IL30879A - 4-oxa-androstanes and process for the manufacture thereof - Google Patents

Description

30879/2 4-0xa-androstanes and process for the manufacture thereof SPARAMEDICA A.G.

C:29101 sodium or lithium borohydride to reduce the 5-ox° moiety to a 5-hydroxy moiety. The treatment with alkali metal borohydride is preferably effected in an inert organic solvent and can be carried out, for example/ below room temperature, at a temperature from the freezing temperature of the solvent to room temperature (suitably in an ice bath) . Suitable solvents include lower alkanols, such as methanol, ethanol and iso-propanol, tetrahydrofuran,: dioxane and dimethylformamide .

Following the reduction, acidification effects cyclization, . i.e., lactonization. This lactonization can be effected using organic acids such as acetic acid or mineral acids such as hydrochloric acid. The acid can be directly added to the cooled reaction mixture' subsequent to the alkali metal borohydride reduction or the 5-hydroxy compound can be isolated and then acidified to effect lactonization, which can be effected at or below room temperature, i.e., from the freezing point of the solvent system to room temperature.

Compounds of formula la wherein X is fluorine may be prepared from compounds of formula III where Xr is bromine or chlorine by a substitution reaction. The substitution is effected by treatment of the formula III compound, or most desirably a lower alk 1 ester thereof, with a fluorine salt such as, for example, silver, potassium or lithium fluoride. A particularly preferred embodiment utilizes silver fluoride as the fluorine salt. In a preferred embodiment the . formula III compound is initially converted to the corresponding lower o a m hod r or to substitution. formula III acid by reaction with diazomethane in: a manner known per se .

■■'·.';■' The substitution reaction is carried out in the presence of an anhydrous inert organic solvent in which both the reactants are soluble. Suitable solvents include for example, dimethyl-sulfoxide , acetonitrile, ketones such as acetone and methyl ethyl ketone, and dimethyl formamide. While the reaction temperature is not critical, it is most desired that the reaction be run at the reflux temperature of the reaction ■medium. Acceleration of the reaction rate can be obtained by the addition of a small amount of water to the reaction medium such as, for example, about 2 ml of H20 per gram of ester compound.

The 6-fluoro seco ester obtained is saponified b treatment with an aqueous base in a lower alkanol, e.g. aqueous methanolic NaOH at room temperature. Lactonization of the resulting 6-fluoro seco acid in the manner described above for the corresponding bromo or chloro. acid results in the desired 6-fluoro compound of formula la..

: In another embodiment of the above substitution reaction a 6-bromoseco acid of formula III can be converted to the corresponding chloro compound of formula III by treatment with a chloride salt, e.g., lithium, chloride . The solvent medium employed may be the same as previously described for the. halo to the reflux temperature of the reaction medium, with temperatures at about the former level being preferred.

Halogenation of starting materials of formula II can also be effected, for example by treatment of. the compound of formula II with sulfuryl bromide or chloride to yield the corresponding 6, 6-dihalo compound (formula Ila), which is, then dehydrohalogenated to yield, the correponding 6-halo-6-ene compound (formula lib) which,, upon treatment with alkali metal borohydride as described above, is hydrogenated to a compound of formula III and then lactonized. The intermediate formula III ■compound/can optionally be halogen exchanged prior to lacton-ization thus to yield a formula la compound having a 6-fluoro substituent . " ' Alternatively, the 6,6-dihalo compound (formula Ila) may be directly converted into a. compound of formula lb b lactonization in the manner previously described herein. These reactions are illustrated by the following scheme in which partial formulae are shown and in which X and X' have the meanings defined above : wherein R^, and X have the meanings defined above. This epoxide opening can be effected by means knwon per se, for example, in aqueous or non-aqueous medium at room temperature or with heating in a solvent such as acetic acid, dioxane, acetone, chloroform or ethanol. The compound of formula V . ■simultaneously lactonizes to a compound of formula la since .■the compound of formula V is formed under acidic conditions. Dehydration of the compound of formula V thus yields a compound •,of formula; la... " ;'· ■. -.

In another route for obtaining compounds of formula. Ia, a compound of formula IV is directly subjected to treatment with halogen, such as bromine or chlorine, in a suitable inert organic solvent, such as carbon tetrachloride or methanol.

This treatment can conveniently be effected at room temperature or below room temperature.

The compounds of formula IV can be prepared by dehydrating the. 5-bydroxy compound obtained by reduction of a compound of formula II. The reduction of the compound of formula II can be effected under nonacidic conditions by catalytic hydrogenat- 30879/2 . includes compounds of these formulae having each of the, possible optical configurations at positions 5 and 6, i.e., four different enantiomers, as well as the racemates. It should be noted, however, that not each of the four possible enantiomers necessarily possesses usefulness as an anti- androgen,. For example, 6e*-bromo-17/3-hydroxy-17*-methyl-½-oxa- androstan-3-one which falls within formula I, i.e., the 5oc,6*- enantiomer, is useful as an anti-androgen, whereas such usefulness has not been found for the other three enantiomers .of this compound. The non-endocrinologlcally useful enantiomers ; of any particular compound are, however, useful in that the · ,. enantiomers are intra-corivertible . Thus, one. A/B- rans enantiomer can be converted to the other A/B-trans enantiomer, ; for example, a S^^-enantiomer can be oonverted to the 5*->6«- enantiomer via equilibration in the presence of bromide ions, for example, via treatment with lithium bromide or sodium bromide. Similarly, the A/B-cis enantiomers can be intra- converted. Moreover, the 5β-enantiomers can be hydrolyzed under alkaline conditions, for example, using aqueous sodium hydroxide to yield the corresponding 3,5-seco-A-nor-5-ol-3-oic acid which can be oxidized, for example, by chromium1 trioxide in the presence of acetic acid/methylene chloride to the correspond ing 3,5-seco-A-nor-5roxo-3-oic acid which then can be cyclized as desoribed herein to yield the A/B-trans enantiomer, I.e., the 5 Besides inhibition of androgenic response to testosterone propionate, anti-androgenic effect can also be shorn by measuring respcnse;.inhibltion to other androgens such as testosterone or fluqxymesterone . 14a- .30879/2 · As mentioned above certain compounds of the present invention and in particular 6c*-bromo-17p-hydroxy-17a-methyl-4-oxa-androstan-3-one are useful as topical anti-acne agents.

For such use these compounds may he formulated for topical application in a manner known per se as gels,' ointments, salves, lotions or creams. Generally, the topioal dosage will contain from about 0.1 to 10 by weight of the compound of formula la. The remainder of the dosage form will consist of conventional topical pharmaceutical carrier materials and can, if desired, contain other pharmaceutically active components.

The endocrinological^ useful compounds of the invention can be administered topically or internally, for example., orally or parenterally. Dosage should be adjusted to individual needs. The active ingredient of formula I, la, lb or VI can be administered in conventional solid and liquid pharmaceutical dosage forms such as capsules, tablets, suppositories, solutions suspensions and; creams. They can contain, conventional pharmaceutical additives such as stearyl alcphql, cetyl alcohol, petrolatum, polyalkylene glycols, water, carnauba wax, lactose, corn starch, calcium stearate or talc. They can be submitted acid was collected by filtration, washed well with water, and dried in an oven at 45° . This gave crude 6/5-bromo- 17/3-hydroxy- 17o<-iTiethyl- 5-oxo-3 i 5-seco-A-norandrostan- 3-oic acid, melting ■·' ; point; 192- 19 ° . g of sodium borohydride was added portionwise over a period of 20 minutes to a solution of 10 . 3 g of the crude 6|3-bromo- 17/3-hydroxy- 17o-methyl- 5-0x0-3 , 5-seco-A-norandrostan- 3-oic acid in 350 ml of methanol, stirred and cooled in an ice- bath. Stirring and cooling was continued for an additional hour ··.·/': The reaction mixture was then acidified with concentrated hydrochloric acid to pH ca. 1 , and after 15 minutes evaporated in vacuo to a small volume. This was diluted with 2 0 ml o water and extracted with one liter of ether. The ethereal extract was washed three times, each time with 50 ml of 2N aqueous sodium carbonate, then dried with anhydrous magnesium sulfate, and evaporated to dryness. This gave a syrupy residue, which after crystallization and several recrystallizations from ether gave 6/3-bromo- 17/3-hydroxy- 17c*-methyl-4-oxa-androstan- 3-one, melting point I63-I7 0 (decomposition) . [<*]^3 - 9 . 6° (c = Ο.39 in methanol) .

Example 2 To a solution of 17 g of crude 6/3-bromo- 17/3 -hydroxy- 17«-methyl-5-oxo-3 , -seco-A-norandrostan-3-oic acid (prepared as described in Example 1 ) in 5^ 0 ml of methanol, was added 1 ml of IN sodium h droxide solution and the reaction mixture of IN hydrochloric acid and diluted with three liters of water. The precipitated acid was separated by filtration, washed with water and dried in an oven at 4 ° . This gave crude 6o*-bromo- 17/3 -hydroxy-17«x-methyl- -oxo-3 i5-seco-A-norandrostan-3-oic acid which upon repeated recrystallization from methanol melted at 201-202 . 5° ; [* ] ^ * ° -13 .7 ° (c = 0 . 59 in tetrahydrofuran) taken on automatic polarimeter, and [oc ] ^ 5 - 18 .2° (c = 1 in tetrahydrofuran) taken on a classical polarimeter.

To a solution of 21 g of the crude 6«x.-bromo- 17/3-hydroxy- i7ot-methyl-5-oxo-3 , 5-seco-A-norandrostan-3-oic acid in 700 ml of methanol, stirred and cooled in an ice-bath, was added .portionwise 21 g of sodium borohydride over a period of 30 -minutes. After the addition was complete, the reaction mixture was stirred and cooled for an additional hour, and then acidified to pH 1 with concentrated hydrochloric acid. The resulting suspension was reduced in vacuo to 200 ml volume, diluted with 600 ml of water, and extracted three times, each time with 00 ml of ether. The ethereal extract was washed twice with 50 ml of 2N aqueous sodium carbonate and then twice with 100 ml of water, then dried with anhydrous magnesium sulfate and evaporated to dryness. The residue crystallized on trituration with ether. As shown by thin layer chromatography, this product contains as major components 6*-bromo- 17 5-hydroxy-Γ/cK-methyl- 4-oxa-androstan-3-one and 6=^-bromo- 17 3-hydroxy- 17^-methyl- - oxa-5 3-androstan-3-one . These compounds were separated from the crude product by fractional crystallization useing acetone carbonate, and- then twice with 50 ml of water. The combined carbonate and water layers were poured into icy concentrated hydrochloric acid, and the precipitated 17/e-hydroxy-17o-methyl- 3 , 5-seco-A-norandrost-5-en-3-oic acid was separated b filtrat- , o ion, washed with water and dried in an oven at 40 . After re-crystallization from ether, it melted at 179 · 5-ΐ8ΐ · 5° . MJ4,5 -46.6° (c = 0. 9 in tetrahydrofuran) .

To a solution of 1.532 g of the 17/8-hydroxy -17 -methy1-3, 5-seco-A-norandrost-5-en-3-bic acid in 100 ml of methanol, stirred at room temperature, was added dropwise 50 ml of 0.1 M solution of bromine in carbon tetrachloride, and the reaction mixture was then diluted with 1 liter of ether. The resultant solution was. washed twice with 100 ml of 2N aqueous sodium carbonate and twice with 100 ml of water, then dried with anhydrous magnesium sulfate and evaporated. It gave a noncrystalline residue, which was chromatographed on a 1 00 g silica gel column. The fractions eluted with ethyl acetate were combined, . and after evaporation gave crystalline 6/?-bromo-17$-hydroxy-17<-methyl-4-oxa-5/3-androstan-3-one . After re-crystallization from ether this compound transformed above 175°, and melted with transformations between 189-I920. oc]2 .B _ i .5°. (o = 0.90 in tetrahydrofuran).

Example 4 A mixture of 1 g of 6c*-bromb-173-hydroxy-17c--methyl-4- - - - evaporated to dryness in vacuo. Water was added to the residue and the mixture was left , to stand overnight at room temperature It was then extracted with $00 ml of ether/ the ethereal . extract was washed. three times with 25 ml of 2N aqueous sodium carbonate, and then twice with 2 ml of water, then dried over anhydrous magnesium sulfate ..and evaporated to dryness. The non-crystalline residue was chromatographed on a 300 g silica gel; column, and the fractions eluted with 15$ ethyl acetate in benzene were combined and gave crystalline 17/3-acetoxy-6o ~bromo 17«<-methyl-H-oxa-5/¾-androstan-3-one . This .material when twice , recrystallized from ether melted at 187- I88 .50, [o ] * 4 - 5 _8o.7° (c = I.48 in tetrahydrofuran) .

In a similar manner 17/S-acetoxy-6o-bromo- 17«.-methyl- - oxa-androstan-3-one was prepared from 60C-bromo- 173-hydroxy- 17°"—methyl- -oxa-androstan-3-one .

Example 5 To a solution of 2 .27 g of 175-acetoxy-5-oxo-3 , 5-seco- A-norandrostan-3-oic acid in a mixture of 135 ml of carbon . tetrachloride and 15 ml of glacial acetic acid was added 1 .6 ml of sulfurylchloride, and the reaction mixture was then stirred at room temperature for 19 hours. Thereafter, the solvent was removed in vacuo, and the residue was dissolved in ether. The ethereal solution was extracted with 2N. sodium carbonate. The carbonate layer was acidified with concentrated hydrochloric To a solution of 1 g of the 6-chloro-17^-hydroxy-5-oxo-3 , 5-seco-A-norandrost-6-en-3-oic acid, stirred and cooled in an ice-bath, was added porti.onwise 1 g of sodium borohydride over a period of 30 minutes. The reaction mixture was then cooled and stirred for an additional hour, acidified with ... 5 ml of concentrated hydrochloric acid and left to stand for two hours at room temperature . After dilution with 1 liter o methylene chloride, the reaction mixture was washed twice with 50 ml of 2N sodium carbonate,, then with water, dried and evaporated. The residue was dissolved in a mixture of ml pyridine and 5 ml acetic anhydride, and left at room temperature for 72 . hours. The solution was then evaporated in vacuo. The resultant residue. was washed with water and after drying it was crystallized from ether giving crystals which after repeated recrystallization from acetone gave 17/S-acetoxy-6c-chloro-4-oxa-5$-androstan-3-one, melting point 29 -300° (with decomposition) . [<*]^4 ,8 -53 « 8° (c = Ο.55 in tetrahydrofuran) .

The mother liquors were purified by chromatography on a . silica gel column, and after recrystallization from acetone-ether (1.: 10 ) gave 17/3-aceto y-6 3-chloro- -oxa-androstan-3-one, melting point I78-I810. [« ] - 8 + 11.9° (c = 1.05 in tetrahydrofuran) .

Example 6 A mixture of 1 .002 g ( 0.004 mole) of 6/$-bromo- 17/3-hydroxy- at room temperature for J days.. The reaction mixture was then diluted with 1 .5 1 of ether, washed with water ( 4 x 100 ml), dried over anhydrous magnesium sulfate and evaporated. The residue, consistin of crystalline material, was recrystallized from acetone to give 6o-chloro- 17/¾-hydroxy- 17=<--methyl-5-oxo-3 , 5-seco-A-noranarostan-3-oic acid, melting point 231-233 · 5° (with decomposition); [oc]*4,3 -l8 . 1° (c = I. 03 in tetrahydro-furan) .

This Gx-chlor^o-seco acid was also obtained as follows ί 17(5 -Hydroxy- 17¾-methyl-5-oxo-3 ,.5-seco-A-norandrostan-3-oic acid ( 30 g) was dissolved with heating in 300 ml of glacial acetic acid, the stirred solution was cooled to room temperature, and, 3 ml of acetic acid saturated with hydrogen chloride (gas) was added followed immediately by 98 . 9 ml (I.06 equiv.. of 1 . 00 molar ) of chlorine in acetic acid (over 5 minutes). After another 5 minutes the colourless solution was diluted with 1300 ml of H20 and cooled in an ice-bath for minutes. The solid was collected, washed with H20, and dried in vacuo at 90° · The above substance ( 29.4 g) in 490 ml of methanol was cooled to ca +3°, ' 95 ml of cold, IN sodium hydroxide solution was added and the mixture was- allowed to remain, at -4-3° or 3 · 5 hours. Cold IN hydrochloric acid ( 100 ml) and H20 ( 980 ml) were added, the mixture was cooled in an ice-bath for 0.5 hour, 3 , 5-seco-A-norandrostan-3-oic acid after drying at 90 had a melting point of 218-221° (dec); [-*]*5 -20.5° (in tetrahydro- furan , c = 1.0 ) .

A 1 1, three-neck, round bottom flask, equipped with an air stirrer, 250 ml dropping, funnel, and calcium chloride drying tube was flame-dried, charged with 1.0 g of lithium borohydride in 100 ml of tetrahydrofuran (previously · filtered over Woelm- neutral · alumina, activity I; 10 ml of tetrahydro-furan/l.O g of alumina), and cooled in a Dry- Ice-acetone bath ( -75° ) . To this was added, over 0.5 hour , a solution of 10 g of. the 6«*-chloro-seco acid prepared as described above in 200 ml of tetrahydrofuran (filtered over alumina, as above).

The reaction was allowed to continue. for 4 hours with. cooling ( -75° ) . and stirring. Excess hydride ' was then decomposed by the : slow addition of 20 ml H20 to the cold solution. The solution was adjusted to ca. pH 1 by the addition of 5 ml of concentrated hydrochloric acid. After warming the mixture to room . temperature the tetrahydrofuran was removed in vacuo ( 35° ) * and the residue, was dissolved in 120 ml of methylene chloride. 200 ml of H20 was added to the solution and the aqueous phase was extracted with two 120 ml portions of methylene chloride. The organic phase was washed with 200 ml of 10$ sodium carbonate, two 200 ml. portions of H20, 200 ml of. saturated sodium chloride solution, and dried (anhydrous sodium sulfate ) . The white solid obtained after removel of the solvent in vacuo ( 60° bath.) had an isomer distribution as determined by nmr analysis of 5«., 6«.: (in CHCI3 , c = 1.0 ) .

A 2.. 1. three-neck, round bottom flask, equipped with an air-stirrer, reflux condenser and a Soxhlet extractor ( 43 x 125 mm thimble), was charged with 30.0 g of the bromo-methyl ester in 675 ml of acetonitrile, and 60 ml of H20. AgF ( 150 g Harshaw Argentous. AgF) was placed in the thimble and. the mixture was refluxed and stirred for 23 hours. The reaction was followed by tic analysis. A brown precipitate was removed b filtration, most of the solvent was removed from the filtrate in vacuo ( 55-60° ) , the residue . was extracted with '750 ml of ether (the aqueous phase was set aside) and the organic phase was washed with three 800 ml. portions of H20 and dried over sodium sulfate. The original aqueous phase was extracted with 500 ml of methylene chloride which, was washed with 200 ml of H20, dried over sodium sulfate and combined with the ether extract. Concentration of the solvent yielded a yellow oil. The oil containing a mixture of isomers was dissolved in methylene chloride and filtered over a column of silica gel (120 g, Merck AG, 0.05-0.2 mm), from which fractions were thereafter obtained as follows.: Fraction Solvent 1,' 2.I.CH2CI2 2 It 3 4 2 1.556 acetone-CH2Cl2 found to have a melting point of 212-215°; M^5 -9.6° (in tetrahydrofuran, c = O.5O).

; The 6«x-fluoro- 17|3-hydroxy- 17o-methyl-5-0x0-3 , 5-seco-A- Example 10 To a solution of l8.2 g of 17/)-tert-butoxy-5-oxo-3,5- : seco-A-norandrostan-3-oic acid in 500 ml of anhydrous ether, stirred and cooled in an ice-bath, was added 2 ml of acetic acid saturated .with hydrogen bromide . This was followed after two minutes b dropwise addition of 9 g bromine diluted with 10 ml of acetic acid. The addition took about twenty minutes and its rate was synchronized with the rate of decolouration of the added bromines in the reaction mixture . The so-obtained "solution was stirred and cooled for an additional fifteen minutes, then transferred into a separatory funnel and washed four times, each time with 7Q0 ml of water. The ethereal layer was dried with anhydrous sodium sulfate and evaporated. to dryness. This gave a syrupy residue which crystallized on tri-. turation with hexane. The product so obtained, after two re- : crystallizations from isopropyl ether, gave 6/i-bromo-Υ]β-tert- . butoxy-5-oxq-3,5-seco-A-norandrostan-3-oic acid, melting point 139-142° (decomposition), M 5' -7 ° (c = 0.1 in d oxane ) .

To a solution of 23·5 S of the crude 6/3-bromo-17/^-tert- butoxy-5-oxo-3,5-sec°-A-norandrostan-3-oic acid in 100 ml of methanol, were added 60 ml of IN sodium "hydroxide solution and 400 ml of water. To the reaction mixture, stirred and cooled in an ice-bath, was added portionwise over 10 minutes 5 S of sodium borohydride . Stirring and cooling was continued for an additional hour. The reaction mixture was then acidified with Kg Per Gram Propylene Glycol 120.00 Ethylenediaminetetraacetic Acid Tetrasodium Salt (EDTAJ 0.10 Distilled Water 597.16 The stearyl alcohol, cetyl alcohol, petrolatum/ propyl parahydroxybenzoate, isopropyl palmitate and polyoxyl 40 stearate were melted at 75° · The mixture was cooled to and maintained a 70° · EDTA and methyl parahydroxybenzoate were dissolved in hot distilled water to which was added the propylene glycol. The solution was mixed at 75° and slowly added to the oil solution prepared previously, using slow agitation. The resultant emulsion was gradually cooled with slow stirring. When the temperature of the ointment reached 55°, a solution of 6*-bromo-Υ]β-hydroxy- 17t -methyl- -oxa-androstan-3-one was added and mixed with the ointment. When the temperature, of the ointment reached 50°, cold water was circulated in the jacket of the kettle and the ointment was cooled to 3°° with stirring. The ointment was then transferred to storage containers.

Example 15 A suppository formulation of 6<*r-bromo- 17/3-hydroxy- 17*.-methyl-4-oxa-androstan-3-one having the following composition was prepared as described hereinafter: Per Tablet Pregelatinlzed Corn Starch 8 . 0 mg . Calcium Stearate 3 . 0 mg Total Weight 205. mg 6ot-Bromo- 17/¾-hydroxy- 17o<-methyl- -oxa-androstan-3-one was mixed with the lactose, corn starch and pregelatinized corn starch in a suitable size mixer. The mix was passed through a comminuting machine fitted with, a screen and with knives ·. · . forward. The mix was returned to the mixer and moistened with water to a thick paste . The moist mass was passed through a screen and the mois granules were dried on pap'er lined trays at 43°C. The dried granules were returned to the mixer, the calcium stearate was added and mixed well. The granules were compressed at a tablet weight of 205 mg, using standard concave punches having a diameter of 0 . 8 cm.

' Example 17 A capsule formulation of 6ot-bromo- 17/9-hydroxy- 17

Claims (1)

1. wherein R , and. A have the meanings defined above, acetyl. i 3 ¾, 44. A compound according to Claim $6 or wherein the 1,2-bond is unsaturated. fi ' A compound according to Claim 4j,. wherein A represents group (a). .46. A compound according to Claim 3j3 or 3^, wherein A represents group (b) and the 1, 2-bond is saturated. †. 6<*-Bromo- h droxy- 17«*-methy 1-4-oxa-androstanyone. ■ t ■ -·■ ■ 4θ\ FluDPo- 17/3-hydroxy- 17< -methy 1 - 4-oxa-androstan 6 Ch 1oro- 173-hydroxy- 17<*-methy 1 - 4-oxa-androstan- 3-one. 6o6-Bromo-17/3-hydroxy-17«<-methyl- -oxa-androst-l-en-3-one . 51. 6, 6-Dichloro-17/3-hydroxy-4-oxa-androstan-3-one