CN104188952A - 抑制组织蛋白酶k的组合物 - Google Patents
抑制组织蛋白酶k的组合物 Download PDFInfo
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- CN104188952A CN104188952A CN201410352975.0A CN201410352975A CN104188952A CN 104188952 A CN104188952 A CN 104188952A CN 201410352975 A CN201410352975 A CN 201410352975A CN 104188952 A CN104188952 A CN 104188952A
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- inhibitor
- cathepsin
- fluoro
- bone
- disease
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Abstract
本发明涉及抑制骨吸收的方法,包括在需要的哺乳动物内,根据每周一次、两周一次、每月二次或每月一次的剂量间隔的连续方案,施用包含组织蛋白酶K抑制剂或其药学上可接受的盐、或它们的混合物的口服药物组合物。
Description
本申请是申请日为2006年2月24日、申请号为200680006286.8、发明名称“抑制组织蛋白酶K的组合物”的中国专利申请的分案申请。
技术领域
本申请涉及一种抑制组织蛋白酶K的组合物。
背景技术
人类和其它哺乳动物中的多种病症涉及异常的骨吸收(boneresorption)或与之相关。这些病症包括但不限于骨质疏松、糖皮质激素引起的骨质疏松、佩吉特氏病、骨转换异常增加、牙周病、牙齿丧失、骨折、类风湿性关节炎、骨关节炎、假体周围骨质溶解、成骨不全、恶性高钙血症、多发性骨髓瘤、和转移性骨病。这些病症中最常见之一为骨质疏松,其以最常见的表现形式出现于经绝后妇女中。骨质疏松为全身性骨骼疾病,其特征为低的骨质量和骨组织的微结构退化,其结果是骨脆性增加和易于骨折。骨质疏松性骨折是老年人发病和死亡的主要原因。多达50%的女性和三分之一的男性可能经历骨质疏松性骨折。大部分老年人群已经具有低的骨密度和高的骨折风险。存在预防和治疗骨质疏松和其它与骨吸收有关疾病的显著需要。因为骨质疏松以及其它与骨丢失(bone loss)有关的病症通常是慢性病,据相信适当的治疗一般需要慢性治疗。
已知半胱氨酸蛋白酶抑制剂如E-64(反式-环氧琥珀酰基-L-亮氨酰胺leucylamide-(4-胍基)丁烷)有效抑制骨吸收。参见Delaisse,JM等,1987,Bone8:305-313,特此将其全文引入作为参考。最近,组织蛋白酶K被克隆并发现其在破骨细胞中有特异表达,参见Tezuka,K等,1994,J Biol Chem269:1106-1109;Shi,GP等,1995,FEBSLett357:129-134;Bromme,D和Okamoto,K,1995,Biol Chem HoppeSeyler376:379-384;Bromme,D等,1996,J BiolChem271:2126-2132;Drake,FH等,1996,J Biol Chem271:12511-12516,特此将它们全文引入作为参考。在克隆同时,发现以骨硬化(osteopetrotic)表型伴骨吸收减少为特征的常染色体隐性病症-致密性成骨不全症与存在于组织蛋白酶K基因中的突变相关。迄今为止,已知在组织蛋白酶K基因中鉴定出的所有突变都消去胶原酶活性。参见GeIb,BD等,1996,Science273:1236-1238;Johnson,MR等,1996,Genome Res6:1050-1055;Hou,W-S等,1999J.Clin.Invest.103,731-738,特此将它们全文引入作为参考。因此,似乎组织蛋白酶K与破骨细胞介导的骨吸收有关。
人I型胶原,骨中主要的胶原,为组织蛋白酶K的优良底物。参见Kafienah,W,等1998,BiochemJ331:727-732,特此将其全文引入作为参考。在使用组织蛋白酶K的反义寡核苷酸的体外实验中,显示出体外骨吸收减少,这可能是由于组织蛋白酶K mRNA的转译减少。参见Inui,T,等,1997,J Biol Chem272:8109-8112,特此将其全文引入作为参考。已经解析了组织蛋白酶K的晶体结构。参见McGrath,ME,等1997,Nat Struct Biol4:105-109;Zhao,B,等,1997,Nat Struct Biol4:109-11,特此将它们全文引入作为参考。而且,已经开发了基于组织蛋白酶K抑制剂的选择性肽。参见Bromme,D,等,1996,Biochem J315:85-89;Thompson,SK,等,1997,Proc Natl Acad Sci USA94:14249-14254,特此将它们全文引入作为参考。因此,组织蛋白酶K抑制剂可减少骨吸收。这样的抑制剂可用于治疗骨吸收有关的病症,例如骨质疏松。
一周和一月的组织蛋白酶K抑制剂的组合物可提供超出其它疗法的治疗优点,可提高方便性、患者顺从性和患者满足感。
发明内容
本发明涉及口服药物组合物,其包括组织蛋白酶K抑制剂或其药学上可接受的盐、或它们的混合物,适用于根据每周一次、两周一次、每月二次或每月一次的剂量间隔的连续方案抑制骨吸收。
具体实施方式
本发明涉及组织蛋白酶K抑制剂或其药学上可接受的盐、或它们的混合物用于制备药剂的用途,其特征在于当根据每周一次、两周一次、每月二次或每月一次的剂量间隔的连续方案在有需要的哺乳动物内施用抑制骨吸收的口服单位剂量时,单次剂量的AUC0-168为大约2.00-80.0μM/h和Cmin为大约10nM至大约200nM。本发明也涉及给需要的哺乳动物施用组织蛋白酶K抑制剂或其药学上可接受的盐、或它们的混合物抑制骨吸收的方法,其特征在于根据每周一次、两周一次、每月二次或每月一次的剂量间隔的连续方案口服单位剂量中,单次剂量的AUC0-168为大约2.00-80.0μM/h和Cmin为大约10nM至大约200nM。
在本发明的实施方案中,哺乳动物尤其人类,鉴定为患有或易患有上消化道病症。在一组实施方案中,上消化道病症为胃肠返流疾病(GERD)、食管炎、消化不良(胃灼热)或溃疡。
在本发明的实施方案中,本发明涉及根据式I的大约2.5mg至大约250mg的组织蛋白酶K抑制剂:
其中R1为被2至7个卤素取代的C1-3烷基;
R2为氢或卤素;
X为N或CH;
D为芳基或杂芳基,其中各自所述的芳基或杂芳基,其可以为单环或双环,任选地在碳或杂原子上被1至4个独立地选自甲基、C1-6卤代烷基、卤素或-SO2R4的取代基取代;
R3为氢、C1-6烷基、C2-6炔基、卤素、氰基、芳基、杂芳基、C3 -8环烷基、杂环基(heterocyclyl)、-OR4、-C(O)N(R5)(R6)、-C(R5)(R6)OH、-C(R5)(R6)N(R4)2、-SOmR4、-SO2N(R4)(R5)、或-SO2N(R5)C(O)(R7);其中所述的烷基、炔基、芳基、杂芳基、环烷基和杂环基任选地在碳或杂原子上被1至5个独立地选自C1-6烷基或卤素的取代基取代;
R4为氢、C1-6烷基、芳基、芳基(C1-4)烷基、杂芳基、杂芳基(C1 -4)烷基、C3-8环烷基、C3-8环烷基(C1-4)烷基、或杂环基(C1-4)烷基;其任选地被一个、两个或三个独立地选自卤素、烷氧基或-SO2R7的取代基取代;
R5为氢、C1-6烷基、或C1-6卤代烷基;
R6为氢、C1-6烷基、或C1-6卤代烷基;
或R5和R6可与它们之间的碳或氮原子一起形成3至6元环;
R7为氢或任选地被一个、两个或三个独立地选自卤素或氰基的取代基取代的C1-6烷基;
m为0至2的整数;
或其盐、立体异构体、N-氧化物衍生物,或者它们的混合物用于制备药剂的用途,该药剂作为口服单位剂量依照每周一次、两周一次、每月二次或每月一次的剂量间隔的连续方案在有需要的哺乳动物内抑制骨吸收。
在本发明的实施方案中,本发明涉及根据式II的大约2.5mg至大约250mg的组织蛋白酶K抑制剂:
其中R1为卤素;
R2为卤素;
R3为氢、C1-6烷基、C1-6卤代烷基、C3-6环烷基、芳基或杂芳基;
或其盐、立体异构体、N-氧化物衍生物,或者它们的混合物用于制备的药剂用途,该药剂作为口服单位剂量依照每周一次、两周一次、每月二次或每月一次的剂量间隔的连续方案在有需要的哺乳动物内抑制骨吸收。
在本发明的实施方案中,本发明涉及给需要的哺乳动物施用根据式I或II的组织蛋白酶K抑制剂或其药学上可接受的盐、或它们的混合物抑制骨吸收的方法,其特征在于根据每周一次、两周一次、每月二次或每月一次的剂量间隔的连续方案的口服单位剂量中,单次剂量的AUC0-168为大约2.00-80.0μM/h和Cmin为大约10nM至大约200nM。
在一组实施方案中,本发明涉及口服药物组合物的用途,其包括大约2.5mg至大约250mg的选自下列的化合物:
N1-(1-氰基环丙基)-4-氟-N2-{(1S)-2,2,2-三氟-1-[4'-(甲磺酰基)-1,1'-联苯-4-基]乙基}-L-亮氨酰胺;
N1-(1-氰基环丙基)-4-氟-N2-{(1S)-2,2,2-三氟-1-[2'-甲基-4'-(甲磺酰基)联苯-4-基]乙基}-L-亮氨酰胺;
N2-{(1S)-1-[4'-(氨基磺酰基)联苯-4-基]-2,2,2-三氟乙基}-N1-(1-氰基环丙基)-4-氟-L-亮氨酰胺;
N1-(1-氰基环丙基)-4-氟-N2-(1S)-2,2,2-三氟-1-(4'-氟联苯-4-基)乙基]-L-亮氨酰胺;
N2-((1S)-1-{4'-[1-(氨羰基)环丙基]联苯-4-基}-2,2,2-三氟乙基)-N1-(1-氰基环丙基)-4-氟-L-亮氨酰胺;
N1-(1-氰基环丙基)-4-氟-N2-((1S)-2,2,2-三氟-1-{4-[4-(三氟甲基)-1,3-噻唑-2-基]苯基}乙基)-L-亮氨酰胺;
N2-((1S)-1-{4'-[1-(氨羰基)环丙基]-2'-氟联苯-4-基}-2,2,2-三氟乙基)-N1-(1-氰基环丙基)-4-氟-L-亮氨酰胺;
N1-(1-氰基环丙基)-N2-((1S)-1-{4'-[(1R)-2,2-二氟-1-羟乙基]联苯-4-基}-2,2,2-三氟乙基)-4-氟-L-亮氨酰胺;
N1-(1-氰基环丙基)-N2-((1S)-1-{4'-[(1S)-2,2-二氟-1-羟乙基]联苯-4-基}-2,2,2-三氟乙基)-4-氟-L-亮氨酰胺;
N1-(1-氰基环丙基)-4-氟-N2-((1S)-2,2,2-三氟-1-{4-[5-甲基-6-(甲磺酰基)吡啶-3-基]苯基}乙基)-L-亮氨酰胺;
N1-(1-氰基环丙基)-N2-{(1S)-1-[4'-(1-氰基环丙基)联苯-4-基]-2,2,2-三氟乙基}-4-氟-L-亮氨酰胺;
N2-[(1S)-1-(4-{5-[1-(氨羰基)环丙基]-3-氯吡啶-2-基}苯基)-2,2,2-三氟乙基]-N1-(1-氰基环丙基)-4-氟-L-亮氨酰胺;
N2-[(1S)-1-(5-{4-[1-(氨羰基)环丙基]-苯基}吡啶-2-基)-2,2,2-三氟乙基]-N1-(1-氰基环丙基)-4-氟-L-亮氨酰胺;
N1-(1-氰基环丙基)-4-氟-N2-((1S)-2,2,2-三氟-1-{5-[4-(甲磺酰基)苯基]吡啶-2-基}乙基)-L-亮氨酰胺;
N1-(1-氰基环丙基)-4-氟-N2-(1S)-2,2,2-三氟-1-[4'-(甲基亚磺酰基)-1,1'-联苯-4-基]乙基}-L-亮氨酰胺;
N1-(氰基环丙基)-N2-{(1S)-2,2-二氟-1-[4'-(甲磺酰基)联苯-4-基]乙基}-4-氟-L-亮氨酰胺;
(1R,2R)-N-(1-氰基环丙基)-5,5-二氟-2-[4-[4-(甲磺酰基)苯基]-1H-吡唑-3-基]环己甲酰胺(cyclohexanecarboxamide);
(1R,2R)-N-(1-氰基环丙基)-5,5-二氟-2-[4-[4-(甲磺酰基)苯基]-1-甲基-1H-吡唑-3-基]环己甲酰胺;
(1R,2R)-N-(1-氰基环丙基)-5,5-二氯-2-[4-[4-(甲磺酰基)苯基]-1-甲基-1H-吡唑-3-基]环己甲酰胺;
(1R,2R)-N-(1-氰基环丙基)-5,5-二氟-2-[4-[4-(甲磺酰基)苯基]-1-(2,2,2-三氟乙基)-1H-吡唑-3-基]环己甲酰胺;
(1R,2R)-N-(1-氰基环丙基)-5,5-二氯-2-[4-[4-(甲磺酰基)苯基]-1-(2,2,2-三氟乙基)-1H-吡唑-3-基]环己甲酰胺;
和它们的盐。
在本发明的另一个实施方案中,本发明涉及在有需要的哺乳动物中抑制骨吸收的方法,给予选自上述化合物的组织蛋白酶K抑制剂。
在本发明的一组实施方案中,组织蛋白酶K抑制剂为N1-(1-氰基环丙基)-4-氟-N2-{(1S)-2,2,2-三氟-1-[4'-(甲磺酰基)-1,1'-联苯-4-基]乙基}-L-亮氨酰胺。
上述化合物的制备方法描述在国际公布的WO 03/075836(其在2003年09月18日出版公开)和WO 2005/000800(其在2005年01月06日出版公开)中。
在本发明的实施方案中,本发明涉及口服药物组合物的用途,包括大约2.5mg至大约250mg的组织蛋白酶K抑制剂和选自下列的其它药物:有机双膦酸盐(bisphosphonate);雌激素受体调节剂;雄激素受体调节剂;破骨细胞质子ATP酶抑制剂;HMG-CoA还原酶抑制剂;整联蛋白受体拮抗剂;成骨细胞合成代谢剂(osteoblast anabolic agent);钙;维生素D;维生素D合成类似物;非甾体抗炎药;选择性环氧化酶-2抑制剂;白介素-1β抑制剂;LOX/COX抑制剂;RANKL抑制剂;和其药学上可接受的盐和它们的混合物。在该实施方案的一组中,该药物是维生素D。在该实施方案的亚组中,维生素D的量为2,800,IU、5,600IU、7,000IU、8,400IU、11,200IU、14,000IU、16,800IU或19,600IU。在该实施方案进一步的亚组中,维生素D每周服用的量为2,800,IU、5,600IU、7,000IU、8,400IU或11,200IU。在该实施方案进一步的亚组中,维生素D每月服用的量为11,200IU、14,000IU、15,400IU、16,800IU或19,600IU。
应当理解本文所述化合物上的取代基和取代型式可由本领域普通技术人员来选择,以提供化学上和代谢上稳定的并可通过本领域已知的技术以及以下所述的那些方法由容易获得的原料轻易地合成的化合物。如果取代基本身被多于一个基团取代,应当理解只要得到的结构稳定,这些多个基团可以在相同的碳或不同的碳上。短语“任选地被一个或多个取代基取代”应当被认为等同于短语“任选地被至少一个取代基取代”,并且在这种情况下,优选的实施方案具有零至三个取代基。
如本文使用的,除非另外指定,“烷基”有意包括具有一个至十个碳原子的支链和直链的饱和脂肪族烃基团。例如,如“C1-C10烷基”中的C1-C10定义为包括具有线性、分枝、或环状排列的1、2、3、4、5、6、7、8、9或10个碳的基团。例如“C1-C10烷基”具体包括甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基,等等。
除非另外指定,“烷氧基”或“烷基氧基”表示如上定义的烷基,其中所述的烷基通过氧桥连接。烷氧基的实例包括甲氧基、乙氧基等
除非另外指定,术语“环烷基”或“碳环”应指总碳原子数三个至八个或者该范围内的任何数目的环状烷烃环(即,环丙基、环丁基、环戊基、环己基、环庚基或环辛基)。
除非另外指定,术语“炔基”是指包含至少1个碳碳三键的2至10个碳原子的直链、支链烃基。至多可存在3个碳碳三键。因此,“C2-C6炔基”表示具有2至6个碳原子的炔基。炔基包括乙炔基、丙炔基和丁炔基。炔基的直链、分枝或环状部分可以包含三键,可以被取代(如果指明为取代的炔基)
在某些情况中,取代基可以用包括零范围的碳定义,例如(C0-C6)亚烷基-芳基。如果芳基为苯基,该定义可包括苯基本身以及-CH2Ph、-CH2CH2Ph、CH(CH3)CH2CH(CH3)Ph等。
本文使用的“芳基”有意表示每个环中最多12原子的任何稳定的单环或双环碳部分,其中至少一个环为芳香族的。这些芳基的实例包括苯基、萘基、四氢萘基、2,3-二氢化茚基、联苯基、菲基、蒽基或苊基。芳基优选的实例为苯基。在芳基取代基为双环并且一个环为非芳香族的情况下,应当理解为经由芳环连接。
本文使用的“杂芳基”表示每个环中最多10原子的稳定的单环、双环或三环,其中至少一个环为芳香族的并且包含1至4个选自O、N和S的杂原子。在该定义范围内的杂芳基包括但不限于:苯并咪唑基、苯并呋喃基、苯并呋咱基、苯并吡唑基、苯并三唑基、苯并噻吩基、苯并唑基、咔唑基、咔啉基、噌啉基、呋喃基、二氢吲哚基(indolinyl)、吲哚基、吲哚吖嗪基、吲唑基、异苯并呋喃基、异吲哚基、异喹啉基(isoquinolyl)、异噻唑基、异唑基、萘并吡啶基、二唑基、唑基、唑啉、异唑啉、吡喃基、吡嗪基、吡唑基、哒嗪基、吡啶并吡啶基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基(quinolyl)、喹喔啉基、四唑基、四唑并吡啶基、噻二唑基、噻唑基、噻吩基、三唑基、二氢苯并咪唑基、二氢苯并呋喃基、二氢苯并噻吩基、二氢苯并唑基、二氢吲哚基(dihydroindolyl)、二氢喹啉基、亚甲二氧基苯、苯并噻唑基、苯并噻吩基、喹啉基(quinolinyl)、异喹啉基(isoquinolinyl)、唑基、四氢喹啉。在杂芳基取代基为双环并且一个环为非芳香族或不包含杂原子的情况中,应当理解分别为经由芳环或经由包含杂原子的环连接。如果杂芳基包含氮原子,应当理解其相应的N-氧化物也包括在本定义中。
如同本领域技术人员所理解,本文使用的“卤代”或“卤素”有意包括氯代、氟代、溴代和碘代。术语“酮基”表示羰基(C=O)。
除非另外指定,术语“卤代烷基”表示如上所定义的烷基,其被一个至五个、优选一个至三个卤素取代。代表性的实例包括但不限于三氟甲基、二氯乙基等。
术语“芳基烷基”包括其中烷基如上定义的烷基部分和包括其中芳基如上定义的芳基部分。芳基烷基的实例包括但不限于为:苄基、氟代苄基、氯代苄基、苯基乙基、苯基丙基、氟苯基乙基、氯苯基乙基。烷基芳基的实例包括但不限于甲苯甲酰(toluyl)、乙基苯基、和丙基苯基。
本文使用的术语“杂芳基烷基”应指包括其中杂芳基如上定义的杂芳基部分并包含烷基部分的系统。杂芳基烷基的实例包括但不限于噻吩基甲基、噻吩基乙基、噻吩基丙基、吡啶基甲基、吡啶基乙基和咪唑基甲基。
术语“环烷基烷基”包括其中烷基如上定义的烷基部分并且还包括其中环烷基如上定义的环烷基部分。环烷基烷基的实例包括但不限于环丙基甲基、环戊基甲基、环己基甲基、环丙基乙基等。
本文使用的术语“杂环烷基”应指包括其中杂环基如上定义的杂环基部分并包含烷基部分的系统。杂环烷基(heterocyclylalkyl)的实例包括但不限于环氧乙烷基(oxiranyl)、吖丁啶基、吡咯烷基、哌啶基、哌嗪基、和吗啉基。
除非另外指定,本文使用的术语:“杂环”或“杂环基”有意表示包含1至4个选自O、N、S、SO、或SO2的杂原子的5-至10-元非芳香性环,并包括双环基团。因此“杂环基”的实例包括但不限于为以下的:哌嗪基、哌啶基、吡咯烷基、吗啉基、硫代吗啉基、四氢吡喃基、二氢哌啶基、四氢噻吩基等等。如果杂环基包含氮原子,应当理解其相应的N-氧化物也包括在本定义中。
本文所述的组织蛋白酶K抑制剂也包括式I化合物的N-氧化物衍生物和保护化的衍生物。例如,当式I化合物包含可氧化的氮原子时,通过本领域众所周知的方法可将氮原子转化为N-氧化物。同样当式I化合物包含基团如羟基、羧基、巯基或其它含氮原子基团时,这些基团可被适当的保护基团保护。适当保护基团的详尽列表可以在T.W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,Inc.1981中找到,其公开的内容在此全文引入作为参考。
每当术语“烷基”或“芳基”或它们任一的前缀词根出现在取代基(例如,芳基C0-8烷基)的名称中时,应当解释为其包括上述给出的对于“烷基”或“芳基”的那些限制。指定的碳原子数(例如,C1-10)应独立地指烷基或环烷基部分中的碳原子数,或指其中烷基作为前缀词根出现的更大取代基的烷基部分的碳原子数。
可以以口服剂型例如以片剂、胶囊(它们各自包括缓释或定时释放制剂)、丸剂、粉剂、颗粒、液体、酏剂、混悬液、糖浆剂和乳剂施用本文所述的组织蛋白酶K抑制剂。
应用本文所述的组织蛋白酶K抑制剂的剂量方案可根据多种因素来选择,其包括患者的类型、种类、年龄、体重、性别和医学上的疾病;要治疗疾病的严重度;给药途径;患者的肾和肝功能;和使用的特定化合物或其盐。普通技术的医师、兽医或临床医师可容易地确定并开出要求预防、阻遏或停止疾病发展的有效量药物。
本发明也包括用于治疗骨质疏松或其它骨病的药物组合物,包括施用含或不含药学上可接受的载体或稀释剂的治疗有效量的本文所述的组织蛋白酶K抑制剂。本发明适用的组合物包括水溶液,其包含本发明化合物和药理学上可接受的载体。本发明的实施方案包括药物组合物,其包含大约2.5mg至大约200mg的选自下列的组织蛋白酶K抑制剂:
N1-(1-氰基环丙基)-4-氟-N2-{(1S)-2,2,2-三氟-1-[4'-(甲磺酰基)-1,1'-联苯-4-基]乙基}-L-亮氨酰胺;
N1-(1-氰基环丙基)-4-氟-N2-{(1S)-2,2,2-三氟-1-[2'-甲基-4'-(甲磺酰基)联苯-4-基]乙基}-L-亮氨酰胺;
N2-{(1S)-1-[4'-(氨基磺酰基)联苯-4-基]-2,2,2-三氟乙基}-N1-(1-氰基环丙基)-4-氟-L-亮氨酰胺;
N1-(1-氰基环丙基)-4-氟-N2-(1S)-2,2,2-三氟-1-(4'-氟联苯-4-基)乙基]-L-亮氨酰胺;
N2-((1S)-1-{4'-[1-(氨羰基)环丙基]联苯-4-基}-2,2,2-三氟乙基)-N1-(1-氰基环丙基)-4-氟-L-亮氨酰胺;
N1-(1-氰基环丙基)-4-氟-N2-((1S)-2,2,2-三氟-1-{4-[4-(三氟甲基)-1,3-噻唑-2-基]苯基}乙基)-L-亮氨酰胺;
N2-((1S)-1-{4'-[1-(氨羰基)环丙基]-2'-氟联苯-4-基}-2,2,2-三氟乙基)-N1-(1-氰基环丙基)-4-氟-L-亮氨酰胺;
N1-(1-氰基环丙基)-N2-((1S)-1-{4'-[(1R)-2,2-二氟-1-羟乙基]联苯-4-基}-2,2,2-三氟乙基)-4-氟-L-亮氨酰胺;
N1-(1-氰基环丙基)-N2-((1S)-1-{4'-[(1S)-2,2-二氟-1-羟乙基]联苯-4-基}-2,2,2-三氟乙基)-4-氟-L-亮氨酰胺;
N1-(1-氰基环丙基)-4-氟-N2-((1S)-2,2,2-三氟-1-{4-[5-甲基-6-(甲磺酰基)吡啶-3-基]苯基}乙基)-L-亮氨酰胺;
N1-(1-氰基环丙基)-N2-{(1S)-1-[4'-(1-氰基环丙基)联苯-4-基]-2,2,2-三氟乙基}-4-氟-L-亮氨酰胺;
N2-[(1S)-1-(4-{5-[1-(氨羰基)环丙基]-3-氯吡啶-2-基}苯基)-2,2,2-三氟乙基]-N1-(1-氰基环丙基)-4-氟-L-亮氨酰胺;
N2-[(1S)-1-(5-{4-[1-(氨羰基)环丙基]-苯基}吡啶-2-基)-2,2,2-三氟乙基]-N1-(1-氰基环丙基)-4-氟-L-亮氨酰胺;
N1-(1-氰基环丙基)-4-氟-N2-((1S)-2,2,2-三氟-1-{5-[4-(甲磺酰基)苯基]吡啶-2-基}乙基)-L-亮氨酰胺;
N1-(1-氰基环丙基)-4-氟-N2-(1S)-2,2,2-三氟-1-[4'-(甲基亚磺酰基)-1,1'-联苯-4-基]乙基}-L-亮氨酰胺;
N1-(1-氰基环丙基)-N2-{(1S)-2,2-二氟-1-[4'-(甲磺酰基)联苯-4-基]乙基}-4-氟-L-亮氨酰胺;
(1R,2R)-N-(1-氰基环丙基)-5,5-二氟-2-[4-[4-(甲磺酰基)苯基]-1H-吡唑-3-基]环己甲酰胺;
(1R,2R)-N-(1-氰基环丙基)-5,5-二氟-2-[4-[4-(甲磺酰基)苯基]-1-甲基-1H-吡唑-3-基]环己甲酰胺;
(1R,2R)-N-(1-氰基环丙基)-5,5-二氯-2-[4-[4-(甲磺酰基)苯基]-1-甲基-1H-吡唑-3-基]环己甲酰胺;
(1R,2R)-N-(1-氰基环丙基)-5,5-二氟-2-[4-[4-(甲磺酰基)苯基]-1-(2,2,2-三氟乙基)-1H-吡唑-3-基]环己甲酰胺;
(1R,2R)-N-(1-氰基环丙基)-5,5-二氯-2-[4-[4-(甲磺酰基)苯基]-1-(2,2,2-三氟乙基)-1H-吡唑-3-基]环己甲酰胺;或它们的盐。
在一组实施方案中,组织蛋白酶K抑制剂为N1-(1-氰基环丙基)-4-氟-N2-{(1S)-2,2,2-三氟-1-[4'-(甲磺酰基)-1,1'-联苯-4-基]乙基}-L-亮氨酰胺或其盐。
在一个示例性的应用中,给正经历组织蛋白酶依赖性疾病治疗的哺乳动物施用适当量的化合物。当用于指定的效果时,本发明口服剂量可为每周每千克体重约0.01mg(mg/kg/周)至约10mg/kg/周,优选0.1~10mg/kg/周,和最优选0.1~5.0mg/kg/周。至于口服给药,优选组合物为包含根据症状调节剂量的2.5mg、3.5mg、5mg、10mg、20mg、25mg、35mg、40mg、50mg、80mg、100mg和200mg活性成分的片剂形式提供给要治疗的患者。药剂通常包含大约2.5mg至大约200mg的活性成分,具体地,2.5mg、3.5mg、5mg、10mg、20mg,25mg、35mg、40mg、50mg、80mg、100mg和200mg的活性成分。有益地,组织蛋白酶K抑制剂可以以单个的每周一次的剂量给药。替代选择地,组织蛋白酶K抑制剂可以以两周一次、每月二次和每月一次的剂量给药。
根据标准药学实践,将本发明化合物单独地,或者优选地在药物组合物中与药学上可接受的载体或稀释剂,任选地与已知的辅剂如明矾(alum)组合,可以给哺乳动物优选人类施用。化合物可口服地给药。
至于口服片剂,通常使用的载体包括乳糖和玉米淀粉,并且通常加入润滑剂如硬脂酸镁。至于胶囊形式的口服给药,有用的稀释剂包括乳糖和干燥的玉米淀粉。至于根据本发明治疗化合物的口服使用,所选择的化合物可以例如以片剂或胶囊的形式,或为水溶液或混悬液的形式给药。至于片剂或胶囊形式的口服给药,活性药物成分可以与口服的、无毒的、药学上可接受的惰性载体如乳糖、淀粉、蔗糖、葡萄糖、甲基纤维素、硬脂酸镁、磷酸二钙、硫酸钙、甘露醇、山梨醇等组合;至于液体形式的口服给药,口服药物成分可以与任何口服的、无毒的、药学上可接受的惰性载体如乙醇、甘油、水、聚乙二醇等组合。此外,当期望或必需时,也可以将适当的粘合剂、润滑剂、崩解剂和着色剂掺入到混合物中。适当的粘合剂包括淀粉、明胶、天然糖如葡萄糖或β-乳糖、玉米甜味剂、天然和合成的胶如阿拉伯胶、西黄蓍胶或海藻酸钠、羧甲基纤维素、聚乙二醇、蜡等等。用于这些剂型中的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、醋酸钠和氯化钠等。崩解剂包括没有限于为淀粉、甲基纤维素、琼脂、膨润土和黄原胶等。当要求口服使用水混悬液时,活性成分可以与乳化和悬浮剂组合。如果想要,可以加入某些甜味剂和/或矫味剂。至于肌内、腹膜内、皮下和静脉内使用,通常制备活性成分的灭菌溶液,并且应当适当调节和缓冲该溶液的pH。至于静脉内使用,应当控制溶质的总浓度以使制剂等渗。
本文所述的组织蛋白酶K抑制剂还可以以脂质体递药系统的形式施用,例如单层小囊泡、单层大囊泡和多层囊泡。脂质体可由多种磷脂形成,例如胆固醇、硬脂胺或磷脂酰胆碱。
本文所述的组织蛋白酶K抑制剂还可以使用单克隆抗体作为化合物分子结合的个体载体递送。本文所述的组织蛋白酶K抑制剂还可以与作为靶向药物载体的可溶性聚合物结合。这样的聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰胺-酚、聚羟基-乙基天冬酰胺-酚、或棕榈酰残基取代的聚环氧乙烷-聚赖氨酸。此外,本文所述的组织蛋白酶K抑制剂可以与生物可降解聚合物类结合,用于实现药物的控制释放,例如聚乳酸、聚羟基乙酸、聚乳酸和聚羟基乙酸的共聚物、聚ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚腈基丙烯酸酯和交联或水凝胶的两亲性嵌段共聚物。
本发明还包括适合组织蛋白酶K抑制剂每周一次、两周一次、每月二次或每月一次给药的周期连续给药方案的药盒,包括许多单位剂量的含有织蛋白酶K抑制剂、其药学上可接受的盐、或它们的混合物的药物组合物。
本发明的实施方案中,组织蛋白酶K抑制剂为N1-(1-氰基环丙基)-4-氟-N2-{(1S)-2,2,2-三氟-1-[4'-(甲磺酰基)-1,1'-联苯-4-基]乙基}-L-亮氨酰胺。
本发明进一步的实施方案中,该药盒是一周一次用药的。在一组发明中,单位剂量包括2.5mg至大约200mg的组织蛋白酶K抑制剂。在亚组发明中,单位剂量包括2.5mg、3.5mg、5mg、10mg、20mg、25mg、35mg、40mg、50mg、80mg、100mg或200mg的组织蛋白酶K抑制剂。在另一组发明中,该药盒适合一周二次(twice-weekly)给药。在一组发明中,单位剂量包括2.5mg至50mg的组织蛋白酶K抑制剂。在亚组发明中,单位剂量包括2.5mg至25mg的组织蛋白酶K抑制剂。在另一组发明中,该药盒适合两周一次或每月二次给药。在一组发明中,单位剂量包括2.5mg至50mg的组织蛋白酶K抑制剂。在亚组发明中,单位剂量包括2.5mg至25mg的组织蛋白酶K抑制剂。
本发明实施方案中,该药盒是气泡式(blister)包装。在一组发明中,药盒还包括在能施用剂量的治疗方案中指定日子的记忆辅助器。在亚组发明中,记忆辅助器为日历插入物。
本发明的实施方案中,该药盒适合在每周的同一天给药。在一组发明中,该药盒适合每周每个星期日给药。
本发明的另一个实施方案为在有需要的哺乳动物内抑制骨丢失的方法,包括给哺乳动物施用治疗有效量的上述任何化合物或任何药物组合物。本发明的另一个实施方案为在有需要的哺乳动物内减少骨丢失的方法,包括给哺乳动物施用治疗有效量的上述任何化合物或任何药物组合物。组织蛋白酶K抑制剂抑制骨吸收中的实用在文献中是已知的,参见Stroup,GB,Lark,MW,Veber,DF.,Bhattacharrya,A,Blake,S,Dare,LC,Erhard,KF,Hoffman,SJ,James,IE,Marquis,RW,Ru,Y,Vasko-Moser,JA,Smith,BR,Tomaszek,T和Gowen,M,“Potent and selective inhibition of human cathepsin K leads toinhibition of bone resorption in vivo in a nonhuman primate”,J.BoneMiner.Res.,16:1739-1746;2001;和Votta,BJ,Levy,MA,Badger,A,Dodds,RA,James,IE,Thompson,S,Bossard,MJ,Carr,T,Connor,JR,Tomaszek,TA,Szewczuk,L,Drake,FH,Veber,D,和Gowen,M,“Peptide aldehyde inhibitors of cathepsin K inhibit boneresorption both in vivo and in vitro”,J.Bone Miner.Res.12:1396-1406;1997。
本发明的另一个实施方案为在有需要的哺乳动物内治疗或预防骨质疏松的方法,包括给哺乳动物施用治疗有效量的上述任何化合物或任何药物组合物。组织蛋白酶K抑制剂治疗或预防骨质疏松中的实用在文献中是已知的,参见Saftig,P,Hunziker,Wehmeyer,O,Jones,S,Boyde,A,Rommerskirch,W,Moritz,JD,Schu,P,和Vonfigura,K,“Impaired osteoclast bone resorption leads to osteopetrosis incathepsin K-deficient mice”,Proc.Natl.Acad.Sci.USA95:13453-13458;1998。
本发明的另一个实施方案为在有需要的哺乳动物内治疗或预防类风湿性关节炎病的方法,包括给哺乳动物施用治疗有效量的上述任何化合物或任何药物组合物。在文献中已知关节周围骨骼的进行性破坏是类风湿性关节炎(RA)患者中关节机能不良和残疾的主要原因,参见Goldring SR,“Pathogenesis of bone erosions in rheumatoid arthritis”,Curr.Opin.Rheumatol.2002;14:406-10。对RA患者关节组织的分析提供了组织蛋白酶K阳性破骨细胞为介导与类风湿性滑液损害有关的病灶骨吸收的细胞类型的证据,参见Hou,W-S,Li,W,Keyszer,G,Weber,E,Levy,R,Klein,MJ,Gravallese,EM,Goldring,SR,Bromme,D,“Comparison of cathepsin K and S expression within theRheumatoid and Osteoarthritic Synovium”,Arthritis Rheumatism2002;46:663-74。另外,全身性骨丢失是与严重RA有关的发病率的主要原因。在慢性RA患者中,髋和脊柱骨折的频率实质性地增加,参见Gould A,Sambrook,P,Devlin J等,“Osteoclastic activation is theprincipal mechanism leading to secondary osteoporosis in rheumatoidarthritis”,J.Rheumatol.1998;25:1282-9。组织蛋白酶K抑制剂在治疗和预防关节下骨内吸收和全身性骨丢失中的实用表示其为药理学介入类风湿性关节炎进展的合理方法。
本发明的另一个实施方案是在需要治疗或预防的哺乳动物内治疗或预防骨关节炎进展的方法,包括给哺乳动物施用治疗有效量的上述任何化合物或任何药物组合物。在文献中已知骨关节炎(OA)伴随可清晰确定的关节变化,包括关节软骨表面腐蚀、关节周围软骨内的骨化/骨赘病、和软骨下的骨质硬化及囊肿形成,参见Oettmeier R,Abendroth,K,“Osteoarthritis and bone:osteologic types of osteoarthritis of thehip”,Skeletal Radiol.1989;18:165-74。最近,已经提议软骨下的骨质硬化对OA的引发和进展具有潜在的影响。当关节对反复性脉冲负载反应时,硬化的软骨下骨更少能减弱和分配通过关节的力,使其横越关节软骨表面受到更大的机械应力。这又in turn加速软骨磨损和纤维化,参见Radin,EL和RoseRM,“Role of subchondral bone in theinitiation and progression of cartilage damage”,Clin.Orthop.1986;213:34-40。通过抗吸收剂如组织蛋白酶K抑制剂抑制过度的关节下骨吸收,会导致软骨下骨转换的抑制,因而对OA进展可能有有利的影响。
除以上假设外,最近在得自OA患者的滑膜和关节软骨样本的滑液成纤维细胞、巨噬细胞样细胞、和软骨细胞中鉴定出组织蛋白酶K的蛋白质表达,参见Hou,W-S,Li,W,Keyszer,G,Weber,E,Levy,R,Klein,MJ,Gravallese,EM,Goldring,SR,Bromme,D,“Comparison of cathepsin K and S expression within the Rheumatoid andOsteoarthritic Synovium”,A rthritis Rheumatism2002;46:663-74;和Dodd,RA,Connor,JR,Drake,FH,Gowen,M,“Expression ofcathepsin K messenger RNA in giant cells and their precursors in humanosteoarthritic synovial tissues”,Arthritis Rheumatism1999;42:1588-93;和Konttinen,YT,Mandelin,J,Li,T-F,SaIo,J,Lassus,J等,“Acidic cysteine endoproteinase cathepsin K in the degeneration ofthe superficial articular hyaline cartilage in osteoarthritis”,ArthritisRheumatism2002;46:953-60。因此,最近这些研究涉及组织蛋白酶K在破坏与骨关节炎进展有关的关节软骨中II型胶原的作用。因此如本发明所述,组织蛋白酶K抑制剂在治疗或预防骨关节炎中的实用包括两种不同的机制,一种是对破骨细胞驱动的软骨下骨转换的抑制,第二种是对OA患者滑膜和软骨中的II型胶原退化的直接抑制。
本发明的另一个实施方案是在需要治疗的哺乳动物内治疗癌症的方法,包括给哺乳动物施用治疗有效量的上述任何化合物或任何药物组合物。在文献中已知组织蛋白酶K在人类乳腺癌、前列腺癌和脊索瘤中表达,病具有基质降解能力,参见Littlewood-EvansAJ,Bilbe G,Bowler WB,Farley D,Wlodarski B,Kokubo T,Inaoka T,Sloane J,Evans DB,Gallagher JA,“The osteoclast-associated protease CathepsinK is expressed in human breast carcinoma”,Cancer Res1997Dec1;57(23):5386-90;Brubaker KD,Vessella RL,True LD,Thomas R,Corey E“cathepsin K mRNA and protein expression in prostate cancerprogression”,J Bone Miner Res200318,222-30;和Haeckel C,KruegerS,Kuester D,Ostertag H,SamiiM,Buehling F,Broemme D,CzerniakB,Roessner A,“Expression of cathepsin K in chordoma”,Hum Pathol2000JuI;31(7):834-40。
本发明的另一个实施方案是在需要治疗的哺乳动物内治疗动脉粥样硬化的方法,包括给哺乳动物施用治疗有效量的上述任何化合物或任何药物组合物。在文献中已知组织蛋白酶K在人粥样斑中表达,病具有显著的弹性蛋白酶活性,参见Sukhova GK,Shi GP,Simon DI,Chapman HA,Libby P,“Expression of the elastolytic cathepsins S and Kin human atheroma and regulation of their production in smooth musclecells”,J Clin Invest1998Aug102,576-83。
本发明的另一个实施方案是在需要治疗的哺乳动物内治疗肥胖症和肥胖症相关疾病的方法,包括给哺乳动物施用治疗有效量的上述任何化合物或任何药物组合物。在文献中已知在若干种小鼠肥胖症模型的脂肪组织中增加了组织蛋白酶KmRNA。在瘦和肥胖的男人中,观察到脂肪组织中组织蛋白酶K基因表达和体重指数之间的显著相关性,参见Chiellini C,Costa M,Novelli SE,Amri EZ,Benzi L,BertaccaA,Cohen P,DelPrato S,Friedman JM,Maffei M,“Identification ofcathepsin K as a novel marker of adiposity in white adipose tissue”,CellPhysiol2003,195,309-21。这些资料表明组织蛋白酶K和脂肪形成及肥胖症之间存在关系。
本发明的另一个实施方案是在需要治疗的哺乳动物内治疗慢性阻塞性肺病的方法,包括给哺乳动物施用治疗有效量的上述任何化合物或任何药物组合物。在文献中已知组织蛋白酶K在肺纤维化中起作用,参见Buhling,F,等,“Pivotal role of cathepsin K in lung fibrosis”,AmJPathol.2004Jun;164(6):2203-16。
本发明的另一个实施方案是在需要治疗的哺乳动物内治疗寄生虫感染的方法,包括给哺乳动物施用治疗有效量的上述任何化合物或任何药物组合物。在文献中已知哺乳动物组织蛋白酶与木瓜酶相似的半胱氨酸蛋白酶有关,而后者在这些寄生虫的生命周期中起重要作用。这些寄生虫涉及下列疾病:疟疾、美洲锥虫病、非洲锥虫病、利什曼病、贾第鞭毛虫病、滴虫病、阿米巴病、血吸虫病、片吸虫病、肺吸虫病和肠内蛔虫病。参见Lecaille F,Kaleta J,Bromme D,“Human andparasitic papain-like cysteine proteases:their role in physiology andpathology and recent developments in inhibitor design”,Chem Rev2002102,4459-88。
本发明的另一个实施方案是在需要治疗的哺乳动物内治疗严重急性呼吸器官综合症(SARS)的方法,包括给哺乳动物施用治疗有效量的上述任何化合物或任何药物组合物。
本发明的另一个实施方案是在需要治疗的哺乳动物内治疗转移性骨病的方法,包括给哺乳动物施用治疗有效量的上述任何化合物或任何药物组合物。在文献中已知破骨细胞是造成骨吸收的原因,并且转移性肿瘤诱导的骨组织破坏和高钙血症是通过破骨细胞实现的。因此,抑制破骨细胞可以预防骨组织破坏和骨转移,参见Miyamoto,T和Suda,T,“Differentiation and function of osteoclasts”,Keio J Med2003Mar;52(1):1-7。
本发明的另一个实施方案是给哺乳动物施用治疗有效量的上述任何化合物或任何药物组合物,用于治疗与组织蛋白酶S有关的哺乳动物疾病,包括阿耳茨海默氏病、动脉粥样硬化、慢性阻塞性肺病、神经性疼痛、伤害感受性疼痛、癌和某些自身免疫性疾病,包括但不限于青少年发作型糖尿病、多发性硬化、寻常天疱疮、格雷夫斯氏病、重症肌无力、全身性红斑狼疮、类风湿性关节炎和桥本氏甲状腺炎;变应性病症,包括但不限于哮喘;和异源免疫应答,包括但不限于器官移植或组织移植排异。在文献中已知组织蛋白酶S的活性与上述疾病状态有关,参见Munger JS,Haass C,Lemere CA,Shi GP,Wong WS,Teplow DB,Selkoe DJ,Chapman HA,“Lysosomal processing of amyloidprecursor protein to A beta peptides:a distinct role for cathepsin S”,Biochem J1995311,299-305;Sukhova GK,Zhang Y,Pan JH,WadaY,Yamamoto T,Naito M,Kodama T,Tsimikas S,Witztum JL,Lu ML,Sakara Y,Chin MT,Libby P,Shi GP,“Deficiency of cathepsin S reducesatherosclerosis in LDL receptor-deficient mice”,J Clin Invest2003111,897-906;Zheng T,Zhu Z,Wang Z,Homer RJ,Ma B,Riese RJ Jr,Chapman HA Jr,Shapiro SD,Elias JA,“Inducible targeting of IL-13to the adult lung causes matrix metalloproteinase-and cathepsin-dependent emphysema”,J Clin Invest2000106,1081-93;Shi GP,Sukhova GK,Kuzuya M,Ye Q,Du J,Zhang Y,Pan JH,Lu ML,ChengXW,Iguchi A,Perrey S,Lee AM,Chapman HA,Libby P,“Deficiencyof the cysteine protease cathepsin S impairs microvessel growth”,Circ Res200392,493-500;和Nakagawa TY,BrissetteWH,Lira PD,GriffithsRJ,Petrushova N,Stock J,McNeish JD,Eastman SE,Howard ED,Clarke SR,Rosloniec EF,Elliott EA,Rudensky AY,“Impaired invariantchain degradation and antigen presentation and diminished collagen-induced arthritis in cathepsin S null mice”,Immunity199910,207-17。
示例性地,本发明为上述任何化合物在制备治疗和/或预防有需要的哺乳动物骨质疏松的药剂中的用途。还进一步示例性地,本发明为上述任何化合物在制备治疗和/或预防下述疾病的药剂中的用途:骨丢失、骨吸收、骨折、转移性骨病和/或与组织蛋白酶功能相关的病症。
本文所述的组织蛋白酶K抑制剂可用于与用于治疗组织蛋白酶介导的疾病的其它药物组合,其中疾病包括但不限于骨质疏松、糖皮质激素引起的骨质疏松、佩吉特氏病、骨转换异常增加、牙周病、牙齿丧失、骨折、类风湿性关节炎、骨关节炎、假体周围骨质溶解、成骨不全、肥胖症、动脉粥样硬化、慢性阻塞性肺病、恶性高钙血症或多发性骨髓瘤。
这些组合的个体成分可以在治疗过程期间的不同时间上单独地施用,或同时地以分开的或单个组合物形式施用。因此,本发明应当理解为包括所有这样的同时或交替的治疗方式,并且相应地解释术语“施用”。应当理解本发明化合物与用于治疗组织蛋白酶介导疾病的其它药物的组合的范围,原则上包括与用于治疗雌激素功能相关的疾病的任何药物组合物的任何组合。
因此本发明的范围包括本文所述组织蛋白酶K抑制剂与选自下列的第二种药物组合的用途:有机双膦酸盐;雌激素受体调节剂;雄激素受体调节剂;破骨细胞质子ATP酶抑制剂;HMG-CoA还原酶抑制剂;整联蛋白受体拮抗剂;成骨细胞合成代谢剂,如PTH;非甾体抗炎药;选择性环氧化酶-2抑制剂;白介素-1β抑制剂;LOX/COX抑制剂;RANKL抑制剂;和其药学上可接受的盐和它们的混合物。本发明的范围还包括抑制骨吸收的方法,其中使用本文所述组织蛋白酶K抑制剂与选自下列的第二种药物组合:有机双膦酸盐;雌激素受体调节剂;雄激素受体调节剂;破骨细胞质子ATP酶抑制剂;HMG-CoA还原酶抑制剂;整联蛋白受体拮抗剂;成骨细胞合成代谢剂,如PTH;非甾体抗炎药;选择性环氧化酶-2抑制剂;白介素-1β抑制剂;LOX/COX抑制剂;RANKL抑制剂;和其药学上可接受的盐和它们的混合物。
本化合物还用于与已知的用于治疗或预防以下疾病的药物的组合中:骨质疏松、糖皮质激素引起的骨质疏松、佩吉特氏病、骨转换异常增加、牙周病、牙齿丧失、骨折、类风湿性关节炎、骨关节炎、假体周围骨质溶解、成骨不全、动脉粥样硬化、肥胖症、慢性阻塞性肺病、转移性骨病、恶性高钙血症或多发性骨髓瘤。目前公开的组织蛋白酶K抑制剂与用于治疗或预防骨质疏松或其它骨病症的其它药物的组合,是在本发明的范围内。本领域普通技术人员将能够基于药物的具体特征和涉及的疾病识别哪种药物组合应当有用。这样的药物包括以下:有机双膦酸盐;雌激素受体调节剂;雄激素受体调节剂;破骨细胞质子ATP酶抑制剂;HMG-CoA还原酶抑制剂;整联蛋白受体拮抗剂;成骨细胞合成代谢剂,如PTH;钙;维生素D或维生素D合成类似物;非甾体抗炎药;选择性环氧化酶-2抑制剂;白介素-1β抑制剂;LOX/COX抑制剂;RANKL抑制剂;和其药学上可接受的盐和它们的混合物。优选的组合为本发明化合物和有机双膦酸盐。另一个优选的组合为本发明化合物和雌激素受体调节剂。另一个优选的组合为本发明化合物和雄激素受体调节剂。另一个优选的组合为本发明化合物和成骨细胞合成代谢剂。
“有机双膦酸盐”包括但不限于以下化学式的化合物
其中n为0至7的整数,和其中A和X独立地选自:H、OH、卤素、NH2、SH、苯基、C1-30烷基、C3-30支链或环烷基、包含两个或三个N的双环结构、C1-30取代的烷基、C1-10烷基取代的NH2、C3-10支链或环烷基取代的NH2、C1-10二烷基取代的NH2、C1-10烷氧基、C1-10烷基取代的硫基、苯硫基、卤代苯硫基、C1-10烷基取代的苯基、吡啶基、呋喃基、吡咯烷基、咪唑基、咪唑并吡啶基、和苄基,使得当n为0时,A和X都不能选自H和OH;或A和X与它们所连接的碳原子或原子一起形成C3-10环。
上述的化学式中,烷基可以是直链的、支链的、或环状的,条件是化学式有足够的原子可选择。C1-30取代的烷基可包括广泛多种的取代基,其非限制性实例包括选自下列的那些:苯基、吡啶基、呋喃基、吡咯烷基、咪唑基(imidazonyl)、NH2、C1-10烷基或二烷基取代的NH2、OH、SH、C1-10烷氧基。
上述化学式也打算包括A和/或X取代基的复杂的碳环、芳香和杂原子结构,其非限制性实例包括萘基、喹啉基、异喹啉基、金刚烷基、和氯代苯基硫基。
本文也可使用双膦酸盐的药学上可接受的盐和衍生物。盐的非限制性实例包括选自下列的那些:碱金属、碱土金属、铵和单、二、三、或四个-C1--C10烷基取代的铵。优选的盐选自下列的那些:钠、钾、钙、镁和铵盐。更优选的盐为钠盐。衍生物的非限制性实例包括选自下列的那些:酯、水合物、和酰胺。
应注意到,本文在提及本发明的治疗药物术语时使用的“双膦酸盐”和“双膦酸盐类”还意欲包括二磷酸盐、双膦酸、和二磷酸、以及这些物质的盐和衍生物。除非特别指出,关于双膦酸盐或双膦酸盐类具体命名法的应用并不意谓限制本发明的范围。因为本领域普通技术人员当前使用的混合命名法,所涉及的本发明双膦酸盐化合物的具体重量或百分数是基于酸有效重量为基础的,除非本文另外指出。例如,短语“选自阿伦膦酸盐、其药学上可接受的盐、和它们的混合物的大约5mg骨吸收抑制性双膦酸盐,是基于阿伦膦酸有效重量为基础的”表示所选择的双膦酸盐化合物的量是基于5mg阿伦膦酸为基础所计算的。用于本文的双膦酸盐的非限制性实例包括以下:
阿伦膦酸盐,也称为阿伦膦酸、4-氨基-1-羟基亚丁基-1,1-双膦酸、阿仑膦酸钠或阿仑膦酸一钠三水合物、4-氨基-1-羟基亚丁基-1,1-双膦酸一钠三水合物。
阿伦膦酸盐描述在1990年5月1日出版的Kieczykowski等人的美国专利4,922,007;1991年5月28日出版的Kieczykowski等人的美国专利5,019,651;1996年4月23日出版的Dauer等人的美国专利5,510,517;1997年7月15日出版的Dauer等人的美国专利5,648,491中,所有文献在此全文引入作为参考。
环庚基氨基亚甲基-1,1-双膦酸,YM175,Yamanouchi(伊卡膦酸盐,以前称为英卡磷酸盐),如1990年11月13日出版的Isomura等人的美国专利4,970,335,在此将其全文引入作为参考。
1,1-二氯亚甲基-1,1-二膦酸(氯膦酸),和其二钠盐(氯膦酸盐、Procter和Gamble)描述在比利时专利672,205(1966)和J.Org.Chem32,4111(1967)中,两篇文献在此全文引入作为参考。
1-羟基-3-(1-吡咯烷基)-亚丙基-1,1-双膦酸(EB-1053)
1-羟基乙烷-1,1-二膦酸(依替膦酸)。
1-羟基-3-(N-甲基-N-戊基氨基)亚丙基-1,1-双膦酸,也称为BM-210955,Boehringer-Mannheim(伊班膦酸盐),描述在1990年5月22日出版的美国专利第4,927,814号中,在此将其全文引入作为参考。
1-羟基-2-咪唑并-(1,2-a)吡啶-3-基亚乙基(米诺膦酸盐)。
6-氨基-1-羟基亚己基-1,1-双膦酸(奈立膦酸盐)。
3-(二甲氨基)-1-羟基亚丙基-1,1-双膦酸(奥帕膦酸盐)。
3-氨基-1-羟基亚丙基-1,1-双膦酸(帕米磷酸盐)。
[2-(2-吡啶基)亚乙基]-1,1-双膦酸(吡磷酸盐)描述在美国专利第4,761,406中,在此将其全文引入作为参考。
1-羟基-2-(3-吡啶基)-亚乙基-1,1-双膦酸(利塞膦酸盐)。
(4-氯苯基)硫代甲烷-1,1-二膦酸(替鲁膦酸盐)如描述在1989年10月24日Breliere等人的美国专利4,876,248,在此将其全文引入作为参考。
1-羟基-2-(1H-咪唑-1-基)亚乙基-1,1-双膦酸(唑来膦酸盐)。
双膦酸盐的非限制性实例包括阿伦膦酸盐、英卡磷酸盐、氯膦酸盐、依替膦酸盐、伊班膦酸盐、伊卡膦酸盐、米诺膦酸盐、奈立膦酸盐、奥帕膦酸盐、帕米磷酸盐、吡磷酸盐(piridronate)、利塞膦酸盐、替鲁膦酸盐、和唑来膦酸盐和其药学上可接受的盐和酯。特别优选的双膦酸盐为阿伦膦酸盐,尤其为阿伦膦酸的钠、钾、钙、镁或铵盐。示例性地,优选的双膦酸盐是阿伦膦酸的钠盐,尤其为水合的阿伦膦酸钠盐。盐可与整摩尔数的水或非整摩尔数的水水合。进一步示例性地,优选的双膦酸盐是水合的阿伦膦酸钠盐,尤其是水合盐为阿伦膦酸一钠三水合物时。
应该认识到可利用两种或更多种双膦酸盐活性物的混合物。
有机双膦酸盐的精确剂量可随着给药方案、选择的具体双膦酸盐、哺乳动物或人的年龄、大小、性别和疾病、要治疗病症的性质和严重度、和其它有关的医学和物理因素。因此,精确的药学有效量不能预先指定,而可由护理师(caregiver)或临床医师容易地确定。适当的量可通过从动物模型和人临床研究的常规实验确定。一般地,选择双膦酸盐的适当量以获得骨吸收抑制效果,即施用双膦酸盐的骨吸收抑制的量。对于人类,双膦酸盐的口服有效剂量一般为大约1.5至大约6000μg/kg体重,优选为大约10至大约2000μg/kg。对于阿伦膦酸一钠三水合物,给普通人施用的剂量通常在大约2mg/天至大约40m/天的范围,优选为大约5mg/天至大约40m/天。在美国目前批准阿伦膦酸一钠三水合物用于预防骨质疏松的剂量为5mg/天,用于治疗骨质疏松的剂量为10mg/天,用于治疗佩吉特氏病的剂量为40mg/天。
在可替代选择的给药方案中,可以以不同于每日的间隔施用双膦酸盐,例如一周一次给药、一周二次给药、两周一次给药、每月二次给药。在一周一次给药方案中,阿伦膦酸一钠三水合物以35mg/周或70mg/周的剂量给药。
“选择性雌激素受体调节剂”是指干涉或抑制雌激素与受体结合的化合物,而不管机制如何。雌激素受体调节剂的实例包括但不限于雌激素、孕激素、雌二醇、屈洛昔芬、雷洛昔芬、拉索昔芬、TSE-424、他莫昔芬、艾多昔芬、LY353381、LY117081、托瑞米芬、氟维司群、4-[7-(2,2-二甲基-1-氧代丙氧基-4-甲基-2-[4-[2-(1-哌啶基)乙氧基]苯基]-2H-1-苯并吡喃-3基]-苯基-2,2-二甲基丙酸酯、4,4'-二羟基二苯甲酮-2,4-二硝基苯基-腙、和SH646。
“雌激素受体β调节剂”为选择地激动和拮抗雌激素受体β(ERβ)的化合物。激动ERβ经由ERβ介导的事件增加色氨酸羟化酶基因(TPH,5-羟色胺合成中的关键酶)的转录。雌激素受体β激动剂的实例可见于2001年11月08日出版的PCT国际公布WO 01/82923,和2002年05月20日出版的WO 02/41835,两篇文献在此全文引入作为参考。
“雄激素受体调节剂”是指干涉或抑制雄激素与受体结合的化合物,而不管机制如何。雄激素受体调节剂的实例包括非那雄胺和其它的5α-还原酶抑制剂、尼鲁米特、氟他胺、比卡鲁胺、利阿唑和醋酸阿比特龙。
“破骨细胞质子ATP酶抑制剂”是指质子ATP酶的抑制剂,其发现在破骨细胞的顶膜上并报道在骨吸收过程中起重要作用。质子泵代表骨吸收抑制剂设计的吸引人的靶目标,潜在性地用于治疗和预防骨质疏松和相关的新陈代谢疾病。参见Farina,C等,“Selective inhibitorsof the osteoclast vacuolar proton A TPase as novel bone antiresorptiveagents”,DDT,4:163-172(1999),在此将其全文引入作为参考。
“HMG-CoA还原酶抑制剂”是指3-羟-3-甲基戊二酰辅酶A还原酶抑制剂。可使用本领域众所周知的测定法容易地鉴定出具有HMG-CoA还原酶抑制剂抑制活性的化合物。例如,参见美国专利4,231,938第6栏和WO 84/02131第30-33页中描述或引用的测定法。当用于本文中时,术语“HMG-CoA还原酶抑制剂”和“HMG-CoA还原酶的抑制剂”具有相同的意义。
可使用的HMG-CoA还原酶抑制剂的实例包括但不限于洛伐他汀(参见美国专利号4,231,938、4,294,926和4,319,039),辛伐他汀(参见美国专利号4,444,784、4,820,850和4,916,239),普伐他汀(参见美国专利号4,346,227、4,537,859、4,410,629、5,030,447和5,180,589),氟伐他汀(参见美国专利号5,354,772、4,911,165、4,929,437、5,189,164、5,118,853、5,290,946和5,356,896),阿托伐他汀(参见美国专利号5,273,995、4,681,893、5,489,691和5,342,952)和西立伐他汀(也称为立伐他汀和参见美国专利号5,177,080)。本方法可使用的这些和另外的HMG-CoA还原酶抑制剂的结构式描述在M.Yalpani,“Cholesterol Lowering Drugs”,Chemistry&Industry,pp.85-89(1996年2月5日)第87页和美国专利号4,782,084和4,885,314中。本文使用的术语HMG-CoA还原酶抑制剂包括具有HMG-CoA还原酶抑制剂活性的化合物的所有药学上可接受的内酯和开环酸形式(即,其中内酯环被打开以形成游离酸)以及盐和酯形式,因此这些盐、酯、开环酸和内酯形式的使用包括在本发明的范围内。内酯部分和其相应的开环酸形式的图解说明;如以下结构I和II所示。
在其中可存在开环酸形式的HMG-CoA还原酶抑制剂中,优选盐和酯形式可由开环酸形成,并且所有这些形式均包括在本文使用的术语“HMG-CoA还原酶抑制剂”的意义内。优选地,HMG-CoA还原酶抑制剂选自洛伐他汀和辛伐他汀,最优选辛伐他汀。本文中,关于HMG-CoA还原酶抑制剂的术语“药学上可接受的盐”意指本发明中应用的化合物的无毒性盐,通常由游离酸与适当的有机或无机碱反应制得,特别是由阳离子如钠、钾、铝、钙、锂、镁、锌和四甲铵所形成的那些盐,以及由胺如铵、乙二胺、N-甲基葡糖胺、赖氨酸、精氨酸、鸟氨酸、胆碱、N,N'-二苄乙二胺、氯普鲁卡因、二乙醇胺、普鲁卡因、N-苄基苯乙胺、1-对氯苄基-2-吡咯烷-1-基-甲基苯并-咪唑、二乙胺、哌嗪、和三(羟甲基)氨基甲烷所形成的那些盐。HMG-CoA还原酶抑制剂盐形式的进一步实例包括但不限于醋酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、硫酸氢盐、硼酸盐、溴化物、乙二胺四乙酸钙、樟脑磺酸盐、碳酸盐、氯化物、克拉维酸盐、柠檬酸盐、二盐酸化物、乙二胺四乙酸盐、乙二磺酸盐、丙酸酯月桂硫酸盐、乙磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、乙醇酰氨基苯胂酸盐(glycollylarsanilate)、己基间苯二酚盐、海巴胺(hydrabamine)、氢溴化物、氢氯化物、羟基萘酸盐(hydroxynapthoate)、碘化物、异硫羰酸盐(isothionate)、乳酸盐、乳糖醛酸盐、月桂酸、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、粘酸盐、萘磺酸盐、硝酸盐、油酸盐、草酸盐、双羟基萘酸盐(pamaote)、棕榈酸盐、泛酸盐(panthothenate)、磷酸盐/二磷酸盐、聚半乳糖醛酸盐、水杨酸盐、硬脂酸盐、碱式醋酸盐、琥珀酸盐、鞣酸盐、酒石酸盐、8-氯茶碱盐(teoclate)、甲苯磺酸盐、三乙基碘化物、和戊酸盐。
所述HMG-CoA还原酶抑制剂化合物的酯衍生物可作为前体药物,当其被吸收进入温血动物的血流中时,可以以这样的方式裂开,以至释放药物形式并允许药物提供改善的治疗效果。
如上面使用的“整联蛋白拮抗剂”是指选择性地拮抗、抑制或阻碍生理学配体与ανβ3整联蛋白结合的化合物,是指选择性地拮抗、抑制或阻碍生理学配体与ανβ5整联蛋白结合的化合物,是指拮抗、抑制或阻碍生理学配体与ανβ3整联蛋白和ανβ5整联蛋白两者结合的化合物,和是指在毛细血管内皮细胞上拮抗、抑制或阻碍表达特定整联蛋白活性的化合物。该术语也指ανβ6、ανβ8、α1β1、α2β1、α5β1、α6β1和α6β4整联蛋白的拮抗剂。该术语也指以下整联蛋白的任意组合的拮抗剂:ανβ3、ανβ5、ανβ6、ανβ8、α1β1、α2β1、α5β1、α6β1和α6β4。H.N.Lode和同事在PNASUSA96:1591-1596(1999)中观察到在根除自发性肿瘤转移中抗血管生成的αv整联蛋白拮抗剂和肿瘤特异性抗体-细胞因子(白细胞介素-2)融合蛋白之间的协同作用。他们的结果提示这种组合有潜力用于治疗癌症和转移性肿瘤的生长。ανβ3整联蛋白受体拮抗剂通过新的不同于当前所有可用药物的机制抑制骨吸收。整联蛋白为介导的细胞-细胞和细胞-基质相互作用的异二聚体跨膜粘着受体。α和β整联蛋白亚单位非共价地相互作用并以二价阳离子依赖方式结合细胞外基质配体。破骨细胞上最丰富的整联蛋白为ανβ3(>107/破骨细胞),它似乎在对细胞迁移和极化极为重要的细胞骨架构建中起限制速率的作用。ανβ3的拮抗作用选自骨吸收抑制、再狭窄抑制、黄斑变性抑制、关节炎抑制、和癌症和转移性生长的抑制。
“成骨细胞合成代谢剂”是指构建骨骼的药物,如PTH。甲状旁腺激素(PTH)或其氨基端片断和类似物的间歇性给药已经在动物和人中显示出预防、停止、部分逆转骨丢失和刺激骨形成。至于讨论可参考Dempster,DW等,“Anabolic actions of parathyroid hormone onbone”,Endocr Rev14:690-709(1993)。研究证明了甲状旁腺激素在刺激骨形成从而增加骨质量和强度中的临床益处。由Neer,RM等,在NewEngJMed3441434-1441(2001)中报告了结果。
另外,已经证实了甲状旁腺激素相关蛋白片断或类似物如PTHrP-(1-36)具有有效的抗尿钙(anticalciuric)作用[参见Syed MA等“Parathyroid hormone-related protein-(1-36)stimulates renal tubularcalcium re-absorption in normal human volunteers:implications for thepathogenesis of humoral hypercalcemia of malignancy”,JCEM86:1525-1531(2001)],并且还可作为有效的合成代谢剂用于治疗骨质疏松。
“维生素D”包括但不限于维生素D3(胆钙化醇)和维生素D2(麦角钙化醇),它们是天然存在的、羟基化生物活性代谢物维生素D:1α-羟基维生素D;25-羟基维生素D,和1α,25-羟基维生素D的生物无活性前体。维生素D2和维生素D3在人类中具有相同的生物效能。当维生素D2或维生素D3进入循环时,可被细胞色素P450-维生素D-25-羟化酶羟化,得到25-羟基维生素D。代谢产物25-羟基维生素D生物学上是无活性的,其在肾内可被细胞色素P450-单氧合酶,25(OH)D-1α-羟化酶进一步羟化,得到1,25-二羟基维生素D。当血清钙减少时,会增加甲状旁腺激素(PTH)的生产,其通过增加25-羟基维生素转换为1,25-二羟基维生素D来调节钙动态平衡和增加血浆钙水平。
据认为,1,25-二羟基维生素D是造成维生素D对钙和骨代谢影响的原因。1,25-二羟基代谢产物是维持钙吸收和骨骼完整所需要的活性激素。通过1,25-二羟基维生素D诱导单核干细胞分化为破骨细胞并维持钙在正常范围内以维持钙动态平衡,这又通过羟磷灰石沉积在骨表面导致骨矿化,参见Holick,MF,“Vitamin D photobiology,metabolism,and clinical applications”,In:DeGroot L,Besser H,BurgerHG,等编.Endocrinology第三版,990-1013(1995)。然而,升高1α25-二羟基维生素D3的水平可导致血中钙浓度的增加和通过骨代谢导致异常控制的钙浓度,引起血钙过多。1α,25-二羟基维生素D3也直接调节骨代谢中破骨细胞的活性,那么可以预期升高的水平会使骨质疏松中骨吸收过度增加。
在本发明的实施方案中,选择维生素D化合物的适当量,以提供给药间隔期间足够的维生素D营养物,而没有干扰组织蛋白酶K抑制剂获得抑制骨吸收效果的能力。对于本发明口服的包括组织蛋白酶K抑制剂和维生素D化合物的组合物,维生素D化合物的量包括大约100IU至大约60,000IU。在本发明的实施方案中维生素D化合物口服量的非限制性实例包括但不限于2,800,IU、5,600IU、7,000IU、8,400IU、11,200IU、14,000IU、16,800IU或19,600IU的剂量。维生素D每周给药口服量的非限制性实例为2,800,IU、5,600IU、7,000IU、8,400IU和11,200IU。维生素D每月给药口服量的非限制性实例为11,200IU、14,000IU、15,400IU、16,800IU或19,600IU。
“合成的维生素D类似物”包括非天然存在的产生维生素D样效果的化合物。
“钙”包括但不限于碳酸钙、柠檬酸钙或任何包含元素钙的其它化合物。钙是人类健康必需的,又是骨骼结构完整所需要的。血钙的离子化部分是生理学上重要的,并通过甲状旁腺激素(PTH)和1,25-二羟基维生素D严密地维持。像这样,血钙减少(或仅仅饮食钙不充分)可迅速地影响PTH和1,25-二羟基维生素D的水平,同样会不利地影响骨骼健康,因而补充钙的供应趋向于降低PTH水平,以减小钙从骨架贮存中除去,同样地会有利于骨骼健康。在本发明的实施方案中钙口服量的非限制性实例包括但不限于元素钙每天分开剂量地1200-1500mg的剂量。
“非甾体抗炎药”或NSAIDs经由环氧合酶(COX)-1和COX-2抑制花生四烯酸的代谢为促炎症反应的前列腺素。NSAIDs的非限制性实例包括:阿斯匹林、布洛芬、萘普生、双氯芬酸、依托度酸、非诺洛芬、氟比洛芬、吲哚美辛、酮洛芬、酮咯酸、美洛昔康、萘丁美酮、奥沙普嗪、吡罗昔康、舒林酸、托美丁、二氟尼柳、甲氯灭酸盐和保泰松。
“选择性环氧化酶-2抑制剂”或COX-2抑制剂是指一类抑制COX-2辅酶的非甾体抗炎药(NSAID),COX-2辅酶为促成身体内疼痛和炎症的因素。COX-2抑制剂的非限制性实例包括:塞来考昔、艾托考昔、帕瑞考昔、罗非考昔、伐地考昔和鲁米考昔。
“白介素-1β抑制剂”或IL-1β是指IL-1的抑制剂,IL-1为单核细胞、巨噬细胞和其它细胞生产的可溶性因子,刺激T淋巴细胞和加强它们对有丝分裂原或抗原的应答。IL-1β抑制剂的非限制性实例包括双醋瑞因和大黄酸(rhein)。
“LOX/COX抑制剂”是指涉及花生四烯酸途径的或所有三个主要酶-即5-LOX,COX-1和COX-2的抑制剂。LOX/COX抑制剂的非限制性实例为利克飞龙(licofelone)。
“RANKL抑制剂”是指受体活性剂NF-kB配体(RANKL)的抑制剂,其先前称为破骨细胞分化因子(ODF)、骨保护素配体(OPGL)和TNF相关的激活引起的细胞因子(TRANCE)。RANKL是破骨细胞形成和成熟的关键刺激剂。RANKL抑制剂的非限制性实例为AMG-162。
如果配制为固定剂量,这样组合的产品应用如下所述剂量范围的本发明化合物和批准剂量范围内的其它活性药物。当组合制剂不适宜时,可替代选择地将本发明化合物与已知的药学上可接受的药物相继地使用。
术语“AUC”或“曲线下面积”是指在约定时间期限内通过血浆浓度-时间曲线所定义的面积,表示在约定时间期限内血浆接触药物的总量。AUC0-24是指化合物施用后的第一个24小时的浓度-时间曲线下的面积。AUC0-168是指化合物施用后的第一个168小时(一周)的浓度-时间曲线下的面积。
术语“Cmin”是指在约定时间期限内药物在血浆中循环的最小浓度。最小浓度的时间通常为紧接另一个药物剂量施用之前。
本文使用的术语“一周一次”和“一周一次给药”表示一周施用一次单位药量(unit dosage),例如组织蛋白酶K抑制剂的单位药量,即七天时期中一次,优选在每周的同一天。在一周一次给药方案中,通常大约每一个七天施用单位药量。一周一次给药方案的非限制性实例为每星期日应必需施用组织蛋白酶K抑制剂的单位药量。习惯上推荐一周一次的单位药量的给药不在连续的天内施用,但是一周一次的给药方案可包括其中落在两个不同周时期内的连续2天施用单位药量的给药方案。
对于“两周一次”给药是指两周时期内施用一次组织蛋白酶K抑制剂的单位药量,即十四天时期中一次,优选在每两周时期内的同一天。在两周一次(twice-weekly)的给药方案中,通常大约每一个十四天施用各单位药量。两周一次给药方案的非限制性实例为每隔一个每星期日应必需施用组织蛋白酶K抑制剂的单位药量。优选地单位药量的给药不在连续的天内施用,但是两周一次的给药方案可包括其中落在两个不同的两周时期内的连续2天施用单位药量的给药方案。
对于“一月两次”给药是指两周时期内施用两次组织蛋白酶K抑制剂的单位药量,即每月日历时期中两次。对于一月两次的方案,优选在每个月相同的两个日期给予用药量。在一月两次的给药方案中,通常大约每十四天至十六天施用各单位药量。一月两次给药方案的非限制性实例为在或大约在每月的第一天和在或大约在每月的第十五天(即中间点)应必需给药。优选地单位药量的给药不在同一天或连续的天内施用,但是一月两次给药方案可包括在月周期或不同月的时期内的连续2天施用单位药量的给药方案。一月两次的方案在本文中定义为不同于和不包括两周一次的给药方案,因为这两个方案具有不同的周期性,导致在长时间期限内施用不同次数的药量。例如在一年时期内,根据一月两次的方案应施用总数大约二十四次的药量(因为一年中有十二历月),而根据两周一次的给药方案应施用总数大约二十六次的药量(因为一年中有大约五十二个周)。
根据通常可接受意义,以大约四周、大约30天或1/12的日历年作为时间计数量度,使用术语“一月一次”。
术语“上消化道病症”是指与上胃肠道(GI)相关的病症,包括但不限于胃肠返流疾病(GERD)、食管炎、消化不良(胃灼热)和溃疡。
关于本发明化合物的术语“给药”和其变型(例如“施用”化合物)表示化合物或化合物的前体药物介入需要治疗的动物系统中。当本发明化合物或其前体药物与一种或多种其它活性药物(例如,细胞毒素剂等)组合提供时,“给药”和其变型各自理解为包括化合物或其前体药物和其它药物同时地和相继地介入。本发明在其范围内包括本发明化合物的前体药物。一般而言,这样的前体药物是本发明化合物的功能性衍生物,其在体内容易转化成所需要的化合物。因此,在本发明的治疗方法中,术语“给药”应包括用具体公开的化合物或可用没有具体公开的但在给患者施用后在体内转化为具体化合物的化合物治疗所述的多种疾病。选择和制备适用的前体药物衍生物的常规过程描述在,例如“Design of Prodrugs”Bundgaard,H编,Elsevier,1985,在此将其全文引入作为参考。这些化合物的代谢产物包括本发明化合物介入生物学的环境所产生的活性种类。
本文使用的术语“组合物”有意包括包含指定量的指定成分的产品,以及直接地或间接地由指定量的指定成分组合得到的任何产品。
本文使用的术语“单位剂量”描述为一次完整地施用的单个单元剂量。
本文使用的术语“治疗有效量”表示在组织、系统、动物或人类中引起研究人员、兽医、医疗医生或临床医生寻求的生物学或医学反应的活性化合物或药物的量。
本文使用的术语疾病的“治疗”或“治疗”疾病包括:预防疾病,即使可能暴露于或易感染疾病但还没有经历或显示疾病症状的哺乳动物不发展成疾病的临床症状;抑制疾病,即停止或减少疾病的发展或其临床症状;或缓解疾病,即引起疾病或其临床症状的消退。
本文使用的术语“骨吸收”是指破骨细胞降解骨的过程。
本发明的这些和其它方面,根据本文所包含的教导应是显而易见的。
给出下列实施例用于说明本发明的目的,不应当解释为限制本发明的范围。
药物组合物
关于下列药物组合物,可使用N1-(1-氰基环丙基)-4-氟-N2-{(1S)-2,2,2-三氟-1-[4'-(甲磺酰基)-1,1'-联苯-4-基]乙基}-L-亮氨酰胺作为组织蛋白酶K抑制剂的实例。
组合物 1
组合物 2
组合物 3
组合物 4
Claims (9)
1.50mg的组织蛋白酶K抑制剂N1-(1-氰基环丙基)-4-氟-N2-{(1S)-2,2,2-三氟-1-[4'-(甲磺酰基)-1,1'-联苯-4-基]乙基}-L-亮氨酰胺或其药学上可接受的盐用于制备用于在有需要的人内抑制骨吸收的药剂的用途,该药剂是根据每周一次的剂量给药方案的口服单位剂型。
2.根据权利要求1的用途,其中该药剂进一步包括维生素D。
3.根据权利要求2的用途,其中维生素D的量为5,600 IU或11,200 IU。
4.根据权利要求1-3任一项的用途,其中口服的单位剂型是片剂。
5.根据权利要求1-3任一项的用途,其中口服的单位剂型是胶囊。
6.根据权利要求1-3任一项的用途,其中口服的单位剂型是液体。
7.根据权利要求1-3任一项的用途,其中人被鉴定为患有或易患有上消化道病症。
8.根据权利要求7的用途,其中上消化道病症为胃肠返流疾病、食管炎、消化不良或溃疡。
9.根据权利要求1-3任一项的用途,用于治疗骨质疏松。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112912367A (zh) * | 2018-08-02 | 2021-06-04 | 英特维特国际股份有限公司 | N1-(1-氰基环丙基)-n2-((1s)-1-{4′-[(1r-2,2-二氟-1-羟基乙基]联苯基-4-基}-2,2,2-三氟乙基)-4-氟-l-亮氨酸酰胺的结晶形式 |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AR055283A1 (es) * | 2004-11-23 | 2007-08-15 | Merck Frosst Canada Ltd | Inhibidores de cisteinproteasa de catepsina |
EP2132173B1 (en) * | 2007-02-26 | 2015-10-07 | Merck Sharp & Dohme Corp. | Formulations for cathepsin k inhibitors |
US20110065800A1 (en) | 2008-05-14 | 2011-03-17 | Haihong Fan | Formulations for cathepsin k inhibitors |
CN103381152A (zh) * | 2013-02-05 | 2013-11-06 | 吉林省金梓源生物科技有限公司 | 杨梅素作为组织蛋白酶k抑制剂的用途 |
EP3019468A4 (en) * | 2013-07-11 | 2017-01-11 | Merck Sharp & Dohme Corp. | Formulations for cathepsin k inhibitors with vitamin d |
WO2015051479A1 (en) | 2013-10-08 | 2015-04-16 | Merck Sharp & Dohme Corp. | Cathepsin cysteine protease inhibitors |
WO2020102323A1 (en) * | 2018-11-14 | 2020-05-22 | Taiwan Liposome Co., Ltd. | Sustained-release pharmaceutical compositions comprising a therapeutic agent for treating diseases due to reduced bone density or cartilage loss and uses thereof |
Family Cites Families (48)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA777769A (en) | 1963-03-18 | 1968-02-06 | H. Roy Clarence | Substituted methylene diphosphonic acid compounds and detergent compositions |
US4330537A (en) * | 1977-12-07 | 1982-05-18 | The Procter & Gamble Company | Compositions for inhibiting mobilization of calcium phosphate in animal tissue |
US4294926A (en) | 1979-06-15 | 1981-10-13 | Merck & Co., Inc. | Hypocholesteremic fermentation products and process of preparation |
US4319039A (en) | 1979-06-15 | 1982-03-09 | Merck & Co., Inc. | Preparation of ammonium salt of hypocholesteremic fermentation product |
US4231938A (en) | 1979-06-15 | 1980-11-04 | Merck & Co., Inc. | Hypocholesteremic fermentation products and process of preparation |
US4444784A (en) | 1980-08-05 | 1984-04-24 | Merck & Co., Inc. | Antihypercholesterolemic compounds |
DK149080C (da) | 1980-06-06 | 1986-07-28 | Sankyo Co | Fremgangsmaade til fremstilling af derivater af ml-236b-carboxylsyre |
JPS5889191A (ja) | 1981-11-20 | 1983-05-27 | Sankyo Co Ltd | 3−ヒドロキシ−ml−236b誘導体の製造法 |
JPS591415A (ja) * | 1982-06-28 | 1984-01-06 | Mochida Pharmaceut Co Ltd | 循環系疾患治療剤 |
FR2531088B1 (fr) | 1982-07-29 | 1987-08-28 | Sanofi Sa | Produits anti-inflammatoires derives de l'acide methylenediphosphonique et leur procede de preparation |
WO1984002131A1 (en) | 1982-11-22 | 1984-06-07 | Sandoz Ag | Analogs of mevalolactone and derivatives thereof, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals |
US5354772A (en) | 1982-11-22 | 1994-10-11 | Sandoz Pharm. Corp. | Indole analogs of mevalonolactone and derivatives thereof |
US4911165A (en) | 1983-01-12 | 1990-03-27 | Ethicon, Inc. | Pliabilized polypropylene surgical filaments |
US4761406A (en) | 1985-06-06 | 1988-08-02 | The Procter & Gamble Company | Regimen for treating osteoporosis |
US4681893A (en) | 1986-05-30 | 1987-07-21 | Warner-Lambert Company | Trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis |
DE3623397A1 (de) | 1986-07-11 | 1988-01-14 | Boehringer Mannheim Gmbh | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
US4782084A (en) | 1987-06-29 | 1988-11-01 | Merck & Co., Inc. | HMG-COA reductase inhibitors |
US4885314A (en) | 1987-06-29 | 1989-12-05 | Merck & Co., Inc. | Novel HMG-CoA reductase inhibitors |
US4820850A (en) | 1987-07-10 | 1989-04-11 | Merck & Co., Inc. | Process for α-C-alkylation of the 8-acyl group on mevinolin and analogs thereof |
CA1339805C (en) | 1988-01-20 | 1998-04-07 | Yasuo Isomura | (cycloalkylamino)methylenebis(phosphonic acid) and medicines containing the same as an active |
US5030447A (en) | 1988-03-31 | 1991-07-09 | E. R. Squibb & Sons, Inc. | Pharmaceutical compositions having good stability |
US5180589A (en) | 1988-03-31 | 1993-01-19 | E. R. Squibb & Sons, Inc. | Pravastatin pharmaceuatical compositions having good stability |
US4916239A (en) | 1988-07-19 | 1990-04-10 | Merck & Co., Inc. | Process for the lactonization of mevinic acids and analogs thereof |
US5118853A (en) | 1988-10-13 | 1992-06-02 | Sandoz Ltd. | Processes for the synthesis of 3-disubstituted aminoacroleins |
US5290946A (en) | 1988-10-13 | 1994-03-01 | Sandoz Ltd. | Processes for the synthesis of 3-(substituted indolyl-2-yl)propenaldehydes |
US4929437A (en) | 1989-02-02 | 1990-05-29 | Merck & Co., Inc. | Coenzyme Q10 with HMG-CoA reductase inhibitors |
US5189164A (en) | 1989-05-22 | 1993-02-23 | Sandoz Ltd. | Processes for the synthesis of syn-(E)-3,5-dihydroxy-7-substituted hept-6-enoic and heptanoic acids and derivatives and intermediates thereof |
US4922007A (en) | 1989-06-09 | 1990-05-01 | Merck & Co., Inc. | Process for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof |
FI94339C (fi) | 1989-07-21 | 1995-08-25 | Warner Lambert Co | Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi |
US5019651A (en) | 1990-06-20 | 1991-05-28 | Merck & Co., Inc. | Process for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (ABP) or salts thereof |
US5177080A (en) | 1990-12-14 | 1993-01-05 | Bayer Aktiengesellschaft | Substituted pyridyl-dihydroxy-heptenoic acid and its salts |
HU9203780D0 (en) | 1991-12-12 | 1993-03-29 | Sandoz Ag | Stabilized pharmaceutical products of hmg-coa reductase inhibitor and method for producing them |
US5298627A (en) | 1993-03-03 | 1994-03-29 | Warner-Lambert Company | Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis |
US5510517A (en) | 1993-08-25 | 1996-04-23 | Merck & Co., Inc. | Process for producing N-amino-1-hydroxy-alkylidene-1,1-bisphosphonic acids |
TW257765B (zh) | 1993-08-25 | 1995-09-21 | Merck & Co Inc | |
AU3359697A (en) * | 1996-07-08 | 1998-02-02 | Yamanouchi Pharmaceutical Co., Ltd. | Bone resorption inhibitors |
WO1999067809A1 (en) * | 1998-06-24 | 1999-12-29 | Merck & Co., Inc. | Compositions and methods for inhibiting bone resorption |
WO2001082923A1 (en) | 2000-02-14 | 2001-11-08 | Merck & Co., Inc. | Estrogen receptor modulators |
AU2002226965B2 (en) | 2000-11-27 | 2006-05-18 | Merck Sharp & Dohme Corp. | Estrogen receptor modulators |
US20040235728A1 (en) | 2001-11-08 | 2004-11-25 | Stoch Selwyn Aubrey | Compositions and methods for treating osteoporosis |
WO2003051373A1 (en) * | 2001-12-13 | 2003-06-26 | Merck & Co., Inc. | Liquid bisphosphonate formulations for bone disorders |
BRPI0308208B8 (pt) * | 2002-03-05 | 2021-05-25 | Axys Pharm Inc | compostos inibidores de catepsina cisteína protease e composições farmacêuticas compreendendo os mesmos |
JP2004256525A (ja) * | 2003-02-06 | 2004-09-16 | Sankyo Co Ltd | N−[1−置換−2−(アリールアミノ)エチル]アミド誘導体 |
CN100393700C (zh) | 2003-06-30 | 2008-06-11 | 麦克弗罗斯特(加拿大)公司 | 组织蛋白酶半胱氨酸蛋白酶抑制剂 |
AU2004296905A1 (en) * | 2003-12-12 | 2005-06-23 | Merck Frosst Canada Ltd | Cathepsin cysteine protease inhibitors |
AR055283A1 (es) * | 2004-11-23 | 2007-08-15 | Merck Frosst Canada Ltd | Inhibidores de cisteinproteasa de catepsina |
WO2006076797A1 (en) * | 2005-01-19 | 2006-07-27 | Merck Frosst Canada Ltd. | Cathepsin k inhibitors and atherosclerosis |
CA2614070C (en) * | 2005-07-06 | 2014-03-25 | Merck Frosst Canada Ltd. | Cathepsin cysteine protease inhibitors |
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Publication number | Priority date | Publication date | Assignee | Title |
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CN112912367A (zh) * | 2018-08-02 | 2021-06-04 | 英特维特国际股份有限公司 | N1-(1-氰基环丙基)-n2-((1s)-1-{4′-[(1r-2,2-二氟-1-羟基乙基]联苯基-4-基}-2,2,2-三氟乙基)-4-氟-l-亮氨酸酰胺的结晶形式 |
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