RIDAFOROLIMUS

• AP 23573
• AP23573
• Deforolimus
• MK 8669
• MK-8669
• MK8669
• Ridaforolimus
• Taltorvic
• UNII-48Z35KB15K

An mTOR inhibitor for the treatment of cancer.

EU WITHDRAWAL IN NOV 2012

Merck, known as MSD outside the U.S. and Canada, announced today that it has formally notified the European Medicines Agency (EMA) of Merck’s decision to withdraw the Marketing Authorisation Application (MAA) for ridaforolimus.

The application for Marketing Authorisation for ridaforolimus was accepted by the EMA in August 2011. At the time of the withdrawal it was under review by the Agency’s Committee for Medicinal Products for Human Use (CHMP). In its letter to the EMA, Merck said that the withdrawal of ridaforolimus was based on the provisional view of the CHMP that the data available to date and provided in the Marketing Authorisation Application were not sufficient to permit licensure of ridaforolimus in the European Union for the maintenance treatment of patients with soft tissue sarcoma or primary malignant bone tumor.

Although the application for these uses was withdrawn, Merck is studying ridaforolimus in combination with other drugs in other tumor types. The withdrawal of the European application of ridaforolimus for the maintenance treatment of patients with soft tissue sarcoma or primary malignant bone tumor does not change Merck’s commitment to the ongoing clinical trials with ridaforolimus.

Ridaforolimus

Description

42-(dimethylphosphinate) Rapamycin (Ridaforolimus) represented by the following formula I:

2. Description of RelatedArt

The mammalian target of Rapamycin (mTOR) is known as a mechanistic target of Rapamycin (H), which is found in the studies of Rapamycin. On the other hand, 42-(dimethylphosphinate) Rapamycin (Ridaforolimus) (I) is a derivative of Rapamycin (II), which is also a kind of mTOR inhibitor. Ridaforolimus (I) can inhibit cell division and possibly lead to tumor cell death. Hence, there are many studies related to solid tumor treatments and blood cancer treatments using Ridaforolimus (I). In addition, in 2011, Merck also applied a certification of this compound against soft tissue and bone cancer.

U.S. Pat. No. 7,091,213 discloses a process for preparing 42-(dimethylphosphinate) Rapamycin (Ridaforolimus) (I), and the process thereof is shown in the following Scheme I.

In this process, a solution of Rapamycin (II) in dichloromethane (DCM) was respectively added with 2,6-di-tert-butyl-4-methylpyridine or 3,5-lutidine as a base, and followed by the addition of a solution of dimethylphosphinic chloride (DMP-Cl) to perform a phosphorylation reaction at 0° C., under a stream of N_2(g). The crude product was purified by flash chromatography (eluted with MeOH/DCM/EtOAc/hexane=1:10:3:3) to provide 42-(dimethyl- phosphinate) Rapamycin (Ridaforolimus) (I), which is a phosphorylated compound at 42-hydroxyl position of Rapamycin (II). In addition, this patent also disclosed a side product of 31,42-bis(dimethyl phosphinate) Rapamycin (III), which is a phosphorylated compound at both 31- hydroxyl position and 42- hydroxyl position of Rapamycin (II).

…………………..

SYNTHESIS

US7091213

Some additional transformations of potential interest to the practitioner are shown below, including the preparation of reagents for generating the described C-43 phosphorus-containing rapalogs:

Preparation of Diakyl/diaryl Chlorophoshates

Preparation of Alkyl Halide Phosphonates

Illustrative routes for using the foregoing sorts of reagents to prepare certain rapalogs of this invention are shown below.

The synthesis of compounds of this invention often involves preparation of an activated form of the desired moiety “J”, such as a phosphoryl chloride as shown above (e.g. (R)(RO)P—Cl or RR′P(═O)—Cl, etc), and reaction of that reagent with rapamycin (or the appropriate rapalog) under conditions yielding the desired product, which may then be recovered from residual reactants and any undesired side products. Protecting groups may be chosen, added and removed as appropriate using conventional methods and materials.

Purification of Compounds of the Invention

A variety of materials and methods for purifying rapamycin and various rapalogs have been reported in the scientific and patent literatures and may be adapted to purification of the rapalogs disclosed herein. Flash chromatography using a BIOTAGE prepacked cartridge system has been particularly effective. A typical protocol is disclosed in the Examples which follow.

Physicochemical Characterization of Compounds of the Invention

The identity, purity and chemical/physical properties of the rapalogs may be determined or confirmed using known methods and materials, including HPLC, mass spectral analysis, X ray crystallography and NMR spectroscopy. High resolution 1D ¹H and ³¹P NMR spectra acquired using a typical relaxation delay of 3 seconds have proved useful, as has reverse phase HPLC analysis (analytical column, 3 micron particle size, 120 ansgstrom pore size, thermostatted to 50° C. with a mobile phase of 50% acetonitrile, 5% methanol and 45% water (all % s by volume), for example, in an isocratic elution system, with elution of product and impurity peaks followed by UV detection at 280 nanometers). Normal phase HPLC may also be used, especially to evaluate the level of residual rapamycin or rapalog by-products. The presence of residual solvent, heavy metals, moisture and bioburden may be assessed using conventional methods.

Example 9

Dimethyl-phosphinic Acid C-43 Rapamycin Ester

Dimethyl-phosphinic Acid C-43 Rapamycin Ester

To a cooled (0° C.) solution of rapamycin (0.1 g, 0.109 mmol) in 1.8 mL of dichloromethane was added 0.168 g (0.82 mmol) of 2,6-di-t-butyl-4-methyl pyridine, under a stream of N₂, followed immediately by a solution of dimethylphosphinic chloride (0.062 g, 0.547 mmol) in 0.2 mL of dichloromethane. The slightly yellow reaction solution was stirred at 0° C., under an atmosphere of N₂, for 3.5 h (reaction monitored by TLC). The cold (0° C.) reaction solution was diluted with ˜20 mL EtOAc then transferred to a separatory funnel containing EtOAc (150 mL) and saturated NaHCO₃ (100 mL). Upon removing the aqueous layer, the organic layer was washed successively with ice cold 1N HCl (1×100 mL), saturated NaHCO₃ (1×100 mL), and brine (1×100 mL), then dried over MgSO₄ and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 1:10:3:3 MeOH/DCM/EtOAc/hexane) to provide 0.092 g of a white solid:

¹H NMR (300 MHz, CDCl₃) d 4.18 (m, 1H), 4.10 (m, 1H), 3.05 (m, 1H), 1.51 (m, 6H);
³¹P NMR (121 MHz, CDCl₃) d 53.6; 1013 m/z (M+Na).

Example 9

Alternative Synthesis

Rapamycin and dichloromethane are charged into a nitrogen-purged reaction flask. The stirred solution is cooled to approximately 0° C. (an external temperature of −5±5° C. is maintained throughout the reaction). A solution of dimethylphosphinic chloride (2.0 molar equivalents) in dichloromethane is then added over a period of approximately 8–13 minutes.

This is followed immediately by the addition of a solution of 3,5-lutidine (2.2 molar equivalents) in dichloromethane over a period of approximately 15–20 minutes. Throughout both additions, the internal temperature of the reaction sssstays below 0° C. The cooled reaction solution is stirred for 1 hour and then transferred, while still cold, to an extractor containing saturated aqueous NaHCO₃ and methyl-t-butyl ether (MTBE), ethyl acetate or diethyl ether. In-process samples are removed at 30 and 60 minute time points.

Samples are prepared in a similar fashion to that described for the reaction workup. Reaction progress is monitored by TLC (1:10:3:3 MeOH/DCM/EtOAc/hexanes) and reverse-phase HPLC analyses. The isolated organic layer is successively washed with ice cold 1N HCl, saturated aqueous NaHCO₃ (2×), saturated aqueous NaCl, and dried over sodium sulfate. Upon filtration and solvent removal, the residue undergoes solvent exchange with acetone followed by concentration in vacuo to provide crude product, which may be analyzed for purity by normal- and reversed-phase HPLC.

…………………….

SYNTHESIS

US20140058081

The process of the present invention is shown in the following Scheme II.

1.  “ARIAD Reports First Quarter 2009 Development Progress and Financial Results- Ridaforolimus New USAN Name to Replace Deforolimus”. ARIAD Pharmaceuticals. 2009. Retrieved 2009-05-07.
2.  “ARIAD – News release”. Phx.corporate-ir.net. Retrieved 2012-10-07.
3.  “ARIAD – News release”. Phx.corporate-ir.net. 2011-03-17. Retrieved 2012-10-07.
4.  “ARIAD – News release”. Phx.corporate-ir.net. 2011-06-06. Retrieved 2012-10-07.