Wisconsin Alumni Research Foundation

Rafal Barycki

Hector Floyd Deluca

Lori A Plum

Margaret Clagett-Dame

Rafal R Sicinski

Katarzyna Plonska-Ocypa

Katarzyna M Barycka

Pawel Grzywacz

Hazel Holden

James Thoden

Izabela K Sibilska

Nirca J Nieves

Mary E Kaiser

Izabela Sibliska

Moisés A Rivera-Bermúdez

Hector F Deluca

Hector Deluca

James B Thoden

Hazel M Holden

Katarzyna Plonskaocypa

Pawel K Grzywacz

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

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. 

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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.

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.

This invention discloses 22-haloacetoxy-homopregnacalciferol analogs and specifically 22-bromoacetoxy-homopregnacalciferol and pharmaceutical uses therefor. This compound exhibits relatively little calcemic activity and does not promote cellular differentiation off 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 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.

22-haloacetoxy-homopregnacalciferol analogs and their uses

This invention discloses 1-desoxy-2-methylene-19-nor-vitamin D analogs, and specifically (20S)-25-hydroxy-1-desoxy-2-methylene-19-nor-vitamin Dand pharmaceutical uses therefor. This compound exhibits relatively high binding activity and pronounced activity in arresting the proliferation of undifferentiated cells and inducing their differentiation to the monocyte thus evidencing use as an anti-cancer agent especially for the treatment or prevention of leukemia, colon cancer, breast cancer, skin cancer or prostate cancer.

1-desoxy-2-methylene-19-nor-vitamin D analogs and their uses

Compounds of formula I are provided where Xand Xare independently selected from H or hydroxy protecting groups. Such compounds are used in preparing pharmaceutical compositions and are useful in treating a variety of biological conditions. 

This invention discloses 2-methylene-19-nor-vitamin D analogs, and specifically (20S)-25-hydroxy-2-methylene-19-nor-vitamin Dand (20R)-25-hydroxy-2-methylene-19-nor-vitamin D, as well as pharmaceutical uses therefor. These compounds exhibit relatively high binding activity and pronounced activity in arresting the proliferation of undifferentiated cells and inducing their differentiation to the monocyte thus evidencing use as an anti-cancer agent especially for the treatment or prevention of osteosarcoma, leukemia, colon cancer, breast cancer, skin cancer or prostate cancer. Although these compounds have relatively low calcemic activities they may also be useful in the treatment of bone diseases due to their ability to act as prodrugs in vivo.

2-methylene-19-nor-vitamin D analogs and their uses

A method of purifying 1&#x3b1;-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol to obtain 1&#x3b1;-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol in crystalline form using precipitation with hexane from ethyl acetate. A method of preparing 1&#x3b1;-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol crystals acceptable for X-ray experiment using precipitation with hexane from benzene by diffusive exchange of the solvents is also described.

Crystallization of 1&#x3b1;-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol

Various compounds such as those having the formula I and XIV where the variables have the values described herein antagonize the vitamin D receptor and are useful in treating conditions such as asthma and in preparing medicaments for use in antagonizing the vitamin D receptor or treating conditions such as asthma 

Vitamin D receptor antagonists and their use in treating asthma

This invention discloses (20R)-23,23-difluoro-2-methylene-19-nor-bishomopregnacalciferol-vitamin D analogs, and specifically (20R)-23,23-difluoro-1&#x3b1;-hydroxy-2-methylene-19-nor-bishomopregnacalciferol, and pharmaceutical uses therefor. This compound exhibits 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 has little, if any, calcemic activity 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.

(20R)-23,23-difluoro-2-methylene-19-nor-bishomopregnacalciferol-vitamin D analogs

This invention discloses (20S)-23,23-difluoro-2-methylene-19-nor-bishomopregnacalciferol-vitamin D analogs, and specifically (20S)-23,23-difluoro-1&#x3b1;-hydroxy-2-methylene-19-nor-bishomopregnacalciferol, and pharmaceutical uses therefor. This compound exhibits 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 has little, if any, calcemic activity 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.

(20S)-23,23-difluoro-methylene-19-nor-bishomopregnacalciferol-vitamin D analogs

2-alkylidene-18,19-dinor-vitamin D compounds are disclosed as well as pharmaceutical uses for these compounds and methods of synthesizing these compounds. These compounds are characterized by low bone calcium mobilization activity and high intestinal calcium transport activity. This results in novel therapeutic agents for the treatment and prophylaxis of diseases where bone formation is desired, particularly osteoporosis, as well as autoimmune diseases such as multiple sclerosis, diabetes mellitus and lupus. These compounds also exhibit 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. These compounds also increase both breaking strength and crushing strength of bones evidencing use in conjunction with bone replacement surgery such as hip and knee replacements.

2-alkylidene-18,19-dinor-vitamin D compounds

This invention discloses 2-methylene-(22E)-25-(1-methylene-hexyl)-26,27-cyclo-22-dehydro-19-nor-vitamin D analogs, and specifically 2-methylene-(22E)-25-(1-methylene-hexyl)-26,27-cyclo-22-dehydro-19-nor-1&#x3b1;,24(R)-dihydroxyvitamin 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 lower activity in vivo on bone calcium mobilization and intestinal calcium transport activity compared to the native hormone 1&#x3b1;,25-dihydroxyvitamin D, 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-(1-methylene-hexyl)-26,27-cyclo-22-dehydro-19-nor-vitamin D analogs

Compounds of formula I are provided where X, Xand X3 are independently selected from H or hydroxy protecting groups. Such compounds are used in preparing pharmaceutical compositions and are useful in treating a variety of biological conditions. 

Growing community of inventors

Madison, WI, United States of America

Rafal Barycki