CN104254521B - 反式-2-癸烯酸衍生物及含有其的药物 - Google Patents
反式-2-癸烯酸衍生物及含有其的药物 Download PDFInfo
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- CN104254521B CN104254521B CN201380022267.4A CN201380022267A CN104254521B CN 104254521 B CN104254521 B CN 104254521B CN 201380022267 A CN201380022267 A CN 201380022267A CN 104254521 B CN104254521 B CN 104254521B
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- 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
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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
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- 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
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- 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
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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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Abstract
本发明涉及新型的反式-2-癸烯酸衍生物或其药学上可接受的盐、以及含有该化合物作为有效成分的药物。本发明化合物即反式-2-癸烯酸衍生物或其药学上可接受的盐,具体而言,用通式(I)(式中,X表示1-吡咯烷基、3-四氢噻唑基、哌啶基等取代基。)表示,作为给与抗癌剂导致的末梢神经障碍的预防或治疗剂,失智症、阿尔茨海默病、帕金森病、糖尿病性神经病变、抑郁症、青光眼、泛自闭症障碍等神经退行性疾病或精神疾病的预防或治疗剂,脊髓损伤的治疗或修复剂、针对各种疼痛疾病的镇痛剂等药物的有用性高。
Description
技术领域
本发明涉及新型反式-2-癸烯酸衍生物或其药学上可接受的盐、及含有该化合物(本申请中,简称为“化合物”时,有时包括其药学上可接受的盐)作为有效成分的药物。具体而言,涉及具有给与抗癌剂导致的末梢神经障碍的预防或治疗作用、神经生长因子(NGF)、脑源性神经营养因子(BDNF)等神经营养因子(neurotrophicfactor)样作用、镇痛作用等药理作用的反式-2-癸烯酸衍生物或其药学上可接受的盐、及含有该化合物作为有效成分的药物。
背景技术
目前,癌(恶性肿瘤)的治疗中,可以分别单独使用或适当组合使用外科手术、照射放射线、化疗。其中,化疗中使用的抗癌剂(抗恶性肿瘤剂)本身具有细胞毒性(细胞障碍性),不仅伤害癌细胞也伤害人的正常细胞,由此产生副作用,因此重要的是以尽可能预防或治疗该副作用并且以发挥充分的抗癌效果的方式对患者给与。
作为给与抗癌剂伴有的副作用,涉及血液障碍、消化器官官障碍、神经障碍等多方面,但最近的倾向是急性或慢性的神经障碍的问题变严重。可以认为这是因为由发挥显著抗癌效果的新型抗癌剂导致的主要副作用大多为神经障碍,对于作为目前治疗的中心的多剂联用疗法产生的影响、血液障碍、消化器官障碍的副作用已经较为改善。如此,对于作为现有癌化疗所伴有的副作用的中心的神经障碍,神经细胞难以再生,一旦发生,没有有效的对策,有时会呈现严重症状,或者形成不可逆的障碍,因此有时也不能继续给与抗癌剂,成为癌治疗方面的重要问题。
给与抗癌剂所伴随的神经障碍除了中枢神经系统、自律神经系统、末梢神经系统之外,也确认到有味觉等感觉器官。其中,发生频率较高的问题是刺痛、灼烧样痛等疼痛;四肢末端的麻痹;灼热感等知觉异常;对冷感刺激的过敏等知觉过敏;感觉消失·感觉麻痹、不协调感等感觉异常;知觉性运动失调、肌力减弱等末梢神经系统的神经障碍。本发明中,引起末梢神经障碍的抗癌剂可以为任何物质,但可以认为给与抗癌剂导致的末梢神经系统的病变以神经轴突的变性为主。轴突内的微管在细胞分裂时形成纺锤体,或者与细胞内小器官的位置、物质输送有关等,在维持细胞的正常功能上发挥重要作用。可以认为紫杉醇、紫杉萜等紫杉烷系药剂、长春新碱、长春碱、长春地辛、长春瑞滨等长春花生物碱系药剂通过以该微管为标靶发挥作用来抑制癌细胞的增殖,因此也伤害正常神经细胞的微管而引起神经障碍的情况较多。另外可以认为,奥沙利铂、卡波铂、顺铂、奈达铂等铂类制剂直接伤害神经细胞,结果次要地导致轴突障碍而引起神经障碍的情况较多。
处于如上情况下,抗癌剂导致的神经毒性的研究是基本上未发展的领域,满足上述紫杉烷系抗癌剂等的副作用即末梢神经障碍的预防或治疗方法并未确立。因此,目前为了缓和麻痹症状而使用甲钴胺等维生素B12制剂、中药的牛车肾气丸等,针对疼痛使用抗抑郁药(盐酸阿米替林)、抗癫痫药(卡马西平)、抗心律不齐药(盐酸美西律)、肾上腺皮质类固醇等,但效果有限。中止给与抗癌剂是控制末梢神经障碍的唯一确实的方法,但中止给与后也会有末梢神经障碍持续或恶化的情况。对于癌治疗,需要给与抗癌剂,但强烈的末梢神经障碍使得继续给与对癌的有效性高的重要的抗癌剂变得困难,成为癌治疗方面的重要问题。根据以上现状,针对抗癌剂导致的末梢神经障碍,临床现场正强烈谋求更有效的预防或治疗剂。
另外,神经细胞是具有信号转导功能的细胞,其损伤表现为重要的脑神经功能的丧失。脑、脊髓的中枢神经中,几乎不能期待轴突的再生,神经细胞发生损伤、变性时,需要保护并活化神经细胞。作为这类生物体防御功能,担任神经细胞的分化、维持生存、突触的功能亢进及损伤了的神经轴突的再生、修复的神经营养因子的作用不可或缺。
神经营养因子中,神经生长因子(NGF)、脑源性神经营养因子(BDNF)、神经营养因子-3(NT-3)及神经营养因子-4/5(NT-4/5)等以NGF作为原型构成具有50%以上序列同源性的神经营养因子家族。分泌至细胞外的神经营养因子与神经细胞膜上的高亲和性受体(Trks)结合时,会在神经细胞内向3个方向转导信号,但借助其中之一即包含MAP激酶(mitogen-activatedprotein(MAP)kinases/extracellularsignal-regulatedproteinkinases1/2(ERK1/2))的活化(磷酸化)的MAP激酶信号转导通路的活化而活化转录因子CREB(cAMP-responseelementbindingprotein),从而控制大多数基因表达。因此,如果能活化借助MAP激酶信号转导通路的信号转导,则会存在导致神经细胞的变性、细胞死的神经障碍的临床应用中的可能性。另外,有BDNF与几种疾病相关的报道。
根据与BDNF的基因多态相关的研究,有BDNF的特定多态与帕金森病、阿尔茨海默病、抑郁症、双向型抑郁症、焦虑症、泛自闭症障碍(AutisticSpectrumDisorder)、青光眼等相关的报道。另外,有亨廷顿病的基因突变小鼠的突触功能低下通过给与BDNF而恢复的报告,有通过给与MAP激酶磷酸化抑制剂引起抑郁状态的报道。
如由上述BDNF的例子所知,神经营养因子显示针对特定神经疾病的治疗效果,具有使轴突发芽并生长的作用。但是,神经营养因子是高分子量的蛋白质,因此存在即使自末梢给与也无法通过血脑屏障从而难以到达脑之类的问题。因此,正在尝试探索用低分子量化合物且具有使神经细胞活化的类神经营养因子作用的药物、促进神经营养因子的产生·分泌的药物。
专利文献1中,公开了碳原子数为8或碳原子数为10至12的脂肪酸或脂肪酸酯具有类神经营养因子作用。然而,专利文献1所述的化合物为一般的脂肪酸或其酯,本发明化合物是指羧酸部分的结构明显不同的脂肪酸或其酯。另外,分别地,本发明化合物的1-((E)-2-癸烯酰基)吡咯烷(化合物1)、1-((E)-2-癸烯酰基)哌啶(化合物5)及1-((E)-2-癸烯酰基)氮杂环庚烷(化合物32)被专利文献2公开,(4-((E)-2-癸烯酰基)吗啉(化合物17)被专利文献3或非专利文献1公开。然而,专利文献2涉及针对软体动物的毒性作用,专利文献3涉及针对病原菌、霉的生长抑制作用。另外,非专利文献1是涉及针对家蝇科昆虫的防虫剂的文献。结果,这些文献中均不存在关于本发明化合物的药物用途或者暗示其的记载。
现有技术文献
专利文献
专利文献1:国际公开第2009/038110号公报
专利文献2:国际公开第2010/123894号公报
专利文献3:美国专利第3294794号公报
非专利文献
非专利文献1:JournalofEconomicEntomology,1970,Vol.63,No.6,p.1752-1755
发明内容
发明要解决的问题
本发明的课题在于提供新型的反式-2-癸烯酸衍生物或其药学上可接受的盐、及含有该化合物作为有效成分的药物,更具体而言,在于提供具有抗癌剂导致的末梢神经障碍的预防或治疗作用(本申请中,“末梢神经障碍”可以用同义词即“神经病变(neuropathy)”代替。另外,“预防”及“治疗”均包括“改善”或“减轻”,“预防剂”及“治疗剂”包括“改善剂”或“减轻剂”)、类神经营养因子作用、镇痛作用等药理作用的药物。
用于解决问题的方案
本发明人等为了解决上述问题进行了深入研究,结果发现,下述通式(I)所示的反式-2-癸烯酸衍生物或其药学上可接受的盐具有优异的抗癌剂导致的末梢神经障碍的预防或治疗作用、类神经营养因子作用、镇痛作用等药理作用。本发明人等基于这些见解进一步进行研究,从而完成了本发明。
即,本发明提供以下化合物及含有该化合物的药物。
(1)一种下述通式(I')所示的反式-2-癸烯酸衍生物或其药学上可接受的盐。
〔式中,X'表示:
(a)被羧基或烷氧基羰基取代的1-吡咯烷基、
(b)3-四氢噻唑基、
(c)被烷基、氧基、羟基、烷氧基、羧基、烷氧基羰基、烷基氨基、烷基氨基烷基、苯基、羧基烷基、烷氧基羰基烷基、氰基或卤代苯基取代的哌啶基、
(d)硫代吗啉基、
(e)任选被烷基、羧基烷基、烷氧基羰基烷基、烷基氨基烷基、环烷基、哌啶基烷基、苯基烷基、吡啶基、嘧啶基、羧基苯基烷基或烷氧基羰基苯基烷基取代的1-哌嗪基、
(f)被苯基取代的1-哌嗪基,其中,所述苯基任选被烷基氨基、卤素、烷氧基、烷基、羟基、羧基烷氧基或烷氧基羰基烷氧基取代、
(g)任选被烷基或烷基氨基烷基取代的1,4-二氮杂环庚烷基、或者
(h)羧基吗啉基。〕
(2)根据前述(1)所述的反式-2-癸烯酸衍生物或其药学上可接受的盐,其中,X'为被羧基或者烷氧基羰基取代的1-吡咯烷基。
(3)根据前述(1)所述的反式-2-癸烯酸衍生物或其药学上可接受的盐,其中,X'为3-四氢噻唑基。
(4)根据前述(1)所述的反式-2-癸烯酸衍生物或其药学上可接受的盐,其中,X'为被烷基、氧基、羟基、烷氧基、羧基、烷氧基羰基、烷基氨基、烷基氨基烷基、苯基、羧基烷基、烷氧基羰基烷基、氰基或者卤代苯基取代的哌啶基。
(5)根据前述(1)所述的反式-2-癸烯酸衍生物或其药学上可接受的盐,其中,X'为硫代吗啉基。
(6)根据前述(1)所述的反式-2-癸烯酸衍生物或其药学上可接受的盐,其中,X'为任选被烷基、羧基烷基、烷氧基羰基烷基、烷基氨基烷基、环烷基、哌啶基烷基、苯基烷基、吡啶基、嘧啶基、羧基苯基烷基或者烷氧基羰基苯基烷基取代的1-哌嗪基。
(7)根据前述(1)所述的反式-2-癸烯酸衍生物或其药学上可接受的盐,其中,X'为被苯基取代的1-哌嗪基,其中所述苯基任选被烷基氨基、卤素、烷氧基、烷基、羟基、羧基烷氧基或者烷氧基羰基烷氧基取代。
(8)根据前述(1)所述的反式-2-癸烯酸衍生物或其药学上可接受的盐,其中,X'为任选被烷基或者烷基氨基烷基取代的1,4-二氮杂环庚烷基。
(9)根据前述(1)所述的反式-2-癸烯酸衍生物或其药学上可接受的盐,其中,X'为羧基吗啉基。
(10)一种药物,其含有下述通式(I)所示的反式-2-癸烯酸衍生物及其药学上可接受的盐的至少一种作为有效成分。
〔式中,X表示:
(a)任选被羧基或烷氧基羰基取代的1-吡咯烷基、
(b)3-四氢噻唑基、
(c)任选被烷基、氧基、羟基、烷氧基、羧基、烷氧基羰基、烷基氨基、烷基氨基烷基、苯基、羧基烷基、烷氧基羰基烷基、氰基或卤代苯基取代的哌啶基、
(d)吗啉基、
(e)任选被羧基取代的硫代吗啉基、
(f)任选被烷基、羧基烷基、烷氧基羰基烷基、烷基氨基烷基、环烷基、哌啶基烷基、苯基烷基、吡啶基、嘧啶基、羧基苯基烷基或烷氧基羰基苯基烷基取代的1-哌嗪基、
(g)被苯基取代的1-哌嗪基,其中,所述苯基任选被烷基氨基、卤素、烷氧基、烷基、羟基、羧基烷氧基或烷氧基羰基烷氧基取代、
(h)1-氮杂环庚烷基、或者
(i)任选被烷基或烷基氨基烷基取代的1,4-二氮杂环庚烷基。〕
(11)根据前述(10)所述的药物,其中,X为任选被羧基或者烷氧基羰基取代的1-吡咯烷基。
(12)根据前述(10)所述的药物,其中,X为3-四氢噻唑基。
(13)根据前述(10)所述的药物,其中,X为任选被烷基、氧基、羟基、烷氧基、羧基、烷氧基羰基、烷基氨基、烷基氨基烷基、苯基、羧基烷基、烷氧基羰基烷基、氰基或者卤代苯基取代的哌啶基。
(14)根据前述(10)所述的药物,其中,X为任选被羧基取代的吗啉基。
(15)根据前述(10)所述的药物,其中,X为硫代吗啉基。
(16)根据前述(10)所述的药物,其中,X为任选被烷基、羧基烷基、烷氧基羰基烷基、烷基氨基烷基、环烷基、哌啶基烷基、苯基烷基、吡啶基、嘧啶基、羧基苯基烷基或者烷氧基羰基苯基烷基取代的1-哌嗪基。
(17)根据前述(10)所述的药物,其中,X为被苯基取代的1-哌嗪基,其中所述苯基任选被烷基氨基、卤素、烷氧基、烷基、羟基、羧基烷氧基或者烷氧基羰基烷氧基取代。
(18)根据前述(10)所述的药物,其中,X为1-氮杂环庚烷基。
(19)根据前述(10)所述的药物,其中,X为任选被烷基或者烷基氨基烷基取代的1,4-二氮杂环庚烷基。
(20)根据前述(10)至(19)中的任一项所述的药物,其为通过给与含有至少1种抗癌剂的药剂产生的末梢神经障碍的预防或治疗剂。
(21)根据前述(20)所述的药物,其中,前述抗癌剂为微管抑制剂。
(22)根据前述(21)所述的药物,其中,前述微管抑制剂为紫杉烷系药剂。
(23)根据前述(22)所述的药物,其中,前述紫杉烷系药剂为紫杉醇或紫杉萜。
(24)根据前述(23)所述的药物,其中,前述紫杉烷系药剂为紫杉醇。
(25)根据前述(21)所述的药物,其中,前述微管抑制剂为长春花生物碱系药剂。
(26)根据前述(25)所述的药物,其中,前述长春花生物碱系药剂为长春新碱。
(27)根据前述(20)所述的药物,其中,前述抗癌剂为铂类制剂。
(28)根据前述(27)所述的药物,其中,前述铂类制剂为奥沙利铂或顺铂。
(29)根据前述(20)至(28)中的任一项所述的药物,其中,前述抗癌剂导致的末梢神经障碍为急性或慢性的疼痛、麻痹、知觉异常、知觉过敏或感觉异常。
(30)根据前述(10)至(19)中的任一项所述的药物,其为类神经营养因子作用剂。
(31)根据前述(30)所述的药物,其中,前述类神经营养因子作用剂为神经退行性疾病或精神疾病的预防或治疗剂。
(32)根据前述(31)所述的药物,其中,前述类神经营养因子作用剂为神经退行性疾病的预防或治疗剂。
(33)根据前述(32)所述的药物,其中,前述神经退行性疾病为失智症、阿尔茨海默病、帕金森病、肌萎缩侧索硬化(ALS)、亨廷顿病、进行性核上性麻痹(PSP)、糖尿病性神经病变或青光眼。
(34)根据前述(31)所述的药物,其中,前述类神经营养因子作用剂为精神疾病的预防或治疗剂。
(35)根据前述(34)所述的药物,其中,前述精神疾病为抑郁症、焦虑性障碍(神经症)或泛自闭症障碍。
(36)根据前述(10)至(19)中的任一项所述的药物,其为脊髓损伤的治疗剂或修复剂。
(37)根据前述(10)至(19)中的任一项所述的药物,其为针对疼痛疾病的镇痛剂。
(38)根据前述(37)所述的药物,其中,前述针对疼痛疾病的镇痛剂为针对关节疼痛的治疗剂。
(39)根据前述(38)所述的药物,其中,前述关节疼痛为骨性关节炎导致的疼痛。
(40)根据前述(39)所述的药物,其中,前述骨性关节炎为膝关节骨性关节炎或髋关节骨性关节炎。
(41)根据前述(10)至(40)中的任一项所述的药物,其为注射剂。
(42)根据前述(10)至(40)中的任一项所述的药物,其为口服剂。
(43)根据前述(41)或(42)中所述的药物,其中,前述注射剂或口服剂为环糊精包合体。
(44)根据前述(10)至(40)中的任一项所述的药物,其为外用剂。
(45)根据前述(44)所述的药物,其中,前述外用剂为贴剂。
(46)根据前述(10)至(19)中的任一项所述的化合物或其药学上可接受的盐,其用于预防或治疗前述(20)至(29)及(31)至(40)中的任一项所述的疾病。
(47)根据前述(10)至(19)中的任一项所述的化合物或其药学上可接受的盐,其用于进行通过给与含有至少1种抗癌剂的药剂产生的末梢神经障碍的预防或治疗。
(48)根据前述(10)至(19)中的任一项所述的化合物或其药学上可接受的盐,其用于进行神经退行性疾病或精神疾病的预防或治疗。
(49)根据前述(10)至(19)中的任一项所述的化合物或其药学上可接受的盐,其用于进行疼痛疾病的预防或治疗。
(50)根据前述(20)至(29)及(31)至(40)中的任一项所述的疾病的预防或治疗方法,其特征在于,对前述(20)至(29)及(31)至(40)中的任一项所述的疾病的患者给与前述(10)至(19)中的任一项所述的化合物或其药学上可接受的盐的有效量。
(51)一种通过给与含有至少1种抗癌剂的药剂而产生的末梢神经障碍的预防或治疗方法,其特征在于,对患者给与前述(10)至(19)中的任一项所述的化合物或其药学上可接受的盐的有效量,所述患者具有通过给与含有至少1种抗癌剂的药剂而产生的末梢神经障碍。
(52)一种神经退行性疾病或精神疾病的预防或治疗方法,其特征在于,对神经退行性疾病或精神疾病的患者给与前述(10)至(19)中的任一项所述的化合物或其药学上可接受的盐的有效量。
(53)一种疼痛疾病的预防或治疗方法,其特征在于,对疼痛疾病的患者给与前述(10)至(19)中的任一项所述的化合物或其药学上可接受的盐的有效量。
(54)前述(10)至(19)中的任一项所述的化合物或其药学上可接受的盐在药物制造中的应用,其中,药物用于治疗前述(20)至(29)及(31)至(40)中的任一项所述的疾病。
(55)前述(10)至(19)中的任一项所述的化合物或其药学上可接受的盐在药物的制造中的应用,其中,药物用于进行通过给与含有至少1种抗癌剂的药剂而产生的末梢神经障碍的预防或治疗。
(56)前述(10)至(19)中的任一项所述的化合物或其药学上可接受的盐在药物的制造中的应用,其中,药物用于进行神经退行性疾病或精神疾病的预防或治疗。
(57)前述(10)至(19)中的任一项所述的化合物或其药学上可接受的盐在镇痛剂的制造中的应用。
发明的效果
本发明化合物作为用于预防或治疗人、动物的四肢末端的麻痹等知觉异常、疼痛等痛觉过敏之类的、由抗癌剂导致的末梢神经系统的神经障碍的药剂是有效的。
另外,本发明化合物具有优异的类神经营养因子作用,因此可以用作类神经营养因子作用剂。该类神经营养因子作用剂通过类神经营养因子作用活化借助MAP激酶信号转导通路的信号转导,作为神经障碍的预防或治疗剂是有用的。神经障碍中,特别是作为失智症、阿尔茨海默病、帕金森病、肌萎缩侧索硬化(ALS)、亨廷顿病、进行性核上性麻痹(PSP)、糖尿病性神经病变、青光眼之类的神经退行性疾病等的预防或治疗剂是有用的。另外,神经障碍中,作为精神疾病的预防改善剂也是有用的。精神疾病中,特别是作为抑郁症、焦虑性障碍(神经症)、泛自闭症障碍等的预防或改善剂是有用的,特别是作为抑郁症、焦虑性障碍(神经症)的预防或治疗剂是有用的。
另外,本发明化合物作为脊髓损伤的治疗剂(脊髓损伤的情况下有时称为“修复剂”)是有用的。
而且,本发明化合物为表现出优异的镇痛作用的化合物,作为用于预防或治疗骨性关节炎等关节疼痛导致的疼痛等各种疼痛性疾病的药剂是有用的。
具体实施方式
本发明涉及下述通式(I')所示的反式-2-癸烯酸衍生物或其药学上可接受的盐。
〔式中,X’表示:
(a)被羧基或者烷氧基羰基取代的1-吡咯烷基、
(b)3-四氢噻唑基、
(c)被烷基、氧基、羟基、烷氧基、羧基、烷氧基羰基、烷基氨基、烷基氨基烷基、苯基、羧基烷基、烷氧基羰基烷基、氰基或卤代苯基取代的哌啶基、
(d)硫代吗啉基、
(e)任选被烷基、羧基烷基、烷氧基羰基烷基、烷基氨基烷基、环烷基、哌啶基烷基、苯基烷基、吡啶基、嘧啶基、羧基苯基烷基或者烷氧基羰基苯基烷基取代的1-哌嗪基、
(f)被苯基取代的1-哌嗪基,其中,所述苯基任选被烷基氨基、卤素、烷氧基、烷基、羟基、羧基烷氧基或者烷氧基羰基烷氧基取代、
(g)任选被烷基或者烷基氨基烷基取代的1,4-二氮杂环庚烷基、或者
(h)羧基吗啉基。〕
另外,本发明涉及含有下述通式(I)所示的反式-2-癸烯酸衍生物及其药学上可接受的盐的至少一种作为有效成分的抗癌剂导致的末梢神经障碍的预防或治疗剂、类神经营养因子作用剂、镇痛剂等药物。通式(I)所示化合物包括前述通式(I')所示的化合物。
〔式中,X表示:
(a)任选被羧基或者烷氧基羰基取代的1-吡咯烷基、
(b)3-四氢噻唑基、
(c)任选被烷基、氧基、羟基、烷氧基、羧基、烷氧基羰基、烷基氨基、烷基氨基烷基、苯基、羧基烷基、烷氧基羰基烷基、氰基或卤代苯基取代的哌啶基、
(d)任选被羧基取代的吗啉基、
(e)硫代吗啉基、
(f)任选被烷基、羧基烷基、烷氧基羰基烷基、烷基氨基烷基、环烷基、哌啶基烷基、苯基烷基、吡啶基、嘧啶基、羧基苯基烷基或烷氧基羰基苯基烷基取代的1-哌嗪基、
(g)被苯基取代的1-哌嗪基,其中,所述苯基任选被烷基氨基、卤素、烷氧基、烷基、羟基、羧基烷氧基或烷氧基羰基烷氧基取代、
(h)1-氮杂环庚烷基、或者
(i)任选被烷基或者烷基氨基烷基取代的1,4-二氮杂环庚烷基。〕
前述通式(I)及(I’)的取代基中,烷基(包括烷基氨基、烷基氨基烷基、羧基烷基、烷氧基羰基烷基、哌啶基烷基、苯基烷基、羧基苯基烷基、烷氧基羰基苯基烷基中的“烷基”)表示任意基团均可,但优选表示甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基等碳原子数1至4的直链状或支链状烷基。另外,烷基氨基(包括烷基氨基烷基中的“烷基氨基”)表示用1或2个烷基取代了的氨基。
烷氧基(包括烷氧基羰基、羧基烷氧基、烷氧基羰基烷氧基中的“烷氧基”)表示任意基团均可,但优选表示甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基等碳原子数1至4的直链状或支链状的烷氧基。
环烷基表示任意基团均可,但优选表示环丙基、环丁基、环戊基、环己基、环庚基、环辛基等碳原子数3至8的环烷基,进一步优选表示碳原子数5或6的环烷基。
卤素(包括卤代苯基中的“卤代”)表示氟、氯、溴、碘等。
本发明的通式(I)所示化合物(包括通式(I’)所示化合物。以下相同)例如按照下述反应式发生反应,并能够使用反式-2-癸烯酸作为原料来制造。
反应式
(式中,X与前述相同。)
通式(I)所示化合物可以通过将通式(II)所示化合物与具有活性氢的通式(III)所示化合物进行脱水缩合来制造。脱水缩合反应可以采用公知的方法。例如,可以使通式(II)所示化合物与通式(III)所示化合物在适当的缩合剂(例如,二环己基碳二亚胺(DCC)、N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺·HCl等)的存在下发生反应。反应可以在一般溶剂(例如,二氯甲烷等)中实施。通式(III)所示化合物的用量通常相对于通式(II)所示化合物1摩尔为0.5至2摩尔(优选为1至1.5摩尔)。
或者,例如,可以在将通式(II)所示化合物暂时转换为羧酸卤化物后,在碱的存在下或非存在下,使通式(3)所示化合物反应。向羧酸卤化物的转化例如可以使用氯化亚硫酰、磺酰氯、三氯化磷、五氯化磷、乙二酰氯、三氯磷酸等卤化剂。作为碱,可列举出三乙胺、吡啶等。通式(III)所示化合物的用量通常相对于通式(II)所示化合物1摩尔为0.5至2摩尔(优选为1至1.5摩尔)。使用碱时,碱的用量通常相对于通式(II)所示化合物1摩尔为1至5摩尔左右。
上述反应结束后,可以使用公知的纯化及分离操作(例如萃取、色谱法、蒸馏、再结晶等)来得到目标化合物。
将如此得到的化合物的例子示于表1至3。以下,称呼各个化合物时,使用表中记载的化合物序号。
[表1]
[表2]
[表3]
[表4]
[表5]
本发明的通式(I)所示化合物为不仅包含上述游离形态,还包含盐、溶剂化物、前体药物的形态的化合物。形成盐时,在用作药物的情况下,优选药学上所允许的盐的形态。作为盐的例子,可列举出:与磷酸、盐酸、硫酸、硝酸、氢溴酸、高氯酸、硫氰酸、硼酸、甲酸、乙酸、卤代乙酸、丙酸、柠檬酸、酒石酸、乳酸、乙醇酸、琥珀酸、葡糖酸、丙二酸、富马酸、氨茴酸、苯甲酸、肉桂酸、对甲苯磺酸、萘磺酸、磺胺酸等酸的加成盐。另外,可列举出与钠、钾等碱金属,钙、镁等碱土金属或者铝等金属的盐,或者与氨、有机胺等碱类的盐。这些盐可以通过公知的方法,由游离的各化合物制造,或者可以相互转换。作为溶剂化物,可列举出:水合物、醇合物等。另外,本发明的通式(I)所示化合物含有不对称碳原子时,也包括光学活性体、消旋体、非对映异构体等各种异构体。本发明化合物形成晶体时,也包括能够形成的各种晶形(晶体多形)。
本发明的通式(I)所示的化合物作为由于给与抗癌剂而引起的末梢神经障碍的预防或治疗作用剂是有用的。作为引发末梢神经障碍的抗癌剂,其一为对微管造成伤害而引起末梢神经障碍的抗癌剂。作为这类药剂,可列举出紫杉醇、紫杉萜等紫杉烷系药剂;长春新碱、长春碱、长春地辛、长春瑞滨等长春花生物碱系药剂。另一个为由于伤害神经细胞导致轴突障碍而引起末梢神经障碍的药剂。作为这类药剂,可列举出奥沙利铂、卡波铂、顺铂、奈达铂等铂类制剂。
作为这些抗癌剂导致的末梢神经障碍,可列举出:刺痛、灼烧之类的痛等疼痛;四肢末端的麻痹;灼热感等知觉异常;对冷感刺激的过敏等知觉过敏;感觉消失·感觉麻痹、不协调感等感觉异常;知觉性运动失调、肌力减弱等。作为本发明化合物的预防或治疗对象的抗癌剂导致的末梢神经障碍不仅为使用一种抗癌剂的单剂疗法中产生的末梢神经障碍,还包括组合给与作用机制不同的多种药剂的多剂组合疗法、在使作用机制不同的药剂能够发挥最大有效性的药剂组合、在给与方法上下工夫的生化调节作用(biochemicalmodulation)疗法中产生的末梢神经障碍。
本发明的通式(I)所示的化合物具有类神经营养因子作用,因此作为类神经营养因子作用剂是有用的,在神经障碍的预防或治疗上是有用的。神经障碍是指由于神经细胞的变性或细胞死而损害其功能的病态,包括神经退行性疾病、精神疾病。神经退行性疾病是指失智症、阿尔茨海默病、帕金森病、肌萎缩侧索硬化(ALS)、亨廷顿病、进行性核上性麻痹(PSP)、糖尿病性神经病变、视神经疾病的青光眼等。精神疾病是指抑郁症(包括双向型抑郁症)、焦虑性障碍(神经症)、综合失调症、泛自闭症障碍等。用于抑郁症时,对于现存的抑郁症治疗剂的三环系抗抑郁药、四环系抗抑郁药、选择性血清素再吸收抑制剂(SSRI)、血清素·去甲肾上腺素再摄取抑制剂(SNRI)等,到出现效果至少需要3至4周,该期间必须定期服药,但期待含有本发明化合物的药物与现有药物相比的速效性。
本发明的通式(I)所示化合物作为脊髓损伤的治疗剂(修复剂)是有用的。由于交通事故、运动事故、老年人的压迫性骨折等使脊髓受到物理性损害的脊髓损伤没有有效的治疗方法,正在研究利用再生医疗的治疗方法。期待含有本发明化合物的药物通过注射、内服、外用等给与能够治疗(修复)脊髓损伤。
另外,本发明的通式(I)所示化合物作为针对各种疼痛疾病的预防或治疗剂是有用的。作为疼痛疾病,例如可列举出膝关节骨性关节炎、髋关节骨性关节炎等骨性关节炎导致的疼痛,关节风湿导致的疼痛等关节疼痛等。
本发明化合物能够与适当的药物用载体、稀释剂适宜组合,而制药化为各种剂形(口服剂、注射剂、外用剂等)的药物。另外,本发明药物也可以为将本发明化合物与其他药物活性成分组合而成的混合剂。而且,本发明药物还可以被制药化为与环糊精等的包合体。由此,会有能够得到增强药理活性、提高稳定性、持续化、处理的容易性等的情况。包合体例如可以将本发明化合物与α‐、β‐或γ‐环糊精按照通常的方法混合来形成。
将本发明化合物做成口服剂时,可以按照将适当的添加剂、例如赋形剂、结合剂、衰变剂、润滑剂、增量剂、增湿剂、缓冲剂、储存剂、香料等适宜组合的处方形成片剂、散剂、颗粒剂或胶囊。另外,做成注射剂时,可以向含有碳原子数10的脂肪酸酯的溶液、悬液中加入稳定剂、储存剂、等张化剂等来形成注射剂。做成外用剂时,例如可以制剂化为贴剂、凝胶剂、软膏、霜剂等外用剂等。也就是说,将本发明化合物与适当的基剂混和、熔融、乳化等来制备,贴剂时将此在支撑物上延展涂布。作为贴剂、凝胶化剂等,例如可以形成使用有机凝胶化剂的组成。需要说明的是,可以根据各外用剂的剂形而适宜选择通常使用的储存剂、抗氧化剂、调味剂、粘合剂等并加入处方。
本发明化合物的理想的给与量可以考虑用法、患者年龄、性别、症状程度等来适当增减,通常成人可以每1日1至1000mg,优选5至300mg,并1日1次或分多次给与。
实施例
以下,列举出实施例来说明本发明,但本发明不限定于这些实施例。
实施例1
1-((E)-2-癸烯酰基)吡咯烷〔化合物1〕的制造
向使用(E)-2-癸烯酸及氯化亚硫酰合成的(E)-2-癸烯酸氯化物(1.9g、0.01mol)的四氢呋喃溶液(20mL)中加入含吡啶(0.79g、0.01mol)的吡咯烷(0.71g、0.01mol)的四氢呋喃溶液(20mL),在温水浴上进行3小时加热回流。蒸馏去除过量的四氢呋喃后,向反应液中加入水,并用乙酸乙酯萃取,水洗后,蒸馏去除乙酸乙酯。将残渣用硅胶柱色谱法(展开溶剂:己烷:乙酸乙酯=1:3)纯化,得到无色油状物的目标化合物(1.4g)。
无色油状物,C14H25NOMW223,ESIMS(positiveionmode:rel.int):m/z246.184[M+Na]+(CalcdforC14H25NONa,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).
实施例2
(S)-1-((E)-2-癸烯酰基)吡咯烷-2-羧酸甲酯〔化合物3〕的制造
在室温下向(E)-2-癸烯酸(0.92mL、5mmol)、L-脯氨酸甲酯盐酸盐(0.91g、5.5mmol)的二氯甲烷(50mL)溶液中加入三乙胺(0.84mL、6mmol)及l-乙基3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(WSC·HCl)(1.05g、5.5mmol)并搅拌24小时。将反应溶液用水、饱和食盐水洗涤后,用无水硫酸钠干燥。用硅胶柱色谱法(己烷:乙酸乙酯=7:3)纯化,得到无色油状物的目标化合物(1.23g、87%)。需要说明的是,以下,起始原料的胺不为盐酸盐时也可以不添加三乙胺。
无色油状物,C16H27NO3MW281.4,EIMS:m/z282[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),4.31-4.35and4.70-4.74(m,1H),5.97and6.25(m,1H),6.61-6.71(m,1H).
实施例3
(S)-1-((E)-2-癸烯酰基)吡咯烷-2-羧酸〔化合物2〕的制造
将化合物3(0.84g、3mmol)溶于甲醇(40mL),在室温下加入1mol/L氢氧化钠水溶液(4mL、NaOH4mmol)并搅拌20小时。减压下蒸馏去除溶剂后,将残渣溶于水,并加入10%柠檬酸水溶液从而将pH调节至大约4。用二氯甲烷萃取,并将有机层用水、饱和食盐水洗涤后,并用无水硫酸钠干燥,得到无色油状物的目标化合物(0.72g、90%)。
无色油状物,C15H25NO3MW267.4,EIMS:m/z268[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),4.23-4.28and4.55-4.59(m,1H),6.25and5.99(m,1H),6.62-6.71(m,1H),12.30-12.70(br,1H).
实施例4
3-((E)-2-癸烯酰基)四氢噻唑〔化合物4〕的制造
使用(E)-2-癸烯酸及四氢噻唑作为起始原料,与实施例1同样操作,制造目标化合物。
无色油状物,C13H23NOSMW241,HR-ESIMS(positiveionmode):m/z264.1443[M+Na]+(CalcdforC13H23NOSNa,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).
实施例5
1-((E)-2-癸烯酰基)哌啶〔化合物5〕的制造
使用(E)-2-癸烯酸及哌啶作为起始原料,与实施例1同样操作,制造目标化合物。
无色油状物,C15H27NOMW237,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)
实施例6
1-((E)-2-癸烯酰基)-4-甲基哌啶〔化合物6〕的制造
使用(E)-2-癸烯酸及4-甲基哌啶作为起始原料,与实施例2同样操作,制造目标化合物。
无色油状物,C16H29NOMW251.4,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).
实施例7
1-((E)-2-癸烯酰基)哌啶-4-酮〔化合物7〕的制造
使用(E)-2-癸烯酸及哌啶-4-酮作为起始原料,与实施例1同样操作,制造目标化合物。
淡黄色油状物,C15H25NO2MW251,HR-ESIMS(positiveionmode):m/z274.1824[M+Na]+(CalcdforC15H25NO2Na,274.1783),1H-NMR(400MHz,CDCl3)δ:0.88(3H,t,J=6.8Hz),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).
实施例8
1-((E)-2-癸烯酰基)-4-羟基哌啶〔化合物8〕的制造
使用(E)-2-癸烯酸及4-羟基哌啶作为起始原料,与实施例2同样操作,制造目标化合物。
无色油状物,C15H27NO2MW253.4,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).
实施例9
1-((E)-2-癸烯酰基)-4-甲氧基哌啶〔化合物9〕的制造
将化合物8(0.62g、2.4mmol)溶于THF(10mL),冰浴下加入氢化钠(矿油中60%)(0.10g、2.6mmol)。冰浴下搅拌混合15分钟后,加入碘甲烷(0.16mL、2.6mmol),在室温下搅拌混合20小时。将反应液加入水中,用乙酸乙酯萃取后,将有机层用水、饱和食盐水洗涤,并用无水硫酸钠干燥。用硅胶柱色谱法(己烷:乙酸乙酯=3:2)纯化,得到淡黄色油状物的目标化合物(0.42g、65%)。
淡黄色油状物,C16H29NO2MW267.4,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).
实施例10
1-((E)-2-癸烯酰基)哌啶-4-羧酸〔化合物10〕的制造
使用化合物11作为起始原料,与实施例3同样操作,制造目标化合物。
白色晶体,mp88-89℃,C16H27NO3MW281.4,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).
实施例11
1-((E)-2-癸烯酰基)哌啶-4-羧酸乙酯〔化合物11〕的制造
使用(E)-2-癸烯酸及异哌啶酸乙酯作为起始原料,与实施例2同样操作,制造目标化合物。
无色油状物,C18H31NO3MW309.4,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).
实施例12
1-((E)-2-癸烯酰基)-4-二甲基氨基哌啶〔化合物12〕的制造
使用(E)-2-癸烯酸及4-二甲基氨基哌啶作为起始原料,与实施例2同样操作,制造目标化合物。
淡黄色油状物,C17H32N2OMW280.5,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).
另外,将油状物的化合物12溶于二氯甲烷,并用氯化氢-二氧杂环己烷处理,制造1-((E)-2-癸烯酰基)-4-二甲基氨基哌啶盐酸盐(晶体、mp185-188℃)。
实施例13
1-((E)-2-癸烯酰基)-4-二乙基氨基哌啶(〔化合物13〕的制造
使用(E)-2-癸烯酸及4-二乙基氨基哌啶作为起始原料,与实施例2同样操作,制造目标化合物。
淡黄色油状物,C19H36N2OMW308.5,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).
实施例14
1-((E)-2-癸烯酰基)-4-二乙基氨基甲基哌啶〔化合物14〕的制造
使用(E)-2-癸烯酸及4-(二乙基氨基甲基)哌啶作为起始原料,与实施例2同样操作,制造目标化合物。
浅红色油状物,C20H38N2OMW322.5,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).
实施例15
1-((E)-2-癸烯酰基)-4-(2-二甲基氨基乙基)哌啶〔化合物15〕的制造
使用(E)-2-癸烯酸及4-(2-二甲基氨基乙基)哌啶作为起始原料,与实施例2同样操作,制造目标化合物。
淡黄色油状物,C19H36N2OMW308.5,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).
实施例16
1-((E)-2-癸烯酰基)-4-苯基哌啶〔化合物16〕的制造
使用(E)-2-癸烯酸及4-苯基哌啶作为起始原料,与实施例1同样操作,制造目标化合物。
无色油状物,C21H31NOMW313,HR-ESIMS(positiveionmode):m/z336.2330[M+Na]+(CalcdforC21H31NONa,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).
实施例17
(4-((E)-2-癸烯酰基)吗啉〔化合物17〕的制造
使用(E)-2-癸烯酸及吗啉作为起始原料,与实施例1同样操作,制造目标化合物。
无色油状物,C14H25NO2MW239,HR-ESIMS(positiveionmode):m/z262.1827[M+Na]+(CalcdforC14H25NO2Na,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).
实施例18
4-((E)-2-癸烯酰基)硫代吗啉〔化合物18〕的制造
使用(E)-2-癸烯酸及硫代吗啉作为起始原料,与实施例1同样操作,制造目标化合物。
无色油状物,C14H25NOSMW255,HR-ESIMS(positiveionmode):m/z278.1575[M+Na]+(CalcdforC14H25NOSNa,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).
实施例19
1-((E)-2-癸烯酰基)-4-甲基哌嗪〔化合物19〕的制造
使用(E)-2-癸烯酸及1-甲基哌嗪作为起始原料,与实施例2同样操作,制造目标化合物。
淡黄色油状物,C15H28N2OMW252.4,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).
实施例20
1-((E)-2-癸烯酰基)-4-异丙基哌嗪〔化合物20〕的制造
使用(E)-2-癸烯酸及1-异丙基哌嗪作为起始原料,与实施例2同样操作,制造目标化合物。
淡黄色油状物,C17H32N2OMW280.5,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).
实施例21
3-[4-((E)-2-癸烯酰基)哌嗪-1-基]丙酮酸〔化合物21〕的制造
使用(E)-2-癸烯酸及3-哌嗪-1-基丙酮酸乙酯2盐酸盐(化合物21的乙基酯)作为起始原料,与实施例2同样操作,制造3-[4-((E)-2-癸烯酰基)哌嗪-1-基]丙酮酸乙酯,通过碱皂化得到白色晶体的目标化合物。
白色晶体,mp53-55℃,C17H30N2O3MW310.4,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).
另外,将低熔点晶体的化合物21溶于二氯甲烷,并用氯化氢-二氧杂环己烷处理,制造3-[4-((E)-2-癸烯酰基)哌嗪-1-基]丙酮酸盐酸盐(晶体、mp201-203℃)。
实施例22
1-((E)-2-癸烯酰基)-4-[2-(二甲基氨基)乙基]哌嗪〔化合物22〕的制造
使用(E)-2-癸烯酸及1-[2-(二甲基氨基)乙基]哌嗪作为起始原料,与实施例1同样操作,制造目标化合物。
油状物,C18H35N3OMW309,HR-ESIMS(positiveionmode):m/z310.2868[M+H]+(calcdforC18H36N3O,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).
实施例23
4-环己基-1-((E)-2-癸烯酰基)哌嗪〔化合物23〕的制造
使用(E)-2-癸烯酸及1-环己基哌嗪作为起始原料,与实施例2同样操作,制造目标化合物。
白色晶体,mp33-34℃,C20H36N2OMW320.5,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).
实施例24
1-((E)-2-癸烯酰基)-4-(2-哌啶-1-基乙基)哌嗪〔化合物24〕的制造
使用(E)-2-癸烯酸及1-[2-(1-哌啶基)乙基]哌嗪作为起始原料,与实施例2同样操作,制造目标化合物。
白色晶体,C21H39N3OMW349.6,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).
实施例25
1-((E)-2-癸烯酰基)-4-苯基哌嗪〔化合物25〕的制造
使用(E)-2-癸烯酸及1-苯基哌嗪作为起始原料,与实施例1同样操作,制造目标化合物。
桃色油状物,C20H30N2OMW314,HR-ESIMS(positiveionmode):m/z337.2244[M+Na]+(CalcdforC20H30N2ONa,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).
实施例26
4-苄基-1-((E)-2-癸烯酰基)哌嗪〔化合物26〕的制造
使用(E)-2-癸烯酸及1-苄基哌嗪2盐酸盐作为起始原料,与实施例2同样操作,制造目标化合物。
白色晶体,mp62-63℃,C21H32N2OMW328.5,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).
实施例27
1-((E)-2-癸烯酰基)-4-(2-苯乙基)哌嗪〔化合物27〕的制造
使用(E)-2-癸烯酸及1-(2-苯乙基)哌嗪2盐酸盐作为起始原料,与实施例2同样操作,制造目标化合物。
白色晶体,mp33-34℃,C22H34N2OMW342.5,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).
实施例28
1-((E)-2-癸烯酰基)-4-(4-二甲基氨基苯基)哌嗪〔化合物28〕的制造
使用(E)-2-癸烯酸及1-(4-二甲基氨基苯基)哌嗪2盐酸盐作为起始原料,与实施例2同样操作,制造目标化合物。
淡褐色晶体,mp73-74℃,C22H35N3OMW357.5,EIMS:m/z357[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),2.87-2.96(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).
实施例29
1-((E)-2-癸烯酰基)-4-(吡啶-4-基)哌嗪〔化合物29〕的制造
使用(E)-2-癸烯酸及1-(4-吡啶基)哌嗪作为起始原料,与实施例1同样操作,制造目标化合物。
淡褐色油状物,C19H29N3OMW315,HR-ESIMS(positiveionmode):m/z316.2349[M+H]+(CalcdforC19H30N3O,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)
实施例30
1-((E)-2-癸烯酰基)-4-(吡啶-2-基)哌嗪〔化合物30〕的制造
使用(E)-2-癸烯酸及1-(2-吡啶基)哌嗪作为起始原料,与实施例1同样操作,制造目标化合物。
无色晶体,mp59-61℃,C19H29N3OMW315,HR-ESIMS(positiveionmode):m/z316.2346[M+H]+(CalcdforC19H29N3O,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)
实施例31
1-((E)-2-癸烯酰基)-4-(嘧啶-2-基)哌嗪〔化合物31〕的制造
使用(E)-2-癸烯酸及1-(2-嘧啶基)哌嗪作为起始原料,与实施例1同样操作,制造目标化合物。
无色晶体,mp93-94℃,C18H28N4OMW316,HR-ESIMS(positiveionmode):m/z339.2155[M+Na]+(CalcdforC18H29N4ONa,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).
实施例32
1-((E)-2-癸烯酰基)氮杂环庚烷〔化合物32〕的制造
使用(E)-2-癸烯酸及六亚甲基亚胺作为起始原料,与实施例1同样操作,制造目标化合物。
淡褐色油状物,C16H29NOMW251,HR-ESIMS(positiveionmode):m/z274.2145[M+Na]+(CalcdforC16H29NONa,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).
实施例33
1-((E)-2-癸烯酰基)-4-甲基-[1,4]二氮杂环庚烷〔化合物33〕的制造
使用(E)-2-癸烯酸及1-甲基-1,4二氮杂环庚烷作为起始原料,与实施例2同样操作,制造目标化合物。
淡黄色油状物,C16H30N2OMW266.4,EIMS:m/z267[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),2.23and2.24(sx2,3H),2.39-2.55(m,4H),3.46-3.58(m,4H),6.34-6.40(m,1H),6.61-6.69(m,1H).
实施例34
1-((E)-2-癸烯酰基)-4-(2-二甲基氨基乙基)-[1,4]二氮杂环庚烷〔化合物34〕的制造
使用(E)-2-癸烯酸及1-(2-二甲基氨基乙基)-1,4二氮杂环庚烷作为起始原料,与实施例2同样操作,制造目标化合物。
淡黄色油状物,C19H37N3OMW323.5,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).
实施例35
2-(1-((E)-2-癸烯酰基)-4-哌啶基)乙酸〔化合物35〕的制造
(1)使用(E)-2-癸烯酸及2-(4-哌啶基)乙酸乙酯盐酸盐作为起始原料,与实施例2同样操作,制造2-(1-((E)-2-癸烯酰基)-4-哌啶基)乙酸乙酯(化合物35的乙基酯)。
(2)与实施例3同样地,通过2-(1-((E)-2-癸烯酰基)-4-哌啶基)乙酸乙酯的碱皂化制造目标化合物。
白色晶体,mp65-66℃,C17H29NO3MW295.4,EIMS:m/z296[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).
实施例36
3-(1-((E)-2-癸烯酰基)-4-哌啶基)丙酸〔化合物36〕的制造
(1)使用(E)-2-癸烯酸及3-(4-哌啶基)丙酮酸乙酯盐酸盐作为起始原料,与实施例2同样操作,制造3-(1-((E)-2-癸烯酰基)-4-哌啶基)丙酸乙酯(化合物36的乙基酯)。
(2)与实施例3同样地,通过3-(1-((E)-2-癸烯酰基)-4-哌啶基)丙酸乙酯的碱皂化制造目标化合物。
无色油状物,C18H31NO3MW309.4,EIMS:m/z310[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).
实施例37
1-((E)-2-癸烯酰基)-4-氰基哌啶〔化合物37〕的制造
使用(E)-2-癸烯酸及哌啶-4-甲腈作为起始原料,与实施例2同样操作,制造目标化合物。
无色油状物,C16H26N2OMW262.4,EIMS:m/z263[M+H]+,1H-NMR(500MHz,DMSO-d6)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).
实施例38
1-((E)-2-癸烯酰基)-4-(4-氯苯基)哌啶〔化合物38〕的制造
使用(E)-2-癸烯酸及4-(4-氯苯基)哌啶作为起始原料,与实施例2同样操作,制造目标化合物。
淡黄色油状物,C21H30ClNOMW347.9,EIMS:m/z348[M+H]+,1H-NMR(500MHz,DMSO-d6)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).
实施例39
[4-[(E)-2-癸烯酰基)哌嗪-1-基]乙酸盐酸盐〔化合物39〕的制造
(1)使用(E)-2-癸烯酸及2-(1-哌嗪基)乙酸乙酯2盐酸盐作为起始原料,与实施例2同样操作,制造[4-[(E)-2-癸烯酰基)哌嗪-1-基]乙酸乙酯(化合物39的游离体的乙基酯)。
(2)与实施例3同样地,通过[4-[(E)-2-癸烯酰基)哌嗪-1-基]乙酸乙酯的碱皂化得到[4-[(E)-2-癸烯酰基)哌嗪-1-基]乙酸(化合物39的游离体)。
(3)将获得的化合物溶于二氯甲烷,并用氯化氢-二氧杂环己烷处理,制造目标化合物。
白色晶体,mp195℃(分解),C16H29ClN2O3MW332.9,EIMS:m/z297[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).
实施例40
4-[4-[(E)-2-癸烯酰基)哌嗪-1-基]丁酸盐酸盐〔化合物40〕的制造
(1)使用(E)-2-癸烯酸及4-(1-哌嗪基)丁酸乙酯2盐酸盐作为起始原料,与实施例2同样操作,制造4-[4-((E)-2-癸烯酰基)哌嗪-1-基]丁酸乙酯(化合物40的游离体的乙基酯)。
(2)与实施例3同样地,通过4-[4-((E)-2-癸烯酰基)哌嗪-1-基]丁酸乙酯的碱皂化得到4-[4-[(E)-2-癸烯酰基)哌嗪-1-基]丁酸(化合物40的游离体)。
(3)将获得的化合物溶于二氯甲烷,并用氯化氢-二氧杂环己烷处理,制造目标化合物。
白色晶体,mp203-205℃,C18H33ClN2O3MW360.9,EIMS:m/z325[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).
实施例41
1-((E)-2-癸烯酰基)-4-(4-氯苯基)哌嗪〔化合物41〕的制造
使用(E)-2-癸烯酸及1-(4-氯苯基)哌嗪作为起始原料,与实施例2同样操作,制造目标化合物。
淡黄色油状物,C20H29ClN2OMW348.9,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).
实施例42
1-((E)-2-癸烯酰基)-4-(4-甲氧基苯基)哌嗪〔化合物42〕的制造
使用(E)-2-癸烯酸及1-(4-甲氧基苯基)哌嗪作为起始原料,与实施例2同样操作,制造目标化合物。
白色晶体,mp50-52℃,C21H32N2O2MW344.5,EIMS:m/z344[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).
实施例43
1-((E)-2-癸烯酰基)-4-(4-甲基苯基)哌嗪〔化合物43〕的制造
使用(E)-2-癸烯酸及1-(对-甲苯基)哌嗪作为起始原料,与实施例2同样操作,制造目标化合物。
白色晶体,mp45-46℃,C21H32N2OMW328.5,EIMS:m/z328[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).
实施例44
1-((E)-2-癸烯酰基)-4-(4-氟苯基)哌嗪〔化合物44〕的制造
使用(E)-2-癸烯酸及1-(4-氟苯基)哌嗪作为起始原料,与实施例2同样操作,制造目标化合物。
淡黄色油状物,C20H29FN2OMW332.5,EIMS:m/z332[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).
实施例45
1-((E)-2-癸烯酰基)-4-(2-氯苯基)哌嗪〔化合物45〕的制造
使用(E)-2-癸烯酸及1-(2-氯苯基)哌嗪作为起始原料,与实施例2同样操作,制造目标化合物。
淡黄色油状物,C20H29ClN2OMW348.9,EIMS:m/z348[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).
实施例46
1-((E)-2-癸烯酰基)-4-(4-羟基苯基)哌嗪〔化合物46〕的制造
使用(E)-2-癸烯酸及4-(1-哌嗪基)苯酚作为起始原料,与实施例2同样操作,制造目标化合物。
浅红色晶体,mp85-87℃,C20H30N2O2MW330.5,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).
实施例47
2-[4-[4-((E)-2-癸烯酰基)哌嗪-1-基]苯氧基]乙酸〔化合物47〕的制造
(1)使用(E)-2-癸烯酸及2-[4-(1-哌嗪基)苯氧基]乙酸乙酯2盐酸盐作为起始原料,与实施例2同样操作,制造2-[4-[4-((E)-2-癸烯酰基)哌嗪-1-基]苯氧基]乙酸乙酯(化合物47的乙基酯)。
(2)与实施例3同样地,通过2-[4-[4-((E)-2-癸烯酰基)哌嗪-1-基]苯氧基]乙酸乙酯的碱皂化制造目标化合物。
白色晶体,mp210℃(分解),C22H32N2O4MW388.5,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).
实施例48
4-[[4-((E)-2-癸烯酰基)哌嗪-1-基]甲基]苯甲酸〔化合物48〕的制造
(1)使用(E)-2-癸烯酸及4-(1-哌嗪基甲基)苯甲酸甲酯2盐酸盐作为起始原料,与实施例2同样操作,制造4-[[4-((E)-2-癸烯酰基)哌嗪-1-基]甲基]苯甲酸甲酯(化合物48的甲基酯)。
(2)与实施例3同样地,通过4-[[4-((E)-2-癸烯酰基)哌嗪-1-基]甲基]苯甲酸甲酯的碱皂化制造目标化合物。
白色晶体,mp114-116℃,C22H32N2O3MW372.5,EIMS:m/z373[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).
实施例49
4-[(E)-2-癸烯酰基]吗啉-3-羧酸〔化合物49〕的制造
(1)使用(E)-2-癸烯酸及吗啉-3-羧酸甲酯盐酸盐作为起始原料,与实施例2同样操作,制造4-[(E)-2-癸烯酰基]吗啉-3-羧酸甲酯(化合物49的甲基酯)。
(2)与实施例3同样地,通过4-[(E)-2-癸烯酰基]吗啉-3-羧酸甲酯的碱皂化制造目标化合物。
淡黄色油状物,C15H25NO4MW283.4,EIMS:m/z284[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),4.45-4.40and5.15-5.18(m,2H),6.05and6.23(dx2,J=15.0Hz,1H),6.88-7.02(m,1H),9.00(br,1H)..
试验例1针对紫杉醇导致的大鼠末梢神经障碍的作用的评价
调查本发明化合物针对给与作为抗癌剂的紫杉醇时产生的副作用即末梢神经障碍、即由机械刺激产生的痛觉超敏(Allodynia)(通常不引起疼痛的触觉刺激导致的激痛)等知觉过敏的效果。将本发明化合物作为试验药给与至大鼠腹腔内,进行机械痛阈测量试验。
(1)紫杉醇诱发末梢神经障碍大鼠的制作及试验药的给与
使用6周龄SD雄性大鼠(1组6只)作为实验动物,将紫杉醇(2mg/kg)以每1天计4次进行腹腔内给与,制作紫杉醇诱发末梢神经障碍大鼠。将试验药在紫杉醇给与开始18至25天后或20至27天后期间内以均达到300μ/kg的方式进行单次腹腔内给与,实施下述机械痛阈测量试验。
(2)机械痛阈测量试验(vonFreytest)
向底部为金属网的透明丙烯酸笼子中放入上述(1)的大鼠,使其驯化约3分钟后,在试验药给与前、给与开始的1小时及5小时后测定对于右后肢的机械刺激的50%反应阈值。
测定根据Chaplan等(JournalofNeuroscienceMethods、53卷、1号、55-63页、1994年)和Dixon等(AnnualReviewofPharmacologyandToxicology、20卷、441-462页、1980年)的方法,使用冯弗雷细丝(vonFreyfilament、NorthCoastMedicalInc.制造)来进行。在8根细丝〔刺激负载(g):0.4、0.6、1.0、2.0、4.0、6.0、8.0、15.0〕中,从2.0g的细丝开始,用细丝轻度弯曲的程度的力对足底垂直地碰触2~3秒,将后肢显示出逃避反应的情况作为阳性反应。另外,去除细丝瞬间出现逃避的情况也判为阳性。出现阳性反应时用低一个强度、未出现反应时用高一个强度的细丝同样进行刺激,将反应从阴性向阳性变化或从阳性向阴性变化的时刻作为最初的2个反应。其后,连续4次用上下法(up-down法)进行刺激。使用对于总计6次的刺激的反应,测定对于机械刺激的50%反应阈值,计算各组的平均值±标准偏差。需要说明的是,在无阳性反应的状态下进行至15.0g的刺激的情况下将15.0g作为50%反应阈值,在阳性反应持续至0.4g的情况下将0.25g作为50%反应阈值。关于试验药给与1小时后或5小时后的50%反应阈值中较高的50%反应阈值,将正常阈值设为15,通过下述式计算50%反应阈值的恢复率(%)。将上述试验结果的一例示于表6及表7。
50%反应阈值的恢复率(%)=(试验药给与1小时后或5小时后的50%反应阈值-试验药给与前的50%反应阈值)÷(正常阈值-试验药给与前的50%反应阈值)×100
[表6]
试验药 | 50%反应阈值的恢复率(%) |
化合物1 | 58.2 |
化合物2 | 23.5 |
化合物4 | 43.7 |
化合物5 | 41.6 |
化合物6 | 33.8 |
化合物7 | 45.2 |
化合物8 | 49.7 |
化合物9 | 35.6 |
化合物10 | 44.6 |
化合物12 | 49.7 |
化合物13 | 23.2 |
化合物14 | 26.0 |
化合物15 | 34.2 |
化合物16 | 38.6 |
化合物17 | 30.6 |
化合物18 | 48.9 |
化合物19 | 19.8 |
化合物20 | 26.9 |
化合物21 | 34.8 |
化合物22 | 29.7 |
化合物23 | 33.0 |
化合物24 | 49.7 |
化合物25 | 55.3 |
化合物26 | 24.1 |
化合物27 | 69.1 |
化合物28 | 20.3 |
化合物29 | 42.8 |
化合物30 | 22.6 |
化合物31 | 22.9 |
化合物32 | 51.1 |
化合物33 | 33.4 |
化合物34 | 35.5 |
[表7]
试验药 | 50%反应阈值的恢复率(%) |
化合物35 | 41.2 |
化合物36 | 42.0 |
化合物37 | 22.4 |
化合物38 | 55.5 |
化合物39 | 16.6 |
化合物40 | 61.6 |
化合物41 | 81.5 |
化合物42 | 45.8 |
化合物43 | 31.3 |
化合物44 | 42.6 |
化合物45 | 33.3 |
化合物46 | 53.7 |
化合物47 | 54.5 |
化合物48 | 56.4 |
根据表6及7所示,可以确认本发明化合物对于给与紫杉醇导致的知觉过敏具有优异的改善作用,对于给与抗癌剂带来的副作用具有减轻作用。另外,可以确认到,本发明化合物即便在使用铂类制剂即奥沙利铂作为抗癌剂时,与使用紫杉烷系的紫杉醇的情况同样地对于知觉过敏具有优异的改善作用。
试验例2MAP激酶的活化(磷酸化)的评价
针对本发明化合物,通过免疫印迹法(westernimmunoblotting),如下所示地测定MAP激酶(ERK1/2)的活化。
从胚胎17天龄的大鼠大脑皮质分散神经细胞,将该神经细胞用含5%胎牛血清的达尔伯克(氏)改良伊格尔(氏)培养基(DMEM)培养1天。在无血清培养基(B27supplement添加Neurobasal、InvitrogenCorporation)中交换培养液,用涂覆过多鸟氨酸的培养皿以2-4万个/cm2的密度培养神经细胞。
3天后,添加本发明化合物并继续培养30分钟。其后,在冰上用以Tris-HCl缓冲液作为基液的含脱磷酸化酶抑制剂的液体回收细胞。使用BCAProteinAssayKit(TAKARABIOINC.)定量获得的细胞萃取液的蛋白质浓度,将一定量的蛋白质(MAP激酶测定用为3μg、磷酸化MAP激酶测定用为5μg)用聚丙烯酰胺凝胶进行电泳。将蛋白质自电泳后的凝胶转印至PVDF膜,一次抗体分别使用抗MAP激酶抗体(CellSignalingTechnologyJapan,K.K)和抗磷酸化MAP激酶抗体(CellSignalingTechnologyJapan,K.K)来实施免疫印迹。
接着,使其与二次抗体即碱性磷酸酶标记抗兔IgG抗体(PromegaCorporation)反应而使酶活性显色,测定MAP激酶(MAPK)及磷酸化MAP激酶(pMAPK)。
需要说明的是,将本发明化合物溶于0.1%DMSO来调节为250μg/mL的浓度。对照(Control)添加0.1%DMSO。
使用ImageJ(BioArtsCorporation)计算强度从而数值化上述获得的电泳凝胶的条带的浓度。用对照的MAPK的数值除以使用本发明化合物时的MAPK的数值,或者用对照的pMAPK的数值除以使用本发明化合物时的pMAPK的数值,求出使用本发明化合物时的MAPK相对于对照的比率以及使用本发明化合物时的pMAPK相对于对照的比率。接着,用获得的pMAPK相对于对照的比率除以获得的MAPK相对于对照的比率,求出pMAPK相对于MAPK的比率。将结果的一例示于表8至表10。
[表8]
pMAPK相对于MAPK的比率 | |
对照 | 1.00 |
化合物4 | 1.47 |
化合物7 | 1.62 |
化合物18 | 1.28 |
[表9]
pMAPK相对于MAPK的比率 | |
对照 | 1.00 |
化合物6 | 1.71 |
化合物14 | 2.08 |
化合物20 | 1.27 |
化合物23 | 1.30 |
化合物24 | 2.58 |
[表10]
pMAPK相对于pMAPK的比率 | |
对照 | 1.00 |
化合物2 | 1.28 |
化合物13 | 1.63 |
化合物21 | 1.54 |
化合物26 | 1.48 |
化合物27 | 1.44 |
由表8至10可知,本发明化合物与对照相比表现出较高的MAP激酶活化(磷酸化),具有类神经营养因子作用。
试验例3施加轻微压力下的MAP激酶的活化(磷酸化)的评价
针对本发明化合物,使用慢性轻微压力诱发性抑郁症模型小鼠,通过免疫印迹法,如下所述地测定MAP激酶(ERK1/2)的活化水平。
(1)慢性轻微压力诱发性抑郁症模型小鼠的制作及试验药的给与
对7周龄ddY系雌性小鼠(n=8~12)进行以下操作。(A)强制游泳15分钟后,正常饲养2天。(B)在倾斜了的笼子中饲养2天后,正常饲养1天。(C)润湿笼子的垫料并饲养1天后,正常饲养1天。(D)在以180转/分钟的速度旋转的笼子中饲养1天后,正常饲养1天。将(A)~(D)进行1次后,进一步重复进行2次(B)~(D)。如此,总计经过3周施加压力作为负荷,从而制作慢性轻微压力诱发性抑郁症模型小鼠。期间,每天1次,经过3周,将本发明化合物溶于含PBS或DMSO等的PBS溶剂作为试验药来口服给与。
(2)MAP激酶及磷酸化MAP激酶的测定
上述施加慢性轻微压力后的行动解析(尾悬挂试验及明暗试验)结束后,自脑中摘除海马体。将海马体和其湿重量的19倍量的裂解液(包含1%NonidetP40〔注册商标〕、1%去氧胆酸钠、2mMEDTA、0.1%十二烷基硫酸钠(sodiumdodecylsulfate)(SDS)、0.15MNaCl、10mg/mL抑酞酶(aprotinin)、10mg/mL亮肽酶素(leupeptin)、50mMNaF、1mM原钒酸钠、1mM苯甲磺酰氟(phenylmethylsulfonylfluoride,PMSF)的20mMTris-盐酸缓冲液(pH7.4):RIPAbuffer)装入微型管(1.5mL),进行超声波破碎。其后,将该小管在冰上静置30分钟后离心(1400×g、15分钟),将上清作为蛋白质萃取液。向蛋白质萃取液中加入1/3量的电泳用样品缓冲液(0.2MTris-盐酸缓冲液(pH7.2)、8%SDS、40%甘油(glycerol)、溴酚蓝(bromophenolblue,BPB)、1/10量的2-巯基乙醇(2-mercaptoethanol),在95℃下进行5分钟加热处理,然后用10%聚丙烯酰胺凝胶进行SDS电泳。
对于MAP激酶(MAPK)及磷酸化MAP激酶(pMAPK)分别进行免疫印迹解析,分别将2μg、5μg的组织萃取蛋白质进行电泳。其后,将蛋白质自凝胶转印至PVDF膜。将转印后的PVDF膜用含5%脱脂牛奶的溶液固定后,使其与抗MAPK抗体、抗pMAPK抗体的各1000倍稀释液在4℃下反应一晩。接着,使其与二次抗体(碱性磷酸酶标记抗小鼠IgG抗体(5000倍稀释))反应,最后在添加有碱性磷酸酶的基质液中培育数分钟,从而使其显色。将各条带的染色强度数值化,求出pMAPK相对于MAPK的比率(n=4~7)。需要说明的是,显著性检验按照邓奈特(氏)检验(Dunnett'stest)来进行。
上述试验的结果是,正常动物对照组的pMAPK相对于MAPK的比率为1.26±0.11,施加轻微压力动物对照组中的相同比率为0.56±0.04,显著降低。给与了本发明化合物的组中的相同比率中,化合物10给与组(1000μg/kg)为1.00±0.04、化合物12给与组(500μg/kg)为1.09±0.04,本发明化合物显著提高施加轻微压力动物对照组中降低的MAPK的磷酸化,显示具有类神经营养因子作用。
试验例4施加轻微压力下的CREB的活化(磷酸化)的评价
针对本发明化合物,使用慢性轻微压力诱发性抑郁症模型小鼠,通过免疫印迹法,与上述试验例3同样测定转录因子CREB的活化水平(磷酸化CREB(pCREB)相对于CREB的比率)(n=3~8),所述转录因子CREB的信号转导通路位于MAPK(ERK1/2)的下游,对神经细胞的功能、记忆·学习能力发挥重要作用。其中,在一次抗体(抗CREB抗体、抗pCREB抗体)为1000倍稀释、二次抗体为10000倍稀释的条件下反应。
上述试验的结果是,正常动物对照组的pCREB相对于CREB的比率为0.95±0.09,施加轻微压力动物对照组中的相同比率为0.50±0.07,显著降低。给与了本发明化合物的组的相同比率中,化合物10给与组(1000μg/kg)为0.94±0.10、化合物12给与组(500μg/kg)为1.08±0.14,本发明化合物与MAPK的磷酸化的情况相同,显著提高施加轻微压力动物对照组中降低的pCREB的比率,表现出具有类神经营养因子作用。
试验例5施加轻微压力所伴有的抑郁症状的抑制效果的评价
对上述试验例3(1)的慢性轻微压力诱发性抑郁症模型小鼠给与作为试验药的本发明化合物后,通过尾悬挂试验进行抑郁症状的抑制效果的评价。也就是说,用手抓住距小鼠尾巴的尖端1cm处,支撑在距地面10cm高度处,观察6分钟,测定作为抑郁症状指标的静止时间的长度。需要说明的是,显著性检验按照Dunnett'stest来进行。
上述尾悬挂试验的结果是,正常动物对照组的静止时间为73.16±9.20秒,施加轻微压力动物对照组的静止时间为157.01±11.97秒,显著延长。以500μg/kg的用量给与了本发明化合物12的组的静止时间为69.26±16.41秒,显示显著的抑郁症状的抑制效果。另外,以1000μg/kg的用量给与了本发明化合物10的组的静止时间为96.03±25.24秒,能够看到抑郁症状的抑制。
试验例6施加轻微压力所伴有的焦虑症状的抑制效果的评价
对上述试验例3(1)的慢性轻微压力诱发性抑郁症模型小鼠给与作为试验药的本发明化合物后,通过明暗试验进行焦虑症状的抑制效果的评价。即,使用高50cm、长50cm、宽25cm的由明室与暗室2个组成的木制长方形装置,将小鼠置于暗室并使其自由探索,计算其后经过5分钟进入明室的次数、滞留在明室的时间。本试验是利用小鼠具有喜欢阴暗处的倾向,难以留在明亮处的习性,但出于好奇心会进行探索活动,而进入明室的性质,来评价小鼠的焦虑水平的试验。需要说明的是,显著性检验按照Dunnett'stest来进行。
上述明暗试验的结果是,正常动物对照组的明室滞留时间为110.74±5.29秒,相对于此,施加轻微压力对照组在明室滞留时间为74.72±4.09秒,显著降低。以500μg/kg的用量给与了本发明化合物12的组的明室滞留时间为108.70±12.06秒,显示显著的焦虑症状的抑制效果。另外,以1000μg/kg的用量给与了本发明化合物10的组的明室滞留时间为107.05±8.29秒,可以看到焦虑症状的抑制。
试验例7针对骨性关节炎模型大鼠的镇痛作用的评价
使用骨性关节炎(Osteoarthritis;OA)的模型动物即单碘乙酸钠(MIA)诱发OA大鼠,进行以下实验来调查本发明镇痛剂的镇痛作用。
(1)MIA诱发OA大鼠的制作
测定6周龄雄性Wistar系大鼠的对于机械刺激的50%反应阈值(测定方法后述),筛选正常对照组。针对正常对照组以外的大鼠,在右膝关节内以300μg/50μL的用量单次给与用生理盐水制备的MIA,并在左膝关节内给与生理食盐液50μL,制作MIA诱发OA大鼠。另外,对正常对照组的两膝的关节内给与生理食盐液50μL。
(2)组编制
实验动物的6周龄雄性Wistar系大鼠中,对于正常对照组之外的大鼠,在上述(1)的MIA给与的24天后测定对于机械刺激的50%反应阈值(测定方法后述)及体重,将1组6只大鼠进行编制,编为正常对照组、发病对照组、试验药给与组的3组。
(3)试验药的给与
用含0.1vol%二甲基亚砜(DMSO)的磷酸缓冲生理食盐液(PBS)制备使用本发明化合物作为试验药的试验药溶液(100μg/mL)。
组刚编制后(MIA给与14日后),对试验药给与组以500μg/kg的用量向腹腔内单次给与试验药溶液。另外,对正常对照组及发病对照组向腹腔内单次给与含0.1vol%DMSO的PBS。
(4)对于机械刺激的50%反应阈值的测定(机械痛阈测量试验)的结果
与试验例1的(2)同样实施机械痛阈测量试验,计算针对由于MIA给与而诱发的OA的痛觉过敏的50%反应阈值的恢复率(%)。将结果的一例示于表11。
表[11]
试验药 | 50%反应阈值的恢复率(%) |
化合物1 | 24.2 |
化合物5 | 35.8 |
化合物22 | 13.2 |
化合物25 | 18.9 |
由表11可知,本发明化合物针对由于MIA给与而诱发的OA的痛觉过敏显示抑制效果,显示作为镇痛剂的有用性。
产业上的可利用性
由上述药理试验结果可以确认,本发明化合物对于针对由于给与抗癌剂而对大鼠产生的机械刺激的痛觉过敏具有优异的治疗效果。因此,本发明化合物作为用于人、动物的四肢末端的麻痹等知觉异常、疼痛等痛觉过敏之类的由抗癌剂导致的末梢神经障碍的预防或治疗的药剂是有效的,有用性极高。
另外,使用大鼠大脑皮质培养神经细胞、慢性轻微压力诱发性抑郁症模型小鼠的海马体的评价中,表现出优异的MAP激酶磷酸化作用及CREB磷酸化作用(类神经营养因子作用)。而且,使用慢性轻微压力诱发性抑郁症模型小鼠的各种试验中,表现出改善抑郁症状、焦虑症状的作用。因此,可以期待本发明化合物作为失智症、阿尔茨海默病、帕金森病、糖尿病性神经病变、抑郁症、青光眼、泛自闭症障碍等的预防或治疗剂、脊髓损伤的修复剂是有用的。
另外,本发明化合物在使用OA模型即MIA诱发OA大鼠的动物实验中,具有优异的镇痛效果、痛觉过敏抑制效果。因此,本发明化合物作为各种疼痛疾病、例如OA等导致的疼痛的预防或治疗剂的有用性高。
Claims (16)
1.一种下述通式(I’)所示的反式-2-癸烯酸衍生物或其药学上可接受的盐,
式(I’)中,X’表示:
(a)被羧基或烷氧基羰基取代的1-吡咯烷基、
(b)3-四氢噻唑基、
(c)被烷基、氧基、羟基、烷氧基、羧基、烷氧基羰基、烷基氨基、烷基氨基烷基、苯基、羧基烷基、烷氧基羰基烷基、氰基或卤代苯基取代的哌啶基、
(d)硫代吗啉基、
(e)任选被烷基、羧基烷基、烷氧基羰基烷基、烷基氨基烷基、环烷基、哌啶基烷基、苯基烷基、吡啶基、嘧啶基、羧基苯基烷基或烷氧基羰基苯基烷基取代的1-哌嗪基、
(f)被苯基取代的1-哌嗪基,其中,所述苯基任选被烷基氨基、卤素、烷氧基、烷基、羟基、羧基烷氧基或烷氧基羰基烷氧基取代、
(g)任选被烷基或烷基氨基烷基取代的1,4-二氮杂环庚烷基、或者
(h)羧基吗啉基,
其中,所述烷基为碳原子数1至4的直链状或支链状烷基,所述烷氧基为碳原子数1至4的直链状或支链状烷氧基,所述环烷基为碳原子数3至8的环烷基。
2.根据权利要求1所述的反式-2-癸烯酸衍生物或其药学上可接受的盐,其中,X'为被羧基或者烷氧基羰基取代的1-吡咯烷基。
3.根据权利要求1所述的反式-2-癸烯酸衍生物或其药学上可接受的盐,其中,X'为3-四氢噻唑基、硫代吗啉基或羧基吗啉基。
4.根据权利要求1所述的反式-2-癸烯酸衍生物或其药学上可接受的盐,其中,X'为被烷基、氧基、羟基、烷氧基、羧基、烷氧基羰基、烷基氨基、烷基氨基烷基、苯基、羧基烷基、烷氧基羰基烷基、氰基或者卤代苯基取代了的哌啶基。
5.根据权利要求1所述的反式-2-癸烯酸衍生物或其药学上可接受的盐,其中,X'为任选被烷基、羧基烷基、烷氧基羰基烷基、烷基氨基烷基、环烷基、哌啶基烷基、苯基烷基、吡啶基、嘧啶基、羧基苯基烷基或者烷氧基羰基苯基烷基取代的1-哌嗪基。
6.根据权利要求1所述的反式-2-癸烯酸衍生物或其药学上可接受的盐,其中,X'为被苯基取代的1-哌嗪基,其中所述苯基任选被烷基氨基、卤素、烷氧基、烷基、羟基、羧基烷氧基或者烷氧基羰基烷氧基取代。
7.根据权利要求1所述的反式-2-癸烯酸衍生物或其药学上可接受的盐,其中,X'为任选被烷基或者烷基氨基烷基取代的1,4-二氮杂环庚烷基。
8.一种药物,其含有下述通式(I)所示的反式-2-癸烯酸衍生物及其药学上可接受的盐的至少一种作为有效成分,
式(I)中,X表示:
(a)被羧基或烷氧基羰基取代的1-吡咯烷基、
(b)3-四氢噻唑基、
(c)被烷基、氧基、羟基、烷氧基、羧基、烷氧基羰基、烷基氨基、烷基氨基烷基、苯基、羧基烷基、烷氧基羰基烷基、氰基或卤代苯基取代的哌啶基、
(d)硫代吗啉基、
(e)任选被烷基、羧基烷基、烷氧基羰基烷基、烷基氨基烷基、环烷基、哌啶基烷基、苯基烷基、吡啶基、嘧啶基、羧基苯基烷基或烷氧基羰基苯基烷基取代的1-哌嗪基、
(f)被苯基取代的1-哌嗪基,其中,所述苯基任选被烷基氨基、卤素、烷氧基、烷基、羟基、羧基烷氧基或烷氧基羰基烷氧基取代、
(g)任选被烷基或烷基氨基烷基取代的1,4-二氮杂环庚烷基、或者
(h)羧基吗啉基,
其中,所述烷基为碳原子数1至4的直链状或支链状烷基,所述烷氧基为碳原子数1至4的直链状或支链状烷氧基,所述环烷基为碳原子数3至8的环烷基。
9.根据权利要求8所述的药物,其为通过给与含至少一种抗癌剂的药剂而产生的末梢神经障碍的预防或治疗剂。
10.根据权利要求8所述的药物,其为神经退行性疾病的预防或治疗剂。
11.根据权利要求8所述的药物,其为精神疾病的预防或治疗剂。
12.根据权利要求11所述的药物,其中,所述精神疾病为抑郁症、焦虑性神经症或泛自闭症障碍。
13.根据权利要求8所述的药物,其为针对疼痛疾病的镇痛剂。
14.根据权利要求8至13中的任一项所述的药物,其为注射剂。
15.根据权利要求8至13中的任一项所述的药物,其为口服剂。
16.根据权利要求8至13中的任一项所述的药物,其为外用剂。
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KR101891986B1 (ko) | 2010-11-02 | 2018-08-27 | 니폰 조키 세야쿠 가부시키가이샤 | 트랜스-2-데센산 유도체 및 이것을 함유하는 의약 |
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2013
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CA2870822C (en) | 2016-06-21 |
EP2842942B1 (en) | 2016-12-07 |
RU2014147728A (ru) | 2016-06-20 |
KR20150013143A (ko) | 2015-02-04 |
US20150087823A1 (en) | 2015-03-26 |
CA2870822A1 (en) | 2013-10-31 |
AU2013253408B2 (en) | 2015-07-09 |
US9428477B2 (en) | 2016-08-30 |
TWI636975B (zh) | 2018-10-01 |
EP2842942A4 (en) | 2015-12-16 |
AU2013253408C1 (en) | 2016-04-21 |
JPWO2013161993A1 (ja) | 2015-12-24 |
JP2017057207A (ja) | 2017-03-23 |
ES2618297T3 (es) | 2017-06-21 |
BR112014026535A2 (pt) | 2017-06-27 |
JP6047152B2 (ja) | 2016-12-21 |
AU2013253408A1 (en) | 2014-11-06 |
RU2602810C2 (ru) | 2016-11-20 |
CN104254521A (zh) | 2014-12-31 |
SG11201406942SA (en) | 2014-11-27 |
IL235267A (en) | 2017-02-28 |
JP6242464B2 (ja) | 2017-12-06 |
HK1203955A1 (zh) | 2015-11-06 |
WO2013161993A1 (ja) | 2013-10-31 |
EP2842942A1 (en) | 2015-03-04 |
TW201400453A (zh) | 2014-01-01 |
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