Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-06-14
2004-02-10
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252190, C514S275000, C544S122000, C544S331000
Reexamination Certificate
active
06689778
ABSTRACT:
TECHNICAL FIELD OF INVENTION
The present invention relates to inhibitors of kinases belonging to the Src family of protein kinases, especially Src and Lck protein kinases. Src kinases are implicated in cancer, immune disorders and bone diseases. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing those compositions in the treatment and prevention of various disorders.
BACKGROUND OF THE INVENTION
Mammalian cells respond to extracellular stimuli by activating signaling cascades that are mediated by members of the mitogen-activated protein (MAP) kinase family, which include the extracellular signal regulated kinases (ERKs), the p38 MAP kinases and the c-Jun N-terminal kinases (JNKs). MAP kinases (MAPKs) are activated by a variety of signals including growth factors, cytokines, UV radiation, and stress-inducing agents. MAPKs are serine/threonine kinases and their activation occur by dual phosphorylation of threonine and tyrosine at the Thr-X-Tyr segment in the activation loop. MAPKs phosphorylate various substrates including transcription factors, which in turn regulate the expression of specific sets of genes and thus mediate a specific response to the stimulus.
One kinase family of particular interest is the Src family of kinases. These kinases are implicated in cancer, immune system dysfunction and bone remodeling diseases. For general reviews, see Thomas and Brugge,
Annu. Rev. Cell Dev. Biol
. (1997) 13, 513; Lawrence and Niu,
Pharmacol. Ther
. (1998) 77, 81; Tatosyan and Mizenina,
Biochemistry
(Moscow) (2000) 65, 49; Boschelli et al.,
Drugs of the Future
2000, 25(7), 717, (2000).
Members of the Src family include the following eight kinases in mammals: Src, Fyn, Yes, Fgr, Lyn, Hck, Lck, and Blk. These are nonreceptor protein kinases that range in molecular mass from 52 to 62 kD. All are characterized by a common structural organization that is comprised of six distinct functional domains: Src homology domain 4 (SH4), a unique domain, SH3 domain, SH2 domain, a catalytic domain (SH1), and a C-terminal regulatory region. Tatosyan et al.
Biochemistry
(Moscow) 65, 49-58 (2000).
Based on published studies, Src kinases are considered as potential therapeutic targets for various human diseases. Mice that are deficient in Src develop osteopetrosis, or bone build-up, because of depressed bone resorption by osteoclasts. This suggests that osteoporosis resulting from abnormally high bone resorption can be treated by inhibiting Src. Soriano et al.,
Cell,
69, 551 (1992) and Soriano et al.,
Cell,
64, 693 (1991).
Suppression of arthritic bone destruction has been achieved by the overexpression of CSK in rheumatoid synoviocytes and osteoclasts. Takayanagi et al.,
J. Clin. Invest.,
104, 137 (1999). CSK, or C-terminal Src kinase, phosphorylates and thereby inhibits Src catalytic activity. This implies that Src inhibition may prevent joint destruction that is characteristic in patients suffering from rheumatoid arthritis. Boschelli et al.,
Drugs of the Future
2000, 25(7), 717, (2000).
Src also plays a role in the replication of hepatitis B virus. The virally encoded transcription factor HBx activates Src in a step required for propagation of the virus. Klein et al.,
EMBO J.,
18, 5019, (1999) and Klein et al.,
Mol.Cell. Biol.,
17, 6427 (1997).
A number of studies have linked Src expression to cancers such as colon, breast, hepatic and pancreatic cancer, certain B-cell leukemias and lymphomas. Talamonti et al.,
J. Clin. Invest.,
91, 53 (1993); Lutz et al.,
Biochem. Biophys. Res.
243, 503 (1998); Rosen et al.,
J. Biol. Chem.,
261, 13754 (1986); Bolen et al.,
Proc. Natl. Acad. Sci. USA,
84, 2251 (1987); Masaki et al.,
Hepatology,
27, 1257 (1998); Biscardi et al.,
Adv. Cancer Res.,
76, 61 (1999); Lynch et al.,
Leukemia,
7, 1416 (1993); Furthermore, antisense Src expressed in ovarian and colon tumor cells has been shown to inhibit tumor growth. Wiener et al.,
Clin. Cancer Res.,
5, 2164 (1999); Staley et al.,
Cell Growth Diff.,
8, 269 (1997).
Other Src family kinases are also potential therapeutic targets. Lck plays a role in T-cell signaling. Mice that lack the Lck gene have a poor ability to develop thymocytes. The function of Lck as a positive activator of T-cell signaling suggests that Lck inhibitors may be useful for treating autoimmune disease such as rheumatoid arthritis. Molina et al.,
Nature,
357, 161 (1992). Hck, Fgr and Lyn have been identified as important mediators of integrin signaling in myeloid leukocytes. Lowell et al.,
J. Leukoc. Diol.,
65, 313 (1999). Inhibition of these kinase mediators may therefore be useful for treating inflammation. Boschelli et al.,
Drugs of the Future
2000, 25(7), 717, (2000).
There is a high unmet medical need to develop new therapeutic agents that are useful in treating the aforementioned conditions associated with Src and Lck kinase activation, especially considering the currently available, relatively inadequate treatment options for the majority of these conditions.
SUMMARY OF THE INVENTION
It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of Src and Lck protein kinases. These compounds have the formula I:
or a pharmaceutically acceptable derivative thereof, wherein A, B, G, R
1
, R
2
, R
3
, and R
4
are as defined below.
These compounds, and pharmaceutically acceptable compositions thereof, are useful for treating or lessening the severity of a variety of disorders including hypercalcemia, osteoporosis, osteoarthritis, cancer, symptomatic treatment of bone metastasis, Paget's disease, autoimmune diseases such as transplant rejection, allergies, rheumatoid arthritis, and leukemia.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a compound of formula I:
or a pharmaceutically acceptable derivative thereof, wherein:
A—B is N—O or O—N;
R
1
is selected from halogen, NO
2
, T
y
R, or TCN;
each T is independently selected from an optionally substituted C
1
-C
6
alkylidene chain, wherein:
one methylene unit of T is optionally replaced by O, NR, NRC(O), C(O)NR, NRC(O)NR, C(O), C(O)CH
2
C(O), C(O)C(O, C(O)O, OC(O), NRSO
2
, S, SO, SO
2
NR, or SO
2
;
y is zero or one;
each R is independently selected from hydrogen or an optionally substituted C
1
-C
6
aliphatic group, or:
two R on the same nitrogen are taken together with the nitrogen to form a 3-7 membered saturated, partially unsaturated, or fully unsaturated ring having 1-2 heteroatoms, in addition to the nitrogen bound thereto, independently selected from nitrogen, oxygen, or sulfur;
R
2
is R or Ar
1
;
G is selected from X
m
R or X
m
Ar
1
;
each m is independently selected from zero or one;
X is selected from O, S, SO, SO
2
, NH, C(O), C(O)NH, NHC(O), NHC(O)NH, SO
2
NH, NHSO
2
, or NHSO
2
NH;
each Ar
1
is independently selected from an optionally substituted ring selected from a 5-7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R
3
is selected from ZQ
n
R
5
or ZQ
n
R
7
, wherein ZQ
n
R
7
is not hydrogen;
Q is an optionally substituted C
1
-C
6
alkylidene chain wherein:
one or two non-adjacent methylene units of Q are optionally and independently replaced by O, NR, NRC(O), C(O)NR, C(O), S, SO, SO
2
, or SO
2
NR; provided that said optionally replaced methylene unit of Q is a methylene unit non-adjacent to R
7
;
each n is independently selected from zero or one;
Z is selected from a valence bond, O, S, SO, SO
2
, NH, C(O), C(O)NH, NHC(O), SO
2
NH, or NHSO
2
;
R
4
is selected from R, halogen, NO
2
, CN, OR, SR, N(R)
2
, NRC(O)R, NRC(O)N(R)
2
, NRCO
2
R, C(O)R, CO
2
R, OC(O)R, C(O)N(R)
2
, OC(O)N(R)
2
, SOR, SO
2
R, SO
2
N(R)
2
, NRSO
2
R, NRSO
2
N(R)
2
, C(O)C(O)R, or C(O)CH
2
C(O)R, or:
two R
4
Bemis Guy
Gao Huai
Harrington Edmund
Ledeboer Mark
Salituro Francesco
Rao Deepak
Robidoux Andrea L. C.
Vertex Pharmaceuticals Incorporated
Vertex Pharmaceuticals Incorporated
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