- High yielding, base catalyzed C6 regioselective amination and N9 alkylation in purine nucleotide
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2,6-Dichloropurine is an interesting new nucleoside which gave regioselectively various 2-derivatized or 6-derivatized purines by using a secondary amines. An efficient, simple and regioselective synthesis of C6 morpholine, N9 alkylated purine nucleoside derivatives were attained via chloro-amine coupling reaction between 2,6-dichloropurine with morpholine followed by commercial alkylation method using DMF and K2CO3. Over the traditionally used protocols and procedure, it have been exhibited advance benefits such as admirable yield, simple reaction conditions and modest influence.
- Dhuda, Gautamkumar,Kapadiya, Khushal,Ladwa, Paresh,Godhaniya, Bhavna,Modha, Jayesh
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Read Online
- Design, Synthesis, and Preclinical Evaluation of Fused Pyrimidine-Based Hydroxamates for the Treatment of Hepatocellular Carcinoma
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Class I histone deacetylases (HDACs) are highly expressed and/or upregulated in hepatocellular carcinoma (HCC) and are associated with aggressiveness, spread, and increased mortality of HCC. Activation of phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway was involved in the development of HCC and acquired resistance to sorafenib. A series of purine or 5H-pyrrolo[3,2-d]pyrimidine based hydroxamates were designed and developed as multitarget drugs to modulate both HDACs and the PI3K/Akt/mTOR pathway. Among 39 cell lines screened, the molecules (e.g., 20e, 20f, and 20q) were the most selective against leukemia, lymphoma, and HCC cells; they also demonstrated target modulation in cancer cell lines and in mice bearing MV4-11 and HepG2 tumors. Compound 20f in particular showed significant single agent oral efficacy in hypervascular liver cancer models (e.g., HepG2, HuH-7, and Hep3B) and was well-tolerated. These encouraging results, along with its favorable target profile and tissue distribution, warrant further development of 20f.
- Chen, Dizhong,Soh, Chang Kai,Goh, Wei Huang,Wang, Haishan
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Read Online
- Piperazinone substitute or derivative thereof, preparation method and application thereof, and pharmaceutical composition
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The invention relates to a piperazinone substitute or a derivative thereof, a preparation method and application thereof, and a pharmaceutical composition, and belongs to the technical field of anti-tumor drugs. The invention designs a piperazinone substituted heterocyclic small molecule compound. The compound shows good affinity to PI3K delta, and the compound can down-regulate the activity of a PI3K pathway in tumor cells, so that the compound shows good inhibitory activity to PI3K delta dependent tumors, and is expected to be used as one of components of a pharmaceutical preparation for treatment of different tumors. The preparation method of the piperazinone substitute is simple and convenient, and the yield is relatively high.
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Paragraph 0153; 0565; 0568-0571
(2021/06/09)
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- PURINES AND METHODS OF THEIR USE
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Disclosed are compounds useful in the treatment of neurological disorders. The compounds described herein, alone or in combination with other pharmaceutically active agents, can be used for treating or preventing neurological diseases.
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Page/Page column 65-66
(2021/12/28)
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- DUAL KINASE-BROMODOMAIN INHIBITORS
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Provided herein are compounds of Formula (I) that are dual inhibitors of kinases and bromo-domain proteins. The disclosure also relates to pharmaceutical compositions containing such compounds, methods for using such compounds in the treatment of cancers, particularly, the treatment of multiple myeloma cancers, and to related uses.
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Page/Page column 106; 213
(2021/12/12)
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- Purine compound obtained based on virtual docking as well as preparation method and application of same
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The invention provides a purine compound obtained based on virtual docking. The purine compound is screened in a virtual screening and pharmacophore manner, through a result of mutual evidence verification of virtual docking design and compound synthesis,
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Paragraph 0035-0040; 0043-0044
(2020/11/26)
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- Design, synthesis and biological evaluation of novel histone deacetylase1/2 (HDAC1/2) and cyclin-dependent Kinase2 (CDK2) dual inhibitors against malignant cancer
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In the current study, we have designed and synthesized a series of novel histone deacetylase1/2 (HDAC1/2) and cyclin-dependent kinase2 (CDK2) dual inhibitors by integrating purine-based pharmacophore into the recognition cap group of CS055. The representative compound 14d with excellent antiproliferative activities towards five solid cancer cells, showed potent inhibitory activities against HDAC1, HDAC2 and CDK2 with IC50 values of 70.7 nM, 23.1 nM and 0.80 μM, respectively. Besides, compound 14d could effectively block the cell cycle in the G2/M phase and induce apoptosis, which might be related to increasing intracellular ROS levels. Importantly, compound 14d exhibited desirable pharmacokinetic (PK) properties with the intraperitoneal bioavailability of 50.8percent in ICR mice, and potent in vivo antitumor activity in the HCT116 xenograft model. Therefore, compound 14d could be considered as a promising lead compound for the development of multitargeting anticancer agents.
- Cheng, Chunhui,Ullah, Sadeeq,Yuan, Qipeng,Yun, Fan
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- Medicinal Chemistry Optimization of a Diaminopurine Chemotype: Toward a Lead for Trypanosoma brucei Inhibitors
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Human African trypanosomiasis (HAT), or sleeping sickness, is caused by the protozoan parasite Trypanosoma brucei and transmitted through the bite of infected tsetse flies. The disease is considered fatal if left untreated. To identify new chemotypes against Trypanosoma brucei, previously we identified 797 potent kinase-targeting inhibitors grouped into 59 clusters plus 53 singleton compounds with at least 100-fold selectivity over HepG2 cells. From this set of hits, a cluster of diaminopurine-derived compounds was identified. Herein, we report our medicinal chemistry investigation involving the exploration of structure-activity and structure-property relationships around one of the high-throughput screening (HTS) hits, N2-(thiophen-3-yl)-N6-(2,2,2-trifluoroethyl)-9H-purine-2,6-diamine (1, NEU-1106). This work led to the identification of a potent lead compound (4aa, NEU-4854) with improved in vitro absorption, distribution, metabolism, and excretion (ADME) properties, which was progressed into proof-of-concept translation of in vitro antiparasitic activity to in vivo efficacy.
- Singh, Baljinder,Diaz-Gonzalez, Rosario,Ceballos-Perez, Gloria,Rojas-Barros, Domingo I.,Gunaganti, Naresh,Gillingwater, Kirsten,Martinez-Martinez, Maria Santos,Manzano, Pilar,Navarro, Miguel,Pollastri, Michael P.
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p. 9912 - 9927
(2020/10/19)
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- Identification of a potent and selective phosphatidylinositol 3-kinase δ inhibitor for the treatment of non-Hodgkin's lymphoma
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PI3Kδ has proved to be an effective target for anti-lymphoma drugs. However, the application of current approved PI3Kδ inhibitors has been greatly limited due to their specific immune-mediated toxicity and increased risk of infection, it is necessary to develop more PI3Kδ inhibitors with new scaffold. In this study, SAR study with respect to piperazinone-containing purine derivatives led to the discovery of a potent and selective PI3Kδ inhibitor, 4-(cyclobutanecarbonyl)-1-((2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-2-one (WNY1613). WNY1613 exhibits good antiproliferative activity against a panel of non-Hodgkin's lymphoma (NHL) cell lines by inducing cancer cell apoptosis and inhibiting the phosphorylation of PI3K and MAPK downstream components. In addition, it can also prevent the tumor growth in both SU-DHL-6 and JEKO-1 xenograft models without observable toxicity. WNY1613 thus could be developed as a promising candidate for the treatment of NHL after subsequent extensive pharmacodynamics and pharmacokinetics investigation.
- Zuo, Wei-Qiong,Hu, Rong,Wang, Wan-Li,Zhu, Yong-Xia,Xu, Ying,Yu, Luo-Ting,Liu, Zhi-Hao,Wang, Ning-Yu
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- Novel purine derivative compounds, preparation method thereof, pharmaceutical compositions and methods of use (by machine translation)
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The invention belongs to the field of pharmaceutical chemicals, relates to mammalian mTOR signal path having effects of inhibiting the formula I compound and its pharmaceutically acceptable salt or hydrate, various substituted group in the general formula I as defined in the specification stated; the formula I compound preparation method: comprising the formula I compound or its pharmaceutically acceptable salt or hydrate of the pharmaceutical composition; the formula I compound or its pharmaceutically acceptable salt or hydrate in use for the production of medicaments, medicament for the treatment of a mammal mTOR path signal moving the diseases caused by the abnormal expression of the. (by machine translation)
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Paragraph 0097; 0099; 0100
(2018/12/05)
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- Synthesis and biological evaluation of 2,6-disubstituted-9H-purine, 2,4-disubstitued-thieno[3,2-d]pyrimidine and -7H-pyrrolo[2,3-d]pyrimidine analogues as novel CHK1 inhibitors
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Checkpoint kinase 1 (CHK1) inhibitors can potentiate the effectiveness of deoxyribonucleic acid (DNA) damaging agents in the treatment of cancer. A novel series of 2,6-disubstituted-9H-purine (3a-p, 5a and 5b), 2,4-disubstituted-thieno[3,2-d]pyrimidine (8
- Tian, Chao,Han, Zifei,Li, Yuanxin,Wang, Meng,Yang, Jiajia,Wang, Xiaowei,Zhang, Zhili,Liu, Junyi
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p. 836 - 848
(2018/04/25)
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- Design, synthesis and evaluation of 4-aminoquinoline-purine hybrids as potential antiplasmodial agents
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A novel series of 4-aminoquinoline-purine hybrids were synthesized and assessed for their antiplasmodial activity against CQ-sensitive and CQ-resistant strains of P. falciparum. It was envisaged that linking of the 4-aminoquinoline pharmacophore (targeting heme-detoxification pathway of malarial parasite) with the purine functionality (targeting plasmodial HG(X)PRT enzyme) will produce a hybrid antiplasmodial agent with increased potency. The synthesized hybrids displayed good antiplasmodial activities against both the sensitive and resistant strains of P. falciparum with up to six-fold better activity (compound 10i, IC50: 0.08?μM) compared to the reference drug CQ (IC50: 0.5?μM) against the resistant strain. The synthesized compounds were also checked for their cytotoxicity towards mammalian cells and with the exception of two compounds out of the twenty synthesized hybrids, all others were non-cytotoxic up to 11.86?μM concentration. Mechanistic heme-binding studies were performed to identify the mechanism of action of the synthesized molecules and good binding interactions were observed. Computational docking studies showed that the most active hybrids dock well within the binding site of HGPRT protein. In silico ADME predictions of the most active hybrids showed that these compounds possess good pharmacokinetic behavior.
- Reddy, P. Linga,Khan, Shabana I.,Ponnan, Prija,Tripathi, Mohit,Rawat, Diwan S.
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supporting information
p. 675 - 686
(2016/12/14)
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- Development of Purine-Based Hydroxamic Acid Derivatives: Potent Histone Deacetylase Inhibitors with Marked in Vitro and in Vivo Antitumor Activities
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In the present study, a series of novel histone deacetylase (HDAC) inhibitors using the morpholinopurine as the capping group were designed and synthesized. Several compounds demonstrated significant HDAC inhibitory activities and antiproliferative effects against diverse human tumor cell lines. Among them, compound 10o was identified as a potent class I and class IIb HDAC inhibitor with good pharmaceutical profile and druglike properties. Western blot analysis further confirmed that 10o more effectively increased acetylated histone H3 than panobinostat (LBH-589) and vorinostat (SAHA) at the same concentration in vitro. In in vivo efficacy evaluations of HCT116, MV4-11, Ramos, and MM1S xenograft models, 10o showed higher efficacy than SAHA or LBH-589 without causing significant loss of body weight and toxicity. All the results indicated that 10o could be a suitable candidate for treatment of both solid and hematological cancer.
- Chen, Yong,Wang, Xiaoyan,Xiang, Wei,He, Lin,Tang, Minghai,Wang, Fang,Wang, Taijin,Yang, Zhuang,Yi, Yuyao,Wang, Hairong,Niu, Ting,Zheng, Li,Lei, Lei,Li, Xiaobin,Song, Hang,Chen, Lijuan
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p. 5488 - 5504
(2016/07/06)
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- FUSED PYRIMIDINE-BASED HYDROXAMATE DERIVATIVES
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The present invention relates to fused pyrimidine-based hydroxamate compounds of formula (I), comprising a hydroxamate group, that are inhibitors of histone deacetylase (HDAC) and kinases. More particularly, the present invention relates to hydroxamate substituted purine or 5H-pyrrolo[3,2-d]pyrimidine derivatives, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of disorders/conditions/diseases involving, relating to or associated with enzymes having histone deacetylase, non-histone deacetylase and kinase activities/functions and/or via unspecified/multi-targeted mechanisms.
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Page/Page column 67
(2015/10/05)
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- NOVEL HETEROCYCLIC DERIVATIVES
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The invention relates to novel heterocyclic compounds of the formula (I) in which all of the variables are as defined in the specification, to their preparation, to their medical use, in particular to their use in the treatment of cancer and neurodegenrative disorders, and to medicaments comprising them.
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Page/Page column 57
(2012/08/27)
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- Lead optimization of purine based orally bioavailable Mps1 (TTK) inhibitors
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Efforts to optimize biological activity, novelty, selectivity and oral bioavailability of Mps1 inhibitors, from a purine based lead MPI-0479605, are described in this Letter. Mps1 biochemical activity and cytotoxicity in HCT-116 cell line were improved. On-target activity confirmation via mechanism based G2/M escape assay was demonstrated. Physico-chemical and ADME properties were optimized to improve oral bioavailability in mouse.
- Kumar, D. Vijay,Hoarau, Christophe,Bursavich, Matthew,Slattum, Paul,Gerrish, David,Yager, Kraig,Saunders, Michael,Shenderovich, Mark,Roth, Bruce L.,McKinnon, Rena,Chan, Ashley,Cimbora, Daniel M.,Bradford, Chad,Reeves, Leslie,Patton, Scott,Papac, Damon I.,Williams, Brandi L.,Carlson, Robert O.
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scheme or table
p. 4377 - 4385
(2012/08/07)
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- BICYCLIC INDOLE-PYRIMIDINE PI3K INHIBITOR COMPOUNDS SELECTIVE FOR P110 DELTA, AND METHODS OF USE
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Formula I (Ia and Ib) compounds wherein (i) X1 is N and X2 is S, (ii) X1 is CR7 and X2 is S, (iii) X1 is N and X2 is NR2, (iv) X1 is CR7 and X2 is O, or (v) X1 is CR7 and X2 is NR2, including stereoisomers, tautomers, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting the delta isoform of PBK, and for treating disorders mediated by lipid kinases such as inflammation, immunological, and cancer. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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Page/Page column 89
(2010/12/26)
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- Novel purine and pyrazolo[3,4-d]pyrimidine inhibitors of PI3 kinase-α: Hit to lead studies
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Series of purine and pyrazolo[3,4-d]pyrimidine inhibitors of phosphatidylinositol-3-kinases (PI3K) have been prepared. The optimized purine inhibitors show good potency in a PI3K p110α (PI3K-α) fluorescence polarization assay with good selectivity versus PI3K p110γ (PI3K-γ) and the mammalian target of rapamycin (mTOR). The related pyrazolo[3,4-d]pyrimidines show potent PI3K-α and mTOR inhibition with good selectivity versus PI3K-γ. Representative compounds showed activity in a cellular proliferation assay against Caco-2 colorectal, LoVo colorectal and PC3MM2 prostate adenocarcinoma cancer cells. Signaling through the PI3K pathway was confirmed via inhibition of phospho-AKT in MDA-361 cells.
- Gilbert, Adam M.,Nowak, Pawel,Brooijmans, Natasja,Bursavich, Matthew G.,Dehnhardt, Christoph,Santos, Efren Delos,Feldberg, Larry R.,Hollander, Irwin,Kim, Stephen,Lombardi, Sabrina,Park, Kaapjoo,Venkatesan, Aranapakam M.,Mallon, Robert
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scheme or table
p. 636 - 639
(2010/06/14)
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- MORPHOLINOPURINE DERIVATIVES
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There is provided a novel compound that inhibits phosphatidylinositol 3-kinase (PI3K) and/or the mammalian target of rapamycin (mTOR) and exhibits anti-tumor activity. The present invention provides a compound represented by the following formula (1) having various substituents that inhibits PI3K and/or mTOR and exhibits anti-tumor activity: wherein R1, R2, R3, R4, Ra, Rb, Rc, and X each have the same meaning as defined in the specification.
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Page/Page column 67-68
(2010/06/14)
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- Novel imidazolopyrimidines as dual PI3-Kinase/mTOR inhibitors
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This article describes the syntheses and SAR of a series of imidazolopyrimidine derivatives, which are evaluated as inhibitors of PI3-Kinase (PI3 K) and mTOR. These compounds were found to be ATP competitive with good tumor cell growth inhibition, and suppression of pathway specific biomakers such as phosphorylation of Akt at T308.
- Venkatesan, Aranapakam M.,Dehnhardt, Christoph M.,Chen, Zecheng,Santos, Efren Delos,Dos Santos, Osvaldo,Bursavich, Matthew,Gilbert, Adam M.,Ellingboe, John W.,Ayral-Kaloustian, Semiramis,Khafizova, Gulnaz,Brooijmans, Natasja,Mallon, Robert,Hollander, Irwin,Feldberg, Larry,Lucas, Judy,Yu, Ker,Gibbons, Jay,Abraham, Robert,Mansour, Tarek S.
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scheme or table
p. 653 - 656
(2010/07/05)
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- PURINE DERIVATIVES USEFUL AS PI3 KINASE INHIBITORS
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This invention provides a compound which is a purine of formula (Ia) or (Ib): and the pharmaceutically acceptable salts thereof that are inhibitors of PI3K and a selective for the p110δ isoform, which is a class Ia PI3 kinase, over other class Ia PI3 kinases and over class Ib kinases. The compounds may be used to treat diseases and disorders arisi from abnormal cell growth, function or behaviour associated with PI3 kinase such as cance immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders.
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Page/Page column 46; 65
(2009/05/28)
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- IMIDAZOLOPYRIMIDINE ANALOGS AND THEIR USE AS PI3 KINASE AND MTOR INHIBITORS
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The present invention relates to Imidazolopyrimidine Analogs, methods of making Imidazolopyrimidine Analogs, compositions comprising an Imidazolopyrimidine Analog, and methods for treating or preventing a PI3K-related disorder comprising administering to a subject in need thereof an effective amount of an Imidazolopyrimidine Analog. The invention also relates to methods for treating or preventing mTOR-related disorders comprising administering to a subject in need thereof an effective amount of an Imidazolopyrimidine Analog.
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Page/Page column 28
(2008/12/08)
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- Purine Derivatives, Compositions Containing Them and Use Thereof
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Purine derivatives of formula (IA1) or (IB1), compositions containing them and use thereof as medicinal products, in particular in oncology, are described
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Page/Page column 9
(2008/12/05)
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- Heterocyclic Compounds For Preventing And Treating Disorders Associated With Excessive Bone Loss
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This invention relates to pyrimidine compounds of formula (I), formula (I′), and formula (I″): and pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein R1, R2, R3, R4, R5/
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Page/Page column 42
(2010/11/30)
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- Novel compounds
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This invention features a compound of formula (I): R1 is aryl or heteroaryl; each of R2 and R4, independently, is H, halogen, CN, alkyl, ORa, or NRaRb; R3 is H, halogen, CN, alky
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- Solution-phase synthesis of 2,6,9-trisubstituted purines
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A simple three-step method for the solution-phase combinatorial synthesis of 2,6,9-trisubstituted purines from 2,6-dichloropurine is described. The synthesis exploits the use of resin capture to remove excess reagent used in the final step.
- Fiorini, Maria T.,Abell, Chris
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p. 1827 - 1830
(2007/10/03)
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