90417-38-2

Usage

Biological Activity

Novel, potent inhibitor of poly(ADP-ribose) polymerase (PARP). K i and IC 50 values are 48 and 400 nM respectively.

InChI:InChI=1/C9H8N2O2/c1-5-10-8-6(9(13)11-5)3-2-4-7(8)12/h2-4,12H,1H3,(H,10,11,13)

Upstream product

• 172462-98-5 2-N-Acetylamino-3-methoxybenzamide 
• 3177-80-8 2-amino-3-methoxybenzoic acid 
• 4920-80-3 3-methoxy-2-nitrobenzoic acid 
• 54905-94-1 8-methoxy-2-methyl-4H-benzo[d][1,3]oxazin-4-one 
• 106782-78-9 3-methoxy-2-aminobenzamide 
• 16064-27-0 8-methoxy-quinazolin-4(3H)-one 
• 90915-45-0 8-methoxy-2-methyl-4-oxo-3,4-dihydroquinazoline 
• 16064-17-8 NU 1026 

Downstream Products

• 154288-10-5 4-chloro-8-hydroxy-2-methyl-quinazoline 

Relevant academic research and scientific papers

Studies towards hypoxia-activated prodrugs of PARP inhibitors

Poly(ADP-ribose)polymerase (PARP) inhibitors (PARPi) have recently been approved for the treatment of breast and ovarian tumors with defects in homologous recombination repair (HRR). Although it has been demonstrated that PARPi also sensitize HRR competent tumors to cytotoxic chemotherapies or radiotherapy, normal cell toxicity has remained an obstacle to their use in this context. Hypoxia-activated prodrugs (HAPs) provide a means to limit exposure of normal cells to active drug, thus adding a layer of tumor selectivity. We have investigated potential HAPs of model PARPi in which we attach a bioreducible “trigger” to the amide nitrogen, thereby blocking key binding interactions. A representative example showed promise in abrogating PARPi enzymatic activity in a biochemical assay, with a ca. 160-fold higher potency of benzyl phthalazinone 4 than the corresponding model HAP 5, but these N-alkylated compounds did not release the PARPi upon one-electron reduction by radiolysis. Therefore, we extended our investigation to include NU1025, a PARPi that contains a phenol distal to the core binding motif. The resulting 2-nitroimidazolyl ether provided modest abrogation of PARPi activity with a ca. seven-fold decrease in potency, but released the PARPi efficiently upon reduction. This investigation of potential prodrug approaches for PARPi has identified a useful prodrug strategy for future exploration.

Total synthesis of penipanoid C, 2-(4-hydroxybenzyl)quinazolin-4(3H)-one and NU1025

The first total synthesis of penipanoid C and 2-(4-hydroxybenzyl)quinazolin-4(3H)-one is reported using a greener mild deep eutectic solvent mediated cyclization strategy with good overall yields. NU1025 drug is also synthesized using the similar protocol.

NEUROLOGICALLY-ACTIVE COMPOUNDS

The present invention relates to neurologically-active compounds, being heterocyclic compounds having two fused 6-membered rings with a nitrogen atom at position 1 and a hydroxy or mercapto group at position 8 with at least one ring being aromatic. Also disclosed are processes for the preparation of these compounds and their use as pharmaceutical or veterinary agents, in particular for the treatment of neurological conditions, more specifically neurodegenerative conditions such as Alzheimer's disease.

Quinazolinone compounds

Phosphate derivatives are disclosed of quinazolinone compounds having structural formula (I) or a pharmaceutically acceptable salt thereof, wherein X' represent hydroxyl, alkyl, alkoxy, or O-Z where Z is a phosphate or phosphate derivative; Y' represents

Resistance-modifying agents. 5.1 Synthesis and biological properties of quinazolinone inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP)

Clinical studies concerning the role of poly(ADP-ribose) polymerase (PARP) in the repair of drug- and radiation-induced DNA damage have been impeded by the poor solubility, lack of potency, and limited specificity of currently available inhibitors. A seri

Benzamide analogs useful as PARP (ADP-ribosyltransferase, ADPRT) DNA repair enzyme inhibitors

A range of 3-oxybenzamide compounds and related quinazolinone compounds are disclosed which can act as potent inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase or PARP enzyme (EC 2.4.2.30), and which thereby can provide useful therapeutic compounds for use in conjunction with DNA-damaging cytotoxic drugs or radiotherapy to potentiate the effects of the latter. The compounds disclosed include 3-benzyloxybenzamides, 3-oxybenzamides in which a chain of 5 or more methylene groups terminate in a halogen atom or in a purin-9-yl moiety, certain benzoxazole-4-carboxamide compounds and certain quinazolinone compounds. In formula X and Y together may form a bride -X-Y- that represents the grouping (a), (b) or (c )wherein R5 is H, alkyl, aryl or aralkyl.

Novel benzimidazole and quinazolinone inhibitors of the DNA repair enzyme Poly(ADP-ribose)polymerase

Two novel series of inhibitors of the DNA repair enzyme poly(ADP-ribose)polymerase (PARP) were synthesized and evaluated for biological activity. In the benzimidazole-4-carboxamide series, the carbamoyl function was restricted into the putative biologically active conformation via an intramolecular hydrogen bond, while for quinazolin-4-[3H]-ones this was achieved by incorporation of the group into a heterocyclic ring. For both series of compounds, syntheses involved acylation of substituted anthranilic acid derivatives, followed by acid- or base-catalysed cyclization. 8-Hydroxyquinazolin-4-[3H]-ones were prepared from the corresponding 8-methoxy compounds by dealkylation with boron tribromide. PARP inhibitory activity was determined in permeabilized L1210 murine leukaemia cells, in comparison with the established inhibitor 3-hydroxybenzamide (IC50 = 8.3 μM). For both series, inhibitory activity varied with the nature of the 2-substituent, with benzimidazole-4-carboxamides proving approximately tenfold more potent than the previously prepared benzoxazole-4-carboxamides. 2-Arylbenzimidazoles were especially active, and 2-(4-methoxyphenyl)benzimidazole-4-carboxamide (IC50 = 60 nM) is the most potent PARP inhibitor reported to date. In the quinazolinone series, a 2-(4-nitrophenyl) substituent, and either an 8-methyl or 8-hydroxy group conferred potent inhibitory activity, with IC50 values of 0.13 and 0.23 μM, respectively, being observed.

BRADYKININ ANTAGONIST QUINOLINES

This invention relates to new heterocyclic compounds and pharmaceutically acceptable salts thereof. More particularly, this invention relates to new heterocyclic compounds and salts thereof which display bradykinin antagonist activity, to processes for preparing these compounds, to a pharmaceutical composition comprising these compounds, and to methods of using same in the prevention and/or the treatment of bradykinin-or bradykinin analogue-mediated diseases such as allergy, inflammation, autoimmune disease, shock, pain, or the like, in human beings or in animals.

Quinazolones: Part XI - Effect of Substituents on Claisen Rearrangement of Allyloxyquinazolones

The Claisen rearrangement of 7-allyloxy-8-methoxy-2-methyl-3-phenylquinazolin-4(3H)-one (I) gives the unusual products 6-allyl-2-ethyl-7,8-dihydroxy-3-phenylquinazolin-4(3H)-one and 7-ethyl-9-hydroxy-2-methyl-6-phenylfuroquinazolin-5(6H)-one (VIb) instead of the expected 6-allyl-7-hydroxy-8-methoxy-2-methyl-3-phenylquinazolin-4(3H)-one (II).