Compositions and methods for the treatment of metabolic and related disorders

Patent metadata

Field	Value
Publication number	US-2018291013-A1
Application number	US-201715803655-A
Country	US
Kind code	A1
Filing date	Nov 3, 2017
Priority date	Feb 2, 2007
Publication date	Oct 11, 2018
Grant date	—

Abstract

The present invention relates to treatment and/or prevention of one or more metabolic disorders utilizing fatostatin A and/or a derivative and/or analog thereof. In other aspects, the compound for treatment and/or prevention of one or more metabolic disorders utilizes an A-B-C tripartite structure, wherein A, B, and C are identical or non-identical structures and are described in detail herein. In specific aspects, the metabolic disorder includes obesity or diabetes, for example.

First claim

1 . A compound of the general formula:

wherein R 1 is hydrogen, methyl, ethyl or propyl;
R 2 , R 3 , and R 4 are the same or different and are selected from the group consisting of:
a1) hydrogen;
a) hydroxy;
b) substituted or unsubstituted C 1-10 alkyl;
c) substituted or unsubstituted C 2-10 alkenyl;
d) substituted or unsubstituted C 2-10 alkynyl;
e) substituted or unsubstituted C 3-6 cycloalkyl;
f) substituted or unsubstituted aryl;
g) substituted or unsubstituted heteroaryl;
wherein said substitutions in b), c), d), e), f), and/or g) are optionally further substituted with 1-5 groups selected from the group consisting of:
1) hydroxy;
2) —(C═O)R a ;
3) —(C═O)OR a ;
4) —(C═O)H;
5) —(C═O)OH;
6) —O(CH 2 ) n COOR a , wherein n=1-10;
7) halo;
8) cyano;
9) carboxy;
10) amino;
11) mono-substituted amino;
12) di-substituted amino;
13) amido;
14) mono-substituted amido;
15) di-substituted amido; and
16) any combination thereof,
wherein in 2), 3), or 6) R a is a C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl, aryl, or heteroaryl;

h) —(C═O)R a ;
i) —(C═O)OR a ;
j) —(C═O)H;
k) —(C═O)OH;
l) —O(CH 2 ) n COOR a , wherein n=1-10,
wherein in h), i), or l), R a is a C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl, aryl or heteroaryl;
m) halo;
n) cyano;
o) carboxy;
p) amino;
q) mono-substituted amino;
r) di-substituted amino,
s) amido;
t) mono-substituted amido; and
u) di-substituted amido;
wherein one or more of said mono-substituted amino, di-substituted amino, mono-substituted amido, and di-substituted amido have a substitution selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl, aryl, heteroaryl, sulfoxide, sulfone, sulfonate, alkyl sulfonate, sulfonic acid, and any combination thereof,
wherein in u) said alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl are optionally further substituted with 1-5 groups selected from the group consisting of:
i) hydroxy;
ii) —(C═O)R a ;
iii) —(C═O)OR a ;
iv) —(C═O)H;
v) —(C═O)OH;
vi) —O(CH 2 ) n COOR a , wherein n=1-10,
wherein in ii), iii), or vi) R a is a C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl, aryl or heteroaryl;
vii) halo;
viii) cyano;
ix) carboxy;
x) amino;
xi) mono-substituted amino;
xii) di-substituted amino;
xiii) amido;
xiv) mono-substituted amido;
xv) di-substituted amido; and
xvi) any combination thereof,

R 5 is substituted alkyl or —SO 2 R wherein R is a substituted alkyl, aryl or heteroaryl; and
Y 1 is nitrogen, Y 2 and Y 3 are the same or different and are sulfur or —CH═;
or a pharmaceutically acceptable salt thereof.

2 . The compound of claim 1 where the pyridine ring is attached at its 4-position to the thiazole ring.

3 . The compound of claim 2 wherein R 1 is methyl, ethyl, or propyl.

4 .- 7 . (canceled)

8 . The compound of claim 2 where R 2 and R 4 are H.

9 . The compound of claim 8 where R 3 is halo.

10 . The compound of claim 2 where R 2 , R 3 , and R 4 are H.

11 . The compound of claim 10 where R 5 is —SO 2 R.

12 . The compound of claim 11 where R is substituted alkyl.

13 . The compound of claim 12 where the alkyl in R is substituted with 1-5 groups selected from the group consisting of hydroxy, —(C═O)R a , —(C═O)OR a , —(C═O)H, —(C═O)OH, —O(CH 2 ) n COOR a , aryl, heteroaryl, fluoro, chloro, bromo, iodo, cyano, carboxy, amino, mono-substituted amino, di-substituted amino, mono-substituted amido, and di-substituted amido and any combination thereof; and wherein n=1-10 and wherein R a is a C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 3-6 cycloalkyl.

14 . The compound of claim 13 where R is substituted with 1-5 fluoro.

15 . The compound of claim 8 where R 5 is substituted alkyl.

16 . The compound of claim 15 where R 5 is alkyl substituted with 1-5 groups selected from the group consisting of hydroxy, —(C═O)R a , —(C═O)OR a , —(C═O)H, —(C═O)OH, —O(CH 2 ) n COOR a , aryl, heteroaryl, fluoro, chloro, bromo, iodo, cyano, carboxy, amino, mono-substituted amino, di-substituted amino, mono-substituted amido, and di-substituted amido and any combination thereof; and wherein n=1-10 and wherein R a is a C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 3-6 cycloalkyl.

17 . The compound of claim 16 where R 5 is alkyl substituted with aryl or heteroaryl.

18 . A compound of the general formula:

wherein R 1 is hydrogen, methyl, ethyl, or propyl;
R 2 , and R 3 are the same or different and are selected from the group consisting of:
a1) hydrogen;
a) hydroxy;
b) substituted or unsubstituted C 1-10 alkyl;
c) substituted or unsubstituted C 2-10 alkenyl;
d) substituted or unsubstituted C 2-10 alkynyl;
e) substituted or unsubstituted C 3-6 cycloalkyl;
f) substituted or unsubstituted aryl;
g) substituted or unsubstituted heteroaryl;
wherein said substitutions in b), c), d), e), f), and/or g) are optionally further substituted with 1-5 groups selected from the group consisting of:
1) hydroxy;
2) —(C═O)R a ;
3) —(C═O)OR a ;
4) —(C═O)H;
5) —(C═O)OH;
6) —O(CH 2 ) n COOR a , wherein n=1-10;
7) halo;
8) cyano;
9) carboxy;
10) amino;
11) mono-substituted amino;
12) di-substituted amino;
13) amido;
14) mono-substituted amido;
15) di-substituted amido; and
16) any combination thereof,
wherein in 2), 3), or 6) R a is a C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl, aryl, or heteroaryl;

h) —(C═O)R a ;
i) —(C═O)OR a ;
j) —(C═O)H;
k) —(C═O)OH;
l) —O(CH 2 ) n COOR a , wherein n=1-10,
wherein in h), i), or l), R a is a C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl, aryl or heteroaryl;
m) halo;
n) cyano;
o) carboxy;
p) amino;
q) mono-substituted amino;
r) di-substituted amino,
s) amido;
t) mono-substituted amido; and
u) di-substituted amido;
wherein one or more of said mono-substituted amino, di-substituted amino, mono-substituted amido, and di-substituted amido have a substitution selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl, aryl, heteroaryl, sulfoxide, sulfone, sulfonate, alkyl sulfonate, sulfonic acid, and any combination thereof,
wherein in u) said alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl are optionally further substituted with 1-5 groups selected from the group consisting of:
i) hydroxy;
ii) —(C═O)R a ;
iii) —(C═O)OR a ;
iv) —(C═O)H;
v) —(C═O)OH;
vi) —O(CH 2 ) n COOR a , wherein n=1-10,
wherein in ii), iii), or vi) R a is a C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-6 cycloalkyl, aryl or heteroaryl;
vii) halo;
viii) cyano;
ix) carboxy;
x) amino;
xi) mono-substituted amino;
xii) di-substituted amino;
xiii) amido;
xiv) mono-substituted amido;
xv) di-substituted amido; and
xvi) any combination thereof;

Y 1 is nitrogen, Y 2 and

Assignees

• Baylor College Medicine
• Univ Kyoto

Inventors

• Uesugi Motonari
• Wakil Salih J
• Abu-Elheiga Lutfi
• Mao Qian
• Kamisuki Shinji
• Kugimiya Akira
• Watanabe Mizuki

Classifications

• C07D277/52

  to sulfur atoms, e.g. sulfonamides · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D417/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D295/073

  with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title