JP2009256208A - Phthalide derivative or pharmaceutically acceptable salt of the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine having sugar production inhibitory activity, and useful for the prevention or treatment of diabetes. <P>SOLUTION: There is provided a compound expressed by formula (I) [wherein, R<SP>1</SP>to R<SP>4</SP>are each the same or different H, a lower alkoxy which may be substituted, or the like; R<SP>5</SP>is H or the like; (n) is an integer of 4 or the like; and A is formula (II) (wherein, (p) is 0 or the like; (q) is 1 or the like; X is S, -NR<SP>6</SP>or -C(R<SP>7</SP>)(R<SP>8</SP>)-; R<SP>6</SP>is a lower alkyl which may be substituted; and R<SP>7</SP>is H or the like; R<SP>8</SP>is hydroxy, a lower alkyl which may be substituted or the like) or the like], or its pharmaceutically acceptable salt. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a novel phthalide derivative or a salt thereof having a blood glucose lowering action and a blood lipid lowering action. More particularly, the present invention relates to a novel compound or a novel pharmaceutical composition containing the compound that is effective in treating or / and preventing hypercholesterolemia, hypertriglyceridemia or diabetes. Further, the present invention relates to a novel intermediate of a novel phthalide derivative or a salt thereof.

  In recent years, the number of diabetic patients is increasing year by year due to changes in lifestyle habits. The number of patients is expected to exceed 300 million by 2025. For this reason, research on causes, prevention, and treatment relating to diabetes has been energetically performed, and therapeutic agents for diabetes such as sulfonylurea, biguanide, and thiazolidine have been developed.

  In recent years, it has been clarified from the analysis results of the onset mechanism of diabetes that there are some deficiencies in insulin action such as insulin action failure and pancreatic β-cell exhaustion in the diabetic state (Non-patent Document 1). That is, it is considered that the increase in sugar production in the liver leads to an increase in blood glucose level due to a defect in the action of insulin, which greatly affects the onset and progression of diabetes. In addition, it is considered that glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), which are the rate-limiting enzymes for sugar production, are increased during the fasting of diabetic patients (Non-patent Document 2).

  In addition to the analysis related to diabetic patients, research has also been conducted on the analysis related to hyperlipidemia patients and the relationship between hypertension, hyperlipidemia and diabetes. Diabetes, hyperlipidemia, hypertension, etc. are considered to be closely related, and when each disease occurs at the same time, they act synergistically and eventually become a fatal arteriosclerotic disease (Myocardial infarction, cerebral infarction, etc.) is thought to easily occur. Therefore, it is considered that simultaneously correcting a plurality of risk factors such as diabetes and hyperlipidemia can be a useful drug for the prevention or / and treatment of arteriosclerotic diseases.

  Under these circumstances, for current hyperlipidemia often observed in diabetic patients and impaired glucose tolerance, current drug treatments for controlling blood glucose levels and blood lipid levels have only been combined with the respective therapeutic agents. . However, in this combination therapy, there are problems such as side effects due to the result of interaction between the respective drugs, and it cannot be said that hyperlipidemia is sufficiently treated in diabetic patients.

  On the other hand, as natural phthalide derivatives, sporotricale represented by the following formula (A) and spirolaxin represented by the following formula (B) are known (Non-patent Document 3).

  Further, as synthetic phthalide derivatives, compounds described in Patent Documents 1 and 2 below are known.

  Patent Document 1 describes a compound represented by the following formula (C).

[Wherein, R ¹ represents an alkoxy group having 1 to 5 carbon atoms, R ² represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 18 carbon atoms, or the like, and R ³ represents the following formula (D)

(Wherein X is CO, CH (OH), etc., Y is CO, CH (OH) or CH (OR ⁴ ), where R ⁴ is an alkyl group having 1 to 5 carbon atoms, etc. Group represented by the following formula (E)

Or a group represented by the following formula (F)

(Wherein Z is CH ₂ or CO). ]

  Patent Document 2 describes a compound represented by the following formula (G).

[Wherein R ¹ represents a hydrogen atom or an alkoxy group having 1 to 4 carbon atoms, and R ² represents a hydrogen atom, a phenyl group, an amino group, a mono- or dialkylamino group, a substituted or unsubstituted pyrrolidino group, a substituted group. Alternatively, it represents an unsubstituted piperidino group, a substituted or unsubstituted piperazino group or a morpholino group, and n represents an integer of 1 to 20. ]

Patent Document 3 describes a compound represented by the following formula (H).

[Wherein R ¹ represents the formula —CO (CH ₂ ) ₃ CO (CH ₂ ) ₂ CH (OH) CH ₃ , —CO (CH ₂ ) ₆ CH (OH) CH ₃ or — (CH ₂ ) ₇ CH ( OH) is a group represented by CH ₃ . ]

  Patent Document 4 describes a compound represented by the following formula I.

[Wherein, R ¹ represents — (CH ₂ ) ₃ —C (═O) — (CH ₂ ) ₂ —C (═O) —CH ₃ , — (CH ₂ ) ₅ —C (═O) — ( CH ₂ ) ₂ —C (═O) —CH ₃ , — (CH ₂ ) ₆ —C (OH) —CH ₃ , — (CH ₂ ) ₆ —C (═O) —CH ₃ and the like. ]

However, only the compounds represented above have been shown to have a lipid-lowering action based on the LDL receptor expression enhancing activity, and phthalide derivatives having an action of inhibiting sugar production in the liver have been used so far. There are no reports.
Endocrinology, 141, 1917 (2000) Molecular Cell, 6, 87 (2000) Phytochemistry, 29 (No.2), 613-616 (1990) International Publication No. 96/010020 Pamphlet JP-A-9-255676 JP-A-9-110781 International Publication No. 96/016053 Pamphlet

  As explained above, in the current aging and satiety era, it is considered that the number of patients with hyperglycemia and hyperlipidemia (high cholesterol and high triglycerides) is increasing. However, due to problems such as side effects, the current comprehensive treatment of hyperglycemia and hyperlipidemia using a combination of multiple drugs is not always sufficient. Therefore, if diabetes is effectively prevented or treated using a different approach from existing anti-diabetic drugs, and the hyperlipidemia often associated with diabetes and impaired glucose tolerance (diabetes reserves) can be improved simultaneously and effectively It is considered that the risk factor of arteriosclerosis can be drastically improved and can be a useful drug for the prevention or / and treatment of arteriosclerotic disease, and development of such a drug is desired.

  As a result of further investigations, the present inventors have found that certain phthalide derivatives have both a blood glucose lowering action and a lipid lowering action. It came to complete.

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

[Wherein, R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom, an optionally substituted lower alkyl, or an optionally substituted lower alkoxy;
R ⁵ is a hydrogen atom, methyl, or ethyl;
n is an integer from 4 to 12;
A is formula (II) or formula (VII).
[(1) Formula (II)

[Wherein, X is a sulfur atom, —NR ⁶ —, or —C (R ⁷ ) (R ⁸ ) —;
p is 0, 1, or 2 (provided that when X is a sulfur atom or —NR ⁶ —, p is 1);
q is an integer of 1 or more (provided that the sum of p and q is 1, 2, or 3, but when X is a sulfur atom or —NR ⁶ —, the sum of p and q is 2 or 3));

R ⁶ is optionally substituted lower alkyl, carbonylmethyl bonded to a 5- or 6-membered saturated heterocycle, optionally substituted phenyl, optionally substituted phenyl lower alkyl, optionally substituted good 5- or 6-membered heterocycle saturated, optionally substituted phenyl-lower alkenyl optionally, -COR ¹¹ or ^-NHCOR 11 ^{{R 11,} is hydrogen atom, optionally substituted lower alkyl, optionally substituted Lower alkoxy, optionally substituted phenyl, optionally substituted amino, optionally substituted 5 or 6 membered saturated heterocyclic ring, or —OR ¹¹¹ (R ¹¹¹ is optionally substituted phenyl, substituted Phenyl lower alkyl, which may be substituted, lower alkenyl which may be substituted, or lower cycloalkyl which may be substituted. . };

R ⁷ is a hydrogen atom, hydroxy, or optionally substituted lower alkoxy;
R ⁸ represents hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, lower alkylsulfonyl, optionally substituted phenyl, optionally substituted phenyl lower alkyl, optionally substituted unsaturated. Terror ring,
-OCOR ¹¹ (R ¹¹ has the same meaning as described above),
—N (R ²² ) SO ₂ R ³³ (R ²² represents a hydrogen atom or lower alkyl, and R ³³ represents phenyl which may be substituted, lower alkyl which may be substituted, or amino which may be substituted. ),
—N (R ²² ) COR ⁴⁴ [R ²² has the same meaning as described above, and R ⁴⁴ represents a hydrogen atom, an optionally substituted lower alkyl, an optionally substituted phenyl, an optionally substituted unsaturated. Tero ring, optionally substituted 5- or 6-membered saturated hetero ring, optionally substituted lower alkoxy, optionally substituted lower cycloalkyl, optionally substituted amino, —OR ²²² {R ²²² is An optionally substituted 5- or 6-membered saturated heterocyclic ring (provided that the nitrogen atom in the saturated heterocyclic ring and the oxygen atom of —OR ²²² are not directly bonded), an optionally substituted phenyl, Optionally substituted phenyl lower alkyl, unsaturated alkyl bonded lower alkyl, optionally substituted lower alkenyl, optionally substituted lower cycloalkyl lower alkyl, 2-indanyl, or It is a lower alkyl to which a 5-membered or 6-membered saturated heterocycle optionally substituted is bonded. }, Or the following formula (III) or the following formula (IV)

{In the formula, R ³³³ is a hydrogen atom, hydroxy, —OCOR ¹¹¹¹ (R ¹¹¹¹ is a hydrogen atom; halogen atom, hydroxy, C _1-4 alkoxy, di (C _1-6 alkyl which may be substituted) amino, C _1-4 alkoxy C _2-4 alkoxy, phenyl C _1-4 alkoxy, phenoxy, C _1-6 alkylsulfonyl, C _1-6 alkoxycarbonylamino, C _1-6 alkoxycarbonyl, C _2-7 alkanoyl or C _3- Lower alkoxy optionally substituted with ₆ cycloalkyl; optionally substituted lower alkyl; optionally substituted 5- or 6-membered saturated heterocyclic ring; or optionally substituted amino.), —NHCOR ^{1111 (R 1111} are the same as defined ^{above.), - COR 1111 (R} 1111 are the same as the It is a taste.), Or the following formula (V)

And r is 0 or 1. }. ],
Formula (VI)

(Where
(A) D is an oxygen atom, —NR ⁴⁴⁴ — or —CH ₂ —,
(A) E is carbonyl and F is optionally substituted C _1-2 alkylene,
(B) E is C _1-2 alkylene which may be substituted, and F is carbonyl,
(C) E and F are methylene, or (d) E and F together with phenyl form a condensed ring;

(B) D is -CONR ^444- and E and F are methylene (wherein the nitrogen atom of NR ⁴⁴⁴ is directly bonded to F); or

(C) D is —CH ₂ NR ⁴⁴⁴ —, E is an optionally substituted C _1-2 alkylene, F is carbonyl (wherein R ⁴⁴⁴ is a hydrogen atom, formyl, substituted Or a lower alkanoyl, wherein the nitrogen atom of NR ⁴⁴⁴ is directly bonded to F), or

—CH ₂ R ⁵⁵ {R ⁵⁵ is C _1-6 alkoxy, or — (CH ₂ ) s—N (R ²² ) (R ⁵⁵⁵ ) (R ²² is as defined above, and R ⁵⁵⁵ is substituted. Phenyl lower alkyl, lower alkoxycarbonyl, or lower alkyl which may be substituted, and s is 0 or 1.). Or R ⁷ and R ^{8 taken} together are —OCH ₂ CH ₂ O—. However, when R ⁷ is hydroxy, R ⁸ is not lower alkoxy. Or

(2) Formula (VII)

Wherein Y is an oxygen atom, or —N (R ⁹ ) — (R ⁹ is a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower cycloalkyl, lower alkyl, optionally substituted. Phenyl lower alkyl, or lower alkyl to which an optionally substituted 5- or 6-membered saturated heterocyclic ring is bonded).

Z is —CH ₂ — or —CO— when Y is an oxygen atom, and is an oxygen atom when Y is —N (R ⁹ ) — (R ⁹ has the same meaning as described above). -CO-;
W is C _1-2 alkylene or — (CH ₂ ) m—NR ⁹ — (wherein R ⁹ has the same meaning as described above, m is 0 or 1, and when m is 1, NR ⁹ (However, when Z is an oxygen atom, W is — (CH ₂ ) m—NR ⁹ —), or W is condensed with phenyl. Forming a ring (provided that Y is —NR ⁹ — and Z is an oxygen atom);
t is 0 or 1. ). ]]

Item 2: X is —N (R ⁶ ) —, or —C (R ⁷ ) (R ⁸ ) —;
R ⁶ is optionally substituted lower alkyl, optionally substituted phenyl, -COR ¹¹ or -NHCOR ^11;
R ⁷ is a hydrogen atom, hydroxy, or an optionally substituted lower alkoxy group;
R ⁸ is optionally substituted lower alkyl, optionally substituted phenyl, optionally substituted phenyl lower alkyl, —OCOR ¹¹ , —N (R ²² ) SO ₂ R ³³ , —N (R ²² ) COR ⁴⁴ , formula (VI), or —CH ₂ R ⁵⁵ ;
n is an integer from 8 to 11;
p is 0 or 1;
q is 2, (R ¹¹ , R ²² , R ³³ , R ⁴⁴ , formulas (VI) and R ⁵⁵ have the same meaning as in claim 1), or a pharmaceutically acceptable compound thereof, Salt.

Item 3: X is —C (R ⁷ ) (R ⁸ ) —;
R ⁷ is a hydrogen atom or hydroxy;
R ⁸ is optionally substituted phenyl, —N (R ²² ) COR ⁴⁴ or formula (VI);
R ⁴⁴ is optionally substituted lower alkoxy or formula (III) (R ²² , formula (III) or formula (VI) has the same meaning as in item 1), or compound according to item 1 or item 2. Or a pharmaceutically acceptable salt thereof.

Item 4: The compound according to claim 1, wherein A is formula (VII), or a pharmaceutically acceptable salt thereof.

Item 5: A compound represented by the following formula (VIII) or a pharmaceutically acceptable salt thereof.

[Wherein R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group;
R ⁵ is a hydrogen atom, a methyl group, or an ethyl group;
B is a halogen atom or a hydroxy group;
n means an integer of 6 to 12. ]

  The phthalide derivative in the present invention has a glucose production inhibitory action, can correct a hyperglycemic state to a normal state, and is effective in preventing or treating diabetes. Moreover, the phthalide derivative in the present invention is effective in preventing or treating hyperlipidemia since it also has a lipid lowering action. Furthermore, since the phthalide derivative in the present invention has both the sugar production inhibitory action and the lipid lowering action, it is effective for metabolic syndrome caused by hyperglycemia or / and hyperlipidemia.

  Although the term in this invention is demonstrated below, the phthalide derivative in this invention is not limited to the meaning of the term demonstrated below.

  Examples of the pharmaceutically acceptable salt of the compound represented by the formula (I) (hereinafter sometimes referred to as the compound of the present invention) include pharmaceutically acceptable compounds having a basic group in the compound of the present invention. It means an acceptable acid addition salt. Specific examples of pharmaceutically acceptable acid addition salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, perchloric acid, phosphoric acid and other inorganic acids, oxalic acid, malonic acid, and succinic acid. , Maleic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, benzoic acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid and other organic acids, glutamic acid, aspartic acid, etc. And acidic amino acids.

  The compounds of the present invention may exist in the form of hydrates or solvates. These hydrates and solvates are also encompassed by the compounds of the present invention. Solvents that form solvates include, for example, alcohols such as ethanol, 1- or 2-propanol, organic acids such as acetic acid, esters such as ethyl acetate, ethers such as tetrahydrofuran and diethyl ether, DMSO, and the like. Can be mentioned.

  Since the compound of the present invention has at least one asymmetric carbon atom, an optical isomer exists.

  The compound of the present invention includes these optically active substances and racemates thereof.

  When the compound of the present invention has two or more asymmetric carbon atoms, stereoisomerism may occur.

  In the compound of the present invention, these stereoisomers and mixtures thereof are included in the compound of the present invention.

  The optically active substance included in the compound of the present invention can be produced using an optically active substance of the compound of the formula (VIII) produced by the production method described later. Alternatively, the final racemate can be obtained by optical resolution according to a conventional method.

In this specification, the term “lower” refers to, for example, C _1-6 , C _1-4 , C _2-4 , C _3-4 , C _2-6 , C _3-6 , C _2-7 , or C _It means _5-6 . Depending on the intended definition, the meaning of the term “lower” may differ. Specifically, for example, “lower alkyl” includes, for example, “C _1-6 alkyl”, and “lower alkenyl” includes, for example, C _2-6 alkenyl. In addition, in the definition described below, having a “substituent” means having a substitutable number of “substituents” at substitutable positions.

  “Halogen atom” includes fluorine atom, chlorine atom, bromine atom or iodine atom. Preferable examples include a fluorine atom or a chlorine atom.

Examples of “lower alkyl” include C _1-6 alkyl, C _1-4 alkyl, and the like. C _1-6 alkyl may be either linear or branched, and specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, Examples include hexyl.

_{Examples of} “hydroxy C _2-6 alkyl” include those in which “C _2-6 alkyl” is substituted with hydroxy. Specific examples of “hydroxy C _2-6 alkyl” include 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 2-hydroxybutyl, 3-hydroxy-3- Examples include methylpropyl, 3-hydroxy-2-methylpropyl, 2-hydroxy-3-methylpropyl, 5-hydroxypentyl, 4-hydroxypentyl, 6-hydroxyhexyl and the like.

“C _1-4 alkyl” may be linear or branched, and specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and the like.

Examples of “lower alkoxy” include C _1-6 alkoxy, C _1-4 alkoxy and the like.

“C _1-6 alkoxy” may be linear or branched, and specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, 3-methyl-butoxy, n-butoxy, isobutoxy, t -Butoxy, n-pentyloxy, isopentyloxy, hexyloxy and the like.

“C _1-4 alkoxy” may be linear or branched, and specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy and the like. . “C _1-4 alkoxy” may be optionally substituted by hydroxy. Specific examples of “C _1-4 alkoxy optionally substituted with hydroxy” include 2-hydroxyethoxy, 3-hydroxypropoxy and the like.

“C _2-4 alkoxy” may be linear or branched, and specific examples include ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy and the like.

Specific examples of “C _1-2 alkylene” include methylene and ethylene.

Examples of “lower alkenyl” include C _2-6 alkenyl.

“C _2-6 alkenyl” includes, for example, a linear, branched or cyclic unsaturated hydrocarbon group having 2 to 6 carbon atoms containing one double bond. Specific examples include vinyl, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, isopropenyl, 1-, 2- or 3-butenyl, 2-, 3- or 4-pentenyl, 2-methyl- 2-butenyl, 3-methyl-2-butenyl, 5-hexenyl, 1-cyclopentenyl, 1-cyclohexenyl, 3-methyl-3-butenyl and the like can be mentioned.

Examples of the “phenyl lower alkenyl” include phenyl C _3-4 alkenyl and the like.

Examples of “phenyl C _3-4 alkenyl” include a group in which one unsaturated hydrocarbon having 3 to 4 carbon atoms having one double bond is bonded to “phenyl”. Specific examples include 3-phenyl-2-propenyl, 3-phenyl-2-methyl-2-propenyl, 3-phenyl-1-propenyl and the like.

Examples of “phenyl lower alkyl” include phenyl C _1-4 alkyl and the like.

_{Examples of the} “phenyl C _1-4 alkyl” include a group in which phenyl is bonded to the “C _1-4 alkyl”. Specific examples include benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl and the like.

Examples of “phenyl C _1-4 alkoxy” include a group in which phenyl is bonded to the above “C _1-4 alkoxy”. The phenyl group may be substituted with 1 to 3 substituents. When there are a plurality of substituents, they may be the same or different independently. Specific examples of the substituent include a halogen atom, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _1-6 alkoxy, amino and the like. Specific examples of “phenyl C _1-4 alkyl” include benzyloxy, phenethyloxy, 2-, 3- or 4-chlorobenzyloxy.

  Examples of the “5-membered or 6-membered saturated heterocycle” include saturated monocyclic 5-membered or 6-membered saturated heterocycle having 1 to 2 oxygen atoms or nitrogen atoms which are the same or different. Specific examples of 5- or 6-membered saturated heterocycle include 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 1- or 2-piperazinyl, 3- or 4 -Morpholinyl, 2- or 4-pyranyl, imidazolidin-2,4-dione-1-yl, 2- or 3-tetrahydrofuryl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl And ureido.

  Examples of the “carbonylmethyl bonded with a 5- or 6-membered saturated heterocycle” include carbonylmethyl bonded with the “5-membered or 6-membered saturated heterocycle”. Specific examples of the “carbonylmethyl bonded with a 5- or 6-membered saturated heterocycle” include 2-pyrrolidinylcarbonylmethyl, 1-pyrrolidinylcarbonylmethyl, 2-pyrazolidinylcarbonylmethyl, 1 -Piperidinylcarbonylmethyl, 2-piperidinylcarbonylmethyl, 1-piperazinylcarbonylmethyl, 4-morpholinylcarbonylmethyl, 3-morpholinylcarbonylmethyl and the like.

  Examples of the “unsaturated heterocycle” include, for example, a monocyclic 5-membered or 6-membered unsaturated heterocycle having one or two sulfur atoms, oxygen atoms or nitrogen atoms which are the same or different, a sulfur atom, an oxygen atom or Examples thereof include bicyclic unsaturated heterocycles having a condensed ring composed of 5 and 6 members or 6 and 6 members having the same or different nitrogen atoms. Specific examples of the unsaturated heterocycle include 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2- or 3-benzothienyl, and thianaphthene. -1,1-dioxide-2-yl and the like.

Examples of the “lower alkyl to which an unsaturated heterocycle is bonded” include “C _1-4 alkyl to which an unsaturated heterocycle is bonded”.

Examples of the “C _1-4 alkyl to which an unsaturated heterocycle is bonded” include a group in which the “ _unsaturated heterocycle” is bonded to the “C _1-4 alkyl”. Specific examples include 2-thienylethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 1- (pyridyl) propyl, (thianaphthen-1,1-dioxide-2-yl) methyl, and the like. It is done.

Examples of “lower cycloalkyl” include C _3-6 cycloalkyl.

Specific examples of “C _3-6 cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

Specific examples of “C _5-6 cycloalkyl” include cyclopentyl, cyclohexyl and the like.

Examples of the “lower cycloalkyl lower alkyl” include a group in which the “lower cycloalkyl” is bonded to the “lower alkyl”. Examples of the “lower cycloalkyl lower alkyl” include C _3-6 cycloalkyl C _1-4 alkyl. Specific examples thereof include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl, 2-cyclopentylethyl, 2-cyclohexylethyl and the like.

Specific examples of “C _1-6 alkylaminocarbonyloxy” include N-methylaminocarbonyloxy, N-ethylaminocarbonyloxy, N- (n-propyl) aminocarbonyloxy, N- (isopropyl) aminocarbonyloxy. N- (n-butyl) aminocarbonyloxy, N- (isobutyl) aminocarbonyloxy, N- (t-butyl) aminocarbonyloxy, N- (n-pentyl) aminocarbonyloxy, N- (isopentyl) aminocarbonyl And oxy, N- (hexyl) aminocarbonyloxy and the like.

Examples of “lower alkanoyl” include “C _2-7 alkanoyl”. Specific examples include acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl, isopentanoyl, n-hexanoyl, isohexanoyl and heptanoyl.

Specific examples of “C _1-6 alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, n-pentyloxycarbonyl, iso Examples include pentyloxycarbonyl and hexyloxycarbonyl.

Specific examples of “C _1-6 alkoxycarbonylamino” include methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, n-butoxycarbonylamino, isobutoxycarbonylamino, t-butoxycarbonylamino. , N-pentyloxycarbonylamino, isopentyloxycarbonylamino, hexyloxycarbonylamino and the like.

Specific examples of “C _1-6 alkylcarbonylamino” include methylcarbonylamino, N-methylcarbonyl-N-methylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, n-butylcarbonylamino, isobutyl. Examples include carbonylamino, t-butylcarbonylamino, n-pentylcarbonylamino, isopentylcarbonylamino, hexylcarbonylamino and the like.

Specific examples of “C _1-4 alkoxy C _2-4 alkoxy” include 2-methoxy-ethoxy, 2-isopropoxy-ethoxy, 3-methoxy-n-propoxy, 3-ethoxy-propoxy, 2-methoxy-n. -Propoxy, 4-methoxy-n-butoxy, 3-methoxy-n-butoxy, 2-methoxy-n-butoxy, 3-methoxy-2-methyl-propoxy, 5-methoxy-n-pentyloxy, 6-methoxy- n-hexyloxy, 2-ethoxy-ethoxy, 3-ethoxy-n-propoxy, 2-ethoxy-n-propoxy, 4-ethoxy-n-butoxy, 3-ethoxy-n-butoxy, 2-ethoxy-n-butoxy , 3-ethoxy-2-methyl-propoxy and the like.

Examples of “lower alkylsulfonyl” include “C _1-6 alkylsulfonyl”. Specific examples include methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, n-butanesulfonyl, n-pentanesulfonyl, and n-hexanesulfonyl.

Examples of the substituent of “optionally substituted C _1-2 alkylene” include a halogen atom, C _1-6 alkyl, hydroxy C _2-6 alkyl and the like, and hydroxy C _2-6 alkyl is preferable. Specific examples of “substituted C _1-2 alkylene” include (2-hydroxyethyl) methylene, (3-hydroxypropyl) methylene, (2-hydroxypropyl) methylene, (4-hydroxybutyl) methylene, (3 -Hydroxybutyl) methylene, (2-hydroxybutyl) methylene, (3-hydroxy-3-methyl-propyl) methylene, (3-hydroxy-2-methyl-propyl) methylene, (2-hydroxy-3-methyl-propyl) ) Methylene, (5-hydroxypentyl) methylene, (4-hydroxypentyl) methylene, (6-hydroxyhexyl) methylene, [(1,1-dimethyl-2-hydroxy) ethyl] methylene, 1- (2-hydroxyethyl) ) Ethylene, 1- (3-hydroxypropyl) ethylene, 1- (2-hydro Xylpropyl) ethylene, 1- (4-hydroxybutyl) ethylene, 1- (3-hydroxybutyl) ethylene, 1- (2-hydroxybutyl) ethylene, 1- (3-hydroxy-3-methyl-propyl) ethylene, 1 -(3-hydroxy-2-methyl-propyl) ethylene, 1- (2-hydroxy-3-methyl-propyl) ethylene, 1- (5-hydroxypentyl) ethylene, 1- (4-hydroxypentyl) ethylene, 1 -(6-hydroxyhexyl) ethylene and the like can be mentioned.

In the “lower alkyl which may be substituted”, the number of substituents when the lower alkyl has a substituent includes, for example, 1 to 3. When there are a plurality of substituents, each may be the same or different. Examples of the lower alkyl in the “optionally substituted lower alkyl” include “C _1-6 alkyl” and the like. Examples of the substituent include C _1-4 alkoxy optionally substituted with a halogen atom, hydroxy, hydroxy, 2-, 3- or 4-pyranyloxy, 1,3-dioxolan-2-yl, C _1-6 alkoxy. Carbonylamino, benzodioxol-5-yl, 3- or 4-morpholinyl, aminocarbonyloxy, C _1-6 alkylaminocarbonyloxy, C _1-6 alkoxycarbonyl, etc.

  Specific examples of “substituted lower alkyl” include trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 2,2,2-trifluoroethyl; 2-hydroxyethyl, 3-hydroxypropyl, 2-methyl. -1-hydroxyethyl, 1-hydroxy-1,1-dimethylmethyl, 2-hydroxypropyl; ethoxymethyl, 2-methoxyethyl, 2,2-dimethoxy-ethyl, 4-methoxybutyl; 3- (2-pyranyloxy) Propyl, 3- (4-pyranyloxy) propyl; 2- (1,3-dioxolan-2-yl) ethyl; 2- (t-butoxy) carbonylaminoethyl, 2- (methoxy) carbonylaminoethyl, 3-[( t-butoxy) carbonylamino] propyl, 4-[(t-butoxy) carbonylamino] butyl; Benzodioxol-5-yl) methyl; 2- (4-morpholinyl) ethyl, 2- (3-morpholinyl) ethyl; 2- (2-hydroxyethoxy) ethyl, 2- (aminocarbonyloxy) ethyl; (N-ethylaminocarbonyloxy) ethyl and the like can be mentioned.

In the “lower alkoxy which may be substituted”, examples of the number of substituents when the lower alkoxy has a substituent include 1 to 3. When there are a plurality of substituents, each may be the same or different. Examples of the lower alkoxy in the “optionally substituted lower alkoxy” include “C _1-6 alkoxy” and the like. Specific examples of the substituent include a halogen atom, hydroxy, C _1-4 alkoxy, di (C _1-6 alkyl which may be substituted) amino, C _1-4 alkoxy C _2-4 alkoxy, phenyl C _1-4. Alkoxy, phenoxy, C _1-6 alkylsulfonyl, C _1-6 alkoxycarbonylamino, C _1-6 alkoxycarbonyl, C _2-7 alkanoyl, C _3-6 cycloalkyl, —OCOR ¹¹¹¹ , —NHCOR ¹¹¹¹ , —COR ¹¹¹¹ , Formula (V), 2,2-dimethyl-1,3-dioxolan-4-yl, and the like (R ¹¹¹¹ and formula (V) have the same meanings as in item 1).

  Specific examples of “substituted lower alkoxy” include 2-fluoroethoxy, 3-fluoropropyloxy, 5-chloropentyloxy, 2,2,2-trichloroethoxy, 2,2,2-trifluoroethoxy, 3 , 3,3-trifluoropropyloxy; 2-hydroxyethoxy, 3-hydroxypropyloxy, 3-hydroxy-2,2-dimethyl-propyloxy, 4-hydroxybutoxy, 3-hydroxy-3-methyl-butoxy; 2 -Methoxyethoxy, 3-ethoxypropyloxy, 3- (isopropyloxy) propyloxy, 2- (isopropyloxy) ethoxy; 2- (N, N-dimethylamino) ethoxy, 2- (N, N-diethylamino) ethoxy; 2- [2- (methoxy) ethoxy] ethoxy; 2-benzyloxyeth 2-phenoxyethoxy, 3-phenoxy-propyloxy; 2-methylsulfonylethoxy; methoxycarbonylmethoxy, ethoxycarbonylmethoxy, n-propyloxycarbonylmethoxy, isopropyloxycarbonylmethoxy, n-butoxycarbonylmethoxy, isobutoxycarbonylmethoxy , T-butoxycarbonylmethoxy, n-pentyloxycarbonylmethoxy, isopentyloxycarbonylmethoxy, n-hexyloxycarbonylmethoxy; methylcarbonylmethoxy, ethylcarbonylmethoxy, n-propylcarbonylmethoxy, isopropylcarbonylmethoxy, n-butylcarbonylmethoxy , Isobutylcarbonylmethoxy, t-butylcarbonylmethoxy, n-pentylcarbonylmeth Cy, isopentylcarbonylmethoxy, hexylcarbonylmethoxy; cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy; 2,2-dimethyl-1,3-dioxolan-5-yl) methoxy; 3- ( Methoxycarbonyloxy) propyloxy, 2- (aminocarbonyloxy) ethoxy, 3- (aminocarbonyloxy) propyloxy, 4- (aminocarbonyloxy) butoxy, 2- (N-ethylaminocarbonyloxy) ethoxy; N-formylamino) pentyloxy, 2- (methoxycarbonylamino) ethoxy, 3- (methoxycarbonylamino) propyloxy, 4- (methoxycarbonylamino) butoxy, 3- (t-butoxycarbonylamino) ) Propyloxy, 5- (t-butoxycarbonylamino) pentyloxy; 3- (t-butylcarbonylamino) propoxy, 4- (methylcarbonylamino) butoxy, 4-formylbutyloxy, 5- (formyloxy) pentyloxy , 4-oxoheptyloxy and the like.

Examples of the number of substituents when the lower alkenyl has a substituent in the “optionally substituted lower alkenyl” include 1 and the like. As the lower alkenyl in the “optionally substituted lower alkenyl”, for example, C _2-6 alkenyl and the like can be mentioned. Specific examples of the substituent include a halogen atom and C _1-6 alkoxycarbonyl.

Specific examples of “substituted C _2-6 alkenyl” include 2-bromo-2-propenyl; 3-methoxycarbonyl-2-propenyl, 3-ethoxycarbonyl-2-propenyl and the like.

In “optionally substituted phenyl lower alkenyl”, examples of the number of substituents when phenyl lower alkenyl has a substituent include 1-2. When there are a plurality of substituents, each may be the same or different. Examples of the phenyl lower alkenyl in the “optionally substituted phenyl lower alkenyl” include phenyl C _3-4 alkenyl and the like. Specific examples of the substituent include hydroxy, C _1-6 alkoxy, nitro and the like.

  Specific examples of “substituted phenyl lower alkenyl” include 3- (4-hydroxy-3-methoxyphenyl) -2-propenyl, 3- (4-nitrophenyl) -2-propenyl and the like.

In the “optionally substituted phenyl lower alkyl”, when the phenyl lower alkyl has a substituent, the number of substituents includes, for example, 1 to 3 for phenyl, and 1 for lower alkyl. . When there are a plurality of substituents, each may be the same or different. Examples of the phenyl lower alkyl in the “optionally substituted phenyl lower alkyl” include “phenyl C _1-4 alkyl”. Specific examples of the substituent include a halogen atom, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _1-4 alkoxy, amino and the like.

  Specific examples of “substituted phenyl lower alkyl” include 2-, 3- or 4-chlorobenzyl, 2-, 3- or 4-bromobenzyl, 2-, 3- or 4-fluorobenzyl, 2,3- 2,4-, 3,4- or 3,5-difluorobenzyl, 2,3,4-trifluorobenzyl, 2,4-, 2,5-, 3,4- or 3,5-dichlorobenzyl, 2-, 3- or 4-chlorophenethyl, 2-, 3- or 4-bromophenethyl, 2-, 3- or 4-fluorophenethyl, 3,4-difluorophenethyl, 3,4-dichlorophenethyl, 4-chlorophenyl 2-propyl, 2-, 3- or 4-hydroxybenzyl, 3,4- or 3,5-dihydroxybenzyl, 2-, 3- or 4-hydroxyphenethyl, 3,4-dihydroxyphenyl Netyl, 4-hydroxyphenylpropyl; 4-trifluoromethylbenzyl, 3,5-bistrifluoromethylbenzyl, 3- or 4-trifluorophenethyl; 3- or 4-trifluoromethoxybenzyl; 3-methylbenzyl, 3, 4-dimethylbenzyl, 3-methylphenethyl, 4-ethylphenethyl, 4-propylphenethyl, 4-n-butylphenethyl, 4-t-butylphenethyl, 2- or 3-methoxybenzyl, 2,4-, 2, 5-, 2,3-, 3,4- or 3,5-dimethoxybenzyl, 2-, 3- or 4-methoxyphenethyl, 3,4-dimethoxyphenethyl, 4-methoxyphenylpropyl, 3,4-dimethoxyphenylpropi 4-methoxyphenylbutyl; 2- or 3-aminobenzyl, 3-di Tylaminobenzyl, 2- or 4-aminophenethyl, 4-dimethylaminophenethyl; 2-fluoro-3-trifluoromethylbenzyl, 2-fluoro-5-trifluoromethylbenzyl, 3-fluoro-5-trifluoromethylbenzyl 4-fluoro-3-trifluoromethylbenzyl, 3-fluoro-4-methoxybenzyl, 3-chloro-4-fluorobenzyl, 3-chloro-4-trifluoromethoxybenzyl, 4-chloro-3-fluorobenzyl, Examples include 4-fluoro-3-methoxybenzyl, 3-chloro-5-fluorobenzyl, 3-methoxy-4-hydroxyphenethyl, 3-methoxy-4-hydroxyphenylpropyl, and the like.

  In the “optionally substituted 5- or 6-membered saturated heterocycle”, the number of substituents when the “5- or 6-membered saturated heterocycle” has a substituent is, for example, 1 to 2 etc. are mentioned. When there are a plurality of substituents, each may be the same or different.

Specific examples of the substituent of the saturated heterocyclic ring include a halogen atom, C _1-6 alkyl, phenyl C _1-4 alkyl, C _1-6 alkoxycarbonyl, C _1-6 alkoxycarbonylamino, C _1-6 alkyl. Examples include aminocarbonyl.

  Specific examples of “substituted 5- or 6-membered saturated heterocycle” include 3-methyl-imidazolidin-2,4-dione-1-yl; 4- (1-t-butoxycarbonyl) piperazinyl, 1- (4-benzyl) piperazinyl; N-methylureido; 4- [1- (methoxycarbonylamino)] piperidinyl, 1- [4- (methoxycarbonylamino)] piperidinyl, 4- [1- (t-butoxycarbonyl) ]] Piperidinyl, 3- [1- (t-butoxycarbonyl)] piperidinyl, 4- [1- (methoxycarbonyl)] piperidinyl, 3- [1- (methoxycarbonyl)] piperidinyl, 4- [1- (ethoxycarbonyl) ]] Piperidinyl, 3- [1- (ethoxycarbonyl)] piperidinyl, 4- [1- (t-butoxycarbonyl)] pipera 2- [1- (t-butoxycarbonyl)] pyrrolidinyl; 1- [4- (t-butoxycarbonylamino)] piperidinyl; 4- [1- (t-butylaminocarbonyl)] piperidinyl; 4- (1 -Benzyl) piperidinyl and the like.

Examples of the “lower alkyl having an optionally substituted 5- or 6-membered saturated heterocycle” include, for example, “C _1-4 having an _optionally substituted 5- or 6-membered saturated heterocycle bound thereto”. Alkyl ". Specific examples include 4- (1-t-butoxycarbonyl) piperazinylmethyl, 2,2-dimethyl-1,3-dioxolan-4-yl-methyl, 2-tetrahydrofurylmethyl, [1- (t- Butoxycarbonyl) pyrrolidin-2-yl] methyl, (2-tetrahydrofuryl) methyl, (3-tetrahydrofuryl) methyl, 2- (4-morpholinyl) ethyl, 2- [4- (1-t-butoxycarbonyl) piperidinyl ], [4- (1-t-butoxycarbonyl) piperidinyl] methyl, 2- (1-piperidinyl) ethyl and the like.

  In the “unsaturated hetero ring which may be substituted”, examples of the number of substituents in the case where the “unsaturated heterocycle” has a substituent include 1-2. When there are a plurality of substituents, each may be the same or different.

Specific examples of the substituent of “substituted unsaturated heterocycle” include a halogen atom, hydroxy, C _1-6 alkyl, C _1-6 alkoxy and the like. Specific examples of “substituted unsaturated heterocycle” include 5-bromo-2-furanyl, 3-hydroxy-2-pyridyl, 3- or 5-chloro-2-pyridyl, 6-methyl-2-pyridyl , 6-methoxy-2-pyridyl and the like.

In the “optionally substituted lower cycloalkyl”, examples of the number of substituents when the lower cycloalkyl has a substituent include 1 and the like. “Lower cycloalkyl” in “optionally substituted lower cycloalkyl” includes, for example, “C _3-6 cycloalkyl” and the like. Examples of the substituent in lower cycloalkyl include C _1-6 alkyl, C _1-6 alkylcarbonylamino, C _1-6 alkoxycarbonylamino and the like.

  Specific examples of “substituted lower cycloalkyl” include 3-methylcyclohexane-1-yl, 4-methyl-cyclohexane-1-yl, 4- (methoxycarbonylamino) cyclohexane-1-yl, 4- (ethoxy Carbonylamino) cyclohexane-1-yl, 4- (t-butoxycarbonylamino) cyclohexane-1-yl, 3- (methoxycarbonylamino) cyclopentan-1-yl, 3- (t-butoxycarbonylamino) cyclopentane- 1-yl and the like can be mentioned.

  In the “lower cycloalkyl lower alkyl which may be substituted”, examples of the number of substituents in the case where the lower cycloalkyl lower alkyl has a substituent include 1-2. When there are a plurality of substituents, each may be the same or different. Examples of the substituent of “optionally substituted lower cycloalkyl lower alkyl” include a halogen atom, hydroxy and the like.

In “optionally substituted amino”, the number of substituents when amino has a substituent includes 1 or 2. When the number of substituents is 2, each may be the same or different. Examples of the substituent of “substituted amino” include C _1-6 alkoxycarbonyl, C _2-7 alkanoyl, phenylcarbonyl, optionally substituted C _1-6 alkyl, C _1-4 alkoxy, phenyl C _{1 -4} alkyl, C _3-6 cycloalkylcarbonyl, (C _1-6 alkoxycarbonyl) piperidinyl, optionally substituted phenyl, and the like.

Specific examples of “substituted amino” include methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, n-butoxycarbonylamino, isobutoxycarbonylamino, t-butoxycarbonylamino, n- Pentyloxycarbonylamino, isopentyloxycarbonylamino, hexyloxycarbonylamino; methylcarbonylamino, N-methylcarbonyl-N-methylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, n-butylcarbonylamino, Isobutylcarbonylamino, t-butylcarbonylamino, n-pentylcarbonylamino, isopentylcarbonylamino, hexylcarbonylamino; Tilamino, ethylamino, isopropylamino, t-butylamino, N- (2-hydroxyethyl) amino, N- [2- (1,3-dioxolan-2-yl) ethyl] amino; N, N-dimethylamino, N, N-diethylamino, N, N-di (n-propyl) amino, N, N-di (n-butyl) amino, N, N-di (n-pentyl) amino, N, N-di (n- (Hexyl) amino, N-methyl-N-ethylamino, N-methyl-N- (n-propyl) amino, N-ethyl-N- (isopropyl) amino, N-methyl-N- (2,2-dimethoxy) Amino, N-methyl-N- (3- (2-pyranyloxy) propyl) amino, N-methyl-N- (2- (1,3-dioxolan-2-yl) ethyl) amino, (2,2,2 -Trifluoroethyl Amino; N-benzylamino, N-phenethylamino, N- (3-phenylpropyl) amino, N- (4-phenylbutyl) amino; N-methyl-N-benzylamino, N-ethyl-N-benzylamino, N- (n-propyl) -N-benzylamino, N-methyl-N-phenethylamino, N-ethyl-N-phenethylamino, N- (n-propyl) -N-phenethylamino, N-methyl-N- Phenylpropylamino, N-ethyl-N-phenylpropylamino, N- (n-propyl) -N-phenylpropylamino, N-methyl-N-phenylbutylamino, N-ethyl-N-phenylbutylamino, N- (N-propyl) -N-phenylbutylamino; N-methyl-N-methoxyamino, N-ethyl-N-methoxyamino, N-propi Ru-N-methoxyamino, N-methyl-N-ethoxyamino; cyclopropylcarbonylamino, cyclobutylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino, 1- (t-butoxycarbonyl) piperidinyl-4-yl-amino, And phenylcarbonylamino, anilino, 2- or 4-trifluoromethyl-anilino and the like. Specific examples in the case of having two substituents include di (optionally substituted C _1-6 alkyl) amino, (optionally substituted C _1-6 alkyl) (phenyl C _1-4 alkyl) amino. , (C _1-6 alkyl which may be substituted) (C _1-4 alkoxy) amino.

Specific examples of the substituent in the “mono (optionally substituted C _1-6 alkyl) amino” include a halogen atom, hydroxy, trifluoromethyl, trifluoromethoxy, 1,3-dioxolan-2-yl and the like. It is done. Preferred examples include hydroxy and the like. Specific examples of “mono (optionally substituted C _1-6 alkyl) amino” include N- (2-hydroxyethyl) amino, N- (2-((1,3-dioxolan) -2-yl) ethyl. ) Amino, (2,2,2-trifluoroethyl) amino and the like.

Specific examples of the substituent in “di (optionally substituted C _1-6 alkyl) amino” include a halogen atom, hydroxy, trifluoromethyl, trifluoromethoxy, 1,3-dioxolan-2-yl and the like. It is done. Specific examples of “di (C _1-6 alkyl) amino” in “di ( _optionally substituted C _1-6 alkyl) amino” include N, N-dimethylamino, N, N-diethylamino, N, N-di (n-propyl) amino, N, N-di (n-butyl) amino, N, N-di (n-pentyl) amino, N, N-di (n-hexyl) amino, N-methyl- N-ethylamino, N-methyl-N- (n-propyl) amino, N-ethyl-N- (isopropyl) amino, N-methyl-N- (2,2-dimethoxy) amino, N-methyl-N- (3- (2-pyranyloxy) propyl) amino, N-methyl-N- (2- (1,3-dioxolan-2-yl) ethyl) amino and the like.

Examples of the number of substituents when “phenyl C _1-4 alkyl” in the “mono (phenyl C _1-4 alkyl) amino” has a substituent include 1 to 3 and the like. When there are a plurality of substituents, they may be independently the same or different. Specific examples of the substituent are the same as the examples of the substituent in the above-mentioned “optionally substituted phenyl C _1-4 alkyl”. Specific examples include N-benzylamino, N-phenethylamino, N- (3-phenylpropyl) amino, N- (4-phenylbutyl) amino and the like.

Specific examples of “(optionally substituted C _1-6 alkyl) (phenyl C _1-4 alkyl) amino” include N-methyl-N-benzylamino, N-ethyl-N-benzylamino, N- ( n-propyl) -N-benzylamino, N-methyl-N-phenethylamino, N-ethyl-N-phenethylamino, N- (n-propyl) -N-phenethylamino, N-methyl-N-phenylpropylamino N-ethyl-N-phenylpropylamino, N- (n-propyl) -N-phenylpropylamino, N-methyl-N-phenylbutylamino, N-ethyl-N-phenylbutylamino, N- (n- Propyl) -N-phenylbutylamino and the like.

Specific examples of “(optionally substituted C _1-6 alkyl) (C _1-4 alkoxy) amino” include N-methyl-N-methoxyamino, N-ethyl-N-methoxyamino, N-propyl- N-methoxyamino, N-methyl-N-ethoxyamino and the like can be mentioned.

  The “optionally substituted phenyl” in “(optionally substituted phenyl) amino” may independently have 1 to 3 identical or different substituents. Examples of the substituent are the same as the examples of the substituent of the “optionally substituted phenyl”. Preferred examples include a halogen atom and trifluoromethyl.

  Specific examples of “(optionally substituted phenyl) amino” include anilino and 4-trifluoromethyl-anilino.

In “optionally substituted phenyl”, examples of the number of substituents when phenyl has a substituent include 1 to 5 and the like. When there are a plurality of substituents, each may be the same or different. Specific examples of the phenyl substituent include halogen atom, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 alkoxy C _2-4 alkoxy, trifluoromethyl, trifluoromethoxy, C _1-6. Examples include alkoxycarbonylamino, 2- or 4-pyranyloxy, 2-, 3- or 4-pyridyl.

  Specific examples of “substituted phenyl” include 2-, 3- or 4-fluorophenyl, 2,3-, 2,4- or 3,5-difluorophenyl, 3,4,5-trifluorophenyl, 1,2,3,4,5-pentafluorophenyl, 2-, 3- or 4-chlorophenyl, 2,3-, 2,4- or 3,5-dichlorophenyl, 2-, 3- or 4-bromophenyl 2,3-, 2,4- or 3,5-dibromophenyl; 2-, 3- or 4-hydroxyphenyl, 2,3-, 2,4- or 3,4-dihydroxyphenyl; -Or 4-methylphenyl, 2,3-, 2,4- or 3,5-dimethylphenyl, 4- (t-butyl) phenyl, 2- or 4-methoxyphenyl, 3,4,5-trimethoxyphenyl 2- or 4- Trifluoromethylphenyl, 3,5-trifluoromethylphenyl; 4-trifluoromethoxyphenyl; 4- (methoxycarbonylamino) phenyl; 4- (2-pyranyloxy) phenyl; 4- (4-pyridyl) phenyl; (2- (methoxy) ethoxy) phenyl; 3-fluoro-4-chlorophenyl; 3-trifluoromethyl-4-chlorophenyl, 2-fluoro-4-methylphenyl, 3,5-difluorophenyl and the like.

  Specific examples of “formula (VI)” include 2,5-dioxo-3-oxa-pyrrolidin-1-yl; 2,5-dioxo-3-oxa-4- (2-hydroxyethyl) -pyrrolidine-1 -Yl; 2,5-dioxo-3-oxa-4- (2-hydroxy-1,1-dimethyl-ethyl) pyrrolidin-1-yl; dihydropyrimidin-2,4-dione-1-yl; 3-methyl -Dihydropyrimidin-2,4-dione-1-yl; 3-ethyl-dihydropyrimidin-2,4-dione-1-yl; 3- (2-hydroxyethyl) dihydropyrimidin-2,4-dione-1- 3-formyl-ureido; 3-methyl-ureido; 3-methylcarbonyl-ureido; 1-methylimidazolidin-2,4-dione-3-yl; 1- (2-hydroxyethyl); ) Imidazolidin-2,4-dione-3-yl; 3-methylimidazolidin-2,4-dione-1-yl; 3-ethylimidazolidin-2,4-dione-1-yl; 3-isopropylimidazo Lysine-2,4-dione-1-yl; 3- (3-hydroxypropyl) imidazolidin-2,4-dione-1-yl; 1,3-dihydrobenzimidazol-2-one-1-yl; pyrrolidine -2,5-dione-1-yl; 1-methyl-2,5-dioxopiperazin-4-yl; 1-methyl-2,3-dioxopiperazin-4-yl and the like.

  Specific examples of “formula (VII)” include 3-methyl-1-oxa-3,8-diazaspiro [4,5] decan-2,4-dione-8-yl; 3- (2-hydroxyethyl) -1-oxa-3,8-diazaspiro [4,5] decane-2,4-dione-8-yl; 4-methyl-1-oxa-4,9-diazaspiro [5,5] undecan-2-one -9-yl; 4- [4- (t-butoxycarbonylamino) butyl] -1-oxa-4,9-diazaspiro [5,5] undecan-2-one-9-yl; 1-oxa-3, 8-Diazaspiro [4,5] decan-2-one-8-yl; 3-cyclopropylmethyl-1-oxa-3,8-diazaspiro [4,5] decan-2-one-8-yl; Benzyl-1-oxa-3,8-diazaspiro [4,5] deca 2-one-8-yl; 3- (2-tetrahydrofurylmethyl) -1-oxa-3,8-diazaspiro [4,5] decan-2-one-8-yl; 3-[(1-t -Butoxycarbonylpyrrolidin-2-yl) methyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one-8-yl; 3- [3- (t-butoxycarbonylamino) propyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one-8-yl; 3- (2-methoxyethyl) -1-oxa-3,8-diaza [4,5] decane- 2-On-8-yl; 3- [2- (1,3-dioxolan-2-yl) ethyl] -1-oxa-3,8-diazaspiro [4,5] decan-2-one-8-yl 1,3,8-triazaspiro [4,5] decane-2,4-dione-8; 3-yl-1,3,8-triazaspiro [4,5] decane-2,4-dione-8-yl; 3- (2-hydroxyethyl) -1,3,8-triazaspiro [4 5] decane-2,4-dione-8-yl; 3- (2-methoxyethyl) -1,3,8-triazaspiro [4,5] decane-2,4-dione-8-yl; 1-methyl -3- (2-hydroxyethyl) -1,3,8-triazaspiro [4,5] decane-2,4-dione-8-yl; 1-oxa-4,9-diazaspiro [4,5] decane- 3-Hon-8-yl; 4H-1,2-dihydro-1,3-benzoxazin-4-one-2-spiro-4'-piperidine and the like.

Specific examples of “(C _1-6 alkoxycarbonyl) piperidinyl” include N-methoxycarbonylpiperidinyl, N-ethoxycarbonylpiperidinyl, N-propoxycarbonylpiperidinyl, N-isopropoxycarbonylpiperidinyl, Nn-butyloxycarbonylpiperidinyl, Nt-butyloxycarbonylpiperidinyl, Nn-pentyloxycarbonylpiperidinyl, Nn-hexyloxycarbonylpiperidinyl.

Specific examples of “in the case where D is an oxygen atom, —NR ⁴⁴⁴ — or —CH ₂ — and D and F together with phenyl to form a condensed ring” in formula (VI) include, for example, 1,3 -Dihydrobenzimidazol-2-one-1-yl and the like.

Specific examples of “W forms a condensed ring with phenyl (provided that Y is —NR ⁹ — and Z is an oxygen atom)” include, for example, 1,2-dihydro-1,3. -Benzoxazin-4-one etc. are mentioned.

  Next, preferred embodiments of the compound of formula (I) will be described.

As the “lower alkyl which may be substituted” in R ¹ , R ² , R ³ and R ⁴ , for example, C _1-6 alkyl and the like are preferable.

Examples of the substituent of “optionally substituted lower alkyl” in R ⁶ , R ⁸ and R ⁴⁴ include C _1-4 optionally substituted with a halogen atom, hydroxy, 3- or 4-morpholinyl, hydroxy. Alkoxy, aminocarbonyloxy, C _1-6 alkylaminocarbonyloxy, benzodioxol-5-yl and the like are preferable.

As the substituent of “lower alkyl which may be substituted” for R ⁴⁴⁴ , for example, hydroxy and the like are preferable.

Examples of the substituent of “lower alkyl which may be substituted” in R ⁹ include a halogen atom, hydroxy, 1,3-dioxolan-2-yl, C _1-6 alkoxycarbonyl, C _1-6 alkoxycarbonylamino, C _1-6 alkylaminocarbonyl and the like are preferable.

As the substituent of “optionally substituted lower alkyl” in R ¹¹ , for example, a halogen atom, hydroxy and the like are preferable.

As the “ ^optionally substituted lower alkyl” for R ³³ and R ¹¹¹¹ , for example, C _1-6 alkyl and the like are preferable.

Examples of the substituent of “lower alkyl which may be substituted” in R ⁵⁵⁵ include C _1-4 alkoxy, 2-, 3- or 4-pyranyloxy, 1,3-dioxolan-2-yl, C _1-6. Alkoxycarbonyl and the like are preferable.

As the “lower alkoxy which may be substituted” in R ¹ , R ² , R ³ and R ⁴ , for example, C _1-6 alkoxy and the like are preferable.

Examples of the substituent of “optionally substituted lower alkoxy” in R ¹¹ and R ⁴⁴ include a halogen atom, hydroxy, C _1-4 alkoxy, C _1-4 alkoxy C _2-4 alkoxy, phenyl C _1-4. Alkoxy, phenoxy, C _1-6 alkoxycarbonylamino, C _3-6 cycloalkyl, —OCOR ¹¹¹¹ , —NHCOR ¹¹¹¹ , —COR ¹¹¹¹ , formula (V) (R ¹¹¹¹ and formula (V) have the same meanings as in item 1. Are preferred).

As the “optionally substituted lower alkoxy” in R ⁷ and R ⁸ , for example, C _1-6 alkoxy and the like are preferable.

Examples of the substituent for “optionally substituted lower alkoxy” in R ¹¹¹¹ include a halogen atom, hydroxy, di (optionally substituted C _1-6 alkyl) amino, C _1-6 alkylsulfonyl, C _1- Preferred are ₆ alkoxycarbonylamino, C _1-6 alkoxycarbonyl, C _2-7 alkanoyl, C _3-6 cycloalkyl and the like.

As the “optionally substituted lower alkenyl” in R ¹¹¹ and R ²²² , for example, C _2-6 alkenyl and the like are preferable.

As the “optionally substituted phenyl lower alkenyl” for R ⁶ , for example, phenyl C _3-4 alkenyl and the like are preferable.

As the “optionally substituted phenyl lower alkyl” in R ⁶ , R ⁸ , R ⁹ , R ¹¹¹ and R ⁵⁵⁵ , for example, phenyl C _1-4 alkyl and the like are preferable.

As the substituent of “optionally substituted phenyl lower alkyl” in R ²²² , for example, a halogen atom and the like are preferable.

As the substituent of “optionally substituted 5- or 6-membered saturated heterocyclic ring” for R ⁶ , for example, C _1-6 alkyl and the like are preferable.

As the substituent of the “optionally substituted 5- or 6-membered saturated heterocyclic ring” for R ¹¹ , for example, C _1-6 alkoxycarbonyl, C _1-6 alkoxycarbonylamino and the like are preferable.

As the substituent of the “optionally substituted 5- or 6-membered saturated heterocyclic ring” for R ⁴⁴ , for example, C _1-6 alkyl and the like are preferable.

Examples of the substituent of the “optionally substituted 5- or 6-membered saturated heterocyclic ring” in R ²²² include phenyl C _1-4 alkyl, C _1-6 alkoxycarbonyl, C _1-6 alkylaminocarbonyl, and the like. Is preferred.

As the “optionally substituted 5- or 6-membered saturated heterocyclic ring” for R ¹¹¹¹ , for example, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl and the like are preferable.

Examples of the “unsaturated heterocyclic ring which may be substituted” in R ⁸ and R ⁴⁴ include, for example, 2- or 3-thienyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2- or 3-benzothienyl, thianaphthen-1,1-dioxide-2-yl and the like are preferable.

As a substituent of “lower cycloalkyl which may be substituted” in R ¹¹¹ , for example, C _1-6 alkoxycarbonylamino and the like are preferable.

As the substituent of “optionally substituted lower cycloalkyl” for R ⁴⁴ , for example, C _1-6 alkyl and the like are preferable.

Examples of the substituent of “optionally substituted amino” in R ¹¹ include, for example, optionally substituted C _1-6 alkyl, phenyl C _1-4 alkyl, (C _1-6 alkoxycarbonyl) piperidinyl, Good phenyl and the like are preferable.

As the substituent of “optionally substituted amino” in R ³³ , for example, optionally substituted C _1-6 alkyl and the like are preferable.

Examples of the substituent of “optionally substituted amino” in R ⁴⁴ include C _1-6 alkoxycarbonyl, C _2-7 alkanoyl, phenylcarbonyl, optionally substituted C _1-6 alkyl, C _1-4. Alkoxy, phenyl C _1-4 alkyl, C _3-6 cycloalkylcarbonyl, optionally substituted phenyl, and the like are preferable.

As the substituent of “ ^optionally substituted amino” in R ¹¹¹¹ , for example, optionally substituted C _1-6 alkyl and the like are preferable.

Examples of the substituent of “optionally substituted phenyl” in R ⁶ , R ⁸ , R ¹¹ and R ⁴⁴ include a halogen atom, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 alkoxy C _2-4 alkoxy, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxycarbonylamino, 2-, 3- or 4-pyranyloxy and the like are preferable.

As the substituent of “optionally substituted phenyl” for R ³³ , for example, C _1-6 alkyl, trifluoromethyl, trifluoromethoxy and the like are preferable.

As “optionally substituted phenyl” in R ¹¹¹ and R ²²² , for example, phenyl and the like are preferable.

In the present invention, X is —N (R ⁶ ) —, or —C (R ⁷ ) (R ⁸ ) —; R ⁶ is an optionally substituted lower alkyl, an optionally substituted phenyl, — COR ¹¹ or —NHCOR ¹¹ ; R ⁷ is a hydrogen atom, hydroxy, or optionally substituted lower alkoxy; R ⁸ is optionally substituted lower alkyl, optionally substituted phenyl, substituted which may be phenyl-lower _{^{alkyl, -OCOR 11, -N (R 22}} ) SO 2 R 33, -N (R 22) COR 44, wherein (VI), or be _-CH 2 ^{R 55;} n is 8 to P is 0 or 1; q is 2 (R ¹¹ , R ²² , R ³³ , R ⁴⁴ , formula (VI) and R ⁵⁵ have the same meanings as in item 1) .) Compounds are preferred.

In the present invention, R ⁷ is a hydrogen atom or hydroxy; R ⁸ is optionally substituted phenyl, —N (R ²² ) COR ⁴⁴ or formula (VI); R ⁴⁴ may be substituted The compound according to Item 1 or Item 2, which is lower alkoxy or Formula (III) (R ²² , Formula (III) or Formula (VI) has the same meaning as in Item 1) is more preferred.

  In the present invention, the compound according to item 1 wherein A is formula (VII) is more preferred.

  In the present invention, a compound of the following formula (Ia) is more preferable.

In the present invention, R ⁶ is a halogen atom, hydroxy, 3- or 4-morpholinyl, C _1-4 alkoxy optionally substituted with hydroxy, aminocarbonyloxy, C _1-6 alkylaminocarbonyloxy or benzodioxole. which may be _{C 1-6} alkyl substituted by 5-yl; 5-membered or 6-membered carbonyl methyl heterocycle saturation bonded in a halogen atom, _{hydroxy, C 1-6 alkyl, C 1-6} alkoxy, C _1-4 alkoxy C _2-4 alkoxy, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxycarbonylamino or phenyl optionally substituted by 2-, 3- or 4-pyranyloxy; phenyl C _1-4 alkyl; heterocycle C _1-6 alkyl of 5-membered or 6-membered substituted saturated; Eniru _{C 3-4} alkenyl; -COR ^11; or ^-NHCOR 11 ^{(. R 11} has the same meaning as in claim 1 above) are preferred.

In the present invention, R ⁸ represents hydroxy; halogen atom, hydroxy, 3- or 4-morpholinyl, C _1-4 alkoxy optionally substituted with hydroxy, aminocarbonyloxy, C _1-6 alkylaminocarbonyloxy or benzodio C _1-6 alkyl optionally substituted with xol-5-yl; C _1-6 alkoxy; C _1-6 alkylsulfonyl; halogen atom, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _{1 -4} alkoxy C _2-4 alkoxy, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxycarbonylamino or phenyl optionally substituted by 2-, 3- or 4-pyranyloxy; phenyl C _1-4 alkyl; substituted An unsaturated heterocycle which may be substituted; —OCOR ¹¹ ; —N (R ²² ) _{^{SO 2 R 33; -N (R}} 22) COR 44; formula (VI); or _{^{-CH 2 R 55 (R 22,}} R 33, R 44 and the formula (VI) has the same meaning as in claim 1 above. ) Is preferred.

In the present invention, R ¹¹ represents a hydrogen atom; a C _1-6 alkyl optionally substituted by a halogen atom or hydroxy; a halogen atom, hydroxy, C _1-4 alkoxy, C _1-4 alkoxy C _2-4 alkoxy, phenyl C _1-4 alkoxy, phenoxy, C _1-6 alkoxycarbonylamino, C _3-6 cycloalkyl, —OCOR ¹¹¹¹ , —NHCOR ¹¹¹¹ , —COR ¹¹¹¹ or C _1-6 alkoxy optionally substituted by formula (V) Halogen atom, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 alkoxy C _2-4 alkoxy, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxycarbonylamino or 2-, 3- Or phenyl optionally substituted with 4-pyranyloxy; Good C _1-6 alkyl, phenyl C _1-4 alkyl, (C _1-6 alkoxycarbonyl) piperidinyl or optionally substituted amino; C _1-6 alkoxycarbonyl or C _1-6 alkoxy A 5- or 6-membered saturated heterocyclic ring which may be substituted with carbonylamino; or —OR ¹¹¹ (R ¹¹¹ , R ¹¹¹¹ and formula (V) have the same meanings as in item 1) is preferred.

In the present ^{invention, R 33} _{is, C 1-6} alkyl, phenyl optionally substituted by trifluoromethyl or _{trifluoromethoxy,} substituted by _{C 1-6} alkyl or optionally substituted _{C 1-6} alkyl, Good amino is preferred.

In the present invention, R ⁴⁴ represents a hydrogen atom; a halogen atom, hydroxy, 3- or 4-morpholinyl, hydroxy optionally substituted C _1-4 alkoxy, aminocarbonyloxy, C _1-6 alkylaminocarbonyloxy or benzo _{C 1-6} alkyl optionally substituted by a dioxol-5-yl; halogen atom, _{hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-4} alkoxy _{C 2-4} alkoxy, trifluoromethyl , Trifluoromethoxy, C _1-6 alkoxycarbonylamino or phenyl optionally substituted with 2-, 3- or 4-pyranyloxy; optionally substituted heterocycle; substituted with C _1-6 alkyl heterocyclic ring may also be 5-membered or 6-membered saturated; halogen atom, _{hydroxy, C 1-4} alkoxy _{Shi, C 1-4} alkoxy _{C 2-4} alkoxy, phenyl _{C 1-4} alkoxy, _{phenoxy, C 1-6 alkoxycarbonylamino, C 3-6} ^{cycloalkyl, -OCOR 1111, -NHCOR 1111, -COR} 1111 or formula which may be substituted by (V) _{C 1-6 alkoxy; C 1-6} which may be _{C 3-6} cycloalkyl substituted with _{alkyl; C 1-6 alkoxycarbonyl, C 2-7} alkanoyl, phenylcarbonyl, substituted which may be _{C 1-6 alkyl, C 1-4} alkoxy, phenyl _{C 1-4 alkyl, C 3-6} cycloalkylcarbonyl, or substituted optionally substituted in phenyl and ^{amino; -OR 222;} or formula (III) or formula ^{(IV) (R 222, R} 1111, formula (III), formula (IV) And formula (V) are as defined above in claim 1.) Are preferred.

In the present invention, R ⁴⁴⁴ is preferably a hydrogen atom, formyl, C _1-6 alkyl optionally substituted with hydroxy, or C _2-7 alkanoyl.

In the present invention, R ⁵⁵ is C _1-6 alkoxy, or — (CH ₂ ) s —N (R ²² ) (R ⁵⁵⁵ ) (s, R ^22, and R ⁵⁵⁵ have the same meanings as in item 1). Is preferred.

In the present invention, R ¹¹¹ is preferably C _3-6 cycloalkyl which may be substituted with phenyl, phenyl C _1-4 alkyl, C _2-6 alkenyl, or C _1-6 alkoxycarbonylamino.

In the present invention, R ²²² is a 5- or 6-membered saturated heterocyclic ring which may be substituted with phenyl C _1-4 alkyl, C _1-6 alkoxycarbonyl or C _1-6 alkylaminocarbonyl (provided that oxygen atom of the nitrogen atom and -OR ²²² in heterocycle are not directly bonded);. phenyl; halogen substituted phenyl C _1-4 alkyl optionally substituted with atoms; C _1-4 alkyl unsaturated heterocyclic ring is bonded C _2-6 alkenyl; a C _3-6 cycloalkyl C _1-4 alkyl optionally substituted with a halogen atom or hydroxy; 2-indanyl; or an optionally substituted 5- or 6-membered saturated heterocycle Bonded C _1-4 alkyl is preferred.

In the present invention, R ¹¹¹¹ represents a hydrogen atom; a halogen atom, hydroxy, di (optionally substituted C _1-6 alkyl) amino, C _1-6 alkylsulfonyl, C _1-6 alkoxycarbonylamino, C _1-6. C _1-6 alkoxy optionally substituted with alkoxycarbonyl, C _2-7 alkanoyl or C _3-6 cycloalkyl; C _1-6 alkyl; optionally substituted 5- or 6-membered saturated heterocycle; or Amino optionally substituted with _optionally substituted C _1-6 alkyl is preferred.

In the present invention, R ⁵⁵⁵ is phenyl C _1-4 alkyl; C _1-6 alkoxycarbonyl; or C _1-4 alkoxy, 2-, 3- or 4-pyranyloxy, 1,3-dioxolan-2-yl or C C _1-6 alkyl optionally substituted with _1-6 alkoxycarbonyl is preferred.

In the present invention, R ¹ , R ² , R ³ and R ⁴ are the same or different and are a hydrogen atom, C _1-6 alkyl or C _1-6 alkyl,
R ⁵ is a hydrogen atom, methyl or ethyl,
n is an integer of 4 to 12,
A is formula (II) or formula (VII),

X is a sulfur atom, —NR ⁶ —, or —C (R ⁷ ) (R ⁸ ) —,
Here, R ⁶ is a halogen atom, hydroxy, 3- or 4-morpholinyl, C _1-4 alkoxy optionally substituted with hydroxy, aminocarbonyloxy, C _1-6 alkylaminocarbonyloxy or benzodioxole- _{C 1-6} alkyl optionally substituted by a 5-yl; 5-membered or 6-membered carbonyl methyl heterocycle saturation bonded in a halogen atom, _{hydroxy, C 1-6 alkyl, C 1-6} alkoxy, _{C 1 -4} alkoxy C _2-4 alkoxy, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxycarbonylamino or phenyl optionally substituted by 2-, 3- or 4-pyranyloxy; phenyl C _1-4 alkyl; C _1-6 hetero ring five- substituted with alkyl or a 6-membered to saturation; off Alkylsulfonyl _{C 3-4} alkenyl; a or -NHCOR ^11,; -COR ¹¹

R ⁷ is a hydrogen atom, hydroxy, or C _1-6 alkoxy;
R ⁸ is hydroxy; halogen atom, hydroxy, 3- or 4-morpholinyl, C _1-4 alkoxy optionally substituted with hydroxy, aminocarbonyloxy, C _1-6 alkylaminocarbonyloxy or benzodioxol-5 -C _1-6 alkyl optionally substituted with yl; C _1-6 alkoxy; C _1-6 alkylsulfonyl; halogen atom, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 alkoxyC _2-4 alkoxy, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxycarbonylamino or phenyl optionally substituted with 2-, 3- or 4-pyranyloxy; phenyl C _1-4 alkyl; optionally substituted unsaturated heterocyclic ^{ring; -OCOR 11; -N (R 22} ) SO 2 R 33 -N ^(R 22) ^{COR 44;} formula (VI); or _-CH 2 ^R a ⁵⁵ ;; or ^{R 7} and ^{R 8} are -OCH ₂ CH ₂ O- and is taken together (however, ^{R 7} is In the case of hydroxy, R ⁸ is not lower alkoxy.);

R ¹¹ represents a hydrogen atom; a C _1-6 alkyl which may be substituted with a halogen atom or hydroxy; a halogen atom, hydroxy, C _1-4 alkoxy, C _1-4 alkoxy C _2-4 alkoxy, phenyl C _1-4 Alkoxy, phenoxy, C _1-6 alkoxycarbonylamino, C _3-6 cycloalkyl, —OCOR ¹¹¹¹ , —NHCOR ¹¹¹¹ , —COR ¹¹¹¹ or C _1-6 alkoxy optionally substituted by formula (V); halogen atom, Hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-4 alkoxy C _2-4 alkoxy, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxycarbonylamino or 2-, 3- or 4-pyranyloxy in optionally substituted phenyl; optionally substituted C _1-6 a be Substituted with _{C 1-6} alkoxycarbonyl or _{C 1-6 alkoxycarbonylamino;} kill, phenyl _{C 1-4 alkyl, (C 1-6} alkoxycarbonyl) piperidinyl or substituted amino which may be substituted in a phenyl and An optionally 5- or 6-membered saturated heterocycle; or -OR ¹¹¹ ;

R ²² is a hydrogen atom or C _1-6 alkyl;
R ³³ is phenyl optionally substituted by C _1-6 alkyl, trifluoromethyl or trifluoromethoxy, C _1-6 alkyl, or amino optionally substituted by C _1-6 alkyl Yes,

R ⁴⁴ represents a hydrogen atom; a halogen atom, hydroxy, 3- or 4-morpholinyl, C _1-4 alkoxy optionally substituted with hydroxy, aminocarbonyloxy, C _1-6 alkylaminocarbonyloxy or benzodioxole- It may be substituted with 5-yl _{C 1-6} alkyl; halogen atom, _{hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-4} alkoxy _{C 2-4} alkoxy, trifluoromethyl, trifluoromethoxy , C _1-6 alkoxycarbonylamino or phenyl optionally substituted with 2-, 3- or 4-pyranyloxy; optionally substituted heterocycle; 5-membered optionally substituted with C _1-6 alkyl or heterocycle 6-membered saturated; halogen atom, _{hydroxy, C 1-4 alkoxy, C 1-4} a Kokishi _{C 2-4} alkoxy, phenyl _{C 1-4} alkoxy, _{phenoxy, C 1-6 alkoxycarbonylamino, C 3-6} ^cycloalkyl, -OCOR ^1111, -NHCOR ^1111, substituted with ^{-COR 1111} or formula (V) which may be _{C 1-6 alkoxy; C 1-6} optionally _{C 3-6} cycloalkyl substituted with _{alkyl; C 1-6 alkoxycarbonyl, C 2-7} alkanoyl, phenylcarbonyl, optionally _{C 1} substituted _-6 alkyl, C _1-4 alkoxy, phenyl C _1-4 alkyl, C _3-6 cycloalkylcarbonyl or amino optionally substituted with optionally substituted phenyl; -OR ²²² ; or formula (III) or formula (IV),

R ¹¹¹ is C _3-6 cycloalkyl optionally substituted with phenyl, phenyl C _1-4 alkyl, C _2-6 alkenyl, or C _1-6 alkoxycarbonylamino;
R ²²² is a 5- or 6-membered saturated hetero ring optionally substituted with phenyl C _1-4 alkyl, C _1-6 alkoxycarbonyl or C _1-6 alkylaminocarbonyl (provided that oxygen atom of the nitrogen atom and ^{-OR 222} are not linked directly);. phenyl; halogen substituted phenyl _{C 1-4} alkyl optionally substituted with atoms; _{C 1-4} alkyl unsaturated heterocyclic ring is _{bonded; C 2- 6} alkenyl; C ₁ to or substituted heterocyclic ring may also be 5-membered or 6-membered saturated is bonded; halogen atoms or which may C _3-6 be cycloalkyl C _1-4 alkyl substituted with hydroxy; 2- indanyl _-4 alkyl,

R ³³³ is a hydrogen atom, hydroxy, —OCOR ¹¹¹¹ , —NHCOR ¹¹¹¹ , —COR ¹¹¹¹ , or formula (V),
R ⁴⁴⁴ is a hydrogen atom, formyl, C _1-6 alkyl optionally substituted with hydroxy, or C _2-7 alkanoyl;
R ⁵⁵ is C _1-6 alkoxy, or — (CH ₂ ) s—N (R ²² ) (R ⁵⁵⁵ ),

R ¹¹¹¹ represents a hydrogen atom; a halogen atom, hydroxy, di (optionally substituted C _1-6 alkyl) amino, C _1-6 alkylsulfonyl, C _1-6 alkoxycarbonylamino, C _1-6 alkoxycarbonyl, C C _1-6 alkoxy optionally substituted with _2-7 alkanoyl or C _3-6 cycloalkyl; C _1-6 alkyl; optionally substituted 5 or 6 membered saturated heterocycle; or optionally substituted Good amino which may be substituted with C _1-6 alkyl,

R ⁵⁵⁵ is phenyl C _1-4 alkyl; C _1-6 alkoxycarbonyl; or C _1-4 alkoxy, 2-, 3- or 4-pyranyloxy, 1,3-dioxolan-2-yl or C _1-6 alkoxy C _1-6 alkyl optionally substituted with carbonyl,

R ⁹ may be substituted with a hydrogen atom; a halogen atom, hydroxy, 1,3-dioxolan-2-yl, C _1-6 alkoxycarbonyl, C _1-6 alkoxycarbonylamino, C _1-6 alkylaminocarbonyl. C _1-6 alkyl; C _3-6 cycloalkyl C _1-4 alkyl optionally substituted with a halogen atom or hydroxy; phenyl C _1-4 alkyl; or 5-membered optionally substituted with C _1-6 alkoxycarbonyl Or a compound of formula (I) that is C _1-4 alkyl bonded with a 6-membered saturated heterocycle (D, E, F, Y, Z, W, p, q, r, s and t are as defined above. 1 and the formula (III), the formula (IV), the formula (V), the formula (VI) and the formula (VII) are the same as those in the above-mentioned item 1).

In the present invention, a compound represented by the following formula (Ia) is more preferable.

[Wherein, R ^333a represents —OCOR ^1111a (R ^1111a represents a hydrogen atom; C _1-6 alkoxy optionally substituted with hydroxy or C _1-4 alkoxy; C _1-6 alkyl; 1-pyrrolidinyl, 1-piperidinyl , 4-morpholinyl; or mono or di (C _1-6 alkyl which may be substituted),), —NHCOR ^1111a (R ^1111a has the same meaning as described above), or formula (Va)

N ^a is 8, 9 or 10. ]

In the present invention, a compound represented by the following formula (Ib) is more preferable.

[Wherein Y ^b is an oxygen atom or —N (R ^9b ) —;
Z ^b, when Y ^b is an oxygen atom is -CH ₂ - or -CO-, Y ^b is -N ^{(R 9b)} - in the case of an oxygen atom or -CO-; W ^b is , _{C 1-2} alkylene or ^{_{- (CH 2) m b -NR}} 9b - ( wherein, m ^b is 0 or 1, if m ^b is 1, the nitrogen atom of NR ^9b directly and Z ^b (However, when Z ^b is an oxygen atom, W ^b is — (CH ₂ ) m ^b —NR ^9b —.); R ^9b is a hydrogen atom; hydroxy, 1 , _{3-dioxolan-2-yl, C 1-6} alkoxycarbonylamino or _{C 1-4 C 1-6} alkyl optionally substituted by _{alkoxy; C 3-6} cycloalkyl _{C 1-4} alkyl; phenyl _{C 1- 4} alkyl; or C _1-6 alkoxy may be 5-membered to be replaced by a carbonyl Ku is an _{C 1-4} alkyl heterocycle 6-membered saturated is bonded; n ^b is a 8, 9 or 10. ]

  In the present invention, a compound represented by the following formula (Ic) is more preferable.

[Where,
D ^c is an oxygen atom, —NR ^444c —, or —CH ₂ —;
(A ^c ) E ^c is carbonyl and F ^c is C _1-2 alkylene optionally substituted with hydroxy C _1-6 alkyl,
(B ^c ) E ^c is C _1-2 alkylene and F ^c is carbonyl,
(C ^c ) E ^c and F ^c are methylene or (d ^c ) E ^c and F ^c together with phenyl form a condensed ring; R ^444c is a hydrogen atom, formyl, hydroxy Optionally substituted C _1-6 alkyl, or C _2-7 alkanoyl; n ^c is 8, 9 or 10. ]

In the present invention, a compound selected from the following compound group is more preferred.
5,7-dimethoxy-3- [11- {4-phenethyl-piperazin-1-yl} undecan-1-yl] phthalide;
5,7-dimethoxy-3- [9- {4- (1,3-benzdioxol-5-yl) methyl-piperazin-1-yl} nonan-1-yl] phthalide;
(R) -5,7-dimethoxy-3- [9- {4- (methoxycarbonylamino) -piperazin-1-yl} nonan-1-yl] phthalide;
(R) -5,7-dimethoxy-3- [8- [4- {2- (methoxycarbonylamino) ethoxycarbonylamino} -piperazin-1-yl] octan-1-yl] phthalide;
(3R) -5,7-dimethoxy-3- [9- [4- {4- (t-butoxycarbonylamino) cyclohexyloxycarbonylamino} -piperazin-1-yl] nonan-1-yl] phthalide;
5,7-dimethoxy-3- [9-{(3S) -3-formylamino-pyrrolidin-1-yl} nonan-1-yl] phthalide;
(R) -5,7-dimethoxy-3- [8- [4- {4- (methoxycarbonylamino) -phenylcarbonylamino} -piperidin-1-yl] octan-1-yl] phthalide; 5,7- Dimethoxy-3- [9- {4- (t-butoxycarbonylamino) -piperidin-1-yl} nonan-1-yl] phthalide;
5,7-dimethoxy-3- [12- {4- (3-hydroxypropoxycarbonylamino) -piperidin-1-yl} dodecan-1-yl] phthalide;
5,7-dimethoxy-3- [9- {4- (2-methoxyethoxycarbonylamino) -piperidin-1-yl} nonan-1-yl] phthalide;
(R) -5,7-dimethoxy-3- [9- {4- (5-formylaminopentyloxy) -piperidin-1-yl} nonan-1-yl] phthalide;
(R) -5,7-dimethoxy-3- [9- [4- {3- (methoxycarbonylamino) propoxycarbonylamino} -piperidin-1-yl] nonan-1-yl] phthalide;
(R) -5,7-dimethoxy-3- [8- [4- {2- (methoxycarbonylamino) ethoxycarbonylamino} -piperidin-1-yl] octan-1-yl] phthalide;
(3R) -5,7-dimethoxy-3- [8- [4- {4- (methoxycarbonylamino) cyclohexyloxycarbonylamino} -piperidin-1-yl] octane-1-yl] phthalide;
(3R) -5,7-dimethoxy-3- [9- [4- {4- (2,2,2-trifluoroethoxycarbonylamino) cyclohexyloxycarbonylamino} -piperidin-1-yl] nonane-1- Yl] phthalide;
(3R) -5,7-dimethoxy-3- [8- [4- {4- (2-methoxyethoxycarbonylamino) cyclohexyloxycarbonylamino} -piperidin-1-yl] nonan-1-yl] phthalide;
(3R) -5,7-dimethoxy-3- [8- {4- (2,4-dioxo-3-methyl-1-imidazolidinyl) -piperidin-1-yl} octane-1-yl] phthalide;
(3R) -5,7-dimethoxy-3- [9- [4- {4- (2-fluoroethoxycarbonylamino) cyclohexyloxycarbonylamino} -piperidin-1-yl] nonan-1-yl] phthalide;
(3R) -5,7-dimethoxy-3- [9- [4- {4- (cyclopropylmethyloxycarbonylamino) cyclohexyloxycarbonylamino} -piperidin-1-yl] nonan-1-yl] phthalide;
5,7-dimethoxy-3- [9- [4- {4-hydroxy-4- (1-methyl-ethyl)}-piperidin-1-yl] nonan-1-yl] phthalide;
(3R) -5,7-dimethoxy-3- [9- {4-hydroxy-4- (4-chloro-3-trifluoromethylphenyl) -piperidin-1-yl} nonan-1-yl] phthalide, 5 , 7-dimethoxy-3- [9- {4- (t-butoxycarbonylaminomethyl) -piperidin-1-yl} nonan-1-yl] phthalide;
5,7-dimethoxy-3- [9- (3-benzyl-1-oxo-3,8-diazaspiro [4,5] decan-2-one-8-yl) nonan-1-yl] phthalide;
5,7-Dimethoxy-3- [9- {3- (2-methoxyethyl) -1-oxa-3,8-diazaspiro [4,5] decan-2-one-8-yl} nonan-1-yl ] Phthalide;
(3R) -5,7-dimethoxy-3- [9- {3- (2-hydroxyethyl) -1-oxa-3,8-diazaspiro [4,5] decane-2,4-dione-8-yl } Nonan-1-yl] phthalide;
(3R) -5,7-dimethoxy-3- [8- (3-methyl-1,3,8-triazaspiro [4,5] decan-2,4-dione-8-yl) octane-1-yl] Phthalide;
(3R) -5,7-dimethoxy-3- [9- {3- (2-hydroxyethyl) -1,3,8-triazaspiro [4,5] decane-2,4-dione-8-yl} nonane -1-yl] phthalide;
5,7-dimethoxy-3- [9- {4- (3-methyl-dihydropyrimidin-2,4-dione-1-yl) -piperidin-1-yl} nonan-1-yl] phthalide;
5,7-Dimethoxy-3- [9- {4- (1,3-dihydrobenzimidazol-2-one-1-yl) piperidin-1-yl} nonan-1-yl] phthalide.

  In the compound of the present invention, a compound in which the absolute configuration at the 3-position of the phthalide skeleton is an R configuration is more preferable.

  The compounds of the present invention also include those prodrugs. The prodrug of the compound according to the present invention is a compound that is converted into a compound of formula (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, enzymatically oxidized, reduced, hydrolyzed, etc. It means a compound that changes to a compound of formula (I), or a compound that undergoes hydrolysis by gastric acid or the like to change to a compound of compound (I).

  Examples of prodrugs of the compound of formula (I) include compounds in which the hydroxyl group of the compound of formula (I) is acetylated, palmitoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated. It is done.

As the production intermediate of the compound of the present invention, the compound of the above formula (VIII) (wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , n and B have the same meaning as in the above item 5). Or a pharmaceutically acceptable salt thereof (hereinafter referred to as a compound of formula (VIII)). The compound of formula (VIII) also includes hydrates or solvates. Moreover, since the compound of Formula (VIII) has one asymmetric carbon, those optical isomers are also included.

In the compound of formula (VIII), R ⁵ is preferably a hydrogen atom.

In the compound of formula (VIII), R ¹ and R ³ are each the same C _1-6 alkyl or C _1-6 alkoxy; R ² and R ⁴ are more preferably a hydrogen atom.

In the compound of formula (VIII), R ¹ and R ³ are each identically C _1-6 alkyl or C _1-6 alkoxy; R ² and R ⁴ are hydrogen atoms; R ⁵ is more hydrogen atoms preferable.

In the compound of formula (VIII), R ¹ and R ³ are each identically C _1-6 alkyl or C _1-6 alkoxy; R ² and R ⁴ are hydrogen atoms; R ⁵ is a hydrogen atom; As the absolute configuration at the 3-position of the phthalide skeleton, the R configuration is most preferable.

  Below, the manufacturing method of this invention compound, the manufacturing method of the compound represented by Formula (VIII), etc. are demonstrated.

  In these reactions, functional group protection and deprotection are described in, for example, “PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, published by John Willy and Sons, 2nd edition” as long as the target reaction product is not hindered. It can be carried out by appropriately selecting various reaction conditions.

  In the production method described below, the “condensation reaction” means a reaction of forming an amide, urea, urethane or ester using an amine, carboxylic acid, alcohol or acid chloride. The condensation reaction is carried out according to the fourth edition of Experimental Chemistry Course 22. You may carry out by the condensing agent or conditions as described in the organic synthesis IV page 258-271 (The Chemical Society of Japan). However, it is not limited to these described reagents or conditions.

The following abbreviations may be used for the simplification described in this specification.
BOP reagent: Benztriazol-1-yl-oxytris (dimethylamino) phosphonium hexafluorophosphate, PyBOP reagent: benzotriazol-1-yl-oxytrispyrrolidinophosphonium hexafluorophosphate, WSC: 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide hydrochloride, DCC: dicyclohexylcarbodiimide, HOBt: 1-hydroxy-1H-benzotriazole monohydrate.

  The compound (I) or a salt thereof of the present invention can be produced according to the following method A or B.

Method A:-
A compound of the formula (I) (wherein A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n have the same meaning as in the above-mentioned item 1) is a compound of the formula (VIII) ( In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n have the same meaning as in the above item 1, and B has the same meaning as in the above term 5).
When (a) B is a halogen atom, the compound is reacted with a compound of formula (J) (wherein A has the same meaning as in the above-mentioned item 1), or (b) when B is hydroxy Reacts a compound of formula (VIII) with a C _6-10 arylsulfonyl halide or (C _1-4 alkyl) sulfonyl halide and the resulting reactive product is converted to a compound of formula (J) (A is as defined above). Meaning). Moreover, it can manufacture by adding the pharmaceutically acceptable salt (For example, inorganic acids, such as hydrochloric acid) of the compound of a formula (J) as needed.

The reaction conditions in Step 1 of Method A are described below.
Examples of the halogen atom used in (a) include chlorine, bromine and iodine, and iodine is preferably used.

Examples of C _6-10 arylsulfonyloxy used in (b) include benzenesulfonyloxy and p-tolylsulfonyloxy, and examples of (C _1-4 alkyl) sulfonyloxy include methanesulfonyloxy and the like. Is mentioned.

In (a), compound (J) or a salt thereof is used in an amount of about 1 mol to an excess, preferably about 1 to about 3 mol, per 1 mol of compound (VIII) or a salt thereof. This reaction is performed in the presence of a base. Examples of the base include pyridine and triethylamine. Furthermore, this reaction includes alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, nitriles such as acetonitrile, N, N-dimethylformamide, N, It can also be carried out in an inert solvent such as amides such as N-dimethylacetamide and sulfoxides such as dimethyl sulfoxide. Moreover, these solvents may be mixed and used at an appropriate ratio, or the reaction may be performed in the absence of a solvent.
The reaction temperature is about -10 ° C to about 100 ° C, preferably about 25 ° C to about 40 ° C. The reaction time is about 30 minutes to about 20 hours, preferably about 1 hour to about 4 hours.

In (b), C _6-10 arylsulfonyl halide or (C _1-4 alkyl) sulfonyl halide is used in an amount of about 1 mol to excess, preferably about 1 to about 3 with respect to 1 mol of compound (VIII) or a salt thereof. Use moles. This reaction is preferably condensed in the presence of a base. Examples of the base include pyridine and triethylamine. Furthermore, this reaction includes alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, nitriles such as acetonitrile, N, N-dimethylformamide, N, It can also be carried out in an inert solvent such as amides such as N-dimethylacetamide and sulfoxides such as dimethyl sulfoxide. Moreover, these solvents may be mixed and used at an appropriate ratio, or the reaction may be performed in the absence of a solvent. The reaction temperature is about -10 ° C to about 100 ° C, preferably about 25 ° C to about 40 ° C. The reaction time is about 30 minutes to about 20 hours, preferably about 1 hour to about 4 hours. The compound obtained in this reaction is reacted with about 1 mol to about an excess amount of the compound of compound (J) or 1 salt thereof per 1 mol of compound (VIII) or a salt thereof according to the same conditions as in the above reaction (a).

In the compound of formula (I), X is —NR ⁶ — (wherein R ⁶ is —COR ¹¹ and R ¹¹ has the same meaning as in the above-mentioned item 1) and —C (R ⁷ ). A compound of (R ⁸ ) — (where R ⁷ is a hydrogen atom, R ⁸ is —N (R ²² ) COR ⁴⁴ , and R ²² and R ⁴⁴ have the meanings as defined in item 1 above). Embedded image means a compound of the formula (XI)), in addition to the method A, can also be produced by the following method B [wherein G is —N (P ¹ ) — or —CH ( NHP ¹⁾ - a and, ^{P 1} _{is, C 1-6} alkoxycarbonyl (e.g., t-butoxycarbonyl, etc.), or optionally substituted benzyl (e.g., benzyl, p- methoxybenzyl or p- nitrobenzyl, etc.) , X is -NR ⁶ - (you here Te, ^{R 6} is -COR ¹¹⁾ or ^{-C. (R 7) (R} 8) - ( wherein, ^{R 7} is a hydrogen atom, ^{R 8} is ^-N (R 22) is ^{COR 44.} R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹¹ , p, q and n have the same meaning as in the above-mentioned item 1 and B has the same meaning as in the above-mentioned item 5. ].

Method B:-
The compound of the formula (VIII) and the compound of the formula (IX) are reacted by the same method as the method A to obtain a compound of the formula (X) (Step 2),
The compound represented by the formula (X) is deprotected, and the resulting compound and P ³ -COR ¹¹ or P ³ -COR ⁴⁴ (P ³ is a halogen atom (eg, chlorine, bromine, etc.), hydroxy, etc., R ¹¹ and R ⁴⁴ have the same meanings as in item 1 above), whereby a compound of formula (XI) can be produced (step 3).

If necessary, it may be introduced R ²² by N- alkylation generally used.
The compound of the formula (VIII) is prepared by the following steps 4 to 9 shown in the following (Chemical Formula 23) [wherein Q is methyl, C _1-4 alkoxymethyl (eg, methoxymethyl, t-butoxymethyl etc.), allyl, substituted Benzyl (eg benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 4-nitrobenzyl etc.) or substituted silyl (eg trimethylsilyl, triethylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, Dimethyl texylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, t-butylmethoxyphenylsilyl, etc.), u is an integer of 4-10, ^{R 1, R 2, R 3} , R 4, R 5, Oyo B has the same meaning as in claim 5 above. It can be manufactured according to

Process 4: A protective group is introduce | transduced into the hydroxyl group of bromo alcohol ( 1 ), and a compound ( 2 ) can be manufactured. Examples of the bromoalcohol include 12-bromo-1-dodecanol, 11-bromo-1-undecanol, 10-bromo-1-decanol, 9-bromo-1-nonanol, 8-bromo-1-octanol, and 7-bromo. Examples include -1-heptanol.

  Examples of the hydroxyl group protecting reaction include alkyl etherification, benzyl etherification, and silyl etherification.

  Examples of the reagent used for alkyl etherification include alkyl halides (for example, methyl iodide, methoxymethyl chloride, t-butoxymethyl chloride, etc.) and the like.

  Examples of the reagent used for benzyl etherification include benzyl halide (eg, benzyl halide (chloride or bromide), 4-methoxybenzyl halide, 3,4-dimethoxybenzyl halide, 4-nitrobenzyl halide, etc.).

  Reagents used for silyl etherification include silyl halides (for example, trimethylsilyl chloride, triethylsilyl chloride, dimethylisopropylsilyl chloride, diethylisopropylsilyl chloride, dimethyl texylsilyl chloride, t-butyldimethylsilyl chloride, t-butyldiphenylsilyl). Chloride, tribenzylsilyl chloride, triphenylsilyl chloride, diphenylmethylsilyl chloride, t-butylmethoxyphenylsilyl bromide, etc.).

In this reaction, an alkyl halide, benzyl halide or silyl halide is used in an amount of about 1 mol to excess, preferably about 1 to about 3 mol, per 1 mol of bromoalcohol ( 1 ). This reaction is performed in the presence of a base. Examples of the base include pyridine, triethylamine, diisopropylethylamine, imidazole and the like. This reaction includes ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, dimethyl It can also be carried out in an inert solvent such as sulfoxides such as sulfoxide. Moreover, you may mix and use these solvents in a suitable ratio. The reaction temperature is about −10 ° C. to about 120 ° C., preferably about 25 ° C. to about 40 ° C. The reaction time is about 30 minutes to about 20 hours, preferably about 1 hour to about 4 hours.

Step 5: A Grignard reagent is prepared using the compound ( 2 ) obtained in Step 4 and magnesium, and reacted with the compound ( 3 ). Compound ( 3 ) can be produced by reacting optionally substituted benzoic acid with N, O-dimethylhydroxylamine in the presence of a condensing agent. Specific examples of the benzoic acid that may be substituted include benzoic acid, 3-methoxybenzoic acid, 3-methylbenzoic acid, 3,5-dimethoxybenzoic acid, and 3,5-dimethylbenzoic acid. It is done. Examples of the condensing agent used in this reaction include DCC, WSC, Bop reagent and the like.

In this reaction, a Grignard reagent is prepared using magnesium in an amount of about 1 mol to an excess, preferably about 1 mol to about 1.5 mol, relative to 1 mol of compound ( 3 ), and then compound ( 2 ) It can be carried out by adding about 1 mol to an excess amount, preferably about 1 mol to about 1.2 mol. This reaction can be carried out in an inert solvent such as ethers such as diethyl ether and tetrahydrofuran. Moreover, you may mix and use these solvents in a suitable ratio. The reaction temperature is about −50 ° C. to about 60 ° C., preferably about 0 ° C. to about 30 ° C. The reaction time is about 30 minutes to about 20 hours, preferably about 1 hour to about 4 hours.

Process 6: A compound ( 5 ) can be manufactured by performing a reductive reaction for the compound ( 4 ) obtained at the process 5 using a reducing agent. The reduction reaction includes a reduction reaction using a reducing reagent (eg, tetrahydrofuran-borane complex, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, lithium borohydride, diisobutyl aluminum hydride, etc.) or a catalyst (eg, And a reduction reaction performed in a hydrogen atmosphere or in the presence of a borane reagent (for example, tetrahydrofuran-borane complex) using palladium carbon, platinum, palladium hydroxide carbon, or the like.

In the reduction reaction using a reducing reagent, the reducing reagent is used in an amount of about 1 mol to excess, preferably about 1 mol to about 1.2 mol. In this reaction, a solvent such as an alcohol solvent (methanol, ethanol, isopropanol, etc.) may be used. When the reaction is carried out in the presence of a borane reagent, about 1 mol to an excess amount, preferably about 1 mol to about 1.2 mol, of a tetrahydrofuran / borane complex 1 mol tetrahydrofuran solution is used. It can be carried out in an inert solvent.
The reaction temperature is about −78 ° C. to about 120 ° C., preferably about 0 ° C. to about 30 ° C. The reaction time is about 30 minutes to about 20 hours, preferably about 1 hour to about 20 hours.
In the reduction reaction using a catalyst, the catalyst can be used in an amount of about 0.05 mol to excess, preferably about 0.25 mol to about 1.5 mol.

This reaction can be performed under a hydrogen atmosphere, and an alcohol solvent (such as methanol, ethanol, isopropanol, etc.) can be used to carry out the reaction with hydrogen at normal pressure or under pressure.
The reaction temperature is about 0 ° C to about 60 ° C, preferably about 15 ° C to about 40 ° C. The reaction time is about 30 minutes to about 20 hours, preferably about 1 hour to about 20 hours.
In the above reduction reaction, a desired optical isomer (R-form or S-form) can be produced by using an asymmetric reducing reagent or asymmetric catalyst.

  Examples of the asymmetric reducing reagent include (+)-or (-)-chlorodiisopinocinfeylborane, 5,5-diphenyl-2-methyl-3,5-propano-1,3,2-oxazaborolidine CBS reagents such as TADDOL (α, α, α ′, α′-tetraaryl-1,3-dioxolane-4,5-dimethanol), oxazaphospholidine-borane, oxazaphospholidine oxide and the like. It is done. Using these, for example, J. Org. Chem., 56, 763 (1991), Angelewan Chem., Int. Ed. 40, 92 (2001), J. Chem. Soc., Chem. Comm., 287 (1992), It can be produced according to the method described in J. Chem. Soc., Perkin Trans. 1, 1998, 1027.

As an asymmetric catalyst, a ligand such as BINAP and a metal catalyst such as ruthenium or rhodium such as Angelwante Chem., Int. Ed. 40, 40 (2001) or J. Am. Chem. Soc., 120, 13529 (1998) Trans-RuCl ₂ [(S) -tolbinap] [(S, S) -dpen], trans-RuCl ₂ [(S) -tolbinap] [(S) -daipen], trans-RuCl ₂ [(S ) -xylbinap] [(S, S) -dpen]. Using these, it can manufacture in accordance with the method of the literature description, for example.

Step 7: Compound ( 6 ) can be produced by using compound ( 5 ) obtained in Step 6 with a halogenating agent (for example, N-iodosuccinide or N-bromosuccinimide). In this reaction, the halogenating agent can be used in an amount of about 1 mol to excess, preferably about 1 mol to about 1.5 mol, per 1 mol of compound ( 5 ). This reaction can be carried out in an inert solvent such as a halogenated hydrocarbon (eg, chloroform, dichloromethane, etc.) or a nitrile solvent (eg, acetonitrile, etc.). Further, these solvents may be mixed in an appropriate ratio and used for the reaction. The reaction temperature is about −50 ° C. to about 120 ° C., preferably about 0 ° C. to about 50 ° C. The reaction time is about 30 minutes to about 20 hours, preferably about 5 hours to about 20 hours.

Process 8: A compound ( 7 ) can be manufactured by cyclizing the compound ( 6 ) obtained at the process 7.
Examples of the cyclization reaction include a cyclization reaction using a palladium catalyst and carbon monoxide, or lithiation of the compound ( 6 ), and accompanying carboxylation and cyclization reaction.
Specific examples of the palladium catalyst catalyst include zero-valent tetrakistriphenylphosphine palladium (0). In this reaction, a palladium catalyst is generally used in an amount of about 0.01 mol to excess, preferably about 0.02 mol to about 0.1 mol, and about 1 mol of carbon monoxide, relative to 1 mol of compound ( 6 ). A mole to excess, preferably from about 1 mole to about 2 moles is used. This reaction is usually preferably carried out in the presence of a base, and examples of the base include pyridine, triethylamine, diisopropylethylamine and the like. This reaction can be carried out in an inert solvent such as amides (eg, N, N-dimethylformamide, N, N-dimethylacetamide and the like). Moreover, you may mix and use these solvents in a suitable ratio. The reaction temperature is about 0 ° C to 120 ° C, preferably about 50 ° C to about 100 ° C. The reaction time is about 1 hour to about 60 hours, preferably about 5 hours to about 20 hours.

The lithiation of compound ( 6 ) and the accompanying cyclization reaction by carboxylation can be carried out according to the following description.
The compound ( 6 ) is replaced with a lithium reagent (for example, n-butyllithium, sec-butyllithium, t-butyllithium, etc.) at about -78 ° C to about 0 ° C, preferably about -78 ° C to about -20 ° C for about The reaction is conducted for about 2 minutes to about 2 hours, preferably about 30 minutes to about 1 hour, followed by blowing an excess amount of carbon dioxide gas into the reaction solution or adding dry ice to the reaction solution. Then, a compound ( 7 ) can be manufactured by processing the obtained compound with an acid and performing cyclization.
Examples of the solvent used include inert solvents such as ethers (tetrahydrofuran, diethyl ether, etc.).
Examples of the acid used include hydrochloric acid, p-toluenesulfonic acid, sulfuric acid and the like.
The reaction temperature in the reaction with the condensing agent is about 0 ° C to about 120 ° C, preferably about 15 ° C to about 60 ° C. The reaction time is about 30 minutes to about 24 hours, preferably about 1 hour to about 5 hours.

Step 9: (i) Production Method of Compound of Formula (VIII) wherein R ⁵ is a Hydrogen Atom (i) -1: Compound of Formula (VIII) where B is Hydroxy Compound ( 7 ) Obtained in Step 5 Can be treated with an acid or base to produce a compound of formula (VIII). The acid or base used in this reaction may be any acid or base. Examples of the acid include hydrochloric acid, trifluoroacetic acid, sulfuric acid and the like. Examples of the base include sodium hydroxide and potassium hydroxide. Is mentioned. In this reaction, the acid or base is used in an amount of about 1 mol to excess, preferably about 1 mol to about 10 mol, per 1 mol of compound ( 7 ). Treatment with an acid or base includes ethers (eg, dioxane, tetrahydrofuran, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), nitrile solvents (eg, acetonitrile, etc.), amides (eg, N, N-dimethylformamide, N, N-dimethylacetamide and the like) or sulfoxides (eg dimethylsulfoxide and the like). Moreover, you may mix and use these solvents in a suitable ratio. The reaction temperature during the treatment with the acid or base is about -50 ° C to about 120 ° C, preferably about 0 ° C to about 50 ° C. The reaction time required for the acid or base treatment is about 30 minutes to about 20 hours, preferably about 1 hour to about 4 hours.
In addition to the conditions described above, the deprotection conditions described in “PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, published by John Willy and Sons, 2nd edition” may be used.

(I) -2: Method for producing compound of formula (VIII) wherein B is a halogen atom B is halogen atom by halogenating the hydroxy group of the compound of formula (VIII) obtained by the deprotection reaction described above A compound of formula (VIII) can be prepared. Examples of the halogen and phosphorus reagent used in the halogenation reaction include halogen (iodine, bromine, chlorine) and phosphorus reagent (for example, triphenylphosphine). In the reaction, about 1 mol to excess, preferably about 1 mol to about 1.5 mol, of halogen is used per 1 mol of compound (7), and about 1 mol to excess, preferably about 1 mol of phosphorus reagent. Mole to about 1.2 mol is used. The reaction is carried out in the presence of a base. Examples of the base include pyridine, triethylamine, imidazole and the like. The reaction can be carried out in an inert solvent such as chlorinated hydrocarbons (eg, chloroform, dichloromethane, etc.). Moreover, you may mix and use these solvents in a suitable ratio. The reaction temperature is about −50 ° C. to 120 ° C., preferably about 0 ° C. to about 30 ° C. The reaction time is about 30 minutes to about 20 hours, preferably about 1 hour to about 4 hours.

(Ii) When R ⁵ is a methyl group or an ethyl group After reacting the compound ( 7 ) with methyl iodide or ethyl iodide, a deprotection reaction similar to that described above is carried out, whereby the compound of the formula (VIII) Can be manufactured. In the reaction, about 1 mol to an excess amount, preferably about 1 mol to about 1.5 mol, of methyl iodide or ethyl iodide is used with respect to 1 mol of the compound ( 7 ). This reaction is preferably performed in the presence of a base. Examples of the base include sodium hydride, lithium diisopropylamine (prepared from n-butyllithium and diisopropylamine according to a conventional method), and the like. The reaction can be carried out in an inert solvent such as ethers such as dioxane and tetrahydrofuran. Moreover, you may mix and use these solvents in a suitable ratio. The reaction temperature is about -78 ° C to about 60 ° C, preferably about -78 ° C to about 0 ° C. The reaction time is about 30 minutes to about 20 hours, preferably about 1 hour to about 20 hours.

As the compound of the formula (J) in Chemical formula 21, a commercially available compound is used.
When the compound of formula (J) is not commercially available, a deprotection reaction is performed on the compounds produced according to the descriptions in (Table 4) to (Table 8) below, and the resulting compound is used. it can. In addition, the manufacturing method of the compound of Formula (J) is not limited to the method of the following (Table 4)-(Table 8).

Method for producing compound of formula (J):
Compound of formula (K) (wherein P ⁴ represents benzyl, benzyloxycarbonyl, diphenylmethyl or (t-butoxy) carbonyl, and A has the same meaning as in item 1 above)

The compound of formula (J) can be produced by carrying out a deprotection reaction.
When the protecting group P ⁴ is benzyl, benzyloxycarbonyl or diphenylmethyl, the reaction for removing the protecting group P ⁴ can be carried out in a hydrogen atmosphere in the presence of a catalyst. When P ⁴ is (t-butoxy) carbonyl, the reaction for removing P ⁴ can be carried out by treatment with an acid. The compound of the formula (K) is commercially available.
In addition, when the compound of formula (K) is not commercially available, it can be produced according to the production method described below or a method common to those skilled in the art.

In the production method represented by Chemical Formula 25, P ⁴ has the same meaning as defined in Chemical Formula 24, and R ⁶ , R ¹¹ , p, and q have the same meaning as in Item 1 above.

Step 10: Method for Producing the Compound of the Formula (K-1a) The compound of the formula (K-1) is prepared by the same method as described in Reference Example 1 using an alkyl halide or according to a method commonly used by those skilled in the art. The compound (K-1a) can be produced. Examples of the alkyl halide include methyl iodide, N- (2-chloroethyl) morpholine, phenethyl chloride, 3,4-methylenedioxybenzyl chloride, cinnamyl bromide, pyrrolidinocarbonylmethyl chloride (2-chloro-1-pyrrolidine). -1-yl-ethanone), morpholinocarbonylmethyl chloride (4- (2-chloroacetyl) morpholine) and the like.

Step 11: Method for Producing Compound of Formula (K-1b) The compound of formula (K-1) is converted to tetrahydro-2H-pyranyloxy C _2-6 alkyl chloride (eg, 2- (2-chloroethoxy) tetrahydro-2H— N-alkylation reaction with pyran, 2- (3-chloropropoxy) tetrahydro-2H-pyranic acid, etc.) or benzyloxy C _2-6 alkyl chloride (eg 3-benzyloxy-1-bromopropane, etc.) Then, the compound of the formula (K-1b) can be produced by deprotecting the protecting group such as acid or catalytic reduction. Alternatively, as in Reference Example 2, 4- (hydroxyC _2-6 alkyl) piperazine (eg, 4- (2-hydroxyethyl) piperazine) and P ⁴ -halide (P ⁴ has the same meaning as described above). The compound of the formula (K-1b) can also be produced by reacting a reagent such as benzyl chloride, benzyl bromide, etc.).

Step 12: Preparation of Compound of Formula (K-1c) (I) Compound of Formula (K-1b) and chlorosulfonyl isocyanate are halogenated hydrocarbons (chloroform, dichloromethane, etc.), amide system (N, N-dimethylformamide) , N, N-dimethylacetamide, etc.).
(II) Then, the compound obtained by the above reaction can be hydrolyzed according to a conventional method to produce a compound of formula (K-1c).

Step 13: Method for Producing Compound of Formula (K-1d) The compound of formula (K-1b) is converted to a compound of formula (K-1d) according to a conventional method using C _1-6 alkylamine (eg, ethylamine) and a condensing agent. ) Can be produced.

Step 14: Method for Producing Compound of Formula (K-2a) The compound of formula (K-2a) can be produced, for example, according to the methods described in Reference Examples 6 and 7.

Step 15: Method for Producing Compound of Formula (K-2b) For the compound of formula (K-2b), a reagent is selected according to the type of R ¹¹ and a formylation reaction (eg, Reference Example 9) or a condensation reaction is performed. (For example, Reference Examples 4 to 5 and Reference Examples 14 to 15 etc.).

  Examples of the reagent include carboxylic acid derivatives (eg, acetic acid, trifluoroacetic acid, sodium 4-hydroxybutyrate, 4-fluorobenzoic acid, etc.), alcohols (eg, methanol, 2-methyl-1-propanol, 2-methoxyethanol, 1,3-propanediol, phenol, benzyl alcohol, allyl alcohol, 4-N-Boc-aminocyclohexanol, etc.), amine derivatives (eg, ethylamine, N, N-diethylamine, benzylamine, aniline, pyrrolidine, morpholine, N -Boc piperazine, 4-amino-1-Boc-piperidine, 4-Boc aminopiperidine, 2- (2-aminoethyl) -1,3-dioxolane and the like.

In formula 26, ^{R E} is hydroxy, amino, means such as t- butoxycarbonyl amino or ^{methoxycarbonyl,, R} F ^means a -OCOR 1111, ^{-NHCOR 1111} or ^{-COR 1111,, R G} is Means hydroxy, t-butoxycarbonylamino, or C _1-6 alkoxycarbonyl, w means an integer of 2 to 6, P ⁴ has the same meaning as defined above, and R ²² , R ³³ , R ¹¹ , R ⁴⁴ , R ¹¹¹¹ , p, q, and r have the same meanings as in item 1 above.

Step 16: Method for Producing Compound of Formula (K-4) Compound (K-3) is converted into sulfonyl chloride (for example, 4- (t-butyl) benzenesulfonyl chloride, 4- (trifluoromethyl) benzenesulfonyl chloride, 4 -(Trifluoromethoxy) benzenesulfonyl chloride, methanesulfonyl chloride, dimethylsulfamoyl chloride, etc.) can be used in the same manner as described in Reference Example 8.
Moreover, you may perform N- sulfonylation reaction, after N-alkylating a compound (K-3) as needed.

Step 17: Method for Producing Compound of Formula (K-5a) The compound of formula (K-5a) can be produced by the same method as in Reference Example 9.

Step 18: compound of formula preparation formula (K-5b) of the compound (K-5b) ^is possible to select a reagent according to the type of ^{R 44,} prepared by a condensation reaction (e.g., Reference Example 5) Can do.

  Examples of the reagent include carboxylic acid derivatives (for example, acetic acid, trifluoroacetic acid, 4-methyl-1-cyclohexanecarboxylic acid, 4-fluorobenzoic acid, pentafluorobenzoic acid, 3,4,5-trimethoxybenzoic acid, thiophene- 2-carboxylic acid, benzothiophene-2-carboxylic acid, picolinic acid, glycolic acid, 3-hydroxypropionic acid, 7-hydroxyheptanoic acid, etc.), alcohol (eg, methanol, 2-propanol, t-butyl alcohol, 3-methyl-1-butanol, 2-methoxyethanol, ethylene glycol monoisopropyl ether, 3-ethoxy-1-propanol, diethylene glycol monomethyl ether, 3-fluoropropan-1-ol, 2,2,2-trifluoroethanol, 3, 3, 3 Trifluoropropan-1-ol, 2- (benzyloxy) ethanol, 3-phenoxy-1-propanol, 1-Boc-4-hydroxypiperidine, 1-benzyl-4-hydroxypiperidine, 4-hydroxytetrahydropyran, 2- Indanol, hydroquinone, benzyl alcohol, 2-chlorobenzyl alcohol, phenethyl alcohol, 2-pyridinemethanol, 3-pyridinemethanol, 4-pyridinemethanol, benzothiophenesulfone-2-methanol, allyl alcohol, cyclopropanemethanol, N- (2 -Hydroxyethyl) piperidine, 1-Boc-4-piperidylmethanol, t-butyl 4- (2-hydroxyethyl) piperazinecarboxylate, N- (2-hydroxyethyl) morpholine, 2,2-dimethyl -1,3-dioxolane-4-methanol, tetrahydrofurfuryl alcohol, tetrahydro-3-furanmethanol, cyclopropanemethanol, methyl glycolate, etc.), amine derivatives (eg, aniline, pyrrolidine, etc.), acid chloride derivatives (eg, 1-chlorocarbonyl-2-imidazolidinone, etc.).

Steps 19 and 20: Method for Producing Compounds of Formula (N) and (O) The compound of formula (K-3) is reacted with a compound of formula (L) or a compound of formula (M) N) or (O) compounds can be prepared.
Examples of the compound of formula (L) or the compound of formula (M) include reagents that are commercially available and easily available. Specifically, for example, 3- (t-butoxycarbonyl) amino-1-propanol, 1,3-propanediol, 5- (t-butoxycarbonyl) amino-1-pentanol, 1,4-butanediol, 1,2-ethylene glycol, 3-methyl-1,3-butanediol, 2,2-dimethyl-1,3-propanediol, 1,4-dioxa-spiro [4,5] decan-8-ol, cyclo Examples include pentanol and cyclohexanol.

  The compound of the formula (L) or the compound of the formula (M) can also be produced by combining a condensation reaction with an alcohol or an amine and a protection or deprotection reaction of the alcohol or amine. For example, a production example in which ethanolamine and methyl chloroformate are subjected to a condensation reaction and the resulting compound is used as the compound of the formula (L) can be mentioned.

Step 21: Production Method of Compound of Formula (K-6a) Using the reagent (P) for the compound of formula (N), the compound of formula (K-6a) is prepared in the same manner as in Reference Example 15 or Reference Example 21 (1). Can be produced.
Specific examples of the reagent (P) include methanol, 2,2,2-trifluoroethanol, n-butanol, 3-methyl-1,3-butanediol, 2-fluoroethanol, dimethylaminoethanol, Examples include diethylaminoethanol, methyl N- (2-hydroxyethyl) carbamate, methyl glycolate, 2-methoxyethanol, ethylamine, t-butylamine, cyclopropanemethanol, and pyrrolidine.

Step 22: Method for Producing Compound of Formula (K-6b) Using the reagent (Q) for the compound of formula (O), the compound of formula (K-6b) is prepared in the same manner as in Reference Example 15 or Reference Example 21 (1). Can be produced.
Specific examples of the reagent (Q) include t-butanol, 2-methoxyethanol, 2-fluoroethanol, 2- (dimethylamino) ethanol and the like.

In Chemical Formula 27, P ⁴ has the same meaning as defined above (Chemical Formula 25), and R ⁷ , R ⁸ , R ¹¹ , p, and q have the same meaning as in Item 1 above.

Step 23: Method for Producing Compound of (K-6c) For the compound of formula (K-6c), the compound of formula (K-4a) is used as a starting material, and a reagent is selected according to the types of R ⁷ and R ⁸ , It can be produced by the same method as described in Reference Examples 32, 34 to 35, and 37. As the compound of the formula (K-4a), a compound obtained by oxidizing an alcohol (for example, 1-benzhydroazetan-3-ol, etc.) by an oxidation reaction (for example, swan oxidation, T-PAP oxidation, etc.) may be used. .

Step 24: compound of Preparation formula (K-6d) of the compound of (K-6d) selects a reagent according to the type of ^{R 11} of a compound of formula (K-4b) as the starting material Reference Example 28 It can be manufactured by the same method as described in ˜30.

In Chemical formula 28, P ⁴ has the same meaning as in the above (Chemical formula 25), and E, F, R ⁴⁴⁴ , p and q have the same meaning as in the above-mentioned item 1.

Step 25: Method for Producing Compound of Formula (K-7a) Using the compound of formula (K-3) or formula (K-4a) as a starting material, for example, in the same manner as in Reference Example 46, formula (K-7a) ) Can be produced.
When F is substituted C _1-2 alkylene, the corresponding compound can be produced, for example, by the same method as in Reference Example 47.

Step 26: Process for the preparation of the compound of formula (K-7b) The compound of formula (K-3) is prepared, for example, according to J. Chem. Soc., Chem. Comm. 1992, 812-813 or Bioorg. Med. Chem. Lett The compound of the formula (K-7b) can be produced by the method described in 2001, 2475-2479 or a modification thereof.

Step 27: Method for Producing Compound of Formula (K-7c) Using the compound of formula (K-3a) or formula (K-4a) as a starting material, for example, in the same manner as in Reference Example 50, formula (K-7c) ) Can be produced.

Step 28: Method for Producing Compound of Formula (K-7d) Using the compound of formula (K-3a) or formula (K-4a) as a starting material, for example, in the same manner as in Reference Example 48 and Reference Example 51, A compound of (K-7d) can be produced.

Step 29: Method for Producing Compound Represented by Formula (K-7e) The compound of formula (K-7e) is produced by reacting the compound of formula (K-3) with, for example, methyl 4-chloroacetoacetate. be able to.

Step 30: Production Method of Compound Represented by Formula (K-7f) Using the compound of formula (K-3a) or formula (K-4a) as a starting material, for example, by the same method as in Reference Example 52, The compound of K-7f) can be produced.

Step 31: Method for Producing Compound of Formula (K-7g) Using the compound of formula (K-3a) or formula (K-4a) as a starting material, for example, in the same manner as in Reference Example 49, formula (K-7g) ) Can be produced. If necessary, a substituent in which R ⁴⁴⁴ is C _2-7 alkanoyl, C _1-6 alkyl, or hydroxy C _2-6 alkyl can also be introduced using a condensation reaction.

Step 32: Method for Producing Compound of Formula (K-7h) By reacting the compound of formula (K-3) with, for example, methyl 5-bromovalerate or methyl 4-bromobutyrate, the compound of formula (K-7h) Compounds can be produced.

Step 33: Method for producing compound of formula (K-8a) A compound of formula (K-4a) and ethylenediamine are subjected to a reductive amination reaction, followed by reaction with diethyl oxalate to give a compound of formula (K-8a). Compounds can be produced.

Step 34: Method for Producing the Compound of the Formula (K-8b) The compound of the formula (K-4a) is reacted with, for example, 2-[(2-chloroacetyl) amino] acetate, and subsequently heated to cyclize. To produce the compound of formula (K-8b).

In the above (Chemical Formula 28), if necessary, a substituent in which R ⁴⁴⁴ is C _2-7 alkanoyl, C _1-6 alkyl, or hydroxy C _2-6 alkyl can also be introduced using a condensation reaction.

In the chemical formula 29, P ⁴ has the same meaning as defined in the above (chemical formula 25), and R ⁹ and m have the same meaning as in the above item 1.

Step 35: Production Method of Compound of Formula (K-9a) Using the compound of formula (K-5) as a starting material, for example, according to the method described in Bioorg. Med. Chem. Lett., 12, 1759 (2002) Can be manufactured.

Step 36: Method for Producing Compound of Formula (K-9b) The compound of formula (K-9b) can be produced by the same method as in Reference Example 40 and Reference Example 41. Further, the compound of formula (K-5) is epoxidized by the same method as in Reference Example 37 (1), then reacted with glycine, and subsequently subjected to an intramolecular cyclization reaction using a condensing agent. The compound of (K-9b) can be produced.

Step 37: Method for producing compound of formula (K-9c) By reacting the compound of formula (K-5) with potassium cyanide to produce cyanohydrin, and subsequently reacting with chlorosulfonyl isocyanate to carry out a cyclization reaction A compound of formula (K-9c) can be prepared.

Step 38: Method for Producing Compound Represented by Formula (K-9d) In the same manner as in Reference Example 42, the compound of formula (K-5) is reacted with sodium cyanide and ammonium carbonate to give the formula (K The compound of -9d) can be produced.

Step 39: Method for Producing Compound of Formula (K-9e) For example, in the same manner as in Reference Example 44, the compound of formula (K-5) is reacted with hydroxyalkylamide to give the compound of formula (K-9e). Can be manufactured.

In the compounds of the compound formulas (K-9a) to (K-9e) in the above (Chemical 29), R ⁹ is C _3-6 cycloalkyl by N-alkylation reaction using a condensation reaction, if necessary. Substituents that are C _1-4 alkyl, phenyl C _1-4 alkyl, optionally substituted C _1-6 alkyl can also be introduced.

  The present invention may provide a pharmaceutical composition containing the compound of the present invention as an active ingredient.

  The present invention may provide a preventive or therapeutic agent for diseases caused by hyperglycemia containing the compound of the present invention as an active ingredient.

  In the present invention, the disease caused by hyperglycemia is diabetes, diabetic complications, obesity, hyperinsulinemia, glucose metabolism abnormality, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism abnormality Alternatively, a prophylactic or therapeutic agent for diseases such as atherosclerosis may be provided.

  The term “hyperglycemia” in the present invention means that the early morning fasting blood glucose of a normal person is said to be 60 to 100 mg / dL, and means that the blood glucose level rises beyond the range in which it is normally adjusted. Specifically, in the 75 g glucose tolerance test, “hyperglycemia” includes a hyperglycemia state.

  Since the compound of the present invention has an excellent blood glucose lowering action, it can be used as a safe preventive and / or therapeutic agent for diabetes for mammals (eg, humans, mice, dogs, rats, cows, etc.). 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 fasting blood glucose is not less than 126 mg / dL or in a blood glucose level after 2 hours of 75 g glucose tolerance test, not less than 200 mg / dL.
Glucose intolerance is defined as a blood glucose level of 140 to 200 mg / dL after 2 hours of 75 g glucose tolerance test.

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

  Hyperlipidemia refers to a condition in which total cholesterol, LDL (low density lipoprotein) cholesterol, and neutral fat are high simultaneously or alone. Specifically, according to the current standard, hyperlipidemia is diagnosed when total cholesterol 220 mg / dL, LDL cholesterol 140 mg / dL, and triglyceride 140 mg / dL are exceeded (all are fasting) ).

Metabolic syndrome refers to a state of easy onset of arteriosclerosis associated with impaired glucose tolerance, hyperlipidemia, and hypertension. Specifically, according to the current standards, the waist is 85 cm and 90 cm for men and women, respectively, and it is necessary to correspond to at least two of the following three items.
1. When the neutral fat level is 150 mg / dL or more and the HDL (high density lipoprotein) cholesterol level is less than 40 mg / dL (or both) 2. 2. If the maximum blood pressure is 130 mmHg or higher and the minimum blood pressure is 85 mmHg or higher (or both). Fasting blood glucose level 110mg / dL or more

  Furthermore, since the compound of the present invention has a hypoglycemic action as well as a hypoglycemic action, it can be used for the treatment or prevention of hyperlipidemia and obesity in the mammal. For example, it is useful for the prevention or treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia and dyslipidemia. In addition, it is useful as a preventive or therapeutic agent for metabolic syndrome associated with obesity (eg, atherosclerosis, hypertension, congestive heart failure, edema, hyperuricemia, gout, etc.).

The route of administration of these prophylactic / therapeutic agents may be either oral or parenteral.
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 preparation used in the present invention may contain a pharmaceutically acceptable ingredient other than the compound of the present invention as an active ingredient. Examples of this component include excipients and stabilizers. These components are not particularly limited as long as the object of the present invention is achieved, and can be used in an appropriate blending ratio. Specific examples of dosage forms include, for example, tablets (including sugar-coated tablets and film-coated tablets), pills, capsules (including microcapsules), granules, fine granules, powders, syrups, emulsions, and suspensions. Injections, inhalants, ointments, eye drops and the like are used. These preparations are prepared according to conventional methods (for example, methods described in the Japanese Pharmacopoeia).

  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.), disintegrating agents (lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch 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.

As the oral preparation carrier, for example, substances commonly used in the pharmaceutical field such as starch, D-mannitol, crystalline cellulose, sodium carboxymethyl cellulose, and the like are used.
As the carrier for injection, for example, distilled water, physiological saline, glucose solution, infusion agent and the like are used. In addition, additives generally used for preparations can be appropriately added.

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.
The melting point in this specification was measured using Yanaco MP-J3.
The conditions for HPLC were HITACHI MODEL D-7000 Chromatography Data Station, the column was Shiseido UG120 (5 μm 4.6 mm ID × 250 mm), and the mobile phase was 0.05% aqueous trifluoroacetic acid: acetonitrile = 60: 40, 25 ° C. Analysis was carried out.

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

The following abbreviations are used for the recrystallization solvents in the following table.
EA: ethyl acetate nH: n-hexane C: chloroform DE: diethyl ether IPA: 2-propanol In the table below, “oil” means an oily substance, and “amorphous” means an amorphous form. Means a substance.
¹ H-NMR: Proton nuclear magnetic resonance In the following table, the symbol dl means a racemate,
The symbols R and S mean absolute configuration.

  Reference Example 1: Production of 1-methyl-piperazine trifluoroacetate salt

(1) A solution of t-butyloxycarbonylpiperazine (5 g) in dichloromethane (100 ml) was ice-cooled, potassium hydroxide (3 g) and methyl iodide (3.8 g) were sequentially added, and the reaction solution was stirred at room temperature for 14 hours. did. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain 4-methyl-1- (t-butyloxycarbonyl) piperazine (3.8 g) as an oil.
(2) A solution of 4-methyl-1- (t-butyloxycarbonyl) piperazine (3.8 g) in methanol (20 ml) was ice-cooled, trifluoroacetic acid (200 ml) was added, and the mixture was stirred at room temperature for 14 hours. The solvent was distilled off under reduced pressure, water was added and the mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired product (6 g) as an oil.

Reference Example 2: Production of 1- (2-ethylaminocarbonyloxyethyl) piperazine

(1) A solution of 1-piperazine ethanol (6 g) in acetonitrile (120 ml) was ice-cooled, triethylamine (6.4 ml) and benzyl bromide (5.5 ml) were sequentially added, and the reaction solution was stirred at room temperature for 14 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain 1-benzyl-4- (2-hydroxyethyl) piperazine (5.8 g) as an oil.
(2) To a solution of 1-benzyl-4- (2-hydroxyethyl) piperazine (2 g) in diisopropylethylamine (20 ml), dimethylaminopyridine (1.1 g) and ethyl isocyanate (968 mg) were added in order at room temperature, Stir at 14 ° C. for 14 hours. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain 1-benzyl-4- (2-ethylaminocarbonyloxyethyl) piperazine (1.5 g) as an oil.
(3) A solution of 1-benzyl-4- (2-ethylaminocarbonyloxyethyl) piperazine (1.5 g) in methanol (40 ml) was ice-cooled, 20% palladium hydroxide / carbon (400 mg) was added, and hydrogen atmosphere was added. Stir at room temperature for 14 hours. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (1 g) as an oil.

Reference Example 3: Production of 1- (2-aminocarbonyloxyethyl) piperazine

(1) A solution of 1-benzyl-4- (2-hydroxyethyl) piperazine obtained in Reference Example 2 (1) in methylene chloride (60 ml) was ice-cooled, and chlorosulfonyl isocyanate (1.9 g) was slowly added dropwise. The reaction was stirred at room temperature for 4 hours. The reaction solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was stirred at room temperature for 24 hours. A 2 mol / l aqueous sodium hydroxide solution was added to adjust the pH to 8, followed by extraction with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain 1-benzyl-4- (2-aminocarbonyloxyethyl) piperazine as an oil.
(2) A solution of 1-benzyl-4- (2-aminocarbonyloxyethyl) piperazine in methanol (30 ml) was ice-cooled, 20% palladium hydroxide / carbon (200 mg) was added, and the mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere. did. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product as an oil.

Reference Example 4: Production of 1- (3-hydroxypropyloxycarbonyl) piperazine

(1) To a solution of 3-benzyloxy-1-propanol (3.5 g) in dimethylformamide (80 ml) was added carbodiimidazole (3.4 g) at room temperature and stirred as it was for 1 hour. Then benzyl 1-piperazinecarboxylate (4.6 g) was added and the reaction was stirred at 60 ° C. for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain 1-benzyloxycarbonyl-4- (3-benzyloxypropyloxycarbonyl) piperazine (6 g) as an oil.
(2) A solution of 1-benzyloxycarbonyl-4- (3-benzyloxypropyloxycarbonyl) piperazine in methanol (150 ml) was ice-cooled, 20% palladium hydroxide / carbon (1.5 g) was added, and room temperature under hydrogen atmosphere For 8 hours. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure to give 4- (3-benzyloxypropyloxycarbonyl) piperazine (3.5 g) as an oil.
(3) 4- (3-benzyloxypropyloxycarbonyl) piperazine (3.5 g) in dioxane (50 ml) -1 mol / l sodium hydroxide aqueous solution (50 ml) was ice-cooled, and di-tert-butyl dicarbonate (3 g) And the reaction was stirred at room temperature for 15 hours. The reaction mixture was ice-cooled, 10% aqueous citric acid solution was added to adjust the pH to 4, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1-t-butyloxycarbonyl-4- (3-benzyloxypropyloxycarbonyl) piperazine (3.9 g) as an oil.
(4) A solution of 1-t-butyloxycarbonyl-4- (3-benzyloxypropyloxycarbonyl) piperazine (3.9 g) in methanol (100 ml) was ice-cooled, and 20% palladium hydroxide / carbon (1.5 g) was added. In addition, the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain 1-t-butyloxycarbonyl-4- (3-hydroxypropyloxycarbonyl) piperazine (2.9 g) as an oil.
(5) A solution of 1-t-butyloxycarbonyl-4- (3-hydroxypropyloxycarbonyl) piperazine (2.9 g) in dioxane (5 ml) was ice-cooled, and a 4 mol / l hydrochloric acid-dioxane solution (10 ml) was added. The reaction was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and azeotroped several times with toluene to obtain the desired hydrochloride (2.4 g) as amorphous.

Reference Example 5: Production of 1- (4-fluorophenylcarbonyl) piperazine

(1) To a solution of 4-benzyloxycarbonylpiperazine (20.8 g) in methylene chloride (300 ml), 4-fluorobenzoic acid (14 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (20 g) 4-dimethylaminopyridine (0.5 g) was sequentially added, and the reaction solution was stirred at room temperature for 14 hours. Water was added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain 1- (4-fluorophenylcarbonyl) -4-benzyloxycarbonylpiperazine (15 g) as an oil.
(2) A solution of 1- (4-fluorophenylcarbonyl) -4-benzyloxycarbonylpiperazine (15 g) in methanol (200 ml) was ice-cooled, 20% palladium hydroxide / carbon (1 g) was added, and room temperature under hydrogen atmosphere For 14 hours. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (10 g) as an oil.

Reference Example 6: Production of 1-methoxycarbonylaminopiperazine

(1) To a solution of benzyl 1-piperazinecarboxylate (5 g) in tetrahydrofuran (100 ml) was added 0.5 mol / l-hydrochloric acid aqueous solution (200 ml) and sodium nitrite at room temperature, and the reaction solution was stirred at room temperature for 2 hours. . The reaction solution was ice-cooled and neutralized with an aqueous sodium hydrogen carbonate solution, extracted with chloroform, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (chloroform-methanol) to obtain 1-nitroso-4-benzyloxycarbonylpiperazine (6.4 g).
(2) To an aqueous solution (29 ml) of 1-nitroso-4-benzyloxycarbonylpiperazine (6.4 g), zinc (6 g) and acetic acid (7.5 ml) were sequentially added at room temperature, followed by stirring at 80 ° C. for 2 hours. The reaction solution was cooled to room temperature and filtered through celite. The filtrate was collected, then neutralized with an aqueous sodium hydrogen carbonate solution and an aqueous sodium hydroxide solution, and filtered through celite. The filtrate was extracted with chloroform, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (chloroform-methanol) to obtain 1-amino-4-benzyloxycarbonylpiperazine (2.3 g).
(3) A solution of 1-amino-4-benzyloxycarbonylpiperazine (1.0 g) in methylene chloride (40 ml) was ice-cooled, and triethylamine (0.9 ml) and methyl chloroformate (0.4 ml) were added. Stir for hours. The reaction solution was ice-cooled, extracted with chloroform, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from ethyl acetate to obtain 1-methoxycarbonylamino-4-benzyloxycarbonylpiperazine (1.1 g).
(4) To a solution of 1-methoxycarbonylamino-4-benzyloxycarbonylpiperazine (1.1 g) in methanol (30 ml), 20% palladium hydroxide / carbon (500 mg) was added at room temperature, and at room temperature under a hydrogen atmosphere for 15 hours. Stir. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (600 mg).

Reference Example 7: Production of 1- (trans-4- (t-butoxycarbonylamino) cyclohexane-1-yl-oxycarbonylamino) piperazine

(1) To a solution of 1-amino-4-benzyloxycarbonylpiperazine (870 mg) obtained in Reference Example 6 (2) in methylene chloride (20 ml) was added triethylamine (1.1 ml) and 4-nitrophenyl chloroformate (860 mg). And stirred at room temperature for 2 hours. Thereafter, a solution of trans-4- (t-butoxycarbonylamino) cyclohexane-1-ol (1.0 g) in methylene chloride (20 ml) was added to the reaction solution at room temperature, and the mixture was stirred for 50 hours while heating under reflux. Water was added to the reaction solution under ice-cooling, extracted with chloroform, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (chloroform-methanol) to give 1- [trans-4- (t-butoxycarbonylamino) cyclohexane-1-yl-oxycarbonylamino] -4-benzyloxycarbonylpiperazine. (600 mg) was obtained.
(2) 1- [trans-4- (t-butoxycarbonylamino) cyclohexane-1-yl-oxycarbonylamino] -4-benzyloxycarbonylpiperazine (600 mg) in methanol (15 ml) solution at room temperature with 20% water Palladium oxide / carbon (600 mg) was added, and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the target compound.

Reference Example 8: Production of 4-methanesulfonylaminopiperidine

(1) A solution of 4-amino-N-benzylpiperidine (2.0 g) in dimethylformamide (20 ml) was ice-cooled, triethylamine (2.1 g) and methanesulfonyl chloride (1.2 g) were added in this order, and the reaction solution was stirred at room temperature. Stir for hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain 4-methanesulfonylamino-N-benzylpiperidine (2.08 g) as an oil.
(2) A methanol (50 ml) solution of 4-methanesulfonylamino-N-benzylpiperidine (2.08 g) was ice-cooled, 20% palladium hydroxide / carbon (500 mg) was added, and the mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere. . The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (1.38 g) as an oil.

Reference Example 9: Production of 3- (S) -formylaminopyrrolidine

(1) A solution of 3- (S) -1-benzyl-3-aminopyrrolidine (1.5 g) in methylene chloride (25 ml) was ice-cooled, and acetic anhydride (1.7 g) and formic acid (1.6 g) were added at 45 ° C. The solution prepared by stirring for 1 hour was added and the reaction was stirred for 1 hour at room temperature. Water was added to the reaction solution, a 2 mol / l sodium hydroxide aqueous solution was added to adjust the pH to 8, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 3- (S) -1-benzyl-3-formylaminopyrrolidine (800 mg) as an oil.
(2) A solution of 3- (S) -1-benzyl-3-formylaminopyrrolidine (800 mg) in methanol (30 ml) was ice-cooled, 20% palladium hydroxide / carbon (250 mg) was added, and a hydrogen atmosphere was performed at room temperature. Stir for 12 hours. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (440 mg) as an oil.

Reference Example 10: Production of 4- (3-methyl-2-oxo-1-imidazolidinyl-carbonylamino) piperidine-

(1) A solution of 4-amino-1-benzylpiperidine (5 g) in methylene chloride (100 ml) was ice-cooled, triethylamine (4 g) and 2-oxo-1-imidazolidinecarbonyl chloride (3.9 g) were added in this order, and the reaction was performed. The solution was stirred at room temperature for 24 hours. Water was added to the reaction solution and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate. The residue was crystallized from ethyl acetate to give 1-benzyl-4- (2-oxo-1-imidazolidinyl-carbonylamino) piperidine (5 g) as a white solid.
(2) A solution of 60% sodium hydride (331 mg) in dimethylformamide (30 ml) was ice-cooled, and 1-benzyl-4- (2-oxo-1-imidazolidinyl-carbonylamino) piperidine (2.5 g) in dimethylformamide ( 30 ml) solution was added and the reaction was stirred at room temperature for 1 hour. Next, methyl iodide (1.2 g) was added at room temperature, and the reaction solution was stirred at 60 ° C. for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 1-benzyl-4- (3-methyl-2-oxo-1-imidazolidinyl-carbonylamino) piperidine (1.8 g) as an oil.
(3) A solution of 1-benzyl-4- (3-methyl-2-oxo-1-imidazolidinyl-carbonylamino) piperidine (1 g) in methanol (40 ml) was ice-cooled, and 20% palladium hydroxide / carbon (400 mg) And stirred at room temperature for 14 hours under hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (700 mg) as amorphous.

Reference Example 11: Production of 4- (trans-4-methylcyclohexane-1-yl-carbonylamino) piperidine

(1) A solution of 1-benzyl-4-aminopiperidine in methylene chloride (50 ml) was ice-cooled, and trans-4-methylcyclohexylcarboxylic acid (750 mg), WSC (1 g) and dimethylaminopyridine (650 mg) were added. And stirred at room temperature for 15 hours. The reaction mixture was ice-cooled, water was added, and the mixture was extracted with chloroform, washed with aqueous sodium hydrogen carbonate solution, 10% aqueous citric acid solution, and water. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1-benzyl-4- (trans-4-methylcyclohexanecarbonylamino) piperidine (310 mg).
(2) To a solution of 1-benzyl-4- (trans-4-methylcyclohexanecarbonylamino) piperidine (310 mg) in methanol (15 ml), 20% palladium hydroxide / carbon (500 mg) was added at room temperature, under a hydrogen atmosphere. Stir at room temperature for 3 hours. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the target compound.

Reference Example 12: Production of 4- (ethoxycarbonylaminocarbonylamino) piperidine-

(1) A solution of 4-amino-1-benzylpiperidine (1.7 g) in tetrahydrofuran (40 ml) was ice-cooled, ethoxycarbonyl isocyanate (1 g) was added, and the reaction solution was stirred at room temperature for 30 minutes. The crude product obtained by evaporating the reaction solvent under reduced pressure was purified by silica gel column chromatography (chloroform-methanol) to obtain 1-benzyl-4- (ethoxycarbonylaminocarbonylamino) piperidine (2.6 g) as a white solid. It was.
(2) A solution of 1-benzyl-4- (ethoxycarbonylaminocarbonylamino) piperidine (2.6 g) in ethanol (60 ml) and ethyl acetate (30 ml) was ice-cooled, and 20% palladium hydroxide / carbon (700 mg) was added. The mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (1.9 g) as amorphous.

Reference Example 13: Production of 4- (t-butylcarbonylaminocarbonylamino) piperidine

(1) Pivaloyl chloride (2.4 g) was added to a petroleum ether (80 ml) suspension of silver cyanate (3 g) at room temperature, and the reaction mixture was stirred at 60 ° C. for 3 hours. The reaction was cooled to room temperature, 4-amino-1-benzylpiperidine (3.8 g) was added and the reaction was stirred at room temperature for 14 hours. Water was added to the reaction solution and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain 1-benzyl-4- (t-butylcarbonylaminocarbonylamino) piperidine (2 g) as a white solid.
(2) A solution of 1-benzyl-4- (t-butylcarbonylaminocarbonylamino) piperidine (1 g) in methanol (40 ml) was ice-cooled, 20% palladium hydroxide / carbon (400 mg) was added, and a hydrogen atmosphere was added at room temperature. For 12 hours. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (710 mg) as amorphous.

Reference Example 14: Production of 4- (2,2,2-trifluoroethylaminocarbonylamino) piperidine-

(1) To a solution of 2,2,2-trifluoroethylamine (2 g) in dimethylformamide (80 ml) was added carbodiimidazole (3.6 g) at room temperature, and the reaction mixture was stirred at room temperature for 1.5 hours. Then 4-amino-1-benzylpiperidine (4.2 g) was added and the reaction was stirred at 60 ° C. for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was crystallized from ethyl acetate / n-hexane to obtain 1-benzyl-4- (2,2,2-trifluoromethylaminocarbonylamino) piperidine (4.9 g) as a white solid.
(2) A solution of 1-benzyl-4- (2,2,2-trifluoromethylaminocarbonylamino) piperidine (1 g) in methanol (40 ml) was ice-cooled, and 20% palladium hydroxide / carbon (400 mg) was added. The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (700 mg) as a white solid.

Reference Example 15: Production of 4-[(1-t-butoxycarbonyl) piperidin-4-yl-oxycarbonylamino] piperidine-

(1) To a solution of 4-hydroxy-N-Boc-piperidine (2 g) in methylene chloride (50 ml), triethylamine (2.8 ml) and 4-nitrophenyl chloroformate (2.1 g) were sequentially added at room temperature. Stir for 1 hour. To the reaction solution was added a solution of 4-amino-1-benzylpiperidine (2 g) in methylene chloride (50 ml) at room temperature, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was ice-cooled, water was added, the mixture was extracted with chloroform, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (chloroform-methanol) to obtain 1-benzyl-4-[(1-t-butoxyaminocarbonyl) piperidine-4-oxycarbonylamino] piperidine (2.85 g). It was.
(2) A solution of 1-benzyl-4-[(1-t-butoxyaminocarbonyl) piperidine-4-oxycarbonylamino] piperidine (2.85 g) in methanol (50 ml) at room temperature with 20% palladium hydroxide / carbon ( 3 g) was added and stirred at room temperature under a hydrogen atmosphere for 18 hours. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain a compound.

Reference Example 16: Production of 4-[(4-methoxycarbonylamino) phenyloxycarbonylamino] piperidine-

(1) A suspension of 4-benzyloxyaniline hydrochloride (3 g) in methylene chloride (80 ml) was ice-cooled, triethylamine (3.9 g) and methyl chlorocarbonate (1.3 g) were added in this order, and the reaction solution was stirred at room temperature. Stir for hours. Water was added to the reaction solution and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained crude product was crystallized from ethyl acetate / n-hexane to give 4-benzyloxy-1-methoxycarbonylaminobenzene (1.8 g) as a white solid.
(2) A solution of 4-benzyloxy-1-methoxycarbonylaminobenzene (1.8 g) in methanol (50 ml) was ice-cooled, 20% palladium hydroxide / carbon (500 mg) was added, and the mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere. did. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain 4-methoxycarbonylaminophenol (1.1 g) as amorphous.
(3) To a solution of 4-methoxycarbonylaminophenol (1.1 g) in methylene chloride (50 ml), triethylamine (1.4 g) and 4-nitrophenyl chloroformate (1.4 g) were sequentially added at room temperature, and the reaction solution was added at room temperature to 1.5 ml. Stir for hours. Next, 4-amino-1-benzylpiperidine (1.3 g) was added at room temperature, and the reaction solution was stirred at room temperature for 14 hours. The methylene chloride layer was washed once with an aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain 1-benzyl-4-[(4-methoxycarbonylaminophenyloxy) carbonylamino] piperidine (1.1 g) as a pale yellow solid. It was.
(4) A solution of 1-benzyl-4-[(4-methoxycarbonylaminophenyloxy) carbonylamino] piperidine (1.1 g) in methanol (30 ml) was ice-cooled, and 20% palladium hydroxide / carbon (300 mg) was added. The mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (840 mg) as an amorphous product.

Reference Example 17: Production of 4- [1- (t-butoxycarbonyl) piperidin-4-yl-methyloxycarbonylamino] piperidine-

(1) A solution of 4-amino-N-benzylpiperidine (2 g) in tetrahydrofuran (100 ml) was ice-cooled, carbodiimidazole (1.8 g) was added, and the reaction solution was stirred at room temperature for 2 hours. Subsequently, 4-hydroxymethyl- (N-Boc) piperidine (2.3 g) was added to the reaction solution, and the reaction solution was stirred at room temperature for 14 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate-n-hexane), and 1-benzyl-4-[(1-t-butoxycarbonylpiperidine] -4-yl-methoxycarbonylamino) piperidine. As an oil (4.6 g).
(2) A solution of 1-benzyl-4-[(1-t-butoxycarbonylpiperidine) -4-yl-methoxycarbonylamino] piperidine (4.6 g) in methanol (100 ml) was ice-cooled, and 20% palladium hydroxide / Carbon was added and stirred at room temperature for 14 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (3.5 g) as an oil.

Reference Example 18: Production of 4- [N- (t-butoxycarbonyl) -N-methylamino] piperidine-

(1) A suspension of 60% sodium hydride (536 mg) in dimethylformamide (40 ml) was ice-cooled, and a solution of 1-benzyl-4- (t-butoxycarbonylamino) piperidine (3 g) in dimethylformamide (10 ml) was added. Slowly added and the reaction stirred at room temperature for 1 hour. Next, methyl iodide (1.9 g) was added at room temperature, and the reaction was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain 1-benzyl-4-[(t-butoxycarbonyl) methylamino] piperidine (1.2 g) as an oil.
(2) A methanol (50 ml) solution of 1-benzyl-4-[(t-butoxycarbonyl) methylamino] piperidine (1.1 g) was ice-cooled, 20% palladium hydroxide / carbon (350 mg) was added, and hydrogen atmosphere was added. The mixture was stirred at room temperature for 7 hours. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain 4-[(t-butoxycarbonyl) methylamino] piperidine (800 mg) as amorphous.

Reference Example 19: Production of 4- (5-formyloxypentan-1-yl-oxycarbonylamino) piperidine

(1) To a solution (10 ml) of carbonyldiimidazole (0.8 g) in tetrahydrofuran is added 5-benzyloxy-1-pentanol (0.97 g) at room temperature, and the reaction mixture is stirred at room temperature for 2 hours. Were added t-butyl 4-aminopiperidine-1-carboxylate (1.0 g) and 4-dimethylaminopyridine (0.5 g), and the mixture was stirred at 60 ° C. for 14 hours. Water was added to the reaction solution to terminate the reaction, followed by extraction with ethyl acetate, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel chromatography (ethyl acetate / n-hexane) to give 1-Boc-4- (5-benzyloxypentan-1-yl-carbonylamino) piperidine (0.76 g). .
(2) 1-Boc-4- (5-benzyloxypentan-1-yl-carbonylamino) piperidine (0.76 g) in ethyl acetate (20 ml) at room temperature with 20% palladium hydroxide / carbon (0.2 g) And stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain 1-Boc-4- (5-hydroxypentan-1-yl-carbonylamino) piperidine (0.6 g).
(3) To a solution of 1-Boc-4- (5-hydroxypentan-1-yl-carbonylamino) piperidine (330 mg) in tetrahydrofuran (10 ml) at room temperature was formic acid (46 mg), triphenylphosphine (262 mg), diethylazo Dicarboxylate (174 mg) was added and stirred at room temperature for 2 hours. Water was added to the reaction solution to terminate the reaction, followed by extraction with ethyl acetate, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (chloroform-methanol) to obtain 1-Boc-4- (5-formyloxypentan-1-yl-carbonylamino) piperidine (150 mg).
(4) Concentrated hydrochloric acid (5 ml) was added to a solution of 1-Boc-4- (5-formyloxypentan-1-yl-carbonylamino) piperidine (150 mg) in ethyl acetate (25 ml) at room temperature, and the reaction solution was stirred at room temperature. Stir for 1 hour. The reaction solvent was distilled off under reduced pressure and azeotroped several times with toluene to obtain the desired hydrochloride as an amorphous substance.

Reference Example 20: Production of 4- (5-formylamino-pentan-1-yl-oxycarbonylamino) piperidine

(1) A solution of 5-amino-1-pentanol (3 g) in methylene chloride (60 ml) was ice-cooled, triethylamine (5.9 g) and benzyl chlorocarbonate (6 g) were slowly added in this order, and the reaction solution was stirred at room temperature for 14 hours. Stir. Water was added to the reaction solution and extracted with chloroform. The chloroform layer was washed with a 10% aqueous citric acid solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 5-benzyloxycarbonylamino-1-pentanol (5 g) as a white solid.
(2) To a solution of 5-benzyloxycarbonylamino-1-pentanol (5 g) in dimethylformamide (90 ml) was added carbodiimidazole (4.7 g) at room temperature, and the reaction solution was stirred at room temperature for 2 hours. Next, 4-amino-1-benzylpiperidine (5.5 g) was added at room temperature, and the reaction solution was stirred at 60 ° C. for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol), and 1-benzyl-4- (5-benzyloxycarbonylaminopentan-1-yl-oxycarbonylamino) piperidine (7.3 g) was oily. Obtained as a thing.
(3) A solution of 1-benzyl-4- (5-benzyloxycarbonylaminopentan-1-yl-oxycarbonylamino) piperidine (3.5 g) in methanol (40 ml) and ethyl acetate (40 ml) was ice-cooled, and 5% Palladium carbon-ethylenediamine complex (350 mg) was added, and the mixture was stirred at room temperature for 12 hours in a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain 1-benzyl-4- (5-aminopentan-1-yl-oxycarbonylamino) piperidine (2.3 g) as an oil.
(4) A solution of 1-benzyl-4- (5-aminopentan-1-yl-oxycarbonylamino) piperidine (2.3 g) in methylene chloride (60 ml) was ice-cooled, and then acetic anhydride (1.5 g) and formic acid were added. A solution prepared by stirring (1.3 g) at 45 ° C. for 1 hour was added, and the reaction was stirred at room temperature for 18 hours. Water was added to the reaction solution, a 2 mol / l sodium hydroxide aqueous solution was added to adjust the pH to 8, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol), and 1-benzyl-4- (5-formylaminopentan-1-yl-oxycarbonylamino) piperidine (1.6 g) as an oily substance. Obtained.
(5) A solution of 1-benzyl-4- (5-formylaminopentan-1-yl-oxycarbonylamino) piperidine (750 mg) in methanol (40 ml) was ice-cooled, and 20% palladium hydroxide / carbon (250 mg) was added. In addition, the mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain 4- (5-formylaminopentan-1-yl-oxycarbonylamino) piperidine (540 mg) as amorphous.

Reference Example 21: Production of 4-[(2-methoxycarbonylamino) ethoxycarbonylamino] piperidine-

(1) An aqueous solution (30 ml) of potassium carbonate (36 g) was added to an aqueous solution (30 ml) of ethanolamine (10 g) at room temperature, and the reaction mixture was ice-cooled, and methyl chloroformate (19 ml) was added dropwise. The reaction mixture was stirred for 6 hours under ice-cooling, saturated brine was added, and the mixture was extracted twice with chloroform, and extracted with methylene chloride and ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 2- (methoxycarbonylamino) ethanol (10 g).
(2) To a solution of 2- (methoxycarbonylamino) ethanol (10 g) in dimethylformamide (15 ml) was added carbodiimidazole (2.7 g) at room temperature, stirred at room temperature for 2 hours, and then 4-amino-1 at room temperature. -A solution of benzylpiperazine 1 (3.2 g) in dimethylformamide (25 ml) was added. After the reaction solution was stirred at 70 ° C. for 15 hours, water was added under ice-cooling, and the mixture was extracted with ethyl acetate. The obtained crude product was recrystallized from ethyl acetate-n-hexane to obtain 1-benzyl-4- [2- (methoxycarbonylamino) ethoxycarbonylamino] piperidine (2.0 g).
(3) To a solution of 1-benzyl-4- [2- (methoxycarbonylamino) ethoxycarbonylamino] piperidine (2.0 g) in methanol (35 ml), 20% palladium hydroxide / carbon (1.0 g) was added at room temperature. The mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure to obtain the desired product.

Reference Example 22: Production of 4- [4- (methylcarbonylamino) butan-1-yl-oxycarbonylamino] piperidine-

(1) 1-Benzyl-4- (4-aminobutan-1-yl-oxycarbonylamino) piperidine (2.3 g) obtained in the same manner as in Reference Example 20 (1) to (3) in methylene chloride (40 ml) The solution was ice-cooled, triethylamine (874 mg) and acetyl chloride (407 mg) were sequentially added, and the reaction mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was crystallized from ethyl acetate / n-hexane to give 1-benzyl-4- [4- (methylcarbonylamino) butan-1-yl-oxycarbonylamino] piperidine (1 g) as a white solid. It was.
(2) A solution of 1-benzyl-4- [4- (methylcarbonylamino) butan-1-yloxycarbonylamino] piperidine (1 g) in methanol (30 ml) was ice-cooled, and 20% palladium hydroxide / carbon (300 mg) ) And stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (730 mg) as amorphous.

Reference Example 23: Production of 4- [3- (aminocarbonyloxy) propan-1-yl-oxycarbonylamino] piperidine

(1) Sodium cyanate (2 g) and trifluoroacetic acid (3.6 g) were sequentially added to a toluene (60 ml) solution of 3-benzyloxy-1-propanol (2.5 g) at room temperature, and the mixture was stirred at 50 ° C. for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate to give 3-benzyloxy-1-aminocarbonyloxypropane (3.3 g) as an oil.
(2) A solution of 3-benzyloxy-1-aminocarbonyloxypropane (4.6 g) in methanol (120 ml) was ice-cooled, 20% palladium hydroxide / carbon (1.2 g) was added, and the mixture was stirred for 6 hours at room temperature in a hydrogen atmosphere. Stir. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure to give 3-hydroxy-1-aminocarbonyloxypropane (2.6 g) as an oil.
(3) To a solution of 3-hydroxy-1-aminocarbonyloxypropane (2.6 g) in dimethylformamide (80 ml) was added carbodiimidazole (3.5 g) at room temperature, and the reaction solution was stirred at room temperature for 2 hours. Next, 4-amino-1-benzylpiperidine (4.1 g) was added at room temperature, and the reaction solution was stirred at 60 ° C. for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform-methanol), and 1-benzyl-4- (3-aminocarbonyloxypropan-1-yl-oxycarbonylamino) piperidine (2.5 g) was a white solid. Got as.
(4) A solution of 1-benzyl-4- (3-aminocarbonyloxypropan-1-yl-oxycarbonylamino) piperidine (1.4 g) in methanol (40 ml) was ice-cooled and 20% palladium hydroxide / carbon (400 mg) And stirred for 14 hours at room temperature under hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (1 g) as an amorphous product.

Reference Example 24: Production of 4- [2- (ethylaminocarbonyloxy) ethoxycarbonylamino] piperidine-

(1) To a solution of 2-benzyloxyethanol (5 g) in methylene chloride (100 ml), ethyl isocyanate (2.3 g) and concentrated hydrochloric acid (1 ml) were sequentially added at room temperature, and the reaction solution was stirred at room temperature for 14 hours. Water was added to the reaction solution and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate-n-hexane) to give ethylcarbamic acid 2-benzyloxyethyl ester (4.1 g) as an oil.
(2) Ethylcarbamic acid 2-benzyloxyethyl ester (4.1 g) in methanol (80 ml) was ice-cooled, 20% palladium hydroxide / carbon (800 mg) was added, and the mixture was stirred at room temperature for 14 hours in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure to give ethylcarbamic acid 2-hydroxyethyl ester (2.4 g) as an oil.
(3) Ethylcarbamic acid 2-hydroxyethyl ester (2.4 g) in dimethylformamide (80 ml) was added with carbodiimidazole (3 g) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. Next, 4-amino-1-benzylpiperidine (3.5 g) was added at room temperature, and the reaction solution was stirred at 60 ° C. for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The residue was crystallized from ethyl acetate-n-hexane to give 1-benzyl-4- [2- (ethylaminocarbonyloxy) ethoxycarbonylamino] piperidine (3.5 g) as a white solid.
(4) A methanol (40 ml) solution of 1-benzyl-4- [2- (ethylaminocarbonyloxy) ethoxycarbonylamino] piperidine (1.4 g) was ice-cooled, and 20% palladium hydroxide / carbon (400 mg) was added. The mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (1 g) as an amorphous product.

Reference Example 25: Production of 4- (4-oxoheptyloxycarbonylamino) piperidine-

(1) 4-Benzyloxybutyric acid (1.9 g), WSC (3 g), and 4-dimethylaminopyridine (0.5 g) were added to a methylene chloride solution (20 ml) of N, O-dimethylhydroxylamine hydrochloride (1.5 g). In order, the reaction was stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with dichloromethane, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate / n-hexane) to obtain 4-benzyloxy-N-methoxy-N-methyl-butyramide (1.4 g).
(2) To a solution of 4-benzyloxy-N-methoxy-N-methyl-butyramide (600 mg) in ethyl acetate (20 ml) was added 20% palladium hydroxide / carbon (200 mg) at room temperature, and at room temperature under a hydrogen atmosphere. Stir for 1 hour. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain 4-hydroxy-N-methoxy-N-methyl-butyramide (300 mg).
(3) 4-Hydroxy-N-methoxy-N-methylbutyramide (300 mg) obtained in the previous reaction was added to a tetrahydrofuran solution (15 ml) of carbonyldiimidazole (324 mg) at room temperature, and the reaction solution was cooled to room temperature. Then, t-butyl 4-aminopiperidine-1-carboxylate (400 mg) and 4-dimethylaminopyridine (100 mg) were added to the reaction solution, and the mixture was stirred at 60 ° C. for 14 hours. Water was added to the reaction solution to terminate the reaction, followed by extraction with ethyl acetate, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (chloroform-methanol) to obtain 1-Boc-4- [3- (methoxymethylcarbamoyl) propoxycarbonylamino) piperidine (400 mg).
(4) A tetrahydrofuran solution of 1.08 mol / l n-propylmagnesium bromide in a tetrahydrofuran solution (10 ml) of 1-Boc-4- [3- (methoxymethylcarbamoyl) propoxycarbonylamino] piperidine (200 mg) at 0 ° C. (1.5 ml) was added dropwise and the reaction was stirred for 1 hour. Saturated ammonium chloride was added to the reaction solution to terminate the reaction, followed by extraction with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain 1-Boc-4- (4-oxoheptyloxycarbonylamino) piperidine (49 mg).
(5) To a solution of 1-Boc-4- (4-oxoheptyloxycarbonylamino) piperidine (150 mg) in ethyl acetate (25 ml) was added concentrated hydrochloric acid (5 ml) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. The reaction solvent was distilled off under reduced pressure and azeotroped several times with toluene to obtain the desired hydrochloride as an amorphous substance.

Reference Example 26: Production of 4-[(1,4-dioxa-spiro [4.5] decan-8-yl) oxycarbonylamino] piperidine

(1) To a solution of 1,4-cyclohexadione monoethylene acetal (3 g) in ethanol (50 ml), sodium borohydride (727 mg) was slowly added at room temperature, and the reaction solution was stirred at room temperature for 20 hours. The reaction solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1,4-dioxa-spiro [4.5] decan-8-ol (2.6 g) as an oil.
(2) To a solution of 1,4-dioxa-spiro [4.5] decan-8-ol (2.6 g) in dimethylformamide (50 ml) was added carbodiimidazole (2.7 g) at room temperature, and the reaction solution was stirred at room temperature. Stir for hours. Then 4-amino-1-benzylpiperidine (3.1 g) was added and the reaction was stirred at 60 ° C. for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) and 1-benzyl-4-[(1,4-dioxa-spiro [4.5] decan-8-yl) oxycarbonylamino]. Piperidine (3.8 g) was obtained as an oil.
(3) A solution of 1-benzyl-4-[(1,4-dioxa-spiro [4.5] decan-8-yl) oxycarbonylamino] piperidine (3.8 g) in methanol (60 ml) was ice-cooled, 10 % Palladium / carbon (800 mg) was added, and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (2.9 g) as a white solid.

Reference Example 27: Production of 4- [trans-4- (2,4-dioxo-oxazolidine-3-yl) cyclohexyloxycarbonylamino] piperidine

(1) A solution of trans-4-aminocyclohexanol (25 g) in methylene chloride (500 ml) was ice-cooled, triethylamine (76 ml) and di-t-butyl dicarbonate (52 g) were added, and the mixture was stirred at room temperature for 15 hours. did. The reaction solution was ice-cooled, saturated aqueous sodium hydrogen carbonate solution was added, extracted with chloroform, the organic layer was washed with water, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was recrystallized using ethyl acetate and n-hexane to obtain 4- (t-butoxycarbonylamino) -1-cyclohexanol (35.5 g).
(2) To a solution of 4- (t-butoxycarbonylamino) -1-cyclohexanol (23.5 g) in methylene chloride (400 ml) was added triethylamine (30 ml) and 4-nitrophenyl chloroformate (23.2 g). After stirring at room temperature for 2 hours, a solution of 4-amino-1-benzylpiperidine (21.9 g) in methylene chloride (400 ml) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 18 hours. The reaction solution was ice-cooled, water was added and the mixture was extracted with chloroform. The obtained crude product was recrystallized from ethyl acetate to obtain 1-benzyl-4- [4- (t-butoxycarbonylamino) -1-cyclohexyloxycarbonylamino] piperidine (27.6 g).
(3) To a methanol solution (30 ml) of 1-benzyl-4- [4- (t-butoxycarbonylamino) -1-cyclohexyloxycarbonylamino] piperidine (2 g) at room temperature, a hydrochloric acid-methanol solution (30 ml) was added. And stirred at room temperature for 15 hours. The reaction solution was distilled off under reduced pressure to obtain 1-benzyl-4- [4-amino-1-cyclohexyloxycarbonylamino] piperidine hydrochloride.
(4) To a solution of methyl glycolate (420 mg) in methylene chloride (20 ml), triethylamine (3.9 ml) and 4-nitrophenyl chloroformate (930 mg) were added at room temperature, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added 1-benzyl-4- [4-amino-1-cyclohexyloxycarbonylamino] piperidine obtained in the previous reaction and a solution of triethylamine (3 ml) in methylene chloride (40 ml), and the mixture was stirred at room temperature for 18 hours. . The reaction solution was ice-cooled, water was added to extract chloroform, the organic layer was washed with water three times, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from ethyl acetate-n-hexane to give 1-benzyl-4- [4- (2,4-dioxooxazolidine-3-yl) -1-cyclohexyloxycarbonylamino] piperidine. (1.2 g) was obtained.
(5) 20% of 1-benzyl-4- [4- (2,4-dioxooxazolidine-3-yl) -1-cyclohexyloxycarbonylamino] piperidine (1.2 g) in methanol (30 ml) at room temperature Palladium hydroxide / carbon (500 mg) was added, and the mixture was stirred at room temperature for 48 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure to obtain the desired product.

Reference Example 28: Production of 4- [4- (methoxycarbonylamino) cyclohexyloxycarbonylamino] piperidine-

(1) A solution of trans-4-aminohexanol (25 g) in methylene chloride (500 ml) was ice-cooled, triethylamine (76 ml) and di-t-butyl dicarbonate (52 g) were added, and the mixture was stirred at room temperature for 15 hours. . The reaction solution was ice-cooled, saturated aqueous sodium hydrogen carbonate solution was added, extracted with chloroform, the organic layer was washed with water, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was recrystallized using ethyl acetate and n-hexane to obtain trans-4- (t-butoxycarbonylamino) -1-cyclohexanol (35.5 g).
(2) To a solution of trans-4- (t-butoxycarbonylamino) -1-cyclohexanol (23.5 g) in methylene chloride (400 ml) was added triethylamine (30 ml) and 4-nitrophenyl chloroformate (23.2 g). After stirring at room temperature for 2 hours, a solution of 4-amino-1-benzylpiperidine (21.9 g) in methylene chloride (400 ml) was added to the reaction solution at room temperature, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was ice-cooled, water was added and the mixture was extracted with chloroform. The organic layer was washed with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from ethyl acetate to obtain 1-benzyl-4- [trans-4- (t-butoxycarbonylamino) -1-cyclohexyloxycarbonylamino] piperidine (27.6 g).
(3) 1-benzyl-4- [trans-4- (t-butoxycarbonylamino) -1-cyclohexyloxycarbonylamino] piperidine (31.7 g) in methanol solution (350 ml) at room temperature and hydrochloric acid methanol solution (350 ml) And stirred at room temperature for 15 hours. After evaporating the reaction solution under reduced pressure, methylene chloride (500 ml) and triethylamine (51 ml) were added at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was ice-cooled, methyl chloroformate (6.8 ml) was added, and the mixture was stirred at room temperature for 2 hr. The reaction solution was ice-cooled, water was added to extract chloroform, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from ethyl acetate to obtain 1-benzyl-4- [trans-4- (methoxycarbonylamino) -1-cyclohexyloxycarbonylamino] piperidine.
(4) To a solution of 1-benzyl-4- [trans-4- (methoxycarbonylamino) -1-cyclohexyloxycarbonylamino] piperidine in methanol (30 ml), 20% palladium hydroxide / carbon (500 mg) was added at room temperature. And stirred for 30 hours at room temperature under hydrogen atmosphere. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure to obtain the desired product.

Reference Example 29: Production of 4-aminocarbonyloxypiperidine

(1) Sodium cyanate (2 g) and trifluoroacetic acid (5.4 g) were added sequentially to a toluene (60 ml) solution of 4-hydroxy-1-benzylpiperidine (3 g) at room temperature, and the reaction solution was stirred at 50 ° C. for 12 hours. did. Water was added to the reaction liquid, 2 mol / l sodium hydroxide aqueous solution was added, pH was adjusted to 8, and chloroform extracted. The chloroform layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was crystallized from ethyl acetate / n-hexane to give 1-benzyl-4-aminocarbonyloxypiperidine (1.8 g) as a white solid.
(2) A methanol (30 ml) solution of 1-benzyl-4-aminocarbonyloxypiperidine (1 g) was ice-cooled, 20% palladium hydroxide / carbon (300 mg) was added, and the mixture was stirred at room temperature for 12 hours in a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (600 mg) as amorphous.

Reference Example 30: Production of 4- [1- (t-butoxycarbonyl) piperidin-4-yl-aminocarbonyloxy] piperidine

(1) To a solution of 1-benzyl-4-hydroxypiperidine (2 g) in methylene chloride (30 ml), triethylamine (2.9 ml) and 4-nitrophenyl chloroformate (2.2 g) were sequentially added at room temperature. Stir for hours. To the reaction solution was added 4-amino-1-Boc-piperidine (2.2 g) in methylene chloride (30 ml) at room temperature, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was ice-cooled, water was added, the mixture was extracted with chloroform, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (chloroform-methanol) to obtain 1-benzyl-4- [1- (t-butoxycarbonyl) piperidin-4-yl-carbonyloxy] piperidine (2.5 g). It was.
(2) A solution of 1-benzyl-4- [1- (t-butoxycarbonyl) piperidin-4-yl-carbonyloxy] piperidine (2.5 g) in methanol (60 ml) at room temperature with 20% palladium hydroxide / carbon ( 2.5 g) was added and stirred at room temperature for 15 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure to obtain the desired product.

Reference Example 31: Production of 4- [4- (t-butoxycarbonylamino) piperidin-1-yl-carbonyloxy] piperidine-

(1) To a solution of 1-benzyl-4-hydroxypiperidine (2 g) in methylene chloride (30 ml), triethylamine (2.9 ml) and 4-nitrophenyl chloroformate (2.2 g) were sequentially added at room temperature. Stir for hours. To the reaction solution was added 4-Boc-aminopiperidine (2.2 g) in methylene chloride (30 ml) at room temperature, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was ice-cooled, water was added, the mixture was extracted with chloroform, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (chloroform-methanol) to give 1-benzyl-4- [4- (t-butoxycarbonylamino) piperidin-1-yl-carbonyloxy] piperidine (3.09 g). Obtained.
(2) 1-benzyl-4- [4- (t-butoxycarbonylamino) piperidin-1-yl-carbonyloxy] piperidine (3.09 g) in a methanol (70 ml) solution at room temperature with 20% palladium hydroxide / carbon (3 g) was added and stirred at room temperature for 15 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure to obtain the desired product.

Reference Example 32: Production of 4-methyl-4-hydroxypiperidine-

(1) A solution of 1-benzylpiperidone (5.1 g) in diethyl ether (80 ml) was cooled to -78 ° C, methyllithium-diethyl ether solution (39 ml) was added, and the reaction solution was stirred at -78 ° C for 1.5 hours. . Water was added to the reaction solution and extracted with diethyl ether. The diethyl ether layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain 1-benzyl-4-methyl-4-hydroxypiperidine (3.8 g) as an oil.
(2) A solution of 1-benzyl-4-methyl-4-hydroxypiperidine (3.8 g) in methanol (100 ml) was ice-cooled, 20% palladium hydroxide / carbon (1 g) was added, and the mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere Stir. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, concentrated hydrochloric acid was added, and the mixture was stirred for a while. The solvent was removed under reduced pressure and azeotroped several times with toluene. The obtained crude product was crystallized from ethanol to obtain the desired hydrochloride (1.5 g).

Reference Example 33: Production of 4- (hydroxydimethylmethyl) piperidine-

(1) A solution of 1-benzylpiperidine-4-carboxylic acid ethyl ester (1.5 g) in diethyl ether (10 ml) was cooled to −78 ° C., methylmagnesium chloride-tetrahydrofuran solution (10.1 ml) was added, and the reaction solution was allowed to cool to room temperature. For 4 hours. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain 1-benzyl-4- (hydroxydimethylmethyl) piperidine (1 g) as an oil.
(2) A solution of 1-benzyl-4- (hydroxydimethylmethyl) piperidine (1 g) in methanol (20 ml) was ice-cooled, 20% palladium hydroxide / carbon (450 mg) was added, and the mixture was stirred at room temperature for 2.5 hours under a hydrogen atmosphere. did. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (600 mg) as amorphous.

Reference Example 34: Production of [4-hydroxy-4- {4- (2-methoxyethoxy) phenyl}] piperidine-

(1) To a solution of 4-bromophenol (3 g) in dimethylformamide (30 ml), 2-bromoethyl methyl ether (2.9 g) and potassium carbonate (2.9 g) were sequentially added at room temperature, and the reaction solution was stirred at 60 ° C. for 15 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain 4-bromo-1-methoxyethoxybenzene (3.1 g) as an oil.
(2) A solution of 4-bromo-1-methoxyethoxybenzene (3.1 g) in tetrahydrofuran (80 ml) was cooled to −78 ° C., n-butyllithium-hexane solution (9.2 ml) was added, and the reaction mixture was stirred for 30 minutes. did. Then 1-benzylpiperidone (2.5 g) was added and the reaction was stirred at -78 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain 1-benzyl- [4-hydroxy-4- (4-methoxyethoxyphenyl)] piperidine (1.4 g) as an oil. .
(3) A solution of 1-benzyl- [4-hydroxy-4- (4-methoxyethoxyphenyl)] piperidine (1.4 g) in methanol (70 ml) was ice-cooled, and 20% palladium hydroxide / carbon (400 mg) was added. The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (1 g) as an amorphous product.

Reference Example 35: Production of [4-hydroxy-4- (3,4,5-trimethoxyphenyl)] piperidine-

(1) A tetrahydrofuran (80 ml) solution of 5-bromo-1,2,3-trimethoxybenzene (3.3 g) is cooled to −78 ° C., an n-butyllithium-hexane solution (9.2 ml) is added, and the reaction solution Was stirred for 30 minutes. Next, 1-benzylpiperidone (2.5 g) was added and the reaction was stirred at -78 ° C for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform-methanol), and 1-benzyl- [4-hydroxy-4- (3,4,5-trimethoxyphenyl)] piperidine (3.4 g) was amorphous. Got as.
(2) A solution of 1-benzyl- [4-hydroxy-4- (3,4,5-trimethoxyphenyl)] piperidine (3.4 g) in methanol (80 ml) was ice-cooled, and 20% palladium hydroxide / carbon ( 800 mg) was added, and the mixture was stirred at room temperature for 11 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure. The crude product was crystallized from methanol to obtain the desired product (2.2 g) as a white solid.

Reference Example 36: Production of (3-phenyl-3-hydroxy) azetidine-

(1) A solution of 1-benzhydroazetan-3-ol (3 g) in methylene chloride (50 ml) was ice-cooled, molecular sieves 4Å (3 g), N-methylmorpholine oxide (2.2 g), tetrapropylammonium pearlate. Nate (221 mg) was added in turn and the reaction was stirred at room temperature for 15 hours. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain 1-benzhydroazetan-3-one (2 g) as an oil.
(2) A solution of bromobenzene (1.3 g) in tetrahydrofuran (50 ml) was cooled to −78 ° C., n-butyllithium-hexane solution (5.3 ml) was added, and the reaction solution was stirred for 30 minutes. Next, 1-benzhydroazetan-3-one (2 g) was added and the reaction was stirred at −78 ° C. for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain 1-benzhydryl- [3-phenyl-3-hydroxy] azetidine (1.3 g) as an amorphous product.
(3) A solution of 1-benzhydryl- [3-phenyl-3-hydroxy] azetidine (2 g) in methanol (50 ml) was ice-cooled, 20% palladium hydroxide / carbon (500 mg) was added, and 8% at room temperature under a hydrogen atmosphere. Stir for hours. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure. The crude product was washed with n-hexane to obtain the desired product (860 mg) as an amorphous product.

Reference Example 37: Production of 4-hydroxy-4- [N- (2-methoxyethyl) -N-methylaminomethyl] piperidine-

(1) A solution of trimethylsulfoxonium iodide (42 g) in dimethylformamide (350 ml) was ice-cooled, sodium hydride (7.6 g) was added, and the reaction solution was stirred at room temperature for 1 hour. Next, a solution of N-benzyl-4-piperidone (24.1 g) in dimethylformamide (100 ml) was added to the reaction solution, and the reaction solution was stirred at 50 ° C. for 14 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The following reaction was performed using the obtained oily crude product 6-benzyl-1-oxa-6-azaspiro [2.5] octane (22 g).
(2) A solution of 6-benzyl-1-oxa-6-azaspiro [2.5] octane (1 g) in ethanol (20 ml) was ice-cooled, and N- (2-methoxyethyl) methylamine (0.48 g) was added. The reaction was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate-n-hexane), 1-benzyl-4-hydroxy-4-[(N-methoxyethyl) methylaminomethyl] piperidine (1.1 g). Was obtained as an oil.
(3) A solution of 1-benzyl-4-hydroxy-4-[(N-methoxyethyl) methylaminomethyl] piperidine (1.1 g) in methanol (20 ml) was ice-cooled, and 20% palladium hydroxide / carbon was added, The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure to obtain the desired product (670 mg) as an oil.

Reference Example 38: Production of 3-methyl-1-oxa-3,8-diazaspiro [4.5] decane-2,4-dione

(1) To a solution of 1-benzyloxycarbonyl-4-cyano-4-hydroxypiperidine (6 g) in toluene (80 ml) was added chlorosulfonyl isocyanate (3.4 g) at room temperature, and the reaction mixture was stirred at 90 ° C. for 16 hours. The reaction solvent was evaporated under reduced pressure, ethanol (50 ml) and concentrated hydrochloric acid (4 ml) were added, and the reaction mixture was stirred with heating under reflux for 4 hours. The reaction solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) and crystallized from chloroform-n-hexane to give 1-oxa-3,8-diazaspiro [4.5] decane-2,4-dione. (4 g) was obtained as a white solid.
(2) A suspension of 60% sodium hydride (158 mg) in dimethylformamide (30 ml) was ice-cooled, and 1-oxa-3,8-diazaspiro [4.5] decane-2,4-dione (1 g) was added. In addition, the reaction was stirred at room temperature for 1 hour. Then methyl iodide (559 mg) was added and the reaction was stirred at 60 ° C. for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 8-benzyl-3-methyl-1-oxa-3,8-diazaspiro [4.5] decane-2,4-dione ( 1.2 g) was obtained as an oil.
(3) A solution of 8-benzyl-3-methyl-1-oxa-3,8-diazaspiro [4.5] decane-2,4-dione (1.2 g) in methanol (40 ml) was ice-cooled and washed with 20% water. Palladium oxide / carbon (400 mg) was added, and the mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (840 mg) as an amorphous product.

Reference Example 39: Production of 1-oxa-3- (2-hydroxyethyl) -3,8-diazaspiro [4.5] decane-2,4-dione

(1) A suspension of 60% sodium hydride (80 mg) in dimethylformamide (5 ml) was ice-cooled and 1-oxa-3,8-diazaspiro [4.5] decane obtained in Reference Example 38 (1) -2,4-dione (0.6 g) was added and the reaction was stirred at room temperature for 1 hour. Next, 2-benzyloxyethyl bromide (430 mg) was added and the reaction was stirred at room temperature for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 8-benzyl-3- (2-benzyloxyethyl) -1-oxa-3,8-diazaspiro [4.5] decane- 2,4-dione (0.4 g) was obtained as an oil.
(2) A solution of 8-benzyl-3- (2-benzyloxyethyl) -1-oxa-3,8-diazaspiro [4.5] decane-2,4-dione (0.4 g) in methanol (20 ml) was added to ice. The mixture was cooled, 20% palladium hydroxide / carbon (400 mg) was added, and the mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (230 mg) as amorphous.

Reference Example 40: Production of 3-cyclopropylmethyl-1-oxa-3,8-diazaspiro [4.5] decan-2-one

(1) A solution of 6-benzyl-1-oxa-6-aza-spiro [2.5] octane (1 g) obtained in (1) of Reference Example 37 in ethanol (15 ml) was ice-cooled and cyclopropylmethyl Amine (0.42 g) was added and the reaction was stirred at room temperature for 14 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate-n-hexane), and 1-benzyl-4-hydroxy-4-[(N-cyclopropylmethyl) aminomethyl] piperidine (1 g) was obtained. Obtained as an oil.
(2) To a solution of 1-benzyl-4-hydroxy-4-[(N-cyclopropylmethyl) aminomethyl] piperidine (1 g) in tetrahydrofuran (15 ml) at room temperature was added carbodiimidazole (0.65 g), and the reaction mixture was Stir at 60 ° C. for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol), and 8-benzyl-3-cyclopropylmethyl-1-oxa-3,8-diazaspiro [4.5] decan-2-one ( 1 g) was obtained as a white solid.
(3) A solution of 8-benzyl-3-cyclopropylmethyl-1-oxa-3,8-diazaspiro [4.5] decan-2-one (0.7 g) in methanol (20 ml) was ice-cooled and washed with 20% water. Palladium oxide / carbon was added, and the mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (0.49 g) as an oil.

Reference Example 41: Production of 4-[(4-t-butoxycarbonylamino) -butan-1-yl] -1-oxa-4,9-diazaspiro [5.5] undecan-2-one-

(1) A solution of the compound 6-benzyl-1-oxa-6-azaspiro [2.5] octane (3 g) obtained in Reference Example 37 (1) in methanol (100 ml) was ice-cooled, and N- (t-butoxy Carbonyl) -1,4-diaminobutane (2.8 g) was added and the reaction was stirred at 50 ° C. for 2 hours. The solvent was distilled off under reduced pressure, and the resulting oily product 1-benzyl-4-hydroxy-4- [4- (t-butoxycarbonylamino) butan-1-yl-aminomethyl] piperidine (5.8 g) was used. The reaction was performed.
(2) 1-Benzyl-4-hydroxy-4- [4- (t-butoxycarbonylamino) butan-1-yl-aminomethyl] piperidine (5.8 g) in dichloromethane (100 ml) in triethylamine (3 g), bromo Methyl acetate (2.5 g) was added and stirred at room temperature for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Using the resulting crude product 1-benzyl-4-hydroxy- [4- {4- (t-butoxycarbonylamino) butan-1-yl}-(t-butoxycarbonylmethyl) aminomethyl] piperidine (6 g) The following reaction was performed.
(3) 1-Benzyl-4-hydroxy- [4- {4- (t-butoxycarbonylamino) butan-1-yl}-(t-butoxycarbonylmethyl) aminomethyl] piperidine (6 g) was used without solvent. The resulting oily product was purified by silica gel column chromatography (ethyl acetate-n-hexane) and 9-benzyl-4- (4-t-butoxycarbonylamino) -butan-1-yl. -1-Oxa-4,9-diazaspiro [5.5] undecan-2-one (2.7 g) was obtained as an oil.
(4) 9-Benzyl-4- (4-t-butoxycarbonylamino] -butan-1-yl-1-oxa-4,9-diazaspiro [5.5] undecan-2-one (2.7 g) of methanol (100 ml) The solution was ice-cooled, 20% palladium hydroxide / carbon (700 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 14 hours.The reaction mixture was filtered through Celite, and the solvent was evaporated under reduced pressure to obtain the desired product (1.95 g) was obtained as an oil.

Reference Example 42: Production of 3-methyl-1,3,8-triazaspiro [4.5] decane-2,4-dione

(1) 1-Benzylpiperidone (10 g) was added to a suspension of sodium cyanide (7 g) and ammonium carbonate (49 g) in ethanol (80 ml) and water (80 ml) at room temperature. Stir for hours. The reaction solution was allowed to stand at room temperature, and the precipitated crystals were collected by filtration and washed with warm water. The obtained crude product was crystallized from ethanol to obtain 8-benzyl-1,3,8-triazaspiro [4.5] decane-2,4-dione (11 g) as a white solid.
(2) A suspension of 60% sodium hydride (540 mg) in dimethylformamide (50 ml) was ice-cooled, and 8-benzyl-1,3,8-triazaspiro [4.5] decane-2,4-dione (3.5 g) was added and the reaction was stirred at room temperature for 1 hour. Then methyl iodide (1.9 g) was added and the reaction was stirred at 60 ° C. for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol), and 8-benzyl-3-methyl-1,3,8-triazaspiro [4.5] decane-2,4-dione (1.6 g). ) Was obtained as an oil.
(3) A solution of 8-benzyl-3-methyl-1,3,8-triazaspiro [4.5] decane-2,4-dione (1.2 g) in methanol (40 ml) was ice-cooled and 20% palladium hydroxide was added. / Carbon (400 mg) was added, and the mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (800 mg) as amorphous.

Reference Example 43: Production of 1-methyl-3- (2-hydroxyethyl) -1,3,8-triazaspiro [4.5] decane-2,4-dione hydrochloride

(1) A suspension of 60% sodium hydride (0.4 g) in dimethylformamide (200 ml) was ice-cooled, and 1-benzylpiperidone in Reference Example 42 (1) was changed to 1-Boc-piperidone. 8-Boc-benzyl-1,3,8-triazaspiro [4.5] decane-2,4-dione (2.7 g) obtained using the procedure was added and the reaction was stirred at room temperature for 1 hour. Then 2-benzyloxyethyl bromide (2.2 g) was added and the reaction was stirred at 50 degrees for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol), and 8-Boc-3-benzyloxymethyl-1,3,8-triazaspiro [4.5] decane-2,4-dione ( 2.6g) was obtained as amorphous.
(2) 8-Boc-3-benzyloxymethyl-1,3,8-triazaspiro [4.5] decane-2,4-dione (1.2 g) in tetrahydrofuran (40 ml) at room temperature at 1 mol / l lithium A solution of t-butoxide in tetrahydrofuran (3 ml) was added and the reaction was stirred for 1 hour. Next, methyl iodide (0.5 g) was added at room temperature, and the mixture was stirred at 60 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) and 8-Boc-1-methyl-3-benzyloxymethyl-1,3,8-triazaspiro [4.5] decane- 2,4-dione (1.0 g) was obtained as amorphous.
(3) To a solution of 8-Boc-1-methyl-3-benzyloxymethyl-1,3,8-triazaspiro [4.5] decane-2,4-dione (1.0 g) in methanol (15 ml) at room temperature. A 10% hydrochloric acid-methanol solution (15 ml) was added, and the mixture was stirred at room temperature for 15 hours. Methanol was distilled off under reduced pressure and extracted with chloroform. After washing twice with water, the solvent was distilled off under reduced pressure to obtain the desired product (0.7 g).

Reference Example 44: Production of 1-oxa-4,8-diazaspiro [4.5] decan-3-one

(1) Glycolic acid amide (1.5 g) and pyrrolidine (0.17 ml) were added to a toluene (50 ml) solution of 1-benzylpiperidone (11.3 g) at room temperature, and the mixture was stirred at 90 ° C. for 15 hours. The reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (chloroform-methanol) to obtain 8-benzyl-1-oxa-4,8-diazaspiro [4.5] decan-3-one (1.2 g).
(2) 20% palladium hydroxide / carbon (1 g) in a solution of 8-benzyl-1-oxa-4,8-diazaspiro [4.5] decan-3-one (1.2 g) in methanol (45 ml) at room temperature And stirred at room temperature for 15 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain 1-oxa-4,8-diazaspiro [4.5] decan-3-one.

Reference Example 45: Production of 4H-1,2-dihydro-1,3-benzoxazin-4-one-2-spiro-4′-piperidine

(1) To a solution of 1-benzylpiperidone (16.6 g) in toluene (50 ml), salicylic acid amide (4 g) and pyrrolidine (0.25 ml) were added at room temperature, and the mixture was stirred at 100 ° C. for 15 hours. The reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (chloroform-methanol) to give 4H-1,2-dihydro-1,3-benzoxazin-4-one-2-spiro-4 '-(N-benzylpiperidine. ) Was obtained (5.78 g).
(2) 4H-1,2-dihydro-1,3-benzoxazin-4-one-2-spiro-4′-piperidine (1 g) in methanol (35 ml) solution at room temperature with 20% palladium hydroxide / carbon (500 mg) was added, and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure to obtain the desired product.

Reference Example 46: Production of 4- (oxazolidine-2,4-dione-3-yl) piperidine

(1) To a solution of methyl glycolate (1.5 g) in dimethylformamide (40 ml) was added carbodiimidazole (2.7 g) at room temperature, and the reaction solution was stirred at room temperature for 2 hours. Then 4-amino-1-benzylpiperidine (3.2 g) was added and the reaction was stirred at 60 ° C. for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain 1-benzyl-4- (oxazolidine-2,4-dione-3-yl) piperidine (4 g) as a white solid.
(2) A solution of 1-benzyl-4- (oxazolidine-2,4-dione-3-yl) piperidine (2 g) in methanol (60 ml) was ice-cooled, 20% palladium hydroxide / carbon (600 mg) was added, The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (1.3 g) as a white solid.

Reference Example 47: Production of 4- [5- (2-hydroxyethyl) oxazolidine-2,4-dione-3-yl] piperidine

(1) To a solution of 2-hydroxy-γ-butyrolactone (1.5 g) in dimethylformamide (30 ml) was added carbodiimidazole (2.4 g) at room temperature, and the reaction solution was stirred at room temperature for 2 hours. Then 4-amino-1-benzylpiperidine (2.8 g) was added and the reaction was stirred at 60 ° C. for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol), 1-benzyl-4- [5- (2-hydroxyethyl) oxazolidine-2,4-dione-3-yl] -piperidine ( 2.9 g) was obtained as an oil.
(2) A solution of 1-benzyl-4- [5- (2-hydroxyethyl) oxazolidine-2,4-dione-3-yl] -piperidine (2.9 g) in methanol (50 ml) was ice-cooled and washed with 20% water. Palladium oxide / carbon (800 mg) was added, and the mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure to obtain the desired product (2.1 g) as amorphous.

Reference Example 48: Production of 1- (piperidin-4-yl) -dihydropyrimidine-2,4-dione

(1) A solution of 4-amino-1-benzylpiperidine (6 g) in ethanol (100 ml) was ice-cooled, ethyl acrylate (3.5 g) was added, and the reaction mixture was stirred at 60 ° C. for 14 hours. The reaction solvent was distilled off under reduced pressure. A solution of the residue in water (100 ml) was ice-cooled, concentrated hydrochloric acid (14 ml) and sodium cyanate (6.1 g) were sequentially added, and the reaction mixture was stirred at 50 ° C. for 14 hours. The reaction mixture was ice-cooled, 1 mol / l aqueous sodium hydroxide solution was added to adjust the pH to 8, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 3- (1-piperidin-4-yl-ureido) -propionic acid ethyl ester (5.5 g) as an oil.
(2) A solution of 3- (1-piperidin-4-yl-ureido) -propionic acid ethyl ester (5.5 g) in methanol (100 ml) was ice-cooled, potassium t-butoxide (2.8 g) was added, and the reaction solution was added. Stir at room temperature for 12 hours. The reaction solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate to obtain 1- (1-benzylpiperidin-4-yl) dihydropyrimidine-2,4-dione (3.2 g) as a white solid.
(3) A solution of 1- (1-benzylpiperidin-4-yl) dihydropyrimidine-2,4-dione (1 g) in methanol (40 ml) was ice-cooled, 20% palladium hydroxide / carbon (400 mg) was added, The mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (640 mg) as an amorphous product.

Reference Example 49: Production of 4- (1-acetylimidazolidin-2-one-3-yl) piperidine-

(1) A solution of 1-benzylpiperidone (5 g) in methanol (150 ml) was ice-cooled, ethylenediamine (15.9 g) and sodium borohydride (1.2 g) were sequentially added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solvent was distilled off under reduced pressure, the residue was ice-cooled, water was added, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To a solution of the residue in acetonitrile (120 ml), carbodiimidazole (6.4 g) was added at room temperature, and the reaction solution was stirred at 60 ° C. for 14 hours. Water was added to the reaction solution and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was crystallized from ethyl acetate / n-hexane to give 1-benzyl-4- (imidazolidin-2-one-3-yl) piperidine (5.1 g) as a white solid.
(2) Acetic anhydride (3 g) and triethylamine (2.9 g) at room temperature in a solution of 1-benzyl-4- (imidazolidin-2-one-3-yl) piperidine (2.5 g) in 1,4-dioxane (60 ml) And N, N-dimethylaminopyridine (1.2 g) were sequentially added, and the reaction solution was stirred at 60 ° C. for 12 hours. Water was added to the reaction solution and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain 1-benzyl-4- (1-acetylimidazolidin-2-one-3-yl) piperidine (2 g) as a white solid. It was.
(3) A solution of 1-benzyl-4- (1-acetylimidazolidin-2-one-3-yl) piperidine (900 mg) in methanol (30 ml) was ice-cooled, and 20% palladium hydroxide / carbon (300 mg) was added. In addition, the mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (600 mg) as amorphous.

Reference Example 50: Production of 4- (1-methylimidazolidin-2,4-dione-3-yl) piperidine-

(1) A solution of 4-amino-1-benzylpiperidine (6 g) in methylene chloride (100 ml) was ice-cooled, triethylamine (6.4 g) and chloroacetyl chloride (4 g) were sequentially added, and the reaction solution was stirred at room temperature for 4 hours. did. Water was added to the reaction solution and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain 1-benzyl-4- (chloroacetylamino) piperidine (6.1 g) as a pale yellow solid.
(2) To a solution of 1-benzyl-4- (chloroacetylamino) piperidine (6.1 g) in dimethylformamide (80 ml) was added sodium cyanate (1.6 g) and tetrabutylammonium iodide (254 mg) in this order at room temperature. The solution was stirred at 90 ° C. for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain 1-benzyl-4- (imidazolidin-2,4-dione-3-yl) piperidine (3.4 g) as an amorphous substance. .
(3) A 60% sodium hydride (322 mg) dimethylformamide (30 ml) suspension was ice-cooled and 1-benzyl-4- (imidazolidin-2,4-dione-3-yl) piperidine (2 g) was added. In addition, the reaction was stirred at room temperature for 1 hour. Then methyl iodide (1.1 g) was added and the reaction was stirred at 60 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol), and 1-benzyl-4- (1-methylimidazolidin-2,4-dione-3-yl) piperidine (1 g) was obtained as an oil. Got as.
(4) A solution of 1-benzyl-4- (1-methylimidazolidin-2,4-dione-3-yl) piperidine (1 g) in methanol (30 ml) was ice-cooled, and 20% palladium hydroxide / carbon (300 mg) ) And stirred at room temperature under a hydrogen atmosphere for 14 hours. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (680 mg) as amorphous.

Reference Example 51: Production of 4- (1-isopropyl-imidazolidin-2,4-dione-3-yl) piperidine

(1) A solution of 4-amino-1-benzylpiperidine (5 g) in tetrahydrofuran (80 m) was ice-cooled, triethylamine (4 g) and ethyl bromoacetate (4.8 g) were added in that order, and the reaction mixture was stirred at 60 ° C. for 6 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain 1-benzyl-4-ethoxycarbonylmethylaminopiperidine (6.9 g) as an oil.
(2) Triethylamine (1.3 g) and carbodiimidazole (2.1 g) were sequentially added to a solution of isopropylamine (751 mg) in tetrahydrofuran (80 ml) at room temperature, and the reaction solution was stirred at room temperature for 1.5 hours. Next, 1-benzyl-4-ethoxycarbonylmethylaminopiperidine (3.5 g) was added at room temperature, and the reaction solution was stirred at 60 ° C. for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. A solution of the residue in methanol (60 ml) was ice-cooled, potassium t-butoxide (1.4 g) was added, and the reaction solution was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, water was added and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol), and 1-benzyl-4- (3-isopropyl-imidazolidin-2,4-dione-1-yl) piperidine (3 g) was oily. Obtained as a thing.
(3) A solution of 1-benzyl-4- (3-isopropyl-imidazolidin-2,4-dione-1-yl) piperidine (1 g) in methanol (40 ml) was ice-cooled, and 20% palladium hydroxide / carbon ( 400 mg) was added, and the mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (700 mg) as amorphous.

Reference Example 52: Production of 4- (pyrrolidin-2,5-dione-1-yl) piperidine-

(1) To a solution of 4-amino-1-benzylpiperidine (3.0 g) in acetic acid (15 ml), succinic anhydride (1.6 g) was added at room temperature and stirred at 110 ° C. for 2 hours, and acetic acid was distilled off under reduced pressure. Later, water was added for dilution. A 2 mol / l sodium hydroxide aqueous solution was added until crystals precipitated in the aqueous solution, followed by extraction with chloroform, drying of the organic layer with sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from ethyl acetate to obtain 1-benzyl-4- (pyrrolidin-2,5-dione-1-yl) piperidine (1.4 g).
(2) 20% palladium hydroxide / carbon (1 g) was added to a solution of 1-benzyl-4- (pyrrolidin-2,5-dione-1-yl) piperidine (500 mg) in methanol (20 ml) at room temperature, The mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure to obtain the desired product.

Reference Example 53: Production of 4- (1-methyl-piperazin-2,5-dione-4-yl) piperidine-

(1) To a solution of N- (chloroacetyl) glycine ethyl ester (2.8 g) in methanol (80 ml) at room temperature, triethylamine (3.2 g) and 4-amino-1-benzylpiperidine (3 g) were sequentially added, and the reaction solution was heated. Stir for 16 hours under reflux. The reaction solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate. A solution of the residue in methanol (80 ml) was ice-cooled, sodium methoxide (1.9 g) was added, and the reaction mixture was stirred with heating under reflux for 14 hr. The reaction solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate to give 1-benzyl-4- (piperazin-2,5-dione-4-yl) piperidine (1.5 g) as an oil.
(2) A solution of sodium hydride (251 mg) in tetrahydrofuran (40 ml) was ice-cooled, and 1-benzyl-4- (piperazin-2,5-dione-4-yl) piperidine (1.5 g) was added. The reaction was stirred at room temperature for 1 hour. Next, methyl iodide (889 mg) was added at room temperature, and the reaction was stirred at 60 ° C. for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 1-benzyl-4- (1-methyl-piperazin-2,5-dione-4-yl) piperidine (800 mg) as a yellow solid.
(3) A solution of 1-benzyl-4- (1-methyl-piperazin-2,5-dione-4-yl) piperidine (800 g) in methanol (30 ml) was ice-cooled, and 20% palladium hydroxide / carbon (300 mg) ) And stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (540 mg) as an amorphous product.

Reference Example 54: Production of 4- (1-methyl-piperazin-2,3-dione-4-yl) piperidine

(1) A solution of 1-benzyl-4-piperidone (5 g) in methanol (120 ml) was ice-cooled, ethylenediamine (9.5 g) and sodium borohydride (1.2 g) were added in that order, and the reaction solution was stirred at room temperature for 2 hours. Stir. The reaction solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate. Dimethyl oxalate (4.7 g) was added to the residual methanol (120 ml) at room temperature, and the reaction mixture was stirred for 14 hours under heating to reflux. The reaction solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate. A solution of the residue in methanol (80 ml) was ice-cooled, sodium methoxide (3.1 g) was added, and the reaction mixture was stirred with heating under reflux for 14 hr. The reaction solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 1-benzyl-4- (piperazin-2,3-dione-4-yl) piperidine (2.5 g) as a white solid.
(2) A solution of sodium hydride (383 mg) in tetrahydrofuran (80 ml) was ice-cooled, and 1-benzyl-4- (piperazin-2,3-dione-4-yl) piperidine (2.5 g) was added. The reaction was stirred at room temperature for 1 hour. Next, methyl iodide (1.36 g) was added at room temperature, and the reaction was stirred at 60 ° C. for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 1-benzyl-4- (1-methyl-piperazin-2,3-dione-4-yl) piperidine (800 mg) as a yellow solid.
(3) A solution of 1-benzyl-4- (1-methyl-piperazin-2,3-dione-4-yl) piperidine (800 g) in methanol (30 ml) was ice-cooled, and 20% palladium hydroxide / carbon (300 mg) ) And stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the desired product (520 mg) as amorphous.

  Example A1: Preparation of 3- (9-iodononan-1-yl) -5,7-dimethoxyphthalide

(1) Production of 3,5, N-trimethoxy-N-methylbenzamide To a solution of 3,5-dimethoxybenzoic acid (250 g) and N, O-dimethylhydroxylamine (147 g) in pyridine (1250 ml) was cooled with ice. Lower WSC (315 g) and HOBt (93 g) were sequentially added, followed by stirring at room temperature for 14 hours. Water (1000 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed twice with a 2 mol / l aqueous sodium hydroxide solution, twice with water and once with saturated brine, filtered over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain the desired product (240 g) as an oil.
¹ H-NMR (CDCl ₃ ) δ ppm: 3.34 (3H, s), 3.60 (3H, s), 3.81 (6H, s), 6.52-6.57 (1H, m), 6.77-6.83 (2H, m)

(2) Production of 9-bromo- (1-t-butyldimethylsilyloxy) nonane To a solution of 9-bromo-1-nonanol (100 g) and imidazole (61 g) in dichloromethane (300 ml) was added t-butyldimethyl under ice cooling. Silyl chloride (74 g) was added and stirred at room temperature for 3 hours. Water (200 ml) was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed 3 times with water and once with saturated brine, filtered over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain the desired product (131 g) as an oil.
¹ H-NMR (CDCl ₃ ) δ ppm: 0.02 (6H, s), 0.87 (9H, s), 1.20-1.62 (12H, m), 1.79-1.92 (2H, m), 3.35-3.44 (2H, t, J = 7.0Hz), 3.55-3.64 (2H, t, J = 6.0Hz)

(3) Production of 10- (t-butyldimethylsilanyloxy) -1- (3,5-dimethoxyphenyl) decan-1-one Magnesium (6.4 g) was suspended in tetrahydrofuran (250 ml), and the mixture was cooled under ice-cooling. -Bromo- (1-t-butyldimethylsilyloxy) nonane (168 g) and a small amount of 1,2-dibromoethane were added, and the mixture was stirred at room temperature for 1 hour. Next, a tetrahydrofuran solution of 3,5, N-trimethoxy-N-methylbenzamide (50 g) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Saturated ammonium chloride solution (200 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed twice with water and once with saturated brine, filtered over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain the desired product (58 g) as an oil.
¹ H-NMR (CDCl ₃ ) δ ppm: 0.02 (6H, s), 0.87 (9H, s), 1.27-1.80 (16H, m), 2.87-2.94 (2H, t, J =), 3.58-3.63 (2H , t, d = 6.6Hz), 3.84 (6H, s), 6.62-6.70 (1H, m), 7.08-7.11 (2H, m)

(4) Production of (R) -10- (t-butyldimethylsilanyloxy) -1- (3,5-dimethoxyphenyl) decan-1-ol Compound 10- (t-butyldimethylsilanyloxy) -1 To a solution of-(3,5-dimethoxyphenyl) decan-1-one (92 g) in tetrahydrofuran (600 ml) under ice cooling, 5,5-diphenyl-2-methyl-3,5-propano-1,3,2- Oxazaborolidine 1.0M tetrahydrofuran solution (22 ml) was added, followed by dropwise addition of 1.0M tetrahydrofuran solution of borane / tetrahydrofuran complex, and the mixture was stirred at room temperature for 2 hours. Water (300 ml) was slowly added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed 3 times with water and once with saturated brine, filtered over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain the desired product (83 g) as an oil.
¹ H-NMR (CDCl ₃ ) δ ppm: 0.02 (6H, s), 0.87 (9H, s), 1.20-1.85 (16H, m), 3.53-3.60 (2H, t, d, J = 6.6 Hz), 3.77 (6H, s), 4.53-4.61 (1H, m), 6.33-6.36 (1H, m), 6.46-6.50 (2H, m)

(5) Production of (R) -10- (t-butyldimethylsilanyloxy) -1- (2-iodo-3,5-dimethoxyphenyl) decan-1-ol Compound 10- (t-butyldimethylsilanyl N-iodosuccinide (47 g) was added to a solution of (oxy) -1- (3,5-dimethoxyphenyl) decan-1-ol (73 g) in chloroform (700 ml), and the mixture was stirred at 50 ° C. for 15 hours. A saturated aqueous sodium thiosulfate solution (200 ml) was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed 7 times with water and once with saturated brine, filtered over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The following reaction was performed using the obtained oily crude product.

(6) Production of (R) -3- [9- (t-butyldimethylsilanyloxy) -nonan-1-yl] -5,7-dimethoxyphthalide (R) -10- (t-butyldimethylsila Nyloxy) -1- (2-iodo-3,5-dimethoxyphenyl) decan-1-ol in N, N-dimethylformamide (700 ml) solution, diisopropylethylamine (180 ml), tetrakistriphenylphosphine palladium (0) (16 g) was added, and the mixture was stirred at 90 ° C. for 63 hours in a carbon monoxide atmosphere. Water (300 ml) was slowly added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed 3 times with water and once with saturated brine, filtered over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain the desired product (58 g) as an oil.
¹ H-NMR (CDCl ₃ ) δppm: 0.04 (6H, s), 0.89 (9H, s), 1.27-1.55 (14H, m), 1.63-1.75 (1H, m), 1.92-2.04 (1H, s) , 3.57 (2H, t, J = 6.6Hz), 3.89 (3H, s), 3.95 (3H, s), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m)

(7) Preparation of (R) -3- (9-iodononan-1-yl) -5,7-dimethoxyphthalide (Example A1) (R) -3- [9- (t-butyldimethylsilanyloxy) ) -Non-1-yl] -5,7-dimethoxyphthalide (58 g) in tetrahydrofuran (700 ml) was added 10% aqueous hydrochloric acid (300 ml) and stirred at room temperature for 1 hour. Water (300 ml) was slowly added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed 3 times with water and once with saturated brine, filtered over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain the desired product (40 g) as a white solid.
¹ H-NMR (CDCl ₃ ) δ ppm: 1.25-2.10 (16H, m), 3.60-3.68 (2H, t, J = 6.6 Hz), 3.90 (3H, s), 3.95 (3H, s), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m)
Subsequently, triphenylphosphine (33 g) and imidazole (16 g) were added to a dichloromethane solution (900 ml) of (R) -3- (9-hydroxynonan-1-yl) -5,7-dimethoxyphthalide (40 g). Then, iodine (32 g) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium thiosulfate solution (300 ml) was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed twice with water and once with saturated brine, filtered over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain the desired product A1 (47 g) as a white solid.
¹ H-NMR (CDCl ₃ ) δ ppm: 1.20-2.20 (16H, m), 3.14-3.22 (2H, t, J = 6.8 Hz), 3.90 (3H, s), 3.95 (3H, s), 5.28-5.32 (1H, dd, J = 7.9Hz, 3.8Hz), 6.40-6.42 (2H, m)

Examples A2 to A7:-
Hereinafter, the compounds of Examples A2 to A7 were produced by changing 9-bromo-1-nonanol in Example A1 (2).

Example A8: Preparation of 3-methyl-3- (9-iodononan-1-yl) -5,7-dimethoxyphthalide

A solution of diisopropylamine (2.6 g) in tetrahydrofuran (70 ml) was cooled to −78 ° C., n-butyllithium (1.6M n-hexane solution, 16.2 ml) was added, and the mixture was stirred at −78 ° C. for 30 minutes. Next, at 0 ° C., the starting material was changed to 12-bromo-1-undecanol and 3- [12- (t-butyldimethylsilanyloxy) dodecane-1- obtained by using the method of A1 (6) was used. Yl] -5,7-dimethoxyphthalide (5.8 g) in tetrahydrofuran (80 ml) -hexamethylphosphoramide (30 ml) was added, and the mixture was stirred at 0 ° C. for 30 min. Next, methyl iodide (4.2 g) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 30 minutes. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate-n-hexane) and 3-methyl-3- [12- (t-butyldimethylsilanyloxy) dodecan-1-yl] -5,7-dimethoxyphthalide. (5.2 g) was obtained as an oil. Hereafter, the target object was manufactured using the method similar to Example A1 (7).
¹ H-NMR (CDCl3) δppm: 1.20-1.37 (18H, m), 1.56 (3H, s), 1.70-2.05 (4H, m), 3.16-3.21 (2H, m), 3.90 (3H, s), 3.95 (3H, s), 6.32-6.40 (2H, m)

  Next, production of the compound of the present invention will be described. In the following examples, the compounds of Examples A1 to A8 or their racemates were appropriately used depending on the stereoisomerism at the 3-position of the phthalide skeleton in the target compound and the number of side chain carbon chains.

Example 1: Production of 5,7-dimethoxy-3- [9- (4-methylpiperazin-1-yl) nonan-1-yl] phthalide

The racemate of Example Compound A1 (8.5 g) and triethylamine (36 ml) were sequentially added to a solution of the compound (6 g) obtained in Reference Example 1 in dimethylformamide (100 ml) at room temperature, and the reaction solution was stirred at room temperature for 60 hours. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain the desired product (3.1 g) as an oil.
¹ H-NMR (CDCl ₃ ) δ ppm: 1.09-1.55 (14H, m), 1.62-1.76 (1H, m), 1.90-2.05 (1H, m), 2.06-2.70 (13H, m), 3.90 (3H, s), 3.95 (3H, s), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m)

Examples 2 to 16:
Example 1 using the compounds obtained in the same manner as in Reference Examples 1 to 3, 6 (1), (2) and 51 by changing the compounds or starting materials obtained in Reference Examples 2 and 3 Example compounds described in Table 2 below were produced in the same manner as described above. The changed raw material was protected and deprotected according to the various reaction conditions described in “PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, published by John Willy and Sons, 2nd edition” as necessary.

Example 17: (R) -5,7-dimethoxy-3- [9- (4-formylpiperazine-1-
Production of [Il] nonan-1-yl] phthalide

The target product (550 mg) was obtained as a white solid in the same manner as in Example 1 using 1-formylpiperazine (307 mg).
Melting point 57-58 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δppm: 1.28-1.70 (16H, m), 1.97 (2H, br), 2.32-2.46 (8H, m), 3.37-3.40 (2H, m), 3.55-3.58 (2H, m), 3.89 (3H, s), 3.95 (3H, m), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m), 8.02 (1H, s)

Examples 18-33:-
The method similar to Example 1 using the compound obtained by the method similar to the said reference examples 4-5, 14, 21 (1) by changing the compound or starting material obtained by the said reference examples 4 and 5 Example compounds described in Table 3 below were produced.

Example 34: Preparation of (R) -5,7-dimethoxy-3- [9- (4-methoxycarbonylaminopiperazin-1-yl) nonan-1-yl] phthalide

Using the compound of Reference Example 6 (600 mg), the target product (530 mg) was obtained in the same manner as in Example 1.
Melting point 133-135 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δppm: 1.26-1.44 (14H, m), 1.62-1.74 (1H, m), 1.92-2.04 (1H, m), 2.30-2.35 (2H, m), 2.57 (4H, br), 2.82 (4H, br), 3.71 (3H, s), 3.89 (3H, s), 3.95 (3H, s), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 5.48 ( 1H, br), 6.40-6.42 (2H, m)

Examples 35-37:-
In the same manner as in Example 1 using the compounds obtained in the same manner as in Reference Examples 7 and 28 (3) to (4) by changing the compound or starting material in Reference Example 7, The example compounds listed in the table were prepared.

Example 38: Preparation of 5,7-dimethoxy-3- [9- (4-methanesulfonylaminopiperidin-1-yl) nonan-1-yl] phthalide

Using the compound (350 mg) obtained in Reference Example 8, the target product (270 mg) was obtained as an oil by the same method as in Example 1.
Melting point 121-124 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δ ppm: 1.19-1.62 (15H, m), 1.63-1.81 (2H, m), 1.90-2.12 (5H, m), 2.29 (2H, t, J = 7.7Hz), 2.84 (2H, d, J = 10.7Hz), 2.99 (3H, s), 3.27-3.40 (1H, m), 3.90 (3H, s), 3.95 (3H, s), 4.33 (1H, d, J = 7.6 Hz), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m)

Examples 39 to 42:-
Example compounds described in Table 5 below were produced in the same manner as in Example 1 except that the starting materials were changed and the compounds obtained in the same manner as in Reference Example 8 were used.

Example 43: Preparation of 5,7-dimethoxy-3- [9-{(3S) -3-formylaminopyrrolidin-1-yl} nonan-1-yl] phthalide-

Using the compound (440 mg) obtained in Reference Example 9, the target product (600 mg) was obtained as a white solid by the same method as in Example 1.
Melting point 52-54 ° C .: (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δppm: 1.27-1.67 (14H, m), 1.67 (2H, br), 2.00 (3H, br), 2.18-2.50 4H, m), 2.52-2.68 (1H, m), 2.93-2.98 (1H, m), 3.89 (3H, s), 3.95 (3H, m), 4.55 (1H, br), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.13 (1H , br), 6.40-6.42 (2H, m), 8.10 (1H, s)

Example 44: (R) -5,7-dimethoxy-3- [9-{(3S) -3- (N-methyl-N-acetylamino) pyrrolidin-1-yl} nonan-1-yl] phthalide Manufacturing

The starting material of Reference Example 11 (1) was changed to 1-benzyl- (3S) -3-aminopyrrolidine and condensed with acetic acid in the same manner as Reference Example 11 (1), followed by Reference Example 18 (1). N-methylation was performed in the same manner as described above, and the resulting compound was deprotected in the same manner as in Reference Example 11 (2). The obtained compound was reacted in the same manner as in Example 1 to obtain the target compound.
¹ H-NMR (CDCl ₃ ) δppm: 1.16-1.67 (21H, m), 1.99 (1H, m), 2.10 (3H, s), 2.11-2.52 (4H, m), 2.62 (1H, m), 3.35 -3.39 (2H, m), 3.89 (3H, s), 3.95 (3H, s), 4.37 (1H, m), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 ( 2H, m)

Example 45: Preparation of (R) -5,7-dimethoxy-3- [9- {4- (formylamino) piperidin-1-yl} nonan-1-yl] phthalide-

The starting material of Reference Example 9 was changed, and the target product was obtained as a white solid by the same method as Example 1 using the compound obtained by the same method as that of Reference Example 9.
Melting point 124-126 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δppm: 1.27-1.67 (18H, m), 1.94-2.09 (4H, m), 2.29-2.34 (2H, m), 2.84 (2H, br), 3.89 (3H, s) , 3.90-3.96 (1H, m), 3.95 (3H, m), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 5.47 (1H, br), 6.40-6.42 (2H, m), 8.13 (1H, s)

Examples 46-56:-
Example compounds described in Table 6 below in the same manner as in Example 1 using the compounds obtained in the same manner as in Reference Examples 11 and 14 by changing the above Reference Examples 10 and 11 or starting materials Manufactured.

Example 57: Preparation of (R) -5,7-dimethoxy-3- [9- {4- (ethoxycarbonylaminocarbonylamino) piperidin-1-yl} nonan-1-yl] phthalide

Using the compound (579 mg) obtained in Reference Example 12, the compound of Example 57 (750 mg) was obtained as an amorphous form in the same manner as in Example 1.
¹ H-NMR (CDCl ₃ ) δppm: 1.26-1.70 (19H, m), 1.93-2.11 (6H, m), 2.28-2.30 (2H, br), 2.78 (2H, br), 3.72 (1H, m) , 3.89 (3H, s), 3.95 (3H, m), 4.16-4.23 (2H, m), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m), 6.82 (1H, br), 7.70-7.72 (1H, br)

Example 58: Preparation of (R) -5,7-dimethoxy-3- [9- {4- (t-butylcarbonylaminocarbonylamino) piperidin-1-yl} nonan-1-yl] phthalide-

Using the compound (579 mg) obtained in Reference Example 13, the compound of Example 58 (800 mg) was obtained as an amorphous form in the same manner as in Example 1.
¹ H-NMR (CDCl ₃ ) δppm: 1.21-1.71 (25H, m), 1.94-2.12 (6H, m), 2.28-2.32 (2H, br), 2.78 (2H, br), 3.73 (1H, m) , 3.89 (3H, s), 3.95 (3H, m), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m), 7.91 (1H, br), 8.47- 8.49 (1H, br)

Examples 59-69:-
The compound obtained in Reference Example 14 or the starting material was changed, and the compound obtained in the same manner as in Reference Example 12, 13 or 14 was used, and the method described in Table 7 below was performed in the same manner as in Example 1. Example compounds were prepared.

Example 70: (R) -5,7-dimethoxy-3- [9- [4- {1- (Nt-butylaminocarbonyl) piperidin-4-yl-oxycarbonylamino} piperidine-1
-Production of yl] nonan-1-yl] phthalide-

The target product was prepared according to Method B.
(1) (R) -5,7-Dimethoxy-3- [9- {4- (N-Boc-aminopiperidin-4-yl) was prepared in the same manner as in Example 1 using the compound of Reference Example 15. -Oxycarbonylamino) piperidin-1-yl} -nonan-1-yl] phthalide (2 g) was obtained.
(2) To a methanol (30 ml) solution of the compound (2 g) obtained in (1) was added hydrochloric acid-methanol solution (30 ml) at room temperature, and the mixture was stirred at room temperature for 15 hours. The reaction solution was distilled off under reduced pressure to give (R) -5,7-dimethoxy-3- [9- {4- (piperidin-4-yl-oxycarbonylamino) piperidin-1-yl} -nonan-1-yl. ] Phthalide hydrochloride (1.5 g) was obtained. To a solution of the obtained compound (500 mg) in methylene chloride (15 ml), triethylamine (0.56 ml) and t-butyl isocyanate (0.11 ml) were sequentially added at room temperature, followed by stirring at room temperature for 1.5 hours. Water was added to the reaction solution and extracted with chloroform. The organic layer was washed with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (chloroform-methanol) and crystallized from ethyl acetate-n-hexane to obtain the desired product (300 mg).
Melting point 147-149 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δppm: 1.26-1.73 (28H, m), 1.87-2.10 (8H, m), 2.29-2.33 (2H, m), 2.84 (2H, br), 3.09-3.14 (2H, m), 3.53-3.57 (3H, m), 3.89 (3H, s), 3.95 (3H, s), 4.59-4.61 (1H, m), 4.79 (1H, br), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m)

Examples 71-93:-
The compounds obtained in Reference Examples 16 and 17 or the starting materials were changed, and the compounds obtained in the same manner as in Reference Examples 14 to 17 were used, and the results are shown in Table 8 below in the same manner as in Example 1. Example compounds were prepared.

Example 94: Preparation of (R) -5,7-dimethoxy-3- [9-{(3S) -3- (methoxycarbonylamino) pyrrolidin-1-yl} nonan-1-yl] phthalide

The compound of Example 94 was produced in the same manner as in Example 1 using the compound obtained in the same manner as in Reference Examples 21 (1) and 15 (2) by changing the starting material, Obtained.
¹ H-NMR (CDCl ₃ ) δppm: 1.27-1.46 (12H, m), 1.65-1.96 (5H, m), 2.30-2.40 (2H, m), 2.45-2.48 (2H, m), 2.59-2.65 ( 2H, m), 2.91 (1H, br), 3.65 (3H, s), 3.89 (3H, s), 3.95 (3H, s), 4.23 (1H, br), 5.17 (1H, br), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m)

Example 95: Preparation of (R) -5,7-dimethoxy-3- [9- {3- (methoxycarbonylamino) azetidin-1-yl} nonan-1-yl] phthalide-

The compound of Example 95 was produced in the same manner as in Example 1 using the compounds obtained in the same manner as in Reference Examples 21 (1) and 15 (2) by changing the starting materials.
Melting point 57-60 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δppm: 1.25-1.48 (14H, m), 1.64-1.73 (1H, m), 1.94-2.02 (1H, m), 2.39-2.42 (2H, m), 2.88 (2H, br), 3.61-3.66 (5H, m), 3.89 (3H, s), 3.95 (3H, s), 4.33-4.35 (1H, m), 5.11 (1H, br), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m)

Example 96: Preparation of (R) -5,7-dimethoxy-3- [8- {3- (methoxycarbonyl) azetidin-1-yl} octane-1-yl] phthalide-

The compound of Example 96 was produced in the same manner as in Example 1 using the compounds obtained in the same manner as in Reference Examples 21 (1) and 15 (2) by changing the starting materials.
Melting point 57-60 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δppm: 1.21-1.45 (12H, m), 1.63-1.73 (1H, m), 1.94-2.02 (1H, m), 2.41 (2H, br), 2.90 (2H, br) , 3.62-3.66 (5H, m), 3.89 (3H, s), 3.95 (3H, s), 4.33 (1H, br), 5.11 (1H, br), 5.28-5.32 (1H, dd, J = 7.4Hz , 3.5Hz), 6.40-6.42 (2H, m)

Example 97: (R) -5,7-dimethoxy-3- [9- [4- {N- (2-methoxyethoxycarbonyl) -N-methyl-amino} piperidin-1-yl] nonan-1-yl ] Production of phthalides

(1) Using the 4-[(t-butoxycarbonyl) methylamino] piperidine (800 mg) obtained in Reference Example 18, in the same manner as in Example 1, (R) -5,7-dimethoxy-3 -[9- [4- {N- (t-Butoxycarbonyl) -N-methyl-amino} piperidin-1-yl] nonan-1-yl] phthalide (1 g) was obtained as an oil.
(2) To a solution of the compound obtained in (1) (850 mg) in ethyl acetate (25 ml) was added concentrated hydrochloric acid (5 ml) at room temperature, and the reaction solution was stirred at room temperature for 1 hour. The reaction solvent was distilled off under reduced pressure and azeotroped several times with toluene to give (R) -5,7-dimethoxy-3- [9- {4- (N-methyl-amino) piperidin-1-yl} nonane-1 -Il] phthalide hydrochloride (800 mg) was obtained as amorphous.
(3) A solution of the compound (400 mg) obtained in (2) above in dimethylformamide (15 ml) was ice-cooled, and diisopropylaminoamine (510 mg) and chloroformic acid 2-methoxyethyl ester (137 mg) were added in this order. The solution was stirred at room temperature for 1 hour. Water was added to the reaction solution and extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain the desired product (270 mg) as an oil.
Melting point 57-60 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δppm: 1.26-1.45 (14H, m), 1.61-1.70 (6H, m), 2.00 (2H, m), 2.34 (2H, m), 2.80 (3H, s), 2.97 (2H, m), 3.39 (3H, s), 3.59-3.62 (2H, m), 3.89 (3H, s), 3.95 (3H, m), 4.09-4.16 (1H, m), 4.22-4.25 (2H , m), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m)

Examples 98-123:-
Example compounds described in Table 9 below were produced in the same manner as in Example 1 except that the starting materials were changed and the compounds obtained in the same manner as in Reference Examples 15 to 19 and Example 97 were used.

Examples 124-138:-
The compounds obtained in Reference Examples 19 to 24 or the starting materials were changed, and the compounds obtained in the same manner as in Reference Examples 19 to 24 were used, and the results are shown in Table 10 below in the same manner as in Example 1. Example compounds were prepared.

Example 139: Preparation of (R) -5,7-dimethoxy-3- [9- {4- (4-formylbutyloxycarbonylamino) piperidin-1-yl} -nonan-1-yl] phthalide-

(1) 4-hydroxymethyl- (N-Boc) piperidine in Reference Example 17 (1) was changed to 1,5-pentanediol, and 4- (5-hydroxypentyloxy) was used in the same manner as in Reference Example 17. Carbonylamino) piperidine was obtained, and then 5,7-dimethoxy-3- [9- {4- (5-hydroxypentyloxycarbonylamino) piperidin-1-yl} nonane- was prepared using the same method as in Example 1. 1-yl] phthalide is obtained.
(2) Oxalyl chloride (0.18 ml) was added dropwise to a methylene chloride solution (10 ml) of dimethyl sulfoxide (0.21 ml) at −78 ° C., and the reaction mixture was stirred for 10 minutes, and then 5,7-dimethoxy-3- [9 A methylene chloride solution (3 ml) of-{4- (5-hydroxypentyloxycarbonylamino) piperidin-1-yl} -nonan-1-yl] phthalide (0.5 g) was added dropwise, and the reaction solution was stirred for 1 hour. Triethylamine was added to the reaction solution, water was further added, extracted with methylene chloride, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (chloroform-methanol) to obtain the desired product (0.4 g).
¹ H-NMR (CDCl ₃ ) δppm: 1.26-2.12 (26H, m), 2.30 (2H, t, J = 8.0Hz), 2.49 (2H, t, J = 8.0Hz), 2.81-2.85 (2H, br ), 3.47-3.49 (1H, br), 3.89 (3H, s), 3.95 (3H, s) 4.06 (2H, t, J = 4.0Hz), 4.55-4.57 (1H, br), 5.28-5.31 (1H , dd, J = 7.8Hz, 3.8Hz), 6.41 (2H, d, J = 3.0Hz), 9.78 (1H, s)

Example 140: Preparation of (R) -5,7-dimethoxy-3- [9- {4- (4-oxoheptyloxycarbonylamino) piperidin-1-yl} nonan-1-yl] phthalide-

The compound of interest was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 25.
¹ H-NMR (CDCl ₃ ) δppm: 0.91 (3H, t, J = 8.0Hz), 1.26-2.06 (26H, m), 2.30 (2H, t, J = 8.0Hz), 2.39 (2H, t, J = 8.0Hz), 2.48 (2H, t, J = 8.0Hz), 2.83-2.87 (2H, br), 3.51-3.55 (1H, br), 3.90 (3H, s), 3.95 (3H, s), 4.03 -4.07 (2H, br), 4.57-4.59 (1H, br), 5.28-5.31 (1H, dd, J = 7.8Hz, 3.8Hz), 6.41 (2H, d, J = 3.0Hz)

Example 141 (135): (R) -5,7-dimethoxy-3- [9- {4- (1,4-dioxaspiro [4.5] decan-8-yloxycarbonylamino) piperidin-1-yl } Nonan-1-yl] phthalide production—

Using the compound obtained in Reference Example 26, the target product (700 mg) was obtained in the same manner as in Example 1.
Melting point 125-127 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δppm: 1.26-2.09 (30H, m), 2.27-2.32 (2H, m), 2.81 (2H, m), 3.49 (1H, m), 3.89 (3H, s), 3.94 (4H, s), 3.95 (3H, m), 4.52 (1H, br), 4.75 (1H, br), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m)

Example 142 (136): Preparation of 5,7-dimethoxy-3- [9-{(4-cyclopentyloxycarbonylamino) piperidin-1-yl} nonan-1-yl] phthalide

4-hydroxymethyl- (N-Boc) piperidine in Reference Example 17 was changed to cyclopentyl alcohol, and the target product was obtained in the same manner as in Reference Example 17 and Example 1.
Melting point 110-113 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δ ppm: 1.23-2.15 (30H, m), 2.32 (2H, t, J = 7.1 Hz), 2.78-2.92 (2H, m), 3.43-3.57 (1H, br), 3.90 (3H, s), 3.95 (3H, s), 4.45-4.54 (1H, m), 5.05-5.13 (1H, br), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40- 6.42 (2H, m)

Example 143: Preparation of (R) -5,7-dimethoxy-3- [9-{(4-hydroxycyclohexane-1-yl) oxycarbonylaminopiperidin-1-yl} nonan-1-yl] phthalide

4-hydroxymethyl-N-Boc-piperidine in Reference Example 17 was changed to 1,4-cyclohexanediol, and the target product was obtained in the same manner as in Reference Example 17 and Example 1.
Melting point 127-129 ° C (ethyl acetate)
¹ H-NMR (CDCl ₃ ) δppm: 1.26-2.07 (31H, m), 2.28-2.33 (2H, m), 2.82 (2H, m), 3.49 (1H, m), 3.71 (1H, m), 3.89 (3H, s), 3.95 (3H, m), 4.59 (1H, br), 4.72 (1H, br), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m)

Examples 144-147:-
Example 144: (R) -5,7-dimethoxy-3- [9-[{trans-4- (2,4-dioxooxazolidin-3-yl) cyclohexane-1-yl-oxycarbonylamino} piperidine- Production of 1-yl] nonan-1-yl] phthalide

Using the compound of Reference Example 27, the target product (270 mg) was obtained in the same manner as in Example 1.
Melting point 119-123 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δppm: 1.26-1.78 (21H, m), 1.92-2.16 (7H, m), 2.28-2.32 (4H, m), 2.82 (2H, br), 3.50 (1H, br) , 3.89 (3H, s), 3.95 (3H, s), 3.89-3.95 (1H, m), 4.52-4.54 (1H, m), 4.60-4.70 (3H, m), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m)

Example 145: (R) -5,7-dimethoxy-3- [8-[{trans-4- (2,4-dioxooxazolidine-3-yl) cyclohexane-1-yl-oxycarbonylamino} piperidine- Production of 1-yl] octane-1-yl] phthalide

Using the compound obtained in Reference Example 27, the desired product was obtained in the same manner as in Example 1.
Melting point 123-129 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δppm: 1.27-1.78 (19H, m), 1.92-2.16 (7H, m), 2.28-2.31 (4H, m), 2.82 (2H, br), 3.50 (1H, br) , 3.89 (3H, s), 3.95 (3H, s), 3.89-3.95 (1H, m), 4.52-4.54 (1H, m), 4.60-4.70 (3H, m), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m)

Example 146: (R) -5,7-dimethoxy-3- [9- [4- {4- (pyrrolidin-1-yl-carbonyloxy) cyclohexane-1-yl-oxycarbonylamino} piperidin-1-yl ] Nonan-1-yl] phthalide production-

Using the compound obtained in Example 143, the target product was obtained by a condensation reaction using pyrrolidine and carbodiimidazole in the same manner as in Reference Example 17.
¹ H-NMR (CDCl ₃ ) δ ppm: 1.23-1.61 (18H, m), 1.62-2.15 (16H, m), 2.30 (2H, t, J = 7.0 Hz), 2.78-2.88 (2H, m), 3.27 -3.56 (5H, m), 3.90 (3H, s), 3.95 (3H, s), 4.51-4.62 (1H, m), 4.63-4.84 (2H, m), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m)

Example 147: (R) -5,7-dimethoxy-3- [9- [4- {trans-4- (methoxycarbonylamino) cyclohexane-1-yl-oxycarbonylamino} piperidin-1-yl] nonane- Production of 1-yl] phthalide

The target product (500 mg) was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 28.
Melting point 140-144 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δppm: 1.12-1.62 (18H, m), 1.68-1.90 (1H, m), 1.90-2.10 (9H, m), 2.25-2.33 (2H, m), 2.75-2.90 ( 2H, m), 3.35-3.60 (2H, m), 3.65 (3H, s), 3.89 (3H, s), 3.95 (3H, s), 4.20-4.35 (3H, m), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m)

Examples 148-176:-
Example compounds described in Table 11 below were prepared in the same manner as in Example 1 using the compounds obtained in Reference Example 28 or the compounds obtained in the same manner as in Reference Example 28 by changing the starting materials. Manufactured.

In addition, Example 169 was manufactured in the procedure shown below according to the said method B.
(1) To a solution of Example Compound 151 (600 mg) in methanol (15 ml) was added 10% hydrochloric acid-methanol solution (15 ml) at room temperature, and the mixture was stirred at room temperature for 15 hours. Methanol was distilled off under reduced pressure to give (R) -5,7-dimethoxy-3- [9- {4- (4-aminocyclohexyloxycarbonylamino) piperidin-1-yl} nonan-1-yl] phthalide hydrochloride. Obtained.
(2) To a solution of 2- (methoxycarbonylamino) ethane-1-yl alcohol (116 mg) obtained in Reference Example 21 (1) in methylene chloride (15 ml) was added triethylamine (0.26 ml) and 4-nitrophenyl chloroformate. (200 mg) was added, and the mixture was stirred at room temperature for 2 hours, and then (R) -5,7-dimethoxy-3- [9- {4- (4-aminocyclohexyloxycarbonylamino) piperidine-1 was added to the reaction solution at room temperature. -Il} nonan-1-yl] phthalide and triethylamine (0.65 ml) in methylene chloride (400 ml) were added and stirred at room temperature for 48 hours. The reaction solution was ice-cooled, water was added and the mixture was extracted with chloroform. The obtained crude product was purified by silica gel chromatography (chloroform-methanol) and recrystallized from ethyl acetate-n-hexane to obtain the desired product (390 mg).

  Example compound 170 was also prepared in the same manner as described above.

Examples 177-178:-
In the same manner as in Example 1 except that cis-4-aminohexanol was used instead of trans-4-aminohexanol in Reference Example 28 and the starting material was changed and the compound obtained in the same manner as in Reference Example 28 was used. The Example compounds described in Table 12 below were produced by the method.

Examples 179-182:-
In place of 4-amino-1-benzylpiperidine in Reference Example 28, 4-amino-1-diphenylmethylazetidine was used, and the starting material was changed and the compound obtained in the same manner as in Reference Example 28 was used. Example compounds described in Table 13 below were prepared in the same manner as in Example 1.

Examples 183 to 186:-
Examples shown in Table 14 were produced in the same manner as in Example 147.

Examples 187-195:-
The compounds obtained in Reference Examples 29 to 31 or the starting materials were changed, and the compounds obtained in the same manner as in Reference Examples 29 to 31 were used, and the results are shown in Table 15 below by the same method as in Example 1. Example compounds were prepared.

Example 196: Preparation of (R) -5,7-dimethoxy-3- [8-{(3S) -3- (ethylaminocarbonyloxy) pyrrolidin-1-yl} octane-1-yl] phthalide-

Example 1 using (S) -3-hydroxypyrrolidine instead of 4-hydroxy-1-benzylpiperidine in Reference Example 30 and changing the starting material and using the compound obtained in the same manner as in Reference Example 30 The target product (800 mg) was produced in the same manner as above.
Melting point 117-118 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δppm: 1.10-1.14 (3H, m), 1.27-1.97 (16H, m), 2.24-2.76 (6H, m), 3.18-3.22 (2H, m), 3.89 (3H, s), 3.95 (3H, m), 4.65 (1H, br), 5.13 (1H, br), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m)

Examples 197-223:-
The same method as in Example 1 using the compounds obtained in Reference Examples 32-35, 4-hydroxy-4-phenylpiperidine or the compounds obtained in the same manner as in Reference Examples 32-35 by changing the starting materials. Example compounds described in Table 16 below were produced.

Example 224: 5,7-dimethoxy-3-methyl-3- [12- (4-hydroxy-4-
Preparation of Phenylpiperidin-1-yl) -dodecan-1-yl] phthalide

The compound of Example 224 was produced in the same manner as in Example 1 using 4-hydroxy-4-phenylpiperidine and Example A8.
Melting point 108-109 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δ ppm: 1.19-1.80 (23H, m), 1.57 (3H, s), 1.91-2.25 (6H, m), 2.42-2.44 (2H, m), 2.88 (2H, m) , 3.89 (3H, s), 3.95 (3H, s), 6.32-6.33 (1H, m), 6.39-6.40 (1H, m), 7.24-7.28 (1H, m), 7.33-7.38 (2H, m) 7.51-7.54 (2H, m)

Examples 225 to 227:-
Example compounds described in Table 17 below were prepared in the same manner as in Example 1 using the compounds obtained in Reference Example 36 or the compounds obtained in the same manner as in Reference Example 36 by changing the starting materials. Manufactured.

Examples 228 to 229:-
Example compounds described in Table 18 below were produced in the same manner as in Example 1 using DL-3- (3-pyridyl) pyrrolidine or DL-3-pyrrolidinol.

Examples 230-237:-
The compound obtained in Reference Example 37, piperidin-4-yl-methylcarbamic acid t-butyl ester, piperidin-4-yl-ethylcarbamic acid t-butyl ester or the starting material was changed in the same manner as in Reference Example 37. Example compounds described in Table 19 below were produced in the same manner as in Example 1 using the obtained compounds.

Example 238: (R) -5,7-dimethoxy-3- [9- (3-methyl-1-oxa-3,8-diazaspiro [4.5] decane-2,4-dione-8-yl) Nonan-1-yl] phthalide production

The target product (650 mg) was produced in the same manner as in Example 1 using the compound obtained in Reference Example 38.
Melting point 79-81 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δ ppm: 1.28-1.79 (14H, m), 1.96-2.20 (6H, m), 2.32-2.40 (2H, m), 2.85-2.89 (2H, m), 3.08 (3H, s), 3.89 (3H, s), 3.95 (3H, m), 5.28-5.32 (1H, dd, J = 7.9Hz, 3.7Hz), 6.40-6.42 (2H, m)

Example 239: (R) -5,7-dimethoxy-3- [9- {3- (2-hydroxyethyl) -1-oxa-3,8-diazaspiro [4.5] decane-2,4-dione −8-yl} nonan-1-yl] phthalide production—

The compound obtained in Reference Example 39 was reacted in the same manner as in Example 1 to obtain the desired product (150 mg) as amorphous.
¹ H-NMR (CDCl ₃ ) δppm: 1.26-2.10 (19H, m), 2.07-2.17 (4H, m), 2.37 (2H, t, J = 7.5Hz), 2.92 (2H, t, J = 8.7Hz ), 3.72 (2H, t, J = 5.1Hz), 3.80 (2H, t, J = 5.1Hz), 3.89 (3H, s), 3.95 (3H, s), 5.28-5.32 (1H, dd, J = 7.9Hz, 3.7Hz), 6.41 (2H, d, J = 2.4Hz)

Examples 240-246:-
By changing the compound obtained in Reference Example 40 or the starting material and using the compound obtained in the same manner as in Reference Example 40, the Example compounds described in Table 20 below were prepared in the same manner as in Example 1. Manufactured.

Example 247: (R) -5,7-dimethoxy-3- [9- [4- {1- (t-butoxycarbonylamino) butyl} -1-oxa-4,9-diazaspiro [5.5] undeca −
2-On-9-yl] nonan-1-yl] phthalide-

Example 247 (34 mg) was obtained as an oil by the same method as in Example 1 using the compound (1.95 g) obtained in Reference Example 41.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.10-2.10 (33H, m), 2.20-2.81 (10H, m), 3.18 (2H, s), 3.90 (3H, s), 3.95 (3H, s), 4.04 (2H, t, J = 6.2Hz) , 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m)

Example 248: 5,7-dimethoxy-3- [9- (4-methyl-1-oxa-4,9-diazaspiro [5.5] undecan-2-one-9-yl) nonan-1-yl] Production of phthalides

A compound obtained by the same method as in Reference Example 41 was used in the same manner as in Example 1 except that methylamine was used instead of N- (t-butoxycarbonyl) -1,4-diaminobutane in Reference Example 41 (1). The compound of Example 248 was produced by the procedure.
¹ H-NMR (CDCl ₃ ) δ ppm: 1.22-2.07 (20H, m), 2.29 (3H, s), 2.39-2.82 (8H, m), 3.18 (2H, s), 3.90 (3H, s), 3.95 (3H, s), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m)

Examples 249-251:-
The compounds obtained in Reference Example 42 or the starting materials were changed, and the compounds obtained in the same manner as in Reference Examples 42 and 39 were used, and the results are shown in Table 21 below in the same manner as in Example 1. Example compounds were prepared.

Example 252: (R) -5,7-dimethoxy-3- [9- {1-methyl-3- (2-hydroxyethyl) -1,3,8-triazaspiro [4.5] decane-2,4 -Dione-8-
Il} nonan-1-yl] phthalide production

Using the compound obtained in Reference Example 43, the compound of Example 252 was obtained as an amorphous product by the same method as in Example 1.
¹ H-NMR (CDCl ₃ ) δppm: 1.26-2.10 (25H, m), 2.99 (3H, s), 3.50-5.65 (2H, br), 3.72 (2H, t, J = 5.0Hz), 3.80 (2H , t, J = 5.0Hz), 3.89 (3H, s), 3.95 (3H, s), 5.28-5.31 (1H, dd, J = 7.9Hz, 3.7Hz), 6.42 (2H, s)

Example 253: (R) -5,7-dimethoxy-3- [8- {1-oxa-4,8-diazaspiro [4.5] decan-3-one-8-yl} octane-1-yl] Production of phthalides

Example 253 was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 44 and the compound of Example A4.
Melting point 117-119 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δppm: 1.28-1.45 (13H, m), 1.63-1.73 (1H, m), 1.81-1.90 (4H, m), 1.94-2.05 (1H, m), 2.32-2.35 ( 2H, m), 2.53 (4H, br), 3.89 (3H, s), 3.95 (3H, s), 4.26 (2H, s), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m), 7.41 (1H, br)

Example 254: (R) -5,7-dimethoxy-3- [9- (1-oxa-4,8-diazaspiro [4.5] decan-3-one-8-yl) nonan-1-yl] Production of phthalides

The compound of Example 254 was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 44.
Melting point 126-128 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δppm: 1.27-1.45 (15H, m), 1.64-1.73 (1H, m), 1.80-1.91 (4H, m), 1.94-2.02 (1H, m), 2.32-2.36 ( 2H, m), 2.52 (4H, br), 3.89 (3H, s), 3.95 (3H, s), 4.26 (2H, s), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m), 7.41 (1H, br)

Example 255: (R) -5,7-dimethoxy-3- [9-{(4H-1,2-dihydro-1,3-benzoxazin-4-one-2-spiro-4'-piperidine)- Production of 1-yl} nonan-1-yl] phthalide

Example 255 (670 mg) was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 45.
Melting point 78-80 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δppm: 1.28-1.48 (13H, m), 1.64-1.74 (1H, m), 1.90-2.10 (4H, m), 2.19-2.22 (2H, m), 2.36-2.50 ( 4H, m), 2.66 (2H, br), 3.89 (3H, s), 3.95 (3H, s), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m ), 6.85-6.98 (2H, m), 7.05-7.09 (1H, m), 7.44-7.48 (1H, m), 7.90-7.92 (1H, m)

Examples 256-258:-
Using the compounds obtained in Reference Examples 46 to 47 or changing the starting materials and using the compounds obtained in the same manner as in Reference Example 46, the methods described in Table 22 below are used in the same manner as in Example 1. Example compounds were prepared.

Examples 259-260:-
The same procedure as in Example 1 was carried out using the compound obtained in the same manner as in Reference Example 46 using 3R- or 3S-amino-1-benzylpyrrolidine instead of 4-amino-1-benzylpiperidine in Reference Example 46. By the method, the compounds shown in Table 23 below were obtained.

Examples 261 to 265:-
In the same manner as in Example 1 using the compound of Reference Example 48 or the compound obtained by the same method as in Reference Example 38 (2) to (3) or Reference Example 39 as a starting material, Table 24 The described example compounds were prepared.

Examples 266-269:-
Using Example 1 or the compound obtained in the same manner as in Reference Example 49 except that acetic anhydride in Reference Example 49 (2) was changed to N-methylation reagent or N-formylation reagent, Example 1 Example compounds described in Table 25 were produced in the same manner.

Example 270: (3R) -5,7-dimethoxy-3- [9- {4- (1-methylimidazolidin-2,4-dione-3-yl) piperidin-1-yl} nonan-1-yl ] Production of phthalides

Example 266 (800 mg) was obtained as a white solid in the same manner as in Example 1 using the compound obtained in Reference Example 50.
Melting point 92-94 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δppm: 1.27-1.74 (18H, m), 1.97-2.05 (4H, m), 2.31-2.51 (4H, m), 2.97 (3H, s), 2.98-3.02 (2H, m), 3.84-3.96 (1H, m), 3.89 (3H, s), 3.95 (3H, m), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m )

Example 271: (3R) -5,7-dimethoxy-3- [9- [4- {1- (2-hydroxyethyl) imidazolidin-2,4-dione-3-yl} piperidin-1-yl] Nonan-1-yl] phthalide production

In the same manner as in Reference Example 39 and Example 1, using 1-benzyl-4- (imidazolidin-2,4-dione-3-yl) piperidine obtained in Reference Example 50 (2), Example 271 was obtained.
¹ H-NMR (CDCl ₃ ) δppm: 1.24-1.76 (17H, m), 1.94-2.05 (4H, m), 2.28-2.50 (4H, m), 2.98-3.02 (2H, m), 3.51-3.54 ( 2H, m), 3.81-3.84 (2H, m), 3.87-3.92 (1H, m), 3.89 (3H, s), 3.95 (3H, m), 3.96 (2H, s), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m)

Examples 272 to 276:-
The compound obtained in Reference Example 51 or the compound obtained in the same manner as in Reference Example 51 by changing the isopropylamine in Reference Example 51 (2), was prepared in the same manner as in Example 1 by the following 26th method. Example compounds described in the table were prepared.

Example 277: (R) -5,7-dimethoxy-3- [9- {4- (pyrrolidine-2,5-
Dione-1-yl) piperidin-1-yl} nonan-1-yl] phthalide-

The compound of Example 277 (430 mg) was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 52.
Melting point 95-97 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δppm: 1.27-1.70 (17H, m), 1.92-2.00 (3H, m), 2.28-2.33 (2H, m), 2.44-2.58 (2H, m), 2.98-3.02 ( 2H, m), 3.89 (3H, s), 3.95 (3H, m), 3.94-4.05 (1H, m), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H , m)

Example 278: Preparation of 5,7-dimethoxy-3- [9- {4- (1,3-dihydrobenzimidazol-2-one-1-yl) piperidin-1-yl} nonan-1-yl] phthalide −

The compound of Example 278 (167 mg) was obtained as crystals by the same method as in Example 1 using 4- (2-keto-1-benzimidazolinyl) piperidine.
Melting point 105-107 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δ ppm: 1.25-1.60 (14H, m), 1.62-1.75 (1H, m), 1.84 (2H, d, J = 12.0 Hz), 1.94-2.07 (1H, m), 2.15 (2H, t, J = 11.1Hz), 2.35-2.61 (4H, m), 3.12 (2H, d, J = 10.2Hz), 3.90 (3H, s), 3.95 (3H, s), 4.31-4.40 ( 1H, m), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m), 6.96-7.16 (3H, m), 7.26-7.34 (1H, m), 10.52 (1H, s)

Example 279: Preparation of 5,7-dimethoxy-3- [9- (4-thiomorpholinyl) nonan-1-yl] phthalide

In the same manner as in Example 1 using thiomorpholine, the compound of Example 279 (167 mg) was obtained as an oil.
¹ H-NMR (CDCl ₃ ) δppm: 1.26-1.46 (12H, m), 1.64-1.67 (2H, m), 1.99 (2H, m), 2.32-2.35 (2H, m), 2.69 (8H, m) , 3.89 (3H, s), 3.95 (3H, s), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m)

Example 280: Preparation of 5,7-dimethoxy-3- [12- (1,4-dioxo-8-azaspiro [4.5] decan-8-yl) dodecan-1-yl] phthalide-

The target product (860 mg) was obtained as a white solid in the same manner as in Example 1 using 1,4-dioxo-8-azaspiro [4.5] decane (323 mg).
Melting point 107-108 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δppm: 1.19-1.78 (24H, m), 1.97-2.05 (2H, m), 2.32-2.37 (2H, m), 2.52 (4H, m), 3.89 (3H, s) , 3.95 (3H, m), 3.95 (4H, s), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m)

Example 281: (R) -5,7-dimethoxy-3- [8- {4- (1-methyl-2,5-dioxopiperazin-4-yl) piperidin-1-yl} octane-1-yl ] Production of phthalides

The target product (650 mg) was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 53.
Melting point 99-101 ° C (ethyl acetate-n-hexane)
¹ H-NMR (CDCl ₃ ) δppm: 1.24-1.78 (14H, m), 1.93-2.17 (6H, m), 2.28-2.33 (2H, m), 2.98 (3H, s), 2.98-3.02 (2H, m), 3.89 (3H, s), 3.90 (2H, s), 3.95 (3H, s), 3.98 (2H, s), 4.36-4.46 (1H, m), 5.28-5.32 (1H, dd, J = 7.4Hz, 3.5Hz), 6.40-6.42 (2H, m)

Example 282: (R) -5,7-dimethoxy-3- [8- {4- (1-methyl-2,3-dioxopiperazin-4-yl) piperidin-1-yl} octane-1-yl ] Production of phthalides

Using the compound obtained in Reference Example 54, the target product (200 mg) was obtained in the same manner as in Example 1.
¹ H-NMR (CDCl ₃ ) δppm: 1.24-1.72 (14H, m), 1.98-2.07 (6H, M), 2.30-2.35 (2H, m), 2.97-3.01 (2H, m), 3.09 (3H, s), 3.45-3.52 (4H, m), 3.89 (3H, s), 3.95 (3H, s), 4.49 (1H, m), 5.28-5.32 1H, dd, J = 7.4Hz, 3.5Hz), 6.40 -6.42 (2H, m)

Pharmacological test example
(1) Inhibition evaluation of sugar production:
Using the rat frozen primary hepatocytes manufactured by BIOPREDIC, the inhibition of the sugar production of the example compounds was evaluated according to the method described below.
The frozen hepatocytes were thawed according to the instruction manual, diluted in Seeding Medium (manufactured by BIOPREDIC), and dispensed into a 96-well collagen plate. After incubating in a 37 ° C. incubator with 5% carbon dioxide concentration for 7 hours, the medium was changed to Dulbecco MEM containing 1 mg / mL bovine serum albumin, penicillin streptomycin, 2 mM pyruvic acid, and glucose. Next day 1 mg / mL Bovine serum albumin, penicillin streptomycin, 2 mM pyruvic acid, 20 mM lactic acid, 10 μM glucagon-containing Dulbecco MEM (without glucose), after adding the medium, add the test substance to a final concentration of 0.1%. The culture was performed under the conditions for 4.5 hours.
After the culture, 10 μL of the culture supernatant was collected, and glucose was quantified using a molecular probe glucose assay kit according to the instruction manual. The results were evaluated by the inhibition rate with respect to the glucose production amount in DMSO control. It shows that the sugar production inhibitory effect of an Example compound is so strong that the density | concentration of an Example compound is low.

  As is apparent from the results of the sugar production inhibition evaluation test in the above examples, the compound of the present invention suppressed hepatic sugar production.

(2) LDL receptor, G6Pase, PEPCK expression test
Using HepG2 cells (obtained from ATCC), the expression level of LDL receptor, the expression level of G6Pase and the expression level of PEPCK are evaluated according to the method described below.
HepG2 is diluted to 3 × 10 ⁵ cells / mL in a medium composed of MEM Earle's salt containing 10% FBS, non-essential amino acids, pyruvate, and penicillin streptomycin, and dispensed into a 12-well polystyrene culture plate. Incubate for 3 days in a 37 ° C incubator with 5% carbon dioxide. Thereafter, the medium is replaced with a medium composed of MEM Earle's salt containing 1 mg / mL bovine serum albumin, non-essential amino acids, pyruvate, and penicillin streptomycin, and further cultured in a 37 ° C. incubator with 5% carbon dioxide concentration for 24 hours. Thereafter, the test substance is added to a final concentration of 0.1%, and cultured under the same conditions for 2 hours.
After culturing, total RNA is obtained using TRIzol (Invitrogen) according to the instruction manual. The total RNA obtained is reverse transcribed using the Superscript First Strand System (Invitrogen).
The obtained cDNA is quantified with Cyber Green Reagent (Applied Biosystems) using a 7900HT Fast real-time PCR system manufactured by Applied Biosystems. Follow the instruction manual. The results are evaluated by standardizing with each mRNA of LDL receptor, G6Pase, and PEPCK with respect to the amount of control mRNA (β-actin). Table 28 shows the primer sequences for β-actin, LDL receptor, G6Pase and PEPCK quantification used at this time.

(3) Evaluation for LDL receptor activity increasing action:
Using human liver cancer cells HepG2 obtained from ATCC, the test was performed according to the protocol shown below.
10% FBS, non-essential amino acids, pyruvate, diluted culture medium composed of MEM Earle's salts containing penicillin streptomycin 1.5x 10 ⁵ cells / mL, polystyrene culture plate of 96 - dispensed at 0.2mL Doo . After 3 days in a 37 ° C incubator with 5% carbon dioxide, wash 3 times with Hank's balanced salt solution containing 10 mM Hepes buffer, 1 mg / ml fatty acid-free bovine serum albumin, and penicillin streptomycin, then 5 mg / ml Lipoprotein-removed human serum, non-essential amino acids, pyruvate, penicillin streptomycin, and MEM Earle's salt containing 10 mM Hepes buffer were exchanged. Human LDL (final concentration 50 μg / mL) and a test substance were added to the medium, and cultured in a 37 ° C. incubator with a 5% carbon dioxide gas concentration for 20 hours. Wash with Hank's balanced salt solution containing 10 mM Hepes buffer, 1 mg / ml fatty acid-free bovine serum albumin and penicillin streptomycin three times, and then immediately remove 5 mg / ml lipoprotein-free human serum, non-essential amino acids, pyruvate, penicillin streptomycin Replace with MEM Earle's salt containing 10 mM Hepes buffer, and add human LDL labeled with DiI (1,1'-dilinoleyl-3,3,3 ', 3'-tetramethylindocarbocyanine perchlorate) at a final concentration of 10 μg / mL And incubated for 3 hours in a 37 ° C. incubator with 5% carbon dioxide concentration.
After incubation, the cells were fixed with glutaraldehyde. Then, after sufficiently washing with water, it was dried at 37 ° C. Next, 100 μL of DMSO was added, and the mixture was thoroughly stirred to extract DiI accumulated in the cells.
The obtained DMI containing DiI was transferred to another black 96-well plate, and the fluorescence intensity was measured with a plate reader (excitation wavelength: 544 nm, measurement wavelength: 590 nm).
The cells after extraction with DMSO were further thoroughly washed with running water, dried at 37 ° C., and stained with 0.05% methylene blue. The cells were sufficiently stained, washed with running water, and dried at 37 ° C. After completion of drying, intracellular methylene blue was extracted with 3% hydrochloric acid.
The methylene blue-containing hydrochloric acid obtained above was transferred to a transparent 96-well plate, and the absorbance was measured with a plate reader (measurement wavelength 665 nm, reference wavelength 414 nm).
The results were quantified and evaluated as follows.
DiI amount incorporated = fluorescence intensity, cell number = absorbance of methylene blue

  From the experimental results shown in Table 29, the compounds of the present invention increased LDL receptor activity. Therefore, it is clear from the results of this test that the compound of the present invention has a lipid lowering action involving the LDL receptor.

The phthalide derivative in the present invention has a glucose production inhibitory action, can correct a hyperglycemic state to a normal state, and is effective in preventing or treating diabetes. Moreover, the phthalide derivative in the present invention is effective in preventing or treating hyperlipidemia since it also has a lipid lowering action. Furthermore, since the phthalide derivative in the present invention has both the sugar production inhibitory action and the lipid lowering action, it is effective for metabolic syndrome caused by hyperglycemia or / and hyperlipidemia.

The base sequence described in SEQ ID NO: 1 is an oligonucleotide sequence used in the pharmacological test (2).

The base sequence set forth in SEQ ID NO: 2 is the sequence of the oligonucleotide used in pharmacological test (2).

The base sequence described in SEQ ID NO: 3 is an oligonucleotide sequence used in pharmacological test (2).

The base sequence described in SEQ ID NO: 4 is an oligonucleotide sequence used in pharmacological test (2).

The base sequence set forth in SEQ ID NO: 5 is the sequence of the oligonucleotide used in pharmacological test (2).

The base sequence set forth in SEQ ID NO: 6 is the sequence of the oligonucleotide used in pharmacological test (2).

The base sequence described in SEQ ID NO: 7 is the sequence of the oligonucleotide used in the pharmacological test (2).

The base sequence set forth in SEQ ID NO: 8 is the sequence of the oligonucleotide used in pharmacological test (2).

Claims (5)

A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[Wherein, R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom, an optionally substituted lower alkyl, or an optionally substituted lower alkoxy;
R ⁵ is a hydrogen atom, methyl, or ethyl;
n is an integer from 4 to 12;
A is formula (II) or formula (VII).
[(1) Formula (II)

[Wherein, X is a sulfur atom, —NR ⁶ —, or —C (R ⁷ ) (R ⁸ ) —;
p is 0, 1, or 2 (provided that when X is a sulfur atom or —NR ⁶ —, p is 1);
q is an integer of 1 or more (provided that the sum of p and q is 1, 2, or 3, but when X is a sulfur atom or —NR ⁶ —, the sum of p and q is 2 or 3));
R ⁶ is optionally substituted lower alkyl, carbonylmethyl bonded to a 5- or 6-membered saturated heterocycle, optionally substituted phenyl, optionally substituted phenyl lower alkyl, optionally substituted good 5- or 6-membered heterocycle saturated, optionally substituted phenyl-lower alkenyl optionally, -COR ¹¹ or ^-NHCOR 11 ^{{R 11,} is hydrogen atom, optionally substituted lower alkyl, optionally substituted Lower alkoxy, optionally substituted phenyl, optionally substituted amino, optionally substituted 5 or 6 membered saturated heterocyclic ring, or —OR ¹¹¹ (R ¹¹¹ is optionally substituted phenyl, substituted Phenyl lower alkyl, which may be substituted, lower alkenyl which may be substituted, or lower cycloalkyl which may be substituted. . };
R ⁷ is a hydrogen atom, hydroxy, or optionally substituted lower alkoxy;
R ⁸ represents hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, lower alkylsulfonyl, optionally substituted phenyl, optionally substituted phenyl lower alkyl, optionally substituted unsaturated. Terror ring,
-OCOR ¹¹ (R ¹¹ has the same meaning as described above),
—N (R ²² ) SO ₂ R ³³ (R ²² represents a hydrogen atom or lower alkyl, and R ³³ represents phenyl which may be substituted, lower alkyl which may be substituted, or amino which may be substituted. ),
—N (R ²² ) COR ⁴⁴ [R ²² has the same meaning as described above, and R ⁴⁴ represents a hydrogen atom, an optionally substituted lower alkyl, an optionally substituted phenyl, an optionally substituted unsaturated. Tero ring, optionally substituted 5- or 6-membered saturated hetero ring, optionally substituted lower alkoxy, optionally substituted lower cycloalkyl, optionally substituted amino, —OR ²²² {R ²²² is An optionally substituted 5- or 6-membered saturated heterocyclic ring (provided that the nitrogen atom in the saturated heterocyclic ring and the oxygen atom of —OR ²²² are not directly bonded), an optionally substituted phenyl, Optionally substituted phenyl lower alkyl, unsaturated alkyl bonded lower alkyl, optionally substituted lower alkenyl, optionally substituted lower cycloalkyl lower alkyl, 2-indanyl, or It is a lower alkyl to which a 5-membered or 6-membered saturated heterocycle optionally substituted is bonded. }, Or the following formula (III) or the following formula (IV)

{In the formula, R ³³³ is a hydrogen atom, hydroxy, —OCOR ¹¹¹¹ (R ¹¹¹¹ is a hydrogen atom; halogen atom, hydroxy, C _1-4 alkoxy, di (C _1-6 alkyl which may be substituted) amino, C _1-4 alkoxy C _2-4 alkoxy, phenyl C _1-4 alkoxy, phenoxy, C _1-6 alkylsulfonyl, C _1-6 alkoxycarbonylamino, C _1-6 alkoxycarbonyl, C _2-7 alkanoyl or C _3- Lower alkoxy optionally substituted with ₆ cycloalkyl; optionally substituted lower alkyl; optionally substituted 5- or 6-membered saturated heterocyclic ring; or optionally substituted amino.), —NHCOR ^{1111 (R 1111} are the same as defined ^{above.), - COR 1111 (R} 1111 , the same Meaning a it.), Or the following formula (V)

And r is 0 or 1. }. ],
Formula (VI)

(Where
(A) D is an oxygen atom, —NR ⁴⁴⁴ —, or —CH ₂ —;
(A) E is carbonyl and F is optionally substituted C _1-2 alkylene,
(B) E is C _1-2 alkylene which may be substituted, and F is carbonyl,
(C) E and F are methylene, or (d) E and F together with phenyl form a condensed ring;
(B) D is —CONR ⁴⁴⁴ — and E and F are methylene (wherein the nitrogen atom of NR ⁴⁴⁴ is directly bonded to F); or (C) D is —CH ₂ NR ⁴⁴⁴ —. Yes, E is C _1-2 alkylene which may be substituted, F is carbonyl (wherein R ⁴⁴⁴ is a hydrogen atom, formyl, lower alkyl which may be substituted, or lower alkanoyl; ⁴⁴⁴ is directly bonded to F.), or —CH ₂ R ⁵⁵ {R ⁵⁵ is C _1-6 alkoxy, or — (CH ₂ ) sN (R ²² ) (R ⁵⁵⁵ ) (R ²² has the same meaning as above, R ⁵⁵⁵ is optionally substituted phenyl lower alkyl, lower alkoxycarbonyl or lower alkyl which may be substituted,, s is 0 or 1 That.) A. Or R ⁷ and R ^{8 taken} together are —OCH ₂ CH ₂ O—. However, when R ⁷ is hydroxy, R ⁸ is not lower alkoxy. Or (2) Formula (VII)

Wherein Y is an oxygen atom, or —N (R ⁹ ) — (R ⁹ is a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower cycloalkyl, lower alkyl, optionally substituted. Phenyl lower alkyl, or lower alkyl to which an optionally substituted 5- or 6-membered saturated heterocyclic ring is bonded).
Z is —CH ₂ — or —CO— when Y is an oxygen atom, and an oxygen atom when Y is —N (R ⁹ ) — (where R ⁹ has the same meaning as described above). Or -CO-;
W is C _1-2 alkylene or — (CH ₂ ) m—NR ⁹ — (wherein R ⁹ has the same meaning as described above, m is 0 or 1, and when m is 1, NR ⁹ (However, when Z is an oxygen atom, W is — (CH ₂ ) m—NR ⁹ —), or W is condensed with phenyl. Forming a ring (provided that Y is —NR ⁹ — and Z is an oxygen atom);
t is 0 or 1. ). ]] X is —N (R ⁶ ) — or —C (R ⁷ ) (R ⁸ ) —;
^{R 6} wherein is an optionally substituted lower alkyl, optionally substituted phenyl, be -COR ¹¹ or -NHCOR ^11;
R ⁷ is a hydrogen atom, hydroxy, or optionally substituted lower alkoxy;
R ⁸ is optionally substituted lower alkyl, optionally substituted phenyl, optionally substituted phenyl lower alkyl, —OCOR ¹¹ , —N (R ²² ) SO ₂ R ³³ , —N (R ²² ) COR ⁴⁴ , formula (VI), or —CH ₂ R ⁵⁵ ;
n is an integer from 8 to 11;
p is 0 or 1;
q is 2, (R ¹¹ , R ²² , R ³³ , R ⁴⁴ , formulas (VI) and R ⁵⁵ have the same meaning as in claim 1), or a pharmaceutically acceptable compound thereof according to claim 1 Salt. X is —C (R ⁷ ) (R ⁸ ) —;
R ⁷ is a hydrogen atom or hydroxy;
R ⁸ is optionally substituted phenyl, —N (R ²² ) COR ⁴⁴ or formula (VI);
R ⁴⁴ is optionally substituted lower alkoxy or formula (III) (R ²² , formula (III) or formula (VI) has the same meaning as in claim 1). Claim 1 or claim 2 The described compound or a pharmaceutically acceptable salt thereof. The compound according to claim 1, wherein A is formula (VII), or a pharmaceutically acceptable salt thereof. A compound represented by the following formula (VIII) or a pharmaceutically acceptable salt thereof.

[Wherein R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group;
R ⁵ is a hydrogen atom, a methyl group, or an ethyl group;
B is a halogen atom or a hydroxy group;
n means an integer of 6 to 12. ]