10′,11′-modified saxitoxins useful for the treatment of pain

Patent metadata

Field	Value
Publication number	US-10106549-B2
Application number	US-201515302964-A
Country	US
Kind code	B2
Filing date	Apr 9, 2015
Priority date	Apr 9, 2014
Publication date	Oct 23, 2018
Grant date	Oct 23, 2018

Abstract

Provided herein are compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds and compositions in treating conditions associated with voltage-gated sodium channel function, for example conditions associated with pain. The compounds are 10′,11′-modified saxitoxins. The compounds are optionally additionally modified at carbon 13. In certain embodiments, the 10′,11′-modified saxitoxins are of Formula I: where R 1 , R 2 and R 3 are as described herein. Also provided herein are methods of treating pain in a mammal comprising administering an effective treatment amount of a 10′,11′ modified saxitoxin or composition to a mammal. In an embodiment, the mammal is a human.

First claim

What is claimed is:

1. A compound according to Formula I:

or a pharmaceutically acceptable salt, stereoisomeric form, tautomeric form or polymorphic form thereof, wherein:
R 1 is hydrogen, halogen, unsubstituted alkyl, substituted alkyl, hydroxylalkyl, heteroalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, ammonioalkyl, alkylammonioalkyl, —O-(unsubstituted alkyl), unsubstituted alkenyl, substituted alkenyl, or unsubstituted phenyl; and
R 2 is hydrogen, hydroxyl, O-(unsubstituted alkyl), O-(unsubstituted alkyl)-(unsubstituted or substituted aryl), —O-(unsubstituted alkyl)-(unsubstituted or substituted heteroaryl), ammonioalkyl, alkylammonioalkyl, —OC(O)-(unsubstituted or substituted alkyl), —OC(O)-(unsubstituted or substituted cycloalkyl), —OC(O)-(unsubstituted or substituted heterocycloalkyl), —OC(O)-(unsubstituted or substituted aryl), —OC(O)-(unsubstituted or substituted heteroaryl), —OC(O)-(unsubstituted alkyl)-(unsubstituted or substituted aryl), —OC(O)-(unsubstituted alkyl)-(unsubstituted or substituted heteroaryl), —OC(O)-(unsubstituted or substituted aryl)-O-(unsubstituted or substituted aryl), —OC(O)NH-(unsubstituted or substituted aryl), —OC(O)CR 101 R 102 R 103 , —OC(O)NH-(unsubstituted or substituted heteroaryl), —OC(O)NH-(unsubstituted alkyl)-(unsubstituted or substituted aryl), —OC(O)NH-(unsubstituted alkyl)-(unsubstituted or substituted heteroaryl), —OSO 3 H, —OS(O) 2 -(unsubstituted alkyl), —OS(O) 2 -(unsubstituted or substituted aryl), —OS(O) 2 -(unsubstituted or substituted heteroaryl), —OS(O) 2 NH 2 , —OS(O) 2 O-(unsubstituted alkyl), —OC(O)-(unsubstituted or substituted aryl)-S(O) 2 -(unsubstituted alkyl), —OS(O) 2 NH 2 , or —OC(O)-(unsubstituted or substituted aryl)-S(O) 2 -(unsubstituted alkyl); or
R 1 and R 2 , together with the two carbon atoms to which they are attached, combine to form a six to ten-membered, unsubstituted carbocyclic ring;
R 3 is hydrogen or —C(O)NR 4 R 5 ;
each of R 4 and R 5 is independently hydrogen, unsubstituted alkyl, or substituted alkyl;
R 101 is hydrogen or unsubstituted alkyl; and
R 102 and R 103 are each independently unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl;
with the proviso that at least one of R 1 and R 2 is not hydrogen;
with the proviso that when R 1 is hydrogen and R 2 is hydroxyl, then R 3 is other than hydrogen, —C(O)NH 2 , —C(O)NHOH, and —C(O)NH(CH 2 ) 13 CH 3 ;
with the proviso that when R 1 is propyl or methyl and R 2 is hydroxyl or —OSO 3 H, then at least one of R 4 and R 5 is unsubstituted or substituted alkyl; and
with the proviso that when R 1 is hydrogen and R 2 is —OSO 3 H, then R 3 is —C(O)NR 4 R 5 and R 4 is hydrogen and R 5 is alkyl, or R 4 is alkyl and R 5 is alkyl other than methyl.

2. The compound of claim 1 where
R 1 is hydrogen, halogen, unsubstituted alkyl, substituted alkyl, —O-(unsubstituted alkyl), hydroxylalkyl, heteroalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, ammonioalkyl, alkylammonioalkyl unsubstituted alkenyl, substituted alkenyl, or unsubstituted phenyl; and
R 2 is hydrogen, hydroxyl, —O-(unsubstituted alkyl), —O-(unsubstituted alkyl)-(unsubstituted or substituted aryl), ammonioalkyl, alkylammonioalkyl, —OC(O)-(unsubstituted or substituted alkyl), —OC(O)-(unsubstituted or substituted cycloalkyl), —OC(O)-(unsubstituted or substituted aryl), —OC(O)-(unsubstituted or substituted heteroaryl), —OC(O)-(unsubstituted alkyl)-(unsubstituted or substituted aryl), —OC(O)-(unsubstituted or substituted aryl)-O-(unsubstituted or substituted aryl), —OC(O)NH-(unsubstituted or substituted aryl), —OC(O)CR 101 R 102 R 103 , —OC(O)NH-(unsubstituted or substituted heteroaryl), —OC(O)NH-(unsubstituted alkyl)-(unsubstituted or substituted aryl), —OSO 3 H, —OS(O) 2 -(unsubstituted alkyl), —OS(O) 2 -(unsubstituted or substituted aryl), —OS(O) 2 NH 2 , —OS(O) 20 -(unsubstituted alkyl), —OC(O)-(unsubstituted or substituted aryl)-S(O) 2 -(unsubstituted alkyl), or —OC(O)-(unsubstituted or substituted aryl)-S(O) 2 -(unsubstituted alkyl); or
R 1 and R 2 , together with the two carbon atoms to which they are attached, combine to form a six to ten-membered, unsubstituted carbocyclic ring;
R 3 is hydrogen or —C(O)NR 4 R 5 ;
each of R 4 and R 5 is independently hydrogen, unsubstituted alkyl, or substituted alkyl;
R 101 is hydrogen or unsubstituted alkyl; and
R 102 and R 103 are each independently unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl; and
where each “substituted alkyl” is independently alkyl substituted with 1, 2, 3, 4, or 5 groups independently selected from halogen, hydroxy, alkylcarbonyl, unsubstituted cycloalkyl, unsubstituted aryl, alkylsulfanyl, —NH 2 , —NH-(unsubstituted alkyl), —NH-(unsubstituted alkyl) 2 , —NH(unsubstituted cycloalkyl), —N(unsubstituted cycloalkyl) 2 , ammonio, alkylammonio, —NH(unsubstituted aryl), —N(unsubstituted aryl) 2 , —O-(unsubstituted alkyl), —O-(unsubstituted cycloalkyl), —O-(unsubstituted aryl), nitro, and cyano;
where each “substituted cycloalkyl” is independently cycloalkyl substituted with 1, 2, or 3 groups independently selected from halogen, hydroxyl, alkylcarbonyl, unsubstituted aryl, substituted aryl, alkylsulfanyl, —NH 2 , —NH(unsubstituted alkyl), —NH(unsubstituted alkyl) 2 , —NH(unsubstituted aryl), —N(unsubstituted aryl) 2 ), —O-(unsubstituted alkyl), —O-(unsubstituted cycloalkyl), —O-(unsubstituted aryl), nitro, cyano, unsubstituted alkyl, and substituted alkyl;
where each “substituted heteroaryl” is heteroaryl substituted with 1, 2, 3, or 4 groups independently selected from halo, unsubstituted alkyl, substituted alkyl, hydroxy, alkylcarbonyl, alkylsulfanyl, haloalkylsulfanyl, —NH 2 , —NH(unsubstituted alkyl), —NH(unsubstituted alkyl) 2 , —NH(unsubstituted cycloalkyl), —N(unsubstituted cycloalkyl) 2 ), —NH(unsubstituted aryl), —N(unsubstituted aryl) 2 ), —O-(unsubstituted alkyl), —O-(substituted alkyl), —O-(unsubstituted cycloalkyl), —O-(unsubstituted aryl), nitro, cyano, unsubstituted phenyl, and substituted phenyl; and
where each “substituted aryl” is independently aryl substituted with 1, 2, 3, or 4 groups independently selected from halo, unsubstituted alkyl, substituted alkyl, hydroxy, alkylcarbonyl, alkylsulfanyl, haloalkylsulfanyl, —NH 2 , —NH(unsubstituted alkyl), —NH(unsubstituted alkyl) 2 , —NH(unsubstituted cycloalkyl), —N(unsubstituted cycloalkyl) 2 ), —NH(unsubstituted aryl), —N(unsubstituted aryl) 2 ), —O-(unsubstituted alkyl), —O-(substituted alkyl), —O-(unsubstituted cycloalkyl), phenyloxy (where the phenyl is optionally substituted with 1 or 2 groups selected from halo, haloalkyl, unsubstituted alkyl, alkoxy, and haloalkoxy), nitro, cyano, unsubstituted phenyl, and phenyl substituted with 1 or 2 groups independently selected from halo, haloalkyl, unsubstituted alkyl, alkoxy, and haloalkoxy.

3. The compound of claim 1 wherein:
R 1 is hydrogen, unsubstituted alkyl, hydroxylalkyl, ammonioalkyl, alkylammonioalkyl, —O-(unsubstituted alkyl), unsubstituted alkenyl, or unsubstituted phenyl;
R 2 is hydroxyl, —O-(unsubstituted alkyl), —O-(unsubstituted alkyl)-(unsubstituted or substituted aryl), ammonioalkyl, —OC(O)-(unsubstituted alkyl), —OC(O)-(unsubstituted or substituted aryl), —OC(O)-(unsubstituted aryl)-O-(unsubstituted aryl), —OC(O)NH-(unsubstituted or substituted aryl), —OS(O) 20 H, —OS(O) 2 -(unsubstituted alkyl),
OS(O) 2 -(unsubstituted or substituted aryl), or —OC(O)-(unsubstituted aryl)-S(O) 2 -(unsubstituted alkyl); and
R 3 is hydrogen, —C(O)NH 2 , or —C(O)NH-(unsubstituted alkyl).

Assignees

• Siteone Therapeutics Inc
• Univ Leland Stanford Junior

Inventors

• Pajouhesh Hassan
• Miljanich George
• Mulcahy John
• Du Bois Justin
• Axtman Matthew
• Walker James
• Merit Jeffrey E

Classifications

• A61P25/02

  for peripheral neuropathies · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07D487/14 Primary

  Ortho-condensed systems · CPC title