CN1152917A - 取代的嘧啶化合物和其用途 - Google Patents
取代的嘧啶化合物和其用途 Download PDFInfo
- Publication number
- CN1152917A CN1152917A CN95194141A CN95194141A CN1152917A CN 1152917 A CN1152917 A CN 1152917A CN 95194141 A CN95194141 A CN 95194141A CN 95194141 A CN95194141 A CN 95194141A CN 1152917 A CN1152917 A CN 1152917A
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- China
- Prior art keywords
- alkyl
- compound
- halogen
- replace
- group
- Prior art date
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- Granted
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 58
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- 229960003638 dopamine Drugs 0.000 claims abstract description 7
- 239000003446 ligand Substances 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 34
- 150000002367 halogens Chemical class 0.000 claims description 34
- 229910052799 carbon Inorganic materials 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 125000000217 alkyl group Chemical group 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
- -1 pyrimidine compound Chemical class 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 3
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- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
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Abstract
本发明涉及如下通式的嘧啶化合物的用途其中R1，R2，R3，A，B和Ar具有在说明书中指明的意义。根据本发明的化合物对多巴胺D3受体具有高的亲和性，因而可被用于治疗响应多巴胺D3配体的病症。
Description
本发明涉及取代的嘧啶化合物和这类化合物的用途。所说的化合物具有有价值的治疗性质，并可特别地用于治疗响响应多巴胺D3配位体的疾病。
所讨论的并具有生理活性的这类化合物在某种程度已被披露。DE2139082和DE2258561描述了带有碱性取代基的嘧啶衍生物和嘧啶酮衍生物作为用于降低血压的药物。这些嘧啶和嘧啶酮衍生物具有下式：
在(A)中，X特别为硫，A为C1-C6亚烷基，而R1，R2，R3，和Z为各种取代基。在(B)中，X和Y各自为氧和硫，A为C2-C6亚烷基，而R和Z为各种取代基。
神经元特别通过G蛋白质-偶合受体接收其信息。有大量物质通过这些受体发挥其作用。其中之一是多巴胺。
确证多巴胺的存在和其作为神经递质的生理功能的发现已被公开。响应多巴胺的细胞与精神分裂症和帕金森病的病因学有关。这些和其它病症用与多巴胺相互作用的药物治疗。
1990，两个亚类的多巴胺受体已被清楚地从药理上定义，即D1和D2受体。
Sokoloff等人，Nature 1990，347：146-151，发现了第三个亚类，即D3受体。它们主要以肢系统表达。D3受体在约一半氨基酸残基的结构上与D1和D2受体不同。
精神抑制药的用作一般归于其对D2受体的亲合性。最近的受体-连接研究已经证明了这一点。根据这些，大多数多巴胺拮抗剂如精神抑制药对D2受体具有高的亲合性，但对D3受体只有低的亲合性。
我们现已惊奇地发现，某些嘧啶化合物对多巴胺D3受体具有高的亲和性而对多巴胺D2受体具有低的亲合性。因而它们是选择性的D3配位体。
因此，本发明涉及通式I嘧啶化合物和其与生理耐受的酸生成的盐的应用：其中A 是可以包含至少一个选自O，S，NR4，CONR4，NR4CO，COO，OCO，和双键或叁键基团的C1-C18亚烷基，B 是或
R1，R2，R3相互独立地选自H，卤素，OR4，NR4R5，SR4，CF3，CN，CO2R4和未取代或被OH、OC1-C8烷基或卤素取代的C1-C8烷基，R4 是H，未取代或被OH，OC1-C8烷基或卤素取代的C1-C8烷基，R5 具有与R4指明的意义或为COR4或CO2R4；Ar 是苯基，吡啶基，嘧啶基或三嗪基，其中Ar具有一至四个取代基，这些取代基各自独立地选自OR5，C1-C8烷基，C2-C6烯基，C2-C6炔基，卤素，CN，CO2R4，NO2，SO2R4，NR4R5，SO2NR4R5，SR4，CF3，CHF2，5-或6-员碳环族芳香或非芳香环，和具有1至3个选自O，S和N的杂原子的5-或6-员杂环族芳香或非芳香环，其中环可以未取代或被C1-C8烷基，Hal，OC1-C8烷基，OH，NO2，CF3取代，并且其中Ar也可以与上面定义的类型的碳环或杂环稠合，用于生产治疗响应多巴胺受体D3拮抗剂或激动剂的病症的药物组合物。
本发明也涉及式I’的嘧啶化合物和其与生理耐受酸所成的盐，其中A，B，Ar，R1，R2和R3具有与权利要求1至8中所述的意义，下式化合物除外
其中R1是OH或SH，R2或R3相互独立地是H，C1-C6烷基，OC1-C6烷基，SC1-C6烷基，CO2H，OH，SH，NR4R5或卤素，其中R4和R5是H或C1-C6烷基，A是SC1-C6烷基，NHC1-C6亚烷基，或N(C1-C6烷基)-C1-C6亚烷基，B是
而Ar是可被一个或多个选自C1-C4烷基，OC1-C4烷基，SC1-C4烷基，NO2，CF3，F，Cl或Br的取代基取代的苯基。
所用的根据本发明的化合物是选择性的多巴胺D3受体配体，它在肢系统(limbic system)中区域选择性地介入，并由于其对D3受体的低亲和性，比作为D2受体拮抗剂的经典种经抑制药具有更小的副作用。因此该化合物可被用于治疗响应多巴胺D3受体拮抗剂或激励剂的病态，例如用于治疗中枢神经系统的病症，尤其是精神分裂症，抑郁，神经机能病和精神病。它们另外可被用于治疗睡眠失调和恶心，并作为抗组胺剂。
在本发明的范围内，下列述语具有下面指明的意义：烷基(也包括在基团如烷氧基，烷基氨基，等中的)意指具有1于8个碳原子、优选地1至6个碳原子，特别是1至4个碳原子的直链或支链烷基。烷基可带有一个或多个互相独立地选自OH和OC1-C8烷基的取代基。
烷基的例子有甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，等等。
亚烷基代表优选地具有2至15个碳原子、特别优选3至10个碳原子的直链或支链基团。
亚烷基可包含至少一个上述基团。这可以-正如被提到的双键或叁键-被安排在亚烷基链的任何位置或在链的终端，以使其将链连接在嘧啶残基上。后者是优选的。当亚烷基包含一个双链或叁链时，在链中至少具有三个碳原子。
卤素是F，Cl，Br，I，尤其是Cl，Br，I。
R1，R2和R3优选相互独立地为H，C1-C8烷基，NR4R5，SR4或OR4，其中R4和R5相互独立地为H或C1-C8烷基。
Ar 可以具有一，二，三或四个取代基，优选一或两个取代基，它们在各种情况下在间位。它们优选地互相独立地选自卤素，CF3，CHF2，CN，NO2，OR4，NR4R5，C1-C8烷基，OC1-C8烷基，苯基和SR4，其中R4和R5是H或C1-C8烷基。如果取代之一是C1-C8烷基，则支链基团、尤其是异丙基或叔丁基是优选的。
Ar优选地具有一个取代基，并尤其为，
其中D1，D2和D3互相独立地为CR或N，而R、X和Y为H或具有上面或下面指明的意义。
Ar优选地为未取代或取代的苯基，2-，3-或4-吡啶基或2-，4(6)-或5-嘧啶基。
当基团Ar的取代基之一是5-或6-员杂环时，其例子有吡咯烷，哌啶，吗啉，哌嗪，吡啶，1，4-二氢吡啶，嘧啶，三嗪，吡咯，噻吩，噻唑，咪唑，噁唑，异噁唑，吡唑或噻二唑残基。
当基团Ar的取代基之一为碳环基团时，它尤其为苯基、环戊基或环己基。
当Ar与碳环或杂环基稠合时，它尤其为萘，二-或四-氢萘，喹啉，二-或四-氢喹啉，吲哚，二氢吲哚，苯并咪唑，苯并噻唑，苯并噻二唑，苯并吡咯或苯并三唑残基。
一个优选的方案包含其中A为可包含至少一个选自O，S，NR3，亚环己基和双键或叁键的C1-C10亚烷基的式I化合物。
另一优选的方案包含式I化合物的应用，其中R1，R2和R3相互独立地为H，可以未取代或被OH，OC1-C8烷基或OH取代的C1-C8烷基，或OH，OC1-C8烷基，SR4或NR4R5，其中R4和R5相互独立地为H或C1-C8烷基，取代的C1-C8烷基；
Ar是苯基，吡啶基或嘧啶基，它们可具有一、二、三或四个选自H，可被OH，OC1-C8烷基取代的C1-C8烷基，OR4，其中R4是H，可被OH，OC1-C8烷基或卤素取代的C1-C8烷基，或CHF2，CF3，CN，卤素，C2-C6烯基，C2-C6炔基，C3-C6环己基，苯基，萘基和具有1至3个选自O，N和S的杂原子的5-或6-员杂环芳基。
另一优选的方案包含下述式I化合物的应用，其中B是或
另一优选的方案是下述式I化合物的应用，其中Ar是可具有一至四个相互独立地选自H，可被OH，OC1-C8烷基或卤素取代的C1-C8烷基的取代基的苯基，或苯基，萘基，吡咯基，CN，NO2，CF3，CHF2，卤素，SO2R4或SR4，其中R4是H或C1-C8烷基，或其中取代基相互独立地选自C1-C8烷基，苯基，CF2，CHF3，CN，NO2，卤素，OC1-C8烷基，或SR4，其中R4是H或C1-C8烷基，而Y是H，C1-C8烷基，Hal或CF3。
另一优选的方案是如下式I化合物的应用，其中Ar是嘧啶基，其上具有一至三个相互独立地选自H，C1-C8烷基，苯基，萘基，C3-C6环己基、OH，OC1-C8烷基，卤素，CN，NO2，CF3，CHF2和具有1至3个选自O，N和S的杂原子的5-或6-员杂环芳香或非芳香基团的取代基。
另一优选的方案是如下式I化合物的应用，其中Ar是吡啶基，它具有一至四个相互独立地选自H，C1-C8烷基，苯基，萘基，OH，OC1-C8烷基烷基，卤素，CF3，CN，C2-C6烯基，C2-C6炔基和具有1至3个选自O，N和S的杂原子的5-或6-员杂环芳基的取代基。
本发明也包含式I化合物与生理上耐受的酸的酸加成盐。合适的生理上耐受的有机和无机酸的例子有盐酸，氢溴酸，磷酸，硫酸，草酸，马来酸，富马酸，乳酸，酒石酸，己二酸或苯甲酸。其它可被使用的酸描述于药剂研究的进展(Fortschritte der Arzneimittelforschung)，卷10，P224往后，Birkhauser出版社，巴塞尔和斯图加特，1966。
式I化合物可具有一个或多个不对称中心。因此本发明不仅包括外消旋体，也包括相关的对映异构体和非对映异构体。本发明在各种情况下也包括互变异构形成。
式I’化合物也可通过类似于在，例如，A.R.Katritzky，C.W.Rees(ed.)，综合杂环化学“Comprehen-sive Heterocyclic Chemistry)”，第一版，Pergamon出版社1984，尤其是卷3，部分2A；D.J.Brown，发表在“杂环化合物化学(The Chemistry of Heterocyclic Compounds)”的“嘧啶”一文，E.C，Taylor编，John Wiley & Sons Inc.NY，尤其是卷16+增刊I+II(1985)和卷52(1994)和其中所引的文献中所述的常规方法制备。制备化合物的方法包括I)使通式II的化合物：
其中Y1是普通离去基，与通式III
H-B-Ar的化合物反应；ii)为了制备其中A是氧或硫或NR4的式I’化合物：使通式IV的化合物其中Z1是O、S或NR4，而A1是C0-C18亚烷基，与通VI化合物反应
Y1-A2-B-Ar其中Y1具有前述意义，而A2是C1-C18亚烷基，其中A1和A2一起具有1至18个碳原子，iii)为了制备其中A包括基团COO或CONR4的或I’化合物：使通式VII的化合物：
或其盐，其中Y2是OH，OC1-C4烷基，Cl，或与CO一起为活化的酯基，而A1具有前述意义，与式VIII化合物反应：
Z1-A2-B-Ar其中A2具有前述意义，Z1为OH或NHR4，iV)为了制备其中A包括OCO或NR4CO基团的或I’化合物：使通式IV化合物
其中Z1是O或NR4，与或X化合物反应：
Y2CO-A2-B-Ar其中A2，B和Y2具有前述意义，并且其中R1，R2，R3，A，B和Ar具有前述意义。
上述反应一般在溶剂中，在室温至所用溶剂的沸点进行。可被使用的溶剂的例子有乙酸乙酯，四氢呋喃，二甲基甲酰胺，二甲氧基乙烷，甲苯，二甲苯或酮，如丙酮或甲基乙基酮。
如果需要，存在酸受体。合适的酸受体有无机碱如碳酸钠或-钾，甲醇钠，乙醇钠，氢化纳或有机碱如三乙胺或吡啶。后者也可作为溶剂。
粗产物以常规方式例如通过过滤，蒸降溶剂或从反应混合物中萃取，等等而分离。产生的化合物可以常规方式例如通过从溶剂中重结晶、层析或转化为酸加成化合物而纯化。
酸加成盐以常规方式通过将游离碱与适当的酸混合而制备，可能在溶液中，在有机溶剂例如低级醇如甲醇，乙醇或丙醇，醚如甲基叔丁基醚，酮如丙酮或甲基乙基酮，或酯如乙酸乙酯中进行。
上述原料被公开于文献中或可通过已知方法制备。
为了治疗上述病症，根据本发明的化合物被以常规方式口服或非肠胃(皮下，静脉内，肌内，腹膜内)给药。给药也可以通过鼻咽道用烟雾或喷雾进行。
剂量取决于患者的年龄，状况和体重以及给药的方式。作为规律、活性物质的目剂量为口服给药每位患者约每天10至1000mg，而非肠胃给药为每位患者每天约1至500mg。
本发明也涉及含有根据本发明的化合物的药物组合物。这些组合物为常用的固体或液体药物给药形式，例如为片剂，包膜片剂，胶囊，粉形，丸形，糖衣片剂，栓剂，溶液或喷雾剂.在这些情况下，活性物质可以与常规药物佐剂如片剂粘合剂，填料，防腐剂，片剂崩解剂，流动调节剂，塑化剂，湿润剂，分散剂，乳化剂，溶剂，缓释剂，抗氧化剂和/或推进气体(见.H.Sucker等.，药物工艺(PharmazeutischeTechnologie)，Thieme出版社，斯图加特，1978)一起加工。以此方式获得的给药形式通常含有1至99％重量的活性物质。
下列实施例用于解释本发明，但不限制它。
实施例14-[3-(4-{3-三氟甲基苯基}哌嗪基)丙硫基]嘧啶a)1-(3-氯苯基)-4-(3-三氟甲基苯基)哌嗪
30g(0.13mol)间三氟甲基苯基哌嗪，23g(0.146mol)1-溴-3-氟丙烯和15g(0.148mol)三乙胺在200ml THF中回流4小时。冷却后抽滤并浓缩。将粘性剩余物溶于乙酸乙酯，用水洗，MgSO4干燥，然后浓缩。残余物包含39g黄色油状产物(定量)。4-[3-(4-{3-三氟甲基苯基}哌嗪基)丙硫基]嘧啶
1.5g(13.4mmol)4-巯基嘧啶，4.3g(14mmol)1-(3-氯丙基)-4-(3-三氟甲基)哌嗪和1.5g(15mmol)三乙胺在5ml DMF中、于100℃搅拌1小时。然后将混合物倒入5％盐酸中，并用MTB萃取。水相用氢氧化钠溶液调成碱性，然后用乙酸乙酯萃取，有机相用MgSO4干燥并浓缩。剩余物通过色谱(流动相：CH2Cl2/CH3OH＝98/2)纯化。得到3.0g黄色油状产物(＝59％产率)。H-NMR[δ，ppm]：1.95(2H)；2.55(2H)；2.65(4H)；3.25(6H)；
7.06(3H)；7.15(1H)；7.35(1H)；8.33(1H)；
8.9(1H)2-[5-(4-{3-三氟甲基苯基}哌嗪基)戊基巯基]嘧啶
2.8g(25mmol)2-巯基嘧啶，4.64g(25mmol)1-溴-5-氯戊烷和2.58g(25.5mmol)三乙胺在100ml THF中回流4小时。冷却后，抽滤并浓缩，剩余物通过色谱(流动相：环己烷/乙酸乙酯＝92/8)纯化。得到2.8g产物(＝52％产物)。b)2-[5-(4-{3-三氟甲基苯基}哌嗪基)戊基巯基]嘧啶
2.8g(12.9mmol)2-(5-氯戊基巯基)嘧啶，3.27g(14.2mmol)间三氟甲基苯基哌嗪和1.44g(14.2mmol)三乙胺在5ml DMF中于90℃搅拌1小时。然后将混合物倒入水中并用CH2Cl2萃取三次，萃取液用MgSO4干燥并浓缩。剩余物与甲基叔丁基醚混合并抽滤，将母液浓缩。色谱(流动相：CH2Cl2/CH3OH＝97/3)纯化产物4.0g产物油状物(＝75％产率)。H-NMR[δ，ppm]：1.54(4H)；1.78(2H)；2.4(2H)；2.6(4H)；
3.18(2H)；3.23(4H)；6.95(1H)；
7.01(3H)；7.1(3H)；7.33(1H)；8.5(1H).
在下面表1中给出的化合物以类似的方式制备
表1 
在下面表2-6中提到的化合物可以由类似方式得到
表2
实施例号 R1 R2 R3 R6 R7 R8 R9 R10 X-Y A B62 H H OH H tBut H Me H CH2-N -CH2- -(CH2)3-63 H H OH H tBut H Ph H CH＝C S -(CH2)3-64 Me H OH H tBut H 1-吡咯 H CH＝C S -(CH2)3-65 H H NH2 H iProp H 2-萘 H CH＝C S -(CH2)3-66 H Me OH H Et H tBut H CH2-N -CH2- -(CH2)3-67 H H OH OMe tBut H H H CH＝C S -(CH2)3-68 H H NH2 OMe CF3 H H H CH＝C S -(CH2)3-69 H H OH H CF3 H tBut H CH2-N -CH2- -(CH2)3-70 H H NHMe OiProp iProp H H H CH2-N O -(CH2)4-71 Me H OH H H CN tBut H CH2-N -CH2- -(CH2)3-72 H H OH H H F tBut H CH＝C S -(CH2)3-73 H Me NH2 H H Cl iProp H CH2-N -CH2- -(CH2)3-74 H H NHMe H tBut H H OMe CH＝C S -(CH2)3-75 H H OH H iProp H H OMe CH2-N -CH2- -(CH2)4-实施例号 R1 R2 R3 R6 R7 R8 R9 R10 X-Y A B
76 H H OH OMe tBut H tBut H CH＝C S -(CH2)3-
77 H H OH OMe tBut H CF3 H CH2-N -CH2- -(CH2)3-
78 Me H OH OMe CF3 H tBut H CH2-N O -(CH2)5-
79 H H NH2 H nProp CN tBut H CH2-N -CH2- -(CH2)3-
80 H Me OH H CF3 CN iProp H CH＝C S -(CH2)3-
81 H H OH H Ph C＝CH tBut H CH2-N -CH2- -(CH2)3-
82 H H NH2 OMe tBut CN H H CH＝C S -(CH2)3-
83 H H NHMe H tBut CN CF3 OMe CH2-N -CH2- -(CH2)5-
84 H H OH OMe nProp F tBut H CH2-N -CH2- -(CH2)4-
85 H H OH H Ph CN tBut Me CH＝C S -(CH2)3-
86 H H OH OMe tBut F H H CH2-N -CH2- -(CH2)3-
87 H H OH H tBut H Me H CH2-N -CH2- -CH2-CH＝CH-CH2-
88 H H OH H tBut H Ph H CH＝C S -CH2-CH＝CH-CH2-
89 Me H OH H tBut H 1-吡咯基 H CH＝C S -CH2-CH＝CH-CH2-
90 H H NH2 H iProp H 2-萘基 H CH＝C S -CH2-C(CH3)＝CH-CH2-
91 H Me OH H Et H tBut H CH2-N -CH2- -CH2-C(CH3)＝CH-CH2-
92 H H OH OMe tBul H H H CH＝C S -CH2-C(CH3)＝CH-CH2-
93 H H NH2 OMe CF3 H H H CH＝C S -CH2-C(CH3)＝CH-CH2-
94 H H OH H CF3 H tBut H CH2-N -CH2- -CH2-CH＝CH-CH2-
95 H H NHMe OiProp iProp H H H CH2-N O -CH2-CH＝CH-CH2-
96 Me H OH H H CN tBut H CH2-N -CH2- -CH2-CH＝CH-CH2-
表2(续)实施例号 R1 R2 R3 R6 R7 R8 R9 R10 X-Y A B97 H H OH H H F tBut H CH＝C S -CH2-C(CH3)＝CH-CH2-98 H Me NH2 H H Cl iProp H CH2-N -CH2- -CH2-C(CH3)＝CH-CH2-99 H H NHMe H tBut H H OMe CH＝C S -CH2-C(CH3)＝CH-CH2-100 H H OH H iProp H H OMe CH2-N -CH2- -CH2-C(CH3)＝CH-CH2-101 H H OH OMe tBut H tBut H CH＝C S -CH2-CH＝CH-CH2-102 H H OH OMe tBut H CF3 H CH2-N -CH2- -CH2-CH＝CH-CH2-103 Me H OH OMe CF3 H tBut H CH2-N O -CH2-CH＝CH-CH2-104 H H NH2 H nProp CN tBut H CH2-N -CH2- -CH2-C(CH3)＝CH-CH2-105 H Me OH H CF3 CN iProp H CH＝C S -CH2-C(CH3)＝CH-CH2-106 H H OH H Ph C＝CH tBut H CH2-N -CH2- -CH2-C(CH3)＝CH-CH2-107 H H NH2 OMe tBut CN H H CH＝C S -CH2-C(CH3)＝CH-CH2-108 H H NHMe H tBut CN CF3 OMe CH2-N -CH2- -CH2-CH＝CH-CH2-109 H H OH OMe nProp F tBut H CH2-N -CH2- -CH2-C(CH3)＝CH-CH2-110 H H OH H Ph CN tBut Me CH＝C S -CH2-C(CH3)＝CH-CH2-111 H H OH OMe tBut F H H CH2-N -CH2- -CH2-CH＝CH-CH2-
表3实施例号 R1 R2 R3 R7 R9 R10 X-Y A B112 H H OH tBut Ph H CH2-N -CH2- -(CH2)3-113 H H OH tBut 2-萘基 H CH2-N S -(CH2)3-114 Me H OH tBut 1-吡咯 H CH2-N S -CH2-CH＝CH-CH2-115 H H NH2 tBut cHex H CH＝C -CH2- -CH2-C(CH3)＝CH-CH2-116 H H OH tBut nHex H CH2-N S -(CH2)3-117 H H OH tBut H OMe CH2-N -CH2- -CH2-C(CH3)＝CH-CH2-118 H Me OH iProp H OMe CH2-N S -CH2-CH＝CH-CH2-119 H H NH2 H CH3 OMe CH＝C NH -(CH2)3-120 H H OH H iProp OMe CH2-N O -(CH2)3-121 H H OH tBut H CH3 CH2-N S -CH2-C(CH3)＝CH-CH2-122 H H OH tBut tBut OMe CH2-N S -(CH2)3-123 Me H OH tBut iProp OMe CH2-N S -CH2-CH＝CH-CH2-124 H H NH2 Ph tBut Cl CH＝C -CH2- -CH2-C(CH3)＝CH-CH2-125 H H OH 2-萘 tBut Me CH2-N S -(CH2)3-126 H H OH tBut CF3 OMe CH2-N -CH2- -CH2-C(CH3)＝CH-CH2-
表4
实施例号 R1 R2 R3 R7 R8 R9 R10 X-Y A B127 H H OH tBut H tBut H CH2-N S -(CH2)3-128 H H OH tBut CN H H CH2-N S -(CH2)3-129 Me H OH tBut H H OMe CH2-N NH -CH2-CH＝CH-CH2-130 H H OH H CN tBu H CH＝C -CH2- -CH2-C(CH3)＝CH-CH2-131 H H NH2 CF3 H tBut H CH2-N S -(CH2)3-132 H H OH nProp H iprop H CH＝C -CH2- -(CH2)3-133 H Me OH H H iProp OMe CH＝C S -(CH2)3-134 H H OH tBut H tBut H CH2-N NH -CH2-CH＝CH-CH2-135 H H OH tBut CN H H CH2-N S -(CH2)4-136 H H NH2 tBut H H OMe CH2-N O -(CH2)3-137 Me H OH H CN tBu H CH＝C S -CH2-C(CH3)＝CH-CH2-138 H H OH CF3 H tBut H CH2-N -CH2- -(CH2)3-139 H H OH nProp H iProp H CH2-N S -(CH2)3-
表4(续)实施例号 R1 R2 R3 R7 R8 R9 R10 X-Y A B140 H H NHMe H H iProp OMe CH2-N S -(CH2)3-141 H H OH nProp CN tBut H CH2-N S -(CH2)4-142 H H OH CF3 CN iProp H CH2-N S -(CH2)3-143 Me H OH Ph C＝CH tBut H CH2-N NH -CH2-CH＝CH-CH2-144 H H OH tBut CN tBut H CH＝C -CH2- -CH2-C(CH3)＝CH-CH2-145 H H NH2 tBut H nProp OMe CH2-N S -(CH2)3-146 H H OH Ph H tBut OMe CH＝C -CH2- -(CH2)5-147 H Me OH CF3 H tBut OMe CH＝C S -(CH2)3-148 H H OH tBut F H Me CH2-N NH -CH2-CH＝CH-CH2-149 H H OH nProp CN tBut Me CH2-N S -CH2-CH＝CH-CH2-150 H H NH2 nProp C＝CH tBut OMe CH＝C -CH2- -CH2-C(CH3)＝CH-CH2-151 H H OH tBut CN H OMe CH2-N S -(CH2)4-
表5
实施例号 R1 R2 R3 R6 R8 R9 R10 X-Y A B152 H H OH OMe H tBut H CH2-N S -(CH2)3-153 H H OH OMe H CF3 H CH2-N S -(CH2)3-154 Me H OH OMe H tBut H CH2-N NH -CH2-CH＝CH-CH2-155 H H OH H CN tBut H CH＝C -CH2- -CH2-C(CH3)＝CH-CH2-156 H H NH2 H F tBut H CH2-N S -(CH2)3-157 H H OH Me Cl iProp H CH＝C -CH2- -(CH2)3-158 H Me OH H H iProp OMe CH＝C S -(CH2)3-159 H H OH H H tBut OMe CH2-N NH -CH2-CH＝CH-CH2-160 H H OH CN H CF3 H CH2-N S -(CH2)4-161 H H NH2 H CN H OMe CH2-N O -(CH2)3-162 Me H OH H H tBu OEt CH＝C S -CH2-C(CH3)＝CH-CH2-163 H H OH H CN tBut H CH2-N -CH2- -(CH2)3-164 H H OH Me H iProp H CH2-N S -(CH2)3-165 H H NHMe OMe H iProp H CH2-N S -(CH2)3-
表5(续)实施例号 R1 R2 R3 R6 R8 R9 R10 X-Y A B166 H H OH OMe CN tBut H CH2-N S -(CH2)3-167 H H OH OMe Me tBut H CH2-N S -(CH2)3-168 Me H OH H CN tBut OMe CH2-N NH -CH2-CH＝CH-CH2-169 H H OH Me H tBut OMe CH＝C -CH2- -CH2-C(CH3)＝CH-CH2-170 H H NH2 H Cl CF3 Me CH2-N S -(CH2)3-171 H H OH OMe CN tBut Me CH＝C -CH2- -(CH2)3-172 H Me OH Me Me iProp Me CH＝C S -(CH2)3-
表6
实施例号 R1 R2 R3 R6 R7 R9 R10 X-Y A B173 H H OH H tBut tBut H CH2-N S -(CH2)3-174 H H OH H tBut Ph H CH2-N S -(CH2)3-175 Me H OH H tBut 1-吡咯基 H CH2-N NH -CH2-CH＝CH-CH2-176 H H OH H 正丙基 tBut H CH＝C -CH2- -CH2-C(CH3)＝CH-CH2-177 H H NH2 H CF3 tBut H CH2-N S -(CH2)3-178 H H OH H 2-萘基 tBut H CH＝C -CH2- -(CH2)3-179 H Me OH OMe tBut H H CH＝C S -(CH2)3-180 H H OH OMe iProp H H CH2-N NH -CH2-CH＝CH-CH2-181 H H OH OMe H CF3 H CH2-N S -(CH2)4-182 H H NH2 H tBut H OMe CH2-N O -(CH2)3-183 Me H OH H iProp H Me CH＝C S -CH2-C(CH3)＝CH-CH2-184 H H OH CN tBut H H CH2-N -CH2- -(CH2)3-185 H H OH H H CF3 Me CH2-N S -(CH2)3-186 H H NHMe H nProp tBut H CH2-N S -(CH2)3-
表6(续)实施例号 R1 R2 R3 R6 R7 R9 R10 X-Y A B187 H H OH OMe tBut iProp H CH2-N S -(CH2)4-188 H H OH OMe CF3 tBut H CH2-N NH -CH2-CH＝CH-CH2-189 Me H OH Me tBut nProp H CH＝C -CH2- -CH2-C(CH3)＝CH-CH2-190 H H OH Me tBut H OMe CH2-N S -(CH2)5-191 H H NH2 OMe tBut tBut OMe CH＝C -CH2- -(CH2)3-192 H H OH Me CF3 tBut OMe CH＝C S -(CH2)3-
药物剂形实施例：A)片剂
下列组合物的片剂以普通方式在压片机中压制
40mg 实施例1的物质
1200mg 玉米淀粉
13.5mg 明胶
45mg 乳糖
2.25mg Aerosil(亚显微态的细分散体的化学纯二
氧化硅)
6.75mg 马铃薯淀粉(为6％膏状物)B)糖衣片剂
20mg 实施例4物质
60mg 片芯组合物
70mg 糖衣组分物
片芯组合物包含9份玉米淀粉，3份乳糖和1份乙烯基吡咯烷酮/乙酸乙烯基酯60∶40共聚物。糖衣组合物包含5份蔗糖，2份玉米淀粉，2份碳酸钙和1份滑石。以此方式生产的糖衣片剂随后装备肠衣。生物学研究—受体-结合研究1)D3结合试验
从国际生物制品保藏机构(Res.Biochemicals Internat.(OneStrath-more Rd.，Natick，MA 01760-2418，USA)获得的克隆过的表达人D3受体的CCL 1.3小鼠成纤维细胞被用于结合研究。细胞制备
D3-表达的细胞在含10％胎牛血清(GIBCO No.041-32400N)；100U/ml青霉素和0.2％链霉素(GIBCO BRL，Gaithersburg，MD，USA)的RPMI-1640中生长。48小时后，细胞用PBS洗涤，并与0.05％含胰蛋白酶的PBS温育5分钟。然后用培养基中和，通过在300×g离心收集细胞。为了裂解细胞，短暂地用裂解缓冲液(5mM tris-HCl，pH7.4，与10％甘油)洗涤沉淀物，然后在浓度为107细胞/ml的裂解缓冲液中，在4℃温育30分钟。细胞在200×g离心10分钟，在液氮中贮存沉淀物。结合试验
为了进行D3受体—结合试验，膜被以约106细胞/250μl试验混合物的浓度悬浮于温育缓冲液(50mM tris-HCl，pH7.4，带有120mM NaCl，5mM KCl，2mMCaCl2，2mM MgCl2，10μM羟基喹啉、0.1％抗坏血酸和0.1％BSA)中，并在30℃与0.1nM 125I-止呕灵在试验物质存在和不存在下温育。非物异性结合用10-6M螺旋哌丁苯测定。
60分钟后，游离的和结合的放射性配体通过在Skatron细胞收集器(Skatron，Lier，Norway)上滤过GF/B玻璃纤维滤器(whatman，England)而公开，滤器用pH7.4的冰-冷tris-HCl缓冲器洗涤。在滤器上收集的放射活性用Packard 2200 CA液体闪烁计数器定量化。
Ki值通过非线性回归分析用，LIGAND程序测定。2)D2结合试验膜制剂a)尾状核(牛的)
将尾状核从牛脑中除去并在冰-冷的0.32M蔗糖溶液中洗涤。测定重量后，该物被弄碎并在5-10体积的蔗糖溶液中用Potter-Evehjem均化机(500rpm)均化。均化液在300×g离心15分钟(4℃)，产生的上层清液在40000×g离心另外15分钟。残渣然后通过再悬浮和离心，用50mM tris-HCl，pH7.4洗两次。该膜在液N2中贮存直至使用。b)纺状体(大鼠)
得自Sprague-Dawtey大鼠的纺状体在冰-冷的0.32M蔗糖溶液中洗涤。测定重量后，脑部分在5-10体积的蔗糖溶液中用Potter-Elvehjem均化机(500rpm)均化。均化液在40000×g离心10分钟(4℃)，然后残渣通过再悬浮和离心，用50mMtris-HCl，0.1nM EDTA和0.01％抗坏血酸(pH7.4)洗涤几次。洗涤过的残渣被再悬浮于上述缓冲液中，并在37℃温育20分钟(以破裂内源性多巴胺)。然后将膜用缓冲液洗两次，部分在液氮中冷冻。膜制剂稳定至多1周。结合试验a)3H-螺旋哌丁苯(D2低)
尾状核在温育缓冲液(mM：tris-HCl50，NaCl120，KCl5，MgCl21，CaCl22，pH7.4)中处理。各种混合物，各1ml，被制备：—总结合：400μg膜+0.2nmol/l 3H-螺旋哌丁基(Du Pont deNemours，NET-565)。—非特异性结合：作为用于总结合的混合物+10μm(+)-butaclamol。—试验物质：作为用于总结合的混合物+增加试验物质浓度。
在25℃湿育60分钟后，混合物在Skatron细胞选择器(得自zinsser，Frankfurt)上滤过GF/B玻璃纤维滤器(whatman，England)，滤器用冰-冷的50mM tris-HCl缓冲液pH7.4洗涤。收集在滤器上的放射活性用Packard 2200CA液体闪烁计数器定量化。
Ki值通过非线性回归分析，用LIGAND程序或通过用Cheng和Prusoff公式转换IC50值而测定。b)3H-ADTN(D2高)
纹状体膜在温育缓冲液(50mM tris-HCl，pH7.4，1mMMnCl2和0.1％抗坏血酸)中处理。
各种混合物，各1ml，被制备。—总结合：300μg湿重+1nM 3H-ADTN(Du Pont deNemours，Customer synthesis)+100nM SCH 23390(D1受体的占有)。—非特异性结合：作为总结合的混合物+50nM螺旋哌丁基。—试验物质：作为总结合的混合物+试验物质的增加浓度。
在25℃温育60分钟后，混合物在Skatron细胞选择器(得自Zinsser，Frankfurt)上滤过GF/B玻璃纤维滤器(whatman，England)，滤器用冰-冷的50mM tris-HCl缓冲液，pH7.4洗涤。收集在滤器上的放射活性用Packard 2200CA液体闪烁计数器定量化。
如a)中进行评价。
在这些试验中，根据本发明的化合物对D3受体显示非常好的亲和性和高的选择性。代表性化合物的结果列于下表7中。
表7
受体结合
| 实施例号 | D3 125I-止呕灵Ki[nM] | D2 3H-螺旋哌丁苯Ki[mM] | 选择性Ki D2/Ki D3 |
| 1213171948 | 4.22.32.83.04.0 | 357142200175480 | 85617158120 |
Claims (17)
1.式I的嘧啶化合物和其与生理耐受酸所成盐的用途：
其中A 是可包含至少一个选自O，S，NR4，CONR4，NR4CO，COO，OCO和双键或叁键基团的C1-C18亚烷基，B是或
R1，R2，R3相互独立地选自H，卤素，OR4，NR4R5，SR4，CF3，CN，CO2R4，和未取代的或被OH，OC1-C8烷基或卤素取代的C1-C8烷基，R4 是H，未取代或被OH，OC1-C8烷基或卤素取代的C1-C8烷基，R5 具有对R4指明的意义，或为COR4或CO2R4；Ar 是苯基，吡啶基，嘧啶基或三嗪基，其中Ar具有一至四个取代基，这些取代基各自独立地选自OR5，C1-C8烷基，C2-C6烯基，C2-C6炔基，卤素，CN，CO2R4，NO2，SO2R4，SO3R4，NR4R5，SO2NR4R5，SR4，CF3，CHF2，5-或6-员碳环族芳香或非芳香环和5-或6-员杂环族芳香或非芳香环，杂环上带有1-3个选自O，S和N的杂原子，这些环可未取代或被C1-C8烷基，卤素，OC1-C8烷基，OH，NO2，CF3取代，并且其中Ar也可以与上面定义的类型的碳环或杂环稠合，用于生产治疗响应多巴胺受体D3拮抗剂或激动剂的病症的药物组合物。
2.根据权利要求1式I嘧啶化合物的用途，其中A 是可包含至少一个选自O，S，NR4，CONR4，NR4CO，COO，OCO和双键或叁键基团的C1-C18亚烷基，B是
或
R1，R2，R3相互独立地选自H，卤素，OR4，NR4R5，SR4，CF3，CN，CO2R4和未取代的或被OH，OC1-C8烷基或卤素取代的C1-C8烷基，R4 是H，未取代或被OH，OC1-C8烷基或卤素取代的C1-C8烷基R5 具有对R4指明的意义，或为COR4或CO2R4；Ar 是苯基，吡啶基，嘧啶基或三嗪基，其中Ar具有一至四个取代基，这些取代基各自独立地选自OR5，C1-C8烷基，C2-C6烯基，C2-C6炔基，卤素，CN，CO2R4，NO2，SO2R4，SO3R4，NR4R5，SO2NR4 R5，SR4，CF3，CHF2，5-或6-员碳环族芳香或非芳香环和5-或6-员杂环族芳香或非芳香环，该杂环上带有1-3个选自O，S和N的杂原子，这些环可未取代或被C1-C8烷基，Hal，OC1-C8烷基，OH，NO2，CF3取代，并且其中Ar也可以与上面定义的类型的碳环或杂环稠合。
3.如权利要求1或2的式I化合物的用途，其中A是可包含氧或硫原子并可包含至少一个选自O，S，NR4和双键或叁键的C3-C10亚烷基。
4.如权利要求前述任一的式I化合物的用途，其中R1，R2和R3相互独立地为H，未取代的或被OH，OC1-C8烷基或OH取代的C1-C8烷基，或OH，OC1-C8烷基、SR4或NR4R5，其中R4和R5相互独立地为H或C1-C8烷基；
Ar是苯基，吡啶基或嘧啶基，它们可具有一，二，三或四个选自H，可被OH，OC1-C8烷基或卤素取代的C1-C8烷基，或OR4，其中R4是H，C1-C8烷基，后者可被OH，OC1-C8烷基或卤素取代，或CHF2，CF3，CN，卤素，C2-C6烯基，C2-C6炔基，C3-C6环己基，苯基，萘基或具有1至3个选自O，N和S的杂原子的5-或6-员杂环芳香基团。
5.如权利要求4中式I化合物的用途，其中B是
或
6.如权利要求4或5中式I化合物的用途，其中R1是H，未取代或被OH，OC1-C8烷基或卤素取代的C1-C8烷基，或OR4，SR4或NR4R5，其中R4和R5相互独立地为H或C1-C8烷基；R2是H，OR4或C1-C8烷基；而R3是氢。
7.如权利要求1-6任一项中式I化合物的用途，其中Ar是具有一至四个相互独立地选自H，C1-C8烷基的取代基的苯基，C1-C8烷基可是未取代的或被OH，OC1-C8烷基或卤素取代的，或苯基，萘基，吡咯基，CN，NO2，CF3，CHF2，卤素，SO2R4或SR4，其中R4是H或C1-C8烷基。
8.如权利要求7中的用途，其中取代基相互独立地选自C1-C8烷基，苯基，CF3，CHF2，CN，NO2，卤素，OC1-C8烷基或SR4，其中R4是H或C1-C8烷基，而Y是H，C1-C8烷基，卤素或CF3。
9.如权利要求7或8中的用途，其中Ar具有一个或两个取代基，它们在各种情况下在间位。
10.如权利要求1至6任一项中式I化合物的用途，其中Ar是具有一至三个相互独立地选自H，C1-C8烷基，苯基，萘基，C3-C6环己基，OH，OC1-C8烷基，卤素，CN，NO2，CF3，CHF2的取代基的嘧啶基，和具有1至3个选自O，N和S的5-或6-员杂环芳香-或非芳香基团。
11.如权利要求1至10任一项中式I化合物的用途，其中
Ar是嘧啶基，它具有一至四个相互独立地选自H，C1-C8烷基，苯基，萘基，OH，OC1-C8烷基，卤素，CF3，CN，C2-C6烯基，C2-C6炔基，和具有1至3个选自O，N和S的杂原子的5-或6-员杂环芳香基团。
12.式I’的嘧啶化合物和其与生理上耐受酸所成的盐，
其中A，B，Ar，R1，R2，和R3具有在权利要求1至8中所述的意义，下式化合物除外其中R1是OH或SH，R2和R3相互独立地为H，C1-C6烷基，OC1-C6烷基，SC1-C6烷基，CO2H，OH，SH，NR4R5或卤素，其中R4和R5为H或C1-C6烷基，A是SC1-C6亚烷基，NHC1-C6亚烷基或N(C1-C6烷基)-C1-C6亚烷基，B是
而Ar是可具有一个或多个选自C1-C4烷基，OC1-C4烷基，SC1-C4烷基，NO2，CF3，F，Cl或Br的取代基的苯基。
13.如权利要求12中的下式化合物
14.下式嘧啶化合物和其生理上耐受的盐： 
15.制备权利要求12、13或14的化合物的方法，包括i)使通式II的化合物：
其中Y1是普通离去基，与通式III
H-B-Ar的化合物反应；ii)为了制备其中A是氧或硫或NR4的式I’化合物：使通式IV的化合物
其中Z1是O，S或NR4，而A1是C0-C18亚烷基，与通式VI化合物反应
Y1-A2-B-Ar其中Y1具有前述意义，而A2是C1-C18亚烷基，其中A1和A2一起具有1至18个碳原子，iii)为了制备其中A包括基团COO或CONR4的式I’化合物：使通式VII的化合物或其盐：其中Y2是OH，OC1-C4烷基，Cl，或与CO一起为活化的酯基，而A1具有前述意义，与式VIII化合物反应：
Z1-A2-B-Ar其中A2具有前述意义，Z1为OH或NHR4，iv)为了制备其中A包括OCO或NR4CO基团的式I’化合物：使通式IV化合物其中Z1是O或NR4，与式X化合物反应：
Y2CO-A2-B-Ar其中A2，B和Y2具有前述意义，并在其中R1，R2，R3，A，B和Ar具有在权利要求9和10中指明的意义。
16.一种药物组合物，含有至少一种如权利要求12，13或14中的式I化合物，并带有或没有生理上可接受的载体和/或辅助物质。
17.一种治疗响应多巴胺D3配体的病症的方法，在权利要求1至11任一项中定义的其中治疗有效量的化合物被对需要这类治疗的人给药。
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| GB0908394D0 (en) | 2009-05-15 | 2009-06-24 | Univ Leuven Kath | Novel viral replication inhibitors |
| GB0913636D0 (en) | 2009-08-05 | 2009-09-16 | Univ Leuven Kath | Novel viral replication inhibitors |
| KR20140003438A (ko) | 2010-11-15 | 2014-01-09 | 카톨리에케 유니버시테이트 루벤 | 항바이러스성 축합 헤테로사이클릭 화합물 |
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| BE756127A (fr) | 1969-09-12 | 1971-03-15 | Hoechst Ag | Ethers heterocycliques et leur preparation |
| GB1345449A (en) * | 1971-05-14 | 1974-01-30 | Science Union & Cie | Pyridylpiperazines and process for their preparation |
| BE787126A (fr) * | 1971-08-04 | 1973-02-05 | Byk Gulden Lomberg Chem Fab | Pyrimidines substituees, procedes de preparation de ces composes et medicaments contenant lesdits composes |
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| BE792206A (zh) * | 1971-12-02 | 1973-06-01 | Byk Gulden Lomberg Chem Fab | |
| CA985683A (en) * | 1972-10-27 | 1976-03-16 | Gilbert Regnier | Procede de preparation de n-amidoethyl piperazines |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1805937B (zh) * | 2003-04-14 | 2012-07-11 | 阿伯特有限及两合公司 | 具有多巴胺d3受体亲和性的n-[(哌嗪基)杂芳基]芳基磺酰胺化合物 |
| CN105541702A (zh) * | 2016-01-27 | 2016-05-04 | 宜春学院 | 类卢扎朵仑结构的芳胺基烷基硫类化合物及其制备方法 |
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