CN104619697A - 作为抗肿瘤和抗增殖剂的1-(取代的磺酰基)-2-氨基咪唑啉的衍生物 - Google Patents
作为抗肿瘤和抗增殖剂的1-(取代的磺酰基)-2-氨基咪唑啉的衍生物 Download PDFInfo
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- CN104619697A CN104619697A CN201480002363.7A CN201480002363A CN104619697A CN 104619697 A CN104619697 A CN 104619697A CN 201480002363 A CN201480002363 A CN 201480002363A CN 104619697 A CN104619697 A CN 104619697A
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- Prior art keywords
- dihydro
- imidazoles
- amine
- alkylsulfonyl
- phenyl
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
-
- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A—HUMAN NECESSITIES
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Abstract
Description
发明领域
本发明涉及具有抗肿瘤活性的新型化合物。特别地,本发明涉及具有在1位上的多种磺酰基取代基以及在4位上的烷基或芳基取代基的2-氨基咪唑啉的新型衍生物、其互变异构体、药学上可接受的盐、水合物、溶剂合物和前药,其制备方法,其作为抗肿瘤药物的用途以及包含其作为活性成分的药物组合物。
发明背景
细胞周期是事件的有序集合,最终造成细胞生长并分裂成两个子细胞。它由四个不同的阶段组成:间隔(gap)1期(G1);合成期(S);间隔2期(G2)以及有丝分裂或细胞分裂期(M)。细胞周期的控制非常复杂,并且涉及多个水平的调控。细胞周期检查点是调控途径,其控制细胞周期转变的顺序和时间,并且在使细胞进一步进展通过周期之前确保例如DNA复制和染色体分离的关键事件正确地完成。
在癌细胞中,正常的调控过程被破坏,并且细胞生长不受控制。人癌细胞的主要异常之一是主要由p53的突变引起的G1期检查点的丧失。因此,G2/M检查点的执行代表新的抗肿瘤剂的有吸引力的作用模式,因为使癌细胞持续停滞在G2/M期通过细胞凋亡触发细胞死亡。
G2/M的进展由数种细胞大分子(包括微管蛋白、微管相关蛋白和发动蛋白(例如驱动蛋白和动力蛋白))紧密调控。靶向G2/M检查点已经用稳定(紫杉烷)或破坏(长春花生物碱)微管形成的药物在临床上验证。另外,还用具有不同的分子靶标的药物(例如万珂(Velcade,蛋白酶体抑制剂))在临床上对G2/M停滞的重要性进行验证。
在本文中我们描述一类新的水溶性的高度有效的化合物,所述化合物能够使肿瘤细胞停滞在G2/M期,但产生与已知的抗有丝分裂剂不同的基因表达谱。用此类药物治疗实体肿瘤癌症可能实现更高的抗癌功效和降低的对于抗有丝分裂剂而言典型的毒副作用。这些化合物衍生自1-(取代的磺酰基)-2-氨基咪唑啉。已经报道结构相关的1-磺胺酰基(sulphanilyl)-2-亚氨基咪唑烷衍生物作为降血糖(anti-glycemic)剂(参见例如GB专利第1174152号),并且公开芳基磺酰基咪唑酮衍生物作为抗肿瘤剂,其活性优于已知的抗肿瘤磺酰脲(美国专利第5,932,742号)。然而,这些化合物不溶于水,这对于通常以高度控制的方式作为缓慢静脉内注射剂给药的细胞毒性抗癌剂而言是严重的缺点。
发明详述
本发明提供一类新的包含连接到1位氮的取代的磺酰基基团以及连接到4位碳的脂族或芳族取代基的2-氨基咪唑啉衍生物,以及其作为抗肿瘤剂的用途。本发明的化合物具有式(I)中呈现的一般结构:
其中:
R1是
(a)氢原子;
(b)取代的或未取代的烷基,优选作为S立体异构体;
(c)取代的或未取代的芳基或杂芳基,优选作为S立体异构体;
R2是
(a)取代的或未取代的烷基;
(b)取代的或未取代的苯基;
(c)5或6元具有1-3个选自氮、氧和硫的杂原子的任选地取代的饱和或不饱和的杂环基;
(d)具有8-10个环原子的饱和或不饱和的稠环碳环基;或者优选地
(e)具有多于6个碳原子以及一个或多个氮、硫和/或氧原子的杂环基团。所述基团可以在单环中或在稠环中包含所述原子,并且可以是饱和或不饱和的且另外被氨基或羧基取代。此类杂环基团的实例包括吲哚基、喹啉基(quinolyl)、苯并二氢吡喃基、苯并咪唑基、苯并噁唑基、苯并噻吩基、苯并呋喃基和喹啉基(quinolinyl)。
X是氢原子、羰基、硫代羰基或亚胺。
如果X是氢原子,则R3不存在。
如果X不为氢,则R3是:
(a)取代的或未取代的线性、支化或环状烷基,其可另外连接到芳族或杂环基团,
(b)取代的或未取代的苯基,
(c)5或6元具有1-3个选自氮、氧和硫的杂原子的任选地取代的饱和或不饱和的杂环基;
(d)NR’(CH2)nR”,其中
R’是氢或烷基,
n是0-3,
R”是未取代的或取代的烷基、环烷基、苯基、苄基、5或6元具有1-3个选自氮、氧和硫的杂原子的任选地取代的饱和或不饱和的杂环基,并且
R’和R”可以连接或不连接;
(e)O(CH2)nR”或S(CH2)nR”,其中R”和n如上文所定义。
本发明也包括上文定义的式(I)的化合物的互变异构体、药学上可接受的盐、水合物、溶剂合物和前药。
如本文所用,除非另有说明,术语“卤代”包括氟代、氯代、溴代或碘代。优选的卤代基团是氟代、氯代和溴代。
如本文所用,术语“烷基”意欲包括作为饱和单价烃基的直链、支化和环状烷基。如本文所用,所述直链烷基可以具有1-20个,优选1-10个,更优选1-7个碳原子。支化和环状烷基可以具有3-20个,优选3-10个,更优选3-7个碳原子。低级烷基表示具有至多7个碳原子的烷基。
如本文所用,除非另有说明,术语“烯基”包括具有至少一个碳-碳双键并且还具有如上文在“烷基”的定义中给出的直链、环状或支化基团的单价烃基。如本文所用,烯基可以具有2-20个,优选2-10个,更优选2-7个碳原子。
如本文所用,除非另有说明,术语“炔基”包括具有至少一个碳-碳三键并且还具有如上文在“烷基”的定义中给出的直链、环状或支化基团的单价烃基。如本文所用,炔基可以具有2-20个,优选2-10个,更优选2-6个碳原子。
如本文所用,除非另有说明,术语“烷氧基”包括O-烷基,其中“烷基”如上文所定义。
如本文所用,除非另有说明,术语“芳基”包括通过移除一个氢衍生自芳烃的有机基团,例如苯基或萘基。如本文所用,芳基可以具有6-18个,优选6-12个,更优选6-10个环碳原子。
如本文所用,除非另有说明,术语“4-10元杂环基”包括包含一个或多个各自选自O、S和N的杂原子的芳族和非芳族杂环基,其中每个杂环基在其环系统中具有4-10个原子。非芳族杂环基包括在其环系统中仅具有4个原子的基团,但芳族杂环基在其环系统中必须具有至少5个原子。4元杂环基的实例是氮杂环丁烷基(衍生自氮杂环丁烷)。5元杂环基的实例是噻唑基,并且10元杂环基的实例是喹啉基。非芳族杂环基的实例是吡咯烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶子基(piperidino)、吗啉代、硫代吗啉代(thiomorpholino)、噻噁烷基、哌嗪基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基(thietanyl)、高哌啶基(homopiperidinyl)、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、1,2,3,6-四氢吡啶基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己烷基、1,3-二氧戊环基、吡唑啉基、二噻烷基、二硫杂环戊烷基、二氢吡喃基、二氢噻吩基、二氢呋喃基、吡唑烷基、咪唑啉基、咪唑烷基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、3H-吲哚基和喹嗪基。芳族杂环基的实例是吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、噌啉基、吲唑基、吲嗪基、酞嗪基、哒嗪基、三嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、噻二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、喹喔啉基、萘啶基和呋喃并吡啶基。衍生自上文列出的化合物的上述基团在可能的情况下可以是C-连接的或N-连接的。例如,衍生自吡咯的基团可以是吡咯-1-基(N-连接的)或吡咯-3-基(C-连接的)。如本文所用,杂环基在其环系统中可以具有至多20个原子。
如本文所用,除非另有说明,短语“药学上可接受的盐”包括可存在于式(I)的化合物中的酸性或碱性基团的盐。
本质上呈碱性的式(I)的化合物能够与多种无机酸和有机酸形成多种盐。可用于制备此类碱性的式(I)的化合物的药学上可接受的酸加成盐的酸是形成无毒性酸加成盐的那些,即包含药理学上可接受的阴离子的盐,例如盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乙酸盐、乳酸盐、水杨酸盐、柠檬酸盐、酸式柠檬酸盐、酒石酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐(gentisinate)、富马酸盐、葡糖酸盐、葡糖醛酸盐(glucaronate)、蔗糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(4,4’-亚甲基双(3-羟基-2-萘甲酸盐))。
那些本质上呈酸性的式(I)的化合物能够与多种药理学上可接受的阳离子形成碱盐。此类盐的实例包括碱金属盐或碱土金属盐,特别是钠盐和钾盐,以及有机胺和铵盐。
某些式(I)的化合物可以具有不对称中心,因此以不同对映异构体形式存在。本发明涉及式(I)的化合物的所有光学异构体和立体异构体以及它们的混合物的用途。式(I)的化合物也可以作为互变异构体存在。本发明涉及所有此类互变异构体以及它们的混合物的用途。
本发明还包括同位素标记的化合物和其药学上可接受的盐,它们与式(I)中所述的化合物相同,但是一个或多个原子被原子质量或质量数不同于自然界中通常所发现的原子质量或质量数的原子代替。可以掺入本发明的化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素,例如分别为2H、3H、13C、14C、15N、18O、17O、35S、18F和36Cl。包含上述同位素和/或其它原子的其它同位素的本发明的化合物、其前药以及所述化合物或所述前药的药学上可接受的盐在本发明的范围之内。某些同位素标记的本发明的化合物,例如掺入如3H和14C的放射性同位素的化合物可用于药物和/或底物组织分布测定。氚化(即3H)和碳-14(即14C)同位素由于其制备简易性和可检测性而是特别优选的。此外,用较重的同位素例如氘(即2H)取代可由于更高的代谢稳定性而提供某些治疗优势,例如延长的体内半衰期或降低的剂量需要,并因此,在一些情况下可为优选的。同位素标记的本发明的式(I)的化合物和其前药通常可通过实施在下文的路线和/或实施例和制备中所公开的步骤,通过用容易获得的同位素标记的试剂代替非同位素标记的试剂来制备。
具有游离氨基、酰胺基、羟基或羧基的式(I)的化合物可以转化成前药。前药包括这样的化合物,其中氨基酸残基或者两个或更多个(例如两个、三个或四个)氨基酸残基的多肽链通过酰胺或酯键共价连接到式(I)的化合物的游离氨基、羟基或羧酸基团。所述氨基酸残基包括但不限于20种天然存在的通常用三字母符号命名的氨基酸,并且还包括4-羟基脯氨酸、羟基赖氨酸、锁链素(demosine)、异锁链素、3-甲基组氨酸、正缬氨酸、β-丙氨酸、γ-氨基丁酸、瓜氨酸、高半胱氨酸、高丝氨酸、鸟氨酸和甲硫氨酸砜。
还包括其它类型的前药。例如,可以将游离羧基衍生为酰胺或烷基酯。所述酰胺和酯基团可以纳入包括但不限于醚、胺和羧酸官能团的基团。可以如D.Fleisher,R.Bong,B.H.Stewart,Advanced Drug Delivery Reviews(1996)19,115中概述的,使用包括但不限于半琥珀酸酯、磷酸酯、二甲基氨基乙酸酯和磷酰氧基甲氧基羰基的基团衍生游离羟基。还包括羟基和氨基的氨基甲酸酯前药,以及羟基的碳酸酯前药和硫酸酯。还包括羟基衍生为(酰氧基)甲基和(酰氧基)乙基醚,其中酰基可以为任选地被包括但不限于醚、胺和羧酸官能团的基团取代的烷基酯,或者其中酰基为如上所述的氨基酸酯。这种类型的前药在R.P.Robinson等人,J.Medicinal Chemistry(1996)39,10中描述。
通过本文提供的方法和通过对其的显而易见的修改,可从合适的原料制备本发明的化合物。在光学异构体可得的情况下,纯的异构体和非对映异构体,以及其任何和所有混合物都意欲包括在权利要求的范围之内。例示的化合物以及其制备方法仅作为实例提供,并且提供所选实施例并不意欲限制本发明的范围。
用于合成式(I)的化合物的优选的一般方法在路线1中提供。在该方法中,将期望的1-取代的-1-叔丁氧基羰基氨基-2-叠氮基乙烷1(通过对之前在EP 0432442中描述的方法略加修改的方法合成)使用10%Pd/C在二氯甲烷或THF中氢化成相应的胺,所述胺未经分离与合适的磺酰氯缩合,得到磺酰胺2。然后,将化合物2通过与溴化氰在-30℃下于三乙胺存在下反应转变成氰基磺酰胺3。在这些条件下,氰基的连接只发生在磺酰胺的氮原子上。当在沸腾的THF或MeOH中于碱(例如三乙胺)存在下加热时,化合物3经历环化而形成2-亚氨基咪唑烷4,然后,可以用在二氯甲烷中的三氟乙酸脱保护,得到期望的2-氨基咪唑啉衍生物5(式I)。化合物3也可以通过用在DCM中的三氟乙酸处理一步转化成5。
我们发现,化合物3和4在小鼠血清中以及在将化合物给药到实验动物时迅速转变成5。正因为如此,我们考虑两种化合物3和4作为式(I)的化合物的前药。
在本发明的特别优选的实施方案中,式(I)中的R2表示杂环系统,特别是二氢吲哚,另外的取代基R3通过羰基连接到R2。用于合成此类化合物的最方便的合成途径在路线2中提供,并且通过类推,它可以容易地应用到二氢吲哚以外的系统。
化合物6如路线1中所述获得。三氟乙酰胺基团的水解伴随咪唑烷环的闭合提供未保护的二氢吲哚7,它可以通过与多种亲电体(例如酰氯、酸酐、异氰酸酯和硫代异氰酸酯)反应来官能化,得到化合物8。Boc保护的移除得到目标化合物9。或者,化合物6的温和水解提供脱保护的中间体10,然后通过与羰基二咪唑反应转变为11。活化的中间体10经历与多种亲核体例如胺、醇、硫醇等的反应,在除去Boc保护后,得到化合物8(式I)。
本发明的另一目的是提供用本发明的化合物治疗患有癌症或另外的特征在于不期望的细胞增殖的疾病的哺乳动物的方法。本发明的方法包括向个体哺乳动物给药足以抑制不期望的细胞增殖或肿瘤生长的治疗有效量的至少一种式(I)的化合物或其前药或药学上可接受的盐。
本发明的化合物的优选用途是用于治疗选自以下的病症:乳腺癌、结肠直肠癌、肺癌、前列腺癌、膀胱癌、脑癌、头颈癌、肾癌(renal cancer、kidney cancer)、鳞状细胞癌、食管癌、胃癌、甲状腺癌、胰腺癌、皮肤癌、骨癌、肝癌、卵巢癌和妇科癌症、肉瘤、黑色素瘤和恶性血液病(急性和慢性淋巴细胞性和髓性白血病、霍奇金淋巴瘤和非霍奇金淋巴瘤、蕈样肉芽肿病、塞扎里综合征(Sézary syndrome))以及恶变前疾病(淋巴增殖性病症)。
本发明的化合物的另一使用领域是与选自哮喘、银屑病、类风湿性关节炎、炎性肠病、全身性红斑狼疮、血管炎、血管过度增殖、糖尿病性视网膜病变、肝硬化和痛风的器官移植、炎性、过敏性或自身免疫疾病中的淋巴细胞增殖有关的病症。
用于治疗此类疾病的化合物的剂量以常见方式随患者的体重和代谢健康状况、任何副作用的严重性以及所用化合物当用于对抗所涉及的肿瘤类型时的相对功效而变化。对于一般的患者群体,优选的初始剂量会通过常规的剂量范围研究来确定,例如在临床研究期间所进行。对于个体患者而言,治疗有效剂量可通过逐步增加向个体给予的量以实现期望的治疗效果而不会引起不可接受的水平的副作用的药物来确定,如目前常规对于其它形式的化学疗法进行的。
本发明的化合物的给药可以通过用于给药治疗剂的任意方法进行,例如口服、静脉内、肌内、皮下或直肠给药。
本发明还提供可用于提供抗增殖(包括抗肿瘤)活性的包含至少一种本发明的化合物的药物组合物。除了包含至少一种本文所述的化合物或其药学上可接受的加成盐或前药以外,所述药物组合物还可以包含添加剂,例如防腐剂、赋形剂、填充剂、润湿剂、结合剂、崩解剂、缓冲剂和/或载体。存在多种用于药物剂型的药学上可接受的添加剂,并且选择合适的添加剂对于药物制剂领域的技术人员而言是常规事务。
所述组合物可以为片剂、胶囊剂、散剂、颗粒剂、栓剂、可重构的粉末或者液体制剂例如口服或无菌肠胃外溶液剂或混悬剂的形式。对于通过注射和/或输注给药,如本领域已知的,可将本发明的组合物或制剂溶解或悬浮在适于注射或输注的媒介物中。此类媒介物包括缓冲或未缓冲的等渗盐水、D5W等。它们还可以包含其它成分,包括其它活性成分。
所述组合物还可以为如本领域已知的,例如在可生物降解或不可生物降解的可注射聚合物微球或微胶囊的基质中、在脂质体中、在乳液中等的控释或持续释放组合物的形式。
本发明的新型化合物可以本身(游离碱)使用,或者以其药学上可接受的水溶性加成盐,例如盐酸盐、氢溴酸盐、乙酸盐、硫酸盐、甲磺酸盐、柠檬酸盐等的形式使用。
通过以下实施例对本发明进行说明。
实施例1
(S)-2-苯基-2-叔丁氧基羰基氨基乙基叠氮化物(1,R1=Ph)的制备。
将甲磺酸(S)-2-苯基-2-叔丁氧基羰基氨基乙酯(15.77g,0.05mol)在50mL DMF中溶解,随后加入叠氮化钠(19.5g,0.3mol)。将混合物在55℃下搅拌24小时,冷却到室温,倾倒到冷水(500mL)中,并剧烈搅拌20分钟。将沉淀通过过滤收集,用水洗涤并干燥,获得9.97g白色固体形式的标题化合物。收率:76%;(MH)+=263;1H NMR(DMSO-d6):1.37(s,9H),3.36-3.50(m,2H),4.69-4.75(m,1H),7.23-7.36(m,5H),7.65-7.68(d,J=9.2Hz,1H)。
实施例2
(S)-1-苯基-1-(叔丁氧基羰基氨基)-2-(1-三氟乙酰基二氢吲哚-5-磺酰基)氨基乙烷(2,R1=Ph,R2X=(1-三氟乙酰基二氢吲哚)-5-基)的制备。
将溶解在250mL二氯甲烷中的(S)-2-苯基-2-叔丁氧基羰基氨基乙基叠氮化物(10.50g,0.04mol)与2.5g 10%Pd/C的混合物在70psi H2下氢化5小时。通过过滤分离催化剂。向滤液中加入三乙胺(8mL),将混合物冷却到-20℃,随后缓慢加入溶解在150mL二氯甲烷中的1-(三氟乙酰基)二氢吲哚-5-磺酰氯(12.56g,0.04mol)。然后,将反应混合物在室温下搅拌过夜。加入水(500mL),并将混合物充分摇荡,分离有机层,与200mL 2%柠檬酸一起摇荡,分离并用MgSO4干燥。通过过滤分离干燥剂。将滤液浓缩,并通过加入己烷沉淀标题产物。收率:17.67g,(86%);(MH)+=514;1H NMR(DMSO-d6):1.33(s,9H),2.85-2.99(m,2H),3.26-3.30(t,J=8.0Hz,2H),4.31-4.35(t,J=8.0Hz,2H),4.53-4.59(m,1H),7.19-7.35(m,6H),7.66-7.68(m,2H),7.72-7.75(t,J=6.0Hz,1H),8.13-8.15(d,J=8.8Hz,1H)。
实施例3
(S)-1-苯基-1-(叔丁氧基羰基氨基)-2-N-氰基-N-(1-三氟乙酰基二氢吲哚-5-磺酰基)氨基乙烷(6,R1=Ph)的制备.
在通风良好的通风柜下(!),将(S)-1-苯基-1-(叔丁氧基羰基氨基)-2-(1-三氟乙酰基二氢吲哚-5-磺酰基)氨基乙烷(10.27g,0.02mol)在二氯甲烷(400mL)和三乙胺(40mL)中的溶液冷却到-50℃,随后,加入3M溴化氰在二氯乙烷(30mL)中的溶液。将反应混合物在-30℃下搅拌30分钟。将反应物从冷却浴移出,一次性加入水(500mL),并将混合物搅拌10分钟。通过加入10%柠檬酸将水层调节到pH~7,并充分摇荡。将有机层分离,用MgSO4干燥并浓缩。在加入乙醚后形成果冻状产物。将产物过滤,用乙醚洗涤并干燥。收率:9.17g(85%);(MH)+=539;1H NMR(DMSO-d6):1.34(s,9H),2.98-3.02(t,J=8.8Hz,2H),3.48-3.62(m,4H),4.67-4.73(m,1H),6.49-6.51(d,J=8.4Hz,1H),7.01(s,1H),7.24-7.33(m,6H),7.41-7.44(dd,J=2.0Hz,J=8.4Hz,1H),7.59-7.62(d,J=9.6Hz,1H)。
实施例4
(S)-4-苯基-1-(二氢吲哚-5-磺酰基)-3-叔丁氧基羰基-4,5-二氢-1H-咪唑-2-亚胺(7,R1=Ph)的制备。
将(S)-1-苯基-1-(叔丁氧基羰基氨基)-2-N-氰基-N-(1-三氟乙酰基二氢吲哚-5-磺酰基)氨基乙烷(8.08g,0.015mol)悬浮在甲醇(100mL)和三乙胺(10mL)中,并在60℃下搅拌过夜。向反应混合物中加入水(200mL),并将甲醇蒸发。将白色沉淀通过过滤收集,干燥,并从二氯甲烷和己烷结晶,得到5.78g标题化合物。收率:87%;(MH)+=443。
实施例5
(S)-4-苯基-1-((N-1-甲基-1H-吡咯-2-基酰基)二氢吲哚-5-磺酰基)-3-叔丁氧基羰基-4,5-二氢-1H-咪唑-2-亚胺(8,R1=Ph,R3=1-甲基-1H-吡咯-2-基)的制备。
向(S)-4-苯基-1-(二氢吲哚-5-磺酰基)-3-叔丁氧基羰基-4,5-二氢-1H-咪唑-2-亚胺(1.33g,0.003mol)在二氯甲烷(25mL)和三乙胺(0.75mL)中的冷却到-20℃的溶液中加入市售的95%纯的溶解在二氯甲烷(5mL)中的1-甲基-1H-吡咯-2-羰酰氯(0.5g,0033mol)。将反应混合物在室温下搅拌过夜。加入水(50mL),充分摇荡,用10%柠檬酸将pH调节到约5。将有机层分离,干燥并蒸发。将粗物质从二氯甲烷-己烷结晶,得到1.27g标题化合物。收率:77%;(MH)+=550。
实施例6-33
下列化合物使用上文描述和例示的方法制备。下表中给出的所有化合物得到与其结构一致的NMR谱,以及当通过以ESI模式运行的质谱表征时,对应于其分子量的正确的母离子信号。在一些情况下,由于在质谱测试期间失去Boc基团,主要的离子的质量会降低100道尔顿。
实施例34
(S)-4-苯基-1-((N-1-甲基-1H-吡咯-2-基酰基)二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺(9,R1=Ph,R3=1-甲基-1H-吡咯-2-基)的制备。
将来自实施例6的(S)-4-苯基-1-((N-1-甲基-1H-吡咯-2-基酰基)二氢吲哚-5-磺酰基)-3-叔丁氧基羰基-4,5-二氢-1H-咪唑-2-亚胺(1.10g;0.002mol)悬浮在二氯甲烷中,并在搅拌下加入苯甲硫醚(thianisole)(0.4mL),随后加入三氟乙酸(4mL)。继续搅拌,直到通过HPLC不再检测到原料(约5-6小时)。将反应混合物用二氯甲烷(20mL)稀释,并加入2mL 2N HCl在乙醚中的溶液。通过加入乙醚(100mL)使产物以盐的形式沉淀。将沉淀通过过滤收集,用乙醚洗涤并干燥。将粗物质在甲醇-水中溶解,并在搅拌下倾倒到1N氢氧化钠水溶液中。将游离碱形式的产物的白色沉淀通过过滤收集,用水洗涤并干燥,获得503mg。收率:56%;(MH)+=450;1H NMR(DMSO-d6):3.12(m,2H),3.26(m,1H),3.78(s,3H),4.10(t,1H),4.37(m,2H),4.74(m,1H),6.12(m,1H),6.38(br s,2H ex),6.78(m,1H),6.98(m,2H),7.05(m,1H),7.19(m,3H),7.74(m,2H),8.01(d,1H)。
实施例35-70
下列化合物使用上文描述和例示的方法制备。下表中给出的所有化合物得到与其结构一致的NMR谱,以及当通过以ESI模式运行的质谱表征时,对应于其分子量的正确的母离子信号。
*-具有R构型的立体异构体
实施例71
(S)-1-苯基-1-(叔丁氧基羰基氨基)-2-N-氰基-N-(二氢吲哚-5-磺酰基)氨基乙烷(10,R1=Ph)的制备。
将来自实施例2的(S)-1-苯基-1-(叔丁氧基羰基氨基)-2-N-氰基-N-(1-三氟乙酰基二氢吲哚-5-磺酰基)氨基乙烷(1.03g,0.002mol)悬浮在15mLMeOH和1.5mL三乙胺中,并在搅拌下温和地加热,直到固体完全溶解。然后,将反应混合物在室温下搅拌6小时。将白色沉淀通过过滤收集,用水洗涤并干燥,获得726mg标题化合物。收率:82%;(MH)+=443。
实施例72
(S)-4-苯基-1-[(咪唑-1-羰基)二氢吲哚-5-磺酰基]-3-叔丁氧基羰基-4,5-二氢-1H-咪唑-2-亚胺(11,R1=Ph,R3=1-甲基-1H-吡咯-2-基)的制备。
将(S)-1-苯基-1-(叔丁氧基羰基氨基)-2-N-氰基-N-(二氢吲哚-5-磺酰基)氨基乙烷(2.215g,0.005mol)、25mL四氢呋喃、2.0mL三乙胺和1,1-羰基二咪唑(2.45g,0.015mol)的混合物在65℃下搅拌36小时。冷却后,将反应混合物用二氯甲烷(100mL)稀释,并与水(2×100mL)一起摇荡。将有机层分离,干燥并蒸发。将粗物质在快速硅胶柱上使用乙酸乙酯进行色谱分离,获得2.175g标题化合物。收率:81%;(MH)+=538。
实施例73
(S)-4-苯基-1-[(3-二甲基氨基丙基氨基)羰基二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺二盐酸盐的制备。
将(S)-4-苯基-1-[(咪唑-1-羰基)二氢吲哚-5-磺酰基]-3-叔丁氧基羰基-4,5-二氢-1H-咪唑-2-亚胺(270mg,0.5mmol)、3mL二甲基氨基甲酰胺和1.5mL二甲基氨基丙基胺的混合物在80℃下搅拌1小时。将溶剂和过量的胺蒸发。将残渣在二氯甲烷(4mL)中溶解,并与三氟乙酸(4mL)一起在室温下搅拌1小时。将溶剂蒸发,并通过制备型HPLC使用0.1%甲酸水溶液-乙腈的梯度对残渣进行纯化。使包含期望产物的流分碱化,并用二氯甲烷萃取。将萃取物干燥,用1N在乙醚中的HCl酸化,并蒸发。将粗产物在水中溶解并冻干,得到139mg标题化合物。收率:51%;(MH)+=471。
实施例74-110
下列化合物使用上文描述和例示的方法制备。下表中给出的所有化合物得到与其结构一致的NMR谱,以及当通过以ESI模式运行的质谱表征时,对应于其分子量的正确的母离子信号。
尽管上文给出的实施例描述了本发明的多个实施方案,但相关领域的技术人员会明白,可以改变本发明的化合物、组合物和方法,以提供其它实施方案以及等效的组合物和方法。
实施例111
使用标准MTT测定法来测定本发明的化合物的细胞生长抑制活性。将源自ATCC(细胞编号:HTB-38)的人结肠肿瘤粘附细胞(HT-29)用测试化合物的DMSO溶液处理,测试溶液中DMSO的最终浓度为0.1%。在时长为72小时的处理后,加入MTT,并在短暂孵育后,将所得到的甲瓒(formazan)在额外的DMSO中溶解,并使用570nm波长扫描溶液。
选择的化合物的抑制活性在下表中给出。
*在暴露于测试化合物72小时后的MTT测定。细胞生长抑制活性的范围定义如下:A:<100nM,B:100-500nM,C:>500nM。
Claims (19)
1.具有式(I)的结构的化合物或其互变异构体、药学上可接受的盐、水合物、溶剂合物或前药,
其中:
R1是
(a)氢原子;
(b)取代的或未取代的烷基;
(c)取代的或未取代的芳基或杂芳基;
(d)如果R1不为H,则其构型可为S或R;
R2是
(a)取代的或未取代的烷基;
(b)取代的或未取代的苯基;
(c)5或6元具有1-3个选自氮、氧和硫的杂原子的任选地取代的饱和或不饱和的杂环基;
(d)具有8-10个环原子的任选地取代的饱和或不饱和的稠环碳环基;
(e)具有8-10个环原子的任选地取代的饱和或不饱和的稠环杂环基,所述环原子包括1-3个选自氮、氧和硫的杂原子;
X是氢原子、羰基、硫代羰基或亚胺,
如果X是氢原子,则R3不存在,
如果X不为氢,则R3是:
(a)取代的或未取代的线性、支化或环状烷基,其可另外连接到芳族或杂环基团,
(b)取代的或未取代的苯基,
(c)5或6元具有1-3个选自氮、氧和硫的杂原子的任选地取代的饱和或不饱和的杂环基;
(d)NR’(CH2)nR”,其中
R’是氢或烷基,
n是0-3,
R”是未取代的或取代的烷基、环烷基、苯基、苄基、5或6元具有1-3个选自氮、氧和硫的杂原子的任选地取代的饱和或不饱和的杂环基,并且
R’和R”可以连接或不连接,
(e)O(CH2)nR”或S(CH2)nR”,其中R”和n如上文所定义。
2.权利要求1的化合物,其中R1是未取代的或取代的烷基、环烷基、芳基、苄基、5或6元具有1-3个选自氮、氧和硫的杂原子的杂环饱和或不饱和的杂环基,所有这些基团任选地具有1-3个选自卤代、烷基、烯基、炔基、羟基、氨基和烷氧基的取代基。
3.权利要求1的化合物,其中R1取代基以S立体化学连接到4,5-二氢-1H-咪唑环。
4.权利要求3的化合物,其中R1是任选地被低级烷基、卤化物或烷氧基取代的苯基。
5.权利要求1的化合物,其中R2是具有多于6个碳原子以及一个或多个氮、硫和/或氧原子的杂环基团;所述基团可以在单环中或在稠环中包含所述原子,并且可以是饱和或不饱和的且另外被氨基或羧基取代。
6.权利要求5的化合物,其中R2是吲哚基、喹啉基、苯并二氢吡喃基、苯并咪唑基、苯并噁唑基、苯并噻吩基、苯并呋喃基和喹啉基。
7.权利要求5的化合物,其中R2是二氢吲哚基并且X表示在1位上连接的羰基基团。
8.权利要求1的化合物,其中R3是未取代的或取代的烷基、杂烷基、芳基、苄基、5或6元具有1-3个选自氮、氧和硫的杂原子的杂环饱和或不饱和的杂环基,所有这些基团任选地具有1-3个选自卤代、烷基、烯基、炔基、羟基、氨基和烷氧基的取代基。
9.权利要求1的化合物,其中R3是:
a.任选地具有1-3个选自卤代、烷基、烯基、炔基、羟基、氨基和烷氧基的取代基的烷氧基、烷硫基、芳氧基或芳硫基;
b.NR’(CH2)nR”,其中R’是氢或烷基;n是0-3;R”是羟基或氨基、未取代的或取代的烷基、苯基、苄基、5或6元具有1-3个选自氮、氧和硫的杂原子的任选地取代的饱和或不饱和的杂环基,并且R’和R”可以连接或不连接。
10.权利要求1的化合物,其中R3是NH(CH2)nR”’;n是0-3;R”’是低级烷基、支化的低级烷基或包含3-7个碳原子的环烷基环。
11.权利要求1的化合物或其互变异构体、药学上可接受的盐、水合物、溶剂合物或前药,所述化合物选自:
1-(苯基磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-(苯基磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-(4-N-甲基氨基苯基磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-(4-N-乙酰基-N-甲基氨基)苯基磺酰基-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-[4-(2-呋喃甲酰基氨基)苯基磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-[4-(1-吡咯烷-2-酮基)苯基磺酰基]-4,5-二氢-1H-咪唑-2-胺,以及
(S)-4-苯基-1-[4-(1-吡咯烷-2,5-二酮基)苯基磺酰基]-4,5-二氢-1H-咪唑-2-胺。
12.权利要求1的化合物或其互变异构体、药学上可接受的盐、水合物、溶剂合物或前药,所述化合物选自:
(S)-4-苯基-1-((N-1-甲基-1H-吡咯-2-基酰基)二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-(呋喃-2-基酰基二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-(5-(2-氨基-4-异丙基-4,5-二氢-1H-咪唑-1-基磺酰基)二氢吲哚-1-基)(呋喃-2-基)甲酮,
(S)-(5-(2-氨基-4-环己基-4,5-二氢-1H-咪唑-1-基磺酰基)二氢吲哚-1-基)(呋喃-2-基)甲酮,
(S)-4-苯基-1-(噻吩-2-基酰基二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-(乙酰基二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-(丙酰基二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-(丁酰基二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-(异丁酰基二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-(噻吩-2-基乙酰基二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-(苯甲酰基二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-(4-硝基苯甲酰基二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-[(4-二甲基氨基苯甲酰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-(4-乙氧基苯甲酰基二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-(苯基乙酰基二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-(甲氧基羰基二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-[(1-乙酰基哌啶-4-基酰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-(环己烷基酰基二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-[(萘-4-基酰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-[(吡啶-3-基酰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-[(4-氨基苯甲酰基)-2-甲基二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-[(异丙基氨基硫代羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-[1-丁酰基-3,4-二氢喹啉-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(R)-4-苯基-1-[1-丁酰基二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(4-氟苯基)-1-(呋喃-2-基酰基二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(4-氟苯基)-1-((1-甲基-1H-吡咯-2-基)二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(2,4-二氟苯基)-1-((1-甲基-1H-吡咯-2-基)二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(4-氯苯基)-1-((1-甲基-1H-吡咯-2-基)二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(4-甲氧基苯基)-1-((1-甲基-1H-吡咯-2-基)二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(3-氯苯基)-1-((1-甲基-1H-吡咯-2-基)二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(2-氯苯基)-1-((1-甲基-1H-吡咯-2-基)二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(3-甲基苯基)-1-((1-甲基-1H-吡咯-2-基)二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(2-甲基苯基)-1-((1-甲基-1H-吡咯-2-基)二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-甲基-1-((1-甲基-1H-吡咯-2-基)二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(3,5-二氯苯基)-1-((1-甲基-1H-吡咯-2-基)二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(嘧啶-2-基)-1-((1-甲基-1H-吡咯-2-基)二氢吲哚-5-磺酰基)-4,5-二氢-1H-咪唑-2-胺,
(S)-1-(二氢吲哚-5-基磺酰基)-4-苯基-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-[(3-二甲基氨基丙基氨基)羰基二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-[(3-二甲基氨基丙基甲基氨基)羰基二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-[(2-甲氧基乙氨基)羰基二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
1-[(2-甲氧基乙氨基)羰基二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-[(2-氨基乙基氨基)羰基二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
1-[(2-氨基乙基氨基)羰基二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-[(1-苄基哌啶-4-基氨基)羰基二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-异丙基-1-[(3-二甲基氨基丙基氨基)羰基二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-环己基-1-[(3-二甲基氨基丙基氨基)羰基二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-[(1-丙基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(4-氟苯基)-1-[(1-丙基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(4-甲氧基苯基)-1-[(1-丙基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(3-氯苯基)-1-[(1-丙基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(3-甲基苯基)-1-[(1-丙基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(2-甲基苯基)-1-[(1-丙基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(2-氯苯基)-1-[(1-丙基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-[(1-丁基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
1-[(1-丁基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(4-氟苯基)-1-[(1-丁基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(4-甲氧基苯基)-1-[(1-丁基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(3-氯苯基)-1-[(1-丁基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(3-甲基苯基)-1-[(1-丁基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(2-甲基苯基)-1-[(1-丁基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(2-氯苯基)-1-[(1-丁基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(4-氯苯基)-1-[(1-丁基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-[(异丙基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-[(环丙基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-[((环丙基甲基)氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-[((环丙基乙基)氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-[(异丁基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-[(叔丁基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-苯基-1-[(新戊基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(2-甲基苯基)-1-[(环丙基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(2-甲基苯基)-1-[((环丙基甲基)氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(2-甲基苯基)-1-[((环丙基乙基)氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(2-甲基苯基)-1-[(新戊基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,
(S)-4-(2-甲基苯基)-1-[(叔丁基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺,以及
(S)-4-(2-甲基苯基)-1-[(异丁基氨基羰基)二氢吲哚-5-磺酰基]-4,5-二氢-1H-咪唑-2-胺。
13.具有式(II)或式(III)的结构的化合物,其为权利要求1的化合物的前药,
其中R1、R2、R3和X如权利要求1中所定义。
14.药物组合物,其包含治疗有效量的权利要求1的化合物或其互变异构体、药学上可接受的盐、水合物、溶剂合物或前药,以及药学上可接受的载体。
15.药物组合物,其包含权利要求1的化合物、其盐、水合物、溶剂合物或前药,以及药学上可接受的载体和抗癌剂。
16.治疗哺乳动物中过度增殖性病症的方法,其包括向所述哺乳动物给药治疗有效量的权利要求1的化合物或其互变异构体、药学上可接受的盐、水合物、溶剂合物或前药。
17.权利要求16的方法,其中所述过度增殖性病症是癌症。
18.权利要求17的方法,其中所述癌症选自乳腺癌、结肠直肠癌、肺癌、前列腺癌、膀胱癌、脑癌、头颈癌、肾癌、鳞状细胞癌、食管癌、胃癌、甲状腺癌、胰腺癌、皮肤癌、骨癌、肝癌、卵巢癌和妇科癌症、肉瘤、黑色素瘤和恶性血液病(急性和慢性淋巴细胞性和髓性白血病、霍奇金淋巴瘤和非霍奇金淋巴瘤、蕈样肉芽肿病、塞扎里综合征)以及恶变前疾病(淋巴增殖性病症)。
19.权利要求16的方法,其中所述过度增殖性病症与选自哮喘、银屑病、类风湿性关节炎、炎性肠病、全身性红斑狼疮、血管炎、血管过度增殖、糖尿病性视网膜病变、肝硬化和痛风的器官移植、炎性、过敏性或自身免疫疾病中的淋巴细胞增殖有关。
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