Arylsulfonanilide derivates

Details Arylsulfonanilide derivates Arylsulfonanilide derivates

2000-09-27

2003-10-07

Celsa, Bennett (Department: 1639)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C514S002600, C514S004300

Reexamination Certificate

active

06630513

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to arylsulfonanilide derivatives and their use as pharmacologically active agents capable of lowering plasma cholesterol levels and inhibiting abnormal cell proliferation.
BACKGROUND
A number of arylsulfonamides have recently been described for the treatment of disorders and conditions arising from abnormal cell proliferation and from elevated plasma cholesterol levels. See, for example, PCT publications WO 97/30677 and WO 98/05315.
Most prevalent among diseases stemming from abnormal cell proliferation is cancer, a generic name for a wide range of cellular malignancies characterized by unregulated growth, lack of differentiation, and the ability to invade local tissues and metastasize. These neoplastic malignancies affect, with various degrees of prevalence, every tissue and organ in the body. A multitude of therapeutic agents have been developed over the past few decades for the treatment of various types of cancer. The most commonly used types of anticancer agents include: DNA-alkylating agents (e.g., cyclophosphamide, ifosfamide), antimetabolites (e.g., methotrexate, a folate antagonist, and 5-fluorouracil, a pyrimidine antagonist), microtubule disruptors (e.g., vincristine, vinblastine, paclitaxel), DNA intercalators (e.g., doxorubicin, daunomycin, cisplatin), and hormone therapy (e.g., tamoxifen, flutamide). The ideal antineoplastic drug would kill cancer cells selectively, with a wide therapeutic index relative to its toxicity towards non-malignant cells. It would also retain its efficacy against malignant cells, even after prolonged exposure to the drug. Unfortunately, none of the current chemotherapies possess an ideal profile. Most possess very narrow therapeutic indexes and, in practically every instance, cancerous cells exposed to slightly sublethal concentrations of a chemotherapeutic agent will develop resistance to such an agent, and quite often cross-resistance to several other antineoplastic agents.
Psoriasis, a common chronic skin disease characterized by the presence of dry scales and plaques, is generally thought to be the result of abnormal cell proliferation. The disease results from hyperproliferation of the epidermis and incomplete differentiation of keratinocytes. Psoriasis often involves the scalp, elbows, knees, back, buttocks, nails, eyebrows, and genital regions, and may range in severity from mild to extremely debilitating, resulting in psoriatic arthritis, pustular psoriasis, and exfoliative psoriatic dermatitis. No therapeutic cure exists for psoriasis. Milder cases are often treated with topical corticosteroids, but more severe cases may be treated with antiproliferative agents, such as the antimetabolite methotrexate, the DNA synthesis inhibitor hydroxyurea, and the microtubule disrupter colchicine.
Other diseases associated with an abnormally high level of cellular proliferation include restenosis, where vascular smooth muscle cells are involved, inflammatory disease states, where endothelial cells, inflammatory cells and glomerular cells are involved, myocardial infarction, where heart muscle cells are involved, glomerular nephritis, where kidney cells are involved, transplant rejection, where endothelial cells are involved, infectious diseases such as HIV infection and malaria, where certain immune cells and/or other infected cells are involved, and the like. Infectious and parasitic agents per se (e.g. bacteria, trypanosomes, fungi, etc) are also subject to selective proliferative control using the subject compositions and compounds.
Accordingly, it is one object of the present invention to provide compounds which directly or indirectly are toxic to actively dividing cells and are useful in the treatment of cancer, viral and bacterial infections, vascular restenosis, inflammatory diseases, autoimmune diseases, and psoriasis.
A further object of the present invention is to provide therapeutic compositions for treating said conditions.
Still further objects are to provide methods for killing actively proliferating cells, such as cancerous, bacterial, or epithelial cells, and treating all types of cancers, infections, inflammatory, and generally proliferative conditions. A further object is to provide methods for treating other medical conditions characterized by the presence of rapidly proliferating cells, such as psoriasis and other skin disorders.
Other objects, features and advantages will become apparent to those skilled in the art from the following description and claims.
SUMMARY OF THE INVENTION
The invention provides novel arylsulfonanilide compounds, as well as methods and compositions relating to novel arylsulfonanilides and their use as pharmacologically active agents. The compounds and compositions find use as pharmacological agents in the treatment of disease states, particularly hypercholesterolemia, atherosclerosis, cancer, bacterial infections, and psoriasis, or as lead compounds for the development of such agents. The compounds of the invention have the formula:
or a pharmaceutically acceptable salt thereof.
In one group of embodiments the letter Y in the above formula represents a linear or cyclic peptide having from four to fourteen amino acid residues or a radical of formula —Aa—Z, wherein Aa is an amino acid or dipeptide residue and Z is selected from hydrogen, —CHO,
For the radicals above, the symbols R
5
, R
6
and R
7
are each independently hydrogen, (C
1
-C
8
)alkyl, (C
1
-C
8
)heteroalkyl, aryl, heteroaryl, aryl(C
1
-C
4
)alkyl, aryl(C
1
-C
4
)heteroalkyl, heteroaryl(C
1
-C
4
)alkyl and heteroaryl(C
1
-C
4
)heteroalkyl. Optionally, R
5
and R
6
are linked together to form a 5- or 6-membered ring. The symbol R
8
represents (C
1
-C
8
)alkyl, (C
1
-C
8
)heteroalkyl, aryl(C
1
-C
4
)alkyl or aryl (C
1
-C
4
)heteroalkyl. The symbols R
9
and R
10
are independently hydrogen, (C
1
-C
8
)alkyl, (C
1
-C
8
)heteroalkyl, aryl(C
1
-C
4
)alkyl and aryl(C
1
-C
4
)heteroalkyl, and are optionally linked together to form a 5- or 6-membered ring.
Returning to the general formula above, the symbols R
1
and R
4
are each independently hydrogen, (C
1
-C
6
)alkyl or (C
1
-C
6
)heteroalkyl. The symbols R
2
and R
3
are each independently hydrogen, halogen, (C
1
-C
8
)alkyl, (C
1
-C
8
)heteroalkyl, —OR
11
, —SR
11
and —NR
11
R
12
, wherein R
11
and R
12
are each independently hydrogen, (C
1
-C
8
)alkyl and (C
1
-C
8
)heteroalkyl. When R
2
and R
3
are attached to adjacent carbon atoms, they are optionally linked together to form a fused 5-, 6- or 7-membered ring.
The symbol Ar represents a substituted aryl group selected from
in which X
1
and X
2
are each independently F, Cl or Br.
The methods of the present invention use pharmaceutical compositions containing compounds of the foregoing description of the general Formula I for the treatment of pathology such as cancer, bacterial infections, psoriasis, hypercholesterolemia, atherosclerosis, pancreatitis, and hyperlipoproteinemia. Briefly, the inventions involve administering to a patient an effective formulation of one or more of the subject compositions.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multi-radicals, having the number of carbon atoms designated (i.e. C
1
-C
10
means one to ten carbons). Examples of saturated hydrocarbon radicals include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and

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