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Retinol derivatives, their use in the treatment of cancer and for potentiating the efficacy of other cytotoxic agents

A technology of solvents and substances, applied in the field of new compounds, can solve problems such as complex preparation

Inactive Publication Date: 2005-09-14
OASMIA PHARMA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This complicates preparation and requires high-pressure homogenization of liquid emulsions

Method used

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  • Retinol derivatives, their use in the treatment of cancer and for potentiating the efficacy of other cytotoxic agents
  • Retinol derivatives, their use in the treatment of cancer and for potentiating the efficacy of other cytotoxic agents
  • Retinol derivatives, their use in the treatment of cancer and for potentiating the efficacy of other cytotoxic agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0138] Example 1. N-retinoyl-L-cysteine ​​and amides and N-retinoyl-L-homo Synthesis of Cysteines and Amides

[0139] Synthesis of L-cysteine ​​and L-homocysteine. Thionyl chloride (3mmol, 0.219ml) was added to 50ml of a suitable alcohol under stirring, and L-cystesulfonic acid monohydrate (1mmol, 187mg) or L-homocystesulfonic acid (1mmol , 183 mg), the mixture was refluxed for 48 hours. The alcohol was evaporated under reduced pressure, and the residue was recrystallized from ethanol. Yields between 85-95% were obtained for all esters.

[0140] Synthesis of L-cysteinesulfonic acid amides and L-homocystesulfonic acid amides. 10ml of an aqueous solution of the appropriate amine (28% NH 3 aqueous solution or 40% methylamine or dimethylamine in water) was added to 5 ml of an aqueous solution (1 mmol) of the methyl ester of the appropriate acid and the resulting solution was allowed to stand for 2-7 days. The solvent and excess amine were removed under reduced pressure and...

Embodiment 2

[0177] Example 2. Effect of compound I-1a in human breast cancer MDA-MB-231 cell line culture Cytotoxicity evaluation related to the final concentration of compound I-1a in the culture

[0178] A stock solution (1 mg / ml) of compound I-la was prepared by dissolving the dry matter in saline. From this solution, working solutions of different concentrations of Compound I-la in MEM containing 5% FBS were prepared by serial dilution for addition to the cultures.

[0179] On day 1 after inoculation, MDA-MB-231 cell cultures were treated with drug solution. Aliquots of working solution (2 μL) of different concentrations of compound I-1a were added to 200 μL of culture, so that the final concentration of compound I-1a in the culture was at 10 -9 -10 -7 between mol / L. In control cultures, 2 μL of medium containing 5% FBS was added as a solvent control.

[0180] After continuous culture for 2 days, the number of viable cells in the culture was counted, and the degree of growth i...

Embodiment 3

[0187] Example 3. Effect of compound I-1b in human breast cancer MDA-MB-231 cell line culture Cytotoxicity evaluation involving the final concentration of compound I-1b in the culture

[0188] A stock solution (1 mg / ml) of Compound I-1b was prepared by dissolving the dry matter in saline. From this solution, working solutions of different concentrations of compound I-lb in MEM containing 5% FBS were prepared by serial dilution for addition to the cultures.

[0189] On day 1 after inoculation, MDA-MB-231 cell cultures were treated with drug solution. Aliquot working solutions (2 μL) of different concentrations of compound I-1b were added to 200 μL of culture, so that the final concentration of compound I-1b in the culture was at 10 -9 -10 -7 between mol / L. In control cultures, 2 μL of medium containing 5% FBS was added as a solvent control. After continuous culture for 2 days, the number of living cells in the culture was counted, and the degree of growth inhibition of ...

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Abstract

A group of new compounds, N-(all-trans-Retinoyl)-L-cysteic acid, N-(13-cis-Retinoyl)-L-cysteic acid, N-(all-trans-Retinoyl)-L-cysteinesulfinic acid, N-(13-cis-Retinoyl)-L-cysteinesulfinic acid, N-(all-trans-Retinoyl)-L-homocysteic acid, N-(13-cis-Retinoyl)-L-homocysteic acid, and sodium salts of these compounds, including sodium salts of their esters and amides, is shown to exhibit therapeutic effects per se, and which compounds in combination with cytotoxic compounds, such as docetaxel, paclitaxel, doxorubicin and mitoxantrone, exhibit a synergistic effect. These compounds make it possible to manufacture new formulations of poorly soluble pharmaceutical compounds, and the present invention discloses a process of manufacturing water-soluble formulations of such compounds, exemplified by docetaxel, and paclitaxel, exhibiting enhanced pharmacological activity, and formulations of water-soluble pharmaceuticals exemplified by doxorubicin and mitoxantrone, exhibiting improved therapeutic efficacy.

Description

field of invention [0001] The present invention relates to novel compounds which have therapeutic properties in themselves and which enhance the efficacy of other therapeutically active compounds, such as cytotoxic compounds used in the treatment of cancer. The novel compounds themselves have been shown to have cytostatic properties. In addition to this, surprisingly, these compounds have been found to enable the preparation of novel formulations of poorly soluble compounds, exemplified here by poorly soluble cytotoxic compounds such as docetaxel and paclitaxel , said formulation exhibits improved solubility and therapeutic efficacy. It has also been found that the compounds enable the preparation of novel formulations of other cytotoxic compounds such as doxorubicin and mitoxantrone which exhibit improved therapeutic efficacy. Furthermore, it has been found that the compounds of the invention, in particular the corresponding cis- and trans-isomers of the compounds of the in...

Claims

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Application Information

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IPC IPC(8): A61K31/198A61K31/223A61P35/00C07C403/22
CPCC07C403/20C07B2200/09C07C2101/16A61P35/00C07C2601/16
Inventor O·斯特勒臣诺克J·阿勒克索夫
Owner OASMIA PHARMA AB
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