HK1136564A - 1-phenyl 1-thio-d-glucitol derivative - Google Patents

Description

1-phenyl-1-thio-D-sorbitol derivatives

Technical Field

The present invention relates to a pharmaceutical agent having an inhibitory activity of sodium-dependent glucose cotransporter 1(SGLT1) and sodium-dependent glucose cotransporter 2(SGLT2) involved in glucose reabsorption in the kidney, in particular, a prophylactic or therapeutic agent for diabetes, a diabetes-related disease, or a diabetic complication.

Background

If diabetes is suffered, the blood glucose level in the fasting state is 126mg/dL or more. Even if the blood glucose level in the fasting state is normal, it is diagnosed as impaired glucose tolerance (hereinafter referred to as igt (impaired glucose tolerance)) when a high blood glucose level of 140 to 200mg/dL is shown after a meal. In recent years, it is thought that delaying the shift from IGT to diabetes may reduce the risk of cardiovascular disorders. For example, in the Daqing IGT and diabetes Study (Da Qing IGT and diabetes Study) conducted in China in 1997, it was reported that the shift from IGT to type 2 diabetes can be significantly inhibited by controlling diet and exercise (see non-patent document 1). In addition, as an example of the effectiveness of drug therapy, it has been reported that the conversion from IGT to type 2 diabetes and the onset of hypertension can be significantly suppressed by administering acarbose, an α -glucosidase inhibitor that inhibits the hydrolase of sugar and delays the absorption of sugar in the small intestine (see non-patent document 2).

From the above, it is important to control IGT by diet therapy, exercise therapy and drug therapy for suppressing the onset of diabetes. However, the number of diabetic patients is increasing year by year, and new therapeutic agents corresponding to various causes and disease states are required.

The fundamental treatment of diabetes is food therapy and exercise therapy, but when it is difficult to maintain regular living habits or when sufficient effects cannot be obtained even by these therapies, it is necessary to adopt drug therapy.

It is known that sodium-dependent glucose cotransporter 1(SGLT1) is expressed at a high frequency in the small intestine epithelium. This SGLT1 is responsible for active transport of glucose or galactose in the small intestine, depending on sodium (see non-patent document 3). In addition, it was confirmed that the expression level of mRNA and protein of SGLT1 was increased in a diabetic rat model (see non-patent document 4). In recent years, examples of synthesis of pyrazole derivatives have been reported in which SGLT1 activity is inhibited, absorption of glucose derived from food is inhibited, and IGT is improved (see patent documents 1 to 6).

In addition, sodium-dependent glucose cotransporter 2(SGLT2) is expressed at a high frequency in the kidney, and glucose that has been filtered in the glomerulus is reabsorbed by SGLT2 (see non-patent document 5). Furthermore, since the SGLT2 inhibitor is administered to diabetic rats to promote excretion of sugar into urine and cause a blood sugar lowering effect, SGLT 2-specific inhibitors are considered as target molecules of novel therapeutic agents for diabetes (see non-patent document 6). Under such a background, studies on SGLT2 inhibitors have been conducted to provide various glucose derivatives (see patent documents 7 and 8).

Therefore, it is considered that if the activities of SGLT1 and SGLT2 can be simultaneously inhibited, a novel therapeutic agent for diabetes having both a postprandial hyperglycemia inhibitory effect by inhibiting SGLT1 and an immediate blood glucose lowering effect by inhibiting SGLT2 can be provided.

Hitherto, 1-thio-D-sorbitol derivatives that strongly inhibit SGLT2 have been reported (see patent document 9). However, 1-phenyl 1-thio-D-sorbitol derivatives which strongly inhibit both SGLT1 and SGLT2 have not been reported.

[ patent document 1 ] International publication No. WO2002/098893 Specification

[ patent document 2 ] International publication No. WO2004/014932 Specification

[ patent document 3 ] International publication No. WO2004/018491 Specification

[ patent document 4 ] International publication No. WO2004/019958 Specification

[ patent document 5 ] International publication No. WO2005/121161 Specification

[ patent document 6 ] description of International publication No. WO2004/050122

[ patent document 7 ] specification of European patent application publication No. 0850948

[ patent document 8 ] International publication No. WO2001/068660 Specification

[ patent document 9 ] International publication No. WO2006/073197 Specification

[ Nonpatent document 1 ] Pan XR, et al, diabetes Care, volume 20, page 534, 1997

Non-patent document 2 j. -l.chiasson, et al.lancent, volume 359, page 2072, 2002

[ Nonpatent document 3 ] W.S.Lee, et al.J.biol.chem.269, p.12032, 1994

[ Nonpatent document 4 ] Y.Fujita, et al Diabetologia Vol.41, p.1459, 1998

[ Nonpatent document 5 ] E.M.Wright, am.J.Physiol.Renal.Physiol., vol.280, p.F 10, 2001

[ Nonpatent document 6 ] G.Toggenburger, et al.biochem.Biophys.acta., Vol.688, p.557, 1982

Disclosure of Invention

The present invention addresses the problem of providing a novel therapeutic agent for diabetes, which has both SGLT1 and SGLT2 activity inhibitory activity and also has an action of inhibiting glucose absorption in the digestive tract and an action of excreting urine glucose.

The present inventors have intensively studied the effect of a substituent of an aglycone of a 1-thio-D-sorbitol derivative on SGLT inhibitory activity in order to solve the above-mentioned problems, and as a result, have found that a combination of compounds (I) to (VII) strongly inhibits both SGLT1 and SGLT2 activities by introducing a certain substituent, thereby completing the present invention.

That is, the present invention is

(1) 1-phenyl 1-thio-D-sorbitol compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or a hydrate of the compound,

[ CHEM 1 ]

(2) A 1-phenyl 1-thio-D-sorbitol compound represented by the formula (II) below or a pharmaceutically acceptable salt thereof or a hydrate thereof,

[ CHEM 2 ]

(3) A 1-phenyl 1-thio-D-sorbitol compound represented by the formula (III) below or a pharmaceutically acceptable salt thereof or a hydrate thereof,

[ CHEM 3 ]

(4) A 1-phenyl 1-thio-D-sorbitol compound represented by the formula (IV) or a pharmaceutically acceptable salt thereof or a hydrate thereof,

[ CHEM 4 ]

(5) A 1-phenyl 1-thio-D-sorbitol compound represented by the formula (V) or a pharmaceutically acceptable salt thereof or a hydrate thereof,

[ CHEM 5 ]

(6) A 1-phenyl 1-thio-D-sorbitol compound represented by the formula (VI) or a pharmaceutically acceptable salt thereof or a hydrate thereof,

[ CHEM 6 ]

(7) 1-phenyl 1-thio-D-sorbitol compound represented by formula (VII) or a pharmaceutically acceptable salt thereof or a hydrate of the compound or the pharmaceutically acceptable salt.

[ CHEM 7 ]

Another embodiment of the present invention is a pharmaceutical agent containing the compounds represented by the above formulae (I) to (VII) or their pharmaceutically acceptable salts or hydrates thereof as an active ingredient.

Another embodiment of the present invention is a pharmaceutical agent containing, as an active ingredient, a compound represented by the above formulae (I) to (VII) or a pharmaceutically acceptable salt thereof or a hydrate thereof as an inhibitor of the activity of sodium-dependent glucose cotransporter 1 and sodium-dependent glucose cotransporter 2.

Another embodiment of the present invention is a prophylactic or therapeutic agent for diabetes, a disease associated with diabetes, or a diabetic complication, characterized by containing a compound represented by the above formula (I) to formula (VII) or a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient.

The compound having a certain substituent incorporated in combination on the aglycone of the 1-thio-D-sorbitol derivative inhibited the activities of both SGLT1 and SGLT 2. In addition, these compounds show excellent hypoglycemic action.

Detailed Description

The terms used in the present invention are defined as follows.

The "pharmaceutically acceptable salt" refers to a salt with an alkali metal, an alkaline earth metal, ammonium, alkylammonium or the like, and a salt with an inorganic or organic acid, and examples thereof include a sodium salt, a potassium salt, a calcium salt, an ammonium salt, an aluminum salt, a triethylammonium salt, an acetate, a propionate, a butyrate, a formate, a trifluoroacetate, a maleate, a tartrate, a citrate, a stearate, a succinate, an ethylsuccinate, a lactobionate, a gluconate, a glucoheptonate, a benzoate, a methanesulfonate, an ethanesulfonate, a 2-hydroxyethanesulfonate, a benzenesulfonate, a p-toluenesulfonate, a dodecylsulfate, a malate, an aspartate, a glutamate, an adipate, a salt with cysteine, a salt with N-acetylcysteine, a hydrochloride, a hydrobromide, a phosphate, a sulfate, a hydroiodide, a nicotinate, a hydrobromide, a salt with an, Oxalate, picrate, thiocyanate, undecanoate, salt with acrylic polymer, salt with carboxyvinyl polymer, and the like.

"hydrate" refers to a pharmaceutically acceptable hydrate of a compound of the invention or a salt thereof. The compound of the present invention or a salt thereof may absorb water, may adsorb water, and may form a hydrate when exposed to the atmosphere or recrystallized. The hydrate of the present invention also includes such a hydrate.

The following describes the production processes of the compounds (I) to (VII) of the present invention.

Preparation method 1

In the formula, R^ARepresents methyl, ethyl, methoxy or methylthio, R^BRepresents a methyl or chloro group, R^CRepresents a benzyl group or an allyl group.

[ CHEM 8 ]

(1) Step 1

Compound (1A) can be produced according to the description of International patent publication No. WO 2006/073197. In addition, the following reference examples can also be prepared. The lithium reagent (2A) can be prepared from the compound (1A) using an organometallic reagent such as n-butyllithium, sec-butyllithium, or tert-butyllithium. The solvent used in the reaction may, for example, be tetrahydrofuran, diethyl ether or toluene. The reaction temperature is-78 ℃ to room temperature, preferably-78 ℃ to-25 ℃. Alternatively, Grignard (Grignard) reagent (2A) can also be prepared using magnesium powder. The solvent used in the reaction may, for example, be tetrahydrofuran, diethyl ether or diglyme. Further, iodine or 1, 2-dibromoethane may be used as an activator of magnesium.

Next, compound (4A) can be obtained by adding thiolactone (3A) to compound (2A). The temperature at which the thiolactone (3A) is added is preferably from-78 ℃ to-25 ℃ in the case where the lithium reagent (2A) is used, and from-15 ℃ to 25 ℃ in the case where the Grignard reagent (2A) is used.

(2) Step 2 (reduction)

Reaction of Compound (4A) with Et₃SiH、i-Pr₃SiH、t-BuMe₂SiH or Ph₂Compound (5A) can be synthesized by reacting SiHCl in the presence of an acid. The acid used in the reaction may, for example, be BF₃·Et₂O、CF₃COOH、MeSO₃H、InCl₃Examples of the solvent include chloroform, dichloromethane, acetonitrile and a mixed solvent of these solvents, and a mixed solvent of acetonitrile and chloroform, acetonitrile and dichloromethane and the like is preferable. Wherein the reaction temperature is-60 ℃ to 25 ℃, preferably-30 ℃ to 25 ℃.

(3) Step 3 (deprotection)

R in Compound (5A) obtained above^CWhen the benzyl group is a benzyl group, the compound of the present invention can be obtained by catalytic hydrogenation in a hydrogen atmosphere using a catalyst such as palladium activated carbon, palladium hydroxide, or platinum-palladium activated carbon to perform debenzylation. Among them, palladium activated carbon and palladium hydroxide are preferable as the catalyst. As theExamples of the solvent used in the reaction include methanol, ethanol, isopropanol, ethyl acetate, acetic acid, and a mixed solvent of these solvents. The reaction temperature is from room temperature to reflux temperature, preferably room temperature.

In addition, BCl may also be used in debenzylation₃、BCl₃·Me₂S、BBr₃、AlCl₃、CF₃COOH, TfOH, and the like. Examples of the solvent used in the reaction include chloroform, methylene chloride, acetonitrile, diethyl ether, tetrahydrofuran, dimethyl sulfide, and anisole. Among them, it is preferable to use CF in dimethyl sulfide₃COOH, TfOH, ethanedithiol. The reaction temperature may be-78 deg.C to 40 deg.C.

R in Compound (5A)^CIs allyl (-CH)₂CH＝CH₂) In this case, potassium tert-butoxide may be reacted in dimethyl sulfoxide to isomerize (-CH ═ CHCH)₃) After that, hydrochloric acid or HgCl is used₂The HgO is removed. Alternatively, Pd (PPh) may be used in the presence of an organic acid such as acetic acid, p-toluenesulfonic acid hydrate, and N, N' -dimethyl barbituric acid₃)₄、PdCl₂And palladium activated carbon, etc. The solvent used in the reaction may, for example, be acetonitrile, diethyl ether or tetrahydrofuran, and the reaction temperature may be from 25 ℃ to 100 ℃.

Preparation method 2

Compound (5A) can also be prepared according to the method shown below. Wherein the symbols in the formula have the same meanings as described above.

[ CHEM 9 ]

(4) Step 4

An aryl lithium reagent can be prepared by using an organometallic reagent such as n-butyllithium, sec-butyllithium, or tert-butyllithium for the intermediate compound (6A) according to the method described in step 1. To this, thiolactone (3AB) is added to give compound (7A). The solvent used in the reaction may, for example, be tetrahydrofuran, diethyl ether or toluene. The reaction temperature is-78 ℃ to room temperature, preferably-78 ℃ to-25 ℃.

(5) Step 5 (acid hydrolysis)

The acetal group in compound (7A) can be hydrolyzed using hydrochloric acid, p-toluenesulfonic acid 1 hydrate, or the like to prepare compound (8A). The solvent used in this case is preferably tetrahydrofuran, ethanol, methanol, water, or a mixed solvent of these solvents. The reaction temperature is 4 ℃ to 60 ℃, preferably room temperature. The reaction time varies depending on the reaction temperature and is 1 to 24 hours.

(6) Step 6

Phenyl lithium reagent compound (10A) can be prepared using n-butyllithium, sec-butyllithium, tert-butyllithium, or the like for 4-substituted toluene (9A). The solvent used in the reaction may, for example, be tetrahydrofuran, diethyl ether or toluene. The reaction temperature is-78 ℃ to room temperature, preferably-78 ℃ to-25 ℃. The reaction time is preferably 5 minutes to 30 minutes. In addition, magnesium metal can also be used to prepare the Grignard reagent (10A). Examples of the solvent used in the reaction include tetrahydrofuran, diethyl ether and diglyme. Subsequently, the compound (11A) can be prepared by reacting the compound (8A) with the reagent (10A).

(7) Step 7 (reduction)

Et treatment of Compound (11A)₃SiH、i-Pr₃SiH、t-BuMe₂SiH or Ph₂Compound (5A) can be synthesized by reacting SiHCl in the presence of an acid. The acid used in the reaction may, for example, be BF₃·Et₂O、CF₃COOH、InCl₃Examples of the solvent include chloroform, dichloromethane, acetonitrile and a mixed solvent of these solvents, and a mixed solvent of acetonitrile and chloroform, acetonitrile and dichloromethane and the like is preferable. Wherein the reaction temperature is-60 ℃ to 25 ℃, preferably-30 ℃ to 0 ℃.

Particularly preferred methods are the following methods. Reduction of a hemiacetal moiety with high reactivity is carried out in an acetonitrile solvent at a reaction temperature of-15 ℃ to-5 ℃ using about 1 equivalent of an acid. Then, the reaction temperature is raised to 0 ℃ to 5 ℃, and about 1 equivalent of acid is added to reduce the hydroxyl at the benzyl position.

Preparation of thiolactone (3A)

[ CHEM 10 ]

Compound (3A) can be synthesized with reference to Yuasa, h., et al.j.chem.soc.perkin trans.1, page 2763, 1990. Alternatively, the synthesis may be carried out according to the above scheme.

(8) Step 8

The hydroxyl group at position 1 of the compound (3B) (which can be prepared by referring to International publication No. WO 04/106352) is protected with a protecting group which is resistant to basic conditions and can be deprotected under neutral or acidic conditions. For example, compound (3C) can be synthesized using 3, 4-dihydro-2H-pyran (3, 4-DHP) and p-toluenesulfonic acid 1 hydrate, protected with tetrahydropyranyl (THP group). In this case, the solvent is preferably tetrahydrofuran, diethyl ether, chloroform or the like.

(9) Step 9

Deprotection of the acetoxy group can be carried out using a base such as sodium methoxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, or triethylamine, and a solvent such as methanol, ethanol, or aqueous methanol can be used. Then, benzyl bromide, benzyl chloride, allyl bromide, or the like is reacted with an appropriate base to obtain compound (3D). Examples of the base include triethylamine, N-ethyl-N, N-diisopropylamine, pyridine, potassium carbonate, calcium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, sodium methoxide, and potassium tert-butoxide, and potassium carbonate, calcium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and sodium hydride are preferable. The solvent used in the reaction may, for example, be N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane or dimethoxyethane, and the reaction temperature is preferably from-20 ℃ to 25 ℃.

(10) Step 10

Then, deprotection of the protecting group at position 1 affords compound (3E). For example, the THP group can be removed by treating compound (3D) with p-toluenesulfonic acid or pyridinium p-toluenesulfonic acid in methanol or ethanol.

(11) Step 11

Finally, compound (3E) is treated with a suitable oxidizing agent to prepare thiolactone (3A). As the oxidizing agent used in the reaction, dimethyl sulfoxide-acetic anhydride, Dess-Martinperiodinane, IBX and the like are preferable, and the reaction temperature is 0 ℃ to 40 ℃.

The compound of the present invention can inhibit the activities of both SGLT1 and SGLT2, improve IGT by inhibiting the glucose absorption action and urine glucose excretion action in the digestive tract, and prevent or treat diabetes.

Therefore, the compound of the present invention can be used as an active ingredient of SGLT1 or SGLT2 inhibitors, or preventive or therapeutic agents for diabetes, diabetes-related diseases, and diabetic complications.

Among them, "diabetes" includes type 1 diabetes, type 2 diabetes, and other types of diabetes caused by specific causes.

Among them, examples of the "diabetes-related diseases" include obesity, hyperinsulinemia, sugar metabolism disorder, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder, hypertension, congestive heart failure, edema, hyperuricemia, and gout.

Among them, the "diabetic complications" can be classified into acute complications and chronic complications.

Examples of the "acute complications" include hyperglycemia (ketoacidosis, etc.) and infections (skin, soft tissue, biliary system, respiratory system, urinary tract infections, etc.).

Examples of the "chronic complications" include microangiopathy (nephropathy, retinopathy), arteriosclerosis (atherosclerosis, myocardial infarction, cerebral infarction, arterial occlusion of lower limbs, etc.), neurological disorders (sensory nerve, motor nerve, autonomic nerve, etc.), and gangrene of the foot.

The main complications are diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.

The dose of the compound of the present invention varies depending on the disease, symptom, body weight, age, sex, administration route, etc., and is preferably 0.1 to 1000mg/kg body weight, more preferably 0.1 to 200mg/kg body weight, and even more preferably 0.1 to 10mg/kg body weight for an adult in 1 day. It can be administered from 1 to several times a day.

The compound of the present invention can be used in combination with a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, a hypotensive agent, an antiobesity agent, a diuretic, an antithrombotic agent, and other agents (hereinafter, simply referred to as a combination drug) having an action mechanism other than the SGLT1 and SGLT2 activity inhibitors, for the purpose of enhancing the action of the compound or reducing the dose of the compound. In this case, the administration time of the compound of the present invention and the combination drug is not limited, and these drugs may be administered to the subject at the same time or at different times. Furthermore, the compounds of the invention and combinations may be administered as 2 preparations containing the respective active ingredients or as a single preparation containing both active ingredients. The dose of the combination drug can be appropriately selected based on the clinically used dose. In addition, the ratio of the compound of the present invention to the drug combination can be appropriately selected depending on the administration subject, the administration route, the disease, symptom, combination, and the like of the subject. For example, in the case of a human being to be administered, 0.01 to 100 parts by weight of the drug combination can be used relative to 1 part by weight of the compound of the present invention.

Examples of the therapeutic agent for diabetes include insulin preparations (e.g., animal insulin preparations extracted from bovine or porcine pancreas; human insulin preparations synthesized by genetic engineering using Escherichia coli or yeast; insulin zinc, protamine zinc insulin; fragments or derivatives of insulin (e.g., INS-1, etc.), oral insulin preparations, insulin resistance improvers (e.g., Pioglitazone (Pioglitazone) or salts thereof (preferably hydrochloride salt), Rosiglitazone (Roglitazone) or salts thereof (preferably maleate salt), Rivoglitazone (CS-011) (R-119702), ciglitazone (Sipoglitazar) (TAK-654), meglitazone (Metaglidasen) (MBX-102), Naveglitazar (LY-519818), MX-6054, Balaglitazone (Balaglitazone) (NN-2344), T-131(AMG131), and gamma agonists, PPAR γ antagonists, PPAR γ/α dual agonists, α -glucosidase inhibitors (e.g., Voglibose (Voglibose), Acarbose (Acarbose), Miglitol (Miglitol), Emiglitate), Biguanides (Biguinoids) (e.g., Phenformin (Phenformin), Metformin (Metformin), Buformin (Buformin) or their salts (e.g., hydrochloride, fumarate, succinate)), insulin secretion promoters (sulfonylureas) (e.g., Tolbutamide (Tolbutamide), Glibenclamide (Glibenclamide), Gliclazide (Gliclazide), Chlorpropamide (Chloropropamide), Tolazamide (Tolazamide), acetylcyclohexamide (Acetohexamide), piridopyramide (Glycramide), glimepiridide (Glimepiride), Glipizide (Glibolipide), Glipizide (Glipizide), Glipizide (meglitinide), meglitinide (Natglinide), calcium salt (meglitinide), or their hydrates (calcium salts), Glipizide), or salts (Natglinide), or their salts (, GPR40 agonist, GPR40 antagonist, GLP-1 receptor agonist (e.g., GLP-1MR agent, Liraglutide (Liraglutide) (NN-2211), Exenatide (Exenatide) (AC-2993) (exendin-4), Exenatide LAR, BIM-51077, Aib (8, 35) hGLP-1(7, 37) NH2, CJC-1131, AVE0010, GSK-716155), Amylin (Amylin) agonist (e.g., pramlintide (pramlintide)), phosphorylated tyrosine phosphatase (Phosphotyrosine) inhibitor (e.g., sodium vanadate), dipeptidyl peptidase (dipeptidyl peptidase) IV inhibitor (e.g., WO 02/038541-described compound, NVP-DPP-278, PT-100, GPR 5/98, vilitinin (Vildagliptin) (LAldliptin F477-64), Sildagliptin (MK-118/431) (MK-64/118), SYR-322, MP-513, T-6666, GRC-8200, etc.), β 3 agonists (e.g., AJ-9677, AZ40140, etc.), gluconeogenesis inhibitors (e.g., glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, fructose-1, 6-bisphosphatase inhibitors), SGLT (sodium-glucose cotransporter), sodium-glucose transporters (e.g., WO04/014931, WO04/089967, WO06/073197, T-1095, Serflozin (GSK-869682), GSK-226 189075, KGT-1251, KGT-1681, KGA-2727, BMS-512148, AVE 8, SAR7226, etc.), 11 β -hydroxysteroid dehydrogenase inhibitors (e.g., WO06/051662, BVT-3498, IN13739), etc.) GPR119 agonist (e.g., PSN-632408, APD-668), adiponectin (adiponectin) or an agonist thereof, IKK inhibitor (e.g., AS-2868), AMPK activator, leptin (leptin) resistance improver, somatostatin receptor agonist, glucokinase activator (e.g., Ro-28-1675), pancreatic lipase inhibitor (e.g., Orlistat (Orlistat), ATL-962), DGAT-1 inhibitor.

As the diabetic complication therapeutic agent, aldose reductase inhibitors (e.g., Tolrestat (Tolrestat), Epalrestat (Epalrestat), zenarestat (zenarestat), zopolrestat (zopolrestat), Minalrestat (Minalrestat), fidarestat (fidarestat), CT-112, neurotrophic factors and enhancers thereof (e.g., NGF, NT-3, BDNF, neurotrophin production and secretion promoters), nerve regeneration promoters (e.g., Y-128), PKC inhibitors (e.g., rubberistat mesylate (LY-333531)), AGE inhibitors (e.g., ALT946, pimagedine (pimagedine), pyratoxanthine, N-phenacylthiozolium bromide (ALT766), ALT-711, ALT-226, pyriproxyfen (Pyridoxamine), and cerebral vascular disease inhibitors (e.g., a cerebral vascular disease-dilating agent), e.g., a cerebral vascular disease-dilating agent (e.g., a cerebral vascular disease-dilating agent), e.g., a tiapridine (a cerebral vascular disease-dilating agent (e, a dilating agent), a cerebral vascular agent (e.g., a cerebral vascular agent (e, a dilating agent, a vasopressin, a, Mexiletine (Mexiletine)), somatostatin receptor agonists (e.g., BIM23190), apoptosis signal-regulating kinase-1 (ASK-1) inhibitors.

As the anti-hyperlipemia agent, statin compounds (e.g., Pravastatin (Pravastatin), Simvastatin (Simvastatin), Lovastatin (Lovastatin), Atorvastatin (atovastatin), Fluvastatin (Fluvastatin), Itavastatin (Itavastatin), Rosuvastatin (Rosuvastatin), Pitavastatin (Pitavastatin) or salts thereof (e.g., sodium salt, calcium salt)), squalene synthase inhibitor (e.g., TAK-475), compounds (e.g., Bezafibrate (Bezafibrate), Clofibrate (Clofibrate), bisfibrate (Simfibrate), Clinofibrate (Clinofibrate)), ACAT inhibitor (e.g., Avasimibe (avasim), ibrutin (Eflucimibe)), anion exchange resin (e.g., Cholestyramine (Cholestyramine)), Probucol (Probucol), nicotinic acid (e.g., nicol), nicotinic acid (e.g., pentazochroman), nicotinic acid (e.g., pentazochytol (nicotinyl alcohol), nicotinic acid (e.g., pentraxin (nicotinyl alcohol), nicotinic acid (e.g., penticotinate (nicotinyl alcohol), nicotinic acid (ester), nicotinic acid (e.g., nicol), nicotinic acid (ester (e), nicotinic acid (ester), nicotinic acid (e), nicotinic acid (e.g, Phytosterols (e.g., soysterol, gamma-oryzanol), CETP inhibitors (e.g., Torcetrapib, JTT-705, JTT-302, FM-VP4, etc.), cholesterol absorption inhibitors (e.g., Ezetimibe (Ezetime), etc.).

As the blood pressure lowering agent, angiotensin converting enzyme inhibitors (e.g., Captopril (Captopril), Enalapril (Enalapril), Delapril (Delapril)), angiotensin II antagonists (e.g., Candesartan cilexetil, Losartan (Losartan), Eprosartan (Eprosartan), Valsartan (Valsartan), Telmisartan (Telmisartan), Irbesartan (Irbesartan), tasosartan (tasosartan), aziartan (aziartan) (TAK-536)), calcium antagonists (e.g., Manidipine (Manidipine), Nifedipine (Nifedipine), Amlodipine (Amlodipine), Efonidipine (Efonidipine), Nicardipine (Nicardipine)), potassium channel openers (e.g., levochromancrypsin (levcrabrazimine), 0652, Clonidine (Clonidine), Clonidine (271121) can be exemplified.

Examples of the antiobesity agent include central antiobesity agents (e.g., Dexfenfluramine (Dexfenfluramine), Fenfluramine (Fenfluramine), phentertiamine (Phentermine), Sibutramine (Sibutramine), Amfepramone (Amfepramone), dexamphetamine (Dexamfetamine), Mazindol (Mazindol), Phenylpropanolamine (Phenylpropanamine), clobenzylamphetamine (Clobenzorex), MCH receptor antagonists (e.g., the compounds described in WO06/035967, SB-568849; SNAP-7941, T-226296), neuropeptide Y antagonists (e.g., CP-422935), cannabinoid (canabinoid) receptor antagonists (e.g., Rimonabant (Rimonabant) (SR-141716), SR-147778), ghrelin (ghrin) antagonists, 11. beta. -steroid inhibitors (34hydroxylase, e.g., hydroxylase-13739, Lipolase (BV-L-13798), and Lipocalcito (BV-L) (Orosta-L), and so on L) (BV-13739, Orosta-L), and so on L-L) can be used as antiobesity agent, DGAT-1 inhibitors, β 3 agonists (e.g., AJ-9677, AZ40140), peptide appetite suppressants (e.g., Leptin (Leptin), CNTF (ciliary neurotrophic factor)), Cholecystokinin (Cholecystokinin) agonists (e.g., lincotript (Lintitript), FPL-15849), feeding inhibitors (e.g., P-57).

As the diuretic, xanthine derivatives (e.g., theobromine sodium salicylate, theobromine calcium salicylate), thiazide agents (e.g., ethylthiazide (Ethiazide), Cyclopenthiazide (Cyclopenthiazide), Trichlormethiazide (trichlorethazide), Hydrochlorothiazide (hydrochlorhiazide), Hydroflumethiazide (Hydroflumethiazide), dicyclomine Hydrochlorothiazide (bentylhydrochlorhiazide), penfluthiazide (penfluzide), Polythiazide (Polythiazide), Methyclothiazide (Methyclothiazide)), aldosterone-resistant agents (e.g., Spironolactone (Spironolactone), Triamterene (Triamterene)), carbonic anhydrase inhibitors (e.g., acetazolamide (acetazolamide)), chlorobenzenesulfonamide agents (e), chlorothalidone (e), meldonide (melphalanide), melphalan (isozamide), hydramide (isopropyl), triamcinonide (isopropyl), and triamcinonide) may be cited.

Examples of the antithrombotic agent include heparin (e.g., heparin sodium, heparin calcium, dalteparin sodium, AVE-5026), warfarin (e.g., warfarin potassium), antithrombin (e.g., Argatroban (Argatroban), Ximelagatran (xmelagatran), Dabigatran (Dabigatran), Odiparcil, Lepirudin (Lepirudin), Bivalirudin (Bivalirudin), dessicin (Desirudin), ART-123, idaparin (Idraparinux), SR-123781, AZD-0837, MCC-977, TGN-255, TGN-167, RWJ-58436, LB-30870, MPC-0920, pembroussin (pegsirudin), Ororg-426751, etc.), thromboplastin (e.g., urokinase), elastase (tetraplatin), thromboplastin (e), thromboplastin (e), thromboplastin (e), etc.), ticlopidine hydrochloride (ticlopidine hydrochloride), cilostazol (cilostazol), ethyl hexacosanoate (ethyl icosapent), beraprost sodium (beraprost sodium), sarpogrelate hydrochloride (sarpogrelate hydrochloride), etc.), anti-Xa inhibitors (e.g., Fondaparinux (Fondaparinux), BAY-59-7939, DU-176B, YM-150, SR-126517, Apixaban (Apixaban), Razaxaban (Razaxaban), LY-517717, MLN-102, Octapanadine, Otamixaban (Otamixaban), EMD-503982, TC-10, CS-303KF0, AVE-3247, GSK-813893, TC-1982, etc.), carboxypeptidase B in plasma (or as an inhibitor of fibrinolysin activity (e.g., thrombin-6265, taecolide), e.g., activated taffe-462, taffe-96462 (taffer) and so on.

The compounds of the invention may be administered orally or non-orally, systemically or locally, as a medicament.

When the compound of the present invention is provided as a pharmaceutical, various forms of pharmaceutical forms such as solid preparations and liquid preparations can be appropriately selected. In this case, a pharmaceutically acceptable carrier may be added. Examples of such carriers include general excipients, extenders, binders, disintegrants, coating agents, sugar coating agents, pH adjusters, dissolving agents, aqueous or non-aqueous solvents, and the like. The compound of the present invention and these carriers can be formulated into tablets, pills, capsules, granules, powders, solutions, emulsions, suspensions, injections, etc.

Examples

The present invention will be described in further detail below with reference to reference examples, examples and test examples.

Reference example 1

Preparation of 2, 3, 4, 6-tetra-O-benzyl-5-thio-D-gluconic acid (glucono) -1, 5-lactone (compound (3AB))

[ CHEM 11 ]

(1) Preparation of tetrahydro-2H-pyran-2-yl 2, 3, 4, 6-tetra-O-acetyl-5-thio-D-glucopyranose

To a solution of 2, 3, 4, 6-tetra-O-acetyl-5-thio-D-glucopyranose (2.0g, 5.49mmoL) in chloroform (40mL) were added 3, 4-dihydro-2H-pyran (1.5mL, 16.5mmoL) and p-toluenesulfonic acid 1 hydrate (104mg, 0.549mmoL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, washing of the organic layer with a saturated saline solution, and drying with anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 1: 1) to obtain the title compound (2.56g) as a pale yellow amorphous.

(2) Preparation of tetrahydro-2H-pyran-2-yl 2, 3, 4, 6-tetra-O-benzyl-5-thio-D-glucopyranose

Subsequently, a 25 wt% methanol solution of sodium methoxide (0.11mL, 0.55mmoL) was added to a methanol solution (2.5g) of tetrahydro-2H-pyran-2-yl-2, 3, 4, 6-tetra-O-acetyl-5-thio-D-glucopyranose (40mL), and the mixture was stirred for 3 hours. Adding a small amount of dry ice, neutralizing the reaction solution, and concentrating the reaction solution. The resulting residue was dissolved in N, N-dimethylformamide (20 mL). The solution was added dropwise to a suspension of sodium hydride (1.3g, 32.9 mmol; 60% oil) and N, N-dimethylformamide (4mL) under ice-cooling. After the reaction mixture was stirred at room temperature for 20 minutes, it was cooled to 4 ℃ and benzyl bromide (5.6g, 32.9mmoL) was added. The reaction mixture was stirred at room temperature for 12 hours, and methanol (5mL) was added thereto and stirred for 30 minutes. Ice water was added to the reaction mixture, which was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 6: 1) to obtain the title compound (3.36g, 96%; 2 steps).

(3) Preparation of 2, 3, 4, 6-tetra-O-benzyl-5-thio-D-glucopyranose

A mixture of tetrahydro-2H-pyran-2-yl 2, 3, 4, 6-tetra-O-benzyl-5-thio-D-glucopyranose (3.30g, 5.15mmoL), pyridinium p-toluenesulfonic acid (518mg, 2.06mmoL) and ethanol (58mL) was stirred at 80 ℃ for 2 hours. The reaction was cooled to room temperature and the solvent was concentrated. The obtained residue was dissolved in ethyl acetate. The solution was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the residue was purified by silica gel column chromatography (hexane: ethyl acetate 3: 1) to give the title compound (2.89g, quant.) as colorless crystals.

¹³C NMR (125MHz, chloroform-d) delta 41.3, 67.8, 71.6, 73.0, 73.2, 75.6, 76.2, 81.9, 82.9, 84.4, 127.5, 127.7, 127.8, 127.9, 128.0, 128.3, 128.4, 128.5, 137.8, 138.3, 138.8.

(4) Preparation of 2, 3, 4, 6-tetra-O-benzyl-5-thio-D-gluconic acid-1, 5-lactone

A mixture of 2, 3, 4, 6-tetra-O-benzyl-5-thio-D-glucopyranose (2.82g, 5.07mmoL), dimethyl sulfoxide (47mL) and acetic anhydride (39mL) was stirred at room temperature for 12 hours. To the reaction mixture was added ice water, followed by extraction with ethyl acetate, and the organic layer was washed with water, a saturated aqueous sodium bicarbonate solution, and a saturated brine, and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 6: 1) to obtain the title compound (2.3g, 82%) as a colorless oil.

¹H NMR (200MHz, chloroform-d) δ ppm 3.70(d, J ═ 4.8Hz, 2H)3.86-4.02(m, 2H)4.09-4.22(m, 2H)4.40-4.68(m, 7H)4.83(d, J ═ 11.4Hz, 1H)7.12-7.41(m, 20H).

Reference example 2

Preparation of 2- [4- (benzyloxy) -5-bromo-2-methylphenyl ] -1, 3-dioxolane (Compound (6A))

[ CHEM 12 ]

(1) Preparation of 1- [4- (benzyloxy) -2-methylphenyl ] ethanone

To a solution of 4 '-hydroxy-2' -methylacetophenone (3.06g, 20mmol) in N, N-dimethylformamide (20mL) were added potassium carbonate (3.66g, 26.4mmol), benzyl bromide (2.7mL, 22.4mmol) and N-Bu₄NI (0.75g, 2.03mmol), stirred at room temperature for 14 h. After the organic layer was separated by adding a saturated aqueous solution of ammonium chloride and water to the reaction mixture under ice-cooling, the organic layer was washed with a 20 wt.% aqueous solution of sodium thiosulfate and a saturated saline solution, and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 8: 1 → 6: 1) to obtain the title compound (5.05g, quant.) as a colorless powder.

1H NMR (300MHz, chloroform-d) δ ppm 2.55(s, 3H)2.57(s, 3H)5.11(s, 2H)6.78-6.86(m, 2H)7.30-7.47(m, 5H)7.75(dd, J ═ 7.93, 1.09Hz, 1H).

(2) Preparation of 4- (benzyloxy) -5-bromo-2-methylbenzoic acid

To a solution of 1- [4- (benzyloxy) -2-methylphenyl ] ethanone (20.9g, 87.1mmol) in acetone (300mL) were added an aqueous solution (100mL) of NaBr (9.86g, 95.9mmol), water (200mL), and Oxone (registered trademark, Oxone monopersulfate chloride, Aldrich) (59.0g, 95.9mmol), and the mixture was stirred at room temperature for 2.5 hours. An aqueous solution (50mL) of sodium sulfite (20g) was added to the reaction mixture under ice-cooling, followed by addition of water and ethyl acetate, and the organic layer was separated. The organic layer was washed with 20 wt.% aqueous sodium sulfite solution, saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure to obtain a mixture (27.2g) of 1- [4- (benzyloxy) -5-bromo-2-methylphenyl ] ethanone and 1- [4- (benzyloxy) -3-bromo-2-methylphenyl ] ethanone. To this solution, a 5% sodium hypochlorite solution (300mL, 255mmol) and an aqueous solution (10mL) of potassium hydroxide (4.80g, 85.3mmol) were added, and after stirring at 120 ℃ for 1 hour, the mixture was cooled to room temperature, and the precipitated insoluble matter was filtered. To the insoluble matter, 2N hydrochloric acid was added, followed by extraction with ethyl acetate, and then the organic layer was washed with 2N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was washed with methanol to give the title compound (16.6g, 59%, 2 steps) as a colorless powder.

1H NMR(300MHz，DMSO-d₆)δppm 2.45-2.57(m，3H)5.28(s，2H)7.18(s，1H)7.31-7.54(m，5H)8.03(s，1H)12.83(brs，1H).

ESI m/z＝319(M-H)，321(M+2-H).

(3) Preparation of 2- [4- (benzyloxy) -5-bromo-2-methylphenyl ] -1, 3-dioxolane

Oxalyl chloride (5mL, 56.9mmol) and N, N-dimethylformamide (6 drops) were added to a suspension of 4- (benzyloxy) -5-bromo-2-methylbenzoic acid (16.6g, 51.7mmol) in chloroform (80mL), and after stirring at room temperature for 1 hour, the reaction mixture was concentrated to give 4- (benzyloxy) -5-bromo-2-methylbenzoyl chloride. Subsequently, a solution of 4- (benzyloxy) -5-bromo-2-methylbenzoyl chloride in chloroform (60mL) was added dropwise to a suspension of N, O-dimethylhydroxylamine hydrochloride (5.55g, 56.9mmol) and triethylamine (15mL, 103mmol) in chloroform (60mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Water and chloroform were added under ice-cooling, the organic layer was separated, and then the organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated saline solution and dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the solvent was distilled off under reduced pressure to give 4- (benzyloxy) -5-bromo-N-methoxy-N-methylbenzamide. Lithium aluminum hydride (1.96g, 51.7mmol) was added to a tetrahydrofuran (150mL) solution thereof at-10 ℃ and stirred at the same temperature for 1 hour. After separating the organic layer by adding 1N hydrochloric acid and ethyl acetate to the reaction mixture, the organic layer was washed with 1N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated saline solution and dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the solvent was distilled off under reduced pressure to obtain 4- (benzyloxy) -5-bromo-2-methylbenzaldehyde. To a toluene (120mL) solution thereof were added ethylene glycol (30mL, 517mmol) and p-toluenesulfonic acid monohydrate (0.50g, 2.58mmol), and the mixture was heated under reflux for 1.5 hours using a Dean-Stark apparatus. Ethyl acetate was added to the reaction mixture, and after separating the organic layer, the organic layer was washed with water, a saturated aqueous sodium bicarbonate solution, and a saturated saline solution, and dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 5: 1). Further, the residue was purified by NH silica gel column chromatography (chloroform) to give the title compound (12.8g, 71%, 3 steps) as a colorless powder.

1H NMR (300MHz, chloroform-d) delta ppm 2.34(s, 3H)3.92-4.19(m, 4H)5.15(s, 2H)5.87(s, 1H)6.74(s, 1H)7.27-7.51(m, 5H)7.72(s, 1H).

ESI m/z＝348.

Reference example 3

Preparation of 2, 3, 4, 6-tetra-O-benzyl-1-C- [2- (phenylmethoxy) -5- (1, 3-dioxolan-2-yl) -4-methylphenyl ] -5-thio-D-glucopyranose (Compound (7A))

[ CHEM 13 ]

In a solution of 2- [4- (benzyloxy) -5-bromo-2-methylphenyl ] -1, 3-dioxolane (12.9g, 36.9mmol) in tetrahydrofuran (100mL), a 2.67M n-butyllithium hexane solution (14.5mL, 36.9mmol) was added dropwise at-78 ℃ under a nitrogen atmosphere, and stirred at the same temperature for 30 minutes. Subsequently, a solution of 2, 3, 4, 6-tetra-O-benzyl-5-thio-D-glucono-1, 5-lactone (9.77g, 17.6mmol) in tetrahydrofuran (40mL) was added dropwise thereto, and the mixture was stirred at the same temperature for 15 minutes. After a saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate, the organic layer was washed with a saturated aqueous ammonium chloride solution and a saturated saline solution, and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 3: 1 → 2: 1) to give the title compound (10.6g, 73%) as a colorless transparent amorphous form.

1H NMR (300MHz, chloroform-d) delta ppm 2.39(s, 3H)3.46-3.72(m, 2H)3.86-4.22(m, 8H)4.43-5.00(m, 8H)5.10(s, 2H)5.92(s, 1H)6.66-6.90(m, 3H)7.00-7.38(m, 23H)7.57(brs, 1H).

ESI m/z＝847(M+Na⁺).

Reference example 4

Preparation of 2, 3, 4, 6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5-formyl-4-methylphenyl ] -5-thio-D-glucopyranose (Compound (8A))

[ CHEM 14 ]

To a solution of 2, 3, 4, 6-tetra-O-benzyl-1-C- [2- (phenylmethoxy) -5- (1, 3-dioxolan-2-yl) -4-methylphenyl ] -5-thio-D-glucopyranose (11.1g, 13.5mmol) in tetrahydrofuran (100mL) was added 6N hydrochloric acid (100mL) under ice-cooling, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture under ice-cooling, extraction was performed with ethyl acetate, and then the organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated saline solution, and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 2: 1) to obtain the title compound (10.1g, quant.) as a pale yellow oily compound.

1H NMR (300MHz, chloroform-d) delta ppm 2.64(s, 3H)3.51-3.70(m, 2H)3.84-4.29(m, 4H)4.46-4.97(m, 8H)5.04-5.24(m, 2H)6.62-6.82(m, 3H)6.99-7.38(m, 23H)7.60(brs, 1H)10.05(s, 1H).

ESI m/z＝803(M+Na⁺).

Reference example 5

Preparation of 1- (benzyloxy) -2-bromo-5-methyl-4- (4-methoxyphenylmethyl) benzene

[ CHEM 15 ]

(1) To a solution of 4- (benzyloxy) -5-bromo-2-methylbenzaldehyde (3.0g, 9.83mmol) in tetrahydrofuran (20mL) was added dropwise a solution of 0.5M 4-methoxyphenylmagnesium bromide in tetrahydrofuran (29.5mL, 14.7mmol) at-18 ℃ and stirred at-15 ℃ for 15 minutes. After a saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate, the organic layer was washed with a saturated aqueous ammonium chloride solution and a saturated saline solution, and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to give [1- (benzyloxy) -2-bromo-5-methylphenyl ] (4-methoxyphenyl) methanol (4.48g) as a colorless oil.

(2) Then, in [1- (benzyloxy) -2-bromo-5-methylphenyl ]]To a mixed solution of (4-methoxyphenyl) methanol (4.40g) in acetonitrile (20mL) and chloroform (20mL) was added Et in this order at 4 ℃₃SiH (3.1mL, 19.7mmol) and BF₃·Et₂O (1.2mL, 9.83 mmol). After stirring at the same temperature for 30 minutes, 2M aqueous potassium hydroxide (20mL) was added. The resulting mixture was extracted with chloroform, and the organic layer was washed with 1M hydrochloric acid and saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate: 10: 1) to obtain the title compound (3.46g, 89%) as a colorless oil.

1H NMR (300MHz, chloroform-d) δ ppm 2.17(s, 3H)3.79(s, 3H)3.82(s, 2H)5.12(s, 2H)6.77(s, 1H)6.82(d, J ═ 8.4Hz, 2H)7.02(d, J ═ 8.4Hz, 2H)7.19-7.45(m, 4H)7.44-7.58(m, 2H).

EI m/z＝396，398.

Reference example 6

Preparation of 1- (benzyloxy) -2-bromo-5-methyl-4- (4-methylbenzyl) benzene

[ CHEM 16 ]

The title compound was synthesized in the same manner as in reference example 5 using 4-methylphenylmagnesium bromide instead of 4-methoxyphenylmagnesium bromide.

1H NMR (300MHz, chloroform-d) delta ppm 2.17(s, 3H)2.31(s, 3H)3.84(s, 2H)5.12(s, 2H)6.76(s, 1H)6.95-7.03(m, 2H)7.04-7.14(m, 2H)7.22-7.58(m, 6H).

EI m/z＝380，382.

Reference example 7

Preparation of 1- (benzyloxy) -2-bromo-4- (4-ethylbenzyl) -5-methylbenzene

[ CHEM 17 ]

(1) Preparation of [4- (benzyloxy) -5-bromo-2-methylphenyl ] (4-ethylphenyl) methanol

To a solution of 1-bromo-4-ethylbenzene (5.00g, 16.4mmol) in tetrahydrofuran (30mL) was added dropwise a solution of 2.66M n-BuLi in hexane (6.47mL, 17.2mmol) at-60 ℃ over 5 minutes. After stirring at the same temperature for 15 minutes, a solution of 4- (benzyloxy) -5-bromo-2-methylbenzaldehyde (3.03g, 16.4mmol) in tetrahydrofuran (15mL) was added dropwise to the solution, and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, the mixture was warmed to room temperature, extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure to obtain the title compound.

(2) Preparation of 1- (benzyloxy) -2-bromo-4- (4-ethylbenzyl) -5-methylbenzene

Then, in [4- (benzyloxy) -5-bromo-2-methylphenyl]To a solution of (4-ethylphenyl) methanol in chloroform (80mL) was added Et sequentially at 0 deg.C₃SiH (3.93mL, 24.6mmol) and BF₃·Et₂O (2.49mL, 19.7mmol), was stirred at the same temperature for 30 minutes. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate, washing of the organic phase with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 98: 2) to obtain the title compound (5.31g, 82%, 2 steps) as a colorless oil.

1H NMR (300MHz, chloroform-d) δ ppm 1.22(t, J ═ 7.62Hz, 3H)2.17(s, 3H)2.61(q, J ═ 7.62Hz, 2H)3.85(s, 2H)5.12(s, 2H)6.76(s, 1H)7.01(d, 2H)7.10(d, 2H)7.27-7.43(m, 4H)7.48(d, 2H).

ESI m/z＝412，414(M+NH₄ ⁺).

Reference example 8

Preparation of 1- (benzyloxy) -2-bromo-5-methyl-4- [4- (methylthio) benzyl ] benzene

[ CHEM 18 ]

The same procedures used in reference example 7 were repeated except for using 4-bromophenylthiomethane instead of 4-bromotoluene to give [4- (benzyloxy) -5-bromo-2-methylphenyl ] [4- (methylthio) phenyl ] methanol (6.93g, 66%).

1H NMR (300MHz, chloroform-d) δ ppm 2.05(d, J ═ 3.6Hz, 1H)2.16(s, 3H)2.47(s, 3H)5.13(s, 2H)5.86(d, J ═ 3.6Hz, 1H)6.73(s, 1H)7.22(s, 4H)7.28-7.51(m, 5H)7.70(s, 1H).

ESI m/z＝463(M-Cl^-).

Then, [4- (benzyloxy) -5-bromo-2-methylphenyl ] [4- (methylthio) phenyl ] methanol was used instead of [4- (benzyloxy) -5-bromo-2-methylphenyl ] (4-ethylphenyl) methanol to give the title compound (6.28g, 94%) as a pale brown oil.

1H NMR (300MHz, chloroform-d) delta ppm 2.15(s, 3H)2.46(s, 3H)3.84(s, 2H)5.12(s, 2H)6.77(s, 1H)6.98-7.06(m, 2H)7.14-7.21(m, 2H)7.23-7.51(m, 6H).

ESI m/z＝430(M+NH₄ ⁺).

Reference example 9

Preparation of 5-bromo-2-chloro-4-methoxybenzaldehyde

[ CHEM 19 ]

(1) Preparation of 1-bromo-4-chloro-2-methoxy-5-methylbenzene

(i) To a solution of 4-chloro-2-methoxy-5-methylaniline (20.2g, 117mmol) in acetone (100mL) was added 48% aqueous hydrogen bromide (50mL, 2.93moL), and an aqueous solution (70mL) of sodium nitrite (10.1g, 146mmol) was added dropwise under ice-cooling, and the mixture was warmed to room temperature and stirred for 1 and a half hour.

(ii) To an aqueous solution (160mL) of copper sulfate 5 hydrate (87.9g, 352mmol) and sodium bromide (36.2g, 352mmol), an aqueous solution (70mL) of sodium sulfite (22.4g, 176mmol) was added dropwise over 20 minutes, and after stirring at room temperature for 30 minutes, the mixture was allowed to stand under ice-cooling conditions. The supernatant was removed by decantation, the resulting precipitate was washed with water (1L) and decantation of the supernatant was repeated 4 times to give copper bromide as colorless powder. To this was added 48% aqueous hydrogen bromide (50mL, 2.93moL), stirred, and the aqueous diazonium salt solution prepared in (i) was added dropwise over 40 minutes under ice-cooling, and stirred at room temperature for 15 hours. The acetone in the reaction solution was distilled off under reduced pressure, the resulting precipitate was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane) to give the title compound (23.5g) as colorless crystals.

(2) Preparation of 1-bromo- (5-bromomethyl) -4-chloro-2-methoxybenzene

Subsequently, N-bromosuccinimide (19.2g) and 2, 2' -azobis (2-methylpropanenitrile) (1.61g) were added to a solution of 1-bromo-4-chloro-2-methoxy-5-methylbenzene (23.2g) in carbon tetrachloride (400mL), and the mixture was refluxed for 1 hour. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure to give the title compound (33.5g) as a colorless oil.

(3) Preparation of (5-bromo-2-chloro-4-methoxyphenyl) methanol

To a solution of 1-bromo- (5-bromomethyl) -4-chloro-2-methoxybenzene (33.4g) in 1, 4-dioxane (350mL) was added an aqueous solution (350mL) of sodium carbonate (52.0g), and the mixture was refluxed for 1 hour. After cooling, water (350mL) was added to the reaction mixture, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure to obtain the title compound (25.8g) as a colorless powder.

(4) Preparation of 5-bromo-2-chloro-4-methoxybenzaldehyde

To a solution of (5-bromo-2-chloro-4-methoxyphenyl) methanol (25.8g) in chloroform (300mL) was added manganese dioxide (129g, 1.48mol), and the mixture was stirred at room temperature for 18 hours. The insoluble matter was removed by Celite filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 50: 1 → 30: 1) to give the title compound (20.0g, 82%, 4 steps) as a colorless powder.

1H NMR (300MHz, chloroform-d) delta ppm 3.99(s, 3H)6.92(s, 1H)8.12(s, 1H)10.27(s, 1H).

Reference example 10

Preparation of 5-bromo-2-chloro-4-hydroxybenzaldehyde

[ CHEM 20 ]

To a solution of 5-bromo-2-chloro-4-methoxybenzaldehyde (18.6g, 74.4mmol) in dimethyl sulfoxide (300mL) was added pyridine hydrochloride (43.0g, 372mmol), and the mixture was stirred at 145 ℃ for 3 hours. The reaction mixture was cooled with ice, a 10% aqueous hydrochloric acid solution was added thereto, the mixture was made acidic, extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure to obtain colorless crystals (20.1 g). It was recrystallized from chloroform to give the title compound (11.7g, 67%) as colorless crystals.

1H NMR(300MHz，DMSO-d₆)δppm 7.07(s，1H)7.96(s，1H)10.08(s，1H)12.05(brs，1H).

Reference example 11

Preparation of 5-bromo-2-chloro-4- (prop-2-en-1-yloxy) benzaldehyde

[ CHEM 21 ]

Allyl bromide (5.61mL, 66.3mmol) was added to a solution of 5-bromo-2-chloro-4-hydroxybenzaldehyde (12.0g, 51.0mmol), tetrabutylammonium iodide (941mg, 2.55mmol), and potassium carbonate (11.3g, 81.5mmol) in N, N-dimethylformamide (250mL), and the mixture was stirred at room temperature for 16 hours. After the reaction solution was cooled with ice, a 10% aqueous hydrochloric acid solution (50mL) was added, followed by addition of water (200mL), extraction with ethyl acetate was performed, and then the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethanol to obtain the title compound (11.5g, 82%) as colorless powder.

1H NMR (300MHz, chloroform-d) δ ppm 4.70(dt, J ═ 5.0, 1.6Hz, 2H)5.40(dq, J ═ 10.6, 1.4Hz, 1H)5.52(dd, J ═ 17.3, 1.1Hz, 1H)6.04(dd, J ═ 17.0, 10.3Hz, 1H)6.90(s, 1H)8.13(s, 1H)10.27(s, 1H).

Reference example 12

Preparation of 1-bromo-4-chloro-5- (4-methoxybenzyl) -2- (prop-2-en-1-yloxy) benzene

[ CHEM 22 ]

(1) Preparation of [ 5-bromo-2-chloro-4- (prop-2-en-1-yloxy) phenyl ] (4-methoxyphenyl) methanol

To a solution of 1-bromo-4-methoxybenzene (1.43mL, 11.43mmol) in tetrahydrofuran (100mL) was added dropwise a solution of 2.64M n-BuLi in hexane (4.54mL, 11.98mmol) at-80 ℃ over 5 minutes. After stirring at the same temperature for 15 minutes, a solution of 5-bromo-2-chloro-4- (prop-2-en-1-yloxy) benzaldehyde (3.00g, 10.89mmol) in tetrahydrofuran (50mL) was added dropwise to the solution, and the mixture was slowly warmed to room temperature and stirred at the same temperature for 30 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure and distilled to remove tetrahydrofuran. This was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure to obtain the title compound (3.79g) as a pale yellow oil.

(2) Preparation of 1-bromo-4-chloro-5- (4-methoxybenzyl) -2- (prop-2-en-1-yloxy) benzene

Then, in [ 5-bromo-2-chloro-4- (prop-2-en-1-yloxy) phenyl]To a solution of (4-methoxyphenyl) methanol (3.77g, 9.83mmol) in chloroform (50mL) was added Et sequentially at 0 deg.C₃SiH (2.35mL, 14.74mmol) and BF₃·Et₂O (1.49mL, 11.79mmol), was stirred at the same temperature for 30 min. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate, washing of the organic phase with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: hexane ═ 1: 4) to obtain the title compound as a colorless oil (1.56g, 39%, 2 steps).

1H NMR (300MHz, chloroform-d) δ ppm 3.79(s, 3H)3.93(s, 2H)4.57(dt, J ═ 5.0, 1.6Hz, 2H)5.32(dd, J ═ 10.6, 1.4Hz, 1H)5.50(d, J ═ 1.6Hz, 1H)5.91-6.15(m, 1H)6.84(d, J ═ 8.7Hz, 2H)6.90(s, 1H)7.09(d, J ═ 8.7Hz, 2H)7.30(s, 1H).

EI m/z＝366，368.

Reference example 13

Preparation of 1-bromo-4-chloro-5- (4-methylbenzyl) -2- (prop-2-en-2-yloxy) benzene

[ CHEM 23 ]

(1) Preparation of [ 5-bromo-2-chloro-4- (prop-2-en-1-yloxy) phenyl ] (4-methylphenyl) methanol

The synthesis was carried out in the same manner as in reference example 12(1) except for using 4-bromotoluene in place of 1-bromo-4-methoxybenzene. Purification by silica gel column chromatography (hexane: ethyl acetate 87: 13) gave the title compound (1.04g, 38%) as a colorless solid.

1H NMR (300MHz, chloroform-d) δ ppm 2.21(d, J ═ 3.57Hz, 1H)2.33(s, 3H)4.55-4.61(m, 2H)5.33(dq, J ═ 10.57, 1.45Hz, 1H)5.47(dq, J ═ 17.31, 1.59Hz, 1H)5.96-6.11(m, 2H)6.84(s, 1H)7.15(d, 2H)7.25(d, 2H)7.80(s, 1H).

(2) Preparation of 1-bromo-4-chloro-5- (4-methylbenzyl) -2- (prop-2-en-2-yloxy) benzene

The synthesis was carried out in the same manner as in reference example 12(2) except for using [ 5-bromo-2-chloro-4- (prop-2-en-1-yloxy) phenyl ] (4-methylphenyl) methanol in place of [ 5-bromo-2-chloro-4- (prop-2-en-1-yloxy) phenyl ] (4-methoxyphenyl) methanol. Purification by silica gel column chromatography (hexane: ethyl acetate 87: 13) gave the title compound (827mg, 83%) as a colorless oil.

1H NMR (300MHz, chloroform-d) δ ppm 2.32(s, 3H)3.96(s, 2H)4.57(dt, J ═ 5.05, 1.59Hz, 2H)5.32(dq, J ═ 10.57, 1.45Hz, 1H)5.48(dq, 1H)5.96-6.11(m, J ═ 17.23, 10.39, 5.15, 5.15Hz, 1H)6.90(s, 1H)7.05(d, 2H)7.11(d, 2H)7.31(s, 1H).

EI m/z＝350，352.

Reference example 14

Preparation of 1-bromo-4-chloro-5- (4-ethylbenzyl) -2- (prop-2-en-1-yloxy) benzene

[ CHEM 24 ]

(1) Preparation of [ 5-bromo-2-chloro-4- (prop-2-en-1-yloxy) phenyl ] (4-ethylphenyl) methanol

The synthesis was carried out in the same manner as in reference example 12(1) except for using 1-bromo-4-ethylbenzene in place of 1-bromo-4-methoxybenzene. Purification by silica gel column chromatography (hexane: ethyl acetate 87: 13) gave the title compound (1.96g, 35%) as a colorless solid.

1H NMR (300MHz, chloroform-d) δ ppm 1.22(t, J ═ 7.54Hz, 3H)2.20(d, J ═ 3.57Hz, 1H)2.63(q, J ═ 7.67Hz, 2H)4.58(dd, J ═ 5.05, 0.70Hz, 2H)5.33(dq, J ═ 10.59, 1.44Hz, 1H)5.48(dq, J ═ 17.25, 1.71, 1.55Hz, 1H)5.95-6.15(m, 2H)6.85(s, 1H)7.17(d, 2H)7.28(d, 2H)7.82(s, 1H).

(2) Preparation of 1-bromo-4-chloro-5- (4-ethylbenzyl) -2- (prop-2-en-2-yloxy) benzene

The synthesis was carried out in the same manner as in reference example 12(2) except for using [ 5-bromo-2-chloro-4- (prop-2-en-1-yloxy) phenyl ] (4-ethylphenyl) methanol in place of [ 5-bromo-2-chloro-4- (prop-2-en-1-yloxy) phenyl ] (4-methoxyphenyl) methanol. Purification by silica gel column chromatography (hexane: ethyl acetate 87: 13) gave the title compound (1.55g, 83%) as a colorless oil.

1H NMR (300MHz, chloroform-d) δ ppm 1.22(t, J ═ 7.54Hz, 3H)2.62(q, J ═ 7.77Hz, 2H)3.97(s, 2H)4.58(dt, J ═ 4.97, 1.55Hz, 2H)5.32(dq, J ═ 10.57, 1.45Hz, 1H)5.48(dq, J ═ 17.25, 1.66Hz, 1H)6.04(dddd, J ═ 17.25, 10.41, 5.13, 4.97Hz, 1H)6.90(s, 1H)7.08(d, 2H)7.13(d, 2H)7.33(s, 1H).

EI m/z＝364，366.

Example 1

(1-A)

Preparation of 2, 3, 4, 6-tetra-O-benzyl-1-C- [2- (phenylmethoxy) -4-methyl-5- (4-methylbenzyl) phenyl ] -5-thio-D-glucopyranose

[ CHEM 25 ]

To a solution of 1- (benzyloxy) -2-bromo-5-methyl-4- (4-methylbenzyl) benzene (3.01g, 7.89mmol) in tetrahydrofuran (15mL) was added dropwise a solution of 2.6Mn-BuLi in hexane (3.3mL, 8.68mmol) at-60 ℃ over 4 minutes. After stirring at the same temperature for 30 minutes, a solution of 2, 3, 4, 6-tetra-O-benzyl-5-thio-D-glucono-1, 5-lactone (2.91g, 5.26mmol) in tetrahydrofuran (10mL) was added dropwise to the solution, and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, the mixture was warmed to room temperature, extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 5: 1) to obtain the title compound (2.44g, 54%) as a pale yellow gum.

1H NMR (300MHz, chloroform-d) δ ppm 2.20(s, 3H)2.27(s, 3H)3.46-3.59(m, 1H)3.65(dd, J ═ 9.6, 2.4Hz, 1H)3.78-4.16(m, 5H)4.43-4.70(m, 5H)4.75-4.97(m, 4H)5.09(s, 2H)6.70-7.42(m, 31H).

(1-B)

Preparation of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [2- (phenylmethoxy) -4-methyl-5- (4-methylphenylmethyl) phenyl ] -1-thioxo-D-sorbitol

[ CHEM 26 ]

In 2, 3, 4, 6-tetra-O-benzyl-1-C- [2- (phenylmethoxy) -4-methyl-5- (4-methylbenzyl) phenyl]To a mixed solution of (2.44g, 2.85mmol) of (E) -5-thio-D-glucopyranose in chloroform (5.0mL) and acetonitrile (12.0mL) was added Et in this order at-15 ℃₃SiH (0.91mL, 5.69mmol) and BF₃·Et₂O (0.43mL, 3.42mmol) was stirred for 1 hour. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate, washing of the organic phase with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate: 8: 1) to obtain the title compound (2.1g, 88%) as a colorless powder.

1H NMR (300MHz, chloroform-d) δ ppm 2.17(s, 3H)2.25(s, 3H)3.01-3.19(m, 1H)3.49-3.60(m, 1H)3.64-3.75(m, 1H)3.77-3.97(m, 5H)3.98-4.11(m, 1H)4.48-4.66(m, 5H)4.85(s, 2H)4.90(d, J ═ 10.7Hz, 1H)4.97-5.11(m, 2H)6.66-7.52(m, 31H).

ESI m/z＝858(M+NH₄ ⁺).

Example 2

(2-A)

Preparation of 2, 3, 4, 6-tetra-O-benzyl-1-C- [2- (phenylmethoxy) -5- (4-methoxybenzyl) -4-methylphenyl ] -5-thio-D-glucopyranose

[ CHEM 27 ]

To a solution of 1- (benzyloxy) -2-bromo-4- (4-methoxybenzyl) -5-methylbenzene (3.46g, 8.71mmol) in tetrahydrofuran (17mL) was added dropwise a solution of 2.6Mn-BuLi in hexane (3.7mL, 9.58mmol) at-50 ℃ over 5 minutes. After stirring at-60 ℃ for 30 minutes, a solution of 2, 3, 4, 6-tetra-O-benzyl-5-thio-D-glucono-1, 5-lactone (3.22g, 5.81mmol) in tetrahydrofuran (10mL) was added dropwise to the solution, and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, the mixture was warmed to room temperature, extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 5: 1) to obtain the title compound (2.22g, 44%) as a pale yellow gum.

1H NMR (300MHz, chloroform-d) δ ppm 2.20(s, 3H)3.47-4.03(m, 10H)4.02-4.21(m, 2H)4.51(s, 2H)4.63(d, J ═ 10.7Hz, 1H)4.73-4.98(m, 4H)5.10(s, 2H)6.48-7.76(m, 31H).

ESI m/z＝895(M+Na⁺).

(2-B)

Preparation of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-methoxybenzyl) -4-methylphenyl ] -1-thio-D-sorbitol

[ CHEM 28 ]

In 2, 3, 4, 6-tetra-O-benzyl-1-C- [2- (phenylmethoxy) -5- (4-methoxybenzyl) -4-methylphenyl]-5-sulfurTo a mixed solution of 2.20g (2.52 mmol) of O-D-glucopyranose in chloroform (6.0mL) and acetonitrile (12.0mL) was added Et sequentially at-15 ℃₃SiH (0.80mL, 5.04mmol) and BF₃·Et₂O (0.38mL, 3.02mmol), and stirred for 1 hour. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate, washing of the organic phase with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 5: 1) to obtain the title compound (2.15g, 99%) as a colorless powder.

1H NMR (300MHz, chloroform-d) δ ppm 2.17(s, 3H)3.00-3.23(m, 1H)3.55(t, J ═ 10.8Hz, 1H)3.66-4.16(m, 10H)4.45-4.65(m, 5H)4.85(s, 2H)4.90(d, J ═ 10.7Hz, 1H)4.96-5.13(m, 2H)6.51-7.46(m, 31H).

ESI m/z＝879(M+Na).

Example 3

(3-A)

Preparation of 2, 3, 4, 6-tetra-O-benzyl-1-C- [2- (phenylmethoxy) -5- [ (4-methoxyphenyl) (hydroxy) methyl ] -4-methylphenyl ] -5-thio-D-glucopyranose

[ CHEM 29 ]

To a mixture of 1-bromo-4-methoxybenzene (520mg, 2.78mmol) and tetrahydrofuran (3mL) was added a solution of 2.6M n-BuLi in hexane (1.01mL, 2.69mmol) at-78 ℃. Subsequently, a solution of 2, 3, 4, 6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5-formyl-4-methylphenyl ] -5-thio-D-glucopyranose (700mg, 0.896mmol) in tetrahydrofuran (3mL) was added, the mixture was stirred for 30 minutes, and the reaction mixture was warmed to room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 2: 1) to give the title compound (570mg, 72%) as a colorless amorphous form.

1H NMR (300MHz, chloroform-d) delta ppm 2.03-2.24(m, 3H)3.51-4.02(m, 9H)4.49-5.16(m, 10H)5.87(brs, 1H)6.73-7.36(m, 31H).

ESI m/z＝911(M+Na⁺)，887(M-H).

(3-B)

Preparation of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-methoxybenzyl) -4-methylphenyl ] -1-thio-D-sorbitol

[ CHEM 30 ]

In the 2, 3, 4, 6-tetra-O-benzyl-1-C- [2- (phenylmethoxy) -5- [ (4-methoxyphenyl) (hydroxy) methyl group]-4-methylphenyl radical]To a solution of-5-thio-D-glucopyranose (570mg, 0.641mmol) in acetonitrile (6.0mL) was added Et sequentially at-10 deg.C₃SiH (0.308mL, 1.93mmol) and BF₃·Et₂O (0.090mL, 1.41mmol) was stirred for 10 min. Chloroform (3.0mL) was added to the reaction solution, followed by BF at 0 deg.C₃·Et₂O (0.090mL, 1.41 mmol). The reaction mixture was stirred at 5 ℃ for 30 minutes, and then saturated aqueous sodium bicarbonate was added thereto, followed by extraction with chloroform, and the organic phase was washed with saturated brine and then dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 5: 1) to obtain the title compound (440mg, 80%) as a colorless powder. The spectroscopic data agree with example 2.

Example 4

Preparation of (1S) -1, 5-anhydro-1- [ 4-methyl-5- (4-methylbenzyl) -2-hydroxyphenyl ] -1-thioxo-D-sorbitol (Compound (I))

[ CHEM 31 ]

A mixture of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [2- (benzyloxy) -4-methyl-5- (4-methylbenzyl) phenyl ] -1-thioxo-D-sorbitol (2.1g, 2.50mmol), 20% palladium hydroxide charcoal (2.06g), and ethyl acetate (20mL) -ethanol (20mL) was stirred under hydrogen at room temperature for 50 hours. Insoluble matter in the reaction mixture was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol: 10: 1) to give the title compound (340mg, 35%) as a colorless powder.

1H NMR (300MHz, methanol-d)₄)δppm 2.07(s，3H)2.27(s，3H)2.92-3.04(m，1H)3.58(dd，J＝10.3，9.0Hz，1H)3.73(dd，J＝11.5，6.6Hz，1H)3.78-3.88(m，3H)3.94(dd，J＝11.5，3.8Hz，1H)4.29(d，J＝10.6Hz，1H)6.60(s，1H)6.94-6.98(m，2H)7.01-7.04(m，2H)7.05(s，1H).

ESI m/z＝408M+NH₄ ⁺)，389(M-H).

Calculated value of elemental analysis C₂₁H₂₆O₅S·H₂O: c, 61.72; h, 6.92. found: c, 61.85; h, 6.78.

Example 5

Preparation of (1S) -1, 5-anhydro-1- [5- (4-methoxybenzyl) -4-methyl-2-hydroxyphenyl ] -1-thioxo-D-sorbitol (Compound (II))

[ CHEM 32 ]

A mixture of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-methoxybenzyl) -4-methylphenyl ] -1-thioxo-D-sorbitol (2.11g, 2.46mmol), 20% palladium hydroxide charcoal (2.1g) and ethyl acetate (20mL) -ethanol (20mL) was stirred under hydrogen at room temperature for 24 h. Insoluble matter in the reaction mixture was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol: 10: 1) to give the title compound (690mg, 69%) as a colorless powder.

1H NMR (300MHz, methanol-d)₄)δppm 2.08(s，3H)2.91-3.06(m，1H)3.26(t，1H)3.59(dd，J＝10.3，8.9Hz，1H)3.68-3.78(m，1H)3.74(s，3H)3.81(s，2H)3.82-3.88(m，1H)3.94(dd，J＝11.3，3.7Hz，1H)4.29(d，J＝10.6Hz，1H)6.60(s，1H)6.69-6.82(m，2H)6.96-7.03(m，2H)7.04(s，1H).

ESI m/z＝429(M+Na⁺)

Calculated value of elemental analysis C₂₁H₂₆O₆S·H₂O: c, 59.27; h, 6.65. found: c, 59.32; h, 6.40.

Example 6

Preparation of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-ethylbenzyl) -4-methylphenyl ] -1-thio-D-sorbitol

[ CHEM 33 ]

To a solution of 1- (benzyloxy) -2-bromo-4- (4-ethylbenzyl) -5-methylbenzene (5.31g, 13.4mmol) in tetrahydrofuran (50mL) was added dropwise a solution of 2.66Mn-BuLi in hexane (5) at-60 ℃ over 5 minutes.05mL, 13.4 mmol). After stirring at the same temperature for 15 minutes, a solution of 2, 3, 4, 6-tetra-O-benzyl-5-thio-D-glucono-1, 5-lactone (6.76g, 12.2mmol) in tetrahydrofuran (25mL) was added dropwise to the solution, and the mixture was stirred at the same temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the temperature was raised to room temperature. This was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. Filtering to remove the drying agent, and distilling under reduced pressure to remove the solvent to obtain 2, 3, 4, 6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5- (4-ethylbenzyl) -4-methylphenyl]-5-thio-D-glucopyranose. This was dissolved in a mixed solution of chloroform (30mL) and acetonitrile (30mL), and cooled to 0 ℃. Then Et was added sequentially₃SiH (2.92mL, 18.3mmol) and BF₃·Et₂O (1.86mL, 14.6mmol) was stirred for 1 hour. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate, washing of the organic phase with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by NH type silica gel column chromatography (hexane: ethyl acetate: 4: 1) and silica gel column chromatography (hexane: ethyl acetate: 87: 13) to obtain the title compound (3.41g, 33%, 2 steps) as a pale yellow gum.

1H NMR (300MHz, chloroform-d) δ ppm 1.16(t, J ═ 8.16Hz, 3H)2.18(s, 3H)2.48-2.61(m, 2H)3.06-3.17(m, 1H)3.54(t, J ═ 8.70Hz, 1H)3.70(d, J ═ 10.26Hz, 1H)3.76-3.98(m, 5H)4.05(d, J ═ 11.81Hz, 1H)4.50-4.64(m, 5H)4.82-4.93(m, 3H)5.00-5.10(m, 2H)6.73(s, 1H)6.78(d, J ═ 6.06Hz, 2H)6.94(br., 3H)7.09-7.19(m, 7.19H) 7.34-7.35H (m, 7H) 6.44H).

ESI m/z＝872(M+NH₄ ⁺)，889(M+Cl^-).

Example 7

Preparation of (1S) -1, 5-anhydro-1- [5- (4-ethylbenzyl) -2-hydroxy-4-methylphenyl ] -1-thioxo-D-sorbitol (Compound (III))

[ CHEM 34 ]

According to the same method as in example 4, the synthesis was carried out using (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-ethylbenzyl) -4-methylphenyl ] -1-thio-D-sorbitol instead of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [2- (benzyloxy) -4-methyl-5- (4-methylbenzyl) phenyl ] -1-thio-D-sorbitol, and after silica gel column chromatography, recrystallization was carried out using ethanol to give the title compound (392mg, 24%).

1H NMR (300MHz, methanol-d 4) δ ppm 1.19(t, J ═ 7.62Hz, 3H)2.08(s, 3H)2.58(q, J ═ 7.56Hz, 2H)2.99(ddd, J ═ 10.22, 6.41, 3.73Hz, 1H)3.25(t, 1H)3.59(dd, J ═ 9.71, 8.47Hz, 1H)3.74(dd, J ═ 11.50, 6.37Hz, 1H)3.85(t, J ═ 9.64Hz, 3H)3.95(dd, J ═ 11.42, 3.81Hz, 1H)4.30(d, J ═ 10.41Hz, 1H)6.61(s, 1H)6.96-7.09(m, 5H).

ESI m/z＝422(M+NH₄ ⁺)，403(M-H)，439(M+Cl^-).

Example 8

Preparation of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [2- (phenylmethoxy) -4-methyl-5- [4- (methylthio) phenylmethyl ] phenyl ] -1-thioxo-D-sorbitol

[ CHEM 35 ]

The title compound was obtained as a pale yellow gum in the same manner as in example 6 except for using 1- (benzyloxy) -2-bromo-5-methyl-4- [4- (methylthio) benzyl ] benzene in place of 1- (benzyloxy) -2-bromo-4- (4-ethylbenzyl) -5-methylbenzene (3.27g, 27%, 2 steps).

1H NMR (300MHz, chloroform-d) δ ppm 2.16(s, 3H)2.39(s, 3H)3.07-3.16(m, 1H)3.49-3.60(m, 1H)3.63-3.75(m, 1H)3.76-4.10(m, 6H)4.42-4.66(m, 5H)4.85(s, 2H)4.90(d, J ═ 10.6Hz, 1H)4.97-5.11(m, 2H)6.69-7.48(m, 31H).

Example 9

Preparation of (1S) -1, 5-anhydro-1- [ 2-hydroxy-4-methyl-5- [4- (methylthio) benzyl ] phenyl ] -1-thioxo-D-sorbitol (Compound IV)

[ CHEM 36 ]

To a mixed solution of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [2- (benzyloxy) -4-methyl-5- [4- (methylthio) benzyl ] phenyl ] -1-thio-D-sorbitol (1.09g, 1.25mmol), dimethyl sulfide (4.5mL), m-cresol (1.2mL), trifluoroacetic acid (7.5mL), and 1, 2-ethanedithiol (0.3mL), trifluoromethanesulfonic acid (1.5mL) was added dropwise at-20 ℃. After stirring at the same temperature for 40 minutes, the reaction solution was poured into a mixture of saturated aqueous sodium carbonate solution and ice. The organic phase was washed with saturated aqueous sodium carbonate and saturated brine in this order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol ═ 50: 1 → 10: 1), followed by recrystallization from ethanol to give the title compound (166mg, 31%) as a colorless powder.

1H NMR (300MHz, methanol-d)₄)δppm 2.08(s，3H)2.43(s，3H)2.99(ddd，J＝10.2，6.4，3.7Hz，1H)3.22-3.31(m，1H)3.59(dd，J＝10.3，9.0Hz，1H)3.74(dd，J＝11.5，6.4Hz，1H)3.80-3.88(m，3H)3.95(dd，J＝11.5，3.7Hz，1H)4.30(d，J＝10.4Hz，1H)6.61(s，1H)6.99-7.08(m，3H)7.11-7.18(m，2H).

ESI m/z＝440(M+NH₄ ⁺)，445(M+Na⁺)，421(M-H)，457(M+Cl^-).

Example 10

(10-A)

Preparation of 1-C- [ 4-chloro-5- (4-methylbenzyl) -2- (prop-2-en-1-yloxy) phenyl ] -2, 3, 4, 6-tetra-O-prop-2-en-1-yl-5-thio-D-glucopyranose

[ CHEM 37 ]

In the same manner as in example 1(1-a), 1-bromo-4-chloro-5- (4-methylbenzyl) -2- (prop-2-en-2-yloxy) benzene was used in place of 1- (benzyloxy) -2-bromo-5-methyl-4- (4-methylbenzyl) benzene, and 2, 3, 4, 6-tetra-O-prop-2-en-1-yl-5-thio-D-glucono-1, 5-lactone was used in place of 2, 3, 4, 6-tetra-O-benzyl-5-thio-D-glucono-1, 5-lactone to give the title compound (426mg, 29%).

1H NMR (300MHz, chloroform-d) δ ppm 2.29(s, 3H)3.34-3.47(m, 1H)3.47-4.31(m, 14H)4.37(dd, J ═ 12.43, 5.75Hz, 1H)4.60(d, J ═ 4.82Hz, 2H)4.88(s, 1H)4.94(d, J ═ 1.55Hz, 1H)5.08-5.38(m, 7H)5.42-5.59(m, 2H)5.78-6.15(m, 4H)6.93(s, 1H)6.98-7.08(m, 4H)7.24(br.s, 1H).

ESI m/z＝644(M+NH₄ ⁺)，625(M-H)，661(M+Cl^-).

(10-B)

Preparation of (1S) -1, 5-anhydro-1- [ 4-chloro-5- (4-methylbenzyl) -2- (prop-2-en-1-yloxy) phenyl ] -2, 3, 4, 6-tetra-O-prop-2-en-1-yl-1-thio-D-sorbitol

[ CHEM 38 ]

In the same manner as in example 1(1-B), 1-C- [ 4-chloro-5- (4-methylbenzyl) -2- (prop-2-en-1-yloxy) phenyl ] -2, 3, 4, 6-tetra-O-prop-2-en-1-yl-5-thio-D-glucopyranose was used in place of 2, 3, 4, 6-tetra-O-benzyl-1-C- [2- (phenylmethoxy) -4-methyl-5- (4-methylbenzyl) phenyl ] -5-thio-D-glucopyranose to give the title compound (271mg, 65%) as a colorless solid.

1H NMR (300MHz, chloroform-d) δ ppm 2.29(s, 3H)2.94-3.04(m, 1H)3.25(t, J ═ 9.09Hz, 1H)3.38-4.20(m, 11H)4.28(d, J ═ 5.60Hz, 2H)4.36(dd, J ═ 12.05, 5.98Hz, 2H)4.54(dt, J ═ 4.97, 1.63Hz, 2H)4.81-4.92(m, 2H)5.09-5.32(m, 7H)5.33-5.51(m, 2H)5.80-6.10(m, 4H)6.86(s, 1H)7.02(td, 2H)7.03(d, 2H)7.22(s, 1H).

ESI m/z＝628(M+NH₄ ⁺)，633(M+Na⁺)，645(M+Cl^-).

Example 11

Preparation of (1S) -1, 5-anhydro-1- [ 4-chloro-2-hydroxy-5- (4-methylbenzyl) phenyl ] -1-thioxo-D-sorbitol (Compound (V))

[ CHEM 39 ]

To a solution of (1S) -1, 5-anhydro-1- [ 4-chloro-5- (4-methylbenzyl) -2- (prop-2-en-1-yloxy) phenyl ] -2, 3, 4, 6-tetra-O-prop-2-en-1-yl-1-thioxo-D-sorbitol (242mg, 0.396mmol) in tetrahydrofuran (8mL) were added N, N-dimethyl barbituric acid (618mg, 3.96mmol) and tetrakis (triphenylphosphine) palladium (91.5mg, 0.0792mmol), and the mixture was stirred at 90 ℃ for 3 hours. The reaction solution was cooled to room temperature, water was then added thereto, the mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol 9: 1), followed by recrystallization from hexane, ethyl acetate, and ethanol to give the title compound (64.2mg, 39%) as pale red powder.

1H NMR (600MHz, methanol-d)₄)δppm 2.26(s，3H)2.95(ddd，J＝10.09，6.42，3.67Hz，1H)3.22(t，J＝8.71Hz，1H)3.53(t，1H)3.67-3.79(m，2H)3.84-3.96(m，3H)4.25(d，J＝10.55Hz，1H)6.80(s，1H)7.01(d，2H)7.03(d，2H)7.12(s，1H).

ESI m/z＝428(M+NH₄ ⁺)，433(M+Na⁺)，409(M-H)，445(M+Cl^-).

Example 12

(12-A)

Preparation of 1-C- [ 4-chloro-5- (4-ethylbenzyl) -2- (prop-2-en-1-yloxy) phenyl ] -2, 3, 4, 6-tetra-O-prop-2-en-1-yl-5-thio-D-glucopyranose

[ CHEM 40 ]

In the same manner as in example 1(1-a), 1-bromo-4-chloro-5- (4-ethylbenzyl) -2- (prop-2-en-2-yloxy) benzene was used in place of 1- (benzyloxy) -2-bromo-5-methyl-4- (4-methylbenzyl) benzene, and 2, 3, 4, 6-tetra-O-prop-2-en-1-yl-5-thio-D-glucono-1, 5-lactone was used in place of 2, 3, 4, 6-tetra-O-benzyl-5-thio-D-glucono-1, 5-lactone to give the title compound (1.00g, 39%).

1H NMR (300MHz, chloroform-d) δ ppm 1.20(t, J ═ 7.62Hz, 3H)2.59(q, J ═ 7.51Hz, 2H)3.37-3.46(m, 1H)3.47-4.42(m, 15H)4.60(d, J ═ 4.35Hz, 2H)4.87(s, 1H)4.92(d, J ═ 3.89Hz, 1H)5.08-5.37(m, 7H)5.41-5.58(m, 2H)5.79-6.14(m, 4H)6.93(s, 1H)7.06(d, 2H)7.07(d, 2H)7.26(br.s., 1H).

ESI m/z＝639(M-H)，675(M+Cl^-).

(12-B)

Preparation of (1S) -1, 5-anhydro-1- [ 4-chloro-5- (4-ethylbenzyl) -2- (prop-2-en-1-yloxy) phenyl ] -2, 3, 4, 6-tetra-O-prop-2-en-1-yl-1-thio-D-sorbitol

[ CHEM 41 ]

The same procedures used in example 1(1-B) were repeated except for using 1-C- [ 4-chloro-5- (4-ethylbenzyl) -2- (prop-2-en-1-yloxy) phenyl ] -2, 3, 4, 6-tetra-O-prop-2-en-1-yl-5-thio-D-glucopyranose in place of 2, 3, 4, 6-tetra-O-benzyl-1-C- [2- (phenylmethoxy) -4-methyl-5- (4-methylphenylmethyl) phenyl ] -5-thio-D-glucopyranose to give the title compound (564mg, 65%) as a colorless solid.

1H NMR (300MHz, chloroform-d) δ ppm 1.20(t, J ═ 7.54Hz, 3H)2.59(q, J ═ 7.82Hz, 2H)2.95-3.04(m, 1H)3.25(t, J ═ 8.55Hz, 1H)3.36-3.94(m, 7H)3.99(d, J ═ 5.60Hz, 2H)4.03-4.19(m, 2H)4.27(d, J ═ 5.75Hz, 2H)4.36(dd, J ═ 12.43, 5.44Hz, 2H)4.54(dt, J ═ 4.82, 1.63Hz, 2H)4.85(dd, J ═ 15.85, 2.64, 2H)5.06-5.32(m, 7.32H) (m, 7.6H) 4.86 (d, 7H) 4.7, 6H) (d, 7.06, 6H) 4.26H, 7.26 Hz, 10H) 4.7H (d, 7.7H).

ESI m/z＝642(M+NH₄ ⁺)，647(M+Na⁺)，659(M+Cl^-).

Example 13

Preparation of (1S) -1, 5-anhydro-1- [ 4-chloro-2-hydroxy-5- (4-ethylbenzyl) phenyl ] -1-thioxo-D-sorbitol (Compound (VI))

[ CHEM 42 ]

In the same manner as in example 11, using (1S) -1, 5-anhydro-1- [ 4-chloro-5- (4-ethylbenzyl) -2- (prop-2-en-1-yloxy) phenyl ] -2, 3, 4, 6-tetra-O-prop-2-en-1-yl-1-thio-D-sorbitol instead of (1S) -1, 5-anhydro-1- [ 4-chloro-5- (4-methylbenzyl) -2- (prop-2-en-1-yloxy) phenyl ] -2, 3, 4, 6-tetra-O-prop-2-en-1-yl-1-thio-D-sorbitol, the title compound was obtained as a pale red powder (97.8mg, 29%).

1H NMR (600MHz, methanol-d)₄)δppm 1.18(t，J＝7.57Hz，3H)2.57(q，J＝7.64Hz，2H)2.96(ddd，J＝10.20，6.53，3.44Hz，1H)3.22(t，J＝8.94Hz，1H)3.54(dd，J＝10.32，8.94Hz，1H)3.71(dd，J＝11.69，6.65Hz，1H)3.76(dd，J＝10.32，8.94Hz，1H)3.86-3.96(m，3H)4.25(d，J＝10.55Hz，1H)6.80(s，1H)7.01-7.07(m，4H)7.14(s，1H).

ESI m/z＝442(M+NH₄ ⁺)，423(M-H)，459(M+Cl^-).

Example 14

(14-A)

Preparation of 1-C- [ 4-chloro-5- (4-methoxybenzyl) -2- (prop-2-en-1-yloxy) phenyl ] -2, 3, 4, 6-tetra-O-prop-2-en-1-yl-5-thio-D-glucopyranose

[ CHEM 43 ]

In the same manner as in example 1(1-a), 1-bromo-4-chloro-5- (4-methoxybenzyl) -2- (prop-2-en-1-yloxy) benzene was used in place of 1- (benzyloxy) -2-bromo-5-methyl-4- (4-methylbenzyl) benzene, and 2, 3, 4, 6-tetra-O-prop-2-en-1-yl-5-thio-D-glucono-1, 5-lactone was used in place of 2, 3, 4, 6-tetra-O-benzyl-5-thio-D-glucono-1, 5-lactone to give the title compound (1.35g, 54%).

1H NMR (300MHz, chloroform-d) δ ppm 3.35-3.47(m, 1H)3.49-3.63(m, 2H)3.69(t, 2H)3.77(s, 3H)3.80-4.42(m, 10H)4.60(d, J ═ 5.0Hz, 2H)4.82-4.99(m, 2H)5.05-5.38(m, 8H)5.41-5.60(m, 2H)5.76-6.17(m, 4H)6.73-6.84(m, 2H)6.92(s, 1H)6.99-7.11(m, 2H)7.34(brs, 1H).

ESI m/z＝660(M+NH₄ ⁺)，641(M-H).

(14-B)

Preparation of (1S) -1, 5-anhydro-1- [ 4-chloro-5- (4-methoxybenzyl) -2- (prop-2-en-1-yloxy) phenyl ] -2, 3, 4, 6-tetra-O-prop-2-en-1-yl-1-thio-D-sorbitol

[ CHEM 44 ]

The title compound (750mg, 56%) was obtained as a colorless solid in the same manner as in example 1(1-B) except for using 1-C- [ 4-chloro-5- (4-methoxybenzyl) -2- (prop-2-en-1-yloxy) phenyl ] -2, 3, 4, 6-tetra-O-prop-2-en-1-yl-5-thio-D-glucopyranose in place of 2, 3, 4, 6-tetra-O-benzyl-1-C- [2- (phenylmethoxy) -4-methyl-5- (4-methylbenzyl) phenyl ] -5-thio-D-glucopyranose.

1H NMR (300MHz, chloroform-d) δ ppm 2.88-3.08(m, 1H)3.25(t, J ═ 9.0Hz, 1H)3.35-4.66(m, 20H)4.73-4.99(m, 2H)5.06-5.33(m, 7H)5.33-5.55(m, 2H)5.72-6.18(m, 4H)6.74-6.83(m, 2H)6.86(s, 1H)7.04(d, J ═ 8.7Hz, 2H)7.21(s, 1H).

ESI m/z＝649(M+Na⁺)，644(M+NH₄ ⁺)，625(M-H).

Example 15

Preparation of (1S) -1, 5-anhydro-1- [ 4-chloro-2-hydroxy-5- (4-methoxybenzyl) phenyl ] -1-thioxo-D-sorbitol (Compound (VII))

[ CHEM 45 ]

The synthesis was carried out in the same manner as in example 11 using (1S) -1, 5-anhydro-1- [ 4-chloro-5- (4-methoxybenzyl) -2- (prop-2-en-1-yloxy) phenyl ] -2, 3, 4, 6-tetra-O-prop-2-en-1-yl-1-thioxo-D-sorbitol instead of (1S) -1, 5-anhydro-1- [ 4-chloro-5- (4-methylbenzyl) -2- (prop-2-en-1-yloxy) phenyl ] -2, 3, 4, 6-tetra-O-prop-2-en-1-yl-1-thioxo-D-sorbitol, after silica gel column chromatography, decolorized with activated carbon (powder) and recrystallized from ethyl acetate to give the title compound (180mg, 38%) as a colorless powder.

1H NMR (300MHz, methanol-d)₄)δppm 2.91-3.05(m，1H)3.24(t，J＝8.9Hz，1H)3.29-3.35(m，2H)3.57(t，J＝9.6Hz，1H)3.66-3.87(m，4H)3.87-4.00(m，3H)4.27(d，J＝10.4Hz，1H)6.74-6.87(m，3H)7.01-7.11(m，2H)7.14(s，1H).

ESI m/z＝449(M+Na⁺)，444(M+NH₄ ⁺)，425(M-H).

Formulation examples

[ TABLE 1 ]

Manufacturing method

The drug was mixed with lactose monohydrate, crystalline cellulose, carboxymethylcellulose calcium and hydroxypropylcellulose, and the mixture was pulverized with a pulverizer. And mixing the crushed mixture for 1 minute by using a stirring granulator, and then granulating for 4-8 minutes by using water. The resulting granulation was dried at 70 ℃ for 40 minutes. The granulated and dried powder was sieved through a 500 μm sieve. The sieved granulated and dried powder was mixed with magnesium stearate in a V-blender at 30rpm for 3 minutes. The resulting granules for compression molding were compressed by a rotary tablet machine to prepare tablets as shown in Table 2.

[ TABLE 2 ]

Test example 1

(1) Cloning and introduction of human SGLT1 or human SGLT2 into expression vector

The human SGLT1 sequence (NM-000343) was reverse transcribed from human small intestine-derived mRNA, amplified, and introduced into pCMV-tag5A (Stratagene). In addition, a human SGLT2 sequence (NM-003041) was prepared from mRNA derived from human kidney in the same manner as above, and introduced into pcDNA3.1+ hygro (Invitrogen). The sequence of each clone was confirmed to be identical to the reported sequence.

(2) Preparation of CHO-k1 cells stably expressing human SGLT1 or human SGLT2

Human SGLT1 and human SGLT2 expression vectors were transfected into CHO-K1 cells using lipofectamine2000 (lipofectamine2000) (Invitrogen). SGLT-expressing cells were cultured in the presence of Geneticin (Geneticin) (SGLT1) or hygromycin B (hygromycin B) (SGLT2) at a concentration of 500. mu.g/mL, and a tolerant strain was selected to obtain specific sugar uptake activity as an index by the following system.

(3) Sodium-dependent carbohydrate uptake inhibition assay for cells

Cells stably expressing human SGLT1 or human SGLT2 were used in sodium-dependent sugar uptake activity inhibition assays.

Cells were pretreated with buffer (140mM choline chloride, 2mM KCl, 1mM CaCl)₂、1mM MgCl₂10mM HEPES/5mM Tris, pH7.4) in 1mL for 20 minutes. The pretreatment buffer is removed, and a test compound-containing buffer for ingestion (comprising [, ])¹⁴C]Methyl alpha-D-glucopyranoside of methyl alpha-D-glucopyranoside (0.1 mM for SGLT1 inhibition and 1mM for SGLT2 inhibition), 140mM NaCl, 2mM KCl, 1mM CaCl₂、1mM MgCl₂10mM HEPES/5mM Tris, pH7.4) and 200. mu.L, and the uptake reaction was carried out at 37 ℃ for 30 minutes (SGLT1) or 1 hour (SGLT 2). After the reaction, the reaction mixture was washed with a washing buffer (10mM methyl α -D-glucopyranoside, 140mM choline chloride, 2mM KCl, 1mM CaCl)₂、1mM MgCl₂10mM HEPES/5mM Tris, pH7.4)1mL of the washed cells were dissolved in 400. mu.L of a 0.2M NaOH solution 2 times. Aquazol 2(Perkin Elmer) was added thereto, and after thorough mixing, the radioactivity was measured by a liquid scintillation counter (Beckman Coulter) to calculate the amount of sugar intake. As a control group, an uptake buffer containing no test compound was prepared. In addition, as a basic intake buffer, an intake buffer containing choline chloride instead of NaCl was prepared.

The amount of sugar intake was measured using test compounds of 6 appropriate concentrations, and the concentration of test compound at which 50% of the amount of sugar intake was suppressed was calculated as IC when the amount of sugar intake in the control group was taken as 100%₅₀The value is obtained.

(4) Results

Table 3 shows SGLT inhibitory activities of compounds (I) to (VII) and compound 98 (disclosed in patent document 9). It was found that the compounds (I) to (VII) in which the ethoxy group of the compound 98 was replaced with a methyl group, an ethyl group, a methoxy group or a methylthio group unexpectedly retained SGLT2 inhibitory activity and showed 3 to 6 times stronger SGLT1 inhibitory activity than the compound 98.

[ TABLE 3 ]

(5) Test example 2

Confirmation test of blood glucose lowering action in db/db mouse

Db/db mice (CLEA, Japan, male, 7-week-old) were used as experimental animals. The test substance was suspended in a 0.5% carboxymethylcellulose (CMC) aqueous solution and prepared to a concentration of 1mg/10 mL. On the current day of the test, the blood glucose values were grouped into groups as far as possible without differences in variance from the average blood glucose value of db/db mice, and the number of the groups was 6. After measuring the body weight of the mice, the prepared test substance suspension was forcibly orally administered in a volume of 10mL/kg by using a feeding tube for oral administration to the mice, and only a 0.5% CMC aqueous solution was administered to the control group. Blood sampling was carried out at a total of 8 points before (0time) and after 0.5, 1, 2, 4, 6, 8, 24 hours of oral administration of the test substances. In addition, the test was performed under conditions of free food intake and water intake.

Blood collection was performed from the orbital sinus (orbital venous sinus) of a diseased animal under ether anesthesia using a heparin-coated blood collection tube, and blood glucose values were measured using a glucose CII Test and light (glucocii-Test Wako) (and Wako pure chemical industries, Ltd.). The intensity of blood glucose lowering action (%) was calculated from the blood glucose level at any time from 0 to 8 hours in each test substance administration group by the trapezoidal method, and the area under the blood glucose level-time curve (AUC) was expressed as the lowering ratio to the control group.

(6) Results

[ TABLE 4 ]

Compound (I)	Blood sugarDecrease intensity of action (%)
		I	48.5
II	49.7
		Compound 98 (disclosed in document 9)	35.0

Industrial applicability

According to the present invention, it is expected to provide a prophylactic or therapeutic agent for diabetes, which comprises, as active ingredients, SGLT1 (sodium-dependent glucose cotransporter 1) that inhibits expression in the small intestine epithelium and SGLT2 (sodium-dependent glucose cotransporter 2) that inhibits expression in the kidney, and which contains, as active ingredients, 1-phenyl 1-thio-D-sorbitol compounds having both an action of inhibiting glucose absorption from the digestive tract and an action of excreting urinary sugar.

Claims (10)

1. 1-phenyl 1-thio-D-sorbitol compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[ CHEM 1 ]

2. 1-phenyl 1-thio-D-sorbitol compound represented by the following formula (II) or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[ CHEM 2 ]

3. 1-phenyl 1-thio-D-sorbitol compound represented by the following formula (III) or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[ CHEM 3 ]

4. 1-phenyl 1-thio-D-sorbitol compound represented by the following formula (IV) or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[ CHEM 4 ]

5. 1-phenyl 1-thio-D-sorbitol compound represented by the following formula (V) or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[ CHEM 5 ]

6. 1-phenyl 1-thio-D-sorbitol compound represented by the following formula (VI) or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[ CHEM 6 ]

7. 1-phenyl 1-thio-D-sorbitol compound represented by the following formula (VII) or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[ CHEM 7 ]

8. A pharmaceutical agent comprising the 1-phenyl 1-thio-D-sorbitol compound or pharmaceutically acceptable salt thereof or hydrate thereof according to any one of claims 1 to 7 as an active ingredient.

9. The medicament of claim 8, which is an inhibitor of the activity of sodium-dependent glucose cotransporter 1 and sodium-dependent glucose cotransporter 2.

10. A prophylactic or therapeutic agent for diabetes, a diabetes-related disease, or a diabetic complication, characterized by comprising the 1-phenyl 1-thio-D-sorbitol compound or a pharmaceutically acceptable salt thereof or a hydrate thereof according to any one of claims 1 to 7 as an active ingredient.