CN113087741A - 大麻二酚衍生物及其制备方法和在医药上的应用 - Google Patents
大麻二酚衍生物及其制备方法和在医药上的应用 Download PDFInfo
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- CN113087741A CN113087741A CN202110020570.7A CN202110020570A CN113087741A CN 113087741 A CN113087741 A CN 113087741A CN 202110020570 A CN202110020570 A CN 202110020570A CN 113087741 A CN113087741 A CN 113087741A
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- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 125000002262 penten-4-yl group Chemical group C=CCC(C)* 0.000 description 1
- 208000033300 perinatal asphyxia Diseases 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
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- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- YAQKNCSWDMGPOY-JEDNCBNOSA-N propan-2-yl (2s)-2-aminopropanoate;hydrochloride Chemical compound Cl.CC(C)OC(=O)[C@H](C)N YAQKNCSWDMGPOY-JEDNCBNOSA-N 0.000 description 1
- 230000001107 psychogenic effect Effects 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
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- MQDVUDAZJMZQMF-UHFFFAOYSA-N pyridin-2-ylurea Chemical compound NC(=O)NC1=CC=CC=N1 MQDVUDAZJMZQMF-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
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- 235000011152 sodium sulphate Nutrition 0.000 description 1
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- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000004014 thioethyl group Chemical group [H]SC([H])([H])C([H])([H])* 0.000 description 1
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- 229910052722 tritium Inorganic materials 0.000 description 1
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Abstract
本发明涉及大麻二酚衍生物及其在医药上的应用,具体而言涉及如通式(I)所示的嘧啶衍生物,或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶,其中,通式(I)中各取代基的定义与说明书的定义相同。
Description
技术领域
本发明涉及大麻二酚衍生物,或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其药物组合物以及在制备药物中的应用。
背景技术
大麻(Cannabis sativa L.)为桑科大麻属一年生草本植物,起源于中亚和东亚,广泛分布于美国、印度、巴西等地。大麻的药用历史悠久,但成瘾性和精神致幻作用,使其临床应用受到极大限制。大麻包含数百种不同的化学物质,大约有70多种成分被称为大麻素,主要包括大麻二酚(cannabidiol,CBD)、大麻酚(cannabinol,CBN)、四氢大麻酚(Tetrahydrocannabinol,THC)及其同系物等,其中大麻二酚(CBD)含量最高。CBD不但能拮抗THC所引发的精神活性,而且具有广泛的治疗特征,对神经疾病包括焦虑、精神分裂、成瘾、神经退行性疾病、新生儿低氧缺血性脑病、癫痫均具有明显的改善作用,另外在抗肿瘤、抗炎、肝肝保护、疼痛、抗焦虑、抗失眠、抗惊厥、抗呕吐、抗痉挛、抗氧化、神经保护的治疗上,也表现出很好的应用前景。但是CBD口服生物利用度低(人口服生物利用度大约6%),需要开发新的技术,以达到改善药物在体内的吸收、分布、转运与代谢过程、提高生物利用度、提高药物对靶部位作用的选择性、降低药物的毒副作用、延长作用时间等的技术效果。
发明内容
本申请的目的是提供新的大麻二酚衍生物,或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药,其药物组合物以及其在制备药物中的应用。
在本申请的一个或多个实施方式中,本申请的化合物被摄入后能够转换为其原型药,且与原型药相比,具有更高的生物利用度(例如口服生物利用度)和更长的半衰期,并且可以提高并改善治疗效果、降低毒副作用。
本申请的一个或多个实施方式提供了通式(I)所示的化合物,或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶:
其中:
X选自氢、羟基、C1-6烷基或者卤素;
Y选自氢、羧基、C1-6烷基或者卤素;
r选自0、1、2或者3;
n选自0、1或者2;
R0选自甲基、C3-8碳环基、-CH2OH、-C(=O)OC1-6烷基、-C(=O)NRb1Rb2或者羧基;
R1选自C1-6烷基,所述的C1-6烷基可以任选进一步被0至3个卤素所取代;
Ra选自H或者C1-6烷基;
Rb、Rc各自独立地选自H、C1-6烷基、氨基酸侧链、-C1-6亚烷基-C3-12碳环或者-C1-6亚烷基-C3-12杂环;所述的C3-12杂环包含1至4个选自N、O或者S的杂原子;所述的C1-6亚烷基、C1-6烷基、C3-12碳环、C3-12杂环任选地进一步被0至3个选自羟基、羧基、卤素、氰基、=O、C1-6烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、-NRb1Rb2、-C(=O)OC1-6烷基、-C(=O)NRb1Rb2、C3-12环烷基、C3-12杂环烷基、C6-12芳基或者C5-12杂芳基的取代基所取代;且作为取代基的所述的C1-6烷基、C1-6杂烷基、C2-6烯基或者C2-6炔基任选进一步被1个或者多个选自羟基、羧基、氰基、卤素、-O-Rb1、-NRb1Rb2、C3-12环烷基、C3-12杂环烷基、C6-12芳基或者C5-12杂芳基的取代基所取代;当所述的氨基酸侧链包含羟基、巯基或羧基时,所述羟基、巯基或羧基任选地被酯化;
Rb1、Rb2各自独立地选自H、C1-6烷基、-C(=O)Rb3或者-C(=O)NRb4Rb5,其中所述的C1-6烷基任选进一步被1个或者多个选自羟基、卤素、C1-6烷基、C1-6烷氧基、C6-12芳基、C5-12杂芳基、C3-12环烷基或者C3-12杂环烷基的取代基所取代;
Rb3选自C1-6烷基、C1-6烷氧基或者C6-12芳基;
Rb4、Rb5各自独立地选自H或者C1-6烷基;或者Rb4与Rb5及N原子形成一个3至12元杂环,所述的3至12元杂环包含1至4个选自N、O或者S的杂原子;
或者,Rb和Rc与其所连接的原子一起形成3至6元碳环或者3至6元杂环,所述3至6元碳环或者3至6元杂环任选进一步被0至3个选自F、Cl、Br、I、羟基、羧基或氨基的取代基所取代,所述的3至6元杂环包含1至4个选自N、O或者S的杂原子;
Rd选自自C1-6烷基、C2-6烯基、C2-6炔基、C3-10碳环、3至10元杂环、-C1-6亚烷基-C3-10碳环、-C1-6亚烷基-3至10元杂环、-C1-6亚烷基-O-C1-6亚烷基-C3-10碳环、-C1-6亚烷基-O-C1-6亚烷基-3至10元杂环或-C1-6亚烷基-O-C1-4烷基,所述C1-6亚烷基、C2-6烯基、C2-6炔基、C1-6烷基、C3-10碳环或3至10元杂环任选进一步被0至4个选自H、F、Cl、Br、I、羟基、羧基、氨基、1-环丙基乙基、C1-4烷基、C1-4烷氧基、-OC(=O)ORd1或-OC(=O)Rd2的取代基所取代,所述3至10元杂环包含1至6个选自N、O或者S的杂原子;
Rd1和Rd2各自独立地选自C1-4烷基、C3-10碳环或3至10元杂环,所述C1-4烷基、C3-10碳环或3至10元杂环任选进一步被0至4个选自H、F、Cl、Br、I、羟基、羧基、C1-4烷基、C1-4烷氧基、C3-10碳环或3至10元杂环的取代基所取代,所述3至10元杂环包含1至6个选自N、O或者S的杂原子;
R3选自选自C1-6烷基、C3-8碳环基或者C2-6烯基,所述的C1-6烷基、C2-6烯基、C3-8碳环基任选进一步被0至3个选自卤素、C3-8碳环基、羟基或者C1-6烷基的取代基所取代;
R选自氨基酸侧链;当所述的氨基酸侧链包含羟基、巯基或羧基时,该羟基、巯基或羧基任选地被酯化;
R5选自C1-12烷基、C1-12杂烷基、C2-12烯基、C2-12炔基、C3-12碳环基、C3-12杂环基、-C1-6亚烷基-C3-12碳环基、-C1-6亚烷基-C3-12杂环基、-NRb1Rb2、-C1-6亚烷基-C(=O)OC1-6烷基或者-C1-6亚烷基-C(=O)NRb1Rb2,且所述的C1-12烷基、C1-12杂烷基、C2-12烯基、C2-12炔基、C1-6亚烷基、C3-12碳环基、C3-12杂环基任选被1个或者多个选自羟基、羧基、卤素、氰基、=O、C1-6烷基、-NRb1Rb2、C3-12碳环基、C3-12杂环基、C2-6烯基、C2-6炔基、-C(=O)OC1-6烷基、-C(=O)C1-6烷基、-C(=O)NRb1Rb2、-S(=O)C1-6烷基或者-S(=O)2C1-6烷基的取代基所取代,且作为取代基的所述的C1-6烷基、C3-12碳环基、C3-12杂环基任选进一步被1个或者多个选自=O、羟基、羧基、卤素、氰基、-C(=O)OC1-6烷基或者-C(=O)C1-6烷基的取代基所取代;
或者,通式(I)可以任选被1个或者多个D原子取代。
本申请的一个或多个实施方式提供通式(II)所示的化合物,或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶:
其中,
R0为甲基或者-CH2OH;
R1为C1-6烷基;
Ra为H;
Rb、Rc各自独立地选自H或者氨基酸侧链;当所述的氨基酸侧链包含羟基、巯基或羧基时,所述羟基、巯基或羧基任选地被酯化;
Rd选自自C1-6烷基、-C3-10碳环或者-3至10元杂环,所述C1-6烷基、C3-10碳环或3至10元杂环任选进一步被0至4个选自H、F、Cl、Br、I、羟基、羧基、氨基、1-环丙基乙基、C1-4烷基、C1-4烷氧基、OC(=O)ORd1或OC(=O)Rd2的取代基所取代,所述3至10元杂环包含1至6个选自N、O或者S的杂原子;
Rd1和Rd2各自独立地为C1-4烷基;
或者,通式(II)任选被1个或者多个D原子取代。
本申请的一个或多个实施方式提供通式(III)所示的化合物,或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶:
其中,
R1为C1-6烷基;
Rd选自自C1-6烷基、-C3-10碳环或者-3至10元杂环,所述C1-6烷基、C3-10碳环或3至10元杂环任选进一步被0至4个选自H、F、Cl、Br、I、羟基、羧基、氨基、1-环丙基乙基、C1-4烷基、C1-4烷氧基、OC(=O)ORd1或OC(=O)Rd2的取代基所取代,所述3至10元杂环包含1至6个选自N、O或者S的杂原子;
Rd1和Rd2各自独立地为C1-4烷基;
或者,通式(IV)的H原子任选被1个或者多个D原子取代。
本申请的一个或多个实施方式提供以下的化合物,或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶,其中该化合物为以下结构之一:
本申请的一个或多个实施方式提供药物组合物,所述药物组合物包含:
(1)本申请的化合物或其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或者共晶;
(2)任选的一种或者多种其他活性成分;以及
(3)药学上可接受的载体和/或赋形剂。
在本申请的一个或多个实施方式中,所述的其他活性成分选自银杏内酯、抗肿瘤剂、抗凝血剂、抗癫痫剂、抗抑郁剂、抗焦虑剂、催眠剂、镇痛剂或者麻醉剂中的一种或多种,或者所述的其他活性成分的立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或共晶。
本申请的一个或多个实施方式提供本申请的化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶或者药物组合物在制备用于治疗创伤后应激障碍、面瘫、中风、偏头痛、冠心病稳定型心绞痛、脑梗塞、血栓栓塞、心肌梗塞、心脏缺血、冠状动脉疾病、高血压、脑缺血、改善性功能、痉挛、急性和慢性疼痛、纤维肌痛、术后疼痛、丛集性头痛、紧张性头痛、背疼、四肢痛、腰痛、颈部疼痛、神经性疼痛、癌痛、三叉神经痛、关节炎疼痛、炎性疼痛、Dravet综合征、Lennox-Gastaut综合征、Prader-Willi综合征、Sturge-Weber综合征、脆性X综合征、焦虑、双相情感障碍、自闭症、广泛性焦虑症、社交焦虑症、癫痫、帕金森氏病、阿尔茨海默氏病、亨廷顿氏病、阿片类药物滥用、酗酒、尼古丁成瘾、厌食症、恶病质、化疗相关恶心呕吐、术后恶心和呕吐、肌萎缩性侧索硬化症(ALS)、Friedreich共济失调、精神分裂症、强迫症、多发性硬化症、抑郁、睡眠障碍、多发性硬化引起的痉挛、肌张力障碍、睡眠呼吸暂停、麻痹性痴呆、记忆力减退或者胶质母细胞瘤的药物中的用途。
本申请的一个或多个实施方式提供了用作药物使用的本申请的上述化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶。
本申请的一个或多个实施方式提供了在治疗以下疾病的方法中使用的本申请的上述化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶:创伤后应激障碍、面瘫、中风、偏头痛、冠心病稳定型心绞痛、脑梗塞、血栓栓塞、心肌梗塞、心脏缺血、冠状动脉疾病、高血压、脑缺血、改善性功能、痉挛、急性和慢性疼痛、纤维肌痛、术后疼痛、丛集性头痛、紧张性头痛、背疼、四肢痛、腰痛、颈部疼痛、神经性疼痛、癌痛、三叉神经痛、关节炎疼痛、炎性疼痛、Dravet综合征、Lennox-Gastaut综合征、Prader-Willi综合征、Sturge-Weber综合征、脆性X综合征、焦虑、双相情感障碍、自闭症、广泛性焦虑症、社交焦虑症、癫痫、帕金森氏病、阿尔茨海默氏病、亨廷顿氏病、阿片类药物滥用、酗酒、尼古丁成瘾、厌食症、恶病质、化疗相关恶心呕吐、术后恶心和呕吐、肌萎缩性侧索硬化症(ALS)、Friedreich共济失调、精神分裂症、强迫症、多发性硬化症、抑郁、睡眠障碍、多发性硬化引起的痉挛、肌张力障碍、睡眠呼吸暂停、麻痹性痴呆、记忆力减退或者胶质母细胞瘤。
本申请的一个或多个实施方式提供了治疗以下疾病的方法,其包括向有此需要的对象给予本申请的上述化合物或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶:创伤后应激障碍、面瘫、中风、偏头痛、冠心病稳定型心绞痛、脑梗塞、血栓栓塞、心肌梗塞、心脏缺血、冠状动脉疾病、高血压、脑缺血、改善性功能、痉挛、急性和慢性疼痛、纤维肌痛、术后疼痛、丛集性头痛、紧张性头痛、背疼、四肢痛、腰痛、颈部疼痛、神经性疼痛、癌痛、三叉神经痛、关节炎疼痛、炎性疼痛、Dravet综合征、Lennox-Gastaut综合征、Prader-Willi综合征、Sturge-Weber综合征、脆性X综合征、焦虑、双相情感障碍、自闭症、广泛性焦虑症、社交焦虑症、癫痫、帕金森氏病、阿尔茨海默氏病、亨廷顿氏病、阿片类药物滥用、酗酒、尼古丁成瘾、厌食症、恶病质、化疗相关恶心呕吐、术后恶心和呕吐、肌萎缩性侧索硬化症(ALS)、Friedreich共济失调、精神分裂症、强迫症、多发性硬化症、抑郁、睡眠障碍、多发性硬化引起的痉挛、肌张力障碍、睡眠呼吸暂停、麻痹性痴呆、记忆力减退或者胶质母细胞瘤。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素包括17F和19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“烃基”是指只含碳、氢两种原子的基团。
“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基,优选为1至8个(例如1、2、3、4、5、6、7、8个)碳原子的烷基,更优选为1至6个碳原子的烷基,进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体;当烷基被取代基时,可以任选进一步被1个或者多个取代基所取代。
“杂烷基”是指烷基至少一个C原子被O、S、N或者P原子取代的基团。非限制性实施例包括硫代甲基、硫代乙基、硫代正丙基、硫代异丙基、硫代正丁基、硫代仲丁基、硫代叔丁基。所述的烷基定义与上文所述的“烷基”定义相同。
“烷氧基”是指烷基中至少1个碳原子被氧原子取代所形成的基团。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷基定义与上文所述的“烷基”定义相同。
“烯基”是指包含1至10个(例如1、2、3、4、5、6、7、8、9、10个)碳-碳双键,由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基,优选2至12个(例如2、3、4、5、6、7、8、9、10、11、12个)碳原子的烯基,更优选2至8个碳原子的烯基,进一步优选2至6个碳原子的烯基。非限制性实施例包括乙烯基、丙烯-2-基、丁烯-2-基、丁烯-2-基、戊烯-2-基、戊烯-4-基、己烯-2-基、己烯-3基、庚烯-2-基、庚烯-3-基、庚烯-4-基、辛烯-3-基、壬烯-3-基、癸烯-4-基和十一烯-3-基。所述的烯基可以任选进一步被1个或者多个取代基所取代。
“炔基”是指包含1至10个(例如1、2、3、4、5、6、7、8、9、或10个)碳-碳叁键,由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基,优选2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子的炔基,更优选2至8个碳原子的炔基,进一步优选2至6个碳原子的炔基。非限制性实施例包括乙炔基、丙炔-1-基、丙炔-2-基、丁炔-1-基、丁炔-2-基、丁炔-3-基、3,3-二甲基丁炔-2-基、戊炔-1-基、戊炔-2-基、己炔-1-基、1-庚炔-1-基、庚炔-3-基、庚炔-4-基、辛炔-3-基、壬炔-3-基、癸炔-4-基、十一炔-3-基、十二炔-4-基。所述的炔基可以任选进一步被1至多个取代基所取代。
“芳基”是指是指取代的或未取代的芳香环,其可以是5至8元(例如5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,其可以是桥环或者螺环,非限制性实施例包括苯基、萘基。所述的芳基可以任选进一步被1个或者多个取代基所取代。
“杂芳基”是指取代的或未取代的芳香环,其可以是3至8元(例如3、4、5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,且包含1至6个(例如1、2、3、4、5、6个)选自N、O或S的杂原子,优选5至8元杂芳基,杂芳基的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上,杂芳基可以是桥环或者螺环,非限制性实施例包括环吡啶基、呋喃基、噻吩基、吡喃基、吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基苯并咪唑基、苯并吡啶基、吡咯并吡啶基。杂芳基任选进一步被1个或多个取代基所取代。
“碳环基”或“碳环”是指饱和或者不饱和的芳香环或者非芳香环。当为芳香环时,其定义与上文“芳基”的定义相同;当为非芳香环时,其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,可以是桥环或者螺环,非限制性实施例包括环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基、 所述的“碳环基”或“碳环”任选进一步被1个或者多个取代基所取代。
“杂环基”或“杂环”是指饱和或不饱和的芳香性杂环或者非芳香性杂环,当为芳香性杂环时,其定义与上文“杂芳基”定义相同;当为非芳香性杂环时,其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,且包含1至4个(例如1、2、3、4个)选自N、O或S的杂原子,优选3至8元杂环基。“杂环基”或“杂环”的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态;“杂环基”或“杂环”可以连接在杂原子或者碳原子上;“杂环基”或“杂环”可以为桥环或者螺环。“杂环基”或“杂环”的非限制性实施例包括环氧乙基、环氧丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、硫杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、氧杂环庚基、硫杂环庚基、氧氮杂卓基、二氮杂卓基、硫氮杂卓基、吡啶基、哌啶基、高哌啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、高哌嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、噻噁烷基、1,3-二噻烷基、二氢呋喃基、二噻戊环基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、3H-吲哚基喹嗪基、N-吡啶基尿素、1,1-二氧硫代吗啉基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。所述的“杂环基”或“杂环”任选进一步被1个或者多个取代基所取代。
“环烷基”是指饱和的环烃基,其环可以为3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至20元(例如4、5、6、7、8、9、10、11、12元)多环体系,环碳原子优选3至10个碳原子,进一步优选3至8个碳原子。“环烷基”非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、1,5-环辛二烯基、1,4-环己二烯基和环庚三烯基等。当环烷基被取代时,可以任选进一步被1个或者多个取代基所取代。
“杂环烷基”是指取代的或未取代的饱和非芳香环基,其可以是3至8元(例如3、4、5、6、7、8元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,且包含1、2或3个选自N、O或S的杂原子,优选3至8元杂环基。“杂环烷基”的环中选择性取代的N、S可被氧化成各种氧化态;“杂环烷基”可以连接在杂原子或者碳原子上;“杂环烷基”可以为桥环或者螺环。“杂环烷基”非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、哌啶基、哌叮基、吗啉基、硫代吗啉基、1,3-二噻烷基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。
当上文所述的“烷基”、“烷氧基”、“烯基”、“炔基”、“芳基”、“杂芳基”、“碳环基”、“碳环”、“杂环基”、“杂环”、“环烷基”、“杂环烷基”或者“杂环基”被取代时,可以任选进一步被0、1、2、3、4、5、6、7、8、9或者10个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、C1-6烷基氨基、=O、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-NRq4Rq5、=NRq6、-C(=O)OC1-6烷基、-OC(=O)C1-6烷基、-C(=O)NRq4Rq5、C3-8环烷基、C3-8杂环烷基、C6-10芳基、C5-10杂芳基、-C(=O)OC6-10芳基、-OC(=O)C6-10芳基、-OC(=O)C5-10杂芳基、-C(=O)OC5-10杂芳基、-OC(=O)C3-8杂环烷基、-C(=O)OC3-8杂环烷基、-OC(=O)C3-8环烷基、-C(=O)OC3-8环烷基、-NHC(=O)C3-8杂环烷基、-NHC(=O)C6-10芳基、-NHC(=O)C5-10杂芳基、-NHC(=O)C3-8环烷基、-NHC(=O)C3-8杂环烷基、-NHC(=O)C2-6烯基或者-NHC(=O)C2-6炔基的取代基所取代,且其中所述的取代基C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、C3-8杂环烷基、C6-10芳基、C5-10杂芳基、-NHC(=O)C6-10芳基、-NHC(=O)C5-10杂芳基、-NHC(=O)C3-8杂环烷基或者-NHC(=O)C3-8环烷基任选进一步被1至3个选自OH、F、Cl、Br、I、C1-6烷基、C1-6烷氧基、-NRq4Rq5或者=O的取代基所取代;Rq1选自C1-6烷基、C1-6烷氧基或者C6-10芳基;Rq2、Rq3选自H或者C1-6烷基;其中,Rq4、Rq5选自H、C1-6烷基、-NH(C=NRq1)NRq2Rq3、-S(=O)2NRq2Rq3、-C(=O)Rq1或者-C(=O)NRq2Rq3,其中所述的C1-6烷基任选进一步被1个或者多个选自OH、F、Cl、Br、I、C1-6烷基、C1-6烷氧基、C6-10芳基、C5-10杂芳基、C3-8环烷基或者C3-8杂环烷基的取代基所取代;或者Rq4与Rq5及N原子形成一个3至8元杂环,所述的杂环可以包含1个或者多个选自N、O或者S的杂原子。
“氨基酸侧链”是指氨基酸分子中除了氨基和羧基之外的基团。
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性,且所述的游离酸通过与无毒的无机碱或者有机碱反应获得的盐,所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物,其中,“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的氨基或者羧基来制备,该修饰可以通过常规的操作或者在体内被除去,而得到母体化合物。当本发明的前药被施予哺乳动物个体时,前药被割裂形成游离的氨基或者羧基。
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体,其中API和CCF的纯态在室温下均为固体,并且各组分间存在固定的化学计量比。共晶是一种多组分晶体,既包含两种中性固体之间形成的二元共晶,也包含中性固体与盐或溶剂化物形成的多元共晶。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生,该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如,“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在,该描述包括其中杂环基被烷基取代的情况,及其中杂环基未被烷基取代的情况。
本发明说明书对具体实施方案进行了详细描述,本领域技术人员应认识到,下述实施方案是示例性的,不能理解为对本发明的限制,对于本领域技术人员来说,在不脱离本发明原理的前提下,通过对本发明进行若干改进和修饰,这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。
具体实施方式
以下实施例详细说明本发明的技术方案,但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS);
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI));
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM);
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm,薄层层析分离纯化产品采用的规格是0.4mm-0.5mm;
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体;
本发明的己知起始原料可以采用或按照本领域已知的方法来合成,或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司;
氮气氛是指反应瓶连接约1L容积的氮气气球;
氢气氛是指反应瓶连接约1L容积的氢气气球;
氢化反应通常抽真空,充入氢气,反复操作3次;
实施例中无特殊说明,反应在氮气氛下进行;
实施例中无特殊说明,溶液是指水溶液;
实施例中无特殊说明,反应的温度为室温,室温最适宜的反应温度,为20℃-30℃;
DCM:二氯甲烷;
EA:乙酸乙酯;
HCl:盐酸;
THF:四氢呋喃;
DMF:N,N-二甲基甲酰胺;
PE:石油醚;
TLC:薄层色谱;
SFC:超临界流体色谱法;
NCS:N-氯代丁二酰亚胺;
Pd(dppf)Cl2:[1,1'-双(二苯基膦)二茂铁]二氯化钯;
实施例
以下实施例详细说明本发明的技术方案,但本发明的保护范围包括但是不限于此。
实施例1
isopropyl((ethoxycarbonyl)(((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)phosphoryl)-L-alaninate
异丙基((乙氧基羰基)(((1'R,2'R)-6-羟基-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1',2',3',4'-四氢-[1,1'-联苯]-2-基)氧基)磷酰基)-L-丙氨酸盐(化合物1)
在干燥的圆底烧瓶中将(二氯磷酰基)甲酸乙酯(0.31g,1.6mmol)溶解于二氯甲烷(1ml),在-60℃下加入三乙胺(0.25mL,1.1eq),然后滴加L-丙氨酸异丙酯盐酸盐(0.16g,0.95mmol,0.6eq)溶解于二氯甲烷的溶液,-60℃下搅拌1.5小时。(1'R,2'R)-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯基]-2,6-二醇1(0.78g,1.6mmol,1eq)和三乙胺(0.5mL,2.2eq)依次加到反应溶液中,然后缓慢升至室温,搅拌过夜。LC-MS监测至反应结束。在0℃下加入氯化铵饱和溶液,在用二氯甲烷萃取。有机相用硫酸钠干燥、旋干,残留物使用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=10:1~1:10),得到标题化合物1异丙基((乙氧基羰基)((((1'R,2'R)-6-羟基-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2',3’,4'-四氢-[1,1'-联苯]-2-基)氧基)磷酰基)-L-丙氨酸盐的异构体1-1(113mg,33.5%产率,黄色油状物)和异构体1-2(64mg,19.3%产率,黄色油状物)。
异构体1-1。
1H NMR(300MHz,Chloroform-d)δ6.78(s,1H),6.49(s,1H),6.04(s,1H),5.54(s,1H),5.07-4.99(m,1H),4.66(s,1H),4.21(s,1H),4.31–4.08(m,3H),3.84–3.77(m,2H),2.49–2.44(m,3H),2.19–2.11(m,1H),2.04-1.55(m,10H),1.39–1.21(m,16H),0.87(t,3H)。
31P NMR(121MHz,Chloroform-d):-2.98。
LC-MS m/z(ESI)=564.19[M+1]。
异构体1-2
1H NMR(300MHz,Chloroform-d)δ6.68(s,1H),6.47(s,1H),6.12(s,1H),5.55(s,1H),5.02-4.94(m,1H),4.52(s,1H),4.35(s,1H),4.28–4.04(m,3H),3.87–3.72(m,2H),2.45–2.40(m,3H),2.19–2.08(m,1H),1.79-1.46(m,10H),1.39–1.21(m,16H),0.84(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.47。
LC-MS m/z(ESI)=564.20[M+1]。
实施例2
ethyl((ethoxycarbonyl)(((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)phosphoryl)-L-alaninate
乙基((乙氧基羰基)(((1'R,2'R)-6-羟基-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2-基)氧基)磷酰基)-L-丙氨酸盐(化合物2)
化合物2的合成与分离方法与化合物1相同,得到标题化合物2的异构体2-1(68mg,8.1%产率,黄色油状物)和异构体2-2(77mg,6.7%产率,黄色油状物)。
异构体2-1
1H NMR(300MHz,Chloroform-d)δ6.78(s,1H),6.49(s,1H),6.04(s,1H),5.54(s,1H),4.65(s,1H),4.42(s,1H),4.22-4.15(m,4H),3.87–3.84(m,1H),3.79–3.72(m,1H),2.49–2.44(m,3H),2.23–2.04(m,2H),1.82–1.52(m,10H),1.41–1.24(m,13H),0.87(t,3H)。
31P NMR(121MHz,Chloroform-d):-2.98。
LC-MS m/z(ESI)=550.22[M+1]。
异构体2-2
1H NMR(300MHz,Chloroform-d)δ6.69(s,1H),6.49(s,1H),6.09(s,1H),5.58(s,1H),4.55(s,1H),4.36(s,1H),4.31-4.10(m,4H),3.87–3.84(m,1H),3.77–3.70(m,1H),2.47–2.42(m,3H),2.20–2.04(m,2H),1.82–1.51(m,10H),1.32–1.22(m,13H),0.86(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.49。
LC-MS m/z(ESI)=550.20[M+1]。
实施例3
benzyl((ethoxycarbonyl)(((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-
1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)phosphoryl)-L-alaninate
苄基((乙氧羰基)(((1'R,2'R)-6-羟基-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2-基)氧基)磷酰基)-L-丙氨酸盐(化合物3)
化合物3的合成与分离方法与化合物1相同,得到标题化合物3的异构体3-1(66mg,5.7%产率,黄色油状物)和异构体3-2(76mg,6.3%产率,黄色油状物)。
异构体3-1
1H NMR(300MHz,Chloroform-d)δ7.39-7.29(m,5H),6.78(s,1H),6.49(s,1H),6.04(s,1H),5.53(s,1H),5.21–5.11(m,2H),4.63(s,1H),4.41(s,1H),4.33-4.10(m,3H),3.87–3.74(m,2H),2.46(t,3H),2.22–2.04(m,2H),1.83–1.20(m,20H),0.86(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.05。
LC-MS m/z(ESI)=612.45[M+1]。
异构体3-2
1H NMR(300MHz,Chloroform-d)δ7.39-7.29(m,5H),6.70(s,1H),6.49(s,1H),6.09(s,1H),5.55(s,1H),5.18–5.09(m,2H),4.54(s,1H),4.36(s,1H),4.27-4.20(m,3H),3.87–3.71(m,2H),2.45(t,3H),2.26–2.10(m,2H),1.83–1.18(m,20H),0.86(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.61。
LC-MS m/z(ESI)=612.53[M+1]。
实施例4
ethyl((((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)(isopropoxycarbonyl)phosphoryl)-L-alaninate
乙基((((1'R,2'R)-6-羟基-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4′-四氢-[1,1′-联苯]-2-基)氧基)(异丙氧基羰基)磷酰基)-L-丙氨酸盐(化合物4)
化合物4的合成与分离方法与化合物1相同,得到标题化合物4的异构体4-1(85mg,7.9%产率,黄色油状物)和异构体4-2(129mg,12%产率,黄色油状物)。
异构体4-1
1H NMR(300MHz,Chloroform-d)δ6.78(s,1H),6.48(s,1H),6.04(s,1H),5.54(s,1H),5.19-5.13(m,1H),4.65(s,1H),4.42(s,1H),4.22-4.14(m,4H),3.87–3.84(m,1H),3.78–3.71(m,1H),2.48–2.43(m,3H),2.22–2.10(m,2H),1.81–1.49(m,10H),1.40–1.1.23(m,15H),0.87(t,3H)。
31P NMR(121MHz,Chloroform-d):-2.86。
LC-MS m/z(ESI)=564.28[M+1]。
异构体4-2
1H NMR(300MHz,Chloroform-d)δ6.70(s,1H),6.48(s,1H),6.07(s,1H),5.58(s,1H),5.17-5.12(m,1H),4.54(s,1H),4.37(s,1H),4.19-4.07(m,4H),3.89–3.86(m,1H),3.75–3.68(m,1H),2.47–2.42(m,3H),2.24–2.05(m,2H),1.79–1.42(m,10H),1.32–1.18(m,15H),0.86(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.39。
LC-MS m/z(ESI)=564.51[M+1]。
实施例5
isopropyl 2-(((ethoxycarbonyl)(((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)phosphoryl)amino)-2-methylpropanoate
异丙基2-(((乙氧羰基)(((1'R,2'R)-6-羟基-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2-基)氧基)磷酰基)氨基)-2-甲基丙酸酯(化合物4)
化合物5的合成与分离方法与化合物1类似,得到标题化合物5的异构体5-1(760mg,4.4%产率,白色固体)和异构体5-2(691mg,4%产率,白色固体)。
异构体5-1
1H NMR(300MHz,Chloroform-d)δ6.78(s,1H),6.45(s,1H),6.09(s,1H),5.48(s,1H),4.57–3.81(m,6H),2.43–1.95(m,5H),1.72–1.50(m,16H),1.26–1.19(m,13H),0.81(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.43。
LC-MS m/z(ESI)=578.47[M+1]。
异构体5-2
1H NMR(300MHz,Chloroform-d)δ6.69(s,1H),6.43(s,1H),6.01(s,1H),5.47(s,1H),5.00–4.92(m,1H),4.46–3.82(m,6H),2.40–1.97(m,5H),1.70–1.44(m,16H),1.21–1.16(m,13H),0.79(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.65。
LC-MS m/z(ESI)=578.65[M+1]。
实施例6
isopropyl((((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrah-ydro-[1,1'-biphenyl]-2-yl)oxy)(isopropoxycarbonyl)phosphoryl)-L-alaninate
异丙基((((1'R,2'R)-6-羟基-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4′-四氢-[1.1′-联苯]-2-基)氧基)(异丙氧基羰基)磷酰基)-L-丙氨酸盐(化合物6)
化合物6的合成与分离方法与化合物1相同,得到标题化合物6的异构体6-1(30mg,1.8%产率,黄色油状物)和异构体6-2(120mg,7,3%产率,白色固体)。
异构体6-1
1H NMR(300MHz,Chloroform-d)δ6.78(s,1H),6.49(s,1H),6.04(s,1H),5.55(s,1H),5.18-5.01(m,2H),4.66(s,1H),4.42(s,1H),4.19–4.16(m,1H),3.88–3.77(m,2H),2.49–2.44(m,3H),2.21–2.05(m,2H),1.79-1.37(m,10H),1.28–1.19(m,19H),0.87(t,3H)。
31P NMR(121MHz,Chloroform-d):-2.89。
LC-MS m/z(ESI)=578.05[M+1]。
异构体6-2
1H NMR(300MHz,Chloroform-d)δ6.70(s,1H),6.49(s,1H),6.08(s,1H),5.59(s,1H),5.17-4.99(m,2H),4.55(s,1H),4.37(s,1H),4.12–3.70(m,3H),2.47–2.42(m,3H),2.21–2.04(m,2H),1.81-1.51(m,10H),1.32–1.19(m,19H),0.87(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.38。
LC-MS m/z(ESI)=578.12[M+1]。
实施例7
isopropyl 2-(((((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)(isopropoxycarbonyl)phosphoryl)amino)-2-methylpropanoate
异丙基2-(((((1'R,2'R)-6-羟基-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2-基)氧基)(异丙氧基羰基)磷酰基)氨基)-2-甲基丙酸酯(化合物7)
化合物7的合成与分离方法与化合物1类似,得到标题化合物7的异构体7-1(21mg,1.2%产率,黄色油状物)和异构体7-2(163mg,9.3%产率,黄色油状物)。
异构体7-1
1H NMR(300MHz,Chloroform-d)δ6.81(s,1H),6.46(s,1H),6.04(s,1H),5.53(s,1H),5.18–5.09(m,1H),5.07-4.99(m,1H),4.62(s,1H),4.40(s,1H),4.19(d,1H),3.86(d,1H),2.47–2.42(m,3H),2.21-2.03(m,2H),1.81–1.21(m,32H),0.85(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.36。
LC-MS m/z(ESI)=592.45[M+1]。
异构体7-2
1H NMR(300MHz,Chloroform-d)δ6.75(s,1H),6.47(s,1H),6.04(s,1H),5.58(s,1H),5.29–5.12(m,1H),5.06-4.98(m,1H),4.55(s,1H),4.38(s,1H),4.12(d,1H),3.87(d,1H),2.48–2.43(m,3H),2.20-2.04(m,2H),1.83–1.20(m,32H),0.86(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.39。
LC-MS m/z(ESI)=592.10[M+1]。
实施例8
ethyl 2-(((ethoxycarbonyl)(((1'R,2'R)-6-hydroxy-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)phosphoryl)amino)-2-methylpropanoate
乙基2-(((((1'R,2'R)-6-羟基-5'-甲基-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2-基)氧基)(异丙氧基羰基)磷酰基)氨基)-2-甲基丙酸酯(化合物8)
化合物8的合成与分离方法与化合物1类似,得到标题化合物8的异构体8-1(180mg,5%产率,黄色油状物)和异构体8-2(175mg,5%产率,黄色油状物)。
异构体8-1
1H NMR(300MHZ,Chloroform-d)δ6.81(s,1H),6.47(s,1H),6.06(s,1H),5.53(s,1H),4.61(s,1H),4.39(s,1H),4.30-4.23(m,2H),4.20-4.12(m,2H),3.84(d,1H),2.45(t,2H),2.18(s,1H),2.10-2.03(m,1H),1.77(s,1H),1.68-1.61(m,2H),1.64(s,6H),1.59-1.48(m,2H),1.56(s,6H),1.30-1.24(m,6H),0.85(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.45。
LC-MS m/z(ESI)=564.40[M+1]。
异构体8-2
1H NMR(400MHZ,Chloroform-d)δ6.74(s,1H),6.47(s,1H),6.07(s,1H),5.56(s,1H),4.54(s,1H),4.36(s,1H),4.32-4.24(m,2H),4.21-4.02(m,2H),3.84(d,12.0Hz,1H),2.44(t,2H),2.19(s,1H),2.10-2.03(m,1H),1.78(s,1H),1.64-1.56(m,2H),1.60(s,3H),1.59(s,3H)1.55-1.47(m,2H),1.49(s,6H),1.32-1.20(m,6H),0.85(t,3H)。
31P NMR(121MHz,Chloroform-d):-3.56。
LC-MS m/z(ESI)=564.40[M+1]。
实施例9
isopropyl((ethoxycarbonyl)((6-hydroxy-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)phosphoryl)-L-alaninate
异丙基((乙氧基羰基)((6-羟基-5'-(甲基-d3)-4-戊基-2'-(丙-1-烯-2-基)-1',2',3',4'-四氢-[1,1'-联苯]-2-基)氧基)磷酰基)-L-丙氨酸盐(化合物9)
第一步:
3-ethoxy-6-(2-hydroxypropan-2-yl)cyclohex-2-en-1-one
3-乙氧基-6-(2-羟丙基-2-基)环己-2-烯-1-酮9b
在-70℃、氮气保护下,将3-乙氧基环己-2-烯-1-酮9a(10.0g,71.0mmol)滴加到二异丙基氨基锂(54mL,107.0mmol,2.0N)的四氢呋喃(100mL)溶液中,滴毕搅拌反应0.5h;滴加丙酮(9.2g,142.0mmol),滴毕继续搅拌3h;TLC检测至反应结束;滴加饱和氯化铵溶液(180mL)淬灭反应,分液,水相用乙酸乙酯(150mL×2)萃取,合并有机相用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到标题化合物9b(黄色油状物,18.0g,产率:99.0%)。
1H NMR(400MHz,DMSO).δ5.29(s,1H),4.93(s,1H),3.98–3.87(m,2H),2.46(dd,J=11.2,5.0Hz,1H),2.37(dt,J=17.4,4.5Hz,1H),2.21(dd,J=12.1,4.7Hz,1H),2.12–2.03(m,1H),1.67(ddd,J=24.2,12.3,5.1Hz,1H),1.27(t,J=7.0Hz,3H),0.99(s,3H),0.73(s,3H)。
LC-MS m/z(ESI)=199.21[M+1]。
第二步:
4-(2-hydroxypropan-2-yl)cyclohex-2-en-1-one
4-(2-羟基丙烷-2-基)环己-2-烯-1-酮9c
在0℃,氮气保护下,将红铝(67mL,234.1mmol,3.5N)滴加到化合物9b(17.0g,78.0mmol)的四氢呋喃(200mL)溶液中,滴毕缓慢升至室温搅拌反应2h;TLC检测至反应结束;降至0℃,滴加饱和氯化铵溶液(13mL)淬灭,抽滤,水相用乙酸乙酯(200mL×2)萃取,合并有机相用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品加入四氢呋喃(40mL)溶解,滴加盐酸水溶液(40mL,2N),滴毕室温搅拌反应1.5h;TLC检测至反应结束,滴加饱和碳酸氢钠溶液淬灭反应,减压浓缩,水相用乙酸乙酯(100mL×4)萃取,合并有机相用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/3)纯化,得到标题化合物9c(无色油状物,5.8g,产率:48.0%)。
1H NMR(400MHz,DMSO)δ7.19(dt,J=10.4,1.9Hz,1H),5.93(dd,J=10.4,2.8Hz,1H),4.58(s,1H),2.44–2.38(m,1H),2.38–2.29(m,2H),2.08–1.96(m,1H),1.62(tdd,J=12.9,9.4,5.0Hz,1H),0.99(s,3H),0.73(s,3H)。
LC-MS m/z(ESI)=155.40[M+1]。
第三步:
4-(2-hydroxypropan-2-yl)-1-(methyl-d3)cyclohex-2-en-1-ol
4-(2-羟基丙烷-2-基)-1-(甲基-d3)环己-2-烯-1-醇9d
在0℃,氮气保护下,将氘代甲基碘化镁(34mL,33.7mmol,1.0N)滴加到无水氯化锂(1.4g,33.7mmol)的四氢呋喃(20mL)溶液中,滴毕搅拌反应0.5h;滴加化合物9c(1.8g,11.2mmol)的四氢呋喃溶液(5mL),滴毕搅拌反应0.5h;TLC检测至反应结束;滴加饱和氯化铵溶液(20mL)淬灭,水相用乙酸乙酯(50mL×3)萃取,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品,经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=2/1)纯化,得到标题化合物9d(白色固体,1.2g,产率:60.0%)。
1H NMR(400MHz,DMSO)δ5.61(d,J=10.4Hz,1H),5.52(d,J=10.6Hz,1H),4.38(s,1H),4.17(s,1H),2.00(ddd,J=10.8,5.1,2.4Hz,1H),1.73–1.65(m,2H),1.57–1.48(m,1H),1.21(dd,J=10.1,6.8Hz,1H),0.99(s,3H),0.73(s,3H)。
LC-MS m/z(ESI)=174.62[M+1]。
第四步:
2'-(2-hydroxypropan-2-yl)-5'-(methyl-d3)-4-pentyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
2'-(2-羟基丙-2-基)-5'-(甲基-d3)-4-戊基-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二酚9e
将4-(2-羟基丙烷-2-基)-1-(甲基-d3)环己-2-烯-1-醇9d(2.37g,13.7mmol),3,5-二羟基戊苯(3.7g,20.6mmol)和4A分子筛(6g)溶于30mL二氯甲烷中,置换氮气,室温搅拌20分钟。最后加入左旋樟脑磺酸(317.8mg,1.37mmol)。室温搅拌1小时。向反应液中加入60mL饱和碳酸氢钠水溶液淬灭反应,乙酸乙酯萃取(30mL×4)。合并有机相,用无水硫酸钠干燥,过滤,浓缩得到粗品。经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/6)纯化,得到标题化合物9e(无色油状物,1.3g,产率:28.5%)。
1H NMR(400MHz,DMSO)δ9.04–8.43(m,2H),6.03(s,2H),4.89(s,1H),3.66(m,2H),2.32(m,3H),2.14–2.06(m,1H),2.02(m,1H),1.88–1.79(m,1H),1.47(m,2H),1.32–1.19(m,5H),0.97(s,3H),0.85(t,3H),0.80(s,3H)。
LC-MS m/z(ESI)=336.20[M+1]。
第五步:
5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol
5'-(甲基-d3)-4-戊基-2'-(丙-1-烯-2-基)-1’,2’,3’,4'-四氢-[1,1'-联苯]-2,6-二酚9f
在0℃下,向反应瓶中依次加入化合物9e(1.3g,3.9mmol)、伯吉斯试剂(1.1g,4.7mmol)和四氢呋喃(10mL),氮气保护下搅拌反应3h;TLC检测至反应结束;加入乙酸乙酯(50mL),有机相用饱和食盐水(40mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品,经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/15)纯化,得到标题化合物9f(无色油状物,794mg,产率:64.0%)。
1H NMR(400MHz,DMSO)δ8.65(s,2H),6.01(s,2H),5.08(s,1H),4.49(d,1H),4.43–4.37(d,1H),3.85–3.78(m,1H),3.08–2.98(m,1H),2.32–2.26(m,2H),2.13–2.04(m,1H),1.95–1.87(m,1H),1.71–1.63(m,1H),1.58(s,3H),1.47(m,2H),1.35–1.22(m,5H),0.86(t,3H)。
LC-MS m/z(ESI)=318.20[M+1]。
第六步
isopropyl((ethoxycarbonyl)((6-hydroxy-5'-(methyl-d3)-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2-yl)oxy)phosphoryl)-L-alaninate
异丙基((乙氧基羰基)((6-羟基-5'-(甲基-d3)-4-戊基-2'-(丙-1-烯-2-基)-1',2',3',4'-四氢-[1,1'-联苯]-2-基)氧基)磷酰基)-L-丙氨酸盐(化合物9)
采用化合物1的合成方法制备得到标题化合物9(69mg,23%产率,黄色油状物)。
LC-MS m/z(ESI)=567.39[M+1]。
以下中间体按照表格中标注方法合成
采用化合物1的合成方法,制备得到如下化合物:
大鼠药代动力学
取健康成年SD大鼠3只,禁食过夜(自由饮水)后,给予灌胃(p.o.)给药(50mg/kg)。于给药后30min、1h、8h从颈静脉丛采血0.1mL。所有血样使用K2EDTA抗凝,随后5℃,3500rpm离心10min分离血浆,于-20℃保存待测。建立LC/MS/MS法测定血浆中的原形药物浓度。
采用上述方法,测得化合物的原型药物在大鼠体内各时间点血药浓度(ng/mL)如下:
编号 | 给药剂量 | 原型药物 | 30min | 1h | 8h |
化合物1 | 50mg/kg | CBD | 1408 | 1754 | 151.7 |
化合物3 | 50mg/kg | CBD | 1376 | 1604 | 145.9 |
化合物5 | 50mg/kg | CBD | 1388 | 1653 | 160.8 |
化合物9 | 50mg/kg | 9f | 1577 | 1993 | 260.5 |
化合物10 | 50mg/kg | 中间体10 | 1409 | 1846 | 164.9 |
化合物11 | 50mg/kg | 中间体11 | 1570 | 1982 | 248.3 |
化合物12 | 50mg/kg | 中间体12 | 1593 | 2027 | 271.1 |
化合物13 | 50mg/kg | 中间体13 | 1568 | 1981 | 260.9 |
化合物14 | 50mg/kg | 中间体14 | 1674 | 2070 | 264.6 |
化合物18 | 50mg/kg | 中间体18 | 1775 | 2280 | 299.1 |
化合物22 | 50mg/kg | 中间体22 | 1401 | 1682 | 143.0 |
化合物24 | 50mg/kg | 中间体24 | 1383 | 1691 | 170.2 |
化合物25 | 50mg/kg | 中间体25 | 1566 | 1940 | 242.2 |
化合物26 | 50mg/kg | 中间体26 | 1559 | 1969 | 268.3 |
化合物27 | 50mg/kg | 中间体27 | 1402 | 1675 | 144.9 |
实验结果表明,本发明化合物经口服灌胃后,可在血浆中检测到原型药物浓度,表明本化合物具有口服吸收特性,且能在体内快速转化为原型药,并且具有比原型药更好的口服生物利用度。
本发明说明书对具体实施方案进行了详细描述,本领域技术人员应认识到,上述实施方案是示例性的,不能理解为对本发明的限制,对于本领域技术人员来说,在不脱离本发明原理的前提下,通过对本发明进行若干改进和修饰,这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。
Claims (7)
1.通式(I)所示的化合物,或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶:
其中:
X选自氢、羟基、C1-6烷基或者卤素;
Y选自氢、羧酸、C1-6烷基或者卤素;
r选自0、1、2或者3;
n选自0、1或者2;
R0选自甲基、C3-8碳环基、-CH2OH、-C(=O)OC1-6烷基、-C(=O)NRb1Rb2或者羧基;
R1选自C1-6烷基,所述的C1-6烷基任选进一步被0至3个卤素所取6代;
Ra选自H或者C1-6烷基;
Rb、Rc各自独立地选自H、C1-6烷基、氨基酸侧链、-C1-6亚烷基-C3-12碳环或者-C1-6亚烷基-C3-12杂环;所述的C3-12杂环包含1至4个选自N、O或者S的杂原子;所述的C1-6亚烷基、C1-6烷基、C3-12碳环、C3-12杂环任选地进一步被0至3个选自羟基、羧基、卤素、氰基、=O、C1-6烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、-NRb1Rb2、-C(=O)OC1-6烷基、-C(=O)NRb1Rb2、C3-12环烷基、C3-12杂环烷基、C6-12芳基或者C5-12杂芳基的取代基所取代;且作为取代基的所述的C1-6烷基、C1-6杂烷基、C2-6烯基或者C2-6炔基任选进一步被1个或者多个选自羟基、羧基、氰基、卤素、-O-Rb1、-NRb1Rb2、C3-12环烷基、C3-12杂环烷基、C6-12芳基或者C5-12杂芳基的取代基所取代;当所述的氨基酸侧链包含羟基、巯基或羧基时,所述羟基、巯基或羧基任选地被酯化;
Rb1、Rb2各自独立地选自H、C1-6烷基、-C(=O)Rb3或者-C(=O)NRb4Rb5,其中所述的C1-6烷基任选进一步被1个或者多个选自羟基、卤素、C1-6烷基、C1-6烷氧基、C6-12芳基、C5-12杂芳基、C3-12环烷基或者C3-12杂环烷基的取代基所取代;
Rb3选自C1-6烷基、C1-6烷氧基或者C6-12芳基;
Rb4、Rb5各自独立地选自H或者C1-6烷基;或者Rb4与Rb5及N原子形成一个3至12元杂环,所述的3至12元杂环包含1至4个选自N、O或者S的杂原子;
或者,Rb和Rc与其所连接的原子一起形成3至6元碳环或者3至6元杂环,所述3至6元碳环或者3至6元杂环任选进一步被0至3个选自F、Cl、Br、I、羟基、羧基或氨基的取代基所取代,所述的3至6元杂环包含1至4个选自N、O或者S的杂原子;
Rd选自C1-6烷基、C2-6烯基、C2-6炔基、C3-10碳环、3至10元杂环、-C1-6亚烷基-C3-10碳环、-C1-6亚烷基-3至10元杂环、-C1-6亚烷基-O-C1-6亚烷基-C3-10碳环、-C1-6亚烷基-O-C1-6亚烷基-3至10元杂环或-C1-6亚烷基-O-C1-4烷基,所述C1-6亚烷基、C2-6烯基、C2-6炔基、C1-6烷基、C3-10碳环或3至10元杂环任选进一步被0至4个选自H、F、Cl、Br、I、羟基、羧基、氨基、1-环丙基乙基、C1-4烷基、C1-4烷氧基、-OC(=O)ORd1或-OC(=O)Rd2的取代基所取代,所述3至10元杂环包含1至6个选自N、O或者S的杂原子;
Rd1和Rd2各自独立地选自C1-4烷基、C3-10碳环或3至10元杂环,所述C1-4烷基、C3-10碳环或3至10元杂环任选进一步被0至4个选自H、F、Cl、Br、I、羟基、羧基、C1-4烷基、C1-4烷氧基、C3-10碳环或3至10元杂环的取代基所取代,所述3至10元杂环包含1至6个选自N、O或者S的杂原子;
R3选自选自C1-6烷基、C3-8碳环基或者C2-6烯基,所述的C1-6烷基、C2-6烯基、C3-8碳环基任选进一步被0至3个选自卤素、C3-8碳环基、羟基或者C1-6烷基的取代基所取代;
R选自氨基酸侧链;当所述的氨基酸侧链包含羟基、巯基或羧基时,所述羟基、巯基或羧基任选地被酯化;
R5选自C1-12烷基、C1-12杂烷基、C2-12烯基、C2-12炔基、C3-12碳环基、C3-12杂环基、-C1-6亚烷基-C3-12碳环基、-C1-6亚烷基-C3-12杂环基、-NRb1Rb2、-C1-6亚烷基-C(=O)OC1-6烷基或者-C1-6亚烷基-C(=O)NRb1Rb2,且所述的C1-12烷基、C1-12杂烷基、C2-12烯基、C2-12炔基、C1-6亚烷基、C3-12碳环基、C3-12杂环基任选被1个或者多个选自羟基、羧基、卤素、氰基、=O、C1-6烷基、-NRb1Rb2、C3-12碳环基、C3-12杂环基、C2-6烯基、C2-6炔基、-C(=O)OC1-6烷基、-C(=O)C1-6烷基、-C(=O)NRb1Rb2、-S(=O)C1-6烷基或者-S(=O)2C1-6烷基的取代基所取代,且作为取代基的所述的C1-6烷基、C3-12碳环基、C3-12杂环基任选进一步被1个或者多个选自=O、羟基、羧基、卤素、氰基、-C(=O)OC1-6烷基或者-C(=O)C1-6烷基的取代基所取代;
或者,通式(I)任选被1个或者多个D原子取代。
2.根据权利要求1所述的化合物,或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶,其中所述化合物为通式(II)所示的化合物:
其中,
R0选自甲基或者-CH2OH;
R1为C1-6烷基;
Ra为H;
Rb、Rc各自独立地选自H或者氨基酸侧链;当所述的氨基酸侧链包含羟基、巯基或羧基时,所述羟基、巯基或羧基任选地被酯化;
Rd选自C1-6烷基、C3-10碳环或者3至10元杂环,所述C1-6烷基、C3-10碳环或3至10元杂环任选进一步被0至4个选自H、F、Cl、Br、I、羟基、羧基、氨基、1-环丙基乙基、C1-4烷基、C1-4烷氧基、-OC(=O)ORd1或-OC(=O)Rd2的取代基所取代,所述3至10元杂环包含1至6个选自N、O或者S的杂原子;
Rd1和Rd2各自独立地为C1-4烷基;
或者,通式(II)任选被1个或者多个D原子取代。
3.根据权利要求2所述的化合物,或者其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶,其中所述化合物为通式(III)所示的化合物:
其中,
R1为C1-6烷基;
Rd选自C1-6烷基、C3-10碳环或者3至10元杂环,所述C1-6烷基、C3-10碳环或3至10元杂环任选进一步被0至4个选自H、F、Cl、Br、I、羟基、羧基、氨基、1-环丙基乙基、C1-4烷基、C1-4烷氧基、-OC(=O)ORd1或-OC(=O)Rd2的取代基所取代,所述3至10元杂环包含1至6个选自N、O或者S的杂原子;
Rd1和Rd2各自独立地为C1-4烷基;
或者,通式(III)任选被1个或者多个D原子取代。
5.药物组合物,所述药物组合物包含:
(1)权利要求1至4中任一项所述的化合物或其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶;
(2)任选的一种或者多种其他活性成分;以及
(3)药学上可接受的载体和/或赋形剂。
6.根据权利要求5的药物组合物,其特征在于,所述的其他活性成分选自银杏内酯、抗肿瘤剂、抗凝血剂、抗癫痫剂、抗抑郁剂、抗焦虑剂、催眠剂、镇痛剂或者麻醉剂中的一种或多种,或者所述的其他活性成分的立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶;优选地,所述银杏内酯为银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯D、银杏内酯J、银杏内酯M、银杏内酯K、银杏内酯L、银杏内酯N、银杏内酯P、银杏内酯Q、白果内酯中的一种或两种及以上以任意比例的组合。
7.权利要求1-4中任一项所述的化合物或其立体异构体、溶剂化物、代谢产物、药学上可接受的盐或共晶或者权利要求5或6所述的药物组合物在制备用于治疗创伤后应激障碍、面瘫、中风、偏头痛、冠心病稳定型心绞痛、脑梗塞、血栓栓塞、心肌梗塞、心脏缺血、冠状动脉疾病、高血压、脑缺血、改善性功能、痉挛、急性和慢性疼痛、纤维肌痛、术后疼痛、丛集性头痛、紧张性头痛、背疼、四肢痛、腰痛、颈部疼痛、神经性疼痛、癌痛、三叉神经痛、关节炎疼痛、炎性疼痛、Dravet综合征、Lennox-Gastaut综合征、Prader-Willi综合征、Sturge-Weber综合征、脆性X综合征、焦虑、双相情感障碍、自闭症、广泛性焦虑症、社交焦虑症、癫痫、帕金森氏病、阿尔茨海默氏病、亨廷顿氏病、阿片类药物滥用、酗酒、尼古丁成瘾、厌食症、恶病质、化疗相关恶心呕吐、术后恶心和呕吐、肌萎缩性侧索硬化症(ALS)、Friedreich共济失调、精神分裂症、强迫症、多发性硬化症、抑郁、睡眠障碍、多发性硬化引起的痉挛、肌张力障碍、睡眠呼吸暂停、麻痹性痴呆、记忆力减退或者胶质母细胞瘤的药物中的用途。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022111587A1 (zh) * | 2020-11-25 | 2022-06-02 | 成都百裕制药股份有限公司 | 大麻素类化合物的制备方法 |
WO2023016495A1 (zh) * | 2021-08-13 | 2023-02-16 | 成都百裕制药股份有限公司 | 含有白果内酯和大麻二酚的药物组合物及其在医药上的应用 |
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US20230059087A1 (en) * | 2020-01-08 | 2023-02-23 | Chengdu Baiyu Pharmaceutical Co., Ltd. | Cannabidiol derivatives, preparation method thereof and use thereof |
AU2022385580A1 (en) * | 2021-11-11 | 2024-05-09 | Cannasoul Analytics Ltd. | Novel cannabinoid derivatives |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000056303A2 (en) * | 1999-03-22 | 2000-09-28 | Immugen Pharmaceuticals, Inc. | Treatment of immune diseases |
US20070093665A1 (en) * | 2005-09-29 | 2007-04-26 | Amr Technology, Inc. | Process for production of delta-9- tetrahydrocannabinol |
CN106928081A (zh) * | 2015-12-31 | 2017-07-07 | 四川海思科制药有限公司 | 稠合环γ‑ 氨基酸衍生物及其制备方法和在医药上的应用 |
WO2018096504A1 (en) * | 2016-11-28 | 2018-05-31 | Kalytera Therapeutics, Inc | Cbd prodrugs, compositions, and methods of administering cbd and cbd prodrugs |
CN108137526A (zh) * | 2015-07-10 | 2018-06-08 | 诺拉姆科有限公司 | 用于生产大麻二酚和△-9-四氢大麻酚的方法 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL150302A (en) * | 2002-01-31 | 2008-07-08 | Naim Menashe | Bicyclic cb2 cannabinoid receptor ligands |
AU2003263895A1 (en) * | 2002-08-16 | 2004-03-03 | Immugen Pharmaceuticals, Inc. | Contraceptive methods and formulations |
WO2015074137A1 (en) * | 2013-11-20 | 2015-05-28 | Mary Lynch | Compositions and methods for treatment of ocular inflammation and pain |
CN106999598B (zh) * | 2014-05-29 | 2022-02-08 | 鲜切发展有限责任公司 | 稳定的大麻素类化合物制剂 |
US9474725B1 (en) * | 2014-06-11 | 2016-10-25 | Poviva Tea, Llc | Food and beverage compositions infused with lipophilic active agents and methods of use thereof |
BR112018015570A2 (pt) * | 2016-01-29 | 2018-12-26 | Univ Mississippi | análogos de canabidiol biologicamente ativos |
-
2021
- 2021-01-07 US US17/772,126 patent/US20230002425A1/en active Pending
- 2021-01-07 WO PCT/CN2021/070728 patent/WO2021139739A1/zh unknown
- 2021-01-07 CN CN202110020570.7A patent/CN113087741B/zh active Active
- 2021-01-07 EP EP21738886.7A patent/EP4088723A4/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000056303A2 (en) * | 1999-03-22 | 2000-09-28 | Immugen Pharmaceuticals, Inc. | Treatment of immune diseases |
US20070093665A1 (en) * | 2005-09-29 | 2007-04-26 | Amr Technology, Inc. | Process for production of delta-9- tetrahydrocannabinol |
CN108137526A (zh) * | 2015-07-10 | 2018-06-08 | 诺拉姆科有限公司 | 用于生产大麻二酚和△-9-四氢大麻酚的方法 |
CN106928081A (zh) * | 2015-12-31 | 2017-07-07 | 四川海思科制药有限公司 | 稠合环γ‑ 氨基酸衍生物及其制备方法和在医药上的应用 |
WO2018096504A1 (en) * | 2016-11-28 | 2018-05-31 | Kalytera Therapeutics, Inc | Cbd prodrugs, compositions, and methods of administering cbd and cbd prodrugs |
Non-Patent Citations (2)
Title |
---|
ANA LAGO-FERNANDEZ,等: "Chapter Eleven - New Methods for the Synthesis of Cannabidiol Derivatives", 《METHODS IN ENZYMOLOGY》 * |
郭蓉,等: "四氢大麻酚和大麻二酚的药理研究进展", 《天然产物研究与开发》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022111587A1 (zh) * | 2020-11-25 | 2022-06-02 | 成都百裕制药股份有限公司 | 大麻素类化合物的制备方法 |
WO2023016495A1 (zh) * | 2021-08-13 | 2023-02-16 | 成都百裕制药股份有限公司 | 含有白果内酯和大麻二酚的药物组合物及其在医药上的应用 |
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