Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-23
2001-09-04
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S256000, C514S314000, C514S343000, C514S381000, C514S391000, C514S408000, C514S422000
Reexamination Certificate
active
06284784
ABSTRACT:
BACKGROUND OF THE INVENTION
Protein kinases serve a regulatory function which is crucial for all aspects of cellular development, differentiation and transformation. One of the largest gene families of non-receptor serine-threonine protein kinases is protein kinase C (PKC). Since the discovery of PKC more than a decade ago by Nishizuka and coworkers (Kikkawa et al.,
J. Biol. Chem.,
257, 13341 (1982)), and its identification as a major receptor for phorbol esters (Ashendel et al.,
Cancer Res.,
43, 4333 (1983)), a multitude of physiological signaling mechanisms have been ascribed to this enzyme. The intense interest in PKC stems from its unique ability to be activated in vitro by diacylglycerol (and its phorbol ester mimetics), an effector whose formation is coupled to phospholipid turnover by the action of growth and differentiation factors.
The PKC gene family consists presently of 11 genes which are divided into four subgroups: 1) classical PKC&agr;, &bgr;
1
, &bgr;
2
(&bgr;
1
and &bgr;
2
are alternately spliced forms of the same gene) and &ggr;, 2) novel PKC&dgr;, &egr;, &eegr;, and &thgr;, 3) atypical PKC&zgr;, &lgr;, &eegr; and &igr; and 4) PKC&mgr;. PKC&mgr; resembles the novel PKC isoforms but differs by having a putative transmembrane domain (reviewed in Blobe et al.,
Cancer Metast. Rev.,
13, 411 (1994)); Hug et al.,
Biochem J.,
291, 329 (1993); Kikkawa et al.,
Ann. Rev. Biochem,
58, 31 (1989)). The &agr;, &bgr;
1
, &bgr;
2
and &ggr; isoforms are Ca
2+
, phospholipid- and diacylglycerol-dependent and represent the classical isoforms of PKC, whereas the other isoforms are activated by phospholipid and diacylglycerol but are not dependent on Ca
2+
. All isoforms encompass 5 variable (V1-V5) regions, and the &agr;, &bgr; and &ggr; isoforms contain four (C1-C4) structural domains which are highly conserved. All isoforms except PKC&agr;, &bgr;, and &ggr; lack the C2 domain, and the &lgr;, &eegr; and &igr; isoforms also lack one of two cysteine-rich zinc finger domains in C1 to which diacylglycerol binds. The C1 domain also contains the pseudosubstrate sequence which is highly conserved among all isoforms, and which serves an autoregulatory function by blocking the substrate-binding site to produce an inactive conformation of the enzyme (House et al.
Science,
238, 1726 (1987)).
Because of these structural features, diverse PKC isoforms are thought to have highly specialized roles in signal transduction in response to physiological stimuli (Nishizuka,
Cancer;
10, 1892 (1989)), as well as in neoplastic transformation and differentiation (Glazer,
Protein Kinase
C, J. F. Kuo, ed., Oxford U. Press (1994) at pages 171-198).
From a pharmacological perspective, PKC has served as a focal point for the design of anticancer drugs (Gescher,
Brit. J. Cancer,
66, 10 (1992)). Antisense expression of either the PKC&agr; cDNA (Ahmad et al.,
Neurosurgery,
35, 904 (1994)) or a phosphorothioate oligodeoxynucleotide (S-oligo)-for PKC&agr; has shown the efficacy of targeting PKC to inhibit the proliferation of A
549
lung carcinoma cells (Dean et al.,
J. Biol. Chem.,
269, 16416 (1994)) and U-87 glioblastoma cells. However, it is not clear which isoforms are most crucial for tumor proliferation and what role different PKC isoforms play in such critical cellular processes as cell proliferation and apoptosis.
Investigations with 12-O-tetradecanoylphorbol-13-acetate (TPA) have provided considerable information on tumor promotion. In the two stage model of skin carcinogenesis, it is believed that initiators bind to DNA and that tumor promoters such as TPA bind non-covalently to membrane-associated high affinity receptors, most likely protein kinase C. Thus, TPA, as well as the known teleocidins, lyngbyatoxins, and aplysiatoxin serve as diacylglycerol mimics, binding to the diacylglycerol site of protein kinase C, thus activating the kinase.
In view of the central role that PKC plays in tumor promotion and signal transduction, PKC is an exciting target for cancer therapy. Oncogenes like src, ras, and sis, elevate phosphatidylinositol turnover; transcription of cellular protooncogenes, including myc, and fos, is mediated by PKC; PKC regulates the activity of the transcriptional activator protein c-jun, and stimulates the multidrug resistance system. There is increasing evidence that the individual PKC isozymes play different, sometimes opposing, roles in biological processes, providing two directions for pharmacological exploitation. One is the design of specific (peferrably, isozyme specific) inhibitors of PKC. This approach is complicated by the fact that the catalytic domain is not the domain primarily responsible for the isotype specificity of PKC. The other approach is to develope isozyme-selective, regulatory site-directed PKC activators. These may provide a way to override the effect of other signal transduction pathways with opposite biological effects. Alternatively, by inducing down-regulation of PKC after acute activation, PKC activators may cause long term antagonism. Dpp (12-deoxyphorbol 13-phenylacetate) and bryostatin are examples of isozyme-selective activators of PKC. Bryostatin is currently in clinical trials as an anti-cancer agent. The bryostatins are known to bind to the regulatory domain of PKC and to activate the enzyme. In mouse skin, they act as strong inhibitors of first stage tumor promotion, and modest inhibitors of complete tumor promotion.
There is a continuing need for novel compounds which can activate PKC. Such compounds may be useful, for example, to effect the selective killing of cancer cells.
SUMMARY OF THE INVENTION
The present invention provides certain substituted 2-pyrrolidinones that are PKC activators. Accordingly, the invention provides a compound of the invention which is a compound of formula I:
wherein
R
1
and R
2
are each independently (C
1
-C
15
)alkyl, (C
2
-C
15
)alkenyl, (C
2
-C
15
) alkynyl, (C
3
-C
8
)cycloalkyl, (C
3
-C
8
)cycloalkyl(C
1
-C
10
)alkyl, (C
3
-C
8
)cycloalkyl(C
1
-C
15
)alkenyl, (C
3
-C
8
)cycloalkyl(C
1
-C
15
)alkynyl, (C
1
-C
15
)alkoxy, (C
1
-C
15
)alkanoyl, (C
1
-C
15
)alkanoyloxy, aryl, heteroaryl, aryl(C
1
-C
6
)alkyl, heteroaryl(C
1
-C
6
)alkyl, aryl(C
2
-C
15
)alkenyl, heteroaryl(C
2
-C
15
)alkenyl, aryl(C
2
-C
15
)alkynyl, heteroaryl(C
2
-C
15
)alkynyl, aryl(C
1
-C
15
)alkoxy, heteroaryl(C
1
-C
15
)alkoxy, aryl(C
1
-C
15
)alkanoyl, heteroaryl(C
1
-C
15
)alkanoyl, aryl(C
1
-C
15
)alkanoyloxy, or heteroaryl(C
1
-C
15
)alkanoyloxy;
wherein any R
1
or R
2
is optionally substituted with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, (C
1
-C
15
)alkyl, (C
2
-C
15
)alkenyl, (C
2
-C
15
)alkynyl, (C
3
-C
8
)cycloalkyl, (C
3
-C
8
)cycloalkyl(C
1
-C
15
)alkyl, (C
3
-C
8
)cycloalkyl-(C
2
-C
15
)alkenyl, (C
3
-C
8
)cycloalkyl(C
2
-C
15
)alkynyl, (C
1
-C
15
)alkoxy, (C
1
-C
15
)alkanoyl, (C
1
-C
15
)alkanoyloxy, C(═O)OR
a
, C(═O)NR
b
R
c
, OC(═O)OR
a
, OC(═O)NR
b
R
c
, and NR
e
R
f
; and wherein any aryl or heteroaryl of R
1
or R
2
is optionally substituted on a non-aromatic carbon by a divalent (C
2
-C
7
)alkylene chain to form a (C
3
-C
8
)spirocycloalkyl;
each R
a
is independently hydrogen or (C
1
-C
6
)alkyl;
each R
b
and R
c
is independently, hydrogen or (C
1
-C
10
)alkyl; or R
b
, and R
c
, together with the nitrogen to which they are attached are a 5-6 membered heterocyclic ring; and
each R
e
and R
f
is independently hydrogen, (C
1
-C
10
)alkyl, (C
1
-C
10
)alkanoyl, phenyl, benzyl, or phenethyl; or R
e
and R
f
together with the nitrogen to which they are attached are a 5-6 membered heterocyclic ring;
or a pharmaceutically acceptable salt thereof.
The invention also provides pharmaceutical compositions comprising a compound of the invention, processes for preparing compounds of the invention and novel intermediates useful for the synthesis of compounds of the invention.
The invention also provides a therapeutic method comprising treating a condition ch
Kozikowski Alan P.
Qiao Lixin
Wang Shaomeng
Georgetown University
Goldberg Jerome D.
Gollin Michael
Haddaway Keith G.
Venable
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