Mannkind Corporation

University of Central Florida Research Foundation, Inc.

Navneet Kaur

Otto Phanstiel

John J Freeman

Kelly Sullivan Kraft

Paul Serwinski

Vincent Pavia

Vinnie Pavia

Otto Phantsiel

Disclosed embodiments relate to improved methods for the synthesis of activated fumarate intermediates and their use in chemical synthesis. Disclosed embodiments describe the synthesis of activated fumarate esters including those derived from activating groups including: 4-nitrophenyl, diphenylphophoryl azide, pivaloyl chloride, chlorosulfonyl isocyanate, p-nitrophenol, MEF, trifluoroacetyl and chlorine, for example, ethyl fumaroyl chloride and the subsequent use of the activated ester in situ. Further embodiments describe the improved synthesis of substituted aminoalkyl-diketopiperazines from unisolated and unpurified intermediates allowing for improved yields and reactor throughput.

Methods for the synthesis of activated ethylfumarates and their use as intermediates

Disclosed embodiments relate to improved methods for the synthesis of activated fumarate intermediates and their use in chemical synthesis. Disclosed embodiments describe the synthesis of activated fumarate esters including those derived from activating groups including: 4-nitrophenyl, diphenylphosphoryl azide, pivaloyl chloride, chlorosulfonyl isocyanate, p-nitrophenol, MEF, trifluoroacetyl and chlorine, for example, ethyl fumaroyl chloride and the subsequent use of the activated ester in situ. Further embodiments describe the improved synthesis of substituted aminoalkyl-diketopiperazines from unisolated and unpurified intermediates allowing for improved yields and reactor throughput.

Several aromatic hydrocarbons di-substituted with a polyamine are described according to formulas selected from compounds 4, 7, 10, 15 and pharmaceutically acceptable salts thereof. The novel dimeric polyamines of the present invention demonstrate enhanced penetration into cells having an upregulated polyamine transport system, such as various types of cancer cells. The disclosed aromatic polyamine dimers provide highly efficient drugs for targeting cancer cells with active polyamine transporters.

Polyamine transporter selective compounds as anti-cancer agents

Disclosed are diagnostic tests helpful in indicating presence of an inflammatory bowel disease (IBD) in a human patient. In one embodiment, the test comprises obtaining a sample of mucosal tissue from the ileum or sigmoid colon of the patient; evaluating sample quality by testing for cadaverine and continuing the diagnostic test if the sample has no detectable cadaverine; testing the cadaverine negative sample for N-acetylated spermine; and correlating a detectable level of N-acetylated spermine in the sample with presence of IBD in the patient. Another, less invasive, method disclosed includes a diagnostic test comprising isolating mononuclear leukocytes from the patient's blood; testing the isolated mononuclear leukocytes for level of spermidine; and correlating a level of spermidine higher than that in mononuclear leukocytes of normal subjects as indicative of an inflammatory bowel disease in the patient.

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Danbury, CT, United States of America

Navneet Kaur