Patent Evaluation: Vitamin D Analogues for the Treatment of Osteoporosis

Summary

Novelty: Methods for the preparation of novel vitamin D₄ derivatives are described. These derivatives are said to have greater biological activity than has been reported for vitamin D₄. Their toxicity is said to be lower than predicted on the basis of their bipotency. The claimed compounds may also be useful for the treatment of abnormal calcium metabolism.

Biology: Tests on serum calcium levels, duodenal calcium transport and toxicity in rats are summarized for 1α-hydroxy vitamin D₄. An oral LD₅₀ (mg/kg) of 1.0, compares with a value of 1.7 for 1α-hydroxy vitamin D₂. Postmenopausal osteoporotic patients (n=60) showed increased bone density relative to untreated controls (n=30) when given >3.0μg/day of 1α-hydroxy vitamin D₄ over a two year period. Monitoring of calcium, creatinine, hydroxyproline, and urea levels indicated no significant metabolic disturbance in the treatment groups. Increased osteocalcin and calcium absorption are reported for renal disease patients which were given 1α-hydroxy vitamin D₄ over one year (n=15).

Chemistry: 1α-Hydroxy vitamin D₄ is named together with 1,25- and 1,24-dihydroxy vitamin D₄ metabolites, which were generated by human liver cells cultured with the 1α-hydroxy compound. A synthetic route from ergosterol, which involves three claimed intermediates, is also disclosed.

Structure: