Adamantane analogs

Patent metadata

Field	Value
Publication number	US-9301950-B2
Application number	US-201013391519-A
Country	US
Kind code	B2
Filing date	Jul 30, 2010
Priority date	Aug 21, 2009
Publication date	Apr 5, 2016
Grant date	Apr 5, 2016

Abstract

Provided are compounds that are capable of modulating the activity of the influenza A virus via interaction with the M2 transmembrane protein. Also provided are methods for treating an influenza A-affected disease state or infection comprising administering a composition comprising one or more compounds that have been identified as being capable of interaction with the M2 protein.

First claim

What is claimed:

1. A compound having the formula (I):

wherein
X is carbon, —NH(H + Cl − ), alkylene, or alkyleneamino;
R 1 is hydrogen, deuterium, halo, hydroxyl, nitro, guanidinyl, —(R 6 )-guanidine, fonnamidinyl, carbonyl, oxime, amino, aminocarbonyl, aminooxy, aralkoxy, or aralkylaminooxy;
R 2 and R 3 are each independently hydrogen, deuterium, hydroxyl, carbonyl, amino, nitro, alkyl, trifluoromethyl, aryl, aminocarbonyl, or —C(═Y)—Z,
or
R 2 and R 3 taken together along with the atom to which they are both attached form a six-membered carbocyclic ring or a dithanyl ring optionally substituted with up to three substituents independently selected from alkyl, aryl, aralkyl, hydroxyl, nitro, amino, and

carbonyl;
Y is O, S, or NH;
Z is amino, —NH—NH 2 , methyloxy, or methylthio;
R 4 is hydrogen, deuterium, or amino;
R 5 is hydrogen or carbonyl; and,
R 6 is —CH(CH 3 )— or —NH—C(═NH)—;
or a stereoisomer, partial stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid hydrate, or N-oxide thereof,
with the proviso that if R 1 is amino and X is methylene or ethylene, R 2 , R 3 , R 4 , and R 5 cannot all be hydrogen.

2. The compound according to claim 1 wherein X is carbon, and R 2 , R 3 , R 4 , and R 5 are each hydrogen.

3. The compound according to claim 2 wherein R 1 is guanidinyl, —(R 6 )-guanidine, formamidinyl, carbonyl, oxime, nitro, aminocarbonyl, aminooxy, aralkoxy, or aralkylaminooxy.

4. The compound according to claim 3 wherein R 6 is —CH(CH 3 )— or —NH—C(═NH)—.

5. The compound according to claim 3 wherein R 1 is (5-methyl-3H-imidazol-4-ylmethylene)-amineoxy or hydroxyamino(imino)methyl.

6. The compound according to claim 1 wherein R 1 and R 5 are both hydrogen.

7. The compound according to claim 6 wherein R 2 is hydrogen and R 3 is hydrogen, hydroxyl, carbonyl, amino, nitro, or —C(═Y)—Z.

8. The compound according to claim 7 wherein X is —NH(H + Cl − ) and R 3 is hydrogen, hydroxyl, amino, or —C(═Y)—Z.

9. The compound according to claim 6 wherein R 2 and R 3 taken together along with the atom to which they are both attached form a six-membered carbocyclic ring or a dithanyl ring optionally substituted with up to three substituents independently selected from alkyl, aryl, aralkyl, hydroxyl, nitro, amino, and carbonyl.

10. The compound according to claim 9 wherein R 2 and R 3 taken together form [1,3]Dithian-5-ylamine.

11. The compound according to claim 9 wherein R 2 and R 3 taken together form cyclohexane optionally substituted with up to three substituents independently selected from alkyl, aryl, aralkyl, hydroxyl, nitro, amino, and carbonyl.

12. The compound according to claim 6 wherein R 4 is hydrogen, and R 2 and R 3 are independently selected from hydroxyl, trifluoromethyl, alkyl, amino, nitro, or aryl.

13. The compound according to claim 1 wherein said compound is
N-Adamantan-1-yl-guanidine;
N-(1-Adamantan-1-yl-ethyl)-guanidine;
O-Adamantan-1-yl-hydroxylamine;
5-Methyl-3H-imidazole-4-carbaldehyde O-adamantan-1-yl-oxime;
Adamantane-1-carboxamidine;
Adamantane amidine hydrochloride;
2,2-spiro adamantyl-1,3-dithian-5-aminium chloride;
N-Hydroxy-adamantane-1-carboxamidine;
4-Aza-tricyclo[4.3.1.13,8]undecane;
4-Azonia-tricyclo[4.3.1.13,8]undecane chloride;

Adamantane-1-carbaldehyde;
Adamantan-2-lamine; Adamantane-2,6-dione;
2-Trifluoromethyl-adamantan-2-ol;
2-(4-amino-cyclyhexyl)-adamantane;
1-Nitro-adamantane;
2-Nitro-adamantane;
2-Methyl-adamantan-2-ol;
2-Methyl-adamantan-2-ylamine;
2-Methyl-2-nitro-adamantane;
2-Trifluoromethyl-adamantan-2-ylamine;
2-(1H-Pyrazol-3-yl)-adamantan-2-ol;
2-Aza-tricyclo[3.3.1.13,7]decan-2-ol; Adamantane-1-carboximidic acid methyl ester;
2-Aza-tricyclo[3.3.1.13,7]decane;
2-Aza-tricyclo[3.3.1.13,7]decan-2-ol;
2-Aza-tricyclo[3.3.1.13,7]dec-2-ylamine;
2-Aza-tricyclo[3.3.1.13,7]decane-2-carboxylic acid amide;
2-Aza-tricyclo[3.3.1.13,7]decane-2-carbothioic acid amide;
2-Aza-tricyclo[3.3.1.13,7]decane-2-carboxamidine;
2-Aza-tricyclo[3.3.1.13,7]decane-2-carboximidic acid methyl ester;
2-Aza-tricyclo[3.3.1.13,7]decane-2-carboximidothioic acid methyl ester;

2-Aza-tricyclo[3.3.1.13,7]decan-1-ol;
1-Chloro-2-aza-tricyclo[3.3.1.13,7]decane;
or a stereoisomer, partial stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid hydrate, and N-oxide thereof.

14. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent, or excipient.

Assignees

• Degrado William F
• Wang Jun
• Univ Pennsylvania

Inventors

• Degrado William F
• Wang Jun

Classifications

• A61K31/44 Primary

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title

• C07D339/08

  Six-membered rings · CPC title

• A61P31/16

  for influenza or rhinoviruses · CPC title

• C07D471/08

  Bridged systems · CPC title

• C07D233/61

  with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms · CPC title