- 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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- Preparation method for catalyzing pyrimidine cyclic hydroxyl chlorination by tetraethylammonium chloride
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The invention discloses a preparation method for catalyzing pyrimidine cyclic hydroxyl chlorination by tetraethylammonium chloride, which comprises the following steps: (1) adding phosphorus oxychloride into a container, adding tetraethylammonium chloride as a catalyst, adding a pyrimidine cyclic hydroxyl compound, and heating to react; (2) preparing an alkali liquor, cooling to 0 DEG C, and slowly dropwise adding an obtained reaction liquid into the alkali liquor for quenching to obtain a target product. The method has the advantages that the provided pyrimidine cyclic hydroxyl chlorination catalysis method is small in environmental pollution, the obtained product is light in color, the catalysis efficiency is high, and the phosphorus oxychloride recovery pressure is small.
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Paragraph 0022-0024
(2020/04/17)
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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; 0032-0034; 0041; 0046-0048
(2020/08/29)
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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 00234; 00235
(2018/08/20)
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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; 0595; 0600-0602
(2019/02/02)
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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; 115
(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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- PYRROLOPYRIMIDINES AS FAK AND ALK INHIBITERS FOR TREATMENT OF CANCERS AND OTHER DISEASES
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Disclosed are compounds which inhibit the activity of focal adhesion kinase (FAK) and anaplastic lymphoma kinase (ALK), compositions containing the compounds, and methods of treating diseases during which FAK and ALK are expressed. The diseases are, for example, cancers.
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Page/Page column 60
(2012/04/23)
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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; scheme or table
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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- 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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- 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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- PYRROLO[2,3-D]PYRIMIDINE DERIVATIVES; THEIR INTERMEDIATES AND SYNTHESIS
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This invention relates to methods and intermediates useful for the synthesis of pyrrolo [2,3-d] pyrimidine compounds. Specifically novel synthetic methods and intermediates for the synthesis of 3- {(3R, 4R)-4-methyl-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-amino}-piperidin-1-yl)-3-oxo-propionitrile and its corresponding citrate salt are disclosed.
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Page/Page column 24
(2010/11/25)
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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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Page/Page column 38
(2008/06/13)
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- DIARYL-PURINE, AZAPURINES AND -DEAZAPURINES AS NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS FOR TREATMENT OF HIV
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This application concerns certain 2-phenylamino-6-aryl amino-, 6-aryloxy-, and 6- arylthio- purines, -azapurines and -deazapurines. These compounds are non-nucleoside reverse transcriptase inhibitors and have potential as anti-HIV treatment.
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Page/Page column 30-31
(2008/06/13)
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- Synthesis and antiviral activity of certain 4-substituted and 2,4-disubstituted 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidines
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Treatment of the sodium salt of 4-chloro-2-(methylthio)pyrrolo[2,3-d]pyrimidine (2) with (2-acetoxyethoxy)methyl bromide (3) has provided 4-chloro-2-(methylthio)-7-[2-acetoxyethoxy)methyl]pyrrolo[2,3-d]pyrim dine (4). Ammonolysis of 4 at room temperature
- Saxena,Hagenow,Genzlinger,Turk,Drach,Townsend
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p. 1501 - 1506
(2007/10/02)
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- 7-Deaza Isosters of 2'-Deoxyxanthosine and 2'-Deoxyspongosine - Synthesis via Glycosylation of 2,4-Dichloro-7H-pyrrolopyrimidine
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7-Deaza-2'-deoxyxanthosine (1a) and 7-deaza-2'-deoxyspongosine (2), two new pyrrolopyrimidine deoxynucleosides, have been prepared by nucleophilic displacement of the chloro substituents of the intermediate 2,4-dichloro-7-2-deoxy-3,5-di-O-(p-toluo
- Seela, Frank,Driller, Hansjuergen,Liman, Ulrich
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p. 312 - 320
(2007/10/02)
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- 7-(β-D-Arabinofuranosyl)-2,4-dichloro-7H-pyrrolopyrimidine - Synthesis, Selective Displacement of Halogen, and Influence of Glyconic Protecting Groups on the Reactivity of the Aglycone
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Selective N-7 glycosylation of 2,4-dichloro-7H-pyrrolopyrimidine (1a) with the arabinohalogenose 5 has been achieved yielding the β-anomer 7a in 67percent yield.Debenzylation with boron trichloride results in the formation of the 2,4-dichloronucleo
- Seela, Frank,Driller, Hansjuergen
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p. 722 - 733
(2007/10/02)
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- Synthesis of 2'-Deoxytubercidin, 2'-Deoxyadenosine, and Related 2'-Deoxynucleosides via a Novel Direct Stereospecific Sodium Salt Glycosylation Procedure
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A general and stereospecific synthesis has been developed for the direct preparation of 2'-deoxy-β-D-ribofuranosylpurine analogues including 2'-deoxyadenosine derivatives.The reaction of the sodium salt of 4-chloropyrrolopyrimidine (4) or 2,4-dichloropyrrolopyrimidine (1) with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranose (25) provided the corresponding N-1,2'-deoxy-β-D-ribofuranosyl blocked derivatives (5 and 2) which, on ammonolysis, gave 2'-deoxytubercidin (6) and 2-chloro-2'-deoxytubercidin (3), respectively, in good yield.This glycosylation also readily proceeds in the presence of a 2-methylthio group.Application of this glycosylation procedure to 4,6-dichloroimidazopyridine (10), 6-chloropurine (16), 2,6-dichloropurine (13), and 4-chloropyrazolopyrimidine (19) gave 2-chloro-2'-deoxy-3-deazaadenosine (12), 2-'-deoxyadenosine (18), 2-chloro-2'-deoxyadenosine (15), and 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)pyrazolopyrimidine (21), respectively.Similarly, glycosylation and ammonolysis of 4,6-dichloro-1H-pyrrolopyridine (22) gave 4,6-dichloro-1-(2-deoxy-β-D-erythro-pentofuranosyl)pyrrolopyridine (24).This stereospecific attachment of the 2-deoxy-β-D-ribofuranosyl moiety appears to be due to a Walden inversion at the C-1 carbon of 25.
- Kazimierczuk, Zygmunt,Cottam, Howard B.,Revankar, Ganapathi R.,Robins, Roland K.
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p. 6379 - 6382
(2007/10/02)
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