Amino(oxo) acetic acid protein tyrosine phosphatase inhibitors

Details Amino(oxo) acetic acid protein tyrosine phosphatase inhibitors Amino(oxo) acetic acid protein tyrosine phosphatase inhibitors

2001-08-22

2003-09-30

Vollano, Jean F. (Department: 1625)

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

Organic compounds

Carboxylic acid esters

C560S037000, C562S433000, C562S442000

Reexamination Certificate

active

06627767

ABSTRACT:

TECHNICAL FIELD
The instant invention is directed to compounds useful for inhibiting protein tyrosine phosphatase PTP1B, preparation of the compounds, compositions containing the compounds, and treatment of diseases using the compounds.
BACKGROUND OF THE INVENTION
PTP1B belongs to a family of protein tyrosine phosphatases involved in the regulation of the cellular signalling mechanisms which are involved in metabolism, growth, proliferation and differentiation (
Science
253:401-6 (1991)). Overexpression or altered activity of tyrosine phosphatase PTP1B can also contribute to the progression of various diseases (
Ann. Rev. Biochem.,
54:897-930 (1985)); and there is evidence which suggests inhibition of protein tyrosine phosphatase PTP1B is therapeutically beneficial for the treatment of diseases such as type I and II diabetes, obesity, autoimmune disease, acute and chronic inflammation, osteoporosis and various forms of cancer (
J. Natl. Cancer Inst.
86:372-8 (1994);
Mol. Cell. Biol.
14:6674-6682 (1994);
The EMBO J.
12:1937-46 (1993);
J. Biol. Chem.
269:30659-30667 (1994); and Biochemical Pharmacology 54:703-711 (1997)).
Because of the important role played by unregulated protein tyrosine phosphatase PTP1B in these diseases, agents which inhibit the enzyme have been the subject of active current research for their clinical potential. Reference is made to WO 99/46236, WO 99/46237, WO 99/46267 and WO 99/46268; and although each teaches certain heteroaryl and heterocycle amino(oxo)acetic acid protein tyrosine phosphatase PTP1B inhibitors, there is still a need for protein tyrosine phosphatase PTP1B inhibitors with modified or improved profiles of activity.
SUMMARY OF THE INVENTION
In the principle embodiment of the instant invention, therefore, are provided protein tyrosine phosphatase PTP1B inhibitors of formula (I):
or therapeutically acceptable salts thereof, wherein
A is selected from N(H), O, S, N═C(H), and C(H)═C(H);
B is selected from N and C(H);
with the proviso that when A is N═C(H) or C(H)═C(H), B is C(H);
d is 0, 1, or 2;
L
1
is a covalent bond or O;
L
2
is selected from CH(R
6
) and CH
2
CH(R
6
);
R
1
is selected from hydrogen and a carboxy protecting group;
R
2
is selected from hydrogen, aminoalkyl, loweralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, (heterocycle)alkyl, hydroxyalkyl, and haloalkyl;
each R
3
is independently selected from hydrogen, loweralkoxy, alkoxyalkyl, alkoxyalkenyl, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkoxy, aryl, arylalkyl, arylalkenyl, arylalkoxy, carboxamido, carboxamidoalkyl, carboxamidoalkenyl, carboxamidoalkoxy, carboxy, carboxyalkyl, carboxyalkenyl, carboxyalkoxy, halo, heteroaryl, heteroarylalkyl, heteroarylalkenyl, and heteroarylalkoxy; or
A is C(H)═C(H), and two of R
3
are on adjacent atoms and, taken together with the atoms to which they are attached, are phenyl, wherein the phenyl can be optionally substituted with one or two substituents independently selected from loweralkoxy, alkoxycarbonylalkenyl, alkoxycarbonylalkoxy, aryl, carboxamidoalkenyl, carboxamidoalkoxy, carboxyalkenyl, carboxyalkoxy, halo, and heteroarylalkoxy;
with the proviso that R
3
is connected to a substitutable carbon atom;
R
4
is selected from hydrogen, alkoxy, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, aryl, arylalkyl, arylalkoxy, arylthioxyalkyl, carboxamidoalkenyl, carboxamidoalkyl, carboxyalkyl, carboxylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkoxy, heteroarylthioxyalkyl, halo, and R
7
-T-;
with the proviso that at when R
4
is hydrogen, at least one of R
3
is other than hydrogen;
R
6
is selected from hydrogen, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle, and (heterocycle)alkyl;
R
7
is selected from aryl and heteroaryl;
T is selected from C(O)N(R
8
), N(R
8
)C(O), N(R
8
), OC(O)N(R
8
), N(R
8
)C(O)O, C(O), OC(O), (O)CO, O, S, S(O), SO
2
, C(O), OC(O)O, N(R
8
)C(O)N(R
8
), and C(O)OC(O);
wherein the asymmetric groups defining T are drawn with their left ends attached to R
7
and their right ends attached to the ring and; and
R
8
is selected from hydrogen and loweralkyl.
In another embodiment of the instant invention are provided compounds of formula (II)
or therapeutically acceptable salts thereof, wherein R
2
and R
4
are defined previously, and R
3
is selected from hydrogen and halo.
In a preferred embodiment of the compounds of formula (II), R
2
is arylalkyl, and R
4
is aryl.
In still another embodiment of the instant invention are provided compounds of formula (III)
or therapeutically acceptable salts thereof, wherein R
2
and R
4
are defined previously; R
3A
is selected from hydrogen, loweralkoxy, alkoxycarbonylalkenyl, alkoxycarbonylalkoxy, aryl, carboxamidoalkenyl, carboxamidoalkoxy, carboxyalkenyl, carboxyalkoxy, halo, and heteroarylalkoxy; and R
3B
is selected from hydrogen and halo.
In a preferred embodiment of the compounds of formula (III), R
2
is hydrogen, arylalkyl, cycloalkyl, or (heterocycle)alkyl; and R
4
is aryl or heteroarylalkoxy.
In still another embodiment of the instant invention are provided compounds of formula (IV)
or therapeutically acceptable salts thereof, wherein R
2
and R
4
are defined previously; R
3b
is selected from hydrogen and aryl; X is selected from CH
2
and N(R
X
); and R
X
is selected from alkanoyl, alkylsulfonyl, arylsulfonyl, aryloyl, arylsulfonyl, carboxamidoalkyl, and (heterocycle)alkyl.
In a preferred embodiment of the compounds of formula (IV), R
2
is hydrogen, arylalkyl, arylalkyl, (heterocycle)alkyl, or aminoalkyl; and R
4
is hydrogen, halo, aryl, alkoxycarbonylalkenyl, carboxyalkenyl, heteroaryl, or carboxamidoalkenyl.
In still another embodiment of the instant invention are provided compounds of formula (V)
or therapeutically acceptable salts thereof, wherein L
1
, R
2
, and R
4
are defined previously; and R
3b
selected from hydrogen and heteroaryl.
In a preferred embodiment of the compounds of formula (V), L
1
is a covalent bond or O; R
2
is hydrogen; and R
4
is hydrogen, halo, aryl, or heteroarylalkoxy.
In still another embodiment of the instant invention are provided compounds of formula (VI)
or therapeutically acceptable salts thereof, wherein R
2
and R
4
are defined previously.
In a preferred embodiment of the compounds of formula (VI), R
2
is hydroxyalkyl or arylalkyl and R
4
is loweralkoxy, alkoxy, or aryl.
In still another embodiment of the instant invention are provided a method for preparing the compounds of
formula (I),
the method comprising:
(a) reacting a compound of formula (Ia)
 or therapeutically acceptable salts thereof,
wherein
A, B, d, L
1
, L
2
, R
1
, and R
2
are defined previously; and
R
4P
is coupling promoter group selected from the group consisting of chloride, bromide, trifluoromethanesulfonate, iodide, and hydroxy,
with a coupling partner, a base, and, optionally, a palladium catalyst; and
(b) optionally hydrolyzing the product of step (a).
In a preferred embodiment of the method, the coupling partner is selected from a substituted alkene, an optionally substituted arylboronic acid, an optionally substituted heteroarylboronic acid, an optionally substituted aryl trialkylstannane, an optionally substituted heteroaryl trialkylstannane, and an optionally substituted alkyl halide; and the palladium catalyst is selected from tetrakistriphenyl-phosphinepalladium(O), palladium(II) bis(triphenyl-phosphine)dichloride, and dipalladium tris(dibenzylidine-acetone).
In still another embodiment of the instant invention is provided a method for inhibiting protein tyrosine phosphatase comprising administering a therapeutically effective amount of a compound of formula (I).
In still another embodiment of the instant invention is provided a method for inhibiting protein tyrosine phosphatase comprising administering a therapeutically effective amount of a compound of formula (II).
In still another embod

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