Tris(hydroxymethyl)aminomethane salts of a small-molecule GLP1R agonist and pharmaceutical compositions and uses thereof
View Patent ↗The invention provides tris(hydroxymethyl)aminomethane salts of a small-molecule GLP1R agonist. The invention further provides solid compositions comprising tris(hydroxymethyl)aminomethane salts of a small-molecule GLP1R agonist. The invention further provides uses of tris(hydroxymethyl)aminomethane salts of a small-molecule GLP1R agonist, e.g., for treating type 1 diabetes, type 2 diabetes, or obesity.
1. A tris(hydroxymethyl)aminomethane salt of (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid.
2. The salt of claim 1 , where the stoichiometric ratio of tris(hydroxymethyl)aminomethane to (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid in the salt is 1:1.
3. A solid composition comprising a tris(hydroxymethyl)aminomethane salt of (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid.
4. The solid composition of claim 3 , where the stoichiometric ratio of tris(hydroxymethyl)aminomethane to (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid in the salt is 1:1.
5. The solid composition of claim 3 , where the solid composition further comprises an evaporation residue.
6. The solid composition of claim 5 , where the evaporation residue comprises at least a portion of the tris(hydroxymethyl)aminomethane salt of (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid.
7. The solid composition of claim 6 , where the evaporation residue further comprises a binder.
8. The solid composition of claim 7 , where the binder is selected from the group consisting of hydroxypropylmethyl cellulose acetate succinate (HPMCAS), polyvinylpyrrolidone (PVP), and hydroxypropylmethylcellulose (HPMC).
9. The solid composition of claim 8 , where the binder is hydroxypropylmethyl cellulose acetate succinate (HPMCAS).
10. The solid composition of claim 7 , where the evaporation residue further comprises a water-soluble surfactant.
11. The solid composition of claim 10 , where the water-soluble surfactant is selected from the group consisting of a polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, and vitamin E d-alpha tocopheryl polyethyleneglycol succinate (vitamin E TPGS).
12. The solid composition of claim 11 , where the water-soluble surfactant is a polyoxyethylene sorbitan fatty acid ester.
13. The solid composition of claim 6 , where the solid composition further comprises a pharmaceutically acceptable basic excipient.
14. The solid composition of claim 13 , where the pharmaceutically acceptable basic excipient is trisodium phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, or a mixture thereof.
15. The solid composition of claim 14 , where the pharmaceutically acceptable basic excipient is a mixture of sodium carbonate and sodium bicarbonate.
16. A method of treating type 2 diabetes, of treating type I diabetes, of treating obesity, or lowering blood glucose, of slowing gastric emptying, of lowering an HbA1c level, of increasing glucose-dependent insulin secretion, of suppressing glucagon secretion, of treating an eating disorder, of modulating a human GLP1 receptor comprising administering to a subject a compound of claim 1 .
17. A method of treating type 2 diabetes, of treating type I diabetes, of treating obesity, or lowering blood glucose, of slowing gastric emptying, of lowering an HbA1c level, of increasing glucose-dependent insulin secretion, of suppressing glucagon secretion, of treating an eating disorder, of modulating a human GLP1 receptor comprising administering to a subject a solid composition of claim 3 .
18. A method of making a solid composition comprising:
mixing a binder and a tris(hydroxymethyl)aminomethane salt of (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid in a solvent to form a solution or suspension; and
removing the solvent from the solution or suspension.
19. The method of claim 18 , wherein the step of removing the solvent comprising spray drying the solution or suspension to form a powder.
20. The method of claim 18 , wherein the step of removing the solvent comprises spraying the solution or suspension onto a solid powder.