Wisconsin Alumni Research Foundation

Pawel Grzywacz

Hector Floyd Deluca

Lori A Plum

Margaret Clagett-Dame

Rafal R Sicinski

Grazia Chiellini

Hazel Holden

James Thoden

Hector F Deluca

Agnieszka Flores

Katarzyna Plonska-Ocypa

James B Thoden

Hazel M Holden

Rafal Barycki

Sumithra Gowlugari

Nirca J Nieves

Angieszka A Flores

Disclosed are methods of purifying the compound (20R,22R)-2-methylene-19-nor-22-methyl-1&#x3b1;,25-dihydroxyvitamin Dto obtain the compound in crystalline form. The methods typically include the steps of dissolving a product containing the compound in a solvent comprising hexane and 2-propanol, cooling the solvent and dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of crystals, and recovering the crystals. Certain diol precursors formed during the synthesis of the compound and its diasteromers also may be obtained in crystalline form using ethyl acetate as a solvent.

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

This invention discloses 2&#x3b1;-methyl and 2&#x3b2;-methyl analogs of 19,26,27-trinor-(20S)-1&#x3b1;-hydroxyvitamin Dand pharmaceutical uses therefor. These compounds 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 as well as skin conditions such as wrinkles, slack skin, dry skin and insufficient sebum secretion. These compounds also have little, if any, calcemic activity and therefore may be used to treat autoimmune disorders or inflammatory diseases in humans as well as renal osteodystrophy. These compounds may also be used for the treatment or prevention of obesity.

This invention discloses 2-methylene-(20S,25R)-19,26-dinor-vitamin D analogs, and specifically 2-methylene-(20S,25R)-19,26-dinor-1&#x3b1;,25-dihydroxyvitamin D, 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.

2-methylene-(20S,25R)-19,26-dinor-vitamin D analogs

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

This invention discloses (20S,22E)-2-methylene-19-nor-22-ene-1&#x3b1;,25-dihydroxyvitamin Danalogs, and specifically(20S,22E)-2-methylene-19-nor-22-ene-1&#x3b1;,25-dihydroxyvitamin D, and pharmaceutical uses therefor. This compound exhibits significant vitamin D receptor binding activity and 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, especially for the treatment or prevention of leukemia, colon cancer, breast cancer, skin cancer or prostate cancer.

Compounds of formula I, II or III are provided where X, Xand Xare independently selected from H and hydroxy protecting groups and Rand Rare independently selected from H or straight or branched chain alkyl groups having from 1 to 8 carbon atoms, straight or branched chain alkenyl groups having from 2 to 8 carbon atoms, straight or branched chain hydroxy-substituted alkyl groups having from 1 to 8 carbon atoms, or straight and branched chain hydroxy-substituted alkenyl groups having from 2 to 8 carbon atoms; and Ris independently selected from straight or branched chain alkyl groups having from 1 to 8 carbon atoms, straight or branched chain alkenyl groups having from 2 to 8 carbon atoms, straight or branched chain hydroxy-substituted alkyl groups having from 1 to 8 carbon atoms, or straight and branched chain hydroxy-substituted alkenyl groups having from 2 to 8 carbon atoms. Such compounds are used in preparing pharmaceutical compositions and are useful in treating a variety of biological conditions. 

2-substituted-1&#x3b1;,25-dihydroxy-19,26,27-trinor vitamin D analogs and uses thereof

A method of purifying (20R,25S)-2-methylene-19,26-dinor-1&#x3b1;,25-dihydroxyvitamin Dto obtain (20R,25S)-2-methylene-19,26-dinor-1&#x3b1;,25-dihydroxyvitamin Din crystalline form. The method includes the steps of preparing a solvent of methanol and water, dissolving a product containing (20R,25S)-2-methylene-19,26-dinor-1&#x3b1;,25-dihydroxyvitamin Dto be purified in the solvent, cooling the solvent and dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of (20R,25S)-2-methylene-19,26-dinor-1&#x3b1;,25-dihydroxyvitamin Dcrystals, and recovering the (20R,25S)-2-methylene-19,26-dinor-1&#x3b1;,25-dihydroxyvitamin Dcrystals.

This invention discloses 2-methylene-19,26-dinor-(20S,22E,25R)-vitamin D analogs, and specifically 2-methylene-19,26-dinor-(20S,22E,25R)-1&#x3b1;,25-dihydroxyvitamin D, and pharmaceutical uses therefor. This compound exhibits 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 no activity in vivo on bone calcium mobilization and relatively low 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-19,26-dinor-(20S,22E,25R)-vitamin D analogs

This invention discloses (20R)-2&#x3b1;-methyl-19,26,27-trinor-vitamin D analogs, and specifically (20R)-2&#x3b1;-methyl-19,26,27-trinor-1&#x3b1;,25-dihydroxyvitamin D, and pharmaceutical uses therefor. This compound exhibits 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 very low 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.

(20R)-2&#x3b1;-methyl-19,26,2-trinor-vitamin D analogs

This invention discloses 2-methylene-19,26-dinor-(20R,22E,25R)-vitamin D analogs, and specifically 2-methylene-19,26-dinor-(20R,22E,25R)-1&#x3b1;,25-dihydroxyvitamin D, and pharmaceutical uses therefor. This compound exhibits 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 very low activity in vivo on bone calcium mobilization and relatively high 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-19,26-dinor-(20R,22E,25R)-vitamin D analogs

13,13-Dimethyl-des-C,D analogs of 1&#x3b1;,25-dihydroxy-19-nor-vitamin Dcompounds and topical composition dosage forms thereof, and methods of treating skin conditions thereof. Exemplary active pharmaceutical ingredients include (1R,3R)-5-[(E)-(S)-11'-hydroxy-5&#x2032;,5&#x2032;,7&#x2032;,11&#x2032;-tetramethyl-dodec-2&#x2032;-enylidene]-2-methylene-cyclohexane-1,3-diol, (1R,3R)-5-[(Z)-(S)-11&#x2032;-hydroxy-5&#x2032;,5&#x2032;,7&#x2032;,11&#x2032;-tetramethyl-dodec-2&#x2032;-enylidene]-2-methylene-cyclohexane-1,3-diol, (1R,3R)-5-[(E)-(R)-11&#x2032;-hydroxy-5&#x2032;,5&#x2032;,7&#x2032;,11&#x2032;-tetramethyl-dodec-2&#x2032;-enylidene]-2-methylene-cyclohexane-1,3-diol, and (1R,3R)-5-[(Z)-(R)-11&#x2032;-hydroxy-5&#x2032;,5&#x2032;,7&#x2032;,11&#x2032;-tetramethyl-dodec-2&#x2032;-enylidene]-2-methylene-cyclohexane-1,3-diol.

This invention discloses 2-methylene-(20S,25S)-19,27-dinor-(22E)-vitamin D analogs, and specifically 2-methylene-(20S,25S)-19,27-dinor-(22E)-1&#x3b1;,25-dihydroxyvitamin D, 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.

2-methylene-(20S,25S)-19,27-dinor-(22E)-vitamin D analogs

Compounds of formula 1 are provided where X, X, and Xare independently selected from H or hydroxy protecting groups, and Rand Rhave the definitions provided herein. Such compounds may be 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

Pawel Grzywacz