CN105377843B - 化合物的新型盐、其制备以及包含其的制剂 - Google Patents
化合物的新型盐、其制备以及包含其的制剂 Download PDFInfo
- Publication number
- CN105377843B CN105377843B CN201480038854.7A CN201480038854A CN105377843B CN 105377843 B CN105377843 B CN 105377843B CN 201480038854 A CN201480038854 A CN 201480038854A CN 105377843 B CN105377843 B CN 105377843B
- Authority
- CN
- China
- Prior art keywords
- base
- methyl
- compound
- cancer
- pyrroles
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
本发明涉及式(II)的新型盐,3‑[(3‑{[4‑(4‑吗啉基甲基)‑1H‑吡咯‑2‑基]亚甲基}‑2‑氧代‑2,3‑二氢‑1H‑吲哚‑5‑基)甲基]‑1,3‑噻唑烷‑2,4‑二酮甲磺酸盐。
Description
本发明涉及式(I)的3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2- 氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮的新型盐:
其制备方法以及包含其的药物组合物。
3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H- 吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮在癌症学领域具有非常有价值的药理学性质。事实上,已经证实3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮具有抑制癌细胞迁移的能力,使其在癌症、尤其是固体转移性肿瘤的治疗中特别有用。所设想的用于治疗的癌症可以提到但不限于如下这些:结肠癌、乳腺癌、肝癌、肾癌、脑癌和食道癌、黑色素瘤、骨髓瘤、卵巢癌、非小细胞肺癌、小细胞肺癌、***癌和胰腺癌,以及肉瘤。
在欧洲专利说明书EP 2281822中记载了3-[(3-{[4-(4-吗啉基甲基)-1H- 吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮的制备和治疗应用,以及其与可药用酸的加成盐,尤其是其盐酸盐。
鉴于该化合物的药用价值,能够以良好的收率、高的纯度和良好的重现性获得该活性化合物是非常重要的。很快发现所用的盐酸盐存在纯化和重结晶的问题,并且收率也很难优化。此外,还观察到了所获得的活性化合物的重现性和一致性的问题。经过大量的研究,终于可以发现一种新的盐,其结合了各种优点,特别是有关纯化、其制备方法的重现性和收率方面的优点,并且还出人意料地具有非常显着地改善活性化合物的溶解度的优点。因此,从物理化学和药代动力学的角度来看,这种新的盐具有作为药物使用所需的所有品质。
因此,本发明涉及3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2- 氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮的新型盐,尤其是式 (II)的3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H- 吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮甲磺酸盐:
其中的符号表示该双键具有Z或E构型。
本发明优选涉及3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮甲磺酸盐的Z异构体。
该新型盐具有如下优点:
-简单并且可重现的以良好收率获得它的方法;
-在水和有机溶剂中增加的溶解度,使其可以进行纯化阶段例如净化,以增加其纯度。
本发明还涉及获得3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2- 氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮甲磺酸盐、尤其是其 Z异构体的方法,其特征在于采用例如按照专利说明书EP 2281822中所述的方法获得的3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3- 二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮作为原料。将该二酮溶于溶剂/水二元体系中,然后加入1至2摩尔当量的甲磺酸并将混合物搅拌至甲磺酸盐析出沉淀。
溶剂有利地为极性溶剂,如乙腈、丙酮、1,4-二氧六环、四氢呋喃、 N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、醇如甲醇、乙醇和异丙醇、水以及这些溶剂的水/有机溶剂混合物。优选地,溶剂/水的比例为 0/100至100/0。
本发明方法的一种变化形式包括使用3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮盐酸盐作为原料;该化合物的获得方式记载于例如专利说明书EP2281822 中。将盐酸盐溶于溶剂/水二元体系中,并通过加入碱将混合物的pH调至8。所形成的盐通过过滤除去。将滤液加热,然后加入甲磺酸。然后将温度缓慢恢复到环境温度,并将得到的甲磺酸盐滤出。更特别的是,使用的溶剂为极性溶剂如乙腈、丙酮、1,4-二氧六环、四氢呋喃、N,N-二甲基甲酰胺、 N,N-二甲基乙酰胺、二甲基亚砜,或醇如甲醇、乙醇和异丙醇。优选的溶剂/水的比例为70/30,尤其是90/10。甲磺酸过量使用,尤其是1至2当量。
本发明的式(II)化合物甚至在变性条件下也具有良好的长时间稳定性:在25℃/60%相对湿度、25℃/90%相对湿度、30℃/65%相对湿度、 40℃/75%相对湿度、或在50℃下,式(II)化合物在6个月后未发生变化。
本发明还涉及包含本发明的式(II)化合物、尤其是它的Z异构体作为活性成分并且包含一种或多种惰性、无毒的适宜赋形剂的药物组合物。在本发明的药物组合物中,尤其可以提到的是那些适用于口服、胃肠外(静脉或皮下)或鼻腔给药的组合物、片剂或糖衣丸、颗粒、舌下含片、胶囊、锭剂、栓剂、霜剂、软膏、皮肤凝胶、注射制剂、可饮用混悬剂和口香糖。
包含本发明的式(II)化合物、尤其是它的Z异构体的药物剂型可用于治疗癌症、尤其是固体转移性肿瘤。所设想的用于治疗的癌症可以提到但不限于,结肠癌、乳腺癌、肝癌、肾癌、脑癌和食道癌、黑色素瘤、骨髓瘤、卵巢癌、非小细胞肺癌、小细胞肺癌、***癌和胰腺癌,以及肉瘤。
有用的剂量可以根据疾病的性质和严重程度、给药途径和患者的年龄和体重而变化。剂量从1mg到1g/天(以碱的量计),一次或分成多次给药。
以下实施例用于说明本发明但不以任何方式对其进行限定。
实施例1:3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮甲磺酸盐,Z异构体
将1.26g 3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3- 二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮加入到100-mL的烧瓶中。加入20mL乙腈/水(90/10)溶液后,将混合物于70℃进行加热。制备包含2mL 甲磺酸和50mL乙腈/水(90/10)混合物的溶液。将5mL形成的溶液加入到反应混合物中,反应混合物变清澈。将溶液冷却至20℃(0.5℃/min,以200 rpm搅拌)。在环境温度下搅拌过夜后,通过过滤分离标题产物并于40℃真空干燥(10毫巴)。
熔点:270-274℃(熔化/分解)
通过其粉末衍射图对标题产物进行表征,用50mg实施例1的化合物进行,将其放置在2片薄膜之间或支持物上,然后上样到Panalytical Xpert-Pro MPD衍射仪(铜对阴极)以透射模式记录,2θ角的范围为3-55°,步长为每步0.017°、35.5秒,从其中可以确定如下晶体参数:
-晶胞参数:β= 94.074(1)°,γ=90°
-空间群:C 1 c 1(9)
-晶胞体积:
还通过实施例1的化合物的单晶的X射线衍射对标题产物进行表征,用 RigakuXtaLAB仪器进行,采用石墨单色器、Mo-Ka辐射。观察到以下晶体参数:
-晶胞参数:β= 93.528(7)°,γ=90°
-空间群:C 1 c 1(9)
-晶胞体积:
在使用粉末获得的参数中观察到的微小差异是由于用单晶获得参数时所用的温度(-100℃)造成的,其导致沿轴a和b的收缩。
还通过如图1所示的X射线粉末衍射图对标题产物进行了表征,该衍射图用Panalytical Xpert-Pro MPD衍射仪(铜对阴极)测定,用晶面间距d、布拉格角2θ(以°±0.2表达)和相对强度(以相对于最强线的百分比表达)进行表达:
X-射线粉末衍射图的特征性布拉格角2θ(以°±0.2进行表达):12.86; 15.13;15.50;17.70;18.25;18.71;20.11;21.46;21.67;21.89;22.29;22.58; 24.57;25.82;26.33。
还通过DSC图对实施例1的化合物进行了表征,将5-10mg样品装入TA仪器DSCQ1000装置中并冷却到0℃。然后将样品以10℃/min的速率加热到300℃。所获得的图谱如图2所示。
实施例2:3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮甲磺酸盐,Z异构体在变性条件下的纯度和稳定性
实施例3:3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮甲磺酸盐,Z异构体的溶解度
将140mg实施例1中获得的化合物在7ml水中的溶液在环境温度下搅拌24小时。用Acrodisc GHP 0.45°μm过滤后,通过HPLC对溶液进行分析。实施例1的化合物的溶解度为14.7mg/ml(或12.1mg/ml,以碱计)。
在相同条件下,3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮,Z异构体的盐酸盐的溶解度为4.3mg/ml(或4mg/ml,以碱计)。
实施例4:3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮甲磺酸盐,Z异构体在pH 2(胃 pH)下的溶解动力学
实施例1的产物的恒表面积溶解动力学(或内在的溶解动力学)在环境温度下、在pH 2(10mL 0.01N盐酸)下用μDiss溶解装置和通过在90巴下压制获得的0.075cm2的颗粒进行测定,以100rpm的搅拌速度搅拌2分钟。
实施例1的产物的溶解动力学为23μg.s-1.cm-2+/-11%。与之相比,相应的盐酸盐的溶解动力学为1.6μg.s-1.cm-2。因此,甲磺酸盐比相应的盐酸盐溶解快约14倍。
实施例5:药物组合物
1000片每片包含5mg剂量的片剂
3-[3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5- 基)甲基]-1,3-噻唑烷-2,4-二酮甲磺酸盐,Z异构体(实施例1)………………………………………………………………………………5g
小麦淀粉……………………………………………………………20g
玉米淀粉……………………………………………………………20g
乳糖…………………………………………………………………30g
硬脂酸镁……………………………………………………………2g
二氧化硅……………………………………………………………1g
羟丙基纤维素………………………………………………………2g
Claims (14)
1.式(II)的3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮甲磺酸盐:
其中的符号表示该双键具有Z或E构型。
2.权利要求1所述的化合物,其是3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮甲磺酸盐的Z异构体。
3.权利要求2所述的化合物,其特征在于其X-射线粉末衍射图具有如下布拉格角2θ,以°±0.2进行表达:12.86;15.13;15.50;17.70;18.25;18.71;20.11;21.46;21.67;21.89;22.29;22.58;24.57;25.82;26.33。
4.权利要求2所述的化合物,其特征在于从用铜对阴极的Panalytical Xpert-Pro MPD衍射仪以透射模式记录的粉末衍射图所获得的如下参数,其中2θ角的范围为3-55°,步长为每步0.017°、35.5秒,从其中可以确定如下晶体参数:
-晶胞参数:β=94.074(1)°,γ=90°
-空间群:C1 c1 (9)
-晶胞体积:
5.获得权利要求1所述的式(II)化合物的方法,其特征在于用3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮作为原料,将其溶于溶剂/水二元体系中,向其中加入1至2摩尔当量的甲磺酸并搅拌至甲磺酸盐析出沉淀,滤出沉淀。
6.获得权利要求1所述的式(II)化合物的方法,其特征在于用3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮盐酸盐作为原料,将其溶于溶剂/水二元体系中,通过加入碱将其pH调至8,通过过滤除去所形成的盐,然后将滤液加热并加入甲磺酸,搅拌溶液并冷却直至甲磺酸盐析出沉淀,滤出沉淀。
7.包含权利要求1至4任意一项所述的式(II)化合物和一种或多种可药用赋形剂的药物组合物。
8.权利要求7所述的药物组合物,其特征在于式(II)化合物是3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮甲磺酸盐的Z异构体。
9.权利要求7或8所述的药物组合物在生产用于治疗结肠癌、乳腺癌、肝癌、肾癌、脑癌和食道癌、黑色素瘤、骨髓瘤、卵巢癌、非小细胞肺癌、小细胞肺癌、***癌和胰腺癌,或肉瘤的药物中的用途。
10.权利要求1至4任意一项所述的式(II)化合物与选自遗传毒性药物、有丝***毒性剂、抗代谢物、蛋白酶体抑制剂和蛋白激酶抑制剂的抗癌剂的联合产品。
11.权利要求10所述的联合产品,其特征在于式(II)化合物是3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮甲磺酸盐的Z异构体。
12.权利要求10或11所述的联合产品在生产用于治疗癌症的药物中的应用。
13.权利要求1至4任意一项所述的式(II)化合物在生产用于与放射疗法联合治疗癌症的药物中的应用。
14.权利要求13所述的应用,其特征在于式(II)化合物是3-[(3-{[4-(4-吗啉基甲基)-1H-吡咯-2-基]亚甲基}-2-氧代-2,3-二氢-1H-吲哚-5-基)甲基]-1,3-噻唑烷-2,4-二酮甲磺酸盐的Z异构体。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR1356870A FR3008411B1 (fr) | 2013-07-12 | 2013-07-12 | Nouveau sel de la 3-[(3-{[4-(4-morpholinylmethyl)-1h-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1h-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione, sa preparation, et les formulations qui le contiennent |
FR13/56870 | 2013-07-12 | ||
PCT/FR2014/051783 WO2015004395A1 (fr) | 2013-07-12 | 2014-07-11 | Nouveau sel de la 3-[(3-{[4-(4-morpholinylméthyl)-1h-pyrrol-2-yl]méthylène}-2-oxo-2,3-dihydro-1h-indol-5-yl)méthyl]-1,3-thiazolidine-2,4-dione, sa préparation, et les formulations qui le contiennent |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105377843A CN105377843A (zh) | 2016-03-02 |
CN105377843B true CN105377843B (zh) | 2019-03-05 |
Family
ID=50424327
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201480038854.7A Expired - Fee Related CN105377843B (zh) | 2013-07-12 | 2014-07-11 | 化合物的新型盐、其制备以及包含其的制剂 |
Country Status (47)
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10245270B2 (en) * | 2013-07-12 | 2019-04-02 | Les Laboratoires Servier | Salt of 3-[(3-{[4-(4-morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione, its preparation, and formulations containing it |
FR3039401B1 (fr) * | 2015-07-31 | 2018-07-13 | Les Laboratoires Servier | Nouvelle association entre le 3-[(3-{[4-(4-morpholinylmethyl)-1h-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1h-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione et un inhibiteur de la tyr kinase du egfr |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1439005A (zh) * | 2000-02-15 | 2003-08-27 | 苏根公司 | 吡咯取代的2-二氢吲哚酮蛋白激酶抑制剂 |
CN101987848A (zh) * | 2009-08-04 | 2011-03-23 | 瑟维尔实验室 | 新的二氢吲哚酮化合物、它们的制备方法以及包含它们的药物组合物 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002032861A2 (en) * | 2000-10-17 | 2002-04-25 | Merck & Co., Inc. | Orally active salts with tyrosine kinase activity |
AR042586A1 (es) * | 2001-02-15 | 2005-06-29 | Sugen Inc | 3-(4-amidopirrol-2-ilmetiliden)-2-indolinona como inhibidores de la protein quinasa; sus composiciones farmaceuticas; un metodo para la modulacion de la actividad catalitica de la proteinquinasa; un metodo para tratar o prevenir una afeccion relacionada con la proteinquinasa |
RU2316554C2 (ru) * | 2001-12-27 | 2008-02-10 | Тереванс, Инк. | Производные индолина, используемые как ингибиторы протеинкиназы |
WO2005040116A2 (en) * | 2003-10-24 | 2005-05-06 | Schering Aktiengesellschaft | Indolinone derivatives and their use in treating disease-states such as cancer |
KR101396639B1 (ko) * | 2005-12-05 | 2014-05-21 | 제노포트 인코포레이티드 | 레보도파 프로드럭 메실레이트, 그것의 조성물 및 그것의용도 |
-
2013
- 2013-07-12 FR FR1356870A patent/FR3008411B1/fr active Active
-
2014
- 2014-06-26 UY UY0001035629A patent/UY35629A/es unknown
- 2014-06-29 JO JOP/2014/0205A patent/JO3292B1/ar active
- 2014-07-11 TW TW105105577A patent/TW201630906A/zh unknown
- 2014-07-11 AU AU2014289059A patent/AU2014289059B2/en not_active Ceased
- 2014-07-11 CA CA2916380A patent/CA2916380C/fr not_active Expired - Fee Related
- 2014-07-11 KR KR1020167003298A patent/KR20160030399A/ko active Application Filing
- 2014-07-11 PL PL14758600T patent/PL3019497T3/pl unknown
- 2014-07-11 EP EP14758600.2A patent/EP3019497B1/fr active Active
- 2014-07-11 AP AP2016008976A patent/AP2016008976A0/xx unknown
- 2014-07-11 SG SG11201510570YA patent/SG11201510570YA/en unknown
- 2014-07-11 EA EA201600101A patent/EA031526B1/ru not_active IP Right Cessation
- 2014-07-11 TW TW103124019A patent/TWI554510B/zh not_active IP Right Cessation
- 2014-07-11 WO PCT/FR2014/051783 patent/WO2015004395A1/fr active Application Filing
- 2014-07-11 JP JP2016524879A patent/JP6532459B2/ja not_active Expired - Fee Related
- 2014-07-11 PE PE2015002679A patent/PE20160079A1/es unknown
- 2014-07-11 LT LTEP14758600.2T patent/LT3019497T/lt unknown
- 2014-07-11 ME MEP-2017-149A patent/ME02735B/me unknown
- 2014-07-11 CN CN201480038854.7A patent/CN105377843B/zh not_active Expired - Fee Related
- 2014-07-11 HU HUE14758600A patent/HUE032568T2/hu unknown
- 2014-07-11 RU RU2016104642A patent/RU2680826C9/ru not_active IP Right Cessation
- 2014-07-11 GE GEAP201414051A patent/GEP201706712B/en unknown
- 2014-07-11 NZ NZ715841A patent/NZ715841A/en not_active IP Right Cessation
- 2014-07-11 MY MYPI2016700018A patent/MY183197A/en unknown
- 2014-07-11 MD MDA20160003A patent/MD4507C1/ro not_active IP Right Cessation
- 2014-07-11 AR ARP140102566A patent/AR096882A1/es unknown
- 2014-07-11 PT PT147586002T patent/PT3019497T/pt unknown
- 2014-07-11 MX MX2016000332A patent/MX360291B/es active IP Right Grant
- 2014-07-11 SI SI201430246A patent/SI3019497T1/sl unknown
- 2014-07-11 KR KR1020187006643A patent/KR20180028554A/ko not_active Application Discontinuation
- 2014-07-11 ES ES14758600.2T patent/ES2632570T3/es active Active
- 2014-07-11 UA UAA201600944A patent/UA114041C2/uk unknown
- 2014-07-11 DK DK14758600.2T patent/DK3019497T3/en active
- 2014-07-11 RS RS20170461A patent/RS55945B1/sr unknown
- 2014-07-11 TN TN2015000566A patent/TN2015000566A1/fr unknown
- 2014-07-11 US US14/904,260 patent/US9925195B2/en not_active Expired - Fee Related
- 2014-07-11 MA MA38759A patent/MA38759B1/fr unknown
-
2016
- 2016-01-04 PH PH12016500017A patent/PH12016500017A1/en unknown
- 2016-01-06 CL CL2016000013A patent/CL2016000013A1/es unknown
- 2016-01-07 CR CR20160012A patent/CR20160012A/es unknown
- 2016-01-07 DO DO2016000005A patent/DOP2016000005A/es unknown
- 2016-01-10 IL IL243526A patent/IL243526B/en not_active IP Right Cessation
- 2016-01-11 GT GT201600004A patent/GT201600004A/es unknown
- 2016-01-11 NI NI201600009A patent/NI201600009A/es unknown
- 2016-01-12 SA SA516370388A patent/SA516370388B1/ar unknown
- 2016-01-12 CU CUP2016000005A patent/CU20160005A7/es unknown
- 2016-08-30 HK HK16110306.0A patent/HK1222172A1/zh unknown
- 2016-09-13 HK HK16110825.2A patent/HK1222655A1/zh not_active IP Right Cessation
-
2017
- 2017-07-04 CY CY20171100714T patent/CY1119259T1/el unknown
- 2017-07-11 HR HRP20171060TT patent/HRP20171060T1/hr unknown
-
2018
- 2018-02-14 US US15/896,273 patent/US20180207171A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1439005A (zh) * | 2000-02-15 | 2003-08-27 | 苏根公司 | 吡咯取代的2-二氢吲哚酮蛋白激酶抑制剂 |
CN101987848A (zh) * | 2009-08-04 | 2011-03-23 | 瑟维尔实验室 | 新的二氢吲哚酮化合物、它们的制备方法以及包含它们的药物组合物 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI373470B (en) | Process for preparing amino crotonyl compounds | |
US20190002483A1 (en) | Novel crystalline forms | |
KR101604501B1 (ko) | N-[2-(다이에틸아미노)에틸]-5-[(5-플루오로-1,2-다이하이드로-2-옥소-3h-인돌-3-일리덴)메틸]-2,4-다이메틸-1h-피롤-3-카복스아미드의 결정 형태 및 이의 제조 방법 | |
KR20120113285A (ko) | 다사티닙 다결정체 및 그의 제조방법과 약물 조성물 | |
NO329618B1 (no) | Nye krystallinske former av forbindelsen ZD1839, solvat derav, fremgangsmate for fremstilling av slike samt farmasoytisk preparat innholdende slike | |
JP2013545812A (ja) | 5−クロロ−n2−(2−イソプロポキシ−5−メチル−4−ピペリジン−4−イル−フェニル)−n4[2−(プロパン−2−スルホニル)−フェニル]−ピリミジン−2,4−ジアミンの結晶形 | |
WO2003103656A1 (ja) | O−置換ヒドロキシアリール誘導体 | |
JP2008506783A (ja) | ミコフェノール酸ナトリウムの結晶形の調製方法 | |
US20090076272A1 (en) | Polymorphs of eszopiclone malate | |
CA2955547C (en) | Crystalline forms of [1,2,4]triazol0[4,3-a]pyridine derivative and crystalline acid salts thereof and use thereof as c-met inhibitor | |
CN102070618B (zh) | 一种化合物及其晶体 | |
WO2016090257A1 (en) | Salts and crystalline forms of 6-acetyl-8-cyclopentyl-5-methyl-2((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d] pyrimidin-7(8h)-one (palbociclib) | |
KR20070072891A (ko) | 타달라필 결정형 및 이의 제조 방법 | |
CN105377843B (zh) | 化合物的新型盐、其制备以及包含其的制剂 | |
ES2863586T3 (es) | Sal del ácido mesílico de un compuesto de aciltiourea, cristal de la misma y proceso para su producción | |
WO2019228171A1 (zh) | 一种稠环嘧啶类化合物的盐、晶型及其制备方法和应用 | |
US20070105885A1 (en) | Novel crystalline polymorphic form of a camptothecin analogue | |
JP2016504364A (ja) | コビシスタット塩 | |
JP2020502043A (ja) | 4’−チオ−2’−フルオロヌクレオシドホスファミド化合物の固体形態及びそのための調製方法及びその使用 | |
TWI535724B (zh) | 埃克替尼磷酸鹽的新晶型及其用途 | |
CN110914246B (zh) | 3-(3,5-二氯-4-羟基苯甲酰)-1,1-二氧代-2,3-二氢-1,3-苯并噻唑的晶型及其盐 | |
CN111566101A (zh) | Cdk4/6抑制剂及其药学上可接受的盐和多晶型物及其应用 | |
CN106432243B (zh) | 一种hedgehog信号通路抑制剂的结晶形式及其制备方法 | |
JP2015231990A (ja) | インダゾロ[5,4−a]ピロロ[3,4−c]カルバゾール化合物の新しい形態 | |
TWI596098B (zh) | 埃克替尼馬來酸鹽的晶型及其用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1222172 Country of ref document: HK |
|
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20190305 Termination date: 20200711 |
|
REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1222172 Country of ref document: HK |