CN1452614A - 芳基哌嗪衍生物及其作为精神药物的用途 - Google Patents
芳基哌嗪衍生物及其作为精神药物的用途 Download PDFInfo
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- CN1452614A CN1452614A CN01815154A CN01815154A CN1452614A CN 1452614 A CN1452614 A CN 1452614A CN 01815154 A CN01815154 A CN 01815154A CN 01815154 A CN01815154 A CN 01815154A CN 1452614 A CN1452614 A CN 1452614A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/40—Nitrogen atoms attached in position 8
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- 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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- C07D209/02—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
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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Abstract
本发明涉及式(I)的芳基哌嗪衍生物，其中R1、R2、A、B、Ar和n代表给定的含义。
Description
本发明涉及芳基哌嗪衍生物及其制备以及作为精神药物的用途。
本发明的芳基哌嗪衍生物及其盐和溶剂化物如通式I所示：
其中A 为包括1或2个氮原子的稠合杂芳族环或杂脂族环，B 为-CO-或-CHOH-或-C(Ar)(OH)-R1和R2彼此独立地为H、烷基、C1-C6或卤素Ar 为未取代的或被卤素、NO2或CN单取代或多取代的苯基或噻
吩，和n 为1、2、3或4。
精神病包括精神分裂症类型的疾病可归因于边缘多巴胺系统活动过度(Snyder等，Science 184：1243-1253，1974)。已将安定剂(neuroleptic)的抗精神病作用归于其D2-拮抗特性(关于受体命名法：基础神经化学(Basic Neurochemistry)，编辑：G.J.Siegel，B.W.Agranoff，R.W.Albers，P.B.Molinoff，第5版，Raven出版公司，纽约，美国，12-13章；其它专业出版物包括：Creese等，Science 192：481-483，1976；Farde等，Psychopharmacology99：28-31，1989；Feeman等，Nature 261：717-719，1976；Wiesel等，Prog.Neuro-Psychopharmacol.& Biol.Psychiat.14：759-767，1990)。因此，根据安定剂与D2受体的结合，形成了关于精神分裂症的典型多巴胺假说。由于其锥体束外的副作用，典型D2拮抗剂的使用严格受限，特别是在长期施用的情况下。锥体束外副作用包括，例如，震颤、运动不能、张力障碍和静坐不能(Cavallaro&Smeraldi，CNS Drugs 4：278-293，1995)。仅有少数抗精神病药仅表现出明显低的锥体束外副作用或根本不产生锥体束外副作用，他们被称为“非典型的安定剂”(kervin，Brit.J.Psychiatry 1964，141-148，1994)。原型的非典型安定剂氯氮平具有非常低的锥体束外副作用，但是会引起其他严重的并发症，例如有时是致命的粒细胞缺乏症(Alvir等，New EngI.J.Med.329：162-167，1993)。
由于5-HT1A激动剂能加强传统多巴胺D2拮抗剂对动物的安定特性(Wadenberg&Ahlenios，J.Neural.Transm.74：195-198，1988)，并可防止多巴胺D2拮抗剂导致的强直性僵硬症(Costall等，Neuropharmacology14：859-868，1975)，因此5-HT1A-拮抗特性是有益的。已在精神分裂症患者中证实了
丁螺环酮(一种具有5-HT1A-拮抗和多巴胺D2-拮抗特性的药品)的效力(Goff等，J.Clin.Psychopharmacol.11：193-197，1991)。除了对5-HT1A受体有明显亲和力的各种多巴胺自身受体激动剂(例如
U-86170F，Lahti等，Naunyn-Schmiedeberg’s Arch.Pharmacol.344：509-513，1991)，
PD1431188(Melzer等，J.Pharmacol.Exp.Ther.274：912-920，1995)和
罗克吲哚(roxindole)(Bartoszyk等，J.Pharmacol.，Exp.Ther.276：41-48，1996)之外，仅开发少数对5-HT1A受体也具有亲和力的多巴胺D2拮抗剂，例如
马扎哌汀 (mazapertine)(Reiz等，J.Mid.Chem.37：1060-1062，1994)、S16924(Millan等，Br.J.Pharmacol.114：156B，1995)或
齐拉西酮 (ziprasidone)(Seeger等，J.Pharmacol.Exp.Ther.275：101-113，1995)。这些已知的化合物在亲和力或特异性方面均有缺点。马扎哌汀对α1受体也表现出亲和力。S16924还具有5-HT2A/C-拮抗特性，齐拉西酮还可与5-HT1D/2A/2C-受体结合。
本发明目的是制备有效的药物，特别是精神药物。本发明的另一目的是制备能与多巴胺D2受体和5-HT1A受体两者结合的有效化合物。
通过式I化合物及其可耐受盐和溶剂化物(如上所示)达到了该目的。
业已发现，式I化合物及其盐具有非常有价值的药理学特性和良好的可耐受性。它们特别可作用于中枢神经系统。具体地说，它们对5-HTIA型和/或多巴胺D2型受体具有高亲和力。
特别优选的是，式I化合物同时表现为5-HT1A受体激动剂和D2受体拮抗剂。未观察到其与另外的5-HT1D/2A/2C受体结合。
采用已知的5-HT1A(5-羟色胺)结合实验和多巴胺结合实验，可测定式I化合物的结合特性。(5-HT1A(5-羟色胺)结合实验：Matzen等，J.Med.Chem.，43，1149-1157(2000)，特别是1156页，并参见Eur.J.Pharmacol.：140，143-155(1987)；多巴胺结合实验：Bttcher等，J.Med.Chem.：35，4020-4026(1992)，并参见J.Neurochem.：46，1058-1067(1986))。
式I化合物不同于上述非典型的安定剂。
本发明化合物能用于治疗与5-羟色胺(serotinin)和多巴胺神经递质体系有关的疾病，所述体系中包含高亲和力的5-羟色胺受体(5-HT1A受体)和/或多巴胺D2受体。施用通式I化合物的最重要适应症可以是任何类型的精神病，特别是精神分裂症类型的精神障碍。此外，化合物也可用于减少认知功能失调，即改善学习和记忆能力。通式I化合物也适于控制Alzheimer病症状。本发明通式I物质还适于预防和控制脑梗塞(脑卒中)，例如脑中风和大脑局部缺血。该物质也适于治疗紊乱病症，例如：儿童和青少年的病理学焦虑状态、过度兴奋、活动过度和注意力障碍，深层(deep-seated)发育障碍，伴有智力低下的社会行为障碍，忧郁症，狭义(OCD)和广义(OCSD)强迫性障碍，某些性功能障碍，睡眠障碍和进食障碍，以及老年痴呆和Alzheimer类型痴呆的精神病学症状，即最广义的中枢神经系统疾病。
通式I化合物和及其可耐受盐和溶剂化物可用作药物的活性成分，例如抗焦虑药、抗抑郁剂、安定剂和/或抗高血压药。Ar 优选苯基，任选被一或多个卤素、-NO2或-CN单-、二-、三-
、四-或五取代。Ar还可代表任选被一或多个卤素、NO2或
-CN单-或二取代的硫代苯基。Ar特别为氟苯基、二氟苯基、
氰基苯基或甲苯基。特别优选地，Ar代表3-氟苯基、2，4-
二氟苯基、3-氰基苯基或4氟苯基，特别是4-氟苯基。B 优选地代表-CO-或-C(Ar)(OH)-，特别-C(4-氟苯基)(OH)-R1和R2彼此独立地优选为H或C1-C6-烷基，其中1-7氢原子任选被氟
代替。R1和/或R2可以是支链或非支链，优选地为甲基，乙
基，丙基、异丙基，正丁基，仲丁基，叔丁基，以及戊
基，1-、2-或3-甲基丁基，1，1-、1，2-或2，2-二甲基丙
基，1-乙基丙基，己基，1-、2-、3-或4-甲基戊基，1，1-
、1，2-、1，3-、2，2-、2，3-或3，3-二甲基丁基，1-或2-乙
基丁基，1-乙基-1-甲基丙基、1-乙基-2-甲基丙基，
1，1，2-或1，2，2-三甲基丙基。特别优选地，R1和/或R2为甲
基、乙基、异丙基、正丙基、正丁基或叔丁基。
也特别优选其中R1和R2同时为H的式I化合物，并且其中R1代表烷基和R2代表H的式I化合物。
优选地，其中基团
具有代表以下结构：特别优选含义为：
卤素为F、CI、Br或I，其中优选F和Cl，特别优选F，n 优选为1、2或3，其中特别优选n等于3。
取代基R1、R2、A、B和Ar彼此独立地代表其各自上述定义。更优选地，取代基的优选含义越多，通式I化合物具有更广泛的定义。选自以下化合物1a-1h及其盐和溶剂化物的化合物是特别优选的：
如果通式I化合物具有光学活性，则在任何可能的组合物中的式I化合物包括任何分离的光学对映体和任选相应的外消旋混合物。
采用酸可将通式I化合物转化成其相应的盐(即酸加成盐)。适用于该反应的酸应提供可耐受(即生物相容性和适当生物利用度)的盐。因此，可由于制备相应酸加成盐的无机酸包括：硫酸或氢卤酸例如盐酸，溴酸或磷酸例如正磷酸，硝酸，氨基磺酸，脂族、脂环族、芳基脂肪族、芳香或杂环一元或多元羧酸，磺酸或硫酸衍生物，例如甲酸，醋酸，丙酸，新戊酸，二乙基乙酸，丙二酸，琥珀酸，庚二酸，富马酸，马来酸，乳酸，酒石酸，苹果酸，苯甲酸，水杨酸，2-苯基丙酸，枸橼酸，葡糖酸，抗坏血酸，烟酸，异烟酸，甲磺酸或乙磺酸，乙烷二磺酸，2-羟基乙磺酸，苯磺酸，对甲苯磺酸，萘单磺酸和萘二磺酸以及硫酸十二烷基酯。
如有需要，可通过用强碱例如氢氧化钠、氢氧化钾或碳酸钠或碳酸钾对其盐进行处理，使通式I化合物释出相应的游离碱，条件是分子上没有其它酸性基团。在上述情况中，也可用强碱处理带有游离酸性基团的通式I化合物而形成盐。适宜的碱为碱金属氢氧化物、碱土金属氢氧化物，或者伯、仲或叔胺形式的有机碱。
通式I化合物的溶剂化物可理解为化学“惰性”溶剂分子与式I化合物因相互吸引而形成的加合物。例如，溶剂化物是一-和二水合物或与醇例如甲醇或乙醇形成的加成化合物。
已知药物可经合成转化成衍生物(例如，转化成烷基或酰基衍生物，转化成糖或寡肽衍生物等)，可在人体代谢中经胞外或胞内酶代谢再转化成通式I的活性化合物。本发明即涉及通式I化合物的“前药衍生物”。
本发明的更进一步主题是利用通式I化合物或其可耐受盐或溶剂化物制备药物，所述药物适用于治疗人或动物病症，特别是中枢神经系统紊乱，例如病理学的紧张状态、抑郁症和/或精神病；用来减少高血压治疗(例如用甲基多巴治疗)过程中的副作用；治疗内分泌和/或妇科疾病，例如，治疗肢端肥大症、性腺机能减退、继发性经闭、经期后(post-menstrual)综合征和青春期不期望的泌乳；并以与特异性麦角生物碱相似的方式用于预防和治疗大脑功能障碍(例如偏头痛)，特别是对老年人；和用于控制和预防脑梗塞(脑中风)，例如脑中风和大脑局部缺血。此外，含有通式I化合物的药物制剂和药物适用于改善认知功能能力和用于治疗Alzheimer病症状。具体地说，该药物适于治疗精神分裂症类型的精神障碍，并可用于控制精神病性焦虑状态。在本发明上下文中，术语“治疗”包括对人或动物疾病的预防和治疗。
通常，可采用类似于已知的、市售药物制剂(例如，溴隐亭和二氢麦角科尔宁制剂)的方式施用通式I物质，优选剂量为0.2-500mg、特别为0.2-15mg/剂量单位。每日剂量单位为0.001-10mg/kg体重。低剂量(0.2-1mg/剂量单位，0.001-0.005mg/kg体重)是特别适于治疗偏头痛的药物制剂。其他适应症优选采用10-50mg/剂量单位的剂量。然而，所施用的剂量取决于许多因素，例如相应成分的效力、患者年龄和体重以及全身状况。
本发明还涉及如权利要求1的式I化合物及其生理学可接受的盐或溶剂化物用作药物活性化合物。
本发明还涉及如权利要求1的式I化合物及其生理学可接受的盐或溶剂化物用作D2受体拮抗剂和5HT1A激动剂。
本发明还涉及如权利要求1的式I化合物及其生理学可接受的盐或溶剂化物用于控制疾病。
本发明另一目的是制备药物制剂的方法，该方法包括采用适宜载体将通式I化合物或其可耐受盐或溶剂化物之一制成适宜的剂型。通式I化合物可与至少一种载体或赋形剂一起制成适宜剂型，如果适宜，也可与其它活性成分适当地组合。
适宜的载体是适于肠内(例如口服)或非肠道或局部给药的有机或无机物质，它们不应与本发明通式I物质起反应。这类载体的示例包括：水、植物油、苯甲醇、醇、聚乙二醇、明胶、碳水化合物例如乳糖和淀粉，硬脂酸镁，滑石和粗矿脂。片剂、包衣片、胶囊剂、糖浆剂、糖汁(juices)、滴剂或栓剂特别适于肠内给药。溶液剂优选为油性或水性溶液，例如混悬剂、乳剂或者植入剂适于非肠道给药。软膏剂、乳膏或粉剂可供外用。通式I化合物也可冻干，所得冻干物经重构得到可注射制剂。
本发明还涉及含有至少一种通式I化合物或至少一种其可耐受盐或溶剂化物的药物，如果适当，还包含例如载体、赋形剂等成分。这些制剂可用作治疗人或动物疾病的药物。
可对上述药物进行灭菌，也可与赋形剂例如润滑剂、防腐剂、稳定剂和/或湿润剂、乳化剂、渗透活性物质、缓冲剂、着色剂或芳香剂一起配制，得到其它药物制剂。
本发明的另一主题是用于制备式I化合物及其盐和溶剂化物的方法，其特征在于：
(a)式II化合物
其中R1、R2和A的定义如上，与式III化合物反应
其中Ar、B和n的定义如上，并且L为离去基团，特别为Cl、甲苯磺酸酯或Br，并且如果B代表-CO-，则基团B任选被氢化、烷基化或芳化，并且如果适当，式I的碱性或酸性化合物经酸或碱处理可转化成其一种盐或溶剂化物。进行烷基化和芳基化时优选采用Grignard试剂或有机锂试剂，优选采用络合氢化物进行氢化。
也可采用已知方法制备式I化合物和起始物，例如文献(例如，标准操作例如Houben-Weyl法，有机化学方法[Methoden derorganischen Chemie]，Georg-Thieme-Verlag，斯图加特)描述的方法，即在已知且适于所述反应的反应条件进行。也可采用已知方法的改良形式，在此不一一赘述。
如有需要，也可就地形成起始物，这样就不必再从反应混合物中分离出来，而立即进一步反应得到式I化合物。
优选地，按以下反应路线制备式I芳基哌嗪衍生物：反应路线1： 其中A、R1和R2的定义如上。
通过以下实施例对本发明加以描述。
借助于电子喷雾电离质谱测定了分子量(M+H+)。由HPLC/MS(HPLC与电子喷雾电离质谱仪联用)测得质谱数据。如同此方法中的惯例，该方法中的数值不是未修饰(unmodified)化合物的分子量，而是质子化的化合物的分子量(即[M+H+])。方法参见以下文献的描述：M.Yamashita，J.B.Fenn，J.Phys.Chem.88，1984，4451-4459；C.K.Meng等，Zeitschrift für Physik D10，1988，361-368；J.B.Fenn等，Science 246，1989，64-71。实施例14-[4-(喹啉-8-基)哌嗪-1-基]-1-(4-氟苯基)丁-1-酮三氯化物二水合物
6g 1-(喹啉-8-基)哌嗪
1和2.8g 4-氯-1-(4-氟苯基)丁-1-酮
2于120°(浴温)加热1小时。冷却混合物，处理用水并用乙酸乙酯萃取。经碳酸钾干燥之后，蒸馏出乙酸乙酯，并将残渣置于硅胶中进行色谱分析，得到
3。
为了形成酸加成盐，将700mg
3溶于20ml乙酸乙酯中，并用乙醇性盐酸酸化。经抽吸滤出结晶的盐酸盐，然后用乙酸乙酯洗涤(mp.119-120°，[M+H]+：378)。实施例24-[4-(喹啉-8-基)哌嗪-1-基]-1-(4-氟苯基)丁-1-醇富马酸盐
将1.3g 4-[4-(喹啉-8-基)哌嗪-1-基]-1-(4-氟苯基)丁-1-酮3溶于25ml甲醇中，搅拌和冷却下分批加入264mg氢硼化钠。混合物于室温下再搅拌2小时，然后于真空中蒸馏出甲醇。残渣用水处理，用32％的NaOH碱化，然后用二氯甲烷萃取。经碳酸钾干燥之后，蒸馏出二氯甲烷并将残渣置于硅胶中进行色谱分析，得到
4。将残渣加热溶于含337mg富马酸的20ml乙醇中，所得溶液于真空中蒸发。残渣用乙酸乙酯处理，经抽吸滤出结晶的富马酸盐，用乙酸乙酯洗涤(mp.145-146°，[M+H]+：380)。实施例31，1-双-(4-氟苯基)-4-[4-(2-甲基喹啉-8-基)哌嗪-1-基)-1-丁醇富马酸盐
于室温下，向在30ml无水四氢呋喃中的镁屑(423mg)与1-溴-4-氟苯(3.05g)的Grignard溶液中，滴加在20ml无水四氢呋喃中的2.2g1-(4-氟苯基)-4-[4-(喹啉-8-基)哌嗪-1-基]丁-1-酮
3。混合物于室温搅拌过夜，然后在冷却下滴加10％氯化铵溶液(25ml)，混合物用乙酸乙酯萃取。经碳酸钾干燥之后，蒸馏出乙酸乙酯，并将残渣置于硅胶中进行色谱分析，得到
5。将残渣加热溶于含290mg富马酸的30ml乙醇中。冷却溶液，经抽吸滤出结晶的富马酸盐，用乙醇和乙酸乙酯洗涤(mp.219-220°，M+：473)。实施例41-(4-氟苯基)-4-[4-(2-甲基喹啉-8-基)哌嗪-1-基]丁-1-酮半富马酸盐
向在60ml乙腈中的4g 1-(2-甲基喹啉-8-基)哌嗪
6、2.43g碳酸钾和20mg碘化钾中，加入3.53g 4-氯-1-(4-氟苯基)丁-1-酮
2，混合物于80°在加热块上搅拌87小时。然后真空中蒸馏出乙腈，残渣用水处理并用二氯甲烷萃取。经碳酸钾干燥之后，蒸馏出二氯甲烷，并将残渣置于硅胶中进行色谱分析，得到
7。
为了形成酸加成盐，将1.2g
7加热溶于含有348mg富马酸的15ml乙醇中。经抽吸滤出冷却下结晶的富马酸盐，并用乙醇洗涤(mp.195-196°，[M+H]+：392)。实施例54-[4-(2-甲基喹啉-8-基)哌嗪-1-基]-1-(4-氟苯基)丁-1-醇倍半富马酸盐
类似于实施例2，采用1.3g(0.0033mol) 4-[4-(2-甲基喹啉-8-基)哌嗪-1-基]-1-
(4-氟苯基)丁-1-酮
7，249mg(0.0066mol) 氢硼化钠，和25ml 甲醇，得到化合物
8。
为了形成酸加成盐，将830mg
8加热溶于含有244mg富马酸的10ml乙醇中，溶液于真空中蒸发。残渣用乙酸乙酯处理，所得晶体经抽吸滤出，用乙酸乙酯洗涤(mp.164-165°，[M+H]+：394)。实施例61，1-双(4-氟苯基)-4-[4-(2-甲基喹啉-8-基)-1-丁醇半富马酸盐乙醇酸酯(ethanoate)
类似于实施例3，采用539mg 镁屑，3.9g(0.022mol) 1-溴-4-氟苯，2.9g(0.007mol) 1-(4-氟苯基)-4-[4-(2-甲基喹啉-8-基)哌嗪-
1-基)丁-1-酮
7，和50ml 无水四氢呋喃得到化合物
9。
为了形成酸加成盐，将2.3g
9加热溶于含有545mg富马酸的20ml乙醇中。经抽吸滤出冷却之后形成的富马酸盐结晶，结晶用乙酸乙酯洗涤(mp.129-130°，[M+H]+：488)。实施例74-[4-(吲哚-4-基)哌嗪-1-基]-1-(4-氟苯基)丁-1-酮二盐酸化物
类似于实施例4，采用4g(0.02mol) 1-(吲哚-4-基)哌嗪
104g(0.02mol) 4-氯-1-(4-氟苯基)丁-1-酮
2，2.8g(0.02mol) 碳酸钾40mg 碘化钾，和75ml 乙腈，得到化合物
11。
为了形成酸加成盐，将800mg碱加温溶于10ml乙醇中，并用乙醇/HCl酸化。冷却之后形成的盐酸盐结晶经抽吸滤出，并用乙醇和醚洗涤(mp.233-234°，[M+H]+：366)。实施例84-[4-(吲哚-4-基)哌嗪-1-基]-1-(4-氟苯基)-1-丁醇二盐酸化物
类似于实施例2，采用1.2g(0.0033mol) 4-[4-(吲哚-4-基)哌嗪-1-基]-1-(4-氟
苯基)丁-1-酮
11250mg(0.0066mol) 氢硼化钠，和30ml 甲醇与20ml 二氯甲烷的混合物，得到化合物
12。
为了形成酸加成盐，将1.1g
12加温溶于乙醇中，并用乙醇性HCl酸化。冷却之后形成的盐酸盐结晶经抽吸滤出，并用乙醇和醚洗涤(mp.227-228°，[M+H]+：368)。
采用适当的前体，可类似地制备以下化合物及其酸加成盐。实施例9-76：
R1 R2 B Ar(9) H H -CO- p-C6H4CN(10) H H -CO- o-C6H4F(11) H H -CO- m-C6H4F(12) H H -CO- p-C6H4Cl(13) H H -CO- m-C6H4Cl(14) H H -CO- C6H5(15) H H -CO- 2-C4H3S(16) H H -CH(OH)- p-C6H4CN(17) H H -CH(OH)- o-C6H4F(18) H H -CH(OH)- m-C6H4F(19) H H -CH(OH)- p-C6H4Cl(20) H H -CH(OH)- m-C6H4Cl(21) H H -CH(OH)- C6H5(22) H H -CH(OH)- 2-C4H3S(23) H H -C(p-C6H4F)(OH)- p-C6H4CN(24) H H -C(p-C6H4F)(OH)- o-C6H4F(25) H H -C(p-C6H4F)(OH)- m-C6H4F(26) H H -C(p-C6H4F)(OH)- p-C6H4Cl(27) H H -C(p-C6H4F)(OH)- m-C6H4Cl(28) H H -C(p-C6H4F)(OH)- C6H5(29) H H -C(p-C6H4F)(OH)- 2-C4H3S(30) H H -C(C6H5)(OH)- p-C6H4F(31) H H -C(C6H5)(OH)- o-C6H4F(32) H H -C(C6H5)(OH)- m-C6H4F(33) H H -C(C6H5)(OH)- p-C6H4Cl(34) H H -C(C6H5)(OH)- m-C6H4Cl
R1 R2 B Ar(35) H H -C(C6H5)(OH)- C6H5(36) H H -C(C6H5)(OH)- 2-C4H3S(37) H CH3 -CO- p-C6H4F(38) H CH3 -CO- o-C6H4F(39) H CH3 -CO- m-C6H4F(40) H CH3 -CO- p-C6H4F(41) H CH3 -CO- m-C6H4F(42) H CH3 -CO- C6H5(43) H CH3 -CO- 2-C4H3S(44) H CH3 -CH(OH)- p-C6H4F(45) H CH3 -CH(OH)- o-C6H4F(46) H CH3 -CH(OH)- m-C6H4F(47) H CH3 -CH(OH)- p-C6H4Cl(48) H CH3 -CH(OH)- m-C6H4Cl(49) H CH3 -CH(OH)- C6H5(50) H CH3 -CH(OH)- 2-C4H3S(51) H CH3 -C(p-C6H4F)(OH)- p-C6H4F(52) H CH3 -C(p-C6H4F)(OH)- o-C6H4F(53) H CH3 -C(p-C6H4F)(OH)- m-C6H4F(54) H CH3 -C(p-C6H4F)(OH)- p-C6H4Cl(55) H CH3 -C(p-C6H4F)(OH)- m-C6H4Cl(56) H CH3 -C(p-C6H4F)(OH)- C6H5(57) H CH3 -C(p-C6H4F)(OH)- 2-C4H3S(58) H CH3 -C(C6H5)(OH)- p-C6H4F(59) H CH3 -C(C6H5)(OH)- o-C6H4F(60) H CH3 -C(C6H5)(OH)- m-C6H4F(61) H CH3 -C(C6H5)(OH)- p-C6H4Cl(62) H CH3 -C(C6H5)(OH)- m-C6H4Cl(63) H CH3 -C(C6H5)(OH)- C6H5(64) H CH3 -C(C6H5)(OH)- 2-C4H3S(65) CH3 H -CO- p-C6H4CN(66) CH3 H -C(C6H5)(OH)- p-C6H4F(67) CH3 H -C(C6H5)(OH)- p-C6H4CN(68) CH3 H -CH(OH)- p-C6H4CN(69) H F -CO- p-C6H4F
R1 R2 B Ar(70) H F -C(C6H5)(OH)- p-C6H4F(71) H F -C(p-C6H4F)(OH)- p-C6H4F(72) H Cl -CH(OH)- p-C6H4F(73) F CH3 -CO- p-C6H4F(74) F CH3 -C(C6H5)(OH)- p-C6H4F(75) F CH3 -C(p-C6H4F)(OH)- p-C6H4F(76) Cl CH3 -CH(OH)- p-C6H4F实施例77-144
R1 R2 B Ar(77) H Cl -CO- p-C6H4F(78) H Cl -CO- o-C6H4F(79) H Cl -CO- m-C6H4F(80) H Cl -CO- p-C6H4Cl(81) H Cl -CO- m-C6H4Cl(82) H Cl -CO- C6H5(83) H Cl -CO- 2-C4H3S(84) H Cl -CH(OH)- p-C6H4F(85) H Cl -CH(OH)- o-C6H4F(86) H Cl -CH(OH)- m-C6H4F(87) H Cl -CH(OH)- p-C6H4Cl(88) H Cl -CH(OH)- m-C6H4Cl(89) H Cl -CH(OH)- C6H5(90) H Cl -CH(OH)- 2-C4H3S(91) H Cl -C(p-C6H4F)(OH)- p-C6H4F
R1 R2 B Ar(92) H Cl -C(p-C6H4F)(OH)- o-C6H4F(93) H Cl -C(p-C6H4F)(OH)- m-C6H4F(94) H Cl -C(p-C6H4F)(OH)- p-C6H4Cl(95) H Cl -C(p-C6H4F)(OH)- m-C6H4Cl(96) H Cl -C(p-C6H4F)(OH)- C6H5(97) H Cl -C(p-C6H4F)(OH)- 2-C4H3S(98) H Cl -C(C6H5)(OH)- p-C6H4F(99) H F -C(C6H5)(OH)- o-C6H4F(100) H F -C(C6H5)(OH)- m-C6H4F(101) H F -C(C6H5)(OH)- p-C6H4Cl(102) H F -C(C6H5)(OH)- m-C6H4Cl(103) H F -C(C6H5)(OH)- C6H5(104) H F -C(C6H5)(OH)- 2-C4H3S(105) H CH3 -CO- p-C6H4F(106) H CH3 -CO- o-C6H4F(107) H CH3 -CO- m-C6H4F(108) H CH3 -CO- p-C6H4Cl(109) H CH3 -CO- m-C6H4Cl(110) H CH3 -CO- C6H5(111) H CH3 -CO- 2-C4H3S(112) H CH3 -CH(OH)- p-C6H4F(113) H CH3 -CH(OH)- o-C6H4F(114) H CH3 -CH(OH)- m-C6H4F(115) H CH3 -CH(OH)- p-C6H4Cl(116) H CH3 -CH(OH)- m-C6H4Cl(117) H CH3 -CH(OH)- C6H5(118) H CH3 -CH(OH)- 2-C4H3S(119) H CH3 -C(p-C6H4F)(OH)- p-C6H4F(120) H CH3 -C(p-C6H4F)(OH)- o-C6H4F(121) H CH3 -C(p-C6H4F)(OH)- m-C6H4F(122) H CH3 -C(p-C6H4F)(OH)- p-C6H4Cl(123) H CH3 -C(p-C6H4F)(OH)- m-C6H4Cl(124) H CH3 -C(p-C6H4F)(OH)- C6H5(125) H CH3 -C(p-C6H4F)(OH)- 2-C4H3S(126) H CH3 -C(C6H5)(OH)- p-C6H4F
R1 R2 B Ar(127) H CH3 -C(C6H5)(OH)- o-C6H4F(128) H CH3 -C(C6H5)(OH)- m-C6H4F(129) H CH3 -C(C6H5)(OH)- p-C6H4Cl(130) H CH3 -C(C6H5)(OH)- m-C6H4Cl(131) H CH3 -C(C6H5)(OH)- C6H5(132) H CH3 -C(C6H5)(OH)- 2-C4H3S(133) CH3 Cl -CO- p-C6H4F(134) CH3 Cl -C(C6H5)(OH)- p-C6H4F(135) CH3 Cl -C(C6H4F)(OH)- p-C6H4F(136) CH3 Cl -CH(OH)- p-C6H4F(137) H F -CO- p-C6H4F(138) H F -C(C6H5)(OH)- p-C6H4F(139) H F -C(p-C6H4F)(OH)- p-C6H4F(140) H Cl -CH(OH)- p-C6H4F(141) F CH3 -CO- p-C6H4F(142) F CH3 -C(C6H5)(OH)- p-C6H4F(143) F CH3 -C(p-C6H4F)(OH)- p-C6H4F(144) Cl CH3 -CH(OH)- p-C6H4F实施例145-212 
R1 R2 B Ar(145) CH3 H -CO- p-C6H4F(146) CH3 H -CO- o-C6H4F(147) CH3 H -CO- m-C6H4F(148) CH3 H -CO- p-C6H4Cl(149) CH3 H -CO- m-C6H4Cl(150) CH3 H -CO- C6H5(151) CH3 H -CO- 2-C4H3S(152) CH3 H -CH(OH)- p-C6H4F(153) CH3 H -CH(OH)- o-C6H4F(154) CH3 H -CH(OH)- m-C6H4F(155) CH3 H -CH(OH)- p-C6H4Cl(156) CH3 H -CH(OH)- m-C6H4Cl(157) CH3 H -CH(OH)- C6H5(158) CH3 H -CH(OH)- 2-C4H3S(159) CH3 H -C(p-C6H4F)(OH)- p-C6H4F(160) CH3 H -C(p-C6H4F)(OH)- o-C6H4F(161) CH3 H -C(p-C6H4F)(OH)- m-C6H4F(162) CH3 H -C(p-C6H4F)(OH)- p-C6H4Cl(163) CH3 H -C(p-C6H4F)(OH)- m-C6H4Cl(164) CH3 H -C(p-C6H4F)(OH)- C6H5(165) CH3 H -C(p-C6H4F)(OH)- 2-C4H3S(166) CH3 H -C(C6H5)(OH)- p-C6H4F(167) CH3 H -C(C6H5)(OH)- o-C6H4F(168) CH3 H -C(C6H5)(OH)- m-C6H4F(169) CH3 H -C(C6H5)(OH)- p-C6H4Cl(170) CH3 H -C(C6H5)(OH)- m-C6H4Cl
R1 R2 B Ar(171) CH3 H -C(C6H5)(OH)- C6H5(172) CH3 H -C(C6H5)(OH)- 2-C4H3S(173) CH3 CH3 -CO- p-C6H4F(174) CH3 CH3 -CO- o-C6H4F(175) CH3 CH3 -CO- m-C6H4F(176) CH3 CH3 -CO- p-C6H4Cl(177) CH3 CH3 -CO- m-C6H4Cl(178) CH3 CH3 -CO- C6H5(179) CH3 CH3 -CO- 2-C4H3S(180) CH3 CH3 -CH(OH)- p-C6H4F(181) CH3 CH3 -CH(OH)- o-C5H4F(182) CH3 CH3 -CH(OH)- m-C6H4F(183) CH3 CH3 -CH(OH)- p-C6H4Cl(184) CH3 CH3 -CH(OH)- m-C6H4Cl(185) CH3 CH3 -CH(OH)- C6H5(186) CH3 CH3 -CH(OH)- 2-C4H3S(187) CH3 CH3 -C(p-C6H4F)(OH)- p-C6H4F(188) CH3 CH3 -C(p-C6H4F)(OH)- o-C6H4F(189) CH3 CH3 -C(p-C6H4F)(OH)- m-C6H4F(190) CH3 CH3 -C(p-C6H4F)(OH)- p-C6H4Cl(191) CH3 CH3 -C(p-C6H4F)(OH)- m-C6H4Cl(192) CH3 CH3 -C(p-C6H4F)(OH)- C6H5(193) CH3 CH3 -C(p-C6H4F)(OH)- 2-C4H3S(194) CH3 CH3 -C(C6H5)(OH)- p-C6H4F(195) CH3 CH3 -C(C6H5)(OH)- o-C6H4F(196) CH3 CH3 -C(C6H5)(OH)- m-C6H4F(197) CH3 CH3 -C(C6H5)(OH)- p-C6H4Cl(198) CH3 CH3 -C(C6H5)(OH)- m-C6H4Cl(199) CH3 CH3 -C(C6H5)(OH)- C6H5(200) CH3 CH3 -C(C6H5)(OH)- 2-C4H3S(201) CH3 H -CO- p-C6H4F(202) CH3 H -C(C6H5)(OH)- p-C6H4F(203) CH3 H -C(C6H4)(OH)- p-C6H4F(204) CH3 H -CH(OH)- p-C6H4F(205) Cl F -CO- p-C6H4F
R1 R2 B Ar(206) Cl F -C(C6H5)(OH)- p-C6H4F(207) F F -C(p-C6H4F)(OH)- p-C6H4F(208) F Cl -CH(OH)- p-C6H4F(209) F CH3 -CO- p-C6H4F(210) F CH3 -C(C6H5)(OH)- p-C6H4F(211) F CH3 -C(p-C6H4F)(OH)- p-C6H4F(212) Cl CH3 -CH(OH)- p-C6H4F实施例213-280
R1 R2 B Ar(213) H H -CO- p-C6H4F(214) H H -CO- o-C6H4F(215) H H -CO- m-C6H4F(216) H H -CO- p-C6H4Cl(217) H H -CO- m-C6H4Cl(218) H H -CO- C6H5(219) H H -CO- 2-C4H3S(220) H H -CH(OH)- p-C6H4F(221) H H -CH(OH)- o-C6H4F(222) H H -CH(OH)- m-C6H4F(223) H H -CH(OH)- p-C6H4Cl(224) H H -CH(OH)- m-C6H4Cl(225) H H -CH(OH)- C6H5(226) H H -CH(OH)- 2-C4H3S(227) H H -C(p-C6H4F)(OH)- p-C6H4F(228) H H -C(p-C6H4F)(OH)- o-C6H4F(229) H H -C(p-C6H4F)(OH)- m-C6H4F
R1 R2 B Ar(230) H H -C(p-C6H4F)(OH)- p-C6H4Cl(231) H H -C(p-C6H4F)(OH)- m-C6H4Cl(232) H H -C(p-C6H4F)(OH)- C6H5(233) H H -C(p-C6H4F)(OH)- 2-C4H3S(234) H H -C(C6H5)(OH)- p-C6H4F(235) H H -C(C6H5)(OH)- o-C6H4F(236) H H -C(C6H5)(OH)- m-C6H4F(237) H H -C(C6H5)(OH)- p-C6H4Cl(238) H H -C(C6H5)(OH)- m-C6H4Cl(239) H H -C(C6H5)(OH)- C6H5(240) H H -C(C6H5)(OH)- 2-C4H3S(241) H CH3 -CO- p-C6H4F(242) H CH3 -CO- o-C6H4F(243) H CH3 -CO- m-C6H4F(244) H CH3 -CO- p-C6H4Cl(245) H CH3 -CO- m-C6H4Cl(246) H CH3 -CO- C6H5(247) H CH3 -CO- 2-C4H3S(248) H CH3 -CH(OH)- p-C6H4F(249) H CH3 -CH(OH)- o-C6H4F(250) H CH3 -CH(OH)- m-C6H4F(251) H CH3 -CH(OH)- p-C6H4Cl(252) H CH3 -CH(OH)- m-C6H4Cl(253) H CH3 -CH(OH)- C6H5(254) H CH3 -CH(OH)- 2-C4H3S(255) H CH3 -C(p-C6H4F)(OH)- p-C6H4F(256) H CH3 -C(p-C6H4F)(OH)- o-C6H4F(257) H CH3 -C(p-C6H4F)(OH)- m-C6H4F(258) H CH3 -C(p-C6H4F)(OH)- p-C6H4Cl(259) H CH3 -C(p-C6H4F)(OH)- m-C6H4Cl(260) H CH3 -C(p-C6H4F)(OH)- C6H5(261) H CH3 -C(p-C6H4F)(OH)- 2-C4H3S(262) H CH3 -C(C6H5)(OH)- p-C6H4F(263) H CH3 -C(C6H5)(OH)- o-C6H4F(264) H CH3 -C(C6H5)(OH)- m-C6H4F
R1 R2 B Ar(265) H CH3 -C(C6H5)(OH)- p-C6H4Cl(266) H CH3 -C(C6H5)(OH)- m-C6H4Cl(267) H CH3 -C(C6H5)(OH)- C6H5(268) H CH3 -C(C6H5)(OH)- 2-C4H3S(269) CH3 H -CO- p-C6H4F(270) CH3 H -C(C6H5)(OH)- p-C6H4F(271) CH3 H -C(C6H4)(OH)- p-C6H4CN(272) CH3 H -CH(OH)- p-C6H4F(273) H F -CO- p-C6H4F(274) H F -C(C6H5)(OH)- p-C6H4F(275) H F -C(p-C6H4F)(OH)- p-C6H4F(276) H Cl -CH(OH)- p-C6H4F(277) F CH3 -CO- p-C6H4F(278) F CH3 -C(C6H5)(OH)- p-C6H4F(279) F CH3 -C(p-C6H4F)(OH)- p-C6H4F(280) Cl CH3 -CH(OH)- p-C6H4F实施例281-348
R1 R2 B Ar(281) H H -CO- p-C6H4CN(282) H H -CO- o-C6H4F(283) H H -CO- m-C6H4F(284) H H -CO- p-C6H4Cl(285) H H -CO- m-C6H4Cl(286) H H -CO- C6H5(287) H H -CO- 2-C4H3S(288) H H -CH(OH)- p-C6H4CN
R1 R2 B Ar(289) H H -CH(OH)- o-C6H4F(290) H H -CH(OH)- m-C6H4F(291) H H -CH(OH)- p-C6H4Cl(292) H H -CH(OH)- m-C6H4Cl(293) H H -CH(OH)- C6H5(294) H H -CH(OH)- 2-C4H3S(295) H H -C(p-C6H4F)(OH)- p-C6H4F(296) H H -C(p-C6H4F)(OH)- o-C6H4F(297) H H -C(p-C6H4F)(OH)- m-C6H4F(298) H H -C(p-C6H4F)(OH)- p-C6H4Cl(299) H H -C(p-C6H4F)(OH)- m-C6H4Cl(300) H H -C(p-C6H4F)(OH)- C6H5(301) H H -C(p-C6H4F)(OH)- 2-C4H3S(302) H H -C(C6H5)(OH)- p-C6H4F(3C3) H H -C(C6H5)(OH)- o-C6H4F(304) H H -C(C6H5)(OH)- m-C6H4F(305) H H -C(C6H5)(OH)- p-C6H4Cl(306) H H -C(C6H5)(OH)- m-C6H4Cl(307) H H -C(C6H5)(OH)- C6H5(308) H H -C(C6H5)(OH)- 2-C4H3S(309) H CH3 -CO- p-C6H4F(310) H CH3 -CO- o-C6H4F(311) H CH3 -CO- m-C6H4F(312) H CH3 -CO- p-C6H4Cl(313) H CH3 -CO- m-C6H4Cl(314) H CH3 -CO- C6H5(315) H CH3 -CO- 2-C4H3S(316) H CH3 -CH(OH)- p-C6H4F(317) H CH3 -CH(OH)- o-C6H4F(318) H CH3 -CH(OH)- m-C6H4F(319) H CH3 -CH(OH)- p-C6H4Cl(320) H CH3 -CH(OH)- m-C6H4Cl(321) H CH3 -CH(OH)- C6H5(322) H CH3 -CH(OH)- 2-C4H3S(323) H CH3 -C(p-C6H4F)(OH)- p-C6H4F
R1 R2 B Ar(324) H CH3 -C(p-C6H4F)(OH)- o-C6H4F(325) H CH3 -C(p-C6H4F)(OH)- m-C6H4F(326) H CH3 -C(p-C6H4F)(OH)- p-C6H4Cl(327) H CH3 -C(p-C6H4F)(OH)- m-C6H4Cl(328) H CH3 -C(p-C6H4F)(OH)- C6H5(329) H CH3 -C(p-C6H4F)(OH)- 2-C4H3S(330) H CH3 -C(C6H5)(OH)- p-C6H4F(331) H CH3 -C(C6H5)(OH)- o-C6H4F(332) H CH3 -C(C6H5)(OH)- m-C6H4F(333) H CH3 -C(C6H5)(OH)- p-C6H4Cl(334) H CH3 -C(C6H5)(OH)- m-C6H4Cl(335) H CH3 -C(C6H5)(OH)- C6H5(336) H CH3 -C(C6H5)(OH)- 2-C4H3S(337) CH3 H -CO- p-C6H4F(338) CH3 H -C(C6H5)(OH)- p-C6H4F(339) CH3 H -C(p-C6H4F)(OH)- p-C6H4F(340) CH3 H -CH(OH)- p-C6H4F(341) H F -CO- p-C6H4F(342) H F -C(C6H5)(OH)- p-C6H4F(343) H F -C(p-C6H4F)(OH)- p-C6H4F(344) H Cl -CH(OH)- p-C6H4F(345) F CH3 -CO- p-C6H4F(346) F CH3 -C(C6H5)(OH)- p-C6H4F(347) F CH3 -C(p-C6H4F)(OH)- p-C6H4F(348) Cl CH3 -CH(OH)- p-C6H4F实施例349-416
R1 R2 B Ar(349) H H -CO- p-C6H4F(350) H H -CO- o-C6H4F(351) H H -CO- m-C6H4F(352) H H -CO- p-C6H4Cl(353) H H -CO- m-C6H4Cl(354) H H -CO- C6H5(355) H H -CO- 2-C4H3S(356) H H -CH(OH)- p-C6H4F(357) H H -CH(OH)- o-C6H4F(358) H H -CH(OH)- m-C6H4F(359) H H -CH(OH)- p-C6H4Cl(360) H H -CH(OH)- m-C6H4Cl(361) H H -CH(OH)- C6H5(362) H H -CH(OH)- 2-C4H3S(363) H H -C(p-C6H4F)(OH)- p-C6H4F(364) H H -C(p-C6H4F)(OH)- o-C6H4F(365) H H -C(p-C6H4F)(OH)- m-C6H4F(366) H H -C(p-C6H4F)(OH)- p-C6H4Cl(367) H H -C(p-C6H4F)(OH)- m-C6H4Cl(368) H H -C(p-C6H4F)(OH)- C6H5(369) H H -C(p-C6H4F)(OH)- 2-C4H3S(370) H H -C(C6H5)(OH)- p-C6H4F(371) H H -C(C6H5)(OH)- o-C6H4F(372) H H -C(C6H5)(OH)- m-C6H4F(373) H H -C(C6H5)(OH)- p-C6H4Cl(374) H H -C(C6H5)(OH)- m-C6H4Cl
R1 R2 B Ar(375) H H -C(C6H5)(OH)- C6H5(376) H H -C(C6H5)(OH)- 2-C4H3S(377) H CH3 -CO- p-C6H4F(378) H CH3 -CO- o-C6H4F(379) H CH3 -CO- m-C6H4F(380) H CH3 -CO- p-C6H4Cl(381) H CH3 -CO- m-C6H4Cl(382) H CH3 -CO- C6H5(383) H CH3 -CO- 2-C4H3S(384) H CH3 -CH(OH)- p-C6H4F(385) H CH3 -CH(OH)- o-C6H4F(386) H CH3 -CH(OH)- m-C6H4F(387) H CH3 -CH(OH)- p-C6H4Cl(388) H CH3 -CH(OH)- m-C6H4Cl(389) H CH3 -CH(OH)- C6H5(390) H CH3 -CH(OH)- 2-C4H3S(391) H CH3 -C(p-C6H4F)(OH)- p-C6H4F(392) H CH3 -C(p-C6H4F)(OH)- o-C6H4F(393) H CH3 -C(p-C6H4F)(OH)- m-C6H4F(394) H CH3 -C(p-C6H4F)(OH)- p-C6H4Cl(395) H CH3 -C(p-C6H4F)(OH)- m-C6H4Cl(396) H CH3 -C(p-C6H4F)(OH)- C6H5(397) H CH3 -C(p-C6H4F)(OH)- 2-C4H3S(398) H CH3 -C(C6H5)(OH)- p-C6H4F(399) H CH3 -C(C6H5)(OH)- o-C6H4F(400) H CH3 -C(C6H5)(OH)- m-C6H4F(40 1) H CH3 -C(C6H5)(OH)- p-C6H4Cl(402) H CH3 -C(C6H5)(OH)- m-C6H4Cl(403) H CH3 -C(C6H5)(OH)- C6H5(404) H CH3 -C(C6H5)(OH)- 2-C4H3S(405) CH3 H -CO- p-C6H4F(406) CH3 H -C(C6H5)(OH)- p-C6H4F(407) CH3 H -C(C6H5F)(OH)- p-C6H4F(408) CH3 H -CH(OH)- p-C6H4F(409) H F -CO- p-C6H4F
R1 R2 B Ar(410) H F -C(C6H5)(OH)- p-C6H4F(411) H F -C(p-C6H4F)(OH)- p-C6H4F(412) H Cl -CH(OH)- p-C6H4F(413) F CH3 -CO- p-C6H4F(414) F CH3 -C(C6H5)(OH)- p-C6H4F(415) F CH3 -C(p-C6H4F)(OH)- p-C6H4F(416) Cl CH3 -CH(OH)- p-C6H4F实施例A：注射用安瓿
采用在3升双蒸水中的2N盐酸，将100g通式I化合物和5g磷酸氢二钠的溶液调至pH6.5，无菌过滤后装入注射用安瓿中，并冻干。所有操作应在无菌条件下进行。每一注射用安瓿含有5mg通式I活性成分。实施例B：
20g通式I化合物与100g大豆卵磷脂和1400g可可脂加温混合，并将混合物倾入空心模(hollow)中。每个栓剂含有20mg活性成分。实施例C：
采用940ml双蒸水，配制包含1g通式I化合物、9.38g NaH2PO4×2H2O、28.48g Na2HPO4×12H2O和0.1g苯扎氯铵的溶液。溶液调至pH6.8，并用双蒸水补至1升，然后进行辐射灭菌。该溶液可以滴眼剂形式用途。实施例D：软膏剂
于无菌条件下，将500mg通式I化合物与99.5g粗矿脂混合制得。实施例E：片剂
按常规方式，将100g通式I化合物、1kg乳糖、600g微晶纤维素、600g玉米淀粉、100g聚乙烯吡咯烷酮、80g滑石和10g硬脂酸镁混合并压片，得到每片含有100mg活性成分的片剂。实施例F：包衣片
按实施例7制备片剂，然后用蔗糖、玉米淀粉、滑石、黄蓍胶和着色剂按已知方式包衣。实施例G：胶囊剂
采用已知方式，将通式I化合物填充到硬明胶胶囊中，制成含5mg活性成分的胶囊。实施例H：吸入喷雾剂
将14g通式I化合物溶于10升等渗盐水溶液。将溶液装入配有泵装置的市售喷雾容器中。溶液可喷入口腔或鼻中。每喷(约0.1ml)的剂量相当于0.14mg通式I化合物。
Claims (10)
1.如式I的芳基哌嗪化合物及其盐和溶剂化物，
其中A 为包括1或2个氮原子的稠合杂芳族环或杂脂族环，B 为-CO-或-CHOH-或-C(Ar)(OH)-R1和R2彼此独立地为H、烷基、C1-C6或卤素Ar 为未取代的或被卤素、NO2或CN单取代或多取代的苯基或噻
吩，和n 为1、2、3或4。
2.如前述权利要求的式I化合物，其特征在于其中基团
具有以下含义之一：
3.选自下列化合物1a-1h的化合物及其盐和溶剂化物：
4.用作药物活性化合物的如权利要求1的式I化合物及其生理学可接受的盐或溶剂化物。
5.用作D2受体拮抗剂和/或5HT1A拮抗剂的如权利要求1的式I化合物及其生理学可接受的盐或溶剂化物。
6.如权利要求1的式I化合物及其生理学可接受的盐或溶剂化物用于控制疾病。
7.药物制剂，其特征在于含有至少一种如权利要求1的式I化合物和/或一种其生理学可接受的盐或溶剂化物。
8.如权利要求1的式I化合物和/或其生理学可接受的盐或溶剂化物在制备药物中的用途。
9.如权利要求1的式I化合物和/或其生理学可接受的盐或溶剂化物在制备用于治疗中枢神经系统疾病、特别是精神分裂症类型的精神障碍以及用于控制精神病性焦虑状态的药物中的用途。
10.制备式I化合物及其盐和溶剂化物的方法，其特征在于使式II化合物：其中R1、R2和A的定义如上，与式III化合物反应
其中Ar、B和n的定义如上，并且L为离去基团，并且如果B代表-CO-，则基团B任选被氢化、烷基化或芳化，和
如果适当，经酸或碱处理，式I的碱性或酸性化合物转化成其一种盐或溶剂化物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10043659A DE10043659A1 (de) | 2000-09-05 | 2000-09-05 | Arylpiperazinderivate |
| DE10043659.5 | 2000-09-05 |
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| Publication Number | Publication Date |
|---|---|
| CN1452614A true CN1452614A (zh) | 2003-10-29 |
Family
ID=7655009
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN01815154A Pending CN1452614A (zh) | 2000-09-05 | 2001-08-07 | 芳基哌嗪衍生物及其作为精神药物的用途 |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US20040014972A1 (zh) |
| EP (1) | EP1326842A1 (zh) |
| KR (1) | KR20030024913A (zh) |
| CN (1) | CN1452614A (zh) |
| AU (1) | AU2001291744A1 (zh) |
| BR (1) | BR0113581A (zh) |
| CA (1) | CA2421219A1 (zh) |
| CZ (1) | CZ2003809A3 (zh) |
| DE (1) | DE10043659A1 (zh) |
| MX (1) | MXPA03001826A (zh) |
| NO (1) | NO20030998D0 (zh) |
| PL (1) | PL360289A1 (zh) |
| SK (1) | SK3612003A3 (zh) |
| WO (1) | WO2002020491A1 (zh) |
| ZA (1) | ZA200302636B (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| ATE424825T1 (de) | 2001-07-20 | 2009-03-15 | Psychogenics Inc | Behandlung von hyperaktivitätsstörungen und aufmerksamkeitsdefiziten |
| WO2004082570A2 (en) * | 2003-03-17 | 2004-09-30 | Bayer Healthcare Ag | Diagnostics and therapeutics for diseases associated with dopamine receptor d2 (drd2) |
| WO2004113333A1 (ja) * | 2003-06-23 | 2004-12-29 | Dainippon Sumitomo Pharma Co., Ltd. | 老人性痴呆症治療剤 |
| ES2250000B1 (es) * | 2004-09-29 | 2007-06-01 | Medichem, S.A. | Procedimiento para la preparacion de ziprasidona. |
| ES2250001B1 (es) * | 2004-09-29 | 2007-06-01 | Medichem, S.A. | Proceso para la purificacion de ziprasidona. |
| KR100660142B1 (ko) * | 2005-01-24 | 2006-12-20 | 이명섭 | 건식 모래 생산 방법 및 그 시스템 |
| TWI320783B (en) | 2005-04-14 | 2010-02-21 | Otsuka Pharma Co Ltd | Heterocyclic compound |
| TW200800959A (en) * | 2005-06-10 | 2008-01-01 | Wyeth Corp | Piperazine-piperidine antagonists and agonists of the 5-HT1a receptor |
| TW200808730A (en) * | 2006-06-09 | 2008-02-16 | Wyeth Corp | Process for synthesizing piperazine-piperidine compounds |
| TW200831096A (en) * | 2006-11-28 | 2008-08-01 | Wyeth Corp | Metabolites of 5-Fluoro-8-{4-[4-(6-methoxyquinolin-8-yl)piperazin-1-yl]piperidin-1-yl} quinoline and methods of preparation and uses thereof |
| PE20090188A1 (es) | 2007-03-15 | 2009-03-20 | Novartis Ag | Compuestos heterociclicos como moduladores de la senda de hedgehog |
| US20100041663A1 (en) | 2008-07-18 | 2010-02-18 | Novartis Ag | Organic Compounds as Smo Inhibitors |
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| DK148392D0 (da) * | 1992-12-09 | 1992-12-09 | Lundbeck & Co As H | Heterocykliske forbindelser |
| WO1998031679A1 (fr) * | 1997-01-21 | 1998-07-23 | Yoshitomi Pharmaceutical Industries, Ltd. | Composes de thiophene et leur application medicinale |
| ES2128266B1 (es) * | 1997-07-08 | 2000-01-16 | Vita Invest Sa | Compuestos derivados de tiofeno y benzotiofeno y utilizacion y composicion correspondientes. |
| EP0900792B1 (en) * | 1997-09-02 | 2003-10-29 | Duphar International Research B.V | Piperazine and piperidine derivatives as 5-HT1A and dopamine D2-receptor (ant)agonists |
-
2000
- 2000-09-05 DE DE10043659A patent/DE10043659A1/de not_active Withdrawn
-
2001
- 2001-08-07 SK SK361-2003A patent/SK3612003A3/sk unknown
- 2001-08-07 KR KR10-2003-7002743A patent/KR20030024913A/ko not_active Application Discontinuation
- 2001-08-07 CZ CZ2003809A patent/CZ2003809A3/cs unknown
- 2001-08-07 PL PL36028901A patent/PL360289A1/xx unknown
- 2001-08-07 CN CN01815154A patent/CN1452614A/zh active Pending
- 2001-08-07 US US10/363,168 patent/US20040014972A1/en not_active Abandoned
- 2001-08-07 WO PCT/EP2001/009108 patent/WO2002020491A1/de not_active Application Discontinuation
- 2001-08-07 EP EP01971882A patent/EP1326842A1/de not_active Withdrawn
- 2001-08-07 BR BR0113581-3A patent/BR0113581A/pt not_active Application Discontinuation
- 2001-08-07 MX MXPA03001826A patent/MXPA03001826A/es unknown
- 2001-08-07 CA CA002421219A patent/CA2421219A1/en not_active Abandoned
- 2001-08-07 AU AU2001291744A patent/AU2001291744A1/en not_active Abandoned
-
2003
- 2003-03-04 NO NO20030998A patent/NO20030998D0/no unknown
- 2003-04-03 ZA ZA200302636A patent/ZA200302636B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CA2421219A1 (en) | 2003-03-03 |
| SK3612003A3 (en) | 2003-07-01 |
| BR0113581A (pt) | 2003-07-15 |
| CZ2003809A3 (cs) | 2003-06-18 |
| DE10043659A1 (de) | 2002-03-14 |
| EP1326842A1 (de) | 2003-07-16 |
| NO20030998L (no) | 2003-03-04 |
| US20040014972A1 (en) | 2004-01-22 |
| WO2002020491A1 (de) | 2002-03-14 |
| KR20030024913A (ko) | 2003-03-26 |
| MXPA03001826A (es) | 2003-06-04 |
| NO20030998D0 (no) | 2003-03-04 |
| AU2001291744A1 (en) | 2002-03-22 |
| ZA200302636B (en) | 2004-09-08 |
| PL360289A1 (en) | 2004-09-06 |
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