Method of modulating NF-kB activity

Details Method of modulating NF-kB activity Method of modulating NF-kB activity

2002-05-24

2003-11-04

Reamer, James H (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C514S344000, C514S346000, C514S352000

Reexamination Certificate

active

06642215

ABSTRACT:

FIELD OF INVENTION
The present invention relates to methods of modulating the activity of NF-&kgr;B and to methods of inhibiting the I&kgr;B complex (IKK) using cyanoguanidine derivatives.
BACKGROUND OF THE INVENTION
Neoplastic diseases are characterised by autonomous growth of cells. Neoplastic diseases may be benign, i.e. the growth is contained and does not spread to other organs or parts of the body. Neoplastic diseases may also be malignant where the growth spreads to other organs or parts of the body by infiltration or metastases. Malignant neoplastic diseases are also known as cancers.
Patients with neoplastic diseases are treated by surgery, ionising radiation, medication, or a combination thereof. Several types of medicaments or drugs for the treatment of neoplastic diseases are known, and one way of classifying these medicaments is suggested in Abeloff et al (Eds.),
Clinical Oncology,
Churchill Livingston Inc., New York, 1995, Medicaments for treatment of neoplastic diseases may conveniently by classified as chemotherapeutic agents, hormonal agents or biological response modifiers.
Chemotherapeutic agents may further be classified according to the mechanism whereby they effect their response as S-triazine derivatives such as altretamine; as enzymes such as asparaginase; as antibiotic agents such as bleomycin, dactinomycin, daunorubicin, doxorubicin, idarubicin, mitomycin and plicamycin; as alkylating agents such as busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamid, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, procarbazine and thiotepa; as antimetabolites such as cladribine, cytarabine, floxuridine, fludarabine, fluoruracil, hydroxyurea, mercaptopurine, methotrexate, pentostatin and thioguanine, and as antimitotic agents such as etoposide, paclitaxel, teniposide, vinblastine and vincristine.
Hormonal agents may be further classified according to the mechanism whereby they effect their response, e.g. as aromatase inhibitors such as aminoglutethimide; as antiestrogens such as tamoxifen, formestan and letrozol; and as antiandrogen such as flutamide.
Biological response modifiers may be further classified according to the mechanism whereby they effect their response as e.g. lymphokines such as aldesleukin; as interferon such as interferon-&agr; and as growth factors such as erythropoietin, filgrastim and sagramostim.
A number of medicaments do not fall naturally within this classification. Examples of such medicaments are anti-proliferative and/or cell differentiating agents such as all-trans retenoic acid or vitamin D analogues such as seocalcitol.
Other types of medicaments based on e.g monoclonal antibodies, tumour necrosis factor, gene therapy and angiogenisis inhibitors have been suggested for treatment of neoplastic diseases, but they are still in the exploratory phase.
Unfortunately, neoplastic cells are very effective in developing biochemical mechanisms that allow cellular resistance to medicaments or ionising radiation. In fact, resistance is a common clinical problem in the therapy of neoplastic diseases [Cun-Yu Wang, Nature Medicine, 5, 412-417, 1999]. In order to overcome this resistance, therapy generally involves more than one medicament or combinations of ionising radiation and medicaments. Several types of resistance are known, e.g. enhanced drug metabolism, altered drug accumulation, drug target amplification and repair of damaged targets. Resistance to apoptosis is another type of multi-drug resistance, that likely explains a significant proportion of treatment failures [Fisher,
Cell,
78, 539-542, 1994]. For convenience, the terms “medicament” and “drug” are used interchangeably, and are intended to indicate the same.
Clearly, there is a need for new and improved methods in the treatment of neoplastic diseases. Direct manipulation of the factors controlling apoptosis (programmed cell death) is a more recently suggested approach to therapy of neoplastic diseases. Apoptosis is a genetically encoded cell death programme characterised by an “active decision” by the cell based on information from its environment, its own internal metabolism, its developmental history, etc to die. Unlike cells undergoing necrosis, cells stimulated to enter apoptosis are often capable of survival, but opt to die for the good of the whole organism. Apoptosis is also different from necrosis in that necrosis is often associated with traumatised tissue and cell bursts, whereas the cells condense in the course of apoptosis, and are degraded intracellularly in a controlled manner [Tran,
Science and Medicine,
6, 18-27, 1999; Williams,
Trends Cell Biol.,
2, 263-267, 1992].
At the cellular level it is well recognised that nuclear factor &kgr;B (NF-&kgr;B) plays a pivotal role in apoptosis. It is also described that an NF-&kgr;B inhibitor, I&kgr;B, and an I&kgr;B kinase complex, IKK, control the level of activated NF&kgr;B [Levkau, 1, 227-233, 1999; Wang,
Science,
274, 784-787, 196; Madrid,
Molecular and Cellular Biology,
5, 1626-1638, 2000]. Accordingly, the NF-&kgr;B-I&kgr;B-IKK system has been suggested as a target in the treatment of neoplastic diseases.
Cusack,
Cancer Research,
60, 2323-2330, 2000 and Wang,
Nature Medicine
5, 412-417, 1999 teach that a particular chemotherapeutic, namely the topoisomerase I inhibitor 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11) promotes the activation of NF-&kgr;B in cells to induce resistance towards itself, and that a adenoviral transfer of an I&kgr;B, I&kgr;B&agr;, to inhibit NF&kgr;B promotes chemosensitivity to treatment with CPT-11.
WO98/37228 teaches that an agent which decreases IKK activity or that alters the association of IKK and I&kgr;B can be useful for allowing apoptosis to occur in a tumour cell by increasing the level of unphosphorylated I&kgr;B, which can bind to NF-&kgr;B and decrease the level of active NF-&kgr;B in the tumour cell.
Rossi, Nature, 403, 103-108, 2000 teaches that cyclopentenone prostaglandins inhibit I&kgr;B kinase, and that this makes cyclopentenone prostaglandins potentially valuable in the treatment of cancers, inflammation and viral infections.
SUMMARY OF THE INVENTION
It has surprisingly been found that a certain class of cyanoguanidine derivatives is capable of modulating the activity of I&kgr;B kinase (abbreviated IKK in the following). By modulating the activity of IKK in the cells it is possible to control the level of activated NF-&kgr;B in the cells. Such cyanoguanidines are therefore considered useful in the treatment of neoplastic diseases and other conditions believed to be affected by the level of activated NF&kgr;B, e.g. inflammation.
Accordingly, in one aspect the invention relates to a method of modulating the level of activated NF-&kgr;B in cells by contacting cells with a compound of general formula I
wherein
n is 0, 1 or 2;
each R independently represents halogen, trifluoromethyl, hydroxy, C
1-4
alkyl, alkoxy or alkoxycarbonyl, nitro, cyano, amino, sulfo or carboxy;
Q is straight or branched, saturated or unsaturated C
4-20
divalent hydrocarbon radical;
X is a bond, O, S, amine, carbonyl, carbonylamino, aminocarbonyl, oxycarbonyloxy, oxycarbonyl, carbonyloxy, aminocarbonyloxy, aminothiocarbonyloxy, oxycarbonylamino or oxythiocarbonylamino;
A is di-(C
1-4
alkoxy)phosphinoyloxy, C
1-4
alkoxycarbonyl, C
1-4
alkoxycarbonylamino, a saturated or unsaturated C
3-12
carbocyclic ring or C
3-12
heterocarbocyclic ring optionally substituted with one or more R
1
; R
1
being independently selected from the group consisting of halogen, trifluoromethyl, hydroxy, C
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkoxycarbonyl, nitro, cyano, amino, carboxy, sulfo, carboxamido, sulfamoyl or C
1-4
hydroxyalkyl;
or a pharmaceutically acceptable salt, N-oxide or N-substituted prodrug thereof, in an amount effective to modulate the activity of IKK.
In another aspect, the invention relates to a method of reducing the anti-apoptotic effect of NF&kgr;B by contacting the cells with

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