Phosphonic acids derivatives as inhibitors of protein...

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

1999-09-17

2001-01-16

Powers, Fiona T. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S086000, C514S092000, C514S107000, C514S120000, C514S121000, C514S125000, C514S129000, C544S243000, C548S113000, C548S119000, C560S009000, C560S037000, C560S055000, C560S060000, C562S011000, C562S020000, C562S023000, C562S024000

Reexamination Certificate

active

06174874

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to a novel class of phosphonic acid derivatives as inhibitors of PTP-1B.
Protein tyrosine phosphates as (Peptizes) 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.
Thus, inhibitors of PTP-1B improve insulin-sensitivity and have utility in preventing or treating Type 1 and Type 2 diabetes, improving glucose tolerance and insulin-sensitivity when there is insulin-resistance. Also, the compounds are useful in treating or preventing obesity. In addition, the compounds are of use in treating or preventing cancer, neurodegenerative diseases and the like.
SUMMARY OF THE INVENTION
A compound represented by formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R
1
is 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
)
0-7
and Het(R
a
)
0-7
;
R
2
is selected from the group consisting of C
1-6
alkyl(R
a
)
0-7
, Aryl(R
a
)
0-7
and Het(R
a
)
0-7
.
When present, each R
a
independently represents a member selected from the group consisting of: Aryl, OH, halo, CO
2
H, CO
2
C
1-6
alkyl, OC
1-10
alkyl, S(O)
y
C
1-6
alkyl, S(O)
y
NR
3′
R
4′
, Het and —P(O)(OH)
2
;
Y
1
and Y
2
represent —(CR
3
R
4
)
a
—X—(CR
3
R
4
)
b
— wherein a and b are integers 0-1 such that the sum of a and b equals 0, 1 or 2,
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—,
and R
3
and R
4
are independently H, halo, C
1-10
alkyl or haloC
1-10
alkyl, or R
3
and R
4
taken together with any intervening atoms represent a 3-7 membered ring;
R
3′
is selected from the group consisting of: H, C
1-6
alkyl, haloC
1-6
alkyl, OH, C(O)C
1-6
alkyl, C(O)Aryl, C(O)Het, C(O)C
1-6
haloalkyl, Aryl and Het;
Z
1
and Z
2
represent —(CR
3
R
4
)
a
—X—(CR
3
R
4
)
b
— wherein X, a, b, R
3
and R
4
are as defined, or Z
1
and Z
2
are taken in conjunction with R
1
and R
2
and represent in combination
 wherein R
1
and R
2
represent carbonyl groups, or —CH
2
NR
1
C(O)NR
2
CH
2
—, with R
1
and R
2
as originally defined;
W
1
and W
2
are each independently selected from the group consisting of: H, 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, CN, C
1-6
alkyl(R
a
)
0-7
, N
3
, 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
3i
R
4i
, S(O)
y
NR
3′
R
4′
, NR
3′
R
4′
and Het, wherein R
3′
is as defined above and R
4′
is selected from the group consisting of: H, C
1-6
alkyl, haloC
1-6
alkyl, Aryl and Het, or the two W
1
groups taken in combination represent a fused phenyl ring;
Aryl represents a 6-14 membered aromatic ring system;
and Het represents a 5-10 membered aromatic ring system containing 1-4 heteroatoms, 0-4 of which are N atoms and 0-1 of which are O or S(O)
y
wherein y is as previously defined, and 0-2 carbonyl groups.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect of the invention, a compound is disclosed represented by formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R
1
is 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
)
0-7
and Het(R
a
)
0-7
;
R
2
is selected from the group consisting of C
1-6
alkyl(R
a
)
0-7
, Aryl(R
a
)
0-7
and Het(R
a
)
0-7
,
when present, each R
a
independently represents a member selected from the group consisting of: Aryl, OH, halo, CO
2
H, CO
2
C
1-6
alkyl, OC
1-10
alkyl, S(O)
y
C
1-6
alkyl, S(O)
y
NR
3′
R
4′
, Het and —P(O)(OH)
2
;
Y
1
and Y
2
represent —(CR
3
R
4
)
a
—X—(CR
3
R
4
)
b
— wherein a and b are integers 0-1 such that the sum of a and b equals 0, 1 or 2,
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—,
and R
3
and R
4
are independently H, halo, C
1-10
alkyl or haloC
1-10
alkyl, or R
3
and R
4
taken together with any intervening atoms represent a 3-7 membered ring;
R
3′
is selected from the group consisting of: H, C
1-6
alkyl, haloC
1-6
alkyl, 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, haloC
1-6
alkyl, Aryl and Het;
Z
1
and Z
2
each represent —(CR
3
R
4
)
a
—X—(CR
3
R
4
)
b
— wherein X, a, b, R
3
and R
4
are as defined and are defined independently for Z
1
and Z
2
, or Z
1
and Z
2
are taken in conjunction with R
1
and R
2
and represent in combination
 wherein R
1
and R
2
represent carbonyl groups, or Z
1
and Z
2
together are —CH
2
NR
1
C(O)NR
2
CH
2
—, with R
1
and R
2
as originally defined;
W
1
and W
2
are each independently selected from the group consisting of: H, 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, CN, C
1-6
alkyl(R
a
)
0-7
, N
3
, 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′
and Het, wherein R
3′
and R
4′
are as defined above, or the two W
1
groups taken in combination represent a fused phenyl ring;
Aryl represents a 6-14 membered aromatic ring system;
and Het represents a 5-10 membered aromatic ring system containing 1-4 heteroatoms, 0-4 of which are N atoms and 0-1 of which are O or S(O)
y
wherein y is as previously defined, and 0-2 carbonyl groups.
In another aspect of the invention that is of particular interest, W
1
and W
2
are independently selected from the group consisting of:
(a) hydrogen,
(b) halo,
(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
,
Within this subset, all other variables are as originally defined.
Mo

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