CN101506210A - 2-苯氧基嘧啶酮类似物 - Google Patents
2-苯氧基嘧啶酮类似物 Download PDFInfo
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- CN101506210A CN101506210A CNA2007800309530A CN200780030953A CN101506210A CN 101506210 A CN101506210 A CN 101506210A CN A2007800309530 A CNA2007800309530 A CN A2007800309530A CN 200780030953 A CN200780030953 A CN 200780030953A CN 101506210 A CN101506210 A CN 101506210A
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- fluorophenyl
- salt
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Abstract
本发明提供一种如右式之2-苯氧基嘧啶酮类似物。其中,代号如本文中说明。这些化合物为可用于活体外或活体内调节特定受体活性之配位体,且特别适用于治疗人类、家庭宠物与家畜动物中与病理性受体活化作用有关之病症。亦提供使用这些化合物治疗这些病症之药物组合物与方法,及使用这些配位体进行受体定位试验之方法。
Description
相关申请案之交叉文献
本申请案主张美国临时申请案60/823,258(2006年8月23日申请)之优先权,其揭示内容已以引用方式并入本文中。
技术领域
本发明一般而言系有关具有有利药物性质之2-苯氧基嘧啶酮类似物。本发明进一步有关此等化合物于治疗与辣椒素受体活化作用有关之病症上、于检测与辣椒素受体结合之其它试剂上及作为检测与定位辣椒素受体之探针上之用途。
背景技术
疼痛知觉,或伤害感觉,系受一群称为「伤害感受器」之特殊感觉神经元之周边末端调节。有多种物理与化学刺激会诱发哺乳动物之此等神经元活化,使得可辨识可能之有害刺激。然而,当伤害感受器之活化作用不当或过度时,可能造成耗弱之急性或慢性疼痛。
神经性疼痛涉及在没有刺激时之疼痛信号传递,典型地系由神经系统受损所致。大多数情况下,认为此等疼痛系因周边系统受到初次伤害后造成周边与中枢神经系统敏化所致(例如:经由直接伤害或全身性疾病)。神经性疼痛典型为灼热、抽痛且其强度不缓和,有时候可能使诱发该疼痛之初次伤害或疾病过程更恶化。
目前对神经性疼痛之处理法大多无效。鸦片(如:吗啡)为强力之止痛剂,但其适用性常受限于其不良副作用,如:肉体上瘾与戒断性质,及呼吸困难、情绪变化与并发便秘之肠蠕动下降、恶心、呕吐及内分泌与自主神经系统改变。此外,神经性疼痛经常对一般类鸦片止痛剂疗法没有反应或仅有部份反应。使用N-甲基-D-天冬胺酸拮抗剂克他命(ketamine)或α(2)-肾上腺素激导性激动剂氯压定(clonidine)可减轻急性或慢性疼痛,并可减少类鸦片剂的用量,但经常因副作用而无法耐受此等制剂。
过去曾使用辣椒素局部治疗慢性与急性疼痛,包括神经性疼痛。辣椒素为一种衍生自茄科(Solanaceae)植物(包括辣椒)之辛辣物质,似乎选择性地作用在咸信可传达疼痛之小直径传入神经纤维(A-δ与C纤维)。对辣椒素之反应特征为在周边组织中持续活化伤害感受器,最后使得周边伤害感受器对一种或多种刺激为去敏化。由动物试验可见,辣椒素似乎藉由打开钙与钠之阳离子选择性信道而激活C纤维膜之去极化。
同样具有类香草醇部份之辣椒素结构类似物亦会引发类似反应。其中一种类似物为树脂毒素(resiniferatoxin)(RTX),系大戟科(Euphorbia)植物之天然产物。类香草醇受体(VR)一词系创造用于说明辣椒素与此等相关的刺激性化合物之神经元膜辨识位置。辣椒素反应受到另一种辣椒素类似物(辣椒素氮呼(capsazepine))之竞争性抑制(进而拮抗),亦受非选择性阳离子信道阻断剂钌红抑制。钌红与VR结合不超过中等亲和性(典型Ki值不超过140μM)。
已有人自大鼠与人类之背根神经节细胞克隆出类香草醇受体。所判别出之第一种类香草醇受体称为第1型类香草醇受体(VR1),在本文中术语「VR1」与「辣椒素受体」可交换使用,系指此型之大鼠与/或人类,及哺乳动物之同系物之受体。VR1于疼痛感受中之角色已采用缺乏此受体之小鼠确认,此种小鼠不会被类香草醇诱发疼痛行为,且对热与发炎之反应已受损。VR1为一种非选择性阳离子信道,当受到高温、低pH与辣椒素受体激动剂时,其开放阀值即下降。打开此辣椒素受体信道后,通常即自表达该受体之神经元与其它附近神经元中释出发炎性肽,提高疼痛反应。受到辣椒素初次活化作用后,辣椒素受体即经由cAMP依赖蛋白质激酶之磷酸化反应,迅速去敏化反应。
由于其有能力在周边组织中去敏化伤害感受器,因此VR1激动剂类香草醇化合物已用为局部麻醉剂。然而,给予激动剂本身可能造成灼热疼痛,而限制其医疗用途。近来已有报告指出,VR1拮抗剂(包括某些非类香草醇化合物)亦适用于治疗疼痛(参见例如:PCT国际申请专利公开案号WO 02/08221、WO 03/062209、WO 04/054582、WO 04/055003、WO 04/055004、WO 04/056774、WO 05/007646、WO 05/007648、WO 05/007652、WO 05/009977、WO 05/009980、WO05/009982、WO 05/049601、WO 05/049613、WO 06/122200与WO06/120481)。
因此,需要会与VR1交互作用,但不会诱发VR1激动剂类香草醇化合物之初期疼痛感受的化合物来治疗慢性与急性疼痛(包括神经性疼痛)及其它特别对辣椒素受体调节作用有反应之病症。本发明可符合此需求,并提供进一步相关优点。
发明内容
本发明提出如式A之2-苯氧基嘧啶酮类似物:
及此等化合物之药学上可接受的盐类、溶剂合物(例如:水合物)与酯类。
式A中:
代表环中包含1、2或3个杂原子的稠合5或6元杂芳基,该杂原子独立选自:O、N与S,其余环原子为碳,其中,该稠合的杂芳基可视需要经取代;较佳为该稠合的杂芳基经0至3个或0至2个独立选自下列的取代基取代:氨基、羟基、C1-C6烷基、C1-C6羟基烷基、(C3-C7环烷基)C0-C2烷基、C1-C6卤烷基、C1-C6烷氧基、C2-C6烷基醚、C1-C6烷酰氧基、C1-C6烷基磺酰基氨基、C1-C6烷酰基氨基与单或二(C1-C6烷基)氨基;
Ar为苯基或5或6元杂芳基,其分别可视需要经取代,且其分别较佳为经0至4个或0至3个独立选自下列的取代基取代:卤素、氰基、氨基、硝基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤烷基、C1-C6羟基烷基、C1-C6烷氧基、C1-C6卤烷氧基、(C3-C7环烷基)C0-C4烷基与单或二(C1-C6烷基)氨基;与
R3代表0至4个或0至3个取代基,该等取代基较佳为独立选自:卤素、羟基、氰基、氨基、硝基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤烷基、C1-C6羟基烷基、C1-C6烷氧基、C1-C6卤烷氧基、(C3-C7环烷基)C0-C4烷基、单或二(C1-C6烷基)氨基与单或二(C1-C6烷基)氨基磺酰基。
本发明进一步提出如式I之2-苯氧基嘧啶酮类似物:
及此等化合物之药学上可接受的盐类、溶剂合物(例如:水合物)与酯类。
式I中:
X为N或CH,其可视需要经R1所代表的取代基取代;与
R1代表0至3个取代基;该等取代基较佳为独立选自:卤素、氰基、氨基、硝基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤烷基、C1-C6羟基烷基、C1-C6烷氧基、C1-C6卤烷氧基、(C3-C7环烷基)C0-C4烷基与单或二(C1-C6烷基)氨基。
某些态样中,式A与式I的化合物为VR1调节剂,其于辣椒素受体结合性分析法中之Ki不超过1微摩尔、500毫微摩尔、100毫微摩尔、50毫微摩尔、10毫微摩尔或1毫微摩尔,及/或其在测定辣椒素受体之激动剂或拮抗剂活性的活体外分析法中之EC50或IC50值不超过1微摩尔、500毫微摩尔、100毫微摩尔、50毫微摩尔、10毫微摩尔或1毫微摩尔。某些具体实施例中,此等VR1调节剂为VR1拮抗剂,且在辣椒素受体活化作用的活体外分析法(例如:本文实例6提供之分析法)中,于等于IC50、10倍IC50或100倍IC50下没有可检测到之激动剂活性。
某些态样中,本文所提供的化合物系标记可检测之标记物(例如:经放射性标记或经萤光素共轭标记)。
本发明进一步在其它态样中提供药物组合物,其包含至少一种2-苯氧基嘧啶酮类似物与生理上可接受的载体或赋形剂组合。
其它态样中,提供降低细胞辣椒素受体的钙传导性之方法,其包括将表达辣椒素受体的细胞(例如:神经元,如:中枢神经系统或周边神经节细胞、膀胱上皮或肺部的细胞)与至少一种本文所说明之VR1调节剂接触。此等接触可于活体内或活体外进行,且通常使用足以于活体外改变类香草醇配位体与VR1之结合性(采用实例5提供之分析法)及/或VR1-媒介之讯息传导(采用实例6提供之分析法)之VR1调节剂浓度进行。
进一步提供抑制类香草醇配位体与辣椒素受体结合之方法。某些具体实施例中,抑制作用系于活体外进行。此等方法包括将辣椒素受体与本文所说明之至少一种VR1调节剂,于足以抑制类香草醇配位体与辣椒素受体结合且此抑制为可检测的用量或浓度下接触。其它具体实施例中,辣椒素受体系在患者体内。此等方法包括使患者体内表达辣椒素受体的细胞与至少一种本文所说明之VR1调节剂,于足以于活体外可检测到其抑制类香草醇配位体与表达克隆辣椒素受体的细胞结合的用量或浓度下接触。
本发明尚提供治疗患者体内对辣椒素受体调节作用有反应之病症之方法,其包括对患者给予治疗有效量之至少一种本文所说明之VR1调节剂。
其它态样中,提供为患者治疗疼痛之方法,其包括对遭受(或有这样危险)疼痛之患者给予治疗有效量之至少一种本文所说明之VR1调节剂。
尚提出治疗患者之瘙痒、尿失禁、膀胱过动症、停经症状、咳嗽与/或打嗝之方法,其包括对遭受(或有这样危险)上述一种或多种病症之患者给予治疗有效量之至少一种本文所说明之VR1调节剂。
其它态样中,尚提出治疗患者的停经症状之方法,其包括对遭受(或有这样危险)此等症状之患者给予治疗有效量之至少一种本文所说明之VR1调节剂。
本发明进一步提供促进肥胖患者减轻体重之方法,其包括对肥胖患者给予治疗有效量之至少一种本文所说明之VR1调节剂。
本发明进一步提供判别与辣椒素受体结合之试验制剂之方法,其包括:(a)将辣椒素受体与本文所说明有标记的化合物,于可使该化合物与辣椒素受体结合之条件下接触,藉以产生已结合之有标记的化合物;(b)于没有试验制剂之存在下,检测相当于已结合之有标记化合物含量之信号;(c)已结合之有标记化合物与试验制剂接触;(d)于试验制剂之存在下,检测相当于已结合之有标记化合物含量之信号;及(e)与(b)步骤检测到之信号比较,检测(d)步骤信号之下降程度。
其它态样中,本发明提供决定样本中是否含有辣椒素受体之方法,其包括:(a)样本与本文所说明化合物,于可使该化合物与辣椒素受体结合之条件下接触;与(b)检测用以指示化合物与辣椒素受体结合程度之信号。
本发明亦提供包装之药物制剂,其包括:(a)于容器中之本文所说明之药物组合物;与(b)使用该组成物治疗对辣椒素受体调节作用有反应之一种或多种病状之说明书,如:疼痛、瘙痒、尿失禁、膀胱过动症、停经症状、咳嗽、打嗝与/或肥胖。
另一态样中,本发明提供制备本文所揭示化合物(包括中间物)之方法。
本发明此等与其它态样将可参考下列详细说明而了解。
具体实施方式
如上述,本发明提出2-苯氧基嘧啶酮类似物。此等化合物可用于活体外或活体内,多方面调节辣椒素受体活性。
术语说明
本文中通常采用标准命名法说明化合物。咸了解,具有不对称中心的化合物(除非另有说明,否则)包括所有光学异构物与其混合物。此外,具有碳-碳双键的化合物可能出现Z与E型,化合物之所有异构型均包括在本发明中,除非另有说明。若化合物呈多种互变异构型时,所示的化合物并不限于任一种特定互变异构物,而意指包括所有互变异构型。本文中某些化合物系以包括代号之通式说明(例如:R1、A)。除非另有说明,否则此等化学式中各代号之定义独立于任何其它代号,化学式中任何出现一次以上之代号每次出现时之定义亦分别独立。
本文所采用术语「2-苯氧基嘧啶酮类似物」包括所有式A化合物,包括彼等式I化合物,及本文所提出其它化学式的化合物(包括任何对映异构物、消旋物与立体异构物),及此等化合物之药学上可接受的盐类、溶剂合物与酯类。
本文所采用「药学上可接受的盐」为适用于与人类或动物之组织接触,不会引起过度毒性与致癌性,且最好没有刺激性、过敏反应或其它问题或并发症之酸或碱盐类。此等盐类包括如:胺之碱性残基之无机与有机酸盐类,及如:羧酸之酸性残基之碱金属或有机盐类。用于形成盐之特定药学上可接受的阴离子包括但不限于:乙酸根、2-乙酰氧基苯甲酸根、抗坏血酸根、苯甲酸根、碳酸氢根、溴化物、乙二胺四乙酸钙、碳酸根、氯化物、柠檬酸根、二氢氯、二磷酸根、二酒石酸根、乙二胺四乙酸根、丙酯月桂基硫酸根(estolate)(乙基琥珀酸根)、甲酸根、富马酸根、葡庚酸根、葡糖酸根(gluceptate)、麸胺酸根、乙醇酸根、乙醇酰基胺苯胂酸根、己基间苯二酸根(hexylresorcinate)、哈巴胺盐(hydrabanine)、氢溴酸盐、氢氯酸根、氢碘酸根、羟基马来酸根、羟基萘酸根、碘化物、羟乙磺酸根、乳酸根、乳糖醛酸根、苹果酸根、马来酸根、扁桃酸根、甲基溴化物、甲基硝酸根、甲基硫酸根、黏酸根(mucate)、萘磺酸根、硝酸根、双羟萘酸根、泛酸根、苯基乙酸根、磷酸根、聚半乳糖醛酸根、丙酸根、水杨酸根、硬脂酸根、次醋酸根、琥珀酸根、胺磺酸根、磺胺酸根、硫酸根、磺酸根包括苯磺酸根、樟脑磺酸根、乙二磺酸根(乙烷-1,2-二磺酸根)、乙磺酸根、2-羟基乙磺酸根、甲磺酸根、三氟甲磺酸根与对甲苯磺酸根、单宁酸根、酒石酸根、氯茶碱根与三乙基碘化物(triethiodide)。同样地,用于形成盐之药学上可接受的阳离子包括但不限于:铵、双芐基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、甲基葡糖胺、普鲁卡因与金属如:铝、钙、锂、镁、钾、钠与锌。习此相关技艺之人士咸了解其它可用于本发明所提供化合物之药学上可接受的盐类。一般而言,药学上可接受的酸或碱盐可由包含碱性或酸性部份之母化合物经由任何习知化学方法合成。简言之,此等盐类之制法可由此等化合物之游离酸或碱型与化学计量之适当碱或酸,于水或有机溶剂中,或于此二者之混合物中反应;通常使用非水性介质,如:醚、乙酸乙酯、乙醇、甲醇、异丙醇或乙腈较佳。
咸了解,本文所提供化合物可以(但不一定要)调配成溶剂合物(例如:水合物)或非共价复合物。此外,多种结晶型与多形体均在本发明范围内。本文亦提供所示化学式的化合物之前药。「前药」为一种不一定完全符合本文所提供化合物结构式要求的化合物,但可在给予患者后,于活体内经修饰产生本文所示化学式的化合物。例如:前药可为本文所提供化合物之醯化衍生物。前药包括其中,羟基、胺或氢硫基键结在任何基团上的化合物,当给予哺乳动物个体后,会分别裂解形成游离羟基、氨基或氢硫基。前药实例包括但不限于:本文所提供化合物中醇与胺官能基之乙酸酯、甲酸酯与苯甲酸酯衍生物。本文所提供化合物之前药制法可修饰化合物中之官能基,使之可于活体内裂解形成母化合物。
本文所采用术语「烷基」指直链或分支链之饱和脂系烃。烷基包括具有1至8个碳原子(C1-C8烷基)、1至6个碳原子(C1-C6烷基)与1至4个碳原子(C1-C4烷基)之基团,如:甲基、乙基、丙基、异丙基、正丁基、第二丁基、第三丁基、戊基、2-戊基、异戊基、新戊基、己基、2-己基、3-己基与3-甲基戊基。「C0-Cn烷基」指单一共价键(C0)或具有1至n个碳原子之烷基;例如:「C0-C4烷基」指单一共价键或C1-C4烷基。某些实施例中,烷基之取代基有明确说明。例如:「羟基烷基」指具有至少一个羟基取代基之烷基。
「伸烷基」系指如上述定义之二价烷基。C1-C2伸烷基为亚甲基或伸乙基;C0-C4伸烷基为单一共价键或具有1、2、3或4个碳原子之伸烷基;C0-C2伸烷基为单一共价键或具有1或2个碳原子之伸烷基。
「烯基」指直链或分支链烯基,其中含有至少一个不饱和碳-碳双键。烯基包括C2-C8烯基、C2-C6烯基与C2-C4烯基,其分别含有2至8个、2至6个或2至4个碳原子,如:乙烯基、烯丙基或异丙烯基。「炔基」指直链或分支链炔基,其包含一个或多个不饱和碳-碳键,其中至少一个为三键。炔基包括C2-C8炔基、C2-C6炔基与C2-C4炔基,其分别含有2至8个、2至6个或2至4个碳原子。
「环烷基」为包含一个或多个饱和及/或部份饱和环之基团,其中所有环成员均为碳,如:环丙基、环丁基、环戊基、环己基、环庚基、环辛基、金刚烷基及如上述基团之部份饱和变体,如:环己烯基。环烷基不包含芳香环或杂环。某些环烷基为C3-C7环烷基,其中环烷基包含一个具有3至7个均为碳之环成员之单环。「(C3-C8环烷基)C0-C4烷基」为利用单一共价键或C1-C4伸烷基链接之C3-C8环烷基。
本文所采用「烷氧基」系指利用氧桥连基附接之如上述烷基。烷氧基包括分别具有1至6个或1至4个碳原子之C1-C6烷氧基与C1-C4烷氧基。代表性烷氧基为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、第二丁氧基、第三丁氧基、正戊氧基、2-戊氧基、3-戊氧基、异戊氧基、新戊氧基、己氧基、2-己氧基、3-己氧基与3-甲基戊氧基。
同样地,「烷基硫」指利用硫桥连基附接之如上述烷基。
「烷基醚」系指直链或分支醚取代基(亦即经烷氧基取代之烷基)。烷基醚包括C2-C8烷基醚、C2-C6烷基醚与C2-C4烷基醚,其分别具有2至8、6或4个碳原子。C2烷基醚之结构式为-CH2-O-CH3。
术语「烷酰基」指其中碳原子呈直链或分支链配置且利用酮基之碳附接之酰基(例如:-(C=O)-烷基)。烷酰基具有指定碳原子数,酮基之碳亦包括在碳原子数内。例如:C2烷酰基为如式-(C=O)CH3之乙酰基;「C1烷酰基」指-(C=O)H。「C1-C6烷酰基」包含1至6个碳原子。
本文所采用术语「烷酰氧基」指利用氧附接之烷酰基(亦即通式结构为-0-C(=O)-烷基之基团)。烷酰氧基包括例如:C1-C6烷酰氧基,其具有1至6个碳原子。
本文所采用术语「烷酰基氨基」系指利用氨基连结基附接之烷酰基(亦即通式结构为-N(R)-C(=O)-烷基之基团,其中R为氢或C1-C6烷基)。烷酰基氨基包括例如:C1-C6烷酰基氨基,其「烷基」部份具有1至6个碳原子(亦即酮桥之碳不包括在指定碳原子数内)。
「烷基磺酰基」系指如式-(SO2)-烷基之基团,其中硫原子为附接点。烷基磺酰基包括分别具有1至6个或1至4个碳原子之C1-C6烷基磺酰基与C1-C4烷基磺酰基。烷基磺酰基之代表性基团之一为甲基磺酰基。
「烷基磺酰基氨基」系指利用氨基连结基附接之烷基磺酰基(亦即通式结构为-N(R)-(SO2)-烷基之基团,其中R为氢或C1-C6烷基)。烷基磺酰基氨基包括例如:具有1至6个碳原子之C1-C6烷基磺酰基氨基。
「氨基磺酰基」系指如式-(SO2)-NH2之基团,其中以硫原子为附接点。术语「单或二(C1-C6烷基)氨基磺酰基」系指如式-(SO2)-NR2之基团,其中以硫原子为附接点,且其中一个R为C1-C6烷基,另一个R为氢或独立选出之C1-C6烷基。
「烷基氨基」系指通式结构为-NH-烷基或-N(烷基)(烷基)之二级或三级胺,其中,各烷基分别独立选自:烷基、环烷基与(环烷基)烷基。此等基团包括例如:单与二(C1-C6烷基)氨基,其中各C1-C6烷基可相同或相异。
「烷基氨基烷基」系指利用伸烷基连结之烷基氨基(亦即通式结构为-伸烷基-NH-烷基或-伸烷基-N(烷基)(烷基)之基团),其中各烷基分别独立选自:烷基、环烷基与(环烷基)烷基。烷基氨基烷基包括例如:单与二(C1-C8烷基)氨基C1-C8烷基、单与二(C1-C6烷基)氨基C1-C6烷基与单与二(C1-C6烷基)氨基C1-C4烷基。「单或二(C1-C6烷基)氨基C0-C6烷基」系指利用单一共价键或C1-C6伸烷基连结之单或二(C1-C6烷基)氨基。代表性烷基氨基烷基如下:
咸了解,术语「烷基氨基」与「烷基氨基烷基」中所采用「烷基」之定义不同于所有其它含烷基(包括环烷基与(环烷基)烷基)(例如:(C3-C7环烷基)C0-C4烷基)中所采用「烷基」之定义。
术语「氨基羰基」系指醯氨基(亦即-(C=O)NH2)。术语「单或二(C1-C6烷基)氨基羰基」系指如式-(C=O)-N(R)2之基团,其中羰基为附接点,其中一个R为C1-C6烷基,另一个R为氢或独立选出之C1-C6烷基。
术语「卤素」系指氟、氯、溴或碘。
「卤烷基」为经一个或多个独立选出之卤素取代之烷基(例如:具有1至6个碳原子之「C1-C6卤烷基」)。卤烷基实例包括(但不限于):单、二或三氟甲基;单、二或三氯甲基;单、二、三、四或五氟乙基;单、二、三、四或五氯乙基;与1,2,2,2-四氟-1-三氟甲基-乙基。典型卤烷基为三氟甲基与二氟甲基。术语「卤烷氧基」系指利用氧桥连结之如上述定义之卤烷基。
不位于两个字母或代号之间之短折线(「-」)系用于表示取代基之附接点。例如:-CONH2系利用碳原子附接。
「杂芳基」为其中至少一个芳香环包含至少一个选自N、O与S中之杂原子之芳香基。杂芳基包括例如:5与6元杂芳基,如:咪唑、呋喃、呋咱、异噻唑、异唑、二唑、唑、吡、吡唑、嗒、吡啶、嘧啶、四唑、噻唑与噻吩。
本文所采用「取代基」指共价键结至兴趣分子中原子之分子部份。例如环取代基可为如:卤素、烷基、卤烷基或其它基团与作为环成员之原子(较佳为碳或氮原子)共价键结之部份。芳香基之取代基通常与环碳原子共价键结。术语「取代」指使用取代基置换分子结构中氢原子,但不可超过所指定原子上之价数,并可由此取代得到化学上安定的化合物(亦即化合物可经单离、特征化及测试其生物活性)。
「视需要经取代」之基团为未经取代或经氢以外之一个或多个合适基团(其可相同或相异)取代在一个或多个可利用之位置,典型为1、2、3、4或5个位置。视需要之取代法亦以「经0至X个取代基取代」之语法表示,其中,X为可使用之取代基最高数目。某些视需要经取代之基团经0至2、3或4个分别独立选出之取代基取代(亦即未经取代或经至多达所示之最高取代基数目取代)。其它视需要经取代之基团经至少一个取代基取代(例如:经1至2、3或4个独立选出之取代基取代)。
术语「VR1」与「辣椒素受体」在本文中交换使用,系指第1型类香草醇受体。除非另有说明,否则此等术语包括大鼠与人类VR1受体(例如:GenBank Accession Numbers AF327067、AJ277028与NM_018727;某些人类VR1cDNA序列及所编码氨基酸序列示于美国专利案案号6,482,611),及在其它物种中发现之其同系物。
「VR1调节剂」亦在本文中称为「调节剂」,为调节VR1活化作用与/或VR1媒介之讯息传导的化合物。本文所明确提供之VR1调节剂为式A化合物及其药学上可接受的盐类、水合物与酯类。某些较佳VR1调节剂不是类香草醇。VR1调节剂可为VR1激动剂或拮抗剂。某些调节剂与VR1结合之Ki低于1微摩尔,较佳为低于500毫微摩尔,100毫微摩尔,10毫微摩尔或1毫微摩尔。测定对VR1之Ki之代表性分析法示于本文中实例5。
若调节剂可检测到其抑制类香草醇配位体与VR1之结合性与/或VR1-媒介之讯息传导时(采用例如:实例6所示之代表性分析法),则视该调节剂为「拮抗剂」;通常此等拮抗剂在实例6所提供之分析法中抑制VR1活化作用之IC50值小于1微摩尔,较佳为小于500毫微摩尔,更佳为小于100毫微摩尔、10毫微摩尔或1毫微摩尔。VR1拮抗剂包括中性拮抗剂(neutral antagonists)与反激动剂。
VR1之「反激动剂」为当不添加类香草醇配位体时,使VR1之活性降至其基础活性以下的化合物。VR1之反激动剂亦可抑制类香草醇配位体在VR1之活性与/或类香草醇配位体与VR1之结合性。VR1之基础活性及因VR1拮抗剂之存在下而降低之VR1活性可采用钙移动性分析法测定,如:实例6之分析法。
VR1之「中性拮抗剂」为抑制类香草醇配位体在VR1上之活性,但不会显著改变受体基础活性的化合物(亦即在实例6所述之钙移动性分析法中,没有类香草醇配位体存在时,VR1活性降低程度不超过10%,较佳为不超过5%,更佳为不超过2%;最佳为没有检测到活性下降)。VR1之中性拮抗剂可抑制类香草醇配位体与VR1结合。
本文所采用「辣椒素受体激动剂」或「VR1激动剂」为提高受体之活性超过受体之基础活性的化合物(亦即加强VR1活化作用与/或VR1所媒介之讯息传导)。辣椒素受体激动剂活性可采用实例6所提供之代表性分析法判别。一般而言,此等激动剂在实例6所提供之分析法中,EC50值小于1微摩尔,较佳为小于500毫微摩尔,更佳为小于100毫微摩尔或10毫微摩尔。
「类香草醇」为任何包含苯基环,且利用两个氧原子与相邻环碳原子键结(其中一个碳原子与苯环上所键结之第三个部份之附接点呈对位)的化合物。辣椒素为一种代表性类香草醇。「类香草醇配位体」为一种类香草醇,其与VR1结合之Ki(依本文所说明方法测定)不超过10μM。类香草醇配位体激动剂包括辣椒素、欧凡尼(olvanil)、N-花生四烯酰基-多巴胺,与树脂毒素(resiniferatoxin)(RTX)。类香草醇配位体拮抗剂包括辣椒素氮呼(capsazepine)与碘代树脂毒素。
「治疗有效量」(或剂量)为当给予患者时,足以为患者提供可识别效益(例如:可检测到缓解至少一种所治疗之病症)时的用量。此等缓解程度可采用任何适当标准检测,包括减轻一种或多种症状,如:疼痛。治疗有效量或剂量通常可使体液(如:血液、血浆、血清、CSF、滑液、淋巴液、细胞间质液、眼泪或尿液)中的化合物浓度为足以于活体外改变类香草醇配位体与VR1之结合性(采用实例5提供之分析法)及/或VR1-媒介之讯息传导(采用实例6提供之分析法)。咸了解,随所给予的化合物而定,可在给予单一剂量后,或依据预定疗程重复给予治疗有效量后,使患者出现显著效果。
「统计上显著」用于本文中系指采用统计显著性之标准参数分析法(如:学生T试验(student′s T test))测定结果与对照组之变异在p<0.1之显著水准内。
「患者」为接受本文所提供化合物处理之任何个体。患者包括人类,及其它动物如:宠物(例如:狗与猫)与家畜。患者可能遭受对辣椒素受体调节作用有反应之病症之一种或多种症状(例如:疼痛、曝露于类香草醇配位体、瘙痒、尿失禁、膀胱过动症、停经症状、呼吸障碍、咳嗽与/或打嗝),或可能没有此等症状(亦即可为有发展出此等症状危险之患者进行预防性处理)。
2-苯氧基嘧啶酮类似物
如上述,本发明提出如式A之2-苯氧基嘧啶酮类似物。某些态样中,此等化合物为可用于多方面之VR1调节剂,包括治疗疼痛(例如:神经性或周边神经所媒介之疼痛)、曝露于辣椒素、曝露于酸、热、光、催泪气体、空气污染物(如:香烟烟雾)、传染媒介(包括病毒、细菌与酵母菌)、胡椒喷雾或相关媒介、呼吸病症如:气喘或慢性阻塞性肺病、瘙痒、尿失禁或膀胱过动症、停经症状、咳嗽或打嗝与/或肥胖。此等化合物亦可用于活体外分析法(例如:受体活性分析法),作为检测与定位VR1之探针,及作为配位体结合性与VR1所媒介讯息传导分析法之标准物。
已发现,本发明中,本文所提供2-苯氧基嘧啶酮类似物至少部份因为于式A与式I之苯氧基部份而具有惊人之高度VR1-调节活性。
如上述,代表稠合的视需要经取代之5或6元杂芳基,其中1、2或3个环成员为分别独立选自:O、N与S之杂原子,其余环成员为碳。某些具体实施例中,经0至2个独立选自下列的取代基取代:C1-C6烷基、(C3-C7环烷基)C0-C2烷基与C1-C6卤烷基。其它具体实施例中,经0至2个独立选自下列的取代基取代:C1-C4烷基、(C3-C5环烷基)C0-C2烷基与C1-C4卤烷基。
其中R′4为氢、C1-C4烷基、(C3-C5环烷基)C0-C2烷基、C1-C4卤烷基、C1-C4羟基烷基、C1-C4烷氧基、C1-C4烷酰基氨基或C1-C4烷基磺酰基氨基。代表性之此等基团包括例如:与其中R2为例如:氢、氰基、芳基、杂芳基、卤素、C1-C4烷基、C1-C4卤烷基或C3-C5环烷基。某些具体实施例中,为或咸了解,此等部份(moieties)之取向系维持如化学式所示者(例如:若为时,则双环核心为
其它具体实施例中,为经0至3个独立选自下列的取代基取代之6元杂芳基:羟基、C1-C6烷基、(C3-C7环烷基)C0-C2烷基、C1-C6卤烷基、C1-C6羟基烷基、C1-C6烷氧基、单(C1-C6烷基)氨基、C1-C6烷酰基氨基或C1-C6烷基磺酰基氨基。代表性之此等基团包括例如:其中,R4代表0至3个,较佳为1至3个独立选自下列的取代基:羟基、C1-C4烷基、(C3-C5环烷基)C0-C2烷基、C1-C4卤烷基、C1-C4羟基烷基、C1-C4烷氧基、单(C1-C4烷基)氨基、C1-C4烷酰基氨基或C1-C4烷基磺酰基氨基。
某些具体实施例中,代号R1代表0至3个,较佳为1至3个独立选自下列的取代基:卤素、氰基、C1-C4烷基与C1-C4卤烷基。例如:R1在某些此等化合物中代表仅一个取代基(例如:位于环Ar之对位上)。其它此等化合物中,至少一个由R1代表的取代基为卤素或CN;此等取代基位于某些此等化合物中6员Ar部份基团之对位。咸了解,式I中之对位系指与Ar部份与嘧啶酮核心之附接点之对位的位置;亦即当X为CH时,位于苯基环之第4位置,及当X为N时,位于吡啶-3-基环之第6位置。
某些具体实施例中,R3代表1至3个独立选自下列的取代基:卤素、氰基、C1-C4烷基、C1-C4卤烷基与C1-C4烷氧基。
某些具体实施例中,式I化合物亦符合式II-VII:
式II 式III 式IV
式V 式VI 式VII
其中R2为氢、C1-C4烷基、C1-C4卤烷基或C3-C5环烷基;R3代表1至3个独立选自下列的取代基:卤素、氰基、C1-C4烷基、C1-C4卤烷基与C1-C4烷氧基;R′4为氢、C1-C4烷基、(C3-C5环烷基)C0-C2烷基、C1-C4卤烷基、C1-C4羟基烷基、C1-C4烷氧基、C1-C4烷酰基氨基或C1-C4烷基磺酰基氨基;与R5为卤素或CN。某些式II-VII之具体实施例中,R′4为H(亦即此等化合物进一步符合式IIa-VIIa之一:
式IIa 式IIIa 式IVa
式Va 式VIa 式VIIa
其中代号如式II-VII之说明。其它具体实施例中,式I化合物进一步符合式VIII或IX:
式VIII 式IX
其中R3代表1至3个独立选自下列的取代基:卤素、氰基、C1-C4烷基、C1-C4卤烷基与C1-C4烷氧基;R4代表0至2个独立选自下列的取代基:羟基、C1-C4烷基、(C3-C5环烷基)C0-C2烷基、C1-C4卤烷基、C1-C4羟基烷基、C1-C4烷氧基、单(C1-C4烷基)氨基、C1-C4烷酰基氨基或C1-C4烷基磺酰基氨基;与R5为卤素或CN。
本文所提供代表性2-苯氧基嘧啶酮类似物与中间物包括但不限于:彼等明确说明于实例1-3中者。咸了解,本文所说明之特定化合物仅为代表例且未限制本发明范围。此外,如上述,所有本发明化合物均可呈游离酸或碱、或药学上可接受的盐。此外,此等化合物之其它型式如:水合物与前药均明确包括在本发明范围内。
本发明某些态样中,本文所提供之2-苯氧基嘧啶酮类似物可检测地改变(调节)VR1活性,其系采用活体外VR1功能性分析法测定,如:钙移动性分析法。可采用VR1配位体结合性分析法为此等活性进行初步筛选。本文所提及之「VR1配位体结合性分析法」系指标准活体外受体结合性分析法,如:实例5所提供者,及「钙移动性分析法」(本文中亦称为「讯息传导分析法」)可依实例6所述进行。简言之,可采用竞争性分析法分析来评价对VR1之结合性,其中由VR1制剂与会结合至VR1(例如:辣椒素受体激动剂如:RTX)之有标记(例如:125I或3H)化合物及无标记之试验化合物反应。本文所提供之分析法中,所使用之VR1最好为哺乳动物VR1,更佳为人类或大鼠VR1。受体可经重组表达或自然表达。VR1制剂可为例如:来自重组表达人类VR1之HEK293或CHO细胞之膜制备物。与可检测地调节类香草醇配位体与VR1结合性的化合物反应时,导致与VR1制剂结合之标记物量会相对于没有化合物时之标记物结合量下降或提高。此下降或提高可决定本文所说明对VR1之Ki。一般而言,在此等分析法中可降低与VR1制剂结合之标记物量的化合物为较佳。
本文所提供某些VR1调节剂在毫微摩尔浓度(亦即次微摩尔)、次毫微摩尔浓度,或低于100皮摩尔(picomolar)、20皮摩尔、10皮摩尔或5皮摩尔下可检测到其调节VR1活性。
如上述,作为VR1拮抗剂的化合物较适用于某些具体实施例。此等化合物之IC50值可采用标准活体外VR1媒介之钙移动性分析法(如实例6所示)测定。简言之,由表达辣椒素受体的细胞与兴趣化合物及可指示细胞内钙浓度之指示剂(例如:膜可通透之钙敏感性染料,如:Fluo-3或Fura-2(Molecular Probes,Eugene,OR),当与Ca++结合时,分别会产生萤光信号)接触。此等接触最好在包含化合物及指示剂一者或两者之缓冲液或培养基中,与细胞反应一次或多次。接触时间应维持足使染料进入细胞中(例如:1-2小时)。细胞经洗涤或过滤排除过量染料后,与类香草醇受体激动剂(例如:辣椒素、RTX或欧凡尼(olvanil))接触,其典型于等于EC50浓度下接触后,然后测定萤光反应。当接触过激动剂的细胞与作为VR1拮抗剂的化合物接触时,该萤光反应通常相较于在没有试验化合物下与激动剂接触的细胞会下降至少20%,较佳为至少50%,更佳为至少80%。本文所提供VR1拮抗剂之IC50较佳为小于1微摩尔,小于100nM,小于10nM或小于1nM。某些具体实施例中,本文所提供VR1拮抗剂在辣椒素受体激动作用的活体外分析法中,于等于IC50的化合物浓度下,没有可检测到之激动剂活性。某些此等拮抗剂在辣椒素受体激动作用的活体外分析法中,于高于100倍IC50的化合物浓度下,没有可检测到之激动剂活性。
其它具体实施例中,以作为辣椒素受体激动剂的化合物较佳。辣椒素受体激动剂活性通常依实例6所述测定。当细胞与1微摩尔作为VR1激动剂的化合物接触时,该萤光反应量通常比与100nM辣椒素接触的细胞所观察到之萤光反应量提高至少30%。本文所提供VR1激动剂之EC50较佳为小于1微摩尔,小于100nM或小于10nM。
VR1调节活性也可,或是取代地,可采用培养之背根神经节分析法(如实例7所述)与/或活体内疼痛缓解分析法(如实例8所述)分析。本文所提供VR1调节剂在本文所提供一种或多种功能性分析法中对VR1活性较佳具有统计上显著之明确效应。
某些具体实施例中,本文所提供VR1调节剂实质上不会调节配位体与其它细胞表面受体如:EGF受体酪胺酸激酶或烟碱乙醯胆碱受体之结合性。换言之,此等调节剂实质上不会抑制细胞表面受体如:人类上皮生长因子(EGF)受体酪胺酸激酶或烟碱乙醯胆碱受体之活性(例如:此等受体之IC50或IC40较佳为大于1微摩尔,最佳为大于10微摩尔)。较佳者,调节剂不会在0.5微摩尔、1微摩尔或更佳为10微摩尔下检测到其抑制EGF受体活性或烟碱乙醯胆碱受体活性。测定细胞表面受体活性之分析法可自商品取得,包括可得自Panvera(Madison,WI)之酪胺酸激酶分析套组。
某些具体实施例中,较佳VR1调节剂为非镇定剂。换言之,在测定疼痛缓解之动物模式中(如:本文实例8所提供之模式),VR1调节剂的用量达充分止痛之最低剂量之两倍剂量时,仅会暂时镇定(亦即持续时间不超过缓解疼痛所维持时间之1/2)或较佳在镇定之动物模式分析法中没有统计上显著之镇定作用(采用Fitzgerald等人说明于(1988)Toxicology 49(2-3):433-9之方法)。较佳者,其剂量达充分止痛之最低剂量之5倍剂量时,不会产生统计上显著之镇定作用。更佳者,本文所提供VR1调节剂在小于25毫克/公斤(较佳为小于10毫克/公斤)之静脉内剂量下、或小于140毫克/公斤(较佳为小于50毫克/公斤,更佳为小于30毫克/公斤)之口服剂量下,不会产生镇定作用。
若需要时,可分析本文所提供化合物之某些药物性质,包括但不限于口服生体可用率(较佳化合物为口服生体可用率程度于其口服剂量小于140毫克/公斤,较佳为小于50毫克/公斤,更佳为小于30毫克/公斤,甚至更佳为小于10毫克/公斤,亦更佳为小于1毫克/公斤与最佳为小于0.1毫克/公斤时允许达医疗有效浓度的化合物)、毒性(较佳化合物当依治疗有效量投药给个体时,应无毒性)、副作用(较佳化合物所产生之副作用应相当于对个体给予治疗有效量安慰剂时之副作用)、血清蛋白质结合性及活体外与活体内半衰期(较佳化合物的活体内半衰期应容许进行Q.I.D.投药法,较佳为T.I.D.投药法,更佳为B.I.D.投药法及最佳为一天一次投药法)。此外,调节CNS VR1活性而治疗疼痛之VR1调节剂可能需要对血脑障壁有不同渗透性,因此当提供上述每日口服总剂量时,可使此等调节作用达医疗有效程度,同时降低脑中用于治疗周边神经所媒介疼痛之VR1调节剂浓度为较佳之作法(亦即此等剂量在脑中(例如:CSF)所产生的化合物浓度应不足以显著调节VR1活性)。可采用相关技艺习知之例行分析法来分析此等性质及判别特别用途之优良化合物。例如:用于预估生体可用率之分析法包括转运通过人类肠单层细胞,包括Caco-2单层细胞。化合物在人体中渗透血脑障壁之性质可采用接受化合物投药(例如:经静脉内)之实验室动物脑中化合物浓度来评估。血清蛋白质结合性可由白蛋白结合性分析法预估。化合物半衰期系与化合物剂量频率成反比。化合物的活体外半衰期可由例如美国专利申请公开案案号2005/0070547中之实例7所述之微粒体半衰期分析法预估。
如上述,本文所提供较佳化合物无毒性。一般而言,本文所采用术语「无毒性」咸了解,系一种相对定义,意指任何经美国食品与药物检验局(「FDA」)核准用于给予哺乳动物(较佳为人类)或符合所制定之标准,可被FDA核准给予哺乳动物(较佳为人类)之物质。此外,极佳之无毒性化合物通常会符合下列一项或多项标准:(1)不会实质上抑制细胞ATP产生;(2)不会显著延长心脏QT间隔;(3)不会造成实质肝肿大,与(4)不会造成实质上肝酵素释出。
如本文所采用,不会实质上抑制细胞ATP产生的化合物为符合美国专利申请公开案案号2005/0070547中实例8所示标准的化合物。换言之,依其中所述,经过100μM此等化合物处理的细胞中ATP含量为未处理细胞中所检测到ATP含量之至少50%。更佳具体实施例中,此等细胞中ATP含量为未处理细胞中所检测到ATP含量之至少80%。
不会显著延长心脏QT间隔的化合物为不会使天竺鼠、迷你猪或狗在接受可使血清中化合物浓度等于EC50或IC50之剂量下投药后于统计上显著延长心脏QT间隔的化合物(由心电图测定)。某些较佳具体实施例中,非经肠式或口服给予0.01、0.05、0.1、0.5、1、5、10、40或50毫克/公斤之剂量不会在统计上显著延长心脏QT间隔。
若实验室囓齿类动物(例如:小鼠或大鼠)每天接受可使血清中化合物浓度等于EC50或IC50之剂量下投药进行5至10天后,所造成之肝对体重比例不超过平行对照组之100%时,该化合物即不会造成实质肝肿大。极更佳之具体实施例中,此等剂量不会使肝肿大程度超过平行对照组之75%或50%。若采用非囓齿类动物(例如:狗)时,此等剂量不应使肝对体重比例超过平行对照组之50%,较佳不超过25%,更佳为不超过10%。此等分析法中,较佳投药剂量包括非经肠式或口服给予0.01、0.05、0.1、0.5、1、5、10、40或50毫克/公斤。
同样地,若化合物之投药量可使血清中浓度等于化合物对VR1之EC50或IC50时之最低剂量两倍浓度后,不会使实验室动物(如:囓齿类)血清中ALT、LDH或AST浓度提高程度超过平行伪处理对照组之100%时,该化合物为不会实质上促进肝酵素释出。极更佳之具体实施例中,此等剂量不会使此等血清浓度超过平行对照组之75%或50%。或者,在活体外肝细胞分析法中,若浓度(于活体外与肝细胞接触及培养之培养基中或其它此等溶液中)等于化合物之EC50或IC50之浓度时,不会使任何此等肝酵素释出至培养基中之量高于平行伪处理之对照组细胞培养基中所观察到之底线值达可检测之程度,则该化合物不会实质上促进肝酵素释出。极佳之具体实施例中,当此等化合物浓度为该化合物EC50或IC50之5倍及较佳为10倍浓度时,不会使任何此等肝酵素释出至培养基中之量高于底线值达可检测之程度。
其它具体实施例中,某些较佳化合物不会在等于化合物对VR1之EC50或IC50之浓度下抑制或诱发微粒体细胞色素P450酵素活性,如:CYP1A2活性、CYP2A6活性、CYP2C9活性、CYP2C19活性、CYP2D6活性、CYP2E1活性或CYP3A4活性。
某些较佳化合物在等于化合物之EC50或IC50之浓度下,不会使细胞裂解(例如:采用小鼠红血球前驱细胞小核分析法、Ames小核分析法、螺旋小核分析法,等等测定)。其它具体实施例中,某些较佳化合物在此等浓度下不会诱发姊妹染色体交换(例如:中国仓鼠卵巢细胞)。
如下文所讨论,为了检测目的,本文所提供之VR1调节剂可标记同位素或放射性。例如:化合物中可能有一个或多个原子被原子量或质量数不同于通常天然存在之原子量或质量数之相同元素置换。本文所提供化合物中可出现之同位素实例包括氢、碳、氮、氧、磷、氟与氯之同位素,如:2H、3H、11C、13C、14C、15N、18O、17O、31P、32P、35S、18F与36Cl。此外,经重同位素如:氘(亦即2H)取代时,可因代谢安定性较高而产生某些医疗优势,例如:提高活体内半衰期或降低所需剂量,因此于有些情况下较有利。
2-苯氧基嘧啶酮类似物制法
2-苯氧基嘧啶酮类似物一般可采用标准合成法制备。起始物可自如:Sigma-Aldrich Corp.(St.Louis,MO)供货商所提供之商品取得,或可由自商品取得之前体采用已建立之方法制备。例如:可采用类似下列反应图所示之合成途径,及合成有机化学相关技艺已知之合成法制备。下列反应图中之代号系指本文所提供化合物所说明之任何基团。
下列反应图与本文中某些缩写包括:
CDCl3 氘化氯仿
δ 化学位移
DCM 二氯甲烷
DMAP 4-二甲基氨基吡啶
DMF 二甲基甲醯胺
DMSO 二甲亚砜
DPPF1,1′-双(二苯基膦基)二茂铁
Et 乙基
EtOAc 乙酸乙酯
EtOH 乙醇
h 小时
1H NMR 质核磁共振
HPLC 高效液相层析法
Hz 赫兹
KOtBu 第三丁醇钾
min 分钟
MS 质谱法
(M+1) 质量+1
Pd2(dba)3参(二亚芐基丙酮)二钯(O)
RT 室温
TFA 三氟乙酸
反应图1
反应图2
反应图3
反应图4
反应图5
反应图6
某些具体实施例中,本文所提供化合物可包含一个或多个不对称碳原子,因此化合物可出现不同立体异构型。此等型式可为例如:消旋物或光学活性型。如上述,所有立体异构型均包括在本发明范围内。尽管如此,仍可能需要得到单一对映异构物(亦即光学活性型)。制备单一对映异构物之标准方法包括不对称合成法与消旋物解析法。消旋物解析法可例如:依一般方法进行如:于解析剂之存在下结晶或使用例如:对掌性HPLC管柱层析。
化合物可在其合成法中使用包含至少一个放射性同位素原子之前驱物进行放射性标记。各放射性同位素较佳为碳(例如:14C)、氢(例如:3H)、硫(例如:35S)或碘(例如:125I)。标记氚的化合物制法亦可于氚化之乙酸中,使用铂催化之交换反应、于氚化之三氟乙酸中,使用酸催化之交换反应、或使用化合物作为受质,与氚气体进行不均相之催化交换反应。此外,某些前体可依需要使用氚气体进行氚-卤素交换反应,使用氚气体还原不饱和键或使用氚硼化钠还原。标记放射性的化合物制法宜由专为合成标记放射性之探针化合物之放射性同位素供货商进行。
医药组成物药物组合物
本发明亦提供药物组合物,其包含一种或多种本文所提供化合物,及至少一种生理上可接受的载体或赋形剂。药物组合物可包含例如:下列一项或多项:水、缓冲液(例如:中性之缓冲生理食盐水或磷酸盐缓冲生理食盐水)、乙醇、矿物油、植物油、二甲亚砜、碳水化合物(例如:葡萄糖、甘露糖、蔗糖或葡聚糖)、甘露糖醇、蛋白质、辅剂、多肽或氨基酸(如:甘胺酸)、抗氧化剂、螯合剂如:EDTA或麸胱甘肽与/或防腐剂。此外,本文所提供之药物组合物中亦可(但不一定)包括其它活性成分。
药物组合物可调配供任何适当投药方式使用,包括例如:局部、口服、经鼻、经直肠或非经肠式投药。本文所采用术语非经肠式包括经皮下、皮内、血管内(例如:静脉内)、肌内、脊髓内、颅内、鞘内、与腹膜内注射,及任何类似之注射或输液(infusion)技术。某些具体实施例中,以适合口服的组合物较佳。此等组合物包括例如:锭剂、糖衣锭、菱形锭、水性或油性悬浮液、可匀散之粉剂或粒剂、乳液、硬性或软性胶囊或糖浆或酏剂。其它具体实施例中,药物组合物可调配成冷冻干燥物。局部投药用调配物可能较适于某些病症(例如:用于治疗皮肤病如:灼伤或瘙痒)。直接投药至膀胱之调配物(膀胱内(intravescular)投药)可能较适于治疗尿失禁与膀胱过动症。
口服用组合物尚可包含一种或多种成分,如:甜味剂、调味剂、着色剂与/或防腐剂,以提供吸引人且适口之制剂。锭剂包含活性成分与适合制造锭剂之生理上可接受的赋形剂混合。此等赋形剂包括例如:惰性稀释剂(例如:碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠)、制粒剂与崩解剂(例如:玉米淀粉或藻酸)、结合剂(例如:淀粉、明胶或金合欢胶)及润滑剂(例如:硬脂酸镁、硬脂酸或滑石)。锭剂可采用标准技术形成,包括干式制粒法、直接压缩法及湿式制粒法。锭剂可以没有包衣或可依已知技术包覆包衣。
口服用调配物亦可呈硬明胶胶囊,其中,活性成分与惰性固体稀释剂混合(例如:碳酸钙、磷酸钙或高岭土),或呈软明胶胶囊,其中,活性成分与水或油介质混合(例如:花生油、液态石蜡或橄榄油)。
水性悬浮液包含活性成分(群)与合适之赋形剂混合,如:悬浮剂(例如:羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯啶酮、黄耆胶与金合欢胶);与匀散剂或湿润剂(例如:天然磷脂如:卵磷脂、伸烷基氧化物与脂肪酸之缩合产物如:聚氧乙烯硬脂酸酯、环氧乙烷与长链脂系醇之缩合产物如:十七伸乙基氧鲸蜡醇、环氧乙烷与衍生自脂肪酸及己糖醇之部份酯之缩合产物如:聚氧乙烯山梨糖醇单油酸酯、或环氧乙烷与衍生自脂肪酸及己糖醇酐之部份酯之缩合产物如:聚乙烯山梨糖醇酐单油酸酯)。水性悬浮液亦可包含一种或多种防腐剂例如:对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯、一种或多种着色剂、一种或多种调味剂与/或一种或多种甜味剂,如:蔗糖或糖精。
油性悬浮液之调配法为取活性成分(群)悬浮于植物油中(例如:花生油、橄榄油、芝麻油或椰子油)或矿物油中如:液态石蜡。油性悬浮液可包含增稠剂如:蜂蜡、硬性石蜡或鲸蜡醇。可添加甜味剂(如:如上述)与/或调味剂以提供适口之口服制剂。此等悬浮液可添加抗氧化剂如:抗坏血酸进行防腐。
适合制备水性悬浮液之可匀散性粉剂与粒剂可加水使活性成分与匀散剂或湿润剂、悬浮剂与一种或多种防腐剂混合。合适之匀散剂或湿润剂及悬浮剂实例已如上述。亦可包含其它赋形剂如:甜味剂、调味剂与着色剂。
药物组合物亦可调配成水包油性乳液。油相可为植物油(例如:橄榄油或花生油)、矿物油(例如:液态石蜡)或其混合物。合适之乳化剂包括天然胶质(例如:金合欢胶或黄耆胶)、天然磷脂(例如:大豆卵磷脂、与衍生自脂肪酸及己糖醇之酯或部份酯)、酸酐(例如:山梨糖醇酐单油酸酯)及衍生自脂肪酸及己糖醇酐之部份酯与环氧乙烷之缩合产物(例如:聚氧乙烯山梨糖醇酐单油酸酯)。乳液亦可包含一种或多种甜味剂与/或调味剂。
糖浆与酏剂可使用甜味剂调配,如:甘油、丙二醇、山梨糖醇或蔗糖。此等调配物亦可包含一种或多种缓和剂、防腐剂、调味剂与/或着色剂。
局部投药用调配物典型地包含局部用媒剂与活性剂(群)组合,可添加或不添加其它可视需选用之成分。合适之局部用媒剂与其它成分系技艺中已知者,且咸了解,其可依特定之物理形式与传送模式选择媒剂。局部用媒剂包括水;有机溶剂如:醇类(例如:乙醇或异丙醇)或甘油;二醇类(例如:丁二醇、异戊间二烯二醇或丙二醇);脂系醇(例如:羊毛脂);水与有机溶剂之混合物,及有机溶剂之混合物如:醇与甘油混合物;以脂质为主之物质如:脂肪酸、酰基甘油(包括油类如:矿物油与天然或合成之脂肪)、磷酸甘油酯、神经鞘脂质与蜡类;以蛋白质为主之物质如:胶原与明胶;以聚硅氧(silicon)为主之物质(包括非挥发性及挥发性);与以烃为主之物质如:小海绵与聚合物母质。组合物可另包括一种或多种适合改善所施用调配物之安定性或有效性之成分,如:安定剂、悬浮剂、乳化剂、黏度调整剂、胶凝剂、防腐剂、抗氧化剂、皮肤渗透加强剂、湿化剂与持续释放性材料。此等成分实例说明于Martindale之The Extra Pharmacopoeia(Pharmaceutical Press,London 1993)与Remington之“The Science and Practice of Pharmacy”,第21版,Lippincott Williams & Wilkins,Philadelphia,PA(2005)。调配物可包括微胶囊,如:羟甲基纤维素或明胶微胶囊、微脂粒、白蛋白微小球、微乳液、毫微粒子或毫微胶囊。
局部用调配物可制成多种物理型式,包括例如:固体、糊剂、乳霜、泡沫物、洗液、凝胶、粉剂、水性液体与乳液。此等药学上可接受的型式之物理外观与黏度可使用调配物中所含乳化剂与黏度调整剂及其用量来控制。固体通常坚实,无法倾倒,经常调配成棒状或杆状或粒状;固体可不透明或透明,其可视需要包含溶剂、乳化剂、湿化剂、软化剂、香料、染料/着色剂、防腐剂与其它可提高或加强最终产物效力之活性成分。乳霜与洗液通常类似,其差异主要在其黏度;洗液与乳霜二者均可能不透明、半透明或澄清,经常包含乳化剂、溶剂与黏度调整剂,及湿化剂、软化剂、香料、染料/着色剂、防腐剂与其它可提高或加强最终产物效力之活性成分。凝胶可制成多种不同黏度,由浓稠或高黏度至稀薄或低黏度。此等调配物如同洗液与乳霜,亦可包含溶剂、乳化剂、湿化剂、软化剂、香料、染料/着色剂、防腐剂与其它可提高或加强最终产物效力之活性成分。液体比乳霜、洗液或凝胶稀薄,通常不包含乳化剂。液态局部产品经常包含溶剂、乳化剂、湿化剂、软化剂、香料、染料/着色剂、防腐剂与其它可提高或加强最终产物效力之活性成分。
适用于局部用调配物之乳化剂包括(但不限于):离子性乳化剂、鲸蜡硬脂基醇、非离子性乳化剂如:聚氧乙烯油基醚、PEG-40硬脂酸酯、鲸蜡硬脂醇醚(ceteareth)-12、鲸蜡硬脂醇醚-20、鲸蜡硬脂醇醚-30、鲸蜡硬脂醇(ceteareth alcohol)、PEG-100硬脂酸酯与硬脂酸甘油酯。合适之黏度调整剂包括(但不限于):保护性胶体或非离子性胶质如:羟乙基纤维素、黄原胶、硅酸镁铝、硅石、微晶蜡、蜂蜡、石蜡与棕榈酸鲸蜡酯。凝胶组合物之形成法可添加胶凝剂如:脱乙醯壳多糖、甲基纤维素、乙基纤维素、聚乙烯醇、聚四元盐、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、聚羧基制剂(carbomer)或胺化甘草酸盐。合适之界面活性剂包括(但不限于):非离子性、两性、离子性与阴离子性界面活性剂。局部用调配物中可使用例如:下列一种或多种:二甲硅酮共多元醇、聚山梨酸酯20、聚山梨酸酯40、聚山梨酸酯60、聚山梨酸酯80、月桂醯胺DEA、椰子醯胺DEA与椰子醯胺MEA、油基甜菜碱、椰子醯胺丙基磷脂酰基PG-二甲基氯化铵与月桂基醚硫酸铵。合适之防腐剂包括(但不限于):抗微生物剂如:对氧苯甲酸甲酯、对氧苯甲酸丙酯、山梨酸、苯甲酸与甲醛,及物理性安定剂与抗氧化剂如:维生素E、抗坏血酸钠/抗坏血酸与五倍子酸丙酯。合适之湿化剂包括(但不限于):乳酸与其它羟基酸与其盐类、甘油、丙二醇与丁二醇。合适之软化剂包括羊毛脂醇、羊毛脂、羊毛脂衍生物、胆固醇、凡士林、新戊酸异硬脂基酯与矿物油。合适之香料与色素包括(但不限于):FD&C红色40号与FD&C黄色5号。局部用调配物中可包含之其它适合之添加成分包括(但不限于)研磨剂、吸收剂、抗结块剂、消泡剂、抗静电剂、收敛剂(例如:美洲金缕梅、酒精与药草萃液如:甘菊萃液)、结合剂/赋形剂、缓冲剂、螯合剂、膜形成剂、调理剂、推进剂、不透明剂、pH调整剂与保护剂。
调配凝胶之合适局部用媒剂实例为:羟丙基纤维素(2.1%);70/30异丙醇/水(90.9%);丙二醇(5.1%);与聚山梨酸酯80(1.9%)。调配泡沫物之合适局部用媒剂实例为:鲸蜡醇(1.1%);硬脂醇(0.5%;季铵盐52(Quaternium 52)(1.0%);丙二醇(2.0%);乙醇95PGF3(61.05%);去离子水(30.05%);P75烃推进剂(4.30%)。所有百分比均以重量计。
传送局部用组合物之典型方式包括使用手指涂抹;使用物理性涂抹器施用如:布、卫生纸、棉花、小棒或刷子;喷洒(包括雾化、气雾或泡沫喷洒);滴药法;倾注;浸泡;及润洗。
药物组合物亦可制成无菌之注射用水性或油性悬浮液。依所使用之媒剂与浓度而定,本文所提供化合物可以悬浮或溶解于媒剂中。此等组合物可依据相关技艺已知之方式,使用如上述之合适匀散剂、湿润剂与/或悬浮剂调配。可接受的媒剂与溶剂中,可使用水、1,3-丁二醇、林格氏(Ringer′s)溶液与等张性氯化钠溶液。此外,可使用无菌之固定油类作为溶剂或悬浮介质。因此任何温和之固定油均可使用,包括合成之单或二酸甘油酯。此外,用于制备注射用组合物之制剂之脂肪酸如:油酸与辅剂如:局部麻醉剂、防腐剂与/或缓冲剂可溶于媒剂中。
药物组合物亦可调配成栓剂(例如:经直肠投药用)。此等组合物之制法可由药物与常温下呈固体,但在直肠温度下却呈液体之合适无刺激性赋形剂混合,因此可于直肠中融化释出药物。合适之赋形剂包括例如:可可奶油与聚乙二醇。
吸入式组合物典型地可呈溶液、悬浮液或乳液形式使用,其可呈干粉投药或呈气雾剂,使用常用之推进剂(例如:二氯二氟甲烷或三氯氟甲烷)投药。
药物组合物可调配成依预定速率释出。实时释放法可藉由例如:舌下投药法达成(亦即经口投药,使活性成份(群)得以迅速经由舌下血管而非消化道吸收)。控制释放之调配物(亦即如:可在投药后减慢及/或延缓活性成份(群)释放之胶囊、锭剂或包衣锭剂)可经例如:口、直肠或皮下植入物投药或植入标靶位置投药。通常,控制释放调配物包含母质及/或肠胃道(或植入位置)中延缓崩解及吸收之包衣,藉以提供延缓作用或长期持续作用。其中一种控制释放调配物为持续释放调配物,其中至少一种活性成份系依恒定速率长期持续释放。较佳者,医疗剂之释放速率会使得血液(例如:血浆)浓度在至少4小时内,较佳为至少8小时内,更佳为至少12小时内,保持在医疗范围内,但低于毒性范围。此等调配物通常可采用习知技术制备,且经由例如:口、直肠或皮下植入物投药,或植入所需标靶位置投药。此等调配物所使用之载体为生物可兼容性且亦为生物可降解性;较佳调配物可相当恒定地释放调节剂。持续释放调配物中之调节剂含量依例如:植入位置、释放速率与期望之期效、及需治疗或预防之病症性质决定。
控制释放法可藉由组合活性成份(群)与本身即可改变释放速率之母质材料及/或利用控制释放包衣达成。释放速率可依相关技艺已知方法变化,包括(a)改变包衣厚度或组成,(b)改变包衣中增塑剂添加量或添加方式,(c)包含其它成份,如:释放修饰剂,(d)改变母质之组成、粒子大小或粒子形状,与(e)透过包衣提供一个或多个信道。持续释放调配物中之调节剂含量依例如:投药方法(例如:植入位置)、释放速率与期望效期、及所治疗或预防病症之性质而异。
本身有或没有控制释放功能之母质材料通常为任何可承载活性成份(群)之材料。例如:可使用缓释材料,如:单硬脂酸甘油酯或二硬脂酸甘油酯。活性成份(群)可在形成剂型(例如:锭剂)之前先与母质材料组合。或者,或另外,活性成份(群)可包覆在包含母质材料之粒子、颗粒、球粒、微粒、小珠或丸粒表面上。此等包覆法可藉由习知方法达成,如:取活性成份(群)溶于水或其它合适溶剂后,喷洒。可视需要先添加其它成份后,再进行包覆(例如:促进活性成份(群)与母质材料结合或为溶液上色)。随后再先以隔离剂包覆母质后,再涂覆控制释放包衣。若需要时,可包埋多重包衣母质单位,形成最终剂型。
某些具体实施例中,控制释放法系利用控制释放包衣达成(亦即可依控制速率释放活性成份(群)至水性介质中之包衣)。控制释放包衣应为强力之连续膜,其平滑、可以承载色素与其它添加物、无毒性、惰性且不沾黏。调控调节剂释放之包衣包括不依赖pH之包衣、依赖pH之包衣(其可用于在胃中释放调节剂)与肠溶性包衣(其容许调配物完整通过胃,再进入小肠,包衣在此时才溶解,由身体吸收其内容物)。咸了解,可使用多重包衣(例如:得以于胃中释放一部份剂量,再延着胃肠道释放另一部份)。例如:一部份活性成份(群)可包覆在肠溶性包衣外面,藉以于胃中释放,母质核心中其余活性成份(群)则因受到肠溶性包衣保护,需直到GI道中才释放。依赖pH之包衣包括例如:虫胶、纤维素乙酸酯酞酸酯、聚乙烯基乙酸酯酞酸酯、羟丙基甲基纤维素酞酸酯、甲基丙烯酸酯共聚物与玉米蛋白。
某些具体实施例中,包衣为疏水性材料,较佳用量应在投药后有效减缓胶凝剂之水合化。合适之疏水性材料包括烷基纤维素(例如:乙基纤维素或羧甲基纤维素)、纤维素醚类、纤维素酯类、丙烯酸聚合物(例如:聚(丙烯酸)、聚(甲基丙烯酸)、丙烯酸与甲基丙烯酸共聚物、甲基丙烯酸甲酯共聚物、甲基丙烯酸乙氧基乙酯、甲基丙烯酸氰基乙酯、甲基丙烯酸烷基醯胺共聚物、聚(甲基丙烯酸甲酯)、聚丙烯醯胺、甲基丙烯酸铵共聚物、甲基丙烯酸氨基烷基酯共聚物、聚(甲基丙烯酸酐)与甲基丙烯酸甘油酯共聚物)与如上述物质之混合物。乙基纤维素之代表性水性匀散液包括例如:(FMC Corp.,Philadelphia,PA)与(Colorcon,Inc.,West Point,PA)),此二者均可依据制商之指示涂覆基质。代表性丙烯酸聚合物包括例如:各种不同(Rohm America,Piscataway,NJ)聚合物,其可依据制造商之指示单独使用或依所需释放形态组合使用。
包含疏水性材料之水性匀散剂之包衣之物理性质可藉由添加一种或多种增塑剂来改良。烷基纤维素之合适增塑剂包括例如:癸二酸二丁基酯、酞酸二乙酯、柠檬酸三乙酯、柠檬酸三丁酯与三醋精。丙烯酸聚合物之合适增塑剂包括例如:柠檬酸酯类,如:柠檬酸三乙酯与柠檬酸三丁酯、酞酸二丁酯、聚乙二醇、丙二醇、酞酸二乙酯、蓖麻油与三醋精。
控制释放之包衣通常采用习知技术涂覆,如:以水性匀散液之形式喷洒。若需要时,包衣可包含孔洞或信道以促进活性成份释放。孔洞与信道可依相关技艺已知方法形成,包括添加有机或无机材料,再自包衣中溶解、萃取或渗滤至使用环境中。某些此等形成孔洞之材料包括亲水性之聚合物,如:羟烷基纤维素(例如:羟丙基甲基纤维素)、纤维素醚类、合成之水溶性聚合物(例如:聚乙烯基吡咯啶酮、交联聚乙烯基吡咯啶酮与聚环氧乙烷)、水溶性聚右旋糖、醣类与多醣及碱金属盐。或者,或另外,控制释放包衣可包括一个或多个孔隙,其可依彼等说明于美国专利案案号3,845,770;4,034,758;4,077,407;4,088,864;4,783,337与5,071,607说明之方法形成。控制释放法亦可利用穿皮式贴布,采用习知技术达成(参见例如:美国专利案案号4,668,232)。
其它控制释放调配物与其成份之实例可参见例如:美国专利案案号5,524,060;4,572,833;4,587,117;4,606,909;4,610,870;4,684,516;4,777,049;4,994,276;4,996,058;5,128,143;5,202,128;5,376,384;5,384,133;5,445,829;5,510,119;5,618,560;5,643,604;5,891,474;5,958,456;6,039,980;6,143,353;6,126,969;6,156,342;6,197,347;6,387,394;6,399,096;6,437,000;6,447,796;6,475,493;6,491,950;6,524,615;6,838,094;6,905,709;6,923,984;6,923,988;与6,911,217;其中有关制备控制释放剂型之教示内容已以引用方式分别并入本文中。
于上述投药法之外或是与上述投药法并用,本文所提供化合物亦可加至食物或饮水中(例如:供投药给非人类动物时,包括宠物(如:狗与猫)与家畜)。动物饲料与饮水组合物之调配可使动物在进食时,同时摄取适量组合物。亦适合使组合物形成可加至饲料或饮水中之预混合物。
该化合物通常给予治疗有效量。较佳之全身剂量不超过每天每公斤体重50毫克(例如:每天每公斤体重约0.001毫克至约50毫克),口服剂量通常高于静脉内投药剂量之约5至20倍(例如:每天每公斤体重0.01至40毫克)。
可与载体材料组合使用形成单一剂量单位之活性成分用量将依例如:所治疗患者、特定之投药模式及共同给予之药物而变化。剂量单位通常包含约10微克至约500毫克活性成分。最佳剂量可采用相关技艺已知之例行试验与方法决定。
药物组合物可包装用于治疗对VR1调节作用有反应之病症(例如:治疗曝露于类香草醇配位体或其它刺激物、疼痛、瘙痒、肥胖或尿失禁)。包装之药物组合物通常包括(i)一容器,内装包含至少一种本文所说明VR1调节剂之药物组合物及(ii)说明书(例如:卷标或包装内页),指示其中所包含的组合物系用于治疗患者对VR1调节作用有反应之病症。
使用方法
本文所提供VR1调节剂可用于多态样改变辣椒素受体之活性与/或活化作用,包括活体内与活体外。某些态样中,VR1拮抗剂可用于活体外或活体内抑制类香草醇配位体激动剂(如辣椒素与/或RTX)与辣椒素受体之结合性。通常,此等方法包括之步骤为由辣椒素受体与一种或多种本文所提供VR1调节剂于类香草醇配位体存在于水溶液中及于适合配位体与辣椒素受体结合之条件下接触。VR1调节剂(群)之含量浓度通常足以于活体外改变类香草醇配位体与VR1之结合性(使用实例5所示之分析法)及/或VR1-媒介之讯息传导(使用实例6所示之分析法)。辣椒素受体可为溶液或悬浮液(例如:含于单离之膜或细胞制剂中),或含于培养或单离的细胞中。某些具体实施例中,辣椒素受体系由患者之神经元细胞表达,且该水溶液为体液。较佳者,可对动物给予一种或多种VR1调节剂,其投药量应使动物体内至少一种体液之VR1调节剂之医疗有效浓度为1微摩尔或以下;较佳为500毫微摩尔或以下;更佳为100毫微摩尔或以下,50毫微摩尔或以下,20毫微摩尔或以下,或10毫微摩尔或以下。例如:此等化合物可以治疗有效量小于20毫克/公斤体重,较佳为小于5毫克/公斤,有时候小于1毫克/公斤给予。
本文亦提供一种调节(较佳为降低)细胞辣椒素受体之讯息传导活性(亦即钙传导性)之方法。此等调节法系由辣椒素受体(活体外或活体内)与一种或多种本文所提供VR1调节剂,于适合调节剂(群)与受体结合之条件下接触而达成。VR1调节剂(群)之含量浓度通常足以于活体外改变类香草醇配位体与VR1之结合性及/或本文所说明之VR1-媒介之讯息传导。受体可在溶液或悬浮液中,含于培养或单离的细胞制剂或在患者体内的细胞中。例如:细胞可为于动物活体内接触之神经元细胞。或者,细胞可为于动物活体内接触之上皮细胞,如:膀胱上皮细胞或呼吸道上皮细胞。讯息传导活性之调节作用可藉由检测其对钙离子传导性(亦称为钙移动性或流量)之影响来分析。讯息传导活性之调节作用亦可藉由检测接受本文所提供一种或多种VR1调节剂治疗之患者症状之改变来分析(例如:疼痛、灼伤感觉、支气管收缩、发炎、咳嗽、打嗝、瘙痒、停经症状、尿失禁或膀胱过动症)。
本文所提供VR1调节剂(群)较佳为经口或局部给予患者(例如:人类),且当调节VR1讯息传导活性时,存在于动物之至少一种体液中。用于此方法于活体外调节VR1讯息传导活性之较佳VR1调节剂浓度为1毫微摩尔或以下,较佳为100皮摩尔或以下,更佳为20皮摩尔或以下,及体液如:血液中的活体内浓度为1微摩尔或以下,500毫微摩尔或以下,或100毫微摩尔或以下。
本发明并提供一种治疗对VR1调节作用有反应之病症之方法。本发明中,术语「治疗」包括改造疾病之治疗法及症状处理,其可为预防性(亦即在症状出现之前处理,以预防、延缓或降低症状之严重性)或医疗性(亦即在症状出现后处理,以降低症状之严重性与/或持续时间)。不论类香草醇配位体之局部含量,若病症之特征为辣椒素受体活性不当,与/或若辣椒素受体活性之调节作用造成病症或其症状减轻时,则称该病症「对VR1调节作用有反应」。此等病症包括例如:因曝露于VR1活化刺激所造成之症状、疼痛、呼吸障碍(如:咳嗽、气喘、慢性阻塞性肺病、慢性支气管炎、纤维性囊肿与鼻炎,包括过敏性鼻炎如:季节性与常年性鼻炎,与非过敏性鼻炎)、抑郁、瘙痒、停经症状、尿失禁、膀胱过动症、听觉受损(例如:耳蜗)、耳鸣、听觉过敏、糖尿病与糖尿病前期病症(例如:胰岛素抗性或葡萄糖耐受性)、打嗝与肥胖,其更详细说明于下文中。此等病症可采用相关技艺已知之标准诊断及追踪。患者可包括人类、家庭宠物与家畜,其剂量如上述。
疗程可能随所使用的化合物与所治疗之特定病症而定。然而,治疗大多数病变时,以每天投药4次或以下之频率较佳。通常,以每天投药2次之剂量疗程更佳,以每天投药1次特别佳。治疗急性疼痛时,需要可迅速达到有效浓度之单一剂量。然而咸了解,对任何特定患者之明确剂量与疗程将依多项因素决定,包括所使用明确化合物之活性、年龄、体重、一般健康情形、性别、饮食、投药时间、投药途径与排泄速度、药物组合与治疗期间特定疾病之严重性。通常,以足以提供有效疗法之最低剂量较佳。可采用适合所治疗或预防病症之医学或兽医学标准追踪患者之医疗有效性。
因曝露于辣椒素受体活化刺激而产生症状之患者包括因热、光、催泪气体或酸而引起灼伤之个体及黏膜曝露于(例如:因食入、吸入或眼睛接触)辣椒素(例如:辣椒或胡椒喷雾)或相关刺激物如:酸、催泪气体、传染媒介(群)或空气污染之个体。所产生之症状(可使用本文所提供VR1调节剂,尤指拮抗剂治疗者)可包括例如:疼痛、支气管收缩与发炎。
可使用本文所提供VR1调节剂治疗之疼痛包括慢性或急性疼痛,包括(但不限于):周边神经所媒介之疼痛(尤指神经性疼痛)。本文所提供化合物可用于治疗例如:乳房切除手术后疼痛综合征、残肢疼痛、幻肢疼痛、口腔神经性疼痛、牙痛(牙齿疼痛)、假牙疼痛、疱疹后神经痛、糖尿病神经性病变、化疗诱发之神经性病变、反射性交感神经失养症、三叉神经痛、骨关节炎(osteoarthritis)、类风湿性关节炎、纤维肌痛、吉兰-拜瑞(Guillain-Barre)综合征、感觉异常性股痛、口腔灼热综合征及/或与神经及神经根伤害有关之疼痛,包括与周边神经障碍有关之疼痛(例如:神经压迫性损害与臂丛撕脱、截肢、周边神经性病变(包括两侧周边神经性病变)、三叉神经痛、非典型颜面疼痛、神经根伤害与蜘蛛膜炎)。其它神经病变性疼痛病症包括灼痛(反射性交感神经失养症-RSD、周边神经损伤后续发)、神经炎(包括例如:坐骨神经炎、周边神经炎、多发神经炎、眼神经炎、发热后神经炎、游走性神经炎、节段神经炎与贡博氏(Gombault′s)神经炎)、神经元炎、神经痛(例如:如上述、颈臂神经痛、颅侧神经痛、膝状神经痛、舌咽神经痛、偏头痛神经痛、自发性神经痛、肋间神经痛、乳房神经痛、下颌关节神经痛、莫顿氏(Morton′s)神经痛、鼻睫状神经痛、枕骨神经痛、红色神经痛、斯卢德氏(Sluder′s)神经痛、脾颚神经痛、眶上神经痛与翼管神经痛)、与手术相关的疼痛、肌肉骨骼疼痛、肌筋膜疼痛综合征、AIDS相关神经性病变、MS相关神经性病变、中枢神经系统疼痛(例如:因脑干损伤、坐骨神经痛、及僵直性脊椎炎引起的疼痛)及脊椎疼痛(包括与脊柱伤害相关的疼痛)。可依本文之说明治疗头痛,包括涉及周边神经活性之头痛。此等疼痛包括例如:窦、簇集(亦即偏头痛神经痛)与紧张性头痛、偏头痛、颞下颔疼痛与上颔窦疼痛。例如:当患者出现偏头痛前之先兆时,即可给予本文所提供的化合物预防偏头痛。其它可依本文所说明治疗之疼痛病症包括沙尔科氏(Charcot′s)疼痛、肠胀气疼痛、耳痛、心脏痛、肌肉痛、眼睛痛、口腔颜面疼痛(例如:牙痛)、腹痛、妇科疼痛(例如:月经疼痛、痛经、与囊肿有关之疼痛、分娩疼痛、慢性骨盆腔疼痛、慢性前列腺炎与子宫内膜异位症)、急性与慢性背痛(例如:下背疼痛)、痛风、瘢痕疼痛、痔疮疼痛、消化不良疼痛、绞痛、神经根疼痛、「非疼痛性」神经性病变、复合区域疼痛综合征、等位疼痛与异位疼痛-包括癌症的相关疼痛,通常称为癌痛(例如:骨癌患者)、与曝露于毒液有关之疼痛(与发炎)(例如:因蛇咬伤、蜘蛛咬伤、或昆虫叮咬)及创伤的相关疼痛(例如:手术后疼痛、会阴切开疼痛、割伤疼痛、挫伤与断骨与烧烫伤疼痛,尤指与其相关的原发性痛觉过敏)。其它可依本文所述治疗之疼痛病症包括与如上述呼吸障碍、自体免疫疾病、免疫缺乏性病变、热潮红、发炎性肠道疾病、胃食道回流综合征(GERD)、肠躁症与/或发炎性肠道疾病相关的疼痛。
某些态样中,本文所提供VR1调节剂可用于治疗机械性疼痛。本文所采用术语「机械性疼痛」指头痛以外之疼痛,其不为神经病变性或因曝露于热、冷或外来化学刺激所致。机械性疼痛包括物理性创伤(不为热或化学烧烫伤或其它曝露到有害化学物质之刺激与/或疼痛)如:手术后疼痛及因割伤、挫伤与断骨引起的疼痛;牙痛、假牙疼痛;神经根疼痛;骨关节炎;类风湿性关节炎;纤维肌痛;感觉异常性股痛;背痛;癌症的相关疼痛;绞痛;腕管综合征;及因骨折、分娩、痔疮、肠部胀气、消化不良及月经引起的疼痛。
可治疗之瘙痒病症包括干癣性瘙痒、因血液透析引起的瘙痒、疟疾引起的(aguagenic)瘙痒,及与外阴前庭炎有关之瘙痒、接触性皮肤、昆虫叮咬与皮肤过敏。可依本文之说明治疗之尿道病症包括尿失禁(包括溢流性失禁、紧迫性失禁与腹部压力性失禁),及过动性或不稳定性膀胱病症(包括膀胱迫肌过度反射、因脊柱造成迫肌过度反射与膀胱过度敏感)。某些此等治疗法中,VR1调节剂经由导管或类似装置投药,可直接注射VR1调节剂至膀胱中。本文所提供化合物亦可用为止咳剂(预防、缓解或压抑咳嗽,包括因给予如:ACE抑制剂所诱发之咳嗽)、用于治疗打嗝、治疗停经症状(如:热潮红)及促进肥胖患者减轻体重。
其它态样中,本文所提供VR1调节剂可用于组合疗法中,供治疗涉及疼痛与/或发炎成分之病症。此等病症包括例如:自体免疫病变与已知具有发炎成分之病理性自体免疫反应,包括(但不限于):关节炎(尤指类风湿性关节炎)、干癣、克隆氏症(Crohn′s disease)、红斑性狼疮、肠躁症、组织移植物排斥与移植器官之过急性排斥。其它此等病症包括创伤(例如:头部或脊柱受伤)、心脏与脑血管疾病与某些传染性疾病。
此等组合疗法中,VR1调节剂之合适剂量通常如上述。消炎剂之剂量与投药方法可参见例如:制造商于Physician′s Desk Reference中之说明。某些具体实施例中,VR1调节剂与消炎剂的组合投药结果可降低消炎剂要产生医疗效果时所需剂量(例如:降低最小之治疗有效量)。因此,本发明组合或组合投药法中,消炎剂之剂量最好低于不与VR1拮抗剂组合投药时,制造商所建议之最高消炎剂剂量。此剂量低于不与VR1拮抗剂组合投药时,制造商所建议之最高消炎剂剂量之3/4时更佳,甚至更佳为低于1/2,极佳为低于1/4,最佳剂量为低于最高剂量之10%。咸了解,组合中VR1拮抗剂成分要达到所需效果时所需剂量同样会受组合中消炎剂成分剂量与效力影响。
某些较佳具体实施例中,VR1调节剂与消炎剂的组合投药法系将一种或多种VR1调节剂与一种或多种消炎剂包装在同一包装中,在同一包装中分装在不同容器中、或由一种或多种VR1拮抗剂与一种或多种消炎剂形成混合物装在同一容器中。较佳混合物系调配成口服投药用(例如:形成丸剂、胶囊、锭剂,等等)。某些具体实施例中,包装中包含卷标,指示该一种或多种VR1调节剂与一种或多种消炎系共同用于治疗发炎疼痛病症。
其它态样中,本文所提供VR1调节剂可与一种或多种其它缓解疼痛之药物组合使用使用。某些此等药物亦为上列之消炎剂。其它此等药物为止痛剂,包括典型作用在一种或多种类鸦片受体亚型(例如:μ、κ与/或δ)之麻醉剂,较佳为作为激动剂或部份激动剂。此等药剂包括鸦片制剂、鸦片制剂衍生物与类鸦片剂,及其药学上可接受的盐与水合物。较佳具体实施例中,麻醉止痛剂之明确实例包括阿芬他泥(alfentanyl)、安依痛(alphaprodine)、阿尼利定(anileridine)、贝齐醯胺(bezitramide)、丁丙诺菲(buprenorphine)、丁啡喃(butorphanol)、可待因(codeine)、二乙酰基二氢吗啡、二乙酰基吗啡、二氢可待因、地芬诺酯(diphenoxylate)、乙基吗啡、芬坦尼(fentanyl)、海若因、氢可酮、氢化吗啡酮(hydromorphone)、异美沙酮(isomethadone)、左旋甲吗凡(levomethorphan)、左旋凡(levorphane)、左吗喃(levorphanol)、麦啶(meperidine)、美索辛(metazocine)、美沙酮(methadone)、甲吗凡(methorphan)、甲基二氢吗啡酮(metopon)、吗啡、纳布啡(nalbuphine)、鸦片萃出物、鸦片液体萃出物、鸦片粉末、鸦片粒剂、生鸦片、鸦片酊剂、羟考酮(oxycodone)、羟氢吗啡酮(oxymorphone)、帕格利(paregoric)、喷他左辛(pentazocine)、派替啶(pethidine)、安唑辛(phenazocine)、去痛定(piminodine)、丙氧吩(propoxyphene)、消旋甲吗喃(racemethorphan)、消旋吗喃(racemorphan)、速芬坦尼(sufentanyl)、蒂巴因(thebaine)与上述制剂之药学上可接受的盐类与水合物。
麻醉止痛剂之其它实例包括:乙醯吩(acetorphine)、乙酰基二氢可待因、乙醯美沙醇(acetylmethadol)、烯丙基普洛定(allylprodine)、α-乙醯美沙醇(alphracetylmethadol)、α-美普定(alphameprodine)、α-美沙醇(alphamethadol)、苯塞定(benzethidine)、苯甲基吗啡、β-乙醯美沙醇(betacetylmethadol)、β-美普定(betameprodine)、β-美沙醇(betamethadol)、3-普洛定(betaprodine)、克尼辛(clonitazene)、可待因甲基溴化物、可待因-N-氧化物、希普吗啡(cyprenorphine)、二氢脱氧吗啡(desomorphine)、右旋莫醯胺(dextromoramide)、二普醯胺(diampromide)、二乙基噻丁烯(diethylthiambutene)、二氢吗啡(dihydromorphine)、二孟赛哚(dimenoxadol)、二甲庚醇(dimepheptanol)、二甲基噻丁烯(dimethylthiamubutene)、二菲定丁酸盐(dioxaphetyl butyrate)、地匹派酮(dipipanone)、羟蒂巴酚(drotebanol)、乙醇、乙基甲基噻丁烯(ethylmethylthiambutene)、依托塔辛(etonitazene)、依托芬(etorphine)、依托利定(etoxeridine)、夫特定(furethidine)、氢化吗啡醇(hydromorphinol)、羟基普地定(hydroxypethidine)、酮基贝米酮(ketobemidone)、左旋莫醯胺(levomoramide)、左旋酚酰基吗喃(levophenacylmorphan)、甲基脱氧吗啡(methyldesorphine)、甲基二氢吗啡、吗啡啶(morpheridine)、吗啡、甲基普醯胺(methylpromide)、吗啡甲基磺酸酯、吗啡-N-氧化物、吗咯吩(myrophin)、纳洛酮(naloxone)、纳曲酮(naltyhexone)、烟可待因(nicocodeine)、烟吗啡(nicomorphine)、去甲基酰基美沙醇(noracymethadol)、去甲基左吗喃(norlevorphanol)、去甲基美沙酮(normethadone)、去甲基吗啡、去甲基比喃酮(norpipanone)、苯他索卡因(pentazocaine)、吩哚散(phenadoxone)、酚安普醯胺(phenampromide)、酚吗喃(phenomorphan)、酚普啶(phenoperidine)、吡咯他醯胺(piritramide)、福尔可定(pholcodine)、普庚索辛(proheptazoine)、备解素(properidine)、丙吡胺(propiran)、消旋莫醯胺(racemoramide)、蒂巴康(thebacon)、三甲普定(trimeperidine)与其药学上可接受的盐类与水合物。
其它明确之代表性止痛剂包括例如:乙醯胺酚(醋胺酚(paracetamol))、布洛芬(ibuprofen)、阿司匹林与其它上述NSAID、NR2B拮抗剂、舒缓素拮抗剂、抗偏头痛剂、抗痉挛剂如:欧卡巴肼(oxcarbazepine)与卡巴肼(carbamazepine)、抗抑郁剂(如:TCA、SSRI、SNRI、P物质拮抗剂,等等)、脊椎阻断剂、喷他左辛(pentazocine)/纳洛酮(naloxone)、麦啶(meperidine)、左吗喃(levorphanol)、丁丙诺菲(buprenorphine)、氢化吗啡酮(hydromorphone)、芬坦尼(fentanyl)、速芬坦尼(sufentanyl)、羟考酮(oxycodone)、羟考酮(oxycodone)/乙醯胺酚、纳布酚(nalbuphine)与羟氢吗啡酮(oxymorphone)。其它止痛剂包括CB2-受体激动剂,如:AM1241、辣椒素受体拮抗剂及会与电压闸控钙信道之α2δ亚单位结合的化合物,如:加巴喷汀(gabapentin)与普加林(pregabalin)。
用于与本文所提供VR1调节剂组合使用之代表性抗偏头痛剂包括CGRP拮抗剂、麦角胺类与5-HT1激动剂,如:舒马曲坦(sumatripan)、纳曲坦(naratriptan)、索马曲坦(zolmatriptan)与利曲坦(rizatriptan)。
其它态样中,本文所提供调节剂可组合使用一种或多种β(2)肾上腺激导性受体激动剂或白三烯受体拮抗剂(例如:抑制半胱胺酰基白三烯CysLT1受体之制剂),用于例如:治疗肺部疾病,如:气喘。CysLT1拮抗剂包括目特路卡(montelukast)、赛弗路卡(zafirlukast)与普安路卡(pranlukast)。
用于治疗或预防咳嗽时,本文所提供VR1调节剂可与其它设计用于治疗此病症之药物组合使用,如:抗生素、消炎剂、半胱胺酰基白三烯类、组织胺拮抗剂、皮质类固醇、类鸦片剂、NMDA拮抗剂、质子帮浦抑制剂、伤害感受素(nociceptin)、神经激肽(NK1、NK2与NK3)与舒缓素(BK1与BK2)受体拮抗剂、类大麻酚、依赖Na+之信道之阻断剂与高传导性Ca+2依赖性K+信道活化剂。明确药剂包括右溴苯纳敏(dexbrompheniramine)加假麻黄碱(pseudoephedrine)、氯雷它定(loratadine)、羟甲唑啉(oxymetazoline)、异丙托溴胺(ipratropium)、沙丁胺醇(albuterol)、贝克美松(beclomethasone)、吗啡、可待因、福尔可定(pholcodeine)与美杀芬(dextromethorphan)。
本发明进一步提出一种治疗尿失禁的组合疗法。此等态样中,本文所提供之调节剂可与设计用于治疗此等病症之药物组成使用,如:雌激素置换疗法、黄体酮同系物、电刺激、钙信道阻断剂、抗痉挛剂、胆碱激导性拮抗剂、抗蕈毒碱药物、三环类抗抑郁剂、SNRI、β肾上腺素能受体激动剂、磷酸二酯酶抑制剂、钾信道开放剂、伤害感受素/欧吩宁(orphanin)FQ(OP4)激动剂、神经激肽(NK1与NK2)拮抗剂、P2X3拮抗剂、肌营养性药物与骶骨神经调节剂。明确药剂包括羟丁宁(oxybutinin)、安普宁(emepronium)、妥乐定(tolterodine)、弗法赛(flavoxate)、弗布吩(flurbiprofen)、妥乐定(tolterodine)、二赛明(dicyclomine)、普菲灵(propiverine)、普本灵(propantheline)、二赛明(dicyclomine)、抑普胺(imipramine)、得西平(doxepin)、得乐西平(duloxetine)、1-去氨基-8-D-精胺酸血管收缩素、蕈毒碱受体拮抗剂,如:妥乐定(tolterodine)与抗胆碱激导性剂,如:欧布汀(oxybutynin)。
此等组合疗法中合适之VR1调节剂剂量通常如上述。其它缓解疼痛之药物剂量与投药方法可参见例如:制造商于Physician′s DeskReference中之说明。某些具体实施例中,VR1调节剂与一种或多种其它缓解疼痛之药物的组合投药结果可降低要产生医疗效果时所需各医疗剂之剂量(例如:其中一种或两种药剂之剂量可小于上述或制造商所建议之最高剂量之3/4、小于1/2、小于1/4、或小于10%)。
用于组合疗法时,如上述药物组合物可进一步包含一种或多种如上述药物。某些此等组合物中,该其它药物为止痛剂。本文亦提供包装之药物制剂,其在同一包装中包含一种或多种VR1调节剂及一种或多种其它药物(例如:止痛剂)。此等包装之药物制剂通常包括(i)一容器,内装包含至少一种本文所说明之VR1调节剂之药物组合物,(ii)一容器,内装包含至少一种如上述其它药物(如:缓解疼痛与/或消炎之药物),及(ii)说明书(例如:卷标或包装内页),指示其中该组合物系同时、分开或依序用于治疗或预防患者对VR1调节作用有反应之病症(如:出现疼痛与/或发炎之病症)。
作为VR1激动剂的化合物亦可用在例如:群体控制(替代催泪气体)或个人保护(例如:呈喷雾调配物)或经由辣椒素受体去敏化作用,作为治疗疼痛、瘙痒、停经症状、尿失禁或膀胱过动症之医疗剂。通常,用于群体控制或个人保护的化合物系依据习知催泪气体或胡椒喷雾技术调配及使用。
另一态样,本发明提供多种本文所提供化合物之非药物活体外与活体内用途。例如:此等化合物可加以标记及用为检测与定位辣椒素受体(于如:细胞制剂或组织切片、制剂或其部份中)之探针。此外,本文所提供包含合适反应基(如:芳基、羰基、硝基或叠氮基)的化合物可用于进行受体结合位置之光亲和性标记试验。此外,本文所提供化合物亦可用为受体活性分析法中之阳性对照组,作为测定候选试剂与辣椒素受体结合之能力之标准物,或作为正子放射断层扫瞄摄影(PET)显影或单光子放射计算机断层扫瞄摄影(SPECT)之放射追踪剂。此等方法可用于判别活体中辣椒素受体。例如:VR1调节剂可采用多种习知技术标记(例如:放射性标记如本文中说明之放射性核种如:氚),与样本培养一段合适之时间(例如:先分析一段结合时间决定)。培养后,排除未结合的化合物(例如:洗涤),采用任何适合所采用标记物之方法检测已结合的化合物(例如:自动放射照相术或闪烁计数法,测定标记放射性的化合物;可采用分光镜分析法检测冷光基团与萤光基团)。依相同方式处理含有有标记的化合物与较高量(例如:超过10倍以上)无标记的化合物作为对照组之平行样本。试验样本中残留可检测之标记物含量高于对照组时,表示样本中含有辣椒素受体。检测分析法(包括培养细胞或组织样本中辣椒素受体之受体自动放射照相术(受体图谱分析))可依Kuhar述于Current Protocols in Pharmacology(1998)John Wiley &Sons,New York中第8.1.1至8.1.9.节中之方法进行。
本文所提供的化合物亦可用于多种习知的细胞分离法。例如:调节剂可连结组织培养板或其它担体之内表面,用为固定亲和性配位体,藉以于活体外单离辣椒素受体(例如:单离表达受体的细胞)。一项较佳具体实施例中,调节剂系连结萤光标记物,如:萤光素,与细胞接触后,使用萤光活化的细胞筛选法(FACS)分析(或单离)。
本文所提供VR1调节剂亦可用于判别其它与辣椒素受体结合之制剂之分析法中。通常,此等分析法为标准竞争性结合分析法,其中以试验化合物置换已结合且有标记之VR1调节剂。简言之,此等分析法系:(a)由辣椒素受体与本文所说明标记放射性之VR1调节剂,于可使VR1调节剂与辣椒素受体结合之条件下接触,藉以产生已结合有标记之VR1调节剂;(b)于没有试验制剂之存在下检测相当于已结合之有标记之VR1调节剂含量之信号;(c)由已结合之有标记之VR1调节剂与试验制剂接触;(d)于试验制剂之存在下检测相当于已结合之有标记之VR1调节剂含量之信号;及(e)与(b)步骤检测到之信号比较,检测(d)步骤信号之下降程度。
下列实例系供说明用,并未加以限制。除非另有说明,否则所有试剂与溶剂均为标准商品级,未再进一步纯化即使用。采用例行修饰法可以变化起始物与其它所采用之步骤,以制成其它本文所提供之其它化合物。
实例
下列实例中,质谱数据为电喷洒MS,系使用加装Waters 600帮浦,Waters 996光二极管排列检测器,Gilson 215自动取样机与Gilson 841微注射器之Micromass Time-of-Flight LCT,以15V或30V锥管电压,在阳离子模式下测得。采用MassLynx(Advanced ChemistryDevelopment,Inc;Torontco,Canada)4.0版软件收集数据及分析。取1微升样本体积注射至50×4.6毫米Chromolith SpeedROD C18管柱中,采用两相线性梯度,依6毫升/分钟之流速冲提。采用220-340nm UV范围内测得之总吸光度计数检测样本。冲提条件为:移动相A为95/5/0.05的水/甲醇/TFA;移动相B为5/95/0.025的水/甲醇/TFA。
梯度:时间(分钟) %B
0 10
0.5 100
1.2 100
1.21 10
注射与注射之间之总操作时间为2分钟。
实例1
代表性中间物制法
此实例说明适用于合成2-苯氧基嘧啶酮衍生物之代表性中间物之制备。
A.3-氮基丙胺酸乙酯
取含氰基二羟醋酸乙酯-2-肟(50克,352毫摩尔)之440毫升水的混合物,使用340毫升饱和NaHCO3水溶液小心处理后,分批添加亚硫酸氢钠(165克,950毫摩尔)。加热反应至内部温度为35℃处理35分钟。冷却至室温后,反应经NaCl(约250克)饱和,以CH2Cl2(6×150毫升)萃取。将合并之CH2Cl2萃液脱水(Na2SO4),过滤与真空浓缩,产生标题化合物之褐色油状物。1H NMR(400MHz,CDCl3)δ 4.43(1H,s),4.34(2H,q,J7.2),2.30(2H,bs),1.35(3H,t,J7.2)。
B.5-氨基-1-甲基-1H-咪唑-4-甲酸乙酯
取含3-氮基丙胺酸乙酯(26.7克,208毫摩尔)与原甲酸三乙酯(34.6毫升,208毫摩尔)之340毫升乙腈混合物加热至90℃,搅拌70分钟。冷却至室温后,添加甲基胺(25.9毫升之33重量%溶液溶于EtOH,208毫摩尔),然后于室温下搅拌20小时。随后真空浓缩反应混合物,溶于约200毫升1N HCl。水溶液经CH2Cl2(3×100毫升)洗涤,以NaHCO3固体碱化至pH=9至10,以CH2Cl2(5×100毫升)萃取。将合并之CH2Cl2萃液脱水(Na2SO4),过滤与浓缩,产生褐色固体。固体于EtOAc中形成浆物,过滤,以Et2O洗涤,产生标题化合物之灰白色固体。1H NMR(400MHz,CDCl3)δ7.03(1H,s),4.88(2H,bs),4.33(2H,q,J7.2),3.45(3H,s),1.37(3H,t,J 7.2)。
C.1-(4-氟苯基)-9-甲基-2-硫酮基-1,2,3,9-四氢-6H-嘌呤-6-酮盐酸
盐
取5-氨基-1-甲基-1H-咪唑-4-甲酸乙酯(8.45克,0.05摩尔)与异硫代氰酸4-氟苯基酯(7.65克,0.05摩尔)于吡啶(125毫升)中,于45℃下搅拌20小时。真空浓缩反应混合物,然后以冰冷水稀释。反应混合物经CH2Cl2(2×250毫升)萃取,以水(200毫升)洗涤,经硫酸镁脱水。真空蒸发滤液,产生红橙色黏性油状之粗制中间产物。该油状物于1%氢氧化钠水溶液(300毫升)中形成浆物,于90℃下加热20小时。冷却反应混合物,滤出固体。真空蒸发滤液以缩减体积(100毫升)。混合物使用浓HCl酸化至pH4.0,于室温下静置一夜。滤出分离出之黄色固体,于70℃下干燥,产生标题化合物。1H NMR(400MHz,DMSO-d6)δ7.8(1H,s),7.2-7.4(4H,m),3.74(3H,s)。
D.2-氯-1-(4-氟苯基)-9-乙基-1,9-二氢-6H-嘌呤-6-酮
取1-(4-氟苯基)-9-甲基-2-硫酮基-1,2,3,9-四氢-6H-嘌呤-6-酮盐酸盐(6.5克,0.021摩尔)悬浮于大量氧氯化磷(150毫升)中,加热至135℃,40小时。反应混合物冷却,真空蒸发,与甲苯共沸2次。所得黏性褐色油状物溶于DCM(200毫升)后,以饱和NaHCO3(水溶液)中和。水层经DCM(2×200毫升)萃取与脱水(MgSO4)。过滤与真空浓缩脱水之萃液,产生淡褐色固体之粗产物。粗产物经快速管柱层析法,使用1至2.5%MeOH/CH2Cl2纯化,产生白色固体之标题化合物。1H NMR(400MHz,CDCl3)δ7.75(1H,s),7.2-7.35(4H,m),3.85(3H,s)。
E.3-氨基吡啶-2-甲酸乙酯
溶于26毫升EtOH之3-氨基吡啶-2-甲酸(6.4克,46.3毫摩尔)与8毫升浓硫酸之混合物加热至回流2天。冷却后,混合物浓缩至约15-20毫升,倒入20克冰中。混合物于冰浴冷却下使用浓缩NH4OH碱化至pH8至9。滤出所得褐色沉淀,滤液经乙醚(4×60毫升)萃取。合并之醚萃液经盐水(4×60毫升)洗涤、脱水(Na2SO4)、过滤与蒸发,产生黄色/褐色固体。此固体与上一份滤液合并,一起使用冷乙醚磨制,产生淡褐色固体之标题化合物。1H NMR(400MHz,CDCl3)δ8.08(1H,m),7.21(1H,m),7.03(1H,m),5.74(2H,bs),4.44(2H,q,J7.2,6.9),1.45(3H,t,J6.9)。
F.3-(4-氟苯基)-2-硫酮基-2,3-二氢吡啶并[3,2-d]嘧啶-4(1H)-酮
取含3-氨基吡啶-2-甲酸乙酯(2.0克,12.0毫摩尔)与异硫代氰酸4-氟苯基酯(1.84克,12.0毫摩尔)之7毫升无水吡啶混合物于45℃下搅拌21小时。冷却后,真空蒸发吡啶,添加冰水至残质中。所得混合物于EtOAc中形成浆物与过滤,产生白色固体之标题化合物。1H NMR(400MHz,DMSO-d6)δ 8.59(1H,m),7.79(2H,m),7.33(4H,m)。
G.2-氯-3-(4-氟苯基)吡啶并[3,2-d]嘧啶-4(3H)-酮
取含3-(4-氟苯基)-2-硫酮基-2,3-二氢吡啶并[3,2-d]嘧啶-4(1H)-酮(2.6克,9.5毫摩尔)之30毫升POCl3混合物加热至135℃,搅拌2天。冷却至室温后,真空排除过量POCl3,残质与甲苯共沸两次。所得黏性褐色油状/固体混合物溶于CH2Cl2,以饱和NaHCO3中和至pH7至8。分层,将CH2Cl2层脱水(Na2SO4)、过滤与蒸发,产生褐色黏性固体。经管柱层析法纯化(CH2Cl2至20%EtOAc/CH2Cl2之梯度)产生灰白色固体之标题化合物。1H NMR(400MHz,CDCl3)δ 8.91(1H,m),8.05(1H,m),7.74(1H,m),7.28(4H,m)。
H.乙酸甲酸酐
添加乙酸酐(35.94克,352毫摩尔)与甲酸(16.20克,352毫摩尔)至圆底烧瓶中,于55℃下加热3小时。反应混合物未再纯化即用于实例I。
I.N-甲酰基-3-氮基丙胺酸乙酯
取3-氮基丙胺酸乙酯(26.9克,210毫摩尔)溶于无水醚(200毫升),于冰/水浴中冷却。滴加乙酸甲酸酐(如上述制成之混合物)。当添加完毕时,使反应混合物回升至室温,于室温下搅拌一夜。真空排除大部份挥发物,藉由与甲苯(100毫升×4)共蒸发来排除残余溶剂。所得红色油状物于醚中擦刮时会沉淀,且所得固体于醚中再结晶,产生白色固体之标题化合物。1H NMR(400MHz,CDCl3)8.32(1H,s),7.26(1H,s),6.46(1H,bs,),5.56(1H,d,J7.8),4.39(2H,q),1.37(3H,t)。
J.5-氨基-1,3-噻唑-4-甲酸乙酯
取N-甲酰基-3-氮基丙胺酸乙酯(11.22克,71.86毫摩尔)溶于无水苯(220毫升)。添加劳森试剂(Lawesson′s reagent)(14.53克,35.93毫摩尔)后,悬浮液回流24小时。真空排除大部份溶剂,将黏性红色残质吸附在硅胶上,后加至硅胶管柱上(冲提溶剂:EtOAc:己烷=50:50),得到黄色固体之标题化合物。1H NMR(400MHz,CDCl3)7.87(1H,s),7.26(1H,s),6.01(2H,宽s),4.38(2H,q),1.41(3H,t)。
K.6-(4-氟苯基)-5-氢硫基[1,3]噻唑并[5,4-d]嘧啶-7(6H)-酮盐酸
盐
添加5-氨基-1,3-噻唑-4-甲酸乙酯(1.05克,6.10毫摩尔)与异硫代氰酸4-氟苯基酯(0.93克,6.10毫摩尔)至吡啶(3.5毫升)中,于45℃下加热15小时。真空排除大部份溶剂,取所得黄色固体溶于CH2Cl2(150毫升),以H2O(20毫升×2)与盐水(20毫升×2)洗涤。取CH2Cl2相经硫酸镁(MgSO4)脱水,减压排除溶剂。所得残质经1% NaOH溶液(37毫升)处理,于90℃下加热15小时。过滤反应混合物,添加浓缩HCl以调整滤液至pH3。真空排除大部份水,将分离出之黄色固体过滤与干燥,产生黄色固体之标题化合物。1H NMR(400MHz,DMSO-d6)8.90(1H,s),7.31(4H,m)。
L5-氯-6-(4-氟苯基)[1,3]噻唑并[5,4-d]嘧啶-7(6H)-酮
添加6-(4-氟苯基)-5-氢硫基[1,3]噻唑并[5,4-d]嘧啶-7(6H)-酮盐酸盐(0.2克,0.633毫摩尔)至POCl3(10毫升),所得溶液于135℃下回流41小时。减压排除大部份挥发物,残余之溶剂与甲苯(50毫升×3)共同蒸发。所得深色固体溶于CH2Cl2(200毫升),以饱和NaHCO3溶液(100毫升×5)、盐水(50毫升×2)洗涤,经硫酸镁脱水。排除溶剂后,经硅胶管柱层析法(EtOAc:己烷=50:50),产生黄色固体之标题化合物。1HNMR(400MHz,CDCl3)8.88(1H,s),7.26(4H,m)。
M.1-(4-溴苯基)-2-氢硫基-9-甲基-1,9-二氢-6H-嘌呤-6-酮盐酸盐
添加5-氨基-1-甲基-1H-咪唑-4-甲酸乙酯(3.50克,20.69毫摩尔)与异硫代氰酸4-溴苯基酯(4.43克,20.69毫摩尔)至吡啶(12毫升)中。溶液于45℃下加热3小时。真空排除大部份溶剂,所得固体溶于CH2Cl2(300毫升)。取CH2Cl2溶液经水(30毫升×2)、盐水(30毫升×2)洗涤,经硫酸镁脱水与真空浓缩。所得黄色固体经1%NaOH水溶液(125毫升)处理,于90℃下加热18小时。反应混合物经过滤,以浓缩HCl将该滤液调至pH3。减压排除大部份水。过滤收集所得固体,固体与甲苯(30毫升×3)共沸,产生黄色固体之标题化合物。1H NMR(400MHz,CD3OD)8.10(1H,s),7.65(2H,d),7.14(2H,d),3.85(3H,s)。
N.1-(4-溴苯基)-2-氯-9-甲基-1,9-二氢-6H-嘌呤-6-酮
添加1-(4-溴苯基)-2-氢硫基-9-甲基-1,9-二氢-6H-嘌呤-6-酮盐酸盐(2.05克,5.49毫摩尔)至POCl3(87毫升),所得溶液于135℃下回流38小时。真空排除大部份挥发物,残余溶剂与甲苯(50毫升×3)共蒸发。取所得深色固体溶于CH2Cl2(300毫升),以饱和NaHCO3溶液(100毫升×5)、盐水(50毫升×2)洗涤,经硫酸镁脱水。真空排除溶剂后,经硅胶管柱层析法(EtOAc;己烷=50:50),产生黄色固体之标题化合物。1HNMR(400MHz,CDCl3)7.51(1H,s),7.67(2H,d),7;14(2H,d),3.83(3H,s);m/z(ES+)340.90(M+)。
实例2
代表性2-苯氧基嘧啶酮衍生物之合成
A.1-(4-溴苯基)-9-甲基-2-(2,3,4-三氟苯氧基)-1,9-二氢-6H-嘌吟
-6-酮(化合物1)
添加1-(4-溴苯基)-2-氯-9-甲基-1,9-二氢-6H-嘌呤-6-酮(150毫克,0.4417毫摩尔)与2,3,4-三氟苯酚(130.8毫克,0.8834毫摩尔)至小瓶中,密封之混合物于140℃下加热搅拌23小时。经硅胶管柱层析法(MeOH:CH2Cl2=0.5:99.5)产生白色固体之标题化合物。1H NMR(400MHz,CDCl3)7.66(3H,m),7.24(2H,m),7.00(2H,m),3.58(3H,s)。MS(M+1):451.08;RT=1.31分钟。依实例6所述测定法测得IC50为100毫微摩尔或以下。
B.1-(4-氟苯基)-9-甲基-2-(3,4,5-三氟苯氧基)-1,9-二氢-6H-嘌呤
-6-酮(化合物2)
取含2-氯-1-(4-氟苯基)-9-乙基-1,9-二氢-6H-嘌呤-6-酮(55.6毫克,0.20毫摩尔)与3,4,5-三氟苯酚(0.40毫摩尔)之混合物加热至140℃,36小时。冷却至室温后,粗混合物经制备性HPLC纯化,产生白色固体之标题化合物。1H NMR(400MHz,DMSO-d6)7.98(1H,s),7.55(2H,m),7.45(2H,m),7.34(2H,m),3.53(3H,S)。m/z=391.05(M+1);RT=0.78分钟。
C.3-(4-氟苯基)-2-[2-氟-3-(三氟甲基)苯氧基]吡啶并[3,2-d]嘧啶
-4(3H)-酮(化合物3)
取含2-氯-3-(4-氟苯基)吡啶并[3,2-d]嘧啶-4(3H)-酮(55毫克,0.20毫摩尔)与2-氟-3-三氟甲基苯酚(50微升,0.40毫摩尔之混合物)加热至140℃,18小时。冷却至室温后,粗混合物经管柱层析法纯化(CH2Cl2至20% EtOAc/CH2Cl2梯度),产生白色固体之标题化合物。1H NMR(400MHz,DMSO-d6)8.71(1H,m),7.83(2H,m),7.70(4H,m),7.45(3H,m)。MS(M+1):420.07;RT=1.13分钟。
D.5-(2,4-二氟苯氧基)-6-(4-氟苯基)[1,3]噻唑并[5,4-d]嘧啶
-7(6H)-酮(化合物4)
添加5-氯-6-(4-氟苯基)[1,3]噻唑并[5,4-d]嘧啶-7(6H)-酮(0.2毫摩尔)与2.4-二氟苯酚(0.4毫摩尔)至小瓶中,密封之混合物于140℃下加热搅拌48小时。经硅胶管柱层析法(MeOH:CH2Cl2=0.5:99.5),产生浅黄色固体之标题化合物。1H NMR(400MHz,CDCl3)8.70(1H,s),7.36(2H,m),7.26(2H,m),7.14(1H,m),6.94(2H,m)。MS(M+1):376.03;RT=1.33分钟。
E.4-[9-甲基-6-氧代-2-(2,3,4-三氟苯氧基)-6,9-二氢-1H-嘌呤-1-基]
苯甲腈(化合物5)
添加1-(4-溴苯基)-9-甲基-2-(2,3,4-三氟苯氧基)-1,9-二氢-6H-嘌呤-6-酮(68毫克,0.1507毫摩尔)、Zn(CN)2(10.6毫克,0.0904毫摩尔)、Pd2(dba)3(4.1毫克,0.0045毫摩尔)与1,1′-双(二苯基膦基)二茂铁(5.0毫克,0.0090毫摩尔)至DMF(1.2毫升)与H2O(0.012毫升)中。以氮气清洗混合物3分钟后,于120℃下加热18小时。使混合物通过硅藻土。添加水(30毫升),所得混合物经CH2Cl2(50毫升×4)萃取。以MgSO4脱除CH2Cl2后,真空排除溶剂。粗产物经管柱层析法纯化(MeOH:CH2Cl2=2:98),产生褐色固体之标题化合物。1H NMR(400MHz,CDCl3)7.86(2H,d,J8),7.65(1H,s),7.53(2h,d,J8),6.95(2H,m),3.59(3H,s)。MS(M+1):398.03;RT=1.22分钟。
F.1-(6-氯吡啶-3-基)-9-甲基-2-(3,4,5-三氟苯氧基)-1H-嘌呤
-6(9H)-酮(化合物6)
步骤1.2-羟基-1-(6-氯吡啶-3-基)-1,9-二氢-6H-嘌呤-6-酮
取5-氨基-1-甲基-1H-咪唑-4-甲酸甲酯(1.0克,0.006摩尔)、2-氯-5-异氰酰基吡啶(1.0克,0.006摩尔)与DMAP(0.4克,0.003摩尔)悬浮于EtOAc(150毫升),所得反应混合物经回流一夜。反应混合物经过滤,以EtOAc洗涤,真空浓缩。将白色残质悬浮于1% NaOH水溶液(53毫升)中,于90℃下搅拌20小时。反应混合物经6N HCl中和,以DCM萃取,产生标题化合物。
步骤2.2-氯-1-(6-氯吡啶-3-基)-1,9-二氢-6H-嘌呤-6-酮
取上述反应之2-羟基-1-(6-氯吡啶-3-基)-1,9-二氢-6H-嘌呤-6-酮悬浮于大量之过量之氧氯化磷(150毫升)中,加热至135℃ 24小时。冷却反应混合物,真空蒸发,再加额外的甲苯进行减压蒸发(2×)。取所得黏性褐色油状物溶于DCM(200毫升)后,以饱和NaHCO3(水溶液)中和。水层经DCM(2×200毫升)萃取与脱水(MgSO4)。脱水之萃液经过滤与真空浓缩,产生淡褐色固体之粗产物。粗产物经快速管柱层析法,使用1至2.5% MeOH/CH2Cl2纯化,产生白色固体之标题化合物。1H NMR(300MHz,CDCl3)δ8.33(s,1H),7.78(s,1H),7.58(d,J=6Hz,1H),7.53(d,J=6Hz,1H)。
步骤3.1-(6-氯吡啶-3-基)-9-甲基-2-(3,4,5-三氟苯氧基)-1H-嘌呤-6(9H)-酮(化合物6)
将1.0M KOtBu之异丙醇溶液(2毫升)添加至3,4,5-三氟苯酚(0.29克,1.86毫摩尔)溶液中,于室温下搅拌20分钟。在所得苯氧化物溶液中添加2-氯-1-(6-氯吡啶-3-基)-1,9-二氢-6H-嘌呤-6-酮(0.5克,1.69毫摩尔)之二甲基乙醯胺溶液(3毫升),于50℃下搅拌所得混合物一夜。冷却所得反应混合物,以饱和NH4Cl溶液中止反应,以DCM(2×50毫升)萃取,脱水(Na2SO4)。有机层经过滤与真空浓缩,产生淡褐色固体之粗产物。粗产物进一步经快速管柱层析法,使用5% MeOH/CH2Cl2纯化,产生白色固体之标题化合物。1H NMR(300MHz,CDCl3)δ 8.41(s,1H),7.55-7.81(m,2H),7.4(brs,1H),6.71-7.02(m,2H),3.85(s,3H)。MS(M+1):408.04;RT=1.48分钟。依实例6所述方法测得之IC50为100毫微摩尔或以下。
G.5-(9-甲基-6-氧代-2-(3,4,5-三氟苯氧基)-6H-嘌呤-1(9H)-基)2-氰
基吡啶(化合物7)
添加1-(6-氯吡啶-3-基)-9-甲基-2-(3,4,5-三氟苯氧基)-1,9-二氢-6H-嘌呤-6-酮(0.3克,0.73毫摩尔)、Zn(CN)2(0.43毫克,3.65毫摩尔)、Pd2(dba)3(0.07克,0.073毫摩尔)与DPPF(0.04克,0.073毫摩尔)至DMF(3毫升)中。以氮气清洗混合物3分钟后,于120℃下加热18小时。添加水(20毫升),所得混合物经DCM(2×20毫升)萃取。取有机层通过硅藻土与Na2SO4,真空排除溶剂。粗产物经硅胶管柱层析法纯化(MeOH:CH2Cl2=2:98),产生白色固体之标题化合物。1H NMR(300MHz,CDCl3)δ8.71(s,1H),7.90(s,2H),7.68(s,1H),7.25(s,2H),6.85-6.89(m,2H),3.65(s,3H,s)。MS(M+1):399.07;RT=1.41分钟。依实例6所述方法测得之IC50为100毫微摩尔或以下。
实例3
其它代表性的2-苯氧基嘧啶酮衍生物
采用例行修饰法,可以变化起始物及增加其它步骤以制成本文所提供之其它化合物。表I所列化合物系采用此等方法制备。于标示「IC50」那行中,*表示依实例6所述方法测得之IC50为100毫微摩尔或以下(亦即使曝露于IC50之辣椒素的细胞萤光反应下降50%时所需此等化合物浓度为100毫微摩尔或以下)。如上述所得质谱数据系以M+1表示于标示「MS」的那栏行中,且滞留时间系以分钟表示于标示「RT」的那行中。
表I
代表性2-苯氧基嘧啶酮衍生物
化合物 名称 MS R T IC 50
化合物 名称 MS R T IC 50
化合物 名称 MS R T IC 50
化合物 各称 MS R T IC 50
化合物 名称 MS R T IC 50
化合物 名称 MS R T IC 50
化合物 名称 MS R T IC 50
化合物 名称 MS R T IC 50
化合物 名称 MS R T IC 50
化合物 名称 MS R T IC 50
化合物 名称 MS R T IC 50
化合物 名称 MS R T IC 50
化合物 名称 MS R T IC 50
实例4
VR1转染的细胞与膜制备物
此实例说明用于辣椒素结合分析法(实例5)之VR1转染的细胞与含VR1的膜制备物之制备方法。
取编码全长度人类辣椒素受体之cDNA(美国专利案No.6,482,611之SEQ ID N0:1、2或3)次克隆至质体pBK-CMV(Stratagene,La Jolla,CA),以于哺乳动物细胞中重组表达。
采用标准方法,使人类胚胎肾脏(HEK293)细胞转染编码全长度之人类辣椒素受体之pBK-CMV表达建构。将经转染细胞在含G418(400微克/毫升)之培养基中筛选两周,得到一群稳定的转染的细胞。经由限制稀释法,自此群细胞中分离独立纯系,以得到纯系之稳定细胞株,供下一个试验使用。
进行放射性配位体结合性试验时,接种细胞至T175细胞培养烧瓶内之不含抗生素之培养基中,生长至约90%密度。随后以PBS洗涤烧瓶,然后以5mM EDTA之PBS收集细胞。以温和离心收集经沉淀的细胞,保存在-80℃下至分析为止。
取先前冷冻的细胞利用组织均质器的帮助于冰冷HEPES均质缓冲液中(5mM KCl、5.8mM NaCl、0.75mM CaCl2、2mM MgCl2、320mM蔗糖与pH7.4之10mM HEPES)来打破细胞。组织均质液先于1000×g(4℃)下离心10分钟以移除核部份及细胞碎片,然后取第一次离心之上清液再于35,000×g(4℃)下离心30分钟,得到部份纯化之膜部份。于分析先将膜以HEPES均质缓冲液再悬浮。取一份膜均质液,利用Bradford方法(BIO-RAD蛋白质分析套组,#500-0001,BIO-RAD,Hercules,CA)测定蛋白质浓度。
实例5
辣椒素受体结合性分析法
本实例说明用于测定化合物对辣椒素(VR1)受体之结合亲和性之辣椒素受体结合性之代表性分析法。
与[3H]树脂毒素(resiniferatoxin)(RTX)之结合分析法基本上系依Szallasi与Blumberg(1992)J.Pharmacol.Exp.Ter.262:883-888中说明之方法进行。此方法中,当结合反应结束后,非专一性RTX结合性会因添加牛α1酸醣蛋白(每支试管100微克)而下降。
[3H]RTX(37Ci/毫摩尔)系由Chemical Synthesis and AnalysisLaboratory,National Cancer Institute-Frederick Cancer Research andDevelopment Center,Frederick,MD合成得到。[3H]RTX亦可自贩售商取得(例如:Amersham Pharmacia Biotech,Inc.;Piscataway,NJ)。
如前述离心实例4之膜均质物,将其再悬浮于均质缓冲液中使得为蛋白质浓度为333微克/毫升。于冰上设置结合分析法混合物,其包含[3H]RTX(比活性2200mCi/毫升)、2微升非放射活性试验化合物、0.25毫克/毫升牛血清白蛋白(Cohn部份V)、与5×104至1×105VR1-转染细胞。使用上述冰冷HEPES均质缓冲液(pH7.4)调整最终体积至500微升(用于竞争结合性分析法)或1,000微升(用于饱和结合性分析法)。非专一结合性之定义为在1μM非放射活性RTX(Alexis Corp.;SanDiego,CA)之存在下之结合性。分析饱和结合性时,[3H]RTX之添加浓度范围为7至1,000pM,稀释1至2次。典型作法为每条饱和结合性曲线收集11个浓度点。
竞争结合性分析法系于60pM[3H]RTX及不同浓度之试验化合物之存在下进行。将分析混合物移至37℃水浴中以开始进行结合性反应,反应60分钟后,将试管置于冰上冷却以中止反应。于WALLAC玻璃纤维滤纸(PERKIN-ELMER,Gaithersburg,MD)(使用前先浸泡1.0%PEI(聚乙烯亚胺)2小时)上过滤将与膜结合之RTX与游离之RTX,及任何与α1酸醣蛋白结合之RTX分离。使滤纸干燥一夜后,添加WALLAC BETA SCINT闪烁计数液,于WALLAC 1205 BETA PLATE计数器上计数。
平衡结合性参数之决定法系代入变构性希尔公式(the allosteric Hillequation),藉由计算机程序FIT P(Biosoft,Ferguson,MO)之助(说明于Szallasi等人之(1993)J.Pharmacol.Exp.Ther.266:678-683)计算数据。本文所提供化合物于此分析法中对辣椒素受体之Ki值小于1μM、100nM、50nM、25nM、10nM或1nM。
实例6
钙移动性分析法
本实例说明用于分析试验化合物之激动剂与拮抗剂活性之代表性钙移动性分析法。
以表达质体转染细胞(依实例4所述),藉以将表达人类辣椒素受体的细胞接种至FALCON黑边透明底板之96孔盘中(#3904,BECTON-DICKINSON,Franklin Lakes,NJ),生长至密度为70至90%。移除96孔盘中之培养基,在各孔中添加FLUO-3AM钙敏感性染料(Molecular Probes,Eugene,OR)(染料溶液:1毫克FLUO-3 AM、440微升DMSO与440微升20%普罗尼克酸(pluronic acid)之DMSO溶液,于克氏-林格氏(Krebs-Ringer)HEPES(KRH)缓冲液(25mM HEPES、5mMKCl、0.96mM NaH2PO4、1mM MgSO4、2mM CaCl2、5mM葡萄糖、1mM羧苯磺胺(probenecid),pH7.4)中稀释1:250,每孔50微升稀释溶液))。以铝箔盖上分析盘,于37℃之含5%CO2环境下反应1至2小时。反应后,移除分析盘中之染料,以KRH缓冲液洗涤细胞一次,再将其悬浮于KRH缓冲液中。
辣椒素EC50之测定法
为了测定试验化合物于表达辣椒素受体的细胞中对辣椒素或其它类香草醇激动剂激动或拮抗钙移动性反应之能力,因此先测定激动剂辣椒素之EC50。在各孔细胞中添加依上述制备之20微升KRH缓冲液与1微升DMSO。采用FLIPR仪器,自动取出100微升含辣椒素之KRH缓冲液加至各孔中。采用FLUOROSKAN ASCENT(Labsystems;Franklin,MA或FLIPR(萤光测定仪显影板读数系统;Molecular Devices,Sunnyvale,CA)仪器追踪辣椒素诱发之钙移动性。以施用激动剂后30至60秒之间所取得数据制成8个点之浓度效应曲线,最终辣椒素浓度为1nM至3μM。采用KALEIDAGRAPH软件(Synergy Software,Reading,PA)将数据代入公式:
y=a*(1/(1+(b/x)c))
以测定该反应之50%激发浓度(EC50)。此公式中,y为最高萤光信号,x为激动剂或拮抗剂(此例中指辣椒素)浓度,a为Emax;b相当于EC50值,与c为希尔系数(Hill coefficient)。
促效激动剂活性测定法
取试验化合物溶于DMSO中,于KRH缓冲液中稀释,立即加至依上述制备的细胞中。亦添加100nM辣椒素(约EC90浓度)至相同96孔盘的细胞中作为阳性对照组。分析孔中试验化合物之最终浓度为0.1nM至5μM之间。
试验化合物作为辣椒素受体之激动剂之能力系藉由测定表达辣椒素受体的细胞被化合物诱发之萤光反应来测定,化合物浓度萤光反应之函数。依上述代入此数据,得到EC50,结果通常小于1微摩尔,较佳为小于100nM,更佳为小于10nM。亦由试验化合物浓度(典型为1μM)诱发之反应相对于由100nM辣椒素诱发之反应计算各试验化合物之效力程度。此数值称为信号百分比(POS),由下列公式计算:
POS=100*试验化合物反应/100nM辣椒素反应
此分析法提供分析试验化合物作为人类辣椒素受体激动剂之强度与效力之定量法。人类辣椒素受体之激动剂通常在小于100μM浓度下诱发可检测之反应,或较佳为小于1μM之浓度,或最佳为小于10nM之浓度。其在1μM浓度时,对人类辣椒素受体之效力程度较佳为大于30POS,更佳为大于80POS。某些激动剂在下文说明之分析法中,于低于4nM的化合物浓度,更佳为低于10μM之浓度,及最佳为低于或等于100μM之浓度下,没有可检测之拮抗剂活性,即证实其基本上没有拮抗剂活性。
拮抗剂活性测定法
取试验化合物溶于DMSO中,以20微升KRH缓冲液稀释,使分析孔中最终试验化合物浓度为1μM至5μM之间,将其加至如上述制备的细胞中。取含已制备的细胞与试验化合物之96孔盘于黑暗中与室温下反应0.5至6小时。应注意,培养时间不可持续超过6小时。即将测定萤光反应之前,方利用FLIPR仪器自动添加100微升含辣椒素之KRH缓冲液至96孔盘各孔中,所添加之浓度为如上述测得之EC50之两倍浓度,最终样本体积为200微升,最终辣椒素浓度等于EC50。分析孔中试验化合物之最终浓度为1μM至5μM之间。辣椒素受体之拮抗剂在10微摩尔或以下浓度,较佳为1微摩尔或以下浓度,使此反应相对于平行对照组(亦即在没有试验化合物之存在下,使用两倍EC50浓度之辣椒素处理的细胞)降低至少约20%,较佳为至少约50%,最佳为至少80%。取相对于在辣椒素之存在下及没有拮抗剂下所观察到之反应降低50%时所需拮抗剂浓度为拮抗剂之IC50,较佳为低于1微摩尔、100毫微摩尔、10毫微摩尔或1毫微摩尔。
数据分析法如下。首先,由其它各实验孔所检测到最高反应扣除阴性对照组孔(没有激动剂)之平均最高相对萤光单位(RFU)反应。其次,计算阳性对照组孔(激动剂孔)之平均最高RFU反应。然后采用下列公式计算各试验化合物之抑制百分比:
抑制百分比=100-100×(试验细胞峰值信号/对照组细胞最峰值信号)
由抑制%数据以试验化合物浓度为函数作图,并采用例如:KALEIDAGRAPH软件(Synergy Software,Reading,PA)由数据拟合公式,决定化合物IC50:
y=m1*(1/(1+(m2/m0)m3))
其中y为抑制百分比,m0为激动剂浓度,m1为最高RFU,m2相当于试验化合物IC50(相对于在激动剂存在下但没有拮抗剂下所观察到之使反应下降50%所需之浓度),m3为希尔系数。或者,试验化合物IC50系使用线性回归决定,其中x为1n(试验化合物浓度),y为1n(抑制百分比/(100-抑制百分比))。抑制百分比高于90%或低于15%之数据则淘汰不用于回归分析。依此方式计算之IC50为e(-截距/斜率)。
某些较佳VR1调节剂为于上述分析法中,于低于4nM的化合物浓度,更佳为低于10μM之浓度,及最佳为低于或等于100μM之浓度下没有可检测之激动剂活性时,即证实其为基本上没有激动剂活性之拮抗剂。
实例7
背根神经节细胞分析法
此实例说明用于分析化合物之VR1拮抗剂或激动剂活性之代表性背根神经节细胞分析法。
依标准方法,自新生老鼠中切下DRG,解离及培养(Aguayo与White(1992)Brain Research 570:61-67)。培养48小时后,洗涤细胞一次,与钙敏感性染料Fluo 4 AM(2.5至10微克/毫升;TefLabs,Austin,TX)反应30至60分钟。然后再洗涤细胞一次。添加辣椒素至细胞中会导致VR1依赖(VR1-dependent)的细胞内钙浓度增加,其可藉由萤光计测定Fluo4萤光之变化而追踪。收集60至180秒之数据,测定最高萤光信号。
拮抗剂分析法中,添加不同浓度的化合物至细胞,然后以化合物浓度为函数画出萤光信号曲线,以判别达到抑制50%辣椒素所活化之反应时所需之浓度或IC50。辣椒素受体之拮抗剂之较佳IC50低于1微摩尔、100毫微摩尔、10毫微摩尔或1毫微摩尔。激动剂分析法中,添加不同浓度的化合物至没有添加辣椒素的细胞中。作为辣椒素受体激动剂的化合物导致VR1依赖的细胞内钙浓度性增加,其可藉由萤光计测量Fluo-4萤光变化而追踪。达到辣椒素活化反应最高信号之50%时所需浓度或EC50,其较佳为低于1微摩尔、低于100毫微摩尔或低于10毫微摩尔。
实例8
测定疼痛缓解之动物模式
此实例说明分析化合物缓解疼痛程度之代表性方法。
A.疼痛缓解试验
下列方法系用于分析疼痛缓解程度。
机械性触痛
基本上依Chaplan等人之(1994)J.Neurosci.Methods 53:55-63及Tal与Eliav之(1998)Pain64(3):511-518中说明之方法分析机械性触痛(对无害刺激产生之异常反应)。取一系列不同刚度之凡弗瑞(von Frey)丝线(典型为一系列8至14条丝线)施加在后脚足底表面上,其力量恰足使丝线弯曲。丝线保持此位置不超过3秒钟或直到大鼠出现阳性触痛反应为止。阳性触痛反应包括举起处理的后脚,立即舔或摇动脚部。采用狄克森上下分析法(Dixon up-down method)决定各丝线之施加顺序与频率。使用此系列中之中等丝线开始试验,随后依向上或向下顺序连续施用,分别依开始时所使用丝线是否出现阴性或阳性反应而定。
若接受此等化合物处理之大鼠相较于未处理对照组或媒剂处理组大鼠需要使用较高刚度之凡弗瑞(von Frey)丝线刺激方可引起阳性触痛反应时,表示该化合物可有效逆转或预防类似机械性触痛之症状。替代地,或另外,可在给予化合物之前及之后测试动物之慢性疼痛。此等分析法中,相较于处理前诱发反应时所需丝线或未经处理或经媒剂处理且亦具慢性疼痛之动物所需丝线,有效化合物可使处理后诱发反应所需丝线刚度提高。试验化合物系于疼痛发作之前或之后投药。当试验化合物在疼痛发作之后投药时,在投药后进行试验10分钟至3小时。
机械性痛觉过敏
基本上依Koch等人之(1996)Analgesia 2(3):157-164说明之方法测定机械性痛觉过敏(对疼痛刺激之反应过度)。取大鼠置于有温热多孔金属地板之个别笼内。在任一只后脚足底表面上温和针刺后,测定后脚抽回之时间期(亦即动物维持其后脚上提,并将其后脚放回地板上之前保持之时间)。
若化合物使后脚抽回之时间期缩短达统计显著性时,则该化合物可降低机械性痛觉过敏。试验化合物系于疼痛发作之前或之后投药。当试验化合物在疼痛发作之后投药时,在投药后进行试验10分钟至3小时。
热痛觉过敏
基本上依Hargreaves等人说明于(1988)Pain.32(1):77-88中方法测定热痛觉过敏(对有害热刺激之反应过度)。简言之,在动物任一只后脚之足底表面施加恒定之辐射热源。抽回后脚之时间(亦即动物移动后脚之前之加热时间期),或称为热阀值或潜伏期,即可决定动物后脚对热之敏感性。
若化合物使抽回后脚之时间延长达统计显著性时(亦即出现反应之热阀值或潜伏期加长),则该化合物可降低热痛觉过敏。试验化合物系于疼痛发作之前或之后投药。当化合物在疼痛发作之后投药时,在投药后进行试验10分钟至3小时。
B.疼痛模式
可采用下列任一种方法诱发疼痛,以测定化合物之止痛效力。总括而言,采用雄性SD大鼠及下列至少一种模式时,本文所提供化合物可在上述至少一种试验法中使疼痛统计上显著降低。
急性发炎疼痛模式
急性发炎疼痛系基本上依Field等人说明于(1997)Br.J.Pharmacol.121(8):1513-1522中之角叉菜胶模式中诱发急性疼痛。取100至200微升1%至2%角叉菜胶溶液注射大鼠后脚中。注射后3至4小时,依上述方法测定动物对热及与机械性刺激之敏感性。在试验前或注射角叉菜胶之前,对动物给予试验化合物(0.01至50毫克/公斤)。化合物可经口或任何非经肠式途径、或局部投药至脚部。在此模式中缓解疼痛的化合物可使机械性触痛与/或热痛觉过敏在统计上显著降低。
慢性发炎疼痛模式
采用下列一种方法诱发慢性发炎疼痛:
1.基本上依Bertorelli等人于(1999)Br.J.Pharmacol.128(6):1252-1258及Stein等人于(1998)Pharmacol.Biochem.Behav.31(2):455-51所述,取200微升完全弗洛伊德氏辅剂(Complete Freund′sAdjuvant)(0.1毫克热杀死与干燥之结核菌(M.Tuberculosis))注射至大鼠后脚中:100微升注入足背,100微升注入足底表面。
2.基本上依Abbadie等人于(1994)J Neurosci.14(10):5865-5871所述,在大鼠之胫骨跗骨关节上注射150微升CFA(1.5毫克)。
其任一方法中,在注射CFA之前,先取得各试验动物后脚对机械及热刺激之个别敏感度基准线。
注射CFA后,依上述测试大鼠之热痛觉过敏、机械性触痛与机械性痛觉过敏。为了证实其发展出症状,在注射CFA后第5、6与7天时才开始进行大鼠试验。第7天时,以试验化合物、吗啡或媒剂处理动物。以口服剂量为1至5毫克/公斤之吗啡作为合适之阳性对照组。典型采用之试验化合物剂量为0.01至50毫克/公斤。化合物可在试验前呈单一大丸剂投药或在试验前,每天投药1、2或3次,进行数天。药物可经口或任何非经肠式途径、或局部投药给动物。
其结果以最高可能效力百分比(MPE)表示。0% MPE之定义为媒剂之止痛效力,100% MPE之定义为动物恢复至注射CFA前之基准线敏感度。在此模式中缓解疼痛的化合物所得到之MPE为至少30%。
慢性神经性疼痛模式
慢性神经性疼痛系基本上依Bennett与Xie于(1988)Pain 33:87-107中所述采用慢性收缩伤害(CCI)处理大鼠坐骨神经而诱发。麻醉大鼠(例如:经腹膜内使用剂量50至65毫克/公斤之戊巴比妥及依需要再增加剂量)。将各后脚侧面刮毛及消毒。采用无菌技术,切开后脚侧面中股。将股二头肌切成钝端,曝露出坐骨神经。在每只动物之其中一只后脚上,依约1至2毫米之间隔,将四条结扎线松弛结扎坐骨神经。另一只脚之坐骨神经则没有结扎且不处理。随后依连续模式盖上肌肉,使用伤口夹或缝合线缝合皮肤。依上述分析大鼠之机械性触痛、机械性痛觉过敏与热痛觉过敏。
当化合物在此模式中,在即将试验前呈单一大丸剂投药或在试验前,每天投药1、2或3次,进行数天(0.01至50毫克/公斤,经口、非经肠式或局部投药)时,该些化合物可在统计上显著降低机械性触痛、机械性痛觉过敏与/或热痛觉过敏。
Claims (56)
1.一种如下式的化合物或其药学上可接受之的盐或水合物:
其中,
代表包含1、2或3个杂原子的稠合5或6元杂芳基,该杂原子独立选自:O、N与S,其余环原子为碳,其中,该稠合的杂芳基经0至3个独立选自下列的取代基取代:氨基、羟基、C1-C6烷基、C1-C6羟基烷基、(C3-C7环烷基)C0-C2烷基、C1-C6卤烷基、C1-C6烷氧基、C2-C6烷基醚、C1-C6烷酰氧基、C1-C6烷基磺酰基氨基、C1-C6烷酰基氨基与单或二(C1-C6烷基)氨基;
Ar为苯基或5或6元杂芳基,其分别经0至4个独立选自下列的取代基取代:卤素、氰基、氨基、硝基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤烷基、C1-C6羟基烷基、C1-C6烷氧基、C1-C6卤烷氧基、(C3-C7环烷基)C0-C4烷基与单或二(C1-C6烷基)氨基;以及
R3代表0至4个独立选自下列的取代基:卤素、羟基、氰基、氨基、硝基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤烷基、C1-C6羟基烷基、C1-C6烷氧基、C1-C6卤烷氧基、(C3-C7环烷基)C0-C4烷基、单或二(C1-C6烷基)氨基与单或二(C1-C6烷基)氨基磺酰基。
2.如权利要求1所述的化合物或其盐或水合物,其中,该化合物如下式:
其中:
代表包含1、2或3个杂原子的稠合5或6元杂芳基,该杂原子独立选自:O、N与S,且其经0至2个独立选自下列的取代基取代:氨基、羟基、C1-C6烷基、C1-C6羟基烷基、(C3-C7环烷基)C0-C2烷基、C1-C6卤烷基、C1-C6烷氧基、C2-C6烷基醚、C1-C6烷酰氧基、C1-C6烷基磺酰基氨基、C1-C6烷酰基氨基与单或二(C1-C6烷基)氨基;
X为N或CH,其任选以R1所代表的取代基取代;
R1代表0至3个独立选自下列的取代基:卤素、氰基、氨基、硝基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤烷基、C1-C6羟基烷基、C1-C6烷氧基、C1-C6卤烷氧基、(C3-C7环烷基)C0-C4烷基与单或二(C1-C6烷基)氨基;及
R3代表0至3个独立选自下列的取代基:卤素、羟基、氰基、氨基、硝基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤烷基、C1-C6羟基烷基、C1-C6烷氧基、C1-C6卤烷氧基、(C3-C7环烷基)C0-C4烷基、单或二(C1-C6烷基)氨基与单或二(C1-C6烷基)氨基磺酰基。
3.如权利要求1或2所述的化合物或其盐或水合物,其中,为经0至2个独立选自下列的取代基取代的5元杂芳基:C1-C4烷基、(C3-C5环烷基)C0-C2烷基与C1-C4卤烷基。
7.如权利要求2至6中任一项所述的化合物或其盐或水合物,其中,R1代表1至3个独立选自下列的取代基:卤素、氰基、C1-C4烷基与C1-C4卤烷基。
8.如权利要求7所述的化合物或其盐或水合物,其中,一个由R1代表的取代基为位于对位的卤素或氰基。
9.如权利要求7或8所述的化合物或其盐或水合物,其中,R1代表仅一个取代基。
10.如权利要求1至9中任一项所述的化合物或其盐或水合物,其中,R3代表1至3个独立选自下列的取代基:卤素、氰基、C1-C6烷基、C1-C6卤烷基与C1-C6烷氧基。
15.如权利要求1所述的化合物或其盐或水合物,其中,该化合物为:
1-(4-溴苯基)-9-甲基-2-(2,3,4-三氟苯氧基)-1,9-二氢-6H-嘌呤-6-酮;
1-(4-氯苯基)-2-(2,3-二氟苯氧基)-9-甲基-1,9-二氢-6H-嘌呤-6-酮;
1-(4-氯苯基)-2-(2,4-二氟苯氧基)-9-甲基-1,9-二氢-6H-嘌呤-6-酮;
1-(4-氯苯基)-2-[2-氟-3-(三氟甲基)苯氧基]-9-甲基-1,9-二氢-6H-嘌呤-6-酮;
1-(4-氯苯基)-9-甲基-2-(2,3,4-三氟苯氧基)-1,9-二氢-6H-嘌呤-6-酮;
1-(4-氯苯基)-9-甲基-2-(2,3,5-三氟苯氧基)-1,9-二氢-6H-嘌呤-6-酮;
1-(4-氯苯基)-9-甲基-2-(2,3,6-三氟苯氧基)-1,9-二氢-6H-嘌呤-6-酮;
1-(4-氯苯基)-9-甲基-2-(2,4,5-三氟苯氧基)-1,9-二氢-6H-嘌呤-6-酮;
1-(4-氯苯基)-9-甲基-2-(2,4,6-三氟苯氧基)-1,9-二氢-6H-嘌呤-6-酮;
1-(4-氯苯基)-9-甲基-2-(3,4,5-三氟苯氧基)-1,9-二氢-6H-嘌呤-6-酮;
1-(4-氟苯基)-2-[2-氟-3-(三氟甲基)苯氧基]-9-甲基-1,9-二氢-6H-嘌呤-6-酮;
1-(4-氟苯基)-2-[3-氟-5-(三氟甲基)苯氧基]-9-甲基-1,9-二氢-6H-嘌呤-6-酮;
1-(4-氟苯基)-9-甲基-2-(2,3,4-三氟苯氧基)-1,9-二氢-6H-嘌呤-6-酮;
1-(4-氟苯基)-9-甲基-2-(2,3,5-三氟苯氧基)-1,9-二氢-6H-嘌呤-6-酮;
1-(4-氟苯基)-9-甲基-2-(2,3,6-三氟苯氧基)-1,9-二氢-6H-嘌呤-6-酮;
1-(4-氟苯基)-9-甲基-2-(2,4,5-三氟苯氧基)-1,9-二氢-6H-嘌呤-6-酮;
1-(4-氟苯基)-9-甲基-2-(2,4,6-三氟苯氧基)-1,9-二氢-6H-嘌呤-6-酮;
1-(4-氟苯基)-9-甲基-2-[3-(三氟甲基)苯氧基]-1,9-二氢-6H-嘌呤-6-酮;
1-(6-氯吡啶-3-基)-9-甲基-2-(3,4,5-三氟苯氧基)-1H-嘌呤-6(9H)-酮;
2-(2,3-二氟-4-甲氧基苯氧基)-1-(4-氟苯基)-9-甲基-1,9-二氢-6H-嘌呤-6-酮;
2-(2,3-二氟-4-甲氧基苯氧基)-9-乙基-1-(4-氟苯基)-1,9-二氢-6H-嘌呤-6-酮;
2-(2,3-二氟苯氧基)-1-(4-氟苯基)-9-甲基-1,9-二氢-6H-嘌呤-6-酮;
2-(2,3-二氟苯氧基)-9-乙基-1-(4-氟苯基)-1,9-二氢-6H-嘌呤-6-酮;
2-(2,3-二甲氧基苯氧基)-3-(4-氟苯基)-7-甲基噻吩并[3,2-d]嘧啶-4(3H)-酮;
2-(2,3-二甲基苯氧基)-1-(4-氟苯基)-9-甲基-1,9-二氢-6H-嘌呤-6-酮;
2-(2,4-二氟苯氧基)-1-(4-氟苯基)-9-甲基-1,9-二氢-6H-嘌呤-6-酮;
2-(2,4-二氟苯氧基)-3-(4-氟苯基)吡啶并[3,2-d]嘧啶-4(3H)-酮;
2-(2,4-二氟苯氧基)-9-乙基-1-(4-氟苯基)-1,9-二氢-6H-嘌呤-6-酮;
2-(2,6-二甲基苯氧基)-1-(4-氟苯基)-9-甲基-1,9-二氢-6H-嘌呤-6-酮;
2-(2-氯-4-氟苯氧基)-1-(4-氯苯基)-9-甲基-1,9-二氢-6H-嘌呤-6-酮;
2-(2-氯-4-氟苯氧基)-1-(4-氟苯基)-9-甲基-1,9-二氢-6H-嘌呤-6-酮;
2-(2-乙基苯氧基)-3-(4-氟苯基)-7-甲基噻吩并[3,2-d]嘧啶-4(3H)-酮;
2-(4-氯-2-氟苯氧基)-1-(4-氯苯基)-9-甲基-1,9-二氢-6H-嘌呤-6-酮;
2-(4-氯-2-氟苯氧基)-1-(4-氟苯基)-9-甲基-1,9-二氢-6H-嘌呤-6-酮;
2-(4-氯-2-氟苯氧基)-3-(4-氯苯基)-7-甲基噻吩并[3,2-d]嘧啶-4(3H)-酮;
2-(4-氯-2-氟苯氧基)-3-(4-氟苯基)-7-甲基噻吩并[3,2-d]嘧啶-4(3H)-酮;
2-(4-氯-2-氟苯氧基)-9-乙基-1-(4-氟苯基)-1,9-二氢-6H-嘌呤-6-酮;
2,3-二氟-4-{[1-(4-氟苯基)-9-甲基-6-氧代-6,9-二氢-1H-嘌呤-2-基]氧}苯甲腈;
2-[2-氯-3-(三氟甲基)苯氧基]-3-(4-氟苯基)吡啶并[3,2-d]嘧啶-4(3H)-酮;
3-(4-氯苯基)-2-(2,4-二氟苯氧基)-7-甲基噻吩并[3,2-d]嘧啶-4(3H)-酮;
3-(4-氯苯基)-7-甲基-2-(2,3,4-三氟苯氧基)噻吩并[3,2-d]嘧啶-4(3H)-酮;
3-(4-氟苯基)-2-(2,3,4-三氟苯氧基)吡啶并[3,2-d]嘧啶-4(3H)-酮;
3-(4-氟苯基)-2-(2-异丙基苯氧基)-7-甲基噻吩并[3,2-d]嘧啶-4(3H)-酮;
3-(4-氟苯基)-2-(2-甲氧基苯氧基)-7-甲基噻吩并[3,2-d]嘧啶-4(3H)-酮;
3-(4-氟苯基)-2-[3-(三氟甲基)苯氧基]吡啶并[3,2-d]嘧啶-4(3H)-酮;
3-(4-氟苯基)-2-[3-氟-5-(三氟甲基)苯氧基]吡啶并[3,2-d]嘧啶-4(3H)-酮;
3-(4-氟苯基)-4-氧代-2-(2,3,4-三氟苯氧基)-3,4-二氢噻吩并[3,2-d]嘧啶-7-甲腈;
3-(4-氟苯基)-7-甲基-2-(2,3,4-三氟苯氧基)噻吩并[3,2-d]嘧啶-4(3H)-酮;
3-(4-氟苯基)-7-甲基-2-(2,3,6-三氟苯氧基)噻吩并[3,2-d]嘧啶-4(3H)-酮;
3-(4-氟苯基)-7-甲基-2-(2-甲基苯氧基)噻吩并[3,2-d]嘧啶-4(3H)-酮;
4-{[1-(4-氯苯基)-9-甲基-6-氧代-6,9-二氢-1H-嘌呤-2-基]氧}-2,3-二氟苯甲腈;
5-(2,3-二氟苯氧基)-6-(4-氟苯基)[1,3]噻唑并[5,4-d]嘧啶-7(6H)-酮;
5-(4-氯-2-氟苯氧基)-6-(4-氟苯基)[1,3]噻唑并[5,4-d]嘧啶-7(6H)-酮;
5-(9-甲基-6-氧代-2-(3,4,5-三氟苯氧基)-6H-嘌呤-1(9H)-基)2-氰基吡啶;
5-[2-氯-3-(三氟甲基)苯氧基]-6-(4-氟苯基)[1,3]噻唑并[5,4-d]嘧啶-7(6H)-酮;
6-(4-氟苯基)-5-(2,3,4-三氟苯氧基)[1,3]噻唑并[5,4-d]嘧啶-7(6H)-酮;
6-(4-氟苯基)-5-(2,3,5-三氟苯氧基)[1,3]噻唑并[5,4-d]嘧啶-7(6H)-酮;
6-(4-氟苯基)-5-(2,4,5-三氟苯氧基)[1,3]噻唑并[5,4-d]嘧啶-7(6H)-酮;
6-(4-氟苯基)-5-(3-(三氟甲基)苯氧基)噻唑并[5,4-d]嘧啶-7(6H)-酮;
6-(4-氟苯基)-5-(3,4,5-三氟苯氧基)[1,3]噻唑并[5,4-d]嘧啶-7(6H)-酮;
6-(4-氟苯基)-5-[2-氟-3-(三氟甲基)苯氧基][1,3]噻唑并[5,4-d]嘧啶-7(6H)-酮;
6-(4-氟苯基)-5-[3-氟-5-(三氟甲基)苯氧基][1,3]噻唑并[5,4-d]嘧啶-7(6H)-酮;
9-乙基-1-(4-氟苯基)-2-(2,3,4-三氟苯氧基)-1,9-二氢-6H-嘌呤-6-酮;
9-乙基-1-(4-氟苯基)-2-(2,3,5-三氟苯氧基)-1,9-二氢-6H-嘌呤-6-酮;
9-乙基-1-(4-氟苯基)-2-(2,4,5-三氟苯氧基)-1,9-二氢-6H-嘌呤-6-酮;或
9-乙基-1-(4-氟苯基)-2-(2,4,6-三氟苯氧基)-1,9-二氢-6H-嘌呤-6-酮。
16.如权利要求1至15中任一项所述的化合物或其盐或水合物,其中,该化合物于辣椒素受体激动作用的活体外分析法中没有可检测到的激动剂活性。
17.如权利要求1至16中任一项所述的化合物或其盐或水合物,其中,该化合物于辣椒素受体钙移动性分析法中的IC50值为1微摩尔或以下。
18.一种药物组合物,其包含与生理上可接受的载体或赋形剂组合的至少一种如权利要求1至17中任一项所述的化合物或其盐或水合物。
19.一种降低细胞辣椒素受体的钙传导性的方法,其包括将表达辣椒素受体的细胞与至少一种如权利要求1至17中任一项所述的化合物或其盐或水合物接触,以降低该辣椒素受体的钙传导性。
20.如权利要求19所述的方法,其中,该细胞是在动物活体内接触。
21.如权利要求20所述的方法,其中,该细胞为神经元细胞。
22.如权利要求20所述的方法,其中,该细胞为膀胱上皮细胞。
23.如权利要求20所述的方法,其中,在接触期间,该化合物或其盐或水合物是存在于该动物的体液中。
24.如权利要求23所述的方法,其中,该化合物或其盐或水合物以5微摩尔或以下浓度存在于该动物血液中。
25.如权利要求23所述的方法,其中,该化合物或其盐或水合物以1微摩尔或以下浓度存在于该动物血液中。
26.如权利要求20所述的方法,其中,该动物为人类。
27.如权利要求20所述的方法,其中,该化合物或其盐或水合物是经口投药。
28.一种于活体外抑制类香草醇配位体与辣椒素受体结合的方法,该方法包括于足以抑制类香草醇配位体与辣椒素受体结合并使该抑制为可检测的条件及用量下将辣椒素受体与至少一种如权利要求1至17中任一项所述的化合物或其盐或水合物接触。
29.一种于患者体内抑制类香草醇配位体与辣椒素受体结合的方法,其包括将表达辣椒素受体的细胞与以足以于活体外抑制类香草醇配位体与表达克隆辣椒素受体的细胞结合并使该抑制为可检测的用量的至少一种如权利要求1至17中任一项所述的化合物或其盐或水合物接触,以抑制患者体内类香草醇配位体与辣椒素受体结合。
30.如权利要求29所述的方法,其中,该患者为人类。
31.如权利要求29所述的方法,其中,该化合物或其盐或水合物以5微摩尔或以下浓度存在于该患者血液中。
32.如权利要求29所述的方法,其中,该化合物或其盐或水合物以1微摩尔或以下浓度存在于该患者血液中。
33.一种治疗患者对辣椒素受体调节作用有反应的病症的方法,其包括对该患者给予治疗有效量的至少一种如权利要求1至17中任一项所述的化合物或其盐或水合物,以减轻该患者的病症。
34.如权利要求33所述的方法,其中,该患者遭受(i)曝露于辣椒素、(ii)因曝露于热引起的灼伤或刺激,(iii)因曝露于光引起的灼伤或刺激,(iv)因曝露于催泪气体、传染媒介、空气污染物或胡椒喷雾引起的灼伤、支气管收缩或刺激,或(v)因曝露于酸引起的灼伤或刺激。
35.如权利要求33所述的方法,其中,该病症为气喘或慢性阻塞性肺病。
36.一种治疗患者疼痛的方法,其包括对遭受疼痛的患者给予治疗有效量的至少一种如权利要求1至17中任一项所述的化合物或其盐或水合物,以减轻患者的疼痛。
37.如权利要求36所述的方法,其中,该化合物或其盐或水合物以5微摩尔或以下浓度存在于该患者血液中。
38.如权利要求36所述的方法,其中,该化合物或其盐或水合物以1微摩尔或以下浓度存在于该患者血液中。
39.如权利要求36所述的方法,其中,该患者遭受神经性疼痛。
40.如权利要求36所述的方法,其中,该疼痛与选自下列的病症有关:乳房切除手术后疼痛综合征、残肢疼痛、幻肢疼痛、口腔神经性疼痛、牙痛、疱疹后神经痛、糖尿病神经性病变、反射性交感神经失养症、三叉神经痛、骨关节炎、类风湿性关节炎、纤维肌痛、吉兰-拜瑞综合征、感觉异常性股痛、口腔灼热综合征、两侧周边神经病变、灼痛、神经炎、神经元炎、神经痛、AIDS相关神经性病变、MS相关神经性病变、脊柱伤害的相关疼痛、手术相关的疼痛、肌肉骨骼疼痛、背痛、头痛、偏头痛、绞痛、分娩、痔疮、消化不良、沙尔科氏疼痛、肠胀气、月经、癌症、曝露于毒液、肠躁症、发炎性肠道疾病与创伤。
41.如权利要求36所述的方法,其中,该患者为人类。
42.一种治疗患者瘙痒的方法,其包括对患者给予治疗有效量的如权利要求1至17中任一项所述的化合物或其盐或水合物,以减轻患者的瘙痒。
43.一种治疗患者的咳嗽或打嗝的方法,其包括对患者给予治疗有效量的如权利要求1至17中任一项所述的化合物或其盐或水合物,以减轻患者的咳嗽或打嗝。
44.一种治疗患者的停经症状的方法,其包括对患者给予治疗有效量的如权利要求1至17中任一项所述的化合物或其盐或水合物,以减轻患者的停经症状。
45.一种治疗患者尿失禁或膀胱过动症的方法,其包括对患者给予治疗有效量的如权利要求1至17中任一项所述的化合物或其盐或水合物,以减轻患者的尿失禁或膀胱过动症。
46.一种促进肥胖患者降低体重的方法,其包括对患者给予治疗有效量的如权利要求1至17中任一项所述的化合物或其盐或水合物,以促进患者降低体重。
47.如权利要求1所述的化合物或其盐或水合物,其中,该化合物已标记放射性。
48.一种判定样本中是否含有辣椒素受体的方法,其包括下列步骤:
(a)将样本与如权利要求1至17中任一项所述的化合物或其盐或水合物于可使该化合物或其盐或水合物与辣椒素受体结合的条件下接触;及
(b)检测代表该化合物或其盐或水合物与辣椒素受体结合程度的信号,以判定样本中是否含有辣椒素受体。
49.如权利要求48所述的方法,其中,该化合物或其盐或水合物已标记放射性,且其中,该检测步骤包括下列步骤:
(i)从已结合的化合物中分离未结合的化合物;及
(ii)检测样本中是否含有已结合的放射性标记。
50.一种包装的药物制剂,其包括:
(a)在容器中的如权利要求18所述的药物组合物;及
(b)使用该组合物治疗疼痛的说明书。
51.一种包装的药物制剂,其包括:
(a)在容器中的如权利要求18所述的药物组合物;及
(b)使用该组合物治疗咳嗽或打嗝的说明书。
52.一种包装的药物制剂,其包括:
(a)在容器中的如权利要求18所述的药物组合物;及
(b)使用该组合物治疗肥胖的说明书。
53.一种包装的药物制剂,其包括:
(a)在容器中的如权利要求18所述的药物组合物;及
(b)使用该组合物治疗尿失禁或膀胱过动症的说明书。
54.一种如权利要求1至17中任一项所述的化合物或其盐或水合物在制造用于治疗对辣椒素受体调节作用有反应病症的药物中的用途。
55.如权利要求54所述的用途,其中,该病症为疼痛、气喘、慢性阻塞性肺病、咳嗽、打嗝、肥胖、停经症状、尿失禁、膀胱过动症、曝露于辣椒素、因曝露于热引起的灼伤或刺激、因曝露于光引起的灼伤或刺激、因曝露于催泪气体、传染媒介、空气污染物或胡椒喷雾引起的灼伤、支气管收缩或刺激、或因曝露于酸引起的灼伤或刺激。
56.一种治疗患者疼痛的方法,其包括对遭受疼痛的患者给予治疗有效量的(i)至少一种如权利要求1至17中任一项所述的化合物或其盐或水合物与(ii)布洛芬的组合,以减轻患者的疼痛。
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Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0509573D0 (en) * | 2005-05-11 | 2005-06-15 | Merck Sharp & Dohme | Therapeutic compounds |
US8003656B2 (en) | 2006-08-23 | 2011-08-23 | Neurogen Corporation | 2-phenoxy pyrimidinone analogues |
EP2025674A1 (de) | 2007-08-15 | 2009-02-18 | sanofi-aventis | Substituierte Tetrahydronaphthaline, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
SI3043784T1 (sl) * | 2013-09-09 | 2019-08-30 | Peloton Therapeutics, Inc. | Aril etri in njihova uporaba |
EP3180340B1 (en) * | 2014-08-11 | 2018-10-10 | Hydra Biosciences, Inc. | Pyrido[2,3-d]pyrimidine-2,4(1h,3h)-dione derivatives |
WO2016144825A1 (en) | 2015-03-11 | 2016-09-15 | Peloton Therapeutics, Inc. | Aromatic compounds and uses thereof |
US10278942B2 (en) | 2015-03-11 | 2019-05-07 | Peloton Therapeutics, Inc. | Compositions for use in treating pulmonary arterial hypertension |
US10155726B2 (en) | 2015-03-11 | 2018-12-18 | Peloton Therapeutics, Inc. | Substituted pyridines and uses thereof |
US10512626B2 (en) | 2015-03-11 | 2019-12-24 | Peloton Therapeautics, Inc. | Compositions for use in treating glioblastoma |
WO2016168510A1 (en) | 2015-04-17 | 2016-10-20 | Peloton Therapeutics, Inc. | Combination therapy of a hif-2-alpha inhibitor and an immunotherapeutic agent and uses thereof |
WO2020146449A1 (en) * | 2019-01-08 | 2020-07-16 | Texas Tech University System | Small molecule analogs of the protein e4orf1 in the treatment and prevention of metabolic disorders |
Family Cites Families (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0364598A4 (en) | 1988-03-02 | 1992-01-15 | Yoshitomi Pharmaceutical Industries, Ltd. | 3,4-dihydrothieno 2,3-d¨pyrimidine compounds and pharmaceutical application thereof |
US5202328A (en) | 1991-03-06 | 1993-04-13 | Merck & Co., Inc. | Substituted fused pyrimidinones |
EP0807633B1 (en) | 1996-05-15 | 2002-11-06 | Pfizer Inc. | Novel 2,3-disubstituted-(5,6)- heteroarylfused-pyrimidine-4-ones |
DK0982992T3 (da) | 1997-05-08 | 2002-10-14 | Aventis Cropscience Uk Ltd | Anvendelse af thienopyrimidiner som fungicider |
US6627755B1 (en) | 1997-06-09 | 2003-09-30 | Pfizer Inc | Quinazolin-4-one AMPA antagonists |
IL125950A0 (en) | 1997-09-05 | 1999-04-11 | Pfizer Prod Inc | Methods of administering ampa receptor antagonists to treat dyskinesias associated with dopamine agonist therapy |
US6323208B1 (en) | 1997-09-05 | 2001-11-27 | Pfizer Inc | Atropisomers of 2,3-disubstituted-(5.6)-heteroaryl fused-pyrimidin-4-ones |
AU2002214546A1 (en) | 2000-09-29 | 2002-04-08 | Cor Therapeutics, Inc. | Bicyclic pyrimidin-4-one based inhibitors of factor xa |
JP2004518732A (ja) | 2001-02-14 | 2004-06-24 | ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー | マトリックスメタロプロテイナーゼ阻害剤としてのチエノ’2,3−dピリミジンジオン誘導体 |
JP4205430B2 (ja) | 2001-03-26 | 2009-01-07 | ノバルティス アクチエンゲゼルシャフト | 疼痛を治療するための、バニロイド受容体アンタゴニストとして、使用するための縮合ピリジン誘導体 |
EP1430161B1 (de) * | 2001-09-28 | 2005-06-15 | DaimlerChrysler AG | Hochfester duplex-/triplex-leichtbaustahl und seine verwendung |
WO2003055848A2 (en) | 2001-12-26 | 2003-07-10 | Bayer Healthcare Ag | Urea derivatives as vr1- antagonists |
AU2003241453A1 (en) | 2002-05-17 | 2003-12-02 | Janssen Pharmaceutica N.V. | Aminotetralin-derived urea modulators of vanilloid vr1 receptor |
TW200401770A (en) | 2002-06-18 | 2004-02-01 | Sankyo Co | Fused-ring pyrimidin-4(3H)-one derivatives, processes for the preparation and uses thereof |
WO2004028440A2 (en) | 2002-09-24 | 2004-04-08 | Bayer Healthcare Ag | Vr1 antagonists for the treatment of urological disorders |
GB0223730D0 (en) | 2002-10-11 | 2002-11-20 | Novartis Ag | Organic compounds |
WO2004037176A2 (en) | 2002-10-21 | 2004-05-06 | Bristol-Myers Squibb Company | Quinazolinones and derivatives thereof as factor xa inhibitors |
CN1894234A (zh) | 2003-03-25 | 2007-01-10 | 武田药品工业株式会社 | 二肽基肽酶抑制剂 |
AU2004290626A1 (en) * | 2003-11-14 | 2005-06-02 | Merck Sharp & Dohme Limited | Bicyclic pyrimidin-4-(3H)-ones and analogues and derivatives thereof which modulate the function of the vanilloid-1 receptor (VR1) |
GB0326633D0 (en) | 2003-11-14 | 2003-12-17 | Merck Sharp & Dohme | Therapeutic agents |
US7544803B2 (en) | 2004-01-23 | 2009-06-09 | Amgen Inc. | Vanilloid receptor ligands and their use in treatments |
GB0412769D0 (en) | 2004-06-08 | 2004-07-07 | Novartis Ag | Organic compounds |
AR051596A1 (es) | 2004-10-26 | 2007-01-24 | Irm Llc | Compuestos heterociclicos condensados nitrogenados como inhibidores de la actividad del receptor canabinoide 1; composiciones farmaceuticas que los contienen y su empleo en la preparacion de medicamentos para el tratamiento de trastornos alimentarios |
GB0509573D0 (en) | 2005-05-11 | 2005-06-15 | Merck Sharp & Dohme | Therapeutic compounds |
US20090298856A1 (en) | 2005-05-11 | 2009-12-03 | Rebecca Elizabeth Brown | 2,3 Substituted fused bicyclic pyrimidin-4(3H)-ones modulating the function of the vanilliod-1receptor (VR1) |
CN1318429C (zh) * | 2005-07-25 | 2007-05-30 | 华中师范大学 | 具有杀菌活性的取代噻吩并[3',2':5,6]吡啶并[4,3-d]嘧啶-4(3H)-酮及制备 |
WO2007056124A2 (en) | 2005-11-04 | 2007-05-18 | Hydra Biosciences, Inc. | Compounds for modulating trpv3 function |
US8003656B2 (en) | 2006-08-23 | 2011-08-23 | Neurogen Corporation | 2-phenoxy pyrimidinone analogues |
AU2007288198A1 (en) | 2006-08-23 | 2008-02-28 | Neurogen Corporation | Haloalkyl-substituted pyrimidinone derivatives |
EP2094704A4 (en) | 2006-11-06 | 2010-12-08 | Neurogen Corp | CIS-CYCLOHEXYL SUBSTITUTED PYRIMIDINONE DERIVATIVES |
WO2008156607A1 (en) | 2007-06-12 | 2008-12-24 | Neurogen Corporation | Substituted pyrimidinones |
WO2009100403A1 (en) | 2008-02-07 | 2009-08-13 | Neurogen Corporation | Substituted aryl pyrimidinones |
WO2009121036A2 (en) | 2008-03-27 | 2009-10-01 | Neurogen Corporation | Substituted aryl pyrimidinone derivatives |
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SV2009003173A (es) | 2010-08-10 |
EP2061794B1 (en) | 2012-12-05 |
US20120208829A1 (en) | 2012-08-16 |
ZA200901163B (en) | 2010-08-25 |
MA30720B1 (fr) | 2009-09-01 |
US8003656B2 (en) | 2011-08-23 |
MX2009002066A (es) | 2009-03-06 |
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CA2660957C (en) | 2016-10-11 |
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JP2010502576A (ja) | 2010-01-28 |
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