CN113444144A - 一种蛋白酶抑制剂及其药物组合物和用途 - Google Patents
一种蛋白酶抑制剂及其药物组合物和用途 Download PDFInfo
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- CN113444144A CN113444144A CN202110696332.8A CN202110696332A CN113444144A CN 113444144 A CN113444144 A CN 113444144A CN 202110696332 A CN202110696332 A CN 202110696332A CN 113444144 A CN113444144 A CN 113444144A
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 24
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 title claims abstract description 11
- 239000000137 peptide hydrolase inhibitor Substances 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 124
- 150000003839 salts Chemical class 0.000 claims abstract description 37
- 239000013078 crystal Substances 0.000 claims abstract description 10
- 241000711573 Coronaviridae Species 0.000 claims abstract description 9
- 239000012453 solvate Substances 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- 238000002360 preparation method Methods 0.000 claims description 31
- 125000003118 aryl group Chemical group 0.000 claims description 25
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
- 229910052805 deuterium Inorganic materials 0.000 claims description 18
- 125000000623 heterocyclic group Chemical group 0.000 claims description 18
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 7
- 125000001188 haloalkyl group Chemical group 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 150000001721 carbon Chemical group 0.000 claims description 4
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000003003 spiro group Chemical group 0.000 claims description 3
- 229940124597 therapeutic agent Drugs 0.000 claims description 3
- FZRKAZHKEDOPNN-UHFFFAOYSA-N Nitric oxide anion Chemical compound O=[N-] FZRKAZHKEDOPNN-UHFFFAOYSA-N 0.000 claims description 2
- 230000000840 anti-viral effect Effects 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical class OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims 1
- 125000003275 alpha amino acid group Chemical group 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 239000002777 nucleoside Substances 0.000 claims 1
- 150000003833 nucleoside derivatives Chemical class 0.000 claims 1
- 229910052711 selenium Inorganic materials 0.000 claims 1
- 241001678559 COVID-19 virus Species 0.000 abstract description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- -1 2-dimethylpentyl Chemical group 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 239000002904 solvent Substances 0.000 description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- 239000000243 solution Substances 0.000 description 29
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 235000019439 ethyl acetate Nutrition 0.000 description 26
- 125000001424 substituent group Chemical group 0.000 description 26
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- 238000000034 method Methods 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 125000006413 ring segment Chemical group 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 125000004429 atom Chemical group 0.000 description 10
- 238000010348 incorporation Methods 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 125000005842 heteroatom Chemical group 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 208000015181 infectious disease Diseases 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 241000700605 Viruses Species 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 125000001183 hydrocarbyl group Chemical group 0.000 description 5
- 230000000155 isotopic effect Effects 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- 208000001528 Coronaviridae Infections Diseases 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
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Abstract
本发明公开了一种蛋白酶抑制剂及其药物组合物和用途,蛋白酶抑制剂含有下式所示的化合物或其立体异构体、药学上可接受的盐、溶剂化物或结晶,
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种蛋白酶抑制剂化合物及其药学上可接受的盐和含有该化合物或其药学上可接受的盐的组合物在制备抗冠状病毒药物中的用途。
背景技术
2019新型冠状病毒(SARS-CoV-2)是一种新型的冠状病毒,具有极强的传播能力。它是一种有包膜的单链RNA病毒,RNA长度达到近30kb,N蛋白(Nucleocapsid)外壳的包膜中含有S(Spikeprotein,刺突蛋白)、M(Membrane protein,膜蛋白)和E(Envelope protein,包膜蛋白)三种蛋白。目前发现的最主要的感染途径是病毒的S蛋白的RBD(ReceptorBinding Domain,受体结合区)与细胞膜表面的ACE2蛋白结合,导致细胞膜与病毒包膜融合,最终病毒感染宿主细胞。
2019新型冠状病毒(SARS-CoV-2)是一种具有囊膜、基因组为线性单股正链的RNA病毒,主要导致肺炎和严重急性呼吸综合症(COVID-19),可伴随肾衰竭,甚至死亡。SARS-CoV-2主要通过呼吸道飞沫或直接接触分泌物传播,也有证据表明可经气溶胶和粪-口途径传播,其传播速度快且范围广泛,严重威胁人类的健康和生命。目前尚无特效的抗SARS-CoV-2药物。临床报道的干扰素、克立芝及一些传统中药方剂对新型冠状病毒引起的肺炎具有治疗效果,但这些药物的抗病毒作用仍需进一步确证。文献报道,磷酸氯喹、瑞德西韦等具有抗新冠病毒SARS-CoV-2作用。目前,核苷类似物瑞德西韦是全球唯一一个获得批准的抗SARS-CoV-2药物,在体外和体内动物模型中均表现出了良好的抗SARS-CoV-2活性。然而,中国的临床试验研究结果显示,其对严重型COVID-19患者的治疗效果并不明显,WHO建议应继续对瑞德西韦的疗效进行全面评估。因此,研发治疗和预防新型冠状病毒SARS-CoV-2感染的抗病毒新药,对于降低COVID-19患者的重症率和死亡率、阻断疫情的蔓延和再度爆发均具有重要意义。
发明内容
本发明的目的是提供具有抗SARS-CoV-2新型冠状病毒作用的化合物。
本发明提供以下所示的发明。
具体涉及一种蛋白酶抑制剂化合物及其药学上可接受的盐和含有该化合物或其药学上可接受的盐的组合物在制备抗冠状病毒药物中的用途。其特征是:
其中:
X为O、S、Se、NH、当X为CH时,可与相邻碳原子形成双键。
Z选自以下一组:氰基、醛、酮酰胺、亚硫酸氢盐、杂环基、-COCOOR2,其中R2是支链或无支链的烷基,-CH(OH)COOR2,其中R2是支链或无支链的烷基,以及-CH(OH)(P=O)(OR6)2,其中R6是烷基、烯基、芳烷基、卤代烷基或取代的或未取代的芳烷基。
Ra是支链或无支链的烷基、环烷基、芳基、芳烷基、烯基、炔基、天然氨基酸侧链;
Rb是-C(O)R、-S(O)2R、-OCH2R、-OR或-(CH2)nR;R选自-CH3、-CF3、或是取代或未被取代的烷基、环烷基、杂环烷基、芳基、杂芳基、芳氧基、杂芳氧基、芳烷氧基、杂芳烷氧基;
Rc,Rd可选自氘、卤素、氰基、或是取代的或未被取代的烷基、环烷基、杂环烷基、芳基、芳烷基、烯基、炔基;n=0-6。Rc,Rd也可与母环形成并环、螺环。
所述的蛋白酶抑制剂化合物选自如下结构,但绝不限于这些化合物:
一种药物组合物,其含有所述的蛋白酶抑制剂化合物、或其制药上可接受的盐、或它们的溶剂化物。
一种所述的药物组合物在制备具有抗新冠病毒(SARS-CoV-2)作用的药物中的应用。
一种所述的药物组合物在制备具有抗新冠病毒(SARS-CoV-2)抑制作用的制剂中的应用。
发明详述
除非另有明确规定,否则以下定义适用:
如本文所用,术语“卤素”或卤是指氟、溴、氯或碘,特别是当与烷基连接时是指氟或氯,并且当在芳基或杂芳基上时还包括溴或碘。
除非另有说明,本文所用的术语“杂原子”是指氮(N)、氧(O)或硫(S)原子。
如本文所用,术语“烷基”是指具有至多10个碳原子的完全饱和的支链或无支链的烃部分。除非另外提供,否则烷基是指具有1至6个碳原子的烃部分。烷基的代表性实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正辛基、正壬基、正癸基等。取代的烷基是含有一个或多个取代基代替氢的烷基,例如1、2或3个取代基,最多达未取代烷基上的存在的氢的数目。如果没有另外说明,烷基的合适取代基可以选自卤素、CN、氧代、羟基、C1-4烷氧基、取代或未取代的C3-6环烷基、取代或未取代的苯基、氨基、(C1-4烷基)氨基、二(C1-4烷基)氨基、C1-4烷硫基、C1-4烷基磺酰基、-C(=O)-C1-4烷基、COOH、COO(C1-4烷基)、-O(C=O)-C1-4烷基,-NHC(=O)C1-4烷基和-NHC(=O)OC1-4烷基;其中,对于取代的环烷基或苯基,取代基是最多三个选自Me、Et、-OMe、-OEt、CF3、卤素、CN、OH和NH2的基团。
如本文所用,术语“卤代烷基”是指如本文所定义的烷基被一个或多个卤素基团取代。卤代烷基可以是单卤代烷基、二卤代烷基、三卤代烷基或包括全卤代烷基的多卤代烷基。单卤代烷基可以在烷基内具有一个氯或氟。氯和氟通常作为在烷基或环烷基上的取代基存在;氟、氯和溴通常存在于芳基或杂芳基上。二卤代烷基和多卤代烷基可以在烷基上具有两个或多个相同的卤素原子或不同的卤素基团的组合。典型地,多卤代烷基含有最多12或10或8或6或4或3或2个卤素基团。卤代烷基的非限制性实例包括氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、2,2,2-三氟乙基、五氟乙基、七氟丙基、二氟氯甲基、二氯氟甲基、二氟乙基、二氟丙基、二氯乙基和二氯丙基。全卤代烷基是指所有氢原子被卤素原子取代的烷基,例如三氟甲基。
如本文所用,术语“烷氧基”是指烷基-O-,其中烷基如上定义。烷氧基的代表性实例包括但不限于甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基、叔丁氧基、戊氧基、己氧基等。通常,烷氧基具有1-6个碳,更通常1-4个碳原子。
如本文所用,术语“卤代烷氧基”是指卤代烷基-O-,其中卤代烷基如上定义。卤代烷氧基的代表性实例包括但不限于氟甲氧基、二氟甲氧基、三氟甲氧基、三氯甲氧基、2-氯乙氧基、2,2,2-三氟乙氧基、1,1,1,3,3,3-六氟-2-丙氧基等等。通常,卤代烷基具有1-4个碳原子。
如本文所用,术语“环烷基”是指3-12个碳原子的饱和或不饱和的非芳族单环、双环、三环或螺环烃基:环烷基可以是不饱和的,并且可以与另一个可以是饱和的、不饱和的或芳族的环稠合,条件是与目标分子式连接的环烷基的环原子不是芳环碳。除非另有说明,否则环烷基是指具有3至9个环碳原子或3至7个环碳原子的环状烃基。优选地,环烷基是具有3-7个环原子的饱和单环,例如环丙基、环丁基、环戊基和环己基,除非另有说明。
取代的环烷基是被一个、或两个、或三个、或多于三个取代基、直至未取代的基团上氢的数目所取代的环烷基。通常,除非另有说明,取代的环烷基将具有1-4个取代基。除非另有说明,合适的取代基独立地选自卤素、羟基、硫醇、氰基、硝基、氧代、C1-C4烷基亚氨基、C1-C4-烷氧基亚氨基、羟基亚氨基、C1-C4烷基、C2-C4-烯基、C2-C4-炔基、C1-C4-烷氧基、C1-C4-硫代烷基、C2-C4-烯氧基、C2-C4-炔氧基、C1-C4-烷基羰基、羧基、C1-C4-烷氧基羰基、氨基、C1-C4-烷基氨基、二-C1-C4-烷基氨基、C1-C4-烷基氨基羰基、二-C1-C4-烷基氨基羰基、C1-C4-烷基羰基氨基,C1-C4-烷基羰基(C1-C4-烷基)氨基、C1-C4-烷基磺酰基、C1C4-烷基氨磺酰基和C1-C4-烷基氨基磺酰基,其中每个上述烃基(例如,烷基、烯基、炔基、烷氧基残基)可以进一步被一个或多个在每次出现时独立选自本文中“烷基”取代基列表的基团取代。环烷基的优选取代基包括C1-C4烷基和上面列出的作为烷基合适取代基的取代基。
如本文所用,术语“芳基”是指环部分中具有6-14个碳原子的芳族烃基。通常,芳基是具有6-14个碳原子、通常为6-10个碳原子的单环、双环或三环芳基,例如苯基或萘基。此外,如本文所用的术语“芳基”是指芳族取代基,其可以是单个芳族环,或稠合在一起的多个芳族环。非限制性实例包括苯基、萘基和1,2,3,4-四氢萘基,条件是四氢萘基通过四氢萘基的芳环的碳与所述式连接。除非另有说明,优选的芳基是苯基。取代的芳基是被1-5个(例如一个、或两个或三个)取代基取代的芳基,所述取代基独立地选自羟基、硫醇、氰基、硝基、C1-C4烷基、C2-C4-烯基、C2-C4-炔基、C1-C4-烷氧基、C1-C4-硫代烷基、C2-C4-烯氧基、C2-C4-炔氧基、卤素、C1-C4-烷基羰基、羧基、C1-C4-烷氧基羰基、氨基、C1-C4-烷基氨基、二-C1-C4-烷基氨基、C1-C4-烷基氨基羰基、二-C1-C4-烷基氨基羰基、C1-C4-烷基羰基氨基、C1-C4-烷基羰基(C1-C4-烷基)氨基、C1-C4-烷基磺酰基、氨磺酰基、C1-C4-烷基氨磺酰基和C1-C4-烷基氨基磺酰基,其中每个上述烃基(例如,烷基、烯基、炔基、烷氧基残基)可以进一步被一个或多个在每次出现时独立选自上面列出的作为烷基合适取代基的基团取代。取代的芳基的优选取代基是C1-4烷基,以及上述作为烷基的合适取代基的那些基团,不包括二价基团如氧代。
类似地,其它基团的各环烷基部分如“芳氧基”、“芳氧基烷基”应具有与上述“芳基”定义中所述相同的含义。
如本文所用,术语“杂环基”是指饱和或部分不饱和但不是芳香族的杂环基,并且可以是单环或多环(在多环的情况下,特别是双环、三环或螺环);并且具有3至14个、更常见的是4至10个、最优选5或6个环原子;其中一个或多个、优选一至四个、尤其是一个或两个环原子是独立地选自O、S和N的杂原子(其余的环原子因此是碳)。即使被描述为例如C5-6原子环,杂环含有至少一个杂原子作为环原子,其它环原子是碳,并且具有所述的环原子数,例如在此示例中是5-6。优选地,杂环基具有一个或两个这样的杂原子作为环原子,并且优选地,杂原子不直接彼此连接。除非另有说明,键合环(即连接到目标式的环)优选具有4-12个、特别是5-7个环原子。杂环基团可以稠合到芳环上,条件是与目标化学式连接的杂环基团的原子不是芳香性的。杂环基团可以通过杂原子(通常为氮)或杂环基团的碳原子与目标式连接。杂环基可以包括稠环或桥环以及螺环,并且只要多环杂环基团的一个环含有杂原子作为环原子。杂环的示例包括四氢呋喃(THF)、二氢呋喃、1,4-二氧六环、吗啉、1,4-二噻烷、哌嗪、哌啶、1,3-二氧戊环、咪唑烷、咪唑啉、吡咯啉、吡咯烷、四氢吡喃、二氢吡喃、氧硫杂环戊烷、二硫杂环戊烷、1,3-二氧六环、1,3-二噻烷、氧硫杂环己烷、硫代吗啉等。
取代的杂环基是独立地被1-5个(例如一个、或两个或三个)取代基取代的杂环基,所述取代基选自上述环烷基的取代基。
类似地,其他基团的各杂环基部分如“杂环基氧基”、“杂环基氧基烷基”、应具有与上述“杂环基”定义中所述相同的含义。
如本文所用,术语“杂芳基”是指5-14元单环-或双环-或三环-芳族环系统,具有1至8个杂原子作为环成员,其余环原子为碳,并且杂原子选自N、O和S。通常,杂芳基是5-10元环系,特别是5-6元单环或8-10元双环基团。典型的杂芳基包括2-或3-噻吩基,2-或3-呋喃基,2-或3-吡咯基,2-、4-或5-咪唑基,1-、3-、4-或5-吡唑基,2-、4-或5-噻唑基,3-、4-或5异噻唑基,2-、4-或5-恶唑基,3-、4-或5-异恶唑基,3-或5-1,2,4-三唑基,4-或5-1,2,3-三唑基,1-或2-四唑基,2-、3-或4-吡啶基,3-或4-哒嗪基,3-、4-或5-吡嗪基,2-吡嗪基和2-、4-或5-嘧啶基。
术语“杂芳基”还指其中杂芳环与一个或多个芳基、环烷基或杂环基环稠合的基团。非限制性实例包括2-、3-、4-、5-、6-、7-或8-喹啉基,1-、3-、4-、5-、6-、7-或8-异喹啉基,2-、3-、4-、5-、6-或7-吲哚基,2-、3-、4-、5-、6-或7-苯并[b]噻吩基,2-、4-、5-、6-或7-苯并恶唑基,2-、4-、5-、6-或7-苯并咪唑基,和2-、4-、5-、6-或7-苯并噻唑基。
取代的杂芳基是含有一个或多个取代基的杂芳基,通常是一个或两个取代基,选自上述适合于芳基的取代基。
类似地,其他基团的各杂芳基部分如“杂芳氧基”、“杂芳氧基烷基”应具有与上述“杂芳基”定义中所述相同的含义。
本文描述了本发明的各种实施方式。将认识到,每个实施例中指定的特征可以与其他指定特征组合以提供本发明的进一步实施方式。
如本文所用,术语“光学异构体”或“立体异构体”是指对于给定的本发明化合物可存在的各种立体异构构型中的任一种,并且包括几何异构体。应该理解,取代基可以连接在碳原子的手性中心。术语“手性”是指在其镜像伴侣上具有不可重叠性质的分子,而术语“非手性”是指可重叠在其镜像伴侣上的分子。因此,本发明包括该化合物的对映异构体、非对映异构体或外消旋体。“对映异构体”是一对彼此不可重叠镜像的立体异构体。一对对映异构体的1:1混合物是一种“外消旋”混合物。该术语在适当时用于指定外消旋混合物。“非对映异构体”是具有至少两个不对称原子的立体异构体,但其不是彼此的镜像。根据Cahnlngold-Prelog‘R-S'系统确定绝对立体化学。当化合物为纯对映体时,每个手性碳上的立体化学可以由R或S指定。绝对构型未知的拆分化合物可以根据它们在钠D线的波长处旋转平面偏振光的方向(右旋或左旋)命名为(+)或(-)。本文所述的某些化合物含有一个或多个不对称中心或轴,并因此可产生对映异构体、非对映异构体和其它立体异构形式,其可根据绝对立体化学定义为(R)-或(S)-。根据起始原料和合成过程的选择,这些化合物能以可能的异构体之一的形式或作为其混合物存在,例如作为纯的光学异构体,或作为异构体混合物,例如外消旋体和非对映异构体混合物,取决于不对称碳原子的数目。本发明意在包括所有这些可能的异构体,包括外消旋混合物、非对映异构体混合物和光学纯形式。光学活性(R)-和(S)-异构体可以使用手性合成子或手性试剂来制备,或者使用常规技术来拆分。如果化合物含有双键,则取代基可以是E或Z构型,除非另有说明。如果化合物含有二取代的环烷基,除非另有说明,环烷基取代基可以具有顺式或反式构型。所有的互变异构形式也意在包括在内。
在许多情况下,本发明化合物能由于存在氨基和/或羧基或类似基团而形成酸和/或碱盐。如本文所用,术语“盐”或“盐类”是指本发明化合物的酸加成盐或碱加成盐。“盐”特别包括“药学可接受的盐”。术语“药学可接受的盐”是指保留本发明化合物的生物有效性和性质并且通常不是生物学上或其他方面不合需要的盐。
药学可接受的酸加成盐可以用无机酸和有机酸形成,例如乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/盐酸、氯茶碱盐、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、马尿酸盐、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、乳糖醛酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、十八酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖醛酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。其他合适盐的列表可见例如“Remington's Pharmaceutical Sciences”,第20版,Mack Publishing Company,Easton,Pa.(1985)和Stahl和Wermuth(Wiley-VCH,Weinheim,Germany,2002)的“Handbook of Pharmaceutical Salts:Properties,Selection,and Use”。可由其衍生盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。可以衍生盐的有机酸包括例如乙酸、丙酸、乙醇酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、甲苯磺酸、磺基水杨酸等。药学上可接受的碱加成盐可以与无机碱或有机碱形成并且可以具有无机或有机平衡离子。用于这种碱盐的无机平衡离子包括例如铵盐和来自元素周期表第I至XII列的金属。在某些实施方式中,平衡离子选自钠、钾、铵、具有1至4个C1-C4烷基的烷基铵、钙、镁、铁、银、锌和铜;特别合适的盐包括铵盐、钾盐、钠盐、钙盐和镁盐。可以衍生盐的有机碱包括例如伯胺、仲胺和叔胺、取代的胺包括天然存在的取代的胺、环胺、碱性离子交换树脂等。合适的有机胺包括异丙胺、苄星青霉素、胆碱、二乙醇胺、二乙胺、赖氨酸、葡甲胺、哌嗪和氨丁三醇。本发明的药学上可接受的盐可以通过常规化学方法由碱性或酸性部分合成。通常,这些盐可以通过使这些化合物的游离酸形式与化学计量量的适当碱(例如Na、Ca、Mg或K氢氧化物、碳酸盐、碳酸氢盐等)反应来制备,或者通过使这些化合物的游离碱形式与化学计算量的合适的酸反应。这样的反应通常在水中或在有机溶剂中或在两者的混合物中进行。通常,在可行的情况下,使用非水介质如醚、乙酸乙酯、四氢呋喃、甲苯、氯仿、二氯甲烷、甲醇、乙醇、异丙醇或乙腈是理想的。
本文给出的任何式也旨在表示化合物的未标记形式(即,化合物中所有原子以天然同位素丰度存在,且非同位素富集)以及同位素富集或标记形式。同位素富集或标记的化合物具有本文给出的通式描述的结构,不同之处在于该化合物的至少一个原子被原子质量或质量数不同于天然存在的原子质量或原子量分布的原子替代。可以掺入本发明的富集或标记化合物的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素,分别如2H、3H、11C、13C、14C、15N、18F、31P、32P、35S、36Cl和125I。本发明包括如本文所定义的各种同位素标记的化合物,例如其中放射性同位素如3H和14C,或其中非放射性同位素如2H和13C的存在显著高于这些同位素的天然丰度的那些化合物。这些同位素标记的化合物可用于代谢研究(例如,用14C)、反应动力学研究(用例如2H或3H)、检测或成像技术如正电子发射断层摄影术(PET)或单光子发射计算机断层摄影术(SPECT)包括药物或底物组织分布测定,或用于患者的放射性治疗。具体地,18F标记的化合物可能对于PET或SPECT研究是特别理想的。式(I)的同位素标记化合物通常可以通过本领域技术人员已知的常规技术或通过类似于所附实施例中所述的方法使用适当的同位素标记试剂代替另外使用的未标记试剂来制备。此外,用较重同位素特别是氘(即2H或D)取代可以提供由更大的代谢稳定性产生的某些治疗优势,例如增加的体内半衰期或降低的剂量需求或改善的治疗指数。这种较重同位素特别是氘的浓度可以由同位素富集因子来定义。如本文所用的术语“同位素富集因子”意指指定同位素的同位素丰度与天然丰度之间的比率。如果本发明化合物中的取代基被表示为氘,则这种化合物对于指定的各氘原子具有至少3500的氘同位素富集因子(在每个指定的氘原子处52.5%的氘掺入),至少4000(60%的氘掺入),至少4500(67.5%氘掺入),至少5000(75%氘掺入),至少5500(82.5%氘掺入),至少6000(90%氘掺入),至少6333.3(95%氘掺入),至少6466.7(97%的氘掺入),至少6600(99%的氘掺入)或至少6633.3(99.5%的氘掺入)。根据本发明的药学上可接受的溶剂化物包括其中结晶溶剂可以被同位素取代的那些,例如D2O、d6-丙酮,d6-DMSO以及具有非富集态溶剂的溶剂合物。
本发明的化合物,即含有能够充当氢键供体和/或受体的基团的式(I)化合物可以能够与合适的共晶形成物形成共晶。这些共晶可以由式(I)化合物通过已知的共晶形成过程制备。此类过程包括研磨、加热、共升华、共熔融或在结晶条件下于溶液中使式(I)化合物与共晶形成物接触并分离由此形成的共晶。因此,本发明进一步提供了包含式(I)化合物的共晶。如本文所用,术语“药学可接受的载体”包括任何和所有溶剂、分散介质、包衣、表面活性剂、抗氧化剂、防腐剂(例如抗菌剂、抗真菌剂)、等渗剂、吸收延迟剂、盐、防腐剂、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、甜味剂、调味剂、染料等及其组合,如本领域技术人员已知(参见例如Remington:The Science and Practice of Pharmacy,第22版)。除了与活性成分不相容的任何常规载体之外,还考虑其在治疗或药物组合物中的用途。
术语“治疗有效量”的本发明化合物是指在对象中引发生物或医学反应的本发明化合物的量,例如,足以减少一种或多种症状、缓解病症、减慢或延迟疾病进展或预防疾病等的量。在一个非限制性实施方式中,术语“治疗有效量”是指当施用于对象时,本发明化合物有效减少与新冠病毒感染相关的一种或多种症状,或缩短新冠病毒感染的症状阶段的持续时间,或减缓新冠病毒感染的进展,或减少或阻止新冠病毒感染引起的潜在病症的恶化的量。
在另一个非限制性实施方式中,术语“治疗有效量”是指当施用于细胞、组织或非细胞生物材料或培养基时,能有效地引起病毒株的复制或增殖速率的统计学显著降低的量。
本文所用术语“对象”是指动物。通常对象是人。
如本文所用,术语“抑制”是指减少或抑制给定的病症、症状或紊乱或疾病,或者显著降低生物活动或过程的基线活性。
如本文所用,任何疾病或紊乱的术语“治疗”、“处治”或“处理”在一个实施方式中指改善所述疾病或紊乱(即减缓或阻滞或减少疾病或其至少一种临床症状的发展)。在另一个实施方式中,“治疗”、“处治”或“处理”是指减轻或改善至少一种身体参数,包括那些患者可能无法识别的身体参数。在另一个实施方式中,“治疗”、“处治”或“处理”是指在身体上(例如稳定可辨别的症状)、生理上(例如稳定身体参数)或两方面调节疾病或紊乱。在另一种实施方式中,“治疗”、“处治”或“处理”是指预防或延迟疾病或紊乱的发展或进展。
如本文所用,如果对象会从某种治疗中于生物学、医学或生活质量上受益,则该对象对该治疗“有需要”。
如本文所使用的,在本发明语境(特别是在权利要求语境)中使用的术语“一个”、“一种”、“所述”以及类似术语应被解释为涵盖单数和复数,除非另有说明或与语境明显矛盾。
本文所述的所有方法可以以任何合适的顺序进行,除非本文另外指出或另外明显与语境相矛盾。本文提供的任何和所有示例或示例性语言(例如“诸如”)的使用仅意在更好地说明本发明,而不是对本发明另行要求保护的范围进行限制。
本发明化合物的任何不对称原子(例如碳等)可以以外消旋或对映体富集例如(R)-、(S)-或(R,S)-构型的形式存在。在某些实施方式中,每个不对称原子具有至50%对映体过量、至少60%对映体过量、至少70%对映体过量、至少80%对映体过量、至少90%对映体过量、至少95%或至少99%对映体过量的(R)-或(S)-构型;即,对于光学活性化合物,通常优选使用一种对映体来基本上排除另一对映体,因此通常优选至少95%的对映体纯度。如果可能,具有不饱和双键的原子上的取代基可以以顺式-(Z)-或反式-(E)-形式存在。因此,如本文所用,本发明化合物可以是可能的异构体、旋转异构体、阻转异构体、互变异构体或其混合物之一的形式,例如基本上纯的几何(顺式或反式)异构体、非对映异构体、光学异构体(对映体)、外消旋体或其混合物。如本文所用,“基本纯”或“基本不含其他异构体”是指相对于优选异构体,产物含有的其他异构体的量按重量计少于5%,并且优选少于2%。得到的异构体混合物可以通常基于组分的物理化学差异,例如通过色谱法和/或分级结晶,分离成纯的或基本纯的几何或光学异构体、非对映异构体、外消旋体。
可通过已知方法将最终产物或中间体的外消旋体拆分成光学对映体,例如通过分离用光学活性酸或碱获得的其非对映异构体盐,并释放光学活性的酸性或碱性化合物。具体地,碱性部分可由此被用来将本发明的化合物拆分成它们的光学对映体,例如通过用光学活性酸例如酒石酸、二苯甲酰酒石酸、二乙酰酒石酸、二-O,O'-对甲苯甲酰基酒石酸、扁桃酸、苹果酸或樟脑-10-磺酸所形成盐的分级结晶。外消旋产物也可以通过手性色谱法拆分,例如使用手性固定相的高压液相色谱(HPLC)。
此外,本发明的化合物,包括它们的盐,也可以以其水合物的形式获得,或者包括用于其结晶的其他溶剂。本发明化合物可以固有地或经设计与可药用溶剂(包括水)形成溶剂合物;因此,本发明意在包括溶剂合和非溶剂合两种形式。术语“溶剂合物”是指本发明化合物(包括其药学上可接受的盐)与一种或多种溶剂分子的分子复合物。此类溶剂分子是药物领域中常用的那些,已知其对接受者无害,例如水、乙醇等。术语“水合物”是指其中溶剂分子是水的复合物。
另一方面,本发明提供药物组合物,其包含本发明化合物或其药学上可接受的盐和至少一种药学可接受的载体。在一些实施方式中,所述组合物包含至少两种药学上可接受的赋形剂或载体。药学上可接受的载体和其它赋形剂是本领域技术人员已知的,并且可以选自例如通过类似施用途径来施用的已批准(注册)配制治疗剂中使用的载体和赋形剂。可以配制药物组合物用于特定的给药途径,例如口服给药、胃肠外给药和直肠给药等。此外,本发明的药物组合物可以以固体形式(包括但不限于胶囊、片剂、丸剂、颗粒剂、粉剂或栓剂)或以液体形式(包括但不限于溶液剂、混悬剂或乳剂)制成。药物组合物可以进行常规的药物操作,例如灭菌和/或可以包含常规的惰性稀释剂、润滑剂或缓冲剂,以及佐剂例如防腐剂、稳定剂、润湿剂、乳化剂和缓冲剂等。在一个实施方式中,配制本发明化合物用于口服递送。通常,这些药物组合物是片剂或明胶胶囊,其包含活性成分(至少一种式(I)化合物)和一种或多种选自以下的赋形剂:
a)稀释剂,例如乳糖、右旋糖、蔗糖、甘露糖醇、山梨糖醇、纤维素和/或甘氨酸;b)润滑剂,例如二氧化硅、滑石、硬脂酸、其镁或钙盐和/或聚乙二醇;对于片剂还有c)粘合剂,例如硅酸镁铝、淀粉糊、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮;如果需要d)崩解剂,例如淀粉、琼脂、海藻酸或其钠盐或泡腾混合物;和/或e)吸收剂、着色剂、调味剂和甜味剂。
根据本领域已知的方法,片剂可以是薄膜包衣或肠溶包衣。
用于口服给药的合适组合物包括以片剂、锭剂、水性或油性混悬剂、可分散粉剂或颗粒剂、乳剂、硬或软胶囊剂或糖浆剂或酏剂形式的有效量的本发明化合物。旨在用于口服使用的组合物根据本领域就制备药物组合物已知的任何方法来制备,并且此类组合物可以含有选自甜味剂、调味剂、着色剂和防腐剂的一种或多种试剂以提供药学上优雅和适口的制品。片剂可含有活性成分,混以适于制造片剂的无毒药学可接受赋形剂。这些赋形剂是例如惰性稀释剂,如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;造粒剂和崩解剂,例如玉米淀粉或海藻酸;粘合剂,例如淀粉、明胶或阿拉伯胶;和润滑剂,例如硬脂酸镁、硬脂酸或滑石。片剂未经包衣或通过已知技术包衣以延迟在胃肠道中的崩解和吸收,从而提供较长时期的持续作用。例如,可以使用延时材料,例如单硬脂酸甘油酯或二硬脂酸甘油酯。口服使用的制剂可以呈现为硬明胶胶囊,其中活性成分混以惰性固体稀释剂,例如碳酸钙、磷酸钙或高岭土,或者呈现为软明胶胶囊,其中活性成分混以水或油性基质,例如花生油、液体石蜡或橄榄油。某些可注射组合物是水性等渗溶液或悬浮液,且栓剂有利地由脂肪乳剂或混悬剂制备。所述组合物可以是灭菌的和/或含有佐剂,如防腐剂、稳定剂、润湿剂或乳化剂、溶液促进剂、调节渗透压的盐和/或缓冲剂。另外,它们也可能含有其他有治疗价值的物质。所述组合物分别根据常规的混合、制粒或包衣方法制备,并且含有约0.1-75%或含有约1-50%的活性成分。
本发明的无水药物组合物和剂型可以使用无水或含水量低的成分和低水分或低湿度条件来制备。无水药物组合物可以制备和储存使其保持其无水性质。因此,使用已知防止暴露于水的材料来包装无水组合物,使得它们可以包含在合适的配方药盒中。合适的包装的实例包括但不限于气密密封箔、塑料、单位剂量容器(例如小瓶)、泡罩包装和条形包装。
本发明进一步提供了药物组合物和剂型,其包含降低作为活性成分的本发明化合物的分解速率的一种或多种试剂。在本文中称为“稳定剂”的这些试剂包括但不限于抗氧化剂如抗坏血酸、pH缓冲剂或盐缓冲剂等。
游离形式或盐形式的式(I)化合物显示出有价值的药理学性质。
作为另一实施方式,本发明提供了式(I)或如本文所述的式(I)范围内任何实施方式的化合物在治疗中的用途。
本发明的化合物可以与一种或多种联合试剂同时或之前或之后施用。本发明的化合物可以通过相同或不同的给药途径分开给药,或者作为联合试剂在同一药物组合物中一起给药。
在一个实施方式中,本发明提供了包含两种或更多种分开的药物组合物的药盒,其中至少一种药物组合物含有式(I)的化合物。另一种药物组合物可含有一种合适的联合试剂。在一个实施方式中,药盒包含用于分开保存所述组合物的装置,例如容器、分开的瓶子或分开的箔包装。这种药盒的一个例子是泡罩包装,如片剂、胶囊等通常所用的包装。
本发明的药盒可以用于施用不同的剂型,例如口服和肠胃外,用于以不同剂量间隔施用分开的组合物,或者用于滴定彼此分开的组合物。为帮助依从性,本发明的药盒通常包含给药指导。
本发明化合物和中间体也可以根据本领域技术人员通常已知的方法互相转化。
本发明化合物具有抗SARS-CoV-2新型冠状病毒作用。
下面结合实施例对本发明作进一步说明。
具体实施方式
实施例1:
化合物12的制备:
将化合物10(20.1g,100mmol)溶解在无水四氢呋喃(300mL)中,然后在-78℃下滴加2.0M的LDA四氢呋喃溶液(60毫升,120毫摩尔),并将混合物在此温度下搅拌1小时,滴加化合物11(26.8克,110毫摩尔)并继续在此温度下搅拌4小时。加入100毫升饱和氯化铵溶液,逐渐升温至室温。用乙酸乙酯萃取,将合并的萃取液用盐水洗涤并经无水硫酸镁干燥,蒸发溶剂,将其通过硅胶柱纯化,用正己烷-乙酸乙酯(10/1至4/1)溶剂系统洗脱,得到化合物12(12.98克,41%)。LC-MS(ESI)m/z([M+1]+)318.1。
化合物13的制备:
化合物12(15.8g,50mmol)和(S)-叔丁基亚磺酰胺(6.67g,55mmol)溶于二氯甲烷(150毫升)
加入无水硫酸铜(16克,100毫摩尔),在室温持续搅拌48小时,悬浮液通过硅藻土过滤并真空浓缩。通过硅胶柱层析纯化(2%EtOAc/己烷→25%EtOAc/己烷),得到化合物13(13.3g,77%)。
LC-MS(ESI)m/z([M+1]+)347.1。
化合物14的制备:
将Et2AlCN(1M的甲苯溶液,11.85mmol,11.85mL)加入THF(24mL),然后加入异丙醇(23.7mmol,1.61mL),搅拌15分钟后,在-78℃下,将Et2AlCN/i-PrOH溶液在25分钟内添加到亚磺酰胺化合物13(2.74g,7.9mmol)的四氢呋喃溶液(55mL)中,在-78℃下搅拌30分钟后,使反应混合物升温至室温。在室温搅拌1小时后,TLC显示原料已完全消耗。将反应混合物冷却至-78℃,并且加入10%碳酸氢钠(20mL)淬灭,并用乙酸乙酯萃取。合并的有机层经无水硫酸钠干燥,过滤并浓缩。柱层析纯化(10→30%EtOAc:正己烷)得到非对映异构体的96:4混合物,用二氯甲烷-正己烷重结晶得到对映体纯的产物14(1.79g,61%)。
LC-MS(ESI)m/z([M+1]+)374.1。
化合物15的制备:
零度下,向化合物14(4.66g,12.5mmol)加入12.5毫升4N的二氧六环HCl溶液,并在此温度下搅拌两小时,减压除去溶剂,并在真空下干燥,得到化合物15。
化合物17的制备:
将化合物15(2.05克,10毫摩尔),化合物16(2.55克,10毫摩尔)溶于80毫升二氯甲烷,依次加入HOBt(2.03克,15毫摩尔)、EDC.HCl(2.88克,15毫摩尔)。零度下,滴加二异丙基乙基胺(6.95毫升,40毫摩尔),逐渐升温至室温并搅拌过夜。减压除去溶剂,加入50毫升饱和氯化铵,用乙酸乙酯萃取三次,有机相用无水硫酸镁干燥,过滤,减压除去溶剂,残留物用硅胶柱层析纯化(正己烷/乙酸乙酯=10/1至1/1),得到化合物17(2.96克,73%)。
LC-MS(ESI)m/z([M+1]+)407.2。
化合物19a和19b的制备:
零度下,向化合物17(2.5克,6.15mmol)加入8毫升4N的HCl溶液,并在此温度下搅拌两小时,减压除去溶剂,并在真空下干燥。向得到化合物中加入40毫升二氯甲烷,依次加入化合物18(1.59克,7.0毫摩尔)、HOBt(1.24克,9.2毫摩尔)、EDC.HCl(1.77克,9.22毫摩尔)。零度下,滴加二异丙基乙基胺(4.28毫升,24.6毫摩尔),逐渐升温至室温并搅拌过夜。减压除去溶剂,加入50毫升饱和氯化铵,用乙酸乙酯萃取三次,有机相用无水硫酸镁干燥,过滤,减压除去溶剂,残留物用硅胶柱层析纯化(二氯甲烷/甲醇=40/1至20/1),得到化合物19a(1.14克,36%)和化合物19b(0.92克,29%)。两个化合物的质谱均为:LC-MS(ESI)m/z([M+1]+)516.2。
化合物26a和26b的制备:
以合成化合物19a和19b的类似方法制备化合物26a和26b,LC-MS(ESI)m/z([M+1]+)516.2。
化合物30a和30b的制备
以合成化合物19a和19b的类似方法制备化合物30a和30b,LC-MS(ESI)m/z([M+1]+)542.3。
实施例2:
化合物103的制备:
向四氢呋喃(100毫升)中加入富马酸二乙酯(3.27毫升,20毫摩尔),DBU(7.22毫升,50毫摩尔),和氨基乙硫醇盐酸盐(2.26克,20毫摩尔)。回流16小时后,将反应物倒入饱和的NaHCO3中,用乙酸乙酯提取。有机层用盐水洗涤,干燥(MgSO4),并在真空中除去溶剂。通过快速硅胶柱层析纯化,用正己烷-乙酸乙酯(10/1至4/1)溶剂系统洗脱,得到硫代吗啉酮103,产量2.51克,62%。
LC-MS(ESI)m/z([M+1]+)204.1。
化合物104的制备:
在0-5℃下,将1N的氢氧化锂溶液(30毫升,30毫摩尔)加入到化合物103(2.03克,10毫摩尔)的四氢呋喃(30毫升)溶液中。将反应混合物的温度升高至室温,并在相同温度下搅拌8小时。用2N盐酸调节PH=2-3,用乙酸乙酯萃取3次,无水硫酸钠干燥,过滤,减压除去溶剂,得到化合物104(1.58克,90%)。LC-MS(ESI)m/z([M+1]+)176.1。
化合物105的制备:
在25-30℃下,将甲苯(15毫升)加入到N,N-碳酰二咪唑(3.34克,20毫摩尔)中,并将反应混合物冷却到0-5℃。将化合物104(3.5克,20毫摩尔)的甲苯(10毫升)溶液加入到反应混合物中,并在相同温度下搅拌3小时。在0-5℃向反应混合物中加入N,O-二甲基羟胺盐酸盐(2.65克,27.1毫摩尔)和二异丙基乙基胺(3.56毫升,20毫摩尔),并在相同温度下搅拌3小时。反应完成后,向反应混合物中加入水,将有机层和水层分离,水层用甲苯萃取。合并有机层,先用5%盐酸洗,然后用10%碳酸氢钠溶液洗,得到的有机层含有化合物105,直接用于下一步反应。LC-MS(ESI)m/z([M+1]+)219.1。
化合物106的制备:
在-15℃至-10℃下,将70%的viridide溶液(8.3毫升)加入到含有化合物105的有机层中,并在同一温度下将反应混合物搅拌45分钟。反应混合物慢慢加到预冷的酒石酸钠钾水溶液中(在8.56克酒石酸钠钾,18毫升水)。将反应混合物的温度提高到20-25℃,并在同一温度下搅拌20分钟。有机层和水层分离,水层用甲苯萃取。合并后的有机层用10%的氯化钠溶液洗,得到的含有化合物106的有机层直接用于下一步反应。
化合物107的制备:
向含有化合物106的甲苯溶液加入(S)-叔丁基亚磺酰胺(3.63g,30mmol)、对甲苯磺酸吡啶盐(250毫克)和无水硫酸镁(4.0克),在室温持续搅拌48小时,悬浮液通过硅藻土过滤并真空浓缩。通过硅胶柱层析纯化(10%EtOAc/己烷→50%EtOAc/己烷),得到化合物107(1.24g,24%)。
LC-MS(ESI)m/z([M+1]+)263.1。
化合物108的制备:
将Et2AlCN(1M的甲苯溶液,11.85mmol,11.85mL)加入THF(24mL),然后加入异丙醇(23.7mmol,1.61mL),搅拌15分钟后,在-78℃下,将Et2AlCN/i-PrOH溶液在25分钟内添加到亚磺酰胺化合物107(2.1g,8.0mmol)的四氢呋喃溶液(50mL)中,在-78℃下搅拌30分钟后,使反应混合物升温至室温。在室温搅拌1小时后,TLC显示原料已完全消耗。将反应混合物冷却至-78℃,并且加入10%碳酸氢钠(20mL)淬灭,并用乙酸乙酯萃取。合并的有机层经无水硫酸钠干燥,过滤并浓缩。柱层析纯化(10→50%EtOAc:正己烷)得到非对映异构体的95:5混合物,用二氯甲烷-正己烷重结晶得到对映体纯的产物108(1.27g,55%)。
LC-MS(ESI)m/z([M+1]+)290.1。
化合物109的制备:
零度下,向化合物108(1.25g,4.4mmol)加入1毫升4N的二氧六环HCl溶液,并在此温度下搅拌两小时,减压除去溶剂,并在真空下干燥,得到化合物109。
化合物110的制备:
将化合物109(885毫克,4.0毫摩尔),化合物16(1.02克,4.0毫摩尔)溶于20毫升二氯甲烷,依次加入HOBt(675毫克,5毫摩尔)、EDC.HCl(0.96克,5毫摩尔)。零度下,滴加二异丙基乙基胺(2.8毫升,16毫摩尔),逐渐升温至室温并搅拌过夜。减压除去溶剂,加入30毫升饱和氯化铵,用乙酸乙酯萃取三次,有机相用无水硫酸镁干燥,过滤,减压除去溶剂,残留物用硅胶柱层析纯化(正己烷/乙酸乙酯=10/1至1/1),得到化合物110(1.18克,70%)。
LC-MS(ESI)m/z([M+1]+)423.2。
化合物22a和22b的制备:
零度下,向化合物110(0.422克,1.0mmol)加入1毫升4N的HCl溶液,并在此温度下搅拌两小时,减压除去溶剂,并在真空下干燥。向得到化合物中加入5毫升二氯甲烷,依次加入化合物18(0.23克,1.0毫摩尔)、HOBt(0.2克,1.5毫摩尔)、EDC.HCl(0.29克,1.5毫摩尔)。零度下,滴加二异丙基乙基胺(0.72毫升,4.0毫摩尔),逐渐升温至室温并搅拌过夜。减压除去溶剂,加入10毫升饱和氯化铵,用乙酸乙酯萃取三次,有机相用无水硫酸镁干燥,过滤,减压除去溶剂,残留物用硅胶柱层析纯化(二氯甲烷/甲醇=40/1至20/1),得到化合物22a(175毫克,33%)和化合物22b(133毫克,25%)。两个化合物的质谱均为:LC-MS(ESI)m/z([M+1]+)532.2。
化合物29的制备:
以合成化合物22的类似方法制备化合物29a、29b,LC-MS(ESI)m/z([M+1]+)均为532.2。
实施例3:
化合物124的制备:
将化合物123(1.97g,10mmol)溶解在无水四氢呋喃(30mL)中,然后在-78℃下滴加2.0M的LDA四氢呋喃溶液(6.0毫升,12.0毫摩尔),并将混合物在此温度下搅拌1小时,滴加化合物11(2.68克,11毫摩尔)并继续在此温度下搅拌4小时。加入10毫升饱和氯化铵溶液,逐渐升温至室温。用乙酸乙酯萃取,将合并的萃取液用盐水洗涤并经无水硫酸镁干燥,蒸发溶剂,将其通过硅胶柱纯化,用正己烷-乙酸乙酯(10/1至4/1)溶剂系统洗脱,得到化合物124(1.06克,33%)。LC-MS(ESI)m/z([M+1]+)314.1。
化合物125的制备:
向化合物124(1.03克,3.3毫摩尔)的二氯甲烷溶液(15毫升)加入(S)-叔丁基亚磺酰胺(0.61g,3.3mmol)、对甲苯磺酸吡啶盐(40毫克)和无水硫酸镁(1.0克),在室温持续搅拌48小时,悬浮液通过硅藻土过滤并真空浓缩。通过硅胶柱层析纯化(10%EtOAc/己烷→50%EtOAc/己烷),得到化合物125(0.79g,70%)。
LC-MS(ESI)m/z([M+1]+)343.1。
化合物126的制备:
将Et2AlCN(1M的甲苯溶液,11.85mmol,11.85mL)加入THF(24mL),然后加入异丙醇(23.7mmol,1.61mL),搅拌15分钟后,在-78℃下,将Et2AlCN/i-PrOH溶液在25分钟内添加到亚磺酰胺化合物125(2.74g,8.0mmol)的四氢呋喃溶液(50mL)中,在-78℃下搅拌30分钟后,使反应混合物升温至室温。在室温搅拌1小时后,TLC显示原料已完全消耗。将反应混合物冷却至-78℃,并且加入10%碳酸氢钠(20mL)淬灭,并用乙酸乙酯萃取。合并的有机层经无水硫酸钠干燥,过滤并浓缩。柱层析纯化(10→50%EtOAc:正己烷)得到非对映异构体的93:7混合物,用二氯甲烷-正己烷重结晶得到对映体纯的产物126(1.77g,60%)。
LC-MS(ESI)m/z([M+1]+)370.1。
化合物127的制备:
零度下,向化合物126(1.85g,5.0mmol)加入1毫升4N的二氧六环HCl溶液,并在此温度下搅拌两小时,减压除去溶剂,并在真空下干燥,得到化合物127。
化合物128的制备:
将化合物127(805毫克,4.0毫摩尔),化合物16(1.02克,4.0毫摩尔)溶于20毫升二氯甲烷,依次加入HOBt(675毫克,5毫摩尔)、EDC.HCl(0.96克,5毫摩尔)。零度下,滴加二异丙基乙基胺(2.8毫升,16毫摩尔),逐渐升温至室温并搅拌过夜。减压除去溶剂,加入30毫升饱和氯化铵,用乙酸乙酯萃取三次,有机相用无水硫酸镁干燥,过滤,减压除去溶剂,残留物用硅胶柱层析纯化(正己烷/乙酸乙酯=10/1至1/1),得到化合物128(1.06克,66%)。
LC-MS(ESI)m/z([M+1]+)403.2。
化合物33a和33b的制备:
零度下,向化合物128(0.40克,1.0mmol)加入1毫升4N的HCl溶液,并在此温度下搅拌两小时,减压除去溶剂,并在真空下干燥。向得到化合物中加入5毫升二氯甲烷,依次加入化合物18(0.23克,1.0毫摩尔)、HOBt(0.2克,1.5毫摩尔)、EDC.HCl(0.29克,1.5毫摩尔)。零度下,滴加二异丙基乙基胺(0.72毫升,4.0毫摩尔),逐渐升温至室温并搅拌过夜。减压除去溶剂,加入10毫升饱和氯化铵,用乙酸乙酯萃取三次,有机相用无水硫酸镁干燥,过滤,减压除去溶剂,残留物用硅胶柱层析纯化(二氯甲烷/甲醇=40/1至20/1),得到化合物33a(179毫克,35%)和化合物33b(103毫克,20%)。两个化合物的质谱均为:LC-MS(ESI)m/z([M+1]+)512.2。
化合物34a和34b的制备:
以合成化合物33a、33b的类似方法制备化合物34a、34b,LC-MS(ESI)m/z([M+1]+)均为512.2。
实施例4:
以4,5-dimethyl-3,6-dihydropyridin-2(1H)-one(CAS:30288-20-1)为原料,参照化合物33a,33b的·合成方法,制备化合物39a、39b、40a、40b:LC-MS(ESI)m/z([M+1]+)均为540.3。
实施例5:
化合物150的制备
将化合物10(20.1g,100mmol)溶解在无水四氢呋喃(300mL)中,然后在-78℃下滴加2.0M的LDA四氢呋喃溶液(120毫升,240毫摩尔),并将混合物在此温度下搅拌1小时,滴加化合物11(26.8克,110毫摩尔)并继续在此温度下搅拌2小时。滴加化合物NFSI(34.65克,110毫摩尔)并继续在此温度下搅拌3小时,加入100毫升饱和氯化铵溶液,逐渐升温至室温。用乙酸乙酯萃取,将合并的萃取液用盐水洗涤并经无水硫酸镁干燥,蒸发溶剂,将其通过硅胶柱纯化,用正己烷-乙酸乙酯(10/1至4/1)溶剂系统洗脱,得到化合物150(7.37克,22%)。LC-MS(ESI)m/z([M+1]+)336.2。
化合物20a和20b的制备:
以化合物150为原料,参照化合物化合物19a、19b的和合成方法制备化合物20a、20b、27a、27b。
四个化合物LC-MS(ESI)m/z([M+1]+)均为534.3。
实施例抗β-冠状病毒SARS-CoV-2COVID-19活性测定:
在12孔一次性细胞培养板中,制备融合的细胞培养物单层.将Vero E6细胞在维持在补充有10%FBS的DMEM中,并补充1%青霉素/链霉素。Vero E6细胞培养物的顶端表面在用1×PBS感染前24小时和1小时洗涤,然后在37℃用1×PBS感染1.5小时。使用表达绿色荧光蛋白(COVID-19RFP)的重组COVID-19、以0.1pfu/细胞的感染复数感染Vero E6细胞。为了Vero E6细胞,除去顶端清洗液,加入病毒接种物,并将接种的培养物在37℃,5%CO 2孵育3小时。除去接种物,Vero E6细胞的顶端表面用500μL 1×PBS洗涤3次以除去残余病毒。以10uM开始制备实施例化合物的3倍系列稀释液,一式三份,并在感染前大约30分钟将其加入培养物基底外侧的Vero E6细胞培养基中。在48小时温育后通过细胞培养物的荧光成像评估病毒复制。此外,通过在Vero细胞单层上通过空斑测定测量Vero E6顶端洗液中感染性病毒的产量以及通过实时PCR测定定量来自总细胞RNA的病毒RNA产量来定量病毒复制。
化合物抗SARS-CoV-2活性测试结果
由以上结果可知,所有化合物显示很高的抑制SARS-CoV-2的效果,因此,实施例化合物可以制备用作由SARS-CoV-2病毒感染所诱发的症状/疾病的治疗药物。
Claims (5)
1.一种蛋白酶抑制剂,其特征是:含有下式所示的化合物或其立体异构体、药学上可接受的盐、溶剂化物或结晶,
其中:
X为O、S、Se或NH,当X为CH时,可与相邻碳原子形成双键。
Z选自以下一组:氰基;醛;酮酰胺;亚硫酸氢盐;杂环基;-COCOOR2,其中R2是支链或无支链的烷基;-CH(OH)COOR2,其中R2是支链或无支链的烷基;以及
-CH(OH)(P=O)(OR6)2,其中R6是烷基、烯基、芳烷基、卤代烷基或取代的或未取代的芳烷基;
Ra是支链或无支链的烷基、环烷基、芳基、芳烷基、烯基、炔基、天然氨基酸侧链;
Rb是-C(O)R、-S(O)2R、-OCH2R、-OR或-(CH2)nR;R选自-CH3、-CF3、或是取代或未被取代的烷基、环烷基、杂环烷基、芳基、杂芳基、芳氧基、杂芳氧基、芳烷氧基、杂芳烷氧基;
Rc,Rd可选自氘、卤素、氰基、或是取代的或未被取代的烷基、环烷基、杂环烷基、芳基、芳烷基、烯基、炔基;n=0-6。
2.根据权利要求1所述的蛋白酶抑制剂,其特征是:Rc,Rd与母环形成并环、螺环。
4.一种含有如权利要求1所述的式(I)所示的化合物或其立体异构体、药学上可接受的盐、溶剂化物或结晶的药物组合物,其特征是:所述药物组合物为抗病毒药物组合物,其中还选择性地包含一种或多种治疗剂,所述治疗剂治选自如下:核苷类药物或其它抗新型冠状病毒药物。
5.一种权利要求4所述的药物组合物在制备具有新冠病毒抑制作用的制剂中的应用。
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