CN102245602A - 用于治疗多发性硬化症的与恶二唑稠合的杂环衍生物 - Google Patents
用于治疗多发性硬化症的与恶二唑稠合的杂环衍生物 Download PDFInfo
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- CN102245602A CN102245602A CN200980151545XA CN200980151545A CN102245602A CN 102245602 A CN102245602 A CN 102245602A CN 200980151545X A CN200980151545X A CN 200980151545XA CN 200980151545 A CN200980151545 A CN 200980151545A CN 102245602 A CN102245602 A CN 102245602A
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Abstract
本发明提供通式(I)化合物,所述化合物用于治疗多发性硬化症和其它疾病。
Description
技术领域
本发明涉及恶二唑,它们作为药物的用途与它们在治疗多发性硬化症及其它疾病中的用途。
发明背景
具体地,本发明涉及通式(I)所示的化合物:
式中,
R1、R2各自独立地表示H、COOR3、CONHR3、Hal、CF3、OCF3、CN、NO2、OH、A、OA、或(CH2)mV(CH2)mW,
V表示O-、-NR3-、-COO-或-CONR3,
W表示COOR3、SO2NH2、CON(R3)2,
Q表示含有1、2或3个氮原子的饱和或不饱和5或6元杂环,
X表示-CH-或-N-,
Y表示Het、Ar或Cyc,
Ra是A、Hal、CF3、OR3、OCF3、(CH2)nOH、(CH2)nOA、(CH2)nOR3、CN、NO2、N(R3)2、CH2N(H)2-p(A)p、(CH2)nSO2N(R3)2、SO2N(R3)2、(CH2)nNR3SO2A、(CH2)nSO2A、(CH2)nN(SO2A)2、NR3CON(R3)2或NR3COA、NR3SO2N(R3)2,
A是具有1至12个碳原子的支链或直链烷基,其中一个或多个(优选是1至7个)氢原子可以被Hal、OR3、CN、COOR3、或N(R3)2取代,且其中一个或多个(优选是1至7个)非相邻的的CH2-基团可以被O、NR3或S取代和/或被-CH=CH-或-C≡C-基团取代,或者表示具有3至7个环碳原子的环烷基或环烷基亚烃基,
Ar表示具有6至14个碳原子的单环或双环不饱和或芳香族碳环,所述碳环可以被A、OR3、N(R3)2、NO2、CN、COOR3、CF3、OCF3、CON(R3)2、NR3COA、NR3CON(R3)2、NR3SO2A、COR3、SO2N(R3)2、SOA或SO2A单取代、二取代或三取代,或者当Ra是Hal、OR3、OCF3、(CH2)nOH、(CH2)nOA、(CH2)nOR3、CN、NO2、N(R3)2、CH2N(H)2-p(A)p、(CH2)nSO2N(R3)2、SO2N(R3)2、(CH2)nNR3SO2A、(CH2)nSO2A、(CH2)nN(SO2A)2、NR3CON(R3)2或NR3COA、NR3SO2N(R3)2时,Ar可以被Hal取代,使得至少有一个与将Ar基团与分子其余部分连接的原子相邻的原子含有上面所述取代基其中之一,
Het表示具有1至4个氮原子、氧原子和/或硫原子的单环或双环饱和、不饱和或芳香族杂环,所述杂环被Hal、A、-[C(R3)2]n-Ar、-[C(R3)2]n-环烷基、OR3、CF3、OCF3、N(R3)2、NR3CON(R3)2、NO2、CN、-[C(R3)2]n-COOR3、-[C(R3)2]n-CON(R3)2、NR3COA、NR3SO2A、COR3、SO2N(R3)2、SOA、和/或SO2A单取代、二取代或三取代,使得至少有一个与将Het基团与分子其余部分连接的原子相邻的原子含有上面所述取代基其中之一,
Cyc表示含有3至7个碳原子的饱和或不饱和碳环,所述碳环被Hal、A、-[C(R3)2]n-Ar、-[C(R3)2]n-环烷基、OR3、CF3、OCF3、N(R3)2、NR3CON(R3)2、NO2、CN、-[C(R3)2]n-COOR3、-[C(R3)2]n-CON(R3)2、NR3COA、NR3SO2A、COR3、SO2N(R3)2、SOA、和/或SO2A取代,使得至少有一个与将Cyc基团与分子其余部分连接的原子相邻的原子含有上面所述取代基其中之一,
Hal是F、Cl、Br或I,
R3是H或A,
p是0、1或2,
n是0、1、2、3或4,
m是0、1、2、3或4,
以及其药学上可接受的衍生物、溶剂化物、互变异构体、盐类及立体异构体,包括它们的各种比例的混合物。
通式(I)及相关结构式所示的化合物与鞘氨醇1-磷酸酯(S1P)受体能较好地结合。S1P是一种活性鞘磷脂代谢物,由造血细胞分泌,在活化的血小板中储存和释放。它作为一个G蛋白偶联受体(GPCR)家族的激动剂起作用。已经有五种鞘氨醇1-磷酸酯受体被识别(S1P1、S1P2、S1P3、S1P4和S1P5,也被称作内皮细胞分化基因,分别是Edg1、Edg5、Edg3、Edg6和Edg8),它们的细胞和组织分布广泛,并且在人类和啮齿动物中是高度保守的。
S1P参与了多种细胞功能,如生存、增殖和免疫反应。本发明的化合物能较好的发挥S1P1/Edg1受体激动剂的作用,因而具有免疫抑制活性,它能调节白细胞的转运,将淋巴细胞封存于次级淋巴组织中,并能干扰有效免疫反应所需的细胞-细胞间相互作用。本发明还涉及含有这些化合物的药物组合物以及治疗或预防疾病的方法。
FTY720或fingolimod是一种非选择性S1P1激动剂,具有免疫抑制活性,对复发-缓解型多发性硬化症具有治疗效果。已有大量文献报道了这个化合物:CysterJG Annu Rev Immunol 23:127-59,2005,Rosen H Nat Rev Immunol 5:560-570,2005,Rosen H Trends Immunol 28:102-107,2007,Yopp AC Clin Transplant 20:788-795,2006,Kappos L N Engl J Med 355:1124-1140,2006,Massberg S N Engl JMed 355:1088-1089,2006。
免疫抑制剂广泛应用于各种自身免疫性疾病和慢性炎症,包括系统性红斑狼疮、慢性类风湿性关节炎、I型糖尿病、炎症性肠道疾病、胆汁性肝硬化、葡萄膜炎和一些其它疾病,如克罗恩病、溃疡性结肠炎、大疱性类天疱疮、结节病、牛皮癣、自身免疫性肌炎、韦格纳肉芽肿、鱼鳞病、Graves眼病、特应性皮炎和哮喘。它们也可作为癌症、淋巴瘤和白血病治疗的化疗方案的一部分。
发明内容
已发现,本发明的化合物是药理学性质和/或其它性质改善的选择性S1P1激动剂。
因此,本发明的化合物优选是S1P1/Edg1受体激动剂,特别是具有与S1P3/Edg3受体相比更好的选择性。S1P1/Edg1受体选择性激动剂具有优于现有治疗方法的优势,并能扩大淋巴细胞隔离剂的治疗窗,以便获得更好的高剂量耐受性,从而提高其疗效。
本发明还涉及单独或与其它活性化合物或治疗药物联合用于改善血管功能的药物的制备。
本发明还涉及通式(I)化合物与免疫调节剂的联合使用,这些免疫调节剂为例如芬戈莫德;环孢菌素类、雷帕霉素类、子囊霉素类或其具有免疫抑制作用的类似物,例如环孢菌素A,环孢菌素G,FK-506,ABT-281,ASM981,雷帕霉素,40-O-(2-羟基)乙基-雷帕霉素等;皮质类固醇;环磷酰胺;咪唑巯嘌呤;甲氨喋呤;来氟米特;咪唑立宾;霉酚酸;霉酚酸吗啉乙酯;15-脱氧精胍菌素;戊酸双氟可龙;二氟孕甾丁酯;阿氯米松双丙酸酯;安西奈德;安吖啶;天冬酰胺酶;氮杂硫代嘌呤;巴利昔单抗;丙酸倍氯米松;倍他米松;醋酸倍他米松;二丙酸倍他米松;倍他米松磷酸酯钠;戊酸倍他米松;布地奈德;卡托普利;氮芥盐酸盐;克拉屈宾;丙酸氯倍他索;醋酸可的松;可的伐唑;环磷酰胺;阿糖胞苷;达克珠单抗;达克霉素;地索奈德;去羟米松;地塞米松;醋酸地塞米松;异烟酸地塞米松;地塞米松甲苯磺酸钠;磷酸地塞米松;特丁酸地塞米松;醋酸双氯松;多柔比星盐酸盐;表阿霉素盐酸盐;氟二氯松;醋酸氟氢可的松;氟氢缩松;特戊酸氟米松;氟尼缩松;醋酸氟轻松;氟轻松;氟可龙;己酸氟可龙;特戊酸氟可龙;氟米龙;醋酸氟泼尼定;丙酸氟替卡松;吉西他滨盐酸盐;哈西奈德;氢化可的松;醋酸氢化可的松;丁酸氢化可的松;半琥珀酸氢化可的松;美法仑;甲泼尼松;巯嘌呤;甲基泼尼松龙;醋酸甲基泼尼松龙;半琥珀酸甲基泼尼松龙;米索前列醇;莫罗单抗-cd3;霉酚酸吗啉乙酯;醋酸帕拉米松;泼那唑啉,泼尼松龙;醋酸泼尼松龙;己酸泼尼松龙;泼尼松龙甲苯磺酸钠;泼尼松龙磷酸钠;泼尼松;泼尼立定;利福霉素;利福霉素钠;他克莫司;沙利度胺;噻替派;特戊酸替可的松;去炎松;曲安奈德半琥珀酸酯;苯曲安奈德;曲安奈德双醋酸酯;己酸丙炎松;具有免疫抑制作用的单克隆抗体,例如白细胞受体单克隆抗体,如MHC,CD2,CD3,CD4,CD7,CD25,CD28,B7,CD40,CD45或CD58或其配基;或其它具有免疫调节活性的化合物,例如CTLA41g或其它粘附分子抑制剂,如mAbs或包括选择素拮抗剂和VLA-4拮抗剂在内的低分子量抑制剂。优选组合物为与环孢菌素A,FK506,雷帕霉素或40-(2-羟基)乙基-雷帕霉素和芬戈莫德的组合。
本发明还涉及一种试剂盒或试剂套装,它包括至少一种如通式(I)所示的化合物,优选与免疫调节剂联用。或者,所述试剂盒由以下独立包装组成:
(a)有效量的通式(I)所示的化合物和/或其药学上可接受的衍生物、溶剂化物和立体异构体,包括其所有比例的混合物,和
(b)有效量的另一种药物活性成。
通式(I)及相关化学式所示的化合物可以从易得的起始原料出发,采用下面的一般方法和步骤合成。值得注意的是,虽然只给出了典型的或优选的实验条件(即反应温度、时间、试剂的摩尔数、溶剂等),但其它实验条件也是可以使用的,除非另有说明。最佳反应条件可能会随特定反应物或溶剂的不同而变化,但是这些条件可以由本技术领域的专业人员用常规的优化程序确定。
根据Advanced Chemistry Development Inc.,ACD/Labs软件“ACD/Name Batch”(7.00版本)标准程序对本发明的化合物进行命名;产品版本号:7.10,发行日期:2003年9月15日。
根据X、Ra、Rb、R1和R2的不同性质,可选取不同的合成策略进行通式(I)及相关结构式化合物的合成。在下列方案列举的合成方法中,Ra、Rb、R1和R2为上面的说明书中所定义的。其中X定义为O或S的通式(I)化合物可通过类似的方法制备。
一般而言,本发明的通式(I)及相关结构式的稠合杂环衍生物可从简单易得的起始原料进行制备。如果起始原料无法购得,则可用标准合成技术制备。在以下实施例中所描述的通用方法和步骤可用于本发明的通式(I)及相关结构式的化合物的制备。
制备X、Ra、Rb、R1和R2符合上述定义的通式(I)和相关结构式化合物的方法如流程1至14所示,这也是本发明的目的。
以下缩写分别具有下述定义:
Ac(乙酰基),ACN(乙腈),AcOH(乙酸),AIBN(偶氮二异丁腈),Boc(叔丁氧羰基),bs(宽的单峰),Bu(丁基),cHex(环己烷),d(双峰),dba(二亚苄基丙酮),DCM(二氯甲烷),DIEA(二异丙基乙基胺),DMAP(1,4-二甲氨基吡啶),DMF(二甲基甲酰胺),DMSO(二甲基亚砜),dppf(1.1,1′-双(二苯基膦基)二茂铁),EDC(1-(3-二甲基-氨基-丙基)-3-乙基碳二亚胺),ESI(电喷雾电离),Et(乙基),g(克),h(小时),HATU(二甲氨基-([1,2,3]三唑并[4,5-b]吡啶-3-基氧代)-亚甲基]-二甲基-铵六氟磷酸酯),HPLC(高效液相色谱),Hz(赫兹),iPr(异丙基),L(升),LC(液相色谱),LG(离去基团),m(米),M(摩尔),m(多峰),Me(甲基),mg(毫克),MHz(兆赫兹),min(分钟),mL(毫升),μL(微升),mm(毫米),μm(微米),mmol(毫摩尔),MS(质谱),Ms(甲磺酰基),NBS(N-溴代琥珀酰亚胺),NMM(N-甲基吗啉),NMP(1,N-甲基吡咯烷酮),NMR(核磁共振),Pd/C(披钯木炭),PG(保护基),Ph(苯基),Pt/C(披铂木炭),Py(吡啶),RT(室温),Rt(保留时间),s(单峰),SPE(固相萃取),TBTU(1,O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲四氟硼酸酯),tBu(叔丁基),TEA(三乙胺),TFA(三氟醋酸),四氢呋喃(四氢呋喃),UPLC(超高效液相色谱),UV(紫外)。
通过使通式(Ia)和(Ic)所示的化合物脱保护,分别得到通式(Ib)和(Id)所示的化合物,或者通过生成恶二唑环可以合成通式(I)所示的化合物。一般来说,通式(Ib)所示的化合物,其中R1、Ra、X、Y、Q和A如上定义,可以通过对通式(Ia)所示的酯衍生物(其中R1、Ra、X、Y、Q和A如上定义,R3更优选自甲基或叔丁基)的水解来制备。采用本技术领域的专业人员所熟知的条件,例如用金属氢氧化物,如氢氧化锂、氢氧化钠或氢氧化钾,在合适的溶剂如THF、甲醇、乙醇或水或其混合物中进行水解或皂化反应。也可以使用酸如HCl或TFA,在合适的溶剂如DCM或者醚如二恶烷或Et2O中反应;反应温度为大约20℃至100℃之间,优选室温;反应时间为几个小时,如1小时至24小时(流程1)。
流程1
或者,通式(Id)所示的化合物,其中R1、R2、Ra、X、Y和Q如上定义,可以采用流程2所示的使通式(Ic)所示的胺化合物脱保护来获得,其中X、Y、R1、R2、和Q如上定义,R3是烷基。更好地,R3是甲基、乙基或叔丁基。使用本技术领域的专业人员所熟知的条件。例如,使用TFA或HCl在合适的溶剂如DCM、二恶烷、Et2O或其混合物中进行酸切割。通式(Ic)所示的化合物在大约10℃至100℃的温度下能够转化为通式(Id)所示的化合物。较佳地,反应温度为大约20℃至50℃之间,优选室温;反应时间为几个小时,如1小时至24小时(流程2)。
流程2
通式(I)所示的化合物,其中R1、R2、Ra、X、Q和Y如上定义,可以采用流程3所示的两步合成法获得。第一步由通式(III)所示的羧酸(其中X、Y和Ra如上定义)与通式(II)所示的胺肟(其中R1、R2和Q如上定义)进行偶联反应。下面的实施例中给出了这种偶联反应的一般方案,使用本技术领域的专业人员所熟知的条件和方法。所使用的标准偶联剂包括但不限于EDC、HATU、TBTU,在有碱或无碱存在的条件下反应,如TEA、DIEA、NMM,合适的溶剂如DCM、ACN、THF或DMF,反应温度在0℃至50℃之间,优选室温;反应时间为几个小时,例如1小时至24小时。
或者,将羧酸衍生物(如酰氯IIIa)与胺肟(II)进行偶联,使用本技术领域的专业人员所熟知的条件和方法,在碱的存在下反应,如TEA、DIEA、NMM,合适的溶剂如DCM、THF或DMF,反应温度在20℃至50℃之间,优选室温,反应时间为几个小时,例如1小时至24小时(流程4)。第二步包括O-取代胺肟(IV)的环化和脱水,生成恶二唑(I)。下面的实施例中给出了用本技术领域的专业人员所熟知的方法制备恶二唑的反应条件,例如在室温至150℃的温度范围内进行环化脱水,一般是150℃,也可以使用微波炉,反应时间为15分钟至24小时,优选30分钟,合适的溶剂如ACN、THF、吡啶、DMF或混合溶剂,在有碱或无碱存在的条件下反应,如DIEA、TEA或四丁基氟化铵。
流程3
流程4
制备下列通式(I)所示化合物的方法在实施例中有比较详细的描述。
5-{5-[4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯基]-1,2,4-恶二唑-3-基}-1H-苯并咪唑
5-[3-(1H-苯并咪唑-5-基)-1,2,4-恶二唑-5-基]-2-(2-甲基哌啶-1-基)苯甲腈
5-{5-[5-甲基-6-(2-甲基哌啶-1-基)吡啶-3-基]-1,2,4-恶二唑-3-基}-1H-苯并咪唑
5-{5-[2-(甲氧基甲基)-2′-甲基二苯基-4-基]-1,2,4-恶二唑-3-基}-1H-苯并咪唑
1-{4-[3-(1H-苯并咪唑-6-基)-1,2,4-恶二唑-5-基]-2′-甲基二苯基-2-基}-N,N-二甲基甲胺
5-{5-[3-(甲氧基甲基)-4-(2-甲基哌啶-1-基)苯基]-1,2,4-恶二唑-3-基}-1H-苯并咪唑
7-氟-5-{5-[4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯基]-1,2,4-恶二唑-3-基}-1H-苯并咪唑
7-甲基-5-{5-[4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯基]-1,2,4-恶二唑-3-基}-1H-苯并咪唑
7-氟-5-{5-[2-(甲氧基甲基)-2′-甲基二苯基-4-基]-1,2,4-恶二唑-3-基}-1H-苯并咪唑
6-{5-[4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯基]-1,2,4-恶二唑-3-基}-1,2,3,4-四氢异喹啉
N-{2-(2-甲基哌啶-1-基)-5-[3-(1,2,3,4-四氢异喹啉-7-基)-1,2,4-恶二唑-5-基]苯基}甲烷磺酰胺
2-(2-甲基哌啶-1-基)-5-[3-(1,2,3,4-四氢异喹啉-7-基)-1,2,4-恶二唑-5-基]苯甲腈
7-{5-[5-甲基-6-(2-甲基吡咯烷-1-基)吡啶-3-基]-1,2,4-恶二唑-3-基}-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯
7-{5-[5-甲基-6-(2-甲基吡咯烷-1-基)吡啶-3-基]-1,2,4-恶二唑-3-基}-1,2,3,4-四氢异喹啉
7-{5-[2-(甲氧基甲基)-2′-甲基二苯基-4-基]-1,2,4-恶二唑-3-基}-1,2,3,4-四氢异喹啉
[7-{5-[2-(甲氧基甲基)-2′-甲基二苯基-4-基]-1,2,4-恶二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]乙酸
5-[5-(2,2′-二甲基二苯基-4-基)-1,2,4-恶二唑-3-基]-1-甲基-1H-吲哚
{5-[5-(2,2′-二甲基二苯基-4-基)-1,2,4-恶二唑-3-基]-1H-吲哚-1-基}乙酸
1-甲基-5-{5-[4-(2-甲基哌啶-1-基)-3-硝基苯基]-1,2,4-恶二唑-3-基}-1H-吲哚
6-甲氧基-5-{5-[4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯基]-1,2,4-恶二唑-3-基}-1H-吲哚-2-羧酸乙酯
6-甲氧基-5-{5-[4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯基]-1,2,4-恶二唑-3-基}-1H-吲哚-2-羧酸
N-[5-[3-(1H-吲哚-5-基)-1,2,4-恶二唑-5-基]-2-(2-甲基哌啶-1-基)苯基]甲烷磺酰胺
5-[3-(1H-吲哚-5-基)-1,2,4-恶二唑-5-基]-2-(2-甲基哌啶-1-基)苯甲腈
5-{5-[3-甲氧基-4-(4-甲基-3-噻吩基)苯基]-1,2,4-恶二唑-3-基}-1H-吲唑
5-[5-(2,2′-二甲基二苯基-4-基)-1,2,4-恶二唑-3-基]-1H-吲唑
5-{5-[2-(甲氧基甲基)-2′-甲基二苯基-4-基]-1,2,4-恶二唑-3-基}-7-甲基-1H-苯并咪唑
5-{5-[4-(2-乙基哌啶-1-基)-3-(甲氧基甲基)苯基]-1,2,4-恶二唑-3-基}-1H-苯并咪唑
5-{5-[4-[(2R)-2-甲基哌啶-1-基]-3-(三氟甲基)苯基]-1,2,4-噁二唑-3-基}-1H-苯并咪唑
5-{5-[4-[(2S)-2-甲基哌啶-1-基]-3-(三氟甲基)苯基]-1,2,4-噁二唑-3-基}-1H-苯并咪唑
[7-{5-[2′-乙基-2-(甲氧基甲基)二苯基-4-基]-1,2,4-噁二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]乙酸
3-[7-{5-[2′-乙基-2-(甲氧基甲基)二苯基-4-基]-1,2,4-恶二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]丙酸
6-{5-[2-(甲氧基甲基)-2′-甲基二苯基-4-基]-1,2,4-噁二唑-3-基}-1H-吲哚-2-羧酸
3-[7-{5-[4-(2-乙基哌啶-1-基)-3-(甲氧基甲基)苯基]-1,2,4-噁二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]丙酸
[7-{5-[4-(2-乙基哌啶-1-基)-3-(甲氧基甲基)苯基]-1,2,4-噁二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]乙酸
3-[7-{5-[2-(甲氧基甲基)-2′-甲基二苯基-4-基]-1,2,4-噁二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]丙酸
[7-{5-[2′-甲基-2-(三氟甲基)二苯基-4-基]-1,2,4-噁二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]乙酸
3-[7-{5-[4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯基]-1,2,4-噁二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]丙酸
[7-{5-[4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯基]-1,2,4-噁二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]乙酸
3-[7-{5-[2′-甲基-2-(三氟甲基)二苯基-4-基]-1,2,4-噁二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]丙酸
3-{6-[5-(2-甲氧基甲基-2′-甲基-二苯基-4-基)-[1,2,4]噁二唑-3-基]-3,4-二氫-1H-异喹啉-2-基}-丙酸
通式(III)所示的化合物,其中Ra、Y和X如上定义,可从商业途径购买或者用标准的合成技术,如下文的实施例中所描述的方法,例如由金属催化偶联反应,或由相应的卤代苯甲酸或苯甲酸烷基酯的芳香亲核取代反应来制备。
另外,通式(III)所示化合物,其中Ra、Y和X如上定义,也可以由金属催化交叉偶联反应,接着水解所生成的酯(VIII)而获得,如下面流程5所示。特别是,它们可以通过采用如流程5所示的共知Suzuki-Miyura反应条件,由通式(VI)化合物(其中X、Ra和R3如上定义,Rc较佳为离去基团)与硼酸(VII)(其中Y如上定义)或硼酸酯衍生物经Suzuki-Miyura偶联反应获得(Miyaura,N.;Suzuki,A.Chem.Rev.1995,95,2457;Takahiro I.and Toshiaki M.,Tetrahedron Lett.2005,46,3573-3577)。Rc较佳为Br、I或磺酸酯,如三氟甲磺酸酯。经典的合成步骤是,通式(VI)所示化合物与硼酸(VII)或硼酸酯用传统的加热方法或使用微波技术加热到不同温度(例如20℃至200℃范围),在碱的存在下,包括但不限于碳酸盐,例如:K2CO3、Na2CO3、Cs2CO3,以及催化量的钯催化剂如Pd(PPh3)4、PdCl2(PPh3)2、Pd(OAc)2的存在下,并加入合适的膦配体如PPh3、S-Phos、X-Phos,在适当的溶剂或混合溶剂如THF、甲苯、二恶烷、甲醇、ACN、DMF、水中进行反应。所有上述不同的组合均可使用。所得的酯(VIII)可以再用本技术领域的专业人员所熟知的反应条件进行水解,包括但不限于使用金属氢氧化物,例如氢氧化锂,氢氧化钠或氢氧化钾,在合适的溶剂如THF、甲醇、乙醇或水及其混合物中进行反应,反应温度在20℃至60℃范围内,较佳为室温,反应时间为几个小时,例如1小时至24小时,得到通式(III)所示化合物。
流程5
另一条制备通式(III)化合物的合成路线,其中Ra、Y和X如上定义,是采用诸如下面的流程6由通式(IX)所示的氨基化合物Y-H(其中Y是含有至少一个NH基团的Het或Cyc)与通式(VIa)所示的化合物(其中Ra、R3和X如上定义),在合适的碱(如TEA、DIEA、NMM)存在下,在溶剂如THF或DMF中,在约20℃升至约100℃的温度下(较佳为室温),反应几个小时,例如1小时至24小时。通式(IX)所示氨基化合物Y-H(其中Y是含有至少一个NH基团的Het或Cyc)也可以作为纯溶剂使用。可按上述和下文实施例描述的条件下将通式(VIII)所示的酯水解成通式(III)化合物。此外,通式(IX)氨基化合物(其中Y是含有至少一个NH基团的Het或Cyc)可以与通式(Xa)化合物加成,反应条件与上述和下文实施例的描述类似。反应产生的通式(XI)化合物可用本技术领域的专业人员所熟知的条件水解成相应的酸(III),这包括但不限于:使用碱如NaOH、KOH,在合适的溶剂(包括但不限于甲醇或水或其混合物)中,在约20℃升至约100℃(较佳为78℃)的温度下,反应5小时至24小时。或者,可将通式(XI)化合物用本技术领域的专业人员所熟知的条件转化成相应的酯(VIII),这包括但不限于:使用酸如HCl、H2SO4,在合适的溶剂(包括但不限于甲醇或乙醇或其混合物)中,在约20℃升至约100℃(较佳为80℃)的温度下,反应1小时至48小时。
较佳地,流程5所描述的路径使用芳香族杂环。较佳地,流程6所描述的路径使用非芳香族胺。
流程6
通式(VIa)至(VIi)所示的化合物或者通过商业途径获得或者按照如以下实施例描述的标准合成技术制备。典型地,当Rc是F、Cl、Br、I或磺酸酯如三氟甲磺酸酯,并且R3如上定义,制备通式(VId)、(VIf)和(VIh)化合物,可先进行相应甲苯甲酰衍生物(VIb)的溴化,紧接着进行溴衍生物(VIc)的SN2反应,所述溴衍生物上有一个合适的基团,包括但不仅限于醋酸盐,如NaOAc的HOAc溶液;醇盐,如NaOA的相应醇、THF或DMF溶液;可作为溶剂的醇,如HOA;胺,如HN(R3)2;或硫醇盐,如NaSA。合适的溶剂包括但不限于THF、MeCN、DMF。反应温度在室温至130℃范围内,也可使用微波(见流程7)。通式(VId)化合物的醋酸酯基的水解采用本技术领域的专业人员所熟知的条件,包括但不限于在氢氧化钠的乙醇溶液中于60℃左右反应,得到通式(VIe)化合物。通式(VIe)化合物可以进一步转化成相应的烷基磺酸酯(VIg),该磺酸酯类似于(VIc),可以用作SN2反应的起始原料,如流程7所示。
流程7
另外,通式(VIe)化合物用合适的还原剂还原通式(VIi)醛来制备,还原剂包括但不限于NaBH4,温度在约0℃升至约50℃(较佳为室温),反应1小时至24小时。可以先通过金属催化交叉偶联反应或SNAr反应将通式(VIi)化合物转化成通式(VIIIa)化合物,然后用合适的还原剂(例如但不限于NaBH4,)将通式(VIIIa)化合物还原得到相应的醇(VIIIb),流程8所示。
流程8
当Rb是(CH2)nNR3SO2A时,其中n=0,A如上定义,并且R3、Y和X如上定义,化合物(VIIIe)可以由通式(VIIIc)化合物合成,如流程9所示。硝基还原后,所生成的胺(VIIId)可以加ASO2Cl转换成磺胺(VIIIe),其中A如上所定义,反应通常在碱的存在下,包括但不限于TEA、DIEA、NMM、吡啶,在溶剂或混合溶剂中进行,如DCM、DMF、吡啶,在约20℃升至约100℃(较佳为50℃)的温度下,反应1小时至48小时。
流程9
另外,通式(III)化合物(其中Ra、Y和X如上定义)可以由通式(XII)化合物经两步反应制备。第一步是卤素-金属交换,用的通常但不完全是烷基锂盐,如nBuLi或tBuLi。第一步在合适的溶剂中进行,所述溶剂包括但不限于Et2O或THF,温度为-20℃至-100℃,典型地-78℃。第二步是气体或固体状态的CO2作为亲电试剂的加成反应,如流程10所示。
流程10
制备下列通式(III)所示化合物的方法:
4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯甲酸
3-氰基-4-(2-甲基哌啶-1-基)苯甲酸
5-甲基-6-(2-甲基哌啶-1-基)烟酸
2-(甲氧基甲基)-2′-甲基二苯基-4-羧酸
2-[(二甲基氨基)甲基]-2′-甲基二苯基-4-羧酸
3-(甲氧基甲基)-4-(2-甲基哌啶-1-基)苯甲酸
4-(2-甲基哌啶-1-基)-3-[(甲基磺酰基)氨基]苯甲酸
5-甲基-6-(2-甲基吡咯烷-1-基)烟酸
2,2′-二甲基-1,1′-二苯基-4-羧酸
4-(2-甲基哌啶-1-基)-3-硝基苯甲酸
3-甲氧基-4-(4-甲基-3-噻吩基)苯甲酸
4-(2-乙基哌啶-1-基)-3-(甲氧基甲基)苯甲酸
2′-乙基-2-(甲氧基甲基)-1,1′-二苯基-4-羧酸
2′-甲基-2-(三氟甲基)二苯基-4-羧酸
4-[(2R)-2-甲基哌啶-1-基]-3-(三氟甲基)苯甲酸
4-[(2S)-2-甲基哌啶-1-基]-3-(三氟甲基)苯甲酸
在实施例中有比较详细的描述。
通式(II)化合物(其中R1、R2和Q如上定义)可以根据流程11所示的方法制备,在相应的通式(XIII)化合物中加入羟胺,在溶剂或混合溶剂如EtOH、水中反应,反应温度在约20℃至约100℃的范围内,较佳为室温,反应时间为几个小时,例如1小时至24小时。
流程11
制备下列通式(II)所示化合物的方法:
N′-羟基-1H-苯并咪唑-5-甲酰亚胺酰胺
7-氟-N′-羟基-1H-苯并咪唑-5-甲酰亚胺酰胺
N′-羟基-7-甲基-1H-苯并咪唑-5-甲酰亚胺酰胺
7-[氨基(羟基亚氨基)甲基]-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯
[7-[氨基(羟基亚氨基)甲基]-3,4-二氢异喹啉-2(1H)-基]乙酸叔丁酯
N-羟基-1-甲基-1H-吲哚-5-甲酰亚胺酰胺
{5-[(羟基氨基)(亚氨基)甲基]-1H-吲哚-1-基}乙酸叔丁酯
5-[氨基(羟基亚氨基)甲基]-6-甲氧基-1H-吲哚-2-羧酸乙酯
N′-羟基-1H-吲哚-5-甲酰亚胺酰胺
N′-羟基-1H-吲唑-5-甲酰亚胺酰胺
3-[7-[氨基(羟基亚氨基)甲基]-3,4-二氢异喹啉-2(1H)-基]丙酸叔丁酯
6-[氨基(羟基亚氨基)甲基]-1H-吲哚-2-羧酸
在实施例中有比较详细的描述。
另外,通过加入保护基团可将通式(XIIIa)所示的胺(其中R1、R2和Q如上定义)转化为通式(XIIIb)化合物,使用的条件已为本领域技术人员所知,并在流程12和实施例中有描述。典型地,用LG-PG来保护氨基,其中LG-是离去基团,包括但不限于Br、I、OMs,PG是保护基团,包括但不限于Boc、Fmoc、Cbz,所用的溶剂如THF或DCM,在碱如DMAP、DIEA、TEA、K2CO3或Cs2CO3存在下,在室温至约100℃的温度下反应1至24小时。
或者,通过N-烷基化反应可将通式(XIIIa)所示的胺转化为通式(XIIIc)化合物,使用的条件已为本领域技术人员所知,并在流程12和实施例中有描述。典型地,用LG-(CH2)mA进行N-烷基化反应,其中A如上定义,LG-是离去基团,包括但不限于Br、I、OMs,所用的溶剂如THF或DCM,在碱如DMAP、DIEA、TEA、K2CO3或Cs2CO3存在下,在室温至约100℃的温度下反应。
流程12
另外,由相应的二氨基化合物(XIV)可获得通式(XIIId)化合物,其中R1和R2如上定义,使用的条件已为本领域技术人员所知,并在流程13和实施例中有描述。典型地,在纯甲酸中使化合物(XIV)与甲酸进行缩聚反应,反应温度为室温至回流温度,反应3至24小时,较佳16小时,形成通式(XIIId)化合物。
流程13
另外,通式(XIII)化合物(其中R1、R2和Q如上定义)可由相应的芳基化合物(XV)(其中与R1、R2和Q如上定义,Rc是Br或F)通过金属催化氰化反应获得,如流程14所示。加入Zn(CN)2,在钯催化剂存在下,包括但不限于Pd2(dba)3或Pd(PPh3)4,可任选地加入配体如dppf(根据Maligres,P.E.et al Tetrahedron Lett.1999,40,8193-8195),和锌衍生物,包括但不仅限于锌粉和Zn(OAc)2(根据Chidambaram,R.et al Tetrahedron Lett.2004,45,1441-1444),于溶剂如DMF中反应,反应温度在室温到150℃的范围之间,通常为100℃,反应产生通式(XIII)化合物。通式(XV)所示的芳基化合物的氰化反应也可以在没有钯存在的情况下进行,使用CuCN在DMF中反应(根据Couture.C.;Paine,A.J.ACN.J.Chem.1985,63,111-120)。
流程14
如果上述的常规合成方法不能获得通式(I)化合物,应该使用本技术领域的专业人员认为适当的其它合成方法。
本发明化合物的药学上可接受的阳离子盐可由酸的形式与适当的碱在共溶剂中反应容易地制备,通常用一当量的碱。常用的碱有氢氧化钠、甲醇钠、乙醇钠、氢化钠、氢氧化钾、甲醇钾、氢氧化镁、氢氧化钙、苄星、胆碱、二乙醇胺、乙二胺、葡甲胺、苄胺、二乙胺、哌嗪和氨丁三醇。溶液浓缩至干或加入非溶剂可以将盐分离出来。在某些情况下,要制备盐可以通过将酸溶液与阳离子溶液(乙基己酸钠,油酸镁)混合,采用能使所需的阳离子盐沉淀的溶剂,也可以其它方式分离,如浓缩和加入非溶剂。
根据更通用的方法,通式(I)及其相关结构式所示的化合物可以采用本技术领域的专业人员所熟知的合适的相互转换技术转换为通式(I)及其相关结构式所示的另一些化合物。
一般来说,通式(I)及其相关结构式所示的任何单个化合物的合成途径取决于每个分子的具体取代基和获得必要中间体的容易程度,再由本技术领域的专业人员对这些因素进行评价。关于所有的保护和脱保护方法,请参见Philip J.Kocienski编着的“保护基”,Georg Thieme Verlag Stuttgart出版社,纽约,1994年,和Theodora W.Greene和Peter G.M.Wuts编着的“有机合成中的保护基”,Wiley Interscience出版社,第3版,1999年。
本发明的化合物可以通过适当溶剂的蒸发结晶而与溶剂分子分离。包含一个碱性中心的通式(I)及其相关结构式所示的化合物的药学上可接受的酸加成盐,可以按照常规的方法加以制备。例如,可将游离碱溶液与一个合适的酸反应,无论是无溶剂或是在适当的溶液中,所得的盐用过滤或减压蒸发反应溶剂的方法进行分离。包含一个酸性中心的通式(I)化合物的药学上可接受的碱加成盐,可以采用类似的方法与合适的碱作用得到。这两种类型的盐可采用离子交换树脂技术生成或互相转化。
根据采取的反应条件,反应时间一般为几分钟至14天之间,反应温度在-30℃和140℃之间,通常为-10℃和90℃之间,优选约0℃和约70℃之间。
通式(I)及其相关结构式所示的化合物还可以通过从它们的一种官能团衍生物与溶媒分解剂或氢解剂作用释放通式(I)化合物而得到。
优选的溶剂解或氢解的起始原料是符合通式(I)及其相关结构式,但含有相应的保护氨基和/或羟基,而不是含一个或多个游离氨基和/或羟基的化合物。优选那些带有氨基保护基而不是H原子连接在N原子上的化合物,特别是带有R′-N基团而不是HN基团的化合物,其中R′表示一个氨基保护基,和/或可以是那些带有羟基保护基而不是羟基H原子的化合物,例如符合通式(I),但带有-COOR”基团,其中R”是指羟基保护基,而不是-COOH基团。
也有可能起始原料分子中存在大量的-相同或不同的-保护氨基和/或羟基。如果存在的保护基团是彼此不同的,在多数情况下它们可以被选择性裂解去除。
术语“氨基保护基”是通用术语,指的是适用于保护(阻止)氨基发生化学反应的基团,但它在分子其它部位需要进行的化学反应结束后容易被脱除。这些基团的典型代表有未取代的或取代的酰基、芳基、芳烷氧基甲基或芳烷基。由于氨基保护基在所需反应(或反应序列)之后会被移除,它们的类型和大小都不是太重要的,但是,优先考虑的还是那些有1-20个,尤其是1-8个碳原子的基团。术语“酰基”是与本方法有关的最广义的理解。它包括来自脂肪族的、芳基脂肪族的、芳香族的或杂环的羧酸或磺酸的酰基,并且特别是烷氧羰基、芳氧羰基和芳烷氧羰基。这样的酰基的例子有烷酰基,如乙酰基、丙酰基和丁酰基;芳烷酰基,如苯乙酰基;芳酰基,如苯甲酰基和甲苯基;芳氧烷酰基,如POA;烷氧羰基,如甲氧羰基、乙氧羰基、2,2,2-三氯乙氧羰基、BOC(叔丁氧羰基)和2-碘乙氧羰基;芳烷氧羰基,如CBZ(“苄氧羰基”)、4-甲氧基苄氧基羰基和FMOC;和芳磺酰基,如Mtr。优选的氨基保护基是BOC和Mtr,还可以是CBZ、Fmoc、苄基和乙酰基。
术语“羟基保护基”也同样是通用术语,指的是适用于保护羟基不发生化学反应的基团,它在分子其它部位需要进行的化学反应结束后容易被脱除。这些基团的典型代表有上面提到的未取代的或取代的芳基、芳烷基或酰基,还可以是烷基。羟基保护基的类型和大小并不是太重要,因为它们在所需的化学反应或反应序列之后会被移除,优先考虑的是有1-20个,尤其是1-10个碳原子的基团。羟基保护基的例子有,特别是苄基、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,其中苄基和叔丁基特别优选。
通式(I)及其相关结构式所示的化合物由它们的官能团衍生物释放得到-根据所使用的保护基-例如使用强酸,最好是用TFA或高氯酸,也可使用强无机酸,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。额外的惰性溶剂的存在是可能的,但并非总是必要的。合适的惰性溶剂较佳为有机溶剂,例如羧酸如醋酸,醚类如THF或二氧六环,酰胺如DMF,卤代烃如DCM,也可以是醇,如甲醇、乙醇或异丙醇,以及水。此外上述溶剂的混合物也是适用的。TFA以过量使用为佳,不需要进一步加入溶剂,而高氯酸最好是以乙酸与70%高氯酸按9∶1的比例混合的形式使用。裂解反应的温度最好控制在月0至约50℃之间,优选15至30℃之间(室温)。
例如,BOC、OBut和Mtr基团,最好使用TFA在DCM溶液中或使用大约3-5N HCl在二恶烷中于15-30℃裂解,而FMOC基团可以使用大约5-50%二甲胺、二乙胺或哌啶在DMF中的溶液于15-30℃裂解。
能用氢解去除的保护基(如CBZ,苄基或从恶二唑衍生物分解释放出脒基)可以在催化剂(例如贵金属催化剂,如钯,最好固定在如碳一类的载体上)存在下通过与氢气作用被裂解。此处合适的溶剂如上所示,特别是例如醇,如甲醇或乙醇,或酰胺,如DMF。氢解一般在约0到100℃之间的温度下和约1至200巴之间的压力下进行,优选的是20-30℃和1-10巴。CBZ基团的氢解很容易成功,例如,用5至10%Pd/C在甲醇中,或用甲酸铵(而不是氢气)在Pd/C上、甲醇/DMF中、于20-30℃反应。
合适的惰性溶剂的例子有烃类,如正己烷、石油醚、苯、甲苯或二甲苯;氯代烃,如三氯乙烯、1,2-二氯乙烷、四氯甲烷、三氟甲苯、氯仿或DCM;醇类,如甲醇、乙醇、异丙醇、正丙醇、正丁醇或叔丁醇;醚,如乙醚、异丙醚、四氢呋喃(THF)或二氧六环;乙二醇醚,如乙二醇单甲醚、乙二醇单乙醚或乙二醇二甲醚(diglyme);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,如甲酸和乙酸;硝基化合物,如硝基甲烷或硝基苯;酯类,如乙酸乙酯,或上述溶剂的混合溶剂。
酯可以皂化,例如,使用乙酸或使用LiOH、NaOH或KOH在水、水/THF、水/THF/乙醇或水/二氧六环中,在0到100℃之间的温度下反应。
游离氨基可以进一步以传统方式用酰氯或酸酐酰化,或用未取代的或取代的卤代烷烷基化,或与CH3-C(=NH)-OEt反应,有利的条件是在惰性溶剂如DCM或THF中,和/或在诸如三乙胺和吡啶的碱的存在下,在-60℃和+30℃之间的温度下进行反应。
在整个说明书中,术语离去基团主要表示的是Cl、Br、I或用化学反应修饰的OH基团,例如,一个活化的酯,咪唑盐或有1-6个碳原子的烷磺酰氧基(优选甲磺酰氧基或三氟甲磺酰氧基)或有6-10个碳原子的芳磺酰氧基(优选苯磺酰氧基或对甲苯磺酰氧基)。
在典型的酰化反应中活化羧基的这一类基团在文献中有描述(例如权威的著作,如Houben-Weyl,Methoden der organischen Chemie[有机化学方法],Georg-Thieme-Verlag,斯图加特)。
活性酯可以很方便地在原位形成,例如通过加入HOBt或N-羟基丁二酰亚胺。
通式(I)及相关结构式还包括光学活性形式(立体异构体)、对映异构体的单体、外消旋体、非对映异构体以及这些化合物的水合物和溶剂化物。术语“化合物的溶剂化物”用来表示这些化合物与惰性溶剂分子由于彼此引力作用而形成的加合物。溶剂化物是,例如,单水合物或双水合物或醇化物。
术语“药学上可用的衍生物”用来表示,例如,通式(I)所示化合物的盐类和所谓的药物前体化合物。
术语“前体药物衍生物”或“前体药物”用来表示用例如烷基或酰基、糖或寡肽修饰的通式(I)化合物,它们在机体内迅速裂解形成活性形式的化合物。
其中也包括可生物降解的本发明化合物的聚合衍生物,例如见Int.J.Pharm.115,61-67(1995)中所述。
通式(I)及相关结构式还包括通式(I)所示化合物的混合物,例如两个非对应异构体的混合物,比例为1∶1,1∶2,1∶3,1∶4,1∶5,1∶10,1∶100或1∶1000。
这些化合物尤其优选的是立体异构化合物的混合物。
在优选的实施方案中,本发明涉及通式(A)所示的化合物,
其中Ra、Rb和R2如上定义,
以及其药学上可接受的衍生物、溶剂化物、互变异构体、盐类及其立体异构体,包括它们的各种比例的混合物。
在另一优选的实施方案中,本发明涉及通式(B)所示的化合物,
其中Ra、Rb和R2如上定义,
以及其药学上可接受的衍生物、溶剂化物、互变异构体、盐类及其立体异构体,包括它们的各种比例的混合物。
在另一优选的实施方案中,本发明涉及通式(C)所示的化合物,
其中R1、Ra和Rb如上定义,
以及其药学上可接受的衍生物、溶剂化物、互变异构体、盐类及其立体异构体,包括它们的各种比例的混合物。
在另一优选的实施方案中,本发明涉及通式(D)所示的化合物,
其中Ra、Rb、R1和R2如上定义,Rd表示H或A,
以及其药学上可接受的衍生物、溶剂化物、互变异构体、盐类及其立体异构体,包括它们的各种比例的混合物。
在另一优选的实施方案中,本发明涉及通式(E)所示的化合物,
其中Y、R1和Ra如上定义,
以及其药学上可接受的衍生物、溶剂化物、互变异构体、盐类及其立体异构体,包括它们的各种比例的混合物。
在另一优选的实施方案中,本发明涉及通式(F)所示的化合物,
其中Y和Ra如上定义,
以及其药学上可接受的衍生物、溶剂化物、互变异构体、盐类及其立体异构体,包括它们的各种比例的混合物。
在另一优选的实施方案中,本发明涉及通式(G)所示的化合物,
其中Y、Ra和R2如上定义,
以及其药学上可接受的衍生物、溶剂化物、互变异构体、盐类及其立体异构体,包括它们的各种比例的混合物。
本发明还提供通式(I)化合物,其中Ar表示具有6至14个碳原子的单环或双环不饱和或芳香族碳环,所述碳环可以被Hal、A、OR3、N(R3)2、NO2、CN、COOR3、CF3、OCF3、CON(R3)2、NR3COA、NR3CON(R3)2、NR3SO2A、COR3、SO2N(R3)2、SOA或SO2A单取代、二取代或三取代,使得至少有一个与将Ar基团与分子其余部分连接的原子相邻的原子含有上面所述取代基其中之一。
Ar较佳地表示具有6个碳原子的单环芳香族碳环,所述碳环可以被Hal、A、OR3、N(R3)2、NO2、CN、COOR3、CF3、OCF3、CON(R3)2、NR3COA、NR3CON(R3)2、NR3SO2A、COR3、SO2N(R3)2、SOA或SO2A单取代、二取代或三取代,使得至少有一个与将Ar基团与分子其余部分连接的原子相邻的原子含有上面所述取代基其中之一,其中R3如上定义。
Ar特别优选地表示下列基团之一:
其中Rb和Re独立地各表示A、Hal、OA、OR3、CF3、OCF3。
Het较佳为6至14元环系统,表示未被进一步取代的,例如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-恶唑基,3-,4-或5-异恶唑基,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,还可以优选自1,2,3-三氮唑-1-,-4-或-5-基,1,2,4-三氮唑-1-,-3-或-5-基,1-或5-四氮唑基,1,2,3-恶二唑-4-或-5-基,1,2,4-恶二唑-3-或-5-基,1,3,4-噻二唑-2-或-5-基,1,2,4-噻二唑-3-或-5-基,1,2,3-噻二唑-4-或-5-基,3-或4-哒嗪基,吡嗪基,1-,2-,3-,4-,5-,6-或7-吲哚基,吲唑基,4-或5-异吲哚基,1-,2-,4-或5-苯并咪唑基,1-,3-,4-,5-,6-或7-苯并吡唑基,2-,4-,5-,6-或7-苯并恶唑基,3-,4-,5-,6-或7-苯并异恶唑基,2-,4-,5-,6-或7-苯并噻唑基,2-,4-,5-,6-或7-苯并异噻唑基,4-,5-,6-或7-苯并-2,1,3-恶二唑基,2-,3-,4-,5-,6-,7-或8-喹啉基,1-,3-,4-,5-,6-,7-或8-异喹啉基,3-,4-,5-,6-,7-或8-辛啉基,2-,4-,5-,6-,7-或8-喹唑啉基,5-或6-喹喔啉基,2-,3-,5-,6-,7-或8-2H-苯并-1,4-恶嗪基,还可以优选自1,3-苯并二唑-5-基,1,4-苯并二恶烷-6-基,2,1,3-苯并噻二唑-4-或-5-基,或2,1,3-苯并恶二唑-5-基。
杂环基团也可以部分或全部被氢化。
因此,Het也可以表示,例如2,3-二氢-2-,-3-,-4-或-5-呋喃基,2,5-二氢-2-,-3-,-4-或-5-呋喃基,四氢-2-或-3-呋喃基,1,3-二-氧杂环戊-4-基,四氢-2-或-3-噻吩基,2,3-二氢-1-,-2-,-3-,-4-或-5-吡咯基,2,5-二氢-1-,-2-,-3-,-4-或-5-吡咯基,1-,2-或3-吡咯烷基,四氢-1-,-2-或-4-咪唑基,2,3-二氢-1-,-2-,-3-,-4-或-5-吡唑基,四氢-1-,-3-或-4-吡唑基,1,4-二氢-1-,-2-,-3-或-4-吡啶基,1,2,3,4-四-氢-1-,-2-,-3-,-4-,-5-或-6-吡啶基,1-,2-,3-或4-哌啶基,2-,3-或4-吗啉基,四氢-2-,-3-或-4-吡喃基,1,4-二氧杂环己烷基,1,3-二氧杂环乙烷-2-,-4-或-5-基,六氢-1-,-3-或-4-哒嗪基,六氢-1-,-2-,-4-或-5-嘧啶基,1-,2-或3-哌嗪基,1,2,3,4-四氢-1-,-2-,-3-,-4-,-5-,-6-,-7-或-8-喹啉基,1,2,3,4-四氢-1-,-2-,-3-,-4-,-5-,-6-,-7-或-8-异喹啉基,2-,3-,5-,6-,7-或8-3,4-二氢-2H-苯并-1,4-恶嗪基,也可以优选自2,3-亚甲基二氧基苯基,3,4-亚甲基二氧基苯基,2,3-亚乙基二氧基苯基,3,4-亚乙基二氧基苯基,3,4-(二氟亚甲基二氧基)苯基,2,3-二氢苯并呋喃-5-或-6-基,2,3-(2-氧代亚甲基二氧基)苯基或3,4-二氢-2H-1,5-苯并二氧杂环庚烷-6-或-7-基,也可以优选自2,3-二氢苯并呋喃基或2,3-二氢-2-氧代呋喃基。
Het较佳地表示具有1或2个氮原子、1或2个氧原子或1或2个硫原子的单环或双环饱和、不饱和或芳香族杂环,所述杂环被Hal、A、-[C(R3)2]n-Ar、-[C(R3)2]n-环烷基、OR3、CF3、OCF3、N(R3)2、NR3CON(R3)2、NO2、CN、-[C(R3)2]n-COOR3、-[C(R3)2]n-CON(R3)2、NR3COA、NR3SO2A、COR3、SO2N(R3)2、SOA、和/或SO2A单取代、二取代或三取代,使得至少有一个与将Het基团与分子其余部分连接的原子相邻的原子含有上面所述取代基其中之一,其中R3如上定义。
当它含有一或多个氮原子时,Het较佳地通过氮原子与分子的其余部分连接。
Het特别优选地表示下列基团之一:
其中Rb和Re独立地各表示A、OA、OR3、CF3、OCF3。
Ra最佳地为-CF3、-CN、-CH3、-CH2OCH3、-CH2N(CH3)2、-NHSO2CH3、-NO2、-OCH3。
Rb特别优选地为C1-C6烷基或C1-C6烷基,其中一个碳原子被氧置换。更好地Rb表示甲基、乙基、-CH2OMe、-CH2Oet。
R3特别优选地为H或具有1至6个碳原子的烷基。
Hal优选地为F、Cl或Br。
较佳地,基团A表示具有1至6个碳原子的支链或直链烷基,其中一或多个氢原子,优选1至2个氢原子,被COOR3或N(R3)2置换,其中一或多个非相邻CH2-基团,优选1至2个非相邻CH2-基团,可被O或NR3置换。
较佳地,通式(I)中下列基团,
表示以下基团之一:
优先考虑选自下列组中的通式(I)化合物:
及其药学上可用的衍生物、溶剂化物、盐类及其立体异构体,包括各种比例的混合物。
在上下文中,所有化学基团和取代基,例如X、Q、Y、R1、R2、R3、Ra、Rb、A、Het、Ar、Cyc,具有与通式(I)下标明的意义相同的定义,除非另有明确规定。
在一实施例中,本发明提供通式(I)化合物,其中Y、X、Ra、R1和R2如上定义,Q表示含有1或2个氮原子的饱和或不饱和5元杂环。
在另一具体实施例中,本发明提供通式(I)化合物,其中X、Y、Ra、R1和R2如上定义,Q表示含有1个氧原子的饱和或不饱和5元杂环。
在另一具体实施例中,本发明提供通式(I)化合物,其中X、Y、Ra、R1和R2如上定义,Q表示含有1个硫原子的饱和或不饱和5元杂环。
在另一具体实施例中,本发明提供通式(I)化合物,其中X、Y、R1、R2和Q如上定义,Ra表示-OMe、-OEt、-CH2OMe、-NHSO2Me、Me、Et、-CF3、CN、和-NO2。
在另一实施例中,本发明提供通式(I)化合物,其中X、R1、R2和Ra如上定义,Q表示含有1个氮原子的饱和6元环,Y表示α-甲基吡咯烷。
在另一优选实施例中,本发明提供通式(I)化合物,其中X、R1、R2和Ra如上定义,Q表示含有1个氮原子的饱和6元环,Y表示α-甲基哌啶。
在另一优选实施例中,本发明提供通式(I)化合物,其中Q、R1和R2如通式(I)下的定义,X是-N-,Y表示α-甲基哌啶,Ra表示甲基。
在另一优选实施例中,本发明提供通式(I)化合物,其中X、R1、R2和Ra如上定义,Q表示含有1或2个氮原子的不饱和5元环,Y是邻甲基苯基。
在另一优选实施例中,本发明提供通式(I)化合物,其中X、R1、R2和Ra如上定义,Q表示含有1或2个氮原子的不饱和5元环,Y是α-甲基哌啶。
在另一优选实施例中,本发明提供通式(I)化合物,其中R1和R2独立地选自H、Hal、COOR3、(CH2)COOR3、C1-C6-烷基、(CH2)2COOR3,R3如上定义。
在另一优选实施例中,本发明提供通式(I)化合物,其中R1和R2独立地选自H、Hal、COOR3、(CH2)COOR3、C1-C6-烷基、(CH2)2COOR3,Ra表示-OMe、-OEt、-CH2OMe、-NHSO2Me、Me、Et、-CF3、CN、和-NO2。
烷基表示含有1至12个(较佳地1至8个,更好地1至6个)碳原子的碳链。烷基特别优选地表示甲基,还可以是乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基,也可以是戊基、1-,2-或3-甲基丁基、1,1-,1,2-或2,2-二甲基丙基、1-乙基丙基、己基、1-,2-,3-或4-甲基戊基、1,1-,1,2-,1,3-,2,2-,2,3-或3,3-二甲基丁基、1-或2-乙基丁基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基、1,1,2-或1,2,2-三甲基丙基。
环烷基较佳地表示甲基环丙基、甲基环丁基、甲基环戊基、甲基环己基或甲基环庚基。
环烷基亚烃基较佳地表示环丙基亚甲基、环丁基亚甲基、环戊基亚甲基、环己基亚甲基、或环庚基亚甲基。
亚烃基较佳地表示亚甲基、亚乙基、亚丙基、亚丁基、亚戊基或亚己基,还可以是支链亚烃基。
药用盐类和其它形式
上述通式I所示的化合物可以其最终的非盐形式使用。另一方面,本发明还涉及这些化合物以其药学上可接受的盐的形式使用,可以采用本技术领域的专业人员已知的程序,从各种有机和无机的酸和碱衍生而来。通式I化合物的药学上可接受的盐形式,绝大部分是用传统方法合成的。如果通式I化合物含有一个酸性中心,如羧基,其合适的盐可以通过此化合物与合适的碱反应而生成相应的碱加成盐。这样的碱包括,如碱金属氢氧化物,包括氢氧化钾、氢氧化钠和氢氧化锂;碱土金属氢氧化物,如氢氧化钡和氢氧化钙;碱金属醇盐,例如乙醇钠或乙醇钾和丙醇钠或丙醇钾;碱金属氢化物,如氢化钠或氢化钾;以及各种有机碱,如哌啶、二乙醇胺和N-甲基谷氨酰胺、苄星、胆碱、二乙醇胺、乙二胺、甲葡胺、苯乙基苄胺、二乙胺、哌嗪和氨丁三醇。通式I所示化合物的铝盐也同样包括在内。对于通式I中包含一个碱性中心的某些化合物的情况,可以将这些化合物与药学上可接受的有机酸和无机酸作用形成它们的酸加成盐,例如卤化氢,如氯化氢、溴化氢或碘化氢;其它矿物酸及其相应的盐,如硫酸盐、硝酸盐和磷酸盐等;和烷基-和单芳基-磺酸,如乙基磺酸、对甲苯磺酸和苯磺酸,以及其它有机酸及其相应的盐,如醋酸盐、三氟醋酸盐、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,通式I化合物药学上可接受的酸加成盐包括以下盐:醋酸盐、己二酸盐、藻酸盐、精氨酸盐、天门冬氨酸盐、苯甲酸盐、苯磺酸盐(besylate)、硫酸氢盐、亚硫酸氢盐、溴化物、丁酸盐、樟脑酸盐、樟脑磺酸盐、辛酸盐、氯化物、氯苯甲酸盐、柠檬酸盐、环戊烷丙酸盐、葡萄糖酸盐、磷酸二氢盐、二硝基苯甲酸盐、十二烷基硫酸盐、乙烷磺酸盐、富马酸盐、粘液酸盐(从粘液酸制得)、半乳糖醛酸盐、葡庚糖酸盐、葡萄糖酸盐、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-羟基乙磺酸盐、碘化物、羟乙基磺酸盐、异丁酸盐、乳酸盐、乳糖酸钠、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、偏磷酸盐、甲磺酸盐、甲基苯甲酸盐、磷酸氢盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、油酸盐、palmoate、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,但这并不代表仅限于此。这两种类型的盐可以使用离子交换树脂技术方便地形成或互相转化。
此外,通式I所示化合物的碱式盐包括铝盐、铵盐、钙盐、铜盐、铁(III)盐、亚铁(II)盐、锂盐、镁盐、锰(III)盐、亚锰(II)盐、钾盐、钠盐和锌盐,但这并不代表仅限于此。在上述盐中,优先考虑铵盐,碱金属盐钠盐和钾盐,和碱土金属盐钙盐和镁盐。通式I所示化合物与药学上可接受的无毒有机碱形成的盐包括下列胺的盐,即伯、仲和叔胺、取代胺,也包括自然存在的取代胺、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、N,N′-二苄基乙二胺(苄星)、二环己胺、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、葡萄糖胺、组氨酸、哈胺、异丙胺、利多卡因、赖氨酸、葡甲胺(N-甲基-D-葡萄糖胺)、吗啉、哌嗪、哌啶、聚酰胺树脂、普鲁卡因、嘌呤、可可碱、三乙醇胺、三乙胺、三甲胺、三丙胺和三(羟甲基)甲胺(氨丁三醇),但这并不代表仅限于此。
含有碱性N基团的本发明通式(I)化合物,可以使用诸如(C1-C4)卤代烃的试剂进行季铵化,例如甲基、乙基、异丙基和叔丁基氯化物、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)卤代烃,例如癸烷基、十二烷基、月桂基、十四烷基和十八烷基氯化物、溴化物和碘化物;以及芳基-(C1-C4)烷基卤化物,例如氯化苄和苯乙基溴。这些盐类化合物可以用来制备水溶性和油溶性的通式I化合物。
上述较优选的药用盐类包括醋酸盐、三氟醋酸盐、苯磺酸盐、柠檬酸盐、富马酸盐、葡萄糖酸盐、半琥珀酸盐、马尿酸盐、盐酸盐、氢溴酸盐、羟乙基磺酸盐、扁桃酸盐、葡甲胺盐、硝酸盐、油酸盐、膦酸盐、特戊酸盐、磷酸钠盐、硬脂酸盐、硫酸盐、磺酰基水杨酸盐、酒石酸盐、硫代苹果酸盐、甲苯磺酸盐和氨丁三醇,但这并不代表仅限于此。
通式(I)所示碱性化合物的酸加成盐,通过将游离碱的形式与足够量的所需酸混合接触的方法制备,使按照常规方式生成相应的盐类。这种游离碱是可以再生的,通过使盐类形式与碱接触,用常规方式分离游离碱。这种游离碱的形式在某种意义上与其相应的盐形式在某些物理特性上是不同的,如在极性溶剂中的溶解性;但是,出于本发明的目的,这些盐类在另一方面也对应于其各自的游离碱形式。
如上所述,通式(I)化合物的药学上可接受的碱加成盐,通过与金属或胺的反应生成,如碱金属和碱土金属或有机胺。优选的金属是钠、钾、镁和钙。优选的有机胺为N,N′-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基-D-葡萄糖胺和普鲁卡因。
通式(I)所示酸性化合物的碱加成盐,通过将游离酸的形式与足够量的所需碱混合接触的方法制备,使按照常规方式生成相应的盐类。这种游离酸是可以再生的,通过使盐类形式与酸接触,用常规方式分离游离酸。这种游离酸的形式在某种意义上与其相应的盐形式在某些物理特性上是不同的,如在极性溶剂中的溶解性;但是,出于本发明的目的,这些盐类在另一方面也对应于其各自的游离酸形式。
如果通式I化合物上含有不止一个可以形成这种类型药学上可接受盐的基团,该通式I化合物也包括复盐。典型的复盐的形式包括,例如,二酒石酸盐、二醋酸盐、二富马酸盐,二葡甲胺盐、二磷酸盐、二钠盐和三盐酸盐,但这并不代表仅限于此。
根据上面所述可以看出,术语“药学上可接受的盐”一词在本说明书前后关联中是指一种活性成分,包括以盐形式之一存在的通式I化合物,特别是如果这种盐的形式赋予了活性成分较其游离形式或任何前面使用的活性成分的其它盐形式更为改善的药代动力学特性。该活性成分的药学上可接受的盐的形式也可以是首次给活性成分提供这种理想的药代动力学性质,这种性质是它以前所没有的,并对于其体内疗效来说,它甚至可以对该活性成分的药效学产生积极的影响。
根据其分子结构,通式I化合物可以是手性的,因此可以各种对映异构体的形式出现。因此,它们可以以外消旋体或光学活性形式存在。
由于本发明化合物的外消旋体或立体异构体的药物活性可能会有所不同,可能需要使用单一的对映体。在这种情况下,最终产品,甚至中间体,都可能需要采用本技术领域的专业人员所熟知的化学或物理方法将其拆分成单一的对映体化合物,或者在合成过程中使用这种对映体化合物。
对于外消旋胺类的情况,通过与光学活性拆分剂的反应从混合物中生成非对映异构体。合适的拆分剂有例如光学活性酸,如R和S构型的酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸、乳酸、合适的N-保护氨基酸(例如N-苯甲酰脯氨酸或N-苯磺酰脯氨酸)或各种光学活性樟脑磺酸。有优势的是色谱法对映体拆分,借助于光学活性拆分剂(例如二硝基苯甲酰苯基甘氨酸、三乙酸纤维素或其它碳水化合物的衍生物,或手性衍生化硅胶固载异丁烯酸聚合物)。适合作此用途的洗脱剂是水或醇的混合溶剂,例如,正己烷/异丙醇/乙腈,比例为例如82∶15∶3。
本发明还涉及通式(I)化合物与至少一个其它药物有效成分联合使用的用途。用于治疗多发性硬化症的优选合用药物如克拉屈滨或另一个合用药如干扰素,例如聚乙二醇化和非聚乙二醇化干扰素,优选β-干扰素和/或改善血管功能的化合物。这些其它药物,如β-干扰素,可以通过如皮下、肌肉注射或口服途径伴随给药或顺序给药。
这些成分可以用作人用和兽用药品。
药物制剂可以剂量单位的形式给药,剂量单位由每单位剂量的活性成分的预设量组成。根据所治疗的病情、给药方式和病人年龄、体重和身体状况的差别,这样一个单位包括的本发明化合物的量可以是,例如,0.5mg到1g,优选是1mg至700mg,尤其是优选5mg至100mg,或者药物制剂可以以剂量单位的形式给药,其中包括每单位剂量的活性成分的预设量。优选的剂量单位制剂包括如上所述活性成分的每日剂量或部分剂量,或相应的其中一部分。此外,这种类型的药物制剂可以用药学领域的专业人员普遍熟知的方法加以制备。
药物制剂可适应于经所需的适当方法给药,例如通过口服(包括口腔或舌下)、直肠、鼻腔、局部(包括口腔、舌下或透皮)、阴道或非肠道(包括皮下、肌肉注射、静脉注射或皮内)方法。这种制剂可以用药学领域的专业人员已知的各种方法制备,例如,将有效成分与辅料或佐剂混合。
适合于口服给药的药物制剂可作为独立的单元给药,例如,胶囊或片剂;粉剂或颗粒剂;在水和非水液体中的溶液或悬浮液;食用泡沫或泡沫食品;或水包油型液体乳剂与油包水型液体乳剂。
因此,举例来说,在口服片剂或胶囊的情况下,活性组成成分可以与口服、无毒、药学上可接受的惰性辅料混合,例如,乙醇、甘油、水等。粉剂则通过将化合物粉碎到一个合适的粒度尺寸,并将它与以类似方式粉碎的药物赋形剂(例如食用碳水化合物,如淀粉或甘露醇)混合的方法来制备。香味剂、防腐剂、分散剂和染料同样也可存在。
胶囊剂的制备是先按照上面所述制备粉末混合物,然后充填到成型的明胶壳中。可在充填操作前将助流剂和润滑剂(例如,高度分散硅酸、滑石粉、硬脂酸镁、硬脂酸钙或固体形式的聚乙二醇)添加到粉末混合物中。崩解剂或增溶剂,例如,琼脂、碳酸钙或碳酸钠,同样可以添加进去,以提高服用胶囊后药物的生物利用度。
此外,如果有需要或有必要,适当的粘合剂、润滑剂和崩解剂以及染料同样可以被添加入到混合物中。合适的粘合剂包括淀粉、明胶、天然糖类(如葡萄糖或β-乳糖、玉米甜味剂)、天然和合成橡胶(如阿拉伯树胶、黄芪胶)或海藻酸钠、羧甲基纤维素、聚乙二醇、蜡,等等。这些剂量形式中使用的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、醋酸钠、氯化钠等。崩解剂包括(但不是仅限于)淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。片剂的制剂过程如下,例如,制备粉末混合物、混合物制粒或干压、添加润滑剂和崩解剂、全部混合物压片制成药片。粉末混合物的制备,按照上面所述,将以适当方式粉碎的化合物与稀释剂或基质混合,也可任意选择地与粘合剂(如羧甲基纤维素、海藻酸盐、明胶或聚乙烯吡咯烷酮)、溶出阻缓剂(如石蜡)、促吸收剂(如季铵盐)和/或吸收剂(如膨润土、高岭土或磷酸氢钙)混合。粉末混合物先经粘合剂加湿再经过筛处理可以形成颗粒,粘合剂为例如糖浆、淀粉糊、阿卡迪亚粘胶或纤维素或高分子材料溶液。制备颗粒的另一种可选方法是,粉末混合物可运行通过制片机,获得形状不均匀的小块,再碎裂形成颗粒。为防止片剂粘附在压片模具上,可以在颗粒中加入润滑剂,硬脂酸、硬脂酸盐、滑石粉或矿物油。然后将该润滑混合物压片制得药片。活性成分还可以与自由流动的惰性辅料混合,然后不经过制粒或干压的步骤,直接压片得到片剂。也可存在由虫胶密封层组成的透明或不透明的保护层,糖或高分子材料层,以及蜡光层。染料可以被添加到这些包衣材料中,以便能够区分不同剂量单位。
口服液,例如,溶液剂、糖浆剂和酏剂,可以以剂量单位的形式制备,以便使某一特定量的制剂包含预定数量的化合物。糖浆剂可以通过将化合物溶解在水溶液中并加入合适的香味剂来制备,而酏剂的制备则用的是无毒醇类溶媒。配制悬浮剂,可以将化合物分散在一种无毒溶媒中。同样可以添加增溶剂和乳化剂(如,乙氧基异硬脂醇和聚氧乙烯山梨醇醚),防腐剂,芳香添加剂,例如,薄荷油或天然甜味剂或糖精,或其它人工甜味剂等。
如果需要的话,口服给药的剂量单位制剂可以封装在微胶囊中。这种制剂也可以制备成药物释放被延长或减缓的形式,例如,将颗粒材料覆盖或包埋于聚合物、蜡等材料中。
通式(I)化合物及其盐、溶剂化物和生理功能衍生物以及其它活性成分也可以以脂质体递送系统的形式给药,例如,小单层脂质体、大单层脂质体和多层脂质体。脂质体可由各种磷脂形成,例如,胆固醇、硬脂胺或磷脂酰胆碱。
通式(I)化合物及其盐、溶剂化物和生理功能衍生物以及其它活性成分,也可以用单克隆抗体作为与该化合物分子相偶联的单个载体进行递药。该化合物也可以偶联到作为靶向药物载体的可溶性聚合物上。这种聚合物可包括棕榈酰基取代的聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰氨基苯酚、聚羟乙基天冬酰氨基苯酚或聚乙烯氧化聚赖氨酸。此外,该化合物还可以偶联到一类适合于实现药物控制释放的可生物降解的聚合物上,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、聚氰基丙烯酸酯和交联或两亲的嵌段共聚物水凝胶。
适合于透皮给药的药物制剂可作为独立的贴膏剂给药,并与受治疗者的表皮长时间紧密接触。因此,举例来说,活性成分可以用离子电渗疗法从贴膏剂中递送进入体内,如在Pharmaceutical Research,3(6),318(1986)中描述的一般条件。
适合于局部给药的化合物可以制成软膏剂、乳膏剂、悬浮剂、乳剂、散剂、溶液剂、贴膏剂、凝胶剂、喷雾剂、气雾剂或油剂。
对于眼部或其它外部组织的治疗,例如口腔和皮肤,应用的最好制剂是局部软膏剂或乳膏剂。在制备软膏剂的制剂过程中,活性成分可以与石蜡基质或可与水混溶的霜类基质一起使用。另外,活性成分与水包油性霜类基质或油包水性基质一起可以制成乳膏剂。
适合于眼部局部应用的药物制剂,包括眼药水,其活性成分是溶解或悬浮在合适的载体中的,尤其是水性溶剂。
适合于口腔局部应用的药物制剂包括锭剂、含片和漱口液。
适合于直肠给药的药物制剂可以以栓剂或灌肠剂的形式给药。
适合于鼻腔给药其载体物质是固体的药物制剂,由具有一定粒度的粗粉组成,例如,粒度范围在20-500微米,采取鼻吸的方式给药,即迅速从置于鼻子附近的装有粉末的容器中,经由鼻腔吸入。作为鼻腔喷雾剂或滴鼻液给药的合适制剂以液体作为载体物质,它包含活性成分的水或油溶液。
适合于吸入给药的药物制剂包含颗粒细粉尘或烟雾,可用各种类型的加压分配器、雾化器、喷雾器或吹药器产生。
适合于阴道给药的药物制剂可以作为阴道栓剂、棉塞、乳膏剂、凝胶剂、贴膏、泡沫或喷雾制剂给药。
适合于非肠道给药的药物制剂,包括水和非水无菌注射液,由抗氧化剂、缓冲液、抑菌剂和溶质组成,通过这一手段使制剂与受治疗者的血液呈现等渗;还包括水和非水无菌悬浮液,其中可包括悬浮介质和增稠剂。该制剂可以装在单剂量或多剂量容器中给药,例如密封安瓿和小瓶,并以冷冻干燥(冻干)状态储存,这样只需要在临用前立即加入无菌载体液体,例如注射用水。
注射液和悬浮液按照处方可以从无菌粉、颗粒剂和片剂制备。
不用说,除上述特别提到的成分以外,这些制剂也可包括关于特定制剂类型的本技术领域人员通用的其它物质,因此,例如,适合口服给药的制剂可以包含芳香剂。
通式(I)所示化合物和其它活性成分的治疗有效量取决于多种因素,包括,例如,动物的年龄和体重、需要治疗的准确病情及其严重程度、制剂的性质和给药方法,并最终由主治医生或兽医确定剂量。然而,一个化合物的有效剂量一般在每日0.1至100mg/kg受治疗者(哺乳动物)体重的范围内,特别是通常在每日1到10mg/kg体重的范围内。因此,一个体重70kg的成年哺乳动物每日的实际剂量通常在70至700mg之间,这个剂量可以作为单一剂量每天服用,通常也可以系列部分剂量每天多次服用(例如,二、三、四、五、六次),使每日总剂量保持相同。盐类或溶剂化物或其生理功能衍生物的有效剂量可确定为化合物本身有效剂量的分数。
本发明还涉及治疗罹患鞘氨醇1-磷酸酯相关疾病的受治疗者的方法,包括给予所述受治疗者有效量的通式I化合物。本发明更优选地涉及一种方法,其中鞘氨醇1-磷酸酯-1相关的疾病是一种自身免疫性疾病或一种与过度活跃的免疫反应有关的病症。
本发明还涉及一种治疗罹患免疫调节异常的受治疗者的方法,包括给予所述受试者对治疗所述免疫调节异常有效的剂量的其它式I化合物。本发明优选涉及一种方法,其中免疫调节异常是一种自身免疫性疾病或慢性炎症疾病,选自下列组内的疾病:肌萎缩侧索硬化症(ALS),系统性红斑狼疮,慢性类风湿性关节炎,I型糖尿病,炎性肠道疾病,胆汁性肝硬化,葡萄膜炎,多发性硬化症,Crohn′s病,溃疡性结肠炎,大疱性类天疱疮,结节病,牛皮癣,自身免疫性肌炎,Wegener′s肉芽肿,鱼鳞病,Graves眼病和哮喘。本发明还涉及一种方法,其中免疫调节异常是骨髓或器官移植排斥反应或移植物抗宿主病。本发明还涉及一种方法,其中免疫调节异常是选自下列组内的疾病:器官或组织移植,移植所带来的移植物抗宿主疾病,自身免疫综合征包括类类风湿性关节炎,系统性红斑狼疮,Hashimoto′s甲状腺炎,多发性硬化症,重症肌无力,I型糖尿病,葡萄膜炎,后葡萄膜炎,过敏性脑脊髓炎,肾小球肾炎,感染后自身免疫性疾病包括风湿热和感染后肾小球肾炎,炎性和过度增殖性皮肤病,牛皮癣,特应性皮炎,接触性皮炎,湿疹性皮炎,脂溢性皮炎,扁平苔藓,天疱疮,大疱性类天疱疮,大疱性表皮松解症,荨麻疹,血管性水肿,血管炎,红斑,皮肤嗜酸细胞增多,红斑狼疮,痤疮,斑秃,角膜结膜炎,春季卡他性结膜炎,Behcet′s病相关性眼葡萄膜炎,角膜炎,疱疹性角膜炎,圆锥形角膜,角膜上皮营养不良,角膜白斑,眼天疱疮,蚕蚀性角膜溃疡,巩膜炎,Graves′眼病,Vogt-Koyanagi-Harada综合征,郝-伯二氏病,花粉变态反应,可逆性气道阻塞性疾病,支气管哮喘,变应性哮喘,内源性哮喘,外源性哮喘,粉尘性哮喘,慢性或顽固性哮喘,晚期哮喘和气道高反应,支气管炎,胃溃疡,局部缺血性疾病和血栓症引起的血管损伤,缺血性肠道疾病,炎症性肠病,坏死性小肠结肠炎,与热烧伤相关的肠病变,腹部疾病,直肠炎,嗜酸细胞性胃肠炎,肥大细胞增多症,Crohn′s病,溃疡性结肠炎,偏头痛,鼻炎,湿疹,间质性肾炎,肺出血肾炎综合征,溶血尿毒综合症,糖尿病性肾病变,多发性肌炎,Guillain-Barre综合征,美尼尔氏病,多发性神经炎,多神经炎,单神经炎,神经根病变,甲状腺功能亢进,Basedow′s病,单纯性红细胞再生障碍,再生障碍性贫血,再生不良性贫血,特发性血小板减少性紫癜,自身免疫性溶血性贫血,粒细胞缺乏症,恶性贫血,巨幼细胞性贫血,红细胞生成不能,骨质疏松症,结节病,纤维化肺,特发性间质性肺炎,皮肌炎,寻常型白癜风,鱼鳞病,光变应性敏感,皮肤T细胞淋巴瘤,慢性淋巴细胞白血病,动脉硬化,动脉粥样硬化,主动脉炎综合征,结节性多动脉炎,非炎性心肌病,硬皮病,Wegener′s肉芽肿,Sjogren′s综合征,肥胖病,嗜酸性筋膜炎,牙龈损伤,牙周组织病,牙槽骨,骨质牙病,肾小球肾炎,男性型脱发或老年性秃发防止头发脱落或使头发长出和/或促进毛发生成和头发生长,肌肉萎缩症,脓皮病和Sezary′s综合征,Addison′s病,器官在保存、移植或缺血性疾病后的缺血再灌注损伤,内毒素引发的休克,伪膜性结肠炎,药物或放疗引起的结肠炎,缺血性急性肾功能不全,慢性肾功能不全,肺氧或药物造成的中毒症,肺癌,肺气肿,白内障,高铁血症,视网膜色素变性,老年性黄斑变性,玻璃体瘢痕形成,角膜碱烧伤,多形性红斑性皮炎,线状IgA大疱性皮炎和粘固剂皮炎,牙龈炎,牙周炎,脓毒症,胰腺炎,环境污染引发的疾病,衰老,癌变,癌转移和低气压病,组胺或白三烯-C4释放引发的疾病,Behcet′s病,自身免疫性肝炎,原发性胆汁性肝硬化,硬化性胆管炎,部分肝切除,急性肝坏死,毒素引起的坏死,病毒性肝炎,休克,或缺氧,乙型病毒性肝炎,非甲型/非乙型肝炎,肝硬化,酒精性肝硬化,肝功能衰竭,暴发性肝功能衰竭,迟发性肝功能衰竭,“慢性加急性”肝功能衰竭,化疗效果增强,巨细胞病毒感染,HCMV感染,艾滋病,癌症,老年痴呆症,创伤,及慢性细菌感染。
优选的通式(I)化合物显示在GTPγS试验中S1P1受体结合的EC50值低于约10μM,更优的是低于约5μM,还更优的是低于约1μM,甚至更优的是低于约0.1μM。最优的是,通式(I)化合物显示对S1P1受体结合的EC50值低于0.01μM。
优选的通式(I)化合物表现出对淋巴细胞减少症具有明显的活性。
优选的通式(I)化合物显示对S1P1受体相对于S1P3受体超过20个数量级的选择性。更好的是,式(I)化合物对S1P1的选择性比对S1P3高50倍,更好的是,高100倍。
下面将通过一些实施例来对本发明进行举例说明,这些实施例不会被解释为视作对本发明保护范围的限制。
具体实施方式
实施例
通式(I)所示的化合物可从易得的原料,采用液相和固相化学技术或混合溶液及固相合成技术,通过多步合成反应制备。合成方法的实施例如以下实施例所示。
除了特殊注明之外,下列所述实验中所采用的商品化起始原料均购自Aldrich或Fluka。
实施例中所提供的HPLC、NMR以及MS数据采用如下方法获取:
HPLC数据:
方法A:HPLC液相柱:XbridgeTM C8柱50mm x 4.6mm,流速为2mL/min;8min洗脱梯度从0.1%三氟醋酸水溶液至0.07%三氟醋酸的乙腈溶液。
方法B:HPLC液相柱:ATLANTIS C18 75x 4.6mm 5U,流速为1mL/min;A-0.1%甲酸B-乙腈。
方法C:HPLC液相柱:C18 BDS,50x 4.6mm,SC\307,流速为0.8mL/min;A-0.1%TFA,B-乙腈:流速为0.8mL/min。
方法D:HPLC液相柱:Waters Xterra 5μ C18(2),250x 4.6mm,流速为1mL/min;30min洗脱梯度从95∶5([10mM碳酸氢铵水溶液]∶MeCN)至MeCN。
UV检测(最大吸收):适用于所有方法。
质谱数据:
方法A:LC/MS Waters ZMD(ESI);GC/MS:GC Agilent 6890N & MS Agilent5973。
方法B:UPLC/MS:Waters Acquity,柱Waters Acquity UPLC BEH C18 1.7m2.1x 50mm,质谱条件:溶剂A(10mM醋酸铵水溶液+5%乙腈),溶剂B(乙腈),在3分钟内洗脱梯度5%B至100%B,UV检测(PDA,230-400nm)以及MS检测(SQ检测器,正离子与负离子ESI模式,锥电压设定为30V)。
1H-NMR数据:
除特殊注明外均采用Bruker DPX-300MHz设备测定。
质谱导向型Autoprep纯化系统:
除特殊注明外,制备型HPLC纯化方法可通过配备有Sunfire Prep C18 OBD色谱柱19x 100mm 5m的Waters公司Fractionlynx系统以质谱导向型自动化纯化系统进行纯化。所有HPLC纯化过程中所采用的洗脱梯度为乙腈/水或乙腈/水/甲酸(0.1%)。
微波反应在Personal Chemistry公司提供的单模式EmrysTM Optimiser微波反应器中进行。
加氢反应在H-CubeTM连续流动氢化反应器中进行-连续的氢化反应在一个流动的系统中进行。反应所需的氢气原位产生。反应在模仿常规HPLC系统的一次性专有CatCartsTM装载催化剂柱中发生。使用触摸屏控制和监测H-Cube反应器的各个操作方面。
中间体1:N′-羟基-1H-苯并咪唑-5-甲酰亚胺酰胺
步骤1:1H-苯并咪唑-5-腈
将3,4-二氨基苯甲腈(1g;7.51mmol)在甲酸(40mL)中的溶液回流加热3小时,然后真空浓缩,得到褐色油残余物。该残余物用乙酸乙酯萃取,饱和NaHCO3水溶液洗涤,MgSO4干燥,并真空蒸发,得到标题化合物,为浅粉红色固体(1.05g,98%)。1H NMR(DMSO-d6):δ12.97(br s,1H),8.48(s,1H),8.16(d,J=0.8Hz,1H),7.76(d,J=8.3Hz,1H),7.59(dd,J=8.3,1.5Hz,1H)。LC/MS(方法B):144.1(M+H)+。
步骤2:N′-羟基-1H-苯并咪唑-5-甲酰亚胺酰胺
将步骤1获得的1H-苯并咪唑-5-腈(1g;6.99mmol)在乙醇(20mL)中的悬液加入羟胺(50%水溶液,2.10mL;34.93mmol),混合物在室温搅拌36小时。真空浓缩溶液,得到标题化合物,为浅粉红色固体(1.15g,93%)。1H NMR(DMSO-d6):δ12.52(br s,1H),9.51(s,1H),8.23(s,1H),7.89(br s,1H),7.56(s,2H),5.80(s,2H)。
中间体2:7-氟-N′-羟基-1H-苯并咪唑-5-甲酰亚胺酰胺
步骤1:5-溴-7-氟-1H-苯并咪唑
将5-溴-2,3-二氨基氟苯(Apollo,3g;14.63mmol)在甲酸(75mL)中的溶液回流加热过夜,然后真空浓缩,得到褐色油。该褐色油用乙酸乙酯萃取,饱和NaHCO3水溶液洗涤,MgSO4干燥,并真空蒸发,得到标题化合物,为浅粉红色固体(2.91g,92%)。1H NMR(DMSO-d6):δ8.30(s,1H),7.62(d,J=1.5Hz,1H),7.27(dd,J=10.3,1.5Hz,2H),3.32(bs,2H)。HPLC(方法A),Rt:2.09min(纯度:97.4%).LC/MS(方法B):216.9(M+H)+。
步骤2:7-氟-1H-苯并咪唑-5-腈
将步骤1获得的5-溴-7-氟-1H-苯并咪唑(2.50g;11.63mmol)、氰化锌(Adrich,819mg;6.98mmol)、三(二亚苄基丙酮)二钯(Adrich,319mg;0.35mmol)、1,1′-双(二苯基膦基)二茂铁(483mg;0.87mmol)、锌(Adrich,30mg;0.47mmol)和乙酸锌(Adrich,85mg;0.47mmol)在干DMF(25mL)中的悬液在隋性气氛下在120℃加热16小时。反应混合物经硅藻土垫过滤,乙酸乙酯洗涤。有机相用水洗涤,MgSO4干燥,真空蒸发,得到褐色固体,该褐色固体在乙醇中研磨,过滤,得到标题化合物,为褐色固体。1H NMR(DMSO-d6)δ13.40(bs,1H),8.55(s,1H),8.04(s,1H),7.51-7.48(d,J=10.7Hz,1H)。LC/MS(方法B):162.1(M+H)+。
步骤3:7-氟-N′-羟基-1H-苯并咪唑-5-甲酰亚胺酰胺
以步骤2获得的7-氟-1H-苯并咪唑-5-腈(750mg;4.65mmol)为原料,按照中间体1步骤2的制备工艺制备标题化合物,所制备的标题化合物为米色固体(814mg,90%)。1H NMR(DMSO-d6)δ12.88(bs,1H),9.67(s,1H),9.30(s,1H),7.68(s,1H),7.33-7.29(m,1H),5.89(s,2H)。LC/MS(方法B):195.1(M+H)+。
中间体3:N′-羟基-7-甲基-1H-苯并咪唑-5-甲酰亚胺酰胺
步骤1:5-溴-7-甲基-1H-苯并咪唑
将5-溴-3-甲基-苯-1,2-二胺(Maybridge,3g;14.92mmol)在甲酸(75mL)中的溶液回流加热16小时。反应混合物真空浓缩,得到褐色油。该褐色油用乙酸乙酯萃取,饱和NaHCO3水溶液洗涤,MgSO4干燥,并真空蒸发,得到标题化合物,为浅黄色固体(3.07g,97%)。1H NMR(DMSO-d6)δ12.92-12.34(bs,1H),8.22(s,1H),7.59(br s,1H),7.17(s,1H),3.33(s,3H)。LC/MS(方法B):211.0(M+H)+。
步骤2:7-甲基-1H-苯并咪唑-5-腈
将步骤1获得的5-溴-7-甲基-1H-苯并咪唑(2.50g;11.63mmol)、氰化锌(934mg;7.96mmol)、三(二亚苄基丙酮)二钯(364mg;0.40mmol)、1,1′-双(二苯基膦基)二茂铁(551mg;0.99mmol)、锌(34mg;0.53mmol)和乙酸锌(97mg;0.53mmol)在干DMF(28mL)中的悬液在隋性气氛下在120℃加热16小时。反应混合物经硅藻土垫过滤,乙酸乙酯洗涤。有机相用水洗涤,MgSO4干燥,真空蒸发,得到褐色固体,该褐色固体在乙醇中研磨,过滤,得到标题化合物,为米色固体。1H NMR(DMSO-d6)δ13.11(br s,1H),8.45(s,1H),8.02-7.90(m,1H),7.42(m,1H),2.54(m,3H)。LC/MS(方法B):158.2(M+H)+。
步骤3:N′-羟基-7-甲基-1H-苯并咪唑-5-甲酰亚胺酰胺
以步骤2获得的7-甲基-1H-苯并咪唑-5-腈(900mg;5.73mmol)为原料,按照中间体1步骤2的制备工艺制备标题化合物,所制备的标题化合物为米色固体(985mg,90%)。1H NMR(DMSO-d6)δ12.60(br s,1H),9.46(s,1H),8.29-7.57(m,3H),5.76(s,2H),2.51(m,3H)。LC/MS(方法B):191.1(M+H)+。
中间体4:7-[-氨基(羟基亚氨基)甲基]-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯
步骤1:7-氰基-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯
将具有催化活性的DMAP加入到7-氰基-1,2,3,4-四氢异喹啉(ABCR,1.58g;10mmol)和二碳酸二叔丁酯(2.61g;12mmol)在CH3CN(50mL)中的悬液中,得到的混合物室温搅拌16小时。不均相混合物真空浓缩,残余物用乙酸乙酯萃取,水洗涤,MgSO4干燥,真空蒸发,得到黄色油,该黄色油经硅柱色谱法(环己烷/乙酸乙酯,先85/15然后80/20)纯化,得到标题化合物,为无色油。1H NMR(DMSO-d6)δ7.70(bs,1H),7.61(dd,J=8,1.6Hz,1H),7.36(d,J=8Hz,1H),4.53(s,2H),3.55(t,J=5.9Hz,2H),2.85(t,J=5.9Hz,2H),1.42(s,9H)。HPLC(方法A),Rt 4.18min(纯度:99.5%)。
步骤2:7-[-氨基(羟基亚氨基)甲基]-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯
以步骤1获得的7-氰基-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯(1.50g;5.81mmol)为原料,按照中间体1步骤2的制备工艺制备标题化合物。真空蒸发溶剂,进一步冻干后得到标题化合物,为灰白色固体(1.35g,80%)。1H NMR(DMSO-d6)δ9.54(s,1H),7.46(m,2H),7.14(d,J=8Hz,1H),5.74(bs,2H),4.49(s,2H),3.54(t,J=5.9Hz,2H),2.76(t,J=5.9Hz,2H),1.49(s,9H)。HPLC(方法A),Rt 2.40min(纯度:99.4%)。LC/MS(方法B):292.2(M+H)+。
中间体5:[7-[氨基(羟基亚氨基)甲基]-3,4-二氢异喹啉-2(1H)-基]乙酸叔丁酯
步骤1:(7-氰基-3,4-二氢异喹啉-2(1H)-基)乙酸叔丁酯
向7-氰基-1,2,3,4-四氢异喹啉(ABCR,2g;12.64mmol)和K2CO3(3.49g,25.28mmol)在CH3CN(40mL)中的悬液加入溴乙酸叔丁酯(1.96mL;13.27mmol),反应混合物室温搅拌4小时。真空蒸发移除溶剂,固体残余物用乙酸乙酯萃取,饱和NaHCO3溶液洗涤,MgSO4干燥,真空蒸发,得到标题化合物,为无色油(3.32g;96%)。1H NMR(DMSO-d6)δ7.55(m,2H),7.30(m,1H),3.72(s,2H),3.31(s,2H),2.86-2.79(m,4H),1.49(s,9H)。LC/MS(方法B):217.1(M+H)+。
步骤2:[7-[氨基(羟基亚氨基)甲基]-3,4-二氢异喹啉-2(1H)-基]乙酸叔丁酯
以步骤1获得的(7-氰基-3,4-二氢异喹啉-2(1H)-基)乙酸叔丁酯(3.32g;12.19mmol)为原料,按照中间体1步骤2的制备工艺制备标题化合物,所制备的标题化合物为浅黄色粉末(3.69g;99%)。1H NMR(DMSO-d6)δ9.50(s,1H),7.43-7.40(m,1H),7.33(m,1H),7.08(d,J=8Hz,1H),5.71(bs,2H),3.68(s,2H),3.30(s,2H),2.78(s,4H),1.43(s,9H)。HPLC(方法A),Rt 1.82min(纯度:91.1%)。LC/MS(方法B):306.2(M+H)+。
中间体6:N-羟基-1-甲基-1H-吲哚-5-甲酰亚胺酰胺
步骤1:1-甲基-1H-吲哚-5-腈
使5-溴吲哚(500mg;2.55mmol)和氰化亚铜(342mg;3.83mmol)在NMP(10mL)中的混合物在微波辐射下加热至100℃,保持30分钟,然后在200℃加热30分钟。反应混合物用水和DCM分隔,有机层用盐水洗涤,真空浓缩,得到粉红色固体。经硅柱色谱法(DCM)纯化,得到白色固体。将该白色固体溶解在DMF(5mL),连续地加入K2CO3(704mg;5.10mmol)和碘甲烷(543mg;3.83mmol)。反应混合物室温搅拌3天,然而在水和乙酸乙酯之间分隔。有机层用盐水洗涤,MgSO4干燥,真空浓缩,得到浅黄色油,静置结晶后得到标题化合物,为乳白色固体(80mg,70%)。LC/MS(方法A):156.9(M+H)+。
步骤2:N-羟基-1-甲基-1H-吲哚-5-甲酰亚胺酰胺
以步骤1获得的1-甲基-1H-吲哚-5-腈(285mg;1.82mmol)在乙醇(3mL)中的溶液为原料,按照中间体1步骤2的制备工艺制备标题化合物,所制备的标题化合物为乳白色固体(325mg,94%)。1H NMR(DMSO-d6)δ9.37(s,1H),7.84(s,1H),7.52-7.48(m,1H),7.40-7.37(m,1H),7.33-7.32(m,1H),6.43(d,J=3Hz,1H),5.70(bs,2H),3.78(s,3H)。
中间体7:{5-[(羟基氨基)(亚氨基)甲基]-1H-吲哚-1-基}乙酸叔丁酯
步骤1:(5-氰基-1H-吲哚-1-基)乙酸叔丁酯
将溴乙酸叔丁酯(0.88mL;5.99mmol)加入到5-氰基吲哚(0.71g;4.99mmol)和K2CO3(1.38g;9.99mmol)在CH3CN(20mL)中的悬液中,得到的混合物回流搅拌16小时。过滤,真空浓缩,得到浅黄色油,静置结晶。将固体在乙醇和己烷的混合物中研磨,得到标题化合物,为乳白色固体(1.26g,98%)。HPLC(方法A),Rt:4.43min(纯度:96.8%)。LC/MS(方法B):256.9(M+H)+。
步骤2:{5-[(羟基氨基)(亚氨基)甲基]-1H-吲哚-1-基}乙酸叔丁酯
以步骤1获得的(5-氰基-1H-吲哚-1-基)乙酸叔丁酯(512mg;2mmol)为原料,按照中间体1步骤2的制备工艺制备标题化合物,所制备的标题化合物为白色固体(558mg,97%)。1H NMR(DMSO-d6)δ9.38(s,1H),7.84(s,1H),7.49-7.45(m,1H),7.33-7.29(m,2H),6.47(d,J=3Hz,1H),5.71(bs,2H),4.99(s,2H),1.40(s,9H)。HPLC(方法A),Rt 2.54min(纯度:94.6%)。LC/MS(方法B):290.0(M+H)+。
中间体8:5-[氨基(羟基亚氨基)甲基]-6-甲氧基-1H-吲哚-2-羧酸乙酯
步骤1:5-溴-6-甲氧基-1H-吲哚-2-羧酸乙酯
将乙醇钠在乙醇中的溶液(由钠(1.92g;83.70mmol)和乙醇(40mL)制备)滴加入3-溴-对甲氧基苯甲醛(4g;18.60mmol)和叠氮乙酸乙酯(ABCR,27.80ml;46.50mmol)在乙醇(60mL)中的冻溶液(-10℃)。滴加完成后,将反应混合物的温度升至0℃,室温搅拌5小时。将非均相混合物倒入冰中,搅拌30分钟。过滤收集固体,真空干燥。固体溶解在二甲苯(60mL)中,加热回流3小时。蒸发溶剂,残余物经硅柱色谱法(环己烷/乙基乙酸酯,80/20)纯化,得到标题化合物,为浅黄色固体。1H NMR(DMSO-d6)δ11.87(s,1H),7.89(s,1H),7.05(s,1H),6.98(s,1H),4.31(q,J=7Hz,2H),3.85(s,3H),1.32(t,J=7Hz,3H)。HPLC(方法A),Rt4.28min(纯度:98.1%)。LC/MS(方法B):297.2(M+H)+。
步骤2:5-氰基-6-甲氧基-1H-吲哚-2-羧酸乙酯
使步骤1获得的5-溴-6-甲氧基-1H-吲哚-2-羧酸乙酯(300mg;1.01mmol)和氰化亚铜(108mg;1.21mmol)在NMP(10mL)中的混合物在微波辐射下加热至200℃,保持30分钟。深色溶液经硅藻土短垫过滤,用DCM洗涤。得到的深红色溶液真空浓缩,在水中沉淀出油状残余物。过滤收集固体,用水彻底洗涤,高真空干燥。经硅柱色谱法(先用DCM后用DCM/MeOH,99/1)纯化,得到标题化合物,为浅粉红色固体。HPLC(方法A),Rt 3.45min(纯度:97.4%)。LC/MS(方法B):243.2(M+H)+。
步骤3:5-[氨基(羟基亚氨基)甲基]-6-甲氧基-1H-吲哚-2-羧酸乙酯
以步骤2获得的5-氰基-6-甲氧基-1H-吲哚-2-羧酸乙酯(120mg;0.49mmol)为原料,按照中间体1步骤2的制备工艺制备标题化合物,所制备的标题化合物为米色固体(135mg,99%)。1H NMR(DMSO-d6)δ9.25(s,1H),7.60(s,1H),7.11(s,1H),6.90(s,1H),5.53(bs,2H),4.31(q,J=7Hz,2H),3.80(s,3H),1.32(t,J=7Hz,3H)。
中间体9:N′-羟基-1H-吲哚-5-甲酰亚胺酰胺
以5-氰基吲哚(2g;14.07mmol)为原料,按照中间体1步骤2的制备工艺制备标题化合物,所制备的标题化合物为褐色固体(2.4g,97%)。HPLC(方法A),Rt0.95min(纯度:88.8%)。LC/MS(方法B):176.1(M+H)+。
中间体10:N′-羟基-1H-吲唑-5-甲酰亚胺酰胺
以1H-吲唑-5-腈(JW-Pharmalab,0.50g;3.49mmol)为原料,按照中间体1步骤2的制备工艺制备标题化合物,所制备的标题化合物为米色固体(560mg,91%)。1H NMR(DMSO-d6)δ13.12(s,1H),9.54(s,1H),8.10(s,1H),8.04(s,1H),7.71(d,J=8.7Hz,1H),7.49(d,J=8.7Hz,1H),5.82(bs,2H)。
中间体11:4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯甲酸
步骤1:4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯甲腈
4-氟-3-(三氟甲基)苯甲腈(Combi-blocks,50g;264.40mmol)和2-甲基哌啶(Acros,156.08mL;1321.98mmol)在DMSO(500mL)中的溶液在氮气气氛下于100℃加热12小时。然后,向反应混合物加入乙醚和水,有机相连续地用水、NaHCO3、和饱和NH4Cl水溶液洗涤。有机物经MgSO4干燥,真空蒸发,得到标题化合物,为米色粉末。1H NMR(DMSO-d6)δ8.19(d,J=2Hz,1H),8.12(dd,J=8.4,2Hz,1H),7.75(d,J=8.2Hz,1H),3.15-3.10(m,1H),2.90-2.85(m,1H),2.60-2.51(m,1H),1.77-1.25(m,6H),0.72(d,J=6.0Hz,3H)。LC/MS(方法B):269.2(M+H)+。
步骤3:4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯甲酸
将步骤1获得的4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯甲腈(28g;104.37mmol)溶解在甲醇(280mL)中,加入氢氧化钠(336mL;5M),反应混合物在100℃加热7小时。然后,将反应混合物冷却至0℃,用盐酸(5N)酸化至pH~2。沉淀出白色产物,过滤,用水洗涤,真空干燥,得到标题化合物,为白色粉末(27.50g;91%)。1H NMR(DMSO-d6)δ13.30(bs,1H),8.20-8.14(m,2H),7.68(d,J=8.2Hz,1H),3.08(m,1H),3.10-3.06(m,1H),2.90-2.86(m,1H),2.59-2.54(m,1H),1.77-1.25(m,6H),0.72(d,J=6.0Hz,3H)。HPLC(方法B)Rt 5.37min(纯度:99.8%)。LC/MS(方法B):288.2(M+H)+。
中间体12:3-氰基-4-(2-甲基哌啶-1-基)苯甲酸
将2-甲基哌啶(2.38mL;20.29mmol)加入到3-氰基-4-氟苯甲酸甲酯(根据J.Med.Chem.2004,47,1339-1350描述的方法由2-氟-5-甲酰基苯甲腈(727mg;4.06mmol)制备)在DMF(4mL)中的溶液中。得到的混合物室温搅拌2天。溶液在乙酸乙酯与水之间分隔,分离两相。有机层用HCl(0.1M)和盐水洗涤,MgSO4干燥。减压蒸发,得到绿色油。将该绿色油溶解在THF(10mL)中,加入LiOH(340mg;8.12mmol)和水(10mL),反应混合物室温搅拌16小时。得到的溶液用水稀释,乙醇洗涤。加入HCl(1M)使水层呈酸性(pH 2),并用乙酸乙酯萃取。有机相用MgSO4干燥,真空浓缩,得到浅黄色油,在乙酸乙酯和正戊烷的混合物中研磨后,沉淀析出标题化合物,为乳白色固体。1H NMR(DMSO-d6)δ13(br s,1H),8.08(d,J=2.1Hz,1H),8.01(dd,J=8.8,2.1Hz,1H),7.18(d,J=8.9Hz,1H),4.12-4.08(m,1H),3.35-3.25(m,2H),1.84-1.53(m,6H),1.09(d,J=6.6Hz,3H)。LC/MS(方法B):243.2(M-H)-;245.2(M+H)+。
中间体13:5-甲基-6-(2-甲基哌啶-1-基)烟酸
步骤1:5-甲基-6-(2-甲基哌啶-1-基)烟腈
将5-氰基-2-氟-3-甲基吡啶(Molekula,1.50g;11.02mmol)和2-甲基哌啶(5.20mL;44.08mmol)的溶液加热至90℃,保持18小时。反应混合物用乙酸乙酯萃取,有机物用MgSO4干燥,真空蒸发,得到标题化合物,为褐色油(2.2g,93%)。1H NMR(DMSO-d6)δ8.46(d,J=2.3Hz,1H),7.82(d,J=2.3Hz,1H),4.01-3.96(m,1H),3.37-3.25(m,2H),3.17-3.09(m,1H),2.22(s,3H),1.72-1.46(m,6H),1.11(d,J=6.6Hz,3H)。HPLC(方法B)Rt 3.60min(纯度:84.5%)。LC/MS(方法A):216.2(M+H)+。
步骤2:5-甲基-6-(2-甲基哌啶-1-基)烟酸
将步骤1获得的5-甲基-6-(2-甲基哌啶-1-基)烟腈(1.0g;4.64mmol)和KOH(1.3g;23.22mmol)在水(60mL)中的溶液回流加热16小时。然后,将反应混合物酸化至pH 3,用乙酸乙酯萃取,得到标题化合物,为黄色固体(1.1g,定量得率)。1H NMR(DMSO-d6)δ12.82(bs,1H),8.58(d,J=2.3Hz,1H),7.88(d,J=2.3Hz,1H),3.85-3.82(m,1H),3.19-3.10(m,2H),2.24(s,3H),1.75-1.44(m,6H),1.04(d,J=6.2Hz,3H)。HPLC(方法B)Rt 1.96min(纯度:92.2%)。LC/MS(方法A):235.2(M+H)+。
中间体14:2-(甲氧基甲基)-2′-甲基二苯基-4-羧酸
步骤1:4-溴-3-(溴甲基)苯甲酸甲酯:
在N2气氛下向4-溴-3-甲基苯甲酸甲酯(50g;218.27mmol)在CHCl3(1000mL)中的溶液一次性地加入NBS(Merck,46.62g;261.93mmol)和α,α′-偶氮二异丁腈(0.72g;4.37mmol)。混合物在70℃搅拌2天。反应混合物冷却至室温,加入水(500mL)。有机层依次用饱和NaHCO3水溶液、水(340mL)和盐水(500mL)洗涤,MgSO4干燥,浓缩,得到标题化合物,为黄色固体。该黄色固体用戊烷(2x 500mL)洗涤,得到标题化合物,为黄色固体。1H NMR(DMSO-d6)δ8.24(d,J=1.91Hz,1H),7.88-7.82(m,2H),4.87(s,2H),3.91(s,3H)。HPLC(方法A)Rt 4.44min(纯度:97.9%)。
步骤2:4-溴-3-(甲氧基甲基)苯甲酸甲酯:
使步骤1获得的4-溴-3-(溴甲基)苯甲酸甲酯(37.50g;121.77mmol)在甲醇(1125mL)中的溶液回流4天。浓缩后,混合物在乙酸乙酯(500mL)与水(200mL)之间分隔。有机层用5%NaHCO3水溶液(200mL)、盐水(200mL)洗涤,MgSO4干燥,浓缩,得到标题化合物,为米色固体(29.8g,94%)。1H NMR(DMSO-d6)δ8.06-8.05(m,1H),7.83(d,J=1.23Hz,2H),4.54(m,2H),3.90(s,3H),3.45(s,3H)。LC/MS(方法B):227.2(M-H)-。HPLC(方法A)Rt 4.42min(纯度:93.0%)。
步骤3:2-(甲氧基甲基)-2′-甲基二苯基-4-羧酸甲酯
将步骤2获得的4-溴-3-(甲氧基甲基)苯甲酸甲酯(40g;154.38mmol;1eq.)、邻甲苯基硼酸(23.09g;169.82mmol;1.10eq.)、K2CO3(106.68g;771.90mmol;5eq.)、四(三苯基膦)钯(0)(1.78g;1.54mmol;0.01eq.)在氮气气氛下溶解在甲苯(200mL)和水(200mL)中。反应混合物经真空净化,然后脱去氮气,再回流1小时。反应混合物冷却至室温,硅藻土过滤,用乙酸乙酯(1000mL)洗涤。滤液浓缩,得到黄色油,该黄色油溶解在乙酸乙酯(800mL)中。有机层用饱和NaHCO3水溶液(250mL)、水(250mL)和盐水(250mL)洗涤,MgSO4干燥,浓缩,得到标题化合物,为黄色油,无需进一步纯化即可使用(41.9g,定量)。HPLC(方法A)Rt 5.34min(纯度:89.4%)。
步骤4:2-(甲氧基甲基)-2′-甲基二苯基-4-羧酸
向步骤3获得的2-(甲氧基甲基)-2′-甲基二苯基-4-羧酸甲酯(40g;147.97mmol)在乙醇(1200mL)中的溶液加入NaOH(88.78mL;5M;443.90mmol),然后,将混合物在60℃加热1小时。反应混合物冷却至室温,真空浓缩,得到黄色固体。加入水,水相用乙酸乙酯洗涤。水相用HCl(1M)酸化,乙酸乙酯萃取,得到标题化合物,为黄色固体(35.1g,92%)。1H NMR(DMSO-d6)δ12.99(br s,1H),8.09(s,1H),7.92-7.89(m,1H),7.33-7.22(m,4H),7.10-7.08(m,1H),4.11(m,2H),3.18(s,3H),1.99(s,3H)。HPLC(方法A)Rt 4.52min(纯度:96.4%)。LC/MS(方法B):255.2(M-H)-。
中间体15:2-[(二甲基氨基)甲基]-2′-甲基二苯基-4-羧酸
步骤1:4-溴-3-(溴甲基)苯甲酸甲酯
向4-溴-3-甲基苯甲酸甲酯(50g;218mmol)在CHCl3(1L)中的溶液加入一次性地加入NBS(46.6g;262mmol)和α,α′-偶氮二异丁腈(0.72g;4.37mmol)。反应混合物在70℃搅拌2天。反应混合物冷却至室温,加入水。有机层依次用饱和NaHCO3水溶液和盐水洗涤,MgSO4干燥,真空浓缩。残余物用正戊烷洗涤,得到标题化合物,为黄色固体。1H NMR(DMSO-d6)δ8.24(d,J=1.9Hz,1H),7.88-7.82(m,2H),4.87(s,2H),3.91(s,3H)。HPLC(方法A):Rt 4.44min(纯度97.9%)。
步骤2:3-[(乙酰基氧基)甲基]-4-溴苯甲酸甲酯
向步骤1获得的4-溴-3-(溴甲基)苯甲酸甲酯(6.5g;21mmol)在乙醇(32.5mL)中的溶液加入乙酸钠(3.46g;42mmol),反应混合物100℃搅拌12小时。真空浓缩后,残余物在乙酸乙酯与水之间分隔。有机层用5%NaHCO3水溶液(200mL)、盐水(200mL)洗涤,MgSO4干燥,真空浓缩。经硅柱色谱法(环己烷/乙酸乙酯,5/1)纯化,得到标题化合物,为白色固体(4.78g,79%)。1H NMR(DMSO-d6)δ8.03(m,1H),7.85-7.84(d,J=1.3Hz,1H),5.18(s,2H),3.87(s,3H),2.11(s,3H)。HPLC(方法A)Rt 4.37min(纯度98.1%)。
步骤3:2-[(乙酰基氧基)甲基]-2′-甲基二苯基-4-羧酸甲酯
将步骤2获得的3-[(乙酰基氧基)甲基]-4-溴苯甲酸甲酯(4.7g;16.4mmol)、邻甲苯基硼酸(2.45g;18mmol)、K2CO3(11.3g;82mmol)和Pd(PPh3)4(1.89g;1.64mmol)在甲苯(23.5mL)和水(23.5mL)中的混合物回流2小时。冷却至室温后,反应混合物经硅藻土过滤,用甲苯(50mL)进一步洗涤。滤液真空浓缩,残余物在乙酸乙酯(250mL)中溶解,用饱和NaHCO3水溶液、水和盐水洗涤,硫酸镁干燥,真空浓缩,得到标题化合物(4.9g,定量),为黄色油。HPLC(方法A)Rt 5.23min(纯度62.3%)。
步骤4:2-[(二甲基氨基)甲基]-2′-甲基二苯基-4-羧酸甲酯
向步骤3获得的2-(羟基甲基)-2′-甲基二苯基-4-羧酸甲酯(2.12g;8.27mmol)在DCM(63.6mL)中的溶液加入0℃的DIEA(7.03mL;41.36mmol)和0℃的甲烷磺酰氯(768μL;9.93mmol),搅拌25分钟。然后,向反应混合物加入二甲基胺(12.41mL;2M;24.81mmol),室温搅拌16小时。反应混合物在DCM和NaOH水溶液(5M)之间分隔。经硅柱色谱法(DCM/[DCM/甲醇2∶1]梯度)纯化,得到标题化合物,为浅黄色固体(2.03g,86%)。1H NMR(DMSO-d6)δ8.27(d,J=1.4Hz,1H),7.95(dd,J=7.8,1.9Hz,1H),7.32-7.18(m,4H),7.06(d,J=7.3Hz,1H),3.94(s,3H),3.24-3.10(m,2H),2.11(s,6H),2.01(s,3H)。HPLC(方法A)Rt 2.90min(纯度100.0%)。LC/MS(方法B):284.1(M-H)-。
步骤5:2-[(二甲基氨基)甲基]-2′甲基二苯基-4-羧酸
对步骤4获得的2-[(二甲基氨基)甲基]-2′-甲基二苯基-4-羧酸甲酯(687mg;2.42mmol)在水(20mL)中的溶液室温下用HCl(12mL;5M;60mmol)处理。反应混合物在105℃回流4小时,真空蒸发,溶解在ACN中,真空蒸发,得到标题化合物,为浅黄色固体(719mg;96%)。1H NMR(DMSO-d6)δ13.23(br s,1H),10.31(br s,1H),8.47(s,1H),8.03(d,J=7.2Hz,1H),7.38-7.31(m,4H),7.20(d,J=7.2Hz,1H),4.32(d,J=13.2Hz,1H),3.87(d,J=13.2Hz,1H),2.61(s,3H),2.50(s,3H),1.98(s,3H)。HPLC(方法A)Rt 2.52min(纯度100.0%)。
中间体16:3-(甲氧基甲基)-4-(2-甲基哌啶-1-基)苯甲酸
步骤1:5-溴-2-(2-甲基哌啶-1-基)苯甲醛
向5-溴-2-氟苯甲醛(13.20g;65.02mmol)在DMSO(160mL)和水(40mL)中的溶液加入2-甲基哌啶(15.35mL;130.04mmol)和无水碳酸钠(13.78g;130.04mmol)。得到的混合物在120℃加热16小时,然后冷却至室温。反应混合物在水和乙醚之间分隔,有机相合并,用盐水(pH 5-6,用HCl调节)洗涤,MgSO4干燥,过滤,真空干燥,得到标题化合物,为褐黄色油(16.3g,89%)。1H NMR(CDCl3,300MHz)δ10.40(s,1H),7.93(d,J=2.5Hz,1H),7.62(dd,J=8.6,2.5Hz,1H),7.12(d,J=8.6Hz,1H),3.17(m,1H),3.06(m,1H),2.81(ddd,J=11.7,7.6,3.9Hz,1H),1.89(m,1H),1.83-1.65(m,3H),1.58-1.42(m,2H),0.91(d,J=6.3Hz,3H)。HPLC(方法A):Rt 2.20min(纯度:93.7%)。LC/MS(方法B):282.1(M+H)+。
步骤2:[5-溴-2-(2-甲基哌啶-1-基)苯基]甲醇
向步骤1获得的5-溴-2-(2-甲基哌啶-1-基)苯甲醛(16.30g;57.76mmol)在甲醇(300mL)中的溶液一次性地加入5℃的硼氢化钠(2.19g;57.76mmol),搅拌30分钟。然后,反应混合物用饱和NH4Cl水溶液稀释,乙酸乙酯萃取。有机层用NH4Cl水溶液、盐水洗涤,MgSO4干燥,真空蒸发,得到标题化合物,为黄色油(15.9g,97%)。1H NMR(CDCl3,300MHz)δ7.38(dd,J=8.5,2.4Hz,1H),7.26(d,J=2.4Hz,1H),7.13(d,J=8.5Hz,1H),6.40(brs,1H),4.86(d,J=13.9Hz,1H),4.67(d,J=13.9Hz,1H),3.06-2.88(m,2H),2.61(td,J=11.4,3.2Hz,1H),1.88-1.58(m,4H),1.53-1.32(m,2H),0.90(d,J=6.2Hz,3H)。C/MS(方法A):285.6(M+H)+。PLC(方法A):Rt 2.13min(纯度:94.9%)。
步骤3:1-[4-溴-2-(甲氧基甲基)苯基]-2-甲基哌啶
向步骤2获得的[5-溴-2-(2-甲基哌啶-1-基)苯基]甲醇(7.9g;27.8mmol)和正乙基二异丙基胺(10.40mL;61.15mmol)在冷却至0℃的无水DCM(150mL)中的溶液加入甲烷磺酰氯(2.36mL;30.57mmol)。反应混合物用甲醇(150mL)稀释,在50℃加热3小时,然后真空移除溶剂,得到褐色油。残余物溶解在乙醚中,用水(pH 8,用NaOH水溶液调节)、饱和NH4Cl水溶液和盐水洗涤。有机层合并,经MgSO4干燥,过滤,减压移除溶剂,得到标题化合物,为褐黄色油(12.97g,92%)。1H NMR(CDCl3,300MHz)δ7.59(d,J=2.5Hz,1H),7.36(dd,J=8.5,2.5Hz,1H),7.03(d,J=8.5Hz,1H),4.60(d,J=12.8Hz,1H),4.52(d,J=12.8Hz,1H),3.44(s,3H),2.96-2.81(m,2H),2.51(m,1H),1.77(m,2H),1.64(m,2H),1.50-1.30(m,2H),0.79(d,J=6.1Hz,3H)。LC/MS(方法B):298.1(M+H)+。
步骤4:3-(甲氧基甲基)-4-(2-甲基哌啶-1-基)苯甲酸
向-78℃的无水乙醚(130mL)加入叔丁基锂(63.79mL;1.50M;95.68mmol)(在戊烷中的溶液),然后缓慢地加入步骤3获得的1-[4-溴-2-(甲氧基甲基)苯基]-2-甲基哌啶(12.97g;43.49mmol)在无水乙醚(20mL)中的溶液。40分钟之后,将反应混合物倒入过量的新鲜碎干冰中,搅拌30分钟,然后用乙醚/乙酸乙酯(1∶1)、水(pH 4-5)稀释。有机层合并,MgSO4干燥,减压移除溶剂,得到黄色油,该黄色油在iPr2O和戊烷中研磨,滤出,用戊烷洗涤,得到标题化合物,为米色粉末。1HNMR(CDCl3,300MHz)δ8.22(d,J=2.1Hz,1H),8.00(dd,J=8.3,2.1Hz,1H),7.17(d,J=8.3Hz,1H),4.60(d,J=12.3Hz,1H),4.55(d,J=12.3Hz,1H),3.46(s,3H),3.17(m,1H),3.02(m,1H),2.63(m,1H),1.88-1.65(m,4H),1.55-1.40(m,2H),0.88(d,J=6.2Hz,3H)。LC/MS(方法B):264.1(M+H)+。
中间体17:4-(2-甲基哌啶-1-基)-3-[(甲基磺酰基)氨基]苯甲酸
步骤1:4-(2-甲基哌啶-1-基)-3-硝基苯甲酸
4-氟-3-硝基苯甲酸乙酯(Chontec,25g;117.28mmol)和2-甲基哌啶(41.54mL;351.84mmol)在DMF(100mL)中的混合物在50℃加热2小时。反应冷却至室温,用水(100mL)稀释,乙酸乙酯萃取,MgSO4干燥,浓缩,得到黄色油。残余物溶解在THF(250mL)中,加入氢氧化锂(14.04g;586.41mmol),然后加入水(250mL)。反应混合物室温搅拌2天。蒸发THF之后,溶液用水稀释,乙醚洗涤。水层用乙酸酸化至pH 5,乙醇萃取,MgSO4干燥,浓缩,得到标题化合物,为黄色固体(24.81g,80%)。1H NMR(DMSO-d6)δ13.09(br s,1H),8.23-8.22(d,J=2.14Hz,1H),8.04-8.01(dd,J=8.72Hz,2.19Hz,1H),7.44-7.41(d,J=8.94Hz,1H),3.63-3.61(m,1H),3.22-3.18(m,1H),2.89-2.85(m,1H),1.78-1.44(m,6H),1.06-1.04(d,J=6.65Hz,3H)。HPLC(方法A)Rt 3.96min(纯度:97.9%)。LC/MS(方法B):265.2(M+H)+;263.2(M+H)-。
步骤2:3-氨基-4-(2-甲基哌啶-1-基)苯甲酸乙酯
将在甲醇/乙酸乙酯1∶1(340mL,0.05M)的溶液中的4-(2-甲基哌啶-1-基)-3-硝基苯甲酸乙酯(5g;17.10mmol)喷射入配置Pd/C筒体(44mm)的流动氢化反应器(H-Cube)中,该反应器的流速为1mL/min,无加热,启动充满H2选项(full H2option),蒸发溶剂后得到标题化合物,为白色固体(4.34g,96%)。1H NMR(DMSO-d6,300MHz)δ7.34-7.33(d,1H),7.21-7.18(dd,J=8.2Hz,1.8Hz,1H),7.06-7.03(d,J=8.1Hz 1H),5.09(br s,2H),4.28-4.26(q,J=7.4Hz,2H),3.11-3.07(m,1H),2.97-2.88(m,1H),2.47-2.3(m,1H),1.83-1.65(m,6H),1.32(t,J=7.4Hz,3H)。HPLC(方法A)Rt 2.60min(纯度:97.8%)。LC/MS(方法B):263.2(M+H)+。
步骤3:4-(2-甲基哌啶-1-基)-3-[(甲基磺酰基)氨基]苯甲酸
将甲烷磺酰氯(1.68mL;21.72mmol)滴加入(加入需时5分钟)Py(10mL)和3-氨基-4-(2-甲基哌啶-1-基)苯甲酸乙酯(5.18g;19.74mmol)在DCM(40mL)中的冻溶液(0℃)中,反应混合物在1小时内升至室温。反应混合物室温搅拌3小时,然后浓缩,残余物溶解在水中。水相用乙酸乙酯萃取。有机相合并,先后用HCl(1M)和盐水洗涤,MgSO4干燥,浓缩,得到黄色油。该黄色油溶解在THF(30mL)中,加入氢氧化锂(2.36g;98.72mmol),然后加入水(30mL)。得到的混合物室温搅拌2天。真空移除THF之后,溶液用水稀释,再乙醚洗涤,用浓盐酸酸化至pH 2。水相用乙酸乙酯萃取,MgSO4干燥,浓缩,得到标题化合物,为米色固体(5.48g,88%)。1H NMR(DMSO-d6)δ12.98(br s,1H),8.53(br s,1H),8.07-8.06(d,J=1.91Hz,1H),7.77-7.73(dd,J=8.34Hz,1.97Hz,1H),7.47-7.45(d,J=8.34Hz,1H),3.43-2.58(m,6H),1.84-1.46(m,6H),0.83-0.81(d,J=6.09Hz,3H)。HPLC(方法A)Rt 2.29min(纯度:99.0%)。
中间体18:5-甲基-6-(2-甲基吡咯烷-1-基)烟酸
步骤1:5-甲基-6-(2-甲基吡咯烷-1-基)烟腈
5-氰基-2-氟-3-甲基吡啶(Molekula,400mg;2.94mmol)在1-丁醇(1mL)、2-甲基吡咯烷(Acros,300mg;3.53mmol)和DIEA(1.52mL;8.82mmol)中的溶液在90℃加热18小时。反应混合物在乙酸乙酯与水之间分隔,用水洗涤,得到标题化合物,为黄色油(600mg,定量)。HPLC(方法A)Rt 1.99min(纯度:96.1%)。LC/MS(方法B):202.1(M+H)+。
步骤2:5-甲基-6-(2-甲基吡咯烷-1-基)烟酸
步骤1获得的5-甲基-6-(2-甲基吡咯烷-1-基)烟腈(591mg;2.94mmol)在水(15mL)和KOH(823mg;14.68mmol)中的溶液回流加热16小时。反应混合物碱化至pH 6,用乙酸乙酯萃取,得到标题化合物,为白色固体。1H NMR(DMSO-d6)δ12.43(s,1H),8.48(d,J=2.2Hz,1H),7.74-7.73(m,1H),4.41-4.32(m,1H),3.81-3.73(m,1H),3.49-3.42(m,1H),2.29(s,3H),2.10-2.04(m,1H),1.94-1.88(m,1H),1.74-1.68(m,1H),1.59-1.52(m,1H),1.25(d,J=6Hz,3H)。HPLC(方法A)Rt 1.45min(纯度:99.8%)。LC/MS(方法B):221.2(M+H)+。
中间体19:2,2′-二甲基-1,1′-二苯基-4-羧酸
步骤1:2,2′-二甲基-1,1′-二苯基-4-羧酸甲酯
向4-溴-3-甲基苯甲酸甲酯(ABCR,15g,65mmol)在甲苯(200mL)和水(200mL)中的溶液加入邻甲苯基硼酸(10.68g,78mmol),再加入碳酸钾(45.25g,32.7mmol)和四(三苯基膦)钯(0)(3.78g,3.3mmol)。混合物脱去氮气,在120℃回流6小时。反应完成后,反应混合物冷却至室温。分离出有机相,减压蒸发。粗化合物通过以己烷为洗脱剂的硅柱,得到标题化合物,为白色固体(15g,95%)。1H NMR(DMSO-d6,400MHz)δ7.91(s,1H),7.83-7.81(m,1H),7.33-7.30(m,2H),7.28-7.26(m,1H),7.25-7.22(m,1H),7.07-7.05(m,1H),3.86-3.81(s,3H),2.09-2(s,3H),1.97-1.92(s,3H)。HPLC(方法B),Rt:3.01min(纯度:98.71%)。
步骤2:2,2′-二甲基-1,1′-二苯基-4-羧酸
向步骤1获得的2,2′-二甲基-1,1′-二苯基-4-羧酸甲酯(15g,62.2mmol)在THF(100mL)中的溶液加入10%氢氧化钠(100mL),混合物在100℃加热过夜。减压移除THF,水性残余物用乙酸乙酯洗涤。水层用HCl(3N)酸化至pH 2-3,用DCM萃取。有机相用水洗涤,硫酸钠干燥,减压浓缩,得到标题化合物,为白色固体(13.5g,95%)。1H NMR:(DMSO-d6,400MHz)δ12.89(bs,1H),7.89(s,1H),7.82-7.80(m,1H),7.32-7.23(m,3H),7.19-7.11(m,1H),7.07-7.05(m,1H),2.04(s,3H),1.98(s,3H)。LC/MS(方法A):227.0(M+H)+。HPLC(方法B),Rt:4.1min(纯度:99.6%)。
中间体20:4-(2-甲基哌啶-1-基)-3-硝基苯甲酸
将4-氟-3-硝基苯甲酸乙酯(Chontech,1g;4.69mmol)和2-甲基哌啶(1.39g;14.07mmol)在DMF(4mL)中的混合物加热至50℃,保持3小时。让反应降至室温,用水稀释,再用乙酸乙酯萃取。有机相经硫酸钠干燥,真空浓缩,得到4-(2-甲基哌啶-1-基)-3-硝基苯甲酸乙酯,为黄色油。残余物溶解在THF(10mL)中,加入氢氧化锂(561.73mg;23.46mmol),然后加入水(10mL)。反应混合物室温搅拌16小时。浓缩,残余物用水稀释,乙醚洗涤。水层用乙酸酸化至pH 5,用乙醚萃取。有机层经硫酸镁干燥,浓缩,得到标题化合物,为黄色固体(1.17g,94%)。1HNMR(DMSO-d6)δ13.07(s,1H),8.23-8.22(d,J=2.13Hz,1H),8.04-8(dd,J=8.96,2.28Hz,1H),7.44-7.41(d,J=8.88Hz,1H),3.64-3.60(m,1H),3.25-3.17(m,1H),2.90-2.84(m,1H),1.82-1.43(m,6H),1.06-1.04(d,J=6.43Hz,3H)。LC/MS(方法A):265.0(M+H)+;263.0(M-H)-。
中间体21:3-甲氧基-4-(4-甲基-3-噻吩基)苯甲酸
步骤1:3-甲氧基-4-(4-甲基-3-噻吩基)苯甲酸甲酯
4-溴-3-甲氧基苯甲酸甲酯(Combi-Blocks,2.50g;10.20mmol)和4-甲基-3-噻吩硼酸(1.59g;11.22mmol)、碳酸钾(7.04g;51mmol)和四(三苯基膦)钯(0)(1.17g;1.02mmol)在甲苯(10mL)和水(10mL)中于氮气气氛下混合。反应混合物脱去氮气10分钟,回流加热3小时。反应混合物冷却至室温,经硅藻垫去过滤,用甲苯洗涤。滤液真空浓缩,得到褐色油。将该褐色油溶解在乙酸乙酯中,有机层用饱和NaHCO3水溶液、水和盐水洗涤,MgSO4干燥,真空滤出,得到褐色油。LC/MS(方法A):262.8(M+H)+。HPLC(方法A)Rt 4.79min(纯度:63.0%)。
步骤2:3-甲氧基-4-(4-甲基-3-噻吩基)苯甲酸
室温向步骤1获得的3-甲氧基-4-(4-甲基-3-噻吩基)苯甲酸甲酯(2.30g;8.77mmol)在乙醇(70mL)中的溶液加入氢氧化钠(5M;5.26mL;26.31mmol)。反应混合物在60℃搅拌1小时。反应混合物真空浓缩,得到褐色固体。将该固体溶解在水中,水相用乙酸乙酯萃取二次。水相用浓盐酸(2mL)酸化至pH 2,然后真空浓缩至形成沉淀(1/3体积)。悬液过滤,真空干燥,得到标题化合物,为褐色固体(1.81g,2步的得率为83%)。1H NMR:(DMSO-d6)δ13.05(s,1H),7.62-7.59(m,2H),7.40-7.39(d,J=3.23Hz,1H),7.32-7.29(d,J=7.48Hz,1H),7.25-7.23(m,1H),3.82(s,3H),2.99(s,3H)。LC/MS(方法A):248.8(M+H)+;246.9(M-H)-。HPLC(方法A)Rt 3.99min(纯度:97.4%)。
中间体22:4-(2-乙基哌啶-1-基)-3-(甲氧基甲基)苯甲酸,盐酸盐
步骤1:5-溴-2-(2-乙基哌啶-1-基)苯甲醛
向5-溴-2-氟苯甲醛(20g,0.099mol)在二甲基亚砜(230mL)和水(70mL)中的溶液加入2-乙基哌啶(14.4mL,0.1083mol)和碳酸钠(20.88g,0.197mol)。得到的混合物在110℃加热30小时。反应混合物冷却至室温,用水(1000mL)稀释,甲基叔丁醚(2x500mL)萃取,再用硫酸钠干燥,减压浓缩。得到的粗产物经硅胶(60-120目)柱色谱法(以石油醚为洗脱剂),纯化,得到标题化合物,为黄色液体。1H NMR(DMSO-d6,400MHz)δ10.15(1H,s),7.70-7.73(2H,d),7.22-7.25(1H,m),3.08-3.13(2H,m),2.84-2.86(1H,m),1.83-1.84(1H,m),1.34-1.67(7H,m),0.62-0.66(3H,t)。
步骤2:[5-溴-2-(2-乙基哌啶-1-基)苯基]甲醇
在氮气气氛下向5-溴-2-(2-乙基哌啶-1-基)苯甲醛(步骤1制备,10g,0.0484mol)在甲醇(100mL)中的溶液分批加入0℃的硼氢化钠(1.28g,0.0484mol)。室温搅拌1小时后,蒸发移除反应混合物中的甲醇。得到的粗产物溶解在水(100mL)中,用乙酸乙酯萃取。分离出的有机层用水洗涤,硫酸钠干燥,减压浓缩,得到标题化合物,为黄色液体(8.8g,88%)。1H NMR(DMSO-d6,400MHz)δ7.54-7.55(1H,s),7.34-7.54(1H,m),7.07-7.09(1H,d),5.17-5.20(1H,t),4.59-4.64(1H,d),4.43-4.48(1H,d),2.77-2.84(2H,m),2.442-2.449(1H,m),1.74(2H,t),1.53-1.56(2H,t),1.32-1.34(2H,m),1.15-1.19(2H,m),0.60-0.64(3H,t)。
步骤3:1-[4-溴-2-(甲氧基甲基)苯基]-2-乙基哌啶
向氢化钠(2.3g,0.093mmol)在干DMF(130mL)中的溶液滴加入0℃的[5-溴-2-(2-乙基环己基)苯基]甲醇(15g,0.0483mol)在DMF(20mL)中的溶液。反应混合物搅拌30分钟之后,在0℃加入碘甲烷。反应混合物用氯化铵饱和水溶液(30mL)淬灭,用水(100mL)稀释,乙酸乙酯萃取,硫酸钠干燥,减压浓缩,得到标题化合物,为黄色液体(15.2g,97%)。1H NMR(CDCl3,400MHz)δ7.59(1H,s),7.34-7.36(1H,d),7.01-7.03(1H,d),4.49-4.59(2H,m),3.43(3H,s),2.87-2.89(1H,d),2.75(1H,bs),2.51(1H,bs),1.79-1.86(2H,m),1.61-1.63(3H,d),1.40(2H,m),0.87-0.88(2H,m),0.60-0.80(3H,t)。
步骤4:4-(2-乙基哌啶-1-基)-3-(甲氧基甲基)苯甲酸,盐酸盐
在-80℃下向4-溴-1-(2-乙基环己基)-2-(甲氧基甲基)苯(1.42g,4.55mmol)在干THF中的溶液滴加入正丁基锂(2.4mL,6.82mmol),混合物搅拌1小时。然后小心地将反应混合物倒入碎干冰(100g)中。一旦释出过量二氧化碳,就用2N HCl水溶液酸化反应混合物。滤出得到的沉淀,干燥,得到标题化合物,为乳白色固体(1000mg;79%)。1H NMR(CD3OD,400MHz)δ8.19-8.21(1H,d),8.07(1H,s),7.91-7.93(1H,d),5.03-5.06(2H,m),3.89(1H,bs),3.65-3.72(5H,m),2.37-2.04(1H,d),2.02-2.14(2H,m),1.72-1.95(3H,m),1.43-1.49(2H,m),0.86-0.90(3H,t)。LC/MS(方法A):278.0(M-H)+。HPLC(方法A)Rt 1.97min(纯度:97.94%)。
中间体23:2′-乙基-2-(甲氧基甲基)-1,1′-二苯基-4-羧酸
步骤1:甲基2′-乙基-2-(甲氧基甲基)-1,1′-二苯基-4-羧酸酯
在氮气气氛下向4-溴-3-(甲氧基甲基)苯甲酸甲酯(中间体28,步骤2)(12g,0.0463mol)在甲苯(150mL)和水(35mL)中的溶液加入2-乙基苯硼酸(9.02g,0.0601mol),再加入碳酸钾(19g,0.1389mol)和Pd(PPh3)4(2.67g,0.0023mol)。反应混合物加热前先脱氮气10分钟。在100℃保持12小时,将反应混合物用乙酸乙酯稀释。有机层依次用碳酸氢盐饱和溶液(1x100mL)、水(2x100mL)和盐水(1x100mL)洗涤。硫酸钠干燥,减压浓缩。残余物经色谱法(硅胶,60-120目,以石油醚/乙酸乙酯为洗脱剂)纯化,得到标题化合物,为浅黄色液体(12g,83%)。1H NMR(CDCl3,400MHz)δ8.24-8.26(1H,s),7.99-8.01(1H,d),7.32-7.38(2H,m),7.22-7.27(2H,m),7.07-7.09(1H,d),4.12-4.21(2H,d),3.93-3.95(3H,s),3.28-3.30(3H,s),2.28-2.43(2H,m),1.01-1.05(3H,t)。
步骤2:2′-乙基-2-(甲氧基甲基)-1,1′-二苯基-4-羧酸
向2′-乙基-2-(甲氧基甲基)-1,1′-二苯基-4-羧酸甲酯(12g,0.0422mol)在THF(150mL)和水(30mL)中的溶液分批加入氢氧化锂一水合物(5.31g,0.127mol)。在室温静置12小时后,反应混合物浓缩,水相用浓HCl酸化,乙酸乙酯萃取。有机层用水和盐水溶液洗涤。溶剂用硫酸钠干燥并减压浓缩,得到标题化合物,为白色固体(9g,80%)。1H NMR(DMSO-d6,300MHz)δ12.9(1H,bs),8.08(1H,s),7.88-7.90(1H,m),7.34-7.35(2H,m),7.21-7.25(2H,m),7.03-7.05(1H,m),4.04-4.13(2H,m),3.16-3.18(3H,s),2.29-2.38(1H,m),2.19-2.24(1H,m),0.92-0.95(3H,m)。LC/MS(方法A):269.0(M-H)-。HPLC(方法B)Rt 5.06min(纯度:97.4%)。
中间体24:2′-甲基-2-(三氟甲基)二苯基-4-羧酸
步骤1:4-溴-3-(三氟甲基)苯甲酸甲酯
室温下在15分钟内向4-溴-3-(三氟甲基)苯甲酸(Acceledev 000625,15g;55.76mmol)在甲醇(300mL)中的悬液滴加入亚硫酰氯(16.18mL;223.04mmol)。反应混合物室温搅拌12小时。溶剂浓缩,粗残余物用乙酸乙酯(500mL)稀释。有机层用饱和NaHCO3水溶液(200mL)、水(200mL)和盐水(200mL)洗涤,MgSO4干燥,浓缩,得到标题化合物,为橙色固体(14.80g,94%)。1H NMR(DMSO-d6,300MHz)δ8.26(m,1H),8.14-8.13(m,2H),3.93(s,3H)。HPLC(方法A)Rt 4.71min(纯度:99.0%)。
步骤2:2′-甲基-2-(三氟甲基)二苯基-4-羧酸甲酯
4-溴-3-(三氟甲基)苯甲酸甲酯(6g;21.20mmol;1eq.)、邻甲苯基硼酸(3.17g;23.32mmol;1.10eq.)、碳酸钾(14.65g;105.99mmol;5eq.)、四(三苯基膦)钯(0)(2.45g;2.12mmol;0.10eq.)在氮气气氛下溶解在甲苯(30mL)和水(30mL)中。反应混合物经真空净化5分钟,然后脱氮气,再回流3小时。反应混合物冷却至室温,硅藻土过滤,用甲苯(200mL)洗涤。滤液浓缩,得到褐色油,该褐色油溶解在乙酸乙酯(200mL)中。有机层用饱和NaHCO3水溶液(50mL)、水(50mL)和盐水(50mL)洗涤,MgSO4干燥,浓缩,得到标题化合物,为褐色油(6.4g,定量)。HPLC(方法A)Rt 5.33min。
步骤3:2′-甲基-2-(三氟甲基)二苯基-4-羧酸
2′-甲基-2-(三氟甲基)二苯基-4-羧酸甲酯(5g;16.99mmol;1eq.)在乙醇(150mL)中的溶液在室温下用氢氧化钠(10.2mL;5M;51mmol;3eq.)处理。反应混合物在60℃搅拌2小时。反应混合物浓缩,得到褐色固体,该固体溶解在水(300mL)中,水相用乙酸乙酯洗二次。水相用浓HCl酸化至pH 2,然后浓缩至沉淀(一半体积)。悬液过滤,得到标题化合物,为米色固体。1H NMR(DMSO-d6,300MHz)δ13.55(br s,1H),8.31(s,1H),8.26-8.23(d,J=7.90Hz,1H),7.51-7.48(d,J=7.90Hz 1H),7.37-7.12(m,4H),1.99(s,3H)。LC/MS(方法A):278.9(M-H)-。HPLC(方法A)Rt 4.57min(纯度:98.7%)。
中间体25:3-[7-[氨基(羟基亚氨基)甲基]-3,4-二氢异喹啉-2(1H)-基]丙酸叔丁酯
步驟1:3-(7-氰基-3,4-二氢异喹啉-2(1H)-基)丙酸叔丁酯
将7-氰基-1,2,3,4-四氢异喹啉(7g;44.3mmol;1eq.)和碳酸钾(10.4g;75.2mmol;1.7eq.)悬于ACN(280mL)中,加入3-溴丙酸叔丁酯(11.5mL;68.6mmol;1.05eq.)。反应混合物加热至70℃,保持24小时。真空移除溶剂,固体残余物在饱和NaHCO3水溶液与乙酸乙酯之间分隔。有机层用盐水洗涤,硫酸镁干燥,过滤,浓缩,得到标题化合物(11.86g;94%),为黄色油。1H NMR(DMSO-d6)δ7.57-7.54(m,2H),7.32-7.29(m,1H),3.59(s,2H),2.87-2.83(t,J=5.94Hz,2H),2.74-2.66(m,4H),2.46-2.42(t,J=7.01Hz,2H),1.39(s,9H)。LC/MS(方法B):287.1(M+H)+。HPLC(方法A)Rt 2.37min(纯度:96.4%)。
步骤2:3-[7-[(Z)-氨基(羟基亚氨基)甲基]-3,4-二氢异喹啉-2(1H)-基]丙酸叔丁酯
将步骤1获得的3-(7-氰基-3,4-二氢异喹啉-2(1H)-基)丙酸叔丁酯(11.85g;41.38mmol;1eq.)悬于乙醇(237mL)中。一次性加入羟胺(6.1mL;206.9mmol;5eq.)。反应混合物室温搅拌48小时。反应混合物真空浓缩,在二异丙醚中研磨,真空浓缩,得到标题化合物,为黄色固体。1H NMR(DMSO-d6)δ9.51(br s,1H),7.43-7.34(m,2H),7.09-7.06(d,J=8.17Hz,1H),5.71(br s,2H),3.56(s,2H),2.79-2.64(m,6H),2.47-2.42(t,J=6.93Hz,2H),1.39(s,9H)。LC/MS(方法B):320.1(M+H)+。HPLC(方法A)Rt 1.57min。
中间体26:4-[(2R)-2-甲基哌啶-1-基]-3-(三氟甲基)苯甲酸
在氮氮气氛下,将4-氟-3-(三氟甲基)苯甲腈(1g;5.29mmol;1eq.)和(R)-(-)-2-甲基哌啶(3.1mL;26.4mmol;5eq.)在DMSO(10mL)中加热至100℃并保持12小时。反应混合物用乙酸乙酯稀释,并用水、NaHCO3饱和溶液和NH4Cl饱和溶液洗涤。有机相用MgSO4干燥,过滤,真空蒸发,得到黄色油,该黄色油无需进一步纯化即可用在下一步驟中。HPLC(方法A)Rt 5.65min。LC/MS(方法B):269.1(M+H)+。
将4-[(2R)-2-甲基哌啶-1-基]-3-(三氟甲基)苯甲腈(1.40g;5.22mmol;1eq.)溶解在甲醇(7mL)中,加入NaOH(5N水溶液,7mL)。反应混合物加热至100℃并保持7小时。反应混合物用5N HCl水溶液酸化至pH 2。得到的沉淀滤出,用水洗涤,得到浅褐色固体。该固体乙醚/环己烷中结晶析出,得到米色固体。1H NMR(DMSO-d6)δ13.29(s,1H),8.23-8.12(m,2H),7.68(d,J=8.4Hz,1H),3.07(m,1H),2.94-2.81(m,1H),2.61-2.45(m,2H),1.75(m,1H),1.67-1.18(m,4H),0.71(d,J=6.1Hz,3H)。HPLC(方法A),Rt 4.80min(纯度:99.9%)。LC/MS(方法B):286.2(M+H)-;288.0(M+H)+。
中间体27:4-[(2S)-2-甲基哌啶-1-基]-3-(三氟甲基)苯甲酸
在氮氮气氛和100℃的条件下,将4-氟-3-(三氟甲基)苯甲腈(1g;5.29mmol;1eq.)和(S)-(+)-2-甲基哌啶(3.1mL;26.4mmol;5eq.)在DMSO(10mL)中加热至100℃并保持12小时。反应混合物用乙酸乙酯稀释,并用水、NaHCO3饱和溶液和NH4Cl饱和溶液洗涤。有机相用MgSO4干燥,过滤,真空蒸发,得到黄色油,该黄色油无需进一步纯化即可用在下一步驟中。LC/MS(方法B):269.0(M+H)+。
将4-[(2S)-2-甲基哌啶-1-基]-3-(三氟甲基)苯甲腈(1.40g;5.22mmol;1eq.)溶解在甲醇(7mL)中,加入NaOH(5N水溶液,7mL)。反应混合物加热至100℃并保持7小时。反应混合物用5N HCl水溶液酸化至pH 2。得到的沉淀滤出,用水洗涤,得到浅褐色固体。该固体乙醚/环己烷中结晶析出,得到米色固体(851mg;两步骤的总得率超过57%)。H NMR(DMSO-d6)δ13.29(s,1H),8.23-8.12(m,2H),7.68(d,J=8.4Hz,1H),3.07(m,1H),2.94-2.81(m,1H),2.61-2.45(m,2H),1.75(m,1H),1.67-1.18(m,4H),0.71(d,J=6.1Hz,3H)。HPLC(方法A),Rt 4.79min(纯度:99.9%)。LC/MS(方法B):286.2(M+H)-;288.0(M+H)+。
中间体28:6-[氨基(羟基亚氨基)甲基]-1H-吲哚-2-羧酸
6-氰基-1H-吲哚-2-羧酸(按照J.Org.Chem.1953,18,345-357描述的方法制备,1g;5.37mmol;1eq.)、羟胺(50%水溶液;1.77mL;26.86mmol;5eq.)在乙醇(10mL)中的溶液室温搅拌14小时,然后再在60℃加热28小时。真空移除溶剂,得到标题化合物,为白色粉末(1.227g;定量得率)。1H NMR(DMSO-d6)δ11.75(s,1H),7.72(s,1H),7.58(d,J=8.5Hz,1H),7.37(dd,J=1.2,8.5Hz,1H),7.00(d,J=1.2Hz,1H),5.76(bs,2H),3.44(q,J=7.1Hz,2H),1.05(t,J=7.1Hz,3H)。
通用程序1:
向中间体酸(1eq.)在DCM(2mL)和正乙基二异丙胺(4eq.)中的悬液加入草酰氯(3eq.)和DMF(具有催化活性),悬液在室温搅拌1至6小时。然后将溶液蒸干,残余物溶解在THF中。将该溶液加入到中间体氨肟(1eq.)和DIEA(3eq.)在THF或ACN中的溶液中。反应混合物经微波辐射加热至150℃,保持30分钟。
通用程序2:
向中间体酸(1.05eq.)和正乙基二异丙胺(2eq.)在0℃的无水DMF(20V)中立即加入hatu(1.05eq.)。30分钟后,立即加入中间体氨肟(1eq.),反应混合物搅拌30分钟至2小时。然后,反应混合物在乙醇与水之间分隔,有机层用盐水洗涤,MgSO4干燥,真空蒸发。残余物溶解在甲苯(20V)和吡啶(10V)中,在95℃加热18小时。
通用程序3:
向中间体酸(1.05eq.)和正乙基二异丙胺(2eq.)在0℃的无水DMF(20V)中立即加入hatu(1.05eq.)。0分钟后,立即加入中间体氨肟(1eq.),反应混合物搅拌30分钟至2小时。然后,反应混合物在乙醇与水之间分隔,有机层用盐水洗涤,MgSO4干燥,真空蒸发。残余物溶解在ACN(20V)和DIEA(2eq.)中,经微波辐射在150℃加热30分钟。
实施例1:5-{5-[4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯基]-1,2,4-恶二唑-3-基}-1H-
苯并咪唑
以中间体11(143mg;0.50mmol)和中间体1(88mg;0.50mmol)为原料,按照通用程序1的制备工艺制备标题化合物。反应混合物经SPE-NH2柱过滤,THF洗涤,然后在减压下蒸发溶剂。蒸发溶剂得到黄色油,该黄色油在DCM/正戊烷混合物中重结昌,得到标题化合物,为乳白色固体。1H NMR(DMSO,d6)δ12.77(s,1H),8.46(dd,J=8.4,2.1Hz,1H),8.40(m,2H),8.34(s,1H),7.97(dd,J=8.5,1.6Hz,1H),7.87(d,J=8.5Hz,1H),7.78(d,J=8.5Hz,1H),3.20-3.14(m,1H),2.99-2.94(m,1H),2.67-2.57(m,1H),1.79(m,2H),1.68-1.27(m,4H),0.76(d,6Hz,3H)。HPLC(方法A)Rt 4.51min(纯度:99.4%)。LC/MS(方法B):428.3(M+H)+。
实施例2:5-[3-(1H-苯并咪唑-5-基)-1,2,4-恶二唑-5-基]-2-(2-甲基哌啶-1-基)苯
甲腈
以中间体12(122mg;0.50mmol)和中间体1(88mg;0.50mmol)为原料,按照通用程序1的制备工艺制备标题化合物。反应混合物经SPE-NH2柱过滤,THF洗涤,然后在减压下蒸发溶剂。反应混合物用乙酸乙酯萃取,有机相合并,用盐水洗涤,硫酸镁干燥,真空浓缩,得到黄色油状残余物。经硅柱色谱法(洗脱剂先用DCM/甲醇98/2再95/5)纯化,得到标题化合物,为乳白色固体。1H NMR(DMSO,d6):δ12.78(s,1H),8.39-8.37(m,2H),8.31(s,1H),8.24(dd,J=8.8,2.2Hz,1H),7.95-7.92(m,1H),7.78-7.75(m,1H),7.32(d,J=8.8Hz,1H),4.23-4.22(m,1H),3.38-3.35(m,2H),1.82-1.57(m,6H),1.17(d,6.6Hz,3H)。HPLC(方法A)Rt 3.65min(纯度:95.1%)。LC/MS(方法B):358.3(M+H)+。
实施例3:5-{5-[5-甲基-6-(2-甲基哌啶-1-基)吡啶-3-基]-1,2,4-恶二唑-3-基}-1H-
苯并咪唑
以中间体13(120mg;0.51mmol)和中间体1(90mg;0.51mmol)为原料,按照通用程序1的制备工艺制备标题化合物。反应混合物经SPE-NH2柱过滤,THF洗涤,然后在减压下蒸发溶剂。反应混合物经硅柱色谱法(洗脱剂为乙酸乙酯/环己烷30/70至100/0)纯化,得到标题化合物,为褐色粉末。1H NMR(DMSO,d6):δ12.78(s,1H),8.39-8.37(m,2H),8.31(s,1H),8.24(dd,J=8.8,2.2Hz,1H),7.95-7.92(m,1H),7.78-7.75(m,1H),7.32(d,J=8.8Hz,1H),4.23-4.22(m,1H),3.38-3.35(m,2H),1.82-1.57(m,6H),1.17(d,6.6Hz,3H)。HPLC(方法A)Rt 2.71min(纯度:86.6%)。LC/MS(方法B):358.3(M+H)+。
实施例4:5-{5-[2-(甲氧基甲基)-2′-甲基二苯基-4-基]-1,2,4-恶二唑-3-基}-1H-苯
并咪唑
以中间体14(807mg;3.15mmol)和中间体1(528mg;3mmol)为原料,按照通用程序2的制备工艺制备标题化合物。反应混合物用乙醚稀释,用水和盐洗涤,并在真空下蒸发,得到米色固体。将该固体溶解在DCM/甲醇的混合物中,经SPE-NH2柱过滤,在DCM/甲醇的混合物中重结晶,得到标题化合物,为褐色粉末。1H NMR(DMSO-d6)δ12.78(bs,1H),8.40(s,1H),8.34(d,J=7Hz,2H),8.19(dd,J=7.9,1.7Hz,1H),7.99(dd,J=8.4,1.4Hz,1H),7.78(d,J=8.2Hz,1H),7.41(d,J=8Hz,1H),7.37-7.27(m,3H),7.14(d,J=7.2Hz,1H),4.24(d,J=12.8Hz,1H),4.17(d,J=12.8Hz,1H),3.26(s,3H),2.04(s,3H).HPLC(方法A)Rt 4min(纯度:98.2%).LC/MS(方法B):397.2(M+H)+。
实施例5:1-{4-[3-(1H-苯并咪唑-6-基)-1,2,4-恶二唑-5-基]-2′-甲基二苯基-2-基}-
N,N-二甲基甲胺
以中间体15(160.55mg;0.52mmol)和中间体1(88.09mg;0.50mmol)为原料,按照通用程序2的制备工艺制备标题化合物。经MD-Autoprep纯化,得到标题化合物,为浅黄色泡沫。1H NMR(DMSO-d6)δ12.78(bs,1H),8.40(s,1H),8.34(d,J=7Hz,2H),8.19(dd,J=7.9,1.7Hz,1H),7.99(dd,J=8.4,1.4Hz,1H),7.78(d,J=8.2Hz,1H),7.41(d,J=8Hz,1H),7.37-7.27(m,3H),7.14(d,J=7.2Hz,1H),4.24(d,J=12.8Hz,1H),4.17(d,J=12.8Hz,1H),3.26(s,3H),2.04(s,3H)。HPLC(方法A)Rt 1.84min(纯度:92.8%)。LC/MS(方法B):410.2(M+H)+。
实施例6:5-{5-[3-(甲氧基甲基)-4-(2-甲基哌啶-1-基)苯基]-1,2,4-恶二唑-3-基}-
1H-苯并咪唑
以中间体16(316mg;1.20mmol)和中间体1(211mg;1.20mmol)为原料,按照通用程序2的制备工艺制备标题化合物,为褐色粉末。1H NMR(CDCl3)δ8.51(s,1H),8.33(d,J=2Hz,1H),8.20(s,1H),8.15(dd,J=8.5,1.6Hz,1H),8.09(dd,J=8.5,2Hz,1H),7.79(d,J=8.5Hz,1H),7.26-7.24(m,1H),4.66(d,J=12.3Hz,1H),4.58(d,J=12.3Hz,1H),3.48(s,3H),3.16-3.12(m,1H),3.04-2.99(m,1H),2.67-2.60(m,1H),1.87-1.67(m,4H),0.88(d,J=6Hz,3H)。HPLC(方法A)Rt 2.37min(纯度:98.4%)。LC/MS(方法B):404.3(M+H)+。
实施例7:7-氟-5-{5-[4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯基]-1,2,4-恶二唑-3-
基}-1H-苯并咪唑
以中间体11(344.74mg;1.20mmol)和中间体2(233mg;1.20mmol)为原料,按照通用程序1的制备工艺制备标题化合物。向反应混合物加入乙醚,用水和盐水洗涤,MgSO4干燥,减压蒸发。经硅柱色谱法(洗脱剂为乙酸乙酯/环己烷40/60至70/30)纯化,得到标题化合物,为白色粉末。1H NMR(DMSO-d6)δ13.14(bs,1H),8.46-8.43(m,2H),8.38(d,J=2Hz,1H),8.17(d,J=1.1Hz,1H),8.15(dd,J=8.5,1.6Hz,1H),7.86(d,J=8.5Hz,1H),7.68(dd,J=8.5,1.1Hz,1H),7.26-7.24(m,1H),3.19-3.15(m,1H),2.97-2.93(m,1H),2.65-2.58(m,1H),1.80-1.77(m,2H),1.63-1.30(m,4H),0.78(d,J=6Hz,3H)。HPLC(方法A)Rt 4.95min(纯度:99.6%)。LC/MS(方法B):446.3(M+H)+。
实施例8:7-甲基-5-{5-[4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯基]-1,2,4-恶二唑-3-
基}-1H-苯并咪唑
以中间体11(344.74mg;1.20mmol)和中间体3(228mg;1.20mmol)为原料,按照通用程序2的制备工艺制备标题化合物。向反应混合物加入乙醚,用水和盐水洗涤,MgSO4干燥,减压蒸发。经硅柱色谱法(洗脱剂为乙酸乙酯/环己烷40/60至70/30)纯化,得到标题化合物,为白色粉末。1H NMR(DMSO-d6)δ12.80(bs,1H),8.47-8.43(m,1H),8.40-8.38(m,1H),8.36(s,1H),8.16(bs,1H),7.86(d,J=8.5Hz,1H),7.76(bs,1H),3.18-3.14(m,1H),2.97-2.94(m,1H),2.65-2.59(m,4H),1.80-1.77(m,2H),1.63-1.33(m,4H),0.78(d,J=6Hz,3H)。HPLC(方法A)Rt 4.54min(纯度:99.9%)。LC/MS(方法B):442.3(M+H)+。
实施例9:7-氟-5-{5-[2-(甲氧基甲基)-2′-甲基二苯基-4-基]-1,2,4-恶二唑-3-基}-
1H-苯并咪唑
以中间体14(307mg;1.20mmol)和中间体2(233mg;1.20mmol)为原料,按照通用程序2的制备工艺制备标题化合物。向反应混合物加入乙醚,用水和盐水洗涤,MgSO4干燥,减压蒸发。经硅柱色谱法(洗脱剂为乙酸乙酯/环己烷40/60至70/30)纯化,得到标题化合物,为白色粉末。1H NMR(DMSO-d6)δ13.16(bs,1H),8.46(s,1H),8.34(d,J=1.2Hz,1H),8.20-8.16(m,2H),7.70(dd,J=11.3,1.2Hz,1H),7.43(d,J=8Hz,1H),7.37-7.26(m,3H),7.16-7.14(m,1H),4.23(d,J=12.5Hz,1H),4.16(d,J=12.5Hz,1H),3.25(s,3H),2.04(s,3H)。HPLC(方法A)Rt 4.23min(纯度:98.6%)。LC/MS(方法B):415.3(M+H)+。
实施例10:7-{5-[4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯基]-1,2,4-恶二唑-3-基}-
1,2,3,4-四氢异喹啉,盐酸盐
步骤1:6-{5-[4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯基]-1,2,4-恶二唑-3-基}-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯
以中间体11(143mg;0.50mmol)和中间体4(145mg;0.50mmol)为原料,按照通用程序1的制备工艺制备标题化合物。反应混合物经SPE-NH2柱过滤,THF洗涤,然后在减压下蒸发溶剂,得到黄色油。经硅柱色谱法(洗脱剂为环己烷/乙酸乙酯,85/15)纯化,得到标题化合物,为无色油。HPLC(方法A)Rt 7.19min(纯度:94.2%)。
步骤2:6-{5-[4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯基]-1,2,4-恶二唑-3-基}-1,2,3,4-四氢异喹啉,盐酸盐
将步骤1获得的6-{5-[4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯基]-1,2,4-恶二唑-3-基}-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯溶解在DCM(3mL)和TFA(1mL)中。得到的溶液室温搅拌1小时,真空蒸发溶剂,得到浅黄色油。该浅黄色油经短的氧化铝柱塞(plug of alumina)过滤(环己烷/乙酸乙酯,先80/20然后50/50),得到浅黄色油,在乙醚/HCl(1M)混合物(1∶1,2mL)中研磨,过滤,用乙醚洗涤,得到标题化合物。1H NMR(DMSO-d6)δ9.30(bs,2H),8.45-8.41(m,1H),8.38(m,1H),8.01-7.98(m,2H),7.86(d,J=8.5Hz,1H),7.46(d,J=8.0Hz,1H),4.41(m,2H),3.54-3.42(m,3H),3.18-3.08(m,3H),2.97-2.93(m,1H),2.65-2.59(m,1H),1.80-1.77(m,2H),1.63-1.30(m,4H),0.78(d,J=6Hz,3H)。HPLC(方法A)Rt 4.61min(纯度:100.0%)。LC/MS(方法B):443.2(M+H)+。
实施例11:N-{2-(2-甲基哌啶-1-基)-5-[3-(1,2,3,4-四氢异喹啉-7-基)-1,2,4-恶二
唑-5-基]苯基}甲烷磺酰胺,盐酸盐
步骤1:6-(5-{4-(2-甲基哌啶-1-基)-3-[(甲基磺酰基)氨基]苯基}-1,2,4-恶二唑-3-基)-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯
以中间体17(156mg;0.50mmol)和中间体4(145mg;0.50mmol)为原料,按照通用程序1的制备工艺制备标题化合物。反应混合物经SPE-NH2柱过滤,THF洗涤,然后在减压下蒸发溶剂,得到黄色油。该黄色油经硅柱色谱法(洗脱剂为环己烷/乙酸乙酯,70/30)纯化,得到标题化合物,为无色粘稠油。HPLC(方法A)Rt5.83min(纯度:97.3%)。
步骤2:N-{2-(2-甲基哌啶-1-基)-5-[3-(1,2,3,4-四氢异喹啉-7-基)-1,2,4-恶二唑-5-基]苯基}甲烷磺酰胺,盐酸盐
将步骤1获得的6-(5-{4-(2-甲基哌啶-1-基)-3-[(甲基磺酰基)氨基]苯基}-1,2,4-恶二唑-3-基)-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯溶解在DCM(3mL)和TFA(1mL)中,得到的溶液室温搅拌2小时。溶液在乙酸乙酯与饱和NaHCO3(pH 8)水溶液之间分隔,分离两相。有机相用盐水洗涤,硫酸钠干燥,真空浓缩,得到无色油。将该无色油溶解在DCM中,经短的氧化铝柱塞(DCM/甲醇,99/1)过滤,得到白色固体。将该白色固体溶解在甲醇(1mL)、乙醚(4mL)和HCl(1M的乙醚溶液,2mL)中。搅拌10分钟之后,混合物浓缩至干,得到标题化合物,为乳白色固体。1HNMR(DMSO-d6)δ9.58(bs,2H),8.67(bs,1H),8.20(m,1H),7.98-7.91(m,3H),7.57-7.55(m,1H),7.47-7.44(m,1H),4.40(m,2H),3.39(m,2H),3.22(s,3H),3.13-3.08(m,3H),2.92-2.88(m,1H),2.61(m,1H),1.79-1.68(m,4H),1.47(m,2H),0.82-0.80(m,3H)。HPLC(方法A)Rt 3.02min(纯度:93.5%)。LC/MS(方法B):468.4(M+H)+。
实施例12:2-(2-甲基哌啶-1-基)-5-[3-(1,2,3,4-四氢异喹啉-7-基)-1,2,4-恶二唑-5-
基]苯甲腈,盐酸盐
步骤1:6-{5-[3-氰基-4-(2-甲基哌啶-1-基)苯基]-1,2,4-恶二唑-3-基}-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯
以中间体12(122mg;0.50mmol)和中间体4(145mg;0.50mmol)为原料,按照通用程序1的制备工艺制备标题化合物。反应混合物经SPE-NH2柱过滤,THF洗涤,然后在减压下蒸发溶剂,得到黄色油。该黄色油经硅柱色谱法(洗脱剂为环己烷/乙酸乙酯,80/20)纯化,得到标题化合物,为白色泡沫。HPLC(方法A)Rt6.35min(纯度:94.8%)。
步骤2:2-(2-甲基哌啶-1-基)-5-[3-(1,2,3,4-四氢异喹啉-7-基)-1,2,4-恶二唑-5-基]苯甲腈,盐酸盐
将步骤1获得的6-{5-[3-氰基-4-(2-甲基哌啶-1-基)苯基]-1,2,4-恶二唑-3-基}-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯溶解在DCM(3mL)和TFA(1mL)中,得到的溶液室温搅拌2小时。溶液在乙酸乙酯与0.1M NaOH(pH 10)之间分隔,分离两相。有机相用盐水洗涤,硫酸钠干燥,真空浓缩,得到无色油。将该无色油溶解在甲醇(1mL)、乙醚(4mL)和HCl(1M的乙醚溶液,2mL)中。搅拌30分钟之后,在惰性气氛下滤出沉淀物,得到标题化合物,为乳白色固体。1H NMR(DMSO-d6)δ9.36(bs,2H),8.36(d,J=2.2Hz,1H),8.21(dd,J=9.2,2Hz,1H),7.98-7.95(m,2H),7.45(d,J=8Hz,1H),7.32(d,J=9Hz,1H),4.40(m,2H),4.25(m,1H),3.40-3.29(m,4H),3.09(m,2H),1.80-1.57(m,6H),1.18(d,J=6.6Hz,3H)。HPLC(方法A)Rt 3.81min(纯度:95.0%)。LC/MS(方法A):400.3(M+H)+。
实施例13:7-{5-[5-甲基-6-(2-甲基吡咯烷-1-基)吡啶-3-基]-1,2,4-恶二唑-3-基}-
3,4-二氢异喹啉-2(1H)-羧酸叔丁酯
以中间体18(120mg;0.54mmol)和中间体4(158mg;0.54mmol)为原料,按照通用程序1的制备工艺制备标题化合物。反应混合物经SPE-NH2柱过滤,THF洗涤,然后在减压下蒸发溶剂,得到褐色油。该褐色油经硅柱色谱法(洗脱剂为环己烷/乙酸乙酯,60/40至100/0)纯化,得到标题化合物,为黄色泡沫(212mg,82%)。1H NMR(DMSO-d6)δ8.72(m,1H),8-7.99(m,1H),7.87-7.84(m,2H),7.38-7.36(m,1H),4.61(m,2H),4.46-4.40(m,1H),3.86-3.80(m,1H),3.61-3.57(m,3H),2.88-2.84(m,2H),2.40(s,3H),2.14-2.01(m,1H),1.98-1.94(m,1H),1.82-1.73(m,1H),1.64-1.57(m,1H),1.44(s,9H),1.17(d,J=6.6Hz,3H)。HPLC(方法A)Rt 4.43min(纯度:94.3%)。LC/MS(方法B):476.4(M+H)+。
实施例14:7-{5-[5-甲基-6-(2-甲基吡咯烷-1-基)吡啶-3-基]-1,2,4-恶二唑-3-基}-
1,2,3,4-四氢异喹啉
0℃下向实施例14(196mg;0.41mmol)在DCM(10mL)中的溶液滴加入TFA(1.27mL;16.48mmol),让温度升至室温。18小时后,溶液在DCM与1M NaOH(pH 10)之间分隔,分离两相。有机相用盐水洗涤,硫酸钠干燥,真空浓缩,得到黄色油。将该黄色油溶解在乙醚(4mL)和HCl(1M的乙醚溶液,2mL)中。搅拌30分钟之后,滤出沉淀物,得到标题化合物,为白色沉淀。HPLC(方法A)Rt 2.01min(纯度:92.5%)。LC/MS(方法B):376.4(M+H)+。
实施例15:7-{5-[2-(甲氧基甲基)-2′-甲基二苯基-4-基]-1,2,4-恶二唑-3-基}-
1,2,3,4-四氢异喹啉,盐酸盐
以中间体14(140mg;0.55mmol)和中间体4(159mg;0.55mmol)为原料,按照通用程序3的制备工艺制备标题化合物。真空移除溶剂,固体残余物在ACN中研磨,过滤。化合物经MD-autoprep纯化,并溶解在HCl的二恶烷溶液中(4M,2mL),室温搅拌18小时,然后真空移除溶剂,在乙醚中研磨,过滤,真空干燥,得到标题化合物,为白色固体。1H NMR(DMSO-d6)δ9.40(bs,2H),8.32(m,1H),8.17-8.15(m,1H),8.02-8(m,2H),7.49-7.28(m,5H),7.15-7.13(m,1H),4.42(bs,2H),4.20-4.18(m,2H),3.42(m,2H),3.25(bs,3H),3.11(bs,2H),2.03(bs,3H)。HPLC(方法A)Rt 4.11min(纯度:98.6%)。LC/MS(方法B):412.3(M+H)+。
实施例16:[7-{5-[2-(甲氧基甲基)-2′-甲基二苯基-4-基]-1,2,4-恶二唑-3-基}-3,4-
二氢异喹啉-2(1H)-基]乙酸,盐酸盐
步骤1:[7-{5-[2-(甲氧基甲基)-2′-甲基二苯基-4-基]-1,2,4-恶二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]乙酸叔丁酯
以中间体14(230mg;0.65mmol)和中间体5(200mg;0.65mmol)为原料,按照通用程序3的制备工艺制备标题化合物。反应混合物真空浓缩,溶解在DCM中,用硅柱色谱法(洗脱剂为环己烷/乙酸乙酯,10/90至80/20)纯化。LC/MS(方法B):526.3(M+H)+。
步骤2:[7-{5-[2-(甲氧基甲基)-2′-甲基二苯基-4-基]-1,2,4-恶二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]乙酸,盐酸盐
将步骤1获得的[7-{5-[2-(甲氧基甲基)-2′-甲基二苯基-4-基]-1,2,4-恶二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]乙酸叔丁酯溶解在HCl的二恶烷(4M,10mL)中,室温搅拌30小时。真空移除溶剂,加入乙醚,滤出固体残余物,将它在热CH3CN中研磨,过滤,得到标题化合物,为浅绿色粉末。1H NMR(DMSO-d6)δ8.32(m,1H),8.17-8.15(m,1H),8.04-8(m,2H),7.49(d,J=8.1Hz,1H),7.42(d,J=7.8Hz,1H),7.36-7.27(m,3H),7.15-7.13(m,1H),4.60(bs,2H),4.24-4.13(m,4H),3.60(bs,2H),3.25-3.22(m,5H),2.03(s,3H)。HPLC(方法A)Rt4.47min(纯度:93.4%)。LC/MS(方法B):470.3(M+H)+。
实施例17:5-[5-(2,2′-二甲基二苯基-4-基)-1,2,4-恶二唑-3-基]-1-甲基-1H-吲哚
以中间体6(94.61mg;0.50mmol)和中间体19(113.14mg;0.50mmol)为原料,按照通用程序1的制备工艺制备标题化合物。反应混合物经SPE-NH2柱过滤,THF洗涤,然后在减压下蒸发溶剂,得到褐色油。该褐色油经硅柱色谱法(洗脱剂为环己烷/乙酸乙酯,90/10)纯化,得到无色油,该无色油在正己烷中结晶,得到标题化合物,为白色固体。HPLC(方法A)Rt 6.23min(纯度:99.5%)。LC/MS(方法A):380.0(M+H)+。
实施例18:{5-[5-(2,2′-二甲基二苯基-4-基)-1,2,4-恶二唑-3-基]-1H-吲哚-1-基}乙
酸
步骤1:{5-[5-(2,2′-二甲基二苯基-4-基)-1,2,4-恶二唑-3-基]-1H-吲哚-1-基}乙酸叔丁酯
以中间体7(144mg;0.50mmol)和中间体19(113mg;0.50mmol)为原料,按照通用程序1的制备工艺制备标题化合物。反应混合物经SPE-NH2柱过滤,THF洗涤,然后在减压下蒸发溶剂,得到褐色油。该褐色油经硅柱色谱法(洗脱剂为环己烷/乙酸乙酯,90/10)纯化,得到标题化合物,为无色油。HPLC(方法A)Rt 6.68min(纯度:98.5%)。LC/MS(方法A):480.1(M+H)+。
步骤2:{5-[5-(2,2′-二甲基二苯基-4-基)-1,2,4-恶二唑-3-基]-1H-吲哚-1-基}乙酸
0℃下,将步骤1获得的{5-[5-(2,2′-二甲基二苯基-4-基)-1,2,4-恶二唑-3-基]-1H-吲哚-1-基}乙酸叔丁酯溶解在DCM(2mL)和TFA(0.50ml)中,让温度升至室温。6小时后,真空蒸发溶剂,得到浅黄色油。经硅柱色谱法(环己烷/乙酸乙酯,先85/15再50/50+1%乙醇)纯化,得到无色油,该无色油在乙醚和正己烷的混合物中研磨,得到标题化合物,为乳白色固体。HPLC(方法A)Rt 5.41min(纯度:97.1%)。LC/MS(方法A):422.0(M-H)-。
实施例19:1-甲基-5-{5-[4-(2-甲基哌啶-1-基)-3-硝基苯基]-1,2,4-恶二唑-3-基}-
1H-吲哚
以中间体6(94mg;0.50mmol)和中间体20(132mg;0.50mmol)为原料,按照通用程序1的制备工艺制备标题化合物。反应混合物经SPE-NH2柱过滤,THF洗涤,然后在减压下蒸发溶剂,得到褐色油。该褐色油经硅柱色谱法(洗脱剂为环己烷/乙酸乙酯,90/10)纯化,得到橙色油,该橙色油在正己烷中研磨,得到标题化合物,为橙色固体。HPLC(方法A)Rt 5.91min(纯度:96.8%)。LC/MS(方法A):418.1(M-H)-。
实施例20:6-甲氧基-5-{5-[4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯基]-1,2,4-恶二
唑-3-基}-1H-吲哚-2-羧酸乙酯
以中间体8(130mg;0.47mmol)和中间体11(143mg;0.50mmol)为原料,按照通用程序1的制备工艺制备标题化合物。反应混合物经SPE-NH2柱过滤,THF洗涤,然后在减压下蒸发溶剂。蒸发溶剂后得到褐色固体,该固体依次用正戊烷、25%DCM的戊烷溶液和小量甲醇洗涤,得到标题化合物,为乳白色固体。HPLC(方法A)Rt 6.31min(纯度:99.2%)。LC/MS(方法A):529.3(M+H)+。
实施例21:6-甲氧基-5-{5-[4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯基]-1,2,4-恶二
唑-3-基}-1H-吲哚-2-羧酸
向实施例20(71mg;0.13mmol)在THF(4.5mL)中的溶液加入氢氧化锂(16mg;0.67mmol)(1.50ml),再加入水(2mL),得到的混合物室温搅拌24小时。溶液用NaOH(0.1M)稀释,乙醚洗涤,并用1M HCl(1M)酸化至pH 1。滤出形成的沉淀物,用水洗涤,高真空干燥,得到标题化合物,为乳白色固体(56mg,83%)。1H NMR(DMSO-d6)δ12.97(bs,1H),11.86(bs,1H),8.45-8.41(m,1H),8.37-8.36(m,1H),8.31(s,1H),7.85(d,J=8.4Hz,1H),7.20(m,1H),7.06(m,1H),3.90(s,1H),3.15(m,1H),2.97-2.93(m,1H),2.64-2.57(m,1H),1.80-1.76(m,2H),1.63-1.29(m,4H),0.78(d,J=6Hz,3H)。HPLC(方法A)Rt 5.43min(纯度:99.1%)。LC/MS(方法A):501.3(M+H)+。
实施例22:N-[5-[3-(1H-吲哚-5-基)-1,2,4-恶二唑-5-基]-2-(2-甲基哌啶-1-基)苯
基]甲烷磺酰胺
以中间体9(87mg;0.47mmol)和中间体17(156mg;0.50mmol)为原料,按照通用程序1的制备工艺制备标题化合物。反应混合物经SPE-NH2柱过滤,THF洗涤,然后在减压下蒸发溶剂。经硅柱色谱法(洗脱剂为环己烷/乙酸乙酯,60/40)纯化后得到黄色粘油,该粘油在DCM/正戊烷混合物中研磨,过滤,得到标题化合物,为黄色固体。1H NMR(DMSO-d6)δ11.45(bs,1H),8.65(s,1H),8.35(m,1H),8.22(d,J=1.8Hz,1H),7.93(dd,J=8.2,1.8Hz,1H),7.82(dd,J=8.4,1.6Hz,1H),7.58-7.54(m,2H),7.48-7.47(m,1H),6.63(bs,1H),3.23(bs,1H),3.13(m,1H),2.91-2.98(m,1H),2.63-2.58(m,1H),1.78-1.68(m,4H),1.49-1.44(m,2H),0.81(d,J=6Hz,3H)。HPLC(方法A)Rt 4.72min(纯度:92.6%)。LC/MS(方法A):452.3(M+H)+。
实施例23:5-[3-(1H-吲哚-5-基)-1,2,4-恶二唑-5-基]-2-(2-甲基哌啶-1-基)苯甲腈
以中间体9(87mg;0.47mmol)和中间体12(122mg;0.50mmol)为原料,按照通用程序1的制备工艺制备标题化合物。反应混合物经SPE-NH2柱过滤,THF洗涤,然后在减压下蒸发溶剂。经硅柱色谱法(洗脱剂为环己烷/乙酸乙酯,70/30)纯化后得到白色固体,该白色固体在乙酸乙酯/正戊烷混合物中重结晶,得到标题化合物,为白色固体。1H NMR(DMSO-d6)δ11.45(bs,1H),8.36-8.34(m,2H),8.23(dd,J=8.9,2.3Hz,1H),7.81(dd,J=8.5,1.5Hz,1H),7.56(d,J=8.5,1H),7.48-7.46(m,1H),7.32(d,J=9Hz,1H),6.60(bs,1H),4.22(m,1H),3.37(m,2H),1.82-1.56(m,6H),1.16(d,J=6.6Hz,3H)。HPLC(方法A)Rt 5.30min(纯度:95.8%)。LC/MS(方法B):382.3(M-H)-。
实施例24:5-{5-[3-甲氧基-4-(4-甲基-3-噻吩基)苯基]-1,2,4-恶二唑-3-基}-1H-吲
唑
以中间体10(120mg;0.48mmol)和中间体21(85mg;0.48mmol)为原料,按照通用程序1的制备工艺制备标题化合物。反应混合物经SPE-NH2柱过滤,THF洗涤,然后在减压下蒸发溶剂。固体残余物溶解在DCM中,加入戊烷使其沉淀,过滤,得到标题化合物,为白色固体。HPLC(方法A)Rt 5.16min(纯度:88.0%)。LC/MS(方法B):387.3(M-H)-。
实施例25:5-[5-(2,2′-二甲基二苯基-4-基)-1,2,4-恶二唑-3-基]-1H-吲唑
以中间体10(93mg;0.53mmol)和中间体19(120mg;0.53mmol)为原料,按照通用程序1的制备工艺制备标题化合物。反应混合物经SPE-NH2柱过滤,THF洗涤,然后在减压下蒸发溶剂。固体残余物溶解在DCM中,加入戊烷使其沉淀,过滤,得到标题化合物,为白色固体。1H NMR(DMSO-d6)δ13.41(bs,1H),8.61(m,1H),8.29(m,1H),8.18(m,1H),8.10-8.05(m,2H),7.76-7.73(m,1H),7.39-7.29(m,4H),7.15-7.12(m,1H),2.14(s,3H),2.04(s,3H)。HPLC(方法A)Rt 5.41min(纯度:89.3%)。LC/MS(方法B):365.4(M-H)-。
实施例26:5-{5-[2-(甲氧基甲基)-2′-甲基二苯基-4-基]-1,2,4-恶二唑-3-基}-7-甲
基-1H-苯并咪唑
以中间体14(308mg;1.2mmol)和中间体3(228mg;1.2mmol)为原料,按照通用程序2的制备工艺制备标题化合物。反应混合物用乙醚稀释,用水和盐水洗涤,真空蒸发。经硅柱色谱法(洗脱剂为乙酸乙酯/环己烷,30/70至70/30)纯化,得到标题化合物,为粉红色粉末。1H NMR(DMSO-d6)δ12.92(br s,0.5H),12.71(brs,0.5H),8.38(d,J=6.0Hz,1H),8.34(d,J=1.3Hz,1H),8.26-8.12(m,2H),7.80(d,J=6.8Hz,1H),7.43(d,J=8.1Hz,1H),7.39-7.25(m,3H),7.16(d,J=7.0Hz,1H),4.27-4.14(m,2H),3.26(s,3H),2.65(s,1.5H),2.62(s,1.5H),2.05(s,3H)。LC/MS(方法B):409.3(M-H)-;411.3(M+H)+。HPLC(方法A)Rt 4.11min(纯度:100.0%)。
实施例27:5-{5-[4-(2-乙基哌啶-1-基)-3-(甲氧基甲基)苯基]-1,2,4-恶二唑-3-基}-
1H-苯并咪唑
以中间体22(377mg;1.2mmol)和中间体1(211mg;1.2mmol)为原料,按照通用程序2的制备工艺制备标题化合物。反应混合物用乙醚稀释,用水和盐水洗涤,真空蒸发。经硅柱色谱法(洗脱剂为乙酸乙酯/环己烷,50/50至80/20)纯化,得到标题化合物,为白色粉末。1H NMR(DMSO-d6)δ12.76(br s,1H),8.39(s,1H),8.32(s,1H),8.19(d,J=2.1Hz,1H),8.07(dd,J=8.4,2.2Hz,1H),7.95(dd,J=8.4,1.5Hz,1H),7.7(d,J=8.4Hz,1H),7.36(d,J=8.5Hz,1H),4.55(s,2H),3.42(s,3H),3.14-3.03(m,2H),2.75-2.64(m,1H),1.90-1.26(m,8H),0.69(t,J=7.4Hz,3H).LC/MS(方法B):416.4(M-H)-;418.4(M+H)+。HPLC(方法A)Rt 2.72min(纯度:100.0%)。
实施例28:5-{5-[4-[(2R)-2-甲基哌啶-1-基]-3-(三氟甲基)苯基]-1,2,4-噁二唑-3-基
}-1H-苯并咪唑
以中间体26(300mg;1.04mmol;1eq.)和中间体1(183.98mg;1.04mmol;1eq.)为原料,按照通用程序3的制备工艺制备标题化合物。蒸发溶剂后,固体残余物在ACN中研磨,过滤,真空干燥,得到标题化合物,为乳白色固体。1H NMR(DMSO-d6)δ12.78(br m,1H),8.50-8.26(m,2H),8.04-7.68(m,3H),3.16(m,1H),3.02-2.90(m,1H),2.69-2.55(m,1H),1.87-1.20(m,6H),0.78(d,J=6.1Hz,3H)。HPLC(方法A),Rt 5.03min(纯度:98.4%)。LC/MS(方法B):426.3(M+H)-;428.1(M+H)+。
实施例29:5-{5-[4-[(2S)-2-甲基哌啶-1-基]-3-(三氟甲基)苯基]-1,2,4-噁二唑-3-基
}-1H-苯并咪唑
以中间体27(300mg;1.04mmol;1eq.)和中间体1(183.98mg;1.04mmol;1eq.)为原料,按照通用程序3的制备工艺制备标题化合物。蒸发溶剂后,固体残余物在ACN中研磨,过滤,真空干燥,得到标题化合物,为乳白色固体。1H NMR(DMSO-d6)δ12.78(br m,1H),8.50-8.26(m,2H),8.04-7.68(m,3H),3.16(m,1H),3.02-2.90(m,1H),2.69-2.55(m,1H),1.87-1.20(m,6H),0.78(d,J=6.1Hz,3H)。HPLC(方法A),Rt 5.04min(纯度:98.4%)。LC/MS(方法B):426.3(M+H)-;428.1(M+H)+。
实施例30:[7-{5-[2′-乙基-2-(甲氧基甲基)二苯基-4-基]-1,2,4-噁二唑-3-基}-3,4-
二氢异喹啉-2(1H)-基]乙酸
步驟1:[7-{5-[2′-乙基-2-(甲氧基甲基)二苯基-4-基]-1,2,4-噁二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]乙酸叔丁酯
以中间体23(162mg;0.6mmol)和中间体5(174mg;0.6mmol)为原料,按照通用程序2的制备工艺制备标题化合物。反应混合物用乙酸乙酯稀释,用水和盐水洗涤,真空蒸发。经硅柱色谱法(洗脱剂为环己烷/(DCM/乙酸乙酯1∶1),90/10至50/50)纯化,得到标题化合物,为黄色油。LC/MS(方法B):541.4(M+H)+。HPLC(方法A)Rt 4.90min(纯度:96.1%)。
步驟2:[7-{5-[2′-乙基-2-(甲氧基甲基)二苯基-4-基]-1,2,4-噁二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]乙酸
将步骤1获得的[7-{5-[2′-乙基-2-(甲氧基甲基)二苯基-4-基]-1,2,4-恶二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]乙酸叔丁酯(135mg;0.25mmol;1eq.)溶解在HCl的二恶烷溶液(3.13mL;4M;12.5mmol;50eq.)中。混合物室温搅拌过夜。移除溶剂。固体残余物在ACN中研磨,过滤,真空干燥,得到标题化合物,为白色固体(93mg,72%)。1H NMR(DMSO-d6)δ8.33(d,J=1.5Hz,1H),8.16(dd,J=8.0,1.9Hz,1H),8.06-7.99(m,2H),7.49(d,J=8.0Hz,1H),7.45(d,J=8.0Hz,1H),7.41(s,1H),7.40(s,1H),7.34-7.27(m,1H),7.12(d,J=7.5Hz,1H),4.61(s,2H),4.27-4.11(m,4H),3.60(s,2H),3.28-3.19(m,5H),2.48-2.23(m,2H),0.99(t,J=7.5Hz,3H)。LC/MS(方法B):484.0(M-H)-;482.1(M+H)+。HPLC(方法A)Rt 4.25min(纯度:98.5%)。
实施例31:3-[7-{5-[2′-乙基-2-(甲氧基甲基)二苯基-4-基]-1,2,4-恶二唑-3-基}-
3,4-二氢异喹啉-2(1H)-基]丙酸
步骤1:3-[7-{5-[2′-乙基-2-(甲氧基甲基)二苯基-4-基]-1,2,4-恶二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]丙酸叔丁酯
以中间体23(162mg;0.6mmol)和中间体25(182mg;0.6mmol)为原料,按照通用程序2的制备工艺制备标题化合物。反应混合物用乙酸乙酯稀释,用水和盐水洗涤,真空蒸发。经硅柱色谱法(洗脱剂为环己烷/(DCM/乙酸乙酯1∶1),90/10至50/50)纯化,得到标题化合物,为黄色油。LC/MS(方法B):555.5(M+H)+。HPLC(方法A)Rt 4.98min。
步骤2:3-[7-{5-[2′-乙基-2-(甲氧基甲基)二苯基-4-基]-1,2,4-恶二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]丙酸
将步骤1获得的3-[7-{5-[2′-乙基-2-(甲氧基甲基)二苯基-4-基]-1,2,4-恶二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]丙酸叔丁酯(183.8mg;0.33mmol;1eq.)溶解在HCl的二恶烷溶液(4.15mL;4M;16.6mmol;50eq.)中。混合物室温搅拌过夜。移除溶剂。经MD-Autoprep纯化,得到标题化合物,为白色粉末。1H NMR(DMSO-d6)δ12.76(br s,1H),10.85(br s,1H),8.33(d,J=1.5Hz,1H),8.16(dd,J=7.9,1.9Hz,1H),8.04(dd,J=8.0,1.6Hz,1H),8.01-7.99(m,1H),7.51(d,J=8.1Hz,1H),7.45(d,J=8.0Hz,1H),7.41(s,1H),7.40(s,1H),7.34-7.27(m,1H),7.12(d,J=7.3Hz,1H),4.60(br s,2H),4.24(d,J=13.0Hz,1H),4.14(d,J=12.8Hz,1H),3.82-3.58(m,4H),3.29-3.18(m,5H),2.94(t,J=7.6Hz,2H),2.47-2.23(m,2H),0.99(t,J=7.5Hz,3H)。LC/MS(方法B):496.4(M-H)-.;498.3(M+H)+。HPLC(方法A)Rt 4.31min(纯度:98.5%)。
实施例32:6-{5-[2-(甲氧基甲基)-2′-甲基二苯基-4-基]-1,2,4-噁二唑-3-基}-1H-吲
哚-2-羧酸
以中间体14(150mg;0.59mmol;1eq.)和中间体30(128.29mg;0.59mmol;1eq.)为原料,按照通用程序3的制备工艺制备标题化合物。蒸发溶剂后,固体残余物在甲醇中重结晶,得到标题化合物(30mg)。1H NMR(DMSO-d6)δ13.25(br s,1H),12.15(br s,1H),8.34(m,1H),8.27(s,1H),8.18(m,1H),7.89-7.79(m,2H),7.47-7.11(m,6H),4.23(d,J=12.7Hz,1H),4.18(d,J=12.7Hz,1H),3.26(s,3H),2.04(s,3H)。HPLC(方法A),Rt 5.61min(纯度:97.4%)。LC/MS(方法B):426.3(M+H)-;428.1(M+H)+。
实施例33:3-[7-{5-[4-(2-乙基哌啶-1-基)-3-(甲氧基甲基)苯基]-1,2,4-噁二唑-3-
基}-3,4-二氢异喹啉-2(1H)-基]丙酸
步驟1:3-[7-{5-[4-(2-乙基哌啶-1-基)-3-(甲氧基甲基)苯基]-1,2,4-噁二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]丙酸叔丁酯
以中间体22(188mg;0.6mmol)和中间体25(182mg;0.6mmol)为原料,按照通用程序2的制备工艺制备标题化合物。反应混合物用乙酸乙酯稀释,用水和盐水洗涤,真空蒸发。经硅柱色谱法(洗脱剂为环己烷/(DCM/乙酸乙酯1∶1),90/10至50/50)纯化,得到标题化合物,为黄色油。LC/MS(方法B):562.3(M+H)+。HPLC(方法A)Rt 3.77min(纯度:95.0%)。
步驟2:3-[7-{5-[4-(2-乙基哌啶-1-基)-3-(甲氧基甲基)苯基]-1,2,4-噁二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]丙酸
将步骤1获得的3-[7-{5-[4-(2-乙基哌啶-1-基)-3-(甲氧基甲基)苯基]-1,2,4-恶二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]丙酸叔丁酯(95mg;0.17mmol;1eq.)溶解在HCl的二恶烷溶液(2.1mL;4M;8.47mmol;50eq.)中。混合物室温搅拌过夜。移除溶剂。固体残余物在ACN中研磨,过滤,真空干燥,得到标题化合物,为橙色固体。1H NMR(DMSO-d6)δ8.18(d,J=2.0Hz,1H),8.07-7.94(m,3H),7.48(d,J=8.1Hz,1H),7.35(d,J=8.3Hz,1H),4.74(d,J=17.0Hz,1H),4.54(s,2H),4.45(d,J=15.2Hz,1H),3.83-3.73(m,1H),3.55-3.37(,7H),3.29-3.05(m,4H),2.93(t,J=7.6Hz,2H),2.79-2.66(m,1H),1.89-1.25(m,8H),0.68(t,J=7.4Hz,3H)。LC/MS(方法B):503.4(M-H)-;505.3(M+H)+。HPLC(方法A)Rt 2.90min(纯度:94.4%)。
实施例34:[7-{5-[4-(2-乙基哌啶-1-基)-3-(甲氧基甲基)苯基]-1,2,4-噁二唑-3-基}-
3,4-二氢异喹啉-2(1H)-基]乙酸
步驟1:[7-{5-[4-(2-乙基哌啶-1-基)-3-(甲氧基甲基)苯基]-1,2,4-噁二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]乙酸叔丁酯
以中间体22(188mg;0.6mmol)和中间体5(174mg;0.6mmol)为原料,按照通用程序2的制备工艺制备标题化合物。反应混合物用乙酸乙酯稀释,用水和盐水洗涤,真空蒸发。经硅柱色谱法(洗脱剂为环己烷/(DCM/乙酸乙酯1∶1),90/10至50/50)纯化,得到标题化合物,为黄色油。LC/MS(方法B):548.3(M+H)+。HPLC(方法A)Rt 3.63min。
步驟2:[7-{5-[4-(2-乙基哌啶-1-基)-3-(甲氧基甲基)苯基]-1,2,4-噁二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]乙酸
将步骤1获得的[7-{5-[4-(2-乙基哌啶-1-基)-3-(甲氧基甲基)苯基]-1,2,4-恶二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]乙酸叔丁酯(176mg;0.32mmol;1eq.)溶解在HCl的二恶烷溶液(4.0mL;4M;16.1mmol;50eq.)中。混合物室温搅拌过夜。移除溶剂。固体残余物在ACN中研磨,过滤,真空干燥,得到标题化合物,为灰色粉末(154mg,84%)。1H NMR(DMSO-d6)δ10.83(br s,1H),8.18(d,J=2.0Hz,1H),8.07-7.97(m,3H),7.49(d,J=8.1Hz,1H),7.35(d,J=8.2Hz,1H),4.71-3.5(m,8H),3.41(s,3H),3.26-3.19(m,2H),3.14-3.05(m,2H),2.76-2.67(m,1H),1.89-1.29(m,8H),0.68(t,3H)。LC/MS(方法B):489.4(M-H)-;491.3(M+H)+。HPLC(方法A)Rt 2.77min(纯度:95.6%)。
实施例35:3-[7-{5-[2-(甲氧基甲基)-2′-甲基二苯基-4-基]-1,2,4-噁二唑-3-基}-
3,4-二氢异喹啉-2(1H)-基]丙酸
步驟1:3-[7-{5-[2-(甲氧基甲基)-2′-甲基二苯基-4-基]-1,2,4-噁二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]丙酸叔丁酯
以中间体14(154mg;0.6mmol)和中间体25(182mg;0.6mmol)为原料,按照通用程序2的制备工艺制备标题化合物。反应混合物用乙酸乙酯稀释,用水和盐水洗涤,真空蒸发。经硅柱色谱法(洗脱剂为环己烷/(DCM/乙酸乙酯1∶1),90/10至50/50)纯化,得到标题化合物,为黄色油。1H NMR(DMSO-d6)δ8.32(d,J=1.6Hz,1H),8.16(dd,J=8.0,2.0Hz,1H),7.87(dd,J=8.0,1.6Hz,1H),7.82(d,J=1.4Hz,1H),7.42(d,J=7.9Hz,1H),7.38-7.26(m,4H),7.15(d,J=7.2Hz,1H),4.25-4.14(m,2H),3.71(s,2H),3.25(s,3H),2.91-2.86(m,2H),2.78-2.70(m,4H),2.53-2.46(m,2H),2.04(s,3H),1.40(s,9H)。LC/MS(方法B):540.1(M+H)+。HPLC(方法A)Rt 4.81min(纯度:97.4%)。
步驟2:3-[7-{5-[2-(甲氧基甲基)-2′-甲基二苯基-4-基]-1,2,4-噁二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]丙酸
将步骤1获得的3-[7-{5-[2-(甲氧基甲基)-2′-甲基二苯基-4-基]-1,2,4-恶二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]丙酸叔丁酯(100mg;0.19mmol;1eq.)溶解在HCl的二恶烷溶液(2.3mL;4M;9.26mmol;50eq.)中。混合物室温搅拌4小时。移除溶剂。固体残余物在ACN中研磨,过滤,真空干燥,得到标题化合物,为白色固体(92mg,95%)。1H NMR(DMSO-d6)δ12.78(br s,1H),10.95(br s,1H),8.33(d,J=1.5Hz,1H),8.16(dd,J=7.9,1.9Hz,1H),8.04(dd,J=8.0,1.5Hz,1H),8.00(d,J=1.4Hz,1H),7.50(d,J=8.1Hz,1H),7.43(d,J=7.9Hz,1H),7.38-7.27(m,3H),7.15(d,1H),4.76-4.14(m,4H),3.79-3.39(m,4H),3.29-3.19(m,5H),2.95(t,J=7.6Hz,2H),2.04(s,3H)。LC/MS(方法B):482.1(M-H)-,484.0(M+H)+。HPLC(方法A)Rt 4.09min(纯度:96.0%)。
实施例36:[7-{5-[2′-甲基-2-(三氟甲基)二苯基-4-基]-1,2,4-噁二唑-3-基}-3,4-二
氢异喹啉-2(1H)-基]乙酸
步驟1:[7-{5-[2′-甲基-2-(三氟甲基)二苯基-4-基]-1,2,4-噁二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]乙酸叔丁酯
以中间体24(168mg;0.6mmol)和中间体5(174mg;0.6mmol)为原料,按照通用程序2的制备工艺制备标题化合物。反应混合物用乙酸乙酯稀释,用水和盐水洗涤,真空蒸发。经MD-Autoprep纯化,得到标题化合物,为黄色油。LC/MS(方法B):550.1(M+H)+。HPLC(方法A)Rt 4.95min。
步驟2:[7-{5-[2′-甲基-2-(三氟甲基)二苯基-4-基]-1,2,4-噁二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]乙酸
将步骤1获得的[7-{5-[2′-甲基-2-(三氟甲基)二苯基-4-基]-1,2,4-恶二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]乙酸叔丁酯(58mg;0.11mmol;1eq.)溶解在HCl的二恶烷溶液(1.3mL;4M;5.28mmol;50eq.)中。混合物室温搅拌8小时。移除溶剂。固体残余物在ACN中研磨,过滤,真空干燥,得到标题化合物,为白色固体。1HNMR(DMSO-d6)δ8.55(d,J=1.5Hz,1H),8.50(dd,J=7.9,1.6Hz,1H),8.07-8.02(m,2H),7.68(d,J=8.0Hz,1H),7.51(d,J=8.1Hz,1H),7.42-7.26(m,3H),7.17(d,J=7.3Hz,1H),4.60(s,2H),4.24(s,2H),3.60(br s,2H),3.26-3.19(m,2H),2.03(s,3H)。LC/MS(方法B):492.1(M-H)-;494.0(M+H)+。HPLC(方法A)Rt 4.29min(纯度:97.9%)。
实施例37:3-[7-{5-[4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯基]-1,2,4-噁二唑-3-
基}-3,4-二氢异喹啉-2(1H)-基]丙酸
步驟1:[7-{5-[2′-甲基-2-(三氟甲基)二苯基-4-基]-1,2,4-噁二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]乙酸叔丁酯
以中间体11(172mg;0.6mmol)和中间体25(182mg;0.6mmol)为原料,按照通用程序3的制备工艺制备标题化合物。反应混合物用乙酸乙酯稀释,用水和盐水洗涤,真空蒸发。经硅柱色谱法(洗脱剂为环己烷/(DCM/乙酸乙酯1∶1),90/10至50/50)纯化,得到标题化合物,为黄色油。LC/MS(方法B):572.2(M+H)+。HPLC(方法A)Rt 5.37min(纯度:95.0%)。
步驟2:3-[7-{5-[4-(2-甲基哌啶啶-1-基)-3-(三氟甲基)苯基]-1,2,4-噁二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]丙酸
将步骤1获得的3-[7-{5-[4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯基]-1,2,4-恶二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]丙酸叔丁酯(166mg;0.29mmol;1eq.)溶解在HCl的二恶烷溶液(3.6mL;4M;14.54mmol;50eq.)中。混合物室温搅拌7.5小时。移除溶剂。固体残余物在ACN中研磨,过滤,真空干燥,得到标题化合物,为白色固体(123mg,72%)。1H NMR(DMSO-d6)δ12.8(br s,1H),11.9(br s,1H),8.44(dd,J=8.4,2.0Hz,1H),8.39(d,J=2.0Hz,1H),8.02(dd,J=8.0,1.6Hz,1H),7.98(s,1H),7.87(d,J=8.7Hz,1H),7.49(d,J=8.1Hz,1H),4.80-4.39(m,2H),3.80-3.13(m,8H),2.99-2.90(m,3H),2.68-2.58(m,1H),1.84-1.74(m,2H),1.69-1.27(m,4H),0.79(d,J=6.2Hz,3H)。LC/MS(方法B):513.2(M-H)-;515.0(M+H)+。HPLC(方法A)Rt 4.72min(纯度:97.7%)。
实施例38:[7-{5-[4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯基]-1,2,4-噁二唑-3-基}-
3,4-二氢异喹啉-2(1H)-基]乙酸
步驟1:[7-{5-[4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯基]-1,2,4-噁二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]乙酸叔丁酯
以中间体11(172mg;0.6mmol)和中间体5(183mg;0.6mmol)为原料,按照通用程序3的制备工艺制备标题化合物。反应混合物用乙酸乙酯稀释,用水和盐水洗涤,真空蒸发。经硅柱色谱法(洗脱剂为环己烷/(DCM/乙酸乙酯1∶1),90/10至50/50)纯化,得到标题化合物,为黄色油。LC/MS(方法B):558.1(M+H)+。HPLC(方法A)Rt 5.30min。
步驟2:[7-{5-[4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯基]-1,2,4-噁二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]乙酸
将步骤1获得的[7-{5-[4-(2-甲基哌啶-1-基)-3-(三氟甲基)苯基]-1,2,4-恶二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]乙酸叔丁酯(211mg;0.38mmol;1eq.)溶解在HCl的二恶烷溶液(4.7mL;4M;18.95mmol;50eq.)中。混合物室温搅拌7.5小时。移除溶剂。固体残余物在ACN中研磨,过滤,真空干燥,得到标题化合物,为浅黄色固体(165mg,76%)。1H NMR(DMSO-d6)δ8.45(dd,J=8.4,1.2Hz,1H),8.38(d,J=1.8Hz,1H),8.04-7.98(m,2H),7.87(d,J=8.5Hz,1H),7.49(d,J=7.9Hz,1H),4.63(s,2H),4.27(s,2H),3.63(s,2H),3.27-3.13(m,3H),2.99-2.92(m,1H),2.67-2.58(m,1H),1.84-1.74(m,2H),1.69-1.23(m,4H),0.79(d,J=6.0Hz,3H)。LC/MS(方法B):499.1(M-H)-;501.0(M+H)+。HPLC(方法A)Rt 4.68min(纯度:96.9%)。
实施例39:3-[7-{5-[2′-甲基-2-(三氟甲基)二苯基-4-基]-1,2,4-噁二唑-3-基}-3,4-
二氢异喹啉-2(1H)-基]丙酸
步骤1:3-[7-{5-[2′-甲基-2-(三氟甲基)二苯基-4-基]-1,2,4-恶二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]丙酸叔丁酯
以中间体24(168mg;0.6mmol)和中间体25(182mg;0.6mmol)为原料,按照通用程序3的制备工艺制备标题化合物。反应混合物用乙酸乙酯稀释,用水和盐水洗涤,真空蒸发。经硅柱色谱法(洗脱剂为环己烷/(DCM/乙酸乙酯1∶1),90/10至50/50)纯化,得到标题化合物,为黄色油。LC/MS(方法B):565.2(M+H)+。HPLC(方法A)Rt 5.00min(纯度:95.4%)。
步骤2:3-[7-{5-[2′-甲基-2-(三氟甲基)二苯基-4-基]-1,2,4-恶二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]丙酸
将步骤1获得的3-[7-{5-[2′-甲基-2-(三氟甲基)二苯基-4-基]-1,2,4-恶二唑-3-基}-3,4-二氢异喹啉-2(1H)-基]丙酸叔丁酯(136.1mg;0.24mmol;1eq.)溶解在HCl的二恶烷溶液(3.0mL;4M;12.07mmol;50eq.)中。混合物室温搅拌7.5小时。移除溶剂。固体残余物在ACN中研磨,过滤,真空干燥,得到标题化合物,为白色固体(105mg,80%)。1H NMR(DMSO-d6)δ12.74(br s,1H),10.98(br s,1H),8.55(d,J=1.3Hz,1H),8.50(dd,J=8.0,1.4Hz,1H),8.05(dd,J=8.0,1.5Hz,1H),8.01(s,1H),7.68(d,J=8.0Hz,1H),7.51(d,J=8.1Hz,1H),7.42-7.26(m,3H),7.17(d,J=7.5Hz,1H),4.58(br s,2H),3.72-3.19(m,6H),2.95(t,J=7.6Hz,2H),2.03(s,3H)。LC/MS(方法B):506.1(M-H)-;508.0(M+H)+。HPLC(方法A)Rt 4.35min(纯度:98.6%)。
实施例40:3-{6-[5-(2-甲氧基甲基-2′-甲基-二苯基-4-基)-[1,2,4]噁二唑-3-基]-
3,4-二氫-1H-异喹啉-2-基}-丙酸
以中间体14和3-[6-[氨基(羟基亚氨基)甲基]-3,4-二氢异喹啉-2(1H)-基]丙酸叔丁酯(后者的制备工艺参照中间体25,以1,2,3,4-四氢异喹啉-6-腈为原料,其中1,2,3,4-四氢异喹啉-6-腈的制备参Synthetic Communications 1995,25,3255-61描述的方法)为原料,按照实施例39的制备工艺制备标题化合物。分离出的标题化合物为浅黄色油。1H NMR(DMSO-d6)δ8.34(d,J=1.5Hz,1H),8.16(dd,J=7.9,1.9Hz,1H),7.95-7.85(m,2H),7.50-7.25(m,5H),7.17(d,1H),4.24(d,J=12.7Hz,1H),4.20(d,J=12.7Hz,1H),3.80(s,2H),3.28(s,3H),3.10-2.75(m,6H),2.70-2.55(m,2H),2.07(s,3H)。LC/MS(方法B):482(M-H)-;484(M+H)+。HPLC(方法D)Rt 17.1min。
实施例41:体外试验
受体结合试验:从表达S1P1或S1P3的CHO细胞制备膜,用于配体和35S-GTPγS结合研究。将细胞悬浮于缓冲液A(50mM TRIS,pH 7.4,2mM EDTA,250mM蔗糖)和1×完全蛋白酶抑制剂混合物(Roche)中,于4℃氮气减压下用细胞破碎装置(Parr Instrument)破碎细胞。于4℃、1000RPM离心10分钟后,将上清液悬浮于缓冲液A,再于4℃、19000RPM离心60分钟。然后将沉淀块悬浮于缓冲液B(10mM HEPES,pH 7.4,1mM EDTA,250mM蔗糖)和1×完全无EDTA蛋白酶抑制剂混合物中,用potter制成匀浆。将膜在液氮中快速冷冻,储存于-80℃。将[33P]鞘氨醇1-磷酸(3000Ci/mmol;AmeriACN Radiolabeled Chemicals,Inc.)加到用DMSO配制的受试化合物中。在96孔板上加入膜和WGA SPA珠(GE Healthcare),使最终体积100μl中含有测试浓度为25pM或10pM(分别对应于S1P1或S1P3)的[33P]鞘氨醇1-磷酸,50mM HEPES,pH 7.5,5mM MgCl2,100mM NaCl,0.4%无脂肪酸BSA,1-5μg/孔的蛋白和100μg/孔的WGA SPA珠。于室温下在振荡器上进行60分钟结合,在PerkinElmer 1450 MicroBeta计数器上测定结合的放射活性,减去有1000倍过量未标记S1P存在下的残余放射活性,计算出特异性结合。用GraphPad Prism程序分析结合数据。
35 S-GTPγS结合的测定:在装有180μl测试缓冲液(20mM HEPES,pH 7.4,10mM MgCl2,2μg/孔Saponin,0.2%无脂肪酸BSA)、140mM NaCl和1.7μM GDP以及用DMSO稀释的受试化合物的96孔Scintiplates(PerkinElmer)的孔中加入如上所述制得的膜(1-10μg蛋白),进行孵育。加入以测试缓冲液配制的20μl 1.5nM[35S]-GTPγS(1100Ci/mmol;GE Healthcare)则试验开始。在振荡器上30℃孵育60分钟后,将板于2000RPM离心10分钟。弃去上清液,在PerkinElmer 1450MicroBeta计数器上测定膜结合的放射活性。将三个平行试验样品的数据平均,表示为对应于无化合物存在时对S1P激活的应答百分率(n=2)。
如上述试验中所测定的,通式(I)化合物作为潜在和选择性S1P1受体激动剂的活性证明了它们具有作为免疫调节剂的实用性。具体地,如上述35S-GTPγS结合试验中所评估的,通式(I)化合物对S1P1受体的EC50与对S1P3受体的EC50之比显示通式(I)化合物对S1P1受体比对S1P3受体更具有选择性。
得到如下结果:
实施例42:评估S1P激动剂体内效应的动物模型——S1P激动剂引起的小鼠
淋巴细胞减少症模型
雌性57BL/6小鼠(Elevage Janvier)(8周龄)口服接受S1P激动剂。给药后2-120小时,在异氟烷麻醉下对肝素化(100IU/kg,ip)小鼠心内或眶后穿刺取血样。用Beckman/Coulter计数器作白细胞(淋巴细胞和中性白细胞)计数。通过红细胞和血小板计数评估血样的质量。
MOG引起的小鼠实验性自身免疫性脑脊髓炎(EAE)模型
在9周龄雌性小鼠(C57BL/6,Elevage Janvier)上通过抗MOG免疫接种引起EAE。小鼠经腹腔注射途径接受Pertussis毒素(Alexis,300ng/小鼠,200μl,以PBS配制)及背部皮下注射以弗氏完全佐剂(DIFCO)配制的含MOG35-55肽(NeoMPS,200μg/小鼠)、结核分枝杆菌(0.25mg/小鼠)的乳剂100μl。两天后,再腹腔注射Pertussis毒素(Alexis,300ng/小鼠,200μl,以PBS配制)。引起EAE后,将小鼠每天称重,用评定麻痹(尾巴、后肢和前肢)、失禁和死亡的15分临床评分对神经损伤进行定量。
临床评分
-1-尾巴
-分数=0正常小鼠运动时尾巴保持直立;
-分数=1如果尾巴末端松弛,有落下趋势;
-分数=2如果尾巴完全松弛,拖在桌子上。
-2-后肢
-分数=0正常小鼠步态有力,脚爪不拖;
-分数=1如下测试中有任何一项为阳性:
-a-翻转试验:将尾巴抓在拇指和食指之间,使动物翻身,观察它自己翻回正常姿势的时间。健康小鼠会立即自己翻回来。有延搁提示后肢软弱。
-b-将小鼠放在金属丝笼顶部,观察它从一边爬到另一边。如果一个或两个后肢经常掉落在金属丝之间,则认为有部分麻痹。
-分数=2前两个试验均为阳性。
-分数=3一个或两个后肢显示麻痹症状,但仍有某些运动,例如动物可短时间抓住和保持在金属丝笼顶部的下面然后离开。
-分数=4当两条后腿均麻痹时,小鼠在移动时拖着这两条腿。
-3-前肢
-分数=0正常小鼠活跃地用前爪抓攀和行走及保持头部直立。
-分数=1可行走但由于一个或两个脚爪软弱而行走困难,例如小鼠抓金属丝笼顶部下方困难被认为是前爪软弱,另一个软弱症状是头部下垂。
-分数=2当一个前肢麻痹时,小鼠不能抓攀,并转向麻痹侧的前肢,此时头部也失去大部分肌张力。
-分数=3小鼠不能移动,够不着食物和水。
-4-膀胱
-分数=0正常小鼠完全控制其膀胱。
-分数=1当小鼠身体后部被尿浸湿时被认为失禁。
-5-死亡
-分数=15。
将上面各类相加,获得每个动物的最终分数。存活动物的最大分数是10。
第12天(麻痹的第一批症状出现),按临床评分和体重减轻程度将小鼠分层分入实验组(n=10)。半治愈治疗始于第14天。
实施例43:药物制剂的制备
制剂1-片剂
将干粉状通式(I)化合物与干明胶粘合剂以1∶2的重量比混合。加入少量硬脂酸镁作为润滑剂。用压片机将混合物压成240-270mg的片剂(每片含80-90mg本发明的活性化合物)。
制剂2-胶囊剂
将干粉状通式(I)化合物与干明胶粘合剂以1∶2的重量比混合。将混合物填充入250mg胶囊(每个胶囊含125mg本发明的活性化合物)。
制剂3-液体制剂
将通式(I)化合物(1250mg)、蔗糖(1.75g)和黄原酸胶(4mg)混合,通过No.10目U.S.筛,然后与预先准备的微晶纤维素和羧甲基纤维素钠(11:89,50mg)水溶液混合。将苯甲酸钠(10mg)、矫味剂和染料用水稀释后于搅拌下加入前者。然后加足够的水,得到总体积5ml。
制剂4-片剂
将干粉状通式(I)化合物与干明胶粘合剂以1∶2的重量比混合。加入少量硬脂酸镁作为润滑剂。用压片机将混合物压成450-900mg的片剂(每片含150-300mg本发明的活性化合物)。
制剂5-注射剂
将通式(I)化合物用灭菌缓冲盐水可注射水性介质溶解成浓度约5mg/ml。
Claims (15)
1.通式(I)所示的化合物:
式中,
R1、R2各自独立地表示H、COOR3、CONHR3、Hal、CF3、OCF3、CN、NO2、OH、A、OA、或(CH2)mV(CH2)mW,
V表示O-、-NR3-、-COO-或-CONR3,
W表示COOR3、SO2NH2、CON(R3)2,
Q表示含有1、2或3个氮原子的饱和或不饱和5或6元杂环,
X表示-CH-或-N-,
Y表示Het、Ar或Cyc,
Ra是A、Hal、CF3、OR3、OCF3、(CH2)nOH、(CH2)nOA、(CH2)nOR3、CN、NO2、N(R3)2、CH2N(H)2-p(A)p、(CH2)nSO2N(R3)2、SO2N(R3)2、(CH2)nNR3SO2A、(CH2)nSO2A、(CH2)nN(SO2A)2、NR3CON(R3)2或NR3COA、NR3SO2N(R3)2,
A是具有1至12个碳原子的支链或直链烷基,其中一个或多个,优选是1至7个),氢原子可以被Hal、OR3、CN、COOR3、或N(R3)2取代,且其中一个或多个,优选是1至7个,非相邻的的CH2-基团可以被O、NR3或S取代和/或被-CH=CH-或-C≡C-基团取代,或者表示具有3至7个环碳原子的环烷基或环烷基亚烃基,
Ar表示具有6至14个碳原子的单环或双环不饱和或芳香族碳环,所述碳环被A、OR3、N(R3)2、NO2、CN、COOR3、CF3、OCF3、CON(R3)2、NR3COA、NR3CON(R3)2、NR3SO2A、COR3、SO2N(R3)2、SOA或SO2A单取代、二取代或三取代,或者当Ra是Hal、OR3、OCF3,(CH2)nOH、(CH2)nOA、(CH2)nOR3、CN、NO2、N(R3)2、CH2N(H)2-p(A)p、(CH2)nSO2N(R3)2、SO2N(R3)2、(CH2)nNR3SO2A、(CH2)nSO2A、(CH2)nN(SO2A)2、NR3CON(R3)2或NR3COA、NR3SO2N(R3)2时,Ar可以被Hal取代,使得至少有一个与将Ar基团与分子其余部分连接的原子相邻的原子含有上面所述取代基其中之一,
Het表示具有1至4个氮原子、氧原子和/或硫原子的单环或双环饱和、不饱和或芳香族杂环,所述杂环被Hal、A、-[C(R3)2]n-Ar、-[C(R3)2]n-环烷基、OR3、CF3、OCF3、N(R3)2、NR3CON(R3)2、NO2、CN、-[C(R3)2]n-COOR3、-[C(R3)2]n-CON(R3)2、NR3COA、NR3SO2A、COR3、SO2N(R3)2、SOA、和/或SO2A单取代、二取代或三取代,使得至少有一个与将Het基团与分子其余部分连接的原子相邻的原子含有上面所述取代基其中之一,
Cyc表示含有3至7个碳原子的饱和或不饱和碳环,所述碳环被Hal、A、-[C(R3)2]n-Ar、-[C(R3)2]n-环烷基、OR3、CF3、OCF3、N(R3)2、NR3CON(R3)2、NO2、CN、-[C(R3)2]n-COOR3、-[C(R3)2]n-CON(R3)2、NR3COA、NR3SO2A、COR3、SO2N(R3)2、SOA、和/或SO2A取代,使得至少有一个与将Cyc基团与分子其余部分连接的原子相邻的原子含有上面所述取代基其中之一,
Hal是F、Cl、Br或I,
R3是H或A,
p是0、1或2,
n是0、1、2、3或4,
m是0、1、2、3或4,
以及其药学上可接受的衍生物、溶剂化物、互变异构体、盐类及立体异构体,包括它们的各种比例的混合物。
2.如权利要求1所述的通式(I)化合物,其中Ar选自以下基团:
式中Rb和Re各自独立地选自A、Hal、OA、OR3、CF3、OCF3。
4.如权利要求1至3中任一项所述的通式(I)化合物,其中Ra选自如下基团:-CH3、-CH2-CH3、-CH2-CH(CH3)2、-CF3、-CH2-CF3、-CH2OCH3、-CH2OCF3、-CH2-N(CH3)2、-CH2-N(CH3)-CH2CH3、CN、NHSO2CH3、NO2、OCH3。
5.如权利要求1至4中任一项所述的通式(I)化合物,其中Rb选自如下基团:-CH3、-CH2-CH3、-CH2-CH(CH3)2、-CF3、-CH2-CF3、-CH2OCH3、-CH2OCH2CH3、-CH2OCF3、-CH2-N(CH3)2、-CH2-N(CH3)-CH2CH3。
7.一种药物组合物,包含权利要求1-6中任一项所述的至少一种化合物和/或其药学上可使用的衍生物、互变异构体、盐、溶剂化物和立体异构体,包括它们的各种比例的混合物,并任选地包含辅料和/或佐剂。
8.一种药物组合物,包含权利要求1-6中任一项所述的至少一种化合物和/或其药学上可使用的衍生物、互变异构体、盐、溶剂化物和立体异构体,包括它们的各种比例的混合物,并包含至少一种其它活性成分。
9.一种试剂盒,包含至少一种如权利要求1-6中任一项所述的化合物和/或其药学上可使用的衍生物、互变异构体、盐、溶剂化物和立体异构体,包括它们的各种比例的混合物,以及至少一种其它活性成分。
10.如权利要求1所述的通式(I)化合物和其药学上可接受的衍生物、溶剂化物、互变异构体、盐、和立体异构体,包括它们的各种比例的混合物,作为药物的用途。
11.如权利要求10所述的化合物和其药用衍生物、盐、互变异构体、溶剂化物和立体异构体,包括它们以各种比例混合的混合物,在制备治疗和/或预防鞘氨醇1-磷酸酯相关性疾病的药物上的用途。
12.如权利要求10或11中一项或多项所述的化合物和其药用衍生物、盐、互变异构体、溶剂化物和立体异构体,包括它们以各种比例混合的混合物,的用途,用于制备治疗和/或预防免疫调节异常的药物上的用途。
13.如权利要求12所述的用途,其中所述免疫调节异常是一种自身免疫性疾病或慢性炎症疾病,选自下列组内的疾病:系统性红斑狼疮、慢性类风湿性关节炎、I型糖尿病、炎性肠道疾病、胆汁性肝硬化、葡萄膜炎、多发性硬化症、肌萎缩侧索硬化症(ALS),Crohn′s病、溃疡性结肠炎、大疱性类天疱疮、结节病、牛皮癣、自身免疫性肌炎、Wegener′s肉芽肿、鱼鳞病、Graves眼病、哮喘、骨髓或器官移植排斥或移植物抗宿主病。
15.通式(I)化合物,所述化合物在GTPγS试验中结合S1P1受体的EC50小于约5μM。
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EP08172177.1 | 2008-12-18 | ||
EP08172177 | 2008-12-18 | ||
US23826109P | 2009-08-31 | 2009-08-31 | |
US61/238,261 | 2009-08-31 | ||
PCT/EP2009/067171 WO2010069949A1 (en) | 2008-12-18 | 2009-12-15 | Oxadiazole fused heterocyclic derivatives useful for the treatment of multiple sclerosis |
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US (1) | US8741923B2 (zh) |
EP (1) | EP2376484B1 (zh) |
JP (1) | JP5855942B2 (zh) |
KR (1) | KR20110100624A (zh) |
CN (1) | CN102245602B (zh) |
AR (1) | AR074700A1 (zh) |
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BR (1) | BRPI0923178A2 (zh) |
CA (1) | CA2743397C (zh) |
EA (1) | EA201170828A1 (zh) |
ES (1) | ES2543205T3 (zh) |
IL (1) | IL213590A0 (zh) |
MX (1) | MX2011006560A (zh) |
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EP2344446A4 (en) | 2008-10-17 | 2012-04-04 | Akaal Pharma Pty Ltd | S1P RECEPTOR MODULATORS |
NZ592748A (en) | 2008-10-17 | 2013-01-25 | Akaal Pharma Pty Ltd | 2-Amino-(oxadiazol-3-yl)-benzofuran derivatives and their use as S1P receptor modulators |
US8399451B2 (en) | 2009-08-07 | 2013-03-19 | Bristol-Myers Squibb Company | Heterocyclic compounds |
US8629282B2 (en) | 2010-11-03 | 2014-01-14 | Bristol-Myers Squibb Company | Heterocyclic compounds as S1P1 agonists for the treatment of autoimmune and vascular diseases |
US8889730B2 (en) | 2012-04-10 | 2014-11-18 | Pfizer Inc. | Indole and indazole compounds that activate AMPK |
EP2958913B1 (en) | 2013-02-20 | 2018-10-03 | LG Chem, Ltd. | Sphingosine-1-phosphate receptor agonists, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent |
UY35338A (es) | 2013-02-21 | 2014-08-29 | Bristol Myers Squibb Company Una Corporación Del Estado De Delaware | Compuestos bicíclicos moduladores de la actividad de s1p1 y composiciones farmacéuticas que los contienen |
EP2970177A1 (en) | 2013-03-15 | 2016-01-20 | Pfizer Inc. | Indole compounds that activate ampk |
UY36274A (es) | 2014-08-20 | 2016-02-29 | Bristol Myers Squibb Company Una Corporación Del Estado De Delaware | Compuestos bicíclicos sustituidos como agonistas selectivos de la actividad del receptor s1p1 acoplado a la proteína g |
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JP2008517915A (ja) * | 2004-10-22 | 2008-05-29 | メルク エンド カムパニー インコーポレーテッド | S1p受容体アゴニストとしての2−(アリール)アザシクリルメチルカルボキシレート、スルホネート、ホスホネート、ホスフィネート及びヘテロ環 |
CA2648303C (en) * | 2006-04-03 | 2014-07-15 | Astellas Pharma Inc. | 5-[monocyclic(hetero)arylsubstituted-1,2,4-oxadliazol-3-yl]-(fused heteroaryl substituted) compounds and their use as s1p1 agonists |
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JP5855942B2 (ja) | 2016-02-09 |
CN102245602B (zh) | 2014-09-10 |
AU2009327133B2 (en) | 2016-04-14 |
WO2010069949A1 (en) | 2010-06-24 |
EA201170828A1 (ru) | 2011-12-30 |
ES2543205T3 (es) | 2015-08-17 |
CA2743397C (en) | 2017-02-28 |
US8741923B2 (en) | 2014-06-03 |
MX2011006560A (es) | 2011-08-03 |
US20110230518A1 (en) | 2011-09-22 |
JP2012512829A (ja) | 2012-06-07 |
CA2743397A1 (en) | 2010-06-24 |
ZA201103405B (en) | 2012-08-29 |
IL213590A0 (en) | 2011-07-31 |
KR20110100624A (ko) | 2011-09-14 |
EP2376484A1 (en) | 2011-10-19 |
AR074700A1 (es) | 2011-02-02 |
AU2009327133A1 (en) | 2010-06-24 |
BRPI0923178A2 (pt) | 2016-02-16 |
EP2376484B1 (en) | 2015-04-22 |
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