Smithkline Beecham Corporation

California Institute of Technology

Robert Philip Hertzberg

Daniel F Veber

Katherine L Widdowson

Melvin Clarence Rutledge, Jr

Anthony Joseph Jurewicz

Peter B Dervan

David A Berges

Randall K Johnson

William D Kingsbury

Ashok D Patil

Balan Chenera

Geoffrey Bainbridge Dreyer

George Wai-Kin Chan

Michael Leo West

John W Westley

Alan James Freyer

Fluorescent lanthanide chelates

The present invention relates to novel compounds and a novel use of phenyl ureas in the treatment of disease states mediated by the chemokine Interleukin-8 (IL-8).

IL-8 receptor antagonists

This invention relates to novel compounds of Formula (I), and a novel use of these compounds in treating chemokine mediated diseases, wherein the chemokine binds to an IL-8 a or b receptor. Compounds of Formula (1) are represented by the structure:

Phenyl urea antagonists of the IL-8 receptor

This invention relates to the novel use of phenyl ureas in the treatment of disease states mediated by the chemokine, Interleukin-8 (IL-8).

The present invention provides a method of treating viral infections by using antiviral substituted indolizino�1,2-b!quinolinone compounds, antiviral substituted indolizino�1,2-b!quinolinone compounds, and pharmaceutical compositions thereof.

Substituted indolizino�1,2-b!quinolinones

This invention relates to novel compounds and a novel use of phenyl ureas in the treatment of disease scates mediated by the chemokine, Interleukin-8 (IL-8). In particular, this invention relates to the novel compounds of Formula (Ia) and their use in treating chemokine mediated diseases wherein the chemokine binds to an IL-8 a or b receptor. Compounds of Formula (Ia) are represented by the structure: ##STR1## wherein interalia, X is oxygen or sulfur;

Coumarin derivatives as retroviral inhibitors

Bifunctional molecules having a DNA intercalator or DNA groove binder linked to ethylene diamine tetraacetic acid such as compounds having the formula: ##STR1## wherein R is methyl or ethyl. Also, the method of cleaving DNA by contact with one of the above-identified molecules in the presence of ferrous ion and oxygen. The process of preparing said molecules by the reaction of P-carboxy methidium halide, p-carboxy ethidium halide, or other DNA intercalator or DNA groove binder with 1-3-diaminopropane followed by condensation with ethylenediamine tetraacetic acid. Distamycin-EDTA.Fe(II)(DE.FE(II)) contains EDTA attached to the amino terminus of the groove binder tripeptide (tris-N-methylpyrrolecarboxamide). De.Fe(II) cleaves DNA contiguous to a five base pair A+T rich sequence. This is a novel and unique molecule and superior in sequence specificity to the naturally occurring antitumor compound used in man, bleomycin which cleaves DNA at a two base pair recognition site. EDTA-distamycin-Fe(II)(ED.Fe(II)) contains EDTA attached to the carboxy terminus of the groove binder tripeptide, tris-N-methylpyrrolecarboxamide. ED.Fe(II) cleaves DNA contiguous to a five base pair A+T rich sequence. Penta-N-methylpyrrolecarboxamide-EDTA.Fe(II)(P5E.Fe(II)) cleaves on opposite strands at the six base pair recognition level in a catalytic reaction. This is the first designed synthetic molecule that approximates the double strand sequence specific cleavage of DNA(4-6 bp recognition level) by the natural substance restriction enzymes, tools which make possible recombinant DNA manipulations. P5E.Fe(II) cuts DNA at sequences not available by the naturally occurring restriction enzymes. The dimers, bis(EDTA-distamycin.Fe(II)) and EDTA-bisdistamycin.Fe(II) which double strand cleave DNA at the eight base pair recognition level (A+T rich).

Bifunctional molecules having a DNA intercalator or DNA groove binder

Novel bifunctional molecules having a DNA intercalator or DNA groove binder linked to ethylene diamine tetraacetic acid such as compounds having the formula: ##STR1## wherein R is methyl or ethyl. Also, the method of cleaving DNA by contact with one of the above-identified molecules in the presence of ferrous ion and oxygen. The process of preparing said molecules by the reaction of P-carboxy methidium halide, p-carboxy ethidium halide, or other DNA intercalator or DNA groove binder with 1-3-diaminopropane followed by condensation with ethylenediamine tetraacetic acid. Distamycin-EDTA.Fe(II)(DE.FE(II)) contains EDTA attached to the amino terminus of the groove binder tripeptide (tris-N-methylpyrrolecarboxamide). DE.Fe(II) cleaves DNA contiguous to a five base pair A+T rich sequence. This is a novel and unique molecule and superior in sequence specificity to the naturally occurring antitumor compound used in man, bleomycin which cleaves DNA at a two base pair recognition site. EDTA-distamycin-Fe(II)(ED.Fe(III)) contains EDTA attached to the carboxy terminus of the groove binder tripeptide, tris-N-methylpyrrolecarboxamide. ED.Fe(II) cleaves DNA contiguous to a five base pair A+T rich sequence. Penta-N-methylpyrrolecarboxamide-EDTA.Fe(II)(P5E.Fe(II)) cleaves DNA on opposite strand at the six base pair recognition level in a catalytic reaction. This is the first designed synthetic molecule that approximates the double strand sequence specific cleavage of DNA(4-6 bp recognition level) by the natural substance restriction enzymes, tools which make possible recombinant DNA manipulations. P5E.Fe(II) cuts DNA at sequences not available by the naturally occurring restriction enzymes. The dimers, bis(EDTA-distamycin.Fe(II) and EDTA-bisdistamycin.Fe(II) which double strand cleave DNA at the eight base pair recognition level (A+T rich).

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Downingtown, PA, United States of America

Robert Philip Hertzberg