CN104781235B - N-[2-{4-[6-氨基-5-(2,4-二氟苯甲酰)-2-氧代吡啶-1(2h)-基]-3,5-二氟苯基}乙基]-l-丙氨酸叔丁酯或其盐、水合物或溶剂合物 - Google Patents
N-[2-{4-[6-氨基-5-(2,4-二氟苯甲酰)-2-氧代吡啶-1(2h)-基]-3,5-二氟苯基}乙基]-l-丙氨酸叔丁酯或其盐、水合物或溶剂合物 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
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- 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
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A61P11/06—Antiasthmatics
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Abstract
本发明提供了以下化合物:N‑[2‑{4‑[6‑氨基‑5‑(2,4‑二氟苯甲酰)‑2‑氧代吡啶‑1(2H)‑基]‑3,5‑二氟苯基}乙基]‑L‑丙氨酸叔丁酯或其盐、水合物或溶剂合物。本发明还提供了包含该化合物以及一种或多种药学上可接受的载体和/或赋形剂的药物组合物。该化合物和组合物可用于抑制p38MAP激酶活性。这样,它们可用于治疗自身免疫性或炎性疾病,或者细胞增殖性疾病。此外,本发明还提供了由本发明化合物的酯基水解产生的酸。该酸是N‑[2‑{4‑[6‑氨基‑5‑(2,4‑二氟苯甲酰)‑2‑氧代吡啶‑1(2H)‑基]‑3,5‑二氟苯基}乙基]‑L‑丙氨酸。
Description
技术领域
本发明涉及氨基酸酯化合物以及包含该氨基酸酯化合物的组合物。本发明还涉及该化合物或组合物在抑制p38 MAP激酶中的应用。此外,本发明涉及由本发明化合物的酯基水解产生的酸。
背景技术
导致诸如TNF-α、IL1-β和IL-8等细胞因子水平升高的包括单核细胞、巨噬细胞和中性粒细胞在内的白细胞的不当活化是一些炎性疾病的致病特征,这些炎性疾病包括类风湿性关节炎、溃疡性结肠炎、克罗恩病、慢性阻塞性肺病(COPD)、哮喘和牛皮癣、以及涉及炎性组分的细胞增殖性疾病。炎症细胞响应各种外界刺激产生细胞因子,导致许多细胞内信号传导机制的活化。其中较为显著的是由调节细胞生长、分化和应激反应的高度保守的信号传导激酶构成的细胞分裂素活化蛋白激酶(MAPK)超家族。哺乳动物细胞包含至少三个MAPK家族:p42/44细胞外信号调节激酶(ERK)MAPK,c-JunNH2-末端激酶(JNK)和p38 MAPK(也称为p38a/Mpk2/RK/SAPK2a/CSBP1/2)。p38 MAPK在其鉴定为激酶后首先被克隆,用脂多糖(LPS)刺激单核细胞之后酪氨酸磷酸化[Han等,Science1994,265,808]。已经描述了哺乳动物p38的其他同系物,包括p38β[Jiang等,J.Biol.Chem,1996,271,17920],p38γ[Li等,Biochem.Biophys.Res.Commun.,1996,228,334]和p38δ[Jiang等,J.Biol.Chem.1997,272,30122]。p38α和p38β表达广泛,p38γ主要限于骨骼肌,并且p38δ主要在肺和肾脏中表达。
宿主防御细胞释放细胞因子以及白细胞对细胞因子和其他促炎应激的响应受到p38 MAPK各种程度的调节[Cuenda等,FEBS Lett,1995,364,229-233]。在其他细胞类型中,p38 MAPK控制应激响应,例如TNF-α刺激支气管上皮细胞产生IL-8和上调LPS-刺激的上皮细胞中的细胞粘附分子ICAM-1。一旦活化,经双特异性激酶MKK3和MKK6的TGY基序的双重磷酸化,p38 MAPK通过转录因子和其他激酶的磷酸化作用而产生效果。MAP激酶活化的蛋白激酶-2(MAPKAP-K2)已鉴定为p38磷酸化的目标。显示缺少MAPKAP-K2的小鼠[Kotlyarov等,Nat.Cell Biol.1999,1,94-97]响应LPS/半乳糖胺介导的内毒素性休克而释放降低水平的TNF-α,IL-1β,IL-6,IL-10和IFN-γ。在mRNA水平调节这些细胞因子以及COX-2的水平。TNF-α的水平通过TNF-αmRNA的3’-UTR中的富AU元件经翻译控制进行调节,而MAPKAP-K2信号传导增加TNF-αmRNA翻译。MAPKAP-K2信号传导导致COX-2、IL-6和巨噬细胞炎症蛋白的mRNA稳定性增加。MAPKAP-K2决定p38MAPK以及转导p38 MAPK信号传导的细胞位置,具有位于其羧基末端的核定位信号以及作为自动抑制结构域的核输出信号[Engel等,EMBO J.1998,17,3363-3371]。在应激细胞中,MAPKAP-K2和p38 MAPK由细胞核迁移进入细胞质,这种迁移仅仅在p38 MAPK催化活化时发生。据信该事件是由于p38 MAPK的磷酸化导致的MAPKAP-K2核输出信号的暴露而驱动的[Meng等,J.Biol.Chem.2002,277,37401-37405]。此外,p38 MAPK直接或间接地导致一些据信介导炎症的转录因子的磷酸化,包括ATF1/2(活化转录因子1/2),CHOP-10/GADD-153(生长停滞和DNA损伤诱导基因153),SAP-1(血清应答因子辅助蛋白-1)和MEF2C(肌细胞增强子因子-2)[Foster等,Drug NewsPerspect.2000,13,488-497]。
在一些实例中已显示,小分子抑制p38 MAPK活性可用于治疗一些由不当细胞因子产生介导的疾病状态,包括类风湿性关节炎、COPD、哮喘和脑缺血。这种模式已成为一些综述的主题[Salituro等,Current Medicinal Chemistry,1999,6,807-823和Kumar等,Nature Reviews Drug Discovery 2003,2,717-726]。
已显示p38 MAPK的抑制剂在类风湿性关节炎的动物模型中是有效的,例如大鼠中胶原诱导的关节炎[Revesz等,Biorg.Med.Chem.Lett.,2000,10,1261-1364]和大鼠中佐剂诱发关节炎[Wadsworth等,J.Pharmacol.Exp.Ther.,1999,291,1685-1691]。在胰腺炎诱发的肺损伤的鼠模型中,用p38 MAPK抑制剂预处理可降低气道和肺水肿中TNF-α的释放[Denham等,Crit.Care Med.,2000,29,628和Yang等,Surgery,1999,126,216]。在OVA-致敏小鼠中在卵清蛋白刺激之前抑制p38 MAPK降低了炎症过敏气道模型中气道的细胞因子和炎症细胞蓄积[Underwood等,J.Pharmacol.Exp.Ther.,2000,293,281]。已观察到在患有炎性肠病的患者中p38 MAP激酶活性增加[Waetzig等,J.Immunol,2002,168,5432-5351]。在心脏肥大[Behr等,Circulation,2001,104,1292-1298]和脑局部缺血[Barone等,J.Pharmacol.Exp.Ther.,2001,296,312-321]的大鼠模型中显示p38 MAPK抑制剂是有效的。
WO 2007/129040和WO 2009/060160都揭示α氨基酸酯是p38 MAP激酶的抑制剂。在揭示的化合物中,酯基团是可以被一种或多种细胞内酯酶水解成羧酸基团的酯基团;并且α氨基酸酯的碳上的取代基形成侧链,其是天然或非天然α氨基酸的侧链。
据称揭示的化合物是p38 MAPK(p38α,β,γ和δ)及其亚型和剪接变体,特别是p38α,p38β和p38β2的强效的选择性抑制剂。因此,化合物可用于医疗用途,例如治疗和预防本文所述的免疫和炎性疾病。该化合物的特征在于,氨基酸基序或氨基酸酯基序分子中存在-NH-CHR1R2,其可以被细胞内羧酸酯酶水解。具有亲脂性氨基酸酯基序的化合物穿过细胞膜,并且由细胞内羧酸酯酶水解成酸。由于其不易于穿过所述细胞膜,所述极性水解产物在细胞中积聚。因此,化合物的p38 MAP激酶活性在细胞内得到延长和增强。本发明化合物涉及国际专利申请WO03076405所涵盖的p38 MAP激酶抑制剂,但区别在于它们具有上述氨基酸酯基序。
WO 2007/129040还揭示了包括在巨噬细胞中选择性蓄积的化合物。已知巨噬细胞通过释放细胞因子,特别是TNFα和IL-1在炎性疾病中发挥关键作用(van Roon等,Arthritis and Rheumatism,2003,1229-1238)。在类风湿性关节炎中,其是维持关节炎症和关节破坏的主要作用物。巨噬细胞也参与肿瘤生长和发育(Naldini和Carraro,Curr Drug Targets Inflamm Allergy,2005,3-8)。因此选择性靶向巨噬细胞增殖的试剂可具有治疗癌症和自体免疫疾病的价值。预期靶向特定细胞类型会引起副作用降低。酯酶基序连接至p38激酶抑制剂的方式确定其是否水解,因而确定是否在不同细胞类型中积聚。具体说,巨噬细胞包含人羧酸酯酶hCE-1而其他细胞类型没有。在WO2007/129040的通式(I)中,当酯酶基序R1CH(R2)NH-的氮不与羰基(-C(=O)-)直接相连时,即Y不是–C(=O),-C(=O)O-或-C(=O)NR3-基团,酯将只能由hCE-1水解,因而抑制剂仅在巨噬细胞中积聚。本文中,除非指定一种或多种“单核细胞”,所述术语一种或多种巨噬细胞用于指示巨噬细胞(包含肿瘤相关巨噬细胞)和/或单核细胞。
WO 2009/060160揭示了一组落在WO 2007/129040一般描述范围内的具体化合物,但并未具体鉴定或示例。这些化合物显示如上所述的巨噬细胞选择性。
发明内容
本发明的发明人发现,化合物N-[2-{4-[6-氨基-5-(2,4-二氟苯甲酰)-2-氧代吡啶-1(2H)-基]-3,5-二氟苯基}乙基]-L-丙氨酸叔丁酯在抑制p38 MAP激酶活性方面意外地好。测试显示,在人血中酯TNF-α抑制的IC50值明显低于相关化合物观察到的人血中酯TNF-α抑制的IC50值。而且,本发明人进行的测试显示,本发明化合物的生物利用度要比结构类似的已知化合物预计的结果要高得多。
因此,本发明提供了以下化合物:N-[2-{4-[6-氨基-5-(2,4-二氟苯甲酰)-2-氧代吡啶-1(2H)-基]-3,5-二氟苯基}乙基]-L-丙氨酸叔丁酯或其药学上可接受的盐、水合物或溶剂合物。
本发明还提供了包含该化合物以及一种或多种药学上可接受的运载体和/或赋形剂的药物组合物。
另一方面,本发明提供了上文所述的化合物或者上文限定的组合物,通过疗法在人或动物体的治疗方法中使用。
本发明还提供了上文所述的化合物或上文限定的组合物用于在体外或体内抑制p38 MAP激酶活性。还提供了上文限定的化合物或上文限定的组合物用于预防或治疗自身免疫或炎性疾病。还提供了上文限定的化合物或上文限定的组合物,在细胞增殖性疾病的治疗中使用。
另一方面,本发明提供了一种抑制p38 MAP激酶活性的方法,该方法包括使该酶与一定量能够有效实现这种抑制的上文限定的化合物或上文限定的组合物接触。还提供了一种治疗或预防对象自身免疫或炎性疾病的方法,该方法包括给予所述对象有效量的上文限定的化合物或上文限定的组合物。还提供了一种治疗对象细胞增殖性疾病的方法,该方法包括给予所述对象有效量的上文限定的化合物或上文限定的组合物。所述治疗可包括缓解或降低细胞增殖性疾病的发病。
又一方面,本发明提供了使用上文限定的化合物或上文限定的组合物在制备用于抑制p38 MAP激酶活性的药物中的应用。还提供了上文限定的化合物或上文限定的组合物在制备用于预防或治疗自身免疫或炎性疾病的药物中的应用。还提供了上文限定的化合物或上文限定的组合物在制备用于治疗细胞增殖性疾病的药物中的应用。
本发明还提供了一种用于抑制p38 MAP激酶活性的试剂,该试剂包含上文限定的化合物或上文限定的组合物作为活性成分。该试剂通常用于预防或治疗自身免疫或炎性疾病。可选地,可用于治疗细胞增殖性疾病。
本发明还提供了一种酸,即N-[2-{4-[6-氨基-5-(2,4-二氟苯甲酰)-2-氧代吡啶-1(2H)-基]-3,5-二氟苯基}乙基]-L-丙氨酸。
具体实施方式
本发明提供了一种化合物,即N-[2-{4-[6-氨基-5-(2,4-二氟苯甲酰)-2-氧代吡啶-1(2H)-基]-3,5-二氟苯基}乙基]-L-丙氨酸叔丁酯。
本发明的化合物可以以盐、水合物或溶剂合物的形式制备。因此,本发明也提供了该化合物的盐、水合物或溶剂合物。通常,所述盐是药学上可接受的盐。
如本文所用,药学上可接受的盐是与药学上可接受的酸或碱形成的盐。药学上可接受的酸包括无机酸和有机酸,无机酸包括例如盐酸、硫酸、磷酸、二磷酸、氢溴酸或硝酸,有机酸包括例如柠檬酸、水杨酸、谷氨酸、乳酸、富马酸、马来酸、苹果酸、抗坏血酸、琥珀酸、酒石酸、苯甲酸、醋酸、甲磺酸、乙磺酸、苯磺酸或对甲苯磺酸。药学上可接受的碱包括碱金属(例如钠或钾)和碱土金属(例如,钙、钡或镁)氢氧化物和有机碱,例如烷基胺、芳烷基胺和杂环胺。合适的有机碱的例子包括但不限于:N-甲基-D-葡萄糖胺、胆碱三(羟甲基)氨基-甲烷、L-精氨酸、L-赖氨酸、N-乙基哌啶、二苄胺。关于合适的盐的综述,参见《药用盐手册:性质、选择及用途》(Handbook of Pharmaceutical Salts:Properties,Selection,and Use),Stahl和Wermuth编著(Wiley-VCH,Weinheim,德国,2002)。
本发明化合物的合适的盐包括作为药学上可接受的盐的例子的本文所述的那些。
本文中使用的术语“溶剂合物”描述了一种包含本发明的化合物和化学计量的一种或多种药学上可接受的溶剂分子(如乙醇)的分子复合物。当该溶剂是水时,则使用术语“水合物”。
为避免疑虑,本发明化合物可以以任何互变异构形式使用。
本发明的化合物包括手性中心。化合物通常是L-丙氨酸衍生物的形式(即,如实施例1所示)。然而,化合物也可以是D-丙氨酸衍生物或者D-和L-形式的混合物。如果存在混合物,优选地至少90%、95%或99%是L-丙氨酸衍生物的形式。
参照实施例部分,下面描述了用于制备本发明化合物的合适的方案和工艺。
起始材料通常是4-氯苯基3-(2,4-二氟苯基)-3-氧代硫赶亚氨逐丙酸酯(propanimidothioate)盐酸盐和2-(4-氨基-3,5-二氟苯基)乙醇。2-(4-氨基-3,5-二氟苯基)乙醇可以采用以下方案制备,类似于实施例部分的方案1:
二氟硝基苯市售可得。阶段1要求在苯环的硝基对位加上乙酸叔丁酯基团。阶段2要求酯基团水解形成相应的酸。阶段3中酸降解形成伯醇。阶段4中硝基还原成胺。
采用WO 2003076405所述实验方法制备4-氯苯基3-(2,4-二氟苯基)-3-氧代硫赶亚氨逐丙酸酯盐酸盐。
然后类似于实施例部分的方案2,采用以下方案合成化合物N-[2-{4-[6-氨基-5-(2,4-二氟苯甲酰)-2-氧代吡啶-1(2H)-基]-3,5-二氟苯基}乙基]-L-丙氨酸叔丁酯。
阶段1中,2-(4-氨基-3,5-二氟苯基)乙醇和4-氯苯基3-(2,4-二氟苯基)-3-氧代硫赶亚氨逐丙酸酯盐酸盐一起反应形成2-(4-{[3-(2,4-二氟苯基)-3-氧代亚氨逐丙酰氨基(propanimidoyl)]氨基}-3,5-二氟苯基)乙酸乙酯。阶段2中,加入丙炔酸形成2-{4-[6-氨基-5-(2,4-二氟苯甲酰基)-2-氧代吡啶-1(2H)-基]-3,5-二氟苯基}乙酸乙酯。阶段3中,乙酸酯基团水解形成醇,阶段4中,所得醇基团氧化形成醛。然后在阶段5,加入L-丙氨酸叔丁酯盐酸盐,形成本发明的化合物。L-丙氨酸叔丁酯盐酸盐市售可得。
本发明还提供了包含该化合物以及一种或多种药学上可接受的载体和/或赋形剂的药物组合物。所述药物组合物通常包含最高达85重量%的本发明化合物。更具体地,其包含最高达50重量%的本发明化合物。优选的药物组合物是无菌且无热原的。
本发明的化合物可以以各种剂型给予。因此,它们可以口服给予,例如作为片剂、含片、胶囊剂、锭剂、水性或油性混悬剂、可分散粉末剂或颗粒剂给予。本发明的化合物也可以胃肠外给予,皮下、静脉内、肌内、胸骨内、经皮或者通过输注技术给予。根据所用的载剂和浓度,可将药物悬浮或溶解于载剂中。优选地,可将辅助试剂(如局部麻醉剂、防腐剂和缓冲剂)溶解于载剂中。该化合物也可以以栓剂给予。该化合物可以以气溶胶的形式通过吸入器或喷雾器吸入给予。
本发明的化合物通常用药学上可接受的载体或稀释剂配制给予。例如,固体口服给药形式可以含有与活性化合物一起给药的增溶剂,例如环糊精或改性环糊精;稀释剂,例如乳糖、右旋糖、蔗糖、纤维素、玉米淀粉或马铃薯淀粉;润滑剂,例如二氧化硅、滑石、硬脂酸、硬脂酸镁或硬脂酸钙、和/或聚乙二醇;粘合剂,例如淀粉、阿拉伯树胶、黄蓍胶、明胶、糖浆、阿拉伯胶、山梨糖醇、甲基纤维素、羧甲基纤维素或聚乙烯吡咯烷酮;解聚剂,例如淀粉、藻酸、藻酸盐或羟乙酸淀粉钠;泡腾剂混合物;染料;甜味剂;润湿剂,例如卵磷脂、聚山梨醇酯、月桂基硫酸盐;以及通常用于药物配制的无毒性和药学上无活性的物质。这些药物制剂可以以已知方式制备,例如通过混合、制粒、压片、糖衣或薄膜包衣工艺进行制备。
用于口服给予的液体分散体可以是溶液、糖浆、乳剂和混悬剂。这类液体制剂可含有常规的添加剂,例如助悬剂(如山梨糖醇、糖浆、甲基纤维素、葡萄糖糖浆、明胶、氢化食用油)、乳化剂(如卵磷脂、去水山梨糖醇单油酸酯或阿拉伯胶)、非水性载剂(可包括食用油,如杏仁油、分馏椰子油,油酯(如甘油)、丙二醇或乙醇)、防腐剂(如对羟基苯甲酸甲酯或丙酯或者山梨酸),需要时还可含有常规的调味剂或着色剂。溶液剂可包含增溶剂,例如环糊精或改性环糊精。糖浆剂可含有例如蔗糖或蔗糖与甘油和/或甘露醇和/或山梨糖醇作为载体。
混悬剂和乳剂可以含有,例如作为载体的天然胶、琼脂、藻酸纳、果胶、甲基纤维素、羧甲基纤维素或者聚乙烯醇。用于肌内注射的混悬剂或者溶液剂可以含有与活性化合物一起给药的药学上可接受的载体,例如无菌水、橄榄油、油酸乙酯、二醇,如丙二醇;增溶剂,例如环糊精或改性环糊精,以及如果需要的话,合适量的盐酸利多卡因。
用于静脉内或输注的溶液剂可以含有,例如作为载体的无菌水和增溶剂,例如环糊精或改性环糊精,或者优选地它们可以是无菌、水性、等张盐水溶液的形式。
对于在皮肤上局部的施用而言,可将药物制成乳膏剂、洗剂或油膏剂。可用于该药物乳膏剂或油膏剂的制剂是本领域熟知的常规制剂,例如药剂学标准教科书如英国药典(British Pharmacopoeia)所述。
对通过吸入的局部应用而言,可将药物制成气雾剂递送(例如通过压力驱动喷射雾化器或超声雾化器),或优选通过推进剂驱动定量气雾剂或无推进剂情况下给予微粉化粉末(例如吸入胶囊或其他“干粉”递送系统)。这类吸入制剂中可含有赋形剂,例如推进剂(如定量气雾剂情况下的氟利根(Frigen))、表面活性物质、乳化剂、稳定剂、防腐剂、调味剂和填料(如粉末吸入器情况下的乳糖)。为了吸入,可用很多能生成和给予具有最佳颗粒尺寸的气雾剂的仪器,使用对患者合适的吸入技术。对定量气雾剂特别是粉末吸入器而言,除了使用衔接子(间隔子、扩展子)和梨形容器(如)和发射喷药器(puffer)喷雾的自动装置()外,还可使用多种技术方法(如或吸入器,例如欧洲专利申请EP 0 505 321所述)。
对眼睛的局部应用而言,可将药物制成合适的无菌水性或非水性载剂中的溶液或混悬剂。还可包括添加剂,例如缓冲剂(如焦亚硫酸钠或依地酸二钠(disodium edeate))、防腐剂(包括杀菌和杀真菌剂如(苯基汞乙酸盐或硝酸盐、苯扎氯铵或氯己定))和增稠剂(如羟丙甲纤维素)。
将治疗有效量的本发明化合物给予对象。应理解,针对任何特定对象的具体剂量水平取决于多种因素,包括所采用具体化合物的活性、年龄、体重、一般健康情况、性别、饮食、给药时间、给药途径、排泄速度、药物组合以及正在治疗的特定疾病的严重程度。最佳剂量水平和给药频率通常由临床实验确定。
常规日剂量最高至50毫克/千克体重,例如0.001-50毫克/千克体重,基于具体化合物的活性、待治疗对象的年龄、体重和状态,疾病的类型和严重程度以及给药频率和途径。优选地,日剂量水平为0.05毫克至2克,优选0.1毫克至10毫克。本发明化合物通常以无毒性的用量给予患者。
本发明还提供了本文限定的化合物或本文限定的组合物用于治疗人体或动物体的方法。
已发现本发明的化合物和组合物能够抑制p38 MAP激酶的活性。因此,本发明的化合物和组合为可用于预防和治疗p38 MAP激酶活性调节的疾病和病症。由p38 MAP激酶活性调节的疾病和病症包括细胞增殖疾病(如癌症和牛皮癣)、多谷氨酰胺疾病(如亨廷顿病)、神经退行性疾病(如阿尔茨海默病)、自身免疫疾病(如类风湿性关节炎)、糖尿病、血液疾病、炎性疾病、心血管疾病、动脉粥样硬化和感染的炎性后遗症。具体例子是细胞增殖性疾病、自身免疫疾病和炎性疾病。
自身免疫疾病通常有炎性成分。这类病症包括急性播散性普秃、ANCA阳性疾病、贝切特病、美洲锥虫病(Chagas’disease)、慢性疲劳综合征、家族性自主神经异常、脑脊髓炎、强直性脊柱炎、再生障碍性贫血、化脓性汗腺炎、自体免疫肝炎、自体免疫卵巢炎、乳糜泻、炎性肠病、克罗恩氏病、1型糖尿病、范可尼综合征、巨细胞性动脉炎、急性肾小球肾炎、肺出血肾炎综合征、格雷夫症、格-巴二氏综合征、桥本氏疾病、亨-舒综合征、川崎病、系统性红斑狼疮、显微结肠炎、显微镜下多动脉炎、混合性结缔组织病、多发性硬化、重症肌无力、阵挛肌阵挛综合征、视神经炎、奥德甲状腺炎(Ord’sthyroiditis)、天疱疮、结节性多动脉炎、多肌痛、类风湿性关节炎、莱特尔综合征、舍格伦综合征、颞动脉炎、韦格纳肉芽肿病、温暖自体免疫溶血性贫血、间质性膀胱炎、莱姆病、硬斑病、牛皮癣、结节病、硬皮病、溃疡性结肠炎和白癜风。
可用本发明化合物和组合物预防或治疗的其他炎性病症包括例如阑尾炎、皮炎、皮肌炎、心内膜炎、纤维组织炎、牙龈炎、舌炎、肝炎、化脓性汗腺炎、虹膜炎、喉炎、乳腺炎、心肌炎、肾炎、中耳炎、胰腺炎、腮腺炎、心外膜炎、腹膜炎(peritonoitis)、咽炎、胸膜炎、肺炎、前列腺炎、肾盂肾炎、和口腔炎、移植物排斥(涉及器官如肾、肝、心、肺、胰腺(如胰岛细胞)、骨髓、角膜、小肠、皮肤同种异体移植物(allograft)、皮肤自体移植物(homograft)和心脏瓣膜异种移植物(xengraft)、血清病以及移植物抗宿主病)、急性胰腺炎、慢性胰腺炎、急性呼吸窘迫综合征、赛塞里综合征(Sexary syndrome)、先天性肾上腺增生、非化脓性甲状腺炎、癌相关高钙血症、天疱疮、大泡疱疹样皮炎、重症多形红斑、剥脱性皮炎、脂溢性皮炎、季节性和常年性变应性鼻炎、支气管哮喘、接触性皮炎、特应性皮炎、药物超敏反应、变应性结膜炎、角膜炎、眼带状疱疹、虹膜炎和虹膜睫状体炎、脉络膜视网膜炎、视神经炎、症状性结节病(symptomatic sarcoidosis)、暴发性或播散性肺结核化疗、成人特发性血小板减少性紫癜、成年继发性血小板减少症、获得性(自体免疫)溶血性贫血、成人白血病和淋巴瘤、儿童急性白血病、局限性肠炎、自体免疫血管炎、多发性硬化、慢性阻塞性肺病、实体器官移植排斥、败血症、原发性胆汁性肝硬化和原发性硬化性胆管炎。
本发明的化合物和组合物可用于预防和治疗炎性和自身免疫疾病性疾病和病症。可以使用本发明化合物和组合物治疗的炎性和自身免疫性和病症包括类风湿性关节炎、牛皮癣关节炎、1型糖尿病、哮喘、炎性肠病、系统性红斑狼疮,和伴随感染病情的炎症(如败血症)、牛皮癣、克罗恩氏病、溃疡性结肠炎、慢性阻塞性肺病、多发性硬化、特应性皮炎和移植物抗宿主病。
本发明的化合物和组合物也可用于治疗细胞增殖性疾病,例如癌症。可以治疗的癌症的例子包括乳腺癌、卵巢癌、肺癌、胰腺癌、肝癌、结肠癌、肾癌、淋巴癌和黑色素瘤。例如,可以治疗的癌症包括乳腺癌、卵巢癌、胰腺癌、肺癌、结肠癌、肾癌、淋巴癌或黑色素瘤。
本发明还涉及一种酸,即:
N-[2-{4-[6-氨基-5-(2,4-二氟苯甲酰)-2-氧代吡啶-1(2H)-基]-3,5-二氟苯基}乙基]-L-丙氨酸。
该酸可以通过本发明化合物的水解进行制备。
如本文所述,本发明的化合物是巨噬细胞选择性的。因此,本发明化合物的酯基可以被包含人羧酸酯酶hCE-1的细胞水解而不被含有hCE-2或hCE-3的细胞水解。因此,该酸在包含hCE-1的细胞内由本发明化合物的酯基水解产生并且该酸在该细胞中选择性积聚。
在以下实施例中进一步阐述本发明。
实施例
根据以下实施例制备本发明的化合物。
缩写
CDI=羰二咪唑
DCM=二氯甲烷
DMF=二甲基甲酰胺
EtOAc=乙酸乙酯
HCl=盐酸
LCMS=高效液相色谱/质谱
MeOH=甲醇
MgSO4=硫酸镁
Na2CO3=碳酸钠
NaHCO3=碳酸氢钠
NMR=核磁共振
STAB=三乙酰氧基硼氢化钠
THF=四氢呋喃
g=克
mg=毫克
mL=毫升
mmol=毫摩尔
市售可得的试剂和溶剂(HPLC级)不需进一步纯化即可使用。使用Buchi旋转蒸发仪除去溶剂。使用Biotage InitiatorTM 8微波合成仪进行微波辐射。使用获自Fluorochem的硅凝胶、粒度40–63μm(230-400目)通过快速色谱柱进行化合物纯化。
在氘代溶剂中于Bruker 300MHz AV光谱仪上记录1H NMR光谱。化学位移(d)以百万分之计。用Kieselgel 60F254(默克公司(Merck))板进行薄层色谱(TLC)分析并用UV光观察。
在Agilent HP1100 LC系统上进行分析型HPLC/MS,使用反相Luna C18柱(3mm,50x 4.6mm),2.25分钟内梯度5-95%B(A=水+0.1%甲酸,B=乙腈+0.1%甲酸),流速=2.25mL/分钟。使用G1315B DAD检测器在220和254nm记录UV光谱。在LC/MSD SL G1956B检测器上于范围m/z 150–800内获得质谱。使用ChemStation和ChemStation数据浏览器(Data Browser)软件对数据进行积分运算和报告。
中间体
中间体1:4-氯苯基3-(2,4-二氟苯基)-3-氧代硫赶亚氨逐丙酸酯盐酸盐
中间体1可以采用WO 2003076405所述实验方案进行制备。
中间体2:2-(4-氨基-3,5-二氟苯基)乙醇
中间体2采用下述方案1所示途径合成。
方案1
阶段1-(3,5-二氟-4-硝基苯基)乙酸叔丁酯
氮气下,1小时内在二氟硝基苯(24.96g,157mmol)和氯乙酸叔丁酯(38.0mL,267mmol)的无水DMF(200mL)溶液中逐滴加入冷的(-35℃)叔丁醇钾(61.61g,549mmol)在无水DMF(200mL)中的悬浮液。反应混合液在-35℃搅拌1.5小时,用2N HCl(240mL)淬灭并用庚烷萃取(4x200mL)。合并的有机萃取物用水(3x200mL)、盐水(200mL)洗涤,干燥(MgSO4),过滤并减压浓缩,形成黄色油状物。柱色谱纯化(含10%EtOAc的庚烷)得到黄色油状物(37.64g)。另外两个批次(10.00g和23.54g的二氟硝基苯)分别得到14.30g和31.39g产物。所有三个批次的1H NMR显示所需化合物和少量未鉴定的杂质的混合物。将3个批次合并,无需进一步纯化即可用于下一阶段。
1H NMR(300MHz,CDCl3)7.05(2H,d,J=8.5Hz),3.56(2H,s),1.46(9H,s)。
阶段2-(3,5-二氟-4-硝基苯基)乙酸
20分钟内将三氟乙酸(150mL)逐滴加入冷的(0℃)(3,5-二氟-4-硝基苯基)乙酸叔丁酯(83.33g,305mmol)的DCM(300mL)溶液中。加入完成后,使得反应混合物升高至室温并搅拌3小时。减压浓缩反应混合物,得到粘性棕色固体。用庚烷研磨后得到黄色固体状的标题化合物(53.29g,两个步骤的产率为67%)。
1H NMR(300MHz,CDCl3)7.08(2H,d,J=8.5Hz),3.74(2H,s),-CO2 H未见。
阶段3-2-(3,5-二氟-4-硝基苯基)乙醇
氮气下,将硼烷-二甲基硫醚复合物(35mL,368mmol)逐滴加入冷的(0℃)(3,5-二氟-4-硝基苯基)乙酸(53.29g,245mmol)的无水THF(500mL)溶液中。加入完成之后,反应混合物升高至室温,搅拌16小时,冷却至0℃,用MeOH(300mL)小心淬灭,减压浓缩后得到棕色油状物。干快速色谱法纯化(含60-80%EtOAc的庚烷)得到橙色油状的标题化合物(38.90g,产率78%)。
1H NMR(300MHz,CDCl3)7.01(2H,d,J=8.7Hz),3.93(2H,t,J=6.2Hz),2.92(2H,t,J=6.2Hz),2.34(1H,br s).
阶段4-2-(4-氨基-3,5-二氟苯基)乙醇
2-(3,5-二氟-4-硝基苯基)乙醇(38.90g,191mmol)溶解在EtOAc(250mL)中。反应容器抽真空并用氮气充满三次。加入钯碳(10重量%,4.00g),容器抽真空并用氮气充满三次。最后,容器抽真空并用氢气充满,配上含氢气的气球。然后,氢气下室温搅拌15小时,再次充满氢气球,混合物再搅拌25小时。反应混合物过滤通过减压浓缩滤液,得到棕色油状物。干快速色谱法纯化(含50%EtOAc的庚烷)得到驼色固体状的标题化合物(20.70g,产率62%)。
1H NMR(300MHz,CDCl3)6.73-6.70(2H,m),3.81(2H,t,J=6.4Hz),2.75(2H,t,J=6.4Hz),-OH和-NH 2未见。
实施例1:N-(2-{4-[6-氨基-5-(2,4-二氟苯甲酰)-2-氧代吡啶-1(2H)-基]-3,5-二氟苯基}乙基)-L-丙氨酸叔丁酯
采用以下方案2所示途径合成实施例1。
方案2
阶段1-2-(4-{[3-(2,4-二氟苯基)-3-氧代亚氨逐丙酰氨基]氨基}-3,5-二氟苯基)乙酸乙酯
2-(4-氨基-3,5-二氟苯基)乙醇(20.71g,120mmol)加入4-氯苯基3-(2,4-二氟苯基)-3-氧代硫赶亚氨逐丙酸酯盐酸盐(41.26g,114mmol)的冰醋酸(400mL)溶液中。反应混合物在80℃搅拌2.5小时,加入乙酸酐(21mL,228mmol)。在80℃再搅拌45分钟后,反应混合物冷却至室温,减压浓缩后得到棕色油状物。用EtOAc研磨得到驼色固体,用乙醚洗涤。固体用NaHCO3的饱和水溶液吸收,剧烈搅拌30分钟。过滤收集固体,用水洗涤,减压干燥,得到驼色固体状的标题化合物(23.36g,产率52%)。
LCMS:m/z 397[M+H]+。
阶段2-2-{4-[6-氨基-5-(2,4-二氟苯甲酰)-2-氧代吡啶-1(2H)-基]-3,5-二氟苯基}乙酸乙酯
氮气下,5分钟内将丙炔酸(5.4mL,88mmol)逐滴加入冷的(0℃)CDI(14.27g,88mmol)的无水THF(400mL)溶液中。加入完成之后,反应混合物升高至室温,搅拌1小时。加入2-(4-{[3-(2,4-二氟苯基)-3-氧代亚氨逐丙酰氨基]氨基}-3,5-二氟-苯基)乙酸乙酯(23.26g,59mmol)的无水THF(200mL)的溶液,反应混合物回流搅拌6.5小时。反应混合物冷却至室温,静置16.5小时。丙炔酸(5.4mL,88mL),CDI(14.27g,88mmol)和THF(200mL)如上文所示进行处理并加入到反应混合物中,接着再回流搅拌6小时。然后反应混合物冷却至室温,减压浓缩后得到棕色油状物。干快速色谱法纯化(含5%MeOH的DCM)得到暗褐色固体,用EtOAc研磨进一步纯化后得到黄色固体状的标题化合物(7.45g,产率28%)。
LCMS:m/z 449[M+H]+和471[M+Na]+。
阶段3-6-氨基-5-(2,4-二氟苯甲酰)-1-[2,6-二氟-4-(2-羟乙基)苯基]吡啶-2(1H)-酮
将2-{4-[6-氨基-5-(2,4-二氟苯甲酰)-2-氧代吡啶-1(2H)-基]-3,5-二氟苯基}乙酸乙酯(7.45g,17mmol)悬浮在6N HCl(80mL)中,反应化合物回流21.5小时。过滤收集固体,用NaHCO3饱和水溶液(200mL)吸收,剧烈搅拌30分钟。过滤收集固体,用水洗涤,真空炉中干燥(40℃),得到驼色固体状的标题化合物。
LCMS:m/z 407[M+H]+和429[M+Na]+。
1H NMR(300MHz,DMSO-d6)7.57(1H,td,J=6.6,8.3Hz),7.41(1H,td,J=2.4,9.7Hz),7.37-7.29(3H,m),7.23(1H,td,J=2.3,8.5Hz),5.74(1H,d,J=9.8Hz),4.78(1H,t,J=5.1Hz),3.76-3.70(2H,m),2.86(2H,t,J=6.7Hz),-NH 2未见
阶段4-{4-[6-氨基-5-(2,4-二氟苯甲酰)-2-氧代吡啶-1(2H)-基]-3,5-二氟苯基}-乙醛
戴斯-马丁氧化剂(1.03g,2.4mmol)加入6-氨基-5-(2,4-二氟苯甲酰)-1-[2,6-二氟-4-(2-羟乙基)苯基]吡啶-2(1H)-酮(823mg,2.0mmol)的DCM(20mL)悬浮液中。反应混合物室温搅拌2小时,用NaHCO3饱和水溶液(10mL)和硫代硫酸钠的饱和水溶液(10mL)淬灭,剧烈搅拌30分钟。分离水层,用DCM(2x20mL)进一步萃取。合并的有机萃取物经干燥(MgSO4),过滤,减压浓缩后得到淡棕色固体状的标题化合物(819mg)。该产物无需进一步纯化即可用于下一阶段。
阶段5-N-(2-{4-[6-氨基-5-(2,4-二氟苯甲酰)-2-氧代吡啶-1(2H)-基]-3,5-二氟苯基}乙基)-L-丙氨酸叔丁酯
L-丙氨酸叔丁酯盐酸盐(552mg,3.0mmol)和STAB(1.29g,6.1mmol)加入{4-[6-氨基-5-(2,4-二氟苯甲酰)-2-氧代吡啶-1(2H)-基]-3,5-二氟苯基}-乙醛(819mg,2.0mmol)的溶液中。反应混合物室温搅拌3.5小时,用Na2CO3的饱和水溶液(20mL)淬灭,剧烈搅拌20分钟。分离水层,用EtOAc(2x20mL)进一步萃取。合并的有机萃取物用盐水(20mL)洗涤,干燥(MgSO4),过滤,减压浓缩后得到黄色油状物。柱色谱纯化(含5%MeOH的DCM)得到淡黄色固体状的标题化合物(492mg,两个步骤的产率为78%)。
LCMS:纯度98%,m/z 534[M+H]+。
1H NMR(300MHz,DMSO-d6)7.58(1H,td,J=6.8,8.3Hz),7.41(1H,td,J=2.3,9.8Hz),7.37-7.30(3H,m),7.23(1H,td,J=2.3,8.5Hz),5.74(1H,d,J=9.8Hz),3.20(1H,d,J=7.0Hz),2.89-2.70(4H,m),1.42(9H,s),1.16(3H,d,J=7.0Hz),-NH 2和-NH-未见
生物活性的测定
p38 MAP激酶活性
在由英国邓迪的奥普斯特(Upstate)进行的试验中测量化合物抑制p38MAP激酶活性的能力。在25μL的最终反应体积中,p38 MAP激酶a(5-10mU)与25mM Tris pH 7.5,0.002mMEGTA,0.33mg/mL髓磷脂碱蛋白,10mM乙酸镁和[g-33p-ATP](比活度约500cpm/pmol,浓度按照需要)进行孵育。加入MgATP混合物启动反应。室温孵育40分钟之后,加入5μL 3%的磷酸溶液终止反应。然后10μL的反应液点样到P30Filtermat上,在75mM磷酸中洗涤三次持续5分钟,一旦在甲醇中之后,进行干燥和闪烁计数。
从DMSO的储液的1/3log稀释系列生成重复数据点。用10μM的顶端浓度开始9个稀释步骤,并且包括“无化合物”的空白。在ATP浓度为或者接近Km时进行标准放射度滤膜结合试验。收集闪烁计数得到的数据并由Prism软件进行自由拟合分析。通过产生的曲线,确定并报告实现50%抑制的浓度。
THP-1细胞的LPS刺激
将100μl THP-1细胞以4x 104细胞/孔的密度接种在V形底的96孔组织培养处理板中,37℃5%CO2中孵育16小时。在100μl组织培养基中加入抑制剂之后2小时,用终浓度1μg/ml的LPS(大肠杆菌菌株005:B5,西格玛公司(Sigma))刺激细胞,在37℃5%CO2中孵育6小时。通过夹心ELISA(安迪生物公司#QTA00B)从无细胞上清液中测量TNF-α水平。
人全血的LPS刺激
采用含肝素的真空采集管(BD公司(Becton Dickinson))通过静脉穿刺获取全血,在等体积的RPMI1640组织培养基(西格玛公司)中稀释。100μl接种到V形底的96孔组织培养处理板中。在100μl RPMI1640培养基中加入抑制剂之后2小时,用终浓度100ng/ml的LPS(大肠杆菌菌株005:B5,西格玛公司(Sigma))刺激全血,在37℃5%CO2中孵育6小时。通过夹心ELISA(安迪生物公司#QTA00B)从无细胞上清液中测量TNF-α水平。
小鼠中血浆暴露
根据以下方法在水中以8%DMSO,92%11.25%羟丙基-β-环糊精配制化合物:化合物完全溶解在100%DMSO中,然后加入羟丙基-β-环糊精溶液。加入HCl水溶液重新溶解形成的细沉淀物,用氢氧化钠水溶液将pH调节至4。
以10mg/kg口服给予雄性CD1小鼠(25-20g)每种化合物,总剂量体积5ml/kg。每个时间点采用三只小鼠。在氟烷/异氟烷麻醉条件下,通过末端心脏穿刺,在以下时间点获取血样:5,15,30,60,120,240和360分钟。血样收集到含NaF/EDTA的预冷却的试管中并混合。样品以7-7.5x g旋转2分钟。吸出血浆并冷冻。
采用三体积的含内标的乙腈,通过蛋白质沉淀制备血浆样品。通过LCMS(Sciex API 3000,HP1100二元泵,CTC PAL)分析上清液。色谱基于Acentis C8(50x 2.1mm)柱和含5-95%乙腈的水/0.1%甲酸的流动相。
采用PK Solutions 2.0(美国科罗拉多州名特的顶峰研究服务公司(SummitResearch Services,Montrose,Colorado)),由血浆浓度与时间分布计算暴露(AUC)。
表1–本发明化合物和结构相关化合物的生物活性
A-D提供了以下数据:
A–酯酶测试(p38激酶A(英杰公司(invitrogen)),IC50(nM);
B–酸酶测试(p38激酶A(英杰公司(invitrogen)),IC50(nM);
C–酯TNF-α抑制(THP-1细胞),IC50(nM);和
D–酯TNF-α抑制(人全血),IC50(nM)。
表2–小鼠中的血浆暴露
结论
表1显示,本发明化合物是p38 MAP激酶非常好的抑制剂。而且,在THP-1细胞和人血中酯TNF-α抑制的IC50值非常低。具体说,考虑到相关化合物观察到的人血中酯TNF-α抑制的IC50值,人血中酯TNF-α抑制的IC50值明显低于期望。
表2显示的AUC数据表明,本发明化合物的生物利用度比结构类似的已知化合物要高得多。
Claims (9)
1.一种化合物:
N-[2-{4-[6-氨基-5-(2,4-二氟苯甲酰)-2-氧代吡啶-1(2H)-基]-3,5-二氟苯基}乙基)-L-丙氨酸叔丁酯,或其药学上可接受的盐。
2.一种药物组合物,其包含如权利要求1所述的化合物以及一种或多种药学上可接受的载体和/或赋形剂。
3.如权利要求1所述的化合物或如权利要求2所述的组合物在制备用于抑制p38MAP激酶活性的药物中的应用。
4.如权利要求1所述的化合物或如权利要求2所述的组合物在制备用于治疗或预防自身免疫性或炎性疾病的药物中的应用。
5.如权利要求4所述的应用,其特征在于,所述疾病是类风湿性关节炎、牛皮癣关节炎、1型糖尿病、哮喘、炎性肠病、系统性红斑狼疮,伴随感染病情的炎症、牛皮癣、慢性阻塞性肺病、多发性硬化、特应性皮炎或移植物抗宿主病。
6.如权利要求5所述的应用,其特征在于,所述疾病是克罗恩氏病或溃疡性结肠炎。
7.如权利要求1所述的化合物或如权利要求2所述的组合物在制备用于治疗细胞增殖性疾病的药物中的应用。
8.如权利要求7所述的应用,其特征在于,所述疾病是癌症。
9.如权利要求7或8所述的应用,其特征在于,所述疾病是乳腺癌、卵巢癌、胰腺癌、肺癌、结肠癌、肾癌、淋巴癌或黑色素瘤。
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