Heavy vitamin B12 derivatives
The invention discussed in this application relates to vitamin B12-based compounds that are useful as quantitative standards, particularly for the assessment of vitamin B12 deficiency.
1. A heavy vitamin B12 having a mass shift of at least +7 over unlabelled vitamin B12, wherein the heavy vitamin B12 comprises seven 13 C atoms and the seven 13 C atoms are located in the dimethylbenzimidazole moiety of the vitamin B12; and the heavy vitamin B12 is a compound of formula (I):
or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof,
wherein R is 5′-deoxyadenosyl, OH, H 2 O, CH 3 , or CN.
2. The heavy vitamin B12 of claim 1 , wherein the heavy vitamin B12 has a mass shift of from +7 to +10 over unlabelled vitamin B12.
3. The heavy vitamin B12 of claim 2 , wherein the heavy vitamin B12 has a mass shift of +7 over unlabelled vitamin B12.
4. The heavy vitamin B12 of claim 2 , wherein the heavy vitamin B12 has a mass shift of +9 over unlabelled vitamin B12.
5. The heavy vitamin B12 of claim 1 , wherein the seven 13 C atoms are located in the dimethylbenzimidazole moiety as follows:
6. The heavy vitamin B12 of claim 1 , wherein the heavy vitamin B12 further comprises one or more 2 H atoms.
7. The heavy vitamin B12 of claim 6 , wherein the heavy vitamin B12 further comprises two 2 H atoms.
8. A pharmaceutical composition including the heavy vitamin B12 of claim 1 , and one or more pharmaceutically acceptable carrier substances, diluents or excipients.
9. The heavy vitamin B12 of claim 1 , wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzenesulfonic, ethane disulfonic, 2-hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaieic, hydroiodic, phenylacetic, alkanoic, sodium, potassium, calcium, aluminum, lithium and ammonium salts.
10. The heavy vitamin B12 of claim 1 , wherein at least 90% of molecules in the heavy vitamin B12 have a single mass shift.
11. The heavy vitamin B12 of claim 1 , wherein at least 95% of molecules in the heavy vitamin B12 have a single mass shift.
12. The heavy vitamin B12 of claim 1 , wherein at least 99% of molecules in the heavy vitamin B12 have a single mass shift.
13. The heavy vitamin B12 of claim 1 , wherein the heavy vitamin B12 has less than 10% of vitamin B12 that has a mass shift of less than 7 atomic mass units over unlabelled vitamin B12.
14. The heavy vitamin B12 of claim 1 , wherein the heavy vitamin B12 has less than 5% of vitamin B12 that has a mass shift of less than 7 atomic mass units over unlabelled vitamin B12.
15. The heavy vitamin B12 of claim 1 , wherein the heavy vitamin B12 has less than 1% of vitamin B12 that has a mass shift of less than 7 atomic mass units over unlabelled vitamin B12.
16. The heavy vitamin B12 of claim 6 , wherein the 2 H atoms are also located in the dimethylbenzimidazole moiety of the vitamin B12.
17. The heavy vitamin B12 of claim 1 , wherein the vitamin B12 is cyanocobalamin.
18. The heavy vitamin B12 of claim 1 , wherein the vitamin B12 is hydroxocobalamin.
19. The heavy vitamin B12 of claim 1 , wherein the vitamin B12 is deoxyadenosylcobalamin.
20. The heavy vitamin B12 of claim 1 , wherein the vitamin B12 is methylcobalamin.