Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2001-03-21
2002-10-15
Vollano, Jean F. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S080000, C514S082000, C562S020000, C564S022000, C564S023000
Reexamination Certificate
active
06465444
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-1tyrosine 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 may improve insulin-sensitivity. They may 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. PTP-1B inhibitors are not currently used in any medications, and new compounds are needed to find compounds that are suitable for medicinal uses
SUMMARY OF THE INVENTION
Compounds represented by formula 1, including pharmaceutically acceptable salts thereof, and prodrugs thereof, are PTP-1B inhibitors that may be useful in the treatment of diabetes and related medical conditions, and may also be useful in the treatment of other PTP-1B mediated diseases or conditions.
In the compounds of formula I:
Each X
1
is independently selected from the group consisting of: H, OH, halogen, CN, CO
2
H, CO
2
C
1-6
alkyl, CO
2
C
2-6
alkenyl, OC
1-6
alkyl, OC
2-6
alkenyl, C(O)C
1-6
alkyl, C(O)C
2-6
alkenyl, OC(O)C
1-6
alkyl, OC(O)C
2-6
alkenyl, S(O)
x
C
1-6
alkyl, S(O)
x
C
2-6
alkenyl, C
1-6
alkyl, C
2-6
alkenyl, S(O)
2
NR
1
R
2
, C(O)NR
1
R
2
, and NR
1
R
2
, wherein each alkyl group and each alkenyl group in each substituent is optionally substituted with one or more groups independently selected from (a) 1-13 halogen atoms and/or (b) 1-2 substituents independently selected from OC
1-3
alkyl, C(O)C
1-3
alkyl, OC(O)C
1-3
alkyl, CO
2
H, and CO
2
C
1-3
alkyl;
X
1
, CF
2
P(O)(OR
5
)
2
and Y
1
S(O)
X
R are substituted onto any position of either ring;
Each x is independently 0, 1, or 2;
R
5
is H;
R
1
and R
2
are each independently selected from the group consisting of H and C
1-4
alkyl, wherein said alkyl substituents are optionally substituted with 1-9 halogen atoms;
Each halogen is independently selected from I, Cl, Br and F;
Y
1
is selected from the group consisting of a bond, a C
1-4
alkylene group, and a C
2-4
alkenylene group, wherein the alkylene group and the alkenylene group are optionally substituted with one or more of the following groups: (a) 1-8 halogen atoms, and/or (b) 1-2 substituents independently selected from OH and OC
1-4
alkyl, where OC
1-4
alkyl is optionally substituted with 1-9 halogen atoms;
R is selected from the group consisting of C
1-10
alkyl, C
2-10
alkenyl, C
2-10
alkadienyl, C
2-10
alkynyl, Ar
1
, and Het
1
, wherein said alkyl, alkenyl, alkadienyl, and alkynyl are optionally substituted with one substituent selected from Ar
1
and Het
1
, and are optionally also substituted with one or more groups independently selected from (a) 1-21 halogen atoms, and (b) 1-2 substituents independently selected from OH, CN, CO
2
H, CO
2
C
1-6
alkyl, CO
2
C
2-6
alkenyl, OC
1-6
alkyl, OC
2-6
alkenyl, OC(O)C
1-6
alkyl, OC(O)C
2-6
alkenyl, C(O)C
1-6
alkyl, C(O)C
2-6
alkenyl, C(O)Aryl, OC(O)Aryl, OAryl, CO
2
Aryl, S(O)C
1-6
alkyl, S(O)
x
C
2-6
alkenyl, S(O)
2
NR
1
R
2
, C(O)NR
1
R
2
, and NR
1
R
2
, wherein said alkyl groups and said alkenyl groups of said substituents are optionally substituted with 1-13 halogen atoms;
Het
1
is a 5-10 membered aromatic ring system comprising 1 ring or 2 rings fused together and 1-4 heteroatoms selected from O, N, S(O)x, and combinations thereof, and 0-2 carbonyl groups, wherein one of the fused rings is optionally a benzene ring, and Het1 is optionally substituted with one or more groups independently selected from (a) one group selected from CF
2
P(O)(OR
5
)
2
, CO
2
H, CF
2
CO
2
H, P(O)(OR
5
)
2
, and SO
2
R
4
, and/or (b) 1-2 groups independently selected from R
3
;
Ar
1
is phenyl or naphthyl, optionally substituted with one or more groups independently selected from (a) one group selected from CF
2
P(O)(OR
5
)
2
, CO
2
H, CF
2
CO
2
H, P(O)(OR
5
)
2
, SO
2
R
4
, and Ar
2
, and/or (b) 1-2 groups selected from R
3
;
Ar
2
is phenyl, naphthyl or a 5-10 membered aromatic ring system comprising 1 ring or 2 rings fused together and 1-4 heteroatoms selected from O, N, S(O)
x
, and combinations thereof, and 0-2 carbonyl groups, wherein one of said fused rings is optionally a benzene ring, wherein Ar
2
is optionally substituted with one or more of the following groups: (a) one group selected from CF
2
P(O)(OR
5
)
2
, CO
2
H, CF
2
CO
2
H, P(O)(OR
5
)
2
, and SO
2
R
4
, and/or (b) 1-2 groups selected from R
3
;
R
3
is selected from the group consisting of halogen, OH, CN, CO
2
H, CO
2
C
1-10
alkyl, CO
2
C
2-10
alkenyl, OC
1-10
alkyl, OC
2-10
alkenyl, C
1-10
alkyl, C
2-10
alkenyl, OC(O)C
1-10
alkyl, OC(O)C
2-10
alkenyl, C(O)C
1-10
alkyl, C(O)C
2-10
alkenyl, C(O)Aryl, OC(O)Aryl, OAryl, CO
2
Aryl, S(O)
x
C
1-10
alkyl, S(O)
x
C
2-10
alkenyl, S(O)
2
NR
1
R
2
, C(O)NR
1
R
2
, NR
1
R
2
, Aryl, and Het, wherein each alkyl group and each alkenyl group of each substituent is optionally substituted with one or more groups independently selected from (a) 1-21 halogen atoms and/or (b) 1-2 substituents independently selected from OH, OC
1-3
alkyl, CO
2
H, CO
2
C
1-3
alkyl, C(O)C
1-3
alkyl, OC(O)C
1-3
alkyl, and phenyl, wherein phenyl is optionally substituted with 1-3 substituents independently selected from OCH
3
, OCF
3
, Cl and F, and the C
1-3
alkyl groups of the substituents are optionally substituted with one or more groups independently selected from (a) 1-7 halogen atoms and/or (b) 1-2 phenyls, wherein said phenyls are optionally substituted with 1
Bayly Christopher
Ohkubo Mitsuru
McGinnis James L.
Merck Frosst Canada & Co.
Vollano Jean F.
Winokur Melvin
LandOfFree
Aryldifluoromethylphosphonic acids with sulfur-containing... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Aryldifluoromethylphosphonic acids with sulfur-containing..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Aryldifluoromethylphosphonic acids with sulfur-containing... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2999625