JPWO2004103946A1 - Carboxylic acid compound and pharmaceutical containing the same - Google Patents

Abstract

The following general formula (1), which has a hypoglycemic action, a plasma insulin lowering action, and a triglyceride lowering action, is useful for the prevention and / or treatment of diabetes, diabetic complications, hyperlipidemia and the like: , M represents an integer of 0 to 4, n represents an integer of 5 to 9, and W represents —CH (OR) — (R represents a hydrogen atom or a protecting group for a hydroxyl group) or —C (═O) —. Or a salt thereof, or an ester thereof.

Description

  The present invention exhibits a powerful hypoglycemic action, plasma insulin lowering action and triglyceride lowering action, and prevention of diseases such as diabetes, diabetic complications, hyperlipidemia, arteriosclerosis and the like without accompanying weight gain and obesity. The present invention relates to a carboxylic acid compound capable of treatment and a medicine containing the same.

Diabetes is a metabolic disease caused by a plurality of causes, and is roughly classified into type 1 due to insulin secretion deficiency and type 2 associated with decreased insulin sensitivity in peripheral tissues. Type 2 diabetes has increased rapidly in recent years against the background of environmental factors such as obesity and overeating, and the worldwide prevalence of diabetes is 5%.
Insulin and sulfonylurea are frequently used for drug treatment of diabetes, but as side effects, hypoglycemia and sulfonylurea cause secondary ineffectiveness due to pancreatic exhaustion. Biguanides improve insulin sensitivity and slightly correct hyperglycemia, but may induce lactic acidosis. A recently developed thiazolidinedione diabetes therapeutic agent has an effect of improving insulin resistance in the periphery (Expert Opinion on Investigative Drugs, 9, pp 1347-1361, 2000), and enables good blood glucose control without causing hypoglycemia However, serious liver damage has been reported as a side effect. For this reason, non-thiazolidinedione insulin resistance improvers are desired.
On the other hand, as non-thiazolidinedione compounds, 2,2-dichloroalkanecarboxylic acid compounds are known to lower blood glucose levels in diabetes model animals and simultaneously exhibit plasma insulin lowering action and plasma triglyceride lowering action. (European Journal of Medicinal Chemistry, 33, pp 775-787, 1998). Hyperinsulinemia suggests insulin resistance, and hyperlipidemia is considered to be a risk factor for arteriosclerosis as an abnormal lipid metabolism associated with diabetes. Therefore, correcting them is important for the prevention and / or treatment of diabetes and diabetic complications.
For example, the following compound A exhibits antidiabetic activity in various animal models (compound 3e described in Eur. J. Med. Chem., 33, pp. 775-787, 1998; Metabolism, 48, pp 34-40, 1999). ), Its efficacy exceeds that of thiazolidinedione compounds. In addition, since it does not show PPARγ activation which is the mechanism of action of thiazolidinedione compounds (Archives of Toxicology, 73, pp440-450, 1999), it clearly shows an action different from thiazolidinedione compounds and reduces side effects. It is expected to lead to

［式中、ｍは０から４の整数を示し、ｎは５から９の整数を示し、Ｗは−ＣＨ（ＯＲ）−（Ｒは水素原子又は水酸基の保護基を示す）又は−Ｃ（＝Ｏ）−を示す］で表される化合物、その塩、又はそのエステルを提供するものである。
また、本発明は、上記一般式（１）［式中、ｍは０から４の整数を示し、ｎは５から９の整数を示し、Ｗは−ＣＨ（ＯＲ）−（Ｒは水素原子又は水酸基の保護基を示す）又は−Ｃ（＝Ｏ）−を示す］で表わされる化合物、生理学的に許容されるその塩、及び生理学的に許容されるそのエステルからなる群から選ばれる物質を有効成分として含む医薬を提供するものである。
上記の医薬は、高脂血症、動脈硬化症、糖尿病、糖尿病合併症、炎症、及び心疾患からなる群から選ばれる疾患の予防及び／又は治療のための医薬として用いることができる。この医薬は、好ましくは、有効成分である上記の物質と薬学的に許容される担体とを含有する医薬組成物として提供される。
別の観点からは、上記の医薬の製造のための上記一般式（１）［式中、ｍは０から４の整数を示し、ｎは５から９の整数を示し、Ｗは−ＣＨ（ＯＲ）−（Ｒは水素原子又は水酸基の保護基を示す）又は−Ｃ（＝Ｏ）−を示す］で表わされる化合物、生理学的に許容されるその塩、及び生理学的に許容されるそのエステルからなる群から選ばれる物質の使用、並びに高脂血症、動脈硬化症、糖尿病、糖尿病合併症、炎症、及び心疾患からなる群から選ばれる疾患の予防及び／又は治療方法であって、上記一般式（１）［式中、ｍは０から４の整数を示し、ｎは５から９の整数を示し、Ｗは−ＣＨ（ＯＲ）−（Ｒは水素原子又は水酸基の保護基を示す）又は−Ｃ（＝Ｏ）−を示す］で表わされる化合物、生理学的に許容されるその塩、及び生理学的に許容されるそのエステルからなる群から選ばれる物質の予防及び／又は治療有効量をヒトを含む哺乳類動物に投与する工程を含む方法が本発明により提供される。For the effective treatment of diabetes and diabetic complications, in addition to the purpose of reducing and avoiding side effects, in addition to the purpose of easily controlling blood glucose levels and avoiding drug interactions in combination with other drugs, A highly active compound or a compound having equivalent or higher activity at a low dose is desired.
From this point of view, compounds that are more active than compound A or compounds that have equivalent or higher activity at lower doses than compound A are useful for the prevention and / or prevention of diabetes and diabetic complications, as well as hyperlipidemia and arteriosclerosis. Or it is expected to be useful for treatment.
Therefore, the present inventor has further studied to find a highly active compound, and as a result, the carboxylic acid compound represented by the following general formula (1) has a strong hypoglycemic action, and does not involve weight gain or obesity. It was found useful as a medicament for preventing and / or treating diabetes, diabetic complications, hyperlipidemia, arteriosclerosis and the like. The present invention has been completed based on the above findings.
That is, the present invention provides the following general formula (1):

[Wherein, m represents an integer of 0 to 4, n represents an integer of 5 to 9, W represents —CH (OR) — (R represents a hydrogen atom or a hydroxyl-protecting group) or —C (= O)-]], a salt thereof, or an ester thereof.
In the general formula (1), m represents an integer of 0 to 4, n represents an integer of 5 to 9, and W represents —CH (OR) — (R represents a hydrogen atom or A compound selected from the group consisting of a compound represented by the following: a hydroxyl protecting group) or -C (= O)-], a physiologically acceptable salt thereof, and a physiologically acceptable ester thereof. The present invention provides a medicine containing as an ingredient.
The above medicament can be used as a medicament for preventing and / or treating a disease selected from the group consisting of hyperlipidemia, arteriosclerosis, diabetes, diabetic complications, inflammation, and heart disease. This medicament is preferably provided as a pharmaceutical composition containing the above-mentioned substance as an active ingredient and a pharmaceutically acceptable carrier.
From another point of view, the above general formula (1) for the manufacture of the above-mentioned pharmaceutical, wherein m represents an integer of 0 to 4, n represents an integer of 5 to 9, and W represents —CH (OR )-(R represents a hydrogen atom or hydroxyl protecting group) or -C (= O)-], a physiologically acceptable salt thereof, and a physiologically acceptable ester thereof And a method for the prevention and / or treatment of a disease selected from the group consisting of hyperlipidemia, arteriosclerosis, diabetes, diabetic complications, inflammation, and heart disease Formula (1) [wherein m represents an integer of 0 to 4, n represents an integer of 5 to 9, W represents —CH (OR) — (R represents a hydrogen atom or a hydroxyl-protecting group) or -C (= O)-], physiologically acceptable salts thereof, and physiology Acceptable method of prevention and / or treatment effective amount of a substance selected from the group consisting of an ester comprising the step of administering to a mammal including human is provided by the present invention.

第一工程：
アルデヒド体（ＩＩ）をテトラヒドロフラン（ＴＨＦ）、ジオキサン、エーテル、又はジメトキシエタン等の不活性溶媒に溶解後、不活性ガスの雰囲気下に対応するハライドより調製したグリニャール試薬（Ｉ）の不活性溶媒溶液を添加し、冷却下ないし室温にて３０分ないし数時間攪拌することで化合物（ＩＩＩ）を製造することができる。
第二工程：
化合物（ＩＩＩ）の水酸基をアセチル基、メトキシメチル基等の適当な保護基で保護する工程である。保護基の種類及び導入条件は、例えば、プロテクティブ・グループス・イン・オーガニック・シンセシス、Ｐ．Ｇ．Ｍ．ブッツ、Ｔ．グリーン編、第３版、１９９９年、ジョン ウィリー アンド サンズ刊などを参照することができる。
第三工程：
本工程は、化合物（ＩＶ）とジクロロ酢酸のエステルとをＴＨＦ、ジオキサン、１，２−ジメトキシエタン、ジメチルホルムアミド（ＤＭＦ）、ジメチルスルホキシド（ＤＭＳＯ）等の溶媒に溶かし、不活性ガスの雰囲気下にアルコキシナトリウム、水素化ナトリウム、リチウムジイソプロピルアミド（ＬＤＡ）等の塩基を加え、室温ないし加熱下に１時間ないし２４時間攪拌することで達成できる。
第四工程：
化合物（Ｖ）の保護された水酸基を脱保護する工程である。水酸基の脱保護の条件は、例えば、プロテクティブ・グループス・イン・オーガニック・シンセシス、Ｐ．Ｇ．Ｍ．ブッツ、Ｔ．グリーン編、第３版、１９９９年、ジョン ウィリー アンド サンズ刊などを参照することができる。なお、次の第五工程で脱保護を同時に行うことができる場合があり、そのような場合にはこの第四工程を省略可能である。
第五工程：
化合物（ＶＩ）をメタノール、エタノール、ＴＨＦ、ジオキサン、１，２−ジメトキシエタン等の溶媒に溶解し、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等の塩基を添加して、冷却下ないし加熱下に１時間ないし２４時間攪拌し、塩酸等の酸を加えて酸性にすることで目的物を製造することができる。
＜合成ルート２＞

第一工程：
化合物（ＶＩＩＩ）を常法に従ってエステル化して化合物（ＩＸ）を製造することができる。エステル化法は特に限定されないが、一般的に用いられる活性エステル化法、混合酸無水物法、又は縮合法など適宜の方法により行うことができる。
第二工程：
化合物（ＩＸ）を四塩化炭素、シクロヘキサン、ベンゼン等の溶媒に溶解し、Ｎ−ブロモこはく酸イミド等のハロゲン化剤を添加し、室温ないし加熱下に１時間ないし２４時間攪拌することで化合物（Ｘ）を得ることができる。反応を促進するために、過酸化ジベンゾイルやアゾビスイソブチロニトリル等のラジカル開始剤を添加してもよい。
第三工程：
化合物（Ｘ）を水、またはアセトン、ＴＨＦ、ＤＭＦ等の有機溶媒と水との混合溶媒に溶解し、硝酸銀、過塩素酸銀等の銀塩、あるいは炭酸水素ナトリウムなどの塩基を添加し、冷却下ないし加熱下に１時間ないし２４時間攪拌することで化合物（ＸＩ）を得ることができる。
第四工程：
本工程は、合成ルート１の第五工程と同様の方法で達成できる。
＜合成ルート３＞

第一工程：
化合物（ＸＩＩＩ）を無溶媒で、またはトルエン、アセトン、又はＤＭＳＯなどの溶媒に溶解し、硫酸、リン酸、シュウ酸、ｐ−トルエンスルホン酸等の酸を添加し、室温ないし加熱下に１時間ないし２４時間攪拌することにより化合物（ＸＩＶ）を得ることができる。
第二工程：
化合物（ＸＩＶ）をクロロホルム、塩化メチレン、ジエチルエーテル等の溶媒に溶解し、この溶液あるいは上記の溶液と炭酸水素ナトリウム水溶液等との混合溶液中に過安息香酸、３−クロロ過安息香酸、トリフルオロ過酢酸等の過酸を添加し、冷却下ないし加熱下に１時間ないし２４時間攪拌することにより化合物（ＸＶ）を得ることができる。
第三工程：
化合物（ＸＶ）をＴＨＦ、酢酸エチル、アルコール類、酢酸等の溶媒に溶解し、パラジウム炭素、ラネーニッケル等の触媒を添加し、常圧又は加圧水素雰囲気下、冷却下ないし加熱下に１時間ないし２４時間攪拌することにより化合物（ＸＶＩ）を得ることができる。
第四工程：
本工程は、合成ルート１の第五工程と同様の方法で達成できる。
＜合成ルート４＞

第一工程：
本工程は、化合物（ＶＩ）をジクロロメタン、アセトン、ジエチルエーテル等の溶媒に溶解し、クロロクロム酸ピリジニウム（ＰＣＣ）、２クロム酸ピリジニウム（ＰＤＣ）等を加え冷却下乃至加熱下に１時間乃至２４時間攪拌することで達成できる。
第二工程：
本工程は、合成ルート１の第五工程と同様の方法で達成できる。
上記の合成ルート１ないし４の各工程の反応後には、常法に従って後処理を行うことができ、目的物を必要に応じて常法により精製した後に次工程の原料として用いることができる。
本発明の化合物のうち光学異性体は、例えばラセミ体の本発明の化合物あるいはその中間体を光学分割する方法により、または本発明の化合物あるいはその中間体の不斉合成などにより得る事ができる。光学分割の方法としては、例えば光学活性な充填剤を用いたクロマトグラフィーによる分割、ジアステレオマー化合物に誘導した後のクロマトグラフィーによる分割、ジアステレオマー塩に誘導した後での再結晶による分割などが挙げられる。不斉合成の方法としては、例えば光学活性な試薬や触媒を用いた不斉酸化反応、不斉還元反応、不斉炭素結合反応、酵素や酵母などの生体触媒を用いた還元、加水分解、エステル化などが挙げられる。
上記の合成ルートにより得られた本発明の化合物は、必要に応じて再結晶法、カラムクロマトグラフィーなどの通常の精製手段を用いて精製することができる。また必要に応じて、常法によって前記した所望の塩又は溶媒和物にすることもできる。なお、本明細書の実施例には、本発明の化合物の製造方法がさらに具体的かつ詳細に記載されているので、当業者は、上記の一般的な製造方法の説明及び実施例の具体的な説明を参照することにより、適宜の反応試薬、出発原料、及び反応条件を適宜選択し、必要に応じてこれらの方法に適宜の改変ないし修飾を加えることによって、本発明の化合物を容易に製造することができる。
本発明の化合物又はその塩は、後記試験例に示すように、ｉｎ ｖｉｖｏ評価系において強力な血漿グルコース降下作用を示すことから、糖尿病、糖尿病合併症、高脂血症、動脈硬化症等の予防及び／又は治療のための医薬の有効成分として有用である。この医薬はヒトを含む哺乳類動物に投与可能であり、体重増加や肥満を伴わないという極めて優れた特徴を有している。
本発明の医薬は、上記一般式（１）［式中、ｍは０から４の整数を示し、ｎは５から９の整数を示し、Ｗは−ＣＨ（ＯＲ）−（Ｒは水素原子又は水酸基の保護基を示す）又は−Ｃ（＝Ｏ）−を示す］で表わされる化合物、生理学的に許容されるその塩、及び生理学的に許容されるそのエステルからなる群から選ばれる物質を有効成分として含む。本発明の医薬としては、上記の物質をそのまま用いてもよいが、一般的には、上記の物質と１又は２以上の製剤用添加物とを含む医薬組成物を調製して投与することが好ましい。本発明の医薬としては、上記の物質を２種以上組み合わせて用いることもできる。
本発明の医薬の投与経路は特に限定されず、経口投与又は非経口投与のいずれの投与経路により投与してもよい。経口投与に適する医薬組成物としては、固形又は液体の医薬組成物のいずれであってもよく、非経口投与に適する医薬組成物としては、例えば、注射剤、点滴剤、坐剤、外用剤、点眼剤、点鼻剤、点耳剤、貼付剤などの製剤形態を例示することができる。
経口用の固形医薬組成物は、例えば、有効成分である上記の物質に賦形剤を加え、さらに必要に応じて結合剤、崩壊剤、滑沢剤、着色剤、又は矯味剤などの製剤用添加物を加えた後、常法により錠剤、顆粒剤、散剤、カプセル剤として調製することができる。製剤用添加物としては、当該分野で一般的に使用されているものを用いることができる。例えば、乳糖、塩化ナトリウム、ブドウ糖、デンプン、微結晶セルロース、珪酸等の賦形剤；水、エタノール、プロパノール、単シロップ、ゼラチン、ヒドロキシプロピルセルロース、メチルセルロース、エチルセルロース、シェラック、ポリビニルピロリドン等の結合剤；カンテン末、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド等の崩壊剤；精製タルク、ステアリン酸塩、ホウ砂、ポリエチレングリコール等の滑沢剤；β−カロチン、黄色三二酸化鉄、カラメル等の着色剤；及び白糖、橙皮等の矯味剤を例示できる。
経口用の液体医薬組成物は、有効成分である上記の物質に矯味剤、安定化剤、又は保存剤など製剤用添加物の１種又は２種以上を加え、常法により内服液剤、シロップ剤、エリキシル剤等として調製することができる。製剤用添加物としては、当該分野で一般的に使用されているものを用いることができる。例えば白糖等の矯味剤；トラガント等の安定化剤；パラオキシ安息香酸エステル等の保存剤が挙げられる。
注射剤は、有効成分である上記の物質に安定化剤又は等張化剤等などの製剤用添加物の１種又は２種以上を添加し、常法により皮下、筋肉、又は静脈内投与用の注射剤として製造することができる。製剤用添加物としては、当該分野で一般的に使用されているものを用いることができる。例えば、ピロ亜硫酸ナトリウム等の安定化剤；塩化ナトリウム等の等張化剤を例示できる。
坐薬は、有効成分である上記の物質に担体及び界面活性剤などの製剤用添加物を加えて常法により製造することができる。製剤用添加物としては、当該分野で一般的に使用されているものを用いることができる。例えば、ポリエチレングリコール、ハードファット等の担体；ポリソルベート８０等の界面活性剤を例示できる。
外用剤は、有効成分である上記の物質に基剤、水溶性高分子、溶媒、界面活性剤、又は保存剤等などの製剤用添加物の１種又は２種以上を加えて、常法により液剤、クリーム剤、ゲル剤、軟膏剤等として製造することができる。製剤用添加物としては、当該分野で一般的に使用されているものを用いることができる。例えば、流動パラフィン、白色ワセリン、精製ラノリン等の基剤；カルボキシビニルポリマー等の水溶性高分子；グリセリン、水等の溶媒；ポリオキシエチレン脂肪酸エステル等の界面活性剤；パラオキシ安息香酸エステル等の保存剤が挙げられる。
点眼剤は、有効成分である上記の物質に安定化剤、等張化剤、又は保存剤等の製剤用添加物の１種又は２種以上を加えて常法により製造することができる。製剤用添加物としては、当該分野で一般的に使用されているものを用いることができる。例えば、ピロ亜硫酸ナトリウム、ＥＤＴＡ等の安定化剤；塩化ナトリウム等の等張化剤；クロロブタノール等の保存剤を例示できる。
点鼻剤は、有効成分である上記の物質に安定化剤、等張化剤、又は保存剤等の製剤用添加物の１種又は２種以上を加えて常法により製造することができる。製剤用添加物としては、当該分野で一般的に使用されているものを用いることができる。例えば、ピロ亜硫酸ナトリウム、ＥＤＴＡ等の安定化剤；塩化ナトリウム等の等張化剤；塩化ベンザルコニウム等の保存剤を例示できる。
点耳剤は、有効成分である上記の物質に安定化剤、等張化剤、又は保存剤等の製剤用添加物の１種又は２種以上を加えて常法により製造することができる。製剤用添加物としては、当該分野で一般的に使用されているものを用いることができる。例えば、ピロ亜硫酸ナトリウム、ＥＤＴＡ等の安定化剤；塩化ナトリウム等の等張化剤；塩化ベンザルコニウム等の保存剤を例示できる。
貼付剤は、有効成分である上記の物質に粘着剤、溶媒、架橋剤、又は界面活性剤等の製剤用添加物の１種又は２種以上を加えて常法により含水型貼付剤、プラスター貼付剤等として製造することができる。製剤用添加物としては、当該分野で一般的に使用されているものを用いることができる。例えば、ポリアクリル酸部分中和物、ポリアクリル酸ナトリウム、ポリアクリル酸２−エチルヘキシル、スチレン−イソプレン−スチレンブロック共重合体等の粘着剤；グリセリン、水等の溶媒；ジヒドロキシアルミニウムアミノアセテート、乾燥水酸化アルミニウムゲル等の架橋剤；ポリオキシエチレン脂肪酸エステル等の界面活性剤を例示できる。
本発明の医薬の投与量は特に限定されず、患者の年齢、体重、及び症状、投与形態、投与経路、及び投与回数などによって適宜選択可能である。通常は、有効成分である上記の物質の質量として成人１日あたり０．１〜１００ｍｇを投与することができる。本発明の医薬は１日１回又は数回に分けて経口投与又は非経口投与することができる。Examples of the salt of the compound represented by the general formula (1) include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; organic base salts such as ammonium salts and trialkylamine salts. Mineral salts such as hydrochloride and sulfate; organic acid salts such as acetate and the like. Of these, physiologically acceptable salts are preferred.
The physiologically acceptable ester of the compound represented by the general formula (1) is an ester formed by the carboxyl group of the compound represented by the general formula (1), and increases the absorption rate from the intestinal tract in oral administration. An ester that is easily hydrolyzed after being absorbed in vivo is preferred. For example, an alkyl ester (the alkyl group may be linear, branched, cyclic, or a combination thereof, for example, having about 1 to 20 carbon atoms, and an oxygen atom in the alkyl chain. Or may contain one or more heteroatoms such as nitrogen atoms and / or unsaturated bonds, and may have one or more arbitrary substituents on the chain), aryl esters, etc. Can be mentioned. More specifically, ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalidyl ester, (5-methyl-2-oxo-1,3 -Dioxolen-4-yl) methyl ester, cyclohexyloxycarbonylethyl ester, and the like, but are not limited thereto. Further, a physiologically acceptable amide of the compound represented by the general formula (1) can also be used, and examples thereof include methylamide.
In the general formula (1), W represents —CH (OR) — (R represents a hydrogen atom or a hydroxyl-protecting group) or —C (═O) —. Examples of the protecting group for the hydroxyl group represented by R include synthetically useful protecting groups (such protecting groups include, for example, Protective Groups in Organic Synthesis, PGM Boots, T.M. Green Edition, 3rd edition, 1999, published by John Willie and Sons, etc.), increases the absorption rate of protected compounds from the intestinal tract and is easily deprotected in vivo, so that R is hydrogen Protecting groups that provide atomic compounds can be used. The latter compound having a protecting group is useful when used as a prodrug according to various purposes. Examples of the protecting group include, but are not limited to, an acetyl group, a palmitoyl group, a propanoyl group, a pivaloyl group, a succinyl group, a fumaryl group, an alanyl group, and a dimethylaminomethylcarbonyl group.
In the general formula (1), m represents an integer of 0 to 4, and n represents an integer of 5 to 9, but m + n is preferably an integer in the range of 8 to 10, and 9 is particularly preferable. . m is preferably an integer of 1 to 3, particularly preferably 1 or 2. n is preferably an integer of 6 to 9, particularly preferably 7 or 8.
The compound represented by the general formula (1), a salt thereof, or an ester thereof may exist as a solvate represented by a hydrate, but any solvate is also encompassed in the scope of the present invention. The The compound represented by the general formula (1) has one asymmetric carbon when R is a hydrogen atom, and the compound of the present invention (hereinafter referred to as “ When referred to as “the compound of the present invention”, the compound represented by the general formula (1) and its ester) may further have one or more asymmetric carbons. Also included within the scope of the invention are stereoisomers such as pure forms of optical isomers or diastereoisomers based on one or more asymmetric carbons, or any mixture of stereoisomers such as racemates.
Among the compounds of the present invention, preferred compounds include 2,2-dichloro-12- (4-chlorophenyl) -10-hydroxydodecanoic acid and 2,2-dichloro-12- (4-chlorophenyl) -11-hydroxydodecane. Mention may be made of the acids, and physiologically acceptable salts and physiologically acceptable esters thereof.
The compound of the present invention can be produced, for example, by the method described in the following synthetic route 1 or synthetic route 4. Further, in the compounds of the present invention, a compound in which m is 0 can also be produced by the method described in Synthesis Route 2. Furthermore, in the compound of the present invention, a compound in which m is 1 can also be produced by the method described in Synthesis Route 3.
(In the following scheme, m and n are as defined above, R ¹ represents a hydroxyl-protecting group, R ² represents an alkyl group, an aryl group, or an allyl group, and X and Y represent a halogen atom. )
<Synthesis route 1>

First step:
An inert solvent solution of Grignard reagent (I) prepared from the corresponding halide in an inert gas atmosphere after the aldehyde (II) is dissolved in an inert solvent such as tetrahydrofuran (THF), dioxane, ether, or dimethoxyethane Is added, and the mixture is stirred for 30 minutes to several hours under cooling to room temperature to produce compound (III).
Second step:
In this step, the hydroxyl group of compound (III) is protected with an appropriate protecting group such as an acetyl group or a methoxymethyl group. Types of protecting groups and introduction conditions are described in, for example, Protective Groups in Organic Synthesis, P.I. G. M.M. Butz, T. You can refer to Green Edition, 3rd edition, 1999, published by John Willie and Sons.
Third step:
In this step, compound (IV) and an ester of dichloroacetic acid are dissolved in a solvent such as THF, dioxane, 1,2-dimethoxyethane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and the mixture is placed in an inert gas atmosphere. This can be achieved by adding a base such as sodium alkoxy, sodium hydride, lithium diisopropylamide (LDA), and stirring for 1 to 24 hours at room temperature or under heating.
Fourth step:
In this step, the protected hydroxyl group of compound (V) is deprotected. The conditions for the deprotection of the hydroxyl group are, for example, Protective Groups in Organic Synthesis, P.I. G. M.M. Butz, T. You can refer to Green Edition, 3rd edition, 1999, published by John Willie and Sons. In some cases, deprotection can be performed simultaneously in the next fifth step, and in such a case, this fourth step can be omitted.
Fifth process:
Compound (VI) is dissolved in a solvent such as methanol, ethanol, THF, dioxane, 1,2-dimethoxyethane, and a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide is added, and the mixture is cooled or heated. The mixture is stirred for 1 to 24 hours and acidified by adding an acid such as hydrochloric acid to produce the desired product.
<Synthetic route 2>

First step:
Compound (IX) can be produced by esterifying compound (VIII) according to a conventional method. The esterification method is not particularly limited, but can be performed by an appropriate method such as an active esterification method, a mixed acid anhydride method, or a condensation method that are generally used.
Second step:
Compound (IX) is dissolved in a solvent such as carbon tetrachloride, cyclohexane or benzene, a halogenating agent such as N-bromosuccinimide is added, and the mixture is stirred for 1 to 24 hours at room temperature or under heating. X) can be obtained. In order to accelerate the reaction, a radical initiator such as dibenzoyl peroxide or azobisisobutyronitrile may be added.
Third step:
Compound (X) is dissolved in water or a mixed solvent of water and an organic solvent such as acetone, THF, DMF, etc., and a silver salt such as silver nitrate or silver perchlorate, or a base such as sodium hydrogen carbonate is added and cooled. Compound (XI) can be obtained by stirring for 1 to 24 hours under or under heating.
Fourth step:
This step can be achieved by the same method as the fifth step of the synthesis route 1.
<Synthetic route 3>

First step:
Compound (XIII) is dissolved without solvent or in a solvent such as toluene, acetone, or DMSO, and an acid such as sulfuric acid, phosphoric acid, oxalic acid, or p-toluenesulfonic acid is added, and it is room temperature to 1 hour under heating. The compound (XIV) can be obtained by stirring for 24 hours.
Second step:
Compound (XIV) is dissolved in a solvent such as chloroform, methylene chloride or diethyl ether, and perbenzoic acid, 3-chloroperbenzoic acid, trifluoro or the like in this solution or a mixed solution of the above solution and an aqueous sodium hydrogen carbonate solution. Compound (XV) can be obtained by adding a peracid such as peracetic acid and stirring for 1 to 24 hours under cooling or heating.
Third step:
Compound (XV) is dissolved in a solvent such as THF, ethyl acetate, alcohols, acetic acid, a catalyst such as palladium carbon, Raney nickel is added, and the mixture is cooled or heated under normal pressure or pressurized hydrogen atmosphere for 1 hour to 24 hours. Compound (XVI) can be obtained by stirring for a period of time.
Fourth step:
This step can be achieved by the same method as the fifth step of the synthesis route 1.
<Synthesis route 4>

First step:
In this step, compound (VI) is dissolved in a solvent such as dichloromethane, acetone, diethyl ether, etc., pyridinium chlorochromate (PCC), pyridinium chromate (PDC), etc. are added, and the mixture is cooled or heated for 1 hour to 24 hours. This can be achieved by stirring for a period of time.
Second step:
This step can be achieved by the same method as the fifth step of the synthesis route 1.
After the reaction in each step of the above synthesis routes 1 to 4, post-treatment can be performed according to a conventional method, and the target product can be used as a raw material for the next step after being purified by a conventional method as necessary.
Among the compounds of the present invention, optical isomers can be obtained, for example, by a method of optical resolution of a racemic compound of the present invention or an intermediate thereof, or by asymmetric synthesis of the compound of the present invention or an intermediate thereof. Examples of the optical resolution include resolution by chromatography using an optically active filler, resolution by chromatography after derivatization to a diastereomeric compound, resolution by recrystallization after derivatization to a diastereomeric salt, etc. Is mentioned. Asymmetric synthesis methods include, for example, an asymmetric oxidation reaction using an optically active reagent or catalyst, an asymmetric reduction reaction, an asymmetric carbon bond reaction, a reduction using a biocatalyst such as an enzyme or yeast, hydrolysis, ester For example.
The compound of the present invention obtained by the above synthesis route can be purified using a conventional purification means such as a recrystallization method or column chromatography, if necessary. If necessary, the desired salt or solvate can be obtained by a conventional method. In addition, since the production method of the compound of the present invention is described more specifically and in detail in the examples of the present specification, those skilled in the art will be able to explain the above general production methods and the specific examples of the examples. The compound of the present invention can be easily produced by appropriately selecting appropriate reaction reagents, starting materials, and reaction conditions by referring to the explanation, and adding appropriate modifications or modifications to these methods as necessary. can do.
Since the compound of the present invention or a salt thereof exhibits a strong plasma glucose lowering action in an in vivo evaluation system as shown in the following test examples, it can prevent diabetes, diabetic complications, hyperlipidemia, arteriosclerosis and the like. And / or useful as an active ingredient of a medicament for treatment. This medicine can be administered to mammals including humans and has an extremely excellent feature that it does not cause weight gain or obesity.
The medicament of the present invention has the above general formula (1) [wherein m represents an integer of 0 to 4, n represents an integer of 5 to 9, and W represents —CH (OR) — (R represents a hydrogen atom or A compound selected from the group consisting of a compound represented by the following: a hydroxyl protecting group) or -C (= O)-], a physiologically acceptable salt thereof, and a physiologically acceptable ester thereof. Contains as an ingredient. As the medicament of the present invention, the above substances may be used as they are. However, in general, it is possible to prepare and administer a pharmaceutical composition containing the above substances and one or more pharmaceutical additives. preferable. As the medicament of the present invention, two or more of the above substances can be used in combination.
The administration route of the medicament of the present invention is not particularly limited, and the administration route may be either oral administration or parenteral administration. The pharmaceutical composition suitable for oral administration may be either a solid or liquid pharmaceutical composition. Examples of the pharmaceutical composition suitable for parenteral administration include injections, drops, suppositories, external preparations, Examples of the dosage form include eye drops, nasal drops, ear drops, and patches.
The solid pharmaceutical composition for oral use is, for example, for the formulation of a binder, a disintegrant, a lubricant, a colorant, a corrigent, etc. After adding an additive, it can prepare as a tablet, a granule, a powder, a capsule by a conventional method. As a pharmaceutical additive, those commonly used in the art can be used. For example, excipients such as lactose, sodium chloride, glucose, starch, microcrystalline cellulose, silicic acid; binders such as water, ethanol, propanol, simple syrup, gelatin, hydroxypropylcellulose, methylcellulose, ethylcellulose, shellac, polyvinylpyrrolidone; Disintegrating agents such as agar powder, sodium lauryl sulfate, monoglyceride stearic acid; lubricants such as purified talc, stearate, borax, polyethylene glycol; coloring agents such as β-carotene, yellow ferric oxide, caramel; and white sugar Examples of flavoring agents such as orange peel.
Oral liquid pharmaceutical compositions are prepared by adding one or more additives for pharmaceutical preparations such as a corrigent, stabilizer, or preservative to the above-mentioned substances that are active ingredients, and using oral liquids and syrups by conventional methods. It can be prepared as an elixir. As a pharmaceutical additive, those commonly used in the art can be used. Examples include flavoring agents such as sucrose; stabilizers such as tragacanth; and preservatives such as paraoxybenzoic acid esters.
For injections, one or more of pharmaceutical additives such as stabilizers, tonicity agents, etc. are added to the above substances that are active ingredients, and are used for subcutaneous, intramuscular, or intravenous administration by conventional methods. It can be manufactured as an injection. As a pharmaceutical additive, those commonly used in the art can be used. For example, stabilizers such as sodium pyrosulfite; and isotonic agents such as sodium chloride can be exemplified.
Suppositories can be produced by a conventional method by adding additives for pharmaceutical preparation such as a carrier and a surfactant to the above-mentioned substances which are active ingredients. As a pharmaceutical additive, those commonly used in the art can be used. Examples thereof include carriers such as polyethylene glycol and hard fat; and surfactants such as polysorbate 80.
External preparations are prepared by adding one or more additives for pharmaceutical preparations such as a base, a water-soluble polymer, a solvent, a surfactant, or a preservative to the above-mentioned substances that are active ingredients. It can be produced as a liquid, cream, gel, ointment and the like. As a pharmaceutical additive, those commonly used in the art can be used. For example, bases such as liquid paraffin, white petrolatum, purified lanolin; water-soluble polymers such as carboxyvinyl polymer; solvents such as glycerin and water; surfactants such as polyoxyethylene fatty acid esters; storage of paraoxybenzoic acid esters and the like Agents.
The eye drops can be produced by a conventional method by adding one or more of pharmaceutical additives such as stabilizers, isotonic agents, or preservatives to the above-mentioned substances that are active ingredients. As a pharmaceutical additive, those commonly used in the art can be used. Examples include stabilizers such as sodium pyrosulfite and EDTA; isotonic agents such as sodium chloride; and preservatives such as chlorobutanol.
Nasal drops can be produced by a conventional method by adding one or more of pharmaceutical additives such as stabilizers, tonicity agents, or preservatives to the above-mentioned substances that are active ingredients. As a pharmaceutical additive, those commonly used in the art can be used. Examples include stabilizers such as sodium pyrosulfite and EDTA; isotonic agents such as sodium chloride; and preservatives such as benzalkonium chloride.
Ear drops can be produced by a conventional method by adding one or more additives for pharmaceutical preparations such as a stabilizer, an isotonic agent, or a preservative to the above-mentioned substance which is an active ingredient. As a pharmaceutical additive, those commonly used in the art can be used. Examples include stabilizers such as sodium pyrosulfite and EDTA; isotonic agents such as sodium chloride; and preservatives such as benzalkonium chloride.
The patch is a hydrous patch or plaster patch by a conventional method by adding one or more additives for preparations such as an adhesive, a solvent, a cross-linking agent, or a surfactant to the above-mentioned substance which is an active ingredient. It can be manufactured as an agent or the like. As a pharmaceutical additive, those commonly used in the art can be used. For example, adhesives such as partially neutralized polyacrylic acid, sodium polyacrylate, 2-ethylhexyl polyacrylate, styrene-isoprene-styrene block copolymer; solvents such as glycerin and water; dihydroxyaluminum aminoacetate, dry water Examples thereof include a crosslinking agent such as aluminum oxide gel; and a surfactant such as polyoxyethylene fatty acid ester.
The dosage of the medicament of the present invention is not particularly limited, and can be appropriately selected depending on the age, weight, and symptoms of the patient, the dosage form, the administration route, the number of administrations, and the like. Usually, 0.1 to 100 mg per day can be administered as the mass of the above-mentioned substance, which is an active ingredient. The medicament of the present invention can be orally or parenterally administered once or several times a day.

本発明の化合物は低用量から作用が認められることから、血漿グルコース低下作用について、ＥＤ_２５値を算出して作用発現用量の比較を行った。表２に本発明の化合物と比較化合物の血漿グルコース低下作用の効力比をＥＤ_２５値でまとめた。本発明の化合物のうち、例２（４）の化合物では０．６ｍｇ／ｋｇ、例４（４）の化合物では１．１ｍｇ／ｋｇ、例５（４）の化合物では０．５ｍｇ／ｋｇであるのに対し、化合物Ａでは２．８ｍｇ／ｋｇであった。すなわち、本発明の化合物は化合物Ａの１／２．５〜１／５．６の用量で同等の血漿グルコース低下作用を示した。
この結果から、本発明の化合物を有効成分として含む医薬には、副作用の軽減や他剤との併用における薬物相互作用の回避が期待できることがわかった。

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the scope of the present invention is not limited to these examples.
Example 1
(1) Synthesis of 10-bromo-1- (4-chlorophenyl) -5-decanol
  Magnesium (591 mg, 24.31 mmol) was added with 5 mL of anhydrous THF and stirred at room temperature under an argon atmosphere. Iodine (10 mg) was added and stirred for 2 hours until the brown color almost disappeared. To the reaction solution, a solution of 4- (4-bromobutyl) chlorobenzene (6.02 g, 24.32 mmol) in anhydrous THF (10 mL) was added dropwise over 10 minutes. After completion of the dropwise addition, stirring was continued at room temperature for 3 hours to prepare a Grignard reagent.
  6-Bromohexanal (4.79 g, 49.58 mmol) was dissolved in 10 mL of anhydrous THF and stirred under ice cooling. The prepared Grignard reagent was added dropwise to this solution over 10 minutes. The reaction solution was returned to room temperature and stirring was continued for 18 hours.
  After completion of the reaction, the reaction mixture was slowly added with 20 mL of purified water and 20 mL of saturated brine under cooling with water and stirred for 20 minutes. This mixture was extracted with diethyl ether (50 mL, 100 mL, 20 mL × 2), and then the extract was washed once with 20 mL of purified water and once with 30 mL of saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give a crude product. As a result, 16.54 g of a pale green oil was obtained. The oil was purified by silica gel column chromatography (eluent n-hexane / ethyl acetate = 10/1) to obtain the desired compound (3.14 g, yield 37.1%) as a colorless oil.
¹H-NMR (CDCl₃) Δ: 1.23-1.67 (12H, m), 1.87 (2H, tt, J = 7, 7 Hz), 2.59 (2H, t, J = 8 Hz), 3.41 (2H, t, J = 7 Hz), 3.58 (1H, m), 7.10 (2H, d, J = 8 Hz), 7.24 (2H, d, J = 8 Hz).
(2) Synthesis of 5-acetoxy-10-bromo-1- (4-chlorophenyl) decane
  10-Bromo-1- (4-chlorophenyl) -5-decanol (3.14 g, 9.03 mmol), 4-dimethylaminopyridine (111 mg, 0.903 mmol) and pyridine (3.97 g, 18.1 mmol) were dissolved in dichloromethane. Dissolved in 50 mL. This solution was ice-cooled and cooled for 10 minutes, and then 50 mL of a dichloromethane solution of acetyl chloride (851 mg, 10.8 mmol) was added dropwise over 10 minutes. After completion of the addition, the mixture was further stirred at room temperature for 3 hours.
  After completion of the reaction, the reaction solution was cooled with water and slowly added with 20 mL of 2 mol / L hydrochloric acid and 20 mL of saturated brine and stirred for 5 minutes. After separating the organic layer, the aqueous layer was further extracted twice with 100 mL of chloroform. The extracts were combined, washed once with 30 mL of purified water and once with 30 mL of saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain 4.33 g of a pale yellow oil as a crude product. The resulting crude product was purified by silica gel flash column chromatography (eluent n-hexane / ethyl acetate = 20/1) to obtain the target compound (3.50 g, yield 99.4%) as a colorless oil. It was.
¹H-NMR (CDCl₃) Δ: 1.22-1.65 (12H, m), 1.84 (2H, tt, J = 7, 7 Hz), 2.02 (3H, s), 2.56 (2H, t, J = 8 Hz), 3.39 (2 H, t, J = 7 Hz), 4.85 (1 H, m), 7.08 (2 H, d, J = 8 Hz), 7.24 (2 H, d, J = 8 Hz) .
(3) Synthesis of methyl 8-acetoxy-2,2-dichloro-12- (4-chlorophenyl) dodecanoate
  5-acetoxy-10-bromo-1- (4-chlorophenyl) decane (3.50 g, 8.97 mmol) was dissolved in 50 mL of DMF and stirred at room temperature in an argon gas atmosphere. To this was added methyl dichloroacetate (5.14 g, 35.9 mmol), and the mixture was cooled with ice. To this solution, sodium hydride (1.50 g, 35.9 mmol) was added at once and stirred for 1 hour, and further stirred at room temperature for 36 hours.
  Under cooling with water, the reaction solution was slowly added with 20 mL of saturated brine and stirred for 5 minutes. Further, 80 mL of water was added, followed by extraction three times with 50 mL of diethyl ether, and then the extract was washed once with 50 mL of purified water and once with 50 mL of saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give a crude product. 6.24 g of a pale yellow oil was obtained. This was purified by silica gel flash column chromatography (eluent n-hexane / ethyl acetate = 20/1) to obtain the target compound (1.43 g, yield 35.5%) as a colorless oil.
¹H-NMR (CDCl₃) Δ: 1.22-1.42 (6H, m), 1.46-1.66 (8H, m), 2.03 (3H, s), 2.40 (2H, m), 2.57 (2H, t, J = 8 Hz), 3.89 (3H, s), 4.85 (1H, m), 7.09 (2H, d, J = 9 Hz), 7.23 (2H, d, J = 9 Hz).
(4) Synthesis of 2,2-dichloro-12- (4-chlorophenyl) -8-hydroxydodecanoic acid
  Methyl 8-acetoxy-2,2-dichloro-12- (4-chlorophenyl) dodecanoate (1.43 g, 3.17 mmol) was dissolved in 40 mL of methanol and stirred under ice cooling. To this solution was added 2 mol / L aqueous lithium hydroxide solution (15.9 mL, 31.7 mmol), and the mixture was stirred for 15 minutes and further stirred at room temperature for 20 hours.
  After completion of the reaction, the reaction mixture was acidified by dropwise addition of 20 mL of saturated brine and 20 mL of 2 mol / L hydrochloric acid under cooling with water, extracted three times with 100 mL of chloroform, and then the extract was once with 50 mL of purified water and saturated brine. The extract was washed once with 50 mL, dried over sodium sulfate, and concentrated under reduced pressure to obtain 1.68 g of a pale yellow oil as a crude product. The resulting crude product was purified by silica gel column chromatography (eluent chloroform / methanol = 20/1 to 2/1) to obtain the target compound (749 mg, yield 59.7%) as a pale yellow oil. .
¹H-NMR (CDCl₃) Δ: 1.24-1.77 (14H, m), 2.43 (2H, m), 2.58 (2H, t, J = 8 Hz), 3.67 (1H, br), 7.09 (2H, d, J = 8 Hz), 7.23 (2H, d, J = 8 Hz).
Example 2
(1) Synthesis of 10-bromo-1- (4-chlorophenyl) -3-decanol
  Magnesium (1.07 g, 44.0 mmol) was added with 20 mL of anhydrous THF and stirred at room temperature under an argon atmosphere. Iodine (10 mg) was added and stirred for 2 hours until the brown color almost disappeared. To this reaction solution was slowly added 4- (2-bromoethyl) chlorobenzene (9.62 g, 43.8 mmol) in 20 mL of anhydrous THF, and the mixture was stirred for 3 hours to prepare a Grignard reagent.
  8-Bromo-1-octanal (10.27 g, 49.6 mmol) was dissolved in 30 mL of anhydrous THF under an argon atmosphere and stirred under ice cooling. The prepared Grignard reagent was added dropwise to this solution over 15 minutes. The reaction solution was returned to room temperature and stirring was continued for 16 hours.
  After completion of the reaction, the reaction mixture was slowly added with 20 mL of purified water and 20 mL of saturated brine under cooling with water and stirred for 20 minutes. This mixture was extracted twice with 100 mL of diethyl ether, and then the extract was washed once with 30 mL of purified water and once with 30 mL of saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give a pale green oil 16 as a crude product. .54 g was obtained. The oil was purified by silica gel column chromatography (eluent n-hexane / ethyl acetate = 8/1 to 4/1) to obtain the target compound (5.85 g, yield 38.3%) as a colorless oil. It was.
¹H-NMR (CDCl₃) Δ: 1.23-1.76 (12H, m), 1.80-1.88 (2H, m), 2.56-2.69 (1H, m), 2.70-2.81 ( 1H, m), 3.40 (2H, t, J = 7 Hz), 3.51-3.66 (1H, m), 7.12 (2H, d, J = 9 Hz), 7.24 (2H, d, J = 9 Hz).
(2) Synthesis of 3-acetoxy-10-bromo-1- (4-chlorophenyl) decane
  10-Bromo-1- (4-chlorophenyl) -3-decanol (5.85 g, 16.8 mmol) was dissolved in 50 mL of dichloromethane. This solution was cooled with ice, 4-dimethylaminopyridine (205 mg, 1.68 mmol) and pyridine (7.38 g, 33.62 mmol) were added, and the mixture was stirred for 10 minutes. To this solution, 50 mL of a dichloromethane solution of acetyl chloride (1.58 g, 20.13 mmol) was added dropwise over 5 minutes, and the mixture was stirred for 20 minutes as it was, and further stirred at room temperature for 30 minutes.
  After completion of the reaction, the reaction solution was cooled with water and slowly added with 20 mL of 2 mol / L hydrochloric acid and 20 mL of saturated brine and stirred for 5 minutes. This was extracted twice with 200 mL of ethyl acetate, and then the extract was washed once with 30 mL of purified water and once with 30 mL of saturated brine, dried over sodium sulfate and concentrated under reduced pressure to give a pale yellow oil as a crude product. 02 g was obtained. The resulting crude product was purified by silica gel column chromatography (eluent n-hexane / ethyl acetate = 20/1) to obtain the target compound (5.17 g, yield 78.8%) as a colorless oil. .
¹H-NMR (CDCl₃) Δ: 1.24-1.60 (10H, m), 1.76-1.89 (4H, m), 2.04 (3H, s), 2.51-2.68 (2H, m) 3.40 (2H, t, J = 7 Hz), 4.86-4.94 (1H, m), 7.10 (2H, d, J = 8 Hz), 7.24 (2H, d, J = 8 Hz).
(3) Synthesis of methyl 10-acetoxy-2,2-dichloro-12- (4-chlorophenyl) dodecanoate
  3-Acetoxy-10-bromo-1- (4-chlorophenyl) decane (5.17 g, 13.26 mmol) was dissolved in 50 mL of DMF and stirred at room temperature under an argon atmosphere. To this solution, methyl dichloroacetate (5.69 g, 39.80 mmol) was added and stirred for 10 minutes, and further stirred at −10 ° C. for 10 minutes. Sodium hydride (1.74 g, 39.79 mmol) was quickly added to the reaction solution, and the mixture was stirred for 1 hour, and further stirred at room temperature for 15 hours.
  After completion of the reaction, the reaction solution was slowly added with 20 mL of saturated brine under water cooling and stirred for 5 minutes. This mixture was extracted twice with 200 mL of diethyl ether, and the extract was washed once with 30 mL of purified water and once with 30 mL of saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give a pale yellow oily product 6 as a crude product. .39 g was obtained. The crude product was purified by silica gel column chromatography (eluent n-hexane / acetone = 20/1) to obtain the target compound (1.68 g, yield 28.0%) as a pale yellow oil.
¹H-NMR (CDCl₃) Δ: 1.22-1.65 (12H, m), 1.76-1.92 (2H, m), 2.04 (3H, s), 2.37-2.46 (2H, m) , 2.50-2.66 (2H, m), 3.89 (3H, s), 4.86-4.96 (1H, m), 7.10 (2H, d, J = 9 Hz), 7 .24 (2H, d, J = 9 Hz).
(4) Synthesis of 2,2-dichloro-12- (4-chlorophenyl) -10-hydroxydodecanoic acid
  Methyl 10-acetoxy-2,2-dichloro-12- (4-chlorophenyl) dodecanoate (1.68 g, 3.72 mmol) was dissolved in 40 mL of methanol and stirred under ice cooling. 2 mol / L lithium hydroxide aqueous solution (18.6 mL, 37.2 mmol) was added to this, and it stirred for 10 minutes, and also stirred at room temperature for 16 hours.
  After completion of the reaction, the reaction mixture was acidified by dropwise addition of 20 mL of saturated brine and 20 mL of 2 mol / L hydrochloric acid under cooling with water, extracted three times with 150 mL of chloroform, and then the extract was extracted once with 30 mL of purified water and saturated brine. The extract was washed once with 30 mL, dried over sodium sulfate, and concentrated under reduced pressure to obtain 1.68 g of a pale yellow oil as a crude product.
  This oily substance was purified by silica gel column chromatography (eluent chloroform / methanol = 10/1 to 2/1). The fraction containing the desired product was concentrated under reduced pressure, dissolved in 300 mL of chloroform, washed with a mixed solution of 30 mL of saturated saline and 30 mL of 2 mol / L hydrochloric acid, and then washed once with 50 mL of purified water and once with 50 mL of saturated brine. This solution was dried over sodium sulfate and concentrated under reduced pressure to obtain 1.32 g of a colorless oil as a crude product. The oil was crystallized by adding n-hexane to obtain 1.30 g of white crystalline powder. This crude crystal was recrystallized from a mixed solvent of ethyl acetate-n-hexane to obtain the target compound (1.00 g, yield 67.9%) as a white crystalline powder.
¹H-NMR (CDCl₃) Δ: 1.26 to 1.52 (10H, m), 1.54 to 1.63 (2H, m), 1.71-1.79 (2H, m), 2.41-2.47 ( 2H, m), 2.60-2.69 (1H, m), 2.72-2.81 (1H, m), 3.67 (1H, br), 7.12 (2H, d, J = 8 Hz), 7.25 (2H, d, J = 8 Hz).
Melting point: 100.0 to 101.7 ° C. (recrystallization solvent: ethyl acetate-n-hexane)
Example 3
(1) Synthesis of methyl 2,2-dichloro-12- (4-chlorophenyl) dodecanoate
  2,2-Dichloro-12- (4-chlorophenyl) dodecanoic acid (47.3 g, 124.5 mmol) was dissolved in 1000 mL of methanol, sulfuric acid (6.10 g, 62.19 mmol) was added, and the mixture was heated to reflux with stirring for 24 hours. .
  The reaction solution was cooled and concentrated under reduced pressure, 500 mL of chloroform and 500 mL of water were added, and the organic layer was separated. The aqueous layer was further extracted with chloroform (100 mL × 3), and the organic layers were combined, washed with water (200 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude target compound (47.35 g, yield). Yield 96.6%) as a pale yellow oil.
¹H-NMR (CDCl₃) Δ: 1.22-1.40 (12H, m), 1.51-1.62 (4H, m), 2.41 (2H, m), 2.56 (2H, t, J = 8 Hz) 3.89 (3H, s), 7.10 (2H, d, J = 8 Hz), 7.23 (2H, d, J = 8 Hz).
(2) Synthesis of methyl 12-bromo-2,2-dichloro-12- (4-chlorophenyl) dodecanoate
  Crude methyl 2,2-dichloro-12- (4-chlorophenyl) dodecanoate (47.25 g, 120.0 mmol) was dissolved in 500 mL of carbon tetrachloride, and 22.42 g (126.0 mmol) of N-bromosuccinimide was dissolved. 2,2′-azoisobutyronitrile (39.4 mg, 0.24 mmol) was added, and the mixture was heated to reflux with stirring under an argon atmosphere for 1 hour. The reaction mixture was cooled, concentrated under reduced pressure, dissolved in 800 mL of ethyl acetate, washed with water (200 mL × 3), saturated brine (200 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude target compound (57.35 g, quantitative) as a pale yellow oil.
¹H-NMR (CDCl₃) Δ: 1.22-1.62 (14H, m), 2.10 (1H, m), 2.24 (1H, m), 2.41 (2H, m), 3.89 (3H, s) ), 4.90 (1H, t, J = 7 Hz), 7.30 (2H, d, J = 9 Hz), 7.33 (2H, d, J = 9 Hz).
(3) Synthesis of methyl 2,2-dichloro-12- (4-chlorophenyl) -12-hydroxydodecanoate
  Crude methyl 12-bromo-2,2-dichloro-12- (4-chlorophenyl) dodecanoate (57.35 g, 120.0 mmol) was dissolved in a mixed solvent of 1000 mL of acetone and 200 mL of water. To this solution, 68.4 mL (132 mmol) of 40% aqueous silver perchlorate solution was added dropwise at room temperature over 10 minutes, and after completion of the addition, the solution was stirred at room temperature for 90 minutes. 200 mL of saturated brine was added to the reaction solution, and the mixture was stirred for 30 minutes. Acetone was distilled off from the filtrate under reduced pressure, and the insoluble matter was combined with a washing solution washed with 500 mL of ethyl acetate, and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate (200 mL × 2), and then the organic layer was washed with water (200 mL) and saturated brine (200 mL). The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent n-hexane / acetone = 8/1 to 2/1) to obtain the target compound (28.97 g, yield 58.9%) as a pale yellow oil.
¹H-NMR (CDCl₃) Δ: 1.22-1.44 (12H, m), 1.51-1.83 (4H, m), 2.40 (2H, m), 3.89 (3H, s), 4.65 (1H, br), 7.27 (2H, d, J = 6 Hz), 7.32 (2H, d, J = 6 Hz).
(4) Synthesis of 2,2-dichloro-12- (4-chlorophenyl) -12-hydroxydodecanoic acid
  Methyl 2,2-dichloro-12- (4-chlorophenyl) -12-hydroxydodecanoate (28.88 g, 70.48 mmol) was dissolved in 300 mL of methanol, and 2 mol / L lithium hydroxide aqueous solution (70.5 mL, 141 mmol) was dissolved. ) And stirred at room temperature for 1 hour. Methanol was distilled off from the reaction solution under reduced pressure, 200 mL of water was added, and 2 mol / L hydrochloric acid was added dropwise under ice cooling to make the solution acidic.
  To this mixture, 800 mL of a chloroform-methanol 10: 1 mixture was added to separate the organic layer, and the aqueous layer was further extracted with a chloroform-methanol 10: 1 mixture (200 mL × 3). The organic layer was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give a colorless oil. The oily substance was inoculated with seed crystals and further dried under reduced pressure with stirring to obtain 27.80 g of a crude target product as a white crystalline powder. This was recrystallized from a mixed solution of diethyl ether-n-hexane to obtain the target compound (16.00 g, yield 57.4%) as a white crystalline powder.
¹H-NMR (CDCl₃) Δ: 1.22-1.45 (12H, m), 1.57 (2H, m), 1.68 (1H, m), 1.78 (1H, m), 2.45 (2H, m) ), 4.03-5.01 (1H, br), 4.70 (1H, dd, J = 8, 6 Hz), 7.27 (2H, d, J = 9 Hz), 7.32 (2H, d) , J = 9 Hz).
Melting point: 62.2-63.5 ° C. (recrystallization solvent: diethyl ether-n-hexane)
Example 4
(1) Synthesis of methyl 2,2-dichloro-12- (4-chlorophenyl) -11-dodecenoate
  Methyl 2,2-dichloro-12- (4-chlorophenyl) -12-hydroxydodecanoate (8.89 g, 21.91 mmol) was dissolved in 300 mL of toluene, and p-toluenesulfonic acid monohydrate (1.67 g, 8.78 mmol) was added, and the mixture was stirred at 80 ° C. for 4 hours. The reaction mixture was washed with 200 mL of water and 10 mL of saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with 100 mL of ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the extract was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/1). The solvent was distilled off under reduced pressure to obtain the target compound (8.38 g, yield 97.6%) as a yellow oil.
¹H-NMR (CDCl₃) Δ: 1.24-1.41 (8H, m), 1.42-1.51 (2H, m), 1.52-1.63 (2H, m), 2.14-2.25 ( 2H, m), 2.37-2.48 (2H, m), 3.89 (3H, s), 6.20 (1H, dt, J = 16, 7 Hz), 6.32 (1H, d, J = 16 Hz), 7.22-7.30 (4H, m).
(2) Synthesis of methyl 2,2-dichloro-12- (4-chlorophenyl) -11,12-epoxide dodecanoate
  Methyl 2,2-dichloro-12- (4-chlorophenyl) -11-dodecenoate (8.38 g, 21.39 mmol) was dissolved in 200 mL of chloroform, and 3-chloroperbenzoic acid (7.38 g, 42.77 mmol) was dissolved. The mixture was further stirred at room temperature for 2 hours. The reaction solution was washed with 200 mL of 5% sodium thiosulfate solution and 200 mL of saturated saline in this order, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 12.24 g of a pale yellow crystal residue. The product was purified by silica gel column chromatography (eluent n-hexane / chloroform = 1/9) to obtain the target compound (8.30 g, yield 95.2%) as a colorless oil.
¹H-NMR (CDCl₃) Δ: 1.23-1.41 (8H, m), 1.42-1.62 (4H, m), 1.62-1.72 (2H, m), 2.36-2.46 ( 2H, m), 2.89 (1H, td, J = 6, 2 Hz), 3.58 (1H, d, J = 2 Hz), 3.89 (3H, s), 7.16-7.22 ( 2H, d, J = 9 Hz), 7.28-7.33 (2H, d, J = 9 Hz).
(3) Synthesis of methyl 2,2-dichloro-12- (4-chlorophenyl) -11-hydroxydodecanoate
  Methyl 2,2-dichloro-12- (4-chlorophenyl) -11,12-epoxydodecanoate (6.87 g, 16.85 mmol) was dissolved in 200 mL of ethyl acetate, and 10% palladium carbon catalyst (-12 ° C. at −12 ° C.) 1.37 g) was added, and the mixture was stirred for 1 hour at the same temperature in a hydrogen gas atmosphere. Palladium on carbon was filtered off and the filtrate was washed with 60 mL of ethyl acetate. The filtrate was distilled off under reduced pressure to obtain 6.89 g of a colorless oily residue. Purification by silica gel column chromatography (eluent n-hexane / ethyl acetate = 8/1 to 4/1) gave the target compound (6.27 g, yield 90.8%) as a colorless oil.
¹H-NMR (CDCl₃) Δ: 1.23-1.64 (14H, m), 2.36-2.46 (2H, m), 2.63 (1H, dd, J = 14, 8 Hz), 2.79 (1H, dd, J = 14, 4 Hz), 3.79 (1H, m), 3.89 (3H, s), 7.15 (2H, d, J = 8 Hz), 7.28 (2H, d, J = 8 Hz).
(4) Synthesis of 2,2-dichloro-12- (4-chlorophenyl) -11-hydroxydodecanoic acid
  Methyl 2,2-dichloro-12- (4-chlorophenyl) -11-hydroxydodecanoate (4.62 g, 11.27 mmol) was dissolved in 25 mL of methanol, and 2 mol / L lithium hydroxide solution (11.3 mL) was cooled with ice water. , 22.60 mmol) was added dropwise over about 5 minutes and stirred at the same temperature for 30 minutes. To the reaction solution, 75 mL of saturated saline was added, and the mixture was acidified by adding dropwise 15 mL of 2 mol / L hydrochloric acid while cooling with ice water, and extracted with chloroform (50 mL, 20 mL × 2). The organic layers were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To this residue, 100 mL of n-hexane was added, and the mixture was stirred and crystallized while cooling with ice water. The crystals were collected by filtration, washed with n-hexane and air-dried to obtain 4.41 g of colorless crystalline powder. The crystals were recrystallized from a mixed solution of ethyl acetate 5 mL-n-hexane 40 mL to obtain the target compound (4.01 g, yield 89.9%) as colorless micro needle crystals.
¹H-NMR (CDCl₃) Δ: 1.24-1.42 (10H, m), 1.42-1.65 (4H, m), 2.38-2.48 (2H, m), 2.67 (1H, dd, J = 14,8 Hz), 2.81 (1H, dd, J = 14, 4 Hz), 3.86 (1H, m), 7.15 (2H, d, J = 8 Hz), 7.27 (2H, d, J = 8 Hz).
Melting point: 84.1-85.8 ° C. (recrystallization solvent: ethyl acetate-n-hexane)
Example 5
(1) Synthesis of 3-benzoyloxy-10-bromo-1- (4-chlorophenyl) decane
  In the same manner as in Example 2 (2), 10-bromo-1- (4-chlorophenyl) -3-decanol (196 mg, 0.564 mmol) and benzoyl chloride (95 mg, 0.676 mmol) were used to obtain the target compound (211 mg, 82.8%) was obtained as a colorless oil.
¹H-NMR (CDCl₃) Δ: 1.24-1.80 (12H, m), 1.80-2.09 (2H, m), 2.57-2.76 (2H, m), 3.34 (2H, t, J = 7 Hz), 5.11-5.22 (1H, m), 7.09 (2H, d, J = 9 Hz), 7.21 (2H, d, J = 9 Hz), 7.44 (2H, t, J = 7 Hz), 7.56 (1H, t, J = 7 Hz), 8.02 (2H, d, J = 7 Hz).
(2) Synthesis of methyl 10-benzoyloxy-2,2-dichloro-12- (4-chlorophenyl) dodecanoate
  In the same manner as in Example 2 (3), from 3-benzoyloxy-10-bromo-1- (4-chlorophenyl) decane (116 mg, 0.257 mmol), the target compound (31.3 mg, yield 23.7%) Was obtained as a colorless oil.
¹H-NMR (CDCl₃) Δ: 1.15-1.82 (12H, m), 1.82-2.11 (2H, m), 2.3-2.44 (2H, m), 2.58-2.76 ( 2H, m), 3.88 (3H, s), 5.11-5.22 (1H, m), 7.10 (2H, d, J = 9 Hz), 7.22 (2H, d, J = 9 Hz), 7.45 (2H, t, J = 7 Hz), 7.57 (1H, t, J = 7 Hz), 8.02 (2H.d, J = 7 Hz).
(3) Optical resolution of methyl 10-benzoyloxy-2,2-dichloro-12- (4-chlorophenyl) dodecanoate
  By high performance liquid chromatography using an optically active column (column: Chiralcel OJ, manufactured by Daicel Chemical Industries, mobile phase n-hexane: 2-propanol 19: 1), 10-benzoyloxy-2,2-dichloro-12- (4 1.28 g of racemic methyl-chlorophenyl) dodecanoate was optically resolved.
  (A) Fractions containing only peak components having a short retention time were combined and concentrated under reduced pressure, and then purified again by flash column chromatography (eluent n-hexane / ethyl acetate = 20/1 to 10/1), (+) Methyl -10-benzoyloxy-2,2-dichloro-12- (4-chlorophenyl) dodecanoate (peak component having a short optically active column Chiralcel OJ retention time) (449 mg, yield 35.1%) as a colorless oil Obtained.
  Optical purity by HPLC area ratio:> 99% ee (Chiralcel OJ, mobile phase n-hexane: 2-propanol 19: 1)
  Specific rotation: [α]_D ²⁷= +8.23 (c 1.15, CHCl₃)
  (B) Fractions containing only peak components with a long retention time were combined and concentrated under reduced pressure, and then purified again by flash column chromatography (eluent n-hexane / ethyl acetate = 20/1 to 10/1), (-) Methyl -10-benzoyloxy-2,2-dichloro-12- (4-chlorophenyl) dodecanoate (peak component having a long optically active column Chiralcel OJ retention time) (432 mg, yield 33.8%) as a colorless oil Obtained.
  Optical purity by HPLC area ratio:> 99% ee (Chiralcel OJ, mobile phase n-hexane: 2-propanol 19: 1)
  Specific rotation: [α]_D ²⁷= -8.06 (c 1.10, CHCl₃)
(4) Synthesis of (+)-2,2-dichloro-12- (4-chlorophenyl) -10-hydroxydodecanoic acid
  (+)-10-benzoyloxy-2,2-dichloro-12- (4-chlorophenyl) dodecanoic acid methyl ester (optically active column Chiralcel OJ former component,> 99% ee) in the same manner as in Example 2 (4) ( The target compound (19.58 g, yield 57.5%) was obtained as a white crystalline powder from 44.2 g, 86.0 mmol).
  Melting point: 103.1-103.6 ° C. (recrystallization solvent: ethyl acetate-n-hexane)
¹H-NMR (CDCl₃) Δ: 1.26 to 1.63 (12H, m), 1.71-1.79 (2H, m), 2.38-2.47 (2H, m), 2.58-2.69 ( 1H, m), 2.70-2.80 (1H, m), 3.68 (1H, br), 7.12 (2H, d, J = 8 Hz), 7.24 (2H, d, J = 8 Hz).
  Optical purity by HPLC area ratio:> 99% ee (Chiralpak AD-RH, mobile phase acetonitrile: 5 mM H₃PO₄Buffer solution 70:30)
  Specific rotation: [α]_D ²³= +8.06 (c 5.00, CHCl₃)
(5) Synthesis of (−)-2,2-dichloro-12- (4-chlorophenyl) -10-hydroxydodecanoic acid
  (-)-10-benzoyloxy-2,2-dichloro-12- (4-chlorophenyl) dodecanoic acid methyl ester (post-component of optically active column Chiralcel OJ,> 99% ee) in the same manner as (4) above (44) The target compound (20.59 g, yield 60.4%) was obtained as a white crystalline powder from 3 g, 86.2 mmol).
  Melting point: 103.0 to 103.7 ° C. (recrystallization solvent: ethyl acetate-n-hexane)
¹H-NMR (CDCl₃) Δ: 1.19-1.63 (12H, m), 1.68-1.85 (2H, m), 2.38-2.47 (2H, m), 2.58-2.68 ( 1H, m), 2.70-2.81 (1H, m), 3.68 (1H, br), 7.12 (2H, d, J = 9 Hz), 7.24 (2H, d, J = 9 Hz).
  Optical purity by HPLC area ratio:> 99% ee (Chiralpak AD-RH, mobile phase acetonitrile: 5 mM H₃PO₄Buffer solution 70:30)
  Specific rotation: [α]_D ²³= -8.02 (c 5.00, CHCl₃)
Example 6
(1) Synthesis of 10-bromo-1- (4-chlorophenyl) -5-methoxymethoxydecane
  10-Bromo-1- (4-chlorophenyl) -5-decanol (14.51 g, 41.7 mmol) obtained in Example 1 (1) and diisopropylethylamine (10.78 g, 83.4 mmol) were dissolved in 200 mL of chloroform. The mixture was stirred under ice cooling. Chloromethyl methyl ether (5.04 g, 62.6 mmol) was added dropwise thereto, and the mixture was stirred for 1 hour under ice cooling, and further stirred at room temperature for 30 hours.
  Under cooling with ice water, 100 mL of 2 mol / L hydrochloric acid was slowly added and stirred, and then the organic layer was separated. After further extraction with chloroform (50 mL × 2) from the aqueous layer, the organic layers were combined, washed once with 50 mL of purified water, then once with 50 mL of saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent n-hexane / ethyl acetate = 20/1) to obtain the target compound (13.30 g, yield 81.4%) as a colorless oil.
  ¹H-NMR (CDCl₃) Δ: 1.22-1.66 (12H, m), 1.86 (2H, quint., J = 7 Hz), 2.58 (2H, t, J = 8 Hz), 3.36 (3H, s) ), 3.41 (2H, t, J = 7 Hz), 3.52 (1H, quint., J = 7 Hz), 4.63 (2H, s), 7.09 (2H, d, J = 8 Hz) , 7.23 (2H, d, J = 8 Hz).
(2) Synthesis of methyl 2,2-dichloro-12- (4-chlorophenyl) -8-methoxymethoxydodecanoate
  In the same manner as in Example 1 (3), 10-bromo-1- (4-chlorophenyl) -5-methoxymethoxydecane (13.30 g, 33.95 mmol) and methyl dichloroacetate (19.42 g, 135.8 mmol) The target compound (4.02 g, yield 26.1%) was thus obtained as a colorless oil.
  ¹H-NMR (CDCl₃) Δ: 1.25-1.64 (14H, m), 2.38-2.44 (2H, m), 2.58 (2H, t, J = 8 Hz), 3.36 (3H, s) , 3.51 (1H, quint., J = 6 Hz), 3.89 (3H, s), 4.63 (2H, s), 7.09 (2H, d, J = 9 Hz), 7.23 ( 2H, d, J = 9 Hz).
(3) Synthesis of methyl 2,2-dichloro-12- (4-chlorophenyl) -8-hydroxydodecanoate
  Methyl 2,2-dichloro-12- (4-chlorophenyl) -8-methoxymethoxydodecanoate (4.02 g, 8.86 mmol) was dissolved in 150 mL of methanol and stirred under ice cooling. Hydrochloric acid 0.2mL was added to this, and it stirred under ice-cooling for 15 minutes, and also stirred at room temperature for 20 hours.
  Chloroform 100mL and purified water 100mL were added to the residue which concentrated the reaction liquid under reduced pressure, and the organic layer was fractionated. After further extraction with chloroform (20 mL × 3) from the aqueous layer, the organic layers were combined, washed once with 50 mL of purified water, then once with 50 mL of saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent n-hexane / ethyl acetate = 10/1 to 5/1) to give the target compound (2.93 g, yield 80.7%) as a colorless oil. Obtained.
  ¹H-NMR (CDCl₃) Δ: 1.22-1.51 (10H, m), 1.54-1.67 (4H, m), 2.39-2.45 (2H, m), 2.59 (2H, t, J = 8 Hz), 3.58 (1 H, m), 3.89 (3 H, s), 7.10 (2 H, d, J = 9 Hz), 7.24 (2 H, d, J = 9 Hz).
(4) Synthesis of methyl 2,2-dichloro-12- (4-chlorophenyl) -8-oxododecanoate
  Methyl 2,2-dichloro-12- (4-chlorophenyl) -8-hydroxydodecanoate (1.50 g, 3.66 mmol) was dissolved in 50 mL of methylene chloride and stirred under ice cooling. To this was slowly added pyridinium chlorochromate (PCC) (1.58 g, purity 98%, 7.33 mmol), followed by stirring for 30 minutes under ice cooling, and further stirring at room temperature for 3 hours.
Under cooling with water, the reaction solution was slowly added with 100 mL of diethyl ether and stirred for 10 minutes. This solution was directly subjected to silica gel column chromatography (eluent chloroform) to remove polar components, and then the solvent was distilled off under reduced pressure. The residue was further purified by silica gel flash column chromatography (eluent n-hexane / ethyl acetate = 20/1 to 10/1) to obtain the target compound (1.35 g, yield 90.4%) as a pale yellow oil. Obtained as a thing.
  ¹H-NMR (CDCl₃) Δ: 1.35 (2H, quint., J = 8 Hz), 1.53-1.65 (8H, m), 2.36-2.44 (6H, m), 2.58 (2H, t) , J = 7 Hz), 3.89 (3H, s), 7.09 (2H, d, J = 8 Hz), 7.23 (2H, d, J = 8 Hz).
(5) Synthesis of 2,2-dichloro-12- (4-chlorophenyl) -8-oxododecanoic acid
  In the same manner as in Example 1 (4), the desired compound (1.15 g, yield 88) was obtained from methyl 2,2-dichloro-12- (4-chlorophenyl) -8-oxododecanoate (1.35 g, 3.31 mmol). 0.2%) as a white crystalline powder.
  Melting point: 48.8-49.7 ° C. (recrystallization solvent: diethyl ether-n-hexane)
¹H-NMR (CDCl₃) Δ: 1.37 (2H, quint., J = 8 Hz), 1.53-1.68 (8H, m), 2.38-2.46 (6H, m), 2.58 (2H, t) , J = 7 Hz), 7.09 (2H, d, J = 9 Hz), 7.23 (2H, d, J = 9 Hz).
Example 7
(1) Synthesis of 10-bromo-1- (4-chlorophenyl) -3-methoxymethoxydecane
  In the same manner as in Example 6 (1), 10-bromo-1- (4-chlorophenyl) -3-decanol (5.80 g, 16.7 mmol) obtained in Example 2 (1) and chloromethyl methyl ether (4 (0.44 g, 40.1 mmol) to give the target compound (5.73 g, yield 87.7%) as a colorless oil.
  ¹H-NMR (CDCl₃): 1.25-1.60 (10H, m), 1.72-1.89 (4H, m), 2.61 (1H, m), 2.70 (1H, m), 3.40 (3H, s), 3.50-3.59 (3H, m), 4.65 (1H, d, J = 7 Hz), 4.68 (1H, d, J = 7 Hz), 7.12 (2H , D, J = 8 Hz), 7.24 (2H, d, J = 8 Hz).
(2) Synthesis of methyl 2,2-dichloro-12- (4-chlorophenyl) -10-methoxymethoxydodecanoate
  10-Bromo-1- (4-chlorophenyl) -3-methoxymethoxydecane (5.70 g, 14.6 mmol) and methyl dichloroacetate (6.23 g, 43.6 mmol) in the same manner as in Example 1 (3) The target compound (645 mg, yield 9.8%) was thus obtained as a pale yellow oil.
  ¹H-NMR (CDCl₃) Δ: 1.23-1.79 (14H, m), 2.41 (2H, m), 2.61 (1H, m), 2.70 (1H, m), 3.40 (3H, s) ), 3.56 (1H, m), 3.89 (3H, s), 4.65 (1H, d, J = 7 Hz), 4.68 (1H, d, J = 7 Hz), 7.12 ( 2H, d, J = 8 Hz), 7.24 (2H, d, J = 8 Hz).
(3) Synthesis of methyl 2,2-dichloro-12- (4-chlorophenyl) -10-hydroxydodecanoate
  In the same manner as in Example 6 (3), methyl 2,2-dichloro-12- (4-chlorophenyl) -10-methoxymethoxydodecanoate (1.09 g, 2.40 mmol) was used to obtain the target compound (842 mg, yield 85. 6%) as a colorless oil.
  ¹H-NMR (CDCl₃) Δ: 1.23-1.63 (12H, m), 1.64-1.82 (2H, m), 2.41 (2H, m), 2.64 (1H, m), 2.77 (1H, m), 3.60 (1H, m), 3.89 (3H, s), 7.13 (2H, d, J = 8 Hz), 7.24 (2H, d, J = 8 Hz).
(4) Synthesis of methyl 2,2-dichloro-12- (4-chlorophenyl) -10-oxododecanoate
  In the same manner as in Example 6 (4), the desired compound (749 mg, yield 89.6%) was obtained from methyl 2,2-dichloro-12- (4-chlorophenyl) -10-hydroxydodecanoate (840 mg, 2.05 mmol). Was obtained as a colorless oil.
  ¹H-NMR (CDCl₃): 1.19-1.42 (6H, m), 1.49-1.61 (4H, m), 2.37 (2H, t, J = 8 Hz), 2.40 (2H, m) , 2.70 (2H, t, J = 8 Hz), 2.86 (2H, t, J = 8 Hz), 3.89 (3H, s), 7.12 (2H, d, J = 8 Hz), 7 .23 (2H, d, J = 8 Hz).
(5) Synthesis of 2,2-dichloro-12- (4-chlorophenyl) -10-oxododecanoic acid
  In the same manner as in Example 1 (4), the desired compound (567 mg, yield 79.9%) was obtained from methyl 2,2-dichloro-12- (4-chlorophenyl) -10-oxododecanoate (735 mg, 1.80 mmol). Was obtained as a pale yellow oil.
¹H-NMR (CDCl₃): 1.19-1.42 (6H, m), 1.47-1.65 (4H, m), 2.39 (2H, m), 2.43 (2H, m), 2.71 (2H, t, J = 8 Hz), 2.86 (2H, t, J = 8 Hz), 7.11 (2H, d, J = 8 Hz), 7.24 (2H, d, J = 8 Hz).
Example 8
(1) Synthesis of methyl 2,2-dichloro-12- (4-chlorophenyl) -11-oxododecanoate
  In the same manner as in Example 6 (4), the objective was obtained from methyl 2,2-dichloro-12- (4-chlorophenyl) -11-hydroxydodecanoate (5.06 g, 12.35 mmol) obtained in Example 4 (3). The compound (4.36 g, yield 86.6%) was obtained as a colorless oil.
  ¹H-NMR (CDCl₃) Δ: 1.17-1.38 (8H, m), 1.49-1.61 (4H, m), 2.36-2.42 (2H, m), 2.44 (2H, t, J = 7 Hz), 3.65 (2H, s), 3.89 (3H, s), 7.13 (2H, d, J = 9 Hz), 7.30 (2H, d, J = 9 Hz).
(2) Synthesis of 2,2-dichloro-12- (4-chlorophenyl) -11-oxododecanoic acid
  In the same manner as in Example 1 (4), the target compound (3.90 g, yield 92) was obtained from methyl 2,2-dichloro-12- (4-chlorophenyl) -11-oxododecanoate (4.36 g, 10.69 mmol). .6%) was obtained as a white crystalline powder.
  Melting point: 56.8-57.8 ° C. (recrystallization solvent: diethyl ether-n-hexane)
¹H-NMR (CDCl₃): 1.18-1.40 (8H, m), 1.50-1.61 (4H, m), 2.40-2.45 (2H, m), 2.45 (2H, t, J = 8 Hz), 3.67 (2H, s), 7.13 (2H, d, J = 9 Hz), 7.30 (2H, d, J = 9 Hz).
Example 9
(1) Synthesis of methyl 2,2-dichloro-12- (4-chlorophenyl) -12-oxododecanoate
  In the same manner as in Example 6 (4), the objective was obtained from methyl 2,2-dichloro-12- (4-chlorophenyl) -12-hydroxydodecanoate (3.07 g, 7.49 mmol) obtained in Example 3 (3). The compound (2.87 g, yield 93.9%) was obtained as a white crystalline powder.
Melting point: 55.2-56.2 ° C. (recrystallization solvent: chloroform-n-hexane)
  ¹H-NMR (CDCl₃) Δ: 1.28-1.41 (10H, m), 1.57 (2H, m), 1.72 (2H, m), 2.41 (2H, m), 2.93 (2H, t) , J = 8 Hz), 3.89 (3H, s), 7.43 (2H, d, J = 9 Hz), 7.90 (2H, d, J = 9 Hz).
(2) Synthesis of 2,2-dichloro-12- (4-chlorophenyl) -12-oxododecanoic acid
  In the same manner as in Example 1 (4), the desired compound (1.74 g, yield 65) was obtained from methyl 2,2-dichloro-12- (4-chlorophenyl) -12-oxododecanoate (2.75 g, 6.74 mmol). 0.5%) as a white crystalline powder.
  Melting point: 82.4-83.0 ° C. (recrystallization solvent: chloroform-n-hexane)
¹H-NMR (CDCl₃) Δ: 1.27-1.42 (10H, m), 1.60 (2H, m), 1.72 (2H, m), 2.45 (2H, m), 2.94 (2H, t) , J = 8 Hz), 7.44 (2H, d, J = 9 Hz), 7.91 (2H, d, J = 9 Hz).
Test example 1
  The in vivo plasma glucose, insulin, and triglyceride lowering effects of the compound A of the present invention and the above compound A and pioglitazone hydrochloride as a comparative compound were measured by the following methods (Metabolism, 48, pp34-40, 1999, Journal of Medical Chemistry, 44, pp2601-2611, 2001).
(1) Measuring method
  C57BL / KsJ db / db mice (Journal of Clinical Investigation, 85, developed at Jackson Laboratory (USA) and known as obesity, hyperlipidemia, hyperinsulinemia and insulin resistance model as test animals pp 962-967, 1990) was used.
  Blood was collected from the orbital venous plexus using 7-week-old db / db mice using heparinized capillaries, and plasma was collected after centrifugation, and the plasma glucose concentration, insulin concentration and triglyceride concentration were measured to perform grouping. The administration of the compound was started from the day after blood collection, and was orally administered once a day for 14 days. Blood was collected from the orbital venous plexus 2 hours after administration of the compound on day 14 after administration. Plasma was collected and plasma glucose concentration, insulin concentration and triglyceride concentration were measured.
  As for plasma glucose concentration, in order to clarify the efficacy ratio of the compound of the present invention and the comparative compound, a dose (ED) that decreases by 25% when the average value in vehicle administration is 100%.₂₅) Was obtained and compared for each of the compounds of the present invention and the comparative compound (Arznimittel-Forschung, 40, pp156-162, 1990).
(2) Results
  Table 1 shows the plasma glucose, insulin, and triglyceride lowering activities of the compounds of the present invention and comparative compounds. From the results shown in Table 1, it can be seen that the compounds of the present invention show a plasma glucose, insulin, and triglyceride lowering action superior to those of Compound A and pioglitazone hydrochloride.

  Since the compound of the present invention has an effect from a low dose, it is ED for plasma glucose lowering effect.₂₅Values were calculated to compare doses of action. Table 2 shows the efficacy ratio of the plasma glucose lowering action of the compound of the present invention and the comparative compound as ED.₂₅Summarized by value. Among the compounds of the present invention, the compound of Example 2 (4) is 0.6 mg / kg, the compound of Example 4 (4) is 1.1 mg / kg, and the compound of Example 5 (4) is 0.5 mg / kg. On the other hand, in compound A, it was 2.8 mg / kg. That is, the compound of the present invention showed an equivalent plasma glucose lowering effect at a dose of 1 / 2.5 to 1 / 5.6 of Compound A.
  From these results, it was found that a drug containing the compound of the present invention as an active ingredient can be expected to reduce side effects and avoid drug interactions in combination with other drugs.

  The compound represented by the above general formula (1), a salt thereof, and an ester thereof have a strong hypoglycemic action, a plasma insulin lowering action, and a triglyceride lowering action. Diabetes mellitus is not accompanied by weight gain and obesity. It is useful as an active ingredient of a medicament that enables prevention and / or treatment of diseases such as diabetic complications, hyperlipidemia, and arteriosclerosis.

Claims (6)

The following general formula (1):

[Wherein, m represents an integer of 0 to 4, n represents an integer of 5 to 9, W represents —CH (OR) — (R represents a hydrogen atom or a hydroxyl-protecting group) or —C (= A compound represented by O)-, a salt thereof, or an ester thereof. The compound according to claim 1, wherein n + m is 9, a salt thereof, or an ester thereof. A compound selected from the group consisting of 2,2-dichloro-12- (4-chlorophenyl) -10-hydroxydodecanoic acid and 2,2-dichloro-12- (4-chlorophenyl) -11-hydroxydodecanoic acid, a salt thereof, Or its esters. The general formula (1) according to claim 1, wherein m represents an integer of 0 to 4, n represents an integer of 5 to 9, and W represents -CH (OR)-(R represents hydrogen. A compound selected from the group consisting of: a compound represented by the formula: a protective group for an atom or a hydroxyl group] or -C (= O)-; a physiologically acceptable salt thereof; A pharmaceutical comprising as an active ingredient. The medicament according to claim 4, for preventing and / or treating a disease selected from the group consisting of hyperlipidemia, arteriosclerosis, diabetes, diabetic complications, inflammation, and heart disease. Furthermore, the pharmaceutical of Claim 4 or 5 of the form of the pharmaceutical composition containing a pharmaceutically acceptable carrier.