WO2022218382A1 - 氘代苯酚衍生物及其制备方法和用途 - Google Patents
氘代苯酚衍生物及其制备方法和用途 Download PDFInfo
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- WO2022218382A1 WO2022218382A1 PCT/CN2022/086856 CN2022086856W WO2022218382A1 WO 2022218382 A1 WO2022218382 A1 WO 2022218382A1 CN 2022086856 W CN2022086856 W CN 2022086856W WO 2022218382 A1 WO2022218382 A1 WO 2022218382A1
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Classifications
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- A—HUMAN NECESSITIES
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- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
- A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
- C07C37/16—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms by condensation involving hydroxy groups of phenols or alcohols or the ether or mineral ester group derived therefrom
Definitions
- the application belongs to the field of medicinal chemistry, and specifically relates to deuterated phenol derivatives and preparation methods and uses thereof.
- 1-10 (1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) hydrogens in Compound A are replaced with deuterium.
- One or more embodiments of the present application provide intermediates for the preparation of deuterated compounds of Compound A, wherein the intermediates are deuterated compounds of the following compounds:
- the intermediate is:
- the above-mentioned preparation method comprises the following steps:
- the above-mentioned preparation method comprises the following steps:
- the third step adding n-butylmagnesium bromide dropwise to the dichloromethane organic solvent of the deuterated compound A-II and dilithium tetrachlorocuprate to react to obtain compound B-XI;
- the fourth step adding boron tribromide dropwise to the dichloromethane solution of the compound B-XI to obtain the deuterated compound A-III;
- Deuterated compound A-III, compound B-VIII and acidic alumina are reacted in dichloroethane organic solvent to obtain deuterated compound A.
- the above-mentioned preparation method comprises the following steps:
- the second step adding diisobutylaluminum hydride dropwise to the tetrahydrofuran solution of the compound B-III to react to obtain the compound B-IV;
- the third step adding 3,4-dihydro-2H-pyran and p-toluenesulfonic acid dropwise to the dichloromethane solution of the compound B-IV to react to obtain the compound B-V;
- the fifth step adding bistrimethylsilylamide lithium dropwise to the tetrahydrofuran solution of the compound B-VI to react, and then adding deuterated acetone to react to obtain the deuterated compound A-I;
- the 6th step the described deuterated A-I compound and p-toluenesulfonic acid are reacted in dehydrated alcohol to obtain compound B-I';
- the seventh step react the compound B-I', compound A-III and acidic alumina in dichloroethane to obtain deuterated compound A.
- One or more embodiments of the present application provide the use of a deuterated compound or composition of the present application in the manufacture of a treatment for a disease associated with the central nervous system.
- the central nervous system related disorder is pain or epilepsy.
- One or more embodiments of the present application provide a deuterated compound or composition of the present application for use as a medicament.
- One or more embodiments of the present application provide deuterated compounds or compositions of the present application for use in the treatment and/or inhibition of central nervous system-related diseases.
- the central nervous system related disorder is pain or epilepsy.
- One or more embodiments of the present application provide a method of treating and/or inhibiting a disease associated with the central nervous system, comprising administering to a subject in need thereof a deuterated compound or composition of the present application.
- the central nervous system related disorder is pain or epilepsy.
- the compounds of the present application show good therapeutic potential for central nervous system related diseases such as pain and epilepsy.
- Deuterium in this application is also called deuterium, which is an isotope of hydrogen and can be represented by D.
- “Pharmaceutically acceptable salt” or “a pharmaceutically acceptable salt thereof” means that a compound of the present invention retains the biological effectiveness and properties of a free acid or free base that is treated with a non-toxic inorganic base or The salt obtained by the reaction of an organic base, and the salt obtained by the reaction of the free base with a non-toxic inorganic acid or organic acid.
- “Pharmaceutical composition” refers to a mixture of one or more of the compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof and other chemical components, wherein “other chemical components” refers to pharmaceutically acceptable Accepted carriers, excipients and/or one or more other therapeutic agents.
- Carrier refers to a material that is not appreciably irritating to the organism and that does not abrogate the biological activity and properties of the administered compound.
- Excipient refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound.
- Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binding agents agent and disintegrant.
- Steps refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
- heterocyclyl optionally substituted with an alkyl group means that the alkyl group may, but need not, be present, and the description includes instances where the heterocyclyl group is substituted with an alkyl group, as well as where the heterocyclyl group is not substituted with an alkyl group happening.
- THP 2-tetrahydropyranyl
- Triethyl phosphoryl acetate (8.1 g, 36.0 mmol) and 5-bromo-2-pentanone 1a (5.0 g, 30.0 mmol) were added dropwise to sodium hydride (1.4 g, 36.0 mmol) at 0°C under nitrogen protection ) solution in tetrahydrofuran (100 mL), the dropwise temperature was raised to room temperature and stirred for 12 h; TLC detected the reaction until the end of the reaction; cooled to 0 °C, water (100 mL) was added dropwise to quench the reaction, extracted with petroleum ether (100 mL ⁇ 2), and the organic phases were combined.
- diisobutylaluminum hydride (35.0 mL, 53.0 mmol) was added dropwise to a solution of compound 1b (5.1 g, 22.0 mmol) in tetrahydrofuran (50 mL), the dropwise addition was completed, and the reaction was stirred for 2 h; TLC was detected until the reaction was completed; saturated aqueous ammonium chloride solution (50 mL) was added dropwise to quench the reaction, suction filtered, rinsed with ethyl acetate (50 mL), the filtrate was extracted with ethyl acetate (100 mL ⁇ 2), and the organic phases were combined with saturated common salt Washed with water (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluent: ethyl acetate/petrole
- lithium bistrimethylsilylamide 13.0 mL, 12.6 mmol
- tetrahydrofuran 90 mL
- Lithium aluminum deuterium hydride (2.4 g, 56.0 mmol) was added portionwise to a solution of methyl 3,5-dimethoxybenzoate (5.0 g, 26.0 mmol) in tetrahydrofuran (50 mL) at 0 °C under nitrogen After the addition was completed, the reaction was stirred for 1 h; TLC detected the reaction until the end of the reaction; water (50 mL) was added dropwise to quench the reaction, extracted with ethyl acetate (100 mL ⁇ 2), the combined organic phases were washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. , filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 3b (colorless oil, 4.3 g, yield: 99.0%).
- the deuterated compound 4 of the present invention showed significantly better pharmacokinetic characteristics than the control compound in mice, indicating that the compound of the present invention would have an obviously excellent pharmacokinetic trend.
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Abstract
本申请涉及化合物A的氘代化合物或者其药物可接受的盐或立体异构体,其中所述化合物A中的一个或多个氢被氘取代,该化合物用于治疗中枢神经系统相关的疾病。
Description
本申请属于药物化学领域,具体涉及氘代苯酚衍生物及其制备方法和用途。
CBG(Cannabigerol,大麻萜酚)首次发现于20世纪60年代,是一种不具有精神活性的大麻素。CBG与CB1和CB2大麻素受体相互作用,也被证实是α-2肾上腺素能受体激动剂,以及5-羟色胺1A受体拮抗剂。CBG具有广泛的治疗特征,药理作用包括抗菌、抗炎、神经保护、缓解神经性疼痛、抗肿瘤生长、刺激食欲、降低眼压等,在神经系统疾病、炎症性肠病、癌症等方面具有潜在的医疗前景。然而,CBG在大多数大麻植物中都以微量存在,常见菌株中含量不到1%,生产成本高。因此,针对CBG进行结构改造、开发低成本的工艺仍为人们研究的热点。
发明内容
本申请的一个或多个实施方式提供化合物A的氘代化合物或者其药物可接受的盐或立体异构体:
其中所述化合物A中的一个或多个氢被氘取代。
在一个或多个实施方式中,所述化合物A中1-10个(1、2、3、4、5、6、7、8、9、或10个)氢被氘取代。
在一个或多个实施方式中,所述氘代化合物为:
本申请的一个或多个实施方式提供制备化合物A的氘代化合物的中间体,其中所述中间体为以下化合物的氘代化合物:
其中所述化合物A-I、化合物B-I、化合物A-II和化合物A-III中的一个或多个氢被氘取代。在一个或多个实施方式中,上述中间体中1-10个(1、2、3、4、5、6、7、8、9、或10个)氢被氘取代。
在一个或多个实施方式中,所述中间体为:
本申请的一个或多个实施方式提供氘代化合物A的制备方法,其包括以下步骤:
其中化合物A-III、化合物B-I和化合物A中的一个或多个氢被氘取代。在一个或多个实施方式中,上述中间体中1-10个(1、2、3、4、5、6、7、8、9、或10个)氢被氘取代。
在一个或多个实施方式中,上述制备方法包括以下步骤:
其中
第一步:将氘代化合物A-I和对甲苯磺酸在二氯甲烷中反应,得到化合物B-I;
第二步:将所述化合物B-I’、化合物A-III和酸性氧化铝在二氯乙烷中反应,得到氘代化合物A。
在一个或多个实施方式中,上述制备方法包括以下步骤:
第一步:将氘代氢化铝锂、化合物B-VII在四氢呋喃有机溶剂中反应,得到化合物B-VIII;
第二步:将化合物B-VIII、化合物A-III、酸性氧化铝在二氯乙烷有机溶剂中反应,得到氘代化合物A。
在一个或多个实施方式中,上述制备方法包括以下步骤:
第一步:将氘代氢化铝锂、化合物B-IX在四氢呋喃有机溶剂中反应,得到化合物B-X;
第二步:将三溴化磷滴加到化合物B-X的二氯甲烷溶液中,得到氘代化合物A-II;
第三步:将正丁基溴化镁滴加到所述氘代化合物A-II、四氯合铜酸二锂的二氯甲烷有机溶剂中进行反应,得到化合物B-XI;
第四步:将三溴化硼滴加到所述化合物B-XI的二氯甲烷溶液中,得到氘代化合物A-III;
第五步:将所述氘代化合物A-III、(E)-3,7-二甲基辛-2,6-二烯-1-醇、酸性氧化铝在二氯乙烷有机溶剂中反应,得到氘代化合物A。
在一个或多个实施方式中,上述制备方法包括以下步骤:
将氘代化合物A-III、化合物B-VIII、酸性氧化铝在二氯乙烷有机溶剂中反应,得到氘代化合物A。
在一个或多个实施方式中,上述制备方法包括以下步骤:
第一步:将化合物B-II、磷酰基乙酸三乙酯在氢化钠的四氢呋喃溶液中反应,得到化合物B-III;
第二步:将二异丁基氢化铝滴加到所述化合物B-III的四氢呋喃溶液中反应,得到化合物B-IV;
第三步:将3,4-二氢-2H-吡喃和对甲苯磺酸滴加到所述化合物B-IV的二氯甲烷溶液中反应,得到化合物B-V;
第四步:将所述化合物B-V和三苯基膦在乙腈中反应,得到化合物B-VI;
第五步:将双三甲基硅基胺基锂滴加到所述化合物B-VI的四氢呋喃溶液中反应,随后滴加氘代丙酮反应,得到氘代化合物A-I;
第六步:将所述氘代A-I化合物和对甲苯磺酸在无水乙醇中反应,得到化合物B-I’;
第七步:将所述化合物B-I’、化合物A-III和酸性氧化铝在二氯乙烷中反应,得到氘代化合物A。
本申请的一个或多个实施方式提供了药物组合物,其包含:
本申请的氘代化合物或者其药物可接受的盐或立体异构体;
任选的一种或者多种其他活性成分;以及
药学上可接受的载体和/或赋形剂。
本申请一个或多个实施方式提供本申请的氘代化合物或组合物在制备用于治疗中枢神经系统相关的疾病中的用途。在一个或多个实施方式中,所述中枢神经系统相关的疾病为疼痛或癫痫。
本申请一个或多个实施方式提供本申请的氘代化合物或组合物,其用作药物。
本申请一个或多个实施方式提供本申请的氘代化合物或组合物,其用于治疗和/或抑制中枢神经系统相关的疾病。在一个或多个实施方式中,所述中枢神经系统相关的疾病为疼痛或癫痫。
本申请一个或多个实施方式提供治疗和/或抑制中枢神经系统相关的疾病的方法,其包括向有此需要的对象给予本申请的氘代化合物或组合物。在一个或多个实施方式中,所述中枢神经系统相关的疾病为疼痛或癫痫。
发明详述
在一个或多个实施方式中,本申请的化合物对中枢神经相关的疾病如疼痛及癫痫显示出良好的治疗潜力。
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。
本申请的氘又叫重氢,是氢的同位素,可用D表示。
“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。
“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。
“THP”表示2-四氢吡喃基。
实施例1
第一步:
(E)-6-溴-3-甲基十六烷-2-烯酸乙酯
ethyl(E)-6-bromo-3-methylhex-2-enoate 1b
在0℃,氮气保护下,将磷酰基乙酸三乙酯(8.1g,36.0mmol)和5-溴-2-戊酮1a(5.0g,30.0mmol)滴加到氢化钠(1.4g,36.0mmol)的四氢呋喃(100mL)溶液中,滴毕升至室温搅拌反应12h;TLC检测至反应结束;降温至0℃,滴加水(100mL)淬灭反应,石油醚(100mL×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,滤液减压浓缩得到残留物,经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/10)纯化,得到标题化合物(E)-6-溴-3-甲基十六烷-2-烯酸乙酯1b(无色油状物,5.1g,产率:72.0%)。
LC-MS m/z(ESI)=235.1[M+1]
第二步:
(E)-6-溴-3-甲基十六烷-2-烯-1-醇
(E)-6-bromo-3-methylhex-2-en-1-ol 1c
在-78℃,氮气保护下,将二异丁基氢化铝(35.0mL,53.0mmol)滴加到化合物1b(5.1g,22.0mmol)的四氢呋喃(50mL)溶液中,滴毕,搅拌反应2h;TLC检测至反应结束;滴加饱和氯化铵水溶液(50mL)淬灭反应,抽滤,乙酸乙酯(50mL)淋洗,滤液用乙酸乙酯(100mL×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,经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/2)纯化,得到标题化合物(E)-6-溴-3-甲基十六烷-2-烯-1-醇1c(黄色油状物,3.8g,产率:92.0%)。
LC-MS m/z(ESI)=175.0[M-17]
第三步:
(E)-2-((6-溴-3-甲基十六烷-2-烯-1-基)氧基)四氢-2H-吡喃
(E)-2-((6-bromo-3-methylhex-2-en-1-yl)oxy)tetrahydro-2H-pyran 1d
在0℃,氮气保护下,将3,4-二氢-2H-吡喃(2.8mL,33.0mmol)和对甲苯磺酸(0.14g,0.83mmol)滴加到化合物1c(3.2g,16.5mmol)的二氯甲烷(40mL)溶液中,滴毕升至室温搅拌反应1h;TLC检测至反应结束;加入饱和碳酸氢钠溶液(20mL)淬灭反应,减压浓缩,水相用石油醚(30mL×3)萃取,饱和食盐水(30mL)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)=1/20)纯化,得到标题化合物(E)-2-((6-溴-3-甲基十六烷-2-烯-1-基)氧基)四氢-2H-吡喃1d(黄色油状物,4.3g,产率:93.0%)。
1H NMR(400MHz,CDCl
3)δ5.42-5.36(m,1H),4.64-4.58(m,1H),4.22(dd,J=12.0,6.4Hz,1H),4.01(dd,J=12.0,7.2Hz,1H),3.87(ddd,J=11.2,7.6,3.3Hz,1H),3.49(dd,J=11.0,5.2Hz,1H),3.37(t,J=6.7Hz,2H),2.19-2.13(m,2H),2.02-1.93(m,2H),1.91-1.76(m,2H),1.66(s,3H),1.56-1.45(m,4H)。
第四步:
(E)-(4-甲基-6-((四氢-2H-吡喃-2-基)氧基)十六烷-4-烯-1-基)三苯基溴化膦
(E)-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)hex-4-en-1-yl)triphenylphosphonium bromide 1e
向反应瓶中依次加入化合物1d(3.6g,12.0mmol)、三苯基膦(5.1g,19.0mmol)和乙腈(4mL),氮气保护下升温至80℃搅拌反应16h;TLC检测至反应结束;降至室温,减压浓缩,残留物加入异丙醚(50mL)打浆30min,抽滤,滤饼烘干,得到标题化合物(E)-(4-甲基-6-((四氢-2H-吡喃-2-基)氧基)十六烷-4-烯-1-基)三苯基溴化膦1e(黄色固体,6.8g,产率:99.0%)。
第五步:
(E)-2-((3-甲基-7-(甲基-d3)辛-2,6-二烯-1-基-8,8,8-d3)氧基)四氢-2H-吡喃
(E)-2-((3-methyl-7-(methyl-d3)octa-2,6-dien-1-yl-8,8,8-d3)oxy)tetrahydro-2H-pyran 1f
在-78℃,氮气保护下,将双三甲基硅基胺基锂(13.0mL,12.6mmol)滴加到化合物1e(6.8g,12.6mmol)的四氢呋喃(90mL)溶液中,滴毕,搅拌反应0.5h;滴加氘代丙酮(0.8g,12.6mmol),滴毕回温至0℃搅拌反应2h,TLC检测至反应结束;加入水(100mL)淬灭反应,石油醚(100mL×2)萃取,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,经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/10)纯化,得到标题化合物(E)-2-((3-甲基-7-(甲基-d3)辛-2,6-二烯-1-基-8,8,8-d3)氧基)四氢-2H-吡喃1f(无色油状物,2.6g,产率:85.0%)。
第六步:
(E)-3-甲基-7-(甲基-d3)辛-2,6-二烯-8,8,8-d3-1-醇
(E)-3-methyl-7-(methyl-d3)octa-2,6-dien-8,8,8-d3-1-ol 1g
向反应瓶中依次加入化合物1f(2.6g,11.0mmol)、对甲苯磺酸(0.2g,1.1mmol)和无水乙醇(10mL),氮气保护下室温搅拌反应2h;TLC检测至反应结束;减压浓缩,残留物加入乙酸乙酯(50mL)溶解,分别用饱和碳酸氢钠溶液(50mL)和饱和氯化钠溶液(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)=1/2)纯化,得到标题化合物(E)-3-甲基-7-(甲基-d3)辛-2,6-二烯-8,8,8-d3-1-醇1g(无色油状物,0.62g,产率:36.0%)。
1H NMR(400MHz,DMSO)δ5.26(t,J=6.4Hz,1H),5.08(t,J=6.9Hz,1H),4.44(dd,J=10.1,4.9Hz,1H),3.93(t,J=5.8Hz,2H),2.07-2.00(m,2H),1.99-1.94(m,2H),1.57(s,3H)。
LC-MS m/z(ESI)=143.20[M-17]
第七步:
(E)-2-(3-甲基-7-(甲基-d3)辛-2,6-二烯-1-基-8,8,8-d3)-5-戊基苯-1,3-二醇
(E)-2-(3-methyl-7-(methyl-d3)octa-2,6-dien-1-yl-8,8,8-d3)-5-pentylbenzene-1,3-diol化合物1
向反应瓶中依次加入化合物1g(0.6g,3.8mmol)、3,5-二羟基戊苯1h(1.0g,5.6mmol)、酸性氧化铝(7.6g,75.0mmol)和二氯乙烷(20mL),氮气保护下升温至85℃搅拌反应30min;TLC检测至反应结束;降至室温,抽滤,乙酸乙酯(30mL×3)淋洗,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)=1/10)纯化,得到标题化合物(E)-2-(3-甲基-7-(甲基-d3)辛-2,6-二烯-1-基-8,8,8-d3)-5-戊基苯-1,3-二醇化合物1(白色固体,0.73g,产率:60.0%)。
1H NMR(400MHz,DMSO)δ8.85(s,2H),6.08(s,2H),5.17(t,J=5.1Hz,1H),5.05(t,J=6.9Hz,1H),3.12(d,J=7.0Hz,2H),2.32(t,J=7.5Hz,2H),1.98(dd,J=9.8,5.2Hz,2H),1.91-1.85(m,2H),1.69(s,3H),1.46(dd,J=14.3,7.1Hz,2H),1.26(dt,J=15.1,5.4Hz,4H),0.86(t,J=6.9Hz,3H)。
LC-MS m/z(ESI)=323.30[M+1]
实施例2
第一步:
(E)-3,7-二甲基八-2,6-二烯-1,1-d2-1-醇
(E)-3,7-dimethylocta-2,6-dien-1,1-d2-1-ol 2b
在-30℃、氮气保护下,将氘代氢化铝锂(2.3g,54.0mmol)分批加到(E)-3,7-二甲基辛-2,6-二烯酸甲酯(5.0g,27.0mmol)的四氢呋喃(50mL)溶液中,加毕搅拌反应1h;TLC检测至反应结束;滴加水(50mL)淬灭反应,乙酸乙酯(100mL*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,滤液减压浓缩得到残留物,经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/1)纯化,得到标题化合物2b(无色油状物,4.2g,产率:97.0%)。
LC-MS m/z(ESI)=139.2[M-17]
第二步:
(E)-2-(3,7-二甲基八-2,6-二烯-1-基-1,1-d2)-5-戊基苯-1,3-二醇
(E)-2-(3,7-dimethylocta-2,6-dien-1-yl-1,1-d2)-5-pentylbenzene-1,3-diol化合物2
向反应瓶中依次加入化合物2b(0.8g,5.1mmol)、3,5-二羟基戊苯(1.1g,6.1mmol)、酸性氧化铝(10.0g,0.10mol)和二氯乙烷(26mL),氮气保护下升温至85℃搅拌反应30min;TLC检测至反应结束;降至室温,抽滤,乙酸乙酯(30mL*3)淋洗,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)=1/10)纯化,得到标题化合物2(白色固体,0.38g,产率:24.0%)。
1H NMR(400MHz,DMSO)δ8.85(s,2H),6.08(s,2H),5.15(s,1H),5.04(t,J=6.9Hz,1H),2.32(t,J=7.6Hz,2H),1.99(dd,J=14.6,6.9Hz,2H),1.93–1.83(m,2H),1.69(d,J=1.1Hz,3H),1.60(s,3H),1.52(d,J=9.4Hz,3H),1.46(dd,J=14.7,7.2Hz,2H),1.31–1.22(m,4H),0.85(t,J=7.0Hz,3H)。
LC-MS m/z(ESI)=319.0[M+1]
实施例3
第一步:
(3,5-二甲氧基苯基)甲烷-d2-醇
(3,5-dimethoxyphenyl)methan-d2-ol 3b
在0℃、氮气保护下,将氘代氢化铝锂(2.4g,56.0mmol)分批加到3,5-二甲氧基苯甲酸甲酯(5.0g,26.0mmol)的四氢呋喃(50mL)溶液中,加毕搅拌反应1h;TLC检测至反应结束;滴加水(50mL)淬灭反应,乙酸乙酯(100mL×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3b(无色油状物,4.3g,产率:99.0%)。
LC-MS m/z(ESI)=171.2[M+1]
第二步:
1-(溴甲基-d2)-3,5-二甲氧基苯
1-(bromomethyl-d2)-3,5-dimethoxybenzene 3c
在0℃,氮气保护下,将三溴化磷(6.4g,23.0mmol)滴加到化合物3b(3.8g,22.0mmol)的二氯甲烷(50mL)溶液中,滴毕搅拌反应0.5h;TLC检测至反应结束;滴加水(50mL)淬灭反应,分液,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, 得到标题化合物3c(白色固体,2.8g,产率:54.0%)。
1H NMR(400MHz,DMSO)δ6.61(d,J=2.3Hz,2H),6.44(t,J=2.3Hz,1H),3.74(s,6H)。
LC-MS m/z(ESI)=233.5[M+1]
第三步:
1,3-二甲氧基-5-(戊基-1,1-d2)苯
1,3-dimethoxy-5-(pentyl-1,1-d2)benzene 3d
在0℃,氮气保护下,将正丁基溴化镁(16.0mL,14.0mmol,1N)滴加到化合物3c(3.2g,12.0mmol),四氯合铜酸二锂(14.0mL,1.2mmol,0.1N)和二氯甲烷(40mL)中,滴毕升至室温搅拌反应15h;TLC检测至反应结束;加入饱和氯化铵溶液(20mL)淬灭反应,乙酸乙酯(50mL×2)萃取,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)=1/30)纯化,得到标题化合物3d(无色油状物,1.9g,产率:67.8%)。
1H NMR(400MHz,CDCl
3)δ6.35(d,J=2.2Hz,2H),6.30(t,J=2.2Hz,1H),3.78(s,6H),1.60(d,J=7.3Hz,2H),1.31(dd,J=8.3,4.7Hz,4H),0.89(t,J=6.8Hz,3H)。
LC-MS m/z(ESI)=211.4[M+1]
第四步:
5-(戊基-1,1-d2)苯-1,3-二醇
5-(pentyl-1,1-d2)benzene-1,3-diol 3e
在0℃,氮气保护下,将三溴化硼(2.6mL,27.0mmol)滴加到化合物3d(1.9g,9.0mmol)的二氯甲烷(30mL)中,滴毕升至室温搅拌反应1.5h;TLC检测至反应结束;加入饱和碳酸氢钠溶液(50mL)淬灭反应,二氯甲烷(100mL×2)萃取,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,经硅胶柱层析(洗脱剂:乙酸乙酯/石油醚(v/v)=1/2)纯化,得到标题化合物3e(白色固体,1.5g,产率:90.3%)。
1H NMR(400MHz,DMSO)δ9.00(s,2H),6.00(dt,J=4.1,2.1Hz,3H),1.49–1.43(m,2H),1.25(ddd,J=9.0,7.1,4.4Hz,4H),0.85(t,J=7.0Hz,3H)。
LC-MS m/z(ESI)=183.2[M+1]
第五步:
(E)-2-((3-甲基-7-(甲基-d3)辛-2,6-二烯-1-基-8,8,8-d3)氧基)四氢-2H-吡喃
(E)-2-((3-methyl-7-(methyl-d3)octa-2,6-dien-1-yl-8,8,8-d3)oxy)tetrahydro-2H-pyran化合物3
向反应瓶中依次加入化合物3e(0.4g,2.7mmol)、(E)-3,7-二甲基辛-2,6-二烯-1-醇(0.5g,2.7mmol)、酸性氧化铝(5.5g,55.0mmol)和二氯乙烷(15mL),氮气保护下升温至85℃搅拌反应30min;TLC检测至反应结束;降至室温,抽滤,二氯甲烷(50mL)淋洗,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)=1/10)纯化,得到标题化合物3(白色固体,0.24g,产率:29.0%)。
1H NMR(400MHz,DMSO)δ8.85(s,2H),6.08(s,2H),5.16(t,J=6.5Hz,1H),5.04(t,J=6.9Hz,1H),3.12(d,J=7.1Hz,2H),1.99(dd,J=14.8,7.0Hz,2H),1.92–1.83(m,2H),1.69(s,3H),1.60(s,3H),1.53(s,3H),1.48–1.42(m,2H),1.30–1.22(m,4H),0.85(t,J=7.0Hz,3H)。
LC-MS m/z(ESI)=319.3[M+1]
实施例4
(E)-2-(3,7-二甲基八-2,6-二烯-1-基-1,1-d2)-5-(戊基-1,1-d2)苯-1,3-二醇
(E)-2-(3,7-dimethylocta-2,6-dien-1-yl-1,1-d2)-5-(pentyl-1,1-d2)benzene-1,3-diol化合物4
向反应瓶中依次加入5-(戊基-1,1-d2)苯-1,3-二醇(0.50g,2.74mmol)、(E)-3,7-二甲基八-2,6-二烯-1,1-d2-1-醇(0.43g,2.74mmol)、酸性氧化铝(5.60g,0.06mol)和二氯乙烷(15mL),氮气保护下升温至85℃搅拌反应30min;TLC检测至反应结束;降至室温,抽滤,乙酸乙酯(50mL×2)淋洗,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)=1/10)纯化,得到标题化合物4(白色固体,72mg,产率:8.3%)。
1H NMR(400MHz,DMSO)δ8.85(s,2H),6.07(s,2H),5.15(s,1H),5.04(t,J=6.3Hz,1H),1.98(t,J=7.1Hz,2H),1.93-1.82(m,2H),1.69(s,3H),1.60(s,3H),1.53(s,3H),1.45(t,J=7.0Hz,2H),1.31–1.21(m,4H),0.85(t,J=6.8Hz,3H)。
LC-MS m/z(ESI)=321.5[M+1]
小鼠药代动力学
取成年健康ICR小鼠6只,分成2组(每组3只),一组给予静脉注射(i.v)给药对照化合物(CBG)(1mg/kg),另一组给予静脉注射(i.v)给药化合物4(1mg/kg)。于给药前(0h)和给药后5min、15min、30min、1h、2h、4h、8h、24h从眼眶处采血0.1mL。所有血样使用EDTA-K2抗凝,随后5℃,3500rpm离心10min分离血浆,于-20℃保存待测。建立LC/MS法测定血浆中的药物浓度。注:对照化合物参照WO2017216362制备。
采用上述方法,测得受试化合物药代动力学结果如下:
AUCall(ng*h/mL) | t1/2(h) | CL(mL/min/kg) | |
对照化合物 | 113 | 0.40 | 145.1 |
化合物4 | 244 | 0.99 | 66.1 |
根据实验结果可知,本发明中氘代化合物4在小鼠体内显示出明显优于对照化合物的药代动力学特征,表明本发明化合物将具有明显优异的药代动力学趋势。
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 (11)
- 根据权利要求6所述的制备方法,其包括以下步骤:第一步:将化合物B-II、磷酰基乙酸三乙酯在氢化钠的四氢呋喃溶液中反应,得到化合物B-III;第二步:将二异丁基氢化铝滴加到所述化合物B-III的四氢呋喃溶液中反应,得到化合物B-IV;第三步:将3,4-二氢-2H-吡喃和对甲苯磺酸滴加到所述化合物B-IV的二氯甲烷溶液中反应,得到化合物B-V;第四步:将所述化合物B-V和三苯基膦在乙腈中反应,得到化合物B-VI;第五步:将双三甲基硅基胺基锂滴加到所述化合物B-VI的四氢呋喃溶液中反应,随后滴加氘代丙酮反应,得到氘代化合物A-I;第六步:将所述氘代A-I化合物和对甲苯磺酸在无水乙醇中反应,得到化合物B-I’;第七步:将所述化合物B-I’、化合物A-III和酸性氧化铝在二氯乙烷中反应,得到氘代化合物A。
- 权利要求1或2所述的化合物在制备用于治疗中枢神经系统相关的疾病中的用途。
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CN103533930A (zh) * | 2011-05-20 | 2014-01-22 | Gw药品有限公司 | 用于治疗神经性疼痛的大麻素类化合物 |
WO2017087795A1 (en) * | 2015-11-19 | 2017-05-26 | Concert Pharmaceuticals, Inc. | Deuterated epi-743 |
WO2020077153A1 (en) * | 2018-10-10 | 2020-04-16 | Canopy Holdings, LLC | Synthesis of cannabigerol |
WO2020092823A1 (en) * | 2018-10-31 | 2020-05-07 | Baymedica, Inc. | Cannabinoid analogs and methods for their preparation |
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CN103533930A (zh) * | 2011-05-20 | 2014-01-22 | Gw药品有限公司 | 用于治疗神经性疼痛的大麻素类化合物 |
WO2017087795A1 (en) * | 2015-11-19 | 2017-05-26 | Concert Pharmaceuticals, Inc. | Deuterated epi-743 |
WO2020077153A1 (en) * | 2018-10-10 | 2020-04-16 | Canopy Holdings, LLC | Synthesis of cannabigerol |
WO2020092823A1 (en) * | 2018-10-31 | 2020-05-07 | Baymedica, Inc. | Cannabinoid analogs and methods for their preparation |
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