CN101863886A - 用作生长激素促分泌素的杂环芳香化合物 - Google Patents
用作生长激素促分泌素的杂环芳香化合物 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
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- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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Abstract
本发明提供了用在刺激生长激素内生成或释放的新颖的杂环芳香化合物,所述化合物具有结构式(I)的通用结构,其中R1、R1’、R2、R3、R4、Xa、Y、Z和n在本文中被描述。本文中提供的化合物可用于治疗肥胖、骨质疏松症(改善骨密度)和用于改善肌肉质量(muscle mass)和肌力。
Description
本申请是分案申请,原申请的申请日为2003年9月2日、申请号为03820864.4(PCT/US2003/027513)、发明名称为“用作生长激素促分泌素的杂环芳香化合物”。
相关申请
本申请要求标题35§119(e)中,2002年9月4日提交的美国临时申请60/408,099,和2003年7月31日提交的美国临时申请60/491,645的优先权,其内容引入本文以作参考。
发明领域
本发明涉及刺激生长激素(growth hormone)的内源生成和/或释放的新颖的杂环芳香化合物(heterocyclic aromatic compounds)。本发明还涉及使用这种化合物的方法和含有这种化合物的药物组合物。
发明背景
生长激素(growth hormone)不仅对线性肌体生长(linear bodygrowth)是重要的,而且对于维持成人生命的肌体组成、代谢和心脏功能也是重要的。事实上,用生长激素进行治疗已经被用于遭受生长激素缺乏之苦的成人和儿童。用生长激素进行治疗已经显示出能减少身体脂肪,增加无脂肪物质,增加肌力,改善骨骼质量和健康。这些与生长激素治疗相关的有益效果显示出,生长激素治疗还可以用于治疗骨质疏松症、老年人的虚弱(frailty)、复杂性骨折、心肌病、肥胖,和一些由如AIDS(艾滋病)、慢性透析、代谢疾病和肾上腺皮质激素治疗引起的氮消耗性症状(nitrogen-wasting conditions)。Johan Svensson,Exp.Opin.Ther.Patents,2000 10(7)1071-1080;Ankersen et al.,DDT,1999,4(11)497-506。还有,也探索了生长激素治疗(growth hormonetherapy)有望用于逆转与衰老有关的变化。
目前生长激素的给药方法是侵入性的,即合成的激素必须通过日常注射给药。因此,如果口服的促分泌素(secretagogue)被引入,它是安全、有效、耐受性好的,那么它将提供对目前的生长激素治疗的具有吸引力的一种替代治疗方法。
生长激素促分泌素(growth hormone secretagogues)是合成制得的肽类和非肽类,能通过在脑垂体和下丘脑水平上作用于一种或多种特异的受体来刺激生长激素的内源生成和/或释放。相应地,口服活性生长激素促分泌素能提供对传统生长激素治疗的吸引人的替代方法,因而提供一种治疗与患者循环系统中生长激素水平相关的许多疾病或障碍的更为方便的方法。
发明概述
根据本发明,提供了新颖的芳香杂环化合物(novel heterocyclicaromatic compounds),具有式I所示的通用结构
其中:
Xa是2-4个稠合或螺旋的环烷基、杂环、芳基或杂芳基环,其中一个或多个所述环可以任意地被1-5个取代基取代,取代基选自Ra和Rb;
R1是一个取代的或未取代的官能基团,选自:烷基、芳基、链烯基、炔基、芳烷基、环烷基、杂环、烷氧基烷基、芳烷氧基烷基(arylalkyloxyalkyl)、芳氧基烷基、杂芳基、环烷基烷氧基烷基(cycloalkylalkoxyalkyl)、杂芳烷氧基(heteroarylalkoxy)、杂芳烷基(heteroarylalkyl)、杂环烷基(heterocycloalkyl)和杂环烷基;
R2、R3和R4分别独立地是一个取代的或未取代的官能基团,选自:氢、烷基、链烯基、炔基、芳基、芳烷基、环烷基、杂环、烷氧基烷基、芳烷氧基烷基、芳氧基烷基、杂芳基、环烷基烷氧基烷基、杂芳烷基和杂环烷基,或R3和R4结合起来能形成3-8元环烷基或杂环,或一个或多个R3和R4能和一个或多个Y和Z结合起来形成单环或双环的环烷基或杂环;
R1′是一个取代的或未取代的官能基团,选自:氢、烷基、环烷基、杂环、芳基和杂芳基;
Y是一个连接基团,选自亚烷基、亚链烯基(alkenylene)、亚炔基、亚芳基和杂亚芳基,所述连接基团可以任意地被一个或多个官能基团取代,官能基团选自烷基、芳基、环烷基、杂环、烷氧基烷基、杂芳基、芳烷基、芳烷氧基烷基、芳氧基烷基、环烷基烷氧基烷基、杂芳烷基和杂环烷基、卤素、-OR5、-OC(O)R5、-CF3、-OCF3、-N(R5)C(O)R5′和-NR5R5′;
R5和R5′每一次出现,都各自独立地选自氢、烷基、环烷基、杂环和芳基,其中R5和R5′每一次出现,可以任意地被一个或多个Rb取代;
Ra和Rb每一次出现,都各自独立地选自烷基、链烯基、炔基、卤素、氰基、羰基、-CN、芳基、芳烷基、芳链烯基(arylalkenyl)、芳炔基(arylalkynyl)、环烷基、烷氧基、烷氧基烷基、芳氧基、芳氧基烷基、杂环、杂芳基、杂芳烷基、-OR2、-NR5R5′、-CF3、-SO2R6、-SO2NR6R6′、-(CH2)mR8和R9;
R6和R6′每一次出现,都各自独立地选自氢、烷基、链烯基、炔基、烷硫烷基(alkylthioalkyl)、烷氧基烷基、芳基、芳烷基、杂环、杂芳基、杂芳烷基、杂环烷基和环烷基,其中R6和R6′每一次出现,都可以任意地被1-3个取代基取代,这些取代基选自卤素、-OR2、烷氧基、杂环烷基、-NR5C(O)NR5R5′、-C(O)NR5R5′、-NR5C(O)R5′、-CN、-NR5SO2R5′、-OC(O)R5、-SO2NR5R5′、-SOR7、-COOH和-C(O)OR7,或R6和R6′结合起来可以被环化形成-(CH2)qX(CH2)s-;
R7每一次出现时,独立地选自C1-C6烷基、芳基和杂芳基,其中R7可以任意地被-(CH2)wOH取代;
R8选自烷氧基、烷氧基羰基、-C(O)NR6R6’、-NR5R5’、-C(O)R6、-NR5C(O)NR5R5和-N-杂芳基;
R9选自杂环烷基、杂芳基、-CN、-(CH2)PN(R6)C(O)R6’、-(CH2)PCN、-(CH2)PC(O)OR6’、-(CH2)PN(R6)C(O)NR6R6’、-(CH2)PN(R6)SO2R6、-(CH2)PC(O)NR6R6’、-(CH2)PC(O)R6、-(CH2)POC(O)OR6、-(CH2)POC(O)R6、-(CH2)POC(O)NR6R6’、-(CH2)PN(R6)SO2NR6R6’、-(CH2)POR6、-(CH2)POC(O)N(R6)(CH2)mOH-(CH2)P SO2R6和-(CH2)POC H2C(O)N(R6)(CH2)mOH;
X选自-CR5R5’-、-O-、-S-、-SO-、-SO2-、-NC(O)OR7、-NC(O)NR5-和-NR5-;
Z是氮;
m是从1到6的整数;
n是从1到6的整数;
p是从0到5的整数;
w是从0到5的整数;和
q和s分别独立地是从1到3的整数,其限制是当R5、R5’、R6或R6’其中之一被连接到羰基基团(如-C(O)R6)或砜基团(如-SO2R6)上时,R5、R5’、R6或R6’不能是氢。
式I的上述定义包括所有药物前体、药物前体酯、立体异构体和药学上可接受的式I化合物的盐。
式I的化合物显示出了作为生长激素促分泌素的活性,即它们刺激生长激素的内源生成(endogenous production)和/或释放,和可用于治疗与生长激素水平相关的疾病或者不适,诸如本文中公开的疾病或障碍。
本发明提供了式I的化合物,使用这种化合物的药物组合物,和使用这种化合物的方法。特别地,本发明提供了包含治疗效果剂量的式I化合物的药物组合物,单独使用或与药学上可接受的载体一起使用。
还有,根据本发明,提供了增加内源生长激素水平的方法或增加生长激素的内源生成或释放的方法,其中治疗有效量的式I化合物被给药于哺乳动物,如人,需要治疗的患者。
还有,根据本发明,提供了预防或治疗与哺乳动物生长激素水平相关的疾病或障碍,诸如本文中描述的,其中治疗有效量的式I化合物被给药于哺乳动物,如人,需要治疗的患者。
本发明的化合物可以单独使用,也可以与本发明的其他化合物并用,或与本文中描述的治疗领域中的其他一种或多种具有活性的试剂并用。
还有,本发明提供了预防、抑制或治疗上文中和下文中描述的疾病,其中治疗有效量的式I化合物和式I的其他化合物和/或至少一种其他类型的治疗剂的并用药物被给药于哺乳动物,如需要治疗的人类患者。
优选其中Xa具有下述结构的式I化合物:
其中:
Q1和Q2分别独立地是环烷基、杂环、芳基或杂芳基环,其中Q1可以被1到四个选自Ra和Rb的取代基取代,和Q2可以被1到四个选自Ra、Rb和Q3的取代基取代;
Q3是一个3到8元的稠合或螺旋环烷基、杂环、芳基或杂芳基环,其中Q3任意地可以被1到5个选自Ra、Rb和Q4的取代基取代;和
Q4是一个3到8元的稠合或螺旋环烷基、杂环、芳基或杂芳基环,其中,Q4任意地可以被1到5个选自Ra和Rb的取代基取代;
A是N或CR11;
B是N或CR11;和
R11是H或键。
进一步的实施方式包括式I所示的化合物,其中Xa具有下述结构:
尽管上面公开的优选的Xa结构在任何特定的环烷基、芳基、杂芳基或杂环上显示出一个或多个Ra和/或Rb取代基,优选的Xa结构不局限于上面举例说明的特异的Ra/Rb取代,也不局限于所需的Ra和/或Rb基团。相反,Rb和/或Ra取代在优选Xa结构、随后的图解方案和权利要求书中的存在,显示了一个或多个Ra/Rb基团可以任意地被连接于Rb/Rb’基团所连接的环上的任何可以利用的附着位置。因此,即使此下文中优选的Xa结构、图解方案、和权利要求书可以参考一个特定的实施方式,应该理解各种其他修改,诸如一个或多个Rb和/或Ra基团的取代,或本领域技术人员熟悉的其他修改和治疗学上等同的化合物可以在本文所要求保护的化合物的范围和精神之内被应用。
优选式I化合物,其中当Ra或Rb是R9时,R6是杂环或烷基,任选地被羟基或卤素取代。
优选式I化合物,其中当Ra或Rb是R9,R6和R6′分别独立地是氢、烷基或环烷基,其中烷基或环烷基任意地被-C(O)OR7或-C(O)NR5R5′取代,或R6和R6′结合起来能被环化形成-(CH2)qX(CH2)s-。
还有,优选式I化合物,其中当Ra或Rb是R9时,R9是(CH2)pC(O)OR6、(CH2)pOC(O)R6、或(CH2)pOC(O)N(R6)(CH2)mOH。
还有,优选式I化合物,其中R9是-(CH2)pN(R6)C(O)OR6′、-(CH2)pN(R6)C(O)NR6R6′、或(CH2)pOC(O)NR6R6′,其中R6和R6′分别独立地是氢或烷基,其中烷基任意地被-C(O)NR5R5′取代,其中R5和R5′分别独立地是氢或烷基。
进一步的优选实施方案包括具有下述结构的式I的化合物:
附加的优选实施方式包括具有下述结构的式I化合物:
本发明化合物全都具有至少一个如在结构式I中用星号标记的不对称中心(asymmetric center)。额外的不对称中心也能存在于该分子中,这取决于分子上的各种取代基的特性。每个此类不对称中心将产生两个旋光异构体,其旨在将所有此类旋光异构体,如分离的、纯的或部分纯化的旋光异构体或它们的外消旋混合物都包括在本发明的范围和精神之内。在不对称中心以式I中的星号表示的情况下,活性更大,因此,更优选的构型是R/S规则确定的R。异构体可以通过传统方法,如层析法或分级结晶方法分离。
发明详述
下面的缩写运用于本文中:
Boc=叔丁氧羰基(tert-butoxycarbonyl)
CBZ=苄氧羰基(benzyloxycarbonyl)(或苄氧羰基,carbobenzoxy)
DIBAL=氢化二异丁基铝
DMAP=4-(二甲氨基)吡啶
DMF=N,N-二甲基甲酰胺
EDAC=1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride)
EtOAc=乙酸乙酯
HOBT=羟基苯并三唑
HPLC=高效液相色谱
LC/MS=高效液相色谱/质谱
MS或Mass Spec=质谱
Pd/C=钯碳(披钯活性木炭,palladium on activated charcoal)
TFA=三氟乙酸
YMC=YMC Co,Ltd.,Kyoto,Japan的商标
g=克
h或hr=小时
min=分钟
ml=毫升
mg=毫克
mol=摩尔
mmol=毫摩尔
nM=纳摩尔
r.t.=室温
Et=乙基
i-Pr=异丙基
Me=甲基Chiral=手性(的)
下面的定义运用于整个说明书中所使用的术语上,除非在具体的情况下另有限制。
除非另外说明,本文中单独或者作为其他基团的部分所使用的术语“烷基(alkyl)”包括,直链和支链烷烃,其正链中含有1-40个碳原子,优选1-20个碳原子,更优选1-6个碳原子,诸如甲基、乙基、丙基、异丙基、丁基、t-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,和类似物。还有,烷基基团,如本文中所定义的,可以在任何可以利用的碳原子上任意地被一个或多个官能团所取代,以形成诸如三氟甲基、3-羟己基、2-羧丙基、2-氟乙基、羧甲基、羧丁基和类似物的烷基基团,这些官能团通常连接到这些链上,诸如但不限于烷基、芳基、链烯基、炔基、羟基、芳烷基、环烷基、环烷烷基(cycloalkylalkyl)、烷氧基、芳烷氧基、烷醇基、氨基、卤代、硫代、氰基、羧基、羰基氨基、酰氨基、卤芳基(haloaryl)、CF3、OCF3、芳氧基、杂芳基、环烷基烷氧基烷基(cycloalkylalkoxyalkyl)、环杂烷基(cycloheteroalkyl)和类似物。
除非另外说明,本文中单独或作为其他基团的部分所运用的术语“环烷基(cycloalkyl)”包括,饱和的或部分不饱和(含有1或2个双键)的环烃基团,其含有1到3个环,包括单环烷基、双环烷基和三环烷基,共含有3到20个成环的碳原子,优选4到10个碳原子,形成该环,且其可以被稠合到1个为芳基描述的芳(族)环上,其包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基、环十二烷基、环己烯基,
其中任何基团可以任意地被1到3个上面为烷基描述的取代基所取代。
本文中单独或作为其他基团的部分所运用的术语“芳基(aryl)”,指在环部分(诸如苯基或萘基)上含有6到10个碳的单环或双环芳香基团,且可以任意地包括1到3个稠合到“芳基”(诸如芳基、环烷基、杂芳基或环杂烷基环)上的附加环,且可以任意地通过1个任何可利用的碳原子被下述基团取代,选自氢、卤素、烷基、卤烷基、烷氧基、卤代烷氧基、链烯基、三氟甲基、三氟甲氧基、炔基、环烷烷基、芴基、环杂烷基、环杂烷烷基(cycloheteroalkylalkyl)、芳基、杂芳基、芳烷基、芳氧基、芳氧基烷基、芳烷氧基、芳硫基(arylthio)、芳唑基、杂芳烷基、杂芳链烯基(heteroarylalkenyl)、杂芳基杂芳基(heteroarylheteroaryl)、杂芳氧基、羟基、硝基、氧代、氰基、氨基、取代氨基,其中该氨基包括1或2个取代基(其为烷基、芳基或定义中提到的任何其他芳基化合物)、硫醇、烷硫基、芳硫基、杂芳硫基、芳硫基烷基、烷氧基芳硫基(alkoxyarylthio)、烷羰基(alkylcarbonyl)、芳羰基(arylcarbonyl)、烷基氨基羰基(alkylaminocarbonyl)、芳基氨基羰基(arylaminocarbonyl)、烷氧羰基、氨羰基、烷羰氧基(alkylcarbonyloxy)、芳羰氧基(arylcarbonyloxy)、烷羰氨基(alkylcarbonylamino)、芳羰氨基(arylcarbonylamino)、芳基亚磺酰基(arylsulfinyl)、芳基亚磺酰基烷基(arylsulfinylalkyl)、芳基亚磺酰基氨基(arylsulfonylamino)或芳基亚磺酰基氨基羰基(arylsulfonaminocarbonyl)、或任何上面说明的烷基取代基。
本文中单独或作为其他基团的部分使用的术语“芳烷基(arylalkyl)”,指上面描述的烷基基团,具有芳基取代基,诸如苯甲基、苯乙基或萘丙基,其中所述芳基和/或烷基基团可以任意地如上面描述的那样被取代。
本文中单独或作为其他基团的部分运用的术语“烷氧基(akoxy)”或“芳氧基(aryloxy)”包括通过氧原子连接的如上面描述的烷基或芳基基团。
除非另外指出,术语“链烯基(alkenyl)”,本文中用作其本身或作为其他基团的部分所使用,是指在正链上具有2到20个碳,优选3到12个碳,更优选2到6个碳的直链或支链原子团,其在正链上包含一个或多个双键,诸如乙烯基、2-丙烯基、3-丁烯基、2-丁烯基、4-戊烯基、3-戊丁烯基、2-己烯基、3-己烯基、2-庚烯基、3-庚烯基、4-庚烯基、3-辛烯基、3-壬烯基、4-癸烯基、3-十一碳烯基、4-十二碳烯基、4,8,12-十四碳三烯基(4,8,12-tetradecatrienyl)和类似物,且其可以任意地被一个或多个上述为烷基定义的官能基团取代。
除非另外指出,本文中单独或作为其他基团的部分运用的术语“炔基(alkynyl)”指正链上具有2到20个碳,优选2到12个碳,更优选2到8个碳的直链或支链原子团,其在正链上包含一个或多个三键,诸如2-丙炔基、3-丁炔基、2-丁炔基、4-戊炔基、3-戊丁炔基、2-己炔基、3-己炔基、2-庚炔基、3-庚炔基、4-庚炔基、3-辛炔基、3-壬炔基、4-癸炔基、3-十一碳炔基、4-十二碳炔基和类似物,且可以任意地被一个或多个上述为烷基定义的官能基团取代。
本文中单独或作为其他基团的部分运用的术语“亚烷基(alkylene)”指上述烷基连接基团,在两个不同碳原子上具有用于与其他基团连接的单键,且可以任意地如上述为“烷基”限定的那样被取代。
本文中单独或作为其他基团的部分运用的术语“亚链烯基(alkenylene)”和“亚炔基(alkynylene)”指链烯基和炔基连接基团,在两个不同碳原子上具有用于与其他基团连接的单键,且可以任意地如上述为“烷基”限定的那样被取代。本文中单独或作为其他基团的部分运用的术语“卤素(halogen)”或“卤(halo)”指氯、溴、氟和碘。
本文中使用的术语“杂芳基(heteroaryl)”指一个5-、6-或7-元的芳香杂环,其包含一个或多个选自氮、硫、氧和/或SO或SO2基团的杂原子。这种环可以被稠合到另一个环烷基、环杂烷基、芳基或杂芳基环上,包括可能的N-氧化物。任意地,杂芳基基团可以被一个或多个通常连接到这些环上的官能基团所取代,诸如为烷基所描述的那些。
术语“杂环(heterocyclo)”、“杂环(heterocycle)”或“杂环的(heterocyclic)”,如在此所用的,代表一个未取代的或取代的、稳定的4-、5-、6-或7-元单环体系,其可以是饱和的或不饱和的,其由碳原子和一个到四个选自N、O、S和/或SO或SO2基团的杂原子组成,其中氮和硫杂原子可以任意地被氧化,氮杂原子可以任意地被季铵化。该杂环可以在任何杂原子或碳原子上被连接,由此产生稳定的结构。这种杂环的例子包括,但不限于,哌啶基、哌嗪基、氧哌啶基、氧哌嗪基和噁二唑基(oxadiazolyl)。任意地,杂环基团可以被一个或多个官能基团,如为烷基描述的那些官能基团取代。
本文中单独或作为其他基团的部分运用的术语“杂环烷基(heterocycloalkyl)”或“杂芳烷基(heteroarylalkyl)”分别指通过烷基连接的杂环或杂芳基基团。
本文中单独或作为其他基团的部分运用的术语“烷氧基烷基(alkoxyalkyl)”或“芳氧基烷基(aryloxyalkyl)”分别指通过烷基连接的烷氧基或芳氧基基团。
本文中单独或作为其他基团的部分运用的术语“杂芳烷氧基(heteroarylalkoxy)”指通过烷氧基团连接的杂芳基基团。
本文中单独或作为其他基团的部分运用的术语“环烷基烷氧基烷基(cycloalkylalkoyalkyl)”和“芳烷氧基烷基(arylalkyloyalkyl)”分别指通过烷氧基基团连接的环烷基基团和芳基基团,也就是依次通过烷基基团连接的。
本文中单独或作为其他基团的部分运用的术语“亚芳基(arylene)”或“杂亚芳基(heteroarylene)”指如上述定义的亚烷基、亚链烯基或亚炔基连接基团,其中所述亚烷基、亚链烯基或亚炔基连接基团在碳链上含有芳基(Ar)或杂芳基(heteroaryl,Het)基团。例子包括,但不限于-(CH2)2-Ar-(CH2)2-或-(CH2)2-Het-(CH2)2-。
在此使用的术语“羰基(carbonyl)”指-C(O)-基团,或当指可能的取代基时,指连接到官能基团或被取代的连接基团中的任何可以利用的碳原子上的(=O)基团。
在此使用的术语“苯氧基(phenoxy)”指通过氧原子连接的苯基取代基。任意地,苯氧基的苯环部分可以被一个或多个官能基团,如为烷基描述的官能基团所取代。
本发明治疗剂的给药方法包括给予有效治疗剂量的本发明试剂。本文中使用的术语“有效治疗量或治疗有效量(therapeutically effectiveamount)”是指通过给予本发明组合物来治疗或预防可治疗症状的治疗剂的用量。该用量是足以呈现出可检测的治疗或预防或改善的效果的量。效果可以包括,如治疗或预防本文中列举的症状。对一个患者的精确有效量将取决于患者的身体大小和健康状况、被治疗的症状的特点和程度、治疗医生的建议和选择给药的治疗方法和治疗方法的组合。因此,预先详细指出确切的有效量是没用的。
能在体内被转换,来提供生物活性剂(即,式I的化合物)的任何化合物是在本发明范围和发明精神内的药物前体(prodrug)。
本文中使用的术语“药物前体酯(prodrug esters)”包括酯和碳酸盐,通过用本领域技术人员熟悉的工艺将式I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,以便生产醋酸盐、新戊酸酯、甲基碳酸盐、苯甲酸盐和类似物。
各种形式的药物前体是本领域公知的,描述于:
a)The Practice of Medicinal Chemistry,Camille G.Wermuth et al.,Ch 31,(Academic Press,1996);
b)Design of Prodrugs,edited by H.Bundgaard,(Elsevíer,1985);和
c)A Textbook of Drug Design and Development,P.Krogsgaard-Larsonand H.Bundgaard,eds.Ch 5,pgs 113-191(Harwood AcademicPublishers,1991)。
所述参考文献引用在此,作为参考。
本发明化合物的所有立体异构体都被考虑,以混合物的形式或以纯的形式或以基本纯的形式。本发明化合物可以在任何包括R取代基的碳原子上具有不对称中心。因此,式I化合物能以对映体、非对映体形式或以它们的混合物的形式存在。制备过程可以利用外消旋物、对映体或非对映体作为起始物质。当制得非对映体或对映体产物时,它们可以通过传统的方法如层析技术或分阶段结晶分离而得。
本发明式I化合物的药学上可接受的盐,包括碱金属盐如锂、钠或钾;碱土金属盐诸如钙或锰;以及锌或铝和其他阳离子诸如铵、胆碱、二乙醇胺、乙二胺、t-丁胺、t-辛胺、去氢松香胺;以及药学上可接受的阴离子,如氯化物、溴化物、碘化物、酒石酸盐、醋酸盐、甲基磺酸盐、马来酸盐、琥珀酸盐、戊二酸盐、硬脂酸盐和天然存在的氨基酸的盐,如精氨酸、赖氨酸、丙氨酸和类似物及其药物前体酯。
通用合成方案
本发明化合物可以依据下述通用合成反应方案和可以被本领域技术人员使用的相关公开文献程序制备而得。示范性试剂、程序和反应条件在下文中和工作实施例中出现。起始物质从市场上可以得到,或能够很容易地被本领域普通技术人员使用已知的方法制备而得。除非另外详细说明,化合物的各种取代基用跟式I同样的方式被定义。
高速模拟(High Speed Analoging,HSA)可以被用于制备化合物,例如,其中中间体具有胺位置(amine position)或活性芳基位置(aromaticposition),诸如卤化的Q1和Q2。
方案I
方案I描述了用于制备式I化合物的一个通用合成顺序。在制备式I化合物中,可以使用一个或多个保护基团,保护和去保护的反应条件可以在“Protective Groups in Organic Synthesis”Greeneet al.,JohnWiley and Sons Inc,1991中找到,或本领域普通技术人员使用的其他方法。
式I化合物可以由式II化合物和胺XXXII,在惰性溶剂中,使用合适的羧酸活化剂制备而得,示范性羧酸活化剂包括异丁基氯甲酸酯(isobutylchloroformate)、羰基二咪唑、二环己基碳二亚胺、五氟苯酚(pentofluorophenol)、三氟醋酸酯(trifluoroacetate)、或I-(3-二甲氨基丙基)-3-乙基碳二亚胺。示范性惰性溶剂包括醚、二氧杂环己烷、四氢呋喃、N,N-二甲基甲酰胺、乙腈或二氯甲烷。如果R3和/或R4是胺保护基团,诸如Boc-、CBZ或三苯甲基,它们将被去保护以提供最终产品。去保护的反应条件可以见“Protective Groups in Organic Synthesis”Greeneet al.,John Wiley and Sons Inc,1991,或本领域普通技术人员使用的其他方法。
化合物XXXII可以由化合物IV的去保护作用制备而得,化合物IV中PG是合适的氨基保护基团,如Boc-,CBZ或三苯甲基等。Boc-的示范性去保护剂是置于二氧杂环己烷中的氯化氢、置于二氯甲烷中的TFA等;用于CBZ的示范性去保护作用是催化氢化;三苯甲基的示范性去保护作用是置于丙酮或四氢呋喃中的氯化氢。
化合物XXXIII可以由化合物XXXIV制备而得。当化合物XXXIV中的C=O是羟基基团时,它能被转化成叠氮基团,然后还原得到化合物XXXIII中的氨基基团(举例如见Lautens et al,J.Org.Chem.(1997)62,5246-5247)。当C=O是羰基基团时,它可以被还原为羟基基团,然后再转化为化合物XXXIII中的氨基基团。可替代地,它可以被转化为O-甲基肟,然后被还原得到化合物XXXIII中的氨基基团。将O-甲基肟还原得到胺的还原作用可以用硼烷四氢呋喃复合物或本领域普通技术人员使用的其他方法进行。
化合物XXXIV可以由化合物XXXVI和化合物XXXV的反应制备而得。化合物XXXV[Y=H、SPh、Cl、NMe(OMe)]能被本领域普通技术人员制得。化合物XXXVI(M=Li、MgBr、MgCl、ZnBr、ZnI)是有机金属中间体,其由合适的前体(X=B、I、Cl)或本领域普通技术人员使用的其他方法制得。有机锌试剂可以通过用如J.Org.Chem.(1991),56,1445或Tetrahedron(1997),53,1925中描述的锌金属对芳基溴或芳基碘处理制备而得。可替代地,它也可以通过用n-BuLi或叔-丁基锂(tert-BuLi)处理芳基溴或芳基碘,再加入溴化锌或碘化锌制备而得。
方案II a
式Ia化合物可以通过,在惰性溶剂中,使用合适的羧酸活化剂和胺III,对式II化合物进行氨解制备而得。示范性羧酸活化剂包括异丁基氯甲酸酯、羰基二咪唑、二环己基碳二亚胺、五氟苯酚三氟醋酸酯、或1-(3-二甲氨基丙基)-3-乙基碳二亚胺。示范性惰性溶剂包括醚,其包括四氢呋喃和二氧杂环己烷、N,N-二甲基甲酰胺、乙腈、或二氯甲烷。如果R3和/或R4是胺保护基团,诸如Boc-或CBZ,它们将被去保护以提供最终产品。去保护作用由本领域普通技术完成,如下面所述。
化合物III可以通过对化合物IV去保护制备而得,化合物IV中G是合适的氨基保护基团,如本领域技术人员经常使用的Boc-、CBZ等。用于Boc-的示范性去保护剂是置于二氧杂环己烷、TFA等中的氯化氢;CBZ的示范性去保护作用是催化氢化。
化合物IV可以通过脱水过程由化合物V制备而得。示范性脱水剂包括POCl 3、SOCl2、HCl、HOAc和Mitsunobu反应。
化合物V可以通过在惰性溶剂中使用合适的羧酸活化剂和胺VI对化合物VII进行氨解制备而得。示范性羧酸活化剂包括异丁基氯甲酸酯、羰基二咪唑、二环己基碳二亚胺、五氟苯酚三氟醋酸酯,或1-(3-二甲氨基丙基)-3-乙基碳二亚胺。示范性惰性溶剂包括醚,其包括四氢呋喃和二氧杂环己烷、N,N-二甲基甲酰胺、乙腈,或二氯甲烷。
尽管化合物VI公开了吡啶环上的两个Rb取代基,该方案不限制于单个Rb基团,也不限制于所需的Rb基团。相反,Rb取代基在方案IIa和随后的方案中的存在,意味着一个或多个Rb基团可以任意地被连接到Rb连接到的环上的任何可利用的位置上。因此,即使方案IIa和随后的方案可以参考特别的实施方案,应该理解各种其他修改,诸如一个或多个Rb基团的取代,或本领域技术人员熟悉的修改,可以运用于本文通用合成方案的范围和精神之内。
方案IIb
可替代地,化合物V,在高温、惰性溶剂中,能通过缩合IX和VIII(其中X是离去基团,诸如卤素)制备而得。示范性惰性溶剂包括DMF(二甲基甲酰胺)、THF(四氢呋喃)、二氧杂环己烷、乙腈、吡啶、和惰性醇如乙醇。示范性温度可以在40-150℃范围内。
化合物IX使用本领域普通技术所用的程序对X进行肼解作用制备而得。
方案IIc
可替代地,化合物IV可在高温、惰性溶剂中通过对化合物XI进行肼解作用制备而得。示范性惰性溶剂包括肼、HOAc、THF、二氧杂环己烷、吡啶和惰性醇如乙醇。示范性温度可以在40到150℃的范围内。
化合物XI可以通过,在惰性溶剂中,使用合适的羧酸活化剂,对XII和VII进行缩合制备而得。示范性羧酸活化剂包括异丁基氯甲酸酯、羰基二咪唑、二环己基碳二亚胺、五氟苯酚三氟醋酸酯、或1-(3-二甲氨基丙基)-3-乙基碳二亚胺。示范性惰性溶剂包括醚,包括四氢呋喃和二氧杂环己烷,N,N-二甲基甲酰胺、乙腈、或二氯甲烷。
方案IIIa
方案IIIa描述了制备式XIII化合物的通用合成顺序,在式XIII化合物中,E可以是CH2、CRaRb、NRa、O、S、SO2、SO、CO、C(O)O、C(O)NRa,且m和n可以各自独立地是0到6的整数,值得说明的是m和n合一起形成一个5-12元的环结构。
化合物XIII可以通过,在惰性溶剂中,使用合适的羧酸活化剂和胺XIV,对式II化合物进行氨解制备而得。示范性羧酸活化剂包括异丁基氯甲酸酯、羰基二咪唑、二环己基碳二亚胺、五氟苯酚三氟醋酸酯、或1-(3-二甲氨基丙基)-3-乙基碳二亚胺。示范性惰性溶剂包括醚,包括四氢呋喃和二氧杂环己烷、N,N-二甲基甲酰胺、乙腈、或二氯甲烷。如果R3和/或R4是胺保护基团,诸如Boc-、或CBZ,它们将被去保护以提供最终产品。去保护作用由下面描述的本领域普通技术完成。
化合物XIV可以由化合物XV的去保护作用制备而得,化合物XV中PG是本领域普通技术所使用的合适的氨基保护基团,如Boc-、CBZ等。Boc-的示范性去保护剂是置于二氧杂环己烷、TFA(三氟乙酸)等中的氯化氢;CBZ的示范性去保护作用是催化氢化。
化合物XVI可通过,在质子溶剂和非质子溶剂中,对化合物X进行脱水作用制备而得。脱水条件可以以单独使用质子溶剂为例,或以与脱水剂包括HOAc、PPTS联合使用为例,或以在惰性溶剂中利用Mitsunobu反应为例。
化合物XVI可以,在惰性溶剂中,由偶联(coupling)化合物IX和化合物XVII制备而得。
方案IVa
方案IVa-IVc可以用与为方案IIIa描述的类似通用程序进行,其中,用中间体XVIIIa、XVIIIb和XVIIIc替代中间体XVIII。m和n可各自独立地是从0到5的整数,值得说明的是m和n合在一起形成一个6-12元的环结构。
方案IVb
方案IVc
方案V
式XIX化合物可以通过,在惰性溶剂中,使用合适的羧酸活化剂,由化合物II和胺XX制备而得。示范性羧酸活化剂包括异丁基氯甲酸酯、羰基二咪唑、二环己基碳二亚胺、五氟苯酚三氟醋酸酯或1-(3-二甲氨基丙基)-3-乙基碳二亚胺。示范性惰性溶剂包括醚、二氧杂环己烷、四氢呋喃、N,N-二甲基甲酰胺、乙腈和二氯甲烷。如果R3和/或R4是胺保护基团,如Boc-、CBZ或三苯甲基,它们将被去保护以提供最终产品。去保护的反应条件可以见“Protective Groups in OrganicSynthesis”Greeneet al.,John Wiley and Sons Inc,1991,或本领域普通技术使用的其他方法。
化合物XX可以由化合物XXI的去保护作用制备而得,化合物XXI中PG是合适的氨基保护基团,如Boc-、CBZ或三苯甲基等。去保护的反应条件可以见“Protective Groups in Organic Synthesis”Greeneet al.,John Wiley and Sons Inc,1991,或本领域普通技术使用的其他方法。Boc-的示范性去保护剂式是置于二氧杂环己烷中氯化氢、置于二氯甲烷中TFA等;CBZ的示范性去保护作用是催化氢化;三苯甲基的示范性去保护剂是置于丙酮或四氢呋喃中的氯化氢。
化合物XXI可由化合物XXII(X=Cl或F)制备而得。化合物XXII首先与羟胺反应得到肟中间体,然后在碱性条件下或用本领域普通技术使用的其他方法对中间体进行环化作用(cyclization)。
化合物XXII可以通过,在惰性试剂如醚、四氢呋喃或甲苯中,用合适的有机锌试剂,对化合物XXIII处理制备而得。有机锌试剂可以通过用如J.Org.Chem.(1991),56,1445或Tetrahedron(1997),53,1925中描述的锌金属对芳基溴或芳基碘处理制备而得。可替代地,它也可以通过用n-BuLi(正丁基锂)或t-BuLi(叔丁基锂)处理芳基溴或芳基碘,再加入溴化锌或碘化锌制备而得。
化合物XXIII可以通过,在惰性溶剂中,使用合适的羧酸活化剂,由式VII化合物和巯基化合物诸如苯硫酚制备而得。示范性羧酸活化剂包括异丁基氯甲酸酯、羰基二咪唑、二环己基碳二亚胺、五氟苯酚三氟醋酸酯、或1-(3-二甲氨基丙基)-3-乙基碳二亚胺。示范性惰性溶剂包括醚、二氧杂环己烷、四氢呋喃、N,N-二甲基甲酰胺、乙腈、或二氯甲烷。
方案VI
化合物XXIV可以通过,在惰性溶剂中,使用合适的羧酸活化剂,由式II化合物和胺XX制备而得。示范性羧酸活化剂包括异丁基氯甲酸酯、羰基二咪唑、二环己基碳二亚胺、五氟苯酚三氟醋酸酯、或1-(3-二甲氨基丙基)-3-乙基碳二亚胺。示范性惰性溶剂包括醚、二氧杂环己烷、四氢呋喃、N,N-二甲基甲酰胺、乙腈、或二氯甲烷。如果R3和/或R4是胺保护基团,诸如Boc-、CBZ或三苯甲基,它们将被去保护以提供最终产品。去保护的反应条件可以见“Protective Groups inOrganic Synthesis”Greeneet al.,John Wiley and Sons Inc,1991,或本领域普通技术所使用的其他方法。
化合物XX可以由化合物XXI的去保护作用制备而得,化合物XXI中PG是合适的氨基保护基团,如Boc-、CBZ或三苯甲基等。去保护的反应条件可以见“Protective Groups in Organic Synthesis”Greeneet al.,John Wiley and Sons Inc,1991,或本领域普通技术所使用的其他方法。Boc-的示范性去保护剂是置于二氧杂环己烷中的氯化氢、置于二氯甲烷中的TFA等;CBZ的示范性去保护作用是催化氢化;三苯甲基示范性去保护剂是置于丙酮或四氢呋喃中的氯化氢。
化合物XXI可由化合物XXII(X=Cl或F)制备而得。化合物XXII首先与羟胺反应得到肟中间体,然后在碱性条件下或用本领域普通技术所使用的其他方法对中间体进行环化作用。
化合物XXII可通过还原叠氮化合物XXV,再用胺保护基团如Boc、CBz或三苯甲基等对获得的胺中间体进行保护作用制备而得。示范性还原反应包括氢化作用或用置于含水四氢呋喃中三苯基膦。对获得的胺中间体进行保护作用的反应条件可以见“Protective Groups inOrganic Synthesis”Greene et al.,John Wiley and Sons Inc,1991,或本领域普通技术人员使用的其他方法。
化合物XXV可用两步程序或本领域其他已知的方法由式XXVI化合物制备而得。用溴处理化合物XXVI得到α-溴酮中间体,其然后用叠氮离子如叠氮纳处理。
化合物XXVI可以用有机金属试剂XXIXa或XXIXb处理由式XXVII化合物制备而得。
化合物XXVII可通过,在惰性试剂中,使用合适的羧酸活化剂和碱,由酸XXVIII和N,O-二甲基-胺盐酸制备而得。示范性羧酸活化剂包括异丁基氯甲酸酯、羰基二咪唑、二环己基碳二亚胺、五氟苯酚三氟醋酸酯、或1-(3-二甲氨基丙基)-3-乙基碳二亚胺。示范性惰性溶剂包括醚、二氧杂环己烷、四氢呋喃、N,N-二甲基甲酰胺、乙腈、或二氯甲烷。可替代地,酸XXVIII可以用草酰氯、亚硫酰氯或本领域其他已知的方法被转化成相应的酰基氯。所获得的酰基氯然后能在惰性溶剂中在碱如三甲胺存在下,与N,O-二甲基-胺盐酸反应。
化合物XXIXa是公知的,如Grignard试剂,且能由本领域使用的已知的方法制备而得。
化合物XXIXb可以通过用MeLi或n-BuLi处理化合物XXXb或本领域使用的已知的方法制备而得。
应用和药物并用
应用
式I的生长激素释放化合物(growth hormone releasting compounds)能给药于动物,包括人,以在体内释放生长激素。例如,该化合物能给药于商业上重要的动物,诸如猪、牛、羊及类似动物,来加速和增加它们的生长速度和生长程度,增加这类动物的奶产量。
本发明在它的范围内包括药物组合物,该药物组合物包含作为活性成分的,至少一种与药物载体或稀释剂有交联的式I化合物。任意地,除了至少一种式I化合物外,药物组合物的活性成分可包含生长促进剂(growth promoting agent)或可包含显示不同活性的其他组分,例如显示抗生性(antibiotic),或其他药物活性物质。
生长促进剂(growth promoting agents)包括,但不局限于TRH(促甲状腺素释放激素)、己烯雌酚(diethylstilbestrol)、茶碱、脑啡肽、E系列的前列腺素,公开于美国专利3,239,345的化合物,如玉米赤霉醇;和公开于美国专利4,036,979的化合物,如舒贝诺司或公开于美国专利4,411,890的肽。
本发明式I公开的化合物的另外一个用途是与其他生长激素促分泌素,如美国专利4,411,890和公开号WO89/07110和WO 89/07111中描述的GHRP-6、GHRP-1;和B-HT920或生长激素释放因子(growthhormone releasing factor)和它的类似物,或生长激素和它的类似物,或生长调节素包括IGF-1和IGF-2并用。本发明式I公开的化合物的还有一个用途是与甲状旁腺激素或二碳磷酸盐化合物如MK-217(阿仑磷酸钠(alendronate))并用于骨质疏松症的治疗。
式I公开的化合物的还有一个用途是与雌激素、睾酮、选择性雌激素受体调节剂,如他莫昔芬(tamoxifen)或雷洛昔芬(raloxifene),或选择性雄激素受体调节剂诸如Edwards,J.P.et al.,Bio.Med.Chem.Let.,9,1003-1008(1999)和Hamann,L.G.et al.,J.Med.Chem.,42,210-212(1999)中公开的选择性雄激素受体调节剂并用,来治疗代谢综合症方面的疾病、维持老年人的肌力和功能、逆转或预防老年人虚弱、刺激和增加肌肉质量和肌力、减弱大手术或创伤之后的蛋白质分解代谢响应(protein catabolic response);减少由慢性疾病如癌症或AIDS(艾滋病)引起的恶病质和蛋白质损失;改善肌肉活动性,和维持皮肤厚度。
本发明化合物的另一个用途是与孕酮受体促效剂(progestinreceptor agonist,″PRA″)并用。
如本领域技术人员所熟知的,生长激素已知的和潜在的用途是变化多端,多种多样的。因此,施用本发明化合物来刺激内源生长激素的释放能具有与生长激素本身相同的效果或用途。
对于本领域技术人员来说,都熟知生长激素目前和潜在的用途是变化多端,多种多样的。因此,式I化合物能用于刺激内源生长激素的释放,因此将具有同生长激素本身相类似的效果或用途。式I化合物能用于刺激生长激素的释放(如在老年人中);维持肌力和功能(如在老年人中);逆转或预防老年人脆性(fraility)或与年龄相关的功能减退(age-related functional decline,″ARFD″);预防糖皮质激素的代谢副作用;预防和治疗骨质疏松症;治疗慢性疲劳综合症(chronic fatiguesyndrome,CFS);治疗选择性手术之后的急性疲劳综合症和肌肉损失;刺激免疫系统,包括改善对种痘的免疫应答;加速伤口愈合;加速骨折恢复(诸如加速髋骨骨折患者的恢复);加速复杂性骨折的愈合,如引发(disctraction)成骨作用;加速牙齿恢复或生长;维持感管功能(如听觉、视觉、嗅觉和味觉);治疗由骨折引起的衰竭;治疗生长障碍;治疗因肾衰竭或肾机能不全引起的生长障碍;治疗心肌病;治疗与慢性肝病相关的消耗性疾病(wasting);治疗血小板减少症;治疗与克罗恩病相关的生长障碍;治疗短肠综合症;治疗过敏性大肠综合症;治疗炎症性肠病;治疗克罗恩病和溃疡性结肠炎;治疗与慢性阻塞性肺病(chronicobstructive pulmonary disease,COPD)相关的衰竭;治疗与移植相关的并发症;治疗生理性矮身材(physiological short stature)包括生长激素缺乏的儿童和慢性疾病相关的矮身材;治疗肥胖和与肥胖相关的生长障碍;治疗厌食症(如与恶病质或老化相关的厌食症);治疗与普-韦二氏综合症和特纳综合症相关的生长障碍;增加患有局部生长激素不敏感综合症(partial growth hormone insensitive syndrome)的患者的生长速度;加速灼伤患者的恢复和减少医院治疗;治疗子宫内生长迟缓、骨骼发育异常、皮质醇增多症和库欣综合征;诱导脉冲式生长激素释放;应激病生长激素的置换;治疗骨软骨发育不良;治疗诺南式综合症;治疗精神分裂症;治疗抑郁症;改善认知功能(如治疗痴呆);治疗阿耳茨海默疾病;治疗延迟性伤口愈合和社会心理丧失(psychosocial deprivation);治疗与肺功能障碍和呼吸依赖性(ventilator dependency)相关的分解代谢;治疗心脏功能障碍(如与瓣膜疾病、心肌梗塞、心肌肥大或充血性心力衰竭相关的心脏功能障碍);降低血压;保护防止心室功能障碍或预防再灌注事件;治疗成人慢性透析;逆转或减缓衰老的分解代谢状;减弱或逆转损伤(如逆转与手术相关的分解代谢状况、充血性心力衰竭、心肌病、灼伤、癌症COPD等)之后的蛋白质分解代谢应答;减少由慢性疾病如癌症或AIDS引起恶病质和蛋白质损失;治疗高胰岛素血症包括胰岛母细胞瘤;辅助排卵诱导治疗;刺激胸腺发育和预防与年龄相关的胸腺功能减退;治疗免疫抑制患者;治疗肌肉缺乏症(sarcopenia);治疗与AIDS相关的衰竭;治疗与多发性硬化或其他神经变性障碍相关的衰竭;改善肌力、灵活性、维持皮肤厚度;头发/指甲生长;治疗代谢动态平衡(metabolic homeostasis)和肾动态平衡(homeostasis)(如体弱的老年人);刺激造骨细胞、骨再塑和软骨生长;调节食物摄取;刺激伴生动物中的免疫系统和治疗伴生动物中老化障碍;促进家畜的生长;刺激羊毛生长;增加家畜奶产量;治疗在哺乳动物(如人)中的胰岛素耐受性包括NIDDM(非胰岛素依赖性糖尿病);治疗在心脏中的胰岛素耐受性;改善睡眠质量和校正由REM睡眠高度增加和REM睡眠潜伏期减少引起的衰老的生长激素不足;治疗低温;治疗脆性,诸如与衰老相关的脆性;治疗充血性心力衰竭;治疗髋骨骨折;治疗具有低T4/T8比例的患者的免疫缺乏;治疗脂肪营养不良(如接受HIV或AIDS治疗剂诸如蛋白酶抑制剂的患者);治疗肌萎缩(如由身体不活动、卧床休养或减少的承重状况(reducedweight-bearing conditions)引起的肌萎缩);治疗肌肉骨骼损伤(如在老年人中);增强蛋白激酶B(PKB)的活性;改善全部肺功能;治疗睡眠障碍;和治疗长期重病(prolonged critical illness)的心脏状况。术语治疗(treatment)也旨在包括预防性治疗。
此外,症状(conditions)、病(diseases)、和疾病(maladies)共同地是指“Syndrome X(X综合症)”或代谢综合症,如JohannssonJ.Clin.Endocrinol.Metab.,82,727-34(1997)中所详述的,可以运用本发明的化合物予以治疗。
药物并用
本发明化合物可以单独使用,或相互并用,和/或与其他生长激素促分泌素并用,或与可用于治疗上述障碍的其他合适的治疗剂并用,这些治疗剂包括:抗糖尿病剂;抗骨骼疏松症剂;抗肥胖剂;抗炎剂;抗焦虑剂;抗抑郁剂;抗高血压剂;抗血小板剂;抗凝血剂和血栓溶解剂;强心苷;胆固醇/脂肪降低剂;盐皮质激素受体拮抗剂;磷酸二酯酶抑制剂;蛋白质酪氨酸激酶抑制剂;甲状腺模拟物(thyroid mimetics)(包括甲状腺受体拮抗剂);合成代谢剂;HIV或AIDS治疗剂;用于治疗阿耳茨海默疾病和其他认知障碍的治疗剂;用于治疗睡眠障碍的治疗剂;抗增殖剂;抗肿瘤剂;和/或抗溃疡药和胃食管反流疾病药物。
与本发明化合物并用的合适的抗糖尿病剂(anti-diabetic agents)的例子包括:双胍类(如甲福明)、葡糖苷酶抑制剂(如阿卡波糖)、胰岛素类(包括胰岛素促分泌素或胰岛素增敏剂)、胰氯茴苯酸类(如瑞格列泰(repaglinide))、磺脲类(如格列美脲(glimepiride)、格列本脲(glyburide)和格列吡嗪)、双胍类/格列本脲并用(如复方盐酸二甲酸胍(glucovance))、噻唑烷二酮类化合物(thiozolidinediones)(如曲格列酮(Troglitazone)、罗格列酮(rosiglitazone)和匹格列酮(pioglitazone))、PPAR-α-促效剂、PPAR-γ-促效剂、PPAR-α/γ-双促效剂、SGLT2抑制剂、脂肪酸结合蛋白抑制剂(aP2),如2000年3月6日提交的美国序列号09/519,079(律师编号LA27)中公开的脂肪酸结合蛋白抑制剂、胰高血糖素-样肽-1(GLP-1)、二肽基肽酶IV(DP4)抑制剂。
与本发明化合物并用的合适的抗骨骼疏松症剂(anti-osteoporosous)包括阿仑磷酸钠、利塞膦酸(risedronate)、雷洛昔芬、降钙素、非甾体孕酮受体促效剂、RANK配体促效剂、钙敏感受体拮抗剂、TRAP抑制剂、选择性雌激素受体调节剂(SERM)、雌激素和AP-1抑制剂;
与本发明化合物并用的合适的抗肥胖剂(anti-obesity agents)包括aP2抑制剂诸如2000年3月6日提交的美国序列号09/519,079(律师编号LA27)中公开的抗肥胖剂,PPARγ拮抗剂、PPARδ促效剂和奥列司他(orlistat)。
与本发明化合物并用的合适的抗炎剂(antinflammatory agents)包括泼尼松、地塞米松、Enbrel、环氧合酶抑制剂(如COX-1和/或COX-2抑制剂,如NSAIDs(非甾体抗炎药物)、阿斯匹林、吲哚美辛、布洛芬、吡罗昔康(piroxicam)、奈普生、塞来考昔(Celebrex)、伟克适(Vioxx))、CTLA4-Ig促效剂/拮抗剂、CD40配体拮抗剂、整合素拮抗剂、α4β7整合素拮抗剂、细胞粘合抑制剂、干扰素γ拮抗剂、ICAM-1、肿瘤坏死因子(TNF)拮抗剂(如因福利美(Infliximab)、OR1384)、前列腺素合成抑制剂、布地奈德、氯苯吩嗪、CNI-1493、CD4拮抗剂(如普立昔单抗(priliximab))、p38丝裂原激活的蛋白激酶抑制剂、蛋白质酪氨酸激酶(PTK)抑制剂、IKK抑制剂和治疗过敏性大肠综合症治疗剂(如泽马可(zelmac)和Maxi-K开放子(Maxi-K openers),诸如美国专利6,184,231B1中公开的Maxi-K开放子)。
与本发明化合物并用的合适的抗焦虑剂(anti-anxiety agents)包括地西西泮(diazepam)、劳拉西泮、丁螺环酮、奥沙西泮和双羟萘酸羟嗪。
与本发明化合物并用的合适的抗抑郁剂包括(anti-depressantsagents)西酞普兰、氟西汀、萘法唑酮、舍曲林和帕罗西汀。
与本发明化合物并用的合适的抗高血压剂(anti-hypertensiveagents)包括β肾上腺素阻滞剂、钙离子通道阻滞剂(L-型和T-型;如地尔硫卓、维拉帕米、硝苯吡啶、安洛地平和mybefradil)、diruetics(如氯噻嗪、氢氯噻嗪、氟甲噻嗪、氢氟甲噻嗪、苄氟噻嗪、甲基氯噻嗪、三氯噻嗪、泊利噻嗪、苄噻嗪、利尿酸tricrynafen、氯噻酮、速尿、musolimine、丁苯氧酸、triamtrenene、氨氯吡咪、安体舒通)、肾素抑制剂、ACE抑制剂(如卡托普利、佐芬普利、福辛普利、依拉普利、ceranopril、cilazopril、地拉普利、喷托普利、喹那普利、雷米普利、赖诺普利)、AT-1受体拮抗剂(如洛沙坦(losartan)、依贝沙坦(Irbesartan)、丙戊沙坦(Valsartan))、ET受体拮抗剂(如sitaxsentan、atrsentan和公开于美国专利5,612,359和6,043,265的化合物)、双ET/AII拮抗剂(如公开于WO 00/01389的化合物)、中性肽链内切酶(NEP)抑制剂、vasopepsidase抑制剂(双NEP-ACE抑制剂)(如奥马曲拉(omapatrilat)和gemopatrilat)、和硝酸盐。
与本发明化合物并用的合适的抗血小板剂(anti-platelet agents)包括GPIIb/IIIa阻剂(如阿昔单抗(abciximab)、埃替非巴肽(eptifibatide)、替罗非班(tirofiban))、P2Y12拮抗剂(如氯吡格雷(clopidogrel)、噻氯匹啶、CS-747)、血栓烷受体拮抗剂(如伊非曲班)、阿斯匹林、和有阿斯匹林或无阿斯匹林的PDE-III抑制剂(如双嘧达莫)。
与本发明化合物并用的合适的强心苷(cardiac glycosides)包括洋地黄和哇巴因。
与本发明化合物并用的合适的胆固醇/脂肪降低剂(cholesterol/lipidlowering agents)包括HMG-CoA还原酶抑制剂(如普伐他汀、洛伐他汀、阿托伐他汀、辛伐他汀、NK-104(a.k.a.伊他伐他汀(itavastatin)或尼伐他汀或nisbastatin)和ZD-4522(a.k.a.罗素他汀(rosuvastatin)或atavastatin或visastatin))、鲨稀合成酶抑制剂、贝特类(fibrates)、胆汁酸螯合剂、ACAT抑制剂、MTP抑制剂、脂氧化酶抑制剂、胆固醇吸收抑制剂和胆固酯转移蛋白抑制剂(如CP-529414)。
与本发明化合物并用的合适的盐皮质激素受体拮抗剂(mineralocorticoid receptor antagonists)包括安体舒通(spironolactone)和eplerinone。
与本发明化合物并用的合适的磷酸二酯酶抑制剂(phospodiesteraseinhibitiors)包括PDEIII抑制剂,诸如西洛他唑,和PDE V抑制剂,诸如西地那非。
与本发明化合物并用的合适的甲状腺模拟物(thyroid mimetics)包括促甲状腺激素、聚甲状腺(polythyroid)、KB-130015和决奈达隆(dronedarone)。
与本发明化合物并用的合适的合成代谢剂包括睾酮和选择性雄激素受体调节剂(SARMs)。
与本发明化合物并用的合适的HIV或AIDS治疗剂包括硫酸茚地那韦、沙奎那维、沙喹那韦甲磺酸酯(saquinavir mesylate)、安普那韦、利托那韦(ritonavir)、咯匹那韦(Lopinavir)、利托那韦/咯匹那韦并用、拉米夫定(lamivudine)、齐多夫定(zidovudine)、拉米夫定/齐多夫定并用、扎西他滨(zalcitabine)、双脱氧胞苷、斯他夫定(stavudine和醋酸甲地孕酮。
与本发明化合物并用的合适的治疗阿耳茨海默疾病和认知障碍的治疗剂包括多奈哌齐(donepezil)、他克林、revastigmine、5HT6、γ分泌酶抑制剂、β分泌酶抑制剂、SK通道阻滞剂、Maxi-K阻滞剂和KCNQs阻滞剂。
与本发明化合物并用的合适的治疗睡眠障碍的治疗剂包括褪黑素类似物、褪黑素受体拮抗剂、ML1B促效剂和GABA/NMDA受体拮抗剂。
与本发明化合物并用的合适的抗增殖剂(anti-proliferative agents)包括环胞霉素A、紫杉醇、FK 506和阿霉素。
与本发明化合物并用的合适的抗肿瘤剂(anti-tumor agents)包括紫杉醇、阿霉素、埃坡霉素、顺铂和碳铂。
本发明化合物还可以与营养补充剂(nutritional supplements),诸如US 5,179,080中描述的营养补充剂并用,尤其可以与乳清蛋白或酪蛋白、氨基酸(诸如亮氨酸、支链氨基酸和羟甲基丁酸盐)、甘油三酯、维生素(如A、B6、B12、叶酸、C、D和E)、矿物质(如硒、锰、锌、铬、钙和钾)、肉碱、硫辛酸、肌酸和辅酶Q-10并用。
上述其他治疗剂,当与本发明化合物并用时,例如,可以以Physicians′Desk Reference(PDR)中所指示的用量或者也可以以由本领域普通技术所确定的用量使用。
本发明的化合物物是药剂,是生长激素促分泌素,可以给药于各种需要治疗的哺乳动物物种,诸如猴、狗、猫、鼠、人等。这些试剂可以系统性给药,如口服或肠胃外给药。
本发明化合物可以以常规的系统性剂型引入,如片剂、胶囊、酏剂或可注射制剂。上述剂型也包括必要的生理上可接受的载体物质、赋形剂、滑润剂、缓冲剂、抗菌剂、填充剂(诸如甘露醇)、抗氧化剂(抗坏血酸或亚硫酸钠)或类似物。尽管肠胃外给药、鼻内给药或气雾给药形式同样相当令人满意,优选口服剂型。
给药剂量必须根据患者的年龄、体重和症状以及给药途径、剂型和用药法,和想要的效果仔细调节。总之,上面描述的剂型可以以每公斤体重约0.0001到约100mg的量给药,或以每天在约1到约1000mg的范围内的量给药,优选每天约5到约500mg,以单剂量或者分次剂量形式,每天1次到4次用药。
实施例
下面的实施例代表本发明的优选实施方式。除非另外指出,所有温度都是℃。
通用实验
方式A:术语HPLC是指Shimadzu公司的高效液相色谱,梯度洗脱(4分钟,0-100%溶剂B[MeOH∶H2O∶0.2%H3PO4]);保留时间1min.;紫外线(uv)检测器设置在220nM;使用YMC C185微米树脂填充的柱子(4.6×50mm)。
在自动Shimadzu系统上,溶剂A(10%MeOH/90%H2O/0.2%TFA)和溶剂B(90%MeOH/10%H2O/0.2%TFA)的混合物被用于制备性反相HPLC(praparative reverse phase HPLC)。制备柱用YMC ODS C18 5微米树脂填充。
方法B:术语HPLC是指Shimadzu公司的高效液相色谱,梯度洗脱(8分钟,0-100%溶剂B[乙腈∶H2O∶0.1%TFA]);保留时间3min.;紫外线检测器设置在220nM;使用Zorbax C185微米树脂填充的柱子(4.6×75mm)。在自动Shimadzu系统上,溶剂A(10%乙腈/90%H2O/0.1%TFA)和溶剂B(90%乙腈/10%H2O/0.1%TFA)的混合物被用于制备性反相HPLC。制备柱用YMC ODS C18 5微米树脂填充。
方法C:术语HPLC是指Shimadzu公司的高效液相色谱,采用0-100%溶剂B[MeOH∶H2O∶0.2%H3PO4])8分钟梯度洗脱;保留时间2min.(分钟);紫外线(uv)检测器设置在220nM;使用Zorbax C185微米树脂填充的柱子(4.6×75mm)。
实施例1
2-氨基-N-[1-(6-溴-[1,2,4]三唑[4,3-a]吡啶-3-基)-3-苯基-丙基]-2-
甲基-丙酰胺
向3-苄氧基-2-叔丁氧基羰基氨基-丙酸(20.0g,67.8mmol)的THF(100ml)溶液中加入N-甲基吗啉(11.2ml,101.7mmol),再逐滴加入氯甲酸异丁酯(11.1ml,74.mmol)。形成白色悬浮液。将该悬浮液在室温下搅拌10min(分钟),然后分三次加入5-溴-吡啶-2-基肼(14.1g,74.6mmol)。将所获得的悬浮液在室温下搅拌1h,然后在减压下除去溶剂,直到浓浆形成。加入水,并搅拌悬浮液以确保固体被充分分散。过滤浅白色固体,用NaOH(1N,100ml),水(100ml)和HCl(1N,100ml)洗涤,再用水(200ml)洗涤,干燥得到1A(31.5g,100%)。
向1A(30g,64.3mmol)的THF(100ml)溶液中加入三苯基膦(20.2g,77.2mmol)和三甲基硅叠氮化合物(10.2ml,77.2mmol)。向该溶液快速滴加入二乙基叠氮羧酸盐(diethyl diazacarboxyate)(DEAD,15.2ml,96.5mmol)。该溶液变热。加完后,允许在室温下搅拌该溶液,直到所有的起始物质被消耗完(<2h)。在减压下除去溶剂得到1B。
将1B(64.3mmol)悬浮于HCl-二氧杂环己烷(160ml,4MHCl,于二氧杂环己烷中)中。在室温下搅拌该悬浮液,直到所有的起始物质被消耗掉。浓缩该悬浮液得到浓浆,然后用THF(100ml)稀释。过滤收集固体,用过量的CH2Cl2、二乙醚冲洗,干燥得到1C(24.5g,99%)。
向2-叔丁氧羰基氨基-2-甲基-丙酸(9.5g,47.9mmol)的THF(100ml)溶液中加入EDAC(11.2g,58.8mmol)和HOBT(8.0g,58.8mmol)、DMAP(4.8g,39.2mmol)和(i-Pr)2NEt(20.5ml,117.6mmol)。将该溶液在室温下搅拌10min,然后加入1C(15g,39.2mmol)。反应在1h内完成,在减压下除去溶剂,将残留物溶解于EtOAc(200ml)。用水(200ml)、NaOH(0.5N,200ml)、HCl(0.5N,200ml)洗涤该有机溶液,再用水(200ml)洗涤。有机层用Na2SO4干燥,浓缩得到白色固体1D(20.0g,90%)。
将1D(1.0g,1.8mmol)溶解于4M HCl-二氧杂环己烷(5ml)中。在室温下搅拌溶液,直到起始物质被消耗完。在减压下蒸发掉溶剂,用二乙醚将白色固体捣碎,得到纯净的标题化合物(0.84g,<99%)。MS(M+H)433,HPLC保留时间2.07min。
实施例2-15
表1中的实施例2-15是使用实施例1中描述的方法合成的,采用合适的起始物质。
表1
实施例16
2-氨基-2-甲基-N-[3-苯基-1-(6-三氟甲基-[1,2,4]三唑[4,3-a]吡啶
-3-基)-丙基]-丙酰胺
向2-叔丁氧羰基氨基-4-苯基-丁酸(2.0g,7.1mmol)的THF(100ml)溶液中加入TEA(0.98ml,7.1mmol),再逐滴加入氯甲酸异丁酯(0.98g,7.1mmol)。形成白色悬浮液。在室温下搅拌该悬浮液10min,然后分三次加入(5-三氟甲基吡啶-2-基)-肼(1.3g,7.1mmol)。在室温下,搅拌所获得的悬浮液1h,然后在减压下除去溶剂,直到形成浓浆。加入水(200ml)并搅拌悬浮液,以确保固体被细微地分散。过滤浅白色固体,用NaOH(1N,100ml)、水(100ml)和HCl(1N,100ml)洗涤,再用水(200ml)洗涤,干燥得到16A(1.9g,100%)。
向16A(1.9g,4.3mmol)的THF(100ml)溶液中加入三苯基膦(1.3g,5.2mmol)和三甲基硅叠氮化合物(0.6g,5.2mmol)。向该溶液快速滴加入二乙基叠氮羧酸盐(DEAD,1.8g,10.8mmol)。该溶液变热。加完后,允许在室温下搅拌该溶液,直到所有的起始物质被消耗完(<2h)。在减压下除去溶剂得到16B。
将16B悬浮于HCl-二氧杂环己烷(160ml,4MHCl,于二氧杂环己烷中)中。在室温下搅拌该悬浮液,直到所有的起始物质被消耗掉。浓缩悬浮液得到浓浆,然后用THF(100ml)稀释。过滤收集固体,用过量的CH2Cl2、二乙醚冲洗固体,干燥得到16C。
向2-叔丁氧羰基氨基-2-甲基-丙酸(27.5g,0.135mmol)的THF(100ml)溶液中,加入EDAC(29.2g,0.15mmol)和HOBT(20mg,0.15mmol)、DMAP(1.5g,0.01mmol)和吡啶。将该溶液在室温下搅拌10min,然后加入16C(52mg,0.123mmol)。反应在<1h内完成。在减压下除去溶剂,将残留物溶解于EtOAc(200ml)。用水(200ml)、NaOH(0.5N,200ml)、HCl(0.5N,200ml)洗涤该有机溶液,再用水(200ml)洗涤。有机层用Na2SO4干燥,浓缩得到白色固体16D。
实施例16
将16D溶解于4M HCl-二氧杂环己烷(5ml)中。在室温下搅拌溶液,直到所有起始物质被消耗掉。在减压下蒸发掉溶剂,将白色固体用二乙醚捣碎,得到纯的产物(29mg,94%)。MS(M+H)406,HPLC保留时间2.3min。
下述化合物通过使用实施例16中描述的程序制备,其以表2中例出的相应的酸(步骤A)、肼(步骤A)和胺(步骤D)起始。
表2
实施例26
6-氨基-N-[2-苯基-1-(6-三氟甲基-[1,2,4]三唑[4,3-a]吡啶-3-yl)-乙基]-
烟碱胺
向2-叔丁氧羰基氨基-3-苯基-丙酸(2.0g,7.1mmol)的THF(100ml)溶液中加入TEA(0.98ml,7.1mmol),再逐滴加入氯甲酸异丁酯(0.98g,7.1mmol)。形成白色悬浮液。在室温下搅拌该悬浮液10min,然后分三次加入(5-三氟甲基-吡啶-2-基)-肼(1.3g,7.1mmol)。在室温搅拌所获得的悬浮液1h,然后在减压下除去溶剂,直到形成浓浆。加入水(200ml),并搅拌悬浮液以确保固体被细微地分散。过滤灰白色固体,用NaOH(1N,100ml)、水(100ml)和HCl(1N,100ml)洗涤,再用水(200ml)洗涤,干燥得到26A(1.9g,100%)。
用实施例16中描述的程序制备实施例26,用26A替代16A、26B替代16B、26C替代16C、26D替代16D。得到的实施例26是白色泡沫。MS(M+H)427,HPLC保留时间2.23min。
用实施例26描述的程序制备下述化合物,如表3中所表示。
表3
实施例36
6-氨基-N-[2-苄氧基-1-(6-三氟甲基-[1,2,4]三唑[4,3-a]吡啶-3-基)-
乙基]-1-烟碱胺
向3-苄氧基-2-叔丁氧羰基氨基-丙酸(2.0g,7.1mmol)的THF(100ml)溶液中加入TEA(0.98ml,7.1mmol),再逐滴加入氯甲酸异丁酯(0.98g,7.1mmol)。形成白色悬浮液。在室温下搅拌该悬浮液10min,然后分三次加入(5-三氟甲基-吡啶-2-基)-肼(1.3g,7.1mmol)。在室温搅拌所获得的悬浮液1h,然后在减压下除去溶剂,直到形成浓浆。加入水(200ml),并搅拌悬浮液以确保固体被细微分散。过滤灰白色固体,用NaOH(1N,100ml)、水(100ml)和HCl(1N,100ml)洗涤,再用水(200ml)洗涤,干燥得到36A(1.9g,100%)。
用实施例16中描述的程序制备实施例36,用36A替代16A、36B替代16B、36C替代16C、36D替代16D。得到的实施例36是白色泡沫。MS(M+H)456,HPLC保留时间2.4min。
用实施例36的程序制备下述化合物,如表4中所表示。
表4
实施例45
2-氨基-N-{2-苄氧基-1-[6-(2-氟-苯基)-[1,2,4]三唑[4,3-a]吡啶-3-基]-
乙基}-2-甲基-丙酰胺
将化合物1D(300mg,0.56mmol)、2-氟苯基硼酸(120mg,0.86mmol)、Pd(OAc)2(5mg,0.022mmol)、三苯基膦(100mg,0.38mmol)和Et3N(0.24ml,1.72mmol)溶解于DMF(2ml)中。将该溶液在110℃下加热12h。将所得的混合物用水(10ml)稀释,并用EtOAc抽提。混和有机部分用NH4OH(10%)和盐水洗涤,并用无水Mg2SO4干燥。在减压下将溶剂蒸发掉,得到粘性液体。产物不纯化,直接用于下一步骤。
实施例45
将45A溶解于4M HCl-二氧杂环己烷(2ml)中。在室温下搅拌该液,直到所有起始物质被消耗掉。在减压下蒸发掉溶剂,用制备HPLC纯化产物,得到标题化合物(129mg,50%)。MS(M+H)447,HPLC保留时间2.47min。
下述化合物通过利用实施例1中制得的中间体以及实施例45中描述的化学程序,用合适的起始物质制备而成,如表5中所表示。
表5
实施例51
2-氨基-N-[2-苄氧基-1-(6-甲磺酰氨-[1,2,4]三唑[4,3-a]吡啶-3-基)-
乙基]-2-甲基-丙酰胺
化合物51A是用5-硝基-2-肼基吡啶代替5-溴-2-肼基吡啶,利用与合成1D同样的程序制备而得。
将化合物51A(1.3g,2.6mmol)溶解于EtOH(60ml)中。在N2下,加入Pd/C(35mg,10%Pd,以重量计)。将混合物在50Psi下氢化3h,得到51B。在减压下除去溶剂,该产物是足够纯的(>90%),并直接用于下面的反应。
将51B(200mg,0.43mmol)溶解于CH2Cl2(5ml)中,并加入吡啶(0.14ml,2.1mmol)。向该溶液加入相应的甲基磺酰氯(0.05ml,0.65mmol)。反应在1.5h内完成。然后用CH2Cl2(25ml)稀释反应,并用HCl(1N,20ml)、水饱和NaHCO3(20ml)洗涤,再用水(20ml)洗涤。在硅胶(5%CH3OH/作为洗脱剂)上利用快速色谱(flash chromatography)进行纯化,得到51C(90mg,40%)。
实施例51
将化合物51C溶解于HCl(4ml,4M,于二氧杂环己烷中)中,在室温下搅拌,直到反应完成。在减压下除去溶剂,化合物用制备HPLC纯化,得到标题化合物,为泡沫形式(60mg,82%)。MS(M+H)447,HPLC保留时间1.73min。
下述表6中的化合物采用实施例51中的程序,用合适的起始物质制备而得。
表6
实施例55
N-[1-(6-乙酰氨基-[1,2,4]三唑[4,3-a]吡啶-3-基)-2-苄氧基-乙基]-2-氨基-
2-甲基-丙酰胺
将化合物51B(130mg,0.28mmol)溶解于CH2Cl2(2ml)中,并加Et3N(0.2ml,1.4mmol)。向该溶液加入乙酰氯(0.026ml,0.36mmol)。在温室下搅拌过夜之后,用CH2Cl2(25ml)稀释反应,用HCl(1N,20ml)、NaHCO3(sat.(饱和的),20ml)洗涤,再用水(20ml)洗涤。粗产物用快速色谱法(5%CH3OH/CH2Cl2)纯化,得到55A(80mg,56%)。
实施例55
将化合物55A溶解于HCl(4ml,4M,于二氧杂环己烷中),并在室温(r.t.)下搅拌,直到反应完成。在减压下除去溶剂,用制备HPLC纯化产物,得到标题化合物,为泡沫形式。MS(M+H)411,HPLC保留时间1.86min。
下述表7中的化合物采用实施例55中描述的程序,用合适的起始物质制备而得。
表7
实施例57
2-氨基-N-[2-苄氧基-1-(6-氯-5-二甲氨基-[1,2,4]三唑[4,3-a]
吡啶-3-基)-乙基]-2-甲基-丙酰胺
化合物57A是用相应的2-肼基吡啶,利用与合成1D同样的程序制备而得。
将置于二甲胺(3ml)中的化合物57A(250mg,0.48mmol)在100℃下加热1.5h。反应用水(10ml)稀释,用EtOAc抽提。混和有机部分用Na2SO4干燥,在减压下蒸发掉溶剂。粗产物用快速色谱法(2%CH3OH/CH2Cl2)纯化,得到57B(140mg,55%)。
实施例57
将57A(140mg,0.26mmol)溶解于HCl(5ml,4M HCl,于二氧杂环己烷中),并在室温下搅拌,直到所有起始物质被消耗掉。利用制备HPLC纯化,得到标题化合物(51mg)。MS(M+H)431,HPLC保留时间2.35min。
下述表8中的化合物采用实施例57中描述的程序,用合适的起始物质合成。
表8
实施例63
2-氨基-N-{2-苄氧基-1-[6-氯-5-(2-甲氧基-乙氧基)-[1,2,4]三唑[4,3-a]
吡啶-3-基]-乙基}-2-甲基-丙酰胺
将置于2-甲氧基-乙醇(1ml)和碳酸铯(155mg,0.48mmol)中的化合物57A(250mg,0.48mmol)在100℃下加热1.5h。反应用水(10ml)稀释,用EtOAc抽提。混和有机部分用Na2SO4干燥,在减压下蒸发掉溶剂,得到63A。
实施例63
将63A溶解于HCl(5ml,4M HCl,于二氧杂环己烷中)中,在室温下搅拌,直到所有起始物质被消耗掉。用制备HPLC纯化,得到标题化合物(18.6mg)。MS(M+H)462,HPLC保留时间2.23min。
下述表9中的化合物采用实施例63中描述的程序,用合适的起始物质合成。
表9
实施例69
3-[1-(2-氨基-2-甲基-丙酰氨基)-2-苄氧基-乙基]-[1,2,4]三唑[4,3-a]
吡啶-6-羧酸甲胺
向置于DMF(10ml)和MeOH(5ml)中的1D(0.7g,1.32mmol)加入1,3-双(二苯基膦)-丙烷(217mg,0.53mmol)、DBU(240mg,1.58mmol)和醋酸钯(148mg,0.66mmol)。除去混合物中的气体,充入一氧化碳并保持在20psi下。反应在85℃下加热过夜。过滤掉催化剂,浓缩溶液。残留物用EtOAc萃取,用水、盐水洗涤,浓缩。粗产物用快速色谱法纯化,得到白色泡沫状的69A。
向置于THF(20ml)中的69A(2.3g,4.5mmol)加入氢氧化锂(40ml的2N溶液)。混合物在室温下干燥3h。加入1N HCI将pH值调节到2。溶液用CH2CI2抽提,洗涤,干燥,浓缩,得到69B。
向69B(150mg,0.3mmol)的CH2Cl2(2ml)溶液中加入EDAC(86mg,0.45mmol)和HOBT(60mg,0.45mmol)和(i-Pr)2NEt(58mg,0.45mmol),然后加入置于THF(0.225ml,0.45mmol)中的2M甲胺溶液。过夜搅拌反应液,然后用EtOAc抽提。有机溶液用水、盐水洗涤,干燥,浓缩得到白色固体69C。
实施例69
将69C溶解于HCl(5ml,4M HCl,于二氧杂环己烷中),在室温下搅拌,直到所有起始物质被消耗掉。利用制备HPLC纯化,得到标题化合物,为油状的。MS(M+H)410,HPLC保留时间2.4min。
下述表10中的化合物采用实施例69中描述的程序,用合适的起始物质合成。
表10
实施例75
甲基-氨基甲酸3-[1-(2-氨基-2-甲基-丙酰氨基)-2-苄氧基-乙基]-
[1,2,4]三唑[4,3-a]吡啶-6-基甲基酯
在-78℃下,向搅拌过的置于CH2Cl2中的59A(50mg,0.098mmol)溶液中,加入置于甲苯(0.4ml,0.58mmol)中的1.5M DIBAL溶液,在室温下过夜搅拌。将溶液冷却到0℃,然后缓慢加入1M酒石酸钠钾(sodium potassium tartarate)溶液。室温下搅拌1.5h。通过一层硅藻土过滤掉形成的沉淀。然后用CH2Cl2抽提,洗涤,干燥,浓缩得到75A。
在0℃下,向置于CH2Cl2(2ml)中的75A(180mg,0.2mmol)加入TEA(60mg,0.6mmol)和异氰酸甲酯(24mg,0.4mmol)。将反应加温到室温,过夜搅拌。将溶液浓缩得到75B。
实施例75
将75B溶解于HCl(5ml,4M HCl,于二氧杂环己烷中)中,在室温下搅拌,直到所有起始物质被消耗掉。利用制备HPLC纯化得到标题化合物,为油状物。MS(M+H)441,HPLC保留时间2.48min。
实施例76
3-[1-(2-氨基-2-甲基-丙酰氨基)-2-苄氧基-乙基]-5,6,7,8-四氢-[1,2,4]三唑
[4,3-a]吡啶-8-羧酸乙酯
在0℃下,向置于醚(500ml)中的冷却过的氢氧化钾(100ml,40%于水中)溶液中,在15min以上的时间里,缓慢地加入1-甲基-3-硝基-1-硝基胍(1-methyl-3-nitro-1-nitoroguanidine)(15g,0.102mol)。将上面的有机相倒入含有30g氢氧化钾的长颈瓶中。5min后,在该醚溶液中缓慢加入置于THF/CH2Cl2(200ml)中的3-苄氧基-2-叔丁氧羰基氨基-丙酸(20.5g,0.069mol)。搅拌5min后,将溶液浓缩得到76A。
向置于250ml MeOH中的76A(22.8mg,74.8mmol)溶液中,加入肼(4.8g,149.8mmol),将混合物回流2天。浓缩溶液得到粗76B。
向置于CH2Cl2(10ml)中的2-氧代-哌啶-3-羧酸乙酯(0.86g,5mmol)的溶液中,加入三甲基氧鎓四氟硼酸盐(0.74g,5mmol),过夜搅拌后,再加入76B(1.5g,5mmol)。将混合物搅拌24h。溶液用CH2Cl2稀释,用水洗涤,干燥,浓缩得到白色泡沫76C(2.5g,<99%)。
将76C(1.3g,2.8mmol)的MeOH(27ml)溶液回流4天。将混合物浓缩得到76D。
向置于CH2Cl2中的76D(1.2g,2.8mmol)中,加入HCl(5ml,4MHCl,于二氧杂环己烷中),在室温下搅拌,直到所有起始物质被消耗掉。浓缩溶液,向残留物的CH2Cl2(15ml)溶液中加入EDAC(0.8g,0.416mmol)和HOBT(0.56g,4.16mmol)和(i-Pr)2NEt(7.15g,55.4mmol)和2-叔丁氧羰基氨基-2-甲基-丙酸(0.68g,3.32mmol)。将反应液搅拌过夜,用EtOAc抽提。有机溶液用水、盐水洗涤,干燥,浓缩。在硅胶(5%CH3OH/CH2Cl2作为洗脱剂)上用快速色谱法纯化,得到76E。
实施例76
将置于CH2Cl2(5ml)中的76E(50mg,0.1mmol),用HCl(2ml,4MHCl,于二氧杂环己烷中)处理,并在室温下搅拌,直到所有起始物质被消耗掉。利用制备HPLC纯化得到标题化合物盐(22mg,55%)。MS(M+H)430,HPLC保留时间2.63min。
实施例77
2-氨基-N-[2-苄氧基-1-(5,6,7,8-四氢-[1,2,4]三唑[4,3-a]吡啶-3-基)-
乙基]-2-甲基-丙酰胺
向76E(0.32g,0.6mmol)的THF(1ml)溶液中加入H2O(4ml)、MeOH(0.5ml)和氢氧化锂(6m的4N溶液)。将混合物在室温下搅拌1.5h。通过缓慢加入IN HCl将溶液的pH值调到2,然后用CH2Cl2抽提,用水、盐水洗涤,干燥,浓缩得到77A(270mg,89%)。
实施例77
向醚(2.5ml)中的77A(135mg,0.27mmol)中,加入甲胺(0.27ml,0.54mmol,2M in THF),HOBT(73mg,0.54mmol)和EDAC(103mg,0.54mmol)。搅拌24h后,溶液用CH2Cl2抽提,用水,盐水洗涤,干燥,浓缩。CH2Cl2(2ml)中的残留物用HCl(1ml 4M HCl,在二氧杂环己烷中)处理,在室温下搅拌,直到所有起始物质被消耗掉。利用制备HPLC纯化,得到标题化合物,为泡沫状(61mg,65%)。MS(M+H)358,HPLC保留时间1.86min。
实施例78
3-[1-(2-氨基-2-甲基-丙酰氨基)-2-苄氧基-乙基]-5,6,7,8-四氢-
[1,2,4]三唑[4,3-a]吡啶-7-羧酸乙酯
向置于CH2Cl2(120ml)中的异烟酸乙酯(ethyl isonipecotate)(20.4g,0.13mmol)溶液中,加入双-叔丁基碳酸氢钠(31.1g,0.13mol)。室温下搅拌5h后,反应用水淬灭,用CH2Cl2抽提,用水、盐水洗涤,干燥,浓缩。在硅胶(1∶6EtOAc/己烷作为洗脱剂)上利用快速色谱法纯化,得到78A。
在室温下向置于水(120ml)和乙腈(25ml)中的78A(10.38g,40.4mmol)溶液加入高碘酸钠(25.9g,121.1mmol)和氧化钌(0.5g,3.63mmol)。搅拌6h后,过滤混合物。残留物用CH2Cl2洗涤,水层用CH2Cl2抽提,干燥,浓缩。CH2Cl2(100ml)中的残留物用HCl(14ml,4M HCl,于二氧杂环己烷中)处理,在室温下搅拌直到所有起始物质被消耗掉。在硅胶(5%CH3OH/CH2Cl2作为洗脱剂)上用快速色谱法纯化,得到78B。
78C通过用78B(1.2g,7.1mmol)和76B(2.9g,7.1mmol)替代2-氧代-哌啶-3-羧酸乙酯,使用76C中描述的方法制备得到。得到的78C是无色的油(3.4g,<99%)。
实施例78通过使用与制备76D相同的方法,用78C替代76C制备而得,提供标题化合物,为泡沫状(17mg)。MS(M+H)430,HPLC保留时间2.56min。
对实施例78进行制备HPLC分离,得到两种非对映异构体,即实 施例78a:MS(M+H)430,HPLC保留时间2.55min,和实施例78b:MS(M+H)430,HPLC保留时间1.89min。
实施例79
3-[1-(2-氨基-2-甲基-丙酰氨基)-2-苄氧基-乙基]-7-苯基-5,6,7,8-四氢
-[1,2,4]三唑[4,3-a]吡啶-7-羧酸甲酯
在0℃下,向置于醚(100ml)中的冷却的氢氧化钾(15ml,40%于水中)溶液,在15min以上的时间里,缓慢地加入1-甲基-3-硝基-1-硝基胍(5g,34mol)。将上面的有机相倒入含有30g氢氧化钾的长颈瓶中。5min后,在该醚溶液中缓慢加入置于THF(20ml)中的4-甲酰基-4-苯基-哌啶-1-羧酸叔丁酯(4.15g,13.6mmol)。搅拌5min后,将溶液浓缩得到79A(4.4g,<99%)。
79B通过用79A(4g,12.5mmol)替代78A,使用78B中描述的方法制备得到,得到的79B是无色的油(3.1g,75%)。
浆置于CH2Cl2/MeOH(6ml/6ml)中的79B(3.1g,9.3mmol)用HCl(5ml,4M HCl,于二氧杂环己烷中)处理,在室温下搅拌,直到所有起始物质被消耗掉。在硅胶(5%CH3OH/CH2Cl2作为洗脱剂)上利用快速色谱法进行纯化,得到79C。
79D通过使用76C中描述的方法,用79C(830mg,35.6mmol)和76B(2.9g,7.1mmol)替代2-氧代-哌啶-3-羧酸乙酯制备而得。所获得的79D是无色的油(2.2g,<99%)。
实施例79通过使用用于与76D、76E和实施例76相同的方法,用79D替代76C、79E替代76D、79F替代76E制得,得到标题化合物,为泡沫状(8.5mg)。MS(M+H)492,HPLC保留时间2.91min。
实施例80和实施例81
对实施例79进行制备HPLC,分离非对映异够体,得到24mg的实施例80(MS(M+H)492,HPLC保留时间2.89min)和34mg的实施例81(MS(M+H)492,HPLC保留时间3.01min)。
实施例82
3-[1-(2-氨基-2-甲基-丙酰氨基)-2-苯氧基-乙基]-5,6,7,8-四氢-
[1,2,4]三唑[4,3-a]吡啶-7-羧酸乙胺
82A利用77A中描述的方法,用78D(200mg,0.38mmol)替代76E制备而得。所获得的82A是无色的油(168mg,89%)。
实施例82
在-40℃下,向置于CH2Cl2(2ml)中的82A(89mg,0.18mmol)的溶液中,加入N-甲基吗啉和异丁基三氯甲烷(24.3mg,0.18mmol)。在-40℃下,搅拌混合物1h。然后加入置于THF(90μl,0.18mmol)中的2M乙胺溶液。将反应缓慢加温到室温,浓缩。将残留物重新溶解于CH2Cl2(2ml)中,用HCl(1ml,4M HCl,于二氧杂环己烷中)处理。并在室温下搅拌,直到所有起始物质被消耗掉。利用制备HPLC纯化得到标题化合物,为盐(14mg,20%)。MS(M+H)429,HPLC保留时间1.89min。
混合物83和83a利用实施例82中描述的程序,用合适的起始物质合成。
实施例84
2-氨基-N-[1-(6-氯-苯并[d]异噁唑-3-基)-4-苯基-丁基]-2-
甲基-丙酰胺
向60ml的EtOH中,缓慢加入Na金属(2.3g,100mmol),并搅拌30min,直到所有钠金属溶解掉。然后加入2-乙酰氨-丙二酸二乙酯(21.7g,100mmol)。在室温下搅拌1h后,加入(3-溴-丙基)-苯(15.2ml,100mmol),然后在75℃加热过夜。混合物用水骤冷,用EtOAc抽提,用Na2SO4干燥,过滤,浓缩。残留物用己烷捣碎,得到白色固体84A(18.7g,81%)。
在室温(RT)下,向1N NaOH(56ml)和置于THF(50ml)中的搅拌过的A(4.3g,18.7mmol)溶液中,加入双-叔丁基碳酸氢钠(4.9g,22.5mmol)。搅拌3h后,加入苯硫醇(3.1g,28.1mmol),EDAC(7.1g,37mmol)和HOBT(5.1g,37mmol),然后将该反应液在室温下搅拌过夜。混合物用EtOAc抽提,用Na2SO4干燥,过滤,浓缩。在硅胶(1∶9EtOAc/己烷作为洗脱剂)上利用快速色谱法进行纯化,得到84B(3.8g,53%)。
在0℃下,在氮中,向置于THF(10ml)中的84B(1.1g,3.8mmol),加入二氯双(三苯基膦)钯(II)(200mg,0.28mmol),然后通过注射器加入置于THF中0.5M的3-氯-4-氟苯锌碘化物(17ml,8.5mmol)。混合物在室温下搅拌3h后,用水淬灭,用EtOAc抽提,用Na2SO4干燥,过滤,浓缩。在硅胶(1∶9EtOAc/己烷作为洗脱剂)上利用快速色谱法进行纯化,得到84C(710mg,45%)。
向置于吡啶(5ml)中的、搅拌过的84C(700mg,1.7mmol)溶液中,加入羟基胺盐酸(240mg,3.4mmol),并在密封管中加热2h。将混合物浓缩,将残留物溶解于DMF(二甲基甲酰胺,5ml)中,加入氢氧化钾(450mg,6.8mmol)。混合物在85C下加热过夜后,用水骤冷,用EtOAc抽提,用Na2SO4干燥,过滤,浓缩。在硅胶(1∶9EtOAc/己烷作为洗脱剂)上利用快速色谱法(flash chromatography)进行纯化,得到白色固体84D(390mg,57%)。
向搅拌过的84D(390mg,0.97mmol)溶液中,加入5ml的20%TFA/CH2Cl2,在室温下搅拌2h。浓缩混合物,将残留物溶解于1NNaOH、水、盐水中,干燥、浓缩。残留物用5ml的CH2Cl 2萃取,加入Boc-2-氨基异丁酸(390mg,1.9mmol)、1-氨羟基苯并三唑水合物(270mg,2mmol)、EDAC(380mg,2mmol)。混合物在室温下搅拌过夜后,用EtOAc抽提,用Na2SO4干燥,过滤,浓缩。在硅胶(1∶9EtOAc/己烷作为洗脱剂)上利用快速色谱法进行纯化,得到白色固体84E(360mg,76%)。
实施例84
将置于1ml的20%TFA/CH2Cl2中的84E(13mg,0.03mmol)溶液搅拌1h,然后浓缩。残留物用制备HPLC纯化,得到标题化合物,为白色固体(34.5mg,53%)。MS(M+H)386,HPLC保留时间3.32min。
实施例85
2-氨基-N-[1-(5-氯-苯并[d]异噁唑-3-基)-4-苯基-丁基]-2-甲基-
丙酰胺
向置于CH2Cl2(5ml)中的2,5-二氯-苯甲酸(3.5g,18.3mmol)的搅拌过的溶液中,加入草酰氯(18.3ml,2M于CH2Cl2中),再加入几滴DMF(二甲基甲酰胺)。将混合物在室温下搅拌2h,并浓缩。将残留物溶解于CH2Cl2(20ml)中,加入TEA(7.6ml,55mmol),再加入盐酸N,O-二甲基羟基胺(N,O-Dimethylhydroxyamine hydrochloride,3.6g,36.6mmol)。混合物在室温下搅拌过夜,并用EtOAc抽提,用Na2SO4干燥,过滤,浓缩。在硅胶(EtOAc/己烷作为洗脱剂)上利用快速色谱法进行纯化,得到淡褐色的固体85A(3g,67%)。
在0℃下,向置于THF(15ml)中的丁-3-炔基-苯(1.5g,11.5mmol)中,利用注射器加入nbuLi(5.3ml,2.5M于己烷中)。搅拌30min后,加入置于5ml THF中的85A(2.4g,10.3mmol),再在0℃下搅拌1h。混合物用水骤冷,用EtOAc抽提,用Na2SO4干燥,过滤,浓缩。在硅胶(1∶9EtOAc/己烷作为洗脱剂)上利用快速色谱法进行纯化,得到黄色液体85B(1.3g,42%)。
向置于MeOH(15ml)和EtOAc(5ml)中的C(1.3g,4.3mmol)加入Pd-C催化剂(260mg,钯以重量计为5%),并在室温下用氢气罐搅拌6h。催化剂被过滤、浓缩。在硅胶(5∶95EtOAc/己烷作为洗脱剂)上利用快速色谱法进行纯化,得到黄色液体85C(1.1g,85%)。
在室温下,利用注射器向置于二氧杂环己烷(5ml)中的搅拌过的85C(900mg,2.9mmol)溶液中,缓慢加入置于二氧杂环己烷(5ml)中的溴(470mg,2.9mmol),然后搅拌过夜。用水骤冷,用EtOAc抽提,用Na2SO4干燥,过滤,浓缩,使残留物通过硅衬垫,得到淡黄色油,作为中间体。将该中间体溶解于丙酮(10ml)中,并加入置于2ml水中的叠氮化钠(200mg,3.1mmol)。混合物在室温下搅拌30min,浓缩,用EtOAc抽提,用Na2SO4干燥,过滤,浓缩。在硅胶(1∶9EtOAc/己烷作为洗脱剂)上利用快速色谱法进行纯化,得到85D(710mg,70%)。
向置于MeOH(10ml)中的85D(710mg,2mmol)中,加入二叔丁基二碳酸酯(1.3g,6mmol)和Pd-C催化剂(70mg,5wt%钯),在室温下用氢气罐搅拌过夜。将催化剂过滤、浓缩。在硅胶(1∶9EtOAc/己烷作为作为洗脱剂)上利用快速色谱法进行纯化,得到白色固体85E(250mg,89%)。
85F通过使用84D中描述的方法,用85E(650mg,1.5mmol)和羟胺基盐酸盐(hydroxylamine hydrochloride,210mg,3mmol)&氢氧化钾(400mg,6mmol)替代84C制备而得。所得到的85F是无色的油(490mg,81%)。
85G通过使用84E中描述的方法,用85F(490mg,1.2mol)和Boc-2-氨基异丁酸(490mg,2.4mmol)替代84D制备而得。所得到的85G是无色的油(490mg,81%)。
使用手性制备HPLC(Chiralpak AD 5cm×50cm)&20%IPA/己烷作为洗脱剂)将85G进行手性分离,得到265mg的85H(保留时间(rt)=6.54min))和265mg的85I(保留时间(rt)=12.85min)。
实施例85
根据实施例84的方法,用3ml的20%TFA/CH2Cl2处理85I(265mg,0.55mmol),得到标题化合物,为白色固体(245mg),纯度是99%。MS(M+H)387,HPLC保留时间3.34min。
实施例86
2-氨基-N-[1-(5-氯-苯并[d]异噁唑-3-基)-4-苯基-丁基]-
2-甲基-丙酰胺
根据实施例84的方法,用20%TFA/CH2Cl2(0.7ml)处理86H(10mg,0.02mmol),得到标题化合物,为白色固体(7.4mg),纯度是99%。MS(M+H)386,HPLC保留时间3.37min。
实施例87
2-氨基-N-[1-(6-甲磺酰-[1,2,4]三唑[4,3-a]吡啶-3-基)-3-苯基-丙基]
-2-甲基-丙酰胺
在室温下,向置于THF(3ml)中的1C(200mg,0.447mmol)中,加入异丙基氯化镁(1.34ml,2.68mmol,2M溶液)。搅拌1h后,加入二甲基二硫化物(94.2mg),搅拌过夜。用水稀释,用CH2Cl2抽提,干燥,浓缩。在硅胶(1∶1EtOAc/己烷作为洗脱剂)上利用快速色谱法进行纯化,得到白色固体87A。
向置于CH2Cl2(1ml)中的87A(15mg,0.03mmol)中,加入m-氯代过苯甲酸(21mg,0.07),搅拌2h。浓缩混合物,重新溶解于CH2Cl2,用1N NaOH、盐水洗涤,干燥,浓缩。在室温下,用4N HCl(1ml)处理置于MeOH(1ml)中的残留物3h,然后浓缩。残留物用1.5ml CH2Cl2和Boc-2-氨基异丁酸(390mg,1.9mmol)吸收,并加入1-HOAT(10mg,0.07mmol)、EDAC(14mg,0.072mmol)和TEA(20μl,0.144mmol)。混合物在室温下搅拌过夜,用EtOAc抽提,用水洗涤,用Na2SO4干燥,过滤,浓缩,得到87B。
实施例87
用4N HCl(1ml)处理置于MeOH(1ml)中的87B溶液,然后浓缩。残留物通过制备HPLC纯化,得到标题化合物,为白色固体(15mg)。MS(M+H)432,HPLC保留时间2.4min。
实施例88
甲基-氨甲酸3-[1-(2-氨基-2-甲基-丙酰氨基)-2-苄氧基-乙基]-7-苯
基
-5,6,7,8-四氢-[1,2,4]三唑[4,3-a]吡啶-7-基甲基酯
在0℃下,向置于CH2Cl2(6ml)中的79E(350mg,0.6mmol)溶液中,加入氢硼化锂(1.2ml,2.4mmol,2M溶液)。将混合物加温到室温,搅拌过夜。反应用pH 3缓冲液淬灭,搅拌30min,用CH2Cl2抽提,用盐水洗涤,干燥,过滤,浓缩,得到粗产物88A(336mg,<99%)。
实施例88
在0℃下,向置于CH2Cl2(3ml)中的88A溶液中,加入TEA(127μl,0.91mmol)和甲基异氰酸酯(35mg,0.61mmol)。将混合物加温到室温,搅拌过夜。CH2Cl2(3ml)中的残留物用HCl(1.5ml,4MHCl,于二氧杂环己烷中)处理,在室温下搅拌,直到所有起始物质被消耗掉。通过制备HPLC纯化和分离,得到两个非对映异够体,即实施例88a:MS(M+H)521,HPLC保留时间2.55min和实施例88b:MS(M+H)521,HPLC保留时间2.92min。
实施例89
2-氨基-N-[2-苄氧基-1-(6-氯-[1,2,4]三唑[4,3-b]哒嗪-3-基)-
乙基]-2-甲基-丙酰胺
在室温下,向置于CH2Cl2(10mL)中的3-苄氧基-2-叔丁氧羰基氨基-丙酸(740mg,2.5mmol)浆状物中,加入EDAC(475mg,2.5mmol)。搅拌1h后,加入(6-氯哒嗪-3-基)肼(362mg,2.5mmol)。2h后,反应用饱和含水NaHCO3淬灭。混合物用EtOAc抽提,过滤,浓缩。在硅胶(1∶2EtOAc/己烷作为洗脱剂)上利用快速色谱法进行纯化,得到89A,为黄色泡沫(730mg,69%)。
在0℃下,向置于乙腈(5mL)中的89A(210mg,0.5mmol)溶液中,加入1,2-二溴-1,1,2,2-四氯乙烷(179mg,0.55mmol),再加入三乙胺(0.31mL,2.2mmol)和三苯基膦(289mg,1.1mmol)。搅拌1h后,将混合物加温到室温,搅拌2h。浓缩溶液,将残留物重新溶解于EtOAc,用1∶1盐水/10%柠檬酸、盐水洗涤,干燥,过滤,浓缩。利用制备HPLC纯化得到89B,为灰白色固体(125mg,62%)。
在0℃下,向MeOH(3.5ml)加入乙酰氯(0.8mL),加入时间超过3min。溶液搅拌1h后,在室温下向溶液加入置于CH2Cl2(0.3ml)中的89B(125mg,0.31mmol)。在室温下,搅拌混合物2h,然后从CH2Cl2中浓缩2次。将残留物重新溶解于CH2Cl2(1mL)中,加入到处于CH2Cl2(2ml)中的由Boc-2-氨基异丁酸(94.4mg,0.46mmol)、HOAT(63.6mg,0.46mmol)和N-甲基吗啉(0.051ml,0.5mmol)组成的浆状物中。搅拌溶液15h,用EtOAc稀释,用饱和酸含水NaHCO3洗涤,干燥,过滤和浓缩。在硅胶(1∶99MeOH/EtOAc作为洗脱剂)上利用快速色谱法进行纯化,得到无色泡沫89C(69mg,46%)。
实施例89
在0℃下,向MeOH(3.5ml)中加入乙酰氯(0.8mL),加入时间超过3min。溶液搅拌1h后,在室温下将溶液加入到置于CH2Cl2(0.3ml)的89C(69mg,0.14mmol)中。在室温下搅拌混合物2h,然后浓缩。将残留物溶解于水,通过尼龙过滤器过滤,冻干,得到标题化合物,为白色无定形固体。MS(M+H)389,HPLC保留时间2.92min。
实施例90
(4-羟基-丁基)-氨甲酸3-[1-(2-氨基-2-甲基-丙酰氨基)-2-苄氧基-乙基]-
咪唑[1,5-a]吡啶-5-基甲基酯
在室温下,在氩气中,向置于DMF(40mL)的、搅拌过的邻苯二甲酰亚胺钾(1.04g,5.15mmol)溶液中,加入(6-溴甲基吡啶-2-基)-甲醇(1.03g,5.11mmol)的DMF溶液(10mL),加入时间超过5min。在40℃下加温浆状物,搅拌过夜。然后在40-55℃下(1Torr,1托),DMF被蒸馏掉。粉末状残留物在CH2Cl2中迅速搅拌20min,通过硅藻土过滤。将残留物重新溶解于CH2Cl2中,用水洗涤,干燥和浓缩,得到90A,为淡白色固体(1.16g,85%)。
向搅拌过的90A(1.2g,4.32mmol)的EtOH(60ml)溶液中,加入肼(0.41mL,13.1mmol),将反应混合物在氩气下回流14h。冷却溶液,通过硅藻土过滤,浓缩滤出液。将残留物重新溶解于MeOH中,冷却,过滤和浓缩,得到(6-氨甲基-吡啶-2-基)-甲醇。在-12℃下,向搅拌过的置于THF(10mL)中的Boc-(O-苯甲基)丝氨酸(1.3g,4.32mmol)和N-甲基吗啉(0.484mL,4.4mmol)溶液中,加入异丁基氯甲酸酯(0.56mL,4.35mmol)。搅拌30min后,加入置于THF的(6-氨甲基吡啶-2-基)-甲醇浆状物,加入时间超过1min。在室温下,搅拌溶液1h。反应用EtOAc稀释,用饱和含水碳酸氢纳溶液洗涤,干燥和浓缩,得到90B(1.9g),为黄色油状物。该材料不经纯化,直接用于下面的反应。
向90B(1.9g,4.3mmol)的DMF(10ml)溶液中,加入咪唑(410mg,6.02mmol)和叔-丁基二甲基-氯化硅(750mg,4.98mmol)。溶液搅拌20h。反应用水淬灭,用EtOAc抽提,过滤,浓缩。在硅胶(19∶81EtOAc/CH2CI2作为洗脱剂)上利用快速色谱法进行纯化,得到无色油90C(1.4g,53%)。
在0℃下,向于置于乙腈中(15mL)的90C(1.4g,2.6mmol)和1,2-二溴-1,1,2,2-四氯乙烷(1.9g,5.8mmol)的浆状物中,加入三苯基膦(1.5g,5.8mmol)和TEA(1.60mL,11.5mmol)。30min后,将所得到的黄色浆状物在室温下搅16h。形成一种红色溶液。浓缩该溶液,在水和EtOAc之间分配,干燥,过滤和浓缩。在硅胶(3∶17EtOAc/CH2Cl2作为洗脱剂)上利用快速色谱法进行纯化,得到90D,为棕褐色的油状物(625mg,46%)。
在0℃下,向MeOH(8mL)中加入乙酰氯(2.0mL),加入时间超过3min。溶液搅拌1h后,将它在0℃下加入到90D(620mg,1.2mmol)中。将该溶液搅拌2h,浓缩。将残留物溶解于CH2Cl2(5mL)中,加入到搅拌过的由Boc-2-氨基异丁酸(370mg,1.82mmol)、HOAt(249mg,1.82mmol)和EDAC(346mg,1.82mmol)组成的浆状物中,再加入N-甲基吗啉(0.3mL,2.7mmol)。将混合物搅拌15h,用CH2Cl2稀释,用饱和含水NaHCO3洗涤,干燥和浓缩。在硅胶(3∶17EtOAc/CH2Cl2作为洗脱剂)上利用快速色谱法进行纯化,得到无色泡沫90E(450mg,77%)。
在0℃下,向置于THF(3mL)的90E(279mg,0.58mmol)和吡啶(0.12mL,1.4mmol)溶液中,加入置于CH2Cl2(3mL)中的4-硝基苯三氯甲烷(256mg,1.3mmol)。将溶液搅拌1h,浓缩。将残留物溶解于THF(5mL)中,再加入4-氨基丁醇(0.5mL)。将该溶液搅拌30min,用EtOAc稀释,用IN NaOH洗涤,干燥和浓缩。在硅胶(EtOAc作为洗脱剂)上利用快速色谱法进行纯化,得到黄色油90F(207mg,60%)。
实施例90
在0℃下,向MeOH(8mL)中加入乙酰氯(2.0mL),加入时间在3min时间以上。搅拌溶液1h之后,在0℃下,将溶液加入到90F(204mg,0.342mmol)中。将溶液搅拌2h,并浓缩。冻干残留物,得到标题化合物,为黄色固体。MS(M+H)498,HPLC保留时间2.64min。
利用实施例90中描述的程序,用合适的起始物质合成下述化合物。实施例263也通过该方法制得。
实施例92
3-[1-(2-氨基-2-甲基-丙酰氨基)-2-苄氧基-乙基]-5,6-二氢-8H-[1,2,4]
三唑[4,3-a]吡嗪-7-羧酸苯甲基酯
向置于CH2Cl2(20ml)的3-氧代-哌嗪-1-羧酸苯甲基酯(1.5g,6.4mmol)溶液中,加入三甲基氧鎓四氟硼酸盐(0.99g,6.72mmol)。将该溶液搅拌60h。加入置于CH2Cl2(20ml)中的(2-苄氧基-1-肼基羰基-乙基)-氨甲酸叔丁酯(2.07g,309.7mmol)溶液,得到清澈溶液。将溶液搅拌2h后,用CH2C l2稀释,用水洗涤,干燥和浓缩,得到白色泡沫92A(3.2g,95%)。
在120℃、60W下,用微波处理置于EtOH(26ml)中的92A(2.6g,4.9mmol)溶液10min。混合物用置于二氧杂环己烷(30ml)中的4N HCl处理30min。浓缩该溶液,并用乙醇共蒸发得到92B(2.8g)。
向2-叔丁氧羰基氨基-2-甲基-丙酸(1.34g,66.1mmol)的CH2Cl2(100ml)溶液中,加入EDAC(1.8g,9.45mmol)和HOBT(1.27g,9.45mmol)、DMAP(0.77g,6.3mmol)和TEA(2.63ml,18.9mmol)。将该溶液搅拌10min,然后加入92B(2.8g,6.3mmol),反应在2h内完成。溶液用CH2Cl2稀释,用水、1N HCl、1N NaOH洗涤,干燥并浓缩。在硅胶(5∶95MeOH/CH2Cl2作为洗脱剂)上利用快速色谱法进行纯化,得到92C(3g),为泡沫状物质。
实施例92
将CH2Cl2中的92C(250mg)溶液,用HCl(30ml,4M HCl,于二氧杂环己烷中)处理,在室温下搅拌1h。将溶液浓缩,残留物用MeOH/EtOAc结晶,得到标题化合物,为不固体状(130mg)。MS(M+H)493,HPLC保留时间2.33min。
实施例93
3-[1-(2-氨基-2-甲基-丙酰氨基)-2-苄氧基-乙基]-5,6-二氢-8H-
[1,2,4]三唑[4,3-a]吡嗪-7-羧酸萘-2-基甲基酯
在氮气中,向置于MeOH(70ml)中的92C(2.6g,4.4mmol)和催化剂披钯碳(30mg)溶液中,加入甲酸铵(1.3g,20.9mmol)。将溶液搅拌3h,通过硅藻土过滤,浓缩,得到93A(2.45g)。
向置于CH2Cl2(0.25ml)中的2-萘甲醇(11mg,0.07mmol)溶液中,加入置于CH2Cl2(0.25ml)的n-甲基吗啉(12μl,0.1mmol)和4-硝基苯三氯甲烷(15mg,0.0735mmol)。将溶液搅拌过夜,再加入置于CH2Cl2(0.08ml)和TEA(0.1ml,0.7mmol)中的93A(32mg,0.07mmol)。将溶液搅拌过夜,用CH2Cl2稀释,用1N HCl、1NaOH、水洗涤,干燥、浓缩,得到93B。
实施例93
将置于CH2Cl2中的93B溶液,用置于CH2Cl2中的TFA处理,并在室温下搅拌1h。浓缩该溶液。残留物用制备HPLC纯化,得到标题化合物。MS(M+H)543,HPLC保留时间2.82min。
用实施例93中描述的程序,用本领域技术人员熟悉的合适的起始物质合成下述化合物。
使用上述的通用合成方案和工作实施例中描述的程序,用本领域技术人员熟悉的合适的起始物质合成下述化合物。
实施例338
在-10℃下,向置于甲苯(200mL)中的n-BuLi(2.5M于THF中,84ml,0.21mol)溶液中,加入n-BuMgCl(2.0M于THF中,52.5ml,0.105mol),加入时间超过10min。将混合物在-10℃下搅拌30min,然后通过另外一个漏斗,加入到置于甲苯(500mL)中的2,6-二溴吡啶(71.07g,0.3mol)中,加入时间超过30min。将所得悬浮液在-10℃下搅拌2.5h,然后通过导管转移到置于甲苯(200mL)中的冷却的DMF溶液中。将溶液在-10℃下搅拌30min,然后加入30%的柠檬酸(300mL)。搅拌30min后,有机相用水(300mL)、盐水(200mL)洗涤,用硫酸钠干燥。过滤之后,浓缩滤出液,得到338A(54.2g),为淡黄色的有色固体。HPLC (A)保留时间1.88min。
将置于甲醇(600mL)中的搅拌过的338A(29.0g,0.151mol)溶液,在水浴中在冷却到12℃,然后分几小批加入硼氢化钠(5.89g,0.16mol),加入时间超过20min。温度不能允许升高到23℃以上。再将混合物搅拌1h,然后小心地用冰冷的10%HCl淬灭,到pH2(总量64mL)。在真空中浓缩反应混合物,产生相当多的泡沫。将残留物重新溶解于二氯甲烷(250mL)中,用5%碳酸钾溶液(150mL,在pH8下)搅拌。水合层用二氯甲烷(每次250mL)抽提2次。混和有机层用硫酸纳干燥,通过硫酸镁过滤,真空中浓缩,得到黄色有色油338B(27.65g)。缓慢结晶该化合物,得到黄色有色固体。MS(M+H+)188,190;HPLC(A)保留时间1.99min。
在室温下、在氩气中,向搅拌过的的338B(25.0g,0.129mol)的DMF(200mL)溶液中,加入咪唑(17.56g,0.258mol),然后,在咪唑溶解之后,一次性加入叔-丁基二甲基氯化硅(23.27g,0.155mol)。能观察到轻微的吸热现象。搅动16h后,反应混合物用冰水(500mL)淬灭,用3×250mL己烷抽提。混和己烷抽提物,用水(150mL)洗涤2次,用盐水洗涤一次。有机层用硫酸纳干燥后,将它们通过硫酸镁过滤,反萃取(stripped),得到338C(39.15g),为浅黄色油状物。MS(M+H)302,304;HPLC(A)保留时间4.56min。
在1L的三颈(3-necked)烧瓶中,装入置于吡啶(500ml)中的338C(38.5g,0.127mol)溶液,一次性用肼(40ml,1.28mol)处理。能看到轻微的吸热现象。将反应混合物搅拌,在氩气中(罐温109-111℃)加热回流45h。在冰浴中冷却到室温后,加入固体碳酸氢钠(11g)。将混合物搅拌1h,反萃取,得到黄色油。加入水(200mL),并在种晶的协助下形成一种固体。破碎固体块,收集,用水(5×100mL)洗涤。为了加速干燥,将固体溶解于醚(500mL)中,用盐水洗涤一次,用硫酸钠干燥,通过硫酸镁过滤。在真空中浓缩有机物质,得到灰白色固体338D(31.5g)。MS(M+H+)254;HPLC(A)保留时间2.53min。
将1L的三颈烧瓶(烘干的)中,装入置于THF(250mL)中的N-(叔丁氧羰基)-D-丝氨酸(35.74g,0.12mol),在氩气中冷却到-13℃(异丙醇/冰浴)。一次性加入N-甲基吗啉(13.74ml,0.125mol)(温度暂时升高到2℃)。将温度再次冷却到-13℃后,以将温度维持在-10℃以下的速度加入异丁基氯甲酸酯(15.69ml,0.12mol)。将反应混合物搅拌20min,然后加入置于THF(100mL)中的338D(30.4g,0.12mol)溶液,加入时间超过15min,加入过程中温度不能升到-5.5℃以上。另外的漏斗用THF(25mL)洗涤,然后将黄色反应浆状物搅拌90min。在-10℃下,用饱和碳酸氢纳(100mL)淬灭,含水层用乙酸乙酯(500mL)抽提2次。混和有机层,用盐水、10%柠檬酸、饱和碳酸氢纳洗涤,用硫酸钠干燥,通过硫酸镁过滤后,真空中除去挥发成分,残留物从二氯甲烷/己烷中反萃取出来,得到338E(63.97g),为黄色泡沫。MS(M+H+)531;HPLC(A)保留时间3.91min。
在-78℃下、在氩气中,向置于THF(800mL)中的338E(93.6g,0.177mol)溶液中,加入三乙胺(196ml,1.41mol)。10min后,以分份方式加入二氯三苯基膦(194.2g,0.583mol),加入时间超过10min。搅拌混合物,过夜(~20h)缓慢加温到室温。除去挥发部分,通过短硅胶柱过滤残留物,用己烷/乙酸乙酯(1∶2)漂洗柱。蒸发合并的滤出物,得到粗的338F(200g,是与三苯基膦氧化物混和的)。MS:(M+H+)513;HPLC(A)保留时间430min。
一个可替代的程序是:在-73℃、在氩气中,向置于THF(800ml)的、搅拌过的338E(63.95g,0.12mol)溶液中,加入三乙胺(134ml,0.964mol)。15min后,以分次方式,加入双氯三苯基膦(132.49g,0.398mol),加入时间超过30min,搅拌1h。然后通过用室温水替代丙酮冷浴将温度升到-10℃。允许将反应混合物温度从-10℃原位过夜加温到室温,然后通过硅藻土过滤,真空中浓缩。将得到的固体溶解于二氯甲烷(750mL),冷却到0℃,用冰冷的10%柠檬酸(100mL)处理。快速搅拌混合物5min,有机层用水、饱和碳酸氢纳洗涤一次,干燥(硫酸镁),过滤和再反萃取,得到338F(167.74g,被三苯基膦氧化物污染),为浅棕色有色固体。
在2℃下,向甲醇(400ml)中逐滴加入乙酰氯(100g),加入时间超过20min。搅拌30min后,在45min内将溶液升至室温。将甲醇溶液直接加入到粗338F(<167g,约0.12mol)中,搅拌混合物3h,在30℃以下真空浓缩。然后将棕色残留物悬浮于THF (500mL)中,时间30min。过滤收集所得固体,重新悬浮于THF(500mL)中30min。过滤之后,在40℃下,真空干燥固体,得到浅黄色有色固体338G(38.6g)。MS(M+H)299;HPLC(A)保留时间1.65min。
在室温下、在氩气中,向置于二氯甲烷中的N-(叔丁氧羰基)-α-甲基丙氨酸(24.39g,0.120mol)和HOBt(18.37g,0.120mol)的经过搅拌的浆状物中,加入固体EDAC(22.83g,0.120mol),加入时间超过10min。将所得的溶液搅1h,然后在室温下将溶液(通过棉塞过滤)加入到置于二氯甲烷中的338G(约0.120mol)和N-甲基吗啉(19.79ml,0.18mol)溶液中。搅拌45h后,反应混合物用饱和碳酸氢纳(200mL)搅拌30min。进行相分离,有机抽提物用盐水、10%柠檬酸(在pH 3下)洗涤一次,用盐水再洗涤一次。有机物用硫酸纳干燥,过滤,滤出液部分蒸发(至约250mL体积),加入醚(约100mL)。过滤所得的固体,得到无色固体338H(30.10g)。浓缩母液,并从三氯甲烷(50mL)和己烷(足以在沸腾溶液中产生混浊)中再结晶出来,得到另外的3.45g。混和两固体,得到338H(33.55g)。mp 155-157deg℃。MS(M+H+)484;HPLC(A)保留时间2.85min。
在0℃下,向置于二氯甲烷(300mL)中的338H(25.63g,0.053mol)悬浮液中,加入吡啶(9.0mL,0.111mol)。10min后,在氮气中,缓慢加入对硝基苯三氯甲烷(21.4g,0.106mol),并将反应液过夜缓慢加温到室温。过滤混合物,固体滤饼用二氯甲烷(100mL)漂洗。真空浓缩滤出液,加入乙酸乙酯和醚(200mL,1∶1),将混合物在室温下搅拌30min。过滤固体,收集粗固体产物。将固体重新悬浮于乙酸乙酯和醚(200mL,1∶1)中3次,得到无色固体338I(38.5g)。MS(M+H+)649;HPLC(A)保留时间3.68min。
在2℃下,向置于无水THF(250mL)中的肌氨酰胺(sarcosinamide)(2.61g,29.6mmol)悬浮液中,加入固体338I(16.0g,24.7mmol),加入时间超过10min。在室温下,搅拌黄色混合物24h。浓缩后,所得的黄色泡沫残留物,用乙酸乙酯(600mL)稀释,用冷1N NaOH(7×100ml)、水(100ml)洗涤,用硫酸镁干燥。在真空中浓缩有机层,得到粗无色固体338J(14.38g)。该材料还可以进一步通过柱层析纯化,用10%甲醇/二氯甲烷洗脱,得到纯的338J(10.47g)。MS(M+H+)531;HPLC(A)保留时间3.91min。
将HCl气体(67.8g,1.86mol)起泡注入冰冷的异丙醇(200mL)中。将所得的溶液冷却到5℃,分批加入固体338J(13.8g,23.1mmol),加入时间超过5min。0℃下30min后,在室温下将反应混合物再搅拌30min,然后真空中浓缩。用异丙醇(100mL)搅拌所得粘液体,通过过滤收集产生的无色固体,得到338(12.65g)。mp 151.4-152.6℃;MS(M+H+)498;HPLC(A)保留时间1.723min。
实施例339
在室温下、在氩气中,向置于THF(300ml)中的由中间体338I(37.41g,0.058mol)和三乙胺(12.06ml,0.087mol)组成的搅拌过的浆状物中,加入吗啉(5.53ml,0.063mol),加入时间超过2min。在5min内形成黄色溶液,反应液搅拌过夜。15h后,真空中浓缩反应溶液,并重新溶解于EtOAc(800mL)中。有机层用饱和碳酸氢纳(5×125mL)洗涤,用5%硫酸氢钾(200mL)、盐水洗涤一次,用饱和碳酸氢钠(100mL)洗涤一次。有机层用硫酸镁干燥,过滤和浓缩,得到无色泡沫37.5g。将该物质从5∶4乙酸乙酯∶己烷中重结晶2次,得到无色固体339A(30.95g)。mp104-106℃,MS(M+H+)597;HPLC(A)保留时间3.58min。
在0℃下,将乙酰氯(50ml,0.637mol)逐滴加入到无水甲醇(200mL)中,加入时间超过30min。30min后,将混合物加温到室温,搅拌1h,然后加入到固体339A(30.2g,0.051mol)中。4h后,浓缩反应混合物,将所得无色无定形体悬浮于THF中,超声波处理30min。过滤,得到无色无定形体,在45℃下干燥15h,得到339(25.75g)。MS(M+H)497;HPLC(A)保留时间2.73min。CHN元素分析:C25H32N6O5~2HCl
使用通用合成方案和上述工作实施例中描述的程序,用本领域技术人员熟悉的合适的起始物质制备下述实施例。
使用通用合成方案和上述工作实施例中描述的程序,用本领域技术人员熟悉的合适的起始物质制备下述实施例。
使用上述实施例90以及通用合成方案和上述工作实施例中描述的程序,用本领域技术人员熟悉的合适的起始物质制备下述实施例。
使用上述实施例92和93中描述的、通用合成方案和上述工作实施例中描述的程序,用本领域技术人员熟悉的合适的起始物质制备下述实施例。
使用通用合成方案和上述工作实施例中描述的程序,用本领域技术人员熟悉的合适的起始物质制备下述实施例。
使用通用合成方案和上述工作实施例中描述的程序,用本领域技术人员熟悉的合适的起始物质制备下述药物前体(pro-drug)实施例。
Claims (14)
1.化合物,其选自下列结构:
5.权利要求1所述的化合物,其中所述化合物的结构为:
7.权利要求1所述的化合物,其中所述化合物的结构为:
8.应用权利要求1所述化合物的方法。
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CN111533745A (zh) * | 2020-05-20 | 2020-08-14 | 成都药明康德新药开发有限公司 | 叔丁基-3-(氨基甲基)二氢-5h-三唑并二氮杂卓-8(9h)-甲酸基酯制法 |
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