CN104230866A - C-芳基葡糖苷sglt2抑制剂和方法 - Google Patents
C-芳基葡糖苷sglt2抑制剂和方法 Download PDFInfo
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- CN104230866A CN104230866A CN201410345395.9A CN201410345395A CN104230866A CN 104230866 A CN104230866 A CN 104230866A CN 201410345395 A CN201410345395 A CN 201410345395A CN 104230866 A CN104230866 A CN 104230866A
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- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
- C07H7/04—Carbocyclic radicals
Abstract
本发明提供了抑制SGLT2的化合物,其具有式(1)的化学结构。本发明还提供了单独应用SGLT2抑制量的上述化合物或联合应用SGLT2抑制量的上述化合物和其它抗糖尿病试剂或其它治疗试剂来治疗糖尿病和相关疾病的方法。
Description
本申请是中国申请号为201210054766.9、发明名称为“C-芳基葡糖苷SGLT2抑制剂和方法”且申请日为2003年5月15日的专利申请的分案申请。
技术领域
本发明涉及C-芳基葡糖苷,它们是在肠和肾中发现的钠依赖型葡糖转运蛋白(SGLT2)的抑制剂,本发明也涉及单独利用此类C-芳基葡糖苷或利用此类C-芳基葡糖苷和一种、两种或更多种其它类型的抗糖尿病试剂和/或一种、两种或更多种其它类型的治疗试剂如降脂试剂的联合(combination)来治疗糖尿病,尤其是II型糖尿病,以及高血糖症,高胰岛素血症,肥胖症,高甘油三酯血症,X综合症,糖尿病并发症,动脉粥样硬化和相关疾病的方法。
背景技术
世界上有大约1亿人患有II型糖尿病(NIDDM),II型糖尿病的特征是由过量的肝糖产生和外周胰岛素抵抗导致的高血糖,但还未找到II型糖尿病的根本病因。高糖血症被认为是糖尿病并发症发生的主要危险因素,并且很可能直接导致在晚期NIDDM中见到的胰岛素分泌受损。可以预测到使NIDDM患者体内血浆葡萄糖正常化能改善胰岛素作用,并抵消糖尿病并发症的发生。可以预料,肾脏中钠依赖型葡萄糖转运蛋白SGLT2的抑制剂将通过提高葡萄糖的排泄而有助于血浆葡萄糖水平的正常化,也有可能使体重正常化。
也希望能开发出新型、安全和具有口服活性的抗糖尿病试剂以补充现有的包括磺酰脲、噻唑烷二酮、二甲双胍和胰岛素在内的疗法,并避免与应用这些其它的试剂有关的可能副作用。
高血糖症是II型糖尿病(NIDDM)的特点,始终如一地控制糖尿 病患者的血浆葡萄糖水平可抵制在晚期疾病阶段发生糖尿病并发症和β细胞衰竭。血浆葡萄糖通常是在肾的肾小球内过滤,并在近端小管中被主动重吸收。SGLT2似乎是在此部位重吸收葡萄糖的主要转运蛋白。SGLT的特异性抑制剂根皮苷(phlorizin)或密切相关的类似物抑制患有糖尿病的啮齿动物和狗体内的这一重吸收过程,通过促进葡萄糖排泄但不发生血糖过低的副作用,从而使血浆葡萄糖水平正常化。已有报道说采用SGLT2抑制剂对患有Zucker糖尿病的大鼠进行长期(6个月)治疗,改善了对糖血症的胰岛素响应,改善了胰岛素敏感性,延迟了这些动物发生肾病和神经病,而且未检测到肾的病状,血浆中也无电解质失衡。通过提高尿液中葡萄糖的排泄,对糖尿病患者SGLT2的选择性抑制有望实现血浆葡萄糖的正常化,因此改善胰岛素敏感性,并延迟发生糖尿病并发症。
葡萄糖在肾中的重吸收90%发生于肾脏皮质近端小管的起始S1段的上皮细胞中,SGLT2很可能是负责这种重吸收的主要转运蛋白。SGLT2是在肾脏近端小管的起始S1段中主要表达的蛋白,由672个氨基酸组成,含有14个跨膜片断。SGLT2的底物特异性、钠依赖性和定位都是与之前在人体皮质近端肾小管中表征的高容量、低亲和性、钠依赖型葡萄糖转运蛋白的性质相一致的。此外,杂交耗竭(hybrid depletion)研究暗示SGLT2是近端小管的S1段中主要的Na+/葡萄糖转运蛋白,原因是由大鼠肾脏皮质的mRNA编码的所有Na依赖型葡萄糖转运活性实质上完全被大鼠SGLT2特异性的反义寡核苷酸抑制。SGLT2是一些形式的家族性糖尿的候选基因,所述的家族性糖尿是一种遗传异常,其中肾脏葡萄糖重吸收受到不同程度破坏。迄今为止,被研究的这些综合症中没有一个对映到染色体16上的SGLT2基因座。然而,对高度同源的啮齿动物的SGLT进行的研究强烈地暗示了SGLT2是肾中主要的钠依赖型葡萄糖转运蛋白,并暗示了已被测定位置的糖尿基因座编码SGLT2调节子。可以预料,对SGLT2的抑制能通过提高糖尿病患者的葡萄糖排泄而降低血浆葡萄糖水平。
在氨基酸水平上与SGLT2有60%一致性的另一种Na依赖型葡萄糖转运蛋白SGLT1在小肠和近端肾小管的更远部分的S3段中被表达。尽管人体SGLT1和SGLT2具有序列相似性,但它们在生物化学上是显 然不同的。对于SGLT1,Na+与被转运的葡萄糖的摩尔比为2∶1,而对于SGLT2,该比率为1∶1。对于SGLT1和SGLT2,Na+的Km值分别为32和250-300mM。对于SGLT1和SGLT2转运蛋白,吸收葡萄糖和不可代谢的葡萄糖类似物α-甲基-D-葡糖吡喃糖苷(AMG)的Km值情况相似,分别为0.8和1.6mM(葡萄糖)以及0.4和1.5mM(AMG)。然而,这两种转运蛋白在对例如半乳糖的糖类的底物特异性方面确有不同,半乳糖仅是SGLT1的底物。
将SGLT活性的特异性抑制剂根皮苷施予几种患有糖尿病的啮齿动物模型和一种患有糖尿病的犬模型体内,可以促进葡萄糖排泄,降低空腹和非空腹时的血浆葡萄糖,并促进葡萄糖的利用而不带来血糖过低的副作用,从而提供了体内的理论证据。利用根皮苷进行两个星期的治疗,未观察到对血浆离子平衡、肾功能或肾形态带来负面的作用。此外,当采用根皮苷向正常的动物给药时,虽然存在糖尿,但也未观察到血糖过低或其它负面作用。据报道,用针对肾脏SGLT的抑制剂进行6个月的给药(Tanabe Seiyaku),改善了肥胖的NIDDM大鼠模型中的空腹和非空腹血浆葡萄糖、胰岛素分泌和利用,并抵制了肾病和神经病的发病而不带来血糖过低或肾脏副作用。
作为口服药物的根皮苷本身是不吸引人的,原因在于它是一种在消化道中水解成其糖苷配基根皮苷配基的非特异性SGLT1/SGLT2抑制剂,而根皮苷配基是针对葡萄糖易化转运的有效抑制剂。并不希望同时对葡萄糖易化转运蛋白(GLUT)进行抑制,原因是认为此类抑制剂加剧了外周胰岛素抵抗,还会致使CNS中的血糖过低。抑制SGLT1还会带来例如遗传性综合症葡萄糖/半乳糖吸收不良(GGM)等严重的不利后果,在GGM中SGLT1共转运蛋白内的突变导致肠内葡萄糖吸收受到破坏和有生命危险的腹泻和脱水。SGLT2和SGLT1之间的生物化学差别以及它们之间的序列差异程度允许鉴别出选择性的SGLT2抑制剂。
家族性糖尿综合症这种病症中,肠内葡萄糖转运以及肾脏对其它离子和氨基酸的转运都是正常的。尽管有时候排泄的葡萄糖水平相当高(110-114g/天),但家族性糖尿综合症患者似乎是发育正常的,具有正常的血浆葡萄糖水平,并且似乎他们的疾病并未带来的重大的健康 缺陷。这些患者的主要明显症状包括贪食,尿频和烦渴,而肾脏似乎具有正常的结构和功能。因此,从迄今为止获得的证据来看,与正常的个体相比,葡萄糖的肾脏重吸收的缺陷似乎具有最小的长期负面后果。
以下的参考文献公开了用于治疗糖尿病的C-芳基葡糖苷SGLT2抑制剂。
其中A是O,S,NH或(CH2)n,n为0-3;
R1,R2和R2a独立地为氢,OH,OR5,烷基,CF3,OCHF2,OCF3,SR5i或卤素等;
R3和R4独立地为氢,OH,OR5a,O-芳基,OCH2-芳基,烷基,环烷基,CF3,-OCHF2,-OCF3,卤素等。据报道,这些化合物是SGLT2转运蛋白的抑制剂,并因此代表了治疗糖尿病及其并发症的一种方式。
WO98/31697公开了下列结构的化合物
其中Ar包括苯基,联苯基,联苯基甲烷,联苯基乙烷和联苯基醚,R1是糖苷,R2是H,OH,氨基,卤素,羧基,烷基,环烷基,或酰胺基,R3是氢,烷基或酰基,k,m和n独立地为1-4。WO98/31697中所公开的化合物中的一部分包括了以下结构的化合物
其中A为O或(CH2)x,x=0-3;R3是氢,烷基或酰基,n为1-4;R2是氢,烷基,OH,NH2,卤素,CO2H或亚酰胺基(carboxirnide),k为1-4。 公开了这些化合物可用于治疗或预防炎症疾病,自身免疫疾病,感染,癌和癌转移,再灌注紊乱,血栓症,溃疡,创伤,骨质疏松症,糖尿病以及动脉粥样硬化。
发明概述
根据本发明,提供了具有结构I
的C-芳基葡糖苷化合物,包括其药学上可接受的盐,其所有的立体异构体,以及其所有的前体药物酯。
式I的化合物具有作为哺乳动物的肠和肾内的钠依赖型葡萄糖转运蛋白的抑制剂的活性,可用于治疗糖尿病以及糖尿病的微血管和大血管并发症,如视网膜病变、神经病、肾病和伤口愈合。
本发明提供了式I的化合物,应用了所述化合物的药物组合物以及所述化合物的应用方法。
此外,根据本发明,还提供了治疗或延缓包括糖尿病并发症在内的糖尿病,尤其是I型和II型糖尿病,和相关疾病的进程或发生,以及增加高密度脂蛋白水平的方法,在所述方法中将治疗有效量的结构I的化合物施予需要治疗的病人,所述的糖尿病并发症包括视网膜病变、神经病、肾病和伤口愈合延迟,而相关疾病例如为胰岛素抵抗(葡萄糖的动态平衡受到破坏),高血糖症,高胰岛素血症,血液中脂肪酸和甘油水平升高,肥胖症,高脂血症包括高甘油三酯血症,X综合症,动脉粥样硬化和高血压。
此外,根据本发明,还提供了治疗如上文和下文中所述的糖尿病和相关疾病的方法,在所述方法中将结构I的化合物和其它类型的抗糖尿病试剂和/或其它类型的治疗试剂如降血脂试剂的组合以治疗有效量施予需要治疗的病人。
统称为“X综合症”(也称为代谢综合症)的状况、疾病和不适在JohannssonJ.Clin.Endocrinol.Metab.,82,727-34(1999)中有详细描述。
在此使用的术语“其它类型的治疗试剂”是指一种或多种抗糖尿病试剂(非式I的SGLT2抑制剂),一种或多种抗肥胖症试剂,抗高血压试剂,抗血小板试剂,抗动脉粥样硬化的试剂和/或一种或多种降脂试剂(包括抗动脉粥状硬化试剂)。
在本发明的上述方法中,所使用的结构I的化合物与一种,两种或更多种其它类型的抗糖尿病试剂和/或一种,两种或更多种其它类型的治疗试剂(取决于实施方式)的重量比的范围在约0.01∶1到约300∶1之间,优选为从约0.1∶1到约10∶1。
发明详述
按照下面的反应流程以及其描述,可以制备出本发明的式I的化合物,其中温度均用摄氏温度表示。
如流程1所示,在溶剂中用碱例如LiOH或NaOH处理式II的化合物,可制备得到本发明的式I的化合物,所述溶剂如比例为1∶2∶3的H2O/THF/MeOH或含水MeOH或含水EtOH。
式II的化合物(一种易于结晶的新型中间体)提供了一种纯化式Ia的粗制化合物的方便手段,所述粗制化合物是α和β差向异构体的混合物。
在含有吡啶和催化剂如二甲基氨基吡啶(DMAP)的溶剂如CH2Cl2中用Ac2O处理式Ia的化合物,可制备得到通式II的化合物。
在路易斯酸催化剂如BF3·Et2O存在的情况下,于-10℃采用还原剂如Et3SiH在溶剂如1∶1的CH2Cl2/MeCN中还原式III的化合物,可制备得到通式Ia的化合物。
作为选择,式II的化合物也可通过这样的方法制备:首先用Ac2O在含有碱例如Hunig’s碱或Et3N和催化剂如DMAP的溶剂如甲苯或CH2Cl2中乙酰化式III的化合物,产生式IV的化合物。
随后,在含有1当量H2O和路易斯酸催化剂如BF3·Et2O的溶剂中,采用还原剂如Et3SiH在20℃进行处理,可将式IV转化为式II的化合物。
式III的化合物可按照流程2所示的方法制备得到:1)在-75℃,向含有式VI的全硅烷化葡糖酸内酯的溶剂如甲苯中加入式V的芳基锂的冷THF溶液。接着,在30分钟之后加入质子酸如甲基磺酰酸(MSA)的甲醇溶液,在20℃搅拌溶液,直到中间体乳醇完全转化为式III的化合物。
在含有碱如N-甲基吗啉的溶剂如THF中,用硅烷化试剂如氯代三甲基硅烷处理商购的D-葡糖酸内酯,可制备得到式VI的化合物。
在-75℃,在溶剂如THF中用烷基锂例如n-丁基锂或t-丁基锂处理式VII的化合物,可制备得到式V的化合物。
在路易斯酸催化剂如BF3·Et2O存在的条件下,于0-20℃,在溶剂如1∶1的CH2Cl2/MeCN中用还原剂如Et3SiH处理式VIII的化合物,可制备得到式VII的化合物。
在含有一当量的路易斯酸如AlCl3或AlBr3的溶剂如CH2Cl2中,用2-氯-5-溴苯甲酰氯对商购的乙氧基苯(苯乙醚)进行Friedel-Craft酰化作用,可制备得到式VIII的化合物。
在含有催化量的DMF的溶剂如CH2Cl2中,用草酰氯处理商购的2-氯-5-溴苯甲酸,可容易地制备得到2-氯-5-溴苯甲酰氯。
如下所列的是本发明的说明书中所采用的各种术语的定义。这些定义用于在整个说明书中独立使用的术语或作为更大基团的一部分来使用的术语(除非在特殊的例子中另加限定)。
在此采用了以下缩写:
Ph=苯基
Bn=苄基
t-Bu=叔丁基
Me=甲基
Et=乙基
TMS=三甲基硅烷基
TBS=叔丁基二甲基硅烷基
THF=四氢呋喃
Et2O=二乙醚
EtOAc=乙酸乙酯
DMF=二甲基甲酰胺
MeOH=甲醇
EtOH=乙醇
i-PrOH=异丙醇
HOAc或AcOH=乙酸
TFA=三氟乙酸
i-Pr2NEt=二异丙基乙胺
Et3N=三乙胺
DMAP=4-二甲基氨基吡啶
NaBH4=硼氢化钠
n-BuLi=n-丁基锂
Pd/C=碳上的钯
KOH=氢氧化钾
NaOH=氢氧化钠
LiOH=氢氧化锂
K2CO3=碳酸钾
NaHCO3=碳酸氢钠
Ar=氩
N2=氮
min=分钟
h或hR=小时
L=升
mL=毫升
μL=微升
g=克
mg=毫克
mol=摩尔
mmol=毫摩尔
meq=毫当量
RT=室温
sat或sat′d=饱和的
aq.=含水的
TLC=薄层色谱
HPLC=高效液相色谱
LC/MS=高效液相色谱/质谱
MS或Mass Spec=质谱
NMR=核磁共振
mp=熔点
除非另外指明,在此单独使用或作为其它基团的一部分而使用的术语“低级烷基”包括含有1到8个碳的直链和支链烃,在此单独使用或作为其它基团的一部分而使用的术语“烷基”和“烷”包括在正链中含有1-20个碳原子,优选是1-10个碳原子,更优选是1-8个碳原子的直链或支链烃,例如甲基,乙基,丙基,异丙基,丁基,叔丁基,异丁基,戊基,己基,异己基,庚基,4,4-二甲基戊基,辛基,2,2,4-三甲基戊基,壬基,癸基,十一烷基,十二烷基,及其各种支链异构体和类似的基因,以及包括1-4个取代基的此类基团,所述的取代基例如卤素,如F、Br、Cl或I或CF3,烷基,烷氧基,芳基,芳氧基,芳基或二芳基,芳烷基,芳基烷氧基,烯基,炔基,环烷基,环烯基,环烷基烷基,环烷基烷氧基,任意取代的氨基,羟基,羟基烷基,酰基,烷酰基,杂芳基,杂芳氧基,环杂烷基,芳基杂芳基,芳基烷氧基羰基,杂芳基烷基,杂芳基烷氧基,芳氧基烷基,芳氧基芳基,烷基氨基,烷酰基氨基,芳基羰基氨基,硝基,氰基,硫醇,卤代烷基,三卤代烷基和/或硫代烷基。
除非另外指明,在此单独使用或作为其它基团的一部分而使用的术语“环烷基”包括含有1-3个环的饱和或部分不饱和(含有1-2个双键)的环状烃,包括单环烷基,双环烷基和三环烷基,其含有3-20个构成所述环的碳原子,优选是3-10个碳原子,且其可与1或2个称为芳基的芳香环相稠合,所述环烷基包括环丙基,环丁基,环戊基,环己基,环庚基,环辛基,环癸基和环十二烷基,环己烯基,
这些基团中的任何一个都可以被1-4个取代基选择性地取代,所述取代 基例如卤素,烷基,烷氧基,羟基,芳基,芳氧基,芳烷基,环烷基,烷基氨基,烷酰基氨基,氧,酰基,芳基羰基氨基,氨基,硝基,氰基,硫醇和/或硫代烷基和/或任何烷基取代基。
在此单独使用或作为其它基团的一部分而使用的术语“烷酰基”是指与羰基相连的烷基。
在此单独使用或作为其它基团的一部分而使用的术语“卤素”或“卤”是指氯,溴,氟和碘,优选为氯和氟。
术语“金属离子”是指碱金属离子如钠、钾或锂,以及碱土金属离子如镁和钙,还有锌和铝。
除非另外指明,在此单独使用或作为其它基团的一部分而使用的术语“芳基(aryl)”或“芳基(Aryl)”是指在环部分含有6-10个碳原子的单环或双环芳香基团(如苯基或萘基,包括1-萘基和2-萘基),可选择性地包括1-3个稠合到碳环或杂环(例如芳基,环烷基,杂芳基或环杂烷基环如
上的其它环,并可在可利用的碳原子上选择性地用1,2或3个选自下列基团的基团取代:氢,卤素,卤代烷基,烷基,卤代烷基,烷氧基,卤代烷氧基,烯基,三氟甲基,三氟甲氧基,炔基,环烷基-烷基,环杂烷基,环杂烷基烷基,芳基,杂芳基,芳烷基,芳氧基,芳氧基烷基,芳基烷氧基,烷氧基羰基,芳基羰基,芳基烯基,氨基羰基芳基,硫代芳基,芳基亚磺酰基,含氮芳基,杂芳基烷基,杂芳基烯基,杂芳基杂芳基,杂芳基氧基,羟基,硝基,氰基,氨基,其氨基包括1或2个取代基的取代氨基(取代基为烷基,芳基或定义中所提到的任何其它芳基化合物),硫醇,硫代烷基,硫代芳基,硫代杂芳基,芳基 硫代烷基,烷氧基芳硫基,烷基羰基,芳基羰基,烷基氨基羰基,芳基氨基羰基,烷氧基羰基,氨基羰基,烷基羰基氧基,芳基羰基氧基,烷基羰基氨基,芳基羰基氨基,芳基亚磺酰基,芳基亚磺酰基烷基,芳基磺酰基氨基和芳基磺酰基氨基羰基,和/或在此提出的任何烷基取代物。
除非另外指出,在此单独使用或作为其它基团的一部分而使用的术语“低级烷氧基”,“烷氧基”,“芳氧基”或“芳烷基氧基”包括与氧原子连接的任何上述的烷基,芳烷基或芳基基团。
除非另外指出,在此单独使用或作为其它基团的一部分而使用的术语“低级硫代烷基”,“硫代烷基”,“硫代芳基”或“芳烷基硫基”包括与硫原子连接的任何上述的烷基,芳烷基或芳基基团。
在此使用的术语“多卤代烷基”是指包括2到9个,优选2到5个例如F或Cl,优选F的卤素取代基的上述“烷基”基团,例如CF3CH2,CF3或CF3CF2CH2。
在此使用的术语“多卤代烷氧基”是指包括2到9个,优选2到5个例如F和Cl,优选F的卤素取代基的上述“烷氧基”或“烷基氧基”基团,例如CF3CH2O,CF3O或CF3CF2CH2O。
在此使用的术语“前体药物酯”包括利用本领域技术人员公知的方法,由式I的化合物的一个或多个羟基与烷基,烷氧基或芳基取代的酰化试剂反应产生乙酸酯,三甲基乙酸酯,甲基碳酸酯,苯甲酸酯以及类似物而形成的酯和碳酸酯。此外,有关羧酸酯和磷酸酯的前体药物酯在本领域是已知的,它们含有如甲基,乙基,苄基等等。
这样的前体药物酯的例子包括:
在结构I的化合物为酸形式的情况下,它们可形成药学上可接受的盐,例如碱金属盐如钠、钾或锂盐,碱土金属盐如钙或镁盐,以及锌或铝和其它阳离子如铵根、胆碱、二乙醇胺、赖氨酸(D或L)、乙二 胺、叔丁基胺、叔辛基胺、三-(羟甲基)氨基甲烷(TRIS)、N-甲基葡糖胺(NMG)和脱氢松香基胺形成的盐。
本发明中化合物的所有立体异构体都是可预期的,包括混合物的形式,纯化的或基本纯化的形式。本发明的化合物可以在包括任一R取代基在内的任何碳原子处具有不对称中心。因此,式I的化台物可以对映体或非对映体的形式存在,或以对映体和非对映体的混合物的形式存在。制备方法可利用外消旋体,对映体或非对映体作为原料。当制备非对映的或对映的产物时,可通过常规方法如色谱法或分级结晶而进行分离。
如果需要,结构I的化合物可与一种或多种其它类型的抗糖尿病试剂和/或一种或多种其它类型的治疗试剂联合使用,它们可以相同的剂型口服给药,独自的口服剂型给药,或通过注射给药。
可以选择与式I的SGLT2抑制剂联合使用的其它类型的抗糖尿病试剂可以是1,2,3或更多种抗糖尿病试剂或抗高血糖试剂,包括胰岛素促分泌剂或胰岛素增敏剂,或优选具有不同于SGLT2抑制的作用机理的抗糖尿病试剂,可包括双胍,磺酰脲,葡糖苷酶抑制剂,PPARγ激动剂如噻唑烷二酮,aP2抑制剂,PPARα/γ双激活剂,二肽酰肽酶IV(DP4)抑制剂,和/或格列奈类药物(meglitinides),以及胰岛素,胰高血糖素样肽-1(GLP-1),PTP1B抑制剂,糖原磷酸化酶抑制剂和/或葡糖-6-磷酸酶抑制剂。
可以选择与式I的SGLT2抑制剂联合使用的其它类型的治疗试剂包括抗肥胖症试剂,抗高血压试剂,抗血小板试剂,抗动脉粥样硬化试剂和/或降脂试剂。
式I的SGLT2抑制剂也可选择与用于治疗糖尿病并发症的试剂联合使用。这些试剂包括PKC抑制剂和/或AGE抑制剂。
相信联合使用结构I的化合物和1,2,3或更多种的其它抗糖尿病试剂所产生的抗高血糖效果优于单独使用这些药物的每一种的可能效果,也优于由这些药物产生的抗高血糖效果的累加。
其它的抗糖尿病试剂可以是口服的抗高血糖试剂,优选双胍如二甲双胍或苯乙双胍或它们的盐,优选盐酸二甲双胍。
在所述的其它抗糖尿病试剂为双胍的情况下,所用的结构I的 化合物与双胍的重量比的范围为从约0.01∶1到约100∶1,优选为从约0.1∶1到约5∶1。
其他的抗糖尿病试剂也可优选为磺酰脲,如格列本脲(glyburide,也称为glibenclamide),格列美脲(glimepiride,公开于专利号为4,379,785的美国专利中),格列吡嗪(glipizide),格列齐特(gliclazide)或氯磺丙脲,其它公知的作用于β细胞的ATP依赖型通道的磺酰脲或其它抗高血糖试剂,优选格列本脲和格列吡嗪,它们可以相同的或不同的口服剂型给药。
所用的结构I的化合物与磺酰脲的重量比的范围为从约0.01∶1到约100∶1,优选为从约0.2∶1到约10∶1。
口服的抗糖尿病试剂还可以是葡糖苷酶抑制剂,例如阿卡波糖(acarbose)(公开于专利号为4,904,769的美国专利中)或米格列醇(miglitol)(公开于专利号为4,639,436的美国专利中),它们可以相同的或不同的口服剂型给药。
所用的结构I的化合物与葡糖苷酶抑制剂的重量比的范围为从约0.01∶1到约100∶1,优选为从约0.5∶1到约50∶1。
结构I的化合物可与PPARγ激动剂如噻唑烷二酮口服抗糖尿病试剂或其它胰岛素增敏剂(在NIDDM病人体内具有胰岛素敏化效果)联合使用,如曲格列酮(troglitazone,Warner-Lambert′s. 公开于专利号为4,572,912的美国专利中),罗格列酮(rosiglitazone,SKB),吡咯列酮(pioglitazone,Takeda),Mitsubishi的MCC-555(公开于专利号为5,594,016的美国专利中),Glaxo-Welcome的GL-262570,英格列酮(englitazone,CP-68722,Pfizer)或达格列酮(darglitazone,CP-86325,Pfizer),沙格列酮(isaglitazone,MIT/J&J),JTT-501(JPNT/P&U),L-895645(Merck),R-119702(Sankyo/WL),NN-2344(Dr.Reddy/NN)或YM-440(Yamanouchi),优选罗格列酮和吡咯列酮。
所用的结构I的化合物与噻唑烷二酮的重量比范围为从约0.01∶1到约100∶1,优选为从约0.2∶1到约10∶1。
用量少于150mg口服抗糖尿病试剂的磺酰脲和噻唑烷二酮可与结构I的化合物一起并入一个单片剂中。
结构I的化合物也可与抗高血糖试剂如胰岛素,或与胰高血糖素样肽-1(GLP-1)如GLP-1(1-36)酰胺,GLP-1(7-36)酰胺,GLP-1(7-37)(如在授予Habener的美国专利5,614,492中公开的,将该文献列于此处以供参考),以及AC2993(Amylen)和LY-315902(Lilly)联合使用,它们可通过注射,鼻内,或通过透皮或口腔设备进行给药。
在存在二甲双胍,磺酰脲如格列本脲,格列美脲,格列比脲(glipyride),格列吡嗪,氯磺丙脲和格列齐特,以及葡糖苷酶抑制剂如阿卡波糖或米格列醇或胰岛素(可注射,经肺,经口腔或口服)的情况下,它们可在按照上面描述在配方中加以采用,用量和剂量如Physician′s Desk Reference(PDR)中所述。
在存在二甲双胍或其盐的情况下,二甲双胍或其盐的使用量的范围为从约500mg到约2000mg/天,可以每日以单一的或分开的剂量进行1到4次给药。
在存在噻唑烷二酮抗糖尿病试剂的情况下,噻唑烷二酮抗糖尿病试剂的使用量范围为从约0.01mg到约2000mg/天,可以每日以单一的或分开的剂量进行1到4次给药。
当存在胰岛素时,胰岛素可在配方中加以采用,用量和剂量如Physician′s Desk Reference中所述。
当存在GLP-1肽的情况下,GLP-1肽可以口服配方的形式给药,可以通过鼻内给药或通过肠胃外的方式给药,如专利号为5,346,701(TheraTech),5,614,492和5,631,224的美国专利所述,将这些文献列于此以作参考。
其它的抗糖尿病试剂也可以是PPARα/γ双激动剂,例如AR-HO39242(Astra/Zeneca),GW-409544(Glaxo-Wellcome),KRP297(Kyorin Merck)以及在Murakami等,″A Novel Insulin Sensitizer Acts As a Coligand for Peroxisome Proliferation-Activated Receptor Alpha(PPAR alpha)and PPAR gamma.Effect on PPAR alpha Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats",Diabetes47,1841-1847(1998)中和在1999年9月22日递交的申请号为60/155,400的美国临时申请(代理人文件号 LA29)中公开的那些试剂,将这些文献的内容在此整入以作参考,采用其中所列的剂量,而优选采用其中指定的优选化合物。
其它的抗糖尿病试剂可以是例如在1999年9月7日递交的申请序列号为09/391,053的美国专利申请以及在1999年4月15日递交的申请号为60/127,745的美国临时申请(代理人文件号LA27*)中所公开的aP2抑制剂,采用其所列的剂量。优选的化合物为以上专利申请中指定为优选的化合物。
其它的抗糖尿病试剂可以是例如在WO99/38501,WO99/46272,WO99/67279(PROBIODRUG),WO99/67278(PROBIODRUG),WO99/61431(PROBIODRUG)中所公开的DP4抑制剂;在Hughes等,Biochemistry,38(36),11597-11603,1999中所公开的NVP-DPP728A(1-[[[2-[(5-氰基吡啶-2-基)氨基]乙基]氨基]乙酰基]-2-氰基-(S)-吡咯烷)(Novartis)(优选);TSL-225(色氨酰-1,2,3,4-四氢异喹啉-3-羧酸)(公开于Yamada等,Bioorg.&Med.Chem.Lett.8(1998)1537-1540);在Ashworth等,Bioorg.&Med.Chem.Lett.,Vol.6,No.22,1163-1166和2745-2748(1996)中所公开的2-cyanopyrrolidides和4-cyanopyrrolidides,采用上述参考文献中所列的剂量。
可选择与本发明的式I的化合物联合使用的格列奈类药物可以是瑞格列奈(repaglinide),那格列奈(nateglinide)(Novartis)或KAD1229(PF/Kissei),优选瑞格列奈。
所用的式I的SGLT2抑制剂与格列奈类药物,PPARγ激动剂,PPARα/γ双激动剂,aP2抑制剂或DP4抑制剂的重量比范围为从约0.01∶1到约100∶1,优选为从约0.2∶1到约10∶1。
可选择与本发明的式I的化合物联合使用的降血脂类试剂或降低脂质的试剂可包括MTP抑制剂,HMG CoA还原酶抑制剂,角鲨烯合成酶抑制剂,纤维酸衍生物,ACAT抑制剂,脂加氧酶抑制剂,胆固醇吸收抑制剂,回肠Na+/胆汁酸协同转运蛋白抑制剂,LDL受体活性的向上调节物,胆汁酸螯合剂,和/或烟酸及其衍生物中的1,2,3或者更多种。
在此使用的MTP抑制剂包括专利号为5,595,872的美国专利, 专利号为5,739,135的美国专利,专利号为5,712,279的美国专利,专利号为5,760,246的美国专利,专利号为5,827,875的美国专利,专利号为5,885,983的美国专利以及1998年10月20日递交的申请序列号为09/175,180的美国专利申请,现专利号为5,962,440的美国专利中所公开的MTP抑制剂。优选的是在以上各份专利和申请中所公开的优选MTP抑制剂。将所有的上述美国专利和申请列于此以作参考。
降血脂类试剂可以是HMG CoA还原酶抑制剂,其包括但不限于如专利号为3,983,140的美国专利中所公开的美伐他汀(mevastatin)和相关的化合物,如专利号为4,231,938的美国专利中所公开的洛伐他汀(lovastatin,莫维诺林(mevinolin))和相关的化合物,如专利号为4,346,227的美国专利中所公开的普伐他汀(pravastatin)和相关的化合物,如专利号为4,448,784和4,450,171的美国专利中所公开的辛找他汀(simvastatin)和相关的化台物。降血脂类试剂也可以是申请号为60/211,594和60/211,595的美国临时专利申请中所公开的化合物。可在此使用的其它HMG CoA还原酶抑制剂包括但不限于专利号为5,354,772的美国专利中所公开的氟伐他汀(fluvastatin),专利号为5,006,530和5,177,080的美国专利中所公开的西立伐他汀(cerivastatin),专利号为4,681,893,5,273,995,5,385,929和5,686,104的美国专利中所公开的阿伐他汀(atorvastatin),专利号为5,011,930的美国专利中所公开的埃塔伐他汀(atavastatin)(Nissan/Sankyo的尼伐他汀(nisvastatin)(NK-104)),专利号为5,260,440的美国专利中所公开的Shionogi-Astra/Zeneca威伐他汀(visastatin)(ZD-4522),以及在专利号为5,753,675的美国专利中公开的相关的斯达汀(statin)化合物,专利号为4,613,610的美国专利中所公开的甲基二羟戊酮(mevalonolactone)衍生物的吡唑类似物,公布号为WO86/03488的PCT申请中所公开的甲基二羟戊酮衍生物的茚类似物,专利号为4,647,576的美国专利中所公开的6-[2-(取代-吡咯-1-基)-烷基]吡喃-2-酮和其衍生物,Searle的SC-45355(一种3-代戊二酸衍生物)二氯乙酸酯,公布号为WO 86/07054的PCT申请中所公开的甲基二羟 戊酮的咪唑类似物,专利号为2,596,393的法国专利中所公开的3-羧基-2-羟基-丙烷-磷酸衍生物,申请号为0221025的欧洲专利申请中所公开的2,3-二取代吡咯,呋喃和噻吩衍生物,专利号为4,686,237的美国专利中所公开的甲基二羟戊酮的萘基衍生物,专利号为4,499,289的美国专利中所公开的八氢萘,公开号为0,142,146 A2的欧洲专利申请中所公开的莫维诺林(洛伐他汀)的酮类衍生物,以及专利号为5,506,219和5,691,322的美国专利申请中所公开的喹啉和吡啶衍生物。
此外,GB2205837中也公开了适用于本发明的用于抑制HMG CoA还原酶的磷酸化合物。
适用于本发明的角鲨烯合成酶抑制剂包括但不限于专利号为5,712,396的美国专利中所公开的α-膦酰基-磺酸酯,在Biller等,J.Med.Chem.,1988,Vol.31,No.10,1869-1871页中所公开的包括类异戊二烯(氧膦基-甲基)磷酸酯的那些角鲨烯合成酶抑制剂,以及例如在专利号为4,871,721和4,924,024的美国专利中和Biller,S.A.,Neuenschwander,K.,Ponpipom,M.M.和Poulter,C.D.,Current Pharmaceutical Design,2,1-40(1996)中所公开的其它公知的角鲨烯合成酶抑制剂。
此外,其它适用于本发明的角鲨烯合成酶抑制剂包括如在P.Ortiz de Montellano等,J.Med.Chem.,1977,20,243-249中所公开的萜类焦磷酸酯,Corey和Volante,J.Am.Chem.Soc.,1976,98,1291-1293中所公开的法呢基二磷酸酯类似物A和前角鲨烯焦磷酸酯(PSQ-PP)类似物,McClard,R.W.等,J.A.C.S.,1987,109,5544中所报道的氧膦基磷酸酯,以及Capson,T.L.,博士论文,1987年6月,犹他大学医药化学系,摘要,目录,第16,17,40-43,48-51,总结中所报道的环丙烷。
适用于本发明的其它降血脂类试剂包括但不限于纤维酸衍生物,如非诺贝特(fenofibrate)、吉非贝齐(gemfibrozil)、安妥明(clofibrate)、苯扎贝特(bezafibrate)、环丙贝特(ciprofibrate)、克利贝特(clinofibrate)等;丙丁酚(Probucol),以及专利号为3,674,836的美国专利中所公开的相关化合物,优选丙丁酚和吉非贝齐; 胆汁酸螯合剂如考来烯胺(cholestyramine),考来替泊(colestipol)和DEAE-Sephadex(),以及lipostabil(Rhone-Poulenc),Eisai E-5050(一种N-取代乙醇胺衍生物);伊马昔尔(imanixil)(HOE-402);四氢泥泊司他汀(tetrahydrolipstatin,THL),istigmastanylphos-phorylcholine(SPC,Roche),氨基环糊精(Tanabe Seiyoku),Ajinomoto AJ-814(甘菊环烃衍生物),甲亚油酰胺(Sumitomo),Sandoz58-035;美国氰胺公司CL-277,082和CL-283,546(二取代脲衍生物),烟酸,阿西莫司(acipimox),阿昔呋喃(acifran),新霉素,对-氨基水杨酸,阿司匹林,专利号为4,759,923的美国专利中所公开的聚(二烯丙基甲胺)衍生物,在专利号为4,027,009的美国专利中所公开的季胺聚(氯化二烯丙基乙基铵)和紫罗烯,以及其它公知的降低血清胆固醇的试剂。
其它的降血脂类试剂可为ACAT抑制剂,如公开于Drugs of the Future24,9-15(1999),(阿伐麦布(Avasimibe));″The ACAT inhibitor,CL-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters",Nicolosi等,Atherosclerosis (Shannon,Irel).(1998),137(1),77-85;"The pharmacological profile of FCE 27677:a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoB100-containing lipoprotein",Ghiselli,Giancarlo,Cardiovasc.Drug Rev.(1998),16(1),16-30;″RP 73163:A bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor″,Smith,C.,等,Bioorg.Med.Chem.Lett.(1996),6(1),47-50;"ACAT inhibitors:physiologic mechanisms for hypolipidemic and anti-atherosclerotic activities in experimental animals",Krause等,Editor(s):Ruffolo,Robert R.,Jr.;Hollinger,Mannfred A.,Inflammation:Mediators Pathways(1995),173-98,Publisher:CRC,Boca Raton,Fla.;″ACAT inhibitors:potential anti-atherosclerotic agents",Sliskovic等,Curr.Med.Chem.(1994),1(3),204-25;″Inhibitors of acyl-CoA:cholesterol O-acyl transferase(ACAT)as hypocholesterolemic agents.6.The first water-soluble ACAT inhibitor with lipid-regulating activity.Inhibitors of acyl-CoA:cholesterol acyltransferase(ACAT).7.Development of a series of substituted N-phenyl-N’-[(l-phenylcyclopentyl)methyl]ureas with enhanced hypocholesterolemic activity",Stout等,Chemtracts:Org.Chem.(1995),8(6),359-62中所公开的ACAT抑制剂,或TS-962(Taisho医药公司)。
降血脂类试剂可以是LD2受体活性的向上调节物,如MD-700(Taisho医药公司)和LY295427(Eli Lilly)。
降血脂类试剂可以是胆固醇吸收抑制剂,优选Schering-Plough的SCH48461,以及在Atherosclerosis 115,45-63(1995)和J.Med.Chem.41,973(1998)中所公开的那些降血脂类试剂。
降血脂类试剂可以是例如在Drugs of the Future,24,425-430(1999)中所公开的回肠Na+/胆汁酸协同转运蛋白抑制剂。
优选的降血脂类试剂为普伐他汀,洛伐他汀,辛找他汀,阿伐他汀,氟伐他汀,西立伐他汀,埃塔伐他汀和罗素他汀(rosuvastatin)。
将以上提及的美国专利在此引入以作参考。用量和剂量按照Physician′s Desk Reference和/或以上所列的专利而采用。
所用的本发明的式I的化合物与降血脂类试剂(在存在的情况下)的重量比的范围为从约500∶1到约1∶500,优选从约100∶1到约1∶100。
必须根据病人的年龄、重量和状况,以及给药途径、剂型、疗程和预期的效果来仔细选择给药剂量。
降血脂类试剂的剂量和配方如在以上讨论的各个专利和申请中所公开的一样。
其它在合适的情况下可采用的降血脂类试剂的剂量和配方可与最近一版Physicians′Desk Reference中所述的一样。
对于口服给药,可采用用量范围从约0.01mg/kg到约500mg,优选从约0.1mg到约100mg的MTP抑制剂每天给药1到4次而获得满意的效果。
优选的口服剂型例如片剂或胶囊可以含有MTP抑制剂,其量为约1到约500mg,优选为约2到约400mg,更优选约5到约250mg, 每天给药1到4次。
对于口服给药,采用如Physician′s Desk Reference中所述的剂量,如剂量范围为从约1到2000mg,优选从约4到200mg的HMGCoA还原酶抑制剂如普伐他汀,洛伐他汀,辛找他汀,阿伐他汀,氟伐他汀或西立伐他汀,可获得满意的效果。
可采用的角鲨烯合成酶抑制剂的剂量范围为从约10mg到约2000mg,优选从约25mg到约200mg。
优选的口服剂型例如片剂或胶囊可以包含HMG CoA还原酶抑制剂,其量为约0.1到约100mg,优选为约5到约80mg,更优选约10到约40mg。
优选的口服剂型例如片剂或胶囊可以包含角鲨烯合成酶抑制剂,其量为从约10到约500mg,优选从约25到约200mg。
其它的降血脂类试剂还可以是脂加氧酶抑制剂,包括15-脂加氧酶(15-LO)抑制剂,例如WO 97/12615中公开的苯并咪唑衍生物,WO97/12613公开的15-LO抑制剂,WO 96/38144公开的异噻唑酮,以及在Sendobry等,"Attenuation of diet-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties,Brit.J.Pharmacology(1997)120,1199-1206和Cornicelli等,″15-Lipoxygenase and its Inhibition:A Novel Therapeutic Target for Vascular Disease",Current Pharmaceutical Design,1999,5,11-20中公开的15-LO抑制剂。
式I的化合物可以与降血脂类试剂以相同的口服剂型或以各自的口服剂型一起服用。
上述的组合物可以按照上述的剂型以单一的或是分开的剂量每天给药1到4次。在开始时对病人用低剂量组合给药,然后逐渐到高剂量组合给药是可取的。
优选的降血脂类试剂是普伐他汀,辛找他汀,洛伐他汀,阿伐他汀,氟伐他汀,西立伐他汀,埃塔伐他汀和罗素他汀。
当选择与式I的SGLT2抑制剂一起使用的其它类型治疗剂为1,2,3或更多种的抗肥胖症试剂时,这样的抗肥胖症试剂可包括β3肾上腺素能激动剂,脂肪酶抑制剂,血清素(和多巴胺)再吸收 抑制剂,甲状腺受体β药物,食欲抑制剂,NPY拮抗剂,瘦素(leptin)类似物和/或MC4激动剂。
可选择与式I的化合物联合使用的β3肾上腺素能激动剂可以是AJ9677(Takeda/Dainippon),L750355(Merck)或CP331648(Pfizer)或其它例如在专利号为5,541,204,5,770,615,5,491,134,5,776,983和5,488,064的美国专利所公开的β3激动剂,优选AJ9677,L750355和CP331648。
可选择与式I的化合物联合使用的脂肪酶抑制剂可以是奥利司他(orlistat)或ATL-962(Alizyme),优选奥利司他。
可选择与式I的化合物联合使用的血清素(和多巴胺)再吸收抑制剂可为西布曲明(sibutramine),托吡酯(topiramate,Johnson&Johnson)或阿索开(axokine,Regeneron),优选西布曲明和托吡酯。
可选择与式I的化合物联合使用的甲状腺受体β化合物可以是WO97/21993(U.Cal SF),WO99/00353(KaroBio)和GB98/284425(KaroBio)中所公开的甲状腺受体配体,优选KaroBio的申请中的化合物。
可选择与式I的化合物联合使用的食欲抑制剂可以是右旋安菲他明(dexamphetamine),芬特明(phentermine),苯丙醇胺或马吲哚(mazindol),优选右旋安菲他明。
上述的各种抗肥胖症试剂可以与式I的化合物为相同的剂型,或为不同的剂型,可以采用本领域公知的或PDR中的剂量和疗程。
可选择与本发明联合使用的抗血小板试剂的例子包括阿昔单抗(abciximab),噻氯匹啶(ticlopidine),埃替非巴肽(eptifibatide),双嘧哌胺醇(dipyridamole),阿司匹林,阿那格雷(anagrelide),替罗非班(tirofiban)和/或氯吡格雷(clopidogrel)。
可选择与本发明联合使用的抗高血压试剂的例子包括ACE抑制剂,钙拮抗剂,α-阻断剂,利尿剂,中心作用试剂(centrallyacting agents),血管紧张素-II拮抗剂,β-阻断剂和血管活性肽酶抑制剂。
ACE抑制剂的例子包括赖诺普利(lisinopril),依拉普利(enalapril),喹那普利(quinapril),苯那普利(benazepril),福 辛普利(fosinopril),雷米普利(ramipril),卡托普利(captopril),依那普利拉(enalaprilat),莫昔普利(moexipril),群拉普利(trandolapril)和培哚普利(perindopri);钙拮抗剂的例子包括氨氯地平(amlodipine),地尔硫卓(diltiazem),硝苯吡啶(nifedipine),异搏定(verapamil),非洛地平(felodipine),尼索地平(nisoldipine),伊拉地平(isradipine)和尼卡地平(nicardipine);α-阻断剂的例子包括特拉唑嗪(terazosin),多沙唑嗪(doxazosin)和哌唑嗪(prazosin);利尿剂的例子包括氢氯噻嗪(hydrochlorothiazide),托拉塞米(torasemide),呋塞米(furosemide),螺旋内酯固酮(spironolactone)和吲达帕胺(indapamide);中心作用试剂的例子包括可乐定(clonidine)和胍法新(guanfacine);血管紧张素-II拮抗剂的例子包括洛沙坦(losartan),缬沙坦(valsartan),伊贝沙坦(irbesartan),坎地沙坦(candesartan)和替米沙坦(telmisartan);β-阻断剂的例子包括美托洛尔(metoprolol),普萘洛尔(propranolol),阿替洛尔(atenolol),卡维地洛(carvedilol)和梭达罗(sotalol);血管活性肽酶抑制剂的例子包括奥帕曲拉(omapatrilat)和gemopatrilat。
在实施本发明的方法时,可以采用与药物载体或稀释剂相联合的药物组合物,所述药物组合物包含有结构I的化合物,含有或不含其它的抗糖尿病试剂和/或降血脂类试剂,或其它类型的治疗剂。可利用常规的固体或液体载体或稀释剂和适于所需的给药方式的药物添加剂来配制药物组合物。所述化合物可以通过口服途径,如以片剂,胶囊,颗粒或粉末的形式向包括人类,猴子,狗等在内的哺乳动物给药,或可以通过肠胃外途径以如可注射制备物的形式进行给药,或可以通过鼻内或经皮的药贴进行给药。对成年人的剂量优选为每天10到2,000 mg,这一剂量可以单剂或分开剂每天给药1到4次。
在无菌的条件下将250mg结构I的化合物放入小瓶中,进行冻干和密封,得到典型的可注射制剂。为了使用,将小瓶内的物质和2 mL生理盐水相混合,得到可注射的制剂。
可采用下列的分析系统测定本发明化合物的SGLT2抑制剂活 性。
分析SGLT2活性
应用标准的分子生物学技术,通过人类肾脏mRNA的反转录和扩增,对人类SGLT2(GeneBank号M95549)的mRNA序列进行克隆。所述cDNA序列被稳定地转染到CHO细胞中,基本上按照Ryan等(1994)中所述的方法分析克隆的SGLT2活性。在Ryan等描述的方法基础上,进行如下改动,评估克隆选择细胞系中的SGLT2活性抑制。细胞在96孔板上生长2-4天,直至每个孔中含有75,000或30,000个细胞,这些细胞存在于F-12营养混合物(Ham′s F-12),10%胎牛血清,300μg/ml Geneticin和青霉素-链霉素中。当细胞汇合时,用10mM Hepes/Tris,pH7.4,137mM N-甲基-D-葡糖胺,5.4mMKC1,2.8mM CaCl2,1.2mM MgSO4洗涤两次。然后在37℃,在10mM Hepes/Tris,pH7.4,137mM NaCl,5.4mM KCl,2.8mM CaCl2,1.2mM MgSO4中使10μm[14C]AMG和10μm抑制剂(最终的DMSO=0.5%)与细胞温育1.5小时。用含有0.5mM根皮苷的冷1XPBS使吸收分析停止,然后用0.1%NaOH裂解细胞。加入MicroScint闪烁液体之后,摇动细胞1小时,然后在TopCount闪烁计数器上测定[14C]AMG的量。分别在NaCl存在和缺乏的情况下测定对照组。为确定ECs0值,在合适的响应范围的2个对数间隔内采用10个抑制剂浓度,并在整个板的范围内对三份同样的板取平均。
Ryan MJ,Johnson G,KirkJ,Fuerstenberg SM,Zager RA和Torok-Storb B.1994.HK-2:an immortalized proximal tubule epithelial cell line from normal adult human kidney.Kidney International45:48-57。
以下的工作实施例代表了本发明的优选实施方式。除非另外指明,所有的温度都为摄氏温度。
A.5-溴-2-氯-4’-乙氧基二苯甲酮
将商购的5-溴-2-氯苯甲酸(250g,1.06mol)加入到含有草酰氯(1.1mol)的450ml CH2Cl2中,搅拌制成悬浮液,再向其中加入1.5mlDMF。一旦气体的气体释放停止,将反应物搅拌过夜,然后采用旋转蒸发器在真空下除去挥发物。将粗制的5-溴-2-氯苯甲酰氯溶解于200ml CH2Cl2中,将黄色的溶液转移至装配有架空的搅拌器和内部温度计的2L三口烧瓶中。将搅拌的混合物冷却到-3℃,然后加入苯乙醚(130g,1.08mol)。通过固体添加漏斗在30分钟的时间内逐渐加入AlCl3(140g,1.07mol),以确保温度不超过4℃。在加入60%的AlCl3之后开始释放的大量HCl气体通过搅拌的浓NaOH溶液吸收。HPLC表明在加料完成之后10分钟,反应完成95%。混合物在4℃搅拌1小时,之后,将反应置于冰上而猝灭反应。然后,用H2O(1L)稀释悬浮液,用CH2Cl2萃取三次。合并的有机萃取物用1N HCl洗涤2次,用H2O洗涤1次,用1M NaOH洗涤2次,用盐水洗涤2次,然后用Na2SO4进行干燥。除去挥发物之后进行HPLC分析,结果表明残留物是邻位/对位异构体的1∶7混合物。从400ml纯EtOH中重结晶2次,得到230g(64%)5-溴-2-氯-4’-乙氧基二苯甲酮。
B.5-溴-2-氯-4’-乙氧基二苯基甲烷
在10℃,将Et3SiH(400ml,2.51mol)和5-溴-2-氯-4’-乙氧基二苯甲酮(390g,1.15mol)加入到900mL1∶2的1,2-二氯乙烷/MeCN混合物中,向上述搅拌的溶液中以一定速度加入BF3·Et2O(150mL,1.58mol),温度不超过20℃。当心在加入过程中适度的放热。在20℃搅拌过夜之后,HPLC表明反应完成了90%。在加入另外的40ml Et3SiH和15ml BF3·Et2O之后,反应加热到50℃进行3hr。(注意升高的温度会增加Ritter反应产物N-乙酰基-5-溴-2-氯-4’-乙氧基二苯基甲胺的形成)。经过冷却,用含有120g KOH的300ml H2O猝灭反应。搅拌2小时之后,对各层进行分离。用CH2Cl2萃取水层2次;合并的有机层用分成几份的300ml2M KOH洗涤1次,用含有10%盐水的H2O洗涤2次以促进相分离,用盐水洗涤2次,然后用Na2SO4干燥。除去挥发物之后,残留物在纯EtOH中重结晶,产生了230g5-溴-2-氯-4’-乙氧基二苯基甲烷的白色固体。
C.2,3,4,6-四-O-三甲基硅烷基-β-D-葡萄糖酸内酯
在Ar环境中,通过滴液漏斗向-5℃的含有葡糖酸内酯(239g,1.34mol)和N-甲基吗啉(1180ml,10.73mol)的2.4L THF搅拌溶液中加入氯代三甲基硅烷(1022mL,8.05mol),滴加速率使温度不超过5℃。1hr后,将搅拌的反应加热到35℃维持5hr,再让反应搅拌过夜,使反应冷却到20℃。用3.6L甲苯稀释之后,将混合物 冷却到0-5℃,然后小心地加入7L H2O,添加速度使温度不超过10℃。注意:加入第一部分H2O便会导致严重的放热。混合之后,使相发生分离,然后将它们分开。用NaH2PO4(2L)水溶液,H2O(1L)和盐水(1L)洗涤有机相。然后采用旋转蒸发器在真空下浓缩有机层;用250mL甲苯两次吸收得到的淡黄色油,再次浓缩得到616g标题化合物。
在Ar环境中,向-78℃的含有B部分的5-溴-2-氯-4’-乙氧基二苯基甲烷(150g,0.46mol)的1.15L1∶2无水THF/甲苯搅拌溶液中滴加含有2.5M n-BuLi的184mL己烷,保证温度保持低于-70℃。加入之后搅拌30分钟,用套管将此溶液转移到-78℃的含有C部分的2,3,4,6-四-O-三甲基硅烷基-β-D-葡萄糖酸内酯(236g,0.51mol)的1.1L甲苯搅拌溶液中,转移速度应使反应保持低于-70℃。溶液在-78℃搅拌30分钟,然后加入含有甲基磺酸(41.8mL,0.64mol)的1L MeOH猝灭反应。反应搅拌过夜,温度升到20℃。HPLC分析显示了与预期的O-甲基葡糖苷的质量相对应的两个新的峰;比率典型地从95∶5变化到80∶20。预期的产物对应于保留时间较短的主要峰。注意:采用更长的反应时间或加入50%以上的甲基磺酸会将所有的异构产物转化为所需的O-甲基葡糖苷。反应一旦完成后,就通过加入含有NaHCO3(37g,0.37mol)的200mL H2O猝灭反应。如果pH不为弱碱性,则加入更多的NaHCO3,然后用H2O稀释2倍,用EtOAc萃取3次。用盐水洗涤合并的EtOAc级分,通过Na2SO4进行干燥。采用旋转蒸发器进行浓缩之后,将残留物溶解于热的甲苯中(150mL)。将得到的溶液倾倒入1升搅拌的己烷中。用真空过滤器收集沉淀,得到的滤饼用500mL己烷洗涤2次,然后在空气 中干燥得到171g标题化合物,其为白色固体。
向-10℃的含有D部分的O-甲基葡糖苷(123g,0.28mol)的1.2L1∶1CH2Cl2/MeCN的搅拌溶液中加入Et3SiH(65.27g,0.56mol),然后加入BF3·Et2O(59.75g,0.42mol),加入速率应使温度保持在-5℃至-10℃之间。将搅拌的溶液升温到0℃保持5hr以上。当HPLC分析表明反应完成时,加入饱和的NaHCO3水溶液(310mL)猝灭反应。采用旋转蒸发器在真空下除去有机挥发物。残留物在2LEtOAc和2L H2O之间进行分配。相分离之后,用分成几份的2LEtOAc萃取H2O层两次。用H2O(2L)和盐水(2L)洗涤合并的有机层,然后通过MgSO4干燥,之后采用旋转蒸发器浓缩,生成104.6g黄色的固化泡沫。将这一残留物溶解在CH2Cl2(750mL)中之后,加入吡啶(200g,2.53mol),然后一次加入Ac2O(261.1g,2.56mol)。由此发生的放热使温度从28℃升高到47℃,在放热平息之后,加入DMAP(1.56g,13mmol)。一旦HPLC分析表明反应即将完成,1.5hr后通过加入H2O(1.8L)使反应淬灭。用CH2Cl2(总体积2.7L)萃取混合物2次,合并的有机层用1N HCl(1.8L)洗涤2次,用盐水(1.8L)洗涤2次,然后采用MgSO4干燥。在采用旋转蒸发器进行浓缩之后,从纯EtOH(750mL)中重结晶残留物,得到89.5g预期的四乙酰化的β-C-葡糖苷,其为白色固体。母液包含了相应的α-C-葡糖苷以及极性更大的呋喃糖异构体。
作为选择,可以利用下面的步骡,使D部分的O-甲基葡糖苷首先乙酰化,然后再还原为预期的四乙酰化C-芳基葡糖苷。
将含有D部分的O-甲基葡糖苷(3.0g,6.8mmol)和二异丙基乙胺(6.9mL,40mmol)的甲苯溶液(45mL)冷却到0℃,然后加入乙酸酐(3.35mL,35.5mmol)和DMAP(84mg,0.68mmol)。使溶液逐步升温到20℃,6小时之后进行的TLC分析表明完全转化为四乙酸盐。加入50mL20%的H3PO4猝灭反应。层与层分离之后,用甲苯萃取水相2次。合并的有机相用50mL H2O洗涤1次,然后在真空下浓缩。将得到的油溶解于20mL甲苯中,再次浓缩得到无需进一步纯化即可利用的稠油(4.15g)。
将上述粗制油(4.15g,6.8mmol)溶于含有1当量H2O(123mg,6.8mmol)的MeCN(60mL)中,将溶液冷却到0℃,然后加入Et3SiH(3.27mL,20.5mmol),再加入BF3·Et2O(1.73mL,13.7mmol)。搅拌1小时之后,使溶液升温到20℃。4hr后,一旦定期的HPLC分析表明反应超过60%时不再有进展,则加入另外的2mL Et3SiH和1mL BF3·Et2O。两小时之后,HPLC分析表明不再剩余原料。加入NaHCO3水溶液猝灭反应之后,搅拌混合物30分钟,然后用EtOAc萃取3次。合并的有机层用含水NaHCO3和盐水洗涤1次,然后用Na2SO4干燥。将在真空下浓缩得到的油溶解于70mL热的25%EtOAc/己烷中。通过冷却结晶出2.45g预期的四乙酰化β-C-芳基葡糖苷,随后通过过滤而分离。
向含有四乙酰化β-C-葡糖苷(27.2g,49mmol)(如E部分所述制备)的480mL2∶3∶1的THF/MeOH/H2O的20℃搅拌溶液中加入LiOH·H2O(2.3g,57mmol)。搅拌过夜之后,用旋转蒸发器除去挥发物。将残留物溶于EtOAc(300mL)中之后,用盐水(150mL)洗涤1次,用含有10mL5%KHSO4溶液的盐水(50mL)洗涤1次,最后用盐水(50mL)洗涤,之后通过Na2SO4进行干燥。用旋转蒸发器除去挥发物,将得到的最小量CH2Cl2中的油在真空下作泡沫化处理,生成20.4g所需的标题所示的C-芳基葡糖苷,其为含有0.11mol%EtOAc的玻璃状米色固体。
HPLC保留时间:7.08min,纯度94%,YMC S5C-184.6×50mm柱,2.5mL/min,在220nm处检测;8min梯度0-100%B,在100%B处维持5min;溶剂A:10%MeOH/H2O+0.2%H3PO4;溶剂B:90%MeOH/H2O+0.2%H3PO4。
1H NMR(500MHz,CD3OD)δ7.33(d,1H,J=6Hz),7.31(d,1H,J=2.2Hz),7.31(dd,1H,J=6Hz,J=2.2Hz),7.07(d,2H,J=8.8Hz),6.78(d,2H,J=8.8Hz),4.07-3.90(m,7H),3.85(d,1H,J=10.6Hz),3.69(dd,1H,J=5.3,10.6Hz),3.42-3.25(m,4H)Hz),1.34(t,3H,J=7Hz)。
13C NMR(125MHz,CD3OD)δ158.8,140.0,139.9,134.4,132.9,131.9,130.8,130.1,128.2,115.5,82.9,82.2,79.7,76.4,71.9,64.5,63.1,39.2,15.2。
采用LC-MS对C21H25ClO6的分析计算值[M+Na+]431;实际值431。
Claims (17)
1.化合物,具有下列结构
或者其药学上可接受的盐,其所有的立体异构体,或其前体药物酯。
2.化合物,具有下列结构
或其药学上可接受的盐,其立体异构体或其前体药物酯。
3.如权利要求2所述的化合物,具有结构
4.药物组合物,包含权利要求2所述的化合物和其药学上可接受的载体。
5.药物联合,包括权利要求4所述的SGLT2抑制剂化合物和除SGLT2抑制剂之外的抗糖尿病试剂,用于治疗糖尿病并发症的试剂,抗肥胖症的试剂,抗高血压的试剂,抗血小板的试剂,抗动脉粥样硬化的试剂,和/或降低脂质的试剂。
6.如权利要求5所述的药物联合,包括所述的SGLT2抑制剂化合物和抗糖尿病试剂。
7.如权利要求6所述的联合,其中所述的抗糖尿病试剂为双胍,磺酰脲,葡糖苷酶抑制剂,PPARγ激动剂,PPARα/γ双激动剂,aP2抑制剂,DP4抑制剂,胰岛素增敏剂,胰高血糖素样肽-1,胰岛素,格列奈类药物,PTP1B抑制剂,糖原磷酸化酶抑制剂,和/或葡萄糖-6-磷酸酶抑制剂中的1,2,3或更多种。
8.如权利要求7所述的联合,其中所述的抗糖尿病试剂为二甲双胍,格列本脲,格列美脲,格列比脲,格列吡嗪,氯磺丙脲,格列齐特,阿卡波糖,米格列醇,吡咯列酮,曲格列酮,罗格列酮,胰岛素,G1-262570,沙格列酮,JTT-501,NN-2344,L895645,YM-440,R-119702,AJ9677,瑞格列奈,那格列奈,KAD1129,AR-HO39242,GW-409544,KRP297,AC2993,LY315902,和/或NVP-DPP-728A中的1,2,3或更多种。
9.如权利要求6所述的联合,其中所述的SGLT2抑制剂化合物与抗糖尿病试剂的重量比范围为从约0.01到约300∶1。
10.如权利要求5所述的联合,其中所述的抗肥胖症的试剂为β-3肾上腺素能激动剂,脂肪酶抑制剂,血清素(和多巴胺)再吸收抑制剂,甲状腺受体β化合物,和/或食欲抑制剂。
11.如权利要求10所述的联合,其中所述的抗肥胖症的试剂为奥利司他,ATL-962,AJ9677,L750355,CP331648,西布曲明,托吡酯,阿索开,右旋安菲他明,芬特明,苯丙醇胺,和/或马吲哚。
12.如权利要求5所述的联合,其中所述的降低脂质的试剂为MTP抑制剂,HMG CoA还原酶抑制剂,角鲨烯合成酶抑制剂,纤维酸衍生物,LDL受体活性的向上调节物,或ACAT抑制剂。
13.如权利要求12所述的联合,其中所述的降低脂质的试剂为普伐他汀,洛伐他汀,辛伐他汀,阿伐他汀,西立伐他汀,氟伐他汀,尼伐他汀,威伐他汀,埃塔伐他汀,罗素他汀,非诺贝特,吉非贝齐,安妥明,阿伐麦布,TS-962,MD-700,和/或LY295427。
14.如权利要求12所述的联合,其中所述的SGLT2抑抑制剂与降低脂质的试剂的重量比范围为从约0.01到约300∶1。
15.治疗或延缓糖尿病,糖尿病性的视网膜病,糖尿病性的神经病,糖尿病性的肾病,伤口愈合延迟,胰岛素抵抗,高血糖症,高胰岛素血症,血液中升高的脂肪酸或甘油水平,高脂血症,肥胖症,高甘油三酯血症,X综合症,糖尿病并发症,动脉粥样硬化或高血压症的发展或发生,或增加高密度脂蛋白水平的方法,所述方法包括采用治疗有效量的权利要求2所述的化合物向需要治疗的哺乳动物给药。
16.如权利要求15所述的方法,其中所述的SGLT2抑制剂化合物具有结构
17.治疗II型糖尿病的方法,包括单独采用治疗有效量的权利要求2所述的化合物或联合采用治疗有效量的权利要求2所述的化合物与其它的抗糖尿病试剂,用于治疗糖尿病并发症的试剂,抗肥胖症的试剂,抗高血压的试剂,抗血小板的试剂,抗动脉粥样硬化的试剂和/或降低脂质的试剂向需要治疗的哺乳动物给药。
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