Nucleosides with antiviral and anticancer activity

Patent metadata

Field	Value
Publication number	US-2016159845-A1
Application number	US-201615044853-A
Country	US
Kind code	A1
Filing date	Feb 16, 2016
Priority date	Dec 9, 2004
Publication date	Jun 9, 2016
Grant date	—

Abstract

The invention provides a compound of formula I:

wherein R 1 -R 6 and X have any of the values described herein, as well as pharmaceutical compositions comprising such compounds and therapeutic methods comprising the administration of such compounds.

First claim

What is claimed is:

1 . A compound of formula I:

wherein:
R 1 is adenine, guanine, cytosine, thymine, 3-deazaadenine, or uracil, optionally substituted by 1, 2, or 3 U; wherein each U is independently halo, hydroxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, hydroxy(C 1 -C 6 )alkyl, —(CH 2 ) 1-4 P(═O)(OR w ) 2 aryl, aryl(C 1 -C 6 )alkyl, or NR x R y ;
R 2 and R 6 are each independently hydrogen, halo, hydroxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, azido, cyano, —N(R z )C(═O)N(R aa )(R ab ), —N(R z )C(═O)OR ac , or NR ad R ae , provided that one of R 2 and R 6 is hydroxy halo, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, trifluoromethyl, cyano, or NR ad R ae ;
R 3 is hydrogen, halo, hydroxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, azido, cyano, —N(R z )C(═O)N(R aa )(R ab ), —N(R z )C(═O)OR ac , or NR ad R ae ;
R 4 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, aryl(C 1 -C 6 )alkyl, or 2-cyanoethyl;
R 5 is an amino acid, a peptide, or NR a R b ;
R 7 is hydrogen, halo, hydroxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, azido, cyano, —N(R z )C(═O)N(R aa )(R ab ), —N(R z )C(═O)OR ac , or NR ad R ae ;
X is oxy, thio, or methylene;
each R a and R b is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or Het; or R a and R b together with the nitrogen to which they are attached form a nitrogen-linked Het;
each R w is independently hydrogen or (C 1 -C 6 )alkyl;
R x and R y are each independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, phenethyl, or (C 1 -C 6 )alkanoyl; or R x and R y together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
R z is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;
R aa and R ab are each independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl; or R aa and R ab together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
R ac is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;
R ad is hydrogen (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;
R ae is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;
wherein any (C 1 -C 6 )alkyl of R 1 -R 7 , R a , R b , R w , R x , R y , R z , R aa , R ab , R ac , R ad , and R ae is optionally substituted with one or more (e.g. 1, 2, 3, or 4) halo, hydroxy, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, azido, cyano, oxo (═O), (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkyl-, aryl, Het, aryl(C 1 -C 6 )alkyl, or Het(C 1 -C 6 )alkyl, or NR aj R ak ; wherein each R aj and R ak is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;
and wherein any aryl or Het may optionally be substituted with one or more substituents selected from the group consisting of halo, hydroxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, and amino;
or a pharmaceutically acceptable salt thereof;
provided that R 2 and R 3 are each not hydroxy when R 1 is adenine, guanine, cytosine, thymine, or uracil, X is oxy, R 5 is an amino acid or a peptide; R 6 is hydrogen, and R 7 is hydrogen; and; provided R 1 is not 3-deazaadenine, when R 2 is hydroxy; R 3 is hydroxy; R 4 is hydrogen; R 5 a nitrogen linked radical of formula III;

wherein R h is benzyl or 3-indolylmethyl; and R j is methyl; x is oxy, R 6 is hydrogen, and R 7 is hydrogen.

Assignees

• Univ Minnesota

Inventors

• Wagner Carston R

Classifications

• A61P31/14

  for RNA viruses · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/12

  Antivirals · CPC title

• C07H19/19

  with arabinosyl as the saccharide radical · CPC title

• C07H19/20

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · CPC title