- Solid-phase synthesis of N-9-substituted 2,8-diaminopurines
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A general and efficient solid-phase synthesis of N-9-substituted 2,8-diaminopurines from 5-nitrouracil is described. The key synthetic transformation employs a carbodiimide-mediated cyclization of a thiourea. Thiourea formation on solid phase is performed
- Cole, Andrew G.,Metzger, Axel,Ahmed, Gulzar,Brescia, Marc-Raleigh,Chan, Ray J.,Wen, James,O'Brien, Linda,Qin, Lan-Ying,Henderson, Ian
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Read Online
- Design, synthesis, and in vitro biological evaluation of novel thiazolopyrimidine derivatives as antileishmanial compounds
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A series of thiazolopyrimidine derivatives was designed and synthesized as a Leishmania major pteridine reductase 1 (LmPTR1) enzyme inhibitor. Their LmPTR1 inhibitor activities were evaluated using the enzyme produced by Escherichia coli in a recombinant way. The antileishmanial activity of the selected compounds was tested in vitro against Leishmania sp. Additionally, the compounds were evaluated for cytotoxic activity against the murine macrophage cell line RAW 264.7. According to the results, four compounds displayed not only a potent in vitro antileishmanial activity against promastigote forms but also low cytotoxicity. Among them, compound L16 exhibited an antileishmanial activity for both the promastigote and amastigote forms of L. tropica, with IC50 values of 7.5 and 2.69 μM, respectively. In addition, molecular docking studies and molecular dynamics simulations were also carried out in this study. In light of these findings, the compounds provide a new potential scaffold for antileishmanial drug discovery.
- Istanbullu, Huseyin,Bayraktar, Gulsah,Akbaba, Hasan,Cavus, Ibrahim,Coban, Gunes,Debelec Butuner, Bilge,Kilimcioglu, Ali Ahmet,Ozbilgin, Ahmet,Alptuzun, Vildan,Erciyas, Ercin
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Read Online
- Method for preparing 2, 4 - dichloro -5 - nitropyrimidine
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The invention discloses a method for preparing 2, 4 - dichloro -5 - nitropyrimidine, wherein, 5 - nitro uracil is put into a reactor, and the reaction is stopped when the product content 50 °C 95% or more is increased to 100 °C dropwise DMF. The dichloroethane layer was removed by filtration, and the 2 mixture 4 -dichloro -5 -nitropyrimidine was distilled off under reduced pressure. The reaction conditions are easy to control, operation is simple, yield is high, production cost is low, safety and environmental protection are achieved, and industrial production can be realized.
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Paragraph 0017; 0020-0032
(2021/09/08)
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- NITRATION
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The present invention relates to a process for preparing a nitrated compound, comprising the step of reacting a compound (A) comprising at least one substituted or unsubstituted aromatic or heteroaromatic ring, wherein said heteroaromatic ring comprises at least one heteroatom selected from the group consisting of oxygen, sulfur, phosphor, selenium and nitrogen, with a compound of formula (I) wherein Y is selected from the group consisting of hydrogen and nitro.
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Page/Page column 36; 37; 49; 39; 53
(2020/05/28)
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- Efficient Phosphorus-Free Chlorination of Hydroxy Aza-Arenes and Their Application in One-Pot Pharmaceutical Synthesis
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The chlorination of hydroxy aza-arenes with bis(trichloromethyl) carbonate (BTC) and SOCl2 has been effectively performed by refluxing with 5 wt % 4-dimethylaminopyridine (DMAP) as a catalyst. Various substrates are chlorinated with high yields. The obtained chlorinated aza-arenes can be used directly with simple workup for succedent one-pot synthesis on a large scale.
- Wang, Jian,Li, Yan-Hui,Pan, Song-Cheng,Li, Ming-Fang,Du, Wenting,Yin, Hong,Li, Jing-Hua
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supporting information
p. 146 - 153
(2020/03/10)
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- Preparation method of chloro-substituted polyhydroxy aza-aromatic ring compound (by machine translation)
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The invention discloses a preparation method, namely BTC and SOCl, of a chloropolyhydroxyl aza heteroaromatic ring compound as a raw material with a polyhydroxy aza heteroaromatic ring compound as a raw material, and a preparation method thereof. 2 As the double chlorination reagent, a chloropolyhydroxyl aza-aromatic ring compound is produced by chlorination reaction with 4 - dimethylaminopyridine (DMAP) as a catalyst at room temperature to reflux temperature of the reaction, as a catalyst. BTC TC TC TC2 /DMDMAP chlorination system has high efficiency, high selectivity and chlorine substitution on a polyhydroxy nitrogen heterocyclic compound; the system can replace POCl3 , The production of phosphorus-containing wastewater is avoided. Using BTC as a chlorination reagent, the reaction by-product was HCl and CO. 2 . From the aspects of industrial wastewater treatment, environmental protection and the like, the advantages thereof are obvious; SOCl is distilled off after the reaction is ended. 2 The quantity is almost no loss, can be used repeatedly, and reduces the process cost. (by machine translation)
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Paragraph 0019; 0020; 0021-0024
(2019/10/01)
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- Sulfide Analogues of Flupirtine and Retigabine with Nanomolar KV7.2/KV7.3 Channel Opening Activity
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The potassium channel openers flupirtine and retigabine have proven to be valuable analgesics or antiepileptics. Their recent withdrawal due to occasional hepatotoxicity and tissue discoloration, respectively, leaves a therapeutic niche unfilled. Metabolic oxidation of both drugs gives rise to the formation of electrophilic quinones. These elusive, highly reactive metabolites may induce liver injury in the case of flupirtine and blue tissue discoloration after prolonged intake of retigabine. We examined which structural features can be altered to avoid the detrimental oxidation of the aromatic ring and shift oxidation toward the formation of more benign metabolites. Structure–activity relationship studies were performed to evaluate the KV7.2/3 channel opening activity of 45 derivatives. Sulfide analogues were identified that are devoid of the risk of quinone formation, but possess potent KV7.2/3 opening activity. For example, flupirtine analogue 3-(3,5-difluorophenyl)-N-(6-(isobutylthio)-2-(pyrrolidin-1-yl)pyridin-3-yl)propanamide (48) has 100-fold enhanced activity (EC50=1.4 nm), a vastly improved toxicity/activity ratio, and the same efficacy as retigabine in vitro.
- Bock, Christian,Surur, Abdrrahman S.,Beirow, Kristin,Kindermann, Markus K.,Schulig, Lukas,Bodtke, Anja,Bednarski, Patrick J.,Link, Andreas
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supporting information
p. 952 - 964
(2019/04/10)
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- Preparation method of 2, 4-dichloro-5-nitropyrimidine
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The invention provides a preparation method of 2, 4-dichloro-5-nitropyrimidine. The preparation method comprises: adding 5-nitropyrimidine into a reactor along with stirring, adding phosphorus oxychloride into the reactor, heating the mixture to 50-100 DEG C, adding DMF into the mixture drop by drop so that the mixture undergoes a reaction until the product content of the reaction solution is 95%or more, carrying out reduced pressure recovery on phosphorus oxychloride, feeding dichloroethane into the reaction solution, carrying out mixing, adding the reaction solution into ice water, carryingout hydrolysis and layering, taking out a dichloroethane layer, and carrying out reduced pressure distillation to obtain a 2, 4-dichloro-5-nitropyrimidine finished product. The preparation method hasthe advantages of easy control of reaction conditions, simple operation, high yield, low production cost, safety and environmental friendliness and realizes industrial production.
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Paragraph 0012-0020
(2019/02/13)
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- Purine compounds, composition and application
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The invention belongs to the technical field of medicine and relates to purine compounds, composition and an application of the composition. The compounds represented as a general formula (I) as well as all possible isomers, pharmaceutical salts or hydrates or the composition of the compounds are used for treating diseases caused by BTK (Bruton tyrosine kinase) and particularly used for treating diffuse large B cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia.
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Paragraph 0066; 0071; 0072
(2017/07/04)
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- Optimisation of LRRK2 inhibitors and assessment of functional efficacy in cell-based models of neuroinflammation
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LRRK2IN1 is a highly potent inhibitor of leucine-rich repeat kinase 2 (LRRK2, IC50 = 7.9 nM), an established target for treatment of Parkinson's disease. Two LRRK2IN1 analogues 1 and 2 were synthesised which retained LRRK2 inhibitory activity (1: IC50 = 72 nM; 2: IC50 = 51 nM), were predicted to have improved bioavailability and were efficacious in cell-based models of neuroinflammation. Analogue 1 inhibited IL-6 secretion from LPS-stimulated primary human microglia with EC50 = 4.26 μM. In order to further optimize the molecular properties of LRRK2IN1, a library of truncated analogues was designed based on docking studies. Despite lacking LRRK2 inhibitory activity, these compounds show antineuroinflammatory efficacy at micromolar concentration. The compounds developed were valuable tools in establishing a cell-based assay for assessing anti-neuroinflammatory efficacy of LRRK2 inhibitors. Herein, we present data that IL-1β stimulated U87 glioma cell line is a reliable model for neuroinflammation, as data obtained in this model were consistent with results obtained using primary human microglia and astrocytes.
- Munoz, Lenka,Kavanagh, Madeline E.,Phoa, Athena F.,Heng, Benjamin,Dzamko, Nicolas,Chen, Ew-Jun,Doddareddy, Munikumar Reddy,Guillemin, Gilles J.,Kassiou, Michael
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supporting information
p. 29 - 34
(2015/03/30)
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- 2,4-Pyrimidinediamine Compounds and Their Uses
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The present invention provides 2,4-pyrimidinediamine compounds that inhibit the IgE and/or IgG receptor signaling cascades that lead to the release of chemical mediators, intermediates and methods of synthesizing the compounds and methods of using the compounds in a variety of contexts, including in the treatment and prevention of diseases characterized by, caused by or associated with the release of chemical mediators via degranulation and other processes effected by activation of the IgE and/or IgG receptor signaling cascades.
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Paragraph 0313
(2015/11/10)
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- Electron-deficient heteroarenium salts: An organocatalytic tool for activation of hydrogen peroxide in oxidations
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A series of monosubstituted pyrimidinium and pyrazinium triflates and 3,5-disubstituted pyridinium triflates were prepared and tested as simple catalysts of oxidations with hydrogen peroxide, using sulfoxidation as a model reaction. Their catalytic efficiency strongly depends on the type of substituent and is remarkable for derivatives with an electron-withdrawing group, showing reactivity comparable to that of flavinium salts which are the prominent organocatalysts for oxygenations. Because of their high stability and good accessibility, 4-(trifluoromethyl)pyrimidinium and 3,5-dinitropyridinium triflates are the catalysts of choice and were shown to catalyze oxidation of aliphatic and aromatic sulfides to sulfoxides, giving quantitative conversions, high preparative yields and excellent chemoselectivity. The high efficiency of electron-poor heteroarenium salts is rationalized by their ability to readily form adducts with nucleophiles, as documented by low pKR+ values (pKR+ red > -0.5 V). Hydrogen peroxide adducts formed in situ during catalytic oxidation act as substrate oxidizing agents. The Gibbs free energies of oxygen transfer from these heterocyclic hydroperoxides to thioanisole, obtained by calculations at the B3LYP/6-311++g(d,p) level, showed that they are much stronger oxidizing agents than alkyl hydroperoxides and in some cases are almost comparable to derivatives of flavin hydroperoxide acting as oxidizing agents in monooxygenases.
- ?turala, Ji?í,Bohá?ová, Soňa,Chudoba, Josef,Metelková, Radka,Cibulka, Radek
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p. 2676 - 2699
(2015/03/18)
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- Efficient synthesis of flupirtine analogues derived from pyrimidine
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The synthesis of novel N2-substituted 5-alkoxycarbonylamino-2,4- diaminopyrimidines, 5-acylamino-2,4-diaminopyrimidines, and 2,4-diamino-5- ureidopyrimidines as analogues of the analgesic flupirtine is described. Copyright
- Hansen, Finn K.,Geffken, Detlef
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scheme or table
p. 321 - 328
(2012/06/04)
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- Synthesis and characterization of 9-methyl-2-morpholin-4-yl-8-substituted phenyl-1H-purine derivatives using polyphosphoric acid (PPA) as an efficient catalyst
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We demonstrate the synthesis of various purine derivatives through the coupling of N4-methyl-2-morpholin-4-yl-pyrimidine-4,5-diamine with various aldehydes by using polyphosphoric acid (PPA) as an efficient catalyst in DMF at reflux temperature
- Sadanandam,Jyothi,Adharvana Chari,Das, Parthasarathi,Mukkanti
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supporting information; experimental part
p. 5521 - 5524
(2011/10/30)
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- PYRIMIDO[5,4-e][1,2,4]TRIAZINES AND USES THEREOF
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The present invention provides a com pound of Formula (I) or a pharmaceutically acceptable derivative, salt or prodrug thereof: Formula (I). The present invention further provides pharmaceutical compositions comprising a compound of formula I and methods of tr eating or preventing viral infections, particularly HCV infections, by admi nistering a compound of Formula (I).
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Page/Page column 27
(2010/08/08)
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- INHIBITORS OF JANUS KINASES
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The instant invention provides for compounds that inhibit the four known mammalian JAK kinases (JAK1, JAK2, JAK3 and TYK2) and PDK1. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting the activity of JAK1, JAK2, JAK3, TYK2 and PDK1 by administering the compound to a patient in need of treatment for myeloproliferative disorders or cancer.
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Page/Page column 77-78
(2010/01/12)
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- Purine cytokine inhibitors
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The present invention relates to 2,8,9-substituted purines which inhibit the extracellular release of inflammatory cytokines, said cytokines responsible for one or more human or higher mammalian disease states. The present invention further relates to com
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Page/Page column 8; 9-10
(2010/11/28)
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- PYRIMIDINES USEFUL AS MODULATORS OF VOLTAGE-GATED ION CHANNELS
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The present invention relates to compounds useful as inhibitors of voltage-gated ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.
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Page 136-137
(2010/02/10)
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- STEROID SPARING AGENTS AND METHODS OF USING SAME
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This invention relates generally to the use of a steroid sparing agent for the preparation of a medicament for the treatment of inflammatory bowel diseases (IBD), asthma, multiple sclerosis (MS), rheumatoid arthritis (RA), graft versus host disease (GVHD), host versus graft disease, and various spondyloarthropathies, comprising administering a steroid sparing immunoglobulin or small molecule composition to a patient in need thereof. The invention also relates generally to combination therapies for the treatment of these conditions.
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Page/Page column 541; 549; 552-553
(2010/02/14)
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- Folate-Synthesizing Enzyme System as Target for Development of Inhibitors and Inhibitor Combinations against Candida albicans - Synthesis and Biological Activity of New 2,4-Diaminopyrimidines and 4′-Substituted 4-Aminodiphenyl Sulfones
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The paper describes the design, synthesis, and testing of inhibitors of folate-synthesizing enzymes and of whole cell cultures of Candida albicans. The target enzymes used were dihydropteroic acid synthase (SYN) and dihydrofolate reductase (DHFR). Several series of new 2,4-diaminopyrimidines were synthesized and tested as inhibitors of DHFR and compared with their activity against DHFR derived from mycobacteria and Escherichia coli. To test for selectivity, also rat DHFR was used. A series of substituted 4-aminodiphenyl sulfones was tested for inhibitory activity against SYN and the I50 values compared to those obtained previously against Plasmodium berghei- and E. coll-derived SYN. Surprisingly, QSAR equations show very similar structural dependencies. To find an explanation for the large difference in the I50 values observed for enzyme inhibition (SYN, DHFR) and for inhibition of cell cultures of Candida, mutant strains with overexpressed efflux pumps and strains in which such pumps are deleted were included in the study and the MICs compared. Efflux pumps were responsible for the low activity of some of the tested derivatives, others showed no increase in activity after pumps were knocked out. In this case it may be speculated that these derivatives are not able to enter the cells.
- Otzen, Thomas,Wempe, Ellen G.,Kunz, Brigitte,Bartels, Rainer,Lehwark-Yvetot, Gudrun,H?nsel, Wolfram,Schaper, Klaus-Jürgen,Seydel, Joachim K.
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p. 240 - 253
(2007/10/03)
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- HETEROCYCLIC COMPOUNDS WHICH INHIBIT LEUKOCYTE ADHESION MEDIATED BY α4 INTEGRINS
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Disclosed are compounds which bind α4 integrins, preferably VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by α4 integrins, preferably VLA-4. Such compounds are useful in the treatment of
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- HETEROARYL COMPOUNDS WHICH INHIBIT LEUKOCYTE ADHESION MEDIATED BY ALPHA-4 INTEGRINS
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Disclosed are compounds which bind 4 integrins, where the 4integrin is preferably VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by 4integrins, where the 4 integrin is preferably VLA-4. Su
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- Method of inhibiting neoplastic cells with 4,5-diaminopyrimidine derivatives
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A method for inhibiting neoplasia, particularly cancerous and precancerous lesions by exposing the affected cells to 4,5-diaminopyrimidine derivatives.
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- 3-(Heteroaryal) alanine derivatives-inhibitors of leukocyte adhesion mediated by VLA-4
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Disclosed are certain 3-(heteroaryl)alanine derivatives which bind VLA-4 and inhibit leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.
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- 1N-ALKYL-N-ARYLPYRIMIDINAMINES AND DERIVATIVES THEREOF
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The present invention provides novel compounds, compounds and pharmaceutical compositions thereof, and methods of using same in the treatment of affective disorders, anxiety, depression, post-traumatic stress disorders, eating disorders, supranuclear palsy, irritable bowel syndrome, immune suppression, Alzheimer'disease, gastrointestinal diseases, anorexia nervosa, drug and alcohol withdrawal symptoms, drug addiction, inflammatory disorders, or fertility problems. The novel compounds provided by this invention are those of formula: wherein R 1, R 3, R 4, R 5, Z, Y, V, X, X', J, K, L, and M are as defined herein.
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Page column 69 - 70
(2010/01/30)
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- 4,5-diaminopyrimidine derivatives and a method for the preparation thereof
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Novel 4,5-diamino pyrimidine derivatives are described by the following general formula I: in which X is a direct bond, C1-4 alkylene, C1-4 alkyleneoxy, C1-4 alkoxyphenyl or phenyl C1-4 alkylene; Y is a direct b
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- Structure-Activity Relations. Part 12. Antibacterial Activity of a Series of 2,4-Diamino-6-substituted 5-(4-pyridylmethylamino)pyrimidines and 2,4-Diamino-5-(4-substituted benzylamino)pyrimidines.
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A series of 6-substituted 2,4-diamino-5-(4-pyridylamino)pyrimidines and of 2,4-diamino-5-(4-substituted benzylamino)pyrimidines has been prepared.Their antibacterial activity towards L. casei, S. aureus and E. coli has been investigated.These activities have been successfully correlated by Hansch-type relations.Dependence on both lipophilicity and electronic (polar) factors has been found.The results are related to the structure and interactions with the receptor.
- Bowden, Keith,Bright, Andrew C.
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p. 514 - 539
(2007/10/02)
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