CN115385846A - 一种吲哚类化合物、其制备方法及应用 - Google Patents
一种吲哚类化合物、其制备方法及应用 Download PDFInfo
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- CN115385846A CN115385846A CN202110568804.1A CN202110568804A CN115385846A CN 115385846 A CN115385846 A CN 115385846A CN 202110568804 A CN202110568804 A CN 202110568804A CN 115385846 A CN115385846 A CN 115385846A
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- -1 Indole compound Chemical class 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title abstract description 6
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title abstract description 6
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 43
- 229910052736 halogen Inorganic materials 0.000 claims description 37
- 150000002367 halogens Chemical class 0.000 claims description 35
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
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- 206010022437 insomnia Diseases 0.000 claims description 10
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 10
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
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- 238000000034 method Methods 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- 239000011630 iodine Substances 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- VIROVYVQCGLCII-UHFFFAOYSA-N amobarbital Chemical compound CC(C)CCC1(CC)C(=O)NC(=O)NC1=O VIROVYVQCGLCII-UHFFFAOYSA-N 0.000 description 2
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- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- XNFNGGQRDXFYMM-PPHPATTJSA-N methyl (2s)-2-amino-3-(1h-indol-3-yl)propanoate;hydrochloride Chemical compound Cl.C1=CC=C2C(C[C@H](N)C(=O)OC)=CNC2=C1 XNFNGGQRDXFYMM-PPHPATTJSA-N 0.000 description 2
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
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- 229960004799 tryptophan Drugs 0.000 description 2
- GBBSUAFBMRNDJC-MRXNPFEDSA-N (5R)-zopiclone Chemical compound C1CN(C)CCN1C(=O)O[C@@H]1C2=NC=CN=C2C(=O)N1C1=CC=C(Cl)C=N1 GBBSUAFBMRNDJC-MRXNPFEDSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- 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 1
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- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 101150096839 Fcmr gene Proteins 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 208000007443 Neurasthenia Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
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- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
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- 229910052797 bismuth Inorganic materials 0.000 description 1
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- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
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- GBBSUAFBMRNDJC-INIZCTEOSA-N eszopiclone Chemical compound C1CN(C)CCN1C(=O)O[C@H]1C2=NC=CN=C2C(=O)N1C1=CC=C(Cl)C=N1 GBBSUAFBMRNDJC-INIZCTEOSA-N 0.000 description 1
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- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- ADIMAYPTOBDMTL-UHFFFAOYSA-N oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 description 1
- 229960004535 oxazepam Drugs 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 229960002695 phenobarbital Drugs 0.000 description 1
- 230000008288 physiological mechanism Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960002060 secobarbital Drugs 0.000 description 1
- KQPKPCNLIDLUMF-UHFFFAOYSA-N secobarbital Chemical compound CCCC(C)C1(CC=C)C(=O)NC(=O)NC1=O KQPKPCNLIDLUMF-UHFFFAOYSA-N 0.000 description 1
- 230000004799 sedative–hypnotic effect Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 230000004617 sleep duration Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- JOFWLTCLBGQGBO-UHFFFAOYSA-N triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-UHFFFAOYSA-N 0.000 description 1
- 229960003386 triazolam Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- HUNXMJYCHXQEGX-UHFFFAOYSA-N zaleplon Chemical compound CCN(C(C)=O)C1=CC=CC(C=2N3N=CC(=C3N=CC=2)C#N)=C1 HUNXMJYCHXQEGX-UHFFFAOYSA-N 0.000 description 1
- 229960004010 zaleplon Drugs 0.000 description 1
- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 description 1
- 229960001475 zolpidem Drugs 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Anesthesiology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种吲哚类化合物、其制备方法及应用。具体的,本发明提供了一种如式I所示的化合物、其药学上可接受的盐或其对映异构体,该化合物能有效缩短睡眠潜伏期、延长睡眠时间,具有较佳的促进睡眠作用。
Description
技术领域
本发明涉及一种吲哚类化合物、其制备方法及应用。
背景技术
据报道,全球有1/4的人受到失眠困扰,中国27%左右的成年人群存在睡眠障碍,并且由于工作和生活压力的增加,失眠发病率和由失眠诱发的多种精神性疾病均在逐年增加。失眠导致生活质量下降,工作效率低下,并伴发和诱发多种疾病,如神经衰弱、抑郁、焦虑、痴呆、高血压、心率失常、肥胖和代谢失调等。由于生活节奏加快,工作压力增加,失眠已成为危害健康和生活质量的全球性高发疾病。
目前临床用治疗失眠的药物主要有:第一代是巴比妥类,包括苯巴比妥、异戊巴比妥、司可巴比妥等,其作用机制是延长GABAA受体的Cl-通道开放时间以及增强GABA介导的Cl-内流;第二代是苯二氮卓类,主要包括地西泮、奥沙西泮、三唑仑等,其作用机制是增加GABAA受体的Cl-通道开放频率;第三代是非苯二氮卓类,有唑吡坦、佐匹克隆、扎来普隆和右佐匹克隆,其作用机制是增强GABA与GABAA受体的作用,增加Cl-通道开放频率或延长开放持续时间,引起神经细胞膜超极化,使其兴奋性下降。
由于失眠的原因多种多样,睡眠的生理机制尚未完全阐明,在全球镇静催眠药物研究领域,新药开发的速度较慢,现有的药物远不能满足失眠患者的需要。
发明内容
本发明所要解决的技术问题是现有的能有效缩短睡眠潜伏期、延长睡眠时间的药物较单一,为此,本发明提供了一种吲哚类化合物、其制备方法及应用。本发明如式I所示的化合物能有效缩短睡眠潜伏期、延长睡眠时间,具有较佳的促进睡眠作用。
本发明提供了一种如式I所示的化合物、其药学上可接受的盐或其对映异构体,
其中,
R1和R2独立地为H、C1~C6烷基、被1个或多个卤素取代的C1~C6烷基、C1~C6烷氧基、被1个或多个卤素取代的C1~C6烷氧基、卤素、-OH、-CN、-NH2或-NO2;
R3为H、-COOR3a或-CONR3bR3c;
R3a、R3b和R3c独立地为H、C1~C6烷基或被1个或多个C6~C10芳基取代的C1~C6烷基。
在某一方案中,如式I所示的化合物、其药学上可接受的盐或其对映异构体里,某些基团具有如下定义,未提及的基团的定义如本发明中任一方案所述(本段内容以下简称为“在某一方案中”),
R1为H、C1~C6烷基、C1~C6烷氧基或卤素。
在某一方案中,R2为H。
在某一方案中,R3a、R3b和R3c独立地为H或C1~C6烷基。
在某一方案中,当R1和R2独立地为C1~C6烷基时,所述C1~C6烷基可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,例如甲基。
在某一方案中,当R1和R2独立地为被1个或多个卤素取代的C1~C6烷基时,所述被1个或多个卤素取代的C1~C6烷基中的C1~C6烷基可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基。
在某一方案中,当R1和R2独立地为被1个或多个卤素取代的C1~C6烷基时,所述被1个或多个卤素取代的C1~C6烷基中的卤素可为氟、氯、溴或碘。
在某一方案中,当R1和R2独立地为C1~C6烷氧基时,所述C1~C6烷氧基可为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、异丁氧基或叔丁氧基,例如甲氧基。
在某一方案中,当R1和R2独立地为被1个或多个卤素取代的C1~C6烷氧基时,所述被1个或多个卤素取代的C1~C6烷氧基中的C1~C6烷氧基可为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、异丁氧基或叔丁氧基。
在某一方案中,当R1和R2独立地为被1个或多个卤素取代的C1~C6烷氧基时,所述被1个或多个卤素取代的C1~C6烷氧基中的卤素可为氟、氯、溴或碘。
在某一方案中,当R1和R2独立地为卤素时,所述卤素可为氟、氯、溴或碘,例如氟。
在某一方案中,当R3a为C1~C6烷基时,所述C1~C6烷基可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,例如甲基。
在某一方案中,当R3b和R3c独立地为C1~C6烷基时,所述C1~C6烷基可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,例如乙基或异丙基。
在某一方案中,当R3a、R3b和R3c独立地为被1个或多个C6~C10芳基取代的C1~C6烷基时,所述被1个或多个C6~C10芳基取代的C1~C6烷基中的C6~C10芳基可为苯基或萘基,例如苯基。
在某一方案中,当R3a、R3b和R3c独立地为被1个或多个C6~C10芳基取代的C1~C6烷基时,所述被1个或多个C6~C10芳基取代的C1~C6烷基中的C1~C6烷基可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基。
在某一方案中,当R3a、R3b和R3c独立地为被1个或多个C6~C10芳基取代的C1~C6烷基时,所述被1个或多个C6~C10芳基取代的C1~C6烷基可为苄基。
在某一方案中,所述-COOR3a可为-COOH或-COOCH3。
在某一方案中,R1为H、C1~C6烷基、C1~C6烷氧基或卤素;
R2为H;
R3为H、-COOR3a或-CONR3bR3c;
R3a、R3b和R3c独立地为H或C1~C6烷基。
在某一方案中,R3为H,R1为C1~C6烷基、C1~C6烷氧基或卤素;或者,R3为-COOR3a或-CONR3bR3c,R1为H。
在某一方案中,当R3为-COOR3a时,所述R3a为C1~C6烷基。
在某一方案中,所述如式I所示化合物为如下任一化合物:
本发明还提供了一种如式I所示的化合物的制备方法,其包括下述步骤:如式A所示的化合物和如式B所示的化合物反应,得到如式I所示的化合物,即可,
其中,R1、R2和R3的定义均同前任一项所述。
本发明还提供了一种药物组合物,其包括物质A和至少一种药用辅料,所述物质A为所述的如式I所示的化合物、其药学上可接受的盐或其对映异构体。
本发明中,上述如式I所示的化合物也可以与一种或多种其他活性成分组合使用;当组合使用时,活性成分可以是分开的组合物,用于在治疗中通过相同或不同的施用途径同时施用或者在不同时间分别施用,或者它们也可以在同一药物组合物中一起施用。
本发明还提供了所述如式I所示的化合物、其药学上可接受的盐或所述药物组合物在制备用于治疗失眠的药物中的应用。
术语“药学上可接受的盐”是指化合物与药学上可接受的(相对无毒、安全、适合于患者使用)酸或碱反应得到的盐。当化合物中含有相对酸性的官能团时,可以通过在合适的惰性溶剂中用足量的药学上可接受的碱与化合物的游离形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于钠盐、钾盐、钙盐、铝盐、镁盐、铋盐、铵盐等。当化合物中含有相对碱性的官能团时,可以通过在合适的惰性溶剂中用足量的药学上可接受的酸与化合物的游离形式接触的方式获得酸加成盐。药学上可接受的酸加成盐包括但不限于盐酸盐、硫酸盐、甲磺酸盐等。具体参见Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl,2002)。
术语“药用辅料”是指生产药品和调配处方时使用的赋形剂和附加剂,是除活性成分以外,包含在药物制剂中的所有物质。具体参见中华人民共和国药典(2020年版)或Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009)。
术语“多个”是指2个或3个。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:提供了一种吲哚类化合物、其制备方法及应用。具体的,本发明如式I所示的化合物能有效缩短睡眠潜伏期、延长睡眠时间,具有较佳的促进睡眠作用。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
实施例1
步骤一:将3-(2-氨乙基)吲哚(2a)(1.00g,6.24mmol,CAS:61-54-1)溶于10mL二氯乙烷中,依次加入EDCI(1.55g,8.11mmol,CAS:25952-53-8),DAMP(60.99mg,0.58mmol,CAS:1122-58-3),DIPEA(5.69mL,34.32mmol,CAS:7087-68-5),在冰浴条件下搅拌30分钟后加入N-Boc-γ-氨基丁酸(1.52g,7.49mmol,CAS:57294-38-9),过夜反应。反应结束后补加30mL的二氯甲烷,用饱和食盐水(30mL×3)进行萃取,收集有机相,用无水硫酸钠进行干燥。将有机相浓缩,浓缩后通过硅胶柱层析(乙酸乙酯:石油醚=2:1,V/V)洗脱,得到黄色油状物3a(1.23g,产率57%)。
3a:1H NMR(400MHz,CD3OD):δ7.56(t,J=6.4Hz,1H),7.33(t,J=6.9Hz,1H),7.08(s,1H),7.07(d,J=7.0Hz,1H),7.00(d,J=6.8Hz,1H),3.48(t,J=6.6Hz,2H),3.02(t,J=5.3Hz,2H),2.95(t,J=6.4Hz,2H),2.15(t,J=6.4Hz,2H),1.72(t,J=5.8Hz,2H),1.43(s,9H).ESI-MS:m/z 346[M+H]+。
下述化合物3b~3d参考3a的合成步骤制备得到。
3b:黄色油状物,产率55%。1H NMR(400MHz,CD3OD):δ7.18(d,J=8.8Hz,1H),7.03(s,1H),7.00(s,1H),6.72(d,J=8.7Hz,1H),3.78(s,3H),3.43(t,J=7.1Hz,2H),2.98(t,J=6.7Hz,2H),2.87(t,J=7.1Hz,2H),2.13(t,J=7.4Hz,2H),1.68(t,J=7.2Hz,2H),1.39(s,9H).ESI-MS:m/z 376[M+H]+。
3c:黄色油状物,产率50%。1H NMR(400MHz,CD3OD):δ7.26(m,1H),7.21(d,J=9.9Hz,1H),7.12(s,1H),6.83(t,J=8.9Hz,1H),3.44(t,J=6.7Hz,2H),3.00(t,J=6.4Hz,2H),2.88(t,J=6.7Hz,2H),2.15(t,J=6.9Hz,2H),1.70(t,J=7.2Hz,2H),1.41(s,9H).ESI-MS:m/z 364[M+H]+。
3d:黄色油状物,产率65%。1H NMR(400MHz,CD3OD):δ7.29(s,1H),7.16(d,J=8.2Hz,1H),6.96(s,1H),6.87(d,J=8.1Hz,1H),3.40(t,J=6.3Hz,2H),2.96(t,J=6.0Hz,2H),2.86(t,J=6.8Hz,2H),2.36(s,3H),2.11(t,J=7.1Hz,2H),1.66(t,J=8.0Hz,2H),1.38(s,9H).ESI-MS:m/z 360[M+H]+。
步骤二:将3a(1.23g,3.57mmol),用5mL二氯甲烷进行溶解。在冰浴条件下,加入2.5mL的三氟乙酸进行反应,反应3小时,反应结束。加热旋干溶剂,用正丁醇(10mL×3)和水(10mL)进行萃取,收集正丁醇相。减压浓缩通过ODS柱色谱(甲醇:水=3:2,V/V)纯化,得到黄色油状物产物4a(0.54g,产率61%)。
4a:1H NMR(400MHz,CD3OD):δ7.47(d,J=7.8Hz,1H),7.25(d,J=8.0Hz,1H),7.03–6.88(m,2H),6.92(t,J=7.2Hz,1H).3.41(t,J=7.0Hz,2H),2.86(t,J=7.1Hz,2H),2.80(t,J=7.1Hz,2H),2.21(t,J=6.9Hz,2H),1.79(t,J=7.2Hz,2H).ESI-MS:m/z 246[M+H]+。
下述化合物4b~4d参考4a的合成步骤制备得到。
4b:黄色油状物,产率66%。1H NMR(400MHz,CD3OD):δ7.18(d,J=6.8Hz,1H),7.01(s,2H),6.72(d,J=7.7Hz,1H),3.79(s,3H),3.44(m,2H),2.87(m,4H),2.27(m,2H),1.85(m,2H).ESI-MS:m/z 276[M+H]+。
4c:白色粉末,产率69%。1H NMR(400MHz,CD3OD):δ7.24(m,1H),7.18(d,J=9.9Hz,1H),7.10(s,1H),6.80(m,1H),3.42(t,J=6.0Hz,2H),2.86(m,4H),2.27(t,J=5.7Hz,2H),1.85(t,J=5.7Hz,2H).ESI-MS:m/z 264[M+H]+。
4d:黄色油状物,产率64%。1H NMR(400MHz,CD3OD):δ7.30(s,1H),7.17(d,J=7.8Hz,1H),6.97(s,1H),6.88(d,J=7.8Hz,1H),3.43(m,2H),2.86(m,4H),2.37(s,3H),2.26(s,2H),1.84(s,2H).ESI-MS:m/z 260[M+H]+。
步骤三:将4a(0.54g,2.20mmol),D-泛酸内酯(0.89g,11.34mmol,CAS:599-04-2)加入到双口瓶中,N2保护,用15mL乙醇溶解后,滴加1.85mL的三乙胺,75℃回流40小时。冷却至室温,浓缩用硅胶柱层析(二氯甲烷∶甲醇=30∶1,V/V)洗脱,得到粗产物后用ODS柱色谱(甲醇∶水=7∶3,V/V)纯化,得到黄色油状物1a(79mg,产率10%)。
1a:1H NMR(400MHz,CD3OD):δ7.53(d,J=7.3Hz,1H),7.30(d,J=7.5Hz,1H),7.13–6.91(m,3H),3.87(s,1H),3.40(m,4H),3.14(m,2H),2.92(m,2H),2.15(m,2H),1.73(m,2H),0.89(s,6H).13C NMR(100MHz,CD3OD):δ176.10,175.39,138.16,128.82,123.42,122.30,119.57,119.28,113.26,112.22,77.48,70.43,41.42,40.34,39.37,34.51,26.91,26.22,21.37,20.97.ESI-MS:m/z 376[M+H]+。
下述化合物1b~1d参考1a的合成步骤制备得到。
1b:黄色油状物,产率8%。1H NMR(400MHz,CD3OD):δ7.20(d,J=8.0Hz,1H),7.03(s,2H),6.73(d,J=8.0Hz,1H),3.88(s,1H),3.80(s,3H),3.45(m,3H),3.37(m,1H),3.16(m,2H),2.89(m,2H),2.17(m,2H),1.74(m,2H),0.91(s,6H).13C NMR(100MHz,CD3OD):δ176.08,175.37,154.93,133.39,129.11,124.23,113.04,112.88,112.55,101.41,77.48,70.43,56.38,41.31,40.32,39.36,34.53,26.91,26.24,21.36,20.96.ESI-MS m/z 406[M+H]+。
1c:黄色油状物,产率10%。1H NMR(400MHz,CD3OD):δ7.23(m,2H),7.10(s,1H),6.81(t,J=7.8Hz,1H),3.88(s,1H),3.44(m,3H),3.40(m,1H),3.16(m,2H),2.87(m,2H),2.16(m,2H),1.74(m,2H),0.90(s,6H).13C NMR(100MHz,CD3OD)δ176.07,175.40,159.97,157.66,134.65,129.14,129.05,125.50,113.52,113.47,112.99,112.89,110.46,110.20,103.99,103.76,77.47,70.43,41.24,40.32,39.35,34.48,26.88,26.12,21.36,20.95.ESI-MS:m/z 394[M+H]+。
1d:黄色油状物,产率15%。1H NMR(400MHz,CD3OD):δ7.32(s,1H),7.19(d,J=8.1Hz,1H),7.00(s,1H),6.90(d,J=7.8Hz,1H),3.88(s,1H),3.46(m,3H),3.36(m,1H),3.16(m,2H),2.89(t,J=6.6Hz,2H),2.39(s,3H),2.16(t,J=7.1Hz,2H),1.74(m,2H),0.91(s,6H).13C NMR(100MHz,CD3OD):δ176.09,175.38,136.52,129.05,128.61,123.93,123.54,118.93,112.76,111.94,77.48,70.43,41.45,40.33,39.37,34.52,26.91,26.23,21.68,21.36,20.96.ESI-MS:m/z 390[M+H]+。
实施例2
步骤一:将L-色氨酸甲酯盐酸盐(5)(1.50g,5.89mmol,CAS:7524-52-9),N-Boc-γ-氨基丁酸(1.00g,4.92mmol,CAS:57294-38-9),EDCI(1.41g,7.4mmol,CAS:25952-53-8),DAMP(71.84mg,0.58mmol,CAS:1122-58-3),DIPEA(5.3mL,35.34mmol,CAS:7087-68-5)溶于20mL四氢呋喃中,常温下搅拌10小时;反应结束后补加40mL二氯甲烷,用饱和食盐水(30mL×3)进行萃取,收集有机相,用无水硫酸钠干燥;浓缩有机相,浓缩后通过硅胶柱层析(乙酸乙酯:石油醚=2:1,V/V)洗脱,得到4-((叔丁氧基羰基)氨基)丁酰基-L-色氨酸甲酯(6)(1.87g,产率93%)。1H NMR(400MHz,CD3OD):δ7.46(d,J=7.3Hz,1H),7.26(d,J=8.1Hz,1H),7.02(m,2H),6.95(t,J=6.8Hz,1H),4.66(m,1H),3.60(s,3H),3.19(m,1H),3.08(m,1H),2.90(m,2H),2.11(m,2H),1.58(m,2H),1.36(s,9H).13C NMR(100MHz,CD3OD):δ175.49,174.10,158.52,138.03,128.72,124.36,122.45,119.82,119.13,112.32,110.80,79.95,54.88,52.65,40.61,33.95,28.76,28.48,27.15.ESI-MS:m/z 404[M+H]+。
步骤二:将4-((叔丁氧基羰基)氨基)丁酰基-L-色氨酸甲酯(6)(1.87g,4.6mmol),用10mL二氯甲烷进行溶解。在冰浴条件下,加入2mL的三氟乙酸进行反应,反应60分钟得到淡蓝色液体。反应结束后,旋干溶剂,用正丁醇(10mL×3)和水(20mL)进行萃取,收集正丁醇相。浓缩后通过ODS色谱柱(甲醇:水=3:2,V/V)纯化,得到4-氨基丁酰基-L-色氨酸甲酯(7)(1.10g,产率85%)。1H NMR(400MHz,CD3OD):δ7.52(d,J=7.2Hz,1H),7.34(d,J=7.0Hz,1H),7.14–6.97(m,3H),4.73(m,1H),3.66(s,3H),3.30(m,1H),3.14(m,1H),2.81(m,2H),2.29(m,2H),1.81(m,2H).13C NMR(100MHz,CD3OD):δ174.40,174.01,138.00,128.63,124.45,122.46,119.83,119.06,112.38,110.71,54.94,52.71,40.10,33.25,28.42,24.20.ESI-MS:m/z 304[M+H]+。
步骤三:将4-氨基丁酰基-L-色氨酸甲酯(7)(1.10g,3.63mmol),D-泛酸内酯(1.17g,11.34mmol,CAS:599-04-2)加入到双口瓶中,N2保护,用15mL乙醇溶解后,滴加3.50mL的三乙胺,75℃回流40小时。冷却至室温。浓缩用TSK gel Toyopearl HW-40F(30-60μm,Toso Co.Ltd.)柱层析(甲醇:水=7:3,V/V)洗脱。得到4-((R)-2,4-二羟基-3,3-二甲基丁酰胺基)丁酰基-L-色氨酸甲酯(1e)(538.65mg,产率45%)。1H NMR(400MHz,CD3OD):δ7.49(d,J=5.6Hz,1H),7.29(d,J=6.0Hz,1H),7.05(m,2H),6.99(t,J=4.6Hz,1H),4.71(m,1H),3.86(s,1H),3.62(s,3H),3.44(d,J=9.1Hz,1H),3.35(d,J=12.3Hz,1H),3.32(d,J=2.0Hz,1H),3.27(d,J=9.1Hz,1H),3.09(m,2H),2.16(m,2H),1.66(m,2H),0.89(s,6H).13CNMR(100MHz,CD3OD):δ176.06,175.33,174.08,138.00,128.69,124.40,122.45,119.82,119.12,112.32,110.78,77.45,70.43,54.98,52.67,40.31,39.18,34.02,28.45,26.69,21.36,20.98.ESI-MS:m/z 434[M+H]+。
步骤四:将4-((R)-2,4-二羟基-3,3-二甲基丁酰胺基)丁酰基-L-色氨酸甲酯(1e)(538.65mg,1.24mmol)加入到20mL的圆底烧瓶中,用甲醇溶解,滴加1mmol/mL NaOH水溶液1.98mL,室温下反应40小时。浓缩用TSK gel Toyopearl HW-40F(30-60μm,Toso Co.Ltd.)柱层析(纯水)洗脱,得到4-((R)-2,4-二羟基-3,3-二甲基丁酰胺基)丁酰基-L-色氨酸(1f)(490mg,95%)。1H NMR(400MHz,D2O)δ7.68(d,J=7.8Hz,1H),7.46(d,J=8.0Hz,1H),7.22(t,J=7.4Hz,1H),7.21(s,1H),7.14(t,J=7.4Hz,1H),4.59(dd,J=8.9,4.7Hz,1H),3.92(s,1H),3.49(d,J=11.2Hz,1H),3.39(dd,J=13.6,5.7Hz,1H),3.37(d,J=11.9Hz,1H),3.10(dd,J=14.7,8.9Hz,1H),2.88(dt,J=14.1,7.2Hz,1H),2.80(dt,J=14.1,7.2Hz,1H),2.11(brt,J=7.4Hz,2H),1.50(tq,J=13.7,6.8Hz,2H),0.89(s,3H),0.86(s,3H).13CNMR(100MHz,D2O):δ178.58,174.86(×2),136.05,127.18,124.06,121.72,119.11,118.59,111.71,110.39,75.79,68.40,55.56,38.55,37.87,33.12,27.49,24.73,20.51,19.13.ESI-MS:m/z 442[M+Na]+,420[M+H]+。
步骤五:
将4-((R)-2,4-二羟基-3,3-二甲基丁酰胺基)丁酰基-L-色氨酸(1f)(100mg,0.24mmol)溶于1mL无水N,N-二甲基甲酰胺(DMF)中,加入HATU(114mg,0.31mmol)和DIPEA(90μL,0.48mmol)。均匀搅拌后,加入二乙胺(40μL,0.36mmol,CAS:109-89-7),将反应混合物在室温下搅拌过夜。反应结束后加入二氯甲烷(20mL),将反应混合物用饱和碳酸氢钠溶液洗涤,用ODS柱色谱纯化(甲醇:水=7:3,V/V)得到黄色油状物1g(50mg,产率44%)。1HNMR(400MHz,CD3OD):δ7.57(d,J=6.9Hz,1H),7.29(d,J=7.7Hz,1H),7.02(m,3H),5.06(m,1H),3.87(s,1H),3.45(d,J=10.4Hz,1H),3.36(d,J=12.4Hz,1H),3.33–3.24(m,2H),3.16–3.10(m,2H),3.11–3.02(m,4H),2.21(d,J=5.6Hz,2H),1.70(d,J=6.1Hz,2H),0.90(s,9H),0.82(m,3H).13C NMR(100MHz,MeOD):δ176.08,174.79,173.28,137.99,128.79,124.67,122.49,119.92,119.19,112.34,110.73,77.47,70.43,51.34,43.16,41.80,40.34,39.27,34.07,29.79,26.73,21.37,21.00,14.08,12.96.ESI-MS:m/z 475[M+H]+。
化合物1h参考1g的合成步骤制备得到。
1h:黄色油状物,产率40%。1H NMR(400MHz,CD3OD):δ7.56(m,1H),7.34–7.21(m,1H),7.09–6.92(m,3H),4.54(m,1H),3.85(m,2H),3.44(m,1H),3.32(m,2H),3.07(m,2H),2.17(m,2H),1.66(m,2H),0.99(s,3H),0.88(s,6H),0.83(s,3H).13C NMR(100MHz,MeOD):δ176.04,175.09,172.98,138.00,128.86,124.55,122.39,119.77,119.43,112.24,110.98,77.47,70.43,55.88,42.52,40.33,39.13,34.10,29.25,26.73,22.41,22.24,21.39,20.99.ESI-MS:m/z 461[M+H]+。
实施例3延长戊巴比妥钠睡眠时间实验
1.实验方法
1.1实验动物:ICR小鼠,SPF级,90只,18±2g,全雄,随机分为9组,每组10只。
1.2实验条件
SPF级动物房,温度20~26℃,湿度40%~70%,明暗交替时间12h/12h。
1.3仪器及试剂
电子秤、灌胃针、生理盐水、戊巴比妥钠
1.4剂量分组及受试样品给予时间
实验动物分为9组,10只/组,分别为空白对照组,6个给药组1b,1c,1d,1e,1g,1h(25mg/kg),和2个阳性对照组(N-乙酰基-5甲氧基色胺和高泛酸)。各组实验动物连续4周分别给予灌胃样品及生理盐水。
2.实验步骤
2.1适应期
实验动物ICR小鼠于屏障系统下喂饲适应环境5~7天,适应期结束时,体重25±2g。
2.2受试样品给予
各剂量组实验动物每天灌胃给予同体积相应剂量浓度受试样品,空白对照组同时给予同体积生理盐水。
2.3检测指标
实验动物每周称重一次,比较各组体重是否具有显著性差异;给予样品1h后,实验动物腹腔注射戊巴比妥钠48mg/kg,注射量为0.1ml/10g体重,之后单只动物置于透明鼠笼中观察睡眠潜伏期和睡眠时长。以小鼠翻正反射消失60s以上作为入睡判断标准。动物注射戊巴比妥钠到翻正反射消失的时间作为睡眠潜伏期,动物翻正反射消失到恢复的时间为动物睡眠时间,比较各化合物能否缩短戊巴比妥钠注射小鼠的入睡潜伏期,延长睡眠时间。行为学实验于每天晚上10:00~12:00在安静、正常光照的实验室进行,温度24~26℃,湿度40%~70%。
3.数据处理和结果判定
4.实验结果
对延长戊巴比妥钠睡眠时间实验的影响
从统计结果可以看出,1b,1c,1d,1e,1g,1h灌胃给药后,睡眠潜伏期较空白对照组缩短,睡眠时长较空白对照组有显著性提高。且优于2种阳性对照药物。
表1:对戊巴比妥钠睡眠时间的影响
注:*p<0.05,**p<0.01,与空白对照组比。
Claims (10)
2.如权利要求1所述的如式I所示的化合物、其药学上可接受的盐或其对映异构体,其特征在于,所述的如式I所示的化合物、其药学上可接受的盐或其对映异构体满足下述条件中的一种或多种:
(1)R1为H、C1~C6烷基、C1~C6烷氧基或卤素;
(2)R2为H;
(3)R3a、R3b和R3c独立地为H或C1~C6烷基。
3.如权利要求1所述的如式I所示的化合物、其药学上可接受的盐或其对映异构体,其特征在于,所述的如式I所示的化合物、其药学上可接受的盐或其对映异构体满足下述条件中的一种或多种:
(1)当R1和R2独立地为C1~C6烷基时,所述C1~C6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;
(2)当R1和R2独立地为被1个或多个卤素取代的C1~C6烷基时,所述被1个或多个卤素取代的C1~C6烷基中的C1~C6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;
(3)当R1和R2独立地为被1个或多个卤素取代的C1~C6烷基时,所述被1个或多个卤素取代的C1~C6烷基中的卤素为氟、氯、溴或碘;
(4)当R1和R2独立地为C1~C6烷氧基时,所述C1~C6烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、异丁氧基或叔丁氧基;
(5)当R1和R2独立地为被1个或多个卤素取代的C1~C6烷氧基时,所述被1个或多个卤素取代的C1~C6烷氧基中的C1~C6烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、异丁氧基或叔丁氧基;
(6)当R1和R2独立地为被1个或多个卤素取代的C1~C6烷氧基时,所述被1个或多个卤素取代的C1~C6烷氧基中的卤素为氟、氯、溴或碘;
(7)当R1和R2独立地为卤素时,所述卤素为氟、氯、溴或碘;
(8)当R3a为C1~C6烷基时,所述C1~C6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;
(9)当R3b和R3c独立地为C1~C6烷基时,所述C1~C6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基;
(10)当R3a、R3b和R3c独立地为被1个或多个C6~C10芳基取代的C1~C6烷基时,所述被1个或多个C6~C10芳基取代的C1~C6烷基中的C6~C10芳基为苯基或萘基;
(11)当R3a、R3b和R3c独立地为被1个或多个C6~C10芳基取代的C1~C6烷基时,所述被1个或多个C6~C10芳基取代的C1~C6烷基中的C1~C6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基。
4.如权利要求1所述的如式I所示的化合物、其药学上可接受的盐或其对映异构体,其特征在于,所述的如式I所示的化合物、其药学上可接受的盐或其对映异构体满足下述条件中的一种或多种:
(1)当R1和R2独立地为C1~C6烷基时,所述C1~C6烷基为甲基;
(2)当R1和R2独立地为C1~C6烷氧基时,所述C1~C6烷氧基为甲氧基;
(3)当R1和R2独立地为卤素时,所述卤素为氟;
(4)当R3a为C1~C6烷基时,所述C1~C6烷基为甲基;
(5)当R3b和R3c独立地为C1~C6烷基时,所述C1~C6烷基为乙基或异丙基;
(6)当R3a、R3b和R3c独立地为被1个或多个C6~C10芳基取代的C1~C6烷基时,所述被1个或多个C6~C10芳基取代的C1~C6烷基中的C6~C10芳基为苯基;
(7)当R3a、R3b和R3c独立地为被1个或多个C6~C10芳基取代的C1~C6烷基时,所述被1个或多个C6~C10芳基取代的C1~C6烷基为苄基。
5.如权利要求1所述的如式I所示的化合物、其药学上可接受的盐或其对映异构体,其特征在于,所述的如式I所示的化合物、其药学上可接受的盐或其对映异构体满足下述条件中的一种或多种:
(1)R3为H,R1为C1~C6烷基、C1~C6烷氧基或卤素;或者,R3为-COOR3a或-CONR3bR3c,R1为H;
(2)当R3为-COOR3a时,所述R3a为C1~C6烷基。
9.一种药物组合物,其特征在于,其包括物质A和至少一种药用辅料,所述物质A为如权利要求1-7中任一项所述的如式I所示的化合物、其药学上可接受的盐或其对映异构体。
10.一种如权利要求1-7中任一项所述的如式I所示的化合物、其药学上可接受的盐或如权利要求9所述的药物组合物在制备用于治疗失眠的药物中的应用。
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