100324-81-0

Basic information

• Product Name: 1-(5-hydroxyhexyl)-3,7-dimethyl-purine-2,6-dione
• Synonyms: 1-(5-hydroxyhexyl)-3,7-dimethyl-purine-2,6-dione;3,7-Dihydro-1-[(5R)-5-hydroxyhexyl]-3,7-dimethyl-1H-purine-2,6-dione;CT 1501R;Lisophylline;ProTec;(R)-Lisofylline;3,7-Dihydro-1-[(5R)-5-hydroxyhexyl]-3,7-diMethyl-
• CAS NO: 100324-81-0
• Molecular Formula: C₁₃H₂₀N₄O₃
• Molecular Weight: 280.32
• Product Categories: Various Metabolites and Impurities;Intermediates & Fine Chemicals;Metabolites & Impurities;Pharmaceuticals;Metabolites & Impurities, Pharmaceuticals, Intermediates & Fine Chemicals
• Mol File: 100324-81-0.mol

Chemical Properties

• Melting Point: 105-107°C
• Boiling Point: 511.2°C at 760 mmHg
• Flash Point: 263°C
• Appearance: /
• Density: 1.32g/cm³
• Vapor Pressure: 2.84E-11mmHg at 25°C
• Refractive Index: 1.62
• Storage Temp.: Hygroscopic, -20°C Freezer, Under Inert Atmosphere
• Solubility: Chloroform, Methanol
• PKA: 15.22±0.20(Predicted)
• Stability: Hygroscopic
• CAS DataBase Reference: 1-(5-hydroxyhexyl)-3,7-dimethyl-purine-2,6-dione(CAS DataBase Reference)
• NIST Chemistry Reference: 1-(5-hydroxyhexyl)-3,7-dimethyl-purine-2,6-dione(100324-81-0)
• EPA Substance Registry System: 1-(5-hydroxyhexyl)-3,7-dimethyl-purine-2,6-dione(100324-81-0)

Safety Data

• Hazardous Substances Data: 100324-81-0(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Applications:
1-(5-hydroxyhexyl)-3,7-dimethyl-purine-2,6-dione is used as an immunomodulator for its ability to inhibit the production of phosphatidic acid during the inflammatory response. This makes it a valuable compound in the development of treatments for various inflammatory conditions.
Used in Anti-Inflammatory Applications:
In the pharmaceutical industry, 1-(5-hydroxyhexyl)-3,7-dimethyl-purine-2,6-dione is used as an anti-inflammatory agent due to its ability to modulate the inflammatory response by inhibiting phosphatidic acid production.
Used in Cell Therapeutics:
1-(5-hydroxyhexyl)-3,7-dimethyl-purine-2,6-dione, under the brand name ProTec, is used in cell therapeutics to leverage its immunomodulatory properties for the treatment of various conditions.

Biological Activity

lisofylline (lsf) is a potent anti-inflammatory agent. lsf is a chiral metabolite of pentoxifylline. (r)-lsf is the biologically active isomer of lsf [1].in vitro: lisofylline preserved β-cell insulin secretion and inhibited dna damage of islets in the presence of il-1β [2]. simultaneous application of lsf and cytokines to ins-1 cells restored insulin secretion, mitochondrial membrane potential, mtt metabolism, and cell viability to control levels. lsf increased β-cell mtt metabolism as well as insulin release and glucose responsiveness [3].

in vivo

in rats subjected to hemorrhagic shock and resuscitation, lsf increased the intestinal and hepatic blood flow. treatment with lsf (15 mg/kg) ameliorated the development of mucosal damage and hyperpermeability. rats treated with lsf showed lower plasma concentrations of the intracellular hepatic enzyme, aspartate aminotransferase. lsf treatment increased concentrations of adenosine triphosphate in intestinal and hepatic tissue [1]. in nod mice, lisofylline suppressed ifn-γ production, reduced the onset of insulitis and diabetes, and inhibited diabetes after transfer of splenocytes from lisofylline-treated donors to nod.scid recipients [2].

references

[1] wattanasirichaigoon s, menconi m j, fink m p. lisofylline ameliorates intestinal and hepatic injury induced by hemorrhage and resuscitation in rats[j]. critical care medicine, 2000, 28(5): 1540-1549.[2] yang z d, chen m, wu r, et al. the anti-inflammatory compound lisofylline prevents type i diabetes in non-obese diabetic mice[j]. diabetologia, 2002, 45(9): 1307-1314.[3] chen m, yang z, wu r, et al. lisofylline, a novel antiinflammatory agent, protects pancreatic β-cells from proinflammatory cytokine damage by promoting mitochondrial metabolism[j]. endocrinology, 2002, 143(6): 2341-2348.

InChI:InChI=1/C13H20N4O3/c1-9(18)6-4-5-7-17-12(19)10-11(14-8-15(10)2)16(3)13(17)20/h8-9,18H,4-7H2,1-3H3/t9-/m1/s1

Upstream product

• 154719-57-0 1-(5,6-oxidohexyl)-3,7-dimethylxanthine 
• 67-56-1 methanol 
• 6493-05-6 pentoxyphylline 
• 67-63-0 isopropyl alcohol 
• 10226-30-9 6-chloro-2-hexanone 
• 83-67-0 theobromine / 
• 6493-06-7 1-(5-hydroxyhexyl)theobromine 
• 624-45-3 levulinic acid methyl ester 
• 108-05-4 vinyl acetate 
• 301329-26-0 lisofylline 
• 21746-88-3 4-epoxy-2-yl-bromobutane 
• 174455-55-1 6-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)hexan-2-yl acetate 
• 5205-39-0 ethyl glutaroyl chloride 
• 13984-57-1 ethyl 5-oxohexanoate 

Downstream Products

• 100324-80-9 (+)-(S)-3,7-dimethyl-1-(5-hydroxyhexyl)-3,7-dihydropurine-2,6-dione 
• 174455-55-1 6-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)hexan-2-yl acetate 
• 174455-55-1 6-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)hexan-2-yl acetate 
• 174455-55-1 6-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)hexan-2-yl acetate 
• 117835-33-3 3-Methyl-5-methylamino-3H-imidazole-4-carboxylic acid (5-methoxy-hexyl)-amide; compound with picric acid 

Relevant articles and documents

Boron-Catalyzed Regioselective Deoxygenation of Terminal 1,2-Diols to 2-Alkanols Enabled by the Strategic Formation of a Cyclic Siloxane Intermediate

The selective deoxygenation of polyols is a frontier in our ability to harness the stereochemical and structural complexity of natural and synthetic feedstocks. Herein, we describe a highly active and selective boron-based catalytic system for the selective deoxygenation of terminal 1,2-diols at the primary position, a process that is enabled by the transient formation of a cyclic siloxane. The method provides an ideal complement to well-known catalytic asymmetric reactions to prepare synthetically challenging chiral 2-alkanols in nearly perfect enantiomeric excess, as illustrated in a short synthesis of the anti-inflammatory drug (R)-lisofylline. Pick the right one! A highly active and selective boron-based catalytic system enables the selective deoxygenation of terminal 1,2-diols at the primary position via the transient formation of a cyclic siloxane. The utility of this method for the preparation of synthetically challenging chiral 2-alkanols was illustrated by a short synthesis of the anti-inflammatory drug (R)-lisofylline.

Remote ester group leads to efficient kinetic resolution of racemic aliphatic alcohols via asymmetric hydrogenation

A highly efficient method for kinetic resolution of racemic aliphatic alcohols without conversion of the hydroxyl group has been realized; the method involves hydrogenation mediated by a remote ester group and is catalyzed by a chiral iridium complex. This powerful, environmentally friendly method provides chiral δ-alkyl-δ-hydroxy esters and δ-alkyl-1,5-diols in good yields with high enantioselectivities even at extremely low catalyst loading (0.001 mol %).

Two-Step Protocol for Iodotrimethylsilane-Mediated Deoxy-Functionalization of Alcohols

We have developed a two-step protocol for iodotrimethylsilane-mediated deoxy-functionalization of primary and secondary alcohols to afford products containing a C?N, C?S, or C?O bond. In the first step the alcohol undergoes iodination with iodotrimethylsilane, and in the second, the iodine atom is replaced by a N, S, or O nucleophile. Compared with traditional Mitsunobu reaction, non-acidic pre-nucleophiles can be used, and the reaction proceeds with retention of configuration. This operationally simple, highly efficient protocol can be used for some natural products and small-molecule drugs containing hydroxy-group.

Chemoenzymatic enantioselective and stereo-convergent syntheses of lisofylline enantiomers via lipase-catalyzed kinetic resolution and optical inversion approach

Highly enantioselective enzymatic kinetic resolution (EKR) of racemic lisofylline is presented for the first time. A comprehensive optimization of the key parameters of lipase-catalyzed transesterification of racemic lisofylline revealed that optimal biocatalytic system consisted of immobilized lipase type B from Candida antarctica (Chirazyme L-2, C-3) suspended in a mixture of 3 equiv of vinyl acetate as an acetyl donor and ethyl acetate as a solvent. Under optimal reaction conditions, the 1 g-scale (Chirazyme L-2, C-3)-catalyzed kinetic resolution of racemic lisofylline furnished both the EKR products in a homochiral form (>99 % ee) with the 50 % conv., and the highest possible enantioselectivity. The best results in terms of the reaction yields (47–50 %) and enantiomeric purity of the kinetically-resolved optically active products were achieved when the preparative-scale EKR was carried out for 2 h at 60 °C. In addition, stereoinversion of the less biologically-relevant (S)-lisofylline into its (R)-enantiomer was successfully achieved via acetolysis of the respective optically pure (S)-mesylate by using 2 equiv of ceasium acetate and catalytic amount of 18-Crown-6 in dry toluene, followed by K2CO3-mediated methanolysis of (R)-acetate. The elaborated EKR methodology together with enantioconvergent strategy provided a useful chemoenzymatic protocol for the synthesis of complementary enantiomers of titled API. Moreover, we report on the first single-crystal X-ray diffraction (XRD) analyses performed for the synthesized lisofylline enantiomers. Insight into the source of CAL-B stereoselectivity toward racemic lisofylline was gained by molecular docking experiments. In silico theoretical predictions matched very well with experimental results.

Role of Chain Length and Degree of Unsaturation of Fatty Acids in the Physicochemical and Pharmacological Behavior of Drug-Fatty Acid Conjugates in Diabetes

Several drug-fatty acid (FA) prodrugs have been reported to exhibit desirable physicochemical and pharmacological profile; however, comparative beneficial effects rendered by different FAs have not been explored. In the present study, four different FAs (linoleic acid, oleic acid, palmitic acid, and α-lipoic acid) were selected based on their chain length and degree of unsaturation and conjugated to Lisofylline (LSF), an antidiabetic molecule to obtain different drug-FA prodrugs and characterized for molecular weight, hydrophobicity, purity, self-assembly, and efficacy in vitro and in vivo in type 1 diabetes model. Prodrugs demonstrated a 2- to 6-fold increase in the plasma half-life of LSF. Diabetic animals treated with prodrugs, once daily for 5 weeks, maintained a steady fasting blood glucose level with a significant increase in insulin level, considerable restoration of biochemical parameters, and preserved β-cells integrity. Among the different LSF-FA prodrugs, LSF-OA and LSF-PA demonstrated the most favorable physicochemical, systemic pharmacokinetic, and pharmacodynamic profiles.

Efficient Transfer Hydrogenation of Ketones using Methanol as Liquid Organic Hydrogen Carrier

Herein, we demonstrate an efficient protocol for transfer hydrogenation of ketones using methanol as practical and useful liquid organic hydrogen carrier (LOHC) under Ir(III) catalysis. Various ketones, including electron-rich/electron-poor aromatic ketones, heteroaromatic and aliphatic ketones, have been efficiently reduced into their corresponding alcohols. Chemoselective reduction of ketones was established in the presence of various other reducible functional groups under mild conditions.

Preparation methods and applications of chiral spirophosphine-nitrogen-phosphine tridentate ligand and iridium catalyst thereof

The invention relates to preparation methods and applications of a chiral spirophosphine-nitrogen-phosphine tridentate ligand SpiroPNP and an iridium catalyst Ir-SpiroPNP thereof. The chiral spirophosphine-nitrogen-phosphine tridentate ligand is a compound represented by a formula I, or a racemate or an optical isomer thereof, or a catalytically acceptable salt thereof, and is mainly structurallycharacterized by having a chiral spiro indane skeleton and a phosphine ligand with a large steric hindrance substituent. The chiral spirophosphine-nitrogen-phosphine tridentate ligand can be synthesized by taking a 7-diaryl/alkylphosphino-7'-amino-1,1'-spiro indane compound with a spiro skeleton as a chiral starting raw material. The iridium catalyst of the chiral spirophosphine-nitrogen-phosphinetridentate ligand is a compound represented by a formula II which is described in the specification, or a raceme or an optical isomer, or a catalytically acceptable salt thereof, can be used for catalyzing asymmetric catalytic hydrogenation reaction of carbonyl compounds, particularly shows high yield (greater than 99%) and enantioselectivity (as high as 99.8% ee) in asymmetric hydrogenation reaction of simple dialkyl ketone, and has practical value.

Kinetic resolution of racemic hydroxy ester via asymmetric catalytic hydrogenation and application thereof

The present invention relates to kinetic resolution of racemic δ-hydroxyl ester via asymmetric catalytic hydrogenation and an application thereof. In the presence of chiral spiro pyridyl phosphine ligand Iridium catalyst and base, racemic δ-hydroxyl esters were subjected to asymmetric catalytic hydrogenation to obtain extent optical purity chiral δ-hydroxyl esters and corresponding 1,5-diols. The method is a new, efficient, highly selective, economical, desirably operable and environmentally friendly method suitable for industrial production. An optically active chiral δ-hydroxyl ester and 1,5-diols can be obtained at very high enantioselectivity and yield with relatively low usage of catalyst. The chiral δ-hydroxyl ester and 1,5-diols obtained by using the method can be used as a critical raw material for asymmetric synthesis of chiral drugs (R)-lisofylline and natural drugs (+)-civet, (?)-indolizidine 167B and (?)-coniine.

PK/PD studies on non-selective PDE inhibitors in rats using cAMP as a marker of pharmacological response

In recent years, phosphodiesterase (PDE) inhibitors have been frequently tested for the treatment of experimental inflammatory and immune disorders. It is suggested that anti-inflammatory properties of PDE inhibitors are related to their ability to increase cAMP levels. The aim of this study was to verify the hypothesis that cAMP may be a useful marker of pharmacological response following administration of non-selective PDE inhibitors (pentoxifylline and (±)-lisofylline) to endotoxemic rats. Male Wistar rats were administered LPS (1?mg?kg?1, i.v.) simultaneously with either compound given at two doses (40 and 80?mg?kg?1, i.v.). Levels of cAMP and both compounds in animal plasma were measured by the validated HPLC methods. Pharmacokinetic-pharmacodynamic analysis was performed using basic and modified indirect response (IDR) models II in Phoenix WinNonlin. The results of this study indicate that, in contrast to pentoxifylline, (±)-lisofylline demonstrates a non-linear pharmacokinetics in rats with endotoxemia. In vitro study using human recombinant PDE4B and PDE7A revealed the occurrence of additive interaction between studied compounds. Moreover, (±)-lisofylline is a more potent inhibitor of PDEs compared to pentoxifylline, as evidenced by lower IC50 values. Following administration of both compounds, levels of cAMP in rat plasma increased in a dose-dependent manner. The modified IDR model II better described cAMP levels over time profiles. The validity of the proposed marker was confirmed by measuring plasma TNF-α levels in the studied animals. In conclusion, cAMP may be used in future preclinical and clinical studies of some PDE inhibitors to evaluate the drug concentration–effect relationship.

COMPOSITIONS AND METHODS FOR THE TREATMENT OF CHRONIC DISEASES AND INFLAMMATORY DISORDERS

The invention relates to the compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, and methods for the treatment of chronic diseases and inflammatory disorders may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of intermittent claudication, obstructed arteries in the limbs, vascular dementia, Peyronie's disease, neuropathic injuries, sickle cell disease, nausea and headaches in the mountains (altitude sickness), acute alcoholic and non-alcoholic steatohepatitis, alcoholic liver disease, fibrotic lesions induced by radiation therapy for cancer, cytokine release syndrome, endometriosis, venous disease, inflammation, cancer, stroke, thrombosis, sepsis, gangrene, infection, type 1 diabetes, type 2 diabetes, pancreatic beta cell degeneration, beta cell dysfunction, respiratory diseases, rheumatoid arthritis, arthritis, osteoarthritis and vascular disease.