CN1535687A - 止痒药物 - Google Patents
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Abstract
本发明涉及一种含有阿片κ受体激动剂作为有效组分的止痒剂、新的***喃季铵盐衍生物和新的***喃-N-氧化物衍生物,它们可用于治疗多种疾病并发的瘙痒。
Description
本申请是1997年11月21日提交的题为“止痒药物”的PCT/JP97/04267号发明专利申请的分案申请,原申请的中国专利申请号97193343.X。
技术领域
本发明涉及一种具有阿片κ受体激动剂活性的化合物和含有该化合物并适于治疗多种疾病引起的瘙痒症的止痒药。
背景技术
瘙痒是皮肤的特有感觉并可在许多伴有炎症的皮肤病中观察到该症状,瘙痒可以由某些内科疾病(恶性肿瘤、糖尿病、肝脏疾病、肾衰竭、血液透析、痛风、甲状腺疾病、血液病、和缺铁症)、妊娠、以及寄生虫病引起,有时,药物和精神因素也会诱发瘙痒。
因瘙痒是一种主观感觉而难以对该指征进行定量和客观地评价、诱发瘙痒的机制还不完全清楚。
至今已知的可诱发瘙痒的刺激物有:组胺、P物质、缓激肽、蛋白酶、***素和阿片肽等。而瘙痒的感觉被认为是由上述瘙痒刺激物作用于位于表皮和真皮接界区域内的多刺激对应性神经末梢(瘙痒受体)、由此产生神经冲动依次在脊髓丘脑束、丘脑、大脑皮层中的传递所引起(“治疗皮肤瘙痒的方法”,宫地良树著,p22,1996,先端医学社)。
瘙痒是一种使患者极感不适并在严重时甚至会妨碍正常生活的症状。在治疗瘙痒时,首先需对皮炎或可能引起瘙痒的基础疾病进行治疗,尤其是在患有皮肤病的情况下,同时也应对因瘙痒致使患者挠破皮肤而导致症状加重的瘙痒症进行必要的治疗。
皮肤挠破是加重皮炎的重要原因,这是由于皮肤受伤将导致皮肤屏障功能的缺损从而极易受到物理或化学刺激性的侵袭和细菌性感染。此外,由于表皮的薄弱化使神经敏感,使瘙痒更易发生,而最终将出现皮肤反复挠破的恶性循环。
举例来说,虽然健康者在睡眠时仅有不超过0.1%的睡眠时间是在抓挠瘙痒的皮肤,但重度特应性皮炎患者在睡眠时的平均抓挠时间却高达24%。假设平均睡眠时间为8小时,患者挠破皮肤的时间竟长达2小时。显然,睡眠时的皮肤挠破使特应性皮炎加重并成为特异性疹病并发的一个诱因(“日经医学”,1996年7月10日号,13页)。
因此,治疗瘙痒本身也极为重要,尤其是在伴随有严重瘙痒症的皮炎疾病中。
通常需要治疗瘙痒的具体皮肤病病例包括:特应性皮炎、神经性皮炎、接触性皮炎、脂溢性皮炎、自体致敏型皮炎、毛虫(caterpillar)皮炎、皮脂缺乏症、老年性皮肤瘙痒、昆虫叮咬、光致敏型皮炎、寻麻疹、痒疹、疱疹、脓疱病、湿疹、癣、苔癣、牛皮癣、疥疮、和寻常粉刺;以及,并发有瘙痒并已构成严重问题的内脏疾病例包括:恶性肿瘤、糖尿病、肝脏疾病、肾衰竭、血液透析、和妊娠。
常用于治疗上述瘙痒症的药物,口服药物主要有,例如抗组胺药和抗过敏药;外用制剂,例如抗组胺药、肾上腺皮质类固醇的外用制剂、非甾体类抗炎药、樟脑、薄荷醇、酚水杨酸、焦油、克罗米通、辣椒素、和湿润剂(尿素、喜疗妥(Hirudoid)和凡士林)。然而,口服药物会产生一些例如显效前有一段滞后时间中枢神经***抑制作用(嗜睡和疲倦感、消氏***障碍等)的不良反应的问题。外用制剂也有一些例如抗瘙痒功效不足、尤其是长期使用类固醇时会引起肾上腺皮质功能低下和反弹现象之类的缺陷和不良反应。
鉴于阿片与瘙痒间的关系,显然阿片不仅具有镇痛作用而且还可成为致瘙痒的化学介质。有关于内源性阿片肽例如β-内啡肽和脑啡肽能够诱发瘙痒的首次报导(B.FjellerActa,Dermato-Venereol.,61(suppl.97),1-34,1981)。业已发现,***和阿片化合物的硬膜外和鞘内给药存在诱发瘙痒的不良反应(J.H.Jaffe和W.R.Martin,Goodman and Gilman’s pharmacological Basis of Theraputics,Macmillan,纽约,1985)。另一方面还发现纳洛酮—一种***拮抗剂能够抑制***鞘内给药诱发的瘙痒(J.Bernstein et al.,J.Invest.Dermatol.,
78,83-83,1982),而肝病的胆汁郁积患者由内源性阿片肽增多所引起的瘙痒症可被***拮抗剂纳美酚(nalmefene)抑制(J.R.Thornton and M.S.Losowsky,Br.Med.J.,
297,1501-1504,1988)。通常认为,阿片激动剂诱发瘙痒而阿片拮抗剂可作为止痒药。近期有迹象表明患特应性皮炎儿童的血清中β-内啡肽浓度要明显高于健康儿童,并有报导称阿片拮抗剂可有效治疗特应性皮炎诱发型瘙痒。(S.Georgala et al.,Dermatol.Sci.
8,125-128,1994)。
因此,较通常现认为阿片系激动剂诱发瘙痒而阿片系拮抗剂却有可能成为止痒药。但现阶段阿片系拮抗剂仍未实际用作止痒药。
本发明的目的在于提供一种强阿片κ受体激动剂以及含有该激动剂,能够解决上述难题且具有快速有效的止痒作用的止痒药。
发明的公开
本发明提供一种具有阿片κ受体激动剂活性的化合物和含有该化合物剂作为有效成分的止痒药。
附图简述
附图1是实施例11的结果图示。
本发明的最佳实施方式
已知的阿片受体有μ、δ、和κ型并发现有分别选择性兴奋相应受体的内源性阿片肽。换言之,β-内啡肽和脑啡肽分别是μ、δ型受体激动剂而强啡肽被证实是κ受体激动剂的内源性阿片肽。包括强啡肽在内的κ受体激动剂对瘙痒的作用机制并不很清楚,但本发明却首次将其澄清。
虽然本发明的κ受体激动剂并不限于与阿片κ受体激动作用相应的特异化学结构特征;但该激动剂对κ受体的选择性却明显高于μ和δ受体的为优选。尤其可例举的是具有阿片κ受体激动活性的***类衍生物或它们的可药用酸加成盐,其中由通式(I)表示的是具有阿片κ受体激动活性的化合物或它们的可药用酸加成盐:
其中,是双键或单键;R1是含有1-5个碳原子的烷基、含有4-7个碳原子的环烷基烷基、含有5-7个碳原子的环链烯基烷基、含有6-12个碳原子的芳基、含有7-13个碳原子的芳烷基、含有4-7个碳原子的链烯基、烯丙基、含有1-5个碳原子的呋喃-2-基烷基、或含有1-5个碳原子的噻吩-2-基烷基;R2是氢、羟基、硝基、含有1-5个碳原子的烷酰氧基、含有1-5个碳原子的烷氧基、含有1-5个碳原子的烷基、或-NR9R10,R9为氢或含1-5个碳原子的烷基;R10为氢、含有1-5个碳原子的烷基、或-C(=O)-R11,R11是氢、苯基、或含有1-5个碳原子的烷基;R3是氢、羟基、和1-5个碳原子的烷酰氧基、或含有1-5个碳原子的烷氧基;A是-XC(=Y)-、-XC(=Y)Z-、-X-、或-XSO2-(其中X、Y和Z各自独立地代表NR4、S、或O,R4是氢、直链或支链的含有1-5个碳原子的烷基、或含有6-12个碳原子的芳基;式中的R4任意相同或不同);B是价键、直链或支链的含有1-14个碳原子的亚烷基(其中的亚烷基可任意至少被下述一个以上的基团取代,如含有1-5个碳原子的烷氧基、含有1-5个碳原子的烷酰氧基、羟基、氟、氯、溴、碘、氨基、硝基、氰基、三氟甲基、和苯氧基;任意有一至三个亚甲基被羰基取代)、直链或支链的非环状不饱和的含有2-14个碳原子的1-3个双键和/或叁键的烃基(其中,该非环状不饱和烃基任意带有至少一个以上选自含有1-5个碳原子的烷氧基、含有1-5碳原子的烷酰氧基、羟基、氟、氯、溴、碘、氨基、硝基、氰基、三氟甲基、和苯氧基的取代基,任意有一至三个亚甲基被羰基取代)、或直链或支链的饱和或不饱和的含有1-14个碳原子的带有1-5个硫醚、醚和/或氨基键的烃基(其中的杂原子不直接与A相连,任意有一至三个亚甲基被羰基取代);R5是氢或具有下列任一基本结构的有机基团:
其中的有机基团任意至少带有一个以上选自1-5个碳原子的烷基、含有1-5个碳原子的烷氧基、含有1-5个碳原子的烷酰氧基、羟基、氟、氯、溴、碘、氨基、硝基、氰基、异硫氰基、三氟甲基、三氟甲氧基、和亚甲二氧基的取代基;R6是氢;R7是氢、羟基、含有1-5个碳原子的烷氧基或含有1-5个碳原子的烷酰氧基、或R6和R7一起表示-O-、-CH2-、-S-;R8是氢、含有1-5个碳原子的烷基或含有1-5个碳原子的烷酰基,并且通式(I)包括(+)、(-)、和(±)异构体,另一种由通式(II)代表的阿片κ受体激动剂为:
其中,是双键或单键;R1是含有1-5个碳原子的烷基、含有4-7个碳原子的环烷基烷基、含有5-7个碳原子的环状链烯基烷基、含有7-13碳原子的芳烷基、含有4-7个碳原子的链烯基或烯丙基;R2是氢、羟基、硝基、含有1-5个碳原子的烷酰氧基、含有1-5个碳原子的烷氧基或含有1-5个碳原子的烷基;R3是氢、羟基、含有1-5个碳原子的烷酰氧基、或含有1-5个碳原子的烷氧基;R4是氢、直链或支链的含有1-5个碳原子的烷基、或含有6-12个碳原子的芳基;A是含有1-6个碳原子的亚烷基、-CH=CH-、或-C≡C-;并且R5是含有下列任一基本结构的有机基团:
其中的有机基团任意至少带有一个以上选自1-5个碳原子的烷基、含有1-5个碳原子的烷氧基、含有1-5个碳原子的烷酰氧基、羟基、氟、氯、溴、碘、硝基、氰基、异硫氰基、三氟甲基、三氟甲氧基和亚甲二氧基的取代基;R6是含有1-5个碳原子的烷基或烯丙基;X-表示可药用加成盐的平衡离子;并且通式(II)包括(+)、(-)、(±)异构体,另一种由通式(III)表示的阿片κ受体激动剂或其酸加成的可药用盐:
其中是双键或单键;R1是含有1-5个碳原子的烷基、含有4-7个碳原子的环烷基烷基、含有5-7个碳原子的环链烯基烷基、含有7-13碳原子的芳烷基、含有4-7个碳原子的链烯基或烯丙基;R2是氢、羟基、硝基、含有1-5个碳原子的烷酰氧基、含有1-5个碳原子的烷氧基或含有1-5个碳原子的烷基;R3是氢、羟基、含有1-5个碳原子的烷酰氧基、或含有1-5个碳原子的烷氧基;R4是氢、直链或支链的含有1-5个碳原子的烷基、或含有6-12个碳原子的芳基;A是含有1-6个碳原子的亚烷基、-CH=CH-、或-C≡C-;并且R5是带有下列任一基本结构的有机基团:
其中的有机基团任意至少带有一个以上选自含有1-5个碳原子的烷基、含有1-5个碳原子的烷氧基、含有1-5个碳原子的烷酰氧基、羟基、氟、氯、溴、碘、硝基、氰基、异硫氰基、三氟甲基、三氟甲氧基和亚甲二氧基的取代基;另外通式(III)包括(+)、(-)、(±)异构体。
除***喃衍生物外可用于治疗瘙痒的化合物,是用通式(IV)表示的阿片κ受体激动剂或其可药用酸加成盐,
其中的R代表两个氢或-O-CH2CH2CH2-;X和Y是氢或氯;Z是O或S;通式(IV)包括(+)、(-)、和(±)异构体,还有一种由通式(V)表示的阿片κ受体激动剂或其可药用酸加成盐:
其中X是氢、氯、或三氟甲基;Y是氢或氯;Z是CH2、-OCH2CH2O-、或NCO2CH3;并且通式(V)包括(+)、(-)、和(±)异构体,另有一种由通式(VI)表示的阿片κ受体激动剂或其可药用酸加成盐:
其中X和Y是氢或氯;Z是CH2、O、或S;并且通式(VI)包括(+)、(-)、和(±)异构体,以及一种由通式(VII)表示的阿片κ受体激动剂或其可药用酸加成盐:
其中X和Y是为氢或氯;并且通式(VII)包括(+)、(-)、(±)异构体。可使用这些阿片κ受体激动剂中的一种或数种作为有效成分来应用。
并发有瘙痒的作为治疗对象的皮肤病例包括:特应性皮炎、神经性皮炎、接触性皮炎、脂溢性皮炎、自体致敏型皮炎、毛虫(caterpil1ar)皮炎、皮脂缺乏症、老年性皮肤瘙痒、昆虫叮咬、光致敏型皮炎、寻麻疹、痒疹、疱疹、脓疱病、湿疹、癣、苔癣、牛皮癣、疥疮、和寻常粉刺。可被治疗的并发有瘙痒的内脏疾病典型例包括:恶性肿瘤、糖尿病、肝脏疾病、肾衰竭、血液透析、和妊娠。此外还可作为治疗眼科疾病或耳鼻喉科疾病并发症的瘙痒。
在通式(I)所示的属于本发明κ受体激动剂的化合物中,R1优选为含有1-5个碳原子的烷基、含有4-7个碳原子的环烷基烷基、具有5-7个碳原子的环链烯基烷基、含有7-13个碳原子的芳烷基、含有4-7个碳原子的链烯基、烯丙基、含有1-5个碳原子的呋喃-2-基-烷基、或含有1-5个碳原子的噻吩-2-基-烷基;并特别优选甲基、乙基、丙基、丁基、异丁基、环丙甲基、烯丙基、苄基、苯乙基、呋喃-2-基-甲基、或噻吩-2-基-甲基。
R2优选是氢、羟基、硝基、乙酰氧基、甲氧基、甲基、 乙基、丙基、氨基、二甲基氨基、乙酰氨基、或苯甲酰氨基;并且特别优选氢、羟基、硝基、乙酰氧基、甲氧基、甲基或二甲基氨基。更优选为氢、羟基、乙酰氧基或甲氧基。
R3优选是氢、羟基、乙酰氧基或甲氧基,并尤其优选为羟基、乙酰氧基或甲氧基。
A优选是(以具体式)-NR4C(=O)-、-NR4C(=S)-、-NR4C(=O)O-、-NR4C(=O)NR4-、-NR4C(=S)NR4-、-NR4C(=O)S-、-OC(=O)-、-OC(=O)O-、-SC(=O)-、-NR4-、-O-、-NR4SO2-、或-OSO2-;并且更优选为-NR4C(=O)-、-NR4C(=S)-、-NR4C(=O)O-、-NR4C(=O)NR4-、-NR4C(=S)NR4-、或-NR4SO2-。或优选-XC(=Y)-(其中X代表NR4-、S、或O,Y代表O、R4为氢或含有1-5个碳原子的烷基)、-XC(=Y)Z-、-X-、或-XSO2-(其中X代表NR4-,Y代表O或S,Z代表NR4或O,并且R4为氢或含有1-5个碳原子的烷基)更优选-XC(=Y)-或-XC(=Y)Z-(其中X代表NR4,Y代表O,Z代表O,并且R4为含有1-5个碳原子的烷基)。其中最优选-XC(=Y)-(其中X代表NR4,Y代表O,R4为含有1-5个碳原子的烷基)。
R4优选是氢、直链或支链的含有1-5个碳原子的烷基;并且特别优选是直链或支链的含有1-5个碳原子的烷基,其中更优选甲基、乙基、丙基、丁基或异丁基。
B优选是-(CH2)n-(n=0-10)、-(CH2)n-C(=O)-(n=1-4)、-CH=CH-(CH2)n-(n=0-4)、-C≡C-(CH2)n-(n=0-4)、-CH2-O-、-CH2-S-、-(CH2)2-O-CH2-、或-CH=CH-CH=CH-(CH2)n-(n=0-4)。特别指出的优选例是-(CH2)n-(n=1-3)、-CH=CH-(CH2)n(n=0-4)、-C≡C-(CH2)n-(n=0-4)、-CH2-O-或-CH2-S-。其中,更优选含有1-3个碳原子的直链亚烷基、-CH=CH-、-C≡C-、-CH2O-、-CH2S-。最优选-CH=CH-、-C≡C-。(当然所述优选例包括那些被上述不同取代基取代或替代的结构组成)。
R5优选是氢或带有下列任一基本结构的有机基团:
其中的有机基团任意含有被至少一个以上选自1-5个碳原子的烷基、含有1-5个碳原子的烷氧基、含有1-5个碳原子的烷酰氧基、羟基、氟、氯、溴、碘、氨基、硝基、氰基、异硫氰基、三氟甲基、三氟甲氧基和亚甲二氧基的取代基取代的结构组成;并且在上述化合物的R5Y中更优选氢、苯基、噻吩基或呋喃基(这些有机基团任意含有被至少一个以上选自1-5个碳原子的烷基、含有1-5个碳原子的烷氧基、含有1-5个碳原子的烷酰氧基、羟基、氟、氯、溴、碘、氨基、硝基、氰基、异硫氰基、三氟甲基、三氟甲氧基和亚甲二氧基的取代基取代的结构组成)。
更具体而言,优选例可包括:氢、苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、3,4-二甲基苯基、3,5-二甲基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、3,4-二甲氧基苯基、3-羟基苯基、4-羟基苯基、3,4-二甲氧基苯基、3-羟基苯基、4-羟基苯基、3,4-二羟基苯基、2-氟苯基、3-氟苯基、4-氟苯基、3,4-二氟苯基、全氟苯基、2-氯苯基、3-氯苯基、4-氯苯基、2,4-二氯苯基、3,4-二氯苯基、2,4,5-三氯苯基、2,4,6-三氯苯基、2-溴苯基、3-溴苯基、4-溴苯基、2-硝基苯基、3-硝基苯基、4-硝基苯基、2-氨基苯基、3-氨基苯基、4-氨基苯基、2-三氟甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、2-三氟甲氧基苯基、3-三氟甲氧基苯基、4-三氟甲氧基苯基、3,4-亚甲二氧基苯基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、环戊基或环己基,但并不局限于上述优选例。
R6和R7优选一起表示-O-、-CH2-或-S-,尤其优选它们一起表示-O-。
R8优选是氢、含有1-5个碳原子的烷基、或含有1-5个碳原子的烷酰基;并且上述化合物中可例举的优选例是氢、甲基、乙基或丙基。特别优选氢。
上述式(I)所示κ受体激动剂可按照日本专利2525552公开的方法制备。
此外,式(II)所示化合物是新的***喃类季铵盐衍生物,为阿片κ受体激动剂。该式中的R1优选为含有1-5个碳原子的烷基、含有5-7个碳原子的环烷基烷基、含有5-7个碳原子的环链烯基烷基、含有7-13个碳原子的芳烷基、含有4-7个碳原子的链烯基、或烯丙基;并且特别优选是甲基、乙基、丙基、丁基、异丁基、环丙基甲基、环丁基甲基、环戊基甲基、环戊烯基甲基、环己烯基甲基、苄基、苯乙基、反式-2-丁烯基、2-甲基-2-丁烯基、或丙烯基。最优选甲基、乙基、丙基、丁基、异丁基、环丙基甲基、苄基、苯乙基或烯丙基。
R2优选是氢、羟基、硝基、乙酰氧基、甲氧基、甲基、乙基或丙基;并且更优选氢、羟基、乙酰氧基、或甲氧基。
R3优选是氢、羟基、含有1-5个碳原子的烷酰氧基、或含有1-5个碳原子的烷氧基;并且更优选氢、羟基、乙酰氧基、或甲氧基。
R4优选是氢、直链或支链的含有1-5个碳原子的烷基、或含有6-12个碳原子的芳基;并且特别优选直链或支链的含有1-5个碳原子的烷基,或其中更优选甲基、乙基、丙基、异丙基、丁基或异丁基。
A优选是含有1-6个碳原子的链烯基、-CH=CH-或-C≡C-;并且其中更优选-CH=CH-或-C≡C-。
R5优选是含有下列任一基本结构的有机基团:
其中的有机基团任意含有被至少一个以上选自1-5个碳原子的烷基、含有1-5个碳原子的烷氧基、含有1-5个碳原子的烷酰氧基、羟基、氟、氯、溴、碘、硝基、氰基、异硫氰基、三氟甲基、三氟甲氧基或亚甲二氧基的取代基任意取代的结构组成;更优选的是苯基、2-氯苯基、3-氯苯基、4-氯苯基、3,4-二氯苯基、2-氟苯基、3-氟苯基、4-氟苯基、3,4-二氟苯基、2-溴苯基、3-溴苯基、4-溴苯基、2-硝基苯基、3-硝基苯基、4-硝基苯基、2-三氟甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、2-三氟甲氧基苯基、3-三氟甲氧基苯基、4-三氟甲氧基苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、3,4-二甲基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、3,4-二甲氧基苯基、2-羟基苯基、3-羟基苯基、4-羟基苯基、3,4-二羟基苯基、3-呋喃基、2-呋喃基、2-噻吩基、3-噻吩基、环戊基和环己基,但优选的并不局限于此。
R6优选为含有1-5个碳原子的烷基或烯丙基;特别优选甲基。
优选的在药物上可接受盐的平衡离子X-包括碘化物离子、溴化物离子、氯化物离子、甲基磺酸盐等,但显然并不局限于此。
式(II)化合物的具体例列于表1中。式(II)化合物包括(+)、(-)和(±)异构体在内。
表1
Q | R1 | R2 | R3 |
O | H | H | H |
O | CH3 | H | H |
O | H | CH3 | H |
O | H | H | CH3 |
O | F | H | H |
O | H | F | H |
O | H | H | F |
O | Cl | H | H |
O | H | Cl | H |
O | H | H | Cl |
O | Br | H | H |
O | H | Br | H |
O | H | H | Br |
O | CF3 | H | H |
O | H | CF3 | H |
O | H | H | CF3 |
O | CN | H | H |
O | H | CN | H |
O | H | H | CN |
Q | R1 | R2 | R3 |
S | H | H | H |
S | CH3 | H | H |
S | H | CH3 | H |
S | H | H | CH3 |
S | F | H | H |
S | H | F | H |
S | H | H | F |
S | Cl | H | H |
S | H | Cl | H |
S | H | H | Cl |
S | Br | H | H |
S | H | Br | H |
S | H | H | Br |
S | CF3 | H | H |
S | H | CF3 | H |
S | H | H | CF3 |
S | CN | H | H |
S | H | CN | H |
S | H | H | CN |
表1(续)
Q | R1 | R2 | R3 |
O | H | H | H |
O | CH3 | H | H |
O | H | CH3 | H |
O | H | H | CH3 |
O | F | H | H |
O | H | F | H |
O | H | H | F |
O | Cl | H | H |
O | H | Cl | H |
O | H | H | Cl |
O | Br | H | H |
O | H | Br | H |
O | H | H | Br |
O | CF3 | H | H |
O | H | CF3 | H |
O | H | H | CF3 |
O | CN | H | H |
O | H | CN | H |
O | H | H | CN |
Q | R1 | R2 | R3 |
S | H | H | H |
S | CH3 | H | H |
S | H | CH3 | H |
S | H | H | CH3 |
S | F | H | H |
S | H | F | H |
S | H | H | F |
S | Cl | H | H |
S | H | Cl | H |
S | H | H | Cl |
S | Br | H | H |
S | H | Br | H |
S | H | H | Br |
S | CF3 | H | H |
S | H | CF3 | H |
S | H | H | CF3 |
S | CN | H | H |
S | H | CN | H |
S | H | H | CN |
表1(续)
Q | R1 | R2 | R3 |
O | H | H | H |
O | CH3 | H | H |
O | H | CH3 | H |
O | H | H | CH3 |
O | F | H | H |
O | H | F | H |
O | H | H | F |
O | Cl | H | H |
O | H | Cl | H |
O | H | H | Cl |
O | Br | H | H |
O | H | Br | H |
O | H | H | Br |
O | CF3 | H | H |
O | H | CF3 | H |
O | H | H | CF3 |
O | CN | H | H |
O | H | CN | H |
O | H | H | CN |
Q | R1 | R2 | R3 |
S | H | H | H |
S | CH3 | H | H |
S | H | CH3 | H |
S | H | H | CH3 |
S | F | H | H |
S | H | F | H |
S | H | H | F |
S | Cl | H | H |
S | H | Cl | H |
S | H | H | Cl |
S | Br | H | H |
S | H | Br | H |
S | H | H | Br |
S | CF3 | H | H |
S | H | CF3 | H |
S | H | H | CF3 |
S | CN | H | H |
S | H | CN | H |
S | H | H | CN |
表1(续)
Q | R1 | R2 | R3 |
O | H | H | H |
O | CH3 | H | H |
O | H | CH3 | H |
O | H | H | CH3 |
O | F | H | H |
O | H | F | H |
O | H | H | F |
O | Cl | H | H |
O | H | Cl | H |
O | H | H | Cl |
O | Br | H | H |
O | H | Br | H |
O | H | H | Br |
O | CF3 | H | H |
O | H | CF3 | H |
O | H | H | CF3 |
O | CN | H | H |
O | H | CN | H |
O | H | H | CN |
Q | R1 | R2 | R3 |
S | H | H | H |
S | CH3 | H | H |
S | H | CH3 | H |
S | H | H | CH3 |
S | F | H | H |
S | H | F | H |
S | H | H | F |
S | Cl | H | H |
S | H | Cl | H |
S | H | H | Cl |
S | Br | H | H |
S | H | Br | H |
S | H | H | Br |
S | CF3 | H | H |
S | H | CF3 | H |
S | H | H | CF3 |
S | CN | H | H |
S | H | CN | H |
S | H | H | CN |
表1(续)
R1 | R2 | R3 | R4 |
C3H5CH2 | OH | OAc | CH3 |
C3H5CH2 | OH | OCH3 | CH3 |
C3H5CH2 | OH | H | CH3 |
C3H5CH2 | OAc | OH | CH3 |
C3H5CH2 | OAc | OAc | CH3 |
C3H5CH2 | OAc | OCH3 | CH3 |
C3H5CH2 | OAc | H | CH3 |
C3H5CH2 | OCH3 | OH | CH3 |
C3H5CH2 | OCH3 | OAc | CH3 |
C3H5CH2 | OCH3 | OCH3 | CH3 |
C3H5CH2 | OCH3 | H | CH3 |
C3H5CH2 | OH | OH | C2H5 |
C3H5CH2 | OH | OH | n-C3H7 |
C3H5CH2 | OH | OH | i-C3H7 |
C3H5CH2 | OH | OH | n-C4H9 |
C3H5CH2 | OH | OH | i-C4H9 |
CH3 | OH | OH | CH3 |
CH3 | OH | OAc | CH3 |
CH3 | OH | OCH3 | CH3 |
CH3 | OAc | OH | CH3 |
CH3 | OAc | OAc | CH3 |
CH3 | OAc | OCH3 | CH3 |
CH3 | OCH3 | OH | CH3 |
CH3 | OCH3 | OAc | CH3 |
CH3 | OCH3 | OCH3 | CH3 |
CH3 | OH | OH | C2H5 |
CH3 | OH | OH | n-C3H7 |
CH3 | OH | OH | i-C3H7 |
CH3 | OH | OH | n-C4H9 |
CH3 | OH | OH | i-C4H9 |
R1 | R2 | R3 | R4 |
CH2CHCH2 | OH | OH | CH3 |
CH2CHCH2 | OH | OAc | CH3 |
CH2CHCH2 | OH | OCH3 | CH3 |
CH2CHCH2 | OAc | OH | CH3 |
CH2CHCH2 | OAc | OAc | CH3 |
CH2CHCH2 | OAc | OCH3 | CH3 |
CH2CHCH2 | OCH3 | OH | CH3 |
CH2CHCH2 | OCH3 | OAc | CH3 |
CH2CHCH2 | OCH3 | OCH3 | CH3 |
CH2CHCH2 | OH | OH | C2H5 |
CH2CHCH2 | OH | OH | n-C3H7 |
CH2CHCH2 | OH | OH | i-C3H7 |
CH2CHCH2 | OH | OH | n-C4H9 |
CH2CHCH2 | OH | OH | i-C4H9 |
CH2CHCH2 | OH | OAc | C2H5 |
PhCH2CH2 | OH | OH | CH3 |
PhCH2CH2 | OH | OAc | CH3 |
PhCH2CH2 | OH | OCH3 | CH3 |
PhCH2CH2 | OAc | OH | CH3 |
PhCH2CH2 | OAc | OAc | CH3 |
PhCH2CH2 | OAc | OCH3 | CH3 |
PhCH2CH2 | OCH3 | OH | CH3 |
PhCH2CH2 | OCH3 | OAc | CH3 |
PhCH2CH2 | OCH3 | OCH3 | CH3 |
PhCH2CH2 | OH | OH | C2H5 |
PhCH2CH2 | OH | OH | n-C3H7 |
PhCH2CH2 | OH | OH | i-C3H7 |
PhCH2CH2 | OH | OH | n-C4H9 |
PhCH2CH2 | OH | OH | i-C4H9 |
PhCH2CH2 | OH | OAc | C2H5 |
表1(续)
R1 | R2 | R3 | R4 |
C3H5CH2 | OH | OAc | CH3 |
C3H5CH2 | OH | OCH3 | CH3 |
C3H5CH2 | OH | H | CH3 |
C3H5CH2 | OAc | OH | CH3 |
C3H5CH2 | OAc | OAc | CH3 |
C3H5CH2 | OAc | OCH3 | CH3 |
C3H5CH2 | OAc | H | CH3 |
C3H5CH2 | OCH3 | OH | CH3 |
C3H5CH2 | OCH3 | OAc | CH3 |
C3H5CH2 | OCH3 | OCH3 | CH3 |
C3H5CH2 | OCH3 | H | CH3 |
C3H5CH2 | OH | OH | C2H5 |
C3H5CH2 | OH | OH | n-C3H7 |
C3H5CH2 | OH | OH | i-C3H7 |
C3H5CH2 | OH | OH | n-C4H9 |
C3H5CH2 | OH | OH | i-C4H9 |
CH3 | OH | OH | CH3 |
CH3 | OH | OAc | CH3 |
CH3 | OH | OCH3 | CH3 |
CH3 | OAc | OH | CH3 |
CH3 | OAc | OAc | CH3 |
CH3 | OAc | OCH3 | CH3 |
CH3 | OCH3 | OH | CH3 |
CH3 | OCH3 | OAc | CH3 |
CH3 | OCH3 | OCH3 | CH3 |
CH3 | OH | OH | C2H5 |
CH3 | OH | OH | n-C3H7 |
CH3 | OH | OH | i-C3H7 |
CH3 | OH | OH | n-C4H9 |
CH3 | OH | OH | i-C4H9 |
R1 | R2 | R3 | R4 |
CH2CHCH2 | OH | OH | CH3 |
CH2CHCH2 | OH | OAc | CH3 |
CH2CHCH2 | OH | OCH3 | CH3 |
CH2CHCH2 | OAc | OH | CH3 |
CH2CHCH2 | OAc | OAc | CH3 |
CH2CHCH2 | OAc | OCH3 | CH3 |
CH2CHCH2 | OCH3 | OH | CH3 |
CH2CHCH2 | OCH3 | OAc | CH3 |
CH2CHCH2 | OCH3 | OCH3 | CH3 |
CH2CHCH2 | OH | OH | C2H5 |
CH2CHCH2 | OH | OH | n-C3H7 |
CH2CHCH2 | OH | OH | i-C3H7 |
CH2CHCH2 | OH | OH | n-C4H9 |
CH2CHCH2 | OH | OH | i-C4H9 |
CH2CHCH2 | OH | OAc | C2H5 |
PhCH2CH2 | OH | OH | CH3 |
PhCH2CH2 | OH | OAc | CH3 |
PhCH2CH2 | OH | OCH3 | CH3 |
PhCH2CH2 | OAc | OH | CH3 |
PhCH2CH2 | OAc | OAc | CH3 |
PhCH2CH2 | OAc | OCH3 | CH3 |
PhCH2CH2 | OCH3 | OH | CH3 |
PhCH2CH2 | OCH3 | OAc | CH3 |
PhCH2CH2 | OCH3 | OCH3 | CH3 |
PhCH2CH2 | OH | OH | C2H5 |
PhCH2CH2 | OH | OH | n-C3H7 |
PhCH2CH2 | OH | OH | i-C3H7 |
PhCH2CH2 | OH | OH | n-C4H9 |
PhCH2CH2 | OH | OH | i-C4H9 |
PhCH2CH2 | OH | OAc | C2H5 |
表1(续)
R1 | R2 | R3 | R4 |
H | H | H | CH3 |
H | H | H | C2H5 |
CH3 | H | H | CH3 |
H | CH3 | H | CH3 |
H | H | CH3 | CH3 |
H | CH3 | CH3 | CH3 |
H | CH3 | H | C2H5 |
H | CH3 | H | n-C3H7 |
H | CH3 | H | i-C3H7 |
H | CH3 | H | n-C4H9 |
H | CH3 | H | i-C4H9 |
OCH3 | H | H | CH3 |
H | OCH3 | H | CH3 |
H | H | OCH3 | CH3 |
H | OCH3 | OCH3 | CH3 |
H | OCH3 | H | C2H5 |
H | OCH3 | H | n-C3H7 |
H | OCH3 | H | i-C3H7 |
H | OCH3 | H | n-C4H9 |
H | OCH3 | H | i-C4H9 |
OH | H | H | CH3 |
H | OH | H | CH3 |
H | H | OH | CH3 |
Cl | H | H | CH3 |
H | Cl | H | CH3 |
H | H | Cl | CH3 |
H | Cl | Cl | CH3 |
H | Cl | Cl | n-C3H7 |
H | Cl | Cl | n-C4H9 |
Br | H | H | CH3 |
H | Br | H | CH3 |
H | H | Br | CH3 |
R1 | R2 | R3 | R4 |
H | Br | Br | CH3 |
H | Br | Br | C2H5 |
F | H | H | CH3 |
H | F | H | CH3 |
H | H | F | CH3 |
H | F | F | CH3 |
H | F | F | C2H5 |
NO2 | H | H | CH3 |
H | NO2 | H | CH3 |
H | H | NO2 | CH3 |
CF3 | H | H | CH3 |
H | CF3 | H | CH3 |
H | H | CF3 | CH3 |
H | H | CF3 | C2H5 |
H | H | CF3 | n-C3H7 |
H | H | CF3 | i-C3H7 |
H | H | CF3 | n-C4H9 |
H | H | CF3 | i-C4H9 |
OCF3 | H | H | CH3 |
H | OCF3 | H | CH3 |
H | H | OCF3 | CH3 |
H | OCF3 | H | C2H5 |
H | OCF3 | H | n-C3H7 |
H | OCF3 | H | i-C3H7 |
H | OCF3 | CF3 | n-C4H9 |
H | OCF3 | H | i-C4H9 |
表1(续)
R1 | R2 | R3 | R4 |
H | H | H | CH3 |
H | H | H | C2H5 |
CH3 | H | H | CH3 |
H | CH3 | H | CH3 |
H | H | CH3 | CH3 |
H | CH3 | CH3 | CH3 |
H | CH3 | H | C2H5 |
H | CH3 | H | n-C3H7 |
H | CH3 | H | i-C3H7 |
H | CH3 | H | n-C4H9 |
H | CH3 | H | i-C4H9 |
OCH3 | H | H | CH3 |
H | OCH3 | H | CH3 |
H | H | OCH3 | CH3 |
H | OCH3 | OCH3 | CH3 |
H | OCH3 | H | C2H5 |
H | OCH3 | H | n-C3H7 |
H | OCH3 | H | i-C3H7 |
H | OCH3 | H | n-C4H9 |
H | OCH3 | H | i-C4H9 |
OH | H | H | CH3 |
H | OH | H | CH3 |
H | H | OH | CH3 |
Cl | H | H | CH3 |
H | Cl | H | CH3 |
H | H | Cl | CH3 |
H | Cl | Cl | CH3 |
H | Cl | Cl | n-C3H7 |
H | Cl | Cl | n-C4H9 |
Br | H | H | CH3 |
H | Br | H | CH3 |
H | H | Br | CH3 |
R1 | R2 | R3 | R4 |
H | Br | Br | CH3 |
H | Br | Br | C2H5 |
F | H | H | CH3 |
H | F | H | CH3 |
H | H | F | CH3 |
H | F | F | CH3 |
H | F | F | C2H5 |
NO2 | H | H | CH3 |
H | NO2 | H | CH3 |
H | H | NO2 | CH3 |
CF3 | H | H | CH3 |
H | CF3 | H | CH3 |
H | H | CF3 | CH3 |
H | H | CF3 | C2H5 |
H | H | CF3 | n-C3H7 |
H | H | CF3 | i-C3H7 |
H | H | CF3 | n-C4H9 |
H | H | CF3 | i-C4H9 |
OCF3 | H | H | CH3 |
H | OCF3 | H | CH3 |
H | H | OCF3 | CH3 |
H | OCF3 | H | C2H5 |
H | OCF3 | H | n-C3H7 |
H | OCF3 | H | i-C3H7 |
H | OCF3 | CF3 | n-C4H9 |
H | OCF3 | H | i-C4H9 |
表1(续)
R1 | R2 | R3 | R4 |
C3H5CH2 | OH | OAc | CH3 |
C3H5CH2 | OH | OCH3 | CH3 |
C3H5CH2 | OH | H | CH3 |
C3H5CH2 | OAc | OH | CH3 |
C3H5CH2 | OAc | OAc | CH3 |
C3H5CH2 | OAc | OCH3 | CH3 |
C3H5CH2 | OAc | H | CH3 |
C3H5CH2 | OCH3 | OH | CH3 |
C3H5CH2 | OCH3 | OAc | CH3 |
C3H5CH2 | OCH3 | OCH3 | CH3 |
C3H5CH2 | OCH3 | H | CH3 |
CH3 | OH | OH | CH3 |
CH3 | OH | OAc | CH3 |
CH3 | OH | OCH3 | CH3 |
CH3 | OAc | OH | CH3 |
CH3 | OAc | OAc | CH3 |
CH3 | OAc | OCH3 | CH3 |
CH3 | OCH3 | OH | CH3 |
CH3 | OCH3 | OAc | CH3 |
CH3 | OCH3 | OCH3 | CH3 |
CH3 | OH | OH | C2H5 |
CH3 | OH | OH | n-C3H7 |
CH3 | OH | OH | i-C3H7 |
CH3 | OH | OH | n-C4H9 |
CH3 | OH | OH | i-C4H9 |
R1 | R2 | R3 | R4 |
CH2CHCH2 | OH | OH | CH3 |
CH2CHCH2 | OH | OAc | CH3 |
CH2CHCH2 | OH | OCH3 | CH3 |
CH2CHCH2 | OAc | OH | CH3 |
CH2CHCH2 | OAc | OAc | CH3 |
CH2CHCH2 | OAc | OCH3 | CH3 |
CH2CHCH2 | OCH3 | OH | CH3 |
CH2CHCH2 | OCH3 | OAc | CH3 |
CH2CHCH2 | OCH3 | OCH3 | CH3 |
CH2CHCH2 | OH | OH | C2H5 |
CH2CHCH2 | OH | OH | n-C3H7 |
CH2CHCH2 | OH | OH | i-C3H7 |
CH2CHCH2 | OH | OH | n-C4H9 |
CH2CHCH2 | OH | OH | i-C4H9 |
PhCH2CH2 | OH | OH | CH3 |
PhCH2CH2 | OH | OAc | CH3 |
PhCH2CH2 | OH | OCH3 | CH3 |
PhCH2CH2 | OAc | OH | CH3 |
PhCH2CH2 | OAc | OAc | CH3 |
PhCH2CH2 | OAc | OCH3 | CH3 |
PhCH2CH2 | OCH3 | OH | CH3 |
PhCH2CH2 | OCH3 | OAc | CH3 |
PhCH2CH2 | OCH3 | OCH3 | CH3 |
PhCH2CH2 | OH | OH | C2H5 |
PhCH2CH2 | OH | OH | n-C3H7 |
PhCH2CH2 | OH | OH | i-C3H7 |
PhCH2CH2 | OH | OH | n-C4H9 |
PhCH2CH2 | OH | OH | i-C4H9 |
表1(续)
R1 | R2 | R3 | R4 |
C3H5CH2 | OH | OAc | CH3 |
C3H5CH2 | OH | OCH3 | CH3 |
C3H5CH2 | OH | H | CH3 |
C3H5CH2 | OAc | OH | CH3 |
C3H5CH2 | OAc | OAc | CH3 |
C3H5CH2 | OAc | OCH3 | CH3 |
C3H5CH2 | OAc | H | CH3 |
C3H5CH2 | OCH3 | OH | CH3 |
C3H5CH2 | OCH3 | OAc | CH3 |
C3H5CH2 | OCH3 | OCH3 | CH3 |
C3H5CH2 | OCH3 | H | CH3 |
CH3 | OH | OH | CH3 |
CH3 | OH | OAc | CH3 |
CH3 | OH | OCH3 | CH3 |
CH3 | OAc | OH | CH3 |
CH3 | OAc | OAc | CH3 |
CH3 | OAc | OCH3 | CH3 |
CH3 | OCH3 | OH | CH3 |
CH3 | OCH3 | OAc | CH3 |
CH3 | OCH3 | OCH3 | CH3 |
CH3 | OH | OH | C2H5 |
CH3 | OH | OH | n-C3H7 |
CH3 | OH | OH | i-C3H7 |
CH3 | OH | OH | n-C4H9 |
CH3 | OH | OH | i-C4H9 |
R1 | R2 | R3 | R4 |
CH2CHCH2 | OH | OH | CH3 |
CH2CHCH2 | OH | OAc | CH3 |
CH2CHCH2 | OH | OCH3 | CH3 |
CH2CHCH2 | OAc | OH | CH3 |
CH2CHCH2 | OAc | OAc | CH3 |
CH2CHCH2 | OAc | OCH3 | CH3 |
CH2CHCH2 | OCH3 | OH | CH3 |
CH2CHCH2 | OCH3 | OAc | CH3 |
CH2CHCH2 | OCH3 | OCH3 | CH3 |
CH2CHCH2 | OH | OH | C2H5 |
CH2CHCH2 | OH | OH | n-C3H7 |
CH2CHCH2 | OH | OH | i-C3H7 |
CH2CHCH2 | OH | OH | n-C4H9 |
CH2CHCH2 | OH | OH | i-C4H9 |
PhCH2CH2 | OH | OH | CH3 |
PhCH2CH2 | OH | OAc | CH3 |
PhCH2CH2 | OH | OCH3 | CH3 |
PhCH2CH2 | OAc | OH | CH3 |
PhCH2CH2 | OAc | OAc | CH3 |
PhCH2CH2 | OAc | OCH3 | CH3 |
PhCH2CH2 | OCH3 | OH | CH3 |
PhCH2CH2 | OCH3 | OAc | CH3 |
PhCH2CH2 | OCH3 | OCH3 | CH3 |
PhCH2CH2 | OH | OH | C2H5 |
PhCH2CH2 | OH | OH | n-C3H7 |
PhCH2CH2 | OH | OH | i-C3H7 |
PhCH2CH2 | OH | OH | n-C4H9 |
PhCH2CH2 | OH | OH | i-C4H9 |
表1(续)
R1 | R2 | R3 | R4 |
H | H | H | CH3 |
H | H | H | C2H5 |
CH3 | H | H | CH3 |
H | CH3 | H | CH3 |
H | H | CH3 | CH3 |
H | CH3 | CH3 | CH3 |
H | CH3 | H | C2H5 |
H | CH3 | H | n-C3H7 |
H | CH3 | H | i-C3H7 |
H | CH3 | H | n-C4H9 |
H | CH3 | H | i-C4H9 |
OCH3 | H | H | CH3 |
H | OCH3 | H | CH3 |
H | H | OCH3 | CH3 |
H | OCH3 | OCH3 | CH3 |
H | OCH3 | H | C2H5 |
H | OCH3 | H | n-C3H7 |
H | OCH3 | H | i-C3H7 |
H | OCH3 | H | n-C4H9 |
H | OCH3 | H | i-C4H9 |
OH | H | H | CH3 |
H | OH | H | CH3 |
H | H | OH | CH3 |
Cl | H | H | CH3 |
H | Cl | H | CH3 |
H | H | Cl | CH3 |
H | Cl | Cl | CH3 |
H | Cl | Cl | n-C3H7 |
H | Cl | Cl | n-C4H9 |
Br | H | H | CH3 |
H | Br | H | CH3 |
H | H | Br | CH3 |
R1 | R2 | R3 | R4 |
H | Br | Br | CH3 |
H | Br | Br | C2H5 |
F | H | H | CH3 |
H | F | H | CH3 |
H | H | F | CH3 |
H | F | F | CH3 |
H | F | F | C2H5 |
NO2 | H | H | CH3 |
H | NO2 | H | CH3 |
H | H | NO2 | CH3 |
CF3 | H | H | CH3 |
H | CF3 | H | CH3 |
H | H | CF3 | CH3 |
H | H | CF3 | C2H5 |
H | H | CF3 | n-C3H7 |
H | H | CF3 | i-C3H7 |
H | H | CF3 | n-C4H9 |
H | H | CF3 | i-C4H9 |
OCF3 | H | H | CH3 |
H | OCF3 | H | CH3 |
H | H | OCF3 | CH3 |
H | OCF3 | H | C2H5 |
H | OCF3 | H | n-C3H7 |
H | OCF3 | H | i-C3H7 |
H | OCF3 | CF3 | n-C4H9 |
H | OCF3 | H | i-C4H9 |
表1(续)
R1 | R2 | R3 | R4 |
H | H | H | CH3 |
H | H | H | C2H5 |
CH3 | H | H | CH3 |
H | CH3 | H | CH3 |
H | H | CH3 | CH3 |
H | CH3 | CH3 | CH3 |
H | CH3 | H | C2H5 |
H | CH3 | H | n-C3H7 |
H | CH3 | H | i-C3H7 |
H | CH3 | H | n-C4H9 |
H | CH3 | H | i-C4H9 |
OCH3 | H | H | CH3 |
H | OCH3 | H | CH3 |
H | H | OCH3 | CH3 |
H | OCH3 | OCH3 | CH3 |
H | OCH3 | H | C2H5 |
H | OCH3 | H | n-C3H7 |
H | OCH3 | H | i-C3H7 |
H | OCH3 | H | n-C4H9 |
H | OCH3 | H | i-C4H9 |
OH | H | H | CH3 |
H | OH | H | CH3 |
H | H | OH | CH3 |
Cl | H | H | CH3 |
H | Cl | H | CH3 |
H | H | Cl | CH3 |
H | Cl | Cl | CH3 |
H | Cl | Cl | n-C3H7 |
H | Cl | Cl | n-C4H9 |
Br | H | H | CH3 |
H | Br | H | CH3 |
H | H | Br | CH3 |
R1 | R2 | R3 | R4 |
H | Br | Br | CH3 |
H | Br | Br | C2H5 |
F | H | H | CH3 |
H | F | H | CH3 |
H | H | F | CH3 |
H | F | F | CH3 |
H | F | F | C2H5 |
NO2 | H | H | CH3 |
H | NO2 | H | CH3 |
H | H | NO2 | CH3 |
CF3 | H | H | CH3 |
H | CF3 | H | CH3 |
H | H | CF3 | CH3 |
H | H | CF3 | C2H5 |
H | H | CF3 | n-C3H7 |
H | H | CF3 | i-C3H7 |
H | H | CF3 | n-C4H9 |
H | H | CF3 | i-C4H9 |
OCF3 | H | H | CH3 |
H | OCF3 | H | CH3 |
H | H | OCF3 | CH3 |
H | OCF3 | H | C2H5 |
H | OCF3 | H | n-C3H7 |
H | OCF3 | H | i-C3H7 |
H | OCF3 | CF3 | n-C4H9 |
H | OCF3 | H | i-C4H9 |
表1(续)
R1 | R2 | R3 | R4 |
C3H5CH2 | OH | OAc | CH3 |
C3H5CH2 | OH | OCH3 | CH3 |
C3H5CH2 | OH | H | CH3 |
C3H5CH2 | OAc | OH | CH3 |
C3H5CH2 | OAc | OAc | CH3 |
C3H5CH2 | OAc | OCH3 | CH3 |
C3H5CH2 | OAc | H | CH3 |
C3H5CH2 | OCH3 | OH | CH3 |
C3H5CH2 | OCH3 | OAc | CH3 |
C3H5CH2 | OCH3 | OCH3 | CH3 |
C3H5CH2 | OCH3 | H | CH3 |
CH3 | OH | OH | CH3 |
CH3 | OH | OAc | CH3 |
CH3 | OH | OCH3 | CH3 |
CH3 | OAc | OH | CH3 |
CH3 | OAc | OAc | CH3 |
CH3 | OAc | OCH3 | CH3 |
CH3 | OCH3 | OH | CH3 |
CH3 | OCH3 | OAc | CH3 |
CH3 | OCH3 | OCH3 | CH3 |
CH3 | OH | OH | C2H5 |
CH3 | OH | OH | n-C3H7 |
CH3 | OH | OH | i-C3H7 |
CH3 | OH | OH | n-C4H9 |
CH3 | OH | OH | i-C4H9 |
R1 | R2 | R3 | R4 |
CH2CHCH2 | OH | OH | CH3 |
CH2CHCH2 | OH | OAc | CH3 |
CH2CHCH2 | OH | OCH3 | CH3 |
CH2CHCH2 | OAc | OH | CH3 |
CH2CHCH2 | OAc | OAc | CH3 |
CH2CHCH2 | OAc | OCH3 | CH3 |
CH2CHCH2 | OCH3 | OH | CH3 |
CH2CHCH2 | OCH3 | OAc | CH3 |
CH2CHCH2 | OCH3 | OCH3 | CH3 |
CH2CHCH2 | OH | OH | C2H5 |
CH2CHCH2 | OH | OH | n-C3H7 |
CH2CHCH2 | OH | OH | i-C3H7 |
CH2CHCH2 | OH | OH | n-C4H9 |
CH2CHCH2 | OH | OH | i-C4H9 |
PhCH2CH2 | OH | OH | CH3 |
PhCH2CH2 | OH | OAc | CH3 |
PhCH2CH2 | OH | OCH3 | CH3 |
PhCH2CH2 | OAc | OH | CH3 |
PhCH2CH2 | OAc | OAc | CH3 |
PhCH2CH2 | OAc | OCH3 | CH3 |
PhCH2CH2 | OCH3 | OH | CH3 |
PhCH2CH2 | OCH3 | OAc | CH3 |
PhCH2CH2 | OCH3 | OCH3 | CH3 |
PhCH2CH2 | OH | OH | C2H5 |
PhCH2CH2 | OH | OH | n-C3H7 |
PhCH2CH2 | OH | OH | i-C3H7 |
PhCH2CH2 | OH | OH | n-C4H9 |
PhCH2CH2 | OH | OH | i-C4H9 |
表1(续)
R1 | R2 | R3 | R4 |
C3H5CH2 | OH | OAc | CH3 |
C3H5CH2 | OH | OCH3 | CH3 |
C3H5CH2 | OH | H | CH3 |
C3H5CH2 | OAc | OH | CH3 |
C3H5CH2 | OAc | OAc | CH3 |
C3H5CH2 | OAc | OCH3 | CH3 |
C3H5CH2 | OAc | H | CH3 |
C3H5CH2 | OCH3 | OH | CH3 |
C3H5CH2 | OCH3 | OAc | CH3 |
C3H5CH2 | OCH3 | OCH3 | CH3 |
C3H5CH2 | OCH3 | H | CH3 |
CH3 | OH | OH | CH3 |
CH3 | OH | OAc | CH3 |
CH3 | OH | OCH3 | CH3 |
CH3 | OAc | OH | CH3 |
CH3 | OAc | OAc | CH3 |
CH3 | OAc | OCH3 | CH3 |
CH3 | OCH3 | OH | CH3 |
CH3 | OCH3 | OAc | CH3 |
CH3 | OCH3 | OCH3 | CH3 |
CH3 | OH | OH | C2H5 |
CH3 | OH | OH | n-C3H7 |
CH3 | OH | OH | i-C3H7 |
CH3 | OH | OH | n-C4H9 |
CH3 | OH | OH | i-C4H9 |
R1 | R2 | R3 | R4 |
CH2CHCH2 | OH | OH | CH3 |
CH2CHCH2 | OH | OAc | CH3 |
CH2CHCH2 | OH | OCH3 | CH3 |
CH2CHCH2 | OAc | OH | CH3 |
CH2CHCH2 | OAc | OAc | CH3 |
CH2CHCH2 | OAc | OCH3 | CH3 |
CH2CHCH2 | OCH3 | OH | CH3 |
CH2CHCH2 | OCH3 | OAc | CH3 |
CH2CHCH2 | OCH3 | OCH3 | CH3 |
CH2CHCH2 | OH | OH | C2H5 |
CH2CHCH2 | OH | OH | n-C3H7 |
CH2CHCH2 | OH | OH | i-C3H7 |
CH2CHCH2 | OH | OH | n-C4H9 |
CH2CHCH2 | OH | OH | i-C4H9 |
PhCH2CH2 | OH | OH | CH3 |
PhCH2CH2 | OH | OAc | CH3 |
PhCH2CH2 | OH | OCH3 | CH3 |
PhCH2CH2 | OAc | OH | CH3 |
PhCH2CH2 | OAc | OAc | CH3 |
PhCH2CH2 | OAc | OCH3 | CH3 |
PhCH2CH2 | OCH3 | OH | CH3 |
PhCH2CH2 | OCH3 | OAc | CH3 |
PhCH2CH2 | OCH3 | OCH3 | CH3 |
PhCH2CH2 | OH | OH | C2H5 |
PhCH2CH2 | OH | OH | n-C3H7 |
PhCH2CH2 | OH | OH | i-C3H7 |
PhCH2CH2 | OH | OH | n-C4H9 |
PhCH2CH2 | OH | OH | i-C4H9 |
本发明式(II)所示化合物可具体按照下列方法制备。
如示意图I所示,化合物的制得通常是式(VIII)(R1、R2、R3、R4、R5以及A的定义同通式(II))所示的17位叔胺经卤代烷、甲基磺酸酯等的烷基化试剂处理而转化为季铵盐来完成:
[示意图I]
R6X表示卤代烷基、CH3SO3R6表示甲基磺酸烷基。
式(VIII)所示的带有17位叔胺的起始原料可以按照日本特许公报2525552中公开的方法制备。
许多烷基化试剂都适宜将式(VIII)所示的17位叔胺转化为季铵盐。之所以常采用碘甲烷、碘乙烷、碘丙烷、碘丁烷、碘丙烯、甲基磺酸甲酯和硫酸二甲酯是由于它们生成季铵盐时的反应相对较快。然而也可任意使用其他例如溴甲烷、溴乙烷、溴丙烷、溴丁烷、溴丙烯、氯甲烷、氯乙烷、氯丙烷、氯丁烷和氯丙烯的烷基化试剂。就溶剂而言,可以将二氯乙烷、氯仿、四氢呋喃、乙酸乙酯、二甲基甲酰胺、乙腈、甲醇、乙醇、丙醇、叔丁醇或丙酮作为反应溶剂单独或结合使用。反应温度优选设定在0℃至溶剂沸点之间,或更优选介于室温至溶剂沸点间;反应时间优选在1-14天、或更优选介于1-10天之间;并且该反应在封闭管内或常压下进行。上述烷基化试剂可以按照相对于每当量叔胺加入1当量或例如进一步过量0.1-5.0当量或更多的量加入。此外还可以将作为碱的碳酸氢钾、碳酸氢钠、碳酸钾或碳酸钠加入以相对于每当量叔胺可以使用一当量,或例如过量0.1-5.0当量或更多过量的碱。
此外,式(III)所示化合物是新的17位***喃N-氧化物衍生物、阿片κ受体激动剂。在该式中,R1优选是含有1-5个碳原子的烷基、含有4-7个碳原子的环烷基烷基、含有5-7个碳原子的环链烯基烷基、含有7-13个碳原子的芳烷基、含有4-7个碳原子的链烯基、或烯丙基;并且特别优选甲基、乙基、丙基、丁基、异丁基、环丙基甲基、环丁基甲基、环戊基甲基、环戊烯基甲基、环己烯基甲基、苄基、苯乙基、反式-2-丁烯基、2-甲基-2-丁烯基、或丙烯基。最优选甲基、乙基、丙基、丁基、异丁基、环丙基甲基、苄基、苯乙基或烯丙基。
R2优选是氢、羟基、硝基、乙酰氧基、甲氧基、甲基、乙基或丙基;并且更优选氢、羟基、乙酰氧基、或甲氧基。
R3优选是氢、羟基、乙酰氧基、或甲氧基。
R4优选是氢、直链或支链的含有1-5个碳原子的烷基或苯基;并且特别优选直链或支链的含有1-5个碳原子的烷基,其中更优选甲基、乙基、丙基、异丙基、丁基或异丁基。
A优选是含有1-6个碳原子的链烯基、-CH=CH-或-C≡C-;并且其中更优选-CH=CH-或-C≡C-。
R5优选是含有下列任一基本结构骨架的有机基团:
其中的有机基团任意含有由至少一个以上选自1-5个碳原子的烷基、含有1-5个碳原子的烷氧基、含有1-5个碳原子的烷酰氧基、羟基、氟、氯、溴、碘、硝基、氰基、异硫氰基、三氟甲基、三氟甲氧基和亚甲二氧基的取代基取代的结构组成;特别优选的是苯基、2-氯苯基、3-氯苯基、4-氯苯基、3,4-二氯苯基、2-氟苯基、3-氟苯基、4-氟苯基、3,4-二氟苯基、2-溴苯基、3-溴苯基、4-溴苯基、2-硝基苯基、3-硝基苯基、4-硝基苯基、2-三氟甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、2-三氟甲氧基苯基、3-三氟甲氧基苯基、4-三氟甲氧基苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、2-呋喃基、3-呋喃基、环戊基和环己基,但显然不局限于此。
式(III)所示化合物的具体例列于表2中,并且式(III)化合物包括(+)、(-)和(±)异构体在内。
表2
R1 | R2 | R3 | R4 |
H | H | H | CH3 |
H | H | H | C2H5 |
H | H | H | n-C3H7 |
H | H | H | i-C3H7 |
H | H | H | n-C4H9 |
H | H | H | i-C4H9 |
CH3 | H | H | CH3 |
H | CH3 | H | CH3 |
H | H | CH3 | CH3 |
CH3 | H | H | C2H5 |
Cl | H | H | CH3 |
H | Cl | H | CH3 |
H | H | Cl | CH3 |
H | Cl | H | C2H5 |
Br | H | H | CH3 |
H | Br | H | CH3 |
H | H | Br | CH3 |
H | Br | H | C2H5 |
F | H | H | CH3 |
H | F | H | CH3 |
H | H | F | CH3 |
H | F | H | C2H5 |
CF3 | H | H | CH3 |
H | CF3 | H | CH3 |
H | H | CF3 | CH3 |
CF3 | H | H | C2H5 |
CN | H | H | CH3 |
H | CN | H | CH3 |
H | H | CN | CH3 |
CN | H | H | C2H5 |
R1 | R2 | R3 | R4 |
H | H | H | CH3 |
H | H | H | C2H5 |
H | H | H | n-C3H7 |
H | H | H | i-C3H7 |
H | H | H | n-C4H9 |
H | H | H | i-C4H9 |
CH3 | H | H | CH3 |
H | CH3 | H | CH3 |
H | H | CH3 | CH3 |
CH3 | H | H | CH3 |
Cl | H | H | CH3 |
H | Cl | H | CH3 |
H | H | Cl | CH3 |
H | Cl | H | C2H5 |
Br | H | H | CH3 |
H | Br | H | CH3 |
H | H | Br | CH3 |
H | Br | H | C2H5 |
F | H | H | CH3 |
H | F | H | CH3 |
H | H | F | CH3 |
H | F | H | C2H5 |
CF3 | H | H | CH3 |
H | CF3 | H | CH3 |
H | H | CF3 | CH3 |
CF3 | H | H | C2H5 |
CN | H | H | CH3 |
H | CN | H | CH3 |
H | H | CN | CH3 |
CN | H | H | C2H5 |
表2(续)
R1 | R2 | R3 | R4 |
C3H5CH2 | OH | OAc | CH3 |
C3H5CH2 | OH | OCH3 | CH3 |
C3H5CH2 | OH | H | CH3 |
C3H5CH2 | OAc | OH | CH3 |
C3H5CH2 | OAc | OAc | CH3 |
C3H5CH2 | OAc | OCH3 | CH3 |
C3H5CH2 | OAc | H | CH3 |
C3H5CH2 | OCH3 | OH | CH3 |
C3H5CH2 | OCH3 | OAc | CH3 |
C3H5CH2 | OCH3 | OCH3 | CH3 |
C3H5CH2 | OCH3 | H | CH3 |
C3H5CH2 | OH | OAc | C2H5 |
C3H5CH2 | OH | OAc | n-C3H7 |
C3H5CH2 | OH | OAc | i-C3H5 |
C3H5CH2 | OH | OCH3 | C2H5 |
C3H5CH2 | OH | OCH3 | n-C3H7 |
CH3 | OH | OH | CH3 |
CH3 | OH | OAc | CH3 |
CH3 | OH | OCH3 | CH3 |
CH3 | OAc | OH | CH3 |
CH3 | OAc | OAc | CH3 |
CH3 | OAc | OCH3 | CH3 |
CH3 | OCH3 | OH | CH3 |
CH3 | OCH3 | OAc | CH3 |
CH3 | OCH3 | OCH3 | CH3 |
CH3 | OH | OH | C2H5 |
CH3 | OH | OH | n-C3H7 |
CH3 | OH | OH | i-C3H7 |
CH3 | OH | OH | n-C4H9 |
CH3 | OH | OH | i-C4H9 |
CH3 | OH | OAc | C2H5 |
R1 | R2 | R3 | R4 |
CH2CHCH2 | OH | OH | CH3 |
CH2CHCH2 | OH | OAc | CH3 |
CH2CHCH2 | OH | OCH3 | CH3 |
CH2CHCH2 | OAc | OH | CH3 |
CH2CHCH2 | OAc | OAc | CH3 |
CH2CHCH2 | OAc | OCH3 | CH3 |
CH2CHCH2 | OCH3 | OH | CH3 |
CH2CHCH2 | OCH3 | OAc | CH3 |
CH2CHCH2 | OCH3 | OCH3 | CH3 |
CH2CHCH2 | OH | OH | C2H5 |
CH2CHCH2 | OH | OH | n-C3H7 |
CH2CHCH2 | OH | OH | i-C3H7 |
CH2CHCH2 | OH | OH | n-C4H9 |
CH2CHCH2 | OH | OH | i-C4H9 |
CH2CHCH2 | OH | OAc | C2H5 |
PhCH2CH2 | OH | OH | CH3 |
PhCH2CH2 | OH | OAc | CH3 |
PhCH2CH2 | OH | OCH3 | CH3 |
PhCH2CH2 | OAc | OH | CH3 |
PhCH2CH2 | OAc | OAc | CH3 |
PhCH2CH2 | OAc | OCH3 | CH3 |
PhCH2CH2 | OCH3 | OH | CH3 |
PhCH2CH2 | OCH3 | OAc | CH3 |
PhCH2CH2 | OCH3 | OCH3 | CH3 |
PhCH2CH2 | OH | OH | C2H5 |
PhCH2CH2 | OH | OH | n-C3H7 |
PhCH2CH2 | OH | OH | i-C3H7 |
PhCH2CH2 | OH | OH | n-C4H9 |
PhCH2CH2 | OH | OH | i-C4H9 |
PhCH2CH2 | OH | OAc | C2H5 |
表2(续)
R1 | R2 | R3 | R4 |
C3H5CH2 | OH | OAc | CH3 |
C3H5CH2 | OH | OCH3 | CH3 |
C3H5CH2 | OH | H | CH3 |
C3H5CH2 | OAc | OH | CH3 |
C3H5CH2 | OAc | OAc | CH3 |
C3H5CH2 | OAc | OCH3 | CH3 |
C3H5CH2 | OAc | H | CH3 |
C3H5CH2 | OCH3 | OH | CH3 |
C3H5CH2 | OCH3 | OAc | CH3 |
C3H5CH2 | OCH3 | OCH3 | CH3 |
C3H5CH2 | OCH3 | H | CH3 |
C3H5CH2 | OH | OAc | C2H5 |
C3H5CH2 | OH | OAc | n-C3H7 |
C3H5CH2 | OH | OAc | i-C3H5 |
C3H5CH2 | OH | OCH3 | C2H5 |
C3H5CH2 | OH | OCH3 | n-C3H7 |
CH3 | OH | OH | CH3 |
CH3 | OH | OAc | CH3 |
CH3 | OH | OCH3 | CH3 |
CH3 | OAc | OH | CH3 |
CH3 | OAc | OAc | CH3 |
CH3 | OAc | OCH3 | CH3 |
CH3 | OCH3 | OH | CH3 |
CH3 | OCH3 | OAc | CH3 |
CH3 | OCH3 | OCH3 | CH3 |
CH3 | OH | OH | C2H5 |
CH3 | OH | OH | n-C3H7 |
CH3 | OH | OH | i-C3H7 |
CH3 | OH | OH | n-C4H9 |
CH3 | OH | OH | i-C4H9 |
CH3 | OH | OAc | C2H5 |
R1 | R2 | R3 | R4 |
CH2CHCH2 | OH | OH | CH3 |
CH2CHCH2 | OH | OAc | CH3 |
CH2CHCH2 | OH | OCH3 | CH3 |
CH2CHCH2 | OAc | OH | CH3 |
CH2CHCH2 | OAc | OAc | CH3 |
CH2CHCH2 | OAc | OCH3 | CH3 |
CH2CHCH2 | OCH3 | OH | CH3 |
CH2CHCH2 | OCH3 | OAc | CH3 |
CH2CHCH2 | OCH3 | OCH3 | CH3 |
CH2CHCH2 | OH | OH | C2H5 |
CH2CHCH2 | OH | OH | n-C3H7 |
CH2CHCH2 | OH | OH | i-C3H7 |
CH2CHCH2 | OH | OH | n-C4H9 |
CH2CHCH2 | OH | OH | i-C4H9 |
CH2CHCH2 | OH | OAc | C2H5 |
PhCH2CH2 | OH | OH | CH3 |
PhCH2CH2 | OH | OAc | CH3 |
PhCH2CH2 | OH | OCH3 | CH3 |
PhCH2CH2 | OAc | OH | CH3 |
PhCH2CH2 | OAc | OAc | CH3 |
PhCH2CH2 | OAc | OCH3 | CH3 |
PhCH2CH2 | OCH3 | OH | CH3 |
PhCH2CH2 | OCH3 | OAc | CH3 |
PhCH2CH2 | OCH3 | OCH3 | CH3 |
PhCH2CH2 | OH | OH | C2H5 |
PhCH2CH2 | OH | OH | n-C3H7 |
PhCH2CH2 | OH | OH | i-C3H7 |
PhCH2CH2 | OH | OH | n-C4H9 |
PhCH2CH2 | OH | OH | i-C4H9 |
PhCH2CH2 | OH | OAc | C2H5 |
表2(续)
R1 | R2 | R3 | R4 |
H | H | H | CH3 |
H | H | H | C2H5 |
H | H | H | n-C3H7 |
H | H | H | i-C3H7 |
H | H | H | n-C4H9 |
H | H | H | i-C4H9 |
CH3 | H | H | CH3 |
H | CH3 | H | CH3 |
H | H | CH3 | CH3 |
CH3 | H | H | C2H5 |
Cl | H | H | CH3 |
H | Cl | H | CH3 |
H | H | Cl | CH3 |
Cl | H | H | C2H5 |
Br | H | H | CH3 |
H | Br | H | CH3 |
H | H | Br | CH3 |
Br | H | H | C2H5 |
F | H | H | CH3 |
H | F | H | CH3 |
H | H | F | CH3 |
F | H | H | C2H5 |
CF3 | H | H | CH3 |
H | CF3 | H | CH3 |
H | H | CF3 | CH3 |
CF3 | H | H | C2H5 |
CN | H | H | CH3 |
H | CN | H | CH3 |
H | H | CN | CH3 |
CN | H | H | C2H5 |
R1 | R2 | R3 | R4 |
H | H | H | CH3 |
H | H | H | C2H5 |
H | H | H | n-C3H7 |
H | H | H | i-C3H7 |
H | H | H | n-C4H9 |
H | H | H | i-C4H9 |
CH3 | H | H | CH3 |
H | CH3 | H | CH3 |
H | H | CH3 | CH3 |
CH3 | H | H | C2H5 |
Cl | H | H | CH3 |
H | Cl | H | CH3 |
H | H | Cl | CH3 |
Cl | H | H | C2H5 |
Br | H | H | CH3 |
H | Br | H | CH3 |
H | H | Br | CH3 |
Br | H | H | C2H5 |
F | H | H | CH3 |
H | F | H | CH3 |
H | H | F | CH3 |
F | H | H | C2H5 |
CF3 | H | H | CH3 |
H | CF3 | H | CH3 |
H | H | CF3 | CH3 |
CF3 | H | H | C2H5 |
CN | H | H | CH3 |
H | CN | H | CH3 |
H | H | CN | CH3 |
CN | H | H | C2H5 |
表2(续)
R1 | R2 | R3 | R4 |
H | H | H | CH3 |
H | H | H | C2H5 |
CH3 | H | H | CH3 |
H | CH3 | H | CH3 |
H | H | CH3 | CH3 |
H | CH3 | CH3 | CH3 |
H | CH3 | H | C2H5 |
H | CH3 | H | n-C3H7 |
H | CH3 | H | i-C3H7 |
H | CH3 | H | n-C4H9 |
H | CH3 | H | i-C4H9 |
OCH3 | H | H | CH3 |
H | OCH3 | H | CH3 |
H | H | OCH3 | CH3 |
H | OCH3 | OCH3 | CH3 |
H | OCH3 | H | C2H5 |
H | OCH3 | H | n-C3H7 |
H | OCH3 | H | i-C3H7 |
H | OCH3 | H | n-C4H9 |
H | OCH3 | H | i-C4H9 |
OH | H | H | CH3 |
H | OH | H | CH3 |
H | H | OH | CH3 |
Cl | H | H | CH3 |
H | Cl | H | CH3 |
H | H | Cl | CH3 |
H | Cl | Cl | CH3 |
H | Cl | Cl | C2H5 |
H | Cl | Cl | n-C3H7 |
H | Cl | Cl | n-C4H9 |
R1 | R2 | R3 | R4 |
Br | H | H | CH3 |
H | Br | H | CH3 |
H | H | Br | CH3 |
H | Br | Br | CH3 |
H | Br | Br | C2H5 |
F | H | H | CH3 |
H | F | H | CH3 |
H | H | F | CH3 |
H | F | F | CH3 |
H | F | F | C2H5 |
NO2 | H | H | CH3 |
H | NO2 | H | CH3 |
H | H | NO2 | CH3 |
CF3 | H | H | CH3 |
H | CF3 | H | CH3 |
H | H | CF3 | CH3 |
H | H | CF3 | C2H5 |
H | H | CF3 | n-C3H7 |
H | H | CH3 | i-C3H7 |
H | H | CF3 | n-C4H9 |
H | H | CF3 | i-C4H9 |
OCF3 | H | H | CH3 |
H | OCF3 | H | CH3 |
H | H | OCF3 | CH3 |
H | OCF3 | H | C2H5 |
H | OCF3 | H | n-C3H7 |
H | OCF3 | H | i-C3H7 |
H | OCF3 | H | n-C4H9 |
H | OCF3 | H | i-C4H9 |
表2(续)
R1 | R2 | R3 | R4 |
H | H | H | CH3 |
H | H | H | C2H5 |
CH3 | H | H | CH3 |
H | CH3 | H | CH3 |
H | H | CH3 | CH3 |
H | CH3 | CH3 | CH3 |
H | CH3 | H | C2H5 |
H | CH3 | H | n-C3H7 |
H | CH3 | H | i-C3H7 |
H | CH3 | H | n-C4H9 |
H | CH3 | H | i-C4H9 |
OCH3 | H | H | CH3 |
H | OCH3 | H | CH3 |
H | H | OCH3 | CH3 |
H | OCH3 | OCH3 | CH3 |
H | OCH3 | H | C2H5 |
H | OCH3 | H | n-C3H7 |
H | OCH3 | H | i-C3H7 |
H | OCH3 | H | n-C4H9 |
H | OCH3 | H | i-C4H9 |
OH | H | H | CH3 |
H | OH | H | CH3 |
H | H | OH | CH3 |
Cl | H | H | CH3 |
H | Cl | H | CH3 |
H | H | Cl | CH3 |
H | Cl | Cl | CH3 |
H | Cl | Cl | C2H5 |
H | Cl | Cl | n-C3H7 |
H | Cl | Cl | n-C4H9 |
R1 | R2 | R3 | R4 |
Br | H | H | CH3 |
H | Br | H | CH3 |
H | H | Br | CH3 |
H | Br | Br | CH3 |
H | Br | Br | C2H5 |
F | H | H | CH3 |
H | F | H | CH3 |
H | H | F | CH3 |
H | F | F | CH3 |
H | F | F | C2H5 |
NO2 | H | H | CH3 |
H | NO2 | H | CH3 |
H | H | NO2 | CH3 |
CF3 | H | H | CH3 |
H | CF3 | H | CH3 |
H | H | CF3 | CH3 |
H | H | CF3 | C2H5 |
H | H | CF3 | n-C3H7 |
H | H | CH3 | i-C3H7 |
H | H | CF3 | n-C4H9 |
H | H | CF3 | i-C4H9 |
OCF3 | H | H | CH3 |
H | OCF3 | H | CH3 |
H | H | OCF3 | CH3 |
H | OCF3 | H | C2H5 |
H | OCF3 | H | n-C3H7 |
H | OCF3 | H | i-C3H7 |
H | OCF3 | H | n-C4H9 |
H | OCF3 | H | i-C4H9 |
表2(续)
R1 | R2 | R3 | R4 |
C3H5CH2 | OH | OAc | CH3 |
C3H5CH2 | OH | OCH3 | CH3 |
C3H5CH2 | OH | H | CH3 |
C3H5CH2 | OAc | OH | CH3 |
C3H5CH2 | OAc | OAc | CH3 |
C3H5CH2 | OAc | OCH3 | CH3 |
C3H5CH2 | OAc | H | CH3 |
C3H5CH2 | OCH3 | OH | CH3 |
C3H5CH2 | OCH3 | OAc | CH3 |
C3H5CH2 | OCH3 | OCH3 | CH3 |
C3H5CH2 | OCH3 | H | CH3 |
C3H5CH2 | OH | OAc | C2H5 |
C3H5CH2 | OH | OAc | n-C3H7 |
C3H5CH2 | OH | OAc | i-C3H5 |
C3H5CH2 | OH | OCH3 | C2H5 |
C3H5CH2 | OH | OCH3 | n-C3H7 |
CH3 | OH | OH | CH3 |
CH3 | OH | OAc | CH3 |
CH3 | OH | OCH3 | CH3 |
CH3 | OAc | OH | CH3 |
CH3 | OAc | OAc | CH3 |
CH3 | OAc | OCH3 | CH3 |
CH3 | OCH3 | OH | CH3 |
CH3 | OCH3 | OAc | CH3 |
CH3 | OCH3 | OCH3 | CH3 |
CH3 | OH | OH | C2H5 |
CH3 | OH | OH | n-C3H7 |
CH3 | OH | OH | i-C3H7 |
CH3 | OH | OH | n-C4H9 |
CH3 | OH | OH | i-C4H9 |
CH3 | OH | OAc | C2H5 |
R1 | R2 | R3 | R4 |
CH2CHCH2 | OH | OH | CH3 |
CH2CHCH2 | OH | OAc | CH3 |
CH2CHCH2 | OH | OCH3 | CH3 |
CH2CHCH2 | OAc | OH | CH3 |
CH2CHCH2 | OAc | OAc | CH3 |
CH2CHCH2 | OAc | OCH3 | CH3 |
CH2CHCH2 | OCH3 | OH | CH3 |
CH2CHCH2 | OCH3 | OAc | CH3 |
CH2CHCH2 | OCH3 | OCH3 | CH3 |
CH2CHCH2 | OH | OH | C2H5 |
CH2CHCH2 | OH | OH | n-C3H7 |
CH2CHCH2 | OH | OH | i-C3H7 |
CH2CHCH2 | OH | OH | n-C4H9 |
CH2CHCH2 | OH | OH | i-C4H9 |
CH2CHCH2 | OH | OAc | C2H5 |
PhCH2CH2 | OH | OH | CH3 |
PhCH2CH2 | OH | OAc | CH3 |
PhCH2CH2 | OH | OCH3 | CH3 |
PhCH2CH2 | OAc | OH | CH3 |
PhCH2CH2 | OAc | OAc | CH3 |
PhCH2CH2 | OAc | OCH3 | CH3 |
PhCH2CH2 | OCH3 | OH | CH3 |
PhCH2CH2 | OCH3 | OAc | CH3 |
PhCH2CH2 | OCH3 | OCH3 | CH3 |
PhCH2CH2 | OH | OH | C2H5 |
PhCH2CH2 | OH | OH | n-C3H7 |
PhCH2CH2 | OH | OH | i-C3H7 |
PhCH2CH2 | OH | OH | n-C4H9 |
PhCH2CH2 | OH | OH | i-C4H9 |
PhCH2CH2 | OH | OAc | C2H5 |
表2(续)
R1 | R2 | R3 | R4 |
C3H5CH2 | OH | OAc | CH3 |
C3H5CH2 | OH | OCH3 | CH3 |
C3H5CH2 | OH | H | CH3 |
C3H5CH2 | OAc | OH | CH3 |
C3H5CH2 | OAc | OAc | CH3 |
C3H5CH2 | OAc | OCH3 | CH3 |
C3H5CH2 | OAc | H | CH3 |
C3H5CH2 | OCH3 | OH | CH3 |
C3H5CH2 | OCH3 | OAc | CH3 |
C3H5CH2 | OCH3 | OCH3 | CH3 |
C3H5CH2 | OCH3 | H | CH3 |
C3H5CH2 | OH | OAc | C2H5 |
C3H5CH2 | OH | OAc | n-C3H7 |
C3H5CH2 | OH | OAc | i-C3H5 |
C3H5CH2 | OH | OCH3 | C2H5 |
C3H5CH2 | OH | OCH3 | n-C3H7 |
CH3 | OH | OH | CH3 |
CH3 | OH | OAc | CH3 |
CH3 | OH | OCH3 | CH3 |
CH3 | OAc | OH | CH3 |
CH3 | OAc | OAc | CH3 |
CH3 | OAc | OCH3 | CH3 |
CH3 | OCH3 | OH | CH3 |
CH3 | OCH3 | OAc | CH3 |
CH3 | OCH3 | OCH3 | CH3 |
CH3 | OH | OH | C2H5 |
CH3 | OH | OH | n-C3H7 |
CH3 | OH | OH | i-C3H7 |
CH3 | OH | OH | n-C4H9 |
CH3 | OH | OH | i-C4H9 |
CH3 | OH | OAc | C2H5 |
R1 | R2 | R3 | R4 |
CH2CHCH2 | OH | OH | CH3 |
CH2CHCH2 | OH | OAc | CH3 |
CH2CHCH2 | OH | OCH3 | CH3 |
CH2CHCH2 | OAc | OH | CH3 |
CH2CHCH2 | OAc | OAc | CH3 |
CH2CHCH2 | OAc | OCH3 | CH3 |
CH2CHCH2 | OCH3 | OH | CH3 |
CH2CHCH2 | OCH3 | OAc | CH3 |
CH2CHCH2 | OCH3 | OCH3 | CH3 |
CH2CHCH2 | OH | OH | C2H5 |
CH2CHCH2 | OH | OH | n-C3H7 |
CH2CHCH2 | OH | OH | i-C3H7 |
CH2CHCH2 | OH | OH | n-C4H9 |
CH2CHCH2 | OH | OH | i-C4H9 |
CH2CHCH2 | OH | OAc | C2H5 |
PhCH2CH2 | OH | OH | CH3 |
PhCH2CH2 | OH | OAc | CH3 |
PhCH2CH2 | OH | OCH3 | CH3 |
PhCH2CH2 | OAc | OH | CH3 |
PhCH2CH2 | OAc | OAc | CH3 |
PhCH2CH2 | OAc | OCH3 | CH3 |
PhCH2CH2 | OCH3 | OH | CH3 |
PhCH2CH2 | OCH3 | OAc | CH3 |
PhCH2CH2 | OCH3 | OCH3 | CH3 |
PhCH2CH2 | OH | OH | C2H5 |
PhCH2CH2 | OH | OH | n-C3H7 |
PhCH2CH2 | OH | OH | i-C3H7 |
PhCH2CH2 | OH | OH | n-C4H9 |
PhCH2CH2 | OH | OH | i-C4H9 |
PhCH2CH2 | OH | OAc | C2H5 |
表2(续)
R1 | R2 | R3 | R4 |
H | H | H | CH3 |
H | H | H | C2H5 |
CH3 | H | H | CH3 |
H | CH3 | H | CH3 |
H | H | CH3 | CH3 |
H | CH3 | CH3 | CH3 |
H | CH3 | H | C2H5 |
H | CH3 | H | n-C3H7 |
H | CH3 | H | i-C3H7 |
H | CH3 | H | n-C4H9 |
H | CH3 | H | i-C4H9 |
OCH3 | H | H | CH3 |
H | OCH3 | H | CH3 |
H | H | OCH3 | CH3 |
H | OCH3 | OCH3 | CH3 |
H | OCH3 | H | C2H5 |
H | OCH3 | H | n-C3H7 |
H | OCH3 | H | i-C3H7 |
H | OCH3 | H | n-C4H9 |
H | OCH3 | H | i-C4H9 |
OH | H | H | CH3 |
H | OH | H | CH3 |
H | H | OH | CH3 |
Cl | H | H | CH3 |
H | Cl | H | CH3 |
H | H | Cl | CH3 |
H | Cl | Cl | CH3 |
H | Cl | Cl | C2H5 |
H | Cl | Cl | n-C3H7 |
H | Cl | Cl | n-C4H9 |
R1 | R2 | R3 | R4 |
Br | H | H | CH3 |
H | Br | H | CH3 |
H | H | Br | CH3 |
H | Br | Br | CH3 |
H | Br | Br | C2H5 |
F | H | H | CH3 |
H | F | H | CH3 |
H | H | F | CH3 |
H | F | F | CH3 |
H | F | F | C2H5 |
NO2 | H | H | CH3 |
H | NO2 | H | CH3 |
H | H | NO2 | CH3 |
CF3 | H | H | CH3 |
H | CF3 | H | CH3 |
H | H | CF3 | CH3 |
H | H | CF3 | C2H5 |
H | H | CF3 | n-C3H7 |
H | H | CH3 | i-C3H7 |
H | H | CF3 | n-C4H9 |
H | H | CF3 | i-C4H9 |
OCF3 | H | H | CH3 |
H | OCF3 | H | CH3 |
H | H | OCF3 | CH3 |
H | OCF3 | H | C2H5 |
H | OCF3 | H | n-C3H7 |
H | OCF3 | H | i-C3H7 |
H | OCF3 | H | n-C4H9 |
H | OCF3 | H | i-C4H9 |
表2(续)
R1 | R2 | R3 | R4 |
H | H | H | CH3 |
H | H | H | C2H5 |
CH3 | H | H | CH3 |
H | CH3 | H | CH3 |
H | H | CH3 | CH3 |
H | CH3 | CH3 | CH3 |
H | CH3 | H | C2H5 |
H | CH3 | H | n-C3H7 |
H | CH3 | H | i-C3H7 |
H | CH3 | H | n-C4H9 |
H | CH3 | H | i-C4H9 |
OCH3 | H | H | CH3 |
H | OCH3 | H | CH3 |
H | H | OCH3 | CH3 |
H | OCH3 | OCH3 | CH3 |
H | OCH3 | H | C2H5 |
H | OCH3 | H | n-C3H7 |
H | OCH3 | H | i-C3H7 |
H | OCH3 | H | n-C4H9 |
H | OCH3 | H | i-C4H9 |
OH | H | H | CH3 |
H | OH | H | CH3 |
H | H | OH | CH3 |
Cl | H | H | CH3 |
H | Cl | H | CH3 |
H | H | Cl | CH3 |
H | Cl | Cl | CH3 |
H | Cl | Cl | C2H5 |
H | Cl | Cl | n-C3H7 |
H | Cl | Cl | n-C4H9 |
R1 | R2 | R3 | R4 |
Br | H | H | CH3 |
H | Br | H | CH3 |
H | H | Br | CH3 |
H | Br | Br | CH3 |
H | Br | Br | C2H5 |
F | H | H | CH3 |
H | F | H | CH3 |
H | H | F | CH3 |
H | F | F | CH3 |
H | F | F | C2H5 |
NO2 | H | H | CH3 |
H | NO2 | H | CH3 |
H | H | NO2 | CH3 |
CF3 | H | H | CH3 |
H | CF3 | H | CH3 |
H | H | CF3 | CH3 |
H | H | CF3 | C2H5 |
H | H | CF3 | n-C3H7 |
H | H | CH3 | i-C3H7 |
H | H | CF3 | n-C4H9 |
H | H | CF3 | i-C4H9 |
OCF3 | H | H | CH3 |
H | OCF3 | H | CH3 |
H | H | OCF3 | CH3 |
H | OCF3 | H | C2H5 |
H | OCF3 | H | n-C3H7 |
H | OCF3 | H | i-C3H7 |
H | OCF3 | H | n-C4H9 |
H | OCF3 | H | i-C4H9 |
表2(续)
R1 | R2 | R3 | R4 |
C3H5CH2 | OH | OAc | CH3 |
C3H5CH2 | OH | OCH3 | CH3 |
C3H5CH2 | OH | H | CH3 |
C3H5CH2 | OAc | OH | CH3 |
C3H5CH2 | OAc | OAc | CH3 |
C3H5CH2 | OAc | OCH3 | CH3 |
C3H5CH2 | OAc | H | CH3 |
C3H5CH2 | OCH3 | OH | CH3 |
C3H5CH2 | OCH3 | OAc | CH3 |
C3H5CH2 | OCH3 | OCH3 | CH3 |
C3H5CH2 | OCH3 | H | CH3 |
C3H5CH2 | OH | OAc | C2H5 |
C3H5CH2 | OH | OAc | n-C3H7 |
C3H5CH2 | OH | OAc | i-C3H5 |
C3H5CH2 | OH | OCH3 | C2H5 |
C3H5CH2 | OH | OCH3 | n-C3H7 |
CH3 | OH | OH | CH3 |
CH3 | OH | OAc | CH3 |
CH3 | OH | OCH3 | CH3 |
CH3 | OAc | OH | CH3 |
CH3 | OAc | OAc | CH3 |
CH3 | OAc | OCH3 | CH3 |
CH3 | OCH3 | OH | CH3 |
CH3 | OCH3 | OAc | CH3 |
CH3 | OCH3 | OCH3 | CH3 |
CH3 | OH | OH | C2H5 |
CH3 | OH | OH | n-C3H7 |
CH3 | OH | OH | i-C3H7 |
CH3 | OH | OH | n-C4H9 |
CH3 | OH | OH | i-C4H9 |
CH3 | OH | OAc | C2H5 |
R1 | R2 | R3 | R4 |
CH2CHCH2 | OH | OH | CH3 |
CH2CHCH2 | OH | OAc | CH3 |
CH2CHCH2 | OH | OCH3 | CH3 |
CH2CHCH2 | OAc | OH | CH3 |
CH2CHCH2 | OAc | OAc | CH3 |
CH2CHCH2 | OAc | OCH3 | CH3 |
CH2CHCH2 | OCH3 | OH | CH3 |
CH2CHCH2 | OCH3 | OAc | CH3 |
CH2CHCH2 | OCH3 | OCH3 | CH3 |
CH2CHCH2 | OH | OH | C2H5 |
CH2CHCH2 | OH | OH | n-C3H7 |
CH2CHCH2 | OH | OH | i-C3H7 |
CH2CHCH2 | OH | OH | n-C4H9 |
CH2CHCH2 | OH | OH | i-C4H9 |
CH2CHCH2 | OH | OAc | C2H5 |
PhCH2CH2 | OH | OH | CH3 |
PhCH2CH2 | OH | OAc | CH3 |
PhCH2CH2 | OH | OCH3 | CH3 |
PhCH2CH2 | OAc | OH | CH3 |
PhCH2CH2 | OAc | OAc | CH3 |
PhCH2CH2 | OAc | OCH3 | CH3 |
PhCH2CH2 | OCH3 | OH | CH3 |
PhCH2CH2 | OCH3 | OAc | CH3 |
PhCH2CH2 | OCH3 | OCH3 | CH3 |
PhCH2CH2 | OH | OH | C2H5 |
PhCH2CH2 | OH | OH | n-C3H7 |
PhCH2CH2 | OH | OH | i-C3H7 |
PhCH2CH2 | OH | OH | n-C4H9 |
PhCH2CH2 | OH | OH | i-C4H9 |
PhCH2CH2 | OH | OH | C2H5 |
表2(续)
R1 | R2 | R3 | R4 |
C3H5CH2 | OH | OAc | CH3 |
C3H5CH2 | OH | OCH3 | CH3 |
C3H5CH2 | OH | H | CH3 |
C3H5CH2 | OAc | OH | CH3 |
C3H5CH2 | OAc | OAc | CH3 |
C3H5CH2 | OAc | OCH3 | CH3 |
C3H5CH2 | OAc | H | CH3 |
C3H5CH2 | OCH3 | OH | CH3 |
C3H5CH2 | OCH3 | OAc | CH3 |
C3H5CH2 | OCH3 | OCH3 | CH3 |
C3H5CH2 | OCH3 | H | CH3 |
C3H5CH2 | OH | OAc | C2H5 |
C3H5CH2 | OH | OAc | n-C3H7 |
C3H5CH2 | OH | OAc | i-C3H5 |
C3H5CH2 | OH | OCH3 | C2H5 |
C3H5CH2 | OH | OCH3 | n-C3H7 |
CH3 | OH | OH | CH3 |
CH3 | OH | OAc | CH3 |
CH3 | OH | OCH3 | CH3 |
CH3 | OAc | OH | CH3 |
CH3 | OAc | OAc | CH3 |
CH3 | OAc | OCH3 | CH3 |
CH3 | OCH3 | OH | CH3 |
CH3 | OCH3 | OAc | CH3 |
CH3 | OCH3 | OCH3 | CH3 |
CH3 | OH | OH | C2H5 |
CH3 | OH | OH | n-C3H7 |
CH3 | OH | OH | i-C3H7 |
CH3 | OH | OH | n-C4H9 |
CH3 | OH | OH | i-C4H9 |
CH3 | OH | OAc | C2H5 |
R1 | R2 | R3 | R4 |
CH2CHCH2 | OH | OH | CH3 |
CH2CHCH2 | OH | OAc | CH3 |
CH2CHCH2 | OH | OCH3 | CH3 |
CH2CHCH2 | OAc | OH | CH3 |
CH2CHCH2 | OAc | OAc | CH3 |
CH2CHCH2 | OAc | OCH3 | CH3 |
CH2CHCH2 | OCH3 | OH | CH3 |
CH2CHCH2 | OCH3 | OAc | CH3 |
CH2CHCH2 | OCH3 | OCH3 | CH3 |
CH2CHCH2 | OH | OH | C2H5 |
CH2CHCH2 | OH | OH | n-C3H7 |
CH2CHCH2 | OH | OH | i-C3H7 |
CH2CHCH2 | OH | OH | n-C4H9 |
CH2CHCH2 | OH | OH | i-C4H9 |
CH2CHCH2 | OH | OAc | C2H5 |
PhCH2CH2 | OH | OH | CH3 |
PhCH2CH2 | OH | OAc | CH3 |
PhCH2CH2 | OH | OCH3 | CH3 |
PhCH2CH2 | OAc | OH | CH3 |
PhCH2CH2 | OAc | OAc | CH3 |
PhCH2CH2 | OAc | OCH3 | CH3 |
PhCH2CH2 | OCH3 | OH | CH3 |
PhCH2CH2 | OCH3 | OAc | CH3 |
PhCH2CH2 | OCH3 | OCH3 | CH3 |
PhCH2CH2 | OH | OH | C2H5 |
PhCH2CH2 | OH | OH | n-C3H7 |
PhCH2CH2 | OH | OH | i-C3H7 |
PhCH2CH2 | OH | OH | n-C4H9 |
PhCH2CH2 | OH | OH | i-C4H9 |
PhCH2CH2 | OH | OAc | C2H5 |
表2(续)
R1 | R2 | R3 | R4 |
C3H5CH2 | OH | OAc | CH3 |
C3H5CH2 | OH | OCH3 | CH3 |
C3H5CH2 | OH | H | CH3 |
C3H5CH2 | OAc | OH | CH3 |
C3H5CH2 | OAc | OAc | CH3 |
C3H5CH2 | OAc | OCH3 | CH3 |
C3H5CH2 | OAc | H | CH3 |
C3H5CH2 | OCH3 | OH | CH3 |
C3H5CH2 | OCH3 | OAc | CH3 |
C3H5CH2 | OCH3 | OCH3 | CH3 |
C3H5CH2 | OCH3 | H | CH3 |
C3H5CH2 | OH | OAc | C2H5 |
C3H5CH2 | OH | OAc | n-C3H7 |
C3H5CH2 | OH | OAc | i-C3H5 |
C3H5CH2 | OH | OCH3 | C2H5 |
C3H5CH2 | OH | OCH3 | n-C3H7 |
CH3 | OH | OH | CH3 |
CH3 | OH | OAc | CH3 |
CH3 | OH | OCH3 | CH3 |
CH3 | OAc | OH | CH3 |
CH3 | OAc | OAc | CH3 |
CH3 | OAc | OCH3 | CH3 |
CH3 | OCH3 | OH | CH3 |
CH3 | OCH3 | OAc | CH3 |
CH3 | OCH3 | OCH3 | CH3 |
CH3 | OH | OH | C2H5 |
CH3 | OH | OH | n-C3H7 |
CH3 | OH | OH | i-C3H7 |
CH3 | OH | OH | n-C4H9 |
CH3 | OH | OH | i-C4H9 |
CH3 | OH | OAc | C2H5 |
R1 | R2 | R3 | R4 |
CH2CHCH2 | OH | OH | CH3 |
CH2CHCH2 | OH | OAc | CH3 |
CH2CHCH2 | OH | OCH3 | CH3 |
CH2CHCH2 | OAc | OH | CH3 |
CH2CHCH2 | OAc | OAc | CH3 |
CH2CHCH2 | OAc | OCH3 | CH3 |
CH2CHCH2 | OCH3 | OH | CH3 |
CH2CHCH2 | OCH3 | OAc | CH3 |
CH2CHCH2 | OCH3 | OCH3 | CH3 |
CH2CHCH2 | OH | OH | C2H5 |
CH2CHCH2 | OH | OH | n-C3H7 |
CH2CHCH2 | OH | OH | i-C3H7 |
CH2CHCH2 | OH | OH | n-C4H9 |
CH2CHCH2 | OH | OH | i-C4H9 |
CH2CHCH2 | OH | OAc | C2H5 |
PHCH2CH2 | OH | OH | CH3 |
PhCH2CH2 | OH | OAc | CH3 |
PhCH2CH2 | OH | OCH3 | CH3 |
PhCH2CH2 | OAc | OH | CH3 |
PhCH2CH2 | OAc | OAc | CH3 |
PhCH2CH2 | OAc | OCH3 | CH3 |
PhCH2CH2 | OCH3 | OH | CH3 |
PhCH2CH2 | OCH3 | OAc | CH3 |
PhCH2CH2 | OCH3 | OCH3 | CH3 |
PhCH2CH2 | OH | OH | C2H5 |
PhCH2CH2 | OH | OH | n-C3H7 |
PhCH2CH2 | OH | OH | i-C3H7 |
PhCH2CH2 | OH | OH | n-C4H9 |
PhCH2CH2 | OH | OH | i-C4H9 |
PhCH2CH2 | OH | OAc | C2H5 |
表2(续)
R1 | R2 | R3 | R4 |
C3H5CH2 | OH | OAc | CH3 |
C3H5CH2 | OH | OCH3 | CH3 |
C3H5CH2 | OH | H | CH3 |
C3H5CH2 | OAc | OH | CH3 |
C3H5CH2 | OAc | OAc | CH3 |
C3H5CH2 | OAc | OCH3 | CH3 |
C3H5CH2 | OAc | H | CH3 |
C3H5CH2 | OCH3 | OH | CH3 |
C3H5CH2 | OCH3 | OAc | CH3 |
C3H5CH2 | OCH3 | OCH3 | CH3 |
C3H5CH2 | OCH3 | H | CH3 |
C3H5CH2 | OH | OAc | C2H5 |
C3H5CH2 | OH | OAc | n-C3H7 |
C3H5CH2 | OH | OAc | i-C3H5 |
C3H5CH2 | OH | OCH3 | C2H5 |
C3H5CH2 | OH | OCH3 | n-C3H7 |
CH3 | OH | OH | CH3 |
CH3 | OH | OAc | CH3 |
CH3 | OH | OCH3 | CH3 |
CH3 | OAc | OH | CH3 |
CH3 | OAc | OAc | CH3 |
CH3 | OAc | OCH3 | CH3 |
CH3 | OCH3 | OH | CH3 |
CH3 | OCH3 | OAc | CH3 |
CH3 | OCH3 | OCH3 | CH3 |
CH3 | OH | OH | C2H5 |
CH3 | OH | OH | n-C3H7 |
CH3 | OH | OH | i-C3H7 |
CH3 | OH | OH | n-C4H9 |
CH3 | OH | OH | i-C4H9 |
CH3 | OH | OAc | C2H5 |
R1 | R2 | R3 | R4 |
CH2CHCH2 | OH | OH | CH3 |
CH2CHCH2 | OH | OAc | CH3 |
CH2CHCH2 | OH | OCH3 | CH3 |
CH2CHCH2 | OAc | OH | CH3 |
CH2CHCH2 | OAc | OAc | CH3 |
CH2CHCH2 | OAc | OCH3 | CH3 |
CH2CHCH2 | OCH3 | OH | CH3 |
CH2CHCH2 | OCH3 | OAc | CH3 |
CH2CHCH2 | OCH3 | OCH3 | CH3 |
CH2CHCH2 | OH | OH | C2H5 |
CH2CHCH2 | OH | OH | n-C3H7 |
CH2CHCH2 | OH | OH | i-C3H7 |
CH2CHCH2 | OH | OH | n-C4H9 |
CH2CHCH2 | OH | OH | i-C4H9 |
CH2CHCH2 | OH | OAc | C2H5 |
PhCH2CH2 | OH | OH | CH3 |
PhCH2CH2 | OH | OAc | CH3 |
PhCH2CH2 | OH | OCH3 | CH3 |
PhCH2CH2 | OAc | OH | CH3 |
PhCH2CH2 | OAc | OAc | CH3 |
PhCH2CH2 | OAc | OCH3 | CH3 |
PhCH2CH2 | OCH3 | OH | CH3 |
PhCH2CH2 | OCH3 | OAc | CH3 |
PhCH2CH2 | OCH3 | OCH3 | CH3 |
PhCH2CH2 | OH | OH | C2H5 |
PhCH2CH2 | OH | OH | n-C3H7 |
PhCH2CH2 | OH | OH | i-C3H7 |
PhCH2CH2 | OH | OH | n-C4H9 |
PhCH2CH2 | OH | OH | i-C4H9 |
PhCH2CH2 | OH | OAc | C2H5 |
本发明式(III)化合物可具体按照下列方法制备。
通常,如示意图2所示,该式(III)化合物是由通式(IX)(R1、R2、R3、R4、R5及A的定义同通式(III))表示的17位叔胺与间氯过苯甲酸、过甲酸、过乙酸、过苯甲酸、三氟过乙酸、过马来酸、和过苯二甲酸等的有机过氧酸经氧化步骤制得,但氧化剂并不局限于此。
[示意图2]
17位带有叔胺的式(IX)可按照日本特许公报2525552公开的方法制备。许多氧化剂都适宜将式(IX)17位叔胺转化为叔胺N-氧化物(III)。间氯过苯甲酸因其生成N-氧化物时的反应较快而成为常用氧化剂。然而也可以采用例如过甲酸、过乙酸、过苯甲酸、三氟过乙酸盐、过马来酸和过苯二甲酸等的其他有机过氧酸。另一方面还可利用反应体系中产生的氧化剂:将叔胺溶解在酸例如甲酸、乙酸或三氟乙酸中,并再加入浓度为3-50%或更优选30-50%的含水过氧化氢。就溶剂而言,可用作反应介质的是:卤代溶剂,例如二氯甲烷、氯仿或1,2-二氯乙烷的;芳香族溶剂,例如苯,甲苯;醚溶剂,例如***或四氢呋喃;醇溶剂,例如甲醇、乙醇、丙醇或叔丁醇。或者,当氧化剂在反应体系中生成时可将相应适宜的酸作为反应介质。
除上述有机过氧酸外还可使用如过氧化氢等的过氧化物。含水过氧化氢可以3-50%的浓度单独使用或将其在上述溶剂中使用。其它适用的氧化剂包括臭氧、叔丁基过氧化氢和氢过氧化枯烯。
通常,氧化剂可在0℃至溶剂沸点或优选室温至溶剂沸点之间,反应数分钟至三天或优选的1至24小时。上述过氧化物可以按照每当量叔胺加入1当量或进一步地,例如比叔胺过量10-100%或更多过量的方式加入。若反应完成时仍有过量的过氧化物(用碘/淀粉试纸很容易地检测出来),则通过加入无机还原剂、例如亚硫酸氢钠、亚硫酸钠,金属催化剂、例如5%的碳载或铝载的铂或钯,或有机还原剂如二甲基硫来实施适当的处理。
其它适宜制备叔胺氧化物的氧化剂包括:溶于溶剂(如三氯甲烷、二氯甲烷、氟代烃或甲烷)中的臭氧,硅胶吸附型臭氧,以及根据需要在有催化剂例如钯化合物的存在下的氢过氧化物,例如叔丁基氢过氧化物。
当成本举足轻重时,例如在工业规模的产品生产中,优选的反应试剂是溶于叔丁醇的30-50%含水过氧化氢。举例来说,数千克***喃衍生物(通式(IX))与溶于沸腾叔丁醇中的50%含水过氧化氢反应2.5小时后可被氧化为***喃-N-氧化衍生物(通式(III))。
此外,本发明式(IV)所示的具有κ受体激动活性的化合物优选为:反-2-(3,4-二氯苯基)-N-甲基-N-[2-(1-吡咯烷基)环己基]乙酰胺;反-N-甲基-N-[2-(1-吡咯烷基)环己基]苯并[b]噻吩-4-乙酰胺;(5β,7β,8α)-3,4-二氯-N-甲基-N-[7-(1-吡咯烷基)-1-氧杂螺[4,5]癸-8-基]苯乙酰胺;(5β,7β,8α)-N-甲基-N-[7-(1-吡咯烷基)-1-氧杂螺[4,5]癸-8-基]苯并[b]呋喃-4-乙酰胺;或(5β,7β,8α)-N-甲基-N-[7-(1-吡咯烷基)-1-氧杂螺[4,5]癸-8-基]苯乙酰胺。式(IV)所示κ受体激动剂可按照J.Szmuszkovicz etal.,J.Mpd.Chem.,25,1125(1982);D.C.Horwell et al.,U.S.PatentAppl.558737(1983);J.Szmuszkovicz et al.,Eur.Patent Appl.EP126612(1984);和P.R.Halfpenny,D.C.Horwell et al.,J.Med.Chem.33,286(1990)公开的方法制备。
本发明式(V)所示的具有κ受体激动活性的化合物优选是:4-[(3,4-二氯苯基)乙酰]-3-[(1-吡咯烷基)甲基]-1-哌嗪羧酸甲酯、1-[(4-三氟甲基苯基)乙酰基]-2-[(1-吡咯烷基)甲基]哌啶、或1-[(3,4-二氯苯基)乙酰基]-2-[(1-吡咯烷基)甲基]哌啶;1-[(3,4-二氯苯基)乙酰基]-4,4-亚乙二氧基-2-[(1-吡咯烷基)甲基]哌啶。式(V)所示κ受体激动剂可以通过A.Naylor et al.,J.Med.Chem.,36,2075(1993);V.Vecchietti etal.,J.Med.Chem.,34,397(1991);ibid.Eur.Patent Appl.EP232,612(1987)、EP 260,041(1988)、EP 275,696(1988);D.I.C.Scopes et al.,J.Med.Chem.,35,490(1992)公开的方法制备。
本发明式(VI)所示的具有κ受体激动活性的化合物优选是:3-(1-甲基吡咯烷)-4-[5,6-二氯-1-1,2-茚满碳酰基]-四氢-1,4-噻嗪。式(VI)所示的κ受体激动剂可按照WO94/05646公开的方法制备。
本发明式(VII)所示的具有κ受体激动活性的化合物优选:2-(3,4-二氯苯基)-N-甲基-N-[1-苯基-2-(1-吡咯烷基)乙基]乙酰胺。式(VII)所示的κ受体激动剂可按照J.J.Barlow etal.,J.Med.Chem.,34,3149(1991)中公开的方法制备。
在上述κ受体激动剂中,通式(I)(III)(IV)(V)(VI)和(VII)所示化合物的药学可接受酸加成盐,包括:无机盐,例如盐酸盐、硫酸盐、硝酸盐、氢溴酸盐、氢碘酸盐、磷酸盐等;有机碳酸盐,例如乙酸盐、乳酸盐、枸椽酸盐、草酸盐、戊二酸盐、苹果酸盐、酒石酸盐、富马酸盐、扁桃酸盐、马来酸盐、苯甲酸盐、邻苯二甲酸盐等;以及有机磺酸盐,例如甲基磺酸盐、乙基磺酸盐、苯磺酸盐、对甲苯磺酸盐、樟脑磺酸盐等。其中优选盐酸盐、氢溴酸盐、磷酸盐、酒石酸盐、甲基磺酸盐及其类似物,显然优选范围并不局限于此。
上述κ受体激动剂可纯化至足够的纯度以作为药物使用,并在通过必要的安全性试验后可以单独或与已知可药用酸、载体、赋形剂等混合成医药组合物的形式经口服或非经口途径给药。
口服制剂可以是片剂或胶囊剂,但当用于治疗皮肤疾病时则优选外用制剂。外用制剂的组成包括脂肪(优选植物油、动物油、蜡、脂肪酸、脂肪醇、矿物油、松节油、凡士林等)、溶剂(优选水、乙醇、甘油、丙二醇、异丙醇、***等)、防腐剂(优选对羟基苯甲酸酯、苯甲酸、水杨酸、山梨酸、苯扎铵、苄乙铵、丙二醇、氯丁醇、苯甲醇、乙醇等)、稳定剂(优选维生素E、丁羟基苯甲醚、二丁基羟基甲苯、亚硫酸盐、乙二胺四乙酸钠等)、阴离子表面活性剂(优选钾皂、药皂、十一碳烯锌、硬脂酸钙、硬脂酸镁、单硬脂酸铝、亚油酸钙、十二烷基硫酸钠等)、非离子表面活性剂(优选单硬脂酸甘油酯、脱水山梨糖醇部分脂肪酸酯、脂肪酸蔗糖酯、硬脂酸-40-聚烃氧基酯、聚乙二醇类、月桂聚乙二醇、聚氧亚乙基-160-聚氧亚丙基-30-二醇、聚氧亚乙基硬化蓖麻油、聚氧亚乙基脱水山梨糖醇部分脂肪酯等)、阳离子表面活性剂(优选苯扎氯胺、氯苯乙胺、氯化十六烷基吡啶盐等)、粉剂(优选氧化锌、氧化锌淀粉、高岭土、连二次硝酸铋、氧化钛、二氧化钛、硫、无水硅酸、滑石粉等)、防腐剂(优选对氧苯甲酸酯、山梨酸、P-氯代-M-二甲苯酚、二氯苯氧基苯酚(irgasan)、六氯苯酚等)、乳化剂(优选***胶粉、西黄耆胶、皂土、羧甲基纤维素钠、甲基纤维素等)、湿润剂(优选甘油、丙二醇、聚乙二醇、1,3-丁二醇、山梨糖醇、聚吡咯烷酮羧酸钠、乳酸钠、透明质酸钠、几丁质衍生物、尿素、氨基酸、氨基酸糖等)。将上组分混合以形成基质,不仅可制成软膏剂、霜剂、润肤剂、涂布剂、贴剂等还可以是外用液体制剂。此外还可制成眼科用的滴眼剂。
κ受体激动剂在药物组合物中的含量没有一个特定的限制范围,但口服用组合物每次剂量通常为0.1μg-1000mg,外用制剂组合物应使每次涂敷能够达到通常的0.001ng/m2-10mg/m2剂量。
[实施例]
本发明将通过实施例加以具体描述。但它们作为本发明的说明而并不使本发明仅限于此。
实施例1
碘化17-环丙基甲基-3,14β-二羟基-4,5α-环氧-17-甲基-6β-(N-甲基-反式-3-(3-呋喃基)丙烯酰胺基)-***喃鎓1
将2.0699g(4.3mmol)17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-(N-甲基-反式-3-(3-呋喃基)丙烯酰胺)***喃、60ml乙酸乙酯、6ml甲醇和1.3ml碘代甲烷全部置于密封容器中,在密封和100℃的条件下搅拌4天。然后向反应溶液中加入60ml甲醇并将析出的固体溶解后,浓缩,向所得残余物中加入400ml蒸馏水。该水溶液用氯仿(100ml×7)洗涤并浓缩水相,所得残余物在乙酸乙酯-甲醇中重结晶,生成的晶体溶解在500ml蒸馏水中。该水溶液用氯仿(100ml×3)洗涤并将水相浓缩,所得残余物在甲醇中重结晶3次,得到102mg本标题化合物。
熔点:202.40-207.9℃(分解)
NMR(500MHz,DMSO-d6)
δ0.38(1H,m),0.60(1H,m),0.70(1H,m),0.78(1H,m),1.23(1.4H,m),1.32(0.6H,m),1.40-1.62(2H,m),1.73(1H,m),1.97-2.22(1H,m),2.63(1H,m),2.75(1H,m),2.84-2.95(1H,m),2.87(1.8H,s),3.02-3.20(1H,m),3.10(1.2H,s),3.22-3.35(1H,m),3.44-3.70(1.6H,m),3.58(3H,s),3.85(2H,m),4.18(0.4H,m),4.80(0.6H,d,J=7.8Hz),4.88(0.4H,d,J=8.3Hz),5.86(0.4H,br s),5.93(0.6H,br s),6.36(0.6H,d,J=15.6Hz),6.63(0.6H,s),6.71(1H,s),6.77(0.4H,d,J=8.3Hz),6.84(0.6H,d,J=7.8Hz),6.89(0.4H,d,J=15.1Hz),6.99(0.4H,s),7.23(0.6H,d,J=15.6Hz),7.36(0.4H,d,J=15.1Hz),7.66(0.6H,s),7.72(0.4H,s),7.92(0.6H,s),8.03(0.4H,s),9.33(0.4H,s),9.72(0.6H,s).
IR(KBr)
ν3460,1649,1595,1454,1410,1321,1158,1139,596cm-1.
Mass(FAB)
m/z491(M+H)+.
元素分析:C29H35N2O5I1·0.5H2O
计算值:C,55.51;H,5.78;N,4.46;I,20.22
实测值:C,55.50;H,5.86;N,4.45;I,20.23
实施例2
碘化17-环丙基甲基-3,14β-二羟基-4,5α-环氧-17-甲基-6β-(N-甲基-3-甲氧基肉桂酰胺基)***喃鎓
2
将2.0014g(3.9mmol)17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-(N-甲基-3-甲氧基肉桂酰胺基)***喃、40ml四氢呋喃、和1.3ml碘代甲烷全部置于密封容器中,在密封容器中、和100℃条件下搅拌8天。向反应溶液加入60ml甲醇,将析出的固体溶解,浓缩并将残余物用120ml氯仿和甲醇混合液溶解;然后用200ml×3蒸馏水萃取。浓缩水相,所得残余物在甲醇-蒸馏水中重结晶4次,得到295mg本标题化合物。
熔点:176.0-183.0℃(分解)
NMR(600MHz,DMSO-d6)
δ0.37(1H,m),0.60(1H,m),0.70(1H,m),0.77(1H,m),1.23(1.4H,m),1.35(0.6H,m),1.43-1.63(2H,m),1.74(1H,m),2.02-2.22(1H,m),2.62(1H,m),2.75(1H,m),2.83-2.96(1H,m),2.90(1.8H,s),3.04-3.19(1H,m),3.15(1.2H,s),3.23-3.35(1H,m),3.50(0.6H,s),3.53(0.4H,s),3.59(
3H,s),3.68(0.6H,m),3.78(1.8H,s),3.80(1.2H,s),3.85(2H,m),4.21(0.4H,m),4.82(0.6H,d,J=7.9Hz),4.89(0.4H,d,J=8.2Hz),5.87(0.4H,br s),5.94(0.6H,br s),6.63(0.6H,d,J=15.0Hz),6.72(0.8H,s),6.76(0.6H,d,J=8.2Hz),6.81(0.6H,d,J=8.2Hz),6.92(0.6H,dd,J=8.2 and 2.1Hz),6.96(0.4H,dd,J=8.2 and 2.1Hz),7.00(0.6H,m),7.09(0.6H,d,J=7.6Hz),7.17(0.4H,d,J=15.3Hz),7.24-7.30(2H,m),7.33(0.4H,t,J=7.9Hz),7.42(0.4H,d,J=15.3Hz),9.35(0.4H,s),9.63(0.6H,s).
IR(KBr)
ν3410,1642,1595,1491,1460,1410,1321,1274,857,793cm-1.
Mass(FAB)
m/z531(M+H)+
元素分析:C32H39N2O5 I1·0.3H2O
计算值:C,57.89;H,6.01;N,4.22;I,19.11
实测值:C,57.80;H,5.86;N,4.22;I,19.14
实施例3
17-环丙基甲基-4,5α-环氧-3,14β-二羟基-6β-[N-甲基-反式-3-(3-呋喃基)丙烯酰胺基]***喃-N-氧化物
3
将600mg(1.26mmol)17-环丙基甲基-4,5α-环氧-3,14β-二羟基-6β-[N-甲基-反-3-(3-呋喃基)丙烯酰胺基]***喃溶解在30ml四氢呋喃中,在0℃、15分钟内向该溶液滴加348mg间氯苯甲酸的8ml四氢呋喃溶液。滴加完毕后,该反应溶液在室温下搅拌约1.5小时,用加入的氯仿/甲醇(4∶1)混合液溶解反应液中析出的固体。浓缩该溶液,所得残余物用柱色谱[装有20g碱性氧化铝并用氯仿/甲醇(10∶0-10∶1)洗脱]纯化,产物以乙酸乙酯-甲醇重结晶,得到473mg本标题化合物(产率为76%)。
熔点:238-239.8℃(分解)
NMR(600MHz,CDCl3)
δ0.38(1H,m),0.45(1H,m),0.76(2H,m),1.34(1H,m),1.46(1H,m),1.61(2H,m),1.76(1H,m),2.25(0.2H,m),2.42(0.8H,m),2.90-3.03(1H,m),3.05(2.4H,s),3.06-3.22(4.6H,m),3.41(2H,m),3.72(0.8H,m),3.79(1H,m),4.58(0.2H,m),4.67(0.8H,d,J=7.0Hz),4.75(0.2H,d,J=7.0Hz),6.35(0.8H,d,J=15.3Hz),6.59(0.2H,d,J=8.2Hz),6.61(0.2H,d,J=15.3Hz),6.64(0.8H,d,J=8.2Hz),6.68(0.8H,s),6.83(0.2H,d,J=8.2Hz),6.91(0.8H,d,J=8.2Hz),7.32(0.8H,d,J=15.3Hz),7.33(1H,s),7.38(0.8H,s),7.43(0.2H,s),7.55(0.2H,d,J=15.3Hz),7.62(0.2H,s),9.49(1H,br s),12.12(1H,br s).
IR(KBr)
ν3420,1653,1605,1504,1408,1321,1160,872cm-1。
Mass(FAB)
m/z493(M+H)+.
元素分析:C28H32N2O6·0.2AcOEt
计算值:C,67.80;H,6.64;N,5.49
实测值:C,67.80;H,6.67;N,5.65
实施例4
17-环丙基甲基-4,5α-环氧-3,14β-二羟基-6β-(N-甲基-3-甲氧基肉桂酰胺基)***喃-N-氧化物
4
将405mg17-环丙基甲基-4,5α-环氧-3,14β-二羟基-6β-(N-甲基-3-甲氧基肉桂酰胺基)***喃溶解在20ml四氢呋喃中,在0℃、10分钟内向上述溶液滴加溶于5ml四氢呋喃中的225mg间氯苯甲酸的溶液。滴加完毕后反应溶液在室温下搅拌约40分钟,浓缩反应液,所得残余物用基于20g碱性氧化铝的柱色谱纯化,产物以乙酸乙酯/甲醇重结晶,得到329mg本标题化合物(产率为79%)。
熔点:234-236.8℃(分解)
NMR(600MHz,CDCl3)
δ0.35(1H,m),0.42(1H,m),0.74(2H,m),1.34(1H,m),1.45(1H,m),1.61(2H,m),1.72(1H,m),1.81(2H,m),2.24(0.3H,m),2.41(0.7H,m),2.86-2.97(1H,m),2.97-3.14(2H,m),3.06(2.1H,s),3.15(0.9H,s),3.32-3.44(2H,m),3.70-3.80(1.7H,m),3.83(3H,s),4.62(0.3H,m),4.70(1H,d,J=7.9Hz),6.57-6.68(0.7H,m),6.58(0.3H,d,J=7.9Hz),6.62(0.7H,d,J=8.2Hz),6.77(0.7H,dd,J=8.2 and 2.1Hz),6.82(0.3H,d,J=8.2Hz),6.84(0.7H,d,J=8.2Hz),6.86(1H,d,J=15.6Hz),6.91(0.3H,dd,J=8.2 and 2.1Hz),6.94(0.7H,d,J=7.3Hz),7.03(0.3H,s),7.11(0.3H,d,J=7.6Hz),7.15(0.7H,t,J=7.9Hz),7.29(0.3H,t,J=7.9Hz),7.40(0.7H,d,J=15.6Hz),7.62(0.3H,d,J=15.3Hz),9.00(1H,br s),12.15(1H,br s).
IR(KBr)
ν3420,1647,1593,1495,1408,1321,1160,917,855cm-1.
Mass(FAB)
m/z533(M+H)+.
元素分析:C31H36N2O6·0.3H2O
计算值:C,69.20;H,6.86;N,5.21
实测值:C,69.11;H,6.87;N,5.21
实施例5
17-环丙基甲基-4,5α-环氧-3,14β-二羟基-6β-[N-甲基-3-(4-三氟甲苯基)丙炔酰胺基]***喃-N-氧化物
5
将413mg17-环丙基甲基-4,5α-环氧-3,14β-二羟基-6β-[N-甲基-3-(4-三氟甲苯基)丙炔酰胺基]***喃溶解在20ml四氢呋喃中,在0℃、15分钟内向该溶液滴加溶于5ml四氢呋喃中的205mg间氯苯甲酸的溶液。滴加完毕后,该反应液在室温下搅拌约1小时,浓缩该溶液,所得残余物用基于20g碱性氧化铝的柱色谱纯化,产物以乙酸乙酯/甲醇重结晶,过滤并真空干燥,制得304mg的本标题化合物(产率为74%)。
熔点:205-208℃(分解)
NMR(600MHz,CDCl3)
δ0.37(1H,m),0.44(1H,m),0.76(2H,m),1.35(0.2H,m),1.47(1.8H,m),1.62(2H,m),1.75(0.2H,m),1.82(0.8H,m),2.27(0.2H,m),2.42(0.8H,m),2.92(0.8H,m),2.99(0.2H,m),3.02-3.12(2H,m),3.05(2.4H,s),3.12-3.22(2H,m),3.31(0.6H,s),3.40(2H,m),3.79(1H,m),4.22(0.8H,m),4.50(0.2H,m),4.74(0.8H,d,J=7.9Hz),4.76(0.2H,d,J=7.9Hz),6.00-7.20(1H,br s),6.56-6.64(1.8H,m),6.83(0.2H,d,J=7.9Hz),7.40(1.6H,d,J=7.9Hz),7.55(1.6H,d,J=8.2Hz),7.64(0.4H,d,J=8.5Hz),7.66(0.4H,d,J=8.5Hz),12.22(1H,br s).
IR(KBr)
ν3420,2224,1615,1506,1408,1325,1170,1129,1067cm-1.
Mass(FAB)
m/z569(M+H)+.
元素分析:C31H31N2O5F3·0.2C6H12·0.1AcOEt
计算值:C,65.89;H,5.80;N,4.71;F,9.59
实测值:C,65.71;H,5.86;N,4.73;F,9.52
实施例6
17-环丙基甲基-4,5α-环氧-3,14β-二羟基-6β-[N-甲基-3-(3-甲苯基)丙炔酰胺基]-***喃-N-氧化物
6
将408mg17-环丙基甲基-4,5α-环氧-3,14β-二羟基-6β-[N-甲基-3-(3-甲苯基)丙炔酰胺基]***喃溶解在20ml四氢呋喃中,在0℃、15分钟内向该溶液滴加溶于5ml四氢呋喃的244mg间氯苯甲酸的溶液。滴加完毕后将反应液在室温下搅拌约1小时,浓缩该反应液,所得残余物用基于20g碱性氧化铝的柱色谱纯化,产物以乙酸乙酯/甲醇重结晶,过滤并真空干燥,制得到269mg本标题化合物(产率为64%)。
熔点:192.0-202.0℃(分解)
NMR(600MHz,CDCl3)
δ0.37(1H,m),0.44(1H,m),0.75(2H,m),1.35(0.3H,m),1.40-1.53(1.7H,m),1.54-1.66(2H,m),1.68-1.85(2H,m),2.20-2.32(0.3H,m),2.31(2.1H,s),2.36(0.9H,s),2.36-2.45(0.7H,m),2.86-3.00(1H,m),3.00-3.22(3H,m),3.03(2.1H,s),3.31(0.9H,s),3.34-3.46(2H,m),3.77(0.3H,m),3.79(0.7H,m),4.30(0.7H,m),4.50(0.3H,m),4.73(0.7H,d,J=8.2Hz),4.75(0.3H,d,J=8.5Hz),6.20-7.20(1H,br s),6.59(0.3H,d,J=8.2Hz),6.60(0.7H,d,J=8.2Hz),6.63(0.7H,d,J=8.2Hz),6.82(0.3H,d,J=8,2Hz),7.04(0.7H,s),7.08(0.7H,d,J=6.1Hz),7.13-7.20(1.4H,m),7.23(0.3H,d,J=7.6Hz),7.26(0.3H,t,J=7.3Hz),7.35(0.3H,d,J=7.6Hz),7.37(0.3H,s),12.22(1H,br s).
IR(KBr)
ν3410,2218,1622,1489,1439,1408,1377,1321,1125,1033,915,690cm-1.
Mass(FAB)
m/z515(M+H)+.
元素分析:C31H34N2O5·0.5H2O
计算值:C,71.11;H,6.74;N,5.35
实测值:C,71.16;H,6.73;N,5.37
实施例7
采用豚鼠回肠摘出标本测定阿片类活性试验。
以Hartley雄性豚鼠作为试验对象。将豚鼠打击致死并切取回肠,回肠肠腔用营养液清洗并仅剥离下其纵向肌。将该纵向肌束悬于装有Krebes-Henseleit溶液(NaCl135mM;KCl4.8mM;CaCl23.4mM;NaH2PO41.2 mM;NaHCO38.3 mM;MgSO42.5mM;和葡萄糖11mM)并保持在37℃下、充有5%二氧化碳与95%氧气混合气的马格纳斯(Magnus)管内。通过分别位于马格纳斯管上端和下端的轮形铂电极以0.5ms、0.1Hz施加电刺激。组织的收缩可通过同质异构传导器记录在多种波动描计器上。
在采用或不采用作为μ拮抗剂的纳洛酮或作为κ拮抗剂的nor-BNI的条件下,积累地加入待测药物,直至由电刺激诱发的标本的收缩达50%被抑制的药物浓度,计算出相应各情况下的IC50。根据拮抗剂使用或不使用时的药效差异,由下列公式计算出Ke值。
Ke=[加入的拮抗剂浓度/(IC50比-1)
IC50比=使用拮抗剂时的IC50/无拮抗剂时的IC50
将化合物
1、
2、
3、
4、
5、
6用作待测药物的结果,得到如表3中的Ke(μ)与Ke(κ)的比值时,Ke(μ)/Ke(κ)=182-∞,表明本发明化合物是选择作用于κ受体的激动剂。
表3.豚鼠回肠摘出标本评估的化合物的阿片类活性
IC
50(nM) Ke(nM)
纳洛酮 nor-BNI
(100nM) (5nM)
1 1.94 16.67 0.03
2 6.71 98.2 0.54
3 1.06 - 0.02
4 4.09 28.7 0.09
5 1.55 29.5 0.19
6 11.3 75.1 0.89
实施例8
通过小鼠输精管摘出标本测定阿片类活性。
试验采用ddy雄性小鼠。从动物身上取出的输精管标本悬挂在装有Krebes-Henseleit溶液(NaCl120.7mM;KCl5.9mM;CaCl22.5mM;NaH2PO41.2mM;NaHCO315.5mM;和葡萄糖11mM)并维持在37℃下、充有由5%二氧化碳与95%氧气组成的混合气体的马格纳斯管中。通过位于马格纳斯管上端和下端的轮形铂电极施加以1.0ms 0.1Hz的电刺激。组织的收缩可通过同质异构传导器记录在多道生理记录仪上。
在使用或不使用作为μ拮抗剂的纳洛酮或作为κ拮抗剂的nor-BNI的两种情况下,积累地加入待测药物,直至对受试对象的电刺激诱发的收缩的抑制作用达50%,计算各实验情况下的IC50,根据使用或不使用拮抗剂时药效差异并基于下列公式计算出Ke值。
Ke=[所加拮抗剂的浓度/(IC50比-1)
IC50比=使用拮抗剂时的IC50/无拮抗剂时的IC50
将化合物1、2、3、4、5和6作为待测药物、根据表4的数据计算Ke(μ)相对于Ke(κ)的比值、以及Ke(δ)相对于Ke(κ)的比值,Ke(μ)/Ke(κ)=18~∞,Ke(δ)/Ke(κ)=15~∞,说明本发明化合物是选择性作用于κ受体的激动剂。
表4.通过小鼠输精管摘出标本测得的化合物阿片类活性
IC50(nM) Ke(nM)
纳洛酮 NTI nor-BNI
(30nM) (10nM) (10nM)
1 4.42 14.18 11.23 0.17
2 5.9 100 25 0.45
3 2.14 30.48 - 0.040
4 1.80 50 11 0.67
5 0.59 5.9 5.0 0.33
6 4.6 - 20 0.26
实施例9
将一种具有选择性κ受体激动活性的阿片化合物,(-)-17-(环丙基甲基)-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-反-3-(3-呋喃基)丙烯酰胺基]***喃盐酸盐
7,
溶解在生理盐水中以制得浓度为40μg/ml的水溶液。将该水溶液以0.2μg/cm2的浓度涂敷在患有荨麻疹的成年男子下肢的三处红赤部位。
结果表明,治疗前为中等强度的瘙痒(等级为“++”)在处理5分钟后被完全消除(等级为“-”)。此后的约5小时内没有出现瘙痒。
实施例10
将化合物7的水溶液涂敷在一位患有特应性皮炎并且并发有严重瘙痒(等级为“+++”)的女性患者的手臂和腿的皮肤表面上。该药物溶液以每10cm2约50μl,涂布药物浓度为0.2μg/cm2,施用在5个部位。作为对比,将吲哚美辛霜剂(药物浓度为7.5mg/g)以相同的方式以75μg/cm2涂布。
如表5所示,在将化合物7的水溶液涂敷5分钟后就能够彻底地消除全部瘙痒。这证明化合物7具有显著的止痒作用。此外,至少在3小时内没有出现瘙痒。相反,患者在使用吲哚美辛霜剂后并没有完全消除瘙痒,可以得出看出在该情况下就止痒活性而言,化合物7比吲哚美辛霜剂更为有效。
表5 κ受体激动剂(化合物
7)和吲哚美辛霜
剂对特应性皮炎诱发型瘙痒的止痒作用
所用药物 | 瘙痒强度(“+++”代表最高强度, “-”代表无瘙痒) | |||
用药前 | 用药后5分钟 | 用药后10分钟 | 用药后3小时 | |
化合物 7水溶液 | +++ | - | - | - |
吲哚美辛消炎膏 | +++ | +++ | + | ± |
实施例11
将κ受体拮抗剂nor-BNI经嘴侧背部皮下给予DDY小鼠,探讨对由此引发的瘙痒,所致小鼠自主地搔痒次数,是否被κ受体激动剂抑制。此时,以pH为4-6的缓冲液代替nor-BNI在鼠嘴侧背部进行皮下注射后,小鼠不产生自主搔痒的行为。
将一种选择性的κ受体激动性的阿片类化合物,即反-2-(3,4-二氯苯基)-N-甲基-N-[2-(1-吡咯烷基)环己基]乙酰胺(参见U-50488H)溶解在生理盐水中,将该水溶液以1、3或10mg/kg的剂量对小鼠进行腹腔内给药,给药30分钟后,将有诱发瘙痒作用的0.1%的nor-BNI溶液以0.1ml/10g(体重)的比例经嘴侧背部皮下给药。给予nor-BNI后60分钟的时间内对搔痒行为的次数进行计数。
将另一对照药,抗组胺药即氯苯吡胺溶解在生理盐水中,并同样从嘴侧背部将此溶液以0.3、1.0和3.0mg/kg的剂量对小鼠进行腹腔内给药。用药30分钟后,同样从嘴侧背部给予nor-BNI。并记录给药60分钟内搔痒行为的次数。第三个试验时,作为空白对照,采用一个生理盐水处理受试组,随后使该受试组接受nor-BNI并在不少于60分钟的时间内对搔痒行为的次数进行计数。上述实验每组动物数均为10只。
结果如图1所示,在生理盐水处理组中,由nor-BNI给药所致的搔痒行为的次数显著增加。而在用U-50488H处理组中,由nor-BNI引起的搔痒行为的次数明显减少。该结果表示待测物质具有显著的止痒作用。另一方面,氯苯吡胺处理组的搔痒行为次数虽然减少,但减少的程度低于U-50488H处理组止痒效果U-50488H更为有效。
实施例12
自日本SLC购买四周龄ddy雄性小鼠并在经驯化后在第五周龄时用于实验。实验前一天,将其嘴侧背部皮肤上的毛发用剪刀剪去。各待测药物都溶解在10%的DMSO中。将待测药物或溶剂经皮下给药进入到小鼠的嘴侧背部。30分钟后,溶解于生理盐水中的化合物48/80以50μl(100μg/每处)的剂量在除毛部位进行皮内给药。然后立即将小鼠放入笼中(10×7×16cm)并观测,在无人的情况下用电视摄象机记录30分钟内所致的搔痒行为。重放录象带并对其后爪在化合物48/80处理部位及其附近区域的搔痒行为次数进行计数。每组包括8-10只受试动物。
待测化合物的搔痒抑制百分率通过下列公式来计算。具有减少瘙痒作用可作为待测物的止痒效果的指标。
搔痒行为抑制率(%)=[1-(A-C/B-C)]×100
A=待测药物受试组的平均搔痒次数
B=用溶剂替换待测药物的受试组的平均搔痒次数
C=用溶剂替换致痒剂的受试组的平均搔痒次数
所用的待测化合物包括:17-环丙基甲基-3,14β-二羟基-4,5α-环氧-17-甲基-6β-(N-甲基-3-甲氧基肉桂酰胺基)-***喃鎓碘化物盐
2、17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-反-3-(3-呋喃基)丙烯酰胺基]***喃-N-氧化物
3、17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-3-(4-三氟甲苯基)丙炔酰胺基]***喃-N-氧化物
5、17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-3-(3-甲基苯基)丙炔酰胺基]***喃-N-氧化物
6、17-(环丙基甲基)-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-反-3-(3-呋喃基)丙烯酰胺基]***喃盐酸盐
7、17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-(N-甲基-3-甲氧基肉桂酰胺基)***喃酒石酸盐
8、17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[N-(1,4-二氧-4-甲氧基-反-2-丁烯基)-N-甲基]***喃甲基磺酸盐
9、17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-(N-甲基-3,4-二氯苯基乙酰胺基)***喃盐酸盐10、17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-(N-甲基肉桂酰胺基)***喃盐酸盐
11、17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6α-(N-甲基-N’-苄基脲基)***喃酒石酸盐
12、17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-(N-甲基苄氧基脲基)-***喃盐酸盐
13、17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-(N-苄氧基脲基)***喃盐酸盐14、17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6α-(N-甲苯基甲基磺酰胺基)***喃盐酸盐
15、17-(环丙基甲基)-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-反-3-(4-溴代-2-噻吩基)丙烯酰胺基]***喃氢溴酸盐
16、17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-3-(苯基)丙炔酰胺基]***喃盐酸盐
17、17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-3-(3-甲基苯基)丙炔酰胺基]***喃盐酸盐18、17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-[N-甲基-3-(4-三氟甲苯基)丙炔醇酰胺基]***喃盐酸盐
19、2-(3,4-二氯苯基)-N-甲基-N-[1-苯基-2-(1-吡咯烷基)乙基]乙酰胺盐酸盐
20、3-(1-吡咯烷基甲基)-4-[5,6-二氯-1-茚碳酰基(indancarbonyl)]-四氢-1,4-噻嗪盐酸盐
21、反-N-甲基-N-[2-(1-吡咯烷基)环己基]苯并[b]噻吩-4-乙酰胺盐酸盐
22、和(5β、7β、8α)-N-甲基-N-[7-(1-吡咯烷基)-1-氧杂螺[4,5]癸-8-基]苯并[b]呋喃-4-乙酰胺盐酸盐
23。
表6概括了试验的结果。试验中的待测化合物以所用剂量显示止痒活性。
表6.多种阿片κ受体激动剂的止痒功效
被测药物 | 剂量(mg/kg) | 抑制率(%) |
化合物 2 | 1.0 | 41 |
化合物 3 | 0.0057 | 64 |
化合物 5 | 0.016 | 55 |
化合物 6 | 0.005 | 45 |
化合物 7 | 0.005 | 58 |
化合物 8 | 0.01 | 72 |
化合物 9 | 1.8 | 52 |
化合物 10 | 0.46 | 14 |
化合物 11 | 0.0018 | 45 |
化合物 12 | 0.07 | 39 |
化合物 13 | 0.07 | 47 |
化合物 14 | 0.31 | 46 |
化合物 15 | 1.88 | 56 |
化合物 16 | 0.0046 | 14 |
化合物 17 | 0.0066 | 90 |
化合物 18 | 0.03 | 92 |
化合物 19 | 0.03 | 40 |
化合物 20 | 0.006 | 62 |
化合物 21 | 0.0003 | 23 |
化合物 22 | 1.2 | 70 |
化合物 23 | 0.0069 | 46 |
工业实用性
本发明的止痒剂含有作为有效组分的阿片κ受体激动剂,并且对并发有瘙痒的皮肤病,例如特应性皮炎、神经性皮炎、接触性皮炎、脂溢性皮炎、自身过敏性皮炎、毛虫(caterpillar)皮炎、皮脂缺乏症、老年性皮肤瘙痒、昆虫叮咬、光致敏型皮炎、荨麻疹、痒疹、疱疹、脓疱病、湿疹、癣、苔藓、牛皮癣、疥疮和寻常痤疮;并发有瘙痒的内脏病症,如恶性肿瘤、糖尿病、肝病、肾衰竭、血液透析和妊娠的治疗都十分有效。
Claims (14)
1.一种含有具有阿片κ受体激动活性的化合物作为有效组分的止痒剂,其中具有阿片κ受体激动活性的化合物是式(II)所示的***喃季铵盐衍生物或其药物可接受的酸加成盐:
其中,是双键或单键;R1是含有1-5个碳原子的烷基、含有4-7个碳原子的环烷基烷基、含有5-7个碳原子的环状链烯基烷基、含有7-13碳原子的芳烷基、含有4-7个碳原子的链烯基、或烯丙基;R2是氢、羟基、硝基、含有1-5个碳原子的烷酰氧基、含有1-5个碳原子的烷氧基、或含有1~5个碳原子的烷基;R3是氢、羟基、含有1-5个碳原子的烷酰氧基、或含有1-5个碳原子的烷氧基;R4是氢、直链或支链的含有1-5个碳原子的烷基、或含有6-12个碳原子的芳基;A是含有1-6个碳原子的亚烷基、-CH=CH-、或-C≡C-;R5是含有下列任一基本结构的有机基团:
2.权利要求1中的止痒剂,其中的***喃季铵盐衍生物如式(II)所示,式中的R1是甲基、乙基、丙基、丁基、异丁基、环丙基甲基、烯丙基、苄基、或苯乙基;R2和R3分别独立地为氢、羟基、乙酰氧基、或甲氧基;R4是氢或直链或支链的含有1-5个碳原子的烷基;A是-CH=CH-、或-C≡C-;R6是甲基。
3.权利要求2中的止痒剂,其中的***喃季铵盐衍生物如式(II)所示,式中的R4是甲基、乙基、丙基、异丙基、丁基、或异丁基。
4.权利要求2中的止痒剂,其中的***喃季铵盐衍生物如式(II)所示,式中的R5是含有下列任一基本结构的有机基团:
Q:O,S
其中的有机基团可以至少含有一个以上选自:含有1-5个碳原子的烷基、含有1-5个碳原子的烷氧基、含有1-5个碳原子的烷酰氧基、羟基、氟、氯、溴、碘、硝基、氰基、异硫氰基、三氟甲基、三氟甲氧基、和亚甲二氧基的取代基。
5.权利要求4中的止痒剂,其中的***喃季铵盐衍生物如式(II)所示,式中的R4是甲基、乙基、丙基、异丙基、丁基、或异丁基。
6.一种止痒的外用制剂,该制剂包括作为有效组分的权利要求1-5任一项中具有阿片κ受体激动活性的化合物。
7.一种式(II)所示的***喃季铵盐衍生物:
其中,是双键或单键;R1是含有1-5个碳原子的烷基、含有4-7个碳原子的环烷基烷基、含有5-7个碳原子的环状链烯基烷基、含有7-13碳原子的芳烷基、含有4-7个碳原子的链烯基、或烯丙基;R2是氢、羟基、硝基、含有1-5个碳原子的烷酰氧基、含有1-5个碳原子的烷氧基、含有1-5个碳原子的烷基;R3是氢、羟基、含有1-5个碳原子的烷酰氧基、或含有1-5个碳原子的烷氧基;R4是氢、直链或支链的含有1-5个碳原子的烷基、或含有6-12个碳原子的芳基;A是含有1-6个碳原子的亚烷基、-CH=CH-、或-C≡C-;R5是含有下列任一基本结构的有机基团:
8.权利要求7中的***喃季铵盐衍生物,其中的R1是甲基、乙基、丙基、丁基、异丁基、环丙基甲基、烯丙基、苄基、或苯乙基;R2和R3分别独立地为氢、羟基、乙酰氧基、或甲氧基;R4是氢或直链或支链的含有1-5个碳原子的烷基;A是-CH=CH-、或-C≡C-;R6是甲基。
9.权利要求8中的***喃季铵盐衍生物,其中的R4是甲基、乙基、丙基、异丙基、丁基、或异丁基。
10.权利要求8中的***喃季铵盐衍生物,其中的R5是含有下列任一基本结构的有机基团:
Q:O,S
其中的有机基团可以至少含有一个以上选自:含有1-5个碳原子的烷基、含有1-5个碳原子的烷氧基、含有1-5个碳原子的烷酰氧基、羟基、氟、氯、溴、碘、硝基、氰基、异硫氰基、三氟甲基、三氟甲氧基、和亚甲二氧基的取代基。
11.权利要求10中的***喃季铵盐衍生物,在式(II)中,其中的R4是甲基、乙基、丙基、异丙基、丁基、或异丁基。
12.含有权利要求7-11中的任一***喃季铵盐衍生物的药物。
13.一种制备式(II)所示化合物的方法,其特征在于:将式(VIII)所示的叔胺用烷基化试剂季铵盐化:
其中,在上述式(VIII)和(II)中,是双键或单键;R1是含有1-5个碳原子的烷基、含有4-7个碳原子的环烷基烷基、含有5-7个碳原子的环状链烯基烷基、含有7-13碳原子的芳烷基、含有4-7个碳原子的链烯基、或烯丙基;R2是氢、羟基、硝基、含有1-5个碳原子的烷酰氧基、含有1-5个碳原子的烷氧基、含有1-5个碳原子的烷基;R3是氢、羟基、含有1-5个碳原子的烷酰氧基、或含有1-5个碳原子的烷氧基;R4是氢、直链或支链的含有1-5个碳原子的烷基、或含有6-12个碳原子的芳基;A是含有1-6个碳原子的亚烷基、-CH=CH-、或-C≡C-;R5是含有下列任一基本结构的有机基团:
14.权利要求13中的方法,其中的烷基化试剂为:含有1-5个碳原子的烷基碘、含有1-5个碳原子的烷基溴、含有1-5个碳原子的烷基氯、含有1-5个碳原子的甲磺酸烷基酯、含有1-5个碳原子的二烷基硫酸、烯丙基碘、烯丙基溴、或烯丙基氯。
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JP31347696 | 1996-11-25 | ||
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CNB97193343XA Division CN1180844C (zh) | 1996-11-25 | 1997-11-21 | 止痒药物 |
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CNA200310123373XA Pending CN1535687A (zh) | 1996-11-25 | 1997-11-21 | 止痒药物 |
CNB2003101225979A Expired - Lifetime CN1291717C (zh) | 1996-11-25 | 1997-11-21 | 止痒药物 |
CNB97193343XA Expired - Lifetime CN1180844C (zh) | 1996-11-25 | 1997-11-21 | 止痒药物 |
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CNB2003101225979A Expired - Lifetime CN1291717C (zh) | 1996-11-25 | 1997-11-21 | 止痒药物 |
CNB97193343XA Expired - Lifetime CN1180844C (zh) | 1996-11-25 | 1997-11-21 | 止痒药物 |
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US (2) | US6174891B1 (zh) |
EP (5) | EP1310251A1 (zh) |
KR (1) | KR100557801B1 (zh) |
CN (3) | CN1535687A (zh) |
AT (3) | ATE291429T1 (zh) |
AU (1) | AU738743B2 (zh) |
CA (1) | CA2244256C (zh) |
DE (3) | DE69728585T2 (zh) |
DK (1) | DK0897726T3 (zh) |
ES (3) | ES2215158T3 (zh) |
NO (1) | NO316309B1 (zh) |
NZ (1) | NZ331001A (zh) |
PT (1) | PT897726E (zh) |
TW (1) | TW542838B (zh) |
WO (1) | WO1998023290A1 (zh) |
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CN106866688A (zh) * | 2015-12-10 | 2017-06-20 | 山东诚创医药技术开发有限公司 | 一种纳呋拉啡的精制方法 |
CN106866688B (zh) * | 2015-12-10 | 2019-05-03 | 山东诚创医药技术开发有限公司 | 一种纳呋拉啡的精制方法 |
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