JP4220827B2 - Benzoic acid derivatives and pharmaceuticals containing the same - Google Patents

Description

【０００９】
[R¹は炭素数1〜8アルキル基、炭素数1〜8アルコキシル基、ハロゲン原子、ニトロ基又はトリフルオロメチル基を示し、R²は-COOR³（基中、R³は水素原子又は炭素数1〜4アルキル基を示す）又は1H-テトラゾール-5-イル基を示し、Ｊは単結合、炭素数1〜8アルキレン基（前記炭素数1〜8アルキレン基の1個の炭素原子は-S-基、-SO-基、-SO₂-基、-O-基又はR⁴-基（基中、R⁴は水素原子又は炭素数1〜4アルキル基を示す）から選択される基によって置き換えられてもよい）、炭素数2〜8アルケニレン（前記炭素数2〜8アルケニレン基の1個の炭素原子は-S-基、-SO-基、-SO₂-基、-O-基又はR⁵-基（基中、R⁵は水素原子又は炭素数1〜4アルキル基を示す）から選択される基によって置き換えられてもよい）を示し、＝C−基、＝C−（炭素数1〜8アルキレン）−基（前記炭素数1〜8アルキレン基の1個の炭素原子は-S-基、-SO-基、-SO₂-基、-O-基又はR⁶-基（基中、R⁶は水素原子又は炭素数1〜4アルキル基を示す）から選択される基によって置き換えられてもよい）又は ＝C−（炭素数2〜8アルケニレン）−基（前記炭素数2〜8アルケニレン基の1個の炭素原子は-S-基、-SO-基、-SO₂-基、-O-基又はR⁷-基（基中、R⁷は水素原子、又は炭素数1〜4アルキル基を示す）から選択される基によって置き換えられてもよい）を示し、Gは炭素環基又はヘテロ環基を示し（前記G基中の炭素環基及びヘテロ環基は以下の(ｉ)〜(ｖ)から選択される1〜4個の基で置換されてもよい。(ｉ)炭素数1〜8アルキル基、(ii)炭素数1〜8アルコキシ基、(iii)ハロゲン原子、(iv)トリフルオロメチル基、(ｖ)ニトロ基）、E¹は1）単結合、2）炭素数1〜8アルキレン基、3)炭素数2〜8アルケニレン基、又は4)炭素数2〜8アルキニレン基を示し、E²は1)−O−基、2)−S−基、又は3)−NR⁸−基（基中、R⁸は水素原子又は炭素数1〜4アルキル基を示す）を示し、E³は1)単結合、又は2)炭素数1〜8アルキレン基を示し、ｍは0又は1を示し、「Ｃｙｃｌ」は、１）環が存在しないか又は2)飽和、一部飽和又は不飽和の5〜7員の炭素環を表わす。]で表される化合物、それらの非毒性塩、それらの酸付加塩又はそれらの水和物を有効成分として含有するペルオキシソーム増殖薬活性化受容体制御剤が知られている（特許文献２参照）。
【００１０】
上記一般式において、R²が-COOR³、R³が水素原子、Ｊが単結合、Gがハロゲン原子で置換された炭素環基（ベンゼン環）、E¹がC1〜8アルキレン基又は2〜8アルケニレン基、E²は−S−基、E³が単結合、ｍは0で Cyc1環が存在しない場合、後記一般式（1）の本発明の安息香酸誘導体に相当する。しかしながら、特許文献２には、本発明の安息香酸誘導体の具体的な記載はなく、更に本発明の一般式（１）で表される安息香酸誘導体又はその塩が、選択的なPPARα活性化作用を有することについても何ら具体的な記載及び示唆もなく、その効果については全く確認されていない。
【００１１】
【特許文献１】
国際公開第97/28149号
【特許文献２】
国際公開第99/11255号
【非特許文献１】
Nature, 347, 645-650, 1990
【非特許文献２】
Cell, 68, pp879-887, 1992
【非特許文献３】
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【非特許文献４】
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【非特許文献５】
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【非特許文献６】
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【非特許文献７】
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【非特許文献８】
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【非特許文献９】
Current Pharmaceutical Design, 3, pp1-14, 1997
【非特許文献１０】
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【非特許文献１１】
Current Opinion in Lipidology, 10, pp245-257, 1999
【非特許文献１２】
The Lancet, 354, pp141-148, 1999
【非特許文献１３】
Journal of Medicinal Chemistry, 43, pp527-550, 2000
【非特許文献１４】
Journal of Cardiovascular Risk, 8, pp195-201, 2001
【非特許文献１５】
Journal of Bioligical Chemistry, 270, 12953-12956, 1995
【非特許文献１６】
Endocrinology, 137, pp4189-4195, 1996
【非特許文献１７】
Trends Endocrinol. Metab., 10, pp9-13, 1999
【非特許文献１８】
J. Clin. Invest., 101, pp1354-1361, 1998
【非特許文献１９】
The Lancet, 349, pp952, 1997
【非特許文献２０】
Proc. Natl. Acad. Sci., 96, pp6102-6106, 1999
【非特許文献２１】
The Journal of Biological Chemistry, 275, pp1873-1877, 2000
【非特許文献２２】
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【非特許文献２３】
Diabetes, 46, 1319-1327, 1997
【非特許文献２４】
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【非特許文献２５】
Proc. Natl. Acad. Sci., 98, pp5306-5311, 2001
【非特許文献２６】
Journal of Biological Chemistry, 276, pp44258-44265, 2001
【非特許文献２７】
Proc. Natl. Acad. Sci., 99, pp303-308, 2002
【００１２】
【発明が解決しようとする課題】
従って本発明の目的は、体重増加、肥満を伴わない、高脂血症、動脈硬化症、糖尿病、糖尿病合併症、炎症、心疾患等の予防及び/又は治療薬として有用であるPPARα選択的活性化化合物を提供することにある。
【００１３】
【課題を解決するための手段】
そこで、本発明者は、PPARのうちαタイプを選択的に活性化する化合物を見出すべく種々検討した結果、後記一般式(1)で表わされる安息香酸誘導体が、PPARαを選択的に活性化し、体重増加、肥満を伴わない、高脂血症、動脈硬化症、糖尿病、糖尿病合併症、炎症、心疾患等の予防及び/又は治療薬として有用であることを見出し、本発明を完成した。
【００１４】
すなわち、本発明は、次の一般式(1)
【００１５】
【化３】

【００１６】
（式中、-A-は-CH₂-CH₂-基、-CH=CH-基、-CH(OH)-CH₂-基又は-C(O)-CH₂-基を示し、Xは酸素原子、NH基又はS(O)_n基（ここでｎは０、１又は２の数を示す））で表される安息香酸誘導体又はその塩を提供するものである。
また、本発明は上記一般式(1)で表わされる安息香酸誘導体又はその塩を有効成分とする医薬を提供するものである。
本発明は上記一般式(1)で表わされる安息香酸誘導体又はその塩を有効成分とするペルオキシソーム増殖薬活性化受容体α活性化剤を提供するものである。
本発明は上記一般式(1)で表わされる安息香酸誘導体又はその塩を有効成分とする高脂血症、動脈硬化症、糖尿病、糖尿病合併症、炎症及び心疾患から選ばれる疾患の予防及び／又は治療剤を提供するものである。
更にまた、本発明は上記一般式(1)で表わされる安息香酸誘導体又はその塩、及び薬学的に許容される担体を含有する医薬組成物を提供するものである。
【００１７】
【発明の実施の形態】
本発明の一般式（１）で表される安息香酸誘導体のうち、-A-が-CH₂-CH₂-基、-CH=CH-基又は-C(O)-CH₂-基であり、XがS(O)_n基（ここで、ｎは前記と同じ））であるのが好ましい。
更には、 次の一般式（１ａ）
【００１８】
【化４】

【００１９】
（式中、-A'-は-CH₂-CH₂-基又は-CH=CH-基を示す）で表される2-[7-(4-クロロフェニル)-6-ヘプテニルチオ]安息香酸、2-[7-(4-クロロフェニル)ヘプチルチオ]安息香酸、又はこれらの塩が、特にPPARα選択的な活性化に優れ好ましい。
【００２０】
本発明の一般式(1)で表わされる安息香酸誘導体の塩としては、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩；アンモニウム塩、トリアルキルアミン塩等の有機塩基塩；塩酸塩、硫酸塩等の鉱酸塩；酢酸塩等の有機酸塩等が挙げられる。これらの塩のうち、アルカリ金属塩、特にナトリウム塩が好ましい。
【００２１】
また本発明の一般式（１）で表される安息香酸誘導体は、水和物に代表される溶媒和物であってもよい。更に、本発明の安息香酸誘導体は、シス、トランスの幾何異性体や光学異性体が存在する場合もあるが、これらの異性体も本発明に含まれる。
【００２２】
本発明の一般式（１）で表される安息香酸誘導体は、例えば以下に記載の合成ルート、又はそれらの一部を適宜組み合わせることにより製造することができる。
【００２３】
（１）合成ルート１
【００２４】
【化５】

【００２５】
（式中のRは炭素数１〜６のアルキル基若しくはアリール基又はアリル基を示し、Yはハロゲン原子を示し、X'は硫黄原子、酸素原子又はNH基を示す）
【００２６】
７−ハロ−１−ヘプタノール（２）を酸化してアルデヒド体（３）とし、これにグリニャール試薬によりクロロフェニル基を導入して化合物（４）を得、これにチオサリチル酸エステル、サリチル酸エステル又はアントラニル酸エステルを反応させて化合物（５）を得、次いでこれを加水分解することにより、化合物（１ｂ）が得られる。以下、工程毎に説明する。
【００２７】
第一工程：7-ハロ-１-ヘプタノール（２）をクロロホルム、ジクロロメタン等の溶媒に溶かし、クロロクロム酸ピリジニウム、ジクロム酸ピリジニウム等の酸化剤を添加後、冷却下又は加熱下に、３０分間〜数時間攪拌する。
第二工程：得られたアルデヒド体（３）をテトラヒドロフラン、ジオキサン、エーテル、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4-クロロフェニルマグネシウムハライドの不活性溶媒溶液を添加し、冷却下又は室温以下にて３０分〜数時間攪拌する。
第三工程：チオサリチル酸エステル、サリチル酸エステル又はアントラニル酸エステルをアセトニトリル、テトラヒドロフラン、ジオキサン、1,2-ジメトキシエタン、N,N-ジメチルホルムアミド、ジメチルスルホキシド、クロロホルム、ジクロロメタン等の溶媒に溶解し、炭酸カリウム、炭酸ナトリウム、ジイソプロピルエチルアミン等の塩基の存在下に前工程で得られたハロゲン体（４）を加え、室温又は加熱下に１〜２４時間加熱する。
第四工程：得られたエステル体（５）を、メタノール、エタノール、テトラヒドロフラン、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、冷却下又は加熱下に １〜２４時間攪拌し、塩酸等の酸を加えて酸性にする。
【００２８】
（２）合成ルート２
【００２９】
【化６】

【００３０】
（式中のR、X'は前記と同じものを示す）
【００３１】
1,7-ジハロヘプタン（６）にグリニャール試薬によりクロロフェニル基を導入して化合物（８）を得、これを加水分解することにより化合物（１ｃ）が得られる。
【００３２】
第一工程：1,7-ジハロヘプタン（６）をテトラヒドロフラン、エーテル、1,2-ジエトキシエタン等の無水溶媒に溶かし、不活性ガス雰囲気下に4-クロルフェニルマグネシウムハライドの不活性溶媒の溶液を加え、冷却下又は加熱下に、１〜４時間攪拌する。この際、塩化銅と塩化リチウム等を触媒として加えてもよい。
第二工程：合成ルート1の第三工程と同様の方法で行う。
第三工程：合成ルート1の第四工程と同様の方法で行う。
【００３３】
(3)合成ルート３
【００３４】
【化７】

【００３５】
（式中のR及びAは前記と同じものを示し、n'は１又は２の整数を示す）
【００３６】
前記合成ルート１又は２によって得られる化合物（９）を酸化して化合物（１０）とし、次いでこれを加水分解することにより化合物（１ｆ）が得られる。
【００３７】
第一工程：原料のスルフィド体（９）をジクロロメタン、クロロホルム等の溶媒に溶解し、更にm-クロロ過安息香酸、過酢酸、過安息香酸等の酸化剤を添加して、冷却下又は加熱下に３０分〜２４時間攪拌する。
第二工程：合成ルート1の第四工程と同様の方法で行う。
【００３８】
（４）合成ルート４
【００３９】
【化８】

【００４０】
（R及びXは前記と同じ同じものを示す）
【００４１】
化合物（１１）を脱水反応に付して化合物（１２）を得、次いでこれを加水分解することにより化合物（１ｇ）が得られる。
【００４２】
第一工程：原料のアルコール体（１１）をトルエン、ベンゼン等の溶媒に溶解し、p-トルエンスルホン酸、メタンスルホン酸等の酸を加えて、室温又は加熱下に３０分〜２４時間攪拌する。
第二工程：合成ルート1の第四工程と同様の方法で行う。
【００４３】
（５）合成ルート５
【００４４】
【化９】

【００４５】
（R及びXは前記と同じものを示す）
【００４６】
化合物（１１）を酸化して化合物（１３）を得、次いでこれを加水分解することにより化合物（１ｈ）が得られる。
【００４７】
第一工程：原料のアルコール体（１１）をクロロホルム、ジクロロメタン等の溶媒に溶かし、二酸化マンガン、クロロクロム酸ピリジニウム、ジクロム酸ピリジニウム、クロム酸等の酸化剤を添加し、1〜２４時間攪拌する。
第二工程：合成ルート1の第四工程と同様の方法で行う。
【００４８】
上記の合成ルートの各工程の反応後に常法に従い後処理及び精製をしてもよい。精製法は、再結晶法、カラムクロマトグラフィー等の通常の精製手段を用いて行うことができる。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。
【００４９】
かくして得られる本発明の一般式（１）で表される安息香酸誘導体又はその塩は、後記実施例１５に示すように、選択的なPPARα活性化作用を有することから、ヒトを含む哺乳類における体重増加、肥満を伴わない、高脂血症、動脈硬化症、糖尿病、糖尿病合併症( 糖尿病性腎症等)、炎症、心疾患等の予防及び/又は治療薬として有用である。
【００５０】
本発明の一般式（１）で表される安息香酸誘導体又はその塩を有効成分とする医薬の投与形態は、特に限定されず治療目的に応じて適宜選択でき、例えば、経口用固形製剤、経口用液体製剤、注射剤、坐剤、外用剤、点眼剤、点鼻剤、点耳剤、貼付剤等のいずれでもよい。これらの製剤は、薬学的に許容される公知の担体を配合し、当業者に公知の製剤方法により製造できる。
【００５１】
経口用固形製剤とする場合は、本発明の一般式（１）で表される安息香酸誘導体又はその塩に、賦形剤、必要に応じて結合剤、崩壊剤、滑沢剤、着色剤、矯味剤、矯臭剤等の担体を加えた後、常法により錠剤、顆粒剤、散剤、カプセル剤等に調製する。
賦形剤としては乳糖、塩化ナトリウム、ブドウ糖、デンプン、微結晶セルロース、珪酸等が、結合剤としては水、エタノール、プロパノール、単シロップ、ゼラチン液、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、リン酸カルシウム、ポリビニルピロリドン等が、崩壊剤としてはカンテン末、炭酸水素ナトリウム、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が、滑沢剤としては精製タルク、ステアリン酸塩、ホウ砂、ポリエチレングリコールが、着色剤としてはβ−カロチン、黄色三二酸化鉄、カルメラ等が、矯味剤としては白糖、橙皮等が挙げられる。
【００５２】
経口用液体製剤とする場合は、本発明の一般式（１）で表される安息香酸誘導体又はその塩に、矯味剤、緩衝剤、安定化剤、保存剤等の担体を加えた後、常法により内服液剤、シロップ剤、エリキシル剤等に調製する。
矯味剤としては白糖等が、緩衝剤としてはクエン酸ナトリウム等が、安定化剤としてはトラガント等が、保存剤としてはパラオキシ安息香酸エステル等が挙げられる。
【００５３】
注射剤とする場合は、本発明の一般式（１）で表される安息香酸誘導体又はその塩に、pH調節剤、安定化剤、等張化剤等の担体を加えた後、常法により皮下、筋肉及び静脈内注射剤に調製する。
pH調節剤としてはリン酸ナトリウム等が、安定化剤としてはピロ亜硫酸ナトリウム等が、等張化剤としては塩化ナトリウム等が挙げられる。
【００５４】
坐薬とする場合は、本発明の一般式（１）で表される安息香酸誘導体又はその塩に、基剤、界面活性剤等の担体を加えた後、常法により調製する。
基剤としてはポリエチレングリコール、ハードファット等が、界面活性剤としてはポリソルベート８０等のポリオキシエチレンソルビタン脂肪酸エステル等が挙げられる。
【００５５】
外用剤とする場合は、本発明の一般式（１）で表される安息香酸誘導体又はその塩に、基剤、水溶性高分子、溶媒、界面活性剤、保存剤等の担体を加えた後、常法により液剤、クリーム剤、ゲル剤、軟膏剤等に調製する。
基剤としては流動パラフィン、白色ワセリン、精製ラノリン等が、水溶性高分子としてはカルボキシビニルポリマー等が、溶媒としてはグリセリン、水等が、界面活性剤としてはポリオキシエチレン脂肪酸エステル等が、保存剤としてはパラオキシ安息香酸エステル等が挙げられる。
【００５６】
点眼剤とする場合は、本発明の一般式（１）で表される安息香酸誘導体又はその塩に、pH調節剤、安定化剤、等張化剤、保存剤等の担体を加えた後、常法により調製する。
pH調節剤としてはリン酸ナトリウム等が、安定化剤としてはピロ亜硫酸ナトリウム、エチレンジアミン四酢酸等が、等張化剤としては塩化ナトリウム等が、保存剤としてはクロロブタノール等が挙げられる。
【００５７】
点鼻剤とする場合は、本発明の一般式（１）で表される安息香酸誘導体又はその塩に、pH調節剤、安定化剤、等張化剤、保存剤等の担体を加えた後、常法により調製する。
pH調節剤としてはリン酸ナトリウム等が、安定化剤としてはピロ亜硫酸ナトリウム、エチレンジアミン四酢酸等が、等張化剤としては塩化ナトリウム等が、保存剤としては塩化ベンザルコニウム等が挙げられる。
【００５８】
点耳剤とする場合は、本発明の一般式（１）で表される安息香酸誘導体又はその塩に、pH調節剤、緩衝剤、安定化剤、等張化剤、保存剤等の担体を加えた後、常法により調製する。
pH調節剤及び緩衝剤としてはリン酸ナトリウム等が、安定化剤としてはピロ亜硫酸ナトリウム、エチレンジアミン四酢酸等が、等張化剤としては塩化ナトリウム等が、保存剤としては塩化ベンザルコニウム等が挙げられる。
【００５９】
貼付剤とする場合は、本発明の一般式（１）で表される安息香酸誘導体又はその塩に、粘着剤、溶媒、架橋剤、界面活性剤等の担体を加えた後、常法により含水型貼付剤、プラスター貼付剤等に調製する。
粘着剤としては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が、溶媒としてはグリセリン、水等が、架橋剤としては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が、界面活性剤としてはポリオキシエチレン脂肪酸エステル等が挙げられる。
【００６０】
本発明の医薬の投与量は年齢、体重、症状、投与形態及び投与回数等によって異なるが、通常は成人に対して一般式（１）で表される安息香酸誘導体として1日1〜1000mgを、1回又は数回に分けて経口投与又は非経口投与するのが好ましい。
【００６１】
【実施例】
以下に実施例を挙げて本発明を具体的に説明するが、本発明はこれらに限定されるものではない。
【００６２】
製造例１ 7-ブロモヘプタナールの合成
クロロクロム酸ピリジニウム(9.94g, 純度90％として41.5 mmol)と酢酸ナトリウム(379mg、4.6mmol)を塩化メチレン150mLに懸濁し、氷冷下にて7-ブロモ-1-ヘプタノール(3.0g、15.4mmol)の塩化メチレン40mL溶液を30分間で滴下した。室温にて30分間攪拌した。反応終了後、ジエチルエーテル300mLを加え希釈し、シリカゲルカラムクロマトグラフィー（溶出液 ジエチルエーテル）で精製し、淡黄色油状の粗目的化合物（2.97g、収率99.9%）を得た。
【００６３】
製造例２ 7-ブロモ-1-(4-クロロフェニル)-1-ヘプチルアルコールの合成
粗7-ブロモヘプタナール(2.97g、15.38mmol)をテトラヒドロフラン 110mLに溶解し、アルゴン雰囲気下0℃にて4-クロロフェニルマグネシウムブロミドの1.0 mol/L ジエチルエーテル溶液 15.5 mL (15.5 mmol)を滴下した。反応終了後、0℃にて飽和塩化アンモニウム水溶液を20mL加えた後、ジエチルエーテルを加えて抽出した。有機相を水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、減圧濃縮し、シリカゲルカラムクロマトグラフィー(溶出液 ヘキサン/酢酸エチル＝５/1)で精製し、黄色油状の目的化合物(4.05g、収率86.2%)を得た。
【００６４】
¹H-NMR(400MHz, CDCl₃)δ:1.28-1.42 (6H, m), 1.66-1.87 (4H, m), 3.39 (2H, t, J= 7Hz), 4.65 (1H, m), 7.27(2H, d, J= 9Hz) , 7.32 (2H, d, J= 9Hz).
【００６５】
製造例３ 2-[7-(4-クロロフェニル)-7-ヒドロキシヘプチルチオ]安息香酸メチルの合成
チオサリチル酸メチル(660mg、3.92mmol)をアセトニトリル30mLに溶解し、炭酸カリウム(542mg、3.92mmol)、7-ブロモ-1-(4-クロロフェニル)ヘプチルアルコール(1.0g、3.27mmol)、ヨウ化カリウム(54mg、3.92mmol)を加え80℃にて2時間攪拌した。反応終了後、酢酸エチルを加え、水、飽和食塩水の順で洗浄し、硫酸ナトリウムで乾燥した。反応液を濾過し、減圧濃縮後、シリカゲルカラムクロマトグラフィー(溶出液 ヘキサン/ 酢酸エチル=5/1)で分離し、淡黄色油状の目的化合物（999mg、収率77.7%）を得た。
【００６６】
¹H-NMR(400MHz, CDCl₃)δ:1.27-1.49 (6H, m), 1.64-1.74 (4H, m), 1.95 (1H, bs), 2.89 (2H, t, J= 7Hz), 3.90 (3H, s), 4.64 (1H, t, J=6 Hz), 7.14 (1H, t, J= 7Hz), 7.25-7.31 (5H, m), 7.42 (1H, t, J= 9Hz), 7.94 (1H, dd, J= 8, 2Hz).
【００６７】
製造例４ 2-[7-(4-クロロフェニル)-6-ヘプテニルチオ]安息香酸メチルの合成 2-[7-(4-クロロフェニル)-7-ヒドロキシヘプチルチオ]安息香酸メチル(863mg、2.196 mmol)をトルエン30mLに溶解し、次にp-トルエンスルホン酸一水和物(46mg、0.242 mmol)を加え120℃にて1時間攪拌した。反応液を室温に戻し酢酸エチルを加え、飽和重曹水、水、飽和食塩水の順に洗浄し、硫酸ナトリウムで乾燥した。反応液を濾過し、減圧濃縮後、シリカゲルカラムクロマトグラフィー(溶出液 ヘキサン/酢酸エチル=10/1)で分離し、淡黄色油状の目的化合物（633mg、収率76.9%）を得た。
【００６８】
¹H-NMR(270MHz, CDCl₃)δ:1.52-1.58(4H, m), 1.75-1.77(2H, m), 2.20-2.22(2H, m), 2.93(2H, t, J= 7Hz), 3.91(3H, s), 6.18(1H, dt, J= 16, 7Hz), 6.32(1H, d, J= 16Hz), 7.14(1H, t, J= 8Hz), 7.25(4H, s), 6.32(1H, d, J= 8Hz), 7.43(1H, t, J= 7Hz), 7.95(1H, dd, J= 8, 1Hz).
【００６９】
製造例５ 1-ブロモ-7-(4-クロロフェニル)ヘプタンの合成
1,7-ジブロモヘプタン107.2 g (415.6 mmol) の無水テトラヒドロフラン 200 ｍL 溶液に塩化銅 198 mg ( 2.0 mmol )、塩化リチウム 170 mg (4.0 mmol) を加え、アルゴン置換した。この懸濁液にアルゴン雰囲気、水冷下、4-クロロフェニルマグネシウムブロミドの1.0 mol/L ジエチルエーテル溶液 300 mL (300 mmol)を30分かけて滴下し、滴下終了後室温で16時間攪拌した。反応液に水冷下、2 mol /L 塩酸 250ｍL、次いでクロロホルム 300 mLを加えた。得られた懸濁液より不溶物をセライトを用いてろ去した後、ろ液から有機層を抽出した。更にクロロホルム( 100 mL ×2)で抽出した有機層を合わせ、水洗（100 ｍL）、飽和食塩水洗（100mL）し硫酸ナトリウムにより除水した後、減圧濃縮した。得られた残留物を減圧蒸留し、126〜136℃/3mm Hgの留分を集め、無色油状の粗目的化合物(24.19 g、収率20.1%)を得た。
【００７０】
^１H-NMR (270MHz, CDCl₃) δ: 1.15-1.70 (8H, m), 1.84 (2H, q, J= 7Hz), 2.57 (2H, t, J= 8Hz ), 3.40 ( 2H, t, J= 7Hz), 7.09 ( 2H, d, J= 8Hz ), 7.23 ( 2H, d, J= 8Hz ).
【００７１】
製造例６ 2-[7-(4-クロロフェニル)ヘプチルチオ]安息香酸メチルの合成
1-ブロモ-7-(4-クロロフェニル)ヘプタン38.49 g (132.9 mmol) のアセトニトリル 200 ｍL溶液に、炭酸カリウム 36.73 g (265.8 mmol)、ヨウ化カリウム 11.03 g (66.45 mmol)を加えた。この混合物にチオサリチル酸メチル33.5 g (純度97％, 199.4 mmol)のアセトニトリル20 mL 溶液を10分かけて滴下し、滴下終了後、室温で30分、ついで浴温60℃で4時間攪拌した。TLCで原料の消失を確認後、減圧濃縮し、残留物に水500 mL、クロロホルム500 mL、2 mol/L塩酸 300 mLを加え、有機層を抽出した。この有機層を水洗（200 ｍL）、飽和食塩水洗（200 ｍL）後、硫酸ナトリウムで除水し、減圧にて留去した残留物をシリカゲルカラムクロマトグラフィー（SiO₂1000 g、溶出液 ヘキサン/酢酸エチル = 30/1）を用いて精製した。目的化合物を含むフラクションを減圧濃縮し、白色油状の目的化合物(31.28 g、収率83.0%)を得た。
【００７２】
^１H-NMR (400MHz, CDCl₃) δ: 1.22-1.62 (8H, m), 1.72 (2H, q, J= 7Hz), 2.56 (2H, t, J= 7Hz), 2.91 (2H, t, J= 7Hz), 3.91 (3H, s), 7.09 (2H, d, J= 8Hz), 7.14 (1H, t, J= 8Hz), 7.23 (2H, d, J= 8Hz), 7.26-7.33 (1H, m), 7.43 (1H, td, J= 8, 2Hz), 7.95 ( 1H, dd, J= 8, 2Hz ).
【００７３】
製造例７ 2-[7-(4-クロロフェニル)ヘプチルスルフィニル]安息香酸メチルの合成
2-[7-(4-クロロフェニル)ヘプチルチオ]安息香酸メチル(320 mg、0.849 mmol)をクロロホルム 10 mL に溶解し、m-クロロ過安息香酸（183 mg、純度80％として0.849 mmol）を加え氷冷下90分間攪拌した。反応液に5％チオ硫酸ナトリウム水溶液5mLを加え有機層を抽出した。この有機層を、水5mL、飽和食塩水5mLで洗浄後、硫酸ナトリウムで乾燥した。この溶液を減圧濃縮し、残留物をフラッシュカラムクロマトグラフィー（溶出液 ヘキサン/酢酸エチル = 1/1）を用いて精製した。目的化合物を含むフラクションを減圧濃縮し、無色油状の目的化合物(231 mg、収率 69.2 %)を得た。
【００７４】
^１H-NMR (270MHz, CDCl₃) δ: 1.21-1.81 (9H, m), 1.96 (1H, m), 2.55 (2H, t, J= 8Hz), 2.66 (1H, m), 3.14 (1H, ddd, J= 13, 10, 7Hz), 3.94 (3H, s), 7.08 (2H, d, J= 8Hz), 7.23 (2H, d, J= 8Hz), 7.56 (1H, t, J= 8Hz), 7.81 (1H, t, J= 8Hz), 8.09 (1H, d, J= 8Hz), 8.25 (1H, d, J= 8Hz).
【００７５】
製造例８ 2-[7-(4-クロロフェニル)ヘプチルスルフォニル]安息香酸メチルの合成
2-[7-(4-クロロフェニル)ヘプチルチオ]安息香酸メチル(320 mg、0.849 mmol)をクロロホルム 10 mL に溶解し、m-クロロ過安息香酸（366 mg、純度80％として1.70 mmol）を加え室温で90分間攪拌した。反応液に5％チオ硫酸ナトリウム水溶液5mLを加え有機層を抽出した。この有機層を、水5mL、飽和食塩水5mLで洗浄後、硫酸ナトリウムで乾燥した。この溶液を減圧濃縮し、残留物をフラッシュカラムクロマトグラフィー（溶出液 ヘキサン/酢酸エチル = 1/1）を用いて精製した。目的化合物を含むフラクションを減圧濃縮し、無色油状の目的化合物(204 mg、収率 58.8 %)を得た。
【００７６】
^１H-NMR (270MHz, CDCl₃) δ: 1.17-1.46 (6H, m), 1.46-1.66 (2H, m), 1.69-1.88 (2H, m), 2.54 (2H, t, J= 8Hz), 3.47 (2H, t, J= 8Hz), 3.96 (3H, s), 7.07 (2H, d, J= 7Hz), 7.22 (2H, d, J= 7Hz), 7.60-7.72 (3H, m), 8.06 (1H, d, J= 6Hz).
【００７７】
製造例９ 2-[7-(4-クロロフェニル)-7-ヒドロキシヘプチルスルフィニル]安息香酸メチルの合成
製造例７と同様にして、2-[7-(4-クロロフェニル)-7-ヒドロキシヘプチルチオ]安息香酸メチル(100 mg、0.254 mmol)から無色油状の目的化合物(69 mg、収率 66 %)を得た。
【００７８】
^１H-NMR (400MHz, CDCl₃) δ: 1.22-1.82 (9H, m), 1.96 (1H, m), 2.64 (1H, m), 3.12(1H, ddd, J= 13, 10, 7Hz), 3.94(3H, s), 4.64(1H, t, J= 7Hz), 7.26 (2H, d, J= 9Hz), 7.31 (2H, d, J= 9Hz), 7.55 (1H, t, J= 8Hz), 7.80 (1H, t, J= 9Hz), 8.08 (1H, d, J= 8Hz), 8.24 (1H, d, J= 8Hz).
【００７９】
製造例１０ 2-[7-(4-クロロフェニル)-6-ヘプテニルスルフィニル]安息香酸メチルの合成
製造例７と同様にして、2-[7-(4-クロロフェニル)-6-ヘプテニルチオ]安息香酸メチル（3.08 g、8.22 mmol ） から無色油状の目的化合物(2.73 g、収率85.0%)を得た。
【００８０】
^１H-NMR (270MHz, CDCl₃) δ: 1.39-1.62 (4H, m), 1.62-1.86 (1H, m), 1.86-2.12 (1H, m), 2.15-2.32 (2H, m), 2.69 (1H, ddd, J= 13, 10, 7Hz), 3.17 (1H, ddd, J= 13, 10, 5Hz), 3.95 (3H, s), 6.17 (1H, dt, J= 16, 7Hz), 6.33 (1H, d, J= 16Hz), 7.21-7.31 (4H, m), 7.59 (1H, m), 7.81 (1H, td, J= 8, 1Hz), 8.09 (1H, dd, J= 8, 1 Hz), 8.26 (1H, dd, J= 8, 1Hz).
【００８１】
製造例１１ 2-[7-(4-クロロフェニル)-7-ヒドロキシヘプチルスルフォニル]安息香酸メチルの合成
製造例８と同様にして、2-[7-(4-クロロフェニル)-7-ヒドロキシヘプチルチオ]安息香酸メチル(89 mg, 0.226 mmol)から白色固体の目的化合物(53.4 mg、収率 56 %)を得た。
【００８２】
¹H-NMR(400MHz, CDCl₃)δ:1.19-1.47(6H, m), 1.57-1.83(4H, m), 3.46(2H, m), 3.96(3H, s), 4.63(1H, dd, J= 7, 6Hz), 7.26(2H, d, J= 8Hz), 7.31(2H, d, J= 8Hz), 7.63-7.71(3H, m), 8.05(1H, d, J= 7Hz).
【００８３】
製造例１２ 2-[7-(4-クロロフェニル)-6-ヘプテニルスルフォニル]安息香酸メチルの合成
製造例４と同様にして、2-[7-(4-クロロフェニル)-7-ヒドロキシヘプチルスルフォニル]安息香酸メチル (30.5 mg、0.075 mmol)から淡黄色油状の目的化合物(25.1 mg、収率86%)を得た。
【００８４】
¹H-NMR(270MHz, CDCl₃)δ:1.40-1.57(4H, m), 1.74-1.92(2H, m), 2.14-2.29(2H, m), 3.51(2H, m), 3.97(3H, s), 6.14(1H, dt, J= 16, 7Hz), 6.32(1H, d, J= 16Hz), 7.20-7.31(4H, m), 7.60-7.73(3H, m), 8.07(1H, d, J= 6Hz).
【００８５】
製造例１３ 2-[7-(4-クロロフェニル)-7-オキソヘプチルチオ]安息香酸メチルの合成
2-[7-(4-クロロフェニル)-7-ヒドロキシヘプチルチオ]安息香酸メチル(99.6mg、0.254mmol)を塩化メチレン2mL溶解し、クロロクロム酸ピリジニウム(60.9 mg、純度90％として0.254mmol)を加え室温にて1時間攪拌した。反応液にジエチルエーテル10mLを加えた溶液部分をシリカゲルカラムにて溶出した（溶出液 ジエチルエーテル）。溶出液を減圧濃縮した残留物をフラッシュカラムクロマトグラフィー（溶出液 ヘキサン/酢酸エチル = 10/1）を用いて精製した。目的化合物を含むフラクションを減圧濃縮し、無色油状の目的化合物(65.0 mg、収率 66 %)を得た。
【００８６】
^１H-NMR (270MHz, CDCl₃) δ: 1.35-1.49 (2H, m), 1.49-1.60 (2H, m), 1.66-1.84 (4H, m), 2.88-2.99 (4H, m), 3.91 (3H, s), 7.14 (1H, t, J= 8Hz), 7.30 (1H, d, J= 8 Hz), 7.38-7.49 (3H, m), 7.89 (2H, d, J= 8Hz), 7.96 (1H, d, J= 8Hz).
【００８７】
製造例１４ 2-[7-(4-クロロフェニル)-7-オキソヘプチルスルフィニル]安息香酸メチルの合成
製造例７と同様にして、2-[7-(4-クロロフェニル)-7-オキソヘプチルチオ]安息香酸メチル(200 mg、0.513 mmol)から白色固体の目的化合物(156 mg、収率 74.7 %)を得た。
【００８８】
^１H-NMR (270MHz, CDCl₃) δ: 1.32-1.85 (7H, m), 1.98 (1H, m), 2.69 (1H, ddd, J= 13, 10, 5Hz), 2.93 (2H, t, J= 7Hz), 3.16 (1H, ddd, J= 13, 10, 7Hz), 3.95 (3H, s), 7.43 (2H, d, J= 8Hz), 7.56 (1H, t, J= 8Hz), 7.81 (1H, t, J= 8Hz), 7.88 (2H, d, J= 8Hz), 8.09 (1H, d, J= 8Hz), 8.27 (1H, d, J= 8Hz).
【００８９】
製造例１５ 2-[7-(4-クロロフェニル)-7-オキソヘプチルスルフォニル]安息香酸メチルの合成
製造例８と同様にして、2-[7-(4-クロロフェニル)-7-オキソヘプチルチオ]安息香酸メチル(200 mg、0.513 mmol)から白色固体の目的化合物(128 mg、収率 59.0 %)を得た。
【００９０】
^１H-NMR (270MHz, CDCl₃) δ: 1.25-1.58 (4H, m), 1.60-1.90 (4H, m), 2.92 (2H, t, J= 7Hz), 3.50 (2H, t, J= 8Hz), 3.97 (3H, s), 7.43 (2H, d, J= 8Hz), 7.61-7.72 (3H, m), 7.88 (2H, d, J= 8Hz), 8.06 (1H, d, J= 6Hz).
【００９１】
実施例１ 2-[7-(4-クロロフェニル)-6-ヘプテニルチオ]安息香酸の合成
2-[7-(4-クロロフェニル)-6-ヘプテニルチオ]安息香酸メチル(1.80g、4.80mmol)をメタノール10mL-テトラヒドロフラン10mLに溶解し、4 mol/L水酸化ナトリウム水溶液3mLを加え室温にて攪拌した。反応終了後、水250ｍＬを加え、0℃にて濃塩酸を加え弱酸性とした。酢酸エチルで抽出し、有機層を水、飽和食塩水の順に洗浄し、硫酸マグネシウムで乾燥した。反応液を濾過し、減圧濃縮後、シリカゲルカラムクロマトグラフィー(溶出液 ヘキサン/酢酸エチル=1/1)で分離し、無色結晶の目的化合物(1.50g、収率86.7％)を得た。
【００９２】
¹H-NMR(400MHz, CDCl₃)δ:1.53-1.54(4H, m), 1.74-1.79(2H, m), 2.20-2.25(2H, m), 2.94(2H, t, J= 7Hz), 6.18(1H, dt, J= 16, 6Hz), 6.33(1H, dd, J= 16, 1Hz), 7.20(1H, t, 8Hz), 7.25(2H, d, J= 1Hz), 7.26(2H, d, J= 1Hz), 7.35(1H, d, J= 8Hz), 7.48(1H, t, J= 8Hz), 8.13(1H, dd, J= 8, 1Hz).
【００９３】
実施例２ 2-[7-(4-クロロフェニル)-6-ヘプテニルチオ]安息香酸ナトリウム塩の合成
2-[7-(4-クロロフェニル)-6-ヘプテニルチオ]安息香酸(1.25g、3.450mmol)をメタノール20 mLに溶解し、ナトリウムメトキシド(205mg、3.795mmol)のメタノール20mL溶液を加えた。全てを溶解し均一にした後、減圧濃縮し、エタノールより再結晶し、無色結晶の目的化合物（1.24g、収率93.9%）を得た。
【００９４】
¹H-NMR(400MHz, CDCl₃+CD₃OD)δ:1.50-1.52 (4H, m), 1.71-1.75 (2H, m), 2.20 (2H, m), 2.91 (2H, t, J= 8Hz), 6.18 (1H, dt, J= 16, 7Hz), 6.34 (1H, d, J= 16Hz), 7.13 (1H, dt, J= 8, 1Hz), 7.25 (4H, s), 7.27 (1H, d, J= 8Hz), 7.35 (1H, dt, J= 8, 1Hz), 8.13 (1H, dd, J= 8, 2Hz).
【００９５】
実施例３ 2-[7-(4-クロロフェニル)ヘプチルチオ]安息香酸の合成
実施例１と同様にして、2-[7-(4-クロロフェニル)ヘプチルチオ]安息香酸メチル（31.28 g、83.0 mmol ）から白色結晶性粉末の目的化合物(19.41 g、収率 64.5 %)を得た。
【００９６】
^１H-NMR (270MHz, CDCl₃) δ: 1.20-1.85 (10H, m), 2.57 (2H, t, J= 8Hz), 2.92 (2H, t, J= 8Hz), 7.09 (2H, d, J= 8Hz), 7.20 (1H, t, J= 8Hz), 7.23 (2H, d, J= 8Hz), 7.34 (1H, d, J= 8Hz), 7.49 (1H, td, J= 8, 1Hz), 8.13 ( 1H, dd, J= 8, 1Hz ).
IR( KBr ): 2925, 1674, 1561, 1492, 1464, 1409, 1317, 1253, 1047, 915, 756 cm^-1
mp 109.1-109.5℃
【００９７】
実施例４ 2-[7-(4-クロロフェニル)ヘプチルチオ]安息香酸ナトリウム塩の合成実施例２と同様にして、2-[7-(4-クロロフェニル)ヘプチルチオ]安息香酸（7.23 g、19.9 mmol ）から白色結晶性粉末の目的化合物(4.25 g、収率 55.4 %)を得た。
【００９８】
^１H-NMR (270MHz, CD₃OD) δ: 7.59 ( 1H, d, J= 8Hz ), 7.33-7.03 ( 7H, m ), 2.84 (2H, t, J= 7Hz), 2.56 (2H, t, J= 8Hz), 1.71-1.23 (10H, m).
【００９９】
実施例５ 2-[7-(4-クロロフェニル)-7-ヒドロキシヘプチルチオ]安息香酸の合成
実施例１と同様にして、2-[7-(4-クロロフェニル)-7-ヒドロキシヘプチルチオ]安息香酸メチル(134mg、0.341mmol)から淡黄色油状の目的化合物(108 mg, 収率83.6%)を得た。
【０１００】
^１H-NMR (270MHz, CDCl₃) δ: 1.12-1.90 (10H, m), 2.91 (2H, t, J= 7Hz), 4.66 (1H, t, J= 7Hz), 7.10-7.39 (6H, m), 7.48 (1H, t, J= 7Hz), 8.11 (1H, d, J= 7Hz).
【０１０１】
実施例６ 2-[7-(4-クロロフェニル)ヘプチルスルフィニル]安息香酸の合成
実施例１と同様にして、2-[7-(4-クロロフェニル)ヘプチルスルフィニル]安息香酸メチル(69 mg、0.18 mmol)から無色油状の目的化合物(68 mg、収率 定量的)を得た。
【０１０２】
^１H-NMR (400MHz, CDCl₃) δ: 1.05-1.63 (8H, m), 1.68(1H, m), 1.93(1H, m), 2.53 (2H, t, J= 8Hz), 2.75(1H, m), 3.17(1H, ddd, J= 13, 10, 7Hz), 7.06 (2H, d, J= 8Hz), 7.20 (2H, d, J= 8Hz), 7.58 (1H, t, J= 8Hz), 7.83 (1H, t, J= 8Hz), 8.16 (1H, d, J= 8Hz), 8.27 (1H, d, J= 8Hz).
【０１０３】
実施例７ 2-[7-(4-クロロフェニル)ヘプチルスルフォニル]安息香酸の合成
実施例１と同様にして、2-[7-(4-クロロフェニル)ヘプチルスルフォニル]安息香酸メチル(107 mg、0.262 mmol)から無色油状の目的化合物(103 mg、収率 定量的)を得た。
【０１０４】
^１H-NMR (400MHz, CDCl₃) δ: 0.93-1.89 (10H, m), 2.52 (2H, t, J= 8Hz), 3.56 (2H, t, J= 8Hz), 7.05 (2H, d, J= 8Hz), 7.20 (2H, d, J= 8Hz), 7.46-7.77 (2H, m), 7.84 (1H, m), 8.11 (1H, m).
【０１０５】
実施例８ 2-[7-(4-クロロフェニル)-7-ヒドロキシヘプチルスルフィニル]安息香酸の合成
実施例１と同様にして、2-[7-(4-クロロフェニル)-7-ヒドロキシヘプチルスルフィニル]安息香酸メチル(10.0 mg、0.024 mmol)から無色油状の目的化合物(10.0 mg、収率 定量的)を得た。
【０１０６】
^１H-NMR (400MHz, CDCl₃) δ: 1.22-1.82 (9H, m), 1.97 (1H, m), 2.70 (1H, m), 3.19(1H, m), 4.65(1H, t, J= 7Hz), 7.21 (2H, d, J= 9Hz), 7.25 (2H, d, J= 9Hz), 7.56 (1H, t, J= 8Hz), 7.78 (1H, t, J= 8Hz), 8.13 (1H, d, J= 8Hz), 8.21 (1H, d, J= 8Hz).
【０１０７】
実施例９ 2-[7-(4-クロロフェニル)-6-ヘプテニルスルフィニル]安息香酸の合成
実施例１と同様にして、2-[7-(4-クロロフェニル)-6-ヘプテニルスルフィニル]安息香酸メチル（2.71 g、6.93 mmol ）から白色結晶性粉末の目的化合物(2.55 g、収率97.6%)を得た。
【０１０８】
^１H-NMR (270MHz, CDCl₃) δ: 1.30-1.60 (4H, m), 1.60-1.86 (1H, m), 1.86-2.10 (1H, m), 2.10-2.30 (2H, m), 2.77 (1H, m), 3.20 (1H, m), 6.13 (1H, dt, J= 16, 7Hz), 6.16 (1H, d, J= 16Hz), 7.10-7.35 (4H, m), 7.56 (1H, t, J= 8Hz), 7.81 (1H, t, J= 8Hz), 8.15 (1H, d, J= 8Hz), 8.26 (1H, d, J= 8Hz).
【０１０９】
実施例１０ 2-[7-(4-クロロフェニル)-7-ヒドロキシヘプチルスルフォニル]安息香酸の合成
実施例１と同様にして、2-[7-(4-クロロフェニル)-7-ヒドロキシヘプチルスルフォニル]安息香酸メチル(10 mg、0.0236 mmol)から無色油状の目的化合物(7.4 mg、収率 77 %)を得た。
【０１１０】
¹H-NMR(400MHz, CDCl₃)δ:1.19-1.58(6H, m), 1.58-1.95(4H, m), 3.51(2H, m), 4.67(1H, dd, J= 8, 5Hz), 7.26-7.49(4H, m), 7.63-7.76(2H, m), 7.97(1H, d, J= 8Hz), 8.08(1H, dd, J= 8, 1Hz).
【０１１１】
実施例１１ 2-[7-(4-クロロフェニル)-6-ヘプテニルスルフォニル]安息香酸の合成
実施例１と同様にして、2-[7-(4-クロロフェニル)-6-ヘプテニルスルフォニル]安息香酸メチル(25.1 mg、0.0617 mmol)から無色油状の目的化合物(32 mg、収率 定量的)を得た。
【０１１２】
¹H-NMR(400MHz, CDCl₃)δ:1.39-1.52(4H, m), 1.72-1.96(2H, m), 2.10-2.32(2H, m), 3.57(2H, t, J= 8Hz), 6.13(1H, dt, J= 16, 7Hz), 6.29(1H, d, J= 16Hz), 7.13-7.37(4H, m), 7.61-7.75(2H, m), 7.83(1H, d, J= 7Hz), 8.10(1H, d, J= 7Hz).
【０１１３】
実施例１２ 2-[7-(4-クロロフェニル)-7-オキソヘプチルチオ]安息香酸の合成 実施例１と同様にして、2-[7-(4-クロロフェニル)-7-オキソヘプチルチオ]安息香酸メチル(136mg、0.348mmol)から白色固体の目的化合物(128 mg、収率97.6%)を得た。
【０１１４】
^１H-NMR (270MHz, CDCl₃) δ: 1.32-1.86 (8H, m), 2.85-3.14 (4H, m), 7.22 (1H, m), 7.32-7.54 (2H, m), 7.43 (2H, d, J= 9Hz), 7.89 (2H, d, J= 9Hz), 8.13 (1H, d, J= 8Hz).
【０１１５】
実施例１３ 2-[7-(4-クロロフェニル)-7-オキソヘプチルスルフィニル]安息香酸の合成
実施例１と同様にして、2-[7-(4-クロロフェニル)-7-オキソヘプチルスルフィニル]安息香酸メチル(156mg、0.383mmol)から白色固体の目的化合物(154 mg、収率 定量的)を得た。
【０１１６】
^１H-NMR (270MHz, CDCl₃) δ: 1.30-1.84 (7H, m), 2.02 (1H, m), 2.74 (1H, m), 2.94 (2H, t, J= 7Hz), 3.21 (1H, m), 7.41 (2H, d, J= 9Hz), 7.58 (1H, t, J= 8Hz), 7.81 (1H, t, J= 8Hz), 7.87 (2H, d, J= 9Hz), 8.17 (1H, d, J= 8Hz), 8.26 (1H, d, J= 8Hz).
【０１１７】
実施例１４ 2-[7-(4-クロロフェニル)-7-オキソヘプチルスルフォニル]安息香酸の合成
実施例１と同様にして、2-[7-(4-クロロフェニル)-7-オキソヘプチルスルフォニル]安息香酸メチル(128 mg、0.303 mmol)から淡黄色固体の目的化合物(113 mg、収率 91.2 %)を得た。
【０１１８】
^１H-NMR (270MHz, CDCl₃) δ: 1.21-1.59 (4H, m), 1.62-1.93 (4H, m), 2.93 (2H, t, J= 7Hz), 3.56 (2H, t, J= 8Hz), 7.42 (2H, d, J= 9Hz), 7.65-7.76 (2H, m), 7.81-7.92 (3H, m), 8.10 (1H, d, J= 7Hz).
【０１１９】
実施例１５
本発明の一般式（1）で表される安息香酸誘導体及び比較化合物として 特許文献２の実施例６（３）と実施例１０（１）に記載されている化合物（以下、それぞれ化合物A、化合物Bと記載する）のPPAR受容体活性化作用を、以下の方法で測定した(Proc.Natl.Acad.Sci., 92, pp7297-7301, 1995, Journal of Biological Chemistry, 269, pp31012-31018, 1994, Proc.Natl.Acad.Sci, 98, pp5306-5311, 2001)。
【０１２０】
【化１０】

【０１２１】
トランスフェクションアッセイ測定
すべてのトランスフェクションアッセイはアフリカミドリザルの腎由来細胞株であるCOS細胞を用いて行った。COS細胞の培養は5％のCO₂濃度で行い、培養液には10％のウシ胎児血清、グルタミン酸及び抗生物質を含有するDMEM培地を用いた。
細胞へのプラスミドのトランスフェクションはリポフェクトアミンを用いた方法で行った。野生型ヒト型PPARの発現ベクターとしてpSG5hPPARα, pSG5hPPARg,及びpcDNA3hPPARδを用いた。レポーターベクターはホタルルシフェラーゼを用い、そのプロモーター領域に6個のヒトapoAIIプロモーター上のPPAR応答配列を含んでいる。更にβ-ガラクトシダーゼの発現ベクターを内部標準として用いた。
細胞へのトランスフェクションの後，化合物を添加したDMEM培地(0.2％血清含有)に交換し、更に16時間の培養を行った。その後、細胞溶解液中のルシフェラーゼ活性及びβ-ガラクトシダーゼ活性を測定した。
なお、化合物の溶解、希釈にはジメチルスルホキシドを用い、細胞への処理の際はＤＭＥＭ培地（0.2％血清含有）にジメチルスルホキシド濃度が0.1％になるように調整した。陽性化合物としてPPARαにはWY14643を、PPARγにはトログリタゾンを( Journal of Medicinal Chemistry, 43, pp527-550, 2000 )、PPARδにはGW501516（ Proc.Natl.Acad.Sci, 98, pp5306-5311, 2001 ）を用いた。
【０１２２】
これらの化合物のhPPARα、hPPARγ、hPPARδアゴニスト活性測定結果を、表１に示す。
【０１２３】
【表１】

【０１２４】
化合物AはhPPARδだけに活性化作用を示し、化合物BはhPPARαとγのEC₅₀値に３倍の選択性を示すにすぎない。一方、本発明の安息香酸誘導体は優れたhPPARα活性化作用と選択性を示し、明らかに化合物A及び化合物Bよりも優れたhPPARα選択性を有する。
【０１２５】
図１に実施例１及び実施例３の安息香酸誘導体のhPPARαを活性化するEC₅₀値の濃度と、その１０及び１００倍の濃度における各アイソフォームの活性化倍率を示す。ここで、No.１はPPARα活性化EC₅₀値の濃度における活性化率を示し、No.２はPPARα活性化EC₅₀値の10倍濃度における活性化率を示し、No.３はPPARα活性化EC₅₀値の100倍濃度における活性化率を示す。
なお、活性化倍率は、化合物を含まない溶媒(ジメチルスルホオキシド)のみを処理した時の活性値をコントロールとし、コントロールに対する倍率で示した。実施例１及び実施例３の化合物はhPPARαを活性化するEC₅₀値の濃度の１０、及び１００倍の濃度においても、hPPARγ及びδを活性化しないことがわかる。
【０１２６】
本発明の一般式（１）で表される安息香酸誘導体又はその塩は、従来公知の化合物よりも明らかに優れたhPPARα選択的活性化作用を有する。
【０１２７】
【発明の効果】
本発明化合物は、PPARのうちαタイプを選択的に活性化する作用を有し、体重増加や肥満を伴なわない、高脂血症、動脈硬化症、糖尿病、糖尿病合併症、炎症、心疾患等の予防及び/又は治療薬として有用である。
【図面の簡単な説明】
【図１】 2-[7-(4-クロロフェニル)-6-ヘプテニルチオ]安息香酸のPPARα活性化EC₅₀値の濃度とその１０倍、１００倍の濃度におけるPPAR活性化率を示す図である。
【図２】 2-[7-(4-クロロフェニル)ヘプチルチオ]安息香酸のPPARα活性化EC₅₀値の濃度とその１０倍、１００倍の濃度におけるPPAR活性化率を示す図である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a benzoic acid derivative that selectively activates a peroxisome proliferator-activated receptor α and a medicine containing the same.
[0002]
[Prior art]
Peroxisome Proliferator Activated Receptor (hereinafter referred to as PPAR) is one of the nuclear receptor families, and three subtypes (α, γ, δ) have been known to date. (Refer nonpatent literature 1-5.).
[0003]
Among these, PPARα is mainly expressed in the liver and is activated by a plasticizer and a fibrate drug such as Wy14643, clofibrate, fenofibrate, bezafibrate, gemfibrozil (see Non-Patent Documents 6 to 7). ).
PPARα activation increases fatty acid β-oxidation and lowers blood triglycerides in mammals. In humans, blood lipids such as low density lipoprotein (LDL) cholesterol and very low density lipoprotein (VLDL) cholesterol are decreased, and PPARα activator is useful as a preventive and / or therapeutic agent for hyperlipidemia and the like. . In addition, PPARα activator is effective as a preventive and / or therapeutic agent for arteriosclerosis and the like because it suppresses the increase of high density lipoprotein (HDL) cholesterol and the expression of cell adhesion factor VCAM-1 in blood vessels. is there. Furthermore, the PPARα activator is useful for the prevention and / or treatment of diabetes, inflammatory diseases, and heart diseases (see Non-Patent Documents 8 to 14).
[0004]
On the other hand, PPARγ is mainly expressed in adipocytes and plays an important role in the differentiation and proliferation of adipocytes. As activators of PPARγ, drugs such as thiazolidine derivatives such as troglitazone, pioglitazone, rosiglitazone are known. These drugs induce hypertrophic adipocytes with reduced insulin sensitivity into small adipocytes with high insulin sensitivity to improve insulin resistance (see Non-Patent Documents 15 to 18). However, it has an unfavorable effect of increasing fat, causing weight gain and obesity in humans (see Non-Patent Document 19), and recently there has been a report showing the possibility of improving insulin resistance even by an antagonist of PPARγ. (See Non-Patent Documents 20 to 22).
[0005]
PPARδ is universally present in the body and has been reported to be involved in lipid metabolism. However, there have been few reports on highly selective PPARδ activators, and the biological significance of PPARδ has been unclear. At present, the structure of the PPARδ activator has been reported in many bibliographies (see Non-Patent Documents 23 to 24), and the PPARδ activator GW501516 has been reported to increase HDL in monkeys (non-patent documents). (See Patent Document 25). However, on the other hand, Compound F (Patent Document 1), which is a PPARδ activator, accumulates lipids in human macrophages (see Non-Patent Document 26), and further, PPARδ activation is demonstrated by experiments using PPARδ-deficient mice. Has been suggested to lead to lipid accumulation (see Non-Patent Document 27). These phenomena are contradictory effects in the progression of atherosclerosis and treatment, and therefore the therapeutic significance of PPARδ has not been elucidated.
[0006]
Therefore, PPARα selective activator with low PPARγ and δ activity prevents hyperlipidemia, arteriosclerosis, diabetes, diabetic complications, inflammation, heart disease, etc. without weight gain and obesity. And / or expected to be useful in therapy.
[0007]
On the other hand, the following general formula
[0008]
[Chemical formula 2]

[0009]
[R¹Represents an alkyl group having 1 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, a halogen atom, a nitro group or a trifluoromethyl group, and R²Is -COOR^Three(R, R^ThreeRepresents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) or 1H-tetrazol-5-yl group, J represents a single bond, an alkylene group having 1 to 8 carbon atoms (one of the aforementioned alkylene groups having 1 to 8 carbon atoms) The carbon atom of -S- group, -SO- group, -SO₂-Group, -O- group or R^Four-Group (in the group, R^FourMay be replaced by a group selected from a hydrogen atom or a C 1-4 alkyl group), a C 2-8 alkenylene (one carbon atom of the C 2-8 alkenylene group is- S-group, -SO- group, -SO₂-Group, -O- group or R^Five-Group (in the group, R^FiveRepresents a hydrogen atom or a group selected from an alkyl group having 1 to 4 carbon atoms)), a = C-group, = C- (C1-C8 alkylene) -group (the above carbon One carbon atom of the number 1 to 8 alkylene group is -S- group, -SO- group, -SO₂-Group, -O- group or R⁶-Group (in the group, R⁶May be replaced by a group selected from a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) or = C- (2-8 alkenylene) -group (the above-mentioned 2-8 alkenylene group) One carbon atom is -S- group, -SO- group, -SO₂-Group, -O- group or R⁷-Group (in the group, R⁷Represents a hydrogen atom or a group selected from a group having 1 to 4 carbon atoms), G represents a carbocyclic group or a heterocyclic group (the carbocyclic group in the G group) And the heterocyclic group may be substituted with 1 to 4 groups selected from the following (i) to (v): (i) an alkyl group having 1 to 8 carbon atoms, (ii) 1 to 8 carbon atoms. Alkoxy group, (iii) halogen atom, (iv) trifluoromethyl group, (v) nitro group), E¹Represents 1) a single bond, 2) an alkylene group having 1 to 8 carbon atoms, 3) an alkenylene group having 2 to 8 carbon atoms, or 4) an alkynylene group having 2 to 8 carbon atoms, and E²Is 1) -O- group, 2) -S- group, or 3) -NR⁸-Group (in the group, R⁸Represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), E^ThreeRepresents 1) a single bond, or 2) an alkylene group having 1 to 8 carbon atoms, m represents 0 or 1, and “Cycl” is 1) a ring does not exist or 2) saturated, partially saturated or unsaturated Represents a 5- to 7-membered carbocyclic ring. And a peroxisome proliferator-activated receptor regulator containing a non-toxic salt, acid addition salt or hydrate thereof as an active ingredient (see Patent Document 2) .
[0010]
In the above general formula, R²-COOR^Three, R^ThreeIs a hydrogen atom, J is a single bond, G is a carbocyclic group substituted with a halogen atom (benzene ring), E¹Is a C1-8 alkylene group or 2-8 alkenylene group, E²-S-group, E^ThreeIs a single bond, m is 0, and when the Cyc1 ring is not present, it corresponds to the benzoic acid derivative of the present invention represented by the following general formula (1). However, Patent Document 2 does not specifically describe the benzoic acid derivative of the present invention, and the benzoic acid derivative represented by the general formula (1) of the present invention or a salt thereof has a selective PPARα activation action. There is no specific description or suggestion about having the above, and no effect has been confirmed.
[0011]
[Patent Document 1]
International Publication No. 97/28149
[Patent Document 2]
International Publication No.99 / 11255
[Non-Patent Document 1]
Nature, 347, 645-650, 1990
[Non-Patent Document 2]
Cell, 68, pp879-887, 1992
[Non-Patent Document 3]
Cell, 97, pp161-163, 1999
[Non-Patent Document 4]
Biochim. Biophys. Acta., 1302, pp93-109, 1996
[Non-Patent Document 5]
Journal of Medicinal Chemistry, 43, pp527-550, 2000
[Non-Patent Document 6]
Journal of the National Cancer Institute, 90, 1702-1709, 1998
[Non-Patent Document 7]
Current Opinion in Lipidology, 10, pp245-257, 1999
[Non-Patent Document 8]
Journal of Atherosclerosis and Thrombosis, 3, pp81-89, 1996
[Non-patent document 9]
Current Pharmaceutical Design, 3, pp1-14, 1997
[Non-Patent Document 10]
Current Opinion in Lipidology, 10, pp151-159, 1999
[Non-Patent Document 11]
Current Opinion in Lipidology, 10, pp245-257, 1999
[Non-Patent Document 12]
The Lancet, 354, pp141-148, 1999
[Non-Patent Document 13]
Journal of Medicinal Chemistry, 43, pp527-550, 2000
[Non-Patent Document 14]
Journal of Cardiovascular Risk, 8, pp195-201, 2001
[Non-Patent Document 15]
Journal of Bioligical Chemistry, 270, 12953-12956, 1995
[Non-Patent Document 16]
Endocrinology, 137, pp4189-4195, 1996
[Non-Patent Document 17]
Trends Endocrinol. Metab., 10, pp9-13, 1999
[Non-Patent Document 18]
J. Clin. Invest., 101, pp1354-1361, 1998
[Non-Patent Document 19]
The Lancet, 349, pp952, 1997
[Non-Patent Document 20]
Proc. Natl. Acad. Sci., 96, pp6102-6106, 1999
[Non-patent document 21]
The Journal of Biological Chemistry, 275, pp1873-1877, 2000
[Non-Patent Document 22]
J. Clin. Invest., 108, 1001-1013, 2001
[Non-Patent Document 23]
Diabetes, 46, 1319-1327, 1997
[Non-patent Document 24]
Journal of Medicinal Chemistry, 43, pp527-550, 2000
[Non-Patent Document 25]
Proc. Natl. Acad. Sci., 98, pp5306-5311, 2001
[Non-Patent Document 26]
Journal of Biological Chemistry, 276, pp44258-44265, 2001
[Non-Patent Document 27]
Proc. Natl. Acad. Sci., 99, pp303-308, 2002
[0012]
[Problems to be solved by the invention]
Therefore, the object of the present invention is to provide PPARα selective activity that is useful as a preventive and / or therapeutic agent for hyperlipidemia, arteriosclerosis, diabetes, diabetic complications, inflammation, heart disease, etc. without weight gain or obesity. It is to provide a chemical compound.
[0013]
[Means for Solving the Problems]
Therefore, as a result of various studies to find a compound that selectively activates the α type in PPAR, the benzoic acid derivative represented by the following general formula (1) selectively activates PPARα, It was found useful as a preventive and / or therapeutic agent for hyperlipidemia, arteriosclerosis, diabetes, diabetic complications, inflammation, heart disease, etc. without weight gain or obesity, and completed the present invention.
[0014]
That is, the present invention provides the following general formula (1)
[0015]
[Chemical 3]

[0016]
(Where -A- is -CH₂-CH₂-Group, -CH = CH- group, -CH (OH) -CH₂-Group or -C (O) -CH₂-Represents a group, X is an oxygen atom, NH group or S (O)_nA benzoic acid derivative represented by a group (where n represents a number of 0, 1 or 2) or a salt thereof is provided.
The present invention also provides a pharmaceutical comprising an benzoic acid derivative represented by the above general formula (1) or a salt thereof as an active ingredient.
The present invention provides a peroxisome proliferator-activated receptor α activator comprising a benzoic acid derivative represented by the above general formula (1) or a salt thereof as an active ingredient.
The present invention relates to the prevention and / or prevention of diseases selected from hyperlipidemia, arteriosclerosis, diabetes, diabetic complications, inflammation and heart disease, which comprises the benzoic acid derivative represented by the above general formula (1) or a salt thereof as an active ingredient. Alternatively, a therapeutic agent is provided.
Furthermore, the present invention provides a pharmaceutical composition comprising a benzoic acid derivative represented by the above general formula (1) or a salt thereof, and a pharmaceutically acceptable carrier.
[0017]
DETAILED DESCRIPTION OF THE INVENTION
Among the benzoic acid derivatives represented by the general formula (1) of the present invention, -A- is -CH.₂-CH₂-Group, -CH = CH- group or -C (O) -CH₂-Group and X is S (O)_nGroup (wherein n is the same as above)).
Furthermore, the following general formula (1a)
[0018]
[Formula 4]

[0019]
(Where -A'- is -CH₂-CH₂2- [7- (4-chlorophenyl) -6-heptenylthio] benzoic acid, 2- [7- (4-chlorophenyl) heptylthio] benzoic acid represented by the formula: These salts are particularly preferable because of their excellent PPARα selective activation.
[0020]
Examples of the salt of the benzoic acid derivative represented by the general formula (1) of the present invention include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt and trialkylamine salt Organic base salts such as hydrochlorides, mineral acid salts such as sulfates, and organic acid salts such as acetates. Of these salts, alkali metal salts, particularly sodium salts are preferred.
[0021]
The benzoic acid derivative represented by the general formula (1) of the present invention may be a solvate represented by a hydrate. Furthermore, the benzoic acid derivative of the present invention may have cis and trans geometric isomers and optical isomers, and these isomers are also included in the present invention.
[0022]
The benzoic acid derivative represented by the general formula (1) of the present invention can be produced, for example, by appropriately combining the synthesis routes described below or a part thereof.
[0023]
(1) Synthesis route 1
[0024]
[Chemical formula 5]

[0025]
(In the formula, R represents an alkyl group having 1 to 6 carbon atoms, an aryl group, or an allyl group, Y represents a halogen atom, and X ′ represents a sulfur atom, an oxygen atom, or an NH group)
[0026]
7-Halo-1-heptanol (2) is oxidized to form an aldehyde (3), and a chlorophenyl group is introduced thereto with a Grignard reagent to obtain a compound (4), to which thiosalicylic acid ester, salicylic acid ester or anthranilic acid is obtained. The compound (1b) is obtained by reacting the ester to obtain the compound (5) and then hydrolyzing the compound. Hereinafter, it demonstrates for every process.
[0027]
First step: 7-halo-1-heptanol (2) is dissolved in a solvent such as chloroform and dichloromethane, and an oxidizing agent such as pyridinium chlorochromate and pyridinium dichromate is added, and then cooled or heated for 30 minutes to Stir for several hours.
Second step: After dissolving the obtained aldehyde (3) in an inert solvent such as tetrahydrofuran, dioxane, ether, dimethoxyethane, etc., an inert solvent solution of 4-chlorophenylmagnesium halide is added under an atmosphere of inert gas. The mixture is stirred for 30 minutes to several hours under cooling or at room temperature or lower.
Third step: Thiosalicylic acid ester, salicylic acid ester or anthranilic acid ester is dissolved in a solvent such as acetonitrile, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, and potassium carbonate. The halogen compound (4) obtained in the previous step is added in the presence of a base such as sodium carbonate or diisopropylethylamine, and heated at room temperature or under heating for 1 to 24 hours.
Fourth step: The obtained ester (5) is dissolved in a solvent such as methanol, ethanol, tetrahydrofuran, dioxane or 1,2-dimethoxyethane, and a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide is added. Add and stir for 1 to 24 hours under cooling or heating and add acid such as hydrochloric acid to make it acidic.
[0028]
(2) Synthesis route 2
[0029]
[Chemical 6]

[0030]
(R and X ′ in the formula are the same as above)
[0031]
A chlorophenyl group is introduced into 1,7-dihaloheptane (6) by a Grignard reagent to obtain compound (8), which is hydrolyzed to obtain compound (1c).
[0032]
First step: Dissolve 1,7-dihaloheptane (6) in an anhydrous solvent such as tetrahydrofuran, ether, 1,2-diethoxyethane, and add an inert solvent solution of 4-chlorophenylmagnesium halide in an inert gas atmosphere. In addition, the mixture is stirred for 1 to 4 hours under cooling or heating. At this time, copper chloride and lithium chloride may be added as a catalyst.
Second step: Performed in the same manner as in the third step of synthesis route 1.
Third step: Performed in the same manner as in the fourth step of synthesis route 1.
[0033]
(3) Synthesis route 3
[0034]
[Chemical 7]

[0035]
(In the formula, R and A are the same as described above, and n ′ represents an integer of 1 or 2.)
[0036]
The compound (9) obtained by the synthetic route 1 or 2 is oxidized to give the compound (10), and then hydrolyzed to obtain the compound (1f).
[0037]
First step: The starting sulfide (9) is dissolved in a solvent such as dichloromethane or chloroform, and an oxidizing agent such as m-chloroperbenzoic acid, peracetic acid or perbenzoic acid is added, and the mixture is cooled or heated. For 30 minutes to 24 hours.
Second step: Performed in the same manner as in the fourth step of synthesis route 1.
[0038]
(4) Synthesis route 4
[0039]
[Chemical 8]

[0040]
(R and X are the same as above)
[0041]
Compound (11) is subjected to a dehydration reaction to obtain compound (12), which is then hydrolyzed to obtain compound (1 g).
[0042]
First step: The raw alcohol (11) is dissolved in a solvent such as toluene or benzene, an acid such as p-toluenesulfonic acid or methanesulfonic acid is added, and the mixture is stirred at room temperature or under heating for 30 minutes to 24 hours. .
Second step: Performed in the same manner as in the fourth step of synthesis route 1.
[0043]
(5) Synthesis route 5
[0044]
[Chemical 9]

[0045]
(R and X are the same as above)
[0046]
Compound (11) is oxidized to obtain compound (13), which is then hydrolyzed to obtain compound (1h).
[0047]
First step: The raw material alcohol (11) is dissolved in a solvent such as chloroform or dichloromethane, and an oxidizing agent such as manganese dioxide, pyridinium chlorochromate, pyridinium dichromate or chromic acid is added and stirred for 1 to 24 hours.
Second step: Performed in the same manner as in the fourth step of synthesis route 1.
[0048]
You may post-process and refine | purify according to a conventional method after reaction of each process of said synthetic route. The purification method can be performed using a normal purification means such as a recrystallization method or column chromatography. If necessary, the desired salt or solvate can be obtained by a conventional method.
[0049]
Since the benzoic acid derivative represented by the general formula (1) of the present invention or the salt thereof thus obtained has a selective PPARα activation action as shown in Example 15 below, the body weight in mammals including humans It is useful as a prophylactic and / or therapeutic drug for hyperlipidemia, arteriosclerosis, diabetes, diabetic complications (diabetic nephropathy, etc.), inflammation, heart disease, etc. without increase or obesity.
[0050]
The dosage form of the pharmaceutical comprising the benzoic acid derivative represented by the general formula (1) of the present invention or a salt thereof as an active ingredient is not particularly limited and can be appropriately selected depending on the therapeutic purpose. For example, oral solid preparations, oral Liquid formulations, injections, suppositories, external preparations, eye drops, nasal drops, ear drops, patches and the like may be used. These preparations can be produced by blending known pharmaceutically acceptable carriers and preparing methods known to those skilled in the art.
[0051]
In the case of a solid preparation for oral use, the benzoic acid derivative represented by the general formula (1) of the present invention or a salt thereof, an excipient, if necessary, a binder, a disintegrant, a lubricant, a colorant, After adding a carrier such as a corrigent and a corrigent, it is prepared into tablets, granules, powders, capsules and the like by conventional methods.
The excipient is lactose, sodium chloride, glucose, starch, microcrystalline cellulose, silicic acid, etc., and the binder is water, ethanol, propanol, simple syrup, gelatin solution, hydroxypropylcellulose, methylcellulose, ethylcellulose, shellac, calcium phosphate, Polyvinyl pyrrolidone, etc., as disintegrant, agar powder, sodium bicarbonate, sodium lauryl sulfate, stearic acid monoglyceride, etc., as lubricant, purified talc, stearate, borax, polyethylene glycol, and β as colorant -Carotene, yellow iron sesquioxide, carmela and the like, and examples of the corrigent include sucrose and orange peel.
[0052]
When an oral liquid preparation is used, a carrier such as a corrigent, buffer, stabilizer, preservative, etc. is added to the benzoic acid derivative represented by the general formula (1) of the present invention or a salt thereof. Prepared into internal liquids, syrups, elixirs, etc. by the method.
Examples of the corrigent include white sugar, examples of the buffer include sodium citrate, examples of the stabilizer include tragacanth, and examples of the preservative include paraoxybenzoate.
[0053]
In the case of an injection, after adding a carrier such as a pH adjuster, a stabilizer and an isotonic agent to the benzoic acid derivative represented by the general formula (1) of the present invention or a salt thereof, Prepare subcutaneous, intramuscular and intravenous injections.
Examples of the pH regulator include sodium phosphate, examples of the stabilizer include sodium pyrosulfite, and examples of the isotonic agent include sodium chloride.
[0054]
In the case of a suppository, it is prepared by a conventional method after adding a carrier such as a base or a surfactant to the benzoic acid derivative represented by the general formula (1) or a salt thereof of the present invention.
Examples of the base include polyethylene glycol and hard fat, and examples of the surfactant include polyoxyethylene sorbitan fatty acid ester such as polysorbate 80.
[0055]
In the case of an external preparation, after adding a carrier such as a base, a water-soluble polymer, a solvent, a surfactant, a preservative to the benzoic acid derivative represented by the general formula (1) of the present invention or a salt thereof. The solution is prepared into a liquid, cream, gel, ointment, etc. by a conventional method.
Liquid paraffin, white petrolatum, purified lanolin, etc. as bases, carboxyvinyl polymer, etc. as water-soluble polymers, glycerin, water, etc. as solvents, polyoxyethylene fatty acid esters, etc. as surfactants are preserved Examples of the agent include paraoxybenzoic acid esters.
[0056]
In the case of an eye drop, after adding a carrier such as a pH adjuster, a stabilizer, an isotonic agent, a preservative to the benzoic acid derivative represented by the general formula (1) of the present invention or a salt thereof, Prepare by conventional methods.
Examples of the pH regulator include sodium phosphate, examples of the stabilizer include sodium pyrosulfite and ethylenediaminetetraacetic acid, examples of the isotonic agent include sodium chloride, and examples of the preservative include chlorobutanol.
[0057]
In the case of a nasal drop, after adding a carrier such as a pH adjuster, a stabilizer, an isotonic agent, a preservative to the benzoic acid derivative represented by the general formula (1) of the present invention or a salt thereof. Prepared by a conventional method.
Examples of pH regulators include sodium phosphate, stabilizers include sodium pyrosulfite and ethylenediaminetetraacetic acid, isotonic agents include sodium chloride, and preservatives include benzalkonium chloride.
[0058]
In the case of ear drops, carriers such as pH adjusters, buffers, stabilizers, isotonic agents, preservatives, etc. are added to the benzoic acid derivative represented by the general formula (1) of the present invention or a salt thereof. After the addition, it is prepared by a conventional method.
Sodium phosphate etc. as pH regulator and buffer, sodium pyrosulfite, ethylenediaminetetraacetic acid etc. as stabilizer, sodium chloride etc. as isotonic agent, benzalkonium chloride etc. as preservative Can be mentioned.
[0059]
In the case of a patch, after adding a carrier such as an adhesive, a solvent, a crosslinking agent, and a surfactant to the benzoic acid derivative represented by the general formula (1) of the present invention or a salt thereof, water is added by a conventional method. Prepared as a mold patch or plaster patch.
Examples of the adhesive include partially neutralized polyacrylic acid, sodium polyacrylate, 2-ethylhexyl polyacrylate, styrene-isoprene-styrene block copolymer, glycerin and water as the solvent, and dihydroxy as the crosslinking agent. Aluminum amino acetate, dry aluminum hydroxide gel, and the like, and surfactants include polyoxyethylene fatty acid esters.
[0060]
The dose of the medicament of the present invention varies depending on age, body weight, symptom, dosage form and number of administrations, but usually 1-1000 mg per day as a benzoic acid derivative represented by the general formula (1) for an adult, It is preferable to administer orally or parenterally in one or several divided doses.
[0061]
【Example】
EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.
[0062]
Production Example 1 Synthesis of 7-bromoheptanal
Pyridinium chlorochromate (9.94 g, 41.5 mmol as 90% purity) and sodium acetate (379 mg, 4.6 mmol) were suspended in 150 mL of methylene chloride, and 7-bromo-1-heptanol (3.0 g, 15.4 mmol) was cooled with ice. ) In 40 mL of methylene chloride was added dropwise over 30 minutes. Stir at room temperature for 30 minutes. After completion of the reaction, 300 mL of diethyl ether was added for dilution, and the residue was purified by silica gel column chromatography (eluent: diethyl ether) to obtain a crude target compound (2.97 g, yield 99.9%) as a pale yellow oil.
[0063]
Production Example 2 Synthesis of 7-bromo-1- (4-chlorophenyl) -1-heptyl alcohol
Crude 7-bromoheptanal (2.97 g, 15.38 mmol) was dissolved in 110 mL of tetrahydrofuran, and 15.5 mL (15.5 mmol) of a 1.0 mol / L diethyl ether solution of 4-chlorophenylmagnesium bromide was added dropwise at 0 ° C. under an argon atmosphere. After completion of the reaction, 20 mL of a saturated aqueous ammonium chloride solution was added at 0 ° C., followed by extraction with diethyl ether. The organic phase was washed with water and saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent hexane / ethyl acetate = 5/1) to give the target compound (4.05 g) as a yellow oil. Yield 86.2%).
[0064]
¹H-NMR (400MHz, CDCl_Three) δ: 1.28-1.42 (6H, m), 1.66-1.87 (4H, m), 3.39 (2H, t, J = 7Hz), 4.65 (1H, m), 7.27 (2H, d, J = 9Hz), 7.32 (2H, d, J = 9Hz).
[0065]
Production Example 3 Synthesis of methyl 2- [7- (4-chlorophenyl) -7-hydroxyheptylthio] benzoate
Methyl thiosalicylate (660 mg, 3.92 mmol) was dissolved in 30 mL of acetonitrile, potassium carbonate (542 mg, 3.92 mmol), 7-bromo-1- (4-chlorophenyl) heptyl alcohol (1.0 g, 3.27 mmol), potassium iodide ( 54 mg, 3.92 mmol) was added, and the mixture was stirred at 80 ° C. for 2 hours. After completion of the reaction, ethyl acetate was added, washed with water and saturated brine in that order, and dried over sodium sulfate. The reaction solution was filtered, concentrated under reduced pressure, and then separated by silica gel column chromatography (eluent hexane / ethyl acetate = 5/1) to obtain the target compound (999 mg, yield 77.7%) as a pale yellow oil.
[0066]
¹H-NMR (400MHz, CDCl_Three) δ: 1.27-1.49 (6H, m), 1.64-1.74 (4H, m), 1.95 (1H, bs), 2.89 (2H, t, J = 7Hz), 3.90 (3H, s), 4.64 (1H, t, J = 6 Hz), 7.14 (1H, t, J = 7Hz), 7.25-7.31 (5H, m), 7.42 (1H, t, J = 9Hz), 7.94 (1H, dd, J = 8, 2Hz ).
[0067]
Production Example 4 Synthesis of methyl 2- [7- (4-chlorophenyl) -6-heptenylthio] benzoate Methyl 2- [7- (4-chlorophenyl) -7-hydroxyheptylthio] benzoate (863 mg, 2.196 mmol) After dissolving in 30 mL of toluene, p-toluenesulfonic acid monohydrate (46 mg, 0.242 mmol) was added and stirred at 120 ° C. for 1 hour. The reaction mixture was returned to room temperature, ethyl acetate was added, washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine in that order, and dried over sodium sulfate. The reaction solution was filtered, concentrated under reduced pressure, and then separated by silica gel column chromatography (eluent hexane / ethyl acetate = 10/1) to obtain the target compound (633 mg, yield 76.9%) as a pale yellow oil.
[0068]
¹H-NMR (270MHz, CDCl_Three) δ: 1.52-1.58 (4H, m), 1.75-1.77 (2H, m), 2.20-2.22 (2H, m), 2.93 (2H, t, J = 7Hz), 3.91 (3H, s), 6.18 ( 1H, dt, J = 16, 7Hz), 6.32 (1H, d, J = 16Hz), 7.14 (1H, t, J = 8Hz), 7.25 (4H, s), 6.32 (1H, d, J = 8Hz) , 7.43 (1H, t, J = 7Hz), 7.95 (1H, dd, J = 8, 1Hz).
[0069]
Production Example 5 Synthesis of 1-bromo-7- (4-chlorophenyl) heptane
To a 200 mL anhydrous tetrahydrofuran solution of 107.2 g (415.6 mmol) of 1,7-dibromoheptane, 198 mg (2.0 mmol) of copper chloride and 170 mg (4.0 mmol) of lithium chloride were added, and the atmosphere was replaced with argon. To this suspension, 300 mL (300 mmol) of a 1.0 mol / L diethyl ether solution of 4-chlorophenylmagnesium bromide was added dropwise over 30 minutes under an argon atmosphere and water cooling, and the mixture was stirred at room temperature for 16 hours after the completion of the addition. To the reaction solution, 2 mL of 2 mol / L hydrochloric acid and 300 mL of chloroform were added under water cooling. The insoluble material was filtered off from the resulting suspension using celite, and the organic layer was extracted from the filtrate. Further, the organic layers extracted with chloroform (100 mL × 2) were combined, washed with water (100 mL), saturated brine (100 mL), dehydrated with sodium sulfate, and concentrated under reduced pressure. The obtained residue was distilled under reduced pressure, and fractions of 126 to 136 ° C./3 mm Hg were collected to obtain a crude target compound (24.19 g, yield 20.1%) as a colorless oil.
[0070]
¹H-NMR (270MHz, CDCl_Three) δ: 1.15-1.70 (8H, m), 1.84 (2H, q, J = 7Hz), 2.57 (2H, t, J = 8Hz), 3.40 (2H, t, J = 7Hz), 7.09 (2H, d , J = 8Hz), 7.23 (2H, d, J = 8Hz).
[0071]
Production Example 6 Synthesis of methyl 2- [7- (4-chlorophenyl) heptylthio] benzoate
To a 200 mL acetonitrile solution of 38.49 g (132.9 mmol) of 1-bromo-7- (4-chlorophenyl) heptane, 36.73 g (265.8 mmol) of potassium carbonate and 11.03 g (66.45 mmol) of potassium iodide were added. To this mixture, a solution of 33.5 g of methyl thiosalicylate (purity 97%, 199.4 mmol) in 20 mL of acetonitrile was added dropwise over 10 minutes. After completion of the addition, the mixture was stirred at room temperature for 30 minutes and then at a bath temperature of 60 ° C. for 4 hours. After confirming the disappearance of the raw materials by TLC, the mixture was concentrated under reduced pressure, and 500 mL of water, 500 mL of chloroform, and 300 mL of 2 mol / L hydrochloric acid were added to the residue, and the organic layer was extracted. The organic layer was washed with water (200 mL) and saturated brine (200 mL), then dehydrated with sodium sulfate, and the residue distilled off under reduced pressure was subjected to silica gel column chromatography (SiO 2).₂Purification was performed using 1000 g, eluent hexane / ethyl acetate = 30/1). The fraction containing the target compound was concentrated under reduced pressure to obtain the target compound (31.28 g, yield 83.0%) as a white oil.
[0072]
¹H-NMR (400MHz, CDCl_Three) δ: 1.22-1.62 (8H, m), 1.72 (2H, q, J = 7Hz), 2.56 (2H, t, J = 7Hz), 2.91 (2H, t, J = 7Hz), 3.91 (3H, s ), 7.09 (2H, d, J = 8Hz), 7.14 (1H, t, J = 8Hz), 7.23 (2H, d, J = 8Hz), 7.26-7.33 (1H, m), 7.43 (1H, td, J = 8, 2Hz), 7.95 (1H, dd, J = 8, 2Hz).
[0073]
Production Example 7 Synthesis of methyl 2- [7- (4-chlorophenyl) heptylsulfinyl] benzoate
Dissolve methyl 2- [7- (4-chlorophenyl) heptylthio] benzoate (320 mg, 0.849 mmol) in 10 mL of chloroform, add m-chloroperbenzoic acid (183 mg, 0.849 mmol as 80% purity) and add ice. Stir for 90 minutes under cooling. The organic layer was extracted by adding 5 mL of 5% aqueous sodium thiosulfate solution to the reaction solution. The organic layer was washed with 5 mL of water and 5 mL of saturated brine and then dried over sodium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (eluent hexane / ethyl acetate = 1/1). The fraction containing the target compound was concentrated under reduced pressure to give the target compound (231 mg, yield 69.2%) as a colorless oil.
[0074]
¹H-NMR (270MHz, CDCl_Three) δ: 1.21-1.81 (9H, m), 1.96 (1H, m), 2.55 (2H, t, J = 8Hz), 2.66 (1H, m), 3.14 (1H, ddd, J = 13, 10, 7Hz ), 3.94 (3H, s), 7.08 (2H, d, J = 8Hz), 7.23 (2H, d, J = 8Hz), 7.56 (1H, t, J = 8Hz), 7.81 (1H, t, J = 8Hz), 8.09 (1H, d, J = 8Hz), 8.25 (1H, d, J = 8Hz).
[0075]
Production Example 8 Synthesis of methyl 2- [7- (4-chlorophenyl) heptylsulfonyl] benzoate
Dissolve methyl 2- [7- (4-chlorophenyl) heptylthio] benzoate (320 mg, 0.849 mmol) in 10 mL of chloroform, add m-chloroperbenzoic acid (366 mg, 1.70 mmol as 80% purity) at room temperature For 90 minutes. The organic layer was extracted by adding 5 mL of 5% aqueous sodium thiosulfate solution to the reaction solution. The organic layer was washed with 5 mL of water and 5 mL of saturated brine and then dried over sodium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (eluent hexane / ethyl acetate = 1/1). The fraction containing the target compound was concentrated under reduced pressure to obtain the target compound (204 mg, yield 58.8%) as a colorless oil.
[0076]
¹H-NMR (270MHz, CDCl_Three) δ: 1.17-1.46 (6H, m), 1.46-1.66 (2H, m), 1.69-1.88 (2H, m), 2.54 (2H, t, J = 8Hz), 3.47 (2H, t, J = 8Hz ), 3.96 (3H, s), 7.07 (2H, d, J = 7Hz), 7.22 (2H, d, J = 7Hz), 7.60-7.72 (3H, m), 8.06 (1H, d, J = 6Hz) .
[0077]
Production Example 9 Synthesis of methyl 2- [7- (4-chlorophenyl) -7-hydroxyheptylsulfinyl] benzoate
In the same manner as in Production Example 7, colorless target oily compound (69 mg, 66% yield) from methyl 2- [7- (4-chlorophenyl) -7-hydroxyheptylthio] benzoate (100 mg, 0.254 mmol) Got.
[0078]
¹H-NMR (400MHz, CDCl_Three) δ: 1.22-1.82 (9H, m), 1.96 (1H, m), 2.64 (1H, m), 3.12 (1H, ddd, J = 13, 10, 7Hz), 3.94 (3H, s), 4.64 ( 1H, t, J = 7Hz), 7.26 (2H, d, J = 9Hz), 7.31 (2H, d, J = 9Hz), 7.55 (1H, t, J = 8Hz), 7.80 (1H, t, J = 9Hz), 8.08 (1H, d, J = 8Hz), 8.24 (1H, d, J = 8Hz).
[0079]
Production Example 10 Synthesis of methyl 2- [7- (4-chlorophenyl) -6-heptenylsulfinyl] benzoate
In the same manner as in Production Example 7, colorless oily target compound (2.73 g, yield 85.0%) was obtained from methyl 2- [7- (4-chlorophenyl) -6-heptenylthio] benzoate (3.08 g, 8.22 mmol). It was.
[0080]
¹H-NMR (270MHz, CDCl_Three) δ: 1.39-1.62 (4H, m), 1.62-1.86 (1H, m), 1.86-2.12 (1H, m), 2.15-2.32 (2H, m), 2.69 (1H, ddd, J = 13, 10 , 7Hz), 3.17 (1H, ddd, J = 13, 10, 5Hz), 3.95 (3H, s), 6.17 (1H, dt, J = 16, 7Hz), 6.33 (1H, d, J = 16Hz), 7.21-7.31 (4H, m), 7.59 (1H, m), 7.81 (1H, td, J = 8, 1Hz), 8.09 (1H, dd, J = 8, 1 Hz), 8.26 (1H, dd, J = 8, 1Hz).
[0081]
Production Example 11 Synthesis of methyl 2- [7- (4-chlorophenyl) -7-hydroxyheptylsulfonyl] benzoate
In the same manner as in Production Example 8, from 2- [7- (4-chlorophenyl) -7-hydroxyheptylthio] methyl benzoate (89 mg, 0.226 mmol) to give the target compound as a white solid (53.4 mg, yield 56%) Got.
[0082]
¹H-NMR (400MHz, CDCl_Three) δ: 1.19-1.47 (6H, m), 1.57-1.83 (4H, m), 3.46 (2H, m), 3.96 (3H, s), 4.63 (1H, dd, J = 7, 6Hz), 7.26 ( 2H, d, J = 8Hz), 7.31 (2H, d, J = 8Hz), 7.63-7.71 (3H, m), 8.05 (1H, d, J = 7Hz).
[0083]
Production Example 12 Synthesis of methyl 2- [7- (4-chlorophenyl) -6-heptenylsulfonyl] benzoate
In the same manner as in Production Example 4, methyl 2- [7- (4-chlorophenyl) -7-hydroxyheptylsulfonyl] benzoate (30.5 mg, 0.075 mmol) was used as a pale yellow oily target compound (25.1 mg, 86% yield). )
[0084]
¹H-NMR (270MHz, CDCl_Three) δ: 1.40-1.57 (4H, m), 1.74-1.92 (2H, m), 2.14-2.29 (2H, m), 3.51 (2H, m), 3.97 (3H, s), 6.14 (1H, dt, J = 16, 7Hz), 6.32 (1H, d, J = 16Hz), 7.20-7.31 (4H, m), 7.60-7.73 (3H, m), 8.07 (1H, d, J = 6Hz).
[0085]
Production Example 13 Synthesis of methyl 2- [7- (4-chlorophenyl) -7-oxoheptylthio] benzoate
2-Methyl 2- [7- (4-chlorophenyl) -7-hydroxyheptylthio] benzoate (99.6 mg, 0.254 mmol) is dissolved in 2 mL of methylene chloride, and pyridinium chlorochromate (60.9 mg, 0.254 mmol as 90% purity) is dissolved. The mixture was further stirred at room temperature for 1 hour. A solution portion obtained by adding 10 mL of diethyl ether to the reaction solution was eluted through a silica gel column (eluent diethyl ether). The residue obtained by concentrating the eluate under reduced pressure was purified using flash column chromatography (eluent hexane / ethyl acetate = 10/1). The fraction containing the target compound was concentrated under reduced pressure to obtain the target compound (65.0 mg, yield 66%) as a colorless oil.
[0086]
¹H-NMR (270MHz, CDCl_Three) δ: 1.35-1.49 (2H, m), 1.49-1.60 (2H, m), 1.66-1.84 (4H, m), 2.88-2.99 (4H, m), 3.91 (3H, s), 7.14 (1H, t, J = 8Hz), 7.30 (1H, d, J = 8Hz), 7.38-7.49 (3H, m), 7.89 (2H, d, J = 8Hz), 7.96 (1H, d, J = 8Hz).
[0087]
Production Example 14 Synthesis of methyl 2- [7- (4-chlorophenyl) -7-oxoheptylsulfinyl] benzoate
In the same manner as in Production Example 7, 2- [7- (4-chlorophenyl) -7-oxoheptylthio] methyl benzoate (200 mg, 0.513 mmol) was used as a white solid target compound (156 mg, yield 74.7%) Got.
[0088]
¹H-NMR (270MHz, CDCl_Three) δ: 1.32-1.85 (7H, m), 1.98 (1H, m), 2.69 (1H, ddd, J = 13, 10, 5Hz), 2.93 (2H, t, J = 7Hz), 3.16 (1H, ddd , J = 13, 10, 7Hz), 3.95 (3H, s), 7.43 (2H, d, J = 8Hz), 7.56 (1H, t, J = 8Hz), 7.81 (1H, t, J = 8Hz), 7.88 (2H, d, J = 8Hz), 8.09 (1H, d, J = 8Hz), 8.27 (1H, d, J = 8Hz).
[0089]
Production Example 15 Synthesis of methyl 2- [7- (4-chlorophenyl) -7-oxoheptylsulfonyl] benzoate
In the same manner as in Production Example 8, from 2- [7- (4-chlorophenyl) -7-oxoheptylthio] methyl benzoate (200 mg, 0.513 mmol) to give the target compound as a white solid (128 mg, yield 59.0%) Got.
[0090]
¹H-NMR (270MHz, CDCl_Three) δ: 1.25-1.58 (4H, m), 1.60-1.90 (4H, m), 2.92 (2H, t, J = 7Hz), 3.50 (2H, t, J = 8Hz), 3.97 (3H, s), 7.43 (2H, d, J = 8Hz), 7.61-7.72 (3H, m), 7.88 (2H, d, J = 8Hz), 8.06 (1H, d, J = 6Hz).
[0091]
Example 1 Synthesis of 2- [7- (4-chlorophenyl) -6-heptenylthio] benzoic acid
2- [7- (4-Chlorophenyl) -6-heptenylthio] methyl benzoate (1.80 g, 4.80 mmol) is dissolved in 10 mL of methanol-10 mL of tetrahydrofuran, 3 mL of 4 mol / L aqueous sodium hydroxide solution is added, and the mixture is stirred at room temperature. did. After completion of the reaction, 250 mL of water was added and concentrated hydrochloric acid was added at 0 ° C. to make it weakly acidic. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and then saturated brine and dried over magnesium sulfate. The reaction solution was filtered, concentrated under reduced pressure, and then separated by silica gel column chromatography (eluent hexane / ethyl acetate = 1/1) to obtain the target compound (1.50 g, yield 86.7%) as colorless crystals.
[0092]
¹H-NMR (400MHz, CDCl_Three) δ: 1.53-1.54 (4H, m), 1.74-1.79 (2H, m), 2.20-2.25 (2H, m), 2.94 (2H, t, J = 7Hz), 6.18 (1H, dt, J = 16 , 6Hz), 6.33 (1H, dd, J = 16, 1Hz), 7.20 (1H, t, 8Hz), 7.25 (2H, d, J = 1Hz), 7.26 (2H, d, J = 1Hz), 7.35 ( 1H, d, J = 8Hz), 7.48 (1H, t, J = 8Hz), 8.13 (1H, dd, J = 8, 1Hz).
[0093]
Example 2 Synthesis of 2- [7- (4-chlorophenyl) -6-heptenylthio] benzoic acid sodium salt
2- [7- (4-Chlorophenyl) -6-heptenylthio] benzoic acid (1.25 g, 3.450 mmol) was dissolved in 20 mL of methanol, and a solution of sodium methoxide (205 mg, 3.795 mmol) in 20 mL of methanol was added. After all was dissolved and homogenized, the filtrate was concentrated under reduced pressure and recrystallized from ethanol to obtain the target compound (1.24 g, yield 93.9%) as colorless crystals.
[0094]
¹H-NMR (400MHz, CDCl_Three+ CD_ThreeOD) δ: 1.50-1.52 (4H, m), 1.71-1.75 (2H, m), 2.20 (2H, m), 2.91 (2H, t, J = 8Hz), 6.18 (1H, dt, J = 16, 7Hz), 6.34 (1H, d, J = 16Hz), 7.13 (1H, dt, J = 8, 1Hz), 7.25 (4H, s), 7.27 (1H, d, J = 8Hz), 7.35 (1H, dt , J = 8, 1Hz), 8.13 (1H, dd, J = 8, 2Hz).
[0095]
Example 3 Synthesis of 2- [7- (4-chlorophenyl) heptylthio] benzoic acid
In the same manner as in Example 1, the target compound (19.41 g, yield 64.5%) as white crystalline powder was obtained from methyl 2- [7- (4-chlorophenyl) heptylthio] benzoate (31.28 g, 83.0 mmol). .
[0096]
¹H-NMR (270MHz, CDCl_Three) δ: 1.20-1.85 (10H, m), 2.57 (2H, t, J = 8Hz), 2.92 (2H, t, J = 8Hz), 7.09 (2H, d, J = 8Hz), 7.20 (1H, t , J = 8Hz), 7.23 (2H, d, J = 8Hz), 7.34 (1H, d, J = 8Hz), 7.49 (1H, td, J = 8, 1Hz), 8.13 (1H, dd, J = 8 , 1Hz).
IR (KBr): 2925, 1674, 1561, 1492, 1464, 1409, 1317, 1253, 1047, 915, 756 cm^-1
mp 109.1-109.5 ℃
[0097]
Example 4 Synthesis of 2- [7- (4-chlorophenyl) heptylthio] benzoic acid sodium salt In the same manner as in Example 2, 2- [7- (4-chlorophenyl) heptylthio] benzoic acid (7.23 g, 19.9 mmol) From the target compound (4.25 g, yield 55.4%) as a white crystalline powder.
[0098]
¹H-NMR (270MHz, CD_ThreeOD) δ: 7.59 (1H, d, J = 8Hz), 7.33-7.03 (7H, m), 2.84 (2H, t, J = 7Hz), 2.56 (2H, t, J = 8Hz), 1.71-1.23 ( 10H, m).
[0099]
Example 5 Synthesis of 2- [7- (4-chlorophenyl) -7-hydroxyheptylthio] benzoic acid
In the same manner as in Example 1, methyl 2- [7- (4-chlorophenyl) -7-hydroxyheptylthio] benzoate (134 mg, 0.341 mmol) was used as a pale yellow oily target compound (108 mg, yield 83.6%). Got.
[0100]
¹H-NMR (270MHz, CDCl_Three) δ: 1.12-1.90 (10H, m), 2.91 (2H, t, J = 7Hz), 4.66 (1H, t, J = 7Hz), 7.10-7.39 (6H, m), 7.48 (1H, t, J = 7Hz), 8.11 (1H, d, J = 7Hz).
[0101]
Example 6 Synthesis of 2- [7- (4-chlorophenyl) heptylsulfinyl] benzoic acid
In the same manner as in Example 1, the desired compound (68 mg, quantitative yield) was obtained as a colorless oil from methyl 2- [7- (4-chlorophenyl) heptylsulfinyl] benzoate (69 mg, 0.18 mmol).
[0102]
¹H-NMR (400MHz, CDCl_Three) δ: 1.05-1.63 (8H, m), 1.68 (1H, m), 1.93 (1H, m), 2.53 (2H, t, J = 8Hz), 2.75 (1H, m), 3.17 (1H, ddd, J = 13, 10, 7Hz), 7.06 (2H, d, J = 8Hz), 7.20 (2H, d, J = 8Hz), 7.58 (1H, t, J = 8Hz), 7.83 (1H, t, J = 8Hz), 8.16 (1H, d, J = 8Hz), 8.27 (1H, d, J = 8Hz).
[0103]
Example 7 Synthesis of 2- [7- (4-chlorophenyl) heptylsulfonyl] benzoic acid
In the same manner as in Example 1, the desired compound (103 mg, quantitative yield) was obtained as a colorless oil from methyl 2- [7- (4-chlorophenyl) heptylsulfonyl] benzoate (107 mg, 0.262 mmol).
[0104]
¹H-NMR (400MHz, CDCl_Three) δ: 0.93-1.89 (10H, m), 2.52 (2H, t, J = 8Hz), 3.56 (2H, t, J = 8Hz), 7.05 (2H, d, J = 8Hz), 7.20 (2H, d , J = 8Hz), 7.46-7.77 (2H, m), 7.84 (1H, m), 8.11 (1H, m).
[0105]
Example 8 Synthesis of 2- [7- (4-chlorophenyl) -7-hydroxyheptylsulfinyl] benzoic acid
In the same manner as in Example 1, methyl 2- [7- (4-chlorophenyl) -7-hydroxyheptylsulfinyl] benzoate (10.0 mg, 0.024 mmol) was used as a colorless oily target compound (10.0 mg, quantitative yield). Got.
[0106]
¹H-NMR (400MHz, CDCl_Three) δ: 1.22-1.82 (9H, m), 1.97 (1H, m), 2.70 (1H, m), 3.19 (1H, m), 4.65 (1H, t, J = 7Hz), 7.21 (2H, d, J = 9Hz), 7.25 (2H, d, J = 9Hz), 7.56 (1H, t, J = 8Hz), 7.78 (1H, t, J = 8Hz), 8.13 (1H, d, J = 8Hz), 8.21 (1H, d, J = 8Hz).
[0107]
Example 9 Synthesis of 2- [7- (4-chlorophenyl) -6-heptenylsulfinyl] benzoic acid
In the same manner as in Example 1, methyl 2- [7- (4-chlorophenyl) -6-heptenylsulfinyl] benzoate (2.71 g, 6.93 mmol) was used as a white crystalline powder (2.55 g, yield 97.6). %).
[0108]
¹H-NMR (270MHz, CDCl_Three) δ: 1.30-1.60 (4H, m), 1.60-1.86 (1H, m), 1.86-2.10 (1H, m), 2.10-2.30 (2H, m), 2.77 (1H, m), 3.20 (1H, m), 6.13 (1H, dt, J = 16, 7Hz), 6.16 (1H, d, J = 16Hz), 7.10-7.35 (4H, m), 7.56 (1H, t, J = 8Hz), 7.81 (1H , t, J = 8Hz), 8.15 (1H, d, J = 8Hz), 8.26 (1H, d, J = 8Hz).
[0109]
Example 10 Synthesis of 2- [7- (4-chlorophenyl) -7-hydroxyheptylsulfonyl] benzoic acid
In the same manner as in Example 1, the desired compound (7.4 mg, yield 77%) was obtained as a colorless oil from methyl 2- [7- (4-chlorophenyl) -7-hydroxyheptylsulfonyl] benzoate (10 mg, 0.0236 mmol). Got.
[0110]
¹H-NMR (400MHz, CDCl_Three) δ: 1.19-1.58 (6H, m), 1.58-1.95 (4H, m), 3.51 (2H, m), 4.67 (1H, dd, J = 8, 5Hz), 7.26-7.49 (4H, m), 7.63-7.76 (2H, m), 7.97 (1H, d, J = 8Hz), 8.08 (1H, dd, J = 8, 1Hz).
[0111]
Example 11 Synthesis of 2- [7- (4-chlorophenyl) -6-heptenylsulfonyl] benzoic acid
In the same manner as in Example 1, the desired compound was obtained as a colorless oil from methyl 2- [7- (4-chlorophenyl) -6-heptenylsulfonyl] benzoate (25.1 mg, 0.0617 mmol) (32 mg, quantitative yield) Got.
[0112]
¹H-NMR (400MHz, CDCl_Three) δ: 1.39-1.52 (4H, m), 1.72-1.96 (2H, m), 2.10-2.32 (2H, m), 3.57 (2H, t, J = 8Hz), 6.13 (1H, dt, J = 16 , 7Hz), 6.29 (1H, d, J = 16Hz), 7.13-7.37 (4H, m), 7.61-7.75 (2H, m), 7.83 (1H, d, J = 7Hz), 8.10 (1H, d, J = 7Hz).
[0113]
Example 12 Synthesis of 2- [7- (4-chlorophenyl) -7-oxoheptylthio] benzoic acid In the same manner as in Example 1, 2- [7- (4-chlorophenyl) -7-oxoheptylthio] benzoic acid The target compound (128 mg, yield 97.6%) as a white solid was obtained from methyl acid (136 mg, 0.348 mmol).
[0114]
¹H-NMR (270MHz, CDCl_Three) δ: 1.32-1.86 (8H, m), 2.85-3.14 (4H, m), 7.22 (1H, m), 7.32-7.54 (2H, m), 7.43 (2H, d, J = 9Hz), 7.89 ( 2H, d, J = 9Hz), 8.13 (1H, d, J = 8Hz).
[0115]
Example 13 Synthesis of 2- [7- (4-chlorophenyl) -7-oxoheptylsulfinyl] benzoic acid
In the same manner as in Example 1, the target compound (154 mg, quantitative yield) was obtained from methyl 2- [7- (4-chlorophenyl) -7-oxoheptylsulfinyl] benzoate (156 mg, 0.383 mmol) as a white solid. Obtained.
[0116]
¹H-NMR (270MHz, CDCl_Three) δ: 1.30-1.84 (7H, m), 2.02 (1H, m), 2.74 (1H, m), 2.94 (2H, t, J = 7Hz), 3.21 (1H, m), 7.41 (2H, d, J = 9Hz), 7.58 (1H, t, J = 8Hz), 7.81 (1H, t, J = 8Hz), 7.87 (2H, d, J = 9Hz), 8.17 (1H, d, J = 8Hz), 8.26 (1H, d, J = 8Hz).
[0117]
Example 14 Synthesis of 2- [7- (4-chlorophenyl) -7-oxoheptylsulfonyl] benzoic acid
In the same manner as in Example 1, methyl 2- [7- (4-chlorophenyl) -7-oxoheptylsulfonyl] benzoate (128 mg, 0.303 mmol) was used as a pale yellow solid of the target compound (113 mg, yield 91.2% )
[0118]
¹H-NMR (270MHz, CDCl_Three) δ: 1.21-1.59 (4H, m), 1.62-1.93 (4H, m), 2.93 (2H, t, J = 7Hz), 3.56 (2H, t, J = 8Hz), 7.42 (2H, d, J = 9Hz), 7.65-7.76 (2H, m), 7.81-7.92 (3H, m), 8.10 (1H, d, J = 7Hz).
[0119]
Example 15
As a benzoic acid derivative represented by general formula (1) and a comparative compound of the present invention, compounds described in Example 6 (3) and Example 10 (1) of Patent Document 2 (hereinafter referred to as Compound A and Compound, respectively) BPAR) was measured by the following method (Proc. Natl. Acad. Sci., 92, pp7297-7301, 1995, Journal of Biological Chemistry, 269, pp31012-31018, 1994). Proc. Natl. Acad. Sci, 98, pp5306-5311, 2001).
[0120]
[Chemical Formula 10]

[0121]
Transfection assay measurement
All transfection assays were performed using COS cells, an African green monkey kidney-derived cell line. COS cell culture is 5% CO₂The DMEM medium containing 10% fetal bovine serum, glutamic acid and antibiotics was used as the culture solution.
Transfection of the plasmid into the cells was performed by a method using lipofectamine. PSG5hPPARα, pSG5hPPARg, and pcDNA3hPPARδ were used as expression vectors for wild-type human PPAR. The reporter vector uses firefly luciferase and contains 6 PPAR response elements on the human apoAII promoter in its promoter region. Furthermore, an expression vector for β-galactosidase was used as an internal standard.
After transfection into cells, the medium was replaced with DMEM medium (containing 0.2% serum) supplemented with the compound, and further cultured for 16 hours. Thereafter, luciferase activity and β-galactosidase activity in the cell lysate were measured.
Dimethyl sulfoxide was used to dissolve and dilute the compound, and the dimethyl sulfoxide concentration was adjusted to 0.1% in the DMEM medium (containing 0.2% serum) during the treatment of the cells. As positive compounds, WY14643 for PPARα, troglitazone for PPARγ (Journal of Medicinal Chemistry, 43, pp527-550, 2000), and GW501516 for PPARδ (Proc. Natl. Acad. Sci, 98, pp5306-5311, 2001) Was used.
[0122]
Table 1 shows the results of measuring hPPARα, hPPARγ, and hPPARδ agonist activity of these compounds.
[0123]
[Table 1]

[0124]
Compound A has an activating effect only on hPPARδ, and Compound B has EC of hPPARα and γ.₅₀It only shows 3 times selectivity in the value. On the other hand, the benzoic acid derivative of the present invention exhibits an excellent hPPARα activation action and selectivity, and clearly has an hPPARα selectivity superior to that of Compound A and Compound B.
[0125]
FIG. 1 shows ECs that activate hPPARα of the benzoic acid derivatives of Example 1 and Example 3.₅₀The concentration of values and the activation magnification of each isoform at concentrations 10 and 100 times are shown. Here, No. 1 is PPARα-activated EC₅₀Shows the activation rate at the concentration of the value, No. 2 is PPARα activated EC₅₀Shows the activation rate at 10 times the concentration, No. 3 is PPARα activated EC₅₀The activation rate at 100-fold concentration is shown.
The activation magnification was shown as a magnification relative to the control, with the activity value when only the solvent containing no compound (dimethylsulfoxide) was treated as a control. The compounds of Example 1 and Example 3 are ECs that activate hPPARα.₅₀It can be seen that hPPARγ and δ are not activated even at concentrations 10 and 100 times the concentration of the values.
[0126]
The benzoic acid derivative represented by the general formula (1) of the present invention or a salt thereof has a hPPARα selective activating action that is clearly superior to a conventionally known compound.
[0127]
【The invention's effect】
The compound of the present invention has an action of selectively activating α type of PPAR, and does not accompany weight gain or obesity, hyperlipidemia, arteriosclerosis, diabetes, diabetic complications, inflammation, heart disease It is useful as a preventive and / or therapeutic agent for the above.
[Brief description of the drawings]
FIG. 1: PPARα-activated EC of 2- [7- (4-chlorophenyl) -6-heptenylthio] benzoic acid₅₀It is a figure which shows the density | concentration of a value, and the PPAR activation rate in the density | concentration of 10 time and 100 time.
FIG. 2: PPARα-activated EC of 2- [7- (4-chlorophenyl) heptylthio] benzoic acid₅₀It is a figure which shows the density | concentration of a value, and the PPAR activation rate in the density | concentration of 10 time and 100 time.

Claims (6)

The following general formula (1)

(Wherein, -A- is -CH ₂ -CH ₂ - group, -CH = CH- group or a -C (O) -CH ₂ - represents a group, X is S (O) _n group (wherein, n Represents an integer of 0, 1 or 2))) or a salt thereof.   The benzoic acid derivative or a salt thereof according to claim 1, wherein the benzoic acid derivative is 2- [7- (4-chlorophenyl) -6-heptenylthio] benzoic acid or 2- [7- (4-chlorophenyl) heptylthio] benzoic acid. . A peroxisome proliferator-activated receptor α activator comprising the benzoic acid derivative or salt thereof according to claim 1 or 2 as an active ingredient. A pharmaceutical comprising the benzoic acid derivative or salt thereof according to claim 1 or 2 as an active ingredient. A preventive and / or therapeutic agent for a disease selected from hyperlipidemia, arteriosclerosis, diabetes, diabetic complications, inflammation and heart disease, comprising the benzoic acid derivative or salt thereof according to claim 1 or 2 as an active ingredient. A pharmaceutical composition comprising the benzoic acid derivative or a salt thereof according to claim 1 or 2, and a pharmaceutically acceptable carrier.

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