Pharmaceutical compositions comprising poh derivatives and methods of use

A composition and drug technology, applied in the field of perillyl alcohol derivatives and isoperillyl alcohol derivatives, can solve the problems of tumor acquired drug resistance and undesired side effects hindering the long-term treatment of chemotherapeutic agents

Pending Publication Date: 2020-02-07
UNIV OF SOUTHERN CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, acquired drug resistance and undesired side effects of initially well-responding tumors are additional problems that often prevent long-term treatment with chemotherapeutic agents

Method used

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  • Pharmaceutical compositions comprising poh derivatives and methods of use
  • Pharmaceutical compositions comprising poh derivatives and methods of use
  • Pharmaceutical compositions comprising poh derivatives and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0124] Example 1: Synthesis of 4-isopropenylcyclohex-1-enylmethyl 2-propylpentanoate (POH-valproate conjugate)

[0125] The reaction scheme is as follows.

[0126]

[0127] Protocol for the synthesis of 4-isopropenylcyclohex-1-enylmethyl 2-propylvalerate (POH-valproate):

[0128] To valproic acid (1, 16.0 g, 110 mmol) was slowly added thionyl chloride (39.6 g, 332 mmol) while maintaining the internal temperature at 10°C. The resulting mixture was allowed to warm to room temperature (RT) and stirred for about 4.0 hours. Excess thionyl chloride was recovered by concentration under vacuum to give valproyl chloride (2) as pale yellow liquid (16.8 g, yield: 94%).

[0129] Valproyl chloride (2, 11.08 g, 68.14 mmol) was slowly added to a mixture of perillyl alcohol (POH 3 , 8.0 g, 52.55 mmol), triethylamine (8.5 g, 84 mmol) and dichloromethane (80 mL), At the same time keep the temperature between 10-15°C. The mixture was stirred at RT for 2.0 h, and then quenched with water (...

Embodiment 2

[0130] Example 2: Synthesis of 2-propyl-pentanoic acid 4-isopropylidene-cyclohex-1-enyl methyl ester (isoPOH-valproate conjugate)

[0131] The reaction scheme is as follows.

[0132]

[0133] Protocol for the synthesis of 4-isopropylidene-cyclohex-1-enylmethyl 2-propyl-valerate (isoPOH-valproate):

[0134] To valproic acid (1, 16.0 g, 110 mmol) was slowly added thionyl chloride (39.6 g, 332 mmol) while maintaining the internal temperature at 10°C. The resulting mixture was allowed to warm to room temperature (RT) and stirred for about 4.0 hours. Excess thionyl chloride was removed by concentration under vacuum to give valproyl chloride (2) as pale yellow liquid (16.8 g, yield: 94%).

[0135] Valproyl chloride (2, 11.08 g, 68.14 mmol) was slowly added to a mixture of isoperillyl alcohol (isoPOH 3 , 8.0 g, 52.55 mmol), triethylamine (8.5 g, 84 mmol) and dichloromethane (80 mL) , while maintaining the temperature between 10-15°C. The mixture was stirred at RT for 2.0 h, an...

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Abstract

The present invention provides for a method of treating a disease such as cancer, comprising the step of administering to a patient a therapeutically effective amount of a perillyl alcohol derivativesuch as a perillyl alcohol ester, or an isoperillyl alcohol derivative such as an isoperillyl alcohol ester. The derivative may be a perillyl alcohol or an isoperillyl alcohol conjugated with a therapeutic agent such as valproic acid. The route of administration may vary, including inhalation, intranasal, oral, transdermal, intravenous, subcutaneous or intramuscular injection.

Description

technical field [0001] The present invention relates to perillyl alcohol (POH) derivatives and isoperillyl alcohol (isoPOH) derivatives. The invention also relates to methods of treating cancer using perillyl alcohol derivatives such as perillyl alcohol esters and isoperillyl alcohol derivatives such as isoperillyl alcohol esters. Background technique [0002] Glioblastoma is the most common form of central nervous system (CNS) cancer and is currently considered largely incurable. Among the various malignant gliomas, anaplastic astrocytoma (grade III) and glioblastoma multiforme (GBM; grade IV) due to their aggressive growth and resistance to currently available therapies , so the prognosis is particularly poor. The current standard of care for glioblastoma consists of surgery, ionizing radiation, and chemotherapy. Despite medical advances in recent years, the prognosis of malignant gliomas has not improved significantly in the past 50 years. Wen et al. Malignant gliomas...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/517A61K9/48
CPCA61K45/06A61K31/20A61K9/0048A61K47/55A61P35/00A61K9/0043A61K31/045
Inventor T·陈D·莱文S·普帕利
Owner UNIV OF SOUTHERN CALIFORNIA
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