CN111183142B - 硼酸衍生物 - Google Patents
硼酸衍生物 Download PDFInfo
- Publication number
- CN111183142B CN111183142B CN201880054929.9A CN201880054929A CN111183142B CN 111183142 B CN111183142 B CN 111183142B CN 201880054929 A CN201880054929 A CN 201880054929A CN 111183142 B CN111183142 B CN 111183142B
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- China
- Prior art keywords
- formula
- ethyl
- benzofuran
- carboxamido
- compound
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- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 72
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- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- PQMFVUNERGGBPG-UHFFFAOYSA-N (6-bromopyridin-2-yl)hydrazine Chemical compound NNC1=CC=CC(Br)=N1 PQMFVUNERGGBPG-UHFFFAOYSA-N 0.000 claims 13
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Abstract
本发明涉及α‑氨基硼酸衍生物。这些化合物可用于抑制免疫蛋白酶体(LMP7)的活性,和用于治疗和/或预防受免疫蛋白酶体活性影响的医学病症,例如炎性和自身免疫性疾病、神经变性疾病、增殖性疾病和癌症。
Description
发明领域
在本发明涉及α-氨基硼酸衍生物。这些化合物可用于抑制免疫蛋白酶体(LMP7)的活性和用于治疗和/或预防受免疫蛋白酶体活性影响的医学病症,例如炎性和自身免疫性疾病、神经变性疾病、增殖性疾病和癌症。特别地,本发明的化合物是选择性的免疫蛋白酶体抑制剂。
发明背景
蛋白酶体(也称为巨蛋白因子(macropain)、多催化蛋白酶和20S蛋白酶)是一种高分子量的多亚基蛋白酶,已在从古细菌到人类的每个检测物种中鉴定出。该酶的天然分子量约为650,000,并且如电子显微镜所揭示的,具有独特的圆柱状形态(Rivett,(1989)Arch.Biochem.Biophys.268:1-8;和Orlowski,(1990)Biochemistry 29:10289-10297)。蛋白酶体亚基的分子量范围为20,000至35,000,并且彼此同源,但与任何其他已知蛋白酶都不同源。
20S蛋白酶体是700kDa的圆柱型多催化蛋白酶复合体,由28个亚基组成,这些亚基分为α-和β-型,排列在4个堆叠的七聚体环中。在酵母和其他真核生物中,7个不同的α亚基形成外环,7个不同的β亚基组成内环。α亚基充当19S(PA700)和1IS(PR68)调节复合体的结合位点,以及对由两个β亚基环形成的内部蛋白水解室的物理屏障。因此,在体内,认为蛋白酶体作为26S颗粒存在(“26S蛋白酶体”)。体内实验已表明蛋白酶体的20S形式的抑制可以很容易地与26S蛋白酶体的抑制相关。
在颗粒形成过程中,β亚基的氨基末端前导序列的切割暴露出氨基末端苏氨酸残基,该残基充当催化亲核试剂。因此,在蛋白酶体中负责催化活性的亚基具有氨基末端亲核残基,并且这些亚基属于N末端亲核试剂(Ntn)ATTY REF:26500-0023WO1水解酶家族(其中亲核N末端残基例如是Cys、Ser、Thr和其他亲核部分)。该家族包括例如青霉素G酰基转移酶(PGA)、青霉素V酰基转移酶(PVA)、谷氨酰胺PRPP酰胺基转移酶(GAT)和细菌糖基天冬酰胺酶。除了普遍表达的β亚基,高等脊椎动物还具备三个干扰素-γ-可诱导的β亚基(LMP7、LMP2和MECLl),其分别替代其正常对应物β5、β1和β2。当所有三个IFN-γ-可诱导亚基都存在时,该蛋白酶体被称为“免疫蛋白酶体”。因此,真核细胞可以不同比率具有两种形式的蛋白酶体。
通过使用不同的肽底物,已经为真核生物20S蛋白酶体定义了三种主要的蛋白水解活性:胰凝乳蛋白酶样活性(CT-L),其在大疏水残基后切割;胰蛋白酶样活性(TL),其在碱性残基后切割;和肽基谷氨酰胺基肽水解活性(PGPH),其在酸性残基后切割。另外两种特征较弱的活性也已归因于蛋白酶体:BrAAP活性,其在支链氨基酸后切割;和SNAAP活性,其在小中性氨基酸后切割。尽管两种形式的蛋白酶体都具有全部五种酶促活性,但是基于特定的底物已经描述了这些形式之间的活性程度的差异。对于两种形式的蛋白酶体,主要的蛋白酶体蛋白水解活性似乎都是由20S核内的不同催化位点贡献的。
在真核生物中,蛋白降解主要通过泛素途径介导,在泛素途径中,破坏靶向的蛋白与该76个氨基酸的多肽泛素连接。一旦被靶向,泛素化的蛋白就可充当26S蛋白酶体的底物,该蛋白酶体通过其三种主要的蛋白水解活性的作用将蛋白切割成短肽。在细胞内蛋白周转中具有一般功能的同时,蛋白酶体介导的降解也在许多过程中起着关键作用,这些过程诸如主要组织相容性复合体(MHC)I型的呈递、细胞凋亡和细胞生存力、抗原加工、NF-κΒ活化和促炎信号的转导。
在涉及蛋白分解的肌肉萎缩性疾病如肌肉营养不良、癌症和艾滋病中蛋白酶体的活性高。证据还表明蛋白酶体在I型MHC分子的抗原加工中可能的作用(Goldberg等人(1992)Nature 357:375-379)。
蛋白酶体参与神经变性疾病和障碍,例如肌萎缩性侧索硬化症(ALS)(J BiolChem 2003,Allen S等人,Exp Neurol 2005,Puttaparthi k等人)、干燥综合征(Arthritis&Rheumatism,2006,Egerer T等人)、系统性红斑狼疮和狼疮性肾炎(SLE/LN)(Arthritis&rheuma 2011,Ichikawa等人,J Immunol,2010,Lang VR等人,Nat Med,2008,Neubert K等人)、肾小球肾炎(J Am Soc nephrol 2011,Bontscho等人)、类风湿性关节炎(Clin Exp Rheumatol,2009,Van der Heiden JW等人)、炎性肠病(IBD)、溃疡性结肠炎、克罗恩病,(Gut 2010,Schmidt N等人,J Immunol 2010,Basler M等人,Clin Exp Immunol,2009,Inoue S等人)、多发性硬化症(Eur J Immunol 2008,Fissolo N等人,J Mol Med2003,Elliott PJ等人,J Neuroimmunol 2001,Hosseini等人,J Autoimmun 2000,Vanderlugt CL等人)、肌萎缩性侧索硬化症(ALS),(Exp Neurol 2005,Puttaparthi k等人,J Biol Chem 2003,Allen S等人)、骨关节炎(Pain 2011,Ahmed s等人,Biomed MaterEng 2008,Etienne S等人)、动脉粥样硬化(J Cardiovasc Pharmacol 2010,Feng B等人)、牛皮癣(Genes&Immunity,2007,Kramer U等人)、重症肌无力(J Immunol,2011,Gomez AM等人)、皮肤纤维化(Thorax 2011,Mutlu GM等人,Inflammation 2011,Koca SS等人,Faseb J2006,Fineschi S等人)、肾纤维化(Nephrology 2011Sakairi T等人)、心脏纤维化(Biochem Pharmacol 2011,Ma y等人)、肝纤维化(Am J Physiol gastrointest LiverPhysiol 2006,Anan A等人)、肺纤维化(Faseb J 2006,Fineschi S et al等人)、免疫球蛋白A肾病(IGa肾病),(Kidney Int,2009,Coppo R等人)、血管炎(J Am Soc nephrol 2011,Bontscho等人)、移植排斥(Nephrol Dial transplant 2011,Waiser J等人)、血液恶性肿瘤(Br J Haematol 2011,singh AV等人,Curr Cancer Drug Target 2011,Chen D等人)和哮喘。
然而,应该指出的是,可商购的蛋白酶体抑制剂既抑制蛋白酶体的组成型形式又抑制其免疫形式。甚至硼替佐米(FDA批准的用于治疗复发性多发性骨髓瘤患者的蛋白酶体抑制剂)也无法区分这两种形式(Altun等人,Cancer Res 65:7896,2005)。此外,硼替佐米的使用与治疗突发疼痛性周围神经病(PN)相关,这种硼替佐米在体外引起的神经变性通过非蛋白酶体依赖机制发生,并且硼替佐米在体外和体内抑制若干非蛋白酶体靶标(Clin.Cancer Res,17(9),2011年5月1日)。
除了常规蛋白酶体抑制剂外,一种新方法也可能特异性地靶向血液学特异性免疫蛋白酶体,从而提高总体效力并减少负面的脱靶作用。已经显示免疫蛋白酶体特异性抑制剂可以对血液来源的细胞显示增强的效力(Curr Cancer Drug Targets,11(3),2011年3月)。
因此,需要提供新的蛋白酶体抑制剂,其对蛋白酶体的一种特定形式具有选择性。特别地,需要提供选择性免疫蛋白酶体抑制剂,其可以用作治疗剂,用于例如在类风湿性关节炎的情况下治疗SLE或其他免疫或自身免疫性障碍。选择性免疫蛋白酶体抑制剂有助于使由组成型蛋白酶体或其他非蛋白酶体靶标的抑制所介导的不良副作用最小化。
WO 2013/092979 A1描述了硼酸衍生物,其显示出对抑制LMP7活性的选择性。但是,用所描述的化合物类型所能达到的选择性程度是有限的,特别是就组成型蛋白酶体的抑制活性的分选而言。
蛋白酶体和免疫蛋白酶体的非特异性抑制剂(如硼替佐米和卡非佐米(Carfilzomib))已证明它们在多发性骨髓瘤适应症中的临床价值。虽然该非特异性特性击中了免疫蛋白酶体以及组成型蛋白酶体的主要成分,它在靶标抑制和临床效力方面被认为是有益的,但是这种非特异性特性通过诱导明显的副作用如血小板减少症、中性粒细胞减少症以及周围神经病变而限制了这些药剂的临床应用性。在某种程度上,该副作用特性可归因于对催化活性的广泛抑制,尤其是对组成型和免疫蛋白酶体的β5亚基的联合抑制。提出了更具选择性的免疫蛋白酶体(尤其是免疫蛋白酶体的β5i亚基)抑制剂PR-924以减少主要副作用的方法例如在2011年由Singh等人(Br.J.Hematology 152(2):155–163):155–163)描述,PR-924是蛋白酶体的LMP7亚基的100倍选择性抑制剂。作者证明了多发性骨髓瘤中免疫蛋白酶体存在高表达水平。作者还描述了LMP7亚基的选择性抑制剂对MM细胞系以及CD138+MM原代患者细胞中细胞死亡的诱导作用,而没有降低健康志愿者的对照PBMC的生存能力,这可以看作是概念上的证明。除了选择性β5i抑制剂的减少副作用特性的概念之外,另一组证明了选择性β5i抑制对耐硼替佐米细胞系生存力的功效,强调了选择性LMP7抑制剂对血液恶性肿瘤应用的价值和潜在前景(D.Niewerth等人/Biochemical Pharmacology89(2014)43–51)。
WO 2016/050356,WO 2016/050355,WO 2016/050359和WO 2016/050358描述了抑制免疫蛋白酶体(LMP7)的活性并提供对组成型蛋白酶体抑制活性的显著分选的化合物。
令人惊讶地发现,本发明的氨基硼酸衍生物对组成型蛋白酶体的抑制活性提供了特别高的分选。此外,它们在血浆-蛋白结合、CYP抑制、PK特性和口服生物利用度方面显示良好的结果。
发明描述
本发明提供式(I)的化合物
其中
LY表示(CH2)m,其中1至4个H原子可被Hal、R3a和/或OR4a置换,和/或其中一个CH2基团可被O、S、SO或SO2置换;
X表示式(xa)、(xb)、(xc)、(xd)、(xe)、(xf)、(xg)、(xh)或(xi)的杂双环或杂三环,各自彼此独立地未取代或被以下单-、二-或三取代:Hal、NO2、CN、R5a、OR5a、CONR5aR5b、NR5aCOR5b、SO2R5a、SOR5a、SO2NR5aR5b、NR5aSO2R5b、NR5aR5b、(CH2)q-R6、COR5a和/或SO2R5a,且其中环CH2基团中的1、2或3个可被CR4aR4b、C=O、O、S、NR5a、SO和/或SO2置换;
((xa)–(xi)的任选的取代基未示出)
Y表示P1、P2或P3;
P1表示直链或支链的C1-C6-烷基或C3-C8-环烷基,各自彼此独立地未取代或被以下单-、二-或三-或四取代:Hal、CN、R3a、OR3a和/或(CH2)q-R6;
P2表示苯基或芳族单环5-、6-或7-元杂环,各自未取代或被以下单-、二-、三-、四-或五取代:Hal、CN、R3a、OH、OR3a、CONR4aR4b、NR3aCOR3b、SO2R3a、SOR3a、NR4aR4b、Ar2、Het2、(CH2)q-SR3a、(CH2)q-N(R4a)2和/或(CH2)q-R6,其中所述杂环体系包含1、2或3个N、O和/或S原子;
P3表示双环8-、9-或10-元烃或杂环,各自彼此独立地未取代或被以下单-、二-、三-、四-或五取代:Hal、CN、R3a、OH、OR3a、CONR4aR4b、NR3aCOR3b、SO2R3a、SOR3a、NR4aR4b、Ar2、Het2、(CH2)q-SR3a、(CH2)q-N(R4a)2和/或(CH2)q-R6,其中所述双环烃或杂环的至少一个环为芳族的,且其中所述杂环体系包含1、2或3个N、O和/或S原子;
Cy1、Cy2、Cy3、Cy4和Cy5各自彼此独立地表示Ar1或Het1;
R1、R2各自彼此独立地表示H或C1-C6-烷基,或R1和R2一起形成根据式(CE)的残基
R3a、R3b各自彼此独立地表示直链或支链的C1-C6-烷基或C3-C8环烷基,其中1至5个H原子可被Hal、CN、OH和/或OAlk置换;
R4a、R4b各自彼此独立地表示H或R3a;
或
R4a和R4b一起形成C3-C8亚烷基;
R5a、R5b各自彼此独立地表示H、R3a、Ar2或Het2;
R6表示OH或OR3a;
T1、T2、T3、T4、T5、T6、T7、T8和T9各自彼此独立地表示O、SO、C=O;
Alk表示直链或支链的C1-C6-烷基;
Ar1代表芳族6-元碳环;
Het1代表具有1至4个N、O和/或S原子的饱和、不饱和或芳族5-或6-元杂环;
Ar2表示苯基,其未取代或被以下单-或二取代:Hal、NO2、CN、R3a、OR3a、CONHR3a、NR3aCOR3b、SO2R3a、SOR3a、NH2、NHR3a、N(R3a)2和/或(CH2)q-R6;
Het2表示具有1至4个N、O和/或S原子的饱和、不饱和或芳族5-或6-元杂环,其未取代或被以下单-或二取代:Hal、NO2、CN、R3a、OH、OR3a、CONHR3a、NR3aCOR3b、SO2R3a、SOR3a、NH2、NHR3a、N(R3a)2、(CH2)q-R6和/或氧代(=O);
q表示1、2、3、4、5或6;
m表示0、1或2;
Hal表示F、Cl、Br或I;
及其前药、溶剂化物、互变异构体、低聚物、加合物和立体异构体以及前述中每一种的药学上可接受的盐,包括它们所有比率的混合物。
本发明的化合物是免疫蛋白酶体亚基LMP7的抑制剂。它们对LMP7相比Beta5(cP)显示出特别高的选择性,并且在溶解性、血浆-蛋白结合、CYP抑制、PK特性和口服生物利用度方面均具有良好的性能。
已知硼酸衍生物,例如式(I)的化合物,其中R1和R2表示H形式低聚物(BoronicAcids.Dennis G.Hall编辑,Copyright2005 WILEY-VCH Verlag,GmbH&Co.KGaA,Weinheim,ISBN 3-527-30991-8)。此类式(I)的化合物的低聚物(特别是但不限于二聚体或三聚体)包括在本发明内。已知的硼酸的环状三聚体例如具有以下结构:
还已知硼酸衍生物例如式(I)的化合物,其中R1和R2表示通过与脂族或芳族的醇、二醇、糖、糖醇、α-羟基酸或包含一个、两个或三个含N/含O官能团(例如-NH2、-CONH2或C=NH、-OH、-COOH)的亲核试剂的反应的H形式加合物,其中在存在三个官能团的情况下,这三个杂原子之一可能形成配位键(“Boronic Acids”Dennis G.Hall编辑,第2版,2011 WILEY-VCH Verlag,GmbH&Co.KGaA,Weinheim,ISBN 978-3-527-32598-6;WO2013128419;WO2009154737)。用预组织的二醇形成加合物特别快。本发明包括式(I)的硼酸化合物的这样的加合物(特别是酯或杂环衍生物)。
应当指出,本发明的化合物在与硼酸残基相邻的碳原子处具有立构中心;在下式(I)*中其用星号(*)表示:
因此,根据式(I)的化合物在该立构中心处表现出两种不同的构型,即(R)-构型和(S)-构型。因此,本发明的化合物可以对映纯形式或作为式(R)-(I)和(S)-(I)的这两种对映异构体的外消旋(1:1)混合物存在。
式(I)的化合物也可以混合物形式存在,其中对映异构体(R)-(I)或(S)-(I)之一相对于另一种过量存在,例如为60:40、70:30、80:20、90:10、95:5等。在本发明的特定的实施方案中,式(Ia)的化合物的式(R)-(I)的立体异构体和式(Ia)的化合物的式(S)-(I)的立体异构体以(R)-(I)与(S)-(I)的如下比率存在:至少90份(R)-(I):不大于10份(S)-(I)、优选至少95份(R)-(I):不大于5份(S)-(I)、更优选至少99份(R)-(I):不大于1份(S)-(I),甚至更优选至少99.5份(R)-(I):不大于0.5份(S)-(I)。在本发明的另一个特定的实施方案中,式(Ia)的化合物的式(S)-(I)的立体异构体和式(Ia)的化合物的式(R)-(I)的立体异构体以(S)-(I)与(R)-(I)的如下比率存在:至少90份(S)-(I):不大于10份(R)-(I),优选至少95份(S)-(I):不大于5份(R)-(I),更优选至少99份(S)-(I):不大于1份(R)-(I),甚至更优选至少99.5份(S)-(I):不大于0.5份(R)-(I)。
式(R)-(I)和(S)-(I)的富集或纯立体异构体可通过本领域已知的常规方法和下文所述的具体方法获得。获得它们的特定方法是使用手性柱材料的制备型柱色谱,例如HPLC或SFC。
本发明的特别优选的实施方案包括式(R)-(I)的化合物,其中与硼酸残基相邻的碳原子处的立构中心具有(R)-构型:
根据式(I)的化合物还可以具有位于不同于与硼酸残基相邻碳原子的碳原子处的另外的立构中心。所有这些立构中心均可以(R)-或(S)-构型出现。
特别地,本发明的化合物在取代基X的碳原子处具有另外的立构中心,其直接连接于式(I))所示的酰胺基CONH的碳原子并且在与桥原子相邻的碳原子处;这些立构中心例如在下式(xa*)中示出,其中它们用星号(*)表示:
(xa*):
((xa*)的任选的取代基未显示)。
(xa*)的可能的立体异构体如下所示:
因此,根据式(I)的化合物在这些立构中心处也表现出两种不同的构型,即(R)-构型和(S)-构型。本发明的化合物在这些立构中心的每一个处可以具有(R)-构型或(S)-构型,或者所述化合物以两种立体异构体的外消旋(1:1)混合物存在。式(I)的化合物也可以其中一种立体异构体比另一种过量的混合物存在,例如为60:40、70:30、80:20、90:10、95:5等。
在上下文中,在示出了具有立构中心的化学结构而没有指明具体的立体化学的情况下,该结构包括所有可能的立体异构体以及它们的混合物。例如,本发明包括立体异构体[(1R)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]-庚烷-2-基]-甲酰氨基}乙基]硼酸;[(1R)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1R,2S,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;[(1R)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,2S,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;[(1R)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1R,2R,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;[(1S)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,2S,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]-硼酸;[(1S)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1R,2R,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]-硼酸;[(1R)-2-[(3R)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,2S,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;[(1R)-2-[(3R)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1R,2R,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;[(1S)-2-[(3R)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,2S,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]-硼酸;[(1S)-2-[(3R)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1R,2R,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;[(1S)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]-庚烷-2-基]甲酰氨基}乙基]硼酸;[(1S)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1R,2S,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]-硼酸;[(1R)-2-[(3R)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;[(1R)-2-[(3R)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1R,2S,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;[(1S)-2-[(3R)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]-硼酸以及[(1S)-2-[(3R)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1R,2S,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]-硼酸。另一组包括在本发明中的示例性立体异构体通过下列的立体异构体表示:[(1R)-2-(1-苯并呋喃-3-基)-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;[(1S)-2-(1-苯并呋喃-3-基)-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;[(1R)-2-(1-苯并呋喃-3-基)-1-{[(1R,2S,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;[(1S)-2-(1-苯并呋喃-3-基)-1-{[(1R,2S,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;[(1R)-2-(1-苯并呋喃-3-基)-1-{[(1S,2S,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;[(1S)-2-(1-苯并呋喃-3-基)-1-{[(1S,2S,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;[(1R)-2-(1-苯并呋喃-3-基)-1-{[(1R,2R,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸和[(1S)-2-(1-苯并呋喃-3-基)-1-{[(1R,2R,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸。给定化合物的不同立体异构体可用于通过NMR、HPLC、SFC或任何其他合适的分析方法对特定样品进行分析表征(例如,用于品质控制目的)。因此,本发明的另一方面涉及根据式(I)的化合物的立体异构体在分析表征方法中的用途。
通常,出现超过一次的本文描述的化合物的所有残基可以相同或不同,即彼此独立。除非另有明确说明,否则上下文中的残基和参数具有对于式(I)指示的含义。因此,本发明特别地涉及式(I)的化合物,其中至少一个所述残基具有以下所指出的优选含义之一。此外,下文所述的所有具体实施方案应包括其衍生物、前药、溶剂化物、互变异构体或立体异构体,以及前述中每一种的生理学上可接受的盐,包括它们所有比率的混合物。
式(xa)、(xb)、(xc)、(xd)、(xe)、(xf)、(xg)、(xh)和(xi)的杂双环或杂三环可以未取代或被以下单-、二-或三取代:Hal、NO2、CN、R5a、OR5a、CONR5aR5b、NR5aCOR5b、SO2R5a、SOR5a、SO2NR5aR5b、NR5aSO2R5b、NR5aR5b、(CH2)q-R6、COR5a和/或SO2R5a。在式(xe)、(xf)、(xg)、(xh)和(xi)的杂双环或杂三环被取代的情况下,所述一个或多个取代基可以连接于桥环之一或稠合环Cy1、Cy2、Cy3、Cy4和Cy5之一。这包括例如这样的化合物,其中一个取代基连接于桥环且一个取代基连接于稠合环Cy1、Cy2、Cy3、Cy4或Cy5。在稠合环Cy1、Cy2、Cy3、Cy4和Cy5之一包含一个或多个CH2基团的情况下,应理解这些基团为式(xe)、(xf)、(xg)、(xh)和(xi)的杂双环或杂三环的“环CH2基团”的一部分,其可被CR4aR4b、C=O、O、S、NR5a、SO或SO2置换。因此,如果式(xe)、(xf)、(xg)、(xh)和(xi)的杂双环或杂三环的环CH2基团中的1、2或3个被CR4aR4b、C=O、O、S、NR5a、SO或SO2置换,则这些环CH2可为桥环和/或稠合环Cy1、Cy2、Cy3、Cy4和Cy5的一部分。这包括例如这样的化合物,其中桥环的一个CH2基团被置换且稠合环Cy1、Cy2、Cy3、Cy4和Cy5的一个CH2基团被置换。
在Y为P3的情况下,其中双环烃或杂环的两个环中的至少一个是芳族环,另一个环可以是饱和、不饱和或芳族环。在这样的实施方案的具体实例中,P3和相邻的基团LY通过P3的芳族环彼此连接。在其他实施方案中,P3和相邻的基团LY通过P3的饱和或不饱和环彼此连接。在P3为双环杂环的情况下,其优选包含1个或2个选自N、O和/或S的杂原子。在P2为芳族单环杂环的情况下,其优选包含1个或2个选自N、O和/或S的杂原子。
在Y为P2且P2为苯基的情况下,其优选未取代或被以下单-、二-或三取代:Hal、CN、R3a、OH、OR3a、CONR4aR4b、NR3aCOR3b、SO2R3a、SOR3a、NR4aR4b、Ar2、Het2、(CH2)q-SR3a、(CH2)q-N(R4a)2和/或(CH2)q-R6。特别优选的是其中P2表示二-或三取代的苯基的实施方案。在那些其中P2表示单取代的苯基的实施方案中,所述取代基优选在3-或4-位。在那些其中P2表示二取代的苯基的实施方案中,所述两个取代基优选在2,3-、2,4-、2,5-或3,4-位(最优选在2,4-或3,4-位)。并且在其中P2表示三取代的苯基的那些实施方案中,所述三个取代基优选在芳族环的2,3,4-位。
在P2表示单环杂环的情况下,该杂环可以是饱和、不饱和或芳族的。
在其中m表示0的实施方案中,LY不存在。
在本发明的上下文中,“C1-C6烷基”是指具有1、2、3、4、5或6个碳原子并且为直链或支链的烷基部分。术语“C3-C6环烷基”是指具有3、4、5或6个碳原子的饱和环状烃基。
术语“未取代的”是指相应的原子团(radical)、基团(group)或部分(moiety)没有H以外的取代基;应用于一个或多个从结构明确或暗示的氢的术语“取代的”表示相应的原子团、基团或部分具有一个或多个H以外的取代基。当原子团具有多个取代基即(至少两个)并且指定了各种取代基的选择时,取代基彼此独立地选择并且不必相同。
术语“碳环”是指环体系,其中所有环成员均为碳原子。
术语“杂环”是指环体系,其中一些环成员是杂原子例如N、O或S。
基团“NRR’”是氨基,其中R和R'例如各自彼此独立地是H或直链或支链的C1-C6-烷基残基(特别是甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基、戊基、己基)。
例如在SOR5a中包括的基团“SO”是这样的基团,其中S和O通过双键(S=O)连接。
例如在COR4a中包括的基团“CO”是这样的基团,其中C和O通过双键(C=O)连接。
术语“亚烷基”是指二价烷基。“亚烷基”是(多)亚甲基(–(CH2)x–)。
氧代基团(=O)为取代基,其可能出现在例如饱和环状残基中,或者在可能的程度内,出现在(部分)不饱和环中,例如特别地在Het1和Het2中。在优选的实施方案中,杂环Het1和Het2任选地带有一个或两个氧代基团。
如本文所用,术语“不饱和的”是指一个部分具有一个或多个不饱和单元。如本文中关于任何环、环状体系、环状部分等所使用的术语“部分不饱和的”是指包括至少一个双键或三键的环状部分。术语“部分不饱和的”旨在涵盖具有多于一个双键或三键的环状部分。
在本发明的上下文中,符号如“O-CH3”和“OCH3”,或“CH2CH2”和“-CH2-CH2-“,具有相同的含义并且可互换使用。
如本文所用,在结构式中箭头或具有垂直虚线的键用来表示与相邻基团的连接点。对于例如,在(xa)中的箭头显示与相邻C=O基团的连接点。
本发明特别重要的实施方案包括式(I)的化合物,其中
R1、R2各自彼此独立地表示H或C1-C4烷基,或者R1和R2一起形成根据式(CE)的残基;和
LY表示CH2或CH2CH2,其中1至2个H原子可被Hal、R3a、OR4a置换(优选1至2个H原子可被F、Cl、CH3、CH2CF3、CH2CHF2、CH2F、CHF2、CF3、OCH3和/或OCF3置换,且最优选LY表示CH2或CH2CH2)。
具体实施方案包括式(I)的化合物,其中T1、T2、T3、T4、T5、T6、T7、T8和T9表示O。
其他具体实施方案包括根据式(I)的化合物,其中
P1表示直链或支链的C1-C6-烷基或C3-C8-环烷基,各自彼此独立地未取代、被以下单-、二-或三取代:Hal、CN、R3a、OR3a和/或(CH2)q-R6;
P2表示苯基、吡啶基、吡咯基、呋喃基、噻吩基、嘧啶基、吡嗪基(pyranzinyl)或哒嗪基,各自彼此独立地未取代、被以下单-、二-或三取代:Hal、CN、R3a、OH、OR3a、CONR4aR4b、NR3aCOR3b、SO2R3a、SOR3a、NR4aR4b、Ar2、Het2、(CH2)q-SR3a、(CH2)q-N(R4a)2和/或(CH2)q-R6;且
P3表示式(ya)、(yb)、(yc)、(yd)、(ye)、(yf)、(yg)、(yh)、(yi)、(yj)、(yk)、(yl)、(ym)、(yn)、(yp)或(yp)的双环残基,各自彼此独立地未取代、被以下单-、二-或三取代:Hal、CN、R3a、OH、OR3a、CONR4aR4b、NR3aCOR3b、SO2R3a、SOR3a、NR4aR4b、Ar2、Het2、(CH2)q-SR3a、(CH2)q-N(R4a)2和/或(CH2)q-R6;
((ya)–(yp)的任选的取代基未示出)
其中
Ea表示O、S、N(Alk)或CH=CH;
Eb表示O、S、N(Alk)、CH2、CH2CH2、OCH2、SCH2或N(Alk)CH2。
在本发明的其他的实施方案中,式(I)的化合物的残基定义如下:
R3a、R3b各自彼此独立地表示直链或支链的C1-C4-烷基或C3-C6环烷基,其中1至3个H原子可被F、Cl和/或置换且其中1或2个H原子可被CN、OH、OCH3和/或OC2H5置换。
本发明的其他实施方案包括根据式(I)的化合物,其中Y表示P2或P3。
其他具体实施方案包括根据式(I)的化合物,其中
X是式(xa1)、(xb1)、(xc1)、(xd1)、(xe1)、(xf1)、(xg1)、(xh1)或(xi1)的式的杂双环或杂三环,各自彼此独立地未取代或被以下单-、二-或三取代:Hal、NO2、CN、R5a、OR5a、CONR5aR5b、NR5aCOR5b、SO2R5a、SOR5a、SO2NR5aR5b、NR5aSO2R5b、NR5aR5b、(CH2)q-R6、COR5a和/或SO2R5a,且其中环CH2基团中的1个可被CR4aR4b、C=O、O、S、NR5a、SO和/或SO2置换:
((xa1)–(xi1)的任选的取代基未示出)
其他具体实施方案包括根据式(I)的化合物,其中
X是式(xa)、(xb)、(xc)、(xd)、(xe)、(xf)、(xg)、(xh)或(xi)的杂双环或杂三环,各自彼此独立地未取代或被以下单-或二取代:F、Cl、CH3、C2H5、CF3、OCH3、OC2H5、COCF3、SCH3、SC2H5、CH2OCH3、N(CH3)2、CH2N(CH3)2和/或N(C2H5)2,且其中环CH2基团中的1或2个可被C(CH3)2、C(C2H5)2、C=O、O、S、NH、NR3a、SO和/或SO2置换(其中R3a优选为甲基、乙基、丙基、异丙基或环丙基)。
重要的实施方案包括式(I)的化合物,其中X是式(xa1)、(xb1)、(xc1)、(xd1)、(xe1)、(xf1)、(xg1)、(xh1)或(xi1)的杂双环或杂三环,各自彼此独立地未取代或被以下单-、二取代:F、Cl、CH3、C2H5、CF3、OCH3、OC2H5、COCF3、SCH3、SC2H5、CH2OCH3、N(CH3)2、CH2N(CH3)2和/或N(C2H5)。
非常具体的实施方案包括式(I)的化合物,其中X是选自以下基团的杂双环或杂三环:
其他实施方案包括式(I)的化合物,其中
P3表示未取代或单-或二取代的1-或2-萘基,其中任选的取代基选自Hal、CN、R3a、OH、OR3a、CONR4aR4b、NR3aCOR3b、SO2R3a、SOR3a、NR4aR4b、Ar2、Het2、(CH2)q-SR3a、(CH2)q-N(R4a)2和/或(CH2)q-R6,
或
(P3是)根据式(Ra)或(Rb)的残基:
其中
Ga、Gb各自彼此独立地表示H、Hal、CN、R3a、OR3a、CONHR3a、CONR3bR3a、CONH2、NR3aCOR3b、SO2R3a、SOR3a、NHR3a、N(R3a)2、(CH2)q-SR3a、(CH2)q-N(R4a)2和/或(CH2)q-R6;
Ka、Kb各自彼此独立地表示H、Hal、CN、R3a、OR3a、CONHR3a、CONR3bR3a、CONH2、NR3aCOR3b、SO2R3a、SOR3a、NHR3a、N(R3a)2、(CH2)q-SR3a、(CH2)q-N(R4a)2和/或(CH2)q-R6;
Ea表示O、S、N(Alk)或CH=CH;
Eb表示O、S、N(Alk)、CH2、CH2-CH2、O-CH2、S-CH2或N(Alk)CH2。
根据式(Rb)的残基在邻近LY的碳原子处带有立构中心;其已在下式(Rb)*中用星号(*)表示:
因此,根据式(Rb)的残基在该立构中心处显示出两种不同的构型,即(R)-构型和(S)-构型。因此,本发明的化合物可以对映纯形式或作为式(R)-(Rb)和(S)-(Rb)的两种对映异构体的外消旋(1:1)混合物存在。
包括根据式(Rb)的残基的式(I)的化合物也可以混合物形式存在,其中对映异构体(R)-(Rb)或(S)-(Rb)之一相对于另一种过量存在,例如为60:40、70:30、80:20、90:10、95:5等。在本发明的特定的实施方案中,式(I)的化合物的式(R)-(Rb)的立体异构体和式(I)的化合物的式(S)-(Rb)的立体异构体以(R)-(Rb)与(S)-(Rb)的如下比率存在:至少90份(R)-(Rb):不大于10份(S)-(Rb)、优选至少95份(R)-(Rb):不大于5份(S)-(Rb)、更优选至少99份(R)-(Rb):不大于1份(S)-(Rb),甚至更优选至少99.5份(R)-(Rb):不大于0.5份(S)-(Rb)。在本发明的另一个特定的实施方案中,式(Rb)的化合物的式(S)-(Rb)的立体异构体和式(I)的化合物的式(R)-(Rb)的立体异构体以(S)-(Rb)与(R)-(Rb)的如下比率存在:至少90份(S)-(Rb):不大于10份(R)-(Rb),优选至少95份(S)-(Rb):不大于5份(R)-(Rb),更优选至少99份(S)-(Rb):不大于1份(R)-(Rb),甚至更优选至少99.5份(S)-(Rb):不大于0.5份(R)-(Rb)。
本发明的特别优选的实施方案包括式(I)的化合物,其中P3是式(S)-(Rb)的残基(其在与LY连接的碳处具有(S)-构型)。
具体的实施方案包括根据式(I)的化合物,其中:
P2表示未取代或单-或二取代的2-或3-噻吩基或未取代或3-、4-、2,3-、2,4-、2,5-、3,4-或2,3,4-取代的苯基,其中在每种情况下任选的取代基独立地选自Hal、CN、R3a、OH、OR3a、CONR4aR4b、NR3aCOR3b、SO2R3a、SOR3a、NR4aR4b、Ar2、Het2、(CH2)q-SR3a、(CH2)q-N(R4a)2和(CH2)q-R6;
P3表示未取代或单-或二取代的1-或2-萘基,其中任选的取代基选自Hal、CN、R3a、OH、OR3a、CONR4aR4b、NR3aCOR3b、SO2R3a、SOR3a、NR4aR4b、Ar2、Het2、(CH2)q-SR3a、(CH2)q-N(R4a)2和/或(CH2)q-R6,
或
(P3是)根据式(Ra)或(Rb)的残基(优选P3是根据式(Ra)或(S)-(Rb)的残基);
Ga、Gb各自彼此独立地表示H、Hal、CN、R3a、OR3a、CONHR3a、CONR3bR3a、CONH2、NR3aCOR3b、SO2R3a、SOR3a、NHR3a、N(R3a)2、(CH2)q-SR3a、(CH2)q-N(R4a)2和/或(CH2)q-R6;
Ka、Kb各自彼此独立地表示H、Hal、CN、R3a、OR3a、CONHR3a、CONR3bR3a、CONH2、NR3aCOR3b、SO2R3a、SOR3a、NHR3a、N(R3a)2、(CH2)q-SR3a、(CH2)q-N(R4a)2和/或(CH2)q-R6;
Ea表示O、S、N(Alk)或CH=CH;
Eb表示O、S、N(Alk)、CH2、CH2-CH2、OCH2、SCH2或N(Alk)CH2。
其他具体实施方案包括式(I)的化合物、其中:
P2表示未取代或单-或二取代的2-或3-噻吩基或未取代或3-、4-、2,3-、2,4-、2,5-、3,4-或2,3,4-取代的苯基,其中在每种情况下任选的取代基独立地选自Hal、CN、R7a、OR7a、CONHR7a、CONR7bR7a、CONH2、NR7aCOR7b、SO2R7a、SOR7a、NHR7a、N(R7a)2、(CH2)p-SR7a、(CH2)p-N(R7a)2和/或(CH2)p-R8;
P3是根据式(Ra)或(Rb)的残基(优选P3是根据式(Ra)或(S)-(Rb)的残基);
Ga、Gb各自彼此独立地表示H、Hal、CN、R7a、OR7a、CONHR7a、CONR7bR7a、CONH2、NR7aCOR7b、SO2R7a、SOR7a、NHR7a、N(R7a)2、(CH2)p-SR7a、(CH2)p-N(R7a)2和/或(CH2)p-R8;
Ka、Kb各自彼此独立地表示H、Hal、CN、R7a、OR7a、CONHR7a、CONR7bR7a、CONH2、NR7aCOR7b、SO2R7a、SOR7a、NHR7a、N(R7a)2、(CH2)p-SR7a、(CH2)p-N(R7a)2和/或(CH2)p-R8;
R7a、R7b各自彼此独立地表示直链或支链的C1-C3-烷基,其中1至3个H原子可被Hal置换;和
R8表示OH或OR7a;和
p表示1或2。
甚至更具体的实施方案包括根据式(I)的化合物,其中:
P2表示未取代或单-或二取代的2-或3-噻吩基或未取代或3-、4-、2,3-、2,4-、2,5-、3,4-或2,3,4-取代的苯基,其中任选的取代基选自F、Cl、CN、CH3、C2H5、CF3、OCH3、OC2H5、COCF3、SCH3、SC2H5、CH2OCH3、N(CH3)2、CH2N(CH3)2或N(C2H5)2;
P3是根据式(Ra)或(Rb)的残基(优选P3是根据式(Ra)或(S)-(Rb)的残基);
Ga、Gb各自彼此独立地表示H、F、Cl、CN、CH3、C2H5、CF3、OCH3、OC2H5、COCF3、SCH3、SC2H5、CH2OCH3、N(CH3)2、CH2N(CH3)2或N(C2H5)2;
Ka、Kb各自彼此独立地表示H、F、Cl、CN、CH3、C2H5、CF3、OCH3、OC2H5、COCF3、SCH3、SC2H5、CH2OCH3、N(CH3)2、CH2N(CH3)2或N(C2H5)2。
特别的实施方案包括式(I)的化合物,其中P3是根据式(Ra)或(Rb)的残基,且其中Ea、Eb各自彼此独立地表示O或S。特别优选的实施方案包括式(I)的化合物,其中P3是根据式(Fa)或(Fb)的残基:
在这些实施方案中,二氢呋喃基残基(Fb)的3位碳原子处的立构中心优选表现为(S)-构型,即,该残基是(任选取代的)(3S)-2,3-二氢苯并呋喃-3-基残基(S)-(Fb)*:
(任选的取代基未示出)。
因此,本发明的其他非常具体的实施方案包括根据式(I)的化合物,其中
P2表示未取代或单-或二取代的2-或3-噻吩基或未取代或3-、4-、2,3-、2,4-、2,5-、3,4-或2,3,4-取代的苯基,其中任选的取代基选自Hal、CN、R3a、OH、OR3a、CONR4aR4b、NR3aCOR3b、SO2R3a、SOR3a、NR4aR4b、Ar2、Het2、(CH2)q-SR3a、(CH2)q-N(R4a)2和/或(CH2)q-R6;
P3表示根据式(Fa)或(S)-(Fb)的残基;
Ga、Gb各自彼此独立地表示H、Hal、CN、R3a、OH、OR3a、CONR4aR4b、NR3aCOR3b、SO2R3a、SOR3a、NR4aR4b、Ar2、Het2、(CH2)q-SR3a、(CH2)q-N(R4a)2和/或(CH2)q-R6;且
Ka、Kb各自彼此独立地表示H、Hal、CN、R3a、OH、OR3a、CONR4aR4b、NR3aCOR3b、SO2R3a、SOR3a、NR4aR4b、Ar2、Het2、(CH2)q-SR3a、(CH2)q-N(R4a)2和/或(CH2)q-R6。
本发明的其他非常具体的实施方案包括根据式(I)的化合物,其中:
P2表示未取代或单-或二取代的2-或3-噻吩基或未取代或3-、4-、2,3-、2,4-、2,5-、3,4-或2,3,4-取代的苯基,其中任选的取代基选自H、Hal、CN、R7a、OR7a、CONHR7a、CONR7bR7a、CONH2、NR7aCOR7b、SO2R7a、SOR7a、NHR7a、N(R7a)2、(CH2)p-SR7a、(CH2)p-N(R7a)2和/或(CH2)p-R8;
P3表示根据式(Fa)或(S)-(Fb)的残基;
Ga、Gb各自彼此独立地表示H、Hal、CN、R7a、OR7a、CONHR7a、CONR7bR7a、CONH2、NR7aCOR7b、SO2R7a、SOR7a、NHR7a、N(R7a)2、(CH2)p-SR7a、(CH2)p-N(R7a)2和/或(CH2)p-R8;
Ka、Kb各自彼此独立地表示H、Hal、CN、R7a、OR7a、CONHR7a、CONR7bR7a、CONH2、NR7aCOR7b、SO2R7a、SOR7a、NHR7a、N(R7a)2、(CH2)p-SR7a、(CH2)p-N(R7a)2和/或(CH2)p-R8;
R7a、R7b各自彼此独立地表示直链或支链的C1-C3-烷基,其中1至3个H原子可被Hal置换;且
R8表示OH或OR7a;且
p表示1或2。
本发明的其他非常具体的实施方案包括根据式(I)的化合物,其中:
P2表示未取代或单-或二取代的2-或3-噻吩基或未取代或3-、4-、2,3-、2,4-、2,5-、3,4-或2,3,4-取代的苯基,其中任选的取代基选自F、Cl、CN、CH3、C2H5、CF3、OCH3、OC2H5、COCF3、SCH3、SC2H5、CH2OCH3、N(CH3)2、CH2N(CH3)2或N(C2H5)2;
P3表示根据式(Fa)或(S)-(Fb)的残基,
Ga、Gb各自彼此独立地表示H、F、Cl、CN、CH3、C2H5、CF3、OCH3、OC2H5、COCF3、SCH3、SC2H5、CH2OCH3、N(CH3)2、CH2N(CH3)2或N(C2H5)2;且
Ka、Kb各自彼此独立地表示H、F、Cl、CN、CH3、C2H5、CF3、OCH3、OC2H5、COCF3、SCH3、SC2H5、CH2OCH3、N(CH3)2、CH2N(CH3)2或N(C2H5)2。
本发明的特定实施方案包括根据式(I)的化合物,其中Y表示P2或P3,优选Y表示P3。
本发明的具体实施方案包括根据式(I)的化合物,其中
LY表示CH2或CH2CH2,其中1或2个H原子可被Hal、R7a、OH和/或OR7a置换,和/或其中一个CH2基团可被O或S置换;
X是式(xa)、(xb)、(xc)、(xd)、(xe)、(xf)、(xg)、(xh)或(xi)的杂双环或杂三环,各自彼此独立地未取代或被以下单-或二取代:F、Cl、CH3、C2H5、CF3、OCH3、OC2H5、COCF3、SCH3、SC2H5、CH2OCH3、N(CH3)2、CH2N(CH3)2和/或N(C2H5)2,且其中环CH2基团中的一个可被C(CH3)2、C(C2H5)2、C=O、O、S、NCH3、SO或SO2置换;
Y表示P2或P3(优选P3);
P2表示未取代或单-或二取代的2-或3-噻吩基或未取代或3-、4-、2,3-、2,4-、2,5-、3,4-或2,3,4-取代的苯基,其中任选的取代基选自H、Hal、CN、R7a、OR7a、CONHR7a、CONR7bR7a、CONH2、NR7aCOR7b、SO2R7a、SOR7a、NHR7a、N(R7a)2、(CH2)p-SR7a、(CH2)p-N(R7a)2和/或(CH2)p-R8;
P3表示根据式(Fa)或(S)-(Fb)的残基;
Ga、Gb各自彼此独立地表示H、Hal、CN、R7a、OR7a、CONHR7a、CONR7bR7a、CONH2、NR7aCOR7b、SO2R7a、SOR7a、NHR7a、N(R7a)2、(CH2)p-SR7a、(CH2)p-N(R7a)2和/或(CH2)p-R8;
Ka、Kb各自彼此独立地表示H、Hal、CN、R7a、OR7a、CONHR7a、CONR7bR7a、CONH2、NR7aCOR7b、SO2R7a、SOR7a、NHR7a、N(R7a)2、(CH2)p-SR7a、(CH2)p-N(R7a)2和/或(CH2)p-R8;
R7a、R7b各自彼此独立地表示直链或支链的C1-C3-烷基,其中1至3个H原子可被Hal置换;且
R8表示OH或OR7a;且
p表示1或2。
Cy1、Cy2、Cy3、Cy4、Cy5各自彼此独立地表示Ar1或Het1;
R1、R2各自彼此独立地表示H或C1-C6-烷基,或R1和R2一起形成根据式(CE)的残基;
T1、T2、T3、T4、T5、T6、T7、T8和T9各自表示O;
Hal表示F、Cl或Br。
本发明的其他非常具体的实施方案包括根据式(R)-(I)-(S)-(Fb)或(R)-(I)-(Fa)的化合物:
其中
Ga、Gb各自彼此独立地表示H、Hal、CN、R7a、OR7a、CONHR7a、CONR7bR7a、CONH2、NR7aCOR7b、SO2R7a、SOR7a、NHR7a、N(R7a)2、(CH2)p-SR7a、(CH2)p-N(R7a)2和/或(CH2)p-R8;
Ka、Kb各自彼此独立地表示H、Hal、CN、R7a、OR7a、CONHR7a、CONR7bR7a、CONH2、NR7aCOR7b、SO2R7a、SOR7a、NHR7a、N(R7a)2、(CH2)p-SR7a、(CH2)p-N(R7a)2和/或(CH2)p-R8;
X是式((xa1)、(xb1)、(xc1)、(xd1)、(xe1)、(xf1)、(xg1)、(xh1)或(xi1)的杂双环或杂三环,各自彼此独立地未取代或被以下单-或二取代:F、Cl、CH3、C2H5、CF3、OCH3、OC2H5、COCF3、SCH3、SC2H5、CH2OCH3、N(CH3)2、CH2N(CH3)2和/或N(C2H5)2,其中环CH2基团中的一个可被C(CH3)2、C(C2H5)2、C=O、O、S、NCH3、SO或SO2置换;
R1、R2表示H或C1-C4-烷基,或R1和R2一起形成根据式(CE)的残基;
R7a、R7b各自彼此独立地表示直链或支链的C1-C3-烷基,其中1至3个H原子可被Hal置换;
R8表示OH或OR7a;且
p表示1或2。
通常,如上所述的根据式(I)的化合物中包括的残基可以具有以下含义:
LY优选表示-CH2-或-CH2-CH2-,其中1至4个H原子可被Hal置换和/或1个H原子可被Hal、R3a和/或OR4a置换,和/或其中1或2个不相邻的CH2基团可被O、SO和/或SO2置换。最优选地,LY表示-CH2-或-CH2-CH2-,其中1-4个H原子可被F或Cl置换和/或1或2个H原子可被OH、甲基、乙基、异丙基、CF3、CF2CF3、OCH3、OCH2CH3、OCH2CH2OH和/或CH2OCH3置换和/或其中LY中的1个CH2基团可被O置换。
R1、R2优选各自彼此独立地表示H或甲基、乙基、正丙基或异丙基,或R1和R2一起形成如上所述的根据式(CE)的残基。最优选地,R1、R2表示H、甲基或乙基,且特别优选R1、R2表示H。
在其中R3a或R3b代表直链或支链的C1-C6烷基的实施方案中,它们优选各自彼此独立地表示直链或支链的甲基、乙基、正丙基或异丙基,其中1至5个H原子可被F、Cl、CN、OH和OAlk置换,其中Alk优选为甲基或乙基。最优选地,R3a和R3b各自彼此独立地表示甲基、乙基、正丙基或异丙基,其中1、2或3个H原子被F、Cl、OH、OCH3、OC2H5或OCH(CH3)2置换。
在其中R3a或R3b彼此独立地代表环状烷基(环烷基)的实施方案中,它们优选彼此独立地表示环丙基、环丁基、环戊基或环己基,各自未取代或被以下单-、二-或三取代:Hal(优选F或Cl)、甲基、乙基、正丙基、OH、CN、OCH3或OC2H5。
R4a和R4b优选各自彼此独立地表示,优选为H、甲基、还有乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基或戊基,其中1、2或3个H原子被F、Cl、OH、OCH3、OC2H5或OCH(CH3)2置换,或R4a和R4b一起形成C3-C6亚烷基。
Y可以表示苯基,1-或2-萘基,4-或5-茚满基,1-、2-、3-、4-、5-、6-或7-吲哚基,1-、2-、4-、5-或6-薁基,1-或2-四氢化萘5-或6-基,2-或3-呋喃基,2-、3-、4-、5-、6-或7-苯并呋喃基,2,3-二氢苯并呋喃-2-或3-基,2-或3-噻吩基,2-或3-苯并噻吩基,2-、3-、4-、5-、6-或7-苯并噻吩基,亚甲二氧基苯基,苯并二氧杂环己烷-6-或7-基或3,4-二氢-1,5-苯并二氧杂环庚烯-6-或-7-基,各自彼此独立地未取代、被以下单-、二取代或三取代:Hal(优选F或Cl)、CN、R3a、OH、OR3a、CONR4aR4b、NR3aCOR3b、SO2R3a、SOR3a、NR4aR4b、Ar2、Het2、(CH2)q-SR3a、(CH2)q-N(R4a)2和/或(CH2)q-R6。特别地,Y可以表示苯基,1-或2-萘基,2-、3-、4-、5-、6-或7-苯并呋喃基,2,3-二氢苯并呋喃-2-或3-基,2-或3-噻吩基,2-或3-苯并噻吩基或苯并二氧杂环己烷-6-或7-基,各自彼此独立地未取代、被以下单-、二取代或三取代:F、Cl、CN、CH3、C2H5、CF3、OCH3、OC2H5、COCF3、SCH3、SC2H5、CH2OCH3、N(CH3)2、CH2N(CH3)2或N(C2H5)2。在Y表示二取代的苯基的情况下,取代基优选在2,4-、2,5-或3,4-位,最优选在2,4-或3,4-位。在Y表示三取代的苯基的情况下,取代基优选在2,3,4-位。
特别地,Y可以表示邻、间-或对-甲苯基,邻、间-或对-乙基苯基,邻、间-或对-丙基苯基,邻、间-或对-异丙基苯基,邻、间-或对-叔丁基苯基,邻、间-或对-乙酰氨基苯基,邻、间-或对-甲氧基苯基,邻、间-或对-乙氧基苯基,邻、间-或对-氟苯基,邻、间-或对-溴苯基,邻、间-或对-氯苯基,邻、间-或对-三氟甲基-苯基,邻、间-或对-三氯甲基-苯基,邻、间-或对-(甲基磺酰基)苯基,邻、间-或对-苯氧基苯基,邻、间-或对-甲氧基甲基-苯基;进一步优选2,4-、2,5-、2,6-或3,4-二甲基苯基,2,4-、2,5-或3,4-二氟苯基,2,4-、2,5-或3,4-二氯苯基,2,4-、2,5-或3,4-二溴苯基,2,5-或3,4-二甲氧基苯基,2,3,4-、2,3,5-、2,3,6-、2,4,6-或3,4,5-三氯苯基,2,3,4-、2,3,5-、2,3,6-、2,4,6-或3,4,5-三氟苯基,2,3,4-、2,3,5-、2,3,6-、2,4,6-或3,4,5-三甲基苯基,2,3,4-、2,3,5-、2,3,6-、2,4,6-或3,4,5-三氟甲基-苯基,2,3,4-、2,3,5-、2,3,6-、2,4,6-或3,4,5-三氯甲基-苯基,2,3,4-、2,3,5-、2,3,6-、2,4,6-或3,4,5-三甲氧基甲基-苯基,2,4,6-三甲氧基苯基,对-碘苯基,2-氟-3-氯苯基,2-氟-3-溴苯基,2,3-二氟-4-溴苯基,3-溴-3-甲氧基苯基,2-氯-3-甲氧基苯基,2-氟-3-甲氧基苯基,2-氯-3-乙酰氨基苯基,2-氟-3-甲氧基苯基,2-氯-3-乙酰氨基苯基,2,3-二甲基-4-氯苯基,2,3-二甲基-4-氟苯基。
Y也可以表示1-或2-萘基,4-或5-茚满基,1-、2-、4-、5-或6-薁基,1-或2-四氢化萘5-或6-基,2-或3-呋喃基,2-、3-、4-、5-、6-或7-苯并呋喃基,2-、3-、4-、5-、6-或7-苯并噻吩基,亚甲基二氧基苯基,苯并二氧杂环己烷-6-或7-基或3,4-二氢-1,5-苯并二氧杂环庚烯-6-或-7-基。Y的特别优选的取代基选自Cl、CN、CH3、C2H5、CF3、OCH3、OC2H5、COCF3、SCH3、SC2H5、CH2OCH3、N(CH3)2、CH2N(CH3)2或N(C2H5)2。
Ar2优选表示苯基,其未取代或被以下单-或二取代:Hal、CN、R3a、OR3a、CONHR3a、NH2、NHR3a和/或N(R3a)2。因此Ar2优选表示例如苯基,邻、间-或对-甲苯基,邻、间-或对-乙基苯基,邻、间-或对-丙基苯基,邻、间-或对-异丙基苯基,邻、间-或对-叔丁基苯基,邻、间-或对-羟基苯基,邻、间-或对-硝基苯基,邻、间-或对-氨基苯基,邻、间-或对-(N-甲基氨基)苯基,邻、间-或对-(N-甲基氨基羰基)苯基,邻、间-或对-乙酰氨基苯基,邻、间-或对-甲氧基苯基,邻、间-或对-乙氧基苯基,邻、间-或对-(N,N-二甲基氨基)苯基,邻、间-或对-(N-乙基氨基)苯基,邻、间-或对-(N,N-二乙基氨基)苯基,邻、间-或对-氟苯基,邻、间-或对-溴苯基,邻、间-或对-氯苯基,邻、间-或对-氰基苯基。
Het2优选表示具有1至4个N、O和/或S原子的饱和、不饱和或芳族5-或6-元杂环,其未取代或被以下单-或二取代:Hal、CN、R3a、OR3a、CONHR3a、NH2、NHR3a和/或N(R3a)2。因此,Het2可以例如表示2-或3-呋喃基,2-或3-噻吩基,1-、2-或3-吡咯基,1-、2-、4-或5-咪唑基,1-、3-、4-或5-吡唑基,2-、4-或5-噁唑基,3-、4-或5-异噁唑基,2-、4-或5-噻唑基,3-、4-或5-异噻唑基,2-、3-或4-吡啶基,2-、4-、5-或6-嘧啶基,咪唑基,吗啉基或哌嗪基。
Alk优选表示甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基、戊基或己基,最优选为甲基、乙基、丙基或异丙基,最优选为甲基、乙基、正丙基或异丙基。
Hal优选表示F、Cl或Br,最优选地为F或Cl。
m优选表示0、1或2,更优选为1或2,最优选为1。
q优选表示0、1、2、3或4,甚至更优选为0、1或2。
本发明的特定实施方案包括选自以下的化合物:
[(1R)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1R,2S,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}-2-(噻吩-3-基)乙基]硼酸;
[(1R)-2-(1-苯并呋喃-3-基)-1-{[(1R,8S)-11-氧杂三环[6.2.1.02,7]十一碳-2(7),3,5-三烯-1-基]甲酰氨基}乙基]硼酸;
[(1S)-2-(1-苯并呋喃-3-基)-1-{[(1R,8S)-11-氧杂三环[6.2.1.02,7]十一碳-2(7),3,5-三烯-1-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(1-苯并呋喃-3-基)-1-{[(1S,8R)-11-氧杂三环[6.2.1.02,7]十一碳-2(7),3,5-三烯-1-基]甲酰氨基}乙基]硼酸;
[(1S)-2-(1-苯并呋喃-3-基)-1-{[(1S,8R)-11-氧杂三环[6.2.1.02,7]十一碳-2(7),3,5-三烯-1-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(1-苯并呋喃-3-基)-1-{[(1R,2S,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(1-苯并呋喃-3-基)-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(1-苯并呋喃-3-基)-1-{[(1R,2R,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1S)-2-(1-苯并呋喃-3-基)-1-{[(1R,2R,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(7-氯-1-苯并呋喃-3-基)-1-{[(1R,2S,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(7-氯-1-苯并呋喃-3-基)-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-[(3R)-7-甲基-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-[(3S)-7-甲基-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1R,8S)-11-氧杂三环[6.2.1.02,7]十一碳-2(7),3,5-三烯-1-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(1-苯并呋喃-3-基)-1-{[(1S,6S,7R)-3-环丙基-4-氧代-10-氧杂-3-氮杂三环[5.2.1.01,5]癸-8-烯-6-基]甲酰氨基}乙基]硼酸;
[(1R)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,8R)-11-氧杂三环[6.2.1.02,7]十一碳-2(7),3,5-三烯-1-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(7-甲基-1-苯并呋喃-3-基)-1-{[(1R,8S)-11-氧杂三环[6.2.1.02,7]十一碳-2,4,6-三烯-1-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(7-甲基-1-苯并呋喃-3-基)-1-{[(1S,8R)-11-氧杂三环[6.2.1.02,7]十一碳-2,4,6-三烯-1-基]甲酰氨基}乙基]硼酸;
[(1R)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,8R)-8-甲基-11-氧杂三环[6.2.1.02,7]十一碳-2,4,6-三烯-1-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(1-苯并呋喃-3-基)-1-{[(1R,8S)-11-氧杂三环[6.2.1.02,7]十一碳-2(7),3,5-三烯-9-基]甲酰氨基}乙基]硼酸;
[(1R)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1R,8S)-8-甲基-11-氧杂三环[6.2.1.02,7]十一碳-2,4,6-三烯-1-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(1-苯并呋喃-3-基)-1-{[(1S,8R)-11-氧杂三环[6.2.1.02,7]十一碳-2(7),3,5-三烯-9-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(2,4-二甲基苯基)-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-环己基-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}-3-苯基丙基]硼酸;
[(1R)-3-甲基-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}丁基]硼酸;
[(1S)-2-(1-苯并呋喃-3-基)-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1S)-2-(1-苯并呋喃-3-基)-1-{[(1R,2S,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(1-苯并呋喃-3-基)-1-{[(1S,2S,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1S)-2-(1-苯并呋喃-3-基)-1-{[(1S,2S,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,2S,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1R,2R,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1S)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,2S,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1S)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1R,2R,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-[(3R)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,2S,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-[(3R)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1R,2R,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1S)-2-[(3R)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,2S,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1S)-2-[(3R)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1R,2R,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1S)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1S)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1R,2S,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-[(3R)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-[(3R)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1R,2S,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1S)-2-[(3R)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1S)-2-[(3R)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1R,2S,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
及其前药、溶剂化物、互变异构体、低聚物、加合物和立体异构体以及前述中每一种的药学上可接受的盐,包括它们所有比率的混合物。
术语化合物的溶剂化物用来指惰性溶剂分子在化合物上的加合物,其由于它们的相互吸引力而形成。溶剂化物是例如单水合物或二水合物或醇化物(alkoxide)。
应当理解,本发明还涉及盐的溶剂化物。
术语药学上可接受的衍生物用来指例如根据本发明的化合物的盐以及所谓的前药化合物。
如本文所用且除非另有说明,否则术语“前药”是指式(I)的化合物的衍生物,其可以在生物学条件下(体外或体内)水解、氧化或以其他方式反应以提供活性化合物、特别是式(I)的化合物。前药的实例包括但不限于式(I)的化合物的衍生物和代谢物,其包括可生物水解的部分如可生物水解的酰胺、可生物水解的酯、可生物水解的氨基甲酸酯、可生物水解的碳酸酯、可生物水解的酰脲和可生物水解的磷酸酯类似物。在某些实施方案中,具有羧基官能团的化合物的前药是羧酸的低级烷基酯。通过酯化分子上存在的任何羧酸部分来方便地形成羧酸酯。前药通常可以使用众所周知的方法来制备,例如Burger的MedicinalChemistry and Drug Discovery第6版(Donald J.Abraham编辑,2001,Wiley)和Designand Application of Prodrugs(H.Bundgaard编辑,1985,Harwood Academic PublishersGmfh)所述的那些方法。
表述“有效量”表示在组织、系统、动物或人中引起(例如由研究人员或医师)所寻求或期望的生物学或医学反应的药物或药物活性成分的量。
另外,表述“治疗有效量”表示与尚未接收该量的相应受试者相比具有以下结果的量:改善的治疗、治愈、预防或消除疾病、综合症、病症、身体不适、障碍或副作用,或还有疾病、身体不适或障碍进展的减少。
表述“治疗有效量”也包括对增加正常生理功能有效的量。
本发明还涉及式(I)的化合物的混合物的用途,例如两种非对映异构体的混合物,例如以1:1、1:2、1:3、1:4、1:5、1:10、1:100或1:1000的比率。
“互变异构体”是指彼此平衡的化合物的异构形式。异构形式的浓度将取决于该化合物存在的环境,并且可以取决于例如该化合物是固体还是在有机或水溶液中而不同。
本发明进一步包括制备如上所述的式(I)的化合物及其药学上可接受的盐、互变异构体和立体异构体的方法,其特征在于式(III)的化合物
与式(VI)的化合物偶联
其中式(III)和式(IV)的所有残基均如上所定义,并且其中所获得的式(Ib)的化合物随后可以在存在或不存在过量的小分子量硼酸下通过用HCl、HBr、HI和/或TFA处理来转化为式(Ia)的化合物。
以下缩写是指下文使用的缩写:
AcOH(乙酸)、ACN(乙腈)、BINAP(2,2'-双(二苯基膦基)-1,1'-联萘)、dba(二亚苄基丙酮)、tBu(叔丁基)、tBuOK(叔丁醇钾)、CDI(1,1'-羰基二咪唑)、DBU(1,8-二氮杂双环[5.4.0]十一碳-7-烯)、DCC(双环己基碳二亚胺)、DCM(二氯甲烷)、DIAD(偶氮二甲酸二异丁酯)、DIC(二异丙基碳二亚胺)、DIEA(二异丙基乙胺)、DMA(二甲基乙酰胺)、DMAP(4-二甲基氨基吡啶)、DMSO(二甲基亚砜)、DMF(N,N-二甲基甲酰胺)、EDC.HCl(1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐)、EtOAc或EE(乙酸乙酯)、EtOH(乙醇)、g(克)、cHex(环己烷)、HATU(二甲基氨基-([1,2,3]三唑并[4,5-b]吡啶-3-基氧基)-亚甲基]-二甲基铵六氟磷酸盐)、HOBt(N-羟基苯并三唑)、HPLC(高效液相色谱)、hr(小时)、MHz(兆赫)、MeOH(甲醇)、min(分钟)、mL(毫升)、mmol(毫摩尔)、mM(毫摩尔浓度)、mp(熔点)、MS(质谱)、MW(微波)、NMM(N-甲基吗啉)、NMR(核磁共振)、NBS(N-溴琥珀酰亚胺)、PBS(磷酸盐缓冲盐水)、PMB(对甲氧基苄基)、PyBOP(苯并三唑-1-基-氧基三吡咯烷子基鏻六氟磷酸盐)、rt(室温)、TBAF(四丁基氟化铵)、TBTU(N,N,N',N'-四甲基-O-(苯并三唑-1-基)脲鎓四氟硼酸盐)、T3P(丙烷膦酸酐)、TEA(三乙胺)、TFA(三氟乙酸)、THF(四氢呋喃)、PetEther(石油醚)、TBME(叔丁基甲基醚)、TLC(薄层色谱)、TMS(三甲基甲硅烷基)、TMSI(三甲基碘硅烷)、UV(紫外)。
通常,式(I)的化合物,其中所有残基均如上定义,可以如方案1中所列从式(III)的化合物获得。
方案1:
第一步在于其中X如上定义的式(III)的化合物与其中R1、R2、LY和Y如上定义的式(IV)的化合物反应。使用本领域技术人员众所周知的由羧酸和标准偶联剂(例如但不限于HATU、TBTU、聚合物负载的1-烷基-2-氯吡啶鎓盐(聚合物负载的Mukaiyama’s试剂)、1-甲基-2-氯吡啶鎓碘化物(Mukaiyama’s试剂)、碳二亚胺(如DCC、DIC、EDC)和HOBt、以及本领域技术人员熟知的其他此类试剂,优选TBTU)制备酰胺的条件和方法,在存在或不存在碱(例如TEA、DIEA、NMM、聚合物负载的吗啉,优选DIEA)下、在合适的溶剂(如DCM、THF或DMF)中、在-10℃至50℃之间的温度(优选在0℃)下持续几个小时(例如1小时至24小时)来进行反应。或者,可以通过本领域技术人员众所周知的方法,例如但不限于用SOCl2、POCl3、PCl5、(COCl)2处理,在存在或不存在催化量的DMF下、在存在或不存在合适的溶剂(如甲苯、DCM、THF)下、在从20℃升高至100℃的温度(优选在50℃)下持续几个小时(例如1小时至24小时),来将式(III)的化合物转化为羧酸衍生物如酰基卤或酸酐。可以使用本领域技术人员熟知的由羧酸衍生物(例如酰氯)和烷基胺制备酰胺的条件和方法,在存在或不存在碱(例如TEA、DIEA、NMM)下、在适合的溶剂(例如DCM、THF或DMF)中、在从20℃升高至100℃的温度(优选在50℃)下持续几个小时(例如1小时至24小时),可实现羧酸衍生物向式(I)的化合物的转化。
在上述方法中,式(III)的化合物与式(IV)的化合物之间的反应优选在选自HATU、TBTU、聚合物负载的1-烷基-2-氯吡啶鎓盐(聚合物负载的Mukaiyama’s试剂)、1-甲基-2-氯吡啶鎓碘化物(Mukaiyama’s试剂)、碳二亚胺的偶联剂的存在下进行。。
可以使用本领域技术人员熟知的水解硼酸酯的方法,由式(Ib)的化合物开始制备式(Ia)的化合物,其中X、LY和Y如上所定义并且其中R1和R2为H,例如但不限于在存在或不存在过量的小分子量硼酸(例如但不限于iBuB(OH)2)下用HCl、HBr、HI、TFA处理(方案2)。
方案2:
式(III)或(IV)的化合物可以商购获得,或者可以通过本领域技术人员众所周知的方法制备。
通常,式(IV)的化合物例如可通过以下方案3a获得:
式(IV)的化合物的合成在WO 2016/050356、WO 2016/050355、WO 2016/050359和WO 2016/050358中进一步描述。
式(III)的化合物例如可以通过方案4、5和6中所述的途径来获得:
方案4:
通过类似的方法,也可以合成取代的7-氧杂-双环[2.2.1]庚烷-2-甲酸。
方案5:
通过类似的方法也可以合成取代的11-氧杂三环[6.2.1.02,7]十一碳-2,4,6,9-四烯-9-甲酸。
方案6:
通过类似的方法,从取代的呋喃-2-甲酸开始,可以合成取代的11-氧杂三环[6.2.1.02,7]十一碳-2,4,6-三烯-1-甲酸。还可以使用取代的邻氨基苯甲酸来合成在芳族部分中具有其他取代基的相应化合物。
如果上组通用合成方法不适用于获得根据式(I)的化合物和/或合成式(I)的化合物的必要中间体,则应当使用本领域技术人员已知的合适制备方法。
通常,任何单个式(I)化合物的合成途径将取决于每个分子的特定取代基以及所需中间体的即时可得性;同样,这些因素是本领域普通技术人员所理解的。有关所有保护和去保护方法,参见Philip J.Kocienski,“Protecting Groups”,Georg Thieme VerlagStuttgart,New York,1994以及Theodora W.Greene和Peter G.M.Wuts,“ProtectiveGroups in Organic Synthesis”,Wiley Interscience,第3版,1999。
本发明的化合物可以通过从适当溶剂的蒸发而结晶来与溶剂分子相关地分离。包含碱性中心的式(I)化合物的药学上可接受的酸加成盐可以常规方式制备。例如,可以用纯净的或在合适溶液中的合适酸处理游离碱的溶液,并且所得的盐通过过滤或通过在反应溶剂的真空下蒸发来分离。药学上可接受的碱加成盐可以类似的方式通过用合适的碱处理包含酸中心的式(I)化合物的溶液来获得。两种类型的盐均可使用离子交换树脂技术形成或相互转化。
取决于所使用的条件,反应时间通常在几分钟和14天之间,并且反应温度在约-30℃和140℃之间,通常在-10℃和90℃之间,特别是在约0℃和约70℃之间。
式(I)的化合物还可以通过用溶剂分解剂或氢解剂处理从它们的功能衍生物中释放出式(I)的化合物而获得。
用于溶剂分解或氢解的优选的原料是符合式(I)但包含相应的受保护的氨基和/或羟基而不是一个或多个游离氨基和/或羟基的那些,优选具有氨基保护基而不是与N原子键合的H原子的那些,特别是具有R'-N基团的那些,其中R'表示氨基保护基而不是HN基团,和/或具有羟基保护基而不是羟基的H原子的那些,例如符合式(I)但具有-COOR”基团的那些,其中R”表示羟基保护基而不是-COOH基团。
原料分子中也可能存在多个(相同或不同的)受保护的氨基和/或羟基。如果存在的保护基彼此不同,则它们在许多情况下可以被选择性地裂解掉。
术语“氨基保护基”是已知的通用术语,并且涉及适合于保护(阻断)氨基免于化学反应、但是在分子中的其他地方已经进行所需的化学反应之后易于除去的基团。这类基团的典型特别是未取代或取代的酰基、芳基、芳烷氧基甲基或芳烷基。由于氨基保护基在所需的反应(或反应序列)之后被除去,因此它们的类型和大小也不是关键性的。然而,优选具有1-20个、特别是1-8个碳原子的那些。术语“酰基”应在与本发明方法有关的最广义上理解。它包括衍生自脂族、芳脂族、芳族或杂环羧酸或磺酸的酰基,特别是烷氧基-羰基、芳氧基羰基,尤其是芳烷氧基羰基。这种酰基的实例是烷酰基,如乙酰基、丙酰基和丁酰基;芳烷酰基,如苯基乙酰基;芳酰基,如苯甲酰基和甲苯基(tolyl);芳氧基烷酰基,如POA;烷氧基羰基,如甲氧基-羰基、乙氧基羰基、2,2,2-三氯乙氧基羰基、BOC(叔丁氧基-羰基)和2-碘乙氧基羰基;芳烷氧基羰基,如CBZ(“苄氧基羰基”)、4-甲氧基苄氧基羰基和FMOC;和芳基-磺酰基,如Mtr。优选的氨基保护基是BOC和Mtr,还有CBZ、Fmoc、苄基和乙酰基。
术语“羟基保护基”同样是已知的通用术语,并且涉及适合于保护羟基免于化学反应、但是在分子中的其他地方已经进行所需的化学反应之后易于除去的基团。这种基团的典型是上述未取代或取代的芳基、芳烷基或酰基,此外还有烷基。羟基保护基的性质和大小不是关键性的,因为它们在所需的化学反应或反应序列之后被再次除去;优选具有1-20个、特别是1-10个碳原子的基团。羟基保护基的实例尤其是苄基、4-甲氧基苄基、对硝基苯甲酰基、对甲苯磺酰基、叔丁基和乙酰基,其中特别优选苄基和叔丁基。
术语“化合物的溶剂化物”用来指惰性溶剂分子在化合物上的加合物,其由于它们的相互吸引力而形成。溶剂化物是例如一水合物或二水合物或醇化物。
式(I)的化合物从其功能衍生物中释放出来-取决于所使用的保护基-例如使用强酸,有利地使用TFA或高氯酸,还使用其他强无机酸(如盐酸或硫酸)、强有机羧酸(如三氯乙酸)或磺酸(如苯磺酸或对甲苯磺酸)。可能存在另外的惰性溶剂,但并非总是必须的。合适的惰性溶剂优选是有机的,例如羧酸如乙酸,醚如THF或二噁烷,酰胺如DMF,卤代烃如DCM,此外还有醇如甲醇、乙醇或异丙醇,和水。此外,上述溶剂的混合物是合适的。优选过量使用TFA而不添加其他溶剂,高氯酸优选以比率为9∶1的乙酸和70%高氯酸的混合物形式使用。裂解的反应温度有利地在约0和约50℃之间,优选在15和30℃(rt)之间。
例如,BOC、OBut和Mtr基团可优选在DCM中使用TFA裂解掉,或在15-30℃下在二噁烷中使用约3至5N的HCl裂解掉,FMOC基团在约15-30℃下使用大约5至50%的二甲胺、二乙胺或哌啶的DMF溶液裂解掉。
可以被氢解去除的保护基团(例如CBZ、苄基、或从其噁二唑衍生物中释放出来的脒基)可以被裂解掉,例如,通过在催化剂(例如,贵金属催化剂,如钯,有利地在诸如碳的载体上)的存在下用氢处理。这里合适的溶剂是上面指出的那些,特别是例如醇如甲醇或乙醇,或酰胺如DMF。氢解通常在约0和100℃之间的温度和约1和200bar之间的压力下进行,优选在20-30℃和1-10bar下进行。CBZ基团的氢解例如在20-30℃下在甲醇中的5%至10%Pd/C上或在甲醇/DMF中的Pd/C上使用甲酸铵(而不是氢)非常成功。
合适的惰性溶剂的实例是烃,如己烷、石油醚、苯、甲苯或二甲苯;氯化烃,如三氯乙烯、1,2-二氯乙烷、四氯甲烷、三氟甲基苯、氯仿或DCM;醇如甲醇、乙醇、异丙醇、正丙醇、正丁醇或叔丁醇;醚,如乙醚、二异丙醚、四氢呋喃(THF)或二噁烷;二醇醚如乙二醇单甲或单乙醚或乙二醇二甲醚(二甘醇二甲醚);酮,如丙酮或丁酮;酰胺如乙酰胺、二甲基乙酰胺、N-甲基吡咯烷酮(NMP)或二甲基甲酰胺(DMF);腈如乙腈;亚砜如二甲基亚砜(DMSO);二硫化碳;羧酸,如甲酸或乙酸;硝基化合物,如硝基甲烷或硝基苯;酯,如EtOAc,或所述溶剂的混合物。
可以例如在0和100℃之间的温度下,在水、水/THF、水/THF/乙醇或水/二噁烷中使用LiOH、NaOH或KOH来使酯皂化。此外,例如可以使用乙酸、TFA或HCl将酯水解。
此外,游离氨基可以使用酰氯或酸酐以常规方式酰化,或使用未取代或取代的烷基卤化物进行烷基化,或与CH3-C(=NH)-OEt反应,有利地在惰性溶剂如DCM或THF中和/或在碱(如三乙胺或吡啶)的存在下,在-60℃和+30℃之间的温度下。
在整个说明书中,术语“离去基团”优选表示Cl、Br、I或反应改性的OH基,例如,活化酯、咪唑根(imidazolide)或具有1至6个碳原子的烷基磺酰氧基(优选甲基磺酰氧基或三氟甲基磺酰氧基)或具有6至10个碳原子的芳基磺酰氧基(优选苯基或对甲苯磺酰氧基)。
在典型的酰化反应中用于活化羧基的该类型的基团在文献中有描述(例如,在标准著作中,如Houben-Weyl,Methoden der organischen Chemie[Methods of OrganicChemistry],Georg-Thieme-Verlag,Stuttgart)。
活化的酯有利地原位形成,例如通过加入HOBt或N-羟基琥珀酰亚胺。
药用盐和其他形式
所述式(I)的化合物可以其最终的非盐形式使用。另一方面,本发明也涉及这些化合物以其药学上可接受的盐形式的使用,其可通过本领域已知的程序衍生自各种有机和无机酸和碱。式(I)的化合物的药学上可接受的盐形式大部分通过常规的方法制备。如果式(I)的化合物含有酸性中心,例如羧基,则其合适的盐之一可通过化合物与合适的碱反应来形成,得到相应的碱-加成盐。这样的碱为例如碱金属氢氧化物,包括氢氧化钾和氢氧化钠;碱土金属氢氧化物,例如氢氧化镁和氢氧化钙;和各种有机碱,例如哌啶、二乙醇胺和N-甲基-葡糖胺(甲葡胺)、苄星(benzathine)、胆碱、二乙醇胺、乙二胺、苯乙苄胺(benethamine)、二乙胺、哌嗪、赖氨酸、L-精氨酸、氨、三乙醇胺、甜菜碱、乙醇胺、吗啉和氨丁三醇。在某些包含碱性中心的式(I)的化合物的情况下,酸-加成盐可通过用药学上可接受的有机和无机酸处理这些化合物来形成,所述有机和无机酸例如氢卤酸,例如盐酸或氢溴酸,其他矿物酸及其相应的盐,例如硫酸盐、硝酸盐或磷酸盐等,和烷基-和单芳基-磺酸盐,例如甲烷磺酸盐、乙烷磺酸盐、甲苯磺酸盐和苯-磺酸盐,和其他有机酸及其相应的盐,例如碳酸盐、乙酸盐、三氟-乙酸盐、酒石酸盐、马来酸盐、琥珀酸盐、柠檬酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐等。因此,式(I)的化合物的药学上可接受的酸-加成盐包括以下:乙酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐(besylate)、硫酸氢盐、亚硫酸氢盐、溴化物、樟脑酸盐(camphorate)、樟脑-磺酸盐、癸酸盐、辛酸盐、氯化物、氯代苯甲酸盐、柠檬酸盐、环己基氨基磺酸盐(cyclamate)、肉桂酸盐、二葡糖酸盐、二氢-磷酸盐、二硝基苯甲酸盐、十二烷基-硫酸盐、乙烷磺酸盐、甲酸盐、羟乙酸盐、富马酸盐、半乳糖二酸盐(galacterate)(来自粘酸)、半乳糖醛酸盐、葡糖庚酸盐、葡糖酸盐、谷氨酸盐、甘油磷酸盐、半-琥珀酸盐、半硫酸盐、庚酸盐、己酸盐、马尿酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基-乙烷-磺酸盐、碘化物、羟乙磺酸盐、异丁酸盐、乳酸盐、乳糖酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、偏磷酸盐、甲烷磺酸盐、甲基苯甲酸盐、单-氢-磷酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、油酸盐、棕榈酸盐、果胶酸盐、过硫酸盐、苯基乙酸盐、3-苯基丙酸盐、磷酸盐、膦酸盐、邻苯二甲酸盐,但这并不表示限制。两种类型的盐均可优选地采用离子-交换树脂技术形成或相互转化。
此外,式(I)的化合物的碱盐包括铝盐、铵盐、钙盐、铜盐、铁(III)盐、铁(II)盐、锂盐、镁盐、锰(lll)盐、锰(II)盐、钾盐、钠盐和锌盐,但这不旨在表示限制。上述盐中优选铵盐;碱金属盐钠盐和钾盐,和碱土金属盐钙盐和镁盐。衍生自药学上可接受的有机非毒性碱的式(I)的化合物的盐包括以下化合物的盐:伯胺、仲胺和叔胺,取代的胺,也包括天然存在的取代的胺,环胺,和碱性离子交换树脂,例如精氨酸、甜菜碱、咖啡因、氯普鲁卡因、胆碱、Ν,Ν'-二苄基-乙二胺(苄星)、二环己基胺、二乙醇-胺、二乙基-胺、2-二乙基-氨基-乙醇、2-二甲基-氨基-乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基-哌啶、葡糖胺、氨基葡糖、组氨酸、海巴明、异丙基-胺、利多卡因、赖氨酸、甲葡胺(N-甲基-D-葡糖胺)、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙醇-胺、三乙胺、三甲胺、三丙基-胺和三(羟基-甲基)-甲基胺(氨丁三醇),但这不旨在表示限制。
包含碱性含氮基团的本发明式(I)的化合物可采用以下试剂季铵化,所述试剂为例如(C1-C4)-烷基卤化物,例如甲基、乙基、异丙基和叔丁基的氯化物、溴化物和碘化物;二(C1-C4)烷基硫酸盐,例如二甲基、二乙基和二戊基硫酸盐;(C10-C18)烷基卤化物,例如癸基、十二烷基、月桂基、十四烷基和十八烷基的氯化物、溴化物和碘化物;和芳基-(C1-C4)烷基卤化物,例如苄基氯和苯乙基溴。水溶性和油溶性式(I)的化合物两者都可采用这样的盐制备。
优选的上述药用盐包括乙酸盐、三氟乙酸盐、苯磺酸盐、柠檬酸盐、富马酸盐、葡糖酸盐、半琥珀酸盐、马尿酸盐、盐酸盐、氢溴酸盐、羟乙磺酸盐、扁桃酸盐、甲葡胺、硝酸盐、油酸盐、膦酸盐、三甲基乙酸盐、磷酸钠、硬脂酸盐、硫酸盐、磺基水杨酸盐、酒石酸盐、硫代苹果酸盐、甲苯磺酸盐和氨丁三醇,但这不旨在表示限制。
碱性式(I)的化合物的酸-加成盐通过使游离碱形式与足量的所需酸接触以致以常规的方式形成盐来制备。游离碱可通过使盐形式与碱接触并以常规的方式分离游离碱来再生。游离碱形式在某些方面(关于某些物理性质,例如在极性溶剂中的溶解性)与其相应的盐形式不同;然而,为了本发明的目的,盐在其他方面对应于其各自的游离碱形式。
如所提及的,式(I)的化合物的药学上可接受的碱-加成盐用金属或胺,例如碱金属和碱土金属或有机胺形成。优选的金属是钠、钾、镁和钙。优选的有机胺是Ν,Ν'-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇-胺、乙二胺、N-甲基-D-葡糖胺和普鲁卡因。
酸性式(I)的化合物的碱-加成盐通过使游离酸形式与足量的所需碱接触以致以常规的方式形成盐来制备。游离酸可通过使盐形式与酸接触并以常规的方式分离游离酸来再生。游离酸形式在某些方面(关于某些物理性质,例如在极性溶剂中的溶解性)与其相应的盐形式不同;然而,为了本发明的目的,盐在其他方面对应于其各自的游离酸形式。
如果式(I)的化合物含有超过一个的能够形成这种类型的药学上可接受的盐的基团,则式I也涵盖复盐。典型的复盐形式包括,例如,二酒石酸盐、二乙酸盐、二富马酸盐、二甲葡胺、二-磷酸盐、二钠和三盐酸盐,但这不旨在表示限制。
根据以上所述,可以发现,本文中的术语“药学上可接受的盐”用来指包含形式为其盐的一种的式(I)的化合物的活性成分,特别是如果与游离形式的活性成分或较早使用的该活性成分的任何其他盐形式相比,这种盐形式赋予活性成分改进的药代动力学性质。活性成分的药学上可接受的盐形式也可首次为这种活性成分提供其较早时不具有的所需药代动力学性质,并可甚至就其体内治疗效力而言对这种活性成分的药效学具有积极影响。
由于其分子结构,式(I)的化合物可以是手性的,并可相应地以各种对映异构形式存在。因此它们可以以外消旋形式或以光学活性形式存在。
由于依据本发明的化合物的外消旋体或立体异构体的药学活性可能不同,因此使用对映异构体可能是合乎需要的。在这些情况下,通过本领域技术人员已知的或甚至在合成中同样使用的化学或物理手段,可将终产物或甚至中间体分离为对映异构体化合物。
在外消旋胺的情况下,通过与光学活性拆分剂反应从混合物形成非对映异构体。合适的拆分剂的实例为光学活性酸,例如以下酸的(R)-和(S)-形式:酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、扁桃酸、苹果酸、乳酸、合适的N-受保护的氨基酸(例如N-苯甲酰基脯氨酸或N-苯磺酰基脯氨酸),或各种光学活性樟脑磺酸。借助于光学活性拆分剂(例如二硝基苯甲酰基苯基甘氨酸、三乙酸纤维素或其他碳水化合物的衍生物或固定在硅胶上的手性衍生的甲基丙烯酸酯聚合物)的色谱对映异构体拆分也是有利的。为了此目的,合适的洗脱剂为水性或醇性溶剂混合物,例如,己烷/异丙醇/乙腈,例如比率为82:15:3。
同位素
此外,式(I)的化合物意图包括其同位素标记的形式。除以下事实以外,式(I)的化合物的同位素标记的形式与该化合物是等同的:所述化合物的一个或多个原子被原子质量或质量数与自然界中常见的所述原子的原子质量或质量数不同的一个或多个原子置换。易于商业购得且可通过众所周知的方法并入式(I)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、31P、32P、35S、18F和36Cl。含有一个或多个上述同位素和/或其他原子的其他同位素的式(I)的化合物、其前药或任一种的药学上可接受的盐意图成为本发明的一部分。同位素标记的式(I)的化合物可以多种有利的方式使用。例如,同位素标记的式(I)的化合物(其中例如已经并入放射性同位素如3H或14C)适合用于药物和/或底物组织分布测定。由于制备简单和优良的可检测性,特别优选这些放射性同位素,即氚(3H)和碳-14(14C)。在式(I)的化合物中并入较重的同位素(例如氘(2H))具有治疗优势,这归因于该同位素标记的化合物的较高代谢稳定性。较高代谢稳定性直接转化为增加的体内半衰期或更低的剂量,在大多数情况下这将代表本发明的优选实施方案。通常,通过进行在合成方案及有关描述中、在实施例部分中和在本文的制备部分中公开的程序,用易得的同位素标记的反应物置换非同位素标记的反应物,可制备同位素标记的式(I)的化合物。
为了通过初级动力学同位素效应控制所述化合物的氧化代谢的目的,还可将氘(2H)并入到式(I)的化合物中。所述初级动力学同位素效应是化学反应速率的变化,其由同位素核的交换导致,继而由在该同位素交换后共价键形成所需的基态能的变化引起。较重同位素的交换通常导致化学键的基态能的降低,因此使限速键断裂的速率降低。如果键断裂发生在沿多产物反应的坐标的鞍点区中或其附近,则可明显改变产物分布比率。例如,如果氘与不可交换位置处的碳原子键合,则kM/kD=2-7的速率差异是典型的。如果将该速率差异成功地应用于易于氧化的式(I)的化合物,则可显著地改变所述化合物的体内分布,并导致改善的药代动力学性质。
在发现和开发治疗剂时,本领域技术人员试图优化药代动力学参数,并同时保持合乎需要的体外性质。有理由推测,具有差的药代动力学性质的许多化合物易于氧化代谢。目前可得到的体外肝微粒体测定提供了关于这类氧化代谢的过程的有价值的信息,所述信息继而允许合理地设计通过对抗这样的氧化代谢而具有提高的稳定性的氘化的式(I)的化合物。由此得到式(I)的化合物的药代动力学性质的显著改善,并且可以关于下列定量地表示:增加的体内半衰期(t1/2)、最大治疗效果时的浓度(Cmax)、剂量响应曲线下的面积(AUC)以及F;以及降低的清除率、剂量及材料成本。
以下内容意图解释上述内容:将具有氧化代谢的多个潜在攻击位点(例如苄基的氢原子和与氮原子键合的氢原子)的式(I)的化合物制备为一系列类似物,其中氢原子的各种组合被氘原子置换,以致于这些氢原子中的一些、大部分或全部被氘原子置换。半衰期测定能够有利地并精确地测定已经改善的氧化代谢抗性的改善程度。以此方式,确定了由于这类氘-氢交换,母体化合物的半衰期可延长至多100%。
式(I)的化合物中的氘-氢交换也可用于实现起始化合物的代谢物谱的有利改变,以便减少或消除不希望的有毒代谢物。例如,如果有毒代谢物通过氧化性碳-氢(C-H)键裂解而产生,则可合理地假定,氘化的类似物将极大地减少或消除不希望的代谢物的产生,即使该特定氧化不是速率决定步骤。关于氘-氢交换的现有技术的其他信息可见于例如Hanzlik等人,J.Org.Chem.55,3992-3997,1990、Reider等人,J.Org.Chem.52,3326-3334,1987、Foster,Adv.Drug Res.14,1-40,1985、Gillette等人,Biochemistry 33(10)2927-2937,1994和Jarman等人Carcinogenesis 16(4),683-688,1993。
本发明涉及药物制剂(优选用于治疗免疫调节异常或癌症),包含:作为活性成分的至少一种式(I)的化合物(特别是治疗有效量的式(I)化合物))和/或其前药、溶剂化物、互变异构体、低聚物、加合物或立体异构体以及前述中的每一种的药学上可接受的盐,包括它们所有比率的混合物;以及药学上可接受的载体。
为了本发明的目的,术语“药物制剂”是指包含一种或多种活性成分和构成载体的一种或多种惰性成分的组合物或产品,以及由任何两种或更多种所述成分的组合、复合或聚集、或由一种或多种所述成分的解离、或由一种或多种所述成分的其他类型反应或相互作用直接或间接地产生的任何产品。因此,本发明的药物制剂包括通过将至少一种本发明的化合物和药学上可接受的载体、赋形剂或媒介混合制成的任何组合物。
本发明的药物制剂还包括进一步包含第二活性成分和/或其前药或溶剂化物以及前述中的每一种的药学上可接受的盐(包括它们所有比率的混合物)的任何组合物,其中第二活性物质成分不是其中所有残基均如上定义的式(I)的化合物。
根据本发明的药物制剂可以用作人类和兽医学中的药物。
为了本发明的目的的,免疫调节异常优选为选自以下的自身免疫性或慢性炎性疾病:系统性红斑狼疮、慢性类风湿性关节炎、炎性肠病、多发性硬化、肌萎缩性侧索硬化症(ALS)、动脉粥样硬化、硬皮病、自身免疫性肝炎、干燥综合征、狼疮肾炎、肾小球肾炎、类风湿性关节炎、牛皮癣、重症肌无力、免疫球蛋白A肾病、血管炎、移植排斥、肌炎、紫癜和哮喘;癌症优选为血液恶性肿瘤或实体瘤,其中所述血液恶性肿瘤优选是选自以下的疾病:恶性B-和T/NK-细胞非霍奇金淋巴瘤如:多发性骨髓瘤、套细胞淋巴瘤、弥漫性大B-细胞淋巴瘤、浆细胞瘤、滤泡性淋巴瘤、免疫细胞瘤、急性淋巴细胞白血病、慢性淋巴细胞白血病和骨髓性白血病;其中所述实体肿瘤优选为选自以下的疾病:炎性乳腺癌、肝癌和结肠癌、肺癌、头颈癌、前列腺癌、胰腺癌、膀胱癌、肾癌、肝细胞癌和胃癌。
药物制剂可以每剂量单位包含预定量的活性成分的剂量单位形式施用。这样的单位可包含例如0.5mg-1g、优选1mg-700mg、特别优选5mg-100mg的根据本发明的化合物,这取决于所治疗的疾病状况、施用方法和患者的年龄、体重和状况,或者药物制剂可以每剂量单位包含预定量的活性成分的剂量单位形式施用。优选的剂量单位制剂是包含如上指出的每日剂量或部分剂量或者其相应分数的活性成分的那些。此外,这类药物制剂可用药学领域通常已知的方法制备。
药物制剂可适于经由任何所需的适宜方法施用,例如口服(包括含服或舌下)、直肠、鼻、局部(包括含服、舌下或透皮)、阴道或胃肠外(包括皮下、肌内、静脉内或皮内)方法。这样的制剂可使用药学领域已知的所有方法制备,通过例如将活性成分与赋形剂或佐剂组合。
适于口服施用的药物制剂可作为独立单位进行施用,所述独立单位例如为胶囊或片剂,粉末剂或颗粒剂,在水性或非水性液体中的溶液剂或混悬剂,可食用的泡沫或泡沫食物,或水包油型液体乳剂或油包水型液体乳剂。
因此,例如在以片剂或胶囊形式口服施用的情况下,可将活性成分组分与口服、无毒且药学上可接受的惰性赋形剂(如乙醇、甘油、水等)组合。粉末剂通过将化合物粉碎至适当细的大小并将其与以相似方式粉碎的药用赋形剂(如可食用的碳水化合物,例如淀粉或甘露醇)混合来制备。也可存在调味剂、防腐剂、分散剂和染料。
通过如上所述制备粉末混合物并填充到成型的明胶壳中,制备胶囊。在进行填充操作前,可在粉末混合物中加入助流剂和润滑剂(如高度分散的硅酸、滑石、硬脂酸镁、硬脂酸钙或固体形式的聚乙二醇)。也可加入崩解剂或增溶剂(如琼脂、碳酸钙或碳酸钠)以提高胶囊被服用后药物的利用度。
另外,如果需要或必要,则也可在混合物中掺入适宜的粘合剂、润滑剂和崩解剂以及染料。适宜的粘合剂包括淀粉、明胶、天然糖(如葡萄糖或β-乳糖)、由玉米制得的甜味剂、天然和合成胶(如阿拉伯胶、黄蓍胶或海藻酸钠)、羧甲基纤维素、聚乙二醇、蜡等。这些剂型中使用的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂包括淀粉、甲基纤维素、琼脂、膨润土、黄原胶等而不限制于此。如下配制片剂:例如,制备粉末混合物,将该混合物制粒或干压,加入润滑剂和崩解剂并将整个混合物压成片剂。通过将以适当方式粉碎的化合物与上述稀释剂或基质混合,并任选地与粘合剂(如羧甲基纤维素、海藻酸盐、明胶或聚乙烯吡咯烷酮)、溶出阻滞剂(如石蜡)、吸收促进剂(如季盐)和/或吸收剂(如膨润土、高岭土或磷酸二钙)混合,制备粉末混合物。可通过用粘合剂(如糖浆、淀粉糊、阿拉伯胶胶浆或者纤维素或聚合物材料的溶液润湿,并压过筛,来将粉末混合物制粒。作为制粒的替代,可使粉末混合物通过压片机,得到形状不均匀的块状物,将其破碎从而形成颗粒。通过加入硬脂酸、硬脂酸盐、滑石或矿物油,可将颗粒润滑,以防止粘附在片剂铸模上。然后,将润滑的混合物压成片剂。也可将活性成分与自由流动的惰性赋形剂组合,然后不进行制粒或干压步骤而直接压成片剂。可存在由虫胶密封层、糖或聚合物材料的层和蜡的光泽层组成的透明或不透明的保护层。可在这些包衣中加入染料以便能区别不同的剂量单位。
口服液体(如溶液剂、糖浆剂和酏剂)可以剂量单位形式制备,以便给定的量包含预先规定量的化合物。糖浆剂可通过将化合物溶解在具有适宜调味剂的水溶液中来制备,而酏剂用无毒的醇性媒介制备。混悬剂可通过将化合物分散于无毒媒介中来配制。也可加入增溶剂和乳化剂(如乙氧基化的异硬脂醇和聚氧乙烯山梨醇醚)、防腐剂、调味添加剂(如薄荷油或天然甜味剂或糖精或其他人工甜味剂等)。
如果需要,则可将用于口服施用的剂量单位制剂包封于微囊中。也可以延长或延迟释放的方式来制备制剂,例如通过将微粒材料包衣或包埋在聚合物、蜡等中来制备制剂。
式(I)的化合物及其盐、溶剂化物和生理学上的功能衍生物以及其他活性成分也可以脂质体递送系统(如小单层囊泡、大单层囊泡和多层囊泡)的形式进行施用。可从各种磷脂(如胆固醇、硬脂胺或磷脂酰胆碱)形成脂质体。
式(I)的化合物及其盐、溶剂化物和生理学上的功能衍生物以及其他活性成分也可以用单克隆抗体作为独立载体递送,其中所述化合物分子与所述单克隆抗体偶联。也可将化合物偶联到作为靶向药物载体的可溶性聚合物上。这样的聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基-甲基丙烯酰氨基苯酚、聚羟基乙基天冬酰氨基苯酚或聚氧化乙烯聚赖氨酸,其被棕榈酰基取代。还可将化合物偶联到一类适于实现药物控释的生物可降解聚合物上,例如聚乳酸、聚-ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二羟基吡喃、聚氰基丙烯酸酯和水凝胶的交联或两亲性嵌段共聚物。
适于透皮施用的药物制剂可作为长效的、与接受者的表皮紧密接触的独立硬膏剂施用。因此,例如,如Pharmaceutical Research,3(6),318(1986)中概括地所述,可用离子电渗疗法使活性成分从硬膏剂递送。
适于局部施用的药用化合物可被配制成软膏剂、乳膏剂、混悬剂、洗剂、粉末剂、溶液剂、糊剂、凝胶剂、喷雾剂、气溶胶或油。
对于眼或其他外部组织(例如口和皮肤)的治疗,制剂优选地以局部用软膏剂或乳膏剂的形式施用。在配制成软膏剂的情况下,可将活性成分与石蜡或水可混溶的乳膏基质一起使用。或者,可用水包油型乳膏基质或油包水型基质将活性成分配制成乳膏剂。
适于局部应用于眼的药物制剂包括滴眼剂,其中将活性成分溶解或混悬在适宜的载体、特别是水性溶剂中。
适于在口中局部应用的药物制剂包括糖锭剂、锭剂和漱口剂。
适于直肠施用的药物制剂可以栓剂或灌肠剂的形式施用。
其中载体物质是固体的适于鼻施用的药物制剂包含具有例如在20-500微米范围内的粒度的粗粉末,其以从鼻中吸入的方式施用,即经由鼻道从靠近鼻的含粉末容器迅速吸入。用液体作为载体物质的作为鼻喷雾剂或滴鼻剂施用的适宜制剂包括活性成分在水或油中的溶液。
适于通过吸入施用的药物制剂包括细微粒粉或雾,所述细微粒粉或雾可通过各种类型的加压分配器用气溶胶、气雾器或吹药器来产生。
适于阴道施用的药物制剂可作为阴道栓、棉条、乳膏剂、凝胶剂、糊剂、泡沫或喷雾制剂来施用。
适于胃肠外施用的药物制剂包括:水性和非水性的无菌注射溶液剂,其包含抗氧化剂、缓冲剂、抑菌剂和溶质,借此使得制剂与要治疗的接受者的血液等张;以及水性和非水性的无菌混悬剂,其可包含混悬介质和增稠剂。制剂可在单剂量或多剂量容器(例如密封的安瓿和小瓶)中施用,并以冷冻干燥(冻干)状态储存,使得仅需在临用前加入无菌载体液体(例如注射目的用水)。按照处方制备的注射溶液剂和混悬剂可从无菌粉末剂、颗粒剂和片剂制备。
不言而喻,除以上特别提及的组分外,制剂还可包含就该特定类型制剂而言在本领域中常用的其他试剂;因此,例如适合口服施用的制剂可包含调味剂。
根据本发明的组合物/制剂可用作人类或兽医学中的药物。
式(I)的化合物和其他活性成分的治疗有效量取决于许多因素,包括例如动物的年龄和体重、需要治疗的确切疾病状况及其严重程度、制剂的性质和施用方法,并最终由治疗医生或兽医来决定。但是,化合物的有效量通常是在0.1-100mg/kg接受者(哺乳动物)体重/天的范围内,特别是通常在1-10mg/kg体重/天的范围内。因此,对于体重为70kg的成年哺乳动物而言,每天的实际量通常在70-700mg之间,其中该量可作为每天的单个剂量施用,或者通常每天以一系列部分剂量(例如2、3、4、5或6个)施用,使得总日剂量相同。盐或溶剂化物的有效量或其生理学上的功能衍生物的有效量可作为化合物本身的有效量的分数来确定。
本发明还涉及根据式(I)或上述任何具体实施方案的化合物和/或其前药、溶剂化物、互变异构体、低聚物、加合物或立体异构体以及前述中每一种的药学上可接受的盐,包括它们所有比率的混合物,用于预防和/或治疗受抑制LMP7影响的医学病症。
本发明涉及根据式(I)或上述任何具体实施方案的化合物和/或其前药、溶剂化物、互变异构体、低聚物、加合物或立体异构体以及前述中每一种的药学上可接受的盐,包括它们所有比率的混合物,用于治疗和/或预防(防止)免疫调节异常或癌症(尤其包括血液恶性肿瘤和实体瘤)。
本发明还涉及治疗患有免疫调节异常或癌症的受试者的方法,包括施用给所述受试者有效于治疗所述免疫调节异常或癌症的量的式(I)的化合物。本发明优选涉及治疗患有自身免疫性或慢性炎性疾病、血液恶性肿瘤或实体瘤的受试者的方法。
所公开的式(I)的化合物可以与其他已知的治疗剂(活性成分)包括抗癌剂组合施用和/或使用。如本文所用,术语"抗癌剂"涉及为了治疗癌症的目的而施用给癌症患者的任何药剂。
上面定义的抗癌治疗可作为单一疗法应用,或除本文中公开的式(I)的化合物以外,还可包括常规手术或放射疗法或药物疗法。这样的药物疗法(例如化学疗法或靶向疗法)可包括一种或多种、但是优选一种下述抗肿瘤剂:
烷化剂
如六甲蜜胺(altretamine)、苯达莫司汀(bendamustine)、白消安(busulfan)、卡莫司汀(carmustine)、苯丁酸氮芥(chlorambucil)、氮芥(chlormethine)、环磷酰胺(cyclophosphamide)、达卡巴嗪(dacarbazine)、异环磷酰胺(ifosfamide)、英丙舒凡(improsulfan)、托西酸酯(tosilate)、洛莫司汀(lomustine)、美法仑(melphalan)、二溴甘露醇(mitobronitol)、二溴卫矛醇(mitolactol)、尼莫司汀(nimustine)、雷莫司汀(ranimustine)、替莫唑胺(temozolomide)、塞替派(thiotepa)、曲奥舒凡(treosulfan)、氧氮芥(mechloretamine)、卡波醌(carboquone);
阿帕齐醌(apaziquone)、福莫司汀(fotemustine)、葡磷酰胺(glufosfamide)、帕利伐米(palifosfamide)、哌泊溴烷(pipobroman)、曲磷胺(trofosfamide)、乌拉莫司汀(uramustine)、TH-3024、VAL-0834;
铂化合物
如卡铂(carboplatin)、顺铂(cisplatin)、依他铂(eptaplatin)、米铂水合物(miriplatine hydrate)、奥沙利铂(oxaliplatin)、洛铂(lobaplatin)、奈达铂(nedaplatin)、吡铂(picoplatin)、沙铂(satraplatin);
DNA改变剂
如氨柔比星(amrubicin)、比生群(bisantrene)、地西他滨(decitabine)、米托蒽醌(mitoxantrone)、丙卡巴肼(procarbazine)、曲贝替定(trabectedin)、氯法拉滨(clofarabine);
安吖啶(amsacrine)、溴他利星(brostallicin)、匹杉琼(pixantrone)、拉罗莫司汀(laromustine)1,3;
拓扑异构酶抑制剂
如依托泊苷(etoposide)、伊立替康(irinotecan)、雷佐生(razoxane)、索布佐生(sobuzoxane)、替尼泊苷(teniposide)、托泊替康(topotecan);
氨萘非特(amonafide)、贝洛替康(belotecan)、依利醋铵(elliptiniumacetate)、伏利拉辛(voreloxin);
微管修饰剂
如卡巴他赛(cabazitaxel)、多西紫杉醇(docetaxel)、艾日布林(eribulin)、伊沙匹隆(ixabepilone)、紫杉醇(paclitaxel)、长春碱(vinblastine)、长春新碱(vincristine)、长春瑞滨(vinorelbine)、长春地辛(vindesine)、长春氟宁(vinflunine);
福他布林(fosbretabulin)、替司他赛(tesetaxel);
抗代谢物
如天冬酰胺酶(asparaginase)3、阿扎胞苷(azacitidine)、左亚叶酸钙(calciumlevofolinate)、卡培他滨(capecitabine)、克拉屈滨(cladribine)、阿糖胞苷(cytarabine)、依诺他滨(enocitabine)、氟脲苷(floxuridine)、氟达拉滨(fludarabine)、氟尿嘧啶(fluorouracil)、吉西他滨(gemcitabine)、巯嘌呤(mercaptopurine)、甲氨蝶呤(methotrexate)、奈拉滨(nelarabine)、培美曲塞(pemetrexed)、普拉曲沙(pralatrexate)、硫唑嘌呤(azathioprine)、硫鸟嘌呤(thioguanine)、卡莫氟(carmofur);
去氧氟尿苷(doxifluridine)、艾西拉宾(elacytarabine)、雷替曲塞(raltitrexed)、沙帕他滨(sapacitabine)、替加氟(tegafur)2,3、三甲曲沙(trimetrexate);
抗癌抗生素
如博来霉素(bleomycin)、放线菌素D(dactinomycin)、多柔比星(doxorubicin)、表柔比星(epirubicin)、伊达比星(idarubicin)、左旋咪唑(levamisole)、米替福新(miltefosine)、丝裂霉素C(mitomycin C)、罗米地辛(romidepsin)、链佐星(streptozocin)、戊柔比星(valrubicin)、净司他丁(zinostatin)、佐柔比星(zorubicin)、柔红霉素(daunurobicin)、普卡霉素(plicamycin);
阿柔比星(aclarubicin)、培洛霉素(peplomycin)、吡柔比星(pirarubicin);
激素/拮抗剂
如阿巴瑞克(abarelix)、阿比特龙(abiraterone)、比卡鲁胺(bicalutamide)、布舍瑞林(buserelin)、卡普睾酮(calusterone)、氯烯雌醚(chlorotrianisene)、地加瑞克(degarelix)、地塞米松(dexamethasone)、雌二醇(estradiol)、氟可龙(fluocortolone)、氟甲睾酮(fluoxymesterone)、氟他胺(flutamide)、氟维司群(fulvestrant)、戈舍瑞林(goserelin)、组氨瑞林(histrelin)、亮丙瑞林(leuprorelin)、甲地孕酮(megestrol)、米托坦(mitotane)、那法瑞林(nafarelin)、诺龙(nandrolone)、尼鲁米特(nilutamide)、奥曲肽(octreotide)、泼尼松龙(prednisolone)、雷洛昔芬(raloxifene)、他莫昔芬(tamoxifen)、α促甲状腺激素(thyrotropin alfa)、托瑞米芬(toremifene)、曲洛司坦(trilostane)、曲普瑞林(triptorelin)、己烯雌酚(diethylstilbestrol);
阿考比芬(acolbifene)、达那唑(danazol)、地洛瑞林(deslorelin)、环硫雄醇(epitiostanol)、orteronel、恩扎鲁胺(enzalutamide)1,3;
芳香酶抑制剂
如氨鲁米特(aminoglutethimide)、阿那曲唑(anastrozole)、依西美坦(exemestane)、法倔唑(fadrozole)、来曲唑(letrozole)、睾内酪(testolactone);
福美坦(formestane);
小分子激酶抑制剂
如克唑替尼(crizotinib)、达沙替尼(dasatinib)、厄洛替尼(erlotinib)、伊马替尼(imatinib)、拉帕替尼(lapatinib)、尼洛替尼(nilotinib)、帕唑帕尼(pazopanib)、瑞戈非尼(regorafenib)、鲁索替尼(ruxolitinib)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、凡他尼布(vandetanib)、威罗菲尼(vemurafenib)、波舒替尼(bosutinib)、吉非替尼(gefitinib)、阿昔替尼(axitinib);
阿法替尼(afatinib)、alisertib、达拉菲尼(dabrafenib)、达克替尼(dacomitinib)、dinaciclib、度维替尼(dovitinib)、恩扎妥林(enzastaurin)、尼达尼布(nintedanib)、乐伐替尼(lenvatinib)、linifanib、linsitinib、马赛替尼(masitinib)、米哚妥啉(midostaurin)、莫替沙尼(motesanib)、奈拉替尼(neratinib)、orantinib、哌立福辛(perifosine)、泊那替尼(ponatinib)、雷多替尼(radotinib)、rigosertib、替匹法尼(tipifarnib)、tivantinib、tivozanib、曲美替尼(trametinib)、pimasertib、丙氨酸布立尼布(brivanib alaninate)、西地尼布(cediranib)、阿帕替尼(apatinib)4、S-苹果酸卡博替尼(cabozantinib S-malate)1,3、依鲁替尼(ibrutinib)1,3、埃克替尼(icotinib)4、buparlisib2、cipatinib4、考比替尼(cobimetinib)1,3、代拉里斯(idelalisib1,3)、fedratinib1、XL-6474;
光敏剂
如甲氧沙林(methoxsalen3);
卟吩姆钠(porfimer sodium)、他拉泊芬(talaporfin)、替莫泊芬(temoporfin);
抗体
如阿仑单抗(alemtuzumab)、贝索单抗(besilesomab)、brentuximab vedotin、西妥昔单抗(cetuximab)、地舒单抗(denosumab)、伊匹木单抗(ipilimumab)、奥法木单抗(ofatumumab)、帕木单抗(panitumumab)、利妥昔单抗(rituximab)、托西莫单抗(tositumomab)、曲妥单抗(trastuzumab)、贝伐单抗(bevacizumab)、培妥单抗(pertuzumab)2,3;
卡妥索单抗(catumaxomab)、依洛珠单抗(elotuzumab)、依帕珠单抗(epratuzumab)、法利珠单抗(farletuzumab)、mogamulizumab、奈昔木单抗(necitumumab)、尼妥珠单抗(nimotuzumab)、阿托珠单抗(obinutuzumab)、ocaratuzumab、奥戈伏单抗(oregovomab)、雷莫芦单抗(ramucirumab)、利妥木单抗(rilotumumab)、司妥昔单抗(siltuximab)、托珠单抗(tocilizumab)、扎芦木单抗(zalutumumab)、扎木单抗(zanolimumab)、马妥珠单抗(matuzumab)、dalotuzumab1,2,3、onartuzumab1,3、雷妥莫单抗(racotumomab)1、tabalumab1,3、EMD-5257974、nivolumab1,3;
细胞因子
如阿地白介素(aldesleukin)、干扰素α(interferon alfa)2、干扰素α2a(interferon alfa2a)3、干扰素α2b(interferon alfa2b)2,3;
西莫白介素(celmoleukin)、他索纳明(tasonermin)、替西白介素(teceleukin)、奥普瑞白介素(oprelvekin)1,3、重组干扰素β-1a(recombinant interferon beta-1a4);
药物缀合物
如地尼白介素(denileukin diftitox)、替伊莫单抗(ibritumomab tiuxetan)、碘苄胍I123(iobenguane I123)、泼尼莫司汀(prednimustine)、曲妥单抗-美坦新(trastuzumab emtansine)、雌莫司汀(estramustine)、吉姆单抗(gemtuzumab)、奥佐米星(ozogamicin)、阿柏西普(aflibercept);
贝辛白介素(cintredekin besudotox)、依度曲肽(edotreotide)、伊珠单抗奥佐米星(inotuzumab ozogamicin)、他那莫单抗(naptumomab estafenatox)、莫奥珠单抗(oportuzumab monatox)、锝(99mTc)阿西莫单抗(arcitumomab)1,3、vintafolide1,3;
疫苗
如sipuleucel3;vitespen3、emepepimut-S3、oncoVAX4、rindopepimut3、troVax4、MGN-16014、MGN-17034;
其他
阿利维A酸(alitretinoin)、贝沙罗汀(bexarotene)、硼替佐米(bortezomib)、依维莫司(everolimus)、伊班膦酸(ibandronic acid)、咪喹莫特(imiquimod)、来那度胺(lenalidomide)、香菇多糖(lentinan)、甲酪氨酸(metirosine)、米法莫肽(mifamurtide)、帕米磷酸(pamidronic acid)、培门冬酶(pegaspargase)、喷司他丁(pentostatin)、sipuleucel3、西佐喃(sizofiran)、他米巴罗汀(tamibarotene)、坦罗莫司(temsirolimus)、沙利度胺(thalidomide)、维A酸(tretinoin)、维莫德吉(vismodegib)、唑来膦酸(zoledronic acid)、伏林司他(vorinostat);
塞来考昔(celecoxib)、西仑吉肽(cilengitide)、恩替司他(entinostat)、依他硝唑(etanidazole)、ganetespib、伊屈诺昔(idronoxil)、iniparib、ixazomib、氯尼达明(lonidamine)、尼莫唑(nimorazole)、帕比司他(panobinostat)、培维A酸(peretinoin)、普利肽新(plitidepsin)、泊马度胺(pomalidomide)、丙考达唑(procodazol)、地磷莫司(ridaforolimus)、他喹莫德(tasquinimod)、telotristat、胸腺法新(thymalfasin)、替拉扎明(tirapazamine)、托多司他tosedostat、曲贝德生(trabedersen)、乌苯美司(ubenimex)、伐司朴达(valspodar)、今又生(gendicine)4、溶链菌(picibanil)4、reolysin4、盐酸瑞螺旋霉素(retaspimycin hydrochloride)1,3、trebananib2,3、维鲁利秦(virulizin)4、卡非佐米(carfilzomib)1,3、内皮他丁(endostatin)4、immucothel4、贝林司他(belinostat)3、MGN-17034;
1Prop.INN(提议的国际非专有名称)
2Rec.INN(推荐的国际非专有名称)
3USAN(美国采用的名称)
4无INN。
本发明还涉及式(I)及相关式的化合物的用途,其与至少一种另外的药物活性成分组合,所述另外的药物活性成分优选为用于治疗多发性硬化的药物例如克拉屈滨(cladribine),或另一种辅助剂,例如干扰素,例如聚乙二醇化或非聚乙二醇化干扰素,优选干扰素β;和/或与改善血管功能的化合物组合或与免疫调节剂组合,所述免疫调节剂例如芬戈莫德(Fingolimod);环孢菌素(cyclosporin)、雷帕霉素(rapamycin)或子囊霉素(ascomycin),或它们的免疫抑制类似物,例如环孢菌素A(cyclosporin A)、环孢菌素G(cyclosporin G)、FK-506、ABT-281、ASM981、雷帕霉素(rapamycin)、40-O-(2-羟基)乙基-雷帕霉素等;皮质类固醇;环磷酰胺(cyclophosphamide);硫唑嘌呤(azathioprene);氨甲喋呤(methotrexate);来氟米特(leflunomide);咪唑立宾(mizoribine);麦考酚酸(mycophenolic add);麦考酚酸吗乙酯(mycophenolate mofetil);15-脱氧精胍菌素(15-deoxyspergualine);戊酸二氟可龙(diflucortolone valerate);二氟泼尼酯(difluprednate);倍他米松二丙酸盐(Alclometasone dipropionate);安西奈德(amcinonide);安吖啶(amsacrine);天冬酰胺酶(asparaginase);硫唑嘌呤(azathioprine);巴利昔单抗(basiliximab);倍可松二丙酸盐(beclometasonedipropionate);倍他米松(betamethasone);倍他米松乙酸盐(betamethasone acetate);倍他米松二丙酸盐(betamethasone dipropionate);倍他米松磷酸钠(betamethasonephosphate sodique);倍他米松戊酸盐(betamethasone valerate);布地奈德(budesonide);卡托普利(captopril);氮芥盐酸盐(chlormethine chlorhydrate);克拉屈滨(cladribine);氯倍他索丙酸盐(clobetasol propionate);可的松乙酸盐(cortisoneacetate);可的伐唑(cortivazol);环磷酰胺(cyclophosphamide);阿糖胞苷(cytarabine);达克珠单抗(daclizumab);放线菌素(dactinomycine);地奈德(desonide);去羟米松(desoximetasone);地塞米松(dexamethasone);地塞米松乙酸盐(dexamethasoneacetate);地塞米松异烟酸盐(dexamethasone isonicotinate);地塞米松间磺基苯甲酸钠(dexamethasone metasulfobenzoate sodique);地塞米松磷酸盐(dexamethasonephosphate);地塞米松叔丁基乙酸盐(dexamethasone tebutate);乙酸二氯松(dichlorisone acetate);多柔比星盐酸盐(doxorubicine chlorhydrate);表柔比星盐酸盐(epirubicine chlorhydrate);氟氯奈德(fluclorolone acetonide);氟氢可的松乙酸盐(fludrocortisone acetate);氟氢缩松(fludroxycortide);氟米松三甲基乙酸盐(flumetasone pivalate);氟尼缩松(flunisolide);氟轻松(fluocinolone acetonide);醋酸氟轻松(fluocinonide);氟可龙(fluocortolone);氟可龙己酸盐(fluocortolonehexanoate);氟可龙三甲基乙酸盐(fluocortolone pivalate);氟米松(fluorometholone);氟泼尼定乙酸盐(fluprednidene acetate);氟替卡松丙酸盐(fluticasone propionate);吉西他滨盐酸盐(gemcitabine chlorhydrate);哈西奈德(halcinonide);氢化可的松(hydrocortisone)、氢化可的松乙酸盐(hydrocortisoneacetate)、氢化可的松丁酸盐(hydrocortisone butyrate)、氢化可的松半琥珀酸盐(hydrocortisone hemisuccinate);美法仑(melphalan);泼尼松(meprednisone);巯嘌呤(mercaptopurine);甲泼尼龙(methylprednisolone);甲泼尼龙乙酸盐(methylprednisolone acetate);甲泼尼龙半琥珀酸盐(methylprednisolonehemisuccinate);米索前列醇(misoprostol);莫罗单抗-cd3(muromonab-cd3);麦考酚酸吗乙酯(mycophenolate mofetil);帕拉米松乙酸盐(paramethasone acetate);泼那唑啉(prednazoline);泼尼松龙(prednisolone);泼尼松龙乙酸盐(prednisolone acetate);泼尼松龙己酸盐(prednisolone caproate);泼尼松龙间磺基苯甲酸钠(prednisolonemetasulfobenzoate sodique);泼尼松龙磷酸钠(prednisolone phosphate sodique);强的松(prednisone);泼尼立定(prednylidene);利福平(rifampicine);利福平钠(rifampicine sodique);他克莫司(tacrolimus);特立氟胺(teriflunomide);沙利度胺(thalidomide);塞替派(thiotepa);氢可的松三甲基乙酸酯(tixocortol pivalate);甲曲安西龙(triamcinolone);曲安奈德半琥珀酸盐(triamcinolone acetonidehemisuccinate);苯曲安奈德(triamcinolone benetonide);双醋曲安西龙(triamcinolone diacetate);己曲安奈德(triamcinolone hexacetonide);免疫抑制单克隆抗体,例如,对白细胞受体的单克隆抗体,例如,MHC、CD2、CD3、CD4、CD7、CD25、CD28、B7、CD40、CD45或CD58或它们的配体;或其他免疫调节化合物,例如CTLA41g,或其他附着分子抑制剂,例如mAbs或低分子量抑制剂包括选择蛋白拮抗剂和VLA-4拮抗剂。优选的组合物具有环孢菌素A、FK506、雷帕霉素(rapamycin)或40-(2-羟基)乙基-雷帕霉素和芬戈莫德(Fingolimod)。这些另外的药物,例如干扰素β,可例如通过皮下、肌内或口服途径同时或顺序施用。
本发明还涉及式(I)和相关式的化合物与至少一种另外的药物活性成分、优选用于治疗癌症的药物(如特别是上述抗癌剂和/或抗肿瘤剂)的组合的用途。
本发明还涉及包括以下的单独包装的套件(药盒):
(a)有效量的式(I)的化合物和/或其前药、溶剂化物、互变异构体、低聚物、加合物或立体异构体以及前述中每一种的药学上可接受的盐,包括它们所有比率的混合物,
和
(b)有效量的另外的药物活性成分。
本发明的化合物可以根据以下方案和实施例的程序使用适当的材料制备,并且通过以下具体实施例进一步举例说明。
此外,通过利用本文所述的程序,结合本领域的普通技术,可以容易地制备本文要求保护的本发明的另外的化合物。然而,实施例中所示出的化合物不应被解释为形成被认为是本发明的唯一种类。实施例进一步说明本发明化合物的制备细节。本领域技术人员将容易理解,以下制备程序的条件和方法的已知变体可用于制备这些化合物。
用于制备本发明化合物的原料可以通过实施例中所述的方法或通过本身已知的方法制备,如合成有机化学的文献中所述和本领域技术人员已知的方法,或可以商业获得。
式(IV)的化合物的合成描述于WO 2016/050356、WO 2016/050355、WO 2016/050359和WO 2016/050358中。
实施例
LCMS:
方法A:Agilent 70108359-Chromolith Speed Rod RP18e 50-4.6mm;极性.m;2.4mL/min;220nm;缓冲液A:0.05%HCOOH/H2O,缓冲液B:0.04%HCOOH/ACN;0.0-2.8min4%-100%缓冲液B;2.8-3.3min 100%缓冲液B;3.3-3.4min 100%-4%缓冲液B。
方法B:Waters XBrigde C8 3.5μm;4.6x50mm;EliteLa Chrom 70173815;8.1min;2ml/min;215nm;缓冲液A:0.05%TFA/H2O;缓冲液B:0.04%TFA/ACN;0.0-0.2min 5%缓冲液B;0.2-8.5min 5%-100%缓冲液B;8.5-10.0min 99%-5%缓冲液。
RT:保留时间。
本发明将通过参考在以下实施例中描述的具体实施方案来说明,但不限于此。除非在方案中另外指出,否则变量具有与上述相同的含义。
除非另有说明,否则所有原料均从商业供应商获得,并且不经进一步纯化即使用。除非另有说明,否则所有温度以℃表示,所有反应在室温下进行。化合物可以通过常规方法如特别是硅胶色谱法或制备型HPLC纯化。
除非另有说明,否则在没有指出具体立体化学的情况下,下文指出的所有结构是指立体异构体的混合物。
中间体1:
步骤1:2-(2,4-二甲基-苄基)-4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷
向1-溴甲基-2,4-二甲基-苯(25.00g;114.40mmol;1.00eq.)的脱气二噁烷(250.00ml)溶液中加入双(频哪醇合)二硼(35.21g;137.28mmol;1.20eq.)、干燥的K2CO3(47.91g;343.19mmol;3.00eq.)和四(三苯基膦)合钯(0)(6623mg;5.72mmol;0.05eq.)。随后在100℃、氮气气氛下将反应混合物加热16小时。反应混合物用二氯甲烷稀释并通过硅藻土。将滤液浓缩。将残余物溶解在乙酸乙酯中并用盐水洗涤。有机层经无水Na2SO4干燥,过滤并浓缩。粗品使用1%乙酸乙酯/石油醚通过柱色谱法纯化,得到2-(2,4-二甲基-苄基)-4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷(11.50g;37.84mmol;33.1%),为无色液体。
1H NMR(400MHz,CDCl3)δ7.04-7.02(m,1H),6.95-6.93(m,1H),6.92-6.90(m,1H),2.28(s,3H),2.25(s,3H),2.23(s,2H),1.24(s,12H)。
步骤2:(1S,2S,6R,8S)-4-(2,4-二甲基-苄基)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷
在氮气气氛下向冰冷的2-(2,4-二甲基-苄基)-4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷(24.00g;79.3mmol;1.0eq.)在乙醚(240.00ml)中的溶液中加入(1S,2S,3R,5S)-2,6,6-三甲基-双环[3.1.1]庚烷-2,3-二醇(20.68g;119.07mmol;1.50eq.),反应混合物在室温下搅拌14小时。TLC分析表明反应完成。反应混合物用盐水洗涤。有机层经无水Na2SO4干燥并浓缩。粗品使用2%乙酸乙酯/石油醚通过快速柱色谱法纯化,得到(1S,2S,6R,8S)-4-(2,4-二甲基-苄基)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(28.00g;82.96mmol;90.0%),为无色油。
1H NMR(400MHz,CDCl3):δ7.05-7.03(m,1H),6.95-6.94(m,1H),6.92-6.90(m,1H),4.27-4.25(m,1H),2.33-2.30(m,9H),2.27-2.17(m,1H),2.05(t,J=5.76Hz,1H),1.90-1.89(m,1H),1.84-1.80(m,1H),1.38(s,3H),1.28(s,3H),1.11-1.09(m,1H),0.91(s,3H)
GCMS:m/z:298.3。
步骤3:(1S,2S,6R,8S)-4-[(S)-1-氯-2-(2,4-二甲基-苯基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷
在氮气的正压下将在四氢呋喃(140.00ml)中的二氯甲烷(37.33ml;583.45mmol;3.00eq.)置于BT-烧瓶(圆底烧瓶)中并用液氮-乙醇混合物冷却至-99℃。通过BT-烧瓶的侧口向其中滴加正丁基锂(1.6M,在THF中)(133.71ml;213.93mmol)(以中等速率,加入约用35分钟),使得内部温度保持在-92℃和-102℃之间。加入后,将反应混合物搅拌25分钟。在反应期间形成白色沉淀(内部温度保持在-90℃和-96℃之间)。随后通过BT-烧瓶的侧口滴加(1S,2S,6R,8S)-4-(2,4-二甲基-苄基)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(58.00g;194.5mmol)的THF(300.00ml)溶液(约40分钟),使得内部温度保持在-94℃和-100℃之间。加入后,将反应混合物搅拌10分钟。随后通过BT-烧瓶的侧口滴加氯化锌(0.5M,在THF中)(388.97ml;194.48mmol)(以中等速率,加入约用35分钟),使得内部温度保持在-94℃和-99℃之间。随后让反应混合物缓慢达到20℃并在20℃下搅拌2.5小时。对反应混合物的等分试样进行后处理并通过1H NMR分析,其表明反应完成。将反应混合物浓缩(浴温30℃)。将残余物在乙醚和饱和NH4Cl溶液之间分配。有机层经无水Na2SO4干燥并浓缩(浴温30℃),得到(1S,2S,6R,8S)-4-[(S)-1-氯-2-(2,4-二甲基-苯基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(75.70g;154.83mmol;79.6%),为白色固体。
1H NMR(400MHz,CDCl3):7.12(d,J=7.64Hz,1H),6.98(s,1H),6.96(d,J=7.68Hz,1H),4.38-4.36(m,1H),3.67-3.62(m,1H),3.18-3.11(m,2H),2.40-2.36(m,2H),2.32(s,3H),2.30(s,3H),2.23-2.20(m,1H),2.08(t,J=5.96Hz,1H),1.93-1.87(m,2H),1.36(s,3H),1.30(s,3H),1.14-1.11(m,1H),0.84(s,3H).7.18-7.08(m,5H),4.37(dd,J=1.32,8.74Hz,1H),3.77-3.75(m,1H),3.67-3.63(m,1H),3.19-3.17(m,1H),3.10-3.08(m,1H),2.36-2.31(m,5H),2.09(t,J=5.84Hz,1H),1.93-1.86(m,4H),1.39(s,3H),1.30(s,3H),1.13-1.10(m,1H),0.84(s,3H)。
GCMS:m/z:346.3。
步骤4:(1S,2S,6R,8S)-4-[(R)-2-(2,4-二甲基-苯基)-1-(1,1,1,3,3,3-六甲基-二硅氮烷-2-基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷
在氮气气氛的正压下将(1S,2S,6R,8S)-4-[(S)-1-氯-2-(2,4-二甲基-苯基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(75.70g;218.35mmol;1.00eq.)的THF(400.00ml)溶液冷却至-78℃。向该溶液中经30分钟时间滴加(双三甲基甲硅烷基)氨基锂(1.0M,在THF中)(262ml;262mmol;1.20eq.)。让反应混合物达到室温并在室温下搅拌18小时。在30℃的温度下蒸发反应混合物。残余物用己烷研磨并过滤形成的固体。让滤液在真空下静置一些时间,如果有任何固体形成则再次过滤。滤液在30℃的温度下浓缩,得到(1S,2S,6R,8S)-4-[(R)-2-(2,4-二甲基-苯基)-1-(1,1,1,3,3,3-六甲基-二硅氮烷-2-基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(80.10g;169.84mmol;77.8%;棕色油)。
1H NMR(400MHz,CDCl3):δ:7.06(d,J=7.64Hz,1H),6.94(s,1H),6.90(d,J=7.80Hz,1H),4.29-4.27(m,1H),3.15-3.10(m,1H),2.87-2.83(m,1H),2.58-2.53(m,1H),2.34-2.32(m,2H),2.30(s,3H),2.28(s,3H),2.15-2.13(m,1H),2.03(t,J=5.88Hz,1H),1.90-1.88(m,1H),1.81-1.77(m,1H),1.39(s,3H),1.32(s,3H),1.01-0.98(m,1H),0.93(s,3H),0.85(s,3H),0.09(s,18H)。
步骤5:(R)-2-(2,4-二甲基-苯基)-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸-4-基)-乙胺盐酸盐
在氮气气氛下将搅拌的(1S,2S,6R,8S)-4-[(R)-2-(2,4-二甲基-苯基)-1-(1,1,1,3,3,3-六甲基-二硅氮烷-2-基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(80.10g;169.84mmol;1.00eq.)的乙醚(400.00ml)溶液冷却至-10℃。向其中滴加2M盐酸/乙醚溶液(212.30ml;424.59mmol;2.50eq.)。反应混合物在室温下搅拌2小时。将反应混合物减压蒸发,得到(R)-2-(2,4-二甲基-苯基)-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸-4-基)-乙胺盐酸盐(63.00g;72.61mmol;42.8%;棕色固体)。
1H NMR(400MHz,DMSO-d6):δ8.19(s,3H),7.05(d,J=7.68Hz,1H),6.95(s,1H),6.90(d,J=8.16Hz,1H),4.31(dd,J=1.80,8.76Hz,1H),3.02-3.00(m,1H),2.99-2.92(m,1H),2.87-2.84(m,1H),2.26-2.24(m,3H),2.26(s,3H),2.24(s,3H),2.03-2.00(m,1H),1.91(t,J=5.68Hz,1H),1.82-1.80(m,1H),1.71-1.66(m,1H),1.31(s,3H),1.21(s,3H),0.98-0.96(m,1H),0.77(s,3H)。
通过类似于针对中间体1所述的序列,可以制备下列化合物
其中基团Y表示以下基团之一:
中间体2:
步骤1:苯并呋喃-3-基甲醇
用冰冷却1-苯并呋喃-3-甲醛(5g,34.2mmol)的甲醇(50mL)溶液并分批加入硼氢化钠(1.9g,51.3mmol)。将反应混合物在室温下搅拌1小时。将反应混合物浓缩并且残余物在饱和氯化铵和乙酸乙酯之间分配。分离有机层,经硫酸钠干燥并浓缩(5.0g,无色液体,98%)。
1H NMR(400MHz,CDCl3):δ7.70-7.68(m,1H),7.62(s,1H),7.52-7.50(m,1H),7.36-7.26(m,2H),4.86(s,2H)。
步骤2:3-(溴甲基)苯并呋喃
用三溴化磷(1.1mL,11.2mmol)处理冷的(0℃)苯并呋喃-3-基甲醇(5.0g,33.7mmol)的乙醚(50mL)溶液,将混合物在0℃下搅拌30分钟。随后将反应混合物倾入冰中并用醚萃取。有机层经硫酸钠干燥并浓缩(7.1g,黄色液体,100%)。
1H NMR(400MHz,CDCl3):δ7.74-7.71(m,2H),7.53(s,1H),7.39-7.31(m,2H),4.65(s,2H)。
步骤3:2-(苯并呋喃-3-基甲基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷
用双(频哪醇合)二硼(10.3g,40.5mmol)、碳酸钾(13.9g,101.0mmol),四(三苯基膦)合钯(0)(1.9g,1.7mmol)处理3-(溴甲基)苯并呋喃(7.1g,33.8mmol)在脱气的1,4-二噁烷(70ml)中的溶液,混合物在100℃下加热12小时。将烧瓶的内容物冷却至室温并经硅藻土床过滤。将滤液浓缩,粗品通过快速柱色谱在硅胶上纯化,用2-5%乙酸乙酯/石油醚洗脱,得到标题化合物(6.1g,69%),为黄色油。
1H NMR(400MHz,CDCl3)δ7.57-7.52(m,2H),7.46-7.44(m,1H),7.30-7.21(m,2H),2.23(s,2H),1.29(s,12H)。
步骤4:2-(苯并呋喃-3-基甲基)硼酸(+)-蒎烷二醇酯
用(1S,2S,3R,5S)-(+)-蒎烷二醇(6.0g,35.4mmol)处理2-(苯并呋喃-3-基甲基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(6.1g,23.6mmol)的乙醚(60ml)溶液。将反应混合物在室温下搅拌12小时,随后混合物用水洗涤两次,然后用盐水洗涤并经无水硫酸钠干燥,然后浓缩。粗产物通过快速柱色谱在硅胶上纯化,用5%乙酸乙酯/石油醚洗脱,得到标题化合物(6.3g,82%)。
1H NMR(400MHz,CDCl3):δ7.58-7.56(m,1H),7.55-7.53(m,1H),7.46-7.44(m,1H),7.28-7.23(m,2H),4.33(dd,J=1.88,8.76Hz,1H),2.34-2.32(m,1H),2.28(s,2H),2.22-2.21(m,1H),2.08(t,J=5.88Hz,1H),1.42(s,3H),1.29(s,3H),1.13(d,J=10.92Hz,1H),0.85(s,3H).GCMS:m/z:310。
步骤5:[(1S)-1-氯-2-(苯并呋喃-3-基甲基)硼酸(+)-蒎烷二醇酯
经20分钟向冷却的(-100℃)二氯甲烷(6.3ml,60.9mmol)和无水四氢呋喃(36ml)的混合物加入正丁基锂(1.6M,在己烷中,14.0ml,(22.3mmol)。在-100℃下搅拌20分钟后,经20分钟加入2-(苯并呋喃-3-基甲基)硼酸(+)-蒎烷二醇酯(6.3g,20.3mmol)的无水THF(22ml)溶液。随后在-100℃下经30分钟加入氯化锌溶液(0.5M,在THF中,36.5mL,18.2mmol)。让混合物达到室温并搅拌18小时并浓缩。向所得的油中加入乙醚和饱和氯化铵。有机层经无水硫酸钠干燥,并真空浓缩(残余物:7.3g,99%)。
1H NMR(400MHz,DMSO-d6):δ7.60-7.57(m,2H),7.49-7.47(m,1H),7.31-7.25(m,2H),4.36-4.34(m,1H),3.31-3.29(m,1H),3.24-3.22(m,1H),2.35-2.31(m,1H),2.14-2.12(m,1H),2.06(t,J=5.84Hz,1H),1.90-1.86(m,2H),1.42(s,3H),1.04(d,J=11.04Hz,1H),0.85(s,3H).GCMS:m/z:358.2。
步骤6:[(1R)-1-[双(三甲基甲硅烷基)氨基]-2-(苯并呋喃-3-基甲基)硼酸(+)-蒎烷二醇酯
向冷却的(-78℃)[(1S)-1-氯-2-(苯并呋喃-3-基甲基)硼酸(+)-蒎烷二醇酯(7.3g,20.3mmol)的40ml无水四氢呋喃溶液中加入双(三甲基甲硅烷基)氨基锂(1M,在THF中,25.5ml,25.5mmol)。让混合物到室温,搅拌18小时并浓缩至干。向所得残余物中加入己烷,然后滤出沉淀的固体。将滤液浓缩,得到所需的粗产物(6.7g,68%)。
1H NMR(400MHz,CDCl3):δ7.60-7.59(m,1H),7.50-7.45(m,2H),7.28-7.24(m,2H),4.31(dd,J=1.56,8.70Hz,1H),3.18-3.14(m,1H),2.92-2.90(m,1H),2.75-2.72(m,1H),2.34-2.30(m,1H),2.15-2.14(m,1H),2.03(t,J=5.68Hz,1H),1.88-1.80(m,2H),1.39(s,3H),1.30(s,3H),1.01(d,J=10.88Hz,1H),0.84(s,3H),0.09(s,18H)。
步骤7:[(1R)-1-氨基-2-(苯并呋喃-3-基甲基)硼酸(+)-蒎烷二醇酯三氟乙酸盐
滴加三氟乙酸(3.2ml,41.7mmol)处理冷却的(0℃)[(1R)-1-[双(三甲基甲硅烷基)氨基]-2-(苯并呋喃-3-基甲基)硼酸(+)-蒎烷二醇酯(6.7g,13.9mmol)的乙醚(30ml)溶液。随后反应混合物在室温下搅拌3小时。观察到沉淀。将反应混合物冷却至0℃并过滤。滤出的固体用冷醚洗涤并在真空下干燥,得到标题化合物(2.3g,白色固体,36%)。
1H NMR(400MHz,DMSO-d6):δ7.66(s,1H),7.61-7.60(m,1H),7.47-7.45(m,1H),7.29-7.20(m,2H),4.30-4.28(m,1H),3.27-3.16(m,3H),2.25-2.13(m,3H),1.94(t,J=5.56Hz,1H),1.86-1.81(m,2H),1.25(s,6H),1.01(d,J=8.00Hz,1H),0.75(s,3H)。
中间体3:2-(7-甲基-苯并呋喃-3-基)-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸-4-基)-乙胺盐酸盐
步骤1:7-甲基-苯并呋喃-3-甲酸乙酯
向2-羟基-3-甲基-苯甲醛(20.00g;139.55mmol;1.00eq.)的二氯甲烷(120mL)溶液中加入四氟硼酸二乙醚络合物(1.88ml;13.96mmol;0.10eq.)。在25-30℃(内部温度)下向所得暗红色混合物中缓慢滴加在二氯甲烷(80mL)中的重氮乙酸乙酯(31.70ml;300.04mmol;2.15eq.),历时约50分钟。16小时后,加入浓H2SO4。将反应混合物搅拌30分钟。随后用固体NaHCO3中和反应混合物,通过硅藻土过滤,将滤液浓缩,得到粗残余物。将残余物通过柱色谱法使用2%乙酸乙酯/石油醚纯化,得到7-甲基-苯并呋喃-3-甲酸乙酯(19.00g;86.83mmol;62.2%;黄色油)。
HPLC(方法A):RT 4.98min(HPLC纯度93%)
1H NMR,400MHz,CDCl3:8.27(s,1H),7.88-7.90(m,1H),7.25-7.29(m,1H),7.17(d,J=7.32Hz,1H),4.39-4.45(m,2H),2.55(s,3H),1.44(t,J=7.16Hz,3H)。
步骤2:(7-甲基-苯并呋喃-3-基)-甲醇
在氮气、-78℃下向7-甲基-苯并呋喃-3-甲酸乙酯(19.00g;86.83mmol;1.00eq.)的二氯甲烷(190.00ml)溶液中滴加二异丁基氢化铝(1.0M,在甲苯中)(191.03ml;191.03mmol;2.20eq.)。让反应混合物达到室温并搅拌1小时。将反应混合物用冰浴冷却,并用1.5N HCl水溶液猝灭。将所得混合物(其具有悬浮在溶剂中的粘性固体物质)用乙酸乙酯稀释并通过硅藻土过滤。用乙酸乙酯和二氯甲烷充分洗涤硅藻土床。蒸发滤液,得到粗残余物。取出残留在硅藻土床中的固体,用乙酸乙酯研磨并过滤。将滤液与粗残余物混合在一起并蒸发。将由此得到的残余物放入乙酸乙酯中,用1.5N HCl水溶液和盐水洗涤。有机层经无水Na2SO4干燥并浓缩。得到的残余物使用40-50%乙酸乙酯/石油醚作为洗脱剂通过快速柱色谱法纯化,得到(7-甲基-苯并呋喃-3-基)-甲醇(8.20g;48.40mmol;55.7%;浅黄色油)。
HPLC(方法A):RT 3.33min.,(HPLC纯度95.7%)。
1H NMR,400MHz,CDCl3:7.64(s,1H),7.50-7.52(m,1H),7.17-7.21(m,1H),7.14(d,J=7.20Hz,1H),4.86-4.86(m,2H),2.54(s,3H)。
步骤3:3-(溴甲基)-7-甲基-苯并呋喃
在氮气气氛下向冰冷却的(7-甲基-苯并呋喃-3-基)-甲醇(8.20g;48.40mmol;1.00eq.)的乙醚(82.00ml)溶液中滴加三溴化磷(1.53ml;16.12mmol;0.33eq.),并将反应混合物在冰冷条件下搅拌30分钟。将反应混合物倾入冰中,用乙醚萃取。将有机层经无水Na2SO4干燥并浓缩,得到3-溴甲基-7-甲基-苯并呋喃(10.00g;44.43mmol;91.8%;无色油)。
1H NMR,400MHz,CDCl3:7.71(s,1H),7.53-7.55(m,1H),7.21-7.25(m,1H),7.16(d,J=7.32Hz,1H),4.65(s,2H),2.48(s,3H)。
步骤4:7-甲基-3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基甲基)-苯并呋喃
向3-溴甲基-7-甲基-苯并呋喃(10.00g;44.43mmol;1.00eq.)在脱气的1,4-二噁烷(100.00ml)中的溶液中加入双(频哪醇合)二硼(13.68g;53.31mmol;1.20eq.)、干燥的K2CO3(18.61g;133.28mmol;3.00eq.)和四(三苯基膦)合钯(0)(2.57g;2.22mmol;0.05eq.)。然后在100℃、氮气气氛下将反应混合物加热16小时。将反应混合物用二氯甲烷稀释并通过硅藻土过滤。浓缩滤液。将残余物溶于乙酸乙酯中,用盐水洗涤。有机层经无水Na2SO4干燥并浓缩。粗品使用2%乙酸乙酯/石油醚通过柱色谱法纯化,得到7-甲基-3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基甲基)-苯并呋喃(5.00g;18.37mmol;41.4%;无色液体)。
1H NMR,400MHz,DMSO-d6:7.65(s,1H),7.33-7.35(m,1H),7.07-7.13(m,2H),2.43(s,3H),2.13(s,2H),1.16(s,12H)。
步骤5:三甲基-4-(7-甲基-苯并呋喃-3-基甲基)-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷
在氮气气氛下向冰冷却的7-甲基-3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基甲基)-苯并呋喃(5.00g;18.37mmol;1.00eq.)的Et2O(50.00ml)溶液中加入1S,2S,3R,5S-(+)-2,3-蒎烷二醇(4.69g;27.56mmol;1.50eq.),并将反应混合物在室温搅拌14小时。TLC分析显示反应完成。用盐水洗涤反应混合物。有机层经无水Na2SO4干燥并浓缩。粗品使用2%乙酸乙酯/石油醚通过快速柱色谱法纯化,得到(1S,2S,6R,8S)-2,9,9-三甲基-4-(7-甲基-苯并呋喃-3-基甲基)-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(5.00g;13.00mmol;70.7%;无色液体)。
GCMS:m/z:324.2
1H NMR,400MHz,CDCl3:7.53-7.55(m,1H),7.39-7.40(m,1H),7.12-7.27(m,1H),7.06-7.08(m,1H),4.31-4.34(m,1H),2.53(s,3H),2.30-2.37(m,1H),2.26(s,2H),2.18-2.23(m,1H),2.07(t,J=5.76Hz,1H),1.84-1.93(m,2H),1.42(s,3H),1.29(s,3H),1.12-1.15(m,1H),0.85(s,3H)。
步骤6:(1S,2S,6R,8S)-4-[1-氯-2-(7-甲基-苯并呋喃-3-基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷
在氮气的正压下将在THF(40mL)中的二氯甲烷(2.96ml;46.26mmol;3.00eq.)加入RB-烧瓶中,并用液氮-乙醇混合物冷却至-95℃。通过RB-烧瓶的侧口向其中滴加正丁基锂(1.6M,在己烷中)(10.60ml;16.96mmol;1.10eq.)(以中等速率,加入约用30分钟),使得内部温度保持在-95℃和-100℃之间。加入后,将反应混合物搅拌20分钟。在反应过程中形成白色沉淀(内部温度保持在-95℃和-100℃之间)。随后通过RB-烧瓶的侧口滴加(1S,2S,6R,8S)-2,9,9-三甲基-4-(7-甲基-苯并呋喃-3-基甲基)-3,5-二氧杂-4-硼杂-三环[6.1.1.02 ,6]癸烷(5.00g;15.42mmol;1.00eq.)的THF(20mL)溶液(约25分钟),以便将内部温度保持在-95℃和-100℃之间。在加入后,立即将氯化锌(0.5M,在THF中)(27.76ml;13.88mmol;0.90eq.)通过RB-烧瓶的侧口滴加(以中等速率,加入约用45分钟),以便将内部温度保持在-95℃和-100℃之间。然后将反应混合物缓慢达到室温并在室温搅拌16小时。浓缩反应混合物(浴温30℃)。将残余物在乙醚和饱和NH4Cl溶液之间分配。分离有机层,经无水Na2SO4干燥并浓缩(浴温30℃),得到(1S,2S,6R,8S)-4-[1-氯-2-(7-甲基-苯并呋喃-3-基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(5.90g;15.83mmol;102.7%;棕色液体)。
1H NMR,400MHz,CDCl3:7.57(s,1H),7.42-7.44(m,1H),7.27(s,1H),7.09-7.18(m,1H),4.34-4.36(m,1H),3.74-3.76(m,1H),3.28-3.30(m,1H),3.20-3.22(m,1H),2.52(s,3H),2.32-2.34(m,1H),2.07(t,J=5.88Hz,1H),1.85-1.91(m,2H),1.42(s,3H),1.29(s,3H),1.06-1.09(m,1H),0.85(s,3H)。
步骤7:((1S,2S,6R,8S)-4-[1-(1,1,1,3,3,3-六甲基-二硅氮烷-2-基)-2-(7-甲基-苯并呋喃-3-基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷
在氮气气氛的正压下将(1S,2S,6R,8S)-4-[1-氯-2-(7-甲基-苯并呋喃-3-基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(5.90g;15.83mmol;1.00eq.)的THF(40.00ml)溶液冷却至-78℃。经30分钟向该溶液滴加(双三甲基甲硅烷基)氨基锂(1.0M,在THF中)(17.41ml;17.41mmol;1.10eq.)。使反应混合物达到室温并在室温搅拌18小时。在30℃蒸发反应混合物,残余物用正己烷研磨,过滤形成的固体。将滤液在30℃下浓缩,得到(1S,2S,6R,8S)-4-[1-(1,1,1,3,3,3-六甲基-二硅氮烷-2-基)-2-(7-甲基-苯并呋喃-3-基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(6.00g;12.06mmol;76.2%;棕黑色油)。
1H NMR,400MHz,CDCl3:7.50(s,1H),7.41-7.43(m,1H),7.12-7.16(m,1H),7.06-7.08(m,1H),4.29-4.32(m,1H),3.17-3.09(m,1H),2.70-2.89(m,1H),2.52-2.70(m,1H),2.52(s,3H),2.28-2.31(m,1H),2.14-2.14(m,1H),2.03(t,J=5.68Hz,1H),1.78-1.89(m,2H),1.39(s,3H),1.31(s,3H),1.01-1.04(m,1H),0.90-0.92(m,2H),0.88(s,3H),0.12(s,18H)。
步骤8:2-(7-甲基-苯并呋喃-3-基)-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸-4-基)-乙胺盐酸盐
在氮气气氛下将搅拌的(1S,2S,6R,8S)-4-[1-(1,1,1,3,3,3-六甲基-二硅氮烷-2-基)-2-(7-甲基-苯并呋喃-3-基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(6.00g;12.06mmol;1.00eq.)的乙醚(60.00ml)溶液冷却至-10℃。向其中滴加2M盐酸的乙醚溶液(15.07ml;30.14mmol;2.50eq.)。反应混合物在室温下搅拌2小时。在30℃下蒸发反应混合物。向残余物中加入乙醚(20mL)并滤出形成的固体,用冷乙醚洗涤,真空干燥,得到2-(7-甲基-苯并呋喃-3-基)-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸-4-基)-乙胺盐酸盐(3.50g;8.98mmol;74.5%;棕橙色固体)。
1H NMR,400MHz,DMSO-d6:8.09(s,3H),7.83(s,1H),7.52-7.53(m,1H),7.12-7.19(m,2H),4.39(dd,J=1.84,8.62Hz,1H),3.07-3.13(m,1H),3.03-3.07(m,2H),2.43(s,4H),2.28-2.30(m,1H),2.07-2.08(m,1H),1.92(t,J=5.68Hz,1H),1.82-1.84(m,1H),1.71-1.75(m,1H),1.19-1.25(m,8H),1.00-1.08(m,1H),0.78(s,3H)。
中间体4:2-(7-氯-苯并呋喃-3-基)-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸-4-基)-乙胺盐酸盐
步骤1:7-氯-苯并呋喃-3-甲酸乙酯:
向3-氯-2-羟基-苯甲醛(25.00g;156.48mmol;1.00eq.)的二氯甲烷(250ml)溶液中加入四氟硼酸二乙醚络合物(2.11ml;15.65mmol;0.10eq.)。在25-30℃(内部温度)下向所得暗红色混合物中缓慢滴加溶于二氯甲烷(50mL)的重氮乙酸乙酯(35.55ml;336.44mmol;2.15eq.),历时约50分钟。16小时后,加入浓H2SO4。将反应混合物搅拌15分钟。然后用固体NaHCO3中和反应混合物,通过硅藻土过滤,浓缩滤液,得到粗残余物。残余物使用2%乙酸乙酯/石油醚通过柱色谱法纯化,得到7-氯-苯并呋喃-3-甲酸乙酯2(18.20g;81.02mmol;51.8%;无色液体)。
1H NMR,400MHz,DMSO-d6:8.88(s,1H),7.95-7.93(m,1H),7.57-7.55(m,1H),7.42(t,J=7.8Hz,1H),4.38-4.33(m,2H),1.35(t,J=7.1Hz,3H)。
步骤2:(7-氯-苯并呋喃-3-基)-甲醇:
在-78℃下向搅拌的7-氯-苯并呋喃-3-甲酸乙酯(450g;2.0089mol;1.00eq.)的DCM(4500ml)溶液中加入1.0M氢化二异丁基铝的甲苯溶液(4017ml;4.0178mol;2.20eq.)。然后使反应混合物缓慢达到室温并在室温搅拌2小时。TLC证实反应完成后,将反应混合物用1.5N HCl(500mL)猝灭,通过硅藻土,用DCM(2000mL)洗涤。滤液用盐水溶液(1×2000mL)洗涤。分离有机层,经Na2SO4干燥,过滤并真空浓缩。粗产物进行柱色谱分离并用15%乙酸乙酯/石油醚洗脱,得到(7-氯-苯并呋喃-3-基)-甲醇3(365g;2.0054mol;99.8%;白色固体泡沫)。
1H NMR,400MHz,DMSO-d6:7.99(s,1H),7.66(dd,J=1.0,7.8Hz,1H),7.41(dd,J=0.8,7.8Hz,1H),7.26(t,J=7.8Hz,1H),5.24(t,J=5.6Hz,1H),4.63-4.62(m,2H)。
步骤3:3-溴甲基-7-氯-苯并呋喃:
在氮气气氛下向冰冷却的(7-氯-苯并呋喃-3-基)-甲醇(365g;2.0054mol;1.00eq.)的乙醚(3650ml)溶液中滴加三溴化磷(62.2ml;0.6618mol;0.33eq.)。将反应混合物在冰浴冷却下搅拌30分钟。随后,将反应混合物倾入冰中,用乙醚萃取。有机层经无水Na2SO4干燥,过滤并浓缩,得到3-溴甲基-7-氯-苯并呋喃(480g;1.9591mol;97.71%;白色固体)。
1H NMR,400MHz,DMSO-d6:8.29(s,1H),7.72(dd,J=1.0,7.8Hz,1H),7.49(dd,J=0.8,7.8Hz,1H),7.36(t,J=7.8Hz,1H),4.90(s,2H)。
步骤4:7-氯-3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基甲基)-苯并呋喃:
向3-溴甲基-7-氯-苯并呋喃(480g;1.9591mol;1.00eq.)在脱气的1,4-二噁烷(4800ml)中的溶液中加入双(频哪醇合)二硼(596.9g;2.3510mol;1.20eq.)、干燥的乙酸钾(576.8g;5.877mol;3.00eq.)和与二氯甲烷络合的[1,1′-双(二苯基膦基)二茂铁]二氯化钯(II)(70.33g;0.0979mol;0.05eq.)。然后将反应混合物在100℃、氮气气氛下加热过夜。将反应混合物用二氯甲烷稀释并通过硅藻土。浓缩滤液。将残余物溶于乙酸乙酯中,用盐水洗涤(1000mL×1)。有机层经无水Na2SO4干燥,过滤并真空浓缩。粗材料使用2%乙酸乙酯/石油醚通过柱色谱法纯化,得到7-氯-3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基甲基)-苯并呋喃(480g;1.6438mol;83.9%;黄色半固体)。
GCMS:m/z:292(柱:DB-5ms(15m x 0.25mm x 0.25μm);载气:氦气,流速:2.0mL/min)。
1H NMR,400MHz,DMSO-d6:7.79(s,1H),7.52(dd,J=1.0,7.8Hz,1H),7.38(dd,J=0.8,7.8Hz,1H),7.27-7.23(m,1H),2.17(s,2H),1.18(s,12H)。
步骤5:(1S,2S,6R,8S)-4-(7-氯-苯并呋喃-3-基-甲基)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷:
在氮气气氛下向冰冷却的7-氯-3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基甲基)-苯并呋喃(480g;1.6438mol;1.00eq.)的乙醚(5000ml)溶液中加入1S,2S,3R,5S-(+)-2,3-蒎烷二醇(335.7g;1.9726mol;1.20eq.)。将反应混合物在室温搅拌16小时。反应混合物用水(2000mL×1)和盐水(1500mL×1)洗涤。有机层经无水Na2SO4干燥,过滤并浓缩。将粗材料使用1%乙酸乙酯/石油醚通过快速色谱法纯化,得到(1S,2S,6R,8S)-4-(7-氯-苯并呋喃-3-基-甲基)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(520g;1.510mol;91.9%;浅黄色半固体)。
GCMS:m/z:344(柱:HP-5MS(12m x 0.20D mm x 0.33μm);载气:氦气,流速:2.0mL/min)
1H NMR,400MHz,DMSO-d6:7.80(s,1H),7.54(dd,J=0.9,7.8Hz,1H),7.38(dd,J=0.7,7.8Hz,1H),7.24(t,J=7.8Hz,1H),4.33(t,J=6.9Hz,1H),2.29-2.24(m,3H),2.14-2.10(m,1H),1.93(t,J=5.4Hz,1H),1.84-1.81(m,1H),1.70-1.65(m,1H),1.31(s,3H),1.21(s,3H),0.98(d,J=10.72Hz,1H),0.78(s,3H)。
步骤6:(1S,2S,6R,8S)-4-[(S)-1-氯-2-(7-氯-苯并呋喃-3-基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷:
在氮气的正压下将在THF(1200mL)中的二氯甲烷(95.7ml;1.499mol;3.00eq.)放入RB-烧瓶中并用液氮-乙醇混合物冷却到-95℃。通过RB-烧瓶的侧口向其中滴加正丁基锂(1.6M,在THF中)(343.6ml;0.549mol;1.10eq.)(以中等速率,加入约用45分钟),以便将内部温度保持在-95℃和-100℃之间,在加入后,将反应混合物搅拌30分钟。在反应过程中形成白色沉淀(内部温度保持在-95℃和-100℃之间)。随后,通过RB-烧瓶的侧口滴加(1S,2S,6R,8S)-4-(7-氯-苯并呋喃-3-基甲基)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(172g;0.4999mol;1.00eq.)的THF(500mL)溶液(约25分钟),使得再次将内部温度保持在-95℃和-100℃之间。在完成加入后,立即通过RB-烧瓶的侧口滴加氯化锌(0.5M,在THF中)(1599.6ml;0.7998mol;1.6eq.)(以中等速率,加入约用40分钟),使得内部温度保持在-95℃和-100℃之间。随后使反应混合物缓慢达到-5℃并在-5℃搅拌1.5小时。通过加入饱和NH4Cl溶液(500mL)猝灭反应混合物。将反应混合物真空浓缩(浴温30℃)。将残余物在乙醚和饱和NH4Cl溶液之间分配。分离有机层,经无水Na2SO4干燥并浓缩(浴温30℃),得到(1S,2S,6R,8S)-4-[(S)-1-氯-2-(7-氯-苯并呋喃-3-基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(205g;0.5214mol;104.5%;橙色油)。
GCMS:m/z:392(柱:ZB-1MS(10m x 0.101D mm x 0.1μm);载气:氦气,流速:2.0mL/min)
1H NMR,400MHz,CDCl3:7.64(s,1H),7.50(d,J=8.00Hz,1H),7.33-7.31(m,1H),7.23-7.21(m,1H),4.36-4.34(m,1H),3.29-3.27(m,1H),3.22-3.20(m,1H),2.34-2.32(m,1H),2.15-2.14(m,1H),2.06(t,J=5.60Hz,1H),1.91-1.83(m,7H),1.36(s,3H),1.29(s,3H),1.05-1.02(m,1H),0.85(s,3H)。
步骤7:(1S,2S,6R,8S)-4-[(R)-2-(7-氯-苯并呋喃-3-基)-1-(1,1,1,3,3,3-六甲基-二硅氮烷-2-基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷:
在氮气气氛的正压下将(1S,2S,6R,8S)-4-[(S)-1-氯-2-(7-氯-苯并呋喃-3-基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(205g;0.5214mol;1.00eq.)的THF(2050ml)溶液冷却至-78℃。经30分钟时间向该溶液中滴加(双-三甲基甲硅烷基)-氨基锂(1.0M,在THF中)(625ml;0.6257mol;1.20eq.)。让反应混合物达到室温并在室温下搅拌18小时。在30℃下蒸发反应混合物的溶剂。残余物用己烷研磨并过滤形成的固体。让滤液在真空下静置一些时间,如果有任何固体形成则再次过滤。将滤液在30℃下浓缩,得到(1S,2S,6R,8S)-4-[(R)-2-(7-氯-苯并呋喃-3-基)-1-(1,1,1,3,3,3-六甲基-二硅氮烷-2-基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(180g;0.3481mol;66.7%;橙色油)。
1H NMR,400MHz,CDCl3:7.63(s,1H),7.51-7.49(m,1H),7.29-7.27(m,1H),7.19-7.15(m,1H),4.32-4.29(m,1H),3.63-3.61(m,1H),3.14-3.12(m,1H),2.87-2.85(m,1H),2.26-2.24(m,1H),2.14-2.12(m,1H),1.88-1.86(m,1H),1.88-1.76(m,2H),1.33(s,3H),1.30(s,3H),1.02-0.99(m,1H),0.85(s,3H),0.07(s,18H)。
步骤8:(R)-2-(7-氯-苯并呋喃-3-基)-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸-4-基)-乙胺盐酸盐:
在氮气气氛下将搅拌的(1S,2S,6R,8S)-4-[(R)-2-(7-氯-苯并呋喃-3-基)-1-(1,1,1,3,3,3-六甲基-二硅氮烷-2-基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(180g;0.348mol)的乙醚(1800ml)溶液冷却至-10℃。向该溶液中滴加盐酸的乙醚溶液(浓度2.0M;435.2ml;0.870mol;2.50eq.)。反应混合物在室温下搅拌2小时(在反应过程中观察到固体沉淀)。将反应混合物蒸发至干,将得到的固体用乙醚(500mL)研磨,随后过滤。用乙醚(3×300mL)洗涤滤饼并真空干燥,得到(R)-2-(7-氯-苯并呋喃-3-基)-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸-4-基)-乙胺盐酸盐(81.5g;0.1992mol;57.2%;灰白色固体)。
1H NMR,400MHz,CDCl3:8.09(s,3H),7.97(s,1H),7.73(dd,J=1.52Hz,7.76Hz,1H),7.44(d,J=7.76Hz,1H),7.31(d,J=7.80Hz,1H),4.42-4.40(m,1H),3.16-3.07(m,3H),2.32-2.27(m,1H),2.10-2.04(m,1H),1.93(t,J=5.56Hz,1H),1.83-1.71(m,2H),1.27(s,3H),1.25(s,3H),1.08-1.02(m,1H),0.79(s,3H)。
中间体5:(R)-2-(2,3-二氢-苯并呋喃-3-基)-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸-4-基)-乙胺盐酸盐
步骤1:(1S,2S,6R,8S)-4-(2,3-二氢-苯并呋喃-3-基甲基)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷
向在微型釜中(1S,2S,6R,8S)-4-苯并呋喃-3-基甲基-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(5.00g;10.72mmol;1.00eq.)的甲醇(100.00ml)溶液中加入碳载钯(10wt%)(2.28g;2.14mmol;0.20eq.)。在5Kg/cm2的H2压力下将内容物氢化3小时。TLC分析显示完全转化。将反应混合物通过硅藻土过滤,蒸发滤液。粗品通过Biotage-Isolera柱色谱法(C18柱;流动相:ACN/H2O;50:50等度)纯化,得到(1S,2S,6R,8S)-4-(2,3-二氢-苯并呋喃-3-基甲基)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(4.10g;13.13mmol;122.5%;浅黄色液体)。
GCMS:m/z:312.3。
步骤2:(1S,2S,6R,8S)-4-[1-氯-2-(7-甲基-苯并呋喃-3-基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷
在氮气的正压下将在THF(40.00ml)中的二氯甲烷(2.46ml;38.44mmol;3.00eq.)放入RB-烧瓶并用液氮-乙醇混合物冷却至-95℃。通过RB-烧瓶的侧口向其中滴加正丁基锂(1.6M,在THF中)(8.81ml;14.09mmol;1.10eq.)(以中等速率,加入约用20分钟),使得内部温度保持在-95℃和-100℃之间。加入后,将反应混合物搅拌25分钟。在反应过程中形成白色沉淀(内部温度保持在-95℃和-100℃之间)。随后通过RB-烧瓶的侧口滴加(1S,2S,6R,8S)-4-(2,3-二氢-苯并呋喃-3-基甲基)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(4.00g;12.81mmol;1.00eq.)的THF(15.00ml)溶液(约25分钟),使得内部温度保持在-95℃和-100℃之间。加入后,通过RB烧瓶的侧口立即滴加氯化锌(0.5M,在THF中)(25.62ml;12.81mmol;1.00eq.)(以中等速率,加入约用25分钟),使得内部温度保持在-95℃和-100℃之间。随后让反应混合物缓慢达到室温并在室温下搅拌18小时。浓缩反应混合物(浴温30℃)。将残余物在乙醚和饱和NH4Cl溶液之间分配。将有机层经无水Na2SO4干燥并浓缩(浴温30℃),得到(1S,2S,6R,8S)-4-[(S)-1-氯-2-(2,3-二氢-苯并呋喃-3-基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(4.60g;12.75mmol;99.5%;黄色油)。
1H NMR,400MHz,CDCl3:7.29(d,J=6.72Hz,1H),7.21-7.10(m,1H),6.90-6.77(m,2H),4.68-4.65(m,1H),4.32-4.29(m,2H),3.65-3.60(m,1H),2.40-2.08(m,4H),1.94-1.85(m,2H),1.42(s,3H),1.33(s,3H),1.22(s,3H),1.17-1.15(m,1H),0.86(s,3H)。
步骤3:(1S,2S,6R,8S)-4-[(R)-2-(2,3-二氢-苯并呋喃-3-基)-1-(1,1,1,3,3,3-六甲基-二硅氮烷-2-基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷
在氮气气氛的正压下将(1S,2S,6R,8S)-4-[(S)-1-氯-2-(2,3-二氢-苯并呋喃-3-基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(4.60g;12.75mmol;1.00eq.)的THF(45.00ml)溶液冷却至-78℃。经30分钟时间向该溶液中滴加(双三甲基甲硅烷基)氨基锂(1.0M,在THF中)(16.58ml;16.58mmol;1.30eq.)。让反应混合物达到室温并在室温下搅拌18小时。反应混合物在30℃下蒸发。残余物用己烷研磨并过滤形成的固体。让滤液在真空下静置一些时间,如果有任何固体形成则再次过滤。在30℃下浓缩滤液,得到(1S,2S,6R,8S)-4-[(R)-2-(2,3-二氢-苯并呋喃-3-基)-1-(1,1,1,3,3,3-六甲基-二硅氮烷-2-基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(3.77g;7.76mmol;60.9%;黄色油)。
1H NMR,400MHz,CDCl3:7.22-7.10(m,2H),6.90-6.79(m,2H),4.62-4.59(m,1H),4.33-4.27(m,1H),2.34-2.20(m,2H),2.07-2.05(m,1H),1.94-1.84(m,2H),1.40(s,3H),1.30(s,3H),1.15-1.13(m,1H),0.86(s,3H),0.10(s,18H)。
步骤4:(R)-2-(2,3-二氢-苯并呋喃-3-基)-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸-4-基)-乙胺盐酸盐
在氮气气氛下将搅拌的(1S,2S,6R,8S)-4-[(R)-2-(2,3-二氢-苯并呋喃-3-基)-1-(1,1,1,3,3,3-六甲基-二硅氮烷-2-基)-乙基]-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸烷(3.77g;7.76mmol;1.00eq.)的Et2O(35.00ml)溶液冷却至-10℃。向其中滴加2N HCl的乙醚溶液(9.70ml;19.41mmol;2.50eq.)。反应混合物在室温下搅拌2小时。反应混合物减压蒸发至干,得到固体。将形成的固体用乙醚研磨,过滤,用乙醚洗涤并真空干燥,得到(R)-2-(2,3-二氢-苯并呋喃-3-基)-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸-4-基)-乙胺盐酸盐(2.30g;5.25mmol;收率67.7%;浅棕色固体)。分析表明在指示的(*)位置存在异构体(~65.50%+20.75%)。
LCMS:4.73min.,86.25%(max),80.47%(220nm),342.20(M+1)。
1H NMR,400MHz,DMSO-d6:8.11(s,3H),7.23-7.19(m,1H),7.13-7.10(m,1H),6.85(t,J=7.40Hz,1H),6.77(d,J=8.04Hz,1H),4.61-4.57(m,1H),4.48-4.45(m,1H),4.25-4.22(m,1H),3.68-3.62(m,1H),2.90-2.85(m,1H),2.34-2.32(m,1H),2.19-2.17(m,1H),2.02-1.99(m,2H),1.89-1.77(m,3H),1.39(s,3H),1.25(s,3H),1.17-1.14(m,1H),0.82(s,3H)。
通过类似于针对中间体2-4所描述的序列,可以制备以下部分的其他实例
如在特定的化合物中,其中基团Y表示以下基团之一:
酸中间体1:(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-甲酸
步骤1:(1S,2R,4R)-7-氧杂-双环[2.2.1]庚烷-2-甲酸(R)-1-苯基-乙酯
在氩气气氛下在0℃搅拌下向7-氧杂-双环[2.2.1]庚烷-2-甲酸(4.680g;31.276mmol,外消旋)的干燥二氯甲烷(最多0,005%H2O)(100ml)溶液中加入(R)-1-苯基-乙醇(4.623ml;37.531mmol)、合成用4-(二甲基氨基)吡啶(DMAP)(3.821g;31.276mmol)和(3-二甲基氨基-丙基)-乙基-碳二亚胺盐酸盐(EDCI)(6.730g;34.404mmol)。随后,将澄清的反应溶液在室温下搅拌过夜。酯形成完成后,通过加入饱和NH4Cl水溶液来猝灭反应。随后,将混合物用CH2Cl2萃取两次。有机层用饱和NaHCO3水溶液和盐水洗涤三次,经Na2SO4干燥,过滤并蒸发至干。粗产物通过快速色谱法纯化(硅胶;正庚烷/乙酸乙酯0-30%乙酸乙酯),得到7.496g(30.43mmol,97.3%)无色油(HPLC:100%纯的非对映异构体混合物)。
通过制备型手性HPLC(Chiralcel OD-H;正庚烷/2-丙烷95:5;220nm)分离非对映异构体混合物,得到(1R,2S,4S)-7-氧杂-双环[2.2.1]庚烷-2-甲酸(R)-1-苯基乙酯(3.22g,无色油,收率41.8%,手性HPLC 100%)和(1S,2R,4R)-7-氧杂-双环[2.2.1]庚烷-2-甲酸(R)-1-苯基-乙酯(3.14g,油,收率40.7%手性HPLC 100%)。
步骤2:(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-甲酸
向(1S,2R,4R)-7-氧杂-双环[2.2.1]庚烷-2-甲酸(R)-1-苯基乙酯(46.74g;182.75mmol;1.00eq.)的THF(233.70ml)溶液中加入碳载钯(10%w/w)(1.94g;1.83mmol;0.01eq.)。在50℃和压力为5bar的H2气氛下将内容物氢化16小时。氢化完成后,将反应混合物通过硅藻土过滤,将滤液蒸发至干,纳入戊烷中。有机层用水萃取两次。随后,将水层冷冻干燥,得到(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-甲酸(22.62g;159.09mmol;收率87.1%),为无色固体。
TLC:氯仿/甲醇(9.5/0.5)Rf 0.5。1H-NMR 400MHz,DMSO-d6:12.16(s,1H),4.66(d,J=4.4Hz,1H),4.54(t,J=4.4Hz,1H),2.57(d,J=35.2Hz,1H),1.91-1.86(m,1H),1.65-1.37(m,4H),1.34-1.33(m,1H).旋光度[]20D=+31.9°;D20=+0,0644°(乙醇,20.16mg/10ml)。
酸中间体2:(1R,2S,4S)-7-氧杂双环[2.2.1]庚烷-2-甲酸
向(1R,2S,4S)-7-氧杂-双环[2.2.1]庚烷-2-甲酸(R)-1-苯基乙酯(4.52g;17.98mmol;1.00eq.)的THF(22.60ml)溶液中加入碳载钯(10%w/w)(0.19g;0.18mmol;0.01eq.)。内容物在50℃、H2气氛下氢化12小时。TLC分析显示启动已完成。反应混合物通过硅藻土过滤,将滤液蒸发,得到(1R,2S,4S)-7-氧杂-双环[2.2.1]庚烷-2-甲酸(2.10g;14.77mmol;82.1%;灰白色固体)。
1H-NMR 400MHz,DMSO-d6:12.16(s,1H),4.66(d,J=4.4Hz,1H),4.54(t,J=4.4Hz,1H),2.57(d,J=35.2Hz,1H),1.91-1.86(m,1H),1.65-1.37(m,4H),1.34-1.33(m,1H)。
酸中间体3:(1S,8R)-8-甲基-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6-三烯-1-甲酸锂(盐)
步骤1:8-甲基-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6,9-四烯-1-甲酸甲酯
在0℃下将亚硝酸异戊酯(3.64ml;27.12mmol)加入到3.72g邻氨基苯甲酸(27.12mmol)和三氟乙酸(0.26ml;3.39mmol)在45ml干燥THF中的溶液中。在0℃下将所得溶液剧烈搅拌几分钟,然后温热至室温。在室温搅拌1小时后,悬浮液的颜色变为黄色。滤出棕色固体,并用干燥THF洗涤,然后将其转移至含有5-甲基-呋喃-2-甲酸甲酯(2.00g;13.56mmol)的合成用乙二醇二甲醚(45.00ml)溶液的烧瓶中。随后将所得混合物逐渐加热至100℃直至分解完成,并在100℃下再搅拌1小时。蒸发溶剂后,将反应混合物通过快速色谱法纯化(硅胶;EE/庚烷梯度;0-25%EE),得到8-甲基-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6,9-四烯-1-甲酸甲酯(1.82g;53.7%;黄色胶),为1:1的立体异构体混合物。
LCMS方法A:(M+H)217.0;Rt 2.03min。
步骤2:(1S,8R)-8-甲基-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6-三烯-1-甲酸甲酯和(1R,8S)-8-甲基-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6-三烯-1-甲酸甲酯
在室温和常压下使用500mg Pd/C(54%水)将8-甲基-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6,9-四烯-1-甲酸甲酯(1.82g,7.28mmol)在18ml EE中的溶液氢化直到反应完成。将反应混合物过滤并将滤液浓缩。使用手性制备型SFC(手性Cel OD-H;CO2/2-丙醇58.5:1.5;220nm)分离残留的粘性油(立体异构体的混合物),得到(1S,8R)-8-甲基-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6-三烯-1-甲酸甲酯(439mg,收率25.3%)和(1R,8S)-8-甲基-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6-三烯-1-甲酸甲酯(449mg,收率25.9%),均为无色油。
LCMS方法A:(M+H)未检测;Rt 2.09min(对于两种化合物相同)。
步骤3:(1S,8R)-8-甲基-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6-三烯-1-甲酸锂(盐)
将(1S,8R)-8-甲基-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6-三烯-1-甲酸甲酯(0.439g;1.84mmol)纳入5ml去离子水中并加入2.5ml THF.LiOH(44mg,1.84mmol),将混合物在氩气下于室温搅拌1小时并蒸发,得到标题化合物,其不经进一步纯化即使用。
LCMS方法A:(M-Li+H-18)187;Rt 1.71min。
酸中间体4:(1R,8S)-8-甲基-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6-三烯-1-甲酸锂
将(1R,8S)-8-甲基-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6-三烯-1-甲酸甲酯(纯度91%;0.449g;1.88mmol)纳入5ml去离子水中并加入2.5ml THF.LiOH(45mg,1.88mmol),将混合物在氩气下于室温搅拌1小时并蒸发,得到标题化合物。
LCMS方法A:(M-Li+H-18)187;Rt 1.71min。
酸中间体5:(1S,8R)-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6-三烯-9-甲酸
步骤1:呋喃-3-甲酸(R)-1-苯基-乙酯
在氩气气氛下于0℃向3-呋喃甲酸(2.00g;17.84mmol)的40ml干燥二氯甲烷溶液中加入(R)-1-苯基-乙醇(2.64ml;21.41mmol)、4-二甲基氨基-吡啶(2.18g;17.85mmol)和(3-二甲基氨基-丙基)-乙基碳二亚胺盐酸盐(3.84g;19.63mmol)。不经进一步冷却而将澄清的反应溶液搅拌3小时。反应溶液用饱和NH4Cl猝灭并用二氯甲烷萃取。有机层用饱和NaHCO3和盐水洗涤3次,经Na2SO4干燥并过滤。蒸发溶剂后,反应混合物通过快速色谱法纯化(硅胶;EE/庚烷梯度;0-30%EE),得到呋喃-3-甲酸(R)-1-苯基-乙酯(3.55g;收率90%;黄色油)。
LCMS方法A:(M+H)未检测;Rt 2.46min。
步骤2:(1R,8R)-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6,9-四烯-9-甲酸(R)-1-苯基乙酯和(1S,8S)-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6,9-四烯-9-甲酸(R)-1-苯基乙酯
在0℃下将亚硝酸异戊酯(1.91ml;14.18mmol)加入邻氨基苯甲酸(1.94g,14.18mmol)和三氟乙酸(0.137ml;1.77mmol)在22ml干燥THF中的溶液中。将得到的溶液在0℃下剧烈搅拌几分钟,然后温热至室温。在室温搅拌1小时后,悬浮液的颜色变为黄色。通过倾析除去液体,并用干燥THF洗涤剩余的棕色固体,然后将其转移至装有呋喃-3-甲酸(R)-1-苯基乙酯(1.60g;7.09mmol)的合成用乙二醇二甲醚(22ml)溶液的烧瓶中。随后将所得混合物逐渐加热至100℃直至分解完成,并在100℃下再搅拌1小时。蒸发溶剂后,将反应混合物通过快速色谱法(硅胶;EE/庚烷梯度;0-35%EE)纯化,得到677mg 11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6,9-四烯-9-甲酸(R)-1-苯基乙酯(677mg,无色油),为非对映异构体混合物。该混合物使用手性制备型HPLC(Chiral Pak AD;正庚烷/乙醇1:1;220nm)分离,得到(1R,8R)-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6,9-四烯-9-甲酸(R)-1-苯基乙酯(190mg,手性HPLC>97%;Rt 7.73min)和(1S,8S)-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6,9-四烯-9-甲酸(R)-1-苯基乙酯(180mg;手性HPLC>96%;Rt 12.53min)。
步骤3:(1S,8R)-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6-三烯-9-甲酸(R)-1-苯基乙酯
在室温和常压下使用500mg Pd/C(54%水)将(1S,8S)-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6,9-四烯-9-甲酸(R)-1-苯基乙酯(0.470g,1.190mmol)的10ml THF溶液氢化,直到反应完成。将反应混合物过滤,将滤液浓缩并通过快速色谱法(硅胶;EE/庚烷梯度;0-60%EE)纯化,得到(1S,8R)-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6-三烯-9-甲酸(R)-1-苯基乙酯(184mg),为无色油。
LCMS方法A:(M+H)未检测;Rt 2.51min.
步骤4:(1S,8R)-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6-三烯-9-甲酸
在室温和常压下使用200mg Pd/C(54%水)将(1S,8R)-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6-三烯-9-甲酸(R)-1-苯基乙酯(0.184g,0.626mmol)的10ml THF溶液氢化过夜。过滤反应混合物,蒸发滤液,得到130mg(1S,8R)-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6-三烯-9-甲酸,为白色固体。
LCMS方法A:(M-18)174;Rt 1.42min。
酸中间体6:(1R,8S)-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6-三烯-9-甲酸
步骤1:(1R,8S)-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6-三烯-9-甲酸(R)-1-苯基乙酯
在室温和常压下使用100mg Pd/C(54%水)将(1R,8R)-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6,9-四烯-9-甲酸(R)-1-苯基乙酯(0.470g,纯度76%,1.22mmol)在10ml THF中的溶液氢化直到反应完成(5分钟)。将反应混合物过滤,将滤液浓缩并通过快速色谱法纯化(硅胶;EE/庚烷梯度;0-50%EE),得到(1R,8S)-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6-三烯-9-甲酸(R)-1-苯基乙酯(107mg,收率30%),为无色蜡。
LCMS方法A:(M+H)未检测;Rt 2.52min。
步骤2:(1R,8S)-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6-三烯-9-甲酸
在室温和常压下使用100mg Pd/C(54%水)将(1S,8R)-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6-三烯-9-甲酸(R)-1-苯基乙酯(0.107g,0.364mmol)的10ml THF溶液氢化过夜。过滤反应混合物,蒸发滤液,得到(1R,8S)-11-氧杂-三环[6.2.1.02,7]十一碳-2,4,6-三烯-9-甲酸(69mg;92%收率),为白色固体。
LCMS方法A:(M+H)未检测;Rt 1.36min。
实施例1:[(1R)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸(1号化合物)
步骤1:(1S,2R,4R)-7-氧杂-双环[2.2.1]庚烷-2-甲酸[(R)-2-(S)-2,3-二氢-苯并呋喃-3-基-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸-4-基)-乙基]-酰胺
在-15℃和氩气气氛下向(R)-2-(S)-2,3-二氢-苯并呋喃-3-基-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸-4-基)-乙胺盐酸盐(0.250g;0.66mmol)的5ml干燥DMF溶液中加入(1S,2R,4R)-7-氧杂-双环[2.2.1]庚烷-2-甲酸(0.113g;0.79mmol)、乙基-二异丙基-胺(0.34ml;1.99mmol)和TBTU(0.70g;2.18mmol)。将黄色反应溶液在-10℃下搅拌1小时,随后在室温下搅拌1小时。将反应溶液用冰冷却,并用乙酸乙酯稀释。分离后,有机相用盐水和饱和NaHCO3溶液洗涤,经硫酸钠干燥,过滤并真空浓缩(浴温30℃)。得到的橙色油首先通过快速色谱法(硅胶;庚烷/EE梯度,0-100%EE)纯化,得到非对映异构体混合物,其使用手性SFC进行分离(ChiralPak AD,CO2:甲醇(88:12)),得到122mg标题化合物(收率39.6%),为无色油。
LCMS方法A:(M+H)466.2;Rt 2.49min
步骤2:[(1R)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸(1号化合物)
在0℃下向(1S,2R,4R)-7-氧杂-双环[2.2.1]庚烷-2-甲酸[(R)-2-(S)-2,3-二氢-苯并呋喃-3-基-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸-4-基)-乙基]-酰胺(0.206g;0.44mmol)在27ml正戊烷和20.6ml甲醇中的两相体系中加入异丁基硼酸(0.180g;1.77mmol)和2N HCl(1.99ml;3.98mmol)。将反应在室温搅拌过夜。分离戊烷相,用戊烷洗涤甲醇水相5次。真空浓缩甲醇相,用冰水稀释并用1N NaOH碱化。然后用DCM萃取(2x)。用1N HCl酸化水相并用DCM萃取(5x)。该有机相经Na2SO4干燥,过滤并蒸发。将残余物溶于乙腈/水中并冻干,得到104mg(收率:71%)标题化合物,为白色固体。
1H NMR(500MHz,DMSO-d6/D2O)d 7.23–7.20(m,1H),7.13–7.09(m,1H),6.86(td,J=7.4,1.0Hz,1H),6.76(d,J=7.8Hz,1H),4.60(d,J=4.7Hz,1H),4.59–4.53(m,2H),4.21(dd,J=9.0,6.7Hz,1H),3.47–3.38(m,1H),2.94–2.89(m,1H),2.59(dd,J=9.0,4.9Hz,1H),1.91–1.84(m,2H),1.71(dd,J=12.0,9.1Hz,1H),1.64–1.42(m,5H)。
LCMS方法A:(M+H)314.2;Rt 1.57min。
实施例2:[(1R)-2-(1-苯并呋喃-3-基)-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸(9号化合物)
步骤1:(1S,2R,4R)-7-氧杂-双环[2.2.1]庚烷-2-甲酸[(R)-2-(苯并呋喃-3-基)-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸-4-基)-乙基]-酰胺
在冰冷却和氩气气氛下向(1S,2R,4R)-7-氧杂-双环[2.2.1]庚烷-2-甲酸(1.87g;13.18mmol)、[二甲基氨基-([1,2,3]三唑并[4,5-b]吡啶-3-基氧基)-亚甲基]-二甲基铵六氟磷酸盐(HATU)(4.62g;14.37mmol)和4-甲基-吗啉(3.29ml;29.94mmol)在70ml干燥DMF中的溶液中加入(R)-2-(苯并呋喃-3-基)-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧杂-4-硼杂三环[6.1.1.02,6]癸-4-基)-乙胺盐酸盐(4.50g;11.98mmol)。将黄色溶液在室温搅拌2.5小时。将反应混合物倾入500ml冰冷却的饱和NaHCO3溶液中并搅拌15分钟。通过真空过滤收集沉淀,并用水洗涤。将获得的固体用乙腈研磨,用MTB-醚稀释,抽吸,得到(1S,2R,4R)-7-氧杂-双环[2.2.1]庚烷-2-甲酸[(R)-2-(苯并呋喃-3-基)-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸-4-基)-乙基]-酰胺(3.26g,收率:58.8%),为白色固体(纯度100%)。
LCMS方法A:(M+H)464.2;Rt 2.57min。
步骤2:[(1R)-2-(1-苯并呋喃-3-基)-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸
在0℃下向(1S,2R,4R)-7-氧杂-双环[2.2.1]庚烷-2-甲酸[(R)-2-苯并呋喃-3-基-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸-4-基)-乙基]-酰胺(ee=97%,3.45mmol;1.60g)在150ml正戊烷和50ml甲醇中的两相体系中加入异丁基硼酸(13.81mmol;1.41g)和1N盐酸(15.54mmol;15.54ml)。将反应在室温下搅拌过夜。分离戊烷相并用戊烷(3×80mL)洗涤甲醇相。真空浓缩甲醇相(浴温低于30℃),用冰水稀释,并用1N NaOH碱化(pH 11-12)。用DCM(3×80mL)萃取该碱溶液。将水相用1N HCl酸化(pH2),并再次用DCM(5x 80mL)萃取。合并的有机相经Na2SO4干燥,过滤并蒸发。将残余物溶于乙腈/水中并冻干,得到0.697g(收率61.3%)标题化合物,为白色固体。
分析数据:见表2。
实施例3:[(1R)-2-(7-氯-1-苯并呋喃-3-基)-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸(13号化合物)
步骤1:(1S,2R,4R)-7-氧杂-双环[2.2.1]庚烷-2-甲酸[(R)-2-(7-氯-苯并呋喃-3-基)-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸-4-基)-乙基]-酰胺
在冰冷却和氩气气氛下向(1S,2R,4R)-7-氧杂-双环[2.2.1]庚烷-2-甲酸(3.77g;26.55mmol)、[二甲基氨基-([1,2,3]三唑并[4,5-b]吡啶-3-基氧基)-亚甲基]-二甲基铵六氟磷酸盐(HATU)(9.30g;28.97mmol)和4-甲基-吗啉(6.63ml;60.34mmol)在148ml干燥DMF中的溶液中加入(R)-2-(7-氯-苯并呋喃-3-基)-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸-4-基)-乙胺盐酸盐(9.90g;24.14mmol)。将黄色溶液在室温搅拌3小时。将反应混合物倒入1升冰冷却的饱和NaHCO3溶液中并搅拌15分钟。通过真空过滤收集沉淀并用水洗涤。将获得的固体用乙腈研磨,用MTB-醚稀释,抽吸,得到(1S,2R,4R)-7-氧杂-双环[2.2.1]庚烷-2-甲酸[(R)-2-(7-氯-苯并呋喃-3-基)-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸-4-基)-乙基]-酰胺(6.9g,收率:56.6%),为白色固体(纯度95%)。
LCMS方法A:(M+H)498.2;Rt 2.70min。
步骤2:[(1R)-2-(7-氯-1-苯并呋喃-3-基)-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸(13号化合物)
在0℃下向(1S,2R,4R)-7-氧杂-双环[2.2.1]庚烷-2-甲酸[(R)-2-(7-氯-苯并呋喃-3-基)-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧杂-4-硼杂-三环[6.1.1.02,6]癸-4-基)-乙基]-酰胺(ee=99%,12.39mmol;6.26g)在220ml正戊烷和125ml甲醇中的两相体系中加入异丁基硼酸(37.17mmol;3.79g)和1N盐酸(55.760mmol;55.760ml)。将反应在室温搅拌过夜。分离戊烷相并用戊烷(3×200mL)洗涤甲醇相。真空浓缩甲醇相(浴温低于30℃),用200mL冰水稀释,并用1N NaOH碱化(pH 12-13)。用DCM(3×200mL)萃取该碱性溶液。水相用1N HCl酸化(pH 2-3),再次用DCM(5x 220mL)萃取。合并的有机相经Na2SO4干燥,过滤并蒸发。将残余物溶于乙腈/水中并冻干,得到3.277g标题化合物,为白色固体。
1H NMR(500MHz,DMSO-d6/D2O)d 7.78(s,1H),7.64–7.60(m,1H),7.42–7.39(m,1H),7.29(t,J=7.8Hz,1H),4.54–4.50(m,1H),4.48–4.45(m,1H),3.15–3.09(m,1H),2.89(dd,J=14.9,5.8Hz,1H),2.77(dd,J=14.9,8.4Hz,1H),2.50(dd,J=9.0,4.9Hz,1H),1.82–1.75(m,1H),1.65(dd,J=11.9,9.0Hz,1H),1.58–1.49(m,2H),1.49–1.39(m,2H)。
Waters XBridge C8 3.5μm 4.6x50mm(A19/533-La Chrom Elite;70173815);8.1min;2mL/min;215nm;缓冲液A:0.05%TFA/H2O;缓冲液B:0.04%TFA/ACN;0.0-0.2min5%缓冲液B;0.2-8.1min 5%-100%缓冲液B;8.1-10.0min 100%-5%缓冲液B:%;Rt4.24min。
UPLC MSWaters Acquity UPLC;CORTECS C18 1,6μm 50-2,1mm;A:H2O+0.05%HCOOH;B:MeCN+0,04%HCOOH;T:30℃;Flow:0,9ml/min;2%->100%B:0->1,0min;100%B:1,0->1,3min:346.1[M+H-H2O];RT 0.61min。
从市售的酸(或通过皂化市售酯而合成的酸)或文献中描述的酸开始,根据实施例1或2的步骤1和2合成了以下化合物:
表1:示例性化合物列表
表2:分析数据
生物活性
LMP7活性的测定:
LMP7抑制的测量基于荧光强度测定在384孔格式板上进行。
将纯化的人免疫蛋白酶体(0.25nM)和在DMSO中的系列稀释化合物(浓度范围从30μM至15pM)或对照品于25℃在包含50mM Tris pH 7.4、0.03%SDS、1mM EDTA和1%DMSO的测定缓冲液中培育20分钟或120分钟(长时间培育)。通过加入浓度为40μM的荧光肽底物Suc-LLVY-AMC(Bachem I-1395)来引发反应。于37℃培育60分钟后,用荧光读数仪(PerkinElmer Envision读数仪或等同物)于λex=350nm和λem=450nm测量荧光强度。
化合物的LMP7活性总结于表3中。除非另外说明,否则结果在培育20分钟后获得。
β5活性的测定:
β5抑制的测量基于荧光强度测定在384孔格式板上进行。
将纯化的人组成型蛋白酶体(1.25nM)和在DMSO中的系列稀释化合物(浓度范围从30μM至15pM)或对照品于25℃在包含50mM Tris pH 7.4、0.03%SDS、1mM EDTA和1%DMSO的测定缓冲液中培育20分钟或120分钟(长时间培育)。通过加入浓度40μM的荧光肽底物Suc-LLVY-AMC(Bachem I-1395)来引发反应。于37℃培育60分钟后,用荧光读数仪(PerkinElmer Envision读数仪或等同物)于λex=350nm和λem=450nm测量荧光强度。
表3示出了根据本发明的化合物的β5活性和它们相对于β5对LMP7的选择性。除非另外说明,否则结果在培育20分钟后获得。
表3:
*:5μM<IC50≤3.0*10-5M,**:0.5μM<IC50<5μM,
***:0.05μM<IC50<0.5μM,****:IC50<0.05μM,
+:选择性<100,++:100≤选择性<300,+++:300≤选择性<500,
++++:500≤选择性<700,+++++:选择性≥700,
n.m.a.,:根据上文所述的方法在给定浓度范围内无可测量的活性,
“长时间培育”表示将样品培育120分钟。
以下实施例关于药物:
实施例A:注射小瓶
使用2N盐酸将100g式(I)的活性成分和5g磷酸氢二钠在3升重蒸水中的溶液调节至pH 6.5,将其无菌过滤,转移至注射小瓶,在无菌条件下冻干并在无菌条件下密封。每个注射小瓶含有5mg的活性成分。
实施例B:栓剂
将20g式(I)的活性成分与100g大豆卵磷脂和1400g可可脂的混合物熔融,倾入模具并使其冷却。每个栓剂含有20mg的活性成分。
实施例C:溶液
由1g式(I)的活性成分、9.38g NaH2PO4·2H2O、28.48g Na2HPO4·12H2O和0.1g苯扎氯铵在940ml重蒸水中制备溶液。将pH调节至6.8,并将溶液补充至1升并通过辐照杀菌。该溶液可以滴眼液形式使用。
实施例D:软膏剂
将500mg式(I)的活性成分与99.5g凡士林在无菌条件下混合。
实施例E:片剂
以常规方式压制1kg式(I)的活性成分、4kg乳糖、1.2kg马铃薯淀粉、0.2kg滑石和0.1kg硬脂酸镁的混合物以产生片剂,使得每个片剂含有10mg的活性成分。
实施例F:糖衣丸
类似于实施例E地压制片剂并随后以常规方式用蔗糖、马铃薯淀粉、滑石、黄芪胶和染料的包衣包覆。
实施例G:胶囊
将2kg式(I)的活性成分以常规方式引入硬质明胶胶囊,使得每个胶囊含有20mg的活性成分。
实施例H:安瓿
将1kg式(I)的活性成分在60升重蒸水中的溶液无菌过滤,转移至安瓿中,在无菌条件下冻干并在无菌条件下密封。每个安瓿含有10mg的活性成分。
Claims (22)
1.式(I)的化合物
其中
LY表示(CH2)m;
X表示式(xa)、(xb)、(xc)、(xd)、(xe)、(xf)、(xg)、(xh)或(xi)的杂双环或杂三环,各自彼此独立地未取代或被Hal、直链或支链的C1-C6-烷基和/或C3-C8环烷基单-、二-或三取代,且其中环CH2基团中的1、2或3个可被C=O置换;
Y表示P1、P2或P3;
P1表示直链或支链的C1-C6-烷基或C3-C8-环烷基,各自彼此独立地未取代或被Hal、直链或支链的C1-C6-烷基和/或C3-C8-环烷基单-、二-或三-或四取代;
P2表示苯基或芳族单环5-、6-或7-元杂环,各自彼此独立地未取代或被Hal、直链或支链的C1-C6-烷基和/或C3-C8环烷基单-、二-、三-、四-或五取代,其中所述杂环体系包含1、2或3个N、O和/或S原子;
P3表示双环8-、9-或10-元烃或杂环,各自彼此独立地未取代或被Hal、直链或支链的C1-C6-烷基和/或C3-C8环烷基单-、二-、三-、四-或五取代,其中所述双环烃或杂环的至少一个环为芳族的,且其中所述杂环体系包含1、2或3个N、O和/或S原子;
Cy1、Cy2、Cy3、Cy4和Cy5各自彼此独立地表示Ar1或Het1;
R1、R2各自彼此独立地表示H;
T1、T2、T3、T4、T5、T6、T7、T8和T9各自彼此独立地表示O;
Ar1代表芳族6-元碳环;
Het1代表具有1至4个N、O和/或S原子的饱和、不饱和或芳族5-或6-元杂环;
m表示1或2;
Hal表示F、Cl、Br或I;
及其立体异构体以及前述中每一种的药学上可接受的盐,包括它们所有比率的混合物。
2.根据权利要求1的式(I)的化合物,其中
P2表示苯基、吡啶基、吡咯基、呋喃基、噻吩基、嘧啶基、吡嗪基或哒嗪基,各自彼此独立地未取代或被Hal、直链或支链的C1-C6-烷基和/或C3-C8环烷基单-、二-或三取代;且
P3表示式(ya)、(yb)、(yc)、(yd)、(ye)、(yf)、(yg)、(yh)、(yi)、(yj)、(yk)、(yl)、(ym)、(yn)、(yo)或(yp)的双环残基,各自彼此独立地未取代或被Hal、直链或支链的C1-C6-烷基和/或C3-C8环烷基单-、二-或三取代;
其中
Ea表示O、S、N(Alk)或CH=CH;
Eb表示O、S、N(Alk)、CH2、CH2CH2、OCH2、SCH2或N(Alk)CH2;
Alk表示直链或支链的C1-C6-烷基;
及其立体异构体以及前述中每一种的药学上可接受的盐,包括它们所有比率的混合物。
3.根据权利要求1-2中任一项的式(I)的化合物,其中Y表示P2或P3;
及其立体异构体以及前述中每一种的药学上可接受的盐,包括它们所有比率的混合物。
6.根据权利要求1-2中任一项的式(I)的化合物,其中X是式(xa)、(xb)、(xc)、(xd)、(xe)、(xf)、(xg)、(xh)或(xi)的杂双环或杂三环,各自彼此独立地未取代或被以下单-、二取代:F、Cl、CH3和/或C2H5;
及其立体异构体以及前述中每一种的药学上可接受的盐,包括它们所有比率的混合物。
7.根据权利要求5的式(I)的化合物,其中X是式(xa1)、(xb1)、(xc1)、(xd1)、(xe1)、(xf1)、(xg1)、(xh1)或(xi1)的杂双环或杂三环,各自彼此独立地未取代或被以下单-、二取代:F、Cl、CH3和/或C2H5;
及其立体异构体以及前述中每一种的药学上可接受的盐,包括它们所有比率的混合物。
9.根据权利要求8的式(I)的化合物,其中Ea、Eb各自表示O或S;
及其立体异构体以及前述中每一种的药学上可接受的盐,包括它们所有比率的混合物。
12.根据权利要求11的式(I)的化合物,其中
P2表示未取代或单-或二取代的2-或3-噻吩基或未取代或3-、4-、2,3-、2,4-、2,5-、3,4-或2,3,4-取代的苯基,其中任选的取代基选自F、Cl、CH3或C2H5;
P3表示根据式(Fa)或(S)-(Fb)的残基,
Ga、Gb各自彼此独立地表示H、F、Cl、CH3或C2H5;
Ka、Kb各自彼此独立地表示H、F、Cl、CH3或C2H5;
及其立体异构体以及前述中每一种的药学上可接受的盐,包括它们所有比率的混合物。
13.根据权利要求1的化合物,其选自:
[(1R)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1R,2S,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}-2-(噻吩-3-基)乙基]硼酸;
[(1R)-2-(1-苯并呋喃-3-基)-1-{[(1R,8S)-11-氧杂三环[6.2.1.02,7]十一碳-2(7),3,5-三烯-1-基]甲酰氨基}乙基]硼酸;
[(1S)-2-(1-苯并呋喃-3-基)-1-{[(1R,8S)-11-氧杂三环[6.2.1.02,7]十一碳-2(7),3,5-三烯-1-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(1-苯并呋喃-3-基)-1-{[(1S,8R)-11-氧杂三环[6.2.1.02,7]十一碳-2(7),3,5-三烯-1-基]甲酰氨基}乙基]硼酸;
[(1S)-2-(1-苯并呋喃-3-基)-1-{[(1S,8R)-11-氧杂三环[6.2.1.02,7]十一碳-2(7),3,5-三烯-1-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(1-苯并呋喃-3-基)-1-{[(1R,2S,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(1-苯并呋喃-3-基)-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(1-苯并呋喃-3-基)-1-{[(1R,2R,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1S)-2-(1-苯并呋喃-3-基)-1-{[(1R,2R,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(7-氯-1-苯并呋喃-3-基)-1-{[(1R,2S,4S)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(7-氯-1-苯并呋喃-3-基)-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-[(3R)-7-甲基-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-[(3S)-7-甲基-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1R,8S)-11-氧杂三环[6.2.1.02,7]十一碳-2(7),3,5-三烯-1-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(1-苯并呋喃-3-基)-1-{[(1S,6S,7R)-3-环丙基-4-氧代-10-氧杂-3-氮杂三环[5.2.1.01,5]癸-8-烯-6-基]甲酰氨基}乙基]硼酸;
[(1R)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,8R)-11-氧杂三环[6.2.1.02,7]十一碳-2(7),3,5-三烯-1-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(7-甲基-1-苯并呋喃-3-基)-1-{[(1R,8S)-11-氧杂三环[6.2.1.02,7]十一碳-2,4,6-三烯-1-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(7-甲基-1-苯并呋喃-3-基)-1-{[(1S,8R)-11-氧杂三环[6.2.1.02,7]十一碳-2,4,6-三烯-1-基]甲酰氨基}乙基]硼酸;
[(1R)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1S,8R)-8-甲基-11-氧杂三环[6.2.1.02,7]十一碳-2,4,6-三烯-1-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(1-苯并呋喃-3-基)-1-{[(1R,8S)-11-氧杂三环[6.2.1.02,7]十一碳-2(7),3,5-三烯-9-基]甲酰氨基}乙基]硼酸;
[(1R)-2-[(3S)-2,3-二氢-1-苯并呋喃-3-基]-1-{[(1R,8S)-8-甲基-11-氧杂三环[6.2.1.02,7]十一碳-2,4,6-三烯-1-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(1-苯并呋喃-3-基)-1-{[(1S,8R)-11-氧杂三环[6.2.1.02,7]十一碳-2(7),3,5-三烯-9-基]甲酰氨基}乙基]硼酸;
[(1R)-2-(2,4-二甲基苯基)-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-2-环己基-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}乙基]硼酸;
[(1R)-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}-3-苯基丙基]硼酸;
[(1R)-3-甲基-1-{[(1S,2R,4R)-7-氧杂双环[2.2.1]庚烷-2-基]甲酰氨基}丁基]硼酸;
及其立体异构体以及前述中每一种的药学上可接受的盐,包括它们所有比率的混合物。
15.一种药物制剂,其包含:作为活性成分的至少一种如权利要求1至13中任一项所定义的式(I)的化合物和/或其立体异构体以及前述中每一种的药学上可接受的盐,包括它们所有比率的混合物;以及药学上可接受的载体。
16.根据权利要求15所述的药物制剂,其还包含第二活性成分,其中所述第二活性成分不同于如权利要求1至13中任一项所定义的式(I)的化合物。
17.如权利要求1至13中任一项所定义的式(I)的化合物或其立体异构体以及前述中每一种的药学上可接受的盐,包括它们所有比率的混合物在制备用于预防和/或治疗受抑制LMP7影响的医学病症的药物中的用途。
18.根据权利要求17的用途,其中所述受抑制LMP7影响的医学病症是免疫调节异常或癌症。
19.根据权利要求18的用途,其中所述癌症是血液恶性肿瘤或实体瘤。
21.根据权利要求19的用途,其中所述血液恶性肿瘤是选自以下的疾病:多发性骨髓瘤、套细胞淋巴瘤、弥漫性大B-细胞淋巴瘤、浆细胞瘤、滤泡性淋巴瘤、免疫细胞瘤、急性淋巴细胞白血病、慢性淋巴细胞白血病和骨髓性白血病;且其中所述实体肿瘤选自:炎性乳腺癌和结肠癌、肺癌、头颈癌、前列腺癌、胰腺癌、膀胱癌、肾癌、肝细胞癌和胃癌。
22.包括以下的单独包装的套件:
(a)有效量的如权利要求1至13中任一项所定义的式(I)的化合物和/或其立体异构体以及前述中每一种的药学上可接受的盐,包括它们所有比率的混合物,
和
(b)有效量的另外的药物活性成分。
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WO2016050355A1 (en) * | 2014-10-01 | 2016-04-07 | Merck Patent Gmbh | Boronic acid derivatives |
CN107001390A (zh) * | 2014-10-01 | 2017-08-01 | 默克专利股份公司 | 硼酸衍生物 |
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CN107074885A (zh) * | 2014-10-01 | 2017-08-18 | 默克专利股份公司 | 硼酸衍生物 |
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KR20200040295A (ko) | 2020-04-17 |
JP2020531510A (ja) | 2020-11-05 |
EP3672977A1 (en) | 2020-07-01 |
AU2018321118A1 (en) | 2020-04-09 |
RU2020111001A3 (zh) | 2022-02-28 |
BR112020003368A2 (pt) | 2020-08-18 |
TWI791595B (zh) | 2023-02-11 |
DK3672977T3 (da) | 2022-09-26 |
PL3672977T3 (pl) | 2022-09-26 |
AU2018321118B2 (en) | 2023-06-15 |
CA3073611A1 (en) | 2019-02-28 |
US20200354382A1 (en) | 2020-11-12 |
US20220153761A1 (en) | 2022-05-19 |
PT3672977T (pt) | 2022-09-23 |
IL272806B1 (en) | 2023-05-01 |
CN111183142A (zh) | 2020-05-19 |
EP3672977B1 (en) | 2022-06-22 |
IL272806A (en) | 2020-04-30 |
IL272806B2 (en) | 2023-09-01 |
JP7189203B2 (ja) | 2022-12-13 |
US11274109B2 (en) | 2022-03-15 |
MX2020001891A (es) | 2020-03-24 |
US11858951B2 (en) | 2024-01-02 |
ES2927283T3 (es) | 2022-11-03 |
RU2020111001A (ru) | 2021-09-24 |
WO2019038250A1 (en) | 2019-02-28 |
TW201920208A (zh) | 2019-06-01 |
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