WO2023166349A2 - 苯基脲类衍生物及其医药用途 - Google Patents

苯基脲类衍生物及其医药用途 Download PDF

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WO2023166349A2
WO2023166349A2 PCT/IB2023/000143 IB2023000143W WO2023166349A2 WO 2023166349 A2 WO2023166349 A2 WO 2023166349A2 IB 2023000143 W IB2023000143 W IB 2023000143W WO 2023166349 A2 WO2023166349 A2 WO 2023166349A2
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group
oxy
phenyl
alkyl
ethyl
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WO2023166349A3 (zh
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冯恩光
秦晋晶
金利锋
金泽武
李园园
熊晓红
雷少伟
沈锡明
楼金芳
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杭州百诚医药科技股份有限公司
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
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Definitions

  • the present invention belongs to the field of medical technology, and relates to a phenylurea derivative and its medical application, specifically to free bases, isomers, and solvents of such compounds Compounds, pharmaceutically acceptable salts and other structural forms; methods for preparing such compounds; compositions containing such compounds and their use for treating furunculosis.
  • GPCRs G silkworm white-coupled receptors
  • Histamine H3 receptors are expressed to a greater extent in the central nervous system and to a lesser extent in the peripheral nervous system. Histamine H3 receptors (H3RJ) are widely expressed in the brain, mainly in areas closely related to memory cognition, such as the cerebral cortex, hippocampus, amygdala, and striatum. Blocking with selective antagonists/inverse agonists Blocking these receptors can increase the release of neurotransmitters such as acetylcholine, poly-E amine or 5-hydroxytryptamine, thereby regulating various neurological behaviors such as learning and memory, wakefulness and sleep (British Journal of Pharmacology, 2008, 154(6), 1166-1 i 81 ).
  • neurotransmitters such as acetylcholine, poly-E amine or 5-hydroxytryptamine
  • Literature shows that histamine H3 receptor ligands can be used to treat cognitive impairment (British Joisiiiial of Pisarmacology, 2008, 154(6), 1166-1181 ) >Dementia (Drag News Perspective. 2010, 23( 2), 99-103 ), attention deficit hyperactivity disorder, obesity (Indian Journal of Pharmacology, 2001, (33), 17-28), schizophrenia ( Biochemical Pharmacology, 2007, 73(8), 1215-1224 ) and Pain. Pain (Journal of Pharmacology and Experimental Therapeutics, 2011, 336(1), 30-37).
  • histamine H3 receptor ligand compounds are mainly divided into 4 ( 5) substituted miri rings There are two categories of mili rings and non-mide rings.
  • Compounds containing mili: rings have the disadvantages of low blood-brain barrier penetration, interaction with cytochrome 1P-450 protein, and liver and eye toxicity.
  • Representatives of non-mide* rings Compound patents: 1 US20020177589/M discloses a novel histamine H3 receptor ligand that can be used to regulate, and the compound in this invention patent can be used to treat Alzheimer's disease and cognitive impairment.
  • the representative compound of this compound is /1BT-239 , has serious cardiac side effects in clinical trials, so that the clinical trials are terminated.
  • WO2012114348Al ⁇ discloses a novel compound as a histamine H3 receptor ligand, which can be used to treat various diseases, such as cognitive impairment, dementia, etc.
  • the H3R antagonist/inverse agonist SamelisantCSUV-N-GSO si which is currently entering the clinic for the treatment of cognitive impairment, is currently under research, and the current phase II clinical indication is narcolepsy.
  • the research on cognitive impairment indications was carried out in the first phase of clinical trials in 2015-20, and there was no progress in the follow-up.
  • @WO2014030170Al discloses pyridazinone derivatives as histamine H3 inhibitors, their use as H3 inhibitors, their preparation methods and their pharmaceutical compositions.
  • the compound of the invention can be used to treat various diseases, such as cognitive impairment, sleep/wake disorder, eating disorder and the like.
  • the PK/PD data was unsatisfactory, so the clinical trial was terminated.
  • H3Rln antagonist/and agonist histamine H3 receptor ligand compounds
  • Ri, R? are each independently selected from hydrogen, Gw alkyl, -C (O) - alkyl or -SfXXh - alkyl; phase, Luo, Rs> Rs are each independently selected from hydrogen, halogen, CM alkyl, CM alkenyl, G" fast group, nitrogen group, hydroxyl" alkenyl group, acyl group Element.
  • R,, R 4 > R 5 , Rs are selected independently Amino group, cyano group, industry group, G ⁇ haloalkyl group, Cj-t, alkylhydroxyl group, G-5 alkylamino group, G-6 alkyl group, E amino group, Ci ⁇ , alkyl group group, Ci. 6 Not limited to benzo heterocycles; or, Rs, Rfi and the carbon atoms on the benzene rings connected to each form a substituted or unsubstituted benzo bicyclic structure; benzo bicyclic structures include but
  • BIOS-A-2 1-(4-((1-cyclobutylpiperin-4-yl)oxy)phenyl-1-3-cyclohexyl ammonium;
  • BIOS-A-3 1-(4-((bcyclobutylpiperidinyl)oxy)phenyl-3-(wumolinylethyl)serve;
  • BI0S-A-4 1-(4-((1cyclo]piperidin-4-yl)peridinyl)phenyl)-3-(2-(piperidinyl-1-yl)nonayl) leg;
  • BIOS-A-5 1-(4-((1-cyclobutyl-4-yl)oxy)phenyl)-3-(2-(pyrrolidin-1-yl)ethyl)adeno ;
  • BIOS-A-6 (R)-l-(4-((l-cyclobutylpiperene 4-yl)oxy)cuerityl)-3 ⁇ (2 ⁇ (2-methylpyrrolidine-1 base) ethyl) gland;
  • BI0S-A-7 1-(4-((1-ring]piperidin-4-yl)oxy)phenyl)-3 ⁇ (2-(4,4-difluoropiperid-1-yl ) ethyl) legs:
  • BIOSES b(4 ⁇ (l-cyclobutylpiperidinyl-oxy)phenyl”3-(thiomorpholylethyl)leg;
  • BIOS-A-9 1 ⁇ (4-((1 ⁇ Cycloj-piperon-4-yl)oxy)benzene)-3-(2-(4-hydroxypiperidyl)ethyl)® h
  • BIOS-A-10 1-(4-((1-Cyclobutylpiperazin-1-yl)oxy)phenyl)-3 ⁇ (2-(Emmethylpiperazin-1-yl)ethyl)adeno ;
  • BIDS-AH (4T (butanyl piperazine) oxy) phenyl) from (2. (isopropyl piperazine 7 work group) ethyl) service;
  • BIOS-A-I2 (J-ylpiperidyl-4-yl)oxy)phenyl)-3-(2-(3-hydroxypiperidyl-1-yl)ethyl)pyridine;
  • BIOS-A-13 1-(4-((1-cyclobutylpiperidinyl)oxy)distillyl)-3-(2-(N-methylpyridine*" I-yl)ethyl base) service:
  • BIOS-A-I4 1-(4-((1-cyclobutylpiperidoyl)oxy)phenyl) ⁇ 3 ⁇ (2 ⁇ (piperazin-1-yl)ethyl)adeno;
  • BIOS-A-15 Cyclobutylpiperazinyl)ethyl>3-(4-((1"cyclobutylpiperazinyl)oxy)phenyl)phenyl);
  • BIOS-A-16 1-(4-(((L-cyclo)piperidine-4"yl)oxy)phenyl)-3-isopropyl:
  • BIQS-A-I7 1-(4-((1-cycloJ-4-yl)oxy)phenyl)-3-(2-(dimethylamino)ethyl)adeno;
  • BIOS-A-18 1 ⁇ 4 ⁇ (1-cyclobutylpiperidyl)oxy)phenyl-3-(2-(diethylamino)ethyl)canthus
  • BIOS-A-19 1-(4-((1"cycloJ-ylpiperidine-4"yl)oxy:)phenyl-3-(2-(ethylamino:)ethyl)P
  • BIOS-A-20 1-(4-((1-Cyclobutylpiperene ⁇ 4 ⁇ yl)oxy)cuidyl)-3 ⁇ (2-mamaethyl)sulfur W;
  • BIOS-A-2I J-Peridin-4-yl)oxy)phenyl) ⁇ 3-(2-(piperidin-4-yl)ethyl)sulfur:;
  • BIOS-/V22 l-(4-((hcyclobutylpiperone 4-yl)oxy)phenylpyridyl)ethyl)thiadenine;
  • BIOS ⁇ A-23 (K) 4-(4-((1-Cyclo[ylpiperone-myl)oxy)phenyl)-3-(2-(2- ⁇ ylpyrrolidinyl-byl) ) ethyl) thiol.
  • heterocyclic group may be a saturated or unsaturated group.
  • heterocyclyl groups include, but are not limited to, pyrrolyl, pyridyl, pyrrolidinyl, pyridyl, pyridyl, tetracyclyl, pyrhenyl, pyridyl-isoclofenyl, pyridyl Base, , dense phagocytyl, azinyl.
  • the aforementioned substances are used for the prevention or treatment of cognitive impairment, dementia, attention deficit hyperactivity disorder, schizophrenia, epilepsy, sleep disorders, sleep apnea, obesity, eating disorders, pain and itching.
  • the aforementioned drugs are used to prevent or treat neuropathic pain, including but not limited to peripheral neuropathic pain or central neuropathic pain.
  • the peripheral neuropathic pain is trigeminal neuralgia, glossopharyngeal neuralgia, acute or chronic inflammatory demyelinating polyradiculopathy, alcoholic polyneuralgia, chemotherapy-induced polyneuropathy, complex Regional pain syndrome, entrapment neuralgia (such as carpal tunnel syndrome &), HIV S sensory neuralgia, iatrogenic neuralgia (such as postmastectomy pain), tumor compression or infiltrating neuralgia, nutritional deficiency-related Neuralgia, diabetic neuralgia, phantom limb pain, postherpetic neuralgia, postradiation plexus pain, radiculopathy (cervical, thoracic or lumbar ID, toxic exposure-related neuralgia or post-traumatic neuralgia.
  • Central neuropathic pain is post-stroke pain, multiple sclerosis-associated pain, Parkinson's disease-associated pain, post-traumatic spinal cord injury pain, syringomyelia, post-ischemic myelopathy, compressive myelopathy, HIV myelopathy or post-radiation myelopathy.
  • the beneficial effects of the present invention are as follows: Based on the histamine H3 receptor tincture, the present invention develops a series of novel structural phenyl derivatives, the series of compounds have The preparation route is simple, the raw materials are easy to obtain, and a series of related biological tests have been carried out on the compound.
  • test results all show that the compound has significant H3 receptor antagonistic activity and can be used as a lead molecule for the prevention or treatment of Diseases associated with H3 receptors.
  • DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The following are specific examples of the present invention to further describe the technical solutions of the present invention, but the scope of protection of the present invention is not limited to these examples. All changes or equivalent substitutions that do not depart from the concept of the present invention are included in the protection scope of the present invention.
  • Code Bn refers to the phenyl group
  • Code DMF refers to the reagent EN-dimethylformamide
  • Code TFA refers to the reagent trichloroacetic acid
  • Code TsCL refers to the reagent p-toluenesulfonyl chloride
  • code TEA refers to the reagent triethylamine
  • code DCM refers to the reagent dichloromethane
  • code Boc refers to the group tert-butoxy group: code Lawesscm reagent: 2,4-bis(p-methoxy phenyl)-1,3-dithio-diphosphetane-2,4 sulfide.
  • the liquid chromatography adopts Waters Sj-mmetw C18 chromatographic column. TLC using GF254 (02S mm). Nuclear Magnetic Resonance Chromatography (NMR) was determined using Braker-400 ® Magnetic Resonance Instrument; Liquid Mass Spectrometry (LCAIS) was used for Waters ZQ Mass Spectrometry Detector (column T: WatersSymmeUy C18, mm, 5 microns, 35 °C), using ESE (+) ion mode.
  • NMR Nuclear Magnetic Resonance Chromatography
  • LCAIS Liquid Mass Spectrometry
  • column T Waters ZQ Mass Spectrometry Detector
  • ESE (+) ion mode ESE (+) ion mode.
  • all operations involving easily oxidized or hydrolyzed raw materials were carried out under nitrogen protection. Unless otherwise stated, the raw materials used in the present invention are all commercially available raw materials.
  • the various reaction raw materials and common intermediates involved in the examples of the present invention can be purchased from the market or obtained by self-made, wherein the raw materials and common intermediates obtained by self-made are required, and the preparation process is described in detail as follows.
  • f Shared Zhonglu Huaixin preparation The synthetic route of intermediate A1 is as follows: Amide Add 4 chloronitrobenzene (compound 1, 3.0 g) and anhydrous N, into a solution of dimethylformamide (5 inL). After the addition is complete, transfer to room temperature and react at 6-station TLC to detect the raw material. The reaction was complete.
  • the reaction solution was quenched with water (320 mL) and mixed uniformly, extracted twice with ethyl acetate, the organic phase was combined, the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a brown Liquid crude product 9.56 go
  • the crude product was dissolved in hydrochloric acid ethyl acetate (30 inL ), and the raw material was completely reacted by reverse W 1-2 ho thin layer chromatography at room temperature.
  • the reaction solution was filtered, the filter cake was rinsed with a small amount of ethyl acetate, and the filter cake was pulled dry to obtain 5.55 g of white solid (namely compound 3), the absorption rate was S4.IC%o
  • reaction solution is concentrated under reduced pressure , the sodium carbonate solution was basified to pH 8-9, extracted three times with ethyl acetate, the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 77 g of a yellow solid (that is, compound 2. Chapter 99%.
  • reaction solution is filtered with diatomaceous earth, and the filter cake is washed with ethanol 4-5 times, the filtrate was concentrated to dryness, then alkalized to pH 9-10 with sodium carbonate solution, extracted three times with ethyl acetate, combined the organic phases, washed the organic phases with saturated brine, dried over anhydrous sodium sulfate, and condensed to obtain Yellow-brown liquid # 4.99 g (namely intermediate A1). Yield 82.68%.
  • Embodiment 5 Preparation of l-(4-((F-cyclobutylportyl)oxy)phenyl)3(2-(pyrrolidinyl)ethyl)leg (BIOS-A-5) The rest of the preparation steps are the same as in Example 3. Obtain 100 mg of off-white solid (i.e. compound BIOS-A-7), yield 80.66%,
  • reaction solution was concentrated to dryness, and the crude product was purified by plate preparation (Petroleum® L ethyl acetate triethylamine-1: 4: 1) to obtain 96 mg of an intermediate in the form of a white solid:
  • the intermediate was reacted in hydrochloric acid-ethyl acetate 3 mL After 2 h, it was filtered and concentrated to obtain 91 mg of the hydrochloride salt as a white solid (that is, the hydrochloride salt of compound BIOS-A-14), and the two-step yield was 6271%.
  • Example 15 4 () (4-cyclobutylpiperazine-1-yl) ethyl), the preparation of (HO-cyclobutylpiperazine-1-yl) oxygen-based quencher (BIOS ⁇ A-15) The remaining preparation steps are the same as in Example 3. Obtained 84 mg of white solid (compound BIOS-zV15), with a yield of 64.91%.
  • Example 25 Safety of Compounds sexual hHHG In cardiac cells, inhibition of the delayed rectifier potassium current (IKr) channel protein encoded by lumian E[her-a-go-go Related Gene (IsERG) is the most important mechanism for drug-induced QT interval prolongation. Due to its special molecular structure, 11ERG can be inhibited by a variety of compounds with different structures, leading to severe arrhythmia. According to statistics, 25-40% of the lead compounds showed varying degrees of WERG-related toxicity. Therefore, early evaluation of compounds' effects on hERG is critical during drug development. On the HEK293 cell line stably expressing 11ERG off-channel, the inhibition rate of compound M hERG channel was detected by manual patch clamp technique, and y.
  • IKr delayed rectifier potassium current
  • IsERG lumian E[her-a-go-go Related Gene
  • the CCI model rats with stable mechanical pain threshold were randomly divided into 3 groups, namely the model group (model), the pregabalin (Pre) group (30 mg/kg ), the BIOS-A-3 group (: 1 mg/kg), administered by intragastric administration at 1 mL/100 g, the sham operation group (sham) and the model group (model) were intragastrically administered the same volume of normal saline, before administration Detect the basic value, detect the mechanical pain threshold at 0.5 h, 1 h, 2 h, 4 h, and 6 h after a single administration, and use one-way analysis of variance and T-test to calculate the p value. The results are shown in Figure L.

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Abstract

本发明公开了一种苯基脲类衍生物，具体涉及该类化合物的游离碱、同分异构体、溶剂化物、及药学上可接受的盐型等结构形式；制备这类化合物的方法：包含该类化合物的组合物及其治疗用途。本发明基于组胺H3受体配体出发，开发了一系列的结构新颖的苯基脲类衍生物，并对该类化合物进行了一系列相关的生物学试验，试验结果均表明该类化含物具有显著的H3受体拮抗活性，可作为先导分子用于预防或治疗与H3受体相关的疾病。

Description

苯基，撅类衍生物及其医药用途 技术领域 本发明属于医药技术领域， 涉及一种苯基脉类衍生物及其医药用途， 具体涉及该类化合物的游离碱、 同分异构体、 溶剂化物、 及药学上可接受的盐型等结构形式； 制备这类化合物的方法； 包含该类化合物的 组合物及其治疔用途。 背景技术 人类基因组计划之后， 组胺受体家族已经扩展到四种不同的 G蚕白偶联受体 ( GPCR) : HK H2. H3 和 H4受体 (Nature Review Drag Discover, 2005, 4, 107-120) 。 组胺 H3受体较大程度上在中枢神经系统中 表达并且较小程度上在周围神经系统中表达。 组胺 H3受体 (H3RJ在脑中广泛表达， 主要表达于大脑皮质， 海马， 杏仁核， 纹状体等这些与记忆认 知能力密切相关的区域。用选择性拮抗剂/反向激动剂阻断这些受体， 可以增加神经递质如乙酰胆碱， 多 E 胺或 5 -羟色胺的释放, 从而调节学习记忆、 觉醒与睡眠等多种神经性行为 (British Journal of Pharmacology, 2008, 154(6), 1166-1 i 81 ) 。 文献表明组胺 H3受体配体可用于治疗认知障碍 (British Joisiiial of Pisarmacology, 2008, 154(6), 1166-1181 ) >痴呆 ( Drag News Perspective. 2010, 23(2), 99-103 )、注意缺陷多动障碍、肥胖症 (Indian Journal of Pharmacology, 2001, (33), 17-28) 、 精神分裂症 ( Biochemical Pharmacology, 2007, 73(8), 1215-1224 ) 和 疼。痛 (Journal of Pharmacology and Experimental Therapeutics, 2011, 336(1), 30-37) 。 目前组胺 H3受体配体类化合物， 主要分为 4 ( 5)位被取代的咪哩环类和非眯理环类两大类。含有咪哩: 环的化合物具有低血脑屏障渗透、与细胞色 1P-450蛋白相互作用以及肝脏和眼毒性的缺点。非咪*坐环类的 代表化合物专利： ① US20020177589/M公开了可用于调节新型组胺 H3受体配体，该发明专利中的化合物可 用于治疗阿尔茨海默症、 认钿障碍。 该化合物中代表化合物为 /1BT-239, 在临床实验中具有严重的心脏副 作用， 使得临床实验终止 ®WO2012114348Al ^开了作为组胺 H3受体配体的新型化合物， 该发明化合物 可用于治疗多种病症， 例如认知障碍、 痴呆等。 在进入临床的药物礼 治疗认知障碍的 H3R拮抗剂 /反向激 动剂 SamelisantCSUV-N-GSO si)目前处于在研状态， 目前临床二期适应症为发作性睡病。 认知障碍适应症研 究于 2015-20勇年开展临床试验一期， 后续无进展。 @WO2014030170Al公开了作为组胺 H3抑制剂的哒嗪 酮衍生物， 以及他们作为 H3抑制剂的用途， 它们的制备方法及其药物组合物。 该发明化合物可用于治疔多 种病症， 例如认知障碍、 睡眠 /觉醒障碍、 饮食障碍等。 但是在进行临床实验时， PK/PD数据不理想， 使得 临床实验终止。 综上所述， 目前虽然已公开了一些组胺 H3受体配体类化合物， 但是迄今为」匚 在该研发领域就一个获 批上 .市的药物一 Pitolisant ( H3Rln抗剂 /及向激动剂) ， 上市的适应症 :是嗜 ■睡症。 SUVN-G3O31等在研药物 处于临床 2期研究的仍是嗜睡? 认知障碍等神经系统疾病的临床研究已经宣告失败。 因此， 亟需寻找和发现结构新颖. 安全性高、 药效优于 Pitolisant. SUVN-G3031S药物的新化学实体， 用于预防或治疗与 H3靶点相关的疾病， 是本领域是技术人员尚未解决的技术难题。
Figure imgf000003_0001
Figure imgf000004_0001
Ri、 R?各自独立的选自氢、 Gw烷基、 - C(O)-烷基或 -SfXXh -烷基； 相、 珞、 Rs> Rs各自独立的选自氢、 卤素、 CM烷基、 CM烯基、 G”快基、 氮基、 羟基 "氤基、 酰
Figure imgf000004_0002
素. 氨基、 羟基、 氤基 "酰胺基、 酬基 . 亚飒基、 CM卤代烷基、 G一 6烷基羟基、 G一 $烷基氨基、 (：誓烷基 酰胺基、 Cm烷基 E风基、 Ci.,5；vE基业 基酰胺基、 G-6烷氧基碉基、 G侦烷
R,、 R4> R5, Rs各自独立的选
Figure imgf000004_0003
胺基、 砚基、 业碉基、 G〈卤代烷基、 Cj-t,烷基羟基、 G-5烷基氨基、 G-6烷基® E胺基、 Ci<,烷基砚基、 Ci .6
Figure imgf000004_0004
Figure imgf000005_0002
Figure imgf000005_0003
不限于苯并杂环； 或， Rs、 Rfi与各自连接的苯环上碳原子共同形成取代或未取代的苯并双环结构； 苯并双环结构包括但
Figure imgf000005_0001
3
Figure imgf000006_0001
BI0S-A-2: 1 -（4-（（1-环丁基哌呢 -4 -基）氧基）苯基卜 3 -环已基腿；
BIOS-A-3: l-（4-（（b环丁基哌噬 4基）氧基）苯基卜 3 -（务吗琳基乙基）服；
BI0S-A-4: 1 -（4-（（1 ■■环］基哌陡 -4-基）滓 £基）苯基）-3-（2-（哌昵 -1-基）九基）腿；
BI0S-A-5: 1 -（4-（（1-环丁基嗽嚏 -4-基）氧基）苯基）-3 -（2-（毗咯烷 -1-基）乙基）腺;
BIOS-A-6:（R）-l-（4-（（l-环丁基哌呢 4基）氧基）翠基）-3~（2~（2 -甲基毗咯烷 -1 ■基）乙基）腺;
BI0S-A-7: 1 -（4-（（1-环］基哌呢 ~4~基）氧基）苯基）-3~（2~（4,4 -二氟哌唯 -1-基）乙基）腿:
BIOSES: b（4＜（l -环丁基哌陡 4基 j氧基）苯基 ”3-（硫代吗嗽基乙基）腿；
BIOS-A-9: 1~（4-（（1~环 J基哌陇 -4 -基）氧基）苯 M）-3-（2-（4 -羟基哌陡基 基）乙基）® h
BIOS -A- 10: 1 -（4-（（1-环丁基哌嚏 4基）氧基）苯基）-3・（2-（牝甲基哌嗪 -1-基）乙基）腺;
BIDS-AH （4T（卜环丁基哌皂牝基）氧基）苯基）自（2・（咨异丙基哌嗪 7工基｝乙基）服；
BIOS-A-I2: J基哌嚏 -4 -基）氧基）苯基）-3-（2-（3 -羟基哌嚏 -1-基）乙基）眠；
BIOS-A-13: 1 -（4-（（1-环丁基哌噬4基）氧基）蒸基）-3-（2-（N-甲呈景唳嗪*" I -基）乙基）服 :
BIOS-A-I4: 1-（4-（（1-环丁基哌呢斗基）氧基）苯基）~3~（2~（哌嗪 -1 -基）乙基）腺；
BIOS-A-15: 环丁基哌嗪土基）乙基＞3-（4-（（1"环丁基哌陡 4基）氧基）苯基）腿；
BIOS-A-16: 1 -（4-（（ L环］基哌噬 -4“基）氧基）苯基）-3 -异丙基服 :
BIQS-A-I7: 1-（4-（（1-环 J基厩呢 ~4~基）氧基）苯基）-3~（2~（二甲氮基）乙基）腺；
BIOS-A-18: 1＜4＜（1 -环丁基哌嚏*基）氧基）苯基卜 3-（2-（二乙氨基）乙基）眦
BIOS-A-19: 1 -（4-（（1"环 J基哌噬 -4“基）氧基：）苯基沪3-（2-（乙氨基：）乙基）邮
BIOS-A-20: 1-（4-（（ 1-环丁基哌呢 ~4~基）氧基）翠基）-3~（2 -吗嘛乙基）硫W；
BIOS-A-2I: J基哌日定 -4 -基）氧基）苯基）~3-（2-（哌呢 ~卜基）乙基）硫服:；
BIOS-/V22: l-（4-（（h环丁基哌陇 4基）氧基）苯基 毗略烷土基）乙基）硫腺；
BIOS^A-23:（K）4-（4-（（l-环「基哌陇-牝基）氧基）苯基）-3-（2-（2-^基毗咯烷-卜基）乙基）硫腿。 前述编号为 BIOS-A-1至 BI0S~A~23的化合物或其药学上可接受的盐， 具体结构式如下：
Figure imgf000006_0002
Figure imgf000007_0001
了一种苯基服类衍生物， 包括如下结构所示的手性化合物或其药学上可接受
Figure imgf000007_0002
-基）氧基）苯基）-3-（2-（2 -甲基毗咯烷」 -基）乙基博；
（Z?）-l-（4-（（l-环丁基哌陇 -4 -基）氧基）苯基）-3-（2-（2 -甲基毗咯烷 -1 -基）乙基）硫服。
Figure imgf000007_0003
电子体系。 杂环基可以是饱和的、 或非饱和的基团。 杂环基的实例包括但不限于毗咯基、 呼噪基、 毗咯烷 基. 咪 H坐基、 毗哩基、 四哇基、 毗噬基. 哇哧基 - 异哇嗽基、 哌嚏基、 ，密噬基、 喊嗪基. 哌嗪基、 味喃基、
Figure imgf000008_0001
的用途。 优选的， 前述的约物用于预防或治疗认知障碍、 痴杲、 注意缺陷多动障碍 '• 精神分裂症、癫痫、 睡眠 障碍、 睡眠呼吸暂停、 肥胖、 进食障碍、 疼痛和瘙痒。 优选的 . 前述的药物用于预防或治疗神经病理性疼痛， 包括但不限于周围性神经病理性疼痛或中枢性 神经病理性疼痛。 更优选的， 周围性神经病理性疼痛为三叉神经痛、舌咽神经痛、 急性或慢性炎性脱髓鞘性多发性神经 根禅经痛、 酒精性多发神经痛、 化疗引起的多发性神经痛、 复杂性区域痛综合征， 嵌压性神经痛 （如腕管 综合 &） , HIV S觉神经痛、 医源性神经痛（如乳腺切除木后疼痛） 、 肿瘤压迫或浸润神经痛、 营养缺陷 相关性神经痛、糖尿病性神经痛、幻肢痛、疱疹后神经痛、放疗后神经丛痛病、神经根病（颈、胸或腰 ID， 毒物接触相关性神经痛或创伤后神经痛。 更优选的， 中枢性神经病理性疼痛为卒中后疼痛、 多发性硬化相关性疼痛、 帕金森病相关性疼痛 "创 伤后脊髓损伤性疼痛、 脊髓空洞症、 缺血后脊髓病、 压迫性脊髓病、 HIV脊髓病或放射后脊髓病。 与现有技术相比， 本发明有益效果如下： 本发明基于组胺 H3受体酊体出发， 开发了一系列的结构新颖的苯基服类衍生物， 该系列化合物具有 制备路线简单， 原料易得的特点， 并对化合物进行了一系列相关的生物学试验， 试验结果均表明该类化台 物具有显著的 H3受体拮抗活性， 可作为先导分子用于预防或治疗与 H3受体相关的疾病。
Figure imgf000009_0001
具体实施方式 以下是本发明的具体实施例， 对本发明的技术方案做进一步的描述， 但是本发明的保护范围并不限于 这些实施例。 凡是不背离本发明构思的改变或等同替代均包括在本发明的保护范围之内。 本发明实施例中涉及的溶剂、 设备， 代号及全称具体如下： 代号 Bn： 指基团苯基； 代号 DMF： 指试剂 EN-二甲基甲酰胺； 代号 TFA： 指试剂三氯乙酸； 代号 TsCL 指试剂对甲苯磺酰氯； 代号 TEA： 指试剂三乙胺： 代号 DCM： 指试剂二氯甲烷； 代号 Boc： 指基团叔丁氧撮基： 代号 Lawesscm reagent: 2,4 -双（对甲氧苯基）-1, 3 -二硫一二磷杂环丁烷 -2, 4硫化物。 本发明提供的目标化合物制备方法中， 液相色谱采用 WatersSj-mmetw C18 色谱柱。 薄层色谱采用 GF254 （02S毫米） 。 核磁共振色谱（NMR）使用 Braker-400 ®磁共振仪测定； 液质连用 （LCAIS）使用 Waters ZQ质谱检测器 （柱 T： WatersSymmeUy C18, 毫米， 5微米， 35 °C） , 采用 ESE （ +） 离子模式。 此外， 凡涉及易氧化或易水解的原料的所有操作都在氮气保护下进行。 除非另有说明， 本发明使用的 原料都是市售原料. 无需进一步纯化可以直接使用。 本发明实施例中涉及的各反应原料、共用中间体等均可通过市售购得或自制获得， 其中需要自制获得 的原料和共用中间体， 制备过程详述如下。 f 共用中闾怀心拘制备: 中间体 A1的合成路线如下: 酰胺
Figure imgf000010_0002
加 4 ■■氯硝基苯 (化合物 1 , 3.0 g) 和无水 N,入匚二甲基甲酰胺 ( 5 inL) 的溶液， 滴加完毕之后转移至室温 反应 6站 薄层色谱检测原料基本反应完全 . 反应液加水 (320 mL) 淬灭并混匀， 乙酸乙酯萃取二次， 有 机相含并， 有机相用食盐水洗涤， 无水硫酸钠干燥， 过滤， 滤液减压浓缩， 得到褐色液体粗品 9.56 go 粗品溶于盐酸 ■■乙酸乙酯 (30 inL ) , 室温下反 W 1-2 ho 薄层色谱检测原料反应完全。 反应液过滤， 滤饼用少量乙酸乙酯冲洗， 滤饼拉干， 得到白色固 ft 5.55 g (即化合物 3 ) ， 吸率 S4.IC%o
MS： 223.1JM+H]% 步骤 2： 1 -环丁基 -财。-硝基苯氧基)哌 R定 (5) 的合成 化合物 3 C5.55 g, 21.45 iiimol)混含于无水甲醇 40 mL中， 加入三乙胺 3 nsL后溶清， 接着加入环丁 酮 (化合物第 2 wL) 和乙酸 (2 mL) , 漆水浴低温搅拌 m 加入割基硼氢化钠 2.槌， 最后移至室温反 应过夜 12 h. 薄层色谱检测原料反应完全 ° 反应液减压浓缩， 碳酸钠溶液碱化至 pH 8-9, 乙酸乙酯萃取三次， 合并有机相， 有机相经饱和食盐 水洗涤， 无水硫酸钠十燥. 浓缩， 得黄色固体 $77 g (即化合物 2 。 收章 99%。
MS： 277 1 [M+H]^o 步骤勿 4-(0环丁基晦睫 4 -基)氧基痒胺 (A1) 的合成： 化合物 S (6.77集 24.50 nmiol)混台于乙醇溶液 180 niL中， 冉加入还原铁粉少6 g"氯化 ® 2.36 g # 水 60 mL, 油浴 80 °C反应 2〜 3乩 薄层色谱检测原料反应完全。 反应液用硅藻土过滤， 乙醇洗涤滤饼 4-5次， 滤液浓缩干， 再加碳酸钠溶液碱化至 pH 9-10, 乙酸乙 酯萃取三次， 合并有机相， 有机相经饱和食盐水洗涤， 无水硫酸钠干燥， 陵缩， 得黄褐色液 # 4.99 g (即 中间体 A1 ) 。 收率 82.68%。
MS： 247.1[M-4-I]\)
Figure imgf000010_0001
中间体 A1 (300 nig, 1.242 mmol) 和 t1® ( i50 niL, 1 491 mmol) 溶于无水二氯甲烷 8 niL, 转移至 冰水浴低温搅拌 10血 m滴加氯甲酸苯酯 187皿， 昴后移至室温反应 27 ho薄层色谱检测原料反应完全。 反应液浓缩干 . 碳酸钠溶液碱化至 pH 8-9, 乙酸乙酯萃取二次， 合并有机相. 有机相经饱和食盐水洗 涤, 无水硫酸钠干燥, 浓缩干, 得褐色粗品 480 mg (即中间体 A力 ° 收率 100%o
MS： 367.2[MH{]\ 三、 共用中闾体心的制备： 中间体 A3的含成路线如下:
Figure imgf000011_0001
中间体 A1 （2.01 g, 8.16 nsmol） 溶于无水二氯甲烷 20 inL, 转移至冰水浴低温搅拌 W成珏 滴加氯 乙基异 '氟酸酯 835 pL, 最后移至室温反应 3-4眼 薄层色谱检测原料反应完全。 反应液过滤，少量二氯甲烷冲洗滤饼，滤饼拉亍，得到白色粉末 1.96 g（即中闾体心） o收率 6&26%。
MS： 3523[M+H仁 以下实施例卜 23为本发明所述的 BK）S~A系列化合物的游离基和 /或其盐酸盐结构的制备例， 需要说 明的是， 除实施例已提及的盐酸盐形式外， BIOS-A系列化合物还可以制备成其它药学上可接受的盐形式,
Figure imgf000011_0002
中间体 A1 ( 100 mg. 0.406 mmol) ＞ 环戊基异氤酸酯 (46心 0.406 mmol) 溶于 4 mL二氯甲烷中, 室温下反应 4-5 ho 薄层色谱检测原料反应完全。 将反应液过滤，用少量二氯甲烷冲洗滤饼，得到白色固体 90 mg (即化台物 BI0S-A-1 ) .收率 62.00%。
MS： 358 1 [M+H]\ lH NMR (400 MHz, DMSO-^) 5 8.07 (s, 1H), 7.24 (d, J = 8.6 Hz, 2H). 6.80 (d, 8.6 Hz. 2H)„ 6.06 (d. J
= 7.2 Hz,
Figure imgf000011_0004
1H), 3.98-3.85
Figure imgf000011_0003
-1.46 (HL 20H), 1.39-1.28 (IXL
2H).
Figure imgf000011_0005
中间体 A2 （260 mg, 0.709 mmol） 、 环己胺 （97成， 0.851 mraol） 与三乙胺 197皿溶于 4 mL乙膳 溶液中， 室温下反应过夜。 薄层色谱检测反应， 原料反应完全。 将反应液浓缩干，粗品用制备板纯化（石油醴： 乙酸乙酯： 三乙胺 =1: I: 0 1），得黄色固体 116 mg（即 化合物 BIOS-A-2） ， 收率 44,04%。 MS： 372.5[MH{]\
]H NMR (400 MHz, DMSO^6) 6 8.61 (& 1H), 7.29 (d, J = 8.6 Hz, 2H), 6.89 (d, J - 8.6 Hz, 2H), 6.29 (s, IH). 4.6B-432 (街， 1H), 3.43 (s, 1H), 2.89^2.54 (m, 4H)5 2.40 (s, 2H), 2J4 (s, 4H), 2.05^1.83 (nx 3H), 1 ,82-1.47 (BL 8H), L37-L23 (BI 4H).
Figure imgf000012_0001
中间体 A3 ( 100 mg, 0.284 nmol) . 吗嗽 ( 100 |1L, 0.853 mmol) 与三乙胺 197 pL裕于 4 mL乙腊溶 液中， 转移至油浴 80。反应 2〜3旗 薄层色谱检测反应 , 原料反应完全。 将反应液浓缩干, 粗品制备板纯化 (石油醒: 乙酸乙酯： 三乙胺 =1 : 4: 1 ) , 得白色固 # 48 mg (即化 合物 BIOS-A-3) , 收率 41.99%.
MS： 4O3. I|M+Hfh：)
]H NMR (400 MHz, DMSO-dQ 5 = 843 (s, 1H), 7,25 (d. J = 9.0 Hz? 2H), 6.81 (d, J = 9.0 Hz, 2H), 5.99 (L -7 = 5.4 Hz, 1H), 4.26- 4.16 (in 1H), 3.59 (t J = 4.6 Hz, 4H)? 3.18 (q. J - 6.2 Hz, 2H). 2.74^2,61 (in 1H), 2,60-2.52 (m, 2H), 237 (I 5.6 Hz, 6H), 2.07-1.83 (m, 6H), 1.83-1.69 (HI, 2H), 1.64-1.50 (风 4H).
Figure imgf000012_0002
]H NMR (400 Tvffiz, DMSO诚) 8 8.57 (s. 1H). 7.26 (d„ J - 8 8 Hz, 2H). 6.81 (d( J - 8 8 Hz, 2H), 6 13 (s, 1H). 4.28-4.16 (m, IH), 3.23^3.13 (m 2H)t 2.82-2.69 (m, 1H), 2.60 (d, J = 5.4 Hz, 2H), 2A7-236 (m, 6H), 2,09-2.06 (in. 2H), 2.02-1.85 (in, 4H), 1.85-4.73 (m, 2H), 1.65-4.50 (m, 8H), 1.45-1.34 (m, 2H). 实施例 5： l-（4-（（F环丁基豚 4基）氧基）苯基）3（2-（毗咯烷土基）乙基）腿（BIOS-A-5） 的制备
Figure imgf000013_0001
其余制备步骤同实施例 3。 得到类白色固体 100 mg (即化合物 BIOS-A-7) , 收率 80.66%,
MS： 437.2[M+H]\
'H NMR (400 MHz, DMSO-rf6) S 8.52 (s, 1H), 7.28 (d, J = 9.0 Hz, 2H), 6.85 (d, .7 = 8.6 Hz, 2H), 6.07 (s, 1H), 4.37 (s, 1H), 3.19 (q, J = 6.2 Hz. 2H). 3.10-3.00 (ni 1H). 2.85 (s, 2H), 2.60-2.50 (m. 7H). 2.48-2.42 (m. 2H). 2.20-1.87 (m, 10H), 1.74-1.55 (m, 3H).
Figure imgf000014_0001
Figure imgf000015_0001
制备步骤同实施例 3。 得到白色固体 92 mg (gp化合物 BIOS-A-12) , 收率 77.7?%。
MS： 4172[M+H]+ O
'H NMR (600 MHz, DMSCMi) 88.40 (s, 1H), 7.24 (d, J= 9.0 Hz, 2H).6.80 (d,J=9.0 Hz, 2H), 5.92 (t.J = 5.4 Hz, 1H). 4.58 (d, J - 5.0 Hz. 1H), 4.24-416 (m, 1H). 3.51-3.44 (m, 1H), 3.15 (q, J - 6.1 Hz, 2H), 2.82 (d, J = 10.8 Hz. 1H). 2.73〜 2.62 (以 2H), 2.57 (s, 2H), 2.41-2.30 (四 2H). 2,07-1.92 (叽 4H). 1.91-1.82 (珥 3H),
Figure imgf000016_0001
中间体 A3 ( 100 mg, 0.284 mmol) 、 1-Boc-哌嗪 ( 158 nig, 0.853 mmol) 与三乙胺 197 pL溶于 4 niL 乙腊溶液中， 转移至油浴 80笆反应 4 薄层色谱检测反应， 原料反应完全。 将反应液浓缩干， 粗品制备板纯化 (石油® L 乙酸乙酩 三乙胺 -1: 4: 1 ) ， 得到白色固体性状的中间 体 96 mg： 中间体在盐酸-乙酸乙酯 3 mL中反应 2 h后， 过滤， 浓缩亍， 得到盐酸盐白色固体 91 mg (即 化合物 BIOS-A-14的盐酸盐) ， 两步收率 6271%。
MS: 402.2[M+H]\
]H NMR (400 WIz; DMSO-^) 8 9 87 (& 1H)( 8.99 (d. J - 10.2 Hz( 1H), 7.32 (d, J二 9 0 Hz( 2H), 6 90 (d, J
= 9.0 Hz, 2H)t 6.68 (s. 1H), 3.63^3.55 (m, 2H), 3.54-3.45 (la 4H). 3.24 (l, J - 6.2 Hz, 2H), 3.19-3.13 (m SH), 2,96-2.76 (IU 2H), 2.41 (L 10.2 Hz, 2H). 2.16^2,12 (m, 4H), 2.04^1.85 (m 2H), 1.80^1.61 (iu 2H). 实施例 15： 4()(4-环丁基哌嗪-卜基)乙基)， (HO环丁基赈嚏 Y -基)氧基猝基燃 (BIOS^A-15)的制 备
Figure imgf000017_0001
余制备步骤同实施例 3。 得到白色固体 84 mg (即化合物 BIOS-zV15) , 收率 64.91%。
MS: 456.3[M+H]+„
'H NMR (400 MHz, DMSOO 5 8.45 (s, 1H), 7.26 (d, J = 8.6 Hz, 2H), 6.83 (d, J= 8.6 Hz, 2H), 5.95 (s, III), 4.27 (s, 1H), 3.18 (d. J - 6 1 Hz, 2H), 2.08~2.99(ni, 1H), 2.86〜 2.58(m, 4H), 2.42^-2.36 (m. 911). 2.09-1.73 (m, 12Hh 1.66-1.62 (in 6H).
Figure imgf000017_0002
JH NMR (400 MHz, DMSO-4) 6 8 61 (s, 1H), 7.29 (d, J = 8.6 Hz, 2H), 6 89 (d, J = 8.6 Hz, 2H), 6 29 (s, 1H), 4.68-4.32 (IU 1H). 4.14-4.09
Figure imgf000017_0003
1H). 3.43 (s. lH：h 2.05-1.83 (风 4H), 1.82-1.47
Figure imgf000017_0004
6H), 1.37-1.23 (IXL
4H). 1.15 (d. J- 5.5 Hz, 6H).
Figure imgf000017_0005
Figure imgf000018_0001
Figure imgf000019_0001
MS: 403.1[M4I-I]\
]H NMR (400 MHz, DMSO-^) 5 8.47 (s, 1H), 7.26 (d, J - 8.8 Hz, 2H)r 6.82 (d, J - 8.8 Hz, 2H). 6.01 (t J = 5.4 Hz. 1H)5 4.28^4.16 (m 1H), 3.21-3.14 (m, 2H). 2.72^2.62 (m, IH), 2.61^2.52 (m 2H)? 2.50^2.37 (m, 8H)5 2,05-1.91 (an 4H), L79-L48 (BI 10H). 化含物 BIOS^V5的合成路线与制备步骤， 参考实施例 & 此处不赘述。
Figure imgf000020_0001
, 2H). 6.03 (s, 1H), 4.21 (s, 1H), 2.82 (d, J = 9.3 Hz, 2H), 2.74 (t, J = 7.8 Hz, III). 2.61 (s. 2H), 2.45 (s, 2H), 2.21 (d? J - 9.0 Hz, 2H), 2.14-2.04 (m, 2H), 2.02-4.86 (m, 4H), 1.85-4.50 (nt 6H), 1.40-4.30 (ni 1H), 1.16^1.03 (ni 5H). 化合物 BIOS-A-6的合成路线与制备步骤, 参考实施例 6, 此处不赘述。 实施例： M： 化合物的组胺 ID受体拮抗活性 以 SUVN-G3O31 为阳性对照， 采用 FLIPR 测定法 ( NHT assay guidance manual: HTS Assay Vdidation-Section 4.3. Analysis (Potency), hUps:/7www.ncbi.rdmjdhgov/books/NBK83783 ) 筛选了月斤合 ”成的 13个目标化合物及 1个阳洼对照化合物的组胺 H3受体拮抗活性， 结果见表 " 表 L 化合物的组胺 H3受体捂抗活性
Figure imgf000020_0002
Figure imgf000021_0001
由表中的受体拮抗活性可却， 部分化合物呈现出较强的组胺 H3受体抑制活性， 大部分化合物活性在 5 nM时比阳性药 SUVN-G3031更佳. 实施例 25： 化合物的安全性 hHHG 在心服细胞中， lumian E[her-a-go-go Related Gene ( IsERG)编码的延迟整流钾电流 (IKr)通道蛋白抑 制是药物导致 QT间期延长最重要的机制。 11ERG因其特殊的分子结构， 使其可被多种不同结构的化合物 抑制， 导致严重的心律失常。据统计， 25-40%的先导化合物款显示出不同程度朋 WERG相关毒性。 因此, 早期评价化台物对 hERG 的影响在药物开发过程中至关重要。 在稳定表达 11ERG离于通道的 HEK293细胞株上，通过手动膜片钳技术检测化合物 M hERG通道的抑 制率， y. 100 BM ER bERG抑制剂西沙比利 (Cisapride) 为对照。 结果如表 2所示， 化合物 B1OS-A-13-BIOS-A-15, BIOS-A-3-BIOS-A-5, BIOS-A-IO , BI0S-A-11 ( 10 uM) W 11ERG通道的抑制率低于 5%,说明受试化合物基本无 hERG抑制活性，即受试化合物的安全性好。 表 2. 化合物对 hERG通道的抑制率
Figure imgf000021_0002
注 ' “一 ”表示未测 实施例 2诳 化合物 BIOS-A-3的疼痛模型活性数据
SD雄性大鼠， 180-20() g, 右后腿， 暴露坐骨神经， 在坐骨神经即将分叉的前段， 采用无菌铭肠线 (4 号， 直径 0.15 nmi) , 松结扎 4个环， 每个环距 1-2 mm, 缝合肌肉和皮肤， 建立慢性缩窄性损伤 (CCJD 模型， 假手术组仅暴露坐骨神经不结扎， 缝合肌肉和皮肤。 3d后观察， 第 7d用电于测痛仪 (I1TC-2391 ) 检测机械刺痛阈值， 连续 2天。 将机械剌痛阈值稳定的 CCI模型大鼠随机分为 3组，分别为模型组 (model)，普瑞巴林 (Pre )组 (30 mg/kg) , BIOS-A-3组 (: 1 mg/kg) , 按 1 mL/100 g灌胃给药, 假手术组 ( sham) 和模型组 (model)灌胃 同体积的生理盐水， 给药前检测基础值， 单次给药后 0.5 h、 1 h、 2 h ■, 4 h、 6 h检测机械痛阈值， 采用单 因素方差分析， T-检验计算 p值， 结果见图 L 结果表明， 对 SD大鼠 CCI裨经病理性疼痛模型， 化合物 BIOS-A-3 1 mg/kg, 可显著提高 CCI模型大 鼠的机械剌痛阈值； 并在给药后 0.5 h、 1 h, 6 h时间点的机械刺痛阈值与模型组有显著性差异 ( P<0.05 ) , 普瑞巴林 30页 g/kg的剂量仅在给药后 0.5 h、 1 h提高 CCI X鼠的机械刺痛阈值与模型组有显著差异， 表 明化合物 BIOS-A-3作用时间更长， 优于晋瑞巴林。 并且， 随着时间增长， 化合物 BIOS-A-3在单个时间 点上对机械剌痛阈值的效果更优于普瑞巴林。

Claims

权 利要 求书
Figure imgf000022_0001
式中：
X 选自。或 $; m 选自 0> 1、 幻 3、 4、 S或 6；
A 选自 Cl-6 izu基、 -NR' R/，、 取代或未取代的 5-8元杂环基、 取代或未取代的 5-8元杂芳基中的 种； 所述的杂环基、 杂芳基上至少有一个取代基， 取代基选自如下基团中的一种或几种： C1-6烷基、 C1-6 烷氧基、 C膈烯基、 C2-6 、 卤素、 氨基、 羟基、 氤基、 酰胺基、 碱基、 亚碱基、 C1 -6卤代烷基、 C1-6 烷基羟基、 C1-6烷基氨基、 Cl-6烷基酰，胺基、 5-6烷基碱基、 5-6烷基亚飒基、 C1 -6卤代烷氧基、 C1-6 烷氧基羟基、 C1-6烷氧基氨基、 Q-6烷氧基酰胺基、 C1-6烷氧基碱基、 C1-6烷氧基亚砌 1基、 3-6元环烷 基、 3-6元杂环基、 芳基、 杂芳基；
R '、 IV ' 各自独立的选自氢、 CL6烷基、 Ci-6烷氧基、 卤素， 氨基、 羟基、 孩基、 臻基、 酰胺基、 氤基、 Cl-6 代烷基、 C抑烷基羟基、 C1-6烷基氨基、 5-6烷基酰胺基、 C1-6卤代烷氧基、 5-6烷氧 基羟基、 C1-6烷氧基氨基、 5-6烷氧墓酰胺基中的一种或几种， 且 RL R' ' 不同时为氢；
Rl、 R2各自独立的选自氢、 CJ-6烷基、 -C(O)-;K基或 -S(O)2 -烷基；
R3、 R4、 R5、 R6各自独立的选自氢、 卤素、 C1-6烷基、 C2-6烯基、 C2-6 >基、 氨基、 羟基、 氟基、 酰胺基、 飙基、 亚飙基、 C1 -6卤代烷基、 5-6烷基羟基、 Cl-6 基氨基" Cl-6 -K基酰胺基 . CH-6烷基飒
Figure imgf000022_0002
R3、 R4 , R5、 R6各自独立的选自氯、 卤素、 C1-6烷基、 C2-6烯基、 C2-6 : Jjfe基、 氨基、 羟基、 氤基、 酰胺基、 飙基 . 亚碉基、 卤代烷基、 5-6烷基羟基、 Cl-6 基氨基、 CL6烷基欧胺基、 5-6烷基嘛 基、 C1-6烷基亚砥基中的一种或几种；
Figure imgf000023_0001
C1-6卤代烷基、 5-6烷基羟基、 以 -6烷基宴基、 C1-6卤代烷氧基、 C1-6 -K氧基羟基、 烷氧基氛基；
R3. R4 , R5 , R6各自独立的选自氢、 卤素、 C1-6烷基、 氨基、 羟基、 5-6卤代烷基、 Cl-6 B基羟 基、 CL6烷基氯基中的一种或几种； 所述的杂环基、 杂芳基中含有至少一个杂原子， 杂原子选自 N、 O或&
4、 根据权利要求 1所述的苯基服类衍生物， 其特征在于， 为具有如下结构通式 IU的化合物或其药学 上可接受的盐：
Figure imgf000023_0002
式中： m 选自 L 2. 3、 4、 5或 6；
R'、 R" 各自独立的选自氢、 5-6烷基、 C1-6烷氧基、 卤索、 氨基、 羟基、 液基、 巍基、 酰胺基 氤基、 C1-6卤代烷基、 C1-6烷基羟基、 C1-6烷基氨基、 C1-6烷基酰胺基、 C1-6卤代烷氧基 C1-6烷氧 基羟基、 以我烷氧基氨基、 5-6烷氧基酰，胺基中的一种或几种， 且 R'、 R' ' 不同时为氢；
R3 , R4、 R5> R6 &自独立的选自氢、 卤素、 C 1-6烷基、 C2-6烯基 ■, C2-6 基、 奏基、 羟基、 WL基、 酰胺基、 飒基' 亚 M基、 C1 -6卤代烷基、 C1-6烷基羟基、 C1-6 ?：；?基氛基、 CL6烷基酰胺基、 CL6烷基砚 基、 C1-6烷基亚飒基中的一神或几种； 或， R3、 R4 与各自连接的苯环上碳原子共同形成取代或未取代的苯并双环结构， 所述的苯并双环结 构包括诅不限于苯并杂环； 或， R5 , R6 与各自连接的苯坏上碳原子共同形成取代或未取代的苯并双环结构； 所述的苯并双环结 构包括但不限丁苯并杂环； 所述的苯并杂环中含有至少一个杂原子， 杂原子选自 N、 O或们
5、 根据权利要求 1所述的苯基脉类衍生物， 其特征在于， 为具有如下结构通式 IV的化合物或其药学 上可接受的盐：
Figure imgf000023_0003
Figure imgf000024_0001
l-（4-（（l ->b J基舐嚏 -4 -基）氧基）苯基）-3 ••外戊基跖
1 -（4-（（1-环丁基哌嚏 =4 -基｝氧基）苯基）-3 -环己基源；
1 -（4-（（1-环丁基哌嚏 4基）氧基）苯 #）-3-（2 -吗嘟基乙基）腺：
1 -（4-（（ !->［->］基哌宪 4 -基）氧基）苯基 哌略 1 -基）乙基）撅；
1 -（4-（（ 1-1-］' I基哌必 4 -基）氧基）苯基卜 3-（2-（毗咯烷 =1 -基）乙基｝腺；
1 -（4-（（1-环丁基 S辰淀 -4 -基）氧基）苯基）-3-（2-（2-S基毗 :咯烷 -1-®）乙基雁； l-（4-（（l-5FT基哌陇 -4 -基）氧基）苯基）-3-（2-（4,4-二氟哌呢 -1 -基）乙基）赂
1-（4-（（ 1 -环 J基哌噬 ~4-基）氧基）苯基卜 3-（硫代吗嘟 .基乙基）服；
1 -（4-（（1-环丁基侬陇 -4 -基）氧基）苯基）-3-（2-（4 -羟基哌噬基 -1-JE）乙基雁；
1 -（4-（（1 基哌建 -4 -基）氧基）苯 S）-3-（2-（4 -甲基哌嗪-卜基）乙基燃； l-（4-（（l-si' J基哌嚏 ~4 -基）氧基）苯基）-3-（2-（4 -异丙基嗽嗪 -1-基） 基）朋 i;
1 -（4-（（1 -环 J基哌陇 -4 -基）氧基）苯基）-3-（2-（3 -羟基哌嚏 -1-基）乙基）腿；
1 -（4-（（1-环丁基哌淀 4 -基｝氧基）苯基）-3-（2-（N-甲基高哌嗪」 .基）乙基）腺；
1 -（4-（（1-环丁基哌嚏 4基）氧基）苯基 哌嗪」 -基）乙基）源； 环丁基哌嗪-卜基）乙基）-3-（4-（（1-环「基哌宪牝基）氧基痒基腆；
"（4« -环丁基哌噬 -4基｝氧基｝苯基）3异丙基腕
1 -（4-（（1-环丁基哌嚏 -4 -基）氧基）苯基）-3-以-（二甲氨基）乙基）服；
1 -（4-（（ ］基哌嚏 -4 ■•基）氧基）苯基）-3-（2-（二乙氨基）乙基）服；
"（4-（（1 -环丁基哌睫 4 ■■基）氧基痒基卜3-（2 ■｛乙氨基）乙基）腺：
1 -（4-（（1-环丁基哌陇 -4 -基）氧基）苯 »-3-（2 -吗麻乙基）硫腺：
1 -（4-（（1-环丁基哌陇 -4 -基）氧基）苯基 哌噬 -1 -基）乙基）硫服； l-（4~（（l-±i' J基哌淀 *4 -基）氧基）苯基）-3-（2-（毗咯烷 T-基）乙基）硫服：
1 -（4-（（1-环丁 '基哌陡 -4 -基）氧基）苯基）-3-（2-（2 -甲基毗咯烷 = 1 -墓｝乙基）硫 ffiL
7、 一种苯基腺类衍生物， 为具有如下结构的化台物或其药学上可接受的盐：
（R）-l-（4-（（I -环［基哌嚏 -4 -基）氧基）苯基）-3-（2-（2-W基毗咯烷 -1 -基）乙基）服；
（R）- 1 -（4-（（ 1 -环 j基哌打定 -4-：基）氧基）苯:基卜3 -（2-（2 -甲基毗咯烷 -1-基）乙基）硫 38。
8、 种药物组合物， 包含至少 *中如权 F-7 中任 项所述的活性组分及至少 吓中药学上可接受的载 体或赋形剂。
9、 - -种制备如权利要求 1〜 7中任一项所述的化合物或权 7所述的药物组合物在预防或治疗与组胺 H3 受体相关的疾病中的用途。
10、 根据权利要求 9所述的用途， 其特征在于， 所述的药物用于预防或治疗认知障碍、 痴呆、 注意缺 陷多动障碍、 精神分裂症、 癫痫、 睡眠障碍、 睡眠呼吸暂停、 肥胖、 迸食障碍、 疼痛和瘙痒。
1K 根据权利要求 9所述拘用途， 其持征在于， 所述的药物用于预防或治疗祥经病理性疼痛， 包括但 不限于周围性神 1经病理性疼痛或中枢性神经病理性疼痛。
PCT/IB2023/000143 2022-03-02 2023-03-02 苯基脲类衍生物及其医药用途 WO2023166349A2 (zh)

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WO2012114348A1 (en) 2011-02-23 2012-08-30 Suven Life Sciences Limited Novel compounds as histamine h3 receptor ligands
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EP2350048A2 (en) * 2008-10-16 2011-08-03 Schering Corporation Azine derivatives and methods of use thereof
MA52850A (fr) * 2018-05-31 2021-04-21 Suven Life Sciences Ltd Méthode de traitement avec un agoniste inverse du récepteur de l'histamine-3

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