(Z)-styrylbenzylsulfones and pharmaceutical uses thereof

Details (Z)-styrylbenzylsulfones and pharmaceutical uses thereof (Z)-styrylbenzylsulfones and pharmaceutical uses thereof

2003-08-21

2004-12-21

Carr, Deborah D. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Sulfur containing

C568S034000, C568S035000, C568S077000

Reexamination Certificate

active

06833480

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to compositions and methods for the treatment of proliferative disorders, including but not limited to cancer.
BACKGROUND OF THE INVENTION
New cell antiproliferative agents, and anticancer therapeutics in particular, are needed which are useful in inhibiting proliferation of and/or killing cancer cells. In particular, such agents are needed which are selective in the killing of proliferating cells such as tumor cells, but not normal cells. Antineoplasitc agents are needed which are effective against a broad range of tumor types.
SUMMARY OF THE INVENTION
It is an object of the invention to provide compounds, compositions and therapeutic methods. The biologically active compounds are in the form of certain substituted (Z)-styrylbenzyl sulfones, and pharmaceutically acceptable salts thereof.
It is an object of the invention to provide compounds, compositions and methods for the treatment of cancer and other cell proliferative diseases.
It is an object of the invention to provide compounds which are selective in killing tumor cells but not normal cells.
It is an object of the invention to provide compounds, compositions and methods for inducing neoplastic cells to selectively undergo apoptosis.
In one aspect, the invention is directed to novel compounds of formula I:
wherein:
R
1
and R
2
are independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, cyano, carboxy, carboxy(C1-C3)alkoxy, hydroxy, (C2-C6)hydroxyalkyl, phosphonato, amino, (C1-C6)acylamino, sulfamyl, acetoxy, di(C1-C6)alkylamino(C2-C6 alkoxy) and trifluoromethyl; and
R
3
and R
4
are independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, cyano, carboxy, carboxy(C1-C3)alkoxy, hydroxy, (C2-C6)hydroxyalkyl, phosphonato, amino, (C1-C6)acylamino, sulfamyl, acetoxy, di(C1-C6)alkylamino(C2-C6 alkoxy) and trifluoromethyl; or
a pharmaceutically acceptable salt thereof.
In some embodiments, the benzyl nucleus (i.e., the ring system containing R
3
and R
4
) is at least monosubstituted, that is, at least one of R
3
and R
4
is other than hydrogen.
In some embodiments, R
1
and R
2
are independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy and acetoxy, while R
3
and R
4
are independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro and amino.
If the benzyl nucleus is substituted, the substituents in one embodiment are located at the 4- and/or 2-positions, that is, the compounds have the formula II:
wherein R
1
, R
2
, R
3
and R
4
are defined as above, wherein at least one or both of R
3
and R
4
are other than hydrogen. In some embodiments, R
4
is other than hydrogen, particularly halogen. In other embodiments, both R
3
and R
4
are other than hydrogen. According to certain embodiments, one or both of R
3
and R
4
are halogen, or all of R
1
, R
2
, R
3
and R
4
are halogen.
While any pattern of substitution for R
1
and R
2
is possible, i.e. 2/4, 2/3, or 3/4, 2/4 substitution is particularly preferred.
According to another embodiment of the invention, (Z)-styryl benzylsulfides are provided which are useful as intermediates in the preparation of (Z)-styryl benzylsulfones. The (Z)-styryl benzylsulfides have the formula:
wherein R
1
, R
2
, R
3
and R
4
are defined as above with respect to formula I.
Selected embodiments of (Z)-styryl benzylsulfide compounds correspond directly to the above-described selected embodiments of (Z)-styryl benzylsulfide compounds, the only difference being the presence of the sulfide group as the precursor of the sulfone group; the latter results from oxidation of the former. For example, the sulfide analogs of the sulfones according to formula III have the formula IV:
wherein R
1
, R
2
, R
3
and R
4
are defined as above with respect to formula III.
According to another embodiment of the invention, pharmaceutical compositions are provided comprising a pharmaceutically acceptable carrier and at least one compound according to formula I, or pharmaceutically acceptable salt thereof.
According to another embodiment of the invention, a method of treating an individual for a cell proliferative disorder comprises administering to said individual an effective amount of at least one compound according to formula I, or pharmaceutically acceptable salt thereof.
According to another embodiment of the invention, a method of inducing apoptosis of tumor cells in an individual afflicted with cancer is provided, comprising administering to said individual an effective amount of at least one compound according to formula I, or pharmaceutically acceptable salt thereof.
The term “alkyl”, by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon radical, including di- and multi-radicals, having the number of carbon atoms designated (i.e. C1-C6 means one to six carbons) and includes straight or branched chain groups. Most preferred is C1-C3 alkyl, particularly ethyl and methyl.
The term “alkoxy” employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy and the higher homologs and isomers. Preferred are C1-C3 alkoxy, particularly ethoxy and methoxy.
The term “(C2-C6)acylamino” means a radical containing a two to six carbon straight or branched chain acyl group attached to a nitrogen atom via the acyl carbonyl carbon. Examples include —NHC(O)CH
2
CH
2
CH
3
and —NHC(O)CH
2
CH
2
CH
2
CH
2
CH
3
.
The term “carboxy(C1-C3)alkoxy” means a radical in which the carboxy group —COOH is attached to a carbon of a straight or branched chain alkoxy group containing one to three carbon atoms. The radical thus contains up to four carbon atoms. Examples include HOC(O)CH
2
CH
2
CH
2
O— and HOC(O)CH
2
CH
2
O—.
The term “di(C1-C6)alkylamino(C2-C6)alkoxy” means (alkyl)
2
N(CH
2
)
n
O— wherein the two alkyl chains connected to the nitrogen atom independently contain from one to six carbon atoms, preferably from one to three carbon atoms, and n is an integer from 2 to 6. Preferably, n is 2 or 3. Most preferably, n is 2, and the alkyl groups are methyl, that is, the group is the dimethylaminoethoxy group, (CH3)
2
NCH
2
CH
2
O—.
The terms “halo” or “halogen” by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
The term “hydroxyalkyl” means an alkyl radical wherein one or more of the carbon atoms is substituted with hydroxy. Examples include —CH
2
CH(OH)CH
3
and —CH
2
CH
2
OH.
The term “phosphonato” means the group —PO(OH)
2
.
The term “sulfamyl” means the group —SO
2
NH
2
.
By “substituted” means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.
By “subject” is meant an animal or a human being.


REFERENCES:
patent: 2532612 (1950-12-01), Doumani
patent: 3185743 (1965-05-01), Combe et al.
patent: 3418101 (1968-12-01), Buchholtz et al.
patent: 3463774 (1969-08-01), Wilhelm et al.
patent: 3514386 (1970-05-01), Oswald et al.
patent: 3917714 (1975-11-01), Richmond
patent: 4161407 (1979-07-01), Campbell
patent: 4386221 (1983-05-01), Hyatt et al.
patent: 4937388 (1990-06-01), Bushell et al.
patent: 5659087 (1997-08-01), Aikins et al.
patent: 5733909 (1998-03-01), Black et al.
patent: 6201154 (2001-03-01), Reddy et al.
patent: 6359013 (2002-03-01), Reddy et al.
patent: 6486210 (2002-11-01), Reddy et al.
patent: WO 99/18068 (1999-04-01), None
patent: WO 00/57872 (2000-10-01), None
patent: WO 00/59495 (2000-10-01), None
patent: WO 01/26645 (2001-04-01), None
U.S. Appl. No. 09/689,281, filed Oct. 11, 2000 of Stephen C. Cosenza et al., for “Method For Protecting Normal Cells From Cytotoxicity Of Chemotherapeutic Agents”.
Pub-Med 9734697, Abstracting Griggs JJ., “Reducing the Toxicity of Anticancer Therapy: New Strategies”, Leuk Res

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