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Synthetic bile acid compositions and methods

Inactive Publication Date: 2008-12-25
KYTHERA BIOPHARMLS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0019]Adequate quantities of suitable bile acid as a defined pharmaceutical composition is herein provided, as well as methods for synthesis thereof. Bile acid compositions and methods so provided are not isolated from mammalian or microbial organisms that naturally produce the bile acids. In one aspect, particular deoxycholic acid pharmaceutical compositions which are free of all moieties of animal origin and of mammalian and/or bacterial pyrogens, and related methods for production and use are provided. In another aspect, adequate quantities of suitable

Problems solved by technology

Despite its attraction as a purported “fat-dissolving” injection, the safety and efficacy of these cosmetic treatments remain ambiguous to most patients and physicians.
Importantly, as with all medicaments from animal sources, there is concern that the animal-derived bile acid products may contain animal pathogens and other harmful agents such as animal or microbial metabolites and toxins, including bacterial toxins such as pyrogens.
Risk assessment and predictions of future events pertaining to prion diseases are difficult to ascertain because of the different modes of transmission, the unpredictable species barriers, the variable distribution of infectivity in tissues, and strain variations found in some diseases.
Bacterial contaminants of food and / or pharmaceutical products are also a serious issue as evidenced by contamination of food stuffs by enterohemoragic E. coli.
Such adverse effects include severe diarrhea, kidney failure and in the extreme situations, death.
Because the exact proportion of deoxy / cheno / cholic is not preselected, this may result in lot-to-lot variation when contemplating manufacturing large amounts of bile acids.
Such lot-to-lot variation can be problematic and may engender additional steps in garnering regulatory approvals or quality control, particularly in efforts to produce a pharmaceutical composition.
Presently, because of the relative abundance of animal carcass-derived bile acids, the industry has not taken steps to either fully chemically synthesize bile acids, or prepare bile acids using phytosterol or microbial starting materials.
And although bile acid derivatives have been synthesized, this work again primarily involved animal-derived bile acids as starting materials for steroid chemistry, due to the low cost and ready availability of animal materials.
Despite historically active efforts in phytosterol research, there are no readily-commercially available phytosterol-derived bile acid pharmaceutical grade compositions.

Method used

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  • Synthetic bile acid compositions and methods
  • Synthetic bile acid compositions and methods
  • Synthetic bile acid compositions and methods

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Androstane-3,11,17-trione (1.13)

[0100]10% of Pd / C (2.5 g, 5 wt %) is added to a solution of hydrocortisone (Compound 1.12) (50.0 g, 138.12 mmol) in DMF (250 mL). The resulting slurry is hydrogenated in a Parr apparatus (50 psi) for 12 h. Upon complete disappearance of starting material, as evidenced by TLC, the crude reaction mixture is filtered through a small plug of Celite, and the solvent is removed under vacuum. Crude product (48.0 g) is obtained as a colorless solid.

[0101]NaBH4 (2.1 g, 55.3 mmol) is added to a solution of the above crude product (48.0 g, 131.86 mmol) in EtOH (500 mL) and CH2Cl2 (500 mL). After 1 hr, acetone (50 mL) and water (150 mL) are added, followed by NaIO4 (70.5 g, 329.6 mmol). The mixture is stirred at room temperature overnight.

[0102]Distilled water (500 mL) is added and the mixture is extracted with ethyl acetate (3×250 mL). The ethyl acetate layer is flushed through a silica-gel plug and the solvent is evaporated to yield 38 g as a col...

example 2

3β-Hydroxy-androstane-11,17-dione (1.14)

[0105]K-selectride® (98.39 mL, 98.01 mmol, 1M solution in THF) is added to a solution of Compound 1.13 (33.0 g, 109.27 mmol) in THF (330 mL) over 15 minutes under an inert atmosphere at −78° C. and is stirred for about 3-4 h at −78° C. The reaction mixture is quenched with aqueous NaOH solution (2M, 70 mL). The crude reaction mixture is diluted with ethyl acetate (500 mL) and the organic layer is washed with water (3×75 mL), saturated brine solution (100 mL) and dried over MgSO4 (75 g). The solvent is removed under vacuum to afford 33 g of crude material. The crude product is subjected to acetylation without purification.

Purification of Crude Material

[0106]The crude material is purified by column chromatography [29(W)×600(L) mm, 230-400 Mesh silica, 200 g], eluting with ethyl acetate / hexane (1:4) [25 mL fractions, 5 mL / min elution, monitored by TLC withp-anisaldehyde charring; Rf for Compound 1.14=0.3 and Rf for Compound 1.13=0.37 in EtOAc / Hex...

example 3

3β-Hydroxyandrostane-11,17-dione acetate (1.15)

[0107]Acetic anhydride (16.6 g, 162.8 mmol) is added to a solution of Compound 1.14 (33.0 g, 108.55 mmol) in pyridine (150 mL) at 0° C. under an inert atmosphere. The resulting reaction mixture is stirred overnight at ambient temperature. Upon completion of the reaction, as evidenced by TLC, pyridine and remaining acetic anhydride are removed under vacuum. The crude residue is diluted with ethyl acetate (500 mL) and washed with water (3×150 mL), saturated brine solution (100 mL) and dried over MgSO4 (75 g). The solvent is evaporated under vacuum and the crude material is purified by column chromatography [59(W)×800(L) mm, 60-120 Mesh silica, 150 g], eluting with ethyl acetate / hexane (1:10) [25 mL fractions, 10 mL / min elution, monitored by TLC with p-anisaldehyde charring; Rf for Compound 1.15=0.38 and Rf for Compound 1.14=0.1 in EtOAc / Hexane (3:7)] to afford Compound 1.15 (19.0 g, 66.4% yield) as a colorless solid. Table 4 describes the...

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Abstract

Bile acids and related compositions and methods of synthesis and use. More specifically, deoxycholic acid and related compositions, said compositions being free of all moieties of animal origin and free of pyrogenic moieties.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit under 35 U.S.C. 119(e) to provisional applications U.S. Ser. No. 60 / 945,035 filed on Jun. 19, 2007 and U.S. Ser. No. 60 / 956,875 filed on Aug. 20, 2007, each of which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0002]The present invention relates broadly to bile acids and related compositions and methods. In one aspect, the present invention relates to deoxycholic acid and related compositions, useful intermediates, and methods for synthesis thereof. In another aspect, the present invention relates to use of the present compositions and methods as pharmaceutical compositions as well as methods for the manufacture thereof. Importantly, the bile acids of the present invention are not isolated from mammalian and microbial organisms naturally producing these acids and thus are free of any toxins and contaminants associated with such organisms.BACKGROUND OF THE INVENTION[0003]Cho...

Claims

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Application Information

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IPC IPC(8): A61K38/08C07J9/00A61K31/575A61P3/00A61K38/02
CPCA61K31/575A61K38/08A61K45/06C07J9/00A61K47/24A61K2300/00A61P3/00
Inventor MORIARTY, ROBERT M.DAVID, NATHANIEL E.MAHMOOD, NADIR AHMEDUDDIN
Owner KYTHERA BIOPHARMLS INC
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