JP5194588B2 - Diabetes preventive or therapeutic agent containing 1-thio-D-glucitol derivative as an active ingredient - Google Patents

Description

  The present invention relates to a medicament containing, as an active ingredient, a 1-thio-D-glucitol derivative that inhibits the activity of sodium-dependent glucose cotransporter 2 (SGLT2) involved in glucose reabsorption in the kidney.

  It is believed that chronic hyperglycemia reduces insulin secretion and insulin sensitivity, which further increases blood sugar and exacerbates diabetes. Hyperglycemia is considered a major risk factor for diabetic complications. Therefore, maintaining a normal blood glucose level seems to improve insulin sensitivity and suppress the development of diabetic complications. So far, biguanide drugs, sulfonylurea drugs, glycosidase inhibitors, insulin resistance improving drugs and the like have been used as antidiabetic drugs. However, side effects such as lactic acidosis for biguanide drugs, hypoglycemia for sulfonylurea drugs, and diarrhea and severe liver dysfunction for glycosidase inhibitors have been reported. Therefore, development of a therapeutic agent for diabetes having a new mechanism of action different from the conventional one is desired.

  It has been shown that phlorizin, a glucose derivative isolated from nature, inhibits the reabsorption of excess glucose in the kidney and promotes the excretion of glucose to have a hypoglycemic effect (Non-Patent Documents 1 and 2). ). Thereafter, it was revealed that this reabsorption of glucose was caused by sodium-dependent glucose cotransporter 2 (SGLT2) present at the S1 site of the renal proximal tubule (Non-patent Document 3). Since it has been shown that phlorizin, a specific SGLT inhibitor, is administered to diabetic rats, it promotes glucose excretion in urine and has a hypoglycemic effect. It came to be considered a target molecule.

  From such a background, many phlorizin-related compounds have been studied and O-aryl glucosides have been disclosed (Patent Documents 1 to 11). However, when O-aryl glucoside is orally administered, the glycoside bond is hydrolyzed by β-glycosidase present in the small intestine, and the absorption efficiency in the unchanged form is poor. Therefore, development of a prodrug is in progress.

  In addition, a compound in which O-aryl glucoside is converted to a chemically stable C-aryl glycoside has been reported (Patent Document 12). Similarly to the above, compounds in which a glucose moiety and aryl or heteroaryl are directly bonded (Patent Documents 13 to 15) have also been reported. However, C-aryl glycosides, which are compounds disclosed in these documents (Patent Documents 12 to 15), have a problem in terms of formulation because there are many amorphous substances (Patent Document 12).

Therefore, it was necessary to crystallize the compound together with an appropriate amino acid such as phenylalanine or proline (Patent Document 16). Therefore, there is a need for a compound that is excellent in crystallinity, easy to be purified, stored, and formulated and easy to handle as a pharmaceutical.

  Already, some of the compounds shown in Patent Documents 1 to 15 are currently undergoing clinical trials, and there is a possibility that new anti-diabetic drugs may be marketed in the future, but for some reason during clinical trials in humans. Since development may be difficult, there is a need for a group of compounds having a new skeleton that is not conventional even though the mechanism of action is the same.

Rossetti, L., et al. J. Clin. Invest., 80, 1037, 1987 Rossetti, L., et al. J. Clin. Invest., 79, 1510, 1987 Kanai, Y., et al. J. Clin. Invest., 93, 397, 1994 European Patent Application No. 0850948 European Patent Application No. 0598359 International Publication No. WO01 / 068660 Pamphlet International Publication No. WO01 / 016147 Pamphlet International Publication No. WO01 / 074834 Pamphlet International Publication No. WO01 / 074835 Pamphlet International Publication No. WO02 / 053573 Pamphlet International Publication No. WO02 / 068439 Pamphlet International Publication No. WO02 / 068440 Pamphlet International Publication No. WO02 / 036602 Pamphlet International Publication No. WO02 / 088157 Pamphlet International Publication No. WO01 / 027128 Pamphlet US Patent Application Publication No. 2001/0041674 International Publication No. WO04 / 013118 Pamphlet International Publication No. WO04 / 080990 Pamphlet US Patent No. US6774112 Specification

  The present invention inhibits the activity of the sodium-dependent glucose cotransporter (SGLT2) involved in glucose reabsorption in the kidney, promotes urinary glucose excretion, and exhibits a hypoglycemic effect. It aims at providing the pharmaceutical which contains a glucitol compound as an active ingredient. An object of the present invention is to provide an excellent SGLT2 activity selective inhibitor. Another object of the present invention is to provide an excellent preventive or therapeutic agent for diabetes, diabetes-related diseases or diabetic complications. Another object of the present invention is to provide a medicament that is excellent in crystallinity and that can be easily purified, stored, and formulated.

  As a result of diligent search for the purpose of solving the above-mentioned problems, the present inventors have discovered a production method in which aryl or heterocycle and 5-thio-glucose are directly bonded, and 1-thio-D- obtained by the method has been found. The present inventors have found that a glucitol derivative has an excellent SGLT2 inhibitory action and have completed the present invention which provides an excellent preventive or therapeutic agent for diabetes, diabetes-related diseases or diabetic complications. In addition, the 1-thio-D-glucitol derivative of the present invention has good crystallinity, so it does not need to be co-crystallized with an amino acid or the like, is easy to purify, store and formulate and is suitable for handling as a pharmaceutical product. I also found out.

Hereinafter, embodiments of the 1-thio-D-glucitol derivative (hereinafter referred to as “the compound of the present invention”) according to the present invention will be described.
One aspect of the present invention is:
Formula I below:

[式中、Ｒ¹、Ｒ²、Ｒ³及びＲ⁴は、同一又は異なって、水素原子、Ｃ_1-6アルキル基、−ＣＯ₂Ｒ^a2、−ＣＯＲ^b1、又はハロゲン原子；−ＮＯ₂及び−ＯＭｅからなる群から選択される１個以上の置換基で置換されてもよいＣ_7-12アラルキル基（式中、Ｒ^a2は、Ｃ_1-6アルキル基を示し、Ｒ^b1はＣ_1-6アルキル基、Ｃ_7-10アラルキル基又はフェニル基を示す。）を示し、
Ａは、−（ＣＨ₂）ｎ−、−ＣＯＮＨ（ＣＨ₂）ｎ−、−ＮＨＣＯ（ＣＨ₂）ｎ−、−Ｏ−、−Ｓ−、−ＮＨ−又は−（ＣＨ₂）ｎＣＨ＝ＣＨ−（式中、ｎは０〜３の整数を示す。）を示し、
Ａｒ¹は、アリレン基、ヘテロアリレン基又はヘテロシクロアルキレン基を示し、
Ａｒ²は、アリール基、ヘテロアリール基又はヘテロシクロアルキル基を示し、
Ｒ⁵、Ｒ⁶、Ｒ⁷、Ｒ⁸、Ｒ⁹及びＲ¹⁰は、同一又は異なって、
(i)水素原子、(ii)ハロゲン原子、(iii)水酸基、(iv)ハロゲン原子及び水酸基からなる群から選択される１個以上の置換基で置換されてもよいＣ_1-8アルキル基、
(v) −（ＣＨ₂）ｍ−Ｑ｛式中、ｍは０〜４の整数を示し、Ｑは−ＣＨＯ、−ＮＨ₂、−ＮＯ₂、−ＣＮ、−ＣＯ₂Ｈ、−ＳＯ₃Ｈ、−ＯＲ^c1、−ＣＯ₂Ｒ^a3、−ＣＯＮＨ₂、−ＣＯＮＨＲ^a4、−ＣＯＮＲ^a5Ｒ^a5、−ＣＯＲ^d1、−ＯＣＯＲ^d2、−ＳＲ^e1、−ＳＯＲ^e2、−ＳＯ₂Ｒ^e3、−ＮＨＣ（＝Ｏ）Ｈ、−ＮＨＣＯＲ^d3、−ＮＨＣＯ₂Ｒ^d4、−ＮＨＣＯＮＨ₂、−ＮＨＳＯ₂Ｒ^e4、−ＮＨＲ^a6又は−ＮＲ^a7Ｒ^a7（式中、Ｒ^a3、Ｒ^a4、Ｒ^a5、Ｒ^a6及びＲ^a7は、Ｃ_1-6アルキル基を示し、Ｒ^c1は、ハロゲン原子で置換されてもよいＣ_1-6アルキル基を示し、Ｒ^d1、Ｒ^d2、Ｒ^d3及びＲ^d4は、Ｃ_1-6アルキル基、Ｃ_7-10アラルキル基、フェニル基又はＣ_3-7シクロアルキル基を示し、Ｒ^e1、Ｒ^e2、Ｒ^e3、及びＲ^e4は、Ｃ_1-6アルキル基、フェニル基又はトリル基を示す。）を示す。｝、
(vi) −Ｏ−（ＣＨ₂）ｍ’−Ｑ’｛式中、ｍ’は１〜４の整数を示し、Ｑ’は水酸基、−ＣＯ₂Ｈ、−ＯＲ^c2、−ＣＯ₂Ｒ^a8、−ＣＯＮＨ₂、−ＣＯＮＨＲ^a9、−ＣＯＮＲ^a10Ｒ^a10、−ＮＨ₂、−ＮＨＲ^a11、−ＮＲ^a12Ｒ^a12又は−ＮＨＣＯ₂Ｒ^d5（式中、Ｒ^a8、Ｒ^a9、Ｒ^a10、Ｒ^a11及びＲ^a12は、Ｃ_1-6アルキル基を示し、Ｒ^c2は、ハロゲン原子で置換されてもよいＣ_1-6アルキル基を示し、Ｒ^d5は、Ｃ_1-6アルキル基、Ｃ_7-10アラルキル基、フェニル基又はＣ_3-7シクロアルキル基である。）を示す。｝、
(vii) −ＯＲ^f｛式中、Ｒ^fは、ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a13（式中、Ｒ^a13はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいＣ_3-7シクロアルキル基、ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a14（式中、Ｒ^a14はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいアリール基、ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a15（式中、Ｒ^a15はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいＣ_7-10アラルキル基、
又はハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a16（式中、Ｒ^a16はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいヘテロシクロアルキル基を示す。｝、
(viii) −ＮＨＲ^g｛式中、Ｒ^gは、ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a17（式中、Ｒ^a17はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいＣ_7-10アラルキル基を示す。｝、
(ix) ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a18（式中、Ｒ^a18はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいＣ_3-7シクロアルキル基、
(x) ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a19（式中、Ｒ^a19はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいアリール基、
(xi) ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a20（式中、Ｒ^a20はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいＣ_7-10アラルキル基、
(xii) ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a21（式中、Ｒ^a21はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいヘテロアリール基、
(xiii) ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a22（式中、Ｒ^a22はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいヘテロシクロアルキル基、
(xiv) Ｃ_2-6アルケニル基又は
(xv) Ｃ_2-6アルキニル基を示す。]で表される1−チオ−D−グルシトール化合物若しくはその製薬学的に許容される塩又はそれらの水和物を有効成分として含有する、糖尿病、糖尿病関連疾患もしくは糖尿病性合併症の予防又は治療剤に関する。

^{Wherein, R 1, R 2, R} 3 and R ⁴ are the same or different, a hydrogen atom, C _1-6 alkyl _{^{group, -CO 2 R a2, -COR b1}} , or a halogen atom; -NO ₂ and A C _7-12 aralkyl group which may be substituted with one or more substituents selected from the group consisting of —OMe (wherein R ^a2 represents a C _1-6 alkyl group, and R ^b1 represents C _{1— 6} alkyl group, C _7-10 aralkyl group or phenyl group.)
A _{is, - (CH 2) n -} , - CONH (CH 2) n -, - NHCO (CH 2) n -, - O -, - S -, - NH- or - (CH ₂₎ nCH = CH- (Wherein n represents an integer of 0 to 3),
Ar ¹ represents an arylene group, heteroarylene group or heterocycloalkylene group,
Ar ² represents an aryl group, a heteroaryl group or a heterocycloalkyl group,
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are the same or different,
(i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) a C _1-8 alkyl group which may be substituted with one or more substituents selected from the group consisting of a halogen atom and a hydroxyl group,
(v) — (CH ₂ ) mQ {wherein m represents an integer of 0 to 4, Q is —CHO, —NH ₂ , —NO ₂ , —CN, —CO ₂ H, —SO ₃ H , —OR ^c1 , —CO ₂ R ^a3 , —CONH ₂ , —CONHR ^a4 , —CONR ^a5 R ^a5 , —COR ^d1 , —OCOR ^d2 , —SR ^e1 , —SOR ^e2 , —SO ₂ R ^e3 , —NHC ( ^{= O) H, -NHCOR d3,} -NHCO 2 R d4, -NHCONH 2, -NHSO 2 R e4, in -NHR ^a6, or -NR ^a7 R ^{a7 (wherein, R a3, R a4, R} a5, R a6 and R ^a7 represents a C _1-6 alkyl group, R ^c1 represents a C _1-6 alkyl group which may be substituted with a halogen atom, and R ^d1 , R ^d2 , R ^d3 and R ^d4 represent C _{1- 6} alkyl group, C _7-10 aralkyl group, phenyl group or C _3-7 cycloalkyl group, R ^e1 , R ^e2 , R ^e3 and R ^e4 are C _1-6 alkyl group, Represents a nyl group or a tolyl group). },
(vi) —O— (CH ₂ ) m′-Q ′ {wherein m ′ represents an integer of 1 to 4, Q ′ represents a hydroxyl group, —CO ₂ H, —OR ^c2 , —CO ₂ R ^a8 , —CONH ₂ , —CONHR ^a9 , —CONR ^a10 R ^a10 , —NH ₂ , —NHR ^a11 , —NR ^a12 R ^a12 or —NHCO ₂ R ^d5 (wherein R ^a8 , R ^a9 , R ^a10 , R ^a11 and R ^a12 represents a C _1-6 alkyl group, R ^c2 represents a C _1-6 alkyl group which may be substituted with a halogen atom, and R ^d5 represents a C _1-6 alkyl group or a C _7-10 aralkyl group. , A phenyl group or a C _3-7 cycloalkyl group. },
(vii) —OR ^f {wherein R ^f is a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a13 (wherein R ^a13 represents a C _1-6 alkyl group). C _3-7 cycloalkyl group, halogen atom; hydroxyl group; C _1-6 alkyl group and —OR ^a14 (wherein R ^a14 represents C _1-6 alkyl) which may be substituted with one or more selected substituents An aryl group which may be substituted with one or more substituents selected from the group consisting of: a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a15 (wherein R ^a15 represents C _A C _7-10 aralkyl group which may be substituted with one or more substituents selected from the group consisting of _1-6 alkyl groups)
Or substituted with one or more substituents selected from the group consisting of a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a16 (wherein R ^a16 represents a C _1-6 alkyl group). Or a heterocycloalkyl group. },
(viii) —NHR ^g {wherein R ^g is a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a17 (wherein R ^a17 represents a C _1-6 alkyl group). A C _7-10 aralkyl group which may be substituted with one or more selected substituents is shown. },
(ix) substituted with one or more substituents selected from the group consisting of a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a18 (wherein R ^a18 represents a C _1-6 alkyl group) A C _3-7 cycloalkyl group, which may be
(x) halogen atom; hydroxyl group; substituted with one or more substituents selected from the group consisting of C _1-6 alkyl group and —OR ^a19 (wherein R ^a19 represents a C _1-6 alkyl group) An aryl group which may be
(xi) halogen atom; hydroxyl group; substituted with one or more substituents selected from the group consisting of C _1-6 alkyl group and —OR ^a20 (wherein R ^a20 represents a C _1-6 alkyl group) A C _7-10 aralkyl group, which may be
(xii) halogen atom; hydroxyl group; substituted with one or more substituents selected from the group consisting of C _1-6 alkyl group and —OR ^a21 (wherein R ^a21 represents a C _1-6 alkyl group) A heteroaryl group which may be
(xiii) halogen atom; hydroxyl group; substituted with one or more substituents selected from the group consisting of a C _1-6 alkyl group and —OR ^a22 (wherein R ^a22 represents a C _1-6 alkyl group) A heterocycloalkyl group which may be
(xiv) a C _2-6 alkenyl group or
(xv) represents a C _2-6 alkynyl group. Or a pharmaceutically acceptable salt thereof, or a hydrate thereof, as an active ingredient, for the prevention or treatment of diabetes, diabetes-related diseases or diabetic complications It relates to the agent.

Another aspect of the present invention is:
The following formula IA:

[式中、Ｒ¹、Ｒ²、Ｒ³及びＲ⁴は、同一又は異なって、水素原子、Ｃ_1-6アルキル基、−ＣＯ₂Ｒ^a2、−ＣＯＲ^b1、又はハロゲン原子；−ＮＯ₂及び−ＯＭｅからなる群から選択される１個以上の置換基で置換されてもよいＣ_7-12アラルキル基（式中、Ｒ^a2は、Ｃ_1-6アルキル基を示し、Ｒ^b1はＣ_1-6アルキル基、Ｃ_7-10アラルキル基又はフェニル基を示す。）を示し、
Ａは、−（ＣＨ₂）ｎ−、−ＣＯＮＨ（ＣＨ₂）ｎ−、−ＮＨＣＯ（ＣＨ₂）ｎ−、−Ｏ−、−Ｓ−、−ＮＨ−又は−（ＣＨ₂）ｎＣＨ＝ＣＨ−（式中、ｎは０〜３の整数を示す。）を示し、
Ａｒ¹は、アリレン基、ヘテロアリレン基又はヘテロシクロアルキレン基を示し、
Ａｒ²は、アリール基、ヘテロアリール基又はヘテロシクロアルキル基を示し、
Ｒ^5'、Ｒ^6'、Ｒ^7'、Ｒ^8'、Ｒ^9'及びＲ^10'は、同一又は異なって、
(i)水素原子、(ii)ハロゲン原子、(iii)水酸基、(iv)ハロゲン原子及び水酸基からなる群から選択される１個以上の置換基で置換されてもよいＣ_1-8アルキル基、
(v) −（ＣＨ₂）ｍ−Ｑ｛式中、ｍは０〜４の整数を示し、Ｑは−ＣＨＯ、−ＮＨ₂、−ＮＯ₂、−ＣＮ、−ＣＯ₂Ｈ、−ＳＯ₃Ｈ、−ＯＲ^c1、−ＣＯ₂Ｒ^a3、−ＣＯＮＨ₂、−ＣＯＮＨＲ^a4、−ＣＯＮＲ^a5Ｒ^a5、−ＣＯＲ^d1、−ＯＣＯＲ^d2、−ＳＲ^e1、−ＳＯＲ^e2、−ＳＯ₂Ｒ^e3、−ＮＨＣ（＝Ｏ）Ｈ、−ＮＨＣＯＲ^d3、−ＮＨＣＯ₂Ｒ^d4、−ＮＨＣＯＮＨ₂、−ＮＨＳＯ₂Ｒ^e4、−ＮＨＲ^a6又は−ＮＲ^a7Ｒ^a7（式中、Ｒ^a3、Ｒ^a4、Ｒ^a5、Ｒ^a6及びＲ^a7は、Ｃ_1-6アルキル基を示し、Ｒ^c1は、ハロゲン原子で置換されてもよいＣ_1-6アルキル基を示し、Ｒ^d1、Ｒ^d2、Ｒ^d3及びＲ^d4は、Ｃ_1-6アルキル基、Ｃ_7-10アラルキル基、フェニル基又はＣ_3-7シクロアルキル基を示し、Ｒ^e1、Ｒ^e2、Ｒ^e3及びＲ^e4は、Ｃ_1-6アルキル基、フェニル基又はトリル基を示す。）を示す。｝、
(vi) −Ｏ−（ＣＨ₂）ｍ’−Ｑ’｛式中、ｍ’は１〜４の整数を示し、Ｑ’は水酸基、−ＣＯ₂Ｈ、−ＯＲ^c2、−ＣＯ₂Ｒ^a8、−ＣＯＮＨ₂、−ＣＯＮＨＲ^a9、−ＣＯＮＲ^a10Ｒ^a10、−ＮＨ₂、−ＮＨＲ^a11、−ＮＲ^a12Ｒ^a12又は−ＮＨＣＯ₂Ｒ^d5（式中、Ｒ^a8、Ｒ^a9、Ｒ^a10、Ｒ^a11及びＲ^a12は、Ｃ_1-6アルキル基を示し、Ｒ^c2は、ハロゲン原子で置換されてもよいＣ_1-6アルキル基を示し、Ｒ^d5は、Ｃ_1-6アルキル基、Ｃ_7-10アラルキル基、フェニル基又はＣ_3-7シクロアルキル基である。）を示す。｝、
(vii) −ＯＲ^f｛式中、Ｒ^fは、ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a13（式中、Ｒ^a13はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいＣ_3-7シクロアルキル基、ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a14（式中、Ｒ^a14はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいアリール基、又はハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a15（式中、Ｒ^a15はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいＣ_7-10アラルキル基を示す。｝、
(viii) −ＮＨＲ^g｛式中、Ｒ^gは、ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a17（式中、Ｒ^a17はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいＣ_7-10アラルキル基を示す。｝、
(ix) ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a18（式中、Ｒ^a18はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいＣ_3-7シクロアルキル基、
(x) ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a19（式中、Ｒ^a19はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいアリール基、
(xi) ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a20（式中、Ｒ^a20はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいＣ_7-10アラルキル基、
(xii) ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a21（式中、Ｒ^a21はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいヘテロアリール基又は
(xiii) ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a22（式中、Ｒ^a22はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいヘテロシクロアルキル基を示す。]で表される1−チオ−D−グルシトール化合物若しくはその製薬学的に許容される塩又はそれらの水和物を有効成分として含有する、糖尿病、糖尿病関連疾患もしくは糖尿病性合併症の予防又は治療剤に関する。

^{Wherein, R 1, R 2, R} 3 and R ⁴ are the same or different, a hydrogen atom, C _1-6 alkyl _{^{group, -CO 2 R a2, -COR b1}} , or a halogen atom; -NO ₂ and A C _7-12 aralkyl group which may be substituted with one or more substituents selected from the group consisting of —OMe (wherein R ^a2 represents a C _1-6 alkyl group, and R ^b1 represents C _{1— 6} alkyl group, C _7-10 aralkyl group or phenyl group.)
A _{is, - (CH 2) n -} , - CONH (CH 2) n -, - NHCO (CH 2) n -, - O -, - S -, - NH- or - (CH ₂₎ nCH = CH- (Wherein n represents an integer of 0 to 3),
Ar ¹ represents an arylene group, heteroarylene group or heterocycloalkylene group,
Ar ² represents an aryl group, a heteroaryl group or a heterocycloalkyl group,
R ^{5 ′} , R ^{6 ′} , R ^{7 ′} , R ^{8 ′} , R ^{9 ′} and R ^{10 ′} are the same or different,
(i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) a C _1-8 alkyl group which may be substituted with one or more substituents selected from the group consisting of a halogen atom and a hydroxyl group,
(v) — (CH ₂ ) mQ {wherein m represents an integer of 0 to 4, Q is —CHO, —NH ₂ , —NO ₂ , —CN, —CO ₂ H, —SO ₃ H , —OR ^c1 , —CO ₂ R ^a3 , —CONH ₂ , —CONHR ^a4 , —CONR ^a5 R ^a5 , —COR ^d1 , —OCOR ^d2 , —SR ^e1 , —SOR ^e2 , —SO ₂ R ^e3 , —NHC ( ^{= O) H, -NHCOR d3,} -NHCO 2 R d4, -NHCONH 2, -NHSO 2 R e4, in -NHR ^a6, or -NR ^a7 R ^{a7 (wherein, R a3, R a4, R} a5, R a6 and R ^a7 represents a C _1-6 alkyl group, R ^c1 represents a C _1-6 alkyl group which may be substituted with a halogen atom, and R ^d1 , R ^d2 , R ^d3 and R ^d4 represent C _{1- 6} alkyl group, C _7-10 aralkyl group, a phenyl group or a C _3-7 cycloalkyl ^{group, R e1, R e2, R} e3 and R ^e4 is, C _1-6 alkyl, phenylene A group or a tolyl group.) Shows a. },
(vi) —O— (CH ₂ ) m′-Q ′ {wherein m ′ represents an integer of 1 to 4, Q ′ represents a hydroxyl group, —CO ₂ H, —OR ^c2 , —CO ₂ R ^a8 , —CONH ₂ , —CONHR ^a9 , —CONR ^a10 R ^a10 , —NH ₂ , —NHR ^a11 , —NR ^a12 R ^a12 or —NHCO ₂ R ^d5 (wherein R ^a8 , R ^a9 , R ^a10 , R ^a11 and R ^a12 represents a C _1-6 alkyl group, R ^c2 represents a C _1-6 alkyl group which may be substituted with a halogen atom, and R ^d5 represents a C _1-6 alkyl group or a C _7-10 aralkyl group. , A phenyl group or a C _3-7 cycloalkyl group. },
(vii) —OR ^f {wherein R ^f is a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a13 (wherein R ^a13 represents a C _1-6 alkyl group). C _3-7 cycloalkyl group, halogen atom; hydroxyl group; C _1-6 alkyl group and —OR ^a14 (wherein R ^a14 represents C _1-6 alkyl) which may be substituted with one or more selected substituents An aryl group which may be substituted with one or more substituents selected from the group consisting of: a hydroxyl group; a C _1-6 alkyl group and —OR ^a15 (wherein R ^a15 represents A C _1-6 alkyl group.) A C _7-10 aralkyl group which may be substituted with one or more substituents selected from the group consisting of: },
(viii) —NHR ^g {wherein R ^g is a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a17 (wherein R ^a17 represents a C _1-6 alkyl group). A C _7-10 aralkyl group which may be substituted with one or more selected substituents is shown. },
(ix) substituted with one or more substituents selected from the group consisting of a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a18 (wherein R ^a18 represents a C _1-6 alkyl group) A C _3-7 cycloalkyl group, which may be
(x) halogen atom; hydroxyl group; substituted with one or more substituents selected from the group consisting of C _1-6 alkyl group and —OR ^a19 (wherein R ^a19 represents a C _1-6 alkyl group) An aryl group which may be
(xi) halogen atom; hydroxyl group; substituted with one or more substituents selected from the group consisting of C _1-6 alkyl group and —OR ^a20 (wherein R ^a20 represents a C _1-6 alkyl group) A C _7-10 aralkyl group, which may be
(xii) halogen atom; hydroxyl group; substituted with one or more substituents selected from the group consisting of C _1-6 alkyl group and —OR ^a21 (wherein R ^a21 represents a C _1-6 alkyl group) A heteroaryl group which may be
(xiii) halogen atom; hydroxyl group; substituted with one or more substituents selected from the group consisting of a C _1-6 alkyl group and —OR ^a22 (wherein R ^a22 represents a C _1-6 alkyl group) A heterocycloalkyl group which may be substituted. Or a pharmaceutically acceptable salt thereof, or a hydrate thereof, as an active ingredient, for the prevention or treatment of diabetes, diabetes-related diseases or diabetic complications It relates to the agent.

A first specific embodiment of the present invention is a 1-thio-D-glucitol compound or a pharmaceutically acceptable salt thereof, or a hydration thereof, wherein Ar ¹ is an arylene group in formula I or formula IA The present invention relates to a preventive or therapeutic agent for diabetes, diabetes-related diseases or diabetic complications, which contains a product as an active ingredient.
One of the above-mentioned embodiments of the present invention is a 1-thio-D-glucitol compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein Ar ¹ is a phenylene group or a naphthylene group in formula I or formula IA. The present invention relates to a preventive or therapeutic agent for diabetes, diabetes-related diseases or diabetic complications containing a hydrate as an active ingredient.
Another aspect of the present invention, A is _{- (CH 2) n -,} - CONH (CH 2) n -, - O- or _{- (CH 2) nCH = CH-} ( wherein, n 0-3 Diabetes, diabetes-related disease or diabetes containing any one of the above-mentioned 1-thio-D-glucitol compounds or pharmaceutically acceptable salts thereof or hydrates thereof as an active ingredient The present invention relates to a preventive or therapeutic agent for sexual complications.
Another embodiment of the present invention contains, as an active ingredient, any one of the above 1-thio-D-glucitol compounds, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein A is —CH ₂ —. The present invention relates to a preventive or therapeutic agent for diabetes, diabetes-related diseases or diabetic complications.
In another embodiment of the present invention, Ar ² is a phenyl group, a thienyl group, a benzo [b] thiophenyl group, a thieno [2,3-b] thiophenyl group, a benzofuranyl group, a benzothiazolyl group, an indolyl group, a pyrrolyl group, an imidazolyl group, Contains any one of the above 1-thio-D-glucitol compounds or pharmaceutically acceptable salts thereof or hydrates thereof, which is a pyrazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group or isoxazolyl group The present invention relates to a preventive or therapeutic agent for diabetes, diabetes-related diseases or diabetic complications.

The first specific aspect of the present invention is in particular:
Formula II below:

[式中、Ｒ¹、Ｒ²、Ｒ³及びＲ⁴は、同一又は異なって、水素原子、Ｃ_1-6アルキル基、−ＣＯ₂Ｒ^a2、−ＣＯＲ^b1、又はハロゲン原子；−ＮＯ₂及び−ＯＭｅからなる群から選択される１個以上の置換基で置換されてもよいＣ_7-12アラルキル基（式中、Ｒ^a2は、Ｃ_1-6アルキル基を示し、Ｒ^b1はＣ_1-6アルキル基、Ｃ_7-10アラルキル基又はフェニル基を示す。）を示し、
Ｒ^A、Ｒ^B、Ｒ^C及びＲ^Dのうち少なくとも１つは水素原子を示し、その他は、
同一又は異なって、(i)水素原子、(ii)ハロゲン原子、(iii)水酸基、(iv)ハロゲン原子及び水酸基からなる群から選択される１個以上の置換基で置換されてもよいＣ_1-8アルキル基、
(v) −（ＣＨ₂）ｍ−Ｑ^A｛式中、ｍは０〜４の整数を示し、Ｑ^Aは−ＮＨ₂、−ＣＯ₂Ｈ、−ＯＲ^c1、−ＣＯ₂Ｒ^a3、−ＣＯＮＨ₂、−ＣＯＮＨＲ^a4、−ＣＯＮＲ^a5Ｒ^a5、−ＣＯＲ^d1、−ＯＣＯＲ^d2、−ＳＲ^e1、−ＳＯＲ^e2、−ＳＯ₂Ｒ^e3、−ＮＨＣ（＝Ｏ）Ｈ、−ＮＨＣＯＲ^d3、−ＮＨＣＯ₂Ｒ^d4、−ＮＨＣＯＮＨ₂、−ＮＨＳＯ₂Ｒ^e4、−ＮＨＲ^a6又は−ＮＲ^a7Ｒ^a7（式中、Ｒ^a3、Ｒ^a4、Ｒ^a5、Ｒ^a6及びＲ^a7は、Ｃ_1-6アルキル基を示し、Ｒ^c1は、ハロゲン原子で置換されてもよいＣ_1-6アルキル基を示し、Ｒ^d1、Ｒ^d2、Ｒ^d3及びＲ^d4は、Ｃ_1-6アルキル基、Ｃ_7-10アラルキル基、フェニル基又はＣ_3-7シクロアルキル基を示し、Ｒ^e1、Ｒ^e2、Ｒ^e3及びＲ^e4は、Ｃ_1-6アルキル基、フェニル基又はトリル基を示す。）を示す。｝、
(vi) −Ｏ−（ＣＨ₂）ｍ’−Ｑ’｛式中、ｍ’は１〜４の整数を示し、Ｑ’は水酸基、−ＣＯ₂Ｈ、−ＯＲ^c2、−ＣＯ₂Ｒ^a8、−ＣＯＮＨ₂、−ＣＯＮＨＲ^a9、−ＣＯＮＲ^a10Ｒ^a10、−ＮＨ₂、−ＮＨＲ^a11、−ＮＲ^a12Ｒ^a12又は−ＮＨＣＯ₂Ｒ^d5（式中、Ｒ^a8、Ｒ^a9、Ｒ^a10、Ｒ^a11及びＲ^a12は、Ｃ_1-6アルキル基を示し、Ｒ^c2は、ハロゲン原子で置換されてもよいＣ_1-6アルキル基を示し、Ｒ^d5は、Ｃ_1-6アルキル基、Ｃ_7-10アラルキル基、フェニル基又はＣ_3-7シクロアルキル基を示す。）を示す。｝、
(vii) −ＯＲ^f｛式中、Ｒ^fは、ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a13（式中、Ｒ^a13はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいＣ_3-7シクロアルキル基、ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a14（式中、Ｒ^a14はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいアリール基または、
ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a15（式中、Ｒ^a15はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいＣ_7-10アラルキル基を示す。｝、
(viii) −ＮＨＲ^g｛式中、Ｒ^gは、ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a17（式中、Ｒ^a17はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいＣ_7-10アラルキル基を示す。｝、
(ix) ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a19（式中、Ｒ^a19はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいアリール基、または
(x) ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a22（式中、Ｒ^a22はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいヘテロシクロアルキル基を示し、
Ｒ^E、Ｒ^F及びＲ^Gは、同一又は異なって、
(i)水素原子、(ii)ハロゲン原子、(iii)水酸基、(iv)ハロゲン原子及び水酸基からなる群から選択される１個以上の置換基で置換されてもよいＣ_1-8アルキル基、
(v) −（ＣＨ₂）ｍ−Ｑ｛式中、ｍは０〜４の整数を示し、Ｑは−ＣＨＯ、−ＮＨ₂、−ＮＯ₂、−ＣＮ、−ＣＯ₂Ｈ、−ＳＯ₃Ｈ、−ＯＲ^c1、−ＣＯ₂Ｒ^a3、−ＣＯＮＨ₂、−ＣＯＮＨＲ^a4、−ＣＯＮＲ^a5Ｒ^a5、−ＣＯＲ^d1、−ＯＣＯＲ^d2、−ＳＲ^e1、−ＳＯＲ^e2、−ＳＯ₂Ｒ^e3、−ＮＨＣ（＝Ｏ）Ｈ、−ＮＨＣＯＲ^d3、−ＮＨＣＯ₂Ｒ^d4、−ＮＨＣＯＮＨ₂、−ＮＨＳＯ₂Ｒ^e4、−ＮＨＲ^a6又は−ＮＲ^a7Ｒ^a7（式中、Ｒ^a3、Ｒ^a4、Ｒ^a5、Ｒ^a6及びＲ^a7は、Ｃ_1-6アルキル基を示し、Ｒ^c1は、ハロゲン原子で置換されてもよいＣ_1-6アルキル基を示し、Ｒ^d1、Ｒ^d2、Ｒ^d3及びＲ^d4は、Ｃ_1-6アルキル基、Ｃ_7-10アラルキル基、フェニル基又はＣ_3-7シクロアルキル基を示し、Ｒ^e1、Ｒ^e2、Ｒ^e3及びＲ^e4は、Ｃ_1-6アルキル基、フェニル基又はトリル基を示す。）を示す。｝、
(vi) −Ｏ−（ＣＨ₂）ｍ’−Ｑ’｛式中、ｍ’は１〜４の整数を示し、Ｑ’は水酸基、−ＣＯ₂Ｈ、−ＯＲ^c2、−ＣＯ₂Ｒ^a8、−ＣＯＮＨ₂、−ＣＯＮＨＲ^a9、−ＣＯＮＲ^a10Ｒ^a10、−ＮＨ₂、−ＮＨＲ^a11、−ＮＲ^a12Ｒ^a12又は−ＮＨＣＯ₂Ｒ^d5（式中、Ｒ^a8、Ｒ^a9、Ｒ^a10、Ｒ^a11及びＲ^a12は、Ｃ_1-6アルキル基を示し、Ｒ^c2は、ハロゲン原子で置換されてもよいＣ_1-6アルキル基を示し、Ｒ^d5は、Ｃ_1-6アルキル基、Ｃ_7-10アラルキル基、フェニル基又はＣ_3-7シクロアルキル基を示す。）を示す。｝、
(vii) −ＯＲ^f｛式中、Ｒ^fは、ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a13（式中、Ｒ^a13はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいＣ_3-7シクロアルキル基、ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a14（式中、Ｒ^a14はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいアリール基、
ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a15（式中、Ｒ^a15はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいＣ_7-10アラルキル基、またはハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a16（式中、Ｒ^a16はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいヘテロシクロアルキル基を示す。｝、
(viii) −ＮＨＲ^g｛式中、Ｒ^gは、ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a17（式中、Ｒ^a17はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいＣ_7-10アラルキル基を示す。｝、
(ix) ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a18（式中、Ｒ^a18はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいＣ_3-7シクロアルキル基、
(x) ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a19（式中、Ｒ^a19はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいアリール基、
(xi) ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a20（式中、Ｒ^a20はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいＣ_7-10アラルキル基、
(xii) ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a21（式中、Ｒ^a21はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいヘテロアリール基又は
(xiii) ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a22（式中、Ｒ^a22はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいヘテロシクロアルキル基、
(xiv) Ｃ_2-6アルケニル基又は
(xv) Ｃ_2-6アルキニル基を示す。]で表される1−チオ−D−グルシトール化合物若しくはその製薬学的に許容される塩又はそれらの水和物（以下では、「第１の具体的な態様１」という）を有効成分として含有する、糖尿病、糖尿病関連疾患もしくは糖尿病性合併症の予防又は治療剤に関する。

^{Wherein, R 1, R 2, R} 3 and R ⁴ are the same or different, a hydrogen atom, C _1-6 alkyl _{^{group, -CO 2 R a2, -COR b1}} , or a halogen atom; -NO ₂ and A C _7-12 aralkyl group which may be substituted with one or more substituents selected from the group consisting of —OMe (wherein R ^a2 represents a C _1-6 alkyl group, and R ^b1 represents C _{1— 6} alkyl group, C _7-10 aralkyl group or phenyl group.)
At least one of R ^A , R ^B , R ^C and R ^D represents a hydrogen atom;
C ₁ may be the same or different and may be substituted with one or more substituents selected from the group consisting of (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) a halogen atom and a hydroxyl group. _-8 alkyl groups,
(v) - (CH ₂₎ in m-Q ^A {wherein, m represents an integer of 0 to 4, Q ^A is _{-NH 2, -CO 2 H, -OR} c1, -CO 2 R a3, -CONH ₂ , —CONHR ^a4 , —CONR ^a5 R ^a5 , —COR ^d1 , —OCOR ^d2 , —SR ^e1 , —SOR ^e2 , —SO ₂ R ^e3 , —NHC (═O) H, —NHCOR ^d3 , —NHCO ₂ R ^d4 , —NHCONH ₂ , —NHSO ₂ R ^e4 , —NHR ^a6 or —NR ^a7 R ^a7 (wherein R ^a3 , R ^a4 , R ^a5 , R ^a6 and R ^a7 represent a C _1-6 alkyl group, R ^c1 represents a C _1-6 alkyl group which may be substituted with a halogen atom, and R ^d1 , R ^d2 , R ^d3 and R ^d4 are a C _1-6 alkyl group, a C _7-10 aralkyl group, a phenyl group, Or a C _3-7 cycloalkyl group, and R ^e1 , R ^e2 , R ^e3 and R ^e4 represent a C _1-6 alkyl group, a phenyl group or a tolyl group. },
(vi) —O— (CH ₂ ) m′-Q ′ {wherein m ′ represents an integer of 1 to 4, Q ′ represents a hydroxyl group, —CO ₂ H, —OR ^c2 , —CO ₂ R ^a8 , —CONH ₂ , —CONHR ^a9 , —CONR ^a10 R ^a10 , —NH ₂ , —NHR ^a11 , —NR ^a12 R ^a12 or —NHCO ₂ R ^d5 (wherein R ^a8 , R ^a9 , R ^a10 , R ^a11 and R ^a12 represents a C _1-6 alkyl group, R ^c2 represents a C _1-6 alkyl group which may be substituted with a halogen atom, and R ^d5 represents a C _1-6 alkyl group or a C _7-10 aralkyl group. _Represents a phenyl group or a C _3-7 cycloalkyl group. },
(vii) —OR ^f {wherein R ^f is a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a13 (wherein R ^a13 represents a C _1-6 alkyl group). C _3-7 cycloalkyl group, halogen atom; hydroxyl group; C _1-6 alkyl group and —OR ^a14 (wherein R ^a14 represents C _1-6 alkyl) which may be substituted with one or more selected substituents An aryl group which may be substituted with one or more substituents selected from the group consisting of:
Substituted with one or more substituents selected from the group consisting of a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a15 (wherein R ^a15 represents a C _1-6 alkyl group). A good C _7-10 aralkyl group is shown. },
(viii) —NHR ^g {wherein R ^g is a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a17 (wherein R ^a17 represents a C _1-6 alkyl group). A C _7-10 aralkyl group which may be substituted with one or more selected substituents is shown. },
(ix) halogen atom; hydroxyl group; substituted with one or more substituents selected from the group consisting of a C _1-6 alkyl group and —OR ^a19 (wherein R ^a19 represents a C _1-6 alkyl group) An aryl group which may be
(x) halogen atom; hydroxyl group; substituted with one or more substituents selected from the group consisting of C _1-6 alkyl group and —OR ^a22 (wherein R ^a22 represents a C _1-6 alkyl group) A heterocycloalkyl group which may be
R ^E , R ^F and R ^G are the same or different and
(i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) a C _1-8 alkyl group which may be substituted with one or more substituents selected from the group consisting of a halogen atom and a hydroxyl group,
(v) — (CH ₂ ) mQ {wherein m represents an integer of 0 to 4, Q is —CHO, —NH ₂ , —NO ₂ , —CN, —CO ₂ H, —SO ₃ H , —OR ^c1 , —CO ₂ R ^a3 , —CONH ₂ , —CONHR ^a4 , —CONR ^a5 R ^a5 , —COR ^d1 , —OCOR ^d2 , —SR ^e1 , —SOR ^e2 , —SO ₂ R ^e3 , —NHC ( ^{= O) H, -NHCOR d3,} -NHCO 2 R d4, -NHCONH 2, -NHSO 2 R e4, in -NHR ^a6, or -NR ^a7 R ^{a7 (wherein, R a3, R a4, R} a5, R a6 and R ^a7 represents a C _1-6 alkyl group, R ^c1 represents a C _1-6 alkyl group which may be substituted with a halogen atom, and R ^d1 , R ^d2 , R ^d3 and R ^d4 represent C _{1- 6} alkyl group, C _7-10 aralkyl group, a phenyl group or a C _3-7 cycloalkyl ^{group, R e1, R e2, R} e3 and R ^e4 is, C _1-6 alkyl, phenylene A group or a tolyl group.) Shows a. },
(vi) —O— (CH ₂ ) m′-Q ′ {wherein m ′ represents an integer of 1 to 4, Q ′ represents a hydroxyl group, —CO ₂ H, —OR ^c2 , —CO ₂ R ^a8 , —CONH ₂ , —CONHR ^a9 , —CONR ^a10 R ^a10 , —NH ₂ , —NHR ^a11 , —NR ^a12 R ^a12 or —NHCO ₂ R ^d5 (wherein R ^a8 , R ^a9 , R ^a10 , R ^a11 and R ^a12 represents a C _1-6 alkyl group, R ^c2 represents a C _1-6 alkyl group which may be substituted with a halogen atom, and R ^d5 represents a C _1-6 alkyl group or a C _7-10 aralkyl group. _Represents a phenyl group or a C _3-7 cycloalkyl group. },
(vii) —OR ^f {wherein R ^f is a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a13 (wherein R ^a13 represents a C _1-6 alkyl group). C _3-7 cycloalkyl group, halogen atom; hydroxyl group; C _1-6 alkyl group and —OR ^a14 (wherein R ^a14 represents C _1-6 alkyl) which may be substituted with one or more selected substituents An aryl group that may be substituted with one or more substituents selected from the group consisting of:
Substituted with one or more substituents selected from the group consisting of a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a15 (wherein R ^a15 represents a C _1-6 alkyl group). A good C _7-10 aralkyl group, or a halogen atom; a hydroxyl group; one selected from the group consisting of a C _1-6 alkyl group and —OR ^a16 (wherein R ^a16 represents a C _1-6 alkyl group) The heterocycloalkyl group which may be substituted by the above substituent is shown. },
(viii) —NHR ^g {wherein R ^g is a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a17 (wherein R ^a17 represents a C _1-6 alkyl group). A C _7-10 aralkyl group which may be substituted with one or more selected substituents is shown. },
(ix) substituted with one or more substituents selected from the group consisting of a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a18 (wherein R ^a18 represents a C _1-6 alkyl group) A C _3-7 cycloalkyl group, which may be
(x) halogen atom; hydroxyl group; substituted with one or more substituents selected from the group consisting of C _1-6 alkyl group and —OR ^a19 (wherein R ^a19 represents a C _1-6 alkyl group) An aryl group which may be
(xi) halogen atom; hydroxyl group; substituted with one or more substituents selected from the group consisting of C _1-6 alkyl group and —OR ^a20 (wherein R ^a20 represents a C _1-6 alkyl group) A C _7-10 aralkyl group, which may be
(xii) halogen atom; hydroxyl group; substituted with one or more substituents selected from the group consisting of C _1-6 alkyl group and —OR ^a21 (wherein R ^a21 represents a C _1-6 alkyl group) A heteroaryl group which may be
(xiii) halogen atom; hydroxyl group; substituted with one or more substituents selected from the group consisting of a C _1-6 alkyl group and —OR ^a22 (wherein R ^a22 represents a C _1-6 alkyl group) A heterocycloalkyl group which may be
(xiv) a C _2-6 alkenyl group or
(xv) represents a C _2-6 alkynyl group. 1-thio-D-glucitol compound represented by the above or a pharmaceutically acceptable salt thereof or a hydrate thereof (hereinafter referred to as “first specific embodiment 1”) as an active ingredient The present invention relates to a preventive or therapeutic agent for diabetes, diabetes-related diseases or diabetic complications.

Another aspect of the present invention is that in Formula II:
R ^A and R ^C are hydrogen atoms,
R ^B is a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-8 alkyl group,
_{-O- (CH 2) m'-Q} '{ wherein, m' is an integer of 1 to 4, Q 'represents a hydroxyl ^{_{group, -CO 2 H, -OR c2,}} -CO 2 R a8, -CONH 2 , -CONHR ^a9 , -CONR ^a10 R ^a10 , -NH ₂ , -NHR ^a11 , -NR ^a12 R ^a12 or -NHCO ₂ R ^d5 (wherein R ^a8 , R ^a9 , R ^a10 , R ^a11 and R ^a12 are A C _1-6 alkyl group, R ^c2 represents a C _1-6 alkyl group which may be substituted with a halogen atom, and R ^d5 represents a C _1-6 alkyl group, a C _7-10 aralkyl group, a phenyl group; Or a C _3-7 cycloalkyl group). } Or —OR ^f1 {wherein R ^f1 is a C _1-6 alkyl group optionally substituted with a halogen atom, or a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a15 (wherein R ^a15 _{Represents a} C _1-6 alkyl group.) A C _7-10 aralkyl group which may be substituted with one or more substituents selected from the group consisting of: },
R ^D is a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-8 alkyl group or —OR ^f2 {wherein R ^f2 is a C _1-6 alkyl group which may be substituted with a halogen atom, or a halogen atom; a hydroxyl group; A C _1-6 alkyl group and —OR ^a15 (wherein R ^a15 represents a C _1-6 alkyl group) which may be substituted with one or more substituents selected from the group consisting of C _7-10 An aralkyl group is shown. },
R ^E and R ^F are the same or different and are a hydrogen atom, a halogen atom, a C _1-8 alkyl group, or —OR ^c3 (R ^c3 represents a C _1-6 alkyl group which may be substituted with a halogen atom. )
R ^G is, (i) a hydrogen atom, (ii) a halogen atom, (iii) hydroxy group, (iv) may be substituted with one or more substituents selected from the group consisting of a halogen atom and a hydroxyl group C _{1- 8} alkyl groups,
(v) — (CH ₂ ) mQ {wherein m represents an integer of 0 to 4, Q is —CHO, —NH ₂ , —NO ₂ , —CN, —CO ₂ H, —SO ₃ H , —OR ^c1 , —CO ₂ R ^a3 , —CONH ₂ , —CONHR ^a4 , —CONR ^a5 R ^a5 , —COR ^d1 , —OCOR ^d2 , —SR ^e1 , —SOR ^e2 , —SO ₂ R ^e3 , —NHC ( ^{= O) H, -NHCOR d3,} -NHCO 2 R d4, -NHCONH 2, -NHSO 2 R e4, in -NHR ^a6, or -NR ^a7 R ^{a7 (wherein, R a3, R a4, R} a5, R a6 and R ^a7 represents a C _1-6 alkyl group, R ^c1 represents a C _1-6 alkyl group which may be substituted with a halogen atom, and R ^d1 , R ^d2 , R ^d3 and R ^d4 represent C _{1- 6} alkyl group, C _7-10 aralkyl group, a phenyl group or a C _3-7 cycloalkyl ^{group, R e1, R e2, R} e3 and R ^e4 is, C _1-6 alkyl, phenylene A group or a tolyl group.) Shows a. },
(vi) —O— (CH ₂ ) m′-Q ′ {wherein m ′ represents an integer of 1 to 4, Q ′ represents a hydroxyl group, —CO ₂ H, —OR ^c2 , —CO ₂ R ^a8 , —CONH ₂ , —CONHR ^a9 , —CONR ^a10 R ^a10 , —NH ₂ , —NHR ^a11 , —NR ^a12 R ^a12 or —NHCO ₂ R ^d5 (wherein R ^a8 , R ^a9 , R ^a10 , R ^a11 and R ^a12 represents a C _1-6 alkyl group, R ^c2 represents a C _1-6 alkyl group which may be substituted with a halogen atom, and R ^d5 represents a C _1-6 alkyl group or a C _7-10 aralkyl group. _Represents a phenyl group or a C _3-7 cycloalkyl group. },
(vii) —OR ^f {wherein R ^f is a halogen atom; a hydroxyl group; a C _1-6 alkyl group and OR ^a13 (wherein R ^a13 represents a C _1-6 alkyl group). A C _3-7 cycloalkyl group _optionally substituted by one or more substituents, a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a14 (wherein R ^a14 represents a C _1-6 alkyl group) An aryl group optionally substituted with one or more substituents selected from the group consisting of: a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a15 (wherein R ^a15 represents C _{1). -6} alkyl group.) C _7-10 aralkyl group optionally substituted with one or more substituents selected from the group consisting of: a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a16 ( ^Wherein R ^a16 represents a C _1-6 alkyl group) and substituted with one or more substituents selected from the group consisting of And represents an optionally heterocycloalkyl group. },
(viii) —NHR ^g {wherein R ^g is a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a17 (wherein R ^a17 represents a C _1-6 alkyl group). A C _7-10 aralkyl group which may be substituted with one or more selected substituents is shown. },
(ix) substituted with one or more substituents selected from the group consisting of a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a18 (wherein R ^a18 represents a C _1-6 alkyl group) A C _3-7 cycloalkyl group, which may be
(x) halogen atom; hydroxyl group; substituted with one or more substituents selected from the group consisting of C _1-6 alkyl group and —OR ^a19 (wherein R ^a19 represents a C _1-6 alkyl group) An aryl group which may be
(xi) halogen atom; hydroxyl group; substituted with one or more substituents selected from the group consisting of C _1-6 alkyl group and —OR ^a20 (wherein R ^a20 represents a C _1-6 alkyl group) A C _7-10 aralkyl group, which may be
(xii) halogen atom; hydroxyl group; substituted with one or more substituents selected from the group consisting of C _1-6 alkyl group and —OR ^a21 (wherein R ^a21 represents a C _1-6 alkyl group) A heteroaryl group which may be
(xiii) halogen atom; hydroxyl group; substituted with one or more substituents selected from the group consisting of a C _1-6 alkyl group and —OR ^a22 (wherein R ^a22 represents a C _1-6 alkyl group) 1-thio-D-glucitol compound or a pharmaceutically acceptable salt thereof or a hydrate thereof represented by a heterocycloalkyl group (hereinafter, referred to as “first specific embodiment 1”). -1 ") as an active ingredient, it relates to a preventive or therapeutic agent for diabetes, diabetes-related diseases or diabetic complications.

Another aspect of the present invention is the first specific aspect 1-1,
R ^B represents a hydrogen atom, a C _1-6 alkyl group, —OR ^f1 (wherein R ^f1 represents a C _1-6 alkyl group which may be substituted with a halogen atom) or a halogen atom;
R ^D is a hydrogen atom, a hydroxyl group, —OR ^f1 {wherein R ^f1 is a C _1-6 alkyl group or halogen atom which may be substituted with a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a15 (Wherein R ^a15 represents a C _1-6 alkyl group) and represents a C _7-10 aralkyl group which may be substituted with one or more substituents selected from the group consisting of: },
Diabetes comprising 1-thio-D-glucitol compound or a pharmaceutically acceptable salt thereof or a hydrate thereof (hereinafter referred to as “first specific embodiment 1-2”) as an active ingredient The present invention relates to a preventive or therapeutic agent for diabetes-related diseases or diabetic complications.

Another aspect of the present invention is the first specific aspect 1-1 or the first specific aspect 1-2.
R ^G is, (i) a hydrogen atom, (ii) a halogen atom, (iii) hydroxy group, (iv) may be substituted with one or more substituents selected from the group consisting of a halogen atom and a hydroxyl group C _{1- 8} alkyl groups,
_{(v) -CO 2 H, (} vi) -OR c1, (vii) -CO 2 R a3, (viii) -CONH 2, (ix) -CONHR a4, (x) -CONR a5 R a5, (xi) ^{-COR d1, (xii) -OCOR d2} , (xiii) -SR e1, (xiv) -SOR e2, (xv) -SO 2 R e3, (xvi) -NHR a6,
(xvii) -NR ^a7 R ^a7
(Wherein R ^a3 , R ^a4 , R ^a5 , R ^a6 and R ^a7 represent a C _1-6 alkyl group, R ^c1 represents a C _1-6 alkyl group which may be substituted with a halogen atom, R ^d1 and R ^d2 represent a C _1-6 alkyl group, a C _7-10 aralkyl group, a phenyl group or a C _3-7 cycloalkyl group, and R ^e1 , R ^e2 and R ^e3 represent a C _1-6 alkyl group. , Phenyl group or tolyl group).
(xviii) —O— (CH ₂ ) m′-Q ′ {wherein m ′ represents an integer of 1 to 4, Q ′ represents a hydroxyl group, —CO ₂ H, —OR ^c2 , —CO ₂ R ^a8 , —CONH ₂ , —CONHR ^a9 , —CONR ^a10 R ^a10 , —NH ₂ , —NHR ^a11 or —NR ^a12 R ^a12 (wherein R ^a8 , R ^a9 , R ^a10 , R ^a11 and R ^a12 are C _{1− 6 represents} an alkyl group, and R ^c2 represents a C _1-6 alkyl group which may be substituted with a halogen atom. },
(xix) —OR ^f {wherein R ^f is a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a13 (wherein R ^a13 represents a C _1-6 alkyl group). C _3-7 cycloalkyl group, halogen atom; hydroxyl group; C _1-6 alkyl group and —OR ^a14 (wherein R ^a14 represents C _1-6 alkyl) which may be substituted with one or more selected substituents An aryl group which may be substituted with one or more substituents selected from the group consisting of: a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a15 (wherein R ^a15 represents C _1-6 alkyl group.) C _7-10 aralkyl group which may be substituted with one or more substituents selected from the group consisting of: a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR substituted with one or more substituents selected from the group consisting of ^a16 (wherein R ^a16 represents a C _1-6 alkyl group). A heterocycloalkyl group which may be substituted; },
(xx) halogen atom; hydroxyl group; substituted with one or more substituents selected from the group consisting of a C _1-6 alkyl group and —OR ^a19 (wherein R ^a19 represents a C _1-6 alkyl group) An aryl group which may be
(xxi) halogen atom; hydroxyl group; substituted with one or more substituents selected from the group consisting of C _1-6 alkyl group and —OR ^a20 (wherein R ^a20 represents a C _1-6 alkyl group) A C _7-10 aralkyl group, which may be
(xxii) substituted with one or more substituents selected from the group consisting of a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a21 (wherein R ^a21 represents a C _1-6 alkyl group) A heteroaryl group which may be
(xxiii) halogen atom; hydroxyl group; substituted with one or more substituents selected from the group consisting of a C _1-6 alkyl group and —OR ^a22 (wherein R ^a22 represents a C _1-6 alkyl group) Diabetes, diabetes-related diseases or diabetics containing 1-thio-D-glucitol compound or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient, which may be a heterocycloalkyl group The present invention relates to preventive or therapeutic agents for complications.

Another aspect of the present invention is the first specific aspect 1-1 or the first specific aspect 1-2.
R ^G is, (i) a hydrogen atom, (ii) a halogen atom, (iii) hydroxy group, (iv) may be substituted with one or more substituents selected from the group consisting of a halogen atom and a hydroxyl group C _{1- 8} alkyl groups,
_{(v) -CO 2 H, (} vi) -OR c1, (vii) -CO 2 R a3, (viii) -CONH 2, (ix) -CONHR a4, (x) -CONR a5 R a5, (xi) ^{-COR d1, (xii) -OCOR d2} , (xiii) -SR e1, (xiv) -SOR e2, (xv) -SO 2 R e3, (xvi) -NHR a6,
(xvii) −NR ^a7 R ^a7
(Wherein R ^a3 , R ^a4 , R ^a5 , R ^a6 and R ^a7 represent a C _1-6 alkyl group, R ^c1 represents a C _1-6 alkyl group which may be substituted with a halogen atom, R ^d1 and R ^d2 represent a C _1-6 alkyl group, a C _7-10 aralkyl group, a phenyl group or a C _3-7 cycloalkyl group, and R ^e1 , R ^e2 and R ^e3 represent a C _1-6 alkyl group. Group, phenyl group or tolyl group).
(xviii) —O— (CH ₂ ) m′-Q ′ {wherein m ′ represents an integer of 1 to 4, Q ′ represents a hydroxyl group, —CO ₂ H, —OR ^c2 , —CO ₂ R ^a8 , —CONH ₂ , —CONHR ^a9 , —CONR ^a10 R ^a10 , —NH ₂ , —NHR ^a11 or —NR ^a12 R ^a12 (wherein R ^a8 , R ^a9 , R ^a10 , R ^a11 and R ^a12 are C _{1− 6 represents} an alkyl group, and R ^c2 represents a C _1-6 alkyl group which may be substituted with a halogen atom. },
(xix) —OR ^f2 {wherein R ^f2 is a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a13 (wherein R ^a13 represents a C _1-6 alkyl group). A C _3-7 cycloalkyl group optionally substituted with one or more selected substituents,
Or substituted with one or more substituents selected from the group consisting of a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a16 (wherein R ^a16 represents a C _1-6 alkyl group). Or a heterocycloalkyl group. }, Or
(xx) halogen atom; hydroxyl group; substituted with one or more substituents selected from the group consisting of a C _1-6 alkyl group and —OR ^a22 (wherein R ^a22 represents a C _1-6 alkyl group) Diabetes, diabetes-related disease or diabetes containing the above-described 1-thio-D-glucitol compound or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient, which may be a heterocycloalkyl group The present invention relates to a preventive or therapeutic agent for sexual complications.

The first specific aspect of the present invention is also, in particular,
Formula III below:

[式中、Ｒ¹、Ｒ²、Ｒ³及びＲ⁴は、同一又は異なって、水素原子、Ｃ_1-6アルキル基、−ＣＯ₂Ｒ^a2、−ＣＯＲ^b1、又はハロゲン原子；−ＮＯ₂及び−ＯＭｅからなる群から選択される１個以上の置換基で置換されてもよいＣ_7-12アラルキル基（式中、Ｒ^a2は、Ｃ_1-6アルキル基を示し、Ｒ^b1はＣ_1-6アルキル基、Ｃ_7-10アラルキル基又はフェニル基を示す。）を示し、
Ｒ^H及びＲ^Iは、同一又は異なって、
水素原子、ハロゲン原子、水酸基、Ｃ_1-8アルキル基、または
−ＯＲ^f1｛式中、Ｒ^f1は、ハロゲン原子で置換されてもよいＣ_1-6アルキル基、または
ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a15（式中、Ｒ^a15はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいＣ_7-10アラルキル基｝であり、
Ａｒ³がチエニル基、ベンゾ[ｂ]チオフェニル基、チエノ[２，３−ｂ]チオフェニル基、ベンゾフラニル基、ベンゾチアゾリル基、インドリル基、ピロリル基、イミダゾリル基、ピラゾリル基、ピリジル基、ピリミジニル基、ピラジニル基またはイソオキサゾリル基であり、
Ｒ^8a及びＲ^9aは、同一又は異なって、水素原子、ハロゲン原子、水酸基、Ｃ_1-8アルキル基又は−ＯＲ^c3（Ｒ^c3は、ハロゲン原子で置換されてもよいＣ_1-6アルキル基を示す。）であり、
Ｒ^10aは、水素原子、ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a19（式中、Ｒ^a19はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいアリール基、又は
ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a21（式中、Ｒ^a21はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいヘテロアリール基を示す。]で表される1−チオ−D−グルシトール化合物若しくはその製薬学的に許容される塩又はそれらの水和物（「第１の具体的な態様２」）を有効成分として含有する、糖尿病、糖尿病関連疾患もしくは糖尿病性合併症の予防又は治療剤に関する。

^{Wherein, R 1, R 2, R} 3 and R ⁴ are the same or different, a hydrogen atom, C _1-6 alkyl _{^{group, -CO 2 R a2, -COR b1}} , or a halogen atom; -NO ₂ and A C _7-12 aralkyl group which may be substituted with one or more substituents selected from the group consisting of —OMe (wherein R ^a2 represents a C _1-6 alkyl group, and R ^b1 represents C _{1— 6} alkyl group, C _7-10 aralkyl group or phenyl group.)
R ^H and R ^I are the same or different,
A hydrogen atom, a halogen atom, a hydroxyl group, a C _1-8 alkyl group, or —OR ^f1 {wherein R ^f1 is a C _1-6 alkyl group optionally substituted with a halogen atom, or a halogen atom; a hydroxyl group; C _{1 A} C _7-10 aralkyl group that may be substituted with one or more substituents selected from the group consisting of a _-6 alkyl group and —OR ^a15 (wherein R ^a15 represents a C _1-6 alkyl group) },
Ar ³ is a thienyl group, benzo [b] thiophenyl group, thieno [2,3-b] thiophenyl group, benzofuranyl group, benzothiazolyl group, indolyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group Or is an isoxazolyl group,
R ^8a and R ^9a are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-8 alkyl group or —OR ^c3 (R ^c3 represents a C _1-6 alkyl group which may be substituted with a halogen atom. And
R ^10a is one or more selected from the group consisting of a hydrogen atom, a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a19 (wherein R ^a19 represents a C _1-6 alkyl group). An aryl group which may be substituted with a substituent, or a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a21 (wherein R ^a21 represents a C _1-6 alkyl group); And a heteroaryl group that may be substituted with one or more substituents. 1-thio-D-glucitol compound represented by the formula: The present invention relates to a preventive or therapeutic agent for diabetes-related diseases or diabetic complications.

A second specific embodiment of the present invention is a 1-thio-D-glucitol compound, or a pharmaceutically acceptable salt thereof, or a hydration thereof, wherein Ar ¹ is a heteroarylene group in formula I or formula IA. The present invention relates to a preventive or therapeutic agent for diabetes, diabetes-related diseases or diabetic complications, which contains a product as an active ingredient.
The second concrete embodiment of the present invention, further, A _{is, - (CH 2) n- (} . Wherein, n represents an integer of 0 to 3) the 1-thio -D- glucitol compound is Alternatively, the present invention relates to a preventive or therapeutic agent for diabetes, diabetes-related diseases or diabetic complications, which contains a pharmaceutically acceptable salt or hydrate thereof as an active ingredient.

The second specific aspect of the present invention is in particular:
Formula IV below:

[式中、Ｒ¹、Ｒ²、Ｒ³及びＲ⁴は、同一又は異なって、水素原子、Ｃ_1-6アルキル基、−ＣＯ₂Ｒ^a2、−ＣＯＲ^b1、又はハロゲン原子；−ＮＯ₂及び−ＯＭｅからなる群から選択される１個以上の置換基で置換されてもよいＣ_7-12アラルキル基（式中、Ｒ^a2は、Ｃ_1-6アルキル基を示し、Ｒ^b1はＣ_1-6アルキル基、Ｃ_7-10アラルキル基又はフェニル基を示す。）を示し、
Ａｒ⁴が、チエニレン基、ベンゾ[ｂ]チオフェニレン基またはピリジレン基であり、
Ｒ^20a及びＲ^21aは、同一又は異なって、水素原子、ハロゲン原子、水酸基、Ｃ_1-8アルキル基又は−ＯＲ^c3（Ｒ^c3は、ハロゲン原子で置換されてもよいＣ_1-6アルキル基を示す。）であり、
Ｒ^J及びＲ^Kは同一又は異なって、水素原子、ハロゲン原子、Ｃ_1-8アルキル基又は−ＯＲ^c3（Ｒ^c3は、ハロゲン原子で置換されてもよいＣ_1-6アルキル基を示す。）であり、
Ｒ^Lは、(i)水素原子、(ii)ハロゲン原子、(iii)水酸基、(iv)ハロゲン原子及び水酸基からなる群から選択される１個以上の置換基で置換されてもよいＣ_1-8アルキル基、(v)−ＣＯ₂Ｈ、(vi)−ＯＲ^c1、(vii)−ＣＯ₂Ｒ^a3、(viii)−ＣＯＮＨ₂、(ix)−ＣＯＮＨＲ^a4、(x)−ＣＯＮＲ^a5Ｒ^a5、(xi)−ＣＯＲ^d1、(xii)−ＯＣＯＲ^d2、(xiii)−ＳＲ^e1、(xiv)−ＳＯＲ^e2、(xv)−ＳＯ₂Ｒ^e3、(xvi)−ＮＨＲ^a6、
(xvii) −ＮＲ^a7Ｒ^a7
（式中、Ｒ^a3、Ｒ^a4、Ｒ^a5、Ｒ^a6及びＲ^a7は、Ｃ_1-6アルキル基を示し、Ｒ^c1は、ハロゲン原子で置換されてもよいＣ_1-6アルキル基を示し、Ｒ^d1及びＲ^d2は、Ｃ_1-6アルキル基、Ｃ_7-10アラルキル基、フェニル基又はＣ_3-7シクロアルキル基を示し、Ｒ^e1、Ｒ^e2及びＲ^e3は、Ｃ_1-6アルキル基、フェニル基又はトリル基を示す。）、
(xviii) −Ｏ−（ＣＨ₂）ｍ’−Ｑ’｛式中、ｍ’は１〜４の整数を示し、Ｑ’は水酸基、−ＣＯ₂Ｈ、−ＯＲ^c2、−ＣＯ₂Ｒ^a8、−ＣＯＮＨ₂、−ＣＯＮＨＲ^a9、−ＣＯＮＲ^a10Ｒ^a10、−ＮＨ₂、−ＮＨＲ^a11又は−ＮＲ^a12Ｒ^a12（式中、Ｒ^a8、Ｒ^a9、Ｒ^a10、Ｒ^a11及びＲ^a12は、Ｃ_1-6アルキル基を示し、Ｒ^c2は、ハロゲン原子で置換されてもよいＣ_1-6アルキル基を示す。）を示す。｝、
(xix) −ＯＲ^f2｛式中、Ｒ^f2は、ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a13（式中、Ｒ^a13はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいＣ_3-7シクロアルキル基、
またはハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a16（式中、Ｒ^a16はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいヘテロシクロアルキル基を示す。｝、又は
(xx) ハロゲン原子；水酸基；Ｃ_1-6アルキル基及び−ＯＲ^a22（式中、Ｒ^a22はＣ_1-6アルキル基を示す。）からなる群から選択される１個以上の置換基で置換されてもよいヘテロシクロアルキル基を示す。]で表される1−チオ−D−グルシトール化合物若しくはその製薬学的に許容される塩又はそれらの水和物を有効成分として含有する、糖尿病、糖尿病関連疾患もしくは糖尿病性合併症の予防又は治療剤に関する。

^{Wherein, R 1, R 2, R} 3 and R ⁴ are the same or different, a hydrogen atom, C _1-6 alkyl _{^{group, -CO 2 R a2, -COR b1}} , or a halogen atom; -NO ₂ and A C _7-12 aralkyl group which may be substituted with one or more substituents selected from the group consisting of —OMe (wherein R ^a2 represents a C _1-6 alkyl group, and R ^b1 represents C _{1— 6} alkyl group, C _7-10 aralkyl group or phenyl group.)
Ar ⁴ is a thienylene group, a benzo [b] thiophenylene group or a pyridylene group,
R ^20a and R ^21a are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-8 alkyl group or —OR ^c3 (R ^c3 represents a C _1-6 alkyl group _optionally substituted with a halogen atom). And
R ^J and R ^K are the same or different and are a hydrogen atom, a halogen atom, a C _1-8 alkyl group or —OR ^c3 (R ^c3 represents a C _1-6 alkyl group which may be substituted with a halogen atom). And
R ^L is C _1- which may be substituted with one or more substituents selected from the group consisting of (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) a halogen atom and a hydroxyl group. ₈ alkyl _{group, (v) -CO 2 H,} (vi) -OR c1, (vii) -CO 2 R a3, (viii) -CONH 2, (ix) -CONHR a4, (x) -CONR a5 R a5 (Xi) -COR ^d1 , (xii) -OCOR ^d2 , (xiii) -SR ^e1 , (xiv) -SOR ^e2 , (xv) -SO ₂ R ^e3 , (xvi) -NHR ^a6 ,
(xvii) −NR ^a7 R ^a7
(Wherein R ^a3 , R ^a4 , R ^a5 , R ^a6 and R ^a7 represent a C _1-6 alkyl group, R ^c1 represents a C _1-6 alkyl group which may be substituted with a halogen atom, R ^d1 and R ^d2 represent a C _1-6 alkyl group, a C _7-10 aralkyl group, a phenyl group or a C _3-7 cycloalkyl group, and R ^e1 , R ^e2 and R ^e3 represent a C _1-6 alkyl group. , Phenyl group or tolyl group).
(xviii) —O— (CH ₂ ) m′-Q ′ {wherein m ′ represents an integer of 1 to 4, Q ′ represents a hydroxyl group, —CO ₂ H, —OR ^c2 , —CO ₂ R ^a8 , —CONH ₂ , —CONHR ^a9 , —CONR ^a10 R ^a10 , —NH ₂ , —NHR ^a11 or —NR ^a12 R ^a12 (wherein R ^a8 , R ^a9 , R ^a10 , R ^a11 and R ^a12 are C _{1− 6 represents} an alkyl group, and R ^c2 represents a C _1-6 alkyl group which may be substituted with a halogen atom. },
(xix) —OR ^f2 {wherein R ^f2 is a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a13 (wherein R ^a13 represents a C _1-6 alkyl group). A C _3-7 cycloalkyl group optionally substituted with one or more selected substituents,
Or substituted with one or more substituents selected from the group consisting of a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a16 (wherein R ^a16 represents a C _1-6 alkyl group). Or a heterocycloalkyl group. }, Or
(xx) halogen atom; hydroxyl group; substituted with one or more substituents selected from the group consisting of a C _1-6 alkyl group and —OR ^a22 (wherein R ^a22 represents a C _1-6 alkyl group) A heterocycloalkyl group which may be substituted. Or a pharmaceutically acceptable salt thereof, or a hydrate thereof, as an active ingredient, for the prevention or treatment of diabetes, diabetes-related diseases or diabetic complications It relates to the agent.

Another aspect of the invention is a compound of formula IV:
1-thio-D, wherein R ^L is a hydrogen atom, a halogen atom, a C _1-8 alkyl group or —OR ^c3 (R ^c3 represents a C _1-6 alkyl group which may be substituted with a halogen atom). -It relates to a preventive or therapeutic agent for diabetes, diabetes-related diseases or diabetic complications, which contains a glucitol compound or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

It is possible to provide an excellent preventive or therapeutic agent for diabetes, diabetes-related diseases or diabetic complications which has an excellent SGLT2 inhibitory action, containing the compound 1-thio-D-glucitol derivative of the present invention as an active ingredient. is there.

The present invention will be described in detail, but is not particularly limited to those exemplified.
Definitions and examples of terms used in the present invention are provided to illustrate the specification and claims, and are provided without limitation.

  The “aryl group” refers to a monocyclic or condensed polycyclic aromatic hydrocarbon group having 6 to 15 carbon atoms, such as a phenyl group, a naphthyl group (including a 1-naphthyl group and a 2-naphthyl group), Examples include a pentarenyl group, an indenyl group, an indanyl group, an azulenyl group, a heptalenyl group, and a fluorenyl group. A phenyl group, a naphthyl group, an indenyl group, an indanyl group or an azulenyl group is preferable, and a naphthyl group or a phenyl group is more preferable.

  The “heteroaryl group” is a monocyclic or condensed aromatic heterocyclic group containing one or more heteroatoms selected from O, S and N. In the case where the aromatic heterocyclic group is a condensed ring, those having a partially hydrogenated monocycle are also included. Examples of such heteroaryl groups include pyrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrrolyl, imidazolyl, (1,2,3) )-And (1,2,4) -triazolyl group, tetrazolyl group, pyranyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, quinolyl group, isoquinolyl group, benzofuranyl group, isobenzofuranyl group, indolyl group, Isoindolyl group, indazolyl group, benzimidazolyl group, benzotriazolyl group, benzoxazolyl group, benzothiazolyl group, benzo [b] thiophenyl group, thieno [2,3-b] thiophenyl group, (1,2)-and ( 1,3) -Benzoxathiol group, chromenyl Group, 2-oxochromenyl group, benzothiadiazolyl group, quinolidinyl group, phthalazinyl group, naphthyridinyl group, quinoxalinyl group, quinazolinyl group, cinolinyl group, carbazolyl group.

  “Heterocycloalkyl group” refers to a heterocycloalkyl group composed of 3 to 12 atoms containing one or more heteroatoms selected from O, S and N. For example, one or more heterocycloalkyl groups in the ring And a cyclic amino group having one or more oxygen atoms and sulfur atoms may be present. Examples of such heterocycloalkyl groups include morpholino group, piperidinyl group, piperazinyl group, 1-pyrrolidinyl group, azepinyl group, thiomorpholino group, oxolanyl group, oxanyl group, dioxolanyl group, and dioxanyl group.

  The “arylene group” represents a divalent aromatic ring group, and means that one is bonded to a 5-thiosugar residue and the other is bonded to —A—. Examples of the arylene group include a phenylene group, a naphthylene group (including a 1-naphthylene group and a 2-naphthylene group), a pentalenylene group, an indenylene group, an indanylene group, an azlenylene group, a heptalenylene group, and a fluorenylene group. A phenylene group, a naphthylene group, an indenylene group, an indanylene group or an azlenylene group is preferable, and a naphthylene group or a phenylene group is more preferable.

  “Heteroarylene group” refers to a divalent aromatic heterocyclic group, one of which is bonded to a 5-thiosugar residue and the other of which is bonded to —A—. Examples of such heteroarylene group include pyrazolylene group, thiazolylene group, isothiazolylene group, thiadiazolylene group, imidazolylene group, furylene group, thienylene group, oxazolylene group, isoxazolylene group, pyrrolylene group, imidazolylene group, (1,2 , 3)-and (1,2,4) -triazolylene groups, tetrazolylene groups, pyranylene groups, pyridylene groups, pyrimidinylene groups, pyrazinylene groups, pyridazinylene groups, quinolylene groups, isoquinolylene groups, benzofuranylene groups, isobenzofuranylene groups, indolylenes Group, isoindolylene group, indazolylene group, benzimidazolylene group, benzotriazolylene group, benzoxazolylene group, benzothiazolylene group, benzo [b] thiophenylene group, chromenylene group, 2-oxochromeni Down group, benzothiadiazine benzoisothiazolyl alkylene group, Kinorijiniren group, phthalazinylene group, naphthyridinylene group, a quinoxalinylene group, a quinazolinylene group, cinnolinylene group, and a carbazolylene group.

“Heterocycloalkylene group” refers to a divalent heterocycloalkyl ring group, one of which is bonded to a 5-thiosugar residue and the other of which is bonded to —A—. Examples of such a heterocycloalkylene group include morpholinylene group, piperidinylene group, piperazinylene group, pyrrolidinylene group, azepinylene group, thiomorpholinylene group, oxolanylene group, oxanylene group, dioxolanylene group, and dioxanylene group.
In the compound of the present invention, depending on the type of Ar ¹ , all three substituents R ⁵ , R ⁶ and R ⁷ may not be bonded to the group.

The “C _1-6 alkyl group” refers to a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n- Examples thereof include a butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, tert-amyl group, 3-methylbutyl group, neopentyl group and n-hexyl group.
The “C _2-6 alkenyl group” refers to a linear or branched aliphatic hydrocarbon group having a double bond having 2 to 6 carbon atoms, such as an ethenyl group, a propenyl group, or a butenyl group. Etc.
The “C _2-6 alkynyl group” refers to a linear or branched aliphatic hydrocarbon group having a triple bond having 2 to 6 carbon atoms, such as ethynyl group, propynyl group, butynyl group, etc. Is mentioned.

“Halogen atom” includes fluorine atom, chlorine atom, bromine atom or iodine atom.
The “C _7-10 aralkyl group” refers to an arylalkyl group having 7 to 10 carbon atoms, and examples thereof include a benzyl group and a phenylethyl group.
The “optionally substituted C _7-12 aralkyl group” in the definitions of R ^{1 to} R ⁴ , R ^{11 to} R ¹⁴ and R ^{21 to} R ²⁴ is a substituted or unsubstituted aralkyl group having 7 to 12 carbon atoms. The substituent of the C _7-12 aralkyl group is at least one selected from the group consisting of a halogen atom, —NO ₂ and —OMe. Preferred substituents are a chlorine atom, —NO ₂ or —OMe. Examples of the substituted C _7-12 aralkyl group include a 4-methoxybenzyl group, a 3,4-dimethoxybenzyl group, a 4-chlorobenzyl group, and a 4-nitrobenzyl group.

The “optionally substituted C _1-8 alkyl group” refers to a substituted or unsubstituted alkyl group having 1 to 8 carbon atoms. The substituent of the C _1-8 alkyl group is one or more selected from the group consisting of a halogen atom and a hydroxyl group. The preferred number of substitution of the halogen atom is 1 to 6, more preferably 1 to 4, and the preferred halogen atom is a chlorine atom and a fluorine atom, and more preferably a fluorine atom. The preferred number of substitutions for the hydroxyl group is 1-6, more preferably 1-3. The substituted C _1-8 alkyl group includes, for example, trifluoromethyl group, difluoromethyl group, 1,1,1-trifluoroethyl group, 1,1,1-trifluoropropyl group, 1,1,1- Examples thereof include a trifluorobutyl group, a 1,3-difluoroprop-2-yl group, a hydroxymethyl group, a hydroxyethyl group (such as a 1-hydroxyethyl group), a hydroxypropyl group, and a hydroxybutyl group. Preferred are a trifluoromethyl group, a difluoromethyl group, a 1,1,1-trifluoroethyl group, a 1,3-difluoroprop-2-yl group, a hydroxymethyl group, and a hydroxyethyl group. A fluoromethyl group, a difluoromethyl group, a 1,1,1-trifluoroethyl group, a hydroxymethyl group and a hydroxyethyl group;

The “C _3-7 cycloalkyl group” refers to a cyclic alkyl group having 3 to 7 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. A cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group is preferable, and a cyclopropyl group or a cyclobutyl group is more preferable.

The “C _1-6 alkyl group _optionally substituted with a halogen atom” refers to a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms. The number of halogen atom substitutions is 1 or more. The preferred number of substitution of the halogen atom is 1 to 6, more preferably 1 to 4, and the preferred halogen atom is a chlorine atom and a fluorine atom, and more preferably a fluorine atom. Examples of the substituted C _1-6 alkyl group include a trifluoromethyl group, a difluoromethyl group, and a 1,1,1-trifluoroethyl group.

The “optionally substituted C _3-7 cycloalkyl group” refers to a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms. The substituent in the cycloalkyl group is a group consisting of a halogen atom, a hydroxyl group, a C _1-6 alkyl group, and —OR ^a13 (or —OR ^a18 ) (R ^a13 and R ^a18 are C _1-6 alkyl groups). Indicates one or more selected.

The “aryl group that may be substituted” refers to a substituted or unsubstituted aryl group. The substituent in the aryl group is selected from the group consisting of a halogen atom, a hydroxyl group, a C _1-6 alkyl group, and —OR ^a14 (or —OR ^a19 ) (R ^a14 and R ^a19 are C _1-6 alkyl groups). 1 or more. Preferred substituents are a halogen atom, a hydroxyl group, a C _1-4 alkyl group, a methoxy group, and an ethoxy group. As for the substituted aryl group, 4-chlorophenyl group, 4-fluorophenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group is mentioned, for example.

The “optionally substituted C _7-10 aralkyl group” refers to a substituted or unsubstituted aralkyl group having 7 to 10 carbon atoms. The substituent in the aralkyl group is a halogen atom, a hydroxyl group,
One or more selected from the group consisting of a C _1-6 alkyl group and —OR ^a15 (or —OR ^a17 or —OR ^a20 ) (R ^a15 , R ^a17 and R ^a20 are C _1-6 alkyl groups) Show. Preferred substituents are a halogen atom, a hydroxyl group, a C _1-4 alkyl group, a methoxy group, and an ethoxy group. Examples of the substituted C _7-10 aralkyl group include a 4-methoxybenzyl group, a 3,4-dimethoxybenzyl group, a 4-chlorobenzyl group, and a 4-chlorophenylethyl group.

The “optionally substituted heteroaryl group” refers to a substituted or unsubstituted heteroaryl group. The substituent in the heteroaryl group represents one or more selected from the group consisting of a halogen atom, a hydroxyl group, a C _1-6 alkyl group, and OR ^a21 (R ^a21 is a C _1-6 alkyl group). Preferred substituents are a halogen atom, a C _1-4 alkyl group, a methoxy group and an ethoxy group, and a methyl group and an ethyl group are more preferred. The substituted heteroaryl group includes, for example, 4-methylthiazol-2-yl group, 2-methylpyridin-5-yl group, 1-methylpyrazol-4-yl group, 1-ethylpyrazol-4-yl group 1-methylpyrrolyl group, 2-methylimidazolyl group, 4-methoxyindolyl group.

The “optionally substituted heterocycloalkyl group” refers to a substituted or unsubstituted heterocycloalkyl group. The substituent in the heterocycloalkyl group is selected from the group consisting of a halogen atom, a hydroxyl group, a C _1-6 alkyl group, and —OR ^a16 (or —OR ^a22 ) (R ^a16 and R ^a22 are C _1-6 alkyl groups). Indicates one or more selected. Preferred substituents are a halogen atom and a C _1-4 alkyl group, and a methyl group and an ethyl group are more preferred. Examples of the substituted heterocycloalkyl group include a 4-methylpiperazin-1-yl group and a 4-ethylpiperazin-1-yl group.

“Pharmaceutically acceptable salt” is a salt with an alkali metal, alkaline earth metal, ammonium, alkylammonium, or the like, a salt with a mineral acid or an organic acid, such as a sodium salt or potassium salt. , Calcium salt, ammonium salt, aluminum salt, triethylammonium salt, acetate, propionate, butyrate, formate, trifluoroacetate, maleate, tartrate, citrate, stearate, succinic acid Salt, ethyl succinate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, paratoluenesulfonate , With lauryl sulfate, malate, aspartate, glutamate, adipate, cysteine , Salts with N-acetylcysteine, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoate And salts with acrylic acid polymers and salts with carboxyvinyl polymers.
“Salts” are salts with alkali metals, alkaline earth metals, ammonium, alkylammonium, etc., salts with mineral acids or organic acids, but also include salts other than pharmaceutically acceptable salts. To do.

  Since some of the compounds and intermediates of the present invention may have chiral centers, they exist as various diastereomeric or enantiomeric forms. In addition, some of the compounds and intermediates of the present invention also exist as keto-enol tautomers, for example. In addition, some of the compounds and intermediates of the present invention also exist as geometric isomers (E-form, Z-form). Accordingly, the compounds and intermediates of the present invention include all the individual isomers described above and mixtures thereof.

As shown in the following test examples, the compound of the present invention exhibits an inhibitory activity on the activity of the sodium-dependent glucose cotransporter (SGLT2) involved in renal glucose reabsorption, and is associated with diabetes, diabetes-related diseases or diabetic complications. It is possible to provide a medicament excellent in the prevention or treatment effect of the disease.
Furthermore, as will be described in detail below, the compound of the present invention is excellent in crystallinity, easy to purify, store and formulate, and easy to handle as a medicine. Among the compounds of the present invention, those having particularly good crystallinity are compounds in which R ^{1 to} R ⁴ are hydrogen in the formulas I, IA, II, III and IV.
The conventional glucitol compound has many amorphous substances, and it has been necessary to crystallize the compound together with an appropriate amino acid such as phenylalanine or proline (US Pat. No. 6,774,112). However, since the compound of the present invention in which glucitol is converted to 1-thio-glucitol has good crystallinity, it does not need to be co-crystallized with an amino acid or the like.
For example, glucitol compound Xa described in US Pat. No. 6,515,117 is described as being glassy and has poor crystallinity. However, the compound Xb of the present invention which is 1-thio-glucitol becomes colorless powder crystals having a melting point of 79.0-83.0 ° C.

Preferred embodiments of the compound of the present invention are listed below.
Preferred examples of the formula I and in IA, A is, - (CH ₂₎ n- (wherein, n is an integer of 0 to 3, preferably n = 1 or 2.), - CONH (CH 2 ) n-(wherein, n is an integer of 0 to 3, preferably from n = 0) or _{-. (CH 2) nCH =} CH- ( where, n is an integer of 0 to 3, Preferably n = 0 or 1.), -O-.
A more preferred example of A is —CH ₂ —.
In formulas I and IA, the preferred binding position for A-Ar ² is the meta position relative to the thiosugar.

Preferred embodiments of the compound of formula II of the present invention are listed below.
In the formula (II), R ^A and R ^C are preferably hydrogen atoms.
A preferred substituent for R ^B is a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-8 alkyl group, or —O— (CH ₂ ) m′-Q ′ {wherein m ′ is an integer of 1 to 4. , M ′ = 1 is preferable. Q ′ is a hydroxyl group, —CO ₂ H, —OR ^c ₂ , —CO ₂ R ^a8 , —CONH ₂ , —CONHR ^a9 , —CONR ^a10 R ^a10 , —NH ₂ , —NHR ^a11 , —NR ^a12 R ^a12 or —NHCO ₂ R ^d5 (wherein R ^a8 , R ^a9 , R ^a10 , R ^a11 and R ^a12 represent a C _1-6 alkyl group, and R ^c2 is a C _1-6 which may be substituted with a halogen atom) Represents an alkyl group, and R ^d5 represents a C _1-6 alkyl group, a C _7-10 aralkyl group, a phenyl group, or a C _3-7 cycloalkyl group. }, Or —OR ^f1 {wherein R ^f1 is a C _1-6 alkyl group optionally substituted with a halogen atom, or a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a15 (wherein R ^a15 represents a C _1-6 alkyl group.) a C _7-10 aralkyl group which may be substituted with one or more substituents selected from the group consisting of:
Among them, R ^B is a hydrogen atom, a C _1-6 alkyl group, a halogen atom, a C _1-6 alkoxy group, —O—CH ₂ -Q ′ {wherein Q ′ is —CO ₂ H or —CO _2. R ^a8 (R ^a8 is as described above) is preferable, and a methyl group, a chlorine atom, or a methoxy group is particularly preferable.
Preferred substituents for R ^D are a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-8 alkyl group, —OR ^f2 {wherein R ^f2 is a C _1-6 alkyl group optionally substituted with a halogen atom, or Substituted with one or more substituents selected from the group consisting of a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a15 (wherein R ^a15 represents a C _1-6 alkyl group). Good C _7-10 aralkyl group}.
Of these, ^RD is preferably a hydrogen atom, a hydroxyl group, or a C _1-6 alkoxy group, and particularly preferably a hydroxyl group or a methoxy group.
Preferable substituents for R ^E and R ^F are the same or different and are a hydrogen atom, a halogen atom, a C _1-8 alkyl group, —OR ^c3 (R ^c3 is a C _1-6 alkyl group which may be substituted with a halogen atom) Is shown.)
Among these, it is preferable that R ^E and R ^F are a hydrogen atom or a fluorine atom.
A preferred substituent for R ^G is a C _1-8 alkyl group which may be substituted with one or more substituents selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, a halogen atom and a hydroxyl group.
In this, the _C1-8 alkyl group which may be substituted by the 1 or more substituent selected from the group which consists of a halogen atom, a hydroxyl group, a halogen atom, and a hydroxyl group is preferable. Particularly preferred are a methyl group, an ethyl group, an isopropyl group, and a hydroxymethyl group.
Other preferred substituents for R ^G are —CO ₂ H, —OR ^c1 , —CO ₂ R ^a3 , —CONH ₂ , —CONHR ^a4 , —CONR ^a5 R ^a5 , —COR ^d1 , —OCOR ^d2 , —SR ^e1 , -SOR ^e2 , -SO ₂ R ^e3 , -NHR ^a6 or -NR ^a7 R ^a7 (wherein R ^a3 , R ^a4 , R ^a5 , R ^a6 and R ^a7 represent a C _1-6 alkyl group, R ^c1 represents a C _1-6 alkyl group which may be substituted with a halogen atom, and R ^d1 and R ^d2 represent a C _1-6 alkyl group, a C _7-10 aralkyl group, a phenyl group or a C _3-7 cyclo group. Represents an alkyl group, and R ^e1 , R ^e2 and R ^e3 represent a C _1-6 alkyl group, a phenyl group or a tolyl group.
Among ^{_{these, -CO 2 H, -OR c1,}} -CO 2 R a3, -SR e1 and ^{-NR a7 R a7 (R c1,} R a3, R e1, R a7 are as defined above) are preferred, in particular, A methoxy group, an ethoxy group, an isopropyloxy group, a methylthio group, and —CO ₂ Me are preferable.
Other preferable substituents for R ^G are —O— (CH ₂ ) m′-Q ′ {wherein m ′ is an integer of 1 to 4, and m ′ = 1 or 2 is preferable. Q ′ is a hydroxyl group, —CO ₂ H, —OR ^c ₂ , —CO ₂ R ^a8 , —CONH ₂ , —CONHR ^a9 , —CONR ^a10 R ^a10 , —NH ₂ , —NHR ^a11 or —NR ^a12 R ^a12 ( In the formula, R ^a8 , R ^a9 , R ^a10 , R ^a11 and R ^a12 represent a C _1-6 alkyl group, R ^c2 represents a C _1-6 alkyl group which may be substituted with a halogen atom, and Indicates. }.
Among _{these, -O-CH 2 CO 2 Me} , -O-CH 2 CO 2 H, -O-CH 2 CONMe 2, -O-CH 2 CH 2 OH, is -O-CH ₂ CH ₂ NMe ₂ Preferred .
Other preferred substituents for R ^G are —OR ^f2 {wherein R ^f2 is a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a13 (wherein R ^a13 represents a C _1-6 alkyl group) A C _3-7 cycloalkyl group optionally substituted with one or more substituents selected from the group consisting of:
Or substituted with one or more substituents selected from the group consisting of a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a16 (wherein R ^a16 represents a C _1-6 alkyl group). Or a heterocycloalkyl group. Or a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a22 (wherein R ^a22 represents a C _1-6 alkyl group), and substituted with one or more substituents selected from the group consisting of It may be a heterocycloalkyl group.
Among these, —O—C _3-7 cycloalkyl group, —O-heterocycloalkyl group, and heterocycloalkyl group are preferable, and tetrahydropyranyloxy group, cyclopentyloxy group, and morpholino group are particularly preferable.

Preferred embodiments of the compound of formula III of the present invention are listed below.
In the formula (III), Ar ³ is a thienyl group, benzo [b] thiophenyl group, thieno [2,3-b] thiophenyl group, benzofuranyl group, benzothiazolyl group, indolyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, pyridyl group , Pyrimidinyl group, pyrazinyl group or isoxazolyl group is preferable.
The substituents on these Ar ³ groups, R ^8a , R ^9a and R ^10a are the same or different and are preferably a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-8 alkyl group or a C _1-6 alkoxy group. .
When Ar ³ is a thienyl group, at least one of R ^8a , R ^9a and R ^10a is a halogen atom; a hydroxyl group; a C _1-6 alkyl group and —OR ^a19 (wherein R ^a19 is a C _1-6 alkyl group). An aryl group which may be substituted with one or more substituents selected from the group consisting of: a hydroxyl group; a C _1-6 alkyl group and —OR ^a21 (wherein R ^a21 represents A C _1-6 alkyl group.) Is a heteroaryl group which may be substituted with one or more substituents selected from the group consisting of: a hydrogen atom, a halogen atom, a C _1-8 alkyl group , C _1-6 alkoxy groups are preferred.

Preferred embodiments of the Formula IV compound of the present invention are listed below.
In the formula (IV), Ar ⁴ is preferably a thienylene group, a benzo [b] thiophenylene group or a pyridylene group. Further, R ^20a , R ^21a , R ^J and R ^K which are substituents on these groups are preferably a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-8 alkyl group, or a C _1-6 alkoxy group. R ^L is preferably the same as the groups ^listed as preferred substituents for R ^G in formula (II).

Preferred specific compounds of the present invention include the following.

(1S) -1,5-Anhydro-1- [3- (4-ethylbenzyl) phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [3- (4-ethoxybenzyl) phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [3-[(1-benzothien-2-yl) methyl] -4-methoxyphenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [4-chloro-3- (4-ethoxybenzyl) phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [3- (4-ethoxybenzyl) -4-methoxyphenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [3-[(1-benzothien-2-yl) methyl] -4-chlorophenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [3-[(1-benzothien-2-yl) methyl] phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [3- (4-ethoxybenzyl) -6-methoxy-phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [3-[(1-benzothien-2-yl) methyl] -6-methoxyphenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [3- (4-ethoxybenzyl) -6-hydroxyphenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [4,6-dimethoxy-3- (4-ethoxybenzyl) phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [3- (4-ethoxybenzyl) -4-fluorophenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [3- (4-ethoxybenzyl) -4-hydroxyphenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [4-chloro-3- (2,5-difluoro-4-ethoxybenzyl) phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [4-chloro-3- (3-fluoro-4-ethoxybenzyl) phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [4-chloro-3- (3-chloro-4-ethoxybenzyl) phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [3- (4-ethoxybenzyl) -4-methylphenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [4-chloro-3- (3,4-dimethoxybenzyl) phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [4-chloro-3- (4-methoxybenzyl) phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [3- (4-ethoxybenzyl) -6-methoxy-4-methylphenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [3- (4-t-butylbenzyl) -4-chlorophenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [4-chloro-3- (2-fluoro-4-ethoxybenzyl) phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [3-[(1-benzothien-2-yl) methyl] -4,6-dimethoxyphenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [4-chloro-3- (4-methylbenzyl) phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [4-chloro-3- (4-methylthiobenzyl) phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [4-chloro-3- (4-hydroxybenzyl) phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [4-chloro-3- (4-ethylbenzyl) phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [4-chloro-3- (4-isopropylbenzyl) phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [4-chloro-3- (4-ethoxy-methylbenzyl) phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [3- (4-ethoxybenzyl) -6-hydroxy-4-methylphenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [3-[(1-benzofuran-2-yl) methyl] -4-chlorophenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [4-chloro-3- (4-ethoxybenzyl) -6-methoxyphenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [3- (4-ethoxybenzyl) -4,6-dihydroxyphenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [3- (4-ethylbenzyl) -6-methoxy-4-methylphenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [4-chloro-3- (4-ethylbenzyl) -6-methoxyphenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [4-chloro-3- (4-isopropylbenzyl) -6-methoxyphenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [3- (4-methylbenzyl) -6-methoxy-4-methylphenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- [3- (4-isopropylbenzyl) -6-methoxy-4-methylphenyl] -1-thio-D-glucitol

  Various production methods of the compound of the present invention are described in detail below, but are not particularly limited to those exemplified. Conventionally, it has been reported that a D-glucitol derivative can be synthesized via a C-aryl glucopyranoside formed by adding one equivalent of aryllithium or an aryl grinder reagent to a gluconolactone derivative (Patent Document 12). . However, 1-thio-glucitol of the present invention could not be produced by the method under the same conditions as described above. As a result of intensive studies, the present inventors have found that 1-thio-glucitol is produced according to the method under the conditions described below.

(Production method 1 of the compound of the present invention)
The formula V compound is obtained from the formula IIA compound (aglycone) and the formula VIII compound (thiolactone) by the method shown in schemes 1-3, and then the formula V compound is reduced as shown in scheme 4 and further removed as necessary. By protecting, the compounds of formula I can be prepared. The synthesis method of the formula IIA compound (aglycone) is shown in schemes 5 to 8, and the synthesis method of the formula VIII compound (thiolactone) is shown in scheme 9.

  Scheme 1: Carbon-carbon bond formation reaction 1 between aglycone and 5-thiosugar.

Scheme 1
（式中、Xはハロゲン原子、特に臭素、ヨウ素または塩素を示す。Ar¹はアリール、ヘテロアリール、ヘテロシクロアルキル基を示し、その他の記号は前記と同意義である。）
スキーム１で示すように、アリールハライド、ヘテロアリールハライドまたはヘテロシクロアルキルハライド（化合物IIＡ）とマグネシウムから調整したGrignard試薬に、チオラクトン（化合物VIII）を加えることで、化合物Vを得ることができる。ここで、チオラクトンに対してGrignard試薬を加える量は、目的とする化合物Vを約１当量得るためには、少なくとも約２当量以上、より好ましくは、約２当量〜約２．２当量である。この時の反応温度は、−２０℃〜２５℃が好ましい。なお、Grignard試薬を調整するときの溶媒としては、ジエチルエーテル、テトラヒドロフラン、ジグリム等が挙げられ、添加物として、ヨウ素または１,２−ジブロモエタンを触媒量用いるとよい。この時の反応温度は２５℃〜１５０℃、好ましくは４０℃〜１００℃である。
また、化合物IIＡと、n−ブチルリチウム、tert−ブチルリチウム及びメシチルリチウム（2,4,6−トリメチルフェニルリチウム）等から選択されるリチウム試薬を、−７８℃〜−２０℃にて作用させて合成したアリールリチウム、ヘテロアリールリチウムまたはヘテロシクロアルキルリチウムは化合物VIIIに対して反応しない。しかし、これらのアリールリチウム、ヘテロアリールリチウムまたはヘテロシクロアルキルリチウムに、臭化マグネシウム（MgBr₂）を加えることでGrignard試薬を調整し、化合物VIIIと反応させることができる。この反応に使用する溶媒としてはジエチルエーテル、テトラヒドロフラン等が挙げられ、反応温度は、−２０℃〜２５℃が好ましい。

Scheme 1
(In the formula, X represents a halogen atom, particularly bromine, iodine or chlorine. Ar ¹ represents an aryl, heteroaryl or heterocycloalkyl group, and other symbols are as defined above.)
As shown in Scheme 1, Compound V can be obtained by adding thiolactone (Compound VIII) to Grignard reagent prepared from aryl halide, heteroaryl halide or heterocycloalkyl halide (Compound IIA) and magnesium. Here, the amount of Grignard reagent added to thiolactone is at least about 2 equivalents, more preferably about 2 equivalents to about 2.2 equivalents, in order to obtain about 1 equivalent of the target compound V. The reaction temperature at this time is preferably -20 ° C to 25 ° C. Examples of the solvent for adjusting the Grignard reagent include diethyl ether, tetrahydrofuran, diglyme, and the like, and iodine or 1,2-dibromoethane may be used in a catalytic amount as an additive. The reaction temperature at this time is 25 ° C to 150 ° C, preferably 40 ° C to 100 ° C.
Further, a compound IIA and a lithium reagent selected from n-butyllithium, tert-butyllithium, mesityllithium (2,4,6-trimethylphenyllithium) and the like are allowed to act at −78 ° C. to −20 ° C. The synthesized aryllithium, heteroaryllithium or heterocycloalkyllithium does not react with compound VIII. However, Grignard reagent can be prepared by adding magnesium bromide (MgBr ₂ ) to these aryllithium, heteroaryllithium or heterocycloalkyllithium, and reacted with compound VIII. Examples of the solvent used in this reaction include diethyl ether, tetrahydrofuran and the like, and the reaction temperature is preferably −20 ° C. to 25 ° C.

  Scheme 2: Carbon-carbon bond formation reaction 2 between aglycone and 5-thiosugar.

Scheme 2
（式中、Ar¹はアリール、ヘテロアリール、ヘテロシクロアルキル基を示し、その他の記号は前記と同意義である。）
さらに、スキーム２で示すように、上記と同様な方法で調整できるアリールリチウム、ヘテロアリールリチウムまたはヘテロシクロアルキルリチウムに金属ハロゲン化物、例えばヨウ化銅（I）や塩化セシウムを加え、トランスメタレーションによって生成した錯体（化合物II’）と、化合物VIIIを反応させて化合物Vを合成することもできる。これらのリチウム試薬を調整する時の反応温度は−７８℃〜−２０℃が好ましく、この反応に使用する溶媒としてはジエチルエーテル、テトラヒドロフラン等が挙げられる。次に、調整したリチウム試薬をヨウ化銅または塩化セシウムとジエチルエーテルのけんだく液に滴下し、錯体II’を調整できる。反応温度は−７８℃〜０℃であり、−２５℃〜０℃が好ましい。次いで、Scheme１と同様な条件でチオラクトンVIIIを加えるか、またはチオラクトンVIIIに錯体II’を加えることで化合物Vを得ることができる。

Scheme 2
(In the formula, Ar ¹ represents an aryl, heteroaryl, or heterocycloalkyl group, and other symbols are as defined above.)
Further, as shown in Scheme 2, a metal halide such as copper (I) iodide or cesium chloride is added to aryllithium, heteroaryllithium or heterocycloalkyllithium that can be prepared in the same manner as described above, and transmetallation is performed. Compound V can also be synthesized by reacting the produced complex (compound II ′) with compound VIII. The reaction temperature when preparing these lithium reagents is preferably −78 ° C. to −20 ° C., and examples of the solvent used in this reaction include diethyl ether and tetrahydrofuran. Next, the prepared lithium reagent can be dropped into a solution of copper iodide or cesium chloride and diethyl ether to prepare complex II ′. The reaction temperature is -78 ° C to 0 ° C, preferably -25 ° C to 0 ° C. Subsequently, compound V can be obtained by adding thiolactone VIII under the same conditions as in Scheme 1 or adding complex II ′ to thiolactone VIII.

  Scheme 3: Carbon-carbon bond forming reaction 3 between aglycone and 5-thiosugar.

Scheme 3
（式中、Ar¹はアリール、ヘテロアリール、ヘテロシクロアルキル基を示し、Ｒ³⁰はＣ_1-8アルキル基又はＣ_3-7シクロアルキル基を示し、その他の記号は前記と同意義である。）
スキーム３に示す方法でチオラクトンVIIIに対して、反応に必要な化合物IIＡの当量を減らすことが可能である。チオラクトンVIIIは１当量のGrignard試薬とは反応しないことを利用し、まず、チオラクトンVIIIに対して約０．８〜約１．２当量、好ましくは約０．９〜約１．０当量のＲ³⁰MgXを加える。この時のＣ_1-8アルキルマグネシウムハライドとしてはイソプロピルマグネシウムクロリド、イソプロピルマグネシウムブロミド、ｔ−ブチルマグネシウムクロリドが良い。また、Ｃ_3-7シクロアルキルマグネシウムハライドとしては、例えば、シクロヘキシルマグネシウムクロリドがあげられる。使用する溶媒としてはジエチルエーテル、テトラヒドロフラン等が良い。また、反応温度は、−２０℃〜２５℃が好ましい。つづいて、化合物IIＡより調整したGrignard試薬IXを加えることで、最初に加えたＲ³⁰MgXと反応することなく選択的にIXと反応し、目的とする化合物Vを得ることができる。Grignard試薬IXの量は、目的とする化合物Vの必要な量に応じて調節でき、約１当量の目的化合物を得るためには、約１当量で十分である。この時の好ましい溶媒はジエチルエーテル、テトラヒドロフランであり、反応温度は−２０℃〜２５℃が好ましい。
この方法によって、高価な化合物IIＡの当量を減らすことができ、１−チオ−グルシトールを効率よく合成することが可能になった。

Scheme 3
(In the formula, Ar ¹ represents an aryl, heteroaryl, or heterocycloalkyl group, R ³⁰ represents a C _1-8 alkyl group or a C _3-7 cycloalkyl group, and the other symbols are as defined above. )
It is possible to reduce the equivalent of compound IIA required for the reaction with respect to thiolactone VIII by the method shown in Scheme 3. Taking advantage of the fact that thiolactone VIII does not react with 1 equivalent of Grignard reagent, first, about 0.8 to about 1.2 equivalents, preferably about 0.9 to about 1.0 equivalents of R ³⁰ relative to thiolactone VIII. Add MgX. The C _1-8 alkyl magnesium halide at this time is preferably isopropyl magnesium chloride, isopropyl magnesium bromide, or t-butyl magnesium chloride. Examples of the C _3-7 cycloalkyl magnesium halide include cyclohexyl magnesium chloride. As a solvent to be used, diethyl ether, tetrahydrofuran or the like is preferable. The reaction temperature is preferably -20 ° C to 25 ° C. Subsequently, the Grignard reagent IX prepared from the compound IIA is added to selectively react with IX without reacting with the initially added R ³⁰ MgX to obtain the target compound V. The amount of Grignard reagent IX can be adjusted according to the required amount of the desired compound V, and about 1 equivalent is sufficient to obtain about 1 equivalent of the desired compound. Preferred solvents at this time are diethyl ether and tetrahydrofuran, and the reaction temperature is preferably -20 ° C to 25 ° C.
By this method, the equivalent of expensive compound IIA can be reduced, and 1-thio-glucitol can be synthesized efficiently.

  Scheme 4: Reduction reaction and deprotection reaction.

Scheme 4
（式中、記号は前記と同意義である。）
次に、スキーム４で示すように、化合物Vを還元し、β型立体選択的に本発明化合物
XIIIを合成することができる。この反応に適切な還元剤としては、Et₃SiH、i-Pr₃SiHまたはPh₂SiHClが用いられ、ルイス酸としては、BF₃・Et₂O、CF₃COOH、InCl₃等が挙げられる。溶媒としては、クロロホルム、ジクロロメタン、アセトニトリル、酢酸エチル、ジエチルエーテル、１，４−ジオキサン、テトラヒドロフランまたはそれらの混合溶媒が挙げられる。この還元反応においては、副生成物として、α体が数％〜１５％の割合で生成するが、試薬や反応溶媒を組み合わせることで、副生成物の割合を減少させることができる。還元剤として好ましい試薬は、Et₃SiH、i-Pr₃SiHであり、より好ましくは、Et₃SiHである。ルイス酸として好ましい試薬は、BF₃・Et₂O、CF₃COOHであり、より好ましくは、BF₃・Et₂Oである。反応温度は−６０℃〜２５℃であるが、好ましくは−４０℃〜０℃である。中でも溶媒の選択が重要で、好ましくはアセトニトリル、アセトニトリル-クロロホルム、アセトニトリル-ジクロロメタン等の、アセトニトリルとの混合溶媒が適している。

Scheme 4
(Wherein the symbols are as defined above)
Next, as shown in Scheme 4, compound V is reduced, and the compound of the present invention is β-stereoselectively.
XIII can be synthesized. As a reducing agent suitable for this reaction, Et ₃ SiH, i-Pr ₃ SiH or Ph ₂ SiHCl is used, and as a Lewis acid, BF ₃ .Et ₂ O, CF ₃ COOH, InCl _{3 and the} like can be mentioned. Examples of the solvent include chloroform, dichloromethane, acetonitrile, ethyl acetate, diethyl ether, 1,4-dioxane, tetrahydrofuran, or a mixed solvent thereof. In this reduction reaction, α-form is generated as a by-product at a ratio of several% to 15%, but the ratio of the by-product can be reduced by combining reagents and reaction solvents. Reagents preferable as the reducing agent are Et ₃ SiH and i-Pr ₃ SiH, and more preferably Et ₃ SiH. Preferred reagents for the Lewis acid are BF ₃ .Et ₂ O and CF ₃ COOH, and more preferably BF ₃ .Et ₂ O. The reaction temperature is −60 ° C. to 25 ° C., preferably −40 ° C. to 0 ° C. Among them, the selection of the solvent is important, and a mixed solvent with acetonitrile such as acetonitrile, acetonitrile-chloroform, acetonitrile-dichloromethane is suitable.

From -OR ²¹ ~-OR ²⁴ of the present invention compounds XIII, was removed by a method combined with R ²¹ to R ²⁴ on the type, into a hydroxyl group, to obtain the present invention compounds Ia.
For example, when R ²¹ , R ²² , R ²³ , and R ²⁴ are a benzyl group or a 4-methoxybenzyl group, a catalyst such as palladium activated carbon, palladium hydroxide, or platinum-palladium activated carbon is used in a hydrogen atmosphere. It can be removed by catalytic hydrogenation. Examples of the solvent used in this reaction include methanol, ethanol, isopropanol, ethyl acetate, acetic acid and the like. Alternatively, it can be removed using a Lewis acid such as BCl ₃ , BCl ₃ .Me ₂ S, BBr ₃ , AlCl ₃ , CF ₃ COOH, TfOH and the like. Examples of the solvent used for this reaction include chloroform, dichloromethane, acetonitrile, diethyl ether, tetrahydrofuran, anisole and the like, and the reaction temperature is preferably -78 ° C to 40 ° C.
When R ²¹ , R ²² , R ²³ , and R ²⁴ are allyl groups (—CH ₂ CH═CH ₂ ), tert-BuOK is allowed to act in dimethyl sulfoxide, followed by isomerization (—CH═CHCH ₃ ). , Hydrochloric acid or HgCl ₂ / HgO. Alternatively, it can be removed using Pd (PPh ₃ ) ₄ , PdCl ₂ , palladium activated carbon, etc. in the presence of an organic acid such as acetic acid, p-toluenesulfonic acid hydrate, N, N′-dimethylbarbituric acid. it can. Examples of the solvent used in this reaction include acetonitrile, diethyl ether, tetrahydrofuran and the like, and the reaction temperature is preferably 25 ° C to 100 ° C.

  Scheme 5: Synthetic method 1 of aglycone moiety.

Scheme 5

（式中、A’は−(CH₂)n’−；n’は０−２の整数、−CH＝CH−、または−C≡C−を示し、Ar¹はアリール、ヘテロアリール、ヘテロシクロアルキル基を示し、その他の記号は前記と同意義である。）
中間体である化合物IIＡにおいてAが−(CH₂)n−（nは１−３の整数）である場合は、国際特許公開WO0127128号を参考に合成することができる。あるいは、スキーム５に従って中間体IIdを製造できる。

Scheme 5

(Wherein A ′ represents — (CH ₂ ) n′—; n ′ represents an integer of 0-2, —CH═CH—, or —C≡C—, Ar ¹ represents aryl, heteroaryl, heterocyclo Represents an alkyl group, and other symbols are as defined above.)
In the compound IIA which is an intermediate, when A is — (CH ₂ ) n — (n is an integer of 1-3), it can be synthesized with reference to International Patent Publication No. WO0127128. Alternatively, Intermediate IId can be prepared according to Scheme 5.

Compound IIa is adjusted to Grignard reagent using 1 equivalent of magnesium as described above. Alternatively, compound IIa is adjusted to monoaryllithium using 1 equivalent of n-butyllithium or tert-butyllithium. Next, compound IIc can be synthesized by adding commercially available compound IIb to Grignard reagent or monoaryllithium. Examples of the solvent used in this reaction include diethyl ether and tetrahydrofuran, and the reaction temperature is preferably -78 ° C to 25 ° C.
Next, compound IIc can be reduced, and for example, Et ₃ SiH, i-Pr ₃ SiH or Ph ₂ SiHCl can be reacted in the presence of a Lewis acid to synthesize compound IId. Examples of the Lewis acid used in this reaction include BF ₃ .Et ₂ O, CF ₃ COOH, InCl _{3 and the} like, and examples of the solvent include chloroform, dichloromethane, acetonitrile or a mixed solvent thereof, preferably acetonitrile- A mixed solvent with acetonitrile such as chloroform and acetonitrile-dichloromethane can be mentioned. The reaction temperature here is −60 ° C. to 25 ° C., preferably −30 ° C. to 25 ° C.

  Scheme 6: Method 2 for synthesizing the aglycone moiety.

Scheme 6
（式中、Mは−O−又は−NH−を示し、Ar¹はアリール、ヘテロアリール、ヘテロシクロアルキル基を示し、その他の記号は前記と同意義である。）
化合物IIeに対して、アリールホウ酸、ヘテロアリールホウ酸またはヘテロシクロアルキルホウ酸誘導体IIfを、パラジウム触媒または銅触媒を用いて塩基の存在下カップリングすることによって、Aが−O−又は−NH−である化合物IIＡを得ることができる。パラジウム触媒としては、例えば、Pd₂(OAc)₂、Pd(dba)₂、パラジウム活性炭、dba:dibenzyliden acetone、 Pd(PPh₃)₄等が挙げられ、銅触媒としては、Cu(OAc)₂等が好ましい。用いる塩基としては、t−BuOK、Na₂CO₃、K₂CO₃、KOH、ピリジン、トリエチルアミン等が挙げられる。この反応に使用する溶媒としては、クロロホルム、ジクロロメタン、N,N−ジメチルホルムアミド、テトラヒドロフラン、ジオキサン、ジメトキシエタン等が挙げられる。

Scheme 6
(In the formula, M represents —O— or —NH—, Ar ¹ represents an aryl, heteroaryl, or heterocycloalkyl group, and other symbols are as defined above.)
By coupling aryl boric acid, heteroaryl boric acid or heterocycloalkyl boric acid derivative IIf to compound IIe in the presence of a base using a palladium catalyst or a copper catalyst, A is —O— or —NH—. Compound IIA can be obtained. Examples of the palladium catalyst include Pd ₂ (OAc) ₂ , Pd (dba) ₂ , palladium activated carbon, dba: dibenzyliden acetone, Pd (PPh ₃ ) _{4 and the} like, and examples of the copper catalyst include Cu (OAc) _{2 and the} like. Is preferred. Examples of the base to be used include t-BuOK, Na ₂ CO ₃ , K ₂ CO ₃ , KOH, pyridine, triethylamine and the like. Examples of the solvent used in this reaction include chloroform, dichloromethane, N, N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane and the like.

  Scheme 7: Aglycon moiety synthesis method 3.

Scheme 7
（式中、Ar¹はアリール、ヘテロアリール、ヘテロシクロアルキル基を示し、その他の記号は前記と同意義である。）
化合物IIgとIIhを用いてFriedel-Crafts反応を行い化合物IIiを得ることができる。この反応に使用するルイス酸としては、AlCl₃、CF₃COOH、EtAlCl₂等が挙げられ、溶媒としては、クロロホルム、ジクロロメタン、トルエン等が挙げられる。ここでの反応温度は−３０℃〜６０℃、好ましくは−１５℃〜２５℃である。次に、スキーム５に示した還元と同様な方法で化合物IIjを得ることができる。さらに、化合物IIjを臭素、臭化ナトリウム、臭化カリウム、臭化水素またはN−ブロモスクシンイミド（NBS）を用いて位置選択的に臭素化し、化合物IIＡを製造することができる。この時の溶媒としては、クロロホルム、ジクロロメタン、CF₃COOH、酢酸等が好ましい。さらに、NBS−CF₃COOH−H₂SO₄の混合物がより好ましい。

Scheme 7
(In the formula, Ar ¹ represents an aryl, heteroaryl, or heterocycloalkyl group, and other symbols are as defined above.)
Compound IIi can be obtained by performing Friedel-Crafts reaction using compounds IIg and IIh. Examples of the Lewis acid used in this reaction include AlCl ₃ , CF ₃ COOH, EtAlCl ₂ , and examples of the solvent include chloroform, dichloromethane, toluene and the like. The reaction temperature here is -30 ° C to 60 ° C, preferably -15 ° C to 25 ° C. Next, compound IIj can be obtained by a method similar to the reduction shown in Scheme 5. Further, compound IIj can be regioselectively brominated using bromine, sodium bromide, potassium bromide, hydrogen bromide or N-bromosuccinimide (NBS) to produce compound IIA. As the solvent at this time, chloroform, dichloromethane, CF ₃ COOH, acetic acid and the like are preferable. Further, a mixture of _{NBS-CF 3 COOH-H 2} SO 4 is more preferable.

  Scheme 8: Method 4 for synthesizing the aglycone moiety.

Scheme 8
（式中、Ar¹はアリール、ヘテロアリール基を示し、その他の記号は前記と同意義である。）
例えば、原料IIkまたはIInの置換基Ｒ⁵およびＲ⁹が共にアルコキシ基である場合はスキーム７にしたがって反応を行うと、臭素化の位置選択性が低下し、目的物を効率よく得られない場合がある。この場合、スキーム８に示すように、ハロゲン化を第一ステップに行ってから、Friedel-Crafts反応、還元の順で実施した方が高収率に化合物IIＡを製造でき、好ましい。この時の各反応の反応条件は、スキーム７に従う。

Scheme 8
(In the formula, Ar ¹ represents an aryl or heteroaryl group, and other symbols are as defined above.)
For example, when the substituents R ⁵ and R ^{9 of} the raw material IIk or IIn are both alkoxy groups, the reaction according to Scheme 7 results in a decrease in the regioselectivity of bromination, and the target product cannot be obtained efficiently. There is. In this case, as shown in Scheme 8, the compound IIA can be produced in a high yield when the halogenation is performed in the first step, followed by the Friedel-Crafts reaction and the reduction, which is preferable. The reaction conditions for each reaction at this time follow Scheme 7.

  Scheme 9: Synthesis of thiolactone.

Scheme 9
（式中、記号は前記と同意義である。）
化合物VIIIはYuasa, H., et al. J. Chem. Soc. Perkin Trans. 1, 2763項，1990年を参考に合成することができる。あるいは、以下に説明するスキーム９に従って合成することができる。

Scheme 9
(Wherein the symbols are as defined above)
Compound VIII can be synthesized with reference to Yuasa, H., et al. J. Chem. Soc. Perkin Trans. 1, 2763, 1990. Or it can synthesize | combine according to the scheme 9 demonstrated below.

  The hydroxyl group at position 1 of compound IIIa (which can be produced with reference to WO 04/106352 pamphlet) is protected with a protecting group that is resistant to basic conditions and deprotectable under neutral or acidic conditions. For example, using 3,4-dihydro-2H-pyran (3,4-DHP), p-toluenesulfonic acid monohydrate, pyridinium-toluenesulfonic acid (PPTS) and protecting with a tetrahydropyranyl group, compound IIIb Synthesize. Examples of the solvent used in this reaction include N, N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, chloroform, dichloromethane, toluene and the like.

Next, the acetyl group of compound IIIb is removed. The acetyl group can be removed using a base such as sodium methoxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, triethylamine, etc., and methanol, ethanol, hydrous methanol, etc. can be used as the solvent. it can. Next, R ¹¹ -R ¹⁴ X such as benzyl bromide, benzyl chloride, allyl bromide, methyl iodide and the like can be reacted with an appropriate base to obtain compound IIIc. Examples of the base include triethylamine, N-ethyl-N, N-diisopropylamine, pyridine, potassium carbonate, calcium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium methoxide, t-BuOK, etc. Potassium carbonate, calcium carbonate, cesium carbonate, sodium hydride. Examples of the solvent used in this reaction include N, N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane and the like, and the reaction temperature is −20 ° C. to 25 ° C.

  Next, the protecting group at the 1-position of compound IIIc is removed to obtain compound IIId. For example, the THP group can be removed by treating compound IIIc with PPTS in methanol or ethanol. Finally, compound IIId can be treated with a suitable oxidizing agent to produce thiolactone VIII. As the oxidizing agent used in this reaction, dimethyl sulfoxide-acetic anhydride, Dess-Martin periodinane, IBX and the like are preferable, and the reaction temperature is 0 ° C to 40 ° C.

(Production method 2 of the compound of the present invention)
When A of the present compound I is — (CH ₂ ) n — (n is an integer of 1-3), it can also be synthesized by the method shown in Scheme 10. Another method for producing the synthetic intermediate VA of Scheme 10 is shown in Scheme 11.

  Scheme 10: Preparation Method 2 of Compound of Formula I

Scheme 10
（式中、Ar¹はアリール、ヘテロアリール基を示し、Yは化合物IIrにおいて臭素原子を示し、化合物IIsにおいてMgBrまたはLiを示し、その他の記号は前記と同意義である。）
市販の化合物IIpをトルエンまたはベンゼン中、エチレングリコールとp-トルエンスルホン酸１水和物と共に加熱還流することで、化合物IIqとする。この時の反応時間は１〜２４時間で、加熱時にジーンスターク等を用いて脱水操作をするとよい。次に、上記製造例１に記載した方法と同様に、化合物IIqのGrignard試薬を調整した後にチオラクトンVIIIを加え化合物IVaを得ることができる。
次に、化合物IVaから本発明化合物Iを製造するための１つのルートを説明する。まず、化合物IVaのエチレンアセタール基を酸で除去し、化合物IVbを得ることができる。この反応に使用する酸としては、塩酸、p-トルエンスルホン酸１水和物、酢酸、過塩素酸、あるいはPh₃CBF₄等が挙げられ、溶媒としては、メタノール、エタノール、アセトン、ジクロロメタン、水、またはそれらの混合物が挙げられる。反応温度は２５℃〜１００℃が好ましい。

Scheme 10
(In the formula, Ar ¹ represents an aryl or heteroaryl group, Y represents a bromine atom in Compound IIr, MgBr or Li in Compound IIs, and the other symbols are as defined above.)
A commercially available compound IIp is heated to reflux together with ethylene glycol and p-toluenesulfonic acid monohydrate in toluene or benzene to obtain compound IIq. The reaction time at this time is 1 to 24 hours, and the dehydration operation may be performed using Gene Stark or the like during heating. Next, similarly to the method described in the above Production Example 1, after preparing the Grignard reagent of Compound IIq, thiolactone VIII can be added to obtain Compound IVa.
Next, one route for producing the present compound I from compound IVa will be described. First, the ethylene acetal group of compound IVa can be removed with an acid to obtain compound IVb. Examples of the acid used in this reaction include hydrochloric acid, p-toluenesulfonic acid monohydrate, acetic acid, perchloric acid, and Ph ₃ CBF _4. Solvents include methanol, ethanol, acetone, dichloromethane, water, and the like. Or mixtures thereof. The reaction temperature is preferably 25 ° C to 100 ° C.

  Next, compound IVc can be synthesized from commercially available bromine derivative IIr by adding compound IVb to Grignard reagent or organolithium IIs that can be prepared in the same manner as described in Preparation Example 1 and Scheme 4 above. it can. Examples of the solvent used in this reaction include diethyl ether, tetrahydrofuran, dimethoxyethane and the like, and the reaction temperature is -78 ° C to 25 ° C.

Furthermore, this invention compound I can be manufactured by reduce | restoring the hydroxyl group in compound IVc similarly to the method described in the manufacturing method 1 and the scheme 4.
In addition, the compound I of the present invention can be synthesized from the compound IVa by another route. First, after reducing the thiosugar hydroxyl group of compound IVa, compound VA can be obtained by removing the ethylene acetal group. These reaction conditions follow the method described above. Next, compound Vx can be obtained by adding compound VA to Grignard reagent or IIs compound which is organolithium. Furthermore, compound I can be synthesized by reacting compound Vx with Et ₃ SiH, i-Pr ₃ SiH or Ph ₂ SiHCl in the presence of a Lewis acid and reducing the hydroxyl group. Examples of the Lewis acid used in this reaction include BF ₃ .Et ₂ O, CF ₃ COOH, InCl _{3 and the} like, and examples of the solvent include chloroform, dichloromethane, acetonitrile or a mixed solvent thereof, preferably acetonitrile- A mixed solvent with acetonitrile, such as chloroform and acetonitrile-dichloromethane, can be mentioned. The reaction temperature here is −60 ° C. to 100 ° C., preferably −10 ° C. to 60 ° C.

  Scheme 11: Synthesis method of intermediate VA.

Scheme 11
（式中、Ar¹はアリール、ヘテロアリール基を示し、その他の記号は前記と同意義である。）
また、中間体ＶＡはスキーム１１のように、化合物Vaをn−BuLiで処理した後に、N,N−ジメチルホルムアミドを加えることで合成することができる。この反応に使用する溶媒としては、テトラヒドロフラン、エーテル等が挙げられ、反応温度は−７８℃〜２５℃が好ましい。

Scheme 11
(In the formula, Ar ¹ represents an aryl or heteroaryl group, and other symbols are as defined above.)
Intermediate VA can be synthesized by treating compound Va with n-BuLi and then adding N, N-dimethylformamide as shown in Scheme 11. Examples of the solvent used in this reaction include tetrahydrofuran, ether and the like, and the reaction temperature is preferably -78 ° C to 25 ° C.

(Production method 3 of the compound of the present invention)
When A of the compound I of the present invention is —CH ₂ —, particularly R ⁸ is a functional group such as —COR ^d or —CO ₂ R ^a , the compound Vb shown in Scheme 12 or intermediate shown in Scheme 13 Still coupling via the body IVf (Espinet, P., et al. Angew. Chem. Int. Ed. Engl. 43, 4704, 2004, Still, JK, Angew. Chem. Int. Ed. Engl 25, 508, 1986).

  Scheme 12: Method 3 for Producing the Compound of Formula I

Scheme 12
（式中、Ar¹はアリール、ヘテロアリール基を示し、Y’は塩素原子又は臭素原子を示し、その他の記号は前記と同意義である。）
市販の化合物IIaを製造法１、スキーム５に記載の方法で１当量のマグネシウムを用いてGrignard試薬を調整する。またはi-PrMgCl-LiCl（Kitagawa, K., et al. Angew. Chem. Int. Ed. Engl. 第39巻，2481項，2000年、Knochel, P., et al. Angew. Chem. Int. Ed. Engl. 第43巻，3333項，2004年）、を用いてアート錯体を調整する。調整した試薬に対して化合物VIIIを加え、化合物IVdを得ることができる。次に、化合物IVdの水酸基を製造法１、スキーム４に記載の方法と同様に還元し、化合物Vaを製造することができる。次に、化合物VaをBu₆Sn₂とパラジウム触媒で処理し、化合物Vbを合成することができる。この反応に使用するパラジウム触媒としては、Pd₂(OAc)₂、Pd(dba)₂、Pd(PPh₃)₄等が挙げられ、溶媒はトルエン等が好ましく、反応温度は６０℃−１２０℃である。

Scheme 12
(In the formula, Ar ¹ represents an aryl or heteroaryl group, Y ′ represents a chlorine atom or a bromine atom, and other symbols are as defined above.)
The Grignard reagent is prepared from commercially available compound IIa by the method described in Production Method 1, Scheme 5 using 1 equivalent of magnesium. Or i-PrMgCl-LiCl (Kitagawa, K., et al. Angew. Chem. Int. Ed. Engl. 39, 2481, 2000, Knochel, P., et al. Angew. Chem. Int. Ed Engl. 43, 3333, 2004). Compound VIII can be added to the prepared reagent to obtain compound IVd. Next, compound Va can be produced by reducing the hydroxyl group of compound IVd in the same manner as described in Production Method 1 and Scheme 4. Next, compound Va can be synthesized by treating compound Va with Bu ₆ Sn ₂ and a palladium catalyst. Examples of the palladium catalyst used in this reaction include Pd ₂ (OAc) ₂ , Pd (dba) ₂ , Pd (PPh ₃ ) _{4 and the} like. The solvent is preferably toluene and the reaction temperature is 60 ° C. to 120 ° C. is there.

Next, Compound Vb and Compound IIt can be treated with a palladium catalyst to synthesize Compound I of the present invention. Examples of the palladium catalyst used in this reaction include Pd ₂ (OAc) ₂ , Pd (dba) ₂ , Pd (PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ , and the solvent is toluene, tetrahydrofuran, N , N-dimethylformamide and the like, and the reaction temperature is 40 ° C-120 ° C.

Scheme 13
（式中、Ar¹はアリール、ヘテロアリール基を示し、その他の記号は前記と同意義である。）
スキーム１３に示す、中間体IVｆと有機スズ化合物IIzとのStilleカップリングによって本発明化合物Ｉを製造することもできる。
中間体IVｆは、以下のように製造することができる。
まず、化合物IVｂの水酸基をスキーム４と同様な条件で還元して、化合物IVeを得ることができる。次に、化合物IVeのヒドロキシメチル基を臭素化することで中間体IVｆを合成することができる。このときの臭素化に用いる方法としては、PPh₃−CBr₄やPPh₃−N-ブロモスクシンイミドの組み合わせを用いることができる。または、メタンスルホニルクロリド、p−トルエンスルホニルクロリド、またはトリフルオロメタンスルホニルクロリドを塩基の存在下スルホン化した後に、NaBrやLiBrを用いて臭素化することができる。このとき使用する溶媒としては、クロロホルム、ジクロロメタン、アセトニトリル、ジエチルエーテル、テトラヒドロフラン、ジオキサン等が挙げられ、塩基としてはNa₂CO₃、K₂CO₃、KOH、ピリジン、トリエチルアミン等が好ましい。

Scheme 13
(In the formula, Ar ¹ represents an aryl or heteroaryl group, and other symbols are as defined above.)
Compound I of the present invention can also be produced by Stille coupling of intermediate IVf and organotin compound IIz shown in Scheme 13.
Intermediate IVf can be produced as follows.
First, compound IVb can be obtained by reducing the hydroxyl group of compound IVb under the same conditions as in Scheme 4. Next, intermediate IVf can be synthesized by brominating the hydroxymethyl group of compound IVe. As a method used for bromination at this time, a combination of PPh ₃ —CBr ₄ and PPh ₃ —N-bromosuccinimide can be used. Alternatively, methanesulfonyl chloride, p-toluenesulfonyl chloride, or trifluoromethanesulfonyl chloride can be sulfonated in the presence of a base and then brominated using NaBr or LiBr. As the solvent used at this time, chloroform, dichloromethane, acetonitrile, diethyl ether, tetrahydrofuran, dioxane and the like can be mentioned, and as the base, Na ₂ CO ₃ , K ₂ CO ₃ , KOH, pyridine, triethylamine and the like are preferable.

(Production Method 4 of the Compound of the Present Invention)
When A of the present compound I is — (CH ₂ ) n ″ — (n ″ is an integer of 0-2), —O—, or —NH—, the compound Vc shown in Scheme 14 was passed. Suzuki coupling (Bellina, F., et al. Synthesis, Vol. 15, 2419, 2004, Miyaura, N., et al. Chem. Rev., Vol. 95, 2457, 1995) Can be synthesized.

  Scheme 14: Method 4 for Producing the Compound of Formula I

Scheme 14

Scheme 14

(Wherein Ar ¹ represents an aryl or heteroaryl group, A ″ represents —O— or —NH—, A ′ ″ represents a bond, —CH ₂ — or —CH═CH—, R ^1k means a C _1-6 alkyl group, and other symbols are as defined above.) After adding Compound Va in tetrahydrofuran with n-butyllithium, tri (C _1-6 alkoxy) borane; ^Apply (OR ^1k ). The reaction temperature at this time is -78 degreeC-25 degreeC. Subsequently, the boric acid derivative Vc can be synthesized by treatment with hydrochloric acid or the like.

Next, Compound Vc and Compound IIu can be treated with a palladium catalyst in the presence of a suitable base to obtain Compound I of the present invention. Examples of the solvent used in this reaction include dioxane, acetonitrile, toluene, dimethoxyethane, tetrahydrofuran, N, N-dimethylformamide, dimethoxyethane / water, ethanol / water, toluene / ethanol, and the base includes t- BuOK, Na ₂ CO ₃ , K ₂ CO ₃ , KOH, pyridine, triethylamine and the like are preferable. Examples of the palladium catalyst include palladium activated carbon, Pd ₂ (OAc) ₂ , Pd (dba) ₂ , Pd (PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) _{2 and the} like. In the case of the reaction of Compound IIu in which A ′ ″ is —CH═CH—, the reaction product is obtained by catalytic hydrogenation shown in Production Method 1, Scheme 4, and A is —C ₂ H ₄ —. Can be converted to certain Formula I compounds.
Moreover, this invention compound I (A = -O- or -NH-) can be obtained from the compound Vc and the compound IIv by using the method shown in the manufacture example 1 and the scheme 6.

(Production Method 5 of Compound of the Present Invention)
A of the present invention Compound _{I, -CONH (CH 2) n -} , - NHCO (CH 2) n- (n is an integer of 0-3) compounds exhibiting is via an intermediate Vd shown in Scheme 15 Or a method via an intermediate Vf shown in Scheme 16.

  Scheme 15: Method 5 for Producing the Compound of Formula I

Scheme 15

Scheme 15

(In the formula, Ar ¹ represents an aryl or heteroaryl group, and the symbols are as defined above.)
The organometallic reagent IIaa can be prepared by treating the compound IIy with an art complex i-PrBu ₂ MgLi that can be prepared from n-BuLi and i-PrMgCl or i-PrMgBr. Compound IVg can be obtained by adding this to thiolactone VIII. Next, the carboxylic acid derivative Vd can be synthesized by reducing the hydroxyl group under the same conditions as in Scheme 4, followed by acid hydrolysis of the t-butyl ester. Examples of the solvent used in this reaction include dioxane, acetonitrile, toluene, dimethoxyethane, tetrahydrofuran, N, N-dimethylformamide, dimethoxyethane / water, ethanol / water, toluene / ethanol, and acids include formic acid and hydrochloric acid. And CF ₃ COOH. Alternatively, the carboxylic acid derivative Vd can also be synthesized by bubbling carbon dioxide after treating the compound Va with n-BuLi. Examples of the solvent used in this reaction include tetrahydrofuran, diethyl ether and the like, and the reaction temperature is preferably -78 ° C to 25 ° C.
Next, the compound Vd and the amine IIw are subjected to dehydration condensation to obtain the compound Ib of the present invention. As the solvent used in this reaction, chloroform, dichloromethane, N, N-dimethylformamide and the like are preferable, and as the dehydrating condensing agent, N, N-dicyclocarbodiimide (DCC), N-ethyl-N′-3-dimethyl is used. Aminopropylcarbodiimide hydrochloride (WSC), N, N-carbonyldiimidazole (CDI), WSC / 1-hydroxybenzotriazole monohydrate and the like are preferable. The reaction temperature here is 0 ° C to 60 ° C.

  Scheme 16: Method 5 'for the preparation of the compound of formula I.

Scheme 16

Scheme 16

(In the formula, Ar ¹ represents an aryl or heteroaryl group, and the symbols are as defined above.)
In scheme 16, compound Vd is reacted with SOCl ₂ or (COCl) ₂ in a solvent to give an acid chloride of compound Vd. Examples of the solvent used in this reaction include chloroform and dichloromethane. To this, sodium azide is allowed to act in the presence of n-Bu ₄ NBr to obtain an acid azide derivative of compound Vd, which is heated to reflux together with t-butanol, whereby compound Ve can be obtained. As the solvent used in this reaction, chloroform, toluene and the like are preferable. The t-butoxycarbonyl group (Boc) of compound Ve can be removed by treating with an appropriate acid to obtain compound Vf. As the acid used for this reaction, hydrochloric acid, CF ₃ COOH and the like are preferable.

Next, the compound Vf and the carboxylic acid IIx can be dehydrated and condensed to obtain the compound Ic of the present invention. As the solvent used in this reaction, chloroform, dichloromethane, N, N-dimethylformamide and the like are preferable, and as the dehydrating condensing agent, N, N-dicyclocarbodiimide (DCC), N-ethyl-N′-3-dimethyl is used. Aminopropylcarbodiimide hydrochloride (WSC), N, N-carbonyldiimidazole (CDI), WSC / 1-hydroxybenzotriazole monohydrate and the like are preferable. The reaction temperature here is 0 ° C to 60 ° C.

In addition, when the substituent R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ or R ¹⁰ on the aryl, heteroaryl or heterocycloalkyl ring of the compound of the present invention is a hydroxyl group or an amino group, this is alkylated. It is also possible to convert substituents by acylation. For example, an example in the case of a hydroxyl group is shown in Scheme 17. Compound Id can be obtained by reacting a hydroxyl group with methyl bromoacetate in the presence of a base. Examples of the solvent used in this reaction include dioxane, acetonitrile, toluene, dimethoxyethane, tetrahydrofuran, N, N-dimethylformamide, and the bases include Na ₂ CO ₃ , K ₂ CO ₃ , KOH, pyridine, triethylamine, and the like. Is preferred.

  Next, the methoxycarbonyl group can be converted to a carboxylic acid by hydrolysis by a method well known to those skilled in the art. The compound Id can be converted to an amide derivative by dehydration condensation with a primary or secondary amine. Alternatively, it can be converted to an alcohol by reducing the carbonyl group of compound Id.

Scheme 17

Scheme 17

The compound of the present invention can inhibit sodium-dependent glucose cotransporter 2 (SGLT2) (J. Clin. Invest., 93, 397, 1994) involved in glucose reabsorption in the kidney.
The compound of the present invention suppresses reabsorption of sugar by inhibiting SGLT2, and can treat diabetes by excreting excess sugar outside the body, so that hyperglycemia can be achieved without imposing a load on the β cells of the pancreas. Correct and improve insulin resistance.

Therefore, the present invention provides a medicament for preventing or treating diseases or conditions that can be improved by inhibiting the activity of SGLT2, such as diabetes, diabetes-related diseases and diabetic complications.
Here, “diabetes” includes type 1 diabetes, type 2 diabetes, and other types of diabetes caused by a specific cause.
Here, “diabetes-related disease” means obesity, hyperinsulinemia, glucose metabolism abnormality, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism abnormality, hypertension, congestive heart failure, edema, high Examples include uricemia and gout.

Here, “diabetic complications” are classified into acute complications and chronic complications.
“Acute complications” include hyperglycemia (such as ketoacidosis), infections (such as skin, soft tissue, biliary system, respiratory system, urinary tract infection) and the like.
“Chronic complications” include microangiopathy (nephropathy, retinopathy), arteriosclerosis (atherosclerosis, myocardial infarction, cerebral infarction, lower limb arterial occlusion, etc.), neuropathy (sensory, motor, Autonomic nerves) and foot gangrene.
The main complications are diabetic retinopathy, diabetic nephropathy, diabetic neuropathy.

  Further, the compound of the present invention can be used in combination with a therapeutic agent for diabetes having a different mechanism of action other than an SGLT2 activity inhibitor, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, a therapeutic agent for hypertension and the like. By combining the compound of the present invention with other drugs, an additive effect can be expected when used in combination with the above diseases, rather than the effect obtained with a single agent.

  Examples of antidiabetics and diabetic complications that can be used in combination include insulin sensitivity enhancers (PPARγ agonists, PPARα / γ agonists, PPARσ agonists, PPARα / γ / σ agonists, etc.), glycosidase inhibitors, biguanides, insulin Secretagogue, insulin preparation, glucagon receptor antagonist, insulin receptor kinase promoter, tripeptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose-6 Phosphatase inhibitor, gluconeogenesis inhibitor, fructose bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, glucokinase activator, D-kaileunositol, glycogen synthase kinase 3 inhibitor, glucagon-like peptide -1, glucagon-like peptide-1 analog, glucagon-like peptide-1 agonist, amylin, amylin analog, amylin agonist, glucocorticoid receptor antagonist, 11β-hydroxysteroid dehydrogenase inhibitor, aldose reductase inhibitor, Protein kinase C inhibitor, γ-aminobutyric acid receptor antagonist, sodium channel antagonist, transcription factor NF-κB inhibitor, IKKβ inhibitor, lipid peroxidase inhibitor, N-acetylated-α-linked-acid-dipeptidase inhibitor Insulin-like growth factor-I, platelet-derived growth factor (PDGF), platelet-derived growth factor (PDGF) analog, epidermal growth factor (EGF), nerve growth factor, carnitine derivative, uridine, 5-hydroxy-1-methylhydantoin , EGB-761, bimoclomol, sulodexide, Y-128, TAK-428 and the like.

Examples of the therapeutic agent for diabetes and the therapeutic agent for diabetic complications include the following drugs.
“Biguanide drugs” include metformin hydrochloride, phenformin, and the like.
Among the “insulin secretion promoters”, sulfonylureas include glyburide (glibenclamide), glipizide, gliclazide, chlorpropamide and the like, and non-sulfonylureas include nateglinide, repaglinide, mitiglinide and the like.

“Insulin preparations” include recombinant human insulin and animal-derived insulin. Moreover, it is classified into three types according to action time, immediate action type (human insulin, human neutral insulin), intermediate type (insulin-human isophene insulin aqueous suspension, human neutral insulin-human isophene insulin aqueous suspension, human Insulin zinc aqueous suspension, insulin zinc aqueous suspension), continuous type (human crystalline insulin zinc suspension) and the like.
Examples of the “glycosidase inhibitor” include acarbose, voglibose, miglitol and the like.
Among the `` insulin sensitivity enhancers '', PPARγ agonists include troglitazone, pioglitazone, rosiglitazone, etc., and PPARα / γdual agonists include MK-767 (KRP-297), Tesaglitazar, LM4156, LY510929, DRF-4823, TY -51501 and the like, and PPARσ agonists include GW-501516 and the like.

Examples of the “tripeptidyl peptidase II inhibitor” include UCL-139.
Examples of dipeptidyl peptidase IV inhibitors include NVP-DPP728A, LAF-237, P32 / 98,
TSL-225 etc. are mentioned.
Examples of the “aldose reductase inhibitor” include ascorbyl gamolenate, tolrestat, epalrestat, fidarestat, solvinyl, ponalrestat, lisarestat, zenarestat and the like.

Examples of the “γ-aminobutyric acid receptor antagonist” include topiramate.
Examples of the “sodium channel antagonist” include mexiletine hydrochloride.
Examples of the “transcription factor NF-κB inhibitor” include dexlipotam.
Examples of the “lipid peroxidase inhibitor” include tirilazad mesylate and the like.
Examples of the “N-acetylated-α-linked-acid-dipeptidase inhibitor” include GPI-5693 and the like.

Examples of the “carnitine derivative” include carnitine and rebasecarnin hydrochloride.
Examples of `` hyperlipidemic and hypertensive drugs '' that can be used in combination include hydroxymethylglutaryl coenzyme A reductase inhibitors, fibrate compounds, β ₃ -adrenergic receptor agonists, AMPK activators, acylcoenzyme A: Cholesterol acyltransferase inhibitor, probucol, thyroid hormone receptor agonist, cholesterol absorption inhibitor, lipase inhibitor, microsomal triglyceride transfer protein inhibitor, lipoxygenase inhibitor, carnitine palmitoyltransferase inhibitor, squalene synthase inhibitor, low specific gravity Lipoprotein receptor promoter, nicotinic acid derivative, bile acid adsorbent, sodium-conjugated bile acid transporter inhibitor, cholesterol ester transport protein inhibitor, angiotensin converting enzyme inhibitor, angiote Singh II receptor antagonists, endothelin converting enzyme inhibitors, endothelin receptor antagonists, diuretics, calcium antagonists, vasodilator antihypertensives, sympatholytic agents, central antihypertensives, alpha ₂ - adrenergic receptor agonists, anti Platelet drugs, uric acid production inhibitors, uric acid excretion promoters, urinary alkalinizing drugs, appetite suppressants, AGE inhibitors, adiponectin receptor agonists, GPR40 agonists, GPR40 antagonists and the like can be mentioned.
Examples of the antihyperlipidemic agent and antihypertensive agent include the following agents.
Examples of the “hydroxymethylglutaryl coenzyme A reductase inhibitor” include fluvastatin, lovastatin, pravastatin, cerivastatin, pitavastatin and the like.
Examples of the “fibrate compound” include bezafibrate, beclobrate, binifibrate and the like.
Examples of the “squalene synthetase inhibitor” include TAK-475, α-phosphonosulfonate derivative (USP5712396) and the like.

Examples of “acyl coenzyme A: cholesterol acyltransferase inhibitor” include CI-1011, NTE-122, FCE-27677, RP-73163, MCC-147, DPU-129 and the like.
Examples of the “low density lipoprotein receptor promoter” include MD-700 and LY-295427.
Examples of the “microsome triglyceride transfer protein inhibitor (MTP inhibitor)” include compounds described in USP5739135, USP5712279, USP5760246 and the like.

  “Appetite suppressants” include adrenergic and noradrenergic agonists (Mazindol, ephedrine, etc.), serotonin agonists (selective serotonin reuptake inhibitors such as Fluvoxamine, etc.), adrenergic / serotonin agonists (Sibutramine, etc.), melanocortin 4 Examples include a receptor (MC4R) agonist, α-melanocyte stimulating hormone (α-MCH), leptin, cocaine-and amphetamine-regulated transcript (CART) and the like.

Examples of the “thyroid hormone receptor agonist” include liothyronine sodium, lepotyroxine sodium and the like.
Examples of the “cholesterol absorption inhibitor” include ezetimibe.
Examples of “lipase inhibitors” include orlistat and the like.
Examples of the “carnitine palmitoyltransferase inhibitor” include etomoxyl.

Examples of the “nicotinic acid derivative” include nicotinic acid, nicotinamide, nicomol, nicorandil and the like.
Examples of the “bile acid adsorbent” include cholestyramine, colestilan, colesevelam hydrochloride and the like.
Examples of the “angiotensin converting enzyme inhibitor” include captolyl, enalapril maleate, alacepril, cilazapril and the like.
Examples of the “angiotensin II receptor antagonist” include candesartan cilexetil, losartan potassium, eprosartan mesylate, olmesartan medoxomil, and the like.
Examples of the “endothelin converting enzyme inhibitor” include CGS-31447, CGS-35066 and the like.
Examples of the “endothelin receptor antagonist” include L-749805, TBC-3214, BMS-182874 and the like.

  For example, in the treatment of diabetes and the like, the compound of the present invention and an insulin sensitivity enhancer (PPARγ agonist, PPARα / γ agonist, PPARσ agonist, PPARα / γ / σ agonist, etc.), glycosidase inhibitor, biguanide drug, insulin secretagogue, A combination with at least one drug selected from the group consisting of insulin preparations and dipeptidyl peptidase IV inhibitors is considered preferable.

  Alternatively, the compound of the present invention, hydroxymethylglutaryl coenzyme A reductase inhibitor, fibrate compound, squalene synthase inhibitor, acylcoenzyme A: cholesterol acyltransferase inhibitor, low density lipoprotein receptor promoter, microsome A combination with at least one drug selected from the group consisting of a triglyceride transfer protein inhibitor and an appetite suppressant is considered preferable.

The medicament of the present invention can be systemically or locally administered orally or parenterally such as rectal, subcutaneous, intramuscular, intravenous and transdermal.
In order to use the compound of the present invention as a medicine, any form of a solid composition, a liquid composition and other compositions may be used, and the optimum one is selected as necessary. The medicament of the present invention can be produced by blending the compound of the present invention with a pharmaceutically acceptable carrier. Specifically, conventional excipients, fillers, binders, disintegrants, coating agents, sugar coatings, pH adjusting agents, solubilizers or aqueous or non-aqueous solvents are added, and tablets are prepared by conventional pharmaceutical techniques Pills, capsules, granules, powders, powders, solutions, emulsions, suspensions, injections, and the like. Examples of excipients and extenders include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, and other commonly used ones. it can.

The compound of the present invention can be formulated by forming an inclusion compound with α, β, γ-cyclodextrin, methylated cyclodextrin or the like.
The dose of the compound of the present invention varies depending on the disease, symptoms, body weight, age, sex, route of administration, etc., but for an adult, it is preferably 0.1 to 1000 mg / kg body weight / day, more preferably 0.1 to 200 mg. / kg body weight / day, which can be administered once or divided into several times a day.

Production Examples Hereinafter, production examples of the aglycone part of the compound of the present invention are shown.
Production Example 1
Synthesis of 2,3,4,6-tetra-O-benzyl-5-thio-D-glucono-1,5-lactone 2,3,4,6-tetra-O-acetyl-5-thio-D-gluco To a solution of pyranose (2.0 g, 5.49 mmol) in chloroform (40 mL) was added 3,4-dihydro-2H-pyran (1.5 mL, 16.5 mmol) and p-toluenesulfonic acid monohydrate (104 mg, 0.549 mmol). Stir at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give pale yellow amorphous tetrahydro-2H-pyran-2- Yle 2,3,4,6-tetra-O-acetyl-5-thio-D-glucopyranose (2.56 g) was obtained.

  Next, 25 wt% sodium methoxide was added to a solution of tetrahydro-2H-pyran-2-yl 2,3,4,6-tetra-O-acetyl-5-thio-D-glucopyranose (2.5 g) in methanol (40 mL). Of methanol (0.11 mL, 0.55 mmol) was added and stirred for 3 hours. A small amount of dry ice was added to neutralize the reaction solution, and then the reaction solution was concentrated. The obtained residue was dissolved in N, N-dimethylformamide (20 mL). This solution was added dropwise to a suspension of sodium hydride (1.3 g, 32.9 mmol; 60% oil) and N, N-dimethylformamide (4 mL) under ice cooling. The reaction mixture was stirred at room temperature for 20 minutes, cooled to 4 ° C., and benzyl bromide (5.6 g, 32.9 mmol) was added. The reaction solution was stirred at room temperature for 12 hours, methanol (5 mL) was added, and the mixture was stirred for 30 minutes. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to give tetrahydro-2H-pyran-2-yl 2,3 , 4,6-tetra-O-benzyl-5-thio-D-glucopyranose (3.36 g, 96%; 3 steps) was obtained.

Tetrahydro-2H-pyran-2-yl 2,3,4,6-tetra-O-benzyl-5-thio-D-glucopyranose (3.30 g, 5.15 mmol), pyridinium p-toluenesulfonic acid (518 mg, 2.06 mmol) ) And ethanol (58 mL) were stirred at 80 ° C. for 2 hours. The reaction was cooled to room temperature and the solvent was concentrated. The obtained residue was dissolved in ethyl acetate. This solution was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 2,3,4,6-tetra-O-benzyl-5-thio-D as colorless crystals. -Glucopyranose (2.89 g, quant) was obtained.
¹³ C NMR (125 MHz, CHLOROFORM-d) σ 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.

A mixture of 2,3,4,6-tetra-O-benzyl-5-thio-D-glucopyranose (2.82 g, 5.07 mmol), dimethyl sulfoxide (47 mL) and acetic anhydride (39 mL) was stirred at room temperature for 12 hours. . Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to give the title compound (2.3 g, 82%) as a colorless oil. Got.
¹ H NMR (200 MHz, CHLOROFORM-d) σ ppm 3.70 (d, J = 4.8 Hz, 2 H) 3.86-4.02 (m, 2 H) 4.09-4.22 (m, 2 H) 4.40-4.68 (m, 7 H) 4.83 (d, J = 11.4 Hz, 1 H) 7.12-
7.41 (m, 20 H).

Production Example 2
Synthesis of 2,3,4,6-tetra-O- (4-methoxybenzyl) -5-thio-D-glucono-1,5-lactone In the same manner as in Production Example 1, instead of benzyl bromide 4- Synthesized using methoxybenzyl chloride.
¹ H NMR (300 MHz, CHLOROFORM-d) σ ppm 3.60-3.66 (m, 2 H) 3.77-3.81 (m, 12 H) 3.81-3.91 (m, 2 H) 4.01-4.15 (m, 2 H) 4.29 -4.58 (m, 7 H) 4.74 (d, J = 11.2 Hz, 1 H) 6.78-6.90 (m, 8 H) 7.03-7.10 (m, 2 H) 7.11-7.30 (m, 6 H).

Production Example 3
Synthesis of 1-bromo-3- (4-ethoxybenzyl) benzene To a mixture of 4-bromophenetole (2.87 g, 0.0143 mol) and tetrahydrofuran (30 mL), a 2.6 M n-butyllithium hexane solution (5.8 mL) is − Added at 78 ° C. After stirring for 0.5 hour, a solution of 3-bromobenzaldehyde (2.65 g, 0.0143 mol) in tetrahydrofuran (15 mL) was added and further stirred for 15 minutes, and the reaction mixture was warmed to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1-5: 1) to give colorless oily (3-bromophenyl ) (4-ethoxyphenyl) methanol (3.94 g, 90%) was obtained.

Next, (3-bromophenyl) (4-ethoxyphenyl) methanol (3.92 g, 0.0128Mol) in chloroform (22 mL) was added at _{-60 ℃, Et 3 SiH (4.09mL} , 0.0256mol) and BF _{3 · Et 2 O (1.47mL, 0.0116mol} ) were added sequentially. After stirring for 1 hour, the reaction was warmed to room temperature. Saturated aqueous sodium carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1) to give the title compound (2.84 g, 76%) as a colorless oil. Got.
¹ H NMR (300 MHz, CHLOROFORM-d) σ ppm 1.40 (t, J = 7.0 Hz, 3 H) 3.88 (s, 2 H) 4.01 (q, J = 7.0 Hz, 2 H) 6.83 (d, J = (8.9 Hz, 2 H) 7.07 (d, J = 8.9 Hz, 2 H) 7.09-7.18 (m, 2 H) 7.29-7.34 (m, 2 H).

Production Example 4
Synthesis of 2- (5-bromo-2-methoxybenzyl) -1-benzothiophene To a mixture of benzo [b] thiophene (6.6 g, 0.049 mol) and tetrahydrofuran (66 mL), a 1.6 M n-butyllithium hexane solution (30.5 mL) was added at -78 ° C. After stirring for 0.5 hour, a solution of 5-bromo-2-methoxybenzaldehyde (10.0 g, 0.047 mol) in tetrahydrofuran (50 mL) was added and the mixture was further stirred for 5 minutes, and the reaction mixture was warmed to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to give (1-benzothien-2-yl) as pale yellow crystals. ) (5-bromo-2-methoxyphenyl) methanol (11.3 g, 69%) was obtained.

Next, (1-benzothien-2-yl) (5-bromo-2-methoxyphenyl) methanol (11.2 g, 0.0321 mol) in chloroform (110 mL) was added to Et ₃ SiH (10.3 mL) at −15 ° C. , 0.0642 mol) and BF ₃ · Et ₂ O (4.10 mL, 0.0321 mol) were added sequentially. After stirring for 0.5 hour, a saturated aqueous sodium bicarbonate solution was added. The mixture was extracted with chloroform, and the organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1) to obtain the title compound (9.84 g, 92%) as yellow crystals.
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 3.84 (s, 3 H) 4.17 (s, 2 H) 6.76 (d, J = 8.7 Hz, 1 H) 7.01 (s, 1 H) 7.19-7.37 (m , 4 H) 7.65 (d, J = 7.8 Hz, 1 H) 7.73 (d, J = 7.8 Hz, 1 H)
EI 332, 334 (M ⁺ , M + 2)

Production Example 5
Synthesis of 2- (5-bromo-2-chlorobenzyl) -1-benzothiophene To a solution of 5-bromo-2-chlorobenzoic acid (10.0 g, 0.0425 mol) in chloroform (20 mL) was added oxalyl chloride (3.78 mL). , 0.0441 mmol) and N, N-dimethylformamide (0.06 mL) were added. The reaction solution was stirred at room temperature for 1 day, and then the reaction solvent was distilled off under reduced pressure. The resulting yellow oil was dissolved in chloroform (20 mL). This solution was added to a mixture of N, O-dimethoxyhydroxylamine hydrochloride (4.56 g, 0.0468 mol), triethylamine (12.3 mL, 0.0882 mol) and chloroform (50 mL) while maintaining the reaction temperature at 5 ° C to 10 ° C. It was added dropwise over a period of minutes. After stirring for 15 minutes, the reaction mixture was warmed to room temperature. Water (20 mL) was added to the reaction solution, the organic layer was separated, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain colorless crystals of 5-bromo-2-chloro-N-methoxy-N-methylbenzamide (11.8 g, 99.7%). This was used in the next reaction without purification.

To a solution of 5-bromo-2-chloro-N-methoxy-N-methylbenzamide (10.8 g, 0.0388 mol) in tetrahydrofuran (108 mL) was added LiAlH ₄ (1.47 g, 0.0388 mol) so that the internal temperature did not exceed −10 ° C. ) Was added little by little. The reaction mixture was stirred at −15 ° C. for 1 hour, saturated aqueous ammonium chloride solution was carefully added, and the precipitated insoluble material was filtered through celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain pale yellow crystalline 5-bromo-2-chlorobenzaldehyde (8.1 g, 95%). This was used in the next reaction without purification.

  To a mixture of benzo [b] thiophene (5.8 g, 0.043 mol) and tetrahydrofuran (58 mL), 1.6 M n-butyllithium hexane solution (26.9 mL) was added at −78 ° C. over 20 minutes. After stirring for 0.5 hour, a solution of 5-bromo-2-chlorobenzaldehyde (9.0 g, 0.041 mol) in tetrahydrofuran (50 mL) was added, and the mixture was further stirred for 5 minutes. The reaction was warmed to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give (1-benzothien-2-yl as a pale yellow oil). ) (5-bromo-2-chlorophenyl) methanol (10.3 g, 71%) was obtained.

Next, (1-benzothien-2-yl) (5-bromo-2-chlorophenyl) methanol (10.2 g, 0.0288 mol) in chloroform (110 mL) was added to Et ₃ SiH (9.2 mL, 0.058 mol) and BF ₃ · Et ₂ O (3.6 mL, 0.029 mol) were sequentially added. The reaction was warmed to room temperature and stirred at that temperature for 10 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the organic phase was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 60: 1) to give the title compound (5.5 g, 56%) as a colorless oil. Got.
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 4.30 (s, 2 H) 6.98-7.06 (m, 1 H) 7.22 -7.37 (m, 4 H) 7.43 (d, J = 2.3 Hz, 1 H) 7.64 -7.71 (m, 1 H) 7.72-7.80 (m, 1 H).
EI 336 (M ⁺ ), 338 (M + 2), 340 (M + 4).

Production Example 6
Synthesis of 1- (benzyloxy) -2-bromo-4- (4-ethoxybenzyl) benzene 3-bromo-4-hydroxybenzaldehyde (5.0 g, 0.025 mol), tetrabutylammonium iodide (0.92 g, 2.5 mmol) To a mixture of potassium carbonate (6.9 g, 0.050 mol) and N, N-dimethylformamide (70 mL), benzyl bromide (3.1 mL, 0.026 mol) was added at room temperature and stirred for 2.5 hours. An ice-water mixture (100 mL) was poured into the reaction solution and stirred for 1 hour. The deposited precipitate was filtered and dried to obtain 4-benzyloxy-3-bromobenzaldehyde (7.1 g, 98%) as a pale yellow powder.

  Next, a 1.6 M n-butyllithium hexane solution (22.9 mL) was added at −78 ° C. to a mixture of 4-bromophenetole (7.3 g, 0.037 mol) and tetrahydrofuran (70 mL). After stirring for 0.5 hour, a solution of 4-benzyloxy-3-bromobenzaldehyde (7.0 g, 0.024 mol) in tetrahydrofuran (70 mL) was added and further stirred for 15 minutes, and the reaction mixture was warmed to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give [4- (benzyloxy) -3 as a colorless oil. -Bromophenyl] (4-ethoxyphenyl) methanol (8.7 g, 86%) was obtained.

Next, [4- (benzyloxy) -3-bromophenyl] (4-ethoxyphenyl) methanol (8.7 g, 0.021 mol) in chloroform (90 mL) was added to Et ₃ SiH (6.7 mL) at −15 ° C. , 0.042 mol) and BF ₃ · Et ₂ O (2.7 mL, 0.021 mol) were sequentially added. After stirring for 1 hour, the reaction mixture was warmed to room temperature. Saturated aqueous sodium carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give the title compound (8.8 g, quant) as a colorless oil. Obtained.
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 1.40 (t, J = 7.0 Hz, 3 H) 3.82 (s, 2 H) 4.00 (q, J = 7.0 Hz, 2 H) 5.12 (s, 2 H) 6.78-6.87 (m, 3 H) 6.98-7.10 (m, 3 H) 7.27-7.50 (m, 6 H).

Production Example 7
Synthesis of 1-bromo-3- (4-ethoxybenzyl) -4-methoxybenzene The compound was prepared in the same manner as in Production Example 3 using 5-bromo-2-methoxybenzaldehyde and 4-bromophenetole.
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 1.40 (t, J = 7.0 Hz, 3 H) 3.79 (s, 3 H) 3.85 (s, 2 H) 4.01 (q, J = 7.0 Hz, 2 H) 6.72 (d, J = 8.6 Hz, 1 H) 6.81 (d, J = 8.7 Hz, 2 H) 7.09 (d, J = 8.7 Hz, 1 H) 7.13 (d, J = 2.5 Hz, 1 H) 7.27 ( dd, J = 8.6, 2.5 Hz, 1 H).

Production Example 8
Synthesis of 1-bromo-3- (4-ethoxybenzyl) -6-methoxybenzene The compound was prepared in the same manner as in Production Example 3 using 3-bromo-4-methoxybenzaldehyde and 4-bromophenetole.
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 1.40 (t, J = 7.0 Hz, 3 H) 3.83 (s, 2 H) 3.86 (s, 3 H) 4.01 (q, J = 7.0 Hz, 2 H) 6.78-6.85 (m, 3 H) 7.03-7.10 (m, 3 H) 7.35 (d, J = 2.2 Hz, 1 H).
EI 320, 322 (M ⁺ , M + 2).

Production Example 9
Synthesis of 2- (3-bromobenzyl) -1-benzothiophene The compound was prepared in the same manner as in Production Example 4 using 3-bromobenzaldehyde and benzo [b] thiophene.
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 4.19 (s, 2 H) 7.02 (s, 1 H) 7.15-7.47 (m, 6 H) 7.65-7.70 (m, 1 H) 7.71-7.77 (m, 1 H).
EI 302, 304 (M ⁺ , M + 2).

Production Example 10
Synthesis of 2- (3-bromo-4-methoxybenzyl) -1-benzothiophene Prepared in the same manner as in Production Example 4 using 3-bromo-4-methoxybenzaldehyde and benzo [b] thiophene.
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 3.89 (s, 3 H) 4.15 (s, 2 H) 6.86 (d, J = 8.4 Hz, 1 H) 7.01 (s, 1 H) 7.16-7.35 (m , 3 H) 7.48 (d, J = 1.9 Hz, 1 H) 7.64-7.70 (m, 1 H) 7.71-7.77 (m, 1 H).
EI 332, 334 (M ⁺ , M + 2).

Production Example 11
Synthesis of 1-bromo-3- (4-ethoxybenzyl) -4,6-dimethoxybenzene Prepared using 5-bromo-2,4-dimethoxybenzaldehyde and 4-bromophenetole in the same manner as in Production Example 3. .
¹ H NMR (200 MHz, CHLOROFORM-d) σppm 1.39 (t, J = 7.0 Hz, 3 H) 3.80 (s, 2 H) 3.82 (s, 3 H) 3.88 (s, 3 H) 4.00 (q, J = 7.0 Hz, 2 H) 6.47 (s, 1 H) 6.75-6.85 (m, 2 H) 7.02-7.12 (m, 2 H) 7.17 (s, 1 H)
EI 350, 352 (M ⁺ , M + 2).

Production Example 12
Synthesis of 1-bromo-3- (4-ethoxybenzyl) -4-fluorobenzene The compound was prepared in the same manner as in Production Example 3 using 5-bromo-2-fluorobenzaldehyde and 4-bromophenetole.
¹ H NMR (200 MHz, CHLOROFORM-d) σppm 1.40 (t, J = 7.0 Hz, 3 H) 3.88 (s, 2 H) 4.01 (q, J = 7.0 Hz, 2 H) 6.79-6.96 (m, 3 H) 7.05-7.16 (m, 2 H) 7.19-7.32 (m, 2 H).
EI 309, 311 (M ⁺ , M + 2).

Production Example 13
Synthesis of 1- (benzyloxy) -4-bromo-2- (4-ethoxybenzyl) benzene Synthesized from 3-bromo-2-hydroxybenzaldehyde in the same manner as in Production Example 6.
¹ H NMR (200 MHz, CHLOROFORM-d) σppm 1.40 (t, J = 6.8 Hz, 3 H) 3.90 (s, 2 H) 4.01 (q, J = 6.8 Hz, 2 H) 5.03 (s, 2 H) 6.72-6.85 (m, 3 H) 7.02-7.13 (m, 2 H) 7.15-7.43 (m, 7 H).

Production Example 14
Synthesis of 1-bromo-4-chloro-3- (4-ethoxy-2,5-difluorobenzyl) benzene Oxygenated 5-bromo-2-chlorobenzoic acid (5.0 g, 0.0212 mol) in chloroform (10 mL) Zalyl chloride (1.89 mL, 0.0220 mol) and N, N-dimethylformamide (0.03 mL) were added and stirred for 3 hours. The yellow oily substance obtained by evaporating the solvent under reduced pressure was dissolved in chloroform (10 mL). To this solution, 2,5-difluorophenetole (3.4 g, 0.0214 mol) was added at −10 ° C., and then aluminum chloride (2.9 g, 0.0214 mol) was added little by little over 5 minutes. After the reaction mixture was stirred at 5 ° C. for 2 hours, ice water was added. This was extracted three times with chloroform. The combined organic layers were washed with 1M hydrochloric acid, water and saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give (5-bromo-2-chlorophenyl) (4- Ethoxy-2,5-difluorophenyl) methanone (5.59 g, 70%) was obtained as colorless crystals.
Next, (5-bromo-2-chlorophenyl) (4-ethoxy-2,5-difluorophenyl) methanone (5.58 g, 0.0149 mol) in chloroform-acetonitrile (1: 1; 60 mL) solution at 4 ° C. Et ₃ SiH (5.93 mL, 0.0371 mol) and BF ₃ · Et ₂ O (2.83 mL, 0.0224 mol) were sequentially added. The reaction mixture was warmed to room temperature, stirred for 12 hours, and further stirred at 45 ° C. for 3 hours. Saturated aqueous sodium carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give the title compound (3.8 g, 71%) as a colorless oil. Got.
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 1.46 (t, J = 7.0 Hz, 3 H) 3.98 (s, 2 H) 4.08 (q, J = 7.0 Hz, 2 H) 6.71 (dd, J = 11.3 , 7.1 Hz, 1 H) 6.82 (dd, J = 11.3, 7.1 Hz, 1 H) 7.18-7.38 (m, 3 H).
EI 360 (M ⁺ ), 362 (M + 2), 364 (M + 4).

Production Example 15
Synthesis of 1-bromo-4-chloro-3- (4-ethoxy-3-fluorobenzyl) benzene Using 5-bromo-2-chlorobenzoic acid and 2-fluorophenetole in the same manner as in Production Example 14. And synthesized.
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 1.44 (t, J = 7.0 Hz, 3 H) 3.97 (s, 2 H) 4.09 (q, J = 7.0 Hz, 2 H) 6.79-6.95 (m, 3 H) 7.18-7.35 (m, 3 H)
EI 342 (M ⁺ ), 344 (M + 2), 346 (M + 4).

Production Example 16
Synthesis of 1-bromo-4-chloro-3- (3-chloro-4-ethoxybenzyl) benzene Using 5-bromo-2-chlorobenzoic acid and 2-chlorophenetole in the same manner as in Production Example 14. And synthesized.
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 1.46 (t, J = 7.0 Hz, 3 H) 3.96 (s, 2 H) 4.08 (q, J = 7.0 Hz, 2 H) 6.85 (d, J = 8.4 (Hz, 1 H) 6.95-7.03 (m, 1 H) 7.18 (d, J = 2.2 Hz, 1 H) 7.23-7.33 (m, 3 H).

Production Example 17
Synthesis of 1-bromo-3- (4-ethoxybenzyl) -4-methylbenzene In the same manner as in Production Example 14, 5-bromo-2-methylbenzoic acid (synthesized with reference to International Patent Publication No. WO0127128) and Synthesized using phenetole.
¹ H NMR (200 MHz, CHLOROFORM-d) σppm 1.40 (t, J = 7.0 Hz, 3 H) 2.18 (s, 3 H) 3.86 (s, 2 H) 4.00 (q, J = 7.0 Hz, 2 H) 6.76-6.87 (m, 2 H) 6.94-7.07 (m, 3 H) 7.17-7.30 (m, 2 H).
EI 304 (M ⁺ ), 306 (M + 2).

Production Example 18
Synthesis of 1-bromo-4-chloro-3- (2,4-dimethoxybenzyl) benzene In the same manner as in Production Example 14, using 5-bromo-2-chlorobenzoic acid and 1,3-dimethoxybenzene Synthesized.
¹ H NMR (200 MHz, CHLOROFORM-d) σppm 3.79 (s, 3 H) 3.80 (s, 3 H) 3.95 (s, 2 H) 6.36-6.53 (m, 2 H) 6.94 (d, J = 8.4 Hz , 1 H) 7.13-7.28 (m, 3 H).

Production Example 19
Synthesis of 1-bromo-4-chloro-3- (4-methoxybenzyl) benzene The compound was synthesized in the same manner as in Production Example 14 using 5-bromo-2-chlorobenzoic acid and anisole.
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 3.80 (s, 3 H) 3.99 (s, 2 H) 6.82-6.89 (m, 2 H) 7.06-7.13 (m, 2 H) 7.19-7.30 (m, 3 H).

Production Example 20
Synthesis of 1-bromo-4-chloro-3- (4-tert-butylbenzyl) benzene Synthesis was performed in the same manner as in Production Example 14 using 5-bromo-2-chlorobenzoic acid and tert-butylbenzene. .
¹ H NMR (200 MHz, CHLOROFORM-d) σppm 1.31 (s, 9 H) 4.03 (s, 2 H) 7.11 (d, J = 7.9 Hz, 2 H) 7.22-7.37 (m, 5 H).

Production Example 21
Synthesis of 1-bromo-4-chloro-3- (4-methylbenzyl) benzene The compound was synthesized in the same manner as in Production Example 14 using 5-bromo-2-chlorobenzoic acid and toluene.
¹ H NMR (200 MHz, CHLOROFORM-d) σppm 2.33 (s, 3 H) 4.02 (s, 2 H) 7.03-7.16 (m, 4 H) 7.18-7.32 (m, 3 H).
EI 294 (M ⁺ ), 296 (M + 2).

Production Example 22
Synthesis of 1-bromo-4-chloro-3- (4-methylthiobenzyl) benzene The compound was synthesized in the same manner as in Production Example 14 using 5-bromo-2-chlorobenzoic acid and thioanisole.
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 2.47 (s, 3 H) 4.01 (s, 2 H) 7.06-7.14 (m, 2 H) 7.17-7.32 (m, 5 H).

Production Example 23
Synthesis of 1-bromo-4-chloro-3- (4-ethylbenzyl) benzene The compound was synthesized in the same manner as in Production Example 14 using 5-bromo-2-chlorobenzoic acid and ethylbenzene.
¹ H NMR (200 MHz, CHLOROFORM-d) σppm 1.23 (t, J = 7.7 Hz, 3 H) 2.63 (q, J = 7.7 Hz, 2 H) 4.02 (s, 2 H) 7.04-7.18 (m, 4 H) 7.18-7.32 (m, 3 H)
EI 308 (M ⁺ ), 310 (M + 2).

Production Example 24
Synthesis of 1-bromo-4-chloro-3- (4-isopropylbenzyl) benzene The compound was synthesized in the same manner as in Production Example 14 using 5-bromo-2-chlorobenzoic acid and cumene.
¹ H NMR (200 MHz, CHLOROFORM-d) σppm 1.22 (s, 3 H) 1.26 (s, 3 H) 2.79-2.97 (m, 1 H) 4.02 (s, 2 H) 7.05-7.32 (m, 7 H ).
EI 322 (M ⁺ ), 324 (M + 2).

Production Example 25
Synthesis of 2- (5-bromo-2-chlorobenzyl) benzofuran In the same manner as in Production Example 5, synthesis was performed using benzofuran instead of benzothiophene.
¹ H NMR (200 MHz, CHLOROFORM-d) σppm 4.20 (s, 2 H) 6.40-6.46 (m, 1 H) 7.13-7.54 (m, 7 H).
EI 319 (M ⁺ ), 321 (M + 2).

Production Example 26
Synthesis of 1-bromo-3- (4-ethoxybenzyl) -6-methoxy-4-methylbenzene 4-methoxy-2-methylbenzoic acid (10 g, 0.060 mol), Fe (0.20 g, 3.61 mmol) and chloroform Bromine (3.87 mL, 0.076 mol) was added dropwise to the mixture of (10 mL) at 5 ° C. The reaction solution was brought to room temperature and stirred for a whole day and night. Chloroform (600 mL) was added, and the soapy solution was washed with 10% sodium hydrogen sulfate (200 mL × 2) and saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting pale yellow powder was recrystallized twice from methanol to give 5-bromo-4-methoxy-2-methylbenzoic acid (4.96 g, 34 %).
Alternatively, 5-bromo-4-methoxy-2-methylbenzoic acid can be synthesized using 4′-hydroxy-2′-methylacetophenone as a starting material. To a solution of 4-hydroxy-2-methylacetophenone (0.552 g, 3.47 mmol) in acetone (10 mL) was added potassium carbonate (0.720 mg, 5.21 mmol) and methyl iodide (0.542 g, 3.82 mmol), and the mixture was stirred at room temperature for 12 hours. . Further, methyl iodide (0.24 g, 1.73 mmol) was added, and the mixture was heated to reflux for 2 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. Chloroform was added to the residue, insoluble matter was filtered off, and the filtrate was concentrated to give 4-methoxy-2-methylacetophenone (0.57 g). Next, oxone (0.79 g, 1.27 mmol) and NaBr (0.13 g, 1.27 mmol) were added to a solution of 4-methoxy-2-methylacetophenone (0.21 g, 1.27 mmol) in acetone (4 mL) -water (4 mL). Stir at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated, washed with water, saturated aqueous sodium carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain a 4: 1 mixture (0.28 g) of 5-bromo-4-methoxy-2-methylacetophenone and 3-bromo-4-methoxy-2-methylacetophenone. It was. Next, a 4: 1 mixture (0.26 g) of 5-bromo-4-methoxy-2-methylacetophenone and 3-bromo-4-methoxy-2-methylacetophenone was added to a 5% NaOCl solution (3 mL) and potassium hydroxide ( 0.92 g) was added and the mixture was heated to reflux for 2.5 hours. After cooling to room temperature, 2M HCl was added to acidify the reaction. The mixture was extracted with ethyl acetate, and the organic phase was washed with 1M HCl and saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was washed with methanol to obtain colorless powdery 5-bromo-4-methoxy-2-methylbenzoic acid (112 mg).
Next, the title compound (5.80 g) was synthesized from 5-bromo-4-methoxy-2-methylbenzoic acid (4.93 g, 0.0201 mol) and phenetole in the same manner as in Production Example 14.
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 1.40 (t, J = 7.0 Hz, 3 H) 2.19 (s, 3 H) 3.82 (s, 2 H) 3.87 (s, 3 H) 4.00 (q, J = 7.0 Hz, 2 H) 6.71 (s, 1 H) 6.77-6.83 (m, 2 H) 6.95-7.04 (m, 2 H) 7.24 (s, 1 H).
EI 335 (M ⁺ ), 337 (M + 2).

Production Example 27
Synthesis of 1-bromo-4-chloro-3- (4-ethoxybenzyl) -6-methoxybenzene 2-bromo-5-chlorophenol (2.85 g, 13.7 mmol; synthesized with reference to International Patent Publication No. WO0109122), carbonic acid A solution of potassium (1.89 g, 13.7 mmol), n-Bu ₄ NI (50 mg, 0.137 mmol), methyl iodide (1.28 mL, 20.6 mmol) and N, N-dimethylformamide (8.0 mL) is stirred for 2 hours. did. Ice water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5) to give colorless oily 2-bromo-5-chloroanisole ( 2.94 g, 97%).
Next, oxalyl chloride (1.23 mL, 15.1 mmol) and N, N-dimethylformamide (2 drops) were added to 4-ethoxybenzoic acid (2.28 g, 13.7 mmol) in chloroform (8 mL) and stirred for 5 hours. The solvent was distilled off under reduced pressure, and the resulting yellow oil was dissolved in chloroform (5 mL). To this solution was added a chloroform solution (10 mL) of 2-bromo-5-chloroanisole (2.94 g, 13.3 mmol) at −10 ° C., and then aluminum chloride (2.07 g, 15.5 mmol) was added little by little over 5 minutes. added. The reaction mixture was stirred at 5 ° C. for 1 hour, then warmed to room temperature and stirred for 13 hours. The reaction mixture was poured into ice water and extracted three times with chloroform. The combined organic layers were washed with 1M hydrochloric acid, water and saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by NH-type silica gel column chromatography (hexane: ethyl acetate = 9: 1) to give (5-bromo-2-chloro-6 -Methoxyphenyl) (4-ethoxyphenyl) methanone (1.53 g, 31%) was obtained as colorless crystals.
Next, a solution of (5-bromo-2-chloro-6-methoxyphenyl) (4-ethoxyphenyl) methanone (1.50 g, 4.06 mmol) in chloroform-acetonitrile (1: 1; 16 mL) was added at −5 ° C. Et ₃ SiH (1.62 mL, 10.1 mmol) and BF ₃ .Et ₂ O (0.772 mL, 6.09 mmol) were sequentially added. The reaction mixture was warmed to room temperature and stirred for 16 hours. Saturated aqueous sodium carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to give the title compound (1.48 g, 99%) as a colorless oil. Got.
¹ H NMR (200 MHz, CHLOROFORM-d) σppm 1.40 (t, J = 7.0 Hz, 3 H) 3.87 (s, 3 H) 3.93 (s, 2 H) 4.01 (q, J = 7.0 Hz, 2 H) 6.77-6.87 (m, 2 H) 6.90 (s, 1 H) 7.03-7.12 (m, 2 H) 7.29 (s, 1 H).
EI 354 (M ⁺ ), 356 (M + 2), 358 (M + 4).

Production Example 28
Synthesis of 1-bromo-4-chloro-3- (4-ethylbenzyl) -6-methoxybenzene Using 4-ethylbenzoic acid instead of 4-ethoxybenzoic acid in the same manner as in Production Example 27 Synthesized.
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 1.22 (t, J = 7.6 Hz, 3 H) 2.62 (q, J = 7.6 Hz, 2 H) 3.87 (s, 3 H) 3.97 (s, 2 H) 6.91 (s, 1 H) 7.04-7.18 (m, 4 H) 7.32 (s, 1 H).
EI 338, 340, 342 (M ⁺ , M + 2, M + 4).

Production Example 29
Synthesis of 1-bromo-4-chloro-3- (4-isopropylbenzyl) -6-methoxybenzene Using 4-isopropylbenzoic acid instead of 4-ethoxybenzoic acid in the same manner as in Production Example 27 Synthesized.
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 1.24 (d, J = 7.0 Hz, 6 H) 2.82-2.94 (m, 1 H) 3.87 (s, 3 H) 3.97 (s, 2 H) 6.91 (s , 1 H) 7.05-7.20 (m, 4 H) 7.33 (s, 1 H).
EI 352, 354, 356 (M ⁺ , M + 2, M + 4).

Production Example 30
Synthesis of 1-benzyloxy-2-bromo-4- (4-ethoxybenzyl) -5-methylbenzene In the same manner as in Production Example 3, instead of 3-bromobenzaldehyde, 4-benzyloxy-3-bromo-6 -Synthesized using methylbenzaldehyde.
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 1.40 (t, J = 7.0 Hz, 3 H) 2.17 (s, 3 H) 3.82 (s, 2 H) 4.00 (q, J = 7.0 Hz, 2 H) 5.12 (s, 2 H) 6.76 (s, 1 H) 6.77-6.85 (m, 2 H) 6.96-7.05 (m, 2 H) 7.27 (s, 1 H) 7.30-7.44 (m, 3 H) 7.45- 7.53 (m, 2 H). EI 410 (M ⁺ ), 412 (M + 2).

Production Example 31
Synthesis of 1-bromo-2,4- (dibenzyloxy) -5- (4-ethoxybenzyl) benzene 5-bromo-2,4-dihydroxybenzoic acid (5.0 g, 0.0215 mol), potassium carbonate (9.8 g , 0.0710 mol), n-Bu ₄ NI (79 mg, 0.215 mmol), benzyl bromide (8.4 mL, 0.0710 mol) and N, N-dimethylformamide (40.0 mL) were stirred for 60 hours. Ice water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in tetrahydrofuran (150 mL). The solution was cooled to −15 ° C. and LiAlH ₄ (1.22 g, 0.0323 mol) was added in small portions. After the mixture was stirred at −5 ° C. for 1.5 hours, more LiAlH ₄ (0.41 g, 0.011 mol) was added. The reaction mixture was stirred at 5 ° C. for 1 hour, saturated aqueous ammonium chloride solution was carefully added, and the precipitated insoluble material was filtered through celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain 5-bromo-2,4- (dibenzyloxy) benzyl alcohol (12.1 g). This was used in the next reaction without purification.
Manganese dioxide (IV) (13.1 g, 0.150 mol) was added to a toluene (150 mL) solution of 5-bromo-2,4- (dibenzyloxy) benzyl alcohol (12.1 g). The mixture was stirred at room temperature for 15 hours, and further stirred at 80 ° C. for 4 hours and at 100 ° C. for 2 hours. Additional manganese dioxide (IV) (4.0 g) was added and the mixture was stirred at 100 ° C. for 4 hours. The mixture was cooled to room temperature, and the insoluble material was filtered through celite. The solid obtained by concentrating the filtrate was recrystallized from a mixed solvent of hexane-ethyl acetate to obtain 5-bromo-2,4- (dibenzyloxy) benzaldehyde (3.6 g, 43%) as a colorless powder. It was.
Next, the title compound was synthesized in the same manner as in Production Example 3 using 5-bromo-2,4- (dibenzyloxy) benzaldehyde instead of 3-bromobenzaldehyde.
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 1.40 (t, J = 7.0 Hz, 3 H) 3.84 (s, 2 H) 4.01 (q, J = 7.0 Hz, 2 H) 4.96 (s, 2 H) 5.07 (s, 2 H) 6.53 (s, 1 H) 6.75-6.82 (m, 2 H) 7.02-7.10 (m, 2 H) 7.20-7.48 (m, 11 H).
EI 525 (M ⁺ ), 527 (M + 2).

Production Example 32
Synthesis of 1-bromo-2-methoxy-4-methyl-5- (4-methylbenzyl) benzene To a solution of 4-methoxy-2-methylbenzoic acid (5.0 g, 0.0300 mol) in chloroform (60 mL), oxalyl Chloride (3.43 mL, 0.0400 mmol) and N, N-dimethylformamide (2 drops) were added. After stirring the reaction solution at room temperature for 1 hour, the reaction solvent was distilled off under reduced pressure. The resulting yellow oil was dissolved in chloroform (60 mL). Toluene (3.52 mL, 0.0330 mol) and aluminum chloride (8.02 g, 0.0601 mol) were added to this solution under ice cooling, and the reaction solution was stirred for 3 hours and a half with ice cooling. To the reaction solution was added 5% hydrochloric acid, and the mixture was extracted with chloroform. The organic phase was washed with 10% hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1) to give (4-methoxy-2-methyl) as a yellow oily substance. Phenyl) (4-methylphenyl) methanone (4.26 g, 58.9%) was obtained.
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 2.39 (s, 3 H) 2.42 (s, 3 H) 3.86 (s, 3 H) 6.74 (dd, J = 8.5, 2.56 Hz, 1 H) 6.81 (d , J = 2.6 Hz, 1 H) 7.21-7.27 (m, 2 H) 7.31 (d, J = 8.4 Hz, 1 H) 7.64-7.71 (m, 2 H)
ESI m / z = 263 (M + Na)
(4-methoxy-2-methylphenyl) (4-methylphenyl) methanone Et ₃ SiH in a mixed solution of chloroform (8 mL) and acetonitrile (32mL) (8.5mL, 0.0531mol) was added, under ice-cooling BF ₃ · Et ₂ O (4.5 mL, 0.0354 mol) was added dropwise. The reaction was warmed to room temperature and stirred at 50 ° C. for 1 hour. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1) to give colorless oil 4-methoxy-2-methyl-1 -(4-Methylbenzyl) benzene (3.89 g, 97%) was obtained.
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 2.21 (s, 3 H) 2.31 (s, 3 H) 3.78 (s, 3 H) 3.88 (s, 2 H) 6.65-6.74 (m, 2 H) 6.97 -7.03 (m, 3H) 7.03-7.11 (m, 2 H)
EI 226 (M ⁺ )
Br ₂ was added dropwise to a solution of 4-methoxy-2-methyl-1- (4-methylbenzyl) benzene in acetic acid (35 mL) under ice cooling. The reaction mixture was stirred at 110 ° C. for 2 hours. Under ice-cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1) to give the title compound as a yellow oil (4.21 g, 80%) Got.
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 2.20 (s, 3 H) 2.31 (s, 3 H) 3.85 (s, 2 H) 3.87 (s, 3 H) 6.71 (s, 1 H) 6.94-7.11 (m, 4 H) 7.26 (s, 1 H).
EI 304 (M ⁺ ), 306 (M + 2).

Production Example 33
Synthesis of 1-bromo-2-methoxy-4-methyl-5- (4-ethylbenzyl) benzene The title compound was synthesized in the same manner as in Production Example 32 using ethylbenzene instead of toluene.
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 1.22 (t, J = 7.6 Hz, 3 H) 2.20 (s, 3 H) 2.61 (q, J = 7.6 Hz, 2 H) 3.85 (s, 2 H) 3.87 (s, 3 H) 6.71 (s, 1 H) 6.97-7.14 (m, 4 H) 7.27 (s, 1 H).
EI 318 (M ⁺ ).

Production Example 34
Synthesis of 1-bromo-2-methoxy-4-methyl-5- (4-isopropylbenzyl) benzene The title compound was synthesized in the same manner as in Production Example 32 using cumene instead of toluene.
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 1.22 (s, 3 H) 1.24 (s, 3 H) 2.21 (s, 3 H) 2.81-2.92 (m, 1 H) 3.85 (bs, 2 H) 3.87 (s, 3 H) 6.71 (s, 1 H) 6.98-7.06 (m, 2 H) 7.10-7.16 (m, 2 H) 7.28 (s, 1 H).
EI 322 (M ⁺ ), 334 (M + 2).

Production Example 35
Synthesis of 2- (4-ethylbenzyl) phenol 1-Bromo-4-ethylbenzene (6.69 g, 0.036 mol) was added to a stirred solution of magnesium (17.2 g) and tetrahydrofuran (50 mL), and the mixture was heated to reflux. Then, a solution of 1-bromo-4-ethylbenzene (97.9 g, 0.529 mol) in tetrahydrofuran (300 mL) was added at room temperature over 2 hours. After stirring at room temperature for 1.5 hours, the reaction solution was cooled to 4 ° C., and a solution of 2-benzyloxybenzaldehyde (100 g, 0.471 mol) in tetrahydrofuran (100 mL) was added over 1 hour. The reaction solution was stirred for 2 hours and then poured into a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5) to give (2-benzyloxyphenyl) (4 -Ethylphenyl) methanol (152 g) was obtained.
¹ H-NMR (CDCl ₃ ) σ 1.23 (t, J = 7.6Hz, 3H), 2.64 (q, J = 7.6Hz, 2H), 2.90 (d, J = 5.6Hz, 1H), 5.03 (s, 2H ), 6.03 (d, 1H, J = 5.6Hz), 6.90-7.37 (m, 12H).
Next, a mixture of (2-benzyloxyphenyl) (4-ethylphenyl) methanol (78.5 g), 10% palladium activated carbon (5.2 g), concentrated hydrochloric acid (10.4 mL), and methanol (850 mL) was placed under a hydrogen atmosphere at room temperature. For 24 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the resulting residue was distilled under reduced pressure to give the title compound (56.8 g) as a colorless oil.
¹ H-NMR (CDCl ₃ ) σppm 1.21 (t, J = 7.7Hz, 3H), 2.62 (q, J = 7.7Hz, 2H), 4.00 (s, 2H), 4.64 (s, 1H), 6.77-7.18 (m, 8H).
EI 213 (M + H).

Production Example 36
Synthesis of 3- (4-ethylphenyloxy) -bromobenzene 3-bromophenol (2.3 g, 13.3 mmol), 4-ethylphenylboronic acid (1.0 g, 6.67 mmol), molecular sieve 4A (14.7 g), Cu ( A solution of OAc) ₂ (1.21 g, 6.67 mmol) and chloroform (25 mL) was stirred at room temperature for 3 minutes, and triethylamine (3.6 mL) and pyridine (2.7 mL) were added. After stirring for 15 hours, the insoluble material was filtered through celite. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5) to obtain 1.89 g of the title compound as a colorless oil.
EI 276 (M +), 278 (M + 2).

Production Example 37
Synthesis of 3-bromo-5- (4-ethoxybenzyl) pyridine To a mixture of 1M isopropylmagnesium chloride in tetrahydrofuran (21.1 mL) and tetrahydrofuran (10 mL) at 4 ° C., 3,5-dibromopyridine (5 g, 0.0211 mol) ) In tetrahydrofuran (25 mL) was added dropwise over 15 minutes. The reaction mixture was stirred at room temperature for 2.5 hours, 4-ethoxybenzaldehyde (2.93 mL, 0.0211 mol) was added, and the mixture was further stirred for 1.5 hours. Under ice-cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give (5-bromopyridin-3-yl) (4 -Ethoxyphenyl) methanol (5.0 g, 77%) was obtained as a yellow oil.
Next, a solution of (5-bromopyridin-3-yl) (4-ethoxyphenyl) methanol (2.5 g, 8.11 mmol) and Et ₃ SiH (5.1 mL, 40.6 mmol) in chloroform at 4 ° C. under trifluoroacetic acid ( 12.5 mL, 0.162 mol) was added dropwise, and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic phase was washed with saturated brine and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound (1.83 g, 77%) as colorless needles. )
1H NMR (300 MHz, CHLOROFORM-d) σppm 1.41 (t, J = 6.99 Hz, 3 H) 3.90 (s, 2 H) 4.02 (q, J = 6.99 Hz, 2 H) 6.85 (d, J = 8.70 Hz , 2 H) 7.07 (d, J = 8.70 Hz, 2 H) 7.59 (t, J = 2.02 Hz, 1 H) 8.40 (s, 1 H) 8.52 (s, 1 H)
ESI m / z = 292 (M + H), 294 (M + 2 + H).

Production Example 38
Synthesis of 1-bromo-3-[(2E or Z) -3- (4-ethylphenyl) prop-2-en-1-yl] benzene
To a mixture of (4-ethylbenzyl) triphenylphosphonium chloride (3.52 g, 8.44 mmol) and tetrahydrofuran (20 mL) was added 2M lithium diisopropylamine (heptane / tetrahydrofuran / ethylbenzene solution, 4.2 mL, 8.4 mmol) under ice-cooling. For 1 hour. This solution was added dropwise to a tetrahydrofuran solution (10 mL) of (3-bromophenyl) acetaldehyde (0.56 g, 2.81 mmol) and stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: chloroform = 20: 1) to give the title compound (0.41 g, 50%, E, colorless oil). / Z mixture).
1H NMR (300 MHz, CHLOROFORM-d) σppm 1.17-1.30 (m, J = 7.41, 7.41, 7.41 Hz, 3 H) 2.56-2.72 (m, 2 H) 3.47-3.68 (m, 2 H) 5.70-6.63 (m, 2 H) 7.04-7.46 (m, 8 H).
EI 300, 302 (M ⁺ , M + 2).

Production Example 39
Synthesis of 3-bromo-7- (4-methylbenzyl) -1-benzothiophene
N-bromosuccinimide (1.01 g, 5.72 mmol) was added to a solution of 7- (4-methylbenzyl) -1-benzothiophene (1.24 g, 5.20 mmol) in acetonitrile (30 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and diluted with ethyl acetate. The organic phase was washed with a 20 wt% aqueous sodium thiosulfate solution and saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 1 to 50: 1) to give the title compound (0.92) as a colorless powder. g, 56%).
1H NMR (300 MHz, CHLOROFORM-d) σppm 2.31 (s, 3 H) 4.12-4.26 (m, 2 H) 7.07-7.23 (m, 5 H) 7.37-7.50 (m, 2 H) 7.72 (d, J = 7.46 Hz, 1 H). EI 316, 318 (M ⁺ , M + 2).

Example 1

２,３,４,６−テトラ−O−ベンジル−１−C−[３−(４−エチルベンジル)フェニル]−５−チオ−D−グルコピラノースの合成
マグネシウム(55mg,2.25mmol)、１−ブロモ−３−(４−エチルベンジル)ベンゼン(496mg，1.80mmol；国際特許公開WO0127128号を参考に合成)及びテトラヒドロフラン(2.0mL)の混合物を1時間加熱還流した。さらに、室温で1時間攪拌した後に、反応液を０℃に冷やした。この溶液に、２,３,４,６−テトラ−O−ベンジル−５−チオ−D−グルコノ−１,５−ラクトン(500mg，0.901mmol)のテトラヒドロフラン(5.0mL)溶液を滴下し、室温で１時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、有機相を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィ−(ヘキサン:酢酸エチル＝5：1)にて精製し、無色油状物の表題化合物(440mg，65％)を得た。
¹H NMR (300 MHz, CHLOROFORM-d) σppm 1.19 (t, J=7.6 Hz, 3 H) 2.59 (q, J=7.6 Hz, 2 H) 3.04 (s, 1 H) 3.48 - 3.57 (m, 1 H) 3.64 (dd, J=10.1, 2.7 Hz, 1 H) 3.74 (d, J=10.1 Hz, 1 H) 3.88 - 4.17 (m, 6 H) 4.41 (d, J=10.1 Hz, 1 H) 4.52 (s, 2 H) 4.65 (d, J=10.7 Hz, 1 H) 4.81 - 4.95 (m, 3 H) 6.67 - 6.74 (m, 2 H) 7.03 - 7.21 (m, 10 H) 7.22 - 7.36 (m, 14 H) 7.47 - 7.57 (m, 2 H)．
ESI m/z = 773 (M+Na)．

Synthesis of 2,3,4,6-tetra-O-benzyl-1-C- [3- (4-ethylbenzyl) phenyl] -5-thio-D-glucopyranose Magnesium (55 mg, 2.25 mmol), 1- A mixture of bromo-3- (4-ethylbenzyl) benzene (496 mg, 1.80 mmol; synthesized with reference to International Patent Publication No. WO0127128) and tetrahydrofuran (2.0 mL) was heated to reflux for 1 hour. Furthermore, after stirring at room temperature for 1 hour, the reaction solution was cooled to 0 ° C. To this solution was added dropwise a solution of 2,3,4,6-tetra-O-benzyl-5-thio-D-glucono-1,5-lactone (500 mg, 0.901 mmol) in tetrahydrofuran (5.0 mL) at room temperature. Stir for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound (440 mg, 65%) as a colorless oil. Got.
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 1.19 (t, J = 7.6 Hz, 3 H) 2.59 (q, J = 7.6 Hz, 2 H) 3.04 (s, 1 H) 3.48-3.57 (m, 1 H) 3.64 (dd, J = 10.1, 2.7 Hz, 1 H) 3.74 (d, J = 10.1 Hz, 1 H) 3.88-4.17 (m, 6 H) 4.41 (d, J = 10.1 Hz, 1 H) 4.52 (s, 2 H) 4.65 (d, J = 10.7 Hz, 1 H) 4.81-4.95 (m, 3 H) 6.67-6.74 (m, 2 H) 7.03-7.21 (m, 10 H) 7.22-7.36 (m , 14 H) 7.47-7.57 (m, 2 H).
ESI m / z = 773 (M + Na).

Example 2
Synthesis of 2,3,4,6-tetra-O-benzyl-1-C- [3- (4-ethylbenzyl) phenyl] -5-thio-D-glucopyranose via an art complex 1-bromo-3- A mixture of (4-ethylbenzyl) benzene (1.0 g, 3.63 mmol) and diethyl ether (10 mL) was cooled to −78 ° C., and a 2.6 M n-butyllithium hexane solution (1.4 mL) was added under a stream of argon. . After stirring for 20 minutes, the reaction mixture was warmed to −20 ° C. and stirred for 45 minutes. This solution was added dropwise using a cannula to a solution of CuI (347 mg, 1.82 mmol) in diethyl ether (10 mL). During dripping, this soapy liquid turned black and was heated to -9 ° C. After dropwise addition, the mixture was stirred at −15 ° C. for 15 minutes, and 2,3,4,6-tetra-O-benzyl-5-thio-D-glucono-1,5-lactone (671 mg, 1.21 mmol) in diethyl ether ( 4.0 mL) solution was added dropwise and stirred for 20 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (1.0 g) as a colorless oil. It was. The NMR spectrum was consistent with Example 1.

Example 3

(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[３−(４−エチルベンジル)フェニル]−１−チオ−D−グルシトールの合成
２,３,４,６−テトラ−O−ベンジル−１−C−[３−(４−エチルベンジル)フェニル]−５−チオ−D−グルコピラノース(410mg，0.546mmol)のジクロロメタン(20mL)溶液に、−１８℃にて、Et₃SiH（0.523mL, 3.28mmol）とBF₃・Et₂O（0.276mL, 2.18mmol）を順次加え、0.5時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出し、有機相を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィ−(ヘキサン:酢酸エチル＝10:１)にて精製し、無色粉末状物質の表題化合物(250mg，62％)を得た。
¹H NMR (300 MHz, CHLOROFORM-d) σppm 1.19 (t, J=7.6 Hz, 3 H) 2.59 (q, J=7.6 Hz, 2 H) 3.05 - 3.16 (m, 1 H) 3.53 (t, J=8.9 Hz, 1 H) 3.67 - 3.99 (m, 8H) 4.47 (d, J=10．0 Hz, 1 H) 4.53 (s, 2 H) 4.60 (d, J=10.7 Hz, 1 H) 4.85 - 4.94 (m, 3 H) 6.62 - 6.69 (m, 2 H) 7.00 - 7.20 (m, 10 H) 7.22 - 7.36 (m, 16 H)．
ESI m/Z = 757 (M+Na).
mp 100.0−102.5℃．

Synthesis of (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [3- (4-ethylbenzyl) phenyl] -1-thio-D-glucitol 2,3 , 4,6-tetra-O-benzyl-1-C- [3- (4-ethylbenzyl) phenyl] -5-thio-D-glucopyranose (410 mg, 0.546 mmol) in dichloromethane (20 mL) At 18 ° C., Et ₃ SiH (0.523 mL, 3.28 mmol) and BF ₃ .Et ₂ O (0.276 mL, 2.18 mmol) were sequentially added and stirred for 0.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give the title compound (250 mg, 62%) as a colorless powdery substance. )
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 1.19 (t, J = 7.6 Hz, 3 H) 2.59 (q, J = 7.6 Hz, 2 H) 3.05-3.16 (m, 1 H) 3.53 (t, J = 8.9 Hz, 1 H) 3.67-3.99 (m, 8H) 4.47 (d, J = 10.0 Hz, 1 H) 4.53 (s, 2 H) 4.60 (d, J = 10.7 Hz, 1 H) 4.85- 4.94 (m, 3 H) 6.62-6.69 (m, 2 H) 7.00-7.20 (m, 10 H) 7.22-7.36 (m, 16 H).
ESI m / Z = 757 (M + Na).
mp 100.0-102.5 ° C.

Example 4

(１S)−１,５−アンヒドロ−１−[３−(４−エチルベンジル)フェニル]−１−チオ−D−グルシトールの合成
(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[３−(４−エチルベンジル)フェニル]−１−チオ−D−グルシトール(200mg，0.272mmol)のジクロロメタン(20mL)溶液に、−７８℃にて、１M BBr₃のジクロロメタン溶液(4.08mL)を滴下した。この温度で、2.5時間攪拌した後に、メタノール(5.0mL)とピリジン(3.0mL)を順次加えた。この混合物を室温まで温め、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィ−(クロロホルム:メタノール＝10:１)にて精製し、無色アモルファスの表題化合物(23mg，23％)を得た。
¹H NMR (300 MHz, METHANOL-d₄) σppm 1.19 (t, J=7.6 Hz, 3 H) 2.58 (q, J=7.6 Hz, 2 H) 2.95 - 3.03 (m, 1 H) 3.20 - 3.28 (m, 1 H) 3.60 (dd, J=10.3, 9.0 Hz, 1 H) 3.70 - 3.78 (m, 3 H) 3.88 - 3.98 (m, 3 H) 7.09 (brs, 5 H) 7.17 - 7.23 (m, 3 H)．
ESI m/z = 397 (M+Na), 373 (M-H)．

Synthesis of (1S) -1,5-anhydro-1- [3- (4-ethylbenzyl) phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [3- (4-ethylbenzyl) phenyl] -1-thio-D-glucitol (200 mg, 0.272 mmol) ) In dichloromethane (20 mL) at −78 ° C. was added dropwise 1 M BBr ₃ in dichloromethane (4.08 mL). After stirring at this temperature for 2.5 hours, methanol (5.0 mL) and pyridine (3.0 mL) were sequentially added. The mixture was warmed to room temperature and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain a colorless amorphous title compound (23 mg, 23%).
¹ H NMR (300 MHz, METHANOL-d ₄ ) σppm 1.19 (t, J = 7.6 Hz, 3 H) 2.58 (q, J = 7.6 Hz, 2 H) 2.95-3.03 (m, 1 H) 3.20-3.28 ( m, 1 H) 3.60 (dd, J = 10.3, 9.0 Hz, 1 H) 3.70-3.78 (m, 3 H) 3.88-3.98 (m, 3 H) 7.09 (brs, 5 H) 7.17-7.23 (m, 3 H).
ESI m / z = 397 (M + Na), 373 (MH).

Example 5

２,３,４,６−テトラ−O−ベンジル−１−C−[２−メトキシ−４−メチル−５−(４−エトキシベンジル)フェニル]−５−チオ−D−グルコピラノースの合成
マグネシウム(41mg，1.67mmol)、１−ブロモ−３−(４−エトキシベンジル)−６−メトキシ−４−メチルベンゼン (0.51g，1.51mmol)及びテトラヒドロフラン(2mL)の混合物に１,２−ジブロモエタン(5滴)を加えた。この混合物を1時間加熱還流した後、室温まで放置してGrignard試薬を調製した。２,３,４,６−テトラ−Ｏ−ベンジル−５−チオ−Ｄ−グルコノ−１,５−ラクトン(0.76g，1.38mmol)のテトラヒドロフラン(5mL)溶液に氷冷下1.0M i−プロピルマグネシウムクロリドのテトラヒドロフラン溶液(1.40mL)及び調製したGrignard試薬を順次滴下し30分間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、有機相を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィ−(ヘキサン:酢酸エチル＝4：1)にて精製し、黄色油状の表題化合物を(0.76g，68％)を得た。
¹H NMR (300 MHz, CHLOROFORM-ｄ) σ ppm 1.37 (t, J=6.92 Hz, 3 H) 2.21 (s, 3 H) 3.51 - 4.20 (m, 12 H) 3.85 - 3.89 (m, 3 H) 4.51 (s, 2 H) 4.65 (d, J=10.72 Hz, 1 H) 4.71 (d, J=5.75 Hz, 1 H) 4.78 - 4.99 (m, 3 H) 6.59 - 7.43 (m, 26 H)

Synthesis of 2,3,4,6-tetra-O-benzyl-1-C- [2-methoxy-4-methyl-5- (4-ethoxybenzyl) phenyl] -5-thio-D-glucopyranose 41 mg, 1.67 mmol), 1-bromo-3- (4-ethoxybenzyl) -6-methoxy-4-methylbenzene (0.51 g, 1.51 mmol) and tetrahydrofuran (2 mL) in a mixture of 1,2-dibromoethane (5 Drop) was added. The mixture was heated to reflux for 1 hour and then allowed to stand at room temperature to prepare Grignard reagent. To a solution of 2,3,4,6-tetra-O-benzyl-5-thio-D-glucono-1,5-lactone (0.76 g, 1.38 mmol) in tetrahydrofuran (5 mL) was added 1.0 M i-propylmagnesium under ice-cooling. A solution of chloride in tetrahydrofuran (1.40 mL) and the prepared Grignard reagent were added dropwise successively and stirred for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound as a yellow oil (0.76 g, 68% )
¹ H NMR (300 MHz, CHLOROFORM-d) σ ppm 1.37 (t, J = 6.92 Hz, 3 H) 2.21 (s, 3 H) 3.51-4.20 (m, 12 H) 3.85-3.89 (m, 3 H) 4.51 (s, 2 H) 4.65 (d, J = 10.72 Hz, 1 H) 4.71 (d, J = 5.75 Hz, 1 H) 4.78-4.99 (m, 3 H) 6.59-7.43 (m, 26 H)

Example 6

(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[２−メトキシ−４−メチル−５−(４−エトキシベンジル)フェニル] −１−チオ−D−グルシトールの合成
２,３,４,６−テトラ−O−ベンジル−１−C−[２−メトキシ−４−メチル−５−(４−エトキシベンジル)フェニル]−５−チオ−D−グルコピラノース(840mg，1.04mmol)のアセトニトリル(18mL)溶液に、−１８℃にて、Et₃SiH（0.415mL, 2.60mmol）とBF₃・Et₂O（0.198mL, 1.56mmol）を順次加え、１時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機相を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィ−(ヘキサン:酢酸エチル＝４:１)にて精製し、表題化合物(640mg，77％)を得た。
¹H NMR (600 MHz, CHLOROFORM-ｄ) σppm 1.35 (t, J=6.88 Hz, 3 H) 2.21 (s, 3 H) 3.02 - 3.21 (m, 1 H) 3.55 (t, J=9.40 Hz, 1 H) 3.71 (s, 1 H) 3.74 - 3.97 (m, 10 H) 4.01 (s, 1 H) 4.45 - 4.56 (m, 3 H) 4.60 (d, J=10.55 Hz, 2 H) 4.86 (s, 2 H) 4.90 (d, J=10.55 Hz, 1 H) 6.58 - 6.76 (m, 5 H) 6.90 (d, J=7.34 Hz, 1 H) 7.09 - 7.19 (m, 5 H) 7.23 - 7.35 (m, 15 H).
ESI m/z = 812 (M+NH₄)．

(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2-methoxy-4-methyl-5- (4-ethoxybenzyl) phenyl] -1-thio- Synthesis of D-glucitol 2,3,4,6-Tetra-O-benzyl-1-C- [2-methoxy-4-methyl-5- (4-ethoxybenzyl) phenyl] -5-thio-D-gluco To a solution of pyranose (840 mg, 1.04 mmol) in acetonitrile (18 mL), Et ₃ SiH (0.415 mL, 2.60 mmol) and BF ₃ .Et ₂ O (0.198 mL, 1.56 mmol) were sequentially added at −18 ° C. Stir for hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the title compound (640 mg, 77%).
¹ H NMR (600 MHz, CHLOROFORM-d) σppm 1.35 (t, J = 6.88 Hz, 3 H) 2.21 (s, 3 H) 3.02-3.21 (m, 1 H) 3.55 (t, J = 9.40 Hz, 1 H) 3.71 (s, 1 H) 3.74-3.97 (m, 10 H) 4.01 (s, 1 H) 4.45-4.56 (m, 3 H) 4.60 (d, J = 10.55 Hz, 2 H) 4.86 (s, 2 H) 4.90 (d, J = 10.55 Hz, 1 H) 6.58-6.76 (m, 5 H) 6.90 (d, J = 7.34 Hz, 1 H) 7.09-7.19 (m, 5 H) 7.23-7.35 (m , 15 H).
ESI m / z = 812 (M + NH ₄ ).

Example 7

(１S)−１,５−アンヒドロ−１−[３−(４−エトキシベンジル)−６−メトキシ−４−メチルフェニル]−１−チオ−D−グルシトールの合成
(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[２−メトキシ−４−メチル−５−(４−エトキシベンジル)フェニル] −１−チオ−D−グルシトール(630mg，0.792mmol)、２０％水酸化パラジウム活性炭（650mg）及び酢酸エチル(10mL)−エタノール(10mL)の混合物を水素雰囲気下、室温で６６時間撹拌した。反応液中の不溶物をセライトを通してろ過し、そのろ液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィ−(クロロホルム:メタノール＝10:１)にて精製し、無色粉末の表題化合物(280mg，81％)を0.5水和物として得た。
1H NMR (600 MHz, METHANOL- d₄) σppm 1.35 (t, J=6.9 Hz, 3 H) 2.17 (s, 3 H) 2.92 - 3.01 (m, 1 H) 3.24 (t, J=8.71 Hz, 1 H) 3.54 - 3.60 (m, 1 H) 3.72 (dd, J=11.5, 6.4 Hz, 1 H) 3.81 (s, 3 H) 3.83 (s, 2 H) 3.94 (dd, J=11.5, 3.7 Hz, 1 H) 3.97 (q, J=6.9 Hz, 2 H) 4.33 (s, 1 H) 6.77 (d, J=8.3 Hz, 2 H) 6.76 (s, 1 H) 6.99 (d, J=8.3 Hz, 2 H) 7.10 (s, 1 H). ESI m/z = 452 (M+NH4+), 493 (M+CH3CO2-). mp 155.0-157.0℃. Anal. Calcd for C₂₃H₃₀O₆S0.5H₂O: C, 62.28; H, 7.06. Found: C, 62.39; H, 7.10.
実施例８

Synthesis of (1S) -1,5-anhydro-1- [3- (4-ethoxybenzyl) -6-methoxy-4-methylphenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2-methoxy-4-methyl-5- (4-ethoxybenzyl) phenyl] -1-thio- A mixture of D-glucitol (630 mg, 0.792 mmol), 20% palladium hydroxide activated carbon (650 mg) and ethyl acetate (10 mL) -ethanol (10 mL) was stirred at room temperature for 66 hours under a hydrogen atmosphere. Insoluble matters in the reaction solution were filtered through celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain the title compound (280 mg, 81%) as a colorless powder as a 0.5 hydrate.
1H NMR (600 MHz, METHANOL- d ₄ ) σppm 1.35 (t, J = 6.9 Hz, 3 H) 2.17 (s, 3 H) 2.92-3.01 (m, 1 H) 3.24 (t, J = 8.71 Hz, 1 H) 3.54-3.60 (m, 1 H) 3.72 (dd, J = 11.5, 6.4 Hz, 1 H) 3.81 (s, 3 H) 3.83 (s, 2 H) 3.94 (dd, J = 11.5, 3.7 Hz, 1 H) 3.97 (q, J = 6.9 Hz, 2 H) 4.33 (s, 1 H) 6.77 (d, J = 8.3 Hz, 2 H) 6.76 (s, 1 H) 6.99 (d, J = 8.3 Hz, 2H) 7.10 (s, 1 H). ESI m / z = 452 (M + NH4 +), 493 (M + CH3CO2-). Mp 155.0-157.0 ℃. Anal. Calcd for C ₂₃ H ₃₀ O ₆ S0.5H ₂ O: C, 62.28; H, 7.06. Found: C, 62.39; H, 7.10.
Example 8

２,３,４,６−テトラ−O−ベンジル−１−C−[２−(ベンジルオキシ)−５−(４−エトキシベンジル)フェニル]−５−チオ−D−グルコピラノースの合成
マグネシウム(175mg，7．20mmol)、１−(ベンジルオキシ)−２−ブロモ−４−(４−エトキシベンジル)ベンゼン(2.29g，5.76mmol)及びテトラヒドロフラン(6.0mL)の混合物に１,２−ジブロモエタン(３滴)を加え、この混合物を1時間加熱還流した。反応液を室温に冷却し、この溶液に、２,３,４,６−テトラ−O−ベンジル−５−チオ−D−グルコノ−１,５−ラクトン(1.6g，2.9mmol)のテトラヒドロフラン(5.0mL)を滴下し、室温で１時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、有機相を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィ−(ヘキサン:酢酸エチル＝6：1)にて精製し、淡黄色粉末の表題化合物(1.48g，59％)を得た。
¹H NMR (300 MHz, CHLOROFORM-d) σppm 1.38 (t, J=7.0 Hz, 3 H) 3.48 - 3.71 (m, 2 H) 3.77 - 4.10 (m, 9 H) 4.51 (brs, 2 H) 4.59 - 4.74 (m, 2 H) 4.77 - 4.94 (m, 3 H) 5.09 (s, 2 H) 6.64 - 7.40 (m, 32 H)．
ESI m/z = 895 (M+Na)．
実施例９

Synthesis of 2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5- (4-ethoxybenzyl) phenyl] -5-thio-D-glucopyranose Magnesium (175 mg , 7.20 mmol), 1- (benzyloxy) -2-bromo-4- (4-ethoxybenzyl) benzene (2.29 g, 5.76 mmol) and tetrahydrofuran (6.0 mL) in a mixture of 1,2-dibromoethane (3 The mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, and 2,3,4,6-tetra-O-benzyl-5-thio-D-glucono-1,5-lactone (1.6 g, 2.9 mmol) in tetrahydrofuran (5.0 g) was cooled to room temperature. mL) was added dropwise and stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to give the title compound (1.48 g, 59%) as a pale yellow powder. )
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 1.38 (t, J = 7.0 Hz, 3 H) 3.48-3.71 (m, 2 H) 3.77-4.10 (m, 9 H) 4.51 (brs, 2 H) 4.59 -4.74 (m, 2 H) 4.77-4.94 (m, 3 H) 5.09 (s, 2 H) 6.64-7.40 (m, 32 H).
ESI m / z = 895 (M + Na).
Example 9

(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[２−(ベンジルオキシ)−５−(４−エトキシベンジル)フェニル]−１−チオ−D−グルシトールの合成
２,３,４,６−テトラ−O−ベンジル−１−C−[２−(ベンジルオキシ)−５−(４−エトキシベンジル)フェニル]−５−チオ−D−グルコピラノース(850mg，0.974mmol)のクロロホルム(8.0mL)−アセトニトリル(8.0mL)溶液に、−２０℃にて、Et₃SiH（0.933mL, 5.84mmol）とBF₃・Et₂O（0.494mL, 3.90mmol）を順次加え、１時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出し、有機相を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィ−(ヘキサン:酢酸エチル＝8:１)にて精製し、無色粉末状物質の表題化合物(810mg，97％)を得た。
¹H NMR (300 MHz, CHLOROFORM-d) σppm 1.36 (t, J=7.0 Hz, 3 H) 3.04 - 3.18 (m, 1 H) 3.54 (t, J=8.4 Hz, 1 H) 3.65 - 3.76 (m, 1 H) 3.77 - 4.06 (m, 8 H) 4.40 - 4.73 (m, 5 H) 4.83 - 5.12 (m, 5 H) 6.62 - 6.87 (m, 5 H) 6.92 - 7.46 (m, 27 H)．
ESI m/z = 879(M+Na)
実施例１０

(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-ethoxybenzyl) phenyl] -1-thio-D Synthesis of Glucitol 2,3,4,6-Tetra-O-benzyl-1-C- [2- (benzyloxy) -5- (4-ethoxybenzyl) phenyl] -5-thio-D-glucopyranose ( 850 mg, 0.974 mmol) in chloroform (8.0 mL) -acetonitrile (8.0 mL) at −20 ° C., Et ₃ SiH (0.933 mL, 5.84 mmol) and BF ₃ .Et ₂ O (0.494 mL, 3.90 mmol) Were sequentially added and stirred for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1) to give the title compound (810 mg, 97%) as a colorless powder. )
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 1.36 (t, J = 7.0 Hz, 3 H) 3.04-3.18 (m, 1 H) 3.54 (t, J = 8.4 Hz, 1 H) 3.65-3.76 (m , 1 H) 3.77-4.06 (m, 8 H) 4.40-4.73 (m, 5 H) 4.83-5.12 (m, 5 H) 6.62-6.87 (m, 5 H) 6.92-7.46 (m, 27 H).
ESI m / z = 879 (M + Na)
Example 10

(１S)−１,５−アンヒドロ−１−[５−(４−エチルベンジル)−２−ヒドロキシフェニル]−１−チオ−D−グルシトールの合成
(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[２−(ベンジルオキシ)−５−(４−エトキシベンジル)フェニル]−１−チオ−D−グルシトール(810mg，0.954mmol)、２０％水酸化パラジウム活性炭（800mg）及び酢酸エチル(5.0mL)−エタノール(5.0mL)の混合物を水素雰囲気下、室温で４６時間撹拌した。反応液中の不溶物をセライトを通してろ過し、そのろ液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィ−(クロロホルム:メタノール＝10:１〜5：1)にて精製し、無色粉末の表題化合物(202mg，53％)を0.7水和物として得た。
¹H NMR (300 MHz, METHANOL-d₄) σppm 1.37 (t, J=7.0 Hz, 3 H) 2.94 - 3.05 (m, 1 H) 3.22 - 3.29 (m, 1 H) 3.60 (m, 1 H) 3.69 - 3.88 (m, 4 H) 3.90 - 4.04 (m, 3 H) 4.33 (d, J=10.6 Hz, 1 H) 6.71 (d, J=8.2 Hz, 1 H) 6.76 - 6.90 (m, 3 H) 7.03 - 7.15 (m, 3 H)．ESI m/z = 429 (M+Na), 405 (M-H)．mp 145.0-150.0℃．Anal. Calcd for C₂₂H₂₈O₆S0.7H₂O: C, 61.00; H, 6.86. Found: C, 60.81; H, 6.89.

Synthesis of (1S) -1,5-anhydro-1- [5- (4-ethylbenzyl) -2-hydroxyphenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-ethoxybenzyl) phenyl] -1-thio-D A mixture of glucitol (810 mg, 0.954 mmol), 20% palladium hydroxide activated carbon (800 mg) and ethyl acetate (5.0 mL) -ethanol (5.0 mL) was stirred at room temperature for 46 hours under a hydrogen atmosphere. Insoluble matters in the reaction solution were filtered through celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1 to 5: 1) to obtain the title compound (202 mg, 53%) as a colorless powder as 0.7 hydrate.
¹ H NMR (300 MHz, METHANOL-d ₄ ) σppm 1.37 (t, J = 7.0 Hz, 3 H) 2.94-3.05 (m, 1 H) 3.22-3.29 (m, 1 H) 3.60 (m, 1 H) 3.69-3.88 (m, 4 H) 3.90-4.04 (m, 3 H) 4.33 (d, J = 10.6 Hz, 1 H) 6.71 (d, J = 8.2 Hz, 1 H) 6.76-6.90 (m, 3 H ) 7.03-7.15 (m, 3 H). ESI m / z = 429 (M + Na), 405 (MH). mp 145.0-150.0 ° C. Anal. Calcd for C ₂₂ H ₂₈ O ₆ S0.7H ₂ O: C, 61.00; H, 6.86. Found: C, 60.81; H, 6.89.

Example 11

(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[４−クロロ−３−(４−エトキシ−2−メチルベンジル)フェニル]−１−チオ−D−グルシトールの合成
マグネシウム(1.11g，45.7mmol)、２−(５−ブロモ−２−クロロフェニル)−１,３−ジオキソラン(9.64g，36.5mmol)及びテトラヒドロフラン(20mL)の混合物に１,２−ジブロモエタン(5滴)を加え、この混合物を2時間加熱還流した。反応液を室温に冷却し、この溶液に、２,３,４,６−テトラ−O−ベンジル−５−チオ−D−グルコノ−１,５−ラクトン(10.14g，36.5mmol)のテトラヒドロフラン(15mL)を滴下し、室温で30分間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、有機相を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィ−(ヘキサン:酢酸エチル＝4：1〜3：1)にて精製し、無色アモルファスの２,３,４,６−テトラ−O−ベンジル−１−C−[４−クロロ−３−(１,３−ジオキソラン−２−イル)フェニル]−５−チオ−D−グルコピラノース (11.81g，87％)を得た。

(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [4-chloro-3- (4-ethoxy-2-methylbenzyl) phenyl] -1-thio- Synthesis of D-glucitol To a mixture of magnesium (1.11 g, 45.7 mmol), 2- (5-bromo-2-chlorophenyl) -1,3-dioxolane (9.64 g, 36.5 mmol) and tetrahydrofuran (20 mL) 1,2- Dibromoethane (5 drops) was added and the mixture was heated to reflux for 2 hours. The reaction was cooled to room temperature, and 2,3,4,6-tetra-O-benzyl-5-thio-D-glucono-1,5-lactone (10.14 g, 36.5 mmol) in tetrahydrofuran (15 mL) was cooled to room temperature. ) Was added dropwise and stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 to 3: 1) to give colorless amorphous 2,3,4. , 6-Tetra-O-benzyl-1-C- [4-chloro-3- (1,3-dioxolan-2-yl) phenyl] -5-thio-D-glucopyranose (11.81 g, 87%). Obtained.

¹ H NMR (300 MHz, CHLOROFORM-d) σ ppm 3.06 (s, 1 H) 3.47-3.58 (m, 1 H) 3.64 (dd, J = 10.0, 2.9 Hz, 1 H) 3.83-4.21 (m, 9 H) 4.48-4.56 (m, 3 H) 4.66 (d, J = 10.6 Hz, 1 H) 4.82-4.97 (m, 3 H) 6.15 (s, 1 H) 6.77 (dd, J = 7.9, 1.5 Hz, 2 H) 7.08-7.21 (m, 5 H) 7.23-7.37 (m, 14 H) 7.55 (dd, J = 8.4, 2.5 Hz, 1 H) 7.92 (d, J = 2.5 Hz, 1 H).

Next, 2,3,4,6-tetra-O-benzyl-1-C- [4-chloro-3- (1,3-dioxolan-2-yl) phenyl] -5-thio-D-glucopyranose To a solution of (6.01 g, 8.12 mmol) in tetrahydrofuran (50 mL) was added 6M hydrochloric acid (120 mL) under ice cooling, and the mixture was stirred at room temperature for 2 days. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give colorless amorphous 2,3,4,6-tetra. -O-Benzyl-1-C- (4-chloro-3-formylphenyl) -5-thio-D-glucopyranose (4.53 g, 80%) was obtained.

¹H NMR (300 MHz, CHLOROFORM-d) σppm 3.14 (s, 1 H) 3.43 - 3.58 (m, 1 H) 3.63 (dd, J=10.0, 2.6 Hz, 1 H) 3.87 - 4.16 (m, 5 H) 4.45 - 4.72 (m, 4 H) 4.80 - 5.05 (m, 3 H) 6.73 (d, J=7.8 Hz, 2 H) 7.02 - 7.43 (m, 19 H) 7.74 (dd, J=8.4, 2.5 Hz, 1 H) 8.06 (d, J=2.5 Hz, 1 H) 10.39 (s, 1 H).

¹ H NMR (300 MHz, CHLOROFORM-d) σppm 3.14 (s, 1 H) 3.43-3.58 (m, 1 H) 3.63 (dd, J = 10.0, 2.6 Hz, 1 H) 3.87-4.16 (m, 5 H ) 4.45-4.72 (m, 4 H) 4.80-5.05 (m, 3 H) 6.73 (d, J = 7.8 Hz, 2 H) 7.02-7.43 (m, 19 H) 7.74 (dd, J = 8.4, 2.5 Hz , 1 H) 8.06 (d, J = 2.5 Hz, 1 H) 10.39 (s, 1 H).

Next, a 2.6 M n-butyllithium hexane solution (1.6 mL) was added to a mixture of 1-bromo-4-ethoxy-2-methylbenzene (0.94 g, 4.37 mmol) and tetrahydrofuran (12 mL) at -78 ° C. It was. After stirring for 1 hour, 2,3,4,6-tetra-O-benzyl-1-C- (4-chloro-3-formylphenyl) -5-thio-D-glucopyranose (1.52 g, 2.18 mmol) Of tetrahydrofuran (10 mL) was added, and the mixture was further stirred for 20 minutes, and the temperature of the reaction mixture was raised to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 2,3,3 as a yellow amorphous diastereomeric mixture. 4,6-Tetra-O-benzyl-1-C- {4-chloro-3-[(4-ethoxy-2-methylphenyl) (hydroxy) methyl] phenyl} -5-thio-D-glucopyranose (1.72 g, 95%).

Then 2,3,4,6-tetra-O-benzyl-1-C- {4-chloro-3-[(4-ethoxy-2-methylphenyl) (hydroxy) methyl] phenyl} -5-thio- Et ₃ SiH (1.98 mL, 12.4 mmol) and BF ₃ • Et ₂ O (1.04 mL, 8.27 mmol) were added sequentially to a solution of D-glucopyranose (1.72 g, 2.06 mmol) in acetonitrile (20 mL) under ice cooling. It was. After stirring for 1 hour, the reaction solution was warmed to room temperature and stirred for 3 hours. A saturated aqueous sodium carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give colorless powdery (1S) -1,5- Anhydro-2,3,4,6-tetra-O-benzyl-1- [4-chloro-3- (4-ethoxy-2-methylbenzyl) phenyl] -1-thio-D-glucitol (1.01 g, 61 %).
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 1.40 (t, J = 7.0 Hz, 3 H) 2.14 (s, 3 H) 3.01-3.12 (m, 1 H) 3.48 (t, J = 8.9 Hz, 1 H) 3.65-4.06 (m, 10 H) 4.46-4.61 (m, 4 H) 4.80-4.91 (m, 3 H) 6.58 (dd, J = 8.2, 2.5 Hz, 1 H) 6.68-6.76 (m, 2 H) 6.81 (d, J = 8.4 Hz, 1 H) 6.98 (d, J = 2.2 Hz, 1 H) 7.10-7.39 (m, 21 H).

Example 12

(1S)−１,５−アンヒドロ−１−[４−クロロ−３−(４−エトキシ−２−メチルベンジル)フェニル]−１−チオ−D−グルシトールの合成
(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[４−クロロ−３−(４−エトキシ−2−メチルベンジル)フェニル]−１−チオ−D−グルシトール (0.99g，1.23mmol)のアニソール(10mL)溶液に、室温にてAlCl₃（0.83g，6.19mmol）を加え、３０分間攪拌した。反応液に氷水を加え、酢酸エチルで抽出し、有機相を1M塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィ−(クロロホルム:メタノール＝10:１)にて精製し、無色アモルファスの表題化合物(55mg，10％)を得た。
¹H NMR (300 MHz, METHANOL-d₄) σppm 1.37 (t, J=6.9 Hz, 3 H) 2.17 (s, 3 H) 2.90 - 3.01 (m, 1 H) 3.14 - 3.24 (m, 1 H) 3.54 (dd, J=10.3, 9.2 Hz, 1 H) 3.60 - 3.76 (m, 3 H) 3.86 - 4.06 (m, 5 H) 6.66 (dd, J=8.6, 2.7 Hz, 1 H) 6.75 (d, J=3.0 Hz, 1 H) 6.85 - 6.95 (m, 2 H) 7.19 (dd, J=8.2, 2.2 Hz, 1 H) 7.35 (d, J=8.2 Hz, 1 H).
ESI m/z = 461 (M+Na), 437 (M-H)．

Synthesis of (1S) -1,5-anhydro-1- [4-chloro-3- (4-ethoxy-2-methylbenzyl) phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [4-chloro-3- (4-ethoxy-2-methylbenzyl) phenyl] -1-thio- To a solution of D-glucitol (0.99 g, 1.23 mmol) in anisole (10 mL) was added AlCl ₃ (0.83 g, 6.19 mmol) at room temperature and stirred for 30 minutes. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain a colorless amorphous title compound (55 mg, 10%). It was.
¹ H NMR (300 MHz, METHANOL-d ₄ ) σppm 1.37 (t, J = 6.9 Hz, 3 H) 2.17 (s, 3 H) 2.90-3.01 (m, 1 H) 3.14-3.24 (m, 1 H) 3.54 (dd, J = 10.3, 9.2 Hz, 1 H) 3.60-3.76 (m, 3 H) 3.86-4.06 (m, 5 H) 6.66 (dd, J = 8.6, 2.7 Hz, 1 H) 6.75 (d, J = 3.0 Hz, 1 H) 6.85-6.95 (m, 2 H) 7.19 (dd, J = 8.2, 2.2 Hz, 1 H) 7.35 (d, J = 8.2 Hz, 1 H).
ESI m / z = 461 (M + Na), 437 (MH).

Example 13

(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[３−[４−(４−テトラヒドロピラニルオキシ)ベンジル]フェニル]−１−チオ−D−グルシトールの合成
1−ブロモ−4−(４−テトラヒドロピラニルオキシ)ベンゼン（0.545ｇ，2.12mmol）とテトラヒドロフラン（6ｍL）の混合物に、2.6 M ｎ−ブチルリチウムヘキサン溶液（0.8ｍL）を−７８℃にて加えた。1.5時間攪拌した後に、２,３,４,６−テトラ−O−ベンジル−１−C−(３−ホルミルフェニル)−５−チオ−D−グルコピラノース(0.70g, 1.06mmol) のテトラヒドロフラン（8ｍL）溶液を加えてさらに3時間攪拌し、反応液を室温まで昇温した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、有機相を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィ−(ヘキサン:酢酸エチル＝２：１)にて精製し、２,３,４,６−テトラ−O−ベンジル−１−C−[３−[[4−(４−テトラヒドロピラニルオキシ)フェニル](ヒドロキシ)メチル]フェニル]−５−チオ−D−グルコピラノース（0.67g, 76%）を得た。

(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [3- [4- (4-tetrahydropyranyloxy) benzyl] phenyl] -1-thio-D -Synthesis of glucitol
To a mixture of 1-bromo-4- (4-tetrahydropyranyloxy) benzene (0.545 g, 2.12 mmol) and tetrahydrofuran (6 mL), a 2.6 M n-butyllithium hexane solution (0.8 mL) was added at -78 ° C. It was. After stirring for 1.5 hours, 2,3,4,6-tetra-O-benzyl-1-C- (3-formylphenyl) -5-thio-D-glucopyranose (0.70 g, 1.06 mmol) in tetrahydrofuran (8 mL) The solution was added and stirred for another 3 hours, and the reaction solution was warmed to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 2,3,4,6-tetra-O—. Benzyl-1-C- [3-[[4- (4-tetrahydropyranyloxy) phenyl] (hydroxy) methyl] phenyl] -5-thio-D-glucopyranose (0.67 g, 76%) was obtained.

Then 2,3,4,6-tetra-O-benzyl-1-C- [3-[[4- (4-tetrahydropyranyloxy) phenyl] (hydroxy) methyl] phenyl] -5-thio-D -To a solution of glucopyranose (0.67 g 0.802 mmol) in acetonitrile (8 mL), add Et ₃ SiH (0.78 mL, 4.90 mmol) and BF ₃ · Et ₂ O (0.41 mL, 3.27 mmol) sequentially at -15 ° C. It was. After stirring for 1 hour, the reaction solution was warmed to room temperature and stirred for 3 hours. A saturated aqueous sodium carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (0.37 g, 57% as a colorless powder). )
1H NMR (300 MHz, CHLOROFORM-d) σ ppm 1.66-1.81 (m, 2 H) 1.88-2.02 (m, 2 H) 3.05-3.15 (m, 1 H) 3.47-3.59 (m, 3 H) 3.64- 4.00 (m, 10 H) 4.33-4.42 (m, 1 H) 4.46 (d, J = 9.95 Hz, 1 H) 4.52 (s, 2 H) 4.60 (d, J = 10.41 Hz, 1 H) 4.84-4.93 (m, 3 H) 6.60-6.67 (m, 2 H) 6.72-6.79 (m, 2 H) 6.99-7.19 (m, 8 H) 7.20-7.35 (m, 16 H). ESI m / Z = 824 ( M + NH4).

Example 14

(１S)−１,５−アンヒドロ−１−[３−[４−(４−テトラヒドロピラニルオキシ)ベンジル]フェニル]−１−チオ−D−グルシトールの合成
(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[３−[４−(４−テトラヒドロピラニルオキシ)ベンジル]フェニル]−１−チオ−D−グルシトールから実施例７と同様な方法で、アモルファス状の表題化合物(18mg)を得た。

Synthesis of (1S) -1,5-anhydro-1- [3- [4- (4-tetrahydropyranyloxy) benzyl] phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [3- [4- (4-tetrahydropyranyloxy) benzyl] phenyl] -1-thio-D -Amorphous title compound (18 mg) was obtained from glucitol in the same manner as in Example 7.

Example 15

２,３,４,６−テトラ−O−アリル−１−C−[４−クロロ−５−(４−エトキシベンジル) −２−メトキシフェニル]−５−チオ−D−グルコピラノースの合成
マグネシウム(171mg，7.03mmol)、１−ブロモ−４−クロロ−３−(４−エトキシベンジル)−６−メトキシベンゼン(2.0g，5.62mmol)及びテトラヒドロフラン(5mL)の混合物に１,２−ジブロモエタン(３滴)を加え、この混合物を３０分間加熱還流した。反応液を室温に冷却し、この溶液に、２,３,４,６−テトラ−O−アリル−５−チオ−D−グルコノ−１,５−ラクトン(1.5g，4.22mmol)のテトラヒドロフラン(20mL)を滴下し、室温で２時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、有機相を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィ−(ヘキサン:酢酸エチル＝6：1→5：1)にて精製し、淡黄色油状物質の表題化合物(1.41g，53％)を得た。
¹H NMR (300 MHz, CHLOROFORM-d) σppm 1.39 (t, J=7.0 Hz, 3 H) 3.36 - 3.47 (m, 1 H) 3.49 - 4.10 (m, 17 H) 4.10 - 4.44 (m, 4 H) 4.84 - 4.97 (m, 2 H) 5.08 - 5.35 (m, 5 H) 5.42 - 5.60 (m, 1 H) 5.75 - 6.07 (m, 3 H) 6.78 (d, J=8.6 Hz, 2 H) 6.92 (s, 1 H) 7.03 (d, J=8.6 Hz, 2 H) 7.32 (brs, 1 H)
ESI m/z = 653 (M+Na), 655(M+2+Na)．

Synthesis of 2,3,4,6-tetra-O-allyl-1-C- [4-chloro-5- (4-ethoxybenzyl) -2-methoxyphenyl] -5-thio-D-glucopyranose Magnesium ( 171 mg, 7.03 mmol), 1-bromo-4-chloro-3- (4-ethoxybenzyl) -6-methoxybenzene (2.0 g, 5.62 mmol) and tetrahydrofuran (5 mL) in a mixture of 1,2-dibromoethane (3 The mixture was heated to reflux for 30 minutes. The reaction solution was cooled to room temperature, and 2,3,4,6-tetra-O-allyl-5-thio-D-glucono-1,5-lactone (1.5 g, 4.22 mmol) in tetrahydrofuran (20 mL) was cooled to room temperature. ) Was added dropwise and stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1 → 5: 1) to give the title compound as a pale yellow oil ( 1.41 g, 53%).
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 1.39 (t, J = 7.0 Hz, 3 H) 3.36-3.47 (m, 1 H) 3.49-4.10 (m, 17 H) 4.10-4.44 (m, 4 H ) 4.84-4.97 (m, 2 H) 5.08-5.35 (m, 5 H) 5.42-5.60 (m, 1 H) 5.75-6.07 (m, 3 H) 6.78 (d, J = 8.6 Hz, 2 H) 6.92 (s, 1 H) 7.03 (d, J = 8.6 Hz, 2 H) 7.32 (brs, 1 H)
ESI m / z = 653 (M + Na), 655 (M + 2 + Na).

Example 16
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-allyl-1- [4-chloro-5- (4-ethoxybenzyl) -2-methoxyphenyl] -1-thio- Synthesis of D-glucitol 2,3,4,6-Tetra-O-allyl-1-C- [4-chloro-5- (4-ethoxybenzyl) -2-methoxyphenyl] -5-thio-D-gluco To a solution of pyranose (1.41 g, 2.23 mmol) in chloroform (20 mL) -acetonitrile (20 mL) at −15 ° C., Et ₃ SiH (2.16 mL, 13.4 mmol) and BF ₃ .Et ₂ O (1.13 mL, 8.92 mmol) ) Were sequentially added and stirred for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give the title compound (895 mg, 65%) as a colorless powdery substance. )
¹ H NMR (300 MHz, CHLOROFORM-d) σppm 1.39 (t, J = 7.0 Hz, 3 H) 2.95-3.04 (m, 1 H) 3.21-3.30 (m, 1 H) 3.41-3.79 (m, 5 H ) 3.81 (s, 3 H) 3.84-4.20 (m, 8H) 4.25-4.42 (m, 4 H) 4.81-4.91 (m, 2 H) 5.09-5.33 (m, 6 H) 5.34-5.52 (m, 1 H) 5.79-6.04 (m, 3 H) 6.78 (d, J = 8.9 Hz, 2 H) 6.87 (s, 1 H) 7.03 (d, J = 8.9 Hz, 2 H) 7.21 (brs, 1 H)
ESI m / z = 637 (M + Na), 639 (M + 2 + Na).

Example 17
Synthesis of (1S) -1,5-anhydro-1- [4-chloro-5- (4-ethoxybenzyl) -2-methoxyphenyl] -1-thio-D-glucitol

(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−アリル−１−[４−クロロ−５−(４−エトキシベンジル) −２−メトキシフェニル]−１−チオ−D−グルシトール(100mg，0.163mmol)、テトラキス（トリフェニルホスフィン）パラジウム（38mg，0.0325mmol）、N,N−ジメチルバルビツル酸（203mg，1.3mmol）及びテトラヒドロフラン (1.0mL)の混合物をアルゴン雰囲気下、９０℃で1.5時間撹拌した。反応液を室温まで冷却し飽和炭酸ナトリウム水溶液に加え、酢酸エチルで抽出し有機相を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィ−(クロロホルム:メタノール＝10:１→5:1)にて精製し、無色粉末状物質の表題化合物(63mg，85％)を得た。
1H NMR (600 MHz, METHANOL- d₄) σppm 1.35 (t, J=6.9 Hz, 3 H) 2.92 - 3.00 (m, 1 H) 3.22 (t, J=8.9 Hz, 1 H) 3.53 - 3.59 (m, 1 H) 3.72 (dd, J=11.7, 6.7 Hz, 1 H) 3.82 (s, 3 H) 3.88 - 3.95 (m, 3 H) 3.99 (q, J=6.9 Hz, 2 H) 6.79 (d, J=8.7 Hz, 2 H) 6.98 (s, 1 H) 7.06 (d, J=8.71Hz, 2 H) 7.20 (s, 1 H). ESI m/z = 477 (M+Na), 479 (M+2+Na), 453 (M-H), 455 (M+2-H). mp 177.0-179.0℃.

(1S) -1,5-Anhydro-2,3,4,6-tetra-O-allyl-1- [4-chloro-5- (4-ethoxybenzyl) -2-methoxyphenyl] -1-thio- A mixture of D-glucitol (100 mg, 0.163 mmol), tetrakis (triphenylphosphine) palladium (38 mg, 0.0325 mmol), N, N-dimethylbarbituric acid (203 mg, 1.3 mmol) and tetrahydrofuran (1.0 mL) under an argon atmosphere And stirred at 90 ° C. for 1.5 hours. The reaction mixture was cooled to room temperature, added to a saturated aqueous sodium carbonate solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1 → 5: 1) to give the title compound (63 mg) as a colorless powdery substance. 85%).
1H NMR (600 MHz, METHANOL- d ₄ ) σppm 1.35 (t, J = 6.9 Hz, 3 H) 2.92-3.00 (m, 1 H) 3.22 (t, J = 8.9 Hz, 1 H) 3.53-3.59 (m , 1 H) 3.72 (dd, J = 11.7, 6.7 Hz, 1 H) 3.82 (s, 3 H) 3.88-3.95 (m, 3 H) 3.99 (q, J = 6.9 Hz, 2 H) 6.79 (d, J = 8.7 Hz, 2 H) 6.98 (s, 1 H) 7.06 (d, J = 8.71 Hz, 2 H) 7.20 (s, 1 H). ESI m / z = 477 (M + Na), 479 (M + 2 + Na), 453 (MH), 455 (M + 2-H) .mp 177.0-179.0 ° C.

Example 18

(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[４−クロロ−３−(ｔ−ブトキシカルボニル)フェニル]−１−チオ−D−グルシトールの合成
2.6 M ｎ−ブチルリチウムヘキサン溶液（1.72ｍL）を1.0 M i−プロピルマグネシウムブロミド テトラヒドロフラン溶液（2.23ｍL）とテトラヒドロフラン(9mL)の混合物に−５℃にて加えた。0.5時間攪拌した後に、反応混合物を−78℃に冷やし、ｔ−ブチル ５−ブロモ−２−クロロベンゾエート(542mg, 1.86mmol)のテトラヒドロフラン(4.0ml)溶液を加えた。この溶液を1時間攪拌した後に、２,３,４,６−テトラ−O−ベンジル−５−チオ−D−グルコノ−１,５−ラクトン(430mg，0.798mmol)のテトラヒドロフラン(3.0mL)溶液を加えてさらに15分間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、有機相を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィ−(ヘキサン:酢酸エチル＝5：1)にて精製し、２,３,４,６−テトラ−O−ベンジル−１−C−[４−クロロ−３−(ｔ−ブトキシカルボニル)フェニル]−５−チオ−D−グルコピラノース(60mg，10％)を得た。
ESI m/z = 789(M+Na), 791(M+2+Na)

Of (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [4-chloro-3- (t-butoxycarbonyl) phenyl] -1-thio-D-glucitol Composition
A 2.6 M n-butyllithium hexane solution (1.72 mL) was added to a mixture of 1.0 M i-propylmagnesium bromide tetrahydrofuran solution (2.23 mL) and tetrahydrofuran (9 mL) at −5 ° C. After stirring for 0.5 hour, the reaction mixture was cooled to −78 ° C. and a solution of t-butyl 5-bromo-2-chlorobenzoate (542 mg, 1.86 mmol) in tetrahydrofuran (4.0 ml) was added. After stirring this solution for 1 hour, a solution of 2,3,4,6-tetra-O-benzyl-5-thio-D-glucono-1,5-lactone (430 mg, 0.798 mmol) in tetrahydrofuran (3.0 mL) was added. In addition, the mixture was further stirred for 15 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 2,3,4,6-tetra-O—. Benzyl-1-C- [4-chloro-3- (t-butoxycarbonyl) phenyl] -5-thio-D-glucopyranose (60 mg, 10%) was obtained.
ESI m / z = 789 (M + Na), 791 (M + 2 + Na)

Next, 2,3,4,6-tetra-O-benzyl-1-C- [4-chloro-3- (t-butoxycarbonyl) phenyl] -5-thio-D-glucopyranose (60 mg, 0.0782 mmol) in chloroform (1.0 mL) -acetonitrile (1.0 mL) at −40 ° C., Et ₃ SiH (0.031 mL, 0.195 mmol) and BF ₃ .Et ₂ O (0.015 mL, 0.117 mmol) were sequentially added. It was. After stirring for 1.5 hours, a saturated aqueous sodium carbonate solution was added, and the organic solvent was concentrated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the title compound (26 mg, 44%).
1H NMR (300 MHz, CHLOROFORM-d) σppm 1.61 (s, 9 H) 3.06-3.21 (m, 1 H) 3.51-3.64 (m, 1 H) 3.66-3.77 (m, 1 H) 3.78-4.06 (m , 5 H) 4.48-4.67 (m, 4 H) 4.84-4.95 (m, 3 H) 6.75 (dd, J = 7.54, 1.79 Hz, 2 H) 7.08-7.20 (m, 5 H) 7.24-7.46 (m , 15 H) 7.77 (d, J = 2.02 Hz, 1 H). ESI m / z = 768 (M + Na), 770 (M + 2 + Na).

Example 19

(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[４−クロロ−３−[[(４−エチルフェニル)アミノ]カルボニル]フェニル]−１−チオ−D−グルシトールの合成
(１S)−１,５−アンヒドロ−１−[４−クロロ−５−(４−エトキシベンジル) −２−メトキシフェニル]−１−チオ−D−グルシトール(30mg, 0.040mmol)のテトラヒドロフラン(2.0mL)溶液の濃塩酸(1.0mL)を加え、反応液を室温にて24時間、40℃にて2時間攪拌した後に、酢酸エチルを加えた。これを水、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[４−クロロ−３−カルボキシフェニル]−１−チオ−D−グルシトールを得た。

(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [4-chloro-3-[[(4-ethylphenyl) amino] carbonyl] phenyl] -1- Synthesis of thio-D-glucitol
(1S) -1,5-Anhydro-1- [4-chloro-5- (4-ethoxybenzyl) -2-methoxyphenyl] -1-thio-D-glucitol (30 mg, 0.040 mmol) in tetrahydrofuran (2.0 mL) ) Concentrated hydrochloric acid (1.0 mL) was added, and the reaction mixture was stirred at room temperature for 24 hours and at 40 ° C. for 2 hours, and then ethyl acetate was added. This was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [4-chloro-3-carboxyphenyl] -1-thio-D-glucitol was obtained.

Next, (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [4-chloro-3-carboxyphenyl] -1-thio-D-glucitol and 4- To a chloroform solution of ethylaniline (13 mg, 0.104 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (13 mg, 0.069 mmol) and 1-hydroxybenzotriazole (9 mg, 0.069 mmol) were added. . The reaction solution was stirred at room temperature for 21 hours, diluted with chloroform, and the organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the above anilide compound (22 mg).
1H NMR (300 MHz, CHLOROFORM-d) σppm 1.26 (t, J = 7.15 Hz, 3 H) 2.65 (q, J = 7.67 Hz, 1 H) 3.06-3.24 (m, 1 H) 3.50-3.61 (m, 1 H) 3.71 (dd, J = 9.87, 3.03 Hz, 1 H) 3.78-4.09 (m, 6 H) 4.52 (s, 2 H) 4.62 (t, J = 10.34 Hz, 2 H) 4.84-4.98 (m , 3 H) 6.75-6.85 (m, 2 H) 7.08-7.56 (m, 25 H) 7.72 (d, J = 2.02 Hz, 1 H). ESI m / Z = 769 (MH). Pale yellow powder.

Example 20

(１S)−１,５−アンヒドロ−１−[４−クロロ−３−[[(４−エチルフェニル)アミノ]カルボニル]フェニル]−１−チオ−D−グルシトールの合成
(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[４−クロロ−３−[[(４−エチルフェニル)アミノ]カルボニル]フェニル]−１−チオ−D−グルシトール(20mg, 0.025mmol)、トリフルオロ酢酸(0.5mL)、ジメチルスルフィド(0.3mL)、m−クレゾール(0.08mL)、エタンジチオール(0.02mL)の混合物に、−15℃にてトリフルオロメタンスルホン酸(0.1mL)を加えた。15分攪拌した後に、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィ−(クロロホルム:メタノール＝10:１)にて精製し、無色粉末状の表題化合物(6mg，54％)を得た。
1H NMR (600 MHz, METHANOL-d₄) σppm 1.23 (t, J=7.57 Hz, 3 H) 2.64 (q, J=7.79 Hz, 2 H) 3.00 - 3.07 (m, 1 H) 3.27 (t, J=8.71 Hz, 1 H) 3.59 - 3.64 (m, 1 H) 3.73 - 3.82 (m, 2 H) 3.89 (d, J=10.09 Hz, 1 H) 3.95 (dd, J=11.69, 3.44 Hz, 1 H) 7.20 (d, J=8.25 Hz, 2 H) 7.47 (s, 2 H) 7.53 (s, 1 H) 7.56 (d, J=8.71 Hz, 2 H). ESI m/Z = 438(M+Na), 440(M+2+Na). colorless powder.

Synthesis of (1S) -1,5-anhydro-1- [4-chloro-3-[[(4-ethylphenyl) amino] carbonyl] phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [4-chloro-3-[[(4-ethylphenyl) amino] carbonyl] phenyl] -1- To a mixture of thio-D-glucitol (20 mg, 0.025 mmol), trifluoroacetic acid (0.5 mL), dimethyl sulfide (0.3 mL), m-cresol (0.08 mL), ethanedithiol (0.02 mL) at −15 ° C. Trifluoromethanesulfonic acid (0.1 mL) was added. After stirring for 15 minutes, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give the title compound (6 mg, 54%) as a colorless powder. Obtained.
1H NMR (600 MHz, METHANOL-d ₄ ) σppm 1.23 (t, J = 7.57 Hz, 3 H) 2.64 (q, J = 7.79 Hz, 2 H) 3.00-3.07 (m, 1 H) 3.27 (t, J = 8.71 Hz, 1 H) 3.59-3.64 (m, 1 H) 3.73-3.82 (m, 2 H) 3.89 (d, J = 10.09 Hz, 1 H) 3.95 (dd, J = 11.69, 3.44 Hz, 1 H ) 7.20 (d, J = 8.25 Hz, 2 H) 7.47 (s, 2 H) 7.53 (s, 1 H) 7.56 (d, J = 8.71 Hz, 2 H). ESI m / Z = 438 (M + Na ), 440 (M + 2 + Na). Colorless powder.

Example 21

(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[３−(ヒドロキシメチル)フェニル]−１−チオ−D−グルシトールの合成
２,３,４,６−テトラ−O−ベンジル−１−C−(３−ホルミルフェニル)−５−チオ−D−グルコピラノース(4.0g, 6.05mmol) クロロホルム(35mL)−アセトニトリル(35mL)溶液に、−15℃にて、Et₃SiH（5.8mL, 36.3mmol）とBF₃・Et₂O（3.1mL, 24.2mmol）を順次加えた。1.5時間攪拌した後に、飽和炭酸水素ナトリウム水溶液を加え、混合物をクロロホルムで抽出し、有機相を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し得られた固体をヘキサン:酢酸エチル＝10:１にて洗浄し、無色粉末状物質の表題化合物(3.2g，77％)を得た。
1H NMR (300 MHz, CHLOROFORM-d) σppm 3.07 - 3.18 (m, 1 H) 3.55 (t, 1 H) 3.72 (dd, 1 H) 3.78 - 4.01 (m, 5 H) 4.46 - 4.69 (m, 6 H) 4.87 - 4.96 (m, 3 H) 6.69 (dd, J=7.69, 1.48 Hz, 2 H) 7.07 - 7.45 (m, 22 H)．

Synthesis of (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [3- (hydroxymethyl) phenyl] -1-thio-D-glucitol 2,3,4 , 6-tetra-O-benzyl-1-C- (3-formylphenyl) -5-thio-D-glucopyranose (4.0 g, 6.05 mmol) in a solution of chloroform (35 mL) -acetonitrile (35 mL) at −15 ° C. And Et ₃ SiH (5.8 mL, 36.3 mmol) and BF ₃ .Et ₂ O (3.1 mL, 24.2 mmol) were sequentially added. After stirring for 1.5 hours, a saturated aqueous sodium hydrogen carbonate solution was added, the mixture was extracted with chloroform, the organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting solid was washed with hexane: ethyl acetate = 10: 1 to obtain the title compound (3.2 g, 77%) as a colorless powdery substance.
1H NMR (300 MHz, CHLOROFORM-d) σppm 3.07-3.18 (m, 1 H) 3.55 (t, 1 H) 3.72 (dd, 1 H) 3.78-4.01 (m, 5 H) 4.46-4.69 (m, 6 H) 4.87-4.96 (m, 3 H) 6.69 (dd, J = 7.69, 1.48 Hz, 2 H) 7.07-7.45 (m, 22 H).

Example 22

(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[３−(ブロモメチル)フェニル]−１−チオ−D−グルシトールの合成
(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[３−(ヒドロキシメチル)フェニル]−１−チオ−D−グルシトール(100mg, 0.155mmol)のテトラヒドロフラン(1.5mL)溶液に4℃にて、メタンスルホニルクロリド(0.018mL)とトリエチルアミン(0.021mL)を加えた。反応混合物を室温で3時間攪拌し、酢酸エチルで希釈した。これを、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し、(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[３−(メタンスルホニルオキシメチル)フェニル]−１−チオ−D−グルシトール(150mg)を得た。次に、(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[３−(メタンスルホニルオキシメチル)フェニル]−１−チオ−D−グルシトール(150mg)、LiBr(40mg, 0.466mmol)とアセトン(3mL)の混合物を2時間室温にて攪拌した。反応液を濃縮後、酢酸エチルと水を加えた。有機層を分離後、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィ−(ヘキサン:酢酸エチル＝５：1)にて精製し、表題化合物を(70mg, 64%)得た。
1H NMR (300 MHz, CHLOROFORM-d) σppm 3.06 - 3.17 (m, 1 H) 3.55 (t, J=8.94 Hz, 1 H) 3.72 (dd, 1 H) 3.78 - 4.02 (m, 5 H) 4.41 - 4.65 (m, 6 H) 4.85 - 4.96 (m, 3 H) 6.66 - 6.72 (m, J=7.46, 2.02 Hz, 2 H) 7.10 - 7.51 (m, 22 H)．
ESI m/z = 726(M+NH₄ ⁺), 728(M+2+ NH₄ ⁺)

Synthesis of (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [3- (bromomethyl) phenyl] -1-thio-D-glucitol
Of (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [3- (hydroxymethyl) phenyl] -1-thio-D-glucitol (100 mg, 0.155 mmol) Methanesulfonyl chloride (0.018 mL) and triethylamine (0.021 mL) were added to a tetrahydrofuran (1.5 mL) solution at 4 ° C. The reaction mixture was stirred at room temperature for 3 hours and diluted with ethyl acetate. This was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to give (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [3- (methanesulfonyloxymethyl). Phenyl] -1-thio-D-glucitol (150 mg) was obtained. Next, (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [3- (methanesulfonyloxymethyl) phenyl] -1-thio-D-glucitol (150 mg ), A mixture of LiBr (40 mg, 0.466 mmol) and acetone (3 mL) was stirred at room temperature for 2 hours. After concentrating the reaction solution, ethyl acetate and water were added. The organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the title compound (70 mg, 64%).
1H NMR (300 MHz, CHLOROFORM-d) σppm 3.06-3.17 (m, 1 H) 3.55 (t, J = 8.94 Hz, 1 H) 3.72 (dd, 1 H) 3.78-4.02 (m, 5 H) 4.41- 4.65 (m, 6 H) 4.85-4.96 (m, 3 H) 6.66-6.72 (m, J = 7.46, 2.02 Hz, 2 H) 7.10-7.51 (m, 22 H).
ESI m / z = 726 (M + NH ₄ ⁺ ), 728 (M + 2 + NH ₄ ⁺ )

Example 23

(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[３−[(１−メチル−1H−ピロール−２−イル)メチル]フェニル]−１−チオ−D−グルシトールの合成
(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[３−(ブロモメチル)フェニル]−１−チオ−D−グルシトール(200mg, 0.282mmol)、1−メチル−２−(トリブチルスタニル)−1H−ピロール(208mg, 0.564mmol)、トリス(ジベンジリデンアセトン)ジパラジウム(38mg, 0.0423mmol)、2−(ジシクロヘキシルホスフィノ)ビフェニル(36mg, 0.0987mmol)、KF(67mg, 1.16mmol)、CsCO₃(257mg, 0.792mmol)と1,4−ジオキサン(5mL)の混合物を60℃で8時間攪拌した。不溶物をろ過した後に、ろ液を濃縮して得られた残渣を、シリカゲルカラムクロマトグラフィ−(ヘキサン:酢酸エチル＝５：1)にて精製し、表題化合物を(190mg, 95%)得た。
1H NMR (300 MHz, CHLOROFORM-d) σppm 3.04 - 3.16 (m, 1 H) 3.32 (s, 3 H) 3.53 (t, J=8.70 Hz, 1 H) 3.67 - 3.75 (m, 1 H) 3.75 - 4.00 (m, 7 H) 4.46 - 4.56 (m, 3 H) 4.60 (d, J=10.57 Hz, 1 H) 4.84 - 4.96 (m, 3 H) 5.89 (dd, J=3.73, 1.55 Hz, 1 H) 6.04 (t, J=3.03 Hz, 1 H) 6.49 - 6.54 (m, 1 H) 6.70 (dd, J=7.62, 1.71 Hz, 2 H) 7.05 - 7.18 (m, 7 H) 7.22 - 7.36 (m, 14 H) 7.39 - 7.46 (m, 1 H). ESI m/Z = 710(M+H), 732(M+Na).

(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [3-[(1-methyl-1H-pyrrol-2-yl) methyl] phenyl] -1- Synthesis of thio-D-glucitol
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [3- (bromomethyl) phenyl] -1-thio-D-glucitol (200 mg, 0.282 mmol), 1 -Methyl-2- (tributylstannyl) -1H-pyrrole (208 mg, 0.564 mmol), tris (dibenzylideneacetone) dipalladium (38 mg, 0.0423 mmol), 2- (dicyclohexylphosphino) biphenyl (36 mg, 0.0987 mmol) , A mixture of KF (67 mg, 1.16 mmol), CsCO ₃ (257 mg, 0.792 mmol) and 1,4-dioxane (5 mL) was stirred at 60 ° C. for 8 hours. The insoluble material was filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound (190 mg, 95%).
1H NMR (300 MHz, CHLOROFORM-d) σppm 3.04-3.16 (m, 1 H) 3.32 (s, 3 H) 3.53 (t, J = 8.70 Hz, 1 H) 3.67-3.75 (m, 1 H) 3.75- 4.00 (m, 7 H) 4.46-4.56 (m, 3 H) 4.60 (d, J = 10.57 Hz, 1 H) 4.84-4.96 (m, 3 H) 5.89 (dd, J = 3.73, 1.55 Hz, 1 H ) 6.04 (t, J = 3.03 Hz, 1 H) 6.49-6.54 (m, 1 H) 6.70 (dd, J = 7.62, 1.71 Hz, 2 H) 7.05-7.18 (m, 7 H) 7.22-7.36 (m , 14 H) 7.39-7.46 (m, 1 H). ESI m / Z = 710 (M + H), 732 (M + Na).

Example 24
Synthesis of (1S) -1,5-anhydro-1- [3-[(1-methyl-1H-pyrrol-2-yl) methyl] phenyl] -1-thio-D-glucitol

(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[３−[(１−メチル−1H−ピロール−２−イル)メチル]フェニル]−１−チオ−D−グルシトール(190mg)、トリフルオロ酢酸(1.0mL)、ジメチルスルフィド(0.6mL)、m−クレゾール(0.16mL)、エタンジチオール(0.04mL)の混合物に、−15℃にてトリフルオロメタンスルホン酸(0.2mL)を加えた。15分攪拌した後に、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィ−(クロロホルム:メタノール＝10:１)にて精製し、無色粉末状の表題化合物(16mg，17％)を得た。
1H NMR (300 MHz, METHANOL-d₄) σppm 2.92 - 3.05 (m, 1 H) 3.19 - 3.29 (m, 1 H) 3.39 (s, 3 H) 3.59 (t, J=9.64 Hz, 1 H) 3.68 - 3.83 (m, 3 H) 3.86 - 4.02 (m, 3 H) 5.80 - 5.87 (m, 1 H) 5.94 (t, J=3.11 Hz, 1 H) 6.55 (d, J=1.87 Hz, 1 H) 7.03 (dd, J=6.99, 1.71 Hz, 1 H) 7.12 - 7.28 (m, 3 H). ESI m/Z = 372(M+Na).

(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [3-[(1-methyl-1H-pyrrol-2-yl) methyl] phenyl] -1- A mixture of thio-D-glucitol (190 mg), trifluoroacetic acid (1.0 mL), dimethyl sulfide (0.6 mL), m-cresol (0.16 mL), ethanedithiol (0.04 mL) was added to trifluoromethanesulfone at -15 ° C. Acid (0.2 mL) was added. After stirring for 15 minutes, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give the title compound (16 mg, 17%) as a colorless powder. Obtained.
1H NMR (300 MHz, METHANOL-d ₄ ) σppm 2.92-3.05 (m, 1 H) 3.19-3.29 (m, 1 H) 3.39 (s, 3 H) 3.59 (t, J = 9.64 Hz, 1 H) 3.68 -3.83 (m, 3 H) 3.86-4.02 (m, 3 H) 5.80-5.87 (m, 1 H) 5.94 (t, J = 3.11 Hz, 1 H) 6.55 (d, J = 1.87 Hz, 1 H) 7.03 (dd, J = 6.99, 1.71 Hz, 1 H) 7.12-7.28 (m, 3 H). ESI m / Z = 372 (M + Na).

Example 25

(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[３−[(４−メトキシ−1H−インドール−１−イル)メチル]フェニル]−１−チオ−D−グルシトールの合成
４−メトキシインドール(83mg, 0.564mmol)のN,N−ジメチルホルムアミド(1.0mL)溶液に、水素化ナトリウム(22mg, 0.564mmol；60％ oil)を加え室温にて２０分間攪拌した。この溶液に、(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[３−(ブロモメチル)フェニル]−１−チオ−D−グルシトール(200mg, 0.282mmol)のN,N−ジメチルホルムアミド(2.0mL)溶液を加え、室温で3時間攪拌し、水を加えた。これを酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィ−(ヘキサン:酢酸エチル＝４：1)にて精製し、表題化合物(290mg)を得た。
1H NMR (300 MHz, CHLOROFORM-d) σppm 3.05 - 3.14 (m, 1 H) 3.46 - 3.56 (m, 1 H) 3.66 - 3.74 (m, 1 H) 3.76 - 3.92 (m, 5 H) 3.95 (s, 3 H) 4.46 (d, J=10.10 Hz, 1 H) 4.52 (s, 2 H) 4.59 (d, J=10.57 Hz, 1 H) 4.84 - 4.93 (m, 3 H) 5.25 (d, J=2.49 Hz, 2 H) 6.46 - 7.39 (m, 29 H). ESI m/z = 793(M+NH₄)

(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [3-[(4-methoxy-1H-indol-1-yl) methyl] phenyl] -1- Synthesis of thio-D-glucitol To a solution of 4-methoxyindole (83 mg, 0.564 mmol) in N, N-dimethylformamide (1.0 mL) was added sodium hydride (22 mg, 0.564 mmol; 60% oil), and the mixture was stirred at room temperature for 20 minutes. Stir for minutes. To this solution was added (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [3- (bromomethyl) phenyl] -1-thio-D-glucitol (200 mg, 0.282). mmol) in N, N-dimethylformamide (2.0 mL) was added, stirred at room temperature for 3 hours, and water was added. This was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the title compound (290 mg).
1H NMR (300 MHz, CHLOROFORM-d) σppm 3.05-3.14 (m, 1 H) 3.46-3.56 (m, 1 H) 3.66-3.74 (m, 1 H) 3.76-3.92 (m, 5 H) 3.95 (s , 3 H) 4.46 (d, J = 10.10 Hz, 1 H) 4.52 (s, 2 H) 4.59 (d, J = 10.57 Hz, 1 H) 4.84-4.93 (m, 3 H) 5.25 (d, J = 2.49 Hz, 2 H) 6.46-7.39 (m, 29 H). ESI m / z = 793 (M + NH ₄ )

Example 26

(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[３−[(４−ヒドロキシフェニル)メチル]フェニル]−１−チオ−D−グルシトールの合成
(４−ブロモフェノキシ)ｔ−ブチル−ジメチルシラン（2.17ｇ）と２,３,４,６−テトラ−O−ベンジル−１−C−(３−ホルミルフェニル)−５−チオ−D−グルコピラノース(2.50g)から、実施例１１と同様な方法で、無色油状の表題化合物(253mg)を得た。
1H NMR (300 MHz, CHLOROFORM-d) σppm 3.03 - 3.15 (m, 1 H) 3.52 (t, J=8.78 Hz, 1 H) 3.66 - 3.74 (m, 1 H) 3.75 - 3.97 (m, 6 H) 4.43 - 4.55 (m, 3 H) 4.56 - 4.74 (m, 3 H) 4.84 - 4.94 (m, 3 H) 6.62 - 6.70 (m, 4 H) 7.00 (d, J=8.70 Hz, 2 H) 7.06 - 7.20 (m, 6 H) 7.21 - 7.41 (m, 16 H)
ESI m/z = 740 (M+NH₄)．

Synthesis of (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [3-[(4-hydroxyphenyl) methyl] phenyl] -1-thio-D-glucitol
(4-Bromophenoxy) t-butyl-dimethylsilane (2.17 g) and 2,3,4,6-tetra-O-benzyl-1-C- (3-formylphenyl) -5-thio-D-glucopyranose (2.50 g) was used to give the title compound (253 mg) as a colorless oil in the same manner as in Example 11.
1H NMR (300 MHz, CHLOROFORM-d) σppm 3.03-3.15 (m, 1 H) 3.52 (t, J = 8.78 Hz, 1 H) 3.66-3.74 (m, 1 H) 3.75-3.97 (m, 6 H) 4.43-4.55 (m, 3 H) 4.56-4.74 (m, 3 H) 4.84-4.94 (m, 3 H) 6.62-6.70 (m, 4 H) 7.00 (d, J = 8.70 Hz, 2 H) 7.06- 7.20 (m, 6 H) 7.21-7.41 (m, 16 H)
ESI m / z = 740 (M + NH ₄ ).

Example 27

(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [3- [4- (2-methoxy-2-oxoethoxy) benzyl] phenyl] -1-thio -Synthesis of D-glucitol
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [3-[(4-hydroxyphenyl) methyl] phenyl] -1-thio-D-glucitol (364 mg , 0.504 mmol) in N, N-dimethylformamide (5 mL) at 4 ° C., potassium carbonate (91 mg, 0.660 mmol) and methyl bromoacetate (0.058 mL, 0.610 mmol) were added and stirred at room temperature for 5 hours. . After adding water, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (334 mg, 83%) as a colorless oil. Obtained.
1H NMR (300 MHz, CHLOROFORM-d) σppm 3.05-3.15 (m, 1 H) 3.52 (t, J = 8.94 Hz, 1 H) 3.66-3.75 (m, 1 H) 3.75-3.98 (m, 10 H) 4.41-4.64 (m, 6 H) 4.83-4.95 (m, 3 H) 6.60-6.79 (m, 4 H) 6.98-7.19 (m, 8 H) 7.22-7.36 (m, 16 H). ESI m / Z = 817 (M + Na).

Example 28

(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[３−[４−(カルボキシメトキシ)ベンジル]フェニル]−１−チオ−D−グルシトールの合成
(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル―１―[３−[[４−(メトキシカルボニルメチルオキシ)フェニル]メチル]フェニル]−１−チオ−D−グルシトール(180mg, 0.226mmol)の水−メタノール−テトラヒドロフラン(１：３：３、1.4ｍL)溶液に水酸化リチウム１水和物(11mg, 0.27mmol)を加え室温にて３０分間攪拌した。反応液を10％ HClを加え酸性にし、析出した残渣を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、乾燥剤を炉別後、溶媒を減圧下留去して、無色粉末状の表題化合物(149mg, 84%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) σppm 3.04 - 3.15 (m, 1 H) 3.46 - 3.58 (m, 1 H) 3.66 - 3.96 (m, 7 H) 4.41 - 4.54 (m, 3 H) 4.55 - 4.63 (m, 3 H) 4.82 - 4.95 (m, 3 H) 6.65 (dd, J=8.00, 1.48 Hz, 2 H) 6.76 (d, J=8.86 Hz, 2 H) 7.00 - 7.36 (m, 24 H)．ESI m/z = 798 (M+NH4), 779 (M-H)．

Synthesis of (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [3- [4- (carboxymethoxy) benzyl] phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [3-[[4- (methoxycarbonylmethyloxy) phenyl] methyl] phenyl] -1-thio- To a solution of D-glucitol (180 mg, 0.226 mmol) in water-methanol-tetrahydrofuran (1: 3: 3, 1.4 mL) was added lithium hydroxide monohydrate (11 mg, 0.27 mmol), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was acidified with 10% HCl, and the precipitated residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure to give the title compound (149 mg, 84%) as a colorless powder.
1H NMR (300 MHz, CHLOROFORM-d) σppm 3.04-3.15 (m, 1 H) 3.46-3.58 (m, 1 H) 3.66-3.96 (m, 7 H) 4.41-4.54 (m, 3 H) 4.55-4.63 (m, 3 H) 4.82-4.95 (m, 3 H) 6.65 (dd, J = 8.00, 1.48 Hz, 2 H) 6.76 (d, J = 8.86 Hz, 2 H) 7.00-7.36 (m, 24 H) . ESI m / z = 798 (M + NH4), 779 (MH).

Example 29

Synthesis of (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [3- [4- (carboxymethoxy) benzyl] phenyl] -1-thio-D-glucitol
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [3- [4- (carboxymethoxy) benzyl] phenyl] -1-thio-D-glucitol (149 mg , 0.191 mmol) in chloroform (2 mL) and 2M dimethylamine in tetrahydrofuran (0.19 mL, 0.382 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (44 mg, 0.229 mmol) and 1- Hydroxybenzotriazole (31 mg, 0.229 mmol) was added. The reaction solution was stirred at room temperature for 1.5 hours, diluted with chloroform, and the organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to obtain the title compound (128 mg, 83%).
1H NMR (300 MHz, CHLOROFORM-d) σppm 2.96 (s, 3 H) 3.05 (s, 3 H) 3.06-3.14 (m, 1 H) 3.52 (t, J = 8.86 Hz, 1 H) 3.68-3.74 ( m, 1 H) 3.76-3.96 (m, 7 H) 4.44-4.54 (m, 3 H) 4.56-4.63 (m, 3 H) 4.85-4.93 (m, 3 H) 6.65 (dd, J = 7.93, 1.55 Hz, 2 H) 6.76-6.83 (m, 2 H) 7.01-7.18 (m, 8 H) 7.22-7.35 (m, 16 H). ESI m / Z = 825 (M + NH ₄ ).

Example 30

(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[３−[[[４−(２−N,N−ジメチルアミノエチル)オキシ]フェニル]メチル]フェニル] −１−チオ−D−グルシトールの合成
(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[３−[４−[２−(ジメチルアミノ)−２−オキソエトキシ)ベンジル]フェニル]−１−チオ−D−グルシトール(88mg, 0.109mmol)のテトラヒドロフラン溶液(2mL)に1.2M ボランテトラヒドロフラン錯体(0.54mL)を4℃にて加え、室温で2時間攪拌した。反応液を4℃に冷却し、メタノールを加え濃縮した。得られた残渣に1,4−ジオキサン(1.0mL)と６M HCｌ(0.5mL)を加え40℃にて2分攪拌した。これに、２M 水酸化ナトリウム水溶液を加えアルカリ性に調整し、これを酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し得られた残渣をNHタイプシリカゲルカラムクロマトグラフィ−(ヘキサン:酢酸エチル＝1：1)にて精製し、表題化合物(43mg, 50%)を無色固体として得た。
1H NMR (300 MHz, CHLOROFORM-d) σppm 2.35 (s, 6 H) 2.68 - 2.81 (m, 2 H) 3.04 - 3.16 (m, 1 H) 3.52 (t, J=8.70 Hz, 1 H) 3.66 - 3.76 (m, 1 H) 3.76 - 4.10 (m, 9 H) 4.47 (d, J=10.10 Hz, 1 H) 4.52 (s, 2 H) 4.60 (d, J=10.72 Hz, 1 H) 4.84 - 4.94 (m, 3 H) 6.65 (dd, J=7.85, 1.32 Hz, 2 H) 6.72 - 6.81 (m, 2 H) 7.00 - 7.18 (m, 8 H) 7.20 - 7.36 (m, 16 H). ESI m/Z = 794(M+H).

(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [3-[[[4- (2-N, N-dimethylaminoethyl) oxy] phenyl] methyl ] Phenyl] -1-thio-D-glucitol synthesis
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [3- [4- [2- (dimethylamino) -2-oxoethoxy) benzyl] phenyl]- To a tetrahydrofuran solution (2 mL) of 1-thio-D-glucitol (88 mg, 0.109 mmol) was added 1.2 M borane tetrahydrofuran complex (0.54 mL) at 4 ° C., and the mixture was stirred at room temperature for 2 hours. The reaction solution was cooled to 4 ° C., methanol was added, and the mixture was concentrated. 1,4-Dioxane (1.0 mL) and 6M HCl (0.5 mL) were added to the resulting residue, and the mixture was stirred at 40 ° C. for 2 minutes. To this, 2M aqueous sodium hydroxide solution was added to make it alkaline, and this was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by NH type silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (43 mg, 50%) as colorless. Obtained as a solid.
1H NMR (300 MHz, CHLOROFORM-d) σppm 2.35 (s, 6 H) 2.68-2.81 (m, 2 H) 3.04-3.16 (m, 1 H) 3.52 (t, J = 8.70 Hz, 1 H) 3.66- 3.76 (m, 1 H) 3.76-4.10 (m, 9 H) 4.47 (d, J = 10.10 Hz, 1 H) 4.52 (s, 2 H) 4.60 (d, J = 10.72 Hz, 1 H) 4.84-4.94 (m, 3 H) 6.65 (dd, J = 7.85, 1.32 Hz, 2 H) 6.72-6.81 (m, 2 H) 7.00-7.18 (m, 8 H) 7.20-7.36 (m, 16 H). ESI m / Z = 794 (M + H).

Example 31

(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[３−[[[４−(２−ヒドロキシエチル)オキシ]フェニル]メチル]フェニル] −１−チオ−D−グルシトールの合成
(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−ベンジル−１−[３−[４−(２−メトキシ−２−オキソエトキシ)ベンジル]フェニル]−１−チオ−D−グルシトール(102mg, 0.128mmol)のテトラヒドロフラン(2.5mL)溶液に、4℃にてLiAlH₄(12mg, 0.321mmol)を加え、2.5時間攪拌した。水を滴下した後に、28％アンモニア水を加え、不溶物を濾過した。ろ液を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し無色結晶の表題化合物(100mg)を得た。
1H NMR (300 MHz, CHLOROFORM-d) σppm 3.06 - 3.14 (m, 1 H) 3.52 (t, J=8.86 Hz, 1 H) 3.67 - 3.74 (m, 1 H) 3.77 - 4.04 (m, 11 H) 4.47 (d, J=9.95 Hz, 1 H) 4.52 (s, 2 H) 4.60 (d, J=10.72 Hz, 1 H) 4.86 - 4.93 (m, 3 H) 6.62 - 6.68 (m, 2 H) 6.73 - 6.79 (m, 2 H) 7.02 - 7.18 (m, 8 H) 7.21 - 7.35 (m, 16 H). ESI m/Z = 784(M+NH4).

(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [3-[[[[4- (2-hydroxyethyl) oxy] phenyl] methyl] phenyl] -1 Synthesis of thio-D-glucitol
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [3- [4- (2-methoxy-2-oxoethoxy) benzyl] phenyl] -1-thio To a solution of -D-glucitol (102 mg, 0.128 mmol) in tetrahydrofuran (2.5 mL) was added LiAlH ₄ (12 mg, 0.321 mmol) at 4 ° C. and stirred for 2.5 hours. After water was added dropwise, 28% aqueous ammonia was added, and insoluble matters were filtered. The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was distilled off under reduced pressure to give the title compound (100 mg) as colorless crystals.
1H NMR (300 MHz, CHLOROFORM-d) σppm 3.06-3.14 (m, 1 H) 3.52 (t, J = 8.86 Hz, 1 H) 3.67-3.74 (m, 1 H) 3.77-4.04 (m, 11 H) 4.47 (d, J = 9.95 Hz, 1 H) 4.52 (s, 2 H) 4.60 (d, J = 10.72 Hz, 1 H) 4.86-4.93 (m, 3 H) 6.62-6.68 (m, 2 H) 6.73 -6.79 (m, 2 H) 7.02-7.18 (m, 8 H) 7.21-7.35 (m, 16 H). ESI m / Z = 784 (M + NH4).

Example 32

２,３,４,６−テトラ−O−アリル−１−C−[５−(４−エトキシベンジル)ピリジン−３−イル]−５−チオ−D−グルコピラノースの合成
実施例１５と同様に３−ブロモ−５−(４−エトキシベンジル)ピリジン(1.83g, 6.26mmol)からグリニアー試薬を調整し、表題化合物(508mg, 29%)を茶色油状物として得た。
1H NMR (300 MHz, CHLOROFORM-d) σppm 1.40 (t, J=6.99 Hz, 3 H) 2.98 - 3.18 (m, 1 H) 3.29 - 3.47 (m, 2 H) 3.56 - 4.05 (m, 12 H) 4.06 - 4.43 (m, 4 H) 4.77 - 4.91 (m, 2 H) 5.07 - 5.37 (m, 7 H) 5.79 - 6.04 (m, 3 H) 6.81 (d, J=8.86 Hz, 2 H) 7.04 (d, J=8.86 Hz, 2 H) 7.72 (s, 1 H) 8.41 (d, J=1.86 Hz, 1 H) 8.70 (d, J=2.18 Hz, 1 H)．ESI m/z = 568 (M+H), 590 (M+Na)．

Synthesis of 2,3,4,6-tetra-O-allyl-1-C- [5- (4-ethoxybenzyl) pyridin-3-yl] -5-thio-D-glucopyranose As in Example 15. The Grineer reagent was prepared from 3-bromo-5- (4-ethoxybenzyl) pyridine (1.83 g, 6.26 mmol) to give the title compound (508 mg, 29%) as a brown oil.
1H NMR (300 MHz, CHLOROFORM-d) σppm 1.40 (t, J = 6.99 Hz, 3 H) 2.98-3.18 (m, 1 H) 3.29-3.47 (m, 2 H) 3.56-4.05 (m, 12 H) 4.06-4.43 (m, 4 H) 4.77-4.91 (m, 2 H) 5.07-5.37 (m, 7 H) 5.79-6.04 (m, 3 H) 6.81 (d, J = 8.86 Hz, 2 H) 7.04 ( d, J = 8.86 Hz, 2 H) 7.72 (s, 1 H) 8.41 (d, J = 1.86 Hz, 1 H) 8.70 (d, J = 2.18 Hz, 1 H). ESI m / z = 568 (M + H), 590 (M + Na).

Example 33

(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−アリル−１−[５−(４−エトキシベンジル)ピリジン−３−イル]−１−チオ−D−グルシトールの合成
実施例１６と同様な方法で、２,３,４,６−テトラ−O−ベンジル−１−C−[５−(４−エトキシベンジル)ピリジン−３−イル]−５−チオ−D−グルコピラノース(508mg, 0.894mmol)から無色油状の表題化合物(137mg, 28%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) σppm 1.40 (t, J=6.99 Hz, 3 H) 2.93 - 3.06 (m, 1 H) 3.25 (t, J=8.94 Hz, 1 H) 3.30 - 3.44 (m, 1 H) 3.49 - 4.05 (m, 12 H) 4.15 (dd, J=12.05, 5.98 Hz, 1 H) 4.24 - 4.42 (m, 3 H) 4.80 - 4.92 (m, 2 H) 5.08 - 5.42 (m, 7 H) 5.78 - 6.03 (m, 3 H) 6.81 (d, J=8.70 Hz, 2 H) 7.03 (d, J=8.70 Hz, 2 H) 7.48 (s, 1 H) 8.42 (dd, J=16.16, 2.18 Hz, 2 H). ESI m/Z = 552(M+H)．

Of (1S) -1,5-anhydro-2,3,4,6-tetra-O-allyl-1- [5- (4-ethoxybenzyl) pyridin-3-yl] -1-thio-D-glucitol In the same manner as in Synthesis Example 16, 2,3,4,6-tetra-O-benzyl-1-C- [5- (4-ethoxybenzyl) pyridin-3-yl] -5-thio-D- A colorless oily title compound (137 mg, 28%) was obtained from glucopyranose (508 mg, 0.894 mmol).
1H NMR (300 MHz, CHLOROFORM-d) σppm 1.40 (t, J = 6.99 Hz, 3 H) 2.93-3.06 (m, 1 H) 3.25 (t, J = 8.94 Hz, 1 H) 3.30-3.44 (m, 1 H) 3.49-4.05 (m, 12 H) 4.15 (dd, J = 12.05, 5.98 Hz, 1 H) 4.24-4.42 (m, 3 H) 4.80-4.92 (m, 2 H) 5.08-5.42 (m, 7 H) 5.78-6.03 (m, 3 H) 6.81 (d, J = 8.70 Hz, 2 H) 7.03 (d, J = 8.70 Hz, 2 H) 7.48 (s, 1 H) 8.42 (dd, J = 16.16 2.18 Hz, 2 H). ESI m / Z = 552 (M + H).

Example 34

(１S)−１,５−アンヒドロ−１−[５−(４−エトキシベンジル)ピリジン−３−イル]−１−チオ−D−グルシトールの合成
実施例１７と同様な方法で、(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−アリル−１−[５−(４−エトキシベンジル)ピリジン−３−イル]−１−チオ−D−グルシトール(137mg, 0.248mmol)から無色粉末状の表題化合物(71mg, 73%)を得た。
1H NMR (600 MHz, METHANOL-d₄) σppm 1.36 (t, J=7.18 Hz, 3 H) 3.01 - 3.05 (m, 1 H) 3.23 - 3.27 (m, 1 H) 3.60 (dd, J=10.32, 8.94 Hz, 1 H) 3.71 - 3.78 (m, 2 H) 3.84 (d, J=10.55 Hz, 1 H) 3.92 - 3.97 (m, 3 H) 3.99 (q, J=7.18 Hz, 2 H) 6.82 - 6.85 (m, 2 H) 7.10 - 7.13 (m, 2 H) 7.64 (t, J=2.06 Hz, 1 H) 8.28 (d, J=2.29 Hz, 1 H) 8.34 (d, J=2.29 Hz, 1 H). ESI m/Z = 392(M+Na), 390(M-H).

Synthesis of (1S) -1,5-anhydro-1- [5- (4-ethoxybenzyl) pyridin-3-yl] -1-thio-D-glucitol In the same manner as in Example 17, (1S)- 1,5-Anhydro-2,3,4,6-tetra-O-allyl-1- [5- (4-ethoxybenzyl) pyridin-3-yl] -1-thio-D-glucitol (137 mg, 0.248 mmol) ) Gave the title compound (71 mg, 73%) as a colorless powder.
1H NMR (600 MHz, METHANOL-d ₄ ) σppm 1.36 (t, J = 7.18 Hz, 3 H) 3.01-3.05 (m, 1 H) 3.23-3.27 (m, 1 H) 3.60 (dd, J = 10.32, 8.94 Hz, 1 H) 3.71-3.78 (m, 2 H) 3.84 (d, J = 10.55 Hz, 1 H) 3.92-3.97 (m, 3 H) 3.99 (q, J = 7.18 Hz, 2 H) 6.82- 6.85 (m, 2 H) 7.10-7.13 (m, 2 H) 7.64 (t, J = 2.06 Hz, 1 H) 8.28 (d, J = 2.29 Hz, 1 H) 8.34 (d, J = 2.29 Hz, 1 H). ESI m / Z = 392 (M + Na), 390 (MH).

Example 35

Of (1S) -1,5-anhydro-2,3,4,6-tetra-O-allyl-1- [5- (4-ethylbenzyl) thiophen-2-yl] -1-thio-D-glucitol Synthesis The title compound (890 mg, 94%) as a yellow oil was obtained from 2-bromo-5- (4-ethylbenzyl) thiophene (1.0 g, 3.55 mmol) in the same manner as in Examples 15 and 16.
1H NMR (300 MHz, CHLOROFORM-d) σppm 1.22 (t, J = 7.62 Hz, 3 H) 2.62 (q, J = 7.62 Hz, 2 H) 2.91-3.03 (m, 1 H) 3.20 (t, J = 9.01 Hz, 1 H) 3.43-3.79 (m, 5 H) 3.90-4.07 (m, 6 H) 4.09-4.18 (m, 1 H) 4.24-4.41 (m, 3 H) 4.92-5.02 (m, 2 H ) 5.09-5.32 (m, 6 H) 5.50-5.66 (m, 1 H) 5.79-6.05 (m, 3 H) 6.61 (d, J = 3.57 Hz, 1 H) 6.85 (d, J = 3.42 Hz, 1 H) 7.07-7.16 (m, 4 H). ESI m / z = 563 (M + Na).

Example 36

(１S)−１,５−アンヒドロ−１−[５−(４−エチルベンジル)チオフェン−２−イル]−１−チオ−D−グルシトールの合成
実施例１７と同様な方法で、(１S)−１,５−アンヒドロ−２,３,４,６−テトラ−O−アリル−１−[５−(４−エチルベンジル)チオフェン−２−イル]−１−チオ−D−グルシトール(890mg, 1.64mmol)から無色粉末状の表題化合物(570mg, 92%)を得た。
1H NMR (300 MHz, METHANOL-d4) σppm 1.20 (t, J=7.62 Hz, 3 H) 2.60 (q, J=7.62 Hz, 2 H) 2.92 - 3.03 (m, 1 H) 3.19 (t, J=8.86 Hz, 1 H) 3.50 - 3.63 (m, 2 H) 3.72 (dd, J=11.58, 6.45 Hz, 1 H) 3.93 (dd, J=11.50, 3.73 Hz, 1 H) 4.03 (t, J=4.97 Hz, 3 H) 6.58 - 6.67 (m, 1 H) 6.83 (d, J=3.57 Hz, 1 H) 7.08 - 7.17 (m, 4 H). ESI m/z = 403 (M+Na), 379 (M-H).

Synthesis of (1S) -1,5-anhydro-1- [5- (4-ethylbenzyl) thiophen-2-yl] -1-thio-D-glucitol In the same manner as in Example 17, (1S)- 1,5-Anhydro-2,3,4,6-tetra-O-allyl-1- [5- (4-ethylbenzyl) thiophen-2-yl] -1-thio-D-glucitol (890 mg, 1.64 mmol) ) Gave the title compound (570 mg, 92%) as a colorless powder.
1H NMR (300 MHz, METHANOL-d4) σppm 1.20 (t, J = 7.62 Hz, 3 H) 2.60 (q, J = 7.62 Hz, 2 H) 2.92-3.03 (m, 1 H) 3.19 (t, J = 8.86 Hz, 1 H) 3.50-3.63 (m, 2 H) 3.72 (dd, J = 11.58, 6.45 Hz, 1 H) 3.93 (dd, J = 11.50, 3.73 Hz, 1 H) 4.03 (t, J = 4.97 Hz, 3 H) 6.58-6.67 (m, 1 H) 6.83 (d, J = 3.57 Hz, 1 H) 7.08-7.17 (m, 4 H). ESI m / z = 403 (M + Na), 379 ( MH).

Example 37

2,3,4,6−テトラ−O−ベンジル−1−C−{3−[(E or Z)−2−(4−エチルフェニル)ビニル]フェニル}−5−チオ−D−グルコピラノースの合成
(4−エチルベンジル)トリフェニルホスホニウムクロリド(1.64g，3.93mmol)とテトラヒドロフラン(20mL)の混合物に氷冷下2Mリチウムジイソプロピルアミン(ヘプタン/テトラヒドロフラン/エチルベンゼン溶液，2.0mL，4.0mmol)を加え、室温にて1時間攪拌した。この溶液を２,３,４,６−テトラ−O−ベンジル−１−C−(３−ホルミルフェニル)−５−チオ−Ｄ−グルコピラノース(0.52g，786μmol)のテトラヒドロフラン溶液(10mL)に滴下し、室温にて１時間攪拌した。反応液に氷冷下、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、有機相を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィ−(ヘキサン:酢酸エチル＝6：1〜3：1)にて精製し、無色油状の表題化合物(0.49g，82％，E/Z mixture)を得た。
1H NMR (300 MHz, CHLOROFORM-d) σppm 1.10 - 1.32 (m, 3 H) 2.48 - 2.74 (m, 2 H) 2.90 - 3.10 (m, J=38.55 Hz, 1 H) 3.47 - 3.71 (m, 2 H) 3.78 - 4.21 (m, 5 H) 4.41 - 4.73 (m, 4 H) 4.80 - 4.99 (m, 3 H) 6.50 - 6.99 (m, 3 H) 7.03 - 7.61 (m, 27 H)．ESI m/z = 785 (M+Na)．

2,3,4,6-Tetra-O-benzyl-1-C- {3-[(E or Z) -2- (4-ethylphenyl) vinyl] phenyl} -5-thio-D-glucopyranose Composition
To a mixture of (4-ethylbenzyl) triphenylphosphonium chloride (1.64 g, 3.93 mmol) and tetrahydrofuran (20 mL) was added 2M lithium diisopropylamine (heptane / tetrahydrofuran / ethylbenzene solution, 2.0 mL, 4.0 mmol) under ice-cooling. For 1 hour. This solution was added dropwise to a tetrahydrofuran solution (10 mL) of 2,3,4,6-tetra-O-benzyl-1-C- (3-formylphenyl) -5-thio-D-glucopyranose (0.52 g, 786 μmol). And stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1 to 3: 1) to give the title compound (0.49 g) as a colorless oil. , 82%, E / Z mixture).
1H NMR (300 MHz, CHLOROFORM-d) σppm 1.10-1.32 (m, 3 H) 2.48-2.74 (m, 2 H) 2.90-3.10 (m, J = 38.55 Hz, 1 H) 3.47-3.71 (m, 2 H) 3.78-4.21 (m, 5 H) 4.41-4.73 (m, 4 H) 4.80-4.99 (m, 3 H) 6.50-6.99 (m, 3 H) 7.03-7.61 (m, 27 H). ESI m / z = 785 (M + Na).

Example 38

(1S)−1,5−アンヒドロ−2,3,4,6−テトラ−O−ベンジル−1−{3−[(E or Z)−2−(4−エチルフェニル)ビニル]フェニル}−1−チオ−D−グルシトールの合成
2,3,4,6−テトラ−O−ベンジル−1−C−{3−[(E or Z)−2−(4−エチルフェニル)ビニル]フェニル}−5−チオ−D−グルコピラノース(0.49g，642μmol)のアセトニトリル（20mL）溶液に、−10℃にてEt₃SiH（0.35mL, 1.92mmol）とBF₃Et₂O（0.20mL, 1.28mmol）を順次加え、同温にて10分間攪拌した。反応液に飽和炭酸ナトリウム水溶液を加え、酢酸エチルで抽出し、有機相を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィ−(ヘキサン:酢酸エチル＝8：１)にて精製し、無色粉末状の表題化合物（0.31g，66%，E/Z mixture）を得た。
1H NMR (300 MHz, CHLOROFORM-d) σppm 1.13 - 1.31 (m, 3 H) 2.46 - 2.72 (m, 2 H) 3.04 - 3.18 (m, 1 H) 3.47 - 3.62 (m, 1 H) 3.68 - 4.02 (m, 6 H) 4.45 - 4.66 (m, 4 H) 4.85 - 4.96 (m, 3 H) 6.49 - 6.80 (m, 3 H) 6.92 - 7.62 (m, 27 H). ESI m/z = 769 (M+Na)．

(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- {3-[(E or Z) -2- (4-ethylphenyl) vinyl] phenyl} -1 Synthesis of thio-D-glucitol
2,3,4,6-tetra-O-benzyl-1-C- {3-[(E or Z) -2- (4-ethylphenyl) vinyl] phenyl} -5-thio-D-glucopyranose ( To a solution of 0.49 g, 642 μmol) in acetonitrile (20 mL), add Et ₃ SiH (0.35 mL, 1.92 mmol) and BF ₃ Et ₂ O (0.20 mL, 1.28 mmol) sequentially at −10 ° C. Stir for minutes. A saturated aqueous sodium carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1) to give the title compound (0.31 g, 66%) as a colorless powder. , E / Z mixture).
1H NMR (300 MHz, CHLOROFORM-d) σppm 1.13-1.31 (m, 3 H) 2.46-2.72 (m, 2 H) 3.04-3.18 (m, 1 H) 3.47-3.62 (m, 1 H) 3.68-4.02 (m, 6 H) 4.45-4.66 (m, 4 H) 4.85-4.96 (m, 3 H) 6.49-6.80 (m, 3 H) 6.92-7.62 (m, 27 H). ESI m / z = 769 ( M + Na).

Example 39

(1S)−1,5−アンヒドロ−1−{3−[2−(4−エチルフェニル)エチル]フェニル}−1−チオ−D−グルシトールの合成
(1S)−1,5−アンヒドロ−2,3,4,6−テトラ−O−ベンジル−1−{3−[(E or Z)−2−(4−エチルフェニル)ビニル]フェニル}−1−チオ−D−グルシトール(0.30g，401μmol)のエタノール(5mL)溶液に20wt%水酸化パラジウムカーボン粉末(300mg)を加え、系内を水素置換した。室温にて３日間攪拌した後、系内の不溶物をセライトろ過にて除去した。溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィ−(クロロホルム:メタノール＝10：1)にて精製し、無色粉末状の表題化合物（13mg，8%）を得た。
1H NMR (300 MHz, METHANOL-d₄) σppm 1.20 (t, J=7.62 Hz, 3 H) 2.59 (q, J=7.62 Hz, 2 H) 2.85 (s, 4 H) 2.95 - 3.07 (m, 1 H) 3.21 - 3.28 (m, 1 H) 3.54 - 3.68 (m, 1 H) 3.69 - 3.83 (m, 3 H) 3.95 (dd, J=11.42, 3.65 Hz, 1 H) 7.00 - 7.11 (m, 5 H) 7.13 - 7.28 (m, 3 H)．ESI m/z = 411 (M+Na), 387 (M-H)．

Synthesis of (1S) -1,5-anhydro-1- {3- [2- (4-ethylphenyl) ethyl] phenyl} -1-thio-D-glucitol
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- {3-[(E or Z) -2- (4-ethylphenyl) vinyl] phenyl} -1 -To a solution of thio-D-glucitol (0.30 g, 401 μmol) in ethanol (5 mL) was added 20 wt% palladium hydroxide carbon powder (300 mg), and the system was replaced with hydrogen. After stirring at room temperature for 3 days, insoluble matters in the system were removed by Celite filtration. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain the title compound (13 mg, 8%) as a colorless powder.
1H NMR (300 MHz, METHANOL-d ₄ ) σppm 1.20 (t, J = 7.62 Hz, 3 H) 2.59 (q, J = 7.62 Hz, 2 H) 2.85 (s, 4 H) 2.95-3.07 (m, 1 H) 3.21-3.28 (m, 1 H) 3.54-3.68 (m, 1 H) 3.69-3.83 (m, 3 H) 3.95 (dd, J = 11.42, 3.65 Hz, 1 H) 7.00-7.11 (m, 5 H) 7.13-7.28 (m, 3 H). ESI m / z = 411 (M + Na), 387 (MH).

Example 40

2,3,4,6-tetra-O-allyl-1-C- {3-[(2E or Z) -3- (4-ethylphenyl) prop-2-en-1-yl] phenyl} -5 Synthesis of thio-D-glucopyranose Magnesium (1.11 g, 45.7 mmol), 1-bromo-3-[(2E or Z) -3- (4-ethylphenyl) prop-2-en-1-yl] benzene 1,2-Dibromoethane (5 drops) was added to a mixture of (0.401 g, 1.33 mmol) and tetrahydrofuran (7 mL) and the mixture was heated to reflux for 1.5 hours. The reaction mixture was cooled to room temperature, and 2,3,4,6-tetra-O-allyl-5-thio-D-glucono-1,5-lactone (0.38 g, 1.06 mmol) in tetrahydrofuran (5 mL) was added to the solution. Was added dropwise and stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (42 mg, 7%) as a colorless oil. Obtained.
1H NMR (300 MHz, CHLOROFORM-d) σppm 1.16-1.30 (m, 3 H) 2.55-2.72 (m, 2 H) 2.90-3.03 (m, 1 H) 3.31-4.44 (m, 16 H) 4.82-4.94 (m, 2 H) 5.09-5.49 (m, 6 H) 5.80-6.05 (m, 5 H) 6.29-6.45 (m, 1 H) 7.08-7.32 (m, 6 H) 7.42-7.52 (m, 2 H ). ESI m / z = 599 (M + Na), 575 (MH).

Example 41

(1S)−2,3,4,6−テトラ−O−アリル−1,5−アンヒドロ−1−{3−[(2E or Z)−3−(4−エチルフェニル)プロパ−2−エン−1−イル]フェニル}−1−チオ−D−グルシトールの合成
2,3,4,6−テトラ−O−アリル−1−C−{3−[(2E or Z)−3−(4−エチルフェニル)プロパ−2−エン−1−イル]フェニル}−5−チオ−D−グルコピラノース (42ｍg，72μmol)のアセトニトリル（3mL）溶液に、−10℃にてEt₃SiH（35μL, 218μmol）とBF₃Et₂O（20μL, 145μmol）を順次加え、同温にて10分間攪拌した。反応液に飽和炭酸ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィ−(ヘキサン:酢酸エチル＝10：１〜8：１)にて精製し、無色油状の表題化合物（28mg，70%）を得た。
1H NMR (300 MHz, CHLOROFORM-d) σppm 1.17 - 1.30 (m, J=7.62, 7.62, 7.62 Hz, 3 H) 2.57 - 2.71 (m, 2 H) 2.95 - 3.05 (m, 1 H) 3.26 (t, J=8.86 Hz, 1 H) 3.50 (d, J=6.68 Hz, 2 H) 3.58 - 3.91 (m, 5 H) 3.94 - 4.21 (m, 3 H) 4.23 - 4.44 (m, 3 H) 4.84 - 4.95 (m, 2 H) 5.09 - 5.52 (m, 8 H) 5.71 - 6.46 (m, 6 H) 7.09 - 7.29 (m, 8 H)．ESI m/z = 583 (M+Na)．

(1S) -2,3,4,6-Tetra-O-allyl-1,5-anhydro-1- {3-[(2E or Z) -3- (4-ethylphenyl) prop-2-ene- Synthesis of 1-yl] phenyl} -1-thio-D-glucitol
2,3,4,6-tetra-O-allyl-1-C- {3-[(2E or Z) -3- (4-ethylphenyl) prop-2-en-1-yl] phenyl} -5 -Add Et ₃ SiH (35 µL, 218 µmol) and BF ₃ Et ₂ O (20 µL, 145 µmol) sequentially to a solution of thio-D-glucopyranose (42 mg, 72 µmol) in acetonitrile (3 mL) at -10 ° C. For 10 minutes. A saturated aqueous sodium carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 8: 1) to give the title compound (28 mg, 28 mg, 70%).
1H NMR (300 MHz, CHLOROFORM-d) σppm 1.17-1.30 (m, J = 7.62, 7.62, 7.62 Hz, 3 H) 2.57-2.71 (m, 2 H) 2.95-3.05 (m, 1 H) 3.26 (t , J = 8.86 Hz, 1 H) 3.50 (d, J = 6.68 Hz, 2 H) 3.58-3.91 (m, 5 H) 3.94-4.21 (m, 3 H) 4.23-4.44 (m, 3 H) 4.84- 4.95 (m, 2 H) 5.09-5.52 (m, 8 H) 5.71-6.46 (m, 6 H) 7.09-7.29 (m, 8 H). ESI m / z = 583 (M + Na).

Example 42

(1S)−1,5−アンヒドロ−1−{3−[(2E or Z)−3−(4−エチルフェニル)プロパ−2−エン−1−イル]フェニル}−1−チオ−D−グルシトールの合成
(1S)−2,3,4,6−テトラ−O−アリル−1,5−アンヒドロ−1−{3−[(2E or Z)−3−(4−エチルフェニル)プロパ−2−エン−1−イル]フェニル}−1−チオ−D−グルシトール(26mg，46μmol)のテトラヒドロフラン(3mL)溶液に、テトラキス(トリフェニルホスフィン)パラジウム(0) (11mg，9μmol)及び1,3−ジメチルバルビツル酸(58mg，370μmol)を加え、2.5時間加熱還流した。反応液に氷冷下、飽和炭酸ナトリウム水溶液を加え、酢酸エチルで抽出し、有機相を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を炉別後、溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィ−(クロロホルム:メタノール＝10：1)にて精製した。さらにシリカゲルカラムクロマトグラフィ−(NH silica gel，クロロホルム:メタノール＝9：1)にて精製し，表題化合物（13mg，72%）を得た。
1H NMR (300 MHz, METHANOL-d₄) σppm 1.14 - 1.27 (m, J=7.98, 7.98, 7.98 Hz, 3 H) 2.54 - 2.68 (m, 2 H) 2.95 - 3.05 (m, 1 H) 3.22 - 3.30 (m, 1 H) 3.51 (d, J=6.37 Hz, 1 H) 3.56 - 3.68 (m, 2 H) 3.70 - 3.83 (m, 3 H) 3.95 (dd, J=11.35, 3.57 Hz, 1 H) 5.72 - 6.59 (m, 2 H) 7.07 - 7.30 (m, 8 H)．ESI m/z = 423 (M+Na), 399 (M-H)．

(1S) -1,5-Anhydro-1- {3-[(2E or Z) -3- (4-ethylphenyl) prop-2-en-1-yl] phenyl} -1-thio-D-glucitol Synthesis of
(1S) -2,3,4,6-Tetra-O-allyl-1,5-anhydro-1- {3-[(2E or Z) -3- (4-ethylphenyl) prop-2-ene- 1-yl] phenyl} -1-thio-D-glucitol (26 mg, 46 μmol) in tetrahydrofuran (3 mL) was added tetrakis (triphenylphosphine) palladium (0) (11 mg, 9 μmol) and 1,3-dimethylbarbitur Acid (58 mg, 370 μmol) was added, and the mixture was heated to reflux for 2.5 hours. A saturated aqueous sodium carbonate solution was added to the reaction solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1). Further purification by silica gel column chromatography (NH silica gel, chloroform: methanol = 9: 1) gave the title compound (13 mg, 72%).
1H NMR (300 MHz, METHANOL-d ₄ ) σppm 1.14-1.27 (m, J = 7.98, 7.98, 7.98 Hz, 3 H) 2.54-2.68 (m, 2 H) 2.95-3.05 (m, 1 H) 3.22- 3.30 (m, 1 H) 3.51 (d, J = 6.37 Hz, 1 H) 3.56-3.68 (m, 2 H) 3.70-3.83 (m, 3 H) 3.95 (dd, J = 11.35, 3.57 Hz, 1 H ) 5.72-6.59 (m, 2 H) 7.07-7.30 (m, 8 H). ESI m / z = 423 (M + Na), 399 (MH).

Example 43

(1S)−1,5−アンヒドロ−1−{3−[3−(4−エチルフェニル)プロピル]フェニル}−1−チオ−D−グルシトールの合成
(1S)−1,5−アンヒドロ−1−{3−[(2E or Z)−3−(4−エチルフェニル)プロパ−2−エン−1−イル]フェニル}−1−チオ−D−グルシトール(13mg，32μmol)のエタノール(2mL)溶液に20wt%水酸化パラジウムカーボン粉末(20mg)を加え、系内を水素置換した。室温にて2日間攪拌した後、系内の不溶物をセライトろ過にて除去した。溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィ−(クロロホルム:メタノール＝9：1)にて精製し、無色粉末状の表題化合物（8mg，62%）を得た。
1H NMR (600 MHz, METHANOL-d₄) σppm 1.20 (t, J=7.57 Hz, 3 H) 1.87 - 1.94 (m, 2 H) 2.56 - 2.63 (m, 6 H) 2.98 - 3.03 (m, 1 H) 3.26 (t, J=8.25 Hz, 1 H) 3.59 - 3.64 (m, J=10.32, 8.94 Hz, 1 H) 3.71 - 3.82 (m, 3 H) 3.95 (dd, J=11.46, 3.67 Hz, 1 H) 7.05 - 7.12 (m, 5 H) 7.14 - 7.25 (m, 3 H).．ESI m/z = 425 (M+Na), 401 (M-H)．

Synthesis of (1S) -1,5-anhydro-1- {3- [3- (4-ethylphenyl) propyl] phenyl} -1-thio-D-glucitol
(1S) -1,5-Anhydro-1- {3-[(2E or Z) -3- (4-ethylphenyl) prop-2-en-1-yl] phenyl} -1-thio-D-glucitol 20 wt% palladium hydroxide carbon powder (20 mg) was added to a solution of (13 mg, 32 μmol) in ethanol (2 mL), and the system was replaced with hydrogen. After stirring at room temperature for 2 days, insoluble matters in the system were removed by Celite filtration. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to obtain the title compound (8 mg, 62%) as a colorless powder.
1H NMR (600 MHz, METHANOL-d ₄ ) σppm 1.20 (t, J = 7.57 Hz, 3 H) 1.87-1.94 (m, 2 H) 2.56-2.63 (m, 6 H) 2.98-3.03 (m, 1 H ) 3.26 (t, J = 8.25 Hz, 1 H) 3.59-3.64 (m, J = 10.32, 8.94 Hz, 1 H) 3.71-3.82 (m, 3 H) 3.95 (dd, J = 11.46, 3.67 Hz, 1 H) 7.05-7.12 (m, 5 H) 7.14-7.25 (m, 3 H). ESI m / z = 425 (M + Na), 401 (MH).

Example 44

Synthesis of 2,3,4,6-tetra-O-allyl-1-C- [7- (4-methylbenzyl) -1-benzothien-3-yl] -5-thio-D-glucopyranose (77 mg , 3.19 mmol), 1,2-dibromoethane (5 drops) to a mixture of 3-bromo-7- (4-methylbenzyl) -1-benzothiophene (0.92 g, 2.90 mmol) and tetrahydrofuran (5 mL), The mixture was heated to reflux for 30 minutes. The reaction solution was cooled to room temperature, and 2,3,4,6-tetra-O-allyl-5-thio-D-glucono-1,5-lactone (0.51 g, 1.45 mmol) was added to this solution under ice cooling. Tetrahydrofuran (5 mL) was added dropwise and stirred for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (0.76 g, 89%) as a yellow oil. Got.
1H NMR (300 MHz, CHLOROFORM-d) σppm 2.31 (s, 3 H) 3.21 (dd, J = 11.81, 6.06 Hz, 1 H) 3.29 (s, 1 H) 3.46-3.93 (m, 6 H) 3.96- 4.02 (m, J = 4.66 Hz, 2 H) 4.15-4.26 (m, 4 H) 4.30 (d, J = 5.75 Hz, 2 H) 4.42 (dd, J = 12.12, 5.91 Hz, 1 H) 4.57-4.78 (m, 2 H) 5.10-5.40 (m, 7 H) 5.80-6.08 (m, 3 H) 7.05-7.17 (m, 5 H) 7.32 (t, 1 H) 7.63 (s, 1 H) 8.19 (d , J = 7.46 Hz, 1 H). ESI m / z = 615 (M + Na), 591 (MH).

Example 45

(1S)−2,3,4,6−テトラ−O−アリル−1,5−アンヒドロ−1−[7−(4−メチルベンジル)−1−ベンゾチエン−3−イル]−1−チオ−D−グルシトールの合成
2,3,4,6−テトラ−O−アリル−1−C−[7−(4−メチルベンジル)−1−ベンゾチエン−3−イル]−5−チオ−D−グルコピラノースから実施例１６と同様な方法で表題化合物(86%)を合成した。
1H NMR (300 MHz, CHLOROFORM-d) σppm 2.31 (s, 3 H) 2.99 - 3.10 (m, 1 H) 3.27 - 3.40 (m, 2 H) 3.66 - 3.87 (m, 5 H) 4.00 (d, J=5.75 Hz, 2 H) 4.15 - 4.26 (m, 4 H) 4.31 (d, J=6.84 Hz, 2 H) 4.40 (dd, J=12.05, 5.83 Hz, 1 H) 4.63 - 4.82 (m, 2 H) 5.09 - 5.37 (m, 7 H) 5.80 - 6.07 (m, 3 H) 7.04 - 7.17 (m, 5 H) 7.32 (t, 1 H) 7.41 (s, 1 H) 7.89 (d, J=7.93 Hz, 1 H). ESI m/z = 599 (M+Na).

(1S) -2,3,4,6-Tetra-O-allyl-1,5-anhydro-1- [7- (4-methylbenzyl) -1-benzothien-3-yl] -1-thio-D -Synthesis of glucitol
From 2,3,4,6-tetra-O-allyl-1-C- [7- (4-methylbenzyl) -1-benzothien-3-yl] -5-thio-D-glucopyranose with Example 16 The title compound (86%) was synthesized in a similar manner.
1H NMR (300 MHz, CHLOROFORM-d) σppm 2.31 (s, 3 H) 2.99-3.10 (m, 1 H) 3.27-3.40 (m, 2 H) 3.66-3.87 (m, 5 H) 4.00 (d, J = 5.75 Hz, 2 H) 4.15-4.26 (m, 4 H) 4.31 (d, J = 6.84 Hz, 2 H) 4.40 (dd, J = 12.05, 5.83 Hz, 1 H) 4.63-4.82 (m, 2 H ) 5.09-5.37 (m, 7 H) 5.80-6.07 (m, 3 H) 7.04-7.17 (m, 5 H) 7.32 (t, 1 H) 7.41 (s, 1 H) 7.89 (d, J = 7.93 Hz , 1 H). ESI m / z = 599 (M + Na).

Example 46

Synthesis of (1S) -1,5-anhydro-1- [7- (4-methylbenzyl) -1-benzothien-3-yl] -1-thio-D-glucitol
(1S) -2,3,4,6-Tetra-O-allyl-1,5-anhydro-1- [7- (4-methylbenzyl) -1-benzothien-3-yl] -1-thio-D A colorless powdery title compound (76%) was synthesized from glucitol in the same manner as in Example 17.
1H NMR (300 MHz, METHANOL-d ₄ ) σppm 2.26 (s, 2 H) 3.03-3.14 (m, 1 H) 3.32-3.40 (m, 1 H) 3.62-3.72 (m, 1 H) 3.77 (dd, J = 11.50, 6.37 Hz, 1 H) 3.93-4.06 (m, 2 H) 4.14 (s, 2 H) 4.32 (d, J = 10.26 Hz, 1 H) 7.01-7.17 (m, 5 H) 7.33 (t , 1 H) 7.48 (s, 1 H) 7.90 (d, J = 7.31 Hz, 1 H). ESI m / z = 439 (M + Na), 415 (MH).

  The compounds of the present invention shown in the following table were obtained by carrying out the same operations as in the above Examples using the corresponding starting materials and reactants. The compounds of the present invention obtained in the above examples are shown in Table 1.

Test example 1
Suspension of rat kidney border membrane vehicle (BBMV) prepared according to the method described in the literature (Aanal. Biochem., 201, 301, 1984) (protein concentration 4 mg / mL) ) 50 μL preincubated at 37 ° C. for 2 minutes, then added to test compound dissolved in DMSO (DMSO final concentration 1%) and 100 mM Mannitol, 100 mM NaSCN or KSCN, 10 mM HEPES / Tris pH 7.4, D-glucose 150 μL of a reaction mixture in which 1 μCi of D- [6- ³ H] glucose (Amersham) was mixed (final concentration 0.1 mM) was added. After reacting at 37 ° C. for 5 seconds, the reaction mixture was quenched with 1 mL of an ice-cold reaction stop solution (150 mM NaCl, 10 mM HEPES / Tris pH 7.4, 0.3 mM phlorizin), and immediately after pore reaction. Using a 0.45 μm size membrane filter (HAWP02500, Millipore), rapid filtration was performed to separate BBMV. The membrane filter was washed three times with 4.5 mL of ice-cold reaction stop solution, dried thoroughly, and then the radioactivity was measured using a liquid scintillation counter (Beckman), and the amount of glucose incorporated into the BBMV on the membrane filter Was quantified.

The glucose concentration when no compound was added was taken as 100%, and the compound concentration (IC ₅₀ value) at which the glucose uptake when a compound was added was inhibited by 50% was calculated.
The results are shown in Table 2.
Table 2

Test example 2
Cloning of human SGLT1 and human SGLT2 and introduction into expression vectors Human SGLT1 sequence (NM_000343) was amplified from human small intestine-derived mRNA after reverse transcription and introduced into pCMV-tag5A (Stratagene). The human SGLT2 sequence (NM_003041) was prepared from human kidney-derived mRNA by the same method and introduced into pcDNA3.1 + hygro (Invitrogen). It was confirmed that the sequence of each clone matched the reported sequence.

Preparation of CHO-k1 cells stably expressing human SGLT1 and human SGLT2 Human SGLT1 and human SGLT2 expression vectors were transfected into CHO-K1 cells using Lipofectamine 2000 (Invitrogen). SGLT-expressing cells were cultured in the presence of geneticin (SGLT1) or hygromycin B (SGLT2) at a concentration of 500 μg / mL, resistant strains were selected, and the glucose uptake specific activity was obtained as an index using the system shown below.

Sodium-dependent glucose uptake inhibition test in cells Cells that stably expressed human SGLT1 or human SGLT2 were used in the sodium-dependent glucose uptake activity inhibition test.
Cells were incubated for 20 minutes in 1 mL of pretreatment buffer (140 mM choline chloride, 2 mM KCl, 1 mM CaCl ₂ , 1 mM MgCl ₂ , 10 mM HEPES / 5 mM Tris, pH 7.4). Remove pretreatment buffer and take up buffer containing test compound ([ ¹⁴ C] methyl-α-D-glucopyranoside with methyl-α-D-glucopyranoside (0.1 mM for SGLT1 inhibition, 1 mM for SGLT2 inhibition) 200 mM of 140 mM NaCl, 2 mM KCl, 1 mM CaCl ₂ , 1 mM MgCl ₂ , 10 mM HEPES / 5 mM Tris, pH 7.4) was added, and an uptake reaction was performed at 37 ° C. for 30 minutes (SGLT1) or 1 hour (SGLT2). After the reaction, the cells are washed twice with 1 mL of washing buffer (10 mM methyl-α-D-glucopyranoside, 140 mM choline chloride 2 mM KCl, 1 mM CaCl ₂ , 1 mM MgCl ₂ , 10 mM HEPES / 5 mM Tris, pH 7.4), 0.2 Dissolved in 400 μL of M NaOH solution. Aquasol 2 (Perkin Elmer) was added and mixed well, and then the radioactivity was measured with a liquid scintillation counter (Beckman Coulter). As a control group, an uptake buffer containing no test compound was prepared. For basal uptake, an uptake buffer solution containing choline chloride instead of NaCl was prepared.
In determining the IC ₅₀ value, the test compound concentration (IC ₅₀ value) at which the sugar uptake amount was inhibited by 50% relative to the sugar uptake amount (100%) of the control group was calculated using 6 appropriate test compound concentrations. . The test results are shown in Table 3.
Table 3

Test example 3
Test to confirm hypoglycemic effect in STZ diabetic rats
1) Preparation of diseased animals and normal control animals 7-week-old SD / IGS rats (Nippon Charles River Co., Ltd., male) were fasted for about 16 hours and then streptozotocin (STZ) 50 mg / kg under ether anesthesia. Was administered into the tail vein to produce pathological animals. Similarly, under ether anesthesia, 1.25 mmol / L citric acid physiological saline 1 mL / kg was administered into the tail vein to obtain normal control animals. One week after administration of STZ or 1.25 mmol / L citrate physiological saline (8 weeks old), the rats were subjected to a hypoglycemic test.
2) Blood glucose lowering test The test substance was suspended in a 0.5% carboxymethylcellulose (CMC) aqueous solution and prepared to a concentration of 3 mg / 5 mL. On the day of the test, the onset of diabetes due to STZ was confirmed according to the following blood sampling method and blood glucose measurement method. Furthermore, the groups were divided so that there was as little difference as possible in the average value and variance of the blood glucose levels of each group, and the number of animals per group was 5 or 6. After measuring the body weight of the rat, the prepared test substance suspension was forcibly administered orally in a volume of 5 mL / kg with a rat oral administration sonde, and only 0.5% CMC aqueous solution was administered to the control group. Blood was collected at a total of 6 points immediately before the test substance administration (0 time) and 1, 2, 4, 6, 8 hours after oral administration. The test was conducted under free feeding and drinking water.
Blood collection was performed using an heparin-coated blood collection tube from the orbital sinus of a diseased animal under ether anesthesia, and the blood glucose level was measured using a glucose CII test Wako. The hypoglycemic action intensity (%) is calculated by calculating the area under the blood glucose level-time curve (AUC) using the trapezoidal method from the blood glucose level at any time from 0 to 8 hours in each test substance administration group. The ratio is shown in Table 4.
Table 4

Test example 4
The test substance for confirming the hypoglycemic effect in db / db mice was prepared by suspending in a 0.5% aqueous carboxymethylcellulose (CMC) solution to a concentration of 3 mg / 10 mL. On the day of the test, according to the blood sampling method and blood glucose level measuring method described below, the groups were divided so that there was as little difference as possible in the mean value and dispersion of the blood glucose level of db / db mice, and the number of mice per group was 5-8. It was. After measuring the body weight of the mouse, the prepared test substance suspension was forcibly administered orally in a volume of 10 mL / kg using a mouse oral administration sonde, and only a 0.5% CMC aqueous solution was administered to the control group. Blood was collected at a total of 6 points immediately before the test substance administration (0 time) and 1, 2, 4, 6, 8 hours after oral administration. The test was conducted under free feeding and drinking water.
Blood collection was performed using an heparin-coated blood collection tube from the orbital sinus of a diseased animal under ether anesthesia, and the blood glucose level was measured using a glucose CII test Wako. The hypoglycemic action intensity (%) is calculated by calculating the area under the blood glucose level-time curve (AUC) using the trapezoidal method from the blood glucose level at any time from 0 to 8 hours in each test substance administration group. Table 5 shows the ratio.
Table 5

According to the present invention, it is possible to provide a 1-thio-D-glucitol compound that exhibits a sodium-dependent glucose cotransporter (SGLT2) inhibitory activity and exhibits a hypoglycemic action by promoting urinary glucose excretion. It is possible to provide an excellent therapeutic agent for diabetes with a simple skeleton. In addition, the 1-thio-D-glucitol derivative of the present invention has good crystallinity, so it does not need to be co-crystallized with an amino acid or the like, is easy to purify, store and formulate, and is suitable for handling as a pharmaceutical product. It has become possible to provide preventive or therapeutic agents for diseases or conditions that can be improved by inhibiting SGLT2, diabetes, immune diseases, and the like.

Claims (2)

(1S) -1,5-anhydro-1- [3- (4-ethylbenzyl) phenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [3- (4-ethoxybenzyl) phenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [3-[(1-benzothien-2-yl) methyl] -4-methoxyphenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [4-chloro-3- (4-ethoxybenzyl) phenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [3- (4-ethoxybenzyl) -4-methoxyphenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [3-[(1-benzothien-2-yl) methyl] -4-chlorophenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [3-[(1-benzothien-2-yl) methyl] phenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [3- (4-ethoxybenzyl) -6-methoxy-phenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [3-[(1-benzothien-2-yl) methyl] -6-methoxyphenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [3- (4-ethoxybenzyl) -6-hydroxyphenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [4,6-dimethoxy-3- (4-ethoxybenzyl) phenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [3- (4-ethoxybenzyl) -4-fluorophenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [3- (4-ethoxybenzyl) -4-hydroxyphenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [4-chloro-3- (2,5-difluoro-4-ethoxybenzyl) phenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [4-chloro-3- (3-fluoro-4-ethoxybenzyl) phenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [4-chloro-3- (3-chloro-4-ethoxybenzyl) phenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [3- (4-ethoxybenzyl) -4-methylphenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [4-chloro-3- (3,4-dimethoxybenzyl) phenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [4-chloro-3- (4-methoxybenzyl) phenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [3- (4-ethoxybenzyl) -6-methoxy-4-methylphenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [3- (4-t-butylbenzyl) -4-chlorophenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [4-chloro-3- (2-fluoro-4-ethoxybenzyl) phenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [3-[(1-benzothien-2-yl) methyl] -4,6-dimethoxyphenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [4-chloro-3- (4-methylbenzyl) phenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [4-chloro-3- (4-methylthiobenzyl) phenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [4-chloro-3- (4-hydroxybenzyl) phenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [4-chloro-3- (4-ethylbenzyl) phenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [4-chloro-3- (4-isopropylbenzyl) phenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [4-chloro-3- (4-ethoxy-methylbenzyl) phenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [3- (4-ethoxybenzyl) -6-hydroxy-4-methylphenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [3-[(1-benzofuran-2-yl) methyl] -4-chlorophenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [4-chloro-3- (4-ethoxybenzyl) -6-methoxyphenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [3- (4-ethoxybenzyl) -4,6-dihydroxyphenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [3- (4-ethylbenzyl) -6-methoxy-4-methylphenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [4-chloro-3- (4-ethylbenzyl) -6-methoxyphenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [4-chloro-3- (4-isopropylbenzyl) -6-methoxyphenyl] -1-thio-D-glucitol,
(1S) -1,5-anhydro-1- [3- (4-methylbenzyl) -6-methoxy-4-methylphenyl] -1-thio-D-glucitol, or
(1S) -1,5-Anhydro-1- [3- (4-isopropylbenzyl) -6-methoxy-4-methylphenyl] -1-thio-D-glucitol
1-thio-D-glucitol or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient, and further comprising an oral solid composition containing lactose and magnesium stearate A drug for the prevention or treatment of diabetes, diabetes-related diseases or diabetic complications, including obesity, hyperinsulinemia, glucose metabolism disorder, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia Selected from the following: diseases, dyslipidemia, hypertension, congestive heart failure, edema, hyperuricemia and gout. The medicament according to claim 1, wherein the dose of 1-thio-D-glucitol or a pharmaceutically acceptable salt thereof or a hydrate thereof is 0.1 to 200 mg / kg body weight / day.