JP2004250460A - Heterocyclic derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a heterocyclic derivative having blood triglyceride-lowering action and LDL-C (low density lipoprotein cholesterol) lowering action and also having hypoglycemic effect, blood insulin lowering effect, HDL-C (high density lipoprotein cholesterol) lowering effect or arteriosclerotic index lowering effect, and thereby useful for preventing and treating hyperlipemia, hypertension, arteriosclerosis, diabetes, adiposis, and the like. <P>SOLUTION: An agent for preventing and treating hyperlipemia comprises the heterocyclic derivative represented by formula (1) or its pharmaceutically permissible salt as an active ingredient or comprises a new compound included in formula (1), wherein, R<SP>1</SP>is a (substituted) aryl, or the like; Het is a bivalent aromatic heterocyclic group; D is an alkylene, an alkenylene, an alkynylene, or the like; E is 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dioxanyl, or the like, which are each substituted with carboxy, an alkoxycarbonyl, hydroxymethyl or N-hydroxycarbamoyl. <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

  The present invention relates to a novel heterocyclic derivative and a pharmaceutically acceptable salt thereof.

  The compound of the present invention has a blood triglyceride lowering effect and a low density lipoprotein cholesterol (hereinafter, referred to as LDL-C) lowering effect, and further has a blood glucose lowering effect, a blood insulin lowering effect, or a high density lipoprotein cholesterol (hereinafter, referred to as LDL-C). HDL-C) or an atherosclerosis index [ratio of non-high-density lipoprotein cholesterol to HDL-C, and is calculated by (total cholesterol value-HDL-C value) / HDL-C value. It has a lowering effect and is useful for the prevention or treatment of coronary artery disease, cerebral infarction, hyperlipidemia, arteriosclerosis, diabetes and the like.

  As a multi-risk group with a high incidence of ischemic heart disease, the insulin resistance syndrome accompanied by abnormal glucose / lipid metabolism and hypertension has attracted attention. Insulin resistance syndrome is a condition that is present in many patients with obesity and non-insulin dependent diabetes mellitus (NIDDM). The lipid metabolism abnormality observed here is mainly an increase in blood triglyceride level and a decrease in HDL-C level due to an increase in chylomicron, ultra-low-density lipoprotein and their intermediate metabolite, remnant lipoprotein (Diabetes, 37, 1595-1607 (1988); Arch. Intern. Med., 149, 1514-1520 (1989); Diabetes Care, 14, 173-194 (1991)).

  Although the possibility that blood triglyceride levels may be an important risk factor for atherosclerotic disease has been discussed more than before, a clear link has not been established. However, recent results using arteriography have been reported to be an independent risk factor for ischemic heart disease (Circulation, 90, 2230-2235, (1994)).

  It is well known from many epidemiological studies that HDL-C level is inversely correlated with the frequency of ischemic heart disease (Circulation, 79, 8-15 (1989)). High-density lipoproteins are thought to reverse cholesterol transfer from extrahepatic tissues to the liver, and have been shown to have anti-atherogenic effects in animal experiments (J. Clin. Invest., 85, 1234-1241 ( 1990); Nature, 353, 265-267 (1991)).

  Large-scale intervention studies have confirmed that blood total cholesterol levels, especially LDL-C levels, are positively correlated with the frequency of onset of ischemic heart disease, and that reducing these decreases the incidence (Lipid Research Clinics Program: JAMA, 251, 351 (1984); Lipid Research Clinics Program: JAMA, 251, 365 (1984)).

  Accordingly, compounds that lower blood triglyceride levels and LDL-C levels and increase HDL-C levels or lower the arteriosclerosis index are useful as anti-atherosclerotic agents, especially as preventive or therapeutic agents for ischemic heart disease. is there. In addition, compounds that improve insulin resistance can reduce blood glucose and blood insulin levels and become other risk factors for arteriosclerotic diseases, such as diabetes, hyperinsulinemia, hypertension, and obesity. It is considered that by improving the condition, an effective preventive or therapeutic effect of arteriosclerosis is exhibited.

  Heretofore, a 2-aryl-5-alkyloxazole derivative or a 2-aryl-5-alkylthiazole derivative represented by the general formula (A) similar to the compound of the present invention has a blood lipid lowering action or a blood glucose lowering action. It is known.

〔式中、環Ａｒ１はアリールを表す。Ｖは酸素又は硫黄を表す。Ａｋ１は水素、アルキル又はハロアルキルを表す。Ａｋ２はアルキレンを表す。Ａｋ３はアルコキシ、アルコキシカルボニル、アシルチオ、アシルアミノ、又はアリールなどで置換されていてもよいアルキレン、アルケニレン又はアルキニレンを表す。Ｑはカルボキシ、２，４−オキサゾリンジオン−５−イル、２，４−チアゾリンジオン−５−イル又は１，２，４−オキサジアゾリジン−３，５−ジオン−２−イルを表す。環Ａｒ２は次の式〔Ｂ１〕又は式〔Ｂ２〕基で表される基である。〕

[In the formula, ring Ar1 represents aryl. V represents oxygen or sulfur. Ak1 represents hydrogen, alkyl or haloalkyl. Ak2 represents alkylene. Ak3 represents alkylene, alkenylene, or alkynylene optionally substituted with alkoxy, alkoxycarbonyl, acylthio, acylamino, or aryl. Q represents carboxy, 2,4-oxazolindione-5-yl, 2,4-thiazolindione-5-yl or 1,2,4-oxadiazolidine-3,5-dione-2-yl. Ring Ar2 is a group represented by the following formula [B1] or formula [B2]. ]

例えば、特許文献１〜５には、上記一般式（Ａ）に含まれる２，４−チアゾリジンジオン誘導体が血中脂質低下作用又は血糖低下作用を有する旨が記載されている。

For example, Patent Documents 1 to 5 describe that the 2,4-thiazolidinedione derivative contained in the general formula (A) has a blood lipid lowering action or a blood glucose lowering action.

  Patent Documents 6 to 10 describe that the 2,4-oxazolidinedione derivative contained in the general formula (A) has a blood lipid lowering action or a blood glucose lowering action.

  Patent Documents 11 to 12 describe that the 1,2,4-oxadiazolidine-3,5-dione derivative contained in the general formula (A) has a blood lipid lowering action or a blood glucose lowering action. I have.

  Patent Documents 13 to 21 describe that the carboxylic acid derivative contained in the general formula (A) has a blood lipid lowering effect or a blood glucose lowering effect.

  The compound represented by the general formula (A) has (1) a 2-aryl-5-alkyloxazole ring or a 2-aryl-5-alkylthiazole ring at one terminal, and (2) a compound at the other terminal. Having carboxy, 2,4-oxazolindione-5-yl, 2,4-thiazolindione-5-yl or 1,2,4-oxadiazolidine-3,5-dione-2-yl; and (3 ) It is characterized by having an aromatic ring such as benzene represented by ring Ar2 in the molecule.

  Patent Document 22 describes that the oxazole derivative represented by the general formula (B) has anti-arthritic activity.

〔式中、Ａｒ３は置換されたフェニル又はチエニルを表す。Ｒ²³は、水素又はアルキルを表す。Ａｋ４炭素数１〜２のアルキレンを表す。Ｒ²⁴、Ｒ²⁵は各々アルキルを表す。Ｑ１はカルボキシ、アルコキシカルボニル、カルバモイル、Ｎ−アルキルカルバモイル、又はＮ，Ｎ−ジアルキルカルバモイルを表す。〕
米国特許第５５３２２５６号明細書 国際公開第９６／０５１８６号パンフレット 特開平７−１８８２２７号公報 特開昭６１−８５３７２号公報 米国特許第５４０１７６１号明細書 特開平９−１２４６２３号公報 国際公開第９５／１８１２５号パンフレット 特開平７−１６５７３５号公報 米国特許第５４６８７６２号明細書 特開平８−９２２２８号公報 米国特許第５５１０３６０号明細書 米国特許第５４８０８９６号明細書 国際公開第９９／４６２３２５号パンフレット 国際公開第９８／００１３７号パンフレット 国際公開第９７／３１９０７号パンフレット 国際公開第９６／３８４１５号パンフレット 特開平９−３２３９８２号公報 特開平８−３２５２６４号公報 特開平５−５０７９２０号公報 米国特許第５５１０３６０号明細書 米国特許第５４８０８９６号明細書 欧州特許出願公開第２２０５７３号明細書

[Wherein, Ar3 represents substituted phenyl or thienyl. R ²³ represents hydrogen or alkyl. Ak4 represents alkylene having 1 to 2 carbon atoms. R ²⁴ and R ²⁵ each represent alkyl. Q1 represents carboxy, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, or N, N-dialkylcarbamoyl. ]
U.S. Pat. No. 5,532,256 WO 96/05186 pamphlet JP-A-7-188227 JP-A-61-85372 U.S. Pat. No. 5,410,761 JP-A-9-124623 WO 95/18125 pamphlet JP-A-7-165735 U.S. Pat. No. 5,468,762 JP-A-8-92228 U.S. Pat. No. 5,510,360 U.S. Pat. No. 5,480,896 International Publication No. 99/462325 pamphlet WO 98/00137 pamphlet WO 97/31907 pamphlet WO 96/38415 pamphlet JP-A-9-323982 JP-A-8-325264 JP-A-5-507920 U.S. Pat. No. 5,510,360 U.S. Pat. No. 5,480,896 EP-A-220573

  An object of the present invention is to have a blood triglyceride lowering action and an LDL-C lowering action, and further have a blood glucose lowering action, a blood insulin lowering action, or an HDL-C increasing action or an atherosclerosis index lowering action. An object of the present invention is to provide an excellent preventive or therapeutic agent for lipemia, arteriosclerosis, diabetes, hypertension, obesity and the like.

  The present inventors have sought for such a compound and have been conducting research. As a result, the present inventors have found that a heterocyclic derivative represented by the following formula [1] can achieve the above object, and have completed the present invention.

  Accordingly, the present invention is a heterocyclic derivative represented by the following formula [1], a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing any of them as an active ingredient.

式中、Ｒ¹はアリール、芳香族複素環基又はシクロアルキルを表す。かかるアリール又は芳香族複素環基は、１〜３個の同一又は異なるアルキル、ハロアルキル、トリハロアルキル、アルコキシ、ハロゲン又はニトロで置換されていてもよい。

In the formula, R ¹ represents an aryl, an aromatic heterocyclic group or cycloalkyl. Such an aryl or aromatic heterocyclic group may be substituted with 1 to 3 identical or different alkyl, haloalkyl, trihaloalkyl, alkoxy, halogen or nitro.

  Het represents a divalent aromatic heterocyclic group. Such aromatic heterocyclic groups may be substituted with alkyl or trihaloalkyl.

  D represents an alkylene, alkenylene, alkynylene or a group represented by the following formula [2].

ＷはＣＨ又は窒素を表す。ｍは１〜１０の整数を表し、ｎは０〜９の整数を表す。但し、ｍ＋ｎは１〜１０の範囲内である整数を表す。

W represents CH or nitrogen. m represents an integer of 1 to 10, and n represents an integer of 0 to 9. Here, m + n represents an integer in the range of 1 to 10.

  E represents a group represented by the following formula [3] or [4].

Ｙは酸素又は硫黄を表す。Ｒ³、Ｒ⁴は同一又は異なって水素又はアルキルを表す。ｐは０〜２の整数を表す。Ｚはカルボキシ、アルコキシカルボニル、ヒドロキシメチル、カルバモイル、Ｎ−ヒドロキシカルバモイル、Ｎ−アルキルカルバモイル、Ｎ，Ｎ−ジアルキルカルバモイル、シアノ、１Ｈ−５−テトラゾリル、１−アルキル−５−テトラゾリル、又は２−アルキル−５−テトラゾリルを表す。

Y represents oxygen or sulfur. R ³ and R ⁴ are the same or different and represent hydrogen or alkyl. p represents an integer of 0 to 2. Z is carboxy, alkoxycarbonyl, hydroxymethyl, carbamoyl, N-hydroxycarbamoyl, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, cyano, 1H-5-tetrazolyl, 1-alkyl-5-tetrazolyl, or 2-alkyl- Represents 5-tetrazolyl.

  However, a heterocyclic derivative in which D is a group represented by the formula [2] and E is a group represented by the formula [4] is excluded.

であり、Ｒ²²が水素、アルキル又はトリハロアルキルであり、Ｄが炭素数１〜２のアルキレンであり、Ｅが式〔４〕であり、Ｙが酸素である化合物には、公知の化合物も含まれる。しかし、式〔１〕で表される化合物が血中トリグリセリド低下作用、及びＬＤＬ−Ｃ低下作用を有し、さらに血糖低下作用、血中インスリン低下作用、又はＨＤＬ−Ｃ増加作用若しくは動脈硬化指数低下作用を併せ持つことは、本発明者らによって初めて見出された。 In the heterocyclic derivative represented by the above formula [1], Het is represented by the following formula [5z]

Wherein R ²² is hydrogen, alkyl or trihaloalkyl, D is alkylene having 1 to 2 carbon atoms, E is the formula [4], and Y is oxygen, including known compounds. It is. However, the compound represented by the formula [1] has a blood triglyceride lowering effect and an LDL-C lowering effect, and further has a blood glucose lowering effect, a blood insulin lowering effect, or an HDL-C increasing effect or a decrease in atherosclerosis index. The combination of effects was first discovered by the present inventors.

In the heterocyclic derivative represented by the above formula [1], Het is the formula [5z], D is alkylene having 1 to 2 carbon atoms, R ²² is hydrogen, alkyl or trihaloalkyl, Compounds other than those in which E is the formula [4] and Y is oxygen are novel compounds that have not been disclosed in any literature.

  Among the compounds [1] according to the present invention, preferred are compounds in which D is alkylene, alkenylene, or alkynylene having 3 to 10 carbon atoms, and one in which Het is represented by the following formula: It is a compound which is a divalent aromatic heterocyclic group represented by [5].

〔式中、Ｘは酸素、硫黄又はＮＲ⁶を表し、Ｒ⁶は水素又はアルキルを表し、Ｒ²は水素、アルキル又はトリハロアルキルを表す。〕
本発明にかかる化合物〔１〕の中で、より好ましい化合物は、Ｈｅｔが式〔５〕で表される二価の芳香族複素環基であり、Ｘが酸素、硫黄又はＮＲ⁶であり、Ｒ⁶が水素又はアルキルであり、Ｒ²が水素、アルキル又はトリハロアルキルであり、Ｄが炭素数３〜１０のアルキレン、アルケニレン又はアルキニレンである化合物である。

[Wherein, X represents oxygen, sulfur or NR ⁶ , R ⁶ represents hydrogen or alkyl, and R ² represents hydrogen, alkyl or trihaloalkyl. ]
Among the compounds [1] according to the present invention, more preferred compounds are those in which Het is a divalent aromatic heterocyclic group represented by the formula [5], X is oxygen, sulfur or NR ⁶ , ^A compound wherein ⁶ is hydrogen or alkyl, R ² is hydrogen, alkyl or trihaloalkyl, and D is alkylene, alkenylene or alkynylene having 3 to 10 carbon atoms.

Among the compounds [1] according to the present invention, more preferred compounds are those in which R ¹ is phenyl optionally substituted with ¹ to 2 alkyl, halogen, trihaloalkyl or alkoxy, and Het is represented by the following formula [ 5a], wherein D is alkylene or alkenylene having 3 to 7 carbon atoms.

〔式中、Ｘは前記と同義である。Ｒ¹⁵はアルキル又はトリハロアルキルを表す。〕
本発明にかかる化合物〔１〕の中で、さらにまた好ましい化合物は、一つには、Ｒ¹が１〜２個のアルキル、ハロゲン、トリハロアルキル又はアルコキシで置換されていてもよいフェニルであり、Ｈｅｔが式〔５ａ〕で表される二価の芳香族複素環基であり、Ｘが酸素、硫黄又はＮＲ⁶であり、Ｒ⁶が水素又はアルキルであり、Ｒ¹⁵がアルキル又はトリハロアルキルであり、Ｄが炭素数３〜５のアルキレン又はアルケニレンであり、Ｅが式〔３〕で表される基であり、ｐが１であり、Ｙが酸素であり、Ｒ³が水素又はアルキルであり、Ｚがカルボキシ又はアルコキシカルボニルである化合物であり、また一つには、Ｒ¹が１〜２個のアルキル、ハロゲン又はアルコキシで置換されていてもよいフェニルであり、Ｈｅｔが式〔５ａ〕で表される二価の芳香族複素環基であり、Ｘが酸素、硫黄又はＮＲ⁶であり、Ｒ⁶が水素又はアルキルであり、Ｒ¹⁵がアルキル又はトリハロアルキルであり、Ｄが炭素数５〜７のアルキレン、アルケニレン又はアルキニレンであり、Ｅが式〔４〕で表される基であり、Ｙが酸素であり、Ｒ³、Ｒ⁴が同一又は異なって水素又はアルキルであり、Ｚがカルボキシ又はアルコキシカルボニルである化合物である。

[Wherein, X is as defined above. R ¹⁵ represents alkyl or trihaloalkyl. ]
Among the compounds [1] according to the present invention, still further preferred compounds are, for example, phenyl in which R ¹ may be substituted with ¹ to 2 alkyl, halogen, trihaloalkyl or alkoxy, Het is a divalent aromatic heterocyclic group represented by the formula [5a], X is oxygen, sulfur or NR ⁶ , R ⁶ is hydrogen or alkyl, R ¹⁵ is alkyl or trihaloalkyl , D is an alkylene or alkenylene having 3 to 5 carbon atoms, E is a group represented by the formula [3], p is 1, Y is oxygen, R ³ is hydrogen or alkyl, A compound wherein Z is carboxy or alkoxycarbonyl; and, in one, R ¹ is phenyl optionally substituted with ¹ to 2 alkyl, halogen or alkoxy, and Het is represented by the formula [5a]. Divalent X is oxygen, sulfur or NR ⁶ , R ⁶ is hydrogen or alkyl, R ¹⁵ is alkyl or trihaloalkyl, and D is alkylene or alkenylene having 5 to 7 carbon atoms. Or a compound in which E is a group represented by the formula [4], Y is oxygen, R ³ and R ⁴ are the same or different and hydrogen or alkyl, and Z is carboxy or alkoxycarbonyl. It is.

Among the compounds [1] according to the present invention, a particularly preferred compound is phenyl, in which R ¹ is optionally substituted with ¹ to 2 alkyl or alkoxy, and Het is represented by the formula [5a]. A divalent aromatic heterocyclic group represented, X is oxygen, R ¹⁵ is alkyl, D is alkylene having 3 to 5 carbon atoms, and E is a group represented by the formula [3]. Wherein p is 1, Y is oxygen, R ³ is alkyl and Z is carboxy, and in one, R ¹ is 1-2 alkyl, halogen or alkoxy. Het is a divalent aromatic heterocyclic group represented by the formula [5a], X is oxygen, R ¹⁵ is alkyl, D is carbon number 5 ~ 7 alkylene, alkenylene or alkynylene, wherein E is represented by the formula [4] A group, Y is oxygen, R ^3, R ⁴ are the same alkyl, a compound Z is carboxy.

Preferred examples of the compound [1] according to the present invention include the following heterocyclic derivatives (1) to (14) or pharmaceutically acceptable salts thereof.
(1) 2-methyl-2- [6- (5-methyl-2-phenyloxazol-4-yl)-(E) -4-hexenyloxy] propionic acid
(2) c-5- [4- (5-Methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylic acid
(3) 2-methyl-2- [6- (5-methyl-2-phenyloxazol-4-yl) -4-hexynyloxy] propionic acid
(4) 2-isobutyl-c-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylic acid
(5) 2-ethyl-c-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylic acid
(6) 2-methyl-c-5- {4- [5-methyl-2- (4-trifluoromethylphenyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid
(7) 2-methyl-c-5- [4- (5-methyl-2-phenyloxazol-4-yl)-(E) -3-butenyl] -1,3-dioxane-r-2-carboxylic acid
(8) c-5- {4- [2- (4-tert-butylphenyl) -5-methyloxazol-4-yl] butyl} -2-methyl-1,3-dioxane-r-2-carboxylic acid
(9) 2-methyl-2- [6- (5-methyl-2-phenyloxazol-4-yl) hexyloxy] propanol
(10) 2-Methyl-2- {6- [5-methyl-2- (p-tolyl) oxazol-4-yl] hexyloxy} propionic acid
(11) 2-methyl-c-5- {4- [5-methyl-2- (p-tolyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid
(12) 2-Methyl-c-5- {4- [5-methyl-2- (3-fluoro-4-methylphenyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2- carboxylic acid
(13) 2-methyl-c-5- {4- [5-methyl-2- (m-tolyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid
(14) 2-methyl-c-5- {4- [5-methyl-2- (3,4-dimethylphenyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid In the present invention, "alkyl" refers to a linear or branched one having 1 to 7 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert. -Butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl. Particularly, straight-chain ones having 1 to 3 carbon atoms are preferable, and examples thereof include methyl, ethyl and n-propyl.

  “Haloalkyl”, “trihaloalkyl”, “alkoxy”, “alkoxycarbonyl”, “N-alkylcarbamoyl”, “N, N-dialkylcarbamoyl”, “1-alkyl-5-tetrazolyl”, and “2-alkyl- Examples of the alkyl portion of "5-tetrazolyl" include the aforementioned alkyl.

  "Cycloalkyl" includes those having 4 to 8 carbon atoms, such as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Particularly, those having 5 to 7 carbon atoms are preferable.

  As the "alkylene", a linear or branched one having 1 to 10 carbon atoms, for example, methylene, ethylene, 1-methylethylene, 2-methylethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, Heptamethylene, octamethylene, nonamethylene, and decamethylene. Those having 3 to 10 carbon atoms are preferred, and those having 3 to 7 carbon atoms are particularly preferred.

  As the "alkenylene", a linear or branched one having 2 to 10 carbon atoms, for example, ethenylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 1-pentenylene , 2-pentenylene, 3-pentenylene, 4-pentenylene, 4-methyl-3-pentenylene, 1-hexenylene, 2-hexenylene, 3-hexenylene, 4-hexenylene, 5-hexenylene, 1-heptenenylene, 2-heptenenylene, 3 -Heptenylene, 4-heptenylene, 5-heptenylene, 6-heptenylene, 1-octenylene, 2-octenylene, 3-octenylene, 4-octenylene, 5-octenylene, 6-octenylene, 7-octenylene, 1-nonenylene, 2-nonenylene , 3-nonenylene, 4-nonenylene, 5- Nenylene, 6-nonenylene, 7-nonenylene, 8-nonenylene, 1-decenylene, 2-decenylene, 3-decenylene, 4-decenylene, 5-decenylene, 6-decenylene, 7-decenylene, 8-decenylene, and 9-decenylene No. Those having 3 to 10 carbon atoms are preferred, and those having 3 to 7 carbon atoms are particularly preferred.

  “Alkynylene” includes linear or branched C 2-10 carbon atoms, for example, ethynylene, 1-propynylene, 2-propynylene, 1-butynylene, 2-butynylene, 3-butynylene, 1-pentynylene , 2-pentynylene, 3-pentynylene, 4-pentynylene, 2-methyl-3-pentynylene, 1-hexynylene, 2-hexynylene, 3-hexynylene, 4-hexynylene, 5-hexynylene, 1-heptinylene, 2-heptinylene, 3 -Heptinylene, 4-heptynylene, 5-heptynylene, 6-heptynylene, 1-octynylene, 2-octynylene, 3-octynylene, 4-octynylene, 5-octynylene, 6-octynylene, 7-octynylene, 1-noninylene, 2-noninylene , 3-noninylene, 4-noninylene, 5- Ninylene, 6-noninylene, 7-noninylene, 8-noninylene, 1-decinylene, 2-decinylene, 3-decinylene, 4-decinylene, 5-decenylene, 6-decinylene, 7-decinylene, 8-decinylene, and 9-decinylene No. Those having 3 to 10 carbon atoms are preferred, and those having 3 to 7 carbon atoms are particularly preferred.

  “Aryl” includes those having 6 to 10 carbon atoms, for example, phenyl, 1-naphthyl and 2-naphthyl. Phenyl is preferred.

  The "aromatic heterocyclic group" includes a 5- to 6-membered aromatic ring group having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, or a benzene condensed ring group thereof. For example, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-indolyl, 2-furyl, 3-furyl, 3-benzofuranyl, 2-thienyl, 3-thienyl, 3-benzothienyl, 2-oxazolyl, 2-thiazolyl , 2-benzothiazolyl, 2-imidazolyl, 4-imidazolyl, 2-benzimidazolyl, 1H-1,2,4-triazol-1-yl, 1H-tetrazol-5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl , Pyridin-1-oxide-2-yl, pyridin-1-oxide-3-yl, pyridin-1-oxide-4-yl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazine -2-yl.

  Examples of the “divalent aromatic heterocyclic group” include a 5- to 6-membered aromatic ring group having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, or a benzene condensed ring group thereof. No. For example, pyrrolylene, indolylene, furanylene, benzofuranylene, thienylene, benzothienylene, oxazolylen, thiazolylen, benzothiazolylen, imidazolylene, benzimidazolylen, 1H-1,2,4-triazolylen, pyridinylene, pyrimidinylene, pyrazinylene, 1,3,5 -Triazinylene.

  "Halogen" includes, for example, fluorine, chlorine, bromine and iodine.

  Examples of the halogen moiety of “haloalkyl” and “trihaloalkyl” include the aforementioned halogens.

  Specific examples of “trihaloalkyl” include trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, and 2,2,2-trichloroethyl.

The compound [1] of the present invention can be produced, for example, by the method described below or the method described in Examples.
Manufacturing method A
The compound [1a] of the present invention in which E is a group represented by the formula [3] and Z is alkoxycarbonyl can be produced by reacting the compound [11] with the compound [22].

〔式中、Ｒ¹、Ｈｅｔ、Ｄ、Ｙ、ｐ、Ｒ³は前記と同義である。Ｒ¹¹はアルキルを表す。〕
本反応は、通常、適当な溶媒（例えば、アセトニトリル、Ｎ，Ｎ-ジメチルホルムアミド（ＤＭＦ）などの極性溶媒、テトラヒドロフラン（ＴＨＦ）、ジエチルエーテルなどのエーテル系溶媒、クロロホルム、塩化メチレンなどのハロゲン化炭化水素系溶媒、酢酸メチル、酢酸エチルなどのエステル系溶媒、ベンゼン、トルエン、ｎ−ヘキサンなどの炭化水素系溶媒、又はこれらの混合溶媒）中、ルイス酸（例えば、三フッ化ホウ素エーテル錯塩）の存在下に、-20〜150 ℃で行うことができる。反応時間は、化合物〔１１〕及び化合物〔２２〕の種類、反応温度によって異なるが、通常、30分〜24時間が適当である。化合物〔２２〕の使用量は化合物〔１１〕に対して 1〜5倍モル量が好ましい。
製法Ｂ
Ｅが式〔４〕で表される基であり、Ｚがカルボキシである本発明化合物〔１ｂ〕は、化合物〔１２〕と化合物〔１３〕とを反応させ、つづいて酸処理することにより製造できる。

[In the formula, R ¹ , Het, D, Y, p, and R ³ have the same meanings as described above. R ¹¹ represents alkyl. ]
This reaction is usually carried out using a suitable solvent (for example, a polar solvent such as acetonitrile or N, N-dimethylformamide (DMF), an ether solvent such as tetrahydrofuran (THF) or diethyl ether, or a halogenated carbon such as chloroform or methylene chloride). A Lewis acid (eg, boron trifluoride ether complex) in a hydrogen solvent, an ester solvent such as methyl acetate or ethyl acetate, a hydrocarbon solvent such as benzene, toluene, or n-hexane, or a mixed solvent thereof. It can be carried out at -20 to 150 ° C in the presence. The reaction time varies depending on the types of the compound [11] and the compound [22] and the reaction temperature, but usually, 30 minutes to 24 hours is appropriate. The amount of compound [22] to be used is preferably 1 to 5 moles compared to compound [11].
Manufacturing method B
The compound [1b] of the present invention wherein E is a group represented by the formula [4] and Z is carboxy can be produced by reacting the compound [12] with the compound [13], followed by acid treatment. .

〔式中、Ｒ¹、Ｈｅｔ、Ｙ、Ｒ³、Ｒ⁴は前記と同義である。Ｌはハロゲン、メタンスルホニルオキシ、トルエンスルホニルオキシなどの脱離基を表す。Ｔはハロゲンを表す。Ｒ¹³、Ｒ¹⁴は同一又は異なってアルキルを表す。Ｄ¹はＤよりも炭素数が１個少ない、アルキレン、アルケニレン又はアルキニレンを表す（Ｄは前記と同義である。）。〕
化合物〔１４〕は、通常、非プロトン性溶媒（例えば、アセトニトリル、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）などの極性溶媒、テトラヒドロフラン（ＴＨＦ）、ジエチルエーテルなどのエーテル系溶媒、クロロホルム、塩化メチレンなどのハロゲン化炭化水素系溶媒、酢酸メチル、酢酸エチルなどのエステル系溶媒、ベンゼン、トルエン、ｎ−ヘキサンなどの炭化水素系溶媒又はこれらの混合溶媒）中、化合物〔１３〕をブチルリチウム又はマグネシウムなどの金属試薬と処理し、次に化合物〔１２〕とヨウ化銅又は臭化銅の存在下に、-80〜150 ℃で反応させることにより製造できる。反応時間は、化合物〔１２〕、化合物〔１３〕及び金属試薬の種類、反応温度によって異なるが、通常、30分〜24時間が適当である。金属試薬及び化合物〔１２〕の使用量は化合物〔１３〕に対して 1〜1.2 倍モル量が好ましい。

[In the formula, R ¹ , Het, Y, R ³ , and R ⁴ have the same meanings as described above. L represents a leaving group such as halogen, methanesulfonyloxy, and toluenesulfonyloxy. T represents halogen. R ¹³ and R ¹⁴ are the same or different and represent alkyl. D ¹ represents an alkylene, alkenylene or alkynylene having one less carbon atom than D (D is as defined above). ]
Compound [14] is usually prepared from an aprotic solvent (eg, a polar solvent such as acetonitrile, N, N-dimethylformamide (DMF), an ether solvent such as tetrahydrofuran (THF) and diethyl ether, chloroform, methylene chloride, etc.). Compound [13] such as butyllithium or magnesium in a halogenated hydrocarbon solvent, an ester solvent such as methyl acetate or ethyl acetate, a hydrocarbon solvent such as benzene, toluene or n-hexane, or a mixed solvent thereof. The compound can be produced by treating with a metal reagent and then reacting the compound [12] with -80 to 150 ° C in the presence of copper iodide or copper bromide. The reaction time varies depending on the type of the compound [12], the compound [13] and the metal reagent, and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of the metal reagent and the compound [12] to be used is preferably 1 to 1.2 times the molar amount of the compound [13].

Compound [1b] can be usually produced by treating with an acid (eg, hydrochloric acid) in an alcohol solvent (eg, methanol, ethanol) at −80 to 80 ° C. for 5 minutes to 24 hours.
Manufacturing method C
The compound [1c] of the present invention in which D is alkenylene in which the unsaturated bond portion is adjacent to Het can also be produced by a Wittig reaction using compound [15] and compound [16].

〔式中、Ｒ¹、Ｈｅｔ、Ｅ、Ｔは前記と同義である。Ｐｈはフェニルを表す。Ｄ²はＤよりも炭素数が２個少ないアルケニレン又は上記の式〔２〕で表される基を表す（Ｄは前記と同義である。）。〕
本反応は、通常、上記の製法Ａと同様の溶媒中、塩基（例えば、水素化ナトリウム）存在下、-20〜150 ℃で行うことができる。反応時間は、化合物〔１５〕及び化合物〔１６〕の種類、反応温度によって異なるが、通常、30分〜24時間が適当である。化合物〔１６〕の使用量は化合物〔１５〕に対して 1〜1.2倍モル量が好ましい。
製法Ｄ
Ｈｅｔが次の式〔５ａ〕

[Wherein, R ¹ , Het, E, and T have the same meanings as described above.] Ph represents phenyl. D ² represents alkenylene having two carbon atoms less than D or a group represented by the above formula [2] (D is as defined above). ]
This reaction can be usually carried out in the same solvent as in the above-mentioned Production Method A, in the presence of a base (for example, sodium hydride) at -20 to 150 ° C. The reaction time varies depending on the types of the compound [15] and the compound [16] and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of compound [16] to be used is preferably 1- to 1.2-fold the molar amount of compound [15].
Manufacturing method D
Het is expressed by the following equation [5a].

〔式中、Ｘ、Ｒ¹⁵は前記と同義である。〕
で表される基であり、Ｅが式〔３〕又は〔４〕で表される基であり、Ｚがアルコキシカルボニルである本発明化合物〔１ｄ〕は、化合物〔１７〕とオキシ塩化リン、塩化チオニル、五酸化リン、Ｄａｖｙ試薬メチル（２，４−ビス（メチルチオ）−１，３−ジチア−２，４−ジホスフェタン−２，４−ジスルフィド）、ローソン試薬（２，４−ビス（４−メトキシフェニル）−１，３−ジチア−２，４−ジホスフェタン−２，４−ジスルフィド）、アンモニア又はアルキルアミンとを反応させることによっても製造できる。オキシ塩化リン、塩化チオニル又は五酸化リンを用いるとオキサゾール誘導体が得られ、Ｄａｖｙ試薬メチル又はローソン試薬を用いるとチアゾール誘導体が得られ、アンモニア又はアルキルアミンを用いるとイミダゾール誘導体が得られる。

[Wherein, X and R ¹⁵ are as defined above. ]
Wherein E is a group represented by the formula [3] or [4], and Z is alkoxycarbonyl. Thionyl, phosphorus pentoxide, Davi reagent methyl (2,4-bis (methylthio) -1,3-dithia-2,4-diphosphetane-2,4-disulfide), Lawesson reagent (2,4-bis (4-methoxy) Phenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide), ammonia or an alkylamine. Using phosphorus oxychloride, thionyl chloride or phosphorus pentoxide gives an oxazole derivative, using a Davy reagent methyl or a Lawesson reagent gives a thiazole derivative, and using ammonia or an alkylamine gives an imidazole derivative.

〔式中、Ｒ¹、Ｄ、Ｒ¹⁵は前記と同義である。Ｅ¹は次の式〔３１〕又は式〔４１〕で表される基を表す。

式中、Ｒ³、Ｒ⁴、Ｒ¹¹、Ｙ、ｐは前記と同義である。〕
本反応は、通常、適当な溶媒（ベンゼン、トルエン、キシレンなどの炭化水素系溶媒、クロロホルム、塩化メチレンなどのハロゲン化炭化水素系溶媒、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）などの極性溶媒、テトラヒドロフラン（ＴＨＦ）、ジエチルエーテルなどのエーテル系溶媒、酢酸又はこれらの混合溶媒）中、-10〜200℃で行うことができる。反応時間は、用いる試薬（例えば、オキシ塩化リン、ローソン試薬、アルキルアミン）の種類、化合物〔１７〕の種類、反応温度によって異なるが、通常、30分〜24時間が適当である。オキシ塩化リン、塩化チオニル、五酸化リン、Ｄａｖｙ試薬メチル、ローソン試薬、アンモニア又はアルキルアミンの使用量は化合物〔１７〕に対して 1〜10倍モル量が好ましい。
製法Ｅ
Ｈｅｔが上記式〔５ａ〕であり、Ｅが式〔４〕で表される基であり、Ｚがアルコキシカルボニルである本発明化合物〔１ｅ〕は、化合物〔１８〕と化合物〔１９〕とを反応させることによっても製造できる。

Wherein R ¹ , D and R ¹⁵ are as defined above. E ¹ represents a group represented by the following formula [31] or formula [41].

In the formula, R ³ , R ⁴ , R ¹¹ , Y, and p are as defined above. ]
This reaction is usually carried out using a suitable solvent (e.g., a hydrocarbon solvent such as benzene, toluene, or xylene; a halogenated hydrocarbon solvent such as chloroform or methylene chloride; a polar solvent such as N, N-dimethylformamide (DMF); (THF), an ether solvent such as diethyl ether, acetic acid, or a mixed solvent thereof) at -10 to 200 ° C. The reaction time varies depending on the type of the reagent used (for example, phosphorus oxychloride, Lawesson's reagent, alkylamine), the type of compound [17], and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of phosphorus oxychloride, thionyl chloride, phosphorus pentoxide, Davy's reagent methyl, Lawesson's reagent, ammonia or alkylamine is preferably 1 to 10 times the molar amount of compound [17].
Manufacturing method E
The compound [1e] of the present invention in which Het is the above formula [5a], E is a group represented by the formula [4], and Z is alkoxycarbonyl, is obtained by reacting the compound [18] with the compound [19]. It can also be manufactured by performing

〔式中、Ｒ¹、Ｒ³、Ｒ⁴、Ｒ¹¹、Ｒ¹⁵、Ｘ、Ｙ、Ｌ、Ｄ¹は前記と同義である。〕
本反応は、通常、上記の製法Ａと同様の溶媒中、塩基（例えば、水素化ナトリウム、炭酸ナトリウム）の存在下に、-20〜150 ℃で行うことができる。反応時間は、化合物〔１８〕及び化合物〔１９〕の種類、反応温度によって異なるが、通常、30分〜24時間が適当である。化合物〔１９〕の使用量は化合物〔１８〕に対して 1〜1.2倍モル量が好ましい。
製法Ｆ
Ｈｅｔが上記式〔５ａ〕である本発明化合物〔１ｄ〕は、化合物〔２０〕と化合物〔２１〕とを反応させることによっても製造できる。

[Wherein, R ¹ , R ³ , R ⁴ , R ¹¹ , R ¹⁵ , X, Y, L, and D ¹ have the same meanings as described above. ]
This reaction can be carried out usually in the same solvent as in the above-mentioned Production Method A, in the presence of a base (eg, sodium hydride, sodium carbonate) at -20 to 150 ° C. The reaction time varies depending on the type of the compound [18] and the compound [19], and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of compound [19] to be used is preferably 1- to 1.2-fold the molar amount of compound [18].
Manufacturing method F
The compound [1d] of the present invention wherein Het is the above formula [5a] can also be produced by reacting the compound [20] with the compound [21].

〔式中、Ｒ¹、Ｒ¹⁵、Ｄ、Ｅ¹、Ｘは前記と同義である。Ｌ¹は塩素又は臭素を表す。〕
本反応は、通常、無溶媒又は上記の製法Ａと同様の溶媒中、塩基（例えば、水素化ナトリウム、炭酸ナトリウム）の存在又は非存在下に、-20〜150 ℃で行うことができる。反応時間は、化合物〔２０〕及び化合物〔２１〕の種類、反応温度によって異なるが、通常、30分〜24時間が適当である。化合物〔２１〕の使用量は化合物〔２０〕に対して 1〜1.2倍モル量が好ましい。
製法Ｇ
Ｚがアルコキシカルボニルである本発明化合物〔１ｇ〕を加水分解することにより、Ｚがカルボキシである本発明化合物〔１ｈ〕を製造することができる。

[Wherein, R ¹ , R ¹⁵ , D, E ¹ , and X have the same meanings as described above. L ¹ represents chlorine or bromine. ]
This reaction can be carried out usually at −20 to 150 ° C. in the absence or presence of a base (eg, sodium hydride, sodium carbonate) without a solvent or in the same solvent as in Production Method A described above. The reaction time varies depending on the types of the compound [20] and the compound [21] and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of compound [21] to be used is preferably 1- to 1.2-fold the molar amount of compound [20].
Manufacturing method G
The compound [1h] of the present invention in which Z is carboxy can be produced by hydrolyzing the compound [1g] of the present invention in which Z is alkoxycarbonyl.

  The compound [1g] of the present invention can be produced by condensing the compound [1h] of the present invention with an alcohol [73] or by reacting the compound with an alkylating agent.

〔式中、Ｒ¹、Ｒ¹¹、Ｈｅｔ、Ｄ、Ｅ¹は前記と同義である。Ｒ⁷が水素を表す場合、Ｒ⁸は水素、ヒドロキシ又はアルキルを表し、Ｒ⁷がアルキルを表す場合、Ｒ⁸はアルキルを表す。Ｅ²は次の式〔３２〕又は式〔４２〕で表される基を表し、Ｅ³は次の式〔３３〕又は式〔４３〕で表される基を表す。

式中、Ｒ³、Ｒ⁴、Ｒ⁷、Ｒ⁸、Ｙ、ｐは前記と同義である。〕
化合物〔１ｇ〕の加水分解は、通常、メタノール、エタノール、イソプロパノール、tert-ブチルアルコールなどのアルコール系溶媒と水の混合溶媒中、酸（例えば、塩酸、硫酸、ｐ−トルエンスルホン酸）又は塩基（例えば、水酸化ナトリウム、水酸化カリウム）の存在下に、-20〜150 ℃で行うことができる。反応時間は、化合物〔１ｇ〕の種類、反応温度によって異なるが、通常、30分〜24時間が適当である。酸又は塩基の使用量は化合物〔１ｇ〕に対して 1〜20倍モル量が好ましい。 Further, by reacting the compound [1h] of the present invention with the compound [82], that is, ammonia, hydroxylamine, alkylamine or dialkylamine, Z is carbamoyl, N-hydroxycarbamoyl, N-alkylcarbamoyl, or N, N- The compound [1i] of the present invention, which is a dialkylcarbamoyl, can be produced.

[In the formula, R ¹ , R ¹¹ , Het, D, and E ¹ have the same meanings as described above. When R ⁷ represents hydrogen, R ⁸ represents hydrogen, hydroxy or alkyl, and when R ⁷ represents alkyl, R ⁸ represents alkyl. E ² represents a group represented by the following formula [32] or [42], and E ³ represents a group represented by the following formula [33] or [43].

In the formula, R ³ , R ⁴ , R ⁷ , R ⁸ , Y, and p are as defined above. ]
The hydrolysis of the compound [1 g] is usually performed by using an acid (eg, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid) or a base ( For example, the reaction can be carried out at -20 to 150 ° C in the presence of sodium hydroxide or potassium hydroxide). The reaction time varies depending on the type of the compound [1 g] and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of the acid or base used is preferably 1 to 20 moles per 1 g of the compound.

  The condensation of the compound [1h] with the alcohol [73] is usually carried out at -20 to 150 ° C. in the presence of an acid (eg, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid) using such alcohol as a solvent. Can be. The reaction time varies depending on the type of the compound [1h] and the alcohol, and the reaction temperature, but usually 30 to 24 hours is appropriate. The amount of the acid to be used is preferably 0.1 to 1.2 moles per mole of the compound [1h].

  Such a condensation reaction is carried out at -20 to 150 ° C. in the same solvent as in the above-mentioned Production Method A, in the presence of a condensing agent (eg, N, N′-dicyclohexylcarbodiimide, 1,1′-carbonyldiimidazole). be able to. The reaction time varies depending on the type of the compound [1h], the alcohol and the condensing agent, and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of the condensing agent to be used is preferably a 1- to 1.2-fold molar amount relative to compound [1h].

  The reaction of the compound [1h] with an alkylating agent (for example, trimethylsilyldiazomethane / methanol, methyl iodide) can be carried out in the same solvent as in the above-mentioned Production Method A at -20 to 150 ° C. The reaction time varies depending on the compound [1h], the kind of the alkylating agent, and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of the alkylating agent to be used is preferably 1 to 2 moles per mole of the compound [1h].

  The reaction between compound [1h] and compound [82] can be carried out in the same manner as in the above-mentioned condensation reaction between compound [1h] and alcohol [73]. The compound [1i] of the present invention can also be produced by reacting a reactive derivative of the compound [1h] with the compound [82] by a known method. Examples of the reactive derivative include those commonly used for amidation, such as acid halides (acid chloride, acid bromide, etc.), mixed acid anhydrides, active amides, and the like.

When, for example, an acid halide is used as the reactive derivative, the reaction is carried out using an aprotic solvent (for example, a polar solvent such as acetonitrile, N, N-dimethylformamide (DMF), an ether-based solvent such as tetrahydrofuran (THF) or diethyl ether). A base (e.g., potassium carbonate, sodium carbonate, sodium bicarbonate) in a halogenated hydrocarbon solvent such as chloroform, methylene chloride, or a hydrocarbon solvent such as benzene, toluene, or n-hexane, or a mixture thereof. The reaction can be carried out at -20 to 100 ° C in the presence of potassium hydrogen carbonate, pyridine, 4-dimethylaminopyridine, triethylamine, sodium hydroxide and the like. The reaction time varies depending on the type of the acid halide and the compound [82], and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of compound [82] to be used is preferably 1- to 1.2-fold the molar amount of the acid halide.
Manufacturing method H
The compound [1k] of the present invention in which D is alkenylene and the unsaturated bond portion thereof is adjacent to Het can also be produced by dehydrogenating the compound [1j] of the present invention in which D is alkylene.

  The compound of the present invention [1k] can also be produced by hydrogenating the compound of the present invention [1m] in which D is alkynylene and the unsaturated bond portion thereof is adjacent to Het.

  Further, the compound [1j] of the present invention can also be produced by hydrogenating the compound [1k] of the present invention.

〔式中、Ｒ¹、Ｈｅｔ、Ｄ²、Ｅ¹は前記と同義である。〕
化合物〔１ｊ〕の脱水素は、通常、上記の製法Ａと同様の溶媒中、Ｎ−ブロモスクシンイミド（ＮＢＳ）又はＮ−クロロスクシンイミド（ＮＣＳ）と-20〜150 ℃で反応させ、次にメタノール、エタノールなどのアルコール溶媒中、塩基（例えば、水酸化ナトリウム、水酸化カリウム）と反応させることにより行うことができる。反応時間は、化合物〔１ｊ〕の種類、反応温度によって異なるが、通常、30分〜24時間が適当である。ＮＢＳ、ＮＣＳ、塩基の使用量は化合物〔１ｊ〕に対して 1〜1.2倍モル量が好ましい。

[In the formula, R ¹ , Het, D ² , and E ¹ have the same meanings as described above. ]
The dehydrogenation of the compound [1j] is usually carried out by reacting N-bromosuccinimide (NBS) or N-chlorosuccinimide (NCS) at -20 to 150 ° C. in the same solvent as in the above-mentioned production method A, and then methanol, The reaction can be carried out by reacting with a base (eg, sodium hydroxide, potassium hydroxide) in an alcohol solvent such as ethanol. The reaction time varies depending on the type of the compound [1j] and the reaction temperature, but usually, 30 minutes to 24 hours is appropriate. The amount of NBS, NCS and base used is preferably 1 to 1.2 times the molar amount of the compound [1j].

  The hydrogenation of the compound [1m] can be usually carried out in an alcohol solvent such as methanol or ethanol in the presence of a palladium catalyst (eg, calcium palladium carbonate, palladium carbon) at -20 to 150 ° C. The reaction time varies depending on the type of the compound [1m], the palladium catalyst, and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of the palladium catalyst to be used is preferably 0.05 to 0.5 mol based on the compound [1 m].

The hydrogenation of the compound [1k] can be usually carried out in an alcohol solvent such as methanol or ethanol in the presence of a palladium catalyst (for example, palladium carbon) at -20 to 150 ° C. The reaction time varies depending on the type of the compound [1k], the palladium catalyst, and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The use amount of the palladium catalyst is preferably 0.05 to 0.2 mol based on the compound [1k].
Manufacturing method I
The compound [1n] of the present invention wherein Z is hydroxymethyl can be produced by reducing the compound [1g] of the present invention wherein Z is alkoxycarbonyl.

〔式中、Ｒ¹、Ｈｅｔ、Ｄ、Ｅ¹は前記と同義である。Ｅ⁴は次の式〔３４〕又は式〔４４〕で表される基を表す。

式中、Ｒ³、Ｒ⁴、Ｙ、ｐは前記と同義である。〕
本反応は、還元剤（例えば、水素化アルミニウムリチウム、水素化ホウ素ナトリウム、水素化ジイソブチルアルミニウムリチウム）を用いて、適当な溶媒（例えば、テトラヒドロフラン（ＴＨＦ）、ジエチルエーテルなどのエーテル系溶媒、Ｎ，Ｎ−ジメチルホルムアミド、ジメチルスルホキシドなどの極性溶媒、メタノール、エタノール、イソプロパノールなどのアルコール系溶媒、又はこれらの混合溶媒）中、-20〜100 ℃で行うことができる。反応時間は、化合物〔１ｇ〕及び反応温度によって異なるが、通常、30分〜24時間が適当である。還元剤の使用量は化合物〔１ｇ〕に対して、0.5 〜2倍モル量が好ましい。
製法Ｊ
Ｅが式〔３〕又は〔４〕で表わされる基であり、Ｚがシアノである本発明化合物〔１ｑ〕は、Ｚがカルバモイル或いはＮ−ヒドロキシカルバモイルである本発明化合物〔１ｐ〕から製造することができる。

[Wherein, R ¹ , Het, D, and E ¹ have the same meanings as described above. E ⁴ represents a group represented by the following formula [34] or formula [44].

In the formula, R ³ , R ⁴ , Y, and p are as defined above. ]
In this reaction, a reducing agent (for example, lithium aluminum hydride, sodium borohydride, lithium diisobutylaluminum hydride) is used, and an appropriate solvent (for example, an ether solvent such as tetrahydrofuran (THF) or diethyl ether; In a polar solvent such as N-dimethylformamide and dimethyl sulfoxide, an alcoholic solvent such as methanol, ethanol and isopropanol, or a mixed solvent thereof at -20 to 100 ° C. The reaction time varies depending on the compound [1 g] and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of the reducing agent to be used is preferably 0.5 to 2 moles per 1 g of the compound.
Manufacturing method J
The compound [1q] of the present invention in which E is a group represented by the formula [3] or [4] and Z is cyano can be produced from the compound [1p] of the present invention in which Z is carbamoyl or N-hydroxycarbamoyl. Can be.

〔式中、Ｒ¹、Ｈｅｔ、Ｄは前記と同義である。Ｅ⁵は次の式〔３５〕又は式〔４５〕で表される基を表し、Ｅ⁶は次の式〔３６〕又は式〔４６〕で表される基を表す。

式中、Ｒ³、Ｒ⁴、Ｙ、ｐは前記と同義である。Ｒ¹²は水素又はヒドロキシを表す。〕
原料としてＺがカルバモイルである化合物、すなわちＲ¹²が水素である化合物を用いる場合、通常、無溶媒又は上記の製法Ａと同様の溶媒中、脱水剤（例えば、五酸化リン、塩化チオニル、無水トリフルオロ酢酸、Ｎ，Ｎ’−ジシクロヘキシルカルボジイミド）で処理することにより行うことができる。反応温度は、−20〜200℃で行われ、反応時間は、化合物〔１ｐ〕、脱水剤の種類、反応温度によって異なるが、通常、30分〜24時間が適当である。脱水剤の使用量は化合物〔１ｐ〕に対して 1〜5倍モル量が好ましい。

[Wherein, R ¹ , Het, and D are as defined above. E ⁵ represents a group represented by the following formula [35] or [45], and E ⁶ represents a group represented by the following formula [36] or formula [46].

In the formula, R ³ , R ⁴ , Y, and p are as defined above. R ¹² represents hydrogen or hydroxy. ]
When a compound in which Z is carbamoyl, that is, a compound in which R ¹² is hydrogen, is used as a raw material, a dehydrating agent (for example, phosphorus pentoxide, thionyl chloride, triethanol anhydride) is usually used without a solvent or in the same solvent as in the above-mentioned Production Method A. Fluoroacetic acid, N, N'-dicyclohexylcarbodiimide). The reaction is carried out at a temperature of -20 to 200 ° C, and the reaction time varies depending on the compound [1p], the type of the dehydrating agent and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of the dehydrating agent to be used is preferably 1 to 5 moles per mole of the compound [1p].

When a compound in which Z is N-hydroxycarbamoyl, that is, a compound in which R ¹² is hydroxy, can be used according to the method of A. Liguori et al. (Synthesis, 168 (1987)).
Manufacturing method K
The compound [1r] of the present invention in which E is a group represented by the formula [3] or [4] and Z is 1H-5-tetrazolyl is obtained by reacting the compound [1q] of the present invention in which Z is cyano with an azide. It can be manufactured by doing.

〔式中、Ｒ¹、Ｈｅｔ、Ｄ、Ｅ⁶は前記と同義である。Ｅ⁷は次の式〔３７〕又は式〔４７〕で表される基を表す。

式中、Ｒ³、Ｒ⁴、Ｙ、ｐは前記と同義である。〕
本反応は、通常、適当な溶媒（メタノール、エタノール、メトキシエタノールなどのアルコール系溶媒、ベンゼン、トルエンなどの炭化水素系溶媒、クロロホルム、塩化メチレンなどのハロゲン化炭化水素系溶媒、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、ジメチルスルホキシドなどの極性溶媒、テトラヒドロフラン（ＴＨＦ）などのエーテル系溶媒或いはこれらの混合溶媒）中、アジ化物（例えば、アジ化ナトリウム、アジドトリメチルシラン、アジドトリメチル錫）存在下に、0〜200℃で行うことができる。また添加物として塩化リチウムや塩化アンモニウムなどを共存させることもできる。反応時間は化合物〔１ｑ〕、アジ化物の種類、反応温度によって異なるが通常30分〜100時間が適当である。
製法Ｌ
Ｅが式〔３〕又は〔４〕で表わされる基であり、Ｚが１−アルキル−５−テトラゾリル又は２−アルキル−５−テトラゾリルである本発明化合物〔１ｓ〕は、Ｚが１Ｈ−５−テトラゾリルである本発明化合物〔１ｒ〕をアルキル化剤と反応させることにより製造することができる。

[Wherein, R ¹ , Het, D, and E ⁶ have the same meaning as described above. E ⁷ represents a group represented by the following formula [37] or [47].

In the formula, R ³ , R ⁴ , Y, and p are as defined above. ]
This reaction is usually carried out in a suitable solvent (alcohol-based solvent such as methanol, ethanol, methoxyethanol, etc .; hydrocarbon-based solvent such as benzene and toluene; halogenated hydrocarbon-based solvent such as chloroform and methylene chloride; N, N-dimethyl). In the presence of an azide (eg, sodium azide, azidotrimethylsilane, azidotrimethyltin) in a polar solvent such as formamide (DMF) and dimethyl sulfoxide, an ether solvent such as tetrahydrofuran (THF) or a mixed solvent thereof, It can be performed at 0 to 200 ° C. In addition, lithium chloride, ammonium chloride, or the like can be coexisted as an additive. The reaction time varies depending on the compound [1q], the kind of azide and the reaction temperature, but is usually appropriate for 30 minutes to 100 hours.
Manufacturing method L
In the compound [1s] of the present invention, wherein E is a group represented by the formula [3] or [4] and Z is 1-alkyl-5-tetrazolyl or 2-alkyl-5-tetrazolyl, Z is 1H-5- It can be produced by reacting the compound [1r] of the present invention, which is tetrazolyl, with an alkylating agent.

〔式中、Ｒ¹、Ｈｅｔ、Ｄ、Ｅ⁷、Ｌは前記と同義である。Ｒ²⁰はアルキルを表す。Ｅ⁸は次の式〔３８〕又は式〔４８〕で表される基を表す。

式中、Ｒ³、Ｒ⁴、Ｙ、ｐ、Ｒ²⁰は前記と同義である。〕
本反応は、例えば、上記の製法Ａと同様の溶媒中、アルキル化剤（例えば、ハロゲン化アルキル、アルキルメシラート、アルキルトシラート）及び塩基の存在下に、0〜150℃で行うことができる。使用される塩基は、有機アミン（例えばピリジン、トリエチルアミン）、金属水素化物（例えば水素化ナトリウム）、無機塩基（例えば炭酸カリウム、炭酸水素ナトリウム、水酸化ナトリウム）などがあげられる。反応時間は、使用する原料の種類、反応温度によって異なるが、通常30分〜100時間が適当である。用いるハロゲン化剤および塩基の使用量は、化合物〔１ｒ〕に対して1〜10倍モル量、好適には、1〜5倍モル量である。

[Wherein, R ¹ , Het, D, E ⁷ , and L are as defined above. R ²⁰ represents alkyl. E ⁸ represents a group represented by the following formula [38] or formula [48].

In the formula, R ³ , R ⁴ , Y, p and R ²⁰ are as defined above. ]
This reaction can be carried out, for example, at 0 to 150 ° C. in the same solvent as in the above-mentioned Production Method A, in the presence of an alkylating agent (eg, alkyl halide, alkyl mesylate, alkyl tosylate) and a base. . Examples of the base used include organic amines (eg, pyridine, triethylamine), metal hydrides (eg, sodium hydride), and inorganic bases (eg, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide). The reaction time varies depending on the type of the starting material used and the reaction temperature, but usually 30 minutes to 100 hours is appropriate. The amount of the halogenating agent and the base to be used is 1- to 10-fold molar amount, preferably 1- to 5-fold molar amount, relative to compound [1r].

  The compound of the present invention may have a tautomer. Each tautomer is also included in the present invention.

  The compounds of the present invention may have geometric isomers based on the presence of a double bond. Each geometric isomer and mixtures thereof are also included in the present invention.

  The compound of the present invention may have a stereoisomer based on the presence of an asymmetric carbon. Each stereoisomer and mixtures thereof are also included in the present invention.

  The stereoisomer can be obtained from the mixture using silica gel column chromatography.

  The stereoisomer can be obtained from the mixture by liquid chromatography using an optically active substance separation column (eg, CHIRALCEL (registered trademark) OD, CHIRALCEL (registered trademark) OF, manufactured by Daicel Corporation). .

  When the compound of the present invention has carboxy, a pharmaceutically acceptable salt can be formed by a known method. Examples of the salt include alkali metal salts (eg, sodium salt, potassium salt), alkaline earth metal salts (eg, calcium salt, magnesium salt), ammonium salts, and salts of organic amines (eg, triethylamine, lysine, arginine). Can be. For example, an alkali metal salt of the compound of the present invention can be obtained by adding one equivalent of sodium hydroxide or potassium hydroxide to the compound of the present invention, preferably in an alcohol solvent.

  The alkaline earth metal salt of the compound of the present invention can be obtained by dissolving the alkali metal salt produced by the above method in water, methanol, ethanol or a mixed solvent thereof and adding one equivalent of calcium chloride or the like.

  When the compound of the present invention is basic, a pharmaceutically acceptable salt can be formed by a known method. Examples of the salt include salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and salts with organic acids such as fumaric acid, maleic acid, methanesulfonic acid, and p-toluenesulfonic acid. For example, the hydrochloride of the compound of the present invention can be obtained by adding 1 equivalent of hydrochloric acid to the compound of the present invention, preferably in an alcohol solvent.

  The compound of the present invention or a salt thereof is isolated from the above reaction mixture by a conventional separation and purification means, for example, extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin layer chromatography, or the like. Purified.

The compound used as a starting material for the production of the compound of the present invention is a known compound or can be produced, for example, by the method described below or the method described in Reference Example.
Compound [11a] wherein D is CH ₂ -D ¹ and Y is oxygen, and Compound [11a] and Y is sulfur [11b] can be produced by the following method.

〔式中、Ｒ¹、Ｈｅｔ、Ｄ¹、ｐ、Ｔ、Ｌは前記と同義である。〕
化合物〔５０〕とアセトンを適当な溶媒（例えば、ベンゼン）中、酸触媒（例えば、ｐ−トルエンスルホン酸）存在下に脱水縮合させて化合物〔５１〕を得ることができる。

[In the formula, R ¹ , Het, D ¹ , p, T, and L are as defined above. ]
Compound [50] and acetone can be dehydrated and condensed in a suitable solvent (eg, benzene) in the presence of an acid catalyst (eg, p-toluenesulfonic acid) to obtain compound [51].

  Compound [52] can be obtained by adding tri-n-butylphosphine and copper iodide to compound [51] in a suitable solvent (eg, dry tetrahydrofuran) and reacting with compound [12] at -60 ° C or lower. it can. Magnesium may be used instead of tri-n-butylphosphine and copper iodide.

  The compound [11a] can be obtained by treating the compound [52] in a suitable solvent (eg, ethanol, methanol) under acidic conditions (eg, adding pyridinium p-toluenesulfonate) at 0 to 100 ° C. .

The compound [11a] is reacted with a brominating agent (triphenylphosphine / carbon tetrabromide, phosphorus tribromide) in a suitable solvent (eg, tetrahydrofuran, benzene) to form a bromide, and then thiourea and- By reacting at 20 to 100 ° C., compound [11b] can be obtained.
Production of Compound [50a] In the compound [50] used as a raw material in the production of the compound [11a], the compound [50a] in which p is 1 can be produced by the following method.

〔式中、Ｄ¹、Ｔは前記と同義である。Ｒ¹⁸はアルキルを表す。〕
化合物〔５３〕とマロン酸ジエステル〔５４〕を適当な溶媒（例えば、乾燥テトラヒドロフラン）中、塩基触媒（例えば、水素化ナトリウム）存在下に-50〜100 ℃で反応させて化合物〔５５〕を得ることができる。

[Wherein, D ¹ and T are as defined above. R ¹⁸ represents alkyl. ]
The compound [53] is reacted with a malonic acid diester [54] in a suitable solvent (eg, dry tetrahydrofuran) in the presence of a base catalyst (eg, sodium hydride) at −50 to 100 ° C. to obtain a compound [55]. be able to.

Compound [55] can be obtained by reacting compound [55] in the same manner as in Production Method I described above.
Production of Compound [50b] In the compound [50] used as a raw material in the production of the compound [11a], the compound [50b] in which p is 0 can be produced by the following method.

〔式中、Ｄ¹、Ｔは前記と同義である。〕
化合物〔５６〕を適当な溶媒（例えば、ジエチルエーテル）中、酸化剤（例えば、四酸化オスミウム）と-20〜50℃で反応させて化合物〔５０ｂ〕を得ることができる。
化合物〔５０ｃ〕の製造
上記の化合物〔１１ａ〕の製造で原料として用いられる化合物〔５０〕において、ｐが２である化合物〔５０ｃ〕は、次の方法によって製造できる。

[Wherein, D ¹ and T are as defined above. ]
Compound [50b] can be obtained by reacting compound [56] with an oxidizing agent (eg, osmium tetroxide) in a suitable solvent (eg, diethyl ether) at −20 to 50 ° C.
Production of Compound [50c] In the compound [50] used as a raw material in the production of the compound [11a], the compound [50c] in which p is 2 can be produced by the following method.

〔式中、Ｄ¹、Ｔ、Ｒ¹⁸は前記と同義である。〕
化合物〔５５〕と化合物〔５８〕を適当な溶媒（例えば、テトラヒドロフラン、エタノール）中、塩基（例えば、ナトリウムエトキシドなどのナトリウムアルコキシド、水素化ナトリウム）存在下、-20℃〜室温で反応させて化合物〔５９〕を得ることができる。

[Wherein D ¹ , T and R ¹⁸ have the same meanings as above. ]
Compound [55] is reacted with compound [58] in a suitable solvent (eg, tetrahydrofuran, ethanol) in the presence of a base (eg, sodium alkoxide such as sodium ethoxide, sodium hydride) at −20 ° C. to room temperature. Compound [59] can be obtained.

  The compound [59] is hydrolyzed in the same manner as in the above-mentioned Production Method G, and then heated to 50 to 150 ° C without solvent or in a suitable solvent (for example, xylene, toluene, ethyl acetate or a mixed solvent thereof). Compound [60] can be obtained by a decarboxylation reaction.

  The compound [60] can be reduced in the same manner as in the above Production Method I to give the compound [50c].

Further, after the compound [60] is esterified by a conventional method, it can be reduced in the same manner as described above to obtain the compound [50c].
In the compound [11] used as a raw material in the production method A of the compound [11c] and the compound [11d] , Het is a group represented by the formula [5a], D is D ¹ -CH ₂ , and p is The compound [11c] wherein Y is oxygen and the compound [11d] wherein Y is sulfur can be produced by the following method.

〔式中、Ｒ¹、Ｒ¹⁵、Ｒ¹⁸、Ｄ¹、Ｘ、Ｌは前記と同義である。〕
化合物〔１８〕とマロン酸ジアルキルを適当な溶媒（例えば、テトラヒドロフラン、エタノール）中、塩基（例えば、ナトリウムエトキシドなどのナトリウムアルコキシド、水素化ナトリウム）存在下、-20℃〜室温で反応させて化合物〔８１〕を得ることができる。

[In the formula, R ¹ , R ¹⁵ , R ¹⁸ , D ¹ , X, and L are as defined above. ]
Reacting the compound [18] with a dialkyl malonate in a suitable solvent (eg, tetrahydrofuran, ethanol) in the presence of a base (eg, sodium alkoxide such as sodium ethoxide, sodium hydride) at -20 ° C to room temperature [81] can be obtained.

  Compound [81c] can be reacted in the same manner as in Production Method I to give compound [11c].

Compound [11d] can be reacted in the same manner as in the reaction of compound [11a] to compound [11b] to give compound [11d].
Production of Compound [13] Compound [13] used as a starting material in Production Method B can be produced by the following method.

〔式中、Ｒ³、Ｒ⁴、Ｒ¹¹、Ｒ¹³、Ｒ¹⁴、Ｄ¹、Ｙ、Ｔは前記と同義である。〕
化合物〔１９〕と化合物〔５３〕を製法Ｅと同様に反応させて化合物〔６１〕を得ることができる。

[Wherein, R ³ , R ⁴ , R ¹¹ , R ¹³ , R ¹⁴ , D ¹ , Y, and T have the same meanings as described above. ]
Compound [19] and compound [53] are reacted in the same manner as in Production Method E to give compound [61].

  Compound [62] can be obtained by treating compound [61] in the same manner as in the hydrolysis in Production method G described above.

The compound [13] can be obtained by reacting the compound [62] with the compound [63] in a suitable solvent (for example, toluene) at 90 to 150 ° C.
Production of Compound [16] Compound [16] used as a starting material in Production Method C can be produced by the following method.

〔式中、Ｅ、Ｄ²、Ｔ、Ｐｈは前記と同義である。〕
化合物〔６４〕とトリフェニルホスフィンを上記の製法Ａと同様の溶媒中、-20〜150 ℃で反応させて化合物〔１６〕を得ることができる。
化合物〔１７〕の製造
製法Ｄで原料として用いられる化合物〔１７〕は、次の方法によって製造できる。

[Wherein, E, D ² , T, and Ph have the same meanings as above.] ]
Compound [16] can be obtained by reacting compound [64] with triphenylphosphine at -20 to 150 ° C in the same solvent as in Production Method A described above.
Production of Compound [17] Compound [17] used as a starting material in Production Method D can be produced by the following method.

〔式中、Ｒ¹、Ｒ¹¹、Ｒ¹⁵、Ｒ¹⁸、Ｅ¹、Ｅ²、Ｄ、Ｔは前記と同義である。〕
化合物〔６５〕と化合物〔６６〕を上記の製法Ａと同様の溶媒中、塩基（例えば、トリエチルアミン、ジメチルアニリン）存在下に-20〜150 ℃で反応させて化合物〔６７〕を得ることができる。

[In the formula, R ¹ , R ¹¹ , R ¹⁵ , R ¹⁸ , E ¹ , E ² , D, and T have the same meanings as described above. ]
Compound [67] can be obtained by reacting compound [65] with compound [66] in the same solvent as in Production Method A above in the presence of a base (eg, triethylamine, dimethylaniline) at -20 to 150 ° C. .

  Compound [69] can be obtained from compound [67] and compound [68] in the same manner as in the production method of compound [59] described above.

  Compound [70] can be obtained from compound [69] in the same manner as in the above-mentioned production method of compound [60].

  Compound [72] is obtained by reacting compound [70] with compound [71] in a suitable solvent (for example, pyridine) at 50 to 110 ° C, adding water and reacting at 30 to 100 ° C. Can be.

The compound [17] can be obtained by reacting the compound [72] with the compound [1h] in the above Production Method G in the same manner as in the production method of the compound [1g].
Production of Compound [68a] In the compound [68] used as a raw material in the production of the compound [17], the compound [68a] in which E ¹ is a group represented by the formula [31] is produced by the following method. it can.

〔式中、Ｄ、Ｔ、Ｙ、ｐ、Ｒ³、Ｒ¹¹は前記と同義である。〕
化合物〔５０〕と同様にして得られる化合物〔７４〕と化合物〔２２〕を上記の製法Ａと同様に反応させて化合物〔６８ａ〕を得ることができる。
化合物〔６８ｂ〕の製造
上記の化合物〔１７〕の製造で原料として用いられる化合物〔６８〕において、Ｅ¹が式〔４１〕で表される基である化合物〔６８ｂ〕は、次の方法によって製造できる。

[Wherein, D, T, Y, p, R ³ and R ¹¹ are as defined above. ]
Compound [68a] can be obtained by reacting compound [74] and compound [22] obtained in the same manner as compound [50] in the same manner as in Production Method A described above.
Production of Compound [68b] In the compound [68] used as a raw material in the production of the compound [17], the compound [68b] in which E ¹ is a group represented by the formula [41] is produced by the following method. it can.

〔式中、Ｄ、Ｔ、Ｙ、Ｒ³、Ｒ⁴、Ｒ¹¹は前記と同義である。〕
化合物〔１９〕と化合物〔７５〕を上記の化合物〔６１〕の製法と同様に反応させて化合物〔６８ｂ〕を得ることができる。
化合物〔１８〕の製造
製法Ｅで原料として用いられる化合物〔１８〕は、次の方法によって製造できる。

[Wherein, D, T, Y, R ³ , R ⁴ , and R ¹¹ have the same meaning as described above. ]
Compound [19] and compound [75] can be reacted in the same manner as in the production of compound [61] to give compound [68b].
Production of Compound [18] Compound [18] used as a starting material in Production Method E can be produced by the following method.

〔式中、Ｒ¹、Ｒ¹¹、Ｒ¹⁵、Ｘ、Ｄ¹、Ｌは前記と同義である。〕
上記の製法Ｄと同様にして得られた化合物〔７６〕から、上記の製法Ｉと同様にして、化合物〔７７〕を得ることができる。

[Wherein, R ¹ , R ¹¹ , R ¹⁵ , X, D ¹ , and L are as defined above. ]
From the compound [76] obtained in the same manner as in the above-mentioned Production Method D, a compound [77] can be obtained in the same manner as in the above-mentioned Production Method I.

Compound [77] and a brominating agent (e.g., triphenylphosphine / carbon tetrabromide) or a sulfonic acid halide (e.g., p-toluenesulfonic acid chloride) in the same solvent as in the above-mentioned Production Method A, -20 to 150 The compound [18] can be obtained by reacting at ℃.
Production of Compound [21] Compound [21] used as a starting material in Production Method F can be produced by the following method.

〔式中、Ｒ¹⁵、Ｄ、Ｅ¹、Ｌ¹は前記と同義である。〕
化合物〔７８〕を適当な溶媒（例えば、塩化メチレン）中、酸化剤（例えば、ｍ−クロロ過安息香酸）と-10℃〜室温で反応させて化合物〔７９〕を得ることができる。

[Wherein, R ¹⁵ , D, E ¹ , and L ¹ have the same meanings as described above. ]
Compound [79] can be obtained by reacting compound [78] with an oxidizing agent (eg, m-chloroperbenzoic acid) in a suitable solvent (eg, methylene chloride) at −10 ° C. to room temperature.

  Compound [79] can be reacted with lithium chloride or lithium bromide in a suitable solvent (eg, dry tetrahydrofuran) at room temperature to give compound [80].

  The compound [80] can be reacted with a Jones reagent (eg, concentrated sulfuric acid and chromium (VI) oxide) in a suitable solvent (eg, acetone) at room temperature to obtain the compound [21].

  Since the compound of the present invention has a blood triglyceride lowering action and an LDL-C lowering action, it is effective in preventing or treating diseases such as hyperlipidemia caused by high blood triglyceride level or high blood total cholesterol level. It is.

The compound of the present invention has a blood triglyceride lowering effect, and a very low density lipoprotein cholesterol (hereinafter, VLDL-C) in KK- ^Ay mice, which are NIDDM model animals exhibiting hypertriglyceridemia, hyperglycemia and hyperinsulinemia. ) And LDL-C lowering effect, and further exhibit a blood glucose lowering effect, a blood insulin lowering effect, or an HDL-C increasing effect or an arteriosclerosis index lowering effect. It is expected to be a prophylactic or therapeutic agent for the disease. Further, the toxicity of the compound of the present invention is sufficiently lower than the effective dose.

  From these facts, the compound of the present invention and the pharmaceutical composition of the present invention are effective for prevention and treatment of arteriosclerosis caused by hyperlipidemia, and for example, myocardial infarction, percutaneous transluminal coronary angioplasty (PTCA) Coronary artery disease including reocclusion after treatment with Percutaneous Transluminal Coronary Angioplasty), angina pectoris and ischemic heart disease caused by coronary artery disease, cerebral infarction including cortical branch infarction and perforator branch infarction, thrombosis and caused by this It can also be applied to the prevention or treatment of arteriosclerosis and the like.

  Furthermore, the compound of the present invention and the pharmaceutical composition of the present invention can also be applied to the prevention or treatment of obesity, hypertension, diabetes, especially non-insulin-dependent diabetes.

  When the compound of the present invention is administered as a medicament, a pharmaceutical composition containing the compound of the present invention as it is or in a pharmaceutically acceptable nontoxic and inert carrier, for example, 0.1 to 99.5%, preferably 0.5 to 90% As an animal, including humans.

  As the carrier, one or more solid, semi-solid or liquid diluents, fillers and other prescription auxiliaries are used. The pharmaceutical compositions are desirably administered in dosage unit form. The pharmaceutical composition of the present invention can be administered intravenously, orally, intraosseously, topically (such as transdermally), or rectally. Needless to say, it is administered in a dosage form suitable for these administration methods. Oral administration is particularly preferred.

  The dose as a pharmaceutical composition for preventing or treating arteriosclerosis is preferably set in consideration of the patient's condition such as age, body weight, administration route, nature and degree of disease, etc. The amount of the active ingredient of the present invention for an adult is in the range of 0.1 to 100 mg / human, preferably 0.5 to 20 mg / human per day. In some cases, lower doses may be sufficient, and conversely, higher doses may be required. It can also be administered in divided doses two to three times a day.

  The present invention can be applied to a pharmaceutical composition for preventing or treating diabetes and other diseases using the same dose as described above.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples, Test Examples, and Formulation Examples of the compound of the present invention, but the present invention is not limited thereto.
Reference Example 1
Diethyl (4-chlorobutyl) malonate To 458 ml of dry tetrahydrofuran (THF), 13.4 g of 60% sodium hydride was added, and 160.6 g of diethyl malonate was added dropwise under ice-cooling and stirring. After the dropwise addition, the mixture was stirred for 15 minutes, and then 57.3 g of 1-bromo-4-chlorobutane was added, followed by stirring at room temperature for 50 hours. The reaction solution was poured into ice water, neutralized with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was distilled under reduced pressure to obtain 26.8 g of the target compound as a colorless oil.
Boiling point 127-130 ° C (5mmHg)
The following compounds were produced in the same manner as in Reference Example 1.
Diethyl (3-chloropropyl) malonate Reference Example 2 Diethyl (5-chloropentyl) malonate
Diethyl (5-hexenyl) malonate To 120 ml of dry tetrahydrofuran (THF) was added 4.9 g of 60% sodium hydride, and 29.5 g of diethyl malonate was added dropwise under ice-cooling and stirring. After the dropwise addition, the mixture was stirred for 15 minutes, 10 g of 6-bromo-1-hexene was added, and the mixture was heated under reflux for 21 hours. The reaction solution was cooled, poured into ice water, neutralized with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 20: 1) to obtain 14.5 g of the objective compound as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.23 to 1.47 (10H, m), 1.84 to 2.11 (4H, m), 3.28 to 3.37 (1H, m), 4.14 to 4.25 (4H, m), 4.91 to 5.05 ( 2H, m),
5.69 to 5.90 (1H, m)
Reference Example 3
8 g of lithium aluminum hydride was added to 214 ml of 6-chloro-2-hydroxymethyl-1-hexanol dry ether, and a solution of 26.7 g of diethyl 4-chlorobutylmalonate / 53 ml of dry ether was added dropwise under ice-cooling and stirring. After stirring at room temperature for 1 hour, the mixture was cooled with ice water, and 173 ml of tetrahydrofuran / 14.7 ml of water was added dropwise little by little. Next, 14.7 ml of 1N sodium hydroxide and 35 ml of water were added, and the mixture was stirred for 15 minutes. Then, insolubles were removed by filtration, and the filtrate was concentrated to obtain 18.2 g of the target compound as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.22 to 1.38 (2H, m), 1.42 to 1.58 (2H, m), 1.68 to 1.88 (3H, m), 2.36 to 2.44 (2H, m), 3.55 (2H, m t), 3.61 to 3.72 (2H, m), 3.77 to 3.88 (2H, m)
The following compound was produced in the same manner as in Reference Example 3.
5-chloro-2-hydroxymethyl-1-pentanol,
7-chloro-2-hydroxymethyl-1-heptanol,
Reference Example 4 for 2-hydroxymethyl-7-octen-1-ol
To 270 ml of methyl acetonitrile c-5- (4-chlorobutyl) -2-methyl-1,3-dioxane-r-2-carboxylate was added 18 g of 6-chloro-2-hydroxymethyl-1-hexanol and 44 g of methyl pyruvate. Was. 65.2 g of boron trifluoride etherate (about 47%) was added to the mixed solution with stirring at room temperature, and the mixture was stirred for 14 hours. The reaction solution was poured into an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 10: 1) to obtain 14.8 g of the objective compound as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 0.99 to 1.11 (2H, m), 1.37 to 1.55 (5H, m), 1.68 to 1.82 (2H, m), 1.95 to 2.09 (1H, m), 3.41 (2H, m t), 3.48-3.60 (2H, m), 3.83 (3H, s), 3.92-4.00 (2H, m)
The following compound was produced in the same manner as in Reference Example 4.
c-5- (3-chloropropyl) -2-methyl-1,3-dioxane-r-2-carboxylate methyl,
Methyl c-5- (5-chloropentyl) -2-methyl-1,3-dioxane-r-2-carboxylate Reference Example 5
[4- (Tetrahydro-2H-pyran-2-yloxy)-(Z) -2-butenyl] malonate diethyl 2- [4-chloro- (Z) -2-butenyloxy] tetrahydro-2H-pyran 100 g in dry tetrahydrofuran It was dissolved in 2000 ml / 600 ml of dry N, N-dimethylformamide, 100 g of diethyl malonate was added, 25 g of 60% sodium hydride was added under ice cooling and stirring, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated, and the residue was subjected to silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 9: 1). Purification gave 65.5 g of an oil of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 1.27 (6H, t), 1.50 to 1.90 (6H, m), 2.67 (2H, t), 3.39 (1H, t), 3.45 to 3.60 (1H, m), 3.80 〜3.95 (1H, m), 4.05〜4.35 (6H, m), 4.61 (1H, dd), 5.45〜5.75 (2H, m)
Reference Example 6
2-hydroxymethyl-6- (tetrahydro-2H-pyran-2-yloxy)-(Z) -4-hexen-1-ol [4- (tetrahydro-2H-pyran-2-yloxy)-(Z) -2 65.5 g of diethyl [butenyl] malonate was dissolved in 650 ml of dry tetrahydrofuran, 15.1 g of sodium borohydride was added, and a solution of 110 g of methanol / 275 ml of tetrahydrofuran was added dropwise with stirring under heating and reflux. Next, 13.18 g of lithium chloride and 11 g of sodium borohydride were added, and the mixture was refluxed for 1.5 hours. The reaction solution was cooled, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated, and the residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, chloroform) to give an oil of the target compound. 22.8 g were obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.40 to 1.90 (7H, m), 2.20 (2H, br), 2.26 (2H, ddd), 3.46 to 3.90 (6H, m), 4.10 to 4.30 (2H, m) , 4.68 (1H, dd), 5.50〜5.80 (2H, m)
Reference Example 7
c-5- [4-Hydroxy- (Z) -2-butenyl] -2-methyl-1,3-dioxane-r-2-carboxylate methyl 2-hydroxymethyl-6- (tetrahydro-2H-pyran-2 To a solution of -yloxy)-(Z) -4-hexen-1-ol 21.79 g, acetonitrile 430 ml and methyl pyruvate 38.57 g, 26.8 g of a boron trifluoride ether complex (about 47%) was added under ice cooling. And stirred at room temperature for 15 hours. The reaction solution was poured into an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 7: 1) to obtain 5.36 g of an oily product of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 1.51 (3H, s), 1.85 (2H, dd), 1.95 to 2.20 (1 H, m), 3.43 (2H, dd), 3,84 (3H, s), 3.95 (2H, dd), 4.14 (2H, dd), 5.44 (1H, ddd), 5.70 (1H, ddd)
Reference Example 8
c-5- [4-Chloro- (Z) -2-butenyl] -2-methyl-1,3-dioxane-r-2-carboxylate methyl c-5- [4-hydroxy- (Z) -2- Butenyl] -2-methyl-1,3-dioxane-r-2-carboxylate (538 mg) was dissolved in N, N-dimethylformamide (12 ml), and 2,4,6-trimethylpyridine (1.13 g) and lithium chloride (396 mg) were added. After 1.07 g of methanesulfonyl chloride was added dropwise under ice cooling, the mixture was stirred at room temperature for 9 hours. The reaction solution was poured into ice water, 0.5N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 9: 1) to obtain 561 mg of an oily substance of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 1.52 (3H, s), 1.89 (2H, dd), 2.00 to 2.20 (1 H, m), 3.45 (2H, dd), 3,85 (3H, s), 3.95 (2H, dd), 4.00 (2H, dd), 5.53 (1H, ddd), 5.72 (1H, ddd)
Reference Example 9
c-5- [4-Iodo- (E) -2-butenyl] -2-methyl-1,3-dioxane-r-2-carboxylic acid In 5 ml of methylacetone , c-5- [4-chloro- (Z) was added. 300 mg of methyl [-2-butenyl] -2-methyl-1,3-dioxane-r-2-carboxylate was dissolved, 1.8 g of sodium iodide was added, and the mixture was heated under reflux for 2 hours. The reaction solution was cooled, ice water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated to obtain 353 mg of an oily substance of the target compound.
_{^{1 H-NMR (CDCl 3)}} δ: 1.51 (3H, s), 1.79 (2H, dd), 2.00~2.20 (1H, m), 3.41 (2H, dd), 3.81 (2H, dd), 3.84 (3H , t), 3.93 (2H, dd), 5.48〜5.93 (2H, m)
Reference example 10
c-5- (4-Iodobutyl) -2-methyl-1,3-dioxane-r-2-carboxylate In 148 ml of methylacetone, c-5- (4-chlorobutyl) -2-methyl-1,3-dioxane- 14.8 g of methyl r-2-carboxylate was dissolved, 44.2 g of sodium iodide was added, and the mixture was stirred at 40 ° C for 22.5 hours. The reaction solution was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated to obtain 19.9 g of an oily substance of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 0.99 to 1.10 (2H, m), 1.30 to 1.45 (2H, m), 1.51 (3H, s), 1.72 to 1.86 (2H, m), 1.97 to 2.08 (1H, m), 3.16 (2H, t), 3.40 (2H, t), 3.83 (3H, s), 3.92 ~ 4.00 (2H, m)
The following compound was produced in the same manner as in Reference Example 10.
methyl c-5- (3-iodopropyl) -2-methyl-1,3-dioxane-r-2-carboxylate and c-5- (5-iodopentyl) -2-methyl-1,3-dioxane -Methyl r-carboxylate Reference Example 11
6-Bromo-1- (tetrahydro-2H-pyran-2-yloxy) -2 -hexyne 13.46 g of 3- (tetrahydro-2H-pyran-2-yloxy) -1-propyne was added to 135 ml of dehydrated tetrahydrofuran under an argon stream. After dissolving and stirring at an internal temperature of −10 ° C., 60 ml of 1.6N n-butyllithium hexane solution was added dropwise over 20 minutes, and the mixture was stirred at the same temperature for 1 hour. After further stirring at room temperature for 1 hour, the internal temperature was lowered to -3 ° C, and 16.7 ml of hexamethylphosphoric triamide (HMPA) was added. Then, at an internal temperature of -10 ° C, 58.14 g of 1,3-dibromopropane was added. It was added all at once and stirred at room temperature for 12 hours. The reaction solution was poured into ice water, extracted with ether, washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was distilled under reduced pressure to obtain 12.0 g of the target compound as a colorless oil.
Boiling point 121-126 ° C (5mmHg)
Reference Example 12
Methyl 2- (6-bromohexyloxy) -2-methylpropionate To 120 ml of dry N, N-dimethylformamide was added 4.0 g of 60% sodium hydride, and 11.81 g of methyl 2-hydroxyisobutyrate was stirred under ice-cooling. The mixture was added dropwise and stirred for 10 minutes. Next, 122 g of 1,6-dibromohexane was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 20: 1) to obtain 6.25 g of the objective compound as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.42 to 1.65 (12H, m), 1.80 to 1.94 (2H, m), 3.32 to 3.45 (4H, m), 3.73 (3H, s)
The following compound was produced in the same manner as in Reference Example 12.
Methyl 2- (5-bromopentyloxy) -2-methylpropionate,
Methyl 2- (7-bromoheptyloxy) -2-methylpropionate,
Methyl 2- (8-bromooctyloxy) -2-methylpropionate,
Ethyl 2-methyl-2- [6- (tetrahydro-2H-pyran-2-yloxy) -4-hexynyloxy] propionate,
Ethyl 2- (6-bromohexyloxy) -2-methylpropionate and 2- [6- (5-methyl-2-phenyloxazol-4-yl)-(E) -4-hexenyloxy] -2- Methyl methyl propionate Reference Example 13
Ethyl 2- (6-hydroxy-4-hexynyloxy) -2-methylpropionate 3.72 g of ethyl 2-methyl-2- [6- (tetrahydro-2H-pyran-2-yloxy) -4-hexynyloxy] propionate The residue was dissolved in ethanol (37 ml), Amberlyst (registered trademark) 15 (372 mg) was added, and the mixture was stirred at 55 to 60 ° C for 1 hour. After cooling, the mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 9: 1 to 3: 1) to obtain 1.98 g of a pale yellow oil of the target compound. .
¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, t), 1.42 (6H, s), 1.70 to 1.83 (2H, m), 2.30 to 2.39 (2H, m), 3.44 to 3.50 (2H, m) , 4.14 to 4.26 (4H, m)
Reference Example 14
Methyl 2-methyl-2- (8-nonenyloxy) propionate To 500 ml of dry N, N-dimethylformamide, 17 g of 60% sodium hydride was added, and 48 g of methyl 2-hydroxyisobutyrate was added dropwise under ice-cooling and stirring. Stirred for minutes. Next, 100 g of 9-bromo-1-nonene (purity: 63.4%) was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was distilled under reduced pressure to obtain 29.9 g of a slightly yellow oily substance of the target compound. Boiling point: 124 to 127 ° C (8 mmHg)
The following compound was produced in the same manner as in Reference Example 14.
Methyl 2- (6-heptenyloxy) -2-methylpropionate,
Methyl 2-methyl-2- (7-octenyloxy) propionate and Methyl 2- (9-decenyloxy) -2-methylpropionate Reference Example 15
Methyl 2- (8,9-epoxynonyloxy) -2-methylpropionate 40 g of methyl 2-methyl-2- (8-nonenyloxy) propionate are dissolved in 320 ml of methylene chloride, and the mixture is stirred under ice-cooling and stirred with 70% 3-chloroform. 40.8 g of perbenzoic acid was added and stirred at room temperature for 15 hours. The reaction solution was filtered to remove insolubles, and the filtrate was concentrated. The residue was dissolved in n-hexane, washed four times with a 10% aqueous potassium carbonate solution, washed with water, dried over anhydrous magnesium sulfate and concentrated. 43.2 g of a colorless oily compound was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.25 to 1.70 (18H, m), 2.44 to 2.48 (1H, m), 2.72 to 2.77 (1H, m), 2.85 to 2.97 (1H, m), 3.34 (2H, t), 3.73 (3H, s)
The following compound was produced in the same manner as in Reference Example 15.
Methyl 2- (6,7-epoxyheptyloxy) -2-methylpropionate,
Methyl 2- (7,8-epoxyoctyloxy) -2-methylpropionate,
Methyl 2- (9,10-epoxydecyloxy) -2-methylpropionate and methyl c-5- (5,6-epoxyhexyl) -2-methyl-1,3-dioxane-r-2-carboxylate Reference Example 16
Methyl 2- (9-chloro-8-hydroxynonyloxy ) -2-methylpropionate 26 g of methyl 2- (8,9-epoxynonyloxy) -2-methylpropionate was dissolved in 260 ml of dry tetrahydrofuran, and lithium chloride was added. 8 g and 7 g of acetic acid were added, and the mixture was stirred at room temperature for 22 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate, washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated to obtain 31.7 g of an oil of the target compound.

The following compound was produced in the same manner as in Reference Example 16.
Methyl 2- (7-chloro-6-hydroxyheptyloxy) -2-methylpropionate,
Methyl 2- (8-chloro-7-hydroxyoctyloxy) -2-methylpropionate,
Methyl 2- (10-chloro-9-hydroxydecyloxy) -2-methylpropionate and c-5- (6-chloro-5-hydroxyhexyl) -2-methyl-1,3-dioxane-r-2 -Methyl carboxylate Reference Example 17
Methyl 2- (9-chloro-8-oxononyloxy) -2-methylpropionate 31 g of methyl 2- (9-chloro-8-hydroxynonyloxy) -2-methylpropionate is dissolved in 465 ml of acetone, and stirred with ice cooling. Below, 46 ml of Jones reagent prepared by adding 10.2 ml of concentrated sulfuric acid and 12 g of chromium (VI) to 45 ml of water was added dropwise. After stirring at room temperature for 3 hours, isopropyl alcohol was added to decompose excess Jones reagent, poured into ice water, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 7.5: 1) to obtain 18.16 g of an oil of the target compound.
_{^{1 H-NMR (CDCl 3)}} δ: 1.24~1.40 (6H, m), 1.41 (6H, s), 1.45~1.75 (4H, m), 2.58 (2H, t), 3.34 (2H, t), 3.73 (3H, s), 4.07 (2H, s)
The following compound was produced in the same manner as in Reference Example 17.
Methyl 2- (7-chloro-6-oxoheptyloxy) -2-methylpropionate,
Methyl 2- (8-chloro-7-oxooctyloxy) -2-methylpropionate,
Methyl 2- (10-chloro-9-oxodecyloxy) -2-methylpropionate and c-5- (6-chloro-5-oxohexyl) -2-methyl-1,3-dioxane-r-2 -Methyl carboxylate Reference Example 18
p- torr suspended oil amino acid diethyl amino malonate hydrochloride 20.5g of methylene chloride 180 ml, after stirring for 30 minutes triethylamine was added 29.4g under ice cooling, was added dropwise chloride p- toluoyl 15 g, Stirred at room temperature for 24 hours. The reaction solution was washed with water, then with dilute hydrochloric acid, washed with water, dried over anhydrous magnesium sulfate and concentrated. Isopropyl ether was added to the residue, and the crystals were collected by filtration and dried to obtain 25.9 g of white crystals of the target compound. Melting point 101-102 ° C
The following compound was produced in the same manner as in Reference Example 18.
Diethyl benzoylaminomalonate,
Diethyl (4-chlorobenzoyl) aminomalonate,
Diethyl (4-fluorobenzoylamino) malonate,
Diethyl (4-trifluoromethylbenzoyl) aminomalonate,
Diethyl (4-tert-butylbenzoyl) aminomalonate and diethyl (4-ethylbenzoyl) aminomalonate Reference Example 19
Ethyl c-5- [5,5-bis (ethoxycarbonyl) -5- (p-toluoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate 20% in 27 ml of dry ethanol 6.6 g of a sodium ethoxide-ethanol solution and 5.4 g of diethyl p-toluoylaminomalonate were added, and the mixture was stirred at room temperature for 30 minutes. Next, a solution of 6.3 g of methyl c-5- (4-iodobutyl) -2-methyl-1,3-dioxane-r-2-carboxylate / 5.4 ml of dry ethanol was added dropwise, and the solution was added at 50 to 60 ° C. for 15 minutes. Stirred for hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 5: 1) to obtain 4.34 g of a slightly yellow crystal of the target compound. Melting point 60-63 ° C
The following compounds were synthesized as in Reference Example 19.
ethyl c-5- (4-benzoylamino-4,4-bis (ethoxycarbonyl) butyl) -2-methyl-1,3-dioxane-r-2-carboxylate;
c-5- (5-benzoylamino-5,5-bis (ethoxycarbonyl) pentyl) -2-methyl-1,3-dioxane-r-2-carboxylate ethyl;
c-5- (6-benzoylamino-6,6-bis (ethoxycarbonyl) hexyl) -2-methyl-1,3-dioxane-r-2-carboxylate;
ethyl c-5- [5,5-bis (ethoxycarbonyl) -5- (4-fluorobenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate;
ethyl c-5- [5,5-bis (ethoxycarbonyl) -5- (4-trifluoromethylbenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate;
ethyl c-5- [5- (4-tert-butylbenzoylamino) -5,5-bis (ethoxycarbonyl) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate;
ethyl c-5- [5-benzoylamino-5,5-bis (ethoxycarbonyl)-(E) -2-pentenyl] -2-methyl-1,3-dioxane-r-2-carboxylate;
5- (5-benzoylamino-5,5-bis (ethoxycarbonyl) pentyl) -2,2-dimethyl-1,3-dioxane,
ethyl c-5- [5,5-bis (ethoxycarbonyl) -5- (4-chlorobenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate;
ethyl c-5- [6,6-bis (ethoxycarbonyl) -6- (p-toluoylamino) hexyl] -2-methyl-1,3-dioxane-r-2-carboxylate;
ethyl c-5- [5,5-bis (ethoxycarbonyl) -5- (3-fluoro-4-methylbenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate; and Ethyl c-5- [5,5-bis (ethoxycarbonyl) -5- (4-ethylbenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate Reference Example 20
Ethyl 2- (7-benzoylamino-7,7-bis (ethoxycarbonyl) heptyloxy) -2-methylpropionate To 5 ml of dry ethanol was added 675 mg of a 20% sodium ethoxide-ethanol solution and 698 mg of diethyl benzoylaminomalonate. And stirred at room temperature for 30 minutes. Next, a solution of 914 mg of methyl 6-bromohexyloxy-2-methylpropionate / 4 ml of dry ethanol was added dropwise, and the mixture was stirred at 50 to 60 ° C. for 15 hours. The reaction solution was poured into an aqueous ice solution and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 5: 1) to obtain 642 mg of the objective compound as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.10 to 1.37 (15H, m), 1.38 (6H, s), 1.42 to 1.60 (2H, m), 2.41 to 2.49 (2H, m), 3.30 (2H, t) , 4.11 to 4.33 (6H, m), 7.40 to 7.60 (4H, m), 7.81 to 7.86 (2H, m)
The following compound was produced in the same manner as in Reference Example 20.
Ethyl 2-methyl-2- [7- (p-toluoylamino) -7,7-bis (ethoxycarbonyl) heptyloxy] propionate,
Ethyl 2- [7-benzoylamino-7,7-bis (ethoxycarbonyl) -4-heptynyloxy] -2-methylpropionate,
Ethyl 2- [7- (4-chlorobenzoylamino) -7,7-bis (ethoxycarbonyl) heptyloxy] -2-methylpropionate,
Ethyl 2- [7,7-bis (ethoxycarbonyl) -7- (4-fluorobenzoylamino) heptyloxy] -2-methylpropionate,
Ethyl 2- [7- (4-tert-butylbenzoylamino) -7,7-bis (ethoxycarbonyl) heptyloxy] -2-methylpropionate,
Ethyl 2- [6-benzoylamino-6,6-bis (ethoxycarbonyl) hexyloxy] -2-methylpropionate,
Ethyl 2- [8-benzoylamino-8,8-bis (ethoxycarbonyl) octyloxy] -2-methylpropionate,
Ethyl 5-benzoylamino-5,5-bis (ethoxycarbonyl) pentanoate,
Ethyl 6-benzoylamino-6,6-bis (ethoxycarbonyl) hexanoate,
Ethyl 5,5-bis (ethoxycarbonyl) -5- (p-toluoylamino) pentanoate and 5- (benzoylamino) -1-bromo-5,5-bis (ethoxycarbonyl)-(E) -2 -Penten Reference Example 21
c-5- [5-carboxy-5- (p-toluoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylic acid c-5- [5,5-bis (ethoxycarbonyl ) -5- (p-Toluoylamino) pentyl] -2-ethyl 4.2-methyl-1,3-dioxane-r-2-carboxylate in 33.6 ml of ethanol and 2.0 g of sodium hydroxide A solution of 8.4 ml of water / water was added, and the mixture was heated under reflux for 5 hours. The reaction solution was concentrated, water was added to the residue, acidified with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated to obtain 3.23 g of a pale yellow oil. The obtained oil was stirred at 130 ° C. for 30 minutes to obtain 3.1 g of white crystals of the target compound. 152-156 ° C
The following compound was produced in the same manner as in Reference Example 21.
c-5- (4-benzoylamino-4-carboxybutyl) -2-methyl-1,3-dioxane-r-2-carboxylic acid,
c-5- (5-benzoylamino-5-carboxypentyl) -2-methyl-1,3-dioxane-r-2-carboxylic acid,
c-5- (6-benzoylamino-6-carboxyhexyl) -2-methyl-1,3-dioxane-r-2-carboxylic acid,
c-5- [5-carboxy-5- (4-fluorobenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylic acid,
c-5- [5-carboxy-5- (4-trifluoromethylbenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylic acid,
c-5- [5- (4-tert-butylbenzoylamino) -5-carboxypentyl] -2-methyl-1,3-dioxane-r-2-carboxylic acid,
c-5- [5-benzoylamino-5-carboxy- (E) -2-pentenyl] -2-methyl-1,3-dioxane-r-2-carboxylic acid,
5- (5-benzoylamino-5-carboxypentyl) -2,2-dimethyl-1,3-dioxane,
2- (7-benzoylamino-7-carboxyheptyloxy) -2-methylpropionic acid,
2- [7-carboxy-7- (p-toluoylamino) heptyloxy] -2-methylpropionic acid,
2- (7-benzoylamino-7-carboxy-4-heptynyloxy) -2-methylpropionic acid,
2- [7-carboxy-7- (4-chlorobenzoylamino) heptyloxy] -2-methylpropionic acid,
2- [7-carboxy-7- (4-fluorobenzoylamino) heptyloxy] -2-methylpropionic acid,
2- [7- (4-tert-butylbenzoylamino) -7-carboxyheptyloxy] -2-methylpropionic acid,
2- (8-benzoylamino-8-carboxyoctyloxy) -2-methylpropionic acid,
2- (6-benzoylamino-6-carboxyhexyloxy) -2-methylpropionic acid,
5-benzoylamino-5-carboxypentanoic acid,
6-benzoylamino-6-carboxyhexanoic acid,
c-5- [5-carboxy-5- (4-chlorobenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylic acid,
c-5- [6-carboxy-6- (p-toluoylamino) hexyl] -2-methyl-1,3-dioxane-r-2-carboxylic acid,
5-carboxy-5- (p-toluoylamino) pentanoic acid,
c-5- [5-carboxy-5- (3-fluoro-4-methylbenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylic acid, and c-5- [5- Carboxy-5- (4-ethylbenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylic acid Reference Example 22
c-5- [5-acetyl-5- (p-toluoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylic acid c-5- [5-carboxy-5- (p -Toluoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylic acid (3.1 g) was dissolved in pyridine (15.5 ml), acetic anhydride (10.2 ml) was added, and the mixture was stirred at 90 ° C. for 1 hour. . Next, 10.2 ml of water was added dropwise, followed by stirring at 90 ° C. for 30 minutes. The reaction solution was cooled, poured into ice water, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, chloroform: methanol = 100: 1) to obtain 2.2 g of a slightly yellow oily substance of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 0.99 to 1.10 (2H, m), 1.15 to 1.45 (4H, m), 1.54 (3H, s), 1.50 to 1.82 (1H, m), 1.84 to 2.15 (2H, m m), 2.27 (3H, s), 2.40 (3H, s), 3.47 (2H, dd), 3.89 ~ 4.04 (2H, m), 4.82 ~ 4.92 (1H, m), 7.01 (1H, d), 7.22 ~ 7.27 (2H, m), 7.68 ~ 7.74 (2H, m)
The following compound was produced in the same manner as in Reference Example 22.
c-5- (4-acetyl-4-benzoylaminobutyl) -2-methyl-1,3-dioxane-r-2-carboxylic acid,
c-5- (5-acetyl-5-benzoylaminopentyl) -2-methyl-1,3-dioxane-r-2-carboxylic acid,
c-5- (6-acetyl-6-benzoylaminohexyl) -2-methyl-1,3-dioxane-r-2-carboxylic acid,
c-5- [5-acetyl-5- (4-fluorobenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylic acid,
c-5- [5-acetyl-5- (4-trifluoromethylbenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylic acid,
c-5- [5-Acetyl-5- (4-tert-butylbenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylic acid c-5- [5-acetyl-5 Benzoylamino- (E) -2-pentenyl] -2-methyl-1,3-dioxane-r-2-carboxylic acid;
5- (5-acetyl-5-benzoylaminopentyl) -2,2-dimethyl-1,3-dioxane,
2- (7-acetyl-7-benzoylaminoheptyloxy) -2-methylpropionic acid,
2- [7-acetyl-7- (p-toluoylamino) heptyloxy] -2-methylpropionic acid,
2- (7-acetyl-7-benzoylamino-4-heptynyloxy) -2-methylpropionic acid,
2- [7-acetyl-7- (4-chlorobenzoylamino) heptyloxy] -2-methylpropionic acid,
2- [7-acetyl-7- (4-fluorobenzoylamino) heptyloxy] -2-methylpropionic acid,
2- [7-acetyl-7- (4-tert-butylbenzoylamino) heptyloxy] -2-methylpropionic acid,
2- (8-acetyl-8-benzoylaminooctyloxy) -2-methylpropionic acid,
2- (6-acetyl-6-benzoylaminohexyloxy) -2-methylpropionic acid,
5-acetyl-5-benzoylaminopentanoic acid,
6-acetyl-6-benzoylaminohexanoic acid,
c-5- [5-acetyl-5- (4-chlorobenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylic acid,
c-5- [6-acetyl-6- (p-toluoylamino) hexyl] -2-methyl-1,3-dioxane-r-2-carboxylic acid,
5-acetyl-5- (p-toluoylamino) pentanoic acid,
c-5- [5-acetyl-5- (3-fluoro-4-methylbenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylic acid,
c-5- [5-Acetyl-5- (4-ethylbenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylic acid and 7-acetyl-7- (benzoylamino)- (E) -4-Heptenoic acid Reference Example 23
Methyl c-5- [5-acetyl-5- (p-toluoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate c-5- [5-acetyl-5- ( p-Toluoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylic acid (2.1 g) was dissolved by adding benzene (44 ml) and methanol (4.2 ml), and stirred under ice-cooling with 2.0M trimethylsilyl. 4.2 ml of a diazomethanehexane solution was added dropwise, stirred for 1 hour, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 2.5: 1) to obtain 0.85 g of the objective compound as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 0.90 to 1.08 (2H, m), 1.10 to 1.40 (4H, m), 1.50 (3H, s), 1.55 to 1.80 (1H, m), 1.85 to 2.16 (2H, m m), 2.27 (3H, s), 2.40 (3H, s), 3.36 (2H, dd), 3.82 (3H, s), 3.92 (2H, dd), 4.80〜4.89 (1H, m), 6.89 (1H , d), 7.25 (2H, d), 7.70 (2H, d)
The following compound was produced in the same manner as in Reference Example 23.
c-5- (4-acetyl-4-benzoylaminobutyl) -2-methyl-1,3-dioxane-r-2-carboxylate methyl,
c-5- (5-acetyl-5-benzoylaminopentyl) -2-methyl-1,3-dioxane-r-2-carboxylate methyl,
c-5- (6-acetyl-6-benzoylaminohexyl) -2-methyl-1,3-dioxane-r-2-carboxylate methyl,
c-5- [5-acetyl-5- (4-fluorobenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate methyl,
c-5- [5-acetyl-5- (4-trifluoromethylbenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate methyl,
methyl c-5- [5-acetyl-5- (4-tert-butylbenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate, and c-5- [5-acetyl -5-benzoylamino- (E) -2-pentenyl] -2-methyl-1,3-dioxane-r-2-carboxylate Reference Example 24
Methyl c-5- [5-acetyl-5- (p-toluoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate c-5- [5-acetyl-5- ( 20 g of p-toluoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylic acid was dissolved in 140 ml of acetonitrile, 14.5 g of methyl iodide and 14.1 g of potassium carbonate were added, and the mixture was heated under reflux for 3 hours. did. The reaction solution was cooled, poured into ice water, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 2: 1) to obtain 10.3 g of the objective compound as a slightly yellow oil.

The following compound was produced in the same manner as in Reference Example 24.
c-5- (5-acetyl-5-benzoylaminopentyl) -2-methyl-1,3-dioxane-r-2-carboxylate methyl,
c-5- [5-acetyl-5- (4-chlorobenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate methyl,
c-5- [6-acetyl-6- (p-toluoylamino) hexyl] -2-methyl-1,3-dioxane-r-2-carboxylate methyl,
c-5- [5-acetyl-5- (3-fluoro-4-methylbenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate methyl and c-5- [5 -Acetyl-5- (4-ethylbenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate Reference Example 25
Methyl 6-acetyl-6-benzoylaminohexanoate 4.35 g of 6-acetyl-6-benzoylaminohexanoic acid was dissolved in 100 ml of methanol, 0.5 ml of concentrated sulfuric acid was added, and the mixture was heated under reflux for 2.5 hours. The reaction solution was cooled, poured into ice water, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated to obtain 4.4 g of pale yellow crystals.
Melting point 59-60 ° C
The following compound was produced in the same manner as in Reference Example 25.
Methyl 2- (7-acetyl-7-benzoylaminoheptyloxy) -2-methylpropionate,
Methyl 2- [7-acetyl-7- (p-toluoylamino) heptyloxy] -2-methylpropionate,
Methyl 2- (7-acetyl-7-benzoylamino-4-heptynyloxy) -2-methylpropionate,
Methyl 2- [7-acetyl-7- (4-chlorobenzoylamino) heptyloxy] -2-methylpropionate,
Methyl 2- [7-acetyl-7- (4-fluorobenzoylamino) heptyloxy] -2-methylpropionate,
Methyl 2- [7-acetyl-7- (4-tert-butylbenzoylamino) heptyloxy] -2-methylpropionate,
Methyl 2- (8-acetyl-8-benzoylaminooctyloxy) -2-methylpropionate,
Methyl 2- (6-acetyl-6-benzoylaminohexyloxy) -2-methylpropionate,
Methyl 5-acetyl-5-benzoylaminopentanoate,
Methyl 5-acetyl-5- (p-toluoylamino) pentanoate and methyl 7-acetyl-7- (benzoylamino)-(E) -4-heptenoate Reference Example 26
1.6 g of 60% sodium hydride of diethyl (3-bromobenzyl) malonate is suspended in 20 ml of dry tetrahydrofuran / 15 ml of dry N, N-dimethylformamide, and 7.6 ml of diethyl malonate is added dropwise under ice-cooling for 15 minutes. Stirred. Next, a solution of 5 g of 3-bromobenzyl bromide / 10 ml of dry tetrahydrofuran was added, and the mixture was stirred for 1 hour under ice cooling. Ice water was added to the reaction solution, which was extracted with ether, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 10: 1) to obtain 5.41 g of the target compound as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, t), 3.81 (2H, d), 3.61 (1H, t), 4.17 (4H, q), 7.10 to 7.20 (2H, m), 7.29 to 7.40 (2H, m)
The following compound was produced in the same manner as in Reference Example 26.
Diethyl (4-bromobenzyl) malonate Reference Example 27
In a stream of diethyl (4-bromophenyl) malonate , 10.85 g of diethyl carbonate was dissolved in 60 ml of benzene, and 2.75 g of 60% sodium hydride was added, followed by heating under reflux. A solution of 5.58 g of ethyl 4-bromophenylacetate / 20 ml of benzene was added dropwise thereto over 1 hour, and the mixture was refluxed for 1 hour. After the reaction solution was cooled and ice water was slowly added dropwise, the organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 10: 1) to obtain 6.45 g of the target compound as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.26 (6H, t), 4.21 (4H, q), 4.56 (1H, s), 7.29 (2H, d), 7.50 (2H, d)
The following compound was produced in the same manner as in Reference Example 27.
Diethyl (3-bromophenyl) malonate Reference Example 28
94 ml of a 1.0 M diisobutylaluminum hydride-toluene solution of 2- (3-bromobenzyl) -1,3-propanediol in toluene was cooled with ice, and 5.41 g of diethyl (3-bromobenzyl) malonate was added under an argon stream. The mixture was added dropwise at a temperature of 15 ° C. or lower, stirred for 30 minutes under ice cooling, then raised to room temperature and stirred for 2 hours. The reaction solution was ice-cooled, 21 ml of methanol was slowly added dropwise, and 41 ml of 2N hydrochloric acid was added dropwise, followed by stirring at room temperature for 20 minutes. The insolubles were removed by filtration, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, chloroform: methanol = 10: 1) to obtain 1.96 g of the target compound as white crystals. 61-63 ° C
The following compound was produced in the same manner as in Reference Example 28.
2- (4-bromobenzyl) -1,3-propanediol,
2- (4-bromophenyl) -1,3-propanediol and 2- (3-bromophenyl) -1,3-propanediol Reference Example 29
1.85 g of 5- (3-bromobenzyl) -2,2-dimethyl-1,3-dioxane 2- (3-bromobenzyl) -1,3-propanediol was dissolved in 8 ml of acetone / 18 ml of benzene, and p- 70 mg of toluenesulfonic acid monohydrate were added. After azeotropic dehydration for 1 hour using a Dean-Stark apparatus, a saturated aqueous solution of sodium bicarbonate was added, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 4: 1) to obtain 1.47 g of the target compound as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.43 (6H, d), 1.90 to 2.10 (1 H, m), 2.60 (2H, d), 3.61 (2H, dd), 3.86 (2H, dd), 7.05 to 7.20 (2H, m), 7.30-7.40 (2H, m)
The following compound was produced in the same manner as in Reference Example 29.
5- (4-bromobenzyl) -2,2-dimethyl-1,3-dioxane,
5- (4-bromophenyl) -2,2-dimethyl-1,3-dioxane and 5- (3-bromophenyl) -2,2-dimethyl-1,3-dioxane Reference Example 30
2,2-dimethyl-5- {3-[(5-methyl-2-phenyloxazol-4-yl) methyl] benzyl} -1,3-dioxane 5- (3-bromobenzyl) -2 under an argon stream. , 2-Dimethyl-1,3-dioxane (1.45 g) was dissolved in dry tetrahydrofuran (7 ml), cooled in a dry ice-acetone bath, and N, N, N ', N'-tetramethylethylenediamine (0.9 ml) was added. Butyllithium (1.6 M hexane solution) was added dropwise at -60 ° C or lower. After stirring for 10 minutes, a suspension of 1.03 g of tri-n-butylphosphine and 0.97 g of copper iodide / 7 ml of dry tetrahydrofuran was added, and the mixture was stirred for 10 minutes. Next, a solution of 1.52 g of 4-iodomethyl-5-methyl-2-phenyloxazole / 7 ml of dry tetrahydrofuran was added dropwise at −60 ° C. or lower, and the mixture was stirred for 15 minutes. did. After adding saturated ammonium chloride to the reaction mixture, the mixture was diluted with water, extracted with ether, filtered to remove insolubles, washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 4: 1) to obtain 0.34 g of a white crystal of the target compound. 85-87 ° C
The following compound was produced in the same manner as in Reference Example 30.
2,2-dimethyl-5- {4-[(5-methyl-2-phenyloxazol-4-yl) methyl] benzyl} -1,3-dioxane,
2,2-dimethyl-5- {4-[(5-methyl-2-phenyloxazol-4-yl) methyl] phenyl} -1,3-dioxane and 2,2-dimethyl-5- {3- [ (5-Methyl-2-phenyloxazol-4-yl) methyl] phenyl} -1,3-dioxane Reference Example 31
550 mg of lithium aluminum hydride was added to 17 ml of dry ether of 5- (5-methyl-2-phenyloxazol-4-yl) -1-pentanol , and the mixture was stirred under ice-cooling with stirring. 3.3 g of methyl 4-yl) -1-pentanoate / 10 ml of dry ether was added dropwise. After stirring at room temperature for 1 hour, the mixture was cooled with ice water and 12 ml of tetrahydrofuran / 0.7 ml of water was added dropwise little by little. Next, after adding 0.7 ml of 1N sodium hydroxide and 2.5 ml of water and stirring for 15 minutes, the insoluble matter was removed by filtration, and the filtrate was concentrated to obtain 2.9 g of a slightly yellow crystal of the target compound. . Melting point 40-42 ° C
The following compound was produced in the same manner as in Reference Example 31.
4- (5-methyl-2-phenyloxazol-4-yl) -1-butanol,
4- [5-methyl-2- (p-tolyl) oxazol-4-yl] -1-butanol,
4- [2- (p-tolyl) -5-trifluoromethyloxazol-4-yl] -1-butanol,
6- [5-methyl-2- (p-tolyl) oxazol-4-yl] -1-hexanol and 6- (5-methyl-2-phenyloxazol-4-yl)-(E) -4-hexene -1-All Reference Example 32
To 62 ml of 4- (5-bromopentyl) -5-methyl-2-phenyloxazole dry ether was added 2.9 g of 5- (5-methyl-2-phenyloxazol-4-yl) -1-pentanol and dissolved, 8.4 g of carbon tetrabromide was added, and 6.6 g of triphenylphosphine was added little by little under ice-cooling and stirring. After the addition, the mixture was stirred at room temperature for 2.5 hours, the reaction solution was filtered to remove insolubles, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 10: 1) to obtain 2.61 g of the objective compound as a pale yellow oil.

The following compound was produced in the same manner as in Reference Example 32.
4- (4-bromobutyl) -5-methyl-2-phenyloxazole,
Ethyl 2- (6-bromo-4-hexynyloxy) -2-methylpropionate,
4- (4-bromobutyl) -5-methyl-2- (p-tolyl) oxazole,
4- (4-bromobutyl) -2- (p-tolyl) -5-trifluoromethyloxazole,
4- (6-bromohexyl) -5-methyl-2- (p-tolyl) oxazole and 4- [6-bromo- (E) -2-hexenyl] -5-methyl-2-phenyloxazole Reference Example 33
[5- (5-Methyl-2-phenyloxazol-4-yl) pentyl] diethyl malonate To 35 ml of dry tetrahydrofuran, 650 mg of 60% sodium hydride was added, and 3.9 g of diethyl malonate was added dropwise under ice-cooling and stirring. After the dropwise addition, the mixture was stirred for 10 minutes, added with 2.5 g of 4- (4-bromopentyl) -5-methyl-2-phenyloxazole, stirred at room temperature for 10 minutes, and then heated and refluxed for 12 hours. The reaction solution was poured into ice water, neutralized with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 10: 1) to obtain 2.75 g of the target compound as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.26 (6H, t), 1.32 to 1.43 (4H, m), 1.55 to 1.75 (2H, m), 1.82 to 2.00 (2H, m), 2.31 (3H, s) , 2.47 (2H, t), 3.31 (1H, t), 4.19 (4H, q), 7.37 ~ 7.47 (3H, m), 7.95 ~ 8.00 (2H, m)
The following compound was produced in the same manner as in Reference Example 33.
[4- (5-methyl-2-phenyloxazol-4-yl) butyl] malonate diethyl,
{4- [5-methyl-2- (p-tolyl) oxazol-4-yl] butyl} malonate diethyl,
{4- [2- (p-tolyl) -5-trifluoromethyloxazol-4-yl] butyl} malonate and [5- (benzoylamino) -5,5-bis (ethoxycarbonyl)-(E ) -2-Pentenyl] diethyl malonate Reference Example 34
637 mg of lithium aluminum hydride was added to 15 ml of dry ether of 4- [6,6-bis (hydroxymethyl) hexyl] -5-methyl-2-phenyloxazole , and [5- (5-methyl-2) was stirred under ice-cooling. 2.6 g of diethyl [-phenyloxazol-4-yl) pentyl] malonate / 10 ml of dry ether were added dropwise. After stirring at room temperature for 2 hours, the mixture was cooled with ice water, and tetrahydrofuran (14 ml) / water (0.8 ml) was added dropwise little by little. Next, 0.8 ml of a 1N aqueous solution of sodium hydroxide and 2.3 ml of water were added, and the mixture was stirred for 15 minutes. Insolubles were removed by filtration, and the filtrate was concentrated to obtain 2.0 g of a white crystal of the target compound. . 71-74 ° C
The following compound was produced in the same manner as in Reference Example 34.
4- [5,5-bis (hydroxymethyl) pentyl] -5-methyl-2-phenyloxazole,
4- [5,5-bis (hydroxymethyl) pentyl] -5-methyl-2- (p-tolyl) oxazole,
4- [5,5-bis (hydroxymethyl) pentyl] -2- (p-tolyl) -5-trifluoromethyloxazole and 4- [5,5-bis (hydroxymethyl) pentyl] -5-ethyl- 2- (p-tolyl) oxazole Reference Example 35
4- {3- [2,2-bis (hydroxymethyl) ethyl] benzyl} -5-methyl-2-phenyloxazole 2,2-dimethyl-5- {3-[(5-methyl-2- A mixture of 320 mg of phenyloxazol-4-yl) methyl] benzyl} -1,3-dioxane, 21 ml of ethanol and 21 mg of pyridinium p-toluenesulfonate (PPTS) was stirred at 55 to 60 ° C. for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, chloroform) to obtain 305 mg of the target compound as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.90 to 2.15 (1H, m), 2.29 (3H, s), 2.35 (2H, br), 2.60 (2H, d), 3.64 (2H, dd), 3.78 (2H , dd), 3.85 (2H, s), 6.90-7.50 (7H, m), 7.85-8.05 (2H, m)
The following compound was produced in the same manner as in Reference Example 35.
4- {4- [2,2-bis (hydroxymethyl) ethyl] benzyl} -5-methyl-2-phenyloxazole,
4- {4- [1,1-bis (hydroxymethyl) methyl] benzyl} -5-methyl-2-phenyloxazole,
4- {3- [1,1-bis (hydroxymethyl) methyl] benzyl} -5-methyl-2-phenyloxazole and 4- [5,5-bis (hydroxymethyl) pentyl] -5-methyl-2 -Phenyloxazole Reference Example 36
Dissolve 4.35 g of methyl 6-acetyl-6-benzoylaminohexanoate in 87 ml of methyl 5- (5-methyl-2-phenyloxazol-4-yl) pentanoate, add 2.9 ml of phosphorus oxychloride, and add 50 ml. Heated to reflux for a minute. The reaction solution was cooled, poured into ice water, neutralized with an aqueous solution of sodium bicarbonate, extracted with ethyl acetate, and washed with saturated saline. After drying over anhydrous magnesium sulfate and concentration, 3.40 g of the target compound was obtained as a pale yellow oil.

  The following compound was produced in the same manner as in Reference Example 36.
Methyl 4- (5-methyl-2-phenyloxazol-4-yl) butanoate,
Methyl 4- [5-methyl-2- (p-tolyl) oxazol-4-yl] butanoate,
Ethyl 6- [5-methyl-2- (p-tolyl) oxazol-4-yl] hexanoate, and
Methyl 6- (5-methyl-2-phenyloxazol-4-yl)-(E) -4-hexenoate
Reference Example 37
1-bromo-3- [2,2-bis (ethoxycarbonyl) -2- (p-toluoylamino) ethyl] benzene
  21.45 g of a 20% sodium ethoxide-ethanol solution and 17.61 g of diethyl p-toluoylaminomalonate were added to 100 ml of dry ethanol, followed by stirring at room temperature for 30 minutes under an argon atmosphere. Next, 15.00 g of 3-bromobenzyl bromide was added dropwise, and the mixture was stirred at 55 ° C for 8 hours. The reaction solution was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to obtain the target compound.
29.82 g were obtained as a yellow oil.
¹H-NMR (CDCl_Three) δ1.31 (6H, t), 2.41 (3H, s), 3.74 (2H, s), 4.30 (4H, q), 6.90-7.40 (7H, m), 7.60-7.70 (2H, m)
Reference Example 38
1-bromo-3- [2-carboxy-2- (p-toluoylamino) ethyl] benzene
  28.93 g of 1-bromo-3- [2,2-bis (ethoxycarbonyl) -2- (p-toluoylamino) ethyl] benzene is dissolved in 200 ml of ethanol, and 9.6 g of sodium hydroxide / 60 ml of water are dissolved. The solution was added and the mixture was heated under reflux for 3 hours. The reaction solution was concentrated, water was added to the residue, and the mixture was washed with diethyl ether. The aqueous layer was acidified with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated to obtain 24.19 g of a colorless oil. The obtained oil was dissolved in 50 ml of ethyl acetate, 150 ml of xylene was added, and the mixture was stirred at 130 ° C. for 15 hours. After evaporating the solvent under reduced pressure, the obtained crystals were washed with diethyl ether to obtain 17.22 g of the desired compound as colorless crystals.
196-197 ° C
Reference Example 39
1- [2-acetyl-2- (p-toluoylamino) ethyl] -3-bromobenzene
  16.84 g of 1-bromo-3- [2-carboxy-2- (p-toluoylamino) ethyl] benzene is dissolved in 85 ml of pyridine, 55 ml of acetic anhydride is added, and the mixture is stirred at 90 to 95 ° C. for 3 hours under an argon atmosphere. did. Next, 55 ml of water was slowly added dropwise so that the maximum temperature became 100 ° C. or lower, and then the mixture was stirred at 60 to 70 ° C. for 20 minutes. The reaction solution was cooled, poured into ice water, and extracted with ethyl acetate. After washing sequentially with 10% hydrochloric acid, water and a saturated aqueous solution of sodium hydrogen carbonate, the solution was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained crystals were washed with isopropyl ether to obtain 13.31 g of the desired compound as slightly brown crystals.
106-107 ° C
Reference Example 40
1-bromo-3-{[5-methyl-2- (p-tolyl) oxazol-4-yl] methyl} benzene
  13.26 g of 1- [2-acetyl-2- (p-toluoylamino) ethyl] -3-bromobenzene was dissolved in 260 ml of toluene, 6.8 ml of phosphorus oxychloride was added, and the mixture was heated under reflux for 3 hours. After cooling, the reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 4: 1) to obtain 10.86 g of a slightly yellow crystal of the target compound.
74-75 ° C
Reference Example 41
3-{[5-methyl-2- (p-tolyl) oxazol-4-yl] methyl} benzaldehyde
  9.48 g of 1-bromo-3-{[5-methyl-2- (p-tolyl) oxazol-4-yl] methyl} benzene, 2.83 g of sodium formate and bis (triphenylphosphine) palladium (II) dichloride N, N-dimethylformamide (30 ml) was added to 0.97 g, and the mixture was stirred at 110 ° C. for 9 hours while passing carbon monoxide. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The insolubles were removed by filtration, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 4: 1) to obtain 3.58 g of colorless crystals of the target compound.
Melting point 98-99 ° C
Reference Example 42
3-{[5-methyl-2- (p-tolyl) oxazol-4-yl] methyl} benzyl alcohol
  3.54 g of 3-{[5-methyl-2- (p-tolyl) oxazol-4-yl] methyl} benzaldehyde was suspended in 35 ml of methanol, and 230 mg of sodium borohydride was added with stirring under ice-cooling. Stirred for .5 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 3.54 g of the target compound as colorless crystals.
97-99 ° C
Reference Example 43
3-{[5-methyl-2- (p-tolyl) oxazol-4-yl] methyl} benzylbromide
  Dissolve 3.52 g of 3-{[5-methyl-2- (p-tolyl) oxazol-4-yl] methyl} benzyl alcohol in 60 ml of dichloromethane and add 3.77 g of triphenylphosphine and 5.17 g of carbon tetrabromide. And stirred at room temperature for 30 minutes. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 4: 1) to obtain 3.96 g of the target compound as colorless crystals. .
Melting point 101-102 ° C
Reference Example 44
3-{[5-methyl-2- (p-tolyl) oxazol-4-yl] methyl} benzylmalonate diethyl
  0.88 g of 60% sodium hydride was added to 15 ml of dry tetrahydrofuran and 7 ml of dry N, N-dimethylformamide, and 4.40 g of diethyl malonate was added dropwise under ice-cooling and stirring. After stirring for 15 minutes after the dropwise addition, a solution of 3.93 g of 3-{[5-methyl-2- (p-tolyl) oxazol-4-yl] methyl} benzyl bromide / 5 ml of dry tetrahydrofuran was added, and the solution was added under ice cooling. Stirred for hours. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 5: 1) to give 3.95 g of the target compound as a colorless oil. Got.
¹H-NMR (CDCl_Three) δ 1.17 (6H, t), 2.25 (3H, s), 2.38 (3H, s), 3.18 (2H, d), 3.62 (1H, t), 4.07 (2H, s), 4.12 (4H, q ), 7.00 ~ 7.30 (6H, m), 7.80 ~ 7.90 (2H, m)
Reference Example 45
2- [3-{[5-methyl-2- (p-tolyl) oxazol-4-yl] methyl} benzyl] -1,3-propanediol
  854 mg of lithium aluminum hydride was added to 30 ml of dry tetrahydrofuran, and 3.94 g of diethyl 3-{[5-methyl-2- (p-tolyl) oxazol-4-yl] methyl} benzylmalonate / dry tetrahydrofuran was stirred under ice-cooling. 10 ml was added dropwise. After stirring at room temperature for 1.5 hours, the mixture was cooled with ice water, 0.85 ml of water, 0.85 ml of a 15% aqueous sodium hydroxide solution and 2.5 ml of water were successively added dropwise and stirred for 15 minutes. After filtering off the insoluble matter, the filtrate was concentrated once, and the residue was dissolved in ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, chloroform: methanol = 20: 1) to obtain 2.32 g of the target compound as colorless crystals.
114-115 ° C
Reference Example 46
Diethyl (3-fluoro-4-methylbenzoyl) aminomalonate
  To a solution of 10.1 g of 3-fluoro-4-methylbenzoic acid and 15.2 g of diethylaminomalonic acid hydrochloride in 200 ml of N, N-dimethylformamide, 9.7 g of 1-hydroxybenzotriazole, 23 ml of triethylamine and 1- (3- 13.8 g of (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were sequentially added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, 10% hydrochloric acid, water and a saturated aqueous solution of sodium hydrogen carbonate in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and isopropyl ether was added to the residue for crystallization to obtain 15.1 g of the desired compound as colorless crystals.
Melting point 102-103 ° C
Reference Example 47
1- (p-toluenesulfonyloxy) -3- [2- (p-tolyl) -5-trifluoromethyloxazol-4-yl] propane
  3- [2- (p-tolyl) -5-trifluoromethyloxazol-4-yl] -1 synthesized according to the literature of Kawase et al. (Chem. Pharm. Bull., 46, 749-756 (1998)). 6.40 g of -propanol was dissolved in 35 ml of dichloromethane, 293 mg of 4- (dimethylamino) pyridine, 4.7 ml of triethylamine and 5.13 g of p-toluenesulfonyl chloride were sequentially added, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction solution, washed with water, 10% hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 10.08 g of the target compound as pale brown crystals.
Melting point 57-58 ° C
Reference Example 48
4- [2- (p-tolyl) -5-trifluoromethyloxazol-4-yl] butanenitrile
  Dissolve 10.08 g of 1- (p-toluenesulfonyloxy) -3- [2- (p-tolyl) -5-trifluoromethyloxazol-4-yl] propane in 40 ml of dimethylsulfoxide, and add 1.16 g of sodium cyanide. The mixture was stirred at 90 ° C. for 2 hours. Water was added to the reaction solution, extracted with diethyl ether, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 6.35 g of the desired compound as pale brown crystals.
Melting point 41-42.5 ° C
Reference Example 49
Methyl 4- [2- (p-tolyl) -5-trifluoromethyloxazol-4-yl] butanoate
  5.28 g of 4- [2- (p-tolyl) -5-trifluoromethyloxazol-4-yl] butanenitrile was dissolved in 40 ml of methanol, and the mixture was stirred for 10 minutes under ice cooling while passing hydrogen chloride gas. The aeration was stopped, the temperature was raised to room temperature, and the mixture was further stirred for 30 minutes. 5 ml of water was added to the reaction solution, stirred for 30 minutes, and left at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate = 4: 1) to obtain 5.63 g of the target compound as colorless crystals.
44.5-45 ° C
Reference Example 50
Methyl 4- (fluoromethyl) benzoate
  25.00 g of methyl 4- (bromomethyl) benzoate, potassium fluoride
150 ml of dry acetonitrile was added to 19.02 g and 9.51 g of calcium fluoride, and the mixture was heated under reflux for 3 days. The reaction solution was once concentrated, 200 ml of acetonitrile was added, insolubles were removed by filtration, and the mixture was concentrated again. The residue was purified by silica gel column chromatography (YMC-GEL (registered trademark) SIL-60-230 / 70, n-hexane: ethyl acetate = 10: 1 to 4: 1), followed by distillation under reduced pressure to obtain the target compound. 14.45 g of a colorless oil was obtained.
Boiling point 118.5 to 119 ° C / 18 mmHg
¹H-NMR (CDCl_Three) δ3.93 (3H, s), 5.44 (2H, d), 7.40 ~ 7.46 (2H, m), 8.03 ~ 8.09 (2H, m)
Reference Example 51
4- (fluoromethyl) benzoic acid
  8.68 g of methyl 4- (fluoromethyl) benzoate was dissolved in 200 ml of methanol, 77 ml of a 1N aqueous sodium hydroxide solution was added dropwise under ice-cooling and stirring, and the mixture was stirred at room temperature for 3.5 hours. After acidification with 1N hydrochloric acid, the precipitated crystals were collected by filtration, and the filtrate was concentrated. The precipitated crystals and the filtrate residue were combined, added with water, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 7.47 g of the target compound as colorless crystals.
Melting point 192-194 ° C
Reference Example 52
4- (fluoromethyl) benzoyl chloride
  6.20 g of 4- (fluoromethyl) benzoic acid was dissolved in 30 ml of benzene, 0.3 ml of N, N-dimethylformamide was added, 4.4 ml of thionyl chloride was added dropwise, and the mixture was stirred at 40 ° C. for 1 hour. The mixture was refluxed for 1 hour. The solvent was distilled off under reduced pressure to obtain 6.70 g of the target compound as a pale yellow oil.
Reference Example 53
Ethyl 6-chloro-2-ethoxycarbonyl-2- (p-toluoylamino) hexanoate
  6.42 g of sodium was added to 390 ml of ethanol and dissolved at room temperature. 78.0 g of diethyl p-toluoylaminomalonate was added, 47.9 g of 1-bromo-4-chlorobutane was added dropwise with heating under reflux, and the mixture was refluxed with heating for 20 hours. The reaction solution was concentrated, water was added to the residue, and the mixture was washed with ethyl acetate. After washing sequentially with 10% hydrochloric acid and water, the extract was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 9: 1) to give the target compound as a colorless oil.
55.7 g were obtained.
¹H-NMR (CDCl_Three) δ1.26 (6H, t), 1.26 ~ 1.42 (2H, m), 1.72 ~ 1.86 (2H, m), 2.41 (3H, s), 2.44 ~ 2.52 (2H, m), 3.51 (2H, t) , 4.28 (4H, q), 7.24-7.28 (2H, m), 7.48 (1H, s), 7.71-7.75 (2H, m)
Reference Example 54
6-chloro-2- (p-toluoylamino) hexanoic acid
  103.2 g of ethyl 6-chloro-2-ethoxycarbonyl-2- (p-toluoylamino) hexanoate was dissolved in 412 ml of methanol, a solution of 24.5 g of sodium hydroxide in 98 ml of water was added, and the mixture was heated under reflux for 16 hours. . The reaction solution was concentrated, ethyl acetate was added to the residue, acidified with hydrochloric acid, and extracted with ethyl acetate. After washing with water, the extract was dried over anhydrous magnesium sulfate and concentrated to obtain 80.0 g of a colorless gum. 75 ml of acetic acid was added to the obtained gum-like substance, and the mixture was heated under reflux for 10 hours. After stirring and cooling, the precipitated crystals were washed with ethyl acetate, and further recrystallized from acetic acid to obtain 26.0 g of the desired compound as colorless crystals.
Melting point 177-181 ° C
Reference Example 55
8-chloro-4- (p-toluoylamino) -3-octanone
  10.0 g of 6-chloro-2- (p-toluoylamino) hexanoic acid was dissolved in 15 ml of dry pyridine, 15 ml of propionic anhydride was added, and the mixture was stirred at 90 ° C for 2.5 hours. Next, 15 ml of water was slowly added dropwise so that the maximum temperature became 85 ° C. or lower, and then the mixture was stirred at 80 ° C. for 20 minutes. The reaction solution was cooled, poured into ice water, and extracted with diethyl ether. After washing with 10% hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline in this order, the extract was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 8: 1 to 4: 1) to obtain 6.0 g of the desired compound as colorless crystals.
85-86 ° C
Reference Example 56
4- (4-chlorobutyl) -5-ethyl-2- (p-tolyl) oxazole
  6.5 g of 8-chloro-4- (p-toluoylamino) -3-octanone was dissolved in 150 ml of toluene, 4.1 ml of phosphorus oxychloride was added, and the mixture was heated under reflux for 1.5 hours. After cooling, the reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 8: 1) to obtain 5.5 g of slightly yellow crystals of the target compound.
¹H-NMR (CDCl_Three) δ 1.27 (3H, t), 1.78-1.87 (4H, m), 2.38 (3H, s), 2.52 (2H, t), 2.67 (2H, q), 3.57 (2H, t), 7.23 (2H , d), 7.84 to 7.89 (2H, m)
Reference Example 57
Diethyl 4- [5-ethyl-2- (p-tolyl) oxazol-4-yl] butylmalonate
  To 32.8 ml of a 21% sodium ethoxide-ethanol solution, 16.7 ml of diethyl malonate was added under reflux with heating, and then 4- (4-chlorobutyl) -5-ethyl-2- (p-tolyl) oxazole 5 0.0 g / 5 ml of ethanol was added dropwise, and the mixture was heated and refluxed for 7 hours under an argon atmosphere. The reaction solution was poured into ice water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 10: 1) to give the desired compound
2.65 g were obtained as a yellow oil.
¹H-NMR (CDCl_Three) δ1.25 (6H, t), 1.29 (3H, t), 1.35-1.46 (2H, m), 1.65-1.73 (2H, m), 1.88-1.99 (2H, m), 2.39 (3H, s) , 2.48 (2H, t), 2.66 (2H, q), 3.32 (1H, t), 4.13 ~ 4.26 (4H, m), 7.22 (2H, d), 7.87 (2H, d)
Reference Example 58
  The following compound was produced in the same manner as in Example 6 described later.
2,2-dimethyl-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane
Methyl 4- (5-methyl-2-phenyloxazol-4-yl) butyrate, and
Methyl 3- (5-methyl-2-phenyloxazol-4-yl) propionate
Reference Example 59
1- (o-toluoylamino) -2-propanol
  18.0 ml of triethylamine was added to 100 ml of a toluene solution of 5.83 g of 1-amino-2-propanol, and 10 ml of a toluene solution of 10.00 g of o-toluoyl chloride was slowly added dropwise with stirring under ice-cooling. After stirring for 30 minutes, the ice bath was removed, and the mixture was further stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with 10% hydrochloric acid, ice water, and a saturated aqueous solution of sodium hydrogen carbonate in that order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from diethyl ether to give 7.25 g of the desired compound as colorless crystals.
Melting point 78-81 ° C
  The following compound was produced in the same manner as in Reference Example 59.
1- (4-fluoromethylbenzoylamino) -2-propanol,
1- (m-toluoylamino) -2-propanol, and
1- (cyclohexylcarbonylamino) -2-propanol
Reference Example 60
1- (o-toluoylamino) -2-propanone
  To a suspension of 7.13 g of 1- (o-toluoylamino) -2-propanol and 15.91 g of diatomaceous earth filter aid in 143 ml of dichloromethane was added 15.91 g of pyridinium chlorochromate with stirring. Stirred for hours. After the reaction solution was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, chloroform), the solvent was distilled off under reduced pressure. The eluate was purified again by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 1: 2) to obtain 5.73 g of the desired compound as colorless crystals.
65-66 ° C
  The following compound was produced in the same manner as in Reference Example 60.
1- (2,4-dimethylbenzoylamino) -2-propanone,
1- (4-fluoromethylbenzoylamino) -2-propanone,
1- (m-toluoylamino) -2-propanone,
1- (3,4-dimethylbenzoylamino) -2-propanone,
1- (4-methoxybenzoylamino) -2-propanone, and
1- (cyclohexylcarbonylamino) -2-propanone
Reference Example 61
Methyl c-5- [5-acetyl-5- (o-toluoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate
  Under an argon atmosphere, 40 ml of a suspension of 1.18 g of 60% sodium hydride in N, N-dimethylformamide was cooled to −25 ° C. in a dry ice-acetone bath, and then 1- (o-toluoylamino) -2- A solution of 5.65 g of propanone in 15 ml of N, N-dimethylformamide was slowly added dropwise. After stirring for 1 hour, a solution of 10.09 g of methyl c-5- (4-iodobutyl) -2-methyl-1,3-dioxane-r-2-carboxylate in 5 ml of N, N-dimethylformamide was slowly added dropwise, and furthermore, Stir for 1 hour. After 1 ml of 1N hydrochloric acid was added to the reaction solution, water was added, and the mixture was extracted with diethyl ether. After washing with a 0.5% aqueous sodium hydroxide solution, the extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 1: 1) to obtain 6.38 g of the desired compound as a colorless oil.
¹H-NMR (CDCl_Three) δ1.01 ~ 1.08 (2H, m), 1.22 ~ 1.39 (4H, m), 1.51 (3H, s), 1.62 ~ 1.71 (2H, m), 1.97 ~ 2.09 (1H, m), 2.28 (3H, m s), 2.44 (3H, s), 3.39 (2H, t), 3.83 (3H, s), 3.94 (2H, dd), 4.84 (1H, q), 6.49 (1H, d), 7.22-7.42 (4H , m)
  The following compound was produced in the same manner as in Reference Example 61.
c-5- [5-acetyl-5- (2,4-dimethylbenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate methyl,
c-5- [5-acetyl-5- (4-fluoromethylbenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate methyl,
c-5- [5-acetyl-5- (m-toluoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate methyl,
c-5- [5-acetyl-5- (3,4-dimethylbenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate methyl,
c-5- [5-acetyl-5- (4-methoxybenzoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate methyl,
methyl c-5- [5-acetyl-5- (2-thenoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate; and
c-5- [5-Acetyl-5- (cyclohexylcarbonylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate methyl
Reference Example 62
1- (3,4-dimethylbenzoylamino) -2-propanol
  To a solution of 5.00 g of 3,4-dimethylbenzoic acid and 2.75 g of 1-amino-2-propanol in 30 ml of N, N-dimethylformamide, 4.95 g of 1-hydroxybenzotriazole, 6.96 ml of triethylamine, 1- (3 -Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (7.02 g) was sequentially added, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed sequentially with 10% hydrochloric acid, ice water and a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 6.28 g of the target compound as colorless crystals.
77-78 ° C
  The following compound was produced in the same manner as in Reference Example 62.
1- (2,4-dimethylbenzoylamino) -2-propanol, and
1- (4-methoxybenzoylamino) -2-propanol
Reference Example 63
Methyl 2- (2-thenoylamino) acetate
  20.24 g of triethylamine was added to 250 ml of a dichloromethane suspension of 12.56 g of methyl 2-aminoacetate hydrochloride, and the mixture was stirred at room temperature for 30 minutes. After cooling with ice, 20 ml of a dichloromethane solution of 14.66 g of 2-thenoyl chloride was slowly added dropwise, and the ice bath was removed, followed by stirring at room temperature for 14 hours. The precipitated crystals were collected by filtration and washed with dichloromethane. One filtrate was evaporated under reduced pressure, and the residue was crystallized by adding t-butyl methyl ether. By combining both, 17.20 g of the target compound was obtained as slightly brown crystals.
¹H-NMR (CDCl_Three) δ3.80 (3H, s), 4.23 (2H, d), 6.62 (1H, br), 7.09 (1H, dd), 7.50 (1H, dd), 7.57 (1H, dd)
Reference Example 64
Sodium 2- (2-thenoylamino) acetate
  20 ml of an aqueous solution of 4.02 g of sodium hydroxide was added to 200 ml of a methanol solution of 16.70 g of methyl 2- (2-thenoylamino) acetate, and the mixture was heated under reflux for 30 minutes. The solvent under reduced pressure was distilled off, and the residue was crystallized by adding isopropanol to obtain 18.03 g of the desired compound as pale yellow crystals.
Reference Example 65
1- (2-thenoylamino) -2-propanone
  42.7 ml of acetic anhydride was added to 44.0 ml of a β-picoline suspension of 16.70 g of sodium 2- (2-thenoylamino) acetate, and the mixture was stirred at room temperature for 3 hours. After cooling with ice, 26.3 ml of ethanol, 129.7 ml of water and 45.2 ml of concentrated hydrochloric acid were slowly added dropwise in that order, and the ice bath was removed for 15 minutes, followed by stirring at room temperature for another 15 minutes. 250 ml of water was added, and the precipitated crystals were collected by filtration and washed with water. 37.0 ml of water was added, and the mixture was heated under reflux for 1 hour. Further, 14.0 g of sodium chloride was added, and the mixture was refluxed for 1 hour. Ethyl acetate was added to the reaction solution, extracted, dried over anhydrous magnesium sulfate, activated carbon (Strong Shirasagi (registered trademark) MOIWY433) was added, and the mixture was stirred at room temperature for 30 minutes. The solvent under reduced pressure was distilled off, and the residue was crystallized by adding t-butyl methyl ether.
7.15 g were obtained as pale brown crystals.
¹H-NMR (CDCl_Three) δ 2.27 (3H, s), 4.34 (2H, d), 6.80 (1H, br), 7.09 (1H, dd), 7.50 (1H, dd), 7.57 (1H, dd)
Reference Example 66
4- [5,5-bis (bromomethyl) pentyl] -5-methyl-2- (p-tolyl) oxazole
  To a solution of 2.25 g of 4- [5,5-bis (hydroxymethyl) pentyl] -5-methyl-2- (p-tolyl) oxazole in 15 ml of N, N-dimethylformamide, 3.92 ml of γ-collidine, bromide 2.57 g of lithium and 2.3 ml of methanesulfonyl chloride were sequentially added, and the mixture was heated and stirred at 80 ° C. for 2.5 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 9: 1) to obtain 1.45 g of the desired compound as a brown oil.
¹H-NMR (CDCl_Three) δ 1.30 ~ 1.55 (2H, m), 1.60 ~ 1.85 (4H, m), 1.95 ~ 2.15 (1H, m), 2.31 (3H, s), 2.38 (3H, s), 2.49 (2H, t) , 2.82 ~ 3.05 (4H, m), 7.38 ~ 7.45 (2H, m), 7.94 ~ 8.01 (2H, m)
Reference Example 67
4- [5,5-bis (acetylthiomethyl) pentyl] -5-methyl-2- (p-tolyl) oxazole
  1.18 g of potassium thiol acetate was added to 4 ml of a solution of 923 mg of 4- [5,5-bis (bromomethyl) pentyl] -5-methyl-2- (p-tolyl) oxazole in polyethylene glycol # 200. The mixture was heated and stirred for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 9: 1) to obtain 830 mg of the desired compound as a brown oil.
¹H-NMR (CDCl_Three) δ 1.35-1.50 (4H, m), 1.55-1.70 (2H, m), 1.75-1.95 (1H, m), 2.32 (3H, s), 2.33 (6H, s), 2.38 (3H, s) , 2.47 (2H, t), 2.82 ~ 3.05 (4H, m), 7.20 ~ 7.25 (2H, m), 7.84 ~ 7.89 (2H, m)
  The following compound was produced in the same manner as in Reference Example 67.
5-methyl-4- (6-acetylthiohexyl) -2- (p-tolyl) oxazole
Reference Example 68
4- [5,5-bis (mercaptomethyl) pentyl] -5-methyl-2- (p-tolyl) oxazole
  8 ml of a 1N aqueous sodium hydroxide solution was added to 8 ml of a methanol solution of 830 mg of 4- [5,5-bis (acetylthiomethyl) pentyl] -5-methyl-2- (p-tolyl) oxazole, and the mixture was heated under reflux for 1 hour. The reaction solution was acidified with 1N hydrochloric acid, extracted with dichloromethane, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 635 mg of the desired compound as a pale yellow oil.
¹H-NMR (CDCl_Three) 1.25 to 195 (9H, m), 2.31 (3H, s), 2.38 (3H, s), 2.48 (2H, t), 2.55 to 2.85 (4H, m), 7.16 to 7.24 (2H, m) , 7.81 to 7.89 (2H, dd)
Reference Example 69
Ethyl 6-iodohexanoate
  26.97 g of sodium iodide was added to 112 ml of an acetone solution of 13.38 g of ethyl 6-bromohexanoate, and the mixture was heated under reflux for 18 hours. After cooling the reaction solution, insolubles were removed by filtration and washed with acetone. The filtrate was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated to give 16.21 g of the desired compound as a red-yellow oil.
¹H-NMR (CDCl_Three) δ1.26 (3H, t), 1.39 ~ 1.51 (2H, m), 1.58 ~ 1.73 (2H, m), 1.78 ~ 1.92 (2H, m), 2.31 (2H, t), 3.19 (2H, t) , 4.13 (2H, q)
Reference example 70
Ethyl 7-acetyl-7- (p-toluoylamino) heptanoate
  100 ml of a suspension of 2.64 g of 60% sodium hydride in N, N-dimethylformamide was cooled to −18 ° C. in an ice-salt bath, and then 12.62 g of 1- (p-toluoylamino) -2-propanone was added. 31 ml of an N, N-dimethylformamide solution was slowly added dropwise. After stirring for 1 hour, 31 ml of a solution of 16.21 g of ethyl 6-iodohexanoate in N, N-dimethylformamide was slowly added dropwise, and the ice bath was removed, followed by stirring at room temperature for further 18 hours. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 3: 1) to obtain 13.13 g of the desired compound as a yellow oil.
¹H-NMR (CDCl_Three) δ 1.20 ~ 1.45 (4H, m), 1.24 (3H, t), 1.54 ~ 1.77 (3H, m), 2.01 ~ 2.08 (1H, m), 2.23 ~ 2.31 (2H, t), 2.40 (3H, t) s), 2.78 (3H, s), 4.11 (2H, q), 4.18 ~ 4.90 (1H, m), 6.90 (1H, d), 7.25 (2H, d), 7.71 (2H, d)
Reference Example 71
Ethyl 2- (6-iodohexyloxy) -2-methylpropionate
  Ethyl 2- (6-bromohexyloxy) -2-methylpropionate
18.52 g of sodium iodide was added to 76 ml of an acetone solution of 12.16 g, and the mixture was refluxed for 18 hours. After cooling the reaction solution, insolubles were removed by filtration and washed with acetone. The filtrate was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate, and concentrated to give 14.46 g of the desired compound as a red-yellow oil.
¹H-NMR (CDCl_Three) δ 1.29 (3H, t), 1.37 ~ 1.40 (4H, m), 1.41 (6H, s), 1.55 ~ 1.62 (2H, m), 1.80 ~ 1.87 (2H, m), 3.19 (2H, t) , 3.56 (2H, t), 4.12 (2H, q)
Reference Example 72
Ethyl 2- [7-acetyl-7- (p-toluoylamino) heptyloxy] -2-methylpropionate
  70 ml of a suspension of 1.81 g of 60% sodium hydride in N, N-dimethylformamide was cooled to −18 ° C. in an ice-salt bath, and 8.67 g of 1- (p-toluoylamino) -2-propanone was added. 21 ml of an N, N-dimethylformamide solution was slowly added dropwise. After stirring for 1 hour, a solution of 14.10 g of ethyl 2- (6-iodohexyloxy) -2-methylpropionate in 21 ml of N, N-dimethylformamide was slowly added dropwise, and the ice bath was removed, followed by stirring at room temperature for further 18 hours. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 3: 1) to obtain 12.20 g of the desired compound as a yellow oil.
¹H-NMR (CDCl_Three) δ 1.23 to 1.41 (6H, m), 1.27 (3H, t), 1.39 (6H, s), 1.51 to 1.57 (2H, m), 1.71 to 1.74 (1H, m), 2.01 to 2.08 (1H, m), 2.27 (3H, s), 2.40 (3H, s), 3.32 (2H, t), 4.17 (2H, q), 4.80〜4.90 (1H, m), 6.89 (1H, d), 7.25 (2H , d), 7.71 (2H, d)
Reference Example 73
7- (benzoylamino) -7-carboxy- (E) -4-heptenoic acid
  To a 170 ml ethanol solution of 8.50 g of diethyl [5- (benzoylamino) -5,5-bis (ethoxycarbonyl)-(E) -2-pentenyl] malonate was added 34 ml of an aqueous solution of 5.53 g of sodium hydroxide. And heated to reflux for 20 hours. The reaction solution was concentrated, water was added to the residue, and the mixture was washed with diethyl ether. The aqueous layer was acidified with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated to obtain 6.58 g of a pale yellow oil. The obtained oil was dissolved in 90 ml of ethyl acetate, 90 ml of xylene was added, and the mixture was stirred at 130 ° C. for 15 hours. After evaporating the solvent under reduced pressure, the obtained crystals were washed with isopropyl ether to obtain 4.52 g of the desired compound as colorless crystals.
138 ° C
Example 1
2-methyl-c-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylate methyl
  36 g of 4- [5,5-bis (hydroxymethyl) pentyl] -5-methyl-2-phenyloxazole was dissolved in 432 ml of acetonitrile, and 25.4 g of methyl pyruvate was added. 35.3 g of boron trifluoride etherate (about 47%) was added to the mixture while stirring at room temperature, and the mixture was refluxed for 2 hours. The reaction solution was cooled, poured into an aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate = 7.5: 1), and the fraction eluted earlier was concentrated to give the target compound as a colorless oil 16.5 g of the product were obtained.
¹H-NMR (CDCl_Three) δ: 1.00 to 1.12 (2H, m), 1.22 to 1.40 (2H, m), 1.55 to 1.70 (5H, m), 1.90 to 2.20 (1H, m), 2.30 (3H, s), 2.45 (2H, t), 3.39 (2H, t), 3.82 (3H, s), 3.95 (2H, dd), 7.37-7.47 (3H, m), 7.92-8.03 (2H, m)
Example 2
2-methyl-t-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylate methyl ester
  The post-fraction of Example 1 was collected and concentrated, and 11 g of the residue was purified again by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 7.5: 1). 0.83 g of a colorless oily product of the target compound was obtained.
¹H-NMR (CDCl_Three) δ: 1.33 ~ 1.44 (3H, m), 1.51 (3H, s), 1.63 ~ 1.78 (4H, m), 2.33 (3H, s), 2.51 (2H, t), 3.75 ~ 3.81 (2H, m) , 3.83 (3H, s), 3.91 ~ 3.99 (2H, m), 7.38 ~ 7.45 (3H, m), 7.96 ~ 8.01 (2H, m)
  The following compounds were produced in the same manner as in Examples 1 and 2.
c-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylate methyl,
methyl t-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylate;
Methyl 2-ethyl-c-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylate;
Methyl 2-isobutyl-c-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylate,
Methyl 2,5-dimethyl-c-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylate,
Methyl 2,5-dimethyl-t-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylate,
Methyl 5-ethyl-2-methyl-c-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylate;
Methyl 5-ethyl-2-methyl-t-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylate;
Methyl 2-methyl-c-5- [3- (5-methyl-2-phenyloxazol-4-yl) propyl] -1,3-dioxane-r-2-carboxylate,
Methyl 2-methyl-t-5- [3- (5-methyl-2-phenyloxazol-4-yl) propyl] -1,3-dioxane-r-2-carboxylate;
2-methyl-c-5- {4-[(5-methyl-2-phenyloxazol-4-yl) methyl] benzyl} -1,3-dioxane-r-2-carboxylate methyl,
2-methyl-c-5- {4-[(5-methyl-2-phenyloxazol-4-yl) methyl] phenyl} -1,3-dioxane-r-2-carboxylate methyl,
2-methyl-c-5- {3-[(5-methyl-2-phenyloxazol-4-yl) methyl] phenyl} -1,3-dioxane-r-2-carboxylate methyl,
Methyl 2-methyl-c-5- {4- [2- (p-tolyl) -5-trifluoromethyloxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylate;
Methyl 2-methyl-c-5- {4- [5-ethyl-2- (p-tolyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylate;
2-Ethyl-c-5- {4- [5-methyl-2- (p-tolyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylate
Example 3
Methyl 2-methyl-c-5- [4- (2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylate
  1.25 g of 4- [5,5-bis (hydroxymethyl) pentyl] -2-phenyloxazole was dissolved in 5 ml of acetonitrile, and 927 mg of methyl pyruvate was added. 1.3 g of boron trifluoride etherate (about 47%) was added to the mixture with stirring at room temperature, and the mixture was stirred at room temperature for 30 hours. The reaction solution was poured into an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: isopropyl ether = 1: 1), the previously eluted fraction was concentrated, and 450 mg of white crystals of the target compound were obtained. Obtained.
71-74 ° C
¹H-NMR (CDCl_Three) δ: 1.01 ~ 1.12 (2H, m), 1.27 ~ 1.43 (2H, m), 1.51 (3H, s), 1.59 ~ 1.74 (2H, m), 1.90 ~ 2.20 (1H, m), 2.56 (2H, m t), 3.39 (2H, t), 3.83 (3H, s), 3.96 (2H, dd), 7.41-7.47 (4H, m), 7.99-8.05 (2H, m)
Example 4
Methyl 2-methyl-t-5- [4- (2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylate
  The post-fraction of Example 3 was collected and concentrated, and the residue was purified again by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: isopropyl ether = 1: 1) to give the target compound. 110 mg of a colorless oil were obtained.
¹H-NMR (CDCl_Three) δ: 1.25 to 1.48 (2H, m), 1.51 (3H, s), 1.63 to 1.80 (5H, m), 2.62 (2H, t), 3.76 to 3.86 (5H, m), 3.92 to 4.00 (2H, m), 7.41 ~ 7.47 (4H, m), 8.00 ~ 8.05 (2H, m)
Example 5
2-methyl-5- {3-[(5-methyl-2-phenyloxazol-4-yl) methyl] benzyl} -1,3-dioxane-2-carboxylate
  To 5 ml of acetonitrile, 297 mg of 4- {3- [2,2-bis (hydroxymethyl) ethyl] benzyl} -5-methyl-2-phenyloxazole and 369 mg of methyl pyruvate were added. To the mixture was added 544 mg of boron trifluoride etherate (about 47%) with stirring at room temperature, and the mixture was stirred at room temperature for 14 hours. The reaction solution was poured into an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 3: 1) to give cis: trans = 2.5: 1 (from the integrated value of NMR). 185 mg of a colorless oil as a mixture was obtained.
Example 6
2-methyl-c-5- {4- [5-methyl-2- (p-tolyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylate methyl
  Dissolve 0.85 g of methyl c-5- [5-acetyl-5- (p-toluoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate in 17 ml of toluene, and add phosphorus oxychloride. 644 mg was added, and the mixture was heated under reflux for 2.5 hours. The reaction solution was cooled, poured into ice water, neutralized with an aqueous solution of sodium bicarbonate, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, chloroform: methanol = 100: 1) to obtain 0.42 g of white crystals of the target compound.
92-94 ° C
Elemental analysis (C_{twenty two}H₂₉NO_FiveAs)
   Calculated value (%) C: 68.20 H: 7.54 N: 3.61
   Obtained value (%) C: 68.07 H: 7.43 N: 3.65
  The following compound was produced in the same manner as in Example 6.
Methyl 2-methyl-c-5- [3- (5-methyl-2-phenyloxazol-4-yl) propyl] -1,3-dioxane-r-2-carboxylate,
Methyl 2-methyl-c-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylate;
Methyl 2-methyl-c-5- [5- (5-methyl-2-phenyloxazol-4-yl) pentyl] -1,3-dioxane-r-2-carboxylate;
c-5- {4- [2- (4-fluorophenyl) -5-methyloxazol-4-yl] butyl} -2-methyl-1,3-dioxane-r-2-carboxylate methyl,
c-5- {4- [2- (4-tert-butylphenyl) -5-methyloxazol-4-yl] butyl} -2-methyl-1,3-dioxane-r-2-carboxylate methyl,
2-methyl-c-5- {4- [5-methyl-2- (4-trifluoromethylphenyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylate methyl,
Methyl 2-methyl-c-5- [4- (5-methyl-2-phenyloxazol-4-yl)-(E) -2-butenyl] -1,3-dioxane-r-2-carboxylate;
Methyl 2-methyl-2- [6- (5-methyl-2-phenyloxazol-4-yl) hexyloxy] propionate,
Methyl 2-methyl-2- {6- [5-methyl-2- (p-tolyl) oxazol-4-yl] hexyloxy} propionate,
Methyl 2-methyl-2- [6- (5-methyl-2-phenyloxazol-4-yl) -4-hexynyloxy] propionate,
Methyl 2- {6- [2- (4-chlorophenyl) -5-methyloxazol-4-yl] hexyloxy} -2-methylpropionate,
Methyl 2- {6- [2- (4-fluorophenyl) -5-methyloxazol-4-yl] hexyloxy} -2-methylpropionate,
Methyl 2- {6- [2- (4-tert-butylphenyl) -5-methyloxazol-4-yl] hexyloxy} -2-methylpropionate;
Methyl 2-methyl-2- [7- (5-methyl-2-phenyloxazol-4-yl) heptyloxy] propionate,
Methyl 2-methyl-2- [5- (5-methyl-2-phenyloxazol-4-yl) pentyloxy] propionate,
Methyl 2- [6- (5-ethyl-2-phenyloxazol-4-yl) hexyloxy] -2-methylpropionate,
Methyl 2-methyl-2- {6- [5-methyl-2- (4-pyridyl) oxazol-4-yl] hexyloxy} propionate,
Methyl 2-methyl-2- {6- [5-methyl-2- (3-pyridyl) oxazol-4-yl] hexyloxy} propionate,
2-methyl-c-5- {4- [5-methyl-2- (4-chlorophenyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylate methyl,
Methyl 2-methyl-c-5- {5- [5-methyl-2- (p-tolyl) oxazol-4-yl] pentyl} -1,3-dioxane-r-2-carboxylate;
Methyl 2-methyl-c-5- {4- [5-methyl-2- (3-fluoro-4-methylphenyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylate ,
Methyl 2-methyl-c-5- {4- [5-methyl-2- (4-ethylphenyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylate;
Methyl 2-methyl-c-5- {4- [5-methyl-2- (2,4-dimethylphenyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylate;
2-methyl-c-5- {4- [2- (4-fluoromethylphenyl) -5-methyloxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylate methyl,
Methyl 2-methyl-c-5- {4- [5-methyl-2- (m-tolyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylate;
Methyl 2-methyl-c-5- {4- [5-methyl-2- (o-tolyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylate;
Methyl 2-methyl-c-5- {4- [5-methyl-2- (3,4-dimethylphenyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylate;
Methyl 2-methyl-c-5- {4- [5-methyl-2- (4-methoxyphenyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylate;
Methyl 2-methyl-c-5- {4- [5-methyl-2- (2-thienyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylate;
2-methyl-c-5- {4- [2-cyclohexyl-5-methyloxazole
-4-yl] butyl} -1,3-dioxane-r-2-carboxylate, and
Ethyl 2-methyl-2- {6- [5-methyl-2- (p-tolyl) oxazol-4-yl] hexyloxy} propionate
Example 7
Methyl 2-methyl-2- [6- (2-phenyloxazol-4-yl) hexyloxy] propionate
  956 mg of benzamide and 1.1 g of methyl 2- (8-chloro-7-oxooctyloxy) -2-methylpropionate were stirred at 120 ° C. for 2 hours. The reaction mixture was cooled, dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate, washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 9: 1) to obtain 658 mg of the target compound as a colorless oil.
¹H-NMR (CDCl_Three) δ: 1.36 to 1.50 (10H, m), 1.55 to 1.80 (4H, m), 2.54 to 2.63 (2H, m), 3.35 (2H, t), 3.73 (3H, s), 7.41 to 7.47 (4H, m), 7.99-8.05 (2H, m)
  The following compound was produced in the same manner as in Example 7.
Methyl 2-methyl-2- [7- (2-phenyloxazol-4-yl) heptyloxy] propionate,
Methyl 2- {7- [2- (4-chlorophenyl) oxazol-4-yl] heptyloxy} -2-methylpropionate,
Methyl 2- {7- [2- (4-fluorophenyl) oxazol-4-yl] heptyloxy} -2-methylpropionate,
Methyl 2- {6- [2- (4-fluorophenyl) oxazol-4-yl] hexyloxy} -2-methylpropionate; and
Methyl 2-methyl-2- [8- (2-phenyloxazol-4-yl) octyloxy] propionate
Example 8
Methyl 2-methyl-2- [7- (2-phenylthiazol-4-yl) heptyloxy] propionate
  783 mg of thiobenzamide and 1.0 g of methyl 2- (9-chloro-8-oxononyloxy) -2-methylpropionate were stirred at 120 ° C. for 2 hours. After cooling, the reaction solution was dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate, washed with water, dried over anhydrous magnesium sulfate and concentrated, and the residue was subjected to silica gel column chromatography (Wakogel (registered trademark) C-200, Purification with n-hexane: ethyl acetate = 9: 1) gave 963 mg of the target compound as a pale yellow oil.
¹H-NMR (CDCl_Three) δ: 1.36 to 1.39 (6H, m), 1.42 (6H, s), 1.54 to 1.61 (2H, m), 1.72 to 1.80 (2H, m), 2.78 to 2.86 (2H, m), 3.31 to 3.38 ( 2H, m), 3.73 (3H, s), 6.87 (1H, s), 7.39 ~ 7.46 (3H, m) 7.91 ~ 7.96 (2H, m)
  The following compound was produced in the same manner as in Example 8.
Methyl 2-methyl-2- [8- (2-phenylthiazol-4-yl) octyloxy] propionate
Example 9
2-methyl-c-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylic acid
  Dissolve 15.76 g of methyl 2-methyl-c-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylate in 215 ml of methanol, A solution of 2.53 g of sodium hydroxide / 28 ml of water was added, and the mixture was refluxed for 4 hours. The reaction was cooled, poured into ice water, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was heated and dissolved in toluene / n-hexane, allowed to cool, and the precipitate was collected by filtration to obtain 13.52 g of the desired product.
¹H-NMR (CDCl_Three) δ: 1.00-1.15 (2H, m), 1.25-1.45 (2H, m), 1.50-1.70 (5H, m), 1.90-2.20 (1H, m), 2.32 (3H, s), 2.52 (2H, m t), 3.49 (2H, dd), 3.99 (2H, dd), 7.40 ~ 7.50 (3H, m), 7.90 ~ 8.05 (2H, m), 9.70 (1H, br)
Elemental analysis (C₂₀H_{twenty five}NO_FiveAs)
   Calculated value (%) C: 66.84 H: 7.01 N: 3.90
   Obtained value (%) C: 66.76 H: 7.09 N: 3.82
Example 10
2-methyl-c-5- {3-[(5-methyl-2-phenyloxazol-4-yl) methyl] benzyl} -1,3-dioxane-r-2-carboxylic acid
  Methyl 2-methyl-5- {3-[(5-methyl-2-phenyloxazol-4-yl) methyl] benzyl} -1,3-dioxane-2-carboxylate (cis: trans = 3: 1 mixture ) 185mg was dissolved in methanol 5ml, 2N sodium hydroxide 0.5ml was added and refluxed for 1 hour. The reaction solution was cooled, poured into ice water, made acidic with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. Ether was added to the residue, and the precipitated crystals were collected by filtration, recrystallized from acetonitrile, and dried to obtain 109 mg of the target compound as white crystals. 147-149 ° C
Elemental analysis (C_{twenty four}H_{twenty five}NO_FiveAs)
   Calculated value (%) C: 70.75 H: 6.18 N: 3.44
   Obtained value (%) C: 70.85 H: 6.26 N: 3.33
Example 11
2-methyl-c-5- {4- [5-methyl-2- (p-tolyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid
  250 mg of methyl 2-methyl-c-5- {4- [5-methyl-2- (p-tolyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylate was added to methanol 2. The mixture was dissolved in 5 ml, a solution of 51 mg of sodium hydroxide / 0.6 ml of water was added, and the mixture was refluxed for 1 hour. The reaction solution was cooled, poured into ice water, made acidic with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. Ether was added to the residue, and the precipitate was collected by filtration. The precipitate was heated and dissolved in acetonitrile, allowed to cool, and then the precipitate was collected by filtration and dried to obtain 196 mg of the desired compound.
Elemental analysis (C_{twenty one}H₂₇NO_FiveAs)
   Calculated value (%) C: 67.54 H: 7.29 N: 3.75
   Obtained value (%) C: 67.57 H: 7.25 N: 3.76
  The compounds of Examples 12 to 52 were produced in the same manner as in Example 11.
Example 12
2-methyl-t-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylic acid
135-140 ° C
¹H-NMR (CDCl_Three) δ: 1.38-1.50 (3H, m), 1.56 (3H, s), 1.60-1.80 (4H, m), 2.33 (3H, s), 2.54 (2H, t), 3.79 (2H, dd), 4.03 (2H, dd), 7.20 (1H, br), 7.40-7.50 (3H, m), 7.90-8.10 (2H, m)
Elemental analysis (C₂₀H_{twenty five}NO_FiveAs)
   Calculated value (%) C: 66.84 H: 7.01 N: 3.90
   Obtained value (%) C: 67.35 H: 7.00 N: 3.77
Example 13
2-methyl-c-5- [5- (5-methyl-2-phenyloxazol-4-yl) pentyl] -1,3-dioxane-r-2-carboxylic acid
135-137 ° C
Elemental analysis (C_{twenty one}H₂₇NO_FiveAs)
   Calculated value (%) C: 67.54 H: 7.29 N: 3.75
   Obtained value (%) C: 67.44 H: 7.34 N: 3.77
Example 14
2-methyl-c-5- [4- (2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylic acid
Elemental analysis (C₁₉H_{twenty three}NO_FiveAs)
   Calculated value (%) C: 66.07 H: 6.71 N: 4.06
   Obtained value (%) C: 66.09 H: 6.75 N: 4.03
Example 15
c-5- [4- (5-Methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylic acid
119-121 ° C
Elemental analysis (C₁₉H_{twenty three}NO_FiveAs)
   Calculated value (%) C: 66.07 H: 6.71 N: 4.06
   Obtained value (%) C: 66.02 H: 6.87 N: 4.18
Example 16
t-5- [4- (5-Methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylic acid
103-105 ° C
Elemental analysis (C₁₉H_{twenty three}NO_FiveAs)
   Calculated value (%) C: 66.07 H: 6.71 N: 4.06
   Obtained value (%) C: 66.07 H: 6.99 N: 4.04
Example 17
2-methyl-t-5- {4- [5-methyl-2- (p-tolyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid
120-122 ° C
Elemental analysis (C_{twenty one}H₂₇NO_FiveAs)
   Calculated value (%) C: 67.54 H: 7.29 N: 3.75
   Observed value (%) C: 67.61 H: 7.35 N: 3.74
Example 18
c-5- {4- [2- (4-tert-butylphenyl) -5-methyloxazol-4-yl] butyl} -2-methyl-1,3-dioxane-r-2-carboxylic acid
Elemental analysis (C_{twenty four}H₃₃NO_FiveAs)
   Calculated value (%) C: 69.37 H: 8.00 N: 3.37
   Obtained value (%) C: 69.26 H: 7.96 N: 3.43
Example 19
c-5- {4- [2- (4-Fluorophenyl) -5-methyloxazol-4-yl] butyl} -2-methyl-1,3-dioxane-r-2-carboxylic acid
Melting point: 138 to 139.5 ° C
Elemental analysis (C₂₀H_{twenty four}FNO_FiveAs)
   Calculated value (%) C: 63.65 H: 6.41 N: 3.71
   Obtained value (%) C: 63.62 H: 6.58 N: 3.69
Example 20
2-methyl-c-5- {4- [5-methyl-2- (4-trifluoromethylphenyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid
Elemental analysis (C_{twenty one}H_{twenty four}F_ThreeNO_FiveAs)
   Calculated value (%) C: 59.01 H: 5.66 N: 3.28
   Obtained value (%) C: 59.14 H: 5.83 N: 3.29
Example 21
2-ethyl-c-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylic acid
Elemental analysis (C_{twenty one}H₂₇NO_FiveAs)
   Calculated value (%) C: 67.54 H: 7.29 N: 3.75
   Obtained value (%) C: 67.05 H: 7.24 N: 3.60
Example 22
2-isobutyl-c-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylic acid
126-130 ° C
Elemental analysis (C_{twenty three}H₃₁NO_FiveAs)
   Calculated value (%) C: 68.80 H: 7.78 N: 3.49
   Obtained value (%) C: 68.72 H: 7.88 N: 3.45
Example 23
2,5-dimethyl-c-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylic acid
147-150 ° C
Elemental analysis (C_{twenty one}H₂₇NO_FiveAs)
   Calculated value (%) C: 67.54 H: 7.29 N: 3.75
   Obtained value (%) C: 68.17 H: 7.76 N: 3.46
Example 24
2,5-dimethyl-t-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylic acid
142-144 ° C
Elemental analysis (C_{twenty one}H₂₇NO_FiveAs)
   Calculated value (%) C: 67.54 H: 7.29 N: 3.75
   Obtained value (%) C: 67.35 H: 7.37 N: 3.44
Example 25
5-ethyl-2-methyl-c-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylic acid
155-158 ° C
Elemental analysis (C_{twenty two}H₂₉NO_FiveAs)
   Calculated value (%) C: 68.20 H: 7.54 N: 3.61
   Obtained value (%) C: 68.18 H: 7.59 N: 3.49
Example 26
5-ethyl-2-methyl-t-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylic acid
126-130 ° C
Elemental analysis (C_{twenty two}H₂₉NO_FiveAs)
   Calculated value (%) C: 68.20 H: 7.54 N: 3.61
   Obtained value (%) C: 67.77 H: 7.57 N: 3.47
Example 27
2-methyl-c-5- [3- (5-methyl-2-phenyloxazol-4-yl) propyl] -1,3-dioxane-r-2-carboxylic acid
131-134 ° C
Elemental analysis (C₁₉H_{twenty three}NO_FiveAs)
   Calculated value (%) C: 66.07 H: 6.71 N: 4.06
   Obtained value (%) C: 65.59 H: 6.69 N: 3.92
Example 28
2-methyl-t-5- [3- (5-methyl-2-phenyloxazol-4-yl) propyl] -1,3-dioxane-r-2-carboxylic acid
Melting point 164-166 ° C
Elemental analysis (C₁₉H_{twenty three}NO_FiveAs)
   Calculated value (%) C: 66.07 H: 6.71 N: 4.06
   Obtained value (%) C: 65.64 H: 6.70 N: 3.91
Example 29
2-methyl-c-5- [4- (5-methyl-2-phenyloxazol-4-yl)-(E) -2-butenyl] -1,3-dioxane-r-2-carboxylic acid
148-150 ° C
Elemental analysis (C₂₀H_{twenty three}NO_FiveAs)
   Calculated value (%) C: 67.21 H: 6.49 N: 3.92
   Obtained value (%) C: 67.26 H: 6.36 N: 3.82
Example 30
2-methyl-5- {4-[(5-methyl-2-phenyloxazol-4-yl) methyl] benzyl} -1,3-dioxane-2-carboxylic acid
A mixture of cis: trans = 4: 1 (from the integrated value of NMR) was obtained.
Elemental analysis (C_{twenty four}H_{twenty five}NO_FiveAs)
   Calculated value (%) C: 70.75 H: 6.18 N: 3.44
   Observed value (%) C: 70.69 H: 6.23 N: 3.45
Example 31
2-methyl-c-5- {4-[(5-methyl-2-phenyloxazol-4-yl) methyl] phenyl} -1,3-dioxane-r-2-carboxylic acid
215-216 ° C
Elemental analysis (C_{twenty three}H_{twenty three}NO_FiveAs)
   Calculated value (%) C: 70.21 H: 5.89 N: 3.56
   Observed value (%) C: 70.02 H: 5.88 N: 3.35
Example 32
2-methyl-c-5- {3-[(5-methyl-2-phenyloxazol-4-yl) methyl] phenyl} -1,3-dioxane-r-2-carboxylic acid
122-124 ° C
Elemental analysis (C_{twenty three}H_{twenty three}NO_FiveAs)
   Calculated value (%) C: 70.21 H: 5.89 N: 3.56
   Actual value (%) C: 70.05 H: 6.08 N: 3.51
Example 33
2-methyl-c-5- {4- [5-methyl-2- (3-pyridyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid
126-129 ° C
Elemental analysis (C₁₉H_{twenty four}N_TwoO_FiveAs)
   Calculated value (%) C: 63.32 H: 6.71 N: 7.77
   Obtained value (%) C: 63.16 H: 6.73 N: 7.57
Example 34
2-methyl-2- [5- (5-methyl-2-phenyloxazol-4-yl) pentyloxy] propionic acid
Melting point 66-68 ° C
Elemental analysis (C₁₉H_{twenty five}NO_Four・ H_TwoO)
   Calculated value (%) C: 65.31 H: 7.79 N: 4.01
   Obtained value (%) C: 65.20 H: 7.84 N: 4.03
Example 35
2-methyl-2- [6- (5-methyl-2-phenyloxazol-4-yl) hexyloxy] propionic acid
Elemental analysis (C₂₀H₂₇NO_FourAs)
   Calculated value (%) C: 69.54 H: 7.88 N: 4.05
   Observed value (%) C: 69.12 H: 7.86 N: 4.11
Example 36
2-methyl-2- [7- (5-methyl-2-phenyloxazol-4-yl) heptyloxy] propionic acid
70-71 ° C
Elemental analysis (C_{twenty one}H₂₉NO_FourAs)
   Calculated value (%) C: 70.17 H: 8.13 N: 3.90
   Actual value (%) C: 70.03 H: 8.15 N: 3.90
Example 37
2-methyl-2- {6- [5-methyl-2- (p-tolyl) oxazol-4-yl] hexyloxy} propionic acid
Elemental analysis (C_{twenty one}H₂₉NO_FourAs)
   Calculated value (%) C: 70.17 H: 8.13 N: 3.90
   Obtained value (%) C: 70.07 H: 8.07 N: 3.92
Example 38
2-methyl-2- [6- (5-methyl-2-phenyloxazol-4-yl) -4-hexynyloxy] propionic acid
Elemental analysis (C₂₀H_{twenty three}NO_FourAs)
   Calculated value (%) C: 70.36 H: 6.79 N: 4.10
   Observed value (%) C: 70.24 H: 6.51 N: 3.90
Example 39
2- {6- [2- (4-chlorophenyl) -5-methyloxazol-4-yl] hexyloxy} -2-methylpropionic acid
Elemental analysis (C₂₀H₂₆ClNO_FourAs)
   Calculated value (%) C: 63.24 H: 6.90 N: 3.69
   Obtained value (%) C: 63.17 H: 6.82 N: 3.82
Example 40
2- {6- [2- (4-fluorophenyl) -5-methyloxazol-4-yl] hexyloxy} -2-methylpropionic acid
Melting point 64-67 ° C
Elemental analysis (C₂₀H₂₆FNO_FourAs)

   Calculated value (%) C: 66.10 H: 7.21 N: 3.85
   Obtained value (%) C: 66.18 H: 7.30 N: 4.06
Example 41
2- {6- [2- (4-tert-butylphenyl) -5-methyloxazol-4-yl] hexyloxy} -2-methylpropionic acid
89-91 ° C
Elemental analysis (C_{twenty four}H₃₅NO_FourAs)
   Calculated value (%) C: 71.79 H: 8.79 N: 3.49
   Obtained value (%) C: 71.79 H: 8.81 N: 3.52
Example 42
2- [6- (5-ethyl-2-phenyloxazol-4-yl) hexyloxy] -2-methylpropionic acid
88.5-89 ° C
Elemental analysis (C_{twenty one}H₂₉NO_FourAs)
   Calculated value (%) C: 70.17 H: 8.13 N: 3.90
   Obtained value (%) C: 70.36 H: 8.07 N: 3.90
Example 43
2-methyl-2- [6- (2-phenyloxazol-4-yl) hexyloxy] propionic acid
75-77 ° C
Elemental analysis (C₁₉H_{twenty five}NO_FourAs)
   Calculated value (%) C: 68.86 H: 7.60 N: 4.23
   Obtained value (%) C: 68.89 H: 7.62 N: 4.27
Example 44
2-methyl-2- [7- (2-phenyloxazol-4-yl) heptyloxy] propionic acid
Melting point 72-75 ° C
Elemental analysis (C₂₀H₂₇NO_FourAs)
   Calculated value (%) C: 69.54 H: 7.88 N: 4.05
   Obtained value (%) C: 69.67 H: 7.89 N: 4.06
Example 45
2-methyl-2- [8- (2-phenyloxazol-4-yl) octyloxy] propionic acid
Melting point 59-61 ° C
Elemental analysis (C_{twenty one}H₂₉NO_FourAs)
   Calculated value (%) C: 70.17 H: 8.13 N: 3.90
   Actual value (%) C: 70.02 H: 8.30 N: 3.91
Example 46
2- {7- [2- (4-chlorophenyl) oxazol-4-yl] heptyloxy} -2-methylpropionic acid
Melting point 91-93 ° C
Elemental analysis (C₂₀H₂₆ClNO_FourAs)
   Calculated value (%) C: 63.24 H: 6.90 N: 3.69
   Obtained value (%) C: 63.39 H: 6.98 N: 3.72
Example 47
2- {7- [2- (4-fluorophenyl) oxazol-4-yl] heptyloxy} -2-methylpropionic acid
Melting point 67-74 ° C
Elemental analysis (C₂₀H₂₆FNO_FourAs)
   Calculated value (%) C: 66.10 H: 7.21 N: 3.85
   Observed value (%) C: 65.90 H: 7.06 N: 3.84
Example 48
2- {6- [2- (4-fluorophenyl) oxazol-4-yl] hexyloxy} -2-methylpropionic acid
80-83 ° C
Elemental analysis (C₁₉H_{twenty four}FNO_FourAs)
   Calculated value (%) C: 65.31 H: 6.92 N: 4.01
   Obtained value (%) C: 65.15 H: 6.77 N: 3.91
Example 49
2-methyl-2- [7- (2-phenylthiazol-4-yl) heptyloxy] propionic acid
71-72 ° C
Elemental analysis (C₂₀H₂₇NO_ThreeAs S)
   Calculated value (%) C: 66.45 H: 7.53 N: 3.87
   Obtained value (%) C: 66.46 H: 7.57 N: 3.98
Example 50
2-methyl-2- [8- (2-phenylthiazol-4-yl) octyloxy] propionic acid
64-70 ° C
Elemental analysis (C_{twenty one}H₂₉NO_ThreeS ・ H_TwoO)
   Calculated value (%) C: 64.09 H: 7.94 N: 3.56
   Obtained value (%) C: 64.67 H: 7.89 N: 3.83
Example 51
2-methyl-2- {6- [5-methyl-2- (4-pyridyl) oxazol-4-yl] hexyloxy} propionic acid
Melting point 91-93 ° C
Elemental analysis (C₁₉H₂₆N_TwoO_FourAs)
   Calculated value (%) C: 65.88 H: 7.56 N: 8.09
   Obtained value (%) C: 65.79 H: 7.52 N: 8.03
Example 52
2-methyl-2- {6- [5-methyl-2- (3-pyridyl) oxazol-4-yl] hexyloxy} propionic acid
¹H-NMR (CDCl_Three) δ: 1.25-1.50 (10H, m), 1.55-1.75 (4H, m), 2.34 (3H, s), 2.50 (2H, t), 3.45 (2H, t), 7.35-7.42 (1H, m) , 8.26-8.30 (1H, m), 8.62-8.66 (1H, m), 9.21-9.22 (1H, m)
Example 53
2-methyl-c-5- [4- (5-methyl-2-phenyloxazol-4-yl)-(E) -3-butenyl] -1,3-dioxane-r-2-carboxylic acid
  7.5 g of methyl 2-methyl-c-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylate was added to N, N-dimethyl After dissolving in 30 ml of formamide, a solution of 3.57 g of N-bromosuccinimide (NBS) / 20 ml of N, N-dimethylformamide was added dropwise under ice-cooling and stirring. After the dropwise addition, the mixture was stirred for 30 minutes, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 7: 1) to obtain 215 mg of an oil. The obtained oil was dissolved in 3 ml of methanol, 70 mg of sodium hydroxide and 0.8 ml of water were added, and the mixture was refluxed for 2.5 hours and concentrated. Ice was added to the residue, acidified with 1N hydrochloric acid, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, ethyl acetate) to obtain 30 mg of the desired product.
¹H-NMR (CDCl_Three) δ: 1.22 (2H, ddd), 1.65 (3H, s), 2.00-2.30 (3H, m), 2.38 (3H, s), 3.51 (2H, dd), 4.02 (2H, dd), 4.20 (1H , br), 6.15-6.40 (2H, m), 7.40-7.60 (3H, m), 7.90-8.20 (2H, m)
Example 54
Potassium 2-methyl-2- [6- (5-methyl-2-phenyloxazol-4-yl)-(E) -4-hexenyloxy] propionate
  To a solution of 920 mg of methyl 2- [6- (5-methyl-2-phenyloxazol-4-yl)-(E) -4-hexenyloxy] -2-methylpropionate in 20 ml of methanol was added 2 ml of an aqueous solution of 206 mg of sodium hydroxide. And heated to reflux for 20 hours. The reaction solution was concentrated, ice water was added to the residue, and the mixture was acidified with 10% hydrochloric acid. After extraction with ethyl acetate, washing with water and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, chloroform) to give 2- [6- (5-methyl-2-phenyloxazol-4-yl)-(E) -4-hexenyl. Oxy] -2-methylpropionic acid (670 mg) was obtained as a colorless oil. 100 mg of the obtained oil was converted to a potassium salt with potassium hydroxide, isopropyl ether was added, and the precipitate was collected by filtration to obtain 88 mg of the desired compound.
Elemental analysis (C₂₀H_{twenty four}NO_FourK1 / 2H_TwoO)
   Calculated value (%) C: 61.51 H: 6.45 N: 3.59
   Obtained value (%) C: 61.56 H: 6.24 N: 3.53
Example 55
2-methyl-2- [6- (5-methyl-2-phenyloxazol-4-yl) hexyloxy] propanol
  1.35 g of lithium aluminum hydride was added to 214 ml of dry ether, and methyl 2-methyl-2- [6- (5-methyl-2-phenyloxazol-4-yl) hexyloxy] propionate 10 was added under ice-cooling and stirring. A solution of 0.7 g / 40 ml of dry ether was added dropwise and stirred for 1 hour. Next, 43 ml of tetrahydrofuran / 1.7 ml of water were added dropwise, 6.3 ml of water and 1.7 ml of a 1N aqueous solution of sodium hydroxide were added, and the mixture was stirred for 15 minutes. Insolubles were removed by filtration, and the filtrate was concentrated. . The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 3: 1) to obtain 8.44 g of the desired product.
Elemental analysis (C₂₀H₂₉NO_Three・ 1 / 2H_TwoO)
   Calculated value (%) C: 70.55 H: 8.88 N: 4.11
   Obtained value (%) C: 70.95 H: 8.67 N: 4.21
  The compounds of Examples 56 to 58 were produced in the same manner as in Example 55.
Example 56
2- {6- [2- (4-tert-butylphenyl) -5-methyloxazol-4-yl] hexyloxy} -2-methylpropanol
¹H-NMR (CDCl_Three) δ: 1.14 (6H, s), 1.34-1.43 (11H, m), 1.45-1.75 (6H, m), 1.95-2.10 (1H, m), 2.31 (3H, s), 2.47 (2H, t) , 3.30-3.41 (4H, m), 7.41-7.45 (2H, m), 7.88-7.92 (2H, m)
Elemental analysis (C_{twenty four}H₃₇NO_Three・ H_TwoO)
   Calculated value (%) C: 71.07 H: 9.69 N: 3.45
   Obtained value (%) C: 70.89 H: 9.32 N: 3.20
Example 57
2-methyl-2- {6- [5-methyl-2- (3-pyridyl) oxazol-4-yl] hexyloxy} propanol
¹H-NMR (CDCl_Three) δ: 1.15 (6H, s), 1.34-1.40 (4H, m), 1.45-1.85 (4H, m), 1.95-2.10 (1H, m), 2.34 (3H, s), 2.45 (2H, t) , 3.31-3.40 (4H, m), 7.27-7.36 (1H, m), 8.22-8.28 (1H, m), 8.61-8.64 (1H, m), 9.20-9.21 (1H, m)
Elemental analysis (C₁₉H₂₈N_TwoO_Three・ H_TwoO)
   Calculated value (%) C: 65.12 H: 8.63 N: 7.99
   Obtained value (%) C: 65.24 H: 8.40 N: 7.73
Example 58
r-2-hydroxymethyl-2-methyl-c-5- {4- [5-methyl-2- (p-tolyl) oxazol-4-yl] butyl} -1,3-dioxane
Melting point 58-59 ° C
Elemental analysis (C_{twenty one}H₂₉NO_FourAs)
   Calculated value (%) C: 70.17 H: 8.13 N: 3.90
   Obtained value (%) C: 69.97 H: 8.05 N: 3.88
Example 59
2-methyl-2- {6- [5-methyl-2- (4-pyridyl) oxazol-4-yl] hexyloxy} propanol methanesulfonate
  210 mg of methyl 2-methyl-2- {6- [5-methyl-2- (4-pyridyl) oxazol-4-yl] hexyloxy} propionate was dissolved in 20 ml of dry ether, and 44 mg of lithium aluminum hydride was added. The mixture was stirred for 30 minutes under ice cooling. Next, 5 ml of tetrahydrofuran / 0.33 ml of water was added dropwise, and the mixture was stirred for 15 minutes. Then, insolubles were removed by filtration, and the filtrate was concentrated. The residue was dissolved in ether, methanesulfonic acid (59 mg) / ether (1 ml) was added, and the precipitated crystals were collected by filtration, washed with ether, and dried to obtain 195 mg of the desired product as pale yellow crystals.
128-130 ° C
Elemental analysis (C₁₉H₂₈N_TwoO_Three・ CH_FourO_ThreeS ・ H_TwoO)
   Calculated value (%) C: 53.79 H: 7.67 N: 6.27
   Obtained value (%) C: 53.87 H: 7.28 N: 6.17
Example 60
2-methyl-c-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carbohydroxamic acid
  350 mg of 2-methyl-c-5- [4- (5-methyl-2-phenyloxazol-4-yl) butyl] -1,3-dioxane-r-2-carboxylic acid was dissolved in 7.5 ml of tetrahydrofuran, and 1 , 1'-carbonyldiimidazole (174 mg) was added, and the mixture was stirred at room temperature for 24 hours. After concentrating the reaction solution, methanol (3 ml) was added to dissolve the mixture, a mixed solution of hydroxylammonium chloride (190 mg) / methanol (6 ml) and triethylamine (336 mg) was added dropwise, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate, washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, chloroform: methanol = 100: 1) to obtain 53.8 mg of the target substance as white crystals.
115-116 ° C
Elemental analysis (C₂₀H₂₆N_TwoO_Five・ 1 / 4H_TwoO)
   Calculated value (%) C: 63.39 H: 7.05 N: 7.39
   Obtained value (%) C: 63.35 H: 6.85 N: 7.37
  The compounds of Examples 61 to 77 were produced in the same manner as in Example 11.
Example 61
2-methyl-c-5- {4- [5-methyl-2- (4-chlorophenyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid
145-146 ° C
Elemental analysis (C₂₀H_{twenty four}ClNO_FiveAs)
   Calculated value (%) C: 60.99 H: 6.14 N: 3.56
   Measured value (%) C: 60.75 H: 6.25 N: 3.36
Example 62
2-methyl-c-5- {5- [5-methyl-2- (p-tolyl) oxazol-4-yl] pentyl} -1,3-dioxane-r-2-carboxylic acid
118-119 ° C
Elemental analysis (C_{twenty two}H₂₉NO_FiveAs)
   Calculated value (%) C: 68.20 H: 7.54 N: 3.61
   Measured value (%) C: 68.20 H: 7.53 N: 3.60
Example 63
2-ethyl-c-5- {4- [5-methyl-2- (p-tolyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid
123-126 ° C
Elemental analysis (C_{twenty two}H₂₉NO_FiveAs)
   Calculated value (%) C: 68.20 H: 7.54 N: 3.61
   Obtained value (%) C: 69.22 H: 7.53 N: 3.21
Example 64
2-methyl-c-5- {4- [5-methyl-2- (3-fluoro-4-methylphenyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid
Elemental analysis (C_{twenty one}H₂₆FNO_FiveAs)
   Calculated value (%) C: 64.44 H: 6.69 N: 3.58
   Obtained value (%) C: 64.49 H: 6.68 N: 3.90
Example 65
2-methyl-c-5- {4- [5-methyl-2- (4-ethylphenyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid
147 ° C
Elemental analysis (C_{twenty two}H₂₉NO_FiveAs)
   Calculated value (%) C: 68.20 H: 7.54 N: 3.61
   Obtained value (%) C: 67.99 H: 7.50 N: 3.76
Example 66
2-methyl-c-5- {4- [2- (p-tolyl) -5-trifluoromethyloxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid
130-131 ° C
Elemental analysis (C_{twenty one}H_{twenty four}F_ThreeNO_FiveAs)
   Calculated value (%) C: 59.01 H: 5.66 N: 3.28
   Obtained value (%) C: 59.11 H: 5.67 N: 3.16
Example 67
2-methyl-c-5- {4- [5-methyl-2- (2,4-dimethylphenyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid
130-131 ° C
Elemental analysis (C_{twenty two}H₂₉NO_FiveAs)
   Calculated value (%) C: 68.20 H: 7.54 N: 3.61
   Measured value (%) C: 68.25 H: 7.53 N: 3.65
Example 68
2-methyl-c-5- {4- [2- (4-fluoromethylphenyl) -5-methyloxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid
144-145 ° C
Elemental analysis (C_{twenty one}H₂₆FNO_FiveAs)
   Calculated value (%) C: 64.44 H: 6.69 N: 3.58
   Obtained value (%) C: 64.35 H: 6.69 N: 3.52
Example 69
2-methyl-c-5- {4- [5-ethyl-2- (p-tolyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid
160-161 ° C
Elemental analysis (C_{twenty two}H₂₉NO_FiveAs)
   Calculated value (%) C: 68.20 H: 7.54 N: 3.61
   Obtained value (%) C: 68.15 H: 7.52 N: 3.56
Example 70
2-methyl-c-5- {4- [5-methyl-2- (p-tolyl) thiazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid
Elemental analysis (C_{twenty one}H₂₇NO_FourAs S)
   Calculated value (%) C: 64.76 H: 6.99 N: 3.60
   Obtained value (%) C: 64.68 H: 6.97 N: 3.64
Example 71
2-methyl-c-5- {4- [5-methyl-2- (m-tolyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid
Elemental analysis (C_{twenty one}H₂₇NO_FiveAs)
   Calculated value (%) C: 67.54 H: 7.29 N: 3.75
   Obtained value (%) C: 67.57 H: 7.22 N: 3.80
Example 72
2-methyl-c-5- {4- [5-methyl-2- (o-tolyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid
121-122 ° C
Elemental analysis (C_{twenty one}H₂₇NO_FiveAs)
   Calculated value (%) C: 67.54 H: 7.29 N: 3.75
   Obtained value (%) C: 67.47 H: 7.29 N: 3.71
Example 73
2-methyl-c-5- {4- [5-methyl-2- (3,4-dimethylphenyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid
Elemental analysis (C_{twenty two}H₂₉NO_FiveAs)
   Calculated value (%) C: 68.20 H: 7.54 N: 3.61
   Measured value (%) C: 68.31 H: 7.53 N: 3.65
Example 74
2-methyl-c-5- {4- [5-methyl-2- (4-methoxyphenyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid
Elemental analysis (C_{twenty one}H₂₇NO₆As)
   Calculated value (%) C: 64.77 H: 6.99 N: 3.60
   Observed value (%) C: 64.80 H: 7.13 N: 3.57
Example 75
2-methyl-c-5- {4- [5-methyl-2- (2-thienyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid
Elemental analysis (C₁₈H_{twenty three}NO_FiveAs S)
   Calculated value (%) C: 59.16 H: 6.34 N: 3.83
   Obtained value (%) C: 59.45 H: 6.32 N: 3.76
Example 76
2-methyl-c-5- {4- [2-cyclohexyl-5-methyloxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid
118-121 ° C
Elemental analysis (C₂₀H₃₁NO_FiveAs)
   Calculated value (%) C: 65.73 H: 8.55 N: 3.83
   Measured value (%) C: 65.75 H: 8.57 N: 3.80
Example 77
2-methyl-c-5- {4- [1,5-dimethyl-2- (p-tolyl) imidazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid
Melting point 192-194 ° C (decomposition)
Elemental analysis (C_{twenty two}H₃₀N_TwoO_Four・ 1H_TwoO)
   Calculated value (%) C: 65.32 H: 7.97 N: 6.93
   Observed value (%) C: 65.36 H: 7.58 N: 6.75
Example 78
Methyl 2-methyl-c-5- [3-{[5-methyl-2- (p-tolyl) oxazol-4-yl] methyl} benzyl] -1,3-dioxane-r-2-carboxylate
  2.38 g of 2- [3-{[5-methyl-2- (p-tolyl) oxazol-4-yl] methyl} benzyl] -1,3-propanediol is dissolved in 38 ml of acetonitrile, and 2.65 g of methyl pyruvate is dissolved. Was added. 3.69 g of boron trifluoride etherate (about 47%) was added to the mixture with stirring at room temperature, and the mixture was stirred at room temperature for 18 hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 4: 1), and the previously eluted fraction was concentrated to give a target compound (752 mg) as a colorless oil. Got.
¹H-NMR (CDCl_Three) δ: 1.49 (3H, s), 2.20 ~ 2.35 (3H, m), 2.25 (3H, s), 2.38 (3H, s), 3.48 (2H, t), 3.80 ~ 3.95 (4H, m), 3.83 (3H, s), 6.92-7.24 (6H, m), 7.80-7.90 (2H, m)
Example 79
Methyl 2-methyl-t-5- [3-{[5-methyl-2- (p-tolyl) oxazol-4-yl] methyl} benzyl] -1,3-dioxane-r-2-carboxylate
  The post-fraction of Example 78 was collected and concentrated to give 294 mg of the target compound as a colorless oil.
¹H-NMR (CDCl_Three) δ: 1.57 (3H, s), 2.20-2.35 (1H, m), 2.25 (3H, s), 2.38 (3H, s), 2.98 (2H, d), 3.70-3.88 (4H, m), 3.82 (3H, s), 3.93 (2H, dd), 7.00 ~ 7.30 (6H, m), 7.87 (2H, d)
Example 80
2-methyl-c-5- [3-{[5-methyl-2- (p-tolyl) oxazol-4-yl] methyl} benzyl] -1,3-dioxane-r-2-carboxylic acid
  968 mg of methyl 2-methyl-c-5- [3-{[5-methyl-2- (p-tolyl) oxazol-4-yl] methyl} benzyl] -1,3-dioxane-r-2-carboxylate Dissolved in methanol (20 ml), added 1N aqueous sodium hydroxide solution (3.3 ml), and heated under reflux for 1.5 hours. The reaction solution was concentrated, water was added to the residue, and the mixture was washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid, extracted with diethyl ether, dried over anhydrous magnesium sulfate, and concentrated. The residue was crystallized by adding diethyl ether and washed with isopropyl ether to give 733 mg of the desired compound as colorless crystals.
151-152 ° C
Elemental analysis (C_{twenty five}H₂₇NO_FiveAs)
   Calculated value (%) C: 71.24 H: 6.46 N: 3.32
   Obtained value (%) C: 71.50 H: 6.42 N: 3.48
Example 81
2-methyl-t-5- [3-{[5-methyl-2- (p-tolyl) oxazol-4-yl] methyl} benzyl] -1,3-dioxane-r-2-carboxylic acid
  It was manufactured in the same manner as in Example 80.
Elemental analysis (C_{twenty five}H₂₇NO_FiveAs)
   Calculated value (%) C: 71.24 H: 6.46 N: 3.32
   Obtained value (%) C: 70.18 H: 6.34 N: 3.31
Example 82
2-methyl-c-5- {4- [5-methyl-2- (p-tolyl) oxazol-4-yl] butyl} -1,3-dithiane-r-2-carboxylic acid
  2 ml of a methanol solution of 124 mg of methyl 2-methyl-c-5- {4- [5-methyl-2- (p-tolyl) oxazol-4-yl] butyl} -1,3-dithiane-r-2-carboxylate To the mixture was added 1 ml of a 1N aqueous sodium hydroxide solution, and the mixture was heated under reflux for 1.5 hours. The reaction solution was concentrated, water was added to the residue, and the mixture was washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated. The residue was crystallized by adding isopropyl ether and washed with n-hexane to obtain 88 mg of the desired compound as colorless crystals.
157-159 ° C
Elemental analysis (C_{twenty one}H₂₇NO_ThreeS_TwoAs)
   Calculated value (%) C: 62.19 H: 6.71 N: 3.45
   Obtained value (%) C: 61.93 H: 6.70 N: 3.40
Example 83
2-methyl-t-5- {4- [5-methyl-2- (p-tolyl) oxazol-4-yl] butyl} -1,3-dithiane-r-2-carboxylic acid
  The target compound was produced in the same manner as in Example 82.
Melting point 162-164 ° C
Elemental analysis (C_{twenty one}H₂₇NO_ThreeS_TwoAs)
   Calculated value (%) C: 62.19 H: 6.71 N: 3.45
   Actual value (%) C: 61.75 H: 6.66 N: 3.42
Example 84
2-methyl-2- {6- [5-methyl-2- (p-tolyl) oxazol-4-yl] hexylthio} propionic acid
  Under an argon atmosphere, 24 mg of pulverized sodium hydroxide was added to 2 ml of acetone solution of 100 mg of 4- (6-acetylthiohexyl) -5-methyl-2- (p-tolyl) oxazole, and the mixture was stirred at room temperature for 2 hours. After adding 20 μl of water to the reaction solution, 113 mg of 1,1,1-trichloro-2-methyl-2-propanol hemihydrate (chloretone) was added, and 96.5 mg of ground sodium hydroxide was added at 30 minute intervals. , And the mixture was further stirred at room temperature for 18 hours. The reaction solution was concentrated, water was added to the residue, and the mixture was extracted with diethyl ether. The organic layer was washed with water, and the washing was acidified with 1N hydrochloric acid, and then extracted with ethyl acetate. The organic layers were combined, washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, chloroform: methanol = 100: 1), and the obtained crystals were washed with n-hexane to give 28.0 mg of the desired compound in pale yellow color Obtained as crystals.
111 ° C
Elemental analysis (C_{twenty one}H₂₉NO_ThreeAs S)
   Calculated value (%) C: 67.17 H: 7.78 N: 3.73
   Obtained value (%) C: 67.33 H: 7.85 N: 3.67
Example 85
2-methyl-2- {6- [5-methyl-2- (p-tolyl) oxazol-4-yl] hexyloxy} propiononitrile
  6.77 g of phosphorus tribromide was added to 94 ml of a benzene solution of 4.90 g of 2-methyl-2- {6- [5-methyl-2- (p-tolyl) oxazol-4-yl] hexyloxy} propionohydroxamic acid. The mixture was heated at reflux for 4 hours. After cooling, the reaction solution was poured into ice water, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 9: 1) to obtain 3.32 g of the desired compound as colorless crystals.
Melting point 36 ° C
Elemental analysis (C_{twenty one}H₂₈N_TwoO_Two・ 1 / 5H_TwoO)
   Calculated value (%) C: 73.31 H: 8.32 N: 8.14
   Obtained value (%) C: 73.21 H: 8.27 N: 7.88
Example 86
5- [1-methyl-1- {6- [5-methyl-2- (p-tolyl) oxazol-4-yl] hexyloxy} ethyl] tetrazole
  To a solution of 2.70 g of 2-methyl-2- {6- [5-methyl-2- (p-tolyl) oxazol-4-yl] hexyloxy} propiononitrile in 27 ml of N, N-dimethylformamide was added sodium azide. 4.12 g and 2.97 g of ammonium chloride were added, and the mixture was stirred at 120 ° C. for 1.5 hours. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, chloroform: methanol = 100: 1 to 50: 1), and recrystallized from isopropyl ether to obtain 1.69 g of the desired compound as colorless crystals. Was.
87 ° C
Elemental analysis (C_{twenty one}H₂₉N_FiveO_TwoAs)
   Calculated value (%) C: 65.77 H: 7.62 N: 18.26
   Obtained value (%) C: 65.67 H: 7.65 N: 17.97
Example 87
2-methyl-c-5- {4- [5-methyl-2- (p-tolyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxamide
  Under an argon atmosphere, 2-methyl-c-5- {4- [5-methyl-2- (p-tolyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylic acid3. 45 g of a tetrahydrofuran solution of 00 g was cooled on ice, and 1.12 ml of triethylamine and then 5 ml of a tetrahydrofuran solution of 959 mg of ethyl chloroformate were added dropwise. After stirring for 45 minutes, 45 ml of tetrahydrofuran saturated with ammonia was added dropwise, and the mixture was further stirred for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained crystals were washed with diethyl ether to obtain the target compound (2.81 g) as colorless crystals.
146-147 ° C
Elemental analysis (C_{twenty one}H₂₈N_TwoO_FourAs)
   Calculated value (%) C: 67.72 H: 7.58 N: 7.52
   Obtained value (%) C: 67.26 H: 7.54 N: 7.39
Example 88
2-methyl-c-5- {4- [5-methyl-2- (p-tolyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carbonitrile
  1. Under an argon atmosphere, 2-methyl-c-5- {4- [5-methyl-2- (p-tolyl) oxazol-4-yl] butyl} -1,3-dioxane-r-2-carboxamide. 2.04 ml of triethylamine was added dropwise to 34 ml of a 27 g solution of tetrahydrofuran. After stirring for 10 minutes under ice cooling, 5 ml of a tetrahydrofuran solution of 1.53 g of trifluoroacetic anhydride was slowly added dropwise, and the mixture was further stirred for 1 hour. Water was added to the reaction solution, and the mixture was extracted with diethyl ether, washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 4: 1) to obtain 2.07 g of the desired compound as colorless crystals.
79-80 ° C
Elemental analysis (C_{twenty one}H₂₆N_TwoO_ThreeAs)
   Calculated value (%) C: 71.16 H: 7.39 N: 7.90
   Obtained value (%) C: 71.01 H: 7.42 N: 7.90
Example 89
Methyl 2-methyl-c-5- {4- [5-methyl-2- (p-tolyl) oxazol-4-yl] butyl} -1,3-dithiane-r-2-carboxylate
  To a solution of 635 mg of 4- [5,5-bis (mercaptomethyl) pentyl] -5-methyl-2- (p-tolyl) oxazole in 20 ml of acetonitrile, 0.344 ml of methyl pyruvate and a boron trifluoride etherate (about
(47%) was added and heated under reflux for 2 hours. After cooling, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 9: 1), and the fraction eluted earlier was concentrated to obtain 124 mg of the target compound as colorless crystals. Was.
¹H-NMR (CDCl_Three) δ: 1.25 ~ 1.55 (4H, m), 1.69 (3H, s), 1.70 ~ 1.90 (3H, m),
2.31 (3H, s), 2.38 (3H, s), 2.40 ~ 2.60 (4H, m), 3.54 (2H, m), 3.77 (3H, s),
7.22 (2H, s), 7.86 (2H, s)
Example 90
Methyl 2-methyl-t-5- {4- [5-methyl-2- (p-tolyl) oxazol-4-yl] butyl} -1,3-dithiane-r-2-carboxylate
  The post-fraction of Example 89 was collected and concentrated to obtain 124 mg of the target compound as a colorless oil.
¹H-NMR (CDCl_Three) δ: 1.30-1.50 (4H, m), 1.55-1.90 (7H, m), 2.31 (3H, s), 2.38 (3H, s), 2.47 (2H, t), 2.58 (2H, dd), 3.07 (2H, dd), 3.11 (2H, s), 7.23 (2H, d), 7.87 (2H, d)
Example 91
2-methyl-2- {6- [5-methyl-2- (p-tolyl) oxazol-4-yl] hexyloxy} propionohydroxamic acid
  3.47 g of hydroxylammonium chloride was added to 20 ml of a methanol solution of 4.84 g of ethyl 2-methyl-2- {6- [5-methyl-2- (p-tolyl) oxazol-4-yl] hexyloxy} propionate. Then, 12.5 ml of a 5M methanolic potassium hydroxide solution was slowly added dropwise with stirring under ice cooling, and the ice bath was removed, followed by stirring at room temperature for 36 hours. The reaction solution was concentrated, and the residue was acidified with a 50% aqueous acetic acid solution. Then, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. Toluene was added to the residue, and the mixture was concentrated. Ethanol was added, and the mixture was concentrated to obtain 4.90 g of the desired compound as a pale yellow oil.
¹H-NMR (CDCl_Three) δ: 1.36 ~ 1.41 (4H, m), 1.38 (6H, s), 1.53 ~ 1.70 (4H, m), 2.31 (3H, s), 2.38 (3H, s), 2.48 (2H, t), 3.37 (2H, t), 7.23 (2H, d), 7.87 (2H, d)
Example 92
Methyl 2-methyl-c-5- {4- [1,5-dimethyl-2- (p-tolyl) imidazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylate
  To a 20 ml xylene solution of 0.80 g of methyl c-5- [5-acetyl-5- (p-toluoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate was added 2M methylamine. Of tetrahydrofuran and 0.84 ml of acetic acid were added, and azeotropic dehydration was performed for 2 hours using a Dean-Stark apparatus. After cooling, the reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, chloroform: methanol = 100: 1) to obtain 634 mg of the desired compound as a pale yellow oil.
¹H-NMR (CDCl_Three) δ: 0.97 to 1.10 (2H, m), 1.20 to 1.40 (2H, m), 1.50 (3H, s), 1.54 to 1.70 (2H, m), 1.90 to 2.15 (1H, m), 2.18 (3H, m) s), 2.38 (3H, s), 2.51 (2H, t), 3.38 (2H, t), 3.53 (3H, s), 3.83 (3H, s), 3.95 (2H, dd), 7.23 (2H, dd) ), 7.45 (2H, dd)
Example 93
Methyl 2-methyl-c-5- {4- [5-methyl-2- (p-tolyl) thiazol-4-yl] butyl} -1,3-dioxane-r-2-carboxylate
  1.01 g of methyl c-5- [5-acetyl-5- (p-toluoylamino) pentyl] -2-methyl-1,3-dioxane-r-2-carboxylate was dissolved in 10 ml of tetrahydrofuran, and 2,4 -Bis (methylthio) -1,3-dithia-2,4-diphosphetane-2,4-disulfide (Davy reagent methyl) (1.42 g) was added, and the mixture was added at 50 to 55 ° C. for 3 hours and further at 70 to 75 ° C. for 3 hours. Stirred for hours. Ethyl acetate was added to the reaction solution, washed sequentially with 10% hydrochloric acid, water, and 10% aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Wakogel (registered trademark) C-200, n-hexane: ethyl acetate = 5: 1) to obtain 384 mg of the desired compound as a pale yellow oil.
¹H-NMR (CDCl_Three) δ1.00 ~ 1.15 (2H, m), 1.23 ~ 1.40 (2H, m), 1.51 (3H, s), 1.60 ~ 1.77 (2H, m), 1.92 ~ 2.14 (1H, m), 2.37 (6H, m s), 2.66 (2H, t), 3.39 (2H, t), 3.83 (3H, s), 3.95 (2H, dd), 7.20 (2H, d), 7.75 (2H, d)
Test example 1
KK-A ^y Effects on sugar and lipid metabolism in mice
  As test drugs, the compounds described in the Examples and troglitazone (Troglitazone, 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -2, a control drug) 4-thiazolidinedione).

KK- ^Ay mice (10-week-old, male), which are NIDDM model animals, were orally administered a predetermined amount of a test drug for 4 days. On the day following the last administration, blood was collected from the tail vein under non-fasting conditions to prepare heparinized plasma, and then blood was collected from the abdominal vena cava under pentobarbital anesthesia to prepare serum. Blood glucose (BG), triglyceride (TG), and insulin (Ins) levels in plasma were measured using glucose CII-Test Wako (manufactured by Wako Pure Chemical Industries, Ltd.), Clintech TG-S (manufactured by Yatron) or triglyceride E-test Wako, respectively. (Manufactured by Wako Pure Chemical Industries), rat insulin measurement kit (manufactured by Morinaga) or Levis Insulin-Mouse-T (manufactured by Shibayagi). Further, the serum VLDL-C value and LDL-C value (hereinafter referred to as (V) LDL-C value) value, total cholesterol (TC) value and HDL-C value can be measured by a high-performance liquid for lipoprotein cholesterol measurement. It measured using the chromatography system (made by Tosoh). (V) The LDL-C value was measured because VLDL-C and LDL-C could not be measured separately. The arteriosclerosis number (AI) was calculated by the following equation.

AI = [(TC value)-(HDL-C value)] / (HDL-C value)
Table 1 shows the results.

本発明化合物は、優れた血中トリグリセリド低下作用、及び（Ｖ）ＬＤＬ−Ｃ低下作用を示した。さらに、本発明化合物は、血糖低下作用、血中インスリン低下作用、又はＨＤＬ−Ｃ増加作用若しくは動脈硬化指数低下作用を示した。本発明化合物が動脈硬化症等の予防又は治療剤として有用であるのが明白である。
製剤例１
錠剤（内服錠）
処方１錠200mg 中
実施例７１の化合物 20 mg
トウモロコシ澱粉 88 mg
結晶セルロース 80 mg
カルボキシメチルセルロースカルシウム 10 mg
軽質無水ケイ酸 1 mg
ステアリン酸マグネシウム 1 mg
この比率の混合末を打錠成形し内服錠とする。
製剤例２
錠剤（内服錠）
処方１錠120mg 中
実施例１１の化合物 1 mg
乳糖 60 mg
トウモロコシ澱粉 30 mg
結晶セルロース 20 mg
ヒドロキシプロピルセルロース 7 mg
ステアリン酸マグネシウム 2 mg
この比率の混合末を打錠成形し内服錠とする。
製剤例３
錠剤（内服錠）
処方１錠180mg 中
実施例７３の化合物 100 mg
乳糖 45 mg
トウモロコシ澱粉 20 mg
低置換度ヒドロキシプロピルセルロース 9 mg
ポリビニルアルコール（部分ケン化物） 5 mg
ステアリン酸マグネシウム 1 mg
この比率の混合末を打錠成形し内服錠とする。

The compound of the present invention exhibited an excellent blood triglyceride lowering action and (V) an LDL-C lowering action. Furthermore, the compound of the present invention exhibited a blood glucose lowering effect, a blood insulin lowering effect, or an HDL-C increasing effect or an arteriosclerosis index lowering effect. It is clear that the compound of the present invention is useful as an agent for preventing or treating arteriosclerosis and the like.
Formulation Example 1
Tablets (oral tablets)
20 mg of the compound of Example 71 in 200 mg of one prescription tablet
Corn starch 88 mg
80 mg crystalline cellulose
Carboxymethylcellulose calcium 10 mg
Light silicic anhydride 1 mg
Magnesium stearate 1 mg
The mixed powder having this ratio is tableted and taken as an internal tablet.
Formulation Example 2
Tablets (oral tablets)
Formulation 1 tablet in 120 mg 1 mg of the compound of Example 11
Lactose 60 mg
Corn starch 30 mg
Microcrystalline cellulose 20 mg
Hydroxypropyl cellulose 7 mg
Magnesium stearate 2 mg
The mixed powder having this ratio is tableted and taken as an internal tablet.
Formulation Example 3
Tablets (oral tablets)
Formulation 1 tablet 180mg in 100mg of the compound of Example 73
Lactose 45 mg
Corn starch 20 mg
Low-substituted hydroxypropylcellulose 9 mg
Polyvinyl alcohol (partially saponified) 5 mg
Magnesium stearate 1 mg
The mixed powder having this ratio is tableted and taken as an internal tablet.

As described above, the compound of the present invention has an excellent blood triglyceride lowering effect and (V) an LDL-C lowering effect, and further has a blood glucose lowering effect, a blood insulin lowering effect, or an increase in HDL-C. Since it has an action or an arteriosclerosis index lowering action, it is effective for prevention and treatment of coronary artery disease, cerebral infarction, hyperlipidemia, arteriosclerosis, diabetes, hypertension, obesity and the like.

Claims (18)

An agent for preventing or treating hyperlipidemia comprising a heterocyclic derivative represented by the following formula [1] or a pharmaceutically acceptable salt thereof as an active ingredient.

In the formula, R ¹ represents an aryl, an aromatic heterocyclic group or cycloalkyl. Such an aryl or aromatic heterocyclic group may be substituted with 1 to 3 identical or different alkyl, haloalkyl, trihaloalkyl, alkoxy, halogen or nitro.
Het represents a divalent aromatic heterocyclic group represented by the following formula [5].

X represents oxygen, sulfur or NR ⁶ , R ⁶ represents hydrogen or alkyl, and R ² represents hydrogen, alkyl or trihaloalkyl.
D represents an alkylene, alkenylene, alkynylene or a group represented by the following formula [2].

W represents CH or nitrogen. m represents an integer of 1 to 10, and n represents an integer of 0 to 9. Here, m + n represents an integer in the range of 1 to 10.
E represents a group represented by the following formula [4].

Y represents oxygen or sulfur. R ³ and R ⁴ are the same or different and represent hydrogen or alkyl. Z is carboxy, alkoxycarbonyl, hydroxymethyl, carbamoyl, N-hydroxycarbamoyl, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, cyano, 1H-5-tetrazolyl, 1-alkyl-5-tetrazolyl, or 2-alkyl- Represents 5-tetrazolyl.
However, a heterocyclic derivative in which D is a group represented by the formula [2] and E is a group represented by the formula [4] is excluded. The agent for preventing or treating hyperlipidemia according to claim 1, wherein D is alkylene, alkenylene or alkynylene having 3 to 10 carbon atoms. R ¹ is phenyl optionally substituted with ¹ to 2 alkyl, halogen, trihaloalkyl or alkoxy; Het is a divalent aromatic heterocyclic group represented by the following formula [5a]; The preventive or therapeutic agent for hyperlipidemia according to claim 2, wherein D is alkylene or alkenylene having 3 to 7 carbon atoms.

In the formula, X represents oxygen, sulfur or NR ⁶ , and R ⁶ represents hydrogen or alkyl. R ¹⁵ represents alkyl or trihaloalkyl. R ¹ is phenyl optionally substituted with ¹ to 2 alkyl, halogen or alkoxy, Het is a divalent aromatic heterocyclic group represented by the formula [5a], and X is oxygen, sulfur Or NR ⁶ , R ⁶ is hydrogen or alkyl, R ¹⁵ is alkyl or trihaloalkyl, D is alkylene, alkenylene or alkynylene having 5 to 7 carbon atoms, and E is represented by the formula [4]. The preventive or therapeutic agent for hyperlipidemia according to claim 3, wherein Y is oxygen, R ³ and R ⁴ are the same or different and are hydrogen or alkyl, and Z is carboxy or alkoxycarbonyl. . R ¹ is phenyl optionally substituted with ¹ to 2 alkyl, halogen or alkoxy, Het is a divalent aromatic heterocyclic group represented by the formula [5a], X is oxygen, , R ¹⁵ is alkyl, D is alkylene, alkenylene or alkynylene having 5 to 7 carbon atoms, E is a group represented by the formula [4], Y is oxygen, and R ³ and R ⁴ are The preventive or therapeutic agent for hyperlipidemia according to claim 4, wherein the same alkyl is used, and Z is carboxy. The agent for preventing or treating hyperlipidemia according to claim 1, which is selected from the group consisting of the following compounds (1) to (4).
(1) 2-methyl-2- [6- (5-methyl-2-phenyloxazol-4-yl)-(E) -4-hexenyloxy] propionic acid
(2) 2-methyl-2- [6- (5-methyl-2-phenyloxazol-4-yl) -4-hexynyloxy] propionic acid
(3) 2-methyl-2- [6- (5-methyl-2-phenyloxazol-4-yl) hexyloxy] propanol
(4) 2-methyl-2- {6- [5-methyl-2- (p-tolyl) oxazol-4-yl] hexyloxy} propionic acid A pharmaceutical composition comprising, as an active ingredient, the heterocyclic derivative according to claim 2 or a pharmaceutically acceptable salt thereof. An agent for preventing or treating arteriosclerosis, comprising the heterocyclic derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. An agent for preventing or treating ischemic heart disease, comprising the heterocyclic derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. An agent for preventing or treating cerebral infarction disease, comprising the heterocyclic derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. An agent for preventing or treating restenosis after PTCA surgery, comprising the heterocyclic derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. An agent for preventing or treating diabetes, comprising the heterocyclic derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. The heterocyclic derivative according to claim 1, or a pharmaceutically acceptable salt thereof. However, compounds in which D is an alkylene having 1 to 6 carbon atoms, E is the formula [4], and Y is oxygen are excluded. 14. The heterocyclic derivative or a pharmaceutically acceptable salt thereof according to claim 13, wherein D is alkylene, alkenylene, or alkynylene having 3 to 10 carbon atoms. R ¹ is phenyl optionally substituted with ¹ to 2 alkyl, halogen, trihaloalkyl or alkoxy; Het is a divalent aromatic heterocyclic group represented by the following formula [5a]; The heterocyclic derivative according to claim 14, wherein D is alkylene or alkenylene having 3 to 7 carbon atoms, or a pharmaceutically acceptable salt thereof.

In the formula, X represents oxygen, sulfur or NR ⁶ , and R ⁶ represents hydrogen or alkyl. R ¹⁵ represents alkyl or trihaloalkyl. R ¹ is phenyl optionally substituted with ¹ to 2 alkyl, halogen or alkoxy, Het is a divalent aromatic heterocyclic group represented by the formula [5a], and X is oxygen, sulfur Or NR ⁶ , R ⁶ is hydrogen or alkyl, R ¹⁵ is alkyl or trihaloalkyl, D is alkylene, alkenylene or alkynylene having 7 carbon atoms, and E is a group represented by the formula [4]. Wherein Y is oxygen, R ³ and R ⁴ are the same or different and are hydrogen or alkyl, and Z is carboxy or alkoxycarbonyl, or a heterocyclic derivative thereof or a pharmaceutically acceptable salt thereof. salt. R ¹ is phenyl optionally substituted with ¹ to 2 alkyl, halogen or alkoxy, Het is a divalent aromatic heterocyclic group represented by the formula [5a], X is oxygen, , R ¹⁵ is alkyl, D is alkylene, alkenylene or alkynylene having 7 carbon atoms, E is a group represented by the formula [4], Y is oxygen, and R ³ and R ⁴ are the same. The heterocyclic derivative according to claim 16, which is alkyl and Z is carboxy, or a pharmaceutically acceptable salt thereof. A heterocyclic derivative selected from the group consisting of the following compounds (1) to (11) or a pharmaceutically acceptable salt thereof.
(1) 2-methyl-2- [6- (5-methyl-2-phenyloxazol-4-yl) hexyloxy] propionic acid
(2) methyl 2-methyl-2- [6- (5-methyl-2-phenyloxazol-4-yl) hexyloxy] propionate,
(3) 2-methyl-2- {6- [5-methyl-2- (p-tolyl) oxazol-4-yl] hexyloxy} propionic acid
(4) Methyl 2-methyl-2- {6- [5-methyl-2- (p-tolyl) oxazol-4-yl] hexyloxy} propionate
(5) 2-methyl-2- [6- (5-methyl-2-phenyloxazol-4-yl) -4-hexynyloxy] propionic acid
(6) Methyl 2-methyl-2- [6- (5-methyl-2-phenyloxazol-4-yl) -4-hexynyloxy] propionate
(7) 2- {6- [2- (4-chlorophenyl) -5-methyloxazol-4-yl] hexyloxy} -2-methylpropionic acid
(8) Methyl 2- {6- [2- (4-chlorophenyl) -5-methyloxazol-4-yl] hexyloxy} -2-methylpropionate
(9) 2-methyl-2- [6- (5-methyl-2-phenyloxazol-4-yl)-(E) -4-hexenyloxy] propionic acid
(10) Methyl 2- [6- (5-methyl-2-phenyloxazol-4-yl)-(E) -4-hexenyloxy] -2-methylpropionate
(11) 2-methyl-2- [6- (5-methyl-2-phenyloxazol-4-yl) hexyloxy] propanol