CN107151236B - 一种2,3-环氧丁二酰衍生物及其制备方法和用途 - Google Patents
一种2,3-环氧丁二酰衍生物及其制备方法和用途 Download PDFInfo
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- CN107151236B CN107151236B CN201610119872.9A CN201610119872A CN107151236B CN 107151236 B CN107151236 B CN 107151236B CN 201610119872 A CN201610119872 A CN 201610119872A CN 107151236 B CN107151236 B CN 107151236B
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/27—Condensation of epihalohydrins or halohydrins with compounds containing active hydrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及一种2,3‑环氧丁二酰衍生物及其制备方法和用途,具体地,本发明涉及式1所示的化合物,其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐。本发明的化合物对组织蛋白酶具有较好的抑制活性和/或选择性,尤其对组织蛋白酶B,可用于治疗与组织蛋白酶相关的多种疾病,例如与组织蛋白酶K有关的骨质疏松症、类风湿性关节炎和骨关节炎,以及埃博拉病毒感染,与组织蛋白酶L、S有关的退行性疾病和自身免疫性疾病,特别是与组织蛋白酶B有关肿瘤疾病,如胃癌、宫颈癌、肺癌、乳腺癌、前列腺癌、膀胱癌、结肠癌、神经胶质瘤、黑色素瘤等。
Description
技术领域
本发明属于医药领域,具体涉及一种2,3-环氧丁二酰衍生物及其制备方法和用途,所述化合可作为组织蛋白酶抑制剂,用于治疗肿瘤、骨质疏松、埃博拉病毒感染、类风湿性关节炎和骨关节炎、自身免疫性疾病或退行性疾病。
背景技术
蛋白酶是人体的主要蛋白水解的参与者,根据蛋白水解机制,可分为丝氨酸蛋白酶、半胱氨酸蛋白酶、天冬氨酰蛋白酶、苏氨酸蛋白酶和金属蛋白酶等。目前研究主要集中在半胱氨酸蛋白酶,而木瓜蛋白酶类半胱氨酸蛋白酶是其最大亚族。哺乳动物中的木瓜蛋白酶类半胱氨酸属于组织蛋白酶(cathepsin)。组织蛋白酶大部分成员存在于溶酶体内,在酸性环境中可被激活,其包括大部分的半胱氨酸蛋白酶,少量的天冬氨酸蛋白酶(组织蛋白酶D,E)和丝氨酸蛋白酶(组织蛋白酶A,G)。根据底物特异性分类,组织蛋白酶又包括肽链内切酶(组织蛋白酶B、F、H、K、L、S、V),肽链端解酶(组织蛋白酶B、C、H、X),氨基肽酶(组织蛋白酶C、H)和羧肽酶(组织蛋白酶B、X)。组织蛋白酶在人体中主要有组织蛋白酶B、C、F、H、K、L、O、S、V、W和X,人体的多种生理和病理过程与它们密切相关。由于组织蛋白酶在序列上具有高度保守性,它们在空间结构上也都由两个几乎同样大小的结构域---L(Left)域和R(Right)域组成,中间是一个“V”形的活性位点沟槽,L结构域中的Cys25和R结构域中的His159、Asn175等活性残基均暴露其中。
组织蛋白酶B是所有半胱氨酸蛋白酶中研究最多的一种,它广泛存在于哺乳动物的各种组织中,是第一个发现与乳腺癌相关的溶酶体蛋白酶,除此之外它还与多种人类肿瘤的发生发展关系密切。肿瘤细胞可分泌组织蛋白酶B,该分泌型的组织蛋白酶B由于缺乏甘露糖-6-磷酸受体识别标记,故不能被摄入溶酶体,而多以酶原的形式存在于胞浆和细胞外。由于肿瘤细胞能够酸化其周围的环境,所以能够激活酶原形成活性组织蛋白酶B,激活的组织蛋白酶B除了自身参与胞外基质成分的降解外,还能激活蛋白水解级联反应,最终生成能够降解多种胞外基质成分的物质。除此之外,较之正常细胞分泌的组织蛋白酶B,肿瘤细胞分泌的组织蛋白酶B在中性及碱性环境中活性不受影响,甚至增高,故而在多种人类和动物的肿瘤中如胃癌、膀胱癌、结肠癌、神经胶质瘤、黑色素瘤等都发现组织蛋白酶B表达水平和(或)活性升高。曾有报道在宫颈癌、肺癌、乳腺癌、前列腺癌等恶性肿瘤组织中发现组织蛋白酶B表达及其活性成倍甚至3到9倍高于邻近正常组织,并认为组织蛋白酶B活性、浓度增高是移行性细胞癌变病人肿瘤侵袭、转移以及预后较差的一个危险因子。
人体正常骨代谢依赖于骨形成及骨吸收之间的动态平衡,骨质疏松症是骨吸收与骨形成代谢失衡,骨吸收大于骨形成所造成的一种疾病,是老年人尤其是绝经期及绝经后妇女中的一种常见病、多发病。骨吸收过程中,破骨细胞首先附着于骨骼表面,形成相对封闭的骨吸收微环境,分泌质子和蛋白水解酶,先溶解骨矿物质,继而降解骨基质,导致骨空洞形成。在溶骨过程中参与骨基质降解的酶主要有两种---半胱氨酸蛋白酶和基质金属蛋白酶,其中发挥主要作用的是半胱氨酸蛋白酶中的组织蛋白酶K,它选择性地大量表达于破骨细胞,其生理作用底物正是在有机骨基质中含量达95%的I型胶原,除此之外它还能降解骨基质中的骨桥接素和骨连接素,是破骨细胞中表达量最高、溶骨活性最强的一种半胱氨酸蛋白酶,它对成骨胶原的降解能力远远高于其他各种基质金属蛋白酶,是骨吸收过程中的一个关键酶,也是近年来骨质疏松研究中的一个热点。除组织蛋白酶K外,在破骨细胞形成的吸收微环境中还存在组织蛋白酶L,它具有很强的胶原溶解作用,也直接参与了骨基质降解。另外有研究证实组织蛋白酶B、S在体内外都显示出骨吸收作用,也与骨质疏松症的形成有关。
类风湿性关节炎(RA)是一种以关节滑膜炎症为特征的慢性全身性自身免疫性疾病,滑膜炎持续反复发作可以导致关节内软骨和骨的破坏,关节功能障碍,甚至残废。骨关节炎(OA)是由于关节软骨退化及关节表面及边缘新骨形成,可动关节发生非炎症性病变,引起关节疼痛的一种常见病。软骨包含两种主要成分:一种为II型胶原,它能形成3-D纤维网状结构,使组织具有可延伸性;另一种为保证软骨具有坚韧性的聚合素;两种蛋白成分中的任意一种过度降解都将导致关节内软骨的破坏。研究发现,II型胶原的降解仅与基质金属蛋白酶(软骨细胞分泌)和组织蛋白酶K有关,组织蛋白酶K在RA和OA病人关节连接处表达水平增高,并且还能被炎症细胞因子进一步激活,表明组织蛋白酶K可能是RA、OA中软骨破坏的主要参与者。另外在许多实验中还发现,RA病人的关节滑膜及滑液中组织蛋白酶B及组织蛋白酶L高表达,而所有出现在炎症性关节连接处的组织蛋白酶都能够水解聚合素,并且组织蛋白酶B还可能通过参与关节处蛋白水解级联反应,通过激活前体基质金属蛋白酶而间接发挥作用。
目前研究中发现埃博拉病毒感染过程与病毒基因编码的I型膜融合蛋白GP有着密切关系,膜融合蛋白GP由GP1和GP2两个亚单位组成。埃博拉病毒粒子有螺旋状核衣壳,外有包膜。包膜病毒需要包膜蛋白与宿主细胞膜或内体膜融合,然后才能将其致病基因进行复制。埃博拉病毒在侵入细胞时,当病毒黏附到细胞表面之后,其包膜融合蛋白GP必须与组织蛋白酶B、L进行接合,使其构象发生变化,才能与宿主细胞内体膜进行融合,然后将其携带的遗传物质注入细胞内部,并在感染细胞内进行大量复制。Bale等研究表明埃博拉病毒蛋白GP1和GP2在酸性条件下不能够独自完成构型变化和介导融合,需要与其它细胞蛋白接合才能发生构型变化。Kathryn Schornberg等研究发表的文章中,通过化学抑制剂和小干扰RNA作用的实验证实了组织蛋白酶B和组织蛋白酶L在埃博拉病毒糖蛋白介导的感染中起作用。研究中证明组织蛋白酶B、L将GP1最终切割成19Kd片段。至于该片段如何触发酶融合和诱导融合,还不明确。Matthew Brecher等,将不同形态的GP与脂质体结合,发现19Kd的片段与脂质体融合需要激活温度最低,说明是最适宜融合的形态。
组织蛋白酶L可以通过催化降解基质膜,促进肿瘤的侵袭、转移,目前已经在肾癌、睾丸癌、乳腺癌、卵巢癌、结肠癌、膀胱癌和甲状腺癌等多种癌症中发现组织蛋白酶L的高表达;组织蛋白酶S在退行性疾病和自身免疫性疾病的发病过程中也都具有重要的作用,它参与主要组织相容性复合体Ⅱ类分子调节的抗原提呈作用,其过量表达与肿瘤的生长、血管的生成和转移密切相关。
本发明的目的在于合成新型组织蛋白酶抑制剂,用于肿瘤、骨质疏松、关节炎、埃博拉病毒感染、类风湿性关节炎、骨关节炎、自身免疫疾病或退行性疾病等疾病的治疗。
发明内容
本发明通过深入的研究,得到了一系列结构新颖的具有环氧琥珀酸结构的衍生物,所述衍生物具有较高的组织蛋白酶(尤其是组织蛋白酶B)抑制活性和/或选择性,本发明即是基于以上发现而完成。
本发明的一个方面涉及式1所示的化合物,其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐,
其中,
R1代表氢原子、C1-C10直链或支链烷基、C3-C10环烷基、C2-C10直链或支链烯基、C2-C10直链或支链炔基、芳基、芳基-C1-C6烷基、杂环基或杂环-C1-C6烷基;
R2代表氢原子、C1-C10直链或支链烷基、C3-C10环烷基、C1-C10烷硫基、C3-C10环烷硫基、C2-C10直链或支链烯基、C2-C10直链或支链炔基、芳基、芳基-C1-C6烷基、杂环基或杂环-C1-C6烷基,任选地,其中所述C1-C10直链或支链烷基、C3-C10环烷基、C1-C10烷硫基、C3-C10环烷硫基、C2-C10直链或支链烯基、C2-C10直链或支链炔基、芳基、芳基-C1-C6烷基、杂环基或杂环-C1-C6烷基各自独立地被一个或多个选自以下的取代基取代:卤素、氨基、氰基、三氟甲基、羟基、硝基、C1-C10烷基、C1-C10烷氧基和C1-C10烷硫基,任选地,其中所述C1-C10烷基、C1-C10烷氧基或C1-C10烷硫基进一步被一个或多个选自上述的取代基取代;
X代表-O-、-N(R5)-;
n为选自0-5的整数,优选1-3;
R3和R4各自独立地代表氢原子、C1-C10直链或支链烷基、C3-C10环烷基、C2-C10直链或支链烯基、C2-C10直链或支链炔基、芳基、芳基-C1-C6烷基、杂环基、杂环-C1-C6烷基或苯稠杂环基,任选地,所述C1-C10直链或支链烷基、C3-C10环烷基、C2-C10直链或支链烯基、C2-C10直链或支链炔基、芳基、芳基-C1-C6烷基、杂环基、杂环-C1-C6烷基或苯稠杂环基各自独立地被一个或多个选自以下的取代基取代:卤素、氨基、氰基、三氟甲基、羟基、硝基、C1-C10烷基、C1-C10烷氧基、C1-C10烷硫基,任选地,其中所述C1-C10烷基、C1-C10烷氧基或C1-C10烷硫基进一步被一个或多个选自上述的取代基取代;
或者,
R3和R4与相连的N原子一起形成5-8元杂环,任选地,所述5-8元杂环被选自以下的一个或多个取代基取代:卤素、羟基、氨基、C1-C10烷基、C1-C10烷氧基、C1-C10烷硫基、芳基、氧基或酯基;
R5代表氢原子、C1-C10直链或支链烷基、芳基、芳基-C1-C6烷基、杂环基或杂环基-C1-C6烷基。
在本发明的一个实施方案中,R1代表氢原子、C1-C10直链或支链烷基、C3-C10环烷基、C2-C10直链或支链烯基或C2-C10直链或支链炔基;优选地,R1代表氢原子、C1-C6直链或支链烷基;优选地,R1代表C1-C4直链或支链烷基,例如甲基或乙基。
在本发明的一个实施方案中,R2代表氢原子、C1-C6直链或支链烷基或芳基-C1-C4烷基;优选地,R2代表C1-C4直链或支链烷基或芳基-C1-C4烷基,例如甲基、乙基或苄基。
在本发明的一个实施方案中,R3和R4各自独立地代表C1-C10直链或支链烷基、C3-C10环烷基、芳基、芳基-C1-C6烷基、杂环基、杂环-C1-C6烷基或苯稠杂环基,任选地,其中所述C1-C10直链或支链烷基、C3-C10环烷基、芳基、芳基-C1-C6烷基、杂环基、杂环-C1-C6烷基或苯稠杂环基各自独立地被一个或多个选自以下的取代基取代:卤素、C1-C10烷基、C1-C10烷氧基和C1-C10烷硫基,任选地,其中所述C1-C10烷基、C1-C10烷氧基或C1-C10烷硫基进一步被一个或多个选自上述的取代基取代;或者,
R3和R4与相连的N原子一起形成5-8元杂环,任选地,其中所述5-8元杂环被选自以下的一个或多个取代基取代:卤素、羟基、氨基、C1-C10烷基、C1-C6烷氧基、C1-C6烷硫基、芳基、氧基或酯基;
优选地,R3和R4各自独立地代表C1-C6直链或支链烷基、芳基-C1-C6烷基,任选地,其中所述C1-C6直链或支链烷基和芳基-C1-C6烷基各自独立地被一个或多个选自卤素、C1-C4烷基和C1-C4烷氧基的取代基取代;或者,
R3和R4与相连的N原子一起形成5-8元杂环,任选地,所述5-8元杂环被一个或多个选自以下的取代基取代:C1-C4烷基、C1-C4烷氧基和芳基;
优选地,R3和R4各自独立地代表C1-C6直链或支链烷基(例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、异丁基、正戊基、3-甲基-丁基、2-甲基-丁基、1-甲基-丁基、2,2-二甲基-丙基、1,1-二甲基-丙基、1,2-二甲基-丙基,1-乙基-丙基、正己基、1-甲基-正戊基、2-甲基-戊基、3-甲基-戊基、4-甲基-戊基、1,1-二甲基-丁基、2,2-二甲基-丁基、3,3-二甲基-丁基、1,2-二甲基-丁基、1,3-二甲基-丁基、2,3-二甲基-丁基、1-乙基-丁基、2-乙基-丁基、1,2,2-三甲基-丙基或1,1,2-三甲基-丙基)、芳基-C1-C6烷基(例如苄基、苯乙基、苯丙基或苯丁基),任选地,其中所述C1-C6直链或支链烷基和芳基-C1-C6烷基各自独立地被一个或多个选自卤素(例如氟、氯、溴或碘)、C1-C4烷基(例如甲基、乙基、丙基或异丙基)、C1-C4烷氧基(例如甲氧基、乙氧基或丙氧基)的取代基取代;或者,
R3和R4与相连的N一起形成5-8元杂环(例如为吡咯烷环、噻唑烷环、恶唑烷环、哌啶环、吗啉环、硫吗啉环、哌嗪环或高哌嗪环),任选地,其中所述5-8元杂环被一个或多个选自以下的取代基取代:羰基、卤素(例如氟、氯、溴或碘)、C1-C4烷基(例如甲基、乙基、丙基或异丙基)、C1-C4烷氧基(例如甲氧基、乙氧基或丙氧基)。
在本发明的一个实施方案中,X为-O-。
在本发明的一个实施方案中,n为选自1-3的整数,优选1或2。
在本发明的一个实施方案中,R1代表氢原子、C1-C10直链或支链烷基、C3-C10环烷基、C2-C10直链或支链烯基、C2-C10直链或支链炔基;
R2代表氢原子、C1-C10直链或支链烷基、C3-C10环烷基、C1-C10烷硫基、C3-C10环烷硫基、C2-C10直链或支链烯基、C2-C10直链或支链炔基、芳基、芳基-C1-C6烷基、杂环基或杂环-C1-C6烷基,任选地,其中所述C1-C10直链或支链烷基、C3-C10环烷基、C1-C10烷硫基、C3-C10环烷硫基、C2-C10直链或支链烯基、C2-C10直链或支链炔基、芳基、芳基-C1-C6烷基、杂环基、杂环-C1-C6烷基各自独立地被一个或多个选自以下的取代基取代:卤素、氨基、氰基、三氟甲基、羟基、硝基、C1-C10烷基、C1-C10烷氧基和C1-C10烷硫基,任选地,其中所述C1-C10烷基或C1-C10烷氧基进一步被一个或多个选自上述的取代基取代;
X为-O-;
n为选自1-3的整数,优选1或2;
R3和R4各自独立地代表氢原子、C1-C10直链或支链烷基、C3-C10环烷基、C2-C10直链或支链烯基、C2-C10直链或支链炔基、芳基、芳基-C1-C6烷基、杂环基、杂环-C1-C6烷基、或苯稠杂环基,任选地,其中所述C1-C10直链或支链烷基、C3-C10环烷基、C2-C10直链或支链烯基、C2-C10直链或支链炔基、芳基、芳基-C1-C6烷基、杂环基、杂环-C1-C6烷基或苯稠杂环基各自独立地被一个或多选自以下的取代基取代:卤素、氨基、氰基、三氟甲基、羟基、硝基、C1-C10烷基、C1-C10烷氧基或C1-C10烷硫基,任选地,其中所述C1-C10烷基、C1-C10烷氧基或C1-C10烷硫基进一步被一个或多个选自上述的取代基取代;或者,
R3和R4与相连的N原子一起形成5-8元杂环,任选地,其中所述5-8元杂环被一个或多个选自以下的取代基取代:卤素、羟基、氨基、C1-C10烷基、C1-C10烷氧基、C1-C10烷硫基、芳基、氧基或酯基。
在本发明的一个具体实施方案中,
R1代表氢原子、C1-C6直链或支链烷基;
R2代表氢原子、C1-C6直链或支链烷基、芳基-C1-C4烷基;
X为-O-;
n为1或2;
R3和R4各自独立地代表C1-C10直链或支链烷基、C3-C10环烷基、芳基、芳基-C1-C6烷基、杂环基、杂环-C1-C6烷基或苯稠杂环基,任选地,其中所述C1-C10直链或支链烷基、C3-C10环烷基、芳基、芳基-C1-C6烷基、杂环基、杂环-C1-C6烷基或苯稠杂环基各自独立地被一个或多个选自以下的取代基取代:卤素、C1-C10烷基、C1-C10烷氧基和C1-C10烷硫基,任选地,其中所述C1-C10烷基、C1-C10烷氧基或C1-C10烷硫基进一步被一个或多个选自上述的取代基取代;或者,
R3和R4与相连的N原子一起形成5-8元杂环,任选地,所述5-8元杂环被选自以下的一个或多个取代基取代:卤素、羟基、氨基、C1-C10烷基、C1-C6烷氧基、C1-C6烷硫基、芳基、氧基或酯基。
在本发明的一个具体实施方案中,
R1代表C1-C4直链或支链烷基;
R2代表C1-C4直链或支链烷基或芳基-C1-C4烷基;
X为-O-;
n为1或2;
R3和R4各自独立地代表C1-C6直链或支链烷基、芳基-C1-C6烷基,任选地,其中所述C1-C6直链或支链烷基和芳基-C1-C6烷基各自独立地被一个或多个选自卤素、C1-C4烷基和C1-C4烷氧基的取代基取代;或者,
R3和R4与相连的N原子一起形成5-8元杂环,任选地,其中所述5-8元杂环被一个或多个选自以下的取代基取代:C1-C4烷基、C1-C4烷氧基和芳基。
在本发明的一个具体实施方案中,所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学或生理学上可接受的盐,其中,所述化合物选自:
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(异戊胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物1);
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(戊胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物2);
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(2-甲基丁胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物3);
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(丙胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物4);
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(己胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物5);
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(2-胺基戊烷基)丁烷]甲酰胺基]环氧琥珀酸(化合物6);
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-甲基哌啶基)丁烷]甲酰胺基]环氧琥珀酸(化合物7);
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-苯并胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物8);
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(异丁胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物9);
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(4-甲氧基苯乙胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物10);
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(四氢吡咯基)丁烷]甲酰胺基]环氧琥珀酸(化合物11);
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(吗啉基)丁烷]甲酰胺基]环氧琥珀酸(化合物12);
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(苯基哌啶基)丁烷]甲酰胺基]环氧琥珀酸(化合物13);
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(2-甲基丁胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物14);
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(新戊胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物15);
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(叔戊胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物16);
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(丙胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物17);
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(己胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物18);
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(叔戊胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物19);
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(4-苯基丁胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物20);
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(对甲基苯乙胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物21);
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(四氢吡咯基)丙烷]甲酰胺基]环氧琥珀酸(化合物22);
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(4-苯基哌啶基)丙烷]甲酰胺基]环氧琥珀酸(化合物23);
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(3-氟苯乙胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物24);
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(吗啉基)丙烷]甲酰胺基]环氧琥珀酸(化合物25);
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(4-甲氧基苯乙胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物26);
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(新戊胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物30);
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(叔戊胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物31);
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(叔丁胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物32);
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(对甲基苯乙胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物33);
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-氟苯乙胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物34);
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(2-乙基哌啶基)丁烷]甲酰胺基]环氧琥珀酸(化合物35);
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(硫代吗啉基)丁烷]甲酰胺基]环氧琥珀酸(化合物36);
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(四氢噻唑基)丁烷]甲酰胺基]环氧琥珀酸(化合物38);
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-胺基戊烷基)丁烷]甲酰胺基]环氧琥珀酸(化合物39);
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(4-苯基丁胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物40);
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3.5-二甲基哌啶基)丁烷]甲酰胺基]环氧琥珀酸(化合物41);
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(2-胺基戊烷基)丙烷]甲酰胺基]环氧琥珀酸(化合物42);
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(3-胺基戊烷基)丙烷]甲酰胺基]环氧琥珀酸(化合物43);
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(异丁胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物44);
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(3-苯并胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物45);
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(硫代吗啉基)丙烷]甲酰胺基]环氧琥珀酸(化合物46);
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(四氢噻唑基)丙烷]甲酰胺基]环氧琥珀酸(化合物47);
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(3-甲基哌啶基)丙烷]甲酰胺基]环氧琥珀酸(化合物48);
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(2-乙基哌啶基)丙烷]甲酰胺基]环氧琥珀酸(化合物49);
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(3.5-二甲基哌啶基)丙烷]甲酰胺基]环氧琥珀酸(化合物50);
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(异戊胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物51);和
(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(戊胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物52)。
本发明的另一方面涉及本发明中任一项所述的式I化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐的制备方法,其包括以下步骤:
(1)化合物A与化合物B经酯化或酰胺化反应生成化合物C;
(2)化合物C选择性水解得到化合物D;
(3)化合物E与化合物F缩合得到化合物G;
(4)化合物G脱氨基保护基得到化合物H;
(5)化合物H与第(2)项得到的化合物D缩合得到式1化合物。
在本发明的一个具体实施方案中,化合物A可由(+/-)-反式-环氧琥珀酸与精氨酸进行手性拆分制得。
在本发明的一个具体实施方案中,其中,第(1)项所述酯化反应可在硫酸存在下进行。
在本发明的一个具体实施方案中,其中,第(2)项所述选择性水解以氢氧化钾作为碱。
在本发明的一个具体实施方案中,其中,第(3)项所述缩合可用DCC、HOBt、EDCI、HATU、HBTU、TBTU或PyBOP等为缩合剂,TEA、DIPEA等为碱。
本发明的第三方面涉及药物组合物,其包含本发明第一方面任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐,以及任选的一种或多种药学可接受的载体或赋形剂。
本发明的再一方面涉及本发明第一方面任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐或本发明第三方面任一项所述的药物组合物在制备组织蛋白酶抑制剂中的用途。
在本发明的一个实施方案中,所述组织蛋白酶选自组织蛋白酶B、C、F、H、K、L、O、S、V、W和X,优选地,所述组织蛋白酶选自组织蛋白酶B、K、L和S。
本发明的再一方面涉及本发明第一方面任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐或本发明第三方面任一项所述的药物组合物在制备治疗/预防/或辅助治疗肿瘤的药物中的用途。
在本发明的一个实施方案中,其中所述肿瘤选自肾癌、淋巴瘤、肺癌、肝癌、胃癌、睾丸癌、肺非小细胞癌、乳腺癌、卵巢癌、结肠癌、膀胱癌和甲状腺癌。
本发明的再一方面涉及本发明第一方面任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐或本发明第三方面任一项所述的药物组合物在制备预防和/或治疗骨质疏松症、埃博拉病毒感染、类风湿性关节炎、骨关节炎、自身免疫疾病或退行性疾病的药物中的用途。
在本发明的一个实施方案中,所述自身免疫疾病选自慢性淋巴性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、慢性溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、类天疱疮、原发性胆汁性肝硬变和多发性脑脊髓硬化症。
在本发明的一个实施方案中,所述退行性疾病选自心血管疾病(例如高血压性心脏病、心肌病、心肌梗死、心脏瓣膜病)、脑功能障碍(例如阿尔兹海默症、唐氏综合症等)以及白内障等。
本发明还涉及本发明第一方面任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐或本发明第三方面任一项所述的药物组合物,其用于抑制组织蛋白酶活性。
在本发明的一个实施方案中,所述组织蛋白酶选自组织蛋白酶B、C、F、H、K、L、O、S、V、W和X,优选地,所述组织蛋白酶选自组织蛋白酶B、K、L和S。
本发明还涉及本发明第一方面任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐或本发明第三方面任一项所述的药物组合物,其用于治疗/预防/或辅助治疗肿瘤。
在本发明的一个实施方案中,其中所述肿瘤选自肾癌、淋巴瘤、肺癌、肝癌、胃癌、睾丸癌、肺非小细胞癌、乳腺癌、卵巢癌、结肠癌、膀胱癌和甲状腺癌。
本发明还涉及本发明第一方面任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐或本发明第三方面任一项所述的药物组合物,其用于预防和/或治疗骨质疏松症、埃博拉病毒感染、类风湿性关节炎、骨关节炎、自身免疫疾病或退行性疾病。
在本发明的一个实施方案中,所述自身免疫疾病选自慢性淋巴性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、慢性溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、类天疱疮、原发性胆汁性肝硬变和多发性脑脊髓硬化症。
在本发明的一个实施方案中,所述退行性疾病选自心血管疾病(例如高血压性心脏病、心肌病、心肌梗死、心脏瓣膜病)、脑功能障碍(例如阿尔兹海默症、唐氏综合症等)以及白内障等。
本发明涉及一种抑制组织蛋白酶活性的方法,其包括向有需要的受试者施用有效量的本发明第一方面任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐或本发明第三方面任一项所述的药物组合物。
在本发明的一个实施方案中,所述组织蛋白酶选自组织蛋白酶B、C、F、H、K、L、O、S、V、W和X,优选地,所述组织蛋白酶选自组织蛋白酶B、K、L和S。
在本发明的一个实施方案中,所述受试者为哺乳动物,例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物;其中,特别优选的受试者为人。
本发明涉及一种治疗/预防/或辅助治疗肿瘤的方法,其包含向有需要的受试者施用有效量的本发明第一方面任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐或本发明第三方面任一项所述的药物组合物。
在本发明的一个实施方案中,其中所述肿瘤选自肾癌、淋巴瘤、肺癌、肝癌、胃癌、睾丸癌、肺非小细胞癌、乳腺癌、卵巢癌、结肠癌、膀胱癌和甲状腺癌。
在本发明的一个实施方案中,所述受试者为哺乳动物,例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物;其中,特别优选的受试者为人。
本发明还涉及一种预防和/或治疗骨质疏松症、埃博拉病毒感染、类风湿性关节炎、骨关节炎、自身免疫疾病或退行性疾病的方法,其包含向有需要的受试者施用有效量的本发明第一方面任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐或本发明第三方面任一项所述的药物组合物。
在本发明的一个实施方案中,所述受试者为哺乳动物,例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物;其中,特别优选的受试者为人。
在本发明的一个实施方案中,所述自身免疫疾病选自慢性淋巴性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、慢性溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、类天疱疮、原发性胆汁性肝硬变和多发性脑脊髓硬化症。
在本发明的一个实施方案中,所述退行性疾病选自心血管疾病(例如高血压性心脏病、心肌病、心肌梗死、心脏瓣膜病)、脑功能障碍(例如阿尔兹海默症、唐氏综合症等)以及白内障等。
以下对本发明的术语进行解释,对于特定的术语,如果本发明中的含义与本领域技术人员通常理解的含义不一致,以本发明中的含义为准;如果在本发明中没有定义,则其具有本领域技术人员通常理解的含义。除非有相反陈述,本发明中使用的术语具有下述含义:
本发明所用术语“C1-C10直链或支链烷基”是指具有1-10个碳原子的直链或支链烷基,例如C1-C6直链或支链烷基、C1-C4直链或支链烷基。具体的实例包括但不限于甲基、乙基、丙基、异丙基、正丁基、仲丁基、叔丁基、异丁基、正戊基、3-甲基-丁基、2-甲基-丁基、1-甲基-丁基、2,2-二甲基-丙基、1,1-二甲基-丙基、1,2-二甲基-丙基,1-乙基-丙基、正己基、1-甲基-正戊基、2-甲基-戊基、3-甲基-戊基、4-甲基-戊基、1,1-二甲基-丁基、2,2-二甲基-丁基、3,3-二甲基-丁基、1,2-二甲基-丁基、1,3-二甲基-丁基、2,3-二甲基-丁基、1-乙基-丁基、2-乙基-丁基、1,2,2-三甲基-丙基和1,1,2-三甲基-丙基等。
本发明所用术语“C1-C10烷氧基”是指具有“C1-C10烷基-O-”结构的基团,例如C1-C6烷氧基、C1-C4烷氧基,其中C1-C10烷基具有与前文所述“C1-C10直链或支链烷基”相同的含义。具体的实例包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、异丁氧基、戊氧基、2-戊氧基、3-戊氧基、异戊氧基、新戊氧基、仲戊氧基、己氧基、2-己氧基和3-己氧基等。
本发明所用术语“C1-C10烷硫基”可与“C1-C10烷氧基”做类似理解,不同之处在于将氧原子替换为硫原子。例如C1-C6烷硫基、C1-C4烷硫基。具体的实例包括但不限于甲硫基、乙硫基、丙硫基、异丙硫基等。
本发明所用术语“C3-C10环烷基”是指具有3-10个碳原子的饱和碳环基团。该环烷基可以是单环或者多环稠合系统,而且可以稠合在芳环上,例如C3-C8环烷基,C5-C8环烷基,C5-C7环烷基,C5-C6环烷基等,具体实例包括但不限于环丙基、环丁基、环戊基和环己基等。
本发明所用术语“C3-C10环烷氧基”是指具有“C3-C10环烷基-O-”结构的基团,其中C3-C10环烷基与前述C3-C10环烷基含义相同。例如C3-C8环烷氧基,C5-C8环烷氧基,C5-C7环烷氧基,C5-C6环烷氧基等。具体的实例包括但不限于环丙氧基、环丁氧基、环戊氧基和环己氧基等。
本发明所用术语“C3-C10环烷硫基”可与C3-C10环烷氧基做类似理解,不同之处在于将氧原子替换为硫原子。例如C3-C8环烷硫基,C5-C8环烷硫基,C5-C7环烷硫基,C5-C6环烷硫基等。具体的实例包括但不限于环丙硫基、环丁硫基、环戊硫基和环己硫基等。
本发明所用术语“C2-C10直链或支链烯基”是指具有2-10个碳原子以及至少一个碳碳双键的直链或支链的烃基,例如C2-C8直链或支链烯基,C2-C6直链或支链烯基,C2-C4直链或支链烯基。具体的实例包括但不限于乙烯基、丙烯基、丁烯基、戊烯基、己烯基等。
本发明所用术语“C2-C10直链或支链炔基”是指具有2-10个碳原子以及至少一个碳碳叁键的直链或支链的烃基,例如C2-C8直链或支链炔基,C2-C6直链或支链炔基,C2-C4直链或支链炔基。具体的实例包括但不限于乙炔基、丙炔基、丁炔基、戊炔基等。
本发明所用术语“卤素”是指氟、氯、溴以及碘。
本发明所用术语“芳基”是指具有单环(如苯基)、多环(如萘基)或其中至少一个环是芳香性的稠合环(如1,2,3,4-四氢萘基)的芳族碳环基,其任选地被一个或多个选自卤素、氨基、氰基、三氟甲基、羟基、硝基、C1-C10烷基、C1-C10烷氧基、C1-C10烷硫基、芳基和杂芳基的取代基取代。具体的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、茚基、苊基、2-氟苯基、3-氟苯基、4-氟苯基、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、联苯基等。
本发明所用术语“芳基烷基”是指被一个或多个前述定义的芳基取代的如前述定义的烷基,例如芳基-Cl-C6烷基,芳基-Cl-C4烷基。具体的实例包括但不限于苄基、苯基乙基、苯丙基、苯丁基等。
本发明所用术语“杂环基”或“杂环”是指含有至少一个至多四个选自N、O或S的杂原子的3-10元单环或多环,可分为脂杂环基和芳杂环基,条件是该基团的环不含两个相邻的O或S原子,优选3-8元(例如3元、4元、5元、6元、7元、8元)脂杂环基或芳杂环基,任选地,所述杂环基还可被一个或多个选自卤素、氨基、氰基、三氟甲基、羟基、硝基、C1-C10烷基、C1-C6卤代烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氨基、二(C1-C6烷基)氨基、C1-C10烷氧基、C1-C6卤代烷氧基、C1-C10烷硫基、芳基和杂芳基的取代基取代。具体的实例包括但不限于环氧乙烷基、氧代环丁烷基、吡咯烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、噻唑基、哌啶基、四氢吡喃基、吗啉基、硫吗啉基、哌嗪基、吡啶基、吡喃基、吡嗪基、嘧啶基、三嗪基、2-甲基哌啶基、3-甲基哌啶基、4-甲基哌啶基、2-乙基哌啶基、3-乙基哌啶基、4-乙基哌啶基、3,5-二甲基哌啶基、2-苯基哌啶基、3-苯基哌啶基、3-苯基哌啶基等。
本发明中所用术语“苯稠杂环基”是指由苯环与杂环化合物稠合而成的基团,如苯并呋喃、吲哚、苯并噻吩、苯并噁唑、苯并咪唑、苯并噻唑、苯并噁二唑、苯并三氮唑、苯并噻二唑、喹啉、苯并四氢呋喃、苯并四氢吡咯、苯并四氢吡喃、苯并哌啶、苯并二氧六环、苯并二甲酰亚氨基或苯并哌嗪等。
本发明中所用术语“多个”包括两个、三个、四个或五个等。
本发明所用术语“旋光异构体”包括本发明通式1化合物的所有可能的光学异构体(例如对映异构体、非对映异构体等)形式,例如,不对称中心各自的R和S构型。
本发明式1化合物或其药学可接受的盐还可以形成溶剂化物,例如水合物、醇合物等,一般来说,与药学可接受的溶剂如水、乙醇等形成的溶剂合物形式与非溶剂合物形式相当。上述化合物还可以是前药或可在体内代谢变化后释放出所述活性成分的形式。选择和制备适当的前药衍生物是本领域技术人员公知技术。
本文所用术语“有效量”是指足以实现所需预防和/或治疗效果的量,例如,实现预防或减轻与待治疗疾病相关的症状的量。
本文所用的术语“治疗”是指治疗性处理和预防性措施,其目的是预防或延缓(减轻)所针对的疾病状态或病症。如果受试者按照本文所述方法接受了治疗量的化合物、或其异构体、溶剂合物、药学可接受的盐或其药物组合物,该受试者一种或多种指征和症状表现出可观察到的和/或可检测出的降低或改善,则受试者被成功地“治疗”了。还应当理解,所述的疾病状态或病症的预防或治疗的不仅包括完全地预防或治疗,还包括未达到完全地预防或治疗,但实现了一些生物学或医学相关的结果。
本发明中所用术语“自身免疫性疾病”是指机体对自身抗原发生免疫反应而导致自身组织伤害所引起的疾病,特指与组织蛋白酶表达或活性升高有关的疾病,例如慢性淋巴性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、慢性溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、类天疱疮、原发性胆汁性肝硬变、多发性脑脊髓硬化症。
本发明所用术语“退行性疾病”是指人类在新陈代谢过程中会产生氧化副产物,这些副产物会导致脱氧核糖核酸、蛋白质和其它大分子的广泛损害,这种损害促进衰老引起的疾病成为退化性疾病,包括癌症、心血管疾病(例如高血压性心脏病、心肌病、心肌梗死、心脏瓣膜病)、免疫系统衰退、脑功能障碍(例如阿尔兹海默症、唐氏综合症等)以及白内障等。
本文所用术语“药物组合物”表示含有一种或多种本文所述化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐,以及药学可接受的载体或赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。这里所述的载体包括但不限于:离子交换剂,氧化铝,硬脂酸铝,卵磷脂,血清蛋白如人血白蛋白,缓冲物质如磷酸盐,甘油,山梨酸,山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物,水,盐或电解质,如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐,胶态氧化硅,三硅酸镁,聚乙烯吡咯烷酮,纤维素物质,聚乙二醇,羧甲基纤维素钠,聚丙烯酸酯,蜂蜡,羊毛脂。所述赋形剂是指在药物制剂中除主药以外的附加物。其性质稳定,与主药无配伍禁忌,不产生副作用,不影响疗效,在常温下不易变形、干裂、霉变、虫蛀、对人体无害、无生理作用,不与主药产生化学或物理作用,不影响主药的含量测定等。如片剂中的黏合剂、填充剂、崩解剂、润滑剂;中药丸剂中的酒、醋、药汁等;半固体制剂软膏剂、霜剂中的基质部分;液体制剂中的防腐剂、抗氧剂、矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、渗透压调节剂、着色剂等均可称为赋形剂。
本发明的化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐或其药物组合物可以通过以下途径给药:胃肠外、局部、静脉内、口服、皮下、动脉内、真皮内、经皮、直肠、颅内、腹膜内、鼻内、肌内途径或作为吸入剂。所述组合物可以任选地与在治疗各种疾病中至少有一定效果的其它试剂联合给药。
本发明的化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐或其药物组合物可根据给药途径配成各种适宜的剂型。
当口服用药时,本发明化合物可制成任意口服可接受的制剂形式,包括但不限于片剂、胶囊、水溶液或水悬浮液。其中,片剂使用的载体一般包括乳糖和玉米淀粉,另外也可加入润滑剂如硬脂酸镁。胶囊制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。任选地,以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。
当皮肤局部施用时,本发明化合物可制成适当的软膏、洗剂或霜剂制剂形式,其中将活性成分悬浮或溶解于一种或多种载体中。软膏制剂可使用的载体包括但不限于:矿物油、液体凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯、乳化蜡和水;洗剂或霜剂可使用的载体包括但不限于:矿物油、脱水山梨糖醇单硬脂酸酯、吐温60、十六烷酯蜡、十六碳烯芳醇、2-辛基十二烷醇、苄醇和水。
本发明化合物还可以无菌注射制剂形式用药,包括无菌注射水或油悬浮液或无菌注射溶液。其中,可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外,灭菌的非挥发油也可用作溶剂或悬浮介质,如单甘油酯或二甘油酯。
本发明的药物制剂包括药学上可实施的任何制剂,例如口服制剂、肠胃外给药制剂等。
在本发明的实施方案中,进行合适的体外或体内测定来确定本发明组合物的效果以及给药是否适用于治疗个体所患疾病或医学疾病状态。这些测定的实例在下文非限制性实施例结合具体疾病或医学治疗进行了描述。通常,足以实现预防或治疗效果的本发明组合物的有效量为约0.001mg/千克体重/天至约10,000mg/千克体重/天。合适的情况下,剂量为约0.01mg/千克体重/天至约1000mg/千克体重/天。剂量范围可以为每天、每两天或每三天约0.01至1000mg/kg宿主体重,更通常为0.1至500mg/kg宿主体重。示例性的治疗方案为每两天一次或每周一次或每月一次给药。通常多次给予所述试剂,单次剂量之间的间隔可以是每天、每周、每月或每年。或者,可以以缓释制剂的形式给予所述试剂,在这种情况下,需要较少的给药频率。剂量和频率根据试剂在受试者中的半衰期而不同。也可以根据是预防性处理还是治疗性处理而不同。在预防性应用中,以相对低频率的间隔长期给予相对低的剂量。在治疗性应用中,有时需要以相对短的间隔给予相对高的剂量,直至疾病的进展被延缓或停止,并优选地直至个体表现出疾病症状的部分或完全改善,在此之后,可以给予患者预防方案。
发明的有益效果
本发明提供了一类环氧琥珀酸衍生物,该类化合物对组织蛋白酶具有较高的抑制活性和/或选择性,尤其是对组织蛋白酶B的抑制活性或选择性,可用于治疗与组织蛋白酶相关的多种疾病,例如与组织蛋白酶K有关的骨质疏松症、类风湿性关节炎和骨关节炎,以及埃博拉病毒感染,与组织蛋白酶L、S有关的退行性疾病和自身免疫性疾病,特别是对组织蛋白酶B有关肿瘤疾病,如胃癌、宫颈癌、肺癌、乳腺癌、前列腺癌、膀胱癌、结肠癌、神经胶质瘤、黑色素瘤等。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
下面实施例中,化合物比旋光度由OA公司polaar 3005型精密自动旋光仪测定,1H-NMR光谱由BrukerARX400型核磁仪测定;FAB质谱由Agilent1260-G6230A高分辨质谱仪测定。
中间体的制备
中间体1:(2S,3S)-环氧乙烷-2,3-二羧酸的制备
把(+/-)-反式-环氧琥珀酸(178g,1.35mol)溶到2600ml甲醇中。在650ml水中加入(234.9g,1.35mol)L-精氨酸,加热使溶解,然后在搅拌的同时逐滴加入到(+/-)-反式-环氧琥珀酸的甲醇溶液中,最后会有大量不溶物出现。加毕,室温下搅拌过夜。抽滤得到沉淀,用甲醇/水(4:1)混合溶剂(1000ml)冲洗沉淀,得到粗品201.2g。用甲醇水(2:1)约3000ml重结晶粗品得到(+)-反式-环氧琥珀酸170.2g,产率82.5%。
1H-NMR(400MHz,D2O)1.54-2.02(4H,m),3.22(2H,t),3.48(2H,s),3.84(1H,t);[α]D+54.7(c=1.00,H20);EI-MS(m/z):[M+H]+133.
中间体2:(2S,3S)-2,3-二乙酯基-环氧乙烷的制备
室温条件下,把(+/-)-反式-环氧琥珀酸(107.1g,0.35mol)加入到1050ml乙醇溶液中悬浮,搅拌,再逐滴加入95%浓硫酸(102.9g,1.05mol),加毕,搅拌回流混合物4.5小时。反应结束后,把混合物中的溶剂旋转蒸发除掉,给瓶中残渣倒入200ml冰水,用乙酸乙酯萃取3次(300ml*3)。合并萃取出的酯层,用饱和碳酸氢钠水溶液(200ml*2),饱和食盐水(200*2)连续洗涤,用无水硫酸镁干燥,抽滤,旋干,得到粗品,用色谱层析柱得到纯品,无色油状液体50.4g,产率76.6%。
1H-NMR(400MHz,CDCl3)1.31(6H,t),3.66(2H,s),4.28(4H,dq);[α]D+110.5(c=1.12,EtOH);EI-MS(m/z):[M+H]+189.
中间体3:(2S,3S)-3-乙酯基-环氧乙烷-2-羧酸的制备
85%氢氧化钾(6.72g,0.1mol)加入到67ml乙醇中,配成氢氧化钾乙醇溶液。把中间体2(18.8g,0.1mol)加入到150ml乙醇中,搅拌,冰浴控温4-6℃,然后逐滴加入氢氧化钾乙醇溶液,加毕继续在4-6℃条件下搅拌1小时,之后升至室温搅拌4小时。反应结束后,把溶剂蒸发掉,加入50ml水,形成溶液,用乙酸乙酯(50ml*2)洗涤。分离出水层,冰浴,用6N盐酸酸化水层PH=2,用乙酸乙酯(70ml*3)萃取。收集酯层用饱和食盐水(70ml*2)洗涤,再用无水硫酸镁干燥,抽滤,再把溶液中的溶剂除掉,得到粗品中间体3(13.1g),无色油状物。不需纯化,直接下一步。
1H-NMR(400MHz,CDCl3)1.27-1.31(3H,t),3.59-3.62(2H,s),4.23-4.25(2H,dq);EI-MS(m/z):[M+H]+161.
中间体4:(2S,3S)-3-(4-硝基苯氧羰基)-环氧乙烷-2-羧酸乙酯的制备
取DCC(12.9g,0.0625mol)溶于乙酸乙酯(26ml),成为乙酸乙酯溶液。中间体3取10g和对硝基苯酚(8.69g,0.0625mol)溶于55ml乙酸乙酯溶液,将温度保持在4-5℃搅拌,缓慢滴入配好的DCC乙酸乙酯溶液,在低温反应3小时,升至室温反应1小时。反应完毕过滤残渣,有机层用乙酸乙酯(20ml)洗涤,乙酸乙酯再过滤,旋蒸溶剂,得到粗品,用乙酸乙酯-环己烷进行重结晶得到中间体4(14.1g,产率65.8%),其为黄色针状。
1H-NMR(400MHz,DMSO)1.26(3H,t),4.06(1H,d),4.08(1H,d),4.24(2H,q),7.58(2H,d),8.36(2H,d);[α]D+114.8(c=1.00,AcOEt);EI-MS(m/z):[M+H]+282.
实施例1(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(异戊胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物1)
1把DCC(10.32g,0.05mol)溶于20ml乙酸乙酯中,成乙酸乙酯溶液。把(12.49g,0.05mol)N-(叔丁氧羰基)-L-蛋氨酸、(4.36g,0.05mol)异戊胺和(6.76g,0.05mol)HOBt溶到35ml乙酸乙酯中,搅拌,冰浴3-8℃。然后逐滴加入前面配好的DCC乙酸乙酯溶液。保持3-8℃搅拌1.5小时,升至室温2.5小时。反应结束过滤掉杂质,用40ml乙酸乙酯洗涤沉淀,合并滤液,用5%盐酸(100ml)、饱和食盐水(100ml)、饱和碳酸氢钠(100ml)、饱和盐水(100ml)依次洗涤。有机层用无水硫酸镁干燥,旋蒸旋干得到粗品14.45g,产率96.1%。不需纯化直接下一步。
2将上一步粗品(18.5g,0.062mol)溶于65ml10%HCl-AcOEt溶液中,搅拌2.5小时。旋蒸溶剂,给残渣加50ml水,再用50ml乙酸乙酯洗涤,把水层用25%氢氧化钠碱化PH>10,乙酸乙酯(50ml*1,25ml*2)萃取。合并有机层用无水硫酸镁干燥,旋干。得粗品,直接下一步。
3上一步粗品(4.39g,0.32mol)和中间体3的(3g,0.32mol)、HOBt2.54g与30ml乙酸乙酯混合,冰浴下逐滴加入3.87gDCC与10ml乙酸乙酯的混合液,冰浴反应3小时。升至室温反应12小时。滤除不溶物,乙酸乙酯洗涤,依次用5%盐酸、饱和食盐水、饱和碳酸氢钠、饱和食盐水洗涤。无水硫酸镁干燥。减压旋干,得粗品,用无水乙醇重结晶得到化合物1。黄色针状粉末3.1g。产率42%
1H-NMR(400MHz,DMSO)0.86(6H,d)1.20-1.31(5H,m)1.54(1H,m)1.79-1.88(2H,m)2.03(3H,s)2.42(2H,m)2.90-3.20(2H,m)3.61(1H,d)3.72(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):361[M+H]+
实施例2(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(戊胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物2)
以正戊胺和中间体3为原料,操作同实施例1,得到化合物2,白色针状粉末。
1H-NMR(400MHz,DMSO)0.86(3H,d)1.17-1.37(9H,m)1.79-1.88(2H,m)2.03(3H,s)2.42(2H,m)2.90-3.20(2H,m)3.61(1H,d)3.72(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):361[M+H]+.
实施例3(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(2-甲基丁胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物3)
以2-甲基丁胺和中间体3为原料,操作同实施例1,得到化合物3,白色针状粉末。
1H-NMR(400MHz,DMSO)0.86(6H,m)1.21-1.50(6H,m)1.79-1.88(2H,m)2.03(3H,s)2.42(2H,m)2.90-3.20(2H,m)3.61(1H,d)3.72(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):361[M+H]+.
实施例4(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(丙胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物4)
以丙胺和中间体3为原料,操作同实施例1,得到化合物4,白色针状粉末。
1H-NMR(400MHz,DMSO)0.80(3H,m)1.21-1.38(5H,m)1.79-1.88(2H,m)2.03(3H,s)2.42(2H,m)2.90-3.20(2H,m)3.61(1H,d)3.72(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):333[M+H]+.
实施例5(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(己胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物5)
以己胺和中间体3为原料,操作同实施例1,得到化合物5白色针状粉末。
1H-NMR(400MHz,DMSO)0.86(3H,t)1.17-1.35(11H,m)1.79-1.88(2H,m)2.03(3H,s)2.42(2H,m)2.90-3.20(2H,m)3.61(1H,d)3.72(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):375[M+H]+.
实施例6(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(2-胺基戊烷基)丁烷]甲酰胺基]环氧琥珀酸(化合物6)
以2-氨基戊烷和中间体3为原料,操作同实施例1,得到化合物6,白色针状粉末。
1H-NMR(400MHz,DMSO)0.86(3H,t)1.01(3H,t)1.21-1.50(7H,m)1.79-1.88(2H,m)2.03(3H,s)2.42(2H,m)3.61(1H,d)3.72(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):361[M+H]+.
实施例7(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-甲基哌啶基)丁烷]甲酰胺基]环氧琥珀酸(化合物7)
以3-甲基哌啶和中间体3为原料,操作同实施例1,得到化合物7,白色固体。
1H-NMR(400MHz,DMSO)0.8(3H,d)1.21(3H,t)1.41-1.97(7H,m)2.03(3H,s)2.42(2H,m)3.50-3.60(5H,m)3.72(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)8.71(1H,d)EI-MS(m/z):373[M+H]+.
实施例8(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-苯并胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物8)
以3-苯丙胺和中间体3为原料,操作同实施例1,得到化合物8,黄色针状粉末。
1H-NMR(400MHz,DMSO)1.21-1.3(5H,m)1.50-1.88(4H,m)2.03(3H,s)2.42(2H,m)3.00-3.10(2H,m)3.61(1H,d)3.72(1H,d)4.16-4.17(2H,m)4.33-4.37(1H,m)7.17-7.27(5H,m)8.13(1H,t)8.63(1H,d)EI-MS(m/z):409[M+H]+.
实施例9(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(异丁胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物9)
以异丁胺和中间体3为原料,操作同实施例1,得到化合物9,白色针状粉末。
1H-NMR(400MHz,DMSO)0.80(6H,d)1.21-1.43(4H,m)1.79-1.88(2H,m)2.03(3H,s)2.42(2H,m)2.90-3.20(2H,m)3.55(1H,m)3.72(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):347[M+H]+
实施例10(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(4-甲氧基苯乙胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物10)
以4-甲氧基苯乙胺和中间体3为原料,操作同实施例1,得到化合物10,白色针状粉末。
1H-NMR(400MHz,DMSO)1.21-1.3(3H,t)1.79-1.88(4H,m)2.03(3H,s)2.42(2H,m)3.00-3.10(2H,m)3.61(1H,d)3.72(1H,d)3.74(3H,s)4.16-4.17(2H,m)4.27-4.28(1H,m)7.05-7.15(4H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):325[M+H]+
实施例11(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(四氢吡咯基)丁烷]甲酰胺基]环氧琥珀酸(化合物11)
以四氢吡咯和中间体3为原料,操作同实施例1,得到化合物11,白色针状粉末。
1H-NMR(400MHz,DMSO)1.21(3H,t)1.79-1.99(6H,m)2.03(3H,s)2.42(2H,m)3.41-3.50(4H,m)3.55(1H,m)3.72(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)8.63(1H,d)EI-MS(m/z):345[M+H]+
实施例12(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(吗啉基)丁烷]甲酰胺基]环氧琥珀酸(化合物12)
以吗啉和中间体3为原料,操作同实施例1,得到化合物12,无色针状粉末。
1H-NMR(400MHz,DMSO)1.21(3H,t)1.79-1.99(2H,m)2.03(3H,s)2.42(2H,m)3.40-3.57(8H,m)3.60(1H,m)3.72(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)8.76(1H,d)EI-MS(m/z):361[M+H]+
实施例13(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(苯基哌啶基)丁烷]甲酰胺基]环氧琥珀酸(化合物13)
以4-苯基哌啶和中间体3为原料,操作同实施例1,得到化合物13,无色针状粉末。
1H-NMR(400MHz,DMSO)1.21(3H,t)1.50-1.90(6H,m)2.03(3H,s)2.42(2H,m)2.65(1H,t)2.75(2H,t)3.15(2H,t)3.60(1H,m)3.72(1H,d)4.12-4.15(2H,m)4.41-4.51(1H,m)7.10-7.38(5H,m)8.81(1H,d)EI-MS(m/z):435[M+H]+.
实施例14(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(新戊胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物30)
以新戊基胺和中间体3为原料,操作同实施例1,得到化合物30,黄色针状粉末。
1H-NMR(400MHz,DMSO)0.86(9H,s)1.22(3H,t)1.80-1.88(2H,m)2.03(3H,s)2.42(2H,m)2.90-3.20(2H,m)3.61(1H,d)3.72(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):361[M+H]+.
实施例15(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(叔戊胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物31)
以叔戊胺和中间体3为原料,操作同实施例1,得到化合物31,白色针状粉末。
1H-NMR(400MHz,DMSO)0.86(9H,t)1.15-1.30(6H,t)1.50-1.88(4H,m)2.03(3H,s)2.42(2H,m)3.61(1H,d)3.72(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)7.51(1H,s)8.51(1H,d)EI-MS(m/z):361[M+H]+.
实施例16(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(叔丁胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物32)
以2-丁胺和中间体3为原料,操作同实施例1,得到化合物32,黄色针状粉末。
1H-NMR(400MHz,DMSO)0.86(3H,t)1.05(3H,d)1.15-1.35(5H,m)1.80-1.88(2H,m)2.03(3H,s)2.42(2H,m)3.61(1H,d)3.72(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)7.99(1H,d)8.66(1H,d)EI-MS(m/z):347[M+H]+.
实施例17(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(对甲基苯乙胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物33)
以对甲基苯乙胺和中间体3为原料,操作同实施例1,得到化合物33,黄色固体。
1H-NMR(400MHz,DMSO)1.21-1.3(3H,t)1.79-1.88(2H,m)2.03(3H,s)2.29(3H,s)2.42(2H,m)3.00-3.10(2H,m)3.61-3.72(4H,m)4.16-4.17(2H,m)4.27-4.28(1H,m))7.05-7.10(4H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):409[M+H]+.
实施例18(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-氟苯乙胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物34)
以3-氟苯乙胺和中间体3为原料,操作同实施例1,得到化合物34,黄色固体。
1H-NMR(400MHz,DMSO)1.21-1.3(3H,t)1.79-1.88(2H,m)2.03(3H,s)2.42(2H,m)2.70-2.75(2H,m)3.61-3.72(4H,m)4.16-4.17(2H,m)4.28-4.32(1H,m)7.05(3H,m)7.30(1H,m)8.17(1H,t)8.63(1H,d)EI-MS(m/z):413[M+H]+.
实施例19(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(2-乙基哌啶基)丁烷]甲酰胺基]环氧琥珀酸(化合物35)
以2-乙基哌啶和中间体3为原料,操作同实施例1,得到化合物35,无色固体。
1H-NMR(400MHz,DMSO)1.21(3H,t)1.41-1.97(10H,m)2.03(3H,s)2.42(2H,m)3.50-3.60(4H,m)3.72(1H,d)4.16-4.17(2H,m)4.41-4.51(1H,m)8.71(1H,d)EI-MS(m/z):387[M+H]+.
实施例20(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(硫代吗啉基)丁烷]甲酰胺基]环氧琥珀酸(化合物36)
以硫代吗啉和中间体3为原料,操作同实施例1,得到化合物36,白色固体。
1H-NMR(400MHz,DMSO)1.21(3H,t)1.79-1.99(2H,m)2.03(3H,s)2.42-2.65(6H,m)3.60(1H,m)3.72(1H,d)3.9(4H.t)4.16-4.17(2H,m)4.27-4.28(1H,m)8.81(1H,d)EI-MS(m/z):377[M+H]+.
实施例21(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(四氢噻唑基)丁烷]甲酰胺基]环氧琥珀酸(化合物38)
以四氢噻唑和中间体3为原料,操作同实施例1,得到化合物38,白色固体。
1H-NMR(400MHz,DMSO)1.21(3H,t)1.79-1.99(2H,m)2.03(3H,s)2.42(2H,m)3.03(2H,m)3.60(1H,m)3.72(1H,d)3.89(2H,m)4.16-4.17(2H,m)4.27-4.28(1H,m)4.44(2H,dd)8.87(1H,d)EI-MS(m/z):363[M+H]+.
实施例22(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-胺基戊烷基)丁烷]甲酰胺基]环氧琥珀酸(化合物39)
以3-氨基戊烷和中间体3为原料,操作同实施例1,得到化合物39,白色针状粉末。
1H-NMR(400MHz,DMSO)0.86(6H,t)1.21-1.43(7H,m)1.79-1.88(2H,m)2.03(3H,s)2.42(2H,m)3.49-3.52(1H,m)3.59(1H,m)3.72(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)7.77(1H,t)8.63(1H,d)EI-MS(m/z):361[M+H]+.
实施例23(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(4-苯基丁胺基)丁烷]甲酰胺基]环氧琥珀酸(化合物40)
以4-苯基丁胺和中间体3为原料,操作同实施例1,得到化合物40,白色固体。
1H-NMR(400MHz,DMSO)1.21-1.3(3H,m)1.35-1.51(4H,m)1.79-1.88(2H,m)2.03(3H,s)2.42(2H,m)2.53(2H,t)3.00-3.10(2H,m)3.57(1H,d)3.67(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)7.17-7.27(5H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):423[M+H]+.
实施例24(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3.5-二甲基哌啶基)丁烷]甲酰胺基]环氧琥珀酸(化合物41)
以3,5-二甲基哌啶和中间体3为原料,操作同实施例1,得到化合物41,无色固体。
1H-NMR(400MHz,DMSO)0.80(6H,m)1.21(3H,t)1.41-1.97(6H,m)2.03(3H,s)2.42(2H,m)3.50-3.60(5H,m)3.72(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)8.71(1H,d)EI-MS(m/z):387[M+H]+
实施例25(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(2-甲基丁胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物14)
1把DCC(10.32g,0.05mol)溶于20ml乙酸乙酯中,成乙酸乙酯溶液。把(15.47g,0.05mol)N-(叔丁氧羰基)-S-苄基-L-半胱氨酸、(3.21g,0.05mol)2-甲基丁胺和(6.76g,0.05mol)HOBt溶到35ml乙酸乙酯中,搅拌,冰浴3-8℃。然后逐滴加入前面配好的DCC乙酸乙酯溶液。保持3-8℃搅拌1.5小时,升至室温2.5小时。反应结束过滤掉杂质,用40ml乙酸乙酯洗涤沉淀,合并滤液,用5%盐酸100ml、饱和食盐水100ml、饱和碳酸氢钠100ml、饱和盐水100ml依次洗涤。有机层用无水硫酸镁干燥,旋蒸旋干得到粗品。得14.85g.不需纯化直接下一步。
2将上一步粗品溶于65ml10%HCl-AcOEt溶液中,搅拌2.5小时。旋蒸溶剂,给残渣加50ml水,再用50ml乙酸乙酯洗涤,把水层用25%氢氧化钠碱化PH>10,乙酸乙酯萃取。合并有机层用无水硫酸镁干燥,旋干。得粗品,直接下一步。
3将中间体4(10g.0.035mol)溶于乙酸乙酯(100ml)溶液,在室温下搅拌,将上一步产物(9.3g,0.035mol)溶于乙酸乙酯(13ml)缓慢滴入该溶液,在室温搅拌4小时。反应结束过滤,滤液用2%饱和氢氧化钠(30ml*2)、饱和食盐水(40ml)、5%盐酸(40ml)和饱和食盐水(40ml*4)依次洗脱,用无水硫酸镁干燥,旋干得到粗品,用柱层析硅胶柱得到化合物无色油状物11.2g,产率58%。
1H-NMR(400MHz,DMSO)0.86(6H,m)1.21-1.50(6H,m)2.50-2.71(2H,m)2.90-3.20(2H,m)3.61-3.72(3H,m)4.16(2H,m)4.56(1H,q)7.10-7.30(5H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):423[M+H]+.
实施例26(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(新戊胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物15)
以新戊基胺和中间体4为原料,操作同实施例25,得到化合物15,黄色油状物。
1H-NMR(400MHz,DMSO)0.86(9H,s)1.22(3H,t)2.50-2.71(2H,m)2.90-3.20(2H,m)3.61-3.72(3H,m)4.16(2H,m)4.56(1H,q)7.10-7.30(5H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):423[M+H]+.
实施例27(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(叔戊胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物16)
以叔戊胺和中间体4为原料,操作同实施例25,得到化合物16,黄色油状物。
1H-NMR(400MHz,DMSO)0.86(9H,t)1.15-1.30(6H,t)1.50-1.88(2H,m)2.50-2.71(2H,m)3.61-3.72(3H,m)4.16-4.34(2H,m)4.56(1H,q)7.10-7.30(5H,m)7.51(1H,s)8.51(1H,d)EI-MS(m/z):423[M+H]+.
实施例28(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(丙胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物17)
以丙胺和中间体4为原料,操作同实施例25,得到化合物17,无色油状物。
1H-NMR(400MHz,DMSO)0.80(3H,m)1.21-1.38(5H,m)2.50-2.71(2H,m)2.90-3.20(2H,m)3.61-3.72(4H,m)4.16-4.34(2H,m)4.56(1H,q)7.10-7.31(5H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):395[M+H]+.
实施例29(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(己胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物18)
化合物18
以己胺和中间体4为原料,操作同实施例25,得到化合物18,黄色固体。
1H-NMR(400MHz,DMSO)0.86(3H,t)1.17-1.35(11H,m)2.71(2H,m)2.90-3.20(2H,m)3.61-3.72(4H,m)4.16-4.34(2H,m)4.56(1H,q)7.10-7.31(5H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):437[M+H]+.
实施例30(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(叔戊胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物19)
以2-丁胺和中间体4为原料,操作同实施例25,得到化合物19,白色固体。
1H-NMR(400MHz,DMSO)0.86(3H,t)1.05(3H,d)1.15-1.35(5H,m)2.50-2.71(2H,m)3.61-3.72(4H,m)4.16-4.34(3H,m)4.56(1H,q)7.10-7.31(5H,m)7.99(1H,d)8.66(1H,d)EI-MS(m/z):409[M+H]+.
实施例31(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(4-苯基丁胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物20)
以4-苯基丁胺和中间体4为原料,操作同实施例25,得到化合物20,无色固体。
1H-NMR(400MHz,DMSO)1.21-1.3(5H,m)1.35-1.88(4H,m)2.50-2.71(2H,m)3.00-3.10(2H,m)3.61-3.72(4H,m)4.16-4.34(2H,m)4.56(1H,q)7.17-7.27(10H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):485[M+H]+.
实施例32(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(对甲基苯乙胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物21)
以对甲基苯乙胺和中间体4为原料,操作同实施例25,得到化合物21,黄色固体。
1H-NMR(400MHz,DMSO)1.21-1.3(3H,t)2.29(3H,s)2.50-2.71(2H,m)3.00-3.10(2H,m)3.61-3.72(4H,m)4.16-4.34(2H,m)4.56(1H,q)7.05-7.30(9H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):471[M+H]+.
实施例33(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(四氢吡咯基)丙烷]甲酰胺基]环氧琥珀酸(化合物22)
以四氢吡咯和中间体4为原料,操作同实施例25,得到化合物22,黄色油状物。
1H-NMR(400MHz,DMSO)1.21(3H,t)1.79-1.99(4H,m)2.50-2.71(2H,m)3.41-3.50(4H,m)3.55(1H,m)3.60-3.72(3H,m)4.16-4.34(2H,m)4.56(1H,q)7.10-7.30(5H,m)8.63(1H,d)EI-MS(m/z):407[M+H]+.
实施例34(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(4-苯基哌啶基)丙烷]甲酰胺基]环氧琥珀酸(化合物23)
以4-苯基哌啶和中间体4为原料,操作同实施例25,得到化合物23,无色油状。
1H-NMR(400MHz,DMSO)1.17(3H,t)1.50-1.90(4H,m)2.55-2.75(5H,m)3.15(2H,t)3.60-3.72(4H,m)4.03-4.18(2H,m)4.56(1H,q)7.10-7.38(10H,m)8.81(1H,d)EI-MS(m/z):473[M+H]+.
实施例35(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(3-氟苯乙胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物24)
以3-氟苯乙胺和中间体4为原料,操作同实施例25,得到化合物24,黄色油状物。
1H-NMR(400MHz,DMSO)1.21-1.3(3H,t)2.50-2.75(4H,m)3.61-3.72(6H,m)4.16-4.34(2H,m)4.56(1H,q)7.05(3H,m)7.10-7.30(6H,m)8.17(1H,t)8.63(1H,d)EI-MS(m/z):475[M+H]+.
实施例36(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(吗啉基)丙烷]甲酰胺基]环氧琥珀酸(化合物25)
以吗啉和中间体4为原料,操作同实施例25,得到化合物25,白色固体。
1H-NMR(400MHz,DMSO)1.21(3H,t)2.50-2.71(2H,m)3.40-3.57(8H,m)3.60-3.72(4H,m)4.16-4.34(2H,m)4.56(1H,q)7.10-7.30(5H,m)8.76(1H,d)EI-MS(m/z):423[M+H]+.
实施例37(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(4-甲氧基苯乙胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物26)
以4-甲氧基苯乙胺和中间体4为原料,操作同实施例25,得到化合物26,白色粉末。
1H-NMR(400MHz,DMSO)1.21-1.3(3H,t)1.79-1.88(2H,m)2.50-2.71(2H,m)3.00-3.10(2H,m)3.6-3.72(4H,m)3.74(3H,s)4.16-4.34(2H,m)4.56(1H,q)7.05-7.30(9H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):487[M+H]+.
实施例38(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(2-胺基戊烷基)丙烷]甲酰胺基]环氧琥珀酸(化合物42)
以2-氨基戊烷和中间体4为原料,操作同实施例25,得到化合物42,白色固体。
1H-NMR(400MHz,DMSO)0.86(3H,t)1.01(3H,t)1.21-1.50(7H,m)2.50-2.71(2H,m)3.61-3.72(4H,m)4.00-4.34(3H,m)4.56(1H,q)7.10-7.30(5H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):423[M+H]+.
实施例39(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(3-胺基戊烷基)丙烷]甲酰胺基]环氧琥珀酸(化合物43)
以3-氨基戊烷和中间体4为原料,操作同实施例25,得到化合物43,白色固体。
1H-NMR(400MHz,DMSO)0.86(6H,t)1.21-1.43(7H,m)2.7(2H,m)2.90-3.20(1H,m)3.55-3.72(4H,m)4.16-4.34(2H,m)4.56(1H,q)7.10-7.31(5H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):423[M+H]+.
实施例40(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(异丁胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物44)
以异丁胺和中间体4为原料,操作同实施例25,得到化合物44,黄色油状。
1H-NMR(400MHz,DMSO)0.80(6H,d)1.21-1.43(4H,m)2.50-2.71(2H,m)2.90-3.20(2H,m)3.55-3.72(4H,m)4.16-4.34(2H,m)4.56(1H,q)7.10-7.30(5H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):409[M+H]+.
实施例41(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(3-苯并胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物45)
以3-苯丙胺和中间体4为原料,操作同实施例25,得到化合物45,黄色油状。
1H-NMR(400MHz,DMSO)1.21-1.3(5H,m)1.50-1.88(2H,m)2.50-2.71(2H,m)3.00-3.10(2H,m)3.61-3.72(4H,m)4.16-4.34(2H,m)4.56(1H,q)7.10-7.27(10H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):471[M+H]+.
实施例42(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(硫代吗啉基)丙烷]甲酰胺基]环氧琥珀酸(化合物46)
以硫代吗啉和中间体4为原料,操作同实施例25,得到化合物46,白色油状。
1H-NMR(400MHz,DMSO)1.21(3H,t)2.42-2.70(6H,m)3.60-3.72(4H,m)3.9(4H.t)4.16-4.34(2H,m)4.56(1H,q)7.10-7.30(5H,m)8.81(1H,d)EI-MS(m/z):439[M+H]+.
实施例43(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(四氢噻唑基)丙烷]甲酰胺基]环氧琥珀酸(化合物47)
以四氢噻唑和中间体4为原料,操作同实施例25,得到化合物47,无色油状。
1H-NMR(400MHz,DMSO)1.21(3H,t)2.50-2.71(2H,m)3.03(2H,m)3.60-3.72(4H,m)3.89(2H,m)4.16-4.34(2H,m)4.44(2H,dd)4.56(1H,q)7.10-7.30(5H,m)8.87(1H,d)EI-MS(m/z):425[M+H]+.
实施例44(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(3-甲基哌啶基)丙烷]甲酰胺基]环氧琥珀酸(化合物48)
以3-甲基哌啶和中间体4为原料,操作同实施例25,得到化合物48,黄色油状。
1H-NMR(400MHz,DMSO)0.8(3H,d)1.21(3H,t)1.41-1.97(5H,m)2.50-2.71(2H,m)3.50-3.72(8H,m)4.16-4.34(2H,m)4.56(1H,q)7.10-7.30(5H,m)8.71(1H,d)EI-MS(m/z):435[M+H]+.
实施例45(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(2-乙基哌啶基)丙烷]甲酰胺基]环氧琥珀酸(化合物49)
以2-乙基哌啶和中间体4为原料,操作同实施例25,得到化合物49,黄色油状。
1H-NMR(400MHz,DMSO)0.90(3H,d)1.21(3H,t)1.41-1.97(8H,m)2.50-2.71(2H,m)3.50-3.72(7H,m)4.16-4.34(2H,m)4.56(1H,q)7.10-7.30(5H,m)8.71(1H,d)EI-MS(m/z):449[M+H]+.
实施例46(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(3.5-二甲基哌啶基)丙烷]甲酰胺基]环氧琥珀酸(化合物50)
以3,5-二甲基哌啶和中间体4为原料,操作同实施例25,得到化合物50,黄色油状。
1H-NMR(400MHz,DMSO)0.80(6H,m)1.21(3H,t)1.41-1.97(4H,m)2.50-2.71(2H,m)3.50-3.72(8H,m)4.16-4.34(2H,m)4.56(1H,q)7.10-7.31(5H,m)8.71(1H,d)EI-MS(m/z):449[M+H]+
实施例47(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(异戊胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物51)
以异戊胺和中间体4为原料,操作同实施例25,得到化合物51,白色油状。
1H-NMR(400MHz,DMSO)0.86(6H,d)1.20-1.31(5H,m)1.54(1H,m)2.50-2.71(2H,m)2.90-3.20(2H,m)3.61-3.72(3H,m)4.16(2H,m)4.56(1H,q)7.10-7.30(5H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):443[M+H]+.
实施例48(2s,3s)-2-乙酯-3-[2-[(s)-3-苄基硫-1-羰基-1-(戊胺基)丙烷]甲酰胺基]环氧琥珀酸(化合物52)
以戊胺和中间体4为原料,操作同实施例25,得到化合物52,白色油状。
1H-NMR(400MHz,DMSO)0.86(3H,d)1.17-1.37(9H,m)2.50-2.70(2H,m)2.90-3.20(2H,m)3.61-3.72(4H,m)4.16(2H,m)4.56(1H,q)7.10-7.30(5H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):443[M+H]+.
实验例:本发明对组织蛋白酶抑制剂的活性评价
本发明涉及组织蛋白酶抑制剂的活性评价可以用以下方法
1.组织蛋白酶K初筛方法:
组织蛋白酶K初筛使用Biovision公司的CathepsinK Inhibitor Screening Kit试剂盒(货号K150-100)进行。
其中待测化合物为上述实施例中制备,阳性化合物FF-FMK为试剂盒中配备,阳性化合物zxy-37(E64d)和zxy-60(CA-074)购自Selleck公司。
1.1准备工作:
1.1.1组织蛋白酶K酶溶液的准备:分别取40ul组织蛋白酶K酶和80ul组织蛋白酶K试剂到3.88ml组织蛋白酶K缓冲溶液中,混合均匀,配成体积为4ml的组织蛋白酶K酶溶液,置于冰上中备用。
1.1.2化合物溶液的准备:将称量好的不同的化合物分别溶于DMSO(甲基亚砜)中,配成浓度为30mM的溶液作为储液,个别不溶的化合物配成浓度为10mM的溶液作为储液;分别将30mM和10mM的化合物储液稀释成为1mM和100uM的DMSO溶液;分别取2ul的1mM和100uM的化合物DMSO溶液到18ul的CTSK缓冲溶液中,配成终浓度为100uM and 10uM的化合物溶液,其中DMSO的浓度为10%。
其中,阳性对照药物分别为zxy-37(E64d)和zxy-60(CA-074)。
1.1.3组织蛋白酶K底物溶液的准备:取160ul组织蛋白酶K底物于3.44ml组织蛋白酶K缓冲溶液中,混合均匀,配成体积为3.6ml的组织蛋白酶K酶溶液,置于冰上中备用。
1.2组织蛋白酶K抑制剂的筛选方法:按照10ul/孔组织蛋白酶K酶溶液(1.1.1中准备的)加到384孔板(ProxiPlate-384Plus,Perkinelmer)中,1000rpm离心1min;再加入化合物溶液(1.1.2中准备的),2ul/孔,每个浓度设置两个平行,1000rpm离心1min,然后于25℃温箱中放置15min;之后加入组织蛋白酶K底物溶液,8ul/孔,1000rpm离心1min;最后置于Enspire中读荧光信号,设置400nm激发光和505nm发射光,37℃连续读数120min。
1.3数据分析:通过ΔRFU(RFU2-RFU1)和时间ΔT(T2-T1)计算出所有样品的斜率(S),包括阴性对照(Enzyme Control,EC)和阳性对照(Inhibitor Control,IC:10uM FF-FMK),计算公式如下:相对抑制率%=(EC斜率-S斜率)/(EC斜率-IC斜率)*100。具体筛选结果参见表1
表1本发明化合物对组织蛋白酶K抑制活性
2.化合物对组织蛋白酶的IC50的检测方法:
化合物对组织蛋白酶B的IC50测定使用Biovision公司的CathepsinB InhibitorScreening Kit试剂盒(货号K147-100)进行;
化合物对组织蛋白酶K的IC50测定使用Biovision公司的CathepsinK InhibitorScreening Kit试剂盒(货号K150-100)进行;
化合物对组织蛋白酶L的IC50测定使用Biovision公司的CathepsinL InhibitorScreening Kit试剂盒(货号K161-100)进行;
化合物对组织蛋白酶S的IC50测定使用Biovision公司的CathepsinS InhibitorScreening Kit试剂盒(货号K149-100)进行。
其中待测化合物为上述实施例中制备,阳性化合物FF-FMK,F-F-FMK,FF-FMK和Z-FF-FMK为试剂盒中配备,阳性化合物zxy-37(E64d)和zxy-60(CA-074)购自Selleck公司。
2.1准备工作:
2.1.1组织蛋白酶溶液的准备:
2.1.1.1组织蛋白酶K溶液的准备:分别取23ul组织蛋白酶K酶和46ul组织蛋白酶K试剂到2231ul组织蛋白酶K缓冲溶液中,混合均匀,配成体积为2.3ml的组织蛋白酶K酶溶液,置于冰上中备用。
2.1.1.2组织蛋白酶B溶液的准备:分别取23ul组织蛋白酶B酶和46ul组织蛋白酶B试剂到2231ul组织蛋白酶B缓冲溶液中,混合均匀,配成体积为2.3ml的组织蛋白酶B酶溶液,置于冰上中备用。
2.1.1.3组织蛋白酶L溶液的准备:取3ul组织蛋白酶L试剂到3ul组织蛋白酶L酶中,混合均匀放置1小时,得到1mU/ul的组织蛋白酶L酶溶液。取24ul组织蛋白酶L缓冲溶液到6ul 1mU/ul的组织蛋白酶L酶溶液中,得到0.2mU/ul的组织蛋白酶L酶溶液。分别取23ul0.2mU/ul组织蛋白酶L酶、46ulDTT到2231ul组织蛋白酶L缓冲溶液中,混合均匀,配成体积为2.3ml的组织蛋白酶L酶溶液,置于冰上中备用。
2.1.1.4组织蛋白酶S溶液的准备:分别取46ul组织蛋白酶S酶到2254ul组织蛋白酶S缓冲溶液中,混合均匀,配成体积为2.3ml的组织蛋白酶S酶溶液,置于冰上中备用。
2.1.2化合物溶液的准备:分别将30mM和10mM的化合物储液和对照化学物在DMSO中按照1:3的比例梯度稀释,最高稀释倍数到19683倍;分别取3ul上述梯度稀释的化合物溶液到27ul组织蛋白酶K、B、L、S缓冲溶液中,混合均匀,混合均匀,其中对照化合物(FF-FMK,F-F-FMK,FF-FMK和Z-FF-FMK)的浓度分别为66.67,22.22,7.41,2.47,0.82,0.27,0.091,0.03,0.01,0.0034和0uM,待测化合物的浓度分别为1000,333.3,111.1,37,12.3,4.1,1.4,0.46,0.15,0.05和0uM,DMSO的终浓度为10%。
2.1.3组织蛋白酶底物溶液的准备:
2.1.3.1组织蛋白酶K取90ul组织蛋白酶K底物于1710ul组织蛋白酶K缓冲溶液中,混合均匀,配成体积为1.8ml的组织蛋白酶K酶溶液,置于冰上中备用。
2.1.3.2组织蛋白酶B取90ul组织蛋白酶B底物于1710ul组织蛋白酶B缓冲溶液中,混合均匀,配成体积为1.8ml的组织蛋白酶B酶溶液,置于冰上中备用。
2.1.3.3组织蛋白酶L取45ul组织蛋白酶L底物于1755ul组织蛋白酶L缓冲溶液中,混合均匀,配成体积为1.8ml的组织蛋白酶L酶溶液,置于冰上中备用。
2.1.3.4组织蛋白酶S取90ul组织蛋白酶S底物于1710ul组织蛋白酶S缓冲溶液中,混合均匀,配成体积为1.8ml的组织蛋白酶S酶溶液,置于冰上中备用。
组织蛋白酶抑制剂的筛选方法:按照10ul/孔组织蛋白酶溶液(2.1.1中准备的)加到384孔板(ProxiPlate-384Plus,Perkinelmer)中,1000rpm离心1min;再加入化合物溶液(2.1.2中准备的),2ul/孔,每个浓度设置两个平行;待测化合物的终浓度分别为100,33.3,11.1,3.7,1.23,0.41,0.14,0.046,0.015,0.005和0uM,其中DMSO的终浓度为1%,1000rpm离心1min,然后于25℃温箱中放置15min;之后加入组织蛋白酶底物溶液,8ul/孔,1000rpm离心1min;最后置于Enspire中读荧光信号,设置400nm激发光和505nm发射光,37℃连续读数120min。
数据分析:通过ΔRFU(RFU2-RFU1)和时间ΔT(T2-T1)计算出所有样品的斜率(S),包括阴性对照(Enzyme Control,EC)和阳性对照(Inhibitor Control,IC:10uM(FF-FMK,F-F-FMK,FF-FMK和Z-FF-FMK),计算公式如下:相对抑制率%=(EC斜率-S斜率)/(EC斜率-IC斜率)*100。最后通过软件GraphPad Prism 5.0拟合出各个化合物的IC50。
对四个酶具体筛选结果参见表2
表2本发明化合物对组织蛋白酶抑制剂活性IC50
上述组织蛋白酶抑制剂活性评价实验表明本发明的式1化合物,特别是化合物5、8、13、34、39、40具有对组织蛋白酶B很强选择性作用,如下表所列:
表3本发明化合物对组织蛋白酶B的选择性
尽管本发明的具体实施方式已经得到详细的描述,本领域技术人员将会理解,根据已经公开的所有教导,可以对那些细节进行各种修改和替换,这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
Claims (8)
1.式1所示化合物、其消旋体或旋光异构体或其药学或上可接受的盐:
其中所述化合物选自:
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(己胺基)丁烷]甲酰胺基]环氧琥珀酸;
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-苯丙胺基)丁烷]甲酰胺基]环氧琥珀酸;
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(苯基哌啶基)丁烷]甲酰胺基]环氧琥珀酸;
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-氟苯乙胺基)丁烷]甲酰胺基]环氧琥珀酸;
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-胺基戊烷基)丁烷]甲酰胺基]环氧琥珀酸;和
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(4-苯基丁胺基)丁烷]甲酰胺基]环氧琥珀酸。
3.药物组合物,其包含权利要求1所述的化合物、其消旋体或旋光异构体或其药学上可接受的盐,以及任选的一种或多种药学可接受的载体。
4.权利要求1所述的化合物、其消旋体或旋光异构体或其药学上可接受的盐或权利要求3的药物组合物在制备抑制组织蛋白酶B的药物中的用途。
5.权利要求4所述的用途,其中所述药物用于治疗/预防/或辅助治疗肿瘤。
6.权利要求5的用途,其中所述肿瘤选自肾癌、淋巴瘤、肺癌、肝癌、胃癌、睾丸癌、乳腺癌、卵巢癌、结肠癌、膀胱癌和甲状腺癌。
7.权利要求5的用途,其中所述肿瘤为非小细胞肺癌。
8.权利要求4所述的用途,其中所述药物用于预防和/或治疗骨质疏松症、埃博拉病毒感染、类风湿性关节炎、骨关节炎、自身免疫疾病或退行性疾病。
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EP3424913B1 (en) | 2023-04-05 |
EP3424913A4 (en) | 2019-08-07 |
EP3424913A1 (en) | 2019-01-09 |
CN107151236A (zh) | 2017-09-12 |
US20190062290A1 (en) | 2019-02-28 |
WO2017148417A1 (zh) | 2017-09-08 |
JP6929866B2 (ja) | 2021-09-01 |
US10647690B2 (en) | 2020-05-12 |
JP2019510755A (ja) | 2019-04-18 |
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