Wisconsin Alumni Research Foundation

The Ohio State University

University of California

The Ohio State Research Foundation

Margaret Clagett-Dame

Hector Floyd Deluca

Lori A Plum

Pawel Grzywacz

Hector F Deluca

Rafal R Sicinski

Rafal Barycki

Grazia Chiellini

Agnieszka Glebocka

Bulli Padmaja Tadi

Robert W Curley, Jr

Sumithra Gowlugari

Julia B Zella

Katarzyna Plonska-Ocypa

Hazel Holden

James Thoden

Agnieszka Flores

Hussein M Abou-Issa

Katarzyna M Barycka

Nirca J Nieves

Joel R Walker

Galal A Alshafie

Katarzyna Sokolowska

Jiasheng Song

Izabela K Sibilska

Bryan R Becklund

Terrence F Meehan

Jamie M Ahrens

Mary E Kaiser

Michael D Collins

Victoria V Abzianidze

James B Thoden

Hazel M Holden

James M Ntambi

Stuart Charles Helfand

William M Westler

Serena M Mershon

Nasim Akhtar

Antonio Mouriño

Derek W Barnett

Jason S Chapman

Margaret A Highland

Izabela Sibliska

Richard E Peterson

Vishal Sikri

Linda A Tephly

Kevin L Weiss

Brian Thomson

Nircaq J Nieves

Moisés A Rivera-Bermúdez

Hector Deluca

Pawel K Grzywacz

Raphal R Sicinski

Katarzyna Plonskaocypa

Angieszka Glebocka

James Wonkee Kim

Disclosed are methods of purifying the compound (22E)-(24R)-2-methylene-22-dehydro-1&#x3b1;,24,25-trihydroxy-19-nor-vitamin Dto obtain the compound in crystalline form. The methods typically include the steps of dissolving (22E)-(24R)-2-methylene-22-dehydro-1&#x3b1;,24,25-trihydroxy-19-nor-vitamin Din a solvent comprising ethyl acetate and hexane to form a solution, allowing crystals of (22E)-(24R)-2-methylene-22-dehydro-1&#x3b1;,24,25-trihydroxy-19-nor-vitamin Dto form and precipitate from the solution, and recovering the crystals of (22E)-(24R)-2-methylene-22-dehydro-1&#x3b1;,24,25-trihydroxy-19-nor-vitamin Dfrom the solution.

Procedure for crystallization of (22E)-(24R)-2-methylene-22-dehydro-1&#x3b1;,24-25-trihydroxy-19-nor-vitamin D

This invention discloses 2-methylene-(22E)-25-hexanoyl-24-oxo-26,27-cyclo-22-dehydro-19-nor-vitamin D analogs, and specifically 2-methylene-(22E)-25-hexanoyl-24-oxo-26,27-cyclo-22-dehydro-19-nor-1&#x3b1;-hydroxyvitamin D, and pharmaceutical uses therefor. This compound exhibits relatively high transcription activity as well as pronounced activity in arresting the proliferation of undifferentiated cells and inducing their differentiation to the monocyte thus evidencing use as an anti-cancer agent and for the treatment of skin diseases such as psoriasis as well as skin conditions such as wrinkles, slack skin, dry skin and insufficient sebum secretion. This compound also shows low activity in vivo on bone calcium mobilization, and therefore may be used to treat autoimmune disorders or inflammatory diseases in humans as well as renal osteodystrophy. This compound may also be used for the treatment or prevention of obesity.

2-methylene-(22E)-25-hexanoyl-24-oxo-26,27-cyclo-22-dehydro-19-nor-vitamin D analogs

Disclosed are methods of administering 2-methylene-19-nor-(20S)-1&#x3b1;,25-dihydroxyvitamin Dto treat primary hyperparathyroidism and/or to treat and/or prevent the symptoms of primary hyperparathyroidism in as subject having or at risk for developing primary hyperparathyroidism, preferably without inducing hypercalcemia in the patient.

Use of 2-methylene-19-NOR-(20S)-1-alpha,25-dihydroxyvitamin D3 to treat primary hyperparathyroidism

Disclosed are pharmaceutical compositions and methods of combination therapy that include or utilize low doses of 2-methylene-19-nor-(20S)-1&#x3b1;,25-dihydroxyvitamin Dand a calcimimetic to treat and/or prevent secondary hyperparathyroidism and/or its accompanying symptoms in a subject having or at risk for developing secondary hyperparathyroidism.

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Disclosed are methods of administering 2-methylene-19-nor-(20S)-1&#x3b1;,25-dihydroxyvitamin Dto treat and/or prevent secondary hyperparathyroidism and/or its accompanying symptoms in a subject having or at risk for developing secondary hyperparathyroidism.

Cyclopropane-containing vitamin D analogs of formulas I and IV are provided. Such compounds may be used in preparing pharmaceutical compositions and are useful in treating a variety of biological conditions. 

Disclosed are methods of administering 2-methylene-19-nor-(20S)-1&#x3b1;,25-dihydroxyvitamin Dto treat and/or prevent secondary hyperparathyroidism and/or its accompanying symptoms in a subject having or at risk for developing secondary hyperparathyroidism, including a subject previously administered a calcimimetic.

Use of 2-methylene-19-nor-(20S)-1&#x3b1;,25-dihydroxyvitamin D3 to prevent secondary hyperparathyroidism or the symptoms thereof

Use of 2-methylene-19-nor-(20S)-1-alpha,25-dihydroxyvitamin D3 to treat secondary hyperparathyroidism in patients previously treated with calcimimetics

Disclosed are (22E)-2-methylene-22-dehydro-1,24,25-trihydroxy-19-nor-vitamin Dcompounds, their biological activities, and various pharmaceutical uses for these compounds. Particularly disclosed are (22E)-(24R)-2-methylene-22-dehydro-1&#x3b1;,24,25-trihydroxy-19-nor-vitamin Dand (22E)-(24S)-2-methylene-22-dehydro-1&#x3b1;,24,25-trihydroxy-19-nor-vitamin D, their biological activities, and various pharmaceutical uses for these compounds.

Compounds of the formula: are described, along with pharmaceutical compositions containing these compounds, and methods of using the compounds to prevent and to treat cancer in mammals, including humans.

C-linked glucuronide of N-(4-hydroxybenzyl) retinone, analogs thereof, and methods of using the same to inhibit neoplastic cell growth

Oral and topical pharmaceutical compositions, kits and methods of treatment thereof for treating various skin disorder including acne, psoriasis, ichthyosis, photoaging, photodamaged skin, and, skin cancer. Exemplary vitamin D analogs as active pharmaceutical ingredients include 2-methylene-19-nor-20(S)-1&#x3b1;-hydroxy-bishomopregnacalciferol, 19-nor-26,27-dimethylene-20(S)-2-methylene-1&#x3b1;,25-dihydroxyvitamin D, 2-methylene-1&#x3b1;,25-dihydroxy-(17E)-17(20)-dehydro-19-nor-vitamin D, 2-methylene-19-nor-(24R)-1&#x3b1;,25-dihydroxyvitamin D, 2-methylene-(20R,25S)-19,26-dinor-1&#x3b1;,25-dihydroxyvitamin D, 2-methylene-19-nor-1&#x3b1;-hydroxy-pregnacalciferol, 1&#x3b1;-hydroxy-2-methylene-19-nor-homopregnacalciferol, (20R)-1&#x3b1;-hydroxy-2-methylene-19-nor-bishomopregnacalciferol, 2-methylene-19-nor-(20S)-1&#x3b1;-hydroxy-trishomopregnacalciferol, 2-methylene-23,23-difluoro-1&#x3b1;-hydroxy-19-nor-bishomopregnacalciferol, 2-methylene-(20S)-23,23-difluoro-1&#x3b1;-hydroxy-19-nor-bishomopregnancalciferol, (2-(3'hydroxypropyl-1&#x2032;,2&#x2032;-idene)-19,23,24-trinor-(20S)-1&#x3b1;-hydroxyvitamin D, 2-methylene-18,19-dinor-(20S)-1&#x3b1;,25-dihydroxyvitamin D, a stereoisomer thereof, a prodrug thereof in oral compositions, a salt thereof, and/or a solute thereof. Compounds that activate retinoic acid receptors, such as retinoyls and retinoyl esters, include 13-cis-retinoic acid, all-trans-retinoic acid, (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexeneyl)nona-2,4,6,8-tetraenoic acid, 9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraenoic acid, 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-napthoic acid, 4-[1-(3,5,5,8,8-pentamethyl-tetralin-2-yl)ethenyl]benzoic acid, retinobenzoic acid, ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]pyridine-3-carboxylate, retinoyl t-butyrate, retinoyl pinacol, retinoyl cholesterol, an isomer thereof, a prodrug thereof for oral compositions, an ester thereof, a salt thereof, and/or, a solute thereof. Combinations of such active ingredients demonstrate synergistic efficacy.

Methods of use to orally and topically treat acne and other skin conditions by administering a 19-nor containing vitamin D analog with or without a retinoid

This invention discloses (20R) and (20S)-24-(p-toluenesulfonyloxy)-25,26,27-trinorvitamin Danalogs, and especially (20R)-25,26,27-trinor-24-(p-methylphenylsulfonate)-vitamin D, its biological activities, and pharmaceutical uses therefor. This compound exhibits relatively little calcemic activity and does not promote cellular differentiation of HL-60 leukemia cells, but rather kills the cells. This cell death activity is found in small cell lung carcinoma also, but not in prostate, bone or ovarian cancer cells. This compound thus causes specific cell death in the absence of changes in calcium levels and without general toxicity in an animal. Therefore it might serve as a useful therapy for treatment of some forms of cancer, such as leukemia and lung cancer.

Growing community of inventors

Deerfield, WI, United States of America

Margaret Clagett-Dame