Pentafluorobenzenesulfonamides and analogs

Details Pentafluorobenzenesulfonamides and analogs Pentafluorobenzenesulfonamides and analogs

1997-07-18

2002-11-19

O'Sullivan, Peter (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S239500, C514S357000, C514S415000, C514S452000, C514S517000, C514S524000, C514S538000, C514S562000, C514S576000, C514S607000, C514S602000, C514S603000, C514S604000, C544S170000, C544S174000, C546S312000, C548S509000, C549S366000, C558S031000, C558S036000, C558S032000, C558S048000, C558S413000, C560S012000, C562S037000, C562S126000, C562S430000, C564S086000, C564S087000, C564S088000, C564S089000, C564S090000, C564S092000, C564S101000

Reexamination Certificate

active

06482860

ABSTRACT:

INTRODUCTION
1. Field of the Invention
The field of the invention is pentafluorobenzenesulfonamide derivatives and analogs and their use as pharmacologically active agents.
2. Background
A number of human diseases stem from processes of uncontrolled or abnormal cellular proliferation. Most prevalent among these 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 methods and compositions relating to novel pentafluorophenylsulfonamide derivatives and analogs and their use as pharmacologically active agents. The compositions find particular use as pharmacological agents in the treatment of disease states, particularly cancer, bacterial infections and psoriasis, or as lead compounds for the development of such agents.
In one embodiment, the invention provides for the pharmaceutical use of compounds of the general formula I and for pharmaceutically acceptable compositions of compounds of formula I:
or a physiologically acceptable salt thereof, wherein:
Y is —S(O)— or —S(O)
2
—;
Z is —NR
1
R
2
or —OR
3
, where R
1
and R
2
are independently selected from
hydrogen,
substituted or unsubstituted (C1-C10)alkyl,
substituted or unsubstituted (C1-C10)alkoxy,
substituted or unsubstituted (C3-C6)alkenyl,
substituted or unsubstituted (C2-C6)heteroalkyl,
substituted or unsubstituted (C3-C6)heteroalkenyl,
substituted or unsubstituted (C3-C6)alkynyl,
substituted or unsubstituted (C3-C8)cycloalkyl,
substituted or unsubstituted (C5-C7)cycloalkenyl,
substituted or unsubstituted (C5-C7)cycloalkadienyl,
substituted or unsubstituted aryl,
substituted or unsubstituted aryloxy,
substituted or unsubstituted aryl-(C3-C8)cycloalkyl,
substituted or unsubstituted aryl-(C5-C7)cycloalkenyl,
substituted or unsubstituted aryloxy-(C3-C8)cycloalkyl,
substituted or unsubstituted aryl-(C1-C4)alkyl,
substituted or unsubstituted aryl-(C1-C4)alkoxy,
substituted or unsubstituted aryl-(C1-C4)heteroalkyl,
substituted or unsubstituted aryl-(C3-C6)alkenyl,
substituted or unsubstituted aryloxy-(C1-C4)alkyl,
substituted or unsubstituted aryloxy-(C2-C4)heteroalkyl,
substituted or unsubstituted heteroaryl,
substituted or unsubstituted heteroaryloxy,
substituted or unsubstituted heteroaryl-(C1-C4)alkyl,
substituted or unsubstituted heteroaryl-(C1-C4)alkoxy,
substituted or unsubstituted heteroaryl-(C1-C4)heteroalkyl,
substituted or unsubstituted heteroaryl-(C3-C6)alkenyl,
substituted or unsubstituted heteroaryloxy-(C1-C4)alkyl, and
substituted or unsubstituted heteroaryloxy-(C2-C4)heteroalkyl,
wherein R
1
and R
2
may be connected by a linking group E to give a substituent of the formula
wherein E represents a bond, (C1-C4) alkylene, or (C1-C4) heteroalkylene, and the ring formed by R
1
, E, R
2
and the nitrogen contains no more than 8 atoms, or preferably the R
1
and R
2
may be covalently joined in a moiety that forms a 5- or 6-membered heterocyclic ring with the nitrogen atom of NR
1
R
2
;
and where R
3
is a substituted or unsubstituted aryl or heteroaryl group.
Substituents for the alkyl, alkoxy, alkenyl, heteroalkyl, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and cycloalkadienyl radicals are selected independently from
—H
—OH
—O—(C1-C10)alkyl
═O
—NH
2
—NH—(C1-C10)alkyl
—N[(C1-C10)alkyl]
2
—SH
—S—(C1-C10)alkyl
-halo
—Si[(C1-C10)alkyl]
3
in a number ranging from zero to (2N+1), where N is the total number of carbon atoms in such radical.
Substituents for the aryl and heteroaryl groups are selected independently from
-halo
—OH
O—R′
—O—C(O)—R′
—NH
2
—NHR′
—NR′R″
—SH
—SR′
—R′
—CN
—NO
2
—CO
2
H
—CO
2
—R′
—CONH
2
—CONH—R′
—CONR′R″
—O—C(O)—NH—R′
—O—C(O)—NR′R″
—NH—C(O)—R′
—NR″—C(O)—R′
—NH—C(O)—OR′
—NR″—C(O)—R′
—NH—C(NH
2
)═NH
—NR′—C(NH
2
)═NH
—NH—C(NH
2
)═NR′
—S(O)—R′
—S(O)
2
—R′
—S(O)
2
—NH—R′
—S(O)
2
—NR′R″
—N
3
—CH(Ph)
2
substituted or unsubstituted aryloxy
substituted or unsubstituted arylamino
substituted or unsubstituted heteroarylamino
substituted or unsubstituted heteroaryloxy

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