Enantiomers of the 1′,6′-isomer of neplanocin A

Patent metadata

Field	Value
Publication number	US-9657048-B2
Application number	US-201514817817-A
Country	US
Kind code	B2
Filing date	Aug 4, 2015
Priority date	Aug 4, 2014
Publication date	May 23, 2017
Grant date	May 23, 2017

Abstract

Enantiomers of 1′,6′-isoneplanocin, including derivatives of the enantiomers of 1′,6′-isoneplanocin, are disclosed along with novel synthetic methods. In particular, a substituted cyclopentane epoxide is synthesized into the enantiomers of 1′,6′-isoneplanocin. Enantiomers of carbocyclic nucleoside analogs of 3-deazaneplanocin to provide D- and L-like 1′,6′-iso-3-deazaneplanocin are also disclosed. The small molecule chemotherapeutic compounds beneficially provide DNA and RNA antiviral activity, demonstrating activity towards, for example, human cytomegalovirus, measles, Ebola, norovirus, dengue, vaccinia and HBV. Compounds exhibiting reduced S-adenosylhomocysteine hydrolase inhibitory effects are disclosed and provide improved toxicity profiles in comparison to neplanocin. The invention provides improved prophylactic and/or therapeutic antiviral efficacy.

First claim

What is claimed is:

1. A neplanocin compound of one of the following formulae:

a pharmaceutically-acceptable prodrug precursor thereof, or salt thereof;
Wherein
R is a hydrogen or a hydroxyl group, halogen, or C 1 -C 4 alkyl optionally substituted with a hydroxyl group,
R2′ is a hydrogen or a hydroxyl group, halogen, or C 1 -C 4 alkyl optionally substituted with a hydroxyl group,
R3′ is a hydrogen or a hydroxyl group, halogen, or C 1 -C 4 alkyl optionally substituted with a hydroxyl group,
R6′ is a hydrogen or halogen,
W is a hydrogen or a halogen,
X is NH 2 , NHR″, NR′R″, NHOH, or hydrogen (wherein the R′ and R″ independently are alkyl, aryl or arylalkyl),
Y is a hydrogen, a hydroxyl group, CH 2 OH, CH 2 NH 2 NHR′, NR′R″ (wherein the R″ and R′ are alkyl, aryl or arylalkyl), CH 2 X (wherein X is a halogen), or a C 1 -C 4 alkyl optionally substituted with a hydroxyl group,
Y′ is a hydrogen, CH 2 OH, CH 2 NH 2 , NRR′, NHR″ (wherein the R″ and R′ are independently alkyl, aryl or arylalkyl), CH 2 X (wherein X is a halogen), or a C 1 -C 4 alkyl optionally substituted with a hydroxyl group, and
Z is a hydrogen, halogen, alkyl or substituted alkyl, or cyano.

2. The neplanocin compound of claim 1 , wherein the formula is the following:

or a pharmaceutically-acceptable prodrug precursor thereof, or salt thereof,
Wherein
R is a hydrogen or a hydroxyl group,
Y′ is a hydrogen, CH 2 OH, and
X is NH 2 or hydrogen.

3. The neplanocin compound of claim 1 , wherein the formula is one of the following:

or a pharmaceutically-acceptable prodrug precursor thereof, or salt thereof,
Wherein
R2′ is a hydrogen, hydroxyl group, or halogen,
R3′ is a hydrogen, hydroxyl group, or halogen,
R6′ is a hydrogen or halogen,
W is a hydrogen or a halogen,
X is NH 2 or hydrogen,
Y is a hydrogen, hydroxyl group, CH 2 X (wherein X is a halogen), or C 1 -C 4 alkyl group optionally substituted with a hydroxyl group, and
Z is a hydrogen, halogen, or alkyl group.

4. The neplanocin compound of claim 3 , wherein the formula is one of the following:

5. The neplanocin compound of claim 3 , wherein Z is a halogen.

6. The neplanocin compound of claim 5 , wherein the formula is one of the following:

7. A neplanocin compound of one of the following formulae:

a pharmaceutically-acceptable prodrug precursor or salt thereof,
wherein X is N, CH, or C (halogen).

8. The neplanocin compound of claim 7 , wherein X is CBr.

9. A pharmaceutical composition for treating a subject with a viral infection or in need of prophylactic antiviral treatment comprising: an antiviral sufficient amount of the neplanocin compound of claim 1 to produce antiviral effects and a pharmaceutically acceptable carrier selected from the group consisting of a diluent, adjuvant, excipient, and vehicle.

10. The pharmaceutical composition of claim 9 , wherein the pharmaceutical composition is formulated into tablets, gelcaps, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels, hydrogels, oral gels, pastes, eye drops, ointments, creams, plasters, drenches, delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols.

11. The pharmaceutical composition of claim 9 , wherein the antiviral amount of neplanocin compound is an amount sufficient to improve, inhibit, prevent or ameliorate the viral infection.

12. The pharmaceutical composition of claim 9 , wherein the antiviral effective amount is an amount that prevents the occurrence or one or more symptoms of the infection or reduces the severity of, or the length of time during which the subject suffers from, one or more symptoms of the infection by at least 50%.

13. The pharmaceutical composition of claim 9 , wherein the antiviral effective amount is an amount that reduces viral replication or kills viral cells by at least 50%.

14. A method of therapeutic treatment of a subject against viral infection comprising: administering a therapeutically effective amount of at least one neplanocin compound of claim 1 to a subject in need of antiviral therapeutic treatment.

15. The method of claim 14 , wherein the administering is by ingestion, injection, infusion, or other bodily administration.

16. The method of claim 14 , wherein the virus is a DNA virus.

17. The method of claim 14 , wherein the virus is a RNA virus.

18. The method of claim 14 , wherein the virus is selected from the group consisting of Arenaviridae, Bunyaviridae, Coronaviridae, Flexiviridae, Hepevirus, Orthomyxoviridae, Paramyxoviridae, Picornaviridae, Togaviridae, Herpesviridae,
Papovaviridae,

Poxviridae, hepatic viruses, and norovirus.

19. The method of claim 18 , wherein the virus is human cytomegalovirus (HCMV), measles, Ebola, norovirus (NOV), dengue, vaccinia or hepatitis B virus (HBV).

20. The method of claim 14 , wherein the virus is Ebola and the neplanocin compound is carbocyclic nucleoside having at least one of the formulae:

a pharmaceutically-acceptable prodrug precursor thereof, or salt thereof,
Wherein
R2′ is a hydrogen, hydroxyl group, or halogen,
R3′ is a hydrogen, hydroxyl group, or halogen,
R6′ is a hydrogen or halogen,
W is a hydrogen or a halogen,
X is NH 2 or hydrogen,
Y is a hydrogen or a hydroxyl group, and
Z is a hydrogen, halogen, or alkyl group.

21. The method of claim 14 , wherein the virus is Ebola and the neplanocin compound has at least one of the following formulae:

22. The method of claim 14 , wherein the amount of neplanocin compound administered is an antiviral effective amount sufficient to improve, inhibit, prevent or ameliorate the viral infection.

23. The method of claim 22 , wherein the antiviral effective amount is an amount that prevents the occurrence or one or more symptoms of the infection or reduces the severity of, or the length of time during which the subject suffers from, one or more symptoms of the infection by at least 50%.

24. The method of claim 14 , wherein the enantiomer neplanocin compound are provided for dual mechanisms of antiviral efficacy.

Assignees

• Univ Auburn

Inventors

• Schneller Stewart W
• Liu Chong
• Chen Qi
• Ye Wei

Classifications

• A61P31/20

  for DNA viruses · CPC title

• A61P31/22

  for herpes viruses · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P31/14

  for RNA viruses · CPC title

• C07H19/16 Primary

  Purine radicals · CPC title