- Design, synthesis and biological evaluation of novel 6-substituted pyrrolo [3,2-d] pyrimidine analogues as antifolate antitumor agents
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A series of novel 6-substituted pyrrolo[3,2-d]pyrimidine analogues (10a, 11a-13a, 15a, 17a, 18a, 27a and 28a) have been designed and synthesized as antifolate antitumor agents. The anti-proliferative activities of these compounds against HL60, A549, H1299, Hela, HCT116 and HT29 tumor cells were evaluated. Most of the compounds exhibited micromolar anti-proliferative potencies. Compound 15a, the most potent one, has GI50 value of 0.73, 1.72, and 8.92 μM against A549, H1299 and HL60 cells, respectively. The cell cycle distribution assay displayed that 15a could increase the accumulation of G2/M-phase cells. 15a showed low potency in induction of apoptosis. However, the inhibition of A549 cell colony formation was observed. These indicated that the tumor cell death relied on the irreversible effect of 15a on clonogenicity and cell proliferation. The identification of targeted pathway of 15a implied that the anti-proliferative potencies of 15a probably act through dual inhibition of thymidylate synthase (TS) and dihydrofolate reductase (DHFR).
- Tian, Chao,Wang, Meng,Han, Zifei,Fang, Fang,Zhang, Zhili,Wang, Xiaowei,Liu, Junyi
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Read Online
- Toward the stereoselective synthesis of zaragozic acid framework: A desilylation-aldol reaction approach
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A convergent synthesis of the C3-C8 fragment of zaragozic acids is described. The key reactions include desilylation-aldol reaction, rearrangement induced by regioselective reductive cleavage, BAIB/TEMPO-Pinnick oxidation, esterification, silylation, and hydrogenolysis.
- Kurniawan, Yudhi D.,Tuck, Kellie L.,Castillón, Sergio,Robinson, Andrea J.
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supporting information
(2021/11/08)
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- Silica-supported HClO4 promotes catalytic solvent- and metal-free O-H insertion reactions with diazo compounds
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Solvent-free O-H insertion reactions in the presence of diazo carbonyl compounds were carried-out in very mild conditions. Unlike the traditional metal-catalysed version, employing rhodium acetate dimer, this method uses eco-friendly silica-supported HClO4 as the catalyst. Only 0.3 mol% of this Br?nsted acid catalyst, that can also be recycled several times, is necessary to guarantee very good yields (up to 97%) in the O-H insertion reactions. Reaction set-up is simple and permitted the preparation of forty-three α-hydroxy and α-alkoxy esters/ketones in just 1 h and at room temperature.
- Gallo, Rafael Douglas C.,Burtoloso, Antonio C. B.
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p. 4547 - 4556
(2018/10/17)
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- Carbene Transfer and Carbene Insertion Reactions Catalyzed by a Mixed-Ligand Copper(I) Complex
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The catalytic activity of the mixed-ligand copper(I) complex [Cu(PPh3)2(κ2-O,O"-lact)] (1) {lact = l-(+)-lactate} has been investigated in carbene transfer and carbene insertion reactions. Complex 1 catalytically promoted the diastereoselective cyclopropanation of olefins in the presence of ethyl diazoacetate (EDA), under mild conditions, and with a low catalyst loading (1 mol-%). In the case of internal alkenes, a trans/cis ratio of up to 93:7 was reached. Moreover, compound 1 easily promoted the insertion of the carbene fragment deriving from the decomposition of ethyl diazoacetate into O–H (alcohols and phenols) and N–H (amine) bonds, with formation of the corresponding ethyl 2-alkoxyacetate, ethyl 2-phenoxyacetate, and ethyl 2-aminoacetate derivatives in good to high yields.
- Brenna, Stefano,Ardizzoia, G. Attilio
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p. 3336 - 3342
(2018/07/13)
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- POLYMYXIN ANALOGS USEFUL AS ANTIBIOTIC POTENTIATORS
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The disclosure provides compounds of the formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of either of the foregoing. The variables A, R1, and R2 are defined in the disclosure. The disclosure further includes pharmaceutical compositions comprising a compound of formula I together with at least one pharmaceutically acceptable carrier. The disclosure also includes a method of sensitizing bacteria to an antibacterial agent, comprising administering to a patient infected with the bacteria, simultaneously or sequentially, a therapeutically effective amount of the antibacterial agent and a compound of formula (I).
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Paragraph 0259
(2017/12/09)
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- Novel Pyrimidine Toll-like Receptor 7 and 8 Dual Agonists to Treat Hepatitis B Virus
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Toll-like receptor (TLR) 7 and 8 agonists can potentially be used in the treatment of viral infections and are particularly promising for chronic hepatitis B virus (HBV) infection. An internal screening effort identified a pyrimidine Toll-like receptor 7 and 8 dual agonist. This provided a novel alternative over the previously reported adenine and pteridone type of agonists. Structure-activity relationship, lead optimization, in silico docking, pharmacokinetics, and demonstration of ex vivo and in vivo cytokine production of the lead compound are presented.
- McGowan, David,Herschke, Florence,Pauwels, Frederik,Stoops, Bart,Last, Stefaan,Pieters, Serge,Scholliers, Annick,Thoné, Tine,Van Schoubroeck, Bertrand,De Pooter, Dorien,Mostmans, Wendy,Khamlichi, Mourad Daoubi,Embrechts, Werner,Dhuyvetter, Deborah,Smyej, Ilham,Arnoult, Eric,Demin, Samu?l,Borghys, Herman,Fanning, Gregory,Vlach, Jaromir,Raboisson, Pierre
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supporting information
p. 7936 - 7949
(2016/11/07)
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- 7-(MORPHOLIN-4-YL)PYRAZOLE[1,5-A]PYRIMIDINE DERIVATIVES WHICH ARE USEFUL FOR THE TREATMENT OF IMMUNE OR INFLAMMATORY DISEASES OR CANCER
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A compound of the general formula (I) wherein Y represents -CH2- or >C=0; R1 is selected from the group consisting of A1, A2 and A3; R2 represents dioxothiomorpholino moiety B1, piperazinyl moiety B2, azetidinyl moiety B3, or piperidinyl moiety B4; R3 is selected from the group consisting of H, halogen, and C1 -C4 alkyl; R4 is selected from the group consisting of C1 -C4 alkyl, C3-C4- cycloalkyl, C1 -C4 alkyl substituted with C1 -C4 alkoxy, and CHF2, and their pharmaceutically acceptable salts. Pharmaceutical compositions comprising said compounds and their use in the treatment of diseases of immune system, inflammatory diseases and cancer.
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Page/Page column 20-21
(2017/07/31)
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- Synthesis and Characterization of 5-Hydroxy-2-(2-phenylethyl)chromone (5-HPEC) and Its Analogues as Non-nitrogenous 5-HT2B Ligands
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The involvement of the neurotransmitter serotonin (5-HT) in numerous physiological functions is often attributed to the diversity of receptors with which it interacts. Ligands targeting serotonin receptor 2B (5-HT2B) have received renewed interest for their potential to help understand the role of 5-HT2B in migraines, drug abuse, neurodegenerative diseases, and irritable bowel syndrome. To date, most of the ligands targeting 5-HT2B have been nitrogen-containing compounds. The natural product 5-hydroxy-2-(2-phenylethyl)chromone (5-HPEC, 5) has been shown previously to act as a non-nitrogenous antagonist for the 5-HT2B receptor (pKi = 5.6). This report describes further progress on the study of the structure-activity relationship of both naturally occurring and synthetic compounds bearing the 2-(2-phenylethyl)chromone scaffold at the 5-HT2B receptor. The inhibitory activity of the newly synthesized compounds (at 10 μM) was tested against each of the 5-HT2 receptors. Following this assay, the binding affinity and antagonism of the most promising compounds were then evaluated at 5-HT2B. Among all the analogues, 5-hydroxy-2-(2-phenylpropyl)chromone (5-HPPC, 22h) emerged as a new lead compound, showing a 10-fold improvement in affinity (pKi = 6.6) over 5-HPEC with reasonable antagonist properties at 5-HT2B. Additionally, ligand docking studies have identified a putative binding pocket for 5-HPPC and have helped understand its improved affinity. (Figure Presented).
- Williams, Dwight A.,Zaidi, Saheem A.,Zhang, Yan
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p. 1859 - 1867
(2015/09/08)
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- 2-SUBSTITUTED-5-HYDROXY-4H-CHROMEN-4-ONES AS NOVEL LIGANDS FOR THE SEROTONIN RECEPTOR 2B (5-HT2B)
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A family of compounds which function as selective ligands for the serotonin receptor 2B (5-HT2B) is identified. Some of the compounds are synthetic non-natural ligands which have a relatively strong interaction with 5-HT2B compared to naturally occurring compounds (some of which are identified for the first time herein as ligands for 5-HT2B). Because the compounds, both naturally occurring and synthetically produced, function as ligands for 5-HT2B they will have application in, for example, the treatment and/or prevention of nervous system disorders such as Alzheimer's disease.
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Page/Page column 33
(2015/09/22)
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- GLUCOSYLCERAMIDE SYNTHASE INHIBITORS
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The invention relates to inhibitors of glucosylceramide synthase (GCS) useful for the treatment of metabolic diseases, such as lysosomal storage diseases, either alone or in combination with enzyme replacement therapy, cystic disease and for the treatment of cancer.
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Page/Page column 167; 168
(2014/04/03)
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- PYRIMIDINE DERIVATIVES FOR THE TREATMENT OF VIRAL INFECTIONS
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This invention relates to pyrimidine derivatives, processes for their preparation, pharmaceutical compositions, and their use in treating viral infections such as HCV or HBV.
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Paragraph 0051; 0052; 0053
(2014/03/21)
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- PYRAZOLO[3,4-D]PYRIMIDIN-4(5H)-ONE DERIVATIVES AS PDE9 INHIBITORS
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A compound of the general formula (I) wherein R1 is selected from the group consisting of phenyl unsubstituted or substituted with 1 to 3 substituents selected from F, Cl, Br, I, CN, -O-C1-C3-alkyl, fluorinated -O-C1-C3-alkyl, -(CH2)mOH and 5-membered heterocyclic group with 1 or 2 heteroatoms selected from N, O and S; and 6- or 10-membered heteroaryl with 1 to 3 heteroatoms selected from O, N and S; R2 and R3 independently of each other represent H atom or straight or branched C1-C3 alkyl; R4 is selected from the group consisting of 4- to 6- membered cycloalkyl, wherein one of carbon atoms can be replaced by O atom, and which is unsubstituted or substituted with one or two halogen atoms,and straight or branched C1-C4 alkyl; Q represents a bond or C1-C3-alkylene, which can be optionally substituted by one to three C1-C3-alkyls; X is selected from the group consisting of O, NR5, and S(O)p; R5 represents H atom or C1-C3alkyl; m is 1, 2 or 3; p is 0, 1 or 2; and salts thereof, for use as a medicament, in particular for treating cognitive function disorders and neurodegenerative diseases.
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Page/Page column 29
(2014/02/16)
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- HERBICIDAL ISOXAZOLO[5,4-B]PYRIDINES
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The invention relates to isoxazolo[5,4-b]pyridine compounds of formula (I), to the agriculturally useful salts of isoxazolo[5,4-b]pyridine compounds of formula (I), and to their use as herbicides.
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Page/Page column 54; 55
(2013/07/25)
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- Enzymatic process for the preparation of butyrolactones
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The invention relates to a process for the preparation of a compound of formula wherein R1 is selected from the group consisting of hydrogen, C2-11-acyl, C4-9-cycloalkanoyl, aryl, aralkyl, aroyl, hetaryl, hetaralkyl and hetaroyl, comprising a biotransformation of a compound of formula wherein R1 is as defined above, wherein said biotransformation is carried out using a polypeptide having aldo-keto reductase activity or a microorganism containing same.
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Paragraph 0077
(2013/09/12)
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- HERBICIDAL ISOXAZOLO[5,4-B]PYRIDINES
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The invention relates to isoxazolo[5,4-b]pyridine compounds of formula (I), to the agriculturally useful salts of isoxazolo[5,4-b]pyridine compounds of formula (I), and to their use as herbicides.
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Page/Page column 61-62
(2012/02/05)
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- PYRIMIDINE DERIVATIVES FOR THE TREATMENT OF VIRAL INFECTIONS
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This invention relates to pyrimidine derivatives, processes for their preparation, pharmaceutical compositions, and their use in treating viral infections such as HCV or HBV.
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Page/Page column 11
(2012/10/18)
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- InCl3 catalyzed carbene insertion into O-H bonds: Efficient synthesis of ethers
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An efficient InCl3 mediated insertion of the carbene fragment (:CHCO2Et), generated in situ from ethyl diazoacetate into O-H bond of a series of saturated and unsaturated alcohols under mild conditions has been developed to afford the corresponding ethers as exclusive products in good to high yields (70-95%) and in shorter reaction times. In the case of unsaturated alcohols, the reaction proceeded with unprecedented selectivity resulting in ethers as the only products and in high yields.
- Radha Krishna, Palakodety,Prapurna, Y. Lakshmi,Alivelu, Munagala
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experimental part
p. 3460 - 3462
(2011/06/27)
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- INHIBITORS OF CATECHOL O-METHYL TRANSFERASE AND THEIR USE IN THE TREATMENT OF PSYCHOTIC DISORDERS
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The present invention relates to 4-pyridinone compounds which are inhibitors of catechol O-methyltransferase (COMT), and are useful in the treatment and prevention of neurological and psychiatric disorders and diseases in which COMT enzyme is involved. The present invention also relates to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which COMT is involved.
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Page/Page column 48-49
(2011/10/03)
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- COMPOUND WITH AGITATION EFFECT ON PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR , AND PREPARATION METHOD AND USE THEREOF
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The present invention provides a novel compound of formula I, which has an agitation effect on the peroxisome proliferator-activated receptor subtype δ (PPARδ), to a pharmaceutical composition comprising the compound, to a process for preparation of the compound and to use of the compound in the manufacture of a medicament for treating or preventing a disease which could be treated or prevented by activating PPARδ thereof, said disease is one or more from the group comprising metabolic syndrome, obesity, dyslipidemia, pathoglycemia, insulin resistance, senile dementia and tumors. The present invention also relates to a new intermediate used in the preparation of the novel compound and a process for preparation of the intermediate.
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Page/Page column 28
(2011/06/24)
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- COMPOUND WITH AGITATION EFFECT ON PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR. PROCESS FOR ITS PREPARATION AND USE THEREOF
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The present invention provides a novel compound of formula I, which has an agitation effect on the peroxisome proliferator-activated receptor subtype δ (PPARδ), to a pharmaceutical composition comprising the compound, to a process for preparation of the compound and to use of the compound in the manufacture of a medicament for treating or preventing a disease which could be treated or prevented by activating PPARδ thereof, said disease is one or more from the group comprising metabolic syndrome, obesity, dyslipidemia, pathoglycemia, insulin resistance, senile dementia and tumors. The present invention also relates to a new intermediate used in the preparation of the novel compound and a process for preparation of the intermediate.
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Page/Page column 18-19
(2012/01/13)
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- HETEROCYCLIC COMPOUNDS AS INHIBITORS OF CXCR2
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The present invention relates to compounds of formula (I) wherein R1, R2, X, Y and Z are as defined in the specification.
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Page/Page column 29-30
(2009/10/21)
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- A radical mediated approach to the stereoselective formal total synthesis of (+)-Sch 642305
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A formal total synthesis of (+)-Sch-642305 is described. The synthesis, which commenced from a simple chiral synthon (5S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one, employed, as a key step, a radical mediated opening of a chiral epoxy alcohol intermediate with Cp2Ti(III)Cl following an efficient method developed by us earlier. The resultant intermediate radical was intramolecularly trapped by the electron deficient double bond present in the molecule to give rise to its highly functionalized six-membered carbocyclic ring in stereoselective manner.
- Chakraborty, Tushar Kanti,Samanta, Rajarshi,Kumar, Pulukuri Kiran
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scheme or table
p. 6925 - 6931
(2009/12/09)
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- Heterocyclic compounds as P2X7 ion channel blockers
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The present invention relates to a novel series of 4,5-diphenyl-2-amino-4,5-dihydro-imidazole derivatives of the formula II: 1 wherein R, R1, R2, R3, R4, R5, X and Y are as defined herein. This invention also relates to methods of making these compounds. The compounds of this invention are P2X7 ion channel blockers and are therefore useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases having an inflammatory component, including inflammatory bowel disease, rheumatoid arthritis and disease conditions associated with the central nervous system, such as stroke, Alzheimer''s disease, etc.
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Page/Page column 75
(2010/02/10)
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- A facile synthesis of 2-benzyloxy/2-(4-isopropylbenzyloxy)-2-methyl-3-(4- substituted phenyl)propanoic acid based insulin sensitizing agents: RSR 13-15 and PKR13-15
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The title compounds (RSR13-15) and (PKR13-15) were prepared by the etherification of benzyl alcohol and 4-isopropylbenzyl alcohol respectively with ethyl-2-bromo-2-methyl-3-(4-substituted phenyl)propanoates in the presence of sodium hydride in THF followed by alkaline hydrolysis of the ethyl esters. The substituted propanoic acids used in this synthetic sequence were prepared by magnesium-methanol reduction of correspondingly substituted propenoic acids, which in turn were prepared via 'Perkin Reaction' of 4-substituted benzaldehydes with propanoic anhydride. The details of the synthetic sequence followed for the preparation of all these compounds having almost all the structural features required for a compound to act as a potent insulin sensitizing agent are reported. Birkhaeuser Boston 2004.
- Verma, Raman K.,Singla, Rubina,Punniyakoti
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p. 660 - 676
(2007/10/03)
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- Benzofurylpyrone derivatives
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There is provided benzofuryl-α-pyrone derivative represented by the following structural formula (I): wherein R1represents a hydrogen atom or an alkyl group of 1 to 5 carbons; R2represents hydrogen, —CO—R5or —SO2/sub
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- RSK INHIBITORS AND THERAPEUTIC USES THEREOF
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The present invention is directed to novel compounds and compositions that have Rsk specific inhibitory activity. In addition, inhibition of Rsk by the present compounds has been discovered to halt the proliferation of cancer cell lines while having little effect on the proliferation rate of normal cells. Therefore, the present invention identifies Rsk as a target for therapeutic intervention in diseased states in which the disease or the symptoms can be ameliorated by inhibition of Rsk catalytic activity.
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- Pyrrolopyrazolopyrimidine compound and medicine comprising the same as active ingredient
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The invention relates to compounds represented by the following general formula (1): STR1 wherein R1 represents an alkyl group, R2 represents an amino group, alkyl group or the like, and R3 represents a nitro group, amino group, heterocyclic group, alkylsulfonylamino group or the like, or salts thereof, medicines comprising such a compound, a preparation process of the compounds, and intermediates useful for preparation thereof. The compounds (1) are useful for the prevention and treatment of a respiratory disease.
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- Enantioselective synthesis of C2-symmetric hexols from β-δ- diketosulfoxides
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An enantioselective synthesis of (1,2S,4S,8S,10S,11)- hexahydroxyundecane, a C2-symmetric hexol precursor of the alkaloid (-)- lythranidine, is described. This convergent synthesis was based on the stereoselective reduction of two different β-δ
- Solladie, Guy,Colobert, Francoise,Denni, Donatienne
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p. 3081 - 3094
(2007/10/03)
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- Insertion of carbenes into O-H bonds of alcohols catalysed by platinum complexes
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The addition of diazoesters to alcohols in the presence of a catalytic amount of platinum complexes provides the corresponding O-H insertion products in good to excellent yields.
- Schils, Raphael,Simal, Francois,Demonceau, Albert,Noels, Alfred F.,Eremenko, Igor L.,Sidorov, Aleksei A.,Nefedov, Sergei E.
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p. 7849 - 7852
(2007/10/03)
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- Organic reactions catalyzed by methylrhenium trioxide: Reactions of ethyl diazoacetate and organic azides
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Methylrhenium trioxide (CH3ReO3 or MTO) catalyzes several classes of reactions of ethyl diazoacetate, EDA. It is the first high valent oxo complex for carbene transfer. Under mild conditions and in the absence of other substrates, EDA was converted to a 9:1 mixture of diethyl maleate and diethyl fumarate. In the presence of alcohols, α-alkoxy ethyl acetates were obtained in good yield. The yields dropped for the larger and more branched alcohols, the balance of material being diethyl maleate and fumarate. An electron-donating group in the para position of phenols favors the formation of α-phenoxy ethyl acetates. The use of EDA to form α-thio ethyl acetates and N-substituted glycine ethyl esters, on the other hand, is hardly affected by the size or structure of the parent thiol or amine, with all of these reactions proceeding in high yield. MTO-catalyzed cycloaddition reactions occur between EDA and aromatic imines, olefins, and carbonyl compounds. Three-membered ring products are formed: aziridines, cyclopropanes, and epoxides, respectively. The reactions favor the formation of trans products, and provide a convenient route for the preparation of aziridines. Intermediate carbenoid and nitrenoid species have been proposed. In the presence of an oxygen source such as an epoxide, ethyl diazoacetate and azibenzil are converted to an oxalic acid monoethyl ester and tobenzil; at the same time the epoxide was converted to an olefin. These results provide further support for the proposed intermediate, a cyclic species containing Re, O, and CHCO2Et (or, occasionally, CPhC(O)Ph)in a three-membered ring.
- Zhu, Zuolin,Espenson, James H.
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p. 9901 - 9907
(2007/10/03)
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- BENZOXAZINONE DERIVATIVE
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A benzoxazinone derivative represented by general formula (I) or a pharmaceutically acceptable acid addition salt thereof, and an anti-inflammatory, a neutrophil infiltration inhibitor and a serine protease inhibitor each containing the derivative as an active ingredient, wherein R, R1, R2 and R3 may be the same or different from one another and each represents hydrogen or lower alkyl; A represents optionally halogenated phenyl, heterocycle or adamantyl; B represents hydrogen or optionally halogenated phenyl or heterocycle; U represents =CH-, =C= or =N-; V represents -O-, -CH2-, =N-, -NH-, -CH= or a single bond; X represents -O-, =CH-, -CH2- or a single bond; Y represents -CH2-, -NH-, -O- or a single bond; Z represents -CO- or -CH2-; and l represents an integer of 0 to 3. This compound has excellent activities of inhibiting serine protease, neutrotaxis, and infiltration of neutrophils into carragheenin-induced pneumocephalus.ψ
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- 4,7-dihydroisothiazolo(5,4-b)pyridine derivatives and cardiovascular treating agents containing said derivatives
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A 4,7-dihydroisothiazole[5,4-b]pyridine derivative represented by the general formula STR1 wherein R1 represents an alkyl group which may be substituted, R2 represents a hydrogen atom, a hydroxyl group, a benzyloxy group, a lower alk
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