Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-12
2002-04-02
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S075000, C514S274000, C514S311000, C514S317000, C514S359000, C514S423000, C514S456000, C423S316000, C544S243000, C544S315000, C544S337000, C544S386000, C546S022000, C546S152000, C546S192000, C548S413000, C549S218000
Reexamination Certificate
active
06365592
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to a novel class of phosphonic and carboxylic acid derivatives that are useful as inhibitors of PTP-1B.
Protein tyrosine phosphatases (PTPases) 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). Lilce other PTPases, PTP-1B has a catalytic domain containing arginine and cysteine residues that are critical to the enzyme's activity (Streuli et al., 1990, EMBO J. 9:2399-2407, Guan et al., 1990, Proc. Natl. Acad. Sci. USA 87:1501-1505; Guan & Dixon, 1991, J. Biol. Chem. 266:17026-17030). The amino terminal 35 amino acid residues of PTP-1B localizes the protein to the endoplasmic reticulum (Frangioni et al., 1992, Cell 68:545-560).
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 iii 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.
Inhibitors of PTP-1B improve insulin-sensitivity and thus have utility in preventing or treating Type 1 and Type 2 diabetes, improving glucose tolerance, improving insulin-sensitivity when there is insulin-resistance and treating or preventing obesity. In addition, the compounds are useful for treating or preventing cancer, neurodegenerative diseases and the like.
SUMMARY OF THE INVENTION
The present invention relates to a compound represented by formula I:
or a pharmaceutically acceptable salt or hydrate thereof wherein:
one of B
1a
, B
1b
, B
2a
and B
2b
represents CF
2
—PO
3
H
2
or CF
2
—CO
2
H,
one of B
1a
, B
1b
, B
2a
and B
2b
represents H,
and the others are selected from the group consisting of:
R
4
, OH, halo, CHF
2
, CF
3
, CHF—CO
2
H, CF
2
—CO
2
H, CF
2
—C(R
5
)(R
6
)OH, CHF—PO
3
H
2
, CH
2
—PO
3
H
2
, C(R
5
)(R
6
)OH, S(O)yR
5
, wherein y is 0, 1 or 2, S(O)
2
NR
5
R
6
, CFHSO
3
H, CF
2
SO
3
H, CFHS(O)
2
NR
5
R
6
, CF
2
S(O)
2
NR
5
R
6
, NR
6
S(O)
2
R
5
, CFH-Hetcy, CF
2
-Hetcy, CH
2
S(O)
2
-Hetcy, CFHS(O)
2
-Hetcy, CF
2
S(O)
2
-Hetcy, CH
2
S-Hetcy, CFHS-Hetcy, CF
2
S-Hetcy, OC(R
5
)(R
6
)F, C(R
5
)(R
6
)F, O—CF
2
CO
2
R
4
, O-CH
2
CO
2
R
4
, C(R
5
)(R
6
)CO
2
R
4
, CO
2
R
4
, CFH-aryl, CF
2
-aryl, CH
2
S(O)
2
-aryl, CFHS(O)
2
-aryl, CF
2
S(O)
2
-aryl, CH
2
S-aryl, CFHS-aryl and CF
2
S-aryl,
such that when one of B
1a
and B
1b
represents CF
2
—CO
2
H, at least one of B
2a
and B
2b
represents CF
2
—PO
3
H
2
or CF
2
—CO
2
H, and when one of B
2a
and B
2b
represents CF
2
—CO
2
H, at least one of B
1a
and B
1b
represents CF
2
—PO
3
H
2
or CF
2
—CO
2
H;
Hetcy is selected from the group consisting of:
(a) a 5-15 membered heteroaryl group containing 1-4 heteroatoms selected from O, S(O)y and N, wherein y is as defined above, and 0-2 carbonyl groups, optionally substituted with 1-4 members selected from R
a
; and
(b) a non-aromatic carbocyclic structure containing 5-15 carbon atoms, interrupted by 1-4 heteroatoms selected from O, S(O)y wherein y is as previously defined, and N, and optionally containing 1-2 carbonyl groups, and optionally substituted with 1-4 members selected from R
a
;
aryl is a 6-10 membered aromatic ring system that is optionally substituted with 1-4 members selected from R
a
;
each R
a
is independently selected from the group consisting of: halo, NO
2
, N
3
, OH, CN, C(O)NH
2
, C(O)NHC
1-3
alkyl, C(O)N(C
1-3
alkyl)
2
, CO
2
H, CO
2
—C
1-10
alkyl, C
1-10
alkyl, C
1-10
haloalkyl, C
1-10
haloalkoxy, C
1-10
alkoxy, C
1-10
alkylthio, C
1-10
alkylsulfinyl, C
1-10
alkylsulfonyl, phenylsulfonyl and phenyl;
X is OH or NH
2
.
Y is selected from the group consisting of: H, C
1-6
alkyl, R
1
ZCO—, R
2
— and R
3
S(O)
2
—;
Z represents a bond or is selected from O, S(O)yCH
2
, NR
4
or CH═CH;
R
4
represents H, C
1-6
alkyl, Hetcy or aryl, said alkyl, Hetcy and aryl being optionally substituted with 1-3 members selected from R
a
;
R
1
is selected from the group consisting of:
(a) C
1-10
alkyl,
(b) C
1-6
fluoroalkyl, optionally substituted with a hydroxy group;
(c) aryl optionally substituted with 1-3 substituents selected from R
a
;
(d) heteroaryl, said heteroaryl group being a monocyclic aromatic ring of 5 atoms, said ring having one heteroatom which is O, S or N, and optionally 1, 2, or 3 additional N atoms; or a monocyclic ring of 6 atoms, said ring having one heteroatom which is O, S or N, and optionally 1, 2, or 3 additional N atoms, said heteroaryl group being optionally substituted with from 1-3 substituents selected from R
a
;
(e) benzoheterocycle in which the heterocycle is a 5, 6, or 7-membered ring containing 1 or 2 heteroatoms selected from O, S and N, optionally containing a carbonyl, sulfinyl or sulfonyl group; said benzoheterocycle being optionally substituted with 1-3 substituents selected from R
a
;
(f) a heterocycloalkyl group of 5, 6 or 7 members which contains 1 or 2 heteroatoms selected from O, S and N, and optionally containing a carbonyl group or a sulfonyl group;
(g) a benzocarbocycle in which the carbocycle is a 5, 6, or 7-membered ring which optionally contains a carbonyl group, optionally substituted with 1-2 substituents selected from R
a
;
(h) a bicyclic heteroaryl group having 8, 9 or 10 members, containing 1 to 5 heteroatoms selected from O, S and N, optionally substituted with 1-2 substituents selected from Ra; and
(i) hydrogen;
R
2
is the acyl residue of an amino acid, the amino group of which may be optionally substituted by an acyl group of the structure R
1
ZCO— or C
1-6
alkyl, and in the case of a dicarboxylic amino acid, the terminal carboxyl may optionally be in the form of a C
1-4
alkyl ester;
R
3
is selected from the group consisting of:
(a) C
1-10
alkyl,
(b) C
1-6
fluoroalkyl, and
(c) C
6-10
aryl optionally substituted as defined above, and
R
5
and R
6
independently represent members selected from the group consisting of: H, C
1-10
alkyl, C
2-10
alkenyl, aryl, Hetcy, CONH
2
, CO
2
H, CO
2
—R
4
, C(O)R
4
, C
1-6
fluoroalkyl, said alkyl aryl, and Hetcy groups being optionally substituted with 1-3 substituents selected from R
a
;
or R
5
and R
6
are taken in combination and represent a 7 membered carbocyclic ring, optionally interrupted with 1-3 heteroatoms selected from O, S(O)y and N, and
Dufresne Claude
Leblanc Yves
Roy Patrick
Wang Zhaoyin
McGinnis James L.
Merck Frosst Canada & Co.
Rose David L.
Shah Mukund J.
Truong Tamthom N.
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