Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-19
2002-07-02
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S445000, C514S447000, C549S029000, C549S068000, C549S070000, C549S072000, C549S074000, C549S076000
Reexamination Certificate
active
06414013
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to thiophene derivatives active as kinase inhibitors and, more in particular, it relates to 3-aminocarbonyl-2-carboxamido-thiophene derivatives, to a process for their preparation, to pharmaceutical compositions comprising them and to their use as therapeutic agents, particularly in the treatment of diseases linked to disregulated protein kinases.
2. Description of the Background
The malfunctioning of protein kinases (PKs) is the hallmark of numerous diseases. A large share of the oncogenes and proto-oncogenes involved in human cancers code for PKs. The enhanced activities of PKs are also implicated in many non-malignant diseases, such as 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.
PKs are also implicated in inflammatory conditions and in the multiplication of viruses and parasites. PKs may also play a major role in the pathogenesis and development of neurodegenerative disorders.
For a general reference to PKs malfunctioning or disregulation see, for instance,
Current Opinion in Chemical Biology
1999,3, 459-465.
SUMMARY OF THE INVENTION
It is an object of the invention to provide compounds which are useful in therapy as agents against a host of diseases caused by a disregulated protein kinase activity.
It is another object to provide compounds which are endowed with multiple protein kinase inhibiting activity.
The present inventors have now discovered that 3-aminocarbonyl-2-carboxamido-thiophene derivatives are endowed with multiple protein kinase inhibiting activity and are thus useful in therapy in the treatment of diseases associated with disregulated protein kinases.
More specifically, the 3-aminocarbonyl-2-carboxamido-thiophene derivatives 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 PKs in the regulation of cellular proliferation, these 3-aminocarbonyl-2-carboxamido-thiophenes 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).
The compounds of this invention, as modulators of apoptosis, may also be 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 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 in different isoforms, her2, raf1, MEK1, MAPK, EGF-R, PDGF-R, FGF-R, IGF-R, PI-3K, weel kinase, Src, Abl, Akt, ILK, PAK, CDKs/Cyclins, Chk, Plk, Nek, cdc7, auroral, aurora2 and thus be effective in the tretment of diseases associated with other protein kinases.
Accordingly, the present invention provides a method for treating diseases caused by and/or associated with an altered protein kinase activity, by administering to a mammal in need thereof an effective amount of a 3-aminocarbonyl-2-carboxamido-thiophene derivative represented by formula (I):
wherein
R
1
and R
2
are, independently from each other, hydrogen, halogen or an optionally substituted group selected from aryl, straight or branched C
1
-C
6
alkyl or aryl C
1
-C
6
alkyl; or, taken together with the thiophene bond to which they are linked, R
1
and R
2
form a —(CH
2
)
m
—(NR
4
)
n
—(CH
2
)
p
— group wherein m and p are, each independently, an integer form 1 to 3, n is 0 or 1 and m+n+p is an integer from 3 to 5; and
R
4
is hydrogen or an optionally substituted straight or branched C
1
-C
6
alkyl group;
R
3
is a group, optionally further substituted, selected from:
i) straight or branched C
1
-C
8
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl or C
2
-C
6
alkylcarbonyl;
ii) aryl;
iii) 3 to 7 membered carbocycle;
iv) 5 to 7 membered heterocycle with from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulphur;
or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the method described above, the disease caused by an altered protein kinase activity is selected from the group consisting of cancer, cell proliferative disorders, Alzheimer's disease, viral infections, auto-immune diseases and neurodegenerative disorders.
Specific types of cancer that may be treated include carcinoma, squamous cell carcinoma, hematopoietic tumors of myeloid or lymphoid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderoma pigmentosum, keratoxanthoma, thyroid follicular cancer and Kaposi's sarcoma.
In another preferred embodiment of the method described above, the cell proliferative disorder is selected from the group consisting of 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.
In addition, the method object of the present invention, also provides tumor angiogenesis and metastasis inhibition. Several 3-aminocarbonyl-2-carboxamido-thophene derivatives are known in the art, mostly as herbicides or synthetic intermediates and only few as therapeutic agents, particularly as anti-inflammatory agents.
See, for a general reference, Chemical Abstracts 108(1988):112332; 85(1976):123697; 112(1990):118758; DE-A-4039734 and FR-A-2035767.
The international patent application WO 98/54116 in the name of Cadus Pharmaceutical Co. discloses thiophene derivatives possessing antitumor activity.
The present invention thus provides a 3-aminocarbonyl-2-carboxamido-thiophene derivative represented by formula (I):
wherein
R
1
and R
2
are, independently from each other, hydrogen, halogen or an optionally substituted group selected from aryl, straight or branched C
1
-C
6
alkyl or aryl C
1
-C
6
alkyl;
or, taken together with the thiophene bond to which they are linked, R
1
and R
2
form a —(CH
2
)
m
—(NR
4
)
n
—(CH
2
)
p
— group wherein m and p are, each independently, an integer form 1 to 3, n is 0 or 1 and m+n+p is an integer from 3 to 5; and
R
4
is hydrogen or an optionally substituted straight or branched C
1
-C
6
alkyl group;
R
3
is a group, optionally further substituted, selected from:
i) straight or branched C
1
-C
8
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl or C
2
-C
6
alkylcarbonyl;
Fancelli Daniele
Pevarello Paolo
Varasi Mario
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Patel Sudhaker B.
Pharmacia & Upjohn S.p.A.
Shah Mukund J.
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