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

Patent metadata

Field	Value
Publication number	US-10787478-B2
Application number	US-201916296752-A
Country	US
Kind code	B2
Filing date	Mar 8, 2019
Priority date	Aug 4, 2014
Publication date	Sep 29, 2020
Grant date	Sep 29, 2020

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 method of treatment of a subject against viral infection comprising:
administering a therapeutically effective amount of at least one neplanocin compound to a subject in need of antiviral treatment, said compound comprising a neplanocin compound of one of the following formulae:

or pharmaceutically-acceptable prodrug precursors and salts 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, NRR′, NHOH, or hydrogen (wherein the R and R′ in NHR and NRR′ are alkyl, aryl or araalkyl),
Y is a hydrogen, a hydroxyl group, CH 2 OH, CH 2 NH 2 (NHR, NRR′, wherein the R and R′ are alkyl, aryl or araalkyl), 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, cyano and derivatives therefrom; and

reducing SAHase inhibition indicated by an IC 50 ≥10.0 nM and providing antiviral efficacy without SAHase inhibition-induced toxicity.

2. The method of claim 1 , wherein the administering is by ingestion, injection, infusion, or other bodily administration.

3. The method of claim 1 , wherein the virus is a DNA virus or an RNA virus.

4. The method of claim 1 , 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.

5. The method of claim 1 , wherein the virus is Ebola and the neplanocin compound is L-like carbocyclic nucleoside having the formula:

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 NIH or hydrogen,
Y is a hydrogen or a hydroxyl group, and
Z is a hydrogen, halogen, or alkyl group;

or pharmaceutically-acceptable prodrug precursors and salts thereof.

6. The method of claim 1 , wherein the virus is Ebola and the neplanocin compound having the following formula:

7. The method of claim 1 , wherein the amount of neplanocin compound administered is an antiviral effective amount sufficient to improve, inhibit, prevent or ameliorate the viral infection.

8. The method of claim 1 , wherein said neplanocin compound comprises the formula of the following:

or pharmaceutically-acceptable prodrug precursors and salts thereof,
wherein
R is a hydrogen or a hydroxyl group,
Y is a hydrogen, a hydroxyl group, or CH 2 OH,
X is NH 2 or hydrogen.

9. The method of claim 1 , wherein said neplanocin compound comprises the formula of the following:

or pharmaceutically-acceptable prodrug precursors and salts 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.

10. The method of claim 1 , wherein said neplanocin compound comprises the formula of the following:

11. The method of claim 1 , wherein Z is a halogen.

12. The method of claim 1 , wherein said neplanocin compound comprises the formula of the following:

13. The method of claim 1 , wherein said neplanocin compound comprises the formula of the following:

or pharmaceutically-acceptable prodrug precursors and salts thereof,
wherein X is N, CH, or C (halogen).

14. The method of claim 1 , wherein Xis CBr.

15. The method of claim 1 , wherein the neplanocin compound is formulated into tablets, gel caps, 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.

16. The method of claim 1 , wherein the therapeutically effective amount of neplanocin compound is an amount sufficient to improve, inhibit, prevent or ameliorate the viral infection.

17. The method of claim 1 , wherein the therapeutically effective amount of neplanocin compound is an amount that reduces viral replication or kills viral cells by at least 50%.

Assignees

• Univ Auburn

Inventors

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

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D473/30

  attached in position 6, e.g. hypoxanthine · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P31/22

  for herpes viruses · CPC title

• A61P31/20

  for DNA viruses · CPC title