Beta lactams as modulators of glutamate uptake and methods for use thereof

Patent metadata

Field	Value
Publication number	US-9975879-B2
Application number	US-201414895681-A
Country	US
Kind code	B2
Filing date	Jun 4, 2014
Priority date	Jun 4, 2013
Publication date	May 22, 2018
Grant date	May 22, 2018

Abstract

Pharmaceutical compositions of the invention comprise compounds, compositions, methods useful for the treatment of drug addiction, drug withdrawal, and diseases or conditions that involve dysregulation of glutamate homeostasis in it etiology.

First claim

What is claimed is:

1. A compound having formula (I):

or hydrates, solvates, pharmaceutically acceptable salts thereof, wherein:

A is selected from the group consisting of
R is selected from the group consisting of hydrogen, C 1-6 linear alkyl, C 1-6 branched alkyl, optionally substituted aryl, C(O)R 2 , C(O)OR 3 , C(O)NR 4a R 4b , SO 2 R 5 , and SO 2 NH 2 ;
R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g and R 1h are each independently selected from the group consisting of hydrogen, C 1-6 linear alkyl, and C 1-6 branch alkyl;
R 2 is selected from the group consisting of C 1-6 linear alkyl, C 1-6 branched alkyl, and optionally substituted aryl;
R 3 is selected from the group consisting of C 1-6 linear alkyl, C 1-6 branched alkyl, and optionally substituted aryl;
R 4a is selected from the group consisting of C 1-6 linear alkyl, C 1-6 branched alkyl, and optionally substituted aryl;
R 4b is selected from the group consisting of C 1-6 linear alkyl, C 1-6 branched alkyl, and optionally substituted aryl;
R 5 is selected from the group consisting of C 1-6 linear alkyl, C 1-6 branched alkyl, and optionally substituted aryl;
R 6 is selected from the group consisting of hydrogen, C 1-6 linear alkyl, and C(O)R 8 ;
R 7a , R 7b , R 7c , and R 7d are each independently selected from the group consisting of are each independently selected from a group consisting of hydrogen, halogen, OH, C 1-6 linear alkyl, C 1-6 branched alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , NHC(O)R 8 , C(O)NHR 8 , C(O)N(R 8 ) 2 , SH, SC 1-6 alkyl, SO 2 NH 2 , SO 2 NHR 8 , SO 2 R 8 , and NHSO 2 R 8 ; and
R 8 is independently selected at each occurrence from a group consisting of hydrogen, C 1-6 linear alkyl, C 1-6 branched alkyl, and C 3-7 cycloalkyl.

2. A compound according to claim 1 wherein R 1b and R 1g are joined together with the atoms to which they are bound to form a ring containing 5, 6, or 7 atoms.

3. A compound according to claim 1 wherein R 1b and R 1f are joined together with the atoms to which they are bound to form a ring containing 5, 6, or 7 atoms.

4. A compound according to claim 1 wherein R 1d and R 1f are joined together with the atoms to which they are bound to form a ring containing 5, 6, or 7 atoms.

5. A compound according to claim 1 wherein R 1b and R 1c are joined together with the atoms to which they are bound to form a ring containing 5 or 6 atoms.

6. A compound of the claim 1 that is:
(3S, 4R)-3-((R)-(1-hydroxy-ethyl)-4-((R)-[1-methyl-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-azetidin-2-one;
tert-butyl 4-((R)-2-((2R,3 S)-3-((R)-1-hydroxyethyl)-4-oxoazetidin-2-yl) propanoyl)piperazine-1-carboxylate;
(3S, 4R)-3-((R)-(1-Hydroxy-ethyl)-4-((R)-(1-methyl-2-oxo-2-piperazin-1-yl-ethyl)-azetidin-2-one;
(3S, 4R)-4-((R)-(1-(4-acetylpiperazin-1-yl)-1-oxopropan-2-yl)-3-((R) (1-hydroxyethyl)azetidin-2-one;
(3 S,4R)-4-((R)-1-(4-ethylpiperazin-1-yl)-1-oxopropan-2-yl)-3-((R)-1-hydroxyethyl)azetidin-2-one;
(3 S,4R)-3-((R)-1-hydroxyethyl)-4-((R)-1-(4-(methyl sulfonyl) piperazin-1-yl)-1-oxopropan-2-yl)azetidin-2-one;
(3 S,4R)-4-((R)-1-(4-cyclohexylpiperazin-1-yl)-1-oxopropan-2-yl)-3-((R)-1-hydroxyethyl)azetidin-2-one;
(3 S,4R)-4-((R)-1-(4-benzoylpiperazin-1-yl)-1-oxopropan-2-yl)-3-((R)-1-hydroxyethyl)azetidin-2-one;
(3 S,4R)-3-((R)-1-hydroxyethyl)-4-((R)-1-oxo-1-(4-phenyl piperazin-1-yl)propan-2-yl)azetidin-2-one;
(3 S,4R)-3-((R)-1-hydroxyethyl)-4-((R)-1-oxo-1-(4-propyl piperazin-1-yl)propan-2-yl)azetidin-2-one;
(3 S,4R)-3-((R)-1-hydroxyethyl)-4-((R)-1-(4-(4-methoxyphenyl) piperazin-1-yl)-1-oxopropan-2-yl)azetidin-2-one;
(3 S,4R)-4-((R)-1-(4-(tert-butyl)piperazin-1-yl)-1-oxopropan-2-yl)-3-((R)-1-hydroxyethyl)azetidin-2-one;
4-((R)-2-((2R,3 S)-3-((R)-1-hydroxyethyl)-4-oxoazetidin-2-yl)propanoyl)piperazine-1-carboxamide;
(3 S,4R)-3-((R)-1-hydroxyethyl)-4-((R)-1-(4-methyl-3,4-dihydro quinoxalin-1(2H)-yl)-1-oxopropan-2-yl)azetidin-2-one;
(R)-1-((2R,3 S)-2-((R)-1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-4-oxoazetidin-3-yl)ethyl acetate;
(R)-1-((2R,3 S)-2-((R)-1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-4-oxoazetidin-3-yl)ethyl butyrate;
(R)-1-((2R,3 S)-2-((R)-1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-4-oxoazetidin-3-yl)ethyl isobutyrate;
(R)-1-((2R,3 S)-2-((R)-1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-4-oxoazetidin-3-yl)ethyl pivalate;
or a pharmaceutically acceptable salt form thereof.

7. A composition comprising an effective amount of at least one compound according to claim 1 .

8. A composition according to claim 7 , further comprising at least one excipient.

9. A composition according to claim 8 , wherein the at least one compound is at least one member selected from the group consisting of:
(3S, 4R)-3-((R)-(1-hydroxy-ethyl)-4-((R)-[1-methyl-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-azetidin-2-one;
tert-butyl 4-((R)-2-((2R,3S)-3-((R)-1-hydroxyethyl)-4-oxoazetidin-2-yl)propanoyl)piperazine-1-carboxylate;
(3S, 4R)-3-((R)-(1-Hydroxy-ethyl)-4-((R)-(1-methyl-2-oxo-2-piperazin-1-yl-ethyl)-azetidin-2-one;
(3S, 4R)-4-((R)-(1-(4-acetylpiperazin-1-yl)-1-oxopropan-2-yl)-3-((R)-(1-hydroxyethyl)azetidin-2-one;
(3 S,4R)-4-((R)-1-(4-ethylpiperazin-1-yl)-1-oxopropan-2-yl)-3-((R)-1-hydroxyethyl)azetidin-2-one;
(3 S,4R)-3-((R)-1-hydroxyethyl)-4-((R)-1-(4-(methyl sulfonyl)piperazin-1-yl)-1-oxopropan-2-yl)azetidin-2-one;
(3 S,4R)-4-((R)-1-(4-cyclohexylpiperazin-1-yl)-1-oxopropan-2-yl)-3-((R)-1-hydroxyethyl)azetidin-2-one;
(3 S,4R)-4-((R)-1-(4-benzoylpiperazin-1-yl)-1-oxopropan-2-yl)-3-((R)-1-hydroxyethyl)azetidin-2-one;
(3 S,4R)-3-((R)-1-hydroxyethyl)-4-((R)-1-oxo-1-(4-phenylpiperazin-1-yl)propan-2-yl)azetidin-2-one;
(3 S,4R)-3-((R)-1-hydroxyethyl)-4-((R)-1-oxo-1-(4-propylpiperazin-1-yl)propan-2-yl)azetidin-2-one;
(3 S,4R)-3-((R)-1-hydroxyethyl)-4-((R)-1-(4-(4-methoxyphenyl)piperazin-1-yl)-1-oxopropan-2-yl)azetidin-2-one;
(3 S,4R)-4-((R)-1-(4-(tert-butyl)piperazin-1-yl)-1-oxopropan-2-yl)-3-((R)-1-hydroxyethyl)azetidin-2-one;
4-((R)-2-((2R, 3 S)-3-((R)-1-hydroxyethyl)-4-oxoazetidin-2-yl)propanoyl)piperazine-1-carboxamide;
(3 S,4R)-3-((R)-1-hydroxyethyl)-4-((R)-1-(4-methyl-3,4-dihydroquinoxalin-1 (2H)-yl)-1-oxopropan-2-yl)azetidin-2-one;
(R)-1-((2R, 3 S)-2-((R)-1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-4-oxoazetidin-3-yl)ethyl acetate;
(R)-1-((2R,3 S)-2-((R)-1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-4-oxoazetidin-3-yl)ethyl butyrate;
(R)-1-((2R,3 S)-2-((R)-1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-4-oxoazetidin-3-yl)ethyl isobutyrate;
(R)-1-((2R,3 S)-2-((R)-1-(4-methylpiperazin-1-yl)-1-oxopropan-2-yl)-4-oxoazetidin-3-yl)ethyl pivalate;
and a pharmaceutically acceptable salt form thereof.

Assignees

• Univ Temple

Inventors

• Abou-Gharbia Magid
• Childers Wayne E
• Martinez Rogelio L
• Ramanjulu Mercy M
• Blass Benjamin E

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D487/08

  Bridged systems · CPC title

• C07D471/08

  Bridged systems · CPC title

• C07D205/08

  with one oxygen atom directly attached in position 2, e.g. beta-lactams · CPC title

• C07D403/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title