175414-77-4

Basic information

• Product Name: Voreloxin
• Synonyms: Voreloxin;AG-7352;SNS-595;SPC-595;AG-7352, 1,4-dihydro-7-[(S,S)-3-Methoxy-4-MethylaMino-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic, (+)-1,4-dihydro-7-[(3S,4S)-3-Methoxy-4-(MethylaMino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid;7-((3S,4S)-3-Methoxy-4-(MethylaMino)pyrrolidin-1-yl)-4-oxo-1-(thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid;1,8-Naphthyridine-3-carboxylic acid, 1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo -1-(2-thiazolyl)-;Voreloxin (SNS-595)
• CAS NO: 175414-77-4
• Molecular Formula: C18H19N5O4S
• Molecular Weight: 401.43956
• Product Categories: API;Inhibitors
• Mol File: 175414-77-4.mol

Chemical Properties

• Appearance: /
• Solubility: insoluble in H2O; insoluble in EtOH; insoluble in DMSO
• CAS DataBase Reference: Voreloxin(CAS DataBase Reference)
• NIST Chemistry Reference: Voreloxin(175414-77-4)
• EPA Substance Registry System: Voreloxin(175414-77-4)

Safety Data

• Hazardous Substances Data: 175414-77-4(Hazardous Substances Data)

Usage

Uses

Voreloxin is a potent Topoisomerase II inhibitor with broad-spectrum anti-tumor activity.

Biological Activity

voreloxin, formerly known as sns-595 or ag-7352, is a novel naphthyridine analog, which is structurally related to the quinolone antibiotics, a chemical class not previously used for the treatmentof cancer.

in vitro

in vitro studies demonstrated voreloxin has broad anti-proliferative activity in 11 tumor cell lines, with ic50 values ranging from 0.04 to 0.97 μm. similar activity was observed in vitro in drug-resistant cell lines, including those that overexpress p-glycoprotein [2].

in vivo

after a single intravenous dose, voreloxin concentrations in tumor were correlated with induction of the apoptosis marker caspase-3. administration of voreloxin at 20 mg/kg weekly inhibited tumor growth (86%). voreloxin demonstrated strong dose-dependent tumor growth inhibition (63–88%) in 10 of 11 solid tumor xenograft models [2].

references

[1] tsuzuki y, tomita k, shibamori k, sato y, kashimoto s, chiba k. synthesis and structure-activity relationships of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids as antitumor agents. part 2. j med chem. 2004;47(8):2097-109.[2] hoch u, lynch j, sato y, kashimoto s, kajikawa f, furutani y, silverman ja. voreloxin, formerly sns-595, has potent activity against a broad panel of cancer cell lines and in vivo tumor models. cancer chemother pharmacol. 2009;64(1):53-65. [3] advani rh, hurwitz hi, gordon ms, ebbinghaus sw, mendelson ds, wakelee ha, hoch u, silverman ja, havrilla na, berman cj, fox ja, allen rs, adelman dc. voreloxin, a first-in-class anticancer quinolone derivative, in relapsed/refractory solid tumors: a report on two dosing schedules. clin cancer res. 2010;16(7):2167-75.

Upstream product

• 685880-17-5 ethyl 1,4-dihydro-7-[(S,S)-3-methoxy-4-methylamino-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylate 
• 174726-89-7 ethyl 2-(2,6-dichloro-3-nicotinoyl)-3-(2-thiazolylamino)acrylate 
• 174726-87-5 ethyl 7-chloro-4-oxo-1-(1,3-thiazol-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylate 
• 372482-03-6 (3S,4S)-3-methoxy-4-(N-methylammmonio)pyrrolidinium di-p-toluenesulphonate 
• 157373-27-8 ethyl 2-[(2,6-dichloropyridin-3-yl)carbonyl]-3-ethoxyacrylate 
• 38496-18-3 2,6-dichloropyridine-3-carboxylic acid 
• 174727-36-7 ethyl 3-(2,6-dichloropyridin-3-yl)-3-oxopropanoate 
• 252574-01-9 (3S,4S)-3-methoxy-4-(N-methylammmonio)pyrrolidinium 
• 429673-86-9 ((3R,4R)-4-Methoxy-pyrrolidin-3-yl)-methyl-amine 
• 429673-86-9 ((3R,4R)-4-Methoxy-pyrrolidin-3-yl)-methyl-amine 

Relevant articles and documents

STABLE SNS-595 COMPOSITIONS AND METHODS OF PREPARATION

Methods of preparing substantially pure SNS-595 substance are disclosed. Also provided are compositions comprising SNS-595 substance that are substantially pure and essentially free of visible particles.

COMPOUNDS AND COMPOSITIONS FOR TREATMENT OF CANCER

Compounds and compositions for treating, preventing or managing cancer are disclosed. The compositions provided herein comprise SNS-595 and N-desmethyl-SNS-595. Also provided are pharmaceutical compositions comprising the compounds and methods of treatment using the compounds and compositions.

METHOD OF PREPARING (+)-1,4-DIHYDRO-7-[(3S,4S)-3METHOXY-4-(METHYLAMINO)-1-PYRROLIDINYL]-4-OXO-1-(2-THIAZOLYL)-1,8-NAPHTHYRIDINE-3-CARBOXYLIC ACID

Methods of preparing (+)-1, 4-dihydro-7-[(3S,45)-3-methoxy-4-(methylamino)-1 - pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid are disclosed. Also provided are pharmaceutical compositions comprising (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid, and methods of treatment using such compositions.

Synthesis and Structure-Activity Relationships of Novel 7-Substituted 1,4-Dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic Acids as Antitumor Agents. Part 2

We have previously reported that a series of 7-substituted 6-fluoro-1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids possess moderate cytotoxic activity. In a further attempt to find clinically useful antitumor agents, we investigated the structure-activity relationships (SARs) of a new series of compounds obtained by changing the C-6 position of the fluorine atom in addition to the C-5 and C-7 positions and evaluating their cytotoxic activity against several murine and human tumor cell lines. Our results showed that the 6-unsubstituted 1,8-naphthyridine structure had the most potent cytotoxic activity against murine P388 leukemia twice that of the 6-fluoro analogue. In addition, introduction of an amino group at the C-5 position did not have any substantial effect on the cytotoxic activity, while both the 5-chloro and 5-trifluoromethyl groups decreased the cytotoxic activity by 5- to 10-fold. Moreover, aminopyrrolidine derivatives at the C-7 position showed more potent cytotoxic activity than other amines or carbon derivatives. Among the 7-(3-aminopyrrolidinyl) derivatives, the trans-3-methoxy-4-methylaminopyrrolidinyl derivative (271) was determined to have potent cytotoxic activity in both in vitro and in vivo assays and high water solubility. Finally, the (S,S)-isomer (AG-7352, 3) of 271, with a cytotoxic activity against human tumor cell lines more potent than that of etoposide, was selected for further development.

Compounds, processes for the preparation thereof and anti-tumor agents

This invention relates to pyridone-carboxylic acid derivatives of the following formula or salts thereof: STR1 wherein R1 is a hydrogen atom, a halogen atom, etc., R2 is a carboxyl group etc., R3 is a hydrogen atom etc., A