Z-styryl sulfone anticancer agents

Organic compounds -- part of the class 532-570 series – Organic compounds – Sulfur containing

Reexamination Certificate

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C568S030000, C568S034000

Reexamination Certificate

active

06201154

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to compositions and methods for the treatment of cancer.
BACKGROUND OF THE INVENTION
Extracellular signals received at transmembrane receptors are relayed into the cells by the signal transduction pathways (Pelech et al.,
Science
257:1335 (1992)) which have been implicated in a wide array of physiological processes such as induction of cell proliferation, differentiation or apoptosis (Davis etal.,
J. Biol. Chem
. 268:14553 (1993)). The Mitogen Activated Protein Kinase (MAPK) cascade is a major signaling system by which cells transduce extracellular cues into intracellular responses (Nishida et al.,
Trends Biochem. Sci
. 18:128 (1993); Blumer et al.,
Trends Biochem. Sci
. 19:236 (1994)). Many steps of this cascade are conserved, and homologous for MAP kinases have been discovered in different species.
In mammalian cells, the Extracellular-Signal-Regulated Kinases (ERKs), ERK-1 and ERK-2 are the archetypal and best-studied members of the MAPK family, which all have the unique feature of being activated by phosphorylation on threonine and tyrosine residues by an upstream dual specificity kinase (Posada et al.,
Science
255:212 (1992); Biggs III et al.,
Proc. Natl. Acad. Sci. USA
89:6295 (1992); Garner et al.,
Genes Dev
. 6:1280 (1992)).
Recent studies have identified an additional subgroup of MAPKs, known as c-Jun NH2-terminal kinases 1 and 2 (JNK-1 and JNK-2), that have different substrate specificities and are regulated by different stimuli (Hibi et al.,
Genes Dev
. 7:2135 (1993)). JNKs are members of the class of stress-activated protein kinases (SPKs). JNKs have been shown to be activated by treatment of cells with UV radiation, pro-inflammatory cytokines and environmental stress (Derijard et al.,
Cell
1025 (1994)). The activated JNK binds to the amino terminus of the c-Jun protein and increases the protein's transcriptional activity by phosphorylating it at ser63 and ser73 (Adler et al.,
Proc. Natl. Acad. Sci. USA
89:5341 (1992); Kwok et al.,
Nature
370:223 (1994)).
Analysis of the deduced primary sequence of the JNKs indicates that they are distantly related to ERKs (Davis,
Trends Biochem. Sci
. 19:470 (1994)). Both ERKs and JNKs are phosphorylated on Tyr and Thr in response to external stimuli resulting in their activation (Davis,
Trends Biochem. Sci
. 19:470 (1994)). The phosphorylation (Thr and Tyr) sites, which play a critical role in their activation are conserved between ERKs and JNKs (Davis,
Trends Biochem. Sci
. 19:470 (1994)). However, these sites of phosphorylation are located within distinct dual phosphorylation motifs: Thr-Pro-Tyr (JNK) and Thr-Glu-Tyr (ERK). Phosphorylation of MAPKs and JNKs by an external signal often involves the activation of protein tyrosine kinases (PTKs) (Gille et al.,
Nature
358:414 (1992)), which constitute a large family of proteins encompassing several growth factor receptors and other signal transducing molecules.
Protein tyrosine kinases are enzymes which catalyze a well defined chemical reaction: the phosphorylation of a tyrosine residue (Hunter et al.,
Annu Rev Biochem
54:897 (1985)). Receptor tyrosine kinases in particular are attractive targets for drug design since blockers for the substrate domain of these kinases is likely to yield an effective and selective antiproliferative agent. The potential use of protein tyrosine kinase blockers as antiproliferative agents was recognized as early as 1981, when quercetin was suggested as a PTK blocker (Graziani et al.,
Eur. J. Biochem
. 135:583-589 (1983)).
The best understood MAPK pathway involves extracellular signal-regulated kinases which constitute the Ras/Raf/MEK/ERK kinase cascade (Boudewijn et al.,
Trends Biochem. Sci
. 20,18 (1995)). Once this pathway is activated by different stimuli, MAPK phosphorylates a variety of proteins including several transcription factors which translocate into the nucleus and activate gene transcription. Negative regulation of this pathway could arrest the cascade of these events.
What are needed are new anticancer chemotherapeutic agents which target receptor tyrosine kinases and which arrest the Ras/Raf/MEK/ERK kinase cascade. Oncoproteins in general, and signal transducing proteins in particular, are likely to be more selective targets for chemotherapy because they represent a subclass of proteins whose activities are essential for cell proliferation, and because their activities are greatly amplified in proliferative diseases.
SUMMARY OF THE INVENTION
It is an object of the invention to provide compounds, compositions and methods for the treatment of cancer and other proliferative diseases. The biologically active compounds are in the form of (Z)-styryl benzylsulfones.
It is a further object of the invention to provide intermediates useful for the preparation of compounds having anticancer activity. The intermediates comprise (Z)-styryl benzylsulfides.
The present invention provides for pharmaceutical compositions comprising a pharmaceutically acceptable carrier and one or more compounds of the formula I
wherein
R
1
is selected from the group consisting of hydrogen, chloro and nitro;
R
2
is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, chloro, bromo, and fluoro; and
R
3
and R
4
are independently selected from the group consisting of hydrogen, lower alkyl, nitro, chloro, bromo, and fluoro;
provided at least one of R
1
or R
2
is hydrogen.
According to one preferred embodiment of the invention, pharmaceutical compositions of compounds of formula I are provided wherein R
1
is hydrogen. More preferably, R
1
and R
3
are hydrogen, and R
2
and R
4
are independently selected from the group consisting of chloro, fluoro and bromo.
According to another embodiment of the invention, novel compounds of formula I are provided where R
1
, R
2
, R
3
and R
4
are defined as above, provided:
(a) at least one of R
1
or R
2
is hydrogen;
(b) R
3
and R
4
may not both be hydrogen when:
(i) R
1
and R
2
are both hydrogen,
(ii) R
1
is chloro and R
2
is hydrogen, or
(iii) R
2
is chloro and R
1
is hydrogen; and
(c) when R
3
is hydrogen and R
4
is methyl:
(i) both R
1
and R
2
may not be hydrogen,
(ii) R
1
may not be chloro when R
2
is hydrogen, and
(iii) R
2
may not be chloro when R
1
is hydrogen.
Preferably, R
1
is hydrogen in the novel compounds of the invention.
According to another embodiment of the invention, novel (Z)-styryl benzylsulfides are provided which are useful as intermediates in the preparation of the biologically active (Z)-styryl benzylsulfones. The (Z)-styryl benzylsulfides have the formula:
wherein:
R
1
is selected from the group consisting of hydrogen, chloro and nitro;
R
2
is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, chloro, bromo, and fluoro, provided that at least one of R
1
or R
2
is hydrogen;
R
3
and R
4
are independently selected from the group consisting of hydrogen, lower alkyl, nitro, chloro, bromo, and fluoro; provided:
(a) at least one of R
1
or R
2
is hydrogen;
(b) R
3
and R
4
may not both be hydrogen when:
(i) R
1
and R
2
are both hydrogen,
(ii) R
1
is chloro and R
2
is hydrogen, or
(iii) R
2
is chloro and R
1
is hydrogen; and
(c) when R
3
is hydrogen and R
4
is methyl:
(i) both R
1
and R
2
may not be hydrogen,
(ii) R
1
may not be chloro when R
2
is hydrogen, and
(iii) R
2
may not be chloro when R
1
is hydrogen.
Preferably, R
1
is hydrogen in the aforementioned intermediates.
By “lower alkyl” is meant straight or branched chain alkyl containing from one to six carbon atoms. The preferred alkyl group is methyl. By “lower alkoxy” is meant straight or branched chain alkoxy containing from one to six carbon atoms. The preferred alkoxy group is methoxy.
According to another embodiment of the invention, a method of treating an individual for cancer or other proliferative disorder is provided, comprising administering to said individual an effective amount of the aforesaid pharmaceutical composition.
In another embodiment, a method of inhibiting growth of t

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