Composition for treating bone disorders
View Patent ↗Disclosed is a new composition of matter, substantially enantiomerically pure (1R,6S)-2-Azabicyclo-[4.3.0]nonane-8,8-diphosphonic acid, methods of preparing this new composition of matter, a pharmaceutical composition comprising the new composition, and administration of the composition in methods of treating bone disorders such as osteoporosis, osteolytic bone metastasis, rheumatoid arthritis and osteoarthritis.
1. A pharmaceutical composition comprising (1R,6S)-2-azabicyclo-[4.3.0]nonane-8,8-diphosphonic acid, or a salt thereof, wherein the pharmaceutical composition is substantially free of (1S6R)-2-azabicyclo-[4.3.0]nonane-8,8-diphosphonic acid, and wherein the pharmaceutical composition is characterized by having an enhanced inhibitory effect on farnesyl pyrophosphate synthase compared to the inhibitory effect of racemic 2-azabicyclo-[4.3.0]nonane-8,8-diphosphonic acid or (1S,6R)-2-azabicyclo-[4.3.0]nonane-8,8-diphosphonic acid substantially free of(1R,6S)-2-azabicyclo-[4.3.0]nonane-8,8-diphosphonic acid.
2. The pharmaceutical composition according to claim 1 , wherein the (1R,6S)-2-azabicyclo-[4.3.0]nonane-8,8-diphosphonic acid, or a salt thereof, is free of (1S,6R)-2-azabicyclo-[4.3.0]nonane-8,8-diphosphonic acid.
3. The pharmaceutical composition according to claim 1 further comprising a pharmaceutically acceptable excipient.
4. The pharmaceutical composition according to claim 3 , wherein the pharmaceutical composition comprises a therapeutically effective amount of the (1R,6S)-2-azabicyclo-[4.3.0]nonane-8,8-diphosphonic acid, or a salt thereof.
5. The pharmaceutical composition according to claim 4 , wherein the therapeutically effective amount of the (1R,6S)-2-azabicyclo-[4.3.0]nonane-8,8-diphosphonic acid, or a salt thereof, is effective in modulating calcium metabolism in a recipient animal or human recipient.
6. The pharmaceutical composition according to claim 1 , wherein the (1R,6S)-2-azabicyclo-[4.3.0]nonane-8,8-diphosphonic acid, or a salt thereof, that is substantially free of (1S,6R)-2-azabicyclo-[4.3.0]nonane-8,8-diphosphonic acid is prepared by a method comprising the steps of:
(a) conversion of [4R-4α,9α,9aα]-1,6-Dioxo-4-phenyloctahydropyrido[2,1-c][1,4]oxazine-9-carboxylic acid methyl ester (Compound 6) having the formula:
to form N-(1R-Phenyl-2-hydroxyethyl)-2S,3R -bis (hydroxymethyl)piperidine (Compound 7) having the formula:
(b) conversion of N-(1R-Phenyl-2-hydroxyethyl)-2S,3R-bis(hydroxymethyl)piperidine (Compound 7) having the formula:
to form 2S,3R -bis(hydroxymethyl)piperidine (Compound 8) having the formula:
(c) conversion of 2S,3R-bis(hydroxymethyl)piperidine (Compound 8) having the formula:
to form N-(p-Toluenesulfony1)-(2S,3R)-piperidine-2,3-dimethyl bis-p-toluenesulfonate (Compound 9) having the formula:
(d) conversion of N-(p-Toluenesulfony1)-(2S,3R)-piperidine-2,3-dimethyl bis-p-toluenesulfonate (Compound 9) having the formula:
to form Tetraethyl 2-p-toluenesulfonyl-(1R,6S)-2azabicyclo[4.3.0]nonane-8,8-diphosphonate (Compound 10) having the formula:
and
(e) conversion of Tetraethyl 2-p-toluenesulfonyl-(1R,6S)-2azabicyclo[4.3 .0]nonane-8,8-diphosphonate (Compound 10) having the formula:
to form (1R,6S)-2-azabicyclo-[4.3.0]nonane-8,8-diphosphonic acid having the formula:
or a salt thereof, that is substantially free of (1S,6R)-2-azabicyclo-[4.3.0]nonane-8,8-diphosphonic acid.