CN116693446A - 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 PDFInfo
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- CN116693446A CN116693446A CN202310192845.4A CN202310192845A CN116693446A CN 116693446 A CN116693446 A CN 116693446A CN 202310192845 A CN202310192845 A CN 202310192845A CN 116693446 A CN116693446 A CN 116693446A
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- Prior art keywords
- alkyl
- cyclobutylpiperidin
- oxy
- phenyl
- hydroxy
- Prior art date
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- LUBJCRLGQSPQNN-UHFFFAOYSA-N 1-Phenylurea Chemical class NC(=O)NC1=CC=CC=C1 LUBJCRLGQSPQNN-UHFFFAOYSA-N 0.000 title claims abstract description 15
- -1 isomer Substances 0.000 claims abstract description 153
- 150000001875 compounds Chemical class 0.000 claims abstract description 129
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- 108090000981 Histamine H3 receptors Proteins 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 239000012453 solvate Substances 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 22
- 125000005189 alkyl hydroxy group Chemical group 0.000 claims description 22
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims description 21
- 125000000623 heterocyclic group Chemical group 0.000 claims description 21
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 125000003368 amide group Chemical group 0.000 claims description 18
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- 125000001424 substituent group Chemical group 0.000 claims description 14
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 13
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- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
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- 206010012289 Dementia Diseases 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
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- NDTSRXAMMQDVSW-UHFFFAOYSA-N benzthiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1N=C2CSCC1=CC=CC=C1 NDTSRXAMMQDVSW-UHFFFAOYSA-N 0.000 description 32
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- 238000006243 chemical reaction Methods 0.000 description 29
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- CKZDBHBPTICGST-UHFFFAOYSA-N 4-(1-cyclobutylpiperidin-4-yl)oxyaniline Chemical compound C1=CC(N)=CC=C1OC1CCN(C2CCC2)CC1 CKZDBHBPTICGST-UHFFFAOYSA-N 0.000 description 7
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
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- LNXDUSQEXVQFGP-UHFFFAOYSA-N n-[4-(1-cyclobutylpiperidin-4-yl)oxyphenyl]-2-morpholin-4-ylacetamide Chemical compound C=1C=C(OC2CCN(CC2)C2CCC2)C=CC=1NC(=O)CN1CCOCC1 LNXDUSQEXVQFGP-UHFFFAOYSA-N 0.000 description 6
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- 125000002883 imidazolyl group Chemical group 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 108091006146 Channels Proteins 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-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
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- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 4
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- DUBLPBOUYRUPIW-UHFFFAOYSA-N 1-cyclobutyl-4-(4-nitrophenoxy)piperidine Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC1CCN(C2CCC2)CC1 DUBLPBOUYRUPIW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
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- 125000006413 ring segment Chemical group 0.000 description 3
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
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- JAHDECSRUJTQCB-UHFFFAOYSA-N 4-(4-nitrophenoxy)piperidine Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC1CCNCC1 JAHDECSRUJTQCB-UHFFFAOYSA-N 0.000 description 2
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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合物具有显著的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
技术领域
本发明属于医药技术领域,涉及一种苯基脲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疗用途。
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蛋白偶联受体(GPCR):H1、H2、H3和H4受体(Nature Review Drug Discovery,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(H3R)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,多巴胺或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),1166-1181)。
文献表明组胺H3受体配体可用于治疗认知障碍(British Journal ofPharmacology,2008,154(6),1166-1181)、痴呆(Drug 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 ofPharmacology 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)位被取代的咪唑环类和非咪唑环类两大类。含有咪唑环的化合物具有低血脑屏障渗透、与细胞色素P-450蛋白相互作用以及肝脏和眼毒性的缺点。非咪唑环类的代表化合物专利:①US20020177589A1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、认知障碍。该化合物中代表化合物为ABT-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。②WO2012114348A1公开了作为组胺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。在进入临床的药物中,治疗认知障碍的H3R拮抗剂/反向激动剂Samelisant(SUVN-G3031)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2015-2017年开展临床试验一期,后续无进展。③WO2014030170A1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疗多种病症,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,但是迄今为止,在该研发领域就一个获批上市的药物—Pitolisant(H3R拮抗剂/反向激动剂),上市的适应症是嗜睡症。SUVN-G3031等在研药物处于临床2期研究的仍是嗜睡症,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-G3031等药物的新化学实体,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。
发明内容
本发明旨在提供一种结构全新的苯基脲类衍生物,可作为组胺H3受体配体化合物,用于预防或治疗与组胺H3受体相关的疾病。
为实现上述发明目的,本发明提供的技术方案具体如下:
一种苯基脲类衍生物,为具有如下结构通式Ⅰ的化合物或其药学上可接受的盐:
式中:
X选自O或S;
m选自0、1、2、3、4、5或6;
A选自C1-6烷基、-NR’R”、取代或未取代的5-8元杂环基、取代或未取代的5-8元杂芳基中的一种;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、C2-6烯基、C2-6炔基、卤素、氨基、羟基、氰基、酰胺基、砜基、亚砜基、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烷基砜基、C1-6烷基亚砜基、C1-6卤代烷氧基、C1-6烷氧基羟基、C1-6烷氧基氨基、C1-6烷氧基酰胺基、C1-6烷氧基砜基、C1-6烷氧基亚砜基、3-6元环烷基、3-6元杂环基、芳基、杂芳基;
R’、R”各自独立的选自氢、C1-6烷基、C1-6烷氧基、卤素、氨基、羟基、羧基、羰基、酰胺基、氰基、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、C1-6烷氧基氨基、C1-6烷氧基酰胺基中的一种或几种,且R’、R”不同时为氢;
R1、R2各自独立的选自氢、C1-6烷基、-C(O)-烷基或-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炔基、氨基、羟基、氰基、酰胺基、砜基、亚砜基、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烷基砜基、C1-6烷基亚砜基中的一种或几种;
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,苯并双环结构包括但不限于苯并杂环;
或,R5、R6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不限于苯并杂环;
杂环基、杂芳基、苯并杂环中含有至少一个杂原子,杂原子选自N、O或S。
优选的,为具有如下结构通式Ⅱ的化合物或其药学上可接受的盐:
式中:
X选自O或S;
m选自0、1、2、3、4、5或6;
A选自取代或未取代的5-8元杂环基、取代或未取代的5-8元杂芳基中的一种;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、C2-6烯基、C2-6炔基、卤素、氨基、羟基、氰基、酰胺基、砜基、亚砜基、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烷基砜基、C1-6烷基亚砜基、C1-6卤代烷氧基、C1-6烷氧基羟基、C1-6烷氧基氨基、C1-6烷氧基酰胺基、C1-6烷氧基砜基、C1-6烷氧基亚砜基、3-6元环烷基、3-6元杂环基、芳基、杂芳基;
R3、R4、R5、R6各自独立的选自氢、卤素、C1-6烷基、C2-6烯基、C2-6炔基、氨基、羟基、氰基、酰胺基、砜基、亚砜基、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烷基砜基、C1-6烷基亚砜基中的一种或几种;
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,苯并双环结构包括但不限于苯并杂环;
或,R5、R6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不限于苯并杂环;
杂环基、杂芳基、苯并杂环中含有至少一个杂原子,杂原子选自N、O或S。
优选的,为具有如下结构通式Ⅱ-1的化合物或其药学上可接受的盐:
m选自1、2、3、4、5或6;
A选自取代或未取代的6元杂环基、取代或未取代的6元杂芳基中的一种;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、卤素、氨基、羟基、C1-6卤代烷基、C1-6烷基羟基、C1-6烷基氨基、C1-6卤代烷氧基、C1-6烷氧基羟基、C1-6烷氧基氨基;
R3、R4、R5、R6各自独立的选自氢、卤素、C1-6烷基、氨基、羟基、C1-6卤代烷基、C1-6烷基羟基、C1-6烷基氨基中的一种或几种;
杂环基、杂芳基中含有至少一个杂原子,杂原子选自N、O或S。
优选的,为具有如下结构通式Ⅲ的化合物或其药学上可接受的盐:
式中:
m选自1、2、3、4、5或6;
R’、R”各自独立的选自氢、C1-6烷基、C1-6烷氧基、卤素、氨基、羟基、羧基、羰基、酰胺基、氰基、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、C1-6烷氧基氨基、C1-6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各自独立的选自氢、卤素、C1-6烷基、C2-6烯基、C2-6炔基、氨基、羟基、氰基、酰胺基、砜基、亚砜基、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烷基砜基、C1-6烷基亚砜基中的一种或几种;
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,苯并双环结构包括但不限于苯并杂环;
或,R5、R6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不限于苯并杂环;
苯并杂环中含有至少一个杂原子,杂原子选自N、O或S。
优选的,为具有如下结构通式IV的化合物或其药学上可接受的盐:
A选自C1-6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炔基、氨基、羟基、氰基、酰胺基、砜基、亚砜基、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烷基砜基、C1-6烷基亚砜基中的一种或几种;
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,苯并双环结构包括但不限于苯并杂环;
或,R5、R6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不限于苯并杂环;
苯并杂环中含有至少一个杂原子,杂原子选自N、O或S。
本发明还提供了一种苯基脲类衍生物,包括编号为BIOS-A-1至BIOS-A-23的具有如下结构所示的化合物、同分异构体或其药学上可接受的盐:
BIOS-A-1:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-环戊基脲;
BIOS-A-2:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-环己基脲;
BIOS-A-3:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-吗啉基乙基)脲;
BIOS-A-4:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(哌啶-1-基)乙基)脲;
BIOS-A-5:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(吡咯烷-1-基)乙基)脲;
BIOS-A-6:(R)-1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(2-甲基吡咯烷-1-基)乙基)脲;
BIOS-A-7:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(4,4-二氟哌啶-1-基)乙基)脲;
BIOS-A-8:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(硫代吗啉基乙基)脲;
BIOS-A-9:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(4-羟基哌啶基-1-基)乙基)脲;
BIOS-A-10:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(4-甲基哌嗪-1-基)乙基)脲;
BIOS-A-11:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(4-异丙基哌嗪-1-基)乙基)脲;
BIOS-A-12:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(3-羟基哌啶-1-基)乙基)脲;
BIOS-A-13:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(N-甲基高哌嗪-1-基)乙基)脲;
BIOS-A-14:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(哌嗪-1-基)乙基)脲;
BIOS-A-15:1-(2-(4-环丁基哌嗪-1-基)乙基)-3-(4-((1-环丁基哌啶-4-基)氧基)苯基)脲;
BIOS-A-16:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-异丙基脲;
BIOS-A-17:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(二甲氨基)乙基)脲;
BIOS-A-18:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(二乙氨基)乙基)脲;
BIOS-A-19:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(乙氨基)乙基)脲;
BIOS-A-20:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-吗啉乙基)硫脲;
BIOS-A-21:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(哌啶-1-基)乙基)硫脲;
BIOS-A-22:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(吡咯烷-1-基)乙基)硫脲;
BIOS-A-23:(R)-1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(2-甲基吡咯烷-1-基)乙基)硫脲。
前述编号为BIOS-A-1至BIOS-A-23的化合物或其药学上可接受的盐,具体结构式如下:
进一步的,本发明还提供了一种苯基脲类衍生物,包括如下结构所示的手性化合物或其药学上可接受的盐:
(R)-1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(2-甲基吡咯烷-1-基)乙基)脲;
(R)-1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(2-甲基吡咯烷-1-基)乙基)硫脲。
本发明所述的“化合物”,包括但不限于化合物的如下情形:游离碱、立体异构体、几何异构体、互变异构体、同位素、药学上可接受的盐、溶剂化物、水合物、前药(酯或磷酸酯)等形式。
本发明所述的“化合物”,可以是不对称的,例如,具有一个或多个立体异构体。除非另有说明,所有立体异构体都包括,如对映异构体和非对映异构体。本发明中含有不对称碳原子的化合物,可以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以通过外消旋混合物拆分、使用手性原料或手性试剂合成的方法获得。
本发明所述的“药学上可接受的盐”是指本发明化合物的盐,由本发明发现的具有特定取代基的化合物与相对无毒的碱制备。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式,获得碱加成盐。药学上可接受的碱加成盐,包括但不限于钠、钾、钙、镁盐、铵或有机氨。例如:碱金属盐、碱土金属盐、其他金属盐、无机碱盐、有机碱盐、无机酸盐、低级烷磺酸盐、芳基磺酸盐、有机酸盐、氨基酸盐等。
除了盐的形式,本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外,前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
含有前述通式结构的化合物,本文中所用的术语具有如下含义:
术语“卤素”,指氟、氯、溴或碘,优选氟、氯或溴。
术语“烷基”,指由碳原子和氢原子组成的直链或支链的饱和烃基团,如C1-6烷基,包括但不限于甲基、乙基、丙基(含正丙基和异丙基)、丁基(含正丁基、异丁基、仲丁基或叔丁基)、戊基(含正戊基、异戊基、新戊基)、正己基、2-甲基己基。
术语“环烷基”,指由碳原子和氢原子组成单环或双环烷基,如C3-8环烷基,包括但不限于环丙基、环丁基、环戊基、环己基、环庚基和环辛基等。
术语“烷氧基”,指通过氧原子相连的直链或支链烷基,如C1-6烷氧基,包括但不限于甲氧基、乙氧基、正丙氧基(含正丙氧基和异丙氧基)、丁氧基(含正丁氧基、异丁氧基、仲丁氧基或叔丁氧基)、戊氧基(含正戊氧基、异戊氧基、新戊氧基)、正己氧基、2-甲基己氧基等。
术语“烷胺基”,指含有氮原子的开链烷基,如C1-6烷胺基,包括但不限于甲胺基、乙胺基、异丙胺基、二甲基胺基、甲基乙基胺基、二乙基胺基等。
术语“芳基”,是指5-12个(整数)碳原子的全碳单环或稠合多环基团,具有完全共轭的π-电子体系,包括但不限于苯环、萘环、蒽环。
术语“杂环基”、“杂芳基”,指具有3-12个(整数)环原子的单环或稠合环,其中有1、2、3个环原子或更多的环原子选自N、O、S中的一个或多个,其余环原子为C,且具有完全共轭或不共轭的π-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吡咯基、吲哚基、吡咯烷基、咪唑基、吡唑基、四唑基、吡啶基、喹啉基、异喹啉基、哌啶基、嘧啶基、吡嗪基、哌嗪基、呋喃基、吡喃基、吗啉基。
本发明提供的上述化合物的制备方法,通过以下步骤制备,但不仅限于以下方法:
反应过程如下:
对位氟代的硝基苯类化合物(原料1)和哌啶醇、氢化钠溶于DMF中反应,然后在盐酸/乙酸乙酯溶液中反应得到中间体1,随后将其与邻环丁酮进行还原胺化反应得到中间体2,在Pd/C氢气氛围中还原得到中间体3,中间体3与异氰酸酯在二氯甲烷中反应得到目标化合物;
或,中间体3与氯代异氰酸酯在二氯甲烷中反应得到中间体4,随后与胺反应得到中间体5或目标化合物;
或,中间体5与劳森试剂反应得到目标化合物。
前述合成方法中涉及的取代基R’、R”、R3、R4、R5、R6,定义如下:
R’、R”各自独立的选自氢、C1-6烷基、C1-6烷氧基、卤素、氨基、羟基、羧基、羰基、酰胺基、氰基、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、C1-6烷氧基氨基、C1-6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各自独立的选自氢、卤素、C1-6烷基、C2-6烯基、C2-6炔基、氨基、羟基、氰基、酰胺基、砜基、亚砜基、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烷基砜基、C1-6烷基亚砜基中的一种或几种;
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但不限于苯并杂环;
或,R5、R6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但不限于苯并杂环;
本发明还提供了一种药物组合物,包含至少一种如前所述的化合物或其药学上可接受的盐作为活性成份,以及至少一种或多种药学上可接受的载体。
本发明所述的“药物组合物”,指一种或多种本发明的化合物或其盐与在本领域中通常接受的用于将生物活性化合物输送至有机体(例如人)的载体的制剂。药物组合物的目的是有利于对有机体给药输送。
本发明所述的化合物或其药学上可接受的盐或其药物组合物的给药途径,包括但不限于口服、直肠、透黏膜、经肠给药,或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。优选的给药途径是口服给药。
本发明还提供了一种制备如前所述的化合物或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。
优选的,前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、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神经痛、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(如腕管综合症)、HIV感觉神经痛、医源性神经痛(如乳腺切除术后疼痛)、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、胸或腰骶)、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受体配体出发,开发了一系列的结构新颖的苯基脲类衍生物,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合物具有显著的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。
附图说明
图1为各实验组在不同时间和不同剂量下的机械刺痛阈值变化图。
图中,与model组比较,*,P<0.05;**,P<0.01;与sham组比较,#,P<0.05;##,P<0.01。
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:指基团苄基;
代号DMF:指试剂N,N-二甲基甲酰胺;
代号TFA:指试剂三氟乙酸;
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:指基团叔丁氧羰基;
代号Lawesson 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WatersSymmetry C18色谱柱。薄层色谱采用GF254(0.25毫米)。核磁共振色谱(NMR)使用Bruker-400核磁共振仪测定;液质连用(LC/MS)使用Waters ZQ质谱检测器(柱子:WatersSymmetry C18,毫米,5微米,35℃),采用ESI(+)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。
一、共用中间体A1的制备:
中间体A1的合成路线如下:
步骤1:4-(4-硝基苯氧基)哌啶(3)合成
在500mL茄形瓶中,将N-Boc-4-羟基哌啶(化合物2,5.14g,25.51mmol)溶于无水N,N-二甲基甲酰胺(40mL),氮气保护下,冰水浴下加入氢化钠粉末(1.02g,25.51mmol),保温反应1h。最后滴加4-氟硝基苯(化合物1,3.0g)和无水N,N-二甲基甲酰胺(5mL)的溶液,滴加完毕之后转移至室温反应6h。薄层色谱检测原料基本反应完全。反应液加水(320mL)淬灭并混匀,乙酸乙酯萃取三次,有机相合并,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9.56g。
粗品溶于盐酸-乙酸乙酯(30mL),室温下反应1~2h。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,得到白色固体5.55g(即化合物3)。收率84.10%。
MS:223.1[M+H]+。
步骤2:1-环丁基-4-(4-硝基苯氧基)哌啶(5)的合成
化合物3(5.55g,21.45mmol)混合于无水甲醇40mL中,加入三乙胺3mL后溶清,接着加入环丁酮(化合物4,2mL)和乙酸(2mL),冰水浴低温搅拌1h。加入氰基硼氢化钠2.1g,最后移至室温反应过夜12h。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,无水硫酸钠干燥,浓缩,得黄色固体6.77g(即化合物5)。收率99%。
MS:277.1[M+H]+。
步骤3:4-((1-环丁基哌啶-4-基)氧基)苯胺(A1)的合成:
化合物5(6.77g,24.50mmol)混合于乙醇溶液180mL中,再加入还原铁粉9.6g、氯化铵2.36g和水60mL,油浴80℃反应2~3h。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pH9~10,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,浓缩,得黄褐色液体4.99g(即中间体A1)。收率82.68%。
MS:247.1[M+H]+。
二、共用中间体A2的制备:
中间体A2的合成路线如下:
中间体A1(300mg,1.242mmol)和吡啶(150mL,1.491mmol)溶于无水二氯甲烷8mL,转移至冰水浴低温搅拌10min,滴加氯甲酸苯酯187μL,最后移至室温反应2~3h。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,浓缩干,得褐色粗品480mg(即中间体A2)。收率100%。
MS:367.2[M+H]+。
三、共用中间体A3的制备:
中间体A3的合成路线如下:
中间体A1(2.01g,8.16mmol)溶于无水二氯甲烷20mL,转移至冰水浴低温搅拌10min,滴加氯乙基异氰酸酯835μL,最后移至室温反应3~4h。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,滤饼拉干,得到白色粉末1.96g(即中间体A3)。收率68.26%。
MS:352.3[M+H]+。
以下实施例1~23为本发明所述的BIOS-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,包括但不限于:硫酸盐、硝酸盐、亚硝酸盐、马来酸盐、富马酸盐、甲酸盐、二甲酸盐、乙酸盐……等等,其制备均可从本发明提供的实施例1~23中得到相应的技术启示。
实施例1:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-环戊基脲(BIOS-A-1)的合成
合成路线如下:
中间体A1(100mg,0.406mmol)、环戊基异氰酸酯(46μL,0.406mmol)溶于4mL二氯甲烷中,室温下反应4~5h。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90mg(即化合物BIOS-A-1),收率62.00%。
MS:358.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.07(s,1H),7.24(d,J=8.6Hz,2H),6.80(d,J=8.6Hz,2H),6.06(d,J=7.2Hz,1H),4.27~4.11(m,1H),3.98~3.85(m,1H),2.73~2.62(m,1H),2.05~1.46(m,20H),1.39~1.28(m,2H).
实施例2:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-环己基脲(BIOS-A-2)的合成
合成路线如下:
中间体A2(260mg,0.709mmol)、环己胺(97μL,0.851mmol)与三乙胺197μL溶于4mL乙腈溶液中,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(石油醚:乙酸乙酯:三乙胺=1:1:0.1),得黄色固体116mg(即化合物BIOS-A-2),收率44.04%。
MS:372.5[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),7.29(d,J=8.6Hz,2H),6.89(d,J=8.6Hz,2H),6.29(s,1H),4.68~4.32(m,1H),3.43(s,1H),2.89~2.54(m,4H),2.40(s,2H),2.14(s,4H),2.05~1.83(m,3H),1.82~1.47(m,8H),1.37~1.23(m,4H).
实施例3:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-吗啉基乙基)脲(BIOS-A-3)的制备
合成路线如下:
中间体A3(100mg,0.284mmol)、吗啉(100μL,0.853mmol)与三乙胺197μL溶于4mL乙腈溶液中,转移至油浴80℃反应2~3h。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(石油醚:乙酸乙酯:三乙胺=1:4:1),得白色固体48mg(即化合物BIOS-A-3),收率41.99%。
MS:403.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ=8.43(s,1H),7.25(d,J=9.0Hz,2H),6.81(d,J=9.0Hz2H),5.99(t,J=5.4Hz,1H),4.26~4.16(m,1H),3.59(t,J=4.6Hz,4H),3.18(q,J=6.2Hz,2H),2.74~2.61(m,1H),2.60~2.52(m,2H),2.37(t,J=5.6Hz,6H),2.07~1.83(m,6H),1.83~1.69(m,2H),1.64~1.50(m,4H).
实施例4:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(哌啶-1-基)乙基)脲(BIOS-A-4)的制备
合成路线如下:
参考实施例3中化合物BIOS-A-3的合成方法,将本实施例的哌啶代替实施例3的吗啉,其余制备步骤同实施例3。得到白色固体76mg(即化合物BIOS-A-4),收率66.81%。
MS:401.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.57(s,1H),7.26(d,J=8.8Hz,2H),6.81(d,J=8.8Hz,2H),6.13(s,1H),4.28~4.16(m,1H),3.23~3.13(m,2H),2.82~2.69(m,1H),2.60(d,J=5.4Hz,2H),2.47~2.36(m,6H),2.09~2.06(m,2H),2.02~1.85(m,4H),1.85~1.73(m,2H),1.65~1.50(m,8H),1.45~1.34(m,2H).
实施例5:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(吡咯烷-1-基)乙基)脲(BIOS-A-5)的制备
合成路线如下:
参考实施例3中化合物BIOS-A-3的合成方法,将本实施例的四氢吡咯代替实施例3的吗啉,其余制备步骤同实施例3。得到白色固体32mg(即化合物BIOS-A-5),收率29.15%。
MS:401.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),7.25(d,J=8.8Hz,2H),6.80(d,J=8.8Hz,2H),6.00(t,J=5.4Hz,1H),4.26~4.14(m,1H),3.21~3.14(m,2H),2.72~2.62(m,1H),2.61~2.52(m,2H),2.50~2.37(m,8H),2.05~1.91(m,4H),1.79~1.48(m,10H).
实施例6:(R)-1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(2-甲基吡咯烷-1-基)乙基)脲(BIOS-A-6)的制备
合成路线如下:
参考实施例3中化合物BIOS-A-3的合成方法,将本实施例的(R)-2-甲基吡咯烷代替实施例3的吗啉,其余制备步骤同实施例3。得到黄色固体74mg(即化合物BIOS-A-6),收率65.05%。
MS:387.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.50(s,1H),7.26(d,J=8.6Hz,2H),6.81(d,J=8.6Hz,2H),6.05(s,1H),4.23(s,1H),2.89(d,J=9.3Hz,2H),2.76(t,J=7.8Hz,1H),2.61(s,2H),2.45(s,2H),2.21(d,J=9.0Hz,2H),2.14~2.04(m,2H),2.02~1.86(m,6H),1.85~1.50(m,6H),1.40~1.30(m,1H),1.16~1.03(m,5H).
实施例7:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(4,4-二氟哌啶-1-基)乙基)脲(BIOS-A-7)的制备
合成路线如下:
参考实施例3中化合物BIOS-A-3的合成方法,将本实施例的4,4-二氟哌啶代替实施例3的吗啉,其余制备步骤同实施例3。得到类白色固体100mg(即化合物BIOS-A-7),收率80.66%。
MS:437.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.52(s,1H),7.28(d,J=9.0Hz,2H),6.85(d,J=8.6Hz,2H),6.07(s,1H),4.37(s,1H),3.19(q,J=6.2Hz,2H),3.10~3.00(m,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).
实施例8:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(硫代吗啉-1-基)乙基)脲(BIOS-A-8)的制备
合成路线如下:
参考实施例3中化合物BIOS-A-3的合成方法,将本实施例的硫代吗啉代替实施例3的吗啉,其余制备步骤同实施例3。得到白色固体73mg(即化合物BIOS-A-8),收率61.41%。
MS:419.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.39(s,1H),7.25(d,J=9.0Hz,2H),6.81(d,J=9.0Hz,2H),5.93(t,J=5.4Hz,1H),4.27~4.16(m,1H),3.16(q,J=6.1Hz,2H),2.79~2.54(m,11H),2.40(t,J=6.4Hz,2H),2.14~1.84(m,6H),1.84~1.71(m,2H),1.68~1.49(m,4H).
实施例9:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(4-羟基哌啶基-1-基)乙基)脲(BIOS-A-9)的制备
合成路线如下:
参考实施例3中化合物BIOS-A-3的合成方法,将本实施例的4-羟基哌啶代替实施例3的吗啉,其余制备步骤同实施例3。得到白色固体107mg(即化合物BIOS-A-9),收率90.45%。
MS:417.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),7.26(d,J=9.0Hz,2H),6.82(d,J=9.0Hz,2H),5.98(s,1H),4.60(s,1H),4.24(s,1H),3.47(s,1H),3.18(d,J=5.9Hz,2H),2.82~2.42(m,5H),2.40(s,2H),2.24~1.68(m,12H),1.67~1.35(m,6H).
实施例10:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(4-甲基哌嗪-1-基)乙基)脲(BIOS-A-10)的制备
合成路线如下:
参考实施例3中化合物BIOS-A-3的合成方法,将本实施例的4-甲基哌嗪代替实施例3的吗啉,其余制备步骤同实施例3。得到白色固体(即化合物BIOS-A-10),收率87.27%。
MS:416.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.46(s,1H),7.25(d,J=9.0Hz,2H),6.81(d,J=9.0Hz,2H),5.95(t,J=5.4Hz,1H),4.26~4.16(m,1H),2.98~2.90(m,2H),2.77~2.65(m,1H),2.58(t,J=5.9Hz,2H),2.40~2.25(m,8H),2.19(s,2H),2.16(s,3H),2.08~1.84(m,6H),1.84~1.71(m,2H),1.67~1.48(m,4H).
实施例11:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(4-异丙基哌嗪-1-基)乙基)脲(BIOS-A-11)的制备
合成路线如下:
参考实施例3中化合物BIOS-A-3的合成方法,将本实施例的4-异丙基哌嗪代替实施例3的吗啉,其余制备步骤同实施例3。得到淡黄色固体114mg(即化合物BIOS-A-11),收率90.48%。
MS:444.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.44(s,1H),7.25(d,J=9.0Hz,2H),6.81(d,J=9.0Hz,2H),5.94(t,J=5.5Hz,1H),4.23(s,1H),3.17(q,J=6.0Hz,2H),2.84~2.54(m,5H),2.48~2.27(m,7H),2.17~1.69(m,9H),1.67~1.49(m,4H),1.06~0.88(m,7H).
实施例12:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(3-羟基哌啶-1-基)乙基)脲(BIOS-A-12)的制备
合成路线如下:
参考实施例3中化合物BIOS-A-3的合成方法,将本实施例的3-羟基哌啶代替实施例3的吗啉,其余制备步骤同实施例3。得到白色固体92mg(即化合物BIOS-A-12),收率77.77%。
MS:417.2[M+H]+。
1H NMR(600MHz,DMSO-d6)δ8.40(s,1H),7.24(d,J=9.0Hz,2H),6.80(d,J=9.0Hz,2H),5.92(t,J=5.4Hz,1H),4.58(d,J=5.0Hz,1H),4.24~4.16(m,1H),3.51~3.44(m,1H),3.15(q,J=6.1Hz,2H),2.82(d,J=10.8Hz,1H),2.73~2.62(m,2H),2.57(s,2H),2.41~2.30(m,2H),2.07~1.92(m,4H),1.91~1.82(m,3H),1.81~1.71(m,4H),1.65~1.50(m,5H),1.46~1.36(m,1H),1.13~1.03(m,1H).
实施例13:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(N-甲基高哌嗪-1-基)乙基)脲(BIOS-A-13)的制备
合成路线如下:
参考实施例3中化合物BIOS-A-3的合成方法,将本实施例的N-甲基高哌嗪代替实施例3的吗啉,其余制备步骤同实施例3。得到白色固体84mg(即化合物BIOS-A-13),收率68.85%。
MS:430.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.49(s,1H),7.25(d,J=9.0Hz,2H),6.81(d,J=9.0Hz,2H),5.99(s,1H),4.26~4.15(m,1H),3.17~3.03(m,5H),2.78~2.63(m,10H),2.35(s,3H),2.31(s,2H),2.09~1.70(m,12H).
实施例14:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(哌嗪-1-基)乙基)脲(BIOS-A-14)的制备
合成路线如下:
中间体A3(100mg,0.284mmol)、1-Boc-哌嗪(158mg,0.853mmol)与三乙胺197μL溶于4mL乙腈溶液中,转移至油浴80℃反应2~3h。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(石油醚:乙酸乙酯:三乙胺=1:4:1),得到白色固体性状的中间体96mg;中间体在盐酸-乙酸乙酯3mL中反应2h后,过滤,浓缩干,得到盐酸盐白色固体91mg(即化合物BIOS-A-14的盐酸盐),两步收率62.71%。
MS:402.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ9.87(s,1H),8.99(d,J=10.2Hz,1H),7.32(d,J=9.0Hz,2H),6.90(d,J=9.0Hz,2H),6.68(s,1H),3.63~3.55(m,2H),3.54~3.45(m,4H),3.24(t,J=6.2Hz,2H),3.19~3.13(m,8H),2.96~2.76(m,2H),2.41(t,J=10.2Hz,2H),2.16~2.12(m,4H),2.04~1.85(m,2H),1.80~1.61(m,2H).
实施例15:1-(2-(4-环丁基哌嗪-1-基)乙基)-3-(4-((1-环丁基哌啶-4-基)氧基)苯基)脲(BIOS-A-15)的制备
合成路线如下:
参考实施例3中化合物BIOS-A-3的合成方法,将本实施例的1-环丁基哌嗪代替实施例3的吗啉,其余制备步骤同实施例3。得到白色固体84mg(即化合物BIOS-A-15),收率64.91%。
MS:456.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.45(s,1H),7.26(d,J=8.6Hz,2H),6.83(d,J=8.6Hz,2H),5.95(s,1H),4.27(s,1H),3.18(d,J=6.1Hz,2H),2.08~2.99(m,1H),2.86~2.58(m,4H),2.42~2.36(m,9H),2.09~1.73(m,12H),1.66~1.62(m,6H).
实施例16:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-异丙基脲(BIOS-A-16)的制备
合成路线如下:
参考实施例1中化合物BIOS-A-1的合成方法,将本实施例的异丙基异氰酸酯代替实施例1的环戊基异氰酸酯,其余制备步骤同实施例1。得到白色固体84mg(即化合物BIOS-A-16),收率62.42%。
MS:456.3[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),7.29(d,J=8.6Hz,2H),6.89(d,J=8.6Hz,2H),6.29(s,1H),4.68~4.32(m,1H),4.14~4.09(m,1H),3.43(s,1H),2.05~1.83(m,4H),1.82~1.47(m,6H),1.37~1.23(m,4H),1.15(d,J=5.5Hz,6H).
实施例17:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(二甲氨基)乙基)脲(BIOS-A-17)的制备
合成路线如下:
参考实施例3中化合物BIOS-A-3的合成方法,将本实施例的二甲胺盐酸盐代替实施例3的吗啉,其余制备步骤同实施例3。得到类白色固体40mg(即化合物BIOS-A-17),收率39.07%。
MS:437.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.52(s,1H),7.28(d,J=9.0Hz,2H),6.85(d,J=8.6Hz,2H),6.07(s,1H),4.37(s,1H),3.10~3.00(m,1H),2.45(t,J=6.1Hz,2H),2.24(s,6H),2.20~2.02(m,6H),1.84~1.55(m,10H).
实施例18:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(二乙氨基)乙基)脲(BIOS-A-18)的制备
合成路线如下:
参考实施例3中化合物BIOS-A-3的合成方法,将本实施例的二乙胺代替实施例3的吗啉,其余制备步骤同实施例3。得到白色固体67mg(即化合物BIOS-A-18),收率60.72%。
MS:389.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.52(s,1H),7.28(d,J=9.0Hz,2H),6.85(d,J=8.6Hz,2H),6.11(s,1H),4.39(s,1H),3.13~3.02(m,1H),2.70(t,J=5.8Hz,2H),2.28~2.21(m,4H),2.20~2.02(m,12H),1.84~1.55(m,10H).
实施例19:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(乙氨基)乙基)脲(BIOS-A-19)的制备
合成路线如下:
参考实施例3中化合物BIOS-A-3的合成方法,将本实施例的乙胺盐酸盐代替实施例3的吗啉,其余制备步骤同实施例3。得到白色固体76mg(即化合物BIOS-A-19),收率74.23%。
MS:361.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.57(s,1H),7.29(d,J=8.9Hz,2H),6.88(d,J=8.9Hz,2H),5.93(t,J=4.7Hz,1H),4.37~4.33(m,1H),3.32(q,J=4.3Hz,2H),2.89~2.82(m,2H),2.83~2.66(m,6H),1.98~1.92(m,4H),1.81~1.74(m,2H),1.77~1.49(m,6H),1.15(t,J=6.0Hz,3H).
实施例20:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-吗啉乙基)硫脲(BIOS-A-20)的制备
合成路线如下:
化合物BIOS-A-3(100mg,0.248mmol)与Lawesson Reagent(101mg,0.248mmol)溶于4mL无水1,4-二氧六环,回流反应16h。薄层色谱检测原料反应完。
将反应液浓缩干,制备板纯化(石油醚:乙酸乙酯:三乙胺=5:4:1),得黄色固体34mg(即化合物BIOS-A-20),收率32.75%。
MS:419.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),7.25(d,J=9.0Hz,2H),7.17(t,J=3.8Hz,1H),6.81(d,J=9.0Hz,2H),4.37~4.32(m,1H),3.69~3.59(m,6H),2.83~2.77(m,1H),2.77~2.66(m,4H),2.59(t,J=5.7Hz,2H),2.52~2.46(m,4H),2.00~1.90(m,4H),1.81~1.49(m,6H).
化合物BIOS-A-3的合成路线与制备步骤,参考实施例3,此处不赘述。
实施例21:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(哌啶-1-基)乙基)硫脲(BIOS-A-21)的制备
合成路线如下:
参考实施例20中化合物BIOS-A-20的合成方法,将本实施例的BIOS-A-4代替实施例20的BIOS-A-3,其余制备步骤同实施例20。得到白色固体47mg(即化合物BIOS-A-21),收率45.49%。
MS:417.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.59(s,1H),7.27(d,J=8.9Hz,2H),6.81(d,J=8.9Hz,2H),6.13(s,1H),4.28~4.18(m,1H),3.25~3.15(m,2H),2.82~2.69(m,1H),2.60(d,J=5.5Hz,2H),2.47~2.36(m,6H),2.08(t,J=5.4Hz,2H),2.02~1.85(m,4H),1.85~1.73(m,2H),1.65~1.50(m,8H),1.45~1.34(m,2H).
化合物BIOS-A-4的合成路线与制备步骤,参考实施例4,此处不赘述。
实施例22:1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(吡咯烷-1-基)乙基)硫脲(BIOS-A-22)的制备
合成路线如下:
参考实施例20中化合物BIOS-A-20的合成方法,将本实施例的BIOS-A-5代替实施例20的BIOS-A-3,其余制备步骤同实施例20。得到白色固体22mg(即化合物BIOS-A-22),收率22.03%。
MS:403.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),7.26(d,J=8.8Hz,2H),6.82(d,J=8.8Hz,2H),6.01(t,J=5.4Hz,1H),4.28~4.16(m,1H),3.21~3.14(m,2H),2.72~2.62(m,1H),2.61~2.52(m,2H),2.50~2.37(m,8H),2.05~1.91(m,4H),1.79~1.48(m,10H).
化合物BIOS-A-5的合成路线与制备步骤,参考实施例5,此处不赘述。
实施例23:(R)-1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(2-甲基吡咯烷-1-基)乙基)硫脲(BIOS-A-23)的制备
合成路线如下:
参考实施例20中化合物BIOS-A-20的合成方法,将本实施例的BIOS-A-6代替实施例20的BIOS-A-3,其余制备步骤同实施例20。得到白色固体15mg(即化合物BIOS-A-23),收率14.52%。
MS:417.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ8.58(s,1H),8.20(s,2H),7.29(d,J=8.6Hz,2H),6.77(d,J=8.6Hz,2H),6.03(s,1H),4.21(s,1H),2.82(d,J=9.3Hz,2H),2.74(t,J=7.8Hz,1H),2.61(s,2H),2.45(s,2H),2.21(d,J=9.0Hz,2H),2.14~2.04(m,2H),2.02~1.86(m,4H),1.85~1.50(m,6H),1.40~1.30(m,1H),1.16~1.03(m,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24:化合物的组胺H3受体拮抗活性
以SUVN-G3031为阳性对照,采用FLIPR测定法(NIH assay guidance manual:HTSAssay Validation-Section 4.3.Analysis(Potency),https://www.ncbi.nlm.nih.gov/books/NBK83783)筛选了所合成的13个目标化合物及1个阳性对照化合物的组胺H3受体拮抗活性,结果见表1。
表1.化合物的组胺H3受体拮抗活性
由表中的受体拮抗活性可知,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5nM时比阳性药SUVN-G3031更佳。
实施例25:化合物的安全性hERG
在心肌细胞中,human Ether-a-go-go Related Gene(hERG)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。hERG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%的先导化合物都显示出不同程度的hERG相关毒性。因此,早期评价化合物对hERG的影响在药物开发过程中至关重要。
在稳定表达hERG离子通道的HEK293细胞株上,通过手动膜片钳技术检测化合物对hERG通道的抑制率,以100nM的hERG抑制剂西沙比利(Cisapride)为对照。
结果如表2所示,化合物BIOS-A-13~BIOS-A-15、BIOS-A-3~BIOS-A-5、BIOS-A-10、BIOS-A-11(10μM)对hERG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
注:“—”表示未测
实施例26:化合物BIOS-A-3的疼痛模型活性数据
SD雄性大鼠,180-200g,右后腿,暴露坐骨神经,在坐骨神经即将分叉的前段,采用无菌铬肠线(4号,直径0.15mm),松结扎4个环,每个环距1-2mm,缝合肌肉和皮肤,建立慢性缩窄性损伤(CCI)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用电子测痛仪(IITC-2391)检测机械刺痛阈值,连续2天。
将机械刺痛阈值稳定的CCI模型大鼠随机分为3组,分别为模型组(model)、普瑞巴林(Pre)组(30mg/kg)、BIOS-A-3组(1mg/kg),按1mL/100g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0.5h、1h、2h、4h、6h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1。
结果表明,对SD大鼠CCI神经病理性疼痛模型,化合物BIOS-A-3(1mg/kg)可显著提高CCI模型大鼠的机械刺痛阈值;并在给药后0.5h、1h、6h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30mg/kg的剂量仅在给药后0.5h、1h提高CCI大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,优于普瑞巴林。并且,随着时间增长,化合物BIOS-A-3在单个时间点上对机械刺痛阈值的效果更优于普瑞巴林。
Claims (11)
1.一种苯基脲类衍生物,为具有如下结构通式Ⅰ的化合物或其药学上可接受的盐:
式中:
X选自O或S;
m选自0、1、2、3、4、5或6;
A选自C1-6烷基、-NR’R”、取代或未取代的5-8元杂环基、取代或未取代的5-8元杂芳基中的一种;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、C2-6烯基、C2-6炔基、卤素、氨基、羟基、氰基、酰胺基、砜基、亚砜基、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烷基砜基、C1-6烷基亚砜基、C1-6卤代烷氧基、C1-6烷氧基羟基、C1-6烷氧基氨基、C1-6烷氧基酰胺基、C1-6烷氧基砜基、C1-6烷氧基亚砜基、3-6元环烷基、3-6元杂环基、芳基、杂芳基;
R’、R”各自独立的选自氢、C1-6烷基、C1-6烷氧基、卤素、氨基、羟基、羧基、羰基、酰胺基、氰基、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、C1-6烷氧基氨基、C1-6烷氧基酰胺基中的一种或几种,且R’、R”不同时为氢;
R1、R2各自独立的选自氢、C1-6烷基、-C(O)-烷基或-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炔基、氨基、羟基、氰基、酰胺基、砜基、亚砜基、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烷基砜基、C1-6烷基亚砜基中的一种或几种;
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但不限于苯并杂环;
或,R5、R6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但不限于苯并杂环;
所述的杂环基、杂芳基、苯并杂环中含有至少一个杂原子,杂原子选自N、O或S。
2.根据权利要求1所述的苯基脲类衍生物,其特征在于,为具有如下结构通式Ⅱ的化合物或其药学上可接受的盐:
式中:
X选自O或S;
m选自0、1、2、3、4、5或6;
A选自取代或未取代的5-8元杂环基、取代或未取代的5-8元杂芳基中的一种;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、C2-6烯基、C2-6炔基、卤素、氨基、羟基、氰基、酰胺基、砜基、亚砜基、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烷基砜基、C1-6烷基亚砜基、C1-6卤代烷氧基、C1-6烷氧基羟基、C1-6烷氧基氨基、C1-6烷氧基酰胺基、C1-6烷氧基砜基、C1-6烷氧基亚砜基、3-6元环烷基、3-6元杂环基、芳基、杂芳基;
R3、R4、R5、R6各自独立的选自氢、卤素、C1-6烷基、C2-6烯基、C2-6炔基、氨基、羟基、氰基、酰胺基、砜基、亚砜基、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烷基砜基、C1-6烷基亚砜基中的一种或几种;
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但不限于苯并杂环;
或,R5、R6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但不限于苯并杂环;
所述的杂环基、杂芳基、苯并杂环中含有至少一个杂原子,杂原子选自N、O或S。
3.根据权利要求2所述的用途,其特征在于,为具有如下结构通式Ⅱ-1的化合物或其药学上可接受的盐:
m选自1、2、3、4、5或6;
A选自取代或未取代的6元杂环基、取代或未取代的6元杂芳基中的一种;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、卤素、氨基、羟基、C1-6卤代烷基、C1-6烷基羟基、C1-6烷基氨基、C1-6卤代烷氧基、C1-6烷氧基羟基、C1-6烷氧基氨基;
R3、R4、R5、R6各自独立的选自氢、卤素、C1-6烷基、氨基、羟基、C1-6卤代烷基、C1-6烷基羟基、C1-6烷基氨基中的一种或几种;
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S。
4.根据权利要求1所述的苯基脲类衍生物,其特征在于,为具有如下结构通式Ⅲ的化合物或其药学上可接受的盐:
式中:
m选自1、2、3、4、5或6;
R’、R”各自独立的选自氢、C1-6烷基、C1-6烷氧基、卤素、氨基、羟基、羧基、羰基、酰胺基、氰基、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、C1-6烷氧基氨基、C1-6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各自独立的选自氢、卤素、C1-6烷基、C2-6烯基、C2-6炔基、氨基、羟基、氰基、酰胺基、砜基、亚砜基、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烷基砜基、C1-6烷基亚砜基中的一种或几种;
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但不限于苯并杂环;
或,R5、R6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但不限于苯并杂环;
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S。
5.根据权利要求1所述的苯基脲类衍生物,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:
式中:
A选自C1-6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炔基、氨基、羟基、氰基、酰胺基、砜基、亚砜基、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烷基砜基、C1-6烷基亚砜基中的一种或几种;
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但不限于苯并杂环;
或,R5、R6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但不限于苯并杂环;
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S。
6.一种苯基脲类衍生物,为具有如下结构的化合物、同分异构体、溶剂化物或其药学上可接受的盐:
1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-环戊基脲;
1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-环己基脲;
1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-吗啉基乙基)脲;
1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(哌啶-1-基)乙基)脲;
1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(吡咯烷-1-基)乙基)脲;
1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(2-甲基吡咯烷-1-基)乙基)脲;
1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(4,4-二氟哌啶-1-基)乙基)脲;
1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(硫代吗啉基乙基)脲;
1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(4-羟基哌啶基-1-基)乙基)脲;
1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(4-甲基哌嗪-1-基)乙基)脲;
1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(4-异丙基哌嗪-1-基)乙基)脲;
1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(3-羟基哌啶-1-基)乙基)脲;
1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(N-甲基高哌嗪-1-基)乙基)脲;
1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(哌嗪-1-基)乙基)脲;
1-(2-(4-环丁基哌嗪-1-基)乙基)-3-(4-((1-环丁基哌啶-4-基)氧基)苯基)脲;
1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-异丙基脲;
1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(二甲氨基)乙基)脲;
1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(二乙氨基)乙基)脲;
1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(乙氨基)乙基)脲;
1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-吗啉乙基)硫脲;
1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(哌啶-1-基)乙基)硫脲;
1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(吡咯烷-1-基)乙基)硫脲;
1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(2-甲基吡咯烷-1-基)乙基)硫脲。
7.一种苯基脲类衍生物,为具有如下结构的化合物或其药学上可接受的盐:
(R)-1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(2-甲基吡咯烷-1-基)乙基)脲;
(R)-1-(4-((1-环丁基哌啶-4-基)氧基)苯基)-3-(2-(2-甲基吡咯烷-1-基)乙基)硫脲。
8.一种药物组合物,包含至少一种如权1~7中任一项所述的活性组分及至少一种药学上可接受的载体或赋形剂。
9.一种制备如权利要求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、进食障碍、疼痛和瘙痒。
11.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。
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