6493-07-8

Usage

Chemical Properties

White Solid

Uses

A metabolite of Pentoxifylline (P276500).

InChI:InChI=1/C11H14N4O4/c1-13-6-12-9-8(13)10(18)15(11(19)14(9)2)5-3-4-7(16)17/h6H,3-5H2,1-2H3,(H,16,17)

Upstream product

• 83-67-0 theobromine / 
• 6493-05-6 pentoxyphylline 
• 6493-12-5 4-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanal 
• 83636-88-8 ethyl 4-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate 

Relevant academic research and scientific papers

Baeyer-Villiger Monooxygenase FMO5 as Entry Point in Drug Metabolism

Flavin-containing monooxygenases (FMOs) are emerging as effective players in oxidative drug metabolism. Until recently, the functions of the five human FMO isoforms were mostly linked to their capability of oxygenating molecules containing soft N- and S-nucleophiles. However, the human FMO isoform 5 was recently shown to feature an atypical activity as Baeyer-Villiger monooxygenase. With the aim of evaluating such an alternative entry point in the metabolism of active pharmaceutical ingredients, we selected and tested drug molecules bearing a carbonyl group on an aliphatic chain. Nabumetone and pentoxifylline, two widely used pharmaceuticals, were thereby demonstrated to be efficiently oxidized in vitro by FMO5 to the corresponding acetate esters with high selectivity. The proposed pathways explain the formation of a predominant plasma metabolite of pentoxifylline as well as the crucial transformation of the pro-drug nabumetone into the pharmacologically active compound. Using the recombinant enzyme, the ester derivatives of both drugs were obtained in milligram amounts, purified, and fully characterized. This protocol can potentially be extended to other FMO5 candidate substrates as it represents an effective and robust bench-ready platform applicable to API screening and metabolite synthesis.

Synthesis and analgesic activity of 3,7-dimethylpurine-2,6-dion-1-yl derivatives of acetic and butanoic acid

Hydrazones are a group of compounds possessing diversified biological activity, anti-inflammatory and analgesic activities. There are also known xanthine derivatives possessing such activity. The aim of our study was to investigate if introduction of hydrazone moiety to 3,7-dimethylpurine-2,6-dion-1-yl acetic and butanoic acid derivatives would enhance the analgesic activity. The designed series of compounds were synthesized in a multi-step procedure. Their pharmacological activity was investigated in the writhing syndrome test. Based on the results the structure-activity relationship was discussed. From the synthesized group of twenty compounds, nineteen were tested in vivo. The analgesic activity of most compounds, except for compound 4, was higher than for acetylsalicylic acid in the writhing syndrome test. Our study showed that the introduction of hydrazone moiety generally enhances analgesic activity of xanthine derivatives, compared to derivatives with free carboxylic group, ester, benzylamide and hydrazide moieties. The presence of hydroxyl moiety or substituent with high electron density does not seem to be necessary for the activity of hydrazone derivatives

Compounds for ceramide-mediated signal transduction

Novel isoquinoloine compounds inhibit inflammatory responses associated with TNF-α and fibroblast proliferation in vivo and in vitro. The compounds of the invention neither appreciably inhibit the activity of cAMP phosphodiesterase nor the hydrolysis of phosphatidic acid, and are neither cytotoxic nor cytostatic. Preferred compounds of the invention are esters. Methods for the use of the novel compounds to inhibit ceramide-mediated intracellular responses to stimuli in vivo (particularly TNF-α) are also described. The methods are expected to be of use in reducing inflammatory responses (for example, after angioplasty), in limiting fibrosis (for example, of the liver in cirrhosis), in inhibiting cell senescence, cell apoptosis and UV induced cutaneous immune suppression.

Immunosuppressive effects of 8-substituted xanthine derivatives

The invention relates to a novel use of 8 substituted xanthine derivatives for the manufacture of a medicament for the treatment of auto-immuno disorders. The invention relates in particular to the use of a xanthine derivative of general formula (I): wherein: R1, R2and R3are independently hydrogen, saturated or unsaturated aliphatic chains which may be straight or branched having 1 to 6 carbon atoms; X and Y are independently oxygen or sulfur; Z1is selected from the group comprising a thienyl; furanyl; cyclopentyl, phenyl or a substituted by Z2or unsubstituted phenyl; wherein Z2is selected from the group comprising phenyl; sulfonic acid; unsubstituted or N-substituted sulfonamide with substituents such as alkyl, aminoalkyl where the amino group may be substituted itself with lower alkyl groups bearing 1 to 4 carbon atoms; nitro; halogen substituted or unsubstituted amino group; aliphatic chain with 1 to 3 carbon atoms; halogenated aliphatic chain with 1 to 3 carbon atoms; aliphatic chain containing ether functions, acids, esters, amides, substituted or unsubstituted amines having 1 to 3 carbon atoms, nitro, sulfonamides or a combination of these functional groups with a maximum length of the chain of 12 atoms, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of auto-immuno disorders.

Substituted xanthines, pteridinediones, and related compounds as potential antiinflammatory agents. Synthesis and biological evaluation of inhibitors of tumor necrosis factor α

A series of analogues of pentoxifylline metabolites were prepared in the purine, pteridine, [1,2,5]-thiadiazolo[3,4-d]pyrimidine, and quinazoline ring systems and evaluated for their ability to inhibit the production of tumor necrosis factor-α (TNFα) in human peripheral blood monocytes stimulated with bacterial lipopolysaccharide (LPS). The more active compounds were also tested for inhibition of cyclic AMP phosphodiesterase type IV (PDE IV) from human neutrophils in order to help determine their mechanism of action. Selected compounds which showed good activity in the in vitro TNFα assay were evaluated in an in vivo LPS-induced leukopenia model in mice. The most potent compounds in the TNFα assay, 6, 31, and 58, inhibited TNFα production at an IC50 of approximately 5 μM for each. Compound 58 was a very poor inhibitor of PDE IV but was the most active at preventing the leukopenia induced by TNFα in mice, providing more than 60% protection at 50 mg/kg. Thus, compounds such as 58, which are good inhibitors of TNFα production but are devoid of PDE IV inhibitory properties, may have potential as new antiinflammatory agents.