Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-02
2002-11-26
Dentz, Bernard (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06486322
ABSTRACT:
The present invention relates to azaindole derivatives and, more in particular, to 1H-pyrrolo[2,3-b]pyridine derivatives, to a process for their preparation, to pharmaceutical compositions comprising them and to their use as therapeutic agents, particularly in the treatment of cancer and cell proliferative disorders.
Several cytotoxic drugs such as, e.g. fluorouracil (5-FU), doxorubicin and camptothecins result to damage DNA or to affect cellular metabolic pathways and thus cause, in many cases, an indirect block of the cell cycle.
Therefore, by producing an irreversible damage to both normal and tumor cells, these agents result in a significant toxicity and side-effects.
In this respect, compounds capable of being highly specific antitumor agents by selectively leading to tumor cell arrest and apoptosis, with comparable efficacy but reduced toxicity than the currently available drugs, are desirable.
It is well known in the art that progression through the cell cycle is governed by a series of checkpoint controls, otherwise referred to as restriction points, which are regulated by a family of enzymes known as the cyclin-dependent kinases (cdk).
In their turn, the cdks themselves are regulated at many levels such as, for instance, binding to cyclins.
The coordinated activation and inactivation of different cyclin/cdk complexes is necessary for normal progression through the cell cycle. Both the critical G1-S and G2-M transitions are controlled by the activation of different cyclin/cdk activities. In G1, both cyclin D/cdk4 and cyclin E/cdk2 are thought to mediate the onset of S-phase. Progression through S-phase requires the activity of cyclin A/cdk2 whereas the activation of cyclin A/cdc2 (cdk1) and cyclin B/cdc2 are required for the onset of metaphases.
For a general reference to cyclins and cyclin-dependent kinases see, for instance, Kevin R. Webster et al. in Exp. Opin. Invest. Drugs, 1998, Vol. 7(6), 865-887.
Checkpoint controls are defective in tumor cells due, in part, to disregulation of cdk activity. For example, altered expression of cyclin E and cdk's has been observed in tumor cells, and deletion of the cdk inhibitor p27 KIP gene in mice has been shown to result in a higher incidence of cancer.
Increasing evidence supports the idea that the cdks are rate-limiting enzymes in cell cycle progression and, as such, represent molecular targets for therapeutic intervention. In particular, the direct inhibition of cdk/cyclin kinase activity should be helpful in restricting the unregulated proliferation of a tumor cell.
It has now been found that the 1H-pyrrolo{2,3-b]pyridine derivatives of the invention are endowed with cdk/cyclin kinase inhibitory activity and are thus useful in therapy as antitumor agents whilst lacking, in terms of both toxicity and side effects, the aforementioned drawbacks known for currently available antitumor drugs.
More specifically, the compounds of this invention are useful in the treatment of a variety of cancers including, but not limited to: carcinoma such as bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of yeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
Due to the key role of cdks in the regulation of cellular proliferation, these azaindoles are also useful in the treatment of a variety of cell proliferative disorders such as, for instance, benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
The compounds of the invention can be useful in the treatment of Alzheimer's disease, as suggested by the fact that cdk5 is involved in the phosphorylation of tau protein (
J. Biochem.,
117, 741-749, 1995;
FEBS Lett.,
459, 421-426, 1999).
The compounds of this invention, as modulators of apoptosis, could be useful in the treatment of cancer, viral infections, prevention of AIDS development in HIV-infected individuals, autoimmune diseases and neurodegenerative disorder.
The compounds of this invention could be useful in inhibiting tumor angiogenesis and metastasis.
The compounds of this invention may also act as inhibitors of other protein kinases, e.g. protein kinase C, her2, raf1, MEK1, MAP kinase, EGF receptor, VEGF receptor, PDGF receptor, IGF receptor, PI3 kinase, weel kinase, Src, Abl and thus be effective in the treatment of diseases associated with other protein kinases.
The compounds of the invention are also useful in the treatment and/or prevention of chemotherapy-induced or radiotherapy-induced alopecia.
Several 1H-pyrrolo[2,3-b]pyridines are known in the art as therapeutic agents. Among them are some cyanoacrylamido derivatives active as tyrosine kinase inhibitors as reported in WO 96/00226, in the name of the applicant. Some other acrylamido-1H-pyrrolo[2,3-b]pyridines are disclosed as antiallergic agents, as reported in Chem. Pharm. Bull., 37(3), 684-7 (1989).
Accordingly, the present invention provides a method for treating cell proliferative disorders associated with an altered cell dependent kinase activity, by administering to a mammal in need thereof an effective amount of a 1H-pyrrolo[2,3-b]pyridine represented by formula (I):
wherein
R is a hydrogen or halogen atom or a group selected from —CN, —OH, —OCOR
4
, —(CH
2
)
n
NH
2
, —(CH
2
)
n
NHR
4
, —(CH
2
)
n
NHCOR
4
, —(CH
2
)
n
NHCONR
4
R
5
, —(CH
2
)
n
NHCOOR
4
, or —(CH
2
)
n
NHSO
2
R
4
, wherein n is either 0 or 1, R
4
and R
5
are, independently from each other, hydrogen or an optionally substituted group selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl or, taken together to the nitrogen atom to which they are bonded, form an optionally substituted heterocyclyl group such as pyrrolidine, piperidine, piperazine and morpholine;
R
1
is hydrogen or an optionally substituted alkyl group;
R
2
is an optionally substituted group selected from alkyl or aryl;
R
3
is hydrogen or a group selected from —CONR
4
R
5
, —COOR
4
, —CONHOR
4
, —SO
2
NHR
4
, alkylsulphonylaminocarbonyl or perfluorinated alkylsulphonylaminocarbonyl; wherein R
4
and R
5
have the above reported meanings;
or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the method described above, the cell proliferative disorder is selected from the group consisting of cancer, Alzheimer's disease, viral infections, auto-immune diseases and neurodegenerative disorders.
Specific types of cancer that may be treated include carcinoma, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
In another preferred embodiment of the method described above, the cell proliferative disorder is selected from benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosi
Brasca Maria Gabriella
Longo Antonio
Orsini Paolo
Pevarello Paolo
Pittalà Valeria
Dentz Bernard
Oblon, Spivak, McClelland, Maier & Neustadt
Pharmacia Italia S.p.A.
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