JP6242464B2 - トランス−2−デセン酸誘導体及びこれを含有する医薬 - Google Patents
トランス−2−デセン酸誘導体及びこれを含有する医薬 Download PDFInfo
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- JP6242464B2 JP6242464B2 JP2016224622A JP2016224622A JP6242464B2 JP 6242464 B2 JP6242464 B2 JP 6242464B2 JP 2016224622 A JP2016224622 A JP 2016224622A JP 2016224622 A JP2016224622 A JP 2016224622A JP 6242464 B2 JP6242464 B2 JP 6242464B2
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- decenoyl
- acid
- decenoic acid
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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Description
(1)下記一般式(I')で表されるトランス-2-デセン酸誘導体又はその薬学的に許容される塩。
(a)カルボキシル若しくはアルコキシカルボニルで置換されている1-ピロリジル、
(b)3-チアゾリジル、
(c)アルキル、オキソ、ヒドロキシ、アルコキシ、カルボキシル、アルコキシカルボニル、アルキルアミノ、アルキルアミノアルキル、フェニル、カルボキシアルキル、アルコキシカルボニルアルキル、シアノ若しくはハロゲノフェニルで置換されているピペリジノ、
(d)チオモルホリノ、
(e)アルキル、カルボキシアルキル、アルコキシカルボニルアルキル、アルキルアミノアルキル、シクロアルキル、ピペリジノアルキル、フェニルアルキル、ピリジル、ピリミジル、カルボキシフェニルアルキル若しくはアルコキシカルボニルフェニルアルキルで置換されていてもよい1-ピペラジル、
(f)アルキルアミノ、ハロゲン、アルコキシ、アルキル、ヒドロキシ、カルボキシアルコキシ若しくはアルコキシカルボニルアルコキシで置換されていてもよいフェニルで置換されている1-ピペラジル、
(g)アルキル若しくはアルキルアミノアルキルで置換されていてもよい1,4-ジアゼパニル、又は、
(h)カルボキシモルホリノ
を表す。〕
(2)X'がカルボキシル若しくはアルコキシカルボニルで置換されている1-ピロリジルである前記(1)記載のトランス-2-デセン酸誘導体又はその薬学的に許容される塩。
(3)X'が3-チアゾリジルである前記(1)記載のトランス-2-デセン酸誘導体又はその薬学的に許容される塩。
(4)X'がアルキル、オキソ、ヒドロキシ、アルコキシ、カルボキシル、アルコキシカルボニル、アルキルアミノ、アルキルアミノアルキル、フェニル、カルボキシアルキル、アルコキシカルボニルアルキル、シアノ若しくはハロゲノフェニルで置換されているピペリジノである前記(1)記載のトランス-2-デセン酸誘導体又はその薬学的に許容される塩。
(5)X'がチオモルホリノである前記(1)記載のトランス-2-デセン酸誘導体又はその薬学的に許容される塩。
(6)X'がアルキル、カルボキシアルキル、アルコキシカルボニルアルキル、アルキルアミノアルキル、シクロアルキル、ピペリジノアルキル、フェニルアルキル、ピリジル、ピリミジル、カルボキシフェニルアルキル若しくはアルコキシカルボニルフェニルアルキルで置換されていてもよい1-ピペラジルである前記(1)記載のトランス-2-デセン酸誘導体又はその薬学的に許容される塩。
(7)X'がアルキルアミノ、ハロゲン、アルコキシ、アルキル、ヒドロキシ、カルボキシアルコキシ若しくはアルコキシカルボニルアルコキシで置換されていてもよいフェニルで置換されている1-ピペラジルである前記(1)記載のトランス-2-デセン酸誘導体又はその薬学的に許容される塩。
(8)X'がアルキル若しくはアルキルアミノアルキルで置換されていてもよい1,4-ジアゼパニルである前記(1)記載のトランス-2-デセン酸誘導体又はその薬学的に許容される塩。
(9)X'がカルボキシモルホリノである前記(1)記載のトランス-2-デセン酸誘導体又はその薬学的に許容される塩。
(a)カルボキシル若しくはアルコキシカルボニルで置換されていてもよい1-ピロリジル、
(b)3-チアゾリジル、
(c)アルキル、オキソ、ヒドロキシ、アルコキシ、カルボキシル、アルコキシカルボニル、アルキルアミノ、アルキルアミノアルキル、フェニル、カルボキシアルキル、アルコキシカルボニルアルキル、シアノ若しくはハロゲノフェニルで置換されていてもよいピペリジノ、
(d)モルホリノ、
(e)カルボキシルで置換されていてもよいチオモルホリノ、
(f)アルキル、カルボキシアルキル、アルコキシカルボニルアルキル、アルキルアミノアルキル、シクロアルキル、ピペリジノアルキル、フェニルアルキル、ピリジル、ピリミジル、カルボキシフェニルアルキル若しくはアルコキシカルボニルフェニルアルキルで置換されていてもよい1-ピペラジル、
(g)アルキルアミノ、ハロゲン、アルコキシ、アルキル、ヒドロキシ、カルボキシアルコキシ若しくはアルコキシカルボニルアルコキシで置換されているフェニルで置換されている1-ピペラジル、
(h)1-アゼパニル、又は、
(i)アルキル若しくはアルキルアミノアルキルで置換されていてもよい1,4-ジアゼパニル
を表す。〕
(11)Xがカルボキシル若しくはアルコキシカルボニルで置換されていてもよい1-ピロリジルである前記(10)記載の医薬。
(12)Xが3-チアゾリジルである前記(10)記載の医薬。
(13)Xがアルキル、オキソ、ヒドロキシ、アルコキシ、カルボキシル、アルコキシカルボニル、アルキルアミノ、アルキルアミノアルキル、フェニル、カルボキシアルキル、アルコキシカルボニルアルキル、シアノ若しくはハロゲノフェニルで置換されていてもよいピペリジノである前記(10)記載の医薬。
(14)Xがカルボキシルで置換されていてもよいモルホリノである前記(10)記載の医薬。
(15)Xがチオモルホリノである前記(10)記載の医薬。
(16)Xがアルキル、カルボキシアルキル、アルコキシカルボニルアルキル、アルキルアミノアルキル、シクロアルキル、ピペリジノアルキル、フェニルアルキル、ピリジル、ピリミジル、カルボキシフェニルアルキル若しくはアルコキシカルボニルフェニルアルキルで置換されていてもよい1-ピペラジルである前記(10)記載の医薬。
(17)Xがアルキルアミノ、ハロゲン、アルコキシ、アルキル、ヒドロキシ、カルボキシアルコキシ若しくはアルコキシカルボニルアルコキシで置換されていてもよいフェニルで置換されている1-ピペラジルである前記(10)記載の医薬。
(18)Xが1-アゼパニルである前記(10)記載の医薬。
(19)Xがアルキル若しくはアルキルアミノアルキルで置換されていてもよい1,4-ジアゼパニルである前記(10)記載の医薬。
(21)前記抗がん剤が微小管阻害剤である前記(20)記載の医薬。
(22)前記微小管阻害剤がタキサン系薬剤である前記(21)記載の医薬。
(23)前記タキサン系薬剤がパクリタキセル又はドセタキセルである前記(22)記載の医薬。
(24)前記タキサン系薬剤がパクリタキセルである前記(23)記載の医薬。
(25)前記微小管阻害剤がビンカアルカロイド系薬剤である前記(21)記載の医薬。
(26)前記ビンカアルカロイド系薬剤がビンクリスチンである前記(25)記載の医薬。
(27)前記抗がん剤が白金製剤である前記(20)記載の医薬。
(28)前記白金製剤がオキサリプラチン又はシスプラチンである前記(27)記載の医薬。
(29)前記抗がん剤による末梢神経障害が急性又は慢性の疼痛、しびれ、知覚異常、知覚過敏又は感覚異常である前記(20)乃至(28)のいずれか一項に記載の医薬。
(30)神経栄養因子様作用剤である前記(10)乃至(19)のいずれか一項に記載の医薬。
(31)前記神経栄養因子様作用剤が神経変性疾患又は精神疾患の予防又は治療剤である前記(30)に記載の医薬。
(32)前記神経栄養因子様作用剤が神経変性疾患の予防又は治療剤である前記(31)に記載の医薬。
(33)前記神経変性疾患が、認知症、アルツハイマー病、パーキンソン病、筋萎縮性脊髄側索硬化症(ALS)、ハンチントン病、進行性核上性麻痺(PSP)、糖尿病性ニューロパシー又は緑内障である前記(32)記載の医薬。
(34)前記神経栄養因子様作用剤が精神疾患の予防又は治療剤である前記(31)に記載の医薬。
(35)前記精神疾患がうつ病、不安障害(神経症)又は自閉症スペクトラムである前記(34)に記載の医薬。
(36)脊髄損傷の治療剤又は修復剤である前記(10)乃至(19)のいずれか一項に記載の医薬。
(37)疼痛疾患に対する鎮痛剤である前記(10)乃至(19)のいずれか一項に記載の医薬。
(38)前記疼痛疾患に対する鎮痛剤が関節痛に対する治療剤である前記(37)記載の医薬。
(39)前記関節痛が変形性関節症による疼痛である前記(38)記載の医薬。
(40)前記変形性関節症が変形性膝関節症又は変形性股関節症である前記(39)記載の医薬。
(41)注射剤である前記(10)乃至(40)のいずれか一項に記載の医薬。
(42)経口剤である前記(10)乃至(40)のいずれか一項に記載の医薬。
(43)前記注射剤又は経口剤がシクロデキストリン包接体である前記(41)又は(42)の医薬。
(44)外用剤である前記(10)乃至(40)のいずれか一項に記載の医薬。
(45)前記外用剤が貼付剤である前記(44)記載の医薬。
(47)少なくとも1種の抗がん剤を含む薬剤の投与により生じる末梢神経障害の予防又は治療するために用いる前記(10)乃至(19)のいずれか一項に記載の化合物又はその薬学的に許容される塩。
(48)神経変性疾患又は精神疾患の予防又は治療するために用いる前記(10)乃至(19)のいずれか一項に記載の化合物又はその薬学的に許容される塩。
(49)疼痛疾患の予防又は治療するために用いる前記(10)乃至(19)のいずれか一項に記載の化合物又はその薬学的に許容される塩。
(50)前記(20)乃至(29)及び(31)乃至(40)のいずれか一項に記載の疾患の患者に、前記(10)乃至(19)のいずれか一項に記載の化合物又はその薬学的に許容される塩の有効量を投与することを特徴とする前記(20)乃至(29)及び(31)乃至(40)のいずれか一項に記載の疾患の予防又は治療方法。
(51)少なくとも1種の抗がん剤を含む薬剤の投与により生じる末梢神経障害を有する患者に前記(10)乃至(19)のいずれか一項に記載の化合物又はその薬学的に許容される塩の有効量を投与することを特徴とする少なくとも1種の抗がん剤を含む薬剤の投与により生じる末梢神経障害の予防又は治療方法。
(52)神経変性疾患又は精神疾患の患者に前記(10)乃至(19)のいずれか一項に記載の化合物又はその薬学的に許容される塩の有効量を投与することを特徴とする神経変性疾患又は精神疾患の予防又は治療方法。
(53)疼痛疾患の患者に前記(10)乃至(19)のいずれか一項に記載の化合物又はその薬学的に許容される塩の有効量を投与することを特徴とする疼痛疾患の予防又は治療方法。
(54)前記(20)乃至(29)及び(31)乃至(40)のいずれか一項に記載の疾患を治療するための医薬の製造における前記(10)乃至(19)のいずれか一項に記載の化合物又はその薬学的に許容される塩の使用。
(55)少なくとも1種の抗がん剤を含む薬剤の投与により生じる末梢神経障害の予防又は治療するための医薬の製造における前記(10)乃至(19)のいずれか一項に記載の化合物又はその薬学的に許容される塩の使用。
(56)神経変性疾患又は精神疾患の予防又は治療するための医薬の製造における前記(10)乃至(19)のいずれか一項に記載の化合物又はその薬学的に許容される塩の使用。
(57)鎮痛剤の製造における前記(10)乃至(19)のいずれか一項に記載の化合物又はその薬学的に許容される塩の使用。
さらに、本発明化合物は、優れた鎮痛作用を示す化合物であり、変形性関節症等の関節痛による疼痛等、種々の疼痛性疾患を予防又は治療するための薬剤として有用である。
(a)カルボキシル若しくはアルコキシカルボニルで置換されている1-ピロリジル、
(b)3-チアゾリジル、
(c)アルキル、オキソ、ヒドロキシ、アルコキシ、カルボキシル、アルコキシカルボニル、アルキルアミノ、アルキルアミノアルキル、フェニル、カルボキシアルキル、アルコキシカルボニルアルキル、シアノ若しくはハロゲノフェニルで置換されているピペリジノ、
(d)チオモルホリノ、
(e)アルキル、カルボキシアルキル、アルコキシカルボニルアルキル、アルキルアミノアルキル、シクロアルキル、ピペリジノアルキル、フェニルアルキル、ピリジル、ピリミジル、カルボキシフェニルアルキル若しくはアルコキシカルボニルフェニルアルキルで置換されていてもよい1-ピペラジル、
(f)アルキルアミノ、ハロゲン、アルコキシ、アルキル、ヒドロキシ、カルボキシアルコキシ若しくはアルコキシカルボニルアルコキシで置換されていてもよいフェニルで置換されている1-ピペラジル、
(g)アルキル若しくはアルキルアミノアルキルで置換されていてもよい1,4-ジアゼパニル、又は、
(h)カルボキシルモルホリノ
を表す。〕
(a)カルボキシル若しくはアルコキシカルボニルで置換されていてもよい1-ピロリジル、
(b)3-チアゾリジル、
(c)アルキル、オキソ、ヒドロキシ、アルコキシ、カルボキシル、アルコキシカルボニル、アルキルアミノ、アルキルアミノアルキル、フェニル、カルボキシアルキル、アルコキシカルボニルアルキル、シアノ若しくはハロゲノフェニルで置換されていてもよいピペリジノ、
(d)カルボキシルで置換さていてもよいモルホリノ、
(e)チオモルホリノ、
(f)アルキル、カルボキシアルキル、アルコキシカルボニルアルキル、アルキルアミノアルキル、シクロアルキル、ピペリジノアルキル、フェニルアルキル、ピリジル、ピリミジル、カルボキシフェニルアルキル若しくはアルコキシカルボニルフェニルアルキルで置換されていてもよい1-ピペラジル、
(g)アルキルアミノ、ハロゲン、アルコキシ、アルキル、ヒドロキシ、カルボキシアルコキシ若しくはアルコキシカルボニルアルコキシで置換されていてもよいフェニルで置換されている1-ピペラジル、
(h)1-アゼパニル、又は、
(i)アルキル若しくはアルキルアミノアルキルで置換されていてもよい1,4-ジアゼパニル
を表す。〕
シクロアルキルとは、いかなるものであってもよいが、好ましくは、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、シクロオクチル等の炭素数3乃至8のシクロアルキル基を表し、さらに好ましくは炭素数5又は6のシクロアルキル基を表す。
ハロゲン(ハロゲノフェニル中の「ハロゲノ」を含む)とは、フッ素、塩素、臭素、ヨウ素等を表す。
上記の反応終了後、公知の精製及び単離操作(例えば、抽出、クロマトグラフィー、蒸留、再結晶等)を用いて、目的化合物を得ることができる。
1-((E)-2-デセノイル)ピロリジン(1-((E)-2-decenoyl)pyrrolidine)〔化合物1〕の製造
(E)-2-デセン酸及び塩化チオニルを用いて合成した(E)-2-デセン酸クロライド (1.9 g、0.01 mol) のテトラヒドロフラン溶液 (20 mL) に、ピリジン(0.79 g、0.01 mol) を含むピロリジン (0.71 g、0.01 mol) のテトラヒドロフラン溶液 (20 mL) を加え、温水浴上で3時間加熱還流した。過剰のテトラヒドロフランを留去後、反応液に水を加えて、酢酸エチルで抽出し、水洗後、酢酸エチルを留去した。残渣をシリカゲルカラムクロマトグラフィー(展開溶媒;ヘキサン:酢酸エチル=1:3)で精製して、目的化合物(1.4 g) を無色油状物質として得た。
無色油状物, C14H25NO MW 223, ESIMS (positive ion mode: rel.int): m/z 246.184 [M+Na]+ (Calcd for C14H25NONa, 246.1834), 1H-NMR (400 MHz, CDCl3) δ: 0.88 (3H, t, J = 6.8 Hz), 1.25・1.32 (8H, m), 1.45 (2H, m), 1.86 (2H, m), 1.96 (2H, m), 2.20 (2H, m), 3.518 (2H, t, J = 7.2 Hz), 3.524 (2H, t, J = 7.2 Hz), 6.09 (1H, d, J = 15.4 Hz), 6.91 (1H, dt, J = 15.4, 6.8 Hz).
(S)-1-((E)-2-デセノイル)ピロリジン-2-カルボン酸メチルエステル((S)-1-((E)-2-decenoyl)pyrrolidine-2-carboxylic acid methyl ester)〔化合物3〕の製造
(E)-2-デセン酸(0.92 mL、5 mmol)、L-プロリンメチルエステル塩酸塩(0.91 g、5.5 mmol)のジクロロメタン(50 mL)溶液にトリエチルアミン(0.84 mL、6 mmol)及びl-エチル3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(WSC・HCl)(1.05 g、5.5 mmol)を室温で加え24時間かき混ぜた。反応溶液を水、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。シリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=7:3)で精製して、目的化合物(1.23 g、87%)を無色油状物として得た。なお、以下、出発原料のアミンが塩酸塩でない場合はトリエチルアミンを添加しなくてもよい。
無色油状物, C16H27NO3 MW 281.4, EIMS: m/z 282 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 7.0 Hz, 3H), 1.21-1.31 (m, 8H), 1.34-1.44 (m, 2H), 1.70-1.97 (m, 3H), 2.02-2.27 (m, 3H), 3.38-3.65 (m, 5H), 4.31-4.35 and 4.70-4.74 (m, 1H), 5.97 and 6.25 (m, 1H), 6.61-6.71 (m, 1H).
(S)-1-((E)-2-デセノイル)ピロリジン-2-カルボン酸((S)-1-((E)-2-decenoyl) pyrrolidine-2-carboxylic acid)〔化合物2〕の製造
化合物3(0.84 g、3 mmol)をメタノール(40 mL)に溶かし、室温で1 mol/L水酸化ナトリウム水溶液(4 mL、NaOH 4 mmol)を加え、20時間かき混ぜた。溶媒を減圧下で留去した後、残渣を水に溶かし、10%クエン酸水溶液を加えてpHを約4に調整した。ジクロロメタンで抽出し、有機層を水、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥して目的化合物(0.72 g、90%)を無色油状物として得た。
無色油状物, C15H25NO3 MW 267.4, EIMS: m/z 268 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 7.0 Hz, 3H), 1.20-1.45 (m, 10H), 1.70-2.27 (m, 6H), 3.37-3.63 (m, 2H), 4.23-4.28 and 4.55-4.59 (m, 1H), 6.25 and 5.99 (m, 1H), 6.62-6.71 (m, 1H), 12.30-12.70 (br, 1H).
3-((E)-2-デセノイル)チアゾリジン(3-((E)-2-decenoyl)thiazolidine)〔化合物4〕の製造
(E)-2-デセン酸及びチアゾリジンを出発原料として用いて、実施例1と同様にして目的化合物を製造した。
無色油状物, C13H23NOS MW 241, HR-ESIMS (positive ion mode): m/z 264.1443 [M+Na]+ (Calcd for C13H23NOSNa, 264.1398), 1H-NMR (400 MHz, CDCl3) δ: 0.88 (3H, t, J = 6.8 Hz), 1.22-1.34 (8H, m), 1.46 (2H, m), 2.22 (2H, m), 3.01 (1H, t, J = 6.1 Hz ), 3.11 (1H, t, J = 6.1 Hz ), 3.83 (1H, t, J = 6.1 Hz ), 3.91 (1H, brt), 4.58 (1H, s), 4.65 (1H, s), 6.11 (1H, d, J = 15.0 Hz) , 6.96 (1H, dt, J = 15.0, 7.3 Hz).
1-((E)-2-デセノイル)ピペリジン(1-((E)-2-decenoyl)piperidine)〔化合物5〕の製造
(E)-2-デセン酸及びピペリジンを出発原料として用いて、実施例1と同様にして目的化合物を製造した。
無色油状物, C15H27NO MW 237, EIMS: m/z 237 [M]+, 1H-NMR (500 MHz, CDCl3) δ: 0.88 (3H, t, J = 7.0 Hz), 1.22-1.34 (8H, m), 1.42-1.47 (2H, m), 1.54-1.59 (4H, m), 1.62-1.68 (2H, m), 2.16-2.21 (2H, m), 3.44-3.65 (4H, m), 6.22-6.26 (1H, m), 6.83 (1H, dt, J = 15.1, 7.1 Hz)
1-((E)-2-デセノイル)-4-メチルピペリジン(1-((E)-2-decenoyl)-4-methylpiperidine)〔化合物6〕の製造
(E)-2-デセン酸及び4-メチルピペリジンを出発原料として用いて、実施例2と同様にして目的化合物を製造した。
無色油状物, C16H29NO MW 251.4, EIMS: m/z 252 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.93-1.11 (m, 8H), 1.20-1.32 (m, 8H), 1.35-1.44 (m, 2H), 1.54-1.67 (m, 3H), 2.12-2.19 (m, 2H), 2.51-2.60 (m, 1H), 2.92-3.11 (m, 1H), 3.96-4.15 (m, 1H), 4.32-4.41 (m, 1H), 6.43 (d, J = 15.0 Hz, 1H), 6.61 (dt, J = 15.0, 7.0 Hz, 1H).
1-((E)-2-デセノイル)ピペリジン-4-オン(1-((E)-2-decenoyl)piperidin-4-one)〔化合物7〕の製造
(E)-2-デセン酸及びピペリジン-4-オンを出発原料として用いて、実施例1と同様にして目的化合物を製造した。
淡黄色油状物, C15H25NO2 MW 251, HR-ESIMS (positive ion mode): m/z 274.1824 [M+Na]+ (Calcd for C15H25NO2Na, 274.1783), 1H-NMR (400 MHz, CDCl3) δ: 0.88 (3H, t, J = 6.8 Hz), 1.22-1.35 (8H, m), 1.47 (2H, m), 2.23 (2H, m), 2.51 (4H, t, J = 6.4 Hz) 3.82-3.97 (4H, m), 6.31 (1H, d, J = 15.2 Hz), 6.97 (1H, dt, J = 15.2, 7.3 Hz).
1-((E)-2-デセノイル)-4-ヒドロキシピペリジン(1-((E)-2-decenoyl)-4-hydroxypiperidine)〔化合物8〕の製造
(E)-2-デセン酸及び4-ヒドロキシピペリジンを出発原料として用いて、実施例2と同様にして目的化合物を製造した。
無色油状物, C15H27NO2 MW 253.4, EIMS: m/z 254 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 7.0 Hz, 3H), 1.20-1.32 (m, 10H), 1.36-1.44 (m, 2H), 1.66-1.76 (m, 2H), 2.13-2.20 (m, 2H), 3.00-3.09 (m, 1H), 3.16-3.25 (m, 1H), 3.65-3.73 (m, 1H), 3.76-3.84 (m, 1H), 3.88-3.96 (m, 1H), 4.74 (d, J = 4.1 Hz, 1H), 6.45 (d, J = 15.0 Hz, 1H), 6.63 (dt, J = 15.0, 7.0 Hz, 1H).
1-((E)-2-デセノイル)-4-メトキシピペリジン(1-((E)-2-decenoyl)-4-methoxypiperidine)〔化合物9〕の製造
化合物8(0.62 g、2.4 mmol)をTHF(10 mL)に溶かし、氷冷下で水素化ナトリウム(鉱油中60%)(0.10 g、2.6 mmol)を加えた。氷冷下で15分間かき混ぜた後、ヨウ化メチル(0.16 mL、2.6 mmol)を加え、室温で20時間かき混ぜた。反応液を水に加え、酢酸エチルで抽出した後、有機層を水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。シリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=3:2)で精製して、目的化合物(0.42 g、65%)を淡黄色油状物として得た。
淡黄色油状物, C16H29NO2 MW 267.4, EIMS: m/z 268 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 7.0 Hz, 3H), 1.20-1.43 (m, 12H), 1.75-1.85 (m, 2H), 2.12-2.19 (m, 2H), 3.08-3.17 (m, 1H), 3.22-3.30 (m, 1H), 3.25 (s, 3H), 3.33-3.42 (m, 1H), 3.70-3.88 (m, 2H), 6.45 (d, J = 15.0 Hz, 1H), 6.63 (dt, J = 15.0, 7.0 Hz, 1H).
1-((E)-2-デセノイル)ピペリジン-4-カルボン酸(1-((E)-2-decenoyl)piperidine-4-carboxylic acid)〔化合物10〕の製造
化合物11を出発原料として用いて、実施例3と同様にして目的化合物を製造した。
白色結晶, mp 88-89℃, C16H27NO3 MW 281.4, EIMS: m/z 281 [M]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 7.0 Hz, 3H), 1.19-1.31 (m, 8H), 1.32-1.46 (m, 4H), 1.77-1.87 (m, 2H), 2.12-2.20 (m, 2H), 2.46-2.54 (m, 1H), 2.71-2.82 (m, 1H), 3.03-3.16 (m, 1H), 3.90-4.00 (m, 1H), 4.18-4.28 (m, 1H), 6.44 (d, J = 15.0 Hz, 1H), 6.63 (dt, J = 15.0, 7.0 Hz, 1H), 12.28 (brs, 1H).
1-((E)-2-デセノイル)ピペリジン-4-カルボン酸エチルエステル(1-((E)-2-decenoyl)piperidine-4-carboxylic acid ethyl ester)〔化合物11〕の製造
(E)-2-デセン酸及びイソニペコチン酸エチルを出発原料として用いて、実施例2と同様にして目的化合物を製造した。
無色油状物, C18H31NO3 MW 309.4, EIMS: m/z 309 [M]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 7.0 Hz, 3H), 1.18 (t, J = 7.0 Hz, 3H), 1.20-1.32 (m, 8H), 1.33-1.49 (m, 4H), 1.80-1.88 (m, 2H), 2.13-2.19 (m, 2H), 2.56-2.64 (m, 1H), 2.71-2.81 (m, 1H), 3.05-3.16 (m, 1H), 3.92-4.07 (m, 1H), 4.07 (q, J = 7.0 Hz, 2H), 4.20-4.28 (m, 1H), 6.45 (d, J = 15.0 Hz, 1H), 6.63 (dt, J = 15.0, 7.0 Hz, 1H).
1-((E)-2-デセノイル)-4-ジメチルアミノピペリジン(1-((E)-2-decenoyl)-4-dimethylaminopiperidine)〔化合物12〕の製造
(E)-2-デセン酸及び4-ジメチルアミノピペリジンを出発原料として用いて、実施例2と同様にして目的化合物を製造した。
淡黄色油状物, C17H32N2O MW 280.5, EIMS: m/z 281 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 7.0 Hz, 3H), 1.13-1.31 (m, 10H), 1.36-1.44 (m, 2H), 1.70-1.79 (m, 2H), 2.12-2.20 (m, 7H), 2.26-2.34 (m, 1H), 2.56-2.65 (m, 1H), 2.93-3.04 (m, 1H), 3.99-4.07 (m, 1H), 4.33-4.41 (m, 1H), 6.45 (d, J = 15.0 Hz, 1H), 6.63 (dt, J = 15.0, 7.0 Hz, 1H).
また、油状物である化合物12を塩化メチレンに溶解して、塩化水素-ジオキサンで処理して、1-((E)-2-デセノイル)-4-ジメチルアミノピペリジン塩酸塩(結晶、mp 185-188℃)を製造した。
1-((E)-2-デセノイル)-4-ジエチルアミノピペリジン(1-((E)-2-decenoyl)-4-diethylaminopiperidine)〔化合物13〕の製造
(E)-2-デセン酸及び4-ジエチルアミノピペリジンを出発原料として用いて、実施例2と同様にして目的化合物を製造した。
淡黄色油状物, C19H36N2O MW 308.5, EIMS: m/z 309 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 7.0 Hz, 3H), 0.95 (t, J = 7.0 Hz, 6H), 1.15-1.31 (m, 10H), 1.36-1.43 (m, 2H), 1.63-1.72 (m, 2H), 2.13-2.20 (m, 2H), 2.45 (q, J = 7.0 Hz, 4H), 2.50-2.60 (m, 1H), 2.65-2.73 (m, 1H), 2.90-3.02 (m, 1H), 4.01-4.10 (m, 1H), 4.39-4.47 (m, 1H), 6.44 (d, J = 15.0 Hz, 1H), 6.61 (dt, J = 15.0, 7.0 Hz, 1H).
1-((E)-2-デセノイル)-4-ジエチルアミノメチルピペリジン(1-((E)-2-decenoyl)-4-diethylaminomethylpiperidine)〔化合物14〕の製造
(E)-2-デセン酸及び4-(ジエチルアミノメチル)ピペリジンを出発原料として用いて、実施例2と同様にして目的化合物を製造した。
淡赤色油状物, C20H38N2O MW 322.5, EIMS: m/z 323 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 7.0 Hz, 3H), 0.93 (t, J = 7.0 Hz, 6H), 0.90-0.97 (m, 2H), 1.20-1.30 (m, 8H), 1.35-1.43 (m, 2H), 1.60-1.80 (m, 3H), 2.10-2.19 (m, 4H), 2.41 (q, J = 7.0 Hz, 4H), 2.51-2.60 (m, 1H), 2.92-3.02 (m, 1H), 3.97-4.06 (m, 1H), 4.33-4.42 (m, 1H), 6.43 (d, J = 15.0 Hz, 1H), 6.61 (dt, J = 15.0, 7.0 Hz, 1H).
1-((E)-2-デセノイル)-4-(2-ジメチルアミノエチル)ピペリジン(1-((E)-2-decenoyl)-4-(2-dimethylaminoethyl)piperidine)〔化合物15〕の製造
(E)-2-デセン酸及び4-(2-ジメチルアミノエチル)ピペリジンを出発原料として用いて、実施例2と同様にして目的化合物を製造した。
淡黄色油状物, C19H36N2O MW 308.5, EIMS: m/z 309 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 7.0 Hz, 3H), 0.90-1.15 (m, 2H), 1.20-1.34 (m, 10H), 1.35-1.43 (m, 2H), 1.48-1.59 (m, 1H), 1.62-1.71 (m, 2H), 2.09 (s, 6H), 2.13-2.22 (m, 4H), 2.50-2.58 (m, 1H), 2.90-3.01 (m, 1H), 3.95-4.05 (m, 1H), 4.32-4.41 (m, 1H), 6.43 (d, J = 15.0 Hz, 1H), 6.60 (dt, J = 15.0, 7.0 Hz, 1H).
1-((E)-2-デセノイル)-4-フェニルピペリジン(1-((E)-2-decenoyl)-4-phenyl piperidine)〔化合物16〕の製造
(E)-2-デセン酸及び4-フェニルピペリジンを出発原料として用いて、実施例1と同様にして目的化合物を製造した。
無色油状物, C21H31NO MW 313, HR-ESIMS (positive ion mode): m/z 336.2330 [M+Na]+ (Calcd for C21H31NONa, 336.2303), 1H-NMR (400 MHz, CDCl3) δ: 0.88 (3H, t, J = 7.2 Hz), 1.22-1.34 (8H, m), 1.46 (2H, m), 1.66 (2H, m), 1.91 (2H, brd), 2.21 (2H, m), 2.66-2.80 (2H, m), 3.15 (1H, brt), 4.14 (1H, brd), 4.84 (1H, brd), 6.29 (1H, d, J = 15.0 Hz), 6.89 (1H, dt, J = 15.0, 7.3 Hz), 7.18-7.24 (3H, m), 7.32 (2H, t, J = 7.4 Hz).
(4-((E)-2-デセノイル)モルホリン(4-((E)-2-decenoyl)morpholine)〔化合物17〕の製造
(E)-2-デセン酸及びモルホリンを出発原料として用いて、実施例1と同様にして目的化合物を製造した。
無色油状物, C14H25NO2 MW 239, HR-ESIMS (positive ion mode): m/z 262.1827 [M+Na]+ (Calcd for C14H25NO2Na, 262.1783), 1H-NMR (400 MHz, CDCl3) δ: 0.88 (3H, t, J = 7.2 Hz), 1.24-1.33 (8H, m), 1.45 (2H, m), 2.20 (2H, m), 3.57 (2H, brs), 3.69 (6H, brs), 6.20 (1H, d, J = 15.2 Hz), 6.91 (1H, dt, J = 15.2, 7.1 Hz).
4-((E)-2-デセノイル)チオモルホリン(4-((E)-2-decenoyl)thiomorpholine)〔化合物18〕の製造
(E)-2-デセン酸及びチオモルホリンを出発原料として用いて、実施例1と同様にして目的化合物を製造した。
無色油状物, C14H25NOS MW 255, HR-ESIMS (positive ion mode): m/z 278.1575 [M+Na]+ (Calcd for C14H25NOSNa, 278.1555), 1H-NMR (400 MHz, CDCl3) δ: 0.88 (3H, t, J = 7.2 Hz), 1.23-1.33 (8H, m), 1.45 (2H, m), 2.20 (2H, m), 2.63 (4H, brs), 3.83 (2H, brs), 3.92 (2H, brs) , 6.20 (1H, d, J = 15.2 Hz), 6.87 (1H, dt, J = 15.2, 7.3 Hz).
1-((E)-2-デセノイル)-4-メチルピペラジン(1-((E)-2-decenoyl)-4-methylpiperazine)〔化合物19〕の製造
(E)-2-デセン酸及び1-メチルピペラジンを出発原料として用いて、実施例2と同様にして目的化合物を製造した。
淡黄色油状物, C15H28N2O MW 252.4, EIMS: m/z 253 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 7.0 Hz, 3H), 1.20-1.31 (m, 8H), 1.35-1.44 (m, 2H), 2.13-2.19 (m, 2H), 2.17 (s, 3H), 2.22-2.30 (m, 4H), 3.45-3.55 (m, 4H), 6.44 (dt, Jd = 14.0 Hz, Jt = 1.1 Hz, 1H), 6.65 (dt, J = 14.0, 7.2 Hz, 1H).
1-((E)-2-デセノイル)-4-イソプロピルピペラジン(1-((E)-2-decenoyl)-4-isopropylpiperazine)〔化合物20〕の製造
(E)-2-デセン酸及び1-イソプロピルピペラジンを出発原料として用いて、実施例2と同様にして目的化合物を製造した。
淡黄色油状物, C17H32N2O MW 280.5, EIMS: m/z 280 [M]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 7.0 Hz, 3H), 0.96 (d, J = 6.5 Hz, 6H), 1.20-1.31 (m, 8H), 1.36-1.42 (m, 2H), 2.11-2.20 (m, 2H), 2.35-2.42 (m, 4H), 2.65 (qq, J = 6.5, 6.5 Hz, 1H), 3.44-3.54 (m, 4H), 6.43 (dt, J = 15.0, 1.1 Hz, 1H), 6.63 (dt, J = 15.0, 7.0 Hz, 1H).
3-[4-((E)-2-デセノイル)ピペラジン-1-イル]プロピオン酸(3-[4-((E)-2-decenoyl)piperazin-1-yl]propionic acid)〔化合物21〕の製造
(E)-2-デセン酸及び3-ピペラジン-1-イルプロピオン酸エチル2塩酸塩(化合物21のエチルエステル)を出発原料として用いて、実施例2と同様にして3-[4-((E)-2-デセノイル)ピペラジン-1-イル]プロピオン酸エチルを製造し、アルカリけん化により目的化合物を白色結晶として得た。
白色結晶, mp 53-55℃, C17H30N2O3 MW 310.4, EIMS: m/z 311 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 7.0 Hz, 3H), 1.19-1.31 (m, 8H), 1.35-1.44 (m, 2H), 2.12-2.20 (m, 2H), 2.32-2.43 (m, 6H), 2.55-2.61 (m, 2H), 3.43-3.57 (m, 4H), 6.45 (d, J = 15.0 Hz, 1H), 6.65 (dt, J = 15.0, 7.0 Hz, 1H), 11.70-12.70 (brs, 1H).
また、低融点結晶である化合物21を塩化メチレンに溶解して、塩化水素-ジオキサンで処理して、3-[4-((E)-2-デセノイル)ピペラジン-1-イル]プロピオン酸塩酸塩(結晶、mp 201-203℃)を製造した。
1-((E)-2-デセノイル)-4-[2-(ジメチルアミノ)エチル]ピペラジン(1-((E)-2-decenoyl)-4-[2-(dimethylamino)ethyl]piperazine)〔化合物22〕の製造
(E)-2-デセン酸及び1-[2-(ジメチルアミノ)エチル]ピペラジンを出発原料として用いて、実施例1と同様にして目的化合物を製造した。
油状物, C18H35N3O MW 309, HR-ESIMS (positive ion mode): m/z 310.2868 [M+H]+ (calcd for C18H36N3O, 310.2858), 1H-NMR (500 MHz, CDCl3) δ: 0.88 (3H, t, J = 7.4 Hz), 1.27・1.31 (8H, m), 1.45 (2H, br t, J = 7.5 Hz), 2.19 (2H, dt, J = 6.9, 8.0 Hz), 2.32 (6H, s), 2.47 (4H, br s), 2.53 (4H, s), 3.56 (2H, br s), 3.68 (2H, br s), 6.21 (1H, d, J = 15.2 Hz), 6.86 (1H, dt, J = 6.9, 15.2 Hz).
4-シクロヘキシル-1-((E)-2-デセノイル) ピペラジン(4-cyclohexyl-1-((E)-2-decenoyl)piperazine)〔化合物23〕の製造
(E)-2-デセン酸及び1-シクロヘキシルピペラジンを出発原料として用いて、実施例2と同様にして目的化合物を製造した。
白色結晶, mp 33-34℃, C20H36N2O MW 320.5, EIMS: m/z 320 [M]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.85 (t, J = 7.0 Hz, 3H), 1.01-1.11 (m, 1H), 1.11-1.21 (m, 4H), 1.21-1.31 (m, 8H), 1.36-1.43 (m, 2H), 1.53-1.59 (m, 1H), 1.68-1.76 (m, 4H), 2.13-2.28 (m, 3H), 2.40-2.48 (m, 4H), 3.41-3.53 (m, 4H), 6.43 (d, J = 15.0 Hz, 1H), 6.64 (dt, J = 15.0, 7.0 Hz, 1H).
1-((E)-2-デセノイル)-4-(2-ピペリジン-1-イルエチル)ピペラジン(1-((E)-2-decenoyl)-4-(2-piperidin-1-ylethyl)piperazine)〔化合物24〕の製造
(E)-2-デセン酸及び1-[2-(1-ピペリジニル)エチル]ピペラジンを出発原料として用いて、実施例2と同様にして目的化合物を製造した。
白色結晶, C21H39N3O MW 349.6, EIMS: m/z 350 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 6.7 Hz, 3H), 1.20-1.31 (m, 8H), 1.32-1.42 (m, 4H), 1.43-1.50 (m, 4H), 2.11-2.20 (m, 2H), 2.27-2.43 (m, 12H), 3.42-3.53 (m, 4H), 6.43 (d, J = 15.0 Hz, 1H), 6.64 (dt, J = 15.0, 7.0 Hz, 1H).
1-((E)-2-デセノイル)-4-フェニルピペラジン(1-((E)-2-decenoyl)-4-phenyl piperazine)〔化合物25〕の製造
(E)-2-デセン酸及び1-フェニルピペラジンを出発原料として用いて、実施例1と同様にして目的化合物を製造した。
桃色油状物, C20H30N2O MW 314, HR-ESIMS (positive ion mode): m/z 337.2244 [M+Na]+ (Calcd for C20H30N2ONa, 337.2256), 1H-NMR (400 MHz, CDCl3) δ: 0.88 (3H, t, J = 6.8 Hz), 1.21-1.36 (8H, m), 1.46 (2H, m), 2.22 (2H, m), 3.18 (4H, t, J = 5.4 Hz), 3.71 (2H, brs), 3.83 (2H, brs), 6.27 (1H, d, J = 15.6 Hz), 6.88-6.96 (4H, m), 7.26-7.30 (2H, m).
4-ベンジル-1-((E)-2-デセノイル)ピペラジン(4-benzyl-1-((E)-2-decenoyl)piperazine)〔化合物26〕の製造
(E)-2-デセン酸及び1-ベンジルピペラジン2塩酸塩を出発原料として用いて、実施例2と同様にして目的化合物を製造した。
白色結晶, mp 62-63℃, C21H32N2O MW 328.5, EIMS: m/z 2329 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 7.0 Hz, 3H), 1.19-1.31 (m, 8H), 1.35-1.42 (m, 2H), 2.11-2.19 (m, 2H), 2.28-2.38 (m, 4H), 3.48 (s, 2H), 3.48-3.57 (m, 4H), 6.43 (d, J = 15.0 Hz, 1H), 6.65 (dt, J = 15.0, 7.0 Hz, 1H), 7.22-7.36 (m, 5H).
1-((E)-2-デセノイル)-4-(2-フェニルエチル)ピペラジン(1-((E)-2-decenoyl)-4-(2-phenylethyl)piperazine)〔化合物27〕の製造
(E)-2-デセン酸及び1-(2-フェネチル)ピペラジン2塩酸塩を出発原料として用いて、実施例2と同様にして目的化合物を製造した。
白色結晶, mp 33-34℃, C22H34N2O MW 342.5, EIMS: m/z 343 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 7.0 Hz, 3H), 1.19-1.31 (m, 8H), 1.36-1.44 (m, 2H), 2.11-2.21 (m, 2H), 2.36-2.45 (m, 4H), 2.52 (dd, J = 6.5, 8.3 Hz, 2H), 2.74 (dd, J = 6.5, 8.3 Hz, 2H), 3.46-3.56 (m, 4H), 6.45 (d, J = 15.0 Hz, 1H), 6.66 (dt, J = 15.0, 7.0 Hz, 1H), 7.15-7.31 (m, 5H).
1-((E)-2-デセノイル)-4-(4-ジメチルアミノフェニル)ピペラジン(1-((E)-2-decenoyl)-4-(4-dimethylaminophenyl)piperazine)〔化合物28〕の製造
(E)-2-デセン酸及び1-(4-ジメチルアミノフェニル)ピペラジン2塩酸塩を出発原料として用いて、実施例2と同様にして目的化合物を製造した。
淡褐色結晶, mp 73-74℃, C22H35N3O MW 357.5, EIMS: m/z 357 [M]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.85 (t, J = 7.0 Hz, 3H), 1.20-1.31 (m, 8H), 1.36-1.46 (m, 2H), 2.15-2.21 (m, 2H), 2.78 (s, 6H), 2.87-2.96 (m, 4H), 3.55-3.74 (m, 4H), 6.49 (d, J = 15.0 Hz, 1H), 6.64-6.72 (m, 3H), 6.86 (d, J = 8.7 Hz, 2H).
1-((E)-2-デセノイル)-4-(ピリジン-4-イル)ピペラジン(1-((E)-2-decenoyl)-4-(pyridin-4-yl)piperazine)〔化合物29〕の製造
(E)-2-デセン酸及び1-(4-ピリジル)ピペラジンを出発原料として用いて、実施例1と同様にして目的化合物を製造した。
淡褐色油状物, C19H29N3O MW 315, HR-ESIMS (positive ion mode): m/z 316.2349 [M+H]+ (Calcd for C19H30N3O, 316.2383), 1H-NMR (400 MHz, CDCl3) δ: 0.89 (3H, t, J = 7.2 Hz), 1.19・1.35 (10H, m), 1.47 (2H, m), 2.23 (2H, m), 2.49 (1H, brs), 3.39 (4H, t, J = 5.4 Hz), 3.70-3.88 (4H, m), 6.25 (1H, d, J = 15.0 Hz), 6.67 (2H, d, J = 6.4 Hz), 6.95 (1H, dt, J = 15.0, 7.3 Hz), 8.31 (2H, d, J = 6.4 Hz)
1-((E)-2-デセノイル)-4-(ピリジン-2-イル)ピペラジン(1-((E)-2-decenoyl)-4-(pyridin-2-yl)piperazine)〔化合物30〕の製造
(E)-2-デセン酸及び1-(2-ピリジル)ピペラジンを出発原料として用いて、実施例1と同様にして目的化合物を製造した。
無色結晶, mp 59-61℃, C19H29N3O MW 315, HR-ESIMS (positive ion mode): m/z 316.2346 [M+H]+ (Calcd for C19H29N3O, 316.2383), 1H-NMR (400 MHz, CDCl3) δ: 0.88 (3H, t, J = 7.2 Hz), 1.22-1.35 (8H, m), 1.47 (2H, m), 2.22 (2H, m), 3.53 (2H, brs), 3.60-3.71 (4H, m), 3.81 (2H, brs), 6.27 (1H, d, J = 15.2 Hz), 6.64-6.69 (2H, t, m), 6.93 (1H, dt, J = 15.2, 7.3 Hz), 7.51 (1H, m), 8.20 (1H, m)
1-((E)-2-デセノイル)-4-(ピリミジン-2-イル)ピペラジン(1-((E)-2-decenoyl)-4-(pyrimidin-2-yl)piperazine)〔化合物31〕の製造
(E)-2-デセン酸及び1-(2-ピリミジル)ピペラジンを出発原料として用いて、実施例1と同様にして目的化合物を製造した。
無色結晶, mp 93-94℃, C18H28N4O MW 316, HR-ESIMS (positive ion mode): m/z 339.2155 [M+Na]+ (Calcd for C18H29N4ONa, 339.2161), 1H-NMR (400 MHz, CDCl3) δ: 0.88 (3H, t, J = 7.2 Hz), 1.22-1.35 (8H, m), 1.47 (2H, m), 2.23 (2H, m), 3.64 (2H, brs), 3.76 (2H, brs), 3.82-3.88 (4H, m), 6.28 (1H, d, J = 15.2 Hz), 6.54 (1H, t, J = 4.9 Hz), 6.93 (1H, dt, J = 15.2, 7.4 Hz), 8.33 (2H, d, J = 4.9 Hz).
1-((E)-2-デセノイル)アゼパン(1-((E)-2-decenoyl)azepane)〔化合物32〕の製造
(E)-2-デセン酸及びヘキサメチレンイミンを出発原料として用いて、実施例1と同様にして目的化合物を製造した。
淡褐色油状物, C16H29NO MW 251, HR-ESIMS (positive ion mode): m/z 274.2145 [M+Na]+ (Calcd for C16H29NONa, 274.2147), 1H-NMR (400 MHz, CDCl3) δ: 0.88 (3H, t, J = 6.8 Hz), 1.24-1.33 (8H, m), 1.45 (2H, m), 1.53-1.60 (4H, m), 1.69-1.77 (4H, m), 2.20 (2H, m), 3.50 (2H, t, J = 6.0 Hz), 3.58 (2H, t, J = 6.2 Hz), 6.22 (1H, d, J = 15.6 Hz), 6.90 (1H, dt, J = 15.6, 7.4 Hz).
1-((E)-2-デセノイル) -4-メチル-[1,4]ジアゼパン(1-((E)-2-decenoyl)-4-methyl-[1,4]diazepane)〔化合物33〕の製造
(E)-2-デセン酸及び1-メチル-1,4ジアゼパンを出発原料として用いて、実施例2と同様にして目的化合物を製造した。
淡黄色油状物, C16H30N2O MW 266.4, EIMS: m/z 267 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 7.0 Hz, 3H), 1.19-1.31 (m, 8H), 1.36-1.45 (m, 2H), 1.71-1.81 (m, 2H), 2.13-2.20 (m, 2H), 2.23 and 2.24 (s x 2, 3H), 2.39-2.55 (m, 4H), 3.46-3.58 (m, 4H), 6.34-6.40 (m, 1H), 6.61-6.69 (m, 1H).
1-((E)-2-デセノイル)-4-(2-ジメチルアミノエチル)-[1,4]ジアゼパン(1-((E)-2-decenoyl)-4-(2-dimethylaminoethyl)-[1,4]diazepane)〔化合物34〕の製造
(E)-2-デセン酸及び1-(2-ジメチルアミノエチル)-1,4ジアゼパンを出発原料として用いて、実施例2と同様にして目的化合物を製造した。
淡黄色油状物, C19H37N3O MW 323.5, EIMS: m/z 324 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 7.0 Hz, 3H), 1.20-1.30 (m, 8H), 1.36-1.44 (m, 2H), 1.67-1.75 (m, 2H), 2.11 (s, 6H), 2.13-2.20 (m, 2H), 2.26-2.31 (m, 2H), 2.48-2.59 (m, 4H), 2.60-2.67 (m, 2H), 3.44-3.57 (m, 4H), 6.33-6.40 (m, 1H), 6.60-6.69 (m, 1H).
2-(1-((E)-2-デセノイル)-4-ピペリジル)酢酸(2-(1-((E)-Dec-2-enoyl)-4-piperidyl)acetic acid)〔化合物35〕の製造
(1) (E)-2-デセン酸及び2-(4-ピペリジル)酢酸エチル塩酸塩を出発原料として用いて、実施例2と同様にして2-(1-((E)-2-デセノイル)-4-ピペリジル)酢酸エチル(化合物35のエチルエステル)を製造した。
(2) 実施例3と同様に2-(1-((E)-2-デセノイル)-4-ピペリジル)酢酸エチルのアルカリけん化により目的化合物を製造した。
白色結晶, mp 65-66℃, C17H29NO3 MW 295.4, EIMS: m/z 296 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.87 (t, J = 7.1 Hz, 3H), 0.96-1.10 (m, 2H), 1.20-1.31 (m, 8H), 1.36-1.43 (m, 2H), 1.63-1.72 (m, 2H), 1.85-1.94 (m, 1H), 2.11-2.18 (m, 4H), 2.53-2.62 (m, 1H), 2.95-3.05 (m, 1H), 3.98-4.05 (m, 1H), 4.32-4.41 (m, 1H), 6.43 (d, J = 15.0 Hz, 1G), 6.61 (dt, Jd = 15.0 Hz, Jt = 7.0 Hz, 1H).
3-(1-((E)-2-デセノイル)-4-ピペリジル)プロパン酸(3-(1-((E)-Dec-2-enoyl)-4-piperidyl)propanoic acid)〔化合物36〕の製造
(1) (E)-2-デセン酸及び3-(4-ピペリジル)プロピオン酸エチル塩酸塩を出発原料として用いて、実施例2と同様にして3-(1-((E)-2-デセノイル)-4-ピペリジル)プロパン酸エチル(化合物36のエチルエステル)を製造した。
(2) 実施例3と同様に3-(1-((E)-2-デセノイル)-4-ピペリジル)プロパン酸エチルのアルカリけん化により目的化合物を製造した。
無色油状物, C18H31NO3 MW 309.4, EIMS: m/z 310 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 6.5 Hz, 3H), 0.90-1.02 (m, 2H), 1.20-1.31 (m, 8H), 1.36-1.51 (m, 5H), 1.63-1.71 (m, 2H), 2.13-2.18 (m, 2H), 2.23 (t, J = 7.5 Hz, 2H), 2.50-2.58 (m, 1H), 2.90-3.00 (m, 1H), 3.98-4.06 (m, 1H), 4.35-4.43 (m, 1H), 6.43 (d, J = 15.0 Hz, 1H), 6.61 (dt, Jd = 15.0 Hz, Jt = 7.0 Hz, 1H), 12.03 (br, 1H).
1-((E)-2-デセノイル)-4-シアノピペリジン(1-((E)-Dec-2-enoyl)-4-cyanopiperidine)〔化合物37〕の製造
(E)-2-デセン酸及びピペリジン-4-カルボニトリルを出発原料として用いて、実施例2と同様にして目的化合物を製造した。
無色油状物, C16H26N2O MW 262.4, EIMS: m/z 263 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.87 (t, J = 6.5 Hz, 3H), 1.20-1.23 (m, 8H), 1.37-1.43 (m, 2H), 1.56-1.69 (m, 2H), 1.81-1.90 (m, 2H), 2.14-2.19 (m, 2H), 3.08-3.14 (m, 1H), 3.20-3.28 (m, 1H), 3.35-3.43 (m, 1H), 3.70-3.83 (m, 2H), 6.45 (d, J = 15.0 Hz, 1H), 6.65 (dt, Jd = 15.0 Hz, Jt = 7.0 Hz, 1H).
1-((E)-2-デセノイル)-4-(4-クロロフェニル)ピペリジン(1-((E)-Dec-2-enoyl)-4-(4-chlorophenyl)piperidine)〔化合物38〕の製造
(E)-2-デセン酸及び4-(4-クロロフェニル)ピペリジンを出発原料として用いて、実施例2と同様にして目的化合物を製造した。
淡黄色油状物, C21H30ClNO MW 347.9, EIMS: m/z 348 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 7.0 Hz, 3H), 1.22-1.32 (m, 8H), 1.32-1.54 (m, 4H), 1.74-1.83 (m, 2H), 2.15-2.21 (m, 2H), 2.26-2.69 (m, 1H), 2.75-2.83 (m, 1H), 3.05-3.15 (m, 1H), 4.12-4.21 (m, 1H), 4.54-4.62 (m, 1H), 6.48 (d, J = 15.0 Hz, 1H), 6.65 (dt, Jd = 15.0 Hz, Jt = 7.0 Hz, 1H), 7.27 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H).
[4-[(E)-2-デセノイル)ピペラジン-1-イル]酢酸塩酸塩([4-[(E)-Dec-2-enoyl]piperazin-1-yl]acetic acid hydrochloride)〔化合物39〕の製造
(1) (E)-2-デセン酸及び2-(1-ピペラジニル)酢酸エチル2塩酸塩を出発原料として用いて、実施例2と同様にして[4-[(E)-2-デセノイル)ピペラジン-1-イル]酢酸エチル(化合物39のフリー体のエチルエステル)を製造した。
(2) 実施例3と同様に[4-[(E)-2-デセノイル)ピペラジン-1-イル]酢酸エチルのアルカリけん化により[4-[(E)-2-デセノイル)ピペラジン-1-イル]酢酸(化合物39のフリー体)を得た。
(3) 得られた化合物を塩化メチレンに溶解して、塩化水素-ジオキサンで処理して目的化合物を製造した。
白色結晶, mp 195℃(分解), C16H29ClN2O3 MW 332.9, EIMS: m/z 297 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.87 (t, J = 7.0 Hz, 3H), 1.20-1.33 (m, 8H), 1.38-1.46 (m, 2H), 2.15-2.21 (m, 2H), 3.20-3.53 (m, 4H), 3.70-4.10 (m, 4H), 4.12 (s, 2H), 6.48 (d, J = 15.0 Hz, 6.73 (dt, Jd = 15.0 Hz, Jt = 7.0 Hz, 1H).
4-[4-[(E)-2-デセノイル)ピペラジン-1-イル]ブタン酸塩酸塩(4-[4-[(E)-Dec-2-enoyl]piperazin-1-yl]butanoic acid hydrochloride)〔化合物40〕の製造
(1) (E)-2-デセン酸及び4-(1-ピペラジニル)酪酸エチル2塩酸塩を出発原料として用いて、実施例2と同様にして4-[4-((E)-2-デセノイル)ピペラジン-1-イル]ブタン酸エチル(化合物40のフリー体のエチルエステル)を製造した。
(2) 実施例3と同様に4-[4-((E)-2-デセノイル)ピペラジン-1-イル]ブタン酸エチルのアルカリけん化により4-[4-[(E)-2-デセノイル)ピペラジン-1-イル]ブタン酸(化合物40のフリー体)を得た。
(3) 得られた化合物を塩化メチレンに溶解して、塩化水素-ジオキサンで処理して目的化合物を製造した。
白色結晶, mp 203-205℃, C18H33ClN2O3 MW 360.9, EIMS: m/z 325 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 7.0 Hz, 3H), 1.20-1.31 (m, 8H), 1.35-1.43 (m, 2H), 1.61-1.69 (m, 2H), 2.13-2.18 (m, 2H), 2.23 (t, J = 7.2 Hz, 2H), 2.26-2.35 (m, 6H), 3.45-3.55 (m, 4H), 6.43 (d, J = 15.0 Hz, 1H), 6.64 (dt, Jd = 15.0 Hz, Jt = 7.0 Hz, 1H).
1-((E)-2-デセノイル)-4-(4-クロロフェニル)ピペラジン(1-((E)-Dec-2-enoyl)-4-(4-chlorophenyl)piperazine)〔化合物41〕の製造
(E)-2-デセン酸及び1-(4-クロロフェニル)ピペラジンを出発原料として用いて、実施例2と同様にして目的化合物を製造した。
淡黄色油状物, C20H29ClN2O MW 348.9, EIMS: m/z 348 [M]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 6.5 Hz, 3H), 1.20-1.31 (m, 8H), 1.37-1.45 (m, 2H), 2.15-2.22 (m, 2H), 3.07-3.18 (m, 4H), 3.60-3.70 (m, 4H), 6.51 (d, J = 15.0 Hz, 1H), 6.70 (dt, Jd = 15.0 Hz, Jt= 7.0 Hz, 1H), 6.90 (d, J = 9.0 Hz, 2H), 7.25 (J = 9.0 Hz, 2H).
1-((E)-2-デセノイル)-4-(4-メトキシフェニル)ピペラジン(1-((E)-Dec-2-enoyl)-4-(4-methoxyphenyl)piperazine)〔化合物42〕の製造
(E)-2-デセン酸及び1-(4-メトキシフェニル)ピペラジンを出発原料として用いて、実施例2と同様にして目的化合物を製造した。
白色結晶, mp 50-52℃, C21H32N2O2 MW 344.5, EIMS: m/z 344 [M]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 6.8 Hz, 3H), 1.20-1.31 (m, 8H), 1.38-1.45 (m, 2H), 2.15-2.21 (m, 2H), 2.94-3.01 (m, 4H), 3.60-3.67 (m, 4H), 3.68 (s, 3H), 6.50 (d, J = 15.0 Hz, 1H), 6.68 (dt, Jd = 15.0 Hz, Jt = 7.0 Hz, 1H), 6.83 (d, J = 9.1 Hz, 2H), 6.91 (d, J = 9.1 Hz, 2H).
1-((E)-2-デセノイル)-4-(4-メチルフェニル)ピペラジン(1-((E)-Dec-2-enoyl)-4-(4-methylphenyl)piperazine)〔化合物43〕の製造
(E)-2-デセン酸及び1-(p-トリル)ピペラジンを出発原料として用いて、実施例2と同様にして目的化合物を製造した。
白色結晶, mp 45-46℃, C21H32N2O MW 328.5, EIMS: m/z 328 [M]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.85 (t, J = 6.9 Hz, 3H), 1.20-1.30 (m, 8H), 1.36-1.45 (m, 2H), 2.20 (s, 3H), 2.15-2.23 (m, 2H), 3.00-3.08 (m, 4H), 3.60-3.70 (m, 4H), 6.50 (d, J = 15.0 Hz, 1H), 6.69 (dt, Jd = 15.0 Hz, Jt = 7.0 Hz, 1H), 6.85 (d, J = 8.5 Hz, 2H), 7.03 (d, J = 8.5 Hz, 2H).
1-((E)-2-デセノイル)-4-(4-フルオロフェニル)ピペラジン(1-((E)-Dec-2-enoyl)-4-(4-fluorophenyl)piperazine)〔化合物44〕の製造
(E)-2-デセン酸及び1-(4-フルオロフェニル)ピペラジンを出発原料として用いて、実施例2と同様にして目的化合物を製造した。
淡黄色油状物, C20H29FN2O MW 332.5, EIMS: m/z 332 [M]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 6.5 Hz, 3H), 1.20-1.31 (m, 8H), 1.37-1.45 (m, 2H), 2.16-2.22 (m, 2H), 3.00-3.09 (m, 4H), 3.62-3.72 (m, 4H), 6.50 (d, J = 15.0 Hz, 1H), 6.69 (dt, Jd = 15.0 Hz, Jt= 7.0 Hz, 1H), 6.95-7.00 (m, 2H), 7.03-7.09 (m, 2H).
1-((E)-2-デセノイル)-4-(2-クロロフェニル)ピペラジン(1-((E)-Dec-2-enoyl)-4-(2-chlorophenyl)piperazine)〔化合物45〕の製造
(E)-2-デセン酸及び1-(2-クロロフェニル)ピペラジンを出発原料として用いて、実施例2と同様にして目的化合物を製造した。
淡黄色油状物, C20H29ClN2O MW 348.9, EIMS: m/z 348 [M]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 ( t, J = 6.5 Hz, 3H), 1.21-1.31 (m, 8H), 1.38-1.45 (m, 2H), 2.15-2.21 (m, 2H), 2.90-2.98 (m, 4H), 3.65-3.75 (m, 4H), 6.50 (d, J = 15.0 Hz, 1H), 6.70 (dt, Jd = 15.0 Hz, Jt = 7.0 Hz, 1H), 7.04-7.08 (m, 1H), 7.13-7.17 (m, 1H), 7.28-7.32 (m, 1H), 7.41-7.45 (m, 1H).
1-((E)-2-デセノイル)-4-(4-ヒドロキシフェニル)ピペラジン(1-((E)-Dec-2-enoyl)-4-(4-hydoroxyphenyl)piperazine)〔化合物46〕の製造
(E)-2-デセン酸及び4-(1-ピペラジニル)フェノールを出発原料として用いて、実施例2と同様にして目的化合物を製造した。
淡赤色結晶, mp 85-87℃, C20H30N2O2 MW 330.5, EIMS: m/z 330 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 7.0 Hz, 3H), 1.20-1.30 (m, 8H), 1.38-1.40 (m, 2H), 2.15-2.21 (m, 2H), 2.87-2.96 (m, 4H), 3.59-3.69 (m, 4H), 6.49 (d, J = 15.0 Hz, 1H), 6.63-6.71 (m, 3H), 6.80 (d, J = 6.8 Hz, 2H), 8.88 (s, 1H).
2-[4-[4-((E)-2-デセノイル)ピペラジン-1-イル]フェノキシ]酢酸(2-[4-[4-((E)-Dec-2-enoyl)piperazin-1-yl]phenoxy]acetic acid)〔化合物47〕の製造
(1) (E)-2-デセン酸及び2-[4-(1-ピペラジニル)フェノキシ]酢酸エチル2塩酸塩を出発原料として用いて、実施例2と同様にして2-[4-[4-((E)-2-デセノイル)ピペラジン-1-イル]フェノキシ]酢酸エチル(化合物47のエチルエステル)を製造した。
(2) 実施例3と同様に2-[4-[4-((E)-2-デセノイル)ピペラジン-1-イル]フェノキシ]酢酸エチルのアルカリけん化により目的化合物を製造した。
白色結晶, mp 210℃(分解), C22H32N2O4 MW 388.5, EIMS: m/z 388 [M]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 ( t, J = 7.0 Hz, 3H), 1.21-1.32 (m, 8H), 1.37-1.45 (m, 2H), 2.15-2.20 (m, 2H), 2.91-3.00 (m, 4H), 3.60-3.71 (m, 4H), 6.50 (d, J = 15.0 Hz, 1H), 6.68 (dt, Jd = 15.0 Hz, Jt = 7.0 Hz, 1H), 6.76 (d, J = 7.1 Hz, 2H), 6.87 (d, J = 7.1 Hz, 2H).
4-[[4-((E)-2-デセノイル)ピペラジン-1-イル]メチル]安息香酸(4-[[4-((E)-Dec-2-enoyl)piperazin-1-yl]methyl]benzoic acid)〔化合物48〕の製造
(1) (E)-2-デセン酸及び4-(1-ピペラジニルメチル)安息香酸メチル2塩酸塩を出発原料として用いて、実施例2と同様にして4-[[4-((E)-2-デセノイル)ピペラジン-1-イル]メチル]安息香酸メチル(化合物48のメチルエステル)を製造した。
(2) 実施例3と同様に4-[[4-((E)-2-デセノイル)ピペラジン-1-イル]メチル]安息香酸メチルのアルカリけん化により目的化合物を製造した。
白色結晶, mp 114-116℃, C22H32N2O3 MW 372.5, EIMS: m/z 373 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J = 7.0 Hz, 3H), 1.20-1.30 (m, 8H), 1.35-1.43 (m, 2H), 2.12-2.18 (m, 2H), 2.30-2.38 (m, 4H), 3.45-3.55 (m, 4H), 3.55 (s, sH), 6.43 (d, J = 15.0 Hz, 1H), 6.64 (dt, Jd = 15.0 Hz, Jt = 7.0 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 12.8 (br, 1H).
4-[(E)-2-デセノイル]モルホリン-3-カルボン酸(4-[(E)-Dec-2-enoyl]morpholine-3-carboxylic acid)〔化合物49〕の製造
(1) (E)-2-デセン酸及びモルホリン-3-カルボン酸メチル塩酸塩を出発原料として用いて、実施例2と同様にして4-[(E)-2-デセノイル]モルホリン-3-カルボン酸メチル(化合物49のメチルエステル)を製造した。
(2) 実施例3と同様に4-[(E)-2-デセノイル]モルホリン-3-カルボン酸メチルのアルカリけん化により目的化合物を製造した。
淡黄色油状物, C15H25NO4 MW 283.4, EIMS: m/z 284 [M+H]+, 1H-NMR (500 MHz, CDCl3) δ: 0.88 (t, J = 7.0 Hz, 3H), 1.22-1.35 (m, 8H), 1.40-1.50 (m, 2H), 2.17-2.26 (m, 2H), 3.10-4.00 (m, 5H), 4.45-4.40 and 5.15-5.18 (m, 2H), 6.05 and 6.23 (d x 2, J = 15.0 Hz, 1H), 6.88-7.02 (m, 1H), 9.00 (br, 1H)..
抗がん剤のパクリタキセルを投与した場合に生じる副作用である末梢神経障害、すなわち機械的刺激によるアロディニア(通常痛みを引き起こさない触覚刺激で惹起される激痛)等の知覚過敏に対する本発明化合物の効果を調べた。本発明化合物を被験薬としてラットに腹腔内投与し、フォン・フライ試験を行った。
実験動物として6週齢のSD雄性ラット(1群6匹)を用い、パクリタキセル(2mg/kg)を1日おきに計4回腹腔内投与して、パクリタキセル誘発末梢神経障害ラットを作製した。被験薬は、パクリタキセルの投与開始18乃至25日後又は20乃至27日後の間に、いずれも300μ/kgとなるように単回腹腔内投与して、下記フォン・フライ試験を実施した。
底が金網の透明アクリルゲージに、上記(1)のラットを入れ、約3分間馴化させた後に、右後肢の機械刺激に対する50%反応閾値を、被験薬投与前、投与開始から1及び5時間後に測定した。
測定は、Chaplanら(Journal of Neuroscience Methods、53巻、1号、55-63頁、1994年)及びDixonら(Annual Review of Pharmacology and Toxicology、20巻、441-462頁、1980年)の方法に準じ、フォン・フライフィラメント(von Frey filament、North Coast Medical Inc.製)を用いて行った。8本のフィラメント〔刺激荷重(g):0.4、0.6、1.0、2.0、4.0、6.0、8.0、15.0〕のうち、2.0gのフィラメントより開始し、軽度にフィラメントが湾曲する程度の力で2〜3秒間、足底に対し垂直に当て、後肢が逃避反応を示した場合を陽性反応とした。また、フィラメントを除去した瞬間に逃避した場合も陽性とした。陽性反応がみられた場合は1つ下の、反応がなかった場合は1つ上の強さのフィラメントで同様に刺激し、反応が陰性から陽性へ又は陽性から陰性へと変化した時点を最初の2反応とした。その後4回連続して同様のup-down法により刺激を行った。合計6回の刺激に対する反応を用いて、機械刺激に対する50%反応閾値を測定し、各群の平均値±標準誤差を算出した。なお、陽性反応がないまま15.0gの刺激まで行った場合は15.0g、陽性反応が0.4gまで続いた場合は0.25gを各々の50%反応閾値とした。被験薬投与1時間後又は5時間後の50%反応閾値のうち高い方の50%反応閾値について、正常閾値を15として、下記の式により、50%反応閾値の回復率(%)を算出した。上記試験結果の一例を表6及び表7に示す。
50%反応閾値の回復率(%)=(被験薬投与1時間後又は5時間後の50%反応閾値−被験薬投与前の50%反応閾値)÷(正常閾値−被験薬投与前の50%反応閾値)×100
本発明化合物について、ウエスタンイムノブロッティングにより、MAPキナーゼ(ERK1/2)の活性化を以下のように測定した。
胎仔17日齢のラット大脳皮質から神経細胞を分散し、該神経細胞を、5%牛胎仔血清を含むダルベコ改変イーグル培地(DMEM)で1日培養した。無血清培地(B27supplement添加Neurobasal、インビトロジェン(株)社)に培養液を交換し、ポリオルニチンコートした培養シャーレにて2-4万個/cm2の密度で神経細胞を培養した。
なお、本発明化合物は、0.1%DMSOに溶解し、250μg/mLの濃度に調整した。対照(Control)は、0.1%DMSOを添加した。
本発明化合物について、慢性マイルドストレス誘導性うつ病モデルマウスを用いて、ウエスタンイムノブロッティングにより、MAPキナーゼ(ERK1/2)の活性化レベルを以下のように測定した。
(1)慢性マイルドストレス誘導性うつ病モデルマウスの作製及び被験薬の投与
7週齢ddY系雌性マウス(n=8〜12)に、次の操作を行った。(A)15分間の強制水泳後、2日間正常飼育する。(B)傾斜させたケージで2日間飼育後、1日間正常飼育する。(C)ケージの床敷きを濡らして1日間飼育後、1日間正常飼育する。(D)180回転/分の速度で回転するケージで1日間飼育後、1日間正常飼育する。(A)〜(D)を1回行った後、さらに、(B)〜(D)を2回繰り返した。このように、合計3週間にわたりストレスを負荷して、慢性マイルドストレス誘導性うつ病モデルマウスを作製した。この間、毎日1回、3週間にわたって、被験薬として本発明化合物をPBS又はDMSO等を含むPBS溶媒に溶解して経口投与した。
上記の慢性マイルドストレス負荷後の行動解析(尾懸垂試験及び明暗試験)が終了した後、脳から海馬を摘出した。海馬とその湿重量の19倍量の破砕液(1%Nonidet P40〔登録商標〕、1%デオキシコール酸ナトリウム、2mM EDTA、0.1%sodium dodecyl sulfate (SDS) 、0.15M NaCl、10mg/mL aprotinin、10mg/mL leupeptin、50 mM NaF、1mMオルトバナジン酸ナトリウム、1mM phenylmethylsulfonyl fluoride (PMSF) を含む20mMトリス塩酸緩衝液(pH 7.4):RIPAバッファー)をマイクロチューブ(1.5mL)にとり、超音波破砕した。その後、当該チューブを30分間氷上で静置してから遠心(1400×g、15分)し、上清をタンパク質抽出液とした。タンパク質抽出液に1/3量の電気泳動用サンプルバッファー(0.2 Mトリス塩酸緩衝液(pH 7.2)、8%SDS、40%glycerol、bromophenol blue (BPB))、1/10量の2-mercaptoethanolを加え、95℃で5分間加熱処理し、10%ポリアクリルアミドゲルでSDS電気泳動を行った。
本発明化合物について、慢性マイルドストレス誘導性うつ病モデルマウスを用いて、ウエスタンブロッティングにより、シグナル伝達経路がMAPK(ERK1/2)の下流に位置し、神経細胞の機能や記憶・学習能に重要な役割を果たす転写因子CREBの活性化レベル(CREBに対するリン酸化CREB(pCREB)の比率)を、上記試験例3と同様に測定した(n=3〜8)。ただし、一次抗体(抗CREB抗体、抗pCREB抗体)は1000倍希釈、二次抗体は10000倍希釈で反応させた。
上記試験例3(1)の慢性マイルドストレス誘導性うつ病モデルマウスに被験薬として本発明化合物を投与した後、尾懸垂試験により抑うつ症状の抑制効果の評価を行った。すなわち、マウスの尾の先端から1cm離れた場所を手でつかみ、床から10cmの高さで支えて、6分間観察し、抑うつ症状の指標となる無動時間の長さを測定した。なお、有意差検定は、Dunnett's testで行った。
上記試験例3(1)の慢性マイルドストレス誘導性うつ病モデルマウスに被験薬として本発明化合物を投与した後、明暗試験により不安症状の抑制効果の評価を行った。すなわち、高さ50cm、縦50cm、横25cm の明室と暗室の2つから成る木製の長方形の装置を用い、暗室にマウスを置き自由に探索させ、その後5分間にわたって明室に侵入した回数、明室に滞在した時間を計測した。本試験は、マウスが暗い場所を好む傾向があり、明るい場所に留まりにくい習性を持つが、好奇心から探索行動を起こし、明室に侵入するという性質を利用して、マウスの不安レベルを評価する試験である。なお、有意差検定は、Dunnett's testで行った。
変形性関節症(Osteoarthritis; OA)のモデル動物であるモノヨード酢酸ナトリウム(MIA)誘発OAラットを用いて、本発明鎮痛剤の鎮痛作用を調べる以下の実験を行った。
(1)MIA誘発OAラットの作製
6週齢雄性Wistar系ラットの機械刺激に対する50%反応閾値(測定方法は後述)を測定して、正常対照群を選別した。正常対照群以外のラットに対し、右膝関節内に生理食塩液で調製したMIAを300μg/50μLの用量で単回投与し、左膝関節内には生理食塩液50μLを投与して、MIA誘発OAラットを作製した。また、正常対照群には、両膝の関節内に生理食塩液50μLを投与した。
実験動物の6週齢雄性Wistar系ラットは、正常対照群以外については上記(1)のMIA投与の24日後に、機械刺激に対する50%反応閾値(測定方法は後述)及び体重を測定して、1群6匹として正常対照群、発症対照群、被験薬投与群の3群に群編成を行った。
被験薬として本発明化合物を用いた被験薬溶液(100μg /mL)は、0.1vol%のジメチルスルホキシド(DMSO)を含むリン酸緩衝生理食塩液(PBS)で調製した。
群編成直後(MIA投与14日後)に、被験薬投与群には500μg/kgの用量で被験薬溶液を腹腔内に単回投与した。また、正常対照群及び発症対照群には0.1vol%DMSO含有PBSを腹腔内に単回投与した。
試験例1の(2)と同様にフォン・フライ試験を実施し、MIA投与により誘発されるOAの痛覚過敏に対する50%反応閾値の回復率(%)を算出した。結果の一例を表11に示す。
また、ラット大脳皮質培養神経細胞や慢性マイルドストレス誘導性うつ病モデルマウスの海馬を用いた評価において、優れたMAPキナーゼリン酸化作用及びCREBリン酸化作用(神経栄養因子様作用)を示した。さらに、慢性マイルドストレス誘導性うつ病モデルマウスを用いた各種試験において、抑うつ症状や不安症状を改善する作用が示された。従って、本発明化合物は、認知症、アルツハイマー病、パーキンソン病、糖尿病性ニューロパシー、うつ病、緑内障、自閉症スペクトラム等の予防又は治療剤、脊髄損傷の修復剤として有用であることが期待される。
また、本発明化合物は、OAモデルであるMIA誘発OAラットを用いた動物実験において、優れた鎮痛効果や痛覚過敏抑制効果を有するものである。従って、本発明化合物は、種々の疼痛疾患、例えば、OA等による疼痛の予防又は治療剤として有用性の高いものである。
Claims (1)
- 下記一般式(II)で表される化合物と下記一般式(III)で表される化合物とを脱水縮合することによる下記一般式(I)で表されるトランス-2-デセン酸誘導体の製造方法。
(a)カルボキシル若しくはアルコキシカルボニルで置換されている1-ピロリジル、
(b)3-チアゾリジル、
(c)アルキル、オキソ、ヒドロキシ、アルコキシ、カルボキシル、アルコキシカルボニル、アルキルアミノ、アルキルアミノアルキル、フェニル、カルボキシアルキル、アルコキシカルボニルアルキル、シアノ若しくはハロゲノフェニルで置換されているピペリジノ、
(d)チオモルホリノ、
(e)アルキル、カルボキシアルキル、アルコキシカルボニルアルキル、アルキルアミノアルキル、シクロアルキル、ピペリジノアルキル、フェニルアルキル、ピリジル、ピリミジル、カルボキシフェニルアルキル若しくはアルコキシカルボニルフェニルアルキルで置換されていてもよい1-ピペラジル、
(f)アルキルアミノ、ハロゲン、アルコキシ、アルキル、ヒドロキシ、カルボキシアルコキシ若しくはアルコキシカルボニルアルコキシで置換されていてもよいフェニルで置換されている1-ピペラジル、
(g)アルキル若しくはアルキルアミノアルキルで置換されていてもよい1,4-ジアゼパニル、又は
(h)カルボキシモルホリノ
を表す。〕
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JP2017057207A (ja) | 2017-03-23 |
CA2870822A1 (en) | 2013-10-31 |
RU2602810C2 (ru) | 2016-11-20 |
KR20150013143A (ko) | 2015-02-04 |
JP6047152B2 (ja) | 2016-12-21 |
AU2013253408B2 (en) | 2015-07-09 |
CN104254521A (zh) | 2014-12-31 |
US20150087823A1 (en) | 2015-03-26 |
JPWO2013161993A1 (ja) | 2015-12-24 |
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AU2013253408A1 (en) | 2014-11-06 |
HK1203955A1 (zh) | 2015-11-06 |
EP2842942A1 (en) | 2015-03-04 |
RU2014147728A (ru) | 2016-06-20 |
CN104254521B (zh) | 2016-05-04 |
EP2842942A4 (en) | 2015-12-16 |
TWI636975B (zh) | 2018-10-01 |
CA2870822C (en) | 2016-06-21 |
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