CN1347318A - Impdh酶抑制剂 - Google Patents
Impdh酶抑制剂 Download PDFInfo
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- CN1347318A CN1347318A CN00806457A CN00806457A CN1347318A CN 1347318 A CN1347318 A CN 1347318A CN 00806457 A CN00806457 A CN 00806457A CN 00806457 A CN00806457 A CN 00806457A CN 1347318 A CN1347318 A CN 1347318A
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- chemical compound
- alkynyl
- branched alkyl
- hydrogen
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Abstract
本发明涉及抑制IMPDH的化合物。本发明还涉及包含这些化合物的药物组合物。本发明化合物和药物组合物特别适于抑制IMPDH酶活性,并因此可有利地用作IMPDH介导的病变的治疗剂。本发明还涉及使用本发明化合物和相关化合物来抑制IMPDH活性的方法。
Description
发明领域
本申请要求下列两件美国临时申请为优先权,其中第一件于1999年3月19日提出申请,申请号60/125,507,第二件于2000年1月7提出申请,申请号60/174,882。
本发明涉及抑制IMPDH的化合物。本发明还涉及包含这些化合物的药物组合物。本发明化合物和药物组合物特别适于抑制IMPDH酶活性,并因此可有利地用作IMPDH介导的病变(processes)的治疗剂。本发明还涉及使用本发明化合物和相关化合物来抑制IMPDH活性的方法。
发明背景
生物体中核苷酸的合成是这些生物体中的细胞进行分裂和复制所必需的。哺乳动物中核苷酸合成可通过下述两条途径中的一条来进行:从头合成途径或补救途径。不同类型细胞在不同程度上使用这些途径。
肌苷-5’-一磷酸脱氢酶(IMPDH;EC 1.1.1.205)是涉及鸟嘌呤核苷酸从头合成的一种酶。IMPDH催化肌苷-5’-一磷酸(IMP)NAD-依赖性地氧化成黄苷-5’-一磷酸(XMP)[Jackson R.C.等人,Nature,256,pp.331-333,(1975)]。
IMPDH在真核生物、细菌和原生动物中普遍存在[Y.Natsumeda& S.F.Carr,Ann.N.Y.Acad.,696,pp.88-93(1993)]。原核生物形式与人体酶有30-40%的序列同源性。已经鉴定了称为I型和II型的人IMPDH的两种同种型,并已测定了其序列[F.R.Collart和E.Huberman,J.Biol. Chem.,263,pp. 15769-15772,(1988);Y.Natsumeda等人,J.Biol. Chem.,265,pp.5292-5295,(1990)]。这两种同种型分别具有514个氨基酸,并具有84%的序列同源性。I型和II型IMPDH在溶液中形成具有分子量为56kDa的亚单位的活性四聚体[Y.Yamada等人,Biochemistry,27,pp.2737-2745(1988)]。
鸟苷核苷酸的从头合成以及因此IMPDH的活性在B和T-淋巴细胞中特别重要。这些细胞依靠从头合成而不是补救合成来生成对促细胞分裂剂或抗原产生增殖反应所必需的足够水平的核苷酸[A.C.Allison等人,Lancet II,1179,(1975)和A.C.A11ison等人,CibaFound.Symp.,48,207,(1977)]。因此,IMPDH是选择性地抑制免疫系统而又不抑制其它细胞增殖的有吸引力的目标。
免疫抑制已经通过抑制多种酶而得到实现,这些酶有例如磷酸酶钙调磷酸酶(通过环孢菌素和FK-506抑制);二氢乳清酸脱氢酶-一种涉及嘧啶生物合成的酶(通过来氟米特和布喹那抑制);激酶FRAP(通过雷怕霉素抑制);和热激蛋白hsp70(通过deoxyspergualin抑制)[参见B. D. Kahan,Immunological Reviews,136,pp.29-49(1993);R. E. Morris,The Journal of Heart and LungTransplantation,12(6),pp.S275-S286(1993)]。
IMPDH抑制剂也是已知的。美国专利5,380,879和5,444,072以及PCT公开WO 94/01105和WO 94/12184描述了霉酚酸(MPA)及其一些衍生物,它们是I型(Ki=33 nM)和II型(Ki=9 nM)人IMPDH的强效、非竞争性、可逆抑制剂。据证明MPA能阻断B和T-淋巴细胞对促细胞分裂剂或抗原的反应[A.C.Allison等人,Ann.N.Y.Acad.Sci.,696,63,(1993)]。
免疫抑制剂例如MPA是治疗抑制排斥和自身免疫性疾病的有用药物[R. E. Morris,Kidney Intl.,49,Suppl. 53,S-26,(1996)]。然而,MPA的特征是具有不良药理特性例如胃肠毒性[L.M.Shaw,等人,Therapeutic Drug Monitoring,17,pp. 690-699,(1995)]。
核苷类似物例如噻唑呋林、利巴韦林和咪唑立宾也抑制IMPDH[L.Hedstrom,等人,Biochemistry,29,pp.849-854(1990)]。然而,这些化合物的缺点是对IMPDH缺乏特异性。
最近据证明霉酚酸莫非替克—在体内迅速释放游离MPA的一种前药能阻止肾移植后的急性肾同种移植物排斥[L.M.Shaw,等人,Therapeutic Drug Monitoring,17,pp.690-699,(1995);H.W. Sollinger,Transplantation,60,pp.225-232(1995)]。然而,几个临床观察限制了该药物的治疗潜力[L.M.Shaw,等人,Therapeutic Drug Monitoring,17,pp.690-699,(1995)]。MPA在体内迅速代谢成没有活性的葡萄糖醛酸化物[A.C.Allison和E. M. Eugui,Immunological Reviews,136,pp. 5-28(1993)]。然后葡萄糖醛酸化物经历肠肝循环,使得MPA积聚在胃肠道中,MPA在胃肠道中不能施加其对免疫系统的IMPDH抑制活性。这大大地降低了药物的体内效力,同时增加了其不良胃肠道副作用。
近来,PCT公开WO 97/40028和WO 98/40381中已描述了不同种类的IMPDH抑制剂。
还已知IMPDH在其它代谢事件中起作用。在迅速增殖的人白血病细胞系和其它肿瘤细胞系中还观察到IMPDH活性的增加,这表明IMPDH是抗癌以及免疫抑制的利用目标[M.Nagai等人,Cancer Res.,51,pp.3886-3890,(1991)]。据表明IMPDH在平滑肌细胞的增殖中起作用,这表明IMPDH抑制剂例如MPA或雷怕霉素可用于预防再狭窄或其它高度增殖性血管疾病[C.R.Gregory等人,Transplantation,59,pp.655-61(1995);PCT公开WO 94/12184;和PCT公开WO94/01105]。
此外,据表明IMPDH在某些病毒感染的细胞系内在病毒复制中起作用[S.F.Carr,J.Biol.Chem.,268,pp.27286-27290(1993)]。与淋巴细胞以及淋巴细胞和肿瘤细胞系类似的是,这意味着从头合成而不是补救合成途径在病毒复制过程中是至关重要的。
因此,人们需要具有改善的药理特征的强效IMPDH抑制剂。这样的抑制剂具有作为免疫抑制剂、抗癌剂、抗血管过度增殖剂、抗炎剂、抗真菌剂、抗牛皮癣剂和抗病毒剂的治疗潜力。
发明概述
本发明提供了可用作IMPDH抑制剂的化合物及其可药用衍生物。本发明化合物可单独使用,或者与其它治疗或预防剂例如抗病毒剂、抗炎剂、抗生素、和免疫抑制剂联合使用,以治疗或预防移植排斥和自身免疫性疾病。
此外,本发明化合物可单独使用,或者与其它治疗或预防剂例如抗病毒剂、抗肿瘤剂、抗癌剂、抗炎剂、抗真菌剂、抗牛皮癣免疫抑制性化疗和再狭窄治疗方案联合使用。
本发明还提供了包含本发明化合物的药物组合物,以及包含另外的IMPDH化合物和免疫抑制剂的多组分组合物。本发明还提供了使用本发明化合物以及其它相关化合物来抑制IMPDH的方法。
发明详述
为了能更充分地理解本发明,下面提供详细描述。在详细描述中,提供下述缩写:缩写符号 试剂或片段Ac 乙酰基Me 甲基Et 乙基Bn 苄基CDI 羰基二咪唑DBU 1,8-二氮杂二环[5.4.0]十一碳-7-烯DIEA 异丙基乙胺DMAP 二甲基氨基吡啶DMF 二甲基甲酰胺DMSO 二甲亚砜DPPA 二苯基磷酸(phosphoryl acid)EDC 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐EtOAc 乙酸乙酯IPA 异丙醇MeCN 乙腈THF 四氢呋喃TEA 三乙胺t-bu 叔丁基BOC 丁氧基羰基
在本文中使用下述术语:
除非另外指出,否则在本文中使用的术语″-SO2-″和″-S(O)2-″是指砜或砜衍生物(即两个附加基团都连接在S上),不是亚磺酸酯。
术语″halo″或″卤素″是指氟、氯、溴或碘。
术语″免疫抑制剂″是指具有免疫反应抑制活性的化合物或药物。免疫抑制剂的实例包括环孢菌素A、FK506、雷怕霉素、来氟米特、deoxyspergualin、强的松、硫唑嘌呤、霉酚酸莫非替克、OKT3、ATAG、干扰素和咪唑立宾。
术语″干扰素″是指所有形式的干扰素,包括但不限于α、β和γ形式的干扰素。
IMPDH介导的疾病是指其中IMPDH酶在疾病的代谢路径中起调控作用的任何疾病。IMPDH介导的疾病的实例包括移植排斥和自身免疫性疾病例如类风湿性关节炎、多发性硬化、青少年糖尿病、哮喘、和炎性肠病、以及炎性疾病、癌症、病毒复制性疾病和血管性疾病。
例如,本发明化合物、组合物以及使用它们的方法可用于治疗移植排斥(例如肾、肝脏、心脏、肺、胰腺(胰岛细胞)、骨髓、角膜、小肠和皮肤同种移植物以及心脏瓣膜异种移植物)、类风湿性关节炎、多发性硬化、青少年糖尿病、哮喘、炎性肠病(局限性回肠炎、溃疡性结肠炎)、狼疮、糖尿病、重症肌无力、牛皮癣、皮炎、湿疹、皮脂溢、肺炎、眼色素层炎、肝炎、格雷夫斯病、桥本甲状腺炎、贝赫切特或斯耶格伦综合征(眼睛/口腔干燥)、恶性或免疫血液性贫血、自发性肾上腺机能不全、多腺自身免疫性综合征、和肾小球性肾炎、硬皮病、扁平苔癣、白斑(皮肤脱色素)、自身免疫性甲状腺炎、和牙槽炎、炎性疾病例如骨关节炎、急性胰腺炎、慢性胰腺炎、哮喘和成人呼吸窘迫综合征、以及用于治疗癌症和肿瘤例如实体瘤、淋巴瘤和白血病、血管性疾病例如再狭窄、狭窄和动脉粥样硬化、以及DNA和RNA病毒复制性疾病例如逆转录病毒疾病、和疱疹。
此外,已知IMPDH酶还存在于细菌中,并因此可调控细菌生长。因此本发明描述的IMPDH-抑制剂化合物、组合物和方法可以单独使用或与其它抗生素联合使用来治疗或预防细菌感染。
本文所用术语″治疗″是指减轻患者中特定疾病的症状,或者改善由特定疾病带来的可查明的测定指标。本文所用术语″患者″是指哺乳动物,包括人。
术语″HBV″、″HCV″和″HGV″分别是指乙肝病毒、丙肝病毒和G型肝炎病毒。
R1和R2分别独立地选自氢;-CF3;-(C1-C6)直链或支链烷基;-(C2-C6)-直链或支链链烯基或炔基;-(C1-C6)-直链或支链烷基-R7;-[(C2-C6)-直链或支链链烯基或炔基]-R7或-R7;并且其中至少一个R1或R2是-(C1-C6)-直链或支链烷基-R7;-[(C2-C6)-直链或支链链烯基或炔基]-R7或-R7
其中在任何所述烷基、链烯基或炔基上有最高达4个氢原子任选且独立地被R3取代;或者
其中R1和R2,作为一种替代方式,连在一起形成四氢呋喃基,其中当R9是氢、(R)-甲基、(R)-乙基或(R)-羟基甲基时,在所述四氢呋喃中的一个氢原子被-OR6或-R7替代,并且当R9是(S)-甲基、(S)-乙基或(S)-羟基甲基时,在所述四氢呋喃中的一个氢原子任选被-OR6或-R7替代;
其中当R9是氢、(R)-甲基、(R)-乙基或(R)-羟基甲基,且各R1和R2独立地为氢、未取代的-(C1-C6)-直链或支链烷基、或未取代的-(C2-C6)-直链或支链链烯基或炔基时,则由-CH(R1)R2代表的化合物部分是C5-C12直链或支链烷基、链烯基或炔基;
每一R3独立地选自卤素、CN、-OR4、或-N(R5)2;
R4选自氢、-(C1-C6)-直链或支链烷基、-(C2-C6)-直链或支链链烯基或炔基、-[(C1-C6)-直链或支链烷基]-R7、-[(C2-C6)-直链或支链链烯基或炔基]-R7、-C(O)-[(C1-C6)-直链烷基]、-C(O)-[(C2-C6)-直链或支链链烯基或炔基]、-C(O)-[(C1-C6)-直链或支链烷基]-N(R8)2、-C(O)[(C2-C6)-直链或支链链烯基或炔基]-N(R8)2、-P(O)(OR8)2、-P(O)(OR8)(R8)、-C(O)-R7、-[(C1-C6)-直链或支链烷基]-CN、-S(O)2N(R5)2或-[(C2-C6)-直链或支链链烯基或炔基]-CN;
每一R5独立地选自氢、-(C1-C6)-直链或支链烷基、-(C2-C6)-直链或支链链烯基或炔基、-[(C1-C6)-直链或支链烷基]-R7、-[(C2-C6)-直链或支链链烯基或炔基]-R7、-[(C1-C6)-直链烷基]-CN、-[(C2-C6)-直链或支链链烯基或炔基]-CN、-[(C1-C6)-直链或支链烷基]-OR4、-[(C2-C6)-直链或支链链烯基或炔基]-OR4、-C(O)-(C1-C6)-直链或支链烷基、-C(O)-[(C2-C6)-直链或支链链烯基或炔基]、-C(O)-R7、-C(O)O-R7、-C(O)O-(C1-C6)-直链或支链烷基、-C(O)O-[(C2-C6)-直链或支链链烯基或炔基]、-S(O)2-(C1-C6)-直链或支链烷基、或-S(O)2-R7;或者当结合在同一氮原子上时,两个R5部分与所述氮原子一起形成3-7元杂环,其中所述杂环任选含有1-3个独立地选自N、O、S、S(O)或S(O)2的另外的杂原子;
R6选自-C(O)-CH3、-CH2-C(O)-OH、-CH2-C(O)-O-tBu、-CH2-CH、或-CH2-C≡CH;
每一R7是单环或二环环系,其中在所述环系中:i.每个环包含3-7个独立地选自C、N、O或S的环原子;ii.不超过4个环原子选自N、O或S;ii i.任一CH2任选被C(O)替代;iv.任一S任选被S(O)或S(O)2替代;
每一R8独立地选自氢或-[C1-C4]-直链或支链烷基;
其中在所述化合物的任一环系中,最高达3个结合在环原子上的氢原子任选且独立地被卤素、羟基、硝基、氰基、氨基、(C1-C4)-直链或支链烷基;O-(C1-C4)-直链或支链烷基、(C2-C4)-直链或支链链烯基或炔基、或O-(C2-C4)-直链或支链链烯基或炔基替代;并且
其中任一环系是任选地苯并稠合的;
R9选自氢、(R)-甲基、(S)-甲基、(R)-乙基、(S)-乙基、(R)-羟基甲基或(S)-羟基甲基;
R10选自-C=N或5-噁唑基;
R11选自卤素、-O-(C1-C3)直链烷基、或-O-(C2-C3)直链链烯基或炔基。
还包括在式(A)范围内的有通过将R1或R2或者R1和R2酯化而形成的前药。这样的前药的实例是下文表中所列出的化合物143-156。
本文所用术语″单环环系″包括饱和、部分不饱和和全不饱和环结构。本文所用术语″二环环系″包括其中每个环独立地为饱和、部分不饱和和全不饱和环的环系。用于本发明化合物的单环和二环环系的实例包括但不限于环戊烷、环戊烯、茚满、茚、环己烷、环己烯、环己二烯、苯、四氢萘、十氢萘、萘、吡啶、哌啶、哒嗪、嘧啶、吡嗪、1,2,3-三嗪、1,2,4-三嗪、1,3,5-三嗪、1,2,3,4-四嗪、1,2,4,5-四嗪、1,2,3,4-四氢喹啉、喹啉、1,2,3,4-四氢异喹啉、异喹啉、噌啉、酞嗪、喹唑啉、喹喔啉、1,5-萘啶、1,6-萘啶、1,7-萘啶、1,8-萘啶、2,6-萘啶、2,7-萘啶、蝶啶、吖啶、吩嗪、1,10-菲咯啉、二苯并吡喃、1-苯并吡喃、吩噻嗪、吩噁嗪、噻蒽、二苯并对二噁英、苯并氧硫杂环己二烯(phenoxathiin)、phenoxthionine、吗啉、硫代吗啉、四氢吡喃、吡喃、苯并吡喃、1,4-二噁烷、1,3-二噁烷、二氢吡啶、二氢吡喃、1-氮茚、奎宁环、三唑并吡啶、β-咔啉、吲嗪、喹嗪、四氢naphtheridine、二氮杂菲、噻喃、四氢吡喃、苯并二噁烷、呋喃、苯并呋喃、四氢呋喃、吡咯、吲哚、噻吩、苯并噻吩、咔唑、吡咯烷、吡唑、异噁唑、异噻唑、咪唑、噁唑、噻唑、1,2,3-三唑、1,2,4-三唑、1,2,3-噁二唑、1,2,4-噁二唑、1,3,4-噁二唑、1,2,5-噁二唑、1,2,3-噻二唑、1,2,4-噻二唑、1,3,4-噻二唑、1,2,5-噻二唑、四唑、苯并噻唑、苯并噁唑、苯并三唑、苯并咪唑、苯并吡唑、苯并异噻唑、苯并异噁唑和嘌呤。
在上述描述范围内的其它单环和二环结构可参见A. R.Katritzky,和C.W.Rees,eds.″综合杂环化学:结构、反应、合成和杂环化合物的应用,Vol. 1-8,″Pergamon Press,NY(1984),该文献的公开内容引入本发明以作参考。
应当理解,杂环可通过能导致形成稳定结构的杂环的任一原子连接在化合物的剩余部分上。
本文所用术语″环原子″是指构成环的骨架原子。这样的环原子选自C、N、O或S,并且与2或3个其它环原子结合(对于二环环系中的一些环原子,会出现与3个其它环原子结合的这种情况)。术语″环原子″不包括氢。
术语″-[(C1-C6)-直链或支链烷基]-X″和″-[(C2-C6)-直链或支链链烯基或炔基]-X″,其中X是表示结合在烷基、链烯基或炔基上的任何基团,是指一个或多个X基团可在任何末端连接在烷基、链烯基或炔基链上。
依据一个优选的实施方案,化合物具有式(I):其中R1和R2如上所定义,或式(IA):其中R9选自(R)-甲基、(S)-甲基、(R)-乙基、(S)-乙基、(R)-羟基甲基或(S)-羟基甲基;且R1、R2、R10。和R11如上所定义。
依据更优选的式IA的实施方案,R9选自(S)-甲基、(S)-乙基、或(S)-羟基甲基甲基。R9最优选为(S)-甲基。其中R9选自(S)-甲基、(S)-乙基、或(S)-羟基甲基甲基,并且-CH(R1)R2所代表的化合物部分是C1-C4直链或支链烷基、或C2-C4直链或支链链烯基或炔基的化合物属于WO 97/40028所公开的化合物。然而,本申请人已经发现,在R9存在(S)定向部分使得化合物具有令人惊奇且出乎意料地增强的IMPDH抑制活性。
依据另一优选的式IA方案,R11选自O-甲基、O-乙基或O-异丙基。
依据更优选的式(I)和(IA)方案,至少一个R1或R2选自氢、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、正戊基、苯基、吡啶基、-CH2OCH3,-CH2CN,-CH2OCH2CH2CN,-CH2C(CH3)2CH2CH2CN,-CH2C(CH2CH3)2CH2CH2CN,-CH2CH2CN,-CH2N(CH2CH2CN)2,-CH2N(CH3)CH2CH2CN,-CH(NH2)CH2CN,-CH2Cl,-CH2OH,-CH2CH2OH,-CH2CH2OH,-CH2CH2CH2CH2OH,-CH2CH2OC(O)CH3,-CH2CH2OC(O)CH2NH2,-CH2CH2NHCH3,-CH2CH2N(CH3)2,-CH2CH2N(CH2CH3)2,-CH2N(CH2CH3)2,-CH2CH2CH2N(CH3)2,-CH2CH2CH2N+(CH3)3,-CH2OCH2CH(CH3)2,-CH2CH2N(CH3)C(O)OC(CH3)3,-CH2N(CH2CH2CN)CH2CH(CH3)2,-CH(CH2CN)N(CH3)2, -CH2CH(CH2CN)NHC(O)OC(CH3)3,其中n是0或1。
依据甚至更优选的式IA方案,一个R1或R2选自氢、乙基或苯基;另一个R1或R2选自-CH2OH、-CH2CN、-CH2CH2CN或CH2N(CH2CH3)2;或者R1和R2一起形成3-四氢呋喃基部分。
依据另一优选的式I方案,R1和R2一起形成被-OR6取代的3-四氢呋喃基部分。
依据另一优选的方案,式A化合物选自在下述表1中列出的任一化合物。
在上表中,一些化合物是作为盐显示的。应当理解,在表内任一给定条目中列出的化合物的范围包括所有形式的所述化合物,而不仅仅是所显示的盐。
当没有具体指出立体化学时,本发明化合物可含有一个或多个不对称碳原子,并因此可作为外消旋体和外消旋体混合物、单一对映体、非对映体混合物和单一非对映体存在。除非另有说明,否则这些化合物的所有异构形式都明确地包括在本发明内。每一导致立体异构的碳可以呈R或S构型。
本发明所预计的取代基和变量的组合仅是能导致形成稳定化合物的组合。本文所用术语″稳定的″是指具有足够稳定性,从而使得能够产生并在足够长时间内保持完整性以用于本文所述目的(例如对哺乳动物进行治疗或预防性给药或者在亲和色谱应用中使用)的化合物。一般情况下,这样的化合物在无水分或其它化学反应性条件下于40℃或更低温度下稳定地存在至少一周。
本文所用的本发明化合物包括其可药用衍生物或前药。″可药用衍生物或前药″是指施用给接受者后能够提供(直接或间接)本发明化合物的本发明化合物的任何可药用盐、酯、酯的盐、或其它衍生物。特别合适的衍生物和前药是当施用给哺乳动物时能提高本发明化合物生物利用度(例如使得口服给药的化合物能更容易地吸收到血液中)或促进母化合物释放到生物腔室(例如脑或淋巴系统)(与母化合物相比)中的衍生物和前药。优选的前药包括提高水溶性或者穿过肠膜的活性运输能力的基团被添加到本发明化合物的结构上的衍生物。
本发明化合物的可药用盐包括与可药用无机或有机酸和碱形成的盐。合适的酸加成盐的实例包括乙酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、葡萄庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、草酸盐、扑酸盐、果胶酯酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐和十一酸盐。碱加成盐包括铵盐,碱金属盐例如钠盐和钾盐,碱土金属盐例如钙盐和镁盐,与有机碱形成的盐例如二环己基铵盐、N-甲基-D-葡糖胺盐,和与氨基酸例如精氨酸、赖氨酸形成的盐等。
也可以用诸如下述的试剂将碱性含氮基团季铵化:低级烷基卤化物例如甲基、乙基、丙基、和丁基氯化物、溴化物和碘化物;二烷基硫酸酯例如二甲基、二乙基、二丁基和二戊基硫酸酯,长链卤化物例如癸基、月桂基、十四烷基和硬脂基氯化物、溴化物和碘化物,芳烷基卤化物例如苄基和苯乙基溴化物等。由此可获得水或油可溶性或可分散的产物。
本发明化合物可用常规技术合成。有利起见,可用易得原料方便地合成这些化合物。更具体来说,本发明化合物可通过在实施例1和2中描述的合成方案,并作一些对于本领域技术人员来说是显而易见的改进来合成得到。
可通过增加合适的官能团来修饰本发明化合物,以提高选择性的生物性质。这样的修饰是本领域已知的,并且包括提高进入给定生物腔室(例如血液、淋巴系统、中枢神经系统)的生物穿透能力、提高口服生物利用度、提高溶解度以容许通过注射给药、改变代谢和改变分泌速度的修饰。
本发明新化合物是IMPDH的优异的配体。因此,这些化合物能够定向和抑制IMPDH酶。抑制作用可通过多种方法测定,包括例如IMP脱氢酶HPLC测定法(测定由IMP和NAD通过酶作用生成XMP和NADH)和IMP脱氢酶分光光度分析法(测定由NAD通过酶作用生成NADH)[参见C.Montero等人,Clinica Chimica Acta,238,pp.169-178(1995)]。
本发明组合物包含本发明化合物或其盐;选自免疫抑制剂、抗癌剂、抗病毒剂、抗炎剂、抗真菌剂、抗生素、或抗血管过度增殖化合物的另外的活性剂;和任何可药用载体、辅料或赋形剂。另外的本发明组合物包含本发明化合物或其盐;和可药用载体、辅料或赋形剂。这样的组合物可任选包含选自免疫抑制剂、抗癌剂、抗病毒剂、抗炎剂、抗真菌剂、抗生素、或抗血管过度增殖化合物的另外的活性剂。优选地,本发明的组合物是药物组合物。
术语″可药用载体或辅料″是指可以与本发明化合物一起施用给患者的载体或辅料,它们不破坏本发明化合物的药理活性,并且当以足以递送治疗量的本发明化合物的量施用时没有毒性。
可应用本发明药物组合物中的可药用载体、辅料和载体包括但不限于离子交换剂,矾土,硬脂酸铝,卵磷脂,半乳化药物递送系统(SEDDS)例如dα-生育酚聚乙二醇1000琥珀酸盐,在药物剂型中使用的表面活性剂例如吐温或其它类似聚合递送基质,血清蛋白例如人血清白蛋白,缓冲物质例如磷酸盐,甘氨酸,山梨酸,山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物,水,盐或电解质例如硫酸钾、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐,胶态二氧化硅,三硅酸镁,聚乙烯吡咯烷酮,基于纤维素的物质,聚乙二醇,羧甲基纤维素钠,聚丙烯酸酯,蜡,聚乙烯-聚氧丙烯嵌段共聚物,聚乙二醇和羊毛脂。也可以使用环糊精例如α-环糊精、β-环糊精、和γ-环糊精,或化学修饰的衍生物例如羟基烷基环糊精,包括2-和3-羟基丙基-β-环糊精、或其它增溶衍生物来促进本发明化合物的递送。
本发明药物组合物可口服给药、非胃肠道给药、通过吸入喷雾给药、局部给药、直肠给药、鼻给药、颊给药、阴道给药或通过植入的贮药装置给药。优选口服给药或注射给药。本发明药物组合物可含有任何常用的无毒可药用载体、辅料或赋形剂。在某些情况下,可用可药用酸、碱或缓冲剂来调节制剂的pH以提高所配制的化合物或其给药剂型的稳定性。本文所用术语非胃肠道包括皮下、皮内、静脉内、肌内、关节内、动脉内、滑膜内、胸骨内、鞘内、损伤部位内、和颅内注射或输注技术。
本发明药物组合物可呈无菌注射剂形式,例如无菌可注射水或油悬浮液。该悬浮液可依据本领域已知技术使用合适的分散剂或润湿剂(例如吐温80)和悬浮剂来配制。无菌注射剂还可以是在无毒可非胃肠道给药用稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如在1,3-丁二醇中的溶液。可使用的可接受的赋形剂和溶剂是甘露醇、水、林格氏溶液、和等渗氯化钠溶液。此外,无菌不挥发油通常用作溶剂或悬浮介质。对于此,可使用温和的不挥发油,包括合成的甘油一酯或甘油二酯。脂肪酸例如油酸及其甘油酯衍生物可用于制备注射剂,也可以使用天然可药用油例如橄榄油或蓖麻油,尤其是其聚氧乙基化变型。这些油溶液或悬浮液也可以含有长链醇稀释剂或分散剂例如在Pharmacopeia Helvetica,Ph.Helv.,中描述的那些,或类似的醇,或羧甲基纤维素,或通常用于配制可药用剂型例如乳剂或悬浮剂的类似分散剂。其它常用表面活性剂例如吐温或司盘和/或其它常用于制备可药用固体、液体或其它剂型的类似乳化剂或生物利用度促进剂也可用于配制的目的。
本发明药物组合物可以以任何口服剂型的形式口服给药,包括但不限于胶囊、片剂、乳剂和水悬浮液、分散剂和溶液。对于口服片剂,常用载体包括乳糖和玉米淀粉。一般还加入润滑剂例如硬脂酸镁。为了以胶囊形式口服给药,适用的稀释剂包括乳糖和无水玉米淀粉。当口服施用水悬浮液和/或乳液时,可将活性组分悬浮或溶解在油相中,并与乳化剂和/或悬浮剂合并。如果需要的话,可加入一些甜味剂和/或矫味剂和/或着色剂。
本发明药物组合物可以以直肠给药用栓剂的形式给药。这些组合物可通过将本发明化合物与在室温是固体、但是在直肠温度是液体并从而将熔化在直肠中以释放出活性组分的适当非刺激性赋形剂混合而制得。这样的材料包括但不限于椰子油、蜂蜡和聚乙二醇。
当所需治疗涉及易于通过局部施用而进入的区域或器官时,局部施用本发明药物组合物是尤其有用的。为了局部施用到皮肤上,应当将药物组合物配制成含有悬浮或溶解在载体中的活性组分的合适的软膏剂。用于局部施用本发明化合物的载体包括但不限于矿物油、液状石蜡、白凡士林、丙二醇、聚氧乙烯聚氧丙烯化合物、乳化蜡和水。或者,可将药物组合物配制成含有悬浮或溶解在具有合适乳化剂的载体中的活性化合物的适当洗剂或霜剂。合适的载体包括但不限于矿物油、脱水山梨醇一硬脂酸酯、聚山梨酯60、鲸蜡基酯蜡、鲸蜡硬脂醇(cetearyl alcohol)、2-辛基十二烷醇、苯甲醇和水。本发明药物组合物还可以通过直肠栓剂或合适的灌肠剂局部施用到肠道下部。本发明也包括局部透皮贴剂。
本发明药物组合物可通过鼻用气雾剂或吸入给药。这样的组合物可依据本领域众所周知的技术制得,并且可制成在盐水中的溶液,使用苯甲醇或其它合适的防腐剂,吸收促进剂以提高生物利用度,碳氟化合物,和/或本领域已知的其它助溶或分散剂。
约0.01-约100mg/kg体重/天、优选约0.5-约75mg/kg体重/天剂量水平的本文所述IMPDH抑制化合物可用于单一治疗和/或联合治疗以预防和治疗IMPDH-介导的疾病。本发明药物组合物一般每天给药约1-约5次,或者连续输注。这样的给药可用作长期或急性治疗。可与载体合并以制得单个剂型的活性组分的量取决于治疗对象和特定给药方式。一般的制剂含有约5%-约95%活性化合物(w/w)。这样的制剂优选含有约20%-约80%活性化合物。
当本发明组合物包含本发明IMPDH抑制剂和一种或多种另外的治疗剂或预防剂时,IMPDH抑制剂和其它治疗剂的剂量水平都应为约10-100%、更优选约10%-80%在单一治疗中通常给药的剂量。另外的活性剂可以作为多剂量方案的一部分与本发明化合物分开给药。或者,那些活性剂可以是与本发明化合物在单一组合物中混合在一起的单一剂型的一部分。
依据一个实施方案,本发明药物组合物包含另外的免疫抑制剂。免疫抑制剂的实例包括但不限于环孢菌素A、FK506、雷怕霉素、来氟米特、deoxyspergualin、强的松、硫唑嘌呤、霉酚酸莫非替克、OKT3、ATAG、干扰素和咪唑立宾。
依据另一实施方案,本发明药物组合物还可包含抗癌剂。抗癌剂的实例包括但不限于顺铂、放线菌素D、阿霉素、长春新碱、长春碱、依托泊苷、安吖啶、米托蒽醌、替尼泊苷、紫杉醇、秋水仙碱、环孢菌素A、吩噻嗪、干扰素和噻吨。
依据另一实施方案,本发明药物组合物还可包含抗病毒剂。抗病毒剂的实例包括但不限于更昔洛韦、丙氧鸟苷、膦酰基甲酸三钠、利巴韦林、d4T、ddI、AZT、和阿昔洛韦。
依据另一实施方案,本发明药物组合物还可包含抗血管过度增殖剂。抗血管过度增殖剂的实例包括但不限于HMG Co-A还原酶抑制剂例如洛伐他丁、血栓烷A2合成酶抑制剂、二十碳五烯酸、西前列烯、曲匹地尔、ACE抑制剂、低分子量肝素、霉酚酸、雷怕霉素和5-(3’-吡啶基甲基)苯并呋喃-2-甲酸。
为了改善患者的状况,如果需要的话,可施用维持剂量的本发明化合物、组合物或组合。然后可根据症状,将给药剂量或频率或二者降低至保持改善状况的水平,当症状已减轻至所需水平时,停止治疗。然而,由于疾病症状的复发,患者可能需要长期的间歇性治疗。
本领域技术人员能够理解,可能需要比上述剂量更低或更高的剂量。对于任何特定患者,具体剂量和治疗方案将取决于多种因素,包括所用具体化合物的活性、年龄、体重、一般健康状况、性别、饮食、给药时间、分泌速度、药物组合、疾病严重程度和病程、患者对该疾病的素因以及治疗医师的判断。
在另一实施方案中,本发明提供了治疗或预防哺乳动物IMPDH-介导的疾病的方法,包括给所述哺乳动物施用任意上述药物组合物和组合的步骤。如果药物组合物仅包含本发明IMPDH抑制剂,这样的方法还可以包括给所述哺乳动物施用选自抗炎剂、免疫抑制剂、抗癌剂、抗病毒剂、或抗血管过度增生化合物的活性剂的步骤。所述另外的活性剂可以在施用IMPDH抑制剂组合物之前、之后施用,或者与IMPDH抑制剂组合物同时施用。
在优选的实施方案中,这些方法可用于在哺乳动物中抑制免疫反应。这样的方法可用于治疗或预防疾病,包括移植排斥(例如肾、肝脏、心脏、肺、胰腺(胰岛细胞)、骨髓、角膜、小肠和皮肤同种异体移植物以及心脏瓣膜异种移植物),移植物对宿主疾病,和自身免疫性疾病例如类风湿性关节炎、多发性硬化、青少年糖尿病、哮喘、炎性肠病(局限性回肠炎、溃疡性结肠炎)、狼疮、糖尿病、重症肌无力、牛皮癣、皮炎、湿疹、皮脂溢、肺炎眼色素层炎、肝炎、格雷夫斯病、桥本甲状腺炎、贝赫切特或斯耶格伦综合征(眼睛/口腔干燥)、恶性或免疫血液性贫血、自发性肾上腺机能不全、多腺自身免疫性综合征、和肾小球性肾炎、硬皮病、扁平苔癣、白斑(viteligo)(皮肤脱色素)、自身免疫性甲状腺炎、和牙槽炎。
这些方法包括给哺乳动物施用包含本发明化合物和可药用辅料的组合物的步骤。在优选的实施方案中,该特定方法还包括给所述哺乳动物施用包含另外的免疫抑制剂和可药用辅料的组合物的步骤。
或者,该方法包括给所述哺乳动物施用包含本发明化合物、另外的免疫抑制剂和可药用辅料的组合物的步骤。
在另一优选的实施方案中,这些方法可用于在哺乳动物中抑制病毒复制。这样的方法可用于治疗或预防由于例如感染下述病毒所致的DNA和RNA病毒疾病:正粘病毒(A和B型流感病毒)、副粘病毒(呼吸道合胞体病毒(RSV)、亚急性硬化全脑炎(SSPE)病毒)麻疹和副流感3型)、疱疹病毒(HSV-1、HSV-2、HHV-6、HHV-7、HHV-8、EB病毒(EBV)、巨细胞病毒(HCMV)和水痘带状疱疹病毒(VZV))、逆转录病毒(HIV-1、HIV-2、HTLV-1、HTLV-2)、黄和瘟病毒(黄热病毒(YFV)、丙肝病毒(HCV)、登革热病毒、牛病毒性腹泻病毒(BVDV)、嗜肝病毒(甲肝病毒(HAV)、乙肝病毒(HBV)、D型肝炎病毒(HDV)、E型肝炎病毒(HEV)、G型肝炎病毒(HGV)、克里米亚-刚果出血热病毒(CCHF)、布尼病毒(Punta Toro病毒、山谷热病毒(RVFV)、和白蛉热Sicilian病毒)、汉坦病毒、Caraparu病毒)、人乳头状瘤病毒、脑炎病毒(La Crosse病毒)、沙粒病毒(Junin和Tacaribe病毒)、呼肠病毒、水疱性口炎病毒、鼻病毒、肠道病毒(脊髓灰质炎病毒、柯萨奇病毒、脑心肌炎病毒(EMC))、拉沙热病毒、和披膜病毒(新培斯和塞姆利基(semlike)森林病毒)和痘病毒(牛痘病毒)、腺病毒、rubiola、和风疹。
这些方法包括给哺乳动物施用包含本发明化合物和可药用辅料的组合物的步骤。在优选的实施方案中,该特定方法还包括给所述哺乳动物施用包含另外的抗病毒剂和可药用辅料的组合物的步骤。
或者,该方法包括给所述哺乳动物施用包含本发明化合物、另外的抗病毒剂和可药用辅料的组合物的步骤。
在另一优选的实施方案中,这些方法可用于抑制哺乳动物中的血管细胞过度增殖。这样的方法可用于治疗或预防疾病,包括再狭窄、狭窄、动脉粥样硬化和其它过度增生性血管疾病。
这些方法包括给哺乳动物施用包含本发明化合物和可药用辅料的组合物的步骤。在优选的实施方案中,该特定方法还包括给所述哺乳动物施用包含另外的抗血管过度增生剂和可药用辅料的组合物的步骤。
或者,该方法包括给所述哺乳动物施用包含本发明化合物、另外的抗血管过度增生剂和可药用辅料的组合物的步骤。
在另一优选的实施方案中,这些方法可用于抑制哺乳动物中的肿瘤和癌症。这样的方法可用于治疗或预防疾病,包括肿瘤和恶性肿瘤例如淋巴瘤、白血病和其它形式的癌症。
这些方法包括给哺乳动物施用包含本发明化合物和可药用辅料的组合物的步骤。在优选的实施方案中,该特定方法还包括给所述哺乳动物施用包含另外的抗肿瘤或抗癌剂和可药用辅料的组合物的步骤。
或者,该方法包括给所述哺乳动物施用包含本发明化合物、另外的抗肿瘤或抗癌剂和可药用辅料的组合物的步骤。
在另一优选的实施方案中,这些方法可用于抑制哺乳动物中的炎症和炎性疾病。这样的方法可用于治疗或预防疾病,包括骨关节炎、急性胰腺炎、慢性胰腺炎、哮喘和成人呼吸窘迫综合征。
这些方法包括给哺乳动物施用包含本发明化合物和可药用辅料的组合物的步骤。在优选的实施方案中,该特定方法还包括给所述哺乳动物施用包含另外的抗炎剂和可药用辅料的组合物的步骤。
为了能更充分地理解本发明,提供下述实施例。这些实施例仅是举例说明,并且不应当理解为以任何方式对本发明范围的限制。
实施例1
合成化合物41A.合成C4
在0℃,向冰醋酸(46mL)、乙酸酐(46mL,485mmol)和2-甲基-5-硝基茴香醚(10.0g,60mmol)的溶液中滴加浓硫酸(6.9mL)。加入完成后,用60分钟分批加入CrO3(8.08g,80.8mmol)。在0℃搅拌15分钟,然后将该反应混合物倒入冰上,通过过滤分离出所得沉淀,用冷水洗涤。通过快速色谱法纯化,用15-50%在己烷中的EtOAc进行梯度洗脱,获得了8.14g(24%,按照回收的原料计为51%)C1,为白色固体。该1H NMR与所需结构一致。
将C1(81.94g,307mmol)在二氧杂环己烷(100mL)中的搅拌悬浮液用浓盐酸(20mL)处理,并加热回流过夜。冷却至室温后,产物C2作为浅黄色结晶固体沉淀出来,产量为40.65g(73.1%)。将滤液浓缩至约80mL体积,通过加入己烷从溶液中获得了第二批产物晶体,获得了8.91g(16.0%)。通过1H NMR和TLC分析鉴定了这两批产物,这两批产物产物与所需物质一致。C2的的总产量为49.56g(89.1%)。
将C2(456mg,2.51mmol)、甲苯磺酰基甲基异氰化物(490mg,2.51mmol)和K2CO3(347mg,251mmol)的溶液溶于甲醇中,并加热回流1.5小时。然后将产物混合物真空浓缩,再溶于CH2Cl2中,用水和盐水洗涤,用硫酸钠干燥,并再次真空浓缩。通过重结晶(Et2O/己烷)获得了纯化产物C3,产量为375mg(68%)。该1H NMR与所需结构一致。
将C3(4.214g,19.1mmol)在EtOAc(150mL)中的溶液用10%Pd/C(1.05g,25 wt.%C3)处理,并在40psi H2(g)(Parr氢化装置)氢化过夜。将该反应混合物过滤,并真空浓缩。通过快速色谱法纯化,用30-40%EtOAc/己烷进行梯度洗脱,获得了纯产物C4,产量为3.4g(93%)。该1H NMR与所需结构一致。B.合成化合物I113
将3-氨基苄基胺(826mg,6.87mmol)和三乙胺(2.39mL,17.18mmol)的溶液用二碳酸二叔丁酯(1.50g,6.87mmol)处理,将该混合物在室温搅拌2小时。然后将该反应用CH2Cl2稀释,用NaHCO3(水溶液)、水和盐水洗涤,干燥(Na2SO4),并真空浓缩。通过快速色谱法纯化,用25%在己烷中的EtOAc进行梯度洗脱,获得了纯的E1,产量为200mg(46%)。该1H NMR与所需结构一致。
将C4(150mg,0.789mmol)和1,1-二羰基咪唑(160mg,0.986mmol)的溶液合并在THF(5mL)中,并在室温搅拌6小时。观察到形成了咪唑沉淀。然后向该混合物中加入E1(351mg,1.58mmol)和N,N-二甲基氨基吡啶(97mg,0.789mmol),并将该混合物回流过夜,获得了均匀溶液。冷却至室温后,将该反应用EtOAc(20mL)稀释,用KHSO4(水溶液)、水、和盐水洗涤,干燥(MgSO4)并浓缩。通过快速色谱法纯化,用20-30-35%在己烷中的丙酮洗脱,获得了纯的I113,产量为164mg(47%)。1H NMR
(500MHz,d6-DMSO)δ8.90(s),8.75(s),8.38(s),7.60
(d),7.51(s),7.3-7.46(m),7.21-7.27(t),7.05(dd),
6.87(d),4.12(d),3.93(s),1.44(s).Rf 0.21(5%
在室温,向I113(250mg,5.76mmol)在CH2Cl2(1mL)内的悬浮液中滴加几当量的三氟乙酸,并搅拌90分钟。将所得溶液在真空汽提,并用CH2Cl2和甲醇研制。通过过滤分离到了纯产物I168,产量为258mg(99%)。该1H NMR与所需产物一致。D.合成化合物41
在室温,向1-甲氧基-2-丙醇(75mg,832μmol)在THF(1.0mL)内的溶液中一次性加入固体1,1’-羰基二咪唑(121mg,749mol)。将所得化合物在室温搅拌过夜,然后依次用TEA(174μL,1.25mmol)、固体化合物I168(376mg,832μmol)、和DMF(1.0mL)处理。将所得溶液在室温搅拌1天,然后用乙酸乙酯稀释,依次用水和盐水洗涤,用硫酸镁干燥,过滤并真空浓缩。然后通过快速色谱法(硅胶,97.5/1.5 CH2Cl2)纯化粗产物。然后将色谱纯化的产物用乙醚/乙酸乙酯的9/1混合物研制,获得了化合物45(65mg,56%收率),为白色粉状固体。1H NMR(500 MHz,丙酮 -d6);8.34(s,1H);8.21(s,1H);8.12(s,1H);7.67(s,1H);7.65(dd,1H);7.50(d,1H);7.47(d,1H);7.43(s,1H);7.25(dd,1H);7.10(dd,1H);6.97(d,1H);6.68(m,1H);4.92(m,1H);4.32(d,2H);4.01(s,3H);3.43(dd,1H);3.33(dd,1H);3.31(s,3H);1.18(d,3H),
其它本发明化合物可通过类似方法,在步骤C中用合适的醇代替1-甲氧基-2-丙醇[即HO-CH(R1)(R2)]来制得。
实施例2
将氰化铜(I)(7.2g,80.8mmol)与2-溴-5-硝基茴香醚(I)(15g,64.6mmol)在NMP(70mL)中合并,并在氮气氛下于150℃加热过夜。用硅藻土处理该混合物,冷却至室温,然后用EtOAc和1.0N NaOH稀释,并搅拌15分钟。将该不均匀混合物经由硅藻土垫过滤,用EtOAc洗涤,分离各相,用EtOAc将水相洗涤3次。将合并的有机相依次用1.0 N NaOH、水、和盐水洗涤,然后用Na2SO4干燥,过滤并真空浓缩。将粗产物溶于CH2Cl2中,经由短的硅胶垫过滤以除去固体和大部分有色杂质,然后真空浓缩,获得了II(10.41g,90%),为褐色-橙色固体。1H NR(500 MHz,CDCl3):7.90(d,1H);7.84(s,1H);7.77(d,1H);4.07(s,3H).
在室温,向II(7.2g,40.4mmol)在EtOAc-EtOH(220-15mL)内的溶液中加入10%Pd/C(1.8g),获得了不均匀的黑色混合物。将该反应置于1大气压(气球)的H2下,加热至50℃,并搅拌过夜。将该反应冷却至室温,通过过滤除去催化剂,将滤液真空浓缩,获得了III(5.56g,93%),为结晶固体。
1H NMR(500 MHz,CDCl3):7.29(d,1H);6.22(d,1H); 6.17
(s,1H);4.20(broad s,2H);3.85(s,3H).
在室温,用10分钟向氯甲酸苯酯(1.6mL,12.82mmol)在EtOAc(20mL)和NaHCO3(~1M,16mL)内的双相混合物中加入III(950mg,6.41mmol)在EtOAc(10mL)中的溶液。将所得不均匀混合物在室温搅拌30分钟,然后分离各相。用盐水洗涤有机相,用Na2SO4干燥,经由硅胶垫过滤,用EtOAc洗涤,并真空浓缩,获得了浓的油状物。将所得油状物在甲苯(30mL)中稀释,用己烷(30mL)处理,获得了浓的沉淀。将该混合物搅拌30分钟,过滤,用1∶1甲苯∶己烷洗涤固体,然后仅用己烷洗涤,并在高度真空下干燥至恒定重量,获得了IV(1.65g,96%),为白色粉末。1H NMR(500 MHz,dmso-d6);10.76(s,1H);7.69(d,1H);7.44(d,1H);7.40(d,1H);7.26(m,3H);7.15(d,1H);3.85(s,3H).B.制备右手侧偶联中间体(R9=S-甲基):
在室温,用30分钟向V(200g,1.21mol)在EtOH(2L)内的溶液中分批加入NaBH4(50.3g,1.33mol),使内温不超过40℃。将该反应在室温搅拌4小时。然后用水(~100mL)处理,真空浓缩,用乙酸乙酯稀释,用水洗涤2次,用饱和碳酸氢钠洗涤一次,用硫酸镁干燥,过滤并真空浓缩,获得了VI(191.7g,95%),为淡黄色固体。
1H NMR(500 MHz,CDCl3):8.21(s,1H);8.09(d,1H);7.70
(d,1H);7.49(dd,1H);5.01(dd,1H);2.45(s,1H);1.52
(d,3H).
在室温,向VI(181g,1.08mol)的溶液中加入DPPA(250mL,1.16mol),加入速度足够慢以将反应温度保持在45℃以下。一旦DPPA加入完成,即向该混合物中加入DBU(177mL,1.18mol),加入速度足够慢以将反应温度保持在45℃以下。加入完成后,将该反应温热至60℃,并在该温度下保持过夜。将所得双相混合物冷却至室温,然后依次用水、0.5 M HCl洗涤。用Na2SO4干燥有机相,过滤,并真空浓缩,获得了黄绿色油状物,不用进一步纯化。1H NMR(500 MHz,CDCl3):8.21(s,1H);8.18(d,1H);7.68(d,1H);7.56(q,1H);4.76(dd,1H);1.59(d,3H).
在室温,用10分钟用VII(8.17g,42.51mmol)在THF-水(80mL-10mL)内的溶液中加入Ph3P(12.3g,46.76mmol)在THF(20mL)中的溶液。立即释放出氮气,并在整个加入过程中保持恒定。然后将该反应在65℃加热过夜,冷却至室温。将该粗产物真空浓缩,用EtOAc稀释,用盐水洗涤,用Na2SO4干燥,并过滤。在室温用10分钟向所得滤液中加入1N HCl/Et2O,形成了沉淀。将该混合物在室温搅拌15分钟,然后过滤。用乙醚洗涤该固体,获得了黄色粉末。将该胺盐酸盐粗产物悬浮在盐水/EtOAc中,并在室温用10N NaOH(5mL,50mmol)处理。将所得混合物在室温搅拌直至所有固体溶解。分离各相,将水相用EtOAc洗涤2次,将合并的有机相用盐水处理,用Na2SO4干燥,过滤,并真空浓缩。将胺粗产物在MeOH(50mL)中稀释,并加到L-(+)-酒石酸(5.33g,35.33mmol)在MeOH(450mL)内的回流溶液中。立即形成了沉淀,然后回流15分钟以使其溶于MeOH混合物中。将内温降至50℃,并在该温度下保持过夜。然后将内温降至30℃,并再保持24小时,然后在室温保持24小时。过滤出所得晶体(钉状物),用甲醇和乙醚洗涤,弃去母液。将所得晶体溶于200mL回流的MeOH中,如上所述缓慢地冷却,过滤,并用MeOH洗涤,然后用乙醚洗涤,获得了第一批VIII(2.21g,20%),为白色固体。将母液真空浓缩,把固体溶于50mL回流的MeOH中,如上所述冷却,过滤,并用MeOH和乙醚洗涤,获得了第二批VIII(1.50g,13%),为白色固体。测定各批产物相应的氨基甲酸苯酯的光学纯度,结果>97%ee。
使用由Daicel Chemical Industries制造并购自ChiralTechnologies的Chiralcel OD柱(0.46cm×25cm)测定对映体过量。所用的流动相是70∶30己烷∶IPA混合物,以0.8ml/分钟的速度等度洗脱65分钟,注射3-4μl 1-2mg/ml氨基甲酸苯酯溶于上述己烷∶IPA混合物中的溶液。所需S-甲基对映体首先在约47.2分钟洗脱下来,不需要的R-甲基对映体在约51.7分钟洗脱下来,同时在约214、254、280nm波长监测。
所用样本都流过具有二极管排列检测器的Hewlett PackardSeries 1050 HPLC。
在室温,向VIII(1.11g,3.51mmol)在EtOAc(20mL)和盐水(20mL)内的不均匀悬浮液中加入10 N NaOH(0.77mL,7.72mmol)。将所得混合物在室温搅拌直至所有盐溶解。然后分离各相,用EtOAc洗涤水相。将合并的有机相用盐水洗涤,用Na2SO4干燥,过滤并真空浓缩。将硝基苄基胺粗产物在7M NH3-MeOH(20mL)中稀释,加入20%Pd(OH)2-C,并在45psi H2下氢化5小时。将所得混合物过滤以除去催化剂,真空浓缩,用CH2Cl2共沸一次,然后置于高度真空下,获得了IX(455mg,95%),为蜡状白色固体。1H NMR(500 MHz,dmso-d6):6.91(dd,1H);6.56(s,1H);6.50(d,1H);6.38(d,1H);4.90(宽s,2H);3.82(q,1H);3.31(宽s,2H);1.18(d,3H).C.制备化合物169
在室温,向3-(R)-羟基戊腈(212mg,2.14mmol)的溶液中一次性加入CDI(521mg,3.21mmol)。将所得混合物在室温搅拌1小时,然后用固体硅胶处理。将该不均匀的混合物剧烈搅拌10分钟,经由短的硅胶垫过滤,用4∶1 EtOAc∶IPA洗涤,真空浓缩,用MeCN共沸2次,然后与在MeCN(2mL)中的IX(350mg,2.57mmol)合并,并在室温搅拌1天。将所得混合物用EtOAc稀释,依次用水和盐水洗涤,用Na2SO4干燥,过滤,浓缩,通过快速色谱法纯化(硅胶,1/2?1/3?0/1己烷/EtOAc?4/1 EtOAc/IPA),获得了X(472mg,84%),为澄清的浓稠油状物。1H NMR(500 MHz,dmso-d6):7.73(d,1H);6.94(dd,1H);6.51(s,1H);6.47(d,1H);6.38(d,1H);4.98(宽s,2H);4.67(m,1H);4.49(m,1H);2.82(m,2H);1.62(m,2H);1.27(d,3H);0.89(dd,3H).
在室温,向X(470mg,1.80mmol)在EtOAc(5 mL)内的溶液中加入IV(440mg,1.63mmol)和TEA(0.23mL,1.63mmol)。将所得混合物加热至回流,并在该温度下搅拌6小时。将所得粗混合物冷却至室温,用EtOAc稀释,用盐水/1N HCl洗涤,然后仅用盐水洗涤,用Na2SO4干燥,过滤并真空浓缩,通过快速色谱法纯化(硅胶,1/1?1/2?1/3?1/4?0/1己烷/EtOAc?4/1 EtOAc/IPA),获得了169(740mg,100%),为白色泡沫状固体。1H NMR(500 MHz,dmso-d6):9.21(s,1H);8.84(s,1H);7.93(d,1H);7.59(d,1H);7.51(s,1H);7.41(s,1H);7.29(d,1H);7.23(dd,1H);7.01(d,1H);6.92(d,1H);4.69(m,1H);4.63(m,1H);3.89(s,3H);2.82(m,2H);2.62(m.2H):1.31(d,3H);0.90(t,3H)
实施例3
IMPDH活性抑制测定
通过改进首次由Magasanik报道的方法测定IMP脱氢酶活性[B.Magasanik等人,J.Biol.Chem.,226,p.339(1957),该文献引入本发明以作参考]。通过在340nm监测由于形成NADH所致的吸收度增加来以分光光度法测定酶活性(?340是6220 M-1 cm-1),该反应混合物含有0.1M磷酸钾8.0、0.5mM EDTA、2mM DTT、200μMIMP和浓度为15-50 nM的酶(II型人IMPDH)。将该溶液在37℃培养10分钟。通过加入终浓度为200μM的NAD来开始反应,并通过在340nm的吸收度线性增加(10分钟)来测定初始速度。为了在标准分光光度计(通路长度为1cm)中读数,比色杯中的终体积为1.0ml。还改进该测定以使得其适应96孔微量滴定板格式;对于这种情况,所有试剂都保持相同,并将终体积降至200μl。
为了分析抑制剂,将测试化合物以20mM的终浓度溶于DMSO中,并加到初始测定混合物中以与酶以2-5%(v/v)的终体积预培养。通过加入NAD来开始反应,并如上所述测定初始速度。通过测定在不同量抑制剂存在下的初始速度,并使用Henderson的紧结合方程(Henderson,P.J.F.(1972)Biochem.J.127,321]将数据拟合来测定Ki。
这些结果如表2所示。类项″A″是指10nM或更低的Ki,类项″B″是指大于10且小于50nM的Ki,类项″C″是指50nM或更大的Ki,″ND″是指没有测定抑制活性。
表2.IMPDH抑制活性
其它本发明化合物也具有IMPDH抑制活性。
实施例4
细胞测定A.分离外周血液单核细胞(PBMCs):使用肝素作为抗凝血剂,从正常的健康志愿者采集人静脉血液。通过在标准条件下用Ficoll-paque梯度或CPT管(Becton-Dickinson)离心来从血液中分离出PBMCs。收获PBMCs,洗涤并重悬在完全RPMI中,计数并稀释至1×106个细胞/mL。B.PBMC和脾细胞增殖测定
将5×104个细胞(人PBMC T细胞)或1×105个细胞(人PBMC B细胞)加到96-孔平板的各个孔中。对于T-细胞测定,向每个孔中加入终浓度为10-20μg/mL的植物血细胞凝集素(PHA)。对于B-细胞测定,向每个孔中加入终浓度为2μg/mL的葡萄球菌蛋白A(SPAS)。
在完全RPMI中制备系列4倍稀释的抑制剂贮备液,并加到细胞中,使化合物终浓度为20μM-20nM,而将DMSO保持在0.1%的终浓度。然后将细胞培养3天。所有样本都以一式三份测定。在该测定的最后24小时,加入含氚的胸腺嘧啶核苷(0.4uCi/孔)。在Betaplate滤器上收获细胞,并在闪烁计数器中计数。使用SoftMax PromTM(Molcular Devices)计算机软件包计算将细胞增殖抑制50%所需的化合物浓度(IC50值)。
这些测定的结果如表3所示。类项″A″是指100nM或更低的IC50,类项″B″是指大于100且小于1000nM的IC50,类项″C″是指1000nM或更大的IC50,″ND″是指在指定的细胞测定中没有测定到抑制活性。
实施例5
抗病毒测定
在各种体外和体内测定中评价化合物的抗病毒效力。例如,可在体外病毒复制测定中测试化合物。体外测定可使用完整细胞或分离的细胞成分。体内测定包括病毒性疾病的动物模型。这样的动物模型的实例包括但不限于用于HBV或HCV感染的啮齿动物模型,用于HBV感染的土拨鼠模型,用于HCV感染的黑猩猩模型。
虽然上文中已经描述了很多本发明实施方案,但是显然可对我们的基本方案作改变以提供使用本发明方法的其它实施方案。因此,应当理解,本发明的范围由权利要求书限定,而不是由上文中举例说明的具体实施方案确定。
Claims (28)
其中
各R1和R2独立地选自氢;-CF3;-(C1-C6)直链或支链烷基;-(C2-C6)-直链或支链链烯基或炔基;-(C1-C6)-直链或支链烷基-R7;-[(C2-C6)-直链或支链链烯基或炔基]-R7或-R7;并且其中至少一个R1或R2是-(C1-C6)-直链或支链烷基-R7;-[(C2-C6)-直链或支链链烯基或炔基]-R7或-R7
其中在任何所述烷基、链烯基或炔基上有最高达4个氢原子任选且独立地被R3取代;和
其中一个R1和R2或R1和R2都任选地被酯化形成前药;或者
其中,作为一种替代方式,R1和R2连在一起形成四氢呋喃基,其中当R9是氢、(R)-甲基、(R)-乙基或(R)-羟基甲基时,在所述四氢呋喃中的一个氢原子被-OR6或-R7替代,并且其中当R9是(S)-甲基、(S)-乙基或(S)-羟基甲基时,在所述四氢呋喃中的一个氢原子任选被-OR6或-R7替代;
其中当R9是氢、(R)-甲基、(R)-乙基或(R)-羟基甲基,且各R1和R2独立地为氢、未取代的-(C1-C6)-直链或支链烷基、或未取代的-(C2-C6)-直链或支链链烯基或炔基时,则由-CH(R1)R2代表的化合物部分是C5-C12直链或支链烷基、链烯基或炔基;
每一R3独立地选自卤素、CN、-OR4、或-N(R5)2;
R4选自氢、-(C1-C6)-直链或支链烷基、-(C2-C6)-直链或支链链烯基或炔基、-[(C1-C6)-直链或支链烷基]-R7、-[(C2-C6)-直链或支链链烯基或炔基]-R7、-C(O)-[(C1-C6)-直链或支链烷基]、-C(O)-[(C2-C6)-直链或支链链烯基或炔基]、-C(O)-[(C1-C6)-直链或支链烷基]-N(R8)2、-C(O)[(C2-C6)-直链或支链链烯基或炔基]-N(R8)2、-P(O)(OR8)2、-P(O)(OR8)(R8)、-C(O)-R7、-S(O)2N(R5)2、-[(C1-C6)-直链或支链烷基]-CN、或-[(C2-C6)-直链或支链链烯基或炔基]-CN;
每一R5独立地选自氢、-(C1-C6)-直链或支链烷基、-(C2-C6)-直链或支链链烯基或炔基、-[(C1-C6)-直链或支链烷基]-R7、-[(C2-C6)-直链或支链链烯基或炔基]-R7、-[(C1-C6)-直链烷基]-CN、-[(C2-C6)-直链或支链链烯基或炔基]-CN、-[(C1-C6)-直链或支链烷基]-OR4、-[(C2-C6)-直链或支链链烯基或炔基]-OR4、-C(O)-(C1-C6)-直链或支链烷基、-C(O)-[(C2-C6)-直链或支链链烯基或炔基]、-C(O)-R7、-C(O)O-R7、-C(O)O-(C1-C6)-直链或支链烷基、-C(O)O-[(C2-C6)-直链或支链链烯基或炔基]、-S(O)2-(C1-C6)-直链或支链烷基、或-S(O)2-R7;或者当结合在同一氮原子上时,两个R5部分与所述氮原子一起形成3-7元杂环,其中所述杂环任选含有1-3个独立地选自N、O、S、S(O)或S(O)2的另外的杂原子;
R6选自-C(O)-CH3、-CH2-C(O)-OH、-CH2-C(O)-O-tBu、-CH2-CN、或-CH2-C≡CH;
每一R7是单环或二环环系,其中在所述环系中:
i.每个环包含3-7个独立地选自C、N、O或S的环原子;
ii.不超过4个环原子选自N、O或S;
iii.任一CH2任选被C(O)替代;
iv.任一S任选被S(O)或S(O)2替代;
每一R8独立地选自氢或-[C1-C4]-直链或支链烷基;
其中在所述化合物的任一环系中,最高达3个结合在环原子上的氢原子任选且独立地被卤素、羟基、硝基、氰基、氨基、(C1-C4)-直链或支链烷基;O-(C1-C4)-直链或支链烷基、(C2-C4)-直链或支链链烯基或炔基、或O-(C2-C4)-直链或支链链烯基或炔基替代;并且
其中任一环系任选地是苯并稠合的;
R9选自氢、(R)-甲基、(S)-甲基、(R)-乙基、(S)-乙基、(R)-羟基甲基或(S)-羟基甲基;
R10选自-C=N或5-噁唑基;
R11选自卤素、-O-(C1-C3)直链烷基、或-O-(C2-C3)直链链烯基或炔基。
2.权利要求1的化合物,其中所述化合物具有式(I):其中R1和R2如权利要求1所定义。
3.权利要求1的化合物,其中所述化合物具有式(IA):
其中R9选自(R)-甲基、(S)-甲基、(R)-乙基、(S)-乙基、(R)-羟基甲基或(S)-羟基甲基;且
R1和R2如权利要求1所定义。
4.权利要求3的化合物,其中R9选自(S)-甲基、(S)-乙基、或(S)-羟基甲基甲基。
5.权利要求4的化合物,其中R9是(S)-甲基。
6.权利要求3的化合物,其中R11选自O-甲基、O-乙基或O-异丙基。
7.权利要求1的化合物,其中:
至少一个R1或R2选自氢、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、正戊基、苯基、吡啶基、-CH2OCH3,-CH2CN,-CH2OCH2CH2CN,-CH2C(CH3)2CH2CH2CN,-CH2C(CH2CH3)2CH2CH2CN,-CH2CH2CN,-CH2N(CH2CH2CN)2,-CH2N(CH3)CH2CH2CN,-CH(NH2)CH2CN,-CH2Cl,-CH2OH,-CH2CH2OH,-CH2CH2OH,-CH2CH2CH2CH2OH,-CH2CH2OC(O)CH3,-CH2CH2OC(O)CH2NH2,-CH2CH2NHCH3,-CH2CH2N(CH3)2,-CH2N(CH2CH3)2,-CH2CH2N(CH2CH3)2,-CH2CH2CH2N(CH3)2,-CH2CH2CH2N+(CH3)3,-CH2OCH2CH(CH3)2,-CH2CH2N(CH3)C(O)OC(CH3)3,-CH2N(CH2CH2CN)CH2CH(CH3)2,-CH(CH2CN)N(CH3)2,-CH2CH(CH2CN)NHC(O)OC(CH3)3,其中n是0或1。
8.权利要求2的化合物,其中R1和R2一起形成在5-位被-OR6取代的3-四氢呋喃基部分。
9.权利要求3的化合物,其中一个R1或R2选自氢、乙基或苯基;另一个R1或R2选自-CH2OH、-CH2CN、-CH2CH2CN或CH2N(CH2CH3)2;或者其中R1和R2一起形成3-四氢呋喃基部分。
10.权利要求1的化合物,其中所述化合物选自在表1中的任一化合物1-187。
11.权利要求10的化合物,其中所述化合物选自在表1中的任一化合物1、23、26、27、29、32、76、80、87、89、98、101、103、104、106、108、110、157、163、169、171、181、185、186或187。
12.包含IMPDH抑制有效量的权利要求1的化合物和可药用载体、辅料或赋形剂的组合物。
13.权利要求12的组合物,其中所述组合物还包含选自免疫抑制剂、抗癌剂、抗病毒剂、抗炎剂、抗真菌剂、抗生素、或抗血管过度增殖化合物的另外的活性剂。
14.治疗或预防哺乳动物中IMPDH-介导的疾病或病症的方法,包括给所述哺乳动物施用权利要求12或13的组合物的步骤。
15.权利要求14的方法,其中所述IMPDH-介导的疾病或病症选自移植排斥、移植物对宿主疾病、自身免疫性疾病。
16.权利要求14的方法,其中给所述哺乳动物施用在单独剂型中的或者作为所述组合物一部分的另外的免疫抑制剂。
17.抑制哺乳动物中病毒复制的方法,包括给所述哺乳动物施用权利要求12或13的组合物的步骤。
18.权利要求17的方法,其中所述哺乳动物患有由选自下述的病毒引起的病毒感染:正粘病毒、副粘病毒、疱疹病毒、逆转录病毒、黄病毒、瘟病毒、嗜肝病毒、布尼病毒、汉坦病毒、Caraparu病毒、人乳头状瘤病毒、脑炎病毒、沙粒病毒、呼肠病毒、水疱性口炎病毒、鼻病毒、肠道病毒、拉沙热病毒、披膜病毒、痘病毒、腺病毒、rubiola、或风疹被抑制。
19.权利要求17的方法,其中给所述哺乳动物施用在单独剂型中的或者作为所述组合物一部分的另外的抗病毒剂。
20.抑制哺乳动物中血管细胞过度增殖的方法,包括给所述哺乳动物施用权利要求12或13的组合物的步骤。
21.权利要求20的方法,其中所述方法是用于治疗或预防再狭窄、狭窄、动脉粥样硬化或其它过度增生性血管疾病。
22.权利要求20的方法,其中给所述哺乳动物施用在单独剂型中的或者作为所述组合物一部分的另外的抗血管过度增殖剂。
23.抑制哺乳动物中肿瘤和癌症的方法,包括给所述哺乳动物施用权利要求12或13的组合物的步骤。
24.权利要求23的方法,其中所述方法是用于治疗或预防淋巴瘤、白血病、和其它类型的癌症。
25.权利要求24的方法,其中给所述哺乳动物施用在单独剂型中的或者作为所述组合物一部分的另外的抗肿瘤或抗癌剂。
26.抑制哺乳动物中炎症或炎性疾病的方法,包括给所述哺乳动物施用权利要求12或13的组合物的步骤。
27.权利要求26的方法,其中所述方法是用于治疗或预防骨关节炎、急性胰腺炎、慢性胰腺炎、哮喘或成人呼吸窘迫综合征。
28.权利要求27的方法,其中给所述哺乳动物施用在单独剂型中的或者作为所述组合物一部分的另外的抗炎剂。
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CN101466693B (zh) * | 2006-05-19 | 2012-12-12 | 阿纳孔达药业公司 | 用作人乳头瘤病毒抑制剂的哌啶衍生物 |
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