CN1491223A - 可用于治疗精神性和神经性疾病的3-二氢吲哚衍生物 - Google Patents
可用于治疗精神性和神经性疾病的3-二氢吲哚衍生物 Download PDFInfo
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- CN1491223A CN1491223A CNA018227481A CN01822748A CN1491223A CN 1491223 A CN1491223 A CN 1491223A CN A018227481 A CNA018227481 A CN A018227481A CN 01822748 A CN01822748 A CN 01822748A CN 1491223 A CN1491223 A CN 1491223A
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- Prior art keywords
- alkyl
- compound
- cycloalkyl
- ethanoyl
- hydrogen
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- 208000012902 Nervous system disease Diseases 0.000 title abstract description 4
- 208000020016 psychiatric disease Diseases 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 96
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 43
- 239000001257 hydrogen Substances 0.000 claims abstract description 42
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 19
- 239000002253 acid Substances 0.000 claims abstract description 18
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 16
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 16
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 16
- 125000006621 (C3-C8) cycloalkyl-(C1-C6) alkyl group Chemical group 0.000 claims abstract description 15
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 14
- 150000002367 halogens Chemical group 0.000 claims abstract description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 13
- 208000028017 Psychotic disease Diseases 0.000 claims abstract description 12
- 125000002252 acyl group Chemical group 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 10
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims abstract description 9
- 125000003118 aryl group Chemical group 0.000 claims abstract description 9
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims abstract description 8
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims abstract description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 4
- -1 C 1-6Alkyl Chemical group 0.000 claims description 40
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 22
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- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 5
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- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 abstract 1
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- 229910052794 bromium Inorganic materials 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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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
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- 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
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Abstract
本发明涉及具有下面通式的化合物或其药学上可接受的酸加成盐在制备用于治疗精神性和神经性疾病,尤其是精神病的药物中的用途,如式Ⅰ:其中R1为酰基、硫代酰基、三氟甲磺酰基,或者R1为R12SO2-、R12OCO-或R12SCO-基团,其中R12为C1-6烷基、C2-6链烯基、C2-6炔基、C3-8环烷基、C3-8环烷基-C1-6烷基或芳基,或者R1为R13R14NCO-、R13R14NCS-基团,其中R13和R14独立为氢、C1-6烷基、C2-6链烯基、C2-6炔基、C3-8环烷基、C3-8环烷基-C1-6烷基或芳基,或者R13和R14与其所连接的N-原子一起形成吡咯烷基、哌啶基或全氢氮杂基团;n为1-6;X为C、CH或N,当X为C时,由X引出的虚线表示键,当X为N或CH时,该虚线不为键;R’、R”和R2独立选自氢和C1-6烷基;并且R3-R11独立选自氢、卤素、氰基、硝基、C1-6烷基、C2-6链烯基、C2-6炔基、C3-8环烷基、C3-8环烷基-C1-6烷基、氨基、C1-6烷基氨基、二(C1-6烷基)氨基、C1-6烷基羰基、氨基羰基、C1-6烷基氨基羰基、二(C1-6烷基)氨基羰基、C1-6烷氧基、C1-6烷硫基、羟基、三氟甲基、三氟甲磺酰基和C1-6烷基磺酰基。
Description
本发明涉及新的一类对多巴胺D4受体具有亲合性的3-二氢吲哚衍生物。这些化合物可用于治疗某些精神性和神经性疾病,尤其是精神病。所述化合物还对5-HT2A受体具有亲合性。
发明背景
美国专利3,751,417号涉及具有下面通式的1-酰基-3-[2-(4-苯基-1-哌嗪基)乙基]二氢吲哚,
其中R1为氢、氯基、溴基、低级烷氧基、硝基、氨基、乙酰氨基或二甲氨基,R2为氢、低级烷氧基或硝基,或者R1和R2一起为亚甲二氧基,R3为氢或甲基,R4为氢或甲基,R5对苯环单取代,为氢、氯基、甲氧基、甲基或三氟甲基,Y为苯甲酰基、对氯苯甲酰基、对硝基苯甲酰基或低级烷酰基。据称该化合物可用作镇静剂和止痛剂。由临床实践已知,镇静剂和止痛剂通常不适合治疗精神病或焦虑症。
US 3,751,416涉及在二氢吲哚环的1位具有氢的类似化合物。这些化合物也被描述作为镇静剂。
US 5,002,948涉及具有下面通式的化合物,
其中R1为氢、卤素、低级烷基、低级链烯基或三氟甲基,X为CH、CH2、NH或CO,虚线表示任选的键,R2为氢、低级烷基、酰基等,Y为O或S,Y’为H、O、S或CH2,R5为氢、低级烷基或链烯基。据描述,该化合物作为5-HT1A配体可用于治疗焦虑、抑郁、攻击行为、酒精滥用和与心血管、胃肠和肾脏有关的疾病。
US 3,900,563涉及据说可用于治疗精神性疾病的化合物。文中所公开的化合物具有通式
,其中X1为5,6-二甲氧基或5,6-亚甲二氧基,Y1为氢或甲基,Z1氢或甲氧基。该化合物在10mg/kg的剂量时将引起动物强直性昏厥,这表明其具有锥体束外副作用。本发明化合物在20mg/kg的剂量时仍不会引起强直性昏厥。
US 4,302,589涉及具有下面通式的取代的顺式-2-甲基-3-[(哌嗪基)和(哌啶子基)乙基]二氢吲哚,
其中R1为氟基、氯基、三氟甲基或甲氧基,R2为氢、氯基和甲氧基,M和A为碳或氮。这些化合物被描述为抗精神病药。
WO 92/22554涉及某些对σ受体具有亲合性的4-(苯基烷基)哌啶。没有提及对多巴胺D4受体的作用。
多巴胺D4受体属于多巴胺D2受体一族,而这类受体被认为是引起精神抑制药的精神抑制效果的原因。已知主要通过D2受体的拮抗作用发挥作用的精神抑制药的副作用是由于D2受体在纹状体以外的脑区域的拮抗作用。但是,多巴胺D4-受体主要位于纹状体以外的脑区域,这意味着多巴胺D4-受体的拮抗作用将不具有锥体束外副作用。这种例子有安定药氯氮平,它对D4受体产生的亲合性高于D2受体,并且缺乏锥体束外副作用(Van Tol等人,Nature 1991,350,610;Hadley Medicinal Research Reviews 1996,16,507-526页,和Sanner Exp.Opin.Ther.Patents 1998,8,383-393页)。
许多被认为是选择性D4受体拮抗剂(L-745,879和U-101958)的D4配体已被证实具有安定潜力(Mansbach等人,Psychopharmacology1998,135,194-200)。但是,最近报导这些化合物在各种体外效能测定中是部分D4受体激动剂(Gazi等人,Br.J.Pharmacol.1998,124,889-896页和Gazi等人,Br.J.Pharmacol.1999,128,613-620)。另外,已证明一种有效的精神抑制药氯氮平是一种沉默拮抗剂(Gazi等人,Br.J.Pharmacol.1999,128,613-620)。
因此,作为部分D4受体激动剂或拮抗剂的D4配体可能对治疗精神病具有有益的作用。
多巴胺D4拮抗剂可能也可用于治疗认知缺陷症(Jentsch等人,Psychopharmacology 1999,142,78-84页)。
也有人提出多巴胺D4拮抗剂有可能用于减轻由用L-多巴治疗帕金森氏病所导致的运动障碍(Tahar等人,Eur.J.Pharmacol.2000,399,183-186)。
另外,注意缺陷多动症的“主要是注意力不集中(primarilyinattentive)”亚型与编码多巴胺D4受体的基因中的串联重复多态性之间的遗传相关性己被公开(McCracken等人,Mol.Psychiatry 2000,5,531-536页)。这清楚表明多巴胺D4受体和注意缺陷多动症之间的联系,并且影响这种受体的配体可以用于治疗这种特定的疾病。
人们已知作为不同血清素受体亚型上的配体的化合物的各种作用。就5-HT2A受体(以前将其称为5-HT2受体)而言,已报导了下面的作用,如:抗抑郁作用和改善睡眠质量(Meert等人,Drug Dev.Res.1989,18,119),减少精神分裂症的和采用典型的精神抑制药治疗精神分裂症病人时引起的锥体束外副作用的负向症状(Gelders BritishJ.Psychiatry 1989,155(suppl.5),33)。另外,选择性5-HT2A拮抗剂可有效地预防和治疗偏头痛(Scrip Report;"Migraine-Current trends inresearch and treatment";PJB Publications Ltd.;May 1991)和治疗焦虑(Colpart等人,Psychopharmacology 1985,86,303-305页和Perregaard等人,Current Opinion in Therapeutic Patents 1993,1,101-128页)。
一些临床研究暗示了攻击性行为中的5-HT2受体亚型。另外,非典型的血清素-多巴胺拮抗剂精神抑制药除具有多巴胺阻滞特性外,还具有5-HT2受体拮抗作用,并且已报导具有抑制攻击性行为的作用(Connor等人,Exp.Opin.Ther.,Patents 1998,8(4),350-351)。
最近,已积累的事实也支持选择性5-HT2A拮抗剂作为可治疗精神病正向症状的药物的基本原理(Leysen等人,Current PharmaceuticalDesign 1997,3,367-390页和Carlsson Current Opinion in CPNSInvestigational Drugs 2000,2(1),22-24页)。
因此,对多巴胺D4和5-HT2A受体具有联合作用的化合物可能对精神分裂症病人的精神性症状具有进一步的改进效果。
发明简述
本发明的目的是提供可作为多巴胺D4受体的部分激动剂或拮抗剂的化合物,特别是对多巴胺D4受体和5-HT2A受体具有联合作用的化合物。
因此,本发明涉及具有下面通式的化合物或其药学上可接受的酸加成盐在制备用于治疗下述疾病的药物中的用途:精神分裂症的positive和negative症状、其它精神病、焦虑症如泛化性焦虑症、恐慌病和强迫性障碍、抑郁症、攻击行为、由常规抗精神病药引发的副作用、偏头痛、认知紊乱、由用L-多巴治疗引发的运动障碍、注意缺陷多动症以及改善睡眠质量,
其中R1为酰基、硫代酰基、三氟甲磺酰基,或者R1为R12SO2-、R12OCO-或R12SCO-基团,其中R12为C1-6烷基、C2-6链烯基、C2-6炔基、C3-8环烷基、C3-8环烷基-C1-6烷基或芳基,或者R1为R13R14NCO-、R13R14NCS-基团,其中R13和R14独立为氢、C1-6烷基、C2-6链烯基、C2-6炔基、C3-8环烷基、C3-8环烷基-C1-6烷基或芳基,或者R13和R14与其所连接的N-原子一起形成吡咯烷基、哌啶基或全氢氮杂基团;
n为1-6;
X为C、CH或N,当X为C时,由X引出的虚线表示键,当X为N或CH时,该虚线不为键;
R’、R”和R2独立选自氢和任选被卤原子取代的C1-6烷基;并且
R3-R11独立选自氢、卤素、氰基、硝基、C1-6烷基、C2-6链烯基、C2-6炔基、C3-8环烷基、C3-8环烷基-C1-6烷基、氨基、C1-6烷基氨基、二(C1-6烷基)氨基、C1-6烷基羰基、氨基羰基、C1-6烷基氨基羰基、二(C1-6烷基)氨基羰基、C1-6烷氧基、C1-6烷硫基、羟基、三氟甲基、三氟甲磺酰基和C1-6烷基磺酰基。
本发明还涉及如上定义的式(I)化合物或其药学上空的接受的酸加成盐,条件是:
(i)当R’、R”、R2-R8、R10-R11为氢,n为2并且R1为乙酰基时,R9可不为氢;
(ii)当R’、R”、R2-R8、R10-R11为氢,X为C或CH,n为2并且R1为乙酰基时,R9可不为CF3或氯基;
(iii)当X为N,n为2或4并且R1为乙酰基时,R7或R11可不为甲氧基;以及
(iv)R4可不为甲氧基。
根据优选实施方案,本发明涉及式(I)化合物的S-对映异构体及其用途。
根据另一实施方案,本发明涉及其中R7和R11为氢的式(I)化合物及其用途。在一个优选实施方案中,本发明涉及其中R10也为氢的这类式(I)化合物及其用途。
另一组优选的化合物是其中X为CH并且虚线为键的化合物。
在一个特别优选的实施方案中,本发明涉及其中R8和R9至少一个为选自卤素、氰基、硝基、C1-6烷基、C2-6链烯基、C2-6炔基、C3-8环烷基、C3-8环烷基-C1-6烷基、氨基、C1-6烷基氨基、二(C1-6烷基)氨基、C1-6烷基羰基、氨基羰基、C1-6烷基氨基羰基、二(C1-6烷基)氨基羰基、C1-6烷氧基、C1-6烷硫基、羟基、三氟甲基、三氟甲磺酰基和C1-6烷基磺酰基的化合物。
特别是R8和R9相同,或者R8为氢,R9如上定义。尤其是R8和R9相同并选自卤素或烷基,特别是甲基。
根据更具体的实施方案,本发明涉及其中n为2或3,优选2的这类式(I)化合物和其中R1为酰基,特别是乙酰基的化合物及其用途。
当R’、R”和R2为C1-6烷基时,优选它们为甲基。
R4优选为氢或卤素,特别是氟基。
在另一个实施方案中,本发明涉及其中R’、R”、R2、R3、R5和R6为氢的上述式(I)化合物。
本发明化合物为多巴胺D4受体的部分激动剂或拮抗剂。所述化合物还对5-HT2A受体具有亲合性。
因此,认为本发明化合物可用于治疗精神分裂症的positive和negative症状、其它精神病、焦虑症如泛化性焦虑症、恐慌病和强迫性障碍、抑郁症、攻击行为、由常规抗精神病药引发的副作用、由用L-多巴治疗引发的运动障碍、偏头痛、认知紊乱、注意缺陷多动症以及改善睡眠质量。
具体而言,认为本发明化合物可用于治疗精神分裂症的positive和negative症状,而不会引起锥体束外副作用。
另一方面,本发明提供了一种药用组合物,该组合物包含至少一种治疗有效量的如上定义的式I化合物或其药学上可接受的酸加成盐,并结合一种或多种药学上可接受的载体或稀释剂。
另一方面,本发明提供一种治疗精神分裂症的positive和negative症状、其它精神病、焦虑症如泛化性焦虑症、恐慌病和强迫性障碍、抑郁症、攻击行为、由常规抗精神病药引发的副作用、偏头痛、认知紊乱、由用L-多巴治疗引发的运动障碍、注意缺陷多动症以及改善睡眠质量的方法,该方法包括给予治疗上可接受量的上述式(I)化合物。
发明详述
通式I化合物可以其旋光异构体的形式存在,这些旋光异构体及其混合物也包括在本发明中。
术语C1-6-烷基是指具有1-6个碳原子(包括1和6)的支化或非支化烷基,如甲基、乙基、1-丙基、2-丙基、1-丁基、2-丁基、2-甲基-2-丙基和2-甲基-1-丙基。
同样,C2-6-链烯基和C2-6-炔基各自指具有2-6个碳原子、分别包括一个双键和一个三键的基团,如乙烯基、丙烯基、丁烯基、乙炔基、丙炔基和丁炔基。
术语C1-6-烷氧基、C1-6-烷硫基、C1-6-烷基磺酰基、C1-6-烷基氨基、C1-6-烷基羰基等指其中烷基为上面定义的C1-6烷基的基团。
术语C3-8-环烷基指具有3-8个碳原子的单环或双环碳环,如环丙基、环戊基、环己基等。
卤素指氟基、氯基、溴基或碘基。
此处所用术语酰基指甲酰基、C1-6-烷基羰基、芳基羰基、芳基-C1-6-烷基羰基、C3-8-环烷基羰基或C3-8-环烷基-C1-6-烷基-羰基,术语硫代酰基为其中羰基被硫代羰基代替的对应酰基。在术语C3-8-环烷基-C1-6-烷基中,C3-8-烷基和C1-6-烷基如上定义。
术语芳基指碳环芳族基团,如苯基或萘基,尤其是苯基,它们可任选被C1-6-烷基取代。
本发明化合物的酸加成盐为与非毒性酸形成的药学上可接受的盐。这些有机酸加成盐的例子为与下面酸形成的盐:马来酸、富马酸、苯甲酸、抗坏血酸、琥珀酸、草酸、双亚甲基水杨酸、甲磺酸、乙二磺酸、乙酸、丙酸、酒石酸、水杨酸、柠檬酸、葡糖酸、乳酸、苹果酸、苦杏仁酸、肉桂酸、柠康酸、天冬氨酸、硬脂酸、棕榈酸、衣康酸、乙醇酸、对氨基苯甲酸、谷氨酸、苯磺酸和茶叶碱乙酸以及8-卤代茶叶碱,例如8-溴茶叶碱。这些无机酸加成盐的例子为与盐酸、氢溴酸、硫酸、氨基磺酸、磷酸和硝酸所形成的盐。
本发明药用组合物或那些根据本发明制备的组合物可以通过合适的方式进行给药,例如以片剂、胶囊剂、粉剂、糖浆剂等形式口服给药,或者以注射用溶液的形式经胃肠外给药。对于制备这些组合物而言,可以采用本领域众所周知的方法,并且可以使用任何药学上可接受的载体、稀释剂、赋形剂或本领域常用的其它添加剂。
将本发明化合物适合于以含0.01-100mg所述化合物的单元剂型进行给药。
通常总的日剂量范围为0.05-500mg的本发明活性化合物,最优选为0.1-50mg的本发明活性化合物。
本发明化合物可以按以下方法制备:
1)用式II的烷基化衍生物对式III的哌嗪、哌啶或四氢吡啶进行烷基化:
其中R’、R”、R1-R11、X、n和虚线如前面所定义,L为离去基团,如卤素、甲磺酸根或甲苯磺酸根;
2)用式IV试剂对式III胺进行还原烷基化:
其中R’、R”、R1-R11、X、n和虚线如前面所定义,E为醛或活化羧酸;
3)还原下式V衍生物中四氢吡啶基环中的双键:
其中R’、R”、R1-R11和n如前面所定义;或者
4)使用羧酸和偶联剂、活化酯、酰氯、异氰酸酯或者通过用光气处理随后加入胺的两步法来酰化式VI的胺:
其中R’、R”、R2-R11、X、n和虚线如前面所定义;由此分离出式I化合物的游离碱或其药学上可接受酸的加成盐。
方法1)的烷基化可方便地在惰性有机溶剂如合适沸点的醇或酮中,优选在有机或无机碱(碳酸钾、二异丙基乙胺或三乙胺)的存在下,在回流温度下实施。或者,在不同于沸点的固定温度下,在一种上述溶剂中或在二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)或N-甲基吡咯烷-2-酮(NMP)中,优选在碱的存在下实施所述烷基化。式II衍生物的烷基化在文献(WO 98/28293)中有描述,式III的胺可通过市场购得或者在文献中有描述。
方法2)的还原烷基化可通过标准文献方法实施。所述反应可以两步法实施,例如用式IV试剂通过标准方法经由酰氯、活化酯或者通过使用羧酸并结合偶联剂如二环己基碳二亚胺对式III胺进行偶合,随后用氢化铝锂或铝烷还原所得的酰胺。通过用标准方法还原相应的吲哚羧酸可以制备式IV的羧酸(参见例如WO 98/28293)。
通常通过在低压(<3个大气压)、帕尔仪器中催化氢化,或者使用还原剂如乙硼烷或NaBH4的三氟乙酸溶液在惰性溶剂如四氢呋喃(THF)、二噁烷或乙醚中原地生成的硼氢衍生物来实施方法3)的双键还原。
方法4)的酰化可方便地通过标准方法经由酰氯、活化酯,或者使用羧酸并结合偶联剂如二环己基碳二亚胺来实施。当酰化剂为氨基甲酰氯或异氰酸酯时,所述酰化生成脲衍生物。脲衍生物也可以采用包括用光气处理,随后加入胺的两步法进行制备。
式VI的中间体化合物通过方法1)和2)所述方法制备。
实验部分
在Büchi SMP-20仪器上测量熔点,所测数据未加校正。在配备有离子喷射源和Shimadzu LC-8A/SLC-10A LC系统的PE Sciex API150EX仪器上得到分析LC-MS数据。LC条件(C18柱,4.6×30mm,粒径3.5μm)为在4分钟内以2mL/分钟的流速用水/乙腈/三氟乙酸(90∶10∶0.05)-水/乙腈/三氟乙酸(10∶90∶0.03)进行的线性梯度洗脱。由UV迹线(254nm)的积分确定纯度。保留时间Rt以分钟计。
通过交替扫描方法得到质谱以获取分子量信息。在低锐孔电压(orifice voltage)(5-20V)得到分子离子MH+,在高锐孔电压(100-200V)得到碎片。
在相同的仪器上进行制备LC-MS-分离。所述LC条件(C18柱,20×50mm,粒径5μm)为在7分钟内以22.7mL/分钟的流速用水/乙腈/三氟乙酸(80∶20∶0.05)-水/乙腈/三氟乙酸(5∶95∶0.03)进行的线性梯度洗脱。通过分流(split-flow)MS检测进行分步收集。
在Bruker Avance DRX500仪器、500.13MHz下或在Bruker AC250仪器、250.13MHz下记录1H NMR波谱。使用氘代氯仿(99.8%D)或二甲基亚砜(99.9%D)作为溶剂。用TMS作为内标。化学位移值以ppm值表示。使用下述缩写表示多种NMR信号:s=单峰,d=双重峰,t=三重峰,q=四重峰,qui=五重峰,h=七重峰,dd=双双重峰,dt=双三重峰,dq=双四重峰,tt=三三重峰,m=多重峰。通常省略对应于酸性质子的NMR信号。通过Karl Fischer滴定确定结晶化合物中水的含量。对于柱层析来说,使用Kieselgel 60型、230-400目ASTM硅胶。对于离子交换色谱来说,使用1g SCX,Varian Mega Bond Elut,220776号Chrompack催化剂。使用前用10%乙酸的甲醇(3mL)溶液对SCX-柱进行预调节。
实施例
中间体的制备
A.胺
4-(3,4-二氯苯基)-3,6-二氢-2H-吡啶
将丁基锂(1.6M己烷溶液,45mL)和四氢呋喃(40mL)的混合物冷却至-65-75℃,随后加入到4-溴-1,2-二氯苯(15g)的四氢呋喃(25mL)溶液中。将所得混合物在-65-75℃搅拌1小时,然后加入4-氧代-哌啶-1-甲酸乙酯(11.5g)。将所得混合物在-65-75℃搅拌1小时,然后再于室温下搅拌3小时。随后通过加入饱和氯化铵水溶液猝灭反应,并用乙酸乙酯萃取水相。将合并的有机萃取液干燥(MgSO4),过滤,真空浓缩,得到4-(3,4-二氯苯基)-4-羟基哌啶-1-甲酸乙酯(12.6g)。将残余物溶于三氟乙酸(100mL)中,并在室温下搅拌16小时。真空除去溶剂,将残余物溶于4M氢氧化钠和乙醇的混合物中,随后回流沸腾48小时。用乙酸乙酯萃取混合物,将合并的有机萃取液干燥(MgSO4),过滤,真空浓缩。将残余物通过快速硅胶层析(洗脱液:乙酸乙酯/4M氨的甲醇溶液1∶1)提纯,得到标题化合物(4.7g)。
4-(3,4-二氯苯基)哌啶
在室温下将4-(3,4-二氯苯基)-4-羟基哌啶-1-甲酸乙酯(6.0g)、三氟乙酸(50mL)和三乙基硅烷(10mL)搅拌16小时。向混合物中加入水和乙酸乙酯,分离各相。用乙酸乙酯萃取水相两次,并将合并的有机萃取液干燥(MgSO4),过滤,真空浓缩(5.8g)。将残余物溶于4M氢氧化钠和乙醇的混合物中,随后回流沸腾24小时。用乙酸乙酯萃取混合物,将合并的有机萃取液干燥(MgSO4),过滤,真空浓缩。将残余物通过快速硅胶层析(洗脱液:乙酸乙酯/4M氨的甲醇溶液1∶1)提纯,得到标题化合物(1.8g)。
本发明化合物的制备
实施例1
1a,(+)-1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]-4-(3,4-二甲基苯
基)哌嗪,盐酸盐
将1-(3,4-二甲基苯基)哌嗪(1.15g)、(+)-1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]溴(WO 98/28293中制备)(1.3g)和碳酸钾(0.7g)在乙腈(20mL)中的混合物加热至85℃下6小时。将混合物冷却至室温,加入硅胶(7g),真空蒸发该混合物,得到白色粉末。将产物通过快速硅胶层析提纯,用乙酸乙酯/三乙胺(99∶1)作洗脱液。收集含产物的流分,真空蒸发。将该产物溶于四氢呋喃中,并添加HCl的乙醚(1.4g)溶液将其转化成盐酸盐。Mp238-240℃.1H NMR(DMSO-d6):2.00-2.08(m,1H);2.15(s,3H),2.20(s,6H),2.30(m,1H),3.10-3.30(m,7H),3.55(m,1H),3.60(m,2H),3.75(m,2H),3.85(m,1H),4.25(m,1H),6.75(d,1H),6.83(s,1H),7.0(t,2H),7.20(t,1H),7.30(d,1H),8.05(d,1H).MS m/z:404(MH+),378.1.以类似方式制备下列化合物:1b,(+)-1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]-4-(4-甲基苯基)哌 嗪,盐酸盐,由4-(4-甲基苯基)哌嗪和(+)-1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]溴制备。
Mp 217-220℃.1H NMR(DMSO-d6):2.00-2.08(m,1H);2.17(s,3H),2.23(s,3H),2.30(m,1H),3.10-3.30(m,7H),3.55(m,1H),3.60(m,2H),3.75(m,2H),3.85(m,1H),4.25(m,1H),6.90(d,2H),7.05(m,3H),7.20(t,1H),7.30(d,1H),8.05(d,1H).MS m/z:404(MH+),364.0.1c,(+)-1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]-4-(4-甲基苯基)哌 啶,由4-(4-甲基苯基)哌啶和(+)-1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]溴制备。Mp 112-114℃.1H NMR(DMSO-d6):1.60-1.80(m,5H);2.00(t,3H),2.17(s,3H),2.23(s,3H),2.40(m,3H),3.00(m,2H),3.45(m,1H),3.60(m,2H),3.80(m,1H),4.20(m,1H),7.00(t,1H),7.10(m,4H),7.20(t,1H),7.30(d,1H),8.05(d,1H).MS m/z:404(MH+),364.1.1d,(+)-1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]-4-(3,4-二氯苯基) 哌嗪,盐酸盐,由4-(3,4-二氯苯基)哌嗪和(+)-1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]溴制备。
Mp 184-186℃.1H NMR(DMSO-d6):2.00-2.08(m,1H);2.15(s,3H),2.30(m,1H),3.10-3.30(m,7H),3.55(m,1H),3.60(m,2H),3.75(m,2H),3.85(m,1H),4.25(m,1H),7.0(m,2H),7.20(t,1H),7.25(m,1H),7.30(d,1H),7.43(d,1H),8.05(d,1H).MS m/z:404(MH+),417.9.1e,(+)-1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]-4-(4-溴苯基)哌嗪, 盐酸盐,由4-(4-溴苯基)哌嗪,盐酸盐和(+)-1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]溴制备。
1H NMR(DMSO-d6):2.00-2.08(m,1H);2.17(s,3H),230(m,1H),3.10-3.30(m,4H),3.55(m,1H),3.60(m,2H),3.70-4.00(m,6H),4.25(m,1H),6.90(d,2H),7.05(t,1H),7.20(t,1H),7.30(d,1H),7.48(d,2H),8.05(d,1H).MS m/z:404(MH+),427.9.1f,1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]-4-(3,4-二氯苯基)-3,6- 二氢-2H-吡啶,盐酸盐,
由4-(3,4-二氯苯基)-3,6-二氢-2H-吡啶和(+)-1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]溴制备。
1H NMR(DMSO-d6):1.95-2.10(m,1H);2.20(s,3H);2.25-2.35(m,1H);2.70-2.80(m,1H);2.80-2.95(m,1H);3.15-3.30(m,3H);3.45-3.55(m,1H);3.60-3.75(m,1H);3.75-3.85(m,1H);3.85-3.90(m,1H);3.95-4.05(m,1H);4.25(t,1H);6.35(s,1H);7.05(t,1H);7.20(t,1H);7.35(d,1H);7.50(d,1H);7.65(d,1H);7.75(s,1H);8.05(d,1H).MS m/z:415(MH+).1g,1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]-4-(3,4-二氯苯基)哌啶, 盐酸盐,
由4-(3,4-二氯苯基)哌啶和(+)-1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]溴制备。
1H NMR(DMSO-d6):1.95-2.35(m,6H);2.20(s,3H);2.80-2.95(m,1H);2.95-3.25(m,4H);3.50(broad s,1H);3.60(d,2H);3.80-3.90(m,1H);4.25(t,1H);7.05(t,1H);7.20(t,1H);7.25(d,1H);7.30(d,1H);7.50(s,1H);7.60(d,1H);8.05(d,1H).MS m/z:417(MH+).
药理测试
以众所周知的可靠的试验来测试本发明的化合物。所述测试如下:
对[3H]YM-09151-2与D4.2受体结合的抑制作用
通过该方法,在体外测试药物对[3H]YM-09151-2(0.06nM)与CHO-细胞中表达的人克隆多巴胺D4.2受体膜结合的抑制作用。所述方法为NEN Life Science Products,Inc.,technical date certificatePC2533-10/96的改进方法。
对[3H]Ketanserin与5-HT2A受体结合的抑制作用
通过体外测定化合物对[3H]Ketanserin(0.50nM)与大鼠脑(皮层)膜的结合的抑制能力,对所述化合物与5-HT2A受体的亲合性进行测试。方法描述于Sánchez等DrugDev.Res.1991,22,239-250页。下表1中给出了测试结果:
化合物 | 在D4-受体上的IC50(nM)或%抑制 | 在5HT2A-受体上的IC50(nM)或%抑制 |
1a | <50/88 | 5.0 |
1b | <50/88 | 15. |
1c | <50/76 | 17. |
1d | <50/86 | 21. |
1e | <50/95 | 17. |
1f | 13 | 27 |
1g | 5.4 | 21 |
表1:结合数据(在50nM下结合的%抑制)。
已发现本发明化合物可有效抑制含氚YM-09151-2与多巴胺D4受体的结合。而且,所述化合物可与5-HT2A受体有效地结合。
也根据Gazi等人在Br.J.Pharmacol.1999,128,613-629页所述的功能测试,对所述化合物进行了测试。在该测试中,所述化合物显示出是在多巴胺D4受体上的部份激动剂或拮抗剂。
还对本发明化合物进行了下面的测试:
对[3H]螺哌隆与大鼠多巴胺D2受体结合的抑制作用
根据Hyttel等人在J Neurochem.1985,44,1615页的方法,通过测定化合物对[3H]螺哌隆与D2受体结合的抑制来测试其对多巴胺D2受体的亲合性。
发现所述化合物对多巴胺D2受体基本上没有或只有微弱的亲和性。
含有四氢吡啶环的本发明化合物,即其中X为CH并且虚线表示键的化合物具有特别优良的药动学特性。
因此,本发明化合物被认为可用于治疗精神分裂症的positive和negative症状、其它精神病、焦虑症如泛化性焦虑症、恐慌病和强迫性障碍、抑郁、由常规抗精神病药引发的副作用、偏头痛、由用L-多巴治疗引发的运动障碍、注意缺陷多动症以及可改善睡眠质量。本发明化合物尤其适于治疗精神分裂症的positive和negative症状,而不会引起锥体束外副作用。
制剂实施例
本发明的药学制剂可根据本领域的常规方法制备。
例如:可以通过混合活性成分与普通辅料和/或稀释剂,随后在常规压片机上压制混合物来制备片剂。辅料或稀释剂的例子包括:玉米淀粉、马铃薯淀粉、滑石、硬脂酸镁、明胶、乳糖、树胶等。可以使用通常用于该目的的任何其它辅料或添加剂如着色剂、调味剂、防腐剂等,条件是它们与活性成分相容。
可以通过下面方法制备注射用溶液:将活性成分和可行的添加剂溶解于部分注射用溶剂中,优选溶解于无菌水中,调节所述溶液至所需体积,对所述溶液进行灭菌,将其装入合适的安瓿或小瓶中。可以加入常规用于本领域的任何合适添加剂如张度剂、防腐剂、抗氧化剂等。
本发明制剂的典型处方实施例如下所示:
1)片剂,含有5.0mg以游离碱计算的本发明化合物:
化合物 5.0mg
乳糖 60mg
玉米淀粉 30mg
羟丙基纤维素 2.4mg
微晶纤维素 19.2mg
交联羧甲基纤维素钠A型 2.4mg
硬脂酸镁 0.84mg
2)片剂,含有0.5mg以游离碱计算的本发明化合物:
化合物 0.5mg
乳糖 46.9mg
玉米淀粉 23.5mg
聚维酮 1.8mg
微晶纤维素 14.4mg
交联羧甲基纤维素钠A型 1.8mg
硬脂酸镁 0.63mg
3)糖浆,每毫升含有:
化合物 25mg
山梨醇 500mg
羟丙基纤维素 15mg
甘油 50mg
对羟基苯甲酸甲酯 1mg
对羟基苯甲酸丙酯 0.1mg
乙醇 0.005ml
调味剂 0.05mg
糖精钠 0.5mg
水 加至1ml
4)注射用溶液,每毫升含有:
化合物 0.5mg
山梨醇 5.1mg
乙酸 0.05mg
糖精钠 0.5mg
水 加至1ml。
Claims (24)
1.具有下面通式的化合物或其药学上可接受的酸加成盐在制备用于治疗下述疾病的药物中的用途:精神分裂症的positive和negative症状、其它精神病、焦虑症如泛化性焦虑症、恐慌病和强迫性障碍、抑郁症、攻击行为、由常规抗精神病药引发的副作用、偏头痛、认知紊乱、由用L-多巴治疗引发的运动障碍、注意缺陷多动症以及改善睡眠质量,
其中R1为酰基、硫代酰基、三氟甲磺酰基,或者R1为R12SO2-、R12OCO-或R12SCO-基团,其中R12为C1-6烷基、C2-6链烯基、C2-6炔基、C3-8环烷基、C3-8环烷基-C1-6烷基或芳基,或者R1为R13R14NCO-、R13R14NCS-基团,其中R13和R14独立为氢、C1-6烷基、C2-6链烯基、C2-6炔基、C3-8环烷基、C3-8环烷基-C1-6烷基或芳基,或者R13和R14与其所连接的N-原子一起形成吡咯烷基、哌啶基或全氢氮杂基团;
n为1-6;
X为C、CH或N,当X为C时,由X引出的虚线表示键,当X为N或CH时,该虚线不为键;
R’、R”和R2独立选自氢和任选被卤素取代的C1-6烷基;并且
R3-R11独立选自氢、卤素、氰基、硝基、C1-6烷基、C2-6链烯基、C2-6炔基、C3-8环烷基、C3-8环烷基-C1-6烷基、氨基、C1-6烷基氨基、二(C1-6烷基)氨基、C1-6烷基羰基、氨基羰基、C1-6烷基氨基羰基、二(C1-6烷基)氨基羰基、C1-6烷氧基、C1-6烷硫基、羟基、三氟甲基、三氟甲磺酰基和C1-6烷基磺酰基。
2.权利要求1的化合物用途,该化合物为S-对映异构体形式。
3.权利要求1-2的化合物用途,其中R7和R11为氢。
4.权利要求3的化合物用途,其中R10为氢。
5.权利要求1-4中任一项的化合物,其中X为CH,虚线表示键。
6.权利要求1-4的化合物用途,其中R8和R9至少一个独立选自卤素、氰基、硝基、C1-6烷基、C2-6链烯基、C2-6炔基、C3-8环烷基、C3-8环烷基-C1-6烷基、氨基、C1-6烷基氨基、二(C1-6烷基)氨基、C1-6烷基羰基、氨基羰基、C1-6烷基氨基羰基、二(C1-6烷基)氨基羰基、C1-6烷氧基、C1-6烷硫基、羟基、三氟甲基、三氟甲磺酰基和C1-6烷基磺酰基。
7.权利要求1-6的化合物用途,其中n为2或3,优选2。
8.权利要求1-7的化合物用途,其中R1为酰基。
9.权利要求8的化合物用途,其中R1为乙酰基。
10.权利要求1-9的用途,其中R4为氢或氟基。
11.权利要求1的化合物用途,其中所述化合物选自:
(+)-1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]-4-(3,4-二甲基苯基)哌嗪、
(+)-1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]-4-(4-甲基苯基)哌嗪、
(+)-1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]-4-(4-甲基苯基)哌啶、
(+)-1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]-4-(3,4-二氯苯基)哌嗪、
(+)-1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]-4-(4-溴苯基)哌嗪、
1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]-4-(3,4-二氯苯基)-3,6-二氢-2H-吡啶,和
1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]-4-(3,4-二氯苯基)哌啶,
或其药学上可接受的盐。
12.一种具有下面通式的3-二氢吲哚衍生物或其药学上可接受的酸加成盐,
其中R1为酰基、硫代酰基、三氟甲磺酰基,或者R1为R12SO2-、R12OCO-或R12SCO-基团,其中R12为C1-6烷基、C2-6链烯基、C2-6炔基、C3-8环烷基、C3-8环烷基-C1-6烷基或芳基,或者R1为R13R14NCO-、R13R14NCS-基团,其中R13和R14独立为氢、C1-6烷基、C2-6链烯基、C2-6炔基、C3-8环烷基、C3-8环烷基-C1-6烷基或芳基,或者R13和R14与其所连接的N-原子一起形成吡咯烷基、哌啶基或全氢氮杂基团;并且
n为1-6;
X为C、CH或N,当X为C时,由X引出的虚线表示键,当X为N或CH时,该虚线不为键;
R’、R”和R2独立选自氢和任选被卤素取代的C1-6烷基;
R3-R11独立选自氢、卤素、氰基、硝基、C1-6烷基、C2-6链烯基、C2-6炔基、C3-8环烷基、C3-8环烷基-C1-6烷基、氨基、C1-6烷基氨基、二(C1-6烷基)氨基、C1-6烷基羰基、氨基羰基、C1-6烷基氨基羰基、二(C1-6烷基)氨基羰基、C1-6烷氧基、C1-6烷硫基、羟基、三氟甲基、三氟甲磺酰基和C1-6烷基磺酰基;条件是
(i)当R’、R”、R2-R8、R10-R11为氢,n为2并且R1为乙酰基时,R9可不为氢;
(ii)当R’、R”、R2-R8、R10-R11为氢,X为C或CH,n为2并且R1为乙酰基时,R9可不为CF3或氯基;
(iii)当X为N,n为2或4并且R1为乙酰基时,R7或R11可不为甲氧基;以及
(iv)R4可不为甲氧基。
13.权利要求12的化合物,该化合物为S-对映异构体形式。
14.权利要求12-13的化合物,其中R7和R11为氢。
15.权利要求14的化合物,其中R10为氢。
16.权利要求12-15中任一项的化合物,其中X为CH,虚线表示键。
17.权利要求12-16的化合物,其中R8和R9至少一个选自卤素、氰基、硝基、C1-6烷基、C2-6链烯基、C2-6炔基、C3-8环烷基、C3-8环烷基-C1-6烷基、氨基、C1-6烷基氨基、二(C1-6烷基)氨基、C1-6烷基羰基、C1-6烷氧基、C1-6烷硫基、羟基、三氟甲基、三氟甲磺酰基和C1-6烷基磺酰基。
18.权利要求12-17的化合物,其中n为2或3,优选2。
19.权利要求12-18的化合物,其中R1为酰基。
20.权利要求19的化合物,其中R1为乙酰基。
21.权利要求12-20的化合物,其中R4为氢或氟,并且R’、R”、R2、R3、R5和R6为氢。
22.权利要求12的化合物,所述化合物选自:
(+)-1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]-4-(3,4-二甲基苯基)哌嗪、
(+)-1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]-4-(4-甲基苯基)哌嗪、
(+)-1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]-4-(4-甲基苯基)哌啶、
(+)-1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]-4-(3,4-二氯苯基)哌嗪、
(+)-1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]-4-(4-溴苯基)哌嗪、
1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]-4-(3,4-二氯苯基)-3,6-二氢-2H-吡啶、和
1-[2-(1-乙酰基-2,3-二氢-1H-吲哚-3-基)乙基]-4-(3,4-二氯苯基)哌啶
或其药学上可接受的盐。
23.一种药物组合物,其特征在于该组合物包含治疗有效量的权利要求12-22中任一项的化合物和一种或多种药学上可接受的载体或稀释剂。
24.一种治疗精神分裂症的positive和negative症状、其它精神病、焦虑症如泛化性焦虑症、恐慌病和强迫性障碍、抑郁症、攻击行为、由常规抗精神病药引发的副作用、偏头痛、认知紊乱、由用L-多巴治疗引发的运动障碍、注意缺陷多动症以及改善睡眠质量的方法,该方法包括给予治疗上可接受的量的权利要求12-22中任一项的化合物。
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