Modulators of protein tyrosine phosphatases (PTPases)

Details Modulators of protein tyrosine phosphatases (PTPases) Modulators of protein tyrosine phosphatases (PTPases)

2001-07-09

2003-09-02

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S301000

Reexamination Certificate

active

06613903

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel thienopyridines, to methods for their preparation, to compositions comprising the compounds, to the use of these compounds as medicaments and their use in therapy, where such compounds of Formula 1 are pharmacologically useful inhibitors or modulators of Protein Tyrosine Phosphatases (PTPases) including PTP1B and T cell PTP,
wherein X, R
1
, R
2
, R
3
, and R
4
are defined more fully below.
It has been found that PTPases play a major role in the modulation and regulation of fundamental cellular signaling mechanisms involved in metabolism, growth, proliferation and differentiation (Fischer et al,
Science
253:401-6 (1991); Tonks and Neel, Cell 87: 365-368 (1996); Neel and Tonks,
Current Opinion in Cell Biology
9: 193-204 (1997); Hunter, Phil. Trans. R. Soc. Lond. B 353: 583-605 (1998); Zhang,
Critical Reviews in Biochemistry and Molecular Biology
33:1-52 (1998)). There is increasing evidence which suggests that inhibition of these PTPases may help treat or manage certain types of diseases such as type 1 and type 2 diabetes, obesity, autoimmune diseases, acute and chronic inflammation, osteoporosis and various forms of cancer. In addition, certain infectious diseases may also be treated or managed by administration PTPase inhibitors (Clemens et al.,
Molecular Microbiology
5: 2617-2620 (1991)).
BACKGROUND OF THE INVENTION
Protein phosphorylation is now well recognized as an important mechanism utilized by cells to transduce and regulate signals during different stages of cellular function (Hunter, vide supra; Chan et al.,
Annu. Rev. Immunol.
12: 555-592 (1994); Zhang,
Curr. Top. Cell. Reg.
35: 21-68 (1997); Matozaki and Kasuga,
Cell. Signal.
8: 113-19 (1996); Fischer et al, vide supra). The level of tyrosine phosphorylation is balanced by the opposing action of protein tyrosine kinases and protein tyrosine phosphatases (PTPases). There are at least two major classes of phosphatases: (1) those that dephosphorylate proteins (or peptides) that contain a phosphate group(s) on a serine or threonine moiety (termed Ser/Thr phosphatases) and (2) those that remove a phosphate group(s) from the amino acid tyrosine (termed protein tyrosine phosphatases or PTPases or PTPs). The PTPases are a family of enzymes that can be classified into two groups: a) intracellular or nontransmembrane PTPases and b) receptor-type or transmembrane PTPases. In addition, dual-specificity phosphatases and low molecular weight phosphatases can also dephosphorylate phosphotyrosyl proteins (WO97/39748, WO97/40017, WO99/15529, WO97/08934, WO98/27065, WO99/46236, WO99/46244, WO99/46267, WO99/46268, WO99/46237).
It has been found that PTPases play a major role in the above modulation and regulation of fundamental cellular signaling mechanisms involved in metabolism, growth, proliferation and differentiation (Fischer et al,
Science
253:401-6 (1991); Tonks and Neel,
Cell
87: 365-368 (1996); Neel and Tonks,
Current Opinion in Cell Biology
9: 193-204 (1997); Hunter,
Phil. Trans. R. Soc. Lond. B
353: 583-605 (1998); Zhang,
Critical Reviews in Biochemistry and Molecular Biology
33:1-52 (1998)). Reports from many laboratories have shown that PTPases can act both as positive and negative regulators of signal transduction processes. PTPases have been implicated in a variety of human diseases, including type land type diabetes, obesity, autoimmune diseases, acute and chronic inflammation, osteoporosis, proliferative disorders including various forms of cancer, growth disorders, and defective platelet aggregation (WO97/39748, WO97/40017, WO99115529, WO97/08934, WO98/27065, WO99/46236, WO99/46244, WO99/46267, WO99/46268, WO99/46237). Accordingly, there is increasing evidence which suggests that inhibition of these PTPases may help treat or manage said diseases (Hunter, vide supra; Neel and Tonks, vide supra; Frangione et al.,
EMBO J.
12: 4843-4856; Zhang,
Curr. Top. Cell. Reg.
35: 21-68 (1997); Zhang, vide supra; Evans and Jallan,
Exp. Opinion. Invest. Drugs
8: 139-160 (1999); Burke and Zhang,
Biopolymers
(
Peptide Science
) 47: 225-241 (1998); Elchebly et al.,
Science
283: 1544-1548 (1999); Wrobel et al.,
J. Med. Chem.
42: 3199-3202 (1999)). In addition, certain infectious diseases may also be treated or managed by administration PTPase inhibitors (Clemens et al.,
Molecular Microbiology
5: 2617-2620 (1991)).
Both selective PTPase inhibitors and inhibitors that bind to several PTPases (non-selective inhibitors) can be used therapeutically to partially or completely restore PTPase-mediated perturbed signal transduction processes and thus for management, treatment or prevention of the above diseases.
WO 99/46267 discloses compounds which are pharmacologically useful inhibitors of PTPases. However, the present invention which represents a novel selection under WO 99/46267, discloses a class of compounds which surprisingly are more potent against protein tyrosine phosphatases (e.g. PTP1 B) than those disclosed in WO 99/46267.
DESCRIPTION OF THE INVENTION
The present invention relates to compounds of the Formula 1 wherein X, R
1
, R
2
, R
3
, and R
4
are defined below;
wherein
X is —C(O)— or —S(O)
2
—;
R
1
and R
2
are independently hydrogen, C
1
-C
6
alkyl, aryl-R
5
—, R
6
—C(O)—O—R
7
— or aryl-R
8
—C(O)—O—R
9
— wherein aryl is phenyl, naphthyl or thiophenyl, which aryl group is optionally substituted with halogen, nitro, trihalomethyl, C
1
-C
6
alkyl or C
1
-C
6
alkyloxy;
R
3
is C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, aryl, aryl-R
10
—, aryl-N(R
35
)—, aryl-R
11
—N(R
36
)—, N(R
37
)(R
38
)—R
39
—, C
1
-C
6
alkyloxy or aryl-R
13
—O— wherein aryl is phenyl, biphenyl, indenyl, naphthyl, imidazolyl, benzo[b]furanyl, 1,2,3-triazolyl, thiophenyl, pyridyl, quinolyl, isoquinolyl, indolyl or benzimidazolyl, which aryl group is optionally substituted with halogen, nitro, cyano, hydroxy, trihalomethyl, C
1
-C
6
alkyl, aryl, aryl-R
14
—, C
1
-C
6
alkyloxy, aryloxy, aryl-R
15
—O—, aryl-N(R
16
)—, R
18
—C(O)—N(R
19
)—, aryl-C(O)—N(R
21
)— or aryl-R
23
—C(O)—N(R
24
)— and wherein aryl is phenyl, naphthyl or thiophenyl;
R
4
is hydrogen, R
27
—O—C(O)—, aryl-R
28
—O—C(O)—, R
29
—C(O)—O—R
30
—OC(O)— or aryl-R
31
—C(O)—O—R
32
—O—C(O)— wherein aryl is phenyl, naphthyl or thiophenyl, which aryl group is optionally substituted with halogen, nitro, cyano, trihalomethyl, aryl, aryl-R
33
—, C
1
-C
6
alkyloxy or aryl-R34—O— and wherein aryl group is phenyl, naphthyl or thiophenyl;
and wherein R
5
, R
7
, R
8
, R
9
, R
10
, R
11
, R
13
, R
14
, R
15
, R
23
, R
28
, R
30
, R
31
, R
32
, R
33
, R
34
, and R
39
independently are C
1
-C
6
alkylene, wherein R
6
, R
12
, R
17
, R
18
, R
20
, R
22
, R
25
, R
27
, R
29
, R
37
, and R
38
independently are C
1
-C
6
alkyl and wherein R
16
, R
19
, R
21
, R
24
, R
35
and R
36
independently are hydrogen or C
1
-C
6
alkyl;
or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form.
The compounds of the invention can be further modified to act as prodrugs.
A preferred prodrug is acetoxymethyl esters or acetoxymethyl carbamates of the compounds of the present invention. As a general procedure preparation of an acetoxymethyl ester is given below (C. Schultz et al,
The Journal of Biological Chemistry,
1993, 268, 6316-6322.):
A carboxylic acid (1 equivalent) is suspended in dry acetonitrile (2 ml per 0.1 mmol). Diisopropyl amine (3.0 equivalents) is added followed by bromomethyl acetate (1.5 equivalents). The mixture is stirred under nitrogen overnight at room temperature. Acetonitrile is removed under reduced pressure to yield an oil which is diluted in ethyl acetate and washed with water (3×). The organic layer is dried over anhydrous magnesium sulfate, filtred and the solvent removal under reduced pressure affording a crude oil. The product is purified by column chromatography on silica gel, using an appropriate solvent system known to those skilled in the art.
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