Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-27
2002-11-12
Solola, T. A. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S323000, C514S414000, C544S143000, C546S187000, C548S466000
Reexamination Certificate
active
06479490
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is directed to 3-indolyl-4-phenyl-1H-pyrrole-2,5-dione derivatives that inhibit glycogen synthase kinase-3&bgr; (GSK-3&bgr;) and are therefore useful in the treatment of mammals having disease states mediated by it. The present invention is also directed to pharmaceutical compositions containing these compounds, methods for preparing them, and methods for their use, in particular methods of treatment of diseases characterized by excess Th2 cytokines and/or an excess IgE production.
2. State of the Art
Glycogen synthase kinase (GSK) is a serine/threonine kinase for which two isoforms, &agr; and &bgr;, have been identified. Glycogen synthase kinase -3&bgr; (GSK-3&bgr;) was originally identified as a protein kinase which phosphorylated and inactivated glycogen synthase a key enzyme regulating insulin-stimulated glycogen synthesis ((see Embi et al.,
Eur. J. Biochem.
107, 519-527, (1980); Rylatt et al.,
Eur. J. Biochem.
107, 529-537, (1980); and Vandenheede et al.,
J. Biol. Chem.
255, 11768-11774, (1980)). Subsequently, it was discovered that GSK-3&bgr; is inhibited upon insulin activation thereby allowing the activation of glycogen synthase. Therefore, inhibition of GSK-3&bgr; stimulates insulin-dependent processes and is useful in the treatment of type 2 diabetes which is characterized by decreased sensitivity to insulin and an increase in blood glucose level. A number of drugs such as 5-iodotubercidin®, metformin®, troglitazonem®, have been used to treat diabetes. These drugs however have limited application because metformin® can cause hypoglycemia, troglitazonem® can cause severe hepatoxicity and 5-iodotubercidin®, a GSK-3 inhibitor, inhibits other serine/threonine and tyrosine kinases.
Recently, it has been discovered that GSK-3&bgr; plays a role in pathogenesis of Alzheimer's disease ((see Lovestone et al.,
Current Biology,
4, 1077-86 (1994), Brownlees et al.,
Neuroreport,
8, 3251-3255 (1997), Takashima et al.,
PNAS
95, 9637-9641 (1998), and Pei et al.,
J Neuropathol. Exp.,
56, 70-78 (1997)) and bipolar disorder (see Chen et al.,
J. Neurochemistry,
72, 1327-1330 (1999)). It has also been discovered that GSK-3&bgr; is involved in blocking of early immune response gene activation via NF-AT and regulation of apoptosis (see Beals et al.,
Science,
275, 1930-33 (1997) and Pap, M. et al.
J. Biochem.
273, 19929-19932, (1998)). Recently, it has also been discovered that GSK-3&bgr; is required for the NF-&kgr;B mediated survival response in the TNF-&agr; signalling pathway involved in the proinflammatory response to infection ((Hoeflich et.al.,
Nature,
406, 86-90 (2000)).
Furthermore, GSK-3&bgr; is also known to regulate the degradation of a protein (&bgr;-catenin) which controls the activity of TCF family of transcription factors ((see., Dale,T. C.,
Biochem. J.
329, 209-223 (1998); Clevers, H. & van de Wetering, M.,
Trends in Genetics
13, 485-489 (1997); Staal, F. J. T. et al.,
International Immunology
11, 317-323 (1999)). The activity of this pathway has been shown to regulate the proliferation of colonic epithelial cells; and the biochemical data and clinical genetics demonstrate that it regulates the development of colon cancer.
Accordingly, there is a need for compounds that would inhibit GSK-3&bgr; and thereby provide a means for combating diseases mediated by it. This invention fulfills this and related needs.
SUMMARY OF THE INVENTION
The present invention is directed to 3-indolyl-4-phenyl-1H-pyrrole-2,5-dione derivatives that inhibit GSK-3&bgr; and are therefore useful in the treatment of mammals having disease states mediated by it such as diabetes, Alzheimer's disease, bipolar disorder, ischemia, traumatic brain injury, and immunodeficiency.
In addition, Applicants have discovered that inhibition of GSK-3&bgr; activity reduces the level of CD4+ T-helper 2 cells (Th2) which produce cytokines such as IL-4, IL-5, IL-13, and promote IgE production and eosinophil differentiation. This is an important discovery because it has been established that Th2 specific cytokines play a key role in the pathogenesis of diseases such as allergies and asthma. Therefore, the compounds of the present invention also provide a novel approach for the treatment of allergies and asthma.
Accordingly, in a first aspect, this invention is directed to 3-indolyl-4-phenyl-1H-pyrrole-2,5-dione derivatives represented by Formula (I):
wherein:
R
1
and R
2
independently represent hydrogen, alkyl, halo, haloalkyl, alkylthio, hydroxy, alkoxy, cyano, nitro, amino, acylamino, monoalkylamino, or dialkylamino;
R
3
represents hydrogen, alkyl, cycloalkyl, heteroalkyl, —COR
7
(wherein R
7
is hydrogen or alkyl), or phenyl optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkylthio, hydroxy, alkoxy, cyano, nitro, amino, acylamino, monoalkylamino, and dialkylamino;
R
4
and R
5
independently represent hydrogen, alkyl, halo, haloalkyl, alkylthio, hydroxy, alkoxy, cyano, nitro, amino, acylamino, monoalkylamino, or dialkylamino;
R
6
is heteroalkyl, heterocyclyl, heterocyclylalkyl, heteroalkylsubstituted heterocyclyl, heteroalkylsubstituted cycloalkyl, hetereosubstituted cycloalkyl, —OR
8
, —S(O)
n
R
8
(wherein n is 0 to 2; and R
8
is heteroalkyl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl), —NR
9
R
10
(wherein R
9
is hydrogen or alkyl and R
10
is heteroalkyl, heteroaralkyl, heterosubstituted cycloalkyl, heterocyclyl, or heterocyclylalkyl), or —X-(alkylene)—Y—Z (wherein X is a covalent bond, —O—, —NH—, or —S(O)
n1
— where n1 is 0 to 2, and Y is —O—, —NH—, or —S—, and Z is heteroalkyl or SiR
11
R
12
R
13
where R
11
, R
12
and R
13
are independently hydrogen or alkyl), or R
6
together with R
4
forms a methylenedioxy or ethylenedioxy group when they are adjacent to each other; or
a pharmaceutically acceptable salt thereof.
The compounds of the present invention exhibit surprisingly effective activity against GSK-3&bgr;. It is contemplated that the improved activity is due to their enhanced bioavailability and increased metabolic stability.
In a second aspect, this invention is directed to a method of treatment of a disease in a mammal treatable by administration of a GSK-3&bgr; inhibitor which method comprises administration of a therapeutically effective amount of a compound of Formula (I) or its pharmaceutically acceptable salt either alone or in combination with other pharmacologically active agents. In particular, the compounds of this invention are useful in treating respiratory diseases such as asthma.
In a third aspect, this invention is directed to pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.
In a fourth aspect, this invention is directed to the use of compounds of Formula (I) in the preparation of medicaments for use in the treatment of diseases mediated by GSK-3&bgr;.
In a fifth aspect, this invention provides processes for preparing compounds of Formula (I).
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Hoeflich, et al., “Requirement for glycogen synthase kinase-3&bgr; in cell survival and NF-kB activation,”Nature,vol. 406 (Jul. 6, 2000), pp 86-90.
Faul, et al., “aA New One Step Synthesis of Maleimides by Condensation of Glyoxylate Esters with Acetamides,”Tetrahedron Letters,vol. 40 (1999), pp 1109-1112.
Davis, et al., “Inhibitors of Protein Kinase C. 1.12,3 Bisarylmaleimides,”J. Med. Chem.,vol. 35:1 (1992) pp 177-184.
Harris, et
Gong Leyi
Grupe Andrew
Peltz Gary Allen
Murray Joseph
Peries Rohan
Solola T. A.
Syntex (U.S.A.) LLC
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