bisphosphonate-prodrug
A technology of prodrugs and drugs, applied in the field of pharmaceutical compositions containing said prodrugs, capable of solving unstated problems
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Embodiment 1
[0091] Bisphosphonate prodrugs based on doxorubicin prodrugs, 6-maleimidocaproylhydrazone derivatives of doxorubicin (DOXO-EMCH) and 3-(mercaptopropylthio)ethylene oxide are described below. Synthesis of base-diphosphonic acids. DOXO-EMCH is an acid-sensitive thiol-conjugated drug and cleaves and releases doxorubicin at pH 5.0 (F. Kratz et al., J. Med. Chem. 2002, 45, 5523-5533).
[0092]
[0093] A suspension of diethylamine (2.28 mL, 21.91 mmol, 1 eq) and paraformaldehyde (3.29 g, 109.56 mmol, 5 eq) in 65 mL of methanol was warmed until it became a colorless solution. The mixture was cooled to room temperature, and tetraethylmethylene-bisphosphonate 7 was added. Then, the reaction mixture was refluxed for 24 h, and the solvent was removed under reduced pressure. The residue was dissolved in toluene, the solution was concentrated and dried in vacuo, yielding 6.0 g (82%) of colorless oil 8.
[0094] Compound 8 1 H NMR (400MHz, CDCl 3 ): δ[ppm]1.34(t,12H,J=7.1Hz),2.69(tt,...
Embodiment 2
[0104] The following describes the bisphosphonate doxorubicin prodrug EMC-Phe-Lys-PABC cleaved by cathepsin B and the four-step synthetic (3-mercaptopropylthio)ethylene-bisphosphonic acid 12 (see above) - Synthesis of Doxo(15) (EMC=6-maleimidocaproic acid; doxo=doxorubicin; PABC=p-aminobenzyloxycarbonyl):
[0105]
[0106] In a final step, 60 mg (3.4 mmol) of EMC-Phe-Lys-PABC-Doxo 15 dissolved in 14 mL of ethanol was added dropwise to 16.7 mg of 12 (3.4 mmol), and the sample was stirred for 30 min. The solvent was centrifuged and removed under high vacuum yielding 140 mg of 16 as a red powder. Using 15% acetonitrile and 85% 20mM sodium phosphate buffer (pH7.0) as mobile phase A and 30% acetonitrile and 70% 20mM sodium phosphate buffer (pH7.0) as mobile phase B, in Synergi MAX-RP 4μm ( 4.6 x 250mm) HPLC to determine the purity. The gradient was 0 to 35 min to 100% phase B and 35 to 40 min to phase A. The flow rate was 1 mL / min. MS(ESI):m / z1457(M+H) + .
Embodiment 3
[0108] The following describes the bisphosphonate doxorubicin prodrug EMC-Val-Ala- Synthesis of PABC-Doxo(18):
[0109]
[0110] The doxorubicin prodrug 22EMC-Val-Ala-PABC-Doxo was synthesized in the following six steps.
[0111] 2.0g Fmoc-Val-OSu (4.58mmol, 1eq) diluted in 10mL THF was added to a solution of 0.43g H-Ala-OH (4.81mmol, 1.05eq) and dissolved in 15mL H 2 O 0.40 g NaHCO 3 (4.81mmol, 1.05eq) solution. The colorless solution immediately became cloudy. Add H 2 A mixture of O, THF and diethyl ether (60 mL, 1:1:1) until a clear solution was obtained. The solution was stirred well at room temperature. After one week the solvent was removed under reduced pressure, and 30 mL of citric acid (15% in water) and 50 mL of ethyl acetate were added, and the mixture was stirred at room temperature for 1 hour. The phases were separated and the aqueous layer was extracted three times with ethyl acetate (3 x 100 mL). The combined organic phases were dried and the solvent ...
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