Peripheral opioid receptor antagonists and uses thereof
The present invention provides a compound of formula I: wherein X − , R 1 , and R 2 are as defined herein, and compositions thereof.
1. A compound of formula I:
wherein:
R 1 and R 2 are each independently C 1-6 aliphatic; and
X − is a suitable anion.
2. The compound according to claim 1 , wherein X − is the anion of a suitable Brønsted acid.
3. The compound according to claim 2 , wherein the Brønsted acid is a hydrogen halide, a carboxylic acid, a sulfonic acid, a sulfuric acid, or a phosphoric acid.
4. The compound according to claim 2 , wherein X − is chloride, bromide, iodide, fluoride, sulfate, bisulfate, tartrate, nitrate, citrate, bitartrate, carbonate, phosphate, malate, maleate, fumarate, sulfonate, methylsulfonate, formate, carboxylate, methylsulfate, trifluoroacetate, or succinate.
5. The compound according to claim 4 , wherein X − is bromide.
6. The compound according to claim 1 , wherein R 1 is C 1-4 aliphatic and R 2 is lower alkyl.
7. The compound according to claim 6 , wherein R 1 is a (cycloalkyl)alkyl group or alkenyl group.
8. The compound according to claim 7 , wherein R 1 is cyclopropyl methyl or allyl and R 2 is methyl.
9. The compound according to claim 1 , wherein said compound is of formula II or II′:
wherein, each X − is a suitable anion.
10. The compound according to claim 1 , wherein said compound is compound II-1 or II-2:
11. A crystalline form of compound II-1 according to claim 10
12. A method comprising the steps of:
(a) providing a sample of (R)—N-methylnaltrexone bromide;
(b) performing an analysis of the sample of (R)—N-methylnaltrexone bromide; and
(c) determining the amount of compound II-1 according to claim 10 in the sample of (R)—N-methylnaltrexone bromide.
13. The method according to claim 12 , wherein step (c) further comprises the step of determining the amount of compound IV-1
in the sample of (R)—N-methylnaltrexone bromide.
14. The method according to claim 13 , wherein step (c) comprises determining that the amount of compound II-1 and compound IV-1 in the sample of (R)—N-methylnaltrexone bromide is less than about 60 ppm, about 10 ppm, about 5 ppm, about 3.3 ppm, about 2.5 ppm, or about 1 ppm total.
15. The method according to claim 13 , wherein step (c) comprises determining that the amount of compound II-1 and compound IV-1 in the sample of (R)—N-methylnaltrexone bromide is less than about 25, about 100, about 125, about 150, about 185, about 187, or about 190 ppm total.
16. A method comprising the steps of:
(a) providing a sample of (R)—N-methylnaltrexone bromide;
(b) providing a sample of the compound II-1 according to claim 10
(c) performing HPLC analysis of the sample of (R)—N-methylnaltrexone bromide and the sample of compound II-1; and
(d) determining the amount of compound II-1 in the sample of (R)—N-methylnaltrexone bromide.
17. A method comprising the steps of:
(a) providing an HPLC chromatogram of a sample of (R)—N-methylnaltrexone bromide;
(b) providing an HPLC chromatogram of a sample of compound II-1:
(c) comparing the HPLC chromatograms and determining the amount of compound II-1 in the sample of (R)—N-methylnaltrexone bromide.
18. A kit comprising the compound of formula I according to claim 1
wherein:
R 1 and R 2 are each independently C 1-6 aliphatic; and
X − is a suitable anion,
and a container containing the compound of formula I.