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New stable salt of 5,10-methylene-(6R)-tetrahydrofolic acid

a technology of tetrahydrofolic acid and hemisulfate salt, which is applied in the direction of biocide, drug composition, inorganic non-active ingredients, etc., can solve the problems of inability to predict the existence of a stable solid (polymorphic) form of a (known) chemical compound with suitable properties, cell death and delay of tumor growth,

Inactive Publication Date: 2016-06-30
MERCK & CIE KG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is concerned with a new salt form of a compound called (6R)-5,10-CH2-THF, which is a hemisulfate salt. This salt form is in a pure form and is in crystalline form, preferably in crystalline anhydrous form. The hemisulfate salt produces a distinct X-ray pattern and has a unique FT-Raman spectrum. The patent is also directed to pharmaceutical compositions containing this new salt and methods for using it in cancer chemotherapy. The technical effect of the invention is the provision of a pure and effective new hemisulfate salt of (6R)-5,10-CH2-THF for use in cancer treatment.

Problems solved by technology

This causes direct inhibition of DNA synthesis and repair, which ultimately results in cell death and delay of tumor growth.
However, there are undesirable properties associated with 5,10-CH2-THF, which up to date limited its pharmaceutical use.
Yet, the existence of a stable solid (polymorphic) form of a (known) chemical compound with these suitable properties cannot be foreseen.

Method used

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  • New stable salt of 5,10-methylene-(6R)-tetrahydrofolic acid
  • New stable salt of 5,10-methylene-(6R)-tetrahydrofolic acid
  • New stable salt of 5,10-methylene-(6R)-tetrahydrofolic acid

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of (6R)-5,10-CH2-THF hemisulfate salt

[0062]A solution of (6S)-tetrahydrofolic acid (16 mmol, 7.93 g) in 78.0 g distilled water was provided in a roundbottom flask at room temperature under N2. The pH of this solution was adjusted to pH 11 by adding (slowly) a 32% NaOH solution. As soon as the solution became clear, a 1.00M HCl solution was added to adjust the pH of the solution to 8.3 at 25° C. The obtained clear solution was cooled to about 0° C., at which temperature it showed a pH of 8.8. By addition of 1M HCl the pH was adjusted to pH=8.6 and 1.44 g of a 36.8% HCHO solution (110 mol %) were added in one portion. Upon completion of the addition the solution was stirred at 0° C. (ice bath) for 1 hour. Active charcoal (0.2 g, Norit C Extra) was added and the reaction mixture was stirred for 30 minutes at 0° C. and then cold filtered over a suction filter to obtain a clear solution, which was used in step (b) without further purification.

[0063](b) A mixture of 55 ml 1M H...

example 2

Characterization

[0064](a) The FT Raman spectrum of (6R)-5,10-CH2-THF hemisulfate salt, recorded using a nominal laser power level of 300 mW and 64 scans is shown in FIG. 1.[0065](b) The corresponding powder X-ray diffractogram, recorded in transmission mode, is shown in FIG. 2.[0066](c) The TG-FTIR thermogram of (6R)-5,10-CH2-THF hemisulfate salt is shown in FIG. 3. It was carried out under N2 flow (to avoid oxidative degradation). The sample shows a loss of 0.5 wt % H2O from ca. 40° C. to 210° C., which is residual water (due to either hygroscopicity or incomplete drying). Decomposition occurs only above 210° C.[0067](d) The DSC thermogram of (6R)-5,10-CH2-THF hemisulfate salt is shown in FIG. 4. Prior to the first heating scan, the sample was equilibrated for three minutes under gaseous nitrogen flow and lost 0.6 wt.-% of its mass during that time. This is consistent with the water content observed in the TG-FTIR thermogram (see FIG. 3) and confirms that this water is loosely boun...

example 3

Stability Testing of (6R)-5,10-CH2-THF hemisulfate salt

[0072](a) Suspension equilibration of (6R)-5,10-CH2-THF hemisulfate salt as starting material at temperatures other than room temperature in a variety of solvents and mixture are summarized in Table 10:

TABLE 10Suspension equilibration stability of(6R)-5,10-CH2-THF hemisulfate saltTemper-Durationature(h: hours;Observa-Solvent(s)(° C.)d: days)tionMeOH / formic acid 1:1502 hNo changeAcOH saturated with L-ascorbic acid501 dNo changeTHF with ~2 mM L-ascorbic acid403 dNo change2-PrOH with ~2 mM L-ascorbic acid403 dNo changePEG4500 / EtOH 1:9 saturated with507 dNo changeL-ascorbic acidH2O 56 dNo changeformic acid / THF 1:310-206 dNo changeAcOH saturated with L-ascorbic acid505 dNo changeMeCN saturated with L-ascorbic acid505 dNo change

[0073](b) Stability in 85% ethanol at room temperature

[0074](6R)-5,10-CH2-THF hemisulfate salt (3.01 g) was dispersed in 100 ml 85% EtOH at room temperature and stirred for 5 h, then filtered and dried at 30° C...

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Abstract

The present invention is directed towards the hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid, preferably in substantially crystalline form, as well as pharmaceutical compositions and uses thereof in therapy, preferably chemotherapy.

Description

FIELD OF TECHNOLOGY[0001]The present invention is directed towards the hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid, preferably in substantially crystalline form, as well as pharmaceutical compositions and uses thereof in therapy, preferably chemotherapy.BACKGROUND OF THE INVENTION[0002]The reduced folate 5,10-methylene-5,6,7,8-tetrahydrofolate (5,10-CH2-THF) is known for its efficacy as a cytostatic agent and has been preferably administered in combination with fluorinated pyrimidines, such as 5-fluorouracil (5-FU), in the treatment of solid tumors (Seley, K. L. IDrugs 4 (1), 99, 2001). 5,10-CH2-THF achieves its chemotherapeutic effect together with the base analogue and 5-FU metabolite 5-FdUMP by inhibiting the enzyme thymidylate synthase (TS). TS catalyses the conversion of deoxyuridylate (dUMP) to deoxythymidylate (dTMP), which is an essential building block for DNA synthesis. Deactivation of TS occurs by formation of a covalent, ternary inhibition complex betwee...

Claims

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Application Information

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IPC IPC(8): C07D487/14
CPCC07D487/14A61P35/00A61K31/519C07D475/04A61K9/19A61K47/02A61K47/12C07D475/12C07D475/14A61P43/00A61K9/20A61K9/48A61K9/0019A61K2300/00C07B2200/13A61K45/06
Inventor MOSER, RUDOLFGROEHN, VIOLAEGGER, THOMASAMMANN, THOMAS
Owner MERCK & CIE KG
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