CN1240382C - 以吡啶并吲哚酮衍生物和抗癌剂为基的药物组合 - Google Patents
以吡啶并吲哚酮衍生物和抗癌剂为基的药物组合 Download PDFInfo
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Abstract
本发明涉及式(I)化合物与几种抗癌剂的组合。
Description
本发明的目的是吡啶并吲哚酮衍生物和抗癌剂的新组合(association),和含有它们的药物组合物。
本发明中可使用的吡啶并吲哚酮衍生物是下式化合物:
式中:
-R1代表氢原子或甲基或乙基;
-R2代表甲基或乙基;或者
-R1和R2一起形成(CH2)3基团;
-r3代表或者任选地被卤原子或甲基或甲氧基取代的苯基,或者噻吩基;
-R4代表氢原子或氯原子或甲基或甲氧基。
曾发现式(I)化合物,即抗癌剂,可以有利地与其它抗癌剂组合。优选的吡啶并吲哚酮衍生物是下式化合物:
式中:
-R1代表氢原子、甲基或乙基;
-R2代表甲基或乙基;或者
-R1和R2一起形成(CH2)3基团;
-R3代表氢原子或卤素原子或甲基或甲氧基;
-R4代表氢原子或氯原子或甲基或甲氧基。
特别优选的吡啶并吲哚酮的衍生物是下式的化合物:
其中:
-R1代表氢原子、甲基或乙基;
-R2代表甲基或乙基;
-R3代表氢原子或卤素原子或甲基或甲氧基;
-R4代表氢原子或氯原子或甲基或甲氧基。
更特别优选吡啶并吲哚酮的衍生物是下式化合物:
式中:
-R1代表甲基或乙基;
-R2代表甲基或乙基;
-R3代表氢原子或卤素原子或甲基或甲氧基;
-R4代表氢原子或氯原子或甲基或甲氧基。
作为例子,本发明的吡啶并吲哚酮衍生物是:
6-氯-1,9-二甲基-3-苯基-1,9-二氢-2H-吡啶并[2,3-b]吲哚-2-酮;
F=178.5-179.5℃;
3-(4-甲氧基苯基)-1,9-二甲基-1,9-二氢-2H-吡啶并[2,3-b]吲哚-2-酮;
F=166-167℃;
1,6,9-三甲基-3-(3-噻吩基)-1,9-二氢-2H-吡啶并[2,3-b]吲哚-2-酮;
RMN(200MHz):2.6ppm:s:3H;4.1ppm:s:3H;4.2ppm:s:3H;7.1ppm:d:1H;7.4-7.9ppm:m:4H;8.3ppm:d:1H;8.7ppm:s:1H。
1,6,9-三甲基-3-苯基-1,9-二氢-2H-吡啶并[2,3-b]吲哚-2-酮;
F=198-199℃;
1,6-二甲基-3-苯基-1,9-二氢-2H-吡啶并[2,3-b]吲哚-2-酮;
RMN(200MHz):2.5ppm:s:3H;3.8ppm:s:3H;7.1ppm:d:1H;7.3-7.5ppm:m:4H;7.75ppm:d:2H;7.8ppm:s:1H;8.4ppm:s:1H;11.8ppm:s:1H。
根据文件FR 97 08409中描述的方法制备式(I)化合物。
已在活体外对人乳房癌细胞系体外试验过式(I)化合物:从美国典型培养物保藏中心可获得的细胞系MDA-MB-231(保藏号HTB26)。
根据J.M.Derocq等人,FEBS Letters,1998,425,第419-425页进行了抗增殖作用的评价:在与式(I)化合物温育96小时之后,测定在处理细胞的DNA中[3H]胸苷掺入率。50%抑制浓度(IC50)定义为抑制细胞增殖50%的浓度。
这些式(I)化合物对于MDA-MB-231细胞系的IC50一般小于10μM。
还对另一种人乳房癌细胞系,即所述多抗性细胞系MDR,并称之MDA-A1,试验了式(I)化合物。E.Collomb,C.Dussert和P.M.Martin在Cytometry,1991,12(1),第15-25页中描述过这种细胞系。
说明这种细胞系的术语“多抗性”,意思是上述细胞系对通常使用的化疗药物,特别是天然来源的抗有丝分裂药物,例如紫杉醇(paclitaxel),长春新碱,长春碱一般来说是不太敏感的。
式(I)化合物对于多抗性细胞系MDA-A1的IC50一般小于10μM。
因此,式(I)化合物抑制肿瘤细胞的增殖,其中包括具有多抗性的细胞增殖。
也按照对免疫低下的小鼠SCID(从英文为严重的合并免疫缺陷)皮下植入人肿瘤异种移植物的模型在活体内评价了几种式(I)化合物。
当移植后6-7天肿瘤达到肿瘤质量约60毫克时开始用式(I)化合物处理动物。该化合物在溶剂中的溶液被以口服途径用药。
在只用溶剂处理的对照动物体内平均肿瘤质量达到约1000毫克时评价抗肿瘤活性:测定T/C比,T代表接受治疗动物的肿瘤的平均重量,C代表对照动物的肿瘤的平均重量。根据Stuart T等人,在J.Med.Chem.,2001,44(11),第1758-1776页中的描述,T/C比小于或等于42%被认为是有效抗肿瘤活性的指征。日服用剂量在50和300毫克/千克之间时,某些式(I)化合物达到T/C比小于20%。
根据参考技术(J.M.Derocq等),对MDA-A1细胞系,即上述所谓的多抗性细胞系,测定了式(I)化合物与另一种抗癌剂组合的抗增殖作用。只用抗癌剂所达到的IC50与用相同抗癌剂和式(I)化合物组合所达到的IC50进行了比较。观察到IC50明显降低。对于某些式(I)吡啶并吲哚酮的衍生物与另一种抗癌剂组合,可以用系数2至100,甚至超过100除IC50。
作为例子,只用紫杉醇达到的IC50与用紫杉醇和1,6,9-三甲基-3-苯基-1,9-二氢-2H-吡啶并[2,3-b]吲哚-2-酮组合达到的IC50进行比较。根据使用的1,6,9-三甲基-3-苯基-1,9-二氢-2H-吡啶并[2,3-b]吲哚-2-酮的浓度,IC50可以被系数除14至100。
试验结果证明,本发明组合成分有协同效应和抗增殖作用的潜力。
根据本发明,与一种(或多种)抗癌活性成分组合时可服用一种或多种式(I)化合物。这些活性成分尤其可以是抗肿瘤化合物,例如烷基化剂类,烷基磺酸酯(二甲磺酸丁酯),达卡巴嗪,甲基苄肼,含氮芥(盐酸氮芥,苯丙氨酸氮芥,苯丁酸氮芥),环磷酰胺,异环磷酰胺;亚硝基脲类,例如亚硝基脲氮芥,罗氮芥,甲环亚硝脲,链脲霉素;抗肿瘤生物碱类,例如长春新碱,长春碱;紫杉碱类,例如紫杉醇;抗肿瘤抗生素类,例如放线菌素;添加剂类,抗肿瘤的抗代谢物类,叶酸盐拮抗剂,甲氨蝶呤;嘌呤合成抑制剂;嘌呤类似物,例如巯基嘌呤,6-硫代鸟嘌呤;嘧啶合成抑制剂类,芳香酶抑制剂类,capécitabine,嘧啶类似物,例如氟尿嘧啶,gemcitabine,阿糖孢苷和阿糖糖苷胞嘧啶;bréquinar;抗癌激素激动剂和拮抗剂类,其中包括他莫昔芬;激酶抑制剂类,imatinib;生长因子抑制剂类;癌瘤学领域起作用的一些抗炎剂类,例如戊聚糖多硫酸盐,皮质类固醇,强的松,地塞米松;抗拓扑异构酶类,例如依托泊苷,antracyclines,其中包括阿霉素,博来霉素,丝裂霉素和méthramycine;抗肿瘤金属络合物类,铂络合物,顺铂,卡铂,奥沙利铂;α干扰素类,三苯基硫代磷酰胺,六甲蜜胺;抗血管生成剂类;免疫治疗辅助剂类。
本发明的这些组合对于预防和治疗由肿瘤细胞增殖引起或加剧的疾病是有效的,其疾病例如是原发性或转移肿瘤,恶性肿瘤和癌,特别是乳房癌;肺癌;小肠癌,结肠癌和直肠癌;呼吸道癌,口咽和咽下癌;食道癌;肝癌,胃癌,胆管癌,胆囊癌,胰腺癌;其中包括肾和尿路上皮在内的尿道癌,膀胱癌;女性生殖道癌,其中包括子宫癌,子宫颈癌,卵巢癌,chloriocarcinome,和绒毛膜上皮癌;男性生殖道癌,其中包括前列腺癌,精囊癌,睾丸癌,生殖细胞肿瘤;内分泌腺体癌,其中包括甲状腺癌,垂体癌,肾上腺癌;皮肤癌,其中包括血管瘤,黑素瘤,肉瘤,其中包括卡波西肉瘤;脑部肿瘤,神经肿瘤,眼部肿瘤,脑膜肿瘤,其中包括星形细胞瘤,神经胶质瘤,成胶质细胞瘤,视网膜母细胞瘤,神经母细胞瘤,神经鞘瘤,听神经神经鞘瘤,脑膜瘤;造血恶性肿瘤生长发育肿瘤,其中包括白血病,绿色肉瘤,浆细胞瘤,蔁状真菌病,T细胞的淋巴瘤或白血病,非霍奇金氏淋巴瘤,恶性血液病,骨髓瘤。
本发明还有一个目的是药物组合物,它们含有治疗有效量的至少一种式(I)化合物或所述化合物的药学可接受的盐,水合物或溶剂合物作为一种或多种活性成分,和治疗有效量的一种(或几种)另外一种或多种抗癌活性成分,以及一种或多种药学可接受的赋形剂。
根据药物剂型和希望的给药方式选择所述的赋形剂,其中包括在现有技术中已知的常规赋形剂。
可以制备,用于预防或治疗上述疾病的口服、舌下、皮下、肌内、静脉内、局部、局域、气管内、经皮或直肠用药的本发明药物组合物,或者动物和人的其它任何适当途径用药的本发明药物组合物。
可以以每千克待治疗哺乳动物体重为0.002至2000毫克的日剂量,优选地0.1至300毫克/千克日剂量使用上述式(I)的化合物。在人身上,根据待治疗者的年龄或治疗类型(预防性或治愈性)改变剂量,优选每天0.02至10000毫克,更特别地,1至3000毫克。
按常规剂量使用与式(I)的化合物组合的抗癌活性成分。
合适的给药剂型包括口服剂型,例如片剂,软胶囊或硬胶囊,粉剂,颗粒剂,和口服溶液或混悬剂,舌下,口腔,气管内,眼内,通过吸入鼻内给药剂型,局部,经皮,皮下,肌内或静脉内给药剂型,直肠给药剂型和植入物用药形式。对于局部涂敷,可以使用本发明组合霜剂,凝胶,软膏或洗剂。
根据常规实践,医师可以根据给药方式,所述患者的年龄,体重和症状确定每个患者合适的剂量。
根据本发明的另一方面,在由肿瘤细胞增殖引起或加重的患者治疗期间,可以同时,依次或分期方式施用一种或几种式(I)化合物和一种(或多种)另外的抗癌活性成分。
本发明组合可以为试剂盒形式,所述的试剂盒装有至少一种式(I)的化合物和一种(或几种)另外的抗癌活性成分。
根据另外一个方面,本发明还涉及由肿瘤细胞增殖引起或加重的疾病的治疗方法,该方法在于让需要治疗的受试者施用治疗有效量的至少一种式(I)的化合物和一种(或多种)另外的抗癌活性成分。
Claims (6)
2.根据权利要求1的组合,其中式(I)的化合物为下式(Ibis)的化合物:
式中:
-R1代表氢原子、甲基或乙基;
-R2代表甲基或乙基;或者
-R1和R2一起形成(CH2)3基团;
-R3代表氢原子或卤素原子或甲基或甲氧基;
-R4代表氢原子或氯原子或甲基或甲氧基。
4.根据权利要求1所述的组合,其中式(I)化合物是其中一种下述化合物:
-6-氯-1,9-二甲基-3-苯基-1,9-二氢-2H-吡啶并[2,3-b]吲哚-2-酮;
-3-(4-甲氧基苯基)-1,9-二甲基-1,9-二氢-2H-吡啶并[2,3-b]吲哚-2-酮;
-1,6,9-三甲基-3-(3-噻吩基)-1,9-二氢-2H-吡啶并[2,3-b]吲哚-2-酮;
-1,6,9-三甲基-3-苯基-1,9-二氢-2H-吡啶并[2,3-b]吲哚-2-酮;
-1,6-二甲基-3-苯基-1,9-二氢-2H-吡啶并[2,3-b]吲哚-2-酮。
5.含有根据权利要求1所述的组合和一种或几种药学可接受赋形剂的药物组合物。
6.治疗肿瘤细胞增殖的试剂盒,该试剂盒含有根据权利要求1所述的组合,这些化合物装在不同的格子中,并且用于同时、依次或分期的方式给药。
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FR0105843A FR2823975B1 (fr) | 2001-04-27 | 2001-04-27 | Nouvelle utilisation de pyridoindolone |
FR01/05843 | 2001-04-27 |
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FR2823975B1 (fr) * | 2001-04-27 | 2003-05-30 | Sanofi Synthelabo | Nouvelle utilisation de pyridoindolone |
FR2846329B1 (fr) * | 2002-10-23 | 2004-12-03 | Sanofi Synthelabo | Derives de pyridoindolone substitues en -3 par un phenyle, leur preparation et leur application en therapeutique |
US7456193B2 (en) | 2002-10-23 | 2008-11-25 | Sanofi-Aventis | Pyridoindolone derivatives substituted in the 3-position by a heterocyclic group, their preparation and their application in therapeutics |
FR2869316B1 (fr) * | 2004-04-21 | 2006-06-02 | Sanofi Synthelabo | Derives de pyridoindolone substitues en -6, leur preparation et leur application en therapeutique. |
FR2892416B1 (fr) | 2005-10-20 | 2008-06-27 | Sanofi Aventis Sa | Derives de 6-heteroarylpyridoindolone, leur preparation et leur application en therapeutique |
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GB1268772A (en) * | 1968-03-15 | 1972-03-29 | Glaxo Lab Ltd | NOVEL alpha-CARBOLINE DERIVATIVES, THE PREPARATION THEREOF AND COMPOSITIONS CONTAINING THE SAME |
US4263304A (en) * | 1978-06-05 | 1981-04-21 | Sumitomo Chemical Company, Limited | 7 H-indolo[2,3-c]isoquinolines |
SU833971A1 (ru) * | 1979-07-10 | 1981-05-30 | Ленинградский Химико-Фармацевтическийинститут | Способ получени 3-фенил-2-оксо- - КАРбОлиНОВ |
SU833972A1 (ru) | 1979-10-26 | 1981-05-30 | Институт Физико-Органической Химиии Углехимии Ah Украинской Ccp | Имидазо(4,5-с)пиридиний иодиды вКАчЕСТВЕ пРОМЕжуТОчНыХ пРОдуКТОВ дл СиНТЕзА фуНгицидОВ |
FR2595701B1 (fr) * | 1986-03-17 | 1988-07-01 | Sanofi Sa | Derives du pyrido-indole, leur application a titre de medicaments et les compositions les renfermant |
US5035252A (en) * | 1990-12-14 | 1991-07-30 | Mondre Steven J | Nicotine-containing dental floss |
EP0755454B1 (en) * | 1994-04-13 | 2008-02-13 | The Rockefeller University | Aav-mediated delivery of dna to cells of the nervous system |
DE19502753A1 (de) * | 1995-01-23 | 1996-07-25 | Schering Ag | Neue 9H-Pyrido[3,4-b]indol-Derivate |
US6486177B2 (en) * | 1995-12-04 | 2002-11-26 | Celgene Corporation | Methods for treatment of cognitive and menopausal disorders with D-threo methylphenidate |
FR2765581B1 (fr) * | 1997-07-03 | 1999-08-06 | Synthelabo | Derives de 3-aryl-1,9-dihydro-2h-pyrido[2,3-b]indol-2-one, leur preparation et leur application en therapeutique |
FR2765582B1 (fr) * | 1997-07-03 | 1999-08-06 | Synthelabo | Derives de 3-alkyl-1,9-dihydro-2h-pyrido[2,3-b]indol-2-one leur preparation et leur application en therapeutique |
WO1999051597A1 (en) * | 1998-04-02 | 1999-10-14 | Neurogen Corporation | Aminoalkyl substituted 5,6,7,8-tetrahydro-9h pyrimidino[2,3-b]indole and 5,6,7,8-tetrahydro-9h-pyrimidino[4,5-b]indole derivatives: crf1 specific ligands |
IT1313592B1 (it) | 1999-08-03 | 2002-09-09 | Novuspharma Spa | Derivati di 1h-pirido 3,4-b indol-1-one. |
US20020156016A1 (en) * | 2001-03-30 | 2002-10-24 | Gerald Minuk | Control of cell growth by altering cell membrane potentials |
FR2823975B1 (fr) * | 2001-04-27 | 2003-05-30 | Sanofi Synthelabo | Nouvelle utilisation de pyridoindolone |
FR2846330B1 (fr) | 2002-10-23 | 2004-12-03 | Sanofi Synthelabo | Derives de pyridoindolone substitues en -3 par groupe heterocyclique, leur preparation et leur application en therapeutique |
FR2846329B1 (fr) | 2002-10-23 | 2004-12-03 | Sanofi Synthelabo | Derives de pyridoindolone substitues en -3 par un phenyle, leur preparation et leur application en therapeutique |
US6958347B2 (en) | 2002-12-18 | 2005-10-25 | Pfizer Inc. | Aminophenanthridinone and aminophenanthridine as NPY-5 antagonists |
FR2869316B1 (fr) * | 2004-04-21 | 2006-06-02 | Sanofi Synthelabo | Derives de pyridoindolone substitues en -6, leur preparation et leur application en therapeutique. |
FR2892416B1 (fr) | 2005-10-20 | 2008-06-27 | Sanofi Aventis Sa | Derives de 6-heteroarylpyridoindolone, leur preparation et leur application en therapeutique |
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