Preparation of phosphatase inhibitors

Details Preparation of phosphatase inhibitors Preparation of phosphatase inhibitors

2001-07-05

2003-07-01

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S602000, C558S413000, C558S414000, C564S084000

Reexamination Certificate

active

06586467

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to the preparation of phosphatase inhibitors that act as phosphotyrosine mimetics. The invention particularly relates to compounds designed to inhibit protein-tyrosine phosphatase 1B, and for the treatment of diabetes.
SUMMARY OF THE RELATED ART
Protein tyrosine kinases (PTK) and protein tyrosine phosphatases (PTP) play an essential role in the regulation of various cellular functions including cell growth, proliferation, differentiation, metabolism and immune responses. They are therefore potentially important targets for therapeutic intervention in a number of diseases, including cancers and diabetes. PTKs generate phosphotyrosyl (pTyr) residues by mediating the phosphorylation of tyrosyl residues. PTPs, in turn, remove pTyr phophates and may play either positive or negative roles in cellular signal transduction.
At present, about 100 enzymes comprise the PTP family and each is either receptor-like or cytoplasmic. One such enzyme is PTP1B, a prototypic intracellular PTP that is expressed in many human tissues and is implicated as a negative regulator of insulin receptor signaling. Recent studies have shown that a correlation exists between levels of PTP1B and insulin resistance states, suggesting that PTP1B may play a role in the insulin resistance associated with diabetes and obesity. Apparently, PTP1B plays a vital role in the dephosphorylation of the insulin receptor. Further, a knockout study has revealed that mice lacking functional PTP1B exhibit increased sensitivity toward insulin and are resistant to obesity (Elchebly, M. et al.,
Science
1999, 283, 1544-1548). These studies suggest that PTP1B inhibitors would be useful in the treatment of insulin resistance and obesity. More importantly, such an inhibitor could function as an agent for the treatment of non-insulin dependent diabetes mellitus without inducing hypoglycemia.
To date, many of the previously reported PTP1B inhibitors have been peptide-based, containing negatively charged sulfate or phosphonic acid derivatives. Most of these compounds have been found to be inefficient in crossing cell membranes and are unstable in vivo. More recently, small organic molecules have been identified as potent and selective inhibitors of PTP1B (Larsen, S. et al. WO 00/53583; Larsen, S. et al., WO 99/11606; Sarmieto, M. et al.,
J. Med. Chem.
2000, 43, 146-155; Wrobel, J. et al.,
J. Med. Chem.
1999, 42, 3199-3202). Still desired is a PTP1B inhibitor that is even less peptidic in nature such that it increases solubility, absorption, cellular penetration and oral availability.
SUMMARY OF THE INVENTION
This invention provides certain tyrosine analogs of Formula I that are useful for treating Type II diabetes mellitus. Specifically, the present invention relates to compounds of Formula I that inhibit the protein tyrosine phosphatase 1B enzyme. Also provided are formulations containing compounds of Formula I and methods of using the compounds to treat a patient in need thereof. In addition, there are described processes for preparing the inhibitory compounds of Formula I.
The present invention relates to PTP1B inhibitors, pharmaceutically acceptable salts and prodrugs thereof useful in the therapeutic or prophylactic treatment of Type II diabetes mellitus. The invention also encompasses pharmaceutical compositions and methods for the treatment of Type II diabetes mellitus.
Accordingly, the compounds of the invention are members of the class of compounds of Formula I:
wherein
R
1
is selected from hydrogen, hydroxy, halogen, amino, monoalkylamino, trifluoromethyl, aminomethyl, cyano, nitro, —COOR
6
, and
heteroaryl optionally substituted with one, two or three groups independently selected from halogen, lower alkyl, hydroxy, amino, mono- or dialkylamino, trifluoromethyl, C(O)R
8
, COOR
8
, C(O)NHR
8
, and OR
8
;
R
2
is selected from hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy, alkoxyalkyl, hydroxyalkyl, lower alkenyl, amino, mono- or dialkylamino, cyano, nitro, trifluromethyl, —CON(R
6
)
2
, —COOR
6
, and
aryl and heteroaryl optionally substituted with one, two or three groups independently selected from halogen, lower alkyl, hydroxy, amino, mono- or dialkylamino, trifluoromethyl, C(O)R
8
, COOR
8
, C(O)NHR
8
, and OR
8
;
R
3
, R
4
, R
5
are independently selected from hydrogen, hydroxy, halogen, lower alkyl, lower alkenyl, cycloalkyl, cyano, —CON(R
6
)
2
and —COOR
6
, and
aryl and heteroaryl optionally substituted with one, two or three groups independently selected from halogen, lower alkyl, hydroxy, amino, mono- or dialkylamino, trifluoromethyl, C(O)R
8
, COOR
8
, C(O)NHR
8
, and OR
8
;
A is selected from lower alkyl, lower alkenyl, lower alkynyl, —C(O)R
7
, —S(O)
2
R
7
, —C(O)NHR
7
, —CO
2
R
7
, —(CH
2
)
n
S(O)
q
R
7
, —(CH
2
)
p
C(O)R
7
, —(CH
2
),
p
C(O)NHR
7
, —(CH
2
)
p
CO
2
R
7
, (CH
2
)
n
OR
7
, and
aryl, heteroaryl, arylalkyl, and heteroarylalkyl, where the ring portion of each is optionally substituted with one, two or three groups independently selected from halogen, lower alkyl, hydroxy, amino, mono- or dialkylamino, trifluoromethyl, C(O)R
8
, COOR
8
, C(O)NHR
8
, and OR
8
;
B is selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, —(CH
2
)
n
S(O)
q
R
7
, —(CH
2
)
p
C(O)R
7
, —(CH
2
)
p
C(O)NHR
7
, —(CH
2
)
p
CO
2
R
7
, (CH
2
)
n
OR
7
, and
aryl, heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl and heteroarylalkynyl, where the ring portion of each is optionally substituted with one, two or three groups independently selected from halogen, lower alkyl, hydroxy, amino, mono- or dialkylamino, trifluoromethyl, C(O)R
8
, COOR
8
, C(O)NHR
8
, and OR
8
;
n is 2-4;
p is 1-2;
q is 0-2;
R
6
is selected from hydrogen, lower alkyl, and lower alkenyl;
R
7
is selected from lower alkyl, or
aryl, heteroaryl, arylalkyl, and heteroarylalkyl, where the ring portion of each is optionally substituted with one, two or three groups independently selected from halogen, lower alkyl, hydroxy, amino, mono- or dialkylamino, trifluoromethyl, C(O)R
8
, COOR
8
, C(O)NHR
8
, and OR
8
; and
R
8
is independently selected from hydrogen, and
lower alkyl, aryl and heteroaryl optionally substituted with one, two or three groups independently selected from lower alkyl, halogen, lower alkoxy, hydroxy, amino, mono- or dialkylamino, and trifluoromethyl.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds encompassed by the instant invention are those described by the general Formula I set forth above, and the pharmaceutically acceptable salts and prodrugs thereof.
Preferred compounds of Formula I are those where R
1
is selected from hydroxy, amino, mono-C
1-2
-alkylamino and —COOH; R
2
is hydrogen; R
3
is selected from hydrogen, fluoro and methyl; R
4
is selected from hydrogen and —COOH; R
5
is —COOH; A is selected from —C(O)R
7
and —S(O)
2
R
7
; B is selected from lower alkyl, aryl-C
2-6
-alkyl, 5-6-membered heteroaryl-C
2-6
-alkyl, and (CH
2
)
n
OR
7
; R
7
is selected from aryl, 5-6 membered heteroaryl, aryl-C
1-3
-alkyl, and heteroaryl-C
1-3
-alkyl; n is 2-4; and R
8
is lower alkyl.
More preferred compounds of Formula I are those where R
1
is selected from hydroxy, amino, and monomethylamino; R
2
is hydrogen; R
3
is selected from hydrogen and fluoro; R
4
is hydrogen; R
5
is —COOH; A is selected from —C(O)R
7
and —S(O)
2
R
7
; B is selected from C
4-6
-alkyl, phenyl-C
3-4
-alkyl, 5-6 membered heteroaryl-C
3-4
-alkyl, and (CH
2
)
n
OR
7
; R
7
is selected from phenyl, 5-6 membered heteroaryl, phenyl-C
1-2
-alkyl, and 5-6 membered heteroaryl-C
1-2
-alkyl; n is 2-4; and R
8
is lower alkyl.
In addition to the compounds of Formula I, the invention encompasses compounds of Formula Ia:
wherein R
1
, R
2
, R
3
, A and B are as defined above for Formula I.
Preferred compounds of Formula Ia are those where R
1
is selected from amino and hydroxy; R
2
is hydrogen; R
3
is selected from hydrogen, fluoro and methyl; A is selected from —C(O)R
7
and —S(O)
2
R
7
; B is selected from arylalkyl, heteroarylalkyl, and (CH
2
)
n
OR
7
; R
7

Affiliated with

Also associated with

Rating

Preparation of phosphatase inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Preparation of phosphatase inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Preparation of phosphatase inhibitors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3056571