CN1561990A - 治疗免疫疾病 - Google Patents
治疗免疫疾病 Download PDFInfo
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- CN1561990A CN1561990A CNA200410062002XA CN200410062002A CN1561990A CN 1561990 A CN1561990 A CN 1561990A CN A200410062002X A CNA200410062002X A CN A200410062002XA CN 200410062002 A CN200410062002 A CN 200410062002A CN 1561990 A CN1561990 A CN 1561990A
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Abstract
本发明提供了治疗与免疫机能障碍相关的疾病的方法、化合物、和组合物。依据本发明方法,将包括至少一种选自5-烷基-间苯二酚衍生物、大麻酚衍生物、大麻二酚衍生物、大麻萜酚衍生物、和它们的组合的化合物的可药用组合物在足以减弱免疫系统机能障碍的条件下施用给患者。本发明还提供了可用于本发明方法中的抗病毒大麻酚衍生物。本发明还提供了烷基化的间苯二酚衍生物,和使用所述烷基化的间苯二酚衍生物来减弱新生物生长的方法。本发明方法和化合物可用于治疗免疫系统疾病,例如HIV疾病和新生物疾病。
Description
本申请是申请号为00807895.5、申请日为2000年3月22日、发明名称为“治疗免疫疾病”的专利申请的分案申请。
发明技术领域
本发明涉及治疗与免疫机能障碍相关的疾病,特别是HIV疾病和新生物疾病。
发明背景
逆转录病毒人免疫缺陷病毒1和2(HIV)是最常见的AIDS病原体。通过一部分病毒包膜蛋白(gp120),HIV以高亲和力特异性地结合T-淋巴细胞上的CD4分子。结合后,病毒与细胞膜融合并内在化。在细胞内,病毒产生逆转录酶,逆转录酶将基因组RNA转录成DNA。之后该逆HIV转录物整合到细胞DNA内,对于细胞生存来说,其在细胞DNA内作为“原病毒”存在。原病毒可潜伏不定时间,或者可以被“激活”以转录mRNA和基因组RNA,导致蛋白合成、装配、形成新的病毒颗粒、从细胞表面芽生出病毒、和细胞死亡。
虽然对引发激活的精确事件尚未充分了解,但是它们似乎能导致内源性细胞因子的释放/生成,这些细胞因子与HIV基因组相互作用以促进翻译。在这方面,需要细胞SP1与HIV促进子(含有几个串联SP1共有序列结合位点)结合来进行潜伏HIV基因组的高水平转录。此外,当结合到HIV增强子(与促进子相邻)中的一个或两个(取决于HIV株)共有序列结合位点上时,NFκB起强效转录激活物的作用。转录因子CREB/ATF、NF-AT、和AP1也增强HIV转录。对于所有逆转录病毒,当原病毒被激活时,会产生结构和酶gag、pol和env基因产物。HIV首先将gag-pol作为融合蛋白转录,该融合蛋白最终被HIV蛋白酶裂解以生成成熟的病毒蛋白。HIV还采用另外的调控蛋白(具体来说是tat和rev基因产物)作为转录增强子以诱导高水平的基因表达。Nef是调节病毒复制水平的另一HIV基因。
虽然对于引发活性病毒复制的这些因子仅有部分了解,但是它们当中有一些包括热激、紫外辐射、其它(例如重复感染)病毒的调控蛋白、炎性细胞因子(例如IL1、IL2、IL4、IL6、IL10、肿瘤坏死因子α(TNFa)、血小板激活因子、干扰素γ(IFNγ))、和氧化氮。许多这些因子是T-细胞激活剂(例如它们促进T-细胞群体的细胞周期和克隆扩增),并且它们被许多B-细胞作为对感染剂(例如HIV)的直接反应而释放出来。这些因子还引发细胞内信号传导事件,促进NFκB的生成和它从其抑制剂中的(IkB)离解。活性NFκB是激活许多细胞基因以及HIV基因组转录的DNA结合蛋白。在这方面,细胞因子例如TNFα和IL-1增强培养的T-细胞中的NFκB活性。
藏匿原病毒的一些细胞表达HIV gp41、gp120、以及其它可能的病毒蛋白,据假定这是通过从原病毒基因组的基本水平的转录进行的。虽然产生了抗这样的HIV蛋白的免疫反应(部分是由于这些蛋白的高度易变性及其改变的糖基化模式),但是这样的免疫反应通常是不完全的,导致潜伏病毒汇聚,从而有力地避免了免疫监督。此外,感染细胞的细胞膜上存在的HIV gp120可通过类似于病毒进入未感染细胞的反应介导感染细胞与未感染抗原呈递细胞(例如树状细胞)之间的融合事件。这样的融合事件并不象细胞免疫反应那样破坏感染细胞,而是通常导致形成短寿命的多核合胞体“巨细胞”,这样的“巨细胞”实际上促进病毒复制。在这方面,虽然潜伏感染的单核细胞和T-淋巴细胞通常是静止的,并且没有任何活性NFκB,但是其它细胞(例如树状细胞)一般含有高水平的活性NFκB。然而,树状细胞不产生SP1,而T-细胞和单核细胞表达活性形式的Sp1。因此,在感染的T-细胞与树状细胞之间形成合胞体使得活性NFκB和SP1进入相同细胞,从而促进HIV基因组的转录。
当成熟HIV从宿主细胞上“芽生出来”时,病毒生命周期结束,保留一定量的细胞膜作为其部分包膜。这些芽生事件经常是在下述细胞膜区域发生的:细胞内粘着分子(ICAMs)与其它表面受体在细胞激活过程中发生融合的区域。因为这样的蛋白位于细胞间接触区域,该现象(称为极性覆盖或极化)可通过将病毒芽生“集中”在相邻细胞上或促进合胞体形成来帮助病毒感染的扩散。此外,释放的病毒颗粒经常含有一些膜结合的ICAMs(例如ICAM-1),并且这样的病毒可通过不涉及gp120-CD4相互作用的相互作用结合细胞(例如外周血液单核细胞)。这样的ICAM-1+ HIV病毒的传染性比ICAM-1-HIV强,并且因为它们被宿主动物的糖蛋白遮蔽,它们被循环宿主抗体中和的可能性更小。HIV可通过促进STAT1α(其结合ICAM-1基因增强子并促进SP1-依赖性转录)的磷酸化而增强细胞粘着分子例如ICAM-1的生成。有趣的是,炎性细胞因子(例如IFNγ)也促进STATα的磷酸化,并且该基因含有一些涉及HIV复制的相同转录因子、尤其是NFκB的共有序列结合位点。
在静止细胞内存在汇聚的潜伏HIV、HIV蛋白的高度易变性及其对免疫监督的相对无视性、和病毒通过获得ICAMs改变其向性的能力都使得病毒能够在面对攻击性宿主免疫反应的情况下复制。随着时间的延长,病毒逐渐毁坏并不断破坏用于消除感染的系统。这种病毒持久存在和复制进程是HIV疾病,其标志是细胞因子信号传导失控、特别是在淋巴系统中的失控,和最终破坏淋巴结。当HIV疾病发展到宿主免疫系统变得没有能力以致于其不能消除机会疾病(例如细菌、真菌、新生物等)的程度时,就形成了AIDS。许多患者在他们的CD4+T-细胞计数降至约200时(大多数健康成人的CD4+T-细胞计数约为1000)开始表现出AIDS症状。
为了预防发展成AIDS,许多当前疗法把目标集中在停止病毒生命周期事件上,一般是把目标直接定在病毒蛋白上。例如,已经产生了gp120抗体来阻断最初的细胞感染。然而,部分由于病毒通过合胞体或直接的细胞-细胞接触而扩散的能力和其获得ICAM分子的能力,这样的努力获得了混合结果。其它疗法采用HIV蛋白酶抑制剂以阻断从rep-cap前体蛋白生成成熟的rep和cap。其它治疗方案采用了抗病毒化合物的组合,其目标是抑制或减弱病毒酶。然而,据估计每约104次复制HIV基因中就会出现一次自发突变(Perelson等人,Science,271,1582-86(1996))。由于这种病毒一般每天会进行约1010次复制,因此对直接作用于病毒蛋白的活性剂产生抗药性是经常发生的。此外,许多治疗方案需要患者遵守非常严格的服药安排,每天要服用大量药丸。患者不能遵守这样的服用方案增加了抗病毒治疗的失败比例。由于存在这些问题,需要能够减弱HIV疾病和其它免疫机能障碍的病程的新方法、化合物、和组合物。
每年有成千上万的人被诊断出患有癌症和其它新生物疾病,并且虽然在癌症治疗方面已经取得了一些进展,但是现有的治疗手段在很多情况下不能获得成功。例如,施用给患者的许多抗癌药物经常对患者体内的非癌细胞具有毒害作用。此外,其生长可被一些药物抑制的许多新生物细胞有时会对这些药物产生抗药性。当然,反应性肿瘤仅代表着各种类型新生物疾病的一小部分,并且对实体瘤例如卵巢癌、乳腺癌、肺癌等有高度活性的药物相当少。因此,患有多种类型恶性肿瘤的患者仍然有复发和死亡的高度危险性。因此一直需要能抑制新生物生长、尤其是实体瘤生长的活性剂。
发明概述
本发明提供了治疗与免疫机能障碍相关的疾病的方法、化合物、和组合物。依据本发明方法,将包括至少一种5-烷基-间苯二酚衍生物化合物的可药用组合物在足以减弱免疫系统机能障碍的条件下施用给患者,其中所述5-烷基-间苯二酚衍生物化合物选自5-烷基间苯二酚类、大麻酚衍生物、大麻二酚衍生物、大麻萜酚(cannabigerol)衍生物、和它们的组合。本发明还提供了可用于本发明方法中的抗病毒大麻酚衍生物。本发明还提供了烷基化的间苯二酚衍生物,和使用所述烷基化的间苯二酚衍生物来减弱新生物生长的方法。本发明方法和化合物可用于治疗免疫系统疾病,例如HIV疾病和新生物疾病。通过下述详细描述可清晰地理解本发明的这些和其它优点以及另外的本发明特征。
发明详述
一方面,本发明提供了治疗与免疫机能障碍相关的疾病的方法。依据该方法,将包括至少一种选自5-烷基间苯二酚衍生物、大麻酚衍生物、大麻二酚衍生物、大麻萜酚衍生物、和它们的组合的化合物的可药用组合物在足以减弱免疫系统机能障碍的条件下施用给患者。
本发明方法能特别有效地治疗人中的HIV疾病、非人灵长目动物中的SIV疾病、或猫科动物中的FIV。虽然不想受任何特定理论的束缚,但是据信本发明方法可能通过多种补充机制促进活性和潜伏感染的T-细胞、单核细胞、和巨噬细胞的静止。这些作用的组合可减弱HIV在宿主免疫系统中复制的能力。在缺乏复制的情况下,免疫系统的未感染组分能更好地将潜伏感染的细胞从患者体内清除出去,并且会发生更少的突变事件。此外,通过减弱HIV复制,本发明方法可降低人与人之间传播(例如围生期和性传播)的概率。的确,其中将组合物施用到粘膜组织(例如阴道或直肠组织)上的本发明方法可妨碍病毒经由这样的组织的摄入,从而降低了初次感染的发生率。因此,本发明提供了预防HIV传播的方法。此外,本发明方法可防止HIV感染所经常伴随的继发病症,例如淋巴结构破坏、CNS病、机会疾病、新生物、以及AIDS消耗综合征。
HIV疾病的治疗可通过监测其对持续施用本发明方法的反应的症状的减弱来进行评价。例如,大多数健康成人的CD4+T-细胞计数为约800-约1200,而如上所速HIV+患者的该计数稳定下降。因此,本发明方法能增加HIV+患者中CD4+T-细胞数目(一般通过分析CD4+/CD8+比例来测定)或者减轻CD4+T-细胞数目的减少。例如,通过定期测定,可在依据本发明方法进行治疗之前和之后测定患者CD4+T-细胞减少的速度。有利地施用本发明方法至少能减缓下降速度,并优选增加CD4+细胞数目的实际增加。类似地,本发明方法可降低患者内病毒负荷(即循环HIV的效价)或减弱其增加。对治疗的有利反应还可通过测定白细胞粘着、淋巴细胞运输、和单核细胞/巨噬细胞移动性(即趋化性测定)来监测。
在一个实施方案中,在可药用组合物中的至少一种化合物可以是5-烷基间苯二酚衍生物。这样的化合物可有利地用于本发明方法,因为它们通常表现出低毒性(参见例如U.S.专利5,859,067)。实例性5-烷基间苯二酚类可具有下述结构式:
式I
其中
R1是:
a)H,
b)C1-4烷基或其酯,
c)COOH,
d)OH,
e)O-C1-5烷基或链烷酰基,所述基团可任选被一或二甲基氨基或乙基氨基取代,
f)含有羧基或氨基的0-CO-C3-10烷基,
g)
其中n=1-8
h)对氨基苄基或C1-7氨基烷基或其有机或无机酸加成盐,对氨基苄基或氨基烷基的异氰酸酯或异硫氰酸酯衍生物,具有1-7个另外的碳原子的氨基烷基的羧基末端衍生物或其盐,该羧基末端衍生物的活化衍生物;或者
i)R1和R2构成式-O(CH2)3-5所示取代基,其中R1和R2与它们所键合的碳原子一起构成一个环,在所述环上至少有一个氢原子可任选被卤素取代,
R2是:
a)H、OH或卤素
b)C1-5羧基或烷氧基,或者
c)R1和R2构成式-O(CH2)3-5所示取代基,其中R1和R2与它们所键合的碳原子一起构成一个环,在所述环上至少有一个氢原子可任选被卤素取代,
R3是
a)(W)m-Y-(Z)n,其中
W是C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,
Y是一条键、O、S、SO、SO2、CO、NH、N(C1-6烷基)、或NCS,
Z是:
i)C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,任选被末端芳环取代,
ii)CN1-3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,或者
iii)苯基或苄基,其中所述基团可任选被卤素、C1-6烷基、C1-6烷氧基、C1-6烷硫基、CN、CF3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,并且其中
m和n相同或不同,并分别为0或1,
b)C5-12烷基或卤代烷基,所述基团可任选被末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,或者
c)C5-12链烯基或链炔基,所述基团可任选被卤素、二硫杂环戊烯(ditholene)、末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同;
R4是:
a)H,
b)OH,
c)C1-6烷氧基或羧基
R5是H或OH;且
R6是
a)H或OH;
b)C1-4烷基、链烯基、链炔基、或其混合物,
c)O-C1-4烷基、链烯基、链炔基、或其混合物,或
d)pryenyl、香叶烯基(gerenyl)、或法呢基,所述基团任选在任意位置被一个或多个卤素取代,
e)(W)m-Y-(Z)n,其中
W是C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,
Y是一条键、O、S、SO、SO2、CO、NH、N(C1-6烷基)、或NCS,
Z是:
i)C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,任选被末端芳环取代,
ii)CN1-3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,或者
iii)苯基或苄基,其中所述基团可任选被卤素、C1-6烷基、C1-6烷氧基、C1-6烷硫基、CN、CF3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,并且其中
m和n相同或不同,并分别为0或1,
f)C5-12烷基或卤代烷基,所述基团可任选被末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,或者
g)C5-12链烯基或链炔基,所述基团可任选被卤素、二硫杂环戊烯、末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同。
式I化合物优选包括OH或OCH3作为R1取代基。在R2优选的取代基为氢、羟基、或甲氧基。当包括式I化合物时,R5优选为甲基或乙基。更优选的式I化合物在R1、R5具有羟基取代基,在R6具有甲基取代基;甚至更优选的是,该化合物在R2有第三个羟基取代基。在R3优选的取代基在本文别处讨论过;然而,本发明提供了式I化合物,其中R3是:
a)(W)m-Y-(Z)n,其中
W是C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,
Y是一条键、O、S、SO、SO2、CO、NH、N(C1-6烷基)、或NCS,
Z是:
i)C5-12烷基、键烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,任选被末端芳环取代,
ii)CN1-3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,或者
iii)苯基或苄基,其中所述基团可任选被卤素、C1-6烷基、C1-6烷氧基、C1-6烷硫基、CN、CF3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,
其中W和Z当中至少有一个包括支链,并且其中m和n相同或不同,并分别为0或1,
b)末端呈支链的C5-12烷基或卤代烷基,所述基团可任选被末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,或者
c)束端呈支链的C5-12链烯基或链炔基,所述基团可任选被卤素、二硫杂环戊烯、末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同。许多这样的化合物表现出了抗肿瘤活性,并且如本文所述可以就这样使用。虽然本发明方法的组合物可包括任意这样的化合物,但是一些优选的化合物如下所示:
式Ib
式1c
式1f
如上所述,式I化合物可在R6具有香叶烯基取代基。在这方面,在本发明可药用组合物中的至少一种化合物可以是下式所示大麻萜酚或其衍生物:
式II
其中
R1是:
a)H,
b)C1-4烷基或其酯,
c)COOH,
d)OH,
e)O-C1-5烷基或链烷酰基,所述基团可任选被一或二甲基氨基或乙基氨基取代,
f)含有羧基或氨基的O-CO-C3-10烷基,
g)
其中n=1-8
h)对氨基苄基或C1-7氨基烷基或其有机或无机酸加成盐,对氨基苄基或氨基烷基的异氰酸酯或异硫氰酸酯衍生物,具有1-7个另外的碳原子的氨基烷基的羧基末端衍生物或其盐,该羧基末端衍生物的活化衍生物;或者
i)R1和R2构成式-O(CH2)3-5所示取代基,其中R1和R2与它们所键合的碳原子一起构成一个环,在所述环上至少有一个氢原于可任选被卤素取代,
R2是:
a)H、OH或卤素
b)C1-6羧基或烷氧基,或者
c)R1和R2构成式-O(CH2)3-5所示取代基,其中R1和R2与它们所键合的碳原子一起构成一个环,在所述环上至少有一个氢原子可任选被卤素取代,
R3是:
a)(W)m-Y-(Z)n,其中
W是C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,
Y是一条键、O、S、SO、SO2、CO、NH、N(C1-6烷基)、或NCS,
Z是:
i)C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,任选被末端芳环取代,
ii)CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,或者
iii)苯基或苄基,其中所述基团可任选被卤素、C1-6烷基、C1-6烷氧基、C1-6烷硫基、CN、CF3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,并且其中
m和n相同或不同,并分别为0或1,
b)C5-12烷基或卤代烷基,所述基团可任选被末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,
c)C5-12链烯基或链炔基,所述基团可任选被卤素、二硫杂环戊烯、末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同;
R5是
a)H
b)C1-4烷基
c)COOH
d)OH,或
e)O-C1-6烷基(醚)或链烷酰基,所述基团可任选被至少一个一或二甲基氨基或乙基氨基取代,
R6是:
a)氢,
b)C1-6烷氧基、C1-6烷硫基、C1-6烷基(优选乙基)、或C1-6卤代烷基,
c)CN,
d)CO2H,
e)CO2-C1-4烷基,
f)C(Y)(Z)-OH,
g)C(Y)(Z)-O-C1-4烷基,或
h)C1-6烷基-CO2-Y,
其中Y和Z分别独立地为H或C1-6烷基,
R7是:
a)羟基(优选β-羟基)或内酯,
b)卤素,
c)C1-6烷氧基、C1-6烷硫基、C1-6烷基、或C1-6卤代烷基,
d)CN,
e)N3,
f)CO2H,
g)CO2-C1-4烷基,
h)C(Y)(Z)-OH,
i)C(Y)(Z)-O-C1-4烷基,
j)C1-6烷基-CO2-Y,或
k)=O或=S,
其中Y和Z分别独立地为H或C1-6烷基,并且其中R7可以在2-5任意位置上。
式I和II化合物可用已知方法由市售原料合成得到(参见例如Dominianni等人,J.Org.Chem.,42,344-46(1977);Baek等人,Arch.Pharm.Res.,19,228-30(1996);Guthrie等人,J.Org.Chem.47,2369-76(1982))。例如,在酸催化下将2,6-二甲氧基苯酚与OH-R3缩合可生成4-烷基苯酚中间体。将酚基转化成二乙基磷酸酯,然后在液氨中用锂金属还原,可生成二甲氧基苯衍生物。之后将该化合物进行一或二脱甲基化(例如用三溴化硼)可分别生成所需的甲氧基苯酚和/或间苯二酚(式I)。在R6有烷基取代基的式I化合物可通过下述方法制得:例如,首先将二甲氧基苯衍生物在R6锂化(lithiation)(例如在Bu/THF存在下),然后暴露于烷化剂(例如甲基或乙基碘化物或硫酸酯)。之后将该化合物进行一或二脱甲基化(例如用三溴化硼)可分别生成所需的在R6有烷基取代基的甲氧基苯酚和/或间苯二酚(式I)。式II化合物可通过例如在酸催化下将在R3具有所需取代基的甲氧基苯酚和/或间苯二酚(式I)与香叶醇缩合(例如在BF3、Et2O、二氧化硅、和CH2Cl2存在下)而制得。当然,这些化合物可通过其它适当方法(有许多是本领域已知的)合成获得。
在另一实施方案中,在本发明可药用组合物中的至少一种化合物是下式所示大麻酚衍生物:
式III
其中
R1是:
a)H,
b)C1-4烷基或其酯,
c)COOH,
d)OH,
e)O-C1-5烷基(醚)或链烷酰基,所述基团可任选被一或二甲基氨基或乙基氨基取代,
f)含有羧基或氨基的O-CO-C3-10烷基,
g)
其中n=1-8,或
h)对氨基苄基或C1-7氨基烷基或其有机或无机酸加成盐,对氨基苄基或氨基烷基的异氰酸酯或异硫氰酸酯衍生物,具有1-7个另外的碳原子的氨基烷基的羧基末端衍生物或其盐,该羧基末端衍生物的活化衍生物;
i)R1和R2构成式-O(CH2)3-5所示取代基,其中R1和R2与它们所键合的碳原子一起构成一个环,在所述环上至少有一个氢原子可任选被卤素取代,
R2是:
a)H、OH或卤素
b)C1-6羧基或烷氧基(优选甲氧基),或者
c)R1和R2构成式-O(CH2)3-5-所示取代基,其中R1和R2与它们所键合的碳原子一起构成一个环,在所述环上至少有一个氢原子可任选被卤素取代,
R3是:
a)(W)m-Y-(Z)n,其中
W是C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,
Y是一条键、O、S、SO、SO2、CO、NH、N(C1-6烷基)、或NCS,
Z是:
i)C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,任选被末端芳环取代,
ii)CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2,其中在酰胺氯原子上的每一C1-4烷基可相同或不同,或者
iii)苯基或苄基,其中所述基团可任选被卤素、C1-6烷基、C1-6烷氧基、C1-6烷硫基、CN、CF3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,并且其中
m和n相同或不同,并分别为0或1,
b)C5-12烷基或卤代烷基,所述基团可任选被末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,或者
c)C5-12链烯基或链炔基,所述基团可任选被卤素、二硫杂环戊烯、末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同;
R6与R6′一起形成=O或=S,或者分别独立地选自:
a)氢,
b)C1-6烷氧基、C1-6烷硫基、C1-6烷基、或C1-6卤代烷基,
c)CN,
d)CO2H,
e)CO2-C1-4烷基,
f)C(Y)(Z)-OH,
g)C(Y)(Z)-O-C1-4烷基,和
h)C1-6烷基-CO2-Y,
其中Y和Z分别独立地为H或C1-6烷基,
R7是:
a)羟基或内酯,
b)卤素,
c)C1-6烷氧基、C1-6烷硫基、C1-6烷基、或C1-6卤代烷基,
d)CN,
e)N3,
f)CO2H,
g)CO2-C1-4烷基,
h)C(Y)(Z)-OH,
i)C(Y)(Z)-O-C1-4烷基,
j)C1-6烷基-CO2-Y,或
k)=O或=S,
其中Y和Z分别独立地为H或C1-6烷基;
Q是:
a)O或S,或
b)N-W,其中W是:
i)氢,
ii)C1-6烷氧基烷基、C1-6烷基、或C1-6卤代烷基
iii)OC1-6烷基、或OC1-6卤代烷基,
iv)CN,
v)C1-6烷基,
vi)C(Y)(Z)C1-4烷基,或
vii)C1-6烷基-CO2-Z,
其中Y和Z分别独立地为H或C1-6烷基。
在本领域已知有一些式III化合物有精神活性,这主要是通过兴奋CB1受体而起作用。在一些应用中,在式III内可以优选采用能优先促进CB2激动剂活性而不是CB1活性的取代基(例如R1-R7、Q、和环C),更优选采用能促进选择性CB2激动剂活性的取代基。在一些实施方案中,为了减轻或消除某些大麻酯(cannabinaoid)的精神活性作用,本发明方法采用选择性CB2激动剂,这样的选择性CB2激动剂优先作用于CB2受体而不是CB1受体。最优选的是,选择性CB2激动剂在其激活CB2受体的浓度下不结合CB1受体。各种选择性CB2激动剂在本领域内是已知的。这样的化合物的实例包括典型和非典型大麻酯、二环大麻酯、氨基烷基吲哚、和类花生酸类物质(eicosanoid)(参见例如Pertwee,Pharmacol.Ther.,74(2),129-80(1997)).为了评价给定化合物是否是选择性CB2激动剂,可使用任意合适的方法评价其对CB2和CB1受体的相对亲和力,例如使用细胞工程来表达受体(Ross等人,Br.J.Pharmacol.,126,665-72(1999)).这样的值一般是以结合常数Ki表示,由Ki可计算出Ki-CB1/Ki-CB2比值。理想情况是,选择性CB2激动剂对于CB2受体的Ki为约100nM-约0.1nM,优选为约25nM-约0.2nM,例如为约15nM-约0.5nM。此外,Ki-CH1/Ki-CB2比值至少为约1.5、更优选为至少约5(例如至少约10)。已知许多化合物具有合适的CB2选择性,适于在本发明方法中用作CB2激动剂。例如,JWH-015具有13.8±4.6nM的Ki-cB2,和27.5的Ki-CB1/Ki-CB2比值;WIN-55,212-2具有.028±0.16nM的Ki-cB2,和6.75的K1-CB1/Ki-CB2比值;5-FΔB-THO具有8.7±3.5nM的Ki-cB2,和6.55的Ki-CB1/Ki-CB2比值;JWH-018具有2.94±2.65nM的Ki-cB2,和3.23的Ki-CB1/Ki-CB2比值;CP-56,667具有23.6±6.5nM的Ki-cB2,和2.61的Ki-CB1/Ki-CB2比值;L759666具有11.8±2.5nM的Ki-cB2,和414.24的Ki-CB1/Ki-CB2比值;L759633具有6.4±2.2nM的Ki-cB2,和162.97的Ki-CB1/Ki-CB2比值(参见上述参考文献)。本领域普通技术人员知道如何测定尚未测定的(或新的)化合物的这些值。除了优先结合CB2受体以外,优选的选择性CB2激动剂表现出比CB1反应强的CB2-定向生理反应。用于差别活性的标准分析测定化合物在细胞工程中抑制药物诱导的环AMP(cAMP)生成的能力,以表达各自的受体,一般是以EC50(最大作用的百分比)表示(Ross等人,Br.J.Pharmacol.,126,665-72(1999))。优选地,选择性CB2激动剂一般表现出大于约10、更通常大于约100(例如大于约500)的EC50-CB2/EC50-CB1比例。已知许多化合物具有合适的CB2选择性,并因此可在本发明方法中用作CB2激动剂。例如,L759656的EC60-CB2/EC50-CB1比例>3000;L759633的EC50-CB2/EC50-CB1比例>1000。本领域普通技术人员知道如何测定尚未测定的(或新的)化合物的这些值。
对于CB2选择性,式III中的R1优选不是OH,OH存在于天然大麻酚和四氢大麻酚化合物中。式III中的R1优选为H、O-C1-4烷基(更优选为甲氧基)或琥珀酸、丙二酸的半酯或丙氨酸的丙氨酸酯及其盐。在另一优选的实施方案中,R1和R2一起构成式-O(CH2)3-5-所示取代基,其中R1和R2与它们所键合的碳原子一起构成一个环,所述环上至少有一个氢原子可任选被卤素取代(例如0,2桥亚丙基(propano)环)。此外,式III中的R2是卤素、优选为碘。R6和R6′优选一起形成=O或者分别是甲基、乙基、或甲氧基。
虽然R7可以在环C的7-10位的任意位置上,但是其优选在该环的9位上。当希望提高CB2选择性时,R7优选为负电性的(例如COOH、卤素、β-羟基、或内酯),并且为了提高活性,其可以被内酯或β-羟基取代。
式III中的环C可以是任一下述环(虚线代表在Δ6a-10a、Δ8-9、或Δ9-10位置的双键):
然而,为了提高CB2选择性,该环优选为芳香环。在这方面,本发明的优选实施方案提供了新的式III抗病毒大麻酚衍生物,其中环C是芳香环。在这样的化合物中,R7优选是负电性的,更优选在C9上。此外,R1优选不是OH,并优选为去氧、酯、或醚。大麻酚衍生物化合物的实例包括:
许多式III化合物是众所周知的,并且其它式III化合物可依据公开的方法制得(参见,例如,国际专利申请WO99/20268(Burstein),和美国专利2,509,386(Adams)、3,799,946(Loev)、3,856,821(Loev)、3,897,306(Vidic等人)、4,064,009(Fukada等人)、4,087,545(Archer等人)、4,142,139(Bindra)、4,309,545(Johnson)、4,599,327(Ngrádi等人)、4,833,073(McNally等人)、4,876,276(Mechoulan等人)、4,973,603(Burstein)、5,338,753(Burstein等人)、5,389,375(ElSohly)、5,440,052(Makriyannis等人)、5,605,906(Lau)、和5,635,530(Mechoulam等人);和Charalambous等人,Pharm.Biochem.Behav.,40,509-12(191),Gareau等人,Bioorg.Med.Chem.Lett.,6(2),189-94(1996),Griffin等人,Br.J.Pharmacol.,126,1575-84(1999),Huffman等人,Bioorg.Med.Chem.Lett.,6,2281-88(1998),Lemberger等人,Clin.Pharmacol.Ther.,18(6),720-26(1975),Loev等人,J.Med.Chem.,16(11),1200-06 9(1973),Loev等人,J.Med.Chem.,17(11),1234-35(1974),Martin等人,Pharm.Biochem.Behav.,46,295-301(1993),Papahatjis等人,J.Med.Chem.,41(7),1195-1200(1998),Pars等人,J.Med.Chem.,19(4),445-53(1976),Pertwee等人.Pharmacol.Ther.,74(2),129-80(1997),Razdan等人,J.Med.Chem.,19(4),454-60(1976),Razdan.Pharmacol.Reviews,38(2)75-149(1980),Reggio等人,J.Med.Chem.,40(20),3312-18(1997),Reggio等人,LifeSci.,56(23/24),2025-32(1995),(Ross等人,Br.J.Pharmacol.,126,665-72(1999),Thomas等人,J.Pharm.Exp.Ther.,285(1),285-92(1998),Wiley等人,J.Pharm.Exp.Ther.,285(1),995-1004(1998),Winn等人,J.Med.Chem.,19(4),461-71(1976),和Xie等人,J.Med.Chem.,41,167-74(1998)).
在其中式III的环C是芳香环的优选实施方案中,这样的化合物还可以通过用已知方法将适当的四氢大麻酚(THC)衍生物分子芳构化而制得(参见,例如,Adams等人,J.Am.Chem.Soc.,62,23401(1940);Ghosh等人,J.Chem.Soc.,1393(1940);和Adams等人,J.Am.Chem.Soc.,70,664(1948)).例如,可通过将这样的化合物与硫在约238-240℃于氮气氛下加热约4小时来使其芳构化(Rhee等人,J.Med.Chem.,40(20),3228-33(1997))。其它合适的方法包括使用催化剂(例如披钯炭)或化学脱氢剂(例如2,3-二氯-5,6-二氰基醌)进行的芳构化(参见,例如美国专利3,799,946(Loev))。
如上所述,在本发明方法的一些应用中,特别是其中组合物中的至少一种化合物是大麻酚衍生物的本发明方法应用中,希望减轻某些这样的化合物所可能具有的有害精神活性。作为在组合物中使用非精神活性大麻酚衍生物(例如选择性CB2激动剂)之外的另一选择,可使用除了能减轻精神活性作用的治疗剂以外的其它药理活性剂。例如,因为某些上述化合物可能对CB1受体施加一些活性,所以经常希望给患者辅助施用选择性CB1拮抗剂。的确,在某些应用中,希望联合施用小剂量的非选择性CB2激动剂(例如Δ8-或Δ9-THC及其衍生物),在这些情况下,施用CB1拮抗剂是优选的。许多合适的选择性CB1拮抗剂是本领域已知的(Rinaldi-Carmona等人,FEBS Lett.,350,240-44(1994),还参见美国专利5,624,941(Barth等人)、5,747,524(Cullinan等人)、5,925,768(Barth等人))。SR-1241716A是特别有效力的,因此是可用于本发明方法的优选选择性CB1拮抗剂。其它优选的选择性CB1拮抗剂是大麻二酚及其衍生物(参见,例如美国专利2,304,669(Adams):Razdan等人,Pharmacol.Reviews,38(2),75-149(1986);Reggio等人,Life Sci.,56(23-24),2025-32(1995)),它们能有效地拮抗CB1受体。除了拮抗CB1以外,大麻二酚和许多其衍生物还能有利地减弱肝脏中的细胞色素P450系统,从而提高了组合物中其它化合物的生物利用度(例如Bornheim等人,Chem.Res.Toxicol.,11,1209-16(1998))。因此,在本发明方法的-些实施方案中,可药用组合物中的至少一种化合物是下式所示大麻二酚或其衍生物:
式IV
其中
R1是:
a)H,
b)C1-4烷基或其酯,
c)COOH,
d)OH,
e)O-C1-5烷基(优选甲氧基)或链烷酰基,所述基团可任选被一或二甲基氨基或乙基氨基取代,
f)含有羧基或氨基的O-CO-C3-10烷基,
g)
其中n=1-8,或
h)对氨基苄基或C1-7氨基烷基或其有机或无机酸加成盐,对氨基苄基或氨基烷基的异氰酸酯或异硫氰酸酯衍生物,具有1-7个另外的碳原子的氨基烷基的羧基末端衍生物或其盐,该羧基末端衍生物的活化衍生物;
i)R1和R2构成式-O(CH2)3-5所示取代基,其中R1和R2与它们所键合的碳原子一起构成一个环,在所述环上至少有一个氢原子可任选被卤素取代,
R2是:
a)H、OH或卤素
b)C1-6羧基或烷氧基,或者
c)R1和R2构成式-O(CH2)3-5所示取代基,其中R1和R2与它们所键合的碳原子一起构成一个环,在所述环上至少有一个氢原子可任选被卤素取代,
R3是
a)(W)m-Y-(Z)n,其中
W是C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,
Y是一条键、O、S、SO、SO2、CO、NH、N(C1-6烷基)、或NCS,Z是:
i)C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,任选被末端芳环取代,
ii)CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,或者
iii)苯基或苄基,其中所述基团可任选被卤素、C1-6烷基、C1-6烷氧基、C1-6烷硫基、CN、CF3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,并且其中
m和n相同或不同,并分别为0或1,
b)C6-12烷基或卤代烷基,所述基团可任选被末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,
c)C6-12链烯基或链炔基,所述基团可任选被卤素、二硫杂环戊烯、末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同;
R5是
a)H
b)C1-4烷基
c)COOH
d)OH,或
e)O-C1-5烷基(醚)或链烷酰基,所述基团可任选被至少一个一或二甲基氨基或乙基氨基取代,
R6是:
a)氢,
b)C1-6烷氧基、C1-6烷硫基、C1-6烷基、或C1-6卤代烷基,
c)CN,
d)CO2H,
e)CO2-C1-4烷基,
f)C(Y)(Z)-OH,
g)C(Y)(Z)-O-C1-4烷基,或
h)C1-6烷基-CO2-Y,
其中Y和Z分别独立地为H或C1-6烷基,
R7是:
a)羟基或内酯,
b)卤素,
c)C1-6烷氧基、C1-6烷硫基、C1-6烷基、C1-6羧基或C1-6卤代烷基,
d)CN,
e)N3,
f)CO2H,
g)CO2-C1-4烷基,
h)C(Y)(Z)-OH,
i)C(Y)(Z)-O-C1-4烷基,
j)C1-6烷基-CO2-Y,或
k)=O或=S,
其中Y和Z分别独立地为H或C1-6烷基,并且其中R7可以在环C的1、2、5、或6位的任何位置上。
除了具有所指出的取代基以外,在任意式I-IV中的R3优选为:
其中W1是H、甲基、或乙基,W2和W3分别独立地为H或甲基,其中W1、W2和W3当中至少有一个不是H和/或被卤代,并且W4是C1-4烷基或卤代烷基,所述基团可任选被芳环取代。R3优选为含有至少一个双键(更优选在C4-C10位置)的支链C6-12烷基,并且该链优选具有奇数数目的碳原子。R3更优选是末端呈支链的或含有末端双键,并且本发明提供了具有这样的取代基的式I-IV化合物。更优选地,R3优选为二甲基庚基(DMH)(例如1′,1′DMH或1’R,2’S DMH)、二甲基己基、或二甲基戊基。例如,R3可以是二-、三-或四甲基戊基、-己基、或-庚基等链(例如1,1,5-三甲基己基、1,1,5,5-四甲基己基、或1,1,5-三甲基-庚-4-烯基)。在一些实例中,R3取代基可具有庞大的末端部分,例如甲基、二甲基、(CH2)1-6-CON(CH3)2、或具有卤代末端碳原子(优选溴)的C6-12卤代烷基。
在本发明上下文中,卤代烷烃、烯烃、和炔烃可具有任意数目的卤素取代基。在优选的实施方案中,卤代烷烃、烯烃、或炔烃在末端碳原子上具有至少一个卤素原子(例如CX1-3,其中X是卤素)。烷基(乙基烯烃和炔烃)可以是直链或支链。此外,化合物可以作为单一的立体异构体或立体异构体混合物(例如外消旋混合物)、或单一的几何异构体(例如E、Z、顺式或反式)或几何异构体混合物存在,所有这些形式的化合物都在本发明范围内。
在实施本发明方法时,可将组合物以适于产生所需疗效的任意量给患者施用任意长的时间,本领域技术人员能够确定可接受的给药方案。例如,当使用本发明方法来治疗HIV疾病时,可通过分析随着剂量增加循环病毒颗粒(病毒负荷)数目和/或CD4+细胞计数来确定最适剂量。如果不通过透皮或缓释制剂连续给药,组合物一般给患者每天给药1-约6次。然而,在某些应用中,以更低的频率施用组合物是适当的。每次剂量一般为约2mg/m3-约1000mg/m3,更优选为约0.01mg/kg/天,约1mg/kg/天,例如约10ng/kg/天-约10mg/kg/天,并且可最高达约100mg/kg/天(例如约250mg/kg/天)。如本文所述,当组合物与其它治疗剂联合使用时,尤其是当细胞色素P450系统被减弱(例如通过大麻二酚衍生物减弱)时,可将这些剂量减少一些。此外,当使用选择性CB1拮抗剂时,其可以以与本发明组合物相同的剂量或组成或者在不同制剂或给药方案中使用。在一些应用中,优选在施用本发明组合物之前(例如至少1-4天前)开始施用选择性CB1拮抗剂,以进一步降低任何残余的CB1受体激活,并防止组合物中的化合物降解。当然,因为在治疗期间某些患者可能对组合物中的一种或多种化合物产生耐受,所以可酌情调节剂量和/或给药方案。此外,当患者对治疗有良好反应和/或注意到任何毒性副作用时,可减少剂量和给药。
由于具有其多种作用,可使用本发明方法来治疗除HIV疾病以外的许多与免疫机能障碍相关的疾病或障碍。例如,本发明方法可治疗自身免疫性疾病(例如系统性红斑狼疮、桥本甲状腺炎、重症肌无力、类风湿性关节炎、多发性硬化、急性热病性多神经炎、肾小球性肾炎等)。本发明方法还可用于治疗引起或取决于炎性病症的疾病(例如局限性回肠炎、溃疡性结肠炎、各种形式的哮喘),并且其能特别有效地治疗多种新生物疾病、微生物(例如分支杆菌、真菌)感染、或病毒感染,尤其是HSV、EB病毒、巨细胞病毒属、HIV、和乙型及丙型肝炎病毒感染。本发明方法还可用于治疗异常的免疫反应、异常的疤痕形成(例如手术粘连或疤痕疙瘩)、同种移植物排斥、动脉粥样硬化和相关心脏病。当然,患者可以是任意种类的动物(例如猴子、猫、狗、马、牛、猪、山羊、和绵羊等)。
当然,当使用本发明方法来治疗与免疫机能障碍相关的疾病时,也可辅助使用其它适当治疗剂。例如,本发明方法可包括辅助施用抗肿瘤剂、抗癌剂、抗生素、抗真菌剂、抗病毒剂(特别是抗逆转录病毒化合物)、抗蠕虫、和杀寄生虫化合物。适于在本发明方法中辅助使用的抗病毒剂的实例包括阿巴卡韦(abacavir)、叠氮胸苷昔多福韦(azidothymidine cidofovir)、甲磺酸地拉夫定(delavirdinemesylate)、去羟肌苷、双脱氧胞苷、依法韦蓝次(efavirenz)、磷卡萘替(foscarnet)、更昔洛韦(ganciclovir)、硫酸印地那韦(indinavir)、拉米夫定、甲磺酸那非那韦(nelfinavir)、奈韦拉平、利托那韦(ritanavir)、沙奎那韦、甲磺酸沙奎那韦、斯塔夫定(stavudine)、扎西他滨等。在治疗肿瘤或新生物生长时,合适的辅助化合物可包括蒽环类抗生素(例如多柔比星、柔红霉素、carinomycin、N-乙酰基阿霉素、佐柔比星、5-亚氨基柔红霉素、和N-乙酰基柔红霉素、以及表柔比星)和植物生物碱(例如长春新碱、长春碱、依托泊苷、椭圆玫瑰树碱和喜树碱)、紫杉醇和docetaxol、米托坦、顺铂、苯芥胆固醇等。适于在本发明中辅助使用的抗炎治疗剂包括甾体和非甾体抗炎化合物(例如强的松、甲泼尼龙、对氟米松、11-fludrocortisol或氟可的松、去炎松、倍他米松和地塞米松、布洛芬、吡罗昔康、倍氯米松;甲氨蝶呤、阿扎立平、苯壬四烯酯、地蒽酚、psoralins);水杨酸酯(例如阿司匹林;和免疫抑制剂例如山地明)。适于在本发明方法中辅助使用的其它药理活性剂包括麻醉剂(例如甲氧氟烷、异氟烷、恩氟烷、三氟溴氯乙烷、和苯佐卡因);抗溃疡剂(例如西咪替丁);抗癫痫药物(例如巴比妥类药物;硫唑嘌呤(一种免疫抑制和抗风湿剂);和肌肉松弛剂(例如丹曲林和地西泮)。此外,本发明方法可以与特定抗体治疗或甾体化合物治疗联合使用来治疗自身免疫性疾病。可以与本发明组合物联合辅助使用的其它药理活性剂包括具有抗微生物或抗炎活性的天然大麻的其它成分(例如大麻萜酚及其衍生物、大麻色素及其衍生物、大麻酚酸及其衍生物、大麻二酚酸及其衍生物、萜类化合物、黄烷醇(例如大麻黄素)等)。
本发明组合物可包含生物活性剂,例如淋巴因子或细胞因子、抗炎剂、抗菌剂、抗病毒剂、抗真菌剂、抗寄生虫剂、抗代谢剂、抗炎剂、血管活性剂、抗肿瘤剂、支气管作用剂、局麻剂、免疫调节剂、酶、激素、生长促进和再生剂、以及神经递质、和细胞受体蛋白和配体等许多其它活性剂。其他生物活性剂的实例有镇痛剂(例如对乙酰氨基酚、阿尼利定、阿司匹林、丁丙诺啡、布他比妥、布托啡诺、水杨酸胆碱、可待因、地佐辛、双氯芬酸、二氟尼柳、二氢可待因、依降钙素、依托度酸、非诺洛芬、氢可酮、氢吗啡酮、布洛芬、酮洛芬、酮咯酸、左吗啡、水杨酸镁、甲氯灭酸盐、甲氯芬那酸、度冷丁、美沙酮、左美丙嗪、吗啡、纳布啡、萘普生、阿片、氧可酮、氧吗啡酮、喷他佐辛、苯巴比妥、丙氧芬、双水杨酯、水杨酸钠、曲马朵、和除上述镇痛剂之外的麻醉类镇痛剂)。也可以使用抗焦虑剂,包括阿普唑仑、溴西泮、丁螺环酮、利眠宁、氯美扎酮、氯氮翁、地西泮、哈拉西泮、羟嗪、酮唑卓、劳拉西泮、眠尔通、奥沙西泮、和普拉西泮等。其它生物活性剂包括与抗精神抑郁有关的抗焦虑剂例如利眠宁、阿米替林、洛沙平、马普替林、和奋乃静等。其它活性组分的例子包括抗炎剂例如非风湿性阿司匹林、水杨酸胆碱、双氯芬酸、二氟尼柳、依托度酸、非诺洛芬、夫洛非宁、氟比洛芬、布洛芬、消炎痛、酮洛芬、lidomide、水杨酸镁、甲氯灭酸盐、甲氯芬那酸、萘丁美酮、萘普生、噁丙嗪、保泰松、吡罗昔康、双水杨酯、水杨酸钠、舒林酸、滕诺息卡、噻洛芬酸、沙利度胺、linomide、和托美丁,以及用于眼睛治疗的抗炎剂(例如双氯芬酸、氟比洛芬、消炎痛、酮咯酸、和双甲丙酰龙(一般用于手术后治疗))、和用于非感染鼻应用的抗炎剂(例如倍氯米松、布地奈德、地塞米松、氟尼缩松、去炎松等);催眠剂(抗失眠/睡眠诱导剂),例如用于治疗失眠症的治疗剂,包括阿普唑仑、溴西泮、地西泮、苯海拉明、多西拉敏、艾司唑仑、氟西泮、哈拉西泮、凯他唑仑、劳拉西泮、硝西泮、普拉西泮、四氟硫安定、羟基安定、三唑仑、唑吡坦和sopiclone等;镇静剂,包括苯海拉明、羟嗪、左美丙嗪、异丙嗪、普鲁泊福、褪黑激素、三甲泼拉嗪等;用于治疗小发作癫痫和震颤等其它病症的镇静剂,例如盐酸阿米替林;利眠宁、异戊巴比妥;速可眠、阿波巴比妥、仲丁比妥、乙氯维诺、格鲁米特、L-色氨酸、甲苯比妥、美索比妥钠盐、盐酸咪达唑仑、奥沙西泮、戊巴比妥钠、苯巴比妥、司可巴比妥钠盐、硫戊巴比妥等。其它活性化合物可包括用于治疗头部创伤(脑损伤/局部缺血)的治疗剂例如盐酸依那朵林(例如用于治疗几种头部损伤),细胞保护剂,和用于治疗绝经、绝经症状(治疗)的治疗剂例如麦角胺、颠茄生物碱和苯巴比妥,用于治疗绝经血管舒缩症状的治疗剂例如可乐定、结合型雌激素和甲羟孕酮、雌二醇、环戊丙酸雌二醇、戊酸雌二醇、雌激素、结合型雌激素、酯化雌酮、硫酸雌酮哌嗪、和乙炔基雌二醇。用于治疗经前期综合征(PMS)的治疗剂的实例有孕酮、孕激素、促性腺释放激素、口服避孕药、达那唑、luprolide acetate、维生素B6;用于治疗情感/精神病治疗的治疗剂,例如三环类抗抑郁剂包括盐酸阿米替林(Elavil)、盐酸阿米替林、奋乃静(Triavil)和盐酸多塞平(Sinequan)。镇定药、抗抑郁剂和抗焦虑剂的实例有地西泮(Valium)、劳拉西泮(Ativan)、阿普唑仑(Xanax)、SSRI’s(选择性血清素再摄取抑制剂)、盐酸氟西汀(Prozac)、盐酸舍曲林(Zoloft)、盐酸帕罗西丁(Paxil)、马来酸氟伏沙明(Luvox)、盐酸文拉法新(Effexor)、血清素、血清素激动剂(芬氟拉明);抗生素(例如氟喹诺酮和四环素);抗组胺药;分解代谢甾体化合物;和血管活性剂(例如B阻断剂和己酮可可碱(Trental))。其它化合物包括大麻酯例如CT-3和HU-210。
如上所述,为了在本发明方法中使用,要将化合物掺入到包括合适载体、并任选含有其它非活性或活性组分的可药用组合物中。这样的组合物适于通过多种常用给药途径施用,例如颊、舌下、皮肤、眼内、耳内、肺、经皮、淋巴内、肿瘤内、腔内、鼻内、皮下、植入、吸入、真皮内、直肠、阴道、透粘膜、肌内、静脉内和关节内途径等。根据所需的施用方式,组合物可包含辅料、胆汁盐、生物可降解聚合物和共聚物、缓冲剂、螫合剂、着色剂、稀释剂、润肤剂、乳化剂、酶抑制剂、水凝胶、亲水剂、脂蛋白和其它脂肪酸衍生物、脂质体和其它微团、微孔膜、粘膜粘着剂、中性和疏水性聚合物及共聚物、微粒系统、香料、成盐酸和碱、半透膜、单一或多肠溶包衣、溶剂(例如醇、二甲亚砜(DMSO)等)、表面活性剂、病毒包膜蛋白或其它组分。
在一种其形式中,本发明组合物可以是包含液体或固体颗粒的气雾剂的吸入制剂,例如本领城已知的吸入制剂。通过吸入施用本发明组合物可治疗炎症带来的支气管病症(例如感冒(鼻病毒)、流感、囊性纤维变性等)。这样的制剂还可包含其它物质例如防腐剂、抗氧化剂、矫味剂、挥发油、缓冲剂、分散剂、表面活性剂等本领域已知物质。这样的制剂还可以以单位形式或容许其重复使用的形式用吸入剂或者在吸入剂中提供。
本发明组合物还可以是局部施用制剂(例如膏剂、霜剂、洗剂、糊剂、凝胶剂、喷雾剂、气雾油等),其中载体是适于局部施用活性剂的稀释剂,例如凡士林、羊毛脂、聚乙二醇、醇等,所述载体可任选包含透皮增强剂。在局部制剂中,载体可以呈适于配霜剂、凝胶剂、膏剂、喷雾剂、气雾剂、贴剂、溶液剂、悬浮剂和乳剂的形式。
还可以将本发明组合物配制成口服给药制剂,例如配制成胶囊、扁囊剂、锭剂、片剂、粉剂、粒剂、溶液、悬浮剂、乳剂、挥发油(特别是大麻种子油)等。这样的制剂一般包括水或非水液体溶液和悬浮液(例如水包油或油包水乳液)。通常将这样的口服制剂包在肠溶包衣中。口服制剂的实例有颊或舌下制剂,包括还可以含有矫味剂和其它已知组分的锭剂,或还可以含有情性基质的软锭剂,所述基质含有例如明胶、甘油、蔗糖、阿拉伯胶、和其它组分以及本领域技术人员已知的填充剂。
本发明组合物还可以是非胃肠道施用制剂,例如可注射溶液和悬浮液。这样的制剂一般还包含物质例如抗氧化剂、缓冲剂、抗菌剂、其它抗病毒剂例如直接作用的复制抑制剂、和使得溶液或悬浮液与接受者的血液等渗的溶质。这样的溶液或悬浮液一般是无菌水或非水可注射溶液或悬浮液,并且还可以包含悬浮剂和增稠剂。这样的制剂一般在密封的安瓿或小瓶中提供。
本发明组合物还可以是缓释制剂,当给药或施用给受治疗者时,这样的制剂能够在预定时间内释放所需量的化合物。或者,本发明组合物可以是经皮制剂,其中的载体适于促进经皮递送活性剂。实例有水和醇溶液、DMSO、油溶液和悬浮液、和水包油或油包水乳液。经皮制剂还可以是离子电渗经皮制剂,其中载体一般可以是水和/或醇溶液、油溶液或悬浮液、和水包油或油包水乳液。这样的制剂还可包含经皮传送促进剂,并且可以以具有经皮递送装置、优选离子电渗递送装置的药盒形式提供,离子电渗递送装置的许多变型是本领域已知的。
本发明组合物的其它制剂包括但不限于可植入的胶囊或药筒(例如用于组织植入)、贴剂、植入物、或栓剂(例如用于直肠或透粘膜给药)。
本发明组合物一般可在给药盒中分发给医师或患者,并且本发明提供了这样的免疫调节药盒。这样的药盒在分隔的容器中包含给药装置(例如注射器和针、吸入器、丸剂、栓剂、透皮给药装置等)和多个单位剂量的上述组合物。在一些药盒中,可预先配制组合物。其它药盒包括用于配制组合物的分隔组分。药盒还可以包含载体或稀释剂、包装箱、说明如何配制组合物(如果适用的话)和使用适当给药装置的说明书。
如上所述,式I化合物具有抗肿瘤或细胞毒害活性,并且本发明提供了抑制新生物(例如新生物细胞或肿瘤)生长的方法,包含在足以抑制新生物生长的条件下将这样的化合物递送到新生物中。不想受任何特定理论的束缚,5-烷基间苯二酚类可引起DNA分裂,从而可能在新生物细胞内诱导细胞程序死亡。对于此,优选在足以增强细胞程序死亡的条件下将烷基化间苯二酚衍生物递送到新生物中。诱导细胞程序死亡所需的准确剂量方案取决于所用化合物的种类、以及是否还使用另外的化合物。对于该方法,可联合使用至少一种其它抗肿瘤剂(例如上述治疗剂)来辅助给药。
在许多应用中,本发明方法可在体内(例如患者内)使用,例如在肿瘤或血恶液质内使用。在一些这样的体内应用中,烷基化间苯二酚衍生物可通过将其引入到体循环中,例如经由胃、肠、口服、或直肠壁途径或经由静脉内注射引入到体循环中来递送到新生物上。在其中新生物是或者包含肿瘤其它应用中,可通过肿瘤内注射递送烷基化间苯二酚衍生物。在某些情况下,这样的给药方式可提高化合物的可能局部浓度。对于这样的体内应用,可视情况而定将化合物配制到本文所述可药用组合物内。
可使用本发明方法来治疗肿瘤生长,所述肿瘤生长优选不需要消除肿瘤或减小肿瘤质量。在这方面,可使用本发明方法来减弱肿瘤生长。这样的作用可例如使得耐药性新生物细胞更易于受其它抗肿瘤剂的影响,并且该方法可以辅助使用其它这样的化合物,许多这样的化合物是本领域已知的(例如阿地白介素、六甲蜜胺、阿米斯丁、天冬酰胺酶、硫唑嘌呤、比卡鲁胺、比卡鲁胺、博莱霉素、白消安、capecitabine、卡铂、卡莫司汀、苯丁酸氮芥、顺铂注射、克拉立平、环磷酰胺、山地明、阿糖孢苷、阿糖孢苷脂质体注射、达卡巴嗪、更生霉素、柔红霉素、denileukin diftitox、右丙亚胺、docetaxel、阿霉素、盐酸阿霉素、雌莫司汀磷酸钠、依托泊苷、磷酸依托泊苷、氟尿苷培门冬酶、磷酸氟达拉滨、氟他胺、盐酸吉西他滨、性瑞林、盐酸谷尼色创、羟基脲、盐酸去甲氧柔红霉素、异环磷酰胺、干扰素α-2a、重组干扰素α-2b、盐酸伊立替康、甲酰四氢叶酸、醋酸亮丙瑞林、左旋咪唑、罗氮芥、L-PAM、L-苯丙氨酸氮芥、氮芥、美法仑、巯基嘌呤、甲氨蝶呤、丝裂霉素、米托坦、盐酸米托蒽醌、尼鲁米特、尼鲁米特、善得定、盐酸奥丹西隆、紫杉醇、氨羟二磷酸二钠、喷司他丁、苯丙氨酸氮芥、普卡霉素、具有卡莫司汀植入物的聚苯丙生20、卟吩姆钠、盐酸丙卡巴肼、rituximab、骨髓生长因子、链脲霉素2-去氧-2-[[(甲基亚硝基氨基)、柠檬酸他莫昔芬、替尼泊苷、睾内酯、硫鸟嘌呤、注射用噻替派、盐酸托泊替堪、柠檬酸托米芬、trastuzumab、维甲酸、葡萄糖醛酸曲美沙特、valrubicin、硫酸长春碱、硫酸长春新碱、酒石酸维诺利宾等)。此外,甚至当肿瘤继续生长时,这样的减弱可用于减缓疾病的进程,并给其它治疗争取了更多时间。实际上,联合治疗使得可使用更小或更大剂量的其它抗肿瘤剂治疗更短或更长时间,由此可能有助于提高疗效和降低副作用。
实施例
虽然本领域技术人员在阅读了上述详细说明后能够充分实施本发明,但是下述实施例能有助于阐明一些本发明特征。当然,因为这些实施例仅是为了举例说明目的,所以它们不是用于以限制方式解释本发明范围,而是将上述本发明说明作为整体进行的扩充。
实施例1
该实施例证明了式I化合物的合成。
将2,6-二甲氧基苯酚(73.4g,0.48mol)、2,6-二甲基-2-庚醇(69.0g,0.48mol)和甲磺酸(95mL)的混合物在50℃搅拌3小时,然后在室温搅拌过夜。在搅拌下将该混合物倒入冰水(600mL)中。用二氯甲烷(2×200mL)萃取该混合物。将该萃取液用水、饱和碳酸氢钠水溶液、饱和氯化钠水溶液洗涤,用无水硫酸钠干燥。将该溶液减压浓缩,获得了产物,为油状物(130g,96%)。该物质的分析(MS(FAB)m/z 281(MH)+;1H NMR(CDCl3)δ0.80(d,6H),1.0-1.1(m,4H),1.27(s,6H),1.40-1.60(m,3H),3.89(s,6H),5.36(s,1H),6.54(s,2H))显示了其是4-(1,1,5-三甲基己基)-2,6-二甲氧基苯酚:
实施例2
该实施例证明了式I化合物的合成。
将得自实施例1的4-(1,1,5-三甲基己基)-2,6-二甲氧基苯酚粗产物(130g,0.46mol)在无水CCl4(100mL)中的溶液在冰浴中冷却,并加入亚磷酸二乙酯(70mL,0.54mol)。向该搅拌混合物中以维持反应混合物的温度低于10℃的速度滴加三乙胺(75mL,0.54mol)。将该反应混合物在冰浴中搅拌2小时,并在室温搅拌过夜。然后将该混合物用二氯甲烷(200mL)稀释,用水、4N氢氧化钠水溶液(100mL)、1N盐酸水溶液(125mL)、水和饱和氯化钠水溶液洗涤。将提取液用无水硫酸钠干燥,并减压浓缩。通过二氧化硅柱色谱法纯化粗产物,用环己烷∶EtOAc(7∶1-3∶1梯度)洗脱,获得了103g(54%)产物,为无色蜡状油。该物质的分析(MS(FAB)m/z 417(MH)+。1HNMR(CDCl3)δ0.81(d,6H),1.0-1.1(m,4H),1.26(s,6H),1.35-1.6(m,9H),3.86(s,6H),4.25-4.38(m,4H),6.53(s,2H))显示其为4-(1,1,5-三甲基己基)-2,6-二甲氧基苯基二乙基磷酸酯:
实施例3
该实施例证明了式I化合物的合成。
将得自实施例2的4-(1,1,5-三甲基己基)-2,6-二甲氧基苯基二乙基磷酸酯(82g,0.197mol)在Et2O(175mL)和THF(35mL)中的溶液缓慢地加到包含在装配有机械搅拌器、温度计、干冰冷凝器和压力平衡式加液漏斗的三颈烧瓶内的液氨(450mL)中,同时以维持蓝色的速度加入新切割的锂丝小片(2.8g,0.40g-原子)。将该反应混合物再搅拌1小时,然后通过加入饱和NH4Cl水溶液(22mL)来中止反应。加入乙醚(220mL),将氨蒸发过夜。用水(220mL)处理该残余物。分离各层,将乙醚层用4N NaOH(200mL)、水(2×200mL)和饱和氯化钠水溶液洗涤。将有机萃取液干燥(MgSO4)并减压浓缩。通过二氧化硅柱色谱法纯化粗产物,用环己烷∶EtOAc(95∶5)洗脱,获得了43g(83%)产物,为无色油状物。该物质的分析(MS(FAB)m/z 265(MH)+;1H NMR(CDCl3)δ0.80(d,6H),1.00-1.10(m,4H),1.26(s,6H),1.4-1.6(m,3H),3.79(s,6H),6.30(m,1H),6.49(m,2H))显示其为4-(1,1,5-三甲基己基)-2,6-二甲氧基苯:
实施例4
该实施例证明了式I化合物的合成。
将得自实施例3的4-(1,1,5-三甲基己基)-2,6-二甲氧基苯(10g,0.038mol)在无水二氯甲烷(100mL)中的溶液在冰浴中冷却,然后用1小时向其中滴加三溴化硼的二氯甲烷溶液(100mL 1M溶液,0.10mol)进行处理。将该混合物在冰浴中搅拌2小时,然后在室温搅拌过夜。将该反应混合物在冰浴中冷却,并小心地用水(100mL)处理。将所得混合物用二氯甲烷(100mL)稀释,并用半饱和碳酸氢钠水溶液处理。分离各层,将有机层减压浓缩至一半体积,并用2N氢氧化钠水溶液(2×75mL)萃取。将该碱性水萃取液冷却,并用1N盐酸水溶液酸化至pH3.0.用Et2O(2×100mL)萃取该酸化的混合物。将乙醚层用饱和氯化钠水溶液洗涤,用无水硫酸镁干燥,并减压浓缩。通过二氧化硅柱色谱法纯化所得粗产物,用环己烷∶EtOAc(8∶1-4∶1梯度)洗脱,获得了8.0g(90%)产物,为无色固体结晶。该物质的分析(Mp 95-96℃。MS(FAB)m/z 237(MH)+;1H NMR(CDCl3)δ0.80(d,6H),1.00-1.10(m,4H),1.23(s,6H),1.40-1.58(m,3H),4.65(s,2H),6.17(m,1H),6.38(m,2H))显示其为4-(1,1,5-三甲基己基)间苯二酚:
实施例5
该实施例证明了式I化合物的合成。
将得自实施例4的4-(1,1,5-三甲基己基)间苯二酚(2g,0.0076mol)在无水二氯甲烷(10mL)中的溶液在冰浴中冷却,并滴加三溴化硼在二氯甲烷中的溶液(2.6mL 1M溶液,0.0026mol)。将该混合物在冷却浴中搅拌2小时,然后在室温搅拌过夜。将该混合物在冰浴中冷却,并用水(10mL)小心地处理,然后用碳酸氢钠水溶液(5mL)处理。分离出有机层,用硫酸镁干燥,并减压浓缩。通过二氧化硅柱色谱法纯化所得残余物,用环己烷∶EtOAc(8∶1-4∶1梯度)洗脱,获得了0.364g(19%)产物,为无色油状物。该物质的分析(MS(FAB)m/z251(MH)+;1H NMR(CDCl3)δ0.80(d,6H),1.00-1.10(m,4H),1.24(s,6H),1.4-1.6(m,3H),3.78(s,3H),4.67(s,1H),6.23(m,1H),6.40(m,1H),6.47(m,1H))显示其为3-甲氧基-5-(1,1,5-三甲基己基)苯酚:
实施例6
该实施例证实了几种本发明化合物的抗病毒活性。
化合物:在SDMSA中制备具有不同浓度的表1所列化合物,并趁新鲜使用。
潜伏感染的细胞:将5×103U1细胞(得自AIDS Research andReference Reagent Program,Bethesda,MD)铺在具有培养基的96-孔板中,所述培养基具有或不具有5ng/ml TNFα和测试化合物。培养3-6天后,评定上清液和细胞。
PBMC分离和冲击处理:将得自健康HIV-和肝炎-阴性患者的外周血液单核细胞(PBMC)洗涤以除去残余的梯度分离物质。然后计数洗涤的细胞,并评价其存活力。该初始制备后,将细胞以1×106个细胞/ml的浓度悬浮在补充有下述物质的RPMI 1640培养基中:15%灭活的胎牛血清、2nM L-谷氨酰胺、100U/ml青霉素、100μg/ml链霉素、和10μg/ml庆大霉素、以及2μg/ml PHA。培养(37℃,5%CO2)2-3天后,通过离心收集细胞,洗涤,并重悬在补充有重组IL-2的相同培养基中。然后维持该培养物直至使用,每3天用新鲜的含IL-12培养基替换1/2体积。
PBMC测定:在准备使用时,将得自最少2个供体并已经用PHA和IL-1冲击处理的PBMCs混合、计数、并通过台盼蓝排除法测定其存活力。然后将细胞以1×106个细胞/ml的浓度重悬在补充有下述物质的RPMI 1640中:15%胎牛血清(热灭活)、2mM L-谷氨酰胺、100U/ml青霉素、100μg/ml链霉素、10μg/ml庆大霉素和IL-2(20U/ml)。然后将50μl细胞分配到96孔平板的内部60个孔中。每个平板包含细胞对照孔(只有细胞)、病毒对照孔(细胞加病毒)、药物毒性对照孔(细胞加测试化合物)、药物比色对照孔(只有药物)以及实验孔(药物加细胞加病毒)。向该微升平板中加入稀释的化合物,然后加入适当预滴定的HIV-1株。用姊妹平板以一式三份的方式分析所有样本以测定化合物毒性。每个孔的终体积为200μl。将分析物在37℃、5%CO2条件下培养7天,然后收集上清液以分析RT活性,和姊妹平板以评定细胞存活力。
单核细胞分离和培养:通过Ficoll海帕克纯化(任选使用重组IFNγ)从健康的HIV-和肝炎-阴性供体中获得外周血液单核细胞(PBM)。7天后,将培养物洗涤以除去未粘着的细胞,加入测试化合物,然后加入HIV-1。感染24小时后,通过除去培养基对培养物进行最后一次洗涤,加入新鲜的测试化合物,将培养物继续培养7天。然后通过用市售ELISA分析试剂表达上清液p24抗原来测定病毒复制。在每一测定中平行使用AZT作为阳性对照。
测定存活力的XTT染色法:通过2,3-二(2-甲氧基-4-硝基-5-磺基苯基)-5-[(苯基氨基)羰基]2H-四唑鎓氢氧化物(XXT)的还原来评定毒性不存在。将含有1mg/ml XTT和0.06μg/ml吩嗪甲硫酸盐(PMS)的50μl溶液加到各孔中,然后将平板在37℃培养4小时。使用粘性平板密封层代替盖子以使密封的平板可以反转数次来将可溶性反应产物混合。培养后,在450nm通过分光光度法读取平板以评定产物的还原程度。
分析p24:通过标准ELISA评定病毒蛋白生成(p24)。
逆转录酶测定:在不含细胞的上清液中测定逆转录酶。将滴定的TTP以5 Ci/ml的浓度重悬在蒸馏水中。制备聚rA和低聚dT作为贮备液,并保持在-20℃。制备新鲜的RT反应缓冲液(125μl 1M EGTA,125μl dH2O,110μl 10%SDS,50μl 1M Tris(pH 7.4),50μl1M DTT,和40MI 1M MgCl2)。然后将这三种溶液以2份TTP、1份聚rA:低聚dT、和1份缓冲液的比例混合在一起。将10μl该反应混合物置于圆底微升平板中,加入15μl含病毒的上清液。将该平板在具有固体载体的水浴中培养60分钟。反应后,将体积点到DE81纸片上,在5%磷酸钠缓冲液中洗涤5次、每次5分钟,在蒸馏水中洗涤2次、每次1分钟,在70%乙醇中洗涤2次、每次1分钟,然后干燥。然后向各样本中加入Opti-Fluor O,并使用闪烁计数器定量测定掺入的放射性。
数据分析;对于每一测定,计算IC50(即50%病毒复制抑制)、TC50(50%细胞毒性)、和选择性指数(SI=IC50/TC50)。所有测试化合物的汇集数据列在表1中。这些结果表明,11-去甲-Δ9-四氢大麻二酚-9-甲酸、大麻二酚、和olivitol、5-(1,1,5-三甲基己基)间苯二酚、和5-(1,1,5-三甲基己基)-2,6-二甲氧基苯酚表现出适度抗病毒活性。olivitol的抗病毒活性在PBMCs和TNFα诱导的U1细胞中比在单核细胞/巨噬细胞或未诱导的U1细胞中更显著。特别要提及大麻酯,这些结果令人惊奇,因为已知的观察表明某些这样的化合物可提高而不是抑制HIV复制(参见,例如Noe等人,Drug of Abuse,Immunomodulation and AIDS的第25章,Friedman等人,Ed.,(Plenum Press,NY 1998))。
实施例7
该实施例证实了式I化合物的抗肿瘤活性。
细胞系:将表2所示细胞系于无菌条件下在具有10%胎牛血清、2mM L-谷氨酰胺、和碳酸氢钠的RPMI 1640或DMEM(“完全培养基”)中繁殖,并在37℃、5%CO2和95%湿度条件下培养。每周将各细胞系传代培养1或2次,并周期性地筛选支原体污染(用抗生素将阳性培养物治疗3代时间)。仅使用不含支原体的培养物来进行抗肿瘤评定。
抗肿瘤评定:收集各细胞系的细胞,使成团以除去培养基,然后重悬在新鲜的完全培养基中。确定细胞数目,并用碘化丙锭染色以测定存活力。用完全培养基将细胞调节至密度为5×103个细胞/ml。用100μl各细胞系样本给组织培养板接种,并将这些平板培养过夜以进行细胞固定和适应。
适应后,将表2所列化合物在完全培养基中稀释。使用8种浓度来处理细胞培养物。对于每一稀释物,分别用100μl给药溶液处理8个孔。每个培养物平板包含细胞对照(8个孔,用完全培养基处理的模拟品)、培养基对照(具有培养基用于减去由培养基条件产生的信号的7个孔)、溶剂对照(8个孔)、和空气空白(1个孔)以校准平板读数计。还用作为细胞毒性阳性对照的单剂量的多柔比星(1μM,8个孔)处理每一细胞系。一旦给药完成,即将细胞在37℃、5%CO2和95%湿度条件下培养。
处理5天后,使用SRB测定法分析细胞的抗肿瘤作用,以计算每一处理的IC50。所得结果如表2所示。这些结果表明,5-(2,6-二甲基-2-庚基)间苯二酚在6个细胞系中表现出77-95μM的IC50,这表明这样的化合物具有抗肿瘤作用。
作为参考文献并入
在该文献任何地方或任何附图中提及或引用的所有来源(例如发明人的证书、专利申请、专利、印刷的出版物、博物馆登记入册或记录、实用新型、世界范围内的网页等)、序列表、或与其并行提交的声明书引入本发明并通过其参考作为本说明书的一部分。
解释指导
前述说明是作为一个整体的本发明完整说明,而不仅仅是其方面的任何特定部分。说明书描述了本发明的“优选实施方案”,包括本发明人所知道的实施其的最佳方式。当然,通过阅读前述说明,这些优选实施方案的变型对于本领城普通技术人员来说是显而易见的。本发明人希望本领城技术人员视情况而定使用这样的变型,并且本发明人打算用除本文具体描述的方式以外的方式实施本发明。因此,本发明包括如通过适用的法律容许的在所附权利要求书中列出的主题的所有变型和同等物。
除非另有说明,否则在前述说明书和下述权利要求书中使用的单数指示(例如“一个”)包括复数。列出一定范围的不连续值是为了用缩写方式独立地指出在该范围内的各个单独值,并且将各单独值就像其单独列出那样引入到说明书中。至于特别是权利要求书,术语“基本上由...组成”是指,除了特定列出的组分或步骤以外,还可以使用不在实质上上影响本发明基本和新颖特征的未列出的组分或步骤。相反,术语“包含”或“具有”是表示,除了所列出的组分或步骤以外,还可以存在任意组分或步骤。术语“由...组成”是指仅存在所列出的组分或步骤,但是不排除这些组分或步骤的同等物可以替代所具体列出的组分或步骤这种可能性。
表1
单核细胞/巨噬细胞评定
用HIV-1(p24) PBMC HIV-1(RT) TNF诱导的U1细胞(RT)
化合物 IC50 TC50 TI IC50 TC50 TI IC50 TC50 TI
0.0021 >4 >1904
0.001 >4 >4000 0.0056 >4 7142 - - -
AZT(μM) 0.0061 >4 655.7 0.0034 >4 1176
0.099 >10 >101.0
DdC(μM) 0.0028 >10 >3,571 0.0876 >10 114 - - -
大麻酚(μg/ml) 7.7 13.07 1.7 6.91 7.66 1.11 5.14 5.26 1.0
大麻二酚(μg/ml) 8.18 22.87 2.8 1.52 7.76 5.11 2.76 7.8 2.8
11-去甲-Δ9-四氢大麻二酚-9-甲酸
(μg/ml) 7.79 76.73 9.8 39.09 71.1 1.82 6.69 23.71 3.55
Δ8四氢大麻酚(μg/ml) >0.1 >0.1 NA 0.08 >0.1 >1.25 0.06 >0.1 >1.667
Δ9tetrahydrocannabinaol(μg/ml) >0.1 >0.1 NA 0.07 >0.1 1.43 0.06 0.088 1.47
EtOH(%) 0.06 >.1 >1.67 >0.1 >0.1 NA >0.1 >0.1 NA
Olivitol(μM) 63.7 75.9 1.19 16.9 >100 5.9 22.5 77.5 3.45
间苯二酚(μM) NA NA NA >200 >200 - NA NA NA
Orcinol(μM) NA NA NA >200 >200 - NA NA NA
5-(1,1,5-三甲基己基)间苯二酚
(μM) NA NA NA 14.8 44.6 3 NA NA NA
5-(1,1,5-三甲基己基)-2,6-二甲氧基
苯酚(μM) NA NA NA 15.8 50.9 3.2 NA NA NA
5-(1,1,5-三甲基己基)-2,6-二甲氧基苯
(μM) NA NA NA >200 >200 - NA NA NA
3-甲氧基-5-(1,1,5-三甲基己基)苯酚
(μM) NA NA NA 39.9 46.4 12 NA NA NA
表2
Claims (59)
1.治疗与免疫机能障碍相关的疾病或病症的方法,该方法包含将含有至少一种选自5-烷基间苯二酚类、大麻酚类、大麻二酚类、大麻萜酚类、和它们的组合的化合物的可药用组合物施用给患有与免疫机能障碍相关的疾病或病症的患者。
2.权利要求1的方法,其中至少一种化合物是下式所示5-烷基间苯二酚衍生物:
其中
R1是:
a)H,
b)C1-4烷基或其酯,
c)COOH,
d)OH,
e)O-C1-5烷基或链烷酰基,所述基团可任选被一或二甲基氨基或乙基氨基取代,
f)含有羧基或氨基的O-CO-C3-10烷基,
g)
其中n=1至8
h)对氨基苄基或C1-7氨基烷基或其有机或无机酸加成盐,对氨基苄基或氨基烷基的异氰酸酯或异硫氰酸酯衍生物,具有1-7个另外的碳原子的氨基烷基的羧基末端衍生物或其盐,该羧基末端衍生物的活化衍生物;或者
i)R1和R2构成式-O(CH2)3-5所示取代基,其中R1和R2与它们所键合的碳原子一起构成一个环,在所述环上至少有一个氢原子可任选被卤素取代,
R2是:
a)H、OH或卤素
b)C1-6羧基或烷氧基,或者
c)R1和R2构成式-O(CH2)3-5所示取代基,其中R1和R2与它们所键合的碳原子一起构成一个环,在所述环上至少有一个氢原子可任选被卤素取代,
R3是
a)(W)m-Y-(Z)n,其中
W是C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,
Y是一个键、O、S、SO、SO2、CO、NH、N(C1-6烷基)、或NCS,
Z是:
i)C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,任选被末端芳环取代,
ii)CN1-3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1- 4烷基)2,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,或者iii)苯基或苄基,其中所述基团可任选被卤素、C1-6烷基、C1-6烷氧基、C1-8烷硫基、CN、CF3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,并且其中
m和n相同或不同,并分别为0或1,
b)C5-12烷基或卤代烷基,所述基团可任选被末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,或者
c)C5-12链烯基或链炔基,所述基团可任选被卤素、二硫杂环戊烯(ditholene)、末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同;
R4是:
a)H,
b)OH,
c)C1-6烷氧基或羧基
R5是H或OH;且
R6是
a)H或OH;
b)C1-4烷基、链烯基、链炔基、或其混合物,
c)O-C1-4烷基、链烯基、链炔基、或其混合物,或
d)pryenyl、香叶烯基(gerenyl)、或法呢基,所述基团任选在任意位置被一个或多个卤素取代,
e)(W)m-Y-(Z)n,其中
W是C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,
Y是一条键、O、S、SO、SO2、CO、NH、N(C1-6烷基)、或NCS,
Z是:
i)C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,任选被末端芳环取代,
ii)CN1-3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1- 4烷基)2,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,或者iii)苯基或苄基,其中所述基团可任选被卤素、C1-6烷基、C1-6烷氧基、C1-6烷硫基、CN、CF3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,并且其中
m和n相同或不同,并分别为0或1,
f)C5-12烷基或卤代烷基,所述基团可任选被末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,或者
g)C5-12链烯基或链炔基,所述基团可任选被卤素、二硫杂环戊烯、末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同。
3.权利要求2的方法,其中R1是OH或OCH3。
4.权利要求2的方法,其中R2是H或OH。
5.权利要求2的方法,其中R3是含有至少一个双键的支链C5-12烷基。
6.权利要求5的方法,其中R3是1,1,5-三甲基己基、1,1,5,5-四甲基己基、或1,1,5-三甲基-庚-4-烯基。
7.权利要求2的方法,其中R6是甲基或乙基。
8.权利要求1的方法,其中至少一种化合物是下式所示大麻酚或其衍生物:
其中
R1是:
a)H,
b)C1-4烷基或其酯,
c)COOH,
d)OH,
e)甲氧基或O-C1-5烷基或链烷酰基,所述基团可任选被一或二甲基氨基或乙基氨基取代,
f)含有羧基或氨基的O-CO-C3-10烷基,
g)
其中n=1-8,或
h)对氨基苄基或C1-7氨基烷基或其有机或无机酸加成盐,对氨基苄基或氨基烷基的异氰酸酯或异硫氰酸酯衍生物,具有1-7个另外的碳原子的氨基烷基的羧基末端衍生物或其盐,该羧基末端衍生物的活化衍生物;
i)R1和R2构成式-O(CH2)3-5所示取代基,其中R1和R2与它们所键合的碳原子一起构成一个环,在所述环上至少有一个氢原子可任选被卤素取代,
R2是:
a)H、OH或卤素
b)C1-6羧基或烷氧基,或者
c)R1和R2构成式-O(CH2)3-5所示取代基,其中R1和R2与它们所键合的碳原子一起构成一个环,在所述环上至少有一个氢原子可任选被卤素取代,
R3是:
a)(W)m-Y-(Z)n,其中
W是C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,
Y是一条键、O、S、SO、SO2、CO、NH、N(C1-6烷基)、或NCS,Z是:
i)C5-12烷基、链烯基、链炔基、或卤代烷基,所述基团可任选被末端芳环取代,
ii)CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1 -4烷基)2,其中在酰胺氢原子上的每一C1-4烷基可相同或不同,或者
iii)苯基或苄基,其中所述基团可任选被卤素、C1-6烷基、C1-6烷氧基、C1-6烷硫基、CN、CF3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,并且其中
m和n相同或不同,并分别为0或1,
b)C5-12烷基或卤代烷基,所述基团可任选被末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,或者
c)C5-12链烯基或链炔基,所述基团可任选被卤素、二硫杂环戊烯、末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同;
R6与R6’一起形成=O或=S,或者分别独立地选自:
a)氢,
b)C1-6烷氧基、C1-6烷硫基、C1-6烷基、或C1-6卤代烷基,
c)CN,
d)CO2H,
e)CO2-C1-4烷基,
f)C(Y)(Z)-OH,
g)C(Y)(Z)-O-C1-4烷基,和
h)C1-6烷基-CO2-Y,
其中Y和Z分别独立地为H或C1-6烷基,
R7是:
a)羟基或内酯,
b)卤素,
c)C1-6烷氧基、C1-6烷硫基、C1-6烷基、或C1-6卤代烷基,
d)CN,
e)N3,
f)CO2H,
g)CO2-C1-4烷基,
h)C(Y)(Z)-OH,
i)C(Y)(Z)-O-C1-4烷基,
j)C1-6烷基-CO2-Y,或
k)=O或=S,
其中Y和Z分别独立地为H或C1-6烷基;
Q是:
a)O或S,或
b)N-W,其中W是:
i)氢,
ii)C1-6烷氧基烷基、C1-6烷基、或C1-6卤代烷基
iii)OC1-6烷基、或OC1-6卤代烷基,
iv)CN,
v)C1-6烷基,
vi)C(Y)(Z)C1-4烷基,或
vii)C1-6烷基-CO2-Z,
其中Y和Z分别独立地为H或C1-6烷基;且
C是:
其中虚线代表在Δ6、Δ8、或Δ9位置的双键。
9.权利要求8的方法,其中R1和R2形成O,2桥亚丙基环。
10.权利要求8的方法,其中R1是H或OH。
11.权利要求8的方法,其中R1是甲氧基。
12.权利要求8的方法,其中R2是碘。
13.权利要求8的方法,其中R3是二甲基庚基(DMH)、二甲基戊基(DMP)、或具有卤代或庞大的末端基团。
14.权利要求13的方法,其中R3是1,1,5-三甲基己基、1,1,5,5-四甲基己基、或1,1,5-三甲基-庚-4-烯基。
15.权利要求8的方法,其中R3是-(CH2)1-6-CON(CH3)2。
16.权利要求8的方法,其中R3包含卤代烷基。
17.权利要求8的方法,其中R6和R6′一起形成=O或分别是甲基、乙基、或甲氧基。
18.权利要求8的方法,其中R7在所述C环的9位上。
19.权利要求8的方法,其中R7是COOH、卤素、β-羟基、或内酯。
20.权利要求1的方法,其中至少一种化合物是下式所示大麻二酚或其衍生物:
其中
R1是:
a)H,
b)C1-4烷基或其酯,
c)COOH,
d)OH,
e)甲氧基或O-C1-5烷基或链烷酰基,所述基团可任选被一或二甲基氨基或乙基氨基取代,
f)含有羧基或氨基的O-CO-C3-10烷基,
g)
其中n=1-8,或
h)对氨基苄基或C1-7氨基烷基或其有机或无机酸加成盐,对氨基苄基或氨基烷基的异氰酸酯或并硫氰酸酯衍生物,具有1-7个另外的碳原子的氨基烷基的羧基末端衍生物或其盐,该羧基末端衍生物的活化衍生物;
i)R1和R2构成式-O(CH2)3-5所示取代基,其中R1和R2与它们所键合的碳原子一起构成一个环,在所述环上至少有一个氢原子可任选被卤素取代,
R2是:
a)H、OH或卤素
b)C1-6羧基或烷氧基,或者
c)R1和R2构成式-O(CH2)3-5所示取代基,其中R1和R2与它们所键合的碳原子一起构成一个环,在所述环上至少有一个氢原子可任选被卤素取代,
R3是
a)(W)m-Y-(Z)n,其中
W是C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,
Y是一条键、O、S、SO、SO2、CO、NH、N(C1-6烷基)、或NCS,
Z是:
i)C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,任选被末端芳环取代,
ii)CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1 -4烷基)2,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,或者
iii)苯基或苄基,其中所述基团可任选被卤素、C1-6烷基、C1-6烷氧基、C1-6烷硫基、CN、CF3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,并且其中
m和n相同或不同,并分别为0或1,
b)C5-12烷基或卤代烷基,所述基团可任选被末端芳环、CN1-3、NCS,CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,
c)C6-12链烯基或链炔基,所述基团可任选被卤素、二硫杂环戊烯、末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同;
R5是
a)H
b)C1-4烷基
c)COOH
d)OH,或
e)O-C1-6烷基或链烷酰基,所述基团可任选被至少一个一或二甲基氨基或乙基氨基取代,
R6是:
a)氢,
b)C1-6烷氧基、C1-6烷硫基、C1-6烷基、或C1-6卤代烷基,
c)CN,
d)CO2H,
e)CO2-C1-4烷基,
f)C(Y)(Z)-OH,
g)C(Y)(Z)-O-C1-4烷基,或
h)C1-6烷基-CO2-Y,
其中Y和Z分别独立地为H或C1-6烷基,
R7是:
a)羟基或内酯,
b)卤素,
c)C1-6烷氧基、C1-6烷硫基、C1-6烷基、C1-6羧基或C1-6卤代烷基,
d)CN,
e)N3,
f)CO2H,
g)CO2-C1-4烷基,
h)C(Y)(Z)-OH,
i)C(Y)(Z)-O-C1-4烷基,
j)C1-6烷基-CO2-Y,或
k)=O或=S,
其中Y和Z分别独立地为H或C1-6烷基,并且其中R7可以在环C的1、2、5、或6位的任何位置上。
21.权利要求1的方法,其中至少一种化合物是下式所示大麻萜酚或其衍生物:
其中
R1是:
a)H,
b)C1-4烷基或其酯,
c)COOH,
d)OH,
e)甲氧基或O-C1-5烷基或链烷酰基,所述基团可任选被一或二甲基氨基或乙基氨基取代,
f)含有羧基或氨基的O-CO-C3-10烷基,
g)
其中n=1-8
h)对氨基苄基或C1-7氨基烷基或其有机或无机酸加成盐,对氨基苄基或氨基烷基的异氰酸酯或异硫氰酸酯衍生物,具有1-7个另外的碳原子的氨基烷基的羧基末端衍生物或其盐,该羧基末端衍生物的活化衍生物;或者
i)R1和R2构成式-O(CH2)3-5所示取代基,其中R1和R2与它们所键合的碳原子一起构成一个环,在所述环上至少有一个氢原子可任选被卤素取代,
R2是:
a)H、OH或卤素
b)C1-6羧基或烷氧基,或者
c)R1和R2构成式-O(CH2)3-5所示取代基,其中R1和R2与它们所键合的碳原子一起构成一个环,在所述环上至少有一个氢原子可任选被卤素取代,
R3是:
a)(W)m-Y-(Z)n,其中
W是C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,
Y是一条键、O、S、SO、SO2、CO、NH、N(C1-6烷基)、或NCS,
Z是:
i)C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,任选被末端芳环取代,
ii)CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1 -4烷基)2,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,或者
iii)苯基或苄基,其中所述基团可任选被卤素、C1-6烷基、C1-6烷氧基、C1-6烷硫基、CN、CF3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,并且其中
m和n相同或不同,并分别为0或1,
b)C5-12烷基或卤代烷基,所述基团可任选被末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,
c)C6-12链烯基或链炔基,所述基团可任选被卤素、二硫杂环戊烯、末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同;
R5是
a)H
b)C1-4烷基
c)COOH
d)OH,或
e)O-C1-5烷基或链烷酰基,所述基团可任选被至少一个一或二甲基氨基或乙基氨基取代,
R6是:
a)氢,
b)C1-6烷氧基、C1-6烷硫基、C1-6烷基、或C1-6卤代烷基,
c)CN,
d)CO2H,
e)CO2-C1-4烷基,
f)C(Y)(Z)-OH,
g)C(Y)(Z)-O-C1-4烷基,或
h)C1-6烷基-CO2-Y,
其中Y和Z分别独立地为H或C1-6烷基,
R7是:
a)羟基或内酯,
b)卤素,
c)C1-6烷氧基、C1-6烷硫基、C1-6烷基、或C1-6卤代烷基,
d)CN,
e)N3,
f)CO2H,
g)CO2-C1-4烷基,
h)C(Y)(Z)-OH,
i)C(Y)(Z)-O-C1-4烷基,
j)C1-6烷基-CO2-Y,或
k)=O或=S,
其中Y和Z分别独立地为H或C1-6烷基,并且其中R7可以在2-5位的任意位置上。
22.权利要求1的方法,其中所述组合物包括至少两种化合物。
23.权利要求1的方法,其中将所述组合物与至少一种抗病毒剂联合辅助施用。
24.权利要求23的方法,其中所述抗病毒剂选自阿巴卡韦、叠氮胸苷昔多福韦、甲磺酸地拉夫定、去羟肌苷、双脱氧胞苷、依法韦蓝次、磷卡萘替、更昔洛韦、硫酸印地那韦、拉米夫定、甲磺酸那非那韦、奈韦拉平、利托那韦、沙奎那韦、甲磺酸沙奎那韦、斯塔夫定和扎西他滨。
25.权利要求1的方法,其中所述患者是选自动物猴子、猫、狗、马、牛、猪、山羊、和绵羊的哺乳动物。
26.权利要求1的方法,其中所述患者是人。
27.权利要求26的方法,其中所述疾病或病症是HIV疾病。
28.权利要求27的方法,其中所述方法是用于减轻所述患者中CD4+细胞的减少。
29.权利要求27的方法,其中所述方法是用于增加所述患者中CD4+细胞的数目。
30.权利要求27的方法,其中所述方法是用于降低所述患者中的病毒负荷。
31.减弱HIV复制并具有下式的大麻酚衍生物:
其中
R1是:
a)H,
b)C1-4烷基或其酯,
c)COOH,
d)OH,
e)O-C1-5烷基或链烷酰基,所述基团可任选被一或二甲基氨基或乙基氨基取代,
f)含有羧基或氨基的O-CO-C3-10烷基,
g)
其中n=1~8,
h)对氨基苄基或C1-7氨基烷基或其有机或无机酸加成盐,对氨基苄基或氨基烷基的异氰酸酯或异硫氰酸酯衍生物,具有1-7个另外的碳原子的氨基烷基的羧基末端衍生物或其盐,该羧基末端衍生物的活化衍生物;
i)R1和R2构成式-O(CH2)3-5所示取代基,其中R1和R2与它们所键合的碳原子一起构成一个环,在所述环上至少有一个氢原子可任选被卤素取代,
R2是:
a)H、OH或卤素
b)C1-6羧基或烷氧基,或者
c)R1和R2构成式-O(CH2)3-5所示取代基,其中R1和R2与它们所键合的碳原子一起构成一个环,在所述环上至少有一个氢原子可任选被卤素取代,
R3是:
a)(W)m-Y-(Z)n,其中
W是C6-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,
Y是一条键、O、S、SO、SO2、CO、NH或N(C1-6烷基),
Z是:
i)C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,任选被末端芳环取代,
ii)CN1-3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1- 4烷基)2,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,或者
iii)苯基或苄基,其中所述基团可任选被卤素、C1-6烷基、C1-6烷氧基、C1-6烷硫基、CN、CF3、CO2H、或CO2C1-4烷基、 CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,并且其中
m和n相同或不同,并分别为0或1,
b)C5-12烷基或卤代烷基,所述基团可任选被末端芳环、CN1-3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,
c)C5-12链烯基或链炔基,所述基团可任选被卤素、二硫杂环戊烯、末端芳环、CN1-3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同;
R6与R6’一起形成=O或=S,或者分别独立地选自:
a)氢,
b)C1-6烷氧基、C1-6烷硫基、C1-6烷基、或C1-6卤代烷基,
c)CN,
d)CO2H,
e)CO2-C1-4烷基,
f)C(Y)(Z)-OH,
g)C(Y)(Z)-O-C1-4烷基,和
h)C1-6烷基-CO2-Y,
其中Y和Z分别独立地为H或C1-6烷基,
R7是:
a)羟基或内酯,
b)卤素,
c)C1-6烷氧基、C1-6烷硫基、C1-6烷基、或C1-6卤代烷基,
d)CN,
e)N3,
f)CO2H,
g)CO2-C1-4烷基,
h)C(Y)(Z)-OH,
i)C(Y)(Z)-O-C1-4烷基,
j)C1-6烷基-CO2-Y,或
k)=O或=S,
其中Y和Z分别独立地为H或C1-6烷基;
Q是:
a)O或S,或
b)N-W,其中W是:
i)氢,
ii)C1-6烷氧基烷基、C1-6烷基、或C1-6卤代烷基
iii)OC1-6烷基、或OC1-6卤代烷基,
iv)CN,
v)C1-6烷基,
vi)C(Y)(Z)C1-4烷基,或
vii)C1-6烷基-CO2-Z,
其中Y和Z分别独立地为H或C1-6烷基。
32.权利要求31的大麻酚衍生物,其中R1是H、酯、或醚。
33.权利要求31的大麻酚衍生物,其中R2是碘。
34.权利要求31的大麻酚衍生物,其中R3是支链烷基、烯烃、或炔烃链。
35.权利要求31的大麻酚衍生物,其中R3是二甲基庚基(DMH)、二甲基戊基(DMP)、或具有卤代或庞大的末端基团。
36.权利要求31的大麻酚衍生物,其中R3是1,1,5-三甲基己基、1,1,5,5-四甲基己基、或1,1,5-三甲基-庚-4-烯基。
37.权利要求31的大麻酚衍生物,其中R3是-(CH2)1-6-CON(CH3)2。
38.权利要求31的大麻酚衍生物,其中R3是卤代烷基。
39.权利要求31的大麻酚衍生物,其中R6和R6′一起形成=O或分别是乙基。
40.权利要求31的大麻酚衍生物,其中R7在所述C环的9位上。
41.权利要求31的大麻酚衍生物,其中R7是COOH、卤素、β-羟基、或内酯。
42.具有下式的烷基化间苯二酚衍生物:
其中
R1是:
a)H,
b)C1-4烷基或其酯,
c)COOH,
d)OH,
e)O-C1-5烷基或链烷酰基,所述基团可任选被一或二甲基氨基或乙基氨基取代,
f)含有羧基或氨基的O-CO-C3-10烷基,
g)
其中n=1-8,或
h)对氨基苄基或C1-7氨基烷基或其有机或无机酸加成盐,对氨基苄基或氨基烷基的异氰酸酯或异硫氰酸酯衍生物,具有1-7个另外的碳原子的氨基烷基的羧基末端衍生物或其盐,该羧基末端衍生物的活化衍生物;
R2是:
H、OH或卤素;或者
R1和R2构成式-O(CH2)3-5-所示取代基,其中R1和R2与它们所键合的碳原子一起构成一个环,在所述环上至少有一个氢原子可任选被卤素取代,
R3是
a)(W)m-Y-(Z)n,其中
W是C6-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,
Y是一条键、O、S、SO、SO2、CO、NH、N(C1-6烷基)、或NCS,
Z是:
i)C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,任选被末端芳环取代,
ii)CN1-3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1- 4烷基)2,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,或者
iii)苯基或苄基,其中所述基团可任选被卤素、C1-6烷基、C1-6烷氧基、C1-6烷硫基、CN、CF3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,
其中W和Z当中至少有一个包含支链,并且其中
m和n相同或不同,并分别为0或1,
b)末端呈支链的C5-12烷基或卤代烷基,所述基团可任选被末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1 -4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,或者
c)末端呈支链的C6-12链烯基或链炔基,所述基团可任选被卤素、二硫杂环戊烯、末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同;
R4是;
a)H,
b)OH,
c)C1-6烷氧基或羧基
R5是H或OH;且
R6是
a)H或OH;
b)C1-4烷基、链烯基、链炔基、或其混合物;
c)O-C1-4烷基、链烯基、链炔基、或其混合物;
d)pryenyl、香叶烯基或法呢基,所述基团任选被卤素取代;
e)(W)m-Y-(Z)n,其中
W是C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,
Y是一条键、O、S、SO、SO2、CO、NH、N(C1-6烷基)、或NCS,
Z是:
i)C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,任选被末端芳环取代,
ii)CN1-3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1- 4烷基)2,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,或者
iii)苯基或苄基,其中所述基团可任选被卤素、C1-6烷基、C1-6烷氧基、C1-6烷硫基、CN、CF3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,
其中W和Z当中至少有一个包含支链,并且其中
m和n相同或不同,并分别为0或1,
f)末端呈支链的C5-12烷基或卤代烷基,所述基团可任选被末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1 -4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,或者
g)末端呈支链的C5-12链烯基或链炔基,所述基团可任选被卤素、二硫杂环戊烯、末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同。
43.权利要求42的烷基化间苯二酚衍生物,其中R1是OH或OCH3。
44.权利要求42的烷基化间苯二酚衍生物,其中R2是H。
45.权利要求42的烷基化间苯二酚衍生物,其中R3是含有至少一个双键的末端呈支链的C6-12烷基。
46.权利要求45的烷基化间苯二酚衍生物,其中R3是1,1,5-三甲基己基、 1,1,5,5~四甲基己基、或1,1,5-三甲基-庚-4-烯基。
47.权利要求42的烷基化间苯二酚衍生物,其中R3包括一个碳原子链,所述链在其C4与C10之间的碳原子上具有至少一个双键。
48.权利要求42的烷基化间苯二酚衍生物,其中R3包括具有奇数数目碳原子的碳原子链。
49.权利要求42的烷基化间苯二酚衍生物,其中R6是甲基或乙基。
50.抑制肿瘤生长的方法,所述方法包含在足以抑制新生物生长的条件下将权利要求42的烷基化间苯二酚衍生物递送到新生物上。
51.权利要求50的方法,其中在足以增强新生物细胞内细胞程序死亡的条件下将烷基化间苯二酚衍生物递送到新生物上。
52.权利要求50的方法,其中将烷基化间苯二酚衍生物与至少一种其它抗肿瘤剂联合辅助施用。
53.权利要求50的方法,其中所述新生物是在肿瘤内,并且所述方法是减弱肿瘤生长。
54.权利要求50的方法,其中所述新生物是在血恶液质内,并且所述方法是减弱血恶液质的生长。
55.权利要求50的方法,其中所述新生物是在体内。
56.权利要求54的方法,其中烷基化间苯二酚衍生物是通过将其引入到体循环中来递送到新生物上。
57.权利要求55的方法,其中烷基化间苯二酚衍生物是经由胃、肠、口服、或直肠壁途径或经由静脉内注射来引入到体循环中。
58.权利要求50的方法,其中烷基化间苯二酚衍生物是通过肿瘤内注射来递送到新生物上。
59.下式所示大麻酚或其衍生物:
其中
R1是:
a)H,
b)C1-4烷基或其酯,
c)COOH,
d)OH,
e)O-C1-5烷基或链烷酰基,所述基团可任选被一或二甲基氨基或乙基氨基取代,
f)含有羧基或氨基的O-CO-C3-10烷基,
g)
其中n=1-8,或
h)对氨基苄基或C1-7氨基烷基或其有机或无机酸加成盐,对氨基苄基或氨基烷基的异氰酸酯或异硫氰酸酯衍生物,具有1-7个另外的碳原子的氨基烷基的羧基末端衍生物或其盐,该羧基末端衍生物的活化衍生物;
i)R1和R2构成式-O(CH2)3-5所示取代基,其中R1和R2与它们所键合的碳原子一起构成一个环,在所述环上至少有一个氢原子可任选被卤素取代,
R2是:
a)H、OH或卤素
b)C1-6羧基或烷氧基,或者
c)R1和R2构成式-O(CH2)3-5所示取代基,其中R1和R2与它们所键合的碳原子一起构成一个环,在所述环上至少有一个氢原子可任选被卤素取代,
R3是:具有下式的末端呈支链的链:
a)(W)m-Y-(Z)n,其中
W是C5-12烷基、链烯基、链炔基、或其混合物,所述基团可任选被至少一个卤素取代,
Y是一条键、O、S、SO、SO2、CO、NH、N(C1-6烷基)、或NCS,
Z是:
i)C5-12烷基、链烯基、链炔基、或卤代烷基,所述基团可任选被末端芳环取代,
ii)CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1 -4烷基)2,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,或者
iii)苯基或苄基,其中所述基团可任选被卤素、C1-6烷基、C1-6烷氧基、C1-6烷硫基、CN、CF3、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,并且其中
m和n相同或不同,并分别为0或1,
b)C5-12烷基或卤代烷基,所述基团可任选被末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同,或者
c)C5-12链烯基或链炔基,所述基团可任选被卤素、二硫杂环戊烯、末端芳环、CN1-3、NCS、CO2H、或CO2C1-4烷基、CONH2、CONHC1-4烷基、或CON(C1-4烷基)2取代,其中在酰胺氮原子上的每一C1-4烷基可相同或不同;
R6与R6′一起形成=O或=S,或者分别独立地选自:
a)氢,
b)C1-6烷氧基、C1-6烷硫基、C1-6烷基、或C1-6卤代烷基,
c)CN,
d)CO2H,
e)CO2-C1-4烷基,
f)C(Y)(Z)-OH,
g)C(Y)(Z)-O-C1-4烷基,和
h)C1-6烷基-CO2-Y,
其中Y和Z分别独立地为H或C1-6烷基,
R7是:
a)羟基或内酯,
b)卤素,
c)C1-6烷氧基、C1-6烷硫基、C1-6烷基、或C1-6卤代烷基,
d)CN,
e)N3,
f)CO2H,
g)CO2-C1-4烷基,
h)C(Y)(Z)-OH,
i)C(Y)(Z)-O-C1-4烷基,
j)C1-6烷基-CO2-Y,或
k)=O或=S,
其中Y和Z分别独立地为H或C1-6烷基;
Q是:
a)O或S,或
b)N-W,其中W是:
i)氢,
ii)C1-6烷氧基烷基、C1-6烷基、或C1-6卤代烷基
iii)OC1-6烷基、或OC1-6卤代烷基,
iv)CN,
v)C1-6烷基,
vi)C(Y)(Z)C1-4烷基,或
vii)C1-6烷基-CO2-Z,
其中Y和Z分别独立地为H或C1-6烷基;且
C是:
其中虚线代表在Δ6、Δ8、或Δ9位置的双键。
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US12567499P | 1999-03-22 | 1999-03-22 | |
US60/125674 | 1999-03-22 | ||
US15159599P | 1999-08-30 | 1999-08-30 | |
US60/151595 | 1999-08-30 |
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CN (2) | CN1561990A (zh) |
AU (1) | AU3910700A (zh) |
BR (1) | BR0009200A (zh) |
CA (1) | CA2367262A1 (zh) |
HU (1) | HUP0203437A3 (zh) |
IL (2) | IL145470A0 (zh) |
WO (1) | WO2000056303A2 (zh) |
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-
2000
- 2000-03-22 BR BR0009200-2A patent/BR0009200A/pt not_active IP Right Cessation
- 2000-03-22 EP EP00918266A patent/EP1189603A2/en not_active Ceased
- 2000-03-22 CN CNA200410062002XA patent/CN1561990A/zh active Pending
- 2000-03-22 HU HU0203437A patent/HUP0203437A3/hu unknown
- 2000-03-22 AU AU39107/00A patent/AU3910700A/en not_active Abandoned
- 2000-03-22 IL IL14547000A patent/IL145470A0/xx active IP Right Grant
- 2000-03-22 CA CA002367262A patent/CA2367262A1/en not_active Abandoned
- 2000-03-22 CN CN00807895A patent/CN1377261A/zh active Pending
- 2000-03-22 JP JP2000606208A patent/JP2002539246A/ja active Pending
- 2000-03-22 US US09/533,386 patent/US6274635B1/en not_active Expired - Fee Related
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CN1377261A (zh) | 2002-10-30 |
EP1189603A2 (en) | 2002-03-27 |
HUP0203437A3 (en) | 2003-07-28 |
IL145470A (en) | 2007-06-03 |
CA2367262A1 (en) | 2000-09-28 |
BR0009200A (pt) | 2001-12-26 |
HUP0203437A2 (en) | 2003-05-28 |
WO2000056303A3 (en) | 2002-01-24 |
AU3910700A (en) | 2000-10-09 |
WO2000056303A2 (en) | 2000-09-28 |
JP2002539246A (ja) | 2002-11-19 |
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IL145470A0 (en) | 2002-06-30 |
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