Phosphonic acid derivatives as inhibitors of protein...

Details Phosphonic acid derivatives as inhibitors of protein... Phosphonic acid derivatives as inhibitors of protein...

2000-12-21

2003-06-24

Vollano, Jean F. (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C514S102000, C514S114000, C514S112000, C562S008000, C562S011000

Reexamination Certificate

active

06583126

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to a novel class of phosphonic acid derivatives that are inhibitors of PTP-1B.
Protein tyrosine phosphatases are a large family of transmembrane or intracellular enzymes that dephosphorylate substrates involved in a variety of regulatory processes (Fischer et al., 1991, Science 253:401-406). Protein tyrosine phosphatase-1B (PTP-1B) is a ~50 kd intracellular protein present in abundant amounts in various human tissues (Charbonneau et al., 1989, Proc. Natl. Acad. Sci. USA 86:5252-5256; Goldstein, 1993, Receptor 3:1-15).
Determining which proteins are substrates of PTP-1B has been of considerable interest. One substrate which has aroused especial interest is the insulin receptor. The binding of insulin to its receptor results in autophosphorylation of the receptor, most notably on tyrosines 1146, 1150, and 1151 in the kinase catalytic domain (White & Kahn, 1994, J. Biol. Chem. 269:1-4). This causes activation of the insulin receptor tyrosine kinase, which phosphorylates the various insulin receptor substrate (IRS) proteins that propagate the insulin signaling event further downstream to mediate insulin's various biological effects.
Seely et al., 1996, Diabetes 45:1379-1385 (“Seely”) studied the relationship of PTP-1B and the insulin receptor in vitro. Seely constructed a glutathione S-transferase (GST) fusion protein of PTP-1B that had a point mutation in the PTP-1B catalytic domain. Although catalytically inactive, this fusion protein was able to bind to the insulin receptor, as demonstrated by its ability to precipitate the insulin receptor from purified receptor preparations and from whole cell lysates derived from cells expressing the insulin receptor.
Ahmad et al., 1995, J. Biol. Chem. 270:20503-20508 used osmotic loading to introduce PTP-1B neutralizing antibodies into rat KRC-7 hepatoma cells. The presence of the antibody in the cells resulted in an increase of 42% and 38%, respectively, in insulin stimulated DNA synthesis and phosphatidyinositol 3′ kinase activity. Insulin receptor autophosphorylation and insulin receptor substrate-1 tyrosine phosphorylation were increased 2.2 and 2.0-fold, respectively, in the antibody-loaded cells. The antibody-loaded cells also showed a 57% increase in insulin stimulated insulin receptor kinase activity toward exogenous peptide substrates.
Recently, Kennedy et al., 1999, Science 283: 1544-1548 showed that protein tyrosine phosphatase PTP-1B is a negative regulator of the insulin signalling pathway, suggesting that inhibitors of this enzyme may be beneficial in the treatment of Type 2 diabetes. Mice lacking PTP-1B are resistant to both diabetes and obesity.
Thus, inhibitors of PTP-1B improve insulin-sensitivity. They have utility in controlling or treating Type 1 and Type 2 diabetes, in improving glucose tolerance, and in improving insulin sensitivity in patients in need thereof. The compounds may also be useful in treating or preventing cancer, neurodegenerative diseases and the like.
SUMMARY OF THE INVENTION
Compounds represented by formula I, including pharmaceutically acceptable salts thereof, and prodrugs thereof, are PTP-1B inhibitors that are useful in the treatment of diabetes and related medical conditions.
In compounds of Formula I, R
1
is phenyl or C
1-6
alkyl, wherein said R
1
is optionally substituted with 1-7 substituents independently selected from —C(O)OH, SC
1-3
alkyl, CN, halogen, —C(O)OC
1-6
alkyl(R
c
)
0-3
, —C(O)NR
a
R
b
, OC
1-6
alkyl(R
c
)
0-3
, C
1-6
alkyl(R
c
)
0-3
, C(O)C
1-6
alkyl(R
c
)
0-3
, —NHC(O)C
1-4
alkyl(R
c
)
0-3
, NHC(O)NHC
1-4
alkyl(R
c
)
0-3
, —NHC(O)NH—Ar, and Het, wherein Ar is phenyl, and wherein Het is a five-membered heteroaryl comprising 1-4 heteroatoms selected from 0-4 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms, where the heteroaryl also optionally comprises 0-2 carbonyl groups in the ring, and Ar and Het are each optionally substituted with 1-3 substituents independently selected from halogen, C
1-3
alkyl, C
1-3
fluoroalkyl, OC
1-3
alkyl, and OC
1-3
fluoroalkyl;
R
a
and R
b
are each independently selected from the group consisting of H and C
1-4
alkyl;
Each R
c
is independently selected from a group consisting of OH, OC
1-3
alkyl, OC
1-3
haloalkyl, C
0-6
alkylene CO
2
H, Aryl, and Aryl substituted with 1-3 substituents independently selected from halogen, C
1-4
alkyl, C
1-4
haloalkyl, OC
1-4
alkyl, and OC
1-4
haloalkyl;
R
2
is 1H-1,2,3-benzotriazol-1-yl, pyridinyl, or phenyl, R
2
being optionally substituted with 1-3 halogens;
Z
1
is a bond;
Z
2
is —C(O)—, S, SO, SO
2
, CH
2
, or a bond;
Y
1
and Y
2
are each a bond or an aliphatic linear or branched hydrocarbon residue having from 1-8 carbon atoms and 0-4 double bonds, optionally also including a cycloalkyl group having 3-6 carbon atoms;
each W
1
is independently selected from H and halogen;
W
2
is selected from the group consisting of H, —OCF
2
CO
2
H, —CF
2
PO
3
H
2
, —C(O)OC
1-6
alkyl, and Ar, wherein Ar is optionally substituted with 1-3 substituents independently selected from halogen, C
1-3
alkyl, C
1-3
fluoroalkyl, OC
1-3
alkyl, and —OC
1-3
fluoroalkyl;
with the proviso that when all W
1
groups are H, R
1
is phenyl, R
2
is phenyl or 1H-1,2,3-benzotriazol-1-yl, and Y
1
and Y
2
are CH
2
, then one or both of R
1
and R
2
are substituted, and R
1
, if substituted, is substituted with a substituent other than fluorine or —SCH
3
.
Methods of treating, controlling, or preventing diabetes, obesity and other related disease and conditions, using the compounds of Formula I are disclosed herein. Pharmaceutical compositions and combination therapies are also disclosed.
DETAILED DESCRIPTION OF THE INVENTION
In a subset of compounds of Formula I as recited above,
Y
1
is —CH
2
—,
Y
2
is C
1-3
alkylene or C
1-3
alkenylene;
and R
1
, R
2
, Z
1
, Z
2
, W
1
, W
2
, R
a
, R
b
, R
c
, and any provisos are as previously defined.
In another subset of compounds of Formula I:
R
1
is phenyl which is optionally substituted with one substituent selected from —C(O)OH, —C(O)OC
1-4
alkyl, —NHC(O)NH—C
6
H
3
(CH
3
)
2
, and —C(O)NR
a
R
b
, wherein R
a
and R
b
are each independently selected from H and C
1-4
alkyl;
R
2
is 1H-1,2,3-benzotriazol-1-yl or phenyl which is optionally substituted with one halogen;
Y
1
is CH
2
;
Y
2
is —CH
2
CH═CH
2
— or —CH
2
—;
W
2
is selected from the group consisting of H, —OCF
2
C(O)OH, —CF
2
PO
3
H
2
, and —C(O)OCH
3
;
and Z
1
, Z
2
, W
1
, R
a
, R
b
, R
c
, and any provisos are as defined above.
Another group of compounds of Formula I is defined as follows:
R
1
is phenyl which is optionally substituted with —C(O)OC
1-4
alkyl;
R
2
is phenyl which is optionally substituted with one halogen;
Z
1
is a bond;
Z
2
is —C(O)—;
Y
1
is —CH
2
—;
Y
2
is —CH
2
CH═CH
2
—;
W
1
is H or a single halogen on the aromatic ring in a position adjacent to —CF
2
PO
3
H
2
; and
W
2
is H.
In another embodiment of this invention,
R
1
is phenyl which is optionally substituted with one substituent selected from (1) —C(O)O—C
1-4
alkyl, (2) —NHC(O)NH-aryl, where aryl is phenyl which is optionally substituted with 1-3 substituents independently selected from C
1-3
alkyl and halogen, and (3) —C(O)NR
a
R
b
, wherein R
a
and R
b
are each independently selected from H and C
1-3
alkyl;
R
2
is phenyl which is optionally substituted with one halogen;
Z
1
is a bond;
Z
2
is —C(O)—;
Y
1
is —CH
2
—;
Y
2
is —CH
2
— or a bond;
W
1
is H or a halogen atom on the aromatic ring in a position adjacent to —CF
2
PO
3
H
2
; and
W
2
and any provisos are as defined in Claim 1.
Finally, specific compounds of Formula I are provided in Table 1, Table 2 and Examples 1-43.
Methods of treating, preventing, or controlling diabetes and other diseases using the compounds of Formula I are disclosed herein. A method of treating, controlling or preventing diabetes and complications thereof in a mammalian patient in need of such treatment includes the administration to the patient an anti-diabetic effective amount of a compound of Formula I. A method of treating, co

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