CN1674884A - 用于治疗疼痛的α-2-δ配体与PDEV抑制剂的协同组合 - Google Patents
用于治疗疼痛的α-2-δ配体与PDEV抑制剂的协同组合 Download PDFInfo
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- CN1674884A CN1674884A CNA038190737A CN03819073A CN1674884A CN 1674884 A CN1674884 A CN 1674884A CN A038190737 A CNA038190737 A CN A038190737A CN 03819073 A CN03819073 A CN 03819073A CN 1674884 A CN1674884 A CN 1674884A
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Abstract
本发明涉及在治疗中应用的α-2-δ配体和PDEV抑制剂的组合,特别是用于治疗、预防或缓解性治疗疼痛,尤其是神经性疼痛。特别优选的α-2-δ配体是加巴喷丁和普加巴林。特别优选的PDEV抑制剂是西地那非、伐地那非和泰地那非。
Description
发明领域
本发明涉及α-2-δ配体和cGMP PDEV(′PDEV′)抑制剂的组合,特别是用于治疗、预防和缓解性治疗疼痛和相关疾病中显示协同效应的组合。
发明背景
α-2-δ配体可被定义为表现出与电压门控钙离子通道α-2-δ(α2δ)亚基高亲和性相互作用而选择性的从猪脑膜中替换3H-加巴喷丁(gabapentin)的化合物。α-2-δ配体也包括不能替换3H-加巴喷丁,但在结构上与能替换的化合物相似的化合物,其被期望在与3H-加巴喷丁稍有不同的位点结合α-2-δ,或可以结合人脑α-2-δ而不是猪脑α-2-δ。它们也可以被认为是GABA类似物。
α-2-δ配体被描述用于许多适应症。最为人熟知的α-2-δ配体,加巴喷丁(NEURONTIN),1-(氨甲基)-环己基乙酸,是第一个在包括US 4024175的同族专利的专利文献描述。该化合物被批准用于治疗癫痫症和神经性疼痛。
第二个α-2-δ配体,普加巴林(pregabalin),(S)-(+)-4-氨基-3-(2-甲基丙基)丁酸,在欧洲专利申请公开号为EP641330中描述为抗惊厥剂,用于治疗癫痫症和在EP0934061中描述用于镇痛。
进一步地WO0128978描述了一系列的α-2-δ配体,特别是(1α,3α,5α)(3-氨基-甲基-二环[3.2.0]庚-3-基)-乙酸,描述如下:
最近,国际专利申请号PCT/IB02/01146(在本发明的优先权日未公开)和公开的WO02/085839,描述了一系列如下结构式的α-2-δ配体:
其中R1和R2各自独立地选自:H、1-6个碳原子的直链或支链烷基、3-6个碳原子的环烷基、苯基和苄基,受限于前提:除式(XVII)的三环辛烷化合物的情况外,R1和R2不同时是H;用于治疗许多适应症,包括疼痛。
国际专利申请PCT/IB03/00976在本发明申请日未公开,描述了式I的化合物,如下:
其中R1为氢或任选地被一到五个氟原子取代的(C1-C6)的烷基;
R2为氢或任选地被一到五个氟原子取代的(C1-C6)的烷基;或
R1、R2和它们所连接的碳一起形成三到六元环烷基环;
R3为(C1-C6)烷基、(C3-C6)环烷基、(C3-C6)环烷基-(C1-C3)烷基、苯基、苯基-(C1-C3)烷基、吡啶基、吡啶基-(C1-C3)烷基、苯基-N(H)-或吡啶基-N(H)-,其中前述的每一个烷基部分均可任选地被一到五个氟原子,优选零到三个氟原子取代,其中所述的苯基和所述的吡啶基以及所述苯基-(C1-C3)烷基和吡啶基-(C1-C3)烷基中的苯基和吡啶基部分分别可被任选地一到三个取代基,优选零到二个取代基取代,所述取代基独立地选自氯、氟、氨基、硝基、氰基、(C1-C3)烷氨基、任选地被一到三个氟原子取代的(C1-C3)烷基和任选地被一到三个氟原子取代的(C1-C3)烷氧基;
R4为氢或任选地被一到五个氟原子取代的(C1-C6)烷基;
R5为氢或任选地被一到五个氟原子取代的(C1-C6)烷基;
R6为氢或(C1-C6)烷基;
和这些化合物的药学可接受的盐。
环鸟苷3’,5’-单磷酸磷酸二酯酶五型(cGMP PDEV)酶抑制剂(′PDEV抑制剂′)是一类特征为对PDEV酶具有高亲合性和选择性,而对其它磷酸二酯酶同工型很低的或无亲合性的化合物,它们被描述对多种适应症有效。特别地,西地那非(Sildenafil)(5-[2-乙氧基-5-(4-甲基-1-哌嗪基磺酰基)苯基]-1-甲基-3-正-丙基-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮)(VIAGRA)已被描述用于治疗多种心血管病症,此外还被成功的证实为第一个口服有效的治疗男性勃起障碍的药物(MED)。PDEV抑制剂在治疗神经疾病中的应用已在欧洲专利申请号为EP1129706和WO01/26659中描述。最近在Jain et al,BrainResearch,909,170-178(2001);Asomoza-Espinosa et al,Eur.J.Pharm.,418,195-200(2001);和Mixcoatl-Zecutal et al,Eur.J.Pharm.,400,81-87(2001)中描述了西地那非的镇痛效应。
发明简述
已发现α-2-δ配体和PDEV抑制剂联合治疗在疼痛治疗方面产生了意想不到的改善。当同时地、顺次地或分别给予时,α-2-δ配体和PDEV抑制剂以协同方式相互作用控制疼痛。这种意想不到的协同作用允许减少每种药物所需的剂量,导致副作用的减小和化合物与治疗的临床有效性增强。
因此,第一方面,本发明提供了包含α-2-δ配体(除普加巴林和加巴喷丁外)和PDEV抑制剂的组合产品。可选择地,排除的配体也包括PCT/IB02/01146中的化合物(i)-(xxv)。
可选择地或另一个方面,本发明提供了包含α-2-δ配体和PDEV抑制剂的协同组合产品。
本发明应用的α-2-δ配体的实例是那些在US4024175中一般性或具体公开的化合物,特别是加巴喷丁,EP641330;特别是普加巴林,US5563175,WO9733858,WO9733859,WO9931057,WO9931074,WO9729101,WO02085839,特别是[(1R,5R,6S)-6-(氨甲基)二环[3.2.0]庚-6-基] 乙酸,WO9931075,特别是3-(1-氨甲基-环己甲基)-4H-[1,2,4]噁二唑-5-酮和C-[1-(1H-四唑-5-基甲基)-环庚基]-甲胺,WO9921824;特别是(3S,4S)-(1-氨甲基-3,4-二甲基-环戊基)-乙酸,WO0190052,WO0128978,特别是(1α,3α,5α)(3-氨基-甲基-二环[3.2.0]庚-3-基)-乙酸,EP0641330,WO9817627,WO0076958;特别是(3S,5R)-3-氨甲基-5-甲基-辛酸,PCT/IB03/00976,特别是(3S,5R)-3-氨基-5-甲基-庚酸,(3S,5R)-3-氨基-5-甲基-壬酸和(3S,5R)-3-氨基-5-甲基-辛酸,EP1178034,EP1201240,WO9931074,WO03000642,WO0222568,WO0230871,WO0230881,WO02100392,WO02100347,WO0242414,WO0232736和WO0228881,和它们的药学可接受的盐和溶剂合物,所有这些被引入本文作为参考。
本发明中优选的α-2-δ配体包括:加巴喷丁、普加巴林、[(1R,5R,6S)-6-(氨甲基)二环[3.2.0]庚-6-基]乙酸、3-(1-氨甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-酮和C-[1-(1H-四唑-5-基甲基)-环庚基]-甲胺、(3S,4S)-(氨甲基-3,4-二甲基-环戊基)-乙酸、(1α,3α,5α)(3-氨基-甲基-二环[3.2.0]庚-3-基)-乙酸、(3S,5R)-3-氨甲基-5-甲基-辛酸、(3S,5R)-3-氨基-5-甲基-庚酸、(3S,5R)-3-氨基-5-甲基-壬酸和(3S,5R)-3-氨基-5-甲基-辛酸。
本发明中有用的环状α-2-δ配体可以描述为如下式(I):
其中X是羧酸或羧酸的生物电子等排体;
n是0、1或2;和
R1、R1a、R2、R2a、R3、R3a、R4和R4a独立地选自H和C1-C6烷基;或
R1和R2或R2和R3一起形成C3-C7环烷基环,其任选地被一或二个选自C1-C6烷基的取代基取代;
或其药学可接受的盐或溶剂合物。
在式(I)中,适当地,R1、R1a、R2a、R3a、R4和R4a是H,R2和R3独立地选自H和甲基;或R1a、R2a、R3a和R4a为H,R1和R2或R2和R3一起形成C3-C7环烷基环,其任选地被一或二个甲基取代基取代。合适的羧酸生物电子等排体选自四唑基和噁二唑酮基。X优选是羧酸。
在式(I)中,优选地,R1、R1a、R2a、R3a、R4和R4a为H,R2和R3独立地选自H和甲基;或R1a、R2a、R3a和R4a为H,R1和R2或R2和R3一起形成C4-C5环烷基环;或者当n为0时,R1、R1a、R2a、R3a、R4和R4a为H且R2和R3形成环戊基环,或当n为1时,R1、R1a、R2a、R3a、R4和R4a为H且R2和R3都为甲基,或R1、R1a、R2a、R3a、R4和R4a为H且R2和R3形成环丁基环;或当n为2时,R1、R1a、R2、R2a、R3、R3a、R4和R4a为H或,当n为0时,R1、R1a、R2a、R3a、R4和R4a为H且R2和R3形成环戊基环。
本发明中有用的非环状α-2-δ配体可以描述为如下式(II):
其中:
n为0或1,R1是氢或(C1-C6)烷基;R2是氢或(C1-C6)烷基;R3是氢或(C1-C6)烷基;R4是氢或(C1-C6)烷基;R5是氢或(C1-C6)烷基且R2是氢或(C1-C6)烷基,或其药学可接受的盐或溶剂合物
根据式(II),合适地,R1为(C1-C6)烷基,R2为甲基,R3-R6为氢,且n为0或1。更适当地,R1为甲基、乙基、正-丙基或正-丁基,R2为甲基,R3-R6为氢且n为0或1。当R2为甲基,R3-R6为氢且n为0时,R1适当地为乙基、正-丙基或正-丁基。当R2为甲基,R3-R6为氢且n为1时,R1适当地为甲基或正丙基。式(II)的化合物适当地为3S,5R构型。
本专利应用的PDEV抑制剂的实例为:EP-A-0463756中公开的吡唑并[3,4-d]嘧啶-7-酮类;EP-A-0526004中公开的吡唑并[4,3-d]嘧啶-7-酮类;公开的国际专利申请WO93/06104中公开的吡唑并[4,3-d]嘧啶-7-酮类;公开的国际专利申请WO 93/07149中公开的同分异构吡唑并[3,4-d]嘧啶-4-酮类;公开的国际专利申请WO 93/12095中公开的喹唑啉并-4-酮类;公开的国际专利申请WO 94/05661中公开的吡啶并[3,2-d]嘧啶-4-酮类;公开的国际专利申请WO 94/00453中公开的嘌呤-6-酮;公开的国际专利申请WO 98/49166中公开的吡唑并[4,3-d]嘧啶-7-酮类;公开的国际专利申请WO 99/54333中公开的吡唑并[4,3-d]嘧啶-7-酮类;EP-A-0995751中公开的吡唑并[4,3-d]嘧啶-4-酮类;公开的国际专利申请WO 00/24745中公开的吡唑并[4,3-d]嘧啶-7-酮类;EP-A-0995750中公开的吡唑并[4,3-d]嘧啶-4-酮类;公开的国际专利申请WO95/19978中公开的六氢吡嗪并[2′,1′:6,1]吡啶并[3,4-b]吲哚-1,4-二酮类;EP-A-1092719和公开的国际专利申请WO99/24433中公开的咪唑并[5,1-f][1,2,4]三嗪-酮类;公开的国际专利申请WO 93/07124中公开的二环化合物,所有这些被引入本文作为参考。
这里应用到的合适的PDEV抑制剂的进一步的实例包括:公开的国际专利申请WO 01/27112中公开的吡唑并[4,3-d]嘧啶-7-酮类;公开的国际专利申请WO 01/27113中公开的吡唑并[4,3-d]嘧啶-7-酮;EP-A-1092718中公开的化合物和EP-A-1092719中公开的化合物;EP-A-1241170中公开的三环化合物;公开的国际专利申请WO02/074774中公开的烷基砜化合物;公开的国际专利申请WO 02/072586中公开的化合物;公开的国际专利申请WO 02/079203中公开的化合物和公开的国际专利申请WO 02/074312中公开的化合物,所有这些被引入本文作为参考。
这里应用到的合适的PDEV抑制剂的再进一步的实例包括:WO03000691,WO02098875,WO02064591,WO02064590和WO0108688中描述的咔啉类衍生物,WO02098877中描述的吡嗪并[1′,2′:1,6]吡啶并[3,4-B]吲哚1,4-二酮衍生物,WO02098428中描述的四环化合物;WO02088123和WO0200656中描述的化合物,WO0238563和WO02000657中描述的稠合吡嗪二酮衍生物,WO0236593中描述的吲哚衍生物;WO0228865和WO0228859中描述的稠合吲嗪衍生物,WO0228858和WO0194345中描述的六氢吡嗪并[1′,2′:1,6]-吡啶并[3,4-B]吲哚-1,4-二酮衍生物,WO0210166中描述的稠和杂环衍生物,WO0200658中描述的环状GMP特异性磷酸二酯酶抑制剂,WO0194347中描述的四环的二酮哌嗪化合物和用途申请WO0219213中描述的化合物,所有这些被引入本文作为参考。
与本发明有关的另一些PDEV抑制剂包括:4-溴-5-(吡啶甲基氨基)-6-[3-(4-氯苯基)-丙氧基]-3(2H)哒嗪酮;1-[4-[(1,3-苯并二氧杂环戊基(dioxol)-5-基甲基)氨基]-6-氯-2-喹唑啉基]-4-哌啶-羧酸,单钠盐;(+)-顺式-5,6a,7,9,9,9a-六氢-2-[4-(三氟甲基)-苯基甲基-5-甲基-环戊-4,5]咪唑并[2,1- b]嘌呤-4(3H)酮;furazlocillin;顺式-2-己基-5-甲基-3,4,5,6a,7,8,9,9a-八氢环戊[4,5]-咪唑并[2,1-b]嘌呤-4-酮;3-乙酰基-1-(2-氯苄基)-2-丙基吲哚-6-羧酸酯;3-乙酰基-1-(2-氯苄基)-2-丙基吲哚-6-羧酸酯;4-溴-5-(3-吡啶基甲基氨基)-6-(3-(4-氯苯基)丙氧基)-3-(2H)哒嗪酮;1-甲基-5(5-吗啉乙酰基-2-正-丙氧基苯基)-3-正-丙基-1,6-二氢-7H-吡唑并(4,3-d)嘧啶-7-酮;1-[4-[(1,3-苯并二氧杂环戊基-5基甲基)氨基]-6-氯-2-喹唑啉基]-4-哌啶羧酸,单钠盐;药品项目编号4516(Glaxo Wellcome);药品项目编号5051(Bayer);药品项目编号5064(Kyowa Hakko;见WO 96/26940);药品项目编号5069(Schering Plough);GF-196960(Glaxo Wellcome);E-8010和E-4010(Eisai);Bay-38-3045 & 38-9456(Bayer);FR229934和FR226807(Fujisawa);和Sch-51866。
根据本发明,应用的优选的PDEV抑制剂包括:
(i)5-[2-乙氧基-5-(4-甲基-1-哌嗪磺酰基)苯基]-1-甲基-3-正-丙基-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮(西地那非),也被称为1-[[3-(6,7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4,3-d]嘧啶-5-基)-4-乙氧苯基]磺酰基]-4-甲基哌嗪(参见EP-A-0463756);
(ii)5-(2-乙氧基-5-吗啉乙酰基苯基)-1-甲基-3-正-丙基-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮(见EP-A-0526004);
(iii)3-乙基-5-[5-(4-乙基哌嗪-1-基磺酰基)-2-正-丙氧基苯基]-2-(吡啶-2-基)甲基-2,6-二氢-7H吡唑并[4,3-d]嘧啶-7-酮(参见WO98/49166);
(iv)3-乙基-5-[5-(4-乙基哌嗪-1-基磺酰基)-2-(2-甲氧基乙氧基)吡啶-3-基]-2-(吡啶-2-基)甲基-2,6-二氢-7H吡唑并[4,3-d]嘧啶-7-酮(参见WO99/54333);
(v)(+)-3-乙基-5-[5-(4-乙基哌嗪-1-基磺酰基)-2-(2-甲氧基-1(R)-甲基乙氧基)吡啶-3-基]-2-甲基-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮,也称作3-乙基-5-{5-[4-乙基哌嗪-1-基磺酰基]-2-([(1R)-2-甲氧基-1-甲基乙基]氧)吡啶-3-基}-2-甲基-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮(参见WO99/54333);
(vi)5-[2-乙基-5-(4-乙基哌嗪-1-基磺酰基)吡啶-3-基]-3-乙基-2-[2-甲氧基乙基]-2,6-二氢-7H吡唑并[4,3-d]嘧啶-7-酮,也被称作1-{6-乙基-5-[3-乙基-6,7-二氢-2-(2-甲氧基乙基)-7-氧代-2H-吡唑并[4,3-d]嘧啶-5-基]-3-吡啶磺酰基}-4-乙基哌嗪(参见WO 01/27113,实施例8);
(vii)5-[2-异-丁氧基-5-(4-乙基哌嗪-1-基磺酰基)吡啶-3-基]-3-乙基-2-(1-甲基哌啶-4-基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮(参见WO 01/27113,实施例15);
(viii)5-[2-乙氧基-5-(4-乙基哌嗪-1-基磺酰基)吡啶-3-基]-3-乙基-2-苯基-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮(参见WO 01/27113,实施例66);
(ix)5-(5-乙酰-2-丙氧基-3-吡啶基)-3-乙基-2-(1-异丙基-3-氮杂环丁基)-2,6-二氢-7H吡唑并[4,3-d]嘧啶-7-酮(参见WO01/27112,实施例124);
(x)5-(5-乙酰基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-氮杂环丁基)-2,6-二氢-7H吡唑并[4,3-d]嘧啶-7-酮(参见WO01/2712,实施例132);
(xi)(6R,12aR)-2,3,6,7,12,12a-六氢-2-甲基-6-(3,4-亚甲基二氧苯基)-吡嗪并[2′,1′:6,1]吡啶并[3,4-b]吲哚-1,4-二酮(泰地那非(tadalafil),IC-351,Cialis)),即公开的国际申请WO95/19978中实施例78和95中的化合物,也是1、3、7和8中的化合物;
(xii)2-[2-乙氧基-5-(4-乙基-哌嗪-1-基-1-磺酰基)-苯基]-5-甲基-7-丙基-3H咪唑并[5,1-f][1,2,4]三嗪-4-酮(伐地那非(Vardenafil)),也称为1-[[3-(3,4-二氢-5-甲基-4-氧代-7-丙基咪唑并[5,1-f]-as-三嗪-2-基)-4-乙氧基苯基]磺酰基]-4-乙基哌嗪,即公开的国际申请WO99/24433中实施例20、19、337和336的化合物;
(xiii)在WO00/27848中公开的吡唑并[4,3-d]嘧啶-4-酮类,特别是N-[[3-(4,7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4,3-d]-嘧啶-5-基)-4-丙氧苯基]磺酰基]-1-甲基2-吡咯烷基丙酰胺[DA-8159(WO00/27848的实施例68)];
(xiv)公开的国际申请WO93/07124中实施例11的化合物;
(xv)4-(4-氯苄基)氨基-6,7,8-三甲氧基喹唑啉;和
(xvi)7,8-二氢-8-氧代-6-[2-丙氧基苯基]-1H-咪唑并[4,5-g]喹唑啉;
(xvii)1-[3-[1-[(4-氟苯基)甲基]-7,8-二氢-8-氧代-1H-咪唑并[4,5-g]喹唑啉-6-基]-4-丙氧基苯基]甲酰胺;
(xviii)5-(5-乙酰基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-氮杂环丁基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;和
(xix)1-{6-乙氧基-5-[3-乙基-6,7-二氢-2-(2-甲氧基乙基)-7-氧代-2H-吡唑并[4,3-d]嘧啶-5-基]-3-吡啶磺酰基}-4-乙基哌嗪;
和其药学可接受的盐或溶剂合物。
通过文献方法来评价PDEV抑制剂的功效和选择性以及随后依照标准制药规范评价其毒性、吸收、代谢和药代动力学等,可以容易地确定任一具体的PDEV抑制剂的适宜性。
优选地,PDEV抑制剂具有小于100纳摩尔的IC50值,更优选小于50纳摩尔,最优选小于10纳摩尔的IC50值。
PDEV抑制剂的IC50值可通过在下文中描述的PDE5试验来确定。
在根据本发明的药物组合物中应用的优选地PDEV抑制剂对PDEV酶是有选择性地。优选它们对PDEV的选择性比PDE3高100倍,更优选高300倍。优选地PDEV抑制剂具有比对PDE3和PDE4均高100倍,更优选高300倍的选择性。选择性的比率很容易由本领域人员确定。PDE3和PDE4酶的IC50值可以用已有文献的方法测定,参见SABallard et al,Journal of Urology,1998,vol.159,2164-2171,之后将详细描述。
本申请有用的PDEV抑制剂可以用下面的式(III)描述:
其中:
A为CH或N;
R1为H、C1到C6的烷基、C3到C6的链烯基、C3到C6的环烷基、C3到C6环烯基、或C1-C3全氟代烷基,其中所述烷基可以是支链或直链的,且其中所述的烷基、链烯基、环烷基或全氟代烷基任选地被一个或多个选自下述的取代基取代:羟基;C1到C4烷氧基;C3到C6环烷基;C1-C3全氟代烷基;被一个或多个选自C1到C3烷基、C1到C4烷氧基、C1到C4卤代烷基或C1到C4卤代烷氧基的取代基取代的苯基,其中所述卤代烷基和卤代烷氧基含有一个或多个卤原子、卤素、CN、NO2、NHR11、NHSO2R12、SO2R12、SO2NHR11、COR11、CO2R11,其中R11为H、C1到C4烷基、C2到C4链烯基、C1到C4烷酰基、C1到C4卤代烷基或C1到C4卤代烷氧基,其中R12为C1到C4烷基、C2到C4链烯基、C1到C4烷酰基、C1到C4卤代烷基或C1到C4卤代烷氧基;NR7R8、CONR7R8或NR7COR11,其中R7和R8各自独立地选自H、C1到C4烷基、C2到C4链烯基,C1到C4烷氧基、CO2R9、SO2R9,其中所述的烷基,链烯基或烷氧基任选地被NR5R6、C1到C4卤代烷基或C1到C4卤代烷氧基取代,其中R9为H、羟基、C2到C3烷基,C1到C4烷酰基或任选地被苯基取代的C1到C4烷基,其中苯基任选地被一个或多个如下取代基取代,所述取代基选自被C1到C4卤代烷基或C1到C4卤代烷氧基任选取代的C1到C4烷基、C1到C4烷氧基、卤素、CN、NO2、NHR11、NHSO2R12、SO2R12、SO2NHR11、COR11或CO2R11;Het1;Het2或Het3;或R1为Het4或苯基,其中所述苯基任选地被一个或多个选自如下的取代基取代:C1到C4烷基、C2到C4链烯基、C1到C4烷氧基、卤素、CN、CF3、OCF3、NO2、NHR11、NHSO2R12、SO2R12、SO2NHR11、COR11、CO2R11;
R2为H、C1到C6烷基、C3到C6链烯基或(CH2)n(C3到C6环烷基)其中n为0、1或2,且其中所述烷基或链烯基任选地被一个或多个氟取代;
R13为OR3或NR5R6;
R3为C1到C6烷基、C3-C6链烯基、C3-C6炔基,C3-C7环烷基、C1-C6全氟代烷基或(C3-C6环烷基)C1-C6烷基,其任选地被一个或两个下述取代基取代,取代基选自:C3到C5环烷基、羟基、C1到C4烷氧基、C3-C6链烯基、C3-C6炔基、苄氧基、NR5R6、苯基、Het1、Het2、Het3或Het4,其中C1到C6烷基和C1到C4烷氧基任选地被如CF3的卤代烷基终止;C3到C6环烷基;Het1、Het2、Het3或Het4;
R4为任选地被OH、NR5R6、CN、CONR5R6或CO2R7取代的C1-C4烷基;任选地被CN、CONR5R6或CO2R7取代的C2-C4链烯基;任选地被NR5R6取代的C2-C4烷酰基;任选地被NR5R6取代的羟基C2-C4烷基;任选地被OH或NR5R6所取代的(C2-C3烷氧基)C1-C2烷基;CONR5R6;CO2R7;卤素;NR5R6;NHSO2NR5R6;NHSO2R8;或苯基或杂环基,二者任一任选地被甲基取代;或R4为吡咯烷基磺酰基、哌啶磺酰基、吗啉磺酰基,或含有取代基的哌嗪-1-基磺酰基,R10在哌嗪基的4位上,其中所述的哌嗪基任选地被一个或两个C1到C4烷基、C1到C3烷氧基、NR7R8或CONR7R8基取代,并且任选地是它的4-N-氧化物形式;
R5和R6各自独立地选自H和任选地被C3到C5环烷基或C1到C4烷氧基取代的C1到C4烷基,或与它们连接的氮原子一起形成氮杂环丁基、吡咯烷基、哌啶基、吗啉基、4-(NR9)-哌嗪基或咪唑基,其中所述基团任选地被甲基或羟基取代;
R10为H;任选地被一个或两个选自羟基、NR5R6、CONR5R6和任选地被C1到C4烷基或C1到C4烷氧基取代的苯基的取代基取代的C1到C6烷基、(C1-C3烷氧基)C2-C6烷基、羟基C2-C6烷基,(R7R8N)C2-C6烷基、(R7R8NCO)C1-C6烷基、CONR7R8、CSNR7R8或C(NH)NR7R8;C2到C6链烯基或Het4;
Het1为N-连接的4-,5-或6-元含氮杂环基,任选地含有一个或多个选自S、N或O的杂原子;
Het2为C-连接的含O、S或N杂原子的5-元杂环基,任选地含有一个或多个选自O或S的杂原子;
Het3为C-连接的含O或S杂原子的6-元杂环基,任选地含有一个或多个选自O、S或N的杂原子;或Het3为C-连接的含三个N杂原子的6-元杂环基;
Het4为C-连接的含一个、两个或三个选自S,O或N的杂原子的4-、5-或6-元杂环基;其中任一所述的杂环基Het1、Het2、Het3或Het4可以是饱和的、部分饱和的或芳香的,其中任一所述的杂环基可以任选地被一个或多个选自C1到C4烷基、C2到C4链烯基、C1到C4烷氧基、卤素、CO2R11、COR11、SO2R12或NHR11取代基取代,和/或其中所述杂环基是苯并稠和的;
或,其中当R13代表OR3或R3NR5时;R1代表Het、烷基Het、芳基或烷基芳基,后面的五个基团都任选地被一个或多个选自卤素、氰基、硝基、低级烷基、卤代(低级烷基)、OR6、OC(O)R7、C(O)R8、C(O)OR9、C(O)NR10R11、NR12R13和SO2NR14R15的取代基取代和/或终止;R2代表H、卤素、氰基、硝基、OR6、OC(O)R7、C(O)R8、C(O)OR9、C(O)NR10R11、NR12R13、SO2NR14R15、低级烷基、Het、烷基Het、芳基或烷基芳基,后面的五个基团都任选地被一个或多个选自卤素、氰基、硝基、低级烷基、卤代(低级烷基),OR6、OC(O)R7、C(O)R8、C(O)OR9、C(O)NR10R11、NR12R13和SO2NR14R15的取代基取代和/或终止;R3代表H、低级烷基,烷基Het或烷基芳基,后面的三个基团都任选地被一个或多个选自卤素、氰基、硝基、低级烷基、卤代(低级烷基),OR6、OC(O)R7、C(O)R8、C(O)OR9、C(O)NR10R11、NR12R13和SO2NR14R15取代和/或终止;R4代表H、卤素、氰基、硝基、卤代(低级烷基)、OR6、OC(O)R7、C(O)R8、C(O)OR9、C(O)NR10R11、NR12R13、NR16Y(O)R17、SOR18、SO2R19R20、C(O)AZ、低级烷基,低级链烯基,低级炔基、Het、烷基Het、芳基、烷基芳基,后面的七个基团都任选地被一个或多个选自卤素、氰基、硝基、低级烷基、卤代(低级烷基),OR6、OC(O)R7、C(O)R8、C(O)OR9、C(O)NR10R11、NR12R13和SO2NR14R15的取代基取代和/或终止;Y代表C或S(O),其中当Y是S(O)时,R16和R17之一个不存在;A代表低级亚烷基;Z代表OR6、卤素、Het或芳基,后面两个基团均任选地被一个或多个选自卤素、氰基、硝基、低级烷基、卤代(低级烷基),OR6、OC(O)R7、C(O)R8、C(O)OR9、C(O)NR10R11、NR12R13和SO2NR14R15的取代基取代;R5、R6、R7、R8、R9、R18、R19和R20独立地代表H或低级烷基;R10和R11独立地代表H或低级烷基,后面的基团任选地被一个或多个选自卤素、氰基、硝基、低级烷基、卤代(低级烷基)、OR6、OC(O)R7、C(O)R8、C(O)OR9、C(O)NR10R11、NR12R13和SO2NR14R15的取代基取代和/或终止,或任选地被一个或多个上述最后11个基团取代的Het或芳基或R10和R11之一是低级烷氧基、氨基或Het,后两者均任选地被低级烷基取代;R12和R13独立地代表H或低级烷基或R12或R13之一是C(O)-低级烷基或C(O)Het,其中Het任选地被低级烷基取代;R14和R15独立地代表H或低级烷基或R14和R15与它们连接地氮原子一起形成杂环;R16和R17独立地代表H或低级烷基,或R16和R17之一是Het或芳基,其中后两个基团均任选地被低级烷基取代;Het代表任选取代的四到十二元杂环基,其可以是芳香性的或非芳香性的,可以含有一个或多个双键,可以是单环或二环的,可以含有一个或多个选自N、S和O的杂原子;
或其药学可接受的盐或溶剂合物。
在式(III)中,PDEV抑制剂可以含有卤素。这里,“卤素”是指氟、氯、溴或碘。
在式(III)中,PDEV抑制剂可以含有一个或多个烷基、烷氧基、链烯基、亚烷基和亚链烯基—其可以是非支链的或支链的。
在式(III)中,根据本发明应用的化合物的优选基团是那些其中:R1为H、甲基或乙基;R2是H、任选地被OH取代的C1-C3烷基或甲氧基;R3是C2-C3烷基或烯丙基;R4是磺酰基哌啶或4-N-(R10)-磺酰基哌嗪-1-基;R5是H、NR7R8或CONR7R8;R10是H、C1-C3烷基、羟基C2-C6烷基、CONR7R8、CSNR7R8或C(NH)NR7R8;R7和R8各自独立地是H或甲基。
在式(III)中,根据本发明应用的其它化合物的其他优选基团是那些其中:R1为任选地被Het取代的C1到C2烷基;2-(吗啉-4-基)乙基或苄基;R2为C2到C4烷基;R13为OR3或NR5R6;R3为任选地被一个或两个选自环丙基、环丁基、OH、甲氧基、乙基、苄氧基、NR5R6、苯基、呋喃-3-基、吡啶-2-基和吡啶-3-基取代的C1到C4烷基;环丁基;1-甲基哌啶-4-基;四氢呋喃-3-基或四氢吡喃-4-基;R5和R6各自独立地选自H和任选地被环丙基或甲氧基取代的C1到C2烷基,或者与它们相连的氮原子一起形成氮杂环丁烷、吡咯烷基或吗啉基;R7和R8与它们相连的氮原子一起形成任选地被一个或两个甲基取代的4-R10-哌嗪基,并且任选地是4-N-氧化物的形式;R10为H,任选地被一或两个选自OH、NR5R6、CONR5R6、任选地被甲氧基、苯并二氧杂环戊基-5-基和苯并二噁烷-2-基取代的苯基的取代基取代的C1到C3烷基基;烯丙基;吡啶-2-基;吡啶-4-基或嘧啶-2-基;He t选自吡啶-2-基;1-环氧吡啶-2-基;6-甲基吡啶-2-基;6-甲氧基吡啶-2-基;哒嗪-3-基;嘧啶-2-基和1-甲基咪唑并-2-基。这些基团的化合物中更优选的化合物是那些其中R1为任选地被Het取代的C1到C2烷基;2-(吗啉-4-基)乙基或苄基;R2为C2到C4烷基;R13为OR3;R3为任选地被环丙基、环丁基、OH、甲氧基、乙氧基、苯基、呋喃-3-基或吡啶-2-基单取代的C1到C4烷基;环丁基;四氢呋喃-3-基或四氢吡喃-4-基;R7和R8与它们相连的氮原子形成4-R10-哌嗪基,任选地是它的4-N-氧化物;R10为任选地被OH单取代的C1到C3烷基;Het选自吡啶-2-基;1-环氧吡啶-2-基;6-甲基吡啶-2-基;6-甲氧基吡啶-2-基;哒嗪-3-基;嘧啶-2-基和1-甲基咪唑并-2-基。
在式(III)中,根据本发明应用的化合物的其他更进一步的优选基团是那些其中:R1为C1到C6烷基或C3到C6链烯基,其中所述的烷基或链烯基可以为支链或直链的,或R1为C3到C6环烷基或C4到C6环烯基,且其中当R1为C1到C3烷基所述烷基被取代;其中当R1为C4到C6烷基、C3到C6链烯基、C3到C6环烷基或C4到C6环烯基时,所述的烷基、链烯基、环烷基或环烯基任选地被取代;一个或多个取代基选自羟基;C1到C4烷氧基;C3到C4环烷基;被一个或多个选自C1到C3烷基,C1到C4烷氧基,C1到C4卤代烷基或C1到C4卤代烷氧基、卤素、CN、NO2、NHR11、NHCOR12、NHSO2R12、SO2R12、SO2NHR11、COR11、CO2R11的取代基取代的苯基,其中所述的卤代烷基和卤代烷氧基含有一个或多个卤原子;NR7R8、CONR7R8或NR7COR11;Het1基,其为N-连接的含氮4-元杂环;Het2基,其为C-连接的含O、S或N杂原子的任选地含有一个或多个选自O、S或N杂原子的5-元杂环,Het3基,其为C-连接的含O或S杂原子的任选地含有一个或多个选自O、S或N杂原子的6-元杂环,或者Het3基,其为C-连接的含有三个N杂原子的6-元杂环;其中R7、R8、R11和R12此处定义同上或R1为C-连接的含有一个选自S、O或N的杂原子的4-或5-元杂环Het4基;Het4基,其为C-连接的含一个、两个或三个选自S或O原子的6-元杂环;Het4基,其为C-连接的含三个N杂原子的6-元杂环;Het4基,其为C-连接的任选地被一个或多个选自C1到C4烷基、C1到C4烷氧基、CO2R11、SO2R12、COR11、NHR11或NHCOR12和任选地包括选自S、O或N另外杂原子的取代基取代的含有一个或两个N杂原子的6-元杂环,其中任一所述的杂环基Het1、Het2、Het3或Het是饱和的、部分饱和的或如需要,芳香的,且任一所述杂环基任选地被一个或多个选自C1到C4烷基、C3到C4链烯基、C1到C4烷氧基、卤素、CO2R11、SO2R12、COR11或NHR11的取代基取代,其中R11此处定义同上,和/或其中任一所述杂环基是苯并-稠和的;或R1是被一个或多个选自CF3、OCF3、SO2R12或CO2R12的取代基取代的苯基,其中R12为任选地被苯基、C1到C4卤代烷基或C1到C4卤代烷氧基取代的C1到C4烷基,其中所述的卤代烷基和卤代烷氧基含有含有一个或多个卤原子;R2为C1到C6烷基;R13为OR3;R3为任选地被一个或两个选自C3到C5环烷基、羟基、C1到C4烷氧基、苄氧基、NR5R6、苯基、呋喃基、四氢呋喃基或吡啶基的取代基取代的C1到C6烷基,其中所述C1到C6烷基和C1到C4烷氧基可任选地被如CF3的卤代烷基所终止;或R3为C3到C6环烷基、1-(C1到C4烷基)哌啶基、四氢呋喃基或四氢吡喃基;R4为在哌嗪基4-位含有一个取代基R10的哌嗪-1-基磺酰基,其中所述哌嗪基任选的被一个或两个C1到C4烷基取代,且任选的为4-N-氧化物的形式;R5和R6分别独立地选自H和C1到C4烷基,其任选地被C3到C5环烷基或C1到C4烷氧基取代,或与它们相连的氮原子一起形成氮杂环丁基、吡咯烷基、哌啶基或吗啉基;R10为H;任选地被一个或两个选自羟基、NR5R6、CONR5R6、任选地被C1到C4烷基或C1到C4烷氧基取代的苯基的取代基取代的C1到C4烷基;C3到C6链烯基;Het4;前提是当R1为被苯基取代的C1到C3烷基时,所述的苯基不被C1到C4烷氧基取代;CN;卤素;CF3;OCF3;或C1到C4烷基。这些化合物中更优选的基团是那些其中:R1为C1到C6烷基,其中所述烷基可以是支链或直链的,R1为C3到C6环烷基,其中当R1为C1到C3烷基时,所述的烷基是被取代的;和其中当R1为C4到C6烷基或C3到C6环烷基时,所述的烷基或环烷基是任选被取代的;一个或多个取代基选自羟基;C1到C2烷氧基;C3到C5环烷基;NR7R8、NR7COR11或COR11,其中R7和R8分别独立地选自H、C1到C4烷基或CO2R9,其中R9和R11此处定义同上;Het1基其为N-连接的含氮4-元杂环;Het3基,其为C-连接的含一个O或S原子,任选含有一个或多个选自O、S或N的杂原子的6-元杂环,或Het3基,其为C-连接的含有三个N杂原子的6-元杂环;或R1为C-连接的含有选自O、S或N杂原子的含S、O或N原子的4-元杂环Het4基;或R1为C-连接的含一个、两个或三个选自S或O杂原子的6-元杂环Het4基,其中所述杂环基Het1、Het2、Het3或Het4可以是饱和的、部分饱和的或芳香的,且任选地被一个或多个选自C1到C4烷基、C1到C4烷氧基、-CO2R11、-SO2R12、-COR11或NHR11的取代基所取代,其中R11和R12此处定义同上,和/或其中任一所述的杂环基都是苯并—稠和的;或R1是由一个或多个选自CF3、-OCF3、-SO2R12、-COR11、-CO2R11的取代基取代的苯基,其中R11和R12此处定义同上;R2是C1到C6烷基;R13是OR3;R3是甲基、乙基、正-丙基、异-丙基、正-丁基、仲丁基、异-丁基、或任选地被一个或两个选自环丙基、环丁基、羟基、甲氧基、乙氧基、苄氧基、苯基、苄基、呋喃-3-基、四氢呋喃-2-基甲基、四氢呋喃-3-基甲基、吡啶-2-基、吡啶-3-基或NR5R6的取代基取代的叔-丁基烷基,其中R5和R6分别独立地选自H和C1到C2烷基;R4为在哌嗪基4-位含有取代基R10的哌嗪-1-基磺酰基,其中所述哌嗪基任选地被一个或两个C1到C4烷基取代,也任选地是4-N-氧化物;R10为H、任选地被一个或两个选自羟基、NR5R6、CONR5R6的取代基取代的C1到C3烷基,其中R5和R6分别独立地选自H、C1到C4烷基和C3链烯基。
在式(III)中,根据本发明应用的化合物的其它优选基团是:R1代表H、低级烷基、Het、烷基Het或烷芳基(其中后四个基团均任选地被一个或多个选自氰基、低级烷基、OR6、C(O)OR9或NR12R13的取代基取代和/或终止);R2代表H,卤素,低级烷基,Het或芳基(其中后三种基团均任选地使用一种或多种如前面所定义的取代基取代和/或终止,优选地用NR12R13或SO2NR14R15);R3代表C1-C4烷基或C3-C4环烷基,其任选地被一个或多个选自卤素、氰基、硝基、低级烷基、卤代(低级烷基)、OR6、OC(O)R7、C(O)R8、C(O)OR9、C(O)NR10R11、NR12R13和SO2NR14R15的取代基取代和/或终止;R4代表卤素、氰基、硝基、C(O)R8、C(O)OR9、C(O)NR10R11、NR12R13、N[Y(O)R17]2、NR16Y(O)R17、SOR18、SO2R19、C(O)AZ、低级烷基、低级炔基、Het或芳基,其中后三种基团均任选地被一种或多个前面所述的取代基所取代和/或终止;并且其中Y、A、Z、R10、R11、R12、R13、R14、R15、R16、R17、R5、R6、R7、R8、R9、R18、R19和Het此处定义同上。在进一步的基团中更优选的是如下化合物,其中:R1代表任选地被取代的低级烷基,更加优选的是低级烷基、低级烷氧基-终止的低级烷基、NR12R13-终止的低级烷基、或N-吗啉基-终止的低级烷基。可选择地,R1可代表4-哌啶基或3-氮杂环丁基,任选地用低级烷基或C(O)OR9取代哌啶基的氮原子。在此类更优选的化合物中,R2代表C(O)NR10R11,NR12R13,任选地被一个或多个O,S或N中断的,或任选地在N位被低级烷基或酰基取代的,或任选被芳基或Het取代的低级烷基。更优选地,当R2是被中断的低级烷基时,中断的原子是一个或多个O和低级烷基化的N,且当R2是芳基时,它是任选取代的苯基或吡啶基。特别优选的进一步基团的化合物是其中:R2代表C(O)NR10R11,NR12R13,任选地被O或N中断C1-4烷基,任选地在N上被低级烷基取代,任选地被苯基取代,任选地被吡啶-2-基、吡啶-3-基、嘧啶-5-基、吡嗪-2-基、吡唑-4-基、噁二唑基-2-基、呋喃-2-基、呋喃-3-基、四氢呋喃-2-基和咪唑并[1,2-a]吡啶-6-基取代。在化合物进一步优选的基团中,R3可以代表低级烷基或环烷基。而且X优选O。这些进一步和更加优选的化合物具有R4代表卤素、低级烷基、低级炔基、任选地被取代的Het、任选地被取代的芳基、C(O)R8、C(O)AZ、C(O)OR9、C(O)NR10R11、NR12R13或NR16Y(O)R17。更优选R4是C(O)R8(例如乙酰基)、卤素(例如碘)、SO2R19(其中R19代表低级烷基)和C(O)NR10R11(例如R10和R11独立代表H和低级烷基,和/或R10和R11之一是低级烷氧基)或NHB,其中B代表H、SO2CH3或C(O)Het。进一步优选的化合物中R4代表碘、低级烷基、低级炔基(后两个基团被C(O)OR9(其中R9代表H或C1-6烷基)取代和/或终止)、N(H)Y(O)R17、N[Y(O)R17]2、被Het或NR12R13(其中R12和R13一起代表被O或N-S(O)2-(任选取代的芳基)中断的C3-5亚烷基)。
本发明应用的更优选的PDEV抑制剂,尤其是与选自加巴喷丁、普加巴林、和(1α,3α,5α)(3-氨基-甲基-二环[3.2.0]庚-3-基)-乙酸及其药学可接受的盐或溶剂合物的α-2-δ配体,选自:
5-[2-乙氧基-5-(4-甲基-1-哌嗪基磺酰基)苯基]-1-甲基-3-正-丙基-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮(西地那非);
(6R,12aR)-2,3,6,7,12,12a-六氢-2-甲基-6-(3,4-亚甲基二氧苯基)-吡嗪并[2′,1′:6,1]吡啶并[3,4-b]吲哚-1,4-二酮(泰地那非,IC-351,Cialis);
2-[2-乙氧基-5-(4-乙基-哌嗪-1-基-1-磺酰基)-苯基]-5-甲基-7丙基-3H-咪唑并[5,1-f][1,2,4]三嗪-4-酮(伐地那非);
5-[2-乙氧基-5-(4-乙基哌嗪-1-基磺酰基)吡啶-3-基]-3-乙基-2-[2-甲氧基乙基]-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
5-(5-乙酰基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-氮杂环丁基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;和
1-{6-乙氧基-5-[3-乙基-6,7-二氢-2-(2-甲氧基乙基)-7-氧代-2H-吡唑并[4,3-d]嘧啶-5-基]-3-吡啶磺酰基}-4-乙基哌嗪;
和其药学可接受的盐和溶剂合物。
特别优选的PDEV抑制剂,尤其是与选自加巴喷丁、普加巴林、(1α,3α,5α)(3-氨基-甲基-二环[3.2.0]庚-3-基)-乙酸及其药学可接受的盐或溶剂合物的α-2-δ配体,是5-[2-乙氧基-5-(4-甲基-1-哌嗪基磺酰基)苯基]-1-甲基-3-正-丙基-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮(西地那非)和其药学可接受的盐或溶剂合物。西地那非柠檬酸盐是优选的盐。
本发明可选择的或另一方面,提供了一种组合,尤其是协同组合,其包括加巴喷丁和PDEV抑制剂,所述PDEV抑制剂选自西地那非、1-{6-乙氧基-5-[3-乙基-6,7-二氢-2-(2-甲氧基乙基)-7-氧代-2H-吡唑并[4,3-d]嘧啶-5-基]-3-吡啶基磺酰基}-4-乙基哌嗪、5-(5-乙酰基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-氮杂环丁基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮、伐地那非或泰地那非,或其药学可接受的盐或溶剂合物。特别优选的组合包含加巴喷丁和西地那非或其药学可接受的盐盐或溶剂合物。
本发明可选择的或另一方面本发明,提供了一种组合,尤其是协同组合,其包含普加巴林和PDEV抑制剂,所述PDEV抑制剂选自西地那非、1-{6-乙氧基-5-[3-乙基-6,7-二氢-2-(2-甲氧基乙基)-7-氧代-2H-吡唑并[4,3-d]嘧啶-5-基]-3-吡啶基磺酰基}-4-乙基哌嗪,5-(5-乙酰基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-氮杂环丁基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮、伐地那非或泰地那非。特别优选的组合包含普加巴林和西地那非。
本发明可选择的或另一方面,提供了一种组合,尤其是协同组合,其包含[(1R,5R,6S)-6-(氨甲基)二环[3.2.0]庚-6-基]乙酸或其药学可接受的盐或溶剂合物,和PDEV抑制剂。适当地,提供了一种组合,其包含[(1R,5R,6S)-6-(氨甲基)二环[3.2.0]庚-6-基]乙酸或其药学可接受的盐或溶剂合物,和PDEV抑制剂,所述PDEV抑制剂选自西地那非,1-{6-乙氧基-5-[3-乙基-6,7-二氢-2-(2-甲氧基乙基)-7-氧代-2H-吡唑并[4,3-d]嘧啶-5-基]-3-吡啶基磺酰基}-4-乙基哌嗪、5-(5-乙酰基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-氮杂环丁基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮、伐地那非或泰地那非或其药学可接受的盐或溶剂合物,优选西地那非或其药学可接受的盐或溶剂合物。
优选的,提供了一种组合,其包含(1α,3α,5α)(3-氨基-甲基-二环[3.2.0]庚-3-基)-乙酸或其药学可接受的盐或溶剂合物,和选自西地那非、1-{6-乙氧基-5-[3-乙基-6,7-二氢2-(2-甲氧基乙基)-7-氧代-2H-吡唑并[4,3-d]嘧啶-5-基]-3-吡啶基磺酰基}-4-乙基哌嗪、5-(5-乙酰基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-氮杂环丁基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮、伐地那非或泰地那非或者其药学可接受的盐或溶剂合物的PDEV抑制剂,优选西地那非或其药学可接受的盐或溶剂合物。
本发明的进一步的优选方案,组合选自:
加巴喷丁和西地那非;
加巴喷丁和伐地那非;
加巴喷丁和泰地那非;
加巴喷丁和1-{6-乙氧基-5-[3-乙基-6,7-二氢-2-(2-甲氧基乙基)-7-氧代-2H-吡唑并[4,3-d]嘧啶-5-基]-3-吡啶基磺酰基}-4-乙基哌嗪;
加巴喷丁和5-(5-乙酰基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-氮杂环丁基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
普加巴林和西地那非;
普加巴林和伐地那非;
普加巴林和泰地那非;
普加巴林和1-{6-乙氧基-5-[3-乙基-6,7-二氢-2-(2-甲氧基乙基)-7-氧代-2H-吡唑并[4,3-d]嘧啶-5-基]-3-吡啶磺酰基}4-乙基哌嗪;
普加巴林和5-(5-乙酰基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-氮杂环丁基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
[(1R,5R,6S)-6-(氨甲基)二环[3.2.0]庚-6-基]乙酸和西地那非;
[(1R,5R,6S)-6-(氨甲基)二环[3.2.0]庚-6-基]乙酸和伐地那非;
[(1R,5R,6S)-6-(氨甲基)二环[3.2.0]庚-6-基]乙酸,和泰地那非;
[(1R,5R,6S)-6-(氨甲基)二环[3.2.0]庚-6-基]乙酸和1-{6-乙氧基-5-[3-乙基-6,7-二氢-2-(2-甲氧乙基)-7-氧代-2H-吡唑并[4,3-d]嘧啶-5-基]-3-吡啶磺酰基}-4-乙基哌嗪;以及
[(1R,5R,6S)-6-(氨甲基)二环[3.2.0]庚-6-基]乙酸和5-(5-乙酰基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-氮杂环丁基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮。
(1α,3α,5α)(3-氨基-甲基-二环[3.2.0]庚-3-基)-乙酸和西地那非;
(1α,3α,5α)(3-氨基-甲基-二环[3.2.0]庚-3-基)-乙酸和伐地那非;
(1α,3α,5α)(3-氨基-甲基-二环[3.2.0]庚-3-基)-乙酸和泰地那非;
(1α,3α,5α)(3-氨基-甲基-二环[3.2.0]庚-3-基)-乙酸和1-{6-乙氧基-5-[3-乙基-6,7-二氢-2-(2-甲氧乙基)-7-氧代-2H-吡唑并[4,3-d]嘧啶-5-基]-3-吡啶磺酰基}-4-乙基哌嗪;以及
(1α,3α,5α)(3-氨基-甲基-二环[3.2.0]庚-3-基)-乙酸和5-(5-乙酰基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-氮杂环丁基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
(3S,4S)-(1-氨甲基-3 4-二甲基-环戊基)-乙酸和西地那非;
(3S,4S)-(1-氨甲基-3,4-二甲基-环戊基)-乙酸和伐地那非;
(3S,4S)-(1-氨甲基-3,4-二甲基-环戊基)-乙酸和泰地那非;
(3S,4S)-(1-氨甲基-3,4-二甲基-环戊基)-乙酸和1-{6-乙氧基-5-[3-乙基-6,7-二氢-2-(2-甲氧乙基)-7-氧代-2H-吡唑并[4,3-d]嘧啶-5-基]-3-吡啶磺酰基}-4-乙基哌嗪,
(3S,4S)-(1-氨甲基-3,4-二甲基-环戊基)-乙酸和5-(5-乙酰基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-氮杂环丁基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮,
或其药学可接受的盐或溶剂合物。
单一剂量形式的本发明组合的适合施用于任何哺乳动物,优选人类。给药可以是每天1次(o.d.)、2次(b.i.d.)或是3次(t.i.d.),优选b.i.d.或t.i.d.,更优选b.i.d.,最优选o.d.。因此,本发明的另一方面,提供了对哺乳动物的治疗、预防或缓解性治疗疼痛的方法,该方法包括每天给予1次、2次或是3次,优选每天2次和3次,更优选每天2次,最优选每天1次有效量的特别是协同作用量的α-2-δ配体和PDEV抑制剂组合。
一种或是多种成分之间的协同作用、效应的最佳范围和产生该效应的每种成分的绝对剂量范围的确定可通过给予需要治疗的病人不同w/w比例范围和剂量的成份来测定。对于人类,对病人进行这种临床研究的复杂性和费用,使这种形式作为研究协同作用的基本模型是不切实际的。然而,从一种物种观察到的协同作用可以预计在其它物种中的效应,如在此所描述的,该研究中测定的协同作用效果和结果也可通过应用药动学和药效学的方法预计在其它物种中需要的有效剂量、血浆浓度比例范围以及绝对剂量和血浆浓度。动物模型与人类身上观察到的效应之间确定的相关性表明,采用经历手术(例如慢性收缩损伤)或者化学药物(例如链佐星)步骤诱导异常性疼痛的啮齿类动物中静态和动态异常性疼痛的测量,是动物中协同作用的最好证实。因为这些模型存在平台效应,他们的值最好根据在神经性疼痛的病人转换为剂量节省优点的协同作用来评估。对治疗神经性疼痛的现有制剂仅产生部分应答的其它动物模型更适合预计产生协同作用的组合的潜力,以在两种成分最大耐受剂量产生提高的最大疗效。
因此,本发明的进一步的方面,提供了用于人类施用的协同组合,其中包含α-2-δ配体和PDEV抑制剂,或其药学可接受的盐或溶剂合物,以相应于非人类动物模型中观察的绝对剂量范围的w/w组合范围给药,其中动物模型优选大鼠模型,主要用于确定协同作用。适当的,相应于非人动物模型中的人类比例范围选自:以重量计,1∶50到50∶1份,1∶50到20∶1,1∶50到10∶1,1∶50到1∶1,1∶20到50∶1,1∶20到20∶1,1∶20到10∶1,1∶20到1∶1,1∶10到50∶1,1∶10到20∶1,1∶10到10∶1,1∶10到1∶1,1∶1到50∶1,1∶1到20∶1和1∶1到10∶1。更优选的,相应于协同的非人类范围的人类范围是,以重量计,1∶10到20∶1份。优选的,相应于非人范围的人范围为以重量计1∶1到10∶1份。对于加巴喷丁和西地那非,相应于非人的协同剂量范围的人范围,优选非人为大鼠模型,为按重量计1∶1到10∶1份。
对于人类,几种试验性的疼痛模型也可在人中使用以证实在动物中协同的药剂也在人中产生了一致的协同作用效果。适合这种目的的人类模型的例子包括热/辣椒素模型(Petersen,K.L.& Rowbotham,M.C.(1999)NeuroReport 10,1511-1516),i.d辣椒素模型(Andersen,O.L.,Felsby,S.,Nicolaisen,L.,Bjerring,P.,Jsesn,T.S.& Arendt-Nielsen,L.(1996)Pain 66,51-62),包括重复辣椒素损伤的使用(Witting,N.,Svesson,P.,ArendtNielsen,L.&Jensen,T.S.(2000)Somatosensory Motor Res.17,5-12)以及累计或卷曲(wind-up)反应(Curatolo,M.等.(2000)Anesthesiology93,1517-1530)。对于这些模型,疼痛强度或痛觉过敏面积的主观评价可以作为终点,也可应用依赖于电生理学或是影像技术(例如功能性磁共振成像)的更加客观的终点(Bornhovd,K.,Quante,M.,Glauche,V.,Bromm,B.,Weiller,C.& Buchel,C.(2002)Brain125,1326-1336)。所有这些模型在给出如下结论之前都需要客观有效的证据:他们提供了在人类中也支持已在动物研究中观察到的组合之协同效应的证据。
本发明用于人类,适当地α-2-δ配体:PDEV抑制剂的比例范围选自:以重量计,1∶50到50∶1份,1∶50到20∶1,1∶50到10∶1,1∶50到1∶1,1∶20到50∶1,1∶20到20∶1,1∶20到10∶1,1∶20到1∶1,1∶10到50∶1,1∶10到20∶1,1∶10到10∶1,1∶10到1∶1,1∶1到50∶1,1∶1到20∶1和1∶1到10∶1,更合适的,1∶10到20∶1,优选1∶1到10∶1。对于加巴喷丁和西地那非的组合,本发明提供了比例范围分别为1∶10到10∶1w/w,更优选1∶5到5∶1的适当剂量。
用于协同的每种成分的最佳剂量可以根据公开的动物模型程序确定。然而,在人类中确定组合中每种成分的全部治疗相关剂量的完全暴露-应答关系研究(甚至是疼痛试验模型)的花费是非常高的。估计以动物产生最佳协同作用的剂量外推出的协同剂量是否能观察到一致的协同效应是非常必要的,至少在初期是必要的。在由动物剂量标定人类剂量时,需要考虑因素如相对体重/体表面积、每种成分的相对吸收、分布、代谢和排泄,以及相对血浆蛋白的结合,由于这些原因,人类(和病人)预测的最佳剂量比例与对动物使用的最佳剂量比例是不太可能相同的。然而本领域技术人员能够理解并且计算动物和人类这两者之间的关系。建立动物与人类效应之间的桥梁关系的关键是在于动物研究中获得的应用每种成分的血浆浓度,由于这些与在人类预测的能够产生效应的每种成分的血浆浓度有关。药动学/药效学的模型(包括方法如等热辐射测量(isobolograms)、相互作用指数和反应表面模型方法)以及模拟也有助于预计人类中协同剂量比例,尤其是当这些成分中的一种或是两种已经在人类身上做过研究时。
确定在动物或人类身上观察到的任一断定的协同作用是否仅仅由于药动学的相互作用是非常重要的。例如一种化合物抑制另外一种化合物的代谢可能给出一种药动协同的假象。在使用加巴喷丁和西地那非的动物研究中,反复抽取血液样品,结果显示与药剂已知的药动学性质相一致,当给予能够诱导协同疼痛相互作用剂量的化合物时没有任何药动学相互作用的证据。这证明与疼痛相关的协同作用是药效学的,这种作用发生在每种药剂与各自的受体和/或酶靶相互作用之后。
因此,根据本发明的另一方面,提供用于人类施用的协同组合,其中包括α-2-δ配体和PDEV抑制剂或其药学可接受的盐或溶剂合物,其中每种成分的剂量范围相当于在非人类的动物模型(优选大鼠模型)中观察的绝对协同范围,大鼠模型主要用于确定协同相互作用。人类应用的α-2-δ配体的合适剂量范围相当于大鼠中1-20mg/kg,优选1-10mg/kg,而PDEV抑制剂的相应剂量范围为0.1-10mg/kg,优选0.1-1mg/kg。对于加巴喷丁和西地那非,人类合适的剂量范围相当于大鼠中产生协同作用的1-10mg/kg剂量范围的加巴喷丁和0.1-1mg/kg的西地那非。
适当地,应用于人类的α-2-δ配体剂量范围选自:1-1200mg,1-500mg,1-100mg,1-50mg,1-25mg,500-1200mg,100-1200mg,100-500mg,50-1200mg,50-500mg,或50-100mg,优选的为50-100mg,一日两次或是一日三次,优选一日三次,而PDEV抑制剂的剂量范围选自:1-200mg,1-100mg,1-50mg,1-25mg,10-100mg,10-50mg或10-25mg,较合适的为10-100mg,一日两次或是一日三次,优选一日三次。对于加巴喷丁和西地那非,合适的剂量范围为50-600mg:10-100mg,每日三次。
本领域技术人员显而易见的是,本发明的α-2-δ配体和PDEV抑制剂组合产生治疗效应必需的血浆浓度依需要治疗的物种和使用的成分而定。例如,对于大鼠应用的加巴喷丁和西地那非,加巴喷丁的Cmax范围为0.520μg/ml到10.5μg/ml,西地那非Cmax范围为0.02μg/ml到2.1μg/ml。
使用标准的PK/PD和差律的方法,外推动物模型观察的血浆浓度值预测不同物种尤其是人类的值是可能的。因此,作为该发明本发明的进一步的方面,提供了一种用于施用于人类的协同组合,包括α-2-δ配体和PDEV抑制剂,其中每种成分的血浆浓度范围相应于非人模型,尤其是大鼠模型中观察到的绝对范围,主要用于确定协同相互作用。优选地,人类血浆浓度范围对于α-2-δ配体相当于大鼠模型中0.05μg/ml到10.5μg/ml,对于PDEV抑制剂相应于0.005μg/ml到2.1μg/ml。对于加巴喷丁和西地那非,人类的血浆浓度范围相当于大鼠模型中的0.05μg/ml到10.5μg/ml范围(对于加巴喷丁)和0.005μg/ml到2.1μg/ml(对于西地那非)。由于大鼠和人类血浆对于两种化合物的蛋白质结合特性相似,上述提到的血浆浓度范围与人类相关。
因此,可选择的一个方面,本发明提供了协同组合,其包括α-2-δ配体和PDEV抑制剂或其药学可接受的盐或溶剂合物,其中每种成分的血浆浓度范围包括高达20μg/ml的Cmax值(对于α-2-δ配体)和高达4μg/ml(对于PDEV抑制剂),优选地分别为0.5μg/ml到10μg/ml和0.02μg/ml到2.1μg/ml,更优选地分别为0.05μg/ml到20μg/ml和0.005μg/ml到4μg/ml。
本发明特别优选的组合包括其中组合的每个变量选自每个变量的合适的参数。甚至本发明更优选的组合包括那些其中每种变量选自更合适的、最合适的、优选的,更优选的变量的参数。
附图简述
图1、(a)加巴喷丁与(b)西地那非对CCI-诱导的静态异常性疼痛的维持的作用。在给药前,确定CCI动物对von Frey毛发的爪缩阈值(PWT)的基线水平(BL)。在给药后达4小时再测量PWT。结果以需要诱导爪缩的力(g)的中位值来表示(垂直条代表第1和第3个四分位数)。在每个时间点,*P<0.05,**P<0.01,***P<0.005表示与载体处理组有显著性差异(Mann Whitney U检验)。
图2、(a)加巴喷丁与(b)西地那非对CCI-诱导的动态异常性疼痛的维持的作用。在给药前,确定右后爪对棉芽刺激的爪缩潜伏期(PWL)的基线水平(BL)。在达4小时后再测定PWL。用PWL的平均值表示结果。垂直条代表±标准误,*P<0.05,**P<0.01表示在每个时间点与载体处理组有显著性差异(ANOVA分析后进行Dunnett′s t-检验)。
图3、固定剂量比例的加巴喷丁与西地那非对CCI-诱导的静态异常性疼痛维持的作用。所有数据用给药后2小时时间点的数据表示。从图1中获得加巴喷丁和西地那非单独的剂量反应数据。加巴喷丁和西地那非组合的固定比例为(a)1∶10(b)1∶1(c)10∶1(d)20∶1。结果用需要诱导缩爪的力(g)的中间值表示(垂直条代表第1和第3个四分位数)。
图4、固定剂量比例的加巴喷丁与西地那非对CCI-诱导的动态异常性疼痛维持的作用。所有数据使用给药后2小时时间点的数据表示。从图2中获得加巴喷丁和西地那非单独的剂量反应关系。加巴喷丁和西地那非组合的固定比例为(a)1∶10(b)1∶1(c)10∶1(d)20∶1。结果以PWL的平均值表示。垂直条代表±标准误*P<0.05,**P<0.01表示在每个时间点与载体处理组有显著性差异(ANOVA分析后进行Dunnett′s t-检验)。
发明详述
本发明的组合可以以非溶剂合物形式和溶剂合物形式存在,包括水合形式。通常,可含有同位素替代的溶剂合物形式(例如D20,d6-丙酮,d6-DMSO),其中包括水合形式,与非溶剂合物形式是等效的,并且属于本发明的范畴。
本发明的某些化合物含有一个或是多个手性中心,每一个中心可存在R或S构型。本发明包括所有对映异构体和差向异构体形式以及它们合适的混合物。非对映异构体或是顺式、反式异构体的分离可以通过常规的技术实现,比如通过分级结晶、色谱法或HPLC分离本发明中一种化合物的立体异构混合物或它们合适的盐及衍生物。
本发明的许多α-2-δ配体是氨基酸。由于氨基酸是两性的,药理相容盐可以是合适的无毒的无机或有机酸或碱的盐。合适的酸式加成盐是乙酸盐、天门冬氨酸盐、苯甲酸盐、苯磺酸盐(besylate)、重碳酸盐/碳酸盐、硫酸氢盐、右旋樟脑磺酸、柠檬酸盐、乙二磺酸盐(edisylate)、乙基磺酸盐(esylate)、延胡索酸盐、葡庚糖酸盐(gluceptate)、葡萄糖酸盐、葡萄糖醛酸酯、hibenzate、盐酸盐/氯化物、氢溴酸盐/溴化物、碘氢化物/碘化物、磷酸氢盐、羟乙磺酸盐、D-与L-乳酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、2-萘磺酸盐、烟碱、硝酸盐、乳清酸盐、palmoate、磷酸盐、糖酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、D-和L-酒石酸盐及甲苯磺酸盐。合适的碱式盐是由碱形成的无毒的盐,实例如钠、钾、铝、钙、镁、锌、胆碱、二乙醇胺、乙醇胺、精氨酸、氨基乙酸、氨丁三醇、benzathine、赖氨酸、甲葡胺和二乙胺盐。带有季铵鎓离子的盐也可以通过四甲基铵鎓离子制备。本发明中的化合物也可以形成两性离子。而且,由于本发明的许多PDEV抑制剂是氨类,且许多α-2-δ配体具有酸性官能团,所以本发明的另一个方面,包括含有两种成分的盐形式,尤其是1∶1的组合。一种合适的组合盐形式是由1∶1的加巴喷丁和西地那非组成的盐。
本发明中化合物的合适氨基酸盐是盐酸盐。合适的盐的综述,参见Stahl与Wermuth的药学可接受的盐手册:性质、选择和使用,Wiley-VCH,Weinheim,Germany(2002)。
包合物、药物宿主包括复合物也包括在本发明的范围中,与前面所述的溶剂合物相比,药物和宿主是以非化学计量存在的。这种复合物的综述,参见J Pharm Sci,
64(8),1269-1288 by Haleblian(August 1975)。
以下本发明中化合物的所有参考文献包括其盐的参考文献和本发明中化合物的溶剂合物、包合物以及它们的盐的参考文献。
它们的多型体也包含在本发明化合物的范畴之内。
上面提到的本发明中化合物的前药也包括在本发明的范畴之中。化学修饰药物或者前体应该与母体具有不同的药动学性质,更易于通过粘膜上皮吸收、更好的盐制剂和/或溶解度,以及提高了的系统稳定性(例如血浆半衰期提高)。这些化学修改可以是
(1)可被例如酯酶或脂肪酶切开的酯或酰胺衍生物。对于酯衍生物,酯基通过已知方法来源于药物分子的羧酸部分。对于酰胺衍生物,酰胺基通过已知方法来源于药物分子的羧酸部分或是胺基部分。
(2)可以被特异或非特异的蛋白酶识别的肽。肽可以通过已知方法与药物分子的胺基或羧酸部分形成酰胺键从而与药物分子偶联。
(3)通过前药形式或修饰的前药形式的膜选择在作用位点聚集的衍生物。
(4)1到3的任意组合。
氨基酰-乙醇酸和-乳酸酯是已知的氨基酸前药(Wermuth C.G.,Chemistry and Industry,1980:433-435)。氨基酸的羰基可以通过已知方法酯化。前药和软药(soft drug)是本领域已知的(PalominoE.,Drugs of the Future,1990;15(4):361-368)。最后两篇引文被引入本文作为参考。
本发明的组合对于疼痛,尤其是神经性疼痛的常规治疗有帮助。生理性的疼痛是一种重要的保护机制,天生用于提示存在来自外界环境的有害刺激。该系统通过一套特殊的基本感觉神经元起作用,且这该系统只能被外周传导机制传导的有害刺激而激活(Millan 1999 Prog.Neurobio.57:1-164一篇综述)。这些感觉纤维已知是伤害感受器,具有轴突直径小、传导速度慢的特点。伤害感受器编码有害刺激的强度、持续时间和性质,依靠局部机体投射到脊髓,也就是刺激的部位。在伤害感受神经纤维上发现了伤害感受器,而该纤维主要有两种类型,A-δ纤维(有髓鞘的)和C纤维(无髓鞘的)。伤害感受器输入产生的反应通过脊髓背角的复杂处理后,直接或通过脑干的中继神经核传导到腹背侧丘脑,然后传导到皮质,产生疼痛的感觉。
强烈的急性疼痛和慢性疼痛可涉及与病生理过程推动的相同通路,而因此停止提供保护性机制,代之以产生多种疾病状态相关联的衰弱征状。疼痛是许多外伤和疾病状态的特征。当经由疾病或外伤对人体组织的实质损伤出现时,伤害感受器的活化特征被改变。在外周的损伤部位周围的体表局部,并主要在伤害感受器终止区存在促进感受致敏作用。这导致在损伤部位和正常组织过敏反应。在急性疼痛中,这些机制是有用的,允许修复机制代替,一旦损伤治愈,过敏性恢复正常。然而在多种慢性疼痛中,过敏性远比治愈过程较持久,其通常是由神经系统损伤导致的。这种损伤通常导致传入神经适应不良(Woolf和Salter 2000 Science 288:1765-1768)。当患者的症状中以不适和非正常的感受为特征时,出现临床疼痛。患者的表现大都不同,并且可能伴有多种疼痛症状。有许多典型的疼痛亚型:1)自发疼痛,可能是钝痛,烧灼样疼痛或是剧痛;2)应答有害刺激的疼痛被夸大(痛觉过敏);3)由正常的无害刺激产生的疼痛(异常性疼痛)(Meyer等,1994疼痛教科书:13-44)。虽然患有背痛、关节疼痛、中枢神经系统外伤或是神经病痛的患者可能具有相似的症状,而潜在的机制是不同的,因此可能需要不同的治疗策略。因此由于不同的病例生理过程的疼痛可被分成多种不同的类别,包括感受损伤的、炎症的和神经疾病性疼痛等。应该注意一些类型的疼痛有多种病因,并因此可能够归于多于一个类别,例如背痛、癌症疼痛可具有感受伤害的炎症和神经病的成分。
感受性伤害疼痛(nocieptive pain)是由组织损伤或可能引起损伤的强烈刺激产生的。由损伤部位的伤害感受器转导刺激并在其终端刺激脊髓激活疼痛。然后通过脊椎束的传至大脑使大脑感知疼痛(Meyer等人,1994 Textbook of Pain:13-44)。伤害感受器的激活活化两种传入神经纤维。有髓鞘的A-δ纤维传导迅速,负责锐痛和剧痛的传导,而无髓鞘的C纤维传导速度慢,传导钝痛或急痛。中度到严重的急性感受伤害疼痛有明显的来自扭伤/挫伤、术后疼痛(任何类型外科手术后疼痛)、创伤疼痛、烧伤、心肌梗死、急性胰腺炎以及肾绞痛的特征,但并不局限于这些。癌症相关的急性疼痛综合症通常是由于治疗的相互作用引起,比如化疗毒性、免疫治疗、激素治疗和放疗。中等到严重的急性感受伤害疼痛是以明显的癌症疼痛和背部疼痛的为特征,但并不局限于此,其中癌症疼痛可由肿瘤相关疼痛(例如骨疼痛、头痛和面部疼痛、内脏痛)或是癌症治疗相关疼痛(例如化疗后综合症、慢性术后疼痛、放疗后疼痛)引起的,而背痛可能由腰间盘突出或脱出或关节面连接、骶髂关节、脊柱旁肌肉或后纵韧带的不正常引起。
神经疼痛被定义为由神经系统的原发性损伤或是功能紊乱引起的疼痛(IASP定义)。神经损伤可能由外伤和疾病引起,因此该名词“神经性疾病疼痛”包括许多由各种病因导致的病症。这些包括但不局限于糖尿病神经病、疱疹后疼痛、背痛、癌症神经病、化疗诱导的神经病、HIV神经病、幻肢痛,腕管症、慢性酒精中毒、甲状腺功能减退、三叉神经痛、尿毒症、外伤诱导的神经病或是维生素缺乏。神经性疾病痛是病理的,因为它没有保护作用。它通常在原始病因消失后仍然存在,并且持续很多年,明显降低患者的生活质量(Woolf和Mannion1999 Lancet 353:1959-1964)。神经痛的症状很难治疗,因为即使是患有相同疾病的患者,症状通常也是异质的(woolf和Decosterd1999 Pain Supp.6:S141-S147;Woolf和Mannion 1999 Lancet 353:1959-1964)。它们包括持续的或阵发的自发性的疼痛,和不正常的激发疼痛,如痛觉过敏(对于有害刺激增加的敏感性)以及异常性疼痛(对于正常的无害刺激的敏感)。
炎症过程是机体对于组织损伤或是外来物质引发的一系列复杂的生化和细胞事件,其能够导致水肿和疼痛(Levine和Taiwo 1994:疼痛教科书:45-56)。关节炎疼痛构成炎症疼痛人群的大多数。类风湿疾病在发达国家是最常见的慢性炎症状况,类风湿关节炎(RA)是病残的常见原因。RA的确切病因未知,而目前的假说认为遗传和微生物因素可能是重要的(Grennan和Jayson 1994疼痛教科书:397-407)。据估计几乎1600万的美国人患有征兆的骨关节炎(OA)或是退行性的关节疾病,其中大多数大于60岁,预计随着人群年龄的增长将增长到4000万,这成为一项重要的公共卫生问题(Houge和Mersfelder 2002Ann Pharmacother.36:679-686;McCarthy等人,1994疼痛教科书:387-395)。大多数患有OA的病人因为疼痛而寻求治疗。关节炎对于心理和机体功能具有显著的影响,并且是之后生活中病残的最主要原因。其它类型的炎症疼痛包括但不限于炎症性肠道疾病(IBD)。
其它类型的疼痛包括但不限于:
-肌肉骨骼障碍,包括但不限于包括肌痛、肌纤维痛、脊椎炎、血清阴性(非类风湿)关节炎、非关节性的风湿病、营养不良性疾病(dystrophinopathy)、糖原分解、多肌炎、脓性肌炎。
-中枢性疼痛或是“丘脑疼痛”被定义为神经系统的损害或是障碍而引起的疼痛,包括但不限于中枢中风后疼痛、多发性硬化、脊髓损伤、帕金森氏病和癫痫症。
-心脏和血管疼痛包括但不限于绞痛、心肌梗死、二尖瓣狭窄、心包炎、Raynaud′s症、硬皮症(sclerodoma)、骨骼肌局部缺血。
-内脏疼痛与胃肠道功能紊乱。内脏包括腹腔内的脏器。这些器官包括性器官、脾脏和部分的消化系统。与内脏相关的疼痛可能是神经病的、感受伤害的和炎症性的,其能分成消化内脏疼痛和非消化内脏疼痛。常见的胃肠道(GI)紊乱包括功能性肠道紊乱(FBD)和炎症性肠道紊乱(IBD)。这些GI紊乱包括大量的疾病,这些目前只有中等程度的控制,其中FBD包括胃-食管逆流、消化不良、应激性肠道综合症(IBS)以及功能性的腹痛综合症(FAPS),IBD包括克隆氏病、回肠炎以及溃疡性结肠炎,这些都经常性地产生内脏性疼痛。其它类型的内脏疼痛包括与痛经、骨盆疼痛、膀胱炎和胰腺炎相关的疼痛。
-头痛包括但不限于偏头痛、先兆偏头痛、无先兆偏头痛、丛发性头疼和紧张性疼痛。
-口面疼痛包括但不限于牙痛、颞下颌肌筋膜疼痛。
因此,进一步的方面,提供同时、顺次或分别使用α-2-δ配体和PDEV抑制剂用于制备治疗、预防或缓解疼痛特别是神经性疾病疼痛的药物,其中α-2-δ配体排除了PCT/IB02/01146中式(i)-(xxv)的化合物以及普加巴林和加巴喷丁,而普加巴林和加巴喷丁的排除只限于治疗神经性疾病疼痛时。作为优选的特征,优选包含上面提到的任何一种组合的用途。
一个可选择的方面,提供了用于治疗、预防或缓解性治疗疼痛,特别是神经性疾病疼痛的方法,包括同时、顺次或分别施用治疗有效量的α-2-δ配体和PDEV抑制剂给需要治疗的哺乳动物,其中α-2-δ配体不包括普加巴林和加巴喷丁,其中,仅限于当治疗神经病时排除普加巴林和加巴喷丁。另一个可选择的方面,排除PCT/IB02/01146中式(i)-(xxv)的化合物。作为优选的特征,方法适当地包含上面提到的任何一种组合。
一个可供选择的方面,提供同时、顺次或分别使用协同组合的α-2-δ配体和PDEV抑制剂用于制备治疗、预防或缓解疼痛特别是神经性疼痛的药物。作为优选的特征,用途适当地包含上面提到的任何一种组合。
一个可供选择的方面,提供包括同时、顺次或分别使用治疗协同有效量α-2-δ配体和PDEV抑制剂施用于需要所述治疗的哺乳动物的一种治疗、预防或缓解疼痛特别是神经性疼痛的方法。作为优选的特征,该方法适当地包含上面提到的任何一种组合。
本发明中α-2-δ配体的生物学活性可利用来源于猪脑组织的[3H]加巴喷丁和α2δ亚单位进行的放射配体结合试验来评价(Gee N.S.,Brown J.P.,Dissanayake V.U.K.,Offord J.,ThurlowR.,Woodruff G.N.,J.Biol.Chem.,1996;271:5879-5776)。结果可以μM或是nM的α2δ亲和力表示。
本发明的PDEV抑制剂对于环鸟苷一磷酸(cGMP)的体外抑制活性可以根据WO01/27113中的详细描述测量它们的IC50值来确定。功能活性可以通过SA Ballard等中描述的方法进行评价(Brit.J.Pharmacology,1996,118(suppl.),摘要153P)
本发明组合的成分可以分别、同时或是顺次给药。本发明的进一步方面提供了一种包装,其包括α-2-δ配体和PDEV的抑制剂的协同组合以及合适的容器。
本发明的组合也可任选地与一种或多种其它有药理活性制剂一起施用。合适的供选择试剂包括:
(i)阿片类镇痛药,例如吗啡、海洛因、氢吗啡酮、氧吗啡酮、左吗啡、左洛啡烷、美沙酮、哌替啶、芬太尼、可卡因、可待因、双氢可待因、氧可酮、氢可酮、丙氧芬、纳美芬、纳洛芬、叔丁啡、布托非诺、纳布啡以及喷他佐辛;
(ii)阿片类拮抗剂,例如纳洛酮、纳曲酮
(iii)非甾体类抗炎药(NSAID),例如阿司匹林、双氯酚酸、difluinsal、依托度酸、芬布芬、非诺洛芬、氟苯柳、氟比洛芬、布洛芬、消炎痛、酮洛芬、酮咯酸、甲氯胺苯酸、甲芬那酸、萘美酮、萘普生、苯恶丙酸、保泰松、吡罗昔康、舒林酸、托美丁、佐美酸以及其药学可接受的盐或溶剂合物;
(iv)巴比妥类镇静剂,例如异戊巴比妥、阿波巴比妥、仲丁比妥、布他比妥、甲基巴比妥、甲巴比妥、美索比妥、戊巴比妥、苯巴比妥、西可巴比妥、他布比妥、theamylal、硫喷妥以及其药学可接受的盐或溶剂合物;
(v)具有镇静作用的苯二氮卓类,例如利眠宁、氯拉卓酸、地西泮、氟西泮、劳拉西泮、奥沙西泮、羟基安定、三唑仑以及其药学可接受的盐或溶剂合物;
(vi)具有镇静作用的H1拮抗剂,例如苯海拉明、吡拉明、异丙嗪、扑尔敏、氯环嗪以及其药学可接受的盐或溶剂合物;
(vii)各种镇静剂,例如多睡丹、眠尔通、安眠酮、氯醛比林以及其药学可接受的盐或溶剂合物;
(viii)骨骼肌松弛剂,例如巴氯芬、托哌酮、卡立普多、氯唑沙宗、环苯扎林、美索巴莫、orphrenadine以及其药学可接受的盐或溶剂合物;
(ix)NMDA受体拮抗剂,例如右甲吗喃((+)-3-羟基-N-甲基吗喃)与它的代谢产物右啡烷((+)-3-羟基-N-甲基吗喃)、氯胺酮、美金刚胺、吡咯并喹啉醌和顺式-4-(膦酸甲基)-2-哌啶羧酸以及其药学可接受的盐或溶剂合物;
(x)α肾上腺素能活性化合物,例如多沙唑嗪、坦洛新、可乐定以及4-氨基-6,7-二甲氧基-2-(5-甲磺酰胺-1,2,3,4-四氢异喹啉-2-基)-5-(2-吡啶基)喹唑啉;
(xi)三环抗抑郁剂,例如地昔帕明、丙咪嗪、阿米替林以及去甲替林;
(xii)抗惊厥剂,例如卡马西平、2-丙基戊酸钠、拉莫三嗪;
(xiii)5羟色胺重摄取抑制剂,例如氟西汀、帕罗西汀、西酞普兰以及舍曲林;
(xiv)混合的5羟色胺-去甲肾上腺素重摄取抑制剂,例如米那普仑、文拉法辛和度洛西汀;
(xv)去甲肾上腺素重摄取抑制剂,例如瑞波西汀;
(xvi)速激肽(NK)拮抗剂,尤其是NK-3、NK-2和NK-1拮抗剂,例如(αR,9R)-7-[3,5-二(三氟甲基)苄基]-8,9,10,11-四氢-9-甲基-5-(4-甲基苯基)-7H-[1,4]二氮芳辛并[2,1-g][1,7]naphthridine-6-13-二酮(TAK-637),5-[[(2R,3S)-2-[(1R)-1-[3,5-二(三氟甲基)苯基]乙氧基-3-(4-氟苯基)-4-吗啉基]甲基]-1,2-二氢-3H-1,2,4-三唑-3-酮(MK-869),lanepitant,dapitant和3-[[2-甲氧基-5-(三氟甲氧基)苯基]甲基氨基]-2-苯基-哌啶(2S,3S);
(xvii)毒蕈碱拮抗剂,例如奥昔布宁、托特罗定、丙哌维林、tropsium chloride以及达非那新;
(xviii)COX-2抑制剂,例如塞内昔布、罗非考昔和伐地考昔;
(xix)非选择性COX抑制剂(优选具有GI保护作用),例如nitroflurbiprofen(HCT-1026);
(xx)煤焦油止痛剂,尤其是醋氨酚;
(xxi)精神抑制药,例如氟哌利多;
(xxii)辣椒素受体激动剂,例如resinferatoxin;
(xxiii)β肾上腺素能化合物,例如普萘洛尔;
(xxiv)局部麻醉剂,例如美西律、利多卡因;
(xxv)皮质类固醇,例如地塞米松;
(xxvi)5羟色胺受体激动剂和拮抗剂;
(xxvii)胆碱能(烟碱)镇痛剂;以及
(xxviii)各种药物,如Tramadol。
因此,本发明涉及组合产品,其含有α-2-δ配体、PDEV抑制剂以及一种或是多种其它治疗药物,比如上面所列药物中的一种,在治疗、预防和缓解疼痛,尤其是神经性疼痛时,同时、分别或顺次给予以上药物的应用。
本发明的组合可以分别给药,但是一种或两种成分通常根据给药途径和标准制药规范,与适当的一种或多种药物赋形剂、稀释剂或是载体混合的形式给药。如果合适,也可以加入辅剂。辅剂是防腐剂、抗氧化剂、香料或是色素。本发明中的化合物可以是即时的,延迟的,缓和的,持续的,脉冲的或控释的类型。
本发明组合物的成分可以例如但不局限于以下给药途径:以片剂,胶囊、多重和纳米颗粒、凝胶、薄膜(包括粘膜粘合剂)、粉末、胚珠囊(ovules)、酏剂、锭剂(包括液体填充的)、咀嚼片、溶液、混悬液和喷雾剂的形式口服、颊下或是舌下给药。如Liang和Chen的Ashley Publications,2001中所描述的,本发明的化合物也通过渗透剂型,或者以高能分散的形式,或以包膜微粒,或以速溶、速释剂型给药。本发明中的化合物可以以结晶或是非结晶产物、冻干或喷雾干燥的形式给药。本发明中化合物的合适的制剂可以是亲水或是疏水基质、离子交换树脂混合物,包衣和未包衣的形式和在US 6,106,864中描述的其他类型。所述药物组合物,例如片剂可以含有赋形剂,如微晶纤维素、乳糖、柠檬酸钠、碳酸钙、二价磷酸钙、甘氨酸、淀粉(优选玉米、马铃薯或是木薯淀粉)、甘露醇、崩解剂,如淀粉羟乙酸钠、交联羧甲纤维素钠和某些复合硅酸盐,和颗粒粘合剂,如聚乙烯吡咯烷酮、羟丙甲基纤维素(HPMC)、甘油三酯、羟丙基纤维素(HPC)、皂土蔗糖、山梨醇、明胶以及阿拉伯胶。而且,润滑剂可加入固形组合物中,例如硬脂酸镁、硬脂酸、甘油山嵛酸酯、PEG以及滑石粉或润湿剂,例如十二烷基硫酸钠。此外还可包括碳水化合物、磷脂和蛋白质等大分子化合物。
快速分散或溶解制剂形式(FDDF)可以含有以下成分:阿斯巴甜、乙酰舒泛钾、柠檬酸、交联羧甲纤维素钠、交联聚维酮、diascorbicacid、丙烯酸乙酯、乙基纤维素、明胶、羟丙甲基纤维素、硬脂酸镁、甘露醇、异丁烯酸甲酯、薄荷调味剂、聚乙二醇、雾化二氧化硅、二氧化硅、羟乙酸淀粉钠、延胡索酸硬脂酸钠、山梨醇或木糖醇。在这里用于描述FDDF的术语分散或溶解取决于所用药物的溶解度,即当药物不溶时,可以制备一种快速分散的剂型,而当药物可溶时,可以制备一种快溶解的剂型。
固体制剂形式如片剂,是通过标准的生产过程制备的,例如直接压片法或湿法、干法或融化制粒,融化凝结法和挤压法。片芯可以根据已知文献中合适的单层或多层包衣材料包衣。
相似类型的固体组合物也可被用作胶囊中的填充物,如凝胶、淀粉或HPMC胶囊。在这点上,优选的赋形剂包括乳糖、淀粉、纤维素、乳糖或高分子量的聚乙二醇。液体组合物可用作在软或硬胶囊中作为填充物,例如明胶胶囊。对于水的或油的混悬液、溶液、糖浆和/或酏剂,本发明中的化合物可以与多种甜味剂或调味剂、着色剂或染料,与乳化和/或悬浮剂以及与稀释剂如水、乙醇、丙二醇、甲基纤维素、褐藻酸或藻酸钠、甘油、油类、水状胶体和它们的组合而组合。而且,含有这些化合物和赋形剂的制剂形式可以是干燥的产品,用于在使用前与水或是其它合适的溶剂重构。
液体形式制剂包括溶液、混悬液和乳剂,例如水或丙二醇水溶液。对于非肠道注射,液体制剂可以用水的聚乙二醇溶液制备。适合口服使用的水溶液可以将活性成分溶解在水里,并按照需要添加适当的着色剂、香料、稳定剂和增稠剂来制备。适合口服的水悬液可以通过将细分的活性成分分散在带有粘性物质,例如天然或是合成的树胶、树脂、甲基纤维素、羧甲基纤维素钠以及其它熟知的混悬剂的水中。
本发明组合的成分也可以通过注射给药,也就是静脉内、肌肉、皮内、十二指肠内或腹膜内、动脉内、鞘内、心室内、尿道内、胸骨内、颅内、脊柱内或皮下给药,或也可以通过输注、无针头注射或是植入注射技术给药。对于胃肠外给药,最好以含有现有技术中已知的其它物质的消毒水溶液、混悬液或是乳液(或系统,这样可以含有分子团)的形式,所述其它物质例如足量的盐和碳水化合物如葡萄糖,以使溶液与血液等渗。如果必要的话,水性溶液应该为适当地缓冲的(优选pH值在3到9之间)。对于一些非胃肠道给药,可以使用消毒的非水性系统(如不挥发油,包括甘油单酯酸或甘油二酯酸以及脂肪酸(包括油酸)。适当的胃肠外给药制剂在无菌条件下例如冷冻的制备可通过本领域技术人员熟知的标准制药技术实现生产。可选择地,活性成分可以为粉末形式,用于在使用前与适当的溶剂(例如无菌、无致热原的水)重构。
而且,本发明组合的成分可以通过鼻内或是吸入给药。它们可以通过带有或不带有包括推进剂的压力容器、泵、喷射器、雾化器(优选使用电流体动力学产生良好喷雾的)或者喷雾器,从干粉吸入器或气雾喷射器喷出的干粉(或者以混合液的形式如与乳糖混合的干混合物单独,或如与磷脂以混合的成分颗粒的)形式方便地给药,推进剂如二氯二氟甲烷、三氯氟代甲烷、二氯四氟乙烷、氢化氟代烷如1,1,1,2-四氟乙烷(HFA 134A[商标])或1,1,1,2,3,3,3-七氟丙烷(HFA 227EA[商标])、二氧化碳、进一步氟化的碳氢化合物如Perflubron(商标)或者其它合适的气体。在使用加压气雾剂的情况下,剂量单位可以通过提供定量传递的阀门来确定。加压容器、泵、喷射器、雾化器或喷雾器可以含有活性成分的溶液或混悬液,例如运用乙醇的混合物(任选的乙醇水溶液)或适当的溶剂用于分散、溶解或延迟释放且可以另外含有润滑剂(例如脱水山梨醇三油酸酯)的溶剂作为推动剂。在吸入器和吹入器中应用的胶囊、水泡和药筒(例如,由明胶或HPMC制备)中可以制剂成包括容纳本发明的粉末混合物、合适的粉末基质(如乳糖或淀粉)和性能改性剂(例如,L-亮氨酸、甘露醇或硬脂酸镁)的形式。
在使用用于吸入的干燥粉末制剂或混悬剂制剂之前,应将本发明组合的成分粉碎成合适吸入的粒径(典型的认为是小于5微米)。粉碎可以通过一系列的方法实现,例如螺旋喷射制粉、流化床喷射制粉、使用超临界流体结晶或喷射烘干。
适于电力流体动力学以产生细雾雾化器中应用的合适溶液制剂,每次启动中可含有1μg到10mg的本发明化合物,每次启动的体积可以在1到100μl之间变化。典型的制剂可以含有本发明中的化合物、丙二醇、灭菌水、乙醇和氯化钠。可以使用其它溶剂替代丙二醇,例如甘油或者聚乙二醇。
可选择的,本发明组合的成分可以局部给予皮肤、粘膜,经皮或透皮给药,例如以凝胶、水凝胶、洗液、溶液、霜剂、软膏、撒粉、敷料、泡沫、薄膜、皮肤贴片、糯米纸囊剂、植入物、海绵、纤维、绷带、微乳剂及其组合的形式。对于这些应用,本发明中的化合物可以悬浮或者溶解于以下的一种或是多种混合液中,例如:矿物油、液体凡士林、白凡士林、丙二醇、聚氧乙烯聚氧丙烯化合物、乳化蜡、不挥发油(包括合成的甘油单酯或甘油二酯)以及包括油酸的脂肪酸、水、脱水山梨糖单硬脂酸酯、聚乙二醇、液体石蜡、聚山梨酯60、十六烷基酯蜡、棕榈醇、2-辛基十二烷醇、苯甲基乙醇、醇如乙醇。可选择的,可使用渗透增强剂。可选择的,应用以纳米颗粒(如大泡囊或脂质体)或悬浮或溶解的形式的聚合物、碳水化合物、蛋白质、磷脂。另外,它们也可以通过离子电渗疗法、电穿孔法、超声透入疗法和超声波导入法递送。
可选择地,本发明组合中的成分也可以直肠给药,例如以栓剂或是阴道栓的形式。也可以通过鞘内给药。例如这些组合物可以通过将药物和适当的非刺激性赋形剂比如可可乳脂、合成甘油酯或者是聚乙二醇混合而制备,其在常温时为固体,而当在腔内则液化和/或溶解释放药物。
本发明组合的成分也可以经眼途径给药。对于眼科应用,化合物可以以微分化形式悬浮于等渗、pH调节的无菌盐水中配制成混悬液,或者优选地以等张的、调节过pH值的无菌盐水溶液制剂。可以加入聚合物,比如交联聚丙烯酸、聚乙烯醇、透明质酸、纤维素聚合物(如羟丙基甲基纤维素、羟乙基纤维素、甲基纤维素),或聚多糖(如gelan胶)。可选择地它们可制备成软膏,如将凡士林或者矿物油掺入到可生物降解的(例如能吸收的凝胶海绵、胶原)或不可生物降解的(例如硅树脂)的植入物、糯米纸囊剂、滴剂、晶状体或是通过磷脂超微渗体或者脂质体的微粒子或者泡囊系统给药。制剂可以任选的与防腐剂如氯苄烷铵结合。此外,组合可以通过离子电渗疗法递送。它们也可以使用如但不局限于滴剂在耳内给药。
本发明组合的成分也可以与环糊精组合使用。已知环糊精与药物分子组成包含和非包含复合物。药物-环糊精复合物的制剂可以改变药物分子的溶解度、溶解率、味道掩蔽、生物利用率和/或稳定性。药物-环糊精复合物一般可用于大多数剂型和给药途径。可选择地,直接与药物络合的环糊精可以作为辅助添加剂,例如载体、稀释剂或者溶解剂。α-,β-和γ环糊精是最常用的,在WO-A-91/11172,WO-A-94/02518和WO-A-98/55148中描述了合适的例子。
术语“给药”包括通过病毒或非病毒技术递送。病毒递送机制包括但不局限于腺病毒载体、腺伴随病毒载体(AAV)、疱疹病毒载体、逆转录病毒载体、慢病毒载体(lentiviral vector)和杆状病毒载体。非病毒递送机制包括脂质介导的转染、脂质体、免疫脂质体、lipofectin、阳离子表面亲和(cationic facial amphiphiles)以及它们的组合等。这些递送机制的给药途径包括但不限于粘膜、鼻、胃肠外、胃肠道、局部或者舌下途径。
因此,本发明的进一步方面,提供了药物组合物,其含有α-2-δ配体(不包括加巴喷丁、普加巴林)、PDEV抑制剂和赋形剂、稀释剂和载体的组合。可选择地,排除还包括PCT/IB02/01146中式(i)-(xxv)的化合物。该组合物适于治疗疼痛,尤其是神经性疼痛。
本发明另一个可选择的方面,提供药物组合物。其含有α-2-δ配体、PDEV抑制剂和适当的赋形剂、稀释剂或是载体的协同组合。优选地该组合物适于治疗疼痛,尤其是神经性疼痛。
对于非人类的动物给药,此处术语“药学的”可用“兽医的”替代。
药物制剂的成分优选使用单位剂量式。在这种形式中,制剂被细分成含有适当数量活性成分的单位剂量。单位剂量可以是包装的制剂,包装含有离散量的制剂,例如包装的片剂、胶囊和小瓶装的或是安瓿装的粉末。单位剂量形式也可以是胶囊剂、片剂、扁囊剂或者是锭剂自身,或者它是合适量的这些中任一种包装形式。单位剂量制剂中活性成分的量可根据根据特定的应用和活性成分的效能而改变或调整。一般,治疗起始使用较小的剂量,该剂量小于该化合物的最佳剂量。此后,以小幅度逐渐增加,直到达到最佳效果。为方便,如果需要,每一天中的总剂量可以分开并分次给予。
对于兽医的应用,根据兽医规范和兽医手术确定最适合某种动物的给药方案以及给药途径,以合适的制剂施用本发明的组合或其兽用可接受的盐或溶剂合物。
生物学实施例
方法
动物
来自Charles River(Margate,Kent,U.K.)的雄性SpragueDawley大鼠(200-250克),每6只为一组分别饲养。所用动物在12小时白天/黑夜循环(在7点钟给予光照),饲养,随意饮食。所有试验是由一位不知药物处理的观察者进行的。
大鼠的CCI手术
使用异氟烷麻醉动物。如Bennett和Xie于1988年描述的方法结扎坐骨神经。在手术过程中,动物被放置在恒温毯子上。在手术准备后,使用钝性剥离器从股二头肌分离股骨中部的坐骨神经。接近坐骨三叉部的部位,使用4根结扎绳(4-osilk)松弛地绑在大约7毫米的与结缔组织分离的神经上,留有大约1毫米的空间。逐层关闭切口,伤口用局部抗生素处理。
组合对于CCI诱导的静态和动态异常性疼痛的维持作用
首先在CCI中单独进行加巴喷丁和西地那非的剂量反应关系。固定比设计后,检测了组合。进行了每种组合固定剂量比的剂量反应。在每一测试日中,给药治疗之前,确定von Frey头发爪缩阈值(PWT)和棉芽爪缩潜伏期(PWL)的基线水平。加巴喷丁口服给药后直接皮下注射给予西地那非,再检测PWT和PWL五小时。静态和动态数据用2小时时间点的数据表示,其代表抗异常性疼痛的作用的峰值。
评价异常性疼痛
使用Semmes-Weinstein von Frey毛发(Stoelting,Illinois,U.S.A.)测定静态异常性疼痛。将动物放入具有金属丝网底部的笼子中,允许接触到动物的爪底部。在试验开始之前,动物已经适应了环境。静态异常性疼痛是通过使用von Frey头发力度递增次序(0.7,1.2,1.5,2,3.6,5.5,8.5,11.8,15.1和29克)接触动物右后爪的底表面,持续达6秒钟。一旦出现缩爪反应,然后再使用递减Von Frey毛发再检测爪,直到缩爪反应消失。最大的29克力产生了缩爪,也就引出了反应,因此其代表一个截断点。引起反应的必需的最小力记录为PWT,单位为克。
动态异常性疼痛是通过棉芽轻轻地划后爪底部表面来评价的。这项操作要在完全适应了环境的大鼠身上进行,其不活跃,以避免记录一般的运动活性。在每一时间点至少测量三次,其平均值代表缩爪潜伏期(PWL)。如果在15秒内没有反应,则终止该操作,并在该缩爪时间点分组动物。因此15秒实际上表示没有缩爪。缩爪反应经常伴有重复的退缩或者是添爪。如果动物在发作的8秒钟之前对棉芽刺激作出反应,则认为存在动态异常性疼痛。
结果
加巴喷丁和西地那非单独对于CCI-诱导的静态和动态异常性疼痛的维持效应
加巴喷丁剂量依赖地(口服10-100mg/kg)阻断静态和动态异常性疼痛的维持,最小有效剂量(MED)为10mg/kg(图1,2)。100mg/kg的剂量能够完全阻断这些反应。西地那非剂量依赖地(皮下注射10-30mg/kg)阻断静态异常性疼痛的维持,最小有效剂量为10mg/kg,30mg/kg时产生大约60%的阻断(图1)。西地那非对于动态异常性疼痛的维持有适度的作用,MED为30mg/kg,产生25%的阻断(图2)。
加巴喷丁与西地那非组合对于CCI-诱导的静态异常性疼痛的效应
在CCI-诱导的静态模型中,加巴喷丁和西地那非在给药后2小时具有峰抗异常性疼痛效应。因此为了清晰,将所有组合数据使用该时间点表示。加巴喷丁和西地那非以固定剂量比例1∶10,1∶1,10∶1和20∶1给药。固定剂量比例1∶10和20∶1后,加巴喷丁和西地那非产生一种额外的相互作用(图3)。然而,证实1∶1和10∶1的固定剂量比对静态异常性疼痛有协同相互作用,分别以总剂量为20mg/kg和11mg/kg完全阻断异常性疼痛(图3)。单独给药时,1∶1的组合代表十倍低的加巴喷丁的剂量和三倍低的西地那非的剂量,而单独给药时,1∶1代表十倍低的加巴喷丁的剂量和三十倍低的西地那非的剂量。
加巴喷丁与西地那非组合对于CCI-诱导的动态异常性疼痛的效应
在CCI-诱导的动态模型中,加巴喷丁和西地那非在给药后2小时具有峰抗异常性疼痛效应。因此为了清晰,将所有组合数据使用该时间点表示。加巴喷丁和西地那非以固定剂量比例1∶10,1∶1,10∶1和20∶1给药。观察到与静态异常性疼痛相似的动态异常性疼痛数据。固定剂量比例1∶10后,20∶1后,加巴喷丁和西地那非组合产生一种额外的相互作用(图4)。然而,证实1∶1和10∶1的固定剂量比对静态异常性疼痛有协同作用,分别以总剂量为20mg/kg和11mg/kg完全阻断。单独给药时,1∶1的组合代表十倍低的加巴喷丁的剂量和三倍低的西地那非的剂量,而单独给药时,1∶1比代表十倍低的加巴喷丁的剂量和三十倍低的西地那非的剂量。
进一步的使用α-2-δ配体(普加巴林)与西地那非的联合,以及与加巴喷丁和另一种PDEV抑制剂,3-乙基-5-[5-(4-乙基-哌嗪-1-磺酰)-2-丙氧基-苯基]-2-吡啶-2基甲基-2,6-二氢-吡唑并[4,3-d]嘧啶-7-酮(化合物AA)的组合在相同模型中也进行类似的试验。这些试验结果下面以表格的形式概括如下(表1和2)。
表1
普加巴林∶西地那非比 | 普加巴林mg/kg) | 西地那非(mg/kg) | 异常性疼痛逆转% | 总剂量 | 相互作用 |
1∶0 | 30 | - | 100 | 30 | - |
0∶1 | - | 30 | 50 | 30 | - |
1∶1 | 10 | 10 | 100 | 20 | 协同 |
10∶1 | 10 | 1 | 100 | 11 | 协同 |
表2
加巴喷丁∶西地那非比 | 加巴喷丁(mg/kg) | 西地那非(mg/kg) | 异常性疼痛逆转% | 总剂量 | 相互作用 |
1∶0 | 100 | - | 100 | 100 | - |
0∶1 | - | 30 | 50 | 30 | - |
10∶1 | 10 | 1 | 100 | 11 | 协同 |
普加巴林与西地那非组合对于CCI-诱导的静态异常性疼痛的效应
在CCI-诱导的静态模型中,普加巴林和西地那非在给药后2小时具有峰抗异常性疼痛效应。以1∶1和10∶1的固定剂量比例给予普加巴林和西地那非。证实这些固定的剂量比对静态异常性疼痛有协同作用,分别以总剂量为20mg/kg和11mg/kg完全阻断异常性疼痛。单独给药时,1∶1的组合代表三倍低的普加巴林的剂量和三倍低的西地那非的剂量,而单独给药时,1∶1比代表三倍低的普加巴林的剂量和三十倍低的西地那非的剂量。
加巴喷丁与化合物AA组合对于CCI-诱导的静态异常性疼痛的效应
在CCI-诱导的静态模型中,加巴喷丁和化合物AA在给药后2小时具有峰抗异常性疼痛效应。以10∶1的固定剂量比例给予加巴喷丁和化合物AA。证实这些固定的剂量比对静态异常性疼痛有协同作用,分别以总剂量为11mg/kg完全阻断异常性疼痛。单独给药时,1∶1的比代表十倍低的加巴喷丁的剂量和三十倍低的化合物AA的剂量。
可以如前述提及的专利参考文献中描述的方法,或基于这些文献本领域技术人员显而易见的方法来制备本发明中合适的PDEV抑制剂。
可以如前述提及的专利参考文献中描述的方法,或基于这些文献本领域技术人员显而易见的方法来制备本发明中合适的α-2-δ配体。
化学实施例
实施例1.(3S,5R)-3-氨基-5-甲基-辛酸盐酸盐(R)-2,6-二甲基-壬-2-烯
0℃下往(S)-香茅基溴(50g,0.228mol)的THF(800mL)溶液中加入LiCl(4.3g),接着加入CuCl2(6.8g)。30分钟后加入氯化甲基镁(152mL,3M的THF溶液,Aldrich),反应液加温至室温。10小时后,反应液冷却至0℃,小心地加入饱和氯化铵溶液。分离生成的两相,水层用乙醚提取。用MgSO4干燥合并的有机相,浓缩得到32.6g(R)-2,6-二甲基-壬-2-烯,93%。不需进一步纯化即可使用。1H NMR(400MHz;CDCl3)δ5.1(m,1H),1.95(m,2H),1.62(s,3H),1.6(s,3H),1.3(m,4H),1.2(m,2H),0.8(s,6H);13C NMR(100MHz;CDCl3)131.13,125.28,39.50,37.35,32.35,25.92,25.77,20.31,19.74,17.81,14.60。
(R)-4-甲基-庚酸往(R)-2,6-二甲基-壬-2-烯(20g,0.13mol)的丙酮溶液中(433mL)加入CrO3(39g,0.39mol)的H2SO4(33mL)/H2O(146mL)溶液,超过50分钟。6小时以后,再加入一定量CrO3(26g,0.26mol)的H2SO4(22mL)/H2O(100mL)混合溶液。12小时后,用盐水稀释溶液,再用乙醚提取。干燥(MgSO4)合并的有机相,浓缩。闪柱层析(梯度从6∶1到2∶1己烷/EtOAc)得到油状物(R)-4-甲基-庚酸,12.1g;65%。MS,m/z(相对丰度):143[M-H,100%]。
(4R,5S)-4-甲基-3-((R)-4-甲基-庚酰)-5-苯基-噁唑烷-2-酮0℃,往(R)-4-甲基-庚酸(19g,0.132mol)和三乙胺(49.9g,0.494mol)的THF(500mL)溶液中加入三甲基乙酰氯(20g,0.17mol)。1小时后,加入LiCl(7.1g,0.17mol),接着加入(4R,5S)-(+)-4-甲基-5-苯基-2-噁唑烷酮)3(30g,0.17mol)。混合物升至室温,16小时后过滤移除滤液,减压浓缩。闪柱层析(7∶1己烷/EtOAc)得到油状物(4R,5S)-4-甲基-3-((R)-4-甲基-庚酰)-5-苯基-噁唑烷-2-酮,31.5g;79%。[α]D=+5.5(c1于CHCl3).MS,m/z(相对丰度):304[M+H,100%]。
(3S,5R)-5-甲基-3-((4R,5S)-4-甲基-2-氧代-5-苯基-噁唑烷-3-羰基)-辛酸叔丁酯-50℃,往(4R,5S)-4-甲基-3-((R)-4-甲基-庚酰)-5-苯基-噁唑烷-2-酮(12.1g,0.04mol)的THF(200ml)溶液中加入二(三甲基硅基)酰胺钠(48mL,1MTHF溶液)。30分钟后,加入溴乙酸叔丁酯(15.6g,0.08mol)。溶液在-50℃搅拌4小时,然后升至室温。16小时后,加入饱和氯化铵水溶液,分为两层。水相用乙醚提取,干燥(MgSO4)合并的有机相,并浓缩。闪柱层析(9∶1己烷/EtOAc)得到白色固体(3S,5R)-5-甲基-3-((4R,5S)-4-甲基-2-氧代-5-苯基-噁唑烷-3-羰基)-辛酸叔丁酯12g,72%。[α]D=+30.2(c1于CHCl3)。13C NMR(100MHz;CDCl3)δ176.47,171.24,152.72,133.63,128.87,125.86,80.85,78.88,55.34,39.98,38.77,38.15,37.58,30.60,28.23,20.38,20.13,14.50,14.28。
(S)-2-((R)-2-甲基-苯基)-琥珀酸4-叔丁酯0℃,往(3S,5R)-5-甲基-3-((4R,5S)-4-甲基-2-氧代-5-苯基-噁唑烷-3-羰基)-辛酸叔丁酯(10.8g,0.025mol)的H2O(73mL)和THF(244mL)混合溶液中加入预混合的LiOH(51.2mL,0.8M溶液)和H2O2(14.6mL,30%溶液)。4小时后,再加入12.8mLLiOH(0.8M溶液)和3.65mLH2O2(30%溶液)。30分钟后,加入酸式亚硫酸钠(7g),亚硫酸钠(13g)和水(60mL),之后加入己烷(100mL)和乙醚(100mL)。分离两层,水相用乙醚提取。合并的有机相浓缩至油状,再溶解于庚烷中(300mL)。滤去生成的固体,干燥(MgSO4)滤液,浓缩得到(S)-2-((R)-2-甲基-苯基)-琥珀酸4-叔丁酯(6g,93%),无需进一步纯化即可使用。MS,m/z(相对丰度):257[M+H,100%]。
(3S,5R)-3-苄氧羰基氨基-5-甲基-辛酸叔丁酯 往(S)-2-((R)-2-甲基-戊基)-琥珀酸4-叔丁酯(6.0g,23.22mmol)和三乙胺(3.64mL,26.19mmol)的甲苯(200mL)溶液用二苯基磷酰基叠氮化物(5.0mL,23.22mL)处理,室温搅拌0.5小时。之后将反应混合物加热回流3小时后,短暂冷却。加入苄醇(7.2mL,69.7mmol),溶液再加热3小时。反应混合物冷却后,用乙醚(200mL)稀释,合并的有机相用饱和NaHCO3和盐水连续洗涤,干燥(Na2SO4)。浓缩的有机组分用色谱(MPLC)纯化,8∶1己烷:乙酸乙酯洗脱,得到(3S,5R)-3-苄氧羰基氨基-5-甲基-辛酸叔丁酯(6.4g,75.8%)。MS:M+1:364.2,308.2。
(3S,5R)-3-氨基-5-甲基-辛酸叔丁酯 往(3S,5R)-3-苄氧羰基氨基-5-甲基-辛酸叔丁酯(2.14g,5.88mmol)的THF(50mL)溶液用Pd/C(0.2g)和50psi通入的H2处理2小时。然后过滤反应混合液,真空浓缩至油状,定量的得到(3S,5R)-3-氨基-5-甲基-辛酸,叔丁酯。MS:M+1:230.2,174.1。
(3S,5R)-3-氨基-5-甲基-辛酸盐酸盐(3S,5R)-氨基-5-甲基-辛酸叔丁酯(2.59g,11.3mmol)的6N HCl(100mL)的浆液加热回流18小时,冷却,用硅藻土过滤。滤液在真空中浓缩至25ml,收集生成的结晶,干燥得(3S,5R)-3-氨基-5-甲基-辛酸盐酸盐,mp142.5-142.7℃(1.2g,50.56%)。从滤液中获得二次产物(0.91g)。分析计算值C9H19NO2·HCl:C:51.55,H:9.61,N:6.68,Cl:16.91.实测值:C:51.69,H:9.72,N:6.56,Cl:16.63。
(3S,5R)-3-氨基-5-甲基-辛酸盐酸盐在30mL甲基叔丁基醚中的5.3g 2S-(2R-甲基-戊基)-琥珀酸-4-叔丁酯与3.5mL三乙胺室温反应,接着与6.4g二苯基磷酰基叠氮化物反应。使反应放热至45℃,搅拌至少4小时,冷却反应混合物至室温,静置至两分离相。弃去下层,上层先用水洗涤,再用稀HCl洗涤。上层与10mL6N HCl水溶液混合,45-65℃条件下搅拌。反应混合液真空蒸馏浓缩至大约10-14mL,冷却至大约5℃析晶。过滤收集产品,用甲苯洗涤产品,再在甲苯中重浆液化。产品在真空中加热干燥,得白色晶体,2.9g,(67%)。产品可以从HCl水溶液中重结晶。mp137℃,HNMR(400MHz,D6DMSO)δ0.84-0.88(重叠的d和t,6H),1.03-1.13(m,1H),1.16-1.37(m,4H),1.57-1.68(m,2H),2.55(dd,1H,J=7,17Hz),2.67(dd,1H,J=6,17Hz),3.40(m,1H),8.1(br s,3H),12.8(br s,1H)。
实施例2.(3S,5R)-氨基-5-甲基-庚酸
甲磺酸(S)-3,7-二甲基-辛-6-炔基酯0℃,往S-(-)-香茅醇(42.8g,0.274mol)和三乙胺(91mL,0.657mol)的CH2Cl2(800mL)中加入甲磺酰氯(26mL,0.329mol)的CH2Cl2(200mL)。0℃下2小时后,溶液先用1N HCl洗涤,再用盐水洗涤。干燥(MgSO4)有机相,浓缩得到油状标题化合物(60.5g,94%)。无需进一步纯化即可使用。MS,m/z(相对丰度):139[100%],143[100%]。
(R)-2,6-二甲基-辛-2-烯0℃,往甲磺酸(S)-3,7-二甲基-辛-6-炔基酯(60g,0.256mol)的THF(1L)中加入氢化铝锂(3.8g,0.128mol)。7小时后,进一步加入3.8g氢化铝锂,溶液升至室温。18小时后,再加入3.8g氢化铝锂。进一步反应21小时,给反应液中小心地加入1N的柠檬酸终止反应,并加入盐水进一步稀释。反应液分为两层,干燥(MgSO4)有机相,浓缩得到油状标题化合物,无需进一步纯化即可使用。MS,m/z(相对丰度):139[M+H,100%]。
(R)-4-甲基-己酸 利用类似(R)-4-甲基-庚酸的制备过程制得油状酸(9.3g,56%)。IR(膜)2963,2931,2877,2675,1107,1461,1414cm-1;MS,m/z(相对丰度):129[M-H,100%]。
(4R,5S)-4-甲基-3-((R)-4-甲基-己酰基)-5-苯基-噁唑烷-2-酮利用类似(4R,5S)-4-甲基-3-((R)-4-甲基-庚酰基)-5-苯基-噁唑烷-2-酮的合成过程制得油状标题化合物(35.7g,95%)。MS,m/z(相对丰度):290[M+H,100]。
(3S,5R)-5-甲基-3-[1-((4R,5S)-4-甲基-2-氧代-5-苯基-噁唑烷-3-基)-甲酰氧基]-庚酸叔丁酯 利用类似(3S,5R)-5-甲基-3-((4R,5S)-4-甲基-2-氧代-5-苯基-噁唑烷-3-羰基)-辛酸叔丁酯制备过程制得下列油状标题化合物(7.48g;31%)。MS,m/z(相对丰度):178[100%],169[100%];[α]D=+21.6(c1于CHCl3溶液)。
(S)-2-((R)-2-甲基-丁基)-琥珀酸-4-叔丁酯 0℃,往(3S,5R)-5-甲基-3-[1-((4R,5S)-4-甲基-2-氧代-5-苯基-噁唑烷-3-基)-甲酰氧基-庚酸叔丁酯(7.26g,0.018mol)的H2O(53mL)和THF(176mL)的混合溶液中加入预混合的LiOH溶液(37mL,0.8M溶液)和H2O2(10.57mL,30%溶液),溶液升至室温。2小时后,加入酸式亚硫酸钠(7g),亚硫酸钠(13g)和水(60mL)。分为两层,水相用乙醚提取。合并的有机相浓缩至油状,再溶解于庚烷中(200mL)。滤去生成的固体,滤液用干燥(MgSO4),浓缩得到油状标题化合物(4.4g),无需进一步纯化即可使用。MS,m/z(相对丰度):243[100%]。
(3S,5R)-3-苄氧羰基氨基-5-甲基-庚酸叔丁酯 该化合物的制备如上所述,起始物为(S)-2-((R)-2-甲基-丁基)琥珀酸4-叔丁酯,得到油状物(3S,5R)-3-苄氧羰基氨基-5-甲基-庚酸叔丁酯(产率73.3%)。1H NMR(400MHz;CDCl3)δ0.84(t,3H,J=7.33Hz),0.89(d,3H,J=6.60Hz),1.12-1.38(m,4H),1.41(s,9H),1.43-1.59(m,2H),2.42(m,2H),4.05(m,1H),5.07(t,2H J=12.95Hz),和7.28-7.34(m,5H)。
(3S,5R)-氨基-5-甲基-庚酸叔丁酯 该化合物的制备如上所述,起始物用(3S,5R)-3-苄氧羰基氨基-5-甲基-庚酸叔丁酯代替(3S,5R)-3-苄氧羰基氨基-5-甲基-辛酸叔丁酯,得到标题化合物。1H NMR(400MHz;CDCl3)δ0.84(重叠t和d,6H),1.08-1.16(m,2H),1.27-1.30(m,2H),1.42(s,9H),1.62(br s,2H),2.15(dd,1H,J=8.54和15.62Hz),2.29(dd,1H,J=4.15和15.37Hz),和3.20(br s,2H)。
(3S,5R)-氨基-5-甲基-庚酸盐酸盐 (3S,5R)-氨基-5-甲基-庚酸叔丁酯(1.44g,6.69mmol)在3N HCl的浆液中加热回流3小时,用硅藻土热过滤,浓缩,干燥。所得固体在乙醚中研细,即得(3S,5R)-3-氨基-5-甲基-庚酸盐酸盐(0.95g,85%)。mp126.3-128.3℃.分析计算值C8H17NO2·HCl 0.1H2O:C:48.65,H:9.29,N:7.09,Cl:17.95.实测值:C:48.61,H:9.10,N:7.27,Cl:17.87 MS:M+1:160.2。
实施例3.(3S,5R)-3-氨基-5-甲基-壬酸
(R)-4-甲基-辛酸 室温下,将氯化锂(0.39g,9.12mmol)和氯化铜(I)(0.61g,4.56mmol)在45ml THF中混合,搅拌15分钟,然后冷却至0℃同时加入乙基溴化镁(1M THF溶液,45mL,45mmol)。逐滴加入(S)-香茅基溴(5.0g,22.8mmol),溶液慢慢加热至室温,搅拌过夜。反应液小心地用饱和NH4Cl(aq)终止反应,在Et2O和饱和NH4Cl(aq)中搅拌30分钟。分为两层,干燥(MgSO4)有机相,浓缩。无需纯化粗(R)-2,6-二甲基-癸-2-烯即可使用。0℃,往(R)-2,6-二甲基-癸-2-烯(3.8g,22.8mmol)的50mL丙酮溶液中加入Jones′试剂(2.7MH2SO4(aq),40mL,108mmol),溶液慢慢升至室温,搅拌过夜。混合物在Et2O和H2O之间分配,两相分层,有机相用盐水洗涤,干燥(MgSO4),浓缩。残余物用闪柱纯化(8∶1己烷∶EtOAc)得到无色油状标题化合物2.14g(59%)。LRMS:m/z156.9(M+)。Jones′试剂是通过混合26.7gCrO3和23mLH2SO4并用H2O稀释至100mL制得的2.7M的溶液。
(4R,5S)-4-甲基-3-((R)-4-甲基-辛酰基)-5-苯基-噁唑烷-2-酮 0℃,往(R)-4-甲基-辛酸(2.14g,13.5mmol)的25mLCH2Cl2中加入3滴DMF,接着加入草酰氯(1.42mL,16.2mmol)导致大量气体生成。溶液直接升至室温,搅拌30分钟,浓缩。同时,在-78℃,往噁唑烷酮(2.64g,14.9mmol)的40mL THF溶液中逐滴加入正-丁基锂(1.6M的己烷溶液,9.3mL,14.9mmol)。混合物搅拌10分钟,此时逐滴加入10mL酰氯的THF。反应液在-78℃搅拌30分钟,直接升至室温,用饱和NH4Cl溶液中止反应。混合物在Et2O和饱和NH4Cl(aq)中分配,用(MgSO4)干燥有机相,浓缩得3.2g无色油状标题化合物。LRMS:m/z318.2(M+)。
(3S,5R)-5-甲基-3-((4R,5S)-4-甲基-2-氧代-5-苯基-噁唑烷-3-羰基)-壬酸叔丁酯 -78℃,往二异丙基胺(1.8mL,12.6mmol)的30mL THF溶液中加入正-丁基锂(1.6M的己烷溶液,7.6mL,12.1mmol),混合物搅拌10分钟,此时逐滴加入(4R,5S)-4-甲基-3-((R)-4-甲基-辛酰基)-5-苯基-噁唑烷-2-酮(3.2g,10.1mmol)的10mL THF溶液。溶液搅拌30分钟,在-50℃,迅速逐滴加入叔丁基溴乙酸酯(1.8mL,12.1mmol),混合物缓慢升温至10℃经历3小时。混合物在Et2O和饱和NH4Cl(aq)中分配,分离相,用(MgSO4)干燥有机相,浓缩。残余物用闪柱纯化(16∶1至8∶1己烷∶EtOAc),得到2.65g无色结晶固体标题化合物(61%),mp=84-86℃。[δ]D23+17.1(c=1.00,CHCl3)。
(S)-2-((R)-2-甲基-己基)-琥珀酸4-叔丁酯 0℃,往(3S,5R)-5-甲基-3-((4R,5S)-4-甲基-2-氧代-5-苯基-噁唑烷-3-羰基)-壬酸叔丁酯(2.65g,6.14mmol)的20mL THF溶液中加入预冷却的(0℃)LiOH一水合物溶液(1.0g,23.8mmol)和过氧化氢(30wt%水溶液,5.0mL)的10mL水溶液。混合物剧烈搅拌90分钟,升至室温,再搅拌90分钟。在0℃,加入100mL 10%NaHSO3(aq)终止反应,然后用Et2O提取。分离相,有机相用盐水洗涤,干燥(MgSO4),浓缩。无需纯化即可使用标题化合物。
(3S,5R)-3-苄氧羰基氨基-5-甲基壬酸叔丁酯 该化合物的制备如上所述,起始物用(S)-2-((R)-2-甲基己基)琥珀酸4-叔丁酯代替(S)-2-((R)-2-甲基戊基)琥珀酸4-叔丁酯得到油状标题化合物(产率71.6%)。1HNMR(400MHz;CDCl3)δ0.81(t,3H,J=4.40Hz),0.85(d,3H,J=6.55Hz),1.06-1.20(m,7H),1.36(s,9H),1.38-1.50(m,2H),2.36(m,2H),3.99(m,1H),5.02(m+s,3H),和7.28-7.28(m,5H)。
(3S,5R)-3-氨基-5-甲基-壬酸叔丁酯 该化合物的制备如上所描述,起始物用(3S,5R)-苄氧羰基氨基-5-甲基-壬酸叔丁基酯代替(3S,5R)-3-苄氧羰基氨基-5-甲基-辛酸叔丁酯。产率=97%.1HNMR(400MHz;CDCl3)δ0.82(重叠d和t,6H),1.02-1.08(m,1H),1.09-1.36(m,6H),1.39(s,9H),1.47(br s,1H),1.80(s,2H),2.13(dd,1H,J=8.54和15.61Hz),和2.27(dd,1H,J=4.15和15.38Hz)。
(3S,5R)-3-氨基-5-甲基-壬酸盐酸盐:将(3S,5R)-3-氨基-5-甲基-壬酸叔丁酯(1.50g,6.16mmol)的3N HCl(100mL)混合加热回流3小时,用硅藻土热过滤,真空浓缩至30mL。收集生成的晶体,用另外的3N HCl洗涤,干燥得到标题化合物,mp142.5-143.3℃。通过过滤获得另外的产品,共1.03g(70.4%)。分析计算值C10H21NO2·HCl:C:53.68,H:9.91,N:6.26,Cl:15.85。实测值:C:53.89,H:10.11,N:6.13.MS:M+1:188.1。
实施例4.(2R,4R)-2-氨甲基-4-甲基-庚酸
5R-甲基-3R-(4S-甲基-2-氧代-5R-苯基噁唑烷-3-羰基)辛酸将(3R,5R)-5-甲基-3-((4S,5R)-4-甲基-2-氧代-5-苯基-噁唑烷-3-羰基)-辛酸叔丁酯(3.9g,9.34mmol)的二氯甲烷(150mL)溶液中加入三氟乙酸(7.21mL,93.4mL),在室温搅拌18小时。在真空除去溶剂和试剂后,残余物在100mL己烷中研磨得到3.38g目标化合物(100%)mp142-143℃。
[4R-甲基-2R-(4S-甲基-2-氧代-5R-苯基噁唑烷-3-羰基)庚基]氨基甲酸苄酯 将二苯基磷酰基叠氮化物(1.2mL,5.48mmol),加入5R-甲基-3R-(4S-甲基-2-氧代-5R-苯基噁唑烷-3-羰基)辛酸(1.98g,5.48mmol)和三乙胺(0.92mL,6.57mmol)溶液中,在室温搅拌30分钟然后加热回流三小时。在短暂的冷却后,将苄醇(2.8mL,27.4mmol)加入反应混合物中,再加热回流3小时。反应液冷却,用乙醚(150mL)稀释,连续用饱和NaHCO3和盐水洗涤,干燥(MgSO4),真空浓缩得油状物。层析(MPLC,用4∶1己烷∶乙基乙酸洗脱)得油状标题化合物(2.0g,78.3%)。MS M+1=467.1。
2R-(苄氧羰基氨甲基)-4R-甲基庚酸 将4R-甲基-2R-(4S-甲基-2-氧代-5R-苯基噁唑烷-3-羰基)庚基]氨基甲酸苄酯(4.12g,8.83mmol)的3∶1 THF∶水(100mL)溶液冷却至0℃,用0.8N LiOH(17.5mL,14mmol)和30%H2O2(4.94ml,44mmol)的混合物处理。反应混合物搅拌3小时后,用NaHSO3(2.37g)浆液和Na2SO3(4.53g)水溶液(30mL)终止反应,搅拌1小时。反应混合物用乙醚(200mL)稀释,分配,有机层用盐水洗涤,干燥(MgSO4)。
浓缩的有机提取物层析(MPLC),用乙酸乙酯洗脱得1.25g 2R-(苄氧羰基氨甲基)-4R-甲基庚酸(46%)。MS M+1=308.1。
(2R,4R)-2-氨基-4-甲基-庚酸盐酸盐 50psi下,将2R-(苄氧羰基氨甲基)-4R-甲基-庚酸(1.25g,4.07mmol)和Pd/C(20%,0.11g)的甲醇(50mL)混合液氢化18小时。滤去催化剂后,真空除去溶剂,所得固体在乙醚中研磨得到(2S,4R)-2-氨基-4-甲基-庚酸盐酸盐(0.28g,40%)。mp226.3-228.0℃.MS M+1=174.0.分析计算值C9H19NO2·0.1H2OC:61.75 H:11.06 N:8.00。实测值C:61.85 H:10.83 N:8.01。
实施例5.2-氨甲基-4,4-二甲基-庚酸盐酸盐
2-氰基-4,4-二甲基-庚-2,6-二烯酸乙酯 将2,2-二甲基-戊-4-烯醇(5.0g,44mmol)、氰基乙酸乙酯(5.12mL,48mmol)、哌啶(1.3mL,14mmol)和乙酸(4.52mL,80mmol)的170mL甲苯溶液在装有Dean-Stark分离器的烧瓶中加热回流18小时。收集器中的几毫升水。冷却反应并用1N HCl、NaHCO3和盐水连续洗涤。干燥(Na2SO4)有机层,浓缩得油状物。油状物经层析,用20%EtOAc的己烷溶液洗脱得两种物质的混合物共8.3g(91%)。1H NMR(400MHz;CDCl3)1.28(s,6H),1.32(t,3H,J=7Hz),2.26(d,2H,J=7.6Hz),4.27(q,2H,J=7.2Hz),5.08(d,1H,J=12Hz),5.10(d,1H,J=4Hz),5.72(m,1H)。
2-氨甲基-4,4-二甲基-庚酸盐酸盐 2-氰基-4,4-二甲基-庚-2,6-二烯酸乙酯(5.88g,28mmol)溶于91mL乙醇和6mL HCl的混合溶剂中,用0.4gPtO2处理。反应在室温和100psi氢气下进行15小时。滤去催化剂,浓缩滤液得油状物2-氨甲基-4,4-二甲基-庚酸乙酯3.8g。MS(APCI):216.2(M+1)+。该油状物在75mL 6N HCl中回流18小时。冷却反应,形成沉淀。固体经过滤,额外的HCl溶液洗涤,乙醚中研磨,得清洁标题化合物。MS(APCI):188.1(M+1)+,186.1(M-1)+。1H NMR(400MHz;CD3OD):0.91(9H,m),1.30(5H,m),1.81(dd,1H,J=7.2Hz,14.4Hz),2.72(1H,m),3.04(2H,m);分析计算值C10H21NO2·HCl:C:53.68,H:9.91,N:6.26,Cl:15.85;实测值:C:53.83,H:10.15,N:6.22,Cl:15.40.MP:229.5-231.0℃。
实施例6.(S)-3-氨基-5,5-二甲基-辛酸
3-(4,4-二甲基-庚酰)-(R)-4-甲基-(S)-5-苯基-噁唑烷-2-酮
将4,4-二甲基-庚酸(1.58g,10mmol)与三乙胺(4.6mL)的50mL THF溶液冷却至0℃并加入2,2-二甲基-丙酰氯(1.36mL)。1个小时后,加入4R-甲基-5S-苯基-噁唑烷-2-酮(1.95g,11mmol)和氯化锂(0.47g,11mmol),并将混合液搅拌18小时。滤过沉淀物,使用额外的THF完全洗涤。真空浓缩滤液,得到油性固体。将固体溶解在200mL的Et2O中,连续用饱和NaHCO3、0.5N HCl和饱和NaCl洗涤,干燥(MgSO4),在真空中浓缩得到油性的标题化合物(3.0g,95%)。1HNMR(400MHz;CDCl3):0.73-0.84(m,12H),1.10-1.22(m,4H),1.46-1.54(m,2H),2.75-2.87(m,2H),4.70(m,1H,J=7Hz),5.59(d,1H,J=7Hz),7.22-7.37(m,5H)。
5,5-二甲基-(S)-3-((R)-4-甲基-2-氧代-(S)-5-苯基-噁唑烷-3-羰基)-辛酸叔丁酯 根据实施例1,5.07g(16mmol)的3-(4,4-二甲基-庚酰基)4-甲基-5-苯基-噁唑烷-2-酮、18mL(1N,18mmol)的NaHMDS溶液和4.72mL(32mmol)溴乙酸叔丁酯制得3.40g(49.3%)结晶固体标题化合物。m.p.:83-85℃。
(S)-2-(2,2-二甲基-戊基)-琥珀酸4-叔丁酯 根据实施例1,用3.4g(7.9mmol)5,5-二甲基-3-(4-甲基-2-酮-5-苯基-噁唑烷-3-羰基)-辛酸叔丁酯、16mL(12.8mmol)的0.8N LiOH和4.5mL的30%H2O2制得2.42g(>100%)油状标题化合物。1HNMR(400MHz;CDCl3):0.77-0.82(m,9H),1.14-1.29(m,5H),1.42(s,9H),1.77(dd,1H,J=8Hz,16Hz),2.36(dd,1H,J=6Hz,16Hz),2.59(dd,1H,J=8Hz,16Hz),2.75-2.85(m,1H)。
(S)-3-苄氧碳酰氨基-5,5-二甲基-辛酸叔丁酯 根据实施例1,用2.14g(7.9mmol)的2-(2,2-二甲基-戊基)-琥珀酸4-叔丁酯,1.7mL的DPPA,1.1mL的Et3N和2.44mL的BnOH制得1.63g(54.8%两步反应)油状标题化合物。1HNMR(400MHz;CDCl3):0.78-0.89(m,9H),1.10-1.30(m,5H),1.36(s,9H),2.39(t,2H,J=5Hz),4.95-4.05(m,1H),5.00(s,2H),5.09(d,1H,J=9.6Hz),7.22-7.30(m,5H)。
(S)-3-氨基-5,5-二甲基-辛酸叔丁酯 根据实施例1,1.63g的3-苄氧碳酰氨基-5,5-二甲基-辛酸叔丁酯和0.2g的20%Pd/C制得标题化合物。MS,m/z,244.2(M+1)+。
(S)-3-氨基-5,5-二甲基-辛酸盐酸盐 根据实施例1,用3N的HCl处理3-氨基-5,5-二甲基-辛酸叔丁酯,制得286mg固体标题化合物。MS(APCI),m/z:188.1(M+1)+.186.1(M-1)+.分析计算值C10H21NO2·HCl·12H2O:C:53.17,H:9.92,N:6.20,Cl:15.69;实测值:C:53.19,H:10.00,N:6.08,Cl:15.25。α=+20°(MeOH)。MP:194.2-195.2℃。
实施例7. 2-氨甲基-3-(1-甲基-环丙基)-丙酸
2-氰基-3-(1-甲基-环丙基)-丙烯酸乙酯 往1-甲基环丙烷-甲醇(Aldrich,1.13mL,11.6mmol)的50mL CH2Cl2溶液中加入中性氧化铝(2.5g),然后再加入PCC(2.5g,11.6mmol),在室温下搅拌混合液3小时。真空下,通过1cm二氧化硅管过滤混合液,使用Et2O洗涤。浓缩滤液得大约5mL。向残余液中加入THF(10mL),氰基乙酸乙酯(1.2mL,11.3mmol),哌啶(5滴),最后加入乙酸(5滴)。室温下搅拌过夜,然后混合液在Et2O和饱和aq.NaHCO3分配。分离相,用盐水洗涤有机相,干燥(MgSO4)并浓缩。残余物通过闪柱色谱(10->15%EtOAc/己烷)得到0.53g(25%)无色油状酯,放置结晶。分析计算值C10H13NO2:C,67.02;H,7.31;N,7.82。实测值:C,66.86;H,7.47;N,7.70。
2-氨甲基-3-(1-甲基-环丙基)-丙酸乙酯。向2-氰基-3-(1-甲基-环丙基)-丙烯酸乙酯(0.45g,2.51mmol)的16mL EtOH:THF(1:1溶液)加入RaNi(0.4g),将混合液放置在48psi的Parr振荡器中振荡15.5小时氢化。然后加入Pearlman′s催化剂(0.5g),再继续氢化另外15小时。随后过滤并浓缩混合物。用2→3→4→5→6→8%的残余物MeOH/CH2Cl2闪式层析滤液,得到无色油性0.25g(54%)的氨基酯。LRMS:m/z 186.1(M+1)。
2-氨甲基-3-(1-甲基-环丙基)-丙酸。0℃下向2-氨甲基-3-(1-甲基-环丙基)-丙酸乙酯(0.25g,1.35mmol)的10mL甲醇溶液中加入10%aq.NaOH(10mL)。混合液在室温下搅拌过夜,然后浓缩移除甲醇。将残液冷却到0℃并使用浓HCl酸化至pH值为2。混合液恢复到室温后,加载到DOWEX-50WX8-100离子交换树脂上,使用H2O洗脱,直到石蕊显示中性。使用5%aq.NH4OH(100mL)继续洗脱,浓缩碱性部分得到0.15g(71%)无色固体状的氨基酸。LRMS:m/z 158.0(M+1)。
实施例8.(3S,5R)-3-氨基-5-甲基-辛酸
(5S)-5-甲基-辛-2,6-二烯酸叔丁酯 在-78℃,向(S)-3-甲基-己-4-烯酸乙酯*(1.0g,6.4mmol)的30mL甲苯溶液中加入DIBAH(1.0M的THF溶液,6.4mL),滴加超过5分钟。-78℃下混合液搅拌45分钟,同时加入5滴甲醇,导致放出大量H2。加入甲醇直到不再有气体放出(大约5mL)。此时移走冷浴,加入大约5mL的饱和酒石酸Na+K+水溶液。当混合液达到室温时,再继续加入饱和酒石酸Na+K+水溶液和Et2O并搅拌,直到液相变得大体澄清(大约1小时)。分离相,然后用盐水洗涤有机相,干燥(MgSO4),浓缩得到大约10mL体积。通过上面描述的方法,将原始的混合液与由10mmol酯制备的另外的乙醛合并,应用的整个体系未纯化。向氯化氢(60%分散于矿物油中)的25mlTHF混悬液中滴加叔丁基-P,P-二甲基膦酰乙酸酯(3.0mL,15mmol)1小时,以使H2的释放受到控制。添加完成后,迅速滴加天然乙醛的甲苯溶液(总体积大约20mL),在室温下搅拌混合物过夜。混合液在Et2O和饱和的NH4Cl溶液中分配,分离相,用盐水洗涤有机相,干燥(MgSO4)并浓缩。使用闪式层析的残余物(0→3→5%EtOAc/己烷)得到淡黄色油状的不饱和酯1.0g(29%,两步):1H NMR(CDCl3)δ6.75(m,1H),5.66(m,1H),5.30(m,2H),2.03-2.29(m,3H),1.58(d,J=6.1Hz,3H),1.41(s,9H),0.91(d,J=6.6Hz,3H)。
根据文献中的方法通过原乙酸三乙酯Johnson-Claisen重排[Hill,R.K.;Soman,R.;Sawada,S.,J.Org.Chem.,1972,37,3737],由(S)-反式-3-戊-2-醇制备*(S)-3-甲基-己-4-烯酸乙酯[Liang,J.;Hoard,D.W.;Van Khau,V.;Martinelli,M.J.;Moher,E.D.;Moore,R.E.;Tius,M.A.J.Org.Chem.,1999,64,1459]。
(3R,5S)-3-[苄基-(1-苯基-乙基)-氨基]-5-甲基-辛-6-烯酸叔丁酯。-78℃下向(S)-(-)-N-苄基-辛-甲基苄基胺(0.60mL,2.85mmol)的9.0mL THF溶液中迅速滴加正-丁基锂(1.6M己烷,1.6mL),出现深粉红色。在-78℃,搅拌混合液30分钟,同时缓慢滴加含有(5S)-5-甲基-辛-2,6-二烯酸叔丁酯(0.5g,2.38mmol)的1.0mL THF溶液,出现淡黄褐色,3小时后变深。-78℃搅拌混合液3小时,然后使用饱和的NH4Cl溶液终止反应。将混合液恢复到室温并搅拌过夜,混合液在EtOAc和饱和的NH4Cl溶液中分配。浓缩相,干燥有机相(MgSO4)并浓缩。残余物闪式层析(3→5%EtOAc/己烷)得到0.52g(52%)的黄色油状氨基酯。1H NMR(CDCl3)δ7.34(m,2H),7.20(m,8H),5.27(m,2H),3.74(m,1H),3.72(d,J=15.9Hz,1H),3.41(d,J=14.9Hz,1H),3.27(m,1H),2.38(m,1H),1.98(dd,J=3.7,14.2Hz,1H),1.81(dd,J=9.3,14.4Hz,1H),1.54(d,J=4.9Hz,3H),1.32(s,9H),1.24(d,J=7.1Hz,3H),0.99(m,2H),0.74(d,J=6.6Hz,3H)。
(3S,5R)-3-氨基-5-甲基-辛酸.向(3R,5S)-3-[苄基-(1-苯基-乙基)-氨基]-5-甲基-辛-6-烯酸叔丁酯(0.92g,2.18mmol)的50mL MeOH溶液中加入20%Pd/C(0.20g),并在Parr震荡器中以48psi氢化23小时。滤过并浓缩混合液。向10mL天然氨基酯的CH2Cl2溶液中加入1.0mL三氟乙酸,溶液在室温下搅拌过夜。浓缩混合液并将残余物溶解在最小量的水中,并加载到DOWEX-50WX8-100离子交换树脂上。用水洗脱柱,直到石蕊显示中性,然后继续用5%NH4OH溶液(100mL)洗脱。将碱性部分浓缩,得到0.25g(66%,两步)的黄白色固体的氨基酸。1H NMR(CD3OD)δ3.41(m,1H),2.36(dd,J=5.1,16.6Hz,1H),2.25(dd,J=8.1,16.6Hz,1H),1.42(m,2H),1.24(m,1H),1.12(m,2H),1.00(m,1H),0.73(d,J=6.4Hz,3H),0.68(t,J=6.8Hz,3H)。LRMS:m/z172.1(M-1)。
实施例9.2-氨甲基-8-甲基-壬酸
使用类似于制备2-氨甲基-4,4,8-三甲基-壬酸的步骤,由6-甲基-1-庚醇制备2-氨甲基-8--甲基-壬酸m/z 202.1(M+)。
2-氨甲基-4,8-二甲基-壬酸
(R)-2,6-二甲基庚烷-1-醇将镁turnings(2.04g,84mmol)和碘晶体悬浮于5mL THF中,加入1-溴-3-甲丁烷(0.3mL,洁净)。加热混合液,开始Grignard构建。剩余的1-溴-3-甲基丁烷(8.63mL,72mmol)稀释在THF(60mL)中并滴加到混合液中。将混合液在室温下搅拌2小时,冷却到-5℃。滴加氯化铜(1.21g,9mmol)和LiCl(0.76g,18mmol)的THF溶液(50mL),保持温度低于0℃。得到的混合液搅拌20分钟,并滴加(R)-3-溴-2-甲基丙醇的THF溶液(20mL),并保持温度低于0℃。混合液缓慢恢复到室温过夜。用羟铵和水终止反应混合液。使用EtOAc稀释混合液并用3×20mL EtOAc萃取。用盐水洗涤有机相,干燥(MgSO4)、滤过并浓缩。残余油用硅胶层析纯化(90/10己烷/EtOAc),得到2.67g的(R)-2,6-二甲基庚烷-1-醇。
(R)-1-碘-2,6-二甲基庚烷在0℃,向载体三苯基磷化氢(6.55g,19.67mmol)的℃H2Cl2的混合液中加入碘(4.99g,19.67mmol)和咪唑(1.33g,19.67mmol)。将混合液加热到室温,搅拌1小时,再冷却到0℃,滴加(R)-2,6-二甲基庚烷-1-醇的CH2Cl2(5mL)。混合液再恢复到室温并搅拌1小时,此时使用硅藻土垫过滤,用CH2Cl2洗涤固体物。浓缩滤液,经硅胶层析纯化粗品,得到(R)-1-碘-2,6-二甲基庚烷(2.44g)。
(4R)-4,8-二甲基壬酸叔丁酯 在-78℃,向二异丙胺(0.827mL,5.9mmol)THF溶液(8mL)中加入正丁基锂(2.65mL的2.6M的戊烷溶液)。溶液在-78℃搅拌30分钟,随后加入叔丁基乙酯(0.8mL,5.9mmol)。-78℃,混合液搅拌2小时,然后加入(R)-1-碘-2,6二甲基庚烷(0.3g,1.18mmol)和HMPA(1.5mL)的THF溶液(1mL)。-78℃,搅拌反应,并且缓慢恢复至室温过夜,然后加热到35℃,使反应完全。加入氯化铵终止反应(饱和水溶液),并且使用EtOAc(2×10mL)萃取混合液。合并有机相,用水洗涤,干燥(MgSO4),滤过并浓缩。硅胶层析(98/2 己烷/EtOAc)得到0.25g的(4R)-4,8-二甲基壬酸叔丁酯。
(4R)-4,8-二甲基壬酸 在0℃,用TFA(6mL)处理25mL(4R)-4,8-二甲基壬酸叔丁酯的CH2Cl2溶液。混合液恢复至室温,搅拌过夜。通过旋转蒸发移除溶剂,并且使用硅胶层析(95/5 己烷/EtOAc)纯化,得到0.962g(4R)-4,8-二甲基壬酸。m/z185(M-)。
3-(4R,8-二甲基-壬酰)-4(S)-甲基-5(R)-苯基-噁唑烷-2-酮使用类似于制备(4R,5S)-4-甲基-3-(R)-4-甲基-庚酰)-5-噁唑烷-2-酮)的步骤制备3-(4R,8-二甲基-壬酰)-4(S)-甲基-5(R)-苯基-噁唑烷-2-酮(1.35g)m/z 346.5(M+)。
[4R,8-二甲基-2R-(4R-甲基-2-氧代-5R-苯基-噁唑烷-3-羰基)-壬基]-氨基甲酸苄酯 在-20℃,向3-(4(R),8-二甲基-壬酰)-4(S)-甲基-5(R)-苯基-噁唑烷-2-酮(1.05g,3.04mmol)的CH2Cl2(12mL)和TiCl4(3.04mL的1M℃H2Cl2溶液)溶液中加入二异丙基乙胺(0.55mL,3.19mmol)。所得的深红溶液在-20℃搅拌30分钟,然后加入N-甲氧甲基苄基氨基甲酸酯(0.652g,3.34mmol)的CH2Cl2(3.5mL)和TiCl4(3.34mL)溶液。混合液在0℃搅拌4小时。加入饱和氯化铵溶液终止反应。使用CH2Cl2(3×15mL)萃取混合液。合并的有机相用1N HCl洗涤,并用NaOH中和,接着用盐水洗涤。干燥(MgSO4),过滤,浓缩并使用硅胶层析纯化有机相(95/5 己烷/EtOAc),得到0.555g[4R,8-二甲基-2R-(4R-甲基-2-氧代-5R-苯基-噁唑烷-3-羰基)-壬基]-氨基甲酸苄酯。
2(R)-(苄氧羰基氨基-甲基)-4(R),8-二甲基-壬酸
使用类似于制备(S)-2-((R)-2-甲基戊基)琥珀酸叔-丁酯的方法制得0.198g2(R)-(苄氧羰基氨基-甲基)-4(R),8-二甲基-壬酸。
2-氨甲基-4,8-二甲基壬酸在20%Pd/C存在的条件下,用氢处理2(R)-(苄氧羰基氨基-甲基)-4(R),8-二甲基-壬酸(0.148g,0.566mmol),过滤并用硅胶层析(85/15℃H2Cl2/MeOH),得到0.082g的2-氨甲基-4,8-二甲基壬酸。m/z 216.3(M+)。
实施例10. 2-氨甲基-4,4,8-三甲基-壬酸
2,2,6-三甲基-庚酸甲酯 在-78℃,向二异丙基胺(1.54mL,11.03mmol)的THF(22mL)溶液中加入正丁基锂(6.89mL 1.6M的己烷溶液)。-78℃下搅拌溶液30分钟,随后加入异丁酸甲酯(0.97mL,8.48mmol)。-78℃下搅拌混合液2小时,然后加入1-碘-4-甲基戊烷(1.8g,8.48mmol)和DMPU(0.55mL,4.24mmol)的THF溶液(6mL)。-78℃下搅拌反应16小时,缓慢达到室温。加入氯化铵(饱和水溶液)终止反应,使用EtOAc(2×10mL)萃取混合液。合并有机相并用水洗涤,干燥(MgSO4)、过滤并浓缩。硅胶层析(99/1 己烷/EtOAc),得到1.57g的2,2,6-三甲基-庚酸甲酯。
2,2,6-三甲基-庚-1-醇 将2,2,6-三甲基-庚酸甲酯(1.97g,10.6mmnol)加入甲苯(65mL)中,冷却到-78℃。滴加DiBALH(12.7mL 1N甲苯溶液)。45分钟后加入1.5mL DiBAlH。2小时后,在-78℃用15mL MeOH终止反应。混合液恢复至室温,然后再冷却到-78℃,加入10mL 1N HCl。使用EtOAc(3×15mL)萃取混合溶液。用盐水洗涤合并的有机相,干燥(MgSO4)、过滤并浓缩。残余油用硅胶层析(95/5 己烷/EtOAc)纯化,得到2,2,6-三甲基-庚-1-醇(0.88g)。m/z159(M+)。
2,2,6-三甲基-庚醛 将氯铬酸吡啶鎓盐(PCC,4.17g,19.4mmol)与中性氧化铝(14.6g)在CH2Cl2中混合,室温下搅拌15分钟。将乙醇稀释在CH2Cl2中,混合液在室温下搅拌2小时。通过一个二氧化硅垫过滤溶液,用CH2Cl2洗涤固体。蒸干滤出液,得到1.05gm/z157(M+)的2,2,6-三甲基-庚醛,无需进一步纯化。
2-氰基-4,4,8-三甲基-壬-2-烯酸苄酯 向2,2,6-三甲基-庚醛(1.05g,6.73mmol)、哌啶(0.19mL,2.01mmol)和苄基氰乙酸酯(1.29g,7.4mmol)的甲苯(50mL)混合液中加入冰乙酸(0.72g,12.1mmol)。烧瓶装配有汽水阀,将混合液加热回流18小时。冷却混合液,用稀HCl处理,分离各层。使用饱和碳酸氢钠洗涤有机相,再用盐水洗涤,干燥(MgSO4)、过滤并浓缩。残余油用硅胶层析法(98/2己烷/EtOAc)纯化,得到1.3g的2-氰基-4,4,8-三甲基-壬-2-烯酸苄酯m/z 314(M+)。
2-氨甲基-4,4,8-三甲基-壬酸在存在20%Pd/C的条件下,用氢处理2-氰基-4,4,8-三甲基-壬-2-烯酸苄酯(1.3g,4.14mmol)THF溶液(50mL),得到氰酸和氰酸甲酯的混合液。硅胶层析纯化混合物得到278mg的80105x41-1-2。随后在MeOH/NH4OH中的RaneyNi存在的条件下,用氢处理该酸,得到0.16g的2-氨甲基-4,4,8-三甲基-壬酸。m/z 230.3(M+)。
实施例11. 2-氨甲基-4-乙基-辛酸
使用类似于2-氨甲基-4,4,8-三甲基-壬酸的制备过程由2-乙基己醛制备2-氨甲基-4-乙基-辛酸。m/z 202.1(M+)。
实施例12. 2-氨甲基-4-乙基-8-甲基-壬酸
使用类似于2-氨甲基-4,4,8-三甲基-壬酸制备的过程,由2,6-二-叔丁基-4-甲基苯基环丙基羧酸酯制备2-氨甲基-8-甲基-壬酸。m/z 230.2(M+)。
实施例13. 3-氨基-2-[1-(4-甲基-戊基)-环丙基甲基]-丙酸
使用类似于2-氨甲基-4,4,8-三甲基-壬酸的制备过程,由2,6-二叔丁基-4甲基苯基环丙基羧酸酯制备2-氨甲基-8-甲基-壬酸。m/z228.2(M+)。
实施例14. 2-氨甲基-4-乙基-己酸
使用类似于制备2-氨甲基-4,8-二甲基-壬酸的过程,由4-乙基己酸制备2-氨甲基-4-乙基-己酸。m/z 174.1。
实施例15. 3(S)-氨基-3,5-二甲基-庚酸
2-甲基-丙烷-2(S)-亚磺酸(1,3-二甲基-亚戊基)-酰胺 加热回流(S)-(-)-2-甲基-2-丙基磺酰胺(500mg,4.1mmol)、4-甲基-2己酮(470mg,4.1mmol)和乙醇钛(IV)(1.7mL,8.3mmol)的溶液18小时。反应混合物倒入20ml盐水快速搅拌。反应混合物用硅藻土滤过,分离有机相。用乙酸乙酯(2×20mL)萃取水相。干燥(Na2SO4)、过滤并浓缩合并的有机物。残余油用硅胶层析法(25%EtOAc的己烷溶液)纯化,得到黄色油状的575mg 2-甲基-丙烷-2(S)-亚磺酸(1,3-二甲基-亚戊基)-酰胺。
3,5-二甲基-3-(2-甲基-丙烷-2(S)-亚磺酰氨基)-庚酸甲酯向-78℃的锂二-(三甲基硅烷基)酰胺(5.1ml 1M的THF溶液)的THF(6mL)溶液中滴加乙酸甲酯((0.41mL,5.1mmol)。搅拌20分钟后,滴加三异丙氧基氯化钛(2.5ml,10mmol)的THF(3mL)溶液。1小时后,在-78℃,滴加2-甲基-丙烷-2(S)-亚磺酸(1,3-二甲基-亚戊基)-酰胺(560mg,2.6mmol)的THF(3mL)溶液。-78℃搅拌反应5小时,然后加入10mL的氯化铵溶液终止反应,并加热至室温。用10mL的水稀释混合液并过滤。用乙酸乙酯(2×20mL)萃取水层。用盐水洗涤合并的有机物,干燥(Na2SO4)、过滤并浓缩。剩余油用硅胶层析(30%EtOAc的己烷溶液)纯化,得到360mg的3,5-二甲基-3-(2-甲基-丙烷-2(S)-亚磺酰氨基)-庚酸甲酯。
3(S)-氨基-3,5-二甲基-庚酸将3,5-二甲基-3-(2-甲基-丙烷-2(S)-亚磺酰氨基)-庚酸甲酯(360mg,1.2mmol)溶解在6NHCl(2mL)和二噁烷(2mL)中,并在100℃加热6小时。将混合液冷却到室温,用水稀释,并用EtOAc(15mL)萃取。使用离子交换层析法纯化有机物,得到3(S)-氨基-3,5-二甲基-庚酸(270mg),然后再使用硅胶层析法(70∶25∶5℃H2Cl2/MeOH/NH4OH)再次纯化,得到203mg白色固体3(S)-氨基-3,5-二甲基-庚酸。m/z 174(C9H19NO2+H)。
实施例16. 3(S)-氨基-3,5-二甲基-壬酸
使用类似于3(S)-氨基-3,5-二甲基-庚酸的制备过程制备3(S)-氨基-3,5-二甲基-壬酸。m/z.202.1(C11H23NO2+H)。
药物组合物实施例
根据本发明,在下面的实施例中,术语“活性化合物”或“活性成分”是指α-2-δ配体与PDEV抑制剂和/或其药学可接受的盐或溶剂合物的合适的组合或单独组分。
i)
片剂组合物
下述组合物A和B可用聚乙烯吡咯酮溶液中的成分(a)到(c)和(a)到(d)的湿法制粒,接着加入硬脂酸镁并压片制备而成。
组合物A
mg/片 mg/片
(a)活性成分 250 250
(b)乳糖B.P. 210 26
(c)淀粉羟乙酸钠 20 12
(d)聚乙烯吡咯烷酮B.P. 15 9
(e)硬脂酸镁
5
3
500 300
组合物B
mg/片 mg/片
(a)活性成分 250 250
(b)乳糖 150 150
(c)Avicel PH 101 60 26
(d)淀粉羟乙酸钠 20 12
(e)聚乙烯吡咯烷酮B.P. 15 9
(f)硬脂酸镁
5
3
500 300
组合物℃
mg/片
活性成分 100
乳糖 200
淀粉 50
聚乙烯吡咯烷酮 5
硬脂酸镁
4
359
下述组合物D和E可以通过用混合成分的直接压片制备。制剂E中应用的乳糖是直接压片类型。
组合物D
mg/片
活性成分 250
硬脂酸镁 4
预胶凝化淀粉NF15
146
400
组合物E
mg/片
活性成分 250
硬脂酸镁 5
乳糖 145
微晶纤维素
100
500
组合物F(控释组合物)
mg/片
(a)活性成分 500
(b)羟丙基甲基纤维素 112
(Methocel K4M Premium)
(c)乳糖B.P. 53
(d)聚乙烯吡咯烷酮B.P.℃ 28
(e)硬脂酸镁
7
700
该组合物可用聚乙烯吡咯酮溶液中的成分(a)到(c)的湿法制粒,接着加入硬脂酸镁并压片制备而成。
组合物G(肠衣片)
组合物℃的肠衣片可以通过使用25mg/片的肠溶聚合物包衣片剂制备,其中的肠溶聚合物如纤维素邻苯二甲酸乙酯、邻苯二甲酸聚乙烯乙酸酯、羟丙基甲基纤维素邻苯二甲酸酯或甲基丙烯酸和甲基丙烯酸甲酯阴离子聚合物(Eudragit L)。除了Eudragit L,这些聚合物还应该含有10%(按使用的聚合物的重量计)的增塑剂,以防止在片剂使用或储存期间膜破裂。适合的塑化剂包括邻苯二甲酸二乙酯、柠檬酸三丁酯和甘油三乙酸酯。
组合物H(肠衣控释片)
组合物F的肠衣片可以通过使用50mg/片的一种肠溶聚合物包裹衣片剂制备,其中的肠溶解聚合物如纤维素邻苯二甲酸乙酯、邻苯二甲酸聚乙烯乙酸酯、羟丙基甲基纤维素邻苯二甲酸酯或甲基丙烯酸和丙烯酸甲酯阴离子聚合物(Eudragit L)。除了Eudragit L,这些聚合物还应该含有10%(按使用的聚合物的重量计)的增塑剂,以防止在片剂使用或储存期间膜破裂。适合的塑化剂包括邻苯二甲酸二乙基酯、柠檬酸三丁酯和甘油三乙酸酯。
(ii)胶囊组合物
组合物A胶囊可以通过混合上述组合物D的成分并将所得混合物填入分成两部分的硬明胶胶囊中制备。组合物B(
以下)可用类似的方法制备。
组合物B
mg/胶囊
(a)活性成分 250
(b)乳糖B.P. 143
(c)淀粉羟乙酸钠 25
(d)硬脂酸镁
2
420
组合物℃
mg/胶囊
(a)活性成分 250
(b)聚乙二醇4000 BP
350
600
可通过熔化Macrogol 4000 BP,将活性成分分散在熔化物中并随即装入两节的硬明胶胶囊中制备。
组合物D
mg/胶囊
活性成分 250
卵磷脂 100
花生油
100
450
可通过将活性成分分散在卵磷脂和花生油中,并将分散体填装入软的、有弹性的胶囊中而制备。
组合物E(控释胶囊)
mg/胶囊
(a)活性成分 250
(b)微晶纤维素 125
(c)乳糖BP 125
(d)乙基纤维素
13
513
控释胶囊制剂可通过使用积压机挤压(a)到(c)的混合成分,然后球化和干燥挤出物而制备。用控释膜(d)包衣干燥的颗粒并装入两节的硬明胶胶囊。
组合物F(肠胶囊)
mg/胶囊
(a)活性成分 250
(b)微晶纤维素 125
(c)乳糖BP 125
(d)纤维素邻苯二甲酸乙酯 50
(e)邻苯二甲酸二乙酯
5
555
肠胶囊组合物可通过使用积压机挤压(a)到(c)的混合成分制备,然后球化和干燥挤出物。用含有塑化剂(e)的控释膜(d)包衣干燥的颗粒并装入两节的硬明胶胶囊。
组合物G(肠衣控释胶囊)
组合物E的肠胶囊可以通过使用50mg/胶囊的肠溶聚合物包衣控释小球制成的,其中的肠溶聚合物如纤维素邻苯二甲酸乙酯、邻苯二甲酸聚乙烯乙酸酯、羟丙基甲基纤维素邻苯二甲酸酯或甲基丙烯酸和丙烯酸甲酯阴离子聚合物(Eudragit L)。除了Eudragit L,这些聚合物还应该含有10%(按使用的聚合物的重量计)的增塑剂,以防止在片剂使用或储存期间膜破裂。适合的塑化剂包括邻苯二甲酸二乙基酯、柠檬酸三丁酯和甘油三乙酸酯。
(iii)静脉注射组合物
活性成分 0.200g
无菌、无热原磷酸缓冲液(pH9.0)至 10ml
在35-40℃将活性成分大部分溶解的磷酸缓冲液中,调至体积,后使用一个无菌微孔过滤器过滤到10ml的无菌玻璃小瓶(1号)中,用无菌盖子和封条密封。
(iv)肌肉注射组合物
活性成分 0.20g
苯甲醇 0.10g
糖原质75 1.45g
注射用水 适量至 3.00ml
将活性成分溶入甘油中。然后加入苯甲醇并溶解,水加至3ml水。然后用无菌微孔过滤器过滤混合液,密封在3ml的无菌玻璃瓶中(1号)。
(v)糖浆组合物
活性成分 0.25g
山梨醇溶液 1.50g
甘油 1.00g
安息香酸钠 0.005g
香料 0.0125ml
纯净水 适量至 5.0ml
将安息香酸钠部分溶入在纯净水中,加入山梨醇溶液。然后加入活性成分并溶解。将所得溶液与甘油混合,然后使用纯化水纯净水调至所需体积。
(vi)栓剂组合物
mg/栓剂
活性成分 250
Hare Fat,BP(Witepsol H15-Dynamit NoBel) 1770
2020
以最高45℃的温度,在蒸汽夹套锅中熔化五分之一的WitepsolH15。活性成分过2001m筛,并加到熔化的基质中,并使用装配有切割头的Silverson搅拌器混合,直到获得稳定的分散。保持混合液45℃,将剩余的Witepsol H15加入到混悬液中,搅拌至均匀混合液。将全部的混悬液过2501m不锈钢筛,持续搅拌,冷却至40℃。在38-40℃温度下,将2.02g的化合物加入到合适塑胶模具中,冷却至室温。
(vii)阴道栓剂组合物
mg/阴道栓剂
活性成分(631m) 250
无水葡萄糖 380
马铃薯淀粉 363
硬脂酸镁
7
1000
将上面的成分直接混合并将所得混合物压制成阴道栓剂。
(viii)透皮贴剂组合物
活性成分 200mg
醇USP 0.1ml
羟乙基纤维素
活性成分和醇USP与羟乙基纤维素胶凝,并装入表面积为10℃m2的透皮装置中。
Claims (16)
1.一种组合,包含协同比率的α-2-δ配体和PDEV抑制剂,或其任一药学可接受的盐或溶剂合物。
2.根据权利要求1的组合,其中α-2-δ配体选自加巴喷丁、普加巴林、[(1R,5R,6S)-6-(氨甲基)二环[3.2.0]庚-6-基]乙酸、3-(1-氨甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-酮和C-[1-(1H-四唑-5-基甲基)-环庚基]-甲胺、(3S,4S)-(1-氨甲基-3,4-二甲基-环戊基)-乙酸、(1α,3α,5α)(3-氨基-甲基-二环[3.2.0]庚-3-基)-乙酸、(3S,5R)-3-氨甲基-5-甲基-辛酸、(3S,5R)-3-氨基-5-甲基-庚酸、(3S,5R)-3-氨基-5-甲基-壬酸和(3S,5R)-3-氨基-5-甲基-辛酸,或其药学可接受的盐或溶剂合物。
3.根据权利要求1或2的组合,其中α-2-δ配体是加巴喷丁,或其药学可接受的盐或溶剂合物。
4.根据权利要求1或2的组合,其中α-2-δ配体是普加巴林,或其药学可接受的盐或溶剂合物。
5.根据权利要求1-4中任一项的组合,其中PDEV抑制剂选自:
5-[2-乙氧基-5-(4-甲基-1-哌嗪磺酰基)苯基]-1-甲基-3-正-丙基-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮(西地那非);
(6R,12aR)-2,3,6,7,12,12a-六氢-2-甲基-6-(3,4-亚甲基二氧苯基)-吡嗪并[2′,1′:6,1]吡啶并[3,4-b]吲哚-1,4-二酮(泰地那非,IC-351);
2-[2-乙氧基-5-(4-乙基-哌嗪-1-基-1-磺酰基)-苯基]-5-甲基-7-丙基-3H-咪唑并[5,1-f][1,2,4]三嗪-4-酮(伐地那非);
5-[2-乙氧基-5-(4-乙基哌嗪-1-基磺酰基)吡啶-3-基]-3-乙基-2-[2-甲氧基乙基]-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
5-(5-乙酰基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-氮杂环丁基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;和
1-{6-乙氧基-5-[3-乙基-6,7-二氢-2-(2-甲氧基乙基)-7-氧代-2H-吡唑并[4,3-d]嘧啶-5-基]-3-吡啶磺酰基}-4-乙基哌嗪;或其药学可接受的盐或溶剂合物。
6.根据权利要求1-5中任一项的组合,其中PDEV抑制剂是西地那非,或其药学可接受的盐或溶剂合物。
7.根据权利要求1-5中任一项的组合,其中PDEV抑制剂是伐地那非,或其药学可接受的盐或溶剂合物。
8.根据权利要求1-5中任一项的组合,其中PDEV抑制剂是泰地那非,或其药学可接受的盐或溶剂合物。
9.用于治疗、预防或缓解性治疗疼痛的权利要求1-8中的组合。
10.根据权利要求9的组合,其中疼痛是神经性疼痛。
11.一种组合,包含α-2-δ配体和PDEV抑制剂,所述α-2-δ配体不包括加巴喷丁、普加巴林和PCT/IB02/01146中的式(i)-(xxv)化合物。
12.权利要求1-8中任一项的组合在制备治疗、预防或缓解性治疗疼痛的药物中的应用。
13.根据权利要12的应用,其中疼痛是神经性疼痛。
14.药物组合物,包含治疗有效量的权利要求1-8中任一项要求的组合和合适的赋形剂或载体。
15.用于人类施用的协同组合,包含以相应于在大鼠CCI诱导的静态异常性疼痛模型中以重量计从1∶1到10∶1份的协同组合范围的w/w组合范围的α-2-δ配体和PDEV抑制剂,或其药学可接受的盐或溶剂合物。
16.用于人类施用的协同组合,包含根据权利要求1-8中任一项的α-2-δ配体和PDEV抑制剂,或其药学可接受的盐或溶剂合物,其中α-2-δ配体和PDEV抑制剂的剂量范围分别为相应于在大鼠CCI诱导的静态异常性疼痛模型中1-10mg/kg和0.1-1mg/kg的协同剂量范围。
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Publication number | Priority date | Publication date | Assignee | Title |
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CN114195661A (zh) * | 2021-12-21 | 2022-03-18 | 苏州楚凯药业有限公司 | 一种苯磺酸米洛巴林的制备方法 |
CN114195661B (zh) * | 2021-12-21 | 2023-12-22 | 苏州楚凯药业有限公司 | 一种苯磺酸米洛巴林的制备方法 |
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