CN101310724A - 腺苷A2a受体拮抗剂的应用 - Google Patents
腺苷A2a受体拮抗剂的应用 Download PDFInfo
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- CN101310724A CN101310724A CNA2008101361548A CN200810136154A CN101310724A CN 101310724 A CN101310724 A CN 101310724A CN A2008101361548 A CNA2008101361548 A CN A2008101361548A CN 200810136154 A CN200810136154 A CN 200810136154A CN 101310724 A CN101310724 A CN 101310724A
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- China
- Prior art keywords
- alkyl
- adenosine
- receptor antagonist
- alkoxyl
- treatment
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 title claims description 162
- 239000002126 C01EB10 - Adenosine Substances 0.000 title claims description 81
- 229960005305 adenosine Drugs 0.000 title claims description 81
- 239000002464 receptor antagonist Substances 0.000 title claims description 68
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- 238000011282 treatment Methods 0.000 claims abstract description 54
- 208000027776 Extrapyramidal disease Diseases 0.000 claims abstract description 40
- 208000014094 Dystonic disease Diseases 0.000 claims abstract description 30
- 208000010118 dystonia Diseases 0.000 claims abstract description 30
- 208000005793 Restless legs syndrome Diseases 0.000 claims abstract description 26
- 230000002265 prevention Effects 0.000 claims abstract description 15
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- 150000001875 compounds Chemical group 0.000 claims description 58
- 229940079593 drug Drugs 0.000 claims description 36
- -1 opioid drug Substances 0.000 claims description 34
- 239000008194 pharmaceutical composition Substances 0.000 claims description 32
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- 238000002360 preparation method Methods 0.000 claims description 24
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- 239000003029 tricyclic antidepressant agent Substances 0.000 claims description 21
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 17
- 229960001078 lithium Drugs 0.000 claims description 17
- 229910052744 lithium Inorganic materials 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 15
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- ZPUCINDJVBIVPJ-LJISPDSOSA-N ***e Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 claims description 8
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- IVTMXOXVAHXCHI-YXLMWLKOSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid;(2s)-3-(3,4-dihydroxyphenyl)-2-hydrazinyl-2-methylpropanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1.NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 IVTMXOXVAHXCHI-YXLMWLKOSA-N 0.000 claims description 5
- BNQDCRGUHNALGH-UHFFFAOYSA-N benserazide Chemical compound OCC(N)C(=O)NNCC1=CC=C(O)C(O)=C1O BNQDCRGUHNALGH-UHFFFAOYSA-N 0.000 claims description 5
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Abstract
本发明公开了用于预防或治疗锥体外综合征(EPS)、张力失常、下肢不宁综合征(RLS)或睡眠中周期性腿动(PLMS)的方法,包括单独施用腺苷A2a受体拮抗剂或者与可用于治疗EPS、张力失常、RLS或PLMS的其它药物联合施用腺苷A2a受体拮抗剂。
Description
本申请为中国发明专利申请200380107087.2(以2003年12月17日为申请日,以“腺苷A2a受体拮抗剂的应用”为发明名称,是PCT国际专利申请PCT/US2003/040456进入中国国家阶段的申请)的分案申请。
技术领域
本发明涉及腺苷A2a受体拮抗剂在治疗以下病症中的应用:在急性及长期使用几乎所有抗精神病药物后发生的,涉及锥体外运动***的多种神经综合征(即锥体外综合征)。本发明还涉及腺苷A2a受体拮抗剂在治疗其他异常运动障碍例如下肢不宁综合征(RLS)和睡眠中周期性腿动(PLMS)方面的应用。
背景技术
锥体外综合征(EPS)为一系列与使用抗精神病药物有关的不利神经反应的通称。有6类不同的EPS-有关神经综合征,其中4种,即张力失常、静坐不能、假性帕金森病(帕金森综合征)及延发性运动障碍在服用抗精神病药物治疗的患者中特别普遍。张力失常是肌肉群,特别是颈部、下颚、背部、咽头及喉头的疼痛痉挛。其最常见于用抗精神病药物治疗的年轻男性,但是也可与使用***、三环类抗抑郁剂、锂和抗惊厥剂例如苯英妥和卡马西平有关。假性帕金森病自身表现为运动不能(强直、僵硬和缓慢随意运动、驼背、曳步行走)和颤抖以及在疗法开始后数周或数月内发生的这些症状。静坐不能自身表现为特制是运动多动的强的、主观内感觉的苦恼或不舒服。常误解为激动或焦虑,此常见的综合征常不能诊断并且对治疗有最小的反应。延发性运动障碍为后期出现的与长期使用精神安定药物有关的综合征。其更常发生于年长患者,并且特性是脸部、眼睑、口部、舌头、四肢和躯体的刻板、反复、不随意、快速的舞蹈症样运动。
EPS在使用典型抗精神病药物时更为盛行,但也曾报导在使用非典型药物时发生。典型抗精神病药物包括洛沙平、氟哌啶醇、氯丙嗪、丙氯拉嗪和替沃噻吨。非典型抗精神病药物包括氯氮平、奥氮平、洛沙平、喹硫平、齐拉西酮和利培酮。
静坐不能也是RLS和PLMS以及PLMD(周期性腿(或肢体)运动障碍)的特征。RLS为一般障碍,其导致患者对于移动其腿有不能抵抗和不愉快的渴望;其常在静止时和/或夜间显现,并且可能会扰乱睡眠。不具典型RLS症状,但会表现周期性腿移动而对睡眠带来不利影响的患者被诊断为PLMS。RLS和PLMS的治疗已包括左旋多巴/卡比多巴、左旋多巴/苄丝肼、多巴胺激动剂如普拉克索和罗匹尼罗(ropinerole),苯并二氮杂类药物,阿片类药物,抗惊厥剂及铁(硫酸亚铁)。RLS和PLMS已广泛述于文献中,例如Saletu等人,神经精神生物学,41,4(2000),第190-9页。
嘌呤核苷酸,腺苷已知为中枢(CNS)和外周神经***中多数生理功能的内源性调节剂。
腺苷通过与一类膜特异性受体来施加其生物作用,这些受体属于G蛋白偶联受体超家族。生物化学及药理研究与分子生物学的进展一起,已经鉴定出至少4种腺苷受体亚型:A1、A2a、A2b和A3。腺苷类似物能够与已经鉴定出的A1、A2a、A2b和A3受体的拮抗剂相互作用。
在CNS中,数据显示A2a受体以高密度存在于基础神经节中,其已知在控制良好运动中很重要。此外,A2a受体的选择性拮抗剂在药理上很重要,因为其表现出降低运动损伤的效力,因而改善了神经变性疾病,例如帕金森病及相关运动障碍(例如亨廷顿舞蹈病)中的功能。A2a拮抗剂似乎表现出,与带来治疗指数提高的当前多巴胺能治疗相比,降低副作用的倾向(例如无运动障碍)。A2a拮抗剂还具有抗抑郁性质和刺激认知功能。一些黄嘌呤相关化合物经发现为A1受体选择性拮抗剂,并且已经发现黄嘌呤和非黄嘌呤化合物具有高的A2a亲和力,而有者不同程度的A2a对A1选择性。腺苷A2a受体拮抗剂已经在现有技术中公开过,例如公开于WO 95/01356和US 6,630,475中。
发明内容
本发明涉及一种治疗或预防锥体外综合征(例如张力失常、静坐不能、假性帕金森病及延发性运动障碍)的方法,包括给有此需要的患者施用治疗有效量的腺苷A2a受体拮抗剂。特别地,本发明方法是用于在用具有诱导EPS副作用的抗精神病药物治疗的患者中治疗或预防EPS。腺苷A2a受体拮抗剂可在EPS症状发作后给药,或腺苷A2a受体拮抗剂可在施用抗精神病药物开始时给药,以预防EPS发生。本发明因此还包括一种治疗或预防由抗精神病药物诱导的EPS的方法,包括给有此需要的患者施用抗精神病药物与腺苷A2a拮抗剂的组合。更特别地,本发明涉及一种使用一些腺苷A2a拮抗剂于单一治疗或联合治疗的方法。
本发明还涉及治疗初级(原发性)张力失常以及在因用三环类抗抑郁剂、锂或抗惊厥剂治疗或曾使用***而导致表现出张力失常的患者中治疗或预防张力失常,包括给有此需要的患者施用治疗有效量的腺苷A2a受体拮抗剂。当张力失常因三环类抗抑郁剂、锂或抗惊厥剂治疗所致时,腺苷A2a受体拮抗剂可在张力失常的症状表现出之后给药,或腺苷A2a受体拮抗剂可在施用三环类抗抑郁剂、锂或抗惊厥剂开始时给药,以预防张力失常发生。本发明因此还包括一种治疗或预防由三环类抗抑郁剂、锂或抗惊厥剂诱导的张力失常的方法,包括给有此需要的患者施用腺苷A2a受体拮抗剂与三环类抗抑郁剂、锂或抗惊厥剂的组合物。
本发明还涉及RLS或PLMS的治疗,包括给有此需要的患者施用治疗有效量的腺苷A2a受体拮抗剂。本发明还包括一种治疗RLS或PLMS的方法,包括给有此需要的患者联合施用腺苷A2a拮抗剂与可用于治疗RLS或PLMS的另一种药物利润左旋多巴/卡比多巴、左旋多巴/苄丝肼、多巴胺激动剂、苯并二氮杂类药物、阿片类药物、抗惊厥剂或铁。
在另一个方面,本发明涉及一种药盒,所述药盒在单一包装的分开容器中,包含联合使用以治疗或预防因抗精神病药物治疗所致EPS的药物组合物,其中一个容器包括在可药用载体中含有效量的腺苷A2a受体拮抗剂的药物组合物,并且其中分开的容器包括含有效量的抗精神病药物的药物组合物。
在另一个方面,本发明涉及一种药盒,所述药盒在单一包装的分开容器中,包含联合使用以治疗或预防因三环类抗抑郁剂、锂或抗惊厥剂治疗所致张力失常的药物组合物,其中一个容器包括在可药用载体中含有效量的腺苷A2a受体拮抗剂的药物组合物,并且其中分开的容器包括含有效量的三环类抗抑郁剂、锂或抗惊厥剂的药物组合物。
在另一个方面,本发明涉及一种药盒,所述药盒在单一包装的分开容器中,包含联合使用以治疗RLS或PLMS的药物组合物,其中一个容器包括在可药用载体中含有效量的腺苷A2a受体拮抗剂的药物组合物,并且其中分开的容器包括含有效量的左旋多巴/卡比多巴、左旋多巴/苄丝肼、多巴胺激动剂、苯并二氮杂类药物、阿片类药物、抗惊厥剂或铁的药物组合物。
本发明还涉及单独或者与上述其它活性剂组合的腺苷A2a受体拮抗剂在制备用于治疗或预防EPS、张力失常、RLS或PLMS的药物中的应用。
附图说明
通过下面的描述与附图可更全面地理解本发明,其中所述附图是关于在Cebus apella猴子中用haloperidol诱导的EPS。
附图1A图示说明了化合物A(1-30mg/kg,p.o.)对于最大EPS分数的影响。
附图1B表示与载体对照组相比,每一治疗组中EPS开始的平均延迟。
具体实施方式
任何腺苷A2a受体拮抗剂都可用于本发明的方法中。可用于本发明方法的合适的腺苷A2a受体拮抗剂可通过下述结合分析来鉴定。合适的腺苷A2a拮抗剂的具体实例包括在一些专利和专利申请中公开的化合物,例如WO 95/01356;US 5,565,460;US 6,630,475 B2;US 5,935,964;WO 03/032996;WO 03/048165;WO 03/048164;WO 03/048163;且WO01/02409。具体来说,这些专利和专利申请公开了以下化合物。
US 6,630,475 B2公开了具式I的化合物
或其可药用盐,其中
R为R1-呋喃基、R1-噻吩基、R1-吡啶基、R1-吡啶基N-氧化物、R1-唑基、R10-苯基、R1-吡咯基或C4-C6环烯基;
X为C2-C6亚烷基或-C(O)CH2-;
Y为-N(R2)CH2CH2N(R3)-、-OCH2CH2N(R2)-、-O-、-S-、-CH2S-、-(CH2)2-NH-或
且
Z为R5-苯基、R5-苯基(C1-C6)烷基、R5-杂芳基、二苯基甲基、R6-C(O)-、R6-SO2-、R6-OC(O)-、R7-N(R8)-C(O)-、R7-N(R8)-C(S)-、
苯基-CH(OH)-或苯基-C(=NOR2)-;或者或当Q为
时,Z还为苯基氨基或吡啶基氨基;
或者
Z和Y一起是
R1为1至3个独立地选自下列的取代基:氢、C1-C6烷基、-CF3、卤素、-NO2、-NR12R13、C1-C6烷氧基、C1-C6烷硫基、C1-C6烷基亚磺酰基和C1-C6烷基磺酰基;
R2和R3独立地选自氢和C1-C6烷基;
m和n独立地为2-3;
Q为
R4为1-2个独立地氢和C1-C6烷基的取代基,或者在同一碳上的两个R4取代基可形成=O;
R5为1至5个独立地选自下列的取代基:氢、卤素、C1-C6烷基、羟基、C1-C6烷氧基、-CN、二((C1-C6)烷基)氨基、-CF3、-OCF3、乙酰基、-NO2、羟基(C1-C6)烷氧基、(C1-C6)烷氧基(C1-C6)烷氧基、二((C1-C6)烷氧基)-(C1-C6)-烷氧基、(C1-C6)-烷氧基(C1-C6)-烷氧基(C1-C6)烷氧基、羧基(C1-C6)-烷氧基、(C1-C6)-烷氧基羰基(C1-C6)-烷氧基、(C3-C6)环烷基(C1-C6)烷氧基、二-((C1-C6)烷基)氨基(C1-C6)烷氧基、吗啉基、(C1-C6)烷基-SO2-、(C1-C6)烷基-SO-(C1-C6)烷氧基、四氢吡喃氧基、(C1-C6)烷基羰基(C1-C6)-烷氧基、(C1-C6)-烷氧基羰基、(C1-C6)烷基羰氧基(C1-C6)-烷氧基、-SO2NH2、苯氧基、
或者相邻的R5取代基一起为-O-CH2-O-、-O-CH2CH2-O-、-O-CF2-O-或-O-CF2CF2-O-,并且与其所连结的碳原子形成环;
R6为(C1-C6)烷基、R5-苯基、R5-苯基(C1-C6)烷基、噻吩基、吡啶基、(C3-C6)环烷基、(C1-C6)烷基-OC(O)-NH-(C1-C6)烷基、二-((C1-C6)烷基)氨基甲基或
R7为(C1-C6)烷基、R5-苯基或R5-苯基(C1-C6)烷基;
R8为氢或C1-C6烷基;或者R7和R8一起为-(CH2)p-A-(CH2)q,其中p和q独立地为2或3,且A为一个键、-CH2-、-S-或-O-,并且与其所连结的氮形成环;
R9为1-2个独立地选自下列的基团:氢、C1-C6烷基、羟基、C1-C6烷氧基、卤素、-CF3和(C1-C6)烷氧基(C1-C6)烷氧基;
R10为1至5个独立地选自下列的取代基:氢、卤素、C1-C6烷基、羟基、C1-C6烷氧基、-CN、-NH2、C1-C6烷基氨基、二-((C1-C6)烷基)氨基、-CF3、-OCF3和-S(O)0-2(C1-C6)烷基;
R11为H、C1-C6烷基、苯基、苄基、C2-C6烯基、C1-C6烷氧基(C1-C6)烷基、二-((C1-C6)烷基)氨基(C1-C6)烷基、吡咯烷基(C1-C6)烷基或哌啶子基(C1-C6)烷基;
R12为H或C1-C6烷基;且
R13为(C1-C6)烷基-C(O)-或(C1-C6)烷基-SO2-。
优选的式I化合物是定义如下的那些:其中R为R1-呋喃基、R1-噻吩基、R1-吡咯基或R10-苯基,更优选为R1-呋喃基。R1优选为氢或卤素。另一组的优选化合物是定义如下的那些:其中X为亚烷基,优选为亚乙基。Y优选为
,其中Q为
,且Q优选为氮。优选地,m和n各为2,且R4为H。Z的优选定义为R5-苯基、R5-杂芳基、R6-C(O)-或R6-SO2-。R5优选为H、卤素、烷基、烷氧基、羟基烷氧基或烷氧基烷氧基。R6优选为R5-苯基。
优选的特定式I化合物是定义如下的式IA化合物
其中R和Z-Y如下表中所定义:
其他有用的腺苷A2a受体拮抗剂包括公开于WO 95/01356中的化合物,例如具下式II的化合物
其中:
A为吡唑、咪唑或***环;
R为氢;C1-C8烷基;C3-C7烯基;C3-C7炔基;C3-C7环烷基;被一或多个卤素原子、羟基、C1-C4烷氧基、C3-C7环烷基、式-NR1R2、-CONR1R2取代的C1-C5烷基;任选被卤素原子、C1-C4烷氧基、C1-C4烷基、硝基、氨基、氰基、C1-C4卤代烷基、C1-C4卤代烷氧基、羧基、甲酰氨基取代的芳基;C7-C10芳烷基,其中芳基部份可以被一或多个上述芳基的取代基取代;式-(CH2)m-Het所示基团,其中Het为含有一或多个选自N、O、S的杂原子的5-6元芳族或非芳族杂环,且m为1至5的整数;
R1、R2可相同或不同,并且为氢、C1-C5烷基、C7-C10芳烷基、苯基,或者与其所连结的氮一起形成氮杂环丁烷环或含有一或多个杂原子如N、O、S的5-6元杂环,且n为2至5的整数。
优选地,式II化合物是定义如下的那些,其中R为氢、C1-C8烷基、芳基或任选被卤素原子取代的C7-C10芳烷基。
US 5,935,964公开了具下式III的有用的腺苷A2a受体拮抗剂化合物
其中A为吡唑、咪唑或***环;
R为
R1和R2可相同或不同,并且是H、OH、卤素、C1-C4烷氧基、C1-C4烷基、硝基、氨基、氰基、C1-C4卤代烷基、C1-C4卤代烷氧基、羧基或甲酰氨基;或OH基,与R1或R2中的一个或R1和R2一起可形成亚甲二氧基-O-CH2-O-;且
n为0-4的整数。
优选的式III化合物是定义如下的那些,其中A为吡唑并[4,3-e]或1,2,3-***并[5,4-e]。
US 5,565,460公开了具式IVA和IVB的有用的腺苷A2a受体拮抗剂化合物,其中式IVA为
其中R1代表氢、取代或未取代的低级烷基或取代或未取代的低级烷酰基;
R2代表氢、取代或未取代的低级烷基、取代或未取代的低级烯基、取代或未取代的环烷基、取代或未取代的芳基、取代或未取代的芳烷基或取代或未取代的杂环基;
R3代表取代或未取代的杂环基;
X代表一个单键、O、S、S(O)、S(O)2或NR4(其中R4代表氢或取代或未取代的低级烷基;或R2和NR4一起形成取代或未取代的4-6元饱和杂环基);
且
A代表N或CR5(其中R5代表氢或取代或未取代的低级烷基);且
其中式IVB为
其中R6代表取代或未取代的芳基或取代或未取代的杂环基;
Y代表O、S或NR7(其中R7代表取代或未取代的低级烷基,取代或未取代的环烷基或取代或未取代的芳基);
R8代表氢、取代或未取代的低级烷基、取代或未取代的低级烯基、取代或未取代的低级炔基、取代或未取代的环烷基、取代或未取代的芳基、取代或未取代的芳烷基或取代或未取代的杂环基;且
B和相邻的两个碳原子一起形成取代或未取代、部份饱和或不饱和、单环或双环的碳环或杂环基团。
WO 03/032996公开了具下式V的有用的腺苷A2a受体拮抗剂化合物
或其可药用盐,其中
R为R1-杂芳基、R10-苯基、C4-C6环烯基、-C(=CH2)CH3、-C≡C-CH3、-C≡C-CH2-OR2、-CH=C(CH3)2、
X为C1-C6亚烷基、-C(O)-CH2-或-C(O)N(R2)-CH2-;
Y为-N(R2)CH2CH2N(R3)-、-OCH2CH2N(R2)-、-O-、-S-、-CH2S-、-(CH2)2-3-N(R2)-、R5-二价杂芳基,
且
Z为R5-苯基、R5-苯基(C1-C6)烷基、R5-杂芳基、R5-双环杂芳基、R5-苯并稠合的杂芳基、二苯基甲基或R6-C(O)-;
或者当Y为
时,
Z还为R6-SO2-、R7-N(R8)-C(O)-、R7-N(R8)-C(S)-或R6OC(O)-;或当Q为
时,Z还为苯基氨基或吡啶基氨基;
或者Z和Y一起为
或者Y和Z一起形成与单环或双环芳基或单环或双环杂芳基环稠合的哌啶基或吡咯烷基环,其中X连接到哌啶基或吡咯烷基环的N原子上;R1为1至3个独立地选自下列的取代基:氢、C1-C6烷基、-CF3、卤素、-NO2、-NR12R13、C1-C6烷氧基、C1-C6烷硫基、C1-C6烷基亚磺酰基、C1-C6烷基磺酰基、-COOR7或-C(O)NR2R3;
R2和R3独立地选自氢和C1-C6烷基;
m和n独立地为2-3;
p和q独立地为0-2;
Q和Q1独立地选自
条件是Q和Q1中至少有一个是
R4为1-2个独立地选自下列的取代基:氢、C1-C6烷基、R1-芳基和R1-杂芳基,或者在同一碳上的两个R4取代基可形成=O;
R5为1至5个独立地选自下列的取代基:氢、卤素、C1-C6烷基、羟基、C1-C6烷氧基、-CN、二-((C1-C6)烷基)氨基、-CF3、-OCF3、乙酰基、-NO2、羟基(C1-C6)烷氧基、(C1-C6)-烷氧基(C1-C6)烷氧基、二-((C1-C6)-烷氧基)(C1-C6)烷氧基、(C1-C6)-烷氧基(C1-C6)-烷氧基-(C1-C6)-烷氧基、羧基(C1-C6)-烷氧基、(C1-C6)-烷氧基羰基(C1-C6)烷氧基、(C3-C6)环烷基(C1-C6)烷氧基、二-((C1-C6)烷基)氨基(C1-C6)烷氧基、吗啉基、(C1-C6)烷基-SO2-、(C1-C6)烷基-SO2-(C1-C6)烷氧基、四氢吡喃氧基、(C1-C6)烷基羰基(C1-C6)-烷氧基、(C1-C6)-烷氧基羰基、(C1-C6)烷基羰氧基(C1-C6)-烷氧基、-SO2NH2、苯氧基、
(R2O)2-P(O)-CH2-O-和(R2O)2-P(O)-;或者相邻的R5取代基一起为-O-CH2-O-、-O-CH2CH2-O-、-O-CF2-O-或-O-CF2CF2-O-,并且与其所连结的碳原子形成环;
R6为(C1-C6)烷基、R5-苯基、R5-苯基(C1-C6)烷基、噻吩基、吡啶基、(C3-C6)环烷基、(C1-C6)烷基-OC(O)-NH-(C1-C6)烷基、二-((C1-C6)烷基)氨基甲基或
R7为(C1-C6)烷基、R5-苯基或R5-苯基(C1-C6)烷基;
R8为氢或C1-C6烷基;或者R7和R8一起为-(CH2)p-A-(CH2)q,其中p和q独立地为2或3,且A为一个键、-CH2-、-S-或-O-,并且与其所连结的氮形成一个环;
R9为1-2个独立地选自下列的取代基:氢、C1-C6烷基、羟基、C1-C6烷氧基、卤素、-CF3和(C1-C6)烷氧基-(C1-C6)烷氧基;
R10为1至5个独立地选自下列的取代基:氢、卤素、C1-C6烷基、羟基、C1-C6烷氧基、-CN、-NH2、C1-C6烷基氨基、二-((C1-C6)烷基)氨基、-CF3、-OCF3、-S(O)0-2(C1-C6)烷基和-CH2-SO2-苯基;
R11为H、C1-C6烷基、苯基、苄基、C2-C6烯基、C1-C6烷氧基(C1-C6)烷基、二-((C1-C6)烷基)氨基(C1-C6)烷基、吡咯烷基(C1-C6)烷基或哌啶子基(C1-C6)烷基;
R12为H或C1-C6烷基;
R13为H、(C1-C6)烷基-C(O)-或(C1-C6)烷基-SO2-;
R14为H、卤素、C1-C6烷基、羟基(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷基、硫代(C1-C6)烷基、(C1-C6)烷硫基(C1-C6)烷基或NR2R3-(C1-C6)烷基;且
R15为H、卤素、C1-C6烷基或C1-C6烷氧基。
优选的式V化合物是定义如下的那些,其中R为R1-呋喃基、R1-噻吩基、R1-吡咯基、R1-吡啶基或R10-苯基,更优选为R1-呋喃基或R10-苯基。R1优选为氢或卤素。R10优选为氢、卤素、烷基或-CF3。另一组优选化合物是定义如下的那些,其中X为亚烷基,优选亚乙基。Y优选为
,其中Q为
,Q优选为氮。优选地,m和n各为2,且R4为H。Z的优选定义为R5-苯基或R5-杂芳基。R5优选为H、卤素、烷基、烷氧基、羟基烷氧基或烷氧基烷氧基。R6优选为R5-苯基。
优选的特定式V化合物是式VA化合物
其中R和Z-Y如下表中所定义:
WO 03/048165公开了具有下式VI的有用的腺苷A2a受体拮抗剂化合物
或所述化合物的可药用盐或溶剂化物,其中:
R选自R1-呋喃基-、R1-噻吩基-、R1-吡咯基-、R1-唑基-、R1-吡咯基-和R10-芳基-;
X为-(CH2)n-;
Y为哌啶基、吡咯烷基或氮杂环庚烷基,芳基或杂芳基部份稠合到Y上相邻的两个碳原子上,其中X连接在哌啶基、吡咯烷基或氮杂环庚烷基的N原子上;
Q为1-4个取代基,所述取代基可相同或不同,且独立地选自氢、环烷基、环杂烷基、氨基、芳基、芳烷基、杂芳基、烷基、CF3、CN、卤素、NO2、烷氧基、烷氧基烷氧基、环烷基烷氧基、酰氧基、烷基氨基、酰基氨基、烷基磺酰氨基、烷基氨基磺酰基、二烷基氨基磺酰基、NH2SO2-和羟基;
n为1至4;
R1为1-3个取代基,所述取代基可相同或不同,并且独立地选自氢、烷基、CF3、卤素和NO2;且
R2为1-3个取代基,所述取代基可相同或不同,并且独立地选自氢、烷基、CF3、卤素、NO2、烷氧基、酰氧基、烷基氨基、酰基氨基、烷基磺酰氨基、烷基氨基磺酰基、二烷基氨基磺酰基、氨基磺酰基和羟基。
在式IV化合物的优选具体实施方案中,Y为
其中A1为N-X,且A2和A3各为CR4R5,或者
A1和A3各为CR4R5,且A2为N-X,或者
A1和A2各为CR4R5,且A3为N-X;
A4为CR4R5;
Z1、Z2、Z3和Z4可相同或不同,并且独立地选自N和CR3,条件是:Z1、Z2、Z3或Z4中有0-2个为N,且其余为CR3;
Z5为NR5、O、S或CR4R5;
Z6为N或CR3;
Z7为N或CR3;
m为0至2的整数;
R3选自氢、环烷基、氨基、芳基、杂芳基、C1-C6-烷基、CF3、CN、卤素、NO2、C1-C6-烷氧基、C1-C6-酰氧基、C1-C6-烷基氨基、C1-C6-酰基氨基、C1-C6-烷基磺酰氨基、C1-C6-烷基氨基磺酰基、C1-C6-二烷基氨基磺酰基、NH2-SO2-和羟基;
R4选自氢、羟基烷基、芳基、芳烷基、C1-C6-烷基、C1-C6-烷氧基、CF3、CN、卤素、羟基和NO2;且
R5为氢或C1-C6烷基。
式VI化合物的优选特定实例包括下式所示化合物:
WO 03/048164公开了具下式VII的有用的腺苷A2a受体拮抗剂化合物
或所述化合物的可药用盐或溶剂化物,其中:
R选自R4-杂芳基、R5-苯基、(C4-C6)环烯基、-C(=CH2)CH3、-C≡C-CH3、
-CH=C(CH3)2、
和-CH=CH-CH3;
R2选自-W-X、-NR19(CH2)m-W-X和-NR19CH(CH3)-W-X;或者
R2选自烷基、烯基和-NR18R19,其中所述烷基、烯基或-NR18R19任选被-W-X取代;
R3选自H、卤素、烷基、三氟甲基、烷氧基、烷氧基烷基、羟基烷基、烷基氨基、烷基氨基烷基、二烷基氨基、二烷基氨基烷基、氨基烷基、芳基、杂芳基和CN;
R4为1至3个取代基,所述取代基可相同或不同,并且独立地选自氢、(C1-C6)烷基、-CF3、卤素、-NO2、-NR15R16、(C1-C6)烷氧基、(C1-C6)烷硫基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基、-COOR7和-C(O)NR6R7;
R5为1至5个取代基,所述取代基可相同或不同,并且独立地选自氢、卤素、(C1-C6)烷基、羟基、(C1-C6)烷氧基、-CN、-NH2、(C1-C6)烷基氨基、二-((C1-C6)烷基)氨基、-CF3、-OCF3、-S(O)0-2(C1-C6)烷基和-CH2-SO2-苯基;
R6和R7可相同或不同,并且各独立地选自氢和(C1-C6)烷基;
R8为1至5个取代基,所述取代基可相同或不同,并且独立地选自氢、卤素、(C1-C6)烷基、羟基、C1-C6烷氧基、-CN、氨基、二-((C1-C6)烷基)氨基、-CF3、-OCF3、乙酰基、-NO2、羟基(C1-C6)烷氧基、(C1-C6)烷氧基(C1-C6)烷氧基、二-((C1-C6)烷氧基)(C1-C6)烷氧基、(C1-C6)烷氧基(C1-C6)烷氧基(C1-C6)烷氧基、羧基(C1-C6)烷氧基、(C1-C6)烷氧基羰基(C1-C6)烷氧基、(C3-C6)环烷基(C1-C6)烷氧基、二-((C1-C6)烷基)氨基(C1-C6)烷氧基、吗啉基、(C1-C6)烷基-SO2-、(C1-C6)烷基-SO2-(C1-C6)烷氧基、四氢吡喃氧基、(C1-C6)烷基羰基(C1-C6)烷氧基、(C1-C6)烷氧基羰基、(C1-C6)烷基羰氧基(C1-C6)烷氧基、-SO2NH2、苯氧基、
-O-CH2-P(O)(OR6)2-和-P(O)(OR6)2-;或者
相邻的R8取代基一起为-O-CH2-O-、-O-CH2CH2-O-、-O-CF2-O-,或者-O-CF2CF2-O-与其所连结的碳原子形成一个环;
R9选自(C1-C6)烷基、R8-芳基-、R8-芳基(C1-C6)烷基-、噻吩基、吡啶基、(C3-C6)环烷基、(C1-C6)烷基-OC(O)-NH-(C1-C6)烷基、二-((C1-C6)烷基)氨基甲基、环杂烷基(C1-C6)烷基、芳氧基(C1-C6)烷基、烷氧基(C1-C6)烷基和
R10为1-2个取代基,所述取代基可相同或不同,并且独立地选自氢、(C1-C6)烷基、R5-芳基和R4-杂芳基,或者在同一碳上的两个R10取代基可形成=O;
R11为氢或(C1-C6)烷基;-C(O)烷基,或者R11和R11一起为-(CH2)p-A-(CH2)q,其中p和q各独立地为2或3,且A选自一个键、-CH2-、-S-和-O-,且与其所连结的氮形成一个环;
R12为1-2个取代基,所述取代基可相同或不同,并且独立地选自氢、(C1-C6)烷基、羟基、(C1-C6)烷氧基、卤素和-CF3;
R13选自H、(C1-C6)烷基、苯基、苄基、(C2-C6)烯基、(C1-C6)烷氧基(C1-C6)烷基、二-((C1-C6)烷基)氨基(C1-C6)烷基、吡咯烷基(C1-C6)烷基或哌啶子基(C1-C6)烷基;
R14选自H、卤素、(C1-C6)烷基或(C1-C6)烷氧基;
R15选自H和(C1-C6)烷基;
R16选自H、(C1-C6)烷基-C(O)-和(C1-C6)烷基-SO2-;
R17选自(C1-C6)烷基、(C1-C6)羟基烷基、(C3-C6)环烷基、(C1-C6)烷氧基(C1-C6)烷氧基、(C1-C6)烷氧基、(C1-C6)烷氧基(C1-C6)烷基、烯丙基、炔丙基、R8-杂芳基-、R8-芳基-和R8-芳基(C1-C6)烷基-;
R18选自一个键、-CH2-、-CH(OH)-、-CH(CH3)-、-C(CH3)n-、-(CH2)n-和-O(CH2)n-;
R19选自H、(C1-C6)烷基、(C1-C6)烷基(C3-C6)环烷基、(C3-C6)环烷基(C1-C6)烷基和(C1-C6)烷氧基(C1-C6)烷基;
Q和Q1可相同或不同,并且各独立地选自
m和n各独立地为1-3;
p和q各独立地为0-2;
s为0-4;
W为芳基或具有1-3个杂原子的杂芳基,所述杂原子可相同或不同,并且独立地选自N、O和S,且其中所述芳基或杂芳基任选被1-3个取代基取代,所述取代基可相同或不同,并且独立地选自烷基、芳基、烷基环烷基、卤素、羟基、羟基烷基、烷氧基、烷基烷氧基、烷氧基烷氧基、-NR6R7、(C2-C6)烯基和-CN,或者
X选自H、NH2、-N(R6)(CH2)s-芳基、-N(R6)(CH2)s-杂芳基、-N(R6)(CH2)m+1-OH和-N(CH3)2,或者
X为-R18-Y-Z;
Y选自-N(R6)CH2CH2N(R7)-、-N(R6)(CH2)n-芳基、-O-CH2CH2N(R6)-、-O-、-S-、-CH2S-、-(CH2)2-3-N(R6)-、R8-二价杂芳基,
Z选自H、烷基、烷氧基烷基、R8-芳基-、R8-芳基(C1-C6)烷基-、R8-杂芳基、R8-双环烷基、氨基烷基、烷基氨基、NH2、-N(R6)(CH2)s-芳基、-N(R6)(CH2)s-杂芳基、-N(R6)C(O)OR17、烷基环杂烷基、环杂烷基、环杂烷基烷基、烷氧基环杂烷基、杂芳基、R8-苯并稠合的杂芳基、二苯基甲基及R9-C(O)-;或者
当Y为
时,Z还可以为-OH、R9-SO2-、R17-N(R11)(CH2)s-C(O)-、R17-OC(O)-、R17-O(CH2)nC(O)-、苯并稠合的杂芳基(CH2)nC(O)-、苯并稠合的杂芳基(CH2)n-或R17-N(R11)-C(S)-;或者
当Q为
时,Z还可以为R17R11N-、苯基氨基或吡啶基氨基;或者Z和Y一起选自
优选的式VII化合物是具有如下结构的那些:
WO 03/048163公开了具下式VIII的有用的腺苷A2a受体拮抗剂化合物
或其可药用盐,其中:
A为C(R1)或N;
R1和R1a独立地选自H、(C1-C6)-烷基、卤素、CN和-CF3;Y为-O-、-S-、-SO-、-SO2-、R5-杂芳二基、R5-亚芳基或
p和q独立地为2-3;
Q和Q1为独立地选自
条件是:Q和Q1中有一个为
R为R5-芳基、R5-杂芳基、R6-(C2-C6)烯基或R6-(C2-C6)炔基;
R2为R5-芳基、R5-杂芳基、R5-芳基(C1-C6)烷基或R5-杂芳基(C1-C6)烷基;或者R2-Y为
U、V和W独立地选自N和CR1,条件是:U、V和W中至少有一个为CR1;
n为1、2或3;且
(a)A为C(R1),且X为-C(R3)(R3a)-、-C(O)-、-O-、-S-、-SO-、-SO2-,R4-亚芳基、R4-亚杂芳基或-N(R9)-;或者A为C(R1),Y为一个键,且X为-C(R3)(R3a)-、-C(O)-、-O-、-S-、-SO-、-SO2-,R4-亚芳基、-N(R9)-或R4-杂芳二基,条件是:当X为-N(R9)-或R4-杂芳二基时,R2不是苯基或苯基-(C1-C6)烷基;或者
(b)A为N,X为-N(R9)-,Y为R5-亚芳基,且R2为
或n为2或3;且
(c)A为N,且X为-C(R3)(R3a)-、-C(O)-、-O-、-S-、-SO-、-SO2-、-N(R9)-、R4-亚芳基或R4-杂芳二基;或者A为N,Y为一个键,且X为-C(O)-、-N(R9)-、R4-亚芳基或R4-杂二芳基;或者A为N,Y为-N(R9a)-、-C(O)N(R9a)-或-O-(CH2)2-N(R9a)-,且X为-N(R9)-;或者A为N,X为-N(R9)-,且Y和R2一起为
或n为0;且
(d)A为N,Y为一个键,X为-N(R9)-,且R2为
(e)A为N,X为-N(R9)-,且Y和R2一起为
其中Z为-C(O)-CH2-、-C(O)-CH(C1-C6烷基)-、-CH2-CH(C1-C6烷基)-或-CH(C1-C6烷基)-CH2-;
R3和R3a独立地选自H、-OH、C1-C6烷基、羟基(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷基、氨基(C1-C6)烷基、(C1-C6)烷基氨基(C1-C6)烷基和二(C1-C6)烷基氨基(C1-C6)烷基;
R4为1-3个选自下列的取代基:H、C1-C6烷基、-OH、(C1-C6)烷氧基、(C1-C6)烷氧基(C1-C6)烷氧基、卤素、-CF3和-CN;
R5为1-3个独立地选自下列的取代基:H、(C1-C6)烷基、-OH、(C1-C6)烷氧基、(C1-C6)烷氧基(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷氧基、卤素、-CF3、-CN、-NH2、(C1-C6)烷基氨基、二(C1-C6)烷基氨基、氨基(C1-C6)烷基、(C1-C6)烷基氨基(C1-C6)烷基、二(C1-C6)烷基氨基(C1-C6)烷基、(C1-C6)烷酰基氨基、(C1-C6)烷磺酰基氨基、(C1-C6)烷硫基、(C1-C6)烷硫基(C1-C6)烷基、R6-(C2-C6)烯基、R6-(C2-C6)炔基、羟基(C1-C6)烷基、(C1-C6)烷氧基-C(O)-氨基或杂环烷基(C1-C6)烷基;
R6为1-3个独立地选自下列的取代基:H、-OH、(C1-C6)烷氧基和卤素;R7和R7a独立地选自H、(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷基、R8-芳基及R8-杂芳基,或者在同一碳上的R7和R7a取代基可形成=O;
R8为1-3个独立地选自下列的取代基:H、(C1-C6)烷基、-OH、(C1-C6)烷氧基、(C1-C6)烷氧基(C1-C6)烷氧基、卤素、-CF3和-CN;
R9和R9a独立地选自H、(C1-C6)烷基、羟基(C2-C6)烷基、(C1-C6)烷氧基(C2-C6)烷基、氨基(C2-C6)烷基、(C1-C6)烷基氨基(C2-C6)烷基、二(C1-C6)烷基氨基(C2-C6)烷基、卤代-(C3-C6)烯基、CF3-(C1-C6)烷基、(C3-C6)烯基、(C3-C6)环烷基和(C3-C6)环烷基-(C1-C6)烷基;
且
R10为H、-C(O)-O-(C1-C6)烷基、R5-芳基、-C(O)-(C1-C6)烷基、-C(O)-(R5-芳基)或R5-芳基-(C1-C6)烷基。
优选的式VIII化合物是其中A为N的那些。R优选为呋喃基。R1a优选为氢。另一组优选的化合物是定义如下的那些,其中X为-O-、-S-、-N(R9)-或R4-亚芳基,其中X为-N(R9)-的化合物是更优选的。R9优选为C1-C6烷基。Y的优选定义为-个键或哌嗪基。R2优选为R5-芳基。当Y和/或R2为
时,
Q优选为N,Q1优选为N,p和q各优选为2,R7和R7a各优选为氢,且R10优选为-C(O)-O-(C1-C6)烷基、-C(O)-(C1-C6)烷基或-C(O)-(R5-芳基)。R5优选为1或2个选自下列的取代基:H、(C1-C6)烷氧基、(C1-C6)烷氧基(C1-C6)烷氧基、卤素和-CF3。R4优选为H、卤素或(C1-C6)烷基。R3和R3a优选独立地选自H和(C1-C6)烷基。R9a优选为H或(C1-C6)烷基。R6优选为氢。
式VIII化合物的优选特定实例包括下式所示化合物
其中R2-Y-(CH2)n-N(R9)-如下表所定义:
WO 01/02409公开了具下式IX的有用的腺苷A2a受体拮抗剂化合物
其中
X为O或S;
R1和R2独立地选自氢、烷基、芳基、羟基、烷氧基、芳氧基、氰基、硝基、CO2R7、COR7、OCOR7、CONR7R8、CONR7NR8R9、OCONR7R8、NR7R8、NR7COR8、NR7CONR8R9、NR7CO2R8、NR7SO2R8、NR7CONR8NR9R10、NR7NR8CO2R9、NR7NR8CONR9R10、NR7SO2NR8R9、SO2R7、SOR7、SR7和SO2NR7R8,或者R1和R2一起形成羰基(C=O)、肟基(C=NOR11)、亚胺基(C=NR11)或肼(C=NNR11R12),或者R1和R2一起形成5、6或7元碳环或杂环;
R3为烷基或芳基;
R4、R5和R6独立地选自氢、烷基、芳基、卤素、羟基、硝基、氰基、烷氧基、芳氧基、CO2R7、COR7、OCOR7、SO2R7、SOR7、SR7、SO2NR7R8、CONR7R8、CONR7NR8R9、OCONR7R8、NR7R8、NR7COR8、NR7CONR8R9、NR7CO2R8、NR7SO2R8、CR7=NOR8、NR7CONR8NR9R10、NR7NR8CO2R9、NR7NR8CONR9R10、SO2NR7NR8R9、NR7SO2NR8R9、NR7NR8SO2R9、NR7NR8CO2R9、NR7NR8R9和NR7CSNR8R9,或者R5和R6一起形成5、6或7元碳环或杂环;且
R7、R8、R9、R10、R11和R12独立地选自氢、烷基和芳基,或其可药用盐或前药。
在此所引的美国专利和申请均引入本文以供参考。腺苷A2a受体拮抗剂通过在所引用的专利和申请中描述的已知方法制备。
本文所用的“患者”指哺乳动物,特别是人类。
预期可施用一种以上的腺苷A2a受体拮抗剂(例如2或3种)来治疗EPS、张力失常、RLS或PLMS;优选施用一种腺苷A2a受体拮抗剂。
引起通过腺苷A2a受体拮抗剂治疗的EPS以及与腺苷A2a受体拮抗剂联合使用的抗精神病药物包括典型和非典型抗精神病药物。典型抗精神病药物包括洛沙平、氟哌啶醇、氯丙嗪、丙氯拉嗪和替沃噻吨。非典型抗精神病药物包括氯氮平、奥氮平、洛沙平、喹硫平、齐拉西酮和利培酮。
引起通过腺苷A2a受体拮抗剂治疗的张力失常的三环类抗抑郁药物包括奋乃静、阿米替林、地昔帕明、多塞平、曲米帕明和普罗替林。可引起张力失常,但还可用于治疗ERLS或PLMS的抗惊厥剂包括苯英妥、卡马西平和加巴喷丁。
可用于治疗RLS和PLMS的多巴胺激动剂包括培高利特、普拉克索、罗匹尼罗、非诺多泮和卡麦角林。
可用于治疗PRLS和PLMS的阿片类药物包括可待因、氢可酮、羟考酮、丙氧芬和曲马多。
抗精神病药物、三环类抗抑郁药物、抗惊厥剂、多巴胺激动剂、阿片类药物和苯并二氮杂类药物可购得,并且述于文献中,例如描述于The Physician’s Desk Reference(Montvale:Meical EconomicsCo.,2001)。
预期二种或多种A2a受体拮抗剂可以与一种或多种其他药物(例如抗精神病药物、三环类抗抑郁剂、抗惊厥剂、多巴胺激动剂、阿片类药物或苯并二氮杂类药物)联合给药,但是一种A2a拮抗剂与一种其他药物联合给药对适应症是优选的。虽然施用A2a拮抗剂和其他药物的分开剂型是优选的,但是也可以将其他药物与与A2a受体拮抗剂在单一剂型中组合来联合治疗或预防EPS、张力失常、RLS或PLMS。
优选的腺苷A2a拮抗剂是在US 6,630,475中描述的那些。
本发明的特别优选的化合物为下式所示化合物A
或其可药用盐或溶剂化物,公开在US 6,630,475及列于式I化合物表中的第一个化合物。
可用于本发明方法的化合物在这些分析中将表现出作为腺苷A2a受体拮抗剂的用途。
人腺苷A
2a
和A
1
受体竞争结合试验方案
膜源:
A2a:人A2a腺苷受体膜,目录号#RB-HA2a,Receptor Biology,Inc.,Beltsville,MD。在膜稀释缓冲液(见下)中稀释至17μg/100μl。
试验缓冲液:
膜稀释缓冲液:Dulbecco磷酸盐缓冲盐水(Gibco/BRL)+10mMMgCl2。
化合物稀释缓冲液:Dubecco磷酸盐缓冲盐水(Gibco/BRL)+10mMMgCl2,补加1.6mg/ml甲基纤维素和16%DMSO。每天临时配制。
配体:
A2a:[3H]-SCH 58261,委托合成,Amersham pharmacia Biotech,Piscataway,NJ.在膜稀释缓冲液中配制1nM的贮备液。最终试验浓度为0.5nM。
A1:[3H]-DPCPX,Amersham pharmacia Biotech,Piscataway,NJ。在膜稀释缓冲液中配制2nM的贮备液。最终试验浓度为1nM。
非特异性结合:
A2a:为测定非特异性结合,加100nM CGS 15923(RBI,Naticx,MA)。在化合物稀释缓冲液中配制400nM的工作贮备液。
A1:为测定非特异性结合,加100μM NECA(RBI,Natick,MA)。在化合物稀释缓冲液中配制400μM的工作贮备液。
化合物稀释:
配制化合物在100%DMSO中的1mM贮备液。将化合物在稀释缓冲液中稀释,然后在从3μM至30PM的范围内于10个浓度下试验。工作贮备液是在化合物稀释缓冲液中配制成最终浓度的4倍。
试验步骤:
试验在深孔96孔板中进行。总试验体积为200μl。加入50μl化合物稀释缓冲液(总配体结合),或50μl CGS 15923工作溶液(A2a非特异性结合),或50μl NECA工作溶液(A1非特异性结合),或50μl药物工作溶液。加入50μl配体贮备液([3H]-SCH 58261用于A2a,[3H]-DPCPX用A1)。加入含有合适受体的100μl稀释膜溶液。将该混合物在室温下温育90分钟,然后用Brandel细胞收获器收取在PackardGF/B滤板上。加入45μl Microscint 20(Packard),用PackardTopcount微闪烁计数器计数。通过用叠式曲线拟合程序(Excel)拟合置换曲线来确定IC50值。Ki值用Cheng-Prusoff方程确定。
氟哌啶醇在大鼠中诱发的僵住症
使用重175-200g的雄性Sprague-Dawley大鼠(Charles River,Calco,Italy)。通过皮下施用多巴胺受体拮抗剂氟哌啶醇(1mg/kg,sc)来诱发僵直状态,90分钟后在垂直载网试验中试验该动物。为进行此试验,将鼠放在一只25×43有机玻璃笼的丝网盖上,该笼与桌面成大约70°角放置。鼠被放在载网上,四肢全都外伸(“蛙姿”)。来用这种不寻常的姿式对于此试验对僵住症的专一性是必不可少的。测定从鼠爪放上到最早的一只爪完全脱离所经过的时间(合宜的潜伏期)最多120秒。
按照0.03-3mg/kg的剂量,口服要评价的选择性A2a腺苷拮抗剂,1和4小时后对动物评分。
在另外的实验中,测定参考化合物L-DOPA(25、50和100mg/kg,ip)的抗僵直作用。
为了由可用于本发明方法的化合物制备药物组合物,惰性可药用载体可以是固体或液体。固体形式的制剂包括粉剂、片剂、可分散颗粒、胶囊剂、扁囊剂和栓剂。粉剂和片剂可以含有大约0.1-约90%的活性组分。合适的固体载体是本领域已知的,例如碳酸镁、硬脂酸镁、滑石、糖、乳糖等。片剂、粉剂、扁囊剂和胶囊剂可以作为适合口服的固体剂型使用。
为制备栓剂,先将一种低熔点蜡例如脂肪酸甘油酯混合物或可可酯熔化,利用搅拌将活性成分均匀地分散于其中。随后将熔化的均匀混合物倒入合适大小的模具中冷却并固化。
液体形式制剂包括溶液剂、混悬剂和乳剂。可提及的实例有用于胃肠外注射的水或水-丙二醇溶液。
液体形式制剂也包括用于鼻内给药的溶液剂。
适合吸入的气雾剂包括溶液和粉末形式的固体,它可以与可药用的载体例如惰性压缩气体组合。
还包括准备在使用前不久转化成用于口服或胃肠外给药的液体形式制剂的固体形式制剂。所述液体形式包括溶液、悬浮液和乳液。
可用于本发明方法的化合物也可以是可透皮释放的。透皮组合物可采用霜剂、洗剂、气雾剂和/或乳剂的形式,并且可以像本领域用于此目的的常规作法一样,包含在基质型或贮库型透皮贴剂中。
腺苷A2a受体拮抗剂和抗精神病药物优选口服给药。
药物制剂优选为单位剂量形式。在这种形式中,制剂被再分成含有适量(例如达到所要求目的的有效量)活性组分的单位剂量。
单位剂量制剂中腺苷A2a受体拮抗剂的量可以根据具体用途从约0.1至1000mg,更优选从约1至300mg之间变动或调节。
使用的准确剂量可根据患者的需要和所治疗的病症的严重程度而变化。各个具体情况下适当剂量的确定是在本领域的技能范围之内。一般来说,治疗开始时先用少于该化合物最佳剂量的较小剂量。然后,以小的增量加大剂量,直到达到在该条件下的最佳效果。为方便起见,总日剂量在需要时可以再分割,一天内分几次给药。
可用于本发明方法的腺苷A2a受体拮抗剂的给药剂量和频度应根据随诊医师考虑诸如患者的年龄、状况和身材等因素以及所治疗症状的严重程度的判断进行调节。腺苷A2a受体拮抗剂的典型建议剂量疗法为约10mg-2000mg/天,优选10-1000mg/天的口服给药,以2至4个均分剂量,以提供EPS、张力失常、RLS或PLMS作用的解除。化合物在此剂量范围内给药时无毒性。
与腺苷A2a受体拮抗剂联合使用其他药物,即抗精神病药物、三环类抗抑郁剂、抗惊厥剂、多巴胺激动剂、苯并二氮杂类药物、阿片类药物、锂或铁的剂量和剂量方案将由随诊医师决定,鉴于包装内容物的允许剂量和剂量方案,考虑到患者的年龄、性别和病症以及疾病的严重性。当联合给药时,腺苷A2a受体拮抗剂和其他药物可同时或依序给药。当组合物的成分优选在不同给药方案下给予,例如一种成分每天施用,另一种每6小时施用时,或当优选的药物组合物是不同的,例如一种优选为片剂,另一种为胶囊时,这是特别有用的。因此有利地在药盒中提供腺苷A2a受体拮抗剂和其他药物,所述药盒在单一包装的分开容器中,包括联合使用以治疗或预防EPS、张力失常、RLS或PLMS的药物组合物,其中一个容器包括在可药用载体中含有有效量的腺苷A2a受体拮抗剂的药物组合物,其中在分开的容器中包括含有适合治疗适应症的有效量的其他药剂的药物组合物。
本领域技术人员将了解,对于组合的一个成分,可以对剂型进行修饰以含有腺苷A2a受体拮抗剂和另一种药剂,例如腺苷A2a受体拮抗剂和抗精神病药物或腺苷A2a受体拮抗剂和多巴胺激动剂。
以下实施例显示使用腺苷A2a受体拮抗剂以减轻卷尾猴(Cebusapella)展现的锥体外综合征(EPS),这些猴子用多巴胺D2受体拮抗剂氟哌啶醇致敏。
实施例
之前事先用氟哌啶醇的慢性作用致敏的7只卷尾猴,当急性施用氟哌啶醇(0.3mg/kg,口服)时,表现出EPS。化合物A以0.3-30mg/kg的剂量与氟哌啶醇一起口服给药。研究使用个体内设计进行,使得交互平衡的设计中各猴子接受全部6种治疗(载体和5个剂量的化合物A)。在全部研究中,7只猴子在施用氟哌啶醇时表现出基准水平的EPS。
化合物A产生在EPS最大分数上的剂量依赖性降低(图1A),以及对EPS开始的剂量依赖性延迟(图1B)。在1mg/kg的剂量下,化合物A防止了一只猴子的EPS开始,并且将EPS开始延迟了1小时。化合物A在3mg/kg的剂量下,防止了两只猴子的EPS开始,并且将其他猴子的EPS开始延迟了几乎2小时。在10和30mg/kg下,化合物A防止了三只猴子的EPS开始,并且将EPS开始延迟了平均2.3-2.9小时。
治疗RLS和PLMS的临床指导已经建立了:见A.L.Chesson等人,Sleep,22,7(1999),第961-8页。腺苷A2a受体拮抗剂在治疗RLS和PLMS方面的效力可由类似于对普拉克索和罗匹尼罗的文献内所述的临床方法确定,Weimerskirch等人,Annals of Pharmacotherapy,35,5(2001),第627-30页。
虽然已经结合上述具体实施方案描述了本发明,但是其许多替代方案、改变和变型对于本领域技术人员来说都是显而易见的。所有这样的替代方案、改变和变型都在本发明实质和范围内。
总的来说,本发明涉及如下方面:
方面1.一种腺苷A2a受体拮抗剂在制备用于治疗或预防锥体外综合征或张力失常的药物中的用途。
方面2.如方面1的用途,其中所述腺苷A2a受体拮抗剂是下式所示化合物
或其可药用盐,其中
R为R1-呋喃基、R1-噻吩基、R1-吡啶基、R1-吡啶基N-氧化物、R1-唑基、R10-苯基、R1-吡咯基或C4-C6环烯基;
X为C2-C6亚烷基或-C(O)CH2-;
Y为-N(R2)CH2CH2N(R3)-、-OCH2CH2N(R2)-、-O-、-S-、-CH2S-、-(CH2)2-NH-或
且
Z为R5-苯基、R5-苯基(C1-C6)烷基、R5-杂芳基、二苯基甲基、R6-C(O)-、R6-SO2-、R6-OC(O)-、R7-N(R8)-C(O)-、R7-N(R8)-C(S)-、
苯基-CH(OH)-或苯基-C(=NOR2)-;或者或当Q为
时,Z还为苯基氨基或吡啶基氨基;
或者
Z和Y一起是
R1为1至3个独立地选自下列的取代基:氢、C1-C6烷基、-CF3、卤素、-NO2、-NR12R13、C1-C6烷氧基、C1-C6烷硫基、C1-C6烷基亚磺酰基和C1-C6烷基磺酰基;
R2和R3独立地选自氢和C1-C6烷基;
m和n独立地为2-3;
Q为
R4为1-2个独立地氢和C1-C6烷基的取代基,或者在同一碳上的两个R4取代基可形成=O;
R5为1至5个独立地选自下列的取代基:氢、卤素、C1-C6烷基、羟基、C1-C6烷氧基、-CN、二((C1-C6)烷基)氨基、-CF3、-OCF3、乙酰基、-NO2、羟基(C1-C6)烷氧基、(C1-C6)烷氧基(C1-C6)烷氧基、二((C1-C6)烷氧基)-(C1-C6)-烷氧基、(C1-C6)-烷氧基(C1-C6)-烷氧基(C1-C6)烷氧基、羧基(C1-C6)-烷氧基、(C1-C6)-烷氧基羰基(C1-C6)-烷氧基、(C3-C6)环烷基(C1-C6)烷氧基、二-((C1-C6)烷基)氨基(C1-C6)烷氧基、吗啉基、(C1-C6)烷基-SO2-、(C1-C6)烷基-SO-(C1-C6)烷氧基、四氢吡喃氧基、(C1-C6)烷基羰基(C1-C6)-烷氧基、(C1-C6)-烷氧基羰基、(C1-C6)烷基羰氧基(C1-C6)-烷氧基、-SO2NH2、苯氧基、
或者相邻的R5取代基一起为-O-CH2-O-、-O-CH2CH2-O-、-O-CF2-O-或-O-CF2CF2-O-,并且与其所连结的碳原子形成环;
R6为(C1-C6)烷基、R5-苯基、R5-苯基(C1-C6)烷基、噻吩基、吡啶基、(C3-C6)环烷基、(C1-C6)烷基-OC(O)-NH-(C1-C6)烷基、二-((C1-C6)烷基)氨基甲基或
R7为(C1-C6)烷基、R5-苯基或R5-苯基(C1-C6)烷基;
R8为氢或C1-C6烷基;或者R7和R8一起为-(CH2)p-A-(CH2)q,其中p和q独立地为2或3,且A为一个键、-CH2-、-S-或-O-,并且与其所连结的氮形成环;
R9为1-2个独立地选自下列的基团:氢、C1-C6烷基、羟基、C1-C6烷氧基、卤素、-CF3和(C1-C6)烷氧基(C1-C6)烷氧基;
R10为1至5个独立地选自下列的取代基:氢、卤素、C1-C6烷基、羟基、C1-C6烷氧基、-CN、-NH2、C1-C6烷基氨基、二-((C1-C6)烷基)氨基、-CF3、-OCF3和-S(O)0-2(C1-C6)烷基;
R11为H、C1-C6烷基、苯基、苄基、C2-C6烯基、C1-C6烷氧基(C1-C6)烷基、二-((C1-C6)烷基)氨基(C1-C6)烷基、吡咯烷基(C1-C6)烷基或哌啶子基(C1-C6)烷基;
R12为H或C1-C6烷基;且
R13为(C1-C6)烷基-C(O)-或(C1-C6)烷基-SO2-。
方面3.方面2的用途,其中所述腺苷A2a受体拮抗剂选自下式化合物
其中R和Z-Y如下表所定义:
或其可药用盐或溶剂化物。
方面4.方面3的用途,其中腺苷A2a受体拮抗剂为下式所示化合物
或其可药用盐或溶剂化物。
方面5.方面1的用途,其中所述锥体外综合征是由于用典型抗精神病药物或非典型抗精神病药物进行治疗所致。
方面6.方面5的用途,其中所述典型抗精神病药物选自洛沙平、氟哌啶醇、氯丙嗪、丙氯拉嗪和替沃噻吨,所述非典型抗精神病药物选自氯氮平、奥氮平、洛沙平、喹硫平、齐拉西酮和利培酮。
方面7.方面5的用途,还包括抗精神病药物在制备用于与腺苷A2a受体拮抗剂药物联合使用的药物中的用途。
方面8.方面7的用途,其中典型抗精神病药物选自洛沙平、氟哌啶醇、氯丙嗪、丙氯拉嗪和替沃噻吨,非典型抗精神病药物选自氯氮平、奥氮平、洛沙平、喹硫平、齐拉西酮和利培酮。
方面9.一种药盒,所述药盒在单一包装的分开容器中,包含联合使用以治疗或预防因抗精神病药物治疗所致EPS的药物组合物,其中一个容器包括在可药用载体中含有效量的腺苷A2a受体拮抗剂的药物组合物,并且其中分开的容器包括含有效量的抗精神病药物的药物组合物。
方面10.方面1的用途,其中所述药物是用于治疗原发性张力失常或由于使用***所致的张力失常。
方面11.方面1的用途,其中所述药物是用于治疗或预防由于用三环类抗抑郁剂、锂或抗惊厥剂治疗所致的张力失常。
方面12.方面11的用途,还包括三环类抗抑郁剂、锂或抗惊厥剂在制备用于与腺苷A2a受体拮抗剂药物联合使用的药物中的用途。
方面13.方面12的用途,其中所述三环类抗抑郁剂选自奋乃静、阿米替林、地昔帕明、多塞平、曲米帕明和普罗替林,并且所述抗惊厥剂选自苯英妥、卡马西平和加巴喷丁。
方面14.一种药盒,所述药盒在单一包装的分开容器中,包含联合使用以治疗或预防因三环类抗抑郁剂、锂或抗惊厥剂治疗所致张力失常的药物组合物,其中一个容器包括在可药用载体中含有效量的腺苷A2a受体拮抗剂的药物组合物,并且其中分开的容器包括含有效量的三环类抗抑郁剂、锂或抗惊厥剂的药物组合物。
方面15.腺苷A2a受体拮抗剂在制备用于治疗下肢不宁综合征或睡眠中周期性腿动的药物中的用途。
方面16.方面15的用途,其中所述腺苷A2a受体拮抗剂如方面2所定义。
Claims (11)
2.权利要求1的用途,其中所述锥体外综合征是由于用典型抗精神病药物或非典型抗精神病药物进行治疗所致。
3.权利要求2的用途,还包括抗精神病药物在制备用于与腺苷A2a受体拮抗剂药物联合使用的药物中的用途。
5.权利要求1的用途,其中所述药物是用于治疗原发性张力失常或由于使用***所致的张力失常。
6.权利要求1的用途,其中所述药物是用于治疗或预防由于用三环类抗抑郁剂、锂或抗惊厥剂治疗所致的张力失常。
7.权利要求6的用途,还包括三环类抗抑郁剂、锂或抗惊厥剂在制备用于与腺苷A2a受体拮抗剂药物联合使用的药物中的用途。
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EP2295047A3 (en) | 2011-05-18 |
EP2269596A2 (en) | 2011-01-05 |
DE60335294D1 (de) | 2011-01-20 |
MXPA05006790A (es) | 2005-09-08 |
NO20053509L (no) | 2005-09-16 |
ZA200504478B (en) | 2006-02-22 |
AU2003304527B2 (en) | 2010-09-09 |
EP2269596A3 (en) | 2011-09-14 |
JP2011006431A (ja) | 2011-01-13 |
EP1578409A1 (en) | 2005-09-28 |
HK1074585A1 (en) | 2005-11-18 |
AU2010214749B2 (en) | 2011-06-09 |
ES2354875T3 (es) | 2011-03-18 |
WO2005044245A1 (en) | 2005-05-19 |
CN1728990A (zh) | 2006-02-01 |
US7414058B2 (en) | 2008-08-19 |
NO20053509D0 (no) | 2005-07-18 |
TWI331036B (en) | 2010-10-01 |
US20040138235A1 (en) | 2004-07-15 |
JP2013136592A (ja) | 2013-07-11 |
BR0317436A (pt) | 2005-11-16 |
AU2010214749A1 (en) | 2010-09-23 |
CN100415217C (zh) | 2008-09-03 |
EP2295047A2 (en) | 2011-03-16 |
JP2006514697A (ja) | 2006-05-11 |
NZ540493A (en) | 2008-04-30 |
TW200505927A (en) | 2005-02-16 |
AU2003304527A1 (en) | 2005-05-26 |
EP1578409B1 (en) | 2010-12-08 |
ATE490775T1 (de) | 2010-12-15 |
US20090029967A1 (en) | 2009-01-29 |
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