JP2011132138A - Carbamate derivative or pharmacologically acceptable salt thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new carbamate derivative having an insulin secretion-promoting action and a hypoglycemic action accompanied by the insulin secretion-promoting action, and to provide a pharmacologically acceptable salt thereof. <P>SOLUTION: There are provided the compound represented by formula (1), or the pharmacologically acceptable salt thereof. In the formula, A is a group represented by formula (a) or the like (m and n are 0, 1 or the like; R<SP>5</SP>is 1 to 6C alkoxycarbonyl which may be substituted or the like); R<SP>1</SP>is 6 to 10C aryl that may be substituted, or the like; R<SP>2a</SP>, R<SP>2b</SP>, R<SP>3a</SP>and R<SP>3b</SP>are each independently H, 1 to 6C alkyl which may be substituted, or the like; p is 1, 2, or the like; q is 0 or the like; X is O or S; Y is O or the like; Z is a single bond, O or the like. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a novel derivative having an insulin secretion promoting action and a blood glucose lowering action associated therewith, or a pharmacologically acceptable salt thereof. More specifically, the present invention relates to a novel compound or a novel pharmaceutical composition containing the compound that is effective in the treatment and / or prevention of diabetes.

  In recent years, due to changes in lifestyle habits, the number of diabetic patients has been increasing year by year, and is expected to exceed 300 million by 2025. For this reason, research on causes, prevention, and treatment related to diabetes has been vigorously conducted. There are mainly two types of diabetes. Insulin-dependent diabetes mellitus (IDDM) caused by a decrease in pancreatic insulin secretion function due to autoimmune diseases and the like, and a decrease in pancreatic insulin secretion function due to pancreatic exhaustion due to continuous high insulin secretion It is divided into the cause of non-insulin dependent diabetes mellitus (NIDDM). More than 95% of Japanese diabetic patients are said to be NIDDM. In patients with moderate symptoms, oral diabetic drugs (for example, insulin secretagogues such as sulfonylureas) are administered and more severe In some cases, insulin preparations are administered.

  Sulfonylurea agents stimulate pancreatic β cells and promote endogenous insulin secretion to lower blood sugar, and insulin preparations more directly and reliably lower blood sugar levels. Although each is an effective therapeutic means, both may cause hypoglycemia depending on the dose and timing. Thus, a better hypoglycemic agent has been eagerly desired.

  The cause of hypoglycemia is largely due to the balance between blood glucose level and drug administration timing. Since sulfonylurea and insulin preparations act regardless of blood sugar level, they act similarly when blood sugar is not elevated, leading to hypoglycemia. Therefore, if the action can be controlled in a blood sugar-dependent manner (that is, if it acts only during hyperglycemia), it can be a drug that does not cause hypoglycemia.

  As the carbamate derivative having an N-substituted piperidinyl group as a partial structure, the following formula (A)

［式中、Ｒ¹は、水素原子、ハロゲン原子等を表し；Ｒ²は、Ｃ_1-6アルキル、Ｃ_3-7シクロアルキル、−ＣＨ₂Ｃ_2-5アルケニル、−ＣＨ₂Ｃ_2-5アルキニル、フェニルまたはベンジルから選択される基で置換された、オキサジアゾールまたはチアジアゾール環を表し；Ｘは、ＮＨまたは酸素原子を表し；ｍは、０、１または２を表し；Ｒ³は、Ｃ_1-6アルキル、ベンジル等を表す。］、下記式（Ｂ）

[Wherein, R ¹ represents a hydrogen atom, a halogen atom or the like; R ² represents C _1-6 alkyl, C _3-7 cycloalkyl, —CH ₂ C _2-5 alkenyl, —CH ₂ C _2-5. Represents an oxadiazole or thiadiazole ring substituted with a group selected from alkynyl, phenyl or benzyl; X represents NH or an oxygen atom; m represents 0, 1 or 2; R ³ represents C ³ _1-6 represents alkyl, benzyl and the like. ], The following formula (B)

［式中、Ｒ₁は、ハロゲン原子、Ｃ_1-5アルキル、ＣＨ₂Ｆ、ＣＨＦ₂からなる基から選択され；Ｒ₂は、水素原子、Ｃ_1-5アルキル、アリール、ハロゲン、ヒドロキシ及びアルコキシからなる基から選択され；Ｒ₃は、水素原子、Ｃ_1-5アルキル等からなる基から選択され；Ｒ₆及びＲ₇は、水素原子、及びＣ_1-4アルキルからなる基から選択されるか、又は一緒になって５〜７員環でもよく；ｎは、１または２であり；ｍは、独立して１又は２である。］、及び下記式（Ｃ）

Wherein R ₁ is selected from the group consisting of a halogen atom, C _1-5 alkyl, CH ₂ F, CHF ₂ ; R ₂ is a hydrogen atom, C _1-5 alkyl, aryl, halogen, hydroxy and alkoxy R ₃ is selected from a group consisting of a hydrogen atom, C _1-5 alkyl and the like; R ₆ and R ₇ are selected from a group consisting of a hydrogen atom and C _1-4 alkyl Or together may be a 5- to 7-membered ring; n is 1 or 2; m is independently 1 or 2. And the following formula (C)

［式中、ＸはＯ，ＮＨまたはＣＨ₂であり、Ｗ、Ｙ、及びＺのいずれか一つは窒素原子で他はＣＨ₂であり、Ｒ¹は置換されていてもよいメトキシであり、Ｒ²は水素原子であり、Ｒ³は水素原子、ＣＯＯＲ⁴等であり、Ｒ⁴は置換されていてもよいＣ_1-8アルキル等、ｎは０〜２の整数であり、ｙは０〜２の整数であり、ｍは０または１である。］で表される化合物が知られている（特許文献１〜３）。

[Wherein, X is O, NH or CH ₂ , any one of W, Y and Z is a nitrogen atom and the other is CH ₂ , and R ¹ is an optionally substituted methoxy, R ² is a hydrogen atom, R ³ is a hydrogen atom, COOR ⁴ or the like, R ⁴ is an optionally substituted C _1-8 alkyl or the like, n is an integer of 0 to 2, and y is 0 to 0 It is an integer of 2 and m is 0 or 1. ] Are known (patent documents 1 to 3).

  However, it is not described in these documents that the compound group having the structure as in the present invention has an insulin secretion promoting action and a blood glucose lowering action associated therewith.

International Publication No. 98/20071 Pamphlet International Publication No. 2004/12684 pamphlet International Publication No. 2004/14425 Pamphlet

  An object of the present invention is to provide a novel compound useful as a therapeutic or prophylactic agent for diabetic diseases, which has a blood glucose lowering action based on an insulin secretion promoting action and is more satisfactory in terms of safety such as a risk of hypoglycemia. There is.

  The inventors of the present invention have made extensive studies in order to solve the above-mentioned problems. As a result, a compound represented by the following formula (1) or a pharmacologically acceptable salt thereof (hereinafter referred to as a compound of the present invention as necessary): Has been found to have an insulin secretion action, and the present invention has been completed.

That is, the present invention is as follows.
Item 1: A compound represented by formula (1) or a pharmacologically acceptable salt thereof.

[Wherein A represents the following (a) to (d)

で表されるいずれか一つの基であり（ここにおいてＲ⁴は下記

(Wherein R ⁴ is the following)

のいずれか一つの基であり；
ｍおよびｎは、各々独立して０、１または２であり；
Ｒ⁵は、シアノ基、置換されていてもよいＣ_1-6アルコキシカルボニル基、置換されていてもよいＣ_3-7シクロアルコキシカルボニル基、置換されていてもよい４員〜７員の飽和複素環オキシカルボニル基、置換されていてもよいアミノカルボニル基、置換されていてもよい４員〜７員の環状アミノカルボニル基、置換されていてもよいＣ_1-6アルキル基、置換されていてもよいＣ_3-7シクロアルキル基、置換されていてもよいＣ_3-7シクロアルキルＣ_1-4アルキル基、置換されていてもよいＣ_1-6アルキルカルボニル基、置換されていてもよいＣ_3-7シクロアルキルカルボニル基、置換されていてもよいＣ_3-7シクロアルキルＣ_1-4アルキルカルボニル基、置換されていてもよいＣ_7-14アラルキル基、置換されていてもよい５員もしくは６員の単環式ヘテロアリール基、置換されていてもよい５員〜１０員の単環式もしくは多環式ヘテロアリールＣ_1-4アルキル基、または置換されていてもよい５員もしくは６員の単環式ヘテロアリールカルボニル基である。）；
Ｒ¹は、置換されていてもよいＣ_6-10アリール基、または置換されていてもよい５員〜１０員の単環式もしくは多環式ヘテロアリール基であり；
Ｒ^2a、Ｒ^2b、Ｒ^3аおよびＲ^3bは、
（ｉ）Ｒ^2a、Ｒ^2b、Ｒ^3аおよびＲ^3bが、各々独立して、水素原子、置換されていてもよいＣ_1-6アルキル基、置換されていてもよいＣ_3-7シクロアルキル基、置換されていてもよいＣ_1-6アルコキシ基、置換されていてもよいＣ_3-7シクロアルコキシ基、置換されていてもよいアミノ基、置換されていてもよい４員〜７員の環状アミノ基、または置換されていてもよい４員〜７員の飽和複素環基であるか、
（ｉｉ）Ｒ^2aおよびＲ^2bが、各々独立して、水素原子、置換されていてもよいＣ_1-6アルキル基、置換されていてもよいＣ_3-7シクロアルキル基、置換されていてもよいＣ_1-6アルコキシ基、置換されていてもよいＣ_3-7シクロアルコキシ基、置換されていてもよいアミノ基、置換されていてもよい４員〜７員の環状アミノ基、または置換されていてもよい４員〜７員の飽和複素環基であり、Ｒ^3aとＲ^3bが、一緒になってオキソ基であるか、または
（ｉｉｉ）Ｒ^2aおよびＲ^2bが、一緒になってオキソ基であり、Ｒ^3aとＲ^3bが、各々独立して、水素原子、置換されていてもよいＣ_1-6アルキル基、置換されていてもよいＣ_3-7シクロアルキル基、置換されていてもよいＣ_1-6アルコキシ基、置換されていてもよいＣ_3-7シクロアルコキシ基、置換されていてもよいアミノ基、置換されていてもよい４員〜７員の環状アミノ基、または置換されていてもよい４員〜７員の飽和複素環基であり；
ｐは１、２、３、または４であり（Ｒ^2aおよびＲ^2bが、一緒になってオキソ基の場合には、ｐは１に限る。）；
ｑは０、１、２または３であり（Ｒ^3aとＲ^3bが、一緒になってオキソ基の場合には、ｑは１に限る。）；
Ｘは、酸素原子、または硫黄原子であり；
Ｙは、酸素原子、硫黄原子、またはＮＲ⁶であり（ここにおいて、Ｒ⁶は、水素原子、置換されていてもよいＣ_1-6アルキル基、または置換されていてもよいＣ_3-7シクロアルキル基である。）；
Ｚは、単結合、ビニレン、エチニレン、酸素原子、硫黄原子、またはＮＲ⁷である（ここにおいて、Ｒ⁷は、水素原子、置換されていてもよいＣ_1-6アルキル基、または置換されていてもよいＣ_3-7シクロアルキル基である。）である。但し、式（１）で表される化合物において、Ｒ¹が、１〜２個のＣ_1-4アルコキシで置換されているフェニルである場合には、Ａが式（ａ）で表される基におけるＲ⁵は、Ｃ_1-6アルコキシカルボニル基、Ｃ_3-7シクロアルコキシカルボニル基、Ｃ_1-6アルキルカルボニル基、Ｃ_3-7シクロアルキルカルボニル基、およびＣ_3-7シクロアルキルＣ_1-4アルキルカルボニル基で表される化合物ではなく、Ｒ¹が、アミノで置換されているフェニルである場合には、Ａが式（ａ）で表される基におけるＲ⁵は、５員もしくは６員の単環式へテロアリール基である化合物ではない。］

Any one of the groups;
m and n are each independently 0, 1 or 2;
R ⁵ represents a cyano group, an optionally substituted C _1-6 alkoxycarbonyl group, an optionally substituted C _3-7 cycloalkoxycarbonyl group, an optionally substituted 4- to 7-membered saturated complex. Ring oxycarbonyl group, optionally substituted aminocarbonyl group, optionally substituted 4- to 7-membered cyclic aminocarbonyl group, optionally substituted C _1-6 alkyl group, optionally substituted A good C _3-7 cycloalkyl group, an _optionally substituted C _3-7 cycloalkyl C _1-4 alkyl group, an optionally substituted C _1-6 alkylcarbonyl group, an optionally substituted C _{3 -7} cycloalkylcarbonyl group, optionally substituted C _3-7 cycloalkyl C _1-4 alkylcarbonyl group, optionally substituted C _7-14 aralkyl group, optionally substituted 5 or 6 Monocyclic hete Aryl group, a substituted monocyclic also be 5-membered to 10-membered optionally or polycyclic heteroaryl C _1-4 alkyl group or a monocyclic heteroaryl-carbonyl 5- may be substituted or 6-membered, It is a group. );
R ¹ is an optionally substituted C _6-10 aryl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group;
R ^2a , R ^2b , R ^3а and R ^3b are
(I) R ^2a , R ^2b , R ^3а and R ^3b are each independently a hydrogen atom, an ^optionally substituted C _1-6 alkyl group, or an ^optionally substituted C _3-7 cycloalkyl group. , An optionally substituted C _1-6 alkoxy group, an optionally substituted C _3-7 cycloalkoxy group, an optionally substituted amino group, an optionally substituted 4- to 7-membered cyclic group An amino group or an optionally substituted 4- to 7-membered saturated heterocyclic group,
(Ii) R ^2a and R ^2b are each independently a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-7 cycloalkyl group, or a substituted A good C _1-6 alkoxy group, an optionally substituted C _3-7 cycloalkoxy group, an optionally substituted amino group, an optionally substituted 4- to 7-membered cyclic amino group, or a substituted An optionally substituted 4- to 7-membered saturated heterocyclic group, and R ^3a and R ^3b together are an oxo group, or (iii) R ^2a and R ^2b are together oxo Each of R ^3a and R ^3b is independently a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-7 cycloalkyl group, also a C _1-6 alkoxy group, an optionally substituted C _3-7 cycloalkoxy group, optionally substituted It is also an amino group, optionally substituted 4-membered to 7-membered cyclic amino group or a substituted 4-membered to 7-membered may be saturated heterocyclic group;
p is 1, 2, 3, or 4 (when R ^2a and R ^2b together are an oxo group, p is limited to 1);
q is 0, 1, 2 or 3 (when R ^3a and R ^3b are together an oxo group, q is limited to 1);
X is an oxygen atom or a sulfur atom;
Y is an oxygen atom, a sulfur atom, or NR ⁶ (wherein R ⁶ is a hydrogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _3-7 cyclohexane). An alkyl group);
Z is a single bond, vinylene, ethynylene, an oxygen atom, a sulfur atom, or NR ⁷ (wherein R ⁷ is a hydrogen atom, an optionally substituted C _1-6 alkyl group, or a substituted _{Or a} C _3-7 cycloalkyl group. However, in the compound represented by the formula (1), when R ¹ is phenyl substituted with ¹ to 2 C _1-4 alkoxy, A is a group represented by the formula (a). R ⁵ in C _1-6 alkoxycarbonyl group, C _3-7 cycloalkoxycarbonyl group, C _1-6 alkylcarbonyl group, C _3-7 cycloalkylcarbonyl group, and C _3-7 cycloalkyl C _1-4 When R ¹ is phenyl substituted with amino, not a compound represented by an alkylcarbonyl group, R ⁵ in the group represented by formula (a) is a 5-membered or 6-membered It is not a compound that is a monocyclic heteroaryl group. ]

Term 2: R ¹ is
A C _6-10 aryl group (the group is
1: halogen atom,
2: C _1-6 alkyl group (the group is
(A) amino (the amino is
(A1) C _1-6 alkyl (the alkyl is
(A11) hydroxy,
(A12) C _1-6 alkoxy,
(A13) carboxyl,
(A14) aminocarbonyl,
(A15) di-C _1-6 alkylamino,
(A16) mono- or di-C _1-6 alkylaminocarbonyl,
(A17) C _1-6 alkylcarbonylamino,
(A18) mono or di-C _1-6 alkylaminocarbonylamino, or (a19) optionally substituted with C _1-6 alkoxycarbonylamino. ),
(A2) C _3-7 cycloalkyl,
(A3) C _3-7 cycloalkyl C _1-4 alkyl,
(A4) a 5- or 6-membered saturated heterocyclic ring (which may be substituted with C _1-6 alkyl),
(A5) 5 or 6 membered saturated heterocyclic-C _1-4 alkyl,
(A6) 5- or 6-membered monocyclic heteroaryl, or (a7) optionally substituted with a 5- or 6-membered monocyclic heteroaryl-C _1-4 alkyl. ),
(B) hydroxy,
(C) a 4- to 7-membered cyclic amino (the ring is
(C1) hydroxy,
(C2) C _1-6 alkyl (the group may be substituted with hydroxy or C _1-6 alkoxy),
(C3) C _1-6 alkoxy, or (c4) optionally substituted with di-C _1-6 alkylamino. ),
(D) aminocarbonyl (the amino may be substituted with one or two groups selected from the group consisting of the above (a1) to (a7)).
(E) C _1-6 alkoxy (the group is
(E1) hydroxy,
(E2) C _1-6 alkoxy,
(E3) C _3-7 cycloalkyl,
(E4) C _3-7 cycloalkoxy,
(E5) a 4-membered to 6-membered saturated heterocyclic ring (the ring may be substituted with C _1-6 alkyl),
(E6) a 4- to 7-membered cyclic amino,
(E7) C _1-6 alkylcarbonylamino,
(E8) Di-C _1-6 alkylamino, or (e9) optionally substituted with di-C _1-6 alkylaminocarbonyl. ),
3: C _1-6 alkylsulfonyl group (the C _1-6 alkyl group is
(A) C _3-7 cycloalkyl, or (b) optionally substituted with a 4-6 membered saturated heterocycle. ),
4: C _3-7 cycloalkylsulfonyl group (this group may be substituted with C _1-6 alkyl),
5: 4-membered to 6-membered saturated heterocyclic sulfonyl group,
6: Amino group (the amino is substituted with one or two groups of the same or different types selected from the group consisting of the above (a1) to (a7)),
7: Aminosulfonyl group (the amino is the same or different 1-2 C _1-6 alkyl (the alkyl is substituted with hydroxy, C _1-4 alkoxy, or di-C _1-6 alkylamino) And may be substituted with
8: 4-membered to 7-membered cyclic amino group (the ring may be substituted with the above (c1) to (c4)),
9: aminocarbonyl group (the amino may be substituted with one or two groups of the same or different types selected from the group consisting of the above (a1) to (a7));
10: 4- to 7-membered cyclic aminocarbonyl group (the ring may be substituted with the above-mentioned (c1) to (c4)),
11: carboxyl group,
12: C _1-6 alkoxy group,
13: C _1-6 alkoxycarbonyl group,
14: C _1-6 alkylcarbonylamino group,
15: C _3-7 cycloalkylcarbonylamino group,
16: C _3-7 cycloalkyl C _1-6 alkylcarbonylamino group,
17: mono- or di-C _1-6 alkylaminocarbonylamino group,
18: C _1-6 alkoxycarbonylamino group,
It may be substituted with 1 to 3 groups of the same or different types selected from the group consisting of a 19: C _6-10 aryl group and a 20: 5-membered or 6-membered monocyclic heteroaryl group. ),
Or a 5- or 6-membered monocyclic heteroaryl group (the heteroaryl is substituted with 1 to 3 groups of the same or different types selected from the group consisting of 1 to 20 in the C _6-10 aryl group) Or a pharmacologically acceptable salt thereof.

Term 3: R ¹ is
A C _6-10 aryl group (the group is
1: halogen atom,
2: C _1-6 alkylsulfonyl group,
3: Aminocarbonyl group (the amino is
(A) C _1-6 alkyl (which may be substituted with hydroxy), and (b) substituted with 1-2 groups selected from the group consisting of C _3-7 cycloalkyl It may be. ),
4: 4- to 7-membered cyclic aminocarbonyl group,
5: Carboxyl group, or 6: C _1-6 alkoxy carboxyl group may be substituted. Or a pharmacologically acceptable salt thereof.

Item 4: A is the following formula (a)

で表される基である、項１〜項３のいずれか一項に記載の化合物、またはその薬理学的に許容される塩。

The compound as described in any one of claim | item 1 -3 which is group represented by these, or its pharmacologically acceptable salt.

Item 5: The compound according to Item 4, wherein m and n are 1, or a pharmaceutically acceptable salt thereof.

Item 6: R ⁵ is
1: C _1-6 alkoxycarbonyl group (the group is
(A) 1 to 6 fluorine atoms,
(B) C _3-7 cycloalkyl (the group is
(I) C _1-6 alkyl,
(Ii) C _3-7 cycloalkyl, or (iii) C _3-7 cycloalkyl C _1-4 alkyl may be substituted. ), Or (c) a 4- to 6-membered saturated heterocyclic ring (the group is
(I) C _1-6 alkyl,
(Ii) C _3-7 cycloalkyl, or (iii) C _3-7 cycloalkyl C _1-4 alkyl may be substituted. ) May be substituted. ),
2: C _3-7 cycloalkoxycarbonyl group (the group is
(A) C _1-6 alkyl,
(B) C _3-7 cycloalkyl, or (c) C _3-7 cycloalkyl C _1-4 alkyl may be substituted. ),
3: 4-membered to 6-membered saturated heterocyclic oxycarbonyl group (the group is
(A) C _1-6 alkyl,
(B) C _3-7 cycloalkyl, or (c) C _3-7 cycloalkyl C _1-4 alkyl may be substituted. ),
4: C _1-6 alkylcarbonyl group,
5: C _3-7 cycloalkylcarbonyl group,
6: C _3-7 cycloalkyl C _1-4 alkylcarbonyl group,
7: C _1-6 alkyl group,
8: C _3-7 cycloalkyl group,
9: C _3-7 cycloalkyl C _1-4 alkyl group,
10: C _7-14 aralkyl group,
11: 5 or 6 membered monocyclic heteroaryl group (the ring is
(A) C _1-6 alkyl,
(B) C _3-7 cycloalkyl, and (c) C _3-7 cycloalkyl C _1-4 alkyl may be substituted with 1 to 3 groups of the same or different types selected from the group consisting of. Or 12: The compound according to any one of Items 1 to 5, which is a cyano group, or a pharmacologically acceptable salt thereof.

Item 7: R ⁵ is
1: C _1-6 alkoxycarbonyl group (the alkoxy may be substituted with 1 to 6 fluorine atoms),
2. A C _3-7 cycloalkoxycarbonyl group (the cycloalkoxy may be substituted with C _1-6 alkyl), or a 3: 5-membered or 6-membered monocyclic heteroaryl group (the ring is represented by C Item 6. The compound according to Item 6, or a pharmacologically acceptable salt thereof, which may be substituted with _1-6 alkyl.

Item 8: The compound according to any one of Items 1 to 7, wherein R ^2a , R ^2b , R ^3a and R ^3b are each independently a hydrogen atom or a C _1-6 alkyl group, or Its pharmacologically acceptable salt.

Item 9: The compound according to Item 8, or a pharmacologically acceptable salt thereof, wherein R ^2a , R ^2b , R ^3a and R ^3b are all hydrogen atoms.

Item 10: The items 1 to 7, wherein R ^2a and R ^2b are each independently a hydrogen atom or a C _1-6 alkyl group, and R ^3a and R ^3b are together an oxo group. The compound according to any one of the above, or a pharmacologically acceptable salt thereof.

Item 11: The compound according to Item 10, or a pharmacologically acceptable salt thereof, wherein R ^2a and R ^2b are both hydrogen atoms.

Item 12: The compound according to any one of Items 1 to 11, or a pharmacologically acceptable salt thereof, wherein p is 2, 3, or 4.

Item 13: The compound according to Item 12, wherein p is 2, or a pharmaceutically acceptable salt thereof.

Item 14: The compound according to Item 12, or a pharmacologically acceptable salt thereof, wherein p is 3.

Item 15: The compound according to any one of Items 1 to 14, or a pharmacologically acceptable salt thereof, wherein q is 0.

Item 16: The compound or pharmacologically acceptable salt according to any one of Items 1 to 15, wherein X is an oxygen atom.

Item 17: The compound or pharmacologically acceptable salt according to any one of Items 1 to 15, wherein X is a sulfur atom.

Item 18: The compound according to any one of Items 1 to 17, or a pharmacologically acceptable salt thereof, wherein Y is an oxygen atom.

Item 19: The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof, wherein Z is a single bond, an oxygen atom, or NR ⁷ .

Item 20: The compound according to Item 19, or a pharmaceutically acceptable salt thereof, wherein Z is a single bond.

Item 21: The compound according to Item 19, or a pharmacologically acceptable salt thereof, wherein Z is an oxygen atom.

Item 22: The compound according to Item 19, or a pharmacologically acceptable salt thereof, wherein Z is NR ⁷ .

Item 23: The compound according to Item 22, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is a C _1-6 alkyl group.

Item 24: A pharmaceutical composition comprising the compound according to any one of Items 1 to 23 or a pharmacologically acceptable salt thereof as an active ingredient.

Item 25: An insulin secretagogue comprising the compound according to any one of Items 1 to 23 or a pharmacologically acceptable salt thereof as an active ingredient.

Item 26: A therapeutic agent for a disease caused by hyperglycemia containing the compound according to any one of Items 1 to 23 or a pharmacologically acceptable salt thereof as an active ingredient.

Item 27: The disease caused by hyperglycemia is diabetes, diabetic complications, obesity, hyperinsulinemia, abnormal glucose metabolism, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, abnormal lipid metabolism or Item 27. The therapeutic agent according to Item 26, which is atherosclerosis.

  Since the compound of the present invention has an insulin secretion promoting action, it is safe for mammals (for example, humans, mice, dogs, rats, cows, etc.), diabetes, impaired glucose tolerance, fasting glucose abnormalities, diabetic complications ( Prevention and / or prevention of obesity, hyperinsulinemia, pancreatitis, chronic liver disease, acromegaly, Cushing's syndrome, pheochromocytoma, glucagonoma, hyperthyroidism, etc. Useful for treatment.

The present invention is described in further detail below.
In the present specification, the number of substituents in the group defined as “may be substituted” or “substituted” is not particularly limited as long as substitution is possible, and is one or more. In addition, unless otherwise specified, the description of each group also applies when the group is a part of another group or a substituent.

  In the present specification, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. Preferably they are a fluorine atom or a chlorine atom.

Examples of the “C _1-6 alkyl group” include linear or branched alkyl groups having 1 to 6 carbon atoms. Specifically, methyl, ethyl, propyl, 1-methylethyl, butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl, pentyl, 3-methylbutyl, 2-methylbutyl, 2,2-dimethyl Examples include propyl, 1-ethylpropyl, 1,1-dimethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl and the like. Preferably, a C1-C4 alkyl group ( _C1-4 alkyl group) is mentioned.

Examples of the “C _3-7 cycloalkyl group” include a _{3- to} 7-membered cycloalkyl group. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Preferably, a C3-C6 cycloalkyl group ( _C3-6 cycloalkyl group) is mentioned.

Examples of the “C _1-6 alkoxy group” include linear or branched alkoxy groups having 1 to 6 carbon atoms. Specifically, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylpropoxy, 1-methylpropoxy, 1,1-dimethylethoxy, pentyloxy, 3-methylbutoxy, 2-methylbutoxy, 2,2 -Dimethylpropoxy, 1-ethylpropoxy, 1,1-dimethylpropoxy, hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutoxy, 2 , 2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy and the like. Preferably, a C1-C4 alkoxy group ( _C1-4 alkoxy group) is mentioned.

"C _3-7 cycloalkyl" moiety of the "C _3-7 cycloalkoxy group" is the same as the "C _3-7 cycloalkyl". Specific examples of “C _3-7 cycloalkoxy group” include, for example, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and the like. Preferably, a C3-C6 cycloalkoxy group ( _C3-6 cycloalkoxy group) is mentioned.

Examples of the “C _1-6 alkoxycarbonyl group” include linear or branched alkoxycarbonyl groups having 1 to 6 carbon atoms. Specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-methylethoxycarbonyl, butoxycarbonyl, 2-methylpropoxycarbonyl, 1-methylpropoxycarbonyl, 1,1-dimethylethoxycarbonyl, and the like.

"C _3-7 cycloalkoxy" portion of the "C _3-7 cycloalkoxy group" is the same as the "C _3-7 cycloalkoxy". Specific examples of the “C _3-7 cycloalkoxy group” include, for example, cyclopropoxycarbonyl, cyclobutoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, cycloheptyloxycarbonyl, and the like. Preferably, a C3-C6 cycloalkoxycarbonyl group ( _C3-6 cycloalkoxycarbonyl group) is mentioned.

"C _1-6 alkyl" moiety of the "C _1-6 alkylcarbonyl group" is the same as the "C _1-6 alkyl". Specific examples of “C _1-6 alkylcarbonyl group” include, for example, methylcarbonyl, ethylcarbonyl, propylcarbonyl, 1-methylethylcarbonyl, butylcarbonyl, 2-methylpropylcarbonyl, 1-methylpropylcarbonyl, or 1,1. -Dimethyl ethyl carbonyl etc. are mentioned.

"C _3-7 cycloalkyl" moiety of the "C _3-7 cycloalkyl group" is the same as the "C _3-7 cycloalkyl". Specific examples of the “C _3-7 cycloalkylcarbonyl group” include, for example, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl and the like. Preferably, a C3-C6 cycloalkyl carbonyl group ( _C3-6 cycloalkyl carbonyl group) is mentioned.

"C _1-6 alkylcarbonyl" portion of the "C _1-6 alkylcarbonyloxy group" is the same as the "C _1-6 alkylcarbonyl". Specific examples of “C _1-6 alkylcarbonyloxy group” include, for example, methylcarbonyloxy and the like.

"C _1-6 alkyl" moiety of the "C _1-6 alkylsulfonyl group" is the same as the "C _1-6 alkyl". Specific examples of the “C _1-6 alkylsulfonyl group” include, for example, methanesulfonyl, ethanesulfonyl, propylsulfonyl, 1-methylethylsulfonyl, 2-methylethylsulfonyl, 1-methylpropylsulfonyl, 2-methylpropylsulfonyl, Examples include 1,1-dimethylethylsulfonyl or butylsulfonyl.

"C _3-7 cycloalkyl" moiety of the "C _3-7 cycloalkyl sulfonyl group" is the same as the "C _3-7 cycloalkyl". Specific examples of the “C _3-7 cycloalkylsulfonyl group” include, for example, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, cycloheptylsulfonyl and the like. Preferably, a C3-C6 cycloalkyl sulfonyl group ( _C3-6 cycloalkyl sulfonyl group) is mentioned.

The “C _3-7 cycloalkyl C _1-4 alkyl group” means a group in which the above “C _3-7 cycloalkyl” is substituted with “C _1-4 alkyl”. Specific examples of “C _3-7 cycloalkyl C _1-4 alkyl group” include, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylsmethyl, cycloheptylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl and the like. Is mentioned. Preferably, a C3-C6 cycloalkyl _C1-4 alkyl group ( _C3-6 cycloalkyl _C1-4 alkyl group) is mentioned.

Examples of the “C _6-10 aryl group” include aryl groups having 6 to 10 carbon atoms, and specific examples include phenyl, 1-naphthyl, 2-naphthyl and the like.

In the “C _6-10 aryl group”, “C ₆ aryl” and one or more hetero atoms selected from a 5-membered or 6-membered nitrogen atom, sulfur atom or oxygen atom are the same or different (for example, 1 to 4). Or a group condensed with a 5- to 6-membered cycloalkyl ring (cyclopentane or cyclohexane). Specific examples of the group include groups represented by the following formulas.

However, in the case of a C _6-10 aryl group that is condensed, only the aromatic ring has a “group” bond. For example, the following formula

で表される「Ｃ_6-10アリール基」の場合には、「基」が４−、５−、６−、または７−位で結合することを意味する。

In the case of the “C _6-10 aryl group” represented by the _formula, it means that the “group” is bonded at the 4-, 5-, 6-, or 7-position.

Examples of the “heteroaryl group” include a 5-membered to 10-membered monocyclic or polycyclic group, and the group includes the same or different heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. It is different and includes one or more (for example, 1 to 4). Preferable examples include a 5-membered or 6-membered monocyclic group, and the like includes one heteroatom selected from a nitrogen atom, a sulfur atom, and an oxygen atom. Specific examples of the “heteroaryl group” include a group represented by the following formula.

  The bond across the ring in the above formula means that the “group” is bonded at a substitutable position in the ring. For example, the following formula

のヘテロアリール基の場合には、２−フリル基、または３−フリル基であることを意味する。

In the case of the heteroaryl group, it means a 2-furyl group or a 3-furyl group.

  Further, when the “heteroaryl group” is a polycyclic group, for example, the following formula

で表される場合には、２−ベンゾフリル、または３−ベンゾフリルの他に、４−、５−、６−または７−ベンゾフリルであってもよい。但し、芳香環と非芳香族環（ピペリジンなど）とが縮環する多環式へテロアリール基の場合には、芳香環のみが「基」の結合手を有する。例えば、下記式

In addition to 2-benzofuryl or 3-benzofuryl, 4-, 5-, 6-, or 7-benzofuryl may be used. However, in the case of a polycyclic heteroaryl group in which an aromatic ring and a non-aromatic ring (such as piperidine) are condensed, only the aromatic ring has a “group” bond. For example, the following formula

で表される「多環式のヘテロアリール基」の場合には、「基」が２−、３−、または４−位で結合することを意味する。

In the case of the “polycyclic heteroaryl group” represented by the formula, it means that the “group” is bonded at the 2-, 3-, or 4-position.

  Examples of the “saturated heterocyclic group” include 4 to 4 heteroatoms selected from 0 to 2 nitrogen atoms, 0 to 1 oxygen atoms, and 0 to 1 sulfur atoms. A 7-membered saturated heterocyclic group and the like. In the group, a carbon atom constituting the ring is a bond of “group”. Specifically, for example, azetidinyl, oxetanyl, tetrahydropyranyl, tetrahydropyridinyl, pyrrolidinyl, oxopyrrolidinyl, oxopiperidinyl, oxopiperazinyl, oxomorpholinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, Examples thereof include thiomorpholinyl, dioxoimidazolidinyl, tetrahydrotriazoloazepinyl, oxodihydroacridinyl, tetrahydrocyclopentachromenyl, oxobenzoxathiolyl, dihydroindenyl, azepanyl or oxoazepanyl.

The “C _7-14 aralkyl group” means a group in which a “C _6-10 aryl group” is substituted with a “C _1-4 alkyl group”. Preferably, a C7-10 aralkyl group ( _C7-10 aralkyl group) is mentioned. Specific examples include benzyl, phenethyl, phenylpropyl, naphthylmethyl, and the like.

“Heteroaryl C _1-4 alkyl group” means a group in which “heteroaryl group” is substituted with “C _1-4 alkyl group”. Preferably, it is a 5-membered or 6-membered monocyclic heteroaryl C _1-4 alkyl group. Specific examples include pyrrolylmethyl and the like.

The "saturated heterocyclic -C _1-4 alkyl group", "saturated heterocyclic group" means a group obtained by substituting the "C _1-4 alkyl group". A 4- to 7-membered saturated heterocyclic-C _1-4 alkyl group is preferable. Specific examples include azetidinylmethyl and the like.

  The “saturated heterocyclic ring” part of the “saturated heterocyclic carbonyl group” is the same as the “saturated heterocyclic ring”. Specific examples of the “saturated heterocyclic carbonyl group” include, for example, a 4-membered to 7-membered saturated heterocyclic carbonyl group. Specifically, tetrahydropyran carbonyl etc. are mentioned, for example.

  The “saturated heterocyclic” part of the “saturated heterocyclic sulfonyl group” is the same as the “saturated heterocyclic ring”. Specific examples of the “saturated heterocyclic sulfonyl group” include, for example, a 4- to 7-membered saturated heterocyclic sulfonyl group. Specifically, tetrahydropyransulfonyl etc. are mentioned, for example.

"C _3-7 cycloalkyl" moiety of the "C _3-7 cycloalkyl C _1-4 alkyl group" is the same as the "C _3-7 cycloalkyl". Preferred is a cycloalkyl C _1-4 alkyl group having 3 to 6 carbon atoms (C _3-6 cycloalkyl C _1-4 alkyl group). Specific examples of “C _3-7 cycloalkyl C _1-4 alkylcarbonyl group” include, for example, cyclopropylmethylcarbonyl and the like.

  The “heteroaryl” part of the “heteroarylcarbonyl group” is the same as the above “heteroaryl”. Specific examples of the “heteroarylcarbonyl group” include, for example, a 5-membered or 6-membered monocyclic heteroarylcarbonyl group. Specific examples include pyrrole carbonyl and the like.

"C _6-10 aryl" moiety of the "C _6-10 aryloxy group" is the same as the "C _6-10 aryl". Specific examples of “C _6-10 aryloxy group” include, for example, phenyloxy and the like.

The “C _7-14 aralkyloxy group” means a group in which the “C _7-14 aralkyl group” is substituted with an oxygen atom. Preferably, it is a C7-10 aralkyloxy group ( _C7-10 aralkyloxy group). Specific examples include benzyloxy, phenethyloxy, phenylpropyloxy, naphthylmethyloxy, and the like.

  The “heteroaryl” part of the “heteroaryloxy group” means a group in which the “heteroaryl group” is substituted with an oxygen atom. Specific examples include pyrrolyloxy and the like.

  The “saturated heterocyclic oxy group” means a group in which the “saturated heterocyclic group” is substituted with an oxygen atom. Preferably, it is a “4- to 7-membered saturated heterocyclic oxy group”. Specific examples include tetrahydropyranyloxy and the like.

  The “saturated heterocyclic oxy” part of the “saturated heterocyclic oxycarbonyl group” is the same as the above “saturated heterocyclic oxy”. Preferably, it is a “4- to 7-membered saturated heterocyclic oxycarbonyl group”. Specific examples include tetrahydropyranyloxycarbonyl and the like.

  Examples of the “optionally substituted amino group” include amino, mono- or di-substituted amino, and 4- to 7-membered cyclic amino.

Examples of the substituent of “mono- or di-substituted amino” include “C _1-6 alkyl”, “C _3-7 cycloalkyl”, “C _3-7 cycloalkyl C _1-4 alkyl”, “4- to 7-membered saturated heterocycle”, “4- to 7-membered saturated heterocycle-C _1-4 alkyl”, “C _6-10 aryl”, “C _7-14 aralkyl”, “5-membered or The same or different 1-2 groups selected from the group consisting of “6-membered monocyclic heteroaryl” and “5-membered or 6-membered monocyclic heteroaryl C _1-4 alkyl”.

Specific examples of “mono-substituted amino” include, for example,
“Mono-C _1-6 alkylamino” (eg, methylamino, etc.),
“C _3-7 cycloalkylamino” (eg, cyclopropylamino, etc.),
“(C _3-7 cycloalkyl C _1-4 alkyl) amino” (eg, cyclopropylmethylamino, etc.),
“4- to 7-membered saturated heterocyclic-amino” (for example, tetrahydropyranylamino and the like),
“(4- to 7-membered saturated heterocyclic-C _1-4 alkyl) amino” (for example, tetrahydropyranylmethylamino and the like),
“(C _6-10 aryl) amino” (for example, phenylamino and the like),
“(C _7-14 aralkyl) amino” (eg, benzylamino),
“(5- or 6-membered monocyclic heteroaryl) amino” (eg, pyrrolylamino, etc.),
“(5- or 6-membered monocyclic heteroaryl C _1-4 alkyl) amino” (for example, pyrrolylmethylamino and the like).

Specific examples of “di-substituted amino” include, for example,
“Di-C _1-6 alkylamino” (eg, dimethylamino, etc.),
“N— (C _1-6 alkyl) -N— (C _3-7 cycloalkyl) amino” (eg, methylcyclopropylamino, etc.),
“N— (C _1-6 alkyl) -N— (5- or 6-membered saturated heterocyclic ring) amino” (for example, methyltetrahydropyranylamino and the like) and the like can be mentioned.

  The “4- to 7-membered cyclic amino group” is, for example, a 4- to 7-membered monocyclic ring having 1 to 3 of the same or different hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. An amino group is mentioned. In the group, a nitrogen atom constituting the ring is a bond of “group”. Specific examples include azetidino, pyrrolidino, imidazolidino, oxazolidino, thiazolidino, piperazino, piperidino, morpholino, thiomorpholino, azepano or oxoazepano.

  The “4- to 7-membered cyclic amino group” may form a condensed ring with a 6-membered aromatic hydrocarbon and a 5-membered or 6-membered heterocycle. Specific examples include “groups” shown below.

"Mono -C _1-6 alkylamino" moiety of the "mono--C _1-6 alkylaminocarbonyl group" is the same as the "mono--C _1-6 alkylamino." Specific examples of the “C _1-6 alkylaminocarbonyl group” include, for example, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, 1-methylethylaminocarbonyl, butylaminocarbonyl, 2-methylpropylaminocarbonyl, 1- Examples thereof include methylpropylaminocarbonyl and 1,1-dimethylethylaminocarbonyl.

"Di -C _1-6 alkylamino" moiety of "di -C _1-6 alkylaminocarbonyl group" is the same as the "di -C _1-6 alkylamino." Specific examples of the “di-C _1-6 alkylaminocarbonyl group” include, for example, dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, di-1-methylethylaminocarbonyl, dibutylaminocarbonyl, di-2-methyl. Examples thereof include propylaminocarbonyl, di-1-methylpropylaminocarbonyl, di-1,1-dimethylethylaminocarbonyl and the like.

"Mono -C _1-6 alkylamino" moiety of the "mono--C _1-6 alkylaminocarbonyl group" is the same as the "mono--C _1-6 alkylamino." Specific examples of “C _1-6 alkylaminocarbonylamino group” include, for example, methylaminocarbonylamino and the like.

"Di -C _1-6 alkylamino" moiety of "di -C _1-6 alkylaminocarbonyl group" is the same as the "di -C _1-6 alkylamino." Specific examples of the “di-C _1-6 alkylaminocarbonylamino group” include dimethylaminocarbonylamino and the like.

"Mono -C _1-6 alkylamino" moiety of the "mono--C _1-6 alkyl aminosulfonyl group" is the same as the "mono--C _1-6 alkylamino." Specific examples of “C _1-6 alkylaminosulfonyl group” include, for example, methylaminosulfonyl.

"Di -C _1-6 alkylamino" moiety of "di -C _1-6 alkylamino sulfonyl group" is the same as the "di -C _1-6 alkylamino." Specific examples of the “di-C _1-6 alkylaminosulfonyl group” include dimethylaminosulfonyl and the like.

"Mono -C _1-6 alkylamino" moiety of the "mono--C _1-6 alkylaminosulfonyl group" is the same as the "mono--C _1-6 alkylamino." Specific examples of “C _1-6 alkylaminosulfonylamino group” include, for example, methylaminosulfonylamino and the like.

"Di -C _1-6 alkylamino" moiety of "di -C _1-6 alkylamino sulfonylamino group" is the same as the "di -C _1-6 alkylamino." Specific examples of the “di-C _1-6 alkylaminosulfonylamino group” include dimethylaminosulfonylamino and the like.

  The “4- to 7-membered cyclic amino” moiety of the “4- to 7-membered cyclic aminocarbonyl group” is the same as the “4- to 7-membered cyclic amino”. As the “4- to 7-membered cyclic aminocarbonyl group”, for example, a 4- to 7-membered monocyclic group having 1 to 3 of the same or different hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. A cyclic aminocarbonyl group is mentioned. Specific examples include azetidinocarbonyl and morpholinocarbonyl.

"C _1-6 alkyl" moiety of the "C _1-6 alkylcarbonylamino group" is the same as the "C _1-6 alkyl". Preferably, it is a C1-C4 alkylcarbonylamino group ( _C1-4 alkylcarbonylamino group). Examples of the “C _1-6 alkylcarbonylamino group” include linear or branched alkylcarbonylamino groups having 1 to 6 carbon atoms. Specific examples include methylcarbonylamino.

"C _3-7 cycloalkyl" moiety of the "C _3-7 cycloalkyl carbonyl group" is the same as the "C _3-7 cycloalkyl". Preferably, it is a C3-C6 cycloalkyl carbonylamino group ( _C3-6 cycloalkyl carbonylamino group). Specific examples include cyclopropylcarbonylamino and the like.

  The “saturated heterocyclic ring” part of the “saturated heterocyclic carbonylamino group” is the same as the “saturated heterocyclic ring”. Specific examples of the “saturated heterocyclic carbonylamino group” include, for example, a 4- to 7-membered saturated heterocyclic carbonyl group. Specific examples include azetidine carbonylamino and the like.

"C _3-7 cycloalkyl" moiety of the "C _3-7 cycloalkyl C _1-4 alkylcarbonylamino group" is the same as the "C _3-7 cycloalkyl". A cycloalkyl C _1-4 alkylamino group having 3 to 6 carbon atoms (C _3-6 cycloalkyl C _1-4 alkylamino group) is preferred. Specific examples include cyclopropylmethylcarbonylamino and the like.

  The “heteroaryl” part of the “heteroarylcarbonylamino group” is the same as the above “heteroaryl”. Specific examples of the “heteroarylcarbonylamino group” include, for example, a 5-membered or 6-membered monocyclic heteroarylcarbonylamino group. Specific examples include pyrrolecarbonylamino and the like.

"C _1-6 alkoxy" moiety of "C _1-6 alkoxycarbonylamino group" is the same as the "C _1-6 alkoxy". Examples of the “C _1-6 alkoxycarbonylamino group” include linear or branched alkoxycarbonylamino groups having 1 to 6 carbon atoms. Specific examples include methoxycarbonylamino and the like.

Examples of the substituent in the “optionally substituted C _1-6 alkyl group” include:
(A) a halogen atom,
(B) a cyano group,
(C) a hydroxy group,
(D) a formyl group,
(E) a C _1-6 alkylcarbonyl group,
(F) a C _1-6 alkylcarbonyloxy group,
(G) a carboxyl group,
(H) amino (the amino is
(H1) C _1-6 alkyl (the alkyl is
(H11) hydroxy,
(H12) C _1-6 alkoxy,
(H13) carboxyl,
(H14) aminocarbonyl,
(H15) di-C _1-6 alkylamino,
(H16) mono- or di-C _1-6 alkylaminocarbonyl,
(H17) C _1-6 alkylcarbonylamino,
(H18) mono or di-C _1-6 alkylaminocarbonylamino, or (h19) C _1-6 alkoxycarbonylamino may be substituted. ),
(H2) C _3-7 cycloalkyl (the ring may be substituted with C _1-6 alkyl),
(H3) C _3-7 cycloalkyl C _1-4 alkyl,
(H4) a 4- to 7-membered saturated heterocyclic ring (the ring may be substituted with a halogen atom or C _1-6 alkyl),
(H5) 4 to 7 membered saturated heterocyclic-C _1-4 alkyl,
(H6) C _6-10 aryl (the ring may be substituted with a halogen atom, C _1-6 alkyl or C _1-6 alkoxy),
(H7) C _7-14 aralkyl (the ring may be substituted with a halogen atom, C _1-6 alkyl or C _1-6 alkoxy),
(H8) 5-membered or 6-membered monocyclic heteroaryl (the ring is substituted with 1 to 3 groups of the same or different species selected from the group consisting of a halogen atom or C _1-6 alkyl) And (h9) a 5- or 6-membered monocyclic heteroaryl C _1-4 alkyl (wherein the ring is the same or different selected from the group consisting of a halogen atom, or C _1-6 alkyl) It may be substituted with 1 to 3 groups, and may be substituted with 1 to 2 groups of the same or different types selected from the group consisting of: ),
(I) a 4- to 7-membered cyclic amino (the ring is
(I1) a halogen atom,
(I2) hydroxy,
(I3) C _1-6 alkyl (the group may be substituted with hydroxy or C _1-6 alkoxy),
(I4) C _1-6 alkoxy,
(I5) amino (the group may be substituted with 1 to 2 C _1-6 alkyl),
May be substituted. ),
(I6) cyano,
(I7) aminocarbonyl (the group may be substituted with 1 to 2 C _1-6 alkyl),
(I7) C _1-6 alkylcarbonyl,
(I8) C _1-6 alkylcarbonylamino, or (i9) C _1-6 alkylsulfonylamino may be substituted. ),
(J) C _1-6 alkoxy (the group is
(J01) hydroxy,
(J02) C _1-6 alkoxy,
(J03) C _3-7 cycloalkoxy,
(J04) a 4-membered to 7-membered saturated heterocyclic ring (which may be substituted with a halogen atom or C _1-6 alkyl),
(J05) 4- to 7-membered cyclic amino (the ring may be substituted with the above (i1) to (i9)),
(J06) 4- to 7-membered cyclic aminocarbonyl (the ring may be substituted with the above (i1) to (i9)),
(J07) C _6-10 aryl group (the group may be substituted with a halogen atom, C _1-4 alkyl, or C _1-4 alkoxy),
(J08) C _1-6 alkylcarbonylamino group,
(J09) mono- or di-C _1-6 alkylamino,
(J10) mono- or di-C _1-6 alkylaminocarbonyl,
(J11) may be substituted with a halogen atom, or (j12) C _3-7 cycloalkyl. ),
(K) a C _3-7 cycloalkoxy group (the ring may be substituted with C _1-6 alkyl),
(L) a C _6-10 aryl group (this group may be substituted with a halogen atom, C _1-4 alkyl, or C _1-4 alkoxy),
(M) a 4-membered to 7-membered saturated heterocyclic ring (which may be substituted with the above (i1) to (i9)),
(N) an optionally substituted aminocarbonyl group,
(O) an optionally substituted aminosulfonyl group,
(P) an optionally substituted aminocarbonyloxy group,
(Q) a C _6-10 aryloxy group (this group may be substituted with a halogen atom, C _1-4 alkyl, or C _1-4 alkoxy),
(R) a C _7-14 aralkyloxy group,
(S) a 5-membered or 6-membered monocyclic heteroaryloxy group (the ring may be substituted with a halogen atom or C _1-6 alkyl),
(T) a 4- to 7-membered saturated heterocyclic oxy group (the ring may be substituted with a halogen atom or C _1-6 alkyl),
(U) a C _1-6 alkylsulfonyl group,
(V) a C _1-6 alkylcarbonylamino group,
(W) a C _1-6 alkoxycarbonyl group,
(X) a C _1-6 alkylsulfonylamino group,
(Y) C _1-6 alkoxycarbonylamino group (z) mono- or di-C _1-6 alkylaminocarbonylamino group, (aa) mono- or di-C _1-6 alkylaminosulfonylamino group, and the like It is done.

  In the “optionally substituted aminocarbonyl group”, “optionally substituted aminosulfonyl group”, and “optionally substituted aminocarbonyloxy group”, “optionally substituted amino” It means a mono-substituted amino group or a di-substituted amino group. Mono- or di-substituted amino substituents are the same as the above-mentioned substituents (h1) to (h9). Specific examples of the “optionally substituted amino” moiety are the same as the above-mentioned “mono-substituted amino” and “di-substituted amino”.

Substituents in “optionally substituted C _1-6 alkylcarbonyl group”, “optionally substituted C _1-6 alkoxycarbonyl group”, and “optionally substituted C _1-6 alkoxycarbonyl group” Examples of the group include one group selected from the group consisting of the above (a) to (aa).

"Optionally substituted C _3-7 cycloalkyl group", "optionally substituted C _3-7 cycloalkyl C _1-4 alkyl group", "optionally substituted C _3-7 cycloalkyl “Carbonyl group”, “optionally substituted C _3-7 cycloalkyl C _1-4 alkylcarbonyl group”, “optionally substituted C _3-7 cycloalkoxy group”, “optionally substituted C _3-7 cycloalkoxycarbonyl group ”,“ optionally substituted 4- to 7-membered cyclic amino group ”,“ optionally substituted 4- to 7-membered cyclic aminocarbonyl group ”,“ substituted ” Examples of the substituent in the “optionally substituted 4- to 7-membered saturated heterocyclic group” and “optionally substituted 4- to 7-membered saturated heterocyclic oxycarbonyl group” include, for example, the above-mentioned “substituted also a C _1-6 alkyl group "and the (a) ~ (a ) One group selected from the group consisting of and the like.

Examples of the substituent of the aryl moiety of the “optionally substituted C _6-10 aryl group” and the “ _optionally substituted C _7-14 aralkyl group” include, for example,
(A2) a halogen atom,
(B2) a cyano group,
(C2) a C _1-6 alkyl group,
(D2) C _1-6 alkylsulfonyl group (the group is
(D21) a halogen atom,
(D22) hydroxy,
(D23) C _1-6 alkoxy,
(D24) C _3-7 cycloalkyl,
(D25) C _3-7 cycloalkoxy,
(D26) di-C _1-6 alkylamino,
(D27) 4-membered to 7-membered cyclic amino, or (d28) 4-membered to 7-membered saturated heterocyclic ring may be substituted. ),
(E2) C _3-7 cycloalkylsulfonyl group (this group may be substituted with C _1-6 alkyl),
(F2) a 4- to 7-membered saturated heterocyclic sulfonyl group (the ring may be substituted with a halogen atom or C _1-6 alkyl),
(G2) an amino group (the amino is substituted with one or two groups of the same or different types selected from the group consisting of the above (h1) to (h9));
(H2) an aminosulfonyl group (the amino is the same or different 1-2 C _1-6 alkyl group (the alkyl is a halogen atom, hydroxy, C _1-4 alkoxy, or di-C _1-6 alkyl); Optionally substituted with amino), optionally substituted with amino).
(I2) a 4- to 7-membered cyclic amino group (the ring may be substituted with the above (i1) to (i9)),
(J2) aminocarbonyl group (the amino may be substituted with one or two groups of the same or different types selected from the group consisting of the above (h11) to (h19));
(K2) a 4- to 7-membered cyclic aminocarbonyl group (the ring may be substituted with the above (i1) to (i9)),
(L2) a 4- to 7-membered saturated heterocyclic ring (the ring may be substituted with the above (i1) to (i9)),
(M2) carboxyl group,
(N2) C _1-6 alkoxy group (this group may be substituted with the above (j01) to (j12)),
(O2) C _1-6 cycloalkoxy group,
(P2) a 4-membered to 7-membered saturated heterocyclic oxy group (the ring may be substituted with the above (i1) to (i9)),
(Q2) C _7-14 aralkyloxy group,
(R2) C _1-6 alkoxycarbonyl group (this group may be substituted with the above (j01) to (j12)),
(S2) C _1-6 alkylcarbonylamino group (the amino may be substituted with C _1-6 alkyl, and the alkyl may be substituted with the above (d21) to (d28)). ,
(T2) C _3-7 cycloalkylcarbonylamino group (the amino may be substituted with C _1-6 alkyl),
(U2) C _3-7 cycloalkyl C _1-4 alkylcarbonylamino group (the amino may be substituted with C _1-6 alkyl),
(V2) a 5- or 6-membered monocyclic heteroarylcarbonylamino group (the amino may be substituted with C _1-6 alkyl),
(W2) a 4- to 7-membered saturated heterocyclic carbonylamino group (the amino may be substituted with C _1-6 alkyl, and the ring is substituted with (i1) to (i9) above) May be good),
(X2) mono- or di-C _1-6 alkylaminocarbonylamino group (the amino may be substituted with C _1-6 alkyl),
(Y2) C _1-6 alkoxycarbonylamino group (the amino may be substituted with C _1-6 alkyl, and the alkoxy may be substituted with the above (j01) to (j12)). ,
(Z2) C _6-10 aryl group, (aa2) 5-membered or 6-membered monocyclic heteroaryl group, and the like.

“Optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group” and “optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group C _{1. -4} alkyl group "and the substituent of the heteroaryl moiety of" _optionally substituted 5- or 6-membered monocyclic heteroarylcarbonyl group "include, for example, the group consisting of the above (a2) to (aa2) The same or different groups selected from the above.

In the compound represented by the formula (1), each R ^2a and R ^2b , or R ^3а and R ^3b are independent. That is, for example, when p is 2, the following formula

で表されるＣ¹およびＣ²に置換した各々のＲ^2aおよびＲ^2bは独立する。従って、Ｃ¹におけるＲ^2aおよびＲ^2bならびにＣ²におけるＲ^2aおよびＲ^2bは独立するので、下記式

Each R ^2a and R ^2b substituted with C ¹ and C ² represented by Therefore, since the R ^2a and R ^2b independently of R ^2a and R ^2b and C ² in C ^1, the following formula

で表される化合物も包含される。また、ｑが２の場合も、各々のＲ^3aおよびＲ^3bは独立する。

The compound represented by these is also included. When q is 2, each R ^3a and R ^3b is independent.

In the compound represented by the formula (1), R ^2a and R ^2b , or R ^3a and R ^3b together represent an oxo group.

で表される基を意味する（式中の定義は、項１と同じである。）。

(The definition in the formula is the same as in item 1).

A preferred embodiment of the present invention will be further described.
A is the following formula (a)

で表される基が好ましく、ｍおよびｎは１が好ましい。

And m and n are preferably 1.

R ⁵ is
1: C _1-6 alkoxycarbonyl group (the alkoxy may be substituted with 1 to 6 halogen atoms),
2: C _3-7 cycloalkoxycarbonyl group (the cycloalkoxy may be substituted with C _1-6 alkyl), or 3: 5-membered or 6-membered monocyclic heteroaryl group (the ring is , _Optionally substituted with C _1-6 alkyl).

R ¹ is a C _6-10 aryl group (the group is
1: halogen atom,
2: C _1-6 alkylsulfonyl group,
3: Aminocarbonyl group (the amino is
(A) C _1-6 alkyl (which may be substituted with hydroxy), or (b) C _3-7 cycloalkyl. Or optionally substituted with a 4: 4 to 7-membered cyclic aminocarbonyl group).

In R ^2a and R ^2b , R ^2a is preferably a hydrogen atom, R ^2b is preferably a hydrogen atom, or a C _1-6 alkyl group.

p and q are
p is 4 and q is 0,
It is preferred that p is 3 and q is 0, or p is 2 and q is 0.

Z is preferably a single bond, an oxygen atom, or NR ⁷ .

R ⁷ is preferably a C _1-6 alkyl group.

  X is preferably an oxygen atom or a sulfur atom.

  Y is preferably an oxygen atom.

  Examples of the “pharmacologically acceptable salt” include acid addition salts and base addition salts. For example, acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, phosphate, citrate, oxalate, acetate, formate And organic acid salts such as propionate, benzoate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, or paratoluenesulfonate, as base addition salts Examples thereof include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt and ammonium salt, organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt and diisopropylammonium salt, and arginine. And amino acid salts such as basic or acidic amino acids such as aspartic acid or glutamic acid.

  Further, the present invention includes a compound represented by the formula (1) or a prodrug thereof, or a pharmaceutically acceptable salt thereof. Moreover, solvates, such as these hydrates or ethanol solvates, are also included. Furthermore, the present invention includes all tautomers of the compound (1) of the present invention, all stereoisomers present, and crystal forms of all embodiments.

  "Prodrug of a compound of formula (1)" term in the present specification means a compound which is converted to compounds of formula (1) by reaction with an enzyme or gastric acid under the physiological conditions in vivo, e.g., enzymatic oxidation Means a compound that undergoes reduction, hydrolysis, etc. to change to the compound of formula (1); a compound that undergoes hydrolysis by gastric acid or the like to change to the compound of formula (1).

  The compound of the present invention may have at least one asymmetric carbon atom. Accordingly, the present invention includes not only racemic forms of the compounds of the present invention but also optically active forms of these compounds. When the compound of the present invention has two or more asymmetric carbon atoms, stereoisomerism may occur. Accordingly, the present invention also includes stereoisomers of these compounds and mixtures thereof.

  Although the manufacturing method of the compound represented by Formula (1) in this invention is demonstrated with an example below, this invention is not limited to this from the first.

  The compound represented by the formula (1) can be synthesized from known compounds by combining known synthesis methods. For example, it can be synthesized by the following method.

Production Method 1: The compound represented by the formula (1a) or a salt thereof can be produced, for example, according to the following reaction formula.

[式中、Ａ、Ｘ、Ｙ、Ｚ、Ｒ¹、Ｒ^2a、Ｒ^2b、Ｒ^3a、Ｒ^3b、ｐおよびｑは項１の記載と同じである。]

[Wherein, A, X, Y, Z, R ¹ , R ^2a , R ^2b , R ^3a , R ^3b , p and q are the same as described in item 1.] ]

  Compound (A-2) can be produced by reacting compound (A-1) with 4-nitrophenyl chloroformate in an inert solvent in the presence or absence of a base. Preferable bases include, for example, triethylamine, diisopropylethylamine, dimethylaminopyridine and the like. As a usage-amount of a base, the range of 1 equivalent-5 equivalent normally is mentioned with respect to a compound (A-1), for example. Moreover, as the usage-amount of 4-nitrophenyl chloroformate, the range of 1 equivalent-5 equivalent normally is mentioned, for example with respect to a compound (A-1). Examples of the inert solvent include dichloromethane, chloroform, and tetrahydrofuran. The reaction temperature is selected from the range of, for example, about 0 ° C. to the boiling point of the solvent.

Step 2:
Formula (1a) can be produced by reacting compound (A-4) with compound (A-4) in the presence of a base in an inert solvent. Preferable bases include, for example, t-butoxy potassium, sodium hydride, triethylamine, diisopropylethylamine and the like. As a usage-amount of a base, the range of 1 equivalent-5 equivalent normally is mentioned with respect to a compound (A-2), for example. Examples of the inert solvent include tetrahydrofuran, dimethylformamide, dimethyl sulfoxide and the like. The reaction temperature is selected from the range of about 0 ° C. to about 130 ° C., for example.

Step 3:
Compound (A-3) can be produced by reacting compound (A-1) with triphosgene in an inert solvent in the presence or absence of a base. Preferable bases include, for example, triethylamine or diisopropylethylamine. As the usage-amount of a base, the range of 1 equivalent-10 equivalent is normally mentioned with respect to a compound (A-1), for example. Moreover, as a usage-amount of a triphosgene, the range of 1 equivalent-5 equivalent normally is mentioned, for example with respect to a compound (A-1). Examples of the inert solvent include dichloromethane, chloroform, tetrahydrofuran, toluene, ethyl acetate, and the like. The reaction temperature is selected from the range of, for example, about 0 ° C. to the boiling point of the solvent.

Step 4:
Formula (1a) can be produced by reacting compound (A-4) with compound (A-4) in an inert solvent in the presence of a base. Preferable bases include, for example, t-butoxy potassium, sodium hydride, triethylamine, diisopropylethylamine and the like. As the usage-amount of a base, the range of 1 equivalent-5 equivalent normally is mentioned with respect to a compound (A-3), for example. Examples of the inert solvent include tetrahydrofuran, dimethylformamide, dimethyl sulfoxide and the like. The reaction temperature is selected from the range of about 0 ° C. to about 130 ° C., for example.

  In the compound of the formula (1) of the present invention, when there is one or more asymmetric points, by using a raw material having the asymmetric point or introducing the asymmetry at an intermediate stage according to a usual method Can be manufactured. For example, in the case of an optical isomer, it can be obtained by using an optically active raw material or performing optical resolution at an appropriate stage of the production process. As an optical resolution method, for example, a compound of the formula (1) or an intermediate thereof in an inert solvent (for example, an alcohol solvent such as methanol, ethanol or 2-propanol, an ether solvent such as diethyl ether, an ester such as ethyl acetate) System solvents, hydrocarbon solvents such as toluene, aprotic solvents such as acetonitrile, and mixed solvents thereof), optically active acids (for example, monocarboxylic acids such as mandelic acid, N-benzyloxyalanine, or lactic acid) , Tartaric acid, dicarboxylic acid such as o-diisopropylidene tartaric acid or malic acid, or sulfonic acid such as camphor sulfonic acid or bromocamphor sulfonic acid), and the like.

  When the compound of formula (1) or an intermediate thereof has an acidic functional group such as a carboxy group, an optically active amine (for example, an organic amine such as α-phenethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine) and a salt are used. It can also be performed by forming.

  The temperature at which the salt is formed is selected from the range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature once to near the boiling point of the solvent. When the precipitated salt is collected by filtration, the yield can be improved by cooling as necessary. The amount of the optically active acid or amine used is in the range of about 0.5 to about 2.0 equivalents, preferably in the range of about 1 equivalent, relative to the substrate. Inert solvent crystals needed (e.g. methanol, ethanol, 2-alcohol solvents propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, hydrocarbon solvent such as toluene, acetonitrile, And a high-purity optically active salt can be obtained. Further, if necessary, the optically resolved salt can be treated with an acid or base by a conventional method to obtain a free form.

Unless otherwise specified, the raw materials and reagents used in the above are commercially available compounds, or can be produced from known compounds using known methods. When the arylamide compound of the present invention, an intermediate thereof, or a raw material compound thereof has a functional group, an appropriate process, that is, a stage in the middle of each production method shown in Production Method 1, if necessary, etc. Thus, according to the ordinary method of those skilled in the art, a carbon increase reaction, a substituent introduction reaction, a functional group conversion reaction, or the like can be performed. These were described in "Experimental Chemistry Course (Edited by the Chemical Society of Japan, Maruzen)" or "Comprehensive Organic Transformation, RC Rallock, (VCH Publishers, Inc, 1989)". A method or the like can be used. Examples of the amplifying reaction include a method in which an ester group is converted into a hydroxymethyl group using a reducing agent such as lithium aluminum hydride, a leaving group is introduced, and a cyano group is introduced. Examples of the functional group conversion reaction include a reaction in which acylation or sulfonylation is performed using an acid halide, a sulfonyl halide, a reaction in which an alkylating agent such as an alkyl halide is reacted, a hydrolysis reaction, a Friedel-Crafts reaction, or a Wittig. Examples thereof include carbon-carbon bond formation reaction such as reaction, oxidation or reduction reaction, and the like.
In addition, when the compound of the present invention, or an intermediate thereof, and a starting compound for each reaction have a functional group such as an amino group, a carboxyl group, a hydroxyl group, or an oxo group, other than the site to be reacted as necessary By protecting these groups with an appropriate protecting group in advance and removing each of the protecting groups after carrying out each reaction or after carrying out several reactions, the desired compound can be obtained. Suitable protecting groups, methods for protecting, and methods for deprotecting are described in detail in “Protective Groups in Organic Synthesis 4th Edition (A John Wiley & Sons, Inc .; 2006)” and the like.

  The term “hyperglycemia” in the present invention means that the blood glucose level rises beyond the range of normal adjustment, while the early morning fasting blood glucose of a healthy person is 60 to 100 mg / dL.

  The compounds of the present invention, because it has an excellent hypoglycemic effect, a mammal (e.g., human, mouse, dog, rat, cow, etc.) can be used as a preventive and / or therapeutic agent for safe diabetes respect. The compound of the present invention can be used as a postprandial hyperglycemia inhibitor and a prophylactic and / or therapeutic agent for diabetes in persons with impaired glucose tolerance or fasting glucose. For example, diabetes, impaired glucose tolerance, fasting glycemia, diabetic complications (eg retinopathy, neuropathy, nephropathy), obesity, hyperinsulinemia, pancreatitis, chronic liver disease, acromegaly, Cushing It is useful for prevention of syndrome, pheochromocytoma, glucagonoma, hyperthyroidism, etc.

“Diabetes” in the present invention means a state in which the fasting blood glucose level is 126 mg / dL or more, or the blood glucose level after 2 hours of the 75 g glucose tolerance test is 200 mg / dL or more.
Glucose tolerance abnormality means that the blood glucose level of 2 hours after a 75-g glucose tolerance test is 140-200 mg / dL.

  Abnormal fasting blood glucose means a fasting blood glucose level in the range of 100 to 126 mg / dL.

Metabolic syndrome refers to an easily developed state of arteriosclerosis associated with impaired glucose tolerance, hyperlipidemia, and hypertension. Specifically, according to the current standards, the waist is 85 cm or more for men and 90 cm or more for women, and it corresponds to two or more of the following three items.
1. Neutral fat value of 150 mg / dL or more, HDL (high density lipoprotein) cholesterol value of less than 40 mg / dL (or both)
2. Maximum blood pressure 130 mmHg or higher, minimum blood pressure 85 mmHg or higher (or both)
3. Fasting blood glucose level 110mg / dL or more

When the compound of the present invention is used as the therapeutic agent (medicine), the content of the compound of the present invention is 0.1 to 100% by weight of the whole drug.
The dosage of the compound of the present invention and the pharmaceutical containing the compound of the present invention varies depending on the administration subject, administration route, disease and the like. For example, when these are orally administered to an adult (about 60 kg) as a therapeutic agent for diabetes or the like, The inventive compound is preferably administered in an amount of about 0.1 to 500 mg, preferably about 1 to 100 mg, more preferably 5 to 100 mg. These amounts can be administered once to several times a day.
The compound of the present invention and the medicament containing the compound of the present invention may be administered before meals, between meals or after meals.

  The compounds of the present invention, when used therapeutically, are used as pharmaceutical compositions as oral or parenteral (eg, intravenous, subcutaneous, or intramuscular injection, topical, rectal, transdermal, or nasal Administration). Examples of compositions for oral administration include tablets, capsules, pills, granules, powders, solutions, suspensions, etc. Examples of compositions for parenteral administration include, for example, injections. Aqueous agents or oily agents, ointments, creams, lotions, aerosols, suppositories, patches and the like can be mentioned. These preparations can be prepared using conventionally known techniques, and can contain non-toxic and inert carriers or excipients usually used in the pharmaceutical field.

  Specifically, the tablet production method is carried out by using the compound of the present invention as it is as an excipient (for example, lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low substitution degree. Hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate, etc.), lubricant (eg, magnesium stearate, calcium stearate, talc, colloidal silica, etc.) , Binder (eg pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullula , Hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc.), disintegrant (lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylstarch sodium, light anhydrous silicic acid, low substituted hydroxy (Propylcellulose etc.) or other suitable additives and mixed evenly, and then granulated by an appropriate method, followed by the addition of a lubricant and the like, or compression molding, or the compound of the present invention as it is, Alternatively, an excipient, a binder, a disintegrant or other suitable additive added and mixed evenly may be directly compression-molded, or may be used as it is in a pre-made granule or with a suitable additive. Plus after mixing evenly Even compression molding can be produced. In the preparation of an injection, a certain amount of the compound of the present invention is dissolved, suspended or emulsified in water for injection, physiological saline, Ringer's solution, etc. in the case of an aqueous solvent, and usually in vegetable oil in the case of a non-aqueous solvent. Alternatively, a certain amount of the compound of the present invention can be taken and sealed in an injection container.

  The compound of the present invention is for the purpose of enhancing its effect, and is a drug such as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, an antihypertensive agent, an antiobesity agent, a diuretic agent, etc. Can be used in combination. The administration timing of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference. Moreover, it is good also as a mixture of this invention compound and a concomitant drug. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.

  Examples of diabetes therapeutic agents include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations synthesized by genetic engineering using Escherichia coli and yeast), insulin resistance improving agents ( Examples, pioglitazone or its hydrochloride, troglitazone, rosiglitazone or its maleate, GI-262570, JTT-501, MCC-555, YM-440, KRP-297, CS-011, etc.), α-glucosidase inhibitor ( Examples, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, metformin, etc.), insulin secretagogues (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, etc. Sulfonylureas; repaglinide, senagrinide, nateglinide, mitiglinide, etc.), dipeptidyl peptidase-IV (DPP-IV) inhibitors (eg, sitagliptin or its phosphate, vildagliptin, alogliptin or its benzoate, denagliptin or its tosylate Etc.), GLP-1, GLP-1 analogs (exenatide, liraglutide, SUN-E7001, AVE010, BIM-51077, CJC1131 etc.), protein tyrosine phosphatase inhibitors (eg, vanadic acid etc.), β3 agonists (eg, GW- 427353B, N-5984, etc.).

  Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (eg, torrestat, epalrestat, zenarestat, zopolestat, minarestat, fidarestat, ranirestat, SK-860, CT-112, etc.), neurotrophic factors (eg, NGF). , NT-3, BDNF, etc.), PKC inhibitors (eg, LY-333531, etc.), AGE inhibitors (eg, ALT946, pimagedin, pyratoxatin, N-phenacylthiazolium bromide (ALT766), etc.), active oxygen elimination Examples thereof include drugs (eg, thioctic acid) and cerebral vasodilators (eg, thioprid, mexiletine, etc.). Antihyperlipidemic agents include HMG-CoA reductase inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin or their sodium salts), squalene synthase inhibitors, ACAT inhibitors, etc. Is mentioned. As an antihypertensive agent, an angiotensin converting enzyme inhibitor (eg, captopril, enalapril, alacepril, delapril, lizinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, etc.), angiotensin II antagonist (eg, olmesartan, medoxomil, candesalmil, candesalmil) Cilexetil, losartan, eprosartan, valsantan, telmisartan, irbesartan, tasosartan, etc.), calcium antagonists (eg, nicardipine hydrochloride, manidipine hydrochloride, nisoldipine, nitrendipine, nilvadipine, amlodipine, etc.).

  Examples of anti-obesity agents include central anti-obesity agents (eg, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, SR-141716A, etc.), pancreatic lipase inhibitors (eg, orlistat, etc.), peptide anorectic agents (Eg, leptin, CNTF (ciliary neurotrophic factor), etc.), cholecystokinin agonists (eg, lynchtrypto, FPL-15849, etc.) and the like. Examples of diuretics include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, pentfurizide, polythiazide. , Methiclotiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.), azosemide, isosorbide , Ethacrynic acid, piretanide, bumetanide, furosemide and the like.

  The concomitant drugs are preferably GLP-1, GLP-1 analog, α-glucosidase inhibitor, biguanide agent, insulin secretagogue, insulin resistance improving agent, DPP-IV inhibitor and the like. Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.

  When the compound of the present invention is used in combination with a concomitant drug, the amount of these drugs used can be reduced within a safe range considering the side effects of the drug. In particular, biguanides can be reduced from normal dosages. Therefore, side effects that may be caused by these drugs can be safely prevented. In addition, the dosage of diabetic complications, antihyperlipidemic agents, antihypertensives, etc. can be reduced, and as a result, side effects that may be caused by these agents can be effectively prevented.

Hereinafter, the present invention will be more specifically described with reference examples, examples, and pharmacological test examples, but the present invention is not limited thereto. The compound was identified by NMR spectrum, HPLC (high performance liquid chromatography) and the like.
NMR in this specification was measured using JEOL JNM-AL series AL300 and AL400.

In the present specification, the following abbreviations may be used.
The following abbreviations are used in NMR data and reference examples and examples.
s: singlet
d: doublet
t: triplet
m: multiplet
br: broad
J: Coupling constant
Hz: Hertz
CDCl _3: deuterated chloroform DMSO-d _6: deuterated dimethyl sulfoxide THF: tetrahydrofuran DMF: N, N-dimethylformamide Me: methyl Et: ethyl t-Bu: 1,1-dimethylethyl Ph: phenyl Boc: t-butoxycarbonyl DIAD : Diisopropyl azodicarboxylate PPh ₃ : Triphenylphosphine DMAP: 4- (N, N-dimethylamino) pyrimidine WSCI: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide

  The present invention will be described more specifically with reference to examples and test examples. However, the present invention is not limited to these examples. In addition, the compound names shown in the following Reference Examples and Examples do not necessarily follow the IUPAC nomenclature.

Example 1:
tert-butyl 4- (2- (2-fluoro-4- (methylsulfonyl) phenylcarbamoyloxy) ethyl) piperidine-1-carboxylate
tert-butyl 4- (2- (2-fluoro-4- (methylsulfonyl) phenylcarbamoyloxy) ethyl) piperidine-1-carboxylate

To a solution of tert-butyl 4- (2-hydroxyethyl) piperidine-1-carboxylate (0.115 g, 0.5 mmol) in tetrahydrofuran (4.0 ml) at 0 ° C. with triethylamine (0.14 ml, 1.0 mmol) and intermediate 1-1 (0.161 g, 0.75 mmol) was added and the reaction solution was stirred at room temperature for 15 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.206 g, 92%).
¹ H-NMR (CDCl ₃ ): δ 8.42-8.38 (m, 1H), 7.73 (brd, J = 9.4 Hz, 1H), 7.67 (dd, J = 9.4, 2.0 Hz, 1H), 7.07 (brs, 1H ), 4.91-4.86 (m, 1H), 4.28 (t, J = 6.5 Hz, 2H), 4.15-4.09 (m, 2H), 3.05 (s, 3H), 2.74-2.66 (m, 2H), 1.71- 1.50 (m, 5H), 1.45 (s, 9H), 1.21-1.11 (m, 2H).

Intermediate 1-1: 2-fluoro-4- (methylsulfonyl) phenyl isocyanate
2-Fluoro-4- (methylsulfonyl) phenyl isocyanate

Triphosgene (2.97 g, 10 mmol) was added to a solution of 2-fluoro-4- (methylsulfonyl) aniline (1.89 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in ethyl acetate (100 ml) at room temperature, and the reaction solution Was heated to reflux for 3 hours. After completion of the reaction, the insoluble material was filtered off and the solvent was distilled off under reduced pressure to obtain the title compound (2.15 g, quant.).
¹ H-NMR (CDCl ₃ ): δ 7.78-7.72 (m, 2H), 7.32-7.27 (m, 1H), 3.09 (s, 3H).

Example 2:
tert-butyl 4- (3- (2-fluoro-4- (methylsulfonyl) phenylcarbamoyloxy) propyl) piperidine-1-carboxylate
tert-butyl 4- (3- (2-fluoro-4- (methylsulfonyl) phenylcarbamoyloxy) propyl) piperidine-1-carboxylate

The title compound was obtained in the same manner as in Example 1 (0.052 g, 38%).
¹ H-NMR (CDCl ₃ ): δ 8.42-8.38 (m, 1H), 7.74-7.71 (m, 1H), 7.67 (dd, J = 10.1, 2.0 Hz, 1H), 7.07 (d, J = 3.2 Hz , 1H), 4.21 (t, J = 6.7 Hz, 1H), 4.16-4.05 (m, 1H), 3.05 (s, 3H), 2.73-2.65 (m, 2H), 1.78-1.67 (m, 4H), 1.45 (s, 9H), 1.42-1.33 (m, 3H), 1.15-1.04 (m, 2H).

Example 3:
tert-butyl 4- (4- (2-fluoro-4- (methylsulfonyl) phenylcarbamoyloxy) butyl) piperidine-1-carboxylate
tert-butyl 4- (4- (2-fluoro-4- (methylsulfonyl) phenylcarbamoyloxy) butyl) piperidine-1-carboxylate

The title compound was obtained in the same manner as in Example 1 using Intermediate 3-1 (0.097 g, 82%).
¹ H-NMR (CDCl ₃ ): δ 8.42-8.38 (m, 1H), 7.73 (brd, J = 9.4 Hz, 1H), 7.67 (dd, J = 9.4, 2.0 Hz, 1H), 7.07 (brd, J = 3.2 Hz, 1H), 4.22 (t, J = 6.6 Hz, 2H), 4.09-4.06 (m, 2H), 3.05 (s, 3H), 2.70-2.63 (m, 2H), 1.73-1.63 (m, 4H), 1.45 (s, 9H), 1.42-1.36 (m, 3H), 1.31-1.26 (m, 2H), 1.14-1.04 (m, 2H).

Intermediate 3-1: tert-butyl 4- (4-hydroxybutyl) piperidine-1-carboxylate
tert-butyl 4- (4-hydroxybutyl) piperidine-1-carboxylate

To a solution of 4- (1- (tert-butoxycarbonyl) piperidin-4-yl) butanoic acid (0.407 g, 1.5 mmol) in tetrahydrofuran (5.0 ml) was added triethylamine (0.25 ml, 1.8 mmol) at −10 ° C. Isobutyl chlorocarbonate (0.21 ml, 1.65 mmol) was added and the reaction solution was stirred at 0 ° C. for 1 hour. Insoluble matter was filtered to obtain a tetrahydrofuran solution of the corresponding acid anhydride. To a solution of sodium borohydride (0.159 mg, 4.2 mmol) in water (7 ml) was added the above acid anhydride tetrahydrofuran solution at −10 ° C., and the reaction solution was stirred at 0 ° C. for 3 hours. A saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.414 g, 100%). ¹ H-NMR (CDCl ₃ ): δ 4.08-4.05 (m, 2H), 3.65 (t, J = 6.5 Hz, 2H), 2.66 (dt, J = 2.4, 13.0 Hz, 2H), 1.66-1.52 (m , 5H), 1.45 (s, 9H), 1.45-1.34 (m, 4H), 1.28-1.23 (m, 2H), 1.12-1.02 (m, 2H).

Example 4:
2,2,2-trifluoroethyl 4- (2- (2-fluoro-4- (methylsulfonyl) phenylcarbamoyloxy) ethyl) piperidine-1-carboxylate
2,2,2-trifluoroethyl 4- (2- (2-fluoro-4- (methylsulfonyl) phenylcarbamoyloxy) ethyl) piperidine-1-carboxylate

To a solution of 2,2,2-trifluoroethanol (8.8 μl, 0.12 mmol) and triethylamine (0.056 ml, 0.4 mmol) in acetonitrile (0.5 ml), add bis (N-succinimidyl) carbonate (0.038 g, 0.15 mmol) to 0. The reaction solution was stirred at room temperature for 1 hour. Intermediate 4-1 (0.038 g, 0.1 mmol) and triethylamine (0.056 ml, 0.4 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.033 g, 70%).
¹ H-NMR (CDCl ₃ ): δ 8.42-8.38 (m, 1H), 7.73 (brd, J = 9.4 Hz, 1H), 7.69 (dd, J = 9.4, 2.0 Hz, 1H), 7.08 (brs, 1H ), 4.48 (q, J = 8.5 Hz, 2H), 4.28 (t, J = 6.5 Hz, 2H), 4.21-4.11 (m, 2H), 3.05 (s, 3H), 2.90-2.77 (m, 2H) , 1.78-1.59 (m, 5H), 1.21 (brs, 2H).

Intermediate 4-1: 2- (piperidin-4-yl) ethyl 2-fluoro-4- (methylsulfonyl) phenylcarbamate
2- (Piperidin-4-yl) ethyl 2-fluoro-4- (methylsulfonyl) phenylcarbamate

To a solution of the compound of Example 1 (0.608 g, 1.38 mmol) in chloroform (7 ml) was added 4 mol / l hydrochloric acid in dioxane (1.1 ml) at 0 ° C., and the reaction solution was stirred at room temperature for 20 hours. The solvent was distilled off under reduced pressure to obtain the title compound (0.475 g, 91%).
¹ H-NMR (CD ₃ OD): δ 8.34-8.29 (m, 1H), 7.75-7.70 (m, 2H), 4.29 (t, J = 6.4 Hz, 2H), 3.41-3.30 (m, 2H), 3.12 (s, 3H), 3.02-2.94 (m, 2H), 2.04-2.00 (m, 2H), 1.83-1.70 (m, 3H), 1.48-1.37 (m, 2H).

Example 5:
1,1,1,3,3,3-hexafluoropropan-2-yl 4- (2- (2-fluoro-4- (methylsulfonyl) phenylcarbamoyloxy) ethyl) piperidine-1-carboxylate
1,1,1,3,3,3-hexafluoropropan-2-yl 4- (2- (2-fluoro-4- (methylsulfonyl) phenylcarbamoyloxy) ethyl) piperidine-1-carboxylate

The title compound was obtained in the same manner as in Example 4 (0.004 g, 7%).
¹ H-NMR (CDCl ₃ ): δ 8.42-8.38 (m, 1H), 7.72 (brd, J = 9.4 Hz, 1H), 7.68 (dd, J = 9.4, 2.0 Hz, 1H), 7.08 (brs, 1H ), 5.79-5.77 (m, 1H), 4.29 (t, J = 6.3 Hz, 2H), 4.21-4.12 (m, 2H), 3.05 (s, 3H), 2.92-2.81 (m, 2H), 1.83- 1.53 (m, 5H), 1.33-1.19 (m, 2H).

Example 6:
2- (1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) ethyl 2-fluoro-4- (methylsulfonyl) phenylcarbamate
2- (1- (3-Isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-yl) ethyl 2-fluoro-4- (methylsulfonyl) phenylcarbamate

To a solution of Intermediate 6-1 (0.022 g, 0.06 mmol) in THF (0.5 ml) -ethyl acetate (0.5 ml), N′-hydroxy-2-methylpropaneimidamide (0.007 g, 0.072 mmol), 1M ZnCl _{2 was} added. Diethyl ether solution (0.20 ml, 0.20 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Further, 1M ZnCl ₂ in diethyl ether (0.12 ml, 0.12 mmol) was added, and the mixture was stirred at room temperature for 15 hours. After evaporating the solvent under reduced pressure, THF (2.0 ml) and 1N hydrochloric acid (0.5 ml) were added, and the mixture was heated to reflux for 7 hours. The solvent was distilled off under reduced pressure, diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.014 g, 50%).
¹ H-NMR (CDCl ₃ ): δ 8.42-8.38 (m, 1H), 7.73 (brd, J = 9.4 Hz, 1H), 7.69 (dd, J = 9.4, 2.0 Hz, 1H), 7.08 (brs, 1H ), 4.30 (t, J = 6.3 Hz, 2H), 4.17-4.11 (m, 2H), 3.09-3.01 (m, 2H), 3.05 (s, 3H), 2.92-2.85 (m, 2H), 1.84- 1.81 (m, 2H), 1.71-1.65 (m, 3H), 1.38-1.23 (m, 2H), 1.30 (d, J = 7.0 Hz, 6H).

Example 7:
2- (1- (5-isopropyl-1,2,4-oxadiazol-3-yl) piperidin-4-yl) ethyl 2-fluoro-4- (methylsulfonyl) phenylcarbamate
2- (1- (5-Isopropyl-1,2,4-oxadiazol-3-yl) piperidin-4-yl) ethyl 2-fluoro-4- (methylsulfonyl) phenylcarbamate

Triethylamine (0.02 ml, 0.14 mmol) and hydroxylamine hydrochloride (0.006 g, 0.085 mmol) were added to an ethanol (2.0 ml) suspension of intermediate 7-1 (0.026 g, 0.07 mmol), and the mixture was stirred at 60 ° C. for 3 hours. Stir. DMF (1.0 ml) and triethylamine (0.02 ml, 0.14 mmol) were added to the composition organism obtained by distilling off the solvent. Further, isobutyric acid (0.0075 g, 0.085 mmol), HOBt (0.014 g, 0.1 mmol) and WSC (0.020 g, 0.1 mmol) were added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for 16 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layers were combined and washed with water and saturated brine. After drying with sodium sulfate, the solvent was distilled off. Toluene (0.5 ml) -DMF (0.5 ml) was added to the obtained crude product, and the mixture was stirred at 80 ° C. for 4 hours. After returning to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.014 g, 43%).
¹ H-NMR (CDCl ₃ ): δ 8.42-8.38 (m, 1H), 7.73 (brd, J = 9.4 Hz, 1H), 7.69 (dd, J = 9.4, 2.0 Hz, 1H), 7.08 (brs, 1H ), 4.30 (t, J = 6.3 Hz, 2H), 4.03-3.99 (m, 2H), 3.11-3.01 (m, 1H), 3.05 (s, 3H), 2.92-2.85 (m, 2H), 1.81- 1.51 (m, 5H), 1.38-1.25 (m, 2H), 1.36 (d, J = 7.0 Hz, 6H).

Intermediate 7-1: 2- (1-cyanopiperidin-4-yl) ethyl 2-fluoro-4- (methylsulfonyl) phenylcarbamate 2- (1-cyanopiperidin-4-yl) ethyl 2-fluoro-4- (methylsulfonyl) ) Phenyl carbamate

Chloroform (2.0 ml) and triethylamine (0.175 ml, 1.25 mmol) were added to the compound of Intermediate 4-1 (0.095 g, 0.25 mmol). Cyanogen bromide (0.033 g, 0.31 mmol) was added under ice cooling, and the reaction solution was stirred at room temperature for 2 hours. Ethyl acetate was added, washed with 5% aqueous potassium hydrogen sulfate solution, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.091 g, crude).

Example 8:
2- (1- (4-methylpyrimidin-2-yl) piperidin-4-yl) ethyl 2-fluoro-4- (methylsulfonyl) phenylcarbamate
2- (1- (4-Methylpyrimidin-2-yl) piperidin-4-yl) ethyl 2-fluoro-4- (methylsulfonyl) phenylcarbamate

A solution of intermediate 4-1 (0.023 g, 0.06 mmol) in acetonitrile (1.0 ml) -DMF (0.5 ml) was added to triethylamine (0.025 ml, 0.18 mmol), 2-chloro-4-methylpyrimidine (0.012 g, 0.09 mmol) was added at room temperature, and the reaction solution was stirred at 50 ° C. for 6 hours. After returning to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.014 g, 55%).
¹ H-NMR (CDCl ₃ ): δ 8.43-8.38 (m, 1H), 8.15 (d, J = 5.0 Hz, 1H), 7.73 (brd, J = 9.4 Hz, 1H), 7.68 (dd, J = 9.4 , 2.0 Hz, 1H), 7.08 (brs, 1H), 6.35 (d, J = 5.0 Hz), 4.83-4.79 (m, 2H), 4.31 (t, J = 6.4 Hz, 2H), 3.05 (s, 3H ), 2.90-2.83 (m, 2H), 2.33 (s, 3H), 1.83-1.54 (m, 5H), 1.33-1.20 (m, 2H).

Example 9:
2- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) ethyl 3-fluoro-4- (methylsulfonyl) phenylcarbamate
2- (1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl) ethyl 3-fluoro-4- (methylsulfonyl) phenylcarbamate

The title compound was obtained in the same manner as in Example 8 (0.020 g, 33%).
¹ H-NMR (CDCl ₃ ): δ 8.17 (s, 2H), 7.85 (t, J = 8.4 Hz, 1H), 7.64 (dd, J = 12.2, 2.0 Hz, 1H), 7.11 (dd, J = 8.6 , 2.0 Hz, 1H), 6.97 (brs, 1H), 4.73-4.69 (m, 2H), 4.28 (t, J = 6.4 Hz, 2H), 3.19 (s, 3H), 2.90-2.82 (m, 2H) , 2.45 (q, J = 7.5 Hz), 2.33 (s, 3H), 1.82-1.78 (m, 2H), 1.72-1.67 (m, 3H), 1.29-1.20 (m, 2H), 1.18 (t, J = 7.5 Hz, 3H).

Example 10:
tert-butyl 4- (2- (4- (methoxycarbonyl) phenylcarbamoyloxy) ethyl) piperidine-1-carboxylate
tert-Butyl 4- (2- (4- (methoxycarbonyl) phenylcarbamoyloxy) ethyl) piperidine-1-carboxylate

The title compound was obtained in the same manner as in Example 1 (0.198 g, 97%).
¹ H-NMR (CDCl ₃ ): δ 8.00 (d, J = 9.7 Hz, 2H), 7.45 (d, J = 9.7 Hz, 2H), 6.76 (brs, 1H), 4.24 (t, J = 6.4 Hz, 2H), 4.11-4.07 (m, 2H), 3.89 (s, 3H), 2.73-2.65 (m, 2H), 1.72-1.58 (m, 5H), 1.45 (s, 9H), 1.21-1.10 (m, 2H).

Example 11: 4-((2- (1- (tert-butoxycarbonyl) piperidin-4-yl) ethoxy) carbonylamino) benzoic acid
4-((2- (1- (tert-butoxycarbonyl) piperidin-4-yl) ethoxy) carbonylamino) benzoic acid

  THF of the compound of Example 10 (0.175 g, 0.43 mmol) (2.0 ml), methanol (0.5 ml) 4N sodium hydroxide aqueous solution at room temperature to a solution (0.52 ml, 2.1 mmol) was added, the reaction solution 6 at 50 ° C. The Stir for hours. Under ice cooling, 1N hydrochloric acid was added to the reaction solution, and the solvent was distilled off under reduced pressure. After azeotroping with toluene, the title compound was obtained (0.303 g, crude).

Example 12:
tert-butyl 4- (2- (4- (dimethylcarbamoyl) phenylcarbamoyloxy) ethyl) piperidine-1-carboxylate
tert-butyl 4- (2- (4- (dimethylcarbamoyl) phenylcarbamoyloxy) ethyl) piperidine-1-carboxylate

To the DMF solution (0.5 ml) of Example 11, dimethylamine hydrochloride (0.013 g, 0.16 mmol), triethylamine (0.075 ml, 0.52 mmol), HOBt (0.027 g, 0.2 mmol), WSC (0.037 g, 0.2 mmol) Was added at room temperature, and the reaction solution was stirred at room temperature for 16 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (0.015 g, 27%).
¹ H-NMR (CDCl ₃ ): δ 7.39 (s, 4H), 6.68 (brs, 1H), 4.21 (t, J = 6.4 Hz, 2H), 4.11-4.05 (m, 2H), 3.03 (s, 6H ), 2.72-2.62 (m, 2H), 1.71-1.53 (m, 5H), 1.43 (s, 9H), 1.21-1.09 (m, 2H).
In the same manner as in Example 12, the following compounds of Examples 13 to 15 were obtained.

Example 13:
tert-butyl 4- (2- (4- (cyclopropylcarbamoyl) phenylcarbamoyloxy) ethyl) piperidine-1-carboxylate
tert-butyl 4- (2- (4- (cyclopropylcarbamoyl) phenylcarbamoyloxy) ethyl) piperidine-1-carboxylate

¹ H-NMR (CDCl ₃ ): δ 7.70 (d, J = 9.6 Hz, 2H), 7.44 (d, J = 9.6 Hz, 2H), 6.75 (brs, 1H), 6.18 (brs, 1H), 4.23 ( t, J = 6.4 Hz, 2H), 4.09-4.07 (m, 2H), 2.91-2.86 (m, 1H), 2.72-2.65 (m, 2H), 1.71-1.52 (m, 5H), 1.45 (s, 9H), 1.19-1.09 (m, 2H), 0.89-0.84 (m, 2H), 0.65-0.62 (m, 2H).

Example 14:
tert-butyl 4- (2- (4- (1-hydroxypropan-2-ylcarbamoyl) phenylcarbamoyloxy) ethyl) piperidine-1-carboxylate
tert-butyl 4- (2- (4- (1-hydroxypropan-2-ylcarbamoyl) phenylcarbamoyloxy) ethyl) piperidine-1-carboxylate

¹ H-NMR (CDCl ₃ ): δ 7.74 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 9.6 Hz, 2H), 6.78 (brs, 1H), 6.23 (brd, J =, 7.2 Hz , 1H), 4.29-4.21 (m, 3H), 4.13-4.07 (m, 2H), 3.08-3.62 (m, 2H), 2.72-2.65 (m, 2H), 1.73-1.52 (m, 5H), 1.45 (s, 9H), 1.29 (d, J = 6.8 Hz, 3H), 1.21-1.09 (m, 2H).

Example 15:
tert-butyl 4- (2- (4- (morpholine-4-carbonyl) phenylcarbamoyloxy) ethyl) piperidine-1-carboxylate
tert-Butyl 4- (2- (4- (Morifolin-4-carbonyl) phenylcarbamoyloxy) ethyl) piperidine-1-carboxylate

¹ H-NMR (CDCl ₃ ): δ 8.00 (brs, 1H), 7.73-7.36 (m, 4H), 6.69 (brs, 1H), 6.23 (brd, J =, 7.2 Hz, 1H), 4.21 (t, J = 6.4 Hz, 3H), 4.10-4.05 (m, 2H), 3.90-3.44 (m, 8H), 2.71-2.62 (m, 2H), 1.70-1.51 (m, 5H), 1.43 (s, 9H) , 1.29 (d, J = 6.8 Hz, 3H), 1.20-1.11 (m, 2H).

Example 16:
tert-butyl 4- (1- (2-fluoro-4- (methylsulfonyl) phenylcarbamoyloxy) propan-2-yloxy) piperidine-1-carboxylate
tert-butyl 4- (1- (2-fluoro-4- (methylsulfonyl) phenylcarbamoyloxy) propan-2-yloxy) piperidine-1-carboxylate

The title compound was obtained in the same manner as in Example 1 using Intermediate 16-2 (0.028 g, 34%).
¹ H-NMR (CDCl ₃ ): δ 8.39 (t, J = 8.1 Hz, 1H), 7.74-7.72 (m, 1H), 7.68 (dd, J = 10.1, 1.9 Hz, 1H), 7.07 (m, 1H ), 4.17 (d, J = 5.1 Hz, 2H), 3.86-3.76 (m, 3H), 3.61-3.55 (m, 1H), 3.11-3.04 (m, 5H), 1.85-1.76 (m, 2H), 1.58-1.45 (m, 2H), 1.44 (s, 9H), 1.21 (d, J = 6.3 Hz, 3H).

Intermediate 16-1: 2- (1- (tert-butoxycarbonyl) piperidin-4-yloxy) propanoic acid
2- (1- (tert-Butoxycarbonyl) piperidin-4-yloxy) propionic acid

To a dioxane solution (30 ml) of 60% sodium hydride (2.6 g, 60 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (3.0 g, 15 mmol) was added at room temperature, and the reaction solution was stirred at room temperature for 30 Stir for minutes. To the reaction solution, a dioxane solution (30 ml) of 2-bromopropionic acid (2.3 g, 15 mmol) was added dropwise and stirred for 24 hours, and then the reaction solution was stirred at 60 ° C. for 9 hours. After returning to room temperature, the reaction solution was poured into ice-cooled water (50 ml) and washed with a hexane / ethyl acetate solution (1: 1, 40 ml). Concentrated hydrochloric acid (6 ml) was added dropwise to the aqueous layer under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (3.9 g, crude).
¹ H-NMR (CDCl ₃ ) (CDCl ₃ ): δ 4.15 (q, J = 6.8 Hz, 1H), 3.90-3.74 (m, 2H), 3.65-3.55 (m, 1H), 3.13-3.00 (m, 2H), 1.93-1.79 (m, 2H), 1.68-1.47 (m, 2H), 1.47 (s, 3H), 1.46 (s, 9H).

Intermediate 16-2: tert-Butyl 4- (1-hydroxypropan-2-yloxy) piperidine-1-carboxylate
tert-butyl 4- (1-hydroxypropan-2-yloxy) piperidine-1-carboxylate

To a solution of intermediate 16-1 compound (0.33 g, 1.2 mmol) and triethylamine (0.2 ml, 1.4 mmol) in THF (6.0 ml) was added isobutyl chloroformate (0.17 ml, 1.3 mmol) at 0 ° C. The solution was stirred at 0 ° C. for 1 hour. The insoluble material was filtered to obtain a mixed acid anhydride THF solution. To the aqueous solution (6.0 ml) of sodium borohydride (0.13 g, 3.3 mmol), the above-mentioned mixed acid anhydride THF solution was added dropwise at −10 ° C. and stirred at 0 ° C. for 3 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.31 g, crude).
¹ H-NMR (CDCl ₃ ): δ 3.88-3.76 (m, 2H), 3.69-3.64 (m, 1H), 3.58-3.52 (m, 2H), 3.47-3.39 (m, 1H), 3.10-3.02 ( m, 2H), 2.05-1.97 (br, 1H), 1.89-1.78 (m, 2H), 1.58-1.47 (m, 2H), 1.44 (s, 9H), 1.10 (d, J = 6.2 Hz, 3H) .

Example 17:
tert-butyl 4-((2- (2-fluoro-4- (methylsulfonyl) phenylcarbamoyloxy) ethyl) (methyl) amino) piperidine-1-carboxylate
tert-butyl 4-((2- (2-fluoro-4- (methylsulfonyl) phenylcarbamoyloxy) ethyl) (methyl) amino) piperidine-1-carboxylate

The title compound was obtained in the same manner as in Example 1 using Intermediate 17-2 (0.113 g, 44%).
¹ H-NMR (CDCl ₃ ): δ 8.41-8.36 (m, 1H), 7.74-7.70 (m, 1H), 7.67 (dd, J = 9.8, 2.0 Hz, 1H), 7.07 (brs, 1H), 4.33 -4.19 (m, 4H), 3.06 (s, 3H), 2.85-2.39 (m, 5H), 1.84-1.76 (m, 2H), 1.45 (s, 9H).

Intermediate 17-1: tert-butyl 4-((2-methoxy-2-oxoethyl) (methyl) amino) piperidine-1-carboxylate
tert-Butyl 4-((2-methoxy-2-oxoethyl) (methyl) amino) piperidine-1-carboxylate

To a DMF (3.0 ml) solution of tert-butyloxycarbonyl-4-methylaminopiperidine (0.214 g, 1.0 mmol), methyl bromoacetate (0.13 ml, 1.4 mmol) and potassium carbonate (0.276 g, 2.0 mmol) were added, The reaction solution was stirred at room temperature for 17 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.316 g, crude).
¹ H-NMR (CDCl ₃ ): δ 4.14-4.09 (m, 2H), 3.73 (s, 3H), 3.38 (s, 2H), 2.75-2.66 (m, 3H), 2.45 (s, 3H), 1.83 -1.80 (m, 2H), 1.65-1.51 (m, 2H), 1.45 (s, 9H).

Intermediate 17-2: tert-butyl 4-((2-hydroxyethyl) (methyl) amino) piperidine-1-carboxylate
tert-butyl 4-((2-hydroxyethyl) (methyl) amino) piperidine-1-carboxylate

A solution of intermediate 16-1 (0.316 g) in tetrahydrofuran (3.0 ml) was added dropwise at 0 ° C. to a suspension of lithium aluminum hydride (0.076 g, 2.0 mmol) in tetrahydrofuran (2.0 ml). The reaction solution was stirred at room temperature for 16 hours, sodium sulfate · 10H ₂ O (0.50 g) was added at 0 ° C., and the mixture was stirred at room temperature overnight. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure to give the title compound (0.283 g, crude).
¹ H-NMR (CDCl ₃ ): δ 4.30-4.16 (m, 2H), 3.63 (t, J = 5.0 Hz, 2H), 2.77-2.63 (m, 5H), 2.32 (s, 3H), 1.83-1.78 (m, 2H), 1.53-1.44 (m, 2H), 1.45 (s, 9H).

Example 18:
tert-butyl 4- (2- (2-fluoro-4- (methylsulfonyl) phenylcarbamothioyloxy) ethyl) piperidine-1-carboxylate
tert-butyl 4- (2- (2-fluoro-4- (methylsulfonyl) phenylcarbamothioyloxy) ethyl) piperidine-1-carboxylate

The title compound was obtained in the same manner as in Example 1 using the compound of Intermediate 18-1 (0.174 g, 0.75 mmol) (0.136 g, 59%).
¹ H-NMR (CDCl ₃ ): δ 8.50-8.22 (m, 2H), 7.75-7.68 (m, 2H), 4.63 (t, J = 6.8 Hz, 2H), 4.13-4.11 (m, 2H), 3.07 (s, 3H), 2.73-2.65 (m, 2H), 1.81-1.72 (m, 4H), 1.69-1.51 (m, 1H), 1.45 (s, 9H), 1.45-1.13 (m, 2H).

Intermediate 18-1: 2-fluoro-1-isothiocyanato-4- (methylsulfonyl) benzene
2-Fluoro-1-isothiocyanate-4- (methylsulfonyl) benzene

To a solution of 2-fluoro 4- (methylsulfonyl) aniline (0.500 g, 2.64 mmol) in acetic acid (3.0 ml) was added 2N aqueous hydrochloric acid (6.0 ml) and thiophosgene (0.25 ml, 3.29 mmol) at 0 ° C. Stir at room temperature for 12 hours. Water was added and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.475 g, 78%).

Example 19:
tert-butyl 4- (2- (2,5-difluoro-4- (methylsulfonyl) phenylcarbamoyloxy) ethyl) piperidine-1-carboxylate
tert-butyl 4- (2- (2,5-difluoro-4- (methylsulfonyl) phenylcarbamoyloxy) ethyl) piperidine-1-carboxylate

The title compound was obtained in the same manner as in Example 1 (0.017 g, 25%).
¹ H-NMR (CDCl ₃ ): δ 8.23-8.18 (m, 1H), 7.69-7.65 (m, 1H), 7.15 (brs, 1H), 4.30 (t, J = 6.5 Hz, 2H), 4.27-4.09 (m, 2H), 3.21 (s, 3H), 2.74-2.66 (m, 2H), 1.73-1.52 (m, 5H), 1.45 (s, 9H), 1.21-1.11 (m, 2H).

Example 20:
tert-butyl 4- (2- (4- (dimethylcarbamoyl) -2-fluorophenylcarbamoyloxy) ethyl) piperidine-1-carboxylate
tert-butyl 4- (2- (4- (dimethylcarbamoyl) -2-fluorophenylcarbamoyloxy) ethyl) piperidine-1-carboxylate

The title compound was obtained in the same manner as in Example 12 (0.041 g, 71%).
¹ H-NMR (CDCl ₃ ): δ 8.11 (t, J = 3.8 Hz, 1H), 7.22-7.15 (m, 2H), 6.92 (brs, 1H), 4.22 (t, J = 6.4 Hz, 2H), 4.09-4.05 (m, 2H), 3.02 (s, 6H), 2.73-2.60 (m, 2H), 1.69-1.57 (m, 5H), 1.42 (s, 9H), 1.25-1.05 (m, 2H).

Example 21:
tert-butyl 4- (2- (4- (cyclopropylcarbamoyl) -3-fluorophenylcarbamoyloxy) ethyl) piperidine-1-carboxylate
tert-butyl 4- (2- (4- (cyclopropylcarbamoyl) -3-fluorophenylcarbamoyloxy) ethyl) piperidine-1-carboxylate

The title compound was obtained in the same manner as in Example 12 (0.035 g, 59%).
¹ H-NMR (CDCl ₃ ): δ 8.01 (d, J = 8.6 Hz, 2H), 7.55 (brd, J = 14.5 Hz, 1H), 7.28 (brs, 1H), 7.00 (dd, J = 8.8, 2.0 Hz, 1H), 6.78 (m, 1H), 4.20 (t, J = 6.4 Hz, 2H), 4.10-4.04 (m, 2H), 2.89 (m, 1H), 2.70-2.60 (m, 2H), 1.70 -1.50 (m, 5H), 1.42 (s, 9H), 1.20-1.04 (m, 2H), 0.87-0.80 (m, 2H).

Example 22:
tert-butyl 4- (1- (2-fluoro-4- (methylsulfonyl) phenylcarbamoyloxy) butan-2-yloxy) piperidine-1-carboxylate
tert-butyl 4- (1- (2-fluoro-4- (methylsulfonyl) phenylcarbamoyloxy) butan-2-yloxy) piperidine-1-carboxylate

実施例１と同様の方法で表題化合物を得た(0.055 g, 31%)。
¹H-NMR (CDCl₃):δ 8.39 (t, J=8.1 Hz, 1H), 7.74-7.72 (m, 1H), 7.68 (dd, J=10.1, 2.0 Hz, 1H), 7.19 (m, 1H), 4.26-4.18 (m, 2H), 3.82-3.76 (m, 2H), 3.60-3.56 (m, 2H), 3.08-3.04 (m, 5H), 1.83-1.79 (m, 2H), 1.62-1.46 (m, 4H), 1.45 (s, 9H), 1.00 (t, J=7.4 Hz, 3H).

The title compound was obtained in the same manner as in Example 1 (0.055 g, 31%).
¹ H-NMR (CDCl ₃ ): δ 8.39 (t, J = 8.1 Hz, 1H), 7.74-7.72 (m, 1H), 7.68 (dd, J = 10.1, 2.0 Hz, 1H), 7.19 (m, 1H ), 4.26-4.18 (m, 2H), 3.82-3.76 (m, 2H), 3.60-3.56 (m, 2H), 3.08-3.04 (m, 5H), 1.83-1.79 (m, 2H), 1.62-1.46 (m, 4H), 1.45 (s, 9H), 1.00 (t, J = 7.4 Hz, 3H).

Example 23:
tert-butyl 4- (4- (2-fluoro-4- (methylsulfonyl) phenylcarbamoyloxy) butanoyl) piperidine-1-carboxylate
tert-butyl 4- (4- (2-fluoro-4- (methylsulfonyl) phenylcarbamoyloxy) butanoyl) piperidine-1-carboxylate

To a solution of intermediate 23-3 (0.087 g, 0.180 mmol) in methanol (20 ml) was added palladium carbon (0.200 g), and the mixture was stirred under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.022 g, 25%).
¹ H-NMR (CDCl ₃ ): δ 7.71-7.67 (m, 1H), 7.60-7.57 (m, 1H), 6.74 (t, J = 8.3 Hz, 1H), 4.15-4.10 (m, 2H), 3.23 (t, J = 6.8 Hz, 2H), 3.04 (s, 3H), 2.78-2.75 (m, 2H), 2.626.8 Hz, 2H), 2.50-2.45 (m, 1H), 1.89-1.51 (m, 4H), 1.45 (s, 9H).

Intermediate 23-1: tert-butyl 4-but-3-enoylpiperidine-1-carboxylate
tert-butyl 4-but-3-enoylpiperidine-1-carboxylate

To a solution of tert-butyl 4- (methoxy (methyl) carbamoyl) piperidine-1-carboxylate (1.56 g, 5.73 mmol) in tetrahydrofuran (30 ml) was added an allylmagnesium bromide solution (8.6 ml, 8.6 mmol) at 0 ° C. The reaction solution was stirred at room temperature for 1 hour. Aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.12 g, 77%).
Intermediate 23-2: tert-butyl 4- (2- (oxiran-2-yl) acetyl) piperidine-1-carboxylate
tert-Butyl 4- (2- (oxiran-yl) acetyl) piperidine-1-carboxylate

M-Chloroperbenzoic acid (1.521 g, 8.818 mmol) was added to a solution of intermediate 23-1 compound (1.117 g, 4.409 mmol) in chloroform (30 ml), and the mixture was stirred at room temperature for 12 hours. Sodium sulfite water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.336 g, 28%).
Intermediate 23-3: tert-butyl 4- (4- (2-fluoro-4- (methylsulfonyl) phenylcarbamoyloxy) but-2-enoyl) piperidine-1-carboxylate
tert-butyl 4- (4- (2-fluoro-4- (methylsulfonyl) phenylcarbamoyloxy) but-2-enoyl) piperidine-1-carboxylate

To a toluene (10 ml) solution of intermediate 1-1 (0.403 g, 1.871 mmol) and intermediate 23-2 (0.336 g, 1.247 mmol), lithium bromide (0.011 g, 0.125 mmol) and hexamethylphosphoramide ( 0.022 g, 0.125 mmol) was added, and the mixture was heated to reflux for 3 hours. After returning to room temperature, water was added and the mixture was extracted with chloroform, and the organic layer was dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.087 g, 14%).

Example 24:
methylcyclopropyl 4- (2- (2-fluoro-4- (methylsulfonyl) phenylcarbamoyloxy) ethyl) piperidine-1-carboxylate
Methylcyclopropyl 4- (2- (2-fluoro-4- (methylsulfonyl) phenylcarbamoyloxy) ethyl) piperidine-1-carboxylate

To a solution of intermediate 4-1 (0.031 g, 0.08 mmol) and triethylamine (0.034 ml, 0.24 mmol) in tetrahydrofuran (1.5 ml) was added 1-methylcyclopropyl 4-nitrophenyl carbonate (0.025 g, 0.104 mmol) at room temperature. For 24 hours. Water was added to the reaction solution, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.038 g, quantitative).
¹ H-NMR (CDCl ₃ ): δ 8.42-8.38 (m, 1H), 7.74-7.72 (m, 1H), 7.66-7.66 (m, 1H), 7.08 (brs, 1H), 4.27 (t, J = 6.5 Hz, 2H), 4.11 (brs, 2H), 3.05 (s, 3H), 2.74-2.68 (m, 2H), 1.72-1.57 (m, 5H), 1.54 (s, 3H), 1.16-1.14 (m , 2H), 0.87-0.84 (m, 2H), 0.64-0.62 (m, 2H).

Pharmacological test example:
Langerhans Islet isolated from ICR mice (8 weeks old) was used to test the insulin secretion promoting ability of the compounds of the present invention. About 200 Langerhans islands isolated using a stereomicroscope were cultured in a cell culture medium supplemented with 10% FBS for 1 hour. Furthermore, it replaced with low glucose (2.8 mM) Krebs-Ringers Buffer (KRB) 1 hour before the reaction start. This was added to each test tube containing the compound solution of the present invention diluted with 0.45 mL of low glucose (2.8 mM) or high glucose (11.1 mM) KRB at a rate of 4 / 0.05 mL. After heating at 37 ° C. for 1 hour, 0.1 mL of the supernatant was gently recovered so that there is no contamination with Langerhans Islet. The collected solution was stored at −20 ° C. until insulin determination. Insulin quantification was performed with an insulin kit (Setty Medical Lab Co., Ltd.).

a) cAMP study
HIT-T15 cells were purchased from Dainippon Sumitomo Pharma Co., Ltd. and cultured in F-12 medium containing 10% fetal bovine serum. HIT-T15 cells were seeded in a 96-well plate at 20,000 cells / 0.1 mL / well and cultured at 37 ° C. for 72 hours. The medium was removed and immediately washed with 0.1 mL of stimulation buffer (0.1% BSA / 1 × Hank's / 20 mM HEPES (pH 7.4)). The solution was removed, and 0.05 mL of a drug diluent (containing the compound of the present invention and 0.5 mM IBMX in a stimulation buffer) was added. After culturing at 37 ° C. for 30 minutes, 0.05 mL of Lysis buffer (1% Triton X-100, 50 mM Phosphate buffer (pH 7.0)) was added and stirred to lyse the cells.
Using a HTRF reagent (HTRF cAMP Dynamic2, Setty Medical Lab Co., Ltd.), cAMP in the cell lysate was quantified according to the protocol. For the measurement, EnVision (Perkin Elmer Japan Co., Ltd.) was used.
The results are shown in Table 1.

b) Insulin secretion test
HIT-T15 cells were seeded in a 96-well plate at 20,000 cells / 0.1 mL / well and cultured at 37 ° C. for 72 hours. Remove the medium, wash once with 0.1 mL of HEPES-balanced Krebs-Ringer bicarbonate buffer (pH 7.4) (KRBB) containing 0.1% bovine serum albumin, add KRBB at 0.1 mL / well, and add 60 mL at 37 ° C. Separate culture was performed. Next, KRBB was removed, KRBB containing 16.7 mM glucose and the compound of the present invention was added at 0.05 mL / well, and cultured at 37 ° C. for 60 minutes. After 60 minutes, 0.03 mL of the supernatant was recovered.

  This recovered solution was diluted 10-fold with PBS (-) containing 0.1% bovine serum albumin, and then insulin measurement kit Insulin bulk (Setty Medical Lab Co., Ltd.) and hamster insulin standard solution (Shiba Goat Co., Ltd.) were used. Insulin concentration was quantified according to the attached protocol. EnVision (Perkin Elmer Japan Co., Ltd.) was used for the measurement. The compound of the present invention showed an excellent insulin secretion promoting action.

c) Cytotoxicity test
HIT-T15 cells were purchased from Dainippon Sumitomo Pharma Co., Ltd. and cultured in F-12 medium containing 10% fetal bovine serum. HIT-T15 cells were seeded in 96-well plates at 20,000 cells / 0.1 mL / well and cultured at 37 ° C. for 48 hours. The medium was removed and immediately washed with warmed 1 × PBS. The evaluation compound was added to 100 μl of F-12 medium containing 10% fetal bovine serum and cultured overnight. After incubation, add 10 μl of Cell Counting Kit-8 (Dojindo Laboratories, Inc.), a reagent for measuring cell proliferation / cytotoxicity, and after culturing for 2 hours, use a microplate reader (Nippon Molecular Devices Co., Ltd.) Absorbance was measured. The compounds of Example 1 and Example 2 did not show cytotoxicity up to 30 μM.

d) hERG inhibition test hERG in CHO cells in which hERG (human ether-a-go-go) gene is stably expressed by whole cell patch clamp method using QPatch HT (Sophion Bioscience A / S). The potassium current was recorded. The hERG current is the tail current when the membrane potential is held at -80 mV in the voltage clamp mode, depolarized to +20 mV for 5 seconds, then depolarized to +20 mV for 20 seconds, and then repolarized to -50 mV for 5 seconds. Amplitude was evaluated. Stimulation was repeated every 15 seconds, and the experiment was performed at room temperature (22 ± 2 ° C.). The compound was administered at a concentration of 4 concentrations per cell for 5 minutes, and the inhibition rate of the inhibited current was calculated as compared with the magnitude of the current before compound adaptation. The 50% inhibitory concentration was calculated by the Hill equation (IC ₅₀ [ΜM]). The following test solutions were used. : Extracellular solution (mM): 2 CaCl ₂ , 1 MgCl ₂ , 10 HEPES, 4 KCl, 145 NaCl, 10 glucose, intracellular solution (mM): 5.4 CaCl ₂ , 1.8 MgCl ₂ , 10 HEPES, 31 KOH, 10 EGTA, 120 KCl, 4 ATP
The results are shown in Table 2. The hERG inhibitory activity IC ₅₀ of the compound of the present invention was 10 μM or more.

  Since the compound of the present invention has an insulin secretion promoting action, it is safe for mammals (for example, humans, mice, dogs, rats, cows, etc.), diabetes, impaired glucose tolerance, fasting glucose abnormalities, diabetic complications ( Prevention and / or prevention of obesity, hyperinsulinemia, pancreatitis, chronic liver disease, acromegaly, Cushing's syndrome, pheochromocytoma, glucagonoma, hyperthyroidism, etc. Useful for treatment.

Claims (23)

The compound represented by Formula (1), or its pharmacologically acceptable salt.

[Wherein A represents the following (a) to (d)

(Wherein R ⁴ is the following,

Any one of the groups;
m and n are each independently 0, 1 or 2;
R ⁵ represents a cyano group, an optionally substituted C _1-6 alkoxycarbonyl group, an optionally substituted C _3-7 cycloalkoxycarbonyl group, an optionally substituted 4- to 7-membered saturated complex. Ring oxycarbonyl group, optionally substituted aminocarbonyl group, optionally substituted 4- to 7-membered cyclic aminocarbonyl group, optionally substituted C _1-6 alkyl group, optionally substituted A good C _3-7 cycloalkyl group, an _optionally substituted C _3-7 cycloalkyl C _1-4 alkyl group, an optionally substituted C _1-6 alkylcarbonyl group, an optionally substituted C _{3 -7} cycloalkylcarbonyl group, optionally substituted C _3-7 cycloalkyl C _1-4 alkylcarbonyl group, optionally substituted aralkyl group, optionally substituted 5 or 6 membered monocycle Hetero ant Group, a substituted monocyclic also be 5-membered to 10-membered optionally or polycyclic heteroaryl C _1-4 alkyl group or a monocyclic heteroaryl-carbonyl 5-membered optionally substituted or 6-membered, It is a group. );
R ¹ is an optionally substituted C _6-10 aryl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group;
R ^2a , R ^2b , R ^3а and R ^3b are
(I) R ^2a , R ^2b , R ^3а and R ^3b are each independently a hydrogen atom, an ^optionally substituted C _1-6 alkyl group, or an ^optionally substituted C _3-7 cycloalkyl group. , An optionally substituted C _1-6 alkoxy group, an optionally substituted C _3-7 cycloalkoxy group, an optionally substituted amino group, an optionally substituted 4- to 7-membered cyclic group An amino group or an optionally substituted 4- to 7-membered saturated heterocyclic group,
(Ii) R ^2a and R ^2b are each independently a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-7 cycloalkyl group, or a substituted A good C _1-6 alkoxy group, an optionally substituted C _3-7 cycloalkoxy group, an optionally substituted amino group, an optionally substituted 4- to 7-membered cyclic amino group, or a substituted An optionally substituted 4- to 7-membered saturated heterocyclic group, and R ^3a and R ^3b together are an oxo group, or (iii) R ^2a and R ^2b are together oxo Each of R ^3a and R ^3b is independently a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-7 cycloalkyl group, also a C _1-6 alkoxy group, an optionally substituted C _3-7 cycloalkoxy group, optionally substituted It is also an amino group, optionally substituted 4-membered to 7-membered cyclic amino group or a substituted 4-membered to 7-membered may be saturated heterocyclic group;
p is 1, 2, 3, or 4 (when R ^2a and R ^2b together are an oxo group, p is limited to 1);
q is 0, 1, 2 or 3 (when R ^3a and R ^3b are together an oxo group, q is limited to 1);
X is an oxygen atom or a sulfur atom;
Y is an oxygen atom, a sulfur atom, or NR ⁶ (wherein R ⁶ is a hydrogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _3-7 cyclohexane). An alkyl group);
Z is a single bond, vinylene, ethynylene, an oxygen atom, a sulfur atom, or NR ⁷ (wherein R ⁷ is a hydrogen atom, an optionally substituted C _1-6 alkyl group, or a substituted _{Or a} C _3-7 cycloalkyl group. However, in the compound represented by the formula (1), when R ¹ is phenyl substituted with ¹ to 2 C _1-4 alkoxy, A is a group represented by the formula (a). R ⁵ in C _1-6 alkoxycarbonyl group, C _3-7 cycloalkoxycarbonyl group, C _1-6 alkylcarbonyl group, C _3-7 cycloalkylcarbonyl group, and C _3-7 cycloalkyl C _1-4 When R ¹ is phenyl substituted with amino, not a compound represented by an alkylcarbonyl group, R ⁵ in the group represented by formula (a) is a 5-membered or 6-membered It is not a compound that is a monocyclic heteroaryl group. ] R ¹ is
A C _6-10 aryl group (the group is
1: halogen atom,
2: C _1-6 alkyl group (the group is
(A) amino (the amino is
(A1) C _1-6 alkyl (the alkyl is
(A11) hydroxy,
(A12) C _1-6 alkoxy,
(A13) carboxyl,
(A14) aminocarbonyl,
(A15) di-C _1-6 alkylamino,
(A16) mono- or di-C _1-6 alkylaminocarbonyl,
(A17) C _1-6 alkylcarbonylamino,
(A18) mono or di-C _1-6 alkylaminocarbonylamino, or (a19) optionally substituted with C _1-6 alkoxycarbonylamino. ),
(A2) C _3-7 cycloalkyl,
(A3) C _3-7 cycloalkyl C _1-4 alkyl,
(A4) a 5- or 6-membered saturated heterocyclic ring (which may be substituted with C _1-6 alkyl),
(A5) 5 or 6 membered saturated heterocyclic-C _1-4 alkyl,
(A6) 5- or 6-membered monocyclic heteroaryl, or (a7) optionally substituted with a 5- or 6-membered monocyclic heteroaryl-C _1-4 alkyl. ),
(B) hydroxy,
(C) a 4- to 7-membered cyclic amino (the ring is
(C1) hydroxy,
(C2) C _1-6 alkyl (the group may be substituted with hydroxy or C _1-6 alkoxy),
(C3) C _1-6 alkoxy, or (c4) optionally substituted with di-C _1-6 alkylamino. ),
(D) aminocarbonyl (the amino may be substituted with one or two groups selected from the group consisting of the above (a1) to (a7)).
(E) C _1-6 alkoxy (the group is
(E1) hydroxy,
(E2) C _1-6 alkoxy,
(E3) C _3-7 cycloalkyl,
(E4) C _3-7 cycloalkoxy,
(E5) a 4-membered to 6-membered saturated heterocyclic ring (the ring may be substituted with C _1-6 alkyl),
(E6) a 4- to 7-membered cyclic amino,
(E7) C _1-6 alkylcarbonylamino,
(E8) Di-C _1-6 alkylamino, or (e9) optionally substituted with di-C _1-6 alkylaminocarbonyl. ) May be substituted. ),
3: C _1-6 alkylsulfonyl group (the C _1-6 alkyl group is
(A) C _3-7 cycloalkyl, or (b) optionally substituted with a 4-6 membered saturated heterocycle. ),
4: C _3-7 cycloalkylsulfonyl group (this group may be substituted with C _1-6 alkyl),
5: 4-membered to 6-membered saturated heterocyclic sulfonyl group,
6: Amino group (the amino is substituted with one or two groups of the same or different types selected from the group consisting of the above (a1) to (a7)),
7: Aminosulfonyl group (the amino is the same or different 1-2 C _1-6 alkyl (the alkyl is substituted with hydroxy, C _1-4 alkoxy, or di-C _1-6 alkylamino) And may be substituted with
8: 4-membered to 7-membered cyclic amino group (the ring may be substituted with the above (c1) to (c4)),
9: aminocarbonyl group (the amino may be substituted with one or two groups of the same or different types selected from the group consisting of the above (a1) to (a7));
10: 4- to 7-membered cyclic aminocarbonyl group (the ring may be substituted with the above-mentioned (c1) to (c4)),
11: carboxyl group,
12: C _1-6 alkoxy group,
13: C _1-6 alkoxycarbonyl group,
14: C _1-6 alkylcarbonylamino group,
15: C _3-7 cycloalkylcarbonylamino group,
16: C _3-7 cycloalkyl C _1-6 alkylcarbonylamino group,
17: mono- or di-C _1-6 alkylaminocarbonylamino group,
18: C _1-6 alkoxycarbonylamino group,
It may be substituted with 1 to 3 groups of the same or different types selected from the group consisting of a 19: C _6-10 aryl group and a 20: 5-membered or 6-membered monocyclic heteroaryl group. ),
Or a 5- or 6-membered monocyclic heteroaryl group (the heteroaryl is substituted with 1 to 3 groups of the same or different types selected from the group consisting of 1 to 20 in the C _6-10 aryl group) Or the pharmacologically acceptable salt thereof. R ¹ is
A C _6-10 aryl group (the group is
1: halogen atom,
2: C _1-6 alkylsulfonyl group,
3: Aminocarbonyl group (the amino is
(A) C _1-6 alkyl (which may be substituted with hydroxy), and (b) substituted with 1-2 groups selected from the group consisting of C _3-7 cycloalkyl It may be. ),
4: 4- to 7-membered cyclic aminocarbonyl group,
5: Carboxyl group, or 6: C _1-6 alkoxy carboxyl group may be substituted. The compound according to claim 2, or a pharmacologically acceptable salt thereof. A is the following formula (a)

The compound as described in any one of Claims 1-3 which is group represented by these, or its pharmacologically acceptable salt. The compound according to claim 4, wherein m and n are 1, or a pharmaceutically acceptable salt thereof. R ⁵ is
1: C _1-6 alkoxycarbonyl group (the group is
(A) 1 to 6 fluorine atoms,
(B) C _3-7 cycloalkyl (the group is
(I) C _1-6 alkyl,
(Ii) C _3-7 cycloalkyl, or (iii) C _3-7 cycloalkyl C _1-4 alkyl may be substituted. ), Or (c) a 4- to 6-membered saturated heterocyclic ring (the group is
(I) C _1-6 alkyl,
(Ii) C _3-7 cycloalkyl, or (iii) C _3-7 cycloalkyl C _1-4 alkyl may be substituted. ) May be substituted. ),
2: C _3-7 cycloalkoxycarbonyl group (the group is
(A) C _1-6 alkyl,
(B) C _3-7 cycloalkyl, or (c) C _3-7 cycloalkyl C _1-4 alkyl may be substituted. ),
3: 4-membered to 6-membered saturated heterocyclic oxycarbonyl group (the group is
(A) C _1-6 alkyl,
(B) C _3-7 cycloalkyl, or (c) C _3-7 cycloalkyl C _1-4 alkyl may be substituted. ),
4: C _1-6 alkylcarbonyl group,
5: C _3-7 cycloalkylcarbonyl group,
6: C _3-7 cycloalkyl C _1-4 alkylcarbonyl group,
7: C _1-6 alkyl group,
8: C _3-7 cycloalkyl group,
9: C _3-7 cycloalkyl C _1-4 alkyl group,
10: C _7-14 aralkyl group,
11: 5 or 6 membered monocyclic heteroaryl group (the ring is
(A) C _1-6 alkyl,
(B) C _3-7 cycloalkyl, and (c) C _3-7 cycloalkyl C _1-4 alkyl may be substituted with 1 to 3 groups of the same or different types selected from the group consisting of. ) Or 12: The compound according to any one of claims 1 to 5, which is a cyano group, or a pharmacologically acceptable salt thereof. R ⁵ is
1: C _1-6 alkoxycarbonyl group (the alkoxy may be substituted with 1 to 6 fluorine atoms),
2. A C _3-7 cycloalkoxycarbonyl group (the cycloalkoxy may be substituted with C _1-6 alkyl), or a 3: 5-membered or 6-membered monocyclic heteroaryl group (the ring is represented by C _1-6 alkyl may be substituted.), The compound of Claim 6, or its pharmacologically acceptable salt. ^{R 2a,} R ^2b, R 3а and R ^3b are each independently hydrogen atom, or a C _1-6 alkyl group A compound according to any one of claims 1 to 7 or a, Pharmacologically acceptable salt. The compound according to claim 8, or a pharmacologically acceptable salt thereof, wherein R ^2a , R ^2b , R ^3а and R ^3b are all hydrogen atoms. R ^2a and R ^2b are each independently a hydrogen atom or a C _1-6 alkyl group, and R ^3a and R ^3b together are an oxo group. Or a pharmacologically acceptable salt thereof. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein R ^2a and R ^2b are both hydrogen atoms. The compound as described in any one of Claims 1-11 whose p is 2, 3, or 4, or its pharmacologically acceptable salt. The compound according to claim 12, wherein p is 2, or a pharmacologically acceptable salt thereof. The compound according to claim 12, wherein p is 3, or a pharmaceutically acceptable salt thereof. The compound as described in any one of Claims 1-14 whose q is 0, or its pharmacologically acceptable salt. The compound or pharmacologically acceptable salt according to any one of claims 1 to 15, wherein X is an oxygen atom. The compound or pharmacologically acceptable salt according to any one of claims 1 to 15, wherein X is a sulfur atom. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Y is an oxygen atom. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein Z is a single bond, an oxygen atom, or NR ⁷ . The compound according to claim 19, or a pharmaceutically acceptable salt thereof, wherein Z is a single bond. The compound according to claim 19, or a pharmaceutically acceptable salt thereof, wherein Z is an oxygen atom. The compound according to claim 19, or a pharmaceutically acceptable salt thereof, wherein Z is NR ⁷ . Salts R ⁷ is a C _1-6 alkyl group, which is a compound according to claim 22, or a pharmaceutically acceptable.