Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-08-25
2003-04-01
Kifle, Bruck (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06541468
ABSTRACT:
FIELD OF THE INVENTION
Novel indolocarbazole derivatives potentially useful for the treatment of dementias characterized by tau hyperphosphorylation [Alzheimer's disease (AD), frontal lobe degeneration (FLD), argyrophilic grains disease, subacute sclerotising panencephalitis (SSPE) as a late complication of viral infections in the CNS], and cancer.
BACKGROUND OF THE INVENTION
Several dementias, most importantly Alzheimer's disease (AD), are characterized by the formation of intracellular aggregates consisting of the microtubule-associated protein tau, termed neurofibrillary tangles (NFT). The importance of this biochemical abnormality for the clinical syndrome of dementia is illustrated by essentially three facts: (I) there is a close correlation between the state of dementia and the extent and density of NFT in various parts of the cortex [e.g., Bancher C. et al. (1993)
Neurosci. Lett
. 162, 179-182)]; (ii) individual neurons containing NFT in the cell body and/or the neurites are morphologically degenerating, i.e., lose synaptic connections and eventually die [Braak E. et al. (1994)
Acta Neuropathol
. 87, 554-567; Callahan L. M. et al., (1995)
Neurobiol. Aging
16, 311-314]; (iii) a certain density of NFT in various otherwise unrelated dementias is always associated with dementia, without exception.
The tau protein contained in NFT is severely hyperphosphorylated [Goedert M. et al. (1995)
Neurobiol. Aging
16, 325-334; Hasegawa M. et al. (1996)
FEBS Lett
. 384, 25-30]. This abnormal phosphorylation renders the protein incompetent to retain its original function, i.e., stabilization of the microtubule cytoskeleton, which is of fundamental importance for the integrity of a neuron [Iqbal K. et al. (1994)
FEBS Lett
. 349, 104-108; Garver T. D. et al. (1996)
J. Neurosci. Res
. 44, 12-20]. This explains-the paucity of intact microtubules in AD brains. Phosphorylation alone is responsible for this effect, as dephosphorylation restores the abilities of tau.
Because of a relationship between tau phosphorylation, cytoskeletal destabilization, synaptic loss and neuronal degeneration, and ultimately dementia, it would be therapeutically desirable to have pharmaceutical means to interfere with the pathological process of tau hyperphosphorylation.
The characteristics of hyperphosphorylated tau in NFT suggest that the protein kinase ERK2 is responsible for the pathological tau modification in AD [Drewes G. et al. (1990)
EMBO J
. 11, 2131-2138; Roder H. M. et al. (1993)
Biochem. Biophys. Res. Commun
. 193, 639-647]. ERK2 may exist in an abnormally activated state in AD [Roder H. M. et al. (1995)
J. Neurochem
. 64, 2203-2212). Inhibition of ERK2 has therefore been suggested as a point of interference to prevent tau hyperphosphorylation, and ultimately to stop NFT formation in neurons.
AD-like tau hyperphosphorylation can be induced in several cellular models (including brain slices), converting tau into a phosphorylation state indistinguishable from tau phosphorylated by ERK2 in vitro. The most convincing cellular models involve PP2A inhibition [Sautiér, P. E. et al.,
Neurodegeneration
3, 53-60 (1994); Harris K. A. et al.,
Ann. Neurol
. 33, 77-87 (
1993)].
However, compounds which inhibit ERK2 and thereby prevent AD-like tau hyperphosphorylation in biological model systems, have previously not been disclosed. Such compounds can be expected to affect processes of neurofibrillary degeneration, tied to tau hyperphosphorylation, in a beneficial manner.
The protein kinases of the ERK family, often termed MAP-kinases, have also been implicated in a variety of important cellular regulation events outside the CNS, such as growth, differentiation and inflammation [e.g., Sale E. M. et al.,
EMBO J
. 14, 674-684 (1995); Pages G. et al.,
Proc. Natl. Acad. Sci. USA
90, 8319-8323 (1993); Cowley S. et al.,
Cell
77, 841-852 (1994)]. Consequently, aberrant ERK activation has been implicated in several diseases characterized by loss of growth and differentiation control. In some tumors constitutive ERK activation is associated with cellular transformation due to dominant (activating) mutations in signal transduction proteins or viral proteins interfering with ERK inactivators [Sontag E. et al.,
Cell
75, 887-897 (1993); Leevers S. J. and Marshall C. J.,
EMBO J
. 11, 569-574 (1992); Gallego G. et al.,
Proc. Natl. Acad. USA
89, 7355-7359 (1992); Gupta S. K. et al.,
J. Biol. Chem
. 267, 7987-7990 (1992)].
The use of the disclosed kinase inhibitors for cancer is also indicated by their ability to inhibit cdc2 kinase. The role of cdc2 and homologous (cdks) kinases in cell cycle control is very well appreciated [Norbury C., and Nurse P.,
Annu. Rev. Biochem
. 61, 441-470 (1992)]. Regulation of these enzymes is essential for both commitment to cell cycle from the resting state (START), and ordered transition through several phases of the cell cycle. The need for regulation is reflected in the existence of numerous positive and negative regulatory features of cdks, such as cyclin subunits, inhibiting (Thr) and activating (Tyr) phosphorylations, and endogenous peptide inhibitors.
Because of this central role of cdks in control of cell cycle and proliferation, they are considered as attractive drug targets for cancer therapies [e.g., Filguera de Azevedo W. et al.,
Proc. Natl. Acad. Sci. USA
93, 2735-2740 (1996)].
DESCRIPTION OF RELATED ART
Indolocarbazole derivatives structurally related to the invention compounds have been described in the literature. The majority of these compounds are derived from the natural product K252a. The production and isolation of K252a was first published by Kase, et al. [
J. of Antibiotics
39, 1059 (1986)]. Subsequent structure elucidation of K252a, b, c and d were reported in the same year by Yasuzawa et al. [
J. of Antibiotics
39, 1072 (1986)]. Since the original disclosure and structure elucidation, K252a has been shown to be active in a variety of enzyme and cell-based assays. In particular, these compounds have demonstrated potent protein kinase C (PKC) activity. The most common uses claimed include: cancer, EP 0 323 171 (priority date Dec. 24, 1987), EP 0 643 966 (priority date Mar. 3, 1993), U.S. Pat. No. 4,923,986 (priority date Mar. 9, 1987), U.S. Pat. No. 4,877,776 (priority date Dec. 24, 1987), WO 94 27982 (priority date May 28, 1993); neurodegenerative disorders, WO 95 07911 (priority date Sep. 16, 1993), WO 94 02488 (priority date Dec. 24, 1992), antimicrobial [Prudhomme et al.,
J. Antibiotics
47, 792 (1994)], and hypertension [Hachisu et al.,
Life Sciences
44, 1351 (1989)].
K252a
In general, prior art compounds related to the invention are derived from K252a and contain the basic core structure where a tetrahydrofuran moiety is attached to the aglycone forming two glycosidic bonds. Modifications of the K252a core structure include additional substituents on the lactam and indole portions, and modifications of the a-hydroxy ester. The tetrahydrofuran oxygen in the core structure limits the opportunities for further modification.
SUMMARY OF THE INVENTION
Incorporation of a carbon at the tetrahydrofuran oxygen position of the K252a core structure significantly alters the core structure by removing the two glycosidic bonds and replacing the electron rich disubstituted atom with an electronically more neutral tetra-substituted moiety. This change also provides additional opportunities to incorporate functional groups that may enhance properties such as potency, selectivity, stability, toxicity, bioavailability, etc. which can result in an improved biological profile and consequently, a better therapeutic agent.
Compounds containing this important modification are completely inaccessible via synthetic methods used to prepare compounds of the prior art.
According to one aspect of the invention, a composition of matter is provided having the formula of Formula I, as follows:
wherein Z is O
Brittelli David R.
Lowinger Timothy B.
Roder Hanno
VanZandt Michael C.
Bayer Corporation
Kifle Bruck
Wolf Greenfield & Sacks P.C.
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