CN106459054A - 新的化合物 - Google Patents
新的化合物 Download PDFInfo
- Publication number
- CN106459054A CN106459054A CN201480079755.3A CN201480079755A CN106459054A CN 106459054 A CN106459054 A CN 106459054A CN 201480079755 A CN201480079755 A CN 201480079755A CN 106459054 A CN106459054 A CN 106459054A
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- China
- Prior art keywords
- phenyl
- compound
- methyl
- ethyl
- disease
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims description 149
- 238000002560 therapeutic procedure Methods 0.000 claims abstract 3
- -1 3- trifluoromethyl-phenyl Chemical group 0.000 claims description 46
- 238000000034 method Methods 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 30
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 29
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 27
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- 238000002360 preparation method Methods 0.000 claims description 11
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- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
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Classifications
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/0012—Galenical forms characterised by the site of application
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- A—HUMAN NECESSITIES
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Abstract
本发明涉及作为具有人嗜中性粒细胞弹性蛋白酶抑制特性的嘧啶酮衍生物的杂环化合物及其在治疗中的用途。
Description
技术领域
本发明涉及作为具有人嗜中性粒细胞弹性蛋白酶(human neutrophil elastase)抑制特性的嘧啶酮衍生物的杂环化合物及其在治疗中的用途。
背景技术
人嗜中性粒细胞弹性蛋白酶(HNE)是在嗜中性粒细胞的嗜苯胺蓝颗粒中发现的32kDa丝氨酸蛋白水解酶。它在多种胞外基质蛋白的降解中起作用,所述胞外基质蛋白包括纤连蛋白、层粘连蛋白、蛋白聚糖类、III型和IV型胶原以及弹性蛋白(Bieth,G.见Regulation of Matrix accumulation,Mecham,R.P.(Eds),Academic Press,NY,USA1986,217-306)。长期以来认为,HNE在体内稳态中起重要作用,这通过降解组织结构蛋白、从而修复和处理受损的组织来实现。通过降解细菌体,它也在对抗细菌侵染的防御中起作用。除了它对基质组织的作用以外,HNE已经牵涉IL-8基因表达的上调,并还诱导肺上皮细胞释放IL-8。在烟草烟雾暴露诱导的慢性阻塞性肺疾病的动物模型中,HNE的小分子抑制剂和蛋白抑制剂会抑制炎症应答和气肿(emphysema)的发展(Wright,J.L.等人Am.J.Respir.Crit.Care Med.2002,166,954-960;Churg,A.等人Am.J.Respir.Crit.CareMed.2003,168,199-207)。因而,HNE可能在基质破坏中和在放大慢性呼吸性疾病的炎症应答(其中嗜中性粒细胞流入是特有的特征)中起作用。实际上,认为HNE在严重肺病中起作用,所述严重肺病包括慢性阻塞性肺疾病(COPD)、囊性纤维化病(CF)、急性呼吸窘迫综合征(ARDS)、肺气肿(pulmonary emphysema)、肺炎和肺纤维化。它也牵涉几种其中涉及组织重塑的心血管疾病,例如,心力衰竭和急性心肌梗塞之后缺血性组织损伤的产生。
COPD是一个综合的(umbrella)术语,包括3种不同的病理状态,它们都促成气流的限制:慢性支气管炎、气肿和小气道疾病。通常,所有3种都会以不同程度存在于呈现出COPD的患者中,所有3种都可能归因于嗜中性粒细胞-介导的炎症,这得到在COPD患者的支气管肺泡渗漏(BAL)液中观察到的嗜中性粒细胞数目增加的支持(Thompson,A.B.;Daughton,D.;等人Am.Rev.Respir.Dis.1989,140,1527-1537)。长期以来认为,COPD的主要病原性决定因素是蛋白酶-抗-蛋白酶平衡(也称作“弹性蛋白酶:抗-弹性蛋白酶假说”),其中HNE和内源性抗蛋白酶(诸如α1-抗胰蛋白酶(α1-AT)、分泌性白细胞蛋白酶抑制剂(SLPI)和前-弹力素)的失衡导致COPD的各种炎性障碍。具有蛋白酶抑制剂α1-抗胰蛋白酶的遗传缺陷的个体发展成肺气肿,其严重性随着时间增加(Laurrell,C.B.;Erikkson,SScand.J.Clin.Invest.1963 15,132-140)。因此,过量的HNE是破坏性的,导致肺形态学的破坏,肺中气道的肺泡附着(attachment)的弹性丧失和破坏(肺气肿),同时增加微血管渗透性和粘液分泌过多(慢性支气管炎)。
到目前为止,本领域已经需要公开几种人嗜中性粒细胞抑制剂。具体地,国际专利申请号WO2011/110858和WO2011/110859描述了一些具有人嗜中性粒细胞弹性蛋白酶抑制特性的嘧啶衍生物及其在治疗中的用途。
尽管如上面所记载到目前为止已经公开了几种HNE抑制剂,仍然需要其它HNE抑制剂。具体地,仍然需要对HNE酶抑制而言具有高效能的其它HNE抑制剂。还特别有利的是,鉴别对HNE酶抑制而言具有高效能的其它HNE抑制剂,且其会表现出作为吸入治疗的适当可开发性(developability)特性。
本发明通过提供本发明的化合物解决了上述需要。
在共同未决的申请PCT/EP2013/076672中描述了其它HNE抑制剂。
发明内容
本发明提供了新的化合物,其是HNE的抑制剂,并且可用于治疗HNE活性在其中发挥作用的疾病或病症。
发明详述
本发明涉及为HNE抑制剂的化合物,所述化合物落入No.PCT/EP2013/076672的式(I)的范围内,但是没有在其中明确地公开。
根据本发明,提供了一种化合物,其选自:
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3a]嘧啶-5-基]-苯基}-乙基)-4-甲氧基-吡啶溴化物;
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-5-基]-苯基}-乙基)-3-羟基-吡啶溴化物;
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-5-基]-苯基}-乙基)-2-甲基-吡啶溴化物;
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-5-基]-苯基}-乙基)-4-羟基甲基-吡啶溴化物;
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-5-基]-苯基}-乙基)-4-异丙基-吡啶溴化物;
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-5-基]-苯基}-乙基)-5-羟基-2-甲基-吡啶溴化物;
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-5-基]-苯基}-乙基)-2,4-二甲基-吡啶溴化物;
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-5-基]-苯基}-乙基)-3,5-二甲基-吡啶溴化物;
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-5-基]-苯基}-乙基)-2-乙基-吡啶溴化物;
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-5-基]-苯基}-乙基)-2-(2-羟基-乙基)-吡啶溴化物;
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-5-基]-苯基}-乙基)-4-乙基-吡啶溴化物。
具体地,本发明提供了一种化合物或其药学上可接受的盐,所述化合物选自下表中列出的那些:
可以以其盐(特别是药学上可接受的盐)、N-氧化物、水合物、溶剂化物和多晶型物的形式制备本发明的化合物。对本文中化合物的任何提及或对“本发明的化合物”的提及等,包括这样的化合物(盐或非盐形式)、N-氧化物、水合物、溶剂化物或多晶型形式。
本发明的化合物可以用于治疗或预防涉及HNE的疾病,例如慢性阻塞性肺疾病(COPD)、支气管扩张、慢性支气管炎、肺纤维化、肺炎、急性呼吸窘迫综合征(ARDS)、肺气肿、吸烟诱发的气肿(smoking-induced emphysema)和囊性纤维化。
因此,本发明的其它方面为:(i)包含本发明的化合物和药学上可接受的载体或赋形剂的药物组合物;和(ii)本发明的化合物用于制备药物的用途,所述药物用于治疗或预防涉及HNE的疾病或病症。
术语“盐”包括碱加成盐和酸加成盐。
术语“药学上可接受的盐”表示本发明的化合物的衍生物,其中如下适当地修饰母体化合物:用常规地认为药学上可接受的任意碱或酸,将可能存在的任意游离酸性或碱性基团转化成对应的加成盐。
本发明的酸性化合物可以与以下物质形成盐(包括药学上可接受的盐):碱,例如碱金属氢氧化物,例如氢氧化钠和氢氧化钾;碱土金属氢氧化物,例如氢氧化钙、氢氧化钡和氢氧化镁;有机碱,例如N-甲基-D-葡糖胺(glucamine)、胆碱三(羟基甲基)氨基-甲烷、L-精氨酸、L-赖氨酸、N-乙基哌啶、二苄胺等。那些为碱性的化合物可以与以下物质形成盐(包括药学上可接受的盐):无机酸,例如氢卤酸如盐酸或氢溴酸、硫酸、硝酸或磷酸等;有机酸例如乙酸、酒石酸、琥珀酸、富马酸、马来酸、苹果酸、水杨酸、柠檬酸、甲磺酸、对甲苯磺酸、苯甲酸、苯磺酸、谷氨酸、乳酸和扁桃酸等。那些具有季氮的化合物也可以与药学上可接受的抗衡离子形成季铵盐,所述抗衡离子例如氯离子、溴离子、乙酸根、甲酸根、对甲苯磺酸根、琥珀酸根、半琥珀酸根、萘-二磺酸根、甲磺酸根、昔萘酸根(xinafoate)等。
在本发明的化合物具有至少一个立体中心的情况下,它们可以作为对映异构体存在。当根据本发明的化合物具有2个或更多个立体中心时,它们可以额外作为非对映异构体存在。应当理解,所有这样的异构体及其任意比例的混合物都被包括在本发明范围内。
显而易见,由通式(I)表示的本发明的化合物至少含有一个立体中心,即由碳原子(1)表示,且因此作为光学立体异构体存在:
在一个实施方案中,本发明涉及式(I)’的化合物,其为如上定义的式(I)化合物,其中碳(1)的绝对构型是下文显示的绝对构型:
在另一个实施方案中,本发明涉及式(I)”的化合物,其为如上定义的式(I)化合物,其中碳(1)的绝对构型是下文显示的绝对构型:
基于以基团的优先性为基础的Cahn-Ingold-Prelog命名法,分配碳(1)的绝对构型。
具体实施方案
本发明的化合物是式(I)的化合物和更具体地式(I)”的化合物或其药学上可接受的盐
其中基团R选自
-4-甲氧基-吡啶基;
-3-羟基-吡啶基;
-2-甲基-吡啶基;
-4-羟基甲基-吡啶基;
-4-异丙基-吡啶基;
-5-羟基-2-甲基-吡啶基;
-2,4-二甲基-吡啶基;
-3,5-二甲基-吡啶基;
-2-乙基-吡啶基;
-2-(2-羟基-乙基)-吡啶基;和
-4-乙基-吡啶基。
实用性(utility)
本发明化合物的治疗效用涉及已知至少部分地由人嗜中性粒细胞弹性蛋白酶的作用介导的任何疾病。例如,本发明化合物对于慢性阻塞性肺疾病(COPD)、囊性纤维化(CF)、支气管扩张、急性呼吸窘迫综合征(ARDS)、肺气肿、肺炎和肺纤维化的治疗可能是有益的。
本发明的化合物可用于治疗炎症性的呼吸障碍,例如哮喘(轻度、中度或重度)、类固醇抵抗型哮喘、支气管炎、慢性阻塞性肺疾病(COPD)、囊性纤维化(CF)、肺水肿、肺栓塞、肺炎、肺结节病、肺气肿、硅沉着病、肺纤维化、肺性高血压、呼吸衰竭、急性呼吸窘迫综合征(ARDS)、气肿、慢性支气管炎、结核病、曲霉菌病和其它真菌感染、过敏性肺炎、肺脉管系统的血管炎性和血栓性障碍、镇咳活性(包括治疗与气道的炎症性和分泌性病症有关的慢性咳嗽)、由呼吸道合胞体病毒、流感、冠状病毒(包括严重急性呼吸综合征、SARS)和腺病毒引起的感染、支气管扩张和肺癌。
本发明还涉及包含本发明化合物作为活性成分的药物制剂。其它化合物可以与本发明化合物结合用于预防和治疗肺的炎性疾病。因此,本发明还涉及用于预防和治疗肺的炎性疾病的药物组合物,所述药物组合物包含治疗有效量的本发明的化合物和一种或多种其它治疗剂。
组合
适合用于与本发明化合物联合治疗的治疗剂包括:(1)皮质类固醇,例如布地奈德、倍氯米松、倍氯米松(例如,作为单丙酸酯或二丙酸酯)、氟尼缩松、氟替卡松(例如作为丙酸酯或糠酸酯)、环索奈德、莫米松(例如作为糠酸酯)、莫米松地奈德、罗氟奈德、氢化可的松、泼尼松、泼尼松龙、甲泼尼龙、萘非可特、地夫可特、乙酸卤泼尼松、氟轻松、醋酸氟轻松、氯可托龙、替泼尼旦、泼尼卡酯、二丙酸阿氯米松、卤米松、利美索龙、丙酸地泼罗酮、曲安西龙、倍他米松、氟氢可的松、去氧皮质酮、罗氟奈德、艾泼诺酯等。类固醇药物可以另外包括处于临床或临床前开发中的用于呼吸性疾病的类固醇,诸如GW-685698、GW-799943、GSK 870086、QAE397、NCX-1010、NCX-1020、NO-地塞米松、PL-2146、NS-126(以前的ST-126)。类固醇药物还可以另外包括处于开发中的具有减少的副作用特性的下一代分子,诸如选择性的糖皮质激素受体激动剂(SEGRA),包括ZK-216348和AZD5423;(2)β2-肾上腺素能受体激动剂,诸如沙丁胺醇、班布特罗、特布他林、非诺特罗、福莫特罗、富马酸福莫特罗、沙美特罗、昔萘酸沙美特罗、阿福特罗、酒石酸阿福特罗、茚达特罗(QAB-149)、卡莫特罗、BI 1744CL、GSK159797(米维特罗)、GSK59790、GSK159802、GSK642444(维兰特罗)、GSK678007、GSK96108、克仑特罗、丙卡特罗、比托特罗、LAS100977(abediterol)、BI1744CL(奥达特罗)和brodxaterol;(3)白三烯调节剂,例如孟鲁司特、扎鲁司特或普仑司特;(4)抗胆碱能剂,例如选择性的毒蕈碱-3(M3)受体拮抗剂诸如异丙托溴铵、噻托铵(tiotropium)、噻托溴铵格隆溴铵、阿地溴铵、LAS34273、GSK656398、GSK233705、GSK 573719(芜地溴铵(umeclidinium))、LAS35201、QAT370和氧托溴铵(oxytropium bromide);(5)磷酸二酯酶-IV(PDE-IV)抑制剂,例如罗氟司特、西洛司特或茶碱;(6)镇咳剂,诸如可待因或右美沙芬;和(7)非甾体类抗炎剂(NSAID),例如布洛芬或酮洛芬;(8)粘液溶解剂,例如N乙酰基半胱氨酸或福多司坦;(9)祛痰药/粘液动力学(mucokinetic)调节剂,例如氨溴索、高渗溶液(例如盐水或甘露醇)或表面活性剂;(10)肽粘液溶解剂,例如重组人脱氧核糖核酶I(阿法链道酶和rhDNA酶)或螺杀菌素;(11)抗生素,例如阿奇霉素、妥布霉素和氨曲南;和(12)p38促分裂原活化蛋白(MAP)激酶抑制剂,诸如GSK 856553和GSK 681323;(12)Janus激酶(JAK)的抑制剂诸如CP-690550或GLPG0634;(13)脾酪氨酸激酶(SYK)抑制剂诸如R406、R343或PRT062607;(14)磷脂酰肌醇3-激酶(PI3K)的δ和/或γ异形体的抑制剂;(15)抗逆转录病毒剂诸如利巴韦林、扎那米韦或拉尼米韦;(16)PPAR-γ激动剂诸如吡格列酮和罗格列酮。
在一个方面,本发明提供了本发明的化合物与其它抗炎药和支气管扩张药组合相组合(即三元组合产品)的吸入给药应用,所述其它抗炎药和支气管扩张药组合包括、但不限于昔萘酸沙美特罗/丙酸氟替卡松维兰特罗/糠酸氟替卡松(BREO ELLIPTATM)、富马酸福莫特罗/布地奈德富马酸福莫特罗/糠酸莫米松、富马酸福莫特罗/二丙酸倍氯米松富马酸福莫特罗/丙酸氟替卡松茚达特罗/糠酸莫米松、茚达特罗/QAE-397、GSK159797/GSK 685698、GSK159802/GSK 685698、GSK642444/GSK 685698、富马酸福莫特罗/环索奈德、酒石酸阿福特罗/环索奈德。
在另一个方面,本发明提供了本发明的化合物与以下组合相组合(即三元组合产品)的吸入给药应用:其它支气管扩张药物组合,尤其是β2激动剂/M3拮抗剂组合,包括、但不限于昔萘酸沙美特罗/噻托溴铵、富马酸福莫特罗/噻托溴铵、富马酸福莫特罗/格隆溴铵(PT003)、BI 1744CL/噻托溴铵、茚达特罗/NVA237、茚达特罗/QAT-370、福莫特罗/LAS34273、芜地溴铵(umeclidinium)/维兰特罗(AnoroTM)、GSK159797/GSK 573719、GSK159802/GSK 573719、GSK642444/GSK 573719、GSK159797/GSK 233705、GSK159802/GSK233705、GSK642444/GSK 233705。
第一种和第二种活性成分的重量比可以变化,并且取决于每种成分的有效剂量。通常,将使用每一种的有效剂量。
本发明化合物的预防剂量或治疗剂量的量级当然将随待治疗病症的严重程度的性质和具体化合物及其给药途径而变化,并且通常将通过药学领域所需的临床试验进行确定。它还将根据单个患者的年龄、重量和应答而变化。一般而言,每日剂量范围将在以下范围内:约0.001mg至约100mg/千克哺乳动物体重,优选0.01mg至约50mg/千克,最优选0.1-10mg/千克,其为单次剂量或分次剂量。另一方面,在某些情况下,可能需要使用这些限度之外的剂量。
组合物
本发明的另一个方面提供了包含本发明的化合物和药学上可接受的载体的药物组合物。在药物组合物中的术语“组合物”意图包括包含活性成分和构成载体的惰性成分(药学上可接受的赋形剂)的产品,以及由任何两种或更多种成分组合、络合或聚集而直接或间接形成的任何产品,或者由一种或更多种成分分解而直接或间接形成的任何产品,或者由一种或更多种成分的其它类型反应或相互作用成分直接或间接形成的任何产品。因此,本发明的药物组合物包括通过混合本发明的化合物、其它活性成分和药学上可接受的赋形剂而制得的任意组合物。
本发明的药物组合物包含本发明的化合物作为活性成分或其药学上可接受的盐,并且还可以含有药学上可接受的载体和任选的其它治疗成分。术语“药学上可接受的盐”表示从药学上可接受的无毒碱或酸(包括无机碱或酸以及有机碱或酸)制备的盐。
任何合适的给药途径可用于给哺乳动物、尤其是人提供有效剂量的本发明的化合物。在治疗用途中,可以通过任何方便的、合适的或有效的途径施用所述活性化合物。合适的给药途径是已知的,且包括口服给药、静脉内给药、直肠给药、胃肠外给药、局部给药、眼给药、鼻给药、含服和肺部给药(通过吸入)。
适合通过吸入法给药的组合物是已知的,并且可包括已知用于这类组合物中的载体和/或稀释剂。所述组合物可以含有0.01-99重量%的活性化合物。优选地,单位剂量包含1μg至10mg量的活性化合物。
通过任何已知的合适方法,可以确定最合适的剂量水平。然而,应当理解,对于任何特定患者的具体量将取决于多种因素,包括使用的具体化合物的活性,患者的年龄、体重、饮食、一般健康和性别,给药时间,给药途径,排泄速率,任何其它药物的使用,以及待治疗的疾病的严重程度。
对于吸入递送,活性化合物优选地为微粒形式。这些微粒可以通过包括喷雾干燥、冷冻干燥和微粉化在内的多种技术制备。
例如,本发明的组合物可制备为悬浮液用于从喷雾器递送,或者制备为在液体推进剂中的气溶胶而用于例如加压定量吸入器(PMDI)中。适用于PMDI的推进剂是本领域技术人员已知的,包括CFC-12、HFA-134a、HFA-227、HCFC-22(CCl2F2)和HFA-152(CH4F2和异丁烷)。
在本发明的一个优选实施方案中,本发明的组合物为干粉形式,用于使用干粉吸入器(DPI)的递送。很多类型的DPI都是已知的。
用于施用递送的微粒可以用有助于递送和释放的赋形剂配制。例如,在干粉制剂中,微粒可以用有助于从DPI流进肺的大载体颗粒配制。合适的载体颗粒是已知的,包括乳糖颗粒;它们可具有大于90μm的质量中值直径。
在基于气溶胶的制剂的情况下,优选的组合物是:
本发明化合物可以与其它药物联合使用,所述其它药物用于治疗/预防/抑制或改善本发明化合物对其有用的疾病或病症。这样的其它药物可以通过其常用的途径和量,与本发明的化合物同时或相继施用。当本发明的化合物与一种或多种其它药物同时使用时,除了本发明化合物以外还含有这样的其它药物的药物组合物是优选的。因此,本发明的药物组合物包括除了本发明化合物以外还含有一种或多种其它活性成分的那些。
本发明的试剂可以以吸入形式施用。可以使用例如气压驱动喷射雾化器或超声雾化器来产生气溶胶,优选地使用推进剂驱动的定量气溶胶,或微粉化活性化合物形式的不含推进剂剂的给药,例如,吸入式胶囊或其它“干粉”递送系统。
可根据所用的吸入器系统,如前所述地施用活性化合物。除了活性化合物之外,给药形式可以额外含有赋形剂,例如,推进剂(例如对于定量气溶胶,可使用氟利昂)、表面活性物质、乳化剂、稳定剂、防腐剂、调味剂、填充剂(例如对于粉末吸入器,可使用乳糖),或者如果合适时,还含有其它活性化合物。
对于吸入目的,可以得到很多种产生和施用具有最合适粒度的气溶胶的系统,其中使用适合患者的吸入技术。除了使用接合管(adaptor)(间隔器(spacer)、扩张器(expander))和梨形容器(例如)和发射吹气喷雾(pufferspray)的自动装置之外,对于定量气溶胶,特别是对于粉末吸入器的情况,可以得到很多种技术方案(例如 或例如EP-A-0505321所述的吸入器)。
合成方法
在本发明的一个方面,提供了根据下文方案A中报道的一般合成途径制备式(I)的化合物的方法。
方案A
通过在有碱诸如三乙胺存在下在溶剂诸如THF中在从0℃至回流的温度与氯甲酸乙酯(或焦碳酸乙酯)反应,可以从式(III)的化合物制备式(IV)的化合物。通过在适当的溶剂中加热,可以将式(IV)的化合物转化成式(I)的化合物。合适的条件包括溶剂诸如IMS的应用和使用微波辐射在高达150℃的温度加热或在溶剂诸如正丁醇中在回流下的常规加热。
根据下面的方案B可以制备式(III)的化合物:
方案B
可以在有酸诸如TMS-多磷酸酯(polyphosphate)存在下在溶剂诸如THF中在从室温至回流的温度使式(V)的化合物与苯甲醛诸如3-溴-4-甲酰基-苄腈和乙酰乙酸酯诸如乙酰乙酸乙酯反应,得到式(VIII)的化合物。通过与氧化剂诸如脲过氧化氢反应,随后在IMS中用水合肼原位处理,可以从式(VIII)的化合物制备式(III)的化合物。
此外,可以根据方案C制备式(I)”的化合物,其为如上定义的式(I)的化合物,其中碳(1)的绝对构型是下面显示的绝对构型
方案C
使用关于方案B中式(V)的化合物向式(VIII)的化合物的转化所述的类似方法,通过与3-溴-4-甲酰基-苯甲酸反应,可以从式(V)的化合物得到式(II)的化合物。可以如下从式(II)的化合物得到式(II)”的化合物,其为式(II)的化合物,其中在立体中心(1)处的绝对构型如在方案C中所报道:在合适的溶剂诸如二烷中与合适的手性胺诸如(+)-辛可宁形成手性非对映异构的盐,随后用酸诸如盐酸处理所述盐以得到对映异构地纯的式(II)”的化合物。可以如下从式(II)”的化合物得到式(VIII)”的化合物,其为式(VIII)的化合物,其中在立体中心(1)处的绝对构型如在方案C中所报道:在有偶联剂诸如羰基二咪唑存在下,在溶剂诸如THF中,在从0℃至室温的温度与氨水反应,得到中间体伯酰胺。使用脱水剂可以实现酰胺向式(VIII)”的化合物的转化。合适的条件包括在从0℃至室温的温度使用溶剂诸如DMF和脱水剂诸如磷酰氯(phosphorous oxychloride)。
使用关于方案A中式(VIII)的化合物向式(I)的化合物的转化所述的类似方法,可以从式(VIII)”的化合物得到式(I)”的化合物,其为如上定义的式(I)的化合物,且其中碳(1)的绝对构型是在方案C(方法A)中所示的绝对构型。可替换地,使用方法B也可以从式(VIII)”的化合物得到式(I)”的化合物,其为如上定义的式(I)的化合物,且其中碳(1)的绝对构型是在方案C中所示的绝对构型;其中可以在有碱诸如2,6-卢剔啶(lutadine)存在下在溶剂诸如二氯甲烷中在从-5至5℃的温度使式(VIII)”的化合物与含有/释放氯羰基的化合物诸如光气或三光气和无水肼反应,得到式(I)”的化合物,其中所有其它基团如关于式(I)的化合物所定义。
技术人员会理解,通过选择适当的手性胺和它的绝对构型,可以得到式(II)’、(VIII)’和(Ia)’的衍生物[它们分别是式(II)、(VIII)和(I)的化合物,其中在立体中心(1)处的绝对构型与在方案C中报道的绝对构型相反]。
在适当的情况下,技术人员可以向在实验部分中具体描述的条件引入合适的变化,以便使合成途径适应本发明的其它化合物的供应。这样的变化包括、但不限于:使用适当的起始原料来制备不同的化合物,反应的溶剂和温度的变化,用类似的化学试剂替代反应物,引入或除去对反应条件和试剂敏感的官能团的保护/去保护阶段,以及引入或除去目的在于进一步官能化化学骨架的特定合成步骤。
可以使用的并在实施例中描述和报道的方法不应当视作限制可用于制备本发明的化合物的合成方法的范围。
用作起始原料或中间体的化合物可以是商购可得的,它们的制备可以具体地描述在文献中,或者它们可以根据在文献中可得到的和技术人员众所周知的方法来制备。
描述的方法是特别有利的,因为通过技术人员已知的任意适当变体易于适当地调控它,从而得到任意期望的本发明的化合物。这样的变体被包含在本发明范围内。
从所有上述内容,技术人员显而易见,任意所述基团可以原样存在或以任意适当地保护的形式存在。具体地,在进行烷基化、酰化、偶联或磺酰化之前,需要适当地保护存在于中间体和实施例中且会产生不希望的副反应和副产物的官能团。同样地,那些相同的被保护的基团的随后去保护可以发生在所述反应结束以后。
在本发明中,除非另有说明,否则术语“保护基”表示被改造以保留它所结合的基团的功能的保护性基团。通常,保护基用于保留氨基、羟基或羧基功能。因此,适当的保护基可以包括,例如,本领域技术人员众所周知的苄基、苄氧基羰基、叔丁氧基羰基、烷基或苄基酯等[关于一般参考,参见,T.W.Green;Protective Groups in Organic Synthesis(Wiley,N.Y.1981)]。
同样地,根据有机合成化学中常用的众所周知的方法,可以完成任意所述基团(例如包括羰基、羟基或氨基)的选择性保护和去保护。
通过将任意游离酸性基团或氨基适当地转化成对应的药学上可接受的盐,可以实现式(I)化合物的任选盐形成。也在该情况下,用于本发明的化合物的任选成盐的工作条件都是在技术人员的普通知识内。
在可得到的情况下,根据本领域众所周知的方法,例如通过制备型HPLC或通过色谱纯化,可以得到式(I)化合物的非对映异构体。使用制备型HPLC和装有手性固定相的柱,同样可以分离式(I)化合物的外消旋混合物,或者使用本领域众所周知的方法进行拆分以得到各对映异构体。此外,可以拆分手性中间体并用于制备本发明的手性化合物。
从所有上述内容,技术人员显而易见,可以方便地修改上面的方法、用于制备本发明的合适化合物的综合的其任意变体,从而使反应条件适应具体需要,例如通过选择适当的缩合剂、溶剂和保护基,视情况而定。
根据方案D可以制备式(Ia)的化合物,即式(I)的化合物,其中R是如上定义的基团。根据方案A和B可以制备式(IX)的化合物,其为式(I)的化合物,其中R是溴或其它合适的活化基团,所述活化基团选自(但是非排它地)Cl、I、OTf。必须明白,根据方案C也可以类似地制备式(I)”的手性化合物。
可以从式(IX)的化合物制备式(XI)的化合物。可以如下使用Heck偶联化学制备式(XI)的化合物:在有适当的催化剂/配体系统诸如Herrmann-Beller催化剂/三丁基膦四氟硼酸盐存在下,在溶剂诸如四乙二醇或二甲氧基乙烷中,在有碱诸如五甲基哌啶存在下,在从室温至160℃的温度,与适当地取代的乙烯基化合物(X)反应。可以在以下水解和还原步骤以后从式(XI)的化合物制备式(XII)的化合物:在溶剂诸如DCM中在-10℃使用酸诸如三氟乙酸以得到中间体醛,并在溶剂诸如MeOH中在从0℃至室温的温度使用还原剂诸如硼氢化钠以得到式(XII)的化合物。使用四溴化碳/三苯基膦的混合物,在溶剂诸如DCM中,在从0℃至50℃的温度,可以从式(XII)的化合物制备式(XIII)的化合物。通常,通过在溶剂诸如乙腈中在从室温至80℃的温度与取代的吡啶R1R2-Pyr(XIX)反应,可以从式(XIII)的化合物得到式(I)的化合物。
方案D
一般实验细节
除非指明,否则反应不是在惰性气氛下进行,并且所有溶剂和市售试剂以接收状态使用。
通过色谱法纯化表示使用Companion纯化系统或Biotage SP1纯化系统的纯化。在使用SPE Si II柱纯化产物的情况下,‘Isolute SPE Si柱’表示含有未键合的活性二氧化硅的不规则颗粒的预填充聚丙烯柱,所述不规则颗粒具有50μm平均大小和标称孔隙率。将含有所需产物(通过TLC和/或LCMS分析鉴别)的级分合并,将有机级分通过蒸发除去,并将剩余的水性级分低压冻干以得到终产物。在已经使用薄层色谱法(TLC)的情况下,它表示使用平板的硅胶TLC,通常是在具有荧光指示剂(254nm)的铝箔平板上的3×6cm硅胶(例如Fluka 60778)。使用Biotage Initiator 60TM进行微波实验,所述Biotage Initiator 60TM使用单模式共振器和动态区调节。可以达到40-250℃的温度,且可以达到至多30巴的压力。
在Varian Unity Inova 400波谱仪(具有运行在400MHz的5mm倒置检测三共振探头)上,或在Bruker Avance DRX 400波谱仪(具有运行在400MHz的5mm倒置检测三共振TXI探头)上,或在Bruker Avance DPX 300波谱仪(具有运行在300MHz的标准5mm双频率探头)上,得到NMR谱。以相对于四甲基硅烷的ppm给出迁移。
使用MDL ISISTM/Draw 2.5SP2软件中的Autonom 2000部件产生化合物名称。
分析LC-MS条件
LC-MS方法1
具有C18-反相柱(30×4.6mm Phenomenex Luna 3μm颗粒尺寸)的Waters ZQ四极质谱仪,洗脱使用A:水+0.1%甲酸;B:MeCN+0.1%甲酸。梯度:
检测-MS,ELS,UV(200μl/min分流至具有线内HP1100PDA检测器的ESI源)
MS电离方法-电喷射(正离子和负离子)
LC-MS方法2
具有C18-反相柱(30×4.6mm Phenomenex Luna 3μm颗粒尺寸)的WatersMicromass ZMD四极质谱仪,洗脱使用A:水+0.1%甲酸;B:MeCN+0.1%甲酸。梯度:
检测-MS,ELS,UV(100μl分流至具有线内紫外检测器的MS)
MS电离方法-电喷射(正离子和负离子)
LC-MS方法3
具有维持在40℃的C18-反相柱(100×2.1mm Acquity BEH 1.7μm颗粒尺寸)的Waters Micromass ZQ2000质谱仪,洗脱使用A:水+0.1%甲酸;B:MeCN+0.1%甲酸。可替换地,在指明的情况下,使用C18-反相(100×2.1mm Acquity UPLC BEH Shield 1.7μm颗粒尺寸)柱。
梯度:
检测-MS,UV PDA
MS电离方法-电喷射(正/负离子)。
LC-MS方法4
具有C18-反相柱(30×4.6mm Phenomenex Luna 3μm颗粒尺寸)的Waters平台LC四极质谱仪,洗脱使用A:水+0.1%甲酸;B:MeCN+0.1%甲酸。梯度:
检测-MS,ELS,UV(分流-200μl/min分流至具有线内HP1100 DAD检测的ESI源)
MS电离方法-电喷射(正离子和负离子)。
LC-MS方法5
具有C18-反相柱(30×4.6mm Luna 3μm颗粒尺寸)的Waters VG平台II四极波谱仪,洗脱使用A:水+0.1%甲酸;B:MeCN+0.1%甲酸。
梯度:
检测-MS,ELS,UV(分流-200μl/min分流至具有线内HP1050 DAD检测的ESI源)
MS电离方法-电喷射(正离子和负离子)
MDAP系统:
仪器:Agilent 1260无限纯化系统。Agilent 6100系列单个四极LC/MS
柱:XSELECT CSH Prep C18 5μm OBD,30X150mm,RT
流动相A:0.1%甲酸水溶液
流动相B:0.1%甲酸在乙腈中的溶液
流量:60ml/min
梯度计划:10%-95%,22min,以特定聚焦的梯度附近为中心
样品注射:20-60mg/ml的在DMSO(+任选的甲酸和水)中的溶液。
在实验部分中使用的缩写:
DCM 二氯甲烷
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
Et2O 乙醚
EtOAc 乙酸乙酯
HPLC 高效液相色谱法
IMS 工业用甲基化酒精
LC-MS 液相色谱法-质谱法
MeCN 乙腈
MDAP 质量导向的自动纯化
NBS N-溴琥珀酰亚胺
Rt 保留时间
RT 室温
THF 四氢呋喃
在下面的操作中,通过“中间体”或“实施例”编号来标识一些起始原料。这仅仅为了辅助熟练的化学家而提供。所述起始原料不一定已经从提及的批料制备。
当提及使用“类似的”或“相似的”操作时,本领域技术人员会明白,这样的操作可能包含微小变化,例如反应温度、试剂/溶剂量、反应时间、后处理条件或色谱纯化条件。
实施例1
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2,
3,5,8-四氢-[1,2,4]三唑并[4,3a]嘧啶-5-基]-苯基}-乙基)-4-甲氧基-吡啶
溴化物
中间体1
3-溴-4-二溴甲基苯甲酸
在配有机械搅拌器的20L凸缘烧瓶中将3-溴-4-甲基苯甲酸(910g,4.23mol,1.0当量)和NBS(2010g,11.29mol,2.67当量)溶解在DCM(8.5L)中。然后加入AIBN(50g,0.3mol,0.07当量)在DCM(1L)中的浆料,并将混合物在N2气氛下在回流冷凝器下在强光(500W)下照射。反应物的内部温度从17℃升高至41℃,且最初的白色悬浮液随着它达到轻轻回流而变成淡橙色悬浮液。共72h以后,反应结束,并将水(5L)加入混浊的橙色溶液中,将其在室温搅拌1h。然后将橙色两相混合物静置过夜,然后在真空中浓缩,得到橙色馏出液和黄褐色悬浮固体。然后将固体通过过滤进行收集,用水(2L)洗涤并抽干2h,得到作为黄褐色潮湿固体的标题化合物(1860g)。
LCMS(方法1):Rt=3.39min,m/z 369,371,373,375[M-H]
1H NMR(300MHz,DMSO):δ8.14-8.03(3H,m),7.36(1H,s)。
中间体2
3-溴-4-甲酰基苯甲酸
将中间体1(1860g,4.23mol,1.0当量)悬浮于水(5L)中,并将浆料加热至40℃的内部温度。然后历时20min加入分成小份的固体Na2CO3(1460g,13.77mol,3.25当量)。在最初加入后产生泡沫,所以加入EtOAc(0.2L)以收缩泡沫和抑制任何进一步起泡。加入结束后,将棕色悬浮液历时40min加热至90℃,然后在90℃搅拌90min,然后历时90min冷却至40℃。加入EtOAc(1.5L),随后经由滴液漏斗加入浓HCl水溶液(0.7L),从而导致CO2气体的剧烈产生和大部分EtOAc的蒸发。加入其它EtOAc(1L)以从冷凝器和反应器壁洗涤起泡的产物,然后加入另外的EtOAc(0.3L),并将稠浆料在室温搅拌过夜。然后将浆料加热至40℃,并经由滴液漏斗在剧烈搅拌下历时45min加入另外的浓HCl水溶液,从而导致CO2气体产生、大部分EtOAc的蒸发和固体的形成。停止搅拌,固体漂浮至水性混合物(pH 1)的顶部。分离大部分水层(约5L),然后加入2-MeTHF(5L)。然后将澄清的水层除去,并将有机层用另外的2-MeTHF稀释至10L,并温热至50℃,得到深橙色溶液。然后将有机层用1M HCl(0.5L)洗涤,蒸发,并与甲苯一起共沸,以得到作为黄褐色固体的标题化合物(960.3g)。
LCMS(方法4):Rt 2.73min,m/z 227[M(79Br)+H]+
1H NMR(300MHz,DMSO):δ10.26(1H,d,J=0.8Hz),8.20(1H,d,J=1.5Hz),
8.08-8.04(1H,m),7.95(1H,d,J=8.0Hz)。
中间体3
4-(2-溴-4-羧基苯基)-6-甲基-2-硫代-1-(3-三氟甲基苯基)-1,2,3,4-四氢嘧
啶-5-甲酸甲酯
将中间体2(458g,2mol,1.0当量)、乙酰乙酸甲酯(274.4g,255mL,2.36mol,1.18当量)和3-三氟甲基苯基硫脲(519g,2.36mol,1.18当量)在N2气氛下装入10L带夹套的反应器中,并悬浮于THF(4.6L)中,并在搅拌下冷却至-10℃(内部温度-3℃)。将多磷酸(1650g,3.6wt当量)在50℃水浴中预温热,然后一次性加入,导致立即放热,且内部温度升高至19℃。然后将得到的橙色混合物以10℃增量温热至75℃达到轻轻回流,并将反应物在该温度搅拌20h。然后将反应物冷却至20℃并将大部分THF在真空中除去,得到深橙色粘稠油,然后将其用水(5L)和Et2O(5L)稀释。将水层分离并再次用Et2O(2×2L)萃取,随后将合并的有机层用水(1L)、盐水(1L)洗涤,并干燥(Na2SO4)和穿过Celite过滤以除去任何细微粒。然后将过滤的溶液在真空中浓缩,得到粘稠的橙色胶质,将其再悬浮于Et2O(约1.5L)中并静置过夜。将得到的悬浮液过滤,并将收集的固体用Et2O(0.5L)冲洗和在真空干燥箱中在50℃(8毫巴)干燥4天以得到标题化合物(754g)。
LCMS(方法1):Rt 3.52min,m/z 529[M(79Br)+H]+
1H NMR(300MHz,DMSO):δ10.15(1H,d,J=3.5Hz),8.11(1H,d,J=1.6Hz),8.05(1H,dd,J=8.1,1.7Hz),7.92-7.64(5H,m),5.80(1H,d,J=2.9Hz),3.53(3H,s),2.07(3H,s)。
中间体4
(S)-4-(2-溴-4-羧基-苯基)-6-甲基-2-硫代-1-(3-三氟甲基-苯基)-1,2,3,4-四
氢-嘧啶-5-甲酸甲酯
将中间体3(151.7g,0.29mol,1.0当量)溶解在二烷(2L)中并加热至80℃。将得到的悬浮液过滤以除去任何无机残余物,并将澄清溶液再次加热至80℃,并加入(+)-辛可宁(88g,0.29mol,1.0当量),产生澄清溶液。使得到的混合物缓慢地冷却和结晶。3h以后,将得到的固体过滤,并用冷二烷洗涤。将固体再悬浮于热二烷(85℃)中并使其冷却和结晶过夜。将得到的晶体滤出,用冷二烷洗涤,并使固体再次从热二烷重结晶。将最终的重结晶固体滤出并风干,得到作为白色固体的中间体(+)-辛可宁盐,83.2g(68%)。
通过在1M HCl和EtOAc之间分配,确定拆分的(+)-辛可宁盐的光学纯度;将有机层分离,在真空中浓缩,然后再溶解在20%IPA/正庚烷(含有0.1%TFA)中,并进行手性分析型HPLC(ChiralPak IA,5μM 4.6×250mm),用20%IPA/正庚烷(+0.1%TFA)在1mL/min和254nm波长洗脱。还通过手性HPLC检查外消旋产物;对于外消旋的样品观察到14.8和42.5分钟的保留时间,且期望的对映异构体在42.5分钟洗脱,并发现是大于99.5ee%。
通过在EtOAc(1L)和1M HCl(1L)之间分配,释放中间体(+)-辛可宁盐(83.2g,101.75mmol)。将水层再次用EtOAc(2×0.5L)萃取,并将合并的有机层用1M HCl(0.5L)洗涤,然后用盐水(0.25L)洗涤,干燥(Na2SO4)并在真空中浓缩,得到作为白色固体的标题化合物(45.45g)。
中间体5
(S)-4-(2-溴-4-氨甲酰基-苯基)-6-甲基-2-硫代-1-(3-三氟甲基-苯基)-1,2,3,
4-四氢-嘧啶-5-甲酸甲酯
将中间体4(93.8g,0.18mol)溶解在THF(1L)中,并逐份加入1,1’-羰基二咪唑(57.5g,0.35mol,2.0当量),并在室温搅拌直到气体产生已经停止。然后逐滴加入氨水溶液(33%,330mL),从而确保内部温度不超过10℃(在最初加入后观察到放热)。将反应物在室温搅拌2h,然后加入盐水并分离各层。将有机相用1M HCl水溶液(2×)洗涤,并将酸性层用EtOAc进一步萃取。将合并的有机层用盐水洗涤,干燥(Na2SO4),过滤并在真空中浓缩,以得到作为无色泡沫的标题化合物(87.3g)。
LCMS(方法2):Rt 3.44min,m/z 528[M(79Br)+H]+
1H NMR(300MHz,DMSO):δ10.12(1H,d,J=2.6Hz),8.12(1H,s),8.11(1H,d,J=1.7Hz),7.96(1H,dd,J=8.1,1.7Hz),7.88-7.77(2H,m),7.75-7.63(3H,m),7.54(1H,s),5.78(1H,s),3.54(3H,s),2.07(3H,s)。
中间体6
(S)-4-(2-溴-4-氰基苯基)-6-甲基-2-硫代-1-(3-三氟甲基苯基)-1,2,3,4-四氢
嘧啶-5-甲酸甲酯
将中间体5(87.3g,0.165mol)溶解在DMF(400mL)中并在冰浴中冷却至0-5℃。然后逐滴加入磷酰氯(62.0g,37.0mL,2.5当量),从而确保内部温度不超过10℃。一旦加入结束,将黄色溶液在0-5℃搅拌15min,然后倒入固体2M Na2CO3和冰的混合物中。黄色沉淀物形成并将浆料老化1h,然后将固体过滤,用水洗涤并在真空干燥箱中在P2O5上面在40-45℃干燥。得到的产物的NMR分析仍然表明起始原料剩余,所以使用另外20mL磷酰氯再次重复反应。得到的固体的NMR表明产物是与POCl3的加成化合物(adduct)。因此,将固体溶解在无水EtOH(1000mL)中,并将悬浮液温热以辅助溶解。然后加入饱和NaHCO3水溶液(250mL),并将混合物加热至40℃和搅拌2h。然后将得到的混合物倒入水(500mL)中,并将得到的白色固体滤出、用水洗涤和风干以得到标题化合物(77.5g)。
LCMS(方法2):Rt 3.94min,m/z 510[M(79Br)+H]+
1H NMR(300MHz,DMSO):δ10.18(1H,d,J=2.7Hz),8.24(1H,d,J=1.5Hz),7.96(1H,dd,J=8.0,1.6Hz),7.89-7.76(3H,m),7.74-7.64(2H,m),5.8(1H,s),3.53(3H,s),2.06(3H,s)。
中间体7
(S)-5-(2-溴-4-氰基苯基)-7-甲基-3-氧代-8-(3-三氟甲基苯基)-2,3,5,8-四
氢-[1,2,4]三唑并[4,3-a]嘧啶-6-甲酸甲酯
将中间体6(30.3g,59.4mmol)溶解在DCM(500mL)中,加入2,6-卢剔啶(19.7mL,169mmol),并将溶液冷却至2℃。在搅拌下,然后历时3min加入三光气(5.58g,18.8mmol)。5min以后,将反应物温热至室温并搅拌25min。将反应物冷却至2-3℃,然后将溶液经由插管转移至冷却(7℃)的肼溶液(1M的在THF中的溶液,170mL)在MeCN(150mL)中的混合物中。将混合物在7℃搅拌另外5min。2.25h以后,将反应混合物用水、10%柠檬酸溶液(以除去残余的卢剔啶)、水和50%饱和盐水洗涤,并将有机相干燥(Na2SO4)、过滤并在真空中浓缩。使用硅胶通过色谱法进一步纯化,并用40%至100%的EtOAc在环己烷中的溶液洗脱,以得到作为乳膏状固体的中间体7(17.8g)。
LCMS(方法3):Rt 3.61min,m/z 534[M(79Br)+H]+
1H NMR(300MHz,CDCl3):δ8.36(1H,s),7.88(1H,d,J=1.5Hz),7.83-7.79(1H,m),7.73(1H,t,J=8.0Hz),7.65-7.60(2H,m),7.59-7.50(2H,m),6.39(1H,d,J=1.0Hz),3.62(3H,s),2.25(3H,d,J=1.0Hz)。
通过Chiralpak IC手性HPLC柱(5μm颗粒尺寸,5%MeOH/DCM,流速5mL/min)分析手性纯度,并得到Rt=5.83min(100%ee)。外消旋的样品(中间体4)给出分别对于第一和第二洗脱的对映异构体为3.58和5.85min的Rt。
中间体8
(R)-5-[2-(2-叔-丁氧基-乙烯基)-4-氰基-苯基]-7-甲基-3-氧代-8-(3-三氟甲
基-苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-6-甲酸甲酯
给高压釜装入中间体7(10g,18.72mmol)、2-甲基-2-乙烯基氧基-丙烷(6.55g,65.50mmol)、三-叔丁基鏻四氟硼酸盐(540mg,1.86mmol)、Herrmann-Beller催化剂(反式-二(μ-乙酸根合(acetato))双(0-二-邻甲苯基-膦基)苄基)二钯(II))(880mg,0.94mmol)、1,2,2,6,6-五甲基哌啶(11.5g,74.20mmol)的混合物。加入四-乙二醇(140mL),并将得到的溶液在氩气下脱气。然后将混合物在150℃加热1h。将混合物冷却,用EtOAc和10%柠檬酸水溶液稀释,并将有机萃取物用水和盐水洗涤,然后干燥(Na2SO4)并在真空中浓缩。将得到的残余物通过色谱法纯化,用25-75%的EtOAc在环己烷中的溶液洗脱,得到作为E/Z异构体的[3:1]混合物和作为黄色泡沫的标题化合物(7.95g)。
LC-MS(方法5):Rt=3.87min,m/z=554.2[M+H]+
中间体9
(R)-5-[4-氰基-2-(2-羟基-乙基)-苯基]-7-甲基-3-氧代-8-(3-三氟甲基-苯
基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-6-甲酸甲酯
将中间体8(7.87g,14.20mmol)在DCM(130mL)中的溶液使用盐/冰浴冷却至-10℃并用TFA(6.35mL,85.47mmol)逐滴处理。将溶液在-10℃搅拌2h以后,将得到的溶液倒入冰冷的Na2CO3水溶液中。将有机相分离,并将水相用DCM(70mL)进一步萃取,并将合并的DCM萃取物返回至-5℃的盐/冰浴。逐份加入硼氢化钠(1.57g,41.42mmol),并在搅拌15分钟以后,将MeOH(32mL)加入得到的混合物中。将反应物在-5℃搅拌1.5h,加入水,并将得到的混合物剧烈搅拌15分钟,然后分离有机相。将水相用DCM进一步萃取,并将合并的有机萃取物用盐水洗涤,干燥(Na2SO4)并在真空中浓缩。将得到的残余物通过色谱法纯化,用EtOAc洗脱,并得到作为乳膏状固体的标题化合物(3.7g)。
LC-MS(方法5):Rt=3.17min,m/z=500.1[M+H]+
中间体10
(R)-5-[2-(2-溴-乙基)-4-氰基-苯基]-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-
2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-6-甲酸甲酯
随着加入四溴甲烷(22.95g,69.1mmol),将中间体9(23g,46.1mmol)在DCM(400mL)中在室温搅拌。然后历时10min分份加入三苯基膦(18.11g,69.1mmol)。将反应混合物在冰中短暂地冷却以便维持室温(发生小的最初放热)。在室温继续搅拌3h。将混合物用水洗涤,将有机相干燥(Na2SO4)、过滤并蒸发,并将残余物色谱分离,用40%至75%的EtOAc在环己烷中的溶液的梯度洗脱,得到作为白色固体的标题化合物(23.6g)。
LC-MS(方法5):Rt=3.83min,m/z=562.1[M(79Br)+H]+
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2, 3,5,8-四氢-[1,2,4]三唑并[4,3a]嘧啶-5-基]-苯基}-乙基)-4-甲氧基-吡啶 溴化物(实施例1)
在密闭试管中将中间体10(30mg,53μmmol)和4-甲氧基吡啶(17.5mg,160μmol)在MeCN(1mL)中的混合物温热至50℃保持18h,然后在真空中浓缩。将粗产物在水和EtOAc之间分配,并将水层分离和冷冻干燥,得到作为白色静电固体(electrostatic solid)的标题化合物(15mg)。
LC-MS(方法3):Rt=3.78min,m/z=591.1[M]+
使用与关于实施例134使用的方法类似的方法,从中间体10和适当地取代的吡啶化合物制备下述实施例:
(续)
(续)
生物学测定
在人嗜中性粒细胞弹性蛋白酶(HNE)酶活性测定中,测试了本发明的化合物的效能。
HNE酶测定
以100μL的总测定体积,在96-孔平板中进行测定。弹性蛋白酶(人白细胞弹性蛋白酶,Sigma E8140)的终浓度为0.00072U/mL。以100μM的终浓度使用肽底物(MeOSuc-Ala-Ala-Pro-Val-AMC,Calbiochem#324740)。在测定缓冲液(0.05M Tris.HCl,0.1M NaCl,0.1MCaCl2,0.0005%brij-35,pH 7.5)中的DMSO的终浓度为1%。通过加入酶,启动酶反应,并在25℃温育30分钟。温育以后,通过以50μg/孔的终浓度加入大豆胰蛋白酶抑制剂(SigmaT9003),停止反应。使用380nm激发波长和460nm发射波长,使用Molecular Devices荧光平板读数器测量荧光。
进行对每种化合物的剂量响应,并将每个实验中化合物的效应表示为对照酶荧光的抑制百分比。绘制剂量响应曲线,并确定化合物效能(IC50)。在至少2个单独实验中试验化合物。
测试的实施例(本发明的代表)的IC50显示在下表中:
实施例 | HNE抑制 |
1-11 | ++++ |
在上表中,如下指示HNE酶抑制(IC50值):>500nM‘+’;100-500nM‘++’;20-100nM‘+++’;<20nM‘++++’。
Claims (8)
1.一种化合物,其选自:
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3a]嘧啶-5-基]-苯基}-乙基)-4-甲氧基-吡啶溴化物;
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-5-基]-苯基}-乙基)-3-羟基-吡啶溴化物;
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-5-基]-苯基}-乙基)-2-甲基-吡啶溴化物;
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-5-基]-苯基}-乙基)-4-羟基甲基-吡啶溴化物;
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-5-基]-苯基}-乙基)-4-异丙基-吡啶溴化物;
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-5-基]-苯基}-乙基)-5-羟基-2-甲基-吡啶溴化物;
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-5-基]-苯基}-乙基)-2,4-二甲基-吡啶溴化物;
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-5-基]-苯基}-乙基)-3,5-二甲基-吡啶溴化物;
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-5-基]-苯基}-乙基)-2-乙基-吡啶溴化物;
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-5-基]-苯基}-乙基)-2-(2-羟基-乙基)-吡啶溴化物;
1-(2-{5-氰基-2-[(R)-6-甲氧基羰基-7-甲基-3-氧代-8-(3-三氟甲基-苯基)-2,3,5,8-四氢-[1,2,4]三唑并[4,3-a]嘧啶-5-基]-苯基}-乙基)-4-乙基-吡啶溴化物;
和它们的药学上可接受的盐。
2.式(I)”的化合物或其药学上可接受的盐
其中基团R选自
-4-甲氧基-吡啶基;
-3-羟基-吡啶基;
-2-甲基-吡啶基;
-4-羟基甲基-吡啶基;
-4-异丙基-吡啶基;
-5-羟基-2-甲基-吡啶基;
-2,4-二甲基-吡啶基;
-3,5-二甲基-吡啶基;
-2-乙基-吡啶基;
-2-(2-羟基-乙基)-吡啶基;和
-4-乙基-吡啶基。
3.药物组合物,其包含如在权利要求1或2中要求保护的化合物和药学上可接受的载体或赋形剂。
4.如在权利要求1或2中要求保护的药物组合物,所述药物组合物适合用于口服施用或通过肺途径施用。
5.如在权利要求1或2中要求保护的化合物,所述化合物用于治疗其中涉及HNE的疾病或病症,或所述化合物用于制备用于治疗其中涉及HNE的疾病或病症的药物。
6.治疗其中涉及HNE的疾病或病症的方法,所述方法包括给遭受这样的疾病的受试者施用有效量的如在权利要求1或2中要求保护的化合物。
7.根据权利要求1或2所使用的化合物或根据权利要求5的治疗方法,其中所述疾病或病症是慢性阻塞性肺疾病(COPD)、支气管扩张、慢性支气管炎、肺纤维化、肺炎、急性呼吸窘迫综合征(ARDS)、肺气肿、吸烟诱发的气肿或囊性纤维化。
8.根据权利要求1或2所使用的化合物或根据权利要求6的治疗方法,其中所述疾病或病症是哮喘、鼻炎、银屑病、特应性皮炎、非特应性皮炎、克罗恩氏病、溃疡性结肠炎或应激性肠病。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007107706A2 (en) * | 2006-03-17 | 2007-09-27 | Argenta Discovery Limited | Dimers of heterocyclic compounds for the treatment of copd |
CN102858774A (zh) * | 2010-03-12 | 2013-01-02 | 奇斯药制品公司 | 嘧啶衍生物及其在治疗呼吸系统疾病比如copd中的用途 |
CN102858773A (zh) * | 2010-03-12 | 2013-01-02 | 奇斯药制品公司 | 嘧啶衍生物及其在治疗呼吸系统疾病比如copd中的用途 |
CN103827117A (zh) * | 2011-09-14 | 2014-05-28 | 奇斯药制品公司 | 作为人嗜中性粒细胞弹性蛋白酶抑制剂的四氢三唑并嘧啶衍生物 |
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SG11201504737RA (en) * | 2012-12-18 | 2015-07-30 | Chiesi Farma Spa | Novel compounds |
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2014
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- 2014-06-12 MX MX2016016371A patent/MX2016016371A/es unknown
- 2014-06-12 RU RU2016148395A patent/RU2016148395A/ru not_active Application Discontinuation
- 2014-06-12 TR TR2018/11041T patent/TR201811041T4/tr unknown
- 2014-06-12 WO PCT/EP2014/062254 patent/WO2015188866A1/en active Application Filing
- 2014-06-12 EP EP14731580.8A patent/EP3154977B1/en active Active
- 2014-06-12 ES ES14731580.8T patent/ES2670018T3/es active Active
- 2014-06-12 CN CN201480079755.3A patent/CN106459054A/zh active Pending
- 2014-06-12 KR KR1020167033907A patent/KR20170016840A/ko not_active Application Discontinuation
- 2014-06-12 US US15/317,274 patent/US9868740B2/en active Active
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007107706A2 (en) * | 2006-03-17 | 2007-09-27 | Argenta Discovery Limited | Dimers of heterocyclic compounds for the treatment of copd |
CN102858774A (zh) * | 2010-03-12 | 2013-01-02 | 奇斯药制品公司 | 嘧啶衍生物及其在治疗呼吸系统疾病比如copd中的用途 |
CN102858773A (zh) * | 2010-03-12 | 2013-01-02 | 奇斯药制品公司 | 嘧啶衍生物及其在治疗呼吸系统疾病比如copd中的用途 |
CN103827117A (zh) * | 2011-09-14 | 2014-05-28 | 奇斯药制品公司 | 作为人嗜中性粒细胞弹性蛋白酶抑制剂的四氢三唑并嘧啶衍生物 |
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MX2016016371A (es) | 2017-05-01 |
PL3154977T3 (pl) | 2018-10-31 |
KR20170016840A (ko) | 2017-02-14 |
ES2670018T3 (es) | 2018-05-29 |
CA2951734A1 (en) | 2015-12-17 |
WO2015188866A1 (en) | 2015-12-17 |
RU2016148395A3 (zh) | 2018-07-12 |
US20170101413A1 (en) | 2017-04-13 |
RU2016148395A (ru) | 2018-07-12 |
US9868740B2 (en) | 2018-01-16 |
TR201811041T4 (tr) | 2018-08-27 |
EP3154977A1 (en) | 2017-04-19 |
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