在贤 孙昌模 李揆焕 崔亨豪 金大训 河兑妗 李在杰 于 2015-10-16 设计创作，主要内容包括：本发明涉及可通过选择新型3-(4-(苄氧基)苯基)-4-己烯酸衍生物和由二肽基肽酶4(Dipeptidyl peptidas e-4,DPPIV)抑制剂类、磺脲(Sulfonylurea)类、噻唑烷二酮(Thiazolidinediones,TZD)类、双胍(Biguanide)类及钠-葡萄糖协同转运蛋白2(sodium/glucose cotransporter 2)抑制剂类药物组成的组中至少一种其它有效成分来以并用或复合剂形态给药的预防或治疗代谢性疾病的药学组合物。可通过利用本发明的组合物来从各种动物糖尿病疾病模型中获得明显优秀的血糖下降效果,从而可有用地适用于针对肥胖、Ⅰ型糖尿病、II型糖尿病、糖耐量减低、胰岛素抵抗综合征、高血糖症、高血脂症、高甘油三酯血症、血胆固醇过多症、异常血脂症、X综合征等的代谢性疾病的预防或治疗用药学组合物。(The present invention relates to a pharmaceutical composition for preventing or treating metabolic diseases, which can be administered in combination or complex form by selecting a novel 3- (4- (benzyloxy) phenyl) -4-hexenoic acid derivative and at least one other active ingredient from the group consisting of Dipeptidyl peptidase 4 (DPPIV) inhibitors, sulphonylurea (sulfourea) inhibitors, Thiazolidinediones (TZDs), biguanides (biguanidines) inhibitors and sodium/glucose cotransporter 2(sodium/glucose cotransporter 2) inhibitors. The composition of the present invention can be used to obtain a remarkably excellent blood glucose lowering effect from various animal diabetic disease models, and thus can be usefully applied to a pharmaceutical composition for the prevention or treatment of metabolic diseases such as obesity, type i diabetes, type II diabetes, impaired glucose tolerance, insulin resistance syndrome, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia and syndrome X.)

1. Use of a composition for the manufacture of a medicament for the prevention or treatment of a metabolic disease, wherein the composition comprises:

(a) a compound represented by chemical formula 1, an optical isomer, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, and

(b) one or more compounds selected from the group consisting of dipeptidyl peptidase 4 inhibitors, sulfonylureas, thiazolidinediones, biguanides, and sodium-glucose cotransporter 2 inhibitors as the second active substance:

chemical formula 1:

in the above-described chemical formula 1,

is a single bond or a double bond;

a and E are independently C or N;

n is an integer of 0 to 1;

x is a single bond or C_1-3A linear or branched alkylene group;

R¹is-H or

R²is-H;

R³is-H, or

R³And R^4AAnd together with the atoms to which they are attached form a phenyl group, and the phenyl group can be substituted with a methoxy group;

R^4Ais-H, -OH, ═ O, Or

R³And R^4AAnd together with the atoms to which they are attached form a phenyl group, and the phenyl group can be substituted by a methoxy group, or

R^4BIs absent; and is

R⁵is-H.

2. The use according to claim 1, wherein the compound represented by the above chemical formula 1 is one selected from the following group of compounds:

(1)3- (4- (3- (4-oxocyclohex-1-enyl) benzyloxy) phenyl) hex-4-enoic acid;

(2)3- (4- (3- (4-hydroxycyclohex-1-enyl) benzyloxy) phenyl) hex-4-enoic acid;

(3)3- (4- (3- (4-hydroxycyclohex-1-enyl) benzyloxy) phenyl) hex-4-enoic acid L-lysine salt;

(4)3- (4- (4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(5)3- (4- (3-cyclohexenyl-4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(6)3- (4- (4- ((4-phenyl-5, 6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(7)3- (4- (4- ((4-phenylpiperazin-1-yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(8)3- (4- (4- ((6-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(9)3- (4- (4- ((4-phenylpiperidin-1-yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(10)3- (4- (4- ((4- (4-fluorophenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(11)3- (4- (4- ((4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(12)3- (4- (4- ((4- (4- (3- (methylsulfonyl) propoxy) phenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(13) (S) -3- (4- (4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(14) (S) -3- (4- (4- ((4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(15) (S) -3- (4- (4- ((4- (4-fluorophenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(16) (S) -potassium 3- (4- (4- ((4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) hex-4-enoate;

(17) (S) -3- (4- (4- ((6-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(18) (S) -3- (4- (4- ((4-phenylpiperidin-1-yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(19) (S) -3- (4- (4- (isoindolin-2-ylmethyl) benzyloxy) phenyl) hex-4-enoic acid;

(20) (S) -3- (4- (4- ((4-phenyl-5, 6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(21) (S) -3- (4- (4- ((4- (4- (methoxymethoxy) phenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(22) (S) -3- (4- (4- ((4- (5-isopropyl-1, 2, 4-oxadiazol-3-yl) piperidin-1-yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(23) (S) -3- (4- (4- ((4- (5-isopropyl-1, 2, 4-oxadiazol-3-yl) piperazin-1-yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(24) (S) -3- (4- (4- ((4- (4- (methylsulfonyl) phenyl) -5, 6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(25) (S) -3- (4- (4- ((4- (4- (3- (methylsulfonyl) propoxy) phenyl) -5, 6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(26) (3S) -3- (4- (4- (1- (3, 4-dihydroisoquinolin-2 (1H) -yl) ethyl) benzyloxy) phenyl) hex-4-enoic acid;

(27) (S) -3- (4- (4- ((4- (4-hydroxyphenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(28) (S) -3- (4- (4- ((4- (4- (3- (methylsulfonyl) propoxy) phenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(29) (S) -sodium 3- (4- (4- (isoindolin-2-ylmethyl) benzyloxy) phenyl) hex-4-enoate;

(30) (S) -3- (4- (4- (isoindolin-2-ylmethyl) benzyloxy) phenyl) hex-4-enoic acid L-lysine salt;

(31) (S) -3- (4- (4- ((4- (4-fluorophenyl) -5, 6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(32) (S) -3- (4- (4- ((4- (4-methoxyphenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(33) (S) -3- (4- (4- ((4- (benzo [ d ] thiazol-2-yl) piperazin-1-yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(34) (S) -3- (4- (4- ((4- (5-propylpyrimidin-2-yl) piperazin-1-yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(35) (S) -3- (4- (4- ((4- (5-cyanopyridin-2-yl) piperazin-1-yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(36) (3S) -3- (4- (4- ((3-phenylpyrrolidin-1-yl) methyl) benzyloxy) phenyl) hex-4-enoic acid;

(37) (S) -sodium 3- (4- (3- (4- (4-methoxyphenyl) piperazin-1-yl) benzyloxy) phenyl) hex-4-enoate;

(38) (S) -3- (4- (4- (2- (6-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) ethyl) benzyloxy) phenyl) hex-4-enoic acid;

(39) (S) -3- (4- (4- (2- (isoindolin-2-yl) ethyl) benzyloxy) phenyl) hex-4-enoic acid;

(40) (S) -3- (4- (4- (2- (3, 4-dihydroisoquinolin-2 (1H) -yl) ethyl) benzyloxy) phenyl) hex-4-enoic acid; and

(41) (S) -3- (4- (4- ((6-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4-enoate sodium.

3. The use according to claim 1, wherein the dipeptidyl peptidase 4 inhibitor is one selected from the group consisting of sitagliptin, vildagliptin, saxagliptin, linagliptin, tigeliptin, alogliptin, rigogliptin, berberine, and lupeol.

4. The use according to claim 1, wherein the sulfonylurea is one selected from the group consisting of butanamide, acetylbenzenesulfonylcyclohexamide, chlorpropamide, tolbutamide, glipizide, glibenclamide, glibornuride, gliquidone, glisoxepide, glipizide and glimepiride.

5. The use according to claim 1, wherein the thiazolidinedione is selected from the group consisting of rosiglitazone, pioglitazone, troglitazone, nateglinide, rosiglitazone, ciglitazone and rhodanine.

6. The use according to claim 1, wherein the biguanide is selected from one of the group consisting of metformin, phenformin, buformin, proguanil, chlorpromoguanil, chlorhexidine, polyaminopropyl biguanide, polyhexamethylene biguanide and alexidine.

7. The use according to claim 1, wherein the above-mentioned sodium-glucose cotransporter 2 inhibitor compound is one selected from the group consisting of engagliflozin, canagliflozin, and dapagliflozin.

8. The use according to claim 1, wherein the mixing weight ratio of the first effective substance and the second effective substance is 0.03:1 to 100: 1.

9. The use according to claim 1, wherein said composition is for activating G protein-coupled receptor 40 enzyme.

10. The use according to claim 1, wherein the metabolic disease is one selected from the group consisting of obesity, type I diabetes, type ii diabetes, impaired glucose tolerance, insulin resistance syndrome, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia and syndrome X.

Technical Field

This patent application claims the priority right of korean application No. 10-2014-0141216, which was filed to korean patent office at 17.10.2014, the disclosure of which is incorporated herein by reference.

The present invention relates to a pharmaceutical composition for preventing or treating metabolic diseases, which can be administered in combination or in a complex form by selecting a novel 3- (4- (benzyloxy) phenyl) -4-hexenoic acid derivative and at least one other active ingredient selected from the group consisting of Dipeptidyl peptidase 4 (DPPIV) inhibitors, sulphonylurea (sulfourea) inhibitors, Thiazolidinediones (TZDs), biguanides (biguanidines) inhibitors and sodium/glucose cotransporter 2(sodium/glucose cotransporter 2) inhibitors.

Background

Diabetes mellitus is a disease that is continuously threatening the health of people as more than 1 million people suffer worldwide.diabetes mellitus can be divided into 2 clinical symptoms of type I and type II type I diabetes mellitus, also known as Insulin Dependent Diabetes Mellitus (IDDM), results from autoimmune destruction of β cells, the pancreas, which is an insulin producing cell, and requires regular administration of exogenous insulin.

On the other hand, in diabetes, high values of glucose accumulate in the blood and urine, thereby causing problems associated with excessive urination, thirst, hunger, fat and protein metabolism. Such diabetes can cause life-threatening complications such as blindness, renal failure, and heart disease, and can cause damage to the retina of the posterior eye, and increase the risk of cataract and glaucoma. Further, the ability to sense pain associated with nerve damage to the legs and feet is impaired, and this also causes serious infection.

Conventionally, there have been used insulin, insulin secretion promoters, glucose lowering effectors (effectors), activators of peroxisome proliferator-activated receptors (PPARs), and the like as current treatments for diabetes. However, there are problems associated with currently available therapies including problems of low responsiveness to treatment with hypoglycemia, weight gain, time, gastrointestinal problems, and edema. In order to introduce a more effective novel therapeutic method according to the above-described problems into the market, studies targeting various fields are being conducted, and studies on a G-protein coupled receptor (GPCR) are being conducted as a specific target.

Recently, a G protein-coupled receptor 40, which is one of G protein-coupled receptors, was found, which is known as free fatty acid receptor 1 (pancreas 1), and is overexpressed in β cells of the pancreas, the calcium concentration in cells was increased by a compound that activates the G protein-coupled receptor 40(FFAR1), whereby the above-mentioned G protein-coupled receptor 40 was known to promote glucose-stimulated insulin secretion (GSIS) (non-patent document 1), and when a G protein-coupled receptor 40 activator was administered to normal mice or mice that are susceptible to diabetes due to gene mutation before the glucose tolerance test, an increase in glucose tolerance was observed, and a short-term increase in plasma insulin level was also observed in mice administered with the above-mentioned G protein-coupled receptor 40 activator, the function of the G protein-coupled receptor 40 was known to cause free fatty acid as a ligand of the G protein-coupled receptor 40 to act on β cells of the pancreas, thereby causing cells to secrete insulin based on glucose concentration β, and to participate in pathological receptor assay of diabetes by the G protein-coupled receptor 40 (nock 2).

Accordingly, the present inventors have confirmed that a novel 3- (4- (benzyloxy) phenyl) -4-hexenoic acid derivative and at least one other active ingredient selected from the group consisting of dipeptidyl peptidase 4 drugs, sulfonylureas, thiazolidinediones, biguanides, and sodium-glucose cotransporter 2 inhibitors are treated in combination to exhibit an excellent blood glucose lowering effect, and thus have completed the present invention.

Throughout this specification, reference is made to a number of papers and patent documents, the contents of which are incorporated herein by reference. The disclosures of the cited articles and patent documents are hereby incorporated by reference in their entirety into the present specification in order to more clearly describe the state of the art to which the present invention pertains and the contents of the present invention.

< Prior Art document >

(non-patent document 0001) Current Drug Targets, 2008, 9, 899-

(non-patent document 0002) Can J Diabetes 2012, 36, 275-.

Disclosure of Invention

Technical problem

An object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of metabolic diseases, which can be administered in combination or combination form by selecting a novel 3- (4- (benzyloxy) phenyl) -4-hexenoic acid derivative, an optical isomer, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, and at least one other active ingredient selected from the group consisting of dipeptidyl peptidase 4 type, sulfonylurea type, thiazolidinedione type, biguanide type and sodium-glucose cotransporter 2 inhibitor type drugs.

Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, the scope of the claims of the invention and the accompanying drawings.

Means for solving the problems

In order to achieve the above objects, the present invention provides a composition for preventing or treating metabolic diseases, comprising (a) a compound represented by chemical formula 1, an optical isomer, a hydrate, a solvate or a pharmaceutically acceptable salt thereof as a first active substance and (b) one or more compounds selected from the group consisting of dipeptidyl peptidase 4 inhibitors, sulfonylureas, thiazolidinediones, biguanides and sodium-glucose cotransporter 2 inhibitors as a second active substance.

Chemical formula 1:

in the above-described chemical formula 1,is a single bond or a double bond; a and E are each independently C, N or O; n is 0 to 5; x is a single bond, C_1-10Linear or branched alkylene of (a); r¹is-H, -OH, halogen, C_1-10Linear or side chain alkyl of, C_1-10Linear or branched alkoxy of, C_5-10Cycloalkyl or C_5-10Cycloalkenyl group of (a); r²、R³And R⁵Are each independently-H, -OH, halogen, C_1-10Linear or side chain alkyl or C_1-10Linear or branched alkoxy groups of (a); wherein R is as defined above²And R³Capable of forming C together with the various atoms to which they are attached_5-10Cycloalkyl of, C_6-10A 5-10 atom heterocycloalkyl group containing one or more heteroatoms selected from the group consisting of N, O and S, or a 5-10 atom heteroaryl group containing one or more heteroatoms selected from the group consisting of N, O and S; r^4Ais-H, -OH, ═ O, unsubstituted or substituted C_6-10Aryl or unsubstituted or substituted C containing one or more heteroatoms selected from the group consisting of N, O and S_5-10Wherein, C is substituted_6-10Aryl and substituted C_5-10One or more of the heteroaryl groups of (a) can be independently selected from the group consisting of-OH, halogen, nitrile, unsubstituted or one or more halogen substituted C_1-5Straight or branched chain alkyl, unsubstituted or one or more halogen substituted C_1-5Straight or side chain alkoxy, C_1-10A linear or branched chain alkyl sulfonyl group of,Andwherein m and q are each independently an integer of 1 to 10, and the unsubstituted or substituted C is_5-10The heteroaryl group of (a) may be fused with a phenyl group (fused); wherein R is as defined above³And R^4ACapable of forming C together with the various atoms to which they are attached_5-10Cycloalkyl of, C_6-10A 5-10 atom heterocycloalkyl group containing one or more heteroatoms selected from the group consisting of N, O and S, or a 5-10 atom heteroaryl group containing one or more heteroatoms selected from the group consisting of N, O and S, and the C_5-10Cycloalkyl of, C_6-10Aryl, heterocycloalkyl having 5 to 10 atoms and heteroaryl having 5 to 10 atoms can be independently substituted by C_1-5Linear or pendant alkoxy substitution; r^4BIs absent or R^4BCan be reacted with R^4BAttached atom and R^4ATogether form C containing one or more heteroatoms selected from the group consisting of N, O and S_5-10A heterocyclic ring.

Wherein the dipeptidyl peptidase 4 inhibitor includes Sitagliptin (Sitagliptin), Vildagliptin (Vildagliptin), Saxagliptin (Saxagliptin), linagliptin (L inagliptin), terliptin (Teneligliptin), Alogliptin (Alogliptin), gemagliptin (Gemigliptin), dulagliptin (Dutogliptin), Berberine (Berberine), lupeol (L upeol), red alder (alnus (Alnusrubra) and dandelion (dandelion coene), the sulphonamide is selected from albendamide (Carbutramide), acetophensulcyclamide (Acetohexamide), propylurea (Chloropamide), Tolbutamide (Tolbuminamide), glitazomide (Tolbumin), glitazobactam), glitazomide (glitazomide), glitazobactam (glitazomide (PEG), glitazobactam (glitazobactam), glitazobactam (E), glitazobactam (E (glitazobactam), glitazobactam (E (glitazobactam), glitazobactam (E (glitazobactam), glitazobactam (E), glitazobactam (E), a (E (R (E (R (.

According to another embodiment of the present invention, there is provided a method for preventing or treating metabolic diseases, comprising the step of administering to a subject (subject) a pharmaceutically effective amount of a composition comprising (a) a compound represented by chemical formula 1, an optical isomer, a hydrate, a solvate or a pharmaceutically acceptable salt thereof as a first active substance and (b) one or more compounds selected from the group consisting of dipeptidyl peptidase 4 inhibitors, sulfonylureas, thiazolidinediones, biguanides and sodium-glucose cotransporter 2 inhibitors as a second active substance.

Chemical formula 1:

the description for the above chemical formula 1 is the same as the detailed description for the composition for preventing or treating metabolic diseases.

In the mixed composition of the first and second effective substances, although side effects according to a specific mixing weight ratio are generated and the effect is not reduced, the mixing weight ratio is not particularly limited, and the first effective substance can be mixed in an appropriate amount to be administered together in consideration of the pathological state of the patient and the known characteristics of the second effective substance. In one embodiment, the above mixing weight ratio is 0.03:1 to 100: 1. in still another embodiment, the above mixing ratio by weight is 0.03:1 to 30: 1, in yet another embodiment, the above mixing ratio by weight is 0.03:1 to 10: 1.

ADVANTAGEOUS EFFECTS OF INVENTION

The novel 3- (4- (benzyloxy) phenyl) -4-hexenoic acid derivative, its optical isomer, hydrate, solvate or pharmaceutically acceptable salt thereof of the present invention, and at least one other active ingredient selected from the group consisting of dipeptidyl peptidase 4 inhibitors, sulfonylureas, thiazolidinediones, biguanides and sodium-glucose cotransporter 2 inhibitors are selected to be used in combination, and as a result, a remarkably excellent blood glucose lowering effect is exhibited in various animal diabetes disease models, and therefore, the above-mentioned derivative, its optical isomer, hydrate, solvate or pharmaceutically acceptable salt thereof, and at least one other active ingredient selected from the group consisting of dipeptidyl peptidase 4 inhibitors, sulfonylureas, thiazolidinediones, biguanides and sodium-glucose cotransporter 2 inhibitors, can be used usefully in combination or combination with one another A pharmaceutical composition for preventing or treating metabolic diseases such as obesity, type I diabetes, type II diabetes, inappropriate sugar tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia and syndrome X, which is administered in a form.

Drawings

FIG. 1 is a graph showing the degree of protein activation of G protein-coupled receptor 40 measured at the concentration of the compounds according to example 9 and comparative examples 1 and 3.

FIG. 2 is a graph showing the concentration of glucagon-like peptide-1 (G L P-1) in the blood when the compound of example 9 and the compound of comparative example 1 were orally administered to rats from Sprague Dawley rat.

Fig. 3 is a graph showing a decrease (%) in blood glucose exhibited when the compound of example 9 or sitagliptin was administered alone or in combination to a food-Induced Obesity model (DIO) mouse.

Fig. 4 is a graph showing a decrease (%) in blood glucose exhibited when the compound of example 9 or glimepiride was administered alone or in combination to food-borne obesity model mice.

Fig. 5 is a graph showing a decrease (%) in blood glucose exhibited when the compound of example 9, rosiglitazone or pioglitazone was administered alone or in combination with the compound of example 9 and rosiglitazone or the compound of example 9 and pioglitazone to a food-borne obesity model mouse.

Fig. 6 is a graph showing a blood glucose decrease (%) exhibited when the compound of example 9 or metformin is administered alone or the compound of example 9 and metformin are administered in combination to Zucker Diabetic adiposity model (Zucker Diabetic fat, ZDF) rats.

Fig. 7 is a graph showing the reduction (%) of blood glucose exhibited when the compound of example 9 or linagliptin was administered alone or in combination to a rat from streptavada.

Fig. 8 is a graph showing a decrease (%) in blood glucose exhibited when the compound of example 9 or engagliflozin was administered alone or when the compound of example 9 and engagliflozin were administered in combination to a rat from spadea.

Fig. 9 is a graph showing a decrease (%) in blood glucose exhibited when the compound of example 9 or metformin was administered alone or in combination to a rat from streptada.

FIG. 10 is a graph showing the results of an in vitro glucagon-like peptide-1 (in vitro G L P-1) secretion assay using NCI-H716 cells.

FIG. 11 is a graph showing the results of in vitro insulin secretion experiments using INS-1 cells derived from rat Insulinoma (Insulinoma) cell lines.

Detailed Description

The present invention will be described in detail below.

According to one embodiment of the present invention, there is provided a composition for preventing or treating metabolic diseases, comprising (a) a compound represented by chemical formula 1, an optical isomer, hydrate, solvate or pharmaceutically acceptable salt thereof as a first active substance and (b) one or more compounds selected from the group consisting of dipeptidyl peptidase 4 inhibitors, sulfonylureas, thiazolidinediones, biguanides and sodium-glucose cotransporter 2 inhibitors as a second active substance.

Chemical formula 1:

in the above-described chemical formula 1,is a single bond or a double bond; a and E are each independently C, N or O; n is 0 to 5; x is a single bond, C_1-10Linear or branched alkylene of (a); r¹is-H, -OH, halogen, C_1-10Linear or side chain alkyl of, C_1-10Linear or branched alkoxy of, C_5-10Cycloalkyl or C_5-10Cycloalkenyl group of (a); r²、R³And R⁵Are each independently-H, -OH, halogen, C_1-10Linear or side chain alkyl or C_1-10Linear or branched alkoxy groups of (a); wherein R is as defined above²And R³Capable of forming C together with the various atoms to which they are attached_5-10Cycloalkyl of, C_6-10A 5-10 atom heterocycloalkyl group containing one or more heteroatoms selected from the group consisting of N, O and S, or a 5-10 atom heteroaryl group containing one or more heteroatoms selected from the group consisting of N, O and S; r^4Ais-H, -OH, ═ O, unsubstituted or substituted C_6-10Aryl or unsubstituted or substituted C containing one or more heteroatoms selected from the group consisting of N, O and S_5-10Wherein, C is substituted_6-10Aryl and substituted C_5-10One or more of the heteroaryl groups of (a) can be independently selected from the group consisting of-OH, halogen, nitrile, unsubstituted or one or more halogen substituted C_1-5Straight or branched chain alkyl, unsubstituted or one or more halogen substituted C_1-5Straight or side chain alkoxy, C_1-10Linear or branched alkanes ofA radical sulfonyl group,Andwherein m and q are each independently an integer of 1 to 10, and the unsubstituted or substituted C is_5-10The heteroaryl group of (a) may be fused with a phenyl group; wherein R is as defined above³And R^4ACapable of forming C together with the various atoms to which they are attached_5-10Cycloalkyl of, C_6-10A 5-10 atom heterocycloalkyl group containing one or more heteroatoms selected from the group consisting of N, O and S, or a 5-10 atom heteroaryl group containing one or more heteroatoms selected from the group consisting of N, O and S, and the C_5-10Cycloalkyl of, C_6-10Aryl, heterocycloalkyl having 5 to 10 atoms and heteroaryl having 5 to 10 atoms can be independently substituted by C_1-5Linear or pendant alkoxy substitution; r^4BIs absent or R^4BCan be reacted with R^4BAttached atom and R^4ATogether form C containing one or more heteroatoms selected from the group consisting of N, O and S_5-10A heterocyclic ring.

In one embodiment of the present invention,is a single bond or a double bond; a and E are independently C, N or O; n is 0 to 3; x is a single bond or C_1-5Straight or branched chain alkylene; r¹is-H, -OH, halogen, C_1-5Linear or side chain alkyl of, C_1-5Linear or branched alkoxy of, C_5-8Cycloalkyl or C_5-8Cycloalkenyl group of (a); r²、R³And R⁵Independently is-H, -OH, halogen, C_1-5Linear or side chain alkyl or C_1-5Linear or branched alkoxy groups of (a); wherein C can be formed together with the various atoms to which they are attached_5-8Cycloalkyl of, C_6-8Containing an aryl radical ofThe above 5-8 membered heterocycloalkyl group containing one or more heteroatoms selected from the group consisting of N, O and S or a 5-8 membered heteroaryl group containing one or more heteroatoms selected from the group consisting of N, O and S; r^4Ais-H, -OH, ═ O, unsubstituted or substituted C_6-8Aryl or unsubstituted or substituted C containing one or more heteroatoms selected from the group consisting of N, O and S_5-8Wherein, C is substituted_6-8Aryl and substituted C_5-8One or more heteroaryl groups can be independently selected from-OH, halogen, nitrile, unsubstituted or one or more halogen substituted C_1-5Straight or branched chain alkyl, unsubstituted or one or more halogen substituted C_1-5Straight or side chain alkoxy, C_1-8Linear or branched alkylsulfonyl of,Andwherein m and q are independently an integer of 1 to 5, and the unsubstituted or substituted C is_5-8The heteroaryl group of (a) may be fused with a phenyl group; wherein R is as defined above³And R^4ACapable of forming C together with the various atoms to which they are attached_5-8Cycloalkyl of, C_6-8A 5-8 membered heterocycloalkyl group containing one or more heteroatoms selected from the group consisting of N, O and S, or a 5-8 membered heteroaryl group containing one or more heteroatoms selected from the group consisting of N, O and S, and the C_5-8Cycloalkyl of, C_6-8Aryl, heterocycloalkyl having 5 to 8 atoms and heteroaryl having 5 to 8 atoms can be independently replaced by C_1-5Linear or pendant alkoxy substitution; r^4BIs absent or R^4BCan be reacted with R^4BAttached atom and R^4ATogether form C containing one or more heteroatoms selected from the group consisting of N, O and S_5-8A heterocyclic ring.

In one embodiment of the inventionIs a single bond or a double bond; a and E are independently C or N; n is 0 to 1; x is a single bond or C_1-3Straight or branched chain alkylene; r¹is-H orR²、R³And R⁵Independently is-H, wherein R is as defined above²And R³Can form phenyl in a linked manner; r^4Ais-H, -OH, ═ O, Wherein R is as defined above³And R^4ACan form together with the various atoms to which they are attached a phenyl group, said phenyl group being capable of being substituted by methoxy; r^4BIs absent or R^4BCan be reacted with R^4BAttached atom and R^4AAre formed together

In one embodiment of the present invention, the compound represented by chemical formula 1 of the present invention is selected from one of the following compound groups.

(1)3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid;

(2)3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid L-lysine salt;

(3)4- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid;

(4)3- (4- (3- (4-oxocyclohexyl-1-enyl) benzyloxy) phenyl) -4-hexenoic acid;

(5)3- (4- (3- (4-hydroxycyclohexyl-1-enyl) benzyloxy) phenyl) -4-hexenoic acid;

(6)3- (4- (3- (4-hydroxycyclohexyl-1-alkenyl) benzyloxy) phenyl) -4-hexenoic acid L-lysine salt;

(7) (3S) -3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid;

(8) (3R) -3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid;

(9) (3S) -3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid L-lysine salt;

(10) (3R) -3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid L-lysine salt;

(11) (3S) -3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid sodium salt;

(12)3- (4- (4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(13)3- (4- (3-cyclohexenyl-4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(14)3- (4- (4- ((4-phenyl-5, 6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(15)3- (4- (4- ((4-phenylpiperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(16)3- (4- (4- ((6-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(17)3- (4- (4- ((4-phenylpiperidin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(18)3- (4- (4- ((4- (4-fluorophenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(19)3- (4- (4- ((4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(20)3- (4- (4- ((4- (4- (3- (methylsulfonyl) propoxy) phenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(21) (S) -3- (4- (4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(22) (S) -3- (4- (4- ((4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(23) (S) -3- (4- (4- ((4- (4-fluorophenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(24) (S) -potassium 3- (4- (4- ((4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoate;

(25) (S) -3- (4- (4- ((6-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(26) (S) -3- (4- (4- ((4-phenylpiperidin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(27) (S) -3- (4- (4- (isoindolin-2-ylmethyl) benzyloxy) phenyl) -4-hexenoic acid;

(28) (S) -3- (4- (4- ((4-phenyl-5, 6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(29) (S) -3- (4- (4- ((4- (4- (methoxymethoxy) phenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(30) (S) -3- (4- (4- ((4- (5-isopropyl-1, 2, 4-oxadiazol-3-yl) piperidin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(31) (S) -3- (4- (4- ((4- (5-isopropyl-1, 2, 4-oxadiazol-3-yl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(32) (S) -3- (4- (4- ((4- (4- (methylsulfonyl) phenyl) -5, 6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(33) (S) -3- (4- (4- ((4- (4- (3- (methylsulfonyl) propoxy) phenyl) -5, 6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(34) (3S) -3- (4- (4- (1- (3, 4-dihydroisoquinolin-2 (1H) -yl) ethyl) benzyloxy) phenyl) -4-hexenoic acid;

(35) (S) -3- (4- (4- ((4- (4-hydroxyphenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(36) (S) -3- (4- (4- ((4- (4- (3- (methylsulfonyl) propoxy) phenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(37) (S) -sodium 3- (4- (4- (isoindolin-2-ylmethyl) benzyloxy) phenyl) -4-hexenoate;

(38) l-lysine (S) -3- (4- (4- (isoindolin-2-ylmethyl) benzyloxy) phenyl) -4-hexenoic acid;

(39) (S) -3- (4- (4- ((4- (4-fluorophenyl) -5, 6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(40) (S) -3- (4- (4- ((4- (4-methoxyphenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(41) sodium (S) -3- (4- (4- ((3, 4-dihydroquinolin-1 (2H) -yl) methyl) benzyloxy) phenyl) -4-hexenoate;

(42) (S) -potassium 3- (4- (4- ((3, 4-dihydroquinolin-1 (2H) -yl) methyl) benzyloxy) phenyl) -4-hexenoate;

(43) (S) -3- (4- (4- ((4- (benzo [ d ] thiazol-2-yl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(44) (S) -3- (4- (4- ((4- (5-propylpyrimidin-2-yl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(45) (S) -3- (4- (4- ((4- (5-cyanopyridin-2-yl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(46) (3S) -3- (4- (4- ((3-phenylpyrrolidin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid;

(47) sodium (S) -3- (4- (4- ((4- (4-methoxyphenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoate;

(48) (S) -3- (4- (4- (2- (6-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) ethyl) benzyloxy) phenyl) -4-hexenoic acid;

(49) (S) -3- (4- (4- (2- (isoindolin-2-yl) ethyl) benzyloxy) phenyl) -4-hexenoic acid;

(50) (S) -3- (4- (4- (2- (3, 4-dihydroisoquinolin-2 (1H) -yl) ethyl) benzyloxy) phenyl) -4-hexenoic acid; and

(51) (S) -3- (4- (4- ((6-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid sodium salt.

The invention is shown by chemical formula 1The compounds shown can be used in the form of pharmaceutically acceptable salts, preferably acid addition salts formed from pharmaceutically acceptable free acids (freeacids). The acid addition salt is selected from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and phosphorous acid, nontoxic organic acids such as aliphatic mono-and dicarboxylic acids, phenyl-substituted alkanoates, hydroxyalkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, and mixtures thereof,Fumaric acidAnd the like. As such pharmaceutically non-toxic salts, there may be mentioned sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, sulfate, phosphate,acetic acid saltPropionate, caprate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexane-1, 6-dioate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, tosylate, chlorobenzenesulfonate, xylenesulfonate, phenyl acetate, phenyl propionate, phenyl butyrate, citrate, lactate, β -hydroxybutyric acid, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt of the present invention can be prepared by a conventional method, for example, by dissolving the derivative of chemical formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., and filtering and drying a precipitate formed by adding an organic acid or an inorganic acid, or by distilling the solvent and an excess amount of the acid under reduced pressure, drying the solvent and the excess amount of the acid, and crystallizing the solvent in the organic solvent.

Also, pharmaceutically acceptable metal salts can be prepared by using a salt group. The alkali metal or alkaline earth metal salt can be obtained by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved salt compound, and evaporating and drying the filtrate. At this time, in terms of pharmacy, the metal salt is preferably used for preparing a sodium salt, a potassium salt or a calcium salt. And, an alkali metal or alkaline earth metal salt is reacted with an appropriate anion salt (e.g., nitric acid) to obtain a salt corresponding to the above metal salt.

Also, amino acids having an amino group attached to an organic acid can be used to prepare pharmaceutically acceptable salts, which are preferably used in the preparation of natural amino acids such as glycine, alanine, phenylalanine, valine, lysine, glutamic acid, etc., in the pharmaceutical aspect, and most preferably used in the preparation of L-lysine.

Also, the present invention includes not only the compound represented by the above chemical formula 1 and pharmaceutically acceptable salts thereof, but also all solvates, optical isomers, hydrates, and the like, which can be prepared from the above compound.

The pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable non-treatment group containing an active ingredient. The pharmaceutically acceptable non-treated group comprising the pharmaceutical composition of the present invention is generally used in the formulation process, and includes lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, and the like, but is not limited thereto. In addition to the above ingredients, the pharmaceutical composition of the present invention may further include lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, and the like. Suitable pharmaceutically acceptable non-treatment groups and formulations are described in detail in Remington's Pharmaceutical Sciences (19the d., 1995).

The amount of the compound of the present invention to be administered to a human body may vary depending on the age, body weight, sex, administration form, health condition and disease level of a patient, and is usually about 0.001 to 100 mg/kg/day, preferably 0.01 to 35 mg/kg/day. When an adult patient having a body weight of 70kg is used as a reference, it is usually 0.07 to 7000 mg/day, preferably 0.7 to 2500 mg/day, and may be further administered pimples 1 to several times per day at regular time intervals according to the judgment of a doctor or pharmacist.

The pharmaceutical composition of the present invention can be administered orally or parenterally, and when administered parenterally, it can be administered by topical application to the skin, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, and the like. Preferably, the pharmaceutical composition of the present invention can be administered orally, and solid preparations for oral administration include tablets, pills, powders, granules, capsules, dragees, etc., which are prepared by mixing one or more compounds of the present invention with at least one excipient, for example, starch, calcium carbonate, sucrose (sucrose), lactose (lactose), gelatin, etc. Besides simple excipients, lubricants such as magnesium stearate and talc may also be used. The liquid preparation for oral administration corresponds to a suspension, an internal solution, an oil, a syrup, or the like, and includes various excipients such as a wetting agent, a sweetener, an aromatic agent, a preservative, and the like, in addition to water and liquid paraffin which are generally used as a simple diluent.

Formulations for oral administration include sterilized aqueous solutions, non-aqueous solvents, suspension solvents, oils, freeze-drying agents, suppositories, and the like. As the nonaqueous solvent and the suspending solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base agent for the suppository, there can be used Vitepsol (witepsol), polyethylene glycol, Tween (tween) 61, cacao butter, lauric glyceride oil, glycerin, gelatin, etc.

The pharmaceutical composition of the present invention can be prepared in a unit volume form or in a multi-volume container by formulating it with a pharmaceutically acceptable non-treatment group and/or excipient according to a method that can be easily accomplished by those skilled in the art. The dosage form may be in the form of a solution, suspension or emulsion in an oil or aqueous medium, or in the form of an extract, powder, granule, tablet or capsule, and may further comprise a dispersing agent or a stabilizer.

In one embodiment of the present invention, the dipeptidyl peptidase-4 inhibitor of the present invention is one selected from the group consisting of sitagliptin, vildagliptin, saxagliptin, linagliptin, tigeliptin, alogliptin, dulagliptin, berberine, lupeol, red alder and dandelion coffee.

In one embodiment of the present invention, the sulfonylureas of the present invention are selected from one of the group consisting of sulfamylurea, acetylbenzenesulfonylcyclohexamide, chlorpropamide, tolbutamide, glipizide, gliclazide, glibenclamide, glibornuride, gliquidone, glimepiride, glipizide and glimepiride.

In one embodiment of the invention, the thiazolidinediones of the invention are selected from one of the group consisting of sigma delta ketone, pioglitazone, troglitazone, nateglinide, rosiglitazone, ciglitazone and rhodanine.

In one embodiment of the present invention, the biguanide of the present invention is one selected from the group consisting of metformin, phenformin, buformin, proguanil, chlorhexidine, polyaminopropylbiguanide, polyhexamethylene biguanide and alexidine.

In one embodiment of the present invention, the sodium-glucose cotransporter 2 inhibitor compound of the present invention is one selected from the group consisting of engagliflozin, canagliflozin, and dapagliflozin.

In one embodiment of the present invention, the mixing weight ratio of the first effective substance and the second effective substance of the present invention is 0.03:1 to 100: 1. in still another embodiment, the above mixing ratio by weight is 0.03:1 to 30: 1, in yet another embodiment, the above mixing ratio by weight is 0.03:1 to 10: 1. however, in the case of the composition of the present invention, particularly, since there is no side effect or a phenomenon such as a decrease in efficacy according to the mixing weight ratio, the mixing weight ratio is not particularly limited, and the first active substance can be administered in combination by mixing an appropriate amount of the first active substance in consideration of the pathological state of the patient, the known properties of the second active substance, and the like.

In one embodiment of the invention, the composition of the invention activates the G protein-coupled receptor 40(G-protein receptor 40) enzyme. G protein-coupled receptor 40 as a receptor (GPCR) coupled to G proteins expressed primarily in insulin-secreting cells of the pancreas, the G protein-coupled receptor 40 expression profile has potential use for the treatment of a variety of metabolic disorders including obesity and diabetes.

In the present invention, as a result of evaluating the receptor activity rate of the G protein-coupled receptor 40 when the compound represented by chemical formula 1, its optical isomer or its pharmaceutically acceptable salt, which is the first active ingredient, is used alone, it was confirmed that the compounds of all examples of the present invention activated the receptor of the G protein-coupled receptor 40 at a low concentration by 50% (EC)₅₀) This revealed that the activity was excellent (see experimental example 1, experimental example 2, and fig. 1).

Further, in the present invention, as a result of evaluating the inhibitory activity rate of the CYP enzyme in relation to the drug metabolism of the compound represented by chemical formula 1, the optical isomer thereof, or the pharmaceutically acceptable salt thereof as the first active ingredient, the compounds of all the examples of the present invention have low inhibitory activity rate of the CYP enzyme, and thus when administered in combination with other drugs, there is no toxicity due to the concentration of the co-administration, and it was confirmed that the co-administration with other drugs can be realized when the complication occurs (see experimental example 3).

Further, in the present invention, as a result of the oral glucose tolerance test of the compound represented by chemical formula 1, its optical isomer, or a pharmaceutically acceptable salt thereof, which is the first active ingredient, it was found that the compound of all examples of the present invention exhibits similar or superior blood glucose lowering effect compared to the conventional known active agent of G protein-coupled receptor 40, and thus the compound has very excellent effect of activating G protein-coupled receptor 40 in vivo (see experimental examples 4, 5, and 6).

In addition, in the present invention, as a result of an experiment for evaluating the increase rate of the concentration of glucagon-like peptide-1 in blood after oral administration of the compound represented by chemical formula 1, its optical isomer, or a pharmaceutically acceptable salt thereof as the first active ingredient, the compound of comparative example 1 exhibited an effect of not increasing the concentration of glucagon-like peptide-1 in blood after administration, as compared to the glucose-treated group (Veh.), but the compound of example 9 of the present invention exhibited an effect of increasing the concentration of glucagon-like peptide-1 in blood when administered to rats in the strea tract (see experimental example 7 and fig. 2).

Furthermore, when the novel 3- (4- (benzyloxy) phenyl) -4-hexenoic acid derivative of the present invention is administered in combination with a representative drug such as a dipeptidyl peptidase 4 inhibitor, a sulfonylurea, a thiazolidinedione, a biguanide, or a sodium-glucose cotransporter 2 inhibitor, a superior blood glucose lowering effect is exhibited compared to the case where the above drugs are administered alone (see tables 8 to 14 and fig. 3 to 9 of experimental examples 8 to 12).

In summary, the pharmaceutical composition of the present invention has an excellent effect of activating the protein of G protein-coupled receptor 40, and therefore has an excellent insulin secretion promoting effect, can be administered in combination with other drugs, and has an excellent effect of activating the protein of G protein-coupled receptor 40 in vivo.

In one embodiment of the present invention, the metabolic disease of the present invention is one selected from the group consisting of obesity, diabetes type I, diabetes type II, impaired glucose tolerance, insulin resistance syndrome, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia and syndrome X. The composition of the present invention can be used for the prevention or treatment of various metabolic diseases which are affected by the blood glucose lowering effect.

The preparation method of the compound represented by chemical formula 1 of the present invention is as follows.

Preparation method 1

As shown in the following reaction formula 1, the method for preparing the compound represented by chemical formula 1 according to the present invention comprises: a step 1 of subjecting a compound represented by chemical formula 2 and a compound represented by chemical formula 3 to a condensation reaction to prepare a compound represented by chemical formula 4; and a step 2 of performing a reduction reaction on the compound represented by chemical formula 4 prepared in the above step 1 to prepare a compound represented by chemical formula 1.

Reaction formula 1:

(in the above reaction scheme 1, R¹、R²、R³、R^4A、R^4B、R⁵A, E, n and X are as defined in the above chemical formula 1; y is C_1-10Linear or side chain alkyl groups of (ii).

Hereinafter, the method for preparing the compound represented by chemical formula 1 according to the present invention will be described in detail according to various steps.

In the method of preparing the compound represented by chemical formula 1 of the present invention, the above step 1 is a step of preparing the compound represented by chemical formula 4 by performing a coupling reaction of the compound represented by chemical formula 2 and the compound represented by chemical formula 3, and more specifically, the above step 1 is a step of performing a Mitsunobu reaction (Mitsunobu reaction) by slowly dropping an azocarboxylate reagent into a solution in which the compound represented by chemical formula 2, the compound represented by chemical formula 3, and triphenylphosphine are mixed at a temperature of-5 ℃ to 10 ℃, thereby preparing the compound represented by chemical formula 4.

At this time, diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) may be used as the above azocarboxylate reagent, and preferably, diisopropyl azodicarboxylate may be used.

Further, Tetrahydrofuran (THF), Dichloromethane (DCM), toluene, acetonitrile, or the like can be used as the reaction solvent, and Tetrahydrofuran (THF) can be preferably used.

Further, the reaction temperature is preferably between 0 ℃ and the boiling point of the solvent, and the reaction time is preferably about 0.5 to 10 hours, although the reaction time is not particularly limited.

In the method of preparing the compound represented by chemical formula 1 of the present invention, the above step 2 is a step of preparing the compound represented by chemical formula 1 by performing a reduction reaction on the compound represented by chemical formula 4 prepared in the above step 1 in the presence of a salt group, and more specifically, a step of reacting the compound represented by chemical formula 4 prepared in the above step 1 with a salt group at normal temperature, thereby preparing the compound represented by chemical formula 1 in which an ester group included in the compound represented by chemical formula 4 is reduced to a carboxyl group.

In this case, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (L iOH), or the like can be used as the salt group, and potassium hydroxide (KOH) can be preferably used.

Further, Tetrahydrofuran (THF), Dichloromethane (DCM), toluene, acetonitrile, or the like can be used as the reaction solvent, and Tetrahydrofuran (THF) can be preferably used.

Further, the reaction temperature is preferably between 0 ℃ and the boiling point of the solvent, and the reaction time is not particularly limited, but the reaction is preferably carried out for 0.5 to 10 hours.

Method for preparing starting material (compound represented by chemical formula 2)

In the above reaction formula 1 of the present invention, as shown in the following reaction formula 2, a method for preparing a compound represented by chemical formula 2 used as a starting material includes: a step 1 of reacting a compound represented by chemical formula 8 and a compound represented by chemical formula 9 to prepare a compound represented by chemical formula 10; a step 2 of reacting the compound represented by chemical formula 10 prepared in the above step 1 with the compound represented by chemical formula 11 to prepare a compound represented by chemical formula 12; and a step 3 of performing a reduction reaction on the compound represented by chemical formula 12 prepared in the above step 2 to prepare a compound represented by chemical formula 2.

Reaction formula 2:

(in the above reaction scheme 2, R¹、R²、R³、R^4A、R^4B、R⁵A, E, n and X are as defined in the above chemical formula 1, and-Otf is trifluoromethanesulfonic group).

Hereinafter, the method for preparing the compound represented by chemical formula 2 according to the present invention will be described in detail according to various steps.

In the method of preparing the compound represented by chemical formula 2 of the present invention, the above step 1 is a step of preparing the compound represented by chemical formula 10 by reacting the compound represented by chemical formula 8 and the compound represented by chemical formula 9, and more specifically, a step of dissolving the compound represented by chemical formula 8, that is, the compound represented by chemical formula 9, in an organic solvent at a temperature of-80 ℃ to-70 ℃, and after slowly dropping a bis (trimethylsilyl) amide metal complex, heating to normal temperature and stirring, thereby preparing the compound represented by chemical formula 10.

At this time, as the above bis (trimethylsilyl) amide metal complex, potassium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, or sodium bis (trimethylsilyl) amide may be used, and preferably, potassium bis (trimethylsilyl) amide may be used.

Further, as the organic solvent, Tetrahydrofuran (THF), diethyl ether, diphenyl ether, diisopropyl ether (DIPE), Dimethylformamide (DMF), Dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), Dichloromethane (DCM), chlorobenzene, toluene, benzene, or the like can be used.

Further, the reaction temperature is preferably between-80 ℃ and the boiling point of the solvent, and the reaction time is preferably 0.5 to 10 hours, although the reaction time is not particularly limited.

In the method of preparing the compound represented by chemical formula 2 of the present invention, the above step 2 is a step of reacting the compound represented by chemical formula 10 prepared in the above step 1 and the compound represented by chemical formula 11 to prepare the compound represented by chemical formula 12, and more specifically, a step of preparing the compound represented by chemical formula 12 by performing a Suzuki coupling reaction (Suzuki coupling reaction) of the compound represented by chemical formula 10 prepared in the above step 1 and the borate compound represented by chemical formula 11 in the presence of a palladium catalyst.

In this case, tetrakis (triphenylphosphine) (Pd (PPh) may be used as the palladium catalyst₃)₄) Bis (triphenylphosphine) palladium (II) dichloride (PdCl)₂(PPh₃)₂) Palladium dichloride (PdCl)₂) Palladium acetate (Pd (OCOCH)₃)₂) Etc., preferably, tetrakis (triphenylphosphine) (Pd (PPh) may be used₃)₄)。

Further, as the organic solvent, Tetrahydrofuran (THF), diethyl ether, diphenyl ether, diisopropyl ether (DIPE), Dimethylformamide (DMF), Dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), Dichloromethane (DCM), chlorobenzene, toluene, benzene, or the like can be used, and preferably, toluene can be used.

Further, the reaction temperature is preferably between 0 ℃ and the boiling point of the solvent, and the reaction time is not particularly limited, but the reaction is preferably carried out for 0.5 to 10 hours.

In the method of preparing the compound represented by chemical formula 2 of the present invention, the above step 3 is a step of preparing the compound represented by chemical formula 2 by performing a reduction reaction on the compound represented by chemical formula 12 prepared in the above step 2 in the presence of a salt group, and specifically, a step of dissolving the compound represented by chemical formula 12 prepared in the above step 2 in an organic solvent and adding a salt group, thereby preparing the compound represented by chemical formula 2 in which an aldehyde group included in the compound represented by chemical formula 12 is reduced to a hydroxyl group.

At this time, the organic solvent isMethanol, ethanol, ethyl acetate, tetrahydrofuran, diethyl ether, or a mixed solution of 2 or more of them, preferably, a mixed solution of tetrahydrofuran: methanol (4: 1).

Also, sodium borohydride (NaBH) may be used as the above salt group₃) Lithium aluminum hydride (L iAlH)₄) Etc., preferably, sodium borohydride (NaBH) can be used₃)。

Further, the reaction temperature is preferably between 0 ℃ and the boiling point of the solvent, and the reaction time is not particularly limited, but the reaction is preferably carried out for 0.5 to 10 hours.

Preparation method 2

As shown in the following reaction formula 3, the method for preparing the compound represented by chemical formula 1 according to the present invention includes: a step 1 of preparing a compound represented by chemical formula 6 by performing a coupling reaction of a compound represented by chemical formula 5 and a compound represented by chemical formula 3; step 2 of performing a methanesulfonic acid reaction (Mesylate reaction) on the compound represented by chemical formula 6 prepared in the above step 1 to prepare a compound represented by chemical formula 7; step 3 of preparing a compound represented by chemical formula 4 by substituting the compound represented by chemical formula 13 at the methanesulfonic acid (Mesylate) position of the compound represented by chemical formula 7 prepared in the above step 2; and a step 4 of performing a reduction reaction on the compound represented by chemical formula 4 prepared in the above step 3 to prepare a compound represented by chemical formula 1.

Reaction formula 3:

(in the above reaction scheme 3, R¹、R²、R³、R^4A、R^4B、R⁵A, E, n and X are as defined in the above chemical formula 1; y is C_1-10Linear or side chain alkyl groups of (ii).

Hereinafter, the method for preparing the compound represented by chemical formula 1 according to the present invention will be described in detail according to various steps.

In the method of preparing the compound represented by chemical formula 1 of the present invention, the above step 1 is a step of performing a coupling reaction of the compound represented by chemical formula 5 and the compound represented by chemical formula 3 to prepare the compound represented by chemical formula 6.

In this case, Tetrahydrofuran (THF), diethyl ether, diphenyl ether, diisopropyl ether (DIPE), Dimethylformamide (DMF), Dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), Dichloromethane (DCM), chlorobenzene, toluene, benzene, or the like can be used as the organic solvent, and Dimethylformamide (DMF) can be preferably used.

Further, cesium carbonate (Cs) may be used as the salt group₂CO₃) Sodium borohydride (NaBH)₃) Lithium aluminum hydride (L iAlH)₄) Etc., preferably, cesium carbonate (Cs) can be used₂CO₃)。

Further, the reaction temperature is preferably between 0 ℃ and the boiling point of the solvent, and the reaction time is not particularly limited, but the reaction is preferably carried out for 0.5 to 10 hours.

In the method of preparing the compound represented by chemical formula 1 according to the present invention, the step 2 is a step of preparing the compound represented by chemical formula 7 by subjecting the compound represented by chemical formula 6 prepared in the step 1 to a methanesulfonic acid reaction (Mesylate reaction) in a solvent.

In this case, methanesulfonyl chloride (MsCl) can be used as a sample for the above-mentioned methanesulfonic acid reaction.

As the organic solvent, Triethylamine (TEA), Tetrahydrofuran (THF), diethyl ether, diphenyl ether, diisopropyl ether (DIPE), Dimethylformamide (DMF), Dimethylacetamide (DMA), Dimethylsulfoxide (DMSO), Dichloromethane (DCM), chlorobenzene, toluene, benzene, or the like can be used, and preferably, Triethylamine (TEA) can be used.

Further, the reaction temperature is preferably between 0 ℃ and the boiling point of the solvent, and the reaction time is not particularly limited, but the reaction is preferably carried out for 0.5 to 10 hours.

In the method of preparing the compound represented by chemical formula 1 according to the present invention, the above step 3 is a step of preparing the compound represented by chemical formula 4 by substituting the methanesulfonic acid (Mesylate) position of the compound represented by chemical formula 7 prepared in the above step 2 for the compound represented by chemical formula 13.

In this case, Tetrahydrofuran (THF), diethyl ether, diphenyl ether, diisopropyl ether (DIPE), Dimethylformamide (DMF), Dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), Dichloromethane (DCM), chlorobenzene, toluene, benzene, and the like can be used as the organic solvent, and Dichloromethane (DCM) can be preferably used.

Further, cesium carbonate (Cs) may be used as the salt group₂CO₃) Sodium borohydride (NaBH)₃) Lithium aluminum hydride (L iAlH)₄) Etc., preferably, cesium carbonate (Cs) can be used₂CO₃)。

Further, the reaction temperature is preferably between 0 ℃ and the boiling point of the solvent, and the reaction time is not particularly limited, but the reaction is preferably carried out for 0.5 to 10 hours.

In the method of preparing the compound represented by chemical formula 1 of the present invention, the above step 4 is a step of preparing the compound represented by chemical formula 1 by subjecting the compound represented by chemical formula 4 prepared in the above step 3 to a reduction reaction in the presence of a salt group, and more specifically, may be a step of reacting the compound represented by chemical formula 4 prepared in the above step 3 with a salt group at normal temperature, thereby preparing the compound represented by chemical formula 1 in which an ester group included in the compound represented by chemical formula 4 is reduced to a carboxyl group.

In this case, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (L iOH), or the like can be used as the salt group, and potassium hydroxide (KOH) can be preferably used.

Further, Tetrahydrofuran (THF), Dichloromethane (DCM), toluene, acetonitrile, or the like can be used as the reaction solvent, and Tetrahydrofuran (THF) can be preferably used.

Further, the reaction temperature is preferably between 0 ℃ and the boiling point of the solvent, and the reaction time is not particularly limited, but the reaction is preferably carried out for 0.5 to 10 hours.

Preparation method 3

The method for preparing a compound represented by chemical formula 1 according to the present invention includes step 1 of performing a ring-opening reaction on a compound represented by chemical formula 1a to prepare a compound represented by chemical formula 1b, as shown in reaction formula 4 below.

Reaction formula 4:

(in the above reaction scheme 4, R¹The same as defined in the above chemical formula 1; the compounds represented by chemical formula 1a and chemical formula 1b are included in the compound represented by chemical formula 1).

Hereinafter, the method for preparing the compound of chemical formula 1 according to the present invention will be described in detail according to various steps.

In the method of preparing a compound of chemical formula 1 of the present invention, the above step 1 is a step of subjecting a compound represented by chemical formula 1a to a ring-opening reaction in the presence of an acid to prepare a compound represented by chemical formula 1b, and more specifically, a step of subjecting a compound represented by chemical formula 1a contained in the compound represented by chemical formula 1a to a ring-opening reaction in the presence of an acid to open a heterocycle of the compound represented by chemical formula 1a, thereby preparing a compound represented by chemical formula 1b containing a carbonyl group.

In this case, an inorganic acid such as hydrochloric acid, sulfuric acid, or phosphoric acid can be used as the acid, and hydrochloric acid is more preferably used.

Further, Tetrahydrofuran (THF), Dichloromethane (DCM), toluene, acetonitrile, or the like can be used as the reaction solvent, and Tetrahydrofuran (THF) can be preferably used.

Further, the reaction temperature is preferably between 0 ℃ and the boiling point of the solvent, and the reaction time is not particularly limited, but the reaction is preferably carried out for 0.5 to 10 hours.

Preparation method 4

The method for preparing the compound represented by chemical formula 1 according to the present invention, as shown in the following reaction formula 5, includes step 1 of subjecting the compound represented by chemical formula 1b to a reduction reaction to prepare the compound represented by chemical formula 1 c.

Reaction formula 5:

(in the above reaction scheme 5, R¹The same as defined in the above chemical formula 1; the compounds represented by chemical formulas 1b and 1c are included in the compound represented by chemical formula 1).

Hereinafter, the method for preparing the compound of chemical formula 1 according to the present invention will be described in detail according to various steps.

In the method of preparing a compound of chemical formula 1 according to the present invention, the above step 1 is a step of subjecting the compound of chemical formula 1b to a reduction reaction in the presence of a salt group to prepare a compound of chemical formula 1c, and more specifically, a step of subjecting the compound of chemical formula 1b, which is one of the compounds of chemical formula 1, to a reduction reaction in the presence of a salt group to prepare a compound of chemical formula 1c in which a carbonyl group of the compound of chemical formula 1b is reduced to a hydroxyl group.

In this case, sodium borohydride (NaBH) may be used as the above salt group₃) Lithium aluminum hydride (L iAlH)₄) Etc., preferably, sodium borohydride (NaBH) can be used₃)。

Further, Tetrahydrofuran (THF), Dichloromethane (DCM), toluene, acetonitrile, or the like can be used as the reaction solvent, and Tetrahydrofuran (THF) can be preferably used.

Further, the reaction temperature is preferably between 0 ℃ and the boiling point of the solvent, and the reaction time is not particularly limited, but the reaction is preferably carried out for 0.5 to 10 hours.

The pharmaceutical composition of the present invention is characterized by activating the enzyme activity of the G protein-coupled receptor 40.

G protein-coupled receptor 40 as a receptor (GPCR) coupled to G proteins expressed primarily in insulin-secreting cells of the pancreas, the G protein-coupled receptor 40 expression profile has potential use for the treatment of a variety of metabolic disorders including obesity and diabetes.

In connection with the above, the receptor activity for the G protein-coupled receptor 40 of the compound represented by chemical formula 1, the optical isomer thereof, or the pharmaceutically acceptable salt thereof of the present inventionAs a result of the evaluation of the rates, it was confirmed that the compounds of all examples of the present invention activated the receptor for G protein-coupled receptor 40 at a low concentration by 50% (EC)₅₀) This revealed that the activity was excellent (see experimental example 1, experimental example 2, and fig. 1).

Further, as a result of evaluating the inhibitory activity rate of the CYP enzyme in relation to the drug metabolism of the compound represented by chemical formula 1 of the present invention, its optical isomer or a pharmaceutically acceptable salt thereof, the compounds of all examples of the present invention have a low inhibitory activity rate of the CYP enzyme, and thus when administered in combination with other drugs, there is no toxicity due to the concentration of the co-administration, and it was confirmed that the co-administration with other drugs can be achieved when complications occur (see experimental example 3).

Further, as a result of an oral glucose tolerance test of the compound represented by chemical formula 1 of the present invention, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, it was found that the compound of all examples of the present invention exhibits a similar or superior blood glucose lowering effect as compared with a conventional known active agent of G protein-coupled receptor 40, and thus the compound has a very superior effect of activating G protein-coupled receptor 40 in vivo (see experimental examples 4, 5, and 6).

Further, as a result of an experiment for evaluating the increase rate of the concentration of glucagon-like peptide-1 in blood after oral administration of the compound represented by chemical formula 1 of the present invention, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, the compound of comparative example 1 exhibited no effect of increasing the concentration of glucagon-like peptide-1 in blood after administration, but the compound of example 9 of the present invention exhibited an effect of increasing the concentration of glucagon-like peptide-1 in blood when administered to rats in the scholaran (see experimental example 7 and fig. 2), compared to the glucose-treated group (Veh).

Furthermore, when the novel 3- (4- (benzyloxy) phenyl) -4-hexenoic acid derivative of the present invention is administered in combination with a representative drug such as dipeptidyl peptidase 4 inhibitors, sulfonylureas, thiazolidinediones, biguanides, or sodium-glucose cotransporter 2 inhibitors, it exhibits an excellent blood glucose lowering effect as compared with the case where the above drugs are administered alone (see tables 8, 9, 10, 11, fig. 3, 4, 5, and 6 of experimental examples 8, 9, 10, and 11).

Accordingly, the compound represented by chemical formula 1 of the present invention has an excellent effect of activating a protein of G protein-coupled receptor 40, thereby having an excellent insulin secretion promoting effect, and can be administered in combination with other drugs, and further, since the effective action of activating the protein of G protein-coupled receptor 40 in vivo is very excellent, the composition comprising the compound represented by chemical formula 1 of the present invention as an active ingredient can be usefully used as a pharmaceutical composition for preventing or treating metabolic diseases such as obesity, type i diabetes, type II diabetes, inappropriate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia and syndrome X.

The compound represented by chemical formula 1 of the present invention can be administered in various dosage forms, i.e., orally, i.e., non-orally, upon clinical administration, and in the case of formulation, can be prepared by using a diluent or excipient such as a conventional filler, extender, binder, wetting agent, disintegrant, surfactant, etc.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, dragees and the like, and are prepared by mixing one or more compounds of the present invention with at least one excipient, for example, starch, calcium carbonate, sucrose, lactose, gelatin or the like. Besides simple excipients, lubricants such as magnesium stearate and talc may also be used. The liquid preparation for oral administration corresponds to a suspension, an internal solution, an oil, a syrup, or the like, and includes various excipients such as a wetting agent, a sweetener, an aromatic agent, a preservative, and the like, in addition to water and liquid paraffin which are generally used as a simple diluent.

Formulations for oral administration include sterilized aqueous solutions, non-aqueous solvents, suspension solvents, oils, freeze-drying agents, suppositories, and the like. As the nonaqueous solvent and the suspending solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base agent for the suppository, there can be used Vitepa sol, polyethylene glycol, Tween 61, cacao butter, lauric glyceride oil, glycerin, gelatin, etc.

The amount of the compound of the present invention to be administered to a human body may vary depending on the age, body weight, sex, administration form, health condition and disease level of a patient, and is usually about 0.001 to 100 mg/kg/day, preferably 0.01 to 35 mg/kg/day. When an adult patient having a body weight of 70kg is used as a reference, it is usually 0.07 to 7000 mg/day, preferably 0.7 to 2500 mg/day, and may be further administered pimples 1 to several times per day at regular time intervals according to the judgment of a doctor or pharmacist.

The present invention will be described in detail below with reference to examples and experimental examples.

However, the following examples and experimental examples are only for illustrating the present invention, and the contents of the present invention are not limited thereto.

< preparation example 1> preparation of ethyl 3- (4-hydroxyphenyl) -4-hexenoate

In a 250m L flask, under nitrogen atmosphere, 3- (4-hydroxyphenyl) -hex-4-enoic acid (20.0g) and ethanol (200m L) were charged, and after completion of dissolution by stirring, sulfuric acid (9.6m L) was slowly dropped at normal temperature, then, reflux stirring was performed for 6 hours or more, and if the reaction was completed, distilled water (150m L) was slowly dropped, then, extraction was performed by charging ethyl acetate (200m L), and several layers extracted were dried under reduced pressure to obtain the objective compound (19.5g, 85.7%).

¹H NMR(400MHz，CDCl₃)：7.25(2H，d)，6.78(2H，d)， 4.95(1H，s)，4.14(2H，m)，4.04(1H，m)，2.68(2H，m)， 1.84(3H，d)，1.29(3H，t)。

< preparation example 2> preparation of ethyl (S) -3- (4-hydroxyphenyl) -4-hexenoate

In a nitrogen atmosphere, (S) -3- (4-hydroxyphenyl) -hex-4-enoic acid (20.0g) and ethanol (200m L) were charged into a 250m L flask, and after completion of dissolution by stirring, sulfuric acid (9.6m L) was slowly dropped at normal temperature, and then, reflux stirring was performed for 6 hours or more, and after completion of the reaction, distilled water (150m L) was slowly dropped, followed by extraction with ethyl acetate (200m L), and several layers extracted were dried under reduced pressure to obtain the objective compound (21.2g, 93.2%).

¹H NMR(400MHz，CDCl₃)：7.25(2H，d)，6.78(2H，d)， 4.95(1H，s)，4.14(2H，m)，4.04(1H，m)，2.68(2H，m)， 1.84(3H，d)，1.29(3H，t)。

< preparation example 3> preparation of ethyl (R) -3- (4-hydroxyphenyl) -4-hexenoate

In a 250m L flask, under nitrogen atmosphere, (R) -3- (4-hydroxyphenyl) -hex-4-enoic acid (20.0g) and ethanol (200m L) were charged, and after completion of dissolution by stirring, sulfuric acid (9.6m L) was slowly dropped at normal temperature, and then, after reflux stirring was performed for 6 hours or more, if the reaction was completed, distilled water (150m L) was slowly dropped, followed by extraction with ethyl acetate (200m L), and several layers extracted were dried under reduced pressure to obtain the target compound (20.6g, 90.6%).

¹H NMR(400MHz，CDCl₃)：7.25(2H，d)，6.78(2H，d)， 4.95(1H，s)，4.14(2H，m)，4.04(1H，m)，2.68(2H，m)， 1.84(3H，d)，1.29(3H，t)。

< production example 4> production of (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) phenyl) methanol

Step 1: preparation of 1, 4-dioxaspiro [4, 5] dec-7-en-8-yl trifluoromethanesulfonate

1, 4-dioxaspiro [4.5] decan-8-one (30.0g) and toluene (300M L) were charged into a 1000M L flask under a nitrogen atmosphere, and after dissolution was completed by stirring, N-phenylbis (trifluoromethanesulfonimide) (64.3g) was added, then a 0.7M bis (trimethylsilyl) amino potassium solution (257M L) was slowly dropped into the flask at a temperature of-78 ℃ by means of a dropping funnel, and after slowly raising the temperature to room temperature, stirring was carried out for 4 hours or more, after completion of the reaction, distilled water (200M L) was slowly dropped, extraction was carried out by ethyl acetate (300M L), and then several layers extracted were dried under reduced pressure to obtain the objective compound (54.7g, 98.8%).

¹H NMR(400MHz，CDCl₃)：5.68(1H，t)，4.01(4H，s)，2.55(2H，t)，2.42(2H，d)，1.92(2H，t)。

Step 2: preparation of 3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzaldehyde

1, 4-dioxaspiro [4.5] dec-7-en-8-yl trifluoromethanesulfonate (54.70g) and toluene (300m L) were charged into a 1000m L flask under a nitrogen atmosphere, and after completion of dissolution by stirring, 3-formylphenylboronic acid (28.7g) and cesium carbonate (156g) were added, followed by cooling to 0 ℃ and slow addition of tetrakis (triphenylphosphine) palladium (11.09g), renewed heating to normal temperature and stirring for 3 hours or more, after completion of the reaction, distilled water (200m L) was slowly dropped, extraction was performed with ethyl acetate (300m L), and then several extracted layers were dried under reduced pressure to obtain the objective compound (45.9g, 99%).

¹H NMR(400MHz，CDCl₃)：10.03(1H，s)，7.92(1H，s)， 7.76(1H，d)，7.67(1H，d)，7.47(1H，t)，6.11(1H，s)，4.05 (4H，s)，2.71(2H，t)，2.51(2H，s)，1.97(2H，t)。

And step 3: preparation of (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) phenyl) methanol

In a nitrogen atmosphere, 3- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) benzaldehyde (46.9g), tetrahydrofuran (160m L) and methanol (40m L) were put into a 500m L flask, and after dissolution was completed by stirring, the flask was cooled to 0 ℃.

¹H NMR(400MHz，CDCl₃)：7.34(1H，s)，7.25(3H，m)， 6.01(1H，m)，4.69(2H，d)，4.04(4H，s)，2.68(2H，m)， 2.48(2H，s)，1.94(2H，t)，1.80(1H，t)。

< production example 5> production of (4- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) phenyl) methanol

Step 1: preparation of 4- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzaldehyde

1, 4-dioxaspiro [4.5] dec-7-en-8-yl trifluoromethanesulfonate (3.0g) and toluene (50m L) were charged into a 250m L flask under a nitrogen atmosphere, and after completion of dissolution by stirring, 3-formylphenylboronic acid (1.8g) and cesium carbonate (8.47g) were added and cooled to 0 ℃.

¹H NMR(400MHz，CDCl₃)：10.00(1H，s)，7.84(2H，d)， 7.57(2H，d)，6.19(1H，s)，4.06(4H，s)，2.71(2H，t)，2.53 (2H，s)，1.97(2H，t)。

Step 2: preparation of (4- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) phenyl) methanol

In a 250m L flask under nitrogen atmosphere, 4- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzaldehyde (2.0g), tetrahydrofuran (40m L) and methanol (10m L) were charged, and after completion of dissolution by stirring, it was cooled to 0 ℃.

¹H NMR(400MHz，CDCl₃)：7.40(2H，d)，7.32(2H，d)， 6.01(1H，m)，4.70(2H，d)，4.13(4H，s)，2.68(2H，t)， 2.49(2H，s)，1.93(2H，t)，1.60(1H，t)。

< preparation example 6> ethyl 3- (4- (4- ((methylsulfonyloxy) methyl) benzyloxy) phenyl) -4-hexenoate

Step 1: preparation of (4- (bromomethyl) phenyl) methanol

5.0g of methyl 4- (bromomethyl) benzoate and 20ml of Methylcellulose (MC) were charged into a flask of 1L under a nitrogen atmosphere, and after completion of dissolution by stirring, 70ml of diisobutylaluminum hydride (DIBA L-H) was slowly dropped at a temperature of-78 ℃.

¹H NMR(400MHz，CDCl₃)：7.42(2H，d)，7.38(2H，d)， 4.73(2H，s)，4.52(2H，m))。

Step 2: preparation of ethyl 3- (4- (4- (hydroxymethyl) benzyloxy) phenyl) -4-hexenoate

In a 500m L flask under a nitrogen atmosphere, 4.0g of ethyl 3- (4-hydroxyphenyl) -4-hexenoate obtained in the above preparation example 1 and 5.0g of (4- (bromomethyl) phenyl) methanol obtained in the above step 1 were added to 50ml of dimethylformamide, and stirring was carried outDissolved, and 9.0g of Cs is instilled₂CO₃Thereafter, the mixture was stirred at room temperature for 12 hours. After completion of the reaction, distilled water was slowly dropped, followed by extraction with ethyl acetate, washing with brine, drying with anhydrous magnesium sulfate, and concentration. Then, separation was performed by silica gel column chromatography, thereby obtaining the objective compound.

¹H NMR(400MHz，CDCl₃)：7.42(2H，d)，7.38(2H，d)， 7.29(2H，d)，6.93(2H，d)，5.06(2H，s)，4.73(2H，d)， 4.15(2H，m)，4.06(1H，m)，2.68(2H，m)，1.84(3H，s)， 1.69(1H，m)，1.24(3H，m)。

And step 3: preparation of ethyl 3- (4- (4- ((methylsulfonyloxy) methyl) benzyloxy) phenyl) -4-hexenoate

In a 500m L flask under nitrogen atmosphere, 3.0g of ethyl 3- (4- (4- (hydroxymethyl) benzyloxy) phenyl) -4-hexenoate obtained in the above step 2 was added to 30ml of methylcellulose, and after dissolving by stirring, 4.0ml of triethylamine was dropped at a temperature of 0 ℃.

¹H NMR(400MHz，CDCl₃)：7.49(4H，m)，7.29(2H，d)， 6.93(2H，d)，5.27(2H，s)，5.08(2H，s)，4.15(2H，m)， 4.06(1H，m)，2.95(3H，s)，2.68(2H，m)，1.84(3H，s)， 1.69(1H，m)，1.24(3H，m)。

< preparation example 7> preparation of ethyl (S) -3- (4- (4- ((methylsulfonyloxy) methyl) benzyloxy) phenyl) -4-hexenoate

Step 1: preparation of ethyl (S) -3- (4- (4- (hydroxymethyl) benzyloxy) phenyl) -4-hexenoate

The title compound was obtained in the same manner as in the above-mentioned step 2 of preparation example 6, except that ethyl (S) -3- (4-hydroxyphenyl) -4-hexenoate was used instead of ethyl 3- (4-hydroxyphenyl) -4-hexenoate.

¹H NMR(400MHz，CDCl₃)：7.42(2H，d)，7.38(2H，d)， 7.29(2H，d)，6.93(2H，d)，5.06(2H，s)，4.73(2H，d)， 4.15(2H，m)，4.06(1H，m)，2.68(2H，m)，1.84(3H，s)， 1.69(1H，m)，1.24(3H，m)。

Step 2: preparation of ethyl (S) -3- (4- (4- ((methylsulfonyloxy) methyl) benzyloxy) phenyl) -4-hexenoate

The objective compound was obtained in the same manner as in the above-mentioned step 3 of preparation example 6, except that ethyl (S) -3- (4- (4- (hydroxymethyl) benzyl) phenyl) -4-hexenoate obtained in the above-mentioned step 1 was used instead of ethyl 3- (4- (4- (hydroxymethyl) benzyloxy) phenyl) -4-hexenoate.

¹H NMR(400MHz，CDCl₃)：7.49(4H，m)，7.29(2H，d)， 6.93(2H，d)，5.27(2H，s)，5.08(2H，s)，4.15(2H，m)， 4.06(1H，m)，2.95(3H，s)，2.68(2H，m)，1.84(3H，s)， 1.69(1H，m)，1.24(3H，m)。

< preparation example 8> preparation of 6-methoxy-1, 2, 3, 4-tetrahydroisoquinoline

Step 1: preparation of 3-methoxyphenethylcarbamic acid ethyl ester

In a flask, under a nitrogen atmosphere, 25g of 2- (3-methoxyphenyl) ethylamine was charged into 300ml of methylcellulose, and after completion of dissolution by stirring, 24.2ml of triethylamine was dropwise added at a temperature of ℃. After 30 minutes, 16.6ml of ethyl chloroformate was slowly dropped, and after 1 hour, if the reaction was completed, distilled water was slowly dropped and extraction was performed with methyl cellulose. Several layers extracted were dried under reduced pressure to obtain the objective compound.

¹H NMR(400MHz，CDCl₃)：7.25(1H，m)，6.79(3H，m)， 4.70(1H，s)，4.13(2H，m)，3.81(3H，s)，3.46(2H，m)， 2.80(2H，m)，1.25(3H，m)。

Step 2: preparation of 6-methoxy-3, 4-dihydroisoquinoline-1 (2H) -one

36g of 3-methoxyphenethylurethane obtained in the above step 1 and 120g of polyphosphoric acid were stirred in a 500m L flask under a nitrogen atmosphere to complete dissolution, and heated under reflux for 3 hours or more, after cooling to room temperature, ethyl acetate and distilled water were slowly dropped to extract 3 times or more, after washing several extracted layers with brine, anhydrous magnesium sulfate was dried to complete concentration, and then, separation was performed by silica gel column chromatography to obtain the target compound.

¹H NMR(400MHz，CDCl₃)：8.03(1H，d)，6.87(1H，d)， 6.72(1H，s)，6.44(1H，s)，3.86(3H，s)，3.57(2H，m)， 2.98(2H，m)。

And step 3: preparation of 6-methoxy-1, 2, 3, 4-tetrahydroisoquinoline

In a nitrogen atmosphere, in a flask, to 150ml tetrahydrofuran is added in the step 2 obtained in 10g 6-methoxy-3, 4-two hydrogen isoquinoline-1 (2H) -ketone, after stirring to complete the dissolution, at 0 degrees C temperature slowly drip 4.3g L AH. in the heating reflux for more than 5 hours, if complete reaction, in slow drip distilled water, ethyl acetate extraction, saline water after washing, dried with anhydrous magnesium sulfate to complete the concentration, then, through solidification to obtain the target compound.

¹H NMR(400MHz，CDCl₃)：6.94(1H，d)，6.73(1H，d)， 6.65(1H，s)，4.14(2H，s)，3.80(3H，s)，3.13(2H，m)， 2.79(2H，m)。

< preparation example 9> preparation of 4- (4- (methylsulfonyl) phenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride

Step 1: preparation of 4- (4- (methylsulfonyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester

In a 1000m L flask under nitrogen atmosphere, 3.31g of 4- (trifluoromethylsulfonyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester and 50ml of toluene were charged, and after completion of dissolution by stirring, 2.0g of 4- (methylsulfonyl) phenylboronic acid was added to complete dissolution of 6.6g of cesium carbonate, then, after cooling to 0 ℃, 1.16g of tetrakis (triphenylphosphine) palladium was slowly added, and further, the temperature was raised to room temperature and stirring was carried out for 3 hours or more, after completion of the reaction, distilled water was slowly dropped, extraction was carried out with ethyl acetate, then, several layers extracted were dried under reduced pressure, and then, the target compound was obtained by silica gel column chromatography.

¹H NMR(400MHz，CDCl₃)：7.92(2H，d)，7.56(2H，d)， 6.21(1H，s)，4.14(2H，d)，3.68(2H，m)，3.07(3H，s)，2.56(2H，s)，1.49(9H，s)。

Step 2: preparation of 4- (4- (methylsulfonyl) phenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride

After 1.4g of tert-butyl 4- (4- (methylsulfonyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate obtained in the above step 1 was dissolved in 20ml of methylcellulose, 10.4ml of 4N hydrochloric acid (HCl) was dropped. After 5 hours, if the reaction is completed, the target compound is obtained by curing after dropping diethyl ether.

¹H NMR(400MHz，D₂O)：7.92(2H，d)，7.56(2H，d)， 6.21(1H，s)，4.14(2H，d)，3.68(2H，m)，3.07(3H，s)， 2.56(2H，s)。

< preparation example 10> preparation of 4- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenol hydrochloride

Step 1: preparation of 4- (4-hydroxyphenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester

The objective compound was obtained in the same manner as in the above-mentioned step 1 of production example 9, except that 4-hydroxyphenylboronic acid was used instead of 4- (methylsulfonyl) phenylboronic acid.

¹H NMR(400MHz，CDCl₃)：7.26(2H，d)，6.83(2H，d)，5.93(1H，s)，5.47(1H，s)，4.07(2H，s)，3.66(2H，m)， 2.50(2H，s)，1.52(9H，s)。

Step 2: preparation of 4- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenol hydrochloride

The objective compound was obtained in the same manner as in step 2 of the above preparation example 9, except that tert-butyl 4- (4-hydroxyphenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate obtained in the above step 1 was used in place of tert-butyl 4- (4- (methylsulfonyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate.

¹H NMR(400MHz，D₂O)：7.26(2H，d)，6.83(2H，d)， 5.93(1H，s)，5.47(1H，s)，4.07(2H，s)，3.66(2H，m)， 2.50(2H，s)。

< preparation example 11> preparation of 4- (4- (3- (methylsulfonyl) propoxy) phenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride

Step 1: preparation of 3- (methylthio) propyl 4-methylbenzenesulfonate

In a 500m L flask under nitrogen atmosphere, 25.4g of 3- (methylthio) propan-1-ol was charged into 500ml of methylcellulose, and after stirring to complete dissolution, 44ml of triethylamine was dropped at a temperature of 0 ℃, after 30 minutes, 46g of TsCl was slowly dropped, and after 1 hour of reaction, after distilled water was slowly dropped, extraction was completed with methylcellulose, several layers extracted were dried under reduced pressure to obtain the objective compound.

¹H NMR(400MHz，CDCl₃)：7.81(2H，d)，7.38(2H，d)， 4.16(2H，m)，2.53(2H，m)，2.47(3H，s)，2.05(3H，s)， 1.94(2H，m)。

Step 2: preparation of 3- (methylsulfonyl) propyl 4-methylbenzenesulfonate

In a flask, under a nitrogen atmosphere, to 150/100ml of tetrahydrofuran/distilled water were charged 62g of 3- (methylthio) propyl 4-methylbenzenesulfonate obtained in the above-described step 1, and after dissolution was completed by stirring, 310g of oxone (oxone) was dropped at a temperature of 0 ℃. After stirring at room temperature for 12 hours, when the reaction was completed, distilled water was slowly dropped, and then extraction was performed with ethyl acetate, followed by washing with brine, drying with anhydrous magnesium sulfate, and concentration to obtain the objective compound.

¹H NMR(400MHz，CDCl₃)：7.81(2H，d)，7.38(2H，d)， 4.20(2H，m)，3.13(2H，m)，2.93(3H，s)，2.48(3H，s)， 2.23(2H，m)。

And step 3: preparation of 4- (4- (3- (methylsulfonyl) propoxy) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester

The objective compound was obtained in the same manner as in step 2 of preparation example 6 above, except that tert-butyl 4- (4-hydroxyphenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate obtained in step 1 of preparation example 10 above and 3- (methylsulfonyl) propyl 4-methylbenzenesulfonate obtained in step 2 above were used.

¹H NMR(400MHz，CDCl₃)：7.34(2H，d)，6.85(2H，d)， 6.00(1H，s)，4.12(2H，s)，3.28(2H，m)，3.18(2H，s)， 2.97(3H，s)，2.72(2H，m)，2.56(2H，m)，2.36(2H，m)， 1.52(9H，s)。

And 4, step 4: preparation of 4- (4- (3- (methylsulfonyl) propoxy) phenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride

The objective compound was obtained in the same manner as in step 2 of the above preparation example 9, except that tert-butyl 4- (4- (3- (methylsulfonyl) propoxy) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate obtained in the above step 3 was used in place of tert-butyl 4- (4- (methylsulfonyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate.

¹H NMR(400MHz，D₂O)：7.34(2H，d)，6.85(2H，d)， 6.00(1H，s)，4.12(2H，s)，3.28(2H，m)，3.18(2H，s)， 2.97(3H，s)，2.72(2H，m)，2.56(2H，m)，2.36(2H，m)。

< preparation example 12> preparation of (3S) -3- (4- (4- (1-bromoethyl) benzyloxy) phenyl) -4-hexenoic acid ethyl ester

Step 1: preparation of 1- (4- (bromomethyl) phenyl) ethanone

To 100ml of CCl in a flask under nitrogen atmosphere₄5.0g of 1-p-tolylethane was charged and after completion of dissolution by stirring, 14.6g of N-bromosuccinimide (NBS) and 6.7g of azobisisobutyric acid were dropwise added at a temperature of 0 ℃Nitrile (AIBN). After the reaction was completed after the reflux by heating for 5 hours or more, distilled water was slowly dropped, followed by extraction with methylcellulose, washing with brine, and drying with anhydrous magnesium sulfate to complete concentration. Then, the target compound was isolated by silica gel column chromatography.

¹H NMR(400MHz，CDCl₃)：7.95(2H，d)，7.50(2H，d)， 4.52(2H，s)，2.62(3H，s)。

Step 2: preparation of ethyl (S) -3- (4- (4-acetylbenzyloxy) phenyl) -4-hexenoate

The objective compound was obtained in the same manner as in step 2 of preparation example 6 above, except that ethyl (S) -3- (4-hydroxyphenyl) -4-hexenoate obtained in preparation example 2 above and 1- (4- (bromomethyl) phenyl) ethanone obtained in step 1 above were used.

¹H NMR(400MHz，CDCl₃)：7.99(2H，d)，7.53(2H，d) 7.31(2H，d)，6.92(2H，d)，5.13(2H，s)，4.15(2H，m)， 4.09(1H，m)，2.75(2H，m)，2.64(3H，s)，1.84(3H，d)， 1.24(3H，m)。

And step 3: preparation of ethyl (3S) -3- (4- (4- (1-hydroxyethyl) benzyloxy) phenyl) -4-hexenoate

In a flask, under a nitrogen atmosphere, 1.0g of ethyl (S) -3- (4- (4-acetylbenzyloxy) phenyl) -4-hexenoate obtained in the above step 2 was charged to 50ml of tetrahydrofuran, and after completion of dissolution by stirring, 0.16g of NaBH4 was dropwise added at a temperature of 0 ℃. After stirring at room temperature for 2 hours or more, when the reaction was completed, distilled water was gradually dropped and extracted with EA, washed with brine, dried over anhydrous magnesium sulfate, and concentrated to obtain the objective compound.

¹H NMR(400MHz，CDCl₃)：8.02(2H，d)，7.57(2H，d) 7.36(2H，d)，6.99(2H，d)，5.21(2H，s)，4.23(2H，m)， 4.17(1H，m)，3.81(1H，s)，2.75(2H，m)，2.64(3H，s)， 1.84(3H，d)，1.24(3H，m)。

And 4, step 4: preparation of ethyl (3S) -3- (4- (4- (1-bromoethyl) benzyloxy) phenyl) -4-hexenoate

In a flask, under a nitrogen atmosphere, to 50ml of methylcellulose was charged 0.76g of ethyl (3S) -3- (4- (4- (1-hydroxyethyl) benzyloxy) phenyl) -4-hexenoate obtained in the above-mentioned step 3, and after completion of dissolution by stirring, 0.6g of triphenylphosphine and 0.75g of CBr were dropped at a temperature of 0 deg.C₄. After stirring at room temperature for 2 hours or more, when the reaction was completed, distilled water was slowly dropped and extracted with EA, washed with brine, dried over anhydrous magnesium sulfate, and concentrated to obtain the objective compound.

¹H NMR(400MHz，CDCl₃)：8.02(2H，d)，7.57(2H，d) 7.36(2H，d)，6.99(2H，d)，5.21(2H，s)，4.23(2H，m)， 4.17(1H，m)，3.92(1H，s)，2.85(2H，m)，2.44(3H，s)， 1.86(3H，d)，1.27(3H，m)。

< preparation example 13> preparation of 2- (piperazin-1-yl) benzo [ d ] thiazole hydrochloride

Step 1: preparation of 4- (benzo [ d ] thiazol-2-yl) piperazine-1-carboxylic acid tert-butyl ester

In a flask, 2.0g of piperazine-1-carboxylic acid tert-butyl ester was put into 100/50ml of AN/distilled water under a nitrogen atmosphere, and after completion of dissolution by stirring, 2.1ml of N, N-Diisopropylethylamine (DIPEA) was dropped at a temperature of 0 ℃. Then, after 0.9g of 2-chlorobenzo [ d ] thiazole was dropped, the mixture was refluxed for 2 hours or more, and when the reaction was completed, distilled water was slowly dropped, and then extracted with EA, washed with brine, dried with anhydrous magnesium sulfate, and concentrated to obtain the objective compound.

¹H NMR(400MHz，CDCl₃)：7.61(1H，d)，7.60(1H，d)， 7.29(1H，m)，7.09(1H，m)，3.77(4H，m)，2.62(4H，m)， 1.52(9H，s)。

Step 2: preparation of 2- (piperazin-1-yl) benzo [ d ] thiazole hydrochloride

The target compound was obtained in the same manner as in step 2 of the above preparation example 9, except that tert-butyl 4- (benzo [ d ] thiazol-2-yl) piperazine-1-carboxylate obtained in the above step 1 was used in place of tert-butyl 4- (4- (methylsulfonyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate.

¹H NMR(400MHz，D₂O)：7.61(1H，d)，7.60(1H，d)， 7.29(1H，m)，7.09(1H，m)，3.77(4H，m)，2.62(4H，m)。

< preparation example 14> preparation of 2- (piperazin-1-yl) -5-propylpyrimidine hydrochloride

Step 1: preparation of 4- (5-propylpyrimidin-2-yl) piperazine-1-carboxylic acid tert-butyl ester

The objective compound was obtained in the same manner as in the above-mentioned step 1 of production example 13, except that 2-chloro-5-propylpyrimidine was used instead of 2-chlorobenzo [ d ] thiazole.

¹H NMR(400MHz，CDCl₃)：8.19(2H，s)，3.77(4H，m)， 2.62(4H，m)，2.41(2H，m)，1.61(2H，m)，1.52(9H，s)， 0.96(3H，m)。

Step 2: preparation of 2- (piperazin-1-yl) -5-propylpyrimidine hydrochloride

The objective compound was obtained in the same manner as in step 2 of the above preparation example 9, except that tert-butyl 4- (5-propylpyrimidin-2-yl) piperazine-1-carboxylate obtained in the above step 1 was used in place of tert-butyl 4- (4- (methylsulfonyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate.

¹H NMR(400MHz，D₂O)：8.19(2H，s)，3.77(4H，m)， 2.62(4H，m)，2.41(2H，m)，1.61(2H，m)，0.96(3H，m)。

< preparation example 15> preparation of 6- (piperazin-1-yl) nicotinonitrile hydrochloride

Step 1: preparation of 4- (5-cyanopyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester

The objective compound was obtained in the same manner as in the above-mentioned step 1 of production example 13, except that 6-chloronicotinonitrile was used in place of 2-chlorobenzo [ d ] thiazole.

¹H NMR(400MHz，CDCl₃)：8.41(1H，s)7.61(1H，d)， 6.59(1H，d)，3.77(4H，m)，2.62(4H，m)，1.52(9H，s)。

Step 2: preparation of 6- (piperazin-1-yl) nicotinonitrile hydrochloride

The objective compound was obtained in the same manner as in step 2 of the above preparation example 9, except that tert-butyl 4- (5-cyanopyridin-2-yl) piperazine-1-carboxylate obtained in the above step 1 was used in place of tert-butyl 4- (4- (methylsulfonyl) phenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate.

¹H NMR(400MHz，D₂O)：8.41(1H，s)7.61(1H，d)，6.59 (1H，d)，3.77(4H，m)，2.62(4H，m)。

< preparation example 16> preparation of ethyl (S) -3- (4- (4- (2- (methylsulfonyloxy) ethyl) benzyloxy) phenyl) -4-hexenoate

Step 1: preparation of 2- (4- (bromomethyl) phenyl) ethanol

5g of 2- (4- (bromomethyl) phenyl) acetic acid and 100ml of tetrahydrofuran were charged into a flask under a nitrogen atmosphere, and after completion of dissolution by stirring, 70ml of a borane-tetrahydrofuran solution was slowly dropped at a temperature of 0 ℃. After stirring for 2 hours, if the reaction is completed, the temperature is lowered to 0 ℃, and after slowly dropping distilled water, extraction is performed using EA. Several layers extracted were dried under reduced pressure to obtain the objective compound.

¹H NMR(400MHz，CDCl₃)：37(2H，d)，7.24(2H，d)， 4.51(2H，s)，3.89(2H，m)，2.89(2H，m)。

Step 2: preparation of ethyl (S) -3- (4- (4- (2-hydroxyethyl) benzyloxy) phenyl) -4-hexenoate

The objective compound was obtained in the same manner as in step 2 of the above production example 6, except that 2- (4- (bromomethyl) phenyl) ethanol obtained in the above step 1 was used instead of (4- (bromomethyl) phenyl) methanol.

¹H NMR(400MHz，CDCl₃)：7.40(2H，d)，7.30(2H，d)， 7.27(2H，d)，6.95(2H，d)，5.04(2H，s)，4.18(2H，m)，4.11(1H，m)，3.89(2H，m)，2.91(2H，m)，2.71(2H，m)， 1.84(3H，s)，1.38(1H，m)，1.25(3H，m)。

And step 3: preparation of ethyl (S) -3- (4- (4- (2- (methylsulfonyloxy) ethyl) benzyloxy) phenyl) -4-hexenoate

The objective compound was obtained in the same manner as in the above-mentioned step 3 of preparation example 6, except that ethyl (S) -3- (4- (4- (2-hydroxyethyl) benzyloxy) phenyl) -4-hexenoate obtained in the above-mentioned step 2 was used instead of ethyl 3- (4- (4- (hydroxymethyl) benzyloxy) phenyl) -4-hexenoate.

¹H NMR(400MHz，CDCl₃)：7.40(2H，d)，7.30(2H，d)， 7.27(2H，d)，6.95(2H，d)，5.04(2H，s)，4.18(2H，m)， 4.11(1H，m)，3.99(2H，m)，2.95(3H，s)，2.93(2H，m)， 2.71(2H，m)，1.84(3H，s)，1.25(3H，m)。

< example 1> preparation of 3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid

Step 1: preparation of ethyl 3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoate

(3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) phenyl) methanol (19.54g) and tetrahydrofuran (80m L) prepared in production example 4 were charged into a 500m L flask under a nitrogen atmosphere, and after completion of dissolution by stirring, ethyl 3- (4-hydroxyphenyl) -4-hexenoate (18.42g) and triphenylphosphine (31.21g) prepared in production example 1 were slowly added, and then diisopropyl azodicarboxylate (23.4m L) was slowly dropped using a dropping funnel at a temperature of 0 ℃ and stirred for 4 hours or more by raising the temperature to normal temperature, and when the reaction was completed, distilled water (200m L) was slowly dropped, and after extraction with ethyl acetate (300m L), some of the extracted layers were dried under reduced pressure to obtain the target compound (32.1g, 87.9%).

¹H NMR(400MHz，CDCl₃)：7.46(1H，s)，7.31(5H，m)， 6.93(2H，d)，6.02(1H，m)，5.04(2H，s)，4.13(2H，m)， 4.08(1H，m)，4.04(4H，s)，2.69(4H，m)，2.49(2H，s)， 1.94(2H，t)，1.84(3H，d)，1.31(3H，t)。

Step 2: preparation of 3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid

In a nitrogen atmosphere, to a 500M L flask, ethyl 3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoate (32.1g), methanol (50M L) and distilled water (50M L) prepared in the above step 1 were charged, and after completion of dissolution by stirring, potassium hydroxide (19.5g) was slowly added at normal temperature and stirred for 1 hour or more, and if the reaction was completed, the pH was acidified to 2 to 3 with 1M hydrochloric acid aqueous solution, extraction was performed with ethyl acetate (300M L), and then, the objective compound (24.1g, 79.9%) was obtained by drying under reduced pressure.

¹H NMR(400MHz，CDCl₃)：7.44(1H，s)，7.34(5H，m)， 6.91(2H，d)，6.00(1H，t)，5.02(2H，s)，4.08(1H，m)， 4.04(4H，s)，2.73(4H，m)，2.48(2H，s)，1.92(2H，t)， 1.82(3H，s)。

< example 2> preparation of 3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid L-lysine salt

3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid (24.1g) prepared in the above example 1 and ethanol (170m L) were charged into a 500m L flask under a nitrogen atmosphere, and after completion of dissolution by stirring, L-lysine (7.33g) was added, then, the reaction temperature was raised to 50 ℃ and stirred at a temperature of 50 ℃ for about 30 minutes, and then cooled again to room temperature and stirred for about 30 minutes, and if the reaction was completed, the produced solid was filtered to obtain the objective compound (31.5g, 73.3%).

¹H NMR(400MHz，D₂O)：7.11(3H，m)，6.99(3H，m)， 6.64(2H，d)，5.65(1H，s)，4.59(2H，s)，3.79(5H，s)，3.60 (1H，t)，2.88(2H，t)，2.35(2H，d)，2.23(2H，s)，2.14(2H， s)，1.75(2H，m)，1.59(7H，m)，1.38(2H，m)。

< example 3> preparation of 4- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid

Step 1: preparation of ethyl 4- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoate

After (4- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) phenyl) methanol (1.5g) prepared in production example 5 and tetrahydrofuran (20m L) were charged into a 100m L flask under a nitrogen atmosphere, and dissolution was completed by stirring, ethyl 3- (4-hydroxyphenyl) -4-hexenoate (1.41g) prepared in production example 1 and triphenylphosphine (2.39g) were slowly added, diisopropyl azodicarboxylate (9.38m L) was slowly dropped using a dropping funnel at a temperature of 0 ℃, after the temperature was raised to room temperature and stirring was completed for 4 hours or more, distilled water (50m L) was slowly dropped, and after extraction was completed with ethyl acetate (100m L), several layers extracted were dried under reduced pressure to obtain the target compound (1.38g, 49.2%).

¹H NMR(400MHz，CDCl₃)：7.42(2H，d)，7.37(2H，d)，7.30(2H，d)，6.92(2H，d)，6.01(1H，s)，5.01(2H，s)， 4.14(2H，m)，4.06(5H，m)，2.70(4H，m)，2.49(2H，s)， 1.94(2H，t)，1.84(3H，d)，1.24(3H，t)。

Step 2: preparation of 4- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid

In a 500M L flask, under nitrogen atmosphere, the 4- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid ethyl ester (1.38g) prepared in the above step 1, methanol (10M L) and distilled water (10M L) were charged, and after completion of dissolution by stirring, potassium hydroxide (1.25g) was slowly added at ordinary temperature and stirred for 1 hour or more, if the reaction was completed, the pH was acidified to 2 to 3 with 1M hydrochloric acid aqueous solution, extraction was performed with ethyl acetate (50M L), and then, the target compound (0.98g, 75.6%) was obtained by drying under reduced pressure.

¹H NMR(400MHz，CDCl₃)：7.41(2H，d)，7.36(2H，d)， 7.29(2H，d)，6.92(2H，d)，6.01(1H，s)，5.01(2H，s)， 4.04(5H，m)，2.77(4H，m)，2.49(2H，s)，1.96(2H，t)， 1.83(3H，d)。

< example 4> preparation of 3- (4- (3- (4-oxocyclohexyl-1-alkenyl) benzyloxy) phenyl) -4-hexenoic acid

3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid (1g) prepared in the above example 1 and tetrahydrofuran (5m L) were charged under a nitrogen atmosphere, and after completion of dissolution by stirring, 6N aqueous hydrochloric acid (5m L) was added and stirred at normal temperature for 1 hour or more, when the reaction was completed, distilled water (50m L) was slowly dropped, and after extraction with ethyl acetate (50m L), some of the extracted layers were dried under reduced pressure to obtain the objective compound (0.76g, 84.6%).

¹H NMR(400MHz，CDCl₃)：7.48(1H，s)，7.40(5H，m)，6.94(2H，d)，6.13(1H，s)，5.07(2H，s)，4.05(1H，m)， 3.10(1.5H，t)，2.93(1.5H，t)，2.82(2H，m)，2.67(2H，t)， 1.85(3H，s)。

< example 5> preparation of 3- (4- (3- (4-hydroxycyclohexyl-1-alkenyl) benzyloxy) phenyl) -4-hexenoic acid

In a 100m L flask under nitrogen atmosphere, 3- (4- (3- (4-oxocyclohexyl-1-alkenyl) benzyloxy) phenyl) -4-hexenoic acid (1g) prepared in the above example 4 and ethanol (10m L) were charged, and after completion of dissolution by stirring, sodium borohydride (0.3g) was added and stirred at room temperature for 3 hours or more, and if the reaction was completed, the pH was acidified to 4 to 5 with 1N hydrochloric acid aqueous solution, extraction was performed with ethyl acetate (100m L) and distilled water (100m L), and several of the extracted layers were dried under reduced pressure to obtain the objective compound (0.81g, 80.6%).

¹H NMR(400MHz，CDCl₃)：7.44(1H，s)，7.33(5H，m)， 6.93(2H，d)，6.02(1H，s)，5.03(2H，s)，4.08(2H，s)，2.78 (2H，m)，2.55(2.5H，m)，2.22(1H，m)，2.04(1H，m)， 1.85(3H，s)。

< example 6> preparation of 3- (4- (3- (4-hydroxycyclohexyl-1-alkenyl) benzyloxy) phenyl) -4-hexenoic acid L-lysine salt

After 3- (4- (3- (4-hydroxycyclohexyl-1-enyl) benzyloxy) phenyl) -4-hexenoic acid (1g) prepared in the above example 5 and ethanol (170m L) were charged into a 100m L flask under a nitrogen atmosphere and dissolved by stirring, L-lysine (0.7g) was added, then, the reaction was heated to 50 ℃ and stirred at 50 ℃ for about 30 minutes, then cooled again to room temperature and stirred for about 30 minutes, and if the reaction was completed, the produced solid was filtered to obtain the objective compound (0.95g, 69.1%).

¹H NMR(400MHz，D₂O)：7.11(3H，m)，6.99(3H，m)， 6.64(2H，d)，5.65(1H，s)，4.59(2H，s)，3.79(1H，s)，3.60 (1H，t)，2.88(2H，t)，2.35(2H，d)，2.23(2H，s)，2.14(2H， s)，1.75(2H，m)，1.59(7H，m)，1.38(2H，m)。

< example 7> preparation of (3S) -3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid

Step 1: preparation of ethyl- (3S) -3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid

(3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) phenyl) methanol (19.54g) and tetrahydrofuran (80m L) prepared in the above production example 4 were put into a 500m L flask under a nitrogen atmosphere, and after completing dissolution by stirring, (S) -3- (4-hydroxyphenyl) -4-hexenoic acid ethyl ester (18.42g) and triphenylphosphine (31.21g) prepared in the above production example 2 were slowly added dropwise, diisopropyl azodicarboxylate (23.4m L) was then slowly dropped at a temperature of 0 ℃ by a dropping funnel and stirred for 4 hours or more by raising the temperature to normal temperature, when the reaction was completed, distilled water (200m L) was slowly dropped, and after extraction with ethyl acetate (300m L), several layers extracted were dried under reduced pressure to obtain the target compound.

¹H NMR(400MHz，CDCl₃)：7.46(1H，s)，7.31(5H，m)， 6.93(2H，d)，6.02(1H，m)，5.04(2H，s)，4.13(2H，m)， 4.08(1H，m)，4.04(4H，s)，2.69(4H，m)，2.49(2H，s)，1.94(2H，t)，1.84(3H，d)，1.31(3H，t)。

Step 2: preparation of (3S) -3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid

Ethyl- (3S) -3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid (32.1g) prepared in the above step 1, methanol (50M L) and distilled water (50M L) were charged into a 500M L flask under a nitrogen atmosphere, and after completion of dissolution by stirring, potassium hydroxide (19.5g) was slowly added at normal temperature and stirred for 1 hour or more, and if the reaction was completed, the pH was acidified to 2 to 3 with 1M aqueous hydrochloric acid, extraction was performed with ethyl acetate (300M L), and then the objective compound (24.1g, 66.2%) was obtained by drying under reduced pressure.

¹H NMR(400MHz，CDCl₃)：7.44(1H，s)，7.34(5H，m)， 6.91(2H，d)，6.00(1H，t)，5.02(2H，s)，4.08(1H，m)， 4.04(4H，s)，2.73(4H，m)，2.48(2H，s)，1.92(2H，t)， 1.82(3H，s)。

< example 8> preparation of (3R) -3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid

Step 1: preparation of ethyl- (3R) -3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid

After (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) phenyl) methanol (19.54g) and tetrahydrofuran (80m L) prepared in preparation example 4 were charged into a 500m L flask under a nitrogen atmosphere, and after dissolution was completed by stirring, (R) -3- (4-hydroxyphenyl) -4-hexenoic acid ethyl ester (18.42g) and triphenylphosphine (31.21g) prepared in preparation example 3 were slowly added, diisopropyl azodicarboxylate (23.4m L) was slowly dropped into the flask at 0 ℃ by a dropping funnel, the temperature was raised to room temperature, and stirring was performed for 4 hours or more, after completion of the reaction, distilled water (200m L) was slowly dropped, and after extraction with ethyl acetate (300m L), several layers extracted were dried under reduced pressure to obtain the target compound.

¹H NMR(400MHz，CDCl₃)：7.46(1H，s)，7.31(5H，m)， 6.93(2H，d)，6.02(1H，m)，5.04(2H，s)，4.13(2H，m)， 4.08(1H，m)，4.04(4H，s)，2.69(4H，m)，2.49(2H，s)， 1.94(2H，t)，1.84(3H，d)，1.31(3H，t)。

Step 2: preparation of (3R) -3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid

Ethyl- (3R) -3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid (32.1g) prepared in the above step 1, methanol (50M L) and distilled water (50M L) were charged into a 500M L flask under a nitrogen atmosphere, and after completion of dissolution by stirring, potassium hydroxide (19.5g) was slowly added at normal temperature and stirred for 1 hour or more, and if the reaction was completed, the pH was acidified to 2 to 3 with 1M aqueous hydrochloric acid, extraction was performed with ethyl acetate (300M L), and then the objective compound (17.3g, 47.5%) was obtained by drying under reduced pressure.

¹H NMR(400MHz，CDCl₃)：7.44(1H，s)，7.34(5H，m)， 6.91(2H，d)，6.00(1H，t)，5.02(2H，s)，4.08(1H，m)， 4.04(4H，s)，2.73(4H，m)，2.48(2H，s)，1.92(2H，t)， 1.82(3H，s)。

< example 9> preparation of (3S) -3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid L-lysine salt

To a 500m L flask under a nitrogen atmosphere were charged (3S) -3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid (24.1g) prepared in the above example 7 and ethanol (170m L), and after completion of dissolution by stirring, L-lysine (7.33g) was added, then, the reaction temperature was raised to 50 ℃, and after stirring at a temperature of 50 ℃ for about 30 minutes, re-cooled to room temperature and stirred for about 30 minutes, and if the reaction was completed, the resulting solid was filtered to obtain the objective compound (22.5g, 69.8%).

¹H NMR(400MHz，D₂O)：7.11(3H，m)，6.99(3H，m)， 6.64(2H，d)，5.65(1H，s)，4.59(2H，s)，3.79(5H，s)，3.60 (1H，t)，2.88(2H，t)，2.35(2H，d)，2.23(2H，s)，2.14(2H， s)，1.75(2H，m)，1.59(7H，m)，1.38(2H，m)。

< example 10> preparation of (3R) -3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid L-lysine salt

(3R) -3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid (24.1g) prepared in the above example 8 and ethanol (170m L) were charged into a 500m L flask under a nitrogen atmosphere, and after completion of dissolution by stirring, L-lysine (7.33g) was added, then, the reaction temperature was raised to 50 ℃ and stirred at a temperature of 50 ℃ for about 30 minutes and then, cooled again to room temperature and stirred for about 30 minutes, and if the reaction was completed, the resulting solid was filtered to obtain the objective compound (16.2g, 71.4%).

¹H NMR(400MHz，D₂O)：7.11(3H，m)，6.99(3H，m)， 6.64(2H，d)，5.65(1H，s)，4.59(2H，s)，3.79(5H，s)，3.60 (1H，t)，2.88(2H，t)，2.35(2H，d)，2.23(2H，s)，2.14(2H， s)，1.75(2H，m)，1.59(7H，m)，1.38(2H，m)。

< example 11> preparation of (3S) -3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid sodium salt

In a 500m L flask under nitrogen atmosphere, (3S) -3- (4- (3- (1, 4-dioxaspiro [4, 5] dec-7-en-8-yl) benzyloxy) phenyl) -4-hexenoic acid (1g) prepared in the above example 7 and ethanol (170m L) were charged, and after completion of dissolution by stirring, a 3N aqueous sodium hydroxide solution (0.77m L) was dropwise added.

¹H NMR(400，CDCl₃)：7.44(1H，s)，7.34(5H，m)，6.91 (2H，d)，6.00(1H，t)，5.02(2H，s)，4.08(1H，m)，4.04 (4H，s)，2.73(4H，m)，2.48(2H，s)，1.92(2H，t)，1.82 (3H，s)

< example 12> preparation of 3- (4- (4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

Step 1: preparation of ethyl (4- (4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) -4-hexenoate

In a flask under nitrogen atmosphere, to 20ml of Dimethylformamide (DMF), 0.5g of 1, 2, 3, 4-tetrahydroisoquinoline was charged, and after completion of dissolution by stirring, 1.2g of cesium carbonate was added at normal temperature. After 30 minutes, after dropping 1.0g of ethyl 3- (4- (4- ((methylsulfonyloxy) methyl) benzyloxy) phenyl) -4-hexenoate obtained in the above preparation example 6, it was stirred at ordinary temperature for 12 hours. When the reaction was completed, after distilled water was slowly dropped, extraction was performed with ethyl acetate, and after washing with brine (brine), drying was performed with anhydrous magnesium sulfate and concentration was completed. Then, the target compound was isolated by silica gel column chromatography.

¹H NMR(400MHz，CDCl₃)：7.38(2H，d)，7.31(2H，d)， 7.22(2H，d)，7.16(3H，m)，6.97(3H，m)，4.98(2H，s)， 4.14(2H，m)，4.09(1H，s)，3.91(1H，d)，3.70(3H，m)， 2.92(4H，s)，2.73(2H，m)，1.83(3H，s)，1.29(3H，m)。

Step 2: preparation of 3- (4- (4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

Into a flask, under a nitrogen atmosphere, 0.7g of (4- (4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid ethyl ester prepared in the above-mentioned step 1 was chargedTetrahydrofuran, methanol and distilled water, and after completing dissolution by stirring, 0.7g of lithium hydroxide was slowly added at normal temperature and stirred for 1 hour or more. When the reaction was completed, the pH was acidified to 2 to 3 with 1M hydrochloric acid aqueous solution, and after extraction with ethyl acetate, the target compound was obtained by drying under reduced pressure.

¹H NMR(400MHz，CDCl₃)：7.38(2H，d)，7.31(2H，d)， 7.22(2H，d)，7.16(3H，m)，6.97(3H，m)，4.98(2H，s)， 4.09(1H，s)，3.91(1H，d)，3.70(3H，m)，2.92(4H，s)， 2.73(2H，m)，1.83(3H，s)。

< example 13> preparation of 3- (4- (3-cyclohexenyl-4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

Step 1: preparation of ethyl (3-cyclohexenyl-4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) -4-hexenoate

Into a flask, under a nitrogen atmosphere, 1.0g of (3-cyclohexenyl-4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) methanol and 30ml of tetrahydrofuran were charged, and after completion of dissolution by stirring, 0.8g of ethyl 3- (4-hydroxyphenyl) -4-hexenoate obtained in the above preparation example 1 and 0.6g of triphenylphosphine were slowly added. Then, 0.5ml of diisopropyl azodicarboxylate was slowly dropped into the mixture at a temperature of 0 ℃ through a dropping funnel, and after the temperature was raised to normal temperature, the mixture was stirred for 4 hours or more. When the reaction was completed, distilled water was slowly dropped, and after extraction with ethyl acetate, several extracted layers were dried under reduced pressure to obtain the target compound.

¹H NMR(400MHz，CDCl₃)：12.56(1H，s)，8.26(1H，d)， 7.43(2H，d)，7.25(6H，m)，7.21(1H，d)，7.02(1H，d)， 6.89(2H，d)，5.46(1H，s)，5.03(2H，s)，4.14(2H，m)， 4.05(1H，s)，3.92(1H，s)，3.70(1H，s)，3.35(1H，s)，3.27 (1H，s)，3.03(1H，s)，2.83(2H，m)，2.01(4H，m)，1.84 (3H，d)，1.51(4H，m)，1.29(3H，m)。

Step 2: preparation of 3- (4- (3-cyclohexenyl-4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in step 2 of the above-mentioned example 12, except for using (3-cyclohexenyl-4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) -4-hexenoic acid ethyl ester instead of (4- (4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid ethyl ester.

¹H NMR(400MHz，CDCl₃)：12.56(1H，s)，8.26(1H，d)， 7.43(2H，d)，7.25(6H，m)，7.21(1H，d)，7.02(1H，d)， 6.89(2H，d)，5.46(1H，s)，5.03(2H，s)，4.05(1H，s)，3.92 (1H，s)，3.70(1H，s)，3.35(1H，s)，3.27(1H，s)，3.03 (1H，s)，2.83(2H，m)，2.01(4H，m)，1.84(3H，d)，1.51 (4H，m)。

< example 14> preparation of 3- (4- (4- ((4-phenyl-5, 6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 12 above except for using 4-phenyl-1, 2, 3, 6-tetrahydropyridine hydrochloride in place of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：7.25(2H，d)，6.78(2H，d)， 4.95(1H，s)，4.14(2H，m)，4.04(1H，m)，2.68(2H，m)， 1.84(3H，d)，1.29(3H，t)。

< example 15> preparation of 3- (4- (4- ((4-phenylpiperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 12 above, except that 1-phenylpiperazine was used in place of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：7.37(2H，d)，7.29(4H，m)， 7.11(2H，d)，6.93(5H，m)，4.96(2H，s)，4.13(1H，s)， 3.66(2H，m)，3.23(4H，s)，2.83(2H，m)，2.66(2H，s)， 1.82(3H，s)。

< example 16> preparation of 3- (4- (4- ((6-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 12 above except for using 6-methoxy-1, 2, 3, 4-tetrahydroisoquinoline obtained in the above preparation example 8 in place of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：7.40(4H，q)，7.26(2H，d)， 6.92(3H，q)，6.66(2H，d)，5.06(2H，s)，3.94(1H，s)， 3.73(3H，s)，3.63(2H，s)，3.35(3H，s)，2.78(2H，t)，2.62 (2H，t)，2.58(2H，s)，1.77(3H，s)

< example 17> preparation of 3- (4- (4- ((4-phenylpiperidin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 12 above except for using 4-phenylpiperidine in place of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：7.44(2H，d)，7.32(2H，d)， 7.23(5H，t)，7.13(2H，d)，6.96(2H，d)，4.92(2H，s)，4.16 (1H，s)，3.85(2H，q)，3.33(2H，t)，2.90(1H，d)，2.78 (1H，m)，2.58(1H，t)，2.38(2H，t)，2.02(2H，m)，1.83 (5H，m)。

< example 18> preparation of 3- (4- (4- ((4- (4-fluorophenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 12 above, except that 1- (4-fluorophenyl) piperazine was used in place of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：7.60(2H，d)，7.46(2H，d)， 7.30(3H，d)，6.97(2H，t)，6.86(4H，m)，5.01(2H，s)， 4.21(2H，s)，4.04(1H，t)，3.50(4H，d)，3.25(4H，s)，2.78 (2H，m)，1.80(3H，d)。

< example 19> preparation of 3- (4- (4- ((4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 12 above, except that 1- (4- (trifluoromethyl) phenyl) piperazine was used in place of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：7.63(2H，d)，7.51(4H，d)， 7.21(2H，d)，6.93(2H，d)，6.74(2H，s)，5.03(2H，s)， 4.13(2H，m)，4.01(1H，t)，3.73(4H，s)，2.96(4H，s)， 2.71(2H，m)，1.78(3H，s)。

< example 20> preparation of 3- (4- (4- ((4- (4- (3- (methylsulfonyl) propoxy) phenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 12 above, except for using 1- (4- (3- (methylsulfonyl) propoxy) phenyl) piperazine hydrochloride instead of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：7.65(2H，d)，7.49(2H，d)， 7.30(2H，d)，6.87(6H，m)，5.07(2H，s)，4.20(2H，d)， 4.08(2H，t)，4.01(1H，t)，6.63(2H，s)，3.49(4H，m)，3.26 (2H，t)，3.01(2H，s)，2.97(3H，s)，2.71(2H，m)，2.34 (2H，m)，1.83(2H，d)。

< example 21> preparation of (S) -3- (4- (4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

Step 1: preparation of ethyl (S) -3- (4- (4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) -4-hexenoate

In a flask under nitrogen atmosphere, to 20ml of dimethylformamide was injected 0.5g of 1, 2, 3, 4-tetrahydroisoquinoline, and after completion of dissolution by stirring, 1.1g of cesium carbonate was added at normal temperature. After 30 minutes, 1.0g of ethyl (S) -3- (4- (4- ((methylsulfonyloxy) methyl) benzyloxy) phenyl) -4-hexenoate obtained in the above preparation example 7 was dropped, followed by stirring at ordinary temperature for 12 hours. When the reaction was completed, after slowly dropping distilled water, extraction was performed with ethyl acetate, and after washing with brine (brine), drying was performed with anhydrous magnesium sulfate and further concentration was completed. Then, the target compound was isolated by silica gel column chromatography.

¹H NMR(400MHz，CDCl₃)：7.38(2H，d)，7.31(2H，d)， 7.22(2H，d)，7.16(3H，m)，6.97(3H，m)，4.98(2H，s)， 4.14(2H，m)，4.09(1H，s)，3.91(1H，d)，3.70(3H，m)， 2.92(4H，s)，2.73(2H，m)，1.83(3H，s)，1.29(3H，m)。

Step 2: preparation of (S) -3- (4- (4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

In a flask, under nitrogen atmosphere, to tetrahydrofuran, methanol and distilled water into the step 1 prepared in 0.5g (S) -3- (4- (4- ((3, 4-two hydrogen isoquinoline-2 (1H) -group) methyl) benzyloxy) phenyl) -4-hexenoic acid ethyl ester, and through stirring to complete the dissolution, at room temperature slowly adding 0.5g lithium hydroxide, and stirring for 1 hours above. If the reaction is completed, the pH is acidified to 2 to 3 with 1M hydrochloric acid aqueous solution, and after extraction with ethyl acetate, the target compound is obtained by drying under reduced pressure.

¹H NMR(400MHz，CDCl₃)：7.38(2H，d)，7.31(2H，d)， 7.22(2H，d)，7.16(3H，m)，6.97(3H，m)，4.98(2H，s)， 4.09(1H，s)，3.91(1H，d)，3.70(3H，m)，2.92(4H，s)，2.73(2H，m)，1.83(3H，s)。

< example 22> preparation of (S) -3- (4- (4- ((4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 21 above, except that 1- (4- (trifluoromethyl) phenyl) piperazine was used in place of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：7.65(2H，d)，7.51(4H，m)， 7.30(2H，d)，6.61(2H，d)，6.85(2H，d)，5.05(2H，s)， 4.21(2H，s)，4.03(1H，t)，3.68(4H，s)，3.49(2H，s)，2.84 (2H，s)，2.70(2H，m)，1.82(3H，s)。

< example 23> preparation of (S) -3- (4- (4- ((4- (4-fluorophenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 21 above except for using 1- (4-fluorophenyl) piperazine instead of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：7.39(2H，d)，7.30(2H，d)， 7.19(2H，d)，6.96(4H，m)，6.87(2H，m)，4.97(2H，s)， 4.10(2H，s)，3.81(1H，d)，3.51(1H，d)，3.15(4H，s)， 2.80(6H，m)，1.82(3H，s)。

< example 24> preparation of potassium (S) -3- (4- (4- ((4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoate

In a flask, 0.4g of (S) -3- (4- (4- ((4- (4-fluorophenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid prepared in the above example 23 and 10ml of ethanol were charged under a nitrogen atmosphere, and after completion of dissolution by stirring, 0.3ml of a 3N aqueous potassium hydroxide solution was dropped. Then, after stirring at room temperature, when the reaction is completed, the reaction solution is concentrated under reduced pressure, and then isopropyl alcohol is added to filter the produced solid, thereby obtaining the target compound.

¹H NMR(400MHz，D₂O)：7.10(4H，m)，6.98(2H，d)， 6.57(4H，d)，6.38(2H，s)，4.55(2H，s)，3.82(1H，s)，3.07 (2H，s)，2.59(4H，s)，2.36(2H，s)，2.13(4H，s)，1.51 (3H，s)。

< example 25> preparation of (S) -3- (4- (4- ((6-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 21 above except for using 6-methoxy-1, 2, 3, 4-tetrahydroisoquinoline in place of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，DMSO)：7.40(4H，q)，7.26(2H，d)， 6.94(3H，m)，6.68(2H，m)，5.06(2H，s)，3.95(1H，t)， 3.70(3H，s)，3.51(2H，s)，3.43(2H，s)，2.77(2H，t)，2.66 (2H，t)，2.57(2H，d)，1.75(3H，d)。

< example 26> preparation of (S) -3- (4- (4- ((4-phenylpiperidin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 21 above except that 4-phenylpiperidine was used instead of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：7.66(2H，d)，7.49(2H，d)， 7.30(7H，m)，6.87(2H，d)，5.04(2H，s)，4.19(2H，s)， 4.06(1H，t)，3.59(2H，d)，2.73(7H，m)，2.00(2H，d)， 1.82(3H，s)。

< example 27> preparation of (S) -3- (4- (4- (isoindolin-2-ylmethyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 21 above, except that isoindoline was used in place of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：7.68(2H，d)，7.47(2H，d)， 7.38(2H，m)，7.30(4H，m)，6.87(2H，d)，5.06(2H，s)， 4.90(2H，s)，4.32(4H，m)，4.05(1H，t)，2.81(2H，m)， 1.83(3H，s)。

< example 28> preparation of (S) -3- (4- (4- ((4-phenyl-5, 6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 21 above except for using 4-phenyl-1, 2, 3, 6-tetrahydropyridine hydrochloride in place of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：7.47(2H，d)，7.36(9H，m)， 6.88(2H，d)，5.99(1H，s)，4.99(2H，s)，4.18(1H，m)， 4.06(2H，m)，3.53(2H，s)，3.22(2H，s)，2.82(4H，m)， 1.82(3H，s)。

< example 29> preparation of (S) -3- (4- (4- ((4- (4- (methoxymethoxy) phenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 21 above except for using 1- (4- (methoxymethoxy) phenyl) piperazine instead of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：7.57(2H，d)，7.46(2H，d)， 7.26(2H，d)，6.97(2H，d)，6.87(2H，d)，6.80(2H，d)， 5.13(2H，s)，5.01(2H，s)，4.13(2H，s)，4.02(1H，t)，3.51 (11H，m)，2.72(2H，m)，1.79(3H，s)。

< example 30> preparation of (S) -3- (4- (4- ((4- (5-isopropyl-1, 2, 4-oxadiazol-3-yl) piperidin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 21 above, except that 3-isopropyl-5- (piperidin-4-yl) -1, 2, 4-oxadiazole was used in place of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：7.63(2H，d)，7.46(2H，d)， 7.30(2H，d)，6.86(2H，d)，5.05(2H，d)，4.13(2H，m)， 4.03(1H，t)，3.61(1H，s)，3.43(2H，s)，3.10(1H，m)，2.92(4H，m)，2.73(2H，m)，2.30(2H，m)，1.83(3H，s)， 1.32(6H，d)。

< example 31> preparation of (S) -3- (4- (4- ((4- (5-isopropyl-1, 2, 4-oxadiazol-3-yl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 21 above, except that 3-isopropyl-5- (piperazin-1-yl) -1, 2, 4-oxadiazole was used in place of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：7.61(2H，d)，7.49(2H，d)， 7.30(2H，d)，6.87(2H，d)，5.05(2H，s)，4.15(4H，m)， 4.02(1H，t)，3.49(3H，m)，2.81(3H，m)，1.83(3H，s)， 1.24(6H，d)。

< example 32> preparation of (S) -3- (4- (4- ((4- (4- (methylsulfonyl) phenyl) -5, 6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 21 above except for using 4- (4- (methylsulfonyl) phenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride obtained in the above-mentioned preparation example 9 in place of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，DMSO)：7.95(2H，d)，7.75(2H，d)， 7.63(2H，d)，7.44(2H，d)，7.30(2H，d)，6.98(2H，d)， 6.37(1H，s)，5.14(2H，s)，4.45(2H，t)，6.97(1H，s)，6.82 (4H，m)，3.27(4H，s)，2.84(2H，s)，2.59(2H，d)，1.77 (3H，s)。

< example 33> preparation of (S) -3- (4- (4- ((4- (4- (3- (methylsulfonyl) propoxy) phenyl) -5, 6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 21 above, except for using 4- (4- (3- (methylsulfonyl) propoxy) phenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride obtained in preparation example 11 above in place of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：7.66(2H，d)，7.49(2H，d)， 7.32(2H，d)，7.15(2H，d)，6.90(2H，d)，6.82(2H，d)， 5.06(2H，s)，4.18(2H，s)，4.09(3H，m)，3.58(2H，s)， 3.26(2H，m)，2.97(3H，s)，2.81(5H，m)，2.62(3H，s)， 2.32(2H，m)，1.96(2H，d)，1.83(3H，s)。

< example 34> preparation of (3S) -3- (4- (4- (1- (3, 4-dihydroisoquinolin-2 (1H) -yl) ethyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 21 above, except that ethyl (3S) -3- (4- (4- (1-bromoethyl) benzyloxy) phenyl) -4-hexenoate obtained in the above preparation example 12 was used instead of ethyl (S) -3- (4- (4- ((methylsulfonyloxy) methyl) benzyloxy) phenyl) -4-hexenoate.

¹H NMR(400MHz，CDCl₃)：12.98(1H，s)，7.61(6H，m)， 7.30(4H，m)，6.92(2H，t)，5.08(2H，s)，4.29(2H，s)， 4.06(1H，s)，3.81(1H，s)，3.51(2H，s)，3.21(2H，m)，2.75(2H，m)，1.95(2H，d)，1.84(3H，s)。

< example 35> preparation of (S) -3- (4- (4- ((4- (4-hydroxyphenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 21 above, except for using 4- (1, 2, 3, 6-tetrahydropyridin-4-yl) phenol hydrochloride obtained in preparation example 10 above in place of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：8.80(1H，s)，7.41(2H，d)， 735(2H，d)，7.28(2H，d)，6.94(2H，d)，6.74(2H，d)，6.63 (2H，d)，5.06(2H，s)，3.94(1H，t)，3.62(3H，s)，2.95 (4H，s)，2.61(2H，d)，1.77(3H，s)。

< example 36> preparation of (S) -3- (4- (4- ((4- (4- (3- (methylsulfonyl) propoxy) phenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 21 above, except for using 1- (4- (3- (methylsulfonyl) propoxy) phenyl) piperazine hydrochloride in place of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：12.32(1H，s)，7.42(4H，m)， 7.29(2H，d)，6.96(2H，d)，6.83(4H，q)，5.06(2H，s)， 4.02(2H，t)，3.92(1H，t)，3.52(2H，s)，3.25(2H，t)，3.01 (7H，m)，2.61(2H，d)，2.09(2H，m)，1.77(3H，d)。

< example 37> preparation of sodium (S) -3- (4- (4- (isoindolin-2-ylmethyl) benzyloxy) phenyl) -4-hexenoate

0.4g of (S) -3- (4- (4- (isoindolin-2-ylmethyl) benzyloxy) phenyl) -4-hexenoic acid prepared in example 27 above and ethanol were charged into a 500m L flask under a nitrogen atmosphere, and after completion of dissolution by stirring, 0.3ml of a 3N aqueous sodium hydroxide solution was dropped.

¹H NMR(400MHz，CDCl₃)：7.09(2H，d)，7.03(2H，d)， 6.97(2H，d)，6.85(2H，m)，6.75(2H，m)，6.57(2H，d)， 4.54(2H，s)，3.81(1H，t)，3.36(4H，s)，3.31(2H，s)，2.33 (2H，d)，1.54(3H，d)。

< example 38> L preparation of lysine (S) -3- (4- (4- (isoindolin-2-ylmethyl) benzyloxy) phenyl) -4-hexenoic acid

After 0.4g of (S) -3- (4- (4- (isoindolin-2-ylmethyl) benzyloxy) phenyl) -4-hexenoic acid prepared in example 27 above and ethanol were charged into a flask under a nitrogen atmosphere and dissolved by stirring, 0.12g of L-lysine was added, and then, the reaction temperature was raised to 50 ℃, and the mixture was stirred at 50 ℃ for about 30 minutes, then, it was cooled again to room temperature and stirred for about 30 minutes, and if the reaction was completed, the formed solid was filtered to obtain the objective compound.

¹H NMR(400MHz，D₂O)：7.03(6H，s)，6.83(2H，s)， 6.74(2H，s)，6.54(2H，s)，4.53(2H，s)，3.77(1H，s)，3.54 (5H，m)，2.88(2H，t)，2.28(2H，s)，1.74(2H，m)，1.62 (3H，m)，1.42(3H，s)，1.35(3H，m)。

< example 39> preparation of (S) -3- (4- (4- ((4- (4-fluorophenyl) -5, 6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 21 above except for using 4- (4-fluorophenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride in place of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：7.69(2H，d)，7.48(2H，d)， 7.32(4H，m)，7.04(2H，t)，6.86(2H，d)，5.90(1H，s)， 5.03(2H，s)，4.30(2H，s)，4.02(1H，t)，3.71(2H，s)，3.54 (2H，s)，3.31(2H，s)，2.73(2H，m)，1.81(3H，d)。

< example 40> preparation of (S) -3- (4- (4- ((4- (4-methoxyphenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 21 above except for using 4- (4-methoxyphenyl) -1, 2, 3, 6-tetrahydropyridine instead of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：7.64(2H，d)，7.48(2H，d)， 7.31(2H，d)，6.94(2H，s)，6.86(4H，t)，5.04(2H，s)，4.21 (2H，s)，4.03(1H，t)，3.78(3H，s)，3.60(2H，s)，3.47(2H，s)，3.05(2H，s)，2.73(2H，m)，1.82(3H，s)。

< example 41> preparation of sodium (S) -3- (4- (4- ((3, 4-dihydroquinolin-1 (2H) -yl) methyl) benzyloxy) phenyl) -4-hexenoate

Step 1: preparation of (S) -3- (4- (4- ((3, 4-dihydroquinolin-1 (2H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 21 above except that 1, 2, 3, 4-tetrahydroquinoline was used in place of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：7.02(2H，d)，6.76(2H，d)， 6.69(2H，d)，6.43(4H，m)，6.21(1H，s)，6.02(1H，s)， 4.24(2H，s)，3.84(3H，s)，2.68(2H，s)，2.37(2H，d)，2.14(2H，s)，1.47(3H，s)，1.35(2H，s)。

Step 2: preparation of sodium (S) -3- (4- (4- ((3, 4-dihydroquinolin-1 (2H) -yl) methyl) benzyloxy) phenyl) -4-hexenoate

The objective compound was obtained in the same manner as in example 37 above, except that (S) -3- (4- (4- ((3, 4-dihydroquinolin-1 (2H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid obtained in step 1 above was used instead of (S) -3- (4- (4- (isoindolin-2-ylmethyl) benzyloxy) phenyl) -4-hexenoic acid.

¹H NMR(400MHz，D₂O)：7.01(2H，d)，6.74(2H，d)， 6.68(2H，d)，6.42(4H，m)，6.15(1H，s)，6.02(1H，s)， 4.25(2H，s)，3.79(3H，s)，2.62(2H，s)，2.34(2H，d)，2.12 (2H，s)，1.45(3H，s)，1.32(2H，s)。

< example 42> preparation of potassium (S) -3- (4- (4- ((3, 4-dihydroquinolin-1 (2H) -yl) methyl) benzyloxy) phenyl) -4-hexenoate

The objective compound was obtained in the same manner as in example 25 above, except for using (S) -3- (4- (4- ((3, 4-dihydroquinolin-1 (2H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid obtained in step 1 of example 41 above in place of (S) -3- (4- (4- ((4- (4-fluorophenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid.

¹H NMR(400MHz，D₂O)：6.97(2H，d)，6.71(2H，d)， 6.63(2H，d)，6.45(2H。s)，6.38(2H，d)，6.13(1H，s)， 5.98(1H，s)，4.20(2H，s)，3.71(3H，m)，2.58(2H，s)， 2.32(2H，s)，2.15(2H，s)，1.43(3H，s)，1.29(2H，s)。

< example 43> preparation of (S) -3- (4- (4- ((4- (benzo [ d ] thiazol-2-yl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 21 above except for using 2- (piperazin-1-yl) benzo [ d ] thiazole hydrochloride obtained in the above preparation example 13 in place of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，DMSO)：10.87(1H，s)，7.85(1H，d)， 7.55(5H，m)，7.31(3H，m)，7.14(2H，t)，6.96(2H，d)， 5.13(2H，s)，4.40(2H，s)，4.17(2H，d)，3.95(1H，t)，3.57 (3H，t)，3.22(3H，s)，2.57(2H，d)，1.78(3H，d)。

< example 44> preparation of (S) -3- (4- (4- ((4- (5-propylpyrimidin-2-yl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 21 above except for using 2- (piperazin-1-yl) -5-propylpyrimidine hydrochloride obtained in the above-mentioned preparation example 14 in place of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：8.20(2H，s)，7.62(2H，d)， 7.47(2H，d)，7.30(2H，d)，6.85(2H，d)，5.08(2H，s)， 4.80(2H，d)，4.17(2H，s)，4.03(1H，t)，3.84(1H，t)，3.43 (2H，s)，2.74(4H，m)，2.43(2H，t)，1.83(3H，d)，1.59 (2H，q)，0.94(3H，t)。

< example 45> preparation of (S) -3- (4- (4- ((4- (5-cyanopyridin-2-yl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 21 above, except that 6- (piperazin-1-yl) nicotinonitrile hydrochloride obtained in the above preparation example 15 was used instead of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，DMSO)：11.20(1H，s)，8.56(1H，s)， 7.99(1H，d)，7.63(1H，d)，7.55(1H，d)，7.27(2H，d)， 7.04(1H，d)，6.95(2H，d)，5.12(2H，s)，4.57(2H，d)， 4.35(2H，s)，3.95(1H，t)，3.39(5H，m)，2.90(2H，m)， 2.59(2H，d)，1.77(3H，d)。

< example 46> preparation of (3S) -3- (4- (4- ((3-phenylpyrrolidin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 21 above except that 3-phenylpyrrolidine was used in place of 1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：12.64(1H，s)，7.66(2H，s)， 7.46(2H，d)，7.32(7H，m)，6.86(2H，d)，5.02(2H，s)， 4.28(2H，m)，4.04(1H，t)，3.87(2H，s)，3.73(1H，s)， 3.18(1H，s)，2.89(1H，m)，2.84(3H，m)，2.61(1H，s)， 2.41(1H，s)，2.19(1H，s)，1.81(3H，d)。

< example 47> preparation of sodium (S) -3- (4- (4- ((4- (4-methoxyphenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoate

The objective compound was obtained in the same manner as in example 37 above, except for using (S) -3- (4- (4- ((4- (4-methoxyphenyl) piperazin-1-yl) methyl) benzyloxy) phenyl) -4-hexenoic acid obtained in example 40 above in place of (S) -3- (4- (4- (isoindolin-2-ylmethyl) benzyloxy) phenyl) -4-hexenoic acid.

¹H NMR(400MHz，MEOC)：7.33(2H，d)，7.26(1H，d)， 7.11(1H，s)，6.96(8H，m)，5.04(2H，s)，4.04(1H，t)， 3.76(3H，s)，3.32(4H，m)，3.21(4H，m)，2.52(2H，m)， 1.80(3H，s)。

< example 48> preparation of (S) -3- (4- (4- (2- (6-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) ethyl) benzyloxy) phenyl) -4-hexenoic acid

Step 1: preparation of ethyl (S) -3- (4- (4- (2- (6-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) ethyl) benzyloxy) phenyl) -4-hexenoate

In a flask under nitrogen atmosphere, to 20ml of dimethylformamide was injected 0.5g of 6-methoxy-1, 2, 3, 4-tetrahydroisoquinoline, and after completion of dissolution by stirring, 1.1g of cesium carbonate was added at normal temperature. After 30 minutes, 1.0g of ethyl (S) -3- (4- (4- (2- (methylsulfonyloxy) ethyl) benzyloxy) phenyl) -4-hexenoate prepared in the above preparation example 16 was dropped and then stirred at room temperature for 12 hours. When the reaction was completed, after distilled water was slowly dropped, extraction was performed with ethyl acetate, and after washing with brine (brine), drying was performed with anhydrous magnesium sulfate and concentration was completed. Then, the target compound was obtained by silica gel column chromatography.

¹H NMR(400MHz，CDCl₃)：7.35(2H，d)，7.30(2H，d)， 7.23(2H，d)，7.00(1H，d)，6.85(2H，d)，6.80(1H，d)， 6.70(1H，d)，5.00(2H，s)，4.30(2H，m)，4.13(2H，m)4.03 (1H，t)，3.80(3H，s)，3.58(6H，m)，3.30(2H，s)，2.78 (2H，m)，1.86(3H，d)，1.28(3H，m)。

Step 2: preparation of (S) -3- (4- (4- (2- (6-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) ethyl) benzyloxy) phenyl) -4-hexenoic acid

In a flask, under nitrogen atmosphere, to tetrahydrofuran, methanol and distilled water into the step 1 prepared in 0.5g (S) -3- (4- (4- (2- (6-methoxy-3, 4-two hydrogen isoquinoline-2 (1H) -group) ethyl) benzyl) 4-hexenoic acid ethyl ester, and through stirring to complete the dissolution, slowly at room temperature adding 0.5g lithium hydroxide, and stirring for more than 1 hours. If the reaction is completed, the pH is acidified to 2 to 3 with 1M hydrochloric acid aqueous solution, and after extraction with ethyl acetate, the target compound is obtained by drying under reduced pressure.

¹H NMR(400MHz，CDCl₃)：7.35(2H，d)，7.30(2H，d)，7.23(2H，d)，7.00(1H，d)，6.85(2H，d)，6.80(1H，d)， 6.70(1H，d)，5.00(2H，s)，4.30(2H，m)，4.03(1H，t)， 3.80(3H，s)，3.58(6H，m)，3.30(2H，s)，2.78(2H，m)， 1.86(3H，d)。

< example 49> preparation of (S) -3- (4- (4- (2- (isoindolin-2-yl) ethyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 48 above, except that isoindoline was used in place of 6-methoxy-1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，CDCl₃)：13.57(1H，s)，7.38(3H，m)， 7.29(7H，m)，6.90(2H，d)，5.03(4H，m)，4.28(2H，s)， 4.08(1H，t)，3.48(2H，m)，3.34(2H，m)，2.80(2H，m)， 1.83(3H，d)。

< example 50> preparation of (S) -3- (4- (4- (2- (3, 4-dihydroisoquinolin-2 (1H) -yl) ethyl) benzyloxy) phenyl) -4-hexenoic acid

The objective compound was obtained in the same manner as in example 48 above except for using 1, 2, 3, 4-tetrahydroisoquinoline in place of 6-methoxy-1, 2, 3, 4-tetrahydroisoquinoline.

¹H NMR(400MHz，DMSO)：7.44(2H，d)，7.38(2H，d)， 7.27(5H，m)，7.22(1H，d)，6.94(2H，d)，5.07(2H，s)， 4.64(1H，d)，4.38(1H，s)，3.95(1H，t)，3.77(1H，s)，3.39 (2H，s)，3.16(4H，m)，2.26(2H，d)，1.77(3H，d)，1.84 (3H，d)，1.29(3H，t)。

< example 51> preparation of sodium (S) -3- (4- (4- ((6-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) -4-hexenoate

The objective compound was obtained in the same manner as in example 37 above, except for using (S) -3- (4- (4- ((6-methoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) benzyloxy) phenyl) -4-hexenoic acid obtained in example 25 above in place of (S) -3- (4- (4- (isoindolin-2-ylmethyl) benzyloxy) phenyl) -4-hexenoic acid.

¹H NMR(400MHz，D32O)：7.10(2H，d)，7.02(2H，d)， 6.95(2H，d)，6.55(2H，d)，6.40(1H，d)，6.34(2H，s)， 4.53(2H，s)，3.83(1H，t)，3.39(3H，s)，3.17(2H，s)，3.05 (2H，s)，2.37(4H，m)，2.20(2H，s)，1.57(3H，s)。

< comparative example 1> preparation of [ (3S) -6- ({ (2', 6' -dimethyl-4 '- [3- (methylsulfonyl) propoxy ] - [1, 1' -biphenyl ] -3-yl) } methoxy) -2, 3-dihydro-1-benzofuran-3-yl ] acetic acid

[ (3S) -6- ({ (2', 6' -dimethyl-4 '- [3- (methylsulfonyl) propoxy ] - [1, 1' -biphenyl ] -3-yl) } methoxy) -2, 3-dihydro-1-benzofuran-3-yl ] acetic acid was prepared by the method disclosed in International patent publication No. 2008/001931.

< comparative example 2> preparation of (3S) -3- (4- { [4- (1 ' H-spiro [ indene-1, 4' -piperidin ] -1 ' -ylmethyl) benzyl ] oxy } phenyl) hex-4-ylthio acid

(3S) -3- (4- { [4- (1 ' H-spiro [ indene-1, 4' -piperidin ] -1 ' -ylmethyl) benzyl ] oxy } phenyl) hex-4-ylthio acid was prepared by the method disclosed in International publication No. WO 2011/046851.

< comparative example 3> preparation of 4- (3-phenoxybenzylamino) phenylpropionic acid

4- (3-Phenoxybenzylamino) phenylpropionic acid is prepared by a known method.

The chemical structural formulae of the compounds prepared in examples 1 to 51 are collated and shown in the following table 1.

TABLE 1

According to another embodiment of the present invention, there is provided a method for preventing or treating a metabolic disease, comprising the step of administering to a subject a pharmaceutically effective amount of a composition comprising (a) a compound represented by chemical formula 1, an optical isomer, hydrate, solvate or pharmaceutically acceptable salt thereof as a first active substance and (b) one or more compounds selected from the group consisting of dipeptidyl peptidase 4 inhibitors, sulfonylureas, thiazolidinediones, biguanides and sodium-glucose cotransporter 2 inhibitors as a second active substance.

Chemical formula 1:

the detailed description of the composition for preventing or treating metabolic diseases described in the above chemical formula 1 is the same as that of the previous case.

In the mixed composition of the first and second effective substances, although side effects according to a specific mixing weight ratio are generated and the effect is not reduced, the mixing weight ratio is not particularly limited, and the first effective substance can be mixed in an appropriate amount to be administered together in consideration of the pathological state of the patient and the known characteristics of the second effective substance. In one embodiment, the above mixing weight ratio is 0.03:1 to 100: 1. in still another embodiment, the above mixing ratio by weight is 0.03:1 to 30: 1, in yet another embodiment, the above mixing ratio by weight is 0.03:1 to 10: 1.

< Experimental example 1> evaluation of degree of Activity of G protein-coupled receptor 40 protein based on 3- (4- (benzyloxy) phenyl) -4-hexenoic acid derivative

In order to evaluate the degree of activation of the G protein-coupled receptor 40 of the novel 3- (4- (benzyloxy) phenyl) -4-hexenoic acid derivative of the present invention, the following experiment was performed.

The degree of activation of the protein of the G protein-coupled receptor 40 of the novel 3- (4- (benzyloxy) phenyl) -4-hexenoic acid derivative of the present invention was evaluated by the change of intracellular calcium concentration based on the protein activity of the G protein-coupled receptor 40 first, the formation transformation into the human G protein-coupled receptor 40 gene (human GPR40 DNA) (Origene, RC218370) was carried out in HEK-293 cells using Fugene HD (Promega, E2311). The formed HEK-293 cells were dispensed into a 96-well black transparent bottom plate (Costar, 3603) and cultured.after 24 hours, the cell culture solution was removed, and 1% of Dulbecco's modified Eagle FBS, DMEM, 50ul) supplemented with Fetal Bovine Serum (Fetal Bovine Serum, RC) was injected into each well, and 50. mu. L of the reagent was administered to each well for the purpose of calcium concentration measurement (U.S.S.S.F., life reagent was cultured in a 20 ℃ culture Medium (Invitro., LTC. culture Medium, 71F.) and cultured at about 20 ℃ under the environment of Invitro.C.The compounds of examples and the compounds of comparative examples 1 and 2 were diluted in 1 × HBSS (Hank's buffered Salt Solution) to which 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES) was added in mM buffer Solution of 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid, and prepared as samples for cell treatment, and after 2 hours had elapsed from the start of culture, the prepared various samples were automatically injected into cells using Flexstation3 equipment from the Millettia molecular devices (molecular devices), and the cells were used to automatically inject the prepared various samplesPro software was used to detect changes in intracellular calcium concentration for about 120 seconds. At this time, as a non-treated group, the change in calcium concentration was detected by injecting dimethyl sulfoxide (DMSO) into the cells. The degree of protein activity of the G protein-coupled receptor 40 is calculated from the result of the detected calcium concentration by the following equation 1, and the EC for the G protein-coupled receptor 40 activity based on the sample is derived₅₀The value is obtained. The results are shown in table 2 below.

Mathematical formula 1:

TABLE 2

In Table 2 above, the A rating is less than 0.20. mu.M; the grade B is 0.20-0.30 mu M; the C level is greater than 0.30. mu.M.

As shown in table 2, it was found that the compounds of the examples of the present invention have an excellent effect of activating the protein of G protein-coupled receptor 40 at a low concentration. In particular, examples 7, 9, 11, 12, 14, 27, 28, 37 and 38 activated the protein of G protein-coupled receptor 40 by 50% at a very low concentration of 0.20 μ M or less, and thus, the ability to increase the intracellular Ca2+ concentration was very excellent as compared with comparative example 1 (B, 0.28 μ M).

Therefore, the novel 3- (4- (benzyloxy) phenyl) -4-hexenoic acid derivative of the present invention has an excellent protein activity rate of the G protein-coupled receptor 40, and exhibits a similar or improved protein activity rate of the G protein-coupled receptor 40, particularly as compared with the conventional antidiabetic agent (comparative example 1) which is known to promote insulin secretion by activating the protein of the G protein-coupled receptor 40, and therefore, a pharmaceutical composition comprising the same as an active ingredient is useful as a pharmaceutical composition for preventing or treating metabolic diseases such as obesity, type i diabetes, type II diabetes, inappropriate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia and X syndrome.

< Experimental example 2> analysis of Calcium flow Rate (Calcium Flux)

To evaluate the calcium flux based on the degree of activation of G protein-coupled receptor 40 of the novel 3- (4- (benzyloxy) phenyl) -4-hexenoic acid derivative of the present invention, it was carried out by millipore (millipore) which is a specialized institution for the assay of G protein-coupled receptors (gpcrassay).

The compounds of examples were dissolved in Dimethyl sulfoxide (DMSO), Phosphate Buffered Saline (PBS), Distilled Water (DW), and the like at a concentration of 3 times in EMD millipore's G protein-coupled receptor analyzer assay buffer (profiler assay buffer). Similarly, for the accuracy of analysis, a treatment-free group (vehicle) and a positive control group (comparative example 1 and comparative example 3) were used. All wells were prepared using an EMD millipore's G protein-coupled receptor analyzer assay buffer. EMDdilipore's G protein-coupled receptor Analyzer assay buffer was a Hank's Balanced salt solution (HBSS, Hanks Balanced solution) containing 20mM HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid hemi-sodium salt (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid)) and 2.5mM Probenecid (4- (dipropylsulfamoyl) benzoic acid)) and pH adjusted to 7.4.