Protein tyrosine phosphatase 1B (PTP-1B) inhibitors...

Details Protein tyrosine phosphatase 1B (PTP-1B) inhibitors... Protein tyrosine phosphatase 1B (PTP-1B) inhibitors...

2000-12-21

2002-09-10

Vollano, Jean F. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Phosphorus esters

C562S025000, C514S075000

Reexamination Certificate

active

06448429

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 Formula I, R
1
and R
2
are selected from the group consisting of: C
1-10
alkyl(R
a
)
0-7
, C
2-10
alkenyl(R
a
)
0-7
, Aryl(R
a
)
0-3
and Het(R
a
)
0-3
;
wherein, each R
a
independently represents a member selected from the group consisting of: Aryl, OH, halogen, CN, CO
2
H, CO
2
C
1-6
alkyl, CO
2
C
2-6
alkenyl, OC
1-10
alkyl, C(O)C
1-6
alkyl, S(O)
y
C
1-6
alkyl, C
1-6
alkyl, C
1-6
haloalkyl, S(O)
y
NR
3
′R
4
′, wherein y is 0, 1, or 2, C(O)NR
3
′R
4
′, NR
3
′R
4
′, and Het, wherein each alkyl group in R
a
is optionally substituted with 1-7 groups independently selected from halogen, OC
1-3
alkyl, CO
2
H, and CO
2
C
1-3
alkyl, and each Het and Aryl in R
a
is optionally substituted with 1-3 groups independently selected from C
1-3
alkyl, halogen, OC
1-3
alkyl, CO
2
H, and CO
2
C
1-3
alkyl;
Aryl is a 6-14 membered carbocyclic aromatic ring system comprising 1-3 phenyl rings, wherein rings are fused together so that adjacent rings share a common side when there is more than one aromatic ring;
Het represents a 5-10 membered aromatic ring system comprising one ring or two fused rings, 1-4 heteroatoms, 0-4 of which are N atoms and 0-2 of which are O or S(O)
y
wherein y is 0-2, and 0-2 carbonyl groups;
Y
1
, Y
2
, Z
1
, and Z
2
each independently represents —(CR
3
R
4
)
a
—X—(CR
3
R
4
)
b
— wherein a and b are integers 0-2 such that the sum of a and b equals 0, 1, 2, or 3;
X represents a bond, O, S(O)
y
, NR
3
′, C(O), OC(O), C(O)O, C(O)NR
3
′, NR
3
′C(O) or —CH═CH—, where y is as previously defined;
R
3
and R
4
are each independently H, halogen, C
1-10
alkyl or C
1-10
haloalkyl;
R
3
′ and R
4
′ are each independently selected from the group consisting of: H, C
1-6
alkyl,C
1-6
haloalkyl, OH, C(O)C
1-6
alkyl, C(O)Aryl, C(O)Het, C(O)C
1-6
haloalkyl, Aryl and Het;
W
1
and W
2
are each in a position on the aromatic ring of Formula I adjacent to the —CF
2
P(O)(OH)
2
substituent and are each independently selected from the group consisting of: OH, CN, halo, OC
1-6
alkyl(R
a
)
0-7
, S(O)
y
C
1-6
alkyl(R
a
)
0-7
, with y equal to 0-2, S(O)
3
H, C
1-6
alkyl(R
a
)
0-7
, CO
2
H, CO
2
C
1-6
alkyl(R
a
)
0-7
, CO
2
C
2-6
alkenyl(R
a
)
0-7
, C(O)C
1-6
alkyl(R
a
)
0-7
, C(O)NR
3
′R
4
′, S(O)
y
NR
3
′R
4
′, NR
3
′R
4
′, Aryl, and Het, wherein R
3
′ and R
4
′ are as defined above; and
W
1
′ and W
2
′ are optionally present on any remaining position on the aromatic ring and are each independently selected from H and from the same groups as W
1
and W
2
.
Methods of treating and controlling diabetes, obesity, and other diseases and conditions using the compounds of Formula I are taught herein. Pharmaceutical compositions and combination treatments are also disclosed herein.
DETAILED DESCRIPTION OF THE INVENTION
In one subset of compounds, W
1
′ and W
2
′ are each independently selected from the group consisting of:
(a) hydrogen,
(b) halogen,
(c) OC
1-6
alkyl(R
a
)
0-7
,
(d) SC
1-6
alkyl(R
a
)
0-7
,
(e) C
1-6
alkyl(R
a
)
0-7
,
(f) CO
2
H,
(g) CO
2
—C
1-6
alkyl(R
a
)
0-7
,
(h) OH,
N(R
3
′)(R
4
′) and
(j) C(O)C
1-6
alkyl(R
a
)
0-7
, and
W
1
and W
2
are each independently selected from the group consisting of:
(a) halogen,
(b) OC
1-6
alkyl(R
a
)
0-7
,
(c) SC
1-6
alkyl(R
a
)
0-7
,
(d) C
1-6
alkyl(R
a
)
0-7
,
(e) CO
2
H,
(f) CO
2
—C
1-6
alkyl(R
a
)
0-7
,
(g) OH,
(h) N(R
3
′)(R
4
′) and
(i) C(O)C
1-6
alkyl(R
a
)
0-7
.
In a subset of the compounds described above, each W
1
′ and W
2
′ represents H, and W
1
and W
2
each independently represents a halogen, C
1-3
alkyl, C
1-3
fluoroalkyl, OC
1-3
alkyl or OC
1-3
fluoroalkyl.
In a more specific subset of the above groups of compounds W
1
and W
2
each represents Br.
In another group of compounds, Y
1
, Y
2
, Z
1
and Z
2
are each independently selected from the group consisting of:
(a) —CH
2
—,
(b) —O—CH
2
—,
(c) —CH
2
—O—,
(d) —CH
2
—O—CH
2
—,
(e) —S—CH
2
—,
(f) —CH
2
—S—,
(g) —CH
2
—S—CH
2
—,
(h) —S(O)
2
—CH
2
—,
(i) —CH
2
—S(O)
2
—,
(j) —CH
2
—S(O)
2
—CH
2
—,
(k) —S(O)
2
—,
(l) —S—,
(m) —O—,
(n) —NR
3
′—,
(o) C(O), and
(p) a direct bond.
In another embodiment of the invention, Y
1
, Y
2
, Z
1
and Z
2
are each independently selected from the group consisting of: (a) —CH
2
—, (b) —O—CH
2
—, (c) —CH
2
—O—, (d) —CH
2
—O—CH
2
—, (e) —S—CH
2
—, (f) —CH
2
—S— and (g) —CH
2
—S—CH
2
—.
In a more specific embodiment of the invention, as described above, Y
1
, Y
2
, Z
1
, and Z
2
are each independently selected from the group consisting of C(O), CH
2
, and a direct bond.
In another subset of compounds, Z
1
is a direct bond, Z
2
is C(O), and Y
1
and Y
2
are each CH
2
.
In another embodiment of the invention as described above, R
1
and R
2
of

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