CN1997374A - 雌激素受体调节剂 - Google Patents
雌激素受体调节剂 Download PDFInfo
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- CN1997374A CN1997374A CNA2005800208719A CN200580020871A CN1997374A CN 1997374 A CN1997374 A CN 1997374A CN A2005800208719 A CNA2005800208719 A CN A2005800208719A CN 200580020871 A CN200580020871 A CN 200580020871A CN 1997374 A CN1997374 A CN 1997374A
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Abstract
本发明涉及化合物及其衍生物、其合成,以及其作为雌激素受体调节剂的应用。本发明化合物为雌激素受体的配体并因此可用于治疗或预防多种与雌激素功能相关的适应症,包括:骨损失、骨折、骨质疏松、转移性骨疾病、佩吉特氏疾病、牙周病、软骨变性、子宫内膜异位、子宫纤维性疾病、热潮红、LDL胆固醇水平升高、心血管疾病、认知功能损害、脑变性疾病、再狭窄、男子乳腺发育、血管平滑肌细胞增殖、肥胖、失禁、炎症、炎症性肠病、性别功能失调、高血压、视网膜变性,和癌症,尤其是乳腺癌、子宫癌和前列腺癌。
Description
发明背景
天然存在和合成的雌激素具有广泛的治疗作用,包括:缓解更年期症状、治疗痤疮、治疗痛经和功能失调性子宫出血、治疗骨质疏松、治疗多毛症、治疗前列腺癌、治疗热潮红以及预防心血管疾病。由于雌激素极具治疗价值,因此发现在雌激素响应性组织中模拟雌激素样作用的化合物是十分令人感兴趣的。
现已发现雌激素受体具有两种形式:ERα和ERβ。配体不同地结合到这两种形式,并且各种形式具有对结合配体的不同组织特异性。因此,有可能存在对ERα或ERβ具有选择性的化合物,由此赋予对特定配体的一定程度的组织特异性。
本领域需要的是可产生如同雌激素替代疗法一样的积极反应但不具有其副作用的化合物。还需要对机体的不同组织表现出选择性作用的雌激素样化合物。
本发明化合物是雌激素受体的配体,因此可用于治疗或预防各种与雌激素功能有关的适应症,包括:骨损失、骨折、骨质疏松、转移性骨疾病、佩吉特氏(Paget`s)疾病、牙周病、软骨变性、子宫内膜异位、子宫纤维性疾病、热潮红、LDL胆固醇水平升高、心血管疾病、认知功能损害、脑变性疾病、再狭窄、男子乳腺发育、血管平滑肌细胞增殖、肥胖、失禁、焦虑、由雌激素不足引起的抑郁、炎症、炎症性肠病、性功能失调、高血压、视网膜变性,和癌症,尤其是乳腺癌、子宫癌和前列腺癌。
发明概要
本发明涉及通过δ-5-雄烯-3-β-17-β-二醇治疗或预防与雌激素功能相关的各种病况的方法。
附图简述
附图1:通过17β-雌二醇(E2、0.2mg/kg)、Δ5-雄烯-3β,17β-二醇(A、5或10mg/kg)或赋形剂(麻油)处理后的野生型和雌激素受体β敲除(βERKO)小鼠的背缝神经核中的孕酮受体(PR)蛋白。动物(n=5/组)被治疗3天,并且在最后一次治疗之后24小时收集大脑和子宫并且处理用于免疫组织化学。尽管ERα和ERβ均在背缝神经核中表达,但是ERβ更加充分且该大脑区域中通过E2的PR诱导主要由ERβ调节。注意在缺乏功能性ERβ的βERKO小鼠中通过E2的PR诱导的衰减和通过A的PR诱导的完全损失。对海马(其中PR完全由ERα调节)中PR免疫反应性细胞的检查显示了在E2-治疗的野生型和βERKO小鼠中的显著表达,在赋形剂或者A(5mg/kg)治疗组中没有PR免疫反应性,且在高剂量A(10mg/kg)组中轻微染色的细胞。这些数据共同显示了以该试验中测试剂量的A的作用由ERβ介导。
附图2:通过17β-雌二醇(E2、0.2mg/kg)、Δ5-雄烯-3 β,17β-二醇(A、5或10mg/kg)或赋形剂(麻油)处理后的野生型和雌激素受体β敲除(βERKO)小鼠的子宫重量。动物(n=5/组)被治疗3天,并且在最后一次治疗之后24小时收集大脑和子宫。在野生型和βERKO小鼠中,E2均显著增加子宫重量,因为该响应通过ERα介导;然而,A仅有适度作用。共同地,在测试剂量下,A证明了在大脑中充分的ER-β活性,且在末梢中对ERα仅有适度活性。
发明详述
本发明涉及通过δ-5-雄烯-3-β-17-β-二醇治疗或预防与雌激素功能相关的各种病况的方法。
本发明的范围还包括由δ-5-雄烯-3-β-17-β-二醇和药学可接受载体组成的药物组合物。本发明还意图包括由药学上可接受的载体和本申请中任意明确公开的化合物组成的药物组合物。本发明还涉及用于制造本发明药物组合物的方法。本发明还涉及用于制造本发明化合物和药物组合物的方法和中间体。本发明的这些和其它方面将从本文含有的教导变得显而易见。
δ-5-雄烯-3-β-17-β-二醇是雌激素受体的选择性调节剂,且因此适用于治疗或预防与哺乳动物中雌激素受体功能相关的各种疾病和病况。具体而言,δ-5-雄烯-3-β-17-β-二醇是ERβ的选择性调节剂且由此适用于治疗或预防与哺乳动物(优选人类)中ERβ功能相关的各种疾病和病况。
各种与雌激素受体功能相关的疾病和病况包括但不限于:骨损失、骨折、骨质疏松、转移性骨疾病、佩吉特氏疾病、牙周病、软骨变性、子宫内膜异位、子宫纤维性疾病、热潮红、LDL胆固醇水平升高、心血管疾病、认知功能损害、脑变性疾病、再狭窄、男子乳腺发育、血管平滑肌细胞增殖、肥胖、失禁、焦虑、由雌激素不足引起的抑郁、炎症、炎症性肠病、性功能失调、高血压、视网膜变性和癌症,尤其是乳腺癌、子宫癌和前列腺癌。在使用当前要求保护的化合物治疗这些病况时,所需治疗量将根据特定疾病变化并且本领域技术人员可以容易确定。虽然治疗和预防都包括在本发明范围内,优选使用这些疾病的治疗。
本发明还涉及通过在有需要的哺乳动物中给药δ-5-雄烯-3-β-17-β-二醇产生雌激素受体调节作用的方法。本发明还涉及通过在有需要的哺乳动物中给药δ-5-雄烯-3-β-17-β-二醇产生雌激素受体激动作用的方法。具体而言,雌激素受体激动作用为ERβ激动作用。
本发明还涉及通过在有需要的哺乳动物中给药本发明化合物和药物组合物治疗或预防与雌激素功能相关的疾病、骨损失、骨折、骨质疏松、转移性骨疾病、佩吉特氏疾病、牙周病、软骨变性、子宫内膜异位、子宫纤维性疾病、热潮红、LDL胆固醇水平升高、心血管疾病、认知功能损害、脑变性疾病、再狭窄、男子乳腺发育、血管平滑肌细胞增殖、肥胖、失禁、焦虑、由雌激素不足引起的抑郁、炎症、炎症性肠病、性功能失调、高血压、视网膜变性,和癌症,尤其是乳腺癌、子宫癌和前列腺癌。本发明实例为治疗或预防抑郁的方法。本发明实例为治疗或预防焦虑的方法。本发明实例为治疗或预防热潮红的方法。本发明实例为治疗或预防癌症的方法。本发明实例为治疗或预防心血管疾病的方法。
本发明的一个实施方案为通过在有需要的哺乳动物中给药本发明化合物和药物组合物治疗或预防癌症,尤其是乳腺癌、子宫癌或前列腺癌的方法。SERMs治疗乳腺癌、子宫癌或前列腺癌的用途在文献中已知,参见T.J.Powles,“Breast cancer prevention”,Oncologist 2002;7(1):60-4;Park,W.C.和Jordan,V.C.,“Selective estrogen receptormodulators(SERMS)and their roles in breast cancer prevention.”Trends Mol Med.2002Feb;8(2):82-8;Wolff,A.C.等人,“Use of SERMsfor the adjuvant therapy of early-stage breast cancer,”Ann N Y AcadSci.2001 Dec;949:80-8;Steiner,M.S.等人,“Selective estrogen receptormodulators for the chemoprevention of prostate cancer,”Urology 2001Apr;57(4Suppl 1):68-72。
本发明的另一实施方案为通过在向需要的哺乳动物给药治疗有效量的任意上述化合物或药物组合物来治疗或预防该哺乳动物中转移性骨疾病的方法。SERMS治疗转移性骨疾病的用途在文献中已知,参见Campisi,C.等人,“Complete resoultion of breast cancer bone metastasisthrough the use of beta-interferon and tamoxifen,”Eur J GynaecolOncol 1993;14(6):479-83。
本发明的另一实施方案为通过向有需要的哺乳动物给药治疗有效量的任意上述化合物或药物组合物来治疗或预防该哺乳动物中男子乳腺发育的方法。SERMS治疗男子乳腺发育的用途在文献中已知,参见Ribeiro,G.和Swindell R.,“Adjuvant tamoxifen for male breastcancer.”Br J Cancer 1992;65:252-254;Donegan,W.,“Cancer of theMale Breast,”JGSM Vol.3,Issue 4,2000。
本发明的另一实施方案为通过向有需要的哺乳动物给药治疗有效量的任意上述化合物或药物组合物治疗或预防更年期后骨质疏松、糖皮质激素骨质疏松、恶性高钙血症、骨损失和骨折的方法。SERMs治疗或预防骨质疏松、恶性高钙血症、骨损失和骨折的用途在文献中已知,参见Jordan,V.C.等人,“Selective estrogen receptor modulation andreduction in risk of breast cancer,osteoporosis and coronary heartdisease,”Natl Cancer Inst 2001 Oct;93(19):1449-57;Bjarnason,NH等人,“Six and twelve month changes in bone turnover are realted toreduction in vertebral fracture risk during 3 years of raloxifenetreatment in postemenopausal osteoporosis,”Osteoporosis Int 2001;12(11):922-3;FentimanI.S.,“Tamoxifen protects against steroid-inducedbone loss,”Eur J Cancer 28:684-685(1992);Rodan,G.A.等人,“Therapeutic Approaches to Bone Diseases,”Science Vol 289,1 Sept.2000。
本发明的另一实施方案为通过向有需要的哺乳动物给药治疗有效量的任意上述化合物或药物组合物治疗或预防该哺乳动物中牙周病或牙损失的方法。SERMs在哺乳动物中治疗牙周病或牙损失的用途在文献中已知,参见Rodan,G.A.等人,“Therapeutic Approaches to BoneDiseases,”Science Vol 289,1 Sept.2000 pp.1508-14。
本发明的另一实施方案为通过向有需要的哺乳动物给药治疗有效量的任意上述化合物或药物组合物治疗或预防该哺乳动物中佩吉特氏疾病的方法。SERMs在哺乳动物中治疗佩吉特氏疾病的用途在文献中已知,参见Rodan,G.A.等人,“Therapeutic Approaches to BoneDiseases,”Science;Vol 289,1 Sept.2000 pp.1508-14。
本发明的另一实施方案为通过向有需要的哺乳动物给药治疗有效量的任意上述化合物或药物组合物治疗或预防该哺乳动物中子宫纤维性疾病的方法。SERMs治疗子宫纤维性疾病或子宫平滑肌瘤的用途在文献中已知,参见Palomba,S.等人,“Effects of raloxifene treatment onuterine leiomyomas in postmenopausal women,”Fertil Steril.2001 Jul;76(l):38-43。
本发明的另一实施方案为通过向有需要的哺乳动物给药治疗有效量的任意上述化合物或药物组合物治疗或预防该哺乳动物肥胖的方法。SERMs治疗肥胖的用途在文献中已知,参见Picard,F.等人,“Effectsof the estrogen antagonist EM-652.HCl on energy balance and lipidmetabolism in ovariectomized rats,”Int J Obes Relat Metab Disord.2000Jul;24(7):830-40。
本发明的另一实施方案为通过向有需要的哺乳动物给药治疗有效量的任意上述化合物或药物组合物治疗或预防该哺乳动物中软骨变性、类风湿性关节炎或骨关节炎的方法。SERMs治疗软骨变性、类风湿性关节炎或骨关节炎的用途在文献中已知,参见Badger,A.M.等人,“Idoxifene,a novel selective estrogen receptor modulator,is effective ina rat model of adjuvant-induced arthritis.”J Pharmacol Exp Ther.1999Dec;291(3):1380-6。
本发明的另一实施方案为通过向有需要的哺乳动物给药治疗有效量的任意上述化合物或药物组合物治疗或预防该哺乳动物中子宫内膜异位的方法。SERMs治疗子宫内膜异位的用途在文献中已知,参见Steven R.Goldstein,“The Effect of SERMs on the Endometrium,”Annals of the New York Academy of Sciences 949:237-242(2001)。
本发明的另一实施方案为通过向有需要的哺乳动物给药治疗有效量的任意上述化合物或药物组合物治疗或预防该哺乳动物中尿失禁的方法。SERMs治疗尿失禁的用途在文献中已知,参见Goldstein,S.R.,“Raloxifene effect on frequency of surgery for pelvic floorrelaxation,”Obstet Gynecol.2001Jul;98(l):91-6。
本发明的另一实施方案为通过向有需要的哺乳动物给药治疗有效量的任意上述化合物或药物组合物治疗或预防该哺乳动物中心血管疾病、再狭窄、降低LDL胆固醇水平和抑制血管平滑肌细胞增生的方法。雌激素对胆固醇的生物合成和心血管健康具有影响。统计上来讲,绝经后妇女和男人中心血管疾病的发病率大致相等;然而,绝经前妇女具有比男人低得多的心血管疾病发病率。由于绝经后妇女缺少雌激素,人们相信雌激素在预防心血管疾病中扮演有益的角色。这种机理还没有被清楚理解,不过证据表明:雌激素可增加肝脏中低密度脂质(LDL)胆固醇受体以除去过量的胆固醇。SERMs治疗或预防心血管疾病、再狭窄、降低LDL胆固醇水平和抑制血管平滑肌细胞增生的用途在文献中已知,参见Nuttall,ME等人,“Idoxifene:a novel selectiveestrogen receptor modulator prevents bone loss and lowers cholesterollevels in ovariectomized rats and decreases uterine weight in intactrats,”Endocrinology 1998 Dec;139(12):5224-34;Jordan,V.C.等人,“Selective estrogen receptor modulation and reduction in risk of breastcancer,osteoporosis and coronary heart disease,”Natl Cancer Inst 2001Oct;93(19):1449-57;Guzzo JA.,“Selective estrogen receptormodulators--a new age of estrogens in cardiovascular disease?,”ClinCardiol 2000 Jan;23(1):15-7;Simoncini T,Genazzani AR.,“Directvascular effects of estrogens and selective estrogen receptormodulators,”Curr Opin Obstet Gynecol 2000 Jun;12(3):181-7。
本发明的另一实施方案为通过向有需要的哺乳动物给药治疗有效量的任意上述化合物或药物组合物治疗或预防该哺乳动物中认知功能损害或脑变性疾病的方法。在模型中雌激素已经表明对认知作用具有有利影响,例如减轻焦虑和抑郁以及治疗或预防阿尔茨海默氏病。通过增加胆碱能功能、神经营养蛋白和神经营养蛋白受体表达,雌激素影响中枢神经系统。雌激素还增加glutamergic突触传递,改变淀粉样前体蛋白加工并提供神经保护。因此,本发明雌激素受体调节剂对于改善认知作用或治疗轻度认知损伤、注意力缺陷障碍、睡眠障碍、易怒、冲动、愤怒管理、多发性硬化和帕金森氏病有利。参见:Sawada,H和Shimohama,S,“Estrogens and Parkinson disease:novel approachfor neuroprotection,”Endocrine.2003 Jun;21(1):77-9;McCullough LD和Hum,PD,“Estrogen and ischemic neuroprotection:an integratedview,”TrendsEndocrinol Metab.2003 Jul;14(5):228-35;以其全文并入此处作为参考。SERMs预防认知作用损伤的用途在文献中已知,参见Yaffe,K.,K.Krueger,S.Sarkar等人,2001.Cognitive function inpostmenopausal women treated with raloxifene.N.Eng.J.Med.344:1207-1213。
本发明的另一实施方案为通过向有需要的哺乳动物给药治疗有效量的任意上述化合物或药物组合物治疗或预防该哺乳动物中抑郁的方法。雌激素预防抑郁的用途已经在本领域公开,参见Carranza-Liram S.,Valentino-Figueroa ML,“Estrogen therapy for depression inpostmenopausal women.”Int J Gynnaecol Obstet 1999 Apr;65(1):35-8。特别地,作为单独的药物或与其它药物组合使用,雌激素受体β(ERβ)选择性激动剂将可用于治疗焦虑或抑郁疾病,包括抑郁、经前抑郁、产后抑郁、经前综合症、狂躁抑郁、焦虑、痴呆、和强迫型行为。临床研究已经表明了天然雌激素17β-雌二醇用于治疗多种抑郁疾病的功效,参见Schmidt PJ,Nieman L,Danaceau MA,Tobin MB,RocaCA,Murphy JH,Rubinow DR.Estrogen replacement inperimenopause-related depression:a preliminary report.Am J ObstetGynecol 183:414-20,2000;和Soares CN,Almeida OP,Joffe H,CohenLS.Efficacy of estradiol for the treatment of depressive disorders inperimenopausal women:a double-blind,randomized,placebo-controlledtrial.Arch Gen Psychiatry.58:537-8,2001;并入本文作为参考。Bethea等人(Lu NZ,Shlaes TA,Gundlah C,Dziennis SE,Lyle RE,Bethea CL.Ovarian steroid action on tryptophan hydroxylase protein and serotonincompared to localization of ovarian steroid receptors in midbrain ofguinea pigs.Endocrine 11:257-67,1999,并入本文作为参考)已经建议:雌激素的抗抑郁活性可通过在含有5-羟色胺的细胞中控制5-羟色胺合成来介导,所述含有5-羟色胺的细胞富集在背缝神经核。
本发明的另一实施方案为通过向有需要的哺乳动物给药治疗有效量的任意上述化合物或药物组合物治疗或预防该哺乳动物中焦虑的方法。雌激素受体在调节情绪过程,例如焦虑中的作用已经在现有技术中公开,参见Krezel,w.等人,“Increased anxiety and synaptic plasticityin estrogen receptor beta-deficient mice.”Proc Natl Acad Sci USA 2001Oct 9;98(21):12278-82。
本发明的另一实施方案为治疗或预防炎症或炎症性肠病的方法。包括克罗恩氏病和ulceratie结肠炎的炎症性肠病为肠部发炎的慢性疾病,通常产生反复的腹部抽筋和腹泻。雌激素受体调节剂治疗炎症或炎症性肠病的作用已经在现有技术中公开,参见Harris,H.A.等人,“Evaluation of an Estrogen Receptor-β Agonist in Animal Models ofHuman Disease,”Endocrinology,Vol.144,No.10 4241-4249。
本发明的另一实施方案为治疗或预防高血压的方法。已经报道了雌激素受体β具有调节血管功能和血压的作用,参见Zhu等人,“Abnormal Vacular Function and Hypertension in Mice Deficient inEstrgoen Receptorβ,”Science,Vol 295,Issue 5554,505-508,18 January2002。
本发明的另一实施方案为在雄性和雌性中治疗或预防性功能失调的方法。雌激素受体调节剂治疗性功能失调的作用已经在现有技术中公开,参见Baulieu,E.等人,“Dehydroepiandrosterone(DHEA),DHEAsulfate,and aging:Contribution of the DHEAge Study to ascociobiomedical issue,”PNAS,April 11,2000,Vol.97,No.8,4279-4282;Spark,Richard F.,“Dehydroepiandrosterone:a springboardhormone for female sexuality,”Fertility and Sterility,Vol.77,No.4,Suppl 4,April 2002,S19-25。
本发明的另一实施方案为治疗或预防视网膜变性的方法。已经表明雌激素具有降低与年老相关的黄斑病发病风险的有利作用,参见SnoW,K.K.等人,“Association between reproductive and hormonalfactors and age-related maculopathy in postmenopausal women,”Americal Journal of Ophthalmology,Vol.134,Issue 6,December 2002,pp.842-48。
本发明实例为δ-5-雄烯-3-β-17-β-二醇在制备用于在有需要的哺乳动物中治疗或预防骨质疏松的药物中的应用。本发明进一步实例为δ-5-雄烯-3-β-17-β-二醇在制备用于在有需要的哺乳动物中治疗或预防骨损失、骨再吸收、骨折、转移性骨疾病或与雌激素功能相关的障碍的药物中的应用。
根据标准药物实践,δ-5-雄烯-3-β-17-β-二醇可给药到哺乳动物,优选人,可单独给药,或优选与药学上可接受的载体或稀释剂组合,任选与已知的助剂例如明矾在药物组合物中组合给药。该化合物可口服给药或肠胃外给药,包括静脉内、肌肉内、腹膜内、皮下、直肠和局部给药途径。
在口服使用的片剂的情况下,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,例如硬脂酸镁。对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。本发明治疗化合物口服使用时,所选化合物可例如以片剂或胶囊的形式给药,或以水溶液或悬浮液的形式给药。当以片剂或胶囊形式口服给药时,活性药物组分可以与口服无毒、药学上可接受的任何惰性载体组合使用,例如乳糖、淀粉、蔗糖、葡萄糖、甲基纤维素、硬脂酸镁、磷酸二钙、硫酸钙、甘露糖醇、山梨糖醇等;当以液态形式口服给药时,口服药物组分可以与任何口服无毒、药学上可接受的惰性载体组合使用,例如乙醇、甘油、水等等。并且当需要或必要时,合适的粘合剂、润滑剂、崩解剂、和着色剂还可加入到混合物中。合适的粘合剂包括淀粉、明胶、天然糖例如葡萄糖或β-乳糖、玉米甜味剂,天然和合成树胶例如阿拉伯胶、黄蓍胶或海藻酸钠、羧甲基纤维素、聚乙二醇、蜡等等。这些剂型中使用的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等等。崩解剂包括但不限于淀粉、甲基纤维素、琼脂、皂土、黄原胶等等。当需要口服使用的水悬剂时,活性组分与乳化剂和悬浮剂组合使用。如果需要的话,可以加入某些甜味剂或调味剂。对于肌肉内、腹膜内、皮下和静脉内应用,通常制备活性组分的无菌溶液,并且溶液的pH应当进行相应的调节和缓冲。对于静脉内应用,为了使制剂等渗,应当控制溶解物的总浓度。
δ-5-雄烯-3-β-17-β-二醇还可以脂质体递送体系给药,例如小单层泡囊、大单层泡囊和多层泡囊。脂质体可由多种磷脂形成,例如胆固醇、十八胺或磷脂酰胆碱。
δ-5-雄烯-3-β-17-β-二醇还可使用作为单个载体的单克隆抗体递送,化合物分子偶联到所述载体上。本发明化合物还可与作为可标靶药物载体的可溶性聚合物结合。这种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-苯酚、聚羟基-乙基天冬酰胺-苯酚,或用棕榈酰基残基取代的聚氧化乙烯-聚赖氨酸。并且,本发明化合物可连接到用于实现药物控释的一类可生物降解聚合物上,例如聚乳酸、聚羟基乙酸、聚乳酸和聚羟基乙酸共聚物、聚(ε-己内酯)、聚羟基丁酸、聚原酸酯、聚缩醛、聚二羟基吡喃、聚氰基丙烯酸酯,以及水凝胶的交联或两亲嵌段共聚物。
δ-5-雄烯-3-β-17-β-二醇还可与用于治疗或预防以下疾病的已知药物组合使用:骨损失、骨折、骨质疏松、转移性骨疾病、佩吉特氏疾病、牙周病、软骨变性、子宫内膜异位、子宫纤维性疾病、热潮红、LDL胆固醇水平升高、心血管疾病、认知功能损害、脑变性疾病、再狭窄、男子乳腺发育、血管平滑肌细胞增殖、肥胖、失禁、焦虑、由雌激素不足引起的抑郁、炎症、炎症性肠病,和癌症,尤其是乳腺癌、子宫癌和前列腺癌。当前公开的化合物与在治疗或预防此处公开的疾病中有用的其它药物的组合也在本发明范围内。本领域普通技术人员将能够认识到,基于药物和疾病的特性,哪些药物组合是有用的。这些药物包括以下:有机二膦酸酯;组织蛋白酶K抑制剂、雌激素或雌激素受体调节剂、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,例如PTH、降血钙素、维生素D或合成维生素D类似物、选择性5-羟色胺再摄取抑制剂(SSRI)、芳香化酶抑制剂;以及药学上可接受的盐或其混合物。优选的组合为本发明化合物和有机二膦酸酯。另一优选组合为本发明化合物和组织蛋白酶K抑制剂。另一优选组合为本发明化合物和雌激素。另一优选组合为本发明化合物和雌激素受体调节剂。另一优选组合为本发明化合物和成骨细胞合成代谢剂。
“有机二膦酸酯”包括但不限于下式化合物:
其中n为0-7的整数并且其中A和X独立地选自H、OH、卤素、NH2、SH、苯基、C1-30烷基、C3-30支化或环烷基、含有两个或三个N的双环结构、C1-30取代烷基、C1-10烷基取代的NH2、C3-10支化或环烷基取代的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,由此当n是0时全部A和X不选自H或OH;或者A和X与其所连接的碳原子一起形成C3-10环。
在上述化学式中,烷基可为直连、支链或环状,条件是为化学式选择足够的原子。C1-30取代烷基可包括多种取代基,其非限制性实例包括选自下组的那些:苯基、吡啶基、呋喃基、吡咯烷基、咪唑基、NH2、C1-10烷基或二烷基取代的NH2、OH、SH、和C1-10烷氧基。
对于A或X取代基,上述化学式还意图包括络合碳环、芳香环和杂环结构,其非限制性实例包括萘基、喹啉基、异喹啉基、金刚烷基和氯代苯硫基。
本文还可使用二膦酸酯药学上可接受的盐和衍生物。盐的非限制性实例包括:碱金属、碱土金属、铵、和单、二、三或四C1-30烷基取代铵。优选的盐为钠、钾、钙、镁和铵盐。更优选钠盐。衍生物非限制性实例包括酯、水合物和酰胺。
应当注意到此处用于治疗剂的术语“二膦酸酯”还意图包括双膦酸酯、二膦酸(biphosphonic acids)、双膦酸(diphosphonic acids),以及这些材料的盐和衍生物。除非另有说明,二膦酸酯的特定命名的使用并不意图限制本发明。
二膦酸盐的非限制性实例包括阿仑膦酸盐、英卡膦酸盐、氯屈膦酸盐、依替膦酸盐、伊班膦酸盐、伊卡膦酸盐、米诺膦酸盐(minodronate)、奈立膦酸盐、奥帕膦酸盐、帕米膦酸盐、吡磷酸盐(piridronate)、利塞膦酸盐、替鲁膦酸盐和zolendronate,及其药学上可接受的盐和酯。特别优选的二膦酸盐为阿仑膦酸盐,尤其是阿仑膦酸的钠、钾、钙、镁或铵盐。优选的二膦酸盐的实例为阿仑膦酸的钠盐,尤其是阿仑膦酸的水合钠盐。盐可用整数摩尔或非整数摩尔水水合。其它优选二膦酸盐的实例为阿伦膦酸的水合钠盐,当水合盐为阿仑膦酸单钠三水合物时尤为如此。
有机二膦酸酯的精确剂量将随着下列因素而改变:给药方案、所选择的具体二膦酸盐、哺乳动物或人类的年龄、大小、性别和健康状况、所治疗病症的性质和严重性以及其它相关的医学和身体因素。对于人,二膦酸盐的有效口服剂量一般为约1.5至约6000μg/kg体重,优选约10-约2000μg/kg体重。在另一给药方案中,除了以每天的间隔给药外,二膦酸盐可以以例如每周一次剂量、每周两次剂量、两周一次剂量和每月两次的剂量给药。在每周一次剂量体系中,阿仑膦酸单钠三水合物将以35毫克/周或70毫克/周的剂量给药。所述二膦酸盐还可每月一次、每六个月一次、每年一次或更低频率给药,参见WO01/97788(2001年12月27日公开)和WO01/89494(2001年11月29日公开)。
“雌激素”包括但不限于天然存在的雌激素[7-雌二醇(E2)、雌甾醇(E1)和雌三醇(E3)]、合成结合雌激素、口服避孕药和硫酸盐化雌激素。参见:Gruber CJ,Tschugguel W,Schneeberger C,Huber JC.,″Production and actions of estrogens″N Engl J Med 2002 Jan 31;346(5):340-52。
“雌激素受体调节剂”指的是不管其机理,干涉或抑制雌激素结合到受体上的化合物。雌激素受体调节剂的例子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、艾多昔酚、LY353381、LY117081、托瑞米芬、氟维司群、4-[7-(2,2-二甲基-1-氧丙氧基-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,以及SH646。
“组织蛋白酶K抑制剂”指的是抑制半胱氨酸蛋白酶组织蛋白酶K活性的化合物。组织蛋白酶K抑制剂的非限制性实例可发现于AxysPharmaceuticals的PCT公开WO00/55126和Merck Frosst Canada &Co.和Axys Pharmaceuticals的WO01/49288中。
不管其机理,“雄激素受体调节剂”指的是干涉或抑制雄激素结合到受体上的化合物。雄激素受体调节剂的实例包括非那雄胺以及其它5α-还原酶抑制剂、尼鲁米特、氟他胺、比卡鲁胺、利阿唑和阿比特龙乙酸盐。
“破骨细胞质子ATP酶抑制剂”指的是质子ATP酶抑制剂,其发现于破骨细胞的顶膜,并且据报道在骨吸收过程中扮演重要角色。这些质子泵代表了设计骨吸收抑制剂的有吸引力的目标,其可潜在用于骨质疏松和相关代谢疾病的治疗和预防。参见C.Farina等人,“Selectiveinhibitors of the osteoclast vacuolar proton ATPase as novel boneantiresorptive agents,”DDT,4:163-172(1999),以其全文并入此处作为参考。
“HMG-CoA还原酶抑制剂”指的是3-羟基-3-甲基戊二酰基-CoA还原酶抑制剂。通过使用本领域公知的测试方法可以很容易的确认对于HMG-CoA还原酶具有抑制活性的化合物。例如,参见US 4,231,938第6栏和WO 84/02131第30-33页中所述或引用的方法。此处使用的术语“HMG-CoA还原酶抑制剂”和“HMG-CoA还原酶的抑制剂”具有相同意义。
可以使用的HMG-CoA还原酶抑制剂的实例包括但不限于洛伐他汀(MEVACOR;参见美国专利US 4,231,938、US 4,294,926和US4,319,039)、辛伐他汀(ZOCOR;参见美国专利US 4,444,784、US4,820,850和US 4,916,239)、帕伐他汀(PRAVACHOL;参见美国专利US 4,346,227、US 4,537,859、US 4,410,629、US 5,030,447和US5,180,589)、氟伐他汀(LESCOL;参见美国专利US 5,354,772、US4,911,165、US 4,929,437、US 5,189,164、US 5,118,853、US 5,290,946和US 5,356,896)、阿托伐他汀(LIPITOR;参见美国专利US5273,995、US 4,681,893、US 5,489,691和US 5,342,952)和西立伐他汀(还称为rivastatin和BAYCHOL;参见美国专利US 5,177,080)。这些和其它可用于本发明方法的HMG-CoA还原酶抑制剂结构式公开在M.Yalpani,″Cholesterol Lowering Drugs″,Chemistry & Industry,pp.85-89(5 February 1996)的第87页和美国专利US 4,782,084和US4,885,314中。此处使用的术语HMG-CoA还原酶抑制剂包括所有药学上可接受的内酯和展开酸形式(亦即其中内酯环打开以形成游离酸)以及具有HMG-CoA还原酶抑制活性的化合物的盐和酯形式,并且这些盐、酯、展开酸和内酯形式的使用也在本发明范围之内。内酯部分及其相应的展开酸形式的实例如下结构I和II所示。
内酯 展开酸
I II
在可存在展开酸形式的HMG-CoA还原酶抑制剂中,盐和酯形式优选由展开酸形成,并且所有这些形式包括在此处使用的术语“HMG-CoA还原酶抑制剂”的范围内。HMG-CoA还原酶抑制剂优选选自洛伐他汀和辛伐他汀,并且最优选辛伐他汀。此处对于HMG-CoA还原酶抑制剂的术语“药学上可接受的盐”将表示本发明使用的化合物的无毒盐,其通常通过游离酸与有机或无机碱的反应制备,特别是由例如钠、钾、铝、钙、锂、镁、锌和四甲铵的阳离子形成的那些,以及由例如氨、乙二胺、N-甲基葡萄糖胺、赖氨酸、精氨酸、鸟氨酸、胆碱、N,N′-二苄基乙二胺、氯普鲁卡因、二乙醇胺、普鲁卡因、N-苄基苯基乙二胺、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)氨基甲烷形成的盐。HMG-CoA还原酶抑制剂盐形式的其它实例可包括但不限于乙酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、硫酸氢盐、酒石酸氢盐、硼酸盐、溴化物、依地酸钙盐、樟脑磺酸盐、碳酸盐、氯化物、克拉维酸盐、柠檬酸盐、二盐酸盐、依地酸盐、乙二磺酸盐、丙酸酯十二烷基硫酸盐(estolate)、乙磺酸盐、富马酸盐、葡庚糖酸盐、葡萄糖酸盐、谷氨酸盐、乙醇酰对氨基苯胂酸盐(glycollylarsanilate)、己基间苯二酚盐、哈胺、氢溴酸盐、盐酸盐、羟萘甲酸盐、碘化物、异硫代硫酸盐、乳酸盐、乳糖酸盐、月桂酸盐、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、双羟萘酸盐、棕榈酸盐、泛酸盐、磷酸盐/二磷酸盐、多聚半乳糖醛酸盐、水杨酸盐、硬脂酸盐、碱式乙酸盐、琥珀酸盐、单宁酸盐、酒石酸盐、氯茶碱盐(teoclate)、甲苯磺酸盐、三乙基碘化物和戊酸盐。
当吸收在温血动物的血流中时,所述HMG-CoA还原酶抑制剂化合物的酯衍生物还可作为前药,可以这种方式裂解以释放药物形式并使得药物得到改善的治疗性能。
如上所述的“整联蛋白受体拮抗剂”指的是选择性拮抗、抑制或阻碍生理学配体结合到αvβ3整联蛋白的化合物,选择性拮抗、抑制或阻碍生理学配体结合到αvβ5整联蛋白的化合物,选择性拮抗、抑制或阻碍生理学配体结合到αvβ3整联蛋白和αvβ5整联蛋白的化合物,以及选择性拮抗、抑制或阻碍在毛细血管内皮细胞表达的特定整联蛋白活性的化合物。该术语还表示αvβ6、αvβ8、α1β1、α2β1、α5β1、α6β1和α6β4整联蛋白的拮抗剂。该术语还表示αvβ3、αvβ5、αvβ6、αvβ8、α1β1、α2β1、α5β1、α6β1和α6β4整联蛋白任意组合的拮抗剂。H.N.Lode和同事在PNAS USA 96:1591-1596(1999)中已经注意到抗血管αv整联蛋白拮抗剂和肿瘤特异性抗体细胞因子(干扰白细胞素-2)融合蛋白标记物在消除自发性肿瘤转移中的协同作用。他们的结果建议这种组合可能用于治疗癌症和转移性肿瘤生长。通过与所有现有药物不同的新机制,αvβ3整联蛋白受体拮抗剂抑制骨吸收。整联蛋白为介导细胞-细胞和细胞-基质相互作用的杂二聚跨膜粘着受体。α和β整联蛋白亚组非共价相互作用,并以依赖于二价阳离子的方式结合细胞外基质配体。破骨细胞上最多的整联蛋白为αvβ3(>107/破骨细胞),其看来在对于细胞转移和极化非常重要的细胞骨架组织中具有限速的作用。αvβ3拮抗作用选自抑制骨吸收、抑制再狭窄、抑制黄斑变性、抑制关节炎,以及抑制癌症和转移性生长。
“成骨细胞合成代谢剂”指的是构造骨骼的药剂,例如PTH。甲状旁腺激素(PTH)或其氨基末端片断和类似物的间断给药已经表明能够在动物和人中预防、阻止、部分逆转骨损失并刺激骨骼形成。D.W.Dempster等人在“Anabolic actions of parathyroid hormone on bone,”Endocr Rev 14:690-709(1993)中进行了论述。研究已经表明甲状旁腺激素在刺激骨骼形成并因而增加骨骼质量和强度中的临床益处。RMNeer等人在New Eng J Med 344 1434-1441(2001)中报导了结果。
此外,甲状旁腺激素相关的蛋白质碎片或类似物,例如PTHrP(1-36)已经表明具有anticalciuric作用(参见M.A.Syed等人,“Parathyroidhormone-related protein-(1-36)renal tubular calcium reabsorption innormal human volunteers:implications for the pathogenesis of humoralhypercalcemia of malignancy,”JCEM 86:1525-1531(2001))并还可作为用于治疗骨质疏松的合成代谢剂。
降血钙素为已知参与钙和磷代谢的主要通过甲状腺产生的32氨基酸肽。通过抑制破骨细胞的活性,降血钙素抑制了骨的再吸收。因而降血钙素可以容许成骨细胞更加有效的作用并且构成骨骼。
“维生素D”包括但不限于维生素D3(胆骨化醇)和维生素D2(麦角钙化醇),其为天然存在的生物学上惰性的维生素D:1α-羟基维生素D:25-羟基维生素D和1α,25-二羟基维生素D的羟基化生物学活性代谢物的前体。维生素D2和维生素D3在人体中具有相同的生物学作用。当维生素D2或维生素D3进入循环时,其通过细胞色素P450-维生素D-25-羟化酶羟基化以产生25-羟基维生素D。25-羟基维生素D呈生物学惰性并且在肾脏中进一步被细胞色素P450-单加氧酶、25(OH)D-1α-羟化酶羟基化以得到1,25-二羟基维生素D。当血钙降低时,甲状旁腺激素(PTH)的产生增加,其通过增加25-羟基维生素D到1,25-二羟基维生素D的转化调节钙体内平衡并增加血浆钙浓度。
1,25-二羟基维生素D被认为在钙和骨新陈代谢时产生维生素D的作用。1,25-二羟基代谢物为保持钙吸收和骨骼完整性所需的活性激素。通过诱导单核干细胞分裂成破骨细胞并通过将钙维持在正常范围,钙体内平衡通过1,25-二羟基维生素D维持,通过钙羟基磷灰石在骨表面的沉积,其导致了骨盐沉积,参见Holick,MF,Vitamin Dphotobiology,metabolism,and clinical applications,In:DeGroot L,Besser H,Burger HG等人编辑,Endocrinology,第3版,990-1013(1995)。然而通过骨新陈代谢,高浓度的1α,25-二羟基维生素D3可能导致血液中钙浓度的增加和钙浓度的异常控制,从而导致高钙血症。1α,25-二羟基维生素D3还可在骨新陈代谢中间接调节破骨活性,并可能期待高浓度以在骨质疏松中增加过量的骨吸收。
“合成维生素D类似物”包括作用类似维生素D的非天然存在的化合物。
选择性5-羟色胺再摄取抑制剂通过增加脑中的血清素的量作用。在治疗抑郁中,SSRIs已经在美国成功使用了十年。SSRIs的非限制性实例包括氟西汀、帕罗西汀、舍曲林、西酞普兰和氟伏沙明。SSRIs还可用于治疗与雌激素功能相关的疾病,例如经前综合症和经前紧张综合症。参见Sundstrom-Poromaa I,Bixo M,Bjorn I,Nordh O.,“Compliance to antidepressant drug therapy for treatment ofpremenstrual syndrome,”J Psychosom Obstet Gynaecol 2000Dec;21(4):205-11。
此处使用的术语“芳香化酶抑制剂”包括能够抑制芳香化酶的化合物,例如市场上可买到的抑制剂,例如:aminoglutemide(CYTANDREN)、阿那曲唑(ARIMIDEX)、来曲唑(FEMARA)、福美斯坦(LENATRON)、依西美坦(AROMASIN)、阿他美坦(1-甲基雄-1,4-二烯-3,17-二酮)、法倔唑(4-(5,6,7,8-四氢咪唑[1,5-a]吡啶-5-基)-苄腈,单盐酸盐)、芬罗唑(4-(3-(4-氟苯基)-2-羟基-1-(1H-1,2,4-三唑-1-基)-丙基)苄腈)、伏氯唑(6-[(4-氯苯基)-1H-1,2,4-三唑-1-基甲基]-1-甲基-1H-苯并三唑)、YM-511(4-[N-(4-溴代苄基)-N-(4-氰基苯基)氨基]-4H-1,2,4-三唑)等等。
如果作为固定剂量配制,这种组合产品以如下所述剂量使用δ-5-雄烯-3-β-17-β-二醇并以许可剂量范围使用其它药学上可接受的活性试剂。当组合剂型不合适时,本发明化合物还可以备选地与已知药学上可接受的药物连续使用。
关于本发明化合物的术语“给药”以及其变体(例如“给药”化合物)指的是将化合物或其前药引入到需要治疗的动物体系中。当本发明化合物或其前药与一种或多种其它活性药物(例如二膦酸盐等)组合提供时,“给药”以及其变化分别理解为包括同时或连续给药化合物或其前药以及其它药物。本发明包括本发明化合物的前药。通常,这种前药为本发明化合物的功能衍生物,其在体内可容易转化为所需化合物。因此在本发明治疗方法中,术语“给药”将包括使用明确公开的化合物,或虽然没有明确公开但在给药到患者后在体内转化为指定化合物的化合物的多种治疗情况。合适的前药衍生物的选择和配制的常规方法已经公开在例如″Design of Prodrugs,″ed.H.Bundgaard,Elsevier,1985中,以其全文引用于此作为参考。这些化合物的代谢物包括在将本发明化合物引入到生物学环境时产生的活性中心。
本发明还包括可用于治疗骨质疏松或其它骨疾病的药物组合物,包括在有或没有药学上可接受的载体或稀释剂的情况下给药治疗有效量的δ-5-雄烯-3-β-17-β-二醇。本发明合适的组合物包括含有δ-5-雄烯-3-β-17-β-二醇和药学上可接受的载体的水溶液,合适的载体例如pH例如7.4的盐水。所述溶液可通过局部弹丸注射引入到患者血液。
当本发明化合物给药到受试的人时,处方医师通常根据年龄、体重、各个患者的反应以及患者症状的严重程度确定日剂量。
在一个示范性应用中,合适量的化合物给药到进行治疗的哺乳动物中。在用于所示作用时,本发明的口服剂量将在约0.01毫克/千克体重/天(毫克/千克/天)到约100毫克/千克/天之间变化,优选0.01-10毫克/千克/天,并且最优选0.1-5.0毫克/千克/分钟。对于口服给药,组合物优选以含有0.01、0.05、0.1、0.5、1.0、2.5、5.0、10.0、15.0、25.0、50.0、100和500毫克活性组分的片剂形式提供,根据症状调整给予治疗患者的剂量。药物一般含有约0.01毫克至约500毫克的活性组分,优选约1毫克至约100毫克的活性组分。对于静脉内途径,在连续输液期间,最优选的剂量范围为约0.1至约10毫克/千克/分钟。有利地,δ-5-雄烯-3-β-17-β-二醇可每天给药一次,或者每日总剂量可分成每日两次、三次或四次。此外,δ-5-雄烯-3-β-17-β-二醇可以通过局部使用适合的鼻内赋形剂以鼻内形式给药,或者使用本领域普通技术人员公知的透皮贴剂形式通过透皮途径给药。为以透皮释放体系形式给药,整个给药方案中应持续给药,而非间歇给药。
δ-5-雄烯-3-β-17-β-二醇可以与其它可用于治疗雌激素-介导的病况的药物组合使用。这种组合的各个组分可在治疗期间的不同时期分别给药,或者以分离或单一组合形式同时给药。本发明因此将理解为包括所有这些同时或交替治疗的方案,并应相应地解释术语“给药”。应当清楚,δ-5-雄烯-3-β-17-β-二醇与其它可用于治疗组织蛋白酶-介导的病况的药物的组合通常包括与可用于治疗与雌激素功能相关病症的任意药物组合物的任意组合。
本发明范围因此包括与选自下组的第二药物的组合使用δ-5-雄烯-3-β-17-β-二醇:有机二膦酸盐、组织蛋白酶K抑制剂、雌激素、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、降血钙素、维生素D、合成维生素D类似物、选择性5-羟色胺再摄取抑制剂、芳香化酶抑制剂;以及药学上可接受的盐或其混合物。本发明这些其它方面将根据此处的教导更加明显。
定义
如本文所用,术语“组合物”意在包括包含特定量特定成分的产品,以及直接或间接地由特定量的特定成分组合所得的任何产品。
此处使用的术语“治疗有效量”指的是研究人员、兽医、内科医生或其它临床医师所追求的在组织、体系、动物或人中产生生物学或医学响应的活性化合物或药物的量。
此处使用的术语疾病的“治疗”包括:疾病的预防,即在可能暴露于或易感染某种疾病却没有经历或显示疾病的症状的哺乳动物中使疾病的临床症状不再发展;疾病的抑制,即阻止或减少疾病或其临床症状的发展;疾病的减轻,即,使疾病或其临床症状退化。
此处使用的术语“骨再吸收”是指破骨细胞降解骨的过程。
使用δ-5-雄烯-3-β-17-β-二醇的剂量方案根据多种因素进行选择,这些因素包括患者的种类、种族、年龄、体重、性别和医学情况;所治疗的适应症的严重程度;给药途径;患者的肾和肝功;以及使用的具体化合物或其盐。普通专业医师、兽医或临床医师可方便地确定和开处方给出预防、治疗或抑制适应症发展的有效量的药物。
在本发明方法中,此处详述的δ-5-雄烯-3-β-17-β-二醇可形成活性组分,并通常与合适的药物稀释剂、赋形剂或载体(此处共同相当于“载体”材料)混合给药,这些药物稀释剂、赋形剂或载体根据预期给药形式和常规药物实践合适的选择,给药形式例如口服片剂、胶囊、酏剂、糖浆等等。本发明化合物可商购或者根据本领域公知的程序制备。
试验
雌激素受体结合测定
将雌激素受体配体结合测定设计为使用氚代雌二醇和重组表达的雌激素受体的闪烁亲近测定法。在bacculoviral表达系统中制备全长的重组人ER-α和ER-β蛋白。ER-α或ER-β提取物用含6mMα-一硫代甘油(monothiolglycerol)的磷酸盐缓冲盐水以1∶400稀释。将每份200μL的稀释的受体制品加到96孔Flashplate的每个孔中。将培养板用SaranWrap覆盖并在4℃下保温过夜。
第二天早晨,将每份20μl含10%牛血清白蛋白的磷酸盐缓冲盐水加到96孔培养板的每个孔中,使之在4℃保温2小时。然后,培养板用200μl缓冲液洗涤,该缓冲液中含20mM Tris(pH7.2)、1mMEDTA、10%甘油、50mM KCl和6mMα-一硫代甘油。为在这些受体包被的培养板中进行测定,往96孔培养板的每个孔中加入178μl的同样的缓冲液。然后往培养板的每个孔中加入20μl 10nM 3H-雌二醇溶液。
在0.01nM至1000nM浓度范围内评价测试化合物。以测试所需终浓度的100倍用100%DMSO制备试验化合物的储备溶液。96孔培养板的测试孔中的DMSO的量应不超过1%。最终加到测定培养板中的是2μl等份的用100%DMSO补足的测试化合物。密封培养板并使其在室温下平衡3小时。在为计数96孔培养板安装的闪烁扫描计数器中对培养板计数。
实施例1-3化合物在IC50=75至大于10000纳米的范围内对雌激素受体α-亚型显示结合亲合力,并且在IC50=5-250纳米的范围内对雌激素受体β-亚型显示结合亲合力。
小鼠强迫游泳实验
重量为20-25g的雄性Swiss Webster小鼠(Bantin and Kingman,Hull,UK)以9只分组居住在湿度和温度受控的房间中,自由进食食物和水。它们维持在12小时光照/黑暗循环,在0700时刻光照,并且允许动物在使用前驯化至少三天。所有程序根据UK Animals(ScientificProcedures)Act(1986)和其相关指导进行。
通过将小鼠置于含深度14cm的水(24-25℃)的玻璃圆筒(高度=25cm;直径10cm)中进行测试。在1分钟时间箱(bins)中记录动物试图逃跑、不动和绕管运动(游泳)的时间5分钟。
ERβ选择性激动剂溶解于麻油中。试验前30分钟SC注射体积为10mL/kg的试验化合物。在强迫游泳试验中减少不动性的试验化合物有可能治疗抑郁。
鼠类大脑孕酮受体(PR)ICC试验
动物给药和组织收集
雌性小鼠(12-16周龄)由售主(C57BL/6s,来自Charles River)切除卵巢且一周后装运。动物在达到Merch动物设施时进食无大豆啮齿类食物,在此用额外的一周来适应新环境。小鼠在早晨口服(每日一次,持续3日)0.2cc赋形剂(20%乙醇∶30%聚乙二醇∶50%水)或者化合物(0.1-30mpk,用于剂量曲线;10mpk,用于单一剂量试验);皮下给药麻油(0.1cc)中的0.2mpk雌二醇17-β。在最后一次给药约24小时之后,用氯胺酮/赛拉嗪深度麻醉动物,并且经心(transcardially)灌注50ml的3.5%丙烯醛和2%多聚甲醛的0.1M磷酸钠缓冲液(PB),pH7.4。立即除去大脑并且置于冰冷的0.1M PB且在4C储存过夜。在0.1M PB中在振动切片机上以40μm切割大脑,转移到冷冻保护剂(0.1M PB中30%蔗糖;30%乙二醇,pH7.4)且储存在-20℃,直到加工用于免疫细胞化学。
免疫化学
在冷的0.1M磷酸盐缓冲盐水(PBS,pH7.4)中洗涤自由漂浮的40μm切片,以彻底除去冷冻保护剂。为确保通过动物的免疫标记一致,采用筛底24孔组织夹持器和含缓冲液的合适的固体有机玻璃盘进行试验。因此,所有切片在整个试验期间在相同溶液/条件下共同培养。为阻止在丙烯醛-固定组织中的非特异性染色,切片在PBS中1%硼氢化钠(NaBH4)中洗涤30分钟,且用PBS漂洗8-10次。通过在PBS中的0.3%过氧化氢和10%甲醇中洗涤组织15分钟,抑制内源性过氧化酶活性。切片在PBS中洗涤,且在1)PBS中2%正常山羊血清,用0.05%Triton X-100(PBST)阻滞1小时,或者2)mouse-on-mouse Ig阻滞剂(载体)阻滞1小时,随后小鼠蛋白浓缩物(载体)阻滞30分钟。切片在稀释到1%正常血清的阻滞缓冲液中由PR抗体在RT培养一夜,且在4C培养一夜,或者在4C培养3夜。采用三种抗体,其中两种识别两种PR异构型:1)兔多克隆[DAKO,1∶2500];2)小鼠单克隆[亲合力生物试剂,1∶700];3)兔单克隆[Lab Vision,SP2克隆“备用”稀释到1∶400];我们目前采用SP2。负控制切片在缓冲液中培养,没有初次抗体。
在初次抗体培养之后,在PBS中洗涤切片且在PBS中生物素化的抗合适物种的二次抗体(IgG)(用于多克隆[1∶600]的抗兔或用于单克隆[1∶250]的抗鼠,均来自Vector Laboratories,Burlingame,CA)和阻滞剂中暴露1小时。在数次PBS洗涤之后,切片暴露于PBS中的卵白素-生物素络合物(ABC Elite kit,Vector Laboratories)30分钟。切片在PBS中洗涤,随后用0.175M醋酸钠缓冲液(pH 7.0;Sigma,St.Louis,MO)洗涤。通过暴露切片到底物3,3’-二氨基联苯胺四氯化物(DAB)、硫酸镍和过氧化氢的0.175M醋酸钠缓冲液3分钟以进行生色反应。反应产物看上去是深蓝-黑色点状色斑,主要在细胞核中。在一次醋酸钠缓冲液漂洗和数次PBS洗涤之后,将切片固定到0.05M PB中凝胶涂覆的玻片上,空气干燥过夜,在上升的乙醇浓度中脱水,在二甲苯中清洁,用DPX固定介质盖住(cover-slipped)。
分析
最初检查所有玻片的组织学质量;任何表现出不好的组织学的大脑在抓图和分析之前被除去。从各大脑中选出4块代表背缝神经核嘴部至尾部范围的切片。在Nikon E-800 Microscope下从各切片识别到背缝神经核的腹内侧部分(含有最高密度的类固醇受体-表达5-羟色胺神经元的区域)。该视区由Nikon数码相机(成像软件(ACT-1))以200倍放大倍数捕获,并且储存到PC。表现出明显PR-免疫活性的细胞数被人工通过手持式细胞计数器量化,或通过指导ImageProPlus软件的Visual Basic程序(由Anil Tarachandani和发明人设计)量化。从所有组的平均细胞数减去赋形剂(负控制)组的平均细胞数,该数据表达为“雌激素激动百分比(正控制)”。
针对PR-免疫活性细胞观察通过各大脑的海马切片。在该大脑区域,PR基因完全由ER-α调节;在经赋形剂处理的动物中,完全没有PR免疫标签,而雌激素处理的小鼠表现出明显的核PR染色。以从“-”(缺乏染色)直到“+++”(表示具有黑色、明显核PR-免疫活性的细胞)的定性方法报导这一结果。
鼠脊TPHI TaqMan试验
动物和治疗组
雌性小鼠(13-16周龄)被切除卵巢(C57/B16,来自CharlesRiver)。给动物进食无大豆啮齿类食物,允许最少1周的时间从手术中恢复并且装运。小鼠在早晨皮下给药(每日一次,持续4日)0.1cc赋形剂(麻油)或者化合物(如所示:3,10,或20mpk)。在第四次给药约6小时之后,用氯胺酮/赛拉嗪深度麻醉小鼠,并且从头颅取出大脑,将小鼠大脑区域中腹部侧上部置于冰上,将冰冷的剃刀以1mm间隔插入该区。下丘脑尾部用作放置第一剃刀刀片的解剖标记物,将4块刀片放置在尾部连续槽中。检查4块切片并且包含了中缝背核最大部分的两块置于含有RNA-later的试管中并且在4℃放置过夜。24小时后从RNALater除去大脑切片并在新鲜管中于-80℃储存。
鼠TPH TaqMan引物和探针序列
鼠TPH1正向引物命名为mTPH-874F,其相应序列是5′-CAC AGTTCA GAT CCC CTC TAC ACT-3’且其跨过核苷酸874至897。鼠TPH1反向引物名为mTPH-962R,其相应序列是5′-GCA AAA CTG GGTTCA GCC AA-3′,且其跨过核苷酸943至962。鼠TPH1探针名为mTPH-926T,其相应序列是5′-AGG AGT TCA TGG CAG GTG TCTGGC TCT-3′,且其跨过核苷酸900至926。鼠TPH1基因库登记号J04758用于设计这些引物和探针从而核苷酸编号基于该序列。
从用于TaqMan分析的鼠脊切片分离总RNA
切片从-80℃除去并且置于FastPrep加工试管中的1.0ml TRIzol试剂中。在FastPrep120均化器中采用具有珠粒基质的Lysing MatrixD试管在6档(setting 6)一次性均化切片30s,随后在加工所有样品之后在6档20s。样品在室温放置5分钟以允许核蛋白络合物的完全离解,随后于4℃在12000×g离心5分钟。将匀浆转移到1.5ml微量离心管并且加入100μl BCP(溴-3-氯丙烷),旋流样品15秒,在室温放置2-3分钟。样品于4℃在12000×g离心15分钟。除去含水层并且置于1.5ml的新的无RNA酶无菌微量离心管。向各样品加入5μl的5mg/ml糖原,旋流样品。向各样品加入500μl异丙醇,将样品旋流15秒,在室温放置10分钟,随后在4℃在12000×g离心15分钟。滗出上清液,用500μl冰冷的75%乙醇洗涤球粒。样品在4℃在12000×g离心15分钟,滗出乙醇并且空气干燥球粒10分钟。将球粒再次悬浮于30μl预温热的RNASecure(60℃),且样品在60℃加热10分钟。样品储存在-80℃,直到DNA酶处理和cDNA合成。
通过用于Taqman分析的wt鼠脊薄片总RNA的DNA酶处理和cDNA制备:采用无DNA试剂盒(Ambion)进行DNA酶处理。
将5μg的总RNA样品等分到96孔板的各孔。将1倍DNA酶I溶液加入各样品(DNA酶I缓冲液,DNA酶I,H2O)。混和反应并且在37℃培养30分钟。通过加入DNA酶灭活试剂珠灭活反应,在室温充分混和3分钟并且在4℃以2500 RPM离心1分钟(进行25μl反应并且通过灭活试剂的1/10体积灭活)。
反转录
将10μl的DNA酶I处理的总RNA加入40μl的1X反转录反应混合物(DEPC H2O,RT缓冲液,MgCl2,dNTP混合物,无规六聚体、RNA酶抑制剂、和MultiScribe RT),并且在25℃培养10分钟,在48℃培养30分钟,在95℃培养5分钟。通过加入EDTA停止反转录。将样品转移到储存板且在-20℃储存。
Taqman分析脊薄片cDNA以确定鼠TPH mRNA的相对水平
将2.5μl的cDNA与22.5μl的TaqMan反应混合物(IXUniversal Master Mix(ABI),20nM正向和反向18S rRNA控制引物,和100nM 18S rRNA控制探针和300nM mTPHl-874F与mTPHl-962R引物,200nM mTPHl-926T探针加入各96孔板。样品在ABIPRISMO7700 Sequence Detection Instrument(Applied Biosystems,Foster City,CA)上测试,收集的数据通过Merck BiometricsTaqManPlus program分析。
药物组合物
作为本发明的具体实施方案,100mgδ-5-雄烯-3-β-17-β-二醇与粉碎得足够细的乳糖一起配制,得到总量为580-590mg,将其填充到0号硬明胶胶囊中。
Claims (10)
1.一种通过向该哺乳动物给药治疗有效量的δ-5-雄烯-3-β-17-β-二醇治疗有需要的哺乳动物中的疾病的方法,其中所述疾病是:骨损失、骨折、骨质疏松、转移性骨疾病、佩吉特氏疾病、牙周病、软骨变性、子宫内膜异位、子宫纤维性疾病、热潮红、LDL胆固醇水平升高、心血管疾病、高血压、视网膜变性、认知功能损害、阿尔茨海默病、脑变性疾病、再狭窄、男子乳腺发育、血管平滑肌细胞增殖、肥胖、失禁、焦虑、由雌激素不足引起的抑郁、炎症、炎症性肠病、性功能失调、或雌激素依赖性癌症。
2.一种药物组合物,包含δ-5-雄烯-3-β-17-β-二醇和另一种选自以下的药物:有机二膦酸酯;组织蛋白酶K抑制剂、雌激素、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、降血钙素、维生素D、合成维生素D类似物、选择性5-羟色胺再摄取抑制剂、芳香化酶抑制剂,或其药学上可接受的盐或其混合物。
3.权利要求1的方法,还包括另一种选自以下的药物:有机二膦酸酯;组织蛋白酶K抑制剂、雌激素、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、降血钙素、维生素D、合成维生素D类似物、选择性5-羟色胺再摄取抑制剂、芳香化酶抑制剂,或其药学上可接受的盐或其混合物。
4.权利要求3的方法,其中该疾病是热潮红。
5.权利要求3的方法,其中该疾病是抑郁。
6.权利要求5的方法,其中该药物是选择性5-羟色胺再摄取抑制剂。
7.权利要求3的方法,其中该药物是有机二膦酸酯。
8.权利要求7的方法,其中该有机二膦酸酯是阿仑膦酸盐。
9.权利要求3的方法,其中该药物是HMG-CoA还原酶的抑制剂。
10.权利要求9的方法,其中该HMG-CoA还原酶的抑制剂是辛伐他汀。
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US9623021B2 (en) | 2007-01-22 | 2017-04-18 | Gtx, Inc. | Nuclear receptor binding agents |
US9604931B2 (en) | 2007-01-22 | 2017-03-28 | Gtx, Inc. | Nuclear receptor binding agents |
US9078888B2 (en) | 2007-01-22 | 2015-07-14 | Gtx, Inc. | Nuclear receptor binding agents |
US20100260772A1 (en) * | 2007-09-28 | 2010-10-14 | The Trustees Of Columbia University In The City Of New York | Methods for treating or preventing diseases associated with low bone mass |
MX2010010799A (es) * | 2008-03-31 | 2011-03-25 | Univ Columbia | Metodo de diagnostico, prevencion y tratamiento de las enfermedades de la masa osea. |
WO2010056992A1 (en) | 2008-11-13 | 2010-05-20 | The Trustees Of Columbia University In The City Of New York | Methods of preventing and treating low bone mass diseases |
AU2014201406B2 (en) * | 2009-06-16 | 2016-08-11 | Endorecherche, Inc. | Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators |
US20100317635A1 (en) * | 2009-06-16 | 2010-12-16 | Endorecherche, Inc. | Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators |
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US5462932A (en) * | 1994-05-17 | 1995-10-31 | Merck & Co., Inc. | Oral liquid alendronate formulations |
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CN114712505B (zh) * | 2022-03-10 | 2023-09-05 | 南方医科大学南方医院 | 维生素d受体激动剂在制备预防和/或治疗炎症性骨丢失的药物中的应用 |
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