Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-01
2003-07-01
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S356000, C514S569000, C424S464000
Reexamination Certificate
active
06586455
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for the treatment of liposarcomas. In another aspect, the present invention relates to compounds and compositions which are useful for carrying out the above-referenced methods.
BACKGROUND OF THE INVENTION
Liposarcoma is the most common soft tissue malignancy in adults, accounting for at least 20% of all sarcomas in this age group. Multiple histologic subtypes of liposarcoma are recognized, including well differentiated, de-differentiated, myxoid, round cell and pleimorphic. The histologic subtype is predictive of both the clinical course of the disease and the ultimate prognosis.
Localized disease is treated primarily with surgery, often in combination with radiotherapy. Metastatic liposarcoma is associated with an extremely poor prognosis, with average five year survival ranging from 70% to 25%, depending on the type of tumor. Unfortunately, conventional chemotherapy for metastatic liposarcoma leads to complete response in only about 10% of cases. Thus, for most patients, conventional chemotherapy is largely palliative.
Induction of terminal differentiation represents a promising alternative to conventional chemotherapy for certain malignancies. For example, the retinoic acid receptor alpha (RAR&agr;), which plays an important role in the differentiation and malignant transformation of cells of myelocytic lineage, has been used as a target for intervention in acute promyelocytic leukemia. Indeed, differentiation therapy with all-trans retinoic acid has become the standard of care for this disease. In view of this success, it has been speculated that nuclear receptors that regulate growth and differentiation of other cell types may also represent potential targets for differentiation therapy.
Recent years have seen important advances in the understanding of the molecular basis of adipocyte differentiation. Central to this process is the induction of the adipocyte-selective nuclear receptor, peroxisome proliferator-activated receptor gamma (PPAR&ggr;). This receptor and its heterodimeric partner, the retinoid X receptor alpha (RXR&agr;), form a DNA binding complex that regulates transcription of adipocyte-specific genes. Expression and activation of PPAR&ggr; in fibroblastic cells triggers the adipocyte gene expression cascade and leads to development of the adipose phenotype.
Accordingly, the development of effective, non-invasive methods for treating liposarcomas would represent a significant advancement in the therapeutic arts.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, we have discovered that PPAR&ggr; is expressed consistently in each of the major histologic types of human liposarcoma. It has further been discovered that maximal activation of PPAR&ggr; with exogenous ligand (a thiazolidinedione or derivative thereof) promotes terminal differentiation of primary human liposarcoma cells. It has still further been discovered that RXR-specific ligands are also potent adipogenic agents in cells expressing the PPAR&ggr;/RXR&agr; heterodimer, and that simultaneous treatment of liposarcoma cells with a thiazolidinedionyl moiety (a PPAR&ggr;-selective class of compounds) and an RXR-specific ligand results in an additive stimulation of differentiation. Accordingly, according to the invention, there have been identified compositions which are useful for the treatment of liposarcomas.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, there are provided methods for the treatment of liposarcomas, said method comprising administering to a subject in need of such treatment an amount of a therapeutic composition effective to ameliorate the effects of neoplastic cell proliferation of liposarcoma cells, wherein said therapeutic composition comprises at least one thiazolidinedione and at least one retinoid X receptor (RXR) selective agonist in a pharmaceutically acceptable carrier therefor. Invention methods can also be used in a prophylactic manner, i.e., to prevent the onset of liposarcoma.
Thiazolidinediones contemplated for use in the practice of the present invention can be described broadly with reference to the general structure I:
wherein:
each of X
1
, X
2
, X
3
, X
4
, X
5
and X
6
is independently carbon, nitrogen, oxygen or sulfur, with the proviso that at least three of the atoms forming the ring are carbon,
A is:
—Y
n
—(CR″R″)
m
—Z,
—Y
n
—(CR″R″)
m′
—O—(CR″R″)
m″
—Z, or
—Y
n
—(CR″R″)
m′
—N(R′″)—(CR″R″)
m″
—Z,
wherein:
Y is —O— or —S—,
n is 0 or 1,
each R″ is independently hydrogen, lower alkyl, substituted lower alkyl, hydroxy, lower alkoxy, thioalkyl, halogen, trifluoromethyl, cyano, nitro, amino, carboxyl, carbamate, sulfonyl or sulfonamide,
R′″ is hydrogen, lower alkyl or substituted alkyl,
m falls in the range of 1 up to 15,
each m′ falls independently in the range of 1 up to 8,
each m″ falls independently in the range of 0 up to 12, and
Z is a thiazolidinedionyl moiety;
R
2
is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, alkenylaryl, substituted alkenylaryl, alkynylaryl, substituted alkynylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, oxyalkyl, poly(alkylene oxide), substituted poly(alkylene oxide); poly(alkylene sulfide), substituted poly(alkylene sulfide), poly(alkylene amine) or substituted poly(alkylene amine); with R
2
having in the range of 1 up to about 15 carbon atoms being preferred;
R
3
is hydrogen, hydroxy, halogen, alkoxy, lower alkyl, substituted lower alkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl; with R
3
having in the range of 0 up to about 6 carbon atoms being preferred;
R
4
is hydrogen, formyl, acyl, lower alkyl, substituted lower alkyl or a thiazolidinedionyl moiety; with R
4
having in the range of 0 up to about 4 carbon atoms being preferred;
R
5
is hydrogen, hydroxy, lower alkoxy, lower alkyl, substituted lower alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or halogen; with R
5
having in the range of 0 up to about 6 carbon atoms being preferred; and
R
6
is hydrogen, hydroxy, lower alkoxy, lower alkyl, substituted lower alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or halogen; with R
6
having in the range of 0 up to about 6 carbon atoms being preferred.
Those of skill in the art recognize that the core ring of structure I can be any one of a number of different aromatic or pseudo-aromatic structures, e.g., a benzene ring, a pyridine ring, a pyrazine, an oxazine, and the like.
As employed herein, “lower alkyl” refers to straight or branched chain alkyl groups having in the range of about 1 up to 4 carbon atoms; “alkyl” refers to straight or branched chain alkyl groups having in the range of about 1 up to 12 carbon atoms; “substituted alkyl” refers to alkyl groups further bearing one or more substituents such as hydroxy, alkoxy (of a lower alkyl group), mercapto (of a lower alkyl group), halogen, trifluoromethyl, cyano, nitro, amino, carboxyl, carbamate, sulfonyl, sulfonamide, heteroatom-containing cyclic moieties, substituted heteroatom-containing cyclic moieties, and the like.
As employed herein, “alkenyl” refers to straight or branched chain hydrocarbyl groups having at least one carbon-carbon double bond, and having in the range of about 2 up to 12 carbon atoms and “substituted alkenyl” refers to alkenyl groups further bearing one or more substituents as set forth above.
As employed herein, “alkynyl” refers to straight or branched chain hydrocarbyl groups having at least one carbon-carbon triple bond, and having in the range of about 2 up to 12 carbon atoms, and “substituted alkynyl” refers to alkynyl groups further bearing one or more substituents as set forth above.
As employed herein, “aryl” refers to aromatic groups having in the range of 6 up to 14
Evans Ronald M.
Forman Barry M.
Spiegelman Bruce M.
Tontonoz Peter
Nguyen Helen
Reiter Stephen E.
The Salk Institute for Biological Studies
Webman Edward J.
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