CN101415695A - 神经酰胺激酶调节 - Google Patents
神经酰胺激酶调节 Download PDFInfo
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- CN101415695A CN101415695A CNA2007800119536A CN200780011953A CN101415695A CN 101415695 A CN101415695 A CN 101415695A CN A2007800119536 A CNA2007800119536 A CN A2007800119536A CN 200780011953 A CN200780011953 A CN 200780011953A CN 101415695 A CN101415695 A CN 101415695A
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Abstract
式(I)的化合物,其中R1是包含至少8个,例如8至22个碳原子的直链、支链或环状脂族、芳族或杂环基团,R2是包含1至12个碳原子的直链、支链或环状脂族、芳族或杂环基团,环A是包含5或6个环成员和1至4个选自N、S、O的杂原子的与同环A相连的苯环稠合的杂环基;前提条件是某些化合物除外,以及无前提条件的该类化合物作为用于由神经酰胺激酶介导的病症的药物的应用。
Description
本发明涉及神经酰胺激酶活性的调节剂。
鞘脂类一直被看作是细胞膜的主要组分之一。最近的证据表明,除结构作用外,鞘脂类还可发挥生物活性脂类的作用并影响信号转导,其作用方式与甘油磷脂类相似。
鞘脂代谢物的生理学活性包括例如诱导细胞凋亡和刺激细胞增殖,并且已经表明,代谢鞘脂类的酶可能参与诱导各种疾病。
例如
-已经表明控制细胞机理的神经酰胺是上面所示酶促反应中的调节剂,例如报道了神经酰胺以炎性细胞因子如TNF-α和IL-1β的第二信使的形式起作用,并且活化了花生四烯酸途径,如磷脂酶A2;并且因此,认为神经酰胺或其代谢物是炎性疾病中的恶化因子;
-神经酰胺在HIV感染患者中加剧了伴有细胞凋亡的CD4+T-细胞减少和脑细胞的HIV感染,
-据报道TNF-α可在2型糖尿病中作为触发剂造成胰岛素耐受性和造成肥胖,而神经酰胺参与了TNF-α的下调;
-公开了神经酰胺触发了脂多糖造成的败血症;
-据报道神经酰胺的增加活化了LDL(其触发了动脉粥样硬化损伤)聚集反应中的鞘磷脂酶;
-已知神经酰胺在放疗和化疗中促进了癌症细胞的细胞凋亡;
-表明在白血病细胞的药物耐受中涉及神经酰胺调节:神经酰胺水平的降低与白血病中的化疗耐受情况有关。
神经酰胺-1-磷酸酯(Cer-1-P)(其是通过神经酰胺激酶的作用例如通过各种神经酰胺衍生物(例如包括N-酰化的衍生物,如N-己酰基-、N-辛酰基-、N-棕榈酰基-D-赤型-鞘氨醇)1位羟基的磷酸化而由神经酰胺产生的)也表现出生理学活性,例如
-在受到钙刺激时由神经酰胺激酶产生的Cer-1-P据称可调节神经元递质从脑突触的释放并调控神经酰胺激酶的作用,因此预期在各种神经元病症(例如包括阿耳茨海默病)的治疗中有价值;
-据信Cer-1-P抑制了各种正常的神经酰胺活性,其可能是通过抑制酸鞘磷脂酶来发挥该作用,因此,预期Cer-1-P调控许多病症,例如炎性病症,例如包括慢性关节炎、HIV-感染、胰岛素耐受性作为触发剂造成的2型糖尿病、肥胖、败血症和动脉粥样硬化;据信该类疾病可以通过神经酰胺激酶的调节进行治疗;
-据信Cer-1-P主要在细胞内起作用,在那里,其促进了囊泡转运。已经表明其参与了吞噬作用,因此可能在炎症过程中起重要作用;
-还已经表明了外源性加入的Cer-1-P的致有丝分裂活性。因此,这种鞘脂代谢物可能与细胞增殖病症(非限制性地包括癌症和牛皮癣)有关。
-已经报道了Cer-1-P介导细胞因子和钙离子载体诱导的花生四烯酸释放,并且进一步表明C-1-P可能直接活化胞质PLA2;这进一步表明Cer-1-P可能在炎性病症中起作用;
-Cer-1-P水平还可能与视觉系统的病理生理学相关(例如易患色素性视网膜炎)。
现在,令人吃惊地提供了调控、例如抑制神经酰胺激酶活性的化合物。
本发明一方面提供了式I的化合物,
其中
R1是包含至少8个,例如8至22个碳原子的直链、支链或环状脂族、芳族或杂环基团,
R2是包含1至12个碳原子的直链、支链或环状脂族、芳族或杂环基团,且
环A是与同环A相连的苯环稠合的杂环基,其包含5或6个,优选5个环成员和1至4个选自N、S、O的杂原子;优选包含两个,优选至少一个氮原子,
前提条件是不包括下列化合物
N-[2-(乙酰氨基)-6-苯并噻唑基]-三环[3.3.1.13,7]癸烷-1-甲酰胺,例如下式的化合物
N-[2-(苯甲酰氨基)-6-苯并噻唑基]-三环[3.3.1.13,7]癸烷-1-甲酰胺,例如下式的化合物
N-[2-(苯甲酰氨基)-6-苯并噻唑基]-3-氯-苯并[b]噻吩-2-甲酰胺,例如下式的化合物
2,3-二氢-N-[2-[(1-氧代丁基)氨基]-6-苯并噻唑基]-1,4-苯并二氧杂环己烯-6-甲酰胺,例如下式的化合物
N-[2-(乙酰氨基)-6-苯并噻唑基]-3-氯-苯并[b]噻吩-2-甲酰胺,例如下式的化合物
N-[2-(丁酰氨基)-1,3-苯并噻唑-6-基]-3-氯-1-苯并噻吩-2-甲酰胺,例如下式的化合物
N-[2-(丁酰氨基)-1,3-苯并噻唑-6-基]-1-苯并呋喃-2-甲酰胺,例如下式的化合物
N-[2-[(环己基羰基)-氨基]-6-苯并噻唑基]-三环[3.3.1.13,7]癸烷-1-甲酰胺,例如下式的化合物
金刚烷-1-甲酸[2-(金刚烷-1-基)-羰基氨基-苯并噻唑-6-基]-酰胺,例如下式的化合物
N-[2,3-二氢-3-氧代-6-[(1-氧代十六烷酰基)-氨基]-苯并[b]-噻吩-2-基]-5-硝基-1H-吲唑-1-甲酰胺,例如下式的化合物
和
N-[2,3-二氢-3-氧代-6-[(1-氧代十六烷酰基)-氨基]-苯并[b]-噻吩-2-基]-2,3,5,6-四氟-4-巯基苯甲酰胺,例如下式的化合物
在式I的化合物中,各单一定义的取代基可以是优选的取代基,例如所定义的取代基彼此独立。
R2含义中的直链、支链或环状脂族基团包括例如
-烷基,例如包括(C1-12)烷基,
-链烯基,例如包括(C2-12)链烯基,
-炔基,例如包括(C2-12)炔基,
-环烷基,例如包括(C3-12)环烷基,
R2含义中的芳族基团例如包括(C6-12)芳基,如苯基。
R2含义中的杂环基团例如包括具有3至12个环成员和1至4个选自N、O、S的杂原子的芳族或脂族杂环基,例如稠合的杂环基。
本文R1含义中所定义的直链、支链或环状脂族、芳族或杂环基团可以未被取代或被取代,例如被取代一次或多次;例如被包含0至18个碳原子的有机化学中的常规取代基所取代。R1含义中的该类取代基例如包括(C1-8)烷基、卤代(C1-8)烷基、(C2-8)链烯基、(C2-8)炔基、羟基、(C1-8)烷氧基、卤代(C1-8)烷氧基、氰基、包含0至8个碳原子的含硫取代基,如巯基、(C1-8)烷基巯基、卤素、NO、硝基、(C6-18)芳基,例如苯基、(C6-18)芳氧基、(C2-12)酰基(包括羰基)、杂环基,例如脂族或芳族杂环基,例如包括包含稠合环(环系)的杂环基,其包含3至12个环成员和1至6个选自N、O、S的杂原子;或氨基,例如未被取代的氨基或被一或两个(C1-8)烷基、(C6-18)芳基、或者被(一个)(C2-13)酰基(包括羰基)取代的氨基;其中酰基包括(C1-8)烷基羰基、(C6-18)芳基羰基或杂环基羰基,例如脂族或芳族杂环基羰基,例如其中杂环基包含单环或稠合环(环系),包含3至18个环成员和1至6个选自N、O、S的杂原子。
本文R2含义中所定义的直链、支链或环状脂族、芳族或杂环基团可以未被取代或被取代,例如被取代一次或多次;例如被包含0至4个碳原子的有机化学中的常规取代基所取代。R2含义中的该类取代基例如包括(C1-4)烷基、卤代(C1-4)烷基、(C2-4)链烯基、(C2-4)炔基、(C3-6)环烷基、羟基、(C1-4)烷氧基、卤代(C1-4)烷氧基、氰基、羧基和羧酸衍生物,如羧酸酯或酰胺,其包含1至4个碳原子(包括羰基)、包含0至4个碳原子的含硫取代基,例如包括巯基、(C1-4)烷基巯基、卤素、NO、硝基、(C2-4)烷基羰基(包括羰基)或氨基,例如未被取代的氨基或被一个或两个(C1-4)烷基或被(一个)(C2-4)烷基羰基(包括羰基)取代的氨基。
在式I的化合物中,与苯环稠合的环A优选地是一种包含1或2个选自N、O、S的杂原子的5-元杂环基团。
环A和其与之相连接的苯环一起更优选地是苯并噻唑基或苯并噁唑基环,更优选地是苯并噻唑基环,
例如式I的化合物优选地是下式的化合物
其中
X是S或O且Y是N,或
Y是S或O且X是N,
优选地X是S或O且Y是N,
更优选地X是S且Y是N;并且
R1和R2如上所定义。
本发明另一方面提供了2,6-二酰氨基-苯并噻唑类或2,6-二酰氨基-苯并噁唑类化合物,其中6位氨基羰基的羰基被包含至少8个,例如8至22个碳原子的直链、支链或环状脂族、芳族或杂环基团所取代,2位氨基羰基的羰基被包含1至8个碳原子的直链、支链或环状脂族、芳族或杂环基团所取代,如2,6-二酰氨基-苯并噻唑类或2,6-二酰氨基-苯并噁唑类,例如2,6-二酰氨基-苯并噻唑类,其中6位氨基羰基的羰基被包含至少8个,例如8至22个碳原子的直链、支链或环状脂族基团所取代,且2位氨基羰基的羰基被包含1至8个碳原子的直链、支链或环状脂族或芳族基团所取代,前提条件如上所述。
在式I的化合物中,优选地
R1是(C8-22)烷基,如(C10-16)烷基、(C8-12)环己基,例如包括桥连的环烷基,如金刚烷基、或(C8-22)杂环基,如稠合的杂环基,例如与苯环稠合的杂环基,例如包括苯并噻唑基、苯并呋喃基、苯并二氧杂环己烯基;indazoinyl,例如其中烷基、环烷基或杂环基被取代或未被取代,例如未被取代或者被(C6-18)芳基,如苯基、(C1-4)烷基、(C1-4)烷氧基、卤素、卤代(C1-4)烷基、卤代(C1-4)烷氧基、硝基、巯基或(C1-4)烷基巯基所取代。
在式I的化合物中,R2优选地是(C1-12)烷基,如(C1-8)烷基、(C3-12)环烷基(C6-12)芳基、或包含最多12个碳原子和1至4个选自N、O、S的杂原子的杂环基,包括稠合的杂环基如苯并噻唑基、苯并呋喃基、苯并二氧杂环己烯基;indazoinyl,包括未被取代的烷基、环烷基、芳基或杂环基,或者被取代一次或多次的烷基、环烷基、芳基或杂环基,例如未被取代的烷基、环烷基、芳基或杂环基或被(C6-18)芳基,如苯基、(C1-4)烷基、(C1-4)烷氧基、卤素、卤代(C1-4)烷基、卤代(C1-4)烷氧基、硝基、巯基或(C1-4)烷基巯基取代的烷基、环烷基、芳基或杂环基。
本发明另一方面提供了一种式I的化合物,其是下式的化合物
其中
R1P是(C8-22)烷基、或任选地被苯基取代的(C8-18)环烷基;并且
R2P是(C1-8)烷基、(C3-12)环烷基或苯基,例如包括(C1-4)烷氧基苯基、(C1-4)二烷氧基苯基,
前提条件是不包括如下化合物
N-[2-(乙酰氨基)-6-苯并噻唑基]-三环[3.3.1.13,7]癸烷-1-甲酰胺,
N-[2-(苯甲酰氨基)-6-苯并噻唑基]-三环[3.3.1.13,7]癸烷-1-甲酰胺,和
金刚烷-1-甲酸[2-(金刚烷-1-基)-羰基氨基-苯并噻唑-6-基]-酰胺。
本发明另一方面提供了选自表1中实施例3、4和5的化合物的式I化合物,例如
3-苯基-金刚烷-1-甲酸(2-苯甲酰氨基-苯并噻唑-6-基)-酰胺,
N-(6-十四烷酰基氨基-苯并噻唑-2-基)-苯甲酰胺,和
金刚烷-1-甲酸[2-(3,4-二甲氧基-苯甲酰氨基)-苯并噻唑-6-基]-酰胺。
本发明所提供的化合物在下文被称为“本发明的化合物”并且包括式I的化合物。式I的化合物包括式Ip和I′p的化合物。
本发明的化合物包括任何形式的化合物,例如游离形式、盐形式、溶剂化物形式以及盐和溶剂化物形式。
本发明另一方面提供了盐形式的本发明化合物。
该类盐优选地包括可药用的盐,但是也包括不可药用的盐,例如其可用于制备/分离/纯化目的。
可以将游离形式的本发明化合物转化成盐形式的相应化合物;并且反之亦然。可以将溶剂化物形式的游离形式或盐形式的本发明化合物转化成非溶剂化物形式的游离形式或盐形式的相应化合物;并且反之亦然。
本发明的化合物可以以异构体及其混合物的形式存在;例如可以为光学异构体、非对映异构体、顺/反构象异构体形式。本发明的化合物可以例如包含不对称碳原子并且因此可以以对映异构体和非对映异构体以及其混合物例如外消旋物的形式存在。就化合物中指定的位置而言,本发明的化合物可以以(R)-、(S)-或(R,S)-构型存在,优选地以(R)-或(S)-构型存在。例如,如果与本发明化合物任何酰胺基团的羰基相连的取代基是烷基或被取代的环烷基,则就可能产生的任何不对称碳原子而言,本发明的化合物可以以(R)-、(S)-或(R,S)-构型存在,优选地以(R)-或(S)-构型存在。
可以酌情对同分异构混合物进行分离,例如根据常规方法进行分离,例如根据与常规方法相似的方法进行分离,从而得到纯的异构体。本发明包括任何异构形式和任何异构混合物形式的本发明的化合物。
在可能存在互变异构体的情况中,本发明还包括本发明化合物的互变异构体。
本发明另一方面提供了一种制备本发明化合物,例如式I化合物的方法,其包括
a)将其中R2如上所定义的式II的化合物
用其中R1如上所定义的式III的化合物酰化,
R1-COOH III
其中羧基为活化形式,或者在活化剂如(1-乙基-3-[3-二甲基氨基丙基]碳二亚胺、1-羟基-7-氮杂苯并三唑的存在下,例如在存在碱如三乙胺的情况下进行酰化,或者
b)将其中R1如上所定义的式IV的化合物
用其中R2如上所定义的式V的化合物酰化,
R2"-COOH V
其中羧基为活化形式,或者在活化剂如(1-乙基-3-[3-二甲基氨基丙基]碳二亚胺、1-羟基-7-氮杂苯并三唑的存在下,例如在存在碱如三乙胺的情况下进行酰化,和
将得自该反应混合物的式I的化合物分离出来:
其中6位氨基的氮被上面所定义的直链、支链或环状脂族、芳族或杂环基团所取代,且其中2位氨基的氮被上面所定义的直链、支链或环状脂族、芳族或杂环基团所取代的2,6-二酰氨基-苯并噻唑类或2,6-二酰氨基-苯并噁唑类化合物例如可以用下面的方法提供
a)用除羰基碳原子外还包含至少8个例如8至22个碳原子的直链、支链或环状脂族、芳族或杂环羧酸分别将其中2位酰胺基团的羰基碳原子被包含1至12个碳原子的直链、支链或环状脂族、芳族或杂环基团所取代的6-氨基-2-酰氨基-苯并噻唑或6-氨基-2-酰氨基-苯并噁唑酰化,其中所述羧酸为活化形式或者在存在活化剂例如(1-乙基-3-[3-二甲基氨基丙基]碳二亚胺、1-羟基-7-氮杂苯并三唑,例如在存在碱如三乙胺的情况下进行酰化,或者
b)用除羰基碳原子外还包含1至12个碳原子的直链、支链或环状脂族、芳族或杂环羧酸分别将其中6位酰胺基团的羰基碳原子被包含至少8个例如8至22个碳原子的直链、支链或环状脂族、芳族或杂环基团所取代的2-氨基-6-酰氨基-苯并噻唑或2-氨基-6-酰氨基-苯并噁唑酰化,其中所述羧酸为活化形式或者在存在活化剂例如(1-乙基-3-[3-二甲基氨基丙基]碳二亚胺、1-羟基-7-氮杂苯并三唑,例如在存在碱如三乙胺的情况下进行酰化,
和
分离出其中6位酰氨基团的羰基碳原子被上面所定义的直链、支链或环状脂族、芳族或杂环基团所取代且其中2位酰氨基团的羰基碳原子被上面所定义的直链、支链或环状脂族、芳族或杂环基团所取代的2,6-二酰氨基-苯并噻唑类或2,6-二酰氨基-苯并噁唑类化合物。
在式II、III、IV或V的中间体(起始材料)中,如果存在官能团,则其可任选地为被保护形式或盐形式(如果存在成盐基团)。可以在任何适宜的阶段除去任选存在的保护基团,例如根据常规方法除去,例如根据与常规方法类似的方法除去。
可以将由此获得的式I的化合物转化成另一种式I的化合物,或者可以将获得的游离形式的式I化合物转化成式I化合物的盐并且反之亦然。
上面的反应是酰化反应或形成肽键的反应,其可以酌情根据常规酰化或成肽键反应来进行,例如根据与该常规方法类似的方法来进行。
式II、III、IV或V的中间体(起始材料)是已知的或者可以根据常规方法或本文所述的方法来进行制备,例如根据与常规方法或本文所述方法类似的方法来进行制备。
例如,式II的化合物可以通过将其中R2如上所定义的式VI的化合物
在存在Sn和HCl的情况下还原并从反应混合物中分离出获得的式II化合物来进行制备。
式VI的化合物例如可以通过将式VII的化合物
用其中R2如上所定义且羧酸基团为活化形式如羧酸卤化物形式的式V的化合物酰化
R2-COOH V
并将式VI的化合物从反应混合物中分离出来来获得。
式IV的化合物例如可以通过将式VIII的化合物
用其中R1如上所定义且羧酸基团为活化形式或者存在活化剂的式III化合物
R1-COOH III
进行酰化并将获得的式IV化合物从反应混合物中分离出来来获得,所述活性剂是例如(1-乙基-3-[3-二甲基氨基丙基]碳二亚胺、1-羟基-7-氮杂苯并三唑,例如在存在碱如三乙胺的情况下进行酰化。
式VIII的化合物例如可以通过将式VII的化合物用氢还原,例如在存在阮内镍的情况下还原来获得。
本发明另一方面提供了其中环A和R1如上所定义的式IV的化合物,例如其中R1是R1p的式IV的化合物;例如其中环A是苯并噻唑基或苯并噁唑基,如苯并噻唑基的式IV的化合物,例如其中R1如上所定义的式
的化合物,如其中R1是金刚烷基、苯基金刚烷基或十二烷基例如正-十二烷基的式IVINT的化合物,如其中R1如实施例部分表1中所定义的式IVINT的化合物。
可以酌情制备本文所述的任何化合物,例如本发明的化合物和式II、III、IV、V、VI、VII和VIII的中间体,例如可以根据常规方法例如本文所述的方法例如与这些方法类似的方法来进行制备。
本发明的化合物例如包括式I、IP和I′P的化合物表现出药理学活性,因此可用作药物。例如,发现本发明的化合物抑制了神经酰胺激酶活性。例如在下面所述的体外神经酰胺激酶试验和以细胞为基础的神经酰胺激酶试验中表明了该类抑制作用;例如还可以在Christine Graf,Philipp Rovina,Loic Tauzin,Andrea Schanzer和Frederic Bornancin,“在神经酰胺激酶过表达细胞中神经酰胺诱导的细胞凋亡增强(Enhanced ceramide-inducedapoptosis in ceramide kinase overespressing cells)”,Biochemical andBiophysical Communications 354(2007),第309-314页所述的神经酰胺激酶试验中表明该类抑制作用。
神经酰胺激酶过表达的细胞对神经酰胺介导的细胞凋亡的敏感性增加。其是神经酰胺激酶活性的直接结果。因此,神经酰胺激酶的抑制剂能将这种增强的敏感性恢复到母细胞(即不过度表达神经酰胺激酶)中的常规水平。因此,对神经酰胺激酶无活性的化合物在这种试验中没有作用。
在下面两个试验的描述中所用的缩写
DETAPAC 二乙烯三胺五乙酸
DMEM培养基 达尔伯克氏改良伊格尔培养基
DTT 二硫苏糖醇
EGTA 乙二醇-二(β-氨基乙基醚)-N,N,N′,N′-四乙酸
MOPS 3-(N-吗啉-4-基)丙烷磺酸
NBD 7-硝基-2,1,3-苯并噁二唑-4-基
HBBS Hank&′s BSS(平衡盐溶液,磷酸盐缓冲至pH 7.0-7.2)
体外神经酰胺激酶试验
该试验是在重组GST-His-CerK上进行的,该重组GST-His-CerK是在昆虫细胞中产生的并且用单步镍-琼脂糖色谱将其纯化至90%。将该纯化了的蛋白冷冻,每份样品在10mM MOPS,pH7.2、300mM KCl、500mM咪唑、2.5mM DTT、5%甘油、0.01% Triton X-100中包含0.5mg/mlGST-His-CerK。
CerK活性试验是以100μl的总体积进行的,其中具有如下组分(终浓度):180μM N-辛酰基-鞘氨醇(C8-神经酰胺)、1mM心脂质、1.5%β-辛基葡糖苷、0.2mM DETAPAC、20mM MOPS,pH 7.2、50mM NaCl、1mMDTT、2mM EGTA、3mM CaCl2、500μM(γ-32P)ATP(40-100mCi/mmol)。通过加入蛋白样品(20μl/试验)来开始反应。该试验中的GST-His-CerK蛋白终浓度为40ng/μl。以10mM的浓度在DMSO中制备化合物储备液并用试验混合物对其进行稀释(DMSO终浓度为1%)。在30℃下培养15分钟。通过加入1ml 1:1的氯仿/甲醇和430μl1M KCl的20mM MOPS pH 7.2溶液来终止反应。取出400μl有机相,用300μl 1M KCl的20mM MOPSpH 7.2溶液进一步进行提取。在涡旋和随后的短时间离心后,取出200μl有机相并直接对其进行计数。在这些条件下,神经酰胺-1-磷酸酯是最终在有机相中可探测到的唯一被磷酸化的产物。
以细胞为基础的神经酰胺激酶试验
将位于24-孔板中的对照COS-1细胞或稳定过表达神经酰胺激酶的COS-1细胞用荧光NBD标记的C6-神经酰胺在包含10%血清的DMEM培养基中处理3小时。随后,将细胞用500μl补加了10mM EDTA的HBSS洗涤。用100μl CH3OH对脂质进行萃取。在转移到Eppendorf管中后,加入100μl CHCl3以及150μl HBSS/EDTA。在涡旋和短时间离心后,收集有机相并用speed-vac将其干燥。最后,将该干燥了的脂质溶解于CHCl3/CH3OH中并用薄层色谱分析对其进行处理,用丁醇/乙酸/水3:1:1作为洗脱剂。将在DMSO中制得的10mM的化合物直接用细胞培养基稀释至适宜浓度。用DMSO作为基质对照。
在上述试验中,用所试验化合物的不同浓度范围测定EC50。将在不存在化合物的情况下获得的活性设定为100%。
在上述试验中,本发明的化合物抑制了纯化的神经酰胺激酶和细胞内神经酰胺激酶的活性,例如本发明的化合物抑制了神经酰胺与神经酰胺激酶的结合。在上述试验中,本发明的化合物表现出从低纳摩尔范围到低微摩尔范围的EC50值。
此外,本发明的化合物在Christine Graf等人(见上)所述的神经酰胺激酶试验中也有活性。
本发明的化合物是神经酰胺激酶(CERK)拮抗剂并且可用于治疗由CERK活性介导的病症。
本文所用的病症包括疾病。
倾向于用CERK拮抗剂成功治疗例如用本发明化合物治疗的由CERK活性介导的病症包括其中CERK活性是疾病起因或对疾病起贡献作用的病症,如由树突细胞(DC)、单核细胞或淋巴细胞引发的免疫应答。
该类病症(疾病)非限制性地包括
例如包括
-与炎症有关的病症
例如包括(慢性)炎性病症、与支气管(例如包括支气管炎)、子宫颈(例如包括宫颈炎)、结膜(例如结膜炎)、食管(例如食管炎)、心肌(例如心肌炎)、直肠(例如直肠炎)、巩膜(例如巩膜炎)、牙龈、涉及骨、肺部炎症(肺泡炎)、气道(例如哮喘,如支气管哮喘、急性呼吸窘迫综合征(ARDS))的炎症有关的病症、炎性皮肤病如接触过敏、特应性皮炎;纤维变性疾病(例如,肺纤维化)、脑炎(encephilitis)、炎性骨质溶解,
-与免疫系统情况有关的病症,
如自身免疫性病症例如包括格雷夫斯病、桥本氏病(慢性甲状腺炎)、多发性硬化、类风湿性关节炎、关节炎、痛风、骨关节炎、硬皮病、狼疮综合征、系统性红斑狼疮、斯耶格伦氏综合征、牛皮癣、炎性肠病(包括克罗恩病、结肠炎,例如溃疡性结肠炎);脓毒病、脓毒性休克、自身免疫性溶血性贫血(AHA)、抗体触发的荨麻疹、天疱疮、肾炎、肾小球性肾炎、Goodpastur综合征、强直性脊柱炎、莱特尔综合征、多肌炎、皮肤肌炎、细胞因子介导的毒性、白介素-2毒性、斑秃、葡萄膜炎、扁平苔藓、大疱性类天疱疮、重症肌无力、I型糖尿病、免疫介导的不孕症如卵巢功能早衰、多腺体衰竭(polyglandular failure)、甲状腺功能减退、寻常型天疱疮、pemphigus l-oliaceus、副肿瘤性天疱疮、自身免疫性肝炎(包括与乙型肝炎病毒(HBV)和丙型肝炎病毒(HCV)有关的肝炎)、阿狄森病、自身免疫性皮肤病,如牛皮癣、疱疹样皮炎、大疱性表皮松解、线性IgA大疱性皮肤病、获得性大疱性表皮松解、儿童的慢性大疱病、恶性贫血、溶血性贫血、白癫风、I型、II型和III型自身免疫性多腺体综合征、自身免疫性甲状旁腺机能减退、自身免疫性垂体炎、自身免疫性卵巢炎、自身免疫性睾丸炎、妊娠性类天疱疮、疤痕性类天疱疮、混合性自发冷球蛋白血症、免疫性血小板减少性紫癜、古德帕斯彻综合征、自身免疫性嗜中性白血球减少症、伊-兰二氏重症肌无力综合征、僵人综合征、脑脊髓炎、急性弥散性脑脊髓炎、格-巴二氏综合征、小脑变性、视网膜病、原发性胆管纤维硬化、硬化性胆管炎、自身免疫性肝炎、谷蛋白敏感性肠病、反应性关节炎性皮疹、多肌炎/皮肤肌炎、混合性结缔组织病、黑奇特综合征、结节性多动脉炎、变应性脉管炎(anguitis)和肉芽肿病(Churg-Strauss病)、多脉管炎(polyangiitis)重叠综合征(过敏性)结节性脉管炎、韦格纳肉芽肿病、颞动脉炎、川畸病、肉样瘤病、寒冷病、乳糜泻,
-与移植有关的病症,
例如包括移植排斥危象和移植后的其它病症,如器官或组织(异种)移植排斥,例如用于例如心、肺、心肺联合、肝、肾、胰腺、皮肤、角膜移植的领受者的治疗、移植物抗宿主病,如骨髓移植后的疾病、局部缺血性再灌注损伤,
-与细胞因子-介导的毒性有关的病症,
例如包括白介素-2毒性,
-与骨有关的病症,
例如包括骨质疏松症、骨关节炎,
-与风湿性病症有关的病症,
例如包括关节炎、类风湿性关节炎、骨关节炎、牛皮癣关节炎、结晶性关节病、痛风、假痛风、焦磷酸钙沉积病、狼疮综合征、系统性红斑狼疮、硬化症、硬皮病(sclerodema)、多发性硬化、动脉粥样硬化、动脉硬化、脊椎关节病、全身性硬化症、反应性关节炎、莱特尔综合征、强直性脊柱炎、多肌炎,
-与肉样瘤病有关的病症,
-与疼痛有关的病症,
例如与CNS病症有关的病症,如多发性硬化、脊髓损伤、坐骨神经痛、失败的背部手术综合征、外伤性脑损伤、癫痫、帕金森病、中风后、脑和脊髓中的血管损伤(例如,梗死、出血、血管畸形);
非中枢性神经性疼痛,例如包括与乳房切除术后疼痛有关的疼痛、幻影感、反射交感性营养不良(RSD)、trigeminal neuralgiaradioculopathy、术后痛、与HIV/AIDS有关的疼痛、癌症疼痛、代谢性神经病(例如,糖尿病性神经病、结缔组织继发的血管性神经病)、与例如肺的癌症、白血病、淋巴瘤或前列腺、结肠或胃的肿瘤有关的副肿瘤性神经病、三叉神经痛、脑神经痛、和疱疹后神经痛;
与外周神经损害有关的疼痛、中枢性痛(即由于脑局部缺血造成的)和各种慢性疼痛即,腰痛、背痛(腰背痛)、炎性和/或风湿性疼痛;
头痛(例如,有先兆的偏头痛、无先兆的偏头痛和其它偏头痛病症)、偶发性和慢性紧张性头痛、紧张性样头痛、丛集性头痛和慢性发作性偏头痛;
内脏痛如胰腺炎、肠膀胱炎、痛经、肠易激综合征、克罗恩病、胆绞痛、输尿管绞痛、心肌梗死和盆腔的疼痛综合征,例如,外阴痛、睾丸痛、尿道综合征和前列腺痛;
急性疼痛,例如术后痛和创伤后痛;
-与感染性病症有关例如与慢性感染性情况有关的病症,
例如包括细菌性病症、中耳炎、莱姆病、甲状腺炎、病毒性病症、寄生虫病症、真菌病症、疟疾,例如疟疾性贫血、脓毒病、重症脓毒病、脓毒性休克,例如内毒素-诱导的脓毒性休克、外毒素-诱导的中毒性休克、感染性(真脓毒性)休克、由革兰氏阴性菌造成的脓毒性休克、盆腔炎性疾病、AIDS、肠炎、肺炎;脑膜炎、脑炎,
-与重症肌无力有关的病症,
-与肾炎有关的病症,
例如包括肾小球性肾炎、间质性肾炎、韦格纳肉芽肿病、纤维变性,
-与癌症和细胞过度增殖有关的病症,
例如包括恶化前的情况、过度增殖性病症、所有类型的癌症、原发性或转移性的癌症、转移性宫颈癌、起源自不受控的细胞增殖的癌症、实体瘤、对诱导正常死亡的信号不应答(无限增殖化)、细胞运动性和侵袭性增加、通过诱导心血管形成而募集血流供应的能力增加(血管生成,例如包括募集血液供应的能力不足、特征在于血管生成改变的病症、与血管生成有关的肿瘤)、遗传不稳定性、基因表达失调、实体瘤,如在WO02066019中所述的实体瘤,包括非小细胞肺癌、宫颈癌;肿瘤生长、淋巴瘤、B-细胞或T-细胞淋巴瘤、良性肿瘤、良性增殖异常病症、肾癌、食管癌、胃癌、肾癌、膀胱癌、乳癌、结肠癌、肺癌、黑素瘤、鼻咽癌、骨癌、卵巢癌、子宫癌;前列腺癌、皮肤癌、白血病、肿瘤新血管形成、血管瘤、脊髓发育异常病症、对诱导正常死亡的信号无应答(无限增殖化)、细胞运动性和侵袭性增加、遗传不稳定性、基因表达失调、(神经)内分泌癌症(类癌)、血癌、淋巴细胞性白血病、成神经细胞瘤;软组织癌、癌症预防,例如预防转移,
-与糖尿病有关的病症,
例如包括糖尿病(I型糖尿病、II型糖尿病、淋巴细胞性白血病)、糖尿病视网膜病、胰岛素依赖性糖尿病、糖尿病、妊娠糖尿病)、胰岛素分泌不足、肥胖;
-与子宫内膜异位、睾丸机能障碍有关的病症,
-与脑和神经有关的病症,
-神经变性病症,例如包括中枢神经系统的病症以及外周神经系统的病症,例如CNS病症,包括中枢神经感染、脑损伤、脑血管病症以及其后遗症、帕金森病、皮质基底(corticobasal)变性、运动神经元疾病、痴呆(包括ALS)、多发性硬化、创伤性病症,包括(创伤和创伤的炎性后果)、外伤性脑损伤、中风、中风后、外伤后脑损伤,
小血管脑血管病、进食障碍;其它痴呆,例如包括阿耳茨海默病、血管性痴呆、Lewy体痴呆、额颞痴呆和与染色体17有关的帕金森综合征、额颞痴呆(包括皮克病)、进行性核麻痹、皮质基底变性、亨廷顿病、丘脑变性、Creutzfeld Jakob痴呆、HIV痴呆、具有痴呆的精神分裂症、科尔萨科夫精神病,
与认知有关的病症,如轻度认知缺损、与年龄有关的记忆力缺损、与年龄有关的认知下降、血管性认知缺损、注意力缺陷病症、注意力缺陷多动症、无学习能力的儿童的记忆力紊乱;与下丘脑-垂体-肾上腺轴有关的情况,
-神经元病症,例如包括神经元迁移病症、紧张不全(肌肉紧张度降低)、肌无力、癫痫发作、发育延迟(身体或精神发育困难)、精神发育迟缓、生长不足、喂养困难、淋巴水肿、头小畸形、影响头和脑的症状、运动功能障碍;
-与眼睛有关的病症,
例如包括葡萄膜视网膜炎、玻璃体视网膜病、角膜病、虹膜炎、虹膜睫状体炎、白内障、葡萄膜炎、糖尿病性视网膜病、色素性视网膜炎、结膜炎、角膜炎,
-与胃肠道有关的病症
例如包括结肠炎、炎性肠病、克罗恩病、溃疡性结肠炎、消化溃疡、胃炎、食管炎,
-与心脏和血管情况有关的病症
-例如包括心血管病症,例如包括心衰、心脏梗塞、心脏肥大、心衰,例如包括心脏泵血失败的所有形式如高输出量和低输出量、急性和慢性、右侧或左侧、心脏收缩期或心脏舒张期,不论原因如何;心肌梗死(MI)、MI预防(一级和二级预防)、MI的急性治疗、并发症的预防;心脏病症、增殖性血管病症、血管炎、结节性多动脉炎、局部缺血的炎性后果、缺血性心脏病、心肌梗死、中风、外周血管病、肺动脉高压,
局部缺血病症,例如包括心肌缺血,例如稳定型心绞痛、不稳定心绞痛、心绞痛、支气管炎;无症状的心律不齐如心房和心室心律失常的所有形式、房性心动过速、心房扑动、心房纤维性颤动、房室折返性心动过速、预激综合征、室性心动过速、心室扑动、心室纤维性颤动、心律不齐的心搏徐缓形式;心律不齐、慢性阻塞性肺病,
高血压,如心脏收缩期或心脏舒张期高血压,例如原发性和继发性高血压,例如包括高血压性血管病,如原发性以及所有类型的继发性动脉高血压、肾、内分泌、神经性高血压等;
其中动脉和/或静脉血流降低,从而使得血液供应和组织氧需求之间失衡的外周血管病症,例如包括动脉粥样硬化、慢性周围动脉闭塞性疾病(PAOD)、急性动脉血栓形成和栓塞、炎性血管病症、雷诺现象和静脉病症;动脉粥样硬化,一种其中血管壁被重构的疾病,例如包括细胞(平滑肌细胞和单核细胞/巨噬细胞炎性细胞)在血管壁内膜的积聚;
低血压,
-与肝和肾有关的病症,
例如包括肾病症、肾病,例如急性肾衰、急性肾病、肝病,例如肝硬化、肝炎、肝衰竭、胆汁阻塞、急性/慢性肝炎、硬化性胆管炎、原发性胆汁性(billiary)肝硬化、急性/慢性间质性/肾小球性肾炎、肉芽肿病,
-与胃或胰腺情况有关的病症
例如包括胃病症,例如胃溃疡、胃肠溃疡、胰腺病症、胰腺疲劳,
-与呼吸道和肺有关的病症
例如包括肺病症、慢性肺病、急性(成人)呼吸窘迫综合征(ARDS)、哮喘、哮喘性支气管炎、支气管扩张、扩散性间质性肺病、尘肺、纤维性肺泡炎、肺纤维化,
-与皮肤和结缔组织情况有关的病症
例如包括湿疹、特应性皮炎、接触性皮炎、牛皮癣、痤疮、皮肤肌炎、Sjorgen′s综合征、Churg-Struass综合征、晒伤、皮肤癌、伤口愈合、荨麻疹、中毒性表皮坏死溶解,
-与变应性情况有关的病症,
例如包括迟发型过敏症、变应性结膜炎、药物过敏、鼻炎、过敏性鼻炎、结节性脉管炎、接触性皮炎。
倾向于用CERK激动剂如本发明的化合物成功治疗的由CERK活性介导的病症(例如包括疾病)优选地包括炎症、免疫例如自身免疫和变应性病症,如类风湿性关节炎、炎性肠病、系统性红斑狼疮、多发性硬化、移植排斥危象、与皮肤和结缔组织情况有关的病症如牛皮癣、癌症和AIDS,更优选类风湿性关节炎、炎性肠病、系统性红斑狼疮、多发性硬化、牛皮癣。
治疗包括治疗和预防。
对于该类治疗而言,适宜的剂量当然将根据例如所用本发明化合物的化学性质和药动学数据、各主体、给药方式以及所治疗情况的性质和严重程度而进行变化。但是,一般而言,为了使较大哺乳动物例如人获得令人满意的结果,所示日剂量范围包括
-约0.001g至约1.5g,如0.001g至1.5g;
-约0.01mg/kg体重至约20mg/kg体重,如0.01mg/kg体重至20mg/kg体重,
例如其可以以最多一天给药四次的分割剂量的形式被给药。
可以用与CERK活性的其它调节剂例如低分子量抑制剂常用的方式和剂量相似的方式和剂量将本发明的化合物给药于较大的哺乳动物,例如人。
本发明的化合物可以通过任何常规途径进行给药,例如可以被肠给药,例如包括鼻、口腔、直肠、口服给药;胃肠外给药,例如包括静脉内、肌内、皮下给药;或局部给药;例如包括表皮、鼻内、气管内给药;通过用于局部传递的医学装置例如支架进行给药,
例如以包衣或未包衣的片剂、胶囊、(可注射的)溶液、固体溶液、混悬液、分散体、固体分散体形式进行给药;例如以安瓿剂、小瓶形式、霜剂、凝胶、糊剂、吸入器粉末、泡沫、酊剂、唇膏、滴剂、喷雾或栓剂形式进行给药。
本发明的化合物可以以可药用盐或游离形式被给药;任选地以溶剂化物形式被给药。盐形式和/或溶剂化物形式的本发明化合物表现出与游离形式本发明化合物活性等级相同的活性。
本发明另一方面提供了
-用作药物的本发明化合物,
-本发明化合物作为药物的应用,
例如用于治疗由神经酰胺激酶活性介导的病症。
在一个优选的实施方案中,本发明提供了本文实施例部分表1中所述化合物作为药物的应用。
对于药学应用而言,可以使用一种或多种本发明的化合物,例如一种本发明化合物或两种或多种本发明化合物的组合,优选地使用一种本发明的化合物。
本发明的化合物可以以药物组合物的形式用作药物。
本发明另一方面提供了一种药物组合物,其包含本发明的化合物与至少一种可药用的赋形剂,例如适宜的载体和/或稀释剂,例如包括填充剂、粘合剂、崩解剂、流动调节剂、润滑剂、糖类或甜味剂、香料、防腐剂、稳定剂、润湿剂和/或乳化剂、增溶剂、用于调节渗透压的盐和/或缓冲剂。
本发明另一方面提供了
-用于治疗由神经酰胺激酶活性介导的病症的本发明的药物组合物。
-本发明的药物组合物用于治疗由神经酰胺激酶活性介导的病症的应用。
本发明另一方面提供了一种治疗由神经酰胺激酶活性介导的病症,例如包括上面所说明的病症的方法,该治疗包括给需要该类治疗的个体施用治疗有效量的本发明化合物;例如药物组合物形式的本发明化合物。
本发明另一方面提供了
-用于制备药物的本发明的化合物,
-本发明的化合物用于制备治疗由神经酰胺激酶活性介导的病症的药物,例如药物组合物形式的药物的应用。
本发明的化合物可单独或者与一种或多种(至少一种)其它的第二种药物联合用于本文所述的任何方法或应用。
本发明另一方面提供了
-本发明化合物与至少一种第二种药物的组合;
-一种包含本发明的化合物与至少一种第二种药物的药物组合;
-一种包含本发明的化合物与至少一种第二种药物和一种或多种可药用赋形剂的药物组合物;
-用于本文所定义的任何方法的与至少一种第二种药物联合的本发明的化合物,例如为药物组合或组合物形式,例如
-一种用作药物的组合、药物组合或药物组合物,其包含本发明的化合物和至少一种第二种药物;
-本发明的化合物与至少一种第二种药物联合作为药物的用途,例如以药物组合或组合物形式应用;
-一种在需要其的个体中治疗由CERK活性介导的病症的方法,其包括相伴或顺序将治疗有效量的本发明化合物和至少一种第二种药物共同给药,例如以药物组合或组合物的形式给药;
-用于制备用于由CERK活性介导的病症的药物的与至少一种第二种药物联合的本发明化合物,例如其为药物组合或组合物形式。
组合包括其中本发明的化合物和至少一种第二种药物位于相同制剂中的固定组合;其中位于独立制剂中的本发明的化合物和至少一种第二种药物在相同包装中被提供的药盒,例如该药盒具有用于共同给药的说明;其中本发明的化合物和至少一种第二种药物被独立包装,但是提供用于相伴或顺序给药的说明的自由组合。
本发明另一方面提供了
-一种药物包装,其包含是本发明化合物的第一种药物和至少一种第二种药物以及用于联合给药的说明;
-一种药物包装,其包含本发明的化合物和用于与至少一种第二种药物联合给药的说明;
-一种药物包装,其包含至少一种第二种药物和用于与本发明化合物联合给药的说明。
与单一治疗相比,用本发明的组合进行治疗可提供改善。
本发明另一方面提供了
-一种药物组合,其包含一定数量本发明的化合物和一定数量的第二种药物,其中所述数量适宜产生协同治疗作用;
-一种改善本发明化合物的治疗效用的方法,其包括将治疗有效量本发明的化合物和第二种药物共同给药例如相伴或顺序给药。
-一种改善第二种药物的治疗效用的方法,其包括将治疗有效量本发明的化合物与第二种药物共同给药例如相伴或顺序给药。
作为组合伴侣的本发明化合物和第二种药物的组合可以用任何常规途径进行给药,例如可以如上面本发明化合物所述那样进行给药。第二种药物可以适宜剂量进行给药,例如以与单一治疗所用剂量相似的剂量进行给药,或者在协同的情况中,甚至可以以低于常规剂量范围的剂量进行给药。
本发明的药物组合物可以根据常规方法例如通过混合、制粒、包衣、溶解或冷冻干燥方法来进行制备,例如可以根据类似方法进行制备。单位剂型可包含例如约0.1mg至约1500mg,如1mg至约1000mg。
包含本发明组合的药物组合物和包含本文所述第二种药物的药物组合物可以被酌情提供,例如根据常规方法例如与常规方法类似的方法被提供,或者可以如本文本发明药物组合物所述那样被提供。
术语“第二种药物”是指化疗药,尤其是除本发明化合物如式I的化合物外的任何化疗药。
例如,本文所用的第二种药物包括
抗炎药、免疫调节药、抗癌药、抗病毒药、抗变态反应药、麻醉药。
倾向于与本发明化合物联用的抗炎和/或免疫调节药(例如包括抗病毒药)包括例如
-调节剂,例如mTOR活性的抑制剂,包括下式的雷帕霉素和雷帕霉素衍生物,
例如包括
40-O-烷基-雷帕霉素衍生物,例如40-O-羟基烷基-雷帕霉素衍生物,例如40-O-(2-羟基)-乙基-雷帕霉素(依维莫司),
32-脱氧-雷帕霉素衍生物和32-羟基-雷帕霉素衍生物,如32-脱氧雷帕霉素,
16-O-取代的雷帕霉素衍生物如16-戊-2-炔氧基-32-脱氧-雷帕霉素、16-戊-2-炔氧基-32(S或R)-二氢-雷帕霉素或16-戊-2-炔氧基-32(S或R)-二氢-40-O-(2-羟基乙基)-雷帕霉素,
在40位氧上被酰化的雷帕霉素衍生物,例如40-[3-羟基-2-(羟基-甲基)-2-甲基丙酸酯]-雷帕霉素(也被称为CCI779),
在40位上被杂环基取代的雷帕霉素衍生物,例如40-表-(四唑基)-雷帕霉素(也被称为ABT578),
所谓的雷帕霉素类似物(rapalogs),例如如WO9802441、WO0114387和WO0364383中所公开的物质,如AP23573,和
以TAFA-93、AP23464、AP23675、AP23841和百利莫司(biolimus)(例如百利莫司A9)的名称公开的化合物。
-调节剂,例如神经钙蛋白的抑制剂,例如环孢菌素A、FK 506;
-具有免疫抑制性质的子囊霉素类,例如ABT-281、ASM981;
-皮质类固醇类;环磷酰胺;咪唑硫嘌呤;来氟米特;咪唑立滨;
-麦考酚酸或盐;例如麦考酚酸莫酯钠;
-15-脱氧司加林(spergualine)或其免疫抑制同系物、类似物或衍生物;
-调节剂,例如bcr-abl酪氨酸激酶活性的抑制剂;
-调节剂,例如c-kit受体酪氨酸激酶活性的抑制剂;
-调节剂,例如PDGF受体酪氨酸激酶活性的抑制剂,例如Gleevec(伊马替尼);
-调节剂,例如p38 MAP激酶活性的抑制剂,
-调节剂,例如VEGF受体酪氨酸激酶活性的抑制剂,
-调节剂,例如PKC活性的抑制剂,例如WO0238561或WO0382859中所公开的化合物,例如实施例56或70的化合物;
-调节剂,例如JAK3激酶活性的抑制剂,例如N-苄基-3,4-二羟基-亚苄基-氰基乙酰胺α-氰基-(3,4-二羟基)-]N-苄基肉桂酰胺(酪氨酸磷酸化抑制剂AG490)、灵菌红素25-C(PNU156804)、[4-(4′-羟基苯基)-氨基-6,7-二甲氧基喹唑啉](WHI-P131)、[4-(3′-溴-4′-羟基苯基)-氨基-6,7-二甲氧基喹唑啉](WHI-P154)、[4-(3′,5′-二溴-4′-羟基苯基)-氨基-6,7-二甲氧基喹唑啉]WHI-P97、KRX-211、3-{(3R,4R)-4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-3-氧代-丙腈,游离形式或可药用盐形式,例如单柠檬酸盐(也被称为CP-690,550)、或如WO2004052359或WO2005066156中公开的化合物;
-调节剂,例如S1P受体活性的激动剂或调节剂,例如任选地被磷酸化的FTY720或其类似物,例如任选地被磷酸化的2-氨基-2-[4-(3-苄氧基苯硫基)-2-氯苯基]乙基-1,3-丙二醇或1-{4-[1-(4-环己基-3-三氟甲基-苄氧基亚氨基)-乙基]-2-乙基-苄基}-氮杂环丁烷-3-甲酸或其可药用的盐;
-免疫抑制的单克隆抗体,例如,白细胞受体例如Blys/BAFF受体、MHC、CD2、CD3、CD4、CD7、CD8、CD20(例如利妥昔单抗与111In或90Y轭合的替伊莫单抗 131I妥司单抗(tositumumab)CD25、CD28、CD33(例如吉姆单抗)、CD40、CD45、CD52(例如阿仑单抗)、CD58、CD80、CD86、IL-2受体(例如达鲁单抗(dacluzimab))、IL6受体(例如妥利单抗(tocilizumab))、IL-12受体、IL-17受体、IL-23受体或其配体的单克隆抗体;
-其它免疫调节化合物,例如具有至少一部分CTLA4或其突变体的细胞外区域例如至少CTLA4或其与非CTLA4蛋白序列相连的突变体的至少细胞外部分,例如CTLA4Ig(例如被称为ATCC 68629)或其突变体的重组结合分子,例如LEA29Y;或抗-CTLA4剂,如依利单抗(ipilimumab);
-调节剂,例如粘附分子活性的抑制剂,例如LFA-1拮抗剂、ICAM-1或-3拮抗剂、VCAM-4拮抗剂或VLA-4拮抗剂,
-调节剂,例如CCR9活性的拮抗剂,
-调节剂,例如MIF活性的抑制剂,
-调节剂,例如TNF-α活性的抑制剂,例如包括结合TNF-α的抗体,例如英夫利昔单抗沙利度胺、利那度胺(lenalidomide)、葛利单抗(golimumab)、阿达木单抗(对人TNFα有特异性的全人免疫球蛋白G(IgG1)单克隆抗体)、依那西普、司土利单抗(certolizumab pegol)CDP 870),
-释放氧化氮的非甾体抗炎药(NSAID),例如包括COX-抑制性供NO药(CINOD);
-磷酸二酯酶,例如调节剂,如PDE4B活性的抑制剂,
-调节剂,例如半胱天冬酶活性的抑制剂,
-调节剂,例如G蛋白偶合受体GPBAR1的激动剂,
-调节剂,例如神经酰胺激酶活性的抑制剂,
-‘多功能抗炎’药(MFAID),例如细胞溶质磷脂酶A2(cPLA2)抑制剂,如与氨基葡聚糖相连的膜-锚定的磷脂酶A2抑制剂;
-抗生素类,如青霉素类、头孢菌素类、红霉素类、四环素类、磺胺类,如磺胺嘧啶、磺胺异噁唑;砜类,如氨苯砜;截短侧耳素类、氟喹诺酮类例如甲硝唑、喹诺酮类如环丙沙星;左氧氟沙星;益生菌(probiotics)和共生的细菌例如乳酸杆菌属、罗伊乳杆菌;
-抗病毒药,如利巴韦林(ribivirin)、阿糖腺苷、阿昔洛韦、更昔洛韦、扎那米韦、磷酸奥塞米韦、泛昔洛韦、阿扎那韦(atazanavir)、金刚烷胺、地达诺新、依法韦仑、膦甲酸、茚地那韦、拉米夫定、那非那韦、利托那韦、沙奎那韦、司他夫定、伐昔洛韦、缬更昔洛韦、civacir、齐多夫定,
-调节剂,例如血蛋白“补体5a”的抑制剂,如Pexelizumab,
-GPBAR1调节剂活性的调节剂,例如激动剂,例如包括抗体和低分子量化合物;
-除本发明化合物外的神经酰胺激酶抑制剂。
倾向于用于与本发明化合物联合的抗炎药包括例如非甾体抗炎药(NSAID)如丙酸衍生物(阿明洛芬、苯恶洛芬、布氯酸、卡洛芬、芬布芬、非诺洛芬、氟洛芬、氟比洛芬、布洛芬、吲哚洛芬、酮洛芬、咪洛芬、萘普生、奥沙普秦、吡洛芬、普拉洛芬、舒洛芬、噻洛芬酸和硫恶洛芬)、乙酸衍生物(消炎痛、阿西美辛、阿氯芬酸、环氯茚酸、双氯芬酸、芬氯酸、芬克洛酸、芬替酸、呋罗芬酸、异丁芬酸、伊索克酸、Oxpinac、舒林酸、噻庚乙酸、托美丁、齐多美辛和佐美酸)、芬那酸衍生物(氟芬那酸、甲氯灭酸、甲酚那酸、尼氟灭酸和托芬那酸)、联苯基甲酸衍生物(二氟尼柳和氟苯柳)、昔康类(伊索昔康、吡罗昔康、舒多昔康和替诺西康)、水杨酸酯类(乙酰水杨酸、柳氮磺胺吡啶)和吡唑酮类(阿扎丙宗、Bezpiperylon、非普拉宗、莫非布宗、羟布宗、保泰松);环氧合酶-2(COX-2)抑制剂如塞来考昔;IV型磷酸二酯酶抑制剂(PDE-IV);趋化因子受体,尤其是CCR1、CCR2和CCR3;降低胆固醇的物质如HMG-CoA还原酶抑制剂(洛伐他汀、辛伐他汀和普伐他汀、氟伐他汀、阿伐他汀和其它他汀类)、螯合剂类(消胆胺和考来替泊)、烟酸、非诺贝酸衍生物(吉非贝特、氯贝特、非诺贝特和苯扎贝特)、和普罗布考;抗胆碱能药如毒蕈碱拮抗剂(异丙托溴铵);其它化合物如茶碱、柳氮磺胺吡啶和氨基水杨酸酯类,例如5-氨基水杨酸以及其前体药物、抗风湿剂。
倾向于用于与本发明化合物联合的抗变态反应药包括例如抗组胺药(H1-组胺拮抗剂),例如溴苯那敏(bromopheniramine)、氯苯那敏、右氯苯那敏、曲普利啶、氯马斯汀、苯海拉明、二苯拉林、曲吡那敏、羟嗪、甲地嗪、异丙嗪、异丁嗪、阿扎他定、赛庚啶、安他唑啉、非尼拉敏、美吡拉敏、阿司咪唑、特非那定、氯雷他定、西替利嗪、非索非那定、脱乙氧羰基氯雷他定,和非甾体平喘药如β2-激动剂(叔丁喘宁、异丙喘宁、非诺特罗、异他啉、沙丁胺醇、比托特罗、沙美特罗和吡布特罗)、茶碱、色甘酸钠、阿托品、异丙托溴铵、白三烯拮抗剂(扎鲁司特、孟鲁司特、普仑司特、异拉司特、泊比司特、SKB-106、203)、白三烯生物合成抑制剂(齐留通、BAY-1005);支气管扩张药、平喘药(肥大细胞稳定剂)。
倾向于用于与mTOR抑制剂联合作为组合伴侣,例如倾向于用于本发明的抗癌药例如包括
i.甾族化合物;例如泼尼松。
ii.腺苷-激酶-抑制剂;其靶向、降低或抑制碱基(nucleobase)、核苷、核苷酸和核酸代谢,如5-碘块菌素(其也被称为7H-吡咯并[2,3-d]嘧啶-4-胺)、5-碘-7-β-D-呋喃核糖基。
iii.增强5-FU-TS键的助剂以及靶向、降低或抑制碱性磷酸酶的化合物,如亚叶酸、左旋咪唑。
iv.肾上腺皮质拮抗剂;其靶向、降低或抑制肾上腺皮质活性和改变皮质类固醇的外周代谢,从而导致17-羟基皮质类固醇降低,如米托坦。
v.AKT途径抑制剂;如靶向、降低或抑制Akt(也被称为蛋白激酶B(PKB))的化合物,如鱼藤素,其也被称为3H-二[1]苯并吡喃并[3,4-b:6’,5’-e]吡喃-7(7aH)-酮),13,13a-二氢-9,10-二甲氧基-3,3-二甲基-,(7aS,13aS);和曲西立滨,其也被称为1,4,5,6,8-五氮杂苊烯-3-胺,1,5-二氢-5-甲基-1-β-D-呋喃核糖基;KP372-1(QLT394)。
vi.烷化剂;其造成DNA烷基化和导致DNA分子以及双股的交联破裂,从而干扰了DNA复制和RNA转录,如氮芥类,例如苯丁酸氮芥、恩比兴、环磷酰胺、异环磷酰胺、美法仑、雌莫司汀;亚硝基脲类(nitrosueras),如卡莫司汀、福莫司汀、罗莫司汀、链佐星(链唑霉素,STZ)、BCNU;Gliadel;达咔巴嗪、双氯乙基甲胺,例如为盐酸盐形式、丙卡巴肼,例如为盐酸盐形式、噻替哌、替莫唑胺、氮芥、丝裂霉素、六甲密胺、白消安、雌莫司汀、乌拉莫司汀。环磷酰胺例如可以以市售形式,例如以商标市售的形式进行给药;异环磷酰胺可以以形式进行给药,替莫唑胺可以以形式进行给药,氮芥可以以形式进行给药,雌莫司汀可以以形式进行给药,链佐星可以以的形式进行给药。
vii.血管发生抑制剂;其靶向、降低或抑制新血管的产生,例如其靶向蛋氨酸氨基肽酶-2(MetAP-2)、巨噬细胞炎症蛋白-1(MIP-1α)、CCL5、TGF-β、脂肪氧合酶、环氧合酶和拓扑异构酶,或者其直接靶向p21、p53、CDK2和胶原合成,例如包括烟曲霉素,其也被称为2,4,6,8-十碳四烯二酸,单[(3R,4S,5S,6R)-5-甲氧基-4-[(2R,3R)-2-甲基-3-(3-甲基-2-丁烯基)环氧乙烷基]-1-氧杂螺环[2.5]辛-6-基]酯,(2E,4E,6E,8E)-(9CI);紫草素,其也被称为1,4-萘二酮,5,8-二羟基-2-[(1R)-1-羟基-4-甲基-3-戊烯基]-(9CI);曲尼司特,其也被称为苯甲酸,2-[[3-(3,4-二甲氧基苯基)-1-氧代-2-丙烯基]氨基];熊果酸;苏拉明;Bengamide或其衍生物、沙利度胺、TNP-470。
ix.抗雌激素药;其在雌激素受体水平拮抗雌激素的作用,例如包括芳香酶抑制剂,其抑制雌激素产生即底物雄甾烯二酮和睾酮分别向雌酮和雌二醇的转化,
例如包括阿他美坦、依西美坦、福美坦、氨鲁米特、罗利米特(roglethimide)、吡鲁米特、曲洛司坦、睾内酯、酮康唑(ketokonazole)、伏氯唑、法倔唑、阿那曲唑、来曲唑、托瑞米芬;比卡鲁胺;氟他胺;他莫昔芬、枸橼酸他莫昔芬;他莫昔芬;氟维司群;雷洛昔芬、盐酸雷洛昔芬。他莫昔芬例如可以以其市售形式例如的形式进行给药;盐酸雷洛昔芬以的形式市售。氟维司群可以如US4659516中公开的那样配制和以的形式市售。
x.抗高钙血症药;其被用于治疗高钙血症,如硝酸镓(III)水合物;和帕米膦酸二钠。
xi.抗代谢物;其抑制或破坏DNA合成,从而导致细胞死亡,如叶酸类,例如甲氨蝶呤、培美曲塞、雷替曲塞;嘌呤类(purins),例如6-巯基嘌呤、克拉屈滨、氯法拉滨(clofarabine);氟达拉滨、硫鸟嘌呤、6-硫代鸟嘌呤、奈拉滨(化合物506)、噻唑呋林(tiazofurin)(抑制了一磷酸次黄嘌呤核苷脱氢酶和三磷酸鸟嘌呤核苷汇集)、喷司他丁(脱氧柯福霉素);阿糖胞苷;Flexuridine;氟尿嘧啶;5-氟尿嘧啶(5-FU)、氟尿苷(5-FUdR)、卡培他滨;吉西他滨;盐酸吉西他滨;羟基脲(例如);DNA脱甲基化剂,如5-氮杂胞嘧啶核苷和地西他滨;氟代亚甲基脱氧胞嘧啶核苷(FmdC)、5-氮杂-2′-脱氧胞嘧啶核苷、曲沙他滨(L-异构体胞嘧啶类似物)、依达曲沙。卡培他滨和吉西他滨例如可以以市售形式如和进行给药。
xii.细胞凋亡诱导剂;其诱导了一系列导致细胞死亡的正常细胞事件,例如选择性诱导了细胞凋亡蛋白XIAP的伴X染色体的(X-linked)哺乳动物抑制剂,或者例如下调BCL-xL;如乙醇,2-[[3-(2,3-二氯苯氧基)丙基]氨基];藤黄酸;恩贝酸,其也被称为2,5-环己二烯-1,4-二酮,2,5-二羟基-3-十一烷基-(9Cl);三氧化二砷
xiii.极光(aurora)激酶抑制剂;其靶向、降低或抑制从G2/M检查点的细胞周期的后期阶段(通向有丝分裂检查点和末期有丝分裂的所有通路);如Binucleine2,其也被称为甲脒,N′-[1-(3-氯-4-氟苯基)-4-氰基-1H-吡唑-5-基]-N,N-二甲基-(9CI)。
xiv.Bruton’s酪氨酸激酶(BTK)抑制剂;其靶向、降低或抑制人和鼠科动物B细胞发育;如土曲霉酸。
xv.神经钙蛋白抑制剂;其靶向、降低或抑制T细胞活化途径,如氯氰菊酯,其也被称为环丙烷甲酸,3-(2,2-二氯乙烯基)-2,2-二甲基-,氰基(3-苯氧基苯基)甲基酯;溴氰菊酯,其也被称为环丙烷甲酸3-(2,2-二溴乙烯基)-2,2-二甲基-(S)-氰基(3-苯氧基苯基)甲基酯,(1R,3R);杀灭菊酯,其也被称为苯乙酸,4-氯-α-(1-甲基乙基)-,氰基(3-苯氧基苯基)甲基酯;和酪氨酸磷酸化抑制剂(Tyrphostin)8;但是不包括环孢菌素或FK506。
xvi.CaM激酶II抑制剂;其靶向、降低或抑制CaM激酶;组成一族结构相关的酶,该酶包括磷酸化酶激酶、肌球蛋白轻链激酶、和CaM激酶I-IV;如5-异喹啉磺酸,4-[(2S)-2-[(5-异喹啉基磺酰基)甲基氨基]-3-氧代-3-(4-苯基-1-哌嗪基)丙基]苯基酯(9CI);苯磺酰胺,N-[2-[[[3-(4-氯苯基)-2-丙烯基]甲基]氨基]甲基]苯基]-N-(2-羟基乙基)-4-甲氧基。
xvii.CD45酪氨酸磷酸酶抑制剂;其靶向、降低或抑制Src-族蛋白-酪氨酸激酶上脱磷酸调节的pTyr残基,其可帮助治疗许多炎性和免疫病症;如膦酸,[[2-(4-溴苯氧基)-5-硝基苯基]羟基甲基]。
xviii.CDC25磷酸酶抑制剂;其靶向、降低或抑制肿瘤中过表达的脱磷酸细胞周期蛋白依赖性激酶;如1,4-萘二酮,2,3-二[(2-羟基乙基)硫基]。
xix.CHK激酶抑制剂;其靶向、降低或抑制抗细胞凋亡蛋白Bcl-2的过表达;如脱溴Hymenialdisine。CHK激酶抑制剂目标是CHK1和/或CHK2。
xx.用于调节染料木素、奥罗莫星和/或酪氨酸磷酸化抑制剂类的控制剂;如黄豆甙元,其也被称为4H-1-苯并吡喃-4-酮,7-羟基-3-(4-羟基苯基);异-奥罗莫星、和酪氨酸磷酸化抑制剂1。
xxi.环氧合酶抑制剂;例如包括Cox-2抑制剂;其靶向、降低或抑制酶Cox-2(环氧合酶-2);如1H-吲哚-3-乙酰胺,1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-N-(2-苯基乙基);5-烷基取代的2-芳基氨基苯基乙酸和衍生物,例如塞来考昔罗非考昔艾托考昔、伐地考昔;或5-烷基-2-芳基氨基苯基乙酸,例如,5-甲基-2-(2’-氯-6’-氟苯氨基)苯基乙酸,鲁米考昔(lumiracoxib);和塞来考昔。
xxii.cRAF激酶抑制剂;其靶向、降低或抑制TNF诱导的E-选择蛋白和血管粘附分子-1的上调;如3-(3,5-二溴-4-羟基亚苄基)-5-碘-1,3-二氢吲哚-2-酮;和苯甲酰胺,3-(二甲基氨基)-N-[3-[(4-羟基苯甲酰基)氨基]-4-甲基苯基]。Raf激酶在细胞分化、增殖和凋亡中作为细胞外信号转导调节激酶起着重要的作用。cRAF激酶抑制剂的目标非限制性地包括RAF1。
xxiii.细胞周期蛋白依赖性激酶抑制剂;其靶向、降低或抑制细胞周期蛋白依赖性激酶,在哺乳动物细胞周期的调节中起作用;如N9-异丙基-奥罗莫星;奥罗莫星;Purvalanol B,其也被称为苯甲酸,2-氯-4-[[2-[[(1R)-1-(羟基甲基)-2-甲基丙基]氨基]-9-(1-甲基乙基)-9H-嘌呤-6-基]氨基]-(9CI);Roascovitine;靛玉红,其也被称为2H-吲哚-2-酮,3-(1,3-二氢-3-氧代-2H-吲哚-2-亚基)-1,3-二氢-(9CI);Kenpaullone,其也被称为吲哚并[3,2-d][1]苯并氮杂卓-6(5H)-酮,9-溴-7,12-二氢-(9CI);Purvalanol A,其也被称为1-丁醇,2-[[6-[(3-氯苯基)氨基]-9-(1-甲基乙基)-9H-嘌呤-2-基]氨基]-3-甲基-,(2R)-(9CI);靛玉红-3’-单肟。细胞周期进程被一系列连续事件调节,该事件包括细胞周期蛋白依赖性激酶(Cdks)和细胞周期蛋白的活化和随后的灭活。Cdks是通过与其调节亚基,细胞周期蛋白结合形成活性杂二聚体复合体的一组丝氨酸/苏氨酸激酶。细胞周期蛋白依赖性激酶抑制剂目标的实例非限制性地包括CDK、AHR、CDK1、CDK2、CDK5、CDK4/6、GSK3β和ERK。
xxiv.半胱氨酸蛋白酶抑制剂;其靶向、降低或抑制在哺乳动物细胞翻转和细胞凋亡中起重要作用的半胱氨酸蛋白酶;如4-吗啉甲酰胺,N-[(1S)-3-氟-2-氧代-1-(2-苯基乙基)丙基]氨基]-2-氧代-1-(苯基甲基)乙基]。
xxv.DNA嵌合剂;其与DNA结合并抑制DNA、RNA和蛋白合成;如普卡霉素、更生霉素。
xxvi.DNA链破裂剂;其造成DNA链分裂和导致DNA合成抑制、抑制了RNA和蛋白合成;如博来霉素。
xxvii.E3连接酶抑制剂;其靶向、降低或抑制E3连接酶,该酶抑制泛素链向蛋白的转移,从而使其在蛋白酶体中降解;如N-((3,3,3-三氟-2-三氟甲基)丙酰基)磺酰胺。
xxviii.内分泌激素;其通过主要作用于脑垂体腺上而造成男性体内激素抑制,净作用是睾酮降低至阉割水平;对女性而言,卵巢雌激素和雄激素合成都被抑制;如醋酸亮丙瑞林;甲地孕酮、醋酸甲地孕酮。
xxix.靶向、降低或抑制表皮生长因子族受体酪氨酸激酶(均或杂二聚体形式的EGFR、ErbB2、(HER-2)、ErbB3、ErbB4)活性的化合物,如抑制EGF受体酪氨酸激酶族成员,例如EGF受体、ErbB1、ErbB2、ErbB3和ErbB4或与EGF或EGF-相关配体结合的化合物、蛋白或抗体,并且特别是在WO 9702266(例如实施例39的化合物)、EP0564409、WO9903854、EP0520722、EP0566226、EP0787722、EP0837063、US5747498、WO9810767、WO9730034、WO9749688、WO9738983并且尤其是WO9630347(例如被称为CP 358774的化合物)、WO9633980(例如被称为ZD 1839的化合物);和WO 9503283(例如被称为ZM105180的化合物)中一般和具体公开的这些化合物、蛋白或单克隆抗体,例如包括双重作用的酪氨酸激酶抑制剂(ErbB1和rbB2)、Lapatinib(GSK572016),例如Lapatinib二甲苯磺酸盐;潘妥单抗(panituzumab)、曲妥单抗西妥昔单抗、Iressa、OSI-774、CI-1033、EKB-569、GW-2016、E1.1、E2.4、E2.5、E6.2、E6.4、E2.11、E6.3或E7.6.3、7H-吡咯并-[2,3-d]嘧啶衍生物(其例如在WO03013541中被公开)、Erlotinib、Gefitinib。Erlotinib可以以其市售形式例如形式被给药,Gefitinib可以以形式被给药,作用于表皮生长因子受体的人单克隆抗体包括ABX-EGFR。
xxx.EGFR、PDGFR酪氨酸激酶抑制剂;如EGFR激酶抑制剂包括酪氨酸磷酸化抑制剂23、酪氨酸磷酸化抑制剂25、酪氨酸磷酸化抑制剂47、酪氨酸磷酸化抑制剂51和酪氨酸磷酸化抑制剂AG 825;2-丙烯酰胺,2-氰基-3-(3,4-二羟基苯基)-N-苯基-(2E);酪氨酸磷酸化抑制剂Ag 1478;薰草菌素A;3-吡啶乙腈,α-[(3,5-二氯苯基)亚甲基]-,(αZ);EGFR、PDGFR酪氨酸激酶抑制剂的实例例如包括酪氨酸磷酸化抑制剂46。PDGFR酪氨酸激酶抑制剂例如包括酪氨酸磷酸化抑制剂46。EGFR激酶抑制剂的目标包括鸟苷酸环化酶(GC-C)HER2、EGFR、PTK和微管蛋白。
xxxi.法尼基转移酶抑制剂;其靶向、降低或抑制Ras蛋白;如a-羟基法尼基膦酸;丁酸,2-[[(2S)-2-[[(2S,3S)-2-[[(2R)-2-氨基-3-巯基丙基]氨基]-3-甲基戊基]氧基]-1-氧代-3-苯基丙基]氨基]-4-(甲基磺酰基)-,1-甲基乙基酯,(2S);手霉素A;L-744,832或DK8G557、Tipifarnib(R115777)、SCH66336(Lonafarnib)、BMS-214662,
xxxii.Flk-1激酶抑制剂;其靶向、降低或抑制Flk-1酪氨酸激酶活性;如2-丙烯酰胺,2-氰基-3-[4-羟基-3,5-二(1-甲基乙基)苯基]-N-(3-苯基丙基)-(2E)。Flk-1激酶抑制剂的目标非限制性地包括KDR。
xxxiii.糖原合成酶激酶-3(GSK3)抑制剂;其靶向、降低或抑制糖原合成酶激酶-3(GSK3);如靛玉红-3’-单肟。在许多细胞过程的信号转导级联中都涉及糖原合成酶激酶-3(GSK-3;tau蛋白激酶I)——一种高保守、普遍表达的丝氨酸/苏氨酸蛋白激酶,其是一种已经表明参与调节不同组细胞功能的蛋白激酶,所说细胞功能包括蛋白合成、细胞增殖、细胞分化、微管组装/分解和细胞凋亡。
xxxiv.组蛋白脱乙酰基酶(HDAC)抑制剂;其抑制组蛋白脱乙酰基酶并具有抗增生活性;如在WO0222577中公开的化合物,尤其是N-羟基-3-[4-[[(2-羟基乙基)[2-(1H-吲哚-3-基)乙基]-氨基]甲基]苯基]-2E-2-丙烯酰胺和N-羟基-3-[4-[[[2-(2-甲基-1H-吲哚-3-基)-乙基]-氨基]甲基]苯基]-2E-2-丙烯酰胺以及其可药用的盐;辛二酰基苯胺(suberoylanilide)异羟肟酸(SAHA);[4-(2-氨基-苯基氨基甲酰基)-苄基]-氨基甲酸吡啶-3-基甲基酯以及其衍生物;丁酸、Pyroxamide、曲古柳菌素A、Oxamflatin、Apicidin、缩酚酸肽;Depudecin;Trapoxin,HC毒素,其也被称为环[L-丙氨酰基-D-丙氨酰基-(S,2S)--氨基--氧代环氧乙烷辛酰基-D-脯氨酰基](9CI);苯丁酸钠、辛二酰基二-异羟肟酸;曲古柳菌素A、BMS-27275、Pyroxamide、FR-901228、丙戊酸。
xxxv.HSP90抑制剂;其靶向、降低或抑制HSP90内在的ATP酶活性;通过泛素蛋白体途径降解、靶向、降低或抑制HSP90客户蛋白。靶向、降低或抑制HSP90内在ATP酶活性的化合物尤其是抑制HSP90的ATP酶活性的化合物、蛋白或抗体,例如,17-烯丙基氨基、17-去甲氧基格尔德霉素(17AAG)、格尔德霉素衍生物;其它格尔德霉素相关化合物;根赤壳菌素和HDAC抑制剂。HSP90抑制剂的其它实例包括格尔德霉素,17-去甲氧基-17-(2-丙烯基氨基)。HSP90抑制剂潜在间接目标包括FLT3、BCR-ABL、CHK1、CYP3A5*3和/或NQ01*2。Nilotinib是BCR-ABL酪氨酸激酶抑制剂的一个实例。
xxxvi.I-κ B-α激酶抑制剂(IKK);其靶向、降低或抑制NF-κB,如2-丙烯腈,3-[(4-甲基苯基)磺酰基]-(2E)。
xxxvii.胰岛素受体酪氨酸激酶抑制剂;其调节磷脂酰肌醇3-激酶、微管相关蛋白和S6激酶的活性;如羟基l-2-萘基甲基膦酸、LY294002。
xxxviii.c-Jun N-末端激酶(JNK)激酶抑制剂;其靶向、降低或抑制JunN-末端激酶;如吡唑蒽酮和/或表没食子儿茶素没食子酸盐。Jun N-末端激酶(JNK)——一种丝氨酸指向的蛋白激酶参与c-Jun和ATF2的磷酸化和活化并在代谢、生长、细胞分化和细胞凋亡中起重要作用。JNK激酶抑制剂的目标非限制性地包括DNMT。
xxxix.微管结合剂;其通过破坏对于有丝分裂和分裂间期细胞功能很重要的微管网络而起作用;如长春花生物碱,例如长春碱、硫酸长春碱;长春新碱、硫酸长春新碱;长春地辛;长春瑞滨;紫杉烷类,如紫杉烷类,例如多西紫杉醇;紫杉醇;海绵内酯类(discodermolides);秋水仙碱、埃坡霉素类以及其衍生物,例如埃坡霉素B或其衍生物。紫杉醇以形式销售;多西紫杉醇以形式销售;硫酸长春碱以VINBLASTIN 形式销售;和硫酸长春新碱以形式销售。还包括紫杉醇的属类形式以及紫杉醇的各种剂型。紫杉醇的属类形式非限制性地包括盐酸倍他洛尔。紫杉醇的各种剂型非限制性地包括以 的形式销售的白蛋白毫微粒型紫杉醇。海绵内酯例如可以如US5010099中所公开的那样获得。还包括在US6194181、WO98/0121、WO9825929、WO9808849、WO9943653、WO9822461和WO0031247中公开的埃坡霉素衍生物。尤其优选的是埃坡霉素A和/或B。
xl.促细胞分裂剂激活蛋白(MAP)激酶-抑制剂;其靶向、降低或抑制促细胞分裂剂激活蛋白,如苯磺酰胺,N-[2-[[[3-(4-氯苯基)-2-丙烯基]甲基]氨基]甲基]苯基]-N-(2-羟基乙基)-4-甲氧基。促细胞分裂剂激活蛋白(MAP)激酶是蛋白丝氨酸/苏氨酸激酶组,其响应许多细胞外刺激而活化并且介导从细胞表面向细胞核的信号转导。其调节一些生理学和病理学细胞现象,包括炎症、细胞凋亡性细胞死亡、致癌性转化、肿瘤细胞侵袭和转移。
xli.MDM2抑制剂;其靶向、降低或抑制MDM2和p53肿瘤抑制剂的相互作用;如反式-4-碘,4’-硼烷基-查耳酮。
xlii.MEK抑制剂;其靶向、降低或抑制MAP激酶MEK的激酶活性;如Sorafenib,例如(Sorafenib甲苯磺酸盐),丁二腈,二[氨基[2-氨基苯基)硫基]亚甲基]。MEK抑制剂的目标非限制性地包括ERK。MEK抑制剂的间接目标非限制性地包括细胞周期蛋白D1。
xliii.基质金属蛋白酶抑制剂(MMP)抑制剂;其靶向、降低或抑制选择性催化多肽键水解的蛋白酶类,包括参与促进肿瘤周围组织结构丧失和促进肿瘤生长、血管发生和转移的酶MMP-2和MMP-9,如放线酰胺素,其也被称为丁二酰胺,N-4-羟基-N1-[(1S)-1-[[(2S)-2-(羟基甲基)-1-吡咯烷基]羰基]-2-甲基丙基]-2-戊基-,(2R)-(9Cl);表没食子儿茶素没食子酸盐;胶原拟肽(peptidomimetic)和非拟肽抑制剂;四环素衍生物,例如,异羟肟酸盐拟肽抑制剂巴马司他;以及其可生物可口服的类似物马立马司他、普啉司他、美他司他(metastat)、辛伐司他、坦诺司他、TAA211、BMS-279251、BAY 12-9566、MMI270B或AAJ996。MMP抑制剂的目标非限制性地包括多肽脱甲酰基酶。
xliv.NGFR酪氨酸-激酶-抑制剂;其靶向、降低或抑制神经生长因子依赖性p140c-trk酪氨酸磷酸化;如酪氨酸磷酸化抑制剂AG 879。NGFR酪氨酸-激酶-抑制剂的目标非限制性地包括HER2、FLK1、FAK、TrkA、和/或TrkC。一种间接目标抑制RAF1的表达。
xlv.p38 MAP激酶抑制剂,包括SAPK2/p38激酶抑制剂;其靶向、降低或抑制p38-MAPK(其是MAPK族成员),如苯酚,4-[4-(4-氟苯基)-5-(4-吡啶基)-1H-咪唑-2-基]。SAPK2/p38激酶抑制剂的实例非限制性地包括苯甲酰胺,3-(二甲基氨基)-N-[3-[(4-羟基苯甲酰基)氨基]-4-甲基苯基]。MAPK族成员是由酪氨酸和苏氨酸残基的磷酸化活化的丝氨酸/苏氨酸激酶。这种激酶被许多细胞应激和炎性刺激磷酸化和活化,认为其参与调节重要的细胞响应如细胞凋亡和炎症反应。
xlvi.p56酪氨酸激酶抑制剂;其靶向、降低或抑制p56酪氨酸激酶(其是一种对T-细胞发育和活化很关键的淋巴组织特异性src族酪氨酸激酶);如虎刺素,其也被称为2-蒽甲醛,9,10-二氢-3-羟基-1甲氧基-9,10-二氧代,酪氨酸磷酸化抑制剂46。p56酪氨酸激酶抑制剂的目标非限制性地包括Lck。Lck与CD4、CD8的胞质区域和IL-2受体的β-链有关,并且认为其参与TCR-介导的T-细胞活化的最早期步骤。
xlvii.PDGFR酪氨酸激酶抑制剂;其靶向、降低或抑制C-kit受体酪氨酸激酶(PDGFR族的一部分)的活性,如靶向、降低或抑制c-Kit受体酪氨酸激酶族的活性,尤其是抑制c-Kit受体。PDGFR酪氨酸激酶抑制剂的目标实例非限制性地包括PDGFR、FLT3和/或c-KIT;如酪氨酸磷酸化抑制剂AG 1296;酪氨酸磷酸化抑制剂9;1,3-丁二烯-1,1,3-三腈,2-氨基-4-(1H-吲哚-5-基);N-苯基-2-嘧啶-胺衍生物,例如伊马替尼(imatinib)、PDGF在正常细胞以及各种疾病状态如癌症、动脉粥样硬化和纤维变性疾病中细胞增殖、趋化性和存活的调节中起重要作用。PDGF族由二聚亚型(PDGF-AA、PDGF-BB、PDGF-AB、PDGF-CC、和PDGF-DD)组成,其通过与两种受体酪氨酸激酶有差别地结合来发挥其细胞作用。PDGFR-α和PDGFR-β分别具有170和180kDa的分子量。
xlviii.磷脂酰肌醇3-激酶抑制剂;其靶向、降低或抑制PI3-激酶;如渥曼青霉素,其也被称为3H-呋喃并[4,3,2-de]茚并[4,5-h]-2-苯并吡喃-3,6,9-三酮,11-(乙酰氧基)-1,6b,7,8,9a,10,11,11b-八氢-1-(甲氧基甲基)-9a,11b-二甲基-,(1S,6bR,9aS,11R,11bR)-(9CI);8-苯基-2-(吗啉-4-基)-色烯-4-酮;槲皮素、槲皮素二水合物。已经表明作为对许多激素和生长因子(包括胰岛素、血小板衍生生长因子、胰岛素样生长因子、表皮生长因子、集落刺激因子和肝细胞生长因子)刺激的响应,PI3-激酶活性增加,并且参与与细胞生长和转化有关的过程。磷脂酰肌醇3-激酶抑制剂的目标实例非限制性地包括Pi3K。
xlix.磷酸酶抑制剂;其靶向、降低或抑制磷酸酶;如斑蝥酸;斑蝥素;和L-亮氨酰胺(leucinamide)、N-[4-(2-羧基乙烯基)苯甲酰基]甘氨酰基-L-α-谷氨酰基-(E)。磷酸酶除去磷酰基和将蛋白恢复为其最初的脱磷酸化状态。因此,该磷酸化-脱磷酸化循环可被看作分子“开关”。
l.铂剂;其包含铂和通过形成DNA分子的股间和股内交联来抑制DNA合成;如卡铂;顺铂(cisplatin);奥沙利铂;顺铂(cisplatinum);沙铂和铂剂如ZD0473、BBR3464。卡铂例如可以以其市售形式,例如的形式给药;和奥沙利铂可以以的形式给药。
li.蛋白磷酸酶抑制剂,包括PP1和PP2抑制剂以及酪氨酸磷酸酶抑制剂;其靶向、降低或抑制蛋白磷酸酶。PP1和PP2A抑制剂的实例包括斑蝥酸和/或斑蝥素。酪氨酸磷酸酶抑制剂的实例非限制性地包括L-P-溴四咪唑草酸盐;2(5H)-呋喃酮,4-羟基-5-(羟基甲基)-3-(1-氧代十六烷基)-,(5R);和苄基膦酸。
本文所用的术语“PP1或PP2抑制剂”是指靶向、降低或抑制Ser/Thr蛋白磷酸酶的化合物。I型磷酸酶(其包括PP1)可以被两种被称为抑制剂-1(I-1)和抑制剂-2(I-2)的热稳定的蛋白抑制。其优先对磷酸化酶激酶的一个亚基去磷酸化。II型磷酸酶被细分为自发起效(PP2A)、CA2+-依赖性(PP2B)和Mg2+-依赖性(PP2C)磷酸酶。
本文所用的术语“酪氨酸磷酸酶抑制剂”是指靶向、降低或抑制酪氨酸磷酸酶的化合物。蛋白酪氨酸磷酸酶(PTPs)最近被归入磷酸酶族。其从蛋白被磷酸化的酪氨酸残基上除去磷酸酯基团。PTPs表现出不同的结构特性并且在细胞增殖、分化、细胞粘附和运动性、以及细胞支架功能的调节中起重要作用。酪氨酸磷酸酶抑制剂的目标实例非限制性地包括碱性磷酸酶(ALP)、类肝素酶、PTPase、和/或前列腺酸性磷酸酶。
lii.PKC抑制剂和PKC δ激酶抑制剂:本文所用的术语“PKC抑制剂”是指靶向、降低或抑制蛋白激酶C以及其同工酶的化合物。蛋白激酶C(PKC)(一种普遍存在的磷脂依赖性酶)参与与细胞增殖、分化和细胞凋亡有关的信号转导。PKC抑制剂的目标实例非限制性地包括MAPK和/或NF-κB。PKC抑制剂的实例非限制性地包括1-H-吡咯并-2,5-二酮,3-[1-[3-(二甲基氨基)丙基]-1H-吲哚-3-基]-4-(1H-吲哚-3-基);二吲哚基马来酰亚胺IX;鞘氨醇,其也被称为4-十八碳烯-1,3-二醇,2-氨基-,(2S,3R,4E)-(9Cl);十字孢碱,其也被称为9,13-环氧-1H,9H-二吲哚并[1,2,3-gh:3′,2′,1′-lm]吡咯并[3,4-j][1,7]苯并二偶氮宁(benzodiazonin)-1-酮、十字孢碱衍生物如在EP0296110中公开的物质,例如米哚妥林;2,3,10,11,12,13-六氢-10-甲氧基-9-甲基-11-(甲基氨基)-,(9S,10R,11R,13R)-(9CI);酪氨酸磷酸化抑制剂51;和金丝桃素,其也被称为菲并[1,10,9,8-opqra]苝-7,14-二酮,1,3,4,6,8,13-六羟基-10,11-二甲基-,立体异构体(6CI,7CI,8CI,9CI)、UCN-01、沙芬戈、BAY43-9006、苔藓抑素1、哌立福辛;llmofosine;RO 318220和RO 320432;GO 6976;Isis 3521;LY333531/LY379196。本文所用的术语“PKC δ激酶抑制剂”是指靶向、降低或抑制PKC的δ同工酶的化合物。该δ同工酶是一种常规的PKC同工酶并且是Ca2+-依赖性的。PKC δ激酶抑制剂的实例非限制性地包括楸毒素,其也被称为2-丙烯-1-酮,1-[6-[(3-乙酰基-2,4,6-三羟基-5-甲基苯基)甲基]-5,7-二羟基-2,2-二甲基-2H-1-苯并吡喃-8-基]-3-苯基-,(2E)-(9CI)。
liii.聚胺合成抑制剂;其靶向、降低或抑制聚胺类精脒;如DMFO,其也被称为(-)-2-二氟甲基鸟氨酸;N1,N12-二乙基精胺4HCl。该聚胺类精脒和精胺对于细胞增殖而言十分重要,但是仍然还不清楚其精确的作用机理。肿瘤细胞具有改变的聚胺内环境稳定,这一点可通过生物合成酶活性增加和聚胺汇集水平升高反映出来。
liv.蛋白体抑制剂;其靶向、降低或抑制蛋白酶体,如阿克拉霉素A;胶霉菌素;PS-341;MLN 341;Bortezomib;Velcade。蛋白体抑制剂的目标实例非限制性地包括O(2)(-)-产NADPH氧化酶,NF-κB、和/或法尼基转移酶,法尼基转移酶I。
lv.PTP1B抑制剂;其靶向、降低或抑制PTP1B——一种蛋白酪氨酸激酶抑制剂;如L-亮氨酰胺,N-[4-(2-羧基乙烯基)苯甲酰基]甘氨酰基-L-α-谷氨酰基-,(E)。
lvi.蛋白酪氨酸激酶抑制剂,包括SRC族酪氨酸激酶抑制剂;Syk酪氨酸激酶抑制剂;和JAK-2和/或JAK-3酪氨酸激酶抑制剂;
本文所用的术语“蛋白酪氨酸激酶抑制剂”是指靶向、降低或抑制蛋白酪氨酸激酶的化合物。蛋白酪氨酸激酶(PTKs)在细胞增殖、分化、代谢、迁移和存活的调节中起重要作用。其被分为受体PTKs和非-受体PTKs。受体PTKs包含具有跨膜部分的单多肽链。这种部分的细胞外末端包含高亲合力配体结合区域,而其胞质末端包含催化核和调节序列。酪氨酸激酶抑制剂的目标实例非限制性地包括ERK1、ERK2,Bruton’s酪氨酸激酶(Btk)、JAK2、ERK1/2、DGFR、和/或FLT3。间接目标实例非限制性地包括TNFα、NO、PGE2、IRAK、iNOS、ICAM-1和/或E-选择蛋白。酪氨酸激酶抑制剂的实例非限制性地包括酪氨酸磷酸化抑制剂AG 126;酪氨酸磷酸化抑制剂Ag 1288;酪氨酸磷酸化抑制剂Ag 1295;格尔德霉素;和染料木素。
非-受体酪氨酸激酶包括Src、Tec、JAK、Fes、Abl、FAK、Csk和Syk族成员。其位于胞浆以及细胞核中。其表现出不同的激酶调节、底物磷酸化作用和功能。这些激酶的失调也与一些人类疾病有关。
本文所用的术语“SRC族酪氨酸激酶抑制剂”是指靶向、降低或抑制SRC的化合物。SRC族酪氨酸激酶抑制剂的实例非限制性地包括PP1,其也被称为1H-吡唑并[3,4-d]嘧啶-4-胺,1-(1,1-二甲基乙基)-3-(1-萘基)-(9Cl);和PP2,其也被称为1H-吡唑并[3,4-d]嘧啶-4-胺,3-(4-氯苯基)-1-(1,1-二甲基乙基)-(9Cl)。
本文所用的术语“Syk酪氨酸激酶抑制剂”是指靶向、降低或抑制Syk的化合物。Syk酪氨酸激酶抑制剂的目标实例非限制性地包括Syk、STAT3、和/或STAT5。Syk酪氨酸激酶抑制剂的实例非限制性地包括Piceatannol,其也被称为1,2-苯二醇,4-[(1E)-2-(3,5-二羟基苯基)乙烯基]-(9Cl)。
本文所用的术语“Janus(JAK-2和/或JAK-3)酪氨酸激酶抑制剂”是指靶向、降低或抑制Janus酪氨酸激酶的化合物。表明Janus酪氨酸激酶抑制剂是具有抗血栓形成、抗过敏和免疫抑制性的抗白血病药。JAK-2和/或JAK-3酪氨酸激酶抑制剂的目标非限制性地包括JAK2、JAK3、STAT3。JAK-2和/或JAK-3酪氨酸激酶抑制剂的间接目标非限制性地包括CDK2。JAK-2和/或JAK-3酪氨酸激酶抑制剂的实例非限制性地包括酪氨酸磷酸化抑制剂AG 490;和2-萘基乙烯基酮。
靶向、降低或抑制c-Abl族成员或其基因融合产物活性的化合物,例如包括PD180970;AG957;或NSC 680410。
lvii.类视色素;其靶向、降低或抑制类视色素依赖性受体;如异维甲酸、维甲酸、阿利维A酸、贝沙罗汀,例如包括与DNA上的视黄酸应当元素相互作用的物质,如异维甲酸(13-顺式-维甲酸)。
lviii.RNA聚合酶II延长抑制剂;其靶向、降低或抑制CHO细胞中胰岛素-刺激的核和胞质p70S6激酶;靶向、降低或抑制RNA聚合酶II转录(其可能依赖于酪蛋白激酶II);和靶向、降低或抑制牛卵母细胞中的胚泡破裂;如5,6-二氯-1-β-D-呋喃核糖基苯并咪唑。
lvix.丝氨酸/苏氨酸激酶抑制剂;其抑制丝氨酸/苏氨酸激酶;如2-氨基嘌呤。丝氨酸/苏氨酸激酶抑制剂的目标实例非限制性地包括dsRNA-依赖性蛋白激酶(PKR)。丝氨酸/苏氨酸激酶抑制剂的间接目标实例非限制性地包括MCP-1、NF-κB、elF2α、COX2、RANTES、IL8、CYP2A5、IGF-1、CYP2B1、CYP2B2、CYP2H1、ALAS-1、HIF-1、红细胞生成素、和/或CYP1A1。
lx.甾醇生物合成抑制剂;其抑制甾醇类如胆固醇的生物合成;如Terbinadine。甾醇生物合成抑制剂的目标实例非限制性地包括角鲨烯环氧酶、和CYP2D6。
lxi.拓扑异构酶抑制剂;包括拓扑异构酶I抑制剂和拓扑异构酶II抑制剂。拓扑异构酶I抑制剂的实例非限制性地包括托泊替康、吉马替康(gimatecan)、依立替康、坎托替康(camptothecan)以及其类似物、9-硝基喜树碱以及大分子喜树碱轭合物PNU-166148(WO9917804中的化合物A1);10-羟基喜树碱,例如其醋酸盐;伊达比星,例如其盐酸盐;依立替康,例如其盐酸盐;依托泊苷;替尼泊苷;托泊替康、盐酸托泊替康;多柔比星;表柔比星、盐酸表柔比星;4’-表柔比星、米托蒽醌,例如盐酸米托蒽醌;柔红霉素、盐酸柔红霉素、戊柔比星、达沙替尼(dasatinib)(BMS-354825)。依立替康例如可以以其市售形式,例如,以商标市售的形式进行给药。托泊替康例如可以以其市售形式,例如,以商标市售的形式进行给药。本文中所用的术语“拓扑异构酶II抑制剂”非限制性地包括蒽环类抗生素,如多柔比星,包括脂质体制剂,例如,柔红霉素,包括脂质体制剂,例如,表柔比星、伊达比星和奈莫柔比星;蒽醌类米托蒽醌和洛索蒽醌;和鬼臼乙叉甙类(podophillotoxines)依托泊苷和替尼泊苷。依托泊苷以形式市售;替尼泊苷以VM形式市售;多柔比星以或形式市售;表柔比星以形式市售;伊达比星以形式市售;和米托蒽醌以形式市售。
lxii.VEGFR酪氨酸激酶抑制剂;其靶向、降低和/或抑制已知参与正常和病理性血管发生的调节的血管原性生长因子和细胞因子。VEGF族(VEGF-A、VEGF-B、VEGF-C、VEGF-D)以及其相应的受体酪氨酸激酶[VEGFR-1(Flt-1)、VEGFR-2(Flk-1、KDR)和VEGFR-3(Flt-4)]在调节血管生成和淋巴管生成(lymphangiogenic)过程的许多方面中起最重要和不可缺少的作用。VEGFR酪氨酸激酶抑制剂的实例包括3-(4-二甲基氨基亚苄基)-2-二氢吲哚酮。靶向、降低或抑制VEGFR活性的化合物尤其是抑制VEGF受体酪氨酸激酶、抑制VEGF受体或者与VEGF结合的化合物、蛋白或抗体,并且特别是这些在下面资料中一般和具体公开的这些化合物、蛋白或单克隆抗体:WO9835958,例如1-(4-氯苯氨基)-4-(4-吡啶基甲基)酞嗪或其可药用的盐,例如其琥珀酸盐;WO0009495、WO0027820、WO0059509、WO9811223、WO0027819和EP0769947;例如M.Prewett等人在Cancer Research 59(1999)5209-5218中、F.Yuan等人在Proc.Natl.Acad.Sci.USA,第93卷,第14765-14770页,1996年12月中、Z.Zhu等人在Cancer Res.58,1998,3209-3214中和J.Mordenti等人在ToxicologicPathology,第27卷,第1期,第14-21页,1999中所述的这些物质;WO0037502和WO9410202;M.S.O′Reilly等人,Cell79,1994,315-328所述的血管他汀;M.S.O′Reilly等人,Cell88,1997,277-285所述的内皮他汀;邻氨基苯甲酸酰胺类;ZD4190;ZD6474(vandetanib);SU5416;SU6668、AZD2171或抗-VEGF抗体或抗-VEGF受体抗体,例如RhuMab(贝伐单抗)。抗体是指完整的单克隆抗体、多克隆抗体、由至少2个完整抗体形成的多特异性抗体、和抗体片段(只要其表现出所需生物学活性即可)。VEGF-R2抑制剂的实例例如包括阿昔替尼(axitinib),
lxiii.促性腺激素释放激素激动剂,如阿巴瑞克、戈舍瑞林、醋酸戈舍瑞林,
lxiv.诱导细胞分化过程的化合物,如视黄酸、α-、γ-或8-生育酚或α-、γ-或8-生育三烯酸。
lxv.二膦酸盐,例如包括依替膦酸(etridonic)、氯膦酸、替鲁膦酸、帕米膦酸、阿仑膦酸、伊班膦酸、利塞膦酸和唑来膦酸。
lxvi.防止硫酸肝素降解的类肝素酶抑制剂,例如PI-88,
lxvii.生物学响应改性剂,优选Alymphokine或干扰素类,例如干扰素α,
lxviii.端粒末端转移酶抑制剂,例如特洛他汀(telomestatin),
lxix.调节剂,如儿茶酚-O-甲基转移酶的抑制剂,例如恩他卡朋,
lxxii.生长激素受体拮抗剂,如培维索孟、非格司亭或吡非司亭(pegfilgrastim)或干扰素α。
lxxvi.癌症疫苗,如MDX-1379。
lxxvii.免疫抑制单克隆抗体,例如白细胞受体或其配体的单克隆抗体,
倾向于用于与本发明化合物联合的麻醉药包括例如乙醇、布比卡因、氯普鲁卡因、左布比卡因、利多卡因、甲哌卡因、普鲁卡因、罗哌卡因、丁卡因、地氟烷、异氟烷、氯胺酮、丙泊酚、七氟醚、可待因、芬太尼、氢吗啡酮、布比卡因灭菌等渗溶液(marcaine)、哌替啶、美沙酮、吗啡、羟考酮、瑞芬太尼、舒芬太尼、布托啡诺、纳布啡、曲马多、苯佐卡因、二丁卡因、氯乙烷、赛洛卡因、非那吡啶。
在下面的实施例中,所有的温度都是摄氏度(℃)。
使用下面的缩写:
DMF N,N-二甲基甲酰胺
EDC (1-乙基-3-[3-二甲基氨基丙基]碳二亚胺
ETOAc 乙酸乙酯
HOAt 1-羟基-7-氮杂苯并三唑,
rt 室温
THF 四氢呋喃
TLC: 薄层色谱
实施例
金刚烷-1-甲酸(2-苯甲酰氨基-苯并噻唑-6-基)-酰胺
将100mg N-(6-氨基-苯并噻唑-2-基)-苯甲酰胺、250mg金刚烷甲酸、24.5mg HOAt、247μl三乙胺和126μl EDC/游离碱)溶解于2ml无水DMF中并将其在60℃下搅拌2小时。将所得混合物用EtOAc稀释,用1N HCl和5% NaHCO3水溶液进行萃取。从所得有机层中蒸发掉溶剂,将蒸发残余物用色谱进行处理。得到金刚烷-1-甲酸(2-苯甲酰氨基-苯并噻唑-6-基)-酰胺。
实施例2
金刚烷-1-甲酸(2-乙酰氨基-苯并噻唑-6-基)-酰胺
将50mg金刚烷-1-甲酸(2-氨基-苯并噻唑-6-基)-酰胺和催化量4-二甲基氨基吡啶在5ml THF和70μl醋酸酐中的混合物在50℃下搅拌一夜。将所得混合物用EtOAc稀释并用0.1N HCl和5% NaHCO3水溶液洗涤。蒸发掉溶剂并将蒸发残余物用色谱进行处理。得到金刚烷-1-甲酸(2-乙酰氨基-苯并噻唑-6-基)-酰胺。
与实施例1或2所述方法类似,但是使用适宜的起始材料(中间体),获得其中R1和R2如下面的表1中所定义的式I的化合物,
其具有表1中标题为“MS或Fp”的列中所示的得自质谱(MS)的分析数据和/或熔点(Fp);
表1
表1中的“EX”表示化合物序号。
表1中的Rf值是在所示溶剂混合物中在硅胶TLC上测得的。
中间体(起始材料)的制备
实施例A
N-(6-氨基-苯并噻唑-2-基)-苯甲酰胺
Aa.N-(6-硝基-苯并噻唑-2-基)-苯甲酰胺)
将1g2-氨基-6-硝基-苯并噻唑、1.04ml三乙胺和0.87ml苯甲酰氯和催化量的4-二甲基氨基吡啶溶解于50ml THF中并将其加热回流4小时。在加热期间,主要形成的3-酰基产物异构化成所需的2-酰胺。用水在室温下将过量的苯甲酰氯水解一夜。将获得的混合物用ETOAc稀释,N-(6-硝基-苯并噻唑-2-基)-苯甲酰胺)形成沉淀,将其滤出。
Ab.N-(6-氨基-苯并噻唑-2-基)-苯甲酰胺)
将300mg N-(6-硝基-苯并噻唑-2-基)-苯甲酰胺)在50ml乙酸中用1g锡粉在搅拌的情况下在室温下处理6小时。将所得的反应混合物用NaOH水溶液中和并将所得的混合物用CH2Cl2进行萃取。蒸发掉溶剂,得到N-(6-氨基-苯并噻唑-2-基)-苯甲酰胺。
实施例B
金刚烷-1-甲酸(2-氨基-苯并噻唑-6-基)-酰胺
Ba)苯并噻唑-2,6-二胺
将2g 2-氨基-6-硝基-苯并噻唑和3g位于200ml CH3OH中的阮内镍在甲醇/THF中在氢气下在室温下进行处理。将所得的混合物过滤,从所得过滤残余物中蒸发掉溶剂。得到苯并噻唑-2,6-二胺。
Bb)金刚烷-1-甲酸(2-氨基-苯并噻唑-6-基)-酰胺
将步骤Ba)中获得的苯并噻唑-2,6-二胺、1.1g金刚烷甲酸、1.3ml EDC(游离碱)、83mg HOAt和1.2ml二异丙基乙基胺的混合物在30ml DMF中在40℃下搅拌3小时。将所得的混合物用EtOAc稀释并用0.1N HCl和5% NaHCO3水溶液洗涤。从所得混合物中蒸发掉溶剂。得到金刚烷-1-甲酸(2-氨基-苯并噻唑-6-基)-酰胺。
Claims (10)
1.式的化合物
其中
R1是包含至少8个,例如8至22个碳原子的直链、支链或环状脂族、芳族或杂环基团,
R2是包含1至12个碳原子的直链、支链或环状脂族、芳族或杂环基团,且
环A是与同环A相连的苯环稠合的杂环基,其包含5或6个环成员和1至4个选自N、S、O的杂原子;
前提条件是不包括下列化合物
N-[2-(乙酰氨基)-6-苯并噻唑基]-三环[3.3.1.13,7]癸烷-1-甲酰胺,
N-[2-(苯甲酰氨基)-6-苯并噻唑基]-三环[3.3.1.13,7]癸烷-1-甲酰胺,
N-[2-(苯甲酰氨基)-6-苯并噻唑基]-3-氯-苯并[b]噻吩-2-甲酰胺,
2,3-二氢-N-[2-[(1-氧代丁基)氨基]-6-苯并噻唑基]-1,4-苯并二氧杂环己烯-6-甲酰胺,
N-[2-(乙酰氨基)-6-苯并噻唑基]-3-氯-苯并[b]噻吩-2-甲酰胺,
N-[2-(丁酰氨基)-1,3-苯并噻唑-6-基]-3-氯-1-苯并噻吩-2-甲酰胺,
N-[2-(丁酰氨基)-1,3-苯并噻唑-6-基]-1-苯并呋喃-2-甲酰胺,
N-[2-[(环己基羰基)-氨基]-6-苯并噻唑基]-三环[3.3.1.13,7]癸烷-1-甲酰胺,
金刚烷-1-甲酸[2-(金刚烷-1-基)-羰基氨基-苯并噻唑-6-基]-酰胺,
N-[2,3-二氢-3-氧代-6-[(1-氧代十六烷酰基)-氨基]-苯并[b]-噻吩-2-基]-5-硝基-1H-吲唑-1-甲酰胺,和
N-[2,3-二氢-3-氧代-6-[(1-氧代十六烷酰基)-氨基]-苯并[b]-噻吩-2-基]-2,3,5,6-四氟-4-巯基苯甲酰胺。
2.2,6-二酰氨基-苯并噻唑类或2,6-二酰氨基-苯并噁唑类化合物,其中6位氨基羰基的羰基被包含至少8个碳原子的直链、支链或环状脂族、芳族或杂环基团所取代,并且2位氨基羰基的羰基被包含1至8个碳原子的直链、支链或环状脂族、芳族或杂环基团所取代,其具有权利要求1所述的前提条件。
4.如权利要求1至3中任意一项所述的化合物,其选自
3-苯基-金刚烷-1-甲酸(2-苯甲酰氨基-苯并噻唑-6-基)-酰胺,
N-(6-十四烷酰基氨基-苯并噻唑-2-基)-苯甲酰胺,和
金刚烷-1-甲酸[2-(3,4-二甲氧基-苯甲酰氨基)-苯并噻唑-6-基]-酰胺。
5.盐形式的如权利要求1或4中任意一项所述的化合物。
6.用作药物的无权利要求1至3的前提条件的如权利要求1至5中任意一项所述的化合物。
7.一种药物组合物,其包含无权利要求1至3的前提条件的如权利要求1至5中任意一项所述的化合物和至少一种药用赋形剂。
8.一种治疗由神经酰胺激酶活性介导的病症的方法,该治疗包括给需要该类治疗的个体施用有效量的无权利要求1至3的前提条件的如权利要求1至5中任意一项所述的化合物。
9.无权利要求1至3的前提条件的如权利要求1至5中任意一项所述的化合物用于制备治疗由神经酰胺激酶活性介导的病症的药物的应用。
10.无权利要求1至3的前提条件的如权利要求1至5中任意一项所述的化合物与至少一种第二种药物的组合。
11.用于如权利要求6、8或9中任意一项所述的应用的无权利要求1至3的前提条件的如权利要求1至5中任意一项所述的化合物与至少一种第二种药物的组合。
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US6323201B1 (en) * | 1994-12-29 | 2001-11-27 | The Regents Of The University Of California | Compounds for inhibition of ceramide-mediated signal transduction |
KR20020084116A (ko) * | 2000-02-07 | 2002-11-04 | 애보트 게엠베하 운트 콤파니 카게 | 2-벤조티아졸릴 우레아 유도체 및 이의 단백질 키나제억제제로서의 용도 |
WO2003030902A1 (en) * | 2001-10-09 | 2003-04-17 | Tularik Inc. | Imidazole derivates as anti-inflammatory agents |
WO2003035602A1 (fr) * | 2001-10-25 | 2003-05-01 | Sankyo Company, Limited | Modulateurs lipidiques |
TW200306819A (en) * | 2002-01-25 | 2003-12-01 | Vertex Pharma | Indazole compounds useful as protein kinase inhibitors |
WO2004014905A1 (en) * | 2002-08-08 | 2004-02-19 | Boehringer Ingelheim Pharmaceuticals, Inc. | Substituted benzimidazole compounds |
CA2553966A1 (en) * | 2004-01-23 | 2005-08-04 | Amgen Inc. | Vanilloid receptor ligands and their use in treatments |
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CN112812111A (zh) * | 2020-03-03 | 2021-05-18 | 中国药科大学 | 苯并噻唑类化合物及医药用途 |
WO2021175234A1 (zh) * | 2020-03-03 | 2021-09-10 | 中国药科大学 | 苯并噻唑类化合物及医药用途 |
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WO2007112914A2 (en) | 2007-10-11 |
EP2004617A2 (en) | 2008-12-24 |
KR20080098443A (ko) | 2008-11-07 |
BRPI0709270A2 (pt) | 2011-06-28 |
AU2007234022A1 (en) | 2007-10-11 |
RU2008142834A (ru) | 2010-05-10 |
GB0606429D0 (en) | 2006-05-10 |
MX2008012399A (es) | 2008-10-09 |
CA2644636A1 (en) | 2007-10-11 |
WO2007112914A3 (en) | 2007-11-29 |
JP2009531365A (ja) | 2009-09-03 |
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