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Publication numberCN1291717 C
Publication typeGrant
Application numberCN 200310122597
Publication date27 Dec 2006
Filing date21 Nov 1997
Priority date25 Nov 1996
Also published asCA2244256A1, CA2244256C, CN1180844C, CN1214634A, CN1530111A, CN1535687A, DE69728585D1, DE69728585T2, DE69732868D1, DE69732868T2, DE69737592D1, DE69737592T2, EP0897726A1, EP0897726A4, EP0897726B1, EP1310251A1, EP1310255A1, EP1310255B1, EP1312361A1, EP1327444A1, EP1327444B1, US6174891, US6316461, WO1998023290A1
Publication number200310122597.9, CN 1291717 C, CN 1291717C, CN 200310122597, CN-C-1291717, CN1291717 C, CN1291717C, CN200310122597, CN200310122597.9
Inventors长濑博, 内海润, 远藤孝, 田中利明, 龟井淳三, 川村邦昭
Applicant东丽株式会社
Export CitationBiBTeX, EndNote, RefMan
External Links: SIPO, Espacenet
Antipruritic
CN 1291717 C
Abstract  translated from Chinese
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、新的吗啡喃季铵盐衍生物和新的吗啡喃-N-氧化物衍生物,它们可用于治疗多种疾病并发的瘙痒。 The present invention relates to an opiate κ receptor agonist as an effective component antipruritic, new morphinan quaternary ammonium salt derivative and new morphinan -N--oxide derivatives which are useful in the treatment of various diseases concurrent itching.
Claims(6)  translated from Chinese
1.一种通式(III)所示的吗啡喃-N-氧化物衍生物或其药物可接受酸加成盐, A general formula (III) morphinan -N- oxide derivative or a pharmaceutically acceptable acid addition salt thereof represented, 其中是单键;R1是环丙基甲基;R2是羟基;R3是羟基;R4是甲基;A是-CH=CH-或-C≡C-;R5是苯基或呋喃基,前提是苯基可以具有选自甲基、甲氧基和三氟甲基的取代基,该通式(III)包括(+)、(-)和(±)异构体。 Wherein  is a single bond; R1 is cyclopropylmethyl; R2 is hydroxy; R3 is hydroxy; R4 is methyl; A is -CH = CH- or -C≡C-; R5 is phenyl or furyl, the premise is a phenyl group which may have selected from methyl, methoxy and trifluoromethyl substituents, the general formula (III) comprises (+), (-) and (±) isomers.
2.按照权利要求1的吗啡喃-N-氧化物衍生物或其药物可接受酸加成盐,其是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]吗啡喃-N-氧化物、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)吗啡喃-N-氧化物、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]吗啡喃-N-氧化物或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]吗啡喃-N-氧化物。 2. The according to claim 1 morphinan -N- oxide derivative or a pharmaceutically acceptable acid addition salt thereof, which is 17-cyclopropylmethyl--4,5α- epoxy -3,14β- dihydroxy - 6β- [N- methyl - trans-3- (3-furyl) acrylamido-yl] -N- oxide morphinan, 17-cyclopropylmethyl--4,5α- epoxy -3,14β- two hydroxy -6β- (N- methyl-3-methoxy-cinnamic amide yl) -N- oxide morphinan, 17-cyclopropylmethyl--4,5α- epoxy -3,14β- dihydroxy -6β - [N- methyl-3- (4-trifluoromethylphenyl) propynyl amido] morphinan -N--oxide or 17-cyclopropylmethyl--4,5α- epoxy -3,14β- two hydroxy -6β- [N- methyl-3- (3-methylphenyl) propynyl amido] morphinan -N- oxide.
3.一种止痒剂,其包含按照权利要求1-2的任一项权利要求的吗啡喃-N-氧化物衍生物或其药物可接受酸加成盐,以及药物可接受载体。 An antipruritic agent comprising according to claim any one of claims 1-2 of claim morphinan -N- oxide derivative or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier.
4.权利要求3的止痒剂,其中所述止痒剂是止痒的外用制剂。 An antipruritic according to claim 3, wherein said anti-itching agent is antipruritic external preparation.
5.一种制备通式(III)所示化合物的方法,其包含用有机羧酸的过氧化物氧化通式(IX)所示的叔胺, A general formula (III) the method shown in the compound comprising an organic carboxylic acid with a peroxide oxidation of formula (IX) as shown in a tertiary amine, 在通式(III)和(IX)中,是单键;R1是环丙基甲基;R2是羟基;R3是羟基;R4是甲基;A是-CH=CH-或-C≡C-;R5是苯基或呋喃基,前提是苯基可以具有选自甲基、甲氧基和三氟甲基的取代基。 In the general formula (III) and (IX) in,  is a single bond; R1 is cyclopropylmethyl; R2 is hydroxy; R3 is hydroxy; R4 is methyl; A is -CH = CH- or -C≡C -; R5 is phenyl or furyl, provided that the phenyl group may have is selected from methyl, methoxy and trifluoromethyl substituents.
6.按照权利要求5的方法,其中该过氧化物是间氯过苯甲酸。 6. The method according to claim 5, wherein the peroxide is m-chloroperbenzoic acid.
Description  translated from Chinese
止痒药物 Anti-itch medication

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。 This application is entitled November 21, 1997 to submit the "anti-itch medication," the PCT / JP97 / 04267 invention No. divisional patent application, Chinese Patent Application No. 97193343.X original application.

技术领域 FIELD

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。 The present invention relates to a compound having opioid κ receptor agonist and an antipruritic activity containing the compound and is adapted to the treatment of various diseases caused by pruritus.

背景技术 BACKGROUND

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。 Itching of the skin and the feeling peculiar to the symptoms observed, itching may be made of certain medical conditions (cancer, diabetes, liver disease, renal failure, hemodialysis, gout, thyroid diseases, blood in many skin diseases accompanied by inflammation disease, and iron deficiency), pregnancy and disease caused by parasites, sometimes, drugs and mental factors can also induce itching.

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。 Pruritus is a subjective feeling because it is difficult for the indications for quantitative and objective evaluation, the mechanism is not entirely clear induced pruritus.

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、前列腺素和阿片肽等。 So far known irritants can trigger itching include: histamine, P substance, bradykinin, proteases, prostaglandins and opioid peptides. 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)。 The itchy feeling is considered by the itch stimuli acting on the epidermis and is located more to stimulate dermal junction region correspondence nerve endings (itching receptors), thereby sequentially generating nerve impulses in the spinothalamic tract, thalamus, cerebral cortex The transfer caused ("method of treating pruritus," Yoshiki Miyachi forward, p22,1996, apex medical community).

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。 Itching is a very patient discomfort and severe symptoms or even impede normal life. 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。 In the treatment of itching, dermatitis or may first need to cause itching of the underlying disease treatment, particularly in the case of suffering from skin diseases, but also to deal with patients because of itching and scratching the skin resulting in exacerbation of symptoms caused by pruritus necessary treatment.

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。 Skin scratching is an important cause aggravation of dermatitis, which is due to skin injury will cause defect skin barrier function and thus vulnerable to physical or chemical irritation invasion and bacterial infections. 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。 In addition, due to the weakness of the epidermal nerve sensitive, so more susceptible to itching, and skin will eventually break the vicious cycle of repeated scratch.

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%。 For example, although only a healthy person during sleep does not exceed 0.1% of sleep time is scratching itchy skin, but severe atopic dermatitis scratching at the average sleep time was as high as 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。 Assuming an average sleep time of eight hours, the patient scratching the skin time was as long as two hours. 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)。 Obviously, skin scratching during sleep makes atopic dermatitis aggravated and become a risk factor for disease-specific rash concurrent ("Nikkei Medicine", 1996 July 10, 13).

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。 Thus, treatment of pruritus itself is also very important, especially in the disease accompanied by severe itching dermatitis diseases.

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。 Usually require specific treatment of itching skin disease cases include: atopic dermatitis, neurodermatitis, contact dermatitis, seborrheic dermatitis, autosensitization dermatitis, caterpillar (caterpillar) dermatitis, sebum deficiency, senile pruritus, insect bites, light sensitization dermatitis, hives, itchy rashes, herpes, impetigo, eczema, psoriasis, lichen, psoriasis, scabies, and acne vulgaris; well, complicated by itching and visceral disease has posed serious problems, including cases : cancer, diabetes, liver disease, renal failure, hemodialysis, and pregnancy.

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)。 Commonly used in drug treatment of the above pruritus, oral drugs are, for example, antihistamines and antiallergics; external preparations, such as antihistamines, adrenocortical steroid external preparations, non-steroidal anti-inflammatory drugs, camphor, menthol, phenol and salicylic acid, tar, crotamiton, capsaicin, and humectants (urea, Hirudoid (Hirudoid) and Vaseline). 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系统抑制作用(嗜睡和疲倦感、消氏系统障碍等)的不良反应的问题。 However, oral medications such as the former will produce some have a lag time markedly inhibitory CNS adverse reactions (drowsiness and fatigue, consumer's system disorders, etc.) issues. 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。 There are also some topical agents such as anti-itching efficacy inadequate, especially defects and adverse reactions will cause adrenal insufficiency and rebound phenomena like the long-term use of steroids.

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。 Given the relationship between opioid and itchy, apparently opioid analgesic effect not only has become a cause itching but also chemical mediators. 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)。 About endogenous opioid peptides such as endorphins and enkephalins can β- induced pruritus first reported (B.FjellerActa, Dermato-Venereol., 61 (suppl.97), 1-34,1981). 业已发现,吗啡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(JHJaffe和WRMartin,Goodman and Gilman's pharmacological Basis of Theraputics,Macmillan,纽约,1985)。 It has been found that the presence of epidural and intrathecal morphine and opiate compounds induced pruritus adverse reactions (JHJaffe and WRMartin, Goodman and Gilman's pharmacological Basis of Theraputics, Macmillan, New York, 1985). 另一方面还发现纳洛酮—一种吗啡拮抗剂能够抑制吗啡鞘内给药诱发的瘙痒(J.Bernsteinet 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吗啡拮抗剂纳美酚(nalmefene)抑制(JRThornton and MSLosowsky,Br.Med.J.,297,1501-1504,1988)。 On the other hand also found naloxone - a morphine antagonist can inhibit intrathecal morphine-induced pruritus, and liver disease (J.Bernsteinet al, J.Invest.Dermatol, 78,83-83,1982..) cholestatic patients increased by endogenous opioid peptides induced pruritus can be satisfied that the United States and phenol morphine antagonist (nalmefene) inhibition (JRThornton and MSLosowsky, 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。 Generally accepted that opiate agonists induce pruritus and opiate antagonists as anti-itch medicine. 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。 Recently there are signs that the risk of atopic dermatitis children's serum β- endorphin concentrations significantly higher than healthy children, and there are reports that the opioid antagonist is effective in treating atopic dermatitis induced type itching. (S.Georgala et al.,Dermatol.Sci.8,125-128,1994)。 (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。 Therefore, it is considered the more usual opiate agonists induce pruritus and opiate antagonist, there is likely to be anti-itch medicine. 但现阶段阿片系拮抗剂仍未实际用作止痒药。 But at this stage opiate antagonist used as an anti-itch medicine yet practical.

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。 Object of the present invention is to provide a strong opioid κ receptor agonist and the agonist containing, can solve the above problems and has a fast and effective antipruritic effect antipruritic.

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。 DISCLOSURE OF THE INVENTION The present invention provides a compound having a κ opioid receptor agonist activity and antipruritic agent containing the compound as an active ingredient.

附图简述附图1是实施例11的结果图示。 BRIEF DESCRIPTION Figure 1 is a diagram illustrating the results of the eleventh embodiment.

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肤。 Preferred embodiment of the present invention known opioid receptors μ, δ, and κ type and were found to have selective excitatory receptors endogenous opioid peptide. 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。 In other words, β- endorphin and enkephalin are μ, δ receptor agonist dynorphin proved to be κ receptor agonists of endogenous opioid peptides. 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。 Including dynorphin κ receptor agonists, including mechanism of action is not clearly itching, but the present invention has for the first time to clarify.

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。 Although the κ receptor agonists of the present invention is not limited to opioid κ receptor agonist activity with the corresponding characteristics of the specific chemical structure; however, the κ receptor agonist selectivity was significantly higher than that of μ and δ receptors are preferred. 尤其可例举的是具有阿片κ受体激动活性的吗啡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: In particular, there may be exemplified opiate κ receptor agonist morphine derivatives or their pharmaceutically acceptable acid addition salt thereof, wherein the compound having the opioid κ receptor agonist represented by the formula (I) is represented by, or The pharmaceutically acceptable acid addition salt thereof: 其中, Among them, 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: Is a double bond or a single bond; R1 is an alkyl group containing 1-5 carbon atoms, containing 4-7 carbon atoms, a cycloalkyl group, containing 5-7 carbon atoms, cycloalkenyl group, comprising an aryl group of 6 to 12 carbon atoms, containing 7-13 carbon atoms, an aralkyl group, an alkenyl group having 4-7 carbon atoms, an allyl group, containing 1-5 carbon atoms, furan-2- group, containing 1-5 carbon atoms, or a thiophene-2-alkyl; R2 is hydrogen, hydroxy, nitro, alkanoyloxy having 1 to 5 carbon atoms, containing 1-5 carbon atoms alkoxy group, an alkyl group having 1-5 carbon atoms, or -NR9R10, R9 is hydrogen or an alkyl group containing 1-5 carbon atoms; R10 is hydrogen, an alkyl group having 1-5 carbon atoms, or -C (= O) -R11, R11 is hydrogen, phenyl, or an alkyl group having 1-5 carbon atoms; R3 is hydrogen, hydroxy, and alkoxy of 1-5 carbon atoms, an acyloxy group, or contains 1 to 5 carbon atoms, an alkoxy group; A is -XC (= Y) -, - XC (= Y) Z -, - X-, or -XSO2- (wherein X, Y and Z each independently represent NR4 , S, or O, R4 is hydrogen, a straight-chain or branched alkyl having 1-5 carbon atoms, or an aryl group containing 6 to 12 carbon atoms; and wherein any of the same or different R4); B is a bond, a straight-chain or branched alkyl having 1 to 14 carbon atoms, an alkylene group (wherein the alkylene group may optionally be substituted with at least one or more groups, such as alkyl containing 1 to 5 carbon atoms, alkoxy, alkanoyloxy having 1-5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, trifluoromethyl, and phenoxy; optionally have one to three sub- methyl substituted with a carbonyl group), straight chain or branched non-cyclic unsaturated chain containing 2-14 carbon atoms and 1-3 double bonds and / or triple bonds hydrocarbon group (wherein the acyclic unsaturated hydrocarbon optionally with at least one or more selected from an alkoxy group having 1-5 carbon atoms, alkanoyloxy having 1-5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, substituted with trifluoromethyl, and phenoxy, optionally with one to three of methylene group substituted with a carbonyl group), or a linear or branched, saturated or unsaturated, containing 1 to 14 carbon atoms, 1- 5 thioether, ether and / or amino bond hydrocarbon (wherein the hetero atom does not directly connected to A, optionally with one to three of methylene group substituted with a carbonyl group); R5 is hydrogen or has the following fundamental structures organic group Mission:

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: Wherein the organic group optionally having at least one or more selected from 1 to 5 carbon atoms, an alkoxy group having 1-5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, a hydroxyl group, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy substituents; R6 is hydrogen; R7 is hydrogen, a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms or an alkanoyloxy group having 1-5 carbon atoms, or R6 and R7 together represent -O -, - CH2 -, - S-; R8 is hydrogen, comprising alkyl group having 1-5 carbon atoms or an alkanoyl group having 1 to 5 carbon atoms, and the general formula (I) comprises (+), (-), and (±) isomers, the other by the general formula (II) represented by the opiate κ receptor agonist is: 其中, Among them, 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: Is a double bond or a single bond; R1 is an alkyl group containing 1-5 carbon atoms, containing 4-7 carbon atoms, a cycloalkyl group, containing 5-7 carbon atoms, a cyclic alkenyl group, containing 7-13 carbon atoms, an aralkyl group, an alkenyl group or an allyl group of 4-7 carbon atoms; R2 is hydrogen, hydroxy, nitro, alkanoyloxy having 1 to 5 carbon atoms, 1 to 5 carbon atoms, an alkoxy group or an alkyl group having 1-5 carbon atoms; R3 is hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms, or containing 1 to 5 carbon atoms, alkoxy; R4 is hydrogen, a straight-chain or branched alkyl having 1-5 carbon atoms, or an aryl group containing 6 to 12 carbon atoms; A is 1 to 6 carbon atoms, an alkylene group , -CH = CH-, or -C≡C-; and R5 is an organic group having the following fundamental structures:

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: Wherein the organic group optionally having at least one or more selected from 1 to 5 carbon atoms, an alkoxy group having 1-5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, a hydroxyl group, fluoro, chloro, bromo, iodo, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy substituents; R6 is alkyl containing 1-5 carbon atoms group or an allyl group; X- represents a pharmaceutically acceptable addition salt counterion; and the formula (II) comprises (+), (-), (±) isomer, and the other by the general formula (III) opioid κ receptor agonist or its pharmaceutically acceptable acid addition salts may be represented by: 其中 Among them 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: Is a double bond or a single bond; R1 is an alkyl group containing 1-5 carbon atoms, containing 4-7 carbon atoms, a cycloalkyl group, containing 5-7 carbon atoms, cycloalkenyl group, comprising 7-13 carbon atoms, an aralkyl group, an alkenyl group or an allyl group of 4-7 carbon atoms; R2 is hydrogen, hydroxy, nitro, alkanoyloxy having 1 to 5 carbon atoms, containing 1 alkoxy group or an alkyl group containing 1-5 carbon atoms to 5 carbon atoms; R3 is hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms, or alkoxy containing 1-5 carbon atoms group; R4 is hydrogen, a straight-chain or branched alkyl having 1-5 carbon atoms, or an aryl group containing 6 to 12 carbon atoms; A is 1 to 6 carbon atoms, an alkylene group, -CH = CH-, or -C≡C-; and R5 with the following fundamental structures is an organic group:

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。 Wherein the organic group may have at least one or more selected from an alkyl group having 1-5 carbon atoms, an alkoxy group having 1-5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, a hydroxyl group , fluorine, chlorine, bromine, iodine, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy substituents; Further general formula (III) comprises (+) , (-), (±) isomers.

除吗啡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, In addition morphinan derivative compound useful in the treatment of itching outer, opioid general formula (IV) represented by κ receptor agonist or a pharmaceutically acceptable acid addition salt thereof, 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: Wherein R represents two hydrogen or -O-CH2CH2CH2-; X and Y is hydrogen or chlorine; Z is O or S; formula (IV) comprises (+), (-), and (±) isomer, There is also a by the formula (V) represents the opioid κ receptor agonist or a pharmaceutically acceptable acid addition salt thereof: 其中X是氢、氯、或三氟甲基;Y是氢或氯;Z是CH2、-OC2CH2O-、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: Wherein X is hydrogen, chloro, or trifluoromethyl; Y is hydrogen or chlorine; Z is CH2, -OC2CH2O-, or NCO2CH3; and the general formula (V) comprises (+), (-), and (±) iso isomer, and another one opioid by the general formula (VI) represented by κ receptor agonist or a pharmaceutically acceptable acid addition salt thereof:

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: Wherein X and Y are hydrogen or chlorine; Z is CH2, O, or S; and the general formula (VI) comprises (+), (-), and (±) isomers, as well as by the general formula (VII) represents the κ opioid receptor agonist or a pharmaceutically acceptable acid addition salt thereof: 其中X和Y是为氢或氯;并且通式(VII)包括(+)、(-)、(±)异构体。 Wherein X and Y are hydrogen or chlorine; and the formula (VII) comprises (+), (-), (±) isomers. 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。 Use these opioid κ receptor agonists of one or several applied as an active ingredient.

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(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。 Concurrent itching of the skin as a treatment target cases include: atopic dermatitis, neurodermatitis, contact dermatitis, seborrheic dermatitis, autosensitization dermatitis, caterpillar (caterpillar) dermatitis, sebum deficiency, senile pruritus , insect bites, light sensitization dermatitis, hives, itchy rashes, herpes, impetigo, eczema, psoriasis, lichen, psoriasis, scabies, and acne vulgaris. 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。 Concurrent therapy may be a typical example of itching visceral disease include: cancer, diabetes, liver disease, renal failure, hemodialysis, and pregnancy. 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。 But can also treat itching and eye diseases as ENT diseases or complications.

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。 In the compounds of formula belonging to κ receptor agonists of the present invention shown in (I), R1 is preferably alkyl having 1-5 carbon atoms, containing 4-7 carbon atoms, cycloalkylalkyl having 5-7 carbon atoms, cycloalkenyl group, containing 7-13 carbon atoms, an aralkyl group, an alkenyl group having 4-7 carbon atoms, an allyl group, containing 1-5 carbon atoms furan-2-yl - alkyl group, or contains 1 to 5 carbon atoms, thiophen-2-yl - alkyl group; and particularly preferably a methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl , allyl, benzyl, phenethyl, furan-2-yl - methyl group, or thiophen-2-yl - methyl.

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。 R2 is preferably hydrogen, hydroxy, nitro, acetoxy, methoxy, methyl, ethyl, propyl, amino, dimethylamino, acetylamino, or benzoylamino; and particularly preferably a hydrogen, a hydroxyl group, nitro, acetoxy, methoxy, methyl or dimethylamino. 更优选为氢、羟基、乙酰氧基或甲氧基。 More preferably hydrogen, hydroxy, acetoxy or methoxy.

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。 R3 is preferably hydrogen, hydroxy, acetoxy or methoxy group, and particularly preferably hydroxy, acetoxy or methoxy.

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-。 A is preferably (in the specific formula) -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-, or -OSO2 -; and more preferably -NR4C (= O) -, - NR4C (= S) -, - NR4C (= O) O -, - NR4C (= O) NR4 -, - NR4C (= S) NR4, or - 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)。 Or preferably -XC (= Y) - (where X stands for NR4, S, or O, Y representative of O, R4 is hydrogen or alkyl containing 1-5 carbon atoms), - XC (= Y) Z -, - X-, or -XSO2- (where X stands for NR4, Y represents O or S, Z representative NR4 or O, and R4 is hydrogen or contains 1 to 5 carbon atoms) is more preferably -XC (= Y) - or -XC (= Y) Z- (wherein X represents NR4, Y representative of O, Z represents O, and R4 is an alkyl group containing 1-5 carbon atoms). 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)。 Most preferably -XC (= Y) - (where X stands for NR4, Y representative of O, R4 is an alkyl group containing 1-5 carbon atoms).

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。 R4 is preferably hydrogen, straight-chain or branched alkyl having 1-5 carbon atoms; and particularly preferably having 1 to 5 carbon atoms, a straight-chain or branched alkyl group, wherein more preferably a methyl, ethyl group, propyl, butyl or isobutyl.

B优选是-(CH2)n-(n=0-10)、-(CH2)nC(=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)。 B is preferably - (CH2) n- (n = 0-10), - (CH2) nC (= 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-, or -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-。 Preferred examples of particular note is - (CH2) n- (n = 1-3), - CH = CH- (CH2) n (n = 0-4), - C≡C- (CH2) n- (n = 0-4), - CH2-O- or -CH2-S-. 其中,更优选含有1-3个碳原子的直链亚烷基、-CH=CH-、-CC-、-CH2O-、-CH2S-。 Wherein, more preferably 1 to 3 carbon atoms, a straight chain alkylene group, -CH = CH -, - CC -, - CH2O -, - CH2S-. 最优选-CH=CH-、-C≡C-。 Most preferably -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)。 (Of course, the above-described preferred embodiment comprises a different group substituted with a substituted or alternative structures that make up).

R5优选是氢或带有下列任一基本结构的有机基团: R5 is preferably hydrogen or an organic group with the following fundamental structures:

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R5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)。 Wherein the organic group optionally containing at least one or more selected from 1 to 5 carbon atoms, an alkoxy group having 1-5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, a hydroxyl group, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy substituents of structures; and the above-mentioned compound R5 is more preferably hydrogen, phenyl, thienyl or furanyl (these organic groups optionally containing at least one or more selected from 1 to 5 carbon atoms, an alkoxy group having 1-5 carbon atoms, containing alkanoyloxy group having 1-5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy substituent substituted structures).

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。 More specifically, preferred examples may include; hydrogen, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl, 3,5- dimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3-hydroxyphenyl, 4-hydroxy phenyl, 3,4-dimethoxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluoro phenyl, 3,4-difluorophenyl, perfluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichloro phenyl, 2,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 3- trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3,4-methylenedioxy-phenyl , 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, cyclopentyl or cyclohexyl, but is not limited to the above-described preferred embodiment.

R6和R7优选一起表示-O-、-CH2-或-S-,尤其优选它们一起表示-O-。 Preferably R6 and R7 together represent -O -, - CH2- or -S-, particularly preferably they together represent -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。 R8 is preferably hydrogen, an alkyl group having 1-5 carbon atoms, or alkanoyl containing 1-5 carbon atoms; and preferable examples of the above compounds can be exemplified by hydrogen, methyl, ethyl or propyl. 特别优选氢。 Particularly preferably hydrogen.

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。 The above-mentioned formula (I), κ receptor agonists may be prepared according to the method disclosed in Japanese Patent No. 2,525,552.

此外,式(II)所示化合物是新的吗啡喃类季铵盐衍生物,为阿片κ受体激动剂。 In addition, the compound of formula (II) is shown in the new morphinan quaternary ammonium salt derivative as opioid κ receptor agonist. 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。 This formula R1 is preferably an alkyl group having 1-5 carbon atoms, containing 5-7 carbon atoms, cycloalkyl groups containing 5-7 carbon atoms, cycloalkenyl group, containing 7- 13 carbon atoms, an aralkyl group, an alkenyl group having 4-7 carbon atoms, or an allyl group; and particularly preferably methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl group, cyclobutylmethyl, cyclopentylmethyl, cyclopentenyl methyl, cyclohexenyl methyl, benzyl, phenethyl, trans-2-butenyl, 2-methyl-2-butenoic alkenyl group, or a propenyl group. 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。 Most preferably methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, benzyl, phenethyl or allyl.

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。 R2 is preferably hydrogen, hydroxy, nitro, acetoxy, methoxy, methyl, ethyl or propyl; and more preferably hydrogen, hydroxy, acetoxy, or methoxy.

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。 R3 is preferably hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms, or containing 1 to 5 carbon atoms, an alkoxy group; and, more preferably hydrogen, hydroxy, acetoxy, or methoxy.

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。 R4 is preferably hydrogen, straight-chain or branched alkyl having 1-5 carbon atoms, or an aryl group containing 6 to 12 carbon atoms; and particularly preferably a straight-chain or branched alkyl having 1 to 5 carbon atoms alkyl, or wherein more preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl.

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-。 A is preferably an alkenyl group having 1 to 6 carbon atoms, -CH = CH- or -C≡C-; and wherein more preferably -CH = CH- or -C≡C-.

R5优选是含有下列任一基本结构的有机基团: R5 is preferably an organic group having the following fundamental structures: 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。 Wherein the organic group optionally containing at least one or more selected from 1 to 5 carbon atoms, an alkoxy group having 1-5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, a hydroxyl group, substituents optionally substituted structure fluoro, chloro, bromo, iodo, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy or a methylenedioxy group of the composition; and more preferably is a phenyl group , 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4- difluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-trifluoromethyl- phenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 3- trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl , 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4- methoxyphenyl, 3,4-dimethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 3-furyl, 2 - furyl, 2-thienyl, 3-thienyl, cyclopentyl and cyclohexyl, but preferably is not limited thereto.

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。 R6 preferably contains 1 to 5 carbon atoms or an allyl group; and particularly preferably methyl.

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。 Preferred pharmaceutically acceptable salts of the counterion X- comprises iodide ion, bromide ion, chloride ion, methanesulfonate, etc., but apparently is not limited thereto.

式(II)化合物的具体例列于表1中。 Examples of the compound of formula (II) are shown in Table 1 below. 式(II)化合物包括(+)、(-)和(±)异构体在内。 The compound of formula (II) comprises (+), (-) and (±) isomers including.

表1 Table 1

表1(续) Table 1 (continued)

表1(续) Table 1 (continued)

表1(续) Table 1 (continued)

表1(续) Table 1 (continued)

表1(续) Table 1 (continued)

表1(续) Table 1 (continued)

表1(续) Table 1 (continued)

表1(续) Table 1 (continued)

表1(续) Table 1 (continued)

表1(续) Table 1 (continued)

表1(续) Table 1 (continued)

表1(续) Table 1 (continued)

表1(续) Table 1 (continued)

本发明式(II)所示化合物可具体按照下列方法制备。 Invention of formula (II) may be present as shown in the specific compounds prepared according to the following methods.

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] As shown in Scheme I, the compound obtained is usually prepared formula (VIII) (R1, R2, R3, R4, R5 and A are as defined for formula) (II) represented by the 17 tertiary alkyl halide, methyl iodide esters such as an alkylating agent and a quaternary ammonium salt to complete the conversion: [schematic I] R6X表示卤代烷基、CH3SO3R6表示甲基磺酸烷基。 R6X represents haloalkyl, CH3SO3R6 represents methyl sulfonic acid group.

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。 Of formula (VIII) with the starting material of tertiary amine 17 may be prepared according to the method shown in Japanese Patent Publication No. 2525552 disclosed.

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。 Many are suitable alkylating reagent of formula (VIII) 17 位 tertiary amine into a quaternary ammonium salt shown. 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。 The reason often used iodomethane, iodoethane, iodopropane, iodobutane, propylene iodide, methyl methanesulfonate and dimethyl sulfate quaternary ammonium salt is generated due to the reaction when they are relatively fast. 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。 However, use may also be any other e.g. methyl bromide, ethyl bromide, propyl bromide, butyl bromide, allyl bromide, methyl chloride, ethyl chloride, propyl chloride, butyl chloride and allyl chloride alkylating agent. 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。 On the solvent concerned, may be dichloroethane, chloroform, tetrahydrofuran, ethyl acetate, dimethylformamide, acetonitrile, methanol, ethanol, propanol, t-butanol or acetone as the reaction solvent alone or in combination. 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。 The reaction temperature is preferably set between 0 ℃ to boiling point of solvent, or more preferably between room temperature to the boiling point between the solvent; reaction time is preferably 1 to 14 days, or more preferably ranging between 1-10 days; and the reaction in performed within a sealed tube or under a normal pressure. 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。 Said alkylating agent can be added according to the equivalent of a tertiary amine is added with respect to 1 equivalent or more for example 0.1 to 5.0 equivalents or more excess amounts. 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。 Also can be used as a base potassium bicarbonate, sodium bicarbonate, potassium carbonate or sodium carbonate is added with respect to the equivalent of one equivalent of a tertiary amine may be used, or, for example 0.1 to 5.0 equivalents excess or more excess of the base.

此外,式(III)所示化合物是新的17位吗啡喃N-氧化物衍生物、阿片κ受体激动剂。 In addition, the compound of formula (III) is shown in a new 17 morphinan N- oxide derivative, κ opioid receptor agonist. 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。 In this formula, R1 is preferably an alkyl group containing 1-5 carbon atoms, containing 4-7 carbon atoms, cycloalkyl group, containing 5-7 carbon atoms, cycloalkenyl group, containing 7 -13 carbon atoms, an aralkyl group, an alkenyl group having 4-7 carbon atoms, or an allyl group; and particularly preferably, methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl group, cyclobutylmethyl, cyclopentylmethyl, cyclopentenyl methyl, cyclohexenyl methyl, benzyl, phenethyl, trans-2-butenyl, 2-methyl-2-butenoic alkenyl group, or a propenyl group. 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。 Most preferably methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, benzyl, phenethyl or allyl.

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。 R2 is preferably hydrogen, hydroxy, nitro, acetoxy, methoxy, methyl, ethyl or propyl; and more preferably hydrogen, hydroxy, acetoxy, or methoxy.

R3优选是氢、羟基、乙酰氧基、或甲氧基。 R3 is preferably hydrogen, hydroxy, acetoxy, or methoxy.

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。 R4 is preferably hydrogen, straight-chain or branched alkyl group or a phenyl group containing 1-5 carbon atoms; and particularly preferably a straight-chain or branched alkyl having 1-5 carbon atoms, wherein more preferably a methyl , ethyl, propyl, isopropyl, butyl or isobutyl.

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-。 A is preferably an alkenyl group having 1 to 6 carbon atoms, -CH = CH- or -C≡C-; and wherein more preferably -CH = CH- or -C≡C-.

R5优选是含有下列任一基本结构骨架的有机基团: R5 is preferably an organic group containing a skeleton of the following fundamental structures: 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。 Wherein the organic group optionally containing at least one or more selected from 1 to 5 carbon atoms, an alkoxy group having 1-5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, a hydroxyl group, fluoro, chloro, bromo, iodo, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy substituents of structures; particularly preferred are phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4- fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-trifluoromethyl-benzene group, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 3- trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-furyl, 3-furyl, cyclopentyl and cyclohexyl, but clearly not limited thereto.

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。 Of formula (III) shown in the specific examples of the compounds listed in Table 2, and the formula (III) compounds include (+), (-) and (±) isomers including.

表2 Table 2

表2(续) TABLE 2 (continued)

表2(续) TABLE 2 (continued)

表2(续) TABLE 2 (continued)

表2(续) TABLE 2 (continued)

表2(续) TABLE 2 (continued)

表2(续) TABLE 2 (continued)

表2(续) TABLE 2 (continued)

表2(续) TABLE 2 (continued)

表2(续) TABLE 2 (continued)

表2(续) TABLE 2 (continued)

表2(续) TABLE 2 (continued)

表2(续) TABLE 2 (continued)

表2(续) TABLE 2 (continued)

本发明式(III)化合物可具体按照下列方法制备。 The compounds of the invention of formula (III) may be embodied according to the following methods.

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。 17 between the tertiary amine and generally, as shown in Scheme 2, the compound of formula (III) is represented by the formula (IX) (R1, R2, R3, R4, R5 and A are as defined for formula (III)) represented by chloroperbenzoic acid, performic acid, peracetic acid, perbenzoic acid, trifluoro peracetic acid, maleic acid, phthalic acid, and the like over an organic peroxy acid obtained by the oxidation step, but an oxidizing agent is not limited thereto.

[示意图2] [Diagram 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。 17 formula (IX) with a tertiary amine may be prepared according to Japanese Patent Publication 2525552 discloses a method. 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)。 Many suitable oxidants are the formula (IX) 17 位 tertiary amine into a tertiary amine N- oxide (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。 M-chloroperbenzoic acid was generated because of the faster reacting N- oxides and become commonly used oxidant. 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。 However, may also be used, for example performic acid, peracetic acid, perbenzoic acid, trifluoroperacetic acetates, maleic acid and phthalic acid, etc. Other organic peroxyacids. 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。 On the other hand the use of an oxidizing agent may also be generated in the reaction system: a tertiary amine is dissolved in an acid such as formic acid, acetic acid or trifluoroacetic acid, and then added at a concentration of 3-50%, or more preferably 30 to 50% aqueous hydrogen peroxide . 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,例如乙醚或四氢呋喃;醇溶剂,例如甲醇、乙醇、丙醇或叔丁醇。 On the solvent, the reaction medium can be used are: halogenated solvents such as methylene chloride, chloroform or 1,2-dichloroethane; aromatic solvents such as benzene, toluene; an ether solvent such as diethyl ether or tetrahydrofuran ; alcohol solvents such as methanol, ethanol, propanol or tert-butanol. 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。 Alternatively, when the oxidant is generated in the reaction system may be a corresponding suitable acid as the reaction medium.

除上述有机过氧酸外还可使用如过氧化氢等的过氧化物。 In addition to the above-mentioned organic peroxy acids such as peracetic may be used outside the hydrogen peroxide oxidation. 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。 Aqueous hydrogen peroxide can be used in concentrations of 3-50% alone or used in the solvent. 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。 Other suitable oxidizing agents include ozone, tertiary butylhydroperoxide and cumene hydroperoxide.

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。 Typically, the oxidizing agent can be at 0 ℃ to boiling point of solvent, or preferably between room temperature to the boiling point of the solvent, for several minutes to three days, or preferably 1 to 24 hours. 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。 Above-mentioned peroxide may be added 1 equivalent or more, for example, a tertiary amine is added over 10 to 100% or more excess excess of tertiary amine per equivalent of ways. 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。 If the reaction is complete the excess peroxide still (with iodine / starch paper easily detected), then by the addition of an inorganic reducing agent such as sodium bisulfite, sodium sulfite, a metal catalyst, e.g., 5% on carbon or aluminum contained platinum or palladium, or an organic reducing agent such as dimethyl sulfide to implement appropriate treatment.

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。 Other oxidants suitable for preparing tertiary amine oxides include: dissolved in a solvent (e.g. chloroform, methylene chloride, fluorinated hydrocarbons or methane) ozone, ozone adsorbed on silica gel, as well as in the presence of a catalyst such as a palladium compound needed under hydroperoxide, such as tert-butyl hydroperoxide.

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。 When the cost of a significant, e.g., in industrial scale production, the preferable reaction agent is 30-50% of tert-butanol was dissolved in aqueous hydrogen peroxide. 举例来说,数千克吗啡喃衍生物(通式(IX))与溶于沸腾叔丁醇中的50%含水过氧化氢反应2.5小时后可被氧化为吗啡喃-N-氧化衍生物(通式(III))。 For example, the number of kg of morphinan derivative (general formula (IX)) was dissolved in boiling tert-butanol and 50% aqueous hydrogen peroxide had reacted after 2.5 hours can be oxidized to oxidized derivatives morphinan -N- (through of formula (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);DCHorwell et al.,USPatentAppl.558737(1983);J.Szmuszkovicz et al.,Eur.Patent Appl.EP126612(1984);和PRHalfpenny,DCHorwell et al.,J.Med.Chem.33,286(1990)公开的方法制备。 Further, the invention of formula (IV) with a compound represented present κ receptor agonist is preferably: trans-2- (3,4-dichlorophenyl) -N- methyl -N- [2- (1- pyrrolidinyl) cyclohexyl] acetamide; trans -N- methyl -N- [2- (1- pyrrolidinyl) cyclohexyl] benzo [b] thiophene -4- acetamide; (5β, 7β, 8α ) -3,4-dichloro -N- methyl -N- [7- (1- pyrrolidinyl) -1-oxa-spiro [4.5] dec-8-yl] benzeneacetamide; (5β, 7β, 8α) -N- methyl -N- [7- (1- pyrrolidinyl) -1-oxa-spiro [4.5] dec-8-yl] benzo [b] furan--4- acetamide ;. or (5β, 7β, 8α) -N- methyl -N- [7- (1- pyrrolidinyl) -1-oxa-spiro [4.5] dec-8-yl] benzeneacetamide of formula ( IV) shown κ receptor agonist in accordance J.Szmuszkovicz etal, J.Mpd.Chem, 25,1125 (1982);... DCHorwell et al, USPatentAppl.558737 (1983); J.Szmuszkovicz et al,. Eur.Patent Appl.EP126612 (1984);., J.Med.Chem.33,286 (1990) discloses a method for preparing and PRHalfpenny, DCHorwell et al.

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。 Agonistic activity of the compounds of formula the present invention preferably has a (V) of the κ receptor are shown: 4 - [(3,4-dichlorophenyl) acetyl] -3 - [(1-pyrrolidinyl) methyl] - 1- piperazine carboxylate, 1 - [(4-trifluoromethylphenyl) acetyl] -2 - [(1-pyrrolidinyl) methyl] piperidine, or a 1 - [(3,4 - dichlorophenyl) acetyl] -2 - [(1-pyrrolidinyl) methyl] piperidine; 1 - [(3,4-dichlorophenyl) acetyl] -4,4-ethylenedioxy -2 - [(1-pyrrolidinyl) methyl] piperidine. 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);DICScopes et al.,J.Med.Chem.,35,490(1992)公开的方法制备。 Of formula (V) as shown in κ agonists can 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);.. DICScopes et al, J.Med.Chem, 35,490 (1992) disclosed methods.

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。 The present invention is of formula (VI) is shown with κ receptor agonist compound is preferably: 3- (1-methyl-pyrrolidine) -4- [5,6-dichloro-indan carbon -1-1,2- acyl] - tetrahydro-1,4-thiazine. 式(VI)所示的κ受体激动剂可按照WO94/05646公开的方法制备。 (VI) prepared as shown in formula κ receptor agonist in accordance with WO94 / 05646 disclosed.

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。 The present invention having the formula shown in (VII) κ receptor agonistic activity of the compounds is preferred: 2- (3,4-dichlorophenyl) -N- methyl -N- [1- phenyl-2- (1- pyrrolidinyl) ethyl] acetamide. 式(VII)所示的κ受体激动剂可按照JJBarlow etal.,J.Med.Chem.,34,3149(1991)中公开的方法制备。 Of formula (VII) κ receptor agonists may be shown in accordance JJBarlow etal., J.Med.Chem., Prepared 34,3149 (1991) disclosed.

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。 In the κ receptor agonists of general formula (I) (III) (IV) (V) (VI) and (VII) as shown in pharmaceutically acceptable acid addition salts of compounds, including: inorganic salts, such as hydrochloric acid salt, sulfate, nitrate, hydrobromide, hydroiodide, phosphate and the like; and organic carbonates such as acetate, lactate, citrate, oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate, phthalate and the like; and organic sulfonates such as methyl sulfonate, ethyl sulfonate acid, benzenesulfonate, p-toluenesulfonate, camphorsulfonate and the like. 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。 Wherein preferably the hydrochloride, hydrobromide, phosphate, tartrate, methanesulfonate, and the like, obviously the preferred range is not limited thereto.

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。 Said κ receptor agonists may be purified to a purity sufficient for use as a drug, and can be used alone or in combination with known forms of pharmaceutical composition by mixing into the necessary safety test after a pharmaceutically acceptable acid, carrier, excipient, etc. orally or oral routes.

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。 Oral formulation may be a tablet or capsule, but it is preferably an external formulation for the treatment of skin diseases. 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、乙醚等)、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(优选阿拉伯胶粉、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)。 The external preparation composition comprising fat (preferably vegetable oils, animal oils, waxes, fatty acids, fatty alcohols, mineral oil, turpentine oil, vaseline, etc.), a solvent (preferably water, ethanol, glycerol, propylene glycol, isopropyl alcohol, ether, etc.), a preservative ( Preferably parabens, benzoic acid, salicylic acid, sorbic acid, benzalkonium, benzethonium chloride, propylene glycol, chlorobutanol, benzyl alcohol, ethanol, etc.), stabilizers (preferably vitamin E, D hydroxybenzoate ether, dibutyl hydroxy toluene, sulfite, sodium edetate, etc.), anionic surfactants (preferably, potassium soap, medicated soap, undecene zinc, calcium stearate, magnesium stearate, monostearate aluminum fatty acid, linoleic acid, calcium, sodium lauryl sulfate, etc.), a non-ionic surfactant (preferably glycerol monostearate, sorbitan partial fatty acid alcohol esters, sucrose fatty acid ester, stearic -40 - polyoxyl esters, polyethylene glycols, lauryl polyethylene glycol, polyoxyethylene polyoxypropylene -30- -160- glycol, polyoxyethylene hardened castor oil, polyoxyethylene ethyl alcohol portion sorbitan fatty ester, etc.), cationic surfactants (preferably, benzalkonium chloride, chloro-phenethylamine, cetylpyridinium chloride salt, etc.), powders (preferably, zinc oxide, zinc oxide, starch, kaolin Even secondary bismuth nitrate, titanium oxide, titanium dioxide, sulfur, anhydrous silicic acid, talc, etc.), a preservative (preferably oxygen-benzoate, sorbic acid, P- chlorinated -M- xylenol, two dichlorophenoxy phenol (irgasan), hexachloro-phenol, etc.), an emulsifier (preferably gum arabic powder, tragacanth, bentonite, sodium carboxymethyl cellulose, methyl cellulose, etc.), a humectant (preferably glycerol , propylene glycol, polyethylene glycol, 1,3-butylene glycol, sorbitol, polyethylene pyrrolidone carboxylate, sodium lactate, sodium hyaluronate, chitin derivatives, urea, amino acids, amino sugars, etc.). 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。 The ingredients are mixed to form a matrix, can be made not only as ointments, creams, lotions, coating agents, stickers and the like may also be topical liquid preparation. 此外还可制成眼科用的滴眼剂。 Furthermore ophthalmic eye drops can also be made.

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。 κ receptor agonist in the pharmaceutical composition in an amount of no particular limits, but the oral composition per dose usually 0.1μg-1000mg, external preparation composition should be applied each time to achieve normal 0.001ng / m2-10mg / m2 dose.

[实施例]本发明将通过实施例加以具体描述。 [Example] The present invention will be described in detail by way of examples. 但它们作为本发明的说明而并不使本发明仅限于此。 However, their use as illustrative of the invention and that the invention is not limited thereto.

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)-吗啡喃1 -3,14β- Dihydroxy -4,5α- epoxy-17-methyl -6β- (N- methyl iodide in Example 1 17-cyclopropylmethyl-embodiment - trans-3- (3-furyl ) acrylamide-based) - morphinan 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)吗啡喃、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。 The 2.0699g (4.3mmol) 17- cyclopropylmethyl -3,14β- dihydroxy -4,5α- epoxy -6β- (N- methyl - trans-3- (3-furyl) acrylamide ) morphinan, 60ml of ethyl acetate, 6ml of methanol and 1.3ml of iodomethane all placed in a sealed container, sealed and stirred under conditions of 100 ℃ of 4 days. 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。 After the reaction solution was then added to 60ml of methanol and the precipitated solid was dissolved and concentrated, the resulting residue was added to 400ml of distilled water. 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。 The aqueous solution with chloroform (100ml × 7) the aqueous phase was washed and concentrated, and the resulting residue was partitioned between ethyl acetate - methanol recrystallized, the resulting crystals were dissolved in 500ml of distilled water. 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。 The aqueous solution with chloroform (100ml × 3) was washed and the aqueous phase was concentrated, the resulting residue was recrystallized from methanol three times, to give 102mg of the title compound.

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(0.5H,s),8.03(0.4H,s),9.33(0.4Hs),9.72(0.6Hs). Melting point: 202.40-207.9 ℃ (decomposition) NMR (500MHz, DMSO-d6) δ0.38 (1H, m), 0.60 (1H, m), 0.70 (1H, m), 0.78 (1H, m), 1.23 (1.4 H, 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 (1.6 H, 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 = 8.3 Hz), 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 (0.5H, s), 8.03 (0.4H , s), 9.33 (0.4Hs), 9.72 (0.6Hs).

IR(KBr)v3460,1649,1595,1454,1410,1321,1158,1139,596cm-1. IR (KBr) v3460,1649,1595,1454,1410,1321,1158,1139,596cm-1.

Mass(FAB)m/z 491(M+H)+. Mass (FAB) m / z 491 (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)吗啡喃2 Elemental analysis: C29H35N2O5I1 · 0.5H2O Calcd: C, 55.51; H, 5.78; N, 4.46; I, 20.22 Found: C, 55.50; H, 5.86; N, 4.45; I, 20.23 Example 2 17- iodide cyclopropylmethyl -3,14β- dihydroxy -4,5α- epoxy-17-methyl -6β- (N- methyl-3-methoxy-cinnamic amide group) morphinan 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)吗啡喃、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。 The 2.0014g (3.9mmol) 17- cyclopropylmethyl -3,14β- dihydroxy -4,5α- epoxy -6β- (N- methyl-3-methoxy-cinnamic amide group) morphinan, 40ml tetrahydrofuran, and methyl iodide 1.3ml all placed in a sealed container, in a sealed container, and at 100 ℃ for 8 days. 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。 60ml of methanol was added to the reaction solution, the precipitated solid was dissolved and concentrated and the residue was dissolved in 120ml of chloroform and methanol mixture; of distilled water and then extracted with 200ml × 3. 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。 The aqueous phase was concentrated, the resulting residue in methanol - distilled water, recrystallized four times, to give 295mg of the title compound.

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). Melting point: 176.0-183.0 ℃ (decomposition) NMR (600MHz, DMSO-d6) δ0.37 (1H, m), 0.60 (1H, m), 0.70 (1H, m), 0.77 (1H, m), 1.23 (1.4 H, 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 (0.4 H, s), 9.63 (0.6H, s).

IR(KBr)v 3410,1642,1595,1491,1460,1410,1321,1274,857,793cm-1.Mass(FAB)m/z 531(M+H)+. IR (KBr) v 3410,1642,1595,1491,1460,1410,1321,1274,857,793cm-1.Mass (FAB) m / z 531 (M + H) +.

元素分析:C32H39N2O5I1·0.3H2O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317-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]吗啡喃-N-氧化物3 Elemental analysis: C32H39N2O5I1 · 0.3H2O Calcd: C, 57.89; H, 6.01; N, 4.22; I, 19.11 Found: C, 57.80; H, 5.86; N, 4.22; I, 19.14 Example 317- Cyclopropyl methyl -4,5α- epoxy -3,14β- dihydroxy -6β- [N- methyl - trans-3- (3-furyl) acrylamido-yl] -N- morphinan-oxide 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]吗啡喃溶解在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。 The 600mg (1.26mmol) 17- cyclopropylmethyl--4,5α- epoxy -3,14β- dihydroxy -6β- [N- methyl - trans-3- (3-furyl) acrylamido-yl] morphinan was dissolved in 30ml of tetrahydrofuran, at 0 ℃, 15 minute period the solution was added dropwise a solution of 348mg between 8ml of tetrahydrofuran-chlorobenzoic acid. 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。 After the dropwise addition, the reaction solution was stirred at room temperature for about 1.5 hours, with the addition of chloroform / methanol (4:1) the reaction mixture was dissolved in the solution precipitated solid. 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%)。 The solution was concentrated, the resulting residue was purified by column chromatography [containing 20g of basic alumina and eluted with chloroform / methanol (10:0-10:1)] was purified, the product with ethyl acetate - methanol and recrystallized to give 473mg of the title compound (76% yield).

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). Melting point: 238-239.8 ℃ (decomposition) 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)v 3420,1653,1605,1504,1408,1321,1160,872cm-1.Mass(FAB)m/z 493(M+H)+. IR (KBr) v 3420,1653,1605,1504,1408,1321,1160,872cm-1.Mass (FAB) m / z 493 (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417-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)吗啡喃-N-氧化物4 Elemental analysis: C28H32N2O6 · 0.2AcOEt Calcd: C, 67.80; H, 6.64; N, 5.49 Found: C, 67.80; H, 6.67; N, 5.65 Example 417-cyclopropylmethyl -4,5α- ring Oxygen -3,14β- dihydroxy -6β- (N- methyl-3-methoxy-cinnamic amide group) morphinan -N- oxide 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)吗啡喃溶解在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。 The 405mg17- cyclopropylmethyl -4,5α- epoxy -3,14β- dihydroxy -6β- (N- methyl-3-methoxy-cinnamic amide group) morphinan was dissolved in 20ml of tetrahydrofuran at 0 ℃, 10 minute period the solution was dissolved in 5ml of tetrahydrofuran was added dropwise a solution of 225mg inter-chlorobenzoic acid. 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%)。 After the addition was complete the reaction solution was stirred at room temperature for about 40 minutes, the reaction solution was concentrated, the resulting residue was purified on 20g of basic alumina column chromatography, and the product with ethyl acetate / methanol and recrystallized to give 329mg of the title compound (yield 79%).

熔点:234-236.8℃(分解)NMR(600MHz,CDCl3)δ·0.35(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). Melting point: 234-236.8 ℃ (decomposition) NMR (600MHz, CDCl3) δ · 0.35 (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)v 3420,1647,1593,1495,1408,1321,1160,917,855cm-1.Mass(FAB)m/z 533(M+H)+. IR (KBr) v 3420,1647,1593,1495,1408,1321,1160,917,855cm-1.Mass (FAB) m / z 533 (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517-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]吗啡喃-N-氧化物5 Elemental analysis: C31H36N2O6 · 0.3H2O Calcd: C, 69.20; H, 6.86; N, 5.21 Found: C, 69.11; H, 6.87; N, 5.21 Example 517- cyclopropylmethyl -4,5α- ring Oxygen -3,14β- dihydroxy -6β- [N- methyl-3- (4-trifluoromethylphenyl) propynyl amido] morphinan -N- oxide 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]吗啡喃溶解在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。 The 413mg17- cyclopropylmethyl -4,5α- epoxy -3,14β- dihydroxy -6β- [N- methyl-3- (4-trifluoromethylphenyl) propynyl amido] morphinan was dissolved in 20ml of tetrahydrofuran, at 0 ℃, 15 minute period and the solution was dissolved in 5ml of tetrahydrofuran was added dropwise a solution of 205mg inter-chlorobenzoic acid. 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%)。 After the dropwise addition, the reaction mixture was stirred at room temperature for about 1 hour, the solution was concentrated, the resulting residue was purified by basic alumina based 20g purified by column chromatography, product was ethyl acetate / methanol recrystallized, filtered and dried in vacuo, to obtain 304mg of the title compound (74% yield).

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). Melting point: 205-208 ℃ (decomposition) 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)v 3420,2224,1615,1506,1408,1325,1170,1129,1067cm-1.Mass(FAB)m/z 569(M+H)+. IR (KBr) v 3420,2224,1615,1506,1408,1325,1170,1129,1067cm-1.Mass (FAB) m / z 569 (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617-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]-吗啡喃-N-氧化物6 Elemental analysis: C31H31N2O5F3 · 0.2C6H12 · 0.1AcOEt Calcd: C, 65.89; H, 5.80; N, 4.71; F, 9.59 Found: C, 65.71; H, 5.86; N, 4.73; F, 9.52 Example 617 cyclopropylmethyl -4,5α- epoxy -3,14β- dihydroxy -6β- [N- methyl-3- (3-methylphenyl) propynyl amido] - morphinan -N--oxide 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]吗啡喃溶解在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。 The 408mg17- cyclopropylmethyl -4,5α- epoxy -3,14β- dihydroxy -6β- [N- methyl-3- (3-methylphenyl) propynyl amido] morphinan was dissolved in 20ml of tetrahydrofuran , and at 0 ℃, 15 minute period and the solution was added dropwise a solution of inter-chlorobenzoic acid 244mg 5ml of tetrahydrofuran. 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%)。 After the addition was complete the reaction was stirred at room temperature for about 1 hour, the reaction solution was concentrated, the resulting residue was purified on 20g of basic alumina column chromatography, and the product with ethyl acetate / methanol recrystallized, filtered and dried in vacuo, The title compound was prepared to give 269mg (64% yield).

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)v 3410,2218,1622,1489,1439,1408,1377,1321,1125,1033,915,690cm-1. Melting point: 192.0-202.0 ℃ (decomposition) 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 (0.7 H, 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) v 3410,2218,1622,1489,1439,1408,1377,1321,1125,1033,915,690cm-1.

Mass(FAB)m/z 515(M+H)+. Mass (FAB) m / z 515 (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 Elemental analysis: C31H34N2O5 · 0.5H2O Calcd: C, 71.11; H, 6.74; N, 5.35 Found: C, 71.16; H, 6.73; N, 5.37 Example 7

采用豚鼠回肠摘出标本测定阿片类活性试验。 Guinea pig ileum was excised specimen measured opioid activity test.

以Hartley雄性豚鼠作为试验对象。 Male Hartley guinea pigs in a test object. 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。 The fatal blow and cut guinea pig ileum, ileal luminal nutrient solution only cleaning and stripping down its longitudinal muscle. 将该纵向肌束悬于装有Krebes-Henseleit溶液(NaCl 135mM;KCl 4.8mM;CaCl23.4mM;NaH2PO41.2mM;NaHCO38.3mM;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。 The longitudinal muscle bundle Krebes-Henseleit solution containing suspended (NaCl 135mM; KCl 4.8mM; CaCl23.4mM; NaH2PO41.2mM; NaHCO38.3mM; MgSO42.5mM; and glucose 11mM) and maintained at 37 ℃, filled with 5% carbon dioxide and 95% oxygen gas mixture Magnus (Magnus) tube. 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。 By Magnus tubes are located upper and lower platinum electrode Wheel 0.5ms, 0.1Hz applied electrical stimulation. 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。 Contractile tissue may be recorded on a polygraph by isomeric Keiki conductor.

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。 Under with or without naloxone as a μ antagonist, or as a κ antagonist nor-BNI conditions, test drug was cumulatively added until the specimen by contraction induced by electric stimulation was inhibited up to 50% of the drug concentration calculate IC50 the respective case. 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。 According pharmacodynamic differences with or without antagonist when, by the following formula to calculate the Ke value.

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。 Ke = [concentration of added antagonist / (IC50 ratio -1) IC50 ratio = IC50 IC50 / antagonists when used without the antagonist compound is used as the test drug 1,2,3,4,5,6 As a result, when obtained as shown in Table 3 Ke (μ) and Ke (κ) ratio, Ke (μ) / Ke (κ) = 182-∞, indicates that the compounds of the present invention is the choice acting on κ receptor agonists.

表3.豚鼠回肠摘出标本评估的化合物的阿片类活性 Opioid activity Table 3. Summary of guinea pig ileum specimens evaluate compounds

实施例8通过小鼠输精管摘出标本测定阿片类活性。 Example 8 mouse vas deferens measuring opioid activity.

试验采用ddy雄性小鼠。 Test using ddy male mice. 从动物身上取出的输精管标本悬挂在装有Krebes-Henseleit溶液(NaCl 120.7mM;KCl 5.9mM;CaCl22.5mM;NaH2PO41.2mM;NaHCO315.5mM;和葡萄糖11M)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。 Vas deferens extracted from the animal suspended specimens containing Krebes-Henseleit solution (NaCl 120.7mM; KCl 5.9mM; CaCl22.5mM; NaH2PO41.2mM; NaHCO315.5mM; and glucose 11M) and maintained at 37 ℃, filled with the Magnus tube gas mixture of 5% carbon dioxide and 95% oxygen in the composition. 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。 Applying electrical stimulation to 1.0ms 0.1Hz located Magnus tube through the top and bottom of the wheel platinum electrodes. 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。 Contractile tissue can be recorded on a multi-channel polygraph by isomeric conductor.

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。 With or without the use of naloxone as a μ antagonist, or as both cases κ antagonist nor-BNI, the test drug was cumulatively added until the contraction induced by electrical stimulation of the subject of the inhibition of 50%, IC50 calculated for each test case, based on the following formula and pharmacodynamic differences Ke values were calculated according to the use or non-use of antagonists.

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。 Ke = [concentration of added antagonist / (IC50 ratio -1) IC50 ratio = IC50 of antagonist / IC50 in the absence of antagonist when the compound 1,2,3,4,5 and 6 as the test drug, calculating Ke (μ) with respect to the ratio of Ke (κ), and Ke (δ) according to the data in Table 4 with respect to the ratio of Ke (κ) of, Ke (μ) / Ke (κ) = 18 ~ ∞, Ke (δ ) / Ke (κ) = 15 ~ ∞, illustrate the compounds of this invention are selective effect on κ receptor agonists.

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) Table 4. mouse vas deferens opioid compounds measured activity IC50 (nM) Ke (nM)

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]吗啡喃盐酸盐7, Example 9 A selective κ opioid receptor agonist compound having, (-) - 17- (cyclopropylmethyl) -3,14β- dihydroxy -4,5α- epoxy -6β- [N - methyl - trans-3- (3-furyl) acrylamido-yl] morphinan hydrochloride 7, 溶解在生理盐水中以制得浓度为40μg/ml的水溶液。 Dissolved in physiological saline to obtain a concentration of 40μg / ml aqueous solution. 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。 The solution is applied to the concentration of 0.2μg / cm2 of adult men in hives at the lower extremity of the three parts of redness.

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“-”)。 The results showed that before treatment for moderate itching (ranked as "++") at 5 minutes after being completely eliminated (ranked as "-"). 此后的约5小时内没有出现瘙痒。 No itching within a further about 5 hours.

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。 Example 10 Compound 7 applied on the aqueous solution in a patient with atopic dermatitis and complicated with severe itching (ranked as "+++") of the female patient's arm and leg skin surface. 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。 The drug solution per 10cm2 of about 50μl, coated drug concentration of 0.2μg / cm2, administered at five sites. 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。 As a comparison, indomethacin cream (drug concentration of 7.5mg / g) in the same manner as 75μg / cm2 coating.

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。 As shown in Table 5, in an aqueous solution of the compound 7 is applied for 5 minutes after all be able to completely eliminate itching. 这证明化合物7具有显著的止痒作用。 This proves that the compound 7 has a significant role in itching. 此外,至少在3小时内没有出现瘙痒。 Further, no itching at least within 3 hours. 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。 In contrast, patients in the use of indomethacin cream does not completely eliminate itching, can be drawn in this case is seen antipruritic activity, the compounds 7 than indomethacin cream more effective.

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 Table 5 κ receptor agonist (compound 7) and indomethacin cream for atopic dermatitis, pruritus itching effect induced by type

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。 Example 11 κ receptor antagonist nor-BNI rostral back after subcutaneous administration of DDY mice to investigate the consequent itching, itching due to the number of mice independently, whether κ receptor agonists inhibited. 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。 At this point, with a pH 4-6 buffer instead of nor-BNI in rat rostral back subcutaneous injection, the mice do not produce self-scratching behavior.

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。 The a selective κ opioid receptor agonistic compounds, i.e., trans-2- (3,4-dichlorophenyl) -N- methyl -N- [2- (1- pyrrolidinyl) ring hexyl] acetamide (see U-50488H) was dissolved in physiological saline, the aqueous solution of 1,3 or 10mg / kg dose the mice were intraperitoneally administered 30 minutes after administration, the effect of induced pruritus 0.1% solution of nor-BNI with 0.1ml / 10g (body weight), the ratio by rostral back subcutaneously. 给予nor-BNI后60分钟的时间内对搔痒行为的次数进行计数。 Within 60 minutes after administration of nor-BNI on the number of scratching behavior was counted.

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。 The other control drug, i.e. antihistamines chlorpheniramine dissolved in physiological saline, and the same from the rostral back the solution to 0.3, 1.0 and 3.0mg / kg dose the mice were intraperitoneally administered. 用药30分钟后,同样从嘴侧背部给予nor-BNI。 30 minutes after administration, nor-BNI give the same side from the back of the mouth. 并记录给药60分钟内搔痒行为的次数。 Within 60 minutes of administration and record the number of scratching behavior. 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。 When the third test, as control, saline-treated using a test group, and then so that the test group received nor-BNI and within less than 60 minutes on the number of scratching behavior was counted. 上述实验每组动物数均为10只。 These experiments were 10 animals in each group number.

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。 The results are shown in Figure 1, in the saline-treated group, a significant increase in the number of times by nor-BNI administration induced scratching behavior. 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。 While using U-50488H treated group, the number of scratching behavior induced by nor-BNI significantly reduced. 该结果表示待测物质具有显著的止痒作用。 This result indicates that the test substance has a significant antipruritic effect. 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。 On the other hand, the number of scratching behavior chlorpheniramine treated group, although reduced, but the extent of decrease is lower than U-50488H treated group antipruritic effect of U-50488H is more effective.

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。 Example 12 purchased from Japan SLC ddy male mice of four weeks old and after acclimation for experiments in the fifth week. 实验前一天,将其嘴侧背部皮肤上的毛发用剪刀剪去。 One day before the experiment, the hair of its rostral back skin cut with scissors. 各待测药物都溶解在10%的DMSO中。 Each drug to be tested were dissolved in 10% DMSO. 将待测药物或溶剂经皮下给药进入到小鼠的嘴侧背部。 The test drug or solvent was administered subcutaneously into rostral back of the mouse. 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。 After 30 minutes, the compound dissolved in physiological saline 48/80 to 50μl (100μg / each place) at a dose of hair removal site intradermal administration. 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。 The mice were then immediately placed in a cage (10 × 7 × 16cm) and observe, in the absence of case records within 30 minutes of scratching behavior induced by television cameras. 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。 Reproducing video tape and thereafter pawl compound 48/80 in the treatment site and the number of scratching behavior was counted in the nearby area. 每组包括8-10只受试动物。 Each group contained 8-10 animals tested.

待测化合物的搔痒抑制百分率通过下列公式来计算。 Itching of the test compound the percentage of inhibition was calculated by the following equation. 具有减少瘙痒作用可作为待测物的止痒效果的指标。 Has the effect of reducing the itching can be used as indicators of analyte itching effect.

搔痒行为抑制率(%)=[1-(AC/BC)]×100A=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)-吗啡喃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]吗啡喃-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]吗啡喃-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]吗啡喃-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]吗啡喃盐酸盐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)吗啡喃酒石酸盐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]吗啡喃甲基磺酸盐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)吗啡喃盐酸盐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)吗啡喃盐酸盐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)吗啡喃酒石酸盐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)-吗啡喃盐酸盐13、17-环丙基甲基-3,14β-二羟基-4,5α-环氧-6β-(N-苄氧基脲基)吗啡喃盐酸盐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)吗啡喃盐酸盐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]吗啡喃氢溴酸盐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]吗啡喃盐酸盐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]吗啡喃盐酸盐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]吗啡喃盐酸盐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。 Scratching behavior inhibition rate (%) = [1- (AC / BC)] × 100A = average number of scratching the test group B = the test drug test drug with a solvent to replace the test group C = average number of times with a solvent itching Replace itch agent itching average number of the test compound test groups used include: 17-cyclopropylmethyl--3,14β- dihydroxy -4,5α- epoxy-17-methyl -6β- (N - methyl-3-methoxy-cinnamic amide yl) - morphinan  cyclopropylmethyl iodide salt 2,17- dihydroxy -4,5α- -3,14β- epoxy -6β- [N- A yl - trans-3- (3-furyl) acrylamido-yl] -N- oxide morphinan cyclopropylmethyl -3,14β- 3,17-dihydroxy -4,5α- epoxy -6β- [ N- methyl-3- (4-trifluoromethylphenyl) propynyl amido] morphinan -N- cyclopropylmethyl -3,14β- oxide 5,17- dihydroxy -4,5α- epoxy -6β- [N- methyl-3- (3-methylphenyl) propynyl amido] morphinan oxide 6,17- -N- (cyclopropylmethyl) -3,14β- dihydroxy - 4,5α- epoxy -6β- [N- methyl - trans-3- (3-furyl) acrylamido-yl] morphinan hydrochloride 7,17- dihydroxy cyclopropylmethyl -3,14β- -4,5α- epoxy -6β- (N- methyl-3-methoxy-cinnamic amide group) morphinan tartrate Preparation of 8,17-dihydroxy-cyclopropylmethyl -3,14β- -4,5α- Epoxy -6β- [N- (1,4- dioxo-4-methoxy - trans-2-butenyl) -N- methyl] morphinan methanesulfonate 9,17- cyclopropyl methyl -3,14β- dihydroxy -4,5α- epoxy -6β- (N- methyl-3,4-dichlorophenyl-acetamido) morphinan hydrochloride 10,17- cyclopropylmethyl yl -3,14β- dihydroxy -4,5α- epoxy -6β- (N- methyl-cinnamic amide group) morphinan hydrochloride 11,17- cyclopropylmethyl -3,14β- dihydroxy -4 , 5α- epoxy -6α- (N- methyl -N'- benzylureido) morphinan tartrate 12,17- cyclopropylmethyl -3,14β- dihydroxy -4,5α- epoxy - 6β- (N- methyl-benzyloxy ureido) - morphinan hydrochloride 13,17- cyclopropylmethyl -3,14β- dihydroxy -4,5α- epoxy -6β- (N- benzyloxycarbonyl ylureido) morphinan hydrochloride 14,17- cyclopropylmethyl -3,14β- dihydroxy -4,5α- epoxy -6α- (N- tolyl methylsulfonylamino) morphinan hydrochloride salt 15,17- (cyclopropylmethyl) -3,14β- dihydroxy -4,5α- epoxy -6β- [N- methyl - trans-3- (4-bromo-2-thienyl) acrylamido-yl] morphinan hydrobromide 16,17-dihydroxy-cyclopropylmethyl -3,14β- -4,5α- epoxy -6β- [N- methyl-3- (phenyl) propyne amido] morphinan hydrochloride 17,17-dihydroxy-cyclopropylmethyl -3,14β- -4,5α- epoxy -6β- [N- methyl-3- (3-methylphenyl) propynyl amido] morphinan hydrochloride 18,17- cyclopropylmethyl -3,14β- dihydroxy -4,5α- epoxy -6β- [N- methyl-3- (4-trifluoromethylphenyl yl) propargyl alcohol amido] morphinan hydrochloride 19,2- (3,4-dichlorophenyl) -N- methyl -N- [1- phenyl-2- (1-pyrrolidinyl) ethyl] acetamide hydrochloride 20,3- (1-pyrrolidinylmethyl) -4- [5,6-dichloro-1-indene carbonyl group (indancarbonyl)] - tetrahydro-1,4-thiazol hydrochloride 21 trans -N- methyl -N- [2- (1- pyrrolidinyl) cyclohexyl] benzo [b] thiophene -4- acetamide hydrochloride 22, and (5β, 7β, 8α) -N- methyl -N- [7- (1- pyrrolidinyl) -1-oxa-spiro [4.5] dec-8-yl] benzo [b] furan--4- acetamide hydrochloride salt 23.

表6概括了试验的结果。 Table 6 summarizes the results of the test. 试验中的待测化合物以所用剂量显示止痒活性。 Test test compound to the dose display antipruritic activity.

表6.多种阿片κ受体激动剂的止痒功效 Table 6. A variety of κ opioid receptor agonist efficacy itching

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。 Industrial Applicability An antipruritic of this invention comprises as an effective component κ opioid receptor agonist, and concurrent itching skin diseases, e.g., atopic dermatitis, neurodermatitis, contact dermatitis, seborrheic dermatitis, their atopic dermatitis, caterpillar (caterpillar) dermatitis, sebum deficiency, senile pruritus, insect bites, light sensitization dermatitis, urticaria, prurigo, herpes, impetigo, eczema, psoriasis, lichen, psoriasis, scabies and acne vulgaris; itching concurrent visceral disease, such as cancer, diabetes, liver disease, kidney failure, hemodialysis and pregnancy treatments are very effective.

Classifications
International ClassificationA61K31/541, A61K31/4025, C07D489/08, A61K31/5377, A61K31/435, A61K31/40, A61K31/485, A61P17/04, C07D489/00
Cooperative ClassificationA61K31/4025, A61K31/40, A61K31/435, C07D489/08, A61K31/485, C07D489/00, A61K31/5377, A61K31/541
European ClassificationA61K31/40, A61K31/435, A61K31/485, C07D489/00, C07D489/08, A61K31/5377, A61K31/4025, A61K31/541
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