- Synthesis and evaluation of FAK inhibitors with a 5-fluoro-7H-pyrrolo[2,3-d]pyrimidine scaffold as anti-hepatocellular carcinoma agents
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Focal adhesion kinase (FAK) is a ubiquitous intracellular non-receptor tyrosine kinase, which is involved in multiple cellular functions, including cell adhesion, migration, invasion, survival, and angiogenesis. In this study, a series of 7H-pyrrolo[2,3-d
- Gong, Chaochao,Huang, Jian,Liu, Yue,Tan, Hanyi,Zhang, Jiawei,Zhang, Qian
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- Synthesis method of tofacitinib citrate
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The invention relates to the technical field of medicinal chemistry, and discloses a synthesis method of tofacitinib citrate. The method comprises 1) preparing 2,4-dihydroxy pyrrolopyrimidine: adding4-aminouracil and anhydrous sodium acetate into water (in a molar ratio of (1: 3)-(1: 5)), heating to 60-80 DEG C, slowly adding a 2-chloroacetaldehyde aqueous solution having a concentration of 40%,stirring to react for 4-6 hours, cooling to room temperature, filtering, washing a solid with water, and drying under reduced pressure to obtain 2,4-dihydroxy pyrrolopyrimidine. According to the synthesis method of tofacitinib citrate, through two times of impurity removal, the purity of the produced tofacitinib citrate finished product is higher, subsequent purification is not needed, the synthesis time is short, the process is simple, the method is suitable for factory production, the production time of the tofacitinib citrate finished product can be saved, the production efficiency of the tofacitinib citrate finished product is improved, and the tofacitinib citrate is more convenient to use.
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Paragraph 0027-0031; 0041-0045
(2020/08/29)
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- Fused-pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating Bruton's tyrosine kinase activity related diseases containing the same as an active ingredient
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The present invention relates to a conjugated pyrimidine derivative, a method for manufacturing the same, and a pharmaceutical composition for preventing or treating Bruton′s tyrosine kinase activity-related diseases containing the same as an active ingredient. The conjugated pyrimidine derivative according to the present invention is excellent in the ability to inhibit the activity of Bruton′s tyrosine kinase or TMD80, and thus can be usefully used for prevention or treatment of diseases related to Bruton′s tyrosine kinase activity, particularly cancer or autoimmune diseases.COPYRIGHT KIPO 2019
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Paragraph 0594-0598
(2019/02/02)
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- SUBSTITUTED BICYCLIC PYRIMIDINE-BASED COMPOUNDS AND COMPOSITIONS AND USES THEREOF
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Novel C-2-substituted bicyclic compounds of Formula I have been prepared and found to be useful as potent inhibitors of hGGPPS by inhibiting geranylgeranylation of proteins and inhibiting the biosynthesis of GGPP. The application is directed to these compounds, to compositions comprising these compounds, and to their use, in particular as medicaments for use in the treatment of cancer and other conditions which are treatable by inhibiting human geranylgeranylation pyrophosphate hGGPPS activity.
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Paragraph 00233; 00234
(2018/08/20)
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- A Anaplastic lymphoma kinase inhibitors (by machine translation)
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The present invention of formula (I) compounds, of formula (I) compounds of the type (II) in the middle of the compound, of formula (III) compound and its preparation method. Formula (I) compound is a small molecule Anaplastic lymphoma kinase (Anaplastic
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Paragraph 0123-0125
(2017/10/14)
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- LRRK2 INHIBITORS AND METHODS OF MAKING AND USING THE SAME
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Compounds having the formula (I), (II), (III) are provided. Compounds of the present disclosure are useful for the treatment of neurodegenerative diseases, such as Parkinson's Disease.
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Page/Page column 114
(2016/09/22)
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- Discovery of a pyrrolopyrimidine (JH-II-127), a highly potent, selective, and brain penetrant LRRK2 inhibitor
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Activating mutations in leucine-rich repeat kinase 2 (LRRK2) are present in a subset of Parkinson's disease (PD) patients and may represent an attractive therapeutic target. Here we report a 2-anilino-4-methylamino-5-chloropyrrolopyrimidine, JH-II-127 (18
- Hatcher, John M.,Zhang, Jinwei,Choi, Hwan Geun,Ito, Genta,Alessi, Dario R.,Gray, Nathanael S.
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supporting information
p. 584 - 589
(2015/05/27)
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- Synthesis and biological evaluation of substituted 2-anilino-7H- pyrrolopyrimidines as PDK1 inhibitors
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An efficient and scalable route for a series of novel substituted 2-anilino-7H-pyrrolopyrimidine compounds as potential inhibitors of PDK1, an important regulator of the PI3K/Akt pathway that is dysregulated in many cancers, was developed and is described. The synthetic strategy was designed around Suzuki and Buchwald-Hartwig cross-couplings of a boronate fragment and various customised anilines sequentially with 2,4-dichloro-7-tosyl-7H- pyrrolopyrimidine. All fragments were constructed separately and cross-coupled to provide access to a range of novel compounds. Biological evaluation of these was undertaken, with modest inhibition observed.
- O'Brien, Nathan J.,Brzozowski, Martin,Wilson, David J.D.,Deady, Leslie W.,Abbott, Belinda M.
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p. 4947 - 4956
(2014/07/07)
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- Novel pyrrolopyrimidine analogues as potent dipeptidyl peptidase IV inhibitors based on pharmacokinetic property-driven optimization
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We previously reported a highly potent DPP-IV inhibitor 6 with low in vivo efficacy. While trying to maintain consistent in vitro and in vivo biological activity, we initiated a pharmacokinetic property-driven optimization to improve the metabolic stability and permeability of inhibitor 6. A simple scaffold replacement of thienopyrimidine with pyrrolopyrimidine (21a) led to significantly improved metabolic stability (4% vs. 65% remaining). Further modification of the pyrrolopyrimidine scaffold to produce compound 21j resulted in much better oral bioavailability than 6. Importantly, compound 21j exhibits greater in vivo efficacy than does 6 and Alogliptin and is worthy of further development.
- Xie, Hui,Zeng, Lili,Zeng, Shaogao,Lu, Xin,Zhang, Guicheng,Zhao, Xin,Cheng, Na,Tu, Zhengchao,Li, Zhiyuan,Xu, Hongjiang,Yang, Ling,Zhang, Xiquan,Huang, Min,Zhao, Junling,Hu, Wenhui
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supporting information; experimental part
p. 205 - 212
(2012/07/17)
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- (2-ARYL-7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)MORPHOLINE COMPOUNDS, THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS, AND THEIR SYNTHESES
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The invention relates to 2-aryl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholine compounds of the Formula I: or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined herein, compositions comprising the compounds, and methods for making and using the compounds
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Page/Page column 20
(2010/02/16)
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- Synthesis and SAR of novel 4-morpholinopyrrolopyrimidine derivatives as potent phosphatidylinositol 3-kinase inhibitors
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Significant evidence suggests that deregulation of the PI3K/Akt pathway is important in tumor progression. Mechanisms include loss of function of the tumor suppressor PTEN and high frequency of mutation of the PI3K p110α isoform in human malignancies. This connection between PI3K and tumor genesis makes PI3K a promising target for cancer treatment. A series of 4- morpholinopyrrolopyrimidine derivatives were synthesized and evaluated as inhibitors of PI3Kα and mTOR, leading to the discovery of PI3Kα selective inhibitors (e.g., 9) and dual PI3Kα/mTOR kinase inhibitors (e.g., 46 and 48). PI3Kα/mTOR dual inhibitors demonstrated inhibition of tumor cell growth in vitro and in vivo and caused suppression of the pathway specific biomarkers [e.g., the phosphorylation of Akt at Thr308 (T308) and Ser473 (S473)] in the human breast cancer cell line MDA361. In addition, compound 46 demonstrated good in vivo efficacy in the MDA361 human breast tumor xenograft model.
- Chen, Zecheng,Venkatesan, Aranapakam M.,Dehnhardt, Christoph M.,Ayral-Kaloustian, Semiramis,Brooijmans, Natasja,Mallon, Robert,Feldberg, Larry,Hollander, Irwin,Lucas, Judy,Yu, Ker,Kong, Fangming,Mansour, Tarek S.
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experimental part
p. 3169 - 3182
(2010/09/15)
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- INHIBITORS OF PROTEIN KINASES
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The present invention is directed to compounds of formula (I)-(II) and pharmaceutically acceptable salts, esters, and prodrugs thereof which are inhibitors of syk and/or JAK kinase. The present invention is also directed to intermediates used in making such compounds, the preparation of such a compound, pharmaceutical compositions containing such a compound, methods of inhibition syk and/or JAK kinase activity, methods of inhibition the platelet aggregation, and methods to prevent or treat a number of conditions mediated at least in part by syk and/or JAK kinase activity, such as undesired thrombosis and Non Hodgkin's Lymphoma.
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Page/Page column 131
(2009/12/05)
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- PROTEIN KINASE INHIBITORS
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Compounds, particularly compounds having spleen tyrosine kinase (Syk) inhibition activity, having the following structure: or a pharmaceutically acceptable salt thereof, wherein R1 is structure (a), (b), (c) or (d): and Ra, Rb, Rc, R2, R3, R4, R5, R6 and R7 are as defined herein. Methods associated with preparation and use of the same, as well as pharmaceutical compositions containing the same, are also disclosed, as well as uses of the same to treat a condition or disorder mediated by a Syk and/or JAK kinase.
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Page/Page column 21
(2009/04/24)
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- PYRROLOPYRIMIDINE COMPOUNDS
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Compounds of formula (I) are A2B receptor antagonists: wherein Ri is optionally substituted aryl or an optionally substituted monocyclic heteroaryl group having 5 or 6 ring atoms; R2 and R3 are independently selected from
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Page/Page column 15-16; 13
(2009/04/25)
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- Xanthine oxidase-activated prodrugs of thymidine phosphorylase inhibitors
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Thymidine phosphorylase (TP) is over-expressed in various tumour types and plays an important role in tumour angiogenesis, growth, invasion and metastasis. The enzymatic activity of TP is required for the angiogenic effect of TP, therefore, inhibitors of TP are of significant interest in cancer chemotherapy. A series of xanthine oxidase (XO) activated prodrugs of known inhibitors of TP have been designed and synthesized with the ultimate intent of improving tumour selectivity and pharmacokinetic characteristics. These prodrugs were not inhibitors of TP, but were selectively oxidized by XO at C-2 and/or C-4 of the uracil ring moiety to generate the desired TP inhibitor. Molecular modelling of both the TP inhibitors and XO-activated prodrugs rationalized their binding in the active site of the human TP crystal structure.
- Reigan, Philip,Gbaj, Abdul,Stratford, Ian J.,Bryce, Richard A.,Freeman, Sally
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p. 1248 - 1260
(2008/09/21)
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- PYRROLOPYRIMIDINE DERIVATIVES USED AS HSP90 INHIBITORS
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Compounds of formula (I) have HSP90 inhibitory activity and are therefore useful in the treatment of, inter alia, cancer: Formula (I) wherein Ri is hydrogen, fluoro, chloro, bromo, or a radical of formula -X-Alk1-(Z)m-(Alk2)n-Q wherein X is -O-, -S- -S(O)-, -SO2-, or -NH-, Z is -O-, -S-, -(C=O)-, -(C=S)-, -S(O)-, -SO2-, -NRA-, or, in either orientation -C(=O)O-, -C(=O)NRA- , -C(=S)NRA-, -SO2NRA-, -NRAC(=O)-, or -NRASO2- wherein RA is hydrogen or C1-C6 alkyl AIk1 and AIk2 are optionally substituted divalent C1-C3 alkylene or C2-C3 alkenylene radicals, m, n and p are independently 0 or 1 , and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; R2 is a radical of formula -(Ar1)p-(Alk1)q-(Z)r-(Alk2)s-Q wherein Ar1 is an optionally substituted aryl or heteroaryl radical, Alk1, Alk2, Z, and Q are as defined above, and p, q, r and s are independently 0 or 1 ; and R3 is cyano (-CN), fluoro, chloro, bromo, methyl in which in which one or more hydrogen atoms are optionally replaced by fluorine atoms, ethyl in which in which one or more hydrogen atoms are optionally replaced by fluorine atoms, cyclopropyl, -OH, -CH2OH, -C(O)NH2, -C(O)CH3, Or -NH2.
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- Mannich-type C-nucleosidations with 7-carba-purines and 4-aminopyrimidines
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Regioselective Mannich-type C-nucleosidations of pyrroline derivatives 3 and 8 with 7-carba-purines and 4-aminopyrimidines occur under mild conditions to afford C(8)- and C(5)-azanucleosides, respectively.
- Han, Bo,Rajwanshi, Vivek,Nandy, Jyoti,Krishnamurthy, Ramanarayanan,Eschenmoser, Albert
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p. 744 - 750
(2007/10/03)
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- Synthesis and enzymatic evaluation of xanthine oxidase-activated prodrugs based on inhibitors of thymidine phosphorylase
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A series of xanthine oxidase-activated prodrugs of known inhibitors of thymidine phosphorylase are described. These prodrugs were oxidised by xanthine oxidase at C-2 and/or C-4 of the uracil ring to generate the desired TP inhibitor. The scheme shows the prodrug of TPI. A series of xanthine oxidase-activated prodrugs of known inhibitors of thymidine phosphorylase has been designed and synthesised to introduce tumour selectivity. These prodrugs were oxidised by xanthine oxidase at C-2 and/or C-4 of the uracil ring to generate the desired TP inhibitor.
- Reigan, Philip,Gbaj, Abdul,Chinje, Edwin,Stratford, Ian J.,Douglas, Kenneth T.,Freeman, Sally
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p. 5247 - 5250
(2007/10/03)
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- Pharmaceutically active bicyclic-heterocyclic amines
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The pharmaceutically active bicyclic heterocyclic amines (XXX) STR1 where W1 is --N= or --CH=; W3 is --N= or --CH=; W5 is --N= or --CR5 -- with the proviso that W5 is --CR5 -- when both W1 and W3 are --N= which are useful as pharmaceuticals in treating mild and/or moderate to severe head injury, subarachnoid hemorrhage and subsequent ischemic stroke, asthma and reduction of mucous formation/secretion in the lung and other diseases and injuries.
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