Oxysterol-therapeutic agent derivative for bone healing
AssigneeWarsaw Orthopedic, Inc.
InventorsRoger E. Harrington, Jerbrena C. Jacobs
Life of this patent
Estimating the term…
Abstract
Oxysterol-therapeutic agent derivatives or OXY133-therapeutic agent derivative compounds and methods of synthesizing the same are provided for use in promoting osteogenesis, osteoinduction and/or osteoconduction. Methods of synthesizing in a single container OXY133-therapeutic agent derivatives having high yields and improved process safety are also provided. Methods for synthesizing OXY133-therapeutic agent derivatives that are stereoselective are also provided.
Claims20
A method of making a derivative of an oxysterol, the method comprising
- (i) reacting a pregnenolone derivative of formula I:
- with an organometallic compound comprising magnesium chloride to form a diol derivative of formula II:
- (ii) reacting the diol derivative of formula II with a borane compound to form an oxysterol or a pharmaceutically acceptable salt thereof of formula III:
- (iii) reacting the compound of formula III with a therapeutic agent to form an oxysterol derivative of formula IV:
- wherein R1 is a protecting group, R3 is a straight-chain alkyl, and R4 is a bisphosphonate moiety, an antibiotic moiety, or a protein, wherein the diol derivative of formula II is in monohydrate form.
A method of making OXY149 methyl ether, the method comprising forming pregnenolone methyl ether of formula Ia:
- by reacting pregnenolone with CH3X in a base, wherein X is a halide and the base is NaOH, KOH or Ca(OH)2;
- reacting pregnenolone methyl ether of formula Ia with hexyl magnesium chloride in tetrahydrofuran to form pregnenolone diol methyl ether of formula IIb:
- reacting pregnenolone diol methyl ether of formula IIb with BH3 and reacting the resulting borane intermediate with hydrogen peroxide to form a OXY133 methyl ether or a pharmaceutically acceptable salt thereof of formula IIIb:
- reacting the OXY133 methyl ether of formula IIIb with succinic anhydride to provide a succinate based linker and further reacting with a compound of formula V
- to obtain a compound of formula VIa (OXY149 methyl ether)
- wherein the pregnenolone diol methyl ether of formula IIb is in monohydrate form.
Dependencies are inferred from the claim text.