- Nitrogen-containing fused tricyclic derivative and application thereof
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The invention discloses a nitrogen-containing fused tricyclic derivative and application thereof, and particularly relates to a novel nitrogen-containing fused tricyclic derivative and a pharmaceutical composition containing the nitrogen-containing fused tricyclic derivative, and the nitrogen-containing fused tricyclic derivative can be used as a selective adenosine A2A receptor antagonist. The invention also relates to a method for preparing the compound and the pharmaceutical composition and application of the compound and the pharmaceutical composition in preparation of drugs for treating adenosine A2A receptor related diseases, especially Parkinson's disease.
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Paragraph 0288; 0290-0293
(2020/05/08)
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- Nitrogen-containing fused tricyclic derivatives and application thereof
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The invention discloses a nitrogen-containing fused tricyclic derivative and application thereof, and particularly relates to a novel nitrogen-containing fused tricyclic derivative and a pharmaceutical composition containing the nitrogen-containing fused tricyclic derivative, and the nitrogen-containing fused tricyclic derivative can be used as a selective adenosine A2A receptor antagonist. The invention also relates to a method for preparing the compound and the pharmaceutical composition and application of the compound and the pharmaceutical composition in preparation of drugs for treating adenosine A2A receptor related diseases, especially Parkinson's disease.
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Paragraph 0239; 0241-0244
(2020/05/11)
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- Development of pyrazolo[3,4-d]pyrimidine-6-amine-based TRAP1 inhibitors that demonstrate in vivo anticancer activity in mouse xenograft models
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TNF Receptor Associated Protein 1 (TRAP1) is a mitochondrial paralog of Hsp90 related to the promotion of tumorigenesis in various cancers via maintaining mitochondrial integrity, reducing the production of reactive oxygen species, and reprogramming cellular metabolism. Consequently, Hsp90 and TRAP1 have been targeted to develop cancer therapeutics. Herein, we report a series of pyrazolo[3,4-d]pyrimidine derivatives that are mitochondria-permeable TRAP1 inhibitors. Structure-based drug design guided the optimization of potency, leading to the identification of compounds 47 and 48 as potent TRAP1 and Hsp90 inhibitors with good metabolic and plasma stability as well as acceptable CYP and hERG inhibition. X-ray co-crystallization studies confirmed both 47 and 48 interact with the ATP binding pocket in the TRAP1 protein. Compounds 47 and 48 demonstrated excellent anticancer efficiency in various cancer cells, with limited toxicity over normal hepatocyte and prostate cells. Mouse PC3 xenograft studies showed 47 and 48 significantly reduced tumor growth.
- Hong, Ki Bum,Kang, Byoung Heon,Kang, Soosung,Kim, Darong,Kim, Dongyoung,Kim, So-Yeon,Lee, Changwook,Lee, Ji Hoon,Yoon, Nam Gu,Yun, Jisu
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- Application of five-membered heterocycle pyrimidine compound
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The invention belongs to the field of medicine and particularly relates to application of a five-membered heterocycle pyrimidine compound with the structural features as shown in formula (I) and the pharmaceutically acceptable salt of the five-membered heterocycle pyrimidine compound serving as nucleotide oxidative damage repairase MTH1 inhibitors. Pharmacological experiment results show that thecompound can evidently inhibit the activity of MTH1 and can be used for preventing and treating clinical diseases related to MTH1.
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Paragraph 0050; 0113; 0114; 0115; 0116
(2018/09/12)
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- Fluorinated adenosine A2A receptor antagonists inspired by preladenant as potential cancer immunotherapeutics
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Antagonism of the adenosine A2A receptor on T cells blocks the hypoxia-adenosinergic pathway to promote tumor rejection. Using an in vivo immunoassay based on the Concanavalin A mouse model, a series of A2A antagonists were studied and identified preladenant as a potent lead compound for development.Molecular modeling was employed to assist drug design and subsequent synthesis of analogs and those of tozadenant, including fluorinated polyethylene glycol PEGylated derivatives. The efficacy of the analogs was evaluated using two in vitro functional bioassays, and compound 29, a fluorinated triethylene glycol derivative of preladenant, was confirmed as a potential immunotherapeutic agent.
- Yuan, Gengyang,Jankins, Tanner C.,Patrick, Christopher G.,Philbrook, Phaethon,Sears, Olivia,Hatfield, Stephen,Sitkovsky, Michail,Vasdev, Neil,Liang, Steven H.,Ondrechen, Mary Jo,Pollastri, Michael P.,Jones, Graham B.
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- nitrogen hybridization guanine nucleoside and its synthetic method and the use of DNA sequencing
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The invention discloses hybrid azaguanosine as well as a synthesis method and an application thereof in DNA sequencing. The synthesis method comprises the steps: removing a protecting group of a compound as shown in formula (III) in the specification under an alkaline condition to obtain a compound as shown in formula (II) in the specification; further demethylating to obtain a compound as shown in formula (I) in the specification, i.e. 7-deaza-7-halogen-8-aza-guanosine, wherein R1 is H or OH, R2 is I, Br or Cl, and R3 is H or a compound shown in the specification. The hybrid azaguanosine disclosed by the invention is a novel reagent for DNA sequencing, which, compared to guanosine failing to substitute nitrogen on 8 sites, is more excellent in base identifying effect and more stable in DNA chain structure. Meanwhile, different from the prior art that 8-site nitrogen-substituted guanosine is complex in synthesis method, low in yield and unsuitable for commercial production, the synthesis method disclosed by the invention is easily available in raw material required, and adopts conventional chemical synthesis reaction; and the method is relatively high in yield, and suitable for wide popularization and application.
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Paragraph 0076-0080
(2016/10/27)
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- Synthesis of novel 2-cyano-7-deaza-8-azapurine- and 2-cyano-8-azapurine- derived nucleosides
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A novel systematic approach to the synthesis of 2-cyano-7-deaza-8-azapurine derived nucleosides is described. It is shown how this chemistry was developed with the labile 2-substituted nitrile position in mind, and also how the same approach is applicable to 2-cyano-8-azapurine derived nucleosides.
- Wainwright, Philip,Maddaford, Adrian,Simms, Michael,Forrest, Neil,Glen, Rebecca,Hart, James,Zhang, Xiurong,Pryde, David C.,Stephenson, Peter T.,Middleton, Donald S.,Guyot, Thierry,Sutton, Scott C.
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supporting information; experimental part
p. 1900 - 1904
(2011/10/08)
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- HETEROCYCLIC GTP CYCLOHYDROLASE 1 INHIBITORS FOR THE TREATMENT OF PAIN
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The present invention relates to the field of small molecule heterocyclic inhibitors of GTP cyclohydrolase (GCH-I), or a tautomer, prodrug, or pharmaceutically acceptable salt thereof. The invention also features pharmaceutical compositions of the compounds and the medical use of these compounds for the treatment or prevention of pain (e.g., inflammatory pain, nociceptive pain, functional pain, or neuropathic pain).
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Page/Page column 77
(2011/04/19)
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- 5-6-BICYCLIC HETEROAROMATIC COMPOUNDS WITH ANTIBACTERIAL ACTIVITY
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Compounds of formula (I) and their pharmaceutically acceptable salts are described. Processes for their preparation, pharmaceutical compositions containing them, their use as medicaments and their use in the treatment of bacterial infections are also described.
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Page/Page column 81
(2009/04/25)
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- Aminopyrimidine-based donor-acceptor chromophores: Push-pull versus aromatic behaviour
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Novel 2-aminopyrimidines substituted with two electron-donor dialkylamino groups and either one dicyanovinyl (4a-d) or one tricyanovinyl (7a-d) electron-acceptor group have been synthesized, and the balance between their push-pull character and their aromatic behaviour has been studied by experimental (spectroscopic, electrochemical and X-ray analysis) and theoretical (DFT/B3LYP/6-31G* *) methods. Calculations reveal that the push-pull character is energetically favoured with respect to the preservation of the aromaticity of the pyrimidine ring. X-ray analysis of 7a confirms the theoretical predictions and reveals a strong distortion from planarity due to the steric interaction between the tricyanovinyl group and the adjacent dialkylamino moieties. In contrast with what would normally be expected for push-pull compounds, the visible-region absorption bands of 4a-d and 7a-d are associated with π-π* electronic transitions and not with intramolecular charge-transfer absorptions. In each compound, both the HOMO and the LUMO are spread over the whole molecule and are not located on the donor and acceptor moieties, respectively, as is the case for typical push-pull chromophores. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Ortiz, Alejandro,Insuasty, Braulio,Torres, M. Rosario,Herranz, M. Angeles,Martin, Nazario,Viruela, Rafael,Orti, Enrique
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- Pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidine adenosine A2a receptor antagonists
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Compounds having the structural formula I or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted phenyl, furanyl, thienyl, pyridyl, pyridyl N-oxide, oxazolyl or pyrrolyl, or cycloalkenyl R1, R2, R3, R4 and R5 are H, alkyl or alkoxyalkyl; and Z is optionally substituted aryl or heteroaryl are disclosed. Also disclosed is the use of compounds of formula I in the treatment of central nervous system diseases, in particular Parkinson's disease, alone or in combination with other agents for treating Parkinson's disease, and pharmaceutical compositions comprising them.
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Page/Page column 9
(2008/06/13)
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- PROCESS FOR PREPARING SUBSTITUTED 5-AMINO-PYRAZOLO-[4,3-E]-1,2,4-TRIAZOLO[1,5-C]PYRIMIDINES
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A process for preparing substituted 5-amino-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidine compounds having an aminoalkyl substituent at the 7-position is disclosed.
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Page/Page column 15
(2008/06/13)
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- Cyclin dependent kinase inhibitors
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A range is disclosed of pyrimidine derivatives (I) which can act as inhibitors of cyclin dependent kinases (CDK's) and which thereby can provide useful therapeutic compounds for use in treatment of tumours or other cell proliferation disorders. The compounds of this invention bind to CDK molecules in a manner that appears to differ from that of known CDK inhibitors such as olomoucine and roscovitine. In formula (I), X is O, S or CHRxwhere Rxis H or C1-4alkyl; D is H or NZ1Z2where Z1and Z2are each independently H, C1-4alkyl, C1-4hydroxyalkyl, optionally substituted aryl or optionally substituted aralkyl; A is selected from H, C1-4alkyl, C1-4alkoxy, hydroxy, CH2(CH2)nOH (n=1-4), and NRa1Ra2where Ra1and Ra2are each independently H or C1-4alkyl; Y is or includes an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring; D′ is H or NZ3Z4where Z3and Z4are each independently H, C1-4alkyl, C1-4hydroxyalkyl, optionally substituted aryl or optionally-substituted aralkyl; E is selected from NO, NO2, N═N—Ar where Ar is an optionally substituted aryl or optionally substituted aralkyl, NRe1Re2or Nre1Nre2Re3(Re1, Re2and Re3each being independently H, C1-4alkyl, C1-4hydroxyalkyl, an optionally substituted aryl or an optionally substituted aralkyl), C(Re)═U (Rebeing hydrogen, C1-4alkyl or substituted alkyl, e.g. hydroxyalkyl, or an unsubstituted or substituted aryl or aralkyl, e.g. benzyl, and U being selected from O, Nre′, NORe′ and N—NRe′Re″ where Re′ and Re″ are each independently H, C1-4alkyl or CONH2), T, CH2T, CHT2and CT3, where T is a halide I, Br, Cl or F.
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Page/Page column 13
(2010/02/05)
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- New strategies for the synthesis of A3 adenosine receptor antagonists
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New A3 adenosine receptor antagonists were synthesized and tested at human adenosine receptor subtypes. An advanced synthetic strategy permitted us to obtain a large amount of the key intermediate 5 that was then submitted to alkylation procedures in order to obtain the derivatives 6-8. These compounds were then functionalised into ureas at the 5-position (compounds 9-11, 18 and 19) to evaluate their affinity and selectivity versus hA3 adenosine receptor subtype; in particular, compounds 18 and 19 displayed a value of affinity of 4.9 and 1.3 nM, respectively. Starting from 5, the synthetic methodologies employed permitted us to perform a rapid and a convenient divergent synthesis. A further improvement allowed the regioselective preparation of the N8-substituted compound 7. This method could be used as an helpful general procedure for the design of novel A3 adenosine receptor antagonists without the difficulty of separating the N8-substituted pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines from the corresponding N 7-isomers.
- Baraldi, Pier Giovanni,Bovero, Andrea,Fruttarolo, Francesca,Romagnoli, Romeo,Tabrizi, Mojgan Aghazadeh,Preti, Delia,Varani, Katia,Borea, Pier Andrea,Moorman, Allan R.
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p. 4161 - 4169
(2007/10/03)
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- 4-Alkoxy-2,6-diaminopyrimidine derivatives: inhibitors of cyclin dependent kinases 1 and 2.
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The cyclin dependent kinase (cdk) inhibitor NU6027, 4-cyclohexylmethoxy-5-nitroso-pyrimidine-2,6-diamine (IC(50) vs cdk1/cyclinB1=2.9+/-0.1 microM and IC(50) vs cdk2/cyclinA3=2.2+/-0.6 microM), was used as the basis for the design of a series of 4-alkoxy-2,6-diamino-5-nitrosopyrimidine derivatives. The synthesis and evaluation of 21 compounds as potential inhibitors of cyclin-dependent kinases 1 and 2 is described and the structure-activity relationships relating to NU6027 have been probed. Simple alkoxy- or cycloalkoxy-groups at the O(4)-position were tolerated, with the 4-(2-methylbutoxy)-derivative (IC(50) vs cdk1/cyclinB1=12+/-2 microM and cdk2/cyclinA3=13+/-4 microM) retaining significant activity. Substitutions at the N(6) position were not tolerated. Replacement of the 5-nitroso substituent with ketone, oxime and semicarbazone groups essentially abolished activity. However, the derivative bearing an isosteric 5-formyl group, 2,6-diamino-4-cyclohexylmethoxy-pyrimidine-5-carbaldehyde, showed modest activity (IC(50) vs cdk1/cyclinB1=35+/-3 microM and cdk2/cyclinA3=43+/-3 microM). The X-ray crystal structure of the 5-formyl compound bound to cdk2 has been determined to 2.3A resolution. The intramolecular H-bond deduced from the structure with NU6027 bound to cdk2 is not evident in the structure with the corresponding formyl compound. Thus the parent compound, 4-cyclohexylmethoxy-5-nitrosopyrimidine-2,6-diamine (NU6027), remains the optimal basis for future structure-activity studies for cyclin-dependent kinase inhibitors in this series.
- Mesguiche, Veronique,Parsons, Rachel J,Arris, Christine E,Bentley, Johanne,Boyle, F Thomas,Curtin, Nicola J,Davies, Thomas G,Endicott, Jane A,Gibson, Ashleigh E,Golding, Bernard T,Griffin, Roger J,Jewsbury, Philip,Johnson, Louise N,Newell, David R,Noble, Martin E M,Wang, Lan Z,Hardcastle, Ian R
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p. 217 - 222
(2007/10/03)
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- Process for the synthesis of pyrazolopyrimidines
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The present invention provides a nucleoside comprising a pyrazolopyrimidine base and a process for producing the same. In particular, the processes of the present invention comprises using a halogenated pyrazolopyrimidine base and removing the halogen after the base is coupled to a sugar moiety. The presence of the halogen on the nucleoside base allows facile and economical production of a large quantity of nucleosides.
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- Adenosine receptor ligands and their use in the treatment of disease
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The invention relates to cyclic heteroaromatic compounds, containing at least one nitrogen atom, and to their use in the manufacture of medicaments for the treatment of diseases, related to adenosine receptor modulators, such as Alzheimer's disease, Parkinson's disease, neuroprotection, schizophrenia, anxiety, pain, respiration deficits, depression, asthma, allergic responses, hypoxia, ischaemia, seizure, substance abuse, sedation and they may be active as muscle relaxants, antipsychotics, anti epileptics, anticonvulsants and cardiaprotective agents.
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- SYNTHESIS OF THE β-D-DEOXYRIBOFURANOSIDE OF 6-AMINO-1H-PYRAZOLO-PYRIMIDIN -4(5H)-ONE - A NEW ISOSTER OF 2'-DEOXYGUANOSINE
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6-Amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-1H-pyrazolopyrimidin-4(5H)-one (8) has been synthesized via regio- and diastereo-selective phase-transfer glycosylation of 6-amino-4-methoxy-1H-pyrazolopyrimidine (4) with 2-deoxy-3,5-di-O-(p-to
- Seela, Frank,Steker, Herbert
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p. 2521 - 2524
(2007/10/02)
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- Chemistry of 5-Pyrimidinecarboxaldehydes
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Selective hydrolysis of 2-amino-4,6-dichloro-5-pyrimidinecarboxaldehyde, 2, gave 2-amino-4-chloro-1,6-dihydro-6-oxo-5-pyrimidinecarboxaldehyde, 5.The oxime of 2 rearranged to 2-amino-4-chloro-1,6-dihydro-6-oxo-5-pyrimidinecarbonitrile, 8.Reaction of 8 wit
- Bell, Lawrence,McGuire, H. Michael,Freeman, G. Andrew
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