Phosphonic acid biaryl derivatives as inhibitors of protein...

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

2000-12-21

2002-11-26

Gerstl, Robert (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C562S023000, C562S024000, C562S025000

Reexamination Certificate

active

06486141

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 and are useful in the treatment of diabetes, obesity, and related conditions.
In these compounds, 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, C
0-6
alkyleneCO
2
H, C
0-6
alkyleneCO
2
C
1-6
alkyl, OC
1-10
alkyl, C
1-6
alkyl, C
1-6
haloalkyl, OC
1-10
alkyleneCO
2
H, S(O)
y
C
1-6
alkyl, S(O)
y
NR
3
′R
4
′, and Het, wherein y is 0, 1, or 2;
Ar represents Aryl or Het, wherein said Aryl or Het is substituted with 1-5 substituents R
b
, wherein optionally 2 R
b
groups can join together to form a 5-7 membered ring fused to Ar, where the fused portion of the 5-7 membered ring may be saturated or may include 1-2 double bonds and may include 1-4 heteroatoms selected from N, S, O, and C(═O) in the fused portion of the ring, said ring optionally being substituted with 1-3 groups independently selected from R
a
;
Aryl is a 6-14 membered carbocyclic aromatic ring system comprising 1-3 phenyl rings, wherein said rings are fused together 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 or S(O)
y
wherein y is 0-2, and 0-2 carbonyl groups;
Each R
b
is independently selected from the group consisting of: OH, CN, halogen, C
0-6
alkyleneOC
1-6
alkyl(R
a
)
0-7
, C
0-6
alkyleneOAryl(R
a
)
0-3
, Het, C
0-6
alkyleneS(O)
y
C
1-6
alkyl(R
a
)
0-7
, with y equal to 0-2, C
0-6
alkyleneS(O)
3
H, C
1-10
alkyl(R
a
)
0-7
, N
3
, C
0-6
alkyleneCO2H, C
0-6
alkyleneCO
2
C
1-6
alkyl(R
A
)
0-7
, C
0-6
alkyleneCO
2
C
2-6
alkenyl(R
a
)
0-7
, C
0-6
alkyleneC(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
′, PO(OR
5
)
2
, and CF
2
PO(OR
5
)
2
, wherein R
3
′ and R
4
′ are as defined above;
Each y is 0, 1 or 2;
Each R
5
is H;
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 each zero or an integer 1 or 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
′(O) or —CH═CH—, where y is as previously defined;
R
3
and R
4
are independently H, halogen, C
1-10
alkyl or C
1-10
haloalkyl;
R
3
′ is 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;
R
4
′ is selected from the group consisting of: H, C
1-6
alkyl, C
1-6
haloalkyl, Aryl and Het;
Each W
1
is independently selected from the group consisting of: H, OH, CN, halogen, OC
1-6
alkyl(R
a
)
0-7,
OAryl(R
a
)
0-3
, 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
, N
3
, C
0-6
alkyleneCO
2
H, C
0-6
alkyleneCO
2
C
1-6
alkyl (R
a
)
0-7
, C
0-6
alkyleneCO
2
C
2-6
alkenyl(R
a
)
0-7
, C
0-6
alkyleneC(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; or alternatively two W
1
groups on adjacent atoms of the aromatic ring are joined together to form a fused phenyl ring, optionally substituted with 1-3 groups R
b
.
Methods of treating, controlling, and preventing diabetes, obesity, and other related diseases and conditions using the compounds having Formula I are provided herein. Pharmaceutical compositions and combination therapies are also disclosed herein.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment of this invention, in compounds having Formula I, W
1
is 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,
(l) N(R
3
′)(R
4
′) and
(m) C(O)C
1-6
alkyl(R
a
)
0-7
.
In another embodiment, each W
1
represents H or halogen.
In another embodiment, Ar represents phenyl, quinolinyl, indolyl or thienopyridinyl.
In a subset of compounds having Formula I, as described above, Ar represents phenyl, which is substituted with 1-2 substituents selected from R
b
, and the phenyl ring to which Ar is connected is unsubstituted.
In a preferred subset of compounds of Formula I, Y
1
, Z
1
and Z
2
are each independently CH
2
or a bond, and Y2 is selected from CH
2
, a bond, —CH
2
CH
2
SCH
2
—, —CH
2
CH
2
OH
2
—, —C(═O)OCH
2
—, —C(═O)OCH
2
CH
2
—, and —C(═O)O—.
In another subset of compounds of Formula I, R
b
is selected from the group consisting of: halogen, C
0-6
alkyleneOC
1-6
alkyl(R
a
)
0-2
, —SC
1-6
alkyl(R
a
)
0-2
, -Ophenyl, tetrazole, C
1-10
alkyl(R
a
)
0-2
, C
0-3
alkyle

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