Johns Hopkins University

Cytochroma Inc.

Hauser, Inc.

Other

University System of Maryland

Yeda Research and Develpment & Co. Ltd

Opko Ireland Global Holdings, Limited

Cyctochroma Inc.

Gary H Posner

Christopher K Murray

Theresa A Shapiro

Uttam Saha

Mehmet Kahraman

Randall J Daughenbaugh

Qun Y Zheng

Poonsakdi Ploypradith

Qiang Wang

Jay A White

Glenville Jones

Kenneth R Crawford

Rachel D Slack

Michael H Parker

Soon Hyung Woo

Byung-Chul Suh

Hong Woon Yang

Hardwin O'Dowd

Suji Xie

Todd D Nelson

Heung Bae Jeon

Bryan T Mott

Lauren E Woodard

Lindsey C Hess

P Martin Petkovich

Curt I Civin

Paul Talalay

Robert H Yolken

Surojit Sur

Yuesheng Zhang

Michelle Rudek

Jae-Kyoo Lee

Gyoonhee Han

Alexander M Jacobine

Edward Korshin

Mario Bachi

John Northrop

Jeffrey S Elias

Alvin S Kalinda

Lorraine V Brando

Mikhail Krasavin

Jae Kyoo Lee

Jennifer Fox

Xiaochun Chen

Chang H Oh

Cheon-Gyu Cho

Maria-Christina White

Jared N Cumming

Kimberly S Petersen

John G D'Angelo

Christopher P Hencken

Andrew S Rosenthal

Deuk Kyu Moon

Steven M Silverman

David R Levine

Ravit Arav-Boger

Tanzina Labonte

Kristina Borstnik

Ik-Hyeon Paik

Andrew J McRiner

HeungBae Jeon

Mark Hatcher

Bethany Halford

Scott Borella

Douglas T Genna

Jennifer R Mazzone

Methods of treating cancer, such as leukemia, via administration of therapeutically effective amounts of artemisinins and second agents are detailed herein. The artemisinins include artesunate, dihydroartemisinin, artemether, arteether, artelinate, and ART-838. The second agents include BCL-2 inhibitors such as ABT-199, ABT-263, and ABT-737; kinase inhibitors such as lestaurtinib, midostaurin, and sorafenib; and anti-neoplastic agents such as cytarabine, doxorubicin, etoposide, cyclophosphamide, triplotide, vinorelbine, cisplatin, and rituximab.

Treatment of leukemia with artemisinin derivatives and combinations with other antineoplastic agents

This present disclosure is directed to novel prodrugs of activated vitamin D3 compounds. The prodrugs can be designed to have one or more beneficial properties, such as selective inhibition of the enzyme CYP24, low calcemic activity, and anti-proliferative activity. Specifically, these prodrugs are 1-deoxy prohormones of active Vitamin D analogs, e.g. analogs of calcitriol. This disclosure is also directed to pharmaceutical and diagnostic compositions containing the prodrugs of the invention, and to their medical use, particularly as prodrugs in the treatment and/or prevention of diseases.

1-deoxy analogs of 1,25-dihydroxyvitamin D3 compounds

Monomeric and dimeric trioxane thioacetals and methods of their use for treating subjects infected with malaria or other parasitic infectious diseases including, but not limited to, toxoplasmic infection; subjects afflicted with psychiatric conditions associated with toxoplasmic infection; and subjects afflicted with cancer.

Trioxane thioacetal monomers and dimers and methods of use thereof

Anilide derivatives of the natural trioxane artemisinin were prepared and evaluated for antimalarial efficacy in-infected mice. Selected anilides derivatives administered orally as one single-digit dose combined with mefloquine hydrochloride were completely curative, i.e., all 5 of the mice in the particular treatment group had no detectable parasitemia on day 30 post infection, gained as much weight by day 30 post infection as the control mice (no infection), and behaved normally.

Monomeric trioxane amide sulfur compounds

Two-carbon linked artemisinin-derived trioxane dimers and methods of their use for treating subjects infected with malaria or other parasitic infectious diseases including, but not limited to, toxoplasmic infection; subjects afflicted with psychiatric conditions associated with toxoplasmic infection; and subjects afflicted with cancer.

Two-carbon linked artemisinin-derived trioxane dimers

The disclosure provides compounds, compositions and methods using these compounds and compositions to stimulate the differentiation of cells and inhibit excessive cell proliferation of certain cells, including cancer cells and skin cells, which may be useful in the treatment of diseases characterized by abnormal cell proliferation and/or cell differentiation such as leukemia, myelofibrosis and psoriasis without the well known effect on calcium metabolism, which gives rise to hypercalcemia.

Low calcemic, highly antiproliferative, analogs of calcitriol

The present invention provides novel 16,23-diene 25-oxime ether analogs of 1,25-dihydroxy vitamin D3, compositions comprising these compounds and methods of using these compounds as inhibitors of CYP24. In particular, the novel compound of the invention are useful for treating diseases which benefit from a modulation of the levels of 1,25-dihydroxy vitamin D3, for example, cell-proliferative disorders.

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Artemisinin-derived monomers and artemisinin dimers are shown to exhibit in-vitro anti-cytomegalovirus (CMV) activity. Artemisinin dimers effectively inhibited CMV replication in human foreskin fibroblasts and human embryonic lung fibroblasts with no cytotoxicity at concentrations required for complete CMV inhibition. Artemisinin dimers were found to be potent and non-cytotoxic inhibitors of CMV replication, which indicates their use as therapeutic agents for the treatment of CMV infection in humans.

Anti-cytomegalovirus activity of artemisinin-derived dimers

Monomeric and dimeric trioxane fluoroaryl amides, 5-carbon-linked, C-10 non-acetal trioxane dimer esters; trioxane silylamides; and trioxane dimer orthoesters and methods of their use for treating subjects infected with malaria or other parasitic infectious diseases including, but not limited to, toxoplasmic infection; subjects afflicted with psychiatric conditions associated with toxoplasmic infection; and subjects afflicted with cancer.

Trioxane monomers and dimers

The disclosure provides novel trioxane sulfur dimers having Formula I: methods for their preparation, pharmaceutical compositions containing these compounds, and methods for treating cancer, proliferative disorders, and/or malaria using these compounds and/or compositions.

Trioxane dimer sulfur compounds

This disclosure provides improved derivatives of artemisinin; pharmaceutical compositions containing these compounds; methods for preparing these compounds and compositions; methods of using these compounds and compositions for preventing, controlling or treating infectious diseases including but not limited to parasitic infectious diseases such asinfection, trypanosome parasite infection, plasmodia parasite infection, and cryptosporidium parasite infection; methods for preventing, controlling or treating toxoplasma infection; and methods for treating psychiatric disorders associated with toxoplasma infection including but not limited to schizophrenia using the disclosed compounds and compositions alone or in combination with one or more antipsychotic drugs.

Artemisinin derivatives

The present invention provides novel D-ring and side-chain analogs of 1&#x3b1;,25-dihydroxyvitamin D, compositions comprising these compounds and methods of using these compounds as selective inhibitors of CYP24. In particular, the compounds of the invention are useful for treating diseases which benefit from a modulation of the levels of 1&#x3b1;,25-dihydroxyvitamin D, for example, cell-proliferative disorders.

The present invention provides novel sulfoximine compounds, compositions comprising these compounds and methods of using these compounds as inhibitors of CYP24. In particular, the compounds of the invention are useful for treating diseases which benefit from a modulation of the levels of 1&#x3b1;,25-dihydroxy vitamin D, for example, cell-proliferative disorders.

In only two steps and in 65% overall yield, natural trioxane artemisinin (I) was converted on gram scale into C-10-carba trioxane dimer (3). This new, very stable dimer was then transformed easily in one additional step into four different dimers (4-7). Alcohol and diol dimers (4 and 5) and ketone dimer (7) are 10 times more antimalarially potent in vitro than artemisinin (I), and alcohol and diol dimers (4 and 5) are strongly inhibitory but not cytotoxic toward several human cancer cell lines. Water-soluble carboxylic acid derivatives (8-10and 12) were easily prepared from dimers (4-6); they are thermally stable even at 60&#xb0; C. for 24 hours, are more orally efficacious as antimalarials than either artelinic acid or sodium artesunate, and have potent and selective anticancer activities. Further derivitization of the alcohol dimers (4 and 17), diol dimer (5) and ketone (7) has produced a number of analogs also antimalarially active in vitro at sub-nanomolar concentrations (most notably: pyridine N-oxides (13, 15, 18, 23, 24 and 25), phosphoric acid triesters (26 and 27), sulfonamide (40) and cyclic carbonate (41)). In addition, dimers (13 and 19) are more efficacious (when administered both orally and i.v.) and less toxic (when administered intraperitoneally to mice as a single dose) than clinically-used sodium artesunate, thereby giving them a better antimalarial therapeutic index than sodium artesunate.

Orally active, antimalarial, anticancer, artemisinin-derived trioxane dimers

The present invention provides novel C24-sulfone analogs of 1&#x3b1;,25-dihydroxy vitamin D, compositions comprising these compounds and methods of using these compounds as selective inhibitors of CYP24. In particular, the compounds of the invention are useful for treating diseases which benefit from a modulation of the levels of 1&#x3b1;,25-dihydroxy vitamin D, for example, cell-proliferative disorders.

Growing community of inventors

Baltimore, MD, United States of America

Gary H Posner