TW201400453A - 反式－２－癸烯酸衍生物及含該衍生物之藥劑 - Google Patents

反式－２－癸烯酸衍生物及含該衍生物之藥劑 Download PDF

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TW201400453A
TW201400453A TW102114986A TW102114986A TW201400453A TW 201400453 A TW201400453 A TW 201400453A TW 102114986 A TW102114986 A TW 102114986A TW 102114986 A TW102114986 A TW 102114986A TW 201400453 A TW201400453 A TW 201400453A
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Taiwan
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group
compound
substituted
agent
decenoic acid
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TW102114986A
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TWI636975B (zh
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Munekazu Iinuma
Shoei Furukawa
Mitsuru Naiki
Tomonori Matsumoto
Kunihiko Higashiura
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Nippon Zoki Pharmaceutical Co
Nagoya Ind Science Res Inst
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    • 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
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    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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    • 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
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Abstract

本發明是關於新穎的反式-2-癸烯酸衍生物或其在藥學上可容許的鹽，以及含有該化合物做為有效成分的藥劑。本發明化合物的反式-2-癸烯酸衍生物或其在藥學上可容許的鹽，具體而言，是以通式(I)表示：□(式中，X表示1-吡咯啶基，3-四氫噻唑基，N-哌啶基等取代基)，做為對於由抗癌劑之投予所引起的末梢神經障礙的預防或治療劑，癡呆症、阿茲海默症、巴金森病、糖尿病性神經病變、憂鬱症、青光眼、自閉症譜系等神經退化疾病或精神疾病的預防或治療劑，脊髓損傷的治療或修復劑，對各種疼痛疾病的鎮痛劑等藥劑，其有用性高。

Description

反式-2-癸烯酸衍生物及含該衍生物之藥劑
本發明是，關於將新穎的反式-2-癸烯酸衍生物或其在藥學上可容許的鹽，及含有該化合物(在本申請案中，單稱「化合物」時，有時會包含其在藥學上可容許的鹽)做為有效成分的藥劑。具體而言，是關於具有由抗癌劑之投予所引起的末梢神經障礙之預防或治療作用，神經成長因子(NGF)或腦源性神經營養因子(BDNF)等類神經營養因子(neurotrophic factor)的作用，鎮痛作用等藥理作用的反式-2-癸烯酸衍生物或其在藥學上可容許的鹽，及含有該化合物做為有效成分的藥劑。
今日，在癌(惡性腫瘤)的治療上，適宜分別單獨或併用外科手術，放射線照射，化學療法。其中，化學療法使用的抗癌劑(抗惡性腫瘤劑)，本來就是具有細胞毒性(細胞障礙性)者，不僅對癌細胞，也會發生傷害人的正常細胞的副作用，因此以在盡可能的預防或治療該副作用下，同時充分發揮抗癌效果之方式對患者投予為重要。
就伴隨於抗癌劑投予的副作用而言，有血液障礙，消化器官障礙，神經障礙等多樣，最近的傾向，特別有急性或慢性的神經障礙問題在增多。這是被認為由於發揮顯著的抗癌效果的新抗癌劑的主要副作用是神經障礙情況較多，以及最近成為治療的中心的多劑併用療法的影響，血液障礙及消化器官障礙的副作用則比較有改善為原因。像這樣，現在伴隨於癌的化學療法的副作用的中心的神經障礙是，由於神經細胞的再生困難，一旦發生就無有效的對策，而呈現嚴重的症狀，或變成不可逆的障礙的情況，也會有不能繼續投予抗癌劑的情況，在癌的治療上成為重要的問題。
伴隨於抗癌劑投予的神經障礙，除了中樞神經系，自律神經系，末梢神經系之外，在味覺等感覺器官也會產生。其中，發生頻率比較高而成為問題的是，刺痛或如火燒一般的痛覺等疼痛，四肢末端的麻木、灼熱感等知覺異常，對冷感刺激的過敏等知覺過敏，感覺消失/感覺麻痺或不調和感等感覺異常，知覺性運動失調，肌力的降低等末梢神經系的神經障礙。本發明中引起末梢神經障礙之抗癌劑是甚麼都可以，但因抗癌劑投予所致的末梢神經系的病變被認為主要是神經軸突的退化所引起的。軸突內的微小管是參與在細胞***時紡錘體的形成，或細胞內胞器的配置或物質輸送等，在細胞的正常功能的維持上扮演重要的角色。紫杉醇(paclitaxel)，歐洲紫杉醇(docetaxel)等紫杉烷(taxane)系藥劑；及敏克瘤(vincristine)，敏畢瘤 (vinblastine)，長春地辛(vindesine)，溫諾平(vinorelbine)等長春花生物鹼類(vinca alkaloids)系藥劑是藉由以此微小管為標靶進行作用而抑制癌細胞的增殖，因此認為經常有正常的神經細胞的微小管也被傷害而引起神經障礙之情形。又，益樂鉑(oxaliplatin)，卡鉑(carboplatin)，順鉑(cisplatin)，奈達鉑(nedaplatin)等鉑製劑，被認為經常有直接傷害神經細胞，結果引起次生性的軸突障礙而引起神經障礙之情形。
在如以上的狀況下，抗癌劑所致的神經毒性的研究是沒有甚麼進展的領域，還沒有確立滿足預防或治療上述紫杉烷系抗癌劑等的副作用的末梢神經障礙之方法。因此，現在，為了緩和麻木症狀而使用甲鈷胺(mecobalamin)等維生素B12製劑或中藥的牛車腎氣丸等，對疼痛則使用抗憂鬱藥(鹽酸阿米替林(amitriptyline hydrochloride)，抗癲癇藥(卡巴氮平，carbamazepine)，抗心律不整藥(鹽酸美西律，mexiletine hydrochloride)及腎上腺皮質類固醇等，但效果有限。中止抗癌劑投予為阻止末梢神經障礙的唯一確實的方法，但投予中止後也會有末梢神經障礙持續或惡化的情況。在癌的治療上抗癌劑的投予是必要的，但強烈的末梢神經障礙會有難以繼續投予對癌有效性高的重要的抗癌劑的情況，成為癌治療上重大的問題。由於如以上的現狀，在臨床現場對於抗癌劑所引起的末梢神經障礙更有效的預防或治療劑有強烈的需求。
又，神經細胞是有情報傳遞功能的細胞，其損傷會成為重大的腦神經功能的喪失而顯現。在腦、脊 髄的中樞神經幾乎不能期望軸突的再生，神經細胞有損傷、退化時，有必要保護、活化神經細胞。做為這種生體防御機制，負責維持神經細胞的分化、生存，突觸(synapse)的功能亢進及損傷的神經軸突的再生、修復的角色之神經營養因子是不可缺少的。
神經營養因子中，神經成長因子(NGF)，腦源性神經營養因子(BDNF)，神經營養素-3(neurotrophin-3；NT-3)及神經營養素-4/5(NT-4/5)等是以NGF為原型(prototype)而構成有50%以上的序列同源性(sequence homology)的神經營養素族。分泌於細胞外的神經營養素與神經細胞膜上的高親和性受體(Trks)結合，則在神經細胞內向3個方向有訊息傳遞，經由其中一個的包含MAP激酶(有絲***活化蛋白激酶/細胞外訊息調節激酶蛋白(mitogen-activated protein(MAP)kinases/extracellular signal-regulated protein kinases,1/2(ERK1/2))的活化(磷酸化)的MAP激酶訊息傳遞路徑的活化而使轉錄因子的CREB(cAMP-response element binding protein)被活化，有許多基因的顯現被控制。因此，能活化經由MAP激酶訊息傳遞路徑活化訊息傳遞時，則在臨床上有可能應用於對神經細胞的退化或細胞死亡為成因的神經障礙。又，有針對BDNF與數個疾病的關連之報告。
由有關BDNF的基因多型性的研究，有報告指出BDNF的特定的多型，與巴金森病，阿茲海默症，憂鬱症，雙極性憂鬱症，焦慮症，自閉症譜系(autism spectrum)，青光眼等有關連。又，有亨丁頓舞蹈症(Huntington’s disease)的基因變異小鼠的突觸功能降低藉由BDNF的投予而恢復的報告，及有由MAP激酶磷酸化抑制劑的投予會引起抑鬱狀態的報告。
神經營養因子，如同由上述BDNF的例也可知，對特定的神經疾病表現治療效果，有使軸突發芽、伸長的作用。但是，神經營養因子是高分子量的蛋白質，因此即使由末梢投予也無法通過血腦障壁而有難以到達腦的問題。於是，有探索低分子量化合物且有使神經細胞活化的類神經營養因子的作用的藥劑、及促進神經營養因子的產生/分泌的藥劑的嘗試。
在專利文獻1，揭示碳數8或碳數10至12的脂肪酸或脂肪酸酯具有類神經營養因子作用。但是，專利文獻1記述的化合物是通常的脂肪酸或其酯，與本發明化合物在羧酸部分的結構明顯不同。又，本發明化合物的1-((E)-2-癸烯醯基)吡咯啶(化合物1)，1-((E)-2-癸烯醯基)哌啶(化合物5)及1-((E)-2-癸烯醯基)氮雜環庚烷(1-((E)-2-Decenoyl)azepane)(化合物32)揭示在專利文獻2中，(4-((E)-2-癸烯醯基)嗎啉(化合物17)揭示在專利文獻3或在非專利文獻1中。但是，專利文獻2是有關對於軟體動物的毒性作用，專利文獻3是有關對於病原菌及黴菌的成長抑制作用。又，非專利文獻1是有關對於家蠅的防蟲劑的文獻。總而言之，在這些文獻上都不存在有關本發明化合物的藥劑用途或其暗示的記述。
先前技術文獻 專利文獻
專利文獻1：國際公開第2009/038110號公報
專利文獻2：國際公開第2010/123894號公報
專利文獻3：美國專利第3294794號公報
非專利文獻
非專利文獻1：Journal of Economic Entomology, 1970, Vol. 63, No.6, p1752-1755
本發明是關於新穎的反式-2-癸烯酸衍生物或其在藥學上可容許的鹽，及含有該化合物做為有效成分的藥劑，更具體而言，是以提供具有抗癌劑所引起的末梢神經障礙的預防或治療作用(在本說明書中，「末梢神經障礙」是可由其同義語的「神經病變(neuropathy)」取代。又，「預防」及「治療」，都包含「改善」或「減輕」，「預防劑」及「治療劑」包含「改善劑」或「減輕劑」)，類神經營養因子的作用，鎮痛作用等藥理作用的藥劑為課題。
本發明者等為了解決上述的課題而精心研究結果，發現下述通式(I)表示的反式-2-癸烯酸衍生物或其在藥學上可容許的鹽，有優異的抗癌劑所引起的末梢神經 障礙的預防或治療作用，類神經營養因子的作用，鎮痛作用等藥理作用。本發明者等根據這些知識再進行研究，而達到本發明的完成。
即，本發明提供下述的化合物及含有該化合物的藥劑。
(1)下述通式(I’)表示的反式-2-癸烯酸衍生物或其在藥學上可容許的鹽。
[式中，X’表示(a)經羧基或烷氧羰基取代的1-吡咯啶基，(b)3-四氫噻唑基(thiazolidinyl)，(c)經烷基，側氧基，羥基，烷氧基，羧基，烷氧羰基，烷胺基，烷胺基烷基，苯基，羧烷基，烷氧羰基烷基，氰基或鹵苯基取代的N-哌啶基，(d)N-硫代嗎啉基，(e)可經烷基，羧烷基，烷氧羰基烷基，烷胺基烷基，環烷基，N-哌啶基烷基，苯烷基，吡啶基，嘧啶基，羧苯基烷基或烷氧羰基苯烷基取代的1-哌基，(f)經由可經烷胺基，鹵素，烷氧基，烷基，羥基，羧烷氧基或烷氧基羰基烷氧基取代的苯基而取代的1-哌基，(g)可經烷基或烷胺基烷基取代的1,4-二氮雜環庚烷基，或 (h)N-羧基嗎啉基]。
(2)前述(1)所述的反式-2-癸烯酸衍生物或其在藥學上可容許的鹽，其中，X’是經羧基或烷氧基羰基取代的1-吡咯啶基。
(3)前述(1)所述的反式-2-癸烯酸衍生物或其在藥學上可容許的鹽，其中，X’是3-四氫噻唑基。
(4)前述(1)所述的反式-2-癸烯酸衍生物或其在藥學上可容許的鹽，其中，X’是經烷基，側氧基，羥基，烷氧基，羧基，烷氧羰基，烷胺基，烷胺基烷基，苯基，羧烷基，烷氧基羰基烷基，氰基或鹵苯基取代的N-哌啶基。
(5)前述(1)所述的反式-2-癸烯酸衍生物或其在藥學上可容許的鹽，其中，X’是N-硫代嗎啉基。
(6)前述(1)所述的反式-2-癸烯酸衍生物或其在藥學上可容許的鹽，其中，X’是可經烷基，羧烷基，烷氧基羰基烷基，烷胺基烷基，環烷基，N-哌啶基烷基，苯烷基，吡啶基，嘧啶基，羧苯烷基或烷氧羰基苯烷基取代的1-哌基。
(7)前述(1)所述的反式-2-癸烯酸衍生物或其在藥學上可容許的鹽，其中，X’是經由可經烷胺基，鹵素，烷氧基，烷基，羥基，羧烷氧基或烷氧基羰基烷氧基取代的苯基而取代的1-哌基。
(8)前述(1)所述的反式-2-癸烯酸衍生物或其在藥學上可容許的鹽，其中，X’是可經烷基或烷胺基烷基取代的 1,4-二氮雜環庚烷基。
(9)前述(1)所述的反式-2-癸烯酸衍生物或其在藥學上可容許的鹽，其中，X’是N-羧基嗎啉基。
(10)含有下述通式(I)表示的反式-2-癸烯酸衍生物及或其在藥學上可容許的鹽的至少一種做為有效成分的藥劑。
[式中，X表示(a)可經羧基或烷氧基羰基取代的1-吡咯啶基，(b)3-四氫噻唑基，(c)可經烷基，側氧基，羥基，烷氧基，羧基，烷氧羰基，烷胺基，烷胺基烷基，苯基，羧烷基，烷氧基羰基烷基，氰基或鹵苯基取代的N-哌啶基，(d)N-嗎啉基，(e)可經羧基取代的N-硫代嗎啉基，(f)經烷基，羧烷基，烷氧羰基烷基，烷胺基烷基，環烷基，N-哌啶基烷基，苯烷基，吡啶基，嘧啶基，羧苯烷基或烷氧羰基苯烷基取代的1-哌基，(g)經由可經烷胺基，鹵素，烷氧基，烷基，羥基，羧烷氧基或烷氧基羰基烷氧基取代的苯基而取代的1-哌基，(h)1-氮雜環庚烷，或 (i)可經烷基或烷胺基烷基取代的1,4-二氮雜環庚烷基]。
(11)前述(10)所述的藥劑，其中，X是可經羧基或烷氧基羰基取代的1-吡咯啶基。
(12)前述(10)所述的藥劑，其中，X是3-四氫噻唑基。
(13)前述(10)所述的藥劑，其中，X是可經烷基，側氧基，羥基，烷氧基，羧基，烷氧基羰基，烷胺基，烷胺基烷基，苯基，羧烷基，烷氧基羰基烷基，氰基或鹵苯基取代的N-哌啶基。
(14)前述(10)所述的藥劑，其中，X是可經羧基取代的N-嗎啉基。
(15)前述(10)所述的藥劑，其中，X是N-硫代嗎啉基。
(16)前述(10)所述的藥劑，其中，X是可經烷基，羧烷基，烷氧基羰基烷基，烷胺基烷基，環烷基，N-哌啶基烷基，苯烷基，吡啶基，嘧啶基，羧苯烷基或烷氧羰基苯烷基取代的1-哌基。
(17)前述(10)所述的藥劑，其中，X是經由可經烷胺基，鹵素，烷氧基，烷基，羥基，羧烷氧基或烷氧羰基烷氧基取代的苯基而取代的1-哌基。
(18)前述(10)所述的藥劑，其中，X是1-氮雜環庚烷基。
(19)前述(10)所述的藥劑，其中，X是可經烷基或烷胺基烷基取代的1,4-二氮雜環庚烷基。
(20)前述(10)至(19)中任一項所述的藥劑，其係含至少1種 抗癌劑的藥劑的投予而引起的末梢神經障礙的預防或治療劑。
(21)前述(20)所述的藥劑，其中，前述抗癌劑是微小管抑制劑。
(22)前述(21)所述的藥劑，其中，前述微小管抑制劑是紫杉烷系藥劑。
(23)前述(22)所述藥劑，其中，前述紫杉烷系藥劑是紫杉醇或歐洲紫杉醇(docetaxel)。
(24)前述(23)所述的藥劑，其中，前述紫杉烷系藥劑是紫杉醇。
(25)前述(21)所述的藥劑，其中，前述微小管抑制劑是長春花生物鹼系藥劑。
(26)前述(25)所述的藥劑，其中，前述長春花生物鹼系藥劑是敏克瘤(vincristine)。
(27)前述(20)所述的藥劑，其中，前述抗癌劑是鉑製劑。
(28)前述(27)所述的藥劑，其中，前述鉑製劑是益樂鉑或順鉑(cisplatin)。
(29)前述(20)至(28)中任一項所述的藥劑，其中，前述由抗癌劑所引起的末梢神經障礙是急性或慢性的疼痛，麻木，知覺異常，知覺過敏或感覺異常。
(30)前述(10)至(19)中任一項所述的藥劑，其係類神經營養因子作用劑。
(31)前述(30)所述的藥劑，其中，前述類神經營養因子作用劑是神經退化疾病或精神疾病的預防或治療劑。
(32)前述(31)所述的藥劑，其中，前述神經營養因子作用劑是神經退化疾病的預防或治療劑。
(33)前述(32)所述的藥劑，其中，前述神經退化疾病是癡呆症，阿茲海默症，巴金森病，肌萎縮性脊髄側索硬化症(ALS)，亨丁頓舞蹈症，進行性核上性麻痺(PSP)，糖尿病性神經病變(diabetic neuropathy)或青光眼。
(34)前述(31)所述的藥劑，其中，前述類神經營養因子作用劑是精神疾病的預防或治療劑。
(35)前述(34)所述的藥劑，其中，前述精神疾病是憂鬱症，焦慮症(神經病)或自閉症譜系。
(36)前述(10)至(19)中任一項所述的藥劑，其係脊髄損傷的治療劑或修復劑。
(37)前述(10)至(19)中任一項所述的藥劑，其係對疼痛疾病的鎮痛劑。
(38)前述(37)所述的藥劑，其中，前述對疼痛疾病的鎮痛劑是對關節痛的治療劑。
(39)前述(38)所述的藥劑，其中，前述關節痛是變形性關節炎所引起的疼痛。
(40)前述(39)所述的藥劑，其中，前述變形性關節炎是變形性膝關節炎或變形性股關節炎。
(41)前述(10)至(40)中任一項所述的藥劑，其係注射劑。
(42)前述(10)至(40)中任一項所述的藥劑，其係口服劑。
(43)前述(41)或(42)的藥劑，其中，前述注射劑或口服劑是環糊精包接體。
(44)前述(10)至(40)中任一項所述藥劑，其係外用劑。
(45)前述(44)所述的藥劑，其中，前述外用劑是貼劑。
(46)一種前述(10)至(19)中任一項所述的化合物或其在藥學上可容許的鹽之用途，係用於預防或治療前述(20)至(29)及(31)至(40)中任一項所述的疾病。
(47)一種前述(10)至(19)中任一項所述的化合物或其在藥學上可容許的鹽之用途，係用於預防或治療含至少1種抗癌劑之藥劑的投予所引起的末梢神經障礙。
(48)一種前述(10)至(19)中任一項所述的化合物或其在藥學上可容許的鹽之用途，係用於預防或治療神經退化疾病或精神疾病。
(49)一種前述(10)至(19)中任一項所述的化合物或其在藥學上可容許的鹽之用途，係用於預防或治療疼痛疾病。
(50)一種前述(20)至(29)及(31)至(40)中任一項所述述的疾病的預防或治療方法，係將前述(10)至(19)中任一項所述的化合物或其在藥學上可容許的鹽的有效量投予於前述(20)至(29)及(31)至(40)中任一項所述的疾病患者。
(51)一種含至少1種抗癌劑的藥劑的投予所引起的末梢神經障礙的預防或治療方法，係將前述(10)至(19)中任一項所述的化合物或其在藥學上可容許的鹽的有效量投予於具有含至少1種抗癌劑的藥劑的投予所引起的末梢神經障礙的患者。
(52)一種神經退化疾病或精神疾病的預防或治療方法，係將前述(10)至(19)中任一項所述的化合物或其在藥學上可容許的鹽的有效量投予於神經退化疾病或精神疾病的患者。
(53)一種疼痛疾病的預防或治療方法，係將前述(10)至(19)中任一項所述的化合物或其在藥學上可容許的鹽的有效量投予於疼痛疾病的患者。
(54)一種前述(10)至(19)中任一項所述的化合物或其在藥學上可容許的鹽的使用，係用於治療前述(20)至(29)及(31)至(40)中任一項所述的疾病的藥劑的製造。
(55)一種前述(10)至(19)中任一項所述的化合物或其在藥學上可容許的鹽的使用，係用於預防或治療含至少1種抗癌劑的藥劑之投予所引起的末梢神經障礙的藥劑的製造。
(56)一種前述(10)至(19)中任一項所述的化合物或其在藥學上可容許的鹽的使用，係用於預防或治療神經退化疾病或精神疾病的藥劑製造。
(57)一種前述(10)至(19)中任一項所述的化合物或其在藥學上可容許的鹽的使用，係用在鎮痛劑的製造。
本發明化合物，有效做為用於預防或治療人及動物的四肢末端的麻木等知覺異常及疼痛等痛覺過敏等由抗癌劑所引起的末梢神經系的神經障礙的藥劑。
又，本發明化合物，由於有優異的類神經 營養因子作用，故可做為類神經營養因子作用劑而使用。此類神經營養因子作用劑，藉由類神經營養因子的作用而將經由MAP激酶訊息傳遞路徑的訊息傳遞活化，有用於做為神經障礙的預防或治療劑。神經障礙中，特別是做為對癡呆症，阿茲海默症，巴金森病，肌萎縮性脊髄側索硬化症(ALS)，亨丁頓舞蹈症，進行性核上性麻痺(PSP)，糖尿病性神經病變，青光眼等神經退化疾病等的預防或治療劑。又，神經障礙中，做為精神疾病的預防改善劑也是有用的。精神疾病中，特別是有用於做為憂鬱症，焦慮症(神經病)，自閉症譜系等的預防或改善劑，特別是有用於做為憂鬱症或焦慮症(神經病)的預防或治療劑。
又，本發明化合物，有用於做為脊髄損傷的治療劑(脊髄損傷時，有時被稱為「修復劑」)。
再者，本發明化合物是表現優異的鎮痛作用的化合物，有用於做為用以預防或治療變形性關節炎等關節痛所引起的疼痛等種種疼痛性疾病的藥劑。
本發明是關於下述通式(I’)表示的反式-2-癸烯酸衍生物或其在藥學上可容許的鹽。
[式中，X’表示 (a)經羧基或烷氧羰基取代的1-吡咯啶基，(b)3-四氫噻唑基(thiazolidinyl)，(c)經烷基，側氧基，羥基，烷氧基，羧基，烷氧羰基，烷胺基，烷胺基烷基，苯基，羧烷基，烷氧羰基烷基，氰基或鹵苯基取代的N-哌啶基，(d)N-硫代嗎啉基，(e)經烷基，羧烷基，烷氧羰基烷基，烷胺基烷基，環烷基，N-哌啶基烷基，苯烷基，吡啶基，嘧啶基，羧苯基烷基或烷氧羰基苯烷基取代的1-哌基，(f)經由可經烷胺基，鹵素，烷氧基，烷基，羥基，羧烷氧基或烷氧基羰基烷氧基取代的苯基而取代的1-哌基，(g)可經烷基或烷胺基烷基取代的1,4-二氮雜環庚烷基，或(h)N-羧基嗎啉基]。
又，本發明是關於含有下述通式(I)表示的反式-2-癸烯酸衍生物及其在藥學上可容許的鹽的至少一種做為有效成分的對於抗癌劑所引起的末梢神經障礙的預防或治療劑，類神經營養因子作用劑，鎮痛劑等藥劑。通式(I)表示的化合物，包含前述通式(I')表示的化合物。
[式中，X表示(a)可經羧基或烷氧基羰基取代的1-吡咯啶基，(b)3-四氫噻唑基， (c)可經烷基，側氧基，羥基，烷氧基，羧基，烷氧羰基，烷胺基，烷胺基烷基，苯基，羧烷基，烷氧基羰基烷基，氰基或鹵苯基取代的N-哌啶基，(d)可經羧基取代的N-嗎啉基，(e)N-硫代嗎啉基，(f)可經烷基，羧烷基，烷氧羰基烷基，烷胺基烷基，環烷基，N-哌啶基烷基，苯烷基，吡啶基，嘧啶基，羧苯烷基或烷氧羰基苯烷基取代的1-哌基，(g)經由可經烷胺基，鹵素，烷氧基，烷基，羥基，羧烷氧基或烷氧基羰基烷氧基取代的苯基而取代的1-哌基，(h)1-氮雜環庚烷，或(i)可經烷基或烷胺基烷基取代的1,4-二氮雜環庚烷基]。
在前述通式(I)及(I’)的取代基中，烷基(含烷胺基，烷胺基烷基，羧烷基，烷氧基羰基烷基，N-哌啶基烷基，苯烷基，羧苯基烷基，烷氧基羰基苯烷基中的「烷基」)是任何一種都可以，理想是表示甲基，乙基，丙基，異丙基，丁基，異丁基，二級丁基，三級丁基等碳數1至4的直鏈狀或分枝狀的烷基。又，烷胺基(含烷胺基烷基中的「烷胺基」)表示經1或2個烷基取代的胺基。
烷氧基(含烷氧基羰基，羧烷氧基，烷氧基羰基烷氧基中的「烷氧基」)是任何一種都可以，但理想是表示甲氧基，乙氧基，正丙氧基，異丙氧基，正丁氧基，異丁氧基，二級丁氧基，三級丁氧基等碳數1至4的直鏈 狀或分枝狀的烷氧基。
環烷基是任何一種都可以，但理想是表示環丙基，環丁基，環戊基，環己基，環庚基，環辛基等碳數3至8的環烷基，再理想是表示碳數5或6的環烷基。
鹵素(含鹵苯基中的「鹵」)表示氟，氯，溴，碘等。
本發明的通式(I)表示的化合物(含通式(I’)表示的化合物。以下同)，例如可依照下述反應式的方式，使用反式-2-癸烯酸做為原料而製造。
反應式 (式中，X與前述相同)
通式(I)表示的化合物，可藉由將通式(II)表示的化合物，與有活性氫的通式(III)表示的化合物進行脫水縮合而製造。脫水縮合反應可採用公知的方法。例如，可將通式(II)表示的化合物與通式(III)表示的化合物，在適當的縮合劑(例如，二環己基碳二醯亞胺(DCC)，N-(3-二甲胺基丙基)-N'-乙基碳二醯亞胺‧HCl等)的存在下反應。反應，通常可在溶媒(例如，二氯甲烷等)中實施。通式(III)表示的化合物的使用量，通常相對於通式(II)表示的化合物 1莫耳為0.5至2莫耳(理想是1至1.5莫耳)。
或者，例如，可將通式(II)表示的化合物先變換為醯鹵(carboxylic halide)後，在鹼的存在下或不存在下，與通式(3)表示的化合物反應。變換成為醯鹵，例如，可使用亞硫醯氯，亞磺醯氯，三氯化磷，五氯化磷，草醯氯，氯化磷醯(phosphoryl chloride)等鹵化劑。就鹼而言，可舉三乙胺，吡啶等。通式(III)表示的化合物的使用量，通常相對於通式(II)表示的化合物1莫耳為0.5至2莫耳(理想是1至1.5莫耳)。使用鹼時，鹼的使用量，通常相對於通式(II)表示的化合物1莫耳為1至5莫耳左右。
上述的反應結束後，可以使用公知的精製及分離操作(例如，萃取，層析法，蒸餾，再結晶等)，得到目的化合物。
如此所得的化合物之例示於第1表至第3表。以下，稱呼個別的化合物時，使用在表中所述的化合物編號。
本發明的通式(I)表示的化合物，不僅是上述的遊離的形態，也包含鹽、溶媒合物、前驅藥物的形態。形成鹽時，做為藥劑而用時，藥學上可容許的鹽的形態為合適。就鹽的例而言，可舉與磷酸，鹽酸，硫酸，硝酸，氫溴酸，過氯酸，硫氰酸，硼酸，甲酸，乙酸，鹵乙酸，丙酸，檸檬酸，酒石酸，乳酸，羥乙酸，琥珀酸，葡萄糖酸，丙二酸，富馬酸，鄰胺苯甲酸，苯甲酸，桂皮酸，對甲苯磺酸，萘磺酸，對胺苯磺酸等酸的加成鹽。又，可舉與鈉、鉀等鹼金屬，鈣、鎂等鹼土類金屬或鋁等金屬的鹽，或者氨、有機胺等鹼類的鹽。這些鹽可依公知的方法，由遊離的各化合物製造，或可互相變換。就溶媒合物而言， 可舉水合物，醇合物等。又，本發明的通式(I)表示的化合物含有不對稱碳時，也包含光學活性體，消旋體，非鏡像異構物等各種異構物。本發明化合物會成為結晶時，也包含可形成的各種結晶形(結晶多形)。
本發明的通式(I)表示的化合物，有用於做為由抗癌劑的投予所引起的末梢神經障礙的預防或治療作用劑。做為引發末梢神經障礙的抗癌劑，有一種是傷害微小管而引起末梢神經障礙之抗癌劑。就這種藥劑而言，可舉紫杉醇、歐洲紫杉醇(docetaxel)等紫杉烷系藥劑，及敏克瘤、敏畢瘤、長春地辛、溫諾平等長春花生物鹼類(vinca alkaloids)系藥劑。另一種是由神經細胞的傷害而引起軸突障礙並引起末梢神經障礙的藥劑。就這種藥劑而言，可舉益樂鉑，卡鉑(carboplatin)，順鉑，奈達鉑(nedaplatin)等鉑製劑。
這些抗癌劑所引起的末梢神經障礙，可舉刺痛或如火燒傷一樣的痛等疼痛，四肢末端的麻木，灼熱感等知覺異常，對冷感刺激的過敏等知覺過敏，感覺消失/感覺麻痺及不調和感等感覺異常，知覺性運動失調，肌力的降低等。本發明化合物做為預防或治療對象的由抗癌劑所引起的末梢神經障礙，不僅是對使用一種抗癌劑的單劑療法所產生的末梢神經障礙，也包含將作用機制不同的數種藥劑組合而投予的多劑併用療法，以及為了使作用機制不同的藥劑能發揮最大的有效性而在藥劑的組合及投予方法上下工夫的生化調節(biochemical modulation)的療法所 發生的末梢神經障礙。
本發明的通式(I)表示的化合物，由於具有類神經營養因子作用之故而有用於做為類神經營養因子作用劑，且在神經障礙之預防或治療上有用。神經障礙是指起因於神經細胞的退化或細胞死而其功能受損害的病態，包含神經退化疾病，精神疾病。神經退化疾病是指癡呆症，阿茲海默症，巴金森病，肌萎縮性脊髄側索硬化症(ALS)，亨丁頓舞蹈症，進行性核上性麻痺(PSP)，糖尿病性神經病變，視神經疾病的青光眼等。精神疾病是指憂鬱症(含雙極性憂鬱症)，焦慮症(神經病)，總合失調症，自閉症譜系等。用於憂鬱症時，以往既有的憂鬱症治療劑的三環系抗憂鬱藥，四環系抗憂鬱藥，選擇性的血清素再吸取抑制藥(specific serotonin reuptake inhibitor,SSRI)，血清素/去甲基腎上腺素(noradrenaline)再吸取抑制藥(SNRI)等需要至少3至4週才會有效果出現，而在此期間需要定期服藥，但期待含有本發明化合物的藥劑比既有的藥劑更有即效性。
本發明的通式(I)表示的化合物，有用於做為脊髄損傷的治療劑(修復劑)。因交通事故，運動事故，高齡者的壓迫骨折等而脊髄受到物理性的損害的脊髄損傷，沒有有效的治療法，在再生醫療上的治療法受到種種的檢討。含有本發明化合物的藥劑，期待可藉注射或內服、外用等投予而治療(修復)脊髄損傷。
又，本發明的通式(I)表示的化合物，有用於做為對種種的疼痛疾病的預防或治療劑。就疼痛疾病而 言，例如，可舉變形性膝關節炎及變形性股關節炎等變形性關節炎引起的疼痛及關節風濕症引起的疼痛等關節痛等。
本發明化合物，可以與適當的醫藥用的承載物或稀釋劑適宜組合而製成各種劑形(口服劑，注射劑，外用劑等)的藥劑。又，本發明藥劑，可以是本發明化合物與其他的醫藥活性成分組合的調配劑。再者，本發明藥劑可以是做為與環糊精等的包接體而製成的製劑。如此，則有可獲得藥理活性的增強，安定性的提高，持續化，處理容易性等的情況。包接體，例如，可藉由將本發明化合物與α-、β-或γ-環糊精以通常的方法混合而形成。
本發明化合物做為口服劑時，可與適當的添加劑，例如賦形劑，結合劑，崩散劑，滑澤劑，增量劑，濕潤化劑，緩衝劑，保存劑，香料等適宜組合的處方製成錠劑，散劑，顆粒劑或膠囊劑。又，做為注射劑時，可在含有碳數10的脂肪酸酯之溶液或懸浮液中添加安定劑，保存劑，等張力劑等而製成注射劑。做為外用劑時，可製成例如貼劑，凝膠劑，軟膏劑(ointment)，乳膏劑(cream)等外用劑等製劑。即，使本發明化合物於適當的基劑中混和，融解，乳化等而調製，若為貼劑時則將此於支撐體上展延塗佈。就貼劑、凝膠劑等而言，例如可製成使用有機凝膠劑的組成的製劑。在這裏，可隨各外用劑的劑形而適宜選擇通常使用的保存劑，抗氧化劑，著香劑，黏著劑等並加在處方中。
本發明化合物的理想的投予量，可考慮用法，患者的年齡，性別，症狀的程度等而適宜地增減，但通常成人每1日1至1000mg，理想是可將5至300mg1日1次或分成數次投予。
實施例
以下，列舉實施例說明本發明，但本發明並不限定於該等實施例。
實施例1
1-((E)-2-癸烯醯基)吡咯啶(1-((E)-2-decenoyl)pyrrolidine)[化合物1]的製造
在使用(E)-2-癸烯酸及亞硫醯氯所合成的氯化(E)-2-癸烯酸(1.9g,0.01mol)的四氫呋喃溶液(20ml)中，添加含有吡啶(0.79g,0.01mol)的吡咯啶(0.71g,0.01mol)的四氫呋喃溶液(20ml)，在溫水浴上加熱回流3小時。將過剩的四氫呋喃餾去後，在反應液中添加水，以乙酸乙酯萃取，水洗後，餾去乙酸乙酯。將殘渣以氧化矽凝膠管柱層析(展開溶媒；己烷：乙酸乙酯=1：3)精製，獲得目的化合物(1.4g)的無色油狀物質。
無色油狀物，C14H25NO MW 223,ESIMS(positive ion mode：rel.int)：m/z246.184[M+Na]+(Calcd for C14H25NONa,246.1834),1H-NMR(400MHz,CDCl3)δ：0.88(3H,t,J=6.8Hz),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=7.2Hz),3.524(2H,t,J=7.2Hz),6.09(1H,d,J=15.4Hz),6.91(1H,dt,J=15.4,6.8Hz).
實施例2
(S)-1-((E)-2-癸烯醯基)吡咯啶-2-羧酸甲酯((S)-1-((E)-2-decenoyl)pyrrolidine-2-carboxylic acid methyl ester)[化合物3]的製造
在(E)-2-癸烯酸(0.92ml,5mmol)、L-脯胺酸甲酯鹽酸鹽(0.91g,5.5mmol)的二氯甲烷(50ml)溶液中，在室溫添加三乙胺(0.84ml,6mmol)及1-乙基3-(3-二甲胺基丙基)碳醯二亞胺鹽酸鹽(WSC‧HCl)(1.05g,5.5mmol)攪拌24小時。將反應溶液以水、飽和食鹽水清洗後，以無水硫酸鈉乾燥。以氧化矽凝膠管柱層析(己烷：乙酸乙酯=7：3)精製，獲得目的化合物(1.23g,87%)的無色油狀物。在這裏，以下，起始原料的胺不是鹽酸鹽時不添加三乙胺也可以。
無色油狀物，C16H27NO3 MW 281.4,EIMS：m/z 282[M+H]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=7.0Hz,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).
實施例3
(S)-1-((E)-2-癸烯醯基)吡咯啶-2-羧酸((S)-1-((E)-2-decenoyl)pyrrolidine-2-carboxylic acid)[化合物2]的製造
將化合物3(0.84g,3mmol)溶解於甲醇(40ml)中，在室溫添加1mol/l氫氧化鈉水溶液(4ml,NaOH 4mmol)，攪拌20小時。將溶媒減壓餾去後，將殘渣溶於水中，添加10%檸檬酸水溶液調整pH為約4。以二氯甲烷萃取，將有機層 以水、飽和食鹽水清洗後，以無水硫酸鈉乾燥而獲得目的化合物(0.72g,90%)的無色油狀物。
無色油狀物，C15H25N03 MW 267.4,EIMS：m/z 268[M+H]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=7.0Hz,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).
實施例4
3-((E)-2-癸烯醯基)四氫噻唑(3-((E)-2-decenoyl)thiazolidine)[化合物4]的製造
使用(E)-2-癸烯酸及四氫噻唑為起始原料，以與實施例1同樣操作而製造目的化合物。
無色油狀物，C13H23NOS MW 241,HR-ESIMS(positive ion mode)：m/z 264.1443[M+Na]+(Calcd for C13H23NOSNa,264.1398),1H-NMR(400MHz,CDCl3)δ：0.88(3H,t,J=6.8Hz),1.22-1.34(8H,m),1.46(2H,m),2.22(2H,m),3.01(1H,t,J=6.1Hz),3.11(1H,t,J=6.1Hz),3.83(1H,t,J=6.1Hz),3.91(1H,brt),4.58(1H,s),4.65(1H,s),6.11(1H,d,J=15.0Hz),6.96(1H,dt,J=15.0,7.3Hz).
實施例5
1-((E)-2-癸烯醯基)哌啶(1-((E)-2-decenoyl)piperidine)[化合物5]的製造
使用(E)-2-癸烯酸及哌啶為起始原料，以與實施例1同樣操作而製造目的化合物。
無色油狀物，C15H27NO MW 237,EIMS：m/z237[M]+,1H-NMR(500MHz,CDCl3)δ：0.88(3H,t,J=7.0Hz),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=15.1,7.1Hz)
實施例6
1-((E)-2-癸烯醯基)-4-甲基哌啶(1-((E)-2-decenoyl)-4-methylpiperidine)[化合物6]的製造
使用(E)-2-癸烯酸及4-甲基哌啶為起始原料，以與實施例2同樣操作而製造目的化合物。
無色油狀物，C16H29NO MW 251.4,EIMS：m/z252[M+H]+,1H-NMR(500MHz,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=15.0Hz,1H),6.61(dt,J=15.0,7.0Hz,1H).
實施例7
1-((E)-2-癸烯醯基)哌啶-4-酮(1-((E)-2-decenoyl)piperidin-4-one)[化合物7]的製造
使用(E)-2-癸烯酸及哌啶-4-酮為起始原料，以與實施例1同樣操作而製造目的化合物。
淡黃色油狀物，C15H25NO2 MW 251,HR-ESIMS(positive ion mode)：m/z 274.1824[M+Na]+(Calcd for C15H25NO2Na,274.1783)，1H-NMR(400MHz,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=6.4Hz),3.82-3.97(4H,m),6.31(1H,d,J=15.2Hz),6.97(1H,dt,J=15.2,7.3Hz).
實施例8
1-((E)-2-癸烯醯基)-4-羥基哌啶(1-((E)-2-decenoyl)-4-hydroxypiperidine)[化合物8]的製造
使用(E)-2-癸烯酸及4-羥基哌啶為起始原料，以與實施例2同樣操作而製造目的化合物。
無色油狀物，C15H27NO2 MW 253.4,EIMS：m/z254[M+H]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=7.0Hz,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=4.1Hz,1H),6.45(d,J=15.0Hz,1H),6.63(dt,J=15.0,7.0Hz,1H).
實施例9
1-((E)-2-癸烯醯基)-4-甲氧基哌啶(1-((E)-2-decenoyl)-4-methoxypiperidine)[化合物9]的製造
將化合物8(0.62g,2.4mmol)溶解於THF(10ml)中，在冰冷下，添加氫化鈉(礦油中60%)(0.10g,2.6mmol)。在冰冷下攪拌15分鐘後，添加碘化甲烷(0.16ml,2.6mmol)，在室溫攪拌20小時。將反應液加入於水中，以乙酸乙酯萃取後，將有機層以水、飽和食鹽水清洗，以無水硫酸鈉乾燥。以氧化矽凝膠管柱層析(己烷：乙酸乙酯=3：2)精製而 獲得目的化合物(0.42g,65%)的淡黃色油狀物。
淡黃色油狀物，C16H29N02 MW 267.4,EIMS：m/z268[M+H]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=7.0Hz,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=15.0Hz,1H),6.63(dt,J=15.0,7.0Hz,1H).
實施例10
1-((E)-2-癸烯醯基)哌啶-4-羧酸(1-((E)-2-decenoyl)piperidine-4-carboxylic acid)[化合物10]的製造
使用化合物11為起始原料，以與實施例3同樣操作而製造目的化合物。
白色結晶，mp 88-89℃,C16H27NO3 MW 281.4,EIMS：m/z281[M]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=7.0Hz,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=15.0Hz,1H),6.63(dt,J=15.0,7.0Hz,1H),12.28(brs,1H).
實施例11
1-((E)-2-癸烯醯基)哌啶-4-羧酸乙酯(1-((E)-2-decenoyl)piperidine-4-carboxylic acid ethyl ester)[化合物11]的製造
使用(E)-2-癸烯酸及異哌啶甲酸(isonipecotic acid)乙酯 為起始原料，以與實施例2同樣操作而製造目的化合物。
無色油狀物，C18H31NO3 MW 309.4,EIMS：m/z309[M]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=7.0Hz,3H),1.18(t,J=7.0Hz,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=7.0Hz,2H),4.20-4.28(m,1H),6.45(d,J=15.0Hz,1H),6.63(dt,J=15.0,7.0Hz,1H).
實施例12
1-((E)-2-癸烯醯基)-4-二甲胺基哌啶(1-((E)-2-decenoyl)-4-dimethylaminopiperidine)[化合物12]的製造
使用(E)-2-癸烯酸及4-二甲胺基哌啶為起始原料，以與實施例2同樣操作而製造目的化合物。
淡黃色油狀物，C17H32N2O MW 280.5,EIMS：m/z281[M+H]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=7.0Hz,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=15.0Hz,1H),6.63(dt,J=15.0,7.0Hz,1H).
又，將油狀物的化合物12溶解於二氯甲烷中，以氯化氫-二烷處理，製造1-((E)-2-癸烯醯基)-4-二甲胺基哌啶鹽酸鹽(結晶，mp 185-188℃)。
實施例13
1-((E)-2-癸烯醯基)-4-二乙胺基哌啶(1-((E)-2- decenoyl)-4-diethylaminopiperidine)[化合物13]的製造
使用(E)-2-癸烯酸及4-二乙胺基哌啶為起始原料，以與實施例2同樣操作而製造目的化合物。
淡黃色油狀物，C19H36N2O MW 308.5,EIMS：m/z309[M+H]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=7.0Hz,3H),0.95(t,J=7.0Hz,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=7.0Hz,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=15.0Hz,1H),6.61(dt,J=15.0,7.0Hz,1H).
實施例14
1-((E)-2-癸烯醯基)-4-二乙胺基甲基哌啶(1-((E)-2-decenoyl)-4-diethylaminomethylpiperidine)[化合物14]的製造
使用(E)-2-癸烯酸及4-(二乙胺基甲基)哌啶為起始原料，以與實施例2同樣操作而製造目的化合物。
淡紅色油狀物，C20H35N2O MW 322.5,EIMS：m/z323[M+H]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=7.0Hz,3H),0.93(t,J=7.0Hz,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=7.0Hz,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=15.0Hz,1H),6.61(dt,J=15.0,7.0Hz,1H).
實施例15
1-((E)-2-癸烯醯基)-4-(2-二甲胺基乙基)哌啶(1-((E)-2-decenoyl)-4-(2-dimethylaminoethyl)piperidine)[化合物15]的製造
使用(E)-2-癸烯酸及4-(2-二甲胺基乙基)哌啶為起始原料，以與實施例2同樣操作而製造目的化合物。
淡黃色油狀物，C19H36N2O MW 308.5,EIMS：m/z309[M+H]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=7.0Hz,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=15.0Hz,1H),6.60(dt,J=15.0,7.0Hz,1H).
實施例16
1-((E)-2-癸烯醯基)-4-苯基哌啶(1-((E)-2-decenoyl)-4-phenyl piperidine)[化合物16]的製造
使用(E)-2-癸烯酸及4-苯基哌啶為起始原料，以與實施例1同樣操作而製造目的化合物。
無色油狀物，C21H31NO MW 313,HR-ESIMS(positive ion mode)：m/z336.2330[M+Na]+(Calcd for C21H31NONa,336.2303),1H-NMR(400MHz,CDCl3)δ：0.88(3H,t,J=7.2Hz),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=15.0Hz),6.89(1H,dt,J=15.0,7.3Hz),7.18-7.24(3H,m),7.32(2H,t,J=7.4Hz).
實施例17
(4-((E)-2-癸烯醯基)嗎啉(4-((E)-2-decenoyl)morpholine)[化合物17]的製造
使用(E)-2-癸烯酸及嗎啉為起始原料，以與實施例1同樣操作而製造目的化合物。
無色油狀物，C14H25NO2 MW 239,HR-ESIMS(positive ion mode)：m/z262.1827[M+Na]+(Calcd for C14H25NO2Na,262.1783),1H-NMR(400MHz,CDCl3)δ：0.88(3H,t,J=7.2Hz),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=15.2Hz),6.91(1H,dt,J=15.2,7.1Hz).
實施例18
4-((E)-2-癸烯醯基)硫代嗎啉(4-((E)-2-decenoyl)thiomorpholine)[化合物18]的製造
使用(E)-2-癸烯酸及硫代嗎啉為起始原料，以與實施例1同樣操作製造目的化合物。
無色油狀物，C14H25NOS MW 255,HR-ESIMS(positive ion mode)：m/z278.1575[M+Na]+(Calcd for C14H25NOSNa,278.1555),1H-NMR(400MHz,CDCl3)δ：0.88(3H,t,J=7.2Hz),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=15.2Hz),6.87(1H,dt,J=15.2,7.3Hz).
實施例19
1-((E)-2-癸烯醯基)-4-甲基哌(1-((E)-2-decenoyl) -4-methylpiperazine)[化合物19]的製造
使用(E)-2-癸烯酸及1-甲基哌為起始原料，以與實施例2同樣操作而製造目的化合物。
淡黃色油狀物，C15H28N2O MW 252.4,EIMS：m/z253[M+H]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=7.0Hz,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=14.0Hz,Jt=1.1Hz,1H),6.65(dt,J=14.0,7.2Hz,1H).
實施例20
1-((E)-2-癸烯醯基)-4-異丙基哌(1-((E)-2-decenoyl)-4-isopropylpiperazine)[化合物20]的製造
使用(E)-2-癸烯酸及1-異丙基哌為起始原料，以與實施例2同樣操作而製造目的化合物。
淡黃色油狀物，C17H32N2O MW 280.5,EIMS：m/z280[M]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=7.0Hz,3H),0.96(d,J=6.5Hz,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=6.5,6.5Hz,1H),3.44-3.54(m,4H),6.43(dt,J=15.0,1.1Hz,1H),6.63(dt,J=15.0,7.0Hz,1H).
實施例21
3-[4-((E)-2-癸烯醯基)哌-1-基]丙酸(3-[4-((E)-2-decenoyl)piperazin-1-yl]propionic acid)[化合物21]的製造
使用(E)-2-癸烯酸及3-哌-1-基丙酸乙酯2鹽酸鹽[化合物21的乙酯]為起始原料，以與實施例2同樣操作而製 造3-[4-((E)-2-癸烯醯基)哌-1-基]丙酸乙酯，由鹼皂化而獲得目的化合物的白色結晶。
白色結晶，mp 53-55℃,C17H30N2O3 MW 310.4,EIMS：m/z311[M+H]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=7.0Hz,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=15.0Hz,1H),6.65(dt,J=15.0,7.0Hz,1H),11.70-12.70(brs,1H).
又，將低融點結晶的化合物21溶解於二氯甲烷中，以氯化氫-二烷處理而製造3-[4-((E)-2-癸烯醯基)哌-1基]丙酸鹽酸鹽(結晶，mp 201-203℃)。
實施例22
1-((E)-2-癸烯醯基)-4-[2-(二甲胺基)乙基]哌(1-((E)-2-decenoyl)-4-[2-(dimethylamino)ethyl]piperazine)[化合物22]的製造
使用(E)-2-癸烯酸及1-[2-(二甲胺基)乙酯]哌為起始原料，以與實施例1同樣操作而製造目的化合物。
油狀物，C18H35N3O MW 309,HR-ESIMS(positive ion mode)：m/z 310.2868[M+H]+(calcd for C18H36N3O,310.2858),1H-NMR(500MHz,CDCl3)δ：0.88(3H,t,J=7.4Hz),1.27-1.31(8H,m),1.45(2H,brt,J=7.5Hz),2.19(2H,dt,J=6.9,8.0Hz),2.32(6H,s),2.47(4H,brs),2.53(4H,s),3.56(2H,brs),3.68(2H,brs),6.21(1H,d,J=15.2Hz),6.86(1H,dt,J=6.9,15.2Hz).
實施例23
4-環己基-1-((E)-2-癸烯醯基)哌(4-cyclohexyl-1-((E)-2-decenoyl)piperazine)[化合物23]的製造
使用(E)-2-癸烯酸及1-環己基哌為起始原料，以與實施例2同樣操作而製造目的化合物。
白色結晶，mp 33-34℃,C20H36N2O MW 320.5,EIMS：m/z320[M]+,1H-NMR(500MHz,DMSO-d6)δ：0.85(t,J=7.0Hz,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=15.0Hz,1H),6.64(dt,J=15.0,7.0Hz,1H).
實施例24
1-((E)-2-癸烯醯基)-4-(2-哌啶-1-基乙基)哌(1-((E)-2-decenoyl)-4-(2-piperidin-1-ylethyl)piperazine)[化合物24]的製造
使用(E)-2-癸烯酸及1-[2-(1-哌基)乙基]哌為起始原料，以與實施例2同樣操作而製造目的化合物。
白色結晶，C21H39N3O MW 349.6,EIMS：m/z350[M+H]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=6.7Hz,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=15.0Hz,1H),6.64(dt,J=15.0,7.0Hz,1H).
實施例25
1-((E)-2-癸烯醯基)-4-苯基哌(1-((E)-2-decenoyl) -4-phenyl piperazine)[化合物25]的製造
使用(E)-2-癸烯酸及1-苯基哌為起始原料，以與實施例1同樣操作而製造目的化合物。
桃色油狀物，C20H30N2O MW 314,HR-ESIMS(positive ion mode)：m/z337.2244[M+Na]+(Calcd for C20H30N2ONa,337.2256),1H-NMR(400MHz,CDCl3)δ：0.88(3H,t,J=6.8Hz),1.21-1.36(8H,m),1.46(2H,m),2.22(2H,m),3.18(4H,t,J=5.4Hz),3.71(2H,brs),3.83(2H,brs),6.27(1H,d,J=15.6Hz),6.88-6.96(4H,m),7.26-7.30(2H,m).
實施例26
4-苯甲基-1-((E)-2-癸烯醯基)哌(4-benzyl-1-((E)-2-decenoyl)piperazine)[化合物26]的製造
使用(E)-2-癸烯酸及1-苯甲基哌2鹽酸鹽為起始原料，以與實施例2同樣操作而製造目的化合物。
白色結晶，mp 62-63℃,C21H32N2O MW 328.5,EIMS：m/z2329[M+H]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=7.0Hz,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=15.0Hz,1H),6.65(dt,J=15.0,7.0Hz,1H),7.22-7.36(m,5H).
實施例27
1-((E)-2-癸烯醯基)-4-(2-苯乙基)哌(1-((E)-2-decenoyl)-4-(2-phenylethyl)piperazine)[化合物27]的製造
使用(E)-2-癸烯酸及1-(2-苯乙基)哌2鹽酸鹽為起始 原料，以與實施例2同樣操作而製造目的化合物。
白色結晶，mp 33-34℃,C22H34N2O MW 342.5,EIMS：m/z343[M+H]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=7.0Hz,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=6.5,8.3Hz,2H),2.74(dd,J=6.5,8.3Hz,2H),3.46-3.56(m,4H),6.45(d,J=15.0Hz,1H),6.66(dt,J=15.0,7.0Hz,1H),7.15-7.31(m,5H).
實施例28
1-((E)-2-癸烯醯基)-4-(4-二甲胺基苯基)哌(1-((E)-2-decenoyl)-4-(4-dimethylaminophenyl)piperazine)[化合物28]的製造
使用(E)-2-癸烯酸及1-(4-二甲胺基苯基)哌2鹽酸鹽為起始原料，以與實施例2同樣操作而製造目的化合物。淡褐色結晶，mp 73-74℃,C22H35N3O MW 357.5,EIMS：m/z 357[M]+,1H-NMR(500MHz,DMSO-d6)δ：0.85(t,J=7.0Hz,3H),1.20-1.31(m,8H),1.36-1.46(m,2H),2.15-2.21(m,2H),2.78(s,6H),2.87-2-2.96(m,4H),3.55-3.74(m,4H),6.49(d,J=15.0Hz,1H),6.64-6.72(m,3H),6.86(d,J=8.7Hz,2H).
實施例29
1-((E)-2-癸烯醯基)-4-(吡啶-4-基)哌(1-((E)-2-decenoyl)-4-(pyridin-4-yl)piperazine)[化合物29]的製造
使用(E)-2-癸烯酸及1-(4-吡啶基)哌為起始原料，以與實施例1同樣操作而製造目的化合物。
淡褐色油狀物，C19H29N3O MW 315,HR-ESIMS(positive ion mode)：m/z 316.2349[M+H]+(Calcd for C19H30N3O,316.2383),1H-NMR(400MHz,CDCl3)δ：0.89(3H,t,J=7.2Hz),1.19-1.35(10H,m),1.47(2H,m),2.23(2H,m),2.49(1H,brs),3.39(4H,t,J=5.4Hz),3.70-3.88(4H,m),6.25(1H,d,J=15.0Hz),6.67(2H,d,J=6.4Hz),6.95(1H,dt,J=15.0,7.3Hz),8.31(2H,d,J=6.4Hz).
實施例30
1-((E)-2-癸烯醯基)-4-(吡啶-2-基)哌(1-((E)-2-decenoyl)-4-(pyridin-2-yl)piperazine)[化合物30]的製造
使用(E)-2-癸烯酸及1-(2-吡啶基)哌為起始原料，以與實施例1同樣操作而製造目的化合物。
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(400MHz,CDCl3)δ：0.88(3H,t,J=7.2Hz),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=15.2Hz),6.64-6.69(2H,t,m),6.93(1H,dt,J=15.2,7.3Hz),7.51(1H,m),8.20(1H,m).
實施例31
1-((E)-2-癸烯醯基)-4-(嘧啶-2-基)哌(1-((E)-2-decenoyl)-4-(pyrimidin-2-yl)piperazine)[化合物31]的製造
使用(E)-2-癸烯酸及1-(2-嘧啶基)哌為起始原料，以與實施例1同樣操作而製造目的化合物。
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(400MHz,CDCl3)δ：0.88(3H,t,J=7.2Hz),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=15.2Hz),6.54(1H,t,J=4.9Hz),6.93(1H,dt,J=15.2,7.4Hz),8.33(2H,d,J=4.9Hz).
實施例32
1-((E)-2-癸烯醯基)氮雜環庚烷(1-((E)-2-decenoyl)azepane)[化合物32]的製造
使用(E)-2-癸烯酸及六亞甲基亞胺為起始原料，以與實施例1同樣操作而製造目的化合物。
淡褐色油狀物，C16H29NO MW 251,HR-ESIMS(positive ion mode)：m/z 274.2145[M+Na]+(Caled for C16H29NONa,274.2147),1H-NMR(400MHz,CDCl3)δ：0.88(3H,t,J=6.8Hz),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=6.0Hz),3.58(2H,t,J=6.2Hz),6.22(1H,d,J=15.6Hz),6.90(1H,dt,J=15.6,7.4Hz).
實施例33
1-((E)-2-癸烯醯基)-4-甲基-[1,4]二氮雜環庚烷(1-((E)-2-decenoyl)-4-methyl-[1,4]diazepane)[化合物33]的製造
使用(E)-2-癸烯酸及1-甲基-1,4二氮雜環庚烷為起始原料，以與實施例2同樣操作而製造目的化合物。
淡黃色油狀物，C16H30N2O MW 266.4,EIMS：m/z 267[M+H]+, 1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=7.0Hz,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×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).
實施例34
1-((E)-2-癸烯醯基)-4-(2-二甲胺基乙基)-[1,4]二氮雜環庚烷(1-((E)-2-decenoyl)-4-(2-dimethylaminoethyl)-[1,4]diazepane)[化合物34]的製造
使用(E)-2-癸烯酸及1-(2-二甲胺基乙基)-1,4二氮雜環庚烷為起始原料，以與實施例2同樣操作而製造目的化合物。
淡黃色油狀物，C19H37N3O MW 323.5,EIMS：m/z324[M+H]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=7.0Hz,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).
實施例35
2-(1-((E)-2-癸烯醯基)-4-哌啶基)乙酸(2-(1-((E)-Dec-2-enoyl)-4-piperidyl)acetic acid)[化合物35]的製造
(1)使用(E)-2-癸烯酸及2-(4-哌啶基)乙酸乙酯鹽酸鹽為起始原料，以與實施例2同樣操作而製造2-(1-((E)-2-癸烯醯基)-4-哌啶基)乙酸乙酯(化合物35的乙酯)。
(2)以與實施例3同樣操作，由2-(1-((E)-2-癸烯醯基)-4- 哌啶基)乙酸乙酯的鹼皂化而製造目的化合物。
白色結晶，mp 65-66℃,C17H29NO3 MW 295.4,EIMS：m/z 296[M+H]+,1H-NMR(500MHz,DMSO-d6)δ：0.87(t,J=7.1Hz,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=15.0Hz,1G),6.61(dt,Jd=15.0Hz,Jt=7.0Hz,1H).
實施例36
3-(1-((E)-2-癸烯醯基)-4-哌啶基)丙酸(3-(1-((E)-Dec-2-enoyl)-4-piperidyl)propanoic acid)[化合物36]的製造
(1)使用(E)-2-癸烯酸及3-(4-哌啶基)丙酸乙酯鹽酸鹽為起始原料，以與實施例2同樣操作而製造3-(1-((E)-2-癸烯醯基)-4-哌啶基)丙酸乙酯(化合物36的乙酯)。
(2)以與實施例3同樣操作，由3-(1-((E)-2-癸烯醯基)-4-哌啶基)丙酸乙酯的鹼皂化而製造目的化合物。
無色油狀物，C18H31NO3 MW 309.4,EIMS：m/z 310[M+H]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=6.5Hz,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=7.5Hz,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=15.0Hz,1H),6.61(dt,Jd=15.0Hz,Jt=7.0Hz,1H),12.03(br,1H).
實施例37
1-((E)-2-癸烯醯基)-4-氰基哌啶(1-((E)-Dec-2-enoyl)-4-cyanopiperidine)[化合物37]的製造
使用(E)-2-癸烯酸及哌啶-4-甲腈(piperidine-4-carbonitrile)為起始原料，以與實施例2同樣操作而製造目的化合物。
無色油狀物，C16H26N2O MW 262.4,EIMS：m/z 263[M+H]+,1H-NMR(500MHz,DMSO-ds)δ：0.87(t,J=6.5Hz,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=15.0Hz,1H),6.65(dt,Jd=15.0Hz,Jt=7.0Hz,1H).
實施例38
1-((E)-2-癸烯醯基)-4-(4-氯苯基)哌啶(1-((E)-Dec-2-enoyl)-4-(4-chlorophenyl)piperidine)[化合物38]的製造
使用(E)-2-癸烯酸及4-(4-氯苯基)哌啶為起始原料，以與實施例2同樣操作而製造目的化合物。
淡黃色油狀物，C21H30ClNO MW 347.9,EIMS：m/z 348[M+H]+,1H-NMR(500MHz,DMSO-ds)δ：0.86(t,J=7.0Hz,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=15.0Hz,1H),6.65(dt,Jd=15.0Hz,Jt=7.0Hz,1H),7.27(d,J=8.5Hz,2H),7.34(d,J=8.5Hz,2H).
實施例39
[4-[(E)-2-癸烯醯基]哌-1-基]乙酸鹽酸鹽([4-[(E)-Dec-2-enoyl]piperazin-1-yl]acetic acid hydrochloride)[化合物39]的製造
(1)使用(E)-2-癸烯酸及2-(1-哌基)乙酸乙酯2鹽酸鹽為起始原料，以與實施例2同樣操作而製造[4-[(E)-2-癸烯醯基]哌-1-基]乙酸乙酯(化合物39的遊離物的乙酯)。
(2)以與實施例3同樣操作，由[4-[(E)-2-癸烯醯基]哌-1-基]乙酸乙酯的鹼皂化而獲得[4-[(E)-2-癸烯醯基]哌-1-基]乙酸(化合物39的遊離物)。
(3)將所得的化合物溶解於二氯甲烷中，以氯化氫-二烷處理而製造目的化合物。
白色結晶，mp 195℃(分解)，C16H29ClN2O3 MW 332.9,EIMS：m/z 297[M+H]+,1H-NMR(500MHz,DMSO-d6)δ：0.87(t,J=7.0Hz,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=15.0Hz),6.73(dt,Jd=15.0Hz,Jt=7.0Hz,1H).
實施例40
4-[4-[(E)-2-癸烯醯基]哌-1-基]丁酸鹽酸鹽(4-[4-[(E)-Dec-2-enoyl]piperazin-1-yl]butanoic acid hydrochloride)[化合物40]的製造
(1)使用(E)-2-癸烯酸及4-(1-哌基)丁酸乙酯2鹽酸鹽為起始原料，以與實施例2同樣操作而製造4-[4-((E)-2-癸烯醯基)哌-1-基]丁酸乙酯(化合物40的遊離物的乙酯)。
(2)以與實施例3同樣操作，由4-[4-((E)-2-癸烯醯基)哌-1-基]丁酸乙酯的鹼皂化而獲得4-[4-[(E)-2-癸烯醯基]哌-1-基]丁酸(化合物40的遊離物)。
(3)將所得的化合物溶解於二氯甲烷中，以氯化氫-二烷處理而製造目的化合物。
白色結晶，mp 203-205℃,C18H33ClN2O3 MW 360.9,EIMS：m/z 325[M+H]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=7.0Hz,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=7.2Hz,2H),2.26-2.35(m,6H),3.45-3.55(m,4H),6.43(d,J=15.0Hz,1H),6.64(dt,Jd=15.0Hz,Jt=7.0Hz,1H).
實施例41
1-((E)-2-癸烯醯基)-4-(4-氯苯基)哌(1-((E)-Dec-2-enoyl)-4-(4-chlorophenyl)piperazine)[化合物41]的製造
使用(E)-2-癸烯酸及1-(4-氯苯基)哌為起始原料，以與實施例2同樣操作而製造目的化合物。
淡黃色油狀物，C20H29ClN2O MW 348.9,EIMS：m/z348[M]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=6.5Hz,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=15.0Hz,1H),6.70(dt,Jd=15.0Hz,Jt=7.0Hz,1H),6.90(d,J=9.0Hz,2H),7.25(J=9.0Hz,2H).
實施例42
1-((E)-2-癸烯醯基)-4-(4-甲氧基苯基)哌(1-((E)-Dec -2-enoyl)-4-(4-methoxyphenyl)piperazine)[化合物42]的製造
使用(E)-2-癸烯酸及1-(4-甲氧基苯基)哌為起始原料，以與實施例2同樣操作而製造目的化合物。
白色結晶，mp 50-52℃,C21H32N2O2 MW 344.5,EIMS：m/z 344[M]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=6.8Hz,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=15.0Hz,1H),6.68(dt,Jd=15.0Hz,Jt=7.0Hz,1H),6.83(d, J=9.1Hz,2H),6.91(d,J=9.1Hz,2H).
實施例43
1-((E)-2-癸烯醯基)-4-(4-甲基苯基)哌(1-((E)-Dec-2-enoyl)-4-(4-methylphenyl)piperazine)[化合物43]的製造
(E)-2-癸烯酸及1-(對甲苯基)哌為起始原料，以與實施例2同樣操作而製造目的化合物。
白色結晶，mp 45-46℃,C21H32N2O MW 328.5,EIMS：m/z 328[M]+,1H-NMR(500MHz,DMSO-d6)δ：0.85(t,J=6.9Hz,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=15.0Hz,1H),6.69(dt,Jd=15.0Hz,Jt=7.0Hz,1H),6.85(d,J=8.5Hz,2H),7.03(d,J=8.5Hz,2H).
實施例44
1-((E)-2-癸烯醯基)-4-(4-氟苯基)哌(1-(E)-Dec-2-enoyl)-4-(4-fluorophenyl)piperazine)[化合物44]的製造
使用(E)-2-癸烯酸及1-(4-氟苯基)哌為起始原料，以 與實施例2同樣操作而製造目的化合物。
淡黃色油狀物，C20H29FN2O MW 332.5,EIMS：m/z 332[M]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=6.5Hz,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=15.0Hz,1H),6.69(dt,Jd=15.0Hz,Jt=7.0Hz,1H),6.95-7.00(m,2H),7.03-7.09(m,2H).
實腕例45
1-((E)-2-癸烯醯基)-4-(2-氯苯基)哌(1-((E)-Dec-2-enoyl)-4-(2-chlorophenyl)piperazine)[化合物45]的製造
使用(E)-2-癸烯酸及1-(2-氯苯基)哌為起始原料，以與實施例2同樣操作而製造目的化合物。
淡黃色油狀物，C20H29ClN2O MW 348.9,EIMS：m/z 348[M]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=6.5Hz,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=15.0Hz,1H),6.70(dt,Jd=15.0Hz,Jt=7.0Hz,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).
實施例46
1-((E)-2-癸烯醯基)-4-(4-羥苯基)哌(1-((E)-Dec-2-enoyl)-4-(4-hydoroxyphenyl)piperazine)[化合物46]的製造
使用(E)-2-癸烯酸及4-(1-哌基)酚為起始原料，以與實施例2同樣操作而製造目的化合物。
淡紅色結晶，mp 85-87℃,C20H30N2O2 MW 330.5,EIMS： m/z330[M+H]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=7.0Hz,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=15.0Hz,1H),6.63-6.71(m,3H),6.80(d,J=6.8Hz,2H),8.88(s,1H).
實施例47
2-[4-[4-((E)-2-癸烯醯基)哌-1-基]苯氧基]乙酸(2-[4-[4-((E)-Dec-2-enoyl)piperazin-1-yl]acetic acid][化合物47]的製造
(1)使用(E)-2-癸烯酸及2-[4-(1-哌基)苯氧基]乙酸乙酯2鹽酸鹽為起始原料，以與實施例2同樣操作而製造2-[4-[4-((E)-2-癸烯醯基)哌-1-基]苯氧基]乙酸乙酯(化合物47的乙酯)。
(2)以與實施例3同樣操作，由2-[4-[4-((E)-2-癸烯醯基)哌-1-基]苯氧基]乙酸乙酯的鹼皂化而製造目的化合物。
白色結晶，mp 210℃(分解)，C22H32N2O4 MW 388.5,EIMS：m/z388[M]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=7.0Hz,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=15.0Hz,1H),6.68(dt,Jd=15.0Hz,Jt=7.0Hz,1H),6.76(d,J=7.1Hz,2H),6.87(d,J=7.1Hz,2H).
實施例48
4-[[4-((E)-2-癸烯醯基)哌-1-基]甲基]苯甲酸(4-[[4-((E)-Dec-2-enoyl)piperazin-1-yl]benzoic acid][化合物48]的 製造
(1)使用(E)-2-癸烯酸及4-(1-哌基甲基)苯甲酸甲酯2鹽酸鹽為起始原料，以與實施例2同樣操作而製造4-[[4-((E)-2-癸烯醯基)哌-1-基]甲基]苯甲酸甲酯(化合物48的甲酯)。
(2)以與實施例3同樣操作，由4-[[4-((E)-2-癸烯醯基)哌-1-基]甲基]苯甲酸甲酯的鹼皂化而製造目的化合物。
白色結晶，mp 114-116℃,C22H32N2O3 MW 372.5,EIMS：m/z 373[M+H]+,1H-NMR(500MHz,DMSO-d6)δ：0.86(t,J=7.0Hz,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=15.0Hz,1H),6.64(dt,Jd=15.0Hz,Jt=7.0Hz,1H),7.44(d,J=8.2Hz,2H),12.8(br,1H).
實施例49
4-[(E)-2-癸烯醯基]嗎啉-3-羧酸(4-[(E)-Dec-2-enoyl]morpholine-3-carboxylic acid)[化合物49]的製造
(1)使用(E)-2-癸烯酸及嗎啉-3-羧酸甲酯鹽酸鹽為起始原料，以與實施例2同樣操作而製造4-[(E)-2-癸烯醯基]嗎啉-3-羧酸甲酯(化合物49的甲酯)。
(2)以與實施例3同樣操作，由4-[(E)-2-癸烯醯基]嗎啉-3-羧酸甲酯的鹼皂化而製造目的化合物。
淡黃色油狀物，C15H25NO4 MW 283.4,EIMS：m/z 284[M+H]+,1H-NMR(500MHz,CDCl3)δ：0.88(t,J=7.0Hz,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×2,J=15.0Hz,1H),6.88-7.02(m,1H),9.00(br,1H).
試驗例1 紫杉醇對大鼠的末梢神經障礙作用的評估
針對將抗癌劑紫杉醇投予時產生的副作用的末梢神經障礙，即對機械性刺激引起的觸感痛(allodynia)(通常不會引起疼痛的觸覺刺激引起的激痛)等知覺過敏，調查本發明化合物的效果。將本發明化合物做為被驗藥而投予至大鼠的腹腔內，實施馮佛雷(von Frey)試驗。
(1)紫杉醇誘發末梢神經障礙大鼠的製作及被驗藥的投予
使用6週齡的SD雄性大鼠(1群6隻)做為實驗動物，將紫杉醇(2mg/kg)每隔1日共計4次腹腔內投予，製作紫杉醇誘發末梢神經障礙大鼠。被驗藥在紫杉醇的投予開始18至25日後或20至27日後之間，都以300μ/kg之量單次腹腔內投予，實施下述的馮佛雷(von Frey)試驗。
(2)馮佛雷試驗(von Frey test)
在底為金屬網的透明壓克力籠中，放入上述(1)的大鼠，約馴化3分鐘後，在被驗藥投予前、投予開始起1及5小時後測定右後肢對於機械刺激的50%反應門檻值。
測定是依照Chaplan等(Journal of Neuroscience Methods,53巻，1號，55-63頁，1994年)及Dixon等(Annual Review of Pharmacology and Toxicology,20巻，441-462頁，1980年)的方法，使用馮佛雷細絲(von Frey filament,North Coast Medical Inc.製)實施。將8條細絲[刺激荷重(g)：0.4,0.6,1.0,2.0,4.0,6.0,8.0,15.0]中，由2.0g的細絲開始，以細絲輕度彎曲程度之力對腳底垂直接觸2至3秒鐘，後肢表現逃避反應時設為陽性反應。又，除去細絲的一瞬間表現逃避時也做為陽性。有陽性反應時則以低一等級，沒有反應時則以高一等級強度的細絲同樣刺激，反應由陰性變化為陽性或由陽性變化為陰性時，做為最初的2反應。之後連續4次做同樣的上升下降法(up-down法)實施刺激。用合計6次的對刺激的反應，測定對機械刺激的50%反應門檻值，算出各群的平均值±標準誤差。這時，沒有陽性反應而做到15.0g的刺激時以15.0g做為50%反應門檻值，陽性反應持續到0.4g時以0.25g做為50%反應門檻值。被驗藥投予1小時後或5小時後的50%反應門檻值中較高的50%反應門檻值，設正常門檻值為15，以下述式算出50%反應門檻值的恢復率(%)。上述試驗結果的一例示於第6表及第7表。
50%反應門檻值的恢復率(%)=(被驗藥投予1小時後或5小時後的50%反應門檻值-被驗藥投予前的50%反應門檻值)÷(正常門檻值-被驗藥投予前的50%反應門檻值)×100
由第6表及第7表，可知本發明化合物對於紫杉醇投予所引起的知覺過敏有優異的改善作用，顯示有減輕由於抗癌劑投予所引起的副作用之作用。又，本發明化合物，做為抗癌劑而使用鉑製劑的益樂鉑時，與使用紫杉烷系的紫杉醇時同樣，對知覺過敏有優異的改善作用。
試驗例2 MAP激酶的活化(磷酸化)的評估
針對本發明化合物依照西方免疫墨點法(western immunoblotting method)，如以下所述方式測定MAP激酶(ERK1/2)的活化。
由胎兒17日齡的大鼠大腦皮質將神經細胞分散，將該神經細胞以含5%胎牛血清的Dulbecco改良Eagle培養基(Dulbecco’s modified Eagle’s medium；DMEM)培養1日。將 培養液換為無血清培養基(添加B27 supplement之Neurobasal，Invitrogen(股)公司)，使用聚鳥胺酸覆蓋的培養皿以2至4萬個/cm2的密度培養神經細胞。
3日後，添加本發明化合物而繼續培養30分鐘。之後，在冰上以Tris-HCl緩衝液為基質的含脫磷酸化酶抑制劑的溶液回收細胞。將所得的細胞萃取液的蛋白質濃度以蛋白濃度測定試劑盒(BCA Protein Assay Kit，Takara Bio(股)公司)定量，將一定量的蛋白質(MAP激酶測定用時3μg，磷酸化MAP激酶測定用時5μg)在聚丙烯醯胺凝膠做電泳。由電泳後的凝膠將蛋白質轉印到PVDF膜，分別使用1次抗體的抗MAP激酶抗體(Cell Signaling Technology公司)與抗磷酸化MAP激酶抗體(Cell Signaling Technology公司)實施西方免疫點墨。
其次，與2次抗體的鹼性磷酸酶標識抗兔IgG抗體(Promega(股)公司)反應而使酶活性發色，測定MAP激酶(MAPK)及磷酸化MAP激酶(pMAPK)。
在這裏，本發明化合物溶解於0.1% DMSO，並調整為250μg/ml的濃度。對照(Control)是添加0.1% DMSO。
上述所得的電泳凝膠的帶域(band)的濃度以Image J(Bio Arts(股)公司)算出強度而數值化。以對照的MAPK的數值除使用本發明化合物時的MAPK的數值，又以對照的pMAPK的數值，除使用本發明化合物時的pMAPK的數值，求使用本發明化合物時的MAPK對對照的比率及使用本發明化合物時的pMAPK對對照的比率。其次，所 得的pMAPK對對照的比率除所得的MAPK對對照的比率，而求pMAPK對MAPK的比率。結果之一例示於第8表至第10表。
第8表至第10表顯示本發明化合物比對照表現較高的MAP激酶的活化(磷酸化)，而有類神經營養因子的作用。
試驗例3 溫和壓力負荷下的MAP激酶的活化(磷酸化)的評估
針對本發明化合物，使用慢性溫和壓力誘導性憂鬱症模型小鼠，以西方免疫墨點法(western immunoblotting method)，依照下述的方法測定MAP激酶(ERK1/2)的活化程度。
(1)慢性溫和壓力誘導性憂鬱症模型小鼠的製作及被驗藥的投予
對7週齡ddY系雌性小鼠(n=8至12)實施下述的操作。(A)強制游泳15分鐘後，正常飼育2日。(B)在傾斜的籠中飼育2日後，正常飼育1日。(C)在濕墊料的籠中飼育1日後，正常飼育1日。(D)在以180轉/分鐘的速度旋轉的籠 中飼育1日後，正常飼育1日。實行(A)至(D)1次後，再將(B)至(D)反覆2次。如此，經過合計3週之久而施加壓力，製作慢性溫和壓力誘導性憂鬱症模型小鼠。在此期間，毎日1次，經過3週之久，將本發明化合物做為被驗藥溶解於含PBS或DMSO等的PBS溶媒而經口投予。
(2)MAP激酶及磷酸化MAP激酶的測定
上述的慢性溫和壓力負荷後的行動解析(尾部懸吊試驗及明暗試驗)結束後，由腦摘出海馬。將海馬及其濕重量的19倍量的破碎液(含有1%Nonidet P40[註冊商標]，1%去氧膽酸鈉(sodium deoxycholate)，2mM EDTA，0.1%十二烷基硫酸鈉(sodium dodecyl sulfate,SDS)，0.15M NaCl，10mg/ml aprotinin，10mg/ml亮抑酶肽(Leupeptin)，50mM NaF，1mM正釩酸鈉，1mM苯甲基磺醯(phenylmethylsulfonyl fluoride,PMSF)的20mM Tris鹽酸緩衝液(pH 7.4)：RIPA緩衝液)放入微量離心管(1.5ml)中，超音波破碎處理。之後，將該管在冰上靜置30分鐘後離心(1400×g，15分鐘)，將上澄液做為蛋白質萃取液。在蛋白質萃取液中添加1/3量的電泳用樣品緩衝液(0.2M Tris鹽酸緩衝液(pH 7.2)，8% SDS，40%甘油，溴酚藍(bromophenol blue(BPB))、1/10量的2-巰乙醇(2-mercaptoethanol)，在95℃加熱處理5分鐘，以10%聚丙烯醯胺凝膠實施SDS電泳。
對MAP激酶(MAPK)及磷酸化MAP激酶(pMAPK)分別實施免疫墨點解析，將個別2μg、5μg的組織萃取蛋白質做電泳。之後，由凝膠將蛋白質轉印至PVDF 膜。轉印後的PVDF膜則以含有5%脫脂奶的溶液做阻斷(blocking)後，與抗MAPK抗體、抗pMAPK抗體之各別1000倍稀釋液在4℃反應一晚。繼而與二次抗體(鹼性磷酸酶標識抗小鼠IgG抗體(5000倍稀釋))反應，最後使用添加有鹼磷酸酶的基質的溶液保溫數分鐘而發色。將各帶域的染色強度數值化，求pMAPK對MAPK的比率(n=4至7)。在這裏，顯著性測驗是以Dunnett’s test實行。
上述試驗的結果，正常動物對照群的pMAPK對MAPK的比率是1.26±0.11，溫和壓力負荷動物對照群的該比率是0.56±0.04而有顯著降低。投予本發明化合物的群的該比率，化合物10投予群(1000μg/kg)是1.00±0.04，化合物12投予群(500μg/kg)是1.09±0.04，本發明化合物在溫和壓力負荷動物對照群中將降低的MAPK的磷酸化顯著提高，表示有類神經營養因子作用。
試驗例4溫和壓力負荷下CREB的活化(磷酸化)的評估
針對本發明化合物，使用慢性溫和壓力誘導性憂鬱症模型小鼠，藉由西方墨點法，將訊息傳遞路徑位在MAPK(ERK1/2)的下游，且在神經細胞的功能及記憶/學習能力上扮演重要的角色的轉錄因子CREB的活化水準(磷酸化CREB(pCREB)對CREB的比率)，以與上述試驗例3同樣方式測定(n=3至8)。但是，一次抗體(抗CREB抗體，抗pCREB抗體)是以1000倍稀釋，二次抗體是以10000倍稀釋進行反應。
上述試驗的結果，正常動物對照群的pCREB對CREB的比率是0.95±0.09，在溫和壓力負荷動物對照群中該比率是0.50±0.07，有顯著降低。
本發明化合物的投予群中該比率，化合物10投予群(1000μg/kg)是0.94±0.10，化合物12投予群(500μg/kg)是1.08±0.14，本發明化合物是與MAPK磷酸化時同樣，將在溫和壓力負荷動物對照群中降低的pCREB比率顯著提高，而有類神經營養因子的作用。
試驗例5伴隨於溫和壓力負荷的抑鬱症狀的抑制效果的評估
將本發明化合物做為被驗藥投予至上述試驗例3(1)的慢性溫和壓力誘導性憂鬱症模型小鼠後，以尾部懸吊試驗評估抑鬱症狀的抑制效果。即，將小鼠的從尾部前端起1cm的地方以手抓住，吊在離地面10cm的高度處，觀察6分鐘，測定成為抑鬱症狀的指標的無動作時間的長度。在這裏，顯著性試驗是依Dunnett’s test實行。
上述尾部懸吊試驗的結果，正常動物對照群的無動作時間是73.16±9.20秒，溫和壓力負荷動物對照群的無動作時間是157.01±11.97秒，有顯著延長。將本發明化合物12以500μg/kg的用量投予的群的無動作時間是69.26±16.41秒，顯示有顯著抑制抑鬱症狀的效果。又，將本發明化合物10以1000μg/kg的用量投予的群的無動作時間是96.03±25.24秒，有抑制抑鬱症狀。
試驗例6隨伴溫和壓力負荷的焦慮症狀的 抑制效果的評估
將本發明化合物做為被驗藥投予至上述試驗例3(1)的慢性溫和壓力誘導性憂鬱症模型小鼠後，以明暗試驗評估焦慮症狀的抑制效果。即，使用高度50cm、長度50cm、寬度25cm的明室及暗室所成的木製的長方形裝置，在暗室內置小鼠使其自由探索，之後計測5分鐘中侵入明室的次數、滯留於明室的時間。本試驗是利用小鼠雖然有喜好暗處的傾向，難於停留在明亮場所的習性，但會由於好奇心而發起探索行動、侵入明室的性質，而評估小鼠的焦慮水準的試驗。在這裏，顯著性試驗是以Dunnett’s test實行。
上述明暗試驗的結果，相對於正常動物對照群的明室滯留時間是110.74±5.29秒，溫和壓力負荷對照群的明室滯留時間是74.72±4.09秒，有顯著降低。將本發明化合物12以500μg/kg的用量投予的群的明室滯留時間是108.70±12.06秒，顯示有顯著抑制焦慮症狀的效果。又，將本發明化合物10以1000μg/kg的用量投予的群的明室滯留時間是107.05±8.29秒，有抑制焦慮症狀。
試驗例7對變形性關節炎模型大鼠的鎮痛作用的評估
使用單碘乙酸鈉(MIA)誘發OA大鼠做為變形性關節炎(Osteoarthritis；OA)的模型動物，實施下述實驗以調查本發明鎮痛劑的鎮痛作用。
(1)MIA誘發OA大鼠的製作
測定6週齡雄性Wistar系大鼠對機械刺激的50%反應 門檻值(測定方法如後述)，選出正常對照群。對於正常對照群以外的大鼠，以300μg/50μl的用量單次投予以生理食鹽水調製的MIA至其右膝關節內，投予生理食鹽水50μl至其左膝關節內，而製作MIA誘發OA大鼠。又，對於正常對照群則投予生理食鹽水50μl至其兩膝的關節內。
(2)群編制
實驗動物的6週齡雄性Wistar系大鼠，對正常對照群以外是在上述(1)的MIA投予的24日後，測定對機械刺激的50%反應門檻值(測定方法在後述)及體重，而編成正常對照群、發病對照群、被驗藥投予群的3群，1群6隻。
(3)被驗藥的投予
使用本發明化合物做為被驗藥的被驗藥溶液(100μg/ml)是以含0.1vol%的二甲基亞碸(DMSO)的磷酸緩衝生理食鹽水(PBS)調製。
在群編成後即時(MIA投予14日後)，對於被驗藥投予群以500μg/kg的用量，單次投予被驗藥溶液至腹腔內。又，對於正常對照群及發病對照群則單次投予含有0.1vol%DMSO的PBS至腹腔內。
(4)測定對機械刺激的50%反應門檻值(馮佛雷(von Frey)試驗)的結果
與試驗例1的(2)同樣地實施馮佛雷(von Frey)試驗，算出由MIA投予所誘發的OA的痛覺過敏的50%反應門檻值的恢復率(%)。結果的一例示於第11表。
由第11表可明白，本發明化合物，對由MIA投予所誘發的OA的痛覺過敏顯示抑制效果，顯示有做為鎮痛劑的有用性。
(產業上的利用可能性)
由上述的藥理試驗結果可明白，本發明化合物對於由抗癌劑的投予而在大鼠產生的對機械刺激的痛覺過敏有優異的治療效果。因此，本發明化合物是有效做為對人及動物的四肢末端的麻木等知覺異常及疼痛等痛覺過敏等由抗癌劑所引起的末梢神經障礙的預防或治療用藥劑，有用性極高。
又，在使用大鼠大腦皮質培養神經細胞及慢性溫和壓力誘導性憂鬱症模型小鼠的海馬的評估中，顯示有優異的MAP激酶磷酸化作用及CREB磷酸化作用(類神經營養因子作用)。再者，在使用慢性溫和壓力誘導性憂鬱症模型小鼠的各種試驗中，顯現改善抑鬱症狀及焦慮症狀的作用。因此，本發明化合物，期待有用於做為對癡呆症，阿茲海默症，巴金森病，糖尿病性神經病變，憂鬱症，青光眼，自 閉症譜系等的預防或治療劑，脊髄損傷的修復劑。
又，本發明化合物，在使用OA模型的MIA誘發OA大鼠之動物實驗中，有更優異的鎮痛效果及痛覺過敏抑制效果。因此，本發明化合物，做為對種種疼痛疾病，例如，OA等所引起的疼痛的預防或治療劑的有用性高。

Claims (16)

  1. 下述通式(I’)表示的反式-2-癸烯酸衍生物或其藥學上可容許的鹽： 式中，X’表示(a)經羧基或烷氧羰基取代的1-吡咯啶基，(b)3-四氫噻唑基(thiazolidinyl)，(c)經烷基、側氧基、羥基、烷氧基、羧基、烷氧羰基、烷胺基、烷胺基烷基、苯基、羧烷基、烷氧羰基烷基、氰基或鹵苯基取代的N-哌啶基，(d)N-硫代嗎啉基，(e)可經烷基、羧烷基、烷氧羰基烷基、烷胺基烷基、環烷基、N-哌啶基烷基、苯烷基、吡啶基、嘧啶基、羧苯基烷基或烷氧羰基苯烷基取代的1-哌基，(f)經由可經烷胺基、鹵素、烷氧基、烷基、羥基、羧烷氧基或烷氧基羰基烷氧基取代的苯基而取代的1-哌基，(g)可經烷基或烷胺基烷基取代的1,4-二氮雜環庚烷基，或(h)N-羧基嗎啉基。
  2. 如申請專利範圍第1項所述的反式-2-癸烯酸衍生物或其在藥學上可容許的鹽，其中，X’是經羧基或烷氧基羰基取代的1-吡咯啶基。
  3. 如申請專利範圍第1項所述的反式-2-癸烯酸衍生物或其在藥學上可容許的鹽，其中，X’是3-四氫噻唑基、N-硫代嗎啉基或N-羧基嗎啉基。
  4. 如申請專利範圍第1項所述的反式-2-癸烯酸衍生物或其在藥學上可容許的鹽，其中，X’是經烷基、側氧基、羥基、烷氧基、羧基、烷氧羰基、烷胺基、烷胺基烷基、苯基、羧烷基、烷氧基羰基烷基、氰基或鹵苯基取代的N-哌啶基。
  5. 如申請專利範圍第1項所述的反式-2-癸烯酸衍生物或其在藥學上可容許的鹽，其中，X’是可經烷基、羧烷基、烷氧基羰基烷基、烷胺基烷基、環烷基、N-哌啶基烷基、苯烷基、吡啶基、嘧啶基、羧苯烷基或烷氧羰基苯烷基取代的1-哌基。
  6. 如申請專利範圍第1項所述的反式-2-癸烯酸衍生物或其在藥學上可容許的鹽，其中，X’是經由可經烷胺基、鹵素、烷氧基、烷基、羥基、羧烷氧基或烷氧基羰基烷氧基取代的苯基而取代的1-哌基。
  7. 如申請專利範圍第1項所述的反式-2-癸烯酸衍生物或其在藥學上可容許的鹽，其中，X’是可經烷基或烷胺基烷基取代的1,4-二氮雜環庚烷基。
  8. 一種藥劑，係含有下述通式(I)表示的反式-2-癸烯酸衍生物及其在藥學上可容許的鹽的至少一種做為有效成分： 式中，X表示(a)可經羧基或烷氧基羰基取代的1-吡咯啶基，(b)3-四氫噻唑基，(c)可經烷基、側氧基、羥基、烷氧基、羧基、烷氧羰基、烷胺基、烷胺基烷基、苯基、羧烷基、烷氧基羰基烷基、氰基或鹵苯基取代的N-哌啶基，(d)可經羧基取代的N-嗎啉基，(e)N-硫代嗎啉基，(f)可經烷基、羧烷基、烷氧羰基烷基、烷胺基烷基、環烷基、N-哌啶基烷基、苯烷基、吡啶基、嘧啶基、羧苯烷基或烷氧羰基苯烷基取代的1-哌基，(g)經由可經烷胺基、鹵素、烷氧基、烷基、羥基、羧烷氧基或烷氧基羰基烷氧基取代的苯基而取代的1-哌基，(h)1-氮雜環庚烷，或(i)可經烷基或烷胺基烷基取代的1,4-二氮雜環庚烷基。
  9. 如申請專利範圍第8項所述的藥劑，係含至少1種抗癌劑的藥劑的投予所引起的末梢神經障礙的預防或治療劑。
  10. 如申請專利範圍第8項所述的藥劑，係神經退化疾病的預防或治療劑。
  11. 如申請專利範圍第8項所述的藥劑，係精神疾病的預防或治療劑。
  12. 如申請專利範圍第11項所述的藥劑，其中，前述精神疾病是憂鬱症、焦慮症(神經病)或自閉症譜系(autism spectrum)。
  13. 如申請專利範圍第8項所述的藥劑，係對疼痛疾病的鎮痛劑。
  14. 如申請專利範圍第8項至第13項中任一項所述的藥劑，係注射劑。
  15. 如申請專利範圍第8項至第13項中任一項所述的藥劑，係口服劑。
  16. 如申請專利範圍第8項至第13項中任一項所述的藥劑，係外用劑。
TW102114986A 2012-04-27 2013-04-26 反式－２－癸烯酸衍生物及含該衍生物之藥劑 TWI636975B (zh)

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