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Novel prodrugs of steroidal cyp17 inhibitors/antiandrogens

Inactive Publication Date: 2011-12-22
TOKAI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0028]Z is a charged group that is charged under normal physiological conditions, wherein the charged group is a quaternary ammonium group of the formula (R3N+)—, wherein each R group is independently C1-C7-branched alkyl, C1-C7-straight-chain alkyl, aryl, alkylaryl, aralkyl, heteroaryl, or two or more R groups together form a ring; a sulfonic acid; a phosphonic acid; a fluoroalkanol; or an acidic hydroxyl group,
[0029]In some embodiments, the invention contemplates a pharmaceutical composition comprising a therapeutically-effective amount of one or more compounds of the invention and one or more pharmaceutically-acceptable excipients, bulking agents, binders, flow ag

Problems solved by technology

However, some initial studies have indicated that compound 5 has low (˜10%) oral bioavailability in rats.

Method used

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  • Novel prodrugs of steroidal cyp17 inhibitors/antiandrogens
  • Novel prodrugs of steroidal cyp17 inhibitors/antiandrogens
  • Novel prodrugs of steroidal cyp17 inhibitors/antiandrogens

Examples

Experimental program
Comparison scheme
Effect test

example 1

Betaine Ester of Abiraterone

[0123]

[0124]A solution of bromoacetic acid (3.0 mmol 417 mg) in dichloromethane (10 mL) is stirred while dicyclohexylcarbodiimide (3.0 mmol, 619 mg), dimethylaminopyridine (0.5 mmol, 61 mg), followed by a solution of abiraterone (2.9 mmol, 1.08 g) in dichloromethane (3 mL) are added. The resultant mixture is stirred at room temperature for four hours. The mixture is filtered to remove precipitated dicyclohexyl urea, and poured into ethyl acetate. The organic layers are washed (1N HCL, 5% sat'd NaHCO3), dried (brine, MgSO4), and concentrated, with purification by column chromatography affording the pure alpha-halo ester.

[0125]The above-prepared bromoester (1.5 mmol, 743 mg) is dissolved in acetone (10 mL) and triethylamine (2.5 mmol, 253 mg, 3504) is added. The mixture is stirred until the steroid starting material is shown to be exhausted by TLC. The reaction mixture is concentrated in vacuo, and the residue is purified by reversed-phase HPLC to afford pu...

example 2

Carnitine Ester of Abiraterone

[0127]

[0128]A solution of R-dimethylmalate (10 mmol, 1.62 g) in THF (40 mL) is cooled at −78° C. and stirred while borane-dimethylsulfide complex (9.5 mmol, 4.75 mL of a 2.0M solution) in THF is added. The mixture is allowed to warm to room temperature and stirred while heating at reflux until exhaustion of the starting diester is indicated by TLC. The reaction mixture is quenched by slow addition of THF-water (1:1, 10 mL), and the resulting mixture is carefully poured into a solution of sodium hydroxide (5M, 10 mL), and stirred overnight. The reaction mixture is concentrated in vacuo, and the residue is taken up into ethyl acetate (50 mL). The organic layer is washed (1N, HCl, 5% sat'd aq NaHCO3), dried (brine, MgSO4), and concentrated in vacuo, with the residue being distilled in vacuo to afford purified methyl R-3,4-dihydroxybutyrate, or the residue may be used directly in the following step.

[0129]A solution of methyl R-3,4-dihydroxybutryate (6 mmol,...

example 3

Gallic Acid Ester of Abiraterone

[0136]

[0137]A solution of abiraterone (2 mmol, 747 mg), 3,4,5-tris[(tert-butyl dimethylsilyl)oxy]benzoic acid (2 mmol, 1.026 g), and 4-dimethylaminopyridine (1.0 mmol, 122 mg) in dichloromethane (10 mL) is stirred while dicyclohexylcarbodiimide (2.0 mmol, 412 mg) is added. The resultant suspension is stirred for three hours, and then filtered to remove precipitated dicyclohexylurea. The filtrate is washed with 1N HCl (2×50 mL), and the acid layers are extracted with dichloromethane (1×100 mL). The combined organics are dried (brine, MgSO4), and concentrated in vacuo to afford a solid. The solid is purified by flash column chromatography (silica gel, CHCl3—MeOH) to afford the pure tris-silyl protected ester.

[0138]The above prepared ester is dissolved in THF (8 mL) and TBAF is added as a THF solution (1M, 6 mL, 6 mmol) and the resultant solution is stirred for two hours at room temperature. The mixture is poured into half-saturated aqueous sodium chlori...

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Abstract

Prodrugs of C-17-heterocyclic-steroidal drugs providing improved oral bioavailability and pharmacokinetics are described. The drugs are inhibitors of human CYP 17 enzyme, as well as potent antagonists of both wild type and mutant androgen receptors (AR), and are useful for the treatment of urogenital and / or androgen-related cancers, diseases and / or conditions, such as human prostate cancer, breast cancer, and prostate hyperplasia. The disclosure describes methods of synthesizing and using the prodrugs in cancer therapy.

Description

CROSS-REFERENCE[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 150,031, filed Feb. 5, 2009, and which is incorporated herein by reference in its entiretyFIELD OF THE INVENTION[0002]This invention provides novel prodrugs of steroidal CYP17 inhibitors for the treatment of urogenital and / or androgen-related cancers, diseases and / or conditions, including castrate-resistant prostrate cancer, the synthesis of these new chemical entities, and to methods of using the same in the treatment of urogenital and / or androgen-related cancers, diseases and / or conditions.BACKGROUND OF THE INVENTION[0003]Prostate cancer (PCA) is the most common malignancy and age-related cause of cancer death worldwide. Apart from lung cancer, PCA is the most common form of cancer in men, and the second leading cause of death in American men. In the United States in 2008, an estimated 186,320 new cases of prostate cancer were expected to be diagnosed and about 28,660 men were expected ...

Claims

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Application Information

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IPC IPC(8): A61K31/675A61P15/00A61P35/00C07J43/00A61K31/58
CPCC07J43/003A61K31/58A61N5/10A61K45/06A61K31/675A61P5/28A61P13/00A61P13/08A61P15/00A61P35/00A61P43/00
Inventor CASEBIER, DAVID
Owner TOKAI PHARMA
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