WO2019134510A1

WO2019134510A1 - Short peptide quaternary ammonium salt compound and use thereof

Info

Publication number: WO2019134510A1
Application number: PCT/CN2018/121939
Authority: WO
Inventors: 蔡家强; 田强; 赵明亮; 吴雷; 王利春; 王晶翼
Original assignee: 四川科伦博泰生物医药股份有限公司
Priority date: 2018-01-03
Filing date: 2018-12-19
Publication date: 2019-07-11
Also published as: CN111315758A

Abstract

Disclosed is a short peptide quaternary ammonium salt compound and a use thereof. In particular, disclosed is a type of short peptide quaternary ammonium salt compound or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester, or a pharmaceutical composition thereof, and a method of preparing the compound and a use in the prevention or treatment of diseases associated with kappa-type opioid receptors. The polyamide compound of the present invention has excellent kappa-type opioid receptor agonist potency, hydrophilic ability and thus reduced penetration of the blood-brain barrier and reduced ability to enter the brain. The compound of the invention has excellent drug properties, such as higher selectivity to kappa-type opioid receptors, reduced addictiveness, improved pharmacokinetic properties, improved safety, good patient compliance, and/or is less prone to induce drug-tolerance.

Description

短肽季铵盐化合物及其用途Short peptide quaternary ammonium salt compound and use thereof

技术领域Technical field

本发明涉及医药领域，具体涉及一种短肽季铵盐化合物，包含其的药物组合物及其在预防或治疗κ阿片样物质受体相关的疾病中的用途。The present invention relates to the field of medicine, and in particular to a short peptide quaternary ammonium salt compound, a pharmaceutical composition comprising the same, and use thereof for preventing or treating a disease associated with kappa opioid receptor.

背景技术Background technique

阿片样物质受体(μ、δ和κ)广泛存在于中枢神经***和外周神经***。传统阿片样物质受体激动剂(如***及其衍生物)是治疗慢性关节炎、炎症性神经痛、术后疼痛以及各种癌症引起的中到重度疼痛的最有效的药物。但全身施用传统阿片类镇痛药物会产生副作用，如呼吸抑制、药物成瘾、便秘、恶心、意识模糊和产生耐受等。κ阿片样物质受体激动剂与μ阿片样物质受体激动剂不同，其不会导致呼吸抑制和便秘，并且研究表明其成瘾性更低(Clark C,Halfpenny P,Hill R等人,J.Med.Chem.,1988,31 831-836)。通过向外周患处直接施用低剂量的κ阿片样物质受体激动剂不会产生全身反应，从而避免了镇定和焦虑等不期望的症状。在机体正常情况下外周施用阿片样物质受体激动剂没有任何镇痛效果，在有炎症或组织损伤时，外周阿片样物质受体功能增强，在施用阿片样物质受体激动剂后发挥镇痛效果(Persson T,Calafat J,Janssen H等人,Biochem.Biophys.Res.Commun.,2002,291,844-854)。另外，机体对于κ阿片样物质受体激动剂也不容易产生耐受(Stein A,Helmke K,Szopko C等人,Dtsch.Med.Wochenschr.,1996,121,255)。Opioid receptors (μ, δ, and κ) are widely present in the central nervous system and the peripheral nervous system. Traditional opioid receptor agonists, such as morphine and its derivatives, are the most effective drugs for the treatment of chronic arthritis, inflammatory neuralgia, postoperative pain, and moderate to severe pain caused by various cancers. However, systemic administration of traditional opioid analgesics can cause side effects such as respiratory depression, drug addiction, constipation, nausea, confusion, and tolerance. Unlike κ opioid receptor agonists, κ opioid receptor agonists do not cause respiratory depression and constipation, and studies have shown that they are less addictive (Clark C, Halfpenny P, Hill R et al, J .Med.Chem., 1988, 31 831-836). Direct administration of a low dose of a kappa opioid receptor agonist to the affected area does not produce a systemic response, thereby avoiding undesirable symptoms such as calming and anxiety. Peripheral administration of opioid receptor agonists does not have any analgesic effect under normal conditions in the body. In the presence of inflammation or tissue damage, peripheral opioid receptor function is enhanced and analgesia is exerted after administration of the opioid receptor agonist. Effect (Persson T, Calafat J, Janssen H et al, Biochem. Biophys. Res. Commun., 2002, 291, 844-854). In addition, the body is also less susceptible to tolerance to kappa opioid receptor agonists (Stein A, Helmke K, Szopko C et al, Dtsch. Med. Wochenschr., 1996, 121, 255).

Auh和Ro等人向SD大鼠右后足跖面注射完全弗氏佐剂(complete Freund’s adjuvant,CFA)引起痛觉过敏，3天后在大鼠右后足跖面注射三种浓度的U50488(一种特异性κ阿片样物质受体激动剂)。该研究结果表明：外周施用κ阿片样物质受体激动剂能明显减轻疼痛和痛觉过敏，并且在高剂量下，抗痛觉过敏作用的性别差异更加明显，这一结果在临床疼痛模型中也进一步得到证实(Auh QS,Ro JY.Neurosci.Lett.,2012,524,111-115)。有报道表明激活κ阿片样物质受体能够抑制炎症痛觉过敏，其机制可能通过nNOS/NO信号通路来刺激PI3Kγ/AKT信号而实现(Cunha TM,Souza GR,Domingues AC等人,Mol.Pain,2012,8,10)。Auh and Ro et al. injected complete Freund's adjuvant (CFA) into the right hind paw of SD rats to induce hyperalgesia. Three days later, three concentrations of U50488 were injected into the right hind paw of the rat. Specific kappa opioid receptor agonist). The results of this study indicate that peripheral administration of κ opioid receptor agonists significantly reduces pain and hyperalgesia, and at high doses, the gender difference in anti-hyperalgesic effects is more pronounced, and this result is further obtained in clinical pain models. Confirmed (Auh QS, Ro JY. Neurosci. Lett., 2012, 524, 111-115). It has been reported that activation of kappa opioid receptors can inhibit inflammatory hyperalgesia, and its mechanism may be achieved by stimulating PI3K gamma/AKT signaling through the nNOS/NO signaling pathway (CunhaTM, Souza GR, Domingues AC et al., Mol. Pain, 2012). , 8, 10).

第一代κ阿片样物质受体激动剂包括螺朵林(Spiradoline)和依那朵林(Enadoline)，将这些药物口服给药后，其可以进入脑部。虽然在起效剂量下，上述药物的副作用要小于***，但还是由于其产生的躁动和致幻等副作用而停止了对其的进一步开发。第二代κ阿片样物质受体激动剂(例如阿西马朵林(Asimadoline))与第一代κ阿片样物质受体激动剂的化学结构类似，但其外周选择性更高(Barber A,Bartoszyk G,Bender H等人,Br.J.Pharmacol.1994,113,1317-1327)。然而由于在许可剂量下的麻醉效果较差，已经放弃将其作为阿片类麻醉品的开发，而是将其用于治疗消化***疾病，例如肠易激综合征(Camilleri M.Neurogastroenterol.Motil.,2008,20,971-979)。The first generation of kappa opioid receptor agonists, including Spiradoline and Enadoline, can be administered to the brain after oral administration of these drugs. Although the above-mentioned drugs have less side effects than morphine at the effective dose, they are stopped from further development due to side effects such as agitation and hallucination. Second-generation kappa opioid receptor agonists (such as Asimadoline) have similar chemical structures to first-generation κ opioid receptor agonists, but have higher peripheral selectivity (Barber A, Bartoszyk G, Bender H et al, Br. J. Pharmacol. 1994, 113, 1317-1327). However, due to the poor anesthetic effect at the licensed dose, it has been abandoned as an opioid narcotics, but is used to treat digestive diseases such as irritable bowel syndrome (Camilleri M. Neurogastroenterol. Motil., 2008, 20, 971-979).

CN101627049B公开了一类具有多酰胺结构的合成肽，其可作为κ阿片样物质受体的配体。CN101627049B discloses a class of synthetic peptides having a polyamide structure which acts as a ligand for a kappa opioid receptor.

虽然现有技术中已经存在一些κ阿片样物质受体激动剂，但是仍然需要具有高度外周选择性的新型κ阿片样物质受体激动剂。Although some kappa opioid receptor agonists already exist in the prior art, there is still a need for novel kappa opioid receptor agonists with high peripheral selectivity.

发明内容Summary of the invention

本申请发明人通过深入的研究和创造性的劳动，惊喜地获得一类新的短肽季铵盐化合物，这类新型短肽季铵盐化合物不仅具有优异的κ阿片样物质受体激动效能(对κ阿片样物质受体的高亲和力)，还具有非常大的亲水能力和由此更小的穿透血脑屏障以及更低的进入脑部的能力。The inventors of the present application have surprisingly obtained a new class of short peptide quaternary ammonium salt compounds through intensive research and creative labor. These novel short peptide quaternary ammonium salt compounds not only have excellent kappa opioid receptor agonistic efficacy (right The high affinity of the kappa opioid receptor) also has a very large hydrophilic capacity and thus a smaller penetration of the blood-brain barrier and a lower ability to enter the brain.

因此，本方面的一方面提供一种短肽季铵盐化合物，或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯，其中所述化合物为含有式(I)结构的盐：Accordingly, an aspect of the present invention provides a short peptide quaternary ammonium salt compound, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, Wherein the compound is a salt comprising a structure of formula (I):

其中：among them:

R _a和R _b各自独立地选自H、氘、卤素、羟基、C _1-6烷氧基、氨基、硝基、氰基、C _1-6烷基、C _1-6卤代烷基、-CONH ₂、C _3-10环烷基、3-10元杂环基、C _6-10芳基和5-10元杂芳基的基团取代；优选H、氘； R _a and R _b are each independently selected from the group consisting of H, hydrazine, halogen, hydroxy, C _1-6 alkoxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, -CONH _a group of C _3-10 cycloalkyl, 3-10 membered heterocyclic, C _6-10 aryl and 5-10 membered heteroaryl; preferably H, hydrazine;

n各自独立的选自0、1、2、3、4、5；n are each independently selected from 0, 1, 2, 3, 4, 5;

p为0～6中的任一整数；优选2～4中任一整数；p is any integer from 0 to 6; preferably any integer from 2 to 4;

R _c和R _d各自独立地选自H、氘、C _1-6烷基、C _1-6卤代烷基、卤素、羟基、C _1-6烷氧基、巯基、C _1-6烷基巯基、氨基、-CONH ₂、C _3-10环烷基、3-10元杂环基、C _6-10芳基和5-10元杂芳基的基团取代；优选H、氘、C _1-6烷基，更优选H、氘、C _1-4烷基； R _c and R _d are each independently selected from the group consisting of H, hydrazine, C _1-6 alkyl, C _1-6 haloalkyl, halogen, hydroxy, C _1-6 alkoxy, fluorenyl, C _1-6 alkyl fluorenyl, Substituent substitution of amino, -CONH ₂ , C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl; preferably H, 氘, C _1-6 An alkyl group, more preferably H, hydrazine, C _1-4 alkyl;

R _x、R _y、R _z各自独立地选自C _1-6烷基、C _3-10环烷基、3-10元杂环基、C _1-6烷氧基烷基、PEG、氧负离子；上述C _1-6烷基、C _3-10环烷基、3-10元杂环基、C _1-6烷氧基烷基、PEG还可任意地被一个或多个羟基、C _1-6烷氧基、氨基、烷胺基、脒基、胍基、叠氮基、卤素、羧酸、酯基、酰胺基、磺酸、磺酰胺、磷酸、磷酸酯、磷酰胺、磷酰胺酯、C _6-10芳基、5-10元杂芳基取代；优选R _x、R _y、R _z各自独立地选自C _1-6烷基；更优选R _x、R _y、R _z各自独立地选自C _1-4烷基； R _x , R _y , R _z are each independently selected from C _1-6 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic, C _1-6 alkoxyalkyl, PEG, oxygen anion The above C _1-6 alkyl group, C _3-10 cycloalkyl group, 3-10 membered heterocyclic group, C _1-6 alkoxyalkyl group, PEG may also be optionally subjected to one or more hydroxyl groups, C _{1- 6} alkoxy, amino, alkylamino, decyl, decyl, azide, halogen, carboxylic acid, ester, amide, sulfonic acid, sulfonamide, phosphoric acid, phosphate, phosphoramide, phosphoramidate, C _6-10 aryl, 5-10 membered heteroaryl substituted; preferably R _x , R _y , R _z are each independently selected from C _1-6 alkyl; more preferably R _x , R _y , R _z are each independently Selected from C _1-4 alkyl;

或者R _x、R _y和R _z中的任意两个与所连氮原子成环，所述的环为4-8元杂环； Or any two of R _x , R _y and R _z are ring-bonded to the nitrogen atom to which they are attached, said ring being a 4-8 membered heterocyclic ring;

R _e可选自： R _{e can} be selected from:

优选R _e为

Preferably R _e is

其中以上对于R _e所述的结构中向左侧伸出的键表示所述结构与式(I)分子的其余部分键接，即： The bond extending to the left in the structure described above for R _e indicates that the structure is bonded to the rest of the molecule of formula (I), namely:

R _e可选自： R _{e can} be selected from:

优选R _e为

Preferably R _e is

所述的盐选自其药学上可接受的盐，其药学上可接受的盐包括但不限于乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己氨磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、盐酸盐、氢溴酸盐、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、糖二酸盐、硬脂酸盐、丁二酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐。优选其药学上可接受的盐选自乙酸盐、盐酸盐和三氟乙酸盐。The salt is selected from pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts thereof include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, Bicarbonate/carbonate, hydrogen sulfate/sulfate, borate, camphorsulfonate, citrate, cyclohexamethanesulfonate, ethanedisulfonate, ethanesulfonate, formate, Fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide/iodide, isethionate, milk Acid salt, malate, maleate, malonate, methanesulfonate, methyl sulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, whey Acid salt, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, sugar diacid salt, stearate, succinate, Tannin, tartrate, tosylate, trifluoroacetate. Preferably, the pharmaceutically acceptable salt thereof is selected from the group consisting of acetates, hydrochlorides and trifluoroacetates.

本发明的另一方面提供一种药物组合物，其包含预防或治疗有效量的本发明所述化合物或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯以及一种或多种药学上可接受的载体。Another aspect of the invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a stereoisomer, polymorph, solvate thereof, or a metabolite thereof, a prodrug thereof, or A pharmaceutically acceptable salt or ester and one or more pharmaceutically acceptable carriers.

在本发明中，所述的药物组合物，其通过口服、静脉内、动脉内、皮下、腹膜内、肌内或经皮途径给药。In the present invention, the pharmaceutical composition is administered orally, intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly or transdermally.

本发明的另一方面提供本发明的化合物，或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯或本发明的药物组合物在制备用于预防或治疗与κ阿片样物质受体相关的疾病的药物中的用途。Another aspect of the invention provides a compound of the invention, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical combination of the invention Use of a medicament for the preparation of a medicament for the prevention or treatment of a disease associated with a kappa opioid receptor.

本发明的另一方面提供本发明的化合物，或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯或本发明的药物组合物，其用于预防或治疗与κ阿片样物质受体相关的疾病。Another aspect of the invention provides a compound of the invention, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical combination of the invention A substance for preventing or treating a disease associated with a kappa opioid receptor.

本发明另一方面提供一种预防或治疗与κ阿片样物质受体相关的疾病的方法，其包括向有此需要的受试者施用有效量的本发明的化合物，或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯或本发明的药物组合物。Another aspect of the invention provides a method of preventing or treating a disease associated with a kappa opioid receptor comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a stereoisomer thereof, A polymorph, a solvate, or a metabolite thereof, a prodrug or a pharmaceutically acceptable salt or ester or a pharmaceutical composition of the invention.

在本发明中，所述的与κ阿片样物质受体相关的疾病选自疼痛、炎症、瘙痒、水肿、低钠血症、低钾血症、肠梗阻、咳嗽和青光眼；优选地，所述疼痛选自神经性疼痛、躯体痛、内脏痛和皮肤痛；优选地，所述疼痛选自关节炎疼痛、肾结石疼痛、子宫痉挛、痛经、子宫内膜异位症、外科手术后疼痛、医疗处理后疼痛、眼部疼痛、耳炎疼痛、癌症疼痛和胃肠道紊乱相关的疼痛。In the present invention, the disease associated with the kappa opioid receptor is selected from the group consisting of pain, inflammation, itching, edema, hyponatremia, hypokalemia, intestinal obstruction, cough and glaucoma; preferably, said The pain is selected from the group consisting of neuropathic pain, somatic pain, visceral pain, and skin pain; preferably, the pain is selected from the group consisting of arthritic pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, post-surgical pain, medical treatment Post-treatment pain, eye pain, otitis pain, cancer pain, and pain associated with gastrointestinal disorders.

本发明另一方面提供本发明的化合物，或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯或本发明的药物组合物用于制备试剂的用途，其中所述试剂用于提高细胞中κ阿片样物质受体水平或活性；优选地，所述细胞为细胞系或来自受试者的细胞；优选地，其用于体内方法中；优选地，其用于体外方法中。Another aspect of the invention provides a compound of the invention, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the invention Use for the preparation of a reagent, wherein the agent is for increasing a level or activity of a kappa opioid receptor in a cell; preferably, the cell is a cell line or a cell from a subject; preferably, it is for use in vivo In the method; preferably, it is used in an in vitro method.

本发明另一方面提供本发明的化合物，或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯或本发明的药物组合物，其用于提高细胞中κ阿片样物质受体水平或活性；优选地，所述细胞为细胞系或来自受试者的细胞；优选地，其用于体内方法中；优选地，其用于体外方法中。Another aspect of the invention provides a compound of the invention, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the invention Is used to increase the level or activity of a kappa opioid receptor in a cell; preferably, the cell is a cell line or a cell from a subject; preferably, it is used in an in vivo method; preferably, it is used In vitro methods.

本发明的另一方面是提供一种提高细胞中κ阿片样物质受体水平或活性的方法，其包括给所述细胞施用有效量的本发明的化合物，或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯或本发明的药物组合物；优选地，所述细胞为细胞系或来自受试者的细胞；优选地，所述方法在体内进行；优选地，所述方法在体外进行。Another aspect of the invention provides a method of increasing the level or activity of a kappa opioid receptor in a cell comprising administering to said cell an effective amount of a compound of the invention, or a stereoisomer, polymorph thereof Or a pharmaceutically acceptable salt or ester thereof or a pharmaceutical composition of the invention; preferably, the cell is a cell line or a cell from a subject; preferably, The method is carried out in vivo; preferably, the method is carried out in vitro.

具体实施方式Detailed ways

定义definition

除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。Unless otherwise defined below, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques that are generally understood in the art, including those that are obvious to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the invention.

术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。The terms "comprising," "comprising," "having," "containing," Or method steps.

如本文中所使用，术语“短肽季铵盐化合物”是指符合本申请中任一通式的化合物、其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯。所述短肽季铵盐化合物优选含有由相同或不同的L-氨基酸或D-氨基酸缩合形成的一个或多个酰胺键。The term "short peptide quaternary ammonium salt compound" as used herein refers to a compound, a stereoisomer, a polymorph, a solvate thereof, or a metabolite thereof, a prodrug thereof, or a compound according to any one of the formulae herein. A pharmaceutically acceptable salt or ester. The short peptide quaternary ammonium salt compound preferably contains one or more amide bonds formed by condensation of the same or different L-amino acid or D-amino acid.

如本文中所使用，术语“烷基”定义为饱和脂肪族烃基，所述饱和脂肪族烃包括直链及支链饱和脂肪族烃基。在一些实施方案中，烷基具有1至6个，例如1至4个碳原子。例如，如本文中所使用，术语“C _1-6烷基”指1至6个碳原子的直链或支链的饱和脂肪族烃基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基或正己基)；在一些实施方案中，所述C _1-6烷基任选地被1或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代C _1-6烷基”或“C _1-6卤代烷基”，例如CF ₃、C ₂F ₅、CHF ₂、CH ₂F、CH ₂CF ₃、CH ₂Cl或-CH ₂CH ₂CF ₃等)。术语“C _1-4烷基”指1至4个碳原子的直链或支链的饱和脂肪族烃基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。 As used herein, the term "alkyl" is defined as a saturated aliphatic hydrocarbon group, and the saturated aliphatic hydrocarbon includes straight-chain and branched saturated aliphatic hydrocarbon groups. In some embodiments, an alkyl group has from 1 to 6, such as from 1 to 4 carbon atoms. For example, as used herein, the term " _C1-6 alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group of 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl) , n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl); in some embodiments, the C _1-6 alkyl is optionally 1 or more (such as 1 Up to 3) suitable substituents such as halogen (wherein the group is referred to as "halogenated C _1-6 alkyl" or "C _1-6 haloalkyl", such as CF ₃ , C ₂ F ₅ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ , CH ₂ Cl or -CH ₂ CH ₂ CF _{3 ,} etc.). The term "C _1-4 alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group of 1 to 4 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl) , sec-butyl or tert-butyl).

如本文中所使用，术语“环烷基”指饱和的单环或多环(诸如双环)烃环基(例如单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，包括螺环、稠合或桥连***(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等)；在一些实施方案中，所述环烷基任选地被1或多个(诸如1至3个)适合的取代基取代。本文中所述环烷基具有3至15个碳原子。例如，术语“C _3-10环烷基”指3至10个成环碳原子的饱和单环或多环(诸如双环)烃环基(例如环丙基、环丁基、环戊基、环己基或双环[1.1.1]戊基)；在一些实施方案中，所述C _3-10环烷基任选地被1或多个(诸如1至3个)适合的取代基取代，例如甲基取代的环丙基。 The term "cycloalkyl" as used herein refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring group (eg, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptane). A cyclyl, cyclooctyl, or bicyclic ring, including spiro, fused or bridged systems (such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl Or a bicyclo[5.2.0]nonyl, decalinyl, and the like; in some embodiments, the cycloalkyl is optionally substituted with one or more (such as from 1 to 3) suitable substituents. The cycloalkyl group described herein has 3 to 15 carbon atoms. For example, the term "C _3-10 cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring group of 3 to 10 ring-forming carbon atoms. (for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[1.1.1]pentyl); in some embodiments, the C _3-10 cycloalkyl is optionally 1 or more (such as 1 to 3) substituted substituents, such as methyl substituted cyclopropyl.

如本文中所使用，术语“杂环基”指饱和或不饱和的单环或双环基团，其在环中具有2、3、4、5、6、7、8或9个碳原子和一个或多个(例如一个、两个、三个或四个)选自O、S、S(＝O)、S(＝O) ₂和NR的含杂原子的基团，其中R表示氢原子、C _1-6烷基或卤代C _1-6烷基；所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。在一些优选的实施方案中，所述杂环基中至少有一个碳原子(例如一个或两个)被氧基(＝O)取代。特别地，3-10元杂环基为具有3-10个成环碳原子及杂原子的基团，例如包括但不限于环氧乙烷基、氮丙啶基、氮杂环丁烷基(azetidinyl)、氧杂环丁烷基(oxetanyl)、四氢呋喃基、二氧杂环戊烯基(dioxolinyl)、吡咯烷基、吡咯烷酮基、咪唑烷基、吡唑烷基、吡咯啉基、四氢吡喃基、哌啶基、吗啉基、二噻烷基(dithianyl)、硫吗啉基、哌嗪基或三噻烷基(trithianyl)。 The term "heterocyclyl," as used herein, refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and one in the ring. Or a plurality (for example, one, two, three or four) of a hetero atom-containing group selected from the group consisting of O, S, S(=O), S(=O) ₂ and NR, wherein R represents a hydrogen atom, C _1-6 alkyl or halo C _1-6 alkyl; the heterocyclic group may be attached to the remainder of the molecule by any one of the carbon atoms or a nitrogen atom, if present. In some preferred embodiments, at least one carbon atom (e.g., one or two) of the heterocyclic groups is substituted with an oxy group (=O). In particular, the 3-10 membered heterocyclic group is a group having 3 to 10 ring-forming carbon atoms and a hetero atom, and includes, for example, but not limited to, an oxiranyl group, an aziridine group, or an azetidinyl group ( Azetidinyl), oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyridyl Oryl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.

如本文中所使用，术语“烷氧基”指烷基-O-基团。“C _1-6烷氧基”是指烷基部分为上述“C _1-6烷基”的直链、或者支链的脂肪族饱和烃氧基，例如可以列举甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、戊基氧基、异戊基氧基、己基氧基等。优选的是C _1-4烷氧基。 The term "alkoxy" as used herein refers to an alkyl-O- group. The "C _1-6 alkoxy group" means a linear or branched aliphatic saturated hydrocarbon group having an alkyl moiety as the above-mentioned "C _1-6 alkyl group", and examples thereof include a methoxy group and an ethoxy group. Propyloxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, hexyloxy and the like. Preferred is a C _1-4 alkoxy group.

如本文中所使用，术语“烷基巯基”指硫原子与烷基连接的基团，指烷基-S-基团。“C _1-6烷基巯基”是指上述C _1-6烷基与硫原子连接的基团，例如可以为甲巯基、乙硫基、丙硫基、异丙硫基。优选为C _1-4烷基巯基。 As used herein, the term "alkylalkyl" refers to a radical to which a sulfur atom is attached to an alkyl group, and refers to an alkyl-S- group. The "C _1-6 alkyl fluorenyl group" means a group in which the above C _1-6 alkyl group is bonded to a sulfur atom, and may, for example, be a decyl group, an ethylthio group, a propylthio group or an isopropylthio group. It is preferably a C _1-4 alkyl fluorenyl group.

如本文中所使用，术语“烷氧基烷基”是指烷基-O-烷基基团；“C _1-6烷氧基烷基”是指烷基部分为上述“C _1-6烷基”的直链、或者支链的脂肪族饱和烃氧基，与O原子连接的烷基可以相同或不同。C _1-6烷氧基烷基的实例如 CH ₃OCH ₂-、CH ₃(CH ₂) ₃O CH ₂CH ₂-、CH ₃OCH(CH ₃)-等。 As used herein, the term "alkoxyalkyl" refers to an alkyl-O-alkyl group; " _C1-6 alkoxyalkyl" refers to an alkyl moiety as described above for " _C1-6 " The linear or branched aliphatic saturated alkoxy group of the group may be the same or different from the alkyl group bonded to the O atom. Examples of the C _1-6 alkoxyalkyl group are CH ₃ OCH ₂ -, CH ₃ (CH ₂ ) ₃ O CH ₂ CH ₂ -, CH ₃ OCH(CH ₃ )- and the like.

如本文中所使用，术语“PEG”为聚乙二醇，其具有HO-(CH ₂CH ₂O) _m-，或者CH ₃(CH ₂) _mO-(CH ₂CH ₂O) _m-结构的基团。 As used herein, the term "PEG" is polyethylene glycol having HO-(CH ₂ CH ₂ O) _m -, or CH ₃ (CH ₂ ) _m O-(CH ₂ CH ₂ O) _m - structure Group.

如本文中所使用，术语“烷胺基”指具有烷基-NH-结构的化学基团。As used herein, the term "alkylamino" refers to a chemical group having an alkyl-NH- structure.

如本文中所使用，术语“酯基”指具有-COORE结构的化学基团，其中RE选自如本文所述的烷基、杂烷基、杂环烷基、环烷基、芳基和杂芳基。The term "ester group" as used herein refers to a chemical group having a -COORE structure, wherein RE is selected from alkyl, heteroalkyl, heterocycloalkyl, cycloalkyl, aryl, and heteroaryl groups as described herein. base.

如本文中所使用，术语“酰胺基””是指通过羰基或磺酰基基团连接至母体分子部分的如下所述的氨基基团。包括“C-酰胺基”或“N-酰胺基”，其中“C-酰胺基”为具有-C(＝O)-NR结构的化学基团；“N-酰胺基”为具有RC(＝O)NH-结构的化学基团，其中R为如本文定义的烷基。As used herein, the term "amido" refers to an amino group as described below attached to the parent molecular moiety through a carbonyl or sulfonyl group, including "C-amido" or "N-amido", Wherein "C-amido" is a chemical group having a -C(=O)-NR structure; "N-amido" is a chemical group having a RC(=O)NH- structure, wherein R is as defined herein Alkyl.

如本文中所使用，术语“磺酰胺基”指“N-磺酰胺基”或“S-磺酰胺基”；“N-磺酰胺基”是指具有烷基-S(＝O) ₂NH-基团；“S-磺酰胺基”是指具有-S(＝O) ₂N-R基团，其中R为如本文定义的烷基。 As used herein, the term "sulfonamido" refers to "N-sulfonamido" or "S-sulfonamido";"N-sulfonamido" refers to having alkyl-S(=O) ₂ NH- A group; "S-sulfonamido" refers to a radical having the group -S(=O) ₂ NR wherein R is alkyl as defined herein.

如本文中所使用，术语“芳基”指具有共轭π电子***的全碳单环或多环芳族基团。例如，如本文中所使用，术语“C _6-10芳基”意指含有6至10个碳原子的芳族基团，诸如苯基或萘基。在一些实施方案中，所述芳基任选地被1或多个(诸如1至3个)适合的取代基取代。 As used herein, the term "aryl" refers to an all-carbon monocyclic or polycyclic aromatic group having a conjugated pi-electron system. For example, as used herein, the term " _C6-10 aryl" means an aromatic group containing from 6 to 10 carbon atoms, such as phenyl or naphthyl. In some embodiments, the aryl group is optionally substituted with one or more (such as 1 to 3) suitable substituents.

如本文中所使用，术语“杂芳基”指含有一个或多个相同或不同杂原子的单环或多环芳族基团，所述杂原子例如是氧、氮或硫；进一步地，所述杂芳基是指单环、双环或三环芳族基团，其具有5、6、8、9、10、11、12、13或14个环原子，特别是1或2或3或4或5或6或9或10个碳原子，且其包含至少一个可以相同或不同的杂原子，所述杂原子例如是氧、氮或硫；并且，所述杂芳基可为苯并稠合的基团。特别地，所述杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、***基、噻二唑基等，以及它们的苯并衍生物；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物。5-10元杂芳基为具有5-10个环原子，且包含至少一个可以相同或不同的杂原子，所述杂原子例如是氧、氮或硫；并且，所述杂芳基可为苯并稠合的基团。The term "heteroaryl" as used herein, refers to a monocyclic or polycyclic aromatic group containing one or more of the same or different heteroatoms, such as oxygen, nitrogen or sulfur; further, A heteroaryl group means a monocyclic, bicyclic or tricyclic aromatic group having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 Or 5 or 6 or 9 or 10 carbon atoms, and which comprise at least one hetero atom which may be the same or different, such as oxygen, nitrogen or sulfur; and the heteroaryl group may be benzofused Group. In particular, the heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl , thiadiazolyl, and the like, and benzo derivatives thereof; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof. a 5-10 membered heteroaryl group having 5 to 10 ring atoms and comprising at least one hetero atom which may be the same or different, such as oxygen, nitrogen or sulfur; and the heteroaryl group may be benzene And a fused group.

如本文中所使用，术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。The term "halo" or "halogen" group, as used herein, is defined to include F, Cl, Br or I.

如本文中所使用，“Ph”基团表示苯基。As used herein, a "Ph" group refers to a phenyl group.

术语“取代”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被所指定的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成基本上稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成基本上稳定的化合物时才是允许的。The term "substituted" means that one or more (eg, one, two, three or four) hydrogens on a specified atom are replaced by a choice of the specified group, provided that the specified atom is not exceeded in the current situation. The lower normal valence and the substitution form a substantially stable compound. Combinations of substituents and/or variables are permissible only if such combinations form a substantially stable compound.

术语“任选地”表示本文中所述基团或取代基可以未被取代或被特定的基团、原子团取代。The term "optionally" means that the group or substituent described herein may be unsubstituted or substituted with a specific group or group of atoms.

如本文中所使用，术语“一个或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个或10个。As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10 under reasonable conditions.

当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。When a bond of a substituent is shown to pass through a bond connecting two atoms in the ring, such a substituent may be bonded to any of the ring-forming atoms in the substitutable ring.

如果本文中所述化合物、基团或取代基被描述为：“任选地”被指定的基团或原子团取代，则是指该化合物、基团或取代基可以(1)未被取代或(2)被所指定的基团或原子团取代。If a compound, group or substituent described herein is described as: "optionally" substituted with a specified group or group of atoms, it is meant that the compound, group or substituent may (1) be unsubstituted or ( 2) Substituted by the specified group or atomic group.

本发明的化合物还可以包含一个或多个(例如一个、两个、三个或四个)同位素置换。例如，在所述化合物中，H可是任何同位素形式，包括1H、 ²H(D或氘)和 ³H(T或氚)；C可是任何同位素形式，包括 ¹²C、 ¹³C和 ¹⁴C；O可是任何同位素形式，包括 ¹⁶O和 ¹⁸O；等。 The compounds of the invention may also comprise one or more (e.g., one, two, three or four) isotopic substitutions. For example, in the compound, H can be in any isotopic form, including 1H, ² H (D or 氘) and ³ H (T or 氚); C can be in any isotopic form, including ¹² C, ¹³ C and ¹⁴ C; However, any isotopic form, including ¹⁶ O and ¹⁸ O;

术语“立体异构体”表示由于化合物中存在至少一个不对称中心而形成的异构体。在具有一个或多个(例如一个、两个、三个或四个)不对称中心的化合物中，其可产生外消旋体、外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地，本发明的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。要理解，本申请的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。The term "stereoisomer" denotes an isomer formed as a result of the presence of at least one asymmetric center in the compound. In compounds having one or more (eg, one, two, three, or four) asymmetric centers, which can produce racemates, racemic mixtures, single enantiomers, diastereoisomers The mixture of the constructs and the individual diastereomers. Specific individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as mixtures (often referred to as tautomers) of two or more different forms in a rapidly balanced structure. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It is to be understood that the scope of the present application covers all such ratios in any ratio (eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99). %) isomer or a mixture thereof.

本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。The invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.

还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。根据在本发明中，药学上可接受的衍生物包括但不限于，药学上可接受的盐、酯、溶剂合物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本发明的化合物或其代谢物或残余物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。It will also be understood that certain compounds of the invention may exist in free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs, which, after administration to a patient in need thereof, are capable of The compounds of the invention or their metabolites or residues are provided directly or indirectly. Thus, when reference is made herein to a "compound of the invention," it is also intended to encompass the various derivative forms described above for the compound.

本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。The pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts and base addition salts thereof.

适合的酸加成盐由形成药学可接受盐的酸来形成。实例包括乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己氨磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、糖二酸盐、硬脂酸盐、丁二酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐。Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, hydrogen sulfate/sulfate, borate, camphorsulfonate , citrate, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate Salt, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonic acid Salt, methanesulfonate, methyl sulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, Phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharide, stearate, succinate, tannic acid, tartrate, tosylate, trifluoroacetic acid salt.

适合的碱加成盐由形成药学可接受盐的碱来形成。实例包括铝盐、精氨酸盐、苄星青霉素盐、钙盐、胆碱盐、二乙胺盐、二乙醇胺盐、甘氨酸盐、赖氨酸盐、镁盐、葡甲胺盐、乙醇胺盐、钾盐、钠盐、氨丁三醇盐及锌盐。Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycinates, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, Potassium salt, sodium salt, tromethamine salt and zinc salt.

适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection,and Use”(Wiley-VCH,2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。在一些优选的实施方案中，所述药学上可接受的盐选自甲酸盐、乙酸盐、盐酸盐和三氟乙酸盐。For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art. In some preferred embodiments, the pharmaceutically acceptable salt is selected from the group consisting of formates, acetates, hydrochlorides, and trifluoroacetates.

如本文中所使用，术语“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的酯，其可在生理条件下水解以释放游离酸或醇形式的本发明的化合物。本发明的化合物本身也可以是酯。本发明的化合物可以溶剂合物和水合物的形式存在，溶剂或水的量可以化学计量比或非化学计量比存在。As used herein, the term "ester" means an ester derived from a compound of the formulae herein, which includes a physiologically hydrolyzable ester which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the invention. compound of. The compounds of the invention may also be esters per se. The compounds of the invention may exist in the form of solvates and hydrates, and the amount of solvent or water may be present in stoichiometric or non-stoichiometric ratios.

在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances formed in vivo upon administration of a compound of the invention.

本发明在其范围内进一步包括本发明的化合物的前药。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。因此，在这些情况中，用于本发明的治疗方法的术语“给药”应包括用所要求保护的化合物中的一种或多种的前药形式来治疗各种疾病或病症，但是在向个体给药后所述前药形式在体内转化成上述化合物。例如，在“Design of Prodrug”,ed.H.Bundgaard,Elsevier,1985中，描述了选择和制备适合的前药衍生物的常规方法。The invention further includes within its scope prodrugs of the compounds of the invention. Typically such prodrugs will be functional group derivatives of the compounds which are readily converted in vivo to the desired therapeutically active compound. Thus, in these instances, the term "administering" for use in the methods of treatment of the invention shall include the treatment of various diseases or conditions with a prodrug form of one or more of the claimed compounds, but The prodrug form is converted to the above compound in vivo after administration to the individual. For example, in "Design of Prodrug", ed. H. Bundgaard, Elsevier, 1985, a conventional method of selecting and preparing suitable prodrug derivatives is described.

在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在Protective Groups in Organic Chemistry,ed.J.F.W.McOmie,Plenum Press,1973；和T.W.Greene&P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley&Sons,1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以除去保护基。In any process for preparing a compound of the invention, it may be necessary and/or desirable to protect a sensitive group or reactive group on any of the molecules of interest, thereby forming a chemically protected form of the compound of the invention. This can be achieved by conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P. GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protecting groups, which are incorporated herein by reference. The protecting group can be removed at a suitable subsequent stage using methods known in the art.

化合物Compound

在一个实施方案中，本发明提供化合物、或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯，其中所述化合物为含有式(I)结构的盐：In one embodiment, the invention provides a compound, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, wherein the compound is Salt of the structure of formula (I):

其中：among them:

R _a和R _b各自独立地选自H、氘、卤素、羟基、C _1-6烷氧基、氨基、硝基、氰基、C _1-6烷基、C _1-6卤代烷基、-CONH ₂、C _3-10环烷基、3-10元杂环基、C _6-10芳基和5-10元杂芳基的基团取代； R _a and R _b are each independently selected from the group consisting of H, hydrazine, halogen, hydroxy, C _1-6 alkoxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, -CONH _a group substitution of a C _3-10 cycloalkyl group, a 3-10 membered heterocyclic group, a C _6-10 aryl group and a 5-10 membered heteroaryl group;

p为0～6中的任一整数；p is any integer from 0 to 6;

R _c和R _d各自独立地选自H、氘、C _1-6烷基、C _1-6卤代烷基、卤素、羟基、C _1-6烷氧基、巯基、C _1-6烷基巯基、氨基、-CONH ₂、C _3-10环烷基、3-10元杂环基、C _6-10芳基和5-10元杂芳基的基团取代； R _c and R _d are each independently selected from the group consisting of H, hydrazine, C _1-6 alkyl, C _1-6 haloalkyl, halogen, hydroxy, C _1-6 alkoxy, fluorenyl, C _1-6 alkyl fluorenyl, a group substitution of an amino group, a -CONH ₂ , a C _3-10 cycloalkyl group, a 3-10 membered heterocyclic group, a C _6-10 aryl group, and a 5-10 membered heteroaryl group;

R _x、R _y、R _z各自独立地选自C _1-6烷基、C _3-10环烷基、3-10元杂环基、C _1-6烷氧基烷基、PEG、氧负离子；上述C _1-6烷基、C _3-10环烷基、3-10元杂环基、C _1-6烷氧基烷基、PEG还可任意地被一个或多个羟基、C _1-6烷氧基、氨基、烷胺基、脒基、胍基、叠氮基、卤素、羧酸、酯基、酰胺基、磺酸、磺酰胺、磷酸、磷酸酯、磷酰胺、磷酰胺酯、C _6-10芳基、5-10元杂芳基取代； R _x , R _y , R _z are each independently selected from C _1-6 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclic, C _1-6 alkoxyalkyl, PEG, oxygen anion The above C _1-6 alkyl group, C _3-10 cycloalkyl group, 3-10 membered heterocyclic group, C _1-6 alkoxyalkyl group, PEG may also be optionally subjected to one or more hydroxyl groups, C _{1- 6} alkoxy, amino, alkylamino, decyl, decyl, azide, halogen, carboxylic acid, ester, amide, sulfonic acid, sulfonamide, phosphoric acid, phosphate, phosphoramide, phosphoramidate, C _6-10 aryl, 5-10 membered heteroaryl substituted;

R _e可选自： R _{e can} be selected from:

其中以上对于R _e所述的基团中向左侧伸出的键表示所述基团与式(I)分子的其余部分键接，即： The bond extending to the left in the above group for R _e means that the group is bonded to the rest of the molecule of formula (I), namely:

R _e可选自： R _{e can} be selected from:

所述的盐选自其药学上可接受的盐，其药学上可接受的盐包括但不限于乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己氨磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、盐酸盐、氢溴酸盐、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、糖二酸盐、硬脂酸盐、丁二酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐。The salt is selected from pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts thereof include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, Bicarbonate/carbonate, hydrogen sulfate/sulfate, borate, camphorsulfonate, citrate, cyclohexamethanesulfonate, ethanedisulfonate, ethanesulfonate, formate, Fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide/iodide, isethionate, milk Acid salt, malate, maleate, malonate, methanesulfonate, methyl sulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, whey Acid salt, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, sugar diacid salt, stearate, succinate, Tannin, tartrate, tosylate, trifluoroacetate.

在本发明的优选实施方案中，R _a和R _b各自独立地选自H、氘、卤素、羟基、C _1-6烷氧基、C _1-6烷基、C _1-6卤代烷基、C _3-10环烷基；更优选的，R _a和R _b各自独立地选自H、氘。 In a preferred embodiment of the invention, R _a and R _b are each independently selected from the group consisting of H, hydrazine, halogen, hydroxy, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl; more preferably, R _a and R _b are each independently selected from H and hydrazine.

在本发明的优选实施方案中，p为2～4中任一整数，即p＝2、3或4。In a preferred embodiment of the invention, p is any integer from 2 to 4, i.e., p = 2, 3 or 4.

在本发明的优选实施方案中，R _c和R _d各自独立地选自H、氘、羟基、C _1-6烷氧基、C _1-6烷基、C _3-10环烷基、3-10元杂环基、C _6-10芳基和5-10元杂芳基的基团取代；更优选地，R _c和R _d各自独立地选自H、氘、C _1-6烷基；进一步优选H、氘、C _1-4烷基。更进一步优选地，R _c和R _d各自独立地选自H、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，优选地，R _c或R _d为异丙基。更优选的，R _c和R _d分别为H和异丙基。 In a preferred embodiment of the invention, R _c and R _d are each independently selected from the group consisting of H, hydrazine, hydroxy, C _1-6 alkoxy, C _1-6 alkyl, C _3-10 cycloalkyl, 3- a group of a 10-membered heterocyclic group, a C _6-10 aryl group and a 5-10 membered heteroaryl group; more preferably, R _c and R _d are each independently selected from the group consisting of H, hydrazine, and C _1-6 alkyl; Further preferred are H, hydrazine, and C _1-4 alkyl groups. Still more preferably, R _c and R _d are each independently selected from H, hydrazine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably, R _c Or R _d is isopropyl. More preferably, R _c and R _d are H and isopropyl, respectively.

在本发明的优选实施方案中，R _x、R _y、R _z各自独立地选自下列取代基：C _1-6烷基、C _3-10环烷基、3-10元杂环基、C _1-6烷氧基烷基、PEG、氧负离子；更优选的，R _x、R _y、R _z各自独立地选自C _1-6烷基；更优选R _x、R _y、R _z各自独立地选自C _1-4烷基。更优选的，R _x、R _y、R _z为甲基。在本发明的优选实施方案中，R _e选自： In a preferred embodiment of the invention, R _x , R _y , R _z are each independently selected from the group consisting of C _1-6 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _1-6 alkoxyalkyl, PEG, oxygen anion; more preferably, R _x , R _y , R _z are each independently selected from C _1-6 alkyl; more preferably R _x , R _y , R _z are each independently It is selected from a C _1-4 alkyl group. More preferably, R _x , R _y , and R _z are a methyl group. In a preferred embodiment of the invention, R _{e is} selected from the group consisting of

更优选的，R _e为

More preferably, R _e is

R _e选自： R _{e is} selected from:

更优选的，R _e为

More preferably, R _e is

在本发明的优选实施方案中，所述的盐选自其药学上可接受的盐，其药学上可接受的盐包括但不限于乙酸盐、盐酸盐、三氟乙酸盐。In a preferred embodiment of the invention, the salt is selected from pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts thereof include, but are not limited to, acetate, hydrochloride, trifluoroacetate.

在本发明的优选实施方案中，所述的化合物，或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯，其中所述的化合物为含有式II所示结构的盐：In a preferred embodiment of the invention, the compound, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, wherein The compound is a salt containing the structure of formula II:

其中：R _x、R _y、R _z、R _e、p如上所定义。 Wherein: R _x , R _y , R _z , R _e , p are as defined above.

在本发明的优选方案中，所述的化合物，或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯，其中所述的化合物为含有式II-1所示结构的盐：In a preferred embodiment of the invention, the compound, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, wherein The compound is a salt containing the structure of formula II-1:

在本发明的优选方案中，所述的化合物，或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯，其中所述的化合物为含有式II-1所示结构的乙酸盐、盐酸盐和三氟乙酸盐。In a preferred embodiment of the invention, the compound, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, wherein The compound is an acetate, hydrochloride and trifluoroacetate salt containing the structure of formula II-1.

在本发明的优选方案中，所述的化合物，或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯，其中所述的化合物为含有式II-2所示结构的盐：In a preferred embodiment of the invention, the compound, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, wherein The compound is a salt containing the structure of formula II-2:

在本发明的优选方案中，所述的化合物，或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯，其中所述的化合物为含有式II-2所示结构的乙酸盐、盐酸盐和三氟乙酸盐。In a preferred embodiment of the invention, the compound, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, wherein The compound is an acetate, hydrochloride and trifluoroacetate salt containing the structure of formula II-2.

在本发明的优选方案中，所述的化合物，或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯，其中所述的化合物为含有式II-3所示结构的盐：In a preferred embodiment of the invention, the compound, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, wherein The compound is a salt containing the structure of formula II-3:

在本发明的优选方案中，所述的化合物，或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯，其中所述的化合物为含有式II-3所示结构的乙酸盐、盐酸盐和三氟乙酸盐。In a preferred embodiment of the invention, the compound, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, wherein The compound is an acetate, hydrochloride and trifluoroacetate salt containing the structure of formula II-3.

制备方法Preparation

在另一方面，提供本发明所述化合物的制备方法，所述的化合物为含有式(I)结构的盐，其选自以下方法：In another aspect, there is provided a process for the preparation of a compound of the invention, said compound being a salt comprising a structure of formula (I) selected from the group consisting of:

方法一：method one:

步骤一：树脂与末端羧基化合物在碱性条件下偶联；所述的碱包括但不限于有机碱和无机碱，优选于DIEA、TEA、NMM；Step 1: the resin is coupled with a terminal carboxyl compound under basic conditions; the base includes, but is not limited to, an organic base and an inorganic base, preferably DIEA, TEA, NMM;

步骤二：在哌啶的DMF溶液中脱Fmoc保护；Step 2: De-Fmoc protection in piperazine in DMF solution;

步骤三：以Fmoc保护的D-氨基酸为底物，在偶联剂作用下，相继与肽树脂偶联；所述的偶联剂包括但不限于：HATU、HBTU、EDCI、PyBOP、 CDI、HOBT；Step 3: using Fmoc-protected D-amino acid as a substrate, and coupling with a peptide resin under the action of a coupling agent; the coupling agent includes but not limited to: HATU, HBTU, EDCI, PyBOP, CDI, HOBT ;

步骤四：在哌啶的DMF溶液中脱Fmoc保护；Step 4: Deprotection of Fmoc in piperazine in DMF solution;

步骤五：以Fmoc保护的D-氨基酸为底物，在偶联剂作用下，相继与肽树脂偶联；所述的偶联剂包括但不限于：HATU、HBTU、EDCI、PyBOP、CDI、HOBT；Step 5: using Fmoc-protected D-amino acid as a substrate, and coupling with a peptide resin under the action of a coupling agent; the coupling agent includes but not limited to: HATU, HBTU, EDCI, PyBOP, CDI, HOBT ;

步骤六：在哌啶的DMF溶液中脱Fmoc保护；Step 6: Deprotection of Fmoc in piperazine in DMF solution;

步骤七：以Fmoc保护的D-氨基酸为底物，在偶联剂作用下，相继与肽树脂偶联；所述的偶联剂包括但不限于：HATU、HBTU、EDCI、PyBOP、CDI、HOBT；Step 7: using Fmoc-protected D-amino acid as a substrate, and coupling with a peptide resin under the action of a coupling agent; the coupling agent includes but not limited to: HATU, HBTU, EDCI, PyBOP, CDI, HOBT ;

步骤八：在哌啶的DMF溶液中脱Fmoc保护；Step 8: Deprotection of Fmoc in piperazine in DMF solution;

步骤九：以Fmoc保护的D-氨基酸为底物，在偶联剂作用下，相继与肽树脂偶联；所述的偶联剂包括但不限于：HATU、HBTU、EDCI、PyBOP、CDI、HOBT；Step 9: using Fmoc-protected D-amino acid as a substrate, and coupling with a peptide resin under the action of a coupling agent; the coupling agent includes but not limited to: HATU, HBTU, EDCI, PyBOP, CDI, HOBT ;

步骤十：在哌啶的DMF溶液中脱Fmoc保护；Step 10: De-Fmoc protection in piperazine in DMF solution;

步骤十一：在酸性条件，肽树脂完成裂解得到化合物，所述的化合物为含有式I所示结构的盐；化合物进行HPLC纯化和转盐得到化合物的盐。Step 11: Under acidic conditions, the peptide resin is cleaved to obtain a compound which is a salt containing the structure of Formula I; the compound is subjected to HPLC purification and salt-transfer to give a salt of the compound.

其中，—A-COOH基团为R _e基团，所述的R _e(若其中有游离氨基，则其被适当的保护基封闭)选自如下结构： Wherein the -A-COOH group is a R _e group, and the R _e (if any of them has a free amino group, which is blocked by a suitable protecting group) is selected from the following structures:

其中以上对于R _e所述的结构中向左侧伸出的键表示所述结构与式(I)分子的其余部分键接，即：R _e(若其中有游离氨基，则其被适当的保护基封闭)选自如下结构： The bond extending to the left in the structure described above for R _e indicates that the structure is bonded to the rest of the molecule of formula (I), ie: R _e (if there is a free amino group therein, it is suitably protected) Base closure) is selected from the following structures:

其余基团如上文所定义。The remaining groups are as defined above.

方法二：Method Two:

步骤一：通式化合物i-1与氨基酸酯通过缩合反应得到通式化合物i-2；Step 1: the compound i-1 and the amino acid ester are obtained by condensation reaction to obtain the compound i-2 of the formula;

步骤二：通式化合物i-2经水解反应和缩合反应得到通式化合物i-3；Step 2: the compound i-2 is hydrolyzed and condensed to obtain the compound i-3;

步骤三：通式化合物i-3经水解反应和缩合反应得到通式化合物i-4；Step 3: the compound i-3 is hydrolyzed and condensed to obtain the compound i-4;

步骤四：通式化合物i-4经水解反应和缩合反应得到通式化合物i-5；Step 4: the compound i-4 is hydrolyzed and condensed to obtain the compound i-5;

步骤五：通式化合物i-5经脱保护基得到化合物，化合物为含有式(I)结构的盐；Step 5: The compound i-5 of the formula is deprotected to obtain a compound, and the compound is a salt containing the structure of the formula (I);

其中，R _e(若其中有游离氨基，则其被适当的保护基封闭)选自： Wherein R _e (if any of them has a free amino group, which is blocked by a suitable protecting group) is selected from the group consisting of:

其中以上对于R _e所述的结构中向左侧伸出的键表示所述结构与式(I)分子的其余部分键接，即：R _e(若其中有游离氨基，则其被适当的保护基封闭)选自： The bond extending to the left in the structure described above for R _e indicates that the structure is bonded to the rest of the molecule of formula (I), ie: R _e (if there is a free amino group therein, it is suitably protected) Base closure) selected from:

其中，PG为氨基保护基，包括但不限于烷氧羰基类、酰基类、烷基类氨基保护基；例如：叔丁氧羰基、苄氧羰基、苄基、芴甲氧羰基、

等； Wherein PG is an amino-protecting group, including but not limited to an alkoxycarbonyl group, an acyl group, an alkyl-based amino protecting group; for example, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a benzyl group, a fluorenylmethoxycarbonyl group,

Wait;

其余基团如上文所定义。The remaining groups are as defined above.

在一些优选的实施方案中，所述缩合反应是将底物溶于溶剂(包括但不限于二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、二甲基亚砜的单一或混合溶剂)中，在合适的温度(-30℃～30℃)下加入缩合剂(包括但不限于：HATU、HBTU、EDCI、PyBOP、CDI、HOBT)，辅料(包括但不限于氯化铜、氯化铜二水合物，氯化铜其他水合物)以及碱(包括但不限于有机碱和无机碱，优选N,N-二异丙基乙胺、N-甲基***啉、4-二甲氨基吡啶)，与相应的氨基酸酯反应合适时间，即可得到高光学纯的目标产物。In some preferred embodiments, the condensation reaction is to dissolve the substrate in a solvent (including but not limited to dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl In a single or mixed solvent of sulfone, a condensing agent (including but not limited to: HATU, HBTU, EDCI, PyBOP, CDI, HOBT) is added at a suitable temperature (-30 ° C ~ 30 ° C), excipients (including but not limited to Copper chloride, copper chloride dihydrate, copper chloride other hydrate) and base (including but not limited to organic bases and inorganic bases, preferably N,N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine), reacted with the corresponding amino acid ester for a suitable period of time to obtain a highly optically pure target product.

在一些优选的实施方案中，所述水解反应是将底物溶于溶剂(包括但不限于四氢呋喃、甲醇、乙醇、水、丙酮、***、甲基叔丁基醚的单一或混合溶剂)，在合适温度下(-30℃～30℃)与碱(包括但不限于有机碱和无机碱，优选氢氧化锂、氢氧化钠、氢氧化钾)反应，即可得到相应的水解产物。In some preferred embodiments, the hydrolysis reaction is a solution in which the substrate is dissolved in a solvent (including but not limited to tetrahydrofuran, methanol, ethanol, water, acetone, diethyl ether, methyl tert-butyl ether). The corresponding hydrolyzate can be obtained by reacting with a base (including but not limited to an organic base and an inorganic base, preferably lithium hydroxide, sodium hydroxide or potassium hydroxide) at a suitable temperature (-30 ° C to 30 ° C).

在一些优选的实施方案中，所述脱保护反应是在脱保护试剂存在下，在室温或加热的条件下进行。优选的脱保护试剂包括氢气、酸性试剂例如三氟乙酸、盐酸、硫酸等、或碱性试剂例如氢氧化钠、氢氧化钾、氢氧化锂、哌啶等。本领域技术人员可以参照本领域常用教科书Greene's Protective Groups in Organic Synthesis(4th Edition)等进行适当的选择和操作，脱除一个或多个保护基。In some preferred embodiments, the deprotection reaction is carried out in the presence of a deprotecting reagent at room temperature or under heating. Preferred deprotecting agents include hydrogen, acidic reagents such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, or alkaline agents such as sodium hydroxide, potassium hydroxide, lithium hydroxide, piperidine, and the like. One skilled in the art can remove one or more protecting groups by appropriate selection and operation with reference to the textbooks commonly used in the art, Greene's Protective Groups in Organic Synthesis (4th Edition) and the like.

药物组合物和治疗方法Pharmaceutical compositions and methods of treatment

在另一方面，本发明提供药物组合物，其包含预防或治疗有效量的本发明的化合物、或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯，以及一种或多种药学上可接受的载体。在另种实施方案中，所述药物组合物还可包含一种或多种其它治疗剂，例如用于预防或治疗κ阿片样物质受体相关的疾病的其它治疗剂。In another aspect, the invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically thereof thereof An acceptable salt or ester, and one or more pharmaceutically acceptable carriers. In another embodiment, the pharmaceutical composition may further comprise one or more additional therapeutic agents, such as other therapeutic agents for preventing or treating a kappa opioid receptor-associated disease.

本发明中“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。"Pharmaceutically acceptable carrier" in the context of the present invention means a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting humans and/or within the scope of sound medical judgment. Tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.

在本发明的药物组合物中可使用的药学上可接受的载体包括但不限于无菌液体，例如水和油，包括那些石油、动物、植物或合成来源的油，例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时，水是示例性载体。还可以使用生理盐水和葡萄糖及甘油水溶液作为液体载体，特别是用于注射液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽糖、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。所述组合物还可以视需要包含少量的湿润剂、乳化剂或pH缓冲剂。口服制剂可以包含标准载体，如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。适合的药学上可接受的载体的实例如在Remington’s Pharmaceutical Sciences(1990)中所述。Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, minerals. Oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol and the like. The composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as needed. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are as described in Remington's Pharmaceutical Sciences (1990).

本发明的药物组合物可以***地作用和/或局部地作用。为此目的，它们可以适合的途径给药，例如通过注射、静脉内、动脉内、皮下、腹膜内、肌内或经皮给药；或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药。The pharmaceutical compositions of the invention may act systemically and/or locally. For this purpose, they may be administered in a suitable route, for example by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, It is administered in the form of an ophthalmic preparation or by inhalation.

对于这些给药途径，可以适合的剂型给药本发明的药物组合物。For these routes of administration, the pharmaceutical compositions of the invention may be administered in a suitable dosage form.

所述剂型包括但不限于片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂、糖浆剂。The dosage forms include, but are not limited to, tablets, capsules, troches, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions. Injectable solutions, elixirs, syrups.

如本文中所使用的术语“有效量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的化合物的量。The term "effective amount" as used herein refers to an amount of a compound that, to a certain extent, relieves one or more symptoms of the condition being treated after administration.

可调整给药方案以提供最佳所需响应。例如，可给药单次推注，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。The dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition.

所给药的本发明的化合物的量会取决于所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言，有效剂量在每日每kg体重约0.0001至约50mg，例如约0.01至约10mg/kg/日(单次或分次给药)。对70kg的人而言，这会合计为约0.007mg/日至约3500mg/日，例如约0.7mg/日至约700mg/日。在一些情况下，不高于前述范围的下限的剂量水平可以是足够的，而在其它情况下，仍可在不引起任何有害副作用的情况下采用较大剂量，条件是首先将所述较大剂量分成数个较小剂量以在一整天中给药。The amount of the compound of the invention administered will depend on the severity of the individual, condition or condition being treated, the rate of administration, the handling of the compound, and the judgment of the prescribing physician. Generally, an effective dose will be from about 0.0001 to about 50 mg per kg body weight per day, for example from about 0.01 to about 10 mg/kg/day (single or divided doses). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, such as from about 0.7 mg/day to about 700 mg/day. In some cases, a dose level that is not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.

本发明的化合物在药物组合物中的含量或用量可以是约0.01mg至约1000mg，适合地是0.1-500mg，优选0.5-300mg，更优选1-150mg，特别优选1-50mg，例如1.5mg、2mg、4mg、10mg、25mg等。The amount or amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg, suitably from 0.1 to 500 mg, preferably from 0.5 to 300 mg, more preferably from 1 to 150 mg, particularly preferably from 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, and the like.

除非另外说明，否则如本文中所使用，术语“治疗(treating)”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一或多种症状。The term "treating" as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies or one or more symptoms of such a condition or condition, or Prevention of such a condition or condition or one or more symptoms of such condition or condition.

如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。"Individual" as used herein includes human or non-human animals. Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, sheep, dogs). , cats, cows, pigs, etc.).

在另种实施方案中，本发明的药物组合物还可以包含一种或多种另外的治疗剂或预防剂，其包括但不限于其它阿片样物质受体激动剂(例如***、芬太尼、羟***酮或羟考酮)、抗抑郁剂、抗惊厥剂、安定剂、抗组织胺剂、离子通道阻断剂、非甾体抗炎药和利尿剂等。In another embodiment, the pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents including, but not limited to, other opioid receptor agonists (eg, morphine, fentanyl, Oxymorphone or oxycodone), antidepressants, anticonvulsants, tranquilizers, antihistamines, ion channel blockers, non-steroidal anti-inflammatory drugs and diuretics.

在另一方面，本发明提供本发明所述的化合物、或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯、或本发明中所述的药物组合物在制备用于预防或治疗与κ阿片样物质受体相关的疾病的药物中的用途。In another aspect, the invention provides a compound of the invention, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or Use of the pharmaceutical composition of the invention in the manufacture of a medicament for the prevention or treatment of a disease associated with a kappa opioid receptor.

在另一方面，本发明提供本发明的化合物或包含其的药物组合物，其用于预防或治疗与κ阿片样物质受体相关的疾病。In another aspect, the invention provides a compound of the invention or a pharmaceutical composition comprising the same for use in preventing or treating a disease associated with a kappa opioid receptor.

在另一方面，本发明提供预防或治疗与κ阿片样物质受体相关的疾病的方法，所述方法包括向需要的个体给药有效量的本发明的化合物或包含其的药物组合物。In another aspect, the invention provides a method of preventing or treating a disease associated with a kappa opioid receptor, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention or a pharmaceutical composition comprising the same.

本发明中所述与κ阿片样物质受体相关的疾病选自疼痛、炎症、瘙痒、水肿、低钠血症、低钾血症、肠梗阻、咳嗽和青光眼。所述疼痛包括神经性疼痛、躯体痛、内脏痛、皮肤痛、关节炎疼痛、肾结石疼痛、子宫痉挛、痛经、子宫内膜异位症、外科手术后疼痛、医疗处理后疼痛、眼部疼痛、耳炎疼痛、癌症疼痛和胃肠道紊乱相关的疼痛。The diseases associated with the kappa opioid receptor described in the present invention are selected from the group consisting of pain, inflammation, itching, edema, hyponatremia, hypokalemia, intestinal obstruction, cough, and glaucoma. The pain includes neuropathic pain, somatic pain, visceral pain, skin pain, arthritic pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, post-surgical pain, pain after medical treatment, eye pain Pain associated with otitis pain, cancer pain, and gastrointestinal disorders.

在另一方面，本发明提供本发明所述的化合物、或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯、或本发明中所述的药物组合物用于制备试剂的用途，其中所述试剂用于提高细胞中κ阿片样物质受体水平或活性。In another aspect, the invention provides a compound of the invention, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or The use of a pharmaceutical composition according to the invention for the preparation of a medicament for increasing the level or activity of a kappa opioid receptor in a cell.

在一些优选的实施方案中，所述细胞为细胞系或来自受试者的细胞。In some preferred embodiments, the cell is a cell line or a cell from a subject.

在一些优选的实施方案中，所述化合物、或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯、或本发明中所述的药物组合物用于体内方法中。In some preferred embodiments, the compound, or a stereoisomer, polymorph, solvate thereof, or metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or in the present invention The pharmaceutical compositions described are for use in an in vivo method.

在一些优选的实施方案中，所述化合物、或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯、或本发明中所述的药物组合物用于体外方法中。In some preferred embodiments, the compound, or a stereoisomer, polymorph, solvate thereof, or metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or in the present invention The pharmaceutical compositions described are for use in an in vitro method.

在另一方面，本发明提供本发明所述的化合物、或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯、或本发明中所述的药物组合物，其用于提高细胞中κ阿片样物质受体水平或活性。In another aspect, the invention provides a compound of the invention, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or The pharmaceutical composition of the invention for use in increasing the level or activity of a kappa opioid receptor in a cell.

在另一方面，本发明提供一种提高细胞中κ阿片样物质受体水平或活性的方法，其包括给所述细胞施用有效量的本发明所述的化合物、或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯、或本发明中所述的药物组合物。In another aspect, the invention provides a method of increasing the level or activity of a kappa opioid receptor in a cell comprising administering to the cell an effective amount of a compound of the invention, or a stereoisomer thereof, A crystalline form, a solvate, or a metabolite thereof, a prodrug or a pharmaceutically acceptable salt or ester, or a pharmaceutical composition as described herein.

在一些优选的实施方案中，所述方法在体内进行。In some preferred embodiments, the method is performed in vivo.

在一些优选的实施方案中，所述方法在体外进行。In some preferred embodiments, the method is performed in vitro.

有益的技术效果Beneficial technical effect

本发明的化合物具有更小的穿透血脑屏障以及更低的进入脑部的能力。在一些优选的实施方案中，本发明的化合物在实现外周镇痛效果的有效浓度下，对中枢神经***具有降低的毒副作用。The compounds of the invention have a smaller ability to penetrate the blood-brain barrier and lower entry into the brain. In some preferred embodiments, the compounds of the invention have reduced toxic side effects on the central nervous system at effective concentrations that achieve peripheral analgesic effects.

当以预防或治疗有效浓度向需要其的个体施用本发明的化合物时，其显示对血脑屏障的穿透能力较低或基本没有穿透血脑屏障的能力。κ阿片样物质受体(下文中也可互换地称为κ受体)分布于人或其它哺乳动物的外周组织(包括皮肤和躯体组织)以及内脏中。还发现在脑中也存在κ受体。外周组织中κ受体的激活可引起疼痛和炎症反应的抑制，而脑中κ受体的激活引起镇静效果并且还可以导致严重的烦躁不安和幻觉。在某些实施方案中，当以有效量施用时，本发明的化合物基本不显示对血脑屏障的穿透，因而最大程度地减小或甚至彻底消除许多对血脑屏障有一定穿透能力的其它κ激动剂的镇静和致幻效果。When a compound of the invention is administered to a subject in need thereof at a prophylactically or therapeutically effective concentration, it exhibits a low or minimal ability to penetrate the blood-brain barrier. The kappa opioid receptor (hereinafter also referred to interchangeably as the kappa receptor) is distributed in peripheral tissues (including skin and body tissues) and viscera of human or other mammals. It has also been found that kappa receptors are also present in the brain. Activation of kappa receptors in peripheral tissues can cause inhibition of pain and inflammatory responses, while activation of kappa receptors in the brain causes sedative effects and can also cause severe irritability and hallucinations. In certain embodiments, when administered in an effective amount, the compounds of the invention exhibit substantially no penetration of the blood-brain barrier, thereby minimizing or even completely eliminating many penetrating abilities to the blood-brain barrier. The sedative and hallucinogenic effects of other κ agonists.

实施例Example

以下结合实施例进一步描述本发明，但提供这些实施例并非意图限制本发明的范围。The invention is further described in the following examples, but the examples are not intended to limit the scope of the invention.

实施例一：Embodiment 1:

(R)-5-((R)-2-((R)-2-((R)-2-氨基-3-苯基丙酰胺基)-3-苯基丙酰胺基)-4-甲基戊酰氨基)-6-(4-氨基-4-羧基哌啶-1-基)-N,N,N-三甲基-6-氧代己酰基-1-铵盐(式II-1)，化合物1为式II-1的三氟乙酸盐(R)-5-((R)-2-((R)-2-((R)-2-Amino-3-phenylpropionamido)-3-phenylpropionamido)-4-A 5-pentylamino)-6-(4-amino-4-carboxypiperidin-1-yl)-N,N,N-trimethyl-6-oxohexanoyl-1-ammonium salt (Formula II-1 ), Compound 1 is a trifluoroacetate salt of formula II-1

实施例一的反应路线如下：The reaction route of the first embodiment is as follows:

步骤一：step one:

称取1.00g的2-CTC Resin置于多肽反应器中，加入8ml二氯甲烷溶胀1个小时，再抽掉多余的溶剂。将SM-2(1.02g，2.20mmol)溶于30ml的二氯甲烷中，在冰浴下加入DIEA(0.42g)，搅拌10分钟，最后加入多肽反应器中，通氮气反应1.5小时。反应完后，再加入5ml的甲醇反应0.5小时。抽干溶剂，用二氯甲烷(20ml)洗涤，再用DMF(20ml)洗涤，抽干，直接用于下一步反应。1.00 g of 2-CTC Resin was weighed into a polypeptide reactor, and 8 ml of dichloromethane was added to swell for 1 hour, and then the excess solvent was removed. SM-2 (1.02 g, 2.20 mmol) was dissolved in 30 mL of dichloromethane, and DIEA (0.42 g) was added to the ice bath, stirred for 10 minutes, and finally added to the peptide reactor and reacted with nitrogen for 1.5 hours. After the reaction was completed, 5 ml of methanol was further added and reacted for 0.5 hour. The solvent was evaporated, washed with dichloromethane (20 ml), and then evaporated

步骤二：Step two:

向多肽反应器中加入10ml哌啶/DMF(V:V＝1:3)，反应5分钟抽掉液体，再次加入10ml哌啶/DMF(V:V＝1:3)，反应15分钟抽掉液体。用DMF洗树脂，并用pH试纸检测最后一次洗涤液，显示为中性，直接用于下一步反应。10 ml of piperidine/DMF (V:V=1:3) was added to the peptide reactor, the liquid was removed by reaction for 5 minutes, and 10 ml of piperidine/DMF (V:V=1:3) was added again, and the reaction was taken for 15 minutes. liquid. The resin was washed with DMF, and the last washing liquid was detected with a pH test paper, which was shown to be neutral and used directly for the next reaction.

步骤三：Step three:

将SM-5(参考文献Journal of Photochemistry and Photobiology A:Chemistry,2014,vol.290,#1,p.101–108)(0.90g，2.20mmol)溶于DMF(30ml)中，在0℃下加入HOBT(0.37g，2.2mmol)和HBTU(0.86g，2.20mmol)，反应5min，再加入DIEA(0.28g，2.20mmol)，0℃下反应5min。将反应液加入固相反应器中反应1小时，用茚三酮显色树脂(加热至110℃)，树脂未变颜色，反应完全，抽掉液体，用DMF洗涤，直接用于下一步反应。SM-5 (reference Journal of Photochemistry and Photobiology A: Chemistry, 2014, vol. 290, #1, p. 101-108) (0.90 g, 2.20 mmol) was dissolved in DMF (30 ml) at 0 °C HOBT (0.37 g, 2.2 mmol) and HBTU (0.86 g, 2.20 mmol) were added, and reacted for 5 min, then DIEA (0.28 g, 2.20 mmol) was added and reacted at 0 ° C for 5 min. The reaction solution was added to a solid phase reactor for 1 hour, and the ninhydrin color developing resin (heated to 110 ° C) was used. The resin did not change color, the reaction was completed, the liquid was taken out, washed with DMF, and used directly for the next reaction.

步骤四：Step four:

向固相反应器中加入20ml的哌啶/DMF(V:V＝1:3)，反应5min抽掉，再加入20ml的哌啶/DMF(V:V＝1:3)，反应15min抽掉。用DMF洗树脂，用pH试纸检测最后一次洗涤废液，显示为中性，直接用于下一步反应。20 ml of piperidine/DMF (V:V=1:3) was added to the solid phase reactor, and the reaction was taken up for 5 minutes, and then 20 ml of piperidine/DMF (V:V=1:3) was added, and the reaction was taken for 15 minutes. . The resin was washed with DMF, and the last washing waste liquid was detected with a pH test paper, which was shown to be neutral and used directly for the next reaction.

步骤五：Step five:

将SM-8(Fmoc-D-Leu-OH)(0.78g，2.20mmol)溶于DMF(10ml)中，在0℃下加入HOBT(0.37g，2.2mmol)和HBTU(0.86g，2.20mmol)，反应5min，再加入DIEA(0.28g，2.20mmol)，0℃下反应5min。将反应液加入固相反应器中反应1小时，用茚三酮显色树脂(加热至110℃)，树脂未变颜色，反应完全，抽掉液体，用DMF洗涤，直接用于下一步反应。SM-8(Fmoc-D-Leu-OH) (0.78 g, 2.20 mmol) was dissolved in DMF (10 mL). EtOAc (0.37 g, 2.2 mmol) and EtOAc (0.86 g, 2.20 mmol) After reacting for 5 min, DIEA (0.28 g, 2.20 mmol) was further added, and the reaction was carried out at 0 ° C for 5 min. The reaction solution was added to a solid phase reactor for 1 hour, and the ninhydrin color developing resin (heated to 110 ° C) was used. The resin did not change color, the reaction was completed, the liquid was taken out, washed with DMF, and used directly for the next reaction.

步骤六：Step six:

步骤七：Step 7:

将SM-11(Fmoc-D-Phe-OH)(0.86g,2.20mmol)溶于DMF(10ml)中，在0℃下加入HOBT(0.37g，2.2mmol)和HBTU(0.86g，2.20mmol)，反应5min，再加入DIEA(0.28g，2.20mmol)，0℃下反应5min。将反应液加入固相反应器中反应1小时，用茚三酮显色树脂(加热至110℃)，树脂未变颜色，反应完全，抽掉液体，用DMF洗涤，直接用于下一步反应。SM-11 (Fmoc-D-Phe-OH) (0.86 g, 2.20 mmol) was dissolved in DMF (10 mL). HOBT (0.37 g, 2.2 mmol) and HBTU (0.86 g, 2.20 mmol) After reacting for 5 min, DIEA (0.28 g, 2.20 mmol) was further added, and the reaction was carried out at 0 ° C for 5 min. The reaction solution was added to a solid phase reactor for 1 hour, and the ninhydrin color developing resin (heated to 110 ° C) was used. The resin did not change color, the reaction was completed, the liquid was taken out, washed with DMF, and used directly for the next reaction.

步骤八：Step 8:

步骤九：Step nine:

将SM-14(Fmoc-D-Phe-OH)(0.86g，2.20mmol)溶于DMF(10ml)中，在0℃下加入HOBT(0.37g，2.2mmol)和HBTU(0.86g，2.20mmol)，反应5min，再加入DIEA(0.28g，2.20mmol)，0℃下反应5min。将反应液加入固相反应器中反应1小时，用茚三酮显色树脂(加热至110℃)，树脂未变颜色，反应完全，抽掉液体，用DMF洗涤。取出树脂真空干燥，直接用于下一步反应。SM-14 (Fmoc-D-Phe-OH) (0.86 g, 2.20 mmol) was dissolved in DMF (10 mL). HOBT (0.37 g, 2.2 mmol) and HBTU (0.86 g, 2.20 mmol) After reacting for 5 min, DIEA (0.28 g, 2.20 mmol) was further added, and the reaction was carried out at 0 ° C for 5 min. The reaction solution was added to a solid phase reactor for 1 hour, and the ninhydrin color developing resin (heated to 110 ° C) was used, the resin was not changed in color, the reaction was completed, the liquid was taken out, and washed with DMF. The resin was taken out and dried under vacuum, and used directly for the next reaction.

步骤十：Step 10:

向固相反应器中加入20ml的哌啶/DMF(V:V＝1:3)，反应5min抽掉，再加入20ml的哌啶/DMF(V:V＝1:3)，反应15min抽掉。用DMF洗树脂，用pH试纸检测最后一次洗涤废液，显示为中性。树脂直接用于下一步反应。20 ml of piperidine/DMF (V:V=1:3) was added to the solid phase reactor, and the reaction was taken up for 5 minutes, and then 20 ml of piperidine/DMF (V:V=1:3) was added, and the reaction was taken for 15 minutes. . The resin was washed with DMF, and the last washing waste liquid was detected with a pH test paper, which was shown to be neutral. The resin was used directly in the next reaction.

步骤十一：Step 11:

将干燥的树脂放于固相反应器中，加入TFA(50ml，含5％的水)，反应1小时，抽取液体，再加入TFA(50ml，含5％的水)，反应0.5小时，抽取液体。合并TFA溶液，旋干得到1.2g粗品。制备型HPLC得到含有式II-1结构的三氟乙酸盐(化合物1)88mg(纯度：97.6％)产品。The dried resin was placed in a solid phase reactor, TFA (50 ml, containing 5% water) was added, and the reaction was carried out for 1 hour, and the liquid was taken out, and then TFA (50 ml, containing 5% of water) was added, and the reaction was carried out for 0.5 hour to extract a liquid. . The TFA solution was combined and dried to give a crude material (1.2 g). Preparative HPLC gave a product of 88 mg (purity: 97.6%) of trifluoroacetate (Compound 1) containing the structure of formula II-1.

ESI-MS(m/z):723.4ESI-MS (m/z): 723.4

¹H NMR(400MHz，DMSO-d ₆)δ7.34-7.22(m,10H),4.81-4.61(m,2H),4.36-4.29(m,1H),4.05-3.95,(m,1H),3.80-3.62(m,4H),3.30-3.29(m,2H),3.28-3.05(m,3H),3.05-2.95(s,9H),2.96-2.81(m,1H),2.15-1.80(m,2H),1.80-1.55(m,6H),1.55-1.40(m,3H),1.39-1.25(m,2H),0.86-0.81(m,6H). ^{1 H NMR (400MHz, DMSO-} d 6) δ7.34-7.22 (m, 10H), 4.81-4.61 (m, 2H), 4.36-4.29 (m, 1H), 4.05-3.95, (m, 1H), 3.80-3.62(m,4H), 3.30-3.29(m,2H), 3.28-3.05(m,3H),3.05-2.95(s,9H),2.96-2.81(m,1H),2.15-1.80(m , 2H), 1.80-1.55 (m, 6H), 1.55-1.40 (m, 3H), 1.39-1.25 (m, 2H), 0.86-0.81 (m, 6H).

实施例二Embodiment 2

将实施例一得到的含有式II-1结构的三氟乙酸盐通过HPLC转盐成含有式II-1结构的乙酸盐。The trifluoroacetate salt of the structure of the formula II-1 obtained in Example 1 was salted by HPLC into an acetate salt containing the structure of the formula II-1.

生物学实验Biological experiment

1、对κ阿片样物质受体激动效能的实验1. Experiment on the agonistic efficacy of κ opioid receptors

通过测定实施例化合物对腺苷酸环化酶活性的抑制能力，来确定本发明的化合物作为κ阿片样物质受体激动剂的效能。The potency of the compounds of the invention as kappa opioid receptor agonists was determined by measuring the ability of the compounds of the examples to inhibit adenylate cyclase activity.

细胞培养：将稳定表达人κ阿片样物质受体(KOR)基因的仓鼠卵巢细胞CHO于含有5％FBS的MEMa plus nucleosides培养基(Invitrogen)中培养。Cell culture: Hamster ovary cells CHO stably expressing the human kappa opioid receptor (KOR) gene were cultured in MESAM plus nucleosides medium (Invitrogen) containing 5% FBS.

刺激：将待测化合物按4倍梯度稀释为11个浓度梯度，转移100nl到384孔板中，然后加入含有NKH477(Tocris)的刺激液(5uL)，将细胞消化、重悬、计数之后取5uL加入至其中，轻轻混匀，并于37℃下孵育30分钟。Stimulation: Dilute the test compound to a concentration gradient of 4 times, transfer 100nl to 384-well plate, then add NKH477 (Tocris) stimulating solution (5uL), digest, resuspend, count and take 5uL Add to it, mix gently, and incubate at 37 ° C for 30 minutes.

检测：采用cAMP检测试剂盒(Cisbio)，按说明书分别加入cAMP D ₂ 和抗cAMP化合物缀合物，将其在室温下孵育1小时。采用envision(Perkin Elmer)读板，使用四参数方程拟合得到EC ₅₀。 Detection: cAMP D ₂ and anti-cAMP compound conjugates were separately added using a cAMP detection kit (Cisbio), and incubated for 1 hour at room temperature. Using envision (Perkin Elmer) plate reader, using a four parameter curve fitting equation EC _50.

试验结果test results

实施例编号Example number	EC ₅₀(pM) EC ₅₀ (pM)
实施例1Example 1	2525

通过以上EC ₅₀结果可见：本发明的实施例化合物对κ阿片样物质受体具有优异的激动效能。本发明的其他化合物对κ阿片样物质受体具有类似优异的激动效能。 ₅₀ results can be seen by the above EC: Example compounds of the invention have excellent agonistic potency at the κ opioid receptor. Other compounds of the invention have similar superior agonistic potency to the kappa opioid receptor.

2、大鼠PK实验2. Rat PK experiment

通过静脉注射(IV)给予雄性SD大鼠实施例一化合物1mg/kg和20mg/kg，溶媒介质均为含氯化钠的10mM醋酸钠缓冲液(pH 4.5±0.2)。IV给药后在不同时间点采集全血和脑组织。全血离心分离取血浆，脑组织加入生理盐水做成脑组织匀浆液，血浆和脑组织匀浆液经沉淀蛋白处理后进行LC-MS/MS分析。Male SD rats were administered intravenously (IV) to a compound of Example 1 at 1 mg/kg and 20 mg/kg, and the vehicle was a sodium chlorate-containing 10 mM sodium acetate buffer (pH 4.5 ± 0.2). Whole blood and brain tissue were collected at different time points after IV administration. Whole blood was centrifuged to separate plasma, and brain tissue was added with physiological saline to prepare brain tissue homogenate. Plasma and brain tissue homogenate were treated with precipitated protein and analyzed by LC-MS/MS.

质谱仪型号为API 5500，液相色谱仪型号为Waters ACQUITY I CLASS***。色谱柱为Thermo Hypersil Gold C18column(50*2.1mm，1.9μm)；流动相A为0.2％甲酸水溶液，流动相B为乙腈；流速为0.4mL/min，柱温为40℃。采用的离子源为ESI源正离子模式，扫描方式为多重反应监测(MRM)。The mass spectrometer model is API 5500 and the liquid chromatograph model is the Waters ACQUITY I CLASS system. The column was Thermo Hypersil Gold C18 column (50*2.1 mm, 1.9 μm); mobile phase A was 0.2% formic acid in water, mobile phase B was acetonitrile; flow rate was 0.4 mL/min, and column temperature was 40 °C. The ion source used is the ESI source positive ion mode, and the scanning mode is multiple reaction monitoring (MRM).

试验结果test results

由上表可看出，在20mg/kg静脉注射给药情况下，实施例一化合物在大鼠血、脑中的暴露量具有明显差异，外周选择性显著，入脑量<0.03％。As can be seen from the above table, in the case of intravenous administration of 20 mg/kg, the exposure amount of the compound of Example 1 in the blood and brain of the rats was significantly different, and the peripheral selectivity was significant, and the amount of brain was <0.03%.

本发明中的缩写具有以下含义：The abbreviations in the present invention have the following meanings:

除本文中描述的那些外，根据前述描述，本发明的多种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。Various modifications of the invention in addition to those described herein will be apparent to those skilled in the art. Such modifications are also intended to fall within the scope of the appended claims. Each of the references (including all patents, patent applications, journal articles, books, and any other publications) cited in this application are hereby incorporated by reference in their entirety.

Claims

一种短肽季铵盐化合物，或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯，其中所述化合物为含有式(I)结构的盐：A short peptide quaternary ammonium salt compound, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, wherein the compound is a formula ( I) Structure of the salt:

其中：among them:

R _a和R _b各自独立地选自H、氘； R _a and R _b are each independently selected from H and hydrazine;

n各自独立的选自0、1、2、3、4、5；n are each independently selected from 0, 1, 2, 3, 4, 5;

p为0～6中的任一整数，优选2～4中任一整数；p is any integer from 0 to 6, preferably any integer from 2 to 4;

R _c和R _d各自独立地选自H、氘、C _1-6烷基，优选H、氘、C _1-4烷基； R _c and R _d are each independently selected from H, hydrazine, C _1-6 alkyl, preferably H, hydrazine, C _1-4 alkyl;

R _x、R _y、R _z各自独立地选自C _1-6烷基，优选C _1-4烷基； R _x , R _y , R _z are each independently selected from C _1-6 alkyl, preferably C _1-4 alkyl;

R _e为
R _e is

所述的盐为其药学上可接受的盐，其药学上可接受的盐选自乙酸盐、盐酸盐和三氟乙酸盐。The salt is a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof is selected from the group consisting of acetate, hydrochloride and trifluoroacetate.
根据权利要求1所述的化合物，或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯，其中所述的化合物为含有式II所示结构的盐：The compound according to claim 1, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, wherein the compound is a formula Salt of the structure shown in II:

其中：R _x、R _y、R _z、R _e、p如权利要求1所定义。 Wherein: R _x , R _y , R _z , R _e , p are as defined in claim 1.
根据权利要求1或2所述的化合物，或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯，其中所述的化合物为含有式II-1所示结构的盐：The compound according to claim 1 or 2, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, wherein the compound is a salt containing the structure of formula II-1:

优选的，所述的化合物为含有式II-1所示结构的乙酸盐、盐酸盐和三氟乙酸盐。Preferably, the compound is an acetate, hydrochloride and trifluoroacetate salt containing the structure of formula II-1.
一种药物组合物，其包含预防或治疗有效量的权利要求1-3中任一项的化合物或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯以及一种或多种药学上可接受的载体。A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1 to 3, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically thereof thereof An acceptable salt or ester and one or more pharmaceutically acceptable carriers.
根据权利要求4所述的药物组合物，其通过口服、静脉内、动脉内、皮下、腹膜内、肌内或经皮途径给药。A pharmaceutical composition according to claim 4 which is administered orally, intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly or transdermally.
权利要求1-3中任一项的化合物，或其立体异构体、多晶型物、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯或者权利要求4或5的药物组合物在制备用于预防或治疗与κ阿片样物质受体相关的疾病的药物中的用途；优选的，所述的与κ阿片样物质受体相关的疾病选自疼痛、炎症、瘙痒、水肿、低钠血症、低钾血症、肠梗阻、咳嗽和青光眼；优选地，所述疼痛选自神经性疼痛、躯体痛、内脏痛和皮肤痛；优选地，所述疼痛选自关节炎疼痛、肾结石疼痛、子宫痉挛、痛经、子宫内膜异位症、外科手术后疼痛、医疗处理后疼痛、眼部疼痛、耳炎疼痛、癌症疼痛和胃肠道紊乱相关的疼痛。A compound according to any one of claims 1 to 3, or a stereoisomer, polymorph, solvate thereof, or a metabolite, prodrug or pharmaceutically acceptable salt or ester thereof, or claim 4 or 5 Use of the pharmaceutical composition for the preparation of a medicament for preventing or treating a disease associated with a kappa opioid receptor; preferably, the disease associated with the kappa opioid receptor is selected from the group consisting of pain, inflammation, and itching , edema, hyponatremia, hypokalemia, intestinal obstruction, cough and glaucoma; preferably, the pain is selected from the group consisting of neuropathic pain, somatic pain, visceral pain and skin pain; preferably, the pain is selected from the group consisting of joints Pain associated with pain, kidney stone pain, uterine cramps, dysmenorrhea, endometriosis, post-surgical pain, post-treatment pain, eye pain, otitis pain, cancer pain, and gastrointestinal disorders.