- Design of biphenyl-substituted diarylpyrimidines with a cyanomethyl linker as HIV-1 NNRTIs via a molecular hybridization strategy
-
The key problems of human immunodeficiency virus (HIV) therapy are the rapid emergence of drug-resistant mutant strains and significant cumulative drug toxicities. Therefore, there is an urgent demand for new anti-HIV agents with low toxicity and broad-spectrum antiviral potency. A series of biphenyl-substituted diarylpyrimidines with a cyanomethyl linker were designed using a molecular hybridization strategy. The cell-based anti-HIV assay showed that most of the compounds exhibited moderate to good activities against wild-type HIV-1 and clinically relevant mutant strains with a more favorable toxicity, and the enzymatic assay showed they had nanomolar activity against reverse transcriptase (RT). Compound 10p exhibited the best activity against wild-type HIV-1 with an EC50 (50% HIV-1 replication inhibitory concentration) value of 0.027 μM, an acceptable CC50 (50% cytotoxic concentration) value of 36.4 μM, and selectivity index of 1361, with moderate activities against the single mutants (EC50: E138K, 0.17 μM; Y181C, 0.87 μM; K103N, 0.9 μM; L100I, 1.21 μM, respectively), and an IC50 value of 0.059 μM against the RT enzyme, which was six-fold higher than nevirapine (NVP). The preliminary structure–activity relationship (SAR) of these new compounds was concluded. The molecular modeling predicted the binding modes of the new compounds with RT, providing molecular insight for further drug design.
- Chen, Fen-Er,Han, Sheng,Lei, Yuan,Pannecouque, Christophe,Yang, Yang,Zhuang, Chunlin,de Clercq, Erik
-
-
- Sulfenyl Ynamides in Gold Catalysis: Synthesis of Oxo-functionalised 4-aminoimidazolyl Fused Compounds by Intermolecular Annulation Reactions
-
Functionalised N-heterocyclic pyridinium N-aminides have been designed and synthesised to evaluate a nitrenoid-based annulation strategy into imidazole-fused oxo-substituted frameworks of importance to medicinal and agrochemical discovery programmes. Sulfenyl substituted ynamides were identified as privileged reactants affording productive gold-catalysed annulation reactions with these and other nitrenoids. This annulation method provides selective and efficient access into geminally amino-sulfenyl substituted nitrogen heterocycles under mild reaction conditions. (Figure presented.).
- Arce, Elsa M.,Lamont, Scott G.,Davies, Paul W.
-
p. 2503 - 2509
(2020/04/30)
-
- Scaffold hopping in discovery of HIV-1 non-nucleoside reverse transcriptase inhibitors: From CH(CN)-DABOs to CH(CN)-dapys
-
Scaffold hopping is a frequently-used strategy in the development of non-nucleoside reverse transcriptase inhibitors. Herein, CH(CN)-DAPYs were designed by hopping the cyano-methylene linker of our previous published CH(CN)-DABOs onto the etravirine (ETR). Eighteen CH(CN)-DAPYs were synthesized and evaluated for their anti-HIV activity. Most compounds exhibited promising activity against wild-type (WT) HIV-1. Compounds B4 (EC50 = 6 nM) and B6 (EC50 = 8 nM) showed single-digit nanomolar potency against WT HIV-1. Moreover, these two compounds had EC50 values of 0.06 and 0.08 μM toward the K103N mutant, respectively, which were comparable to the reference efavirenz (EFV) (EC50 = 0.08 μM). The preliminary structure-activity relationship (SAR) indicated that introducing substitutions on C2 of the 4-cyanophenyl group could improve antiviral activity. Molecular docking predicted that the cyano-methylene linker was positioned into the hydrophobic cavity formed by Y181/Y188 and V179 residues.
- Chen, Fen-Er,Li, Ting-Ting,Pannecouque, Christophe,Zhuang, Chun-Lin,de Clercq, Erik
-
-
- Synthesis method of 4-chloro-2-methylthiopyrimidine
-
The invention belongs to the technical field of organic synthesis, in particular to a synthesis method of 4-chloro-2-methylthiopyrimidine. The method includes taking 2-thiouracil as a raw material, dimethyl sulfate as a methylation reagent, thionyl chloride and phosphorus oxychloride as a chlorination reagent, and synthesizing the 4-chloro-2-methylthiopyrimidine through methylation and chlorination.The dimethyl sulfate is taken as the methylation reagent to replace methyl bromide or methyl iodide, and thus the safety of the reaction is increased, and the cost is decreased; sodium hydroxide istaken as alkali to replace sodium methoxide or butyl lithium, and thus the safety of the reaction is increased, and the cost is reduced; toluene is taken as a reaction solvent, and thus the dosage ofthe chlorinated reagent is greatly reduced, the reaction safety is greatly improved, the cost is reduced, and the post-treatment operation is simplified; and the sulfoxide chloride and the phosphorusoxychloride are taken as the mixed chlorinating reagent, and thus the reaction yield is greatly improved.
- -
-
Paragraph 0022; 0023; 0024; 0025-0028; 0037-009
(2019/06/30)
-
- BF3·SMe2 for Thiomethylation, Nitro Reduction and Tandem Reduction/SMe Insertion of Nitrogen Heterocycles
-
Herein, a general, solvent-free and straightforward thiomethylation of electron deficient heterocycles using BF3·SMe2 as a dual thiomethyl source and Lewis acidic activator is presented. A range of heterocycles including pyrimidine, pyrazine, pyridazine, thiazole and purine derivatives were successfully substituted using this method. An unexpected reductive property of BF3·SMe2 towards nitropyridines was also discovered including an intriguing tandem reduction/SMe insertion process in certain substrates. Notable features of the present work include its convenience and use of a non-malodorous reagent while the discovery of novel chemical transformations using BF3·SMe2 provides fundamental new insights into the reactivity of this commonly employed reagent.
- S?derstr?m, Marcus,Zamaratski, Edouard,Odell, Luke R.
-
p. 5402 - 5408
(2019/06/27)
-
- A new and efficient protocol for the synthesis of the key intermediate of palbociclib
-
A new and efficient synthesis of 6-bromo-8-cyclopentyl-5-methyl-2-(methylsulfinyl)-pyrido[2,3-d]pyrimidin-7(8H)-one, a key intermediate of Palbociclib, starting from thiouracil was described. This protocol involved methylation, nucleophilic substitution, bromination, nucleophilic substitution, Heck reaction, ring closure, oxidation, and bromination to afford a key intermediate of Palbociclib with approximately 35% overall yield. The advantages of this developed synthetic strategy included improved overall yield, inexpensive starting materials, and readily controllable and cleaner reaction conditions.
- Li, Shuting,Yang, Wanfeng,Ji, Min,Cai, Jin,Chen, Junqing
-
-
- NOVEL IN-VIVO PROBE FOR REAL TIME LONGITUDINAL MONITORING OF INDUCIBLE NITRIC-OXIDE SYNTHASE IN LIVING CELLS AND ANIMALS
-
The present disclosure relates to an in vivo fluorescent or radioactive probe represented by a compound of formula I which is capable of longitudinal imaging of inducible nitric oxide synthase (iNOS) expression in living cells and living animals on a real time basis. The probe of the present disclosure can exhibit specific and high affinity binding to the iNOS enzyme with reduced enzyme inhibitory property and also enables longitudinal monitoring of iNOS expression along with its activity or NO production in a same experimental subject throughout the progression of a physiological or disease process without employing separate subjects as controls and experimental. The present disclosure further provides a rapid and inexpensive real time method for visualizing iNOS expression and its activity in living cells and living animals precisely, conveniently and reversibly along with simultaneous in vivo imaging of its catalytic product, nitric oxide (NO) in live physiological settings.
- -
-
Paragraph 0074
(2018/06/06)
-
- Structural modifications of diarylpyrimidines (DAPYs) as HIV-1 NNRTIs: Synthesis, anti-HIV activities and SAR
-
30 new analogues of diarylpyrimidines were synthesized for further structural modifications, involving not only the linker but also the wing α of DAPYs. The anti-HIV-1 activities of all target molecules were evaluated, and most of them exhibited potent anti-HIV-1 (WT) activities and low cytotoxicities. Among which, compound 4g showed excellent activities against WT HIV-1 with an EC50 value of 5.8?nM and SI of up to 26,034. Another compound 4ab bearing a novel pyridinyl Wing α also displayed attractive activities. The structure-activity relationship (SAR) study was also summarized.
- Lu, Huan-Huan,Xue, Ping,Zhu, Yuan-Yuan,Ju, Xiu-Lian,Zheng, Xiao-Jiao,Zhang, Xun,Xiao, Ting,Pannecouque, Christophe,Li, Ting-Ting,Gu, Shuang-Xi
-
p. 2491 - 2497
(2017/04/03)
-
- A Palumbo vial preparation method of the key intermediate (by machine translation)
-
The invention discloses a Palumbo Xilin key intermediate 6 - bromo - 2 - methyl sulfonyl - 8 - cyclopentyl - 5 - methyl pyridine and (2, 3 - d) pyrimidine - 7 (8 H) - ketone. The method uses the thiourea pyrimidine as the starting material, by methylation, chloro, bromo synthesis of 5 - bromo - 4 - chloro - 2 - methylthio-pyrimidine, then with the cyclopentamine alkylation, with 2 - butenoic acid by the heck reaction, then the intramolecular acylation reaction for the synthesis of 2 - methylthio - 8 - cyclopentyl - 5 - methyl pyridine and (2, 3 - d) pyrimidine - 7 (8 H) - one, finally with the NBS reaction for the preparation of 6 - bromo - 2 - methyl sulfonyl - 8 - cyclopentyl - 5 - methyl pyridine and (2, 3 - d) pyrimidine - 7 (8 H) - one. The preparation process of the present invention short step, not using the dangerous process, simple and convenient operation, low cost of raw materials, to meet the using requirements of the people. (by machine translation)
- -
-
Paragraph 0008; 0010
(2018/03/24)
-
- Industrial synthesis method of rilpivirine and intermediate compound
-
The invention discloses an industrial synthesis method of rilpivirine. A compound as shown in a formula I and compound hydrochloride as shown in a formula VI react to obtain rilpivirine. The invention further discloses an intermediate compound as shown in the formula I and a synthesis method of the intermediate compound. Compared with the prior art, the synthesis method is simple to operate, mild in condition, high in yield and purity and suitable for industrial production.
- -
-
Paragraph 0028; 0038-0040
(2017/10/07)
-
- Heterocyclic Ring and Carbocyclic Derivative
-
The present invention provides novel compounds having a P2X3 and/or P2X2/3 receptor antagonistic effect, e.g. a compound of Formula (I): wherein R2 is a hydrogen atom or the like; ring A is five- to seven-cycloalkane or th
- -
-
Paragraph 0279-0280
(2016/02/18)
-
- A New Synthesis of 2-Aminoindoles and 6-Aminopyrrolo[3,2- d ]pyrimidines from π-Deficient 1,2-Dihaloarenes and Geminal Enediamines
-
An efficient approach for the synthesis of fused 2-aminopyrroles via geminal enediamines and π-deficient 1,2-dihaloarenes is presented. The two-step methodology includes aromatic nucleophilic substitution of the activated halogen of dihaloarene with enediamine C-nucleophilic center followed by Cu-catalyzed intramolecular N-arylation. This approach allows access to a variety of 2-amino-6-nitroindoles and 6-aminopyrrolo[3,2-d]pyrimidines (including N-mono- and N,N-disubstituted) in moderate and good yields under mild conditions.
- Mishina, Maria S.,Ivanov, Alexander Yu.,Lobanov, Pavel S.,Dar'In, Dmitrii V.
-
supporting information
p. 2851 - 2862
(2016/08/30)
-
- Synthesis and biological evaluation of DAPY-DPEs hybrids as non-nucleoside inhibitors of HIV-1 reverse transcriptase
-
A series of new DAPY-DPEs hybrids, combined the important pharmacophores of DAPYs and DPEs, has been synthesized and biologically evaluated for their anti-HIV activities against wild-type HIV-1 strain IIIB, double RT mutant (K103N + Y181C) strain RES056 and HIV-2 strain ROD in MT-4 cell cultures. Many promising candidates with potent inhibitory activity (wild-type) within the EC50 range from 0.16 to 0.013 μM were obtained. In particular, 3c, 3p, 3r and 3s displayed low nM level EC50 values (35, 13, 50 and 17 nM, respectively) and high selectivity (9342, 25131, 2890 and 11338, respectively), which were much more potent than NVP (EC50 = 0.31 μM, SI = 48), 3TC (EC50 = 2.24 μM, SI > 39), DDI (EC50 = 23.20 μM, SI > 9) and DLV (EC50 = 0.65 μM, SI > 67), and comparable to AZT (EC50 = 0.0071 μM, SI > 13144) and EFV (EC50 = 0.0062 μM, SI > 1014). The HIV-1 reverse transcriptase inhibitory assay confirmed that these DAPY-DPEs hybrids targeted HIV-1 RT. Molecular simulation was performed to investigate the potential binding mode of the newly synthesized compounds. And reasonable explanation for the activity results was discussed with docking method.
- Wu, Hai-Qiu,Yao, Jin,He, Qiu-Qin,Chen, Wen-Xue,Chen, Fen-Er,Pannecouque, Christophe,De Clercq, Erik,Daelemans, Dirk
-
p. 624 - 631
(2015/01/30)
-
- A novel family of diarylpyrimidines (DAPYs) featuring a diatomic linker: Design, synthesis and anti-HIV activities
-
To improve the conformational flexibility and positional adaptability of the traditional diarylpyrimidines (DAPYs), a family of diarylpyrimidines featuring a C-N diatomic linker between the left wing benzene ring and the central pyrimidine was firstly des
- Gu, Shuang-Xi,Qiao, Heng,Zhu, Yuan-Yuan,Shu, Qi-Chao,Liu, Hui,Ju, Xiu-Lian,De Clercq, Erik,Balzarini, Jan,Pannecouque, Christophe
-
p. 6587 - 6593
(2015/10/19)
-
- Heterocyclic derivative and pharmaceutical composition comprising the same
-
The present invention provides novel compounds having a P2X3 and/or P2X2/3 receptor antagonistic effect. A pharmaceutical composition having a P2X3 and/or P2X2/3 receptor antagonistic effect comprising a compoun
- -
-
Page/Page column 227
(2016/01/10)
-
- HETEROCYCLIC COMPOUND
-
The present invention provides an agent for the prophylaxis or treatment of autoimmune diseases (e.g., psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus etc.) and the like, which has a superior Tyk2 inhibitory action. The present invention relates to a compound represented by the formula wherein each symbol is as defined in the specification, or a salt thereof.
- -
-
Paragraph 0766
(2015/03/03)
-
- Design and synthesis of a new series of modified CH-diarylpyrimidines as drug-resistant HIV non-nucleoside reverse transcriptase inhibitors
-
This article reports the design, synthesis and antiviral evaluation of a new series of non-nucleoside reverse transcriptase inhibitors (NNRTIs). The basic skeleton of these target 18 molecules is diarylpyrimidine featuring a substituted amino group between the pyrimidine scaffold and the aryl wing. All of the new compounds have been characterized by spectra analysis. The entire target molecules were evaluated for their in vitro anti-HIV activity with controlling group of FDA approved drugs. Most of them showed good to potent activities against wild-type (WT) HIV-1 with IC50 values in the range of 0.0175-69.21 μM. 2-(4-Cyanophenylamino)-4-(2- cyanovinylphenylhydrazonomethyl)pyrimidine (1d) displayed potent anti-HIV-1 activity against WT HIV-1 with a selectivity index (SI) of 106367 and an IC 50 value of 1.75 nM, which was 47 fold lower than that of AZT. Compound 1d also showed a broad-spectrum inhibitory activity, with an IC 50 value of 5.33 μM and 5.05 μM against both HIV-1 double-mutated (K103N/Y181C) strain and HIV-2 strain, respectively. The preliminary structure-activity relationship (SAR) was also investigated. The binding modes with HIV-1 RT for both the wild type and mutant type have also been discussed.
- Meng, Ge,Liu, Yang,Zheng, Aqun,Chen, Fener,Chen, Wenxue,De Clercq, Erik,Pannecouque, Christophe,Balzarini, Jan
-
p. 600 - 611
(2014/07/08)
-
- Structural modifications of CH(OH)-DAPYs as new HIV-1 non-nucleoside reverse transcriptase inhibitors
-
A series of CR2(OH)-diarylpyrimidine derivatives (CR 2(OH)-DAPYs) featuring a hydrophobic group at CH(OH) linker between wing I and the central pyrimidine were synthesized and evaluated for their anti-HIV activity in MT-4 cell cultur
- Yan, Zi-Hong,Huang, Xia-Yun,Wu, Hai-Qiu,Chen, Wen-Xue,He, Qiu-Qin,Chen, Fen-Er,De Clercq, Erik,Pannecouque, Christophe
-
p. 2535 - 2541
(2014/05/06)
-
- Synthesis and biological evaluation of CHX-DAPYs as HIV-1 non-nucleoside reverse transcriptase inhibitors
-
A series of new diarylpyrimidines (DAPYs) characterized by a halogen atom on the methylene linker between wing I and the central pyrimidine ring was synthesized and evaluated for their anti-HIV activity in MT-4 cell cultures. The two most promising compou
- Yan, Zi-Hong,Wu, Hai-Qiu,Chen, Wen-Xue,Wu, Yan,Piao, Hu-Ri,He, Qiu-Qin,Chen, Fen-Er,De Clercq, Erik,Pannecouque, Christophe
-
p. 3220 - 3226
(2014/06/09)
-
- INHIBITORS OF IRAK4 ACTIVITY
-
The present invention relates to compounds which modulate interleukin-l (IL-1 ) receptor-associated kinase 4 (IRAK4) and are useful in the prevention or treatment of inflammatory, cell proliferative and immune-related conditions and diseases. Specifically, provided herein are inhibitors of IRAK4 of Formula I and pharmaceutical compositions comprising such inhibitors, as well as methods therewith for treating IRAK4-mediated or -associated conditions or diseases.
- -
-
Page/Page column 41
(2014/05/07)
-
- NOVEL HETEROCYCLIC DERIVATIVES AND PHARMACEUTICAL COMPOSITION CONTAINING SAME
-
The present invention provides novel compounds having a P2X3 and/or P2X2/3 receptor antagonistic effect. A pharmaceutical composition having a P2X3 and/or P2X2/3 receptor antagonistic effect comprising a compoun
- -
-
Paragraph 0352; 0353
(2013/06/28)
-
- HETEROCYCLYL PYRIMIDINE ANALOGUES AS TYK2 INHIBITORS
-
The present invention relates to compounds of formula (I), wherein R, R1, X1 to X5 have the meaning as cited in the description and the claims. Said compounds are useful as TYK2 inhibitors for the treatment or prophylaxis
- -
-
Page/Page column 64
(2014/01/07)
-
- A general regioselective synthesis of 2,4-diarylpyrimidines from 2-thiouracil through two orthogonal cross-coupling reactions
-
A novel efficient synthesis of 2,4-diarylpyrimidines was developed based on phosphonium-mediated Suzuki coupling of 2-(methylsulfanyl)pyrimidin-4(3H)-one (at position 4) followed by the Liebeskind-Srogl cross-coupling (at position 2) under microwave irradiation. Georg Thieme Verlag Stuttgart · New York.
- ?erňová, Miroslava,Pohl, Radek,Klepetá?ová, Blanka,Hocek, Michal
-
supporting information; scheme or table
p. 1305 - 1308
(2012/06/30)
-
- PYRIDINE- 2- DERIVATIVES AS SMOOTHENED RECEPTOR MODULATORS
-
The present application relates to compounds of Formula (I), and Formula (II), or pharmaceutically acceptable salt thereof, wherein A, X, Y, Z, e, f, R1, R2, R3, R4, R5, R5b, R6, R7, R8, R9, R10, R11,R20, R21, R22 and R23 are defined herein. These novel pyridine derivatives that are useful in therapy, in particular for treating diseases or conditions mediated by Smo, including the treatment of abnormal cell growth, such as cancer, in mammals. Additional embodiments relate to methods of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
- -
-
Page/Page column 52
(2012/05/05)
-
- Design, synthesis and biological evaluation of cycloalkyl arylpyrimidines (CAPYs) as HIV-1 NNRTIs
-
A series of 18 cycloalkyl arylpyrimidines (CAPYs) were designed from lead compounds diarylpyrimidines (DAPYs), synthesized and evaluated for in vitro anti-HIV activity. Among them, the compound 1p displayed potent anti-HIV-1 activity against WT HIV-1 with an EC50 value of 0.055 μM and a selectivity index (SI) >7290. The preliminary structure-activity relationship (SAR) of this new series of compounds was also investigated, which enriched the SAR of diarylpyrimidines (DAPYs).
- Gu, Shuang-Xi,Yang, Shi-Qiong,He, Qiu-Qin,Ma, Xiao-Dong,Chen, Fen-Er,Dai, Hui-Fang,Clercq, Erik De,Balzarini, Jan,Pannecouque, Christophe
-
supporting information; experimental part
p. 7093 - 7099
(2012/01/03)
-
- Synthesis and structure-activity relationship of novel diarylpyrimidines with hydromethyl linker (CH(OH)-DAPYs) as HIV-1 NNRTIs
-
A series of 26 diarylpyrimidines, characterized by the hydroxymethyl linker between the left wing benzene ring and the central pyrimidine, were synthesized and evaluated for in vitro anti-HIV activity. Most of the compounds exhibited moderate to excellent
- Gu, Shuang-Xi,He, Qiu-Qin,Yang, Shi-Qiong,Ma, Xiao-Dong,Chen, Fen-Er,Clercq, Erik De,Balzarini, Jan,Pannecouque, Christophe
-
experimental part
p. 5117 - 5124
(2011/10/04)
-
- SUBSTITUTED PYRIMIDINES
-
The present invention relates to substituted pyrimidines useful as HIF prolyl hydroxylase inhibitors to treat anemia and like conditions.
- -
-
Page/Page column 54-55
(2011/11/06)
-
- SUBSTITUTED PYRIMIDINES
-
The present invention relates to substituted pyrimidines useful as HIF prolyl hydroxylase inhibitors to treat anemia and like conditions.
- -
-
Page/Page column 53-54
(2011/11/06)
-
- Synthesis of nitrogen bicyclic scaffolds: Pyrimido[1,2-a]pyrimidine-2,6- diones
-
The multi-step synthesis of 1,3,7-trisubstituted pyrimido[1,2-a] pyrimidinediones starting from isothiocyanates is described. These nitrogen bicycles were prepared by an iterative sequence of functionalization/ cyclocondensation reactions. [4+2] Cycloaddition reactions took place between diazadienic chains and various acyl chlorides providing sophisticated heterobicycles.
- Grosjean, Sylvain,Triki, Smail,Meslin, Jean-Claude,Julienne, Karine,Deniaud, David
-
experimental part
p. 9912 - 9924
(2011/02/22)
-
- Lead optimization of diarylpyrimidines as non-nucleoside inhibitors of HIV-1 reverse transcriptase
-
Antiviral agents: A series of CN-CH2-DAPY analogues were identified as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) against HIV-1. Most of the newly synthesized compounds exhibited strong activity against wild-type HIV-1.
- Zeng, Zhao-Sen,Liang, Yong-Hong,Feng, Xiao-Qing,Chen, Fen-Er,Pannecouque, Christophe,Balzarini, Jan,De Clercq, Erik
-
scheme or table
p. 837 - 840
(2011/02/24)
-
- NOVEL PHENYL(4-PHENYLPYRIMIDIN-2-YL)AMINE DERIVATIVES, THEIR PREPARATION, AS MEDICAMENTS, PHARMACEUTICAL COMPOSITIONS AND IN PARTICULAR AS IKK INHIBITORS
-
The disclosure relates to a compound of formula (I): wherein R, R2, R3, R4, R5, Z, W and D are as defined in the specification, to compositions containing them, to processes for preparing them, and to their use in the treatment or prevention of conditions
- -
-
Page/Page column 20
(2010/04/23)
-
- 2-ANILINO-4-HETEROARYL PYRIMIDINE DERIVATIVES, AND PREPARATION THEREOF AS MEDICAMENTS, PHARMACEUTICAL COMPOSITIONS, AND IN PARTICULAR IKK INHIBITORS
-
The disclosure relates to a compound of formula (I): wherein R, R2, R3, R4, R5, z, D and W are as defined in the specification, to compositions containing them, to processes for preparing them, and to their use in the treatment or prevention of conditions capable of being modulated by the inhibition of the activity of protein kinases.
- -
-
Page/Page column 20-21
(2010/05/13)
-
- One-pot synthesis of meridianins and meridianin analogues via indolization of nitrosoarenes
-
Meridianins, marine alkaloids known as kinase inhibitors with an indole skeleton, and meridianin analogues were produced regioselectively and in moderate to good yields by thermal annulation of nitrosoarenes with 2-amino-4-ethynylpyrimidine and 2-chloro-4-ethynylpyrimidine, respectively, through a novel and atom-economical indolization process.
- Tibiletti, Francesco,Simonetti, Marco,Nicholas, Kenneth M.,Palmisano, Giovanni,Parravicini, Matteo,Imbesi, Federico,Tollari, Stefano,Penoni, Andrea
-
experimental part
p. 1280 - 1288
(2010/04/02)
-
- New compounds
-
The present invention encompasses compounds of general formula (1) wherein R1, R2, R4, X, m, n and p are defined as in claim 1, which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, and their use for preparing a pharmaceutical composition having the above-mentioned properties.
- -
-
Page/Page column 18
(2009/07/10)
-
- Novel 2,4-Dianilinopyrimidine Derivatives, the Preparation Thereof, Their Use as Medicaments, Pharmaceutical Compositions and, in Particular, as IKK Inhibitors
-
The disclosure relates to compounds of formula (I): wherein R1-R5, A and Y are as defined in the disclosure, to compositions comprising said compounds, and to processes for making and methods of using the same.
- -
-
Page/Page column 67
(2008/12/04)
-
- Design, synthesis, and activity of 2-imidazol-1-ylpyrimidine derived inducible nitric oxide synthase dimerization inhibitors
-
By the screening of a combinatorial library for inhibitors of nitric oxide (NO) formation by the inducible isoform of nitric oxide synthase (iNOS) using a whole-cell assay, 2-(imidazol-1-yl)pyrimidines were identified. Compounds were found to inhibit the dimerization of iNOS monomers, thus preventing the formation of the dimeric, active form of the enzyme. Optimization led to the selection of the potent, selective, and orally available iNOS dimerization inhibitor, 21b, which significantly ameliorated adjuvant-induced arthritis in a rat model. Analysis of the crystal structure of the 21b-iNOS monomer complex provided a rationalization for both the SAR and the mechanism by which 21b blocks the formation of the protein-protein interaction present in the dimeric form of iNOS.
- Davey, David D.,Adler, Marc,Arnaiz, Damian,Eagen, Keith,Erickson, Shawn,Guilford, William,Kenrick, Margaret,Morrissey, Michael M.,Ohlmeyer, Mike,Pan, Gonghua,Paradkar, Vidyadhar M.,Parkinson, John,Polokoff, Mark,Saionz, Kurt,Santos, Cecile,Subramanyam, Babu,Vergona, Ron,Wei, Robert G.,Whitlow, Marc,Ye, Bin,Zhao, Zuchun,Devlin, James J.,Phillips, Gary
-
p. 1146 - 1157
(2007/10/03)
-
- 2,4-diamino-pyrimidines as aurora inhibitors
-
The present invention encompasses compounds of general formula (1) wherein R1 to R3 are defined as in claim 1, which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, and the use thereof for preparing a pharmaceutical composition having the above-mentioned properties.
- -
-
Page/Page column 20
(2008/06/13)
-
- 2-ANILINO-4-AMINOALKYLENEAMINOPYRIMIDINES
-
The present invention relates to 2-arylamino-4-(aminoalkylene)aminopyrimidines inhibitors which are inhibitors and therefore inhibit Protein Kinase C-alpha (PKC-α). The PKC-α inhibitors of the present invention are important for improving myocardial intracellular calcium cycling, resulting in improved myocardial contraction and relaxation performance and thereby slowing the progression of heart failure. The present invention further relates to compositions comprising said 2-arylamino-4-(aminoalkylene)amino-pyrimidines and to methods for controlling, abating, or otherwise slowing the progression of heart failure.
- -
-
Page/Page column 8; 10; 11
(2008/06/13)
-
- 2-Anilino-4-(Heterocyclic) Amino-Pyrimidines
-
The present invention relates to 2-arylamino-4-(heterocyclic)aminopyrimidines inhibitors which are inhibitors and therefore inhibit Protein Kinase C-alpha (PKC-α). The PKC-α inhibitors of the present invention are important for improving myocardial intracellular calcium cycling, resulting in improved myocardial contraction and relaxation performance and thereby slowing the progression of heart failure. The present invention further relates to compositions comprising said 2-arylamino-4-(heterocyclic)amino-pyrimidines and to methods for controlling, abating, or otherwise slowing the progression of heart failure.
- -
-
Page/Page column 10; 13
(2008/06/13)
-
- Synthesis of 2-bromomethyl-3-hydroxy-2-hydroxymethyl-propyl pyrimidine and theophylline nucleosides under microwave irradiation. Evaluation of their activity against hepatitis B virus
-
Alkylation of 2-methylthiopyrimidin-4(1H)-one (1a) and its 5(6)-alkyl derivatives 1b - d as well as theophylline (7) with 2,2- bis (bromomethyl)-1,3-diacetoxypropane (2) under microwave irradia-tion gave the corresponding acyclonucleosides 1-[(3-acetoxy-2-acetoxymethyl-2-bromomethyl) prop-1- yl ]-2-methyl-thio pyrmidin-4(1H)-ones 3a - d and 7-[(3-acetoxy-2- acetoxymethyl-2-bromomethyl)prop-1- yl]theophylline (8), which upon further irradiation gave the double-headed acyclonucleosides 1,1 ′-[(2,2- diacetoxymethyl)-1,3-propylidene]- bis [(2-(methylthio)-pyrimidin-4(1H)-ones] 4a - c , and 7,7 ′-[(2,2-diacetoxymethyl)-1,3-propylidene]- bis (theophylline) (9). The deacetylated derivatives were obtained by the action of sodium methoxide. The activity of deacetylated nucleosides against Hepatitis B virus was evaluated. Compound 5b showed moderate inhibition activity against HBV with mild cytotoxicity. Copyright Taylor & Francis Group, LLC.
- Ashry,Rashed,Abdel-Rahman,Awad,Rasheed
-
p. 925 - 939
(2008/02/08)
-
- Synthesis and biological evaluation of new pyrimidine derivatives
-
4-Oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine (2-thiouracil) 1 is reacted with a series of diazotized aromatic amines to give compounds 2a-f. On the other hand compound 1 is s-methylated by methyl iodide giving 4-oxo-2-methylthioxo 1,2,3,4-tetrahydropyrimid
- Fathalla,Radwan,Awad,Mohamed
-
p. 980 - 985
(2007/10/03)
-
- CYCLIC COMPOUNDS
-
There is provided a CRF receptor antagonist comprising a compound of the formula (I): A-W-Ar wherein, A is a group represented by the formula (A1) or (A2) (wherein, ring Aa is a 5-or 6-membered ring which may be further substituted; ring Ab is a 5-or 6-membered ring which may be further substituted; ring Ac is a 5- or 6-membered ring which may be substituted; R1 is optionally substituted alkyl, substituted amino, substituted hydroxy, etc.; X is carbonyl, -O-, -S-, etc.; Y1, Y2 and Q are independently optionally substituted carbon or nitrogen; … is a single or double bond); W is a bond, optionally substituted methylene, optionally substituted imino, -O-, -S-, etc.; Ar is optionally substituted aryl or optionally substituted heteroaryl; or a salt thereof or a prodrug thereof.
- -
-
Page/Page column 172-173
(2010/02/14)
-
- 1,4-DISUBSTITUTED ISOQUINILONE DERIVATIVES AS RAF-KINASE INHIBITORS USEFUL FOR THE TREATMENT OF PROLIFERATIVE DISEASES
-
This invention relates to compounds of formula (I) wherein the variable substituents are described herein. The compounds are useful for the treatment of conditions and diseases characterized by an aberrant MAP kinase signaling pathway, such as cancer.
- -
-
Page/Page column 49
(2010/02/11)
-
- Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade
-
The invention relates to substituted polycyclic aryl and heteroaryl pyrimidinone compounds useful as inhibitors of serine proteases of the coagulation cascade and compounds, compositions and methods for anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular diseases.
- -
-
Page/Page column 117-118
(2010/01/31)
-
- A facile preparation of n2-arylisocytosines
-
N2-Arylisocytosines were obtained in good yields varying from 59 to 96% by a simple two-step process starting from 2-thiouracil via readily accessible 2-(methylthio)pyrimidin-4(3H)-one.
- Spychala, Jaroslaw
-
p. 1943 - 1949
(2007/10/03)
-
- New Approach to the Synthesis of β-2'-Deoxyribonucleosides: Intramolecular Vorbrueggen Coupling
-
Silylation of the O2,5'-linked nucleoside 7 followed by treatment with trimethylsilyl triflate affords the O2,5'-anhydro nucleoside 9 and its hydrolysis product the β-anomer of the 2'-deoxyuridine 10 in good yield in the first example of an oxygen-bridged intramolecular Vorbrueggen coupling.
- Jung, Michael E.,Castro, Claire
-
p. 807 - 808
(2007/10/02)
-
- Tautomerism and infrared spectra of thiouracils. Matrix isolation and ab initio studies
-
A study of the infrared (IR) spectra of a variety of thiouracils isolated in low-temperature inert matrices demonstrated that 2- and 4-thiouracils together with their N1- and N3-methylated derivatives as well as 2,4-dithiouracil exist under these conditions only in the oxothione or dithione tautomeric forms. In contrast, S2- and S4-methylated derivatives under the same conditions exist as a mixture of hydroxy and oxo tautomeric forms. The ratio of concentrations of the tautomers K(o/h) = ([oxo]/[hydroxy]) and the free energy differences, ΔG, were experimentally estimated from the ratio of the absorbances of the NH and OH stretches. The values obtained are K(o/h) = 1.5 and ΔG = -1.7 kJ/mol for 2-(methylthio)uracil and K(o/h) = 0.5 and ΔG = +2.5 kJ/mol for 4-(methylthio)-6-methyluracil. An assignment of the observed infrared bands, particularly those related to the C=S stretching vibrations, is proposed on the basis of the comparison of the matrix spectra from different derivatives and of the spectra calculated by using ab initio methods (3-21G* basis set).
- Rostkowska,Szczepaniak,Nowak,Leszczynski,KuBulat,Person
-
p. 2147 - 2160
(2007/10/02)
-
- The Tautomeric Equilibria of Thio Analogues of Nucleic Acid Bases. Part 1. 2-Thiouracil: Background, Preparation of Model Compounds, and Gas-phase Proton Affinities
-
The preparation is reported of all four the monoalkyl derivatives of 2-thiouracil and four of the six possible dialkyl derivatives required as models for a study of the tautomeric equilibria by physical methods.Gas-phase proton affinities are determined using ion cyclotron resonance mass spectrometry, and are used to provide quantitative estimates of individual tautomer stabilities in the vapour state.These quantitative results agree well with qualitative deductions of predominant structures for the monoalkyl derivatives from i.r. spectroscopy.
- Katritzky, Alan R.,Baykut, Gokhan,Rachwal, Stanislaw,Szafran, Miroslaw,Caster, Kenneth C.,Eyler, John
-
p. 1499 - 1506
(2007/10/02)
-