Treatment of gastroparesis with triazaspiro[4.5]decanone

1. A method of treating or alleviating one or more symptoms of gastroparesis or a disorder characterized by delayed gastric emptying in a subject, or increasing the serum prolactin concentration in a subject, comprising administering to the subject a therapeutically effective amount of a salt of 3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid and maleic acid.

2. The method of claim 1 , wherein the gastroparesis is diabetic or idiopathic gastroparesis.

3. The method of claim 1 , wherein the one or more symptoms are abdominal pain, belching, bloating, early satiety, epigastric pain or discomfort, excess gas, heartburn, loss of appetite, nausea, postprandial fullness, regurgitation, swollen abdomen, vomiting, or a combination thereof.

4. The method of claim 1 , wherein the one or more symptoms are abdominal pain, bloating, early satiety, epigastric pain or discomfort, nausea, postprandial fullness, vomiting, or a combination thereof.

5. The method of claim 1 , wherein the one or more symptoms are belching, bloating, heartburn, indigestion, nausea, regurgitation, vomiting, or a combination thereof.

6. The method of claim 1 , wherein the therapeutically effective amount of the salt of 3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid and maleic acid is the amount sufficient to increase the serum prolactin level to a concentration ranging from about 10 to about 500 ng/mL.

7. The method of claim 6 , wherein the therapeutically effective amount of the salt of 3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid and maleic acid is the amount sufficient to increase the serum prolactin level to a concentration ranging from about 50 to about 200 ng/mL.

8. The method of claim 1 , wherein the molar ratio of the maleic acid to 3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid is about 1.

9. The method of claim 1 , wherein the therapeutically effective amount is ranging from about 1 to about 250 mg per day as measured in the amount of 3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid or the salt.

10. The method of claim 9 , wherein the therapeutically effective amount is ranging from about 5 to 200 mg per day as measured in the amount of 3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid or the salt.

11. The method of claim 9 , wherein the therapeutically effective amount is about 10, about 25, about 50, or about 100 mg per day as measured in the amount of 3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid or the salt.

12. The method of claim 1 , wherein the therapeutically effective amount is the amount sufficient to provide an arithmetic mean AUC ∞ of 3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid ranging from about 1 to about 500 ng·hr/mL.

13. The method of claim 12 , wherein the therapeutically effective amount is the amount sufficient to provide an arithmetic mean AUC ∞ of 3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid ranging from about 10 to about 200 ng·hr/mL.

14. The method of claim 1 , wherein the therapeutically effective amount is the amount sufficient to provide an arithmetic mean peak plasma concentration (C max ) of 3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid ranging from about 1 to about 500 ng/mL.

15. The method of claim 12 , wherein the therapeutically effective amount is the amount sufficient to provide an arithmetic mean peak plasma concentration (C max ) of 3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid ranging from about 5 to about 50 ng/mL.

16. The method of claim 1 , wherein the therapeutically effective amount is the amount sufficient to provide an average steady-state plasma concentration of 3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid ranging from about 1 to about 500 ng/mL.

17. The method of claim 16 , wherein the therapeutically effective amount is the amount sufficient to provide an average steady-state plasma concentration of 3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid ranging from about 5 to about 100 ng/mL.

18. The method of claim 1 , wherein the therapeutically effective amount is the amount sufficient to provide an average trough plasma concentration of 3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid ranging from about 0.01 to about 50 ng/mL.

19. The method of claim 18 , wherein the therapeutically effective amount is the amount sufficient to provide an average trough plasma concentration of 3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid ranging from about 0.2 to about 10 ng/mL.

20. The method of claim 1 , wherein the salt of 3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid and maleic acid is administered orally or parenterally.

21. The method of claim 20 , wherein the salt of 3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid and maleic acid is administered under fasted conditions.

22. The method of claim 21 , wherein the salt of 3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid and maleic acid is administered at least 30 minutes before a meal.

23. The method of claim 21 , wherein the salt of 3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid and maleic acid is administered at least 1 hour after a meal.