JPWO2004011430A1 - Sodium channel inhibitor - Google Patents

Abstract

The object of the present invention is to provide a sodium channel inhibitor having an analgesic effect on neuropathic pain, comprising a piperidine derivative and a pharmaceutically acceptable salt thereof as an active ingredient. Piperidine derivatives and pharmaceutically acceptable salts thereof, which are active ingredients of channel inhibitors, are characterized by having an amide, sulfonamide, urea or carbonyl structure in the substituent of the nitrogen atom of piperidine.

Description

  The present invention relates to a sodium channel inhibitor having an analgesic effect on neuropathic pain, and a piperidine derivative and a pharmaceutically acceptable salt thereof, including a piperidine derivative and a pharmaceutically acceptable salt thereof as an active ingredient. Relating to salt.

Voltage-gated sodium channels are proteins responsible for the generation and propagation of nerve action potentials. The voltage-gated sodium channel has a large α subunit in which four 6-transmembrane domains are repeated and two small β subunits as a common structure. The main channel function is the α subunit. To date, it is known that there are more than 10 types of α subunits (Goldin AL, Anals of the New York Academy of Sciences 868: 38-50, 1999). Each voltage-gated sodium channel subtype exhibits a different distribution in central and peripheral nervous tissue. They regulate nerve excitability and play an important role in regulating the physiological function of each tissue. It has also been suggested to be deeply involved in various pathological conditions (Goldin AL, Annual Review of Physiology 63: 871-94, 2001).
In recent years, it has become clear that voltage-gated sodium channels are deeply involved in pain neurotransmission, and sodium channel agonists are expected to be excellent pain therapeutic agents, particularly neuropathic pain therapeutic agents ( Non-patent document 1).
Neuropathic pain means pain due to peripheral or central nervous system dysfunction, and includes pain of diabetic neuropathy, cancer pain, trigeminal neuralgia, phantom limb pain, postherpetic pain, thalamic pain, and the like. Clinical images of neuropathic pain are painful to tighten, painful to burn, hyperalgesia and allodynia (allodynia).
In the medical field, nonsteroidal anti-inflammatory drugs and narcotic analgesics such as morphine are used for the purpose of pain relief.In recent years, antiarrhythmic drugs and anticonvulsants, which are sodium channel inhibitors, are also used for pain relief. Came to be used.
Non-steroidal anti-inflammatory drugs are not completely satisfied with analgesic effects, and also have problems of side effects such as gastrointestinal disorders and kidney injuries. Narcotic analgesics such as morphine have a high effect mainly on nociceptive pain, but have serious problems of side effects on the digestive system, respiratory system and central nervous system. In general, these drugs have a weak effect on neuropathic pain.
Existing sodium channel inhibitors, such as antiarrhythmic drugs such as lidocaine and mexiletine, and anticonvulsants such as carbamazepine, have come to be used for pain relief. However, these sodium channel inhibitors have central side effects such as convulsions and sleepiness, or peripheral undesirable effects such as bradycardia, so that it is difficult to increase the dose sufficiently, and as a result, sufficient analgesic effect cannot be obtained. There was a point.
As described above, no analgesic has yet been found that has a useful effect in the treatment of neuropathic pain and is excellent in safety. Accordingly, there is a need for novel sodium channel inhibitors and therapeutic agents for neuropathic pain that have a particularly high analgesic effect on neuropathic pain and have reduced side effects.
As a compound having a piperidine skeleton that is a sodium channel inhibitor and a therapeutic agent for neuropathic pain, a derivative having a phenoxymethyl at the 3-position of piperidine (see Patent Document 1), and a derivative having a substituent containing phenylamino at the 4-position ( Patent Document 2), derivatives having a substituent consisting of arylcyanomethyl at the 4-position (see Patent Document 3), derivatives having a pyridyl or quinolyl-substituted alkyl at the 1-position (see Patent Document 4), and having a spiro structure Derivatives (see Patent Document 5) have been reported.
On the other hand, although not a sodium channel inhibitor or a neuropathic pain therapeutic agent, compounds having a piperidine skeleton are reported in Patent Documents 6 to 19.
However, these patent documents do not disclose or suggest sodium channel inhibitors and therapeutic agents for neuropathic pain.
Below, patent documents and non-patent documents as background art are listed.
[Patent Literature]
Patent Literature 1: European Patent Publication No. 869119 Patent Literature 2: European Patent Publication No. 1182193 Patent Literature 3: European Patent Publication No. 254894 Patent Literature 4: European Patent Publication No. 1254904 Patent Literature 5: PCT International Patent Publication WO00 / 75116 Patent Document 6: French Published Patent No. 2706894 Publication Patent Reference 7: PCT International Publication Brochure WO93 / 3014 Patent Publication 8: PCT International Publication Brochure WO96 / 33713 Patent Publication 9: PCT International Publication Brochure WO2001 No. 7436 Patent Document 10: PCT International Publication Pamphlet WO 97/10207 Patent Document 11: European Patent Publication No. 628551 Patent Document 12: US Pat. No. 6,656,364 Patent Document 13: PCT International Publication Pamphlet WO Patent Document 14: PCT International Publication Brochure WO99 / 31060 Patent Document 15: PCT International Publication Brochure WO98 / 43956 Patent Document 16: PCT International Publication Brochure WO93 / 20065 Patent Document 17: PCT International Publication Brochure WO2003 / No. 35641 Patent Document 18: PCT International Publication Pamphlet WO2001 / 85690 Patent Document 19: US Pat. No. 6,100,209 [Non-patent Document]
Non-Patent Document 1: Taylor CP, Current Pharmaceutical Design 2: 375-388, 1996

（上記式（Ｉ−Ａ）中の記号は以下の意味を示す。
Ｃｙ^１：置換されていてもよいアリール又は置換されていてもよいヘテロ環、
Ｒ^１：Ｈ、ＯＨ、低級アルキル−Ｏ−又はハロ
（但し、上記式（Ｉ−Ａ）において、ピペリジン環４位に、Ｃｙ^１−（Ｏ）ｎ^１−ＡＬＫ^１−（Ｏ）ｎ^２−で示される基が置換し、かつピペリジン環３位と４位との結合が二重結合である場合には、Ｒ^１は存在しない。）、
ＡＬＫ^１：低級アルキレン、低級アルケニレン、又は低級アルキニレン、
ＡＬＫ^２：低級アルキレン、
Ｌ^１：−ＮＲ^２ＣＯ−、−ＣＯＮＲ^２−、−ＣＯ−、−ＮＲ^２ＳＯ_２−、−ＳＯ_２ＮＲ^２−、−ＮＲ^２ＣＯＮＲ^３−又は−ＮＲ^２ＣＯＣＯ−で示される基、
Ｒ^２及びＲ^３：同一又は異なって、Ｈ、低級アルキル、低級アルケニル、（下記ａ群から選択される基で置換されていてもよいアリール）−低級アルキル、又は（下記ａ群から選択される基で置換されていてもよいヘテロアリール）−低級アルキル、
［ａ群：ハロ、ＨＯ−、低級アルキル−Ｏ−］
Ｌ^２：結合、−（Ｏ）ｎ^４−（下記ｂ群から選択される置換基で置換されていてもよい低級アルキレン）−（Ｏ）ｎ^５−、又は低級アルケニレン
［ｂ群：アリール、ＨＯ−、低級アルキル−Ｏ−］
Ｄ：Ｈ、又は下記に示される基
（基）

（上記基中の記号は以下の意味を示す。
Ｃｙ^２：ヘテロ環基又は炭化水素環基、
Ｒ^４及びＲ^５：同一又は異なって、（１ａ）置換されていてもよい低級アルキル、（２ａ）シクロアルキル、（３ａ）置換されていてもよいアリール、（４ａ）低級アルキル−ＣＯ−、（５ａ）ＨＯＯＣ−、（６ａ）低級アルキル−Ｏ−ＣＯ−、（７ａ）Ｈ_２ＮＣＯ−、（８ａ）Ｈ_２ＮＳＯ_２−、（９ａ）低級アルキル−ＮＨＣＯ−、（１０ａ）低級アルキル−ＮＨＳＯ_２−、（１１ａ）（低級アルキル）_２−ＮＣＯ−、（１２ａ）（低級アルキル）_２−ＮＳＯ_２−、（１３ａ）Ｈ_２Ｎ−、（１４ａ）置換されていてもよい低級アルキル−ＮＨ−、（１５ａ）（置換されていてもよい低級アルキル）_２−Ｎ−、（１６ａ）置換されていてもよいアリール−ＮＨ−、（１７ａ）低級アルキル−ＣＯＮＨ−、（１８ａ）低級アルキル−ＳＯ_２ＮＨ−、（１９ａ）置換されていてもよい低級アルキル−Ｏ−ＣＯＮＨ−、（２０ａ）ＨＯ−、（２１ａ）置換されていてもよい低級アルキル−Ｏ−、（２２ａ）シクロアルキル−Ｏ−、（２３ａ）ヘテロ環基−Ｏ−、（２４ａ）ＨＳ−、（２５ａ）低級アルキル−Ｓ−、（２６ａ）シクロアルキル−Ｓ−、（２７ａ）シアノ、（２８ａ）ニトロ、（２９ａ）オキサイド、（３０ａ）ハロ、又は（３１ａ）置換されていてもよいヘテロ環基）、
−−−−−：単結合又は二重結合、
ｎ^１、ｎ^２、ｎ^３、ｎ^４、ｎ^５、及びｎ^６：同一又は異なって０又は１、但し、ｎ^１＋ｎ^２とｎ^４＋ｎ^５とは同一又は異なって０又は１）。
本発明においては、前記式（Ｉ−Ａ）中の記号Ｃｙ^１で示される基が、下記ｃ群から選択された置換基で置換されていてもよいアリール又は下記ｃ群から選択された置換基で置換されていてもよいヘテロアリールであることが好ましい。
［ｃ群：（１）低級アルキル、（２）シクロアルキル、（３）ハロ低級アルキル、（４）アリール−低級アルキル、（５）アリール、（６）ＨＯＯＣ−、（７）低級アルキル−Ｏ−ＣＯ−、（８）低級アルキル−ＣＯ−、（９）アリール−ＣＯ−、（１０）低級アルキル−ＳＯ_２−、（１１）Ｈ_２ＮＣＯ−、（１２）Ｈ_２ＮＳＯ_２−、（１３）低級アルキル−ＨＮＣＯ−、（１４）（低級アルキル）_２−ＮＣＯ−、（１５）低級アルキル−ＨＮＳＯ_２−、（１６）（低級アルキル）_２−ＮＳＯ_２−、（１７）ヘテロ環−ＣＯ−、（１８）Ｈ_２Ｎ−、（１９）低級アルキル−ＮＨ−、（２０）（低級アルキル）_２−Ｎ−、（２１）低級アルキル−ＣＯＮＨ−、（２２）低級アルキル−Ｏ−ＣＯＮＨ−、（２３）低級アルキル−ＳＯ_２ＮＨ−、（２４）ＨＯ−、（２５）低級アルキル−Ｏ−、（２６）シクロアルキル−低級アルキル−Ｏ−、（２７）アリール−低級アルキル−Ｏ−、（２８）メチレンジオキシ、（２９）エチレンジオキシ、（３０）１又は２個の低級アルキル基で置換されていてもヘテロ環、（３１）１又は２個のオキソ（＝Ｏ）で置換されていてもよいヘテロ環基、（３２）シアノ、（３３）ニトロ、（３４）オキソ（Ｏ＝）、（３５）ハロ］
また、本発明においては、前記式（Ｉ−Ａ）中の記号Ｒ^４及びＲ^５で示される基が、（１ｂ）下記ｄ群から選択された置換基で置換されていてもよい低級アルキル、（２ｂ）シクロアルキル、（３ｂ）下記ｄ群から選択された置換基で置換されていてもよいアリール、（４ｂ）低級アルキル−ＣＯ−、（５ｂ）ＨＯＯＣ−、（６ｂ）低級アルキル−Ｏ−ＣＯ−、（７ｂ）Ｈ_２ＮＣＯ−、（８ｂ）Ｈ_２ＮＳＯ_２−、（９ｂ）低級アルキル−ＮＨＣＯ−、（１０ｂ）低級アルキル−ＮＨＳＯ_２−、（１１ｂ）（低級アルキル）_２−ＮＣＯ−、（１２ｂ）（低級アルキル）_２−ＮＳＯ_２−、（１３ｂ）Ｈ_２Ｎ−、（１４ｂ）下記ｄ群から選択された置換基で置換されていてもよい低級アルキル−ＮＨ−、（１５ｂ）（下記ｄ群から選択された置換基で置換されていてもよい低級アルキル）_２−Ｎ−、（１６ｂ）下記ｄ群から選択された置換基で置換されていてもよいアリール−ＮＨ−、（１７ｂ）低級アルキル−ＣＯＮＨ−、（１８ｂ）低級アルキル−ＳＯ_２ＮＨ−、（１９ｂ）下記ｄ群から選択された置換基で置換されていてもよい低級アルキル−Ｏ−ＣＯＮＨ−、（２０ｂ）ＨＯ−、（２１ｂ）下記ｄ群から選択された置換基で置換されていてもよい低級アルキル−Ｏ−、（２２ｂ）シクロアルキル−Ｏ−、（２３ｂ）ヘテロ環基−Ｏ−、（２４ｂ）ＨＳ−、（２５ｂ）低級アルキル−Ｓ−、（２６ｂ）シクロアルキル−Ｓ−、（２７ｂ）シアノ、（２８ｂ）ニトロ、（２９ｂ）オキサイド、（３０ｂ）ハロ、又は（３１ｂ）下記ｄ群から選択された置換基で置換されていてもよいヘテロ環基であることが好ましい。
［ｄ群：（１）低級アルキル、（２）シクロアルキル、（３）ハロ低級アルキル、（４）アリール−低級アルキル、（５）アリール、（６）ＨＯＯＣ−、（７）低級アルキル−Ｏ−ＣＯ−、（８）低級アルキル−ＣＯ−、（９）低級アルキル−ＳＯ_２−、（１０）Ｈ_２ＮＣＯ−、（１１）Ｈ_２ＮＳＯ_２−、（１２）低級アルキル−ＨＮＣＯ−、（１３）（低級アルキル）_２−ＮＣＯ−、（１４）低級アルキル−ＨＮＳＯ_２−、（１５）（低級アルキル）_２−ＮＳＯ_２−、（１６）ヘテロ環−ＣＯ−、（１７）Ｈ_２Ｎ−、（１８）低級アルキル−ＮＨ−、（１９）（低級アルキル）_２−Ｎ−、（２０）低級アルキル−ＣＯＮＨ−、（２１）低級アルキル−Ｏ−ＣＯＮＨ−、（２２）低級アルキル−ＳＯ_２ＮＨ−、（２３）ＨＯ−、（２４）低級アルキル−Ｏ−、（２５）シクロアルキル−低級アルキル−Ｏ−、（２６）アリール−低級アルキル−Ｏ−、（２７）メチレンジオキシ、（２８）エチレンジオキシ、（２９）１又は２個の低級アルキル基で置換されていてもヘテロ環、（３０）１又は２個のオキソ（＝Ｏ）で置換されていてもよいヘテロ環基、（３１）シアノ、（３２）ニトロ、（３３）オキソ（Ｏ＝）、（３４）ハロ］
また、本発明においては、前記式（Ｉ−Ａ）中の記号Ｌ^１で示される基が、−ＮＲ^２ＣＯ−、−ＣＯＮＲ^２−、−ＮＲ^２ＳＯ_２−、又は−ＳＯ_２ＮＲ^２−であることが好ましい。
本発明のナトリウムチャネル阻害剤は、好ましくは、神経因性疼痛治療薬又は糖尿病性神経障害の疼痛治療薬である。
また、本発明によれば、ナトリウムチャネル阻害薬の製造のための上述のナトリウムチャネル阻害剤の有効成分であるピペリジン誘導体及びその製薬学的に許容される塩の使用が提供される。
また、本発明によれば、神経因性疼痛治療薬の製造のための上述のナトリウムチャネル阻害剤の有効成分であるピペリジン誘導体及びその製薬学的に許容される塩の使用が提供される。
また、本発明によれば、糖尿病性神経障害の疼痛治療薬の製造のための上述のナトリウムチャネル阻害剤の有効成分であるピペリジン誘導体及びその製薬学的に許容される塩の使用が提供される。
また、本発明によれば、上述のナトリウムチャネル阻害剤の有効成分であるピペリジン誘導体及びその製薬学的に許容される塩の治療有効量を患者に投与することを含む、ナトリウムチャネルに起因する疾患の治療方法が提供される。
また、本発明によれば、上述のナトリウムチャネル阻害剤の有効成分であるピペリジン誘導体及びその製薬学的に許容される塩の治療有効量を患者に投与することを含む、神経因性疼痛の治療方法が提供される。
また、本発明によれば、上述のナトリウムチャネル阻害剤の有効成分であるピペリジン誘導体及びその製薬学的に許容される塩の治療有効量を患者に投与することを含む、糖尿病性神経障害の疼痛の治療方法が提供される。
また、本発明によれば、下記式（Ｉ−Ｂ）で示されるピペリジン誘導体及びその製薬学的に許容される塩が提供される。
（式（Ｉ−Ｂ））

（上記式（Ｉ−Ｂ）中の記号は以下の意味を示す。
Ｃｙ^１：置換されていてもよいアリール又は置換されていてもよいヘテロ環、
Ｒ^１：Ｈ、ＯＨ、低級アルキル−Ｏ−又はハロ
（但し、上記式（Ｉ−Ｂ）において、ピペリジン環４位に、Ｃｙ^１−（Ｏ）ｎ^１−ＡＬＫ^１−（Ｏ）ｎ^２−で示される基が置換し、かつピペリジン環３位と４位との結合が二重結合である場合には、Ｒ^１は存在しない。）、
ＡＬＫ^１：低級アルキレン、低級アルケニレン、又は低級アルキニレン、
ＡＬＫ^２：低級アルキレン、
Ｌ^１：−ＮＲ^２ＣＯ−、−ＣＯＮＲ^２−、−ＣＯ−、−ＮＲ^２ＳＯ_２−、−ＳＯ_２ＮＲ^２−、−ＮＲ^２ＣＯＮＲ^３−又は−ＮＲ^２ＣＯＣＯ−で示される基、
Ｒ^２及びＲ^３：同一又は異なって、Ｈ、低級アルキル、低級アルケニル、（下記ａ群から選択される基で置換されていてもよいアリール）−低級アルキル、又は（下記ａ群から選択される基で置換されていてもよいヘテロアリール）−低級アルキル、
［ａ群：ハロ、ＨＯ−、低級アルキル−Ｏ−］
Ｌ^２：結合、−（Ｏ）ｎ^４−（下記ｂ群から選択される置換基で置換されていてもよい低級アルキレン）−（Ｏ）ｎ^５−、又は低級アルケニレン
［ｂ群：アリール、ＨＯ−、低級アルキル−Ｏ−］
Ｄ：Ｈ、又は下記に示される基
（基）

（上記基中の記号は以下の意味を示す。
Ｃｙ^２：ヘテロ環基又は炭化水素環基、
Ｒ^４及びＲ^５：同一又は異なって、（１ａ）置換されていてもよい低級アルキル、（２ａ）シクロアルキル、（３ａ）置換されていてもよいアリール、（４ａ）低級アルキル−ＣＯ−、（５ａ）ＨＯＯＣ−、（６ａ）低級アルキル−Ｏ−ＣＯ−、（７ａ）Ｈ_２ＮＣＯ−、（８ａ）Ｈ_２ＮＳＯ_２−、（９ａ）低級アルキル−ＮＨＣＯ−、（１０ａ）低級アルキル−ＮＨＳＯ_２−、（１１ａ）（低級アルキル）_２−ＮＣＯ−、（１２ａ）（低級アルキル）_２−ＮＳＯ_２−、（１３ａ）Ｈ_２Ｎ−、（１４ａ）置換されていてもよい低級アルキル−ＮＨ−、（１５ａ）（置換されていてもよい低級アルキル）_２−Ｎ−、（１６ａ）置換されていてもよいアリール−ＮＨ−、（１７ａ）低級アルキル−ＣＯＮＨ−、（１８ａ）低級アルキル−ＳＯ_２ＮＨ−、（１９ａ）置換されていてもよい低級アルキル−Ｏ−ＣＯＮＨ−、（２０ａ）ＨＯ−、（２１ａ）置換されていてもよい低級アルキル−Ｏ−、（２２ａ）シクロアルキル−Ｏ−、（２３ａ）ヘテロ環基−Ｏ−、（２４ａ）ＨＳ−、（２５ａ）低級アルキル−Ｓ−、（２６ａ）シクロアルキル−Ｓ−、（２７ａ）シアノ、（２８ａ）ニトロ、（２９ａ）オキサイド、（３０ａ）ハロ、又は（３１ａ）置換されていてもよいヘテロ環基）、
−−−−−：単結合又は二重結合、
ｎ^１、ｎ^２、ｎ^３、ｎ^４、ｎ^５、及びｎ^６：同一又は異なって０又は１、但し、ｎ^１＋ｎ^２とｎ^４＋ｎ^５とは同一又は異なって０又は１、
なお、上記式（Ｉ−Ｂ）中の記号は、下記（ｉ）〜（ｖｉｉ）に示す関係を満たす。
（ｉ）Ｃｙ^２がフェニルの場合、Ｃｙ^１はアリール、ＡＬＫ^１は炭素数２位以上の低級アルキレン、ｎ^１は０かつＲ^１はＨ、
（ｉｉ）Ｃｙ^２がアダマンタンの場合、ＡＬＫ^１は炭素数２位以上の低級アルキレン、
（ｉｉｉ）Ｃｙ^２がピリジン以外の単環式ヘテロ環の場合、ＡＬＫ^１は炭素数２位以上の低級アルキレン、
（ｉｖ）Ｃｙ^２が２環式ヘテロ環の場合、Ｃｙ^１はアリール又は置換されていてもよいヘテロ環、Ｌ^１は−ＮＲ^２ＣＯ−、−ＣＯ−、−ＮＲ^２ＳＯ_２−、−ＳＯ_２ＮＲ^２−、−ＮＲ^２ＣＯＮＲ^３−又は−ＮＲ^２ＣＯＣＯ−で示される基、
（ｖ）Ｌ^１が−ＮＲ^２ＳＯ_２−で示される基の場合、ｎ^１は０、
（ｖｉ）基−Ｌ^１−Ｌ^２−Ｄが−ＣＯＮＲ^２−低級アルキルの場合、ｎ^１は０、
（ｖｉｉ）Ｌ^１が−ＣＯ−で示される基の場合、Ｒ^１はＨ）
本発明においては、前記式（Ｉ−Ｂ）中の記号Ｃｙ^１で示される基が、下記ｃ群から選択された置換基で置換されていてもよいアリール又は下記ｃ群から選択された置換基で置換されていてもよいヘテロアリールであることが好ましい。
［ｃ群：（１）低級アルキル、（２）シクロアルキル、（３）ハロ低級アルキル、（４）アリール−低級アルキル、（５）アリール、（６）ＨＯＯＣ−、（７）低級アルキル−Ｏ−ＣＯ−、（８）低級アルキル−ＣＯ−、（９）アリール−ＣＯ−、（１０）低級アルキル−ＳＯ_２−、（１１）Ｈ_２ＮＣＯ−、（１２）Ｈ_２ＮＳＯ_２−、（１３）低級アルキル−ＨＮＣＯ−、（１４）（低級アルキル）_２−ＮＣＯ−、（１５）低級アルキル−ＨＮＳＯ_２−、（１６）（低級アルキル）_２−ＮＳＯ_２−、（１７）ヘテロ環−ＣＯ−、（１８）Ｈ_２Ｎ−、（１９）低級アルキル−ＮＨ−、（２０）（低級アルキル）_２−Ｎ−、（２１）低級アルキル−ＣＯＮＨ−、（２２）低級アルキル−Ｏ−ＣＯＮＨ−、（２３）低級アルキル−ＳＯ_２ＮＨ−、（２４）ＨＯ−、（２５）低級アルキル−Ｏ−、（２６）シクロアルキル−低級アルキル−Ｏ−、（２７）アリール−低級アルキル−Ｏ−、（２８）メチレンジオキシ、（２９）エチレンジオキシ、（３０）１又は２個の低級アルキル基で置換されていてもヘテロ環、（３１）１又は２個のオキソ（＝Ｏ）で置換されていてもよいヘテロ環基、（３２）シアノ、（３３）ニトロ、（３４）オキソ（Ｏ＝）、（３５）ハロ］
また、本発明においては、前記式（Ｉ−Ｂ）中の記号Ｒ^４及びＲ^５で示される基が、（１ｂ）下記ｄ群から選択された置換基で置換されていてもよい低級アルキル、（２ｂ）シクロアルキル、（３ｂ）下記ｄ群から選択された置換基で置換されていてもよいアリール、（４ｂ）低級アルキル−ＣＯ−、（５ｂ）ＨＯＯＣ−、（６ｂ）低級アルキル−Ｏ−ＣＯ−、（７ｂ）Ｈ_２ＮＣＯ−、（８ｂ）Ｈ_２ＮＳＯ_２−、（９ｂ）低級アルキル−ＮＨＣＯ−、（１０ｂ）低級アルキル−ＮＨＳＯ_２−、（１１ｂ）（低級アルキル）_２−ＮＣＯ−、（１２ｂ）（低級アルキル）_２−ＮＳＯ_２−、（１３ｂ）Ｈ_２Ｎ−、（１４ｂ）下記ｄ群から選択された置換基で置換されていてもよい低級アルキル−ＮＨ−、（１５ｂ）（下記ｄ群から選択された置換基で置換されていてもよい低級アルキル）_２−Ｎ−、（１６ｂ）下記ｄ群から選択された置換基で置換されていてもよいアリール−ＮＨ−、（１７ｂ）低級アルキル−ＣＯＮＨ−、（１８ｂ）低級アルキル−ＳＯ_２ＮＨ−、（１９ｂ）下記ｄ群から選択された置換基で置換されていてもよい低級アルキル−Ｏ−ＣＯＮＨ−、（２０ｂ）ＨＯ−、（２１ｂ）下記ｄ群から選択された置換基で置換されていてもよい低級アルキル−Ｏ−、（２２ｂ）シクロアルキル−Ｏ−、（２３ｂ）ヘテロ環基−Ｏ−、（２４ｂ）ＨＳ−、（２５ｂ）低級アルキル−Ｓ−、（２６ｂ）シクロアルキル−Ｓ−、（２７ｂ）シアノ、（２８ｂ）ニトロ、（２９ｂ）オキサイド、（３０ｂ）ハロ、又は（３１ｂ）下記ｄ群から選択された置換基で置換されていてもよいヘテロ環基であることが好ましい。
［ｄ群：（１）低級アルキル、（２）シクロアルキル、（３）ハロ低級アルキル、（４）アリール−低級アルキル、（５）アリール、（６）ＨＯＯＣ−、（７）低級アルキル−Ｏ−ＣＯ−、（８）低級アルキル−ＣＯ−、（９）低級アルキル−ＳＯ_２−、（１０）Ｈ_２ＮＣＯ−、（１１）Ｈ_２ＮＳＯ_２−（１２）低級アルキル−ＨＮＣＯ−、（１３）（低級アルキル）_２−ＮＣＯ−、（１４）低級アルキル−ＨＮＳＯ_２−、（１５）（低級アルキル）_２−ＮＳＯ_２−、（１６）ヘテロ環−ＣＯ−、（１７）Ｈ_２Ｎ−、（１８）低級アルキル−ＮＨ−、（１９）（低級アルキル）_２−Ｎ−、（２０）低級アルキル−ＣＯＮＨ−、（２１）低級アルキル−Ｏ−ＣＯＮＨ−、（２２）低級アルキル−ＳＯ_２ＮＨ−、（２３）ＨＯ−、（２４）低級アルキル−Ｏ−、（２５）シクロアルキル−低級アルキル−Ｏ−、（２６）アリール−低級アルキル−Ｏ−、（２７）メチレンジオキシ、（２８）エチレンジオキシ、（２９）１又は２個の低級アルキル基で置換されていてもヘテロ環、（３０）１又は２個のオキソ（＝Ｏ）で置換されていてもよいヘテロ環基、（３１）シアノ、（３２）ニトロ、（３３）オキソ（Ｏ＝）、（３４）ハロ］
また、本発明においては、前記式（Ｉ−Ｂ）中の記号Ｌ^１で示される基が、−ＮＲ^２ＣＯ−、−ＣＯＮＲ^２−、−ＮＲ^２ＳＯ_２−、又は−ＳＯ_２ＮＲ^２−であることが好ましい。
また、本発明においては、前記式（Ｉ−Ｂ）中の記号ＤにおけるＣｙ^２で示される基が、ヘテロ環基であることが好ましい。
また、本発明においては、前記式（Ｉ−Ｂ）で示されるピペリジン誘導体が、Ｎ−［２−（４−フェネチルピペリジノ）エチル］イソニコチンアミド、Ｎ−［２−（４−フェネチルピペリジノ）エチル］ピリジン−２−カルボキサミド、Ｎ−［２−（４−フェネチルピペリジノ）エチル］ニコチンアミド、４−イソプロポキシ−Ｎ−［２−（４−フェネチルピペリジノ）エチル］ニコチンアミド、３−メトキシ−Ｎ−［２−（４−フェネチルピペリジノ）エチル］イソニコチンアミド、Ｎ−［２−（４−フェネチルピペリジノ）エチル］ビシクロ［２．２．１］ヘプタン−２−カルボキサミド、Ｎ−（２−｛４−［（２−エチルフェノキシ）メチル］ピペリジノ｝エチル）−４−モルホリノニコチンアミド、Ｎ−（２−｛４−［（２−エチルフェノキシ）メチル］ピペリジノ｝エチル）−２−（３−ヒドロキシピロリジン−１−イル）イソニコチンアミド、２−メチル−Ｎ−［２−（４−フェネチルピペリジノ）エチル］イミダゾ［１，２−ａ］ピリジン−３−カルボキサミド、Ｎ−（２−｛４−［２−（２−メトキシフェニル）エチル］ピペリジノ｝エチル）ニコチンアミド、Ｎ−（２−｛４−［２−（２−メトキシフェニル）エチル］ピペリジノ｝エチル）−２−オキソ−１，２−ジヒドロイソニコチンアミド、Ｎ−（２−｛４−［２−（３−クロロフェニル）エチル］ピペリジノ｝エチル）ニコチンアミド、Ｎ−［２−（４−フェネチルピペリジノ）エチル］チオフェン−２−カルボキサミド、（Ｚ）−Ｎ−［２−（４−スチリルピペリジノ）エチル］ニコチンアミド、（Ｅ）−Ｎ−（２−｛４−［２−（２，６−ジメチルフェニル）ビニル］ピペリジノ｝エチル）ニコチンアミド、Ｎ−（２−｛４−［（２，６−ジメチルフェニル）エチニル］ピペリジノ｝エチル）ニコチンアミド、Ｎ−［２−（３−フェネチルピペリジノ）エチル］ニコチンアミド、Ｎ−［２−（４−フェネチルピペリジノ）エチル］ベンズアミド、Ｎ−ｔｅｒｔ−ブチル−３−（４−フェネチルピペリジノ）プロパンアミド、及びＮ−ベンジル−Ｎ−［２−（４−フェネチルピペリジノ）エチル］ニコチンアミドからなる群より選ばれる少なくとも一種の化合物であることが好ましい。
また、本発明においては、前記式（Ｉ−Ｂ）中の記号Ｃｙ^１で示される基が、下記ｅ群から選択された基であることが好ましい。
［ｅ群：（１）（ＣＮ，ハロ，ＮＯ_２，ヘテロ環，アルキル，ハロ−アルキル−，ＨＯ，シクロアルキル−アルキル−Ｏ−，アルキル−Ｏ−，ＨＯＯＣ，アルキル−Ｏ−ＣＯ−，Ｈ_２ＮＣＯ−，アルキル−Ｎ−ＣＯ−，ヘテロ環−ＣＯ−，アリール−ＣＯ−，Ｈ_２Ｎ，アルキル−Ｎ−，アルキルＣＯ−Ｎ−，又はアルキル−ＳＯ_２−Ｎ−）で置換されていてもよいアリール、（２）Ｎ，Ｓ，Ｏから選択された１以上の原子からなる架橋されていてもよい飽和ヘテロ環、（３）Ｎ，Ｓ，Ｏから選択された１以上の原子からなる不飽和ヘテロ環］
また、本発明においては、前記式（Ｉ−Ｂ）中の記号Ｃｙ^１で示される基が、下記ｆ群から選択された基であることが好ましい。
［ｆ群：（１）（ＣＮ，ハロ，ＮＯ_２，ヘテロ環，アルキル，ハロ−アルキル−，ＨＯ，シクロアルキル−アルキル−Ｏ−，アルキル−Ｏ−，ＨＯＯＣ，アルキル−Ｏ−ＣＯ−，Ｈ_２ＮＣＯ−，アルキル−Ｎ−ＣＯ−，ヘテロ環−ＣＯ−，アリール−ＣＯ−，Ｈ_２Ｎ，アルキル−Ｎ−，アルキルＣＯ−Ｎ−，アルキル−ＳＯ_２−Ｎ−）で置換されていてもよいフェニル，ナフチル、（２）オクタヒドロ−イソインドール，フラン，チオフェン，ベンゾフラン，ベンゾチオフェン，ベンゾチアゾール，キノリン，インドール，ベンゾイミダゾール，テトラゾール，１，３−ベンゾジオキソール（オキソ），イミダゾール，ピリジン］
また、本発明においては、前記式（Ｉ−Ｂ）中の記号Ｄで示される基が、下記ｇ群から選択された基であることが好ましい。
［ｇ群：（１）炭素数３〜１０個の架橋されていてもよい飽和炭素環、（２）不飽和炭素環、（３）Ｎ，Ｓ，Ｏから選択された１以上の原子からなる架橋されていてもよい飽和ヘテロ環、（４）Ｎ，Ｓ，Ｏから選択された１以上の原子からなる不飽和ヘテロ環］
また、本発明においては、前記式（Ｉ−Ｂ）中の記号Ｄで示される基が、下記ｈ群から選択された基であることが好ましい。
［ｈ群：（１）炭素数３〜１０の架橋されていてもよいシクロアルキル，フェニル，ナフチル，インデン、（２）モルホリン，ピロリジン，１−アザ−ビシクロ［２．２．１］ヘプタン，４，５，６，７−テトラヒドロ−１Ｈ−ベンズイミダゾール、（３）ピリジル，テトラゾリル，ピペリジン，トリアゾリル，ピラゾール，チオフェン，チアゾール，ピラジン，ベンゾイミダゾール，インドール，インダゾール，イミダゾ［１，２−ａ］ピリジン，フラン，キノリル，イソキノリル，ベンゾフラン，ベンゾ［ｂ］チオフェン，ピリミジン，イソオキサゾール］
また、本発明によれば、上述のピペリジン誘導体及びその製薬学的に許容される塩と製薬学的に許容される担体とを含有する医薬組成物が提供される。
以下、本発明の、前記式（Ｉ−Ａ）又は（Ｉ−Ｂ）で示されるピペリジン誘導体及びその製薬学的に許容される塩（以下、「本発明化合物」ということがある）並びにそれらを有効成分とするナトリウムチャネル阻害剤につき詳細に説明する。
［定義等］
本明細書中の構造式の定義において、特に断わらない限り「低級」なる用語は炭素数が１〜６個の直鎖又は分岐状の炭素鎖を意味する。
「低級アルキル」として、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ−ブチル、ｔｅｒｔ−ブチル、ペンチル、イソペンチル、ネオペンチル、ｔｅｒｔ−ペンチル、ヘキシル、イソヘキシル等のＣ_{１ −６}アルキルが挙げられ、好ましくは、メチル又はエチルである。
「低級アルケニル」として、例えば、ビニル、プロペニル、アリル、ブテニル、ペンテニル、ヘキセニル等のＣ_２−６アルケニルが挙げられ、好ましくは、ビニルである。
「低級アルキレン」として、例えば、メチレン、エチレン、トリメチレン、プロピレン、テトラメチレン、１，１−ジメチルエチレン、１，２−ジメチルエチレン等のＣ_１−６アルキレンが挙げられ、好ましくは、メチレン又はエチレンである。
「低級アルケニレン」として、例えば、ビニレン、プロペニレン、ブテニレン等のＣ_２−６アルケニレンが挙げられ、好ましくは、ビニレンである。
「低級アルキニレン」として、例えば、エチニレン、プロピニレン、ブチニレン等のＣ_２−６アルキニレンが挙げられ、好ましくは、エチニレンである。
「アリール」とは、炭素数が６〜１４個の１〜３環系芳香族炭化水素環基を意味し、例えば、フェニル、ナフチル、アントリル、フェナントリル等が挙げられ、好ましくは、フェニル又はナフチルである。
「シクロアルキル」とは、架橋されていてもよい炭素数が３〜１４個の１〜３環系脂肪族飽和炭化水素環基を意味し、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、ビシクロヘプチル、ビシクロオクチル、ビシクロノニル、ビシクロデカニル、トリシクロノニル、トリシクロデカニル（アダマンチル等）、トリシクロウンデカニル、トリシクロドデカニル等が挙げられ、好ましくは、シクロペンチル、シクロヘキシル、シクロヘプチル、ビシクロヘプチル、又はトリシクロデカニルである。
「シクロアルケニル」とは、上記シクロアルキル基の１〜３個の任意の単結合が２重結合になった不飽和脂肪族炭化水素環基を意味し、例えば、シクロブテニル、シクロペンテニル、シクロヘキセニル、シクロヘプテニル、シクロオクテニル等が挙げられる。
「炭化水素環基」とは、上記シクロアルキル、シクロアルケニル若しくはアリール、又はそれらの縮合環基若しくはスピロ環基を意味し、上記アリール及びシクロアルキルの説明にて記載した縮合環基以外の縮合環基として、例えば、インダニル、インデニル、テトラヒドロナフチル等が挙げられる。炭化水素環基は、好ましくは、シクロペンチル、シクロヘキシル、シクロヘプチル、ビシクロヘプチル、トリシクロデカニル、フェニル、ナフチル、又はインデニルである。
「含酸素ヘテロシクロアルキル」とは、上記シクロアルキルの任意の１又は２個の炭素原子が、酸素原子に置換されたものを意味し、例えば、オキシラニル、オキセタニル、テトラヒドロフリル、テトラヒドロピラニル、ジオキサニル等が挙げられる。
「ヘテロシクロアルキル」とは、上記シクロアルキルの任意の１〜３個の炭素原子が、窒素、酸素、及び硫黄原子からなる群より選ばれる１〜３種のヘテロ原子に置換されたもの又は架橋されたものを意味し、例えば、アジリジニル、オキシラニル、アゼチジニル、オキセタニル、ピロリジル、テトラヒドロフリル、テトラヒドロチエニル、ピペリジル、ピペラジル、テトラヒドロピラニル、テトラヒドロチオピラニル、モルホリニル、チオモルホリニル、アザビシクロヘプチル、ジアザビシクロヘプチル、アザビシクロオクチル等が挙げられる。
「ヘテロシクロアルケニル」とは、上記シクロアルケニルの任意の１〜３個の炭素原子が、窒素、酸素、及び硫黄原子からなる群より選ばれる１〜３種のヘテロ原子に置換されたものを意味し、例えば、ピロリニル、ジヒドロフリル、ジヒドロチエニル、ジヒドロピリジル、テトラヒドロピリジル、ジヒドロピラニル、ジヒドロチオピラニル等が挙げられる。
「ヘテロアリール」とは、窒素、酸素、及び硫黄原子からなる群より選ばれる１〜３種のヘテロ原子を１〜３個有する、原子数が５〜１４個の１〜３環系ヘテロアリールを意味し、例えば、ピロリル、イミダゾリル、ピラゾリル、トリアゾリル、テトラゾリル、フリル、オキサゾリル、チエニル、チアゾリル、ピリジル、ピリダジル、ピリミジル、ピラジル、トリアジル、インドリル、イソインドリル、ベンズイミダゾリル、ベンゾピラゾリル、ピロロピリジル、イミダゾピリジル、ベンゾフリル、ベンゾチエニル、キノリル、イソキノリル、キノキサリル、フロピリジル、チエノピリジル等が挙げられ、好ましくは、ピリジルである。
「ヘテロ環基」とは、上記ヘテロシクロアルキル、ヘテロシクロアルケニル若しくはヘテロアリール、又はそれらの縮合環基若しくはスピロ環基、或いはこの縮合環基又はスピロ環基と炭化水素環基とが縮合環又はスピロ環を形成した基を意味し、上記ヘテロシクロアルキル及びヘテロアリールの説明にて記載した縮合環基以外の縮合環基として、例えば、ジヒドロイソインドリル、オクタヒドロイソインドリル、テトラヒドロベンズイミダゾリル等が挙げられる。ヘテロ環基は、好ましくは、ヘテロアリールである。
「ハロ」としては、フルオロ、クロロ、ブロモ、ヨードが挙げられ、好ましくは、フルオロ又はクロロである。
「置換されていてもよい」とは、１〜３種の置換基１〜４個で置換されていてもよいことを意味し、その置換基として、例えば、（１）低級アルキル、（２）シクロアルキル、（３）ハロ低級アルキル、（４）アリール−低級アルキル、（５）アリール、（６）ＨＯＯＣ−、（７）低級アルキル−Ｏ−ＣＯ−、（８）低級アルキル−ＣＯ−、（９）アリール−ＣＯ−、（１０）低級アルキル−ＳＯ_２−、（１１）Ｈ_２ＮＣＯ−、（１２）Ｈ_２ＮＳＯ_２−、（１３）低級アルキル−ＨＮＣＯ−、（１４）（低級アルキル）_２−ＮＣＯ−、（１５）低級アルキル−ＨＮＳＯ_２−、（１６）（低級アルキル）_２−ＮＳＯ_２−、（１７）ヘテロ環−ＣＯ−、（１８）Ｈ_２Ｎ−、（１９）低級アルキル−ＮＨ−、（２０）（低級アルキル）_２−Ｎ−、（２１）低級アルキル−ＣＯＮＨ−、（２２）低級アルキル−Ｏ−ＣＯＮＨ−、（２３）低級アルキル−ＳＯ_２ＮＨ−、（２４）ＨＯ−、（２５）低級アルキル−Ｏ−、（２６）シクロアルキル−低級アルキル−Ｏ−、（２７）アリール−低級アルキル−Ｏ−、（２８）メチレンジオキシ、（２９）エチレンジオキシ、（３０）１又は２個の低級アルキル基で置換されていてもヘテロ環、（３１）１又は２個のオキソ（＝Ｏ）で置換されていてもよいヘテロ環基、（３２）シアノ、（３３）ニトロ、（３４）オキソ（Ｏ＝）、（３５）ハロ等が挙げられる。
「ハロ低級アルキル」とは、１又は２種の上記ハロ１〜３個に置換された上記低級アルキルを意味し、例えば、トリフルオロメチル、トリフルオロエチル、トリクロロメチル、トリクロロエチル等が挙げられる。
本発明化合物は、置換基の種類によっては光学異性体（光学活性体、ジアステレオマー等）又は幾何異性体が存在する。従って本発明化合物には、これらの光学異性体又は幾何異性体の混合物や単離されたものも含まれる。
また、本発明化合物は酸付加塩又は塩基との塩を形成することができる。例えば、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸等の無機酸；ギ酸、酢酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フマール酸、マレイン酸、乳酸、リンゴ酸、クエン酸、酒石酸、炭酸、ピクリン酸、メタンスルホン酸、エタンスルホン酸、グルタミン酸等の有機酸との酸付加塩；ナトリウム、カリウム、マグネシウム、カルシウム、アルミニウム等の無機塩基；メチルアミン、エチルアミン、モノエタノールアミン、ジエタノールアミン、トリエタノールアミン、シクロヘキシルアミン、リジン、オルニチン等の有機塩基との塩を挙げることができる。さらに、本発明化合物及びその製薬学的に許容されるその塩は、水和物、エタノール等の溶媒和物や結晶多形を形成することができる。
さらに、本発明化合物には、生体内において代謝されて本発明化合物及びその製薬学的に許容される塩に変換される化合物、いわゆるプロドラッグもすべて含まれる。本発明化合物のプロドラッグを形成する基としては、Ｐｒｏｇ．Ｍｅｄ．５：２１５７−２１６１（１９８５）に記載されている基や、広川書店１９９０年刊「医薬品の開発」第７巻分子設計１６３〜１９８に記載されている基が挙げられる。具体的には、加水分解、加溶媒分解により、又は生理学的条件の下で本発明化合物の１級アミン又は２級アミン、ＨＯ−、ＨＯＣ（＝Ｏ）−等に変換できる基であり、例えば、ＨＯ−のプロドラッグとしては、置換されてもよい低級アルキル−ＣＯＯ−、置換されてもよいアリール−ＣＯＯ−、ＲＯ−ＣＯ−置換されてもよい低級アルキレン−ＣＯＯ−（ＲはＨ−又は低級アルキルを示す。以下同様）、ＲＯ−ＣＯ−置換されてもよい低級アルケニレン−ＣＯＯ−、ＲＯ−ＣＯ−低級アルキレン−Ｏ−低級アルキレン−Ｃ−ＯＯ−、ＲＯ−ＣＯ−ＣＯＯ−、ＲＯＳＯ_２−置換されてもよい低級アルケニレン−ＣＯＯ−、フタリジル−Ｏ−、５−メチル−１，３−ジオキソレン−２−オン−４−イル−メチルオキシ等が挙げられる。
［製造法］
本発明化合物は、その基本骨格或いは置換基の種類に基づく特徴を利用し、種々の合成法を適用して製造することができる。以下にその代表的な化合物（Ｉａ）〜（Ｉｅ）の製造法について説明する。
（第一製法）
本発明化合物（Ｉａ）は、文献公知の製法により又は下記反応式に示すように、常法による化合物（Ｖ）と化合物（ＶＩ）とのアミド化反応により製造することができる。本反応は、例えば、カルボジイミド等の縮合剤を用いて行うことができる。所望により、１−ヒドロキシベンゾトリアゾール等の触媒を用いてもよい。また、本反応は、化合物（ＶＩ）を対応する酸クロライド、酸ブロマイド、又は酸無水物に変換した後、化合物（Ｖ）と反応させてもよい。この際所望により、トリエチルアミン等の塩基を用いてもよい。反応溶媒としては、例えば、Ｎ，Ｎ−ジメチルホルムアミド、テトラヒドロフラン、ジオキサン等を用いることができ、反応温度は、冷却から加熱下までの間のいずれかの温度である。
化合物（Ｖ）は、化合物（ＩＩ）を化合物（ＩＩＩ）を用い常法によりアルキル化を行い、その後Ｙをアミノに変換することにより得ることができる。アルキル化反応は、例えば、Ｎ，Ｎ−ジメチルホルムアミド、テトラヒドロフラン、又はジオキサン等を溶媒として、冷却から加熱下までの間のいずれかの温度で行うことができる。所望により、炭酸カリウム又は水素化ナトリウム等の塩基を用いてもよい。Ｙのアミノへの変換は、例えば、Ｙがシアノの場合は還元により、Ｙが保護されたアミノの場合は通常の脱保護（Ｐｒｏｔｅｃｔｉｖｅ ｇｒｏｕｐｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｓｅｓｉｓ，（ｓｅｃｏｎｄ ｅｄ．ｏｒ ｔｈｉｒｄ ｅｄ．，ＪＯＨＮ ＷＩＬＥＹ ＆ ＳＯＮＳ，ＩＮＣ．）により化合物（Ｖ）を製造することができる。
また、本発明化合物（Ｉｄ）は、下記反応式に示すように、上記アルキル化と同様の方法で、化合物（ＩＩ）と化合物（ＩＸ）とのアルキル化反応により製造することができる。
（反応式）

又は、
（反応式）

（上記反応式中、Ｙは、アシル又はフタイロイル等で保護されたアミノ又はシアノ等の容易にアミノに変換できる基を意味する。Ｘは、ハロ、メシルオキシ又はトシルオキシ等の脱離基を意味する。以下、同様である。）
（第二製法）
本発明化合物（Ｉｂ）は、下記反応式に示すように、化合物（ＩＩ）と化合物（ＶＩＩ）との還元的アミノ化反応により製造することができる。本反応は、例えば、酢酸等を溶媒とした酸性条件下、トリアセトキシ水素化ホウ素ナトリウム等の還元剤を用いて行うことができる。また、本反応は、冷却から室温下までの間のいずれかの温度で行うことができる。
（反応式）

（上記反応式中、ＡＬＫ^３はＡＬＫ^２より炭素数が１つ少ない低級アルキレンを意味する。以下同様である。）
（第三製法）
本発明化合物（Ｉｃ）は、下記反応式に示すように、化合物（ＩＩ）と化合物（ＶＩＩＩ）とのマイケル付加反応により製造することができる。本反応は、例えば、トルエン、Ｎ，Ｎ−ジメチルホルムアミド、又はジオキサン等を溶媒として、室温から加熱下までの間のいずれかの温度で行うことができる。
（反応式）

（第四製法）
本発明化合物（Ｉｅ）は、下記反応式に示すように、化合物（Ｖ）とイソシアネート誘導体（Ｘ）との反応により製造することができる。本反応は、反応溶媒として、例えば、トルエン、テトラヒドロフラン、ジオキサン等を用いることができる。また、本反応は、冷却から加熱下までの間のいずれかの温度で行うことができる。イソシアネート誘導体（Ｘ）は、対応するカルボン酸とリン酸アジド等の酸アジドとを反応させるクルチウス（Ｃｕｒｔｉｕｓ）転移により容易に製造することができる。
（反応式）

このように製造された本発明化合物は、アルキル化、置換、還元、酸化等の反応に付すことにより、別の誘導体に容易に導くことができる。
［原料合成］
本発明化合物の原料化合物は、特許文献４（欧州特許公開第１２５４９０４号公報）、Ｊ．Ｏｒｇ．Ｃｈｅｍ．，２２，１３７６（１９５７）、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，４２，２０８７（１９９９）、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，４１，６０２５（２０００）、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，３６，３４６５（１９９５）等に記載された合成法に準じて製造することができる。
例えば、化合物（ＩＩａ）は、下記反応式に示すように、上記と同様に化合物（ＸＩＶ）又は（ＸＶＩ）のアミノの保護基を脱保護することにより製造することができる。化合物（ＸＩＶ）は、化合物（ＸＩ）を塩基性条件下アセチレン誘導体（ＸＩＩ）と反応させ、その後脱水を行うことで製造することができる。また、化合物（ＸＶＩ）は、化合物（ＸＶ）をウィッティッヒ（Ｗｉｔｔｉｇ）反応に付すことで得ることができる。さらに、化合物（ＩＩａ）は、化合物（ＸＩＶ）又は（ＸＶＩ）を還元後、アミノの保護基を脱保護することにより製造することができる。
さらに、同様な方法により化合物（ＩＩａ）の位置異性体も製造することができる。
化合物（ＩＩ）中の記号ｎ^１及びｎ^２の何れかが１の場合は、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，４２，２０８７（１９９９）、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，４１，６０２５（２０００）、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，３６，３４６５（１９９５）に記載された方法に準じて、容易に製造することができる。
（反応式）

（上記反応式中、Ｚは、アミノの保護基を意味する。以下同様である。）
このようにして製造された本発明化合物は遊離のまま、或いはその塩として単離される。本発明化合物の塩は遊離の塩基である本発明化合物に通常の造塩反応を付すことにより製造することができる。
また、本発明化合物及びその塩は、その水和物、その溶媒和物、或いは、結晶多形の物質として単離精製される。単離精製は、抽出、濃縮、留去、結晶化、濾過、再結晶、各種クロマトグラフィー等の通常の化学操作を適用して行われる。
各種の異性体は、適当な原料化合物を選択することにより、或いは異性体間の物理的性質の差を利用して分離することができる。例えば、光学異性体は、適当な原料を選択することにより、或いは、ラセミ化合物のラセミ分割法（例えば、一般的な光学活性な酸とのジアステレオマー塩に導き、光学分割する方法等）により立体化学的に純粋な異性体に導くことができる。
［処方］
本発明化合物は、一般的に用いられている種々の処方を適用できる。以下にその代表的な処方について説明する。
本発明化合物及び製薬学的に許容されるその塩の１又は２種以上を有効成分として含有する医薬組成物は、製薬学的に許容される担体を含むことができ、通常、製剤化に用いられる担体や賦形剤、その他の添加剤を用いて、錠剤、散剤、細粒剤、顆粒剤、カプセル剤、丸剤、液剤、注射剤、座剤、軟膏、貼付剤等に調製され、経口的（舌下投与を含む）又は非経口的に投与される。
本発明化合物及び製薬学的に許容されるその塩のヒトに対する臨床投与量は適用される患者の症状、体重、年齢、性別、投与ルート等を考慮して個々の場合に応じて適宜決定されるが、通常、成人１人当たり、１日につき１ｍｇ〜１０００ｍｇ、好ましくは、１０ｍｇ〜２００ｍｇの範囲で１日１回から数回に分け経口投与されるか、成人１人当たり、１日につき１ｍｇ〜５００ｍｇの範囲で、１日１回から数回に分け静脈内投与されるか、又は、１日１時間〜２４時間の範囲で静脈内持続投与される。もちろん、前述のように、投与量は種々の条件で変動するので、上記投与量より少ない量で十分な場合もある。
本発明による経口投与のための固体組成物としては、錠剤、散剤、顆粒剤等が用いられる。このような固体組成物においては、１つ又はそれ以上の活性物質が、少なくとも１つの不活性な希釈剤、例えば、乳糖、マンニトール、ブドウ糖、ヒドロキシプロピルセルロース、微結晶セルロース、デンプン、ポリビニルピロリドン、メタケイ酸アルミン酸マグネシウムと混合される。組成物は、常法に従って、不活性な希釈剤以外の添加剤、例えば、ステアリン酸マグネシウム等の滑沢剤；デンプン、繊維素グリコール酸カルシウム等の崩壊剤；ラクトース等の安定化剤；グルタミン酸又はアスパラギン酸等の溶解補助剤を含有していてもよい。錠剤又は丸剤は、必要により、ショ糖、ゼラチン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロースフタレート等の糖衣又は胃溶性若しくは腸溶性のフィルムで被膜してもよい。
経口投与のための液体組成物は、製薬学的に許容される乳濁剤、溶液剤、懸濁剤、シロップ剤、エリキシル剤等を含み、一般的に用いられる不活性な希釈剤、例えば、精製水、エタノール等を含む。この組成物は不活性な希釈剤以外に、可溶化又は溶解補助剤、湿潤剤、懸濁剤等の補助剤、甘味剤、風味剤、芳香剤、防腐剤等を含んでいてもよい。
非経口投与のための注射剤は、無菌の水性又は非水性の溶液剤、懸濁剤、乳濁剤を含む。水性の溶液剤、懸濁剤は、例えば、注射剤用蒸留水、生理食塩水を含む。非水溶性の溶液剤、懸濁剤としては、例えば、プロピレングリコール、ポリエチレングリコール、オリーブ油等の植物油；エタノール等のアルコール類；ポリソルベート８０（商品名）等がある。このような組成物は、さらに、等張化剤、防腐剤、湿潤剤、乳化剤、分散剤、安定化剤（例えば、ラクトース）、可溶化、溶解補助剤等の添加剤を含んでもよい。これらは、例えば、バクテリア保留フィルターを通す濾過、殺菌剤の配合、又は照射によって無菌化される。これらはまた、無菌の固体組成物を製造し、使用前に、無菌水又は無菌の注射溶媒に溶解して使用することもできる。
さらに、本発明化合物は、上記疾患の治療剤又はナトリウムチャネル阻害剤以外の機序で疼痛に有効な薬剤と共に使用してもよい。併用可能な疼痛に有効な薬剤として、麻薬性鎮痛薬、解熱性鎮痛薬、非ステロイド抗炎症薬等が挙げられる。  The object of the present invention is to use a piperidine derivative and a pharmaceutically acceptable salt thereof as an active ingredient, particularly a sodium channel inhibitor having an analgesic effect on neuropathic pain, and a piperidine derivative and a pharmaceutically acceptable salt thereof. It is to provide an acceptable salt.
  In order to achieve the above object, the present inventors have conducted extensive research on piperidine derivatives. As a result, piperidine derivatives in which the nitrogen atom substituent of piperidine has an amide, sulfonamide, urea or carbonyl structure, and pharmaceutically The present invention was completed by finding that an acceptable salt has a strong inhibitory activity on sodium channels and has a useful action in streptozotocin-induced diabetic neuropathy mice and L5 / L6 spinal nerve ligation rats, which are pathological animal models. I let you.
  According to the present invention, a sodium channel inhibitor containing the following piperidine derivatives and pharmaceutically acceptable salts thereof as active ingredients, and piperidine derivatives and pharmaceutically acceptable salts thereof are provided. That is,
  A sodium channel inhibitor containing a piperidine derivative represented by the following formula (IA) and a pharmaceutically acceptable salt thereof as an active ingredient.
(Formula (IA))

(The symbols in the above formula (IA) have the following meanings.
Cy¹: Aryl which may be substituted or heterocycle which may be substituted,
R¹: H, OH, lower alkyl-O- or halo
(However, in the above formula (IA), at the 4-position of the piperidine ring, Cy is¹-(O) n¹-ALK¹-(O) n²When the group represented by-is substituted and the bond between the 3-position and 4-position of the piperidine ring is a double bond, R¹Does not exist. ),
ALK¹: Lower alkylene, lower alkenylene, or lower alkynylene,
ALK²: Lower alkylene,
L¹: -NR²CO-, -CONR²-, -CO-, -NR²SO₂-, -SO₂NR²-, -NR²CONR³-Or-NR²A group represented by COCO-;
R²And R³: The same or different, H, lower alkyl, lower alkenyl, (aryl optionally substituted with a group selected from group a below) -lower alkyl, or (substituted with a group selected from group a below) Optionally heteroaryl) -lower alkyl,
[Group a: halo, HO-, lower alkyl-O-]
L²: Bond,-(O) n⁴-(Lower alkylene optionally substituted with a substituent selected from group b below)-(O) n⁵-Or lower alkenylene
[Group b: aryl, HO-, lower alkyl-O-]
D: H or a group shown below
(Base)

(The symbols in the above groups have the following meanings.
Cy²: Heterocyclic group or hydrocarbon ring group,
R⁴And R⁵: (1a) optionally substituted lower alkyl, (2a) cycloalkyl, (3a) optionally substituted aryl, (4a) lower alkyl-CO-, (5a) HOOC-, (6a) Lower alkyl-O—CO—, (7a) H₂NCO-, (8a) H₂NSO₂-, (9a) lower alkyl-NHCO-, (10a) lower alkyl-NHSO₂-, (11a) (lower alkyl)₂-NCO-, (12a) (lower alkyl)₂-NSO₂-, (13a) H₂N-, (14a) optionally substituted lower alkyl-NH-, (15a) (optionally substituted lower alkyl)₂-N-, (16a) optionally substituted aryl-NH-, (17a) lower alkyl-CONH-, (18a) lower alkyl-SO₂NH-, (19a) optionally substituted lower alkyl-O-CONH-, (20a) HO-, (21a) optionally substituted lower alkyl-O-, (22a) cycloalkyl-O-, (23a) heterocyclic group -O-, (24a) HS-, (25a) lower alkyl-S-, (26a) cycloalkyl-S-, (27a) cyano, (28a) nitro, (29a) oxide, ( 30a) halo, or (31a) an optionally substituted heterocyclic group),
------: Single bond or double bond,
n¹, N², N³, N⁴, N⁵And n⁶: Same or different, 0 or 1, provided that n¹+ N²And n⁴+ N⁵Is the same or different from 0 or 1).
  In the present invention, the symbol Cy in the formula (IA)¹Is preferably an aryl optionally substituted with a substituent selected from the following group c or a heteroaryl optionally substituted with a substituent selected from the following group c.
[Group c: (1) lower alkyl, (2) cycloalkyl, (3) halo lower alkyl, (4) aryl-lower alkyl, (5) aryl, (6) HOOC-, (7) lower alkyl-O- CO-, (8) lower alkyl-CO-, (9) aryl-CO-, (10) lower alkyl-SO₂-, (11) H₂NCO-, (12) H₂NSO₂-, (13) lower alkyl-HNCO-, (14) (lower alkyl)₂-NCO-, (15) lower alkyl-HNSO₂-, (16) (lower alkyl)₂-NSO₂-, (17) Heterocyclic -CO-, (18) H₂N-, (19) lower alkyl-NH-, (20) (lower alkyl)₂-N-, (21) lower alkyl-CONH-, (22) lower alkyl-O-CONH-, (23) lower alkyl-SO₂NH-, (24) HO-, (25) lower alkyl-O-, (26) cycloalkyl-lower alkyl-O-, (27) aryl-lower alkyl-O-, (28) methylenedioxy, (29 ) Ethylenedioxy, (30) a heterocyclic group which may be substituted with 1 or 2 lower alkyl groups, (31) a heterocyclic group which may be substituted with 1 or 2 oxo (═O), ( 32) Cyano, (33) Nitro, (34) Oxo (O =), (35) Halo]
  In the present invention, the symbol R in the formula (IA)⁴And R⁵(1b) lower alkyl optionally substituted with a substituent selected from the following d group, (2b) cycloalkyl, (3b) substituted with a substituent selected from the following d group Aryl, (4b) lower alkyl-CO-, (5b) HOOC-, (6b) lower alkyl-O-CO-, (7b) H₂NCO-, (8b) H₂NSO₂-, (9b) lower alkyl-NHCO-, (10b) lower alkyl-NHSO₂-, (11b) (lower alkyl)₂-NCO-, (12b) (lower alkyl)₂-NSO₂-, (13b) H₂N-, (14b) Lower alkyl-NH- which may be substituted with a substituent selected from the following group d, (15b) (Lower alkyl optionally substituted with a substituent selected from group d below) )₂-N-, (16b) aryl-NH-, which may be substituted with a substituent selected from the following group d, (17b) lower alkyl-CONH-, (18b) lower alkyl-SO₂NH-, (19b) Lower alkyl-O-CONH- which may be substituted with a substituent selected from the following group d, (20b) HO-, (21b) Substituted with a substituent selected from the following group d Lower alkyl-O-, (22b) cycloalkyl-O-, (23b) heterocyclic group -O-, (24b) HS-, (25b) lower alkyl-S-, (26b) cycloalkyl -S-, (27b) cyano, (28b) nitro, (29b) oxide, (30b) halo, or (31b) a heterocyclic group optionally substituted with a substituent selected from the following group d. Is preferred.
[Group d: (1) lower alkyl, (2) cycloalkyl, (3) halo lower alkyl, (4) aryl-lower alkyl, (5) aryl, (6) HOOC-, (7) lower alkyl-O- CO-, (8) lower alkyl-CO-, (9) lower alkyl-SO₂-, (10) H₂NCO-, (11) H₂NSO₂-, (12) lower alkyl-HNCO-, (13) (lower alkyl)₂-NCO-, (14) lower alkyl-HNSO₂-, (15) (lower alkyl)₂-NSO₂-, (16) heterocycle -CO-, (17) H₂N-, (18) lower alkyl-NH-, (19) (lower alkyl)₂-N-, (20) lower alkyl-CONH-, (21) lower alkyl-O-CONH-, (22) lower alkyl-SO₂NH-, (23) HO-, (24) lower alkyl-O-, (25) cycloalkyl-lower alkyl-O-, (26) aryl-lower alkyl-O-, (27) methylenedioxy, (28 ) Ethylenedioxy, (29) a heterocyclic group which may be substituted with 1 or 2 lower alkyl groups, (30) a heterocyclic group which may be substituted with 1 or 2 oxo (═O), ( 31) Cyano, (32) Nitro, (33) Oxo (O =), (34) Halo]
  In the present invention, the symbol L in the formula (IA)¹Is a group represented by —NR²CO-, -CONR²-, -NR²SO₂-Or -SO₂NR²-Is preferred.
  The sodium channel inhibitor of the present invention is preferably a neuropathic pain therapeutic agent or a pain therapeutic agent for diabetic neuropathy.
  Moreover, according to this invention, use of the piperidine derivative which is an active ingredient of the above-mentioned sodium channel inhibitor for manufacture of a sodium channel inhibitor, and its pharmaceutically acceptable salt is provided.
  In addition, according to the present invention, there is provided use of a piperidine derivative which is an active ingredient of the above-mentioned sodium channel inhibitor and a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for neuropathic pain.
  Further, according to the present invention, there is provided use of a piperidine derivative which is an active ingredient of the above-mentioned sodium channel inhibitor and a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for diabetic neuropathy pain. .
  Further, according to the present invention, a disease caused by a sodium channel, comprising administering to a patient a therapeutically effective amount of a piperidine derivative which is an active ingredient of the above-mentioned sodium channel inhibitor and a pharmaceutically acceptable salt thereof. A method of treatment is provided.
  In addition, according to the present invention, treatment of neuropathic pain comprising administering to a patient a therapeutically effective amount of a piperidine derivative that is an active ingredient of the above-mentioned sodium channel inhibitor and a pharmaceutically acceptable salt thereof. A method is provided.
  Further, according to the present invention, pain in diabetic neuropathy comprising administering to a patient a therapeutically effective amount of a piperidine derivative that is an active ingredient of the above-mentioned sodium channel inhibitor and a pharmaceutically acceptable salt thereof. A method of treatment is provided.
  The present invention also provides a piperidine derivative represented by the following formula (IB) and a pharmaceutically acceptable salt thereof.
(Formula (IB))

(The symbols in the above formula (IB) have the following meanings.
Cy¹: Aryl which may be substituted or heterocycle which may be substituted,
R¹: H, OH, lower alkyl-O- or halo
(However, in the above formula (IB), the 4-position of the piperidine ring has Cy¹-(O) n¹-ALK¹-(O) n²When the group represented by-is substituted and the bond between the 3-position and 4-position of the piperidine ring is a double bond, R¹Does not exist. ),
ALK¹: Lower alkylene, lower alkenylene, or lower alkynylene,
ALK²: Lower alkylene,
L¹: -NR²CO-, -CONR²-, -CO-, -NR²SO₂-, -SO₂NR²-, -NR²CONR³-Or-NR²A group represented by COCO-;
R²And R³: The same or different, H, lower alkyl, lower alkenyl, (aryl optionally substituted with a group selected from group a below) -lower alkyl, or (substituted with a group selected from group a below) Optionally heteroaryl) -lower alkyl,
[Group a: halo, HO-, lower alkyl-O-]
L²: Bond,-(O) n⁴-(Lower alkylene optionally substituted with a substituent selected from group b below)-(O) n⁵-Or lower alkenylene
[Group b: aryl, HO-, lower alkyl-O-]
D: H or a group shown below
(Base)

(The symbols in the above groups have the following meanings.
Cy²: Heterocyclic group or hydrocarbon ring group,
R⁴And R⁵: (1a) optionally substituted lower alkyl, (2a) cycloalkyl, (3a) optionally substituted aryl, (4a) lower alkyl-CO-, (5a) HOOC-, (6a) Lower alkyl-O—CO—, (7a) H₂NCO-, (8a) H₂NSO₂-, (9a) lower alkyl-NHCO-, (10a) lower alkyl-NHSO₂-, (11a) (lower alkyl)₂-NCO-, (12a) (lower alkyl)₂-NSO₂-, (13a) H₂N-, (14a) optionally substituted lower alkyl-NH-, (15a) (optionally substituted lower alkyl)₂-N-, (16a) optionally substituted aryl-NH-, (17a) lower alkyl-CONH-, (18a) lower alkyl-SO₂NH-, (19a) optionally substituted lower alkyl-O-CONH-, (20a) HO-, (21a) optionally substituted lower alkyl-O-, (22a) cycloalkyl-O-, (23a) heterocyclic group -O-, (24a) HS-, (25a) lower alkyl-S-, (26a) cycloalkyl-S-, (27a) cyano, (28a) nitro, (29a) oxide, ( 30a) halo, or (31a) an optionally substituted heterocyclic group),
------: Single bond or double bond,
n¹, N², N³, N⁴, N⁵And n⁶: Same or different, 0 or 1, provided that n¹+ N²And n⁴+ N⁵Is the same or different from 0 or 1,
  In addition, the symbol in the said formula (IB) satisfy | fills the relationship shown to following (i)-(vii).
(I) Cy²Cy is phenyl¹Is aryl, ALK¹Is lower alkylene having 2 or more carbon atoms, n¹Is 0 and R¹Is H,
(Ii) Cy²If is adamantane, ALK¹Is lower alkylene having 2 or more carbon atoms,
(Iii) Cy²When A is a monocyclic hetero ring other than pyridine, ALK¹Is lower alkylene having 2 or more carbon atoms,
(Iv) Cy²Cy is a bicyclic heterocycle¹Is aryl or an optionally substituted heterocycle, L¹Is -NR²CO-, -CO-, -NR²SO₂-, -SO₂NR²-, -NR²CONR³-Or-NR²A group represented by COCO-;
(V) L¹-NR²SO₂In the case of a group represented by-, n¹Is 0,
(Vi) group -L¹-L²-D is -CONR²-For lower alkyl, n¹Is 0,
(Vii) L¹Is a group represented by -CO-, R¹Is H)
  In the present invention, the symbol Cy in the formula (IB)¹Is preferably an aryl optionally substituted with a substituent selected from the following group c or a heteroaryl optionally substituted with a substituent selected from the following group c.
[Group c: (1) lower alkyl, (2) cycloalkyl, (3) halo lower alkyl, (4) aryl-lower alkyl, (5) aryl, (6) HOOC-, (7) lower alkyl-O- CO-, (8) lower alkyl-CO-, (9) aryl-CO-, (10) lower alkyl-SO₂-, (11) H₂NCO-, (12) H₂NSO₂-, (13) lower alkyl-HNCO-, (14) (lower alkyl)₂-NCO-, (15) lower alkyl-HNSO₂-, (16) (lower alkyl)₂-NSO₂-, (17) Heterocyclic -CO-, (18) H₂N-, (19) lower alkyl-NH-, (20) (lower alkyl)₂-N-, (21) lower alkyl-CONH-, (22) lower alkyl-O-CONH-, (23) lower alkyl-SO₂NH-, (24) HO-, (25) lower alkyl-O-, (26) cycloalkyl-lower alkyl-O-, (27) aryl-lower alkyl-O-, (28) methylenedioxy, (29 ) Ethylenedioxy, (30) a heterocyclic group which may be substituted with 1 or 2 lower alkyl groups, (31) a heterocyclic group which may be substituted with 1 or 2 oxo (═O), ( 32) Cyano, (33) Nitro, (34) Oxo (O =), (35) Halo]
  In the present invention, the symbol R in the formula (IB)⁴And R⁵(1b) lower alkyl optionally substituted with a substituent selected from the following d group, (2b) cycloalkyl, (3b) substituted with a substituent selected from the following d group Aryl, (4b) lower alkyl-CO-, (5b) HOOC-, (6b) lower alkyl-O-CO-, (7b) H₂NCO-, (8b) H₂NSO₂-, (9b) lower alkyl-NHCO-, (10b) lower alkyl-NHSO₂-, (11b) (lower alkyl)₂-NCO-, (12b) (lower alkyl)₂-NSO₂-, (13b) H₂N-, (14b) Lower alkyl-NH- which may be substituted with a substituent selected from the following group d, (15b) (Lower alkyl optionally substituted with a substituent selected from group d below) )₂-N-, (16b) aryl-NH-, which may be substituted with a substituent selected from the following group d, (17b) lower alkyl-CONH-, (18b) lower alkyl-SO₂NH-, (19b) Lower alkyl-O-CONH- which may be substituted with a substituent selected from the following group d, (20b) HO-, (21b) Substituted with a substituent selected from the following group d Lower alkyl-O-, (22b) cycloalkyl-O-, (23b) heterocyclic group -O-, (24b) HS-, (25b) lower alkyl-S-, (26b) cycloalkyl -S-, (27b) cyano, (28b) nitro, (29b) oxide, (30b) halo, or (31b) a heterocyclic group optionally substituted with a substituent selected from the following group d. Is preferred.
[Group d: (1) lower alkyl, (2) cycloalkyl, (3) halo lower alkyl, (4) aryl-lower alkyl, (5) aryl, (6) HOOC-, (7) lower alkyl-O- CO-, (8) lower alkyl-CO-, (9) lower alkyl-SO₂-, (10) H₂NCO-, (11) H₂NSO₂-(12) lower alkyl-HNCO-, (13) (lower alkyl)₂-NCO-, (14) lower alkyl-HNSO₂-, (15) (lower alkyl)₂-NSO₂-, (16) heterocycle -CO-, (17) H₂N-, (18) lower alkyl-NH-, (19) (lower alkyl)₂-N-, (20) lower alkyl-CONH-, (21) lower alkyl-O-CONH-, (22) lower alkyl-SO₂NH-, (23) HO-, (24) lower alkyl-O-, (25) cycloalkyl-lower alkyl-O-, (26) aryl-lower alkyl-O-, (27) methylenedioxy, (28 ) Ethylenedioxy, (29) a heterocyclic group which may be substituted with 1 or 2 lower alkyl groups, (30) a heterocyclic group which may be substituted with 1 or 2 oxo (═O), ( 31) Cyano, (32) Nitro, (33) Oxo (O =), (34) Halo]
  In the present invention, the symbol L in the formula (IB)¹Is a group represented by —NR²CO-, -CONR²-, -NR²SO₂-Or -SO₂NR²-Is preferred.
  In the present invention, the Cy in the symbol D in the formula (IB)²Is preferably a heterocyclic group.
  In the present invention, the piperidine derivative represented by the formula (IB) is N- [2- (4-phenethylpiperidino) ethyl] isonicotinamide, N- [2- (4-phenethylpi). Peridino) ethyl] pyridine-2-carboxamide, N- [2- (4-phenethylpiperidino) ethyl] nicotinamide, 4-isopropoxy-N- [2- (4-phenethylpiperidino) ethyl] nicotine Amido, 3-methoxy-N- [2- (4-phenethylpiperidino) ethyl] isonicotinamide, N- [2- (4-phenethylpiperidino) ethyl] bicyclo [2.2.1] heptane- 2-carboxamide, N- (2- {4-[(2-ethylphenoxy) methyl] piperidino} ethyl) -4-morpholinonicotinamide, N- (2- {4-[(2-ethyl Enoxy) methyl] piperidino} ethyl) -2- (3-hydroxypyrrolidin-1-yl) isonicotinamide, 2-methyl-N- [2- (4-phenethylpiperidino) ethyl] imidazo [1,2- a] pyridine-3-carboxamide, N- (2- {4- [2- (2-methoxyphenyl) ethyl] piperidino} ethyl) nicotinamide, N- (2- {4- [2- (2-methoxyphenyl) ) Ethyl] piperidino} ethyl) -2-oxo-1,2-dihydroisonicotinamide, N- (2- {4- [2- (3-chlorophenyl) ethyl] piperidino} ethyl) nicotinamide, N- [2 -(4-phenethylpiperidino) ethyl] thiophene-2-carboxamide, (Z) -N- [2- (4-styrylpiperidino) ethyl] nicotinamide, (E -N- (2- {4- [2- (2,6-dimethylphenyl) vinyl] piperidino} ethyl) nicotinamide, N- (2- {4-[(2,6-dimethylphenyl) ethynyl] piperidino} Ethyl) nicotinamide, N- [2- (3-phenethylpiperidino) ethyl] nicotinamide, N- [2- (4-phenethylpiperidino) ethyl] benzamide, N-tert-butyl-3- (4 It is preferably at least one compound selected from the group consisting of -phenethylpiperidino) propanamide and N-benzyl-N- [2- (4-phenethylpiperidino) ethyl] nicotinamide.
  In the present invention, the symbol Cy in the formula (IB)¹Is preferably a group selected from the following group e.
[E group: (1) (CN, halo, NO₂, Heterocycle, alkyl, halo-alkyl-, HO, cycloalkyl-alkyl-O-, alkyl-O-, HOOC, alkyl-O-CO-, H₂NCO-, alkyl-N-CO-, heterocycle-CO-, aryl-CO-, H₂N, alkyl-N-, alkylCO-N-, or alkyl-SO₂-N-) optionally substituted aryl, (2) optionally bridged saturated heterocycle consisting of one or more atoms selected from N, S, O, (3) from N, S, O Unsaturated heterocycle consisting of one or more selected atoms]
  In the present invention, the symbol Cy in the formula (IB)¹Is preferably a group selected from the following group f.
[Group f: (1) (CN, halo, NO₂, Heterocycle, alkyl, halo-alkyl-, HO, cycloalkyl-alkyl-O-, alkyl-O-, HOOC, alkyl-O-CO-, H₂NCO-, alkyl-N-CO-, heterocycle-CO-, aryl-CO-, H₂N, alkyl-N-, alkylCO-N-, alkyl-SO₂-N-) optionally substituted phenyl, naphthyl, (2) octahydro-isoindole, furan, thiophene, benzofuran, benzothiophene, benzothiazole, quinoline, indole, benzimidazole, tetrazole, 1,3-benzodio Xol (oxo), imidazole, pyridine]
  In the present invention, the group represented by the symbol D in the formula (IB) is preferably a group selected from the following g group.
[Group g: (1) one or more atoms selected from (1) a saturated carbocyclic ring having 3 to 10 carbon atoms, (2) an unsaturated carbocyclic ring, and (3) N, S, O A saturated heterocyclic ring which may be bridged, (4) an unsaturated heterocyclic ring composed of one or more atoms selected from N, S and O]
  In the present invention, the group represented by the symbol D in the formula (IB) is preferably a group selected from the following group h.
[Group h: (1) cycloalkyl, phenyl, naphthyl, indene optionally having 3 to 10 carbon atoms, (2) morpholine, pyrrolidine, 1-aza-bicyclo [2.2.1] heptane, 4 , 5,6,7-tetrahydro-1H-benzimidazole, (3) pyridyl, tetrazolyl, piperidine, triazolyl, pyrazole, thiophene, thiazole, pyrazine, benzimidazole, indole, indazole, imidazo [1,2-a] pyridine, Furan, quinolyl, isoquinolyl, benzofuran, benzo [b] thiophene, pyrimidine, isoxazole]
  Moreover, according to this invention, the pharmaceutical composition containing the above-mentioned piperidine derivative and its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier is provided.
  Hereinafter, the piperidine derivative of the present invention represented by the formula (IA) or (IB) and a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as “the compound of the present invention”) and those The sodium channel inhibitor as an active ingredient will be described in detail.
[Definition etc.]
  In the definition of the structural formula in this specification, the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms unless otherwise specified.
  Examples of “lower alkyl” include C such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl and the like._{1 -6}An alkyl is mentioned, Preferably it is methyl or ethyl.
  Examples of “lower alkenyl” include C, such as vinyl, propenyl, allyl, butenyl, pentenyl, hexenyl, etc._2-6An alkenyl is mentioned, Preferably it is vinyl.
  Examples of “lower alkylene” include C such as methylene, ethylene, trimethylene, propylene, tetramethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, and the like._1-6An alkylene is mentioned, Preferably it is a methylene or ethylene.
  Examples of “lower alkenylene” include C such as vinylene, propenylene, butenylene, etc._2-6An alkenylene is mentioned, Preferably it is vinylene.
  Examples of “lower alkynylene” include C such as ethynylene, propynylene and butynylene._2-6An alkynylene is mentioned, Preferably it is an ethynylene.
  “Aryl” means a 1 to 3 ring aromatic hydrocarbon ring group having 6 to 14 carbon atoms, and examples thereof include phenyl, naphthyl, anthryl, phenanthryl, etc., preferably phenyl or naphthyl. is there.
  “Cycloalkyl” means a 1 to 3 ring aliphatic saturated hydrocarbon ring group having 3 to 14 carbon atoms which may be bridged. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , Cyclooctyl, bicycloheptyl, bicyclooctyl, bicyclononyl, bicyclodecanyl, tricyclononyl, tricyclodecanyl (adamantyl, etc.), tricycloundecanyl, tricyclododecanyl, etc., preferably cyclopentyl, Cyclohexyl, cycloheptyl, bicycloheptyl, or tricyclodecanyl.
  “Cycloalkenyl” means an unsaturated aliphatic hydrocarbon ring group in which any one to three single bonds of the cycloalkyl group are double bonds, such as cyclobutenyl, cyclopentenyl, cyclohexenyl, Examples include cycloheptenyl and cyclooctenyl.
  “Hydrocarbon ring group” means the above cycloalkyl, cycloalkenyl or aryl, or a condensed ring group or a spiro ring group thereof, and a condensed ring other than the condensed ring group described in the description of the above aryl and cycloalkyl. Examples of the group include indanyl, indenyl, tetrahydronaphthyl and the like. The hydrocarbon ring group is preferably cyclopentyl, cyclohexyl, cycloheptyl, bicycloheptyl, tricyclodecanyl, phenyl, naphthyl, or indenyl.
  “Oxygen-containing heterocycloalkyl” means one in which any one or two carbon atoms of the above cycloalkyl are substituted with an oxygen atom, for example, oxiranyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, dioxanyl. Etc.
  “Heterocycloalkyl” is a bridge in which any one to three carbon atoms of the cycloalkyl are substituted with one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms. For example, aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, piperazyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azabicycloheptyl, diazabicycloheptyl And azabicyclooctyl.
  “Heterocycloalkenyl” means one to three carbon atoms of the cycloalkenyl substituted with one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms. Examples thereof include pyrrolinyl, dihydrofuryl, dihydrothienyl, dihydropyridyl, tetrahydropyridyl, dihydropyranyl, dihydrothiopyranyl and the like.
  “Heteroaryl” refers to 1 to 3 ring heteroaryl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms and having 5 to 14 atoms. Meaning, for example, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, oxazolyl, thienyl, thiazolyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl, triazyl, indolyl, isoindolyl, benzimidazolyl, benzopyrazolyl, pyrrolopyridyl, imidazopyridyl, benzofuryl, Examples include benzothienyl, quinolyl, isoquinolyl, quinoxalyl, furopyridyl, thienopyridyl, and preferably pyridyl.
  “Heterocyclic group” means the above heterocycloalkyl, heterocycloalkenyl or heteroaryl, or a condensed ring group or spiro ring group thereof, or a condensed ring group or a spiro ring group and a hydrocarbon ring group. Means a group that forms a spiro ring, and examples of the condensed ring group other than the fused ring group described in the above description of heterocycloalkyl and heteroaryl include dihydroisoindolyl, octahydroisoindolyl, tetrahydrobenzimidazolyl, and the like. Is mentioned. The heterocyclic group is preferably heteroaryl.
  “Halo” includes fluoro, chloro, bromo and iodo, preferably fluoro or chloro.
  The term “which may be substituted” means that it may be substituted with 1 to 4 substituents of 1 to 3 types. Examples of the substituent include (1) lower alkyl, (2) Cycloalkyl, (3) halo lower alkyl, (4) aryl-lower alkyl, (5) aryl, (6) HOOC-, (7) lower alkyl-O-CO-, (8) lower alkyl-CO-, ( 9) Aryl-CO-, (10) Lower alkyl-SO₂-, (11) H₂NCO-, (12) H₂NSO₂-, (13) lower alkyl-HNCO-, (14) (lower alkyl)₂-NCO-, (15) lower alkyl-HNSO₂-, (16) (lower alkyl)₂-NSO₂-, (17) Heterocyclic -CO-, (18) H₂N-, (19) lower alkyl-NH-, (20) (lower alkyl)₂-N-, (21) lower alkyl-CONH-, (22) lower alkyl-O-CONH-, (23) lower alkyl-SO₂NH-, (24) HO-, (25) lower alkyl-O-, (26) cycloalkyl-lower alkyl-O-, (27) aryl-lower alkyl-O-, (28) methylenedioxy, (29 ) Ethylenedioxy, (30) a heterocyclic group which may be substituted with 1 or 2 lower alkyl groups, (31) a heterocyclic group which may be substituted with 1 or 2 oxo (═O), ( 32) Cyano, (33) Nitro, (34) Oxo (O =), (35) Halo and the like.
  “Halo lower alkyl” means the above lower alkyl substituted with 1 to 2 kinds of the above halos, for example, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl and the like.
  The compound of the present invention has an optical isomer (optically active form, diastereomer, etc.) or geometric isomer depending on the type of substituent. Therefore, the compound of the present invention includes these optical isomers or mixtures of geometric isomers and isolated isomers.
  The compound of the present invention can form an acid addition salt or a salt with a base. For example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid; formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, apple Acid, citric acid, tartaric acid, carbonic acid, picric acid, acid addition salts with organic acids such as methanesulfonic acid, ethanesulfonic acid and glutamic acid; inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; methylamine, ethylamine, Mention may be made of salts with organic bases such as monoethanolamine, diethanolamine, triethanolamine, cyclohexylamine, lysine and ornithine. Furthermore, the compounds of the present invention and pharmaceutically acceptable salts thereof can form hydrates, solvates such as ethanol, and crystal polymorphs.
  Furthermore, the compound of the present invention includes all compounds that are metabolized in vivo and converted into the compound of the present invention and pharmaceutically acceptable salts thereof, so-called prodrugs. Examples of groups that form prodrugs of the compounds of the present invention include Prog. Med. 5: 2157-2161 (1985) and the groups described in Hirokawa Shoten 1990 "Drug Development", Volume 7, Molecular Design 163-198. Specifically, it is a group that can be converted into a primary amine or secondary amine of the compound of the present invention by hydrolysis, solvolysis, or under physiological conditions, HO—, HOC (═O) —, etc., for example , HO- as prodrugs include optionally substituted lower alkyl-COO-, optionally substituted aryl-COO-, RO-CO- optionally substituted lower alkylene-COO- (where R is H- or Lower alkyl, the same applies hereinafter), RO-CO-optionally substituted lower alkenylene-COO-, RO-CO-lower alkylene-O-lower alkylene-C-OO-, RO-CO-COO-, ROSO₂-Lower alkenylene-COO- which may be substituted, phthalidyl-O-, 5-methyl-1,3-dioxolen-2-one-4-yl-methyloxy and the like.
[Production method]
  The compound of the present invention can be produced by applying various synthesis methods utilizing characteristics based on the basic skeleton or the type of substituent. The production methods of the representative compounds (Ia) to (Ie) will be described below.
(First manufacturing method)
  The compound (Ia) of the present invention can be produced by a known method in the literature or by an amidation reaction of the compound (V) and the compound (VI) by a conventional method as shown in the following reaction formula. This reaction can be performed using, for example, a condensing agent such as carbodiimide. If desired, a catalyst such as 1-hydroxybenzotriazole may be used. In this reaction, compound (VI) may be converted to the corresponding acid chloride, acid bromide, or acid anhydride and then reacted with compound (V). At this time, a base such as triethylamine may be used if desired. As the reaction solvent, for example, N, N-dimethylformamide, tetrahydrofuran, dioxane and the like can be used, and the reaction temperature is any temperature from cooling to heating.
  Compound (V) can be obtained by subjecting compound (II) to alkylation by a conventional method using compound (III), and then converting Y to amino. The alkylation reaction can be performed at any temperature between cooling and heating using, for example, N, N-dimethylformamide, tetrahydrofuran, dioxane or the like as a solvent. If desired, a base such as potassium carbonate or sodium hydride may be used. The conversion of Y to amino can be accomplished, for example, by reduction when Y is cyano, or normal deprotection when Y is protected (Protective group Organic Synthesis, (second ed. Or third ed., JOHN WILEY & (SONS, INC.) Can produce compound (V).
  Moreover, this invention compound (Id) can be manufactured by the alkylation reaction of a compound (II) and a compound (IX) by the method similar to the said alkylation, as shown to the following reaction formula.
(Reaction formula)

Or
(Reaction formula)

(In the above reaction formula, Y means a group that can be easily converted to amino, such as amino or cyano protected with acyl or phthaloyl. X means a leaving group such as halo, mesyloxy, or tosyloxy. The same applies hereinafter.)
(Second manufacturing method)
  The compound (Ib) of the present invention can be produced by a reductive amination reaction between the compound (II) and the compound (VII) as shown in the following reaction formula. This reaction can be performed, for example, using a reducing agent such as sodium triacetoxyborohydride under acidic conditions using acetic acid or the like as a solvent. In addition, this reaction can be performed at any temperature between cooling and room temperature.
(Reaction formula)

(In the above reaction formula, ALK³Is ALK²It means lower alkylene having 1 fewer carbon atoms. The same applies hereinafter. )
(Third manufacturing method)
  The compound (Ic) of the present invention can be produced by a Michael addition reaction between the compound (II) and the compound (VIII) as shown in the following reaction formula. This reaction can be performed at any temperature between room temperature and under heating using, for example, toluene, N, N-dimethylformamide, dioxane or the like as a solvent.
(Reaction formula)

(Fourth manufacturing method)
  The compound (Ie) of the present invention can be produced by reacting the compound (V) with an isocyanate derivative (X) as shown in the following reaction formula. In this reaction, for example, toluene, tetrahydrofuran, dioxane or the like can be used as a reaction solvent. Further, this reaction can be carried out at any temperature between cooling and heating. The isocyanate derivative (X) can be easily produced by a Curtius transition in which a corresponding carboxylic acid is reacted with an acid azide such as phosphoric acid azide.
(Reaction formula)

  The compound of the present invention thus produced can be easily led to another derivative by subjecting it to a reaction such as alkylation, substitution, reduction, and oxidation.
[Raw material synthesis]
  The starting compound of the compound of the present invention is disclosed in Patent Document 4 (European Patent Publication No. 1254904), J. Pat. Org. Chem. , 22, 1376 (1957), J. Am. Med. Chem. , 42, 2087 (1999), Tetrahedron Lett. , 41, 6025 (2000), Tetrahedron Lett. , 36, 3465 (1995) and the like.
  For example, compound (IIa) can be produced by deprotecting the amino protecting group of compound (XIV) or (XVI) as described above, as shown in the following reaction formula. Compound (XIV) can be produced by reacting compound (XI) with acetylene derivative (XII) under basic conditions, followed by dehydration. Compound (XVI) can be obtained by subjecting compound (XV) to a Wittig reaction. Further, compound (IIa) can be produced by reducing compound (XIV) or (XVI) and then deprotecting the amino protecting group.
  Furthermore, the regioisomer of compound (IIa) can also be produced by the same method.
  Symbol n in compound (II)¹And n²If any of these is 1, J. Med. Chem. , 42, 2087 (1999), Tetrahedron Lett. , 41, 6025 (2000), Tetrahedron Lett. , 36, 3465 (1995).
(Reaction formula)

  (In the above reaction formula, Z means an amino protecting group. The same shall apply hereinafter.)
  The compound of the present invention thus produced is isolated as it is or as a salt thereof. The salt of the compound of the present invention can be produced by subjecting the compound of the present invention which is a free base to a usual salt formation reaction.
  The compounds of the present invention and salts thereof are isolated and purified as hydrates, solvates or crystalline polymorphic substances. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatography.
  Various isomers can be separated by selecting an appropriate raw material compound or by utilizing a difference in physical properties between isomers. For example, optical isomers can be obtained by selecting appropriate raw materials, or by racemic resolution of racemates (for example, diastereomeric salts with general optically active acids and optical resolution). It can lead to a stereochemically pure isomer.
[Prescription]
  The compound of the present invention can be applied to various commonly used formulations. The typical prescription will be described below.
  The pharmaceutical composition containing one or more of the compounds of the present invention and pharmaceutically acceptable salts thereof as an active ingredient can contain a pharmaceutically acceptable carrier and is usually used for formulation. Prepared in the form of tablets, powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, ointments, patches, etc. (Including sublingual administration) or parenterally.
  The clinical doses of the compound of the present invention and pharmaceutically acceptable salts thereof to humans are appropriately determined according to individual cases in consideration of the symptoms, body weight, age, sex, route of administration, etc. of the applied patient. Is usually orally administered in an amount of 1 mg to 1000 mg per adult per day, preferably in the range of 10 mg to 200 mg once to several times a day, or 1 mg to 500 mg per adult per day. In the range, it is intravenously administered once to several times a day, or it is continuously administered intravenously in the range of 1 hour to 24 hours per day. Of course, as described above, the dose varies depending on various conditions, and therefore a dose smaller than the above dose may be sufficient.
  As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, one or more active substances are present in at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate. Mixed with magnesium aluminate. According to a conventional method, the composition comprises additives other than an inert diluent, for example, a lubricant such as magnesium stearate; a disintegrator such as starch and calcium calcium glycolate; a stabilizer such as lactose; You may contain solubilizing agents, such as aspartic acid. Tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a gastric or enteric film, if necessary.
  Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, commonly used inert diluents such as Contains purified water, ethanol, etc. In addition to the inert diluent, this composition may contain solubilizing or solubilizing aids, wetting agents, suspending agents and other adjuvants, sweeteners, flavoring agents, fragrances, preservatives and the like.
  Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of the water-insoluble solution and suspension include vegetable oils such as propylene glycol, polyethylene glycol and olive oil; alcohols such as ethanol; polysorbate 80 (trade name) and the like. Such compositions may further contain additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg lactose), solubilizers, solubilizers and the like. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide, or irradiation. They can also be used by producing a sterile solid composition and dissolving it in sterile water or a sterile injection solvent before use.
  Further, the compound of the present invention may be used together with a drug effective for pain by a mechanism other than the therapeutic agent for the above diseases or a sodium channel inhibitor. Drugs effective for pain that can be used in combination include narcotic analgesics, antipyretic analgesics, non-steroidal anti-inflammatory drugs and the like.

Hereinafter, the piperidine derivative of the present invention and a pharmaceutically acceptable salt thereof (the compound of the present invention) will be described in more detail with reference to examples which are the best mode for carrying out the present invention. However, the present invention is not limited to these examples.
Hereinafter, the chemical structural formula (general formula) of each compound obtained in the examples of the piperidine derivative of the present invention and the pharmaceutically acceptable salt thereof (the compound of the present invention), the number of the example using the compound Specific structures are shown in Tables 1 to 25, and physicochemical properties of these compounds are shown in Tables 26 to 37, respectively. Tables 1 to 37 are shown together with Tables 39 to 48 described later at the end of this specification.
Moreover, the manufacture example of the raw material compound used in the Example is concretely demonstrated by the reference examples 1-101.
The symbols in Tables 1 to 37 have the following meanings.
[Ex. : Example number, Me: methyl, Et: ethyl, Pr: propyl, iPr: isopropyl, Bu: butyl, iBu: isobutyl, tBu: tert-butyl, Ph: phenyl, Ac: acetyl, Bn: benzyl, cBu: cyclobutyl , CPen: cyclopentyl, cHex: cyclohexyl, cHep: cycloheptyl, Salt: salt, fumarate: fumarate, difumarate: difumarate, dimaleate, structure: NMR, nuclear magnetic resonance spectrum (unless otherwise specified, DMSO-d ₆ TMS internal standard, □), MS: mass spectrum (m / z) ([(M + H) ⁺ ] or [(M−H) ⁻ ], FAB or ESI), Data: physicochemical properties]

2- (4-phenethylpiperidino) ethylamine 200 mg in N, N-dimethylformamide 5 ml solution at room temperature 127 mg isonicotinic acid, 174 mg 1-hydroxybenzotriazole and 1-ethyl-3- (3-dimethylaminopropyl) ) 248 mg of carbodiimide hydrochloride was added, and the mixture was stirred at room temperature overnight and concentrated. To this were added 50 ml of chloroform and 15 ml of a saturated aqueous sodium hydrogen carbonate solution, the organic layer was separated, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 20: 1: 0.1) to obtain 258 mg of pale orange crystals. The obtained crystals were dissolved in 10 ml of ethyl acetate, 382 μl of 4N hydrochloric acid-ethyl acetate was added, and the solvent was distilled off under reduced pressure. The residue was crystallized from ethanol-tetrahydrofuran, and the precipitated crystals were collected by filtration. This was recrystallized from ethanol-tetrahydrofuran to obtain 219 mg of N- [2- (4-phenethylpiperidino) ethyl] isonicotinamide dihydrochloride. Tables 1 and 26 show chemical structural formulas and physical properties of the obtained compounds.
Hereafter, it carried out similarly to Example 1, and obtained the compound of Examples 2-265 (Tables 1-15 and Tables 26-33).

To a solution of 200 mg of 2- (4-phenethylpiperidino) ethylamine in 10 ml of tetrahydrofuran was added 180 ml of triethylamine and 133 mg of thiophene-2-carbonyl chloride in 3 ml of tetrahydrofuran at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. To this were added 20 ml of ethyl acetate and 30 ml of saturated aqueous sodium hydrogen carbonate solution, the organic layer was separated, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 20: 1: 0.1) to obtain 295 mg of yellow crystals. The obtained crystals were dissolved in 10 ml of ethanol, 4N hydrochloric acid-ethyl acetate 220 μl was added, and the solvent was distilled off under reduced pressure. The residue was crystallized from ethanol, and the precipitated crystals were collected by filtration. This was recrystallized from ethanol to obtain 242 mg of N- [2- (4-phenethylpiperidino) ethyl] thiophene-2-carboxamide monohydrochloride. Tables 15 and 33 show the chemical structural formulas and physical properties of the obtained compounds.
Thereafter, the compounds of Examples 267 to 367 were obtained in the same manner as in Example 266 (Tables 15 to 20 and Tables 33 to 36).

To a solution of 439 mg of 4- [2- (4-methoxyphenyl) ethyl] piperidine in 7 ml of chloroform was added a solution of N- (2-oxoethyl) adamantane-1-carboxamide 664 mg in chloroform 3 ml and acetic acid 1.2 ml at room temperature. After stirring for minutes, 636 mg of sodium triacetoxyborohydride was added under ice cooling, and the mixture was stirred at room temperature for 38 hours. To this was added 30 ml of a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted twice with 20 ml of chloroform. The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 30: 1: 0.1) to obtain a yellow oil. The obtained oil was dissolved in 5 ml of ethanol, 210 μl of 4N hydrochloric acid-ethyl acetate was added, and the mixture was concentrated. The residue was crystallized from acetone-diethyl ether, and the precipitated crystals were collected by filtration. This was recrystallized from acetone-diethyl ether to obtain 114 mg of N- (2- {4- [2- (4-methoxyphenyl) ethyl] piperidino} ethyl) adamantane-1-carboxamide monohydrochloride. Tables 20 and 36 show the chemical structural formulas and physical properties of the obtained compounds.
The compounds of Examples 369 to 375 were obtained in the same manner as in Example 368 (Tables 20 to 21 and Table 36).

To a solution of 6-chloro-N- [2- (4-phenethylpiperidino) ethyl] pyridine-2-carboxamide in 260 mg of ethanol was added 162 mg of potassium tert-butoxide, and the mixture was stirred overnight at 150 ° C. in a sealed tube. did. After allowing to cool, 50 ml of water was added to this, and extracted three times with 50 ml of chloroform. The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 30: 1: 0.1) to obtain 239 mg of a brown oily substance. This was dissolved in ethanol (5.0 ml), 4N hydrochloric acid-ethyl acetate (330 μl) and diethyl ether were added, and the mixture was stirred at room temperature. The precipitated crystals were collected by filtration and recrystallized from ethanol-diethyl ether to obtain 76 mg of 6-ethoxy-N- [2- (4-phenylpiperidino) ethyl] pyridine-2-carboxamide monohydrochloride. Tables 22 and 36 show the chemical structural formulas and physical properties of the obtained compounds.
Thereafter, the compounds of Examples 377 to 390 were obtained in the same manner as in Example 376 (Tables 21 and 36).

Methyl 2- (2- {1- [2- (nicotinoylamino) ethyl] -4-piperidyl} ethyl) benzoate To a solution of 990 mg of methanol in 10 ml of methanol was added 3 ml of 10% aqueous sodium hydroxide, and the mixture was heated to reflux for 3 hours. After allowing to cool, 10% hydrochloric acid was added to adjust the pH to 3, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol), and the obtained crystals were recrystallized from ethanol-ethyl acetate to give 2- (2- {1- [2- (nicotinoylamino) ethyl] -4 450 mg of -piperidyl} ethyl) benzoic acid was obtained. Tables 21 and 36 show the chemical structural formulas and physical properties of the obtained compounds.
Thereafter, the compounds of Examples 392 to 395 were obtained in the same manner as in Example 391 (Tables 22 and 36).

tert-Butyl 4- [2- (4-phenethylpiperidino) ethylcarbamoyl] cyclohexyl carbamate 291 mg in ethanol 10 ml solution was added 4N hydrochloric acid-ethyl acetate 1.20 ml at room temperature and stirred at 50 ° C. for 1 hour. The solvent was distilled off under reduced pressure. The residue was crystallized from ethanol-tetrahydrofuran, and the precipitated crystals were collected by filtration. This was recrystallized from ethanol-tetrahydrofuran to obtain 169 mg of 4-amino-N- [2- (4-phenethylpiperidino) ethyl] cyclohexanecarboxamide dihydrochloride. Tables 21 and 36 show the chemical structural formulas and physical properties of the obtained compounds.
Thereafter, the compound of Example 399 was obtained in the same manner as in Example 396 (Table 22 and Table 37).

To a solution of 4-phenethylpiperidine (380 mg) in toluene (10 ml) was added N-tert-butylacrylamide (255 mg) at room temperature, and the mixture was stirred at 90 ° C. for 15 hours and concentrated. This was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 30: 1: 0.1) to obtain 520 mg of a light brown solid. 500 mg of the obtained solid was dissolved in 2 ml of ethyl acetate, 470 μl of 4N hydrochloric acid-ethyl acetate and 10 ml of ethyl acetate were added, and the mixture was stirred at room temperature. The precipitated crystals were collected by filtration to obtain 467 mg of N-tert-butyl-3- (4-phenethylpiperidino) propanamide monohydrochloride. Tables 22 and 37 show the chemical structural formulas and physical properties of the obtained compounds.
Thereafter, the compounds of Examples 401 to 411 were obtained in the same manner as Example 400 (Tables 22 to 23 and Table 37).

To a solution of N- [2- (4-phenethylpiperidino) ethyl] nicotinamide 200 mg in N, N-dimethylformamide 5 ml was added 78 μl of benzyl bromide and 26 mg of 60% sodium hydride under ice cooling, and at room temperature. After stirring overnight, the mixture was concentrated. This was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 30: 1: 0.1) to obtain 178 mg of a pale yellow oil. The obtained oily substance was dissolved in 2 ml of ethanol, a solution of 75 mg of oxalic acid in 1 ml of ethanol and 2 ml of diethyl ether were added, and the mixture was stirred at room temperature. The precipitated crystals were collected by filtration and recrystallized from ethanol-diethyl ether to obtain 174 mg of N-benzyl-N- [2- (4-phenethylpiperidino) ethyl] nicotinamide 1 oxalate. . Tables 23 and 37 show chemical structural formulas and physical properties of the obtained compounds.
Thereafter, the compounds of Examples 413 to 439 were obtained in the same manner as in Example 412 (Tables 23 to 24 and Table 37).

To a solution of 50 mg of 4-phenethylpiperidine in 2 ml of N, N-dimethylformamide were added 73 mg of potassium carbonate and 63 mg of 2-bromoacetophenone under ice cooling, and the mixture was stirred for 30 minutes under ice cooling, and then ethyl acetate and water were added. . The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain 42 mg of a colorless solid. 40 mg of the obtained solid was dissolved in 2 ml of ethyl acetate, 80 μl of 4N hydrochloric acid-ethyl acetate was added, and the mixture was stirred at room temperature. The precipitated crystals were collected by filtration to obtain 51 mg of 2- (4-phenethylpiperidino) -1-phenylethanone monohydrochloride. Tables 24 and 37 show chemical structural formulas and physical properties of the obtained compounds.
Thereafter, the compound of Example 441 was obtained in the same manner as in Example 440.

  To a solution of 171 mg of 2-phenylbenzoic acid in 5 ml of toluene, 132 μl of triethylamine and 204 μl of diphenylphosphoric acid azide were added at room temperature, stirred for 1 hour at 80 ° C. The solution was added and stirred at 80 ° C. for 3 hours. After standing to cool, 100 ml of chloroform and 30 ml of saturated aqueous sodium hydrogen carbonate solution were added to this, the organic layer was separated, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 30: 1: 0.1) to obtain 420 mg of a pale yellow oil. The obtained oil was dissolved in 10 ml of ethyl acetate, 246 μl of 4N hydrochloric acid-ethyl acetate was added, and the solvent was distilled off under reduced pressure. The residue was crystallized from tetrahydrofuran-diethyl ether, and the precipitated crystals were collected by filtration. This was recrystallized from tetrahydrofuran-diethyl ether to obtain 310 mg of 1-biphenyl-2-yl-3- [2- (4-phenethylpiperidino) ethyl] urea monohydrochloride. Tables 25 and 37 show chemical structural formulas and physical properties of the obtained compounds.

  To a solution of 221 mg of N- [2- (4-phenethylpiperidino) ethyl] nicotinamide in 5 ml of methylene chloride was added 161 mg of 77% m-chloroperbenzoic acid at room temperature, and the mixture was stirred at room temperature for 1.5 hours. To this were added 50 ml of chloroform and 15 ml of a saturated aqueous sodium hydrogen carbonate solution, the organic layer was separated, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 20: 1: 0.1) to obtain 223 mg of white crystals. The obtained crystals were recrystallized from ethanol-diethyl ether to obtain 84 mg of N- [2- (1-oxide-4-phenethylpiperidino) ethyl] nicotinamide. Tables 25 and 37 show chemical structural formulas and physical properties of the obtained compounds.

3-Benzyloxy-N- [2- (4-phenethylpiperidino) ethyl] isonicotinamide 0.15 g of 10% palladium on carbon was added to a solution of 517 mg of acetic acid and subjected to catalytic reduction at room temperature overnight at normal pressure. Later, insoluble matters were filtered and the filtrate was concentrated. To this were added 50 ml of chloroform and 15 ml of a saturated aqueous sodium hydrogen carbonate solution, the organic layer was separated, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 10: 1: 0.1) to obtain 123 mg of pale orange crystals. The obtained crystals were dissolved in 10 ml of ethanol, 174 μl of 4N hydrochloric acid-ethyl acetate was added, and the solvent was distilled off under reduced pressure to obtain crystals. Ethanol-ether was added to the crystals and stirred, and the crystals were collected by filtration. This was recrystallized from ethanol-ether to obtain 80 mg of 3-hydroxy-N- [2- (4-phenethylpiperidino) ethyl] isonicotinamide dihydrochloride. Tables 25 and 37 show chemical structural formulas and physical properties of the obtained compounds.
Hereafter, the manufacturing method of the raw material compound used in the Example is demonstrated by Reference Examples 1-101.
(Reference Example 1)
Phenylacetylene and (N-benzyloxycarbonyl) piperidin-4-one are reacted in tetrahydrofuran in the presence of potassium tert-butoxide to give benzyl 4-hydroxy- (4-phenylethynyl) piperidine-1-carboxylate. Prepared (MS: 336).
(Reference Example 2)
Benzyl 4-hydroxy- (4-phenylethynyl) piperidine-1-carboxylate is reacted in toluene in the presence of p-toluenesulfonic acid monohydrate to give benzyl 4-phenylethynyl-1,2,3,6. -Tetrahydropyridine-1-carboxylate was prepared (MS: 318).
(Reference Example 3)
Benzyl 4-hydroxy-4-[(2-pyridyl) ethynyl] piperidine-1-carboxylate is reacted in pyridine in the presence of phosphorus oxychloride to give benzyl 4-[(2-pyridyl) ethynyl] -1,2 , 3,6-tetrahydropyridine-1-carboxylate was prepared (MS: 319).
(Reference Example 4)
In the same manner as in Reference Example 3, benzyl 4-[(3-pyridyl) ethynyl] -1,2,3,6-tetrahydropyridine-1-carboxylate was produced (MS: 319).
(Reference Example 5)
Benzyl 4-phenylethynyl-1,2,3,6-tetrahydropyridine-1-carboxylate was reduced with 10% palladium on carbon in acetic acid under hydrogen atmosphere to produce 4-phenethylpiperidine (MS: 190 ).
(Reference Example 6)
(3-Chlorobenzyl) (triphenyl) phosphonium bromide and tert-butyl 4-formylpiperidine-1-carboxylate are reacted in N, N □ dimethylformamide in the presence of 60% sodium hydride to obtain E, Tert-butyl 4- [2- (3-chlorophenyl) vinyl] piperidine-1-carboxylate was prepared as a mixture of Z isomers (MS: 322).
(Reference Examples 7 to 15)
In the same manner as in Reference Example 6, the raw material compounds shown in Table 38 were produced. Table 38 shows the chemical structural formula (general formula) of this raw material compound, the reference example number (Rex.), The specific constitution and physicochemical properties of this raw material compound.
(Reference Example 16)
tert-Butyl 4- [2- (3-chlorophenyl) vinyl] piperidine-1-carboxylate was reduced in ethyl acetate under hydrogen atmosphere with 10% palladium on carbon to give tert-butyl 4- [2- (3- Chlorophenyl) ethyl] piperidine-1-carboxylate was prepared (MS: 324).
(Reference Examples 17-25)
In the same manner as in Reference Example 16, the raw material compounds shown in Table 39 were produced. Table 39 shows the chemical structural formula (general formula) of this raw material compound, the reference example number (Rex.), The specific constitution and physicochemical properties of this raw material compound.
(Reference Example 26)
tert-Butyl 4- [2- (3-chlorophenyl) ethyl] piperidine-1-carboxylate was reacted in ethyl acetate in the presence of hydrochloric acid to produce 4- [2- (3-chlorophenyl) ethyl] piperidine. (MS: 224).
(Reference Examples 27 to 35)
In the same manner as in Reference Example 26, the raw material compounds shown in Table 40 were produced. Table 40 shows the chemical structural formula (general formula) of this raw material compound, the reference example number (Rex.), The specific constitution and physicochemical properties of this raw material compound.
(Reference Example 36)
Diethyl 2-methylbenzyl phosphate and 4-pyridinecarbaldehyde were reacted in tetrahydrofuran in the presence of potassium tert-butoxide. The crude product was reduced with platinum oxide in acetic acid under hydrogen atmosphere to produce 4- [2- (2-methylphenyl) ethyl] piperidine (MS: 204).
(Reference Examples 37 to 39)
In the same manner as in Reference Example 36, the raw material compounds shown in Table 41 were produced. Table 41 shows the chemical structural formula (general formula) of this raw material compound, the reference example number (Rex.), The specific constitution and physicochemical properties of this raw material compound.
(Reference Example 40)
Ethyl 1-benzylpiperidine-4-carboxylate was produced by reacting ethyl isonipecotate with benzyl chloride in tetrahydrofuran in the presence of potassium carbonate. This was reduced with lithium aluminum hydride in tetrahydrofuran to produce (1-benzylpiperidin-4-yl) methanol. This was reacted in dimethyl sulfoxide in the presence of triethylamine and sulfur trioxide pyridine complex to produce 1-benzylpiperidin-4-ylcarbaldehyde. This was reacted in methylene chloride in the presence of carbon tetrabromide, triphenylphosphine, and triethylamine to produce 1-benzyl-4- (2,2-dibromovinyl) piperidine. This was reacted in tetrahydrofuran in the presence of n-butyllithium to produce 1-benzyl-4-ethynylpiperidine. This was reacted in dimethylformamide in the presence of bromobenzene, triethylamine, cuprous iodide and tetrakis (triphenylphosphine) palladium to produce 1-benzyl-4-phenylethynylpiperidine. This was reacted in methylene chloride in the presence of methyl chloroformate to produce methyl 4-phenylethynylpiperidine-1-carboxylate. This was reacted in isopropyl alcohol in the presence of a 10% aqueous potassium hydroxide solution to produce 4-phenylethynylpiperidine (MS: 186).
(Reference Example 41)
In the same manner as in Reference Example 40, 4- [2- (2,6-dimethylphenyl) ethynyl] piperidine was produced (MS: 214).
(Reference Example 42)
4-Phenethylpiperidine and bromoacetonitrile were reacted in N, N-dimethylformamide in the presence of potassium carbonate to produce (4-phenethylpiperidino) acetonitrile (MS: 229).
(Reference Examples 43 to 46)
In the same manner as in Reference Example 42, the raw material compounds shown in Table 42 were produced. Table 42 shows the chemical structural formula (general formula) of this raw material compound, the reference example number (Rex.), The specific constitution and physicochemical properties of this raw material compound.
(Reference Example 47)
(4-Vinylpiperidino) acetonitrile and 2-bromochlorobenzene are reacted in acetonitrile in the presence of triethylamine, o-tolylphosphine, and palladium acetate to give {4- [2- (2-chlorophenyl) vinyl] piperidino} acetonitrile. Prepared (MS: 261).
(Reference Example 48)
Similarly to Reference Example 47, {4- [2- (2,6-dimethylphenyl) vinyl] piperidino} acetonitrile was produced (MS: 255).
(Reference Example 49)
(4-Hydroxymethylpiperidino) acetonitrile and phenol were reacted in tetrahydrofuran in the presence of triphenylphosphine and diisopropyl azodicarboxylate to produce (4-phenoxymethylpiperidino) acetonitrile (MS: 231).
(Reference Example 50)
[4- (2-Ethylphenoxymethyl) piperidino] acetonitrile was produced in the same manner as in Reference Example 49 (MS: 259).
(Reference Example 51)
4- [2- (3-chlorophenyl) ethyl] piperidine and N-tert-butoxycarbonyl-2-bromoethylamine are reacted in N, N-dimethylformamide in the presence of potassium carbonate to give N-tert-butoxycarbonyl- (2- {4- [2- (3-Chlorophenyl) ethyl] piperidino} ethyl) amine was prepared (MS: 367).
(Reference Examples 52-55)
In the same manner as in Reference Example 51, the raw material compounds shown in Table 43 were produced. Table 43 shows the chemical structural formula (general formula) of this raw material compound, the reference example number (Rex.), The specific constitution and physicochemical properties of this raw material compound.
(Reference Example 56)
N-tert-butoxycarbonyl- [2- (4-phenylethynylpiperidino) ethyl] amine is reacted in methanol with quinoline and 5% palladium-barium sulfate in a hydrogen atmosphere to give (Z) -N- tert-Butoxycarbonyl- [2- (4-styrylpiperidino) ethyl] amine was prepared (MS: 331).
(Reference Example 57)
4-Phenethylpiperidine and 2-nitropropane are reacted in 1,4-dioxane in the presence of a 1N aqueous sodium hydroxide solution and a 37% formalin aqueous solution to give 1- (2-methyl-2-nitropropyl) -4. -Phenethylpiperidine was prepared (MS: 291).
(Reference Example 58)
(4-Phenethylpiperidino) acetonitrile was reacted in tetrahydrofuran in the presence of lithium aluminum hydride to produce 2- (4-phenethylpiperidino) ethylamine (MS: 233).
(Reference Examples 59-66)
In the same manner as in Reference Example 58, the raw material compounds shown in Table 44 were produced. Table 44 shows the chemical structural formula (general formula) of this raw material compound, the reference example number (Rex.), The specific constitution and physicochemical properties of this raw material compound.
(Reference Example 67)
N-tert-butoxycarbonyl- (2- {4- [2- (3-chlorophenyl) ethyl] piperidino} ethyl) amine is reacted in ethyl acetate in the presence of 4N hydrochloric acid □ ethyl acetate (2- { 4- [2- (3-Chlorophenyl) ethyl] piperidino} ethyl) amine was prepared (MS: 267).
(Reference Examples 68-71)
In the same manner as in Reference Example 67, the raw material compounds shown in Table 45 were produced. Table 45 shows the chemical structural formula (general formula) of this raw material compound, the reference example number (Rex.), The specific constitution and physicochemical properties of this raw material compound.
(Reference Example 72)
1- (2-Methyl-2-nitropropyl) -4-phenethylpiperidine is reduced in methanol under a hydrogen atmosphere in the presence of 1N hydrochloric acid and 10% palladium carbon to give 1,1-dimethyl-2- (4 -Phenethylpiperidino) ethylamine hydrochloride was prepared (MS: 261).
(Reference Example 73)
4-Phenethylpiperidine and ethyl acrylate were reacted in toluene to produce ethyl 3- (4-phenethylpiperidino) propionate (MS: 290).
(Reference Example 74)
3-methoxy-4-cyanopyridine was reacted in ethanol in the presence of sodium hydroxide to produce 3-methoxyisonicotinic acid (MS: 152).
(Reference Example 75)
4-Chloronicotinic acid was reacted in isopropanol in the presence of potassium tert-butoxide to produce 4-isopropoxynicotinic acid (MS: 180).
(Reference Examples 76-79)
In the same manner as in Reference Example 75, the raw material compounds shown in Table 46 were produced. Table 46 shows the chemical structural formula (general formula) of this raw material compound, the reference example number (Rex.), The specific constitution and physicochemical properties of this raw material compound.
(Reference Example 80)
4-chloronicotinic acid and morpholine were reacted in isopropanol to produce 4-morpholinonicotinic acid (MS: 207).
(Reference Examples 81-86)
In the same manner as in Reference Example 80, the raw material compounds shown in Table 47 were produced. Table 47 shows the chemical structural formula (general formula) of this raw material compound, the reference example number (Rex.), The specific constitution and physicochemical properties of this raw material compound.
(Reference Example 87)
Isopropyl 2-chloroisonicotinate and 3-hydroxypyrrolidine were reacted in isopropanol to produce isopropyl 2- (3-hydroxypyrrolidino) isonicotinate (MS: 251).
(Reference Examples 88-93)
In the same manner as in Reference Example 87, the raw material compounds shown in Table 48 were produced. Table 48 shows the chemical structural formula (general formula) of this raw material compound, the reference example number (Rex.), The specific constitution and physicochemical properties of this raw material compound.
(Reference Example 94)
Isopropyl 2- (3-hydroxypyrrolidino) isonicotinate was reacted in ethanol in the presence of a 1N aqueous sodium hydroxide solution to produce 2- (3-hydroxypyrrolidino) isonicotinic acid (MS: 207). .
(Reference Examples 95-100)
In the same manner as in Reference Example 94, the raw material compounds shown in Table 49 were produced. Table 49 shows the chemical structural formula (general formula) of this raw material compound, the reference example number (Rex.), The specific constitution and physicochemical properties of this raw material compound.
(Reference Example 101)
Tetrahydrofurfurylamine and 2-chloroisonicotinic acid in toluene under argon atmosphere, bis (dibenzylideneacetone) palladium, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl and sodium tert- The reaction was conducted in the presence of butoxide to produce 2-tetrahydrofurfurylaminoisonicotinic acid (MS: 221).

（ストレプトゾトシン誘発糖尿病性神経障害動物における鎮痛作用）
本発明化合物のうち代表的な化合物の神経因性疼痛の抑制効果はストレプトゾトシン（ＳＴＺ）誘発糖尿病性神経障害マウスにおける鎮痛作用の評価により確認した。評価は、Ｋａｍｅｉらの方法（Ｐｈａｒｍａｃｏｌｏｇｙ Ｂｉｏｃｈｅｍｉｓｔｒｙ ＆ Ｂｅｈａｖｉｏｒ ３９，５４１−５４４，１９９１）を一部改変して行った。
雄性４週齢ＩＣＲマウスに２００ｍｇ／ｋｇ体重のＳＴＺを腹腔内投与し、糖尿病性神経障害モデルを作成した。鎮痛作用の評価法はｔａｉｌ ｐｉｎｃｈ ｔｅｓｔを採用した。すなわち、鎮痛作用は尾をクランメで挟んでから動物が振り向き反応をとるまでの潜時の延長幅（秒）として検出した。ＳＴＺ投与後１４日目に試験化合物投与前試験を行い、試験化合物投与前反応潜時を測定した。試験化合物投与前反応潜時が３秒以下の動物のみを翌日（ＳＴＺ投与後１５日目）の試験化合物評価試験に供した。試験化合物評価試験においては試験化合物投与後反応潜時を測定した。試験化合物は３０ｍｇ／ｋｇを反応潜時測定の４５分前に経口投与した。結果を表５１に示す。試験化合物の鎮痛作用は、（試験化合物投与後反応潜時）−（試験化合物投与前反応潜時）の計算式によって潜時の延長幅（秒）として表す。
代表的な本発明化合物では、約１〜５秒の潜時の延長幅（秒）を示した。別途、本発明化合物の代わりに化合物を含まない溶媒（１０％ｗ／ｗ ＤＭＳＯ／水）で同様に試験した結果、潜時の延長幅（秒）は、０．６９±０．３８秒（平均値±標準偏差）であった。
通常、この鎮痛試験では、約１秒以上は活性があると考えられ、１．５秒を超えると優れた活性があり、約２秒を超えるものは非常に優れた鎮痛作用があると評価される。従って、試験した実施例化合物は、比較例１及び２に比べ、優れた活性を有するものである。さらにこれら化合物のうち、例えば、実施例１、１９、３１６及び４１２等はメキシレチンの約３秒に比べ同等以上であった。

比較例１：（特許文献４：欧州特許公開第１２５４９０４号公報）の実施例３０８に記載の化合物
比較例２：（特許文献４：欧州特許公開第１２５４９０４号公報）の実施例３３４に記載の化合物
（Ｌ５／Ｌ６脊髄神経結紮ラットにおける抗アロディニア効果）
神経因性疼痛における主要な症状の一つは触刺激に対する顕著な反応閾値低下（アロディニア）である。本発明化合物のうち代表的な化合物の神経因性疼痛の抗アロディニア効果はＬ５／Ｌ６脊髄神経結紮ラットにおける鎮痛作用の評価により確認した。評価は、Ｋｉｍ ａｎｄ Ｃｈｕｎｇの方法（Ｐａｉｎ ５０，３５５−３６３，１９９２）を一部改変して行った。
ペントバルビタール麻酔下において、雄性５又は６週齢ＳＤラットの左側のＬ５及びＬ６腰神経を絹糸で結紮する手術を施した。鎮痛作用の評価法はｖｏｎ Ｆｒｅｙｈａｉｒ ｔｅｓｔを採用した。すなわち、動物の後足裏を毛髪（ｈａｉｒ）でつつき、足上げ反応を起こす最小の毛髪の強度を機械刺激に対する反応閾値（１０ｇ ｇｒａｍ）とした。動物の結紮側足の反応閾値は手術後７日目から１４日目の間においては顕著に低下している（アロディニアの状態にある）ことが予備検討により確認出来たため、試験化合物の抗アロディニア効果は手術後７日目から１４日目の間の何れかの日に評価した。試験化合物評価前日に、試験化合物投与前反応閾値を測定した。試験化合物投与前反応閾値の群間の平均値の差及び群内のばらつきが小さくなるよう動物を４−５群に分けた。試験化合物評価試験においては試験化合物投与後反応閾値を測定した。試験化合物を反応閾値測定の３０分前に経口投与した。試験化合物の抗アロディニア作用の効力は、溶媒投与群の手術側足及び非手術側足の閾値をそれぞれ０％及び１００％と定義して算出したＥＤ_５０値として表す。
本発明化合物には約２〜３ｍｇ／ｋｇのＥＤ_５０値を示す化合物があり、メキシレチンの約７０ｍｇ／ｋｇと比べ非常に強力である。
上記試験によって、本発明化合物のうち代表的な化合物は、ナトリウムチャネル阻害作用を示すことが確認された。また、病態動物モデルである糖尿病性神経障害マウス及びＬ５／Ｌ６脊髄神経結紮ラットにおいて、経口投与で鎮痛作用を示すこと及び公知化合物より効果が優れていることが確認された。

Since the piperidine derivative of the present invention and a pharmaceutically acceptable salt thereof (the compound of the present invention) have a sodium channel inhibitory action, they are preferably used for drugs, particularly therapeutic drugs for diseases involving sodium channels and symptoms associated with the diseases. Is useful as an analgesic for neuropathic pain.
For example, neuropathic pain means pain due to peripheral or central nervous system dysfunction, and includes pain of diabetic neuropathy, cancer pain, trigeminal neuralgia, phantom limb pain, postherpetic pain, thalamic pain, etc. .
[Pharmacological test]
Hereinafter, a sodium channel inhibitory action test using a representative compound of the compounds of the present invention and an animal test using mice and rats will be described in detail.
(Sodium (Na) channel inhibition test)
Among the compounds of the present invention, the sodium channel inhibitory action of representative compounds was confirmed by [ ¹⁴ C] guanidine uptake experiments using rat brain tissue. [ ¹⁴ C] guanidine incorporation experiments were performed by modifying the method of Bonisch et al. (British Journal of Pharmacology 108, 436-442, 1993). [ ¹⁴ C] guanidine, a sodium tracer, was used to measure the inhibitory activity of [ ¹⁴ C] guanidine induced by veratridine, a sodium channel activator, on rat neuronal cortical primary neurons.
a. Preparation of rat cerebral cortex primary neuron culture system Pregnant rats (Wistar, female, 19 days of gestation) were anesthetized with ether and killed by exsanguination by carotid artery amputation. The fetus was extracted from the pregnant rat, disinfected with ethanol for disinfection, and then the cerebral cortex was extracted. The cerebral cortex was digested with papain, dispersed in a culture medium, and seeded on a 96-well white plate coated with poly-L-lysine at a density of 2.5 × 10 ⁵ cells / well, and a CO ₂ incubator (37 ° C., 5% The cells were cultured for 2 days in CO ₂ ).
b. Evaluation of test compound Each well was washed once with assay buffer (135 mM Choline Cl, 5 mM KCl, 1 mM MgSO ₄ , 5.5 mM Glucose, 1 mg / mL BSA, 10 mM Hepes-Tris, pH 7.4), and then assay buffer was used. In addition, incubation was performed at 25 ° C. for 10 minutes. Thereafter, the reaction solution (test compound, [ ¹⁴ C] guanidine and 100 μM veratridine) was substituted, and incubation was performed at 25 ° C. for 15 minutes. The reaction was stopped by washing three times with a cold washing buffer (135 mM NaCl, 5 mM KCl, 1 mM MgSO ₄ , 10 mM Hepes-Tris, pH 7.4). After adding 17 μL of 0.1 M NaOH to each well and stirring, 100 μL of scintillator was added and further stirred, and the radioactivity was measured with a liquid scintillation counter. The amount of sodium channel-specific uptake in each experiment was the portion of total uptake that was inhibited by 1 mM mexiletine. The effect of the test compound on the sodium channel is expressed as a 50% inhibition rate (IC ₅₀ value) for specific uptake.
As shown in Table 50, the compound of the present invention had a compound showing an IC ₅₀ value of about 1 to 30 μM, which was stronger than about 70 μM of mexiletine.

(Analgesic action in animals with streptozotocin-induced diabetic neuropathy)
The inhibitory effect of representative compounds among the compounds of the present invention on neuropathic pain was confirmed by evaluation of analgesic activity in streptozotocin (STZ) -induced diabetic neuropathy mice. Evaluation was carried out by partially modifying the method of Kamei et al. (Pharmacology Biochemistry & Behavior 39, 541-544, 1991).
200 mg / kg body weight of STZ was intraperitoneally administered to male 4-week-old ICR mice to prepare a diabetic neuropathy model. Tail pinch test was adopted as a method for evaluating analgesic action. That is, the analgesic action was detected as the extension width (seconds) of the latency from the time when the tail was sandwiched between the clams to the time when the animal turned around. On the 14th day after STZ administration, a test compound pre-administration test was conducted, and the response latency before test compound administration was measured. Only animals whose reaction latency before test compound administration was 3 seconds or less were subjected to the test compound evaluation test on the next day (15 days after STZ administration). In the test compound evaluation test, the reaction latency after administration of the test compound was measured. The test compound was orally administered at 30 mg / kg 45 minutes before measuring the response latency. The results are shown in Table 51. The analgesic action of the test compound is expressed as an extension width (second) of the latency by a calculation formula of (response latency after test compound administration) − (response latency before test compound administration).
A typical compound of the present invention exhibited an extension (second) of a latency of about 1 to 5 seconds. Separately, as a result of the same test using a solvent not containing a compound (10% w / w DMSO / water) instead of the compound of the present invention, the latency extension (second) was 0.69 ± 0.38 seconds (average) Value ± standard deviation).
Usually, in this analgesic test, it is considered that the activity is active for about 1 second or more, the activity is excellent when the time exceeds 1.5 seconds, and the property that the activity exceeds about 2 seconds is evaluated as having a very excellent analgesic effect. The Therefore, the tested Example compounds have superior activity compared to Comparative Examples 1 and 2. Furthermore, among these compounds, for example, Examples 1, 19, 316, 412 and the like were equivalent or better than about 3 seconds of mexiletine.

Comparative Example 1: Compound described in Example 308 of (Patent Document 4: European Patent Publication No. 1254904) Comparative Example 2: Compound described in Example 334 of (Patent Document 4: European Patent Publication No. 1254904) (Anti-allodynia effect in L5 / L6 spinal nerve ligation rats)
One of the major symptoms in neuropathic pain is a marked decrease in the threshold of response to touch (allodynia). The antiallodynic effect of neuropathic pain of representative compounds among the compounds of the present invention was confirmed by evaluation of analgesic action in L5 / L6 spinal nerve ligated rats. The evaluation was carried out by partially modifying the method of Kim and Chung (Pain 50, 355-363, 1992).
Under pentobarbital anesthesia, surgery was performed to ligate the left L5 and L6 lumbar nerves of male 5 or 6 week old SD rats with silk thread. The von Freyhair test was adopted as a method for evaluating the analgesic action. That is, the back of the animal's hind paw was pierced with hair, and the minimum hair strength that caused a foot-lifting reaction was defined as a response threshold (10 g gram) for mechanical stimulation. It was confirmed by preliminary examination that the reaction threshold of the ligation side foot of the animal was markedly lowered (from the allodynia state) between the 7th and 14th day after the operation. Therefore, the antiallodynic effect of the test compound Was evaluated on any day between day 7 and day 14 after surgery. On the day before the test compound evaluation, the reaction threshold before administration of the test compound was measured. The animals were divided into 4-5 groups so that the difference in the average value of the reaction threshold before administration of test compound and the variation within the group were reduced. In the test compound evaluation test, the reaction threshold was measured after test compound administration. Test compounds were administered orally 30 minutes before reaction threshold measurements. The efficacy of the anti-allodynia action of the test compound is expressed as an ED ₅₀ value calculated by defining the threshold values for the surgical and non-operative foot in the solvent administration group as 0% and 100%, respectively.
The compound of the present invention have compounds showing _{ED 50} values of about 2-3 mg / kg, which is very strong compared to about 70 mg / kg of mexiletine.
From the above test, it was confirmed that representative compounds of the present invention show sodium channel inhibitory action. In addition, it was confirmed that in diabetic neuropathy mice and L5 / L6 spinal nerve ligation rats, which are pathological animal models, exhibit analgesic action by oral administration and are more effective than known compounds.

Claims (19)

A sodium channel inhibitor containing a piperidine derivative represented by the following formula (IA) and a pharmaceutically acceptable salt thereof as an active ingredient.
(Formula (IA))

(The symbols in the above formula (IA) have the following meanings.
Cy ¹ : aryl which may be substituted or heterocycle which may be substituted,
R ¹ : H, OH, lower alkyl-O— or haloALK ¹ : lower alkylene, lower alkenylene, or lower alkynylene,
ALK ² : lower alkylene,
^{L 1: -NR 2 CO -,} - CONR 2 -, - CO -, - NR 2 SO 2 -, - SO 2 NR 2 -, - NR 2 CONR 3 - , or ^-NR 2 groups represented by COCO-,
R ² and R ^{3 are the} same or different and are selected from H, lower alkyl, lower alkenyl, (aryl optionally substituted with a group selected from group a below) -lower alkyl, or (selected from group a below) Heteroaryl optionally substituted with a group) -lower alkyl,
[Group a: halo, HO-, lower alkyl-O-]
L ² : bond, — (O) n ⁴ — (lower alkylene optionally substituted with a substituent selected from group b below) — (O) n ⁵ —, or lower alkenylene [group b: aryl, HO -, Lower alkyl-O-]
D: H or a group (group) shown below

(The symbols in the above groups have the following meanings.
Cy ² : heterocyclic group or hydrocarbon ring group,
R ⁴ and R ⁵ : the same or different, (1a) optionally substituted lower alkyl, (2a) cycloalkyl, (3a) optionally substituted aryl, (4a) lower alkyl-CO—, ( 5a) HOOC -, (6a) lower alkyl _{-O-CO -, (7a)} H 2 NCO -, (8a) H 2 NSO 2 -, (9a) lower alkyl -NHCO -, (10a) lower alkyl -NHSO ₂ -, (11a) (lower _{alkyl) 2 -NCO -, (12a)} ( lower _{alkyl) 2 -NSO 2 -, (13a} ) H 2 N -, (14a) an optionally substituted lower alkyl -NH-, (15a) (optionally substituted lower _alkyl) 2 -N -, _(16a) optionally substituted aryl -NH -, (17a) lower alkyl -CONH -, (18a) lower alkyl -SO ₂ NH -, (19a) an optionally substituted lower alkyl -O-CONH -, (20a) HO -, (21a) an optionally substituted lower alkyl -O -, (22a) cycloalkyl - O-, (23a) heterocyclic group -O-, (24a) HS-, (25a) lower alkyl-S-, (26a) cycloalkyl-S-, (27a) cyano, (28a) nitro, (29a) Oxide, (30a) halo, (31a) optionally substituted heterocyclic group),
------ : single bond or double bond,
n ¹ , n ² , n ³ , n ⁴ , n ⁵ , and n ⁶ : the same or different 0 or 1, provided that n ¹ + n ² and n ⁴ + n ⁵ are the same or different 0 or 1). The group represented by the symbol Cy ¹ in the formula (IA) is substituted with an aryl which may be substituted with a substituent selected from the following group c or a substituent selected from the following group c The sodium channel inhibitor according to claim 1, comprising a piperidine derivative which is a good heteroaryl and a pharmaceutically acceptable salt thereof as an active ingredient.
[Group c: (1) lower alkyl, (2) cycloalkyl, (3) halo lower alkyl, (4) aryl-lower alkyl, (5) aryl, (6) HOOC-, (7) lower alkyl-O- CO -, (8) lower alkyl -CO -, (9) aryl -CO -, (10) lower alkyl _{-SO 2 -, (11) H} 2 NCO -, (12) H 2 NSO 2 -, (13) lower alkyl -HNCO -, (14) (lower _alkyl) 2 -NCO -, ₍₁₅₎ lower alkyl -HNSO ₂ -, (16) (lower _{alkyl) 2 -NSO 2 -, (17} ) a heterocyclic -CO-, _{(18) H 2 N -,} (19) lower alkyl -NH -, (20) (lower _alkyl) 2 -N -, ₍₂₁₎ lower alkyl -CONH -, (22) lower alkyl -O-CONH -, ( 23) Lower alkyl-S _{2 NH -, (24) HO} -, (25) lower alkyl -O -, (26) cycloalkyl - lower alkyl -O -, (27) aryl - lower alkyl -O -, (28) methylenedioxy, ( 29) ethylenedioxy, (30) a heterocyclic group which may be substituted with 1 or 2 lower alkyl groups, (31) a heterocyclic group which may be substituted with 1 or 2 oxo (═O), (32) Cyano, (33) Nitro, (34) Oxo (O =), (35) Halo] The groups represented by the symbols R ⁴ and R ⁵ in the formula (IA) are (1b) lower alkyl optionally substituted with a substituent selected from the following group d, (2b) cycloalkyl, ( 3b) aryl optionally substituted with a substituent selected from the following group d, (4b) lower alkyl-CO—, (5b) HOOC—, (6b) lower alkyl-O—CO—, (7b) H _{2 NCO -, (8b) H} 2 NSO 2 -, (9b) lower alkyl -NHCO -, (10b) lower alkyl -NHSO ₂ -, (11b) (lower _{alkyl) 2 -NCO -, (12b)} ( lower alkyl ) ₂ -NSO _2- , (13b) H ₂ N-, (14b) lower alkyl-NH- optionally substituted with a substituent selected from group d below, (15b) (selected from group d below) Substituted with Lower _alkyl) 2 -N be -, (16b) below d aryl which may be substituted with selected substituents from the group -NH -, (17b) lower alkyl -CONH -, (18b) lower alkyl - SO ₂ NH—, (19b) Lower alkyl-O—CONH— optionally substituted with a substituent selected from group d below, (20b) HO—, (21b) A substituent selected from group d below (22b) cycloalkyl-O-, (23b) heterocyclic group -O-, (24b) HS-, (25b) lower alkyl-S-, (26b) A cycloalkyl-S-, (27b) cyano, (28b) nitro, (29b) oxide, (30b) halo, or (31b) a heterocyclic group optionally substituted with a substituent selected from group d below. Sodium channel inhibitor according to paragraph 1 or claim 2 to piperidine derivatives and pharmaceutically acceptable salt thereof as an active ingredient that.
[Group d: (1) lower alkyl, (2) cycloalkyl, (3) halo lower alkyl, (4) aryl-lower alkyl, (5) aryl, (6) HOOC-, (7) lower alkyl-O- CO -, (8) lower alkyl -CO -, (9) lower alkyl _{-SO 2 -, (10) H} 2 NCO -, (11) H 2 NSO 2 -, (12) lower alkyl -HNCO -, (13 ) (lower _alkyl) 2 -NCO -, (14) lower alkyl -HNSO ₂ -, (15) (lower _{alkyl) 2 -NSO 2 -, (16} ) heterocyclic _{-CO -, (17) H 2} N-, (18) a lower alkyl -NH -, (19) (lower _alkyl) 2 -N -, (20) a lower alkyl -CONH -, (21) lower alkyl -O-CONH -, (22) lower alkyl _-SO 2 NH -, (23) HO- (24) lower alkyl-O-, (25) cycloalkyl-lower alkyl-O-, (26) aryl-lower alkyl-O-, (27) methylenedioxy, (28) ethylenedioxy, (29) Heterocycle which may be substituted with 1 or 2 lower alkyl groups, (30) Heterocyclic group which may be substituted with 1 or 2 oxo (═O), (31) Cyano, (32) Nitro , (33) Oxo (O =), (34) Halo] A piperidine derivative in which the group represented by the symbol L ¹ in the formula (IA) is —NR ² CO—, —CONR ² —, —NR ² SO ₂ —, or —SO ₂ NR ² —, and pharmaceuticals thereof The sodium channel inhibitor according to any one of claims 1 to 3, comprising a salt that is pharmaceutically acceptable as an active ingredient. The sodium channel inhibitor according to any one of claims 1 to 4, which is a therapeutic agent for neuropathic pain. The sodium channel inhibitor according to any one of claims 1 to 5, which is a therapeutic agent for pain of diabetic neuropathy. Use of a piperidine derivative which is an active ingredient of a sodium channel inhibitor according to any one of claims 1 to 4 and a pharmaceutically acceptable salt thereof for the manufacture of a sodium channel inhibitor. Use of a piperidine derivative and a pharmaceutically acceptable salt thereof as an active ingredient of a sodium channel inhibitor according to any one of claims 1 to 4 for the manufacture of a therapeutic agent for neuropathic pain . A piperidine derivative which is an active ingredient of a sodium channel inhibitor according to any one of claims 1 to 4 and a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic drug for pain of diabetic neuropathy Use of. Administering a therapeutically effective amount of a piperidine derivative and a pharmaceutically acceptable salt thereof as an active ingredient of the sodium channel inhibitor according to any one of claims 1 to 4, A method for treating diseases caused by sodium channels. Administering a therapeutically effective amount of a piperidine derivative and a pharmaceutically acceptable salt thereof as an active ingredient of the sodium channel inhibitor according to any one of claims 1 to 4, A method of treating neuropathic pain. Administering a therapeutically effective amount of a piperidine derivative and a pharmaceutically acceptable salt thereof as an active ingredient of the sodium channel inhibitor according to any one of claims 1 to 4, A method for treating pain in diabetic neuropathy. Piperidine derivatives represented by the following formula (IB) and pharmaceutically acceptable salts thereof.
(Formula (IB))

(The symbols in the above formula (IB) have the following meanings.
Cy ¹ : aryl which may be substituted or heterocycle which may be substituted,
R ¹ : H, OH, lower alkyl-O— or haloALK ¹ : lower alkylene, lower alkenylene, or lower alkynylene,
ALK ² : lower alkylene,
^{L 1: -NR 2 CO -,} - CONR 2 -, - CO -, - NR 2 SO 2 -, - SO 2 NR 2 -, - NR 2 CONR 3 - , or ^-NR 2 groups represented by COCO-,
R ² and R ^{3 are the} same or different and are selected from H, lower alkyl, lower alkenyl, (aryl optionally substituted with a group selected from group a below) -lower alkyl, or (selected from group a below) Heteroaryl optionally substituted with a group) -lower alkyl,
[Group a: halo, HO-, lower alkyl-O-]
L ² : bond, — (O) n ⁴ — (lower alkylene optionally substituted with a substituent selected from group b below) — (O) n ⁵ —, or lower alkenylene [group b: aryl, HO -, Lower alkyl-O-]
D: H or a group (group) shown below

(The symbols in the above groups have the following meanings.
Cy ² : heterocyclic group or hydrocarbon ring group,
R ⁴ and R ⁵ : the same or different, (1a) optionally substituted lower alkyl, (2a) cycloalkyl, (3a) optionally substituted aryl, (4a) lower alkyl-CO—, ( 5a) HOOC -, (6a) lower alkyl _{-O-CO -, (7a)} H 2 NCO -, (8a) H 2 NSO 2 -, (9a) lower alkyl -NHCO -, (10a) lower alkyl -NHSO ₂ -, (11a) (lower _{alkyl) 2 -NCO -, (12a)} ( lower _{alkyl) 2 -NSO 2 -, (13a} ) H 2 N -, (14a) an optionally substituted lower alkyl -NH-, (15a) (optionally substituted lower _alkyl) 2 -N -, _(16a) optionally substituted aryl -NH -, (17a) lower alkyl -CONH -, (18a) lower alkyl -SO ₂ NH -, (19a) an optionally substituted lower alkyl -O-CONH -, (20a) HO -, (21a) an optionally substituted lower alkyl -O -, (22a) cycloalkyl - O-, (23a) heterocyclic group -O-, (24a) HS-, (25a) lower alkyl-S-, (26a) cycloalkyl-S-, (27a) cyano, (28a) nitro, (29a) Oxide, (30a) halo, or (31a) an optionally substituted heterocyclic group),
------ : single bond or double bond,
n ¹ , n ² , n ³ , n ⁴ , n ⁵ , and n ⁶ : the same or different 0 or 1, provided that n ¹ + n ² and n ⁴ + n ⁵ are the same or different 0 or 1,
In addition, the symbol in the said formula (IB) satisfy | fills the relationship shown to following (i)-(vii).
(I) When Cy ² is phenyl, Cy ¹ is aryl, ALK ¹ is lower alkylene having 2 or more carbon atoms, n ¹ is 0 and R ¹ is H,
(Ii) When Cy ² is adamantane, ALK ¹ is a lower alkylene having 2 or more carbon atoms,
(Iii) When Cy ² is a monocyclic hetero ring other than pyridine, ALK ¹ is a lower alkylene having 2 or more carbon atoms,
(Iv) When Cy ² is a bicyclic heterocycle, Cy ¹ is aryl or an optionally substituted heterocycle, L ¹ is —NR ² CO—, —CO—, —NR ² SO ₂ —, —SO _{^{2 NR 2 -, - NR 2}} CONR 3 - , or ^-NR 2 groups represented by COCO-,
(V) when L ¹ is a group represented by —NR ² SO ₂ —, n ¹ is 0;
(Vi) when the group -L ¹ -L ² -D is -CONR ² -lower alkyl, n ¹ is 0,
(Vii) When L ¹ is a group represented by -CO-, R ¹ is H) The group represented by the symbol Cy ¹ in the formula (IB) is substituted with an aryl which may be substituted with a substituent selected from the following group c or a substituent selected from the following group c The piperidine derivative according to claim 13, which is a good heteroaryl, and a pharmaceutically acceptable salt thereof.
[Group c: (1) lower alkyl, (2) cycloalkyl, (3) halo lower alkyl, (4) aryl-lower alkyl, (5) aryl, (6) HOOC-, (7) lower alkyl-O- CO -, (8) lower alkyl -CO -, (9) aryl -CO -, (10) lower alkyl _{-SO 2 -, (11) H} 2 NCO -, (12) H 2 NSO 2 -, (13) lower alkyl -HNCO -, (14) (lower _alkyl) 2 -NCO -, ₍₁₅₎ lower alkyl -HNSO ₂ -, (16) (lower _{alkyl) 2 -NSO 2 -, (17} ) a heterocyclic -CO-, _{(18) H 2 N -,} (19) lower alkyl -NH -, (20) (lower _alkyl) 2 -N -, ₍₂₁₎ lower alkyl -CONH -, (22) lower alkyl -O-CONH -, ( 23) Lower alkyl-S _{2 NH -, (24) HO} -, (25) lower alkyl -O -, (26) cycloalkyl - lower alkyl -O -, (27) aryl - lower alkyl -O -, (28) methylenedioxy, ( 29) ethylenedioxy, (30) a heterocyclic group which may be substituted with 1 or 2 lower alkyl groups, (31) a heterocyclic group which may be substituted with 1 or 2 oxo (═O), (32) Cyano, (33) Nitro, (34) Oxo (O =), (35) Halo] The groups represented by the symbols R ⁴ and R ⁵ in the formula (IB) are (1b) lower alkyl optionally substituted with a substituent selected from the following group d, (2b) cycloalkyl, ( 3b) aryl optionally substituted with a substituent selected from the following group d, (4b) lower alkyl-CO—, (5b) HOOC—, (6b) lower alkyl-O—CO—, (7b) H _{2 NCO -, (8b) H} 2 NSO 2 -, (9b) lower alkyl -NHCO -, (10b) lower alkyl -NHSO ₂ -, (11b) (lower _{alkyl) 2 -NCO -, (12b)} ( lower alkyl ) ₂ -NSO _2- , (13b) H ₂ N-, (14b) lower alkyl-NH- optionally substituted with a substituent selected from the following group d, (15b) (selected from the following group d) Substituted with Lower _alkyl) 2 -N be -, (16b) below d aryl which may be substituted with selected substituents from the group -NH -, (17b) lower alkyl -CONH -, (18b) lower alkyl - SO ₂ NH—, (19b) Lower alkyl-O—CONH— optionally substituted with a substituent selected from group d below, (20b) HO—, (21b) A substituent selected from group d below (22b) cycloalkyl-O-, (23b) heterocyclic group -O-, (24b) HS-, (25b) lower alkyl-S-, (26b) A cycloalkyl-S-, (27b) cyano, (28b) nitro, (29b) oxide, (30b) halo, or (31b) a heterocyclic group optionally substituted with a substituent selected from group d below. Range paragraph 13 or 14 piperidine derivatives and pharmaceutically acceptable salt thereof according to the preceding claims that.
[Group d: (1) lower alkyl, (2) cycloalkyl, (3) halo lower alkyl, (4) aryl-lower alkyl, (5) aryl, (6) HOOC-, (7) lower alkyl-O- CO -, (8) lower alkyl -CO -, (9) lower alkyl _{-SO 2 -, (10) H} 2 NCO -, (11) H 2 NSO 2 -, (12) lower alkyl -HNCO -, (13 ) (lower _alkyl) 2 -NCO -, (14) lower alkyl -HNSO ₂ -, (15) (lower _{alkyl) 2 -NSO 2 -, (16} ) heterocyclic _{-CO -, (17) H 2} N-, (18) a lower alkyl -NH -, (19) (lower _alkyl) 2 -N -, (20) a lower alkyl -CONH -, (21) lower alkyl -O-CONH -, (22) lower alkyl _-SO 2 NH -, (23) HO- (24) lower alkyl-O-, (25) cycloalkyl-lower alkyl-O-, (26) aryl-lower alkyl-O-, (27) methylenedioxy, (28) ethylenedioxy, (29) Heterocycle which may be substituted with 1 or 2 lower alkyl groups, (30) Heterocyclic group which may be substituted with 1 or 2 oxo (═O), (31) Cyano, (32) Nitro , (33) Oxo (O =), (34) Halo] The group represented by the symbol L ¹ in the formula (IB) is —NR ² CO—, —CONR ² —, —NR ² SO ₂ —, or —SO ₂ NR ² —. Item 16. A piperidine derivative according to any one of Items 15 to 15 and a pharmaceutically acceptable salt thereof. The piperidine derivative according to any one of claims 13 to 16, and the pharmaceutically acceptable group thereof, wherein the group represented by Cy ² in the symbol D in the formula (IB) is a heterocyclic group. Salt. The piperidine derivative represented by the formula (IB) is N- [2- (4-phenethylpiperidino) ethyl] isonicotinamide, N- [2- (4-phenethylpiperidino) ethyl] pyridine- 2-carboxamide, N- [2- (4-phenethylpiperidino) ethyl] nicotinamide, 4-isopropoxy-N- [2- (4-phenethylpiperidino) ethyl] nicotinamide, 3-methoxy-N -[2- (4-phenethylpiperidino) ethyl] isonicotinamide, N- [2- (4-phenethylpiperidino) ethyl] bicyclo [2.2.1] heptane-2-carboxamide, N- ( 2- {4-[(2-ethylphenoxy) methyl] piperidino} ethyl) -4-morpholinonicotinamide, N- (2- {4-[(2-ethylphenoxy) methyl] pipe Dino} ethyl) -2- (3-hydroxypyrrolidin-1-yl) isonicotinamide, 2-methyl-N- [2- (4-phenethylpiperidino) ethyl] imidazo [1,2-a] pyridine- 3-carboxamide, N- (2- {4- [2- (2-methoxyphenyl) ethyl] piperidino} ethyl) nicotinamide, N- (2- {4- [2- (2-methoxyphenyl) ethyl] piperidino } Ethyl) -2-oxo-1,2-dihydroisonicotinamide, N- (2- {4- [2- (3-chlorophenyl) ethyl] piperidino} ethyl) nicotinamide, N- [2- (4- Phenethylpiperidino) ethyl] thiophene-2-carboxamide, (Z) -N- [2- (4-styrylpiperidino) ethyl] nicotinamide, (E) -N- (2- {4- [2 (2,6-dimethylphenyl) vinyl] piperidino} ethyl) nicotinamide, N- (2- {4-[(2,6-dimethylphenyl) ethynyl] piperidino} ethyl) nicotinamide, N- [2- (3 -Phenethylpiperidino) ethyl] nicotinamide, N- [2- (4-phenethylpiperidino) ethyl] benzamide, N-tert-butyl-3- (4-phenethylpiperidino) propanamide, and N- The piperidine derivative according to claim 13, which is at least one compound selected from the group consisting of benzyl-N- [2- (4-phenethylpiperidino) ethyl] nicotinamide and a pharmaceutically acceptable salt thereof. salt. A pharmaceutical composition comprising the piperidine derivative according to any one of claims 13 to 18 and a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.