Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-08-12
2002-05-14
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C548S364100, C548S371400, C514S407000, C514S254050, C544S140000, C544S371000
Reexamination Certificate
active
06387900
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to 3(5)-ureido-pyrazole derivatives, to a process for their preparation, to pharmaceutical compositions containing them and to their use as therapeutic agents, particularly in the treatment of cancer and proliferative disorders.
2. Discussion of the Background
Several cytotoxic drugs such as, e.g. fluorouracil (5-FU), doxorubicin and camptothecins, cause damage to 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 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 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.
SUMMARY OF THE INVENTION
It is an object of the invention to provide compounds which are useful in treating cell proliferative disorders associated with an altered cell dependent kinase activity. It is another object to provide compounds which have cdk/cyclin kinase inhibitory activity. It is another object of the invention to provide compounds which are useful in therapy as antitumor agents but lack, in terms of both toxicity and side effects, the drawbacks associated with currently available antitumor drugs as discussed above.
The present inventors have now discovered that 3-ureido-pyrazoles have cdk/cyclin kinase inhibitory activity and are thus useful in therapy as antitumor agents and lack, in terms of both toxicity and side effects, the aforementioned drawbacks of known 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 myeloid 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 3-ureido-pyrazole derivatives are also useful in the treatment of a variety of cell proliferative disorders such as, for instance, benign prostate hyperplasia, familial adenomatosis polyposis, neurofibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
The compounds of the invention may 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).
The compounds of this invention, as modulators of apoptosis, may also useful in the treatment of cancer, viral infections, prevention of AIDS development in HIV-infected individuals, autoimmune diseases and neurodegenerative disorders.
The compounds of this invention may also be useful in inhibiting tumor angiogenesis and metastasis.
The compounds of this invention may also act as inhibitors of other protein kineses, e.g. protein kinase C, her2, raf1, MEK1, MAP kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase, weel kinase, Src, Ab1 and thus be effective in the treatment of diseases associated with other protein kineses.
Accordingly, the present invention provides a method for the treatment of cell proliferative disorders associated with an altered cell dependent kinase activity, comprising administering to a mammal in need thereof an effective amount of a compound represented by formula (I):
where
R is a C
3
-C
6
cycloalkyl group optionally substituted with a straight or branched C
1
-C
6
alkyl group or is a C
1
-C
6
alkyl or arylalkyl group, which is optionally substituted with one or more hydroxy, halogen, nitro, cyano, oxo, carboxy, amino, alkylamino, dialkylamino, alkylcarbonylamino, alkoxycarbonylamino, alkoxycarbonylalkylamino, aminocarbonylalkylamino, N-alkyl-N-carbonylamino, N-cycloalkyl-N-alkylaminoalkyl, aminoalkyl, aminocarbonyl, alkyl, cycloalkyl, alkylthio, alkoxy, alkylcarbonyl, alkylsulphonyl, alkylsulphonylamino, aminosulphonyl, alkoxycarbonyl, aryl, arylalkyl, aryloxy, arylthio, arylsulphonyl, arylamino, arylcarbonyl, N-alkyl-piperazinyl, 4-morpholinyl, perfluorinated C
1
-C
4
alkyl, C
2
-C
4
alkenyl, C
2
-C
4
alkynyl, C
2
-C
4
aminoalkynyl or C
2
-C
4
hydroxyalkynyl substituents;
R
1
is —CH
2
)
n
—R
3
;
n is 0 or an integer from 1 to 4;
R
3
is hydrogen, hydroxy, amino, or a group selected from the group consisting of cycloalkyl, aryl and heterocyclyl, which is optionally substituted with one or more hydroxy, halogen, nitro, cyano, oxo, carboxy, amino, alkylamino, dialkylamino, alkylcarbonylamino, alkoxycarbonylamino, alkoxycarbonylalkylamino, aminocarbonylalkylamino, N-alkyl-N-carbonylamino, N-cycloalkyl-N-alkylaminoalkyl, aminoalkyl, aminocarbonyl, alkyl, cycloalkyl, alkylthio, alkoxy, alkylcarbonyl, alkylsulphonyl, alkylsulphonylamino, aminosulphonyl, alkoxycarbonyl, aryl, arylalkyl, aryloxy, arylthio, arylsulphonyl, arylamino, arylcarbonyl, N-alkyl-piperazinyl, 4-morpholinyl, perfluorinated C
1
-C
4
alkyl, C
2
-C
4
alkenyl, C
2
-C
4
alkynyl, C
2
-C
4
aminoalkynyl or C
2
-C
4
hydroxyalkynyl substituents;
R
2
is hydrogen, or
R
2
and R
1
, together with the nitrogen atom to which they are bonded, form a heterocyclyl or heteroaryl group, which is optionally substituted with one or more hydroxy, halogen, nitro, cyano, oxo, carboxy, amino, alkylamino, dialkylamino, alkylcarbonylamino, alkoxycarbonylamino, alkoxycarbonylalkylamino, aminocarbonylalkylamino, N
Fritzen Edward L.
Orsini Paolo
Pevarello Paolo
Pierce Betsy S.
Traquandi Gabriella
Liu Hong
Pharmacia & Upjohn S.p.A.
Raymond Richard L.
LandOfFree
3(5)-ureido-pyrazole derivatives process for their... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 3(5)-ureido-pyrazole derivatives process for their..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 3(5)-ureido-pyrazole derivatives process for their... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2819583