Cysteine protease inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-10647709-B2
Application number	US-201615192113-A
Country	US
Kind code	B2
Filing date	Jun 24, 2016
Priority date	Feb 1, 2012
Publication date	May 12, 2020
Grant date	May 12, 2020

Abstract

The invention provides for novel cysteine protease inhibitors and compositions comprising novel cysteine protease derivatives. The invention further provides for methods for treatment of neurodegenerative diseases comprising administration novel cysteine protease inhibitors or compositions comprising novel cysteine protease inhibitors. In some embodiments, the cysteine protease inhibitors are calpain inhibitors.

First claim

What is claimed:

1. A method of treating Alzheimer's disease in a subject in need thereof comprising administration of a therapeutically effective amount of a compound having a structure of formula (I-a):

wherein,
R 1 is CO 2 H or —CO 2 (C 1 -C 4 )-alkyl;
R 2 is hydrogen or —(C 1 -C 4 )-alkyl;
R 4 is —(CH 2 )-thiazolyl;
R 5 is —(C 1 -C 6 )-alkyl-R 6 , —(C 2 -C 5 )-alkenyl, —(C 2 -C 5 )-alkynyl, —(CH 2 ) n -aryl, or
—(CH 2 ) n -heteroaryl, wherein said aryl or heteroaryl are substituted with one or more R 7 groups;
R 6 is —N(R 10 )C(O)R 8 or —N(R 10 )S(O) 2 R 8 ;
R 7 is independently halogen, —(C 1 -C 3 )-alkyl, aryl, methylenedioxyphenyl, or —S(O) 2 N(R 10 ) 2 , wherein said aryl is optionally substituted with one or more R 9 groups;
R 8 is-(C 1 -C 6 )-alkyl-R 11 or aryl, wherein aryl is optionally substituted with one or more R 9 groups;
R 9 is independently hydrogen, halogen, —(C 1 -C 4 )-alkyl, —(C 1 -C 4 )-haloalkyl, —(C 2 -C 4 )-alkynyl, CN, NO 2 , —S(O) 2 N(R 10 ) 2 , or

R 10 is independently hydrogen or —(C 1 -C 4 )-alkyl;
R 11 is hydrogen of

n is an integer from 0-4; and
p is an integer from 0-3.

2. A method of increasing long-term potentiation in a subject comprising administration of a therapeutically effective amount of a compound having a structure of formula (I-a),

wherein,
R 1 is CO 2 H or —CO 2 (C 1 -C 4 )-alkyl;
R 2 is hydrogen or —(C 1 -C 4 )-alkyl;
R 4 is —(CH 2 )-thiazolyl;
R 5 is-(C 1 -C 6 )-alkyl-R 6 , —(C 2 -C 5 )-alkenyl, —(C 2 -C 5 )-alkynyl, —(CH 2 ) n -aryl, or
(CH 2 ) n -heteroaryl, wherein said aryl or heteroaryl are substituted with one or more R 7 groups;
R 6 is —N(R 10 )C(O)R 8 or —N(R 10 )S(O) 1 R 8 ;
R 7 is independently halogen, —(C 1 -C 3 )-alkyl, aryl, methylenedioxyphenyl, or —S(O) 2 N(R 10 ) 2 , wherein said aryl is optionally substituted with one or more R 9 groups;
R 8 is-(C 1 -C 6 )-alkyl-R 11 or aryl, wherein aryl is optionally substituted with one or more R 9 groups;
R 9 is independently hydrogen, halogen, —(C 1 -C 4 )-alkyl, —(C 1 -C 4 )-haloalkyl, —(C 2 -C 4 )-alkynyl, CN, NO 2 , —S(O) 2 N(R 10 ) 2 , or

R 10 is independently hydrogen or —(C 1 -C 4 )-alkyl;
R 11 is hydrogen or

n is an integer from 0-4; and
p is an integer from 0-3.

3. A method of improving memory in a subject comprising administration of a therapeutically effective amount of a compound having a structure of formula (I-a),

wherein,
R 1 is CO 2 H or —CO 2 (C 1 -C 4 )-alkyl;
R 2 is hydrogen or —(C 1 -C 4 )-alkyl;
R 4 is —(CH 2 )-thiazolyl;
R 5 is-(C 1 -C 6 )-alkyl-R 6 , —(C 2 -C 5 )-alkenyl, —(C 2 -C 5 )-alkynyl, —(CH 2 ) n -aryl, or
(CH 2 ) n -heteroaryl, wherein said aryl or heteroaryl are substituted with one or more R 7 groups;
R 6 is —N(R 10 )C(O)R 8 or)-N(R 10 )S(O) 2 R 8 ;
R 7 is independently halogen, —(C 1 -C 3 )-alkyl, aryl, methylenedioxyphenyl, or —S(O) 2 N(R 10 ) 2 , wherein said aryl is optionally substituted with one or more R 9 groups;
R 8 is-(C 1 -C 6 )-alkyl-R 11 or aryl, wherein aryl is optionally substituted with one or more R 9 groups;
R 9 is independently hydrogen, halogen, —(C 1 -C 4 )-alkyl, —(C 1 -C 4 )-haloalkyl, —(C 2 -C 4 )-alkynyl, CN, NO 2 ,—S(O) 2 N(R 10 ) 2 , or

R 10 is independently hydrogen or —(C 1 -C 4 )-alkyl;
R 11 is hydrogen or

n is an integer from 0-4; and
p is an integer from 0-3.

4. The method of claim 3 , wherein the subject has Alzheimer's Disease.

5. The method of claim 1 , wherein the compound is formulated as a pharmaceutical composition.

6. The method of claim 5 , wherein the pharmaceutical composition is formulated: as a sterile injectable solution or dispersion, for intravenous or oral administration, or for transmucosal or transdermal administration.

7. The method of claim 1 , wherein
(a) R 1 is —CO 2 H or —CO 1 (C 1 -C 2 )-alkyl;
R 2 is hydrogen or —(C 1 -C 2 )-alkyl;
R 5 is —(CH 2 ) n -phenyl, or —(CH 2 ) n -heteroaryl, wherein said phenyl or heteroaryl are substituted with one or more R 7 groups;
R 7 is independently halogen, —(C 1 -C 3 )-alkyl, phenyl, methylenedioxyphenyl, or —S(O) 2 N(R 10 ) 2 , wherein said phenyl is optionally substituted with one or more R 9 groups;
R 9 is independently hydrogen, halogen, —(C 1 -C 2 )-alkyl, —(C 1 -C 2 )-haloalkyl, —(C 2 -C 4 )-alkynyl, CN, NO 2 , —S(O) 2 N(R 10 ) 2 , or

R 10 is independently hydrogen or —(C 1 -C 2 )-alkyl;
n is an integer from 0-2; and
p is an integer from 0-1;
(b) R 1 is —CO 2 H or —CO 2 (C 1 -C 2 )-alkyl;
R 2 is hydrogen or —(C 1 -C 2 )-alkyl;
R 5 is —(CH 2 )-triazolyl, wherein said triazolyl is substituted with an R 7 group;
R 7 is phenyl optionally substituted with one or more R 9 groups;
R 9 is independently halogen, —(C 1 -C 2 )-alkyl, —(C 1 -C 2 )-haloalkyl, —(C 2 -C 4 )-alkynyl, CN, NO 2 , —S(O) 2 N(R 10 ) 2 , or

R 10 is independently hydrogen or —(C 1 -C 2 )-alkyl;
and
p is an integer from 0-1;
(c) R 1 is —CO 2 H or —CO 2 (C 1 -C 2 )-alkyl;
R 2 is hydrogen or —(C 1 -C 2 )-alkyl;
R 5 is —(CH 2 )-triazolyl, wherein said triazolyl is substituted with an R 7 group;
R 7 is phenyl optionally substituted with one or more R 9 groups;
R 9 is independently halogen, —(C 1 -C 2 )-alkyl, —(C 1 -C 2 )-haloalkyl, —(C 2 -C 4 )-alkynyl, CN, NO 2 , —S(O) 2 N(R 10 ) 2 , or

R 10 is independently hydrogen or methyl; and
p is an integer from 0-1; or
(d) R 1 is —CO 2 H or —CO 2 (C 1 -C 2 )-alkyl;
R 2 is hydrogen;
R 5 is

R 7 is phenyl optionally substituted with one or more R 9 groups;
R 9 is independently halogen, —(C 1 -C 2 )-alkyl, —(C 1 -C 2 )-haloalkyl, —(C 2 -C 3 )-alkynyl, NO 2 , —S(O) 2 NH 2 , or

and
p is an integer from 0-1.

8. The method of claim 1 , wherein the compound is:
(2S,3S)-3-((S)-1-(4-(4-fluorophenyl)thiazol-2

Assignees

• Univ Columbia
• Univ Illinois

Inventors

• Thatcher Gregory R J
• Schiefer Isaac Thomas
• Arancio Ottavio
• Fa Mauro

Classifications

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D409/12

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

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D405/12

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

• C07D303/48

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals · CPC title