Pharmaceutical drug candidates and methods for preparation thereof
View Patent ↗The present invention is directed to methods of preparation of sulfonate derivatized compounds, e.g., 3-amino-1-propanesulfonic acid and 1,3-propanedisulfonic acid disodium salt with increased purity, with reduced potential for toxic by-products, and that are pharmaceutically useful, e.g., for the treatment of amyloidosis.
1. A method of preparation of a purity-enhanced pharmaceutical drug candidate comprising:
opening a sultone ring with a nucleophile, such that a purity-enhanced sulfonate derivatized pharmaceutical drug candidate is produced,
wherein the sulfonate derivatized pharmaceutical drug candidate is selected from the group consisting of 1,3-propanedisulfonic acid disodium salt, 1,3-propanedisulfonic acid, 1,4-butanedisulfonic acid disodium salt, 3-amino-1-propanesulfonic acid, 3-amino-1-propanesulfonic acid, sodium salt, 3-(dimethylamino)-1-propanesulfonic acid, 3-(1,2,3,6-tetrahydropyridinyl)-1-propanesulfonic acid, 3-(1,2,3,4-tetrahydroisoquinolinyl)-1-propanesulfonic acid, 3-(4-cyano-4-phenylpiperidin-1-yl)-1-propanesulfonic acid, 3-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-propanesulfonic acid, 3-[4-(4-bromophenyl)-4-hydroxypiperidin-1-yl]-1-propanesulfonic acid, 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1-propanesulfonic acid, 3-(4-acetyl-4-phenylpiperidin-1-yl)-1-propanesulfonic acid, 3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]-1-propanesulfonic acid, 3-tryptamino-1-propanesulfonic acid, 3-(1,2,3,4-tetrahydro-naphthylamino)-1-propanesulfonic acid, 3-(1-adamantylamino)-1-propanesulfonic acid, 3-(2-norbornylamino)-1-propanesulfonic acid, 3-(2-admantylamino)-1-propanesulfonic acid, 3-(4-(hydroxy-2-pentyl)amino)-1-propanesulfonic acid, 3-nonylamino-1-propanesulfonic acid, and 3-(t-butylamino)-1-propanesulfonic acid.
2. The method of claim 1 , wherein the purity-enhanced pharmaceutical drug candidate comprises less than or equal to 5% of by-products.
3. The method of claim 1 , wherein the purity-enhanced pharmaceutical drug candidate is significantly free of organic by-products.
4. The method of claim 1 , wherein the purity-enhanced pharmaceutical drug candidate is significantly free of nitrogen-containing organic by-products.
5. The method of claim 1 , wherein the purity-enhanced pharmaceutical drug candidate is significantly free of inorganic by-products.
6. The method of claim 1 , wherein the purity-enhanced pharmaceutical drug candidate comprises a sulfonate derivatized compound that is prepared in large scale.
7. The method of claim 1 , wherein the sultone ring opening reaction is represented by:
wherein n=1 or 2; Nu is the nucleophile; M is a hydrogen or a salt-forming group; R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently hydrogen, or a substituted or unsubstituted alkyl group.
8. The method of claim 1 , wherein the sultone ring opening reaction is represented by:
wherein n=1 or 2, and Nu is the nucleophile.
9. The method of claim 1 , wherein the pharmaceutical drug candidate is useful in inhibiting amyloid deposition in a subject.
10. The method of claim 1 , wherein the pharmaceutical drug candidate is useful in treating amyloidosis in a subject.
11. The method of claim 1 , wherein the pharmaceutical drug candidate is useful in treating or preventing an amyloid-related disease in a subject.
12. The method of claim 11 , wherein the amyloid related disease is selected from the group consisting of Alzheimer's disease, cerebral amyloid angiopathy, inclusion body myositis, macular degeneration, AA amyloidosis, AL amyloidosis, Down's syndrome, Mild Cognitive Impairment, type II diabetes, and hereditary cerebral hemorrhage.
13. The method of claim 1 , wherein the sulfonate derivatized pharmaceutical drug candidate is 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof.
14. The method of claim 1 , wherein the sulfonate derivatized pharmaceutical drug candidate is 3-amino-1-propanesulfonic acid or a pharmaceutically acceptable salt thereof.
15. The method of claim 1 , wherein the sulfonate derivatized pharmaceutical drug candidate is 3-(dimethylamino)-1-propanesulfonic acid or a pharmaceutically acceptable salt thereof.
16. The method of claim 1 , wherein the sulfonate derivatized pharmaceutical drug candidate is 3-(1-adamantylamino)-1-propanesulfonic acid or a pharmaceutically acceptable salt thereof.
17. The method of claim 1 , wherein the sulfonate derivatized pharmaceutical drug candidate is 3-(t-butylamino)-1-propanesulfonic acid or a pharmaceutically acceptable salt thereof.