CS198126B2 - Process for preparing 9 alpha-fluoro-llbeta,21-dihydroxy-16-alpha,17 alpha-/isopropylidenoxy/-1,4-pregnadien-3,20-dion-21 valerane - Google Patents

Description

(54) A process for the preparation of aa-fluoro-11 (Z1-dihydroxy-1Ba-4a-fisopropylidenoxy) -1,4-pregnadien-3,20-dione-21-valerane

The invention relates to a process for the preparation of 9α-fluoro-11β, 1,21-dihydroxy-16α, 17α- (isopropylidenoxy) -1,4-pregnadien-3,20-dione-21-valerane, hereinafter referred to as triamcinolone acetonide-21-valeran.

It is well known that steroids can be used topically and their use in this regard has met with varying success. A more effective steroid for topical administration is needed. It has now been found that triamcinolone acetonide-21-valeran as an active ingredient in a topical composition is a highly effective anti-inflammatory agent. This compound is more potent in the vasoconstrictor assay than previously used compounds, including triamcinolone acetonide, as an anti-inflammatory agent.

The process for preparing triamcinolone acetonide-21-valeran is characterized by reacting triamcinolone acetonide with at least a stoichiometric amount of n-valeryl chloride in an inert organic solvent such as pyridine at a temperature in the range of 50-125 ° C for 0.5 to 2 hours.

Triamcinolone acetonide-21-valeran as an active ingredient can be prepared by adding n-valeryl chloride to a cooled, stirred solution of triamcinolone acetonide. The mixture was then heated to reflux and cooled to room temperature. The mixture was. diluted with ice water and extracted with a solvent such as chloroform. The chloroform extract was washed with water, dilute hydrochloric acid, dilute sodium bicarbonate and finally saturated brine. The chloroform extract was evaporated under reduced pressure. The product was triturated with acetone / n-hexane, 1: 19. Filtration gave the product 9α-fluoro-11β, 21-dihydroxy-16α, 17α- (isopropylidenedioxy) -1,4-pregnadisine-3,20-dione-21 This sterold product can be used in various conventional topical pharmaceutical preparations at a concentration of, for example, 0.01 to 0.50%, as topical ointments at similar concentrations or as washing solutions etc.

Compositions containing the active compound of the invention may be in the form of the following standard topical pharmaceutical preparations: solutions, suspensions, lotions, ointments, creams, sprays, powders, foams, etc. These preparations may contain buffers such as phosphate, citrate or tartrate. surfactants such as polyoxyethylene (20) sorbitan monooleate (polysorbate 80), which is a complex of a mixture of polyoxyethylene ethers of mixed oleic acid esters, sorbitan anhydrides, and an oxylated target. an octylphenol formaldehyde FC polymer which is a surface tension reducing agent. Preservatives such as. methyl and propyl parabens, which are methyl and propyl esters of p-hydroxybenzoic acid, potassium sorbate, benzyl alcohol and the like. Oil, waxes, fats and the like can be used as emollients, and vaseline, sheep wool grease ( anhydrous lanolin), squalene, spermacet and the like. Stabilizers such as talc, clay, plant colloids, carboxymethylcellulose, carboxypolymethylene and the like can also be used; as well as fragrances such as lavender, lemon, gardenia, etc. These preparations may be filled into pressurized containers and a suitable, commonly used spraying agent such as trichlorofluoromethane, dichlorodifluoromethane or 1,2-dichloro-1,1,2,2-tetrafluoromethane may be added.

Triamcinolinacetonide-21-valeran was tested in comparison with various other steroids having known local anti-inflammatory activity according to the vasoconstrictor method. This assay is described in the following publications: "Topical Activities of Betamethasone Esters in Man," by A.W. McKenzie and R.M. Atkinson, Archives of Dermatology 89, 741-746 (1964). "Method for Comparing Percutaneous Absorption of Steroids, A.W. McKenzie and R. B. Stoughton, Archives of Dermatology 86, 6.08-610. (1962) - "Percutaneous Absorption of Steroids," by W. W. McKenzie, Archives of Dermatology 86, 611-614 (1962).

For the assay, various compounds were prepared by serial dilution in 95% alcohol to give concentrations of 1: 10,000 to 1: 6,250,000 at 5 levels. Two hundredths of a millimeter of each dilution is applied to the inner side of the forearm of ten people. Triamcinolinacetonide is applied at the same dilution to the second forearm. Application sites are covered for 16-20 hours and then observed to determine the presence or absence of vasoconstriction; the intensity of vasoconstriction is scaled.

The results are shown in the following table, which shows the relative potency of steroids compared to triamcinolone acetonide.

Table

The relative effectiveness of steroids compared to triamcinolone acetonide in a vasoconstrictor test in humans.

Compound: Relative potency (triamcinolone acetonide = 1.0)

Triamcinolone acetonide-21-valeran 2.6 triamcinolone-21-valeran 0.105 triamcinolone-16-acetate-21-valeran 0.01 triamcinolone-16-valeran 0.021 triamcolon-16-acetate-17-21-methylorthovaleran 0.040 triamcinolone-16, 17 , 21-orthovaleran 0.089

1,2-dihydrotriamcinolone acetonide-21-valeran 1,6 triamcinolone acetonide-21-tarc.

Butyl acetate 0.021 triamcinolone acetonide-21-tetrahydropyranyl ether 0.72 triamcinol-16,17-cyclic carbonate-21-ethyl carbonate 0.03

The results show that triamcinolone acetonide-21-valeran has a 2.6 fold potency in this assay compared to triamcinolone acetonide. All other steroids tested have considerably less potency and only one compound has greater potency than triamcinolone acetonide.

The following examples describe the preparation of triamcinolone acetonide-21-valeran and its use

Component Percentage Range (g / g) Living in various topical formulations. Parts are by weight unless otherwise stated.

Example 1

Triamcinolone acetonide-21-valeran 0.01-0.5

Preparation of 9'-Fluoro-11 ', 21'-dihydroxy-16''

17 '- (Isopropylidenedioxy) -1,4-pregnadien-3,21-dione-21-valerane

To a stirred solution of 3.0 g (6.9 mmol) of triacinolone acetonide in 50 ml of ice / water cooled pyridine was added dropwise 1.68 ml (14.1 mmol) of n-valeryl chloride. After addition of the material, the cooling bath was removed. The reaction mixture was refluxed for an hour, cooled to room temperature and allowed to stand overnight at room temperature. The reaction mixture is poured while stirring to about

1.5 liters of ice and water. The aqueous solution was extracted with chloroform (4.times.100 ml). The chloroform extract was washed with water, dilute hydrochloric acid, dilute sodium bicarbonate and finally saturated saline. The chloroform extract was dried overnight over anhydrous magnesium sulfate and then evaporated to dryness. The solid was triturated with acston / hexane (1:19, 25 mL). The product was filtered off to give 3.03 g (84.5% yield) of a colorless product. Evaporation of the filtrate gave an additional 0.33 g (total; yield)

93.5%). Crystallization from acetone / n-hexane gave a sample having the following properties: mp 262.5-263.5 ° C on a Kofler block; DTA, single cndotherm 264 ° C. IR (KBr): 3390, 1754, 1733, 1672, 1626, 1166, and 1058 cm @ ^-1 ;

pUzQH (( _D ²⁵ ° + 93 ° ^, 1 ^: 1; 1) C = 408, CHCl 3 1 dm; A _max

238 nm (εΙδ, Ο, ΟΟ). Purity by column chromatography 99%.

Analysis for C29H39O7F:

Calcd. C 67.16; H, 7.58; F, 3.66; Found: C, 67.15; H, 7.75; F 3.82.

glyceryl monostearate NF squalene ( ⁺ ) polysorbate 60 ( ^{+ +} ) 1 - 5 polysorbate 80 USP ( ^{+ +} ) 1 - 5 spermacet 5 - 20 stearyl alcohol USP 5 - 20 sorbitol solution USP 1 - 10 preservatives 3 - 5 distilled water qs up to 100 ( ⁺ ) squalene = 2,6,10,15,19,23-hexamethyltetracosan ( ^{+ +} ) polysorbate = polyoxyethylene sorbitan monooleate

The ingredients are mixed in a conventional manner to prepare a topical pharmaceutical cream, a white cream which may contain, for example, depending on the percentage of ingredients selected, 0.01, 0.025, 0.1 or 0.5% sterol. Example 1 a d 3

Topical application ointment containing a variable percentage of triamcinolone acetonide-21-valeran

Component percentage range (g / g) triamcinolone acetonide-21-valeran 0.01-0.5

Example 2 White Vaseline U. S. P. 100

Topical cream containing a variable percentage of triamcinolone acetonide-21-valeran

The components are mixed in a conventional manner to give a colorless ointment which may contain a range of 181212 percent (g / g, for example 0.01, 0.025, 0.10 or 0.50% steroid).

Optionally, an antibacterial component, such as neomycin, may be added in an amount of 0.1-3% (g / gj, as sulfate in micronized form).

Example 4

Topical foam containing triamcinolone acetonide-21-valeran

Component Weight range (mg / container i Triamcinolonacetonid- -21-valeran 0.5 - 50 Arlacel (§) 60 ( ⁺ j 20 - 50 Myrj 59 ® ( ⁺ ) 300-500 glyceryl monostearate 100-300 cetylalkohol 70 - 100 sorbit 70% 300 - 400 propylparaben 3 - 5 methylparaben 10 - 15 Veegum neutraP 15 - 20 distilled water 6 - 10 (g / container Freon® 12/144 (40 / 60j (+ + 1,3-) ⁺ j 2.0 (g / container) ( ⁺ j Arlacel = sorbitan monostearate

(+ +) Myrj = polyoxyethylene fat fatty acid derivative ( ^{+ +} '] dichlorodifluoromethane (1,2-dichloro-1,1,2,2-tetrafluoroethane)

The components are mixed in a conventional manner, filled into containers and then pressurized with freon.

Example 5

Eye ointment containing a variable percentage of triammonolone acetonide-21-valeran

Component

Triamcinolone acetonide-21-valeran 0.1 - 0.50 mineral oil, light N.F. 1 - 5 white vaseline U. S. P. up to 100

The ingredients are mixed in a conventional manner to give an off-white eye ointment. Optionally, an antibacterial component, such as neomycin, may be added in the form of a micronized sulfate salt.

Example 6

Topical wash solution containing a variable percentage of triamcinolone acetonide-21-valeran

Component

Percentage range (g / gj

Triamcinolone acetonide-21-valeran Polawas PD 34 ( ^{+ +} j Volpo 20 (+) ^R oleyl alcohol methylparaben propyleneparaben squalene potassium sorbate 70% sorbitol solution

0.01-0.5

3-5

0.5 - 2 - 5

0.12 - 0.2 0.02 - 0.06 - 5

0.05 - 0.25 - 10 to 100 distilled water ( ⁺ ) Volpo 20 = polyoxyethylene ether of oleyl alcohol ( ^{+ +} ) Polawax = reaction products of higher fatty alcohols and ethylene oxide

The ingredients are mixed in a conventional manner to obtain an opaque creamy wash solution.

Example 7

Ointment for topical application

Component Percentage Range (g / g)

198Í26

Triamcinolone acetonide-21-valeran 0.01 - 0.5 polyethylene glycol 400 U. S. P. 5 - 20% white Vaseline U. S. P. up to 100%

The ingredients are mixed to give a colorless ointment.

Optionally, an antibacterial component, such as neomycin, may be added in an amount in the range of 0.1-3% (g / g), such as sulfate in micronized form.

Claims (1)

SUBJECT A process for the preparation of 9α-fluoro-1,13,21-dihydroxy-16α, 17α- (isopropylidenoxy) -1,4-pregnadiene-3,20-dione 21-valerane, characterized in that at least one reaction is carried out with triamcinolone acetonide. a stoichiometric amount of n-valeryl chloride in an inert organic solvent such as pyridine at a temperature in the range of 50-125 ° C for 0.5 to 2 hours. Severograíia, n. P., Plant 7, Most