CN1680367A - 取代的2－（2,6－二氧哌啶－3－基)－邻苯二甲酰亚胺和－1－氧异二氢吲哚及降低肿瘤坏死因子α水平的方法 - Google Patents
取代的2－（2,6－二氧哌啶－3－基)－邻苯二甲酰亚胺和－1－氧异二氢吲哚及降低肿瘤坏死因子α水平的方法 Download PDFInfo
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Abstract
本发明涉及可降低哺乳动物体内TNFα水平的取代的2－(2，6－二氧哌啶－3－基)邻苯二甲酰亚胺和1－氧－2－(2，6－二氧哌啶－3－基)异二氢吲哚，其中典型的例子是1－氧－2－(2，6－二氧－3－甲基哌啶－3－基)－4，5，6，7－四氟异二氢吲哚。
Description
技术领域
本申请是国家申请号为98805614.3的专利申请的分案申请。
本发明涉及取代的2-(2，6-二氧哌啶-3-基)-邻苯二甲酰亚胺和取代的2-(2，6-二氧哌啶-3-基)-1-氧异二氢吲哚，通过服用这类化合物来降低哺乳动物体内肿瘤坏死因子α水平、治疗炎症和自身免疫疾病的方法，以及这样的衍生物的药物组合物。
背景技术
肿瘤坏死因子α(TNFα)是主要由单核巨噬细胞对各种免疫刺激剂的应答而释放的细胞因子。将其施加于动物和人时，可引起炎症、发热、心血管影响、出血、凝血及类似于急性感染和休克状态所见的急性反应。因此，在很多疾病状态均可伴有TNFα产生过量或失控。这些疾病包括内毒素血症和/或中毒性休克综合征{Tracey等，Nature 330，662-664(1987)和Hinshaw等，Circ.Shock30，279-292(1990)}；恶病质{Dezube等，Lancet，335(8690)，662(1990)}和成人呼吸窘迫综合征，其中从患者肺呼出气中检出TNFα的浓度超出12,000pg/mL{Millar等，Lancet 2(8665)，712-714(1989)}。重组TNFα全身输注也导致ARDS中所见的改变{Ferrai-Baliviera等，Arch.Surg.124(12)，1400-1405(1989)}。
TNFα似乎涉及骨吸收疾病，包括关节炎。当发作时，白细胞会产生骨吸收，资料提示TNFα与其发作有关{Bertolini等，Nature 319，516-518(1986)和Johnson等，Endocrinology 124(3)，1424-1427(1989).}在体内、外试验中还证明，TNFα通过刺激破骨细胞形成和激活，同时抑制成骨细胞的功能，从而刺激骨吸收和抑制骨生成。尽管TNFα可能涉及很多骨吸收性疾病，包括关节炎，但最令人非相信不可的与疾病的联系是肿瘤或宿主组织TNFα的产生与伴有高钙血症的恶性程度之间的关联{Calci.Tissue Int.(US)46(Suppl.)，S3-10(1990)}。急性同种异型骨髓移植后，在移植物对宿主反应中，主要并发症伴有血清TNFα水平的提高{Holler等，Blood，75(4)，1011-1016(1990)}。
脑疟疾是伴有TNFα高血浓度的致死性超急性神经综合征，是疟疾患者中出现的最严重的并发症。血清TNFα水平与疟疾急性发作患者疾病的严重程度和预后直接相关{Grau等N.Engl.J.Med.320(24)，1586-1591(1989)}。
已知巨噬细胞诱导的血管生成由TNFα介导。Leibovich等{Nature，329，630-632(1987)}在大鼠角膜和发育中的小鸡绒毛***上证明，很低剂量的TNFα即引起体内毛细血管的形成，提示TNFα在炎症、伤口修复和肿瘤生长上是诱导血管生成的因素。TNFα的产生还与癌性疾病、特别是诱发肿瘤相关联{Ching等，Brit.J.Cancer，(1955)72，339-343和Koch，Progress inMedicinal Chemistry，22，166-242(1985)}。
TNFα还在慢性肺部炎症性疾病方面起作用。硅石颗粒的沉积导致矽肺，一种纤维变性反应引起的进行性呼吸衰竭疾病。抗TNFα抗体完全阻断硅石引起的小鼠肺纤维变性{Pignet等，Nature，344：245-247(1990)}。在硅石和石棉沉着病导致纤维变性的动物模型上证明，血清和分离出的巨噬细胞中有高水平TNFα的产生{Bissonnette等，Inflammation 13(3)，329-339(1989)}。还有人发现，从肺类肉瘤病患者取出的肺泡巨噬细胞与从正常供体而来的巨噬细胞相比，该疾病自发性释放大量TNFα{Baughman等，J.Lab.Clin.Med.115(1)，36-42(1990)}。
TNFα还与再灌注(称作再灌注损伤)后的炎症反应有关，是缺血流后组织损伤的主要原因{Vedder等，PNAS 87，2643-2646(1990)}。TNFα还能改变内皮细胞的性质，具有各种促凝血活性，如产生组织因子促凝血活性提高和抗凝血蛋白C途径的抑制，以及下调凝血调节蛋白的表达{Sherry等，J.Cell Biol.107，1269-1277(1988)}。TNFα具有促炎症活性，该活性与TNFα的早期产生(在炎症初期)使其更象是几种重要疾病(包括但不限于心肌梗塞、卒中和循环休克)中组织损伤的介质。特别重要的可以是TNFα诱导的粘合分子如细胞间粘合分子(ICAM)或内皮白细胞粘合分子(ELAM)在内皮细胞上的表达{Munro等，Am.J.Path.135(1)，121-132(1989)}。
用抗TNFα单克隆抗体封闭TNFα已被证明对类风湿性关节炎{Elliot等，Int.J.Pharmac.1995 17(2)，141-145}和Crohn’s病{von Dullemen等，Gastroenterology，1995 109(1)，129-135}有益。
此外，现已知道，TNFα是轮状病毒复制包括HIV-1激活的潜在激活剂{Duh等，Proc.Nat.Acad.Sci.86，5974-5978(1989)；Poll等，Proc.Nat.Acad.Sci.87，782-785(1990)；Monto等，Blood 79，2670(1990)；Clouse等，J.Immunol.142，431-438(1989)；Poll等，AIDS Res.Hum.Retrovirus，191-197(1992)}。AIDS由人免疫缺陷病毒(HIV)感染T淋巴细胞而引起。至少有三种类型或三株HIV已被鉴定出来，即HIV-1，HIV-2和HIV-3。作为HIV感染的结果，T细胞介导的免疫受损，受感染的个体出现严重的机会感染和/或异常新生物。HIV进入T淋巴细胞需要激活T淋巴细胞。其他病毒(如HIV-1和HIV-2)在T细胞激活后感染T淋巴细胞，这些病毒蛋白的表达和/或复制由这种T细胞激活所介导或维持。一旦被激活的T淋巴细胞感染了HIV，该T淋巴细胞必须继续维持激活状态，以使HIV基因表达和/或HIV复制。细胞因子，特别是TNFα，通过在维持T淋巴细胞活化上起作用而参与活化T细胞介导的HIV蛋白表达和/或病毒复制。因此，在HIV感染的个体上，诸如通过阻止或抑制细胞因子(值得注意的是TNFα)的产生来干扰细胞因子的活性，有助于限制HIV感染引起的淋巴细胞的维持。
单核细胞、巨噬细胞和相关的细胞(如枯否氏细胞和胶质细胞)也参与HIV感染的维持。这些细胞象T细胞一样，是病毒复制的靶细胞，病毒复制的水平依赖于细胞的激活状态，{Rosenberg等，The Immunopathogenesis of HIVInfection，Advances in Immunology，57(1989)}。细胞因子(如TNFα)已被证明在单核细胞和/或巨噬细胞上激活HIV复制{Poli等，Proc.Natl.Acad.Sci.，87，782-784(1990)}，因此，阻止或抑制细胞因子的产生或其活性有助于限制HIV侵入T细胞。另外的研究将TNFα鉴定为体外HIV激活的共同因子，并提供了细胞的胞质中已发现的核调节蛋白起作用的明确的作用机制(Osborn等，PNAS 86 2336-2340)。该证据揭示，TNFα合成的减少通过降低转录从而减少病毒产生，可在HIV感染中具有抗病毒效应。
潜伏在T细胞和巨噬细胞株内的HIV的AIDS病毒复制可被TNFα诱导{Folks等，PNAS 86，2365-2368(1989)}。有人提出，该病毒诱导活性的分子机理系通过TNFα激活细胞胞质中所见基因调节蛋白(NFκB)的能力，促进HIV结合于病毒调节基因序列(LTR)而进行复制{Osborn等，PNAS 86：2336-2340(1989)}。有人提出，伴有恶病质的AIDS中的TNFα系血清TNFα的提高及患者外周血液单核细胞中高水平自发性TNFα产生所致{Wright等，J.Immunol.141(1).99-104(1988)}。如上面提到的类似的理由，TNFα参与其他病毒感染{如细胞肥大包涵体病毒(CMV)、流感病毒、腺病毒和疱疹病毒族)的各种作用。
核因子κB(NFκB)是多效转录激活剂(Lenardo等，Cell 1989，58，227-29)。NFκB作为转录激活剂参与各种疾病和炎症状态，被认为能调节细胞因子(包括但不限于TNFα)的水平，并且也是HIV转录的激活剂{Dbaibo等，J.Biol.Chem.1993，17762-66；Duh等，Proc，.Natl.Acad.Sci.1989，86，5974-78；Bachelerie等，Nature 1991，350，709-12；Boswas等，J.Acquired ImmuneDeficiency Syndrome 1993，6，778-786；Suzuki等，Biochem.And Biophys.Res.Comm.1993.193.277-83；SuZuki等，Biochem.And Biophys.Res Comm.1992.189，1709-15；Suzuki等，Biochem.Mol.Bio.Int.1993，31(4)，693-700；Shakhov等，Proc.Natl.Acad.Sci.USA 1990，171，35-47；和Staal等，Proc.Natl.Acad.Sci.USA 1990，87，9943-47)。因此，抑制NFκB结合可调节细胞因子基因的转录，通过这一调节和其他机制，用于抑制众多疾病。本说明书中描述的化合物可抑制核内NFκB的作用，从而用于治疗各种疾病，包括但不限于类风湿性关节炎、类风湿性脊椎炎、骨关节炎、其他关节炎、脓毒性休克、脓毒症、内毒素性体克、移植物抗宿主疾病、消耗性疾病、克罗恩氏病、炎性肠疾病、溃疡性结肠炎、多发性硬化、全身性红斑狼疮、麻风中的ENL、HIV、AIDS及AIDS中的机会感染。TNFα和NTκB水平受逆反馈环的支配。如上所述，本发明的化合物对TNFα和NFκB的水平均有影响。
很多细胞功能由3’，5’-环-磷酸腺苷(cAMP)水平介导。这些细胞功能可造成炎性状态和包括哮喘、炎症和其他病状的疾病{Lowe和Cheng，Drugs ofthe Future，17(9)，799-807，1992)。现已证明，炎性白细胞中cAMP的升高抑制这些细胞的活性和炎性介质(包括TNFα和NFκB)的随后释放。cAMP水平的升高还导致呼吸道平滑肌的松驰。
因此，降低TNFα水平和/或提高cAMP水平构成治疗很多炎症、感染性、免疫学或恶性疾病的有价值的治疗战略。这些疾病包括但不限于脓毒性休克、脓毒症、内毒素性休克、血液动力学休克和脓毒综合征、梗塞后再灌注损伤、疟疾、分支杆菌感染、脑脊膜炎、牛皮癣、充血性心力衰竭、纤维化疾病、恶病质、移植物排斥、癌症、自身免疫性疾病、AIDS的机会性感染、类风湿性关节炎、类风湿性脊椎炎、骨关节炎、其他关节炎病症、克罗恩氏病、溃疡性结肠炎、多发性硬化、全身红斑狼疮、麻风中的ENL、放射损伤和高氧性肺泡损伤。关于抑制TNFα效应的以往的努力涉及从利用***和强的松龙之类甾体药物到使用多克隆和单克隆抗体{Beutler等，Science 234，470-474(1985)；WO 92/11383}。
发明内容
本发明基于这样的发现，即本说明书较完整描述的某些种类的非多肽类化合物可降低TNFα的水平。
本发明特别是以下通式I所示化合物
其中：
X和Y中一个是C＝O，X和Y中另一个是C＝O或CH2：
(i)R1、R2、R3和R4各自独立地为卤原子、1-4个碳原子的烷基或1-4个碳原子的烷氧基，或(ii)R1、R2、R3和R4之一为-NHR5，其余的R1、R2、R3和R4为氢原子；
R5为氢原子或1-8个碳原子的烷基；
R6为氢原子、1-8个碳原子的烷基、苄基(benzo)、氯原子或氟原子；
R7为间亚苯基或对亚苯基或-(CnH2n)-，其中的n为0-4；
R8和R9各自独立地为氢原子或1-8个碳原子的烷基，或者R8和R9一起表示四亚甲基、1，5-亚戊基、1，6一亚己基或-CH2CH2XCH2CH2-，其中的X为-O-、-S-或-NH-；
R10为氢原子、1-8个碳原子的烷基或苯基；
(b)含有一个可被质子化的氮原子的所述化合物的酸加成盐。
第一组较佳的化合物是通式I中至少R1、R2、R3、R4和R6之一不为氢原子的化合物。其中，更好的是R1、R2、R3、R4各自独立地为卤原子、1-4个碳原子的烷基或1-4个碳原子的烷氧基，R6为氢原子、甲基、乙基或丙基，R8和R9各自独立地为氢原子或甲基，R10为氢原子的一组化合物。这些化合物中更好的是R7为间亚苯基或对亚苯基的化合物，或R7为-(CnH2n)-的化合物，其中的n为0-4。
第二组较佳的化合物是通式I中R1、R2、R3和R4之一为-NH2，其余的R1、R2、R3和R4为氢原子，R6为氢原子、甲基、乙基或丙基，R8和R9各自独立地为氢原子或甲基，R10为氢原子的一组化合物。这些化合物中更好的是R7为间亚苯基或对亚苯基的化合物，或R7为-(CnH2n)-的化合物，其中的n为0-4。
术语“烷基”指含有1-8个碳原子的直链或支链一价饱和烃链。这样的烷基的代表为甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基。烷氧基指通过醚氧原子键合到分子其余部分的烷基。这样的烷氧基的代表为甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基和叔丁氧基。R1、R2、R3和R4以氯、氟、甲基或甲氧基为佳。
在有资格的专门医师指导下，式I化合物被用来抑制TNFα的不期望有的作用。这些化合物可单独地或与其它治疗剂(包括抗生素、甾类化合物等)合用，给需要治疗的哺乳动物口服给药、直肠给药或胃肠外给药。
本发明的化合物还可局部用于由过量TNFα的产生分别介导或加剧的局部病症的治疗或预防，例如病毒感染(如由疱疹病毒引起的感染)或病毒性结膜炎、牛皮癣、特应性皮炎等。
这些化合物还可用于需要阻止或抑制TNFα产生的人以外的哺乳动物的兽医治疗。在动物上处理(治疗或预防)的TNFα介导的疾病包括上面所述的那些病症，但特别是病毒感染。其例子包括猫免疫缺陷病毒、马感染性贫血病毒、羊关节炎病毒、绵羊脱髓鞘性脑白质炎病毒和梅迪(maedi)病毒，以及其它慢病毒(lentiviruses)。
通过甲醛和通式IIA
表示的中间体的起始反应可制备上述化合物。其中，X和Y的含义如上所述；
R1、R2、R3和R4各自独立地表示卤原子、1-4个碳原子的烷基、1-4个碳原子的烷氧基或(ii)R1、R2、R3和R4之一为硝基或被保护的氨基，其余的R1、R2、R3和R4为氢原子；R6为氢原子、1-8个碳原子的烷基、苄基(benzo)、氯原子或氟原子。
然后，利用公知的方法使所得的通式II表示的N-羟甲基中间体和通式IV表示的羧酸衍生物进行偶合反应，
其中的Hal表示氯原子、溴原子或碘原子等反应性卤原子。
此处所用的保护基指在最终的治疗化合物中一般见不到但在合成的某个阶段为了保护化学操作过程中可能改变的基团而有意引入的基团。在合成的较后阶段除去这种保护基，带有这种保护基的化合物基本上作为化学中间体有其重要性(尽管有些衍生物也显示生物活性)。因此，保护基的确切结构并不严格要求。在大量标准著作中，描述了用于形成和除去保护基的种种反应，这些著作包括例如“Protective Groups in Organic Chemistry”，Plemun Press，London and New York，1973；Greene，Th.W.″Protective Groups in OrganicSynthesis“，Wiley，New York，1981；″The Peptides″，Vol.I，Schroderand Lubke，Academic Press，London and New York，1965；″Methoden derOrganischen Chemie″，Houben-Weyl，4th Edition，Vol.15/I，Georg ThiemeVerlag，Stuttgart 1974，它们揭示的内容结合于此作为参考。
氨基可利用酰基以酰胺的形式保护起来，该酰基可在温和条件下选择性地除去，特别是苄氧基羰基、甲酰基或在羰基的1-位或α-位上有支链的低级烷酰基，特别是叔烷酰基，如三甲基乙酰基，在羰基的α位上被取代的低级烷酰基，如三氟乙酰基。
偶合剂包括二环己基碳二亚胺和N，N，-羰基二咪唑等试剂。
偶合反应后，利用常规方法使通式V表示的化合物胺化，例如，在碘化钠的存在下使该化合物与胺发生反应。
或者，使通式III表示的化合物与通式IVA表示的被保护的氨基羧酸进行反应，
其中的Z表示被保护的氨基。
偶合反应后，氨基保护基团Z被除去。
前述反应中，如果R1、R2、R3和R4之一为硝基，则通过催化氢化作用可将硝基转变为氨基；如果R1、R2、R3和R4之一为被保护的氨基，则保护基团被分解获得R1、R2、R3和R4之一为氨基的相应化合物。
除了作为中间体之外，通式IIA表示的某些其他化合物自身就具备降低哺乳动物体内肿瘤坏死因子α的生物学活性，这些化合物由通式IIB表示，
其中，X和Y之一为C＝O，另一为C＝O或CH2；(i)R1、R2、R3和R4各自独立地为卤原子、1-4个碳原子的烷基、1-4个碳原子的烷氧基或(ii)R1、R2、R3和R4之一为-NHR5，其余的R1、R2、R3和R4为氢原子；R5为氢原子或1-8个碳原子的烷基或CO-R7-CH(R10)NR8R9，其中R7、R8、R9和R10如前所述；R6为1-8个碳原子的烷基、苄基(benzo)、氯原子或氟原子。
某些通式IIA表示的中间体在相关申请Serial Nos.08/690,258和08/701,494中被揭示，这些被揭示的中间体在此供本发明参考。另外，在三乙胺等酸性接受体存在下，使R1、R2、R3和R4适当取代的邻溴甲基苯甲酸烷酯和α-R6取代的α-氨基戊二酰亚胺的盐反应也能够获得X和Y之一为C＝O，另一为CH2的化合物。
在乙酸或乙酸钠存在下，使R1、R2、R3和R4适当取代的邻苯二甲酸酐与α-R6-取代的α-氨基戊二酰亚胺的盐反应也可制得X和Y都为C＝O的通式IIA表示的化合物。
使氨基被保护的α-R6-取代的谷氨酰胺进行环化反应就可制得用于前述反应的α-R6-取代的α-氨基戊二酰亚胺的盐。例如，上述环化反应可在二甲基氨基吡啶等酸性接受体的存在下，使上述谷氨酰胺与N，N’-羰基二咪唑反应而进行。反应结束后，利用适当的方法可除去保护基团。例如，如果保护基团为N-苄氧基羰基，则利用催化氢化反应可除去该基团。
使α-R6-取代的谷氨酸与乙酸酐进行反应获得α-R6-取代的谷氨酸酐，然后，使氨基被保护的α-R6-取代的谷氨酸酐与氨发生反应就可获得α-R6-取代的谷氨酰胺。
通式I和IIB的化合物具有手性中心，可以旋光异构体的形式存在。当具有2个手性中心时，这些异构体的外消旋体及其各自的异构体，以及非对映异构体均在本发明的范围内。外消旋体可直接使用，或可用物理方法，如通过使用手性吸附剂的色谱法将其分离成各个异构体。或者，可以手性形式制备各个异构体，或用化学方法，通过与手性酸成盐从混合物中分离各个异构体，例如，10-樟脑磺酸、樟脑酸、α-溴代樟脑酸、甲氧基乙酸、酒石酸、二乙酰基酒石酸、苹果酸、吡啶烷酮-5-羧酸等的各个对映体，然后将拆分开的一个碱或两个碱均游离出来，可任意地重复此过程，以获得基本上没有另一个的任何一个或两个各自的异体构，即光学纯度＞95％的形式。
本发明还涉及通式I和IIB化合物的生理学上可接受的无毒酸加成盐。这样的盐包括从有机和无机酸生成的盐，例如(但不限于)，盐酸、氢溴酸。磷酸、硫酸、甲磺酸、乙酸、酒石酸、乳酸、琥珀酸、柠檬酸、苹果酸、马来酸、山梨酸、阿康酸、水杨酸、苯二甲酸、双羟萘酸、庚酸等。
口服剂型包括片剂、胶囊剂、糖锭剂(dragees)，及类似形状的压制的药物剂型，每单位剂量包含1-100mg药物。可用含20-100mg/ml的等渗盐水溶液作为非胃肠道给药，包括肌肉、鞘内、静脉内和动脉内途径给药。使用从常规载体如可可脂制成的栓剂可进行直肠给药。
药物组合物包括一种或几种通式I、IIB的化合物，以及至少一种药学上可接受的载体、稀释剂或赋形剂。在制备这些组合物时，通常将活性成分与赋形剂混合，或用赋形剂稀释，或包在可以胶囊或药囊形式存在的载体中。当赋形剂起稀释剂作用时，它可以是固体、半固体或液体材料作为赋形剂、载体或活性成分的介质。因此，组合物可以是片剂、丸剂、粉剂、酏剂、混悬剂、乳剂、溶液剂、糖浆剂、软和硬明胶胶囊、栓剂、灭菌可注射溶液和灭菌包装粉剂。合适的赋形剂的例子包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇。淀粉、***胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素，制剂还可包括润滑剂(如滑石粉、硬脂酸镁和矿物油)，湿润剂，乳化剂和悬浮剂，防腐剂(如羟基苯甲酸甲酯和丙酯)，甜味剂或矫味剂。
组合物以制成单位剂量形式为宜，即适合作为单一剂量的物理学上分开的单位，或准备以一次或多次剂量方案对人和其他哺乳动物投药的单一剂量的预定部分，每一单位包含为产生所期望的治疗效应而计算出预定量的活性物质，以及合适的药剂学赋形剂。采用本领域熟知的方法，可将组合物制成给患者投药后能立即、持续或缓慢释放活性成分的制剂。
口服剂型包括片剂、胶囊剂、糖锭剂(dragees)，及类似形状的压缩的药物剂型，每单位剂量包含1-100mg药物。可用含20-100mg/ml的等渗盐水溶液作为非胃肠道给药，包括肌肉、鞘内、静脉和动脉途径给药。使用从常规载体如可可脂制成的栓剂可进行直肠给药。
药物组合物包括一种或几种通式I的化合物，以及至少一种药学上可接受的载体、稀释剂或赋形剂。在制备这些组合物时，通常将活性成分与赋形剂混合，或用赋形剂稀释，或包在可以胶囊或药囊形式存在的载体中。当赋形剂起稀释剂作用时，它可以是固体、半固体或液体材料作为赋形剂、载体或活性成分的介质。因此，组合物可以是片剂、丸剂、粉剂、酏剂、混悬剂、乳剂、溶液剂、糖浆剂、软和硬明胶胶囊、栓剂、灭菌可注射溶液和灭菌包装粉剂。合适的赋形剂的例子包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇。淀粉、***胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素，制剂还可包括润滑剂(如滑石粉、硬脂酸镁和矿物油)，湿润剂，乳化剂和悬浮剂，防腐剂(如羟基苯甲酸甲酯和丙酯)，甜味剂或矫味剂。
组合物以制成单位剂量形式为宜，即适合作为单一剂量的物理学上分开的单位，或准备以一次或多次剂量方案对人和其他哺乳动物投药的单一剂量的预定部分，每一单位包含为产生所期望的治疗效应而计算出预定量的活性物质，以及合适的药剂学赋形剂。采用本领域熟知的方法，可将组合物制成给患者投药后能立即持续或缓慢释放活性成分的制剂。
下面的实施例将进一步作为本发明实质的典型，但不应看作对其范围的限制，该范围只能由所附的权利要求来限定。
具体实施方式
实施例1
N-苄氧基羰基-α-甲基-谷氨酸
在0～5℃的温度及搅拌状态下，在α-甲基-D，L-谷氨酸(10g，62mmol)的2N氢氧化钠(62mL)中加入氯甲酸苄酯(12.7g，74.4mmol)，历时30分钟。加料结束后在室温下搅拌反应混合液，历时3小时。在搅拌过程中滴加2N氢氧化钠(33mL)将反应液的pH值控制在11。然后用***(60ml)萃取反应液。在冰浴中冷却水层，用4N盐酸(34mL)酸化，将pH值调为1。接着，用乙酸乙酯(3×100mL)萃取反应液，再用盐水(60mL)洗涤合并后的乙酸乙酯提取液，用硫酸镁干燥。真空除去溶剂，获得15.2g(83％)为油状的N-苄氧基羰基-α-甲基-谷氨酸。
1H NMR(CDCl3)
δ8.73(m，5H)，5.77(b，1H)，5.09(s，2H)，2.45-2.27(m，4H)，2.0(s，3H)
与上述同样操作，由α-乙基-D，L-谷氨酸和α-丙基-D，L-谷氨酸可分别获得N-苄氧基羰基-α-乙基-谷氨酸和N-苄氧基羰基-α-丙基-谷氨酸。
实施例2
N-苄氧基羰基-α-甲基-谷氨酸酐
在氮气氛围中搅拌加热回流N-苄氧基羰基-α-甲基-谷氨酸(15g，51mmol)和乙酸酐(65mL)的混合液，历时30分钟。使反应液冷却至室温后，真空浓缩，获得油状N-苄氧基羰基-α-甲基-谷氨酸酐(15.7g)，它不用进一步精制就可直接用于下一步反应。
1H NMR(CDCl3)
δ7.44-7.26(m，5H)，5.32-5.30(m，2H)，5.11(s，1H)，2.69-2.61(m，2H)，2.40-2.30(m，2H)，1.68(s，3H)
与上述同样操作，由N-苄氧基羰基-α-乙基-谷氨酸和N-苄氧基羰基-α-丙基-谷氨酸可分别获得N-苄氧基羰基-α-乙基-谷氨酸酐和N-苄氧基羰基-α-丙基-谷氨酸酐。
实施例3
N-苄氧基羰基-α-氨基-α-甲基-异谷氨酰胺
在冰水浴中冷却搅拌下的N-苄氧基羰基-α-甲基-谷氨酸酐(14.2g，51.5mmol)的二氯甲烷(100mL)溶液，然后在经过冷却的溶液中吹入氨气，历时2小时。在室温下搅拌反应液，历时17小时，再用水(2×50mL)萃取。接着在冰水浴中冷却合并的水层，用4N盐酸(32mL)酸化，将pH值调整到1，再用乙酸乙酯(3×80mL)萃取反应液，然后用盐水(60mL)对合并的乙酸乙酯提取液进行洗涤，并用硫酸镁干燥。真空除去溶剂，获得11.5g N-苄氧基羰基-α-氨基α-甲基-异谷氨酰胺。
1H NMR(CDCl3/DMSO)
δ7.35(m，5H)，7.01(s，1H)，6.87(s，1H)，6.29(s，1H)，5.04(s，2H)，2.24-1.88(m，4H)，1.53(s，3H)
与上述同样操作，由N-苄氧基羰基-α-乙基-谷氨酸酐和N-苄氧基羰基-α-丙基-谷氨酸酐可分别获得N-苄氧基羰基-α-氨基-α-乙基-异谷氨酰胺和N-苄氧基羰基-α-氨基-α-丙基-异谷氨酰胺。
实施例4
N-苄氧基羰基-α-氨基-α-甲基戊二酰亚胺
在氮气氛围中，使搅拌下的N-苄氧基羰基-α-氨基-α-甲基-异谷氨酰胺(4.60g，15.6mmol)、1，1’-羰基二咪唑(2.80g，17.1mmol)、4-二甲基氨基吡啶(0.05g)的四氢呋喃(50mL)溶液加热回流17小时，然后真空浓缩反应液，获得油状物，将该油状物混合入水(50mL)中，历时1小时。过滤所得的悬浮液，用水洗涤固状物，自然干燥后，获得3.8g为白色固体的粗品。再用快速层析法(二氯甲烷∶乙酸乙酯＝8∶2)对粗品进行精制，获得2.3g(50％)为白色固体的N-苄氧基羰基-α-氨基-α-甲基戊二酰亚胺。
熔点：150.5-152.5℃
1H NMR(CDCl3)
δ8.21(s，1H)，7.34(s，5H)，5.59(s，1H)，5.08(s，2H)，2.74-2.57(m，3H)，2.28-2.25(m，1H)，1.54(s，3H)
13C NMR(CDCl3)
δ174.06，171.56，154.68，135.88，128.06，127.69，127.65，66.15，54.79，29.14，28.70，21.98
HPLC：Waters Nova-Pak C18柱，4微米，3.9×150mm，1mL/min，240nm，20/80CH3CN/0.1％H3PO4(aq)，7.56分钟(100％)
分析计算值(C14H16N2O4)：
C，60.86，H，5.84，N，10.14
实测值：
C，60.88，H，5.72，N，10.07
与上述同样操作，由N-苄氧基羰基-α-氨基-α-乙基-异谷氨酰胺和N-苄氧基羰基-α-氨基-α-丙基-异谷氨酰胺可分别获得N-苄氧基羰基-α-氨基-α-乙基-戊二酰亚胺和N-苄氧基羰基-α-氨基-α-丙基-戊二酰亚胺。
实施例5
盐酸α-氨基-α-甲基-戊二酰亚胺
在温热条件下将N-苄氧基羰基-α-氨基-α-甲基戊二酰亚胺(2.3g，8.3mmol)溶于乙醇(200mL)中，然后冷却至室温，在该溶液中加入4N盐酸(3mL)和10％Pd/C(0.4g)。接着在50psi的氢气压力下，在帕尔仪器中进行氢化反应，历时3小时。然后在反应液中加水(50mL)，使产物溶解，再用经过水洗(50mL)的硅藻土过滤反应液，真空浓缩滤液，获得固体残渣。将该固状物混合入乙醇(20mL)中，历时30分钟。过滤所得淤浆，获得1.38g(93％)为白色固体的盐酸α-氨基-α-甲基-戊二酰亚胺。
1H NMR(DMSO-d6)
δ11.25(s，1H)，8.92(s，3H)，2.84-2.51(m，2H)，2.35-2.09(m，2H)，1.53(s，3H)
HPLC：Waters Nova-Pak C18柱，4微米，1mL/min，240nm，20/80CH3CN/0.1％H3PO4(aq)，1.03分钟(94.6％)
与上述同样操作，由N-苄氧基羰基-α-氨基-α-乙基-戊二酰亚胺和N-苄氧基羰基-α-氨基-α-丙基-戊二酰亚胺可分别获得盐酸α-氨基-α-乙基-戊二酰亚胺和盐酸α-氨基-α-丙基-戊二酰亚胺。
实施例6
3-(3-硝基苯二甲酰亚氨基)-3-甲基哌啶-2，6-二酮
在氮气氛围中，将搅拌下的盐酸α-氨基-α-甲基-戊二酰亚胺(1.2g，6.7mmol)、3-硝基邻苯二甲酸酐(1.3g，6.7mmol)、乙酸钠(0.6g，7.4mmol)的乙酸(30mL)溶液加热回流6小时。然后冷却反应液，真空浓缩，将所得固状物混合入水(30mL)和二氯甲烷(30mL)中，历时30分钟。过滤悬浮液，用二氯甲烷洗涤所得固体，真空干燥(60℃，＜1mm)，获得1.44g(68％)为灰白色固体的3-(3-硝基苯二甲酰亚氨基)-3-甲基哌啶-2，6-二酮。
熔点：265-266.5℃
1H NMR(DMSO-d6)
δ11.05(s，1H)，8.31(dd，J＝1.1，7.9Hz，1H)，8.16-8.03(m，2H)，2.67-2.49(m，3H)，2.08-2.02(m，1H)，1.88(s，3H)
13C NMR(DMSO-d6)
δ172.20，171.71，165.89，163.30，144.19，136.43，133.04，128.49，126.77，122.25，59.22，28.87，28.49，21.04
HPLC：Waters Nova-Pak C18柱，4微米，1mL/min，240nm，20/80CH3CN/0.1％H3PO4(aq)，7.38分钟(98％)
分析计算值(C14H11N3O6)：
C，53.00，H，3.49，N，13.24
实测值：
C，52.77，H，3.29，N，13.00
与上述同样操作，由盐酸α-氨基-α-乙基-戊二酰亚胺和盐酸α-氨基-α-丙基-戊二酰亚胺可分别获得3-(3-硝基苯二甲酰亚氨基)-3-乙基哌啶-2，6-二酮和3-(3-硝基苯二甲酰亚氨基)-3-丙基哌啶-2，6-二酮。
实施例7
3-(3-氨基苯二甲酰亚氨基)-3-甲基哌啶-2，6-二酮
在温热条件下将3-(3-硝基苯二甲酰亚氨基)-3-甲基哌啶-2，6-二酮(0.5g，1.57mmol)溶于丙酮(250mL)中，然后冷却至室温，在氮气氛围中，在该溶液中加入10％Pd/C(0.1g)。接着在50psi氢气压力下，在帕尔仪器中进行氢化反应，历时4小时。用硅藻土过滤反应液，滤饼用丙酮(50mL)洗涤。真空浓缩滤液，获得黄色固体。将该黄色固体混合入乙酸乙酯(10mL)中，历时30分钟。过滤所得淤浆，干燥(60℃，＜1mm)，获得0.37g(82％)为黄色固体的3-(3-氨基苯二甲酰亚氨基)-3-甲基哌啶-2，6-二酮。
熔点：268-269℃
1H NMR(DMSO-d6)
δ10.98(s，1H)，7.44(dd，J＝7.1，7.3Hz，1H)，6.99(d，J＝8.4Hz，1H)，6.94(d，J＝6.9Hz，1H)，6.52(s，2H)，2.71-2.47(m，3H)，2.08-1.99(m，1H)，1.87(s，3H)
13C NMR(DMSO-d6)
δ172.48，172.18，169.51，168.06，146.55，135.58，131.80，121.51，110.56，108.30，58.29，29.25，28.63，21.00
HPLC：Waters Nova-Pak C18柱，4微米，1mL/min，240nm，20/80CH3CN/0.1％H3PO4(aq)，5.62分钟(99.18％)
分析计算值(C14H13N3O4)：
C，58.53，H，4.56，N，14.63
实测值：
C，58.60，H，4.41，N，14.36
与上述同样操作，由3-(3-硝基苯二甲酰亚氨基)-3-乙基哌啶-2，6-二酮和3-(3-硝基苯二甲酰亚氨基)-3-丙基哌啶-2，6-二酮可分别获得3-(3-氨基苯二甲酰亚氨基)-3-乙基哌啶-2，6-二酮和3-(3-氨基苯二甲酰亚氨基)-3-丙基哌啶-2，6-二酮。
实施例8
2-溴甲基-3-硝基苯甲酸甲酯
使搅拌下的2-甲基-3-硝基苯甲酸甲酯(17.6g，87.1mmol)和N-溴琥珀酰亚胺(18.9g，105mmol)的四氯化碳(243mL)溶液加热微微回流过夜，用于加热的是100W的灯泡，它与反应容器的距离为2cm。18小时后，使反应液冷却至室温，并过滤。用水(2×120mL)和盐水(120mL)洗涤滤液后，用硫酸镁干燥，然后真空除去溶剂，用快速层析法精制(己烷∶乙酸乙酯＝8∶2)所得粗品，获得22g(93％)为黄色固体的2-溴甲基-3-硝基苯甲酸甲酯。
熔点：69-72℃
1H NMR(CDCl3)
δ8.13-8.09(dd，J＝3.6，7.86Hz，1H)，7.98-7.93(dd，J＝1.32，8.13Hz，1H)，7.57-7.51(t，J＝7.97Hz，1H)，5.16(s，2H)，4.0(s，3H)
13C NMR(CDCl3)
δ65.84，150.56，134.68，132.64，132.36，129.09，53.05，22.70
HPLC：Waters Nova-Pak C18柱，4微米，1mL/min，240nm，40/60CH3CN/0.1％H3PO4(aq)，8.2分钟99％
分析计算值(C9H8NO4Br)：
C，39.44，H，2.94，N，5.11，Br，29.15
实测值：
C，39.51，H，2.79，N，5.02，Br，29.32
实施例9
3-(1-氧-4-硝基异二氢吲哚-1-基)-3-甲基哌啶-2，6-二酮
在搅拌下的盐酸α-氨基-α-甲基戊二酰亚胺(2.5g，14.0mmol)和2-溴甲基-3-硝基苯甲酸甲酯(3.87g，14.0mmol)的二甲基甲酰胺(40mL)中加入三乙胺(3.14g，30.8mmol)，然后在氮气氛围中使反应液加热回流6小时，冷却后真空浓缩。接着，将所得固体混合入水(50mL)和二氯甲烷中，历时30分钟，过滤所得淤浆，固状物用二氯甲烷洗涤，并真空干燥(60℃，＜1mm)，获得2.68g(63％)为灰白色的3-(1-氧-4-硝基异二氢吲哚-1-基)-3-甲基哌啶-2，6-二酮。
熔点：233-235℃
1H NMR(DMSO-d6)
δ10.95(s，1H)，8.49-8.46(d，J＝8.15Hz，1H)，8.13-8.09(d，J＝7.43Hz，1H)，7.86-7.79(t，J＝7.83Hz，1H)，5.22-5.0(dd，J＝19.35，34.6Hz，2H)，2.77-2.49(m，3H)，2.0-1.94(m，1H)，1.74(S，3H)
13C NMR(DMSO-d6)
δ173.07，172.27，164.95，143.15，137.36，135.19，130.11，129.32，126.93，57.57，48.69，28.9，27.66，20.6
HPLC：Waters Nova-Pak C18柱，4微米，1mL/min，240nm，20/80CH3CN/0.1％H3PO4(aq)，4.54分钟99.6％
分析计算值(C14H13N3O5)：
C，55.45，H，4.32，N，13.86
实测值：
C，52.16，H，4.59，N，12.47
用等当量的盐酸α-氨基-α-乙基戊二酰亚胺和盐酸α-氨基-α-丙基戊二酰亚胺代替盐酸α-氨基-α-甲基戊二酰亚胺可分别获得3-(1-氧-4-硝基异二氢吲哚-1-基)-3-乙基哌啶-2，6-二酮和3-(1-氧-4-硝基异二氢吲哚-1-基)-3-丙基哌啶-2，6-二酮。
实施例10
3-(1-氧-4-氨基异二氢吲哚-1-基)-3-甲基哌啶-2，6-二酮
在温热条件下将3-(1-氧-4-硝基异二氢吲哚-1-基)-3-甲基哌啶-2，6-二酮(1.0g，3.3mmol)溶于甲醇(500mL)中，并冷却至室温。然后，在氮气氛围中，在上述溶液中加入10％Pd/C(0.3g)。接着在50psi的氢气压力下，使上述反应液在帕尔仪器中进行加氢反应，历时4小时。然后用硅藻土过滤反应液，并用甲醇(50mL)洗涤硅藻土，真空浓缩滤液，获得灰白色固体。再将该固体混合入二氯甲烷(20mL)中，历时30分钟。过滤所得淤浆，并干燥所得固体(60℃，＜1mm)，获得0.54g(60％)为白色固体的3-(1-氧-4-氨基异二氢吲哚-1-基)-3-甲基哌啶-2，6-二酮。
熔点：268-270℃
1H NMR(DMSO-d6)
δ10.85(s，1H)，7.19-7.13(t，J＝7.63Hz，1H)，6.83-6.76(m，2H)，5.44(s，2H)，4.41(s，2H)，2.71-2.49(m，3H)，1.9-1.8(m，1H)，1.67(s，3H)
13C NMR(DMSO-d6)
δ173.7，172.49，168.0，143.5，132.88，128.78，125.62，116.12，109.92，56.98，46.22，29.04，27.77，20.82
HPLC：Waters Nova-Pak C18柱，4微米，1mL/min，240nm，20/80CH3CN/0.1％H3PO4(aq)，1.5分钟(99.6％)
分析计算值(C14H15N3O3)：
C，61.53，H，5.53，N，15.38
实测值：
C，58.99，H，5.48，N，14.29
由3-(1-氧-4-硝基异二氢吲哚-1-基)-3-乙基哌啶-2，6-二酮和3-(1-氧-4-硝基异二氢吲哚-1-基)-3-丙基哌啶-2，6-二酮可分别获得3-(1-氧-4-氨基异二氢吲哚-1-基)-3-乙基哌啶-2，6-二酮和3-(1-氧-4-氨基异二氢吲哚-1-基)-3-丙基哌啶-2，6-二酮。
实施例11
按照以下步骤能够获得每片含50mg 1-氧-2-(2，6-二氧-3-甲基哌啶-3-基)-4，5，6，7-四氟异二氢吲哚的片剂。
组成(1000片)
1-氧-2-(2，6-二氧-3-甲基哌啶-3-基)-4，5，6，7- 50.0g
四氟异二氢吲哚
乳糖 50.7g
麦淀粉 7.5g
聚乙二醇6000 5.0g
滑石粉 5.0g
硬脂酸镁 1.8g
软化水 q.s.
首先，使固体组分过孔径为0.6mm的筛子，然后混合活性组分、乳糖、滑石粉、硬脂酸镁和一半量的淀粉，另一半淀粉被悬浮在40mL水中，再将该悬浮液加入100mL沸腾的聚乙二醇水溶液中，接着，将所得的糊状物加入到粉末状物质中，并将混合物制成颗粒状，如有必要，还可添加水。然后在35℃的温度下彻夜干燥颗粒物，再过孔径为1.2mm的筛子整粒，最后压片，获得直径为6mm、且两边内凹的片剂。
实施例12
按照以下步骤能够获得每片含100mg 1-氧-2-(2，6-二氧哌啶-3-基)-4-氨基异二氢吲哚的片剂。
组成(1000片)
1-氧-2-(2，6-二氧哌啶-3-基)-4-氨基异二氢吲哚 100.0g
乳糖 100.0g
麦淀粉 47.0g
硬脂酸镁 3.0g
首先，使所有固体组分过孔径为0.6mm的筛子，然后混合活性组分、乳糖、硬脂酸镁和一半量的淀粉，另一半淀粉被悬浮在40mL水中，再将该悬浮液加入100mL沸腾的水中，接着，将所得的糊状物加入到粉末状物质中，并将混合物制为颗粒状，如有必要，还可添加水。然后在35℃的温度下彻夜干燥颗粒物，再通过孔径为1.2mm的筛子整粒，最后压片，获得直径为6mm、且两边内凹的片剂。
实施例13
按照以下步骤能够获得每片含有75mg 2-(2，6-二氧-3-甲基哌啶-3-基)-4-氨基邻苯二甲酰亚胺的咀嚼片剂。
组成(1000片)
2-(2，6-二氧-3-甲基哌啶-3-基)-4-氨基邻苯二甲酰亚胺 75.0g
甘露糖醇 230.0g
乳糖 150.0g
滑石粉 21.0g
甘氨酸 12.5g
硬脂酸 10.0g
糖精 1.5g
5％明胶溶液 q.s.
首先，使所有固体组分过孔径为0.25mm的筛子，然后混合甘露糖醇和乳糖，并在其中加入明胶溶液，造粒，再通过孔径为2mm的筛子，并在50℃的温度下干燥，然后再通过孔径为1.7mm的筛子。接着，小心地混合2-(2，6-二氧-3-甲基哌啶-3-基)-4-氨基邻苯二甲酰亚胺、甘氨酸和糖精，再添加甘露糖醇、乳糖颗粒、硬脂酸和滑石粉，然后充分混合，压成直径为10mm、两边凹陷、上面有一个槽的片剂。
实施例14
按照以下步骤能够获得每片含10mg 2-(2，6-二氧乙基哌啶-3-基)-4-氨基邻苯二甲酰亚胺的片剂。
组成(1000片)
2-(2，6-二氧乙基哌啶-3-基)-4-氨基邻苯二甲酰亚胺 10.0g
乳糖 328.5g
玉米淀粉 17.5g
聚乙二醇6000 5.0g
滑石粉 25.0g
硬脂酸镁 4.0g
软化水 q.s.
首先，使所有固体组分通过孔径为0.6mm的筛子，然后充分混合酰亚胺活性组分、乳糖、滑石粉、硬脂酸镁和一半量的淀粉，另一半淀粉被悬浮在65mL水中，再将该悬浮液加入260mL沸腾的聚乙二醇水溶液中，接着，将所得的糊状物加入到粉末状物质中，并将混合物制成颗粒，如有必要，还可添加水。然后在35℃的温度下彻夜干燥颗粒物，再通过孔径为1.2mm的筛子整粒，最后压片，获得直径为10mm、两边内凹、且上面有一个槽的片剂。
实施例15
按照以下步骤能够获得每个胶囊含100mg 1-氧-2-(2，6-二氧-3-甲基哌啶-3-基)-4，5，6，7-四氟异二氢吲哚的明胶干填胶囊剂。
组成(1000粒胶囊)
1-氧-2-(2，6-二氧-3-甲基哌啶-3-基)-4，5，6，7- 100.0g
四氟异二氢吲哚
微晶纤维素 30.0g
十二烷基硫酸钠 2.0g
硬脂酸镁 8.0g
首先，使十二烷基硫酸钠通过孔径为0.2mm的筛子而添加入1-氧-2-(2，6-二氧-3-甲基哌啶-3-基)-4，5，6，7-四氟异二氢吲哚中，充分混合10分钟后，再使微晶纤维素通过孔径为0.9mm的筛子而添加入上述混合物中，然后充分混合10分钟。接着，使硬脂酸镁通过孔径为0.8mm的筛子而添加入混合物中，再混合3分钟，最后将上述混合物(每个胶囊装入140mg)装入型号为0(拉长型)的明胶干填胶囊中。
实施例16
按照以下步骤能够获得0.2％注射剂或输液。
1-氧-2-(2，6-二氧-3-甲基哌啶-3-基)-4，5，6，7- 5.0g
四氟异二氢吲哚
氯化钠 22.5g
pH7.4的磷酸缓冲液 300.0g
软化水 加到2500.0mL
首先将1-氧-2-(2，6-二氧-3-甲基哌啶-3-基)-4，5，6，7-四氟异二氢吲哚溶于1000mL水中，用微孔滤膜过滤后，添加缓冲液，然后加水使容量达到2500mL。最后将上述溶液装入玻璃安瓿(每个瓶装入1.0或2.5mL溶液，即分别含2.0或5.0mg酰亚胺)中。
Claims (10)
1.下式(I)化合物或其盐：
2.根据权利要求1所述的化合物，其光学纯度大于95％。
3.根据权利要求1所述的化合物，它是(R)-3-(3-氨基苯二甲酰亚氨基)-3-甲基哌啶-2，6-二酮或(S)-3-(3-氨基苯二甲酰亚氨基)-3-甲基哌啶-2，6-二酮。
4.一种药物组合物，它包含如权利要求1，2或3所述的化合物和药学上可接受地载体、稀释剂或赋形剂。
5.根据权利要求4所述的药物组合物，它用来降低哺乳动物的TNFα水平或治疗炎症、自身免疫疾病、癌性疾病或癌症。
6.根据权利要求4所述的药物组合物，其中所述的组合物为片剂、胶囊剂、糖锭剂、扁性胶囊剂、溶液剂、混悬剂、乳剂、粉剂、气雾剂、喷雾剂、栓剂、棉塞、***环、锭剂、软膏剂、霜剂、糊剂、泡沫剂或凝胶剂。
7.根据权利要求4所述的药物组合物，其中所述的组合物为口服给药、非胃肠道给药、局部外用给药、直肠给药、舌下给药、颊部给药、***给药、透皮给药或基础给药的形式。
8.一种降低TNFα水平或治疗哺乳动物中炎症、自身免疫疾病、癌性疾病或癌症的方法，它包括给予下式(I)化合物或其盐：
9.根据权利要求8所述的方法，其中化合物为式(I)化合物的光学异构体。
10.根据权利要求8所述的方法，其中化合物的光学纯度＞95％。
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Families Citing this family (155)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6228879B1 (en) | 1997-10-16 | 2001-05-08 | The Children's Medical Center | Methods and compositions for inhibition of angiogenesis |
| US6429221B1 (en) | 1994-12-30 | 2002-08-06 | Celgene Corporation | Substituted imides |
| US6518281B2 (en) * | 1995-08-29 | 2003-02-11 | Celgene Corporation | Immunotherapeutic agents |
| US5635517B1 (en) * | 1996-07-24 | 1999-06-29 | Celgene Corp | Method of reducing TNFalpha levels with amino substituted 2-(2,6-dioxopiperidin-3-YL)-1-oxo-and 1,3-dioxoisoindolines |
| HU228769B1 (en) * | 1996-07-24 | 2013-05-28 | Celgene Corp | Substituted 2(2,6-dioxopiperidin-3-yl)phthalimides and -1-oxoisoindolines and their use for production of pharmaceutical compositions for mammals to reduce the level of tnf-alpha |
| ATE327228T1 (de) * | 1997-11-18 | 2006-06-15 | Celgene Corp | Substituierte 2-(2,6-dioxo-3-fluoropiperidine-3- yl)-isoindoline und ihre verwendung zum reduzieren des tnf-alpha spiegels |
| US5955476A (en) * | 1997-11-18 | 1999-09-21 | Celgene Corporation | Substituted 2-(2,6-dioxo-3-fluoropiperidin-3-yl)-isoindolines and method of reducing inflammatory cytokine levels |
| CA2321920C (en) * | 1998-03-16 | 2010-05-25 | Hon-Wah Man | 2-(2,6-dioxopiperidin-3-yl)isoindoline derivatives, their preparation and their use as inhibitors of inflammatory cytokines |
| WO2000055134A1 (en) | 1999-03-18 | 2000-09-21 | Celgene Corporation | Substituted 1-oxo- and 1,3-dioxoisoindolines and their use in pharmaceutical compositions for reducing inflammatory cytokine levels |
| US7629360B2 (en) | 1999-05-07 | 2009-12-08 | Celgene Corporation | Methods for the treatment of cachexia and graft v. host disease |
| US6458810B1 (en) | 2000-11-14 | 2002-10-01 | George Muller | Pharmaceutically active isoindoline derivatives |
| AU2002253795B2 (en) * | 2000-11-30 | 2007-02-01 | The Children's Medical Center Corporation | Synthesis of 4-Amino-Thalidomide enantiomers |
| US20030045552A1 (en) | 2000-12-27 | 2003-03-06 | Robarge Michael J. | Isoindole-imide compounds, compositions, and uses thereof |
| US7091353B2 (en) * | 2000-12-27 | 2006-08-15 | Celgene Corporation | Isoindole-imide compounds, compositions, and uses thereof |
| WO2003086373A1 (en) * | 2002-04-12 | 2003-10-23 | Celgene Corporation | Methods for identification of modulators of angiogenesis, compounds discovered thereby, and methods of treatment using the compounds |
| US7498171B2 (en) | 2002-04-12 | 2009-03-03 | Anthrogenesis Corporation | Modulation of stem and progenitor cell differentiation, assays, and uses thereof |
| US7968569B2 (en) * | 2002-05-17 | 2011-06-28 | Celgene Corporation | Methods for treatment of multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione |
| CN102429908A (zh) | 2002-05-17 | 2012-05-02 | 细胞基因公司 | 用于治疗和控制多发性骨髓瘤的方法及组合物 |
| US7393862B2 (en) | 2002-05-17 | 2008-07-01 | Celgene Corporation | Method using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for treatment of certain leukemias |
| USRE48890E1 (en) | 2002-05-17 | 2022-01-11 | Celgene Corporation | Methods for treating multiple myeloma with 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione after stem cell transplantation |
| US20100129363A1 (en) * | 2002-05-17 | 2010-05-27 | Zeldis Jerome B | Methods and compositions using pde4 inhibitors for the treatment and management of cancers |
| MXPA04011310A (es) * | 2002-05-17 | 2005-02-14 | Celgene Corp | Metodo y composiciones que utilizan farmacos inhibidores selectivos de citocinas para el tratamiento y el manejo de canceres y otras enfermedades. |
| US7323479B2 (en) * | 2002-05-17 | 2008-01-29 | Celgene Corporation | Methods for treatment and management of brain cancer using 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-methylisoindoline |
| US7189740B2 (en) * | 2002-10-15 | 2007-03-13 | Celgene Corporation | Methods of using 3-(4-amino-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for the treatment and management of myelodysplastic syndromes |
| JP2006510606A (ja) * | 2002-10-15 | 2006-03-30 | セルジーン・コーポレーション | 骨髄異形成症候群を治療および管理するための選択的サイトカイン阻害剤の使用方法およびそれを含む組成物 |
| US8404717B2 (en) * | 2002-10-15 | 2013-03-26 | Celgene Corporation | Methods of treating myelodysplastic syndromes using lenalidomide |
| US8404716B2 (en) | 2002-10-15 | 2013-03-26 | Celgene Corporation | Methods of treating myelodysplastic syndromes with a combination therapy using lenalidomide and azacitidine |
| EP1900369A1 (en) | 2002-10-15 | 2008-03-19 | Celgene Corporation | Methods of using and compositions comprising immunomodulatory compounds for the treatment and management of myelodysplastic syndromes |
| US11116782B2 (en) | 2002-10-15 | 2021-09-14 | Celgene Corporation | Methods of treating myelodysplastic syndromes with a combination therapy using lenalidomide and azacitidine |
| MXPA05004182A (es) * | 2002-10-24 | 2005-06-08 | Celgene Corp | Metodos de uso y composiciones que contienen compuestos inmunomoduladores para el tratamiento, modificacion y manejo del dolor. |
| US20040087558A1 (en) * | 2002-10-24 | 2004-05-06 | Zeldis Jerome B. | Methods of using and compositions comprising selective cytokine inhibitory drugs for treatment, modification and management of pain |
| US20050203142A1 (en) * | 2002-10-24 | 2005-09-15 | Zeldis Jerome B. | Methods of using and compositions comprising immunomodulatory compounds for treatment, modification and management of pain |
| JP2006508950A (ja) * | 2002-10-31 | 2006-03-16 | セルジーン・コーポレーション | 黄斑変性の治療用組成物 |
| US20040091455A1 (en) * | 2002-10-31 | 2004-05-13 | Zeldis Jerome B. | Methods of using and compositions comprising immunomodulatory compounds for treatment and management of macular degeneration |
| TW200501945A (en) | 2002-11-06 | 2005-01-16 | Celgene Corp | Methods and compositions using selective cytokine inhibitory drugs for treatment and management of cancers and other diseases |
| US8034831B2 (en) * | 2002-11-06 | 2011-10-11 | Celgene Corporation | Methods for the treatment and management of myeloproliferative diseases using 4-(amino)-2-(2,6-Dioxo(3-piperidyl)-isoindoline-1,3-dione in combination with other therapies |
| US7563810B2 (en) * | 2002-11-06 | 2009-07-21 | Celgene Corporation | Methods of using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione for the treatment and management of myeloproliferative diseases |
| KR20050086715A (ko) * | 2002-11-18 | 2005-08-30 | 셀진 코포레이션 | (-)-3-(3,4-디메톡시-페닐)-3-(1-옥소-1,3-디히드로-이소인돌-２-일)-프로피온아미드를 포함하는 조성물 및 그의 사용방법 |
| AU2003294311B8 (en) * | 2002-11-18 | 2008-06-05 | Celgene Corporation | Method of using and compositions comprising (+)-3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide |
| US7320992B2 (en) | 2003-08-25 | 2008-01-22 | Amgen Inc. | Substituted 2,3-dihydro-1h-isoindol-1-one derivatives and methods of use |
| UA83504C2 (en) * | 2003-09-04 | 2008-07-25 | Селджин Корпорейшн | Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione |
| US20080027113A1 (en) * | 2003-09-23 | 2008-01-31 | Zeldis Jerome B | Methods of Using and Compositions Comprising Immunomodulatory Compounds for Treatment and Management of Macular Degeneration |
| US7612096B2 (en) * | 2003-10-23 | 2009-11-03 | Celgene Corporation | Methods for treatment, modification and management of radiculopathy using 1-oxo-2-(2,6-dioxopiperidin-3yl)-4-aminoisoindoline |
| US20050100529A1 (en) * | 2003-11-06 | 2005-05-12 | Zeldis Jerome B. | Methods of using and compositions comprising immunomodulatory compounds for the treatment and management of asbestos-related diseases and disorders |
| EP1684758A4 (en) * | 2003-11-06 | 2009-02-18 | Celgene Corp | METHODS AND COMPOSITIONS USING THALIDOMIDE FOR THE TREATMENT AND MANAGEMENT OF CANCERS AND OTHER DISEASES |
| EP1692128A1 (en) | 2003-11-19 | 2006-08-23 | Signal Pharmaceuticals LLC | Indazole compounds and methods of use thereof as protein kinase inhibitors |
| US20050143344A1 (en) * | 2003-12-30 | 2005-06-30 | Zeldis Jerome B. | Methods and compositions using immunomodulatory compounds for the treatment and management of central nervous system disorders or diseases |
| KR101224262B1 (ko) | 2004-03-22 | 2013-01-21 | 셀진 코포레이션 | 면역조절 화합물을 포함하는 피부 질환 또는 장애의 치료및 관리용 조성물 및 이의 사용 방법 |
| US20050222209A1 (en) * | 2004-04-01 | 2005-10-06 | Zeldis Jerome B | Methods and compositions for the treatment, prevention or management of dysfunctional sleep and dysfunctional sleep associated with disease |
| JP2007532642A (ja) * | 2004-04-14 | 2007-11-15 | セルジーン・コーポレーション | 脊髄形成異常症候群の治療及び管理のための選択的サイトカイン阻害薬の使用法、及びそれを含む組成物 |
| MXPA06011798A (es) * | 2004-04-14 | 2007-01-16 | Celgene Corp | Metodos de uso y composiciones que comprenden compuestos inmunomoduladores para el tratamiento y manejo de sindromes mielodisplasticos. |
| CN101163489A (zh) * | 2004-04-23 | 2008-04-16 | 细胞基因公司 | 用于治疗和控制肺高血压的包含免疫调节化合物的组合物及其使用方法 |
| CA2565447A1 (en) * | 2004-05-05 | 2005-12-01 | Celgene Corporation | Method of using and compositions comprising immunomodulatory compounds for the treatment and management of myeloproliferative diseases |
| KR20070057907A (ko) * | 2004-09-03 | 2007-06-07 | 셀진 코포레이션 | 치환된 2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린의제조 방법 |
| KR20070085454A (ko) * | 2004-10-28 | 2007-08-27 | 셀진 코포레이션 | 중추신경계 손상의 치료 및 관리를 위하여 ｐｄｅ４조절제를 사용하는 방법 및 조성물 |
| WO2006058008A1 (en) * | 2004-11-23 | 2006-06-01 | Celgene Corporation | Methods and compositions using immunomodulatory compounds for treatment and management of central nervous system injury |
| CA2595711A1 (en) * | 2005-01-25 | 2006-08-03 | Celgene Corporation | Methods and compositions using 4-amino-2-(3-methyl-2,6-dioxopiperidin-3-yl)-isoindole-1-3-dione |
| CN100383139C (zh) | 2005-04-07 | 2008-04-23 | 天津和美生物技术有限公司 | 可抑制细胞释放肿瘤坏死因子的哌啶-2，6-二酮衍生物 |
| US20060270707A1 (en) * | 2005-05-24 | 2006-11-30 | Zeldis Jerome B | Methods and compositions using 4-[(cyclopropanecarbonylamino)methyl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione for the treatment or prevention of cutaneous lupus |
| WO2007005972A1 (en) * | 2005-06-30 | 2007-01-11 | Celgene Corporation | Processes for the preparation of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds |
| US20070038298A1 (en) * | 2005-06-30 | 2007-02-15 | Sulner Joseph W | Repair of tympanic membrane using placenta derived collagen biofabric |
| US7928280B2 (en) * | 2005-07-13 | 2011-04-19 | Anthrogenesis Corporation | Treatment of leg ulcers using placenta derived collagen biofabric |
| US20070021762A1 (en) * | 2005-07-13 | 2007-01-25 | Qing Liu | Ocular plug formed from placenta derived collagen biofabric |
| ES2434946T3 (es) | 2005-08-31 | 2013-12-18 | Celgene Corporation | Compuestos de isoindol imida y composiciones que los comprenden y métodos para usarlo |
| PL1928492T3 (pl) | 2005-09-01 | 2011-09-30 | Celgene Corp | Immunologiczne zastosowania związków immunomodulujących do szczepionki i przeciwzakaźnego leczenia choroby |
| US20080138295A1 (en) * | 2005-09-12 | 2008-06-12 | Celgene Coporation | Bechet's disease using cyclopropyl-N-carboxamide |
| US20070066512A1 (en) * | 2005-09-12 | 2007-03-22 | Dominique Verhelle | Methods and compositions using immunomodulatory compounds for the treatment of disorders associated with low plasma leptin levels |
| CN1939922B (zh) * | 2005-09-27 | 2010-10-13 | 天津和美生物技术有限公司 | 可抑制细胞释放肿瘤坏死因子的5H-噻吩[3，4-c]吡咯-4，6-二酮衍生物 |
| DK1957633T3 (en) * | 2005-10-13 | 2014-03-17 | Anthrogenesis Corp | Immunomodulation USING PLACE SPEECH STEM CELLS |
| US20070155791A1 (en) * | 2005-12-29 | 2007-07-05 | Zeldis Jerome B | Methods for treating cutaneous lupus using aminoisoindoline compounds |
| JP2009521931A (ja) * | 2005-12-29 | 2009-06-11 | アントフロゲネシス コーポレーション | 胎盤幹細胞を収集及び保存するための改善された組成物、及び該組成物の使用方法 |
| US20080064876A1 (en) * | 2006-05-16 | 2008-03-13 | Muller George W | Process for the preparation of substituted 2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione |
| CL2007002218A1 (es) | 2006-08-03 | 2008-03-14 | Celgene Corp Soc Organizada Ba | Uso de 3-(4-amino-1-oxo-1,3-dihidro-isoindol-2-il)-piperidina 2,6-diona para la preparacion de un medicamento util para el tratamiento de linfoma de celula de capa. |
| WO2008021391A1 (en) * | 2006-08-15 | 2008-02-21 | Anthrogenesis Corporation | Umbilical cord biomaterial for medical use |
| RU2448101C2 (ru) * | 2006-08-30 | 2012-04-20 | Селджин Корпорейшн | 5-замещенные изоиндолиновые соединения |
| US8877780B2 (en) | 2006-08-30 | 2014-11-04 | Celgene Corporation | 5-substituted isoindoline compounds |
| CA2660806C (en) * | 2006-08-30 | 2015-06-16 | Celgene Corporation | 5-substituted isoindoline compounds |
| SI2066656T1 (sl) | 2006-09-26 | 2012-06-29 | Celgene Corp | Zamenjani derivati kinazolinona kot protitumorska sredstva |
| US20080131522A1 (en) * | 2006-10-03 | 2008-06-05 | Qing Liu | Use of placental biomaterial for ocular surgery |
| US8071135B2 (en) | 2006-10-04 | 2011-12-06 | Anthrogenesis Corporation | Placental tissue compositions |
| KR20210018526A (ko) | 2006-10-06 | 2021-02-17 | 안트로제네시스 코포레이션 | 천연(텔로펩티드) 태반 콜라겐 조성물 |
| CN101186611B (zh) | 2006-11-15 | 2011-05-18 | 天津和美生物技术有限公司 | 可抑制细胞释放肿瘤坏死因子的吡咯啉-2-酮衍生物及其制备和应用 |
| US10494607B2 (en) * | 2007-02-12 | 2019-12-03 | Celularity, Inc. | CD34+,CD45−placental stem cell-enriched cell populations |
| CN101657206B (zh) | 2007-02-12 | 2013-07-03 | 人类起源公司 | 利用胎盘干细胞治疗炎性疾病 |
| WO2009020590A1 (en) | 2007-08-07 | 2009-02-12 | Celgene Corporation | Methods for treating lymphomas in certain patient populations and screening patients for said therapy |
| SG176442A1 (en) | 2007-09-26 | 2011-12-29 | Celgene Corp | 6-, 7-, or 8-substituted quinazolinone derivatives and compositions comprising and methods of using the same |
| NZ599825A (en) | 2007-09-28 | 2014-10-31 | Anthrogenesis Corp | Tumor suppression using human placental perfusate and human placenta-derived intermediate natural killer cells |
| EP2235213A2 (en) | 2007-12-20 | 2010-10-06 | Celgene Corporation | Use of micro-rna as a biomarker of immunomodulatory drug activity |
| US20090232796A1 (en) * | 2008-02-20 | 2009-09-17 | Corral Laura G | Method of treating cancer by administering an immunomodulatory compound in combination with a cd40 antibody or cd40 ligand |
| EP3354646A1 (en) | 2008-10-29 | 2018-08-01 | Celgene Corporation | Isoindoline compounds for use in the treatment of cancer |
| WO2010093434A1 (en) | 2009-02-11 | 2010-08-19 | Celgene Corporation | Isotopologues of lenalidomide |
| EP2411506B1 (en) | 2009-03-25 | 2018-11-07 | Celularity, Inc. | Tumor suppression using human placenta-derived intermediate natural killer cells and immunomodulatory compounds |
| MX2011008554A (es) | 2009-05-19 | 2011-10-06 | Celgene Corp | Formulaciones de 4-amino-2-(2,6-dioxopiperidin-3-il) isoindolin-1,3-diona. |
| US20120134969A1 (en) | 2009-05-25 | 2012-05-31 | Hiroshi Handa | Pharmaceutical composition containing nuclear factor involved in proliferation and differentiation of central neuronal cells |
| CN101696205B (zh) | 2009-11-02 | 2011-10-19 | 南京卡文迪许生物工程技术有限公司 | 3-(取代二氢异吲哚-2-基)-2,6-哌啶二酮多晶型物和药用组合物 |
| US8716252B2 (en) | 2009-12-22 | 2014-05-06 | Celgene Corporation | (Methylsulfonyl) ethyl benzene isoindoline derivatives and their pharmaceutical uses |
| MX337566B (es) | 2010-01-05 | 2016-03-10 | Celgene Corp | Combinación de un compuesto inmunomodulador y una artemisinina o un derivado de ésta para tratar cáncer. |
| RS58523B1 (sr) | 2010-02-11 | 2019-04-30 | Celgene Corp | Derivati arilmetoksi izoindolina i kombinacije koje ih obuhvataju i postupci njihove upotrebe |
| CA2794096A1 (en) | 2010-04-07 | 2011-10-13 | Celgene Corporation | Methods for treating respiratory viral infection |
| WO2012078492A1 (en) | 2010-12-06 | 2012-06-14 | Celgene Corporation | A combination therapy with lenalidomide and a cdk inhibitor for treating multiple myeloma |
| US8969315B2 (en) | 2010-12-31 | 2015-03-03 | Anthrogenesis Corporation | Enhancement of placental stem cell potency using modulatory RNA molecules |
| JP6132773B2 (ja) | 2011-01-10 | 2017-05-24 | セルジーン コーポレイション | Ｐｄｅ４及び／又はサイトカインの阻害剤としてのフェネチルスルホンイソインドリン誘導体 |
| CA3109687A1 (en) | 2011-03-11 | 2012-09-20 | Celgene Corporation | Solid forms of 3-(5-amino-2-methyl-4-oxo-4h-quinazolin-3-yl)-piperidine-2,6-dione, and their pharmaceutical compositions and uses |
| US9090585B2 (en) | 2011-03-28 | 2015-07-28 | Deuterx, Llc | 2,6-dioxo-3-deutero-piperdin-3-yl-isoindoline compounds |
| MX2013012083A (es) | 2011-04-18 | 2014-04-16 | Celgene Corp | Biomarcadores para el tratamiento de mieloma multiple. |
| EP3096142A3 (en) | 2011-04-29 | 2017-03-08 | Celgene Corporation | Methods for the treatment of cancer and inflammatory diseases using cereblon as a predictor |
| EP3443968A1 (en) | 2011-06-01 | 2019-02-20 | Celularity, Inc. | Treatment of pain using placental stem cells |
| WO2012177678A2 (en) | 2011-06-22 | 2012-12-27 | Celgene Corporation | Isotopologues of pomalidomide |
| US9884042B2 (en) | 2011-09-14 | 2018-02-06 | Celgene Corporation | Formulations of cyclopropanecarboxylic acid {2-[(1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide |
| KR102035362B1 (ko) | 2011-12-27 | 2019-10-22 | 셀진 코포레이션 | (+)-2-[1-(3-에톡시-4-메톡시-페닐)-2-메탄술포닐-에틸]-4-아세틸아미노이소인돌린-1,3-디온의 제제 |
| EP2858667A1 (en) | 2012-06-06 | 2015-04-15 | Bionor Immuno AS | Hiv vaccine |
| WO2014004990A2 (en) | 2012-06-29 | 2014-01-03 | Celgene Corporation | Methods for determining drug efficacy using cereblon-associated proteins |
| JP2015524811A (ja) | 2012-07-27 | 2015-08-27 | セルジーン コーポレイション | イソインドリン−１，３−ジオン化合物の調製プロセス |
| US9221788B2 (en) | 2012-08-09 | 2015-12-29 | Celgene Corporation | Salts and solid forms of (S)-3-(4- (4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and compositions comprising and methods of using the same |
| US9587281B2 (en) | 2012-08-14 | 2017-03-07 | Celgene Corporation | Cereblon isoforms and their use as biomarkers for therapeutic treatment |
| US9694015B2 (en) | 2012-09-10 | 2017-07-04 | Celgene Corporation | Methods for the treatment of locally advanced breast cancer |
| JP6359563B2 (ja) | 2013-01-14 | 2018-07-18 | デュートルクス・リミテッド・ライアビリティ・カンパニーＤｅｕｔｅＲｘ， ＬＬＣ | ３−（５置換−４−オキソキナゾリン−３（４ｈ）−イル）−３−ジュウテロピペリジン−２，６−ジオン誘導体 |
| AU2014215458A1 (en) | 2013-02-05 | 2015-08-13 | Anthrogenesis Corporation | Natural killer cells from placenta |
| EP2764866A1 (en) | 2013-02-07 | 2014-08-13 | IP Gesellschaft für Management mbH | Inhibitors of nedd8-activating enzyme |
| AU2014236597A1 (en) | 2013-03-14 | 2015-09-24 | Deuterx, Llc | 3-(substituted-4-oxo-quinazolin-3(4H)-yl)-3-deutero-piperidine-2,6-dione derivatives |
| WO2014172429A1 (en) | 2013-04-17 | 2014-10-23 | Signal Pharmaceuticals, Llc | Combination therapy comprising a tor kinase inhibitor and an imid compound for treating cancer |
| WO2015007337A1 (en) | 2013-07-19 | 2015-01-22 | Bionor Immuno As | Method for the vaccination against hiv |
| WO2015200795A1 (en) | 2014-06-27 | 2015-12-30 | Celgene Corporation | Compositions and methods for inducing conformational changes in cereblon other e3 ubiquitin ligases |
| AU2015305449B2 (en) | 2014-08-22 | 2021-05-06 | Celgene Corporation | Methods of treating multiple myeloma with immunomodulatory compounds in combination with antibodies |
| PT3214081T (pt) | 2014-10-30 | 2020-08-31 | Kangpu Biopharmaceuticals Ltd | Derivado de isoindolina, seu intermediário, seu método de preparação, sua composição farmacêutica e sua utilização |
| HUE065109T2 (hu) | 2015-06-26 | 2024-05-28 | Celgene Corp | Eljárások Kaposi-szarkóma vagy KSHV-indukált limfóma kezelésére immunomodulátor vegyületek alkalmazásával, valamint biomarkerek alkalmazása |
| US9809603B1 (en) | 2015-08-18 | 2017-11-07 | Deuterx, Llc | Deuterium-enriched isoindolinonyl-piperidinonyl conjugates and oxoquinazolin-3(4H)-yl-piperidinonyl conjugates and methods of treating medical disorders using same |
| WO2017117118A1 (en) | 2015-12-28 | 2017-07-06 | Celgene Corporation | Compositions and methods for inducing conformational changes in cereblon and other e3 ubiquitin ligases |
| ITUB20169994A1 (it) | 2016-01-14 | 2017-07-14 | Phf Sa | Nuove forme cristalline di farmaci immunomodulatori |
| WO2018102786A1 (en) | 2016-12-03 | 2018-06-07 | Juno Therapeutics, Inc. | Methods for modulation of car-t cells |
| PL3618842T3 (pl) | 2017-05-01 | 2024-02-19 | Juno Therapeutics, Inc. | Kombinacja terapii komórkowej i związku immunomodulującego |
| BR112019025403A2 (pt) | 2017-06-02 | 2020-08-18 | Juno Therapeutics Inc | artigos de fabricação e métodos para tratamento usando terapia celular adotiva |
| JP2020526194A (ja) | 2017-06-29 | 2020-08-31 | ジュノー セラピューティクス インコーポレイテッド | 免疫療法薬と関連する毒性を評価するためのマウスモデル |
| WO2019067792A1 (en) | 2017-09-28 | 2019-04-04 | Celularity, Inc. | TUMOR CONTROL WITH INTERMEDIATE NATURAL KILLER CELLS DERIVED FROM HUMAN PLACENTA (PINK) IN COMBINATION WITH ANTIBODY |
| WO2019089858A2 (en) | 2017-11-01 | 2019-05-09 | Juno Therapeutics, Inc. | Methods of assessing or monitoring a response to a cell therapy |
| BR112020008323A2 (pt) | 2017-11-01 | 2020-11-03 | Juno Therapeutics Inc | anticorpos e receptores de antígenos quiméricos específicos para antígeno de maturação de células b |
| CN111372585A (zh) | 2017-11-16 | 2020-07-03 | C4医药公司 | 用于靶蛋白降解的降解剂和降解决定子 |
| MA51184A (fr) | 2017-12-15 | 2020-10-21 | Juno Therapeutics Inc | Molécules de liaison à l'anti-cct5 et procédés d'utilisation associés |
| EP3755718A1 (en) | 2018-02-21 | 2020-12-30 | Celgene Corporation | Bcma-binding antibodies and uses thereof |
| CN111902141A (zh) | 2018-03-26 | 2020-11-06 | C4医药公司 | 用于ikaros降解的羟脑苷脂结合剂 |
| EP3781156A4 (en) | 2018-04-16 | 2022-05-18 | C4 Therapeutics, Inc. | SPIROCYCLIC COMPOUNDS |
| WO2020051235A1 (en) | 2018-09-04 | 2020-03-12 | C4 Therapeutics, Inc. | Compounds for the degradation of brd9 or mth1 |
| WO2020097403A1 (en) | 2018-11-08 | 2020-05-14 | Juno Therapeutics, Inc. | Methods and combinations for treatment and t cell modulation |
| EP3880669A1 (en) | 2018-11-13 | 2021-09-22 | Biotheryx, Inc. | Substituted isoindolinones |
| EP3880238A1 (en) | 2018-11-16 | 2021-09-22 | Juno Therapeutics, Inc. | Methods of dosing engineered t cells for the treatment of b cell malignancies |
| EP3886875B1 (en) | 2018-11-30 | 2024-05-08 | Juno Therapeutics, Inc. | Methods for treatment using adoptive cell therapy |
| EP3897636A4 (en) | 2018-12-19 | 2022-09-07 | Celgene Corporation | SUBSTITUTED 3-((3-AMINOPHENYL)AMINO)PIPERIDINE-2,6-DIONE COMPOUNDS, COMPOSITIONS THEREOF AND METHODS OF TREATING THEREOF |
| CN113453679A (zh) | 2018-12-20 | 2021-09-28 | C4医药公司 | 靶向蛋白降解 |
| CA3123303A1 (en) | 2019-01-29 | 2020-08-06 | Juno Therapeutics, Inc. | Antibodies and chimeric antigen receptors specific for receptor tyrosine kinase like orphan receptor 1 (ror1) |
| WO2020181232A1 (en) | 2019-03-06 | 2020-09-10 | C4 Therapeutics, Inc. | Heterocyclic compounds for medical treatment |
| WO2022152821A1 (en) | 2021-01-13 | 2022-07-21 | Monte Rosa Therapeutics Ag | Isoindolinone compounds |
| WO2023220655A1 (en) | 2022-05-11 | 2023-11-16 | Celgene Corporation | Methods to overcome drug resistance by re-sensitizing cancer cells to treatment with a prior therapy via treatment with a t cell therapy |
| WO2023220641A2 (en) | 2022-05-11 | 2023-11-16 | Juno Therapeutics, Inc. | Methods and uses related to t cell therapy and production of same |
| WO2023250400A1 (en) | 2022-06-22 | 2023-12-28 | Juno Therapeutics, Inc. | Treatment methods for second line therapy of cd19-targeted car t cells |
| WO2024097905A1 (en) | 2022-11-02 | 2024-05-10 | Celgene Corporation | Methods of treatment with t cell therapy and immunomodulatory agent maintenance therapy |
Family Cites Families (56)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3378763D1 (en) * | 1982-04-02 | 1989-02-02 | Takeda Chemical Industries Ltd | Condensed pyrrolinone derivatives, and their production |
| US4849441A (en) * | 1986-12-25 | 1989-07-18 | Kyowa Hakko Kogyo Co., Ltd. | Isoindolin-1-one derivative and antiarrhythmic agent |
| US4808402A (en) * | 1987-05-29 | 1989-02-28 | Northwestern University | Method and compositions for modulating neovascularization |
| DK24089D0 (da) * | 1989-01-20 | 1989-01-20 | Hans Bundgaard | Novel prodrug derivatives of biologically active agents containing hydroxyl groups or nh-acidic groups |
| GB9109645D0 (en) | 1991-05-03 | 1991-06-26 | Celltech Ltd | Recombinant antibodies |
| AU1531492A (en) * | 1991-02-14 | 1992-09-15 | Rockefeller University, The | Method for controlling abnormal concentration tnf alpha in human tissues |
| AU661299B2 (en) * | 1991-04-17 | 1995-07-20 | Grunenthal Gmbh | New thalidomide derivatives, method of manufacture and use thereof in medicaments |
| US6228879B1 (en) | 1997-10-16 | 2001-05-08 | The Children's Medical Center | Methods and compositions for inhibition of angiogenesis |
| US20010056114A1 (en) | 2000-11-01 | 2001-12-27 | D'amato Robert | Methods for the inhibition of angiogenesis with 3-amino thalidomide |
| US5629327A (en) * | 1993-03-01 | 1997-05-13 | Childrens Hospital Medical Center Corp. | Methods and compositions for inhibition of angiogenesis |
| US5463063A (en) * | 1993-07-02 | 1995-10-31 | Celgene Corporation | Ring closure of N-phthaloylglutamines |
| US5698579A (en) | 1993-07-02 | 1997-12-16 | Celgene Corporation | Cyclic amides |
| DE4422237A1 (de) * | 1994-06-24 | 1996-01-04 | Gruenenthal Gmbh | Verwendung von Lactamverbindungen als pharmazeutische Wirkstoffe |
| US5795368A (en) * | 1996-03-01 | 1998-08-18 | O.I. Corporation | Microtrap sample concentrator and methods of use |
| DE19613976C1 (de) * | 1996-04-09 | 1997-11-20 | Gruenenthal Gmbh | Thalidomid-Prodrugs mit immunmodulatorischer Wirkung |
| US6281230B1 (en) | 1996-07-24 | 2001-08-28 | Celgene Corporation | Isoindolines, method of use, and pharmaceutical compositions |
| US5798368A (en) | 1996-08-22 | 1998-08-25 | Celgene Corporation | Tetrasubstituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines and method of reducing TNFα levels |
| ES2529190T3 (es) * | 1996-07-24 | 2015-02-17 | Celgene Corporation | 2-(2,6-dioxopiperidin-3-il)-ftalimidas sustituidas por amino para reducir los niveles de TNF-alfa |
| US5635517B1 (en) | 1996-07-24 | 1999-06-29 | Celgene Corp | Method of reducing TNFalpha levels with amino substituted 2-(2,6-dioxopiperidin-3-YL)-1-oxo-and 1,3-dioxoisoindolines |
| HU228769B1 (en) | 1996-07-24 | 2013-05-28 | Celgene Corp | Substituted 2(2,6-dioxopiperidin-3-yl)phthalimides and -1-oxoisoindolines and their use for production of pharmaceutical compositions for mammals to reduce the level of tnf-alpha |
| CA2262906C (en) | 1996-08-12 | 2006-10-31 | Celgene Corporation | Novel immunotherapeutic agents and their use in the reduction of cytokine levels |
| DK1586322T3 (da) | 1996-11-05 | 2008-12-01 | Childrens Medical Center | Sammensætninger indeholdende thalidomid og dextamethason til behandling af cancer |
| US5955476A (en) | 1997-11-18 | 1999-09-21 | Celgene Corporation | Substituted 2-(2,6-dioxo-3-fluoropiperidin-3-yl)-isoindolines and method of reducing inflammatory cytokine levels |
| US5874448A (en) * | 1997-11-18 | 1999-02-23 | Celgene Corporation | Substituted 2-(2,6 dioxo-3-fluoropiperidin-3-yl)-isoindolines and method of reducing TNFα levels |
| CA2321920C (en) * | 1998-03-16 | 2010-05-25 | Hon-Wah Man | 2-(2,6-dioxopiperidin-3-yl)isoindoline derivatives, their preparation and their use as inhibitors of inflammatory cytokines |
| US6673828B1 (en) | 1998-05-11 | 2004-01-06 | Children's Medical Center Corporation | Analogs of 2-Phthalimidinoglutaric acid |
| SK12832001A3 (sk) * | 1999-03-12 | 2002-01-07 | Boehringer Ingelheim Pharmaceuticals, Inc. | Protizápalové látky, spôsob ich výroby, farmaceutický prostriedok s ich obsahom a ich použitie |
| WO2000055134A1 (en) | 1999-03-18 | 2000-09-21 | Celgene Corporation | Substituted 1-oxo- and 1,3-dioxoisoindolines and their use in pharmaceutical compositions for reducing inflammatory cytokine levels |
| US7182953B2 (en) | 1999-12-15 | 2007-02-27 | Celgene Corporation | Methods and compositions for the prevention and treatment of atherosclerosis restenosis and related disorders |
| MXPA02009665A (es) | 2000-03-31 | 2005-09-08 | Celgene Corp | Inhibicion de actividad de ciclooxigenasa-2. |
| US6458810B1 (en) | 2000-11-14 | 2002-10-01 | George Muller | Pharmaceutically active isoindoline derivatives |
| AU2002253795B2 (en) | 2000-11-30 | 2007-02-01 | The Children's Medical Center Corporation | Synthesis of 4-Amino-Thalidomide enantiomers |
| US20030045552A1 (en) | 2000-12-27 | 2003-03-06 | Robarge Michael J. | Isoindole-imide compounds, compositions, and uses thereof |
| US7091353B2 (en) | 2000-12-27 | 2006-08-15 | Celgene Corporation | Isoindole-imide compounds, compositions, and uses thereof |
| EP1389203B8 (en) | 2001-02-27 | 2010-03-10 | The Governement of the United States of America, represented by The Secretary Department of Health and Human services | Analogs of thalidomide as angiogenesis inhibitors |
| WO2003014315A2 (en) | 2001-08-06 | 2003-02-20 | The Children's Medical Center Corporation | Synthesis and anti-tumor activity of nitrogen substituted thalidomide analogs |
| WO2003086373A1 (en) | 2002-04-12 | 2003-10-23 | Celgene Corporation | Methods for identification of modulators of angiogenesis, compounds discovered thereby, and methods of treatment using the compounds |
| US7498171B2 (en) | 2002-04-12 | 2009-03-03 | Anthrogenesis Corporation | Modulation of stem and progenitor cell differentiation, assays, and uses thereof |
| US7968569B2 (en) | 2002-05-17 | 2011-06-28 | Celgene Corporation | Methods for treatment of multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione |
| CN102429908A (zh) | 2002-05-17 | 2012-05-02 | 细胞基因公司 | 用于治疗和控制多发性骨髓瘤的方法及组合物 |
| US7323479B2 (en) | 2002-05-17 | 2008-01-29 | Celgene Corporation | Methods for treatment and management of brain cancer using 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-methylisoindoline |
| US7189740B2 (en) | 2002-10-15 | 2007-03-13 | Celgene Corporation | Methods of using 3-(4-amino-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for the treatment and management of myelodysplastic syndromes |
| MXPA05004182A (es) | 2002-10-24 | 2005-06-08 | Celgene Corp | Metodos de uso y composiciones que contienen compuestos inmunomoduladores para el tratamiento, modificacion y manejo del dolor. |
| US20050203142A1 (en) | 2002-10-24 | 2005-09-15 | Zeldis Jerome B. | Methods of using and compositions comprising immunomodulatory compounds for treatment, modification and management of pain |
| JP2006508950A (ja) | 2002-10-31 | 2006-03-16 | セルジーン・コーポレーション | 黄斑変性の治療用組成物 |
| US20040091455A1 (en) | 2002-10-31 | 2004-05-13 | Zeldis Jerome B. | Methods of using and compositions comprising immunomodulatory compounds for treatment and management of macular degeneration |
| US7563810B2 (en) | 2002-11-06 | 2009-07-21 | Celgene Corporation | Methods of using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione for the treatment and management of myeloproliferative diseases |
| UA83504C2 (en) | 2003-09-04 | 2008-07-25 | Селджин Корпорейшн | Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione |
| US20050100529A1 (en) | 2003-11-06 | 2005-05-12 | Zeldis Jerome B. | Methods of using and compositions comprising immunomodulatory compounds for the treatment and management of asbestos-related diseases and disorders |
| WO2005055929A2 (en) | 2003-12-02 | 2005-06-23 | Celgene Corporation | Methods and compositions for the treatment and management of hemoglobinopathy and anemia |
| US20050143344A1 (en) | 2003-12-30 | 2005-06-30 | Zeldis Jerome B. | Methods and compositions using immunomodulatory compounds for the treatment and management of central nervous system disorders or diseases |
| KR101224262B1 (ko) | 2004-03-22 | 2013-01-21 | 셀진 코포레이션 | 면역조절 화합물을 포함하는 피부 질환 또는 장애의 치료및 관리용 조성물 및 이의 사용 방법 |
| US20050222209A1 (en) | 2004-04-01 | 2005-10-06 | Zeldis Jerome B | Methods and compositions for the treatment, prevention or management of dysfunctional sleep and dysfunctional sleep associated with disease |
| MXPA06011798A (es) | 2004-04-14 | 2007-01-16 | Celgene Corp | Metodos de uso y composiciones que comprenden compuestos inmunomoduladores para el tratamiento y manejo de sindromes mielodisplasticos. |
| CN101163489A (zh) | 2004-04-23 | 2008-04-16 | 细胞基因公司 | 用于治疗和控制肺高血压的包含免疫调节化合物的组合物及其使用方法 |
| CA2565447A1 (en) | 2004-05-05 | 2005-12-01 | Celgene Corporation | Method of using and compositions comprising immunomodulatory compounds for the treatment and management of myeloproliferative diseases |
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