Mesylate salt

The ferrioxamines are a family of linear and cyclic siderophores built up from l-amino-5-(hydroxyamino)alkanes and succinic and acetic acids. Figure 47 shows ferrioxamine B, a linear trihydroxamic acid, which is probably the best-known example. The mesylate salt of the deferri form of ferrioxamine B is used in the clinical treatment of iron-overloaded patients. 

As described above, a series of 5-pyridylaminothiazoles had been designed and synthesised as highly potent and selective antagonists at the adenosine A3 receptor (Press et al. 2004). It was essentially an extension of the structure-activity relationship to involve 5-imidazo and 5-triazolo substituted aminothiazoles which enabled the rapid identification of several dual A2B/A3 receptor antagonists with acceptable selectivity over the A and A2a receptors. Of the lead compounds, the mesylate salt of 3-[5-(meth-ylimidazol-l-yl)-2-(pyrazin-2-ylamino)-thiazol-4-yl benzonitrile (QAF805) was considered to be the superior compound (Compound 5f - Press et al. 2005). 

The mesylate salt is formed by dissolving the free base in methanol and by adding methanesulfonic acid (1 eq). The solution is diluted with diethyl ether until the salt crystallizes out of solution. The crystals are collected and dried to afford the mesyl salt of the title compound, MP 215°-216°C. 

The mesylate salt may be formed by dissolving the free base in methanol and methanesulfonic acid (1 eq) is added. 

Sometimes, especially when fluoride sails are used as the reagents for the ring opening of aziridines, the substrate can be activated by quaternization to the corresponding A/.A-dialkyl-aziridinium compound, which reacts more readily with the fluoride anion than the aziridine itself. Thus, the tV.A -diallylaziridinium mesylate salts 23 have been employed in ring opening reactions of aziridine derivatives of pyranosides. " " ... 

Gemifloxacin is off-white, amorphous solid from chloroform-ethanol. It has only a slight characteristic odor. However, the mesylate salt is a white to light brown solid. 

The melting point of lomefloxacin was determined visually (11). The melting range for lomefloxacin was 235-245° C for the solid collected immediately after titrating to pH 7 (the zwitterionic species). The range for the mesylate salt was 314-319° C. The Merck Index reports the melting point for lomefloxacin to be 239-240.5° C and the hydrochloride salt to be 290-300° C. The salt form decomposes at that temperature (12). 

The vast majority of salt forms are developed to enhance the aqueous solubihty of drug substances. In some cases, a salt may be preferred with reduced solubihty for use in suspension formulations where solubihty as low as possible is optimum to prevent Ostwald ripening, for taste masking or to prepare a sustained release product. Chlorpromazine is marketed as a tablet and syrup using the hydrochloride salt but the insoluble embonate salt is used in suspension formulations to extend the duration of achon and minimize taste problems. Occasionahy the selection of a salt with only modest aqueous solubihty may be more suitable for use in tablet products prepared by wet granulation. For example, prochlorperazine maleate is used in Stemehl tablets rather than the highly soluble mesylate salt. 

David, J. Snodin, Residues of genotoxic alkyl mesylates in mesylate salt drug substances real or imaginary problems Regulatory Toxicology and Pharmacology, 45 (1), 79-90, 2006. www.emea.europa.eu/htms/human/swp/swpHn.htm CPMP/SWP/5199/02. 

Nelflnavir mesylate is a protease inhibitor that inhibits human immunodeficiency virus (HIV) protease, the enzyme required to form functional proteins in HIV-infected cells. It is indicated in the treatment or HIV infection in combination with other antiretroviral agents. Nelflnavir is a non-peptidic protease inhibitor that is active against both HIV-1 and HIV-2 and is formulated as the mesylate salt of a basic amine. The mean IC95 for HTV-1 in various in vitro assays is 59 nM. Like most drugs in this class, nelfinavir was a product of rational drug design. 

The synthesis was aimed at improving the formation of the two quaternary mesylate salts 486 and 482. The synthesis of mesylate 486 is the most direct procedure and is described first. 

The 14,15-double bond present in tabersonine was introduced into the /3-ethyl isomer of lactam 491 by treatment with LDA-diphenyl disulfide followed by oxidation and elimination to give the a,fl-unsaturated lactam 492. Murphy s law operated at this point, for upon lithium aluminum hydride reduction, 492 gave only a 5% yield of the amino alcohol 493. An alternative procedure was therefore developed. Hydrolysis gave a carboxylic acid, and treatment with ethyl chloroformate and triethylamine followed by sodium borohydride in aqueous THF gave a lactam alcohol 494, which after silylation was reduced with lithium aluminum hydride to amino alcohol 493 in 58% overall yield from 492. Mesylation and elimination of HC1 in refluxing chloroform gave the unsaturated mesylate salt 482. The same salt was prepared previously by Ziegler and Bennett... 

The general techniques used were also applied to the synthesis of natural alkaloids in the quebrachamine and Aspidosperma series (233). The oxidative cyclization step in the previous step proceeded in only 30-40% yield. In order to improve this process, a more reactive intermediate was used. Condensation of tryptamine with the highly reactive aldehyde-ester 529 gave the lactam 530 as a mixture of C-3 isomers in 90% yield. Lithium aluminum hydride reduction, catalytic reduction, and mesylation gave the familiar mesylate salt 486. Nucleophilic attack by cyanide ion in dimethyl-formamide produced the nine-membered ring intermediates 531 and 532. Hydrolysis and methylation with diazomethane gave vincadine (185) and... 

It seems that under the conditions applied the mesylate salts interconverted presumably via a seco intermediate. 

In order to support this assumption the N -methyl derivative and from that the mesylate salt ( ) was prepared. Reaction of the latter in DMF with NaCN afforded - as expected - a single product i.e. no epimerisation occured. The nitrile was also prepared by selective methylation of the corresponding indole derivative (26). 

Despite the potential advantage of salt formation, many compounds do not form salts. Even when salts are formed, they may have limited aqueous solubility. For example, aqueous solubilities of hydrochloride and mesylate salt forms of the weakly basic drug ziprasidone were 80 and 890 ttg/mL, respectively, and, because of such low solubility, the dissoiution of salts was incomplete, and the human bioavailability was variable (Thombre et al. 2011). There is also the potential that the salts may convert to the less soluble free base or acid form in the diffusion layer, thus coating the surface of the dissolving solid, and preventing further dissolution of the salt (Serajuddin 2007). 

Fig. 13.3 Structures of the tyrosine kinase inhibitors imatinib, a phenylaminopyrimidine derivative, and the 4-aminoquinazoline derivatives, gefitinib and erlotinib. Imatinib is marketed as the mesylate salt...

Deshpande P, Bhavsar S, Chugh Y, Yeole R, De Souza N, Patel M (2005) Novel polymorphs of racemic dextrorotatory and levorotatory enantiomers of l-cyclopropyl-6-fluoro-8-methoxy-7-(4-amino-3,3-dimethylpiperidinl-yl)-l,4-dihydro-4-oxoquinoline-3-carboxylic acid and hydrochloride and mesylate salts. WO Patent 66154, 21 July 2005 Takahashi Lt, Hagiwara T, Hayakawa 1 (2002) Preparation of fluoroquinoUne drug with reduced effect on the heart. WO Patent 76458,3 Oct 2002... 

Cycloneopentyl, cyclo(dimethylaatinoethyl) pyrophosphate zirconate, di mesyl salt Liquid Color Tan... 

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