Synta Pharmaceuticals Corporation

Other

Takayo Inoue

Keizo Koya

Lijun Sun

Shoujun Chen

Noriaki Tatsuta

Elena Kostik

Zhi-Qiang Xia

Guiqing Liang

Farid Vaghefi

Weiwen Ying

Jun Jiang

Kevin Paul Foley

Zhenjian Du

Hao Li

Yaming Wu

Christopher Borella

Mei Zhang

Dan Zhou

The invention relates to compounds of structural formula (I): 

Compounds for the treatment of proliferative disorders

Provided is a method of identifying Hsp90 inhibitors with substantially less ocular toxicity or with substantially improved ocular toxicity profile. The method comprises measuring the respective concentrations of an Hsp90 inhibitor in the retina and plasma at certain time points following the administration of the Hsp90 inhibitor in a subject, and determining the concentration ratio of the Hsp90 inhibitor between retina and plasma, where a certain ratio is indicative that the Hsp90 inhibitor has substantially less ocular toxicity. The method also includes identifying an Hsp90 inhibitor with substantially less ocular toxicity, or with a substantially improved ocular toxicity profile, by determining the elimination rate of the Hsp90 inhibitor from the retina following administration of the Hsp90 inhibitor, where a certain elimination rate is indicative that the Hsp90 inhibitor will induce substantially less ocular toxicity.

Methods of identifying HSP90 inhibitors with less ocular toxicity

Disclosed herein are oral formulations of bis(thio-hydrazide amides) compounds of the following structural formula (I): or a pharmaceutically acceptable salt thereof, wherein R, R, R, R, R, R, Z, and Y are defined herein. 

Oral formulations of bis(thiohydrazide amides)

Disclosed are bis(thio-hydrazide amide) disalts and pharmaceutical compositions thereof. Also disclosed are methods of using bis(thio-hydrazide amide) disalts to treat cancer.

Bis(thio-hydrazide amide) salts for treatment of cancers

Disclosed are bis(thio-hydrazide amide) disalts, which are represented by Structural Formula (I):  Y is a covalent bond or a substituted or unsubstituted straight chained hydrocarbyl group. R-Rare independently &#x2014;H, an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group, or Rand Rtaken together with the carbon and nitrogen atoms to which they are bonded, and/or Rand Rtaken together with the carbon and nitrogen atoms to which they are bonded, form a non-aromatic heterocyclic ring optionally fused to an aromatic ring. Z is &#x2014;O or &#x2014;S. Mis a pharmaceutically acceptable monovalent cation and Mis a pharmaceutically acceptable divalent cation. Also, disclosed are pharmaceutical compositions comprising a bis(thio-hydrazide amide) disalt described above. Further disclosed are methods of treating a subject with cancer. The methods comprise the step of administering an effective amount of a bis(thio-hydrazide amide) disalt described above.

Disclosed are bis(thio-hydrazide amide) disalts, which are represented by Structural Formula (I):  Also, disclosed are pharmaceutical compositions comprising a bis(thio-hydrazide amide) disalt described above. Further disclosed are methods of treating a subject with cancer. The methods comprise the step of administering an effective amount of a bis(thio-hydrazide amide) disalt described above.

BIS (thio-hydrazide amide) salts for treatment of cancers

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Malden, MA, United States of America

Takayo Inoue