Nucleoside analog salts with improved solubility and methods of forming same

Patent metadata

Field	Value
Publication number	US-2016002240-A1
Application number	US-201414770655-A
Country	US
Kind code	A1
Filing date	Mar 17, 2014
Priority date	Mar 15, 2013
Publication date	Jan 7, 2016
Grant date	—

Abstract

Disclosed are salts of nucleoside analogs and methods of forming the salts. An anion of a nucleoside analog is paired with a permanent counter cation to form a salt that has decreased melting point and increased aqueous solubility compared to the nucleoside compound prior to the salt formation. Also a cation of a nucleoside analog is paired with a permanent counter anion to form a salt that has decreased melting point and increased aqueous solubility compared to the nucleoside compound prior to the salt formation. The nucleoside analog in some embodiments has therapeutic activity such as antiviral. The permanent counter cation or anion in some embodiments has bioactivity such as antibacterial or being a vitamin.

First claim

1 . A salt, comprising: at least one kind of anion that is anion of a nucleoside analog and at least one kind of cation that is a permanent counter cation, or at least one kind of cation that is a cation of a nucleoside analog and at least one kind of anion that is a permanent counter anion, wherein the aqueous solubility of the salt is greater than the aqueous solubility of the nucleoside analog.

2 . The salt of claim 1 , wherein the nucleoside analog comprises an ionizable purine or pyrimidine base.

3 . The salt of claim 1 , wherein the nucleoside analog comprises a guanosine analog antiviral drug.

4 . The salt of claim 3 , wherein the guanosine analog antiviral drug comprises acyclovir or a pharmaceutically effective salt thereof.

5 . The salt of claim 1 , wherein the cation is an aprotic cation including quaternary nitrogen or a phosphorous or sulfur-containing analog thereof.

6 . The salt of claim 1 , wherein the cation is an ammonium cation of the structure NR 1 R 2 R 3 R 4 , wherein R 1 , R 2 , R 3 , and R 4 are each independently selected from substituted or unsubstituted C 1-20 alkyl, substituted or unsubstituted C 2-20 alkenyl, substituted or unsubstituted C 2-20 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted C 1-20 heteroalkyl, substituted or unsubstituted C 2-20 heteroalkenyl, substituted or unsubstituted C 2-20 heteroalkynyl, or substituted or unsubstituted heteroaryl, or substituted or unsubstituted carbonyl.

7 . The salt of claim 1 , wherein the cation is a phosphonium cation of the structure + PR 1 R 2 R 3 R 4 , wherein R 1 , R 2 , R 3 , and R 4 are each independently selected from substituted or unsubstituted C 1-20 alkyl, substituted or unsubstituted C 2-20 alkenyl, substituted or unsubstituted C 2-20 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted C 1-20 heteroalkyl, substituted or unsubstituted C 2-20 heteroalkenyl, substituted or unsubstituted C 2-20 heteroalkynyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted carbonyl.

8 . The salt of claim 1 , wherein the cation is a sulfonium cation of the structure + SR 1 R 2 R 3 wherein R 1 , R 2 , and R 3 are each independently selected from substituted or unsubstituted C 1-20 alkyl, substituted or unsubstituted C 2-20 alkenyl, substituted or unsubstituted C 2-20 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted C 1-20 heteroalkyl, substituted or unsubstituted C 2-20 heteroalkenyl, substituted or unsubstituted C 2-20 heteroalkynyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted carbonyl.

9 . The salt of claim 1 , wherein the cation is selected from the group consisting of N,N,N,N-tetraalkylammonium, N,N-dialkylpyrrolidinium, N-substituted pyridinium, N-substituted picolinium, N,N-disubstituted imidazolium, tetraalkylphosphonium, and trialkylsulfonium.

10 . (canceled)

11 . The salt of claim 1 , wherein the cation is an antibacterial cation.

12 . The salt of claim 1 , wherein the cation is a long-chain tetraalkylammonium compound.

13 . The salt of claim 1 , wherein the anion of the nucleoside analog comprises anion of acyclovir and the cation is selected from a group consisting of choline, tetrabutylphosphonium, tributylmethylammonium, and trimethylhexadecylammonium.

14 . The salt of claim 1 , wherein the aqueous solubility of the salt is at least 100 times greater than the aqueous solubility of the nucleoside analog.

15 . (canceled)

16 . (canceled)

17 . The salt of claim 1 , wherein the salt is an ionic liquid at a temperature from about −30° C. to about 150° C.

18 . The salt of claim 1 , wherein the salt is an ionic liquid at a temperature from about 0° C. to about 120° C.

19 . The salt of claim 1 , wherein the salt is choline acyclovir.

20 . The salt of claim 1 , wherein the salt is tributylmethylammonium acyclovir or trimethylhexadecylammonium acyclovir.

21 . The salt of claim 1 , wherein the salt is tetrabutylphosphonium acyclovir.

22 . The salt of claim 1 , wherein the salt is acyclovir docusate or acyclovir chloride.

23 . The salt of claim 1 , wherein the anion is fluoride, chloride, bromide, iodide, C 1 -C 6 carboxylate, trifluoroacetate, docusate, saccharinate, acesulfamate, piperacillinate, penicillinate, folate, ibuprofenate, salicylate, acetylsalicylate, sulfacetamidate, naproxenate, benzoate, diclofenac, trans-cinnamate, or long chain polyunsaturated fatty acid carboxylate.

24 . (canceled)

25 . A method of preventing and treating viral infection in an individual, the method comprising administering an effective amount of the salt of claim 1 to an individual.

26 - 35 . (canceled)

Assignees

• Univ Alabama

Inventors

• Rogers Robin D

Classifications

• C07C215/40

  with quaternised nitrogen atoms bound to carbon atoms of the carbon skeleton · CPC title

• C07F9/5407

  Acyclic saturated phosphonium compounds · CPC title

• C07C309/17

  containing carboxyl groups bound to the carbon skeleton · CPC title

• C07C211/63

  having quaternised nitrogen atoms bound to acyclic carbon atoms · CPC title

• C07D473/18 Primary

  one oxygen and one nitrogen atom, e.g. guanine · CPC title