CN1720226A - 用于治疗和控制骨髓增生性疾病的选择性的细胞因子抑制药物的使用方法和包括其的组合物 - Google Patents
用于治疗和控制骨髓增生性疾病的选择性的细胞因子抑制药物的使用方法和包括其的组合物 Download PDFInfo
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
Abstract
公开了治疗、预防和/或控制骨髓增生性疾病的方法。具体的方法包括单独或与第二活性剂和/或与进行血液或细胞的移植相结合,给以选择性的细胞因子抑制药物、或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。特定的第二活性剂能够抑制过量生成造血干细胞或者使一种或多种MPD症状得到改善。还公开了适合用于本发明方法中的药物组合物、单一单位剂型、和试剂盒。
Description
1.发明领域
本发明涉及治疗、预防和/或控制骨髓增生性疾病和相关综合症的方法,其包括单独或者与其它治疗结合给以选择性的细胞因子抑制药物。
2.发明背景
2.1MPD的病理学
骨髓增生性疾病(MPD)是指一类具有造血干细胞纯系异常特征的病症。参见例如Current Medical Diagnosis & Treatment,499页(第37版,Tierney等人编,Appleton & Lange,1998)。因为干细胞会产生脊髓、红细胞、和血小板细胞,因此,在所有这些细胞系中都可以看见定性和定量的变化。同前。
MPD被进一步根据主要增生的骨髓细胞类型进行细分。红血球过量被分为″真性红细胞增多症(PRV)″或″奥斯勒氏病″类型,血小板过量被分为″原发性(或特发性)血小板增多症(thrombocythemia)(PT)″类型,粒细胞过量被分为″慢性骨髓性白血病(CML)″类型。MPD的第四子类是″原因不明的骨髓组织异生(AMM)″,其特征在于骨髓纤维化和骨髓外血细胞生成。(Cecil Textbook of Medicine,922页(第20版,Bennett和Plum编,W.B.Saunders Company,1996)。这些病症被归在一起是因为所述疾病可以从一种形式转化为另一种,并且因为一般都会看到混合病症。上述Tierney等的文章,499页。所有的脊髓增生病都可能自然或者因突变治疗而发展成急性白血病。同前。
大部分具有PRV的患者都存在与血容量扩大以及血液粘度增加有关的症状,同前,在500页。常见的陈诉包括头痛,眩晕,耳鸣,视力模糊,以及疲劳。同前。在75%的病例中,脾有可触知性增大,但是当成象时,几乎都存在脾肿大的情况。同前。血栓症是最常见的PRV并发症,并且是这种病症中发病和死亡的主要病因。血栓症看起来与血粘度增加和血小板功能异常有关。同前。百分之六十具有PRV的患者都是男性,并且目前中值年龄是60岁。在40岁以下的成年人中很少发生。同前。
血栓症还是遭受PT的患者常见的并发症。(Cecil Textbook ofMedicine,922页(第20版,Bennett和Plum编,W.B.Saunders Company,1996)。每微升血小板计数≥6×105已经开始被诊断为PT。Tefferi等人,Mayo Clin Proc 69:651(1994)。大部分患者在被诊断为PT时是无症状的,通常是通过偶然发现外周血液血小板计数增加而被诊断出来的。Bennett和Plum,同前,在922页。但是,大约四分之一的患者或者具有血栓形成或者具有出血情况。同前。PT很少转变成急性白血病或AMM,且大部分患者具有正常的预期寿命。同前,在923页。然而,具有PT的患者中,至少有三分之一的最终要遭受严重的血栓出血并发症。同前。
在CML患者中,通常在早期时保持正常的骨髓功能。上述Tierney等的文章,503页。这种病通常保持稳定数年,之后转变成更明显的恶性病。同前。CML最终会发展成原始细胞危象(blastcrisis),这很难与急性白血病区分开来。同前。CML通常是中年人(目前的中值年龄是42岁)的一种病症,同前。在没有感染、骨骼疼痛、和脾肿大的情况下,疾病的加速往往与发烧有关。同前。CML实验结果的标志之一是,白细胞计数增加:诊断时,中值白细胞计数是150,000/微升。同前。CML的中值存活率是3-4年。同前,在505页。一旦该疾病发展到加速或者摧毁性的程度,存活率通常就要按月来计。同前。
AMM的特征在于骨髓纤维化、脾肿大、和成白红细胞增多的周围血液图像中具有泪状红细胞异形。上述Tierney等人的文章,502页。AMM在超过50岁的成年人中发病,并且在发病通常是隐伏的。同前。随后在该疾病的过程中,当骨髓逐渐变得更加纤维化时,发生骨髓衰竭。同前。贫血变得很严重。同前。可能发生痛苦的脾梗塞急性发作。在AMM晚期时还会发生严重的骨骼疼痛和肝功能衰竭。同前。从诊断时间到中值存活率大约是5年时间。同前,在503页。
对于MPD的确切病因还不清楚。新近资料提出,其涉及到某些生长因子。比如,在PRV和PT两者中,与正常的红色祖细胞相反,在没有促红细胞生成素的情况下,由于对于类似胰岛素的生长因子I的超敏性,奥斯勒氏病红色祖细胞可能会在体外增加。Harrisort′sPrinciples of lnternal Medicine,701页(第15版,Braunwald等人编,McGraw-Hil1,2001)。在AMM中,过量生成III型胶原蛋白已经被认为是由血小板衍生的生长因子或转变生长因子β(TGF-β)造成的。同前。在703页;也可参见Martyr-,Leuk Lyinphoina 6:1(1991)。
在某些MPD形式中,能看到特定的染色体变化。比如,有文件表明,有很小百分比的未经治疗的PRV患者有非随机的染色体异常,如20q-、三体性8或9,而20q-、13q-、三体性1q在AMM患者中常见。Harrison′s Principles of Internal Medicine,701-3页(第15版,Braunwald等编,McGraw-Hill,2001)。在90%以上具有典型CML的患者以及某些具有PRV的患者的骨髓细胞中存在费城染色体。参见,例如,Kurzrock等,N Engl J Med 319:990(1988)。费城染色体是由染色体9和22的长臂之间物质的平衡易位产生的。在染色体9的长臂谱带q34上发生断裂时,细胞癌基因C-ABL易位到称作断点簇区域(bcr)的染色体22的位置上。这两种遗传序列的并列产生新的混合基因(BCR/ABL),其编码一种新型的分子量为210,000kD的蛋白质(P210)。该P210蛋白质,一种酪氨酸激酶,可能在引起CML细胞的无控增殖中起作用。参见例如,Daley等,Science 247:824(1990)。
在暴露于电离辐射下时,CML类型MPD的危险也会增加。1945年日本原子弹爆炸中的幸存者已经具有增加的CML发病率,峰值发生在爆炸5-12年之后,并且看来与剂量有关。Cecil Textbook ofMedicine,925-926页(第20版,Bennett和Plum编,W.B.SaundersCompany,1996)。强直性脊柱炎和子宫颈癌的辐射治疗已经增加了CML的发病率。同前。
MPD发病率的变化取决于疾病的形式。CML构成美国所有白血病病例的1/5。同前,在920页。在美国,每年大约诊断出4300例新的CML病例,占MPD病例的一大半(eMedicine网址,骨髓增生性疾病)。每年,每1,000,000人中就诊断出5-17名PRV。同前。因为在这种病症方面的流行病学研究不充分,因此PT和AMM的准确发病率还不曾知晓。同前。国际上,CML看起来以近似相等的频率影响着所有的种族。据报道说,PRV在日本较低,即,每年第1,000,000人有2例。同前。
2.2MPD的治疗
PRV的治疗选择是放血。Current Medical Diagnosis &Treatinent,501页(第37版,Tierney等编,Appleton & Lange,1998)。每周除去一单元血液(大约500毫升),直到血细胞比容低于45%。同前。因为反复的放血会产生缺铁症,因此,对放血的要求不得不逐步降低。同前。重要的是要避免使用医学补铁手段,因为这可能会妨碍放血计划的目标。同前。
在更严重的PRV病例中,使用骨髓抑制疗法。同前。一种广泛使用的骨髓抑制剂是羟基脲。同前。羟基脲是抑制核糖核苷酸还原酶的口服制剂。Bennett和Plum,同前,在924页。常用量是经口500-1500mg/d,在不把嗜中性粒细胞计数降低到<2000/微升的情况下,调节得使血小板保持<500,000/微升。Tierney等,同前,在501页。羟基脲的副作用包括轻微的胃肠不适,可逆的嗜中性白血球减少症,和粘膜皮肤损害。Bennett和Plum,同前,在924页。也可以使用白消安,剂量为4-6mg/d,使用4-8周。上述Tierney等人的文章,501页。α-干扰素已经表明具有一定的控制该疾病的能力。常用量是2-5百万单位,每周皮下注射3次。同前。阿那格雷也已经被许可用于治疗血小板增多症。同前。一些骨髓抑制剂,如烷基化剂和放射性磷(32p),已经表明有增加的使PRV转化为急性白血病的危险。同前。长期使用骨髓抑制剂可能会导致严重的骨髓抑制延长。
大部分权威机构都同意,PT的治疗应该旨在降低具有血栓症历史以及具有心血管危险因子的患者的血小板水平。Bennett和Plum,同前,在923页。但是,还没有看到特定疗法的优点,考虑的因素有可获得的治疗剂可能会引起白血病。同前。当治疗方法确定时,起始药物是羟基脲或阿那格雷。同前,在924页。阿那格雷是一种可能涉及到抑制巨核细胞成熟的口服制剂。同前。起始剂量是0.5mg,每天施用4次。同前。这一制剂在患有心脏病的老年患者中相对禁用。同前。α-阿尔法干扰素也可以用于治疗PT。同前。
目前,对于AMM没有特异疗法。上述Tierney等人的文章,502页。AMM的控制是针对症状的。贫血患者在输血中输以红细胞。同前。在1/3的病例中,雄激素如康复龙(每天口服200mg)、或睾酮会有助于降低输血需求,但是女性对此容忍性差。同前。脾切除术适用于脾肿大症的治疗,这导致经常发生疼痛的急性发作、严重的血小板减少、或不能接受的高的红细胞输血需求。同前。α-干扰素(皮下注射2-5百万单位,每周3次)在某些病例中会产生好转。同前。
CML不需要即时治疗,除非白细胞(WBC)计数超过200,000每微升,或者有白细胞停滞的迹象(阴茎异常勃起;静脉血栓形成;精神混乱;或者呼吸困难),或者出现脾梗塞。同前,在504页。标准的CML疗法由组成包括服用羟基脲。同前。羟基脲必须无间断地施用,因为中断药物后几天的时间内白细胞计数就会升高。同前。重组体α-干扰素已经在很大程度上代替了羟基脲作为初步治疗的选择,并且既可以延长慢性期的持续时间,又可以延长总的存活率。同前。干扰素,不象其它的缓和药剂,可以抑制费城染色体并允许出现细胞遗传学正常的细胞。同前。
尽管对CML慢性期的骨髓抑制疗法的响应很使人满意,但是,治疗仅仅起缓和作用,疾病始终是致命的。同前。唯一可利用的有疗效的疗法是外源性骨髓移植。同前。这一治疗对于具有HLA-匹配同胞的60岁以下的成年人是有效的。同前。大约60%的成年人在骨髓移植后能长期健康地生活。同前。但是,这种治疗受到给体源和患者年龄的限制。对于移植后复发的CML患者,输给来自骨髓给体的T淋巴细胞的免疫疗法可以产生持久的症状缓解作用。同前,在504-5页。CML的原始细胞危象可以用柔红霉素、cincristine、和强的松治疗(用于治疗急性淋巴母细胞性白血病),尽管症状的缓解通常时间很短。同前,在505页。
为了找到新的治疗CML的方法,已经进行了坚持不懈的努力。比如,合成的BCR/ABL激酶抑制剂,ST1571,诱导选择性地抑制t(9;22)-载带的肿瘤细胞在体外的生长和患者的某些响应。参见例如,Buchdunger等,Proc.Natl.Acad.Sci.USA 92:2558-2562(1995);和Buchdunger等,Cancer Res.,56:100-104(1996)。还可参见,Harrison′s Principles of Internal Medicine,714页(第15版,Braunwald等编,McGraw-Hill,2001)。根据早期的临床试验,通过用阻断RAS插入到膜中的法尼基转移酶抑制剂抑制RAS可能会在CML中具有抗癌活性。参见Braunwald等,同前,在714页。使用BCR/ABL肽作为肿瘤疫苗的临床前的努力看来似乎很有前途。同前。人们正在尝试,在再输注之前,使用BCR/ABL反义寡核苷酸来从自体造血先祖清除残余的白血病细胞,将作为在不诱导出GVHD(移植-对宿主疾病)的情况下,在最小残余疾病(缓解期,其中白血病细胞计数低于可以通过传统技术检测的值,通常≤1010恶性细胞)的设定前提下诱导出GVL的方法(移植-对抗-白血病)该方法处于研究之中。同前。
因为大多数用于治疗MPD的疗法只以症状为靶点,并且使用的大部分药剂具有严重的副作用,有导致严重骨髓抑制或者使病症转化为急性白血病的危险,因此,非常需要找到新的MPD治疗方法,该方法或者以病症的根本原因为靶点,或者能提高当前治疗方法的有效性和安全性。
2.3选择性的细胞因子抑制药物
被称作SeICIDsTM(Celgene Corporation)或选择性细胞因子抑制药物的化合物已经被合成并经过测试。这些化合物强效抑制TNF-α的生成,但是却在由IL1β和IL12诱导的LPS上显示适度的抑制效果,对于IL6,甚至在高浓度下也不能抑制。另外,SeICIDsTM倾向于产生适度的IL 10激活。L.G.Corral,等,Ann.Rheum.Dis.58:(第I补编),1107-1113(1999)。
选择性细胞因子抑制药物的另一个特征是,它们是强效的PDE4抑制剂。PDE4是在人体骨髓中和淋巴细胞系中发现的一种重要的磷酸二酯酶同功酶。该酶通过降解普遍存在的第二信使cAMP并将其保持在较低细胞水平而在调节细胞活性方面起关键的作用。同前。PDE4的抑制活性会导致cAMP浓度增加,从而使细胞因子诱导的LPS得到调节,包括在单核细胞及淋巴细胞中抑制TNF-α的产生。
3.发明概述
本发明包含治疗和预防骨髓增生性疾病(″MPD″)的方法,其包括给予需要这种治疗的患者治疗或预防有效量的本发明的选择性细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。本发明也包括控制MPD(例如,增长症状缓解时间)的方法,其包括给予需要这种治疗的患者治疗或预防有效量的选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。
本发明的一个实施方案包括将一种或多种选择性的细胞因子抑制药物与目前用于治疗、预防或控制MPD的通用疗法结合使用,后者例如但不限于,羟基脲,阿那格雷,干扰素,激酶抑制剂,癌症化学疗法,干细胞移植及其它移植。
本发明的另一个实施方案包括一种降低或预防与MPD疗法有关的副作用的方法,其包括给予需要这种治疗或预防的患者适量的本发明的选择性细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药,其用量足以降低与MPD疗法有关的副作用。该实施方案包括使用本发明的选择性细胞因子抑制药物来预防或治疗与使用MPD疗法有关的副作用。该实施方案包括提高患者对于MPD疗法的耐受性。
本发明的另一个实施方案包括一种增加MPD治疗的治疗效能的方法,其包括给予需要这种增加的治疗效能的患者适量的本发明的选择性细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药,其用量足以增加MPD治疗的治疗效能。
本发明进一步包括适合用于治疗、预防和/或控制MPD的药物组合物、单一单位剂型、和试剂盒,其包括本发明的选择性细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。
4.发明的详细说明
本发明的第一实施方案包括治疗和预防骨髓增生性疾病(″MPD″)的方法,其包括给予需要这种治疗或预防的患者治疗或预防有效量的本发明的选择性细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。该实施方案包括治疗、预防或控制特定的MPD亚型,例如但不限于,真性红细胞增多症(PRV)、原发性血小板增多症(PT)、慢性骨髓性白血病(CML)、和原因不明的骨髓组织异生(AMM)。
这里使用的术语″骨髓增生性疾病″或″MPD″意思是指,具有以下一种或多种特征的造血干细胞病症:过量生成一种或多种血液有形元素的多种可能性的造血祖细胞的克隆扩充(例如,增加的红细胞计数,增加的白血细胞数,和/或增加的血小板计数),费城染色体或bcr-abl基因的存在,外周血液的显微镜涂片上泪状的红细胞异形,血液造影中成白红细胞增多,巨大的血小板异常,具有网状或胶原蛋白纤维化的细胞过多的骨髓,具有低百分比前髓细胞和母细胞的显著的左移脊髓系列,脾肿大、血栓症、发展到急性白血病的危险或具有损害形态学的细胞髓。除非另有说明,术语″骨髓增生性疾病″或″MPD″包括:真性红细胞增多症(PRV),原发性血小板增多症(PT),慢性骨髓性白血病(CML),和原因不明的骨髓组织异生(AMM)。在一个特定的实施方案中,术语″骨髓增生性疾病″或″MPD″不包括白血病。特定的MPD类型是PRV,PT,CML和AMM。
本发明的另一个实施方案包括控制MPD的方法,其包括给予需要这种控制的患者预防有效量的选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。
本发明的另一个实施方案包括药物组合物,其包含选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。
本发明还包括单一单位剂型,其包含选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。
本发明的另一个实施方案包括治疗和预防和/或控制MPD的方法,其包含给予需要这种治疗、预防和/或控制的患者治疗或预防有效量的本发明的选择性细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药,和治疗或预防有效量的第二活性剂。
第二活性剂的实例包括但是不局限于,细胞因子、皮质甾类、核糖核苷酸还原酶抑制剂、血小板抑制剂、全反式视黄酸、激酶抑制剂、拓扑异构酶抑制剂、法尼基转移酶抑制剂、反义寡核苷酸、疫苗、抗癌药、抗真菌药、抗炎药、免疫抑制或骨髓抑制剂、和常规MPD疗法。
不受限于理论,人们相信,某些选择性的细胞因子抑制药物可以与常规的或其它的MPD治疗或控制疗法以互补的或协同的方式发挥作用。我们也相信,在治疗或控制MPD的过程中,某些选择性的细胞因子抑制药物起作用的机理与常规的及其它疗法的机理不同。另外,我们相信,某些选择性的细胞因子抑制药物,当给予那些难以用常规骨髓及外骨髓增殖疾病治疗方法治疗以及难以用沙利度胺治疗的患者时是有效的。这里使用的术语″难治的″意思是指,患者对于MPD治疗的响应通过临床标准检验不能令人满意,例如,没有显示或者只显示有很小的症状或实验结果的好转。
同时也相信,某些疗法可能会降低或消除与本发明某些选择性的细胞因子抑制药物有关的特定的副作用,从而使得可以给患者给以更大量的选择性的细胞因子抑制药物和/或增加患者的顺应性。此外还相信,某些选择性的细胞因子抑制药物可能会降低或消除与其它MPD疗法有关的特定的副作用,从而使得可以给患者给以更大量的这种疗法和/或增加患者的顺应性。
本发明的另一个实施方案包括一种试剂盒,其包含:包括选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药的药物组合物,和第二活性剂和/或使用说明书。本发明还包括包含单一单位剂型的试剂盒。
本发明的另一个实施方案包括逆转、降低或避免与在遭受MPD的患者中给以用于治疗MPD的活性剂有关的副作用的方法,其包括给予需要这种处理的患者治疗或预防有效量的选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。活性剂的实例包括但是不局限于本发明中描述的第二活性剂(参见部分4.2.)。
与用于治疗MPD的活性剂有关的副作用的实例包括但是不局限于:转化成急性白血病;严重的骨髓抑制;胃肠毒性,例如不限于,早期和晚期形成的腹泻和胃肠气胀;胃肠出血;恶心;呕吐;厌食症;嗜中性白血球白细胞减少症;贫血;嗜中性白血球减少症;乏力;腹部痛性痉挛;发烧;疼痛;体重减轻;脱水;脱发;呼吸困难;失眠;眩晕,粘膜炎,口干症,粘膜与皮肤损害,和肾衰竭。
因为在MPD的一定阶段会向白血病转化发展,所以可能需要外周血液干细胞、造血干细胞制剂或骨髓移植。不受限于理论,我们相信,在遭受MPD的患者中联用选择性的抑制药物和干细胞移植,会提供独特的和出乎意外的协同作用。尤其是,我们相信,选择性的细胞因子抑制药物显示出免疫调节活性,当同时与移植疗法一起使用时,可以提供另外的或协同的效应。
本发明的选择性细胞因子抑制药物可以与移植疗法结合使用,以减少与移植植入方法有关的并发症和有关移植物抗宿主疾病(GVHD)危险。因此,本发明包括一种治疗、预防和/或控制MPD的方法,其包括在移植疗法之前、过程中或之后,给予患者(例如人)选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。
本发明还包括药物组合物、单一单位剂型、和试剂盒,其包括一种或多种本发明的选择性细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物或前药,第二活性成分,和/或用于移植疗法的血液或细胞。例如,试剂盒可以包含一种或多种本发明的化合物,用于移植的干细胞和免疫抑制剂,和抗生素或其它药物。
4.1选择性的细胞因子抑制药物
用于本发明的化合物包括外消旋、立体异构纯的或立体异构富集的选择性的细胞因子抑制药物,具有选择性细胞因子抑制活性的立体异构或对映异构纯的化合物,和其可药用的盐、溶剂化物、水合物、立体异构体、包合物、和前药。优选用于本发明的化合物是Celgene公司已知的选择性的细胞因子抑制药物(SelCIDsTM)。
这里使用的且除非另有陈述,用于本发明的术语″SeICIDsTM″包括小分子药物,例如,非肽有机小分子,蛋白质,核酸,低聚糖或其它大分子。优选的化合物抑制TNF-α的形成。此外,化合物也可以对LPS诱导的IL1β和IL12具有适度的抑制作用。更优选,本发明的化合物是有效的PDE4抑制剂。PDE4是在人类脊髓和淋巴血统细胞中发现的主要磷酸二酯酶同功酶中的一种。该酶在调节细胞活动方面起着决定性的作用,它是通过使普遍存在的第二信使cAMP降解并将其保持在较低的细胞内水平而起作用的。不受限于理论,对于PDE4活性的抑制会使cAMP水平增加,从而调节LPS诱导的细胞因子,包括抑制单核细胞以及淋巴细胞中TNF-α的形成。
选择性的细胞因子抑制药物的特定实例包括,但是不局限于,美国专利5,605,914中公开的环状亚胺;美国专利5,728,844和5,728,845中分别公开的环烷基酰胺和环烷基腈;美国专利5,801,195和5,736,570中公开的芳基酰胺(例如,一个实施方案是N-苯甲酰基-3-氨基-3-(3′,4′-二甲氧基苯基)-丙酰胺);美国专利5,703,098中公开的酰亚胺/酰胺醚和醇(例如3-邻苯二甲酰亚氨基-3-(3′,4′-二甲氧基苯基)丙烷-1-醇);美国专利5,658,940中公开的琥珀酰亚胺和马来酰亚胺(例如3-(3′,4′,5′,6′-四氢邻苯二甲酰亚胺基)-3-(3″,4″-二甲氧基苯基)丙酸甲酯);WO99/06041中公开的亚氨基和酰胺基取代的烷醇异羟肟酸和美国专利6,020,358中公开的取代的苯乙基砜;和美国专利6,046,221中所述的芳基酰胺,如N-苯甲酰基-3-氨基-3-(3′,4′-二甲氧基苯基)丙酰胺。这里所述的每一专利和专利申请的全部内容在此引入作为参考。本发明的选择性细胞因子抑制药物不包括沙利度胺。
另外的选择性的细胞因子抑制药物属于一类合成化合物,其典型的实施方案包括3-(1,3-二氧苯并-[f]异吲哚-2-基)-3-(3-环戊氧基-4-甲氧苯基)丙酰胺和3-(1,3-二氧代-4-氮杂异吲哚-2-基)-3-(3,4-二甲氧基苯基)-丙酰胺。
其它特定的选择性的细胞因子抑制药物属于美国专利5,698,579和5,877,200公开的一类非多肽环酰胺,两者都在此引入。有代表性的环酰胺包括下式的化合物:
其中n值为1、2或3;
R5是邻-亚苯基,其是未取代的或被1-4个取代基取代,所述取代基每一个都独立地选自硝基,氰基,三氟甲基,乙氧甲酰基,甲氧甲酰基,丙氧甲酰基,乙酰基,氨基甲酰基,乙酰氧基,羧基,羟基,氨基,烷氨基,二烷基氨基,酰基胺基,1-10个碳原子的烷基,1-10个碳原子的烷基,和卤素,
R7是(i)苯基或被一个或多个取代基取代的苯基,其中所述取代基各自独立地选自硝基,氰基,三氟甲基,乙氧甲酰基,甲氧甲酰基,丙氧甲酰基,乙酰基,氨基甲酰基,乙酰氧基,羧基,羟基,氨基,1-10个碳原子的烷基,1-10个碳原子的烷氧基,和卤素,(ii)未取代的或被1-3个取代基取代的苄基,所述取代基选自硝基,氰基,三氟甲基,乙氧甲酰基,甲氧甲酰基,丙氧甲酰基,乙酰基,氨基甲酰基,乙酰氧基,羧基,羟基,氨基,1-10个碳原子的烷基,1-10个碳原子的烷氧基,和卤素,(iii)萘基,和(iv)苄氧基;
R12是-OH,1-12个碳原子的烷氧基,或-NR8R9,
R8是氢或1-10个碳原子的烷基;和
R9是氢,1-10个碳原子的烷基,-COR10,或-SO2R10,其中R10是氢、1-10个碳原子的烷基、或苯基。
这一种类的具体化合物包括,但是不局限于:
3-苯基-2-(1-氧代异二氢吲哚-2-基)丙酸;
3-苯基-2-(1-氧代异二氢吲哚-2-基)丙酰胺;
3-苯基-3-(1-氧代异二氢吲哚-2-基)丙酸;
3-苯基-3-(1-氧代异二氢吲哚-2-基)丙酰胺;
3-(4-甲氧苯基)-3-(1-氧代异二氢吲哚-基)丙酸;
3-(4-甲氧苯基)-3-(1-氧代异二氢吲哚-基)丙酰胺;
3-(3,4-二甲氧基苯基)-3-(1-氧代异二氢吲哚-2-基)丙酸;
3-(3,4-二甲氧基苯基)-3-(1-氧代异二氢吲哚-2-基)-丙酰胺;
3-(3,4-二甲氧基苯基)-3-(1-氧代异二氢吲哚-2-基)丙酰胺;
3-(3,4-二乙氧基苯基)-3-(1-氧代异二氢吲哚-基)丙酸;
3-(1-氧代异二氢吲哚-2-基)-3-(3-乙氧基-4-甲氧苯基))丙酸甲酯;
3-(1-氧代异二氢吲哚-2-基)-3-(3-乙氧基-4-甲氧苯基))丙酸;
3-(1-氧代异二氢吲哚-2-基)-3-(3-丙氧基-4-甲氧苯基))丙酸;
3-(1-氧代异二氢吲哚-2-基)-3-(3-丁氧基-4-甲氧苯基))丙酸;
3-(1-氧代异二氢吲哚-2-基)-3-(3-丙氧基-4-甲氧苯基)丙酰胺;
3-(1-氧代异二氢吲哚-2-基)-3-(3-丁氧基-4-甲氧苯基)丙酰胺;
3-(1-氧代异二氢吲哚-2-基)-3-(3-丁氧基-4-甲氧苯基)丙酸甲酯和,
3-(1-氧代异二氢吲哚-2-基)-3-(3-丙氧基-4-甲氧苯基))丙酸甲酯。
其它具体的选择性的细胞因子抑制药物包括WO99/06041中公开的亚酰胺和酰胺基取代的链烷醇异羟肟酸,其在此引入作为参考。这种化合物的实例包括但是不局限于:
其中,R1和R2,当彼此独立考虑时,各自为氢,低级烷基,或者,当与其连接的所述的碳原子合起来时,R1和R2是邻亚苯基,邻亚萘基,或亚环己烷-1,2-二基,其为未取代的或被1-4个取代基取代,所述取代基各自独立地选自硝基,氰基,三氟甲基,乙氧甲酰基,甲氧甲酰基,丙氧甲酰基,乙酰基,氨基甲酰基,乙酰氧基,羧基,羟基,氨基,烷基氨基,二烷基氨基,酰基胺基,1-10个碳原子的烷基,1-10个碳原子的烷氧基,和卤素;
R3是被1-4个取代基取代的苯基,所述取代基选自硝基,氰基,三氟甲基,乙氧甲酰基,甲氧甲酰基,丙氧甲酰基,乙酰基,氨基甲酰基,乙酰氧基,羧基,羟基,氨基,1-10个碳原子的烷基,1-10个碳原子的烷氧基,1-10个碳原子的烷硫基,苄氧基,3-6个碳原子的环烷氧基,C4-C6-环亚烷基甲基,C3-C10亚烷基甲基,茚满氧基,和卤素;
R4是氢,1-6个碳原子的烷基,苯基,或苄基;
R4′是氢或1-6个碳原子的烷基;
R5是-CH2-,-CH2-CO-,-SO2-,-S-,或-NHCO-;
n的值为0、1、或2;和
所述包含有能够质子化的氮原子的化合物的酸加成盐。
另外用于本发明的具体的选择性的细胞因子抑制药物包括,但是不局限于:
3-(3-乙氧基-4-甲氧苯基)-N-羟基-3-(1-氧代异二氢吲哚基)丙酰胺;
3-(3-乙氧基-4-甲氧苯基)-N-甲氧基-3-(1-氧代异二氢吲哚基)丙酰胺;
N-苄氧基-3-(3-乙氧基-4-甲氧苯基)-3-邻苯二甲酰亚胺基丙酰胺;
N-苄氧基-3-(3-乙氧基-4-甲氧苯基)-3-(3-硝基邻苯二甲酰亚胺基)丙酰胺;
N-苄氧基-3-(3-乙氧基-4-甲氧苯基)-3-(1-氧代异二氢吲哚)丙酰胺;
3-(3-乙氧基-4-甲氧苯基)-N-羟基-3-邻苯二甲酰亚胺基丙酰胺;
N-羟基-3-(3,4-二甲氧基苯基)-3-邻苯二甲酰亚胺基丙酰胺;
3-(3-乙氧基-4-甲氧苯基)-N-羟基-3-(3-硝基邻苯二甲酰亚胺基)丙酰胺;
N-羟基-3-(3,4-二甲氧基苯基)-3-(1-氧代异二氢吲哚基)丙酰胺;
3-(3-乙氧基-4-甲氧苯基)-N-羟基-3-(4-甲基苯二酰亚氨基)丙酰胺;
3-(3-环戊氧基-4-甲氧苯基)-N-羟基-3-邻苯二甲酰亚胺基丙酰胺;
3-(3-乙氧基-4-甲氧苯基)-N-羟基-3-(1,3-二氧代-2,3-二氢-1H-苯并[f]异吲哚-2-基)丙酰胺;
N-羟基-3-3-(2-丙氧基)-4-甲氧基苯基)-3-邻苯二甲酰亚胺基丙酰胺;
3-(3-乙氧基-4-甲氧苯基)-3-(3,6-二氟邻苯二甲酰亚胺基)-N-羟基-丙酰胺;
3-(4-氨基邻苯二甲酰亚胺基)-3-(3-乙氧基-4-甲氧苯基)-N-羟基-丙酰胺;
3-(3-氨基邻苯二甲酰亚胺基)-3-(3-乙氧基-4-甲氧苯基)-N-羟基丙酰胺;
N-羟基-3-(3,4-二甲氧基苯基)-3-(1-氧代异二氢吲哚)丙酰胺;
3-(3-环戊氧基-4-甲氧苯基)-N-羟基-3-(1-氧代异二氢吲哚基)丙酰胺;和
N-苄氧基-3-(3-乙氧基-4-甲氧苯基)-3-(3-硝基邻苯二甲酰亚胺基)丙酰胺。
另外的用于本发明的选择性的细胞因子抑制药物包括在苯基上取代有氧代异二氢吲哚基团的取代的苯乙基砜。这类化合物的实例包括,但是不局限于,美国专利6,020,358中公开的那些,其在此引入,包括以下结构式:
其中,标有*的碳原子构成手性中心;
Y是C=O,CH2,SO2,或CH2C=O;R1、R2、R3、和R4中的每一个均彼此独立地为氢,卤素,1-4个碳原子的烷基,1-4个碳原子的烷氧基,硝基,氰基,羟基,或-NR8R9;或者相邻碳原子上的R1、R2、R3和R4中的任何两个和所述的亚苯基环一起,为亚萘基;
R5和R6中的每一个均彼此独立地为氢,1-4个碳原子的烷基,1-4个碳原子的烷氧基,氰基,或最多含18个碳原子的环烷氧基;
R7是羟基,1-8个碳原子的烷基,苯基,苄基,或-NR8′R9′;
R8和R9中的每一个彼此独立地为氢,1-8个碳原子的烷基,苯基,或苄基,或者R8和R9中的一个是氢,另一个是-COR10或-SO2R10,或者R8和R9合起来是四亚甲基,五亚甲基,六亚甲基,或-CH2CH2X1CH2CH2-,其中,X1是-O-,-S-或-NH-;和
R8′和R9′中的每一个彼此独立地为氢,1-8个碳原子的烷基,苯基,或苄基,或者R8′和R9′中的一个是氢,另一个是-OCR10′或-SO2R10′,或者R8′和R9′合起来是四亚甲基,五亚甲基,六亚甲基,或-CH2CH2X2CH2CH2-,其中,X2是-O-,-S-或-NH-。
应当理解,虽然为方便起见,上述化合物被确定为苯乙基砜类,但是它们包括其中R7是-NR8′R9′的磺酰胺。
这类化合物的特定的组是其中Y是C=O或CH2的化合物。
这类化合物的另一特定的组是,其中R1、R2、R3、和R4中的每一个均彼此独立地为氢,卤素,甲基,乙基,甲氧基,乙氧基,硝基,氰基,羟基,或-NR8R9的化合物,其中R8和R9彼此独立地为氢或甲基,或R8和R9中的一个为氢,另一个为-COCH3。
特定的化合物是,其中R1、R2、R3、和R4中的一个是-NH2,其余是氢的化合物。
特定的化合物是,其中R1、R2、R3、和R4中的一个是-NHCOCH3,其余是氢的化合物。
特定的化合物是,其中R1、R2、R3、和R4中的一个是-N(CH3)2,其余是氢的化合物。
这类化合物的另一优选的组是,其中R1、R2、R3、和R4中的一个是甲基,其余是氢的化合物。
特定的化合物是,其中R1、R2、R3、和R4中的一个是氟,其余是氢的化合物。
特定的化合物是,其中R5和R6各自彼此独立地为氢,甲基,乙基,丙基,甲氧基,乙氧基,丙氧基,环戊氧基或环己氧基的化合物。
特定的化合物是,其中R5是甲氧基,R6是单环烷氧基,多环烷氧基,和苯并环烷氧基的化合物。
特定的化合物是,其中R5是甲氧基,R6是乙氧基的化合物。
特定的化合物是,其中R7为羟基,甲基,乙基,苯基,苄基或-NR8′R9′的化合物,其中R8′和R9′彼此独立地为氢或甲基。
特定的化合物是,其中R7为甲基,乙基,苯基,苄基或-NR8′R9′的化合物,其中R8′和R9′彼此独立地为氢或甲基。
特定的化合物是其中R7是甲基的化合物。
特定的化合物是其中R7是-NR8′R9′的那些化合物,其中R8′和R9′各自独立地为氢或甲基。
其它特定的选择性的细胞因子抑制药物包括200年12月30日、Muller等人提交的美国临时申请60/436,975中发现的氟烷氧基-取代的-1,3-二氢异吲哚基化合物,其在此全文引入作为参考。有代表性的氟烷氧基-取代的-1,3-二氢异吲哚基化合物包括下式的化合物:
其中:Y是-C(O)-、-CH2、-CH2C(O)-、-C(O)CH2-、或SO2;
Z是-H,-C(O)R3,-(C0-1-烷基)-SO2-(C1-4-烷基),-C1-8-烷基,-CH2OH,CH2(O)(C1-8-烷基)或-CN;
R1和R2彼此独立地是-CHF2,-C1-8-烷基,-C3-18-环烷基,或-(C1-10-烷基)(C3-18-环烷基),且R1和R2中至少一个是CHF2;
R3是-NR4R5,-烷基,-OH,-O-烷基,苯基,苄基,取代的苯基,或取代的苄基;
R4和R5彼此独立地是-H,-C1-8-烷基,-OH,-OC(O)R6;
R6是-C1-8-烷基,-氨基(C1-8-烷基),-苯基,-苄基,或-芳基;
X1、X2、X3、和X4各自独立地是-H,-卤素,-硝基,-NH2,-CF3,-C1-6-烷基,-(C0-4-烷基)-(C3-6-环烷基),(C0-4-烷基)-NR7R8,(C0-4-烷基)-N(H)C(O)-(R8),(C0-4-烷基)-N(H)C(O)N(R7R8),(C0-4-烷基)-N(H)C(O)O(R7R8),(C0-4-烷基)-OR8,(C0-4-烷基)-咪唑基,(C0-4-烷基)-吡咯基,(C0-4-烷基)-噁二唑基,或(C0-4-烷基)-三唑基,或者X1、X2、X3、和X4中的两个可以连接在一起形成环烷基或杂环烷基环,(例如,X1和X2、X2和X3、X3和X4、X1和X3、X2和X4、或X1和X4可以形成3、4、5、6、或7元环,该环可以是芳环,从而与异吲哚基环形成双环体系);和
R7和R8彼此独立地是H,C1-9-烷基,C3-6-环烷基,(C1-6-烷基)-(C3- 6-环烷基),(C1-6-烷基)-N(R7R8),(C1-6-烷基)-OR8,苯基,苄基,或芳基;
或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。
优选的化合物包括但是不局限于:
3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-丙酸;
3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-N,N-二甲基-丙酰胺;
3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-丙酰胺;
3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-3-(1,3-二氧代-1,3-二氢-异吲哚-2-基)-丙酸;
3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-3-(1,3-二氧代-1,3-二氢-异吲哚-2-基)-N-羟基-丙酰胺;
3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-3-(7-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-丙酸甲酯;
3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-3-(7-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-丙酸;
3-(3-环丙基甲氧基-4-二氟甲氧基-苯基-3-(7-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-)-N,N-二甲基-丙酰胺;
3-(7-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-N,N-二甲基-丙酰胺;
3-(4-二氟甲氧基-3-乙氧基-苯基)-3-(7-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-丙酸甲酯;
3-(7-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸甲酯;
3-[7-(环丙烷羰基-氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸甲酯;
3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸甲酯;
3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸;
3-[7-(环丙烷羰基-氨基)-1-氧代-1,3-二氢-异吲哚-2-基]-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸;
{2-[2-氨甲酰基-1-(4-二氟甲氧基-3-乙氧基-苯基)-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-环丙烷甲酸酰胺;
{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-二甲基氨甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-环丙烷甲酸;
{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-羟基氨甲酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-环丙烷甲酸酰胺;
3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酰胺;
3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-N,N-二甲基-丙酰胺;
3-(7-乙酰氨基-1-氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-N-羟基-丙酰胺;
3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酸;
3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-丙酰胺;
3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-N,N-二甲基-丙酰胺;
3-(4-乙酰氨基-1,3-二氧代-1,3-二氢-异吲哚-2-基)-3-(4-二氟甲氧基-3-乙氧基-苯基)-N-羟基-丙酰胺;
{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-甲烷磺酰基-1-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-环丙烷甲酸酰胺;
N-{2-[1-(4-二氟甲氧基-3-乙氧基-苯基)-2-甲烷磺酰基1-乙基]-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基}-乙酰胺;和
{2-[2-氨甲酰基-1-(4-二氟甲氧基-3-乙氧基-苯基)-乙基]-7-氯-3-氧代-2,3-二氢-1H-异吲哚-4-基}-环丙烷甲酸酰胺。
其它选择性的细胞因子抑制药物包括2003年3月12日、Muller等人提交的美国临时申请60/454,155中发现的7-酰氨基取代的异吲哚基化合物,其在此全文引入作为参考。
有代表性的7-酰氨基取代的异吲哚基化合物包括下式的化合物:
其中:Y是-C(O)-、-CH2、-CH2C(O)-或SO2;
X是H;
Z是(C0-4-烷基)-C(O)R3,C1-4-烷基,(C0-4-烷基)-OH,(C1-4-烷基)-O(C1-4-烷基),(C1-4-烷基)-SO2(C1-4-烷基),(C0-4-烷基)-SO(C1-4-烷基),(C0-4-烷基)-NH2,(C0-4-烷基)-N(C1-8-烷基)2,(C0-4-烷基)-N(H)(OH),CH2NSO2(C1-4-烷基);
R1和R2独立地是C1-8-烷基、环烷基,或(C1-4-烷基)环烷基;
R3是NR4R5、OH、或O-(C1-8-烷基);
R4是H;
R5是-OH,或-OC(O)R6;
R6是C1-8-烷基,氨基-(C1-8-烷基),(C1-8-烷基)-(C3-6-环烷基),C3-6-环烷基,苯基,苄基,或芳基;
或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药;或下式的化合物:
其中:
Y是-C(O)-,-CH2,-CH2C(O)-,或SO2;
X是卤素,-CN,-NR7R8,-NO2,或-CF3,
W是
Z是(C0-4烷基)-SO2(C1-4-烷基),-(C0-4烷基)-CN,-(C0-4烷基)-C(O)R3,C1-4-烷基,(C0-4-烷基)OH,(C0-4-烷基)O(C1-4-烷基),(C0-4-烷基)SO(C1-4-烷基),(C0-4-烷基)NH2,(C0-4-烷基)N(C1-8-烷基)2,(C0- 4-烷基)N(H)(OH),或(C0-4-烷基)NSO2(C1-4-烷基);
W是-C3-6-环烷基,-(C1-8烷基)-(C3-6-环烷基),-(C0-8-烷基)-(C3-6环烷基)-NR7R8,(C0-8-烷基)-NR7R8,(C0-4-烷基)-CHR9-(C0-4-烷基)-NR7R8;
R1和R2彼此独立地为C1-8烷基,环烷基,或(C1-4-烷基)环烷基;
R3是C1-8-烷基,NR4R5,OH,或O-(C1-8烷基);
R4和R5彼此独立地为H,C1-8-烷基,(C0-8-烷基)-(C3-6-环烷基),OH,或-OC(O)R6;
R6是C1-8-烷基,(C0-8-烷基)-(C3-6-环烷基),氨基-(C1-8-烷基),苯基,苄基,或芳基;
R7和R8彼此独立地是H,C1-8-烷基,(C0-8烷基)-(C3-6-环烷基),苯基,苄基,芳基,或者可以与它们所连接的原子一起形成3-7元杂环烷基或杂芳基环;
R9是C1-4-烷基,(C0-4-烷基)芳基,(C0-4-烷基)-(C3-6-环烷基),(C0-4-烷基)-杂环;
或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。
还有其它选择性的细胞因子抑制药物包括2003年3月12日、Muller等人提交的美国临时申请60/454,149中发现的N-烷基-异羟肟酸-异吲哚基化合物,其在此全文引入作为参考。
有代表性的N-烷基异羟肟酸-异吲哚基化合物包括下式的化合物:
其中:
Y是-C(O)-,-CH2,-CH2C(O)-,或SO2;
R1和R2彼此独立地为C1-8-烷基,CF2H,CF3,CH2CHF2,环烷基,或(C1-8-烷基)环烷基;
Z1是H,C1-6-烷基,-NH2-NR3R4或OR5;
Z2是H或C(O)R5;
X1、X2、X3和X4彼此独立地是H,卤素,NO2,OR3,CF3,C1-6-烷基,(C0-4-烷基)-C3-6-环烷基),(C0-4-烷基)-N-(R8R9),(C0-4-烷基)-NHC(O)-(R8),(C0-4-烷基)-NHC(O)CH(R8)(R9),(C0-4-烷基)-NHC(O)N(R8R9),(C0-4-烷基)-NHC(O)O(R8),(C0-4-烷基)-O-R8,(C0-4-烷基)-咪唑基,(C0-4-烷基)-吡咯基,(C0-4-烷基)-噁二唑基,(C0-4烷基)-三唑基或(C0-4-烷基)-杂环;
R3、R4、和R5彼此独立地是H,C1-6烷基,O-C1-6-烷基,苯基,苄基,或芳基;
R6和R7彼此独立地是H或C1-6-烷基;
R8和R9彼此独立地是H,C1-9烷基,C3-6-环烷基,(C1-6-烷基)-(C3-6-环烷基),(C0-6-烷基)-N(R4R5),(C1-6-烷基)-OR5,苯基,苄基,芳基,哌啶基,哌嗪基,吡咯烷基,吗啉代,或C3-7-杂环烷基;
或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。
具体的选择性的细胞因子抑制药物包括,但是不局限于:
2-[1(-3-乙氧基-4-甲氧基苯基)-2-甲基-磺酰基乙基]异二氢吲哚-1-酮;
2-[1-(3-乙氧基-4-甲氧基苯基)-2-(N,N-二甲基-氨基磺酰基)乙基]异二氢吲哚-1-酮;
2-[1-(3-乙氧基-4-甲氧基苯基)-2-甲基-磺酰基乙基]异二氢吲哚-1,3-二酮;
2-[1-(3-乙氧基-4-甲氧基苯基)-2-甲基-磺酰基乙基]-5-硝基-异二氢吲哚-1,3-二酮;
2-[1-(3-乙氧基-4-甲氧基苯基)-2-甲基-磺酰基乙基]-4-硝基异二氢吲哚-1,3-二酮;
2-[1-(3-乙氧基-4-甲氧基苯基)-2-乙基磺酰基乙基]-4-氨基异二氢吲哚-1,3-二酮;
2-[1-(3-乙氧基-4-甲氧基苯基)-2-甲基磺酰基乙基]-5-甲基异二氢吲哚-1,3-二酮;
2-[1-(3-乙氧基-4-甲氧基苯基)-2-甲基磺酰基乙基]-5-乙酰氨基异二氢吲哚-1,3-二酮;
2-[1-(3-乙氧基-4-甲氧基苯基)-2-甲基磺酰基乙基]-4-二甲基氨基异二氢吲哚-1,3-二酮;
2-[1-(3-乙氧基-4-甲氧基苯基)-2-甲基磺酰基乙基]-5-二甲基氨基异二氢吲哚-1,3-二酮;
2-[1-(3-乙氧基-4-甲氧基苯基)-2-甲基磺酰基乙基]苯并[e]异二氢吲哚-1,3-二酮;
2-[1-(3-乙氧基-4-甲氧基苯基)-2-甲基磺酰基乙基]-4-甲氧基异二氢吲哚-1,3-二酮;
1-(3-环戊氧基-4-甲氧基苯基)-2-甲基磺酰基乙基-胺;
2-[1-(3-环戊氧基-4-甲氧基苯基)-2-甲基磺酰基乙基]异二氢吲哚-1,3-二酮;和
2-[1-(3-环戊氧基-4-甲氧基苯基)-2-甲基磺酰基乙基]-4-二甲基氨基异二氢吲哚-1,3-二酮。
另外的选择性的细胞因子抑制药物包括G.Muller等人在以下临时专利申请中公开的对映异构纯化合物:2002年3月20日提交的美国临时专利申请60/366,515和60/366,516;2003年1月7日提交的美国临时专利申请60/438,450和60/438,448;2003年3月5日提交的美国临时专利申请60/452,460,所有这些均在此引入作为参考。优选的化合物包括2-[1-(3-乙氧基-4-甲氧苯基)-2-甲基磺酰基乙基]-4-乙酰氨基异二氢吲哚-1,3-二酮的对映体和3-(3,4-二甲氧基苯基)-3-(1-氧代-1,3-二氢异吲哚-2-基)-丙酰胺的对映体。
优选用于本发明的选择性的细胞因子抑制药物是3-(3,4-二甲氧基苯基)-3-(1-氧代-1,3-二氢异吲哚-2-基)-丙酰胺和{2-[1-(3-乙氧基-4-甲氧基苯基)-2-甲基磺酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-环丙烷甲酸酰胺,其可购自Celgene公司,Warren,NJ.,3-(3,4-二甲氧基苯基)-3-(1-氧代-1,3-二氢异吲哚-2-基)-丙酰胺具有以下化学结构:
{2-[1-(3-乙氧基-4-甲氧基苯基)-2-甲基磺酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-环丙烷甲酸酰胺具有以下化学结构:
本发明的化合物或者可以商购,或者可以根据本发明中公开的专利或者专利出版物中描述的方法制备。另外,对于光学纯的组合物,可以不对称地合成,或者使用已知的拆分剂或用手性柱以及其它标准的有机合成化学法拆分。
如在这里使用的并且除非另有陈述,术语″可药用的盐″包括该术语所涉及的化合物的无毒酸和碱加成盐。可接受的无毒酸加成盐包括源自于本领域已知的有机和无机酸或碱的那些盐,其包括,例如,盐酸,氢溴酸,磷酸,硫酸,甲烷磺酸,乙酸,酒石酸,乳酸,琥珀酸,柠檬酸,苹果酸,马来酸,山梨酸,乌头酸,水杨酸,邻苯二甲酸,介子酸(embolic acid),庚酸,等。
性质上是酸性的化合物能够与各种各样可药用的碱形成盐。可用于制备这种酸性化合物的可药用的碱加成盐的碱是形成无毒碱加成盐,即,包含药理学上可接受的阳离子的盐的那些碱,其例如但不限于,碱金属或碱土金属盐以及尤其是钙、镁、钠或钾盐。适当的有机碱包括,但是不局限于,N,N-二苄基乙二胺,氯普鲁卡因,胆碱,二乙醇胺,乙二胺,甲葡胺(N-甲基葡糖胺),赖氨酸,和普鲁卡因。
如在这里使用的并且除非另有陈述,术语″前药″意思指可以水解、氧化、或在生物条件(体外或体内)下的其它反应得到所述化合物的所述化合物的衍生物。前药的实例包括,但是不局限于,包括可生物水解的部分如可生物水解的酰胺、可生物水解的酯、可生物水解的氨基甲酸酯、可生物水解的碳酸酯、可生物水解的酰脲、以及可生物水解的磷酸酯类似物的选择性的细胞因子抑制药物的衍生物。前药的其它实例包括含有-NO、-NO2、ONO、或-ONO2部分的选择性的细胞因子抑制药物的衍生物。前药通常可以使用公知的方法制备,如以下文献中描述的方法:Burger′s Medicinal Chemistry andDrug Discovery,172-178,949-982(Manfred E.Wolffed.,第5版,1995),和Design of Prodrugs(H.Bundgaard编,Elselvier,NewYork 1985)。
如在这里使用的并且除非另有陈述,术语″可生物水解的酰胺″、″可生物水解的酯″、″可生物水解的氨基甲酸酯″、″可生物水解的碳酸酯″、″可生物水解的酰脲″、″可生物水解的磷酸酯″分别意指化合物的酰胺、酯、氨基甲酸酯、碳酸酯、酰脲、或者磷酸酯,它们或者,1)不干扰化合物的生物活性但是可以使化合物具有有利的体内性质,如吸收、持续作用时间、作用的开始;或者2)没有生物学活性,但是在体内却转化为生物学活性化合物。
可生物水解的酯的实例包括,但是不局限于,低级烷基酯,低级酰氧基烷基酯(如乙酰氧基甲基酯、乙酰氧基乙基酯、氨基羰基氧甲基酯、特戊酰氧甲基酯、和特戊酰氧基乙基酯),内酯基酯(如酞基和硫代酞基酯),低级烷氧基酰氧基烷基酯(如甲氧基羰基氧甲基酯、乙氧基羰基氧乙基酯和异丙氧基羰基氧乙基酯),烷氧基烷基酯,胆碱酯,和酰胺基烷基酯(如乙酰氨基甲基酯)。可生物水解的酰胺的实例包括,但是不局限于,低级烷基酰胺,α-氨基酸酰胺,烷氧基酰基酰胺,和烷氨基烷基羰基酰胺。可生物水解的氨基甲酸脂的实例包括,但是不局限于,低级烷基胺,取代的乙二胺,氨基酸,羟烷基胺,杂环和杂芳香胺,和聚醚胺。
不同的选择性的细胞因子抑制药物包含一个或多个手性中心,并且可以以对映异构体的外消旋混合物或非对映体的混合物形式存在。本发明包括使用立体异构纯的这类化合物,以及使用这些形式的混合物。例如,在本发明的方法和组合物中可以使用包括等量或不等量的选择性细胞因子抑制药物的对映异构体的混合物。本发明中公开的具体化合物的纯化的(R)或(S)对映异构体可以基本上以不含其它对映异构体的形式使用。
如在这里使用的并且除非另有陈述,术语″立体异构纯″意思指组合物包括化合物的一种立体异构体并且基本上不含该化合物其它的立体异构体。例如,具有一个手性中心的化合物的立体异构纯的组合物将基本上不含该化合物相反的对映异构体。具有两手性中心的化合物的立体异构纯的组合物将基本上不含该化合物其它的非对映体。
典型的立体异构纯的化合物包括大于约80重量%的所述化合物的一种立体异构体,和低于约20重量%的该化合物的其它立体异构体,更优选大于约90%的所述化合物的一种立体异构体,和低于约10重量%的该化合物的其它立体异构体,甚至更优选大于约95%的所述化合物的一种立体异构体,和低于约5重量%的该化合物的其它立体异构体,最优选大于约97%的所述化合物的一种立体异构体,和低于约3重量%的该化合物的其它立体异构体。
如在这里使用的并且除非另有陈述,术语″立体异构富集″意思指组合物包括大于约60重量%的化合物的一种立体异构体,优选大于约70重量%,更优选大于约80重量%的化合物的一种立体异构体。
如在这里使用的并且除非另有陈述,术语″对映异构纯″意思是指具有一个手性中心的化合物的立体异构纯的组合物。类似地,术语″立体异构富集″意思是指具有一个手性中心的化合物的立体异构富集的组合物。
应该注意到的是,如果在画出的结构和对该结构给出的名称之间存在矛盾的话,画出的结构被认为更有分量。另外,如果结构或结构的一部分的立体化学没有显示为,例如粗线或虚线表示的话,该结构或该结构的一部分应被解释为包括其所有的立体异构体。
4.2第二活性成分
一种或多种第二活性成分可以与本发明的选择性细胞因子抑制药物结合使用。优选,第二活性成分,或药剂能够抑制过量生成造血干细胞或者使一种或多种MPD症状得到改善。
第二活性剂可以是,但是不局限于,小分子(例如,合成的无机、有机金属、或有机分子),大分子,合成药物,肽,多肽,蛋白质,核酸,抗体等。公知的可用于、或已经用于或目前正在用于预防、治疗或改善一种或多种MPD症状的任何药剂都可以与本发明结合使用。具体的药剂包括,但是不局限于,抗癌剂(例如,抗代谢物、抗生素、烷基化剂、微管抑制剂、甾体激素、DNA-修复酶抑制剂、激酶抑制剂、法尼基转移酶抑制剂、反义寡核苷酸、免疫调节剂、抗体、疫苗、和adnosine(脱氨酶抑制剂),全反式视黄酸(如,三氧化二砷),血小板抑制剂(例如,阿斯匹林、潘生丁、噻氯匹定、阿那格雷),抗凝剂(例如,依诺肝素、肝素、华法林),溶解血栓剂(例如,阿克伐司(tPA)、阿尼普酶、链激酶、尿激酶),抗纤维化剂(例如,青霉胺、苏拉明、clochicine),用于治疗出血的药剂(例如,氨基己酸、硫酸鱼精蛋白、维生素K),以及用于治疗贫血的药剂(例如,维生素K、叶酸)。
本发明也包括使用天然的、天然生成的、和重组的蛋白质。本发明还包括在体内显示至少一些它们所基于的蛋白质药理学活性的天然存在的蛋白质的突变体和衍生物(例如,改性形式)。突变体的实例包括,但是不局限于,具有与蛋白质的天然存在形式中相应的残基不同的一种或多种氨基酸残基的蛋白质。术语″突变体″还包括缺乏通常在其天然存在形式中存在的碳水化合物部分的蛋白质(例如,非葡糖化的形式)。衍生物的实例包括,但是不局限于PEG化的衍生物和融合蛋白质,如通过将IgG1或IgG3融合到蛋白质或所考虑的蛋白质的活性部分上形成的蛋白质。参见例如,Penichet,M.L.和Morrison,S.L.,J.Immunol.Methods 248:91-101(2001)。
本发明进一步包括使用免疫细胞或血液以及骨髓干细胞移植。例如,对CML患者可以通过输给抑制白血病细胞生长的给体白血球而进行治疗。Slavin等,Transfus Apheresis Sci 27(2):159-66(2002)。
可用于本发明各种实施方案,包括本发明的方法、剂量疗法、鸡尾酒疗法、药物组合物和剂型以及试剂盒,的抗癌药物的实例,包括但是不局限于:阿西维辛;阿柔比星;阿考达唑盐酸盐;阿克罗宁;阿多来新;阿地白介素;六甲基蜜胺;安波霉素;阿美蒽醌乙酸盐;本发明的aminoglutethan免疫调节化合物;安吖啶;阿纳托唑;氨曲霉素;天冬酰胺酶;曲林菌素;阿扎胞苷;阿扎替派;阿佐霉素;巴马司他;苯佐替派;比卡鲁胺;比生群盐酸盐;双奈法德二甲磺酸盐;比折来新;博来霉素硫酸盐;布喹那钠盐;溴匹立明;白消安;放线菌素C;二甲睾酮;卡醋胺;卡贝替姆;卡铂;卡氮芥;卡柔比星盐酸盐;卡析来新;西地芬戈;塞来昔布(COX-2抑制剂);瘤可宁;西罗霉素;顺铂;克拉屈滨;crisnatol甲磺酸盐;环磷酰胺;阿糖胞苷;达卡巴嗪;放线菌素D;柔红霉素盐酸盐;地西他滨;右奥马铂;地扎呱宁;地扎呱宁甲磺酸盐;地吖醌;达卡巴嗪;多西他奇;阿霉素;阿霉素盐酸盐;屈洛昔芬;屈洛昔芬柠檬酸盐;屈他雄酮丙酸盐;偶氮霉素;依达曲沙;依氟鸟氨酸盐酸盐;依沙芦星;蒽洛铂;恩普氨酯;依匹哌啶;表柔比星盐酸盐;厄布洛唑;依索比星盐酸盐;雌莫司汀;雌莫利汀磷酸钠;依他硝唑;依托泊苷;依托泊苷磷酸酯;氯苯乙嘧胺;法倔唑盐酸盐;法扎拉滨;芬维A胺;5-氟去氧尿苷;氟阿腺苷磷酸盐;氟尿嘧啶;氟西他滨;磷喹酮;磷曲星钠;吉西他滨;吉西他滨盐酸盐;羟基脲;伊达比星盐酸盐;异环磷酰胺;伊莫福新;白介素II(包括重组体白介素II、或rIL2);干扰素α-2a;干扰素α-2b;干扰素α-n1;干扰素α-n3;干扰素β-Ia;干扰素γ-Ib;异丙铂;依立替康;依立替康盐酸盐;兰乐肽乙酸盐;来曲唑;亮氨酰脯氨酸醋酸盐;利阿唑盐酸盐;洛美曲索钠;环己亚硝脲;洛索蒽醌盐酸盐;马索丙考;美登素;氮芥盐酸盐;甲地孕酮醋酸盐;甲烯雌醇醋酸酯;左旋苯丙氨酸氮芥;美诺立尔;巯基嘌呤;甲氨喋呤;甲氨喋呤钠;氯苯氨啶;美妥替哌;米丁度胺;丝裂卡菌素;丝裂红素;米托菌素;米托马星;丝裂霉素;米托司培;米托坦;米托蒽醌盐酸盐;霉酚酸;诺考达唑;诺拉霉素;oblimersen;奥马铂;奥昔舒仑;紫杉醇;培门冬酶;培利霉素;溴新斯的明;培洛霉素硫酸盐;过磷酰胺;双溴丙基哌嗪;哌泊舒凡;吡罗蒽醌盐酸盐;普卡霉素;普洛美坦;卟吩姆钠;泊非霉素;泼尼莫司汀;盐酸丙卡巴肼;嘌罗霉素;嘌罗霉素盐酸盐;吡唑霉素;利波腺苷;本发明的rogletan免疫调节化合物;沙芬戈;沙芬戈盐酸盐;司莫司汀;辛曲秦;sparfosate sodium;司帕霉素;螺旋锗盐酸盐;螺莫司汀;螺铂;链黑菌素;链脲霉素;磺氯苯脲;他利霉索;tecogalan钠;泰索帝;替加氟;替洛蒽醌盐酸盐;替莫泊芬;替尼泊苷;替罗昔隆;睾内脂;硫咪嘌呤;硫鸟嘌呤;硫替哌;噻唑呋林(tiazofurin);替拉扎明;托瑞米芬柠檬酸盐;曲托龙乙酸盐;曲西立滨磷酸盐;三甲曲沙;三甲曲沙葡糖醛酸盐;曲普瑞林;妥布氯唑盐酸盐;尿嘧啶氮芥;马瑞替派;伐普肽;维替泊芬;硫酸长春碱;硫酸长春新碱;长春地辛;长春地辛硫酸盐;长春匹定硫酸盐;长春甘酯硫酸盐;环氧长春碱硫酸盐;长春瑞宾酒石酸盐;异长春碱硫酸盐;长春利定硫酸盐;伏氯唑;折尼泊;净司他丁;佐柔比星盐酸盐。其它的抗癌药包括,但是不限于20-表-1,25-二羟基维生素D3;5-乙炔基尿嘧啶;阿比特龙;阿柔比星;acylfalvene;adecypenol;阿多来新;阿地白介素;AL1-TK拮抗剂;六甲基蜜胺;氨莫司汀;二氨酚;氨磷汀;氨基乙酰丙酸;氨柔比星;安吖啶;阿那格雷;阿纳托(司)唑;穿心莲内酯;血管生成抑制剂;拮抗剂D;拮抗剂G;antarelix;抗背部化形态形成蛋白质-1;抗雄激素,前列腺癌药;抗雌激素药;抗(恶性)肿瘤物质;反义寡核苷酸;阿非迪霉素甘氨酸盐;细胞凋亡基因调节剂;凋亡调节剂,脱嘌呤核酸;ara-CDP-D1-PTBA;精氨酸脱氨酶;asulacrine;阿他美坦;阿莫司汀;axinastatin 1;axinastatin 2;axinastatin 3;阿扎司琼;azatoxin;重氮酪氨酸;浆果赤霉素III衍生物;balanol;巴马司他;BCR/ABL拮抗剂;benzochlorins;苯甲酰基癌基因抑活药;β-内酰胺衍生物;β-alethine;β-clamycin B;白桦脂酸;bFGF抑制剂;比卡鲁胺;比生群;双氮丙定基精氨;双奈法德;bistratene A;比折来新;breflate;溴匹立明;布多替钛;buthionine磺基肟;钙泊三醇;calphostin C;喜树碱衍生物;金丝雀I(canarypox)1-2;卡培他滨;碳酰胺-氨基-三唑;羧基酰胺基三唑;CaRest M3;CARN 700;软骨衍生的抑制剂;卡折来新;酪蛋白激酶抑制剂(ICOS);粟精胺;天蚕抗菌肽B;西曲瑞克;chlorlns;氯喹噁啉磺酰胺;西卡前列素;顺-卟啉;克拉屈滨;氯米芬类似物;克霉唑;collismycin A;collismycin B;combretastatin A4;combretastatin同系物;conagenin;crambescidin 816;crisnatol;cryptophycin 8;cryptophycin A衍生物;curacin A;环戊烷蒽醌(cyclopentanthraquinones);cycloplatam;cypemycin;cytarabineocfosfate;溶细胞因子;cytostatin;达昔单抗;地西他滨;dehydrodidemnin B;地洛瑞林;地塞米松;dexifosfamide;地拉佐生;右维拉帕米;地吖醌;didemnin B;didox;diethylnorspermine;二氢-5-氮胞苷;二氢紫杉酚,9-;二氧杂霉菌素(dioxamycin);二苯基螺莫司汀;多西他奇;二十二烷醇;多拉司琼;去氧氟尿苷;屈洛昔芬;屈大麻酚;duocarmycin SA;依布硒啉;依考莫司汀;依地福新;依决洛单抗;依氟鸟氨酸;榄香烯;乙嘧替氟;表阿霉素;依立雄胺;雌莫司汀类似物;雌激素激动剂;雌激素拮抗剂;依他硝唑;依托泊苷磷酸盐;依西美坦;法倔唑;法扎拉滨;芬维A胺;非格司亭;非那司提;flavopiridol;flezelastine;fluasterone;氟达拉滨;fluorodaunorunicin盐酸盐;福酚美克;福麦斯坦;磷曲星;福莫司汀;钆texaphyrin;硝酸镓;加洛他滨;加尼瑞克;白明胶酶抑制剂;吉西他滨;谷胱甘肽抑制剂;hepsulfam;heregulin;己撑二乙酰胺;金丝桃素;伊班磷酸;伊达比星;碘昔芬;伊决孟酮;伊莫福新;伊洛马司他;本发明的azoacridones的免疫调节化合物;咪喹莫特;免疫刺激剂肽;胰岛素样生长因子-1受体抑制物;干扰素激动剂;干扰素;白介素;碘苄胍;碘阿霉素;ipomeanol,4-;伊罗普拉;伊索拉定;isobengazole;isohomohalicondrin B;伊他司琼;jasplakinolide;kahalalide F;lamellarin-N三乙酸盐;兰乐肽;leinamycin;来诺拉提;香菇糖硫酸盐;leptolstatin;来曲唑;白血病抑制因子;白血球阿尔法干扰素;亮丙瑞林+雌激素+孕酮;亮丙瑞林;左旋四咪唑;利阿唑;直链聚胺类似物;亲脂性二糖肽;亲脂性铂化合物;lissoclinamide 7;洛铂;胍乙基磷酸丝氨酸;洛美曲索;氯尼达明;洛索蒽醌;洛伐他丁;洛索立宾;勒托替康;镥texaphyrin;lysofylline;溶解肽;美坦生;mannostatin A;马马司他;马索丙考;maspin;基质溶解因子抑制剂;基质金属蛋白酶抑制剂;美诺立尔;merbarone;meterelin;methioninase;甲氧氯普胺;MIF抑制剂;米非司酮;米替福新;米立司亭;错配的双链RNA;米托胍腙;二溴卫矛醇;丝裂霉素类似物;米托萘胺;mitotoxin成纤维细胞生长因子-皂草素(saporin);米托蒽醌;莫法罗汀;莫拉司亭;单克隆抗体,人绒毛膜促性腺激素;单磷酰脂质A+成肌细胞壁SK栓;莫哌达醇;多重耐药性基因抑制剂;基于多重肿瘤抑制因子1-的疗法;氮芥类抗癌剂;mycaperoxide B;分支杆菌细胞壁提取物;myriaporone;N-acetyldinaline;N-取代的苯甲酰胺;那法瑞林;nagrestip;纳洛酮+喷他佐辛;napavin;naphterpin;那托司亭;萘达铂;萘莫柔比星;萘立膦酸;中性肽链内切酶;尼鲁米特;nisamycin;一氧化氮调节剂;硝基氧抗氧化剂;nitrullyn;06-苄基鸟嘌呤;奥曲肽;okicenone;低聚核苷酸;奥那司酮;奥丹西隆;奥丹西隆;oracin;口服的细胞因子诱导物;奥乌铂;奥沙特隆;奥沙利铂;oxaunomycin;紫杉醇;紫杉醇类似物;紫杉醇衍生物;palauamine;palmitoylrhizoxin;帕米磷酸;panaxytriol;帕诺米芬;parabactin;帕折普汀;培门冬酶;peldesine;木聚硫钠;喷司他丁;pentrozole;潘氟隆;过磷酰胺;紫苏子醇(perillyakcohol);phenazinomycin;乙酸苯酯;磷酸酯酶抑制剂;溶链菌制剂;盐酸毛果芸香碱;吡柔比星;吡曲克李;placetin A;placetinB;纤溶酶原激活物抑制剂;铂配合物;铂化合物;铂-三胺配合物;卟菲尔钠;波非霉素;强的松;丙基双吖啶酮;前列腺素J2;蛋白酶体抑制剂;基于蛋白A的免疫调节剂;蛋白激酶C抑制剂;蛋白激酶C抑制剂,微藻(microalgal);蛋白质酪氨酸磷酸酯酶抑制剂;嘌呤核苷磷酸化酶抑制剂;紫红素;pyrazoloacridine;吡醇羟乙酯血红蛋白聚氧乙烯轭合物;raf拮抗剂;雷替曲塞;雷莫司琼;ras法呢基蛋白质转移酶抑制剂;ras抑制剂;ras-GAP抑制剂;脱甲基化的retelliptine;Re186依替膦酸铼;根霉素;核糖酶;RIIrctinamide;本发明的rogletan免疫调节化合物;rohitukine;罗莫肽;罗喹美克;rubiginone B1;ruboxyl;沙芬戈;saintopin;SarCNU;sarcophytol A;沙莫司亭;Sdi 1模拟物;司莫司汀;衰老衍生的抑制剂1;感官低聚核苷酸;信号转导抑制剂;信号转导调节剂;单链抗原结合蛋白;西佐喃;索布佐生;borocaptate钠;苯基乙酸钠;solverol;促生长因子结合蛋白;索纳明;sparfosic酸;spicamycin D;螺莫司汀;splenopentin;spongistatin 1;squalamine;干细胞抑制剂;干细胞分裂抑制剂;stipiamide;溶基质素抑制剂;sulfinosine;超活性血管活性肠肽拮抗剂;suradista;苏拉明;八氢吲嗪三醇;合成氨基葡糖多糖;他莫司汀;他莫昔芬甲碘化物;牛磺莫司汀;他佐罗汀;tecogalan钠;替加氟;tellurapyrylium;端粒末端转移酶抑制剂;temoporfm;替尼泊苷;tetrachlorodecaoxide;tetrazomine;thaliblastine;thiocoraline;促血小板生成素;促血小板生成素模拟物;胸腺法新;促胸腺生成素受体激动剂;胸腺曲南;促甲状腺激素;ethyletiopurpurin锡;替拉扎明;titanocene二氯化物;topsentin;托瑞米芬;全能性干细胞生长因子;翻译抑制剂;维甲酸;triacetyluridine;曲西立滨;三甲曲沙;曲普瑞林;曲匹西隆;妥罗雄脲;酪氨酸激酶抑制剂;酪氨酸磷酸化抑制剂(tyrphostins);UBC抑制剂;乌苯美司;泌尿生殖窦衍生的生长抑制因子;尿激酶受体拮抗体;代普肽;variolin B;媒介体系,红血球基因疗法;维拉雷琐;veramine;黄雀;维替泊芬;长春瑞宾;vinxaltine;vitaxin;伏氯唑;扎诺特隆;折尼铂;zilascorb;和净司他丁斯酯。优选的抗癌药是已经表明在MPD患者中具有治疗效果的那些药物,例如,干扰素-a,羟基脲,白消安,阿那格雷,柔红霉素,cincristine,皮质甾类激素(例如,强的松,倍氯米松,可的松,地塞米松,氟氢可的松,氢化可的松,甲基强的松龙),激酶抑制剂,局部异构酶抑制剂,法尼基转移酶抑制剂,疫苗和反义核苷酸。
激酶抑制剂的实例包括,但是不局限于,化合物ST1571,imatinib甲磺酸盐(Kantarjian等,Clin Cancer Res.8(7):2167-76(2002)),和以下美国专利中公开的那些化合物:6,245,759、6,399,633、6,383,790、6,335,156、6,271,242、6,242,196、6,218,410、6,218,372、6,057,300、6,034,053、5,985,877、5,958,769、5,925,376、5,922,844、5,911,995、5,872,223、5,863,904、5,840,745、5,728,868、5,648,239、5,587,459,所有这些均全文在此引入作为参考。优选的激酶抑制剂包括,但是不局限于,直接BCR/ABL激酶或其它与MPD病理生理学有关的激酶作为靶点的那些抑制剂,例如,ST1571,和imatinib甲磺酸盐。
拓扑异构酶抑制剂的实例包括,但是不局限于,喜树碱;依立替康;SN-38;topotecan;9-氨基喜树碱;GG-211(GI147211);DX-8951f;IST-622;rubitecan;pyrazoloacridine;XR-5000;saintopin;UCE6;UCE1022;TAN-1518A;TAN-1518B;KT6006;KT6528;ED-110;NB-506;ED-110;NB-506;和rebeccamycin;bulgarein;DNA窄沟粘合剂如Hoescht dye 33342和Hoechst dye 33258;两面针碱;花椒路宁;表小檗碱;coralyne;β-lapachone;BC-4-1;以及其可药用的盐,溶剂化物,包合物和前药。参见,例如,Rothenberg,M.L.,Annals of Oncology 8:837-855(1997);和Moreau,P.,等,J.Med.Chem.41:1631-1640(1998)。可用于本发明方法和组合物中的喜树碱衍生物的实例参见例如,以下美国专利:6,043,367;6,040,313;5,932,588;5,916,896;5,889,017;5,801,167;5,674,874;5,658,920;5,646,159;5,633,260;5,604,233;5,597,829;5,552,154;5,541,327;5,525,731;5,468,754;5,447,936;5,446,047;5,401,747;5,391,745;5,364,858;5,340,817;5,244,903;5,227,380;5,225,404;5,180,722;5,122,606;5,122,526;5,106,742;5,061,800;5,053,512;5,049,668;5,004,758;4,981,968;4,943,579;4,939,255;4,894,456;和4,604,463,每一个均在此引入作为参考。优选的拓扑异构酶抑制剂包括,但是不局限于,DX-8951f,依立替康,SN-38和其可药用的盐、溶剂化物、包合物、和前药。
法尼基转移酶抑制剂的实例包括,但是不限于,R115777,BMS-214662,(综述参见Caponigro,Anticancer Drugs 13(8):891-897(2002)),以及例如以下美国专利公开的那些:6,458,935,6,451,812,6,440,974,6,436,960,6,432,959, 6,420,387,6,414,145,6,410,541,6,410,539,6,403,581,6,399,615,6,387,905,6,372,747,6,369,034,6,362,188,6,342,765,6,342,487,6,300,501,6,268,363,6,265,422,6,248,756,6,239,140,6,232,338,6,228,865,6,228,856,6,225,322,6,218,406,6,211,193,6,187,786,6,169,096,6,159,984,6,143,766,6,133,303,6,127,366,6,124,465,6,124,295,6,103,723,6,093,737,6,090,948,6,080,870,6,077,853,6,071,935,6,066,738,6,063,930,6,054,466,6,051,582,6,051,574,6,040,305,所有这些均全文在此引入作为参考。
在本发明的一个实施方案中,第二活性剂是用于MPD基因疗法的药剂。例如,反义寡核苷酸可以阻断致癌基因的编码指令,从而使它不能指示形成相应的导致细胞转变成恶性细胞的癌蛋白质。反义寡核苷酸的实例包括但是不局限于,以下美国专利公开的那些:6,277,832,5,998,596,5,885,834,5,734,033,和5,618,709,所有这些均全文在此引入作为参考。
在本发明的另一个实施方案中,第二活性剂是蛋白质,其融合蛋白,或分泌蛋白质的疫苗,其中所述蛋白质是IL-2,IL-10,IL-12,IL-18,G-CSF,GM-CSF,EPO,或其药理学活性突变体或衍生物。在一些情况下,对本领域技术人员来说显而易见,不优选G-CSF、GM-CSF和EPO。例如,在不使用干细胞移植的方法中,不优选使用G-CSF、GM-CSF和EPO。在优选实施方案中,所述蛋白质是抗体或连接到化学毒素或放射性同位素上的抗体,它们在MPD患者中定靶到特定的过度生成的细胞上并将其消灭。
这种抗体包括但是不局限于,rituximab(Rituxan),刺孢霉素(calicheamycin)(Mylotarg),ibritumomab tiuxetan(Zevalin),和tositumomab(Bexxar)。
在本发明特定的实施方案中,第二活性剂是可以在MPD患者中诱导特定抗原的抗恶性细胞免疫应答的疫苗。这种疫苗的非限定性实例参见美国专利6,432,925,其在此引入作为参考。
在本发明的又一个实施方案中,第二活性剂是一种能够在MPD患者中逆转多种抗病性的药剂。在MPD患者中过度生成的细胞,其机理可能使得它们逃避化学疗法的杀伤作用。人们正在研究新的药剂来降低对于用在治疗白血病的重要化学治疗药物的抗药性。这种药剂的非限定性实例参见美国专利6,225,325,其在此引入作为参考。
可以与本发明结合使用的其它药剂包括但是不局限于,以下美国专利公开的那些:6,096,300,6,420,391,6,326,205,5,866,332,6,458,349,6,420,378,6,399,664,6,395,771,6,346,246,6,333,309,6,331,642,6,329,497,6,326,378,6,313,129,6,306,393,6,303,646,6,265,427,6,262,053,6,258,779,6,251,882,6,231,893,6,225,323,6,221,873,6,218,412,6,204,364,6,187,287,6,183,988,6,183,744,6,172,112,6,156,733,6,143,738,6,127,406,6,121,320,6,107,520,6,107,457,6,075,015,和6,063,814,所有这些均全文在此引入作为参考。
4.3治疗和控制方法
本发明的方法包括预防、治疗和/或控制各种类型MPD的方法。除非另作说明,这里使用的术语″治疗″和″预防″包括抑制或降低一种或多种与MPD有关的症状或实验结果的严重程度或数值大小。
与MPD有关的症状包括但是不局限于,头痛,眩晕,耳鸣,视力模糊,疲劳,盗汗,低烧,全身瘙痒,鼻出血,视力模糊,脾肿大,腹部胀满,血栓症,出血增加,贫血,脾梗塞,严重的骨骼疼痛,肝脏血细胞生成,腹水,食道静脉曲张,肝功能衰竭,呼吸窘迫,和阴茎异常勃起。与MPD有关的实验结果包括但是不局限于,过量生成一种或多种有形血液元素的多种可能性的造血祖细胞的克隆扩充(例如,红细胞计数增加,白细胞计数增加和/或血小板计数增加),存在费城染色体或bcr-abl基因,在外周血液的显微镜涂片上有泪状异形红细胞,异形成白红细胞增多的血液图象,巨大的异常血小板,具有网状或胶原蛋白纤维化的细胞过多的骨髓,以及具有低百分比前髓细胞和胚细胞的显著左移的脊髓系列。除非另作说明,这里使用的术语″治疗″是指在MPD症状出现之后给以组合物,而″预防″则是指在症状出现之前施用,特别对处于MPD危险之中的患者施用。除非另有陈述,这里使用的术语″控制″包括在已经遭受到MPD的患者中预防MPD的再发生,延长已经遭受到MPD的患者保持症状缓解的时间,和/或预防处于会遭受MPD的危险之中的患者发生MPD。
本发明包括治疗或预防具有原发和继发性MPD的患者的方法。它还包括治疗那些先前已经治疗过MPD的患者,以及那些先前没有治疗过MPD的患者的方法。因为具有MPD的患者具有异原的临床表现和不同的临床结果,因此,很显然,可能需要对患者根据其严重性和阶段,依照其预后和正在进行的疗法进行阶段划分。
实际上,本发明的方法和组合物可用在对具有一种或多种类型MPD的患者进行各种阶段的治疗,所述MPD类型包括但不限于,真性红细胞增多症(PRV),原发性血小板增多(PT),慢性骨髓性白血病(CML),以及原因不明的骨髓组织异生(AMM)。
本发明涉及的方法包括对遭受或可能遭受到MPD的患者(例如人)给以本发明选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。特定的患者群包括老年人,即,年龄为60岁和60岁以上以及超过35岁的人。具有家族MPD或白血病史的患者也是优选的预防疗法的候选者。
在本发明的一个实施方案中,用于这里所述的状况时,对选择性细胞因子抑制药物所推荐的日剂量范围为每天约1毫克到约10,000毫克,以一日一次的剂量施用,或者优选在一天中以分开的剂量施用。更具体地说,日剂量是每天以同样等分的剂量施用两次。具体地说,日剂量范围应该是每天约1毫克到约5,000毫克,更具体地说,为每天约10毫克到约2,500毫克,每天约100毫克到约800毫克,每天约100毫克到约1200毫克,或每天约25毫克到约2,500毫克。在对患者进行控制时,疗法应该是在开始时给以较低的剂量,也许是约1毫克到约2,500毫克,如果必要的话,根据患者的普遍应答情况,每天增加到最高达约200毫克到约5,000毫克,或者以单个剂量施用或者以分开的剂量施用。
在特定的实施方案中,3-(3,4-二甲氧基苯基)-3-(1-氧代-1,3-二氢异吲哚-2-基)-丙酰胺可以优选以每天约400、800、1,200、2,500、5,000或10,000毫克的量分两个等分剂量施用。
4.3.1与第二活性剂的组合疗法
本发明特定的方法包括给以:1)本发明的选择性细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药,和2)第二活性剂或活性成分。本发明的选择性细胞因子抑制药物的实例是在本发明中公开的(参见,例如,部分4.1),第二活性剂的实例在本发明中也有公开(参见,例如部分4.2)。
在特定的实施方案中,一种或多种选择性的细胞因子抑制药物将与一种或多种用来治疗、控制、或预防骨髓及外骨髓增殖疾病的疗法结合施用。非限定性的实例是将本发明的选择性细胞因子抑制药物与抗癌鸡尾酒疗法的施用结合使用,后者例如但不限于,包括阿糖胞苷和蒽环霉素(例如,柔红霉素或伊达比星)的疗法。
向患者给以选择性的细胞因子抑制药物和第二活性剂可以同时或顺序通过相同或不同的施用途径进行。用于特定活性剂的具体的施用途径适合与否将取决于活性剂本身(例如,它是否可以经口施用而不会在进入血流之前分解)和要治疗的疾病。选择性细胞因子抑制药物的优选的施用途径是口服。用于本发明第二活性剂或成分的优选的施用途径是本领域技术人员公知的,参见,例如,Plzysicians′Desk Reference,1755-1760(第56版,2002)。
在一个实施方案中,第二活性剂经静脉内或皮下施用,每天一或两次,施用量为约1-约1000毫克,约5-约500毫克,约10-约350毫克,或者约50-约200毫克。第二活性剂的具体用量将取决于使用的具体药剂、要治疗或控制的MPD的类型、MPD的严重性和阶段,以及本发明选择性细胞因子抑制药物的量和同时给予患者的任何任选的其它活性剂的量。在一个特定的实施方案中,第二活性剂是干扰素-α,羟基脲,阿那格雷,三氧化二砷,ST1571,imatinib甲磺酸盐,DX-8951f,R115777,长春新碱,柔红霉素,强的松或者其组合。干扰素-α的施用量为皮下施用2-5百万单位,每周3次。羟基脲的施用量为口服给以约500-约1500毫克/天,调节得使血小板保持低于500,000/微升,而不使中性粒细胞计数降低到<2000/微升。
4.3.2与移植疗法一起使用
在另一个实施方案中,本发明包括一种治疗、预防和/或控制MPD的方法,其包括与移植疗法结合给以本发明的选择性细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。如本发明其它地方讨论的那样,MPD的治疗基于疾病的阶段和机理。因为在MPD的一定阶段会不可避免地向白血病转化发展,所以可能需要外周血液干细胞、造血干细胞制剂或骨髓移植。本发明的选择性细胞因子抑制药物和移植疗法的联用会提供独特的和出乎意外的协同作用。尤其是,本发明选择性的细胞因子抑制药物显示出免疫调节活性,当同时与移植疗法一起用于具有MPD的患者时,可以提供另外的或协同的效应。本发明选择性的细胞因子抑制药物可以与移植疗法结合使用,以减少与移植植入方法有关的并发症和有关移植物抗宿主疾病(GVHD)危险。因此,本发明包括一种治疗、预防和/或控制MPD的方法,其包括在脐带血、胎盘血、外周血液干细胞、造血干细胞制剂或者骨髓移植之前、过程中或之后,给予患者(例如人)本发明的选择性细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。适合用于本发明方法中的干细胞的实例参见R.Hariri等人于2002年4月12日提交的美国临时专利申请60/372,348,其全部内容在此引入作为参考。
4.3.3循环疗法
在某些实施方案中,本发明的预防或者治疗剂被循环给予患者。循环疗法包括给以活性剂一段时间,然后停止一段时间,之后重复这种顺序施用。循环疗法可以降低对于一种或多种疗法的抗药性的发展,避免或者降低一种疗法的副作用,和/或提高所述治疗效能。
因此,在本发明的一个特定的实施方案中,本发明的选择性细胞因子抑制药物每天以单一或等分剂量施用4-6周,然后停止一周或两周。本发明还允许增加剂量循环的频率、数目和长度。因此,本发明的另一个特定的实施方案包括,与单独施用时典型的循环相比,把本发明选择性的细胞因子抑制药物施用更多的循环。在本发明又一个特定的实施方案中,本发明选择性的细胞因子抑制药物施用周期数将更大,这样的周期数通常将在不给以第二活性成分的患者中产生有剂量限定的毒性。
在一个实施方案中,本发明的选择性细胞因子抑制药物每天施用并连续用药3或4周,剂量为约0.1-约150毫克/天,之后停止一两周。
在本发明的一个实施方案中,本发明的选择性细胞因子抑制药物和第二活性成分口服施用,在4-6周的循环过程中,先给以本发明的选择性细胞因子抑制药物,30-60分钟之后给以第二活性成分。在本发明的另一个实施方案中,每一循环在约90分钟的时间内,通过静脉内输液给以本发明选择性的细胞因子抑制药物和第二活性成分的组合。通常,在向患者给以组合治疗的过程中,循环数将为约1-约24个循环,更通常是约2-约16个循环,甚至更通常是约4-约8个循环。
4.4药物组合物和单一单位剂型
药物组合物可用于制备单独的单一单位剂型。本发明的药物组合物和剂型包括选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。本发明的药物组合物和剂型还可以包括一种或多种赋形剂。
本发明的药物组合物和剂型也可以包括一种或多种另外的活性成分。因此,本发明的药物组合物和剂型包括本发明中公开的活性成分(例如,选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物或前药、和第二活性成分)。任选的另外的活性成分的实例在本发明中也有公开(参见,例如部分4.2)。
本发明的单一单位剂型适合于经口服,粘膜(例如,鼻、舌下、阴道、口腔、或直肠),或胃肠外(例如,皮下、静脉内、快速浓注、肌内、或动脉内),透皮或经皮施用给患者。剂型的实例包括但是不局限于:片剂;囊片;胶囊,例如软弹性胶囊;扁囊剂;锭剂;糖锭;分散液;栓剂;粉末;气雾剂(例如,鼻喷入剂或吸入剂);凝胶剂;适合于口服或粘膜施用与患者的液体剂型,包括混悬剂(例如,水或非水液体混悬剂,水包油乳液,或油包水液体乳液),溶液,和酏剂;适合于胃肠外给以患者的液体剂型;和可以重新组成以提供适合于肠胃外施用的液体剂型的无菌固体(如,晶体或无定形固体)。
本发明剂型的组成、形状、和类型通常将取决于它们的用途。例如,用于急性治疗疾病的剂型可以包含,比用于慢性治疗相同病的剂型更大量的一种或多种活性成分。类似地,胃肠处的剂型可以包含比用于治疗相同疾病的口服剂型较小量的一种或多种活性成分。本发明所包括的特定剂型的这些和其它的方式将彼此不同,并且对本领域技术人员来说将是显而易见的,参见,例如,Remington′sPharmaceutical Scienees,第18版,Mack Publishing,EastonPA(1990)。
典型的药物组合物和剂型包括一种或多种赋形剂。适当的赋形剂对制药领域的技术人员来说是众所周知的,在本发明中提供其非限定性的实例。特定的赋形剂是否适合于引入到药物组合物或剂型中将取决于本领域众所周知的许多因素,其包括但不限于,如何将剂型给予患者的方式。例如,口服剂型,如片剂可以包含不适合用于胃肠外剂型中的赋形剂。特定的赋形剂适合与否也可能取决于剂型中具体的活性成分。例如,某些赋形剂如乳糖、或者当暴露于水时,可能会加速某些活性成分的分解。包括伯或仲胺的活性成分特别容易受到这种加速分解的影响。因此,本发明包括含有,如果有的话,很少量乳糖(和)其它单或二糖的药物组合物和剂型。这里使用的术语″不含乳糖″意思指,即使有,乳糖的存在量也不足以基本上增加活性成分的降解速率。
本发明不含乳糖的组合物可以包括本领域众所周知的赋形剂,其列于,例如美国药典(USP)25-NF 20(2002)。一般说来,不含乳糖的组合物以药学上相容的和可药用的量包括活性成分,粘合剂/填料,润滑剂。优选的不含乳糖的剂型包括活性成分,微晶纤维素,预糊化的淀粉,和硬脂酸镁。
本发明进一步包括包含活性成分的无水药物组合物和剂型,因为水可能会促进某些化合物的降解。例如,为了测定特性如贮藏期限或配方随着时间的稳定性,把加入水(例如5%)作为模拟长期存放的方式是药物领域普遍接受的。参见,例如,Jens T.Carstensen,DrugStability:Principles & Practice,第2版,Marcel Dekker,NY,1995,379-80页。事实上,水和加热都会促进某些化合物的分解。因此,水在配方中的作用可能是非常重要的,因为水分和/或湿度是配方制造、操作、包装、储存、装运、和使用过程中经常会遇到的。
本发明的无水药物组合物和剂型可以使用无水或包含低水分的成分和低水分或低湿度条件制备。如果预计在制造、包装和/或储存过程中会相当多地与水分和/或湿度接触时,包括乳糖和至少一种含有伯或仲胺的活性成分的药物组合物和剂型优选是无水的。
无水药物组合物的制备和储存应该使得它保持其无水的性质。因此,对无水组合物,优选使用能防止其暴露于水的材料包装,以便使它们能够包括在适当的配方试剂盒中。适当的包装的实例包括但是不局限于,气密箔,塑料,单位剂量容器(例如,管瓶),泡罩包装,和条带包装。
本发明进一步包括含有一种或多种能降低活性成分分解速率的化合物的药物组合物和剂型。这种化合物,在本发明中被称为″稳定剂″,其包括但是不局限于,抗氧化剂如抗坏血酸,pH值缓冲剂,或盐缓冲剂。
像赋形剂的量和类型一样,剂型中活性成分的量和具体的类型也会取决于多个因素,例如但不限于,所述剂型被给予患者的途径。但是,本发明典型的剂型是以约1-约1,200毫克的量包括选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。典型的剂型是以约1、2、5、10、25、50、100、200、400、800、1,200、2,500、5,000或10,000毫克的量包括选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。在特定的实施方案中,优选的剂型是以约400、800或1,200毫克的量包括3-(3,4-二甲氧基苯基)-3-(1-氧代-1,3-二氢异吲哚-2-基)-丙酰胺。典型的剂型包括含量为1-约1000毫克,约5-约500毫克,约10-约350毫克,或约50-约200毫克的第二活性成分。当然,第二活性成分的具体用量将取决于使用的具体的药剂,要治疗或控制的MPD类型,和选择性细胞因子抑制药物的量以及同时给予患者的任何任选的另外的活性剂的量。
4.4.1口服剂型
适合于口服的本发明的药物组合物可以以离散剂型存在,例如但不限于,片剂(例如,嚼片),囊片,胶囊,和液体(例如,矫味糖浆)。这种剂型包含预定量的活性成分,并可以通过本领域技术人员公知的制药方法制备。通常参见,Remington′s Pharmaceutical Sciences,第18版,Mack Publishing,Easton PA(1990)。
本发明典型的口服剂型是通过以紧密混合物的形式将活性成分与至少一种赋形剂根据通用的药物配合技术结合在一起来制备。根据希望施用的制剂形式,赋形剂可以呈各式各样的形式。例如,适合用于口服液体或气雾剂剂型的赋形剂包括,但是不局限于,水,二醇,油,醇,矫味剂,防腐剂,和着色剂。适合用于固体口服剂型(例如,粉末、片剂、胶囊、和囊片)的赋形剂的实例包括但是不局限于,淀粉,糖,微结晶纤维素,稀释剂,成粒剂,润滑剂,粘合剂,和崩解剂。
因为它们施用容易,所以片剂和胶囊是最有利的口服单位剂型,在这种情况下使用固体赋形剂。如果希望的话,片剂可以通过标准的水或非水方法包衣。这种剂型可以通过任何制药方法制备。一般说来,药物组合物和剂型是通过将活性成分与液态载体、细分散的固态载体、或两者均匀而紧密地混合,然后如果必要的话,将产品成型为希望的形状来制备的。
例如,片剂可以通过压缩或模塑来制备。压制片可以通过在适当的机器中压缩自由流动形式,例如粉末或颗粒的、任选与赋形剂混合的活性成分来制备。模制片可以通过在适当的机器中把湿润的粉末状化合物与惰性液体稀释剂的混合物进行模塑来制备。
可用于本发明口服剂型的赋形剂的实例包括但是不局限于,粘合剂,填充剂,崩解剂,和润滑剂。适合用于药物组合物和剂型中的粘合剂包括但是不局限于,玉米淀粉,马铃薯淀粉,或其它淀粉,明胶,天然和合成的树胶例如阿拉伯胶,海藻酸钠,海藻酸,其它藻朊酸盐,粉末状黄蓍胶,瓜尔胶,纤维素及其衍生物(例如,乙基纤维素、纤维素醋酸酯、羧甲基纤维素钙、羧甲基纤维素钠),聚乙烯基吡咯烷酮,甲基纤维素,预糊化的淀粉,羟丙基甲基纤维素(例如,2208、2906、2910),微晶纤维素,和其混合物。
微晶纤维素的适当形式包括但是不局限于,以AVICEL-PH-101、AVICEL-PH-103、AVICEL-RC-581、AVICEL-PH-105销售的物质(得自FMC Corporation,American Viscose Division,Avicel Sales,Marcus Hook,PA),和其混合物。具体的粘合剂是以AVICEL-RC-581销售的微晶纤维素和羧甲基纤维素钠的混合物。适当的无水或低水分赋形剂或添加剂包括AVICEL-PH-103TM和Starch 1500 LM。
适合用于本发明公开的药物组合物和剂型中的填充剂的实例包括但是不局限于,滑石粉,碳酸钙(例如,颗粒或粉末),微晶纤维素,粉末状纤维素,葡萄糖结合剂,高岭土,甘露糖醇,硅酸,山梨糖醇,淀粉,预糊化的淀粉,和其混合物。本发明药物组合物中的粘合剂或填充剂通常的存在量为药物组合物或剂型的约50-约99重量%。
在本发明的组合物中使用崩解剂,是用来在片剂暴露于水相环境中时使片剂崩解。包含太多崩解剂的片剂可能会在储藏时崩解,而包含太少崩解剂的片剂则有可能不会以希望的速率崩解或者不会在希望的条件下崩解。因此,应该使用既不太多也不太少的、不会不利地改变活性成分释放的充分量的崩解剂来形成本发明的固体口服剂型。使用的崩解剂的量将随着配方类型不同而不同,并且对本领域普通技术人员来说会很容易觉察到。典型的药物组合物包括约0.5-约15重量%的崩解剂,优选约1-约5重量%的崩解剂。
可用于本发明药物组合物和剂型中的崩解剂包括但是不局限于,琼脂,海藻酸,碳酸钙,微晶纤维素,交联羧甲基纤维素钠,交聚维酮,波拉克林钾,淀粉羟基乙酸钠,马铃薯或木薯淀粉,其它淀粉,预糊化的淀粉,其它淀粉,粘土,其它褐藻胶,其它纤维素,树胶,和其混合物。
可用于本发明药物组合物和剂型中的润滑剂包括但是不局限于,硬脂酸钙,硬脂酸镁,矿物油,轻质矿物油,甘油,山梨糖醇,甘露糖醇,聚乙二醇,其它二醇,硬脂酸,月桂基硫酸钠,滑石粉,氢化植物油(例如,花生油、棉子油、葵花油、芝麻油、橄榄油、玉米油、和豆油),硬脂酸锌,油酸乙酯,月桂酸乙酯,琼脂,和其混合物。另外的润滑剂包括,例如,胶态硅胶(AEROSIL 200,W.R.GraceCo,Baltimore,MD制造,凝聚的合成二氧化硅气雾剂(由DegussaCo.,Plano,TX销售),CAB-O-SIL(热解二氧化硅产品,由Cabot Co.,Boston,MA销售),和其混合物。如果完全使用,润滑剂的通常用量为低于它们所引入的药物组合物或剂型的约1重量%。
本发明优选的固体口服剂型包括选择性的细胞因子抑制药物,无水乳糖,微晶纤维素,聚乙烯吡咯烷酮,硬脂酸,胶态无水二氧化硅,和明胶。
4.4.2延迟释放剂型
本发明的活性成分可以以受控释放方式或通过本领域普通技术人员众所周知的输送装置施用。实例包括但是不局限于,以下美国专利描述的那些:3,845,770;3,916,899;3,536,809;3,598,123;和4,008,719,5,674,533,5,059,595,5,591,767,5,120,548,5,073,543,5,639,476,5,354,556,和5,733,566,每一个均在此引入作为参考。这种剂型可用于提供一种或多种活性成分的缓慢或受控释放,其使用,例如羟丙基甲基纤维素、其它的聚合基质、凝胶剂、渗透膜、渗透性体系、多层涂层、微粒、脂质体、微球体、或其组合来提供不同比例的释放分布图。为了用在本发明的活性成分上,本领域普通技术人员公知的适当的受控释放配方,包括本发明中描述的那些,可以很容易地选择。因此,本发明包括适合于口服的单一单位剂型,例如但不限于,适合于受控释放的片剂、胶囊、凝胶胶囊、和囊片。
所有受控释放的药物产品都有一个共同的目标,就是获得比非受控对应部分提高的药物疗法。理想的是,在药物治疗中使用的最佳设计的受控释放制剂,其特征在于使用最少的药物物质来在最短的时间内医治或控制所述状况。受控释放配方优点包括药物活性延长,剂量频率降低,和患者顺应性增加。另外,受控释放配方可用于影响作用开始的时间或其它特性,例如药物的血液水平,因此可以影响副(例如,不利)作用的发生。
大多数受控释放配方被设计成最初释放适量的能立即产生希望的治疗作用的药物(活性成分),然后逐步并不断地释放其它量的药物以在持续的时间期限内保持治疗或预防作用的水平。为了在身体内保持恒定的药物浓度,药物必须以将能代替被代谢和排出体外的药物的量的速度从剂型中释放出来。活性成分的受控释放可以被各种条件促进,其包括但不限于,pH值,温度,酶,水,或其它生理条件或化合物。
4.4.3胃肠外的剂型
胃肠外的剂型可以通过各种途径给予患者,其包括但不限于,皮下、静脉内(包括快速浓注)、肌内、和动脉内。因为它们的施用通常绕过患者对于杂质的防御,因此,胃肠外的剂型优选是无菌的,或者在对患者施用之前能够被消毒。胃肠外剂型的实例包括但是不局限于,准备用于注射的溶液、准备溶解或悬浮在可药用的注射介质中的干燥产品、准备用于注射的混悬剂、和乳液。
可用于提供本发明胃肠外剂型的适当的介质对本领域技术人员来说是众所周知。实例包括,但是不局限于:注射用水USP;水介质,例如但不限于,氯化钠注射液,Ringer′s注射液,葡萄糖注射液,葡萄糖和氯化钠注射液,以及乳酸盐化的Ringer′s注射液;可与水混溶的介质,例如但不限于,乙醇,聚乙二醇,和聚丙二醇;和非水介质,例如但不限于,玉米油,棉子油,花生油,芝麻油,油酸乙酯,肉豆蔻酸异丙酯,和苯甲酸苄酯。
增加本发明中公开的一种或多种活性成分溶解性的化合物也可以引入到本发明的胃肠外剂型中。例如,环糊精及其衍生物可用于增加选择性细胞因子抑制药物及其衍生物的溶解性。参见,例如,美国专利5,134,127,其在此引入作为参考。
4.4.4局部和粘膜剂型
本发明的局部和粘膜剂型包括但是不局限于,喷雾剂,气雾剂,溶液,乳液,混悬剂,或本领域技术人员公知的其它形式。参见,例如,Remington′s Pharmaceutical Sciences,第16版和18版,MackPublishing,Easton PA(1980 & 1990);和Introduction toPharmaceutical Dosage Forms,第4版,Lea & Febiger,Philadelphia(1985)。适合于治疗口腔内粘膜组织的剂型可以配制成嗽口水或口服凝胶剂的形式。
适当的赋形剂(例如,载体和稀释剂)及其它可用于提供本发明包括的局部和粘膜剂型的物质是药物技术领域普通技术人员众所周知的,并且取决于给定药物组合物或剂型将施用的特定的组织。考虑到这一点,典型的赋形剂包括但是不局限于,用于形成溶液、乳液或凝胶剂的水,丙酮,乙醇,乙二醇,丙二醇,1,3-丁二醇,肉豆蔻酸异丙酯,棕榈酸异丙酯,矿物油,和其混合物,它们是无毒的,并且是可药用的。如果希望的话,也可以将增湿剂或湿润剂加入到药物组合物和剂型中。这种另外的成分的实例是本领域众所周知的,参见,例如,Remington′s Pharmaceutical Sciences,第16和18版,Mack Publishing,Eaton PA(1980 & 1990)。
也可以调节药物组合物或剂型的pH值,以改进一种或多种活性成分的递送。类似地,为了改进递送,可以调节溶剂载体的极性、其离子强度、或渗透压。化合物,例如硬脂酸酯也可以加入到药物组合物或剂型中,以便有利地改变一种或多种活性成分的亲水性或亲油性以改进递送。在这点上,硬脂酸酯可以起到用于配制的脂质介质的作用,作为乳化剂或表面活性剂,和作为递送增强或渗透增强剂。不同的活性成分的盐、水合物或溶剂化物可用于进一步调节所得组合物的性质。
4.4.5试剂盒
通常,本发明的活性成分优选不同时或以相同的施用途径给予患者。因此,本发明包括试剂盒,当由执业医生使用时,它们可以简化对患者给以适当量的活性成分。
本发明典型的试剂盒包括一种剂型的选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。本发明涉及的试剂盒可以进一步包括另外的活性成分,例如但不限于,干扰素-α,羟基脲,阿那格雷,三氧化二砷,ST1571,imatinib甲磺酸盐,DX-8951f,R115777,长春新碱,柔红霉素,强的松,或其药理学上活性的突变体或衍生物,或其组合。另外的活性成分的实例包括但是不局限于,本发明中公开的那些(参见,例如,部分4.2)。
本发明的试剂盒可以进一步包括用来给以活性成分的设备。这种设备的实例包括但是不局限于,注射器,滴袋,贴片,和吸入器。
本发明的试剂盒可以进一步包括用于移植的细胞或血液以及可用于给以一种或多种活性成分的可药用的介质。例如,如果活性成分是在用于肠胃外施用时必须重新组成的固态形式,则试剂盒可以包括适当介质的密封容器,其中活性成分可以溶解其中形成适合于肠胃外施用的无颗粒的无菌溶液。可药用的介质的实例包括但是不局限于:注射用水USP;水介质,例如但不限于,氯化钠注射液,Ringer′s注射液,葡萄糖注射液,葡萄糖和氯化钠注射液,以及乳酸盐化的Ringer′s注射液;可与水混溶的介质,例如但不限于,乙醇,聚乙二醇,和聚丙二醇;和非水介质,例如但不限于,玉米油,棉子油,花生油,芝麻油,油酸乙酯,肉豆蔻酸异丙酯,和苯甲酸苄酯。
5.实施例
以下研究旨在进一步举例说明本发明而不限定其范围。
5.1药理学和毒理学研究
进行一系列非临床的药理学和毒理学研究,以支持选择性细胞因子抑制药物在受试验的人中的临床评价。
除非另有说明,这些研究根据国际上承认的研究设计准则进行,并遵照良好实验室操作规范(Good Laboratory Practice(GLP))的要求。
在体外试验中表征3-(3,4-二甲氧基苯基)-3-(1-氧代-1,3-二氢异吲哚-2-基)-丙酰胺的药理学性质,包括与沙利度胺的活性比较。研究检测3-(3,4-二甲氧基苯基)-3-(1-氧代-1,3-二氢异吲哚-2-基)-丙酰胺在产生各种细胞因子方面的作用。
另外,在狗身上进行3-(3,4-二甲氧基苯基)-3-(1-氧代-1,3-二氢异吲哚-2-基)-丙酰胺的安全药理学研究,并进一步检测化合物对ECG参数的影响作为灵长目3个重复剂量毒性研究的一部分。
5.2调节细胞因子的生成
在人体PBMC和人类全血的LPS-刺激后,体外研究3-(3,4-二甲氧基苯基)-3-(1-氧代-1,3-二氢异吲哚-2-基)-丙酰胺抑制产生TNF-α的效果(Muller等人,Bioorg.Med.Chem.Lett.,9:1625-1630,1999)。测定在人体PBMC和人类全血的LPS-刺激后,3-(3,4-二甲氧基苯基)-3-(1-氧代-1,3-二氢异吲哚-2-基)-丙酰胺用于抑制TNF-α产生的IC50值。
5.3毒理学研究
在麻醉的狗身上研究3-(3,4-二甲氧基苯基)-3-(1-氧代-1,3-二氢异吲哚-2-基)-丙酰胺对心血管和呼吸机能的影响。使用两组小猎兔犬(2只/性别/组)。一组只接收3个剂量的介质,另一组接收3个增加剂量的3-(3,4-二甲氧基苯基)-3-(1-氧代-1,3-二氢异吲哚-2-基)-丙酰胺(400,800,和1,200毫克/公斤/天)。在所有的情况下,3-(3,4-二甲氧基苯基)-3-(1-氧代-1,3-二氢异吲哚-2-基)-丙酰胺或介质的剂量都是连续地通过颈静脉输液施用,施用间隔至少30分钟。
与介质对照组相比较,在所有的剂量下,3-(3,4-二甲氧基苯基)-3-(1-氧代-1,3-二氢异吲哚-2-基)-丙酰胺诱导的心血管和呼吸变化都是最小的。
这里提到的所有专利均全文引入作为参考。在这里描述的本发明的实施方案只是本发明范围的一种示例。本发明完全的范围最好参考所附的权利要求进行理解。
Claims (40)
1.治疗或预防骨髓增生性疾病的方法,其包括给予需要这种治疗或预防的患者治疗或预防有效量的选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。
2.控制骨髓增生性疾病的方法,其包括给予需要这种控制的患者预防有效量的选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。
3.治疗或预防骨髓增生性疾病的方法,其包括给予需要这种治疗或预防的患者治疗或预防有效量的选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药,和治疗或预防有效量的至少一种第二活性剂。
4.控制骨髓增生性疾病的方法,其包括给予需要这种控制的患者预防有效量的本发明选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药,和治疗或预防有效量的至少一种第二活性剂。
5.权利要求1-4任何一项的方法,其中所述患者难以用通用的骨髓增生性疾病治疗法治疗。
6.权利要求1-4任何一项的方法,其中所述患者难以用包括沙利度胺的骨髓增生性疾病治疗法治疗。
7.权利要求3或4的方法,其中第二活性剂能够抑制过量生成造血干细胞或者使骨髓增生性疾病的一种或多种症状得到改善。
8.权利要求3或4的方法,其中,第二活性剂是细胞因子、皮质甾类、核糖核苷酸还原酶抑制剂、血小板抑制剂、抗凝剂、溶解血栓剂、抗纤维化剂、全反式视黄酸、激酶抑制剂、拓扑异构酶抑制剂、法尼基转移酶抑制剂、反义寡核苷酸、抗体、用于逆转多药耐药性的药剂、疫苗、骨髓抑制剂或抗癌药。
9.权利要求8的方法,其中,第二活性剂是干扰素-α,羟基脲,阿那格雷,白消安,三氧化二砷,ST1571,imatinib甲磺酸盐,DX-8951f,R115777,长春新碱,柔红霉素,强的松,或其药理学上活性的突变体或衍生物,或者其组合。
10.权利要求1-4任何一项的方法,其中所述骨髓增生性疾病是真性红细胞增多症,原发性血小板增多,慢性骨髓性白血病或原因不明的骨髓组织异生。
11.权利要求1-4任何一项的方法,其中,骨髓增生性疾病是原发性或继发性的。
12.权利要求1-4任何一项的方法,其中,选择性的细胞因子抑制药物是3-(3,4-二甲氧基苯基)-3-(1-氧代-1,3-二氢异吲哚-2-基)-丙酰胺。
13.权利要求12的方法,其中选择性的细胞因子抑制药物是对映异构纯的。
14.权利要求1-4任何一项的方法,其中,选择性的细胞因子抑制药物是{2-[1-(3-乙氧基-4-甲氧基苯基)-2-甲磺酰基-乙基]-3-氧代-2,3-二氢-1H-异吲哚-4-基}-环丙甲酰胺。
15.权利要求14的方法,其中选择性的细胞因子抑制药物是对映异构纯的。
16.权利要求1-4任何一项的方法,其中,选择性的细胞因子抑制药物具有下式(I):
其中n值为1、2或3;
R5是邻-亚苯基,其是未取代的或被1-4个取代基取代,所述每一个取代基都独立地选自硝基,氰基,三氟甲基,乙氧甲酰基,甲氧甲酰基,丙氧甲酰基,乙酰基,氨基甲酰基,乙酰氧基,羧基,羟基,氨基,烷氨基,二烷基氨基,酰胺基,1-10个碳原子的烷基,1-10个碳原子的烷基,和卤素,
R7是(i)苯基或被一个或多个取代基取代的苯基,其中所述取代基各自独立地选自硝基,氰基,三氟甲基,乙氧甲酰基,甲氧甲酰基,丙氧甲酰基,乙酰基,氨基甲酰基,乙酰氧基,羧基,羟基,氨基,1-10个碳原子的烷基,1-10个碳原子的烷氧基,和卤素,(ii)未取代的或被1-3个取代基取代的苄基,所述取代基选自硝基,氰基,三氟甲基,乙氧甲酰基,甲氧甲酰基,丙氧甲酰基,乙酰基,氨基甲酰基,乙酰氧基,羧基,羟基,氨基,1-10个碳原子的烷基,1-10个碳原子的烷氧基,和卤素,(iii)萘基,和(iv)苄氧基;
R12是-OH,1-12个碳原子的烷氧基,或
R8是氢或1-10个碳原子的烷基;和
R9是氢,1-10个碳原子的烷基,-COR10,或-SO2R10,其中R10是氢、1-10个碳原子的烷基、或苯基。
17.权利要求16的方法,其中选择性的细胞因子抑制药物是对映异构纯的。
18.权利要求1-4任何一项的方法,其中,选择性的细胞因子抑制药物具有下式(II):
其中,R1和R2,当彼此独立时,各自为氢,低级烷基,或者,当与其连接的所述的碳原子合起来时,R1和R2是邻亚苯基,邻亚萘基,或环己烯-1,2-二基,其为未取代的或被1-4个取代基取代,所述取代基各自独立地选自硝基,氰基,三氟甲基,乙氧甲酰基,甲氧甲酰基,丙氧甲酰基,乙酰基,氨基甲酰基,乙酰氧基,羧基,羟基,氨基,烷基氨基,二烷基氨基,酰胺基,1-10个碳原子的烷基,1-10个碳原子的烷氧基,和卤素;
R3是被1-4个取代基取代的苯基,所述取代基选自硝基,氰基,三氟甲基,乙氧甲酰基,甲氧甲酰基,丙氧甲酰基,乙酰基,氨基甲酰基,乙酰氧基,羧基,羟基,氨基,1-10个碳原子的烷基,1-10个碳原子的烷氧基,1-10个碳原子的烷硫基,苄氧基,3-6个碳原子的环烷氧基,C4-C6-环亚烷基甲基,C3-C10亚烷基甲基,茚满氧基,和卤素;
R4是氢,1-6个碳原子的烷基,苯基,或苄基;
R4′是氢或1-6个碳原子的烷基;
R5是-CH2-,-CH2-CO-,-SO2-,-S-,或-NHCO-;和
n的值为0、1、或2。
19.权利要求18的方法,其中选择性的细胞因子抑制药物是对映异构纯的。
20.权利要求1-4任何一项的方法,其中,选择性的细胞因子抑制药物具有下式(III):
其中,标有*的碳原子构成手性中心;
Y是C=O,CH2,SO2,或CH2C=O;
R1、R2、R3、和R4中的每一个均彼此独立地为氢,卤素,1-4个碳原予的烷基,1-4个碳原子的烷氧基,硝基,氰基,羟基,或-NR8R9;或者相邻碳原子上的R1、R2、R3和R4中的任何两个和所述的亚苯基环一起,为亚萘基;
R5和R6中的每一个均彼此独立地为氢,1-4个碳原子的烷基,1-4个碳原子的烷氧基,氰基,或多达18个碳原子的环烷氧基;
R7是羟基,1-8个碳原子的烷基,苯基,苄基,或-NR8′R9′;
R8和R9中的每一个彼此独立地为氢,1-8个碳原子的烷基,苯基,或苄基,或者R8和R9中的一个是氢,另一个是-COR10或-SO2R10,或者R8和R9合起来是四亚甲基,五亚甲基,六亚甲基,或-CH2CH2X1CH2CH2-,其中,X1是-O-,-S-或-NH-;和
R8′和R9′中的每一个彼此独立地为氢,1-8个碳原子的烷基,苯基,或苄基,或者R8′和R9′中的一个是氢,另一个是-COR10′或-SO2R10′,或者R8′和R9′合起来是四亚甲基,五亚甲基,六亚甲基,或-CH2CH2X2CH2CH2-,其中,X2是-O-,-S-或-NH-。
21.权利要求20的方法,其中,选择性的细胞因子抑制药物是对映异构纯的。
22.治疗、预防或控制骨髓增生性疾病的方法,其包括在患者中进行脐带血、胎盘血、外周血液干细胞、造血干细胞制剂或者骨髓移植之前、过程中或之后,给予需要这种治疗、预防或控制的患者治疗或预防有效量的选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。
23.在遭受到骨髓增生性疾病的患者中降低或避免与使用第二活性剂有关的副作用的方法,其包括给予需要这种降低或避免的患者治疗或预防有效量的选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。
24.权利要求23的方法,其中第二活性剂能够抑制过量生成造血干细胞或者使骨髓增生性疾病的一种或多种症状得到改善。
25.权利要求23的方法,其中第二活性剂是细胞因子、皮质甾类、核糖核苷酸还原酶抑制剂、血小板抑制剂、抗凝剂、溶解血栓剂、抗纤维化剂、全反式视黄酸、激酶抑制剂、拓扑异构酶抑制剂、法尼基转移酶抑制剂、反义寡核苷酸、抗体、用于逆转多药耐药性的药剂、疫苗、骨髓抑制剂或抗癌药。
26.权利要求25的方法,其中第二活性剂是干扰素-α,羟基脲,阿那格雷,白消安,三氧化二砷,ST1571,imatinib甲磺酸盐,DX-8951f,R115777,长春新碱,柔红霉素,强的松,其药理学上活性的突变体或衍生物。
27.权利要求23的方法,其中副作用是转化为急性白血病;严重的骨髓抑制;胃肠毒性;胃肠出血;恶心;呕吐;厌食症;白血球减少症;贫血;嗜中性白血球减少症;乏力;腹部痉挛;发烧;疼痛;体重减轻;脱水;脱发;呼吸困难;失眠;眩晕;粘膜炎;口干症;粘膜与皮肤损害;或肾衰竭。
28.增加骨髓增生性疾病治疗效能的方法,其包括给予需要这种治疗效能增加的患者治疗有效量的选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药,和治疗或预防有效量的第二活性剂。
29.权利要求28的方法,其中,在向患者给以第二活性剂之前,给以治疗有效量的选择性的细胞因子抑制药物、或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。
30.权利要求28的方法,其中,在向患者给以第二活性剂的过程中,给以治疗有效量的选择性的细胞因子抑制药物、或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。
31.权利要求28的方法,其中,向患者给以第二活性剂之后,给以治疗有效量的选择性的细胞因子抑制药物、或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药。
32.一种药物组合物,其包括有效量的用以治疗、预防或控制骨髓增生性疾病的选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药,和载体。
33.一种药物组合物,其包括选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药和第二活性剂。
34.权利要求33的药物组合物,其中第二活性剂能够抑制过量生成造血干细胞或者使骨髓增生性疾病的一种或多种症状得到改善。
35.权利要求33的药物组合物,其中,第二活性剂是细胞因子、皮质甾类、核糖核苷酸还原酶抑制剂、血小板抑制剂、抗凝剂、溶解血栓剂、抗纤维化剂、全反式视黄酸、激酶抑制剂、拓扑异构酶抑制剂、法尼基转移酶抑制剂、反义寡核苷酸、抗体、用于逆转多药耐药性的药剂、疫苗、骨髓抑制剂或抗癌药。
36.权利要求35的药物组合物,其中,第二活性剂是干扰素-α,羟基脲,阿那格雷,白消安,三氧化二砷,ST1571,imatinib甲磺酸盐,DX-8951f,R115777,长春新碱,柔红霉素,强的松,或其药理学上活性的突变体或衍生物,或者其组合。
37.一种试剂盒,其包括:
包括选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药的药物组合物;和
包括能够逆转抑制过量生成造血干细胞的第二活性剂的药物组合物。
38.一种试剂盒,其包括:
包括选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药的药物组合物;和
脐带血,胎盘血,外周血液干细胞,造血干细胞制剂或骨髓。
39.一种试剂盒,其包括:
包括选择性的细胞因子抑制药物,或其可药用的盐、溶剂化物、水合物、立体异构体、包合物、或前药的药物组合物;
包括第二活性剂的药物组合物,其中第二活性剂是细胞因子,皮质甾类,核糖核苷酸还原酶抑制剂,血小板抑制剂,抗凝剂,溶解血栓剂,抗纤维化剂,全反式视黄酸,激酶抑制剂,拓扑异构酶抑制剂,法尼基转移酶抑制剂,反义寡核苷酸,抗体,用于逆转多药耐药性的药剂,疫苗,骨髓抑制剂或抗癌药;和
脐带血,胎盘血,周围血液干细胞,造血干细胞制剂或骨髓。
40.权利要求37-39任何一项的试剂盒,其进一步包括用于施用药物组合物或单一单位剂型的设备。
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WO2021036937A1 (zh) * | 2019-08-23 | 2021-03-04 | 中国科学院上海药物研究所 | Pde3抑制剂与细胞因子联合治疗肿瘤的应用 |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2021036937A1 (zh) * | 2019-08-23 | 2021-03-04 | 中国科学院上海药物研究所 | Pde3抑制剂与细胞因子联合治疗肿瘤的应用 |
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MXPA05004777A (es) | 2005-07-22 |
JP2006507324A (ja) | 2006-03-02 |
CA2505003A1 (en) | 2004-05-27 |
WO2004043336A3 (en) | 2004-07-29 |
WO2004043336A2 (en) | 2004-05-27 |
KR20050072790A (ko) | 2005-07-12 |
EP1569903A2 (en) | 2005-09-07 |
BR0316002A (pt) | 2005-09-13 |
EP1569903A4 (en) | 2009-07-29 |
NZ540384A (en) | 2008-06-30 |
AU2003226361B2 (en) | 2009-01-22 |
IL168444A (en) | 2010-12-30 |
ZA200503653B (en) | 2006-08-30 |
AU2003226361A1 (en) | 2004-06-03 |
US20060165649A1 (en) | 2006-07-27 |
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