CN116964064A - 协同大麻素酯、其盐和用途 - Google Patents
协同大麻素酯、其盐和用途 Download PDFInfo
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- CN116964064A CN116964064A CN202280019080.8A CN202280019080A CN116964064A CN 116964064 A CN116964064 A CN 116964064A CN 202280019080 A CN202280019080 A CN 202280019080A CN 116964064 A CN116964064 A CN 116964064A
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- cannabinoid
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Abstract
大麻素酯及其可溶性盐与协同或加成治疗对应物及其稳定制剂,以及它们的可食用、饮料和医药应用。协同或添加剂大麻素酯可以用作药物或前药,用于治疗与大麻素受体的调节或偏向调节相关的各种病症,包括但不限于疼痛和炎症、关节炎、癌症、青光眼、神经退行性病症、多发性硬化、肾纤维化、纤维化病症、精神健康病症、成瘾、运动功能病症以及胃肠和代谢病症。
Description
技术领域
本发明涉及药物化学领域,具体而言,涉及大麻素酯、它们的盐与协同或附加治疗对应物以及用于治疗、减轻人类或动物受试者疾病症状的用途。
背景技术
内源性大麻素系统介导许多重要的生理功能,包括神经可塑性和学习、情绪和动机、食欲和胃肠运动以及免疫调节。至少有两种类型的GI蛋白偶联大麻素受体已在哺乳动物中分离并得到充分表征:a)CB1:位于中央和外周,主要参与神经递质稳态;b)CB2:位于外周并与免疫系统相连。这些受体代表了各种疾病的有希望的治疗靶点,包括慢性疼痛、炎症、神经退行性疾病、癫痫、成瘾、失眠、癌症、肥胖和厌食症。近年来,设计特定的大麻素配体来控制这些疾病引起了越来越多的关注。
大麻素受体可以通过化合物的异形基团,即所谓的大麻素来调节。它们可分为三大类:a)内源性或内源性大麻素(例如花生四烯酰乙醇酰胺);b)天然或植物大麻素,它们是大麻物种的活性成分(例如δ-9-四氢大麻酚
(THC)和大麻二酚(CBD));c)合成的(例如大麻隆),如下表1所示。
表1:大麻素的代表性例子
大麻素的临床效用已在许多病症的治疗中得到证实。GW Pharmaceuticals的是THC和CBD的1:1混合物口腔喷雾剂,已在许多国家被批准作为成人多发性硬化症相关的神经性疼痛和痉挛的辅助治疗。Bausch Health Co.的CesametTM(大麻隆)是一种合成大麻素,用于通过CB1受体介导的相互作用作为止吐剂口服给药。
尽管具有临床潜力,但从苜蓿中提取的天然大麻素(植物大麻素)是高度亲脂性的(具有6-7的log P值),微溶于水(水溶解度=2-10μg/mL在23℃)、化学性质不稳定(特别是在溶液中通过光、温度和自氧化作用),具有粘性,吸收不稳定,起效延迟,首过代谢广泛,血浆蛋白结合率高,分布容积大,全身生物利用度低口服给药后,导致不可预测的作用时间过程和长半衰期(t1/2)。此外,熏制草本的临床益处是短暂的,并且与粘膜损伤、严重的不良反应和接触致癌副产物有关。此外,THC可以穿过血脑屏障(BBB)并激活中枢CB1,从而产生不必要的精神作用。为了克服这些限制,已经开发了多种制剂和药物递送方法,包括共溶解、络合、表面活性剂和载体辅助方法,迄今为止,成功有限。
另一方面,已经报道了几种合成衍生物和前药并广泛用于调节CB1和CB2。例如,Full Spectrum Laboratories Ltd.的WO2017/216362A1公开了大麻素前药及其生产、配方和用途。该参考文献仅公开了有机和氨基酸的酯,例如琥珀酸和缬氨酸。
Mallinckrodt Inc.的WO2004/043946A1公开了高度结晶的芳基磺酸THC酯。它们可以重结晶以进行纯化,并且在室温下在空气中是稳定的,允许在水解后无限期地储存和回收纯THC。该参考文献没有公开这些酯的任何药理作用或临床效用。
Watanabe等人(Chem Pharm Bull 27:3009-3014,1979)报道了δ-8-THC葡糖苷酸和硫酸酯的化学合成,以研究它们在大鼠中的水解、急性毒性和代谢处置。然而,没有描述任何这些酯的药理学或生物学效用。
Juntunen等人(Eur.J.Pharm.Sci.19,37-43,2003)报道了anandamide的水溶性磷酸酯前药的合成。磷酸盐官能团在pH 7.4时使母体内源性大麻素的水溶性增加了>16500倍,并降低了血压正常兔的眼压。该研究没有调查任何临床上更有用的植物大麻素,也没有报告这种花生四烯酸乙醇胺磷酸酯或其盐的任何其他药理作用或临床用途。
另一方面,已知大麻素与其他治疗剂通过单独、顺序或同时给药的组合的临床益处。例如,以色列BOL Pharma Ltd.的W02020021545A1;美国Companion Sciences,LLC的W02020009950A1;美国Essential Green Goodness LLC的US10398776B1公开了一种组合疗法,包括用于治疗炎症性关节疾病或减轻疼痛的单独治疗剂,包括大麻二酚(CBD)、软骨素、氨基葡萄糖和甲基磺酰甲烷(MSM)。尽管很有希望,但这种治疗方法受到以下事实的阻碍:这些药物表现出不同的药代动力学特征,因此它们不能同时到达其靶组织。特别是葡萄糖胺在50分钟后达到其最大血浆水平,而CBD需要4-6小时才能达到其最大血浆水平。在其他PK参数如分布、代谢率和消除中也观察到同样的显着差异。众所周知,两种具有协同作用或相加作用的分子却具有两种不同的PK行为,这是药物发现和开发过程中的一大挑战。
为了最大限度地减少现有技术中的限制,需要具有优化的物理化学、药代动力学(PK)和药效学(PD)特性以用于特定临床应用的新的协同大麻素衍生物。
发明内容
根据本发明的大麻素化合物是大麻素的不稳定酯及其与其他协同或相加治疗对应物的盐。这些新化合物旨在通过不止一种作用机制提供多种治疗益处。这是通过使用大麻素酯和另一种具有不同治疗效果的对应物来实现的。酯类对人体或动物体内的酶水解或化学水解敏感,以释放母体大麻素和协同或相加治疗对应物,从而调节内源性大麻素系统和其他协同受体和组织。
在一个实施方案中,大麻素化合物是大麻素的硫酸酯或半硫酸酯以及它们与其他协同或相加治疗对应物的盐。
在另一个实施方案中,大麻素化合物是大麻素的单磷酸酯、二磷酸酯或三磷酸酯以及它们与其他协同或相加治疗对应物的盐。
在另一个实施方案中,大麻素化合物是大麻素与其他协同或相加治疗对应物的碳酸酯。
在另一个实施方案中,大麻素化合物是大麻素与其他协同或相加治疗对应物的氨基甲酸酯。
在另一个实施方案中,大麻素化合物是大麻素和其他协同或相加治疗对应物的硝酸酯。
在另一个实施方案中,大麻素化合物是大麻素和其他协同或相加治疗对应物的硼酸酯。
在一个实施方案中,大麻素化合物是大麻素的磺酸酯和它们与其他协同或相加治疗对应物的盐。
在一个实施方案中,大麻素化合物是大麻素的膦酸酯及其与其他协同或相加治疗对应物的盐。
在一个实施方案中,大麻素化合物是大麻素的二膦酸酯及其与其他协同或相加治疗对应物的盐。
在另一个实施方案中,大麻素化合物是THC的硫酸酯,由结构式1表示:
在另一个实施方案中,大麻素化合物是CBD的硫酸酯,由结构式2和3表示:
在另一个实施方案中,大麻素化合物是THC的磷酸酯,由结构式4表示:
在另一个实施方案中,大麻素化合物是CBD的磷酸酯,由结构式5和6表示:
在另一个实施方案中,大麻素化合物是CBD的混合磷酸酯和硫酸酯,由结构式7表示:
在另一个实施方案中,大麻素化合物是THC的碳酸酯,由结构式8表示:
在另一个实施方案中,大麻素化合物是CBD的碳酸酯,由结构式9和10表示:
在另一个实施方案中,大麻素化合物是CBD的混合碳酸酯和硫酸酯,由结构式11表示:
在另一个实施方案中,大麻素化合物是CBD的混合碳酸酯和磷酸酯,由结构式12表示:
在另一个实施方案中,大麻素化合物是THC的氨基甲酸酯,由结构
式13表示:
在另一个实施方案中,大麻素化合物是CBD的氨基甲酸酯,由结构
式14和15表示:
在另一个实施方案中,大麻素化合物是CBD的混合氨基甲酸酯和硫酸酯,由结构式16表示:
在另一个实施方案中,大麻素化合物是CBD的混合氨基甲酸酯和磷酸酯,由结构式17表示:
在另一个实施方案中,大麻素化合物是THC的硝酸酯,由结构式18表示:
在另一个实施方案中,大麻素化合物是CBD的硝酸酯,由结构式19和20表示:
在另一个实施方案中,大麻素化合物是CBD的混合硝酸酯和硫酸酯,由结构式21表示:
在另一个实施方案中,大麻素化合物是CBD的混合硝酸酯和磷酸酯,由结构式22表示:
在另一个实施方案中,大麻素化合物是THC的硼酸酯,由结构式23表示:
在另一个实施方案中,大麻素化合物是CBD的硼酸酯,由结构式24和25表示:
在另一个实施方案中,大麻素化合物是CBD的混合硼酸酯和硫酸酯,由结构式26表示:
在另一个实施方案中,大麻素化合物是CBD的混合硼酸盐和磷酸酯,由结构式27表示:
在另一个实施方案中,大麻素化合物是THC的硫酸酯盐,由结构式28表示:
在另一个实施方案中,大麻素化合物是CBD的硫酸酯盐,由结构式29和30表示:
在另一个实施方案中,大麻素化合物是磷酸酯盐THC,由结构式31和32表示:
在另一个实施方案中,大麻素化合物是磷酸酯盐CBD,由结构式33-39表示:
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在另一个实施方案中,大麻素化合物是CBD的混合磷酸酯和硫酸酯盐,由结构式40-43表示:
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在另一个实施方案中,大麻素化合物是CBD的混合碳酸盐和硫酸酯盐,由结构式45表示:
在另一个实施方案中,大麻素化合物是CBD的混合碳酸盐和磷酸酯盐,由结构式46和47表示:
在另一个实施方案中,大麻素化合物是CBD的混合氨基甲酸酯和硫酸酯盐,由结构式48表示:
在另一个实施方案中,大麻素化合物是CBD的混合氨基甲酸酯和磷酸酯盐,由结构式49和50表示:
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在另一个实施方案中,大麻素化合物是由结构式51表示的CBD的混合硝酸盐和硫酸酯盐:
在另一个实施方案中,大麻素化合物是CBD的混合硝酸盐和磷酸酯盐,由结构式52和53表示:
在另一个实施方案中,大麻素化合物是CBD的混合硼酸盐和硫酸酯盐,由结构式54表示:
在另一个实施方案中,大麻素化合物是CBD的混合硼酸盐和磷酸酯盐,由结构式55和56表示:
在另一个实施方案中,大麻素化合物是由结构式57表示的磺酸酯:
在另一个实施方案中,大麻素化合物是结构式58表示的THC的磺酸酯:
在另一个实施方案中,大麻素化合物是由结构式59表示的CBD的磺酸酯:
在另一个实施方案中,大麻素化合物是由结构式60表示的磺酸酯盐,其中“Cann”是指大麻素和酯可以与大麻素上的任何碳原子相连:
在另一个实施方案中,大麻素化合物是结构式61表示的THC的磺酸酯盐:
在另一个实施方案中,大麻素化合物是由结构式62表示的CBD的磺酸酯盐:
在另一个实施方案中,大麻素化合物是由结构式63表示的膦酸酯,其中“Cann”是指大麻素并且该酯可以连接至大麻素上的任何碳原子:
在另一个实施方案中,大麻素化合物是结构式64表示的THC的膦酸酯:
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在另一个实施方案中,大麻素化合物是由结构式65表示的CBD的膦酸酯:
在另一个实施方案中,大麻素化合物是由结构式66和67表示的膦酸酯盐,
其中“Cann”是指大麻素并且该酯可以连接至大麻素上的任何碳原子:
在另一个实施方案中,大麻素化合物是结构式68和69表示的THC的膦酸酯盐:
在另一个实施方案中,大麻素化合物是由结构式70和71表示的CBD的膦酸酯盐:
在另一个实施方案中,大麻素化合物是由结构式72表示的二膦酸酯,
其中“Cann”是指大麻素并且该酯可以连接至大麻素上的任何碳原子:
在另一个实施方案中,大麻素化合物是由结构式73-77表示的二膦酸酯盐,其中“Cann”指大麻素并且该酯可以连接至大麻素上的任何碳原子:
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在另一个实施方案中,大麻素化合物是结构式78表示的THC的二膦酸酯:
在另一个实施方案中,大麻素化合物是由结构式79和80表示的CBD的二膦酸酯:
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在另一个实施方案中,大麻素化合物是结构式81表示的THC的二膦酸酯盐:
在另一个实施方案中,大麻素化合物是由结构式82和83表示的CBD:
在另一个实施方案中,式1-83中由R基团表示的第二化合物选自与大麻素组合具有协同或相加效应的组。
在另一个实施方案中,由式1-83中的R基团表示的第二化合物是第二大麻素,其具有适合与第一大麻素连接的官能团。官能团可以包括硫醇、羟基、氨基、腈、氰酸酯、异氰酸酯、硫氰酸酯、异硫氰酸酯、叠氮化物、羧酸、酸酐、烯烃、炔烃、醛、酮、环氧化物或酚官能团。第二大麻素可以选自天然、合成、半合成、生物合成或内源性大麻素。第二大麻素可选自包括δ-9-四氢大麻酚(THC)、δ-8-四氢大麻酚(THC)、大麻二酚(CBD)、大麻酚(CBN)、大麻酚酸(CBNA)、大麻萜酚(CBG)、大麻萜酚(CBG)、大麻萜酚(CBGV)、大麻色烯(CBC)、大麻双环醇(CBL)、大麻萜酚(CBV)、四氢次大麻酚(THCV)、次大麻二酚(CBDV)、次大麻萜酚酸(CBCV)、大麻萜酚单乙醚(CBGM)、大麻萜酚酸单乙醚(CBGAM)、大麻二酚酸(CBDA)、大麻萜酚(CBGVA)、大麻色烯酸(CBCA)、大麻色烯酸(CBCA)、大麻二酚单甲醚(CBDM)、大麻二酚-C4(CBD-C4)、次大麻二酚(CBDVA)、大麻二酚(CBD-C1)、δ-9-四氢大麻酚酸A(THCA-A),δ-9-四氢大麻酚酸B(THCA-B),δ-9-四氢大麻酚酸-C4(THCA-C4),δ-8-四氢大麻酚酸(δ-8-THCA),δ-8-四氢大麻酚(δ-8-THC),δ-9-四氢大麻酚-C4(THC-C4),δ-9-四氢大麻酚酸(THCA-C1),δ-9-四氢大麻酚-Cl(THC-Cl)、四氢次大麻酚酸(THCVA)、大麻二环酸(CBLA)、大麻二环醇(CBL)、大麻二环酚(CBLV)、大麻艾尔松酸A(CBEA-A)、大麻艾尔松酸B(CBEA-B)、大麻艾尔松(CBE)、次大麻酚、大麻酚-C4(CBN-C4)、大麻酚甲醚(CBNM)、大麻二酚(CBN-C1)、大麻酚-C2(CBN-C2)、大麻二酚(CBND)、大麻二酚(CBVD)、大麻三酚(CBT)、大麻三酚酚(CBTV)、脱氢大麻呋喃(DCBF)、大麻呋喃、大麻衣兰(CBT)、大麻三酚(CBR)、‘11-羟基四氢大麻素(11-OH-THC)、‘11-去甲-9-羧基-四氢大麻酚’(THC-COOH)其衍生物、类似物、盐、混合物和组合。
在另一个实施方案中,由式1-83中的R基团表示的协同或加成化合物具有适合与第一大麻素连接的官能团。官能团可以包括硫醇、羟基、氨基、腈、氰酸酯、异氰酸酯、硫氰酸酯、异硫氰酸酯、叠氮化物、羧酸、酸酐、烯烃、炔烃、醛、酮、环氧化物或酚官能团。第二协同或相加治疗对应物是在与大麻素一起施用时在治疗一种或多种病症中具有协同或相加作用的化合物。第二协同或附加治疗对应物可选自天然、合成、半合成、生物合成或内源化合物。第二协同或附加治疗对应物可选自包括葡糖胺、裸盖菇素、裸盖菇素、普瑞巴林、加巴喷丁、托吡酯、对乙酰氨基酚、布洛芬、吗啡、咖啡酸、左旋多巴、香豆酸、槲皮素、类黄酮、水杨酸、百里酚、丁香酚、恩他卡朋、托卡朋、雌激素、选择性5-羟色胺再摄取抑制剂(SSRI)、雄激素和皮质类固醇。优选地,第二协同或相加治疗对应物选自葡糖胺、裸盖菇素、羟基二甲色胺、普瑞巴林、加巴喷丁和托吡酯。
在另一个实施方案中,式28-83中由基团B+表示的抗衡离子选自具有协同或相加效应的组。
在另一个实施方案中,式28-83中由基团B+表示的抗衡离子选自具有适合与第一大麻素制备盐的官能团的基团。B+可以选自包括环状胺、无环胺、乙醇胺衍生物、芳族胺、脂肪族胺、氨基糖、氨基聚合物、氨基低聚物和氨基酸的组。
在另一个实施方案中,协同或加成化合物,由式28-83中的B+基团表示。B+可以选自包括葡糖胺、裸盖菇素、裸盖菇素、普瑞巴林、加巴喷丁、托吡酯、吗啡、左旋多巴、选择性5-羟色胺再摄取抑制剂(SSRI)的组。
在其他实施方案中,当大麻素盐具有两个羟基时,大麻素盐可以包含两种治疗剂组分。在这样的实施方案中,两种治疗剂组分可以相同或不同。
在另一个实施方案中,根据本发明的大麻素化合物的某些实施方案可以证明一个或多个期望的特征,包括改进的稳定性、更高的溶解度、更高的效力或改进的PK或PD性质。
在另一个实施方案中,根据本发明的水溶性大麻素酯可用于食用、饮料和药物应用。酯可以是半酯、全酯、混合酯或盐。
在另一个实施方案中,根据本发明的水溶性大麻素酯可用于局部、注射或口服应用。
在另一个实施方案中,大麻素酯是具有另一种协同作用或添加剂碱的水溶性盐的形式。
本发明的另一个实施方案是通过合成或半合成方法生产大麻素化合物的方法。该方法包括以下步骤:
a.将具有至少一个羟基的大麻素溶解在合适的非质子有机溶剂中。
b.在碱或有机碱存在下使大麻素溶液与酯转移试剂反应。
c.在常规加热、微波加热或超声处理下加热反应以产生产物。
d.使用快速色谱、萃取、蒸馏、升华或结晶纯化产品。
在另一个实施方案中,非质子有机溶剂选自吡啶、甲苯、四氢呋喃、卤代烃、二甲苯和己烷。
某些优选的实施方案包括硫酸酯和硫酸酯盐,而其他实施方案包括其他类型的酯和酯盐。无论酯是硫酸酯还是其他类型的酯或酯盐,都可以使用适合特定类型酯的酯转移试剂。
在另一个实施方案中,硫酸酯转移试剂选自游离氯磺酸、保护和游离磺酸、保护和游离硫酸、三氧化硫、三氧化硫络合物、三氧化硫吡啶、碱金属二硫酸盐、磺酰基咪唑盐、N-羟基琥珀酰亚胺-硫酸盐和三丁基磺胺甜菜碱。
在另一个实施方案中,碳酸酯转移试剂可以选自光气、三氯乙酰氯、1,1'-羰基二咪唑(CDI)、1,1'-羰基双(2-甲基咪唑)、N,/N'-二琥珀酰亚胺基碳酸酯、4-硝基苯基氯甲酸酯、双(4-硝基苯基)碳酸酯、双(五氟苯基)碳酸酯,然后任选地用碱、水或醇处理。
在另一个实施方案中,氨基甲酸酯转移试剂可以选自光气、三氯乙酰氯、1,1'-羰基二咪唑(CDI)、1,1'-羰基双(2-甲基咪唑)、N,/N'-二琥珀酰亚胺基碳酸酯、4-硝基苯基氯甲酸酯、双(4-硝基苯基)碳酸酯、双(五氟苯基)碳酸酯,然后任选用氨或任何单或二取代胺处理。
在另一个实施方案中,磷酸盐转移试剂可以选自磷酸二(4-硝基苯基)磷酸盐、二苯基磷酸盐、对氧磷-乙基、4-硝基苯基磷酸双(环己基铵)盐、4-硝基苯基)磷酸钠盐、4-硝基苯基)磷酸钠盐水合物、4-硝基苯基二氯磷酸盐、二苯基磷酰氯、氯磷酸二乙酯、氯磷酸二甲酯或氯磷酸二异丙酯、二磷酰氯,然后任选用水、氨、取代胺或任何醇处理。
在另一个实施方案中,硝酸盐转移试剂可以选自四氟硼酸硝鎓、六氟锑酸亚硝鎓、六氟锑酸硝鎓、亚硝酸钠、亚硝酸钾、亚硝酸铵、亚硝酸银、亚硝酸镉、硝酸钠、硝酸钾、硝酸铵、硝酸银、硝酸盐、硝酸镉、硝酸、1-硝基吡咯烷-2,5-二酮、1-硝基吡咯烷-2-酮、2-硝基异吲哚啉-1,3-二酮、2-硝基苯并[d]异噻唑-3(2H)-酮1,1-二氧化物或2,5-二硝基苯并[d]异噻唑-3(2H)-酮1,1-二氧化物。
在另一个实施方案中,双膦酸盐转移试剂可以选自甲膦酸(亚甲基二膦酸)、甲膦酰氯、亚甲基双(二氯化膦)、依替膦酸盐、阿仑膦酸盐、伊班膦酸盐、米诺膦酸盐、瑞西膦酸盐、替鲁膦酸盐、唑来膦酸盐、酯、半酯或任何以前的试剂。
在另一个实施方案中,硼酸盐转移试剂可以选自硼酸、四硼酸钠、双(频哪醇)二硼、(二甲基苯基甲硅烷基)硼酸频哪醇酯、4,4,5,5-四甲基-1,3,2-二氧硼烷,2-甲氧基-4,4,5,5-四甲基-1,3,2-二氧硼烷,2-乙氧基-4,4,5,5-四甲基-1,3,2-二氧硼烷,2-异丙氧基-4,4,5,5-四甲基-1,3,2-二氧硼烷、硼酸三异丙酯、硼酸三乙酯、硼酸三甲酯、三氯化硼、氯硼烷、氯硼烷甲酯、B-氯儿茶酚硼烷、B-溴儿茶酚硼烷、儿茶酚硼烷、溴二甲基硼烷和然后任选地用水、氨、取代的胺或醇处理。
在另一个实施方案中,THC硫酸酯盐的各种盐和形式可以根据以下式84中说明的方法生产。当在水溶液中与1.2当量的选定碱一起搅拌时,吡啶抗衡离子可以被另一种选定的协同碱或添加剂碱取代,定量产率(95-99%)和分析纯度(95-98%)为无定形粉末,并作为非水溶液中的结晶化合物。反应溶液中至少存在一些水性溶剂对于促进用目标抗衡离子置换吡啶很重要。对于某些具有高溶解度的目标抗衡离子,反应可能完全在水中进行。对于具有低溶解度的目标抗衡离子,可以使用水性和非水性溶剂的混合物来促进反应。优选地,水和乙醇以1:1的比例使用,但也可以使用其他非水溶剂。
在另一个实施方案中,CBD硫酸酯盐的各种盐和形式可以根据以下结构式85中说明的方法生产。当在水溶液中与1.2当量的选定碱一起搅拌时,吡啶抗衡离子可以被另一种选定的协同碱或添加剂碱取代,定量产率(95-99%)和分析纯度(95-98%)为无定形粉末,并作为非水溶液中的结晶化合物。
在另一个实施方案中,THC硫酸酯盐的葡糖胺盐可以根据如下式86所示的一锅两步反应顺序生产,以获得定量产率(90-99%)和分析的目标硫酸盐纯度(95-98%)。温度在65-90℃之间,压力在5-20帕之间,反应时间在吡啶中4-8小时之间。式86的方法的第一步是通过将THC与吡啶三氧化硫在吡啶中在65-90℃和5-20帕压力之间混合2-4小时将THC转化为THC硫酸酯盐。该反应效率高,使用的试剂安全、操作方便,可提供定量收率、分析纯度不低于95%的目标硫酸酯盐。第二步是反离子置换,如式84和85中所述,以葡糖胺作为抗衡离子。第一步和第二步之间不需要纯化步骤,它们可以立即在同一反应容器中依次进行。或者,该反应可以平行反应进行,其中第一步以大规模反应进行,粗产物分成多个单独的反应,以使用不同的抗衡离子进行第二步。
在另一个实施方案中,CBD硫酸酯的葡糖胺盐可以根据下式87所示的方法生产,以获得定量产率(90-99%)和分析纯度(95-98%)的目标硫酸盐.温度在65-90℃之间,压力在5-20帕之间,反应时间在吡啶中4-8小时之间。
在另一个实施方案中,THC硫酸酯盐的赛洛辛盐可以根据以下结构式88中说明的方法生产,以获得定量产率(90-99%)和分析纯度(95-98%)的目标硫酸盐)。温度在65-90℃之间,压力在5-20帕之间,反应时间在吡啶中4-8小时之间。
在另一个实施方案中,大麻二酚硫酸酯的羟基二甲色胺盐可以根据下式89中说明的方法生产,以获得定量产率(90-99%)和分析纯度(95-98%)的目标硫酸盐.温度在65-90℃之间,压力在5-20帕之间,反应时间在吡啶中4-8小时之间。
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在另一个实施方案中,THC磷酸酯盐的葡糖胺盐可以根据下式90所示的方法生产,以获得定量产率(90-99%)和分析纯度(95-98%)的目标磷酸盐)。温度约为50℃,压力在5-20帕之间,在四氢呋喃中反应时间在4-8小时之间(THF)。
在另一个实施方案中,CBD磷酸酯的葡糖胺盐可以根据下式91中说明的方法生产,以获得定量产率(90-99%)和分析纯度(95-98%)的目标磷酸盐.温度约为50℃,压力在5-20帕之间,反应时间在四氢呋喃(THF)中为4-8小时。
在另一个实施方案中,THC磷酸酯盐的赛洛辛盐可以根据以下结构式92中说明的方法生产,以获得定量产率(90-99%)和分析纯度(95-98%)的目标磷酸盐)。温度约为50℃,压力在5-20帕之间,反应时间在四氢呋喃(THF)中为4-8小时。
在另一个实施方案中,CBD磷酸酯的羟基二甲色胺盐可以根据下式93所示的方法生产,以获得定量产率(90-99%)和分析纯度(95-98%)的目标磷酸盐.温度约为50℃,压力在5-20帕之间,反应时间在四氢呋喃(THF)中为4-8小时。
在某些实施方案中,大麻素酯可以作用于外周和中央组织中的一个或两个。
在另一个实施方案中,大麻素酯受到外围限制,使得它们缺乏THC的中心精神活性特性。
在另一个实施方案中,大麻素酯可用于控制多种病症,包括疼痛和炎症、精神健康障碍、癌症、青光眼、神经退行性疾病、多发性硬化症、肾纤维化、纤维化障碍、成瘾、运动功能障碍和胃肠和代谢紊乱和其他对大麻素受体调节有反应或已知可通过施用一种或多种大麻素治疗的病症。
在另一个实施方案中,大麻素酯可用于人类和动物应用。
在某些实施方案中,大麻素酯对口服递送系统特别有用。此外,它们可以配制用于局部、鼻内、眼科或肠胃外给药系统。
在另一个实施方案中,大麻素酯包括作为单独的半酯、全酯、盐或它们的混合物的所有可能的异构体(立体异构体或结构异构体)。
在另一个实施方案中,根据本发明的大麻素酯的药物制剂包括其他协同或添加剂成分,包括其他大麻素、植物化学物质、镇痛剂和抗炎剂。
当与其他大麻素相比时,本发明公开了具有改善的PK和PD谱的大麻素化合物,包括更好的稳定性、溶解度和味道、有效的吸收和分布以及效力,其可以提供有效的疾病控制和治疗效果。
发明描述
本公开涉及大麻素化合物,特别是可用作大麻素药物或前药的大麻素酯,涉及生产大麻素酯及其盐与协同或添加剂治疗对应物的方法,涉及食用、饮料和药物制剂这些化合物涉及通过向患者施用大麻素酯来调节内源性大麻素系统的方法,以及治疗疼痛、神经性疼痛、炎症、神经退行性疾病、多发性硬化症、脊髓和脑损伤、创伤后应激障碍、癫痫和其他运动功能障碍、小儿癫痫症、成瘾、失眠、恶心和呕吐、癌症、肾纤维化、肥胖和其他代谢紊乱、精神分裂症、抑郁症、强迫症、焦虑症、精神疾病、睡眠障碍、纤维肌痛、抽动秽语综合征、青光眼、克罗恩病、炎症性肠病、丛集性头痛、厌食症和其他通过给患者施用大麻素酯的病症。
根据本发明的大麻素酯或它们的活性代谢物可以作为CB1或CB2之一或两者的配体,或通过非受体介导的机制发挥它们的作用。由于本发明的某些示例性实施方案的独特药代动力学,一些实施方案可用作偏向调节剂(激动剂、拮抗剂、部分激动剂、反向激动剂等)以选择性结合第一大麻素受体而不是第二大麻素受体,例如CB1、CB2或受试者中的任何其他内源性大麻素受体。它们还可以调节其他靶点和受体,包括COX酶、脂肪酸酰胺水解酶(FAAH)、瞬时受体电位阳离子通道亚家族V(TrpV)、过氧化物酶体增殖物激活受体、假定的异常大麻二酚受体、离子通道、配体门控离子通道和其他G蛋白偶联受体。
与基础大麻素化合物相比,根据本发明的某些示例性实施方案的化合物显示出2,000-5,000倍的水溶性增加。某些示例性化合物在各种pH条件下也显示出良好的稳定性。虽然这些示例性化合物在pH 1.2(空腹模拟胃液)下快速水解,但它们在pH 5.1、6.8和7.4(空腹模拟肠液)下显示出良好的稳定性。此外,某些示例性化合物已显示芳基硫酸酯酶和β-葡糖苷酸酶都能够在6小时内分解化合物初始量的约50%。在大鼠药代动力学研究中,某些示例性化合物已显示口服剂量的吸收和相对生物利用度增加10倍,允许使用1/10大麻素的常规剂量,适用于每日一次的给药方案。
术语“酯”包括其任何比率的所有可能的半酯、全酯、盐和异构体,包括立体异构体、对映异构体、非对映异构体、互变异构体和混合物。优选地,酯是半酯或盐。优选地,它们是纯化合物的盐。
术语“大麻素”涉及具有至少一个羟基的大麻素。它包括内源性、合成、半合成或天然大麻素,包括:δ-9-四氢大麻酚(THC)、δ-8-四氢大麻酚(THC)、大麻二酚(CBD)、大麻酚(CBN)、大麻酚酸(CBNA)、大麻酚(CBG)、大麻酚(CBG)、大麻二酚(CBGV)、大麻色素(CBC)、大麻二环酚(CBL)、大麻酚(CBV)、四氢大麻酚(THCV)、大麻二酚(CBDV)、大麻二酚(CBCV)、大麻酚单乙醚(CBGM)、大麻二酚酸单乙醚(CBGAM)大麻二酚酸(CBDA),大麻二酚(CBGVA),大麻二色酸(CBCA),大麻二色二酸(CBCA),大麻二酚单甲醚(CBDM),大麻二酚-C4(CBD-C4),大麻二酚(CBDVA)),大麻二酚(CBD-C1),δ-9-四氢大麻酚酸A(THCA-A)、δ-9-四氢大麻酚酸B(THCA-B)、δ-9-四氢大麻酚酸-C4(THCA-C4)、δ-8-四氢大麻酚酸(δ-8-THCA)、δ-8-四氢大麻酚酸(δ-8-THC)、δ-9-四氢大麻酚-C4(THC-C4)、δ-9-四氢大麻酚-Cl(THCA-Cl)、δ-9-四氢大麻酚-Cl(THC-Cl)、四氢次大麻酚酸(THCVA)、大麻双环酚酸(CBLA)、大麻双环酚(CBL)、大麻双环酚(CBLV)、大麻酚酚酸A(CBEA-A)、大麻艾尔松酸B(CBEA-B)、大麻艾尔松(CBE)、大麻酚-C4(CBN-C4)、大麻酚甲醚(CBNM)、大麻二酚(CBN-C1)、大麻酚-C2(CBN-C2)、大麻二酚(CBND)、大麻二酚(CBVD)、大麻三酚(CBT)、大麻三酚(CBTV)、脱氢大麻呋喃(DCBF)、大麻呋喃、大麻硝(CBT)、大麻三酚(CBR)、‘11-羟基四氢大麻酚’(11-OH-THC)、‘11-去甲-9-羧基-四氢大麻酚’(THC-COOH)及其衍生物、合成类似物、相关化学结构和盐、及其混合物和组合。
术语“羟基”涉及醇或酚OH或其等排体(例如,SH或NH2)。
术语“盐”是指具有协同或累加治疗对应物的盐。术语“盐”还指pKa大于3的有机碱的盐,包括:乙醇胺衍生物(三乙醇胺);精氨酸、赖氨酸)、氨基糖(例如精氨酸、赖氨酸)氨基聚合物和低聚物(脱乙酰化软骨素、脱乙酰化透明质酸)、芳香族或脂肪族胺(例如葡糖胺)、氨基聚合物和低聚物(脱乙酰化软骨素、脱乙酰化透明质酸)。4-氨基嘧啶)或其他环状氮化合物(例如苯胺、4-氨基嘧啶)。氮丙啶、氮杂环丁烷、二氮杂环丁烷、咪唑啉、吡唑烷、3-吡咯啉、三唑、咪唑、吡咯烷、哌啶、吡啶、哌嗪、哒嗪、嘧啶、吡嗪、吗啉、二氧化硫吗啉、噻嗪、吡咯里嗪、氮杂吲哚、氮杂吲唑、嘌呤、吡唑并嘧啶、喹啉、十氢喹啉、氮杂环辛烷)、裸藻红、裸藻星、普瑞巴林、加巴喷丁、托吡酯、吗啡、左旋多巴、选择性5-羟色胺再摄取抑制剂(SSRI)。
术语“前药”旨在包括可能需要在人体内活化的目标化合物的酯。酯或它们的盐可以是活性的(等效的或更有效的)或无活性的化合物。优选地,它们是活跃的。在施用于人类或动物受试者后,它们经历酶促或化学活化以释放游离药物。
如本文所用,术语“药物制剂”是指本文所述的一种或多种化合物或其药学上可接受的盐或其他协同或附加治疗对应物与其他生理学上可接受的载体和赋形剂的混合物。药物制剂(例如固体或液体剂型)的目的是促进将化合物施用于对象动物或人。
本公开中的术语“受试者”是指人类患者,但不限于人类并且可以包括动物。
如本文所用,术语“施用”包括将本文所述的化合物和组合物引入患者的所有方式,包括但不限于口服、静脉内、肌内、透皮、吸入、口腔、眼部、阴道、直肠等。本文所述的化合物和组合物可以以单位剂型或含有常规无毒药学上可接受的载体、佐剂和赋形剂的制剂形式给药。
在优选的实施方案中,本发明的大麻素酯由式28、29、32、34、61、62、69和71中的实例表示。优选地,大麻素酯是与协同或累加治疗对应物的盐的形式。优选地,葡萄糖胺、裸盖菇素、羟基二甲色胺、普加巴林、加巴喷丁、托吡酯、吗啡、左旋多巴、选择性5-羟色胺再摄取抑制剂(SSRI)(例如西酞普兰)、氨磺必利、鲁拉西酮、帕利哌酮、帕利哌酮棕榈酸酯、利培酮、齐拉西酮、培罗西酮、阿霉素、美哌隆、阿立哌唑、溴吡唑、卡利拉嗪、奥氮平、喹硫平、氟西汀、降钙素、伪麻黄碱、吡拉西坦、左乙拉西坦、西他列汀、西洛多辛、氢氯噻嗪、依泽替米贝、普萘洛尔、阿替洛尔、纳多洛尔、吲哚洛尔、索洛尔拉莫三嗪、噻加宾、普瑞巴林、阿米替林、去甲替林和组胺。
在另一个优选的实施方案中,本发明的大麻素酯由式28、29、32、34、61、62、69和71中的实施例表示。优选地,大麻素酯呈与协同或附加治疗对应物。优选地,鸦片受体拮抗剂的盐,例如洛哌丁胺和地芬诺酯;阿片受体激动剂,例如他喷他多,或具有混合激动剂-拮抗剂和/或阿片受体部分激动作用的药物,例如纳布啡、丁丙诺啡和喷他佐辛。这些优选的实施方案在下表2中说明,其中碱(B)可以是下表3中列出的任何碱。
表2:示例性大麻素酯盐。
表3:示例性碱基。
条目 | 碱基(B) |
a | 葡糖胺 |
b | 鹦鹉热素 |
c | 普瑞巴林 |
d | 加巴喷丁 |
e | 托吡酯 |
f | 吗啡 |
g | 左旋多巴 |
h | 西酞普兰 |
式1至83中的侧基R可以是另一种大麻素、其他活性成分或非活性基团。优选地,R是另一种具有协同或相加活性的化合物。其他大麻素优选是THC或CBD,但可以是具有羟基、氨基或酚官能团的任何其他大麻素。合适的大麻素的例子包括大麻酚(CBN)、大麻酚酸(CBNA)、大麻酚(CBG)、大麻酚(CBG)、大麻酚(CBGV)、大麻色烯(CBC)、大麻二环醇(CBL)、大麻酚(CBV)、四氢大麻酚(THCV))、大麻二酚(CBDV)、大麻二酚(CBCV)、大麻二酚单乙醚(CBGM)、大麻二酚酸一乙醚(CBGAM)、大麻二酚酸(CBDA)、大麻二酚(CBGV A)、大麻二酚酸(CBCA)、大麻二酚酸(CBCA)、大麻二酚单甲醚(CBDM),大麻二酚-C4(CBD-C4)、次大麻二酚(CBDV A)、大麻二酚(CBD-C1)、δ-9-四氢大麻酚酸A(THCA-A)、δ-9-四氢大麻酚酸B(THCA-B)、δ-9-四氢大麻酚酸-C4(THCA-C4)、δ-8-四氢大麻酚酸(δ-8-THCA)、δ-8-四氢大麻酚酸(δ-8-THC)、δ-9-四氢大麻酚-C4(THC-C4)、δ-9-四氢大麻酚-C1(THC-C1)、四氢次大麻酚酸(THCV A)、大麻二环酚(CBLA)、大麻二环酚(CBLA)、大麻二环醇(CBL)、大麻二环酚(CBLV)、大麻艾尔松酸A(CBEA-A)、大麻艾尔松酸B(CBEA-B)、大麻艾尔松(CBE)、次大麻酚、大麻酚-C4(CBN-C4)、大麻酚甲醚(CBNM)、大麻二酚(CBN-C1)、大麻酚-C2(CBN-C2)、大麻二酚(CBND)、大麻二酚(CBVD)、大麻三酚(CBT)、大麻三酚酚(CBT)、脱氢大麻呋喃(DCBF)、大麻呋喃、大麻衣兰(CBT)、大麻三酚(CBR)、‘11-羟基四氢大麻酚(11-OH-THC)、‘11-去甲-9-羧基-四氢大麻酚’(THC-COOH)及其衍生物、合成类似物、相关化学结构和盐、及其混合物和组合。其它活性成分优选为对乙酰氨基酚或布洛芬,但可包括阿片样物质或具有至少一个羟基、氨基或酚官能团的其它药物。非活性基团优选为H,但可以是甲基、乙基或另一种无环饱和烃基(即CnH2n+1)、芳基或另一种环状饱和烃基(即CnH2n-1),或它们的电子等排体和类似物。
反离子,在本文中也称为碱,由B+表示在式28至83中,可以是环状胺、无环胺、乙醇胺衍生物、芳族胺、脂肪族胺、氨基糖、氨基聚合物、氨基低聚物或氨基酸。优选地,它是三乙醇胺、叔丁胺、精氨酸或赖氨酸,但可以是氨、三乙胺、三甲胺、三丙胺、三丁胺和其他相关的胺和衍生物,包括伯、仲和叔。芳香胺优选苯胺或4-氨基嘧啶,但可以是萘胺、对氨基苯磺酸、4-氨基苯甲酸和其他相关胺、类似物和衍生物。侧基还可以优选哌嗪或吗啉,但可以是氮丙啶、氮杂环丁烷、二氮杂环丁烷、咪唑啉、吡唑烷、3-吡咯啉、三唑、咪唑、吡咯烷、哌啶、吡啶、哒嗪、嘧啶、吡嗪、二氧化硫吗啉、噻嗪、吡咯里嗪、氮杂吲哚、氮杂吲唑、嘌呤、吡唑并嘧啶、喹啉、十氢喹啉、氮杂环辛烷或它们的衍生物、类似物和电子等排体。
由式28-83中的B+基团表示的治疗离子优选地选自具有协同或相加效应的组。优选地,它是葡糖胺、裸盖菇素、羟基二甲色胺、普瑞巴林、加巴喷丁、托吡酯、吗啡、左旋多巴或选择性5-羟色胺再摄取抑制剂(SSRI)(例如西酞普兰)。
大麻素酯可以通过合成的、半合成的、微生物的、酶促的和合成生物学方法,以及通过大麻属的遗传操作来制备。优选地,它们可以根据式84-93中描述的反应由具有至少一个羟基的任何大麻素制备。优选地,大麻素是THC或CBD,并且羟基是酚羟基。改变反应条件可以产生其他衍生物和类似物。
可以制备药物制剂,包括大麻素酯或其任何药学上可接受的盐,以及一种或多种药学上可接受的载体或赋形剂。优选地,该制剂是用于口腔和口腔粘膜应用的固体或液体剂型。
大麻素酯的某些示例性实施方案的药代动力学特征比相应的母体大麻素更有利。例如,某些示例性葡糖胺大麻素硫酸盐的Cmax(最大血浆浓度)比母体大麻素高10倍。因此,与母体大麻素相比,药物制剂可能含有较低有效剂量的这些大麻素硫酸酯盐。此外,示例性大麻素硫酸酯盐具有比母体大麻素更小的可变吸收。下表中显示了某些示例性大麻素硫酸酯的PK曲线,包括半衰期(T1/2)、最大血浆浓度(Cmax)和达到Cmax的时间(Tmax)。
酯盐的某些示例性实施方案在模拟的胃和肠介质下的酶和化学稳定性比相应的母体大麻素更有利。例如,CBD可以在模拟的胃和肠道介质下短时间内释放(5%到20%在10到30分钟内释放)。与相应的母体大麻素相比,示例性大麻素硫酸酯盐也显示出有利的毒性。此外,某些示例性大麻素硫酸酯盐显示出比母体大麻素高5,000至30,000倍的水溶性。
除了活性成分之外,制剂还可以含有协同或添加剂成分,其可以包括:δ-9-四氢大麻酚(THC)、δ-8-四氢大麻酚(THC)、大麻二酚(CBD)、大麻酚(CBN)、大麻酚酸(CBNA)、大麻萜酚(CBG)、大麻萜酚(CBG)、大麻萜酚(CBGV)、大麻色烯(CBC)、大麻双环醇(CBL)、大麻萜酚(CBV)、四氢次大麻酚(THCV)、大麻二酚(CBDV)、大麻萜酚(CBCV)、大麻萜酚单乙醚(CBGM)、大麻萜酚酸单乙醚(CBGAM)、大麻二酚酸(CBDA)、大麻萜酚酸(CBDA)、大麻萜酚酸(CBDA)。大麻二酚(CBDVA)、大麻二酚(CBD-C1)、δ-9-四氢大麻酚酸A(THCA-A)、δ-9-四氢大麻酚酸B(THCA-B)、δ-9-四氢大麻酚酸-C4(THCA-C4)、δ-8-四氢大麻酚酸(δ-8-THC)、δ-9-四氢大麻酚-C4(THC-C4)、δ-9-四氢大麻酚-Cl(THC-C1)、四氢次大麻酚酸(THCVA)、大麻二环酚酸(CBLA)、大麻二环酚(CBL)、大麻二环酚(CBL)、大麻二环酚(CBL)大麻酚-C4(CBN-C4)、大麻酚甲醚(CBNM)、大麻二酚(CBN-C1)、大麻酚-C2(CBN-C2)、大麻二醇(CBND)、次大麻二酚(CBVD)、大麻三醇(CBT)、次大麻三酚(CBTV)、脱氢大麻呋喃(DCBF)、大麻呋喃、大麻硝(CBT)、大麻三酚(CBR)、“11-羟基四氢大麻酚”(11-OH-THC)、“11-nor-9-羧基-四氢大麻酚”(THC-COOH)及其衍生物、合成类似物、相关化学结构和盐,以及它们的混合物和组合;乳香,包括乳香精油和齿叶乳香树,生姜,辣椒素,樟脑,多酚,包括槲皮素,鞣花酸,姜黄素和白藜芦醇,植物甾醇,碳水化合物,包括6-磷酸甘露糖;精油,包括百里酚和香芹酚,萜类化合物,包括角鲨烯、番茄红素、对伞花烃、芳樟醇,及其衍生物和类似物,或它们的混合物或组合。优选地,所述制剂包含针对所选大麻素酯化合物的附加协同或添加剂成分。
根据本发明设计的化合物可以通过口腔粘膜、鼻腔、口服、眼部、透皮和肠胃外途径递送。优选地,它们通过口服途径或经皮递送。
根据本发明的大麻素酯可用于各种应用,包括食品、饮料和医疗应用。优选地,它们可以用于治疗炎症和疼痛、精神健康障碍以及对大麻素受体的调节有反应的其他相关病症。与一些其他相关类似物相比,这些酯的盐的优选实施方案更稳定且水溶性更好,吸收得到改善,药代动力学和药效学分布也得到优化。它们可能有助于治疗炎症、疼痛、精神健康障碍和相关病症,以快速缓解症状并为患者提供持久的缓解。
例子
实施例1:CBD硫酸酯吡啶盐的制备
向具有橡胶帽、Teflon隔膜和搅拌棒的反应管中装入大麻二酚(CBD)(1.58g,5mmol,1当量)、Py.SO3(97%)(0.96g,6mmol,1.2当量)和3mL无水吡啶。反应管用氩气冲洗并在Monowave 中在5-20帕的压力下在70℃下加热4小时。冷却至室温后,在减压(100mbar)和50℃下蒸发吡啶,得到所需产物,为粘性油状物(2.36g,定量产率)。任选地,产物可以不经纯化直接用于下文实施例2的方法中。当使用其他溶剂(如二氯甲烷或四氢呋喃)、室温或大气压时,得到的产率较低(<50%)。当使用更高的温度(大于100℃)时,会观察到分解。
吡啶-1-鎓(1′R,2′R)-6-羟基-5′-甲基-4-戊基-2-胺
(d,J.7=5.49Hz,2H),8.50(d,.J=7.94Hz,1H),8.01(t,J=6.56Hz,2H),6.08-7.16(m,2H),5.30(br.s.,1H),4.44(br.s.,2H),3.75-4.22(m,1H),2.67-3.15(m,1H),1.77-2.57(m,6H),1.64(s,6H),1.34(br.s.,6H),0.71-1.01(m,3H);13C NMRδ157.67,153.34,150.34,146.52,144.41,142.62,133.57,128.31,127.02,118.17,113.92,111.00,110.65,46.42,38.50,36.63,32.77,32.03,31.80,30.82,23.88,23.69,19.55,14.52;C21H29O5 S-的HRMS m/z,计算值:393.1741,实测值:393.1740。
实施例2:反离子交换的一般程序
任选地,上述实施例1的方法的产物的吡啶抗衡离子可以在定量产率(95-99%)和分析纯度(95-98%)作为无定形粉末时被其他选择的碱代替根据以下方法,在水溶液中与1.2当量的所选碱(例如葡糖胺或赛洛辛)一起搅拌。水溶液可以是乙醇:水、甲醇:水、吡啶:水和/或异丙醇:水的1:1混合物。或者,水可以与其他有机溶剂如丙酮、THF或氯仿混合。当反离子交换反应在非水溶液(例如,无水乙醇或甲醇,或无水吡啶)中进行时,得到结晶形式的目标硫酸盐。
向具有聚乙烯塞和搅拌棒的反应小瓶中装入优选根据实施例1的方法生产的吡啶CBD硫酸盐(0.47g,1mmol,1当量),选择的碱(1.2mmol,1.2当量))和5mL的H2O或乙醇或H2O:乙醇溶液(1:1)。将反应在室温搅拌2-4小时以产生乳状乳液,将其冷却至-80℃,将溶剂冷冻干燥,优选使用2.5升台式冷冻,得到所需的无定形产物定量收率的粉末,无需进一步纯化。以下示例性CBD硫酸酯盐可以根据实施例2的方法通过选择合适的碱与溶液中的吡啶鎓CBD硫酸酯混合来制备。
(2R,R,4R,5S,6R)-2,4,5-三羟基-6-(羟甲基)四氢
-7.18(m,2H),5.39(d,J=3.36Hz,2H),4.43(s,2H),3.87-4.01(m,1H),3.71-3.84(m,4H),3.34-3.36(m,1H),3.06-3.22(m,1H),2.87-3.05(m,1H),1.68-2.84(m,6H),1.64(s,6H),1.28-1.37(m,6H),0.78-0.96(m,3H);13C NMRδ157.28、152.99、150.34、142.78、134.39、126.71、117.98、1133.76、111.85、111.00、90.76、90.76、73.33、733、71.61 31.88、31.68、30.55、23.88、23.57、19.47、14.52;C21H29O5S-的HRMS m/z,计算值:393.1741,实测值:393.1740。
本发明的其他示例性实施方案是用于治疗患有已知对大麻素治疗有反应的病症或疾病的患者的药物组合物。这些药物组合物包含本文公开的化合物或其药学上可接受的盐,以及一种或多种药学上可接受的稀释剂或赋形剂,或两者。
实施例3:每个硬明胶胶囊包含:
配料 | 质量(mg) | 功能 |
氨基葡萄糖大麻二酚-硫酸盐 | 25 | 催化剂 |
硫酸氨基葡萄糖 | 750 | 催化剂 |
微晶纤维素pH102 | 315 | 稀释剂 |
硬脂酸镁 | 30 | 润滑剂 |
二氧化硅 | 30 | 助流剂 |
实施例4:每个硬明胶胶囊含有:
配料 | 质量(mg) | 功能 |
氨基葡萄糖大麻二酚-硫酸盐 | 25 | 催化剂 |
硫酸氨基葡萄糖 | 750 | 催化剂 |
硫酸软骨素 | 600 | 催化剂 |
甲磺酰甲烷 | 300 | 催化剂 |
微晶纤维素ph102 | 140 | 稀释剂 |
硬脂酸镁 | 30 | 润滑剂 |
二氧化硅 | 30 | 助流剂 |
实施例5:每个硬明胶胶囊含有:
配料 | 质量(mg) | 功能 |
氨基葡萄糖大麻二酚-硫酸盐 | 25 | 催化剂 |
酸氨基葡萄糖 | 750 | 催化剂 |
硫酸软骨素 | 600 | 催化剂 |
微晶纤维素ph101 | 140 | 稀释剂 |
聚维酮k30 | 60 | 粘结剂 |
交联羧甲基纤维素钠 | 60 | 崩解剂 |
硬脂酸镁 | 30 | 润滑剂 |
二氧化硅 | 30 | 助流剂 |
实施例6:每个硬明胶胶囊包含:
配料 | 质量(mg) | 功能 |
氨基葡萄糖大麻二酚-硫酸盐 | 25 | 催化剂 |
酸氨基葡萄糖 | 750 | 催化剂 |
硫酸软骨素 | 600 | 催化剂 |
甲磺酰甲烷 | 600 | 催化剂 |
胶原蛋白 | 200 | 催化剂 |
微晶纤维素ph102 | 140 | 稀释剂 |
硬脂酸镁 | 30 | 润滑剂 |
二氧化硅 | 30 | 助流剂 |
实施例7:每片药片包含:
配料 | 质量(mg) | 功能 |
氨基葡萄糖大麻二酚-硫酸盐 | 25 | 催化剂 |
预胶化淀粉 | 120 | 稀释剂 |
甘露醇 | 300 | 稀释剂 |
羟丙基甲基纤维素 | 15 | 粘结剂 |
共聚维酮 | 20 | 崩解剂 |
滑石 | 5 | 润滑剂 |
二氧化硅 | 5 | 助流剂 |
实施例8:每100克乳膏含有以下配方
配料 | 质量(mg) | 功能 |
硫酸组胺大麻二酚 | 750 | 催化剂 |
硫酸氨基葡萄糖 | 2500 | 催化剂 |
失水山梨醇单硬脂酸酯 | 0.75 | 乳化剂 |
吐温6 | 3 | 表面活性剂 |
十六醇十八醇混合物 | 6 | 稳定器 |
丙二醇 | 5 | 溶剂 |
苄乙二醇 | 1 | 共溶剂 |
甲醇 | 0.14 | 防腐剂 |
丁羟甲苯 | 0.02 | 抗氧化剂 |
中链甘油三酯 | 8 | 乳膏基质 |
肉豆蔻酸异丙酯 | 5 | 润肤剂 |
纯净水 | 100 | 运输剂 |
术语“药学上可接受的稀释剂”或“药学上可接受的赋形剂”是指药学上可接受的材料、组合物或媒介物,例如液体或固体填充剂、溶剂或包封材料,其参与携带或运输任何主题组合物或其组分。每种载体在与主题组合物及其组分相容并且对患者无害的意义上必须是“可接受的”。可用作药学上可接受的载体的材料的一些实例包括:(1)糖,例如乳糖和麦芽糖;(2)淀粉,如玉米淀粉和胶凝淀粉;(3)纤维素及其衍生物,如羧甲基纤维素盐和羟丙基甲基纤维素;(4)增稠剂,如明胶和黄蓍胶;(5)共聚维酮等崩解剂;(6)其他辅料,如可可脂、栓剂蜡、无菌产品用无热原水等;(7)药物制剂中使用的其他无毒相容物质。
已经参照示例性实施例描述和说明了本发明;然而,本领域的技术人员将理解,可以进行各种改变,并且可以用等价物代替其中的元件,而不背离所附权利要求中所阐述的本发明的范围。因此,本发明不限于本文所公开的实施例。
Claims (127)
1.一种大麻素化合物,包含大麻素的不稳定酯与协同或相加的治疗对应物。
2.如权利要求1所述的大麻素化合物,其中所述不稳定酯是选自下组的酯:硫酸盐、半硫酸盐、单磷酸盐、二磷酸盐、三磷酸盐、碳酸盐、氨基甲酸盐、硝酸盐、硼酸盐、磺酸盐、膦酸盐,和双膦酸盐。
3.根据权利要求2所述的大麻素化合物,其中所述大麻素选自:δ-9-四氢大麻酚(THC)、δ-8-四氢大麻酚(THC)、大麻二酚(CBD)、大麻酚(CBN)、大麻酚酸(CBNA)、大麻酚(CBG)、大麻酚(CBG)、大麻酚(CBGV)、大麻色素(CBC)、大麻二环醇(CBL)、大麻酚(CBV)、四氢大麻酚(THCV)、大麻二酚(CBDV)、大麻色素(CBCV)、大麻酚单乙醚(CBGM)、大麻二酚酸单乙醚(CBGAM)大麻二酚酸(CBDA)、大麻二酚(CBGV A)、大麻二色酸(CBCA)、大麻二色二酸(CBCA)、大麻二酚单甲醚(CBDM)、大麻二酚-C4(CBD-C4),大麻二酚(CBDVA),大麻二酚(CBD-C1),δ-9-四氢大麻酚酸A(THCA-A),δ-9-四氢大麻酚酸B(THCA-B),δ-9-四氢大麻酚酸-C4(THCA-C4)、δ-8-四氢大麻酚酸(δ-8-THCA)、δ-8-四氢大麻酚(δ-8-THC)、δ-9-四氢大麻酚-C4(THC-C4)、δ-9-四氢大麻酚酸(THCA-C1)、δ-9-四氢大麻素-Cl(THC-C1)、四氢大麻二酚酸(THCVA)、大麻二环酸(CBLA)、大麻二环醇(CBL)、大麻二环素(CBLV),大麻酚A(CBEA-A),大麻酚B(CBEA-B),大麻酚(CBE),大麻素,大麻酚-C4(CBN-C4),大麻酚甲醚(CBNM),大麻酚(CBN-C1),大麻酚-C2(CBN-C2)、大麻二酚(CBND)、大麻二酚(CBVD)、大麻三醇(CBT)、大麻三酚(CBTV)、脱氢大麻酚(DCBF)、大麻呋喃、大麻素(CBT)、大麻酚(CBR)、'11-羟基四氢大麻酚(11-OH-THC),'11-nor-9-羧基-四氢大麻酚'(THC-COOH)。
4.根据权利要求3所述的大麻素化合物,其中所述治疗对应物是第二大麻素,其具有适于与所述大麻素形成不稳定酯键的官能团。
5.如权利要求4所述的大麻素化合物,其中所述官能团选自:硫醇、羟基、氨基、腈、氰酸酯、异氰酸酯、硫氰酸酯、异硫氰酸酯、叠氮化物、羧酸、酸酐、烯烃、炔烃、醛、酮、环氧化物和酚醛。
6.权利要求3的大麻素化合物,其中所述治疗对应物选自:葡糖胺、裸盖菇素、赛洛辛、普瑞巴林、加巴喷丁、托吡酯、对乙酰氨基酚、布洛芬、吗啡、咖啡酸、左旋多巴、香豆酸、槲皮素、类黄酮、水杨酸、百里酚、丁香酚、恩他卡朋、托卡朋、雌激素、选择性血清素再摄取抑制剂(SSRI)、雄激素和皮质类固醇。
7.根据权利要求3所述的大麻素化合物,其中所述不稳定酯是酯盐并且所述治疗对应物是所述酯盐的抗衡离子并且具有适合与所述大麻素制备酯盐的官能团。
8.如权利要求7所述的大麻素化合物,其中所述抗衡离子是伯胺、仲胺或叔胺,所述伯胺、仲胺或叔胺选自:环状胺、无环胺、乙醇胺衍生物、芳族胺、脂族胺、氨基糖、氨基聚合物、氨基低聚物和氨基酸。
9.根据权利要求8所述的大麻素化合物,其中所述抗衡离子选自:三乙醇胺、丁胺、精氨酸、赖氨酸、氨、三乙胺、三甲基胺、三丙基胺和三丁基胺。
10.根据权利要求8所述的大麻素化合物,其中所述抗衡离子是选自下组的芳族胺:苯胺、4-氨基嘧啶、萘胺、对氨基苯磺酸和4-氨基苯甲酸。
11.根据权利要求7所述的大麻素化合物,其中所述抗衡离子选自:哌嗪、吗啉、氮丙啶、氮杂环丁烷、二氮杂环丁烷、咪唑啉、吡唑烷、3-吡咯啉、三唑、咪唑、吡咯烷、哌啶、吡啶、哒嗪、嘧啶、吡嗪、二氧化硫吗啉、噻嗪、吡咯里西啶、氮杂吲哚、氮杂吲唑、嘌呤、吡唑并嘧啶、喹啉、十氢喹啉和偶氮烷。
12.根据权利要求7所述的大麻素化合物,其中,所述抗衡离子选自由以下组成的组:葡糖胺、蝶兰、蝶兰、普瑞巴林、加巴喷丁、托吡酯、吗啡、左旋多巴、选择性5-羟色胺再摄取抑制剂(SSRI)(例如,西酞普兰)、阿米巴普利、鲁拉西酮、帕潘立酮、帕潘立酮棕榈酸酯、利培酮、齐拉西酮、过螺酮、多柔比星、美梨酮、阿立哌唑、布雷哌唑、吡拉嗪、奥氮平、喹硫平、氟西汀、降钙素、盐酸伪麻黄碱、吡拉西坦、左乙拉西坦、西格列汀、西洛他汀、氢氯噻嗪、依折麦布、普拉洛尔、阿替洛尔、卡替洛尔、卡诺普洛尔、雌二醇、噻吗洛尔、地丁洛尔、普萘洛尔、卡维二醇、卡替洛尔、卡诺普洛尔、醋丁醇、美洛尔、地丁洛尔、奈必洛尔、卡维地尔、卡替洛尔、米诺拉洛尔、阿维地平、地地平、美利地平、卡尼洛尔、依地平、苯地平、溴莫尼定、硼替佐米、雷迪帕韦、达西他韦、奥姆达韦、埃伐布韦、拉米夫定、多巴胺、5-羟色胺、左旋多巴、普拉克索、罗匹阿司匹林、罗替戈汀、阿扑吗啡、他克林、利凡斯的明、多奈哌齐、加兰他明、维加巴阿司匹林、拉莫三嗪、替格宾、普瑞巴林、阿米替林、去甲替林和组胺。
13.权利要求2的大麻素化合物,其中所述大麻素化合物是式1的化合物:
其中R是治疗对应物。
14.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式2的化合物:
其中R是治疗对应物。
15.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式3的化合物:
其中每个R是独立选择的治疗对应物。
16.根据权利要求2所述的大麻素化合物,其中所述大麻素化合物是式4的化合物:
其中每个R是独立选择的治疗对应物。
17.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式5的化合物:
其中每个R是治疗对应物,独立选择。
18.根据权利要求2所述的大麻素化合物,其中所述大麻素化合物是式6的化合物:
其中每个R是独立选择的治疗对应物。
19.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式7化合物:
其中每个R是独立选择的治疗对应物。
20.权利要求2的大麻素化合物,其中所述大麻素化合物是式8化合物:
其中R是治疗对应物。
21.权利要求2的大麻素化合物,其中所述大麻素化合物是式9化合物:
其中R是治疗对应物。
22.根据权利要求2所述的大麻素化合物,其中所述大麻素化合物是式10的化合物:
其中每个R是独立选择的治疗对应物。
23.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式11的化合物:
其中每个R是独立选择的治疗对应物。
24.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式12的化合物:
其中每个R是独立选择的治疗对应物。
25.根据权利要求2所述的大麻素化合物,其中所述大麻素化合物是式13的化合物:
其中每个R是独立选择的治疗对应物。
26.根据权利要求2所述的大麻素化合物,其中所述大麻素化合物是式14的化合物:
其中每个R是独立选择的治疗对应物。
27.根据权利要求2所述的大麻素化合物,其中所述大麻素化合物是式15的化合物:
其中每个R是独立选择的治疗对应物。
28.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式16的化合物:
其中每个R是独立选择的治疗对应物。
29.根据权利要求2所述的大麻素化合物,其中所述大麻素化合物是式17的化合物:
其中每个R是独立选择的治疗对应物。
30.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式18的化合物:
31.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式19的化合物:
32.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式20的化合物:
33.权利要求2的大麻素化合物,其中所述大麻素化合物是式21的化合物:
其中R是治疗对应物。
34.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式22的化合物:
其中每个R是独立选择的治疗对应物。
35.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式23的化合物:
其中每个R是独立选择的治疗对应物。
36.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式24的化合物:
其中每个R是独立选择的治疗对应物。
37.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式25的化合物:
其中每个R是独立选择的治疗对应物。
38.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式26的化合物:
其中每个R是独立选择的治疗对应物。
39.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式27的化合物:
其中每个R是独立选择的治疗对应物。
40.根据权利要求2所述的大麻素化合物,其中所述大麻素化合物是式28的化合物:
其中B是治疗对应物。
41.权利要求40的大麻素,其中所述治疗对应物选自:葡糖胺、赛洛辛、普瑞巴林、加巴喷丁、托吡酯、吗啡、左旋多巴和西酞普兰。
42.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式29的化合物:
其中B是治疗对应物。
43.权利要求42的大麻素,其中所述治疗对应物选自:葡糖胺、赛洛辛、普瑞巴林、加巴喷丁、托吡酯、吗啡、左旋多巴和西酞普兰。
44.根据权利要求2所述的大麻素化合物,其中所述大麻素化合物是式30的化合物:
其中每个B是独立选择的治疗对应物。
45.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式31的化合物:
其中每个R和B是独立选择的治疗对应物。
46.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式32的化合物:
其中每个B是独立选择的治疗对应物。
47.权利要求46的大麻素化合物,其中所述治疗对应物选自:葡糖胺、赛洛辛、普瑞巴林、加巴喷丁、托吡酯、吗啡、左旋多巴和西酞普兰。
48.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式33的化合物:
其中每个R和B是独立选择的治疗对应物。
49.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式34的化合物:
其中每个B是独立选择的治疗对应物。
50.权利要求49的大麻素化合物,其中所述治疗对应物选自:葡糖胺、赛洛辛、普瑞巴林、加巴喷丁、托吡酯、吗啡、左旋多巴和西酞普兰。
51.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式35的化合物:
其中每个R和B是独立选择的治疗对应物。
52.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式36的化合物:
其中每个R和B是独立选择的治疗对应物。
53.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式37的化合物:
其中每个R和B是独立选择的治疗对应物。
54.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式38的化合物:
其中每个R和B是独立选择的治疗对应物。
55.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式39的化合物:
其中每个B是独立选择的治疗对应物。
56.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式40的化合物:
其中每个R和B是独立选择的治疗对应物。
57.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式41的化合物:
其中每个R和B是独立选择的治疗对应物。
58.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式42的化合物:
其中每个B是独立选择的治疗对应物。
59.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式43的化合物:
其中每个R和B是独立选择的治疗对应物。
60.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式44的化合物:
其中每个R和B是独立选择的治疗对应物。
61.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式45的化合物:
其中每个R和B是独立选择的治疗对应物。
62.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式46的化合物:
其中每个R和B是独立选择的治疗对应物。
63.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式47的化合物:
其中每个R和B是独立选择的治疗对应物。
64.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式48的化合物:
其中每个R和B是独立选择的治疗对应物。
65.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式49的化合物:
其中每个R和B是独立选择的治疗对应物。
66.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式50的化合物:
其中每个R和B是独立选择的治疗对应物。
67.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式51的化合物:
其中B是治疗对应物。
68.根据权利要求2所述的大麻素化合物,其中所述大麻素化合物是式52的化合物:
其中每个R和B是独立选择的治疗对应物。
69.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式53的化合物:
其中每个B是独立选择的治疗对应物。
70.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式54的化合物:
其中每个R和抗衡离子B是独立选择的治疗对应物。
71.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式55的化合物:
其中每个R和抗衡离子B是独立选择的治疗对应物。
72.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式56的化合物:
其中每个R和抗衡离子B是独立选择的治疗对应物。
73.权利要求2的大麻素化合物,其中所述大麻素化合物是式57的化合物:
其中Cann是大麻素并且R是治疗对应物。
74.权利要求73的大麻素化合物,其中所述大麻素化合物是式58的化合物:
其中R是治疗对应物。
75.权利要求73的大麻素化合物,其中所述大麻素化合物是式59的化合物:
其中R是治疗对应物。
76.权利要求2的大麻素化合物,其中所述大麻素化合物是式60的化合物:
其中Cann是大麻素并且B是治疗对应物。
77.权利要求76的大麻素化合物,其中所述大麻素化合物是式61的化合物:
其中B是治疗对应物。
78.权利要求77的大麻素,其中所述治疗对应物选自:葡糖胺、赛洛辛、普瑞巴林、加巴喷丁、托吡酯、吗啡、左旋多巴和西酞普兰。
79.如权利要求76所述的大麻素化合物,其中所述大麻素化合物是式62的化合物:
其中B是治疗对应物。
80.权利要求79的大麻素,其中所述治疗对应物选自:葡糖胺、赛洛辛、普瑞巴林、加巴喷丁、托吡酯、吗啡、左旋多巴和西酞普兰。
81.根据权利要求2所述的大麻素化合物,其中所述大麻素化合物是式63的化合物:
其中每个R是独立选择的治疗对应物。
82.根据权利要求81所述的大麻素化合物,其中所述大麻素化合物是式64的化合物:
其中每个R是独立选择的治疗对应物。
83.如权利要求81所述的大麻素化合物,其中所述大麻素化合物是式65的化合物:
其中每个R是独立选择的治疗对应物。
84.权利要求2的大麻素化合物,其中大麻素化合物是式66的化合物:
其中Cann是大麻素并且每个R和B是治疗对应物,独立选择。
85.如权利要求84所述的大麻素化合物,其中所述大麻素化合物是式68的化合物:
其中每个R和B是独立选择的治疗对应物。
86.如权利要求84所述的大麻素化合物,其中所述大麻素化合物是式70的化合物:
其中每个R和B是独立选择的治疗对应物。
87.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式67的化合物:
其中每个B是独立选择的治疗对应物。
88.根据权利要求87所述的大麻素化合物,其中所述大麻素化合物是式69的化合物:
其中每个B是独立选择的治疗对应物。
89.权利要求88的大麻素,其中所述治疗对应物选自:葡糖胺、赛洛辛、普瑞巴林、加巴喷丁、托吡酯、吗啡、左旋多巴和西酞普兰。
90.如权利要求87所述的大麻素化合物,其中所述大麻素化合物是式71的化合物:
其中每个B是独立选择的治疗对应物。
91.根据权利要求90所述的大麻素,其中所述治疗对应物选自:葡糖胺、赛洛辛、普瑞巴林、加巴喷丁、托吡酯、吗啡、左旋多巴和西酞普兰。
92.权利要求2的大麻素化合物,其中大麻素化合物是式72的化合物:
其中Cann是大麻素并且每个R是治疗对应物,独立选择。
93.权利要求2的大麻素化合物,其中大麻素化合物是式73的化合物:
其中Cann是大麻素并且每个R和B是治疗对应物,独立选择。
94.权利要求2的大麻素化合物,其中大麻素化合物是式74的化合物:
其中Cann是大麻素并且每个R和B是治疗对应物,独立选择。
95.权利要求2的大麻素化合物,其中大麻素化合物是式75的化合物:
其中Cann是大麻素并且每个R和B是治疗对应物,独立选择。
96.权利要求2的大麻素化合物,其中大麻素化合物是式76的化合物:
其中Cann是大麻素并且每个R和B是治疗对应物,独立选择。
97.权利要求2的大麻素化合物,其中大麻素化合物是式77的化合物:
其中Cann是大麻素并且每个B是治疗对应物,独立选择。
98.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式78的化合物:
其中每个R是独立选择的治疗对应物。
99.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式79的化合物:
其中每个R是独立选择的治疗对应物。
100.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式80的化合物:
其中每个R是独立选择的治疗对应物。
101.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式81的化合物:
其中每个R和B是独立选择的治疗对应物。
102.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式82的化合物:
其中每个R和B是独立选择的治疗对应物。
103.如权利要求2所述的大麻素化合物,其中所述大麻素化合物是式83的化合物:
其中每个R和B是独立选择的治疗对应物。
104.一种药物制剂,其包含大麻素与第一协同或相加治疗对应物的不稳定酯和与大麻素具有协同或相加效应的第二活性成分。
105.根据权利要求104所述的药物制剂,其中所述第二活性成分选自由以下组成的组:δ-9-四氢大麻酚(THC)、δ-8-四氢大麻酚(THC)、大麻二酚(CBD)、大麻酚(CBN)、大麻酚酸(CBNA)、大麻萜酚(CBG)、大麻萜酚(CBG)、大麻萜酚(CBGV)、大麻色烯(CBC)、大麻双环醇(CBL)、大麻萜酚(CBV)、四氢次大麻酚(THCV)、次大麻二酚(CBDV)、次大麻萜酚酸(CBCV)、大麻萜酚单乙醚(CBGM)、大麻萜酚酸单乙醚(CBGAM)、大麻二酚酸(CBDA)、大麻萜酚(CBGVA)、大麻色烯酸(CBCA)、大麻色烯酸(CBCA)、大麻二酚单甲醚(CBDM)、大麻二酚-C4(CBD-C4)、大麻二酚(CBDVA)、大麻二酚(CBD-C1)、δ-9-四氢大麻酚酸A(THCA-A)、δ-9-四氢大麻酚酸B(THCA-B)、δ-9-四氢大麻酚酸-C4(THCA-C4)、δ-8-四氢大麻酚酸(δ-8-THCA)、δ-8-四氢大麻酚(δ-8-THC)、δ-9-四氢大麻酚-C4(THC-C4)、δ-9-四氢大麻酚酸(THCA-C1),δ-9-四氢大麻酚-Cl(THC-Cl)、四氢次大麻酚酸(THCVA)、大麻二环酸(CBLA)、大麻二环醇(CBL)、大麻二环酚(CBLV)、大麻艾尔松酸A(CBEA-A)、大麻艾尔松酸B(CBEA-B)、大麻艾尔松(CBE)、次大麻酚、大麻酚-C4(CBN-C4)、大麻酚甲醚(CBNM)、大麻二酚(CBN-C1)、大麻酚-C2(CBN-C2)、大麻二醇(CBND)、次大麻二酚(CBVD)、大麻三醇(CBT)、次大麻三酚酚(CBTV)、脱氢大麻呋喃(DCBF)、大麻呋喃、大麻衣兰(CBT)、大麻三酚(CBR)、‘11-羟基四氢大麻酚(11-OH-THC)、‘11-去甲-9-羧基-四氢大麻酚’(THC-COOH)、乳香属物种、乳香、齿叶乳香、姜、辣椒素、樟脑、多酚、槲皮素、鞣花酸、姜黄素和白藜芦醇、植物甾醇、碳水化合物(包括甘露糖-6-磷酸酯)、精油(包括百里酚和香芹酚)、萜类(包括角鲨烯)芳樟醇及其衍生物、类似物、盐、混合物和组合。
106.根据权利要求104所述的药物制剂,其中所述药物制剂为硬明胶胶囊的形式,包含25mg葡糖胺CBD-硫酸盐、750mg葡糖胺硫酸盐、315mg微晶纤维素pH102、30mg硬脂酸镁和30mg二氧化硅。
107.如权利要求104所述的药物制剂,其中所述药物制剂为硬明胶胶囊的形式,包含25mg的葡糖胺CBD-硫酸盐、750mg的葡糖胺硫酸盐、600mg的硫酸软骨素、300mg的甲磺酰甲烷、140mg微晶纤维素pH102、30mg硬脂酸镁和30mg二氧化硅。
108.根据权利要求104所述的药物制剂,其中所述药物制剂为硬明胶胶囊的形式,包含25mg的葡糖胺CBD-硫酸盐、750mg的葡糖胺硫酸盐、600mg的硫酸软骨素、140mg的微晶纤维素pH102,60mg聚维酮K30,60mg交联羧甲基纤维素钠,30mg硬脂酸镁和30mg二氧化硅。
109.如权利要求104所述的药物制剂,其中所述药物制剂是硬明胶胶囊的形式,包含25mg氨基葡萄糖CBD-硫酸盐、750mg氨基葡萄糖硫酸盐、600mg硫酸软骨素、300mg甲磺酰甲烷、200mg胶原蛋白、140mg微晶纤维素pH102、30mg硬脂酸镁和30mg二氧化硅。
110.根据权利要求104所述的药物制剂,其中所述药物制剂为片剂形式,包含25mg葡糖胺CBD-硫酸盐、120mg预胶化淀粉、300mg甘露醇、20mg共聚维酮、5mg滑石粉和5mg二氧化硅。
111.根据权利要求104所述的药物制剂,其中所述药物制剂为乳膏剂形式,包含750mg组胺CBD-硫酸盐、2500mg硫酸葡糖胺、0.75mg脱水山梨糖醇单硬脂酸酯、3mg吐温60、6mg鲸蜡硬脂醇、丙二醇5mg、苯甲醇1mg、对羟基苯甲酸甲酯0.14mg、丁基羟基甲苯0.02mg、中链甘油三酯8mg、肉豆蔻酸异丙酯5mg和纯净水填充每100g奶油。
112.一种生产大麻素化合物的方法,所述大麻素化合物包含大麻素与协同或相加治疗对应物的不稳定酯,包括以下步骤:将具有不稳定抗衡离子的大麻素酯盐与形式为的治疗对应物混合一种碱,其中混合步骤在水性溶剂的存在下进行。
113.根据权利要求112所述的方法,其中所述水性溶剂是水性溶剂和非水性溶剂的1:1混合物。
114.权利要求112的方法,其中在混合步骤中加入的治疗对应物的量大于大麻素酯盐的量。
115.权利要求114的方法,其中在混合步骤中添加的大麻素酯盐与治疗对应物的比率为1:1 2
116.根据权利要求112所述的方法,其中所述大麻素酯盐是大麻素硫酸酯盐,并且其中所述不稳定抗衡离子是吡啶,并且所述方法还包括通过将大麻素与吡啶混合来生产所述大麻素硫酸酯盐的较早步骤吡啶中的三氧化硫。
117.权利要求116的方法,其中生产大麻素硫酸酯盐的较早步骤在高于室温和大气压的升高的温度和压力下进行。
118.根据权利要求117所述的方法,其中所述升高的温度和压力在65-90℃之间和5-20帕之间。
119.根据权利要求118所述的方法,其中所述大麻素是THC并且所述治疗对应物是葡糖胺。
120.根据权利要求118所述的方法,其中所述大麻素是CBD并且所述治疗对应物是葡糖胺。
121.根据权利要求118所述的方法,其中所述大麻素是THC并且所述治疗对应物是裸盖菇素。
122.根据权利要求118所述的方法,其中所述大麻素是CBD并且所述治疗对应物是裸盖菇素。
123.根据权利要求118所述的方法,其中所述大麻素是THC并且所述治疗对应物是加巴喷丁或相关的加巴喷丁。
124.根据权利要求118所述的方法,其中所述大麻素是CBD并且所述治疗对应物是加巴喷丁或相关的加巴喷丁。
125.根据权利要求118所述的方法,其中所述大麻素是THC并且所述治疗对应物是普瑞巴林或相关的加巴喷丁。
126.根据权利要求118所述的方法,其中所述大麻素是CBD并且所述治疗对应物是普瑞巴林或相关的加巴喷丁。
127.权利要求1-103的大麻素化合物或权利要求104-111的药物制剂在治疗、减轻或减轻患有选自以下的一种或多种病症、障碍或疾病的人或动物受试者的症状中的用途包括:疼痛、神经性疼痛、炎症、神经退行性疾病、多发性硬化症、脊髓和脑损伤、创伤后应激障碍、癫痫、小儿癫痫症、成瘾、失眠、恶心和呕吐、癌症、肾纤维化、肥胖症、精神分裂症、抑郁症、强迫症、焦虑症、精神疾病、睡眠障碍、纤维肌痛、图雷特综合征、青光眼、克罗恩病、炎症性肠病、丛集性头痛和厌食症。
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