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

Patent metadata

Field	Value
Publication number	US-10759750-B2
Application number	US-201716096830-A
Country	US
Kind code	B2
Filing date	Apr 27, 2017
Priority date	Apr 29, 2016
Publication date	Sep 1, 2020
Grant date	Sep 1, 2020

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 its etiology.

First claim

What is claimed is:

1. A compound having formula (I):

including pharmaceutically acceptable salts thereof, wherein:
A is selected from the group consisting of

e is 1 or 2;
g is 1, 2, or 3;
n is 1 or 2;
m is 1, 2, or 3;
q is 1, 2, 3, 4, 5, or 6;
R 1 is selected from the group consisting of hydrogen, C 1-6 linear alkyl, C 3-7 branched alkyl, optionally substituted aryl, C(O)R 2 , C(O)OR 3 , C(O)NR 4a R 4b , SO 2 R 5 , SO 2 NH 2 , and SO 2 NR 5a R 5b ;
each occurrence of R 2 is independently selected from the group consisting of hydrogen, C 1-6 linear alkyl, C 3-7 branched alkyl, C 3-7 cycloalkyl, and optionally substituted aryl;
each occurrence of R 3 is independently selected from the group consisting of C 1-6 linear alkyl, C 3-7 branched alkyl, C 3-7 cycloalkyl, and optionally substituted aryl;
each occurrence of R 4a is independently selected from the group consisting of C 1-6 linear alkyl, C 3-7 branched alkyl, C 3-7 cycloalkyl, and optionally substituted aryl;
each occurrence of R 4b is independently selected from the group consisting of C 1-6 linear alkyl, C 3-7 branched alkyl, C 3-7 cycloalkyl, and optionally substituted aryl;
each occurrence of R 5 is independently selected from the group consisting of C 1-6 linear alkyl, C 3-7 branched alkyl, C 3-7 cycloalkyl, and optionally substituted aryl;
R 5a is selected from the group consisting of C 1-6 linear alkyl, C 3-7 branched alkyl, C 3-7 cycloalkyl, and optionally substituted aryl;
R 5b is selected from the group consisting of C 1-6 linear alkyl, C 3-7 branched alkyl, C 3-7 cycloalkyl, and optionally substituted aryl;
R 6 is selected from the group consisting of hydrogen, C 1-6 linear alkyl, C 3-7 branched alkyl, C 3-7 cycloalkyl, and C(O)R 8 ;
R 7a is selected from the group consisting of hydrogen, C 1-6 linear alkyl, C 3-7 branched alkyl, C 1-6 linear alkoxy, C 3-7 branched alkoxy, and optionally substituted aryl;
R 7b is selected from the group consisting of hydrogen, C 1-6 linear alkoxy, C 3-7 branched alkoxy;
R 7c hydrogen, C 1-6 linear alkyl, C 3-7 branched alkyl, and optionally substituted aryl; each occurrence of R 8 is independently selected from the group consisting of hydrogen, C 1-6 linear alkyl, C 3-7 branched alkyl, and C 3-7 cycloalkyl;
R 9 is selected from the group consisting of hydrogen, C 1-6 linear alkyl, C 3-7 branched alkyl, C 1-6 linear alkoxy, C 3-7 branched alkoxy, optionally substituted aryl, NR 12a R 12b NHC(O)R 13 , NHC(O)OR 13 , NHSO 2 R 5 , and NHSO 2 NH 2 ;
R 10 is selected from the group consisting of hydrogen, C 1-6 linear alkyl, and C 3-7 branched alkyl;
R 11a is selected from the group consisting of hydrogen, C 1-6 linear alkyl, C 3-7 branched alkyl, C(O)R 2 , C(O)OR 3 , C(O)NR 4a R 4b , SO 2 R 5 , and SO 2 NH 2 ;
R 11b is selected from the group consisting of hydrogen, C 1-6 linear alkyl, and C 3-7 branched alkyl; or R 11a and R 11b may optionally be joined together with the atoms to which they are bound to form a ring containing 3, 4, or 5 atoms; or R 11a and R 11b may optionally be joined together with the atoms to which they are bound to form a ring containing 6 or 7 atoms, optionally containing an group selected from oxygen, sulfur and NR 14 ;
each occurrence of R 12a and R 12b is independently selected from the group consisting of hydrogen, C 1-6 linear alkyl, and C 3-7 branched alkyl, or R 12a and R 12b may optionally be joined together with the atoms to which they are bound to form a ring containing 3, 4, 5, 6, or 7 atoms;
each occurrence of R 13 is independently selected from the group consisting of hydrogen, C 1-6 linear alkyl, and C 3-7 branched alkyl;
R 14 is selected from the group consisting of hydrogen, C 1-6 linear alkyl, and C 3-7 branched alkyl;
X is selected from the group consisting of CR 15a R 15b and NR 16 ;
R 15a is selected from the group consisting of hydrogen, C 1-6 linear alkyl, C 3-7 branched alkyl NR 12a R 12b , NHC(O)R 13 , and NHC(O)OR 13 ;
R 15b is selected from the group consisting of hydrogen, C 1-6 linear alkyl, and C 3-7 branched alkyl;
R 16 is selected from the group consisting of hydrogen, C 1-6 linear alkyl, C 3-7 branched alkyl, optionally substituted aryl, optionally substituted benzyl, C(O)R 2 , C(O)OR 3 , C(O)NR 4a R 4b , SO 2 R 5 , and SO 2 NH 2 ; and
R 17a and R 17b are at each occurrence independently selected from the group consisting of hydrogen and C 1-6 alkyl.

2. The compound of claim 1 , wherein the compound of formula (I) is a compound having formula (II):

including pharmaceutically acceptable salts thereof.

3. The compound of claim 1 , wherein the compound of formula (I) is a compound having formula (III):

including pharmaceutically acceptable salts thereof.

4. The compound of claim 1 , wherein the compound of formula (I) is a compound having (IV):

including pharmaceutically acceptable salts thereof.

5. The compound of claim 1 , wherein the compound of formula (I) is a compound having formula (V):

including pharmaceutically acceptable salts thereof.

6. The compound of claim 1 , wherein the compound of formula (I) is a compound having formula (VI):

including pharmaceutically acceptable salts thereof.

7. The compound of claim 1 , wherein the compound of formula (I) is a compound having formula (VII):

including pharmaceutically acceptable salts thereof.

8. The compound of claim 1 , wherein the compound of formula (I) is a compound having formula (VIII):

including pharmaceutically acceptable salts thereof.

9. The compound of claim 1 , wherein the compound of formula (I) is a compound having formula (IX):

including pharmaceutically acceptable salts thereof.

10. The compound of claim 1 , wherein the compound of formula (I) is a compound having formula (X):

including pharmaceutically acceptable salts thereof.

11. The compound of claim 1 , wherein the compound of formula (I) is a compound having formula (XI):

including pharmaceutically acceptable salts thereof.

12. The compound of claim 1 , wherein t

Assignees

• Temple University—Of the Commonwealth System of Higher Education

Inventors

• Abou-Gharbia Magid A
• Blass Benjamin E
• Childers Wayne E
• Ramanjulu Mercy
• Morton George C

Classifications

• C07D471/10

  Spiro-condensed systems · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D401/06

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