IL27072A - Pharmaceutical compositions comprising steroidal hemiacetals of the androstane and pregnane series and some new compounds of these series - Google Patents

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING STEROIDAL HEMIACETALS OF THE ANPROSTANE AND PREGNANE SERIES, AND SOMR HEW COMPOUNDS OF THESE SERIES* raormKif imoa g»»¾»imap ti^¾¾»ag! a»»«aw rnnpw P.A. 27072 II This invention concerns novel steroids having contraceptive activity and a process for their preparation.

Many of the oral contraceptive steroids previously proposed* particularly those which occur naturally, give rise to unwanted side effects such as weight increase and salt and water retention* We have now found that certain steroid hemiacetals, which are more precisely defined hereinafter* are suitable for use as oral contraceptives and substantially avoid the above disadvantages* These substances are also useful steroidal aldosterone blockers* According to the present invention we provide pharmaceutical compositions comprising steroidal hemiacetals of the skeletal formula wherein Y is a keto group, a ketalized keto group, hydroxy or an acyloxy group, Z is hydroxy or fluorine, R is an oxygen atom which is joined to the 11- or osition, is a β-eliminatable halogen or tosyl substituent or represents a carbon-carbon bond joined to the osition R1 is a group COCHgX, where X is a hydrogen or halogen atom, and 2 R is a hydrogen atom or hydroxy or acyloxy group or R1 is a hydroxy group and 2 R is an aliphatic hydrocarbon group which may* ifi desired, carry one or more halogen atoms as substituents and 19-ethers and 19-estere thereof, together with a pharmaceutically acceptable carrier.

Where R is an acyloxy group it is preferably a lower aliphatic acyloxy group having 1 — 6 carbon atoms e.g. an acetoxy or propionoxy grou R may, for example, be a methyl, vinyl or ethynyl group or a vinyl or ethynyl group carrying an aliphatic substituent; such an aliphatic substituent may be saturated or may possess double or triple bonds and preferably possesses up to 6 2 carbon atoms. Thus, for example, R may be a straight or branched lower alkenyl or alkynyl group e.g. a butadiynyl group.

Where Y is a grouping convertible to a keton group atom, it may, for example, be a hydroxyl group or an acyloxy group such as acetoxy. Those compounds in which Y is ketonic oxygen are preferred, however, for their activity as oral contraceptives.

R3 preferably represents a carbon-carbon bond joined to the -position; where R represents a β-eliniinatable halogen or tosyl substituent, the compounds will still be active due to elimination under physiological conditions but are also of use as intermediates. may thus advantageously be a halogen atom, e.g. a chlorine or bromine atom 19-Esters are preferably lower aliphatic, or aromatic acylates e.g. acetates.

P.A. 27072 II As indicated above, the steroids of formula I possess antifertility activity on oral administration which is substantially free from somatropic effects leading to loss of libido, weight gain and water and salt retention.

On account of their aldo sterone-bloeking activity, the new compositions lead to a urinary retention of potassium and will block the urinary excretion of potassium induced by aldosterone. They are, therefore, useful either per se or in combination with diuretic agents in the treatment of cirrhosis of the liver, congestive heart failure, and other edematous states arising from the hypersecretion or diminished metabolism of the hormone aldosterone. Their medical use leads in these cases to a diuresis without an attendant loss of potassium and the complications which this would normally entail. Also, they may be used in the treatment of hypertension. 17a-Bthynyl-19-oxo-androst- -ene-lip-173-diol-3-one-11 ,19-hemiacetal is a potent oral contraceptive agent and is also an extremely efficient inhibitor of the action of aldosterone and has a high lever of estrogenic activity. These properties make it an extremely useful compound for estrogen replacement therapy and especially in geriatric medicine. The corresponding compound with the 17 -acetyl side chain is somewhat less active as a contraceptive agent and as an aldosterone blocker* It is, however, substantially free of estrogenic activity. The 19-fluoro derivative of this 17p-acetyl compound is an extremely efficient aldosterone blocker and is free of estrogenic activity. and also has potential as a contraceptive agent* Its use is indicated in cases where an estrogenic effect is not desired. The corresponding 19-fluoro-6, 19-ether is also an active aldosterone blocker and has potential as an active contraceptive agent without estrogenic activity. 21-Deso ycortisol 11β , 19-hemiacetal also possesses marked aldosterone blocking and diuretic activity.

The substances of formula I all appear to be orally active.

According to a further feature of the invention, therefore, we provide pharmaceutical compositions containing one or more compounds according to the invention, together with one or more pharmaceutical carriers or excipients.

The active compounds in the compositions according to the invention thus comprise compounds of skeletal formula I wherein R1 is a group COCHgX, where X is a hydrogen atom, and R 2 is a hydrogen atom or an acyloxy 1 2 ' group or R is a hydroxyl group and R is a vinyl or ethynyl group or aliphatic hydrocarbon groups as substituents.

P.A. 27072/11 The compositions according to the invention may take the form or oral, parenteral or rectal prepara ions* The perferred mode of administration is in oral formulations, for example, lozenges, tablets, capsules, dragees, and like dosage-unit forms as well as syrups, elixirs, emulsions, etc* The pharmaceutical carrier or exciplent may, for example, be of the kind conventional for such formulations, e*g* starch, lactose, talc, magnesium stearate etc* in tablets* dragees and lozenges, gelatin for capsules and for the liquid preparations water or oil containing suspending, emulsifying, dispensing, thickening, flavouring agents etc* Parenteral formulations will comprise the active steroid in solution or suspension in a parenterally acceptable liquid, for example sterile water, oils such as peanut oil or ethyl oleate, oily emulsions etc.

Rectal formulations will comprise a suppository base, for example a polyglycol or carbowax base, The dosage unit forms of the compositions according to the invention preferably comprise 0.05 to 100 *mg. of active steroid, advantageously 0.1 to 50 mg. Units containing 1.0 to 25 mg are especially convenient.

Examples of useful dosage units are tablets for oral administration containing 2.5 or 25 mg of active substance.

The compositions will be administered at a daily dose level in the range 1 to 25 mg per day, for example 2 to 10 mg per day. The regimen may be as follows; 1) about 5 mg/day, days per cycle, 2) about 5 mg/day for 3-5 days following ovulation, 3) about 5 mg/day for 3-5 days following coitus, 4) 1-2 mg/day.

Advantageously, the contraceptive compositions may contain a minor proportion of an oestrogenic or pro-oestrogenic substance, for example one of the compounds described in our ponding No. 23298 cognate application / Μ// > There are also advantages in including a conventional progestational agent during the latter stage of monthly treatment in order to prepare the endometrium for the normal menstrual cycle.

The antialdosterone or diuretic preparations advantageously include carbonic anhydrase inhibitors, such as dichlorphenamide or acetazolamide derivatives; thiazide diuretics, in particular, triehlormethazide ; xanthene diuretics; ethacrynic acid derivatives; and/or triampterene derivatives. 19-fluoro- The/ new compounds according to the invention may be prepared e the oximino group of a compound of the skeletal formula (where Y, R , R and R have the meanings given above and one group ^" is hydrogen while the other is a hydroxyl group) in ketone- group protected form where Y ia/ke ojiis ©xyge», followed if required "by hydrolysis of the protected ketone group or groups and/or replacement of the 19-hydroxy groups b fluorine.

The ketone-protected form of the compound of formula II may, for example, carry a ketal e-?-%hi©ke*al-gre p at the 3-position and, where R"'" is COGHgX, the carbonyl group in the 20-position may also be in protected form, for example, in the form of a ketal ea?-4ki«-hre- a-b-grotrp. During the hydrolysis of the oximino group to form the required hemiacetal, the ketone-protecting groups will remain protected so that the 19-oxo group initially formed will cyclise 6-or the spontaneously with the/ll-hydroxy group without side reactions taking place. The hydrolysis of the oximino group is advantageously effected by the action of nitrous acid under weakly acid conditions e.g. using a soluble nitrite in the presence of a carboxylic acid such as acetic acid. The hydrolysis of the ketone-protecting groups may be effected using a mineral acid, e.g. hydrochloric, hydrobromic, sulphuric, perchloric or phosphoric acid.

Where the grouping Y is a grouping convertible to a ketone function and a 3-keto compound is ultimately required, the conversion may be effected after introduction of the hemiacetal grouping. Thus, for example, a 3-ketal or 3-acetal may be subjected to acid hydrolysis or a 3-acyloxy group may be hydrolysed to a - oxidising agent.

Where R is a β-eliminatable substituent , this can he eliminated by treatment with acid and may thus be eliminated during one of the hydrolysis stages described above „ One particularly useful method is to use intermediates having an acyloxy group in the 3-position and a β-eliminatable substituent at the 5a-position. After hemiacetal formation aeeejjding-te-iiie - ^ocj-eAs.^£-ti*s--i» s.i*-fei&i¾r hydrolysis followed by oxidation under acid conditions yields the desired Δ^-3-keto structure.

The replacement of the 19-hydroxy group by fluorine may be effected in any convenient way, for example by conventional techniques. Thus ? for example, the 19-hydroxy compound may be reacted with a fluorinating reagent such as HP in an inert solvent such as tetrahydrofuran or tetrahydrofuran/chloroform or with phosphorus trifluoride, antimony pentafluoride etc. Alternatively the 19- hydroxy group may be first replaced by a reactive ester group such as an aromatic, araliphatic or aromatic sulphonyloxy group e.g. a mesyloxy a tosyloxy-group, or a halogen atom e.g. a chlorine or bromine atom, followed by reaction with fluoride ions and thus avoids use of HP. The reaction with fluoride ions may be effected in situ during the reaction to replace the 19-hydroxy group by the ester group. The replacement of- he 19-hydroxy group may be effected by reaction with a chlorinating or brominating reagent, e.g. phosphorus oxchloride or oxybromide etc. or with reagents such as mesyl chloride or mesyl bromide. The source of fluoride ions may, for example, be an alkali metal or alkaline earth metal fluoride, e.g. sodium or potassium fluoride and the reaction is preferably effected in an inert solvent which enables fluoride ions to be liberated a polar cyclic ether solvent such as tetra- hydrofuran etc. Less reactive esters of the 19-hydroxy group, for example esters with carboxylic acids e.g. aliphatic araliphatic or HP. The corresponding 19-ethers, e.g. aliphatic, araliphatic or aromatic ethers may also be used in the reaction with HP.

A still further method of producing the 19-fluoro-cyclic ethers is to react the intermediate 19-oxime II with a nitroso fluorinating agent, such as nitrosyl fluoride, nitrosyl tetra-fluoroborate , or with a nitrosylating agent such as nitrosyl chloride or bromide in the presence of fluoride ions.

The oxime of formula II may be prepared by photolysis of a nitrite of the skeletal formula (where Y has the above meaning and Br is a β^-liminatable substituent or a bond to the 4(5) - position) in ketone-protected form, by irradiation with UY light of a wavelength absorb-ed by the nitrite group.

The photolysis may be effected in solution in an inert solvent, preferably one which does not absorb any of the photolysing radiation. The nitrite starting material may be prepared by reaction of the corresponding 11-hydroxy compound with a nitrosylating reagent e.g. a nitrosyl halide such as nitrosyl chloride. The reaction is advantageously effected in the presence of an acid binding agent e.g. a tertiary base such as pyridine. Where a further OH group is present, as in the ΙΤβ-hydroxy compounds, this will also be nitrosylated but due to the low reactivity of the 11-nitrito group, the unwanted additional nitrito group can be removed selectively by solvolysis; thus, for example, the 11β , 17β-¾Ϊ3~η ΪΓίΐο compound can be converted to the 11-nitrito-17-hydroxy compound simply by heating in a lower alkanol such as methanol.

The 11-hydroxy compound can be prepared by reduction of the corresponding 11-one, e0 3 using a metal hydride reducing agent such as sodium borohydride or lithium aluminium hydride „ i Where compounds are required in which is hydroxyl and R is an aliphatic group , this grouping at the 17-position can be introduced by reacting the corresponding compound 17-one/with an appropriate organo-metallic compound such as a Grrignard reagent or, in the case of the ethynyl compounds an alkali metal acetylide. The introduction of such a grouping may be effected conveniently before reduction of the 11-one, e0g» by reacting the corresponding 11,17-dione with the appropriate reagents The ethynyl group is conveniently introduced by passing acetylene into a solution of the dione in an inert solvent following by addition of an alkali metal t-alkoxide.

For the better understanding of the invention, the following Examples are given by way of illustration only; all temperatures are in °Cs- -5he Δ^—&ndrostene-3 ? 11 , 17-trione (9 g.) was heated at reflux with 2-methyl-2-ethyl dioxolane (160 cc) and p-toluenesulphonic acid (150 mg0)<, Butanone (100 cc) was slowly, fractionally distilled over a period of 5°5 hours » The residue was diluted with benzene which was then washed with sodium bicarbonate and water , dried, and evaporated in vacuo » Crystallization from aqueous methanol gave 7» 3 g. ( 7096) of the desired monoketal, m.p, 189 - 94°0 = The analytical sample (methylene chloride-ether) had mop. 194 - 197°; C^J^ + 55°; 1735(vs), 1705 (vs)^" ' 1670(w) cm."1 Anal. Calcd. for c2iH28°4s Ci 75o21» H> 8.19i 0, 18.58.

. A solution of the monoketal prepared in (a) above (7 ) in dry 3s 2 benzene-ether (450 cc) was stirred and flushed with N2° Then a slow stream of acetylene (purified through HgO and HgSO^) was passed into the reaction mixture for a total of 4 hours.

After the first hou s potassium tertiary amylate (prepared by heating at reflux potassium (7 go ) ) in freshly distilled t-amyl alcohol (225 cc) until the metal dissolved) was added rapidly. At the end of the 4 hours, the reaction mixture was flushed with g c It was diluted with 2:3 benzene-ether (1.1). Small portions of saturated aqueous NH^Cl (500 cc) were added. After separation of the phases j the aqueous layer was extracted with 1:1 benzene-ether and with ether. The organic layer was washed with water until colourless washes were obtained. Then the solution was dried and evaporated on the roto vac. Crystallization from aqueous methanol gave 7.2 g. (96?S).

The analytical sample (methylene chloride-ether) had m.p. 236 242% " 7D9 - 71.7° (c 1.74); 3590(m), 3330(s), 2125(w), 1710(va), I670(w) cm,"1 ■ • Anal. Calcd. for C23H3004: C, 74.54; H, 8.16; 0, 17.28.

C, 74.53; H, 8.17; 0, 17.51. 3-one (c) 17a~Bthynyl-113 , 173°dihydroxy-A -androsten^-5-monoketal .

The 11-one from (b) above (4.5 go ) in methanol (215 cc) was treated with sodium borohydride (5 g. ) in water (63 cc) and lo sodium hydroxide in methanol (75 cc). The reaction mixture was heated at reflux overnight. The addition of water and saturated aqueous sodium chloride gave platelets of the desired 11β-hydroxy compound. Crystallization from methylene dichloride/ methanol gave in three crops a total of 2.9 g» (64 -5$)« ??ί 3700(m), 3600(s), 3400(m), 1100(vs) on."1 AJ^'5' - Analo Crystallized from methylene dichloride/methanol (dried at 100° in vacuo for 3 days) - prisms - m.p, 255 - 8°C.

G2 H32^4 re¾uires: 0, 74.16; H, 8,66; 0, 17.18, Pound; 0, 73»89; H, 8.70. (d) 17a-Ethynyl-androst-5-ene-113 ,173-diol-3-one-3-monoethylene ketal-113-nitrite „ A solution of 17a~ethynyl-androst-5-en-113 , 173-diol-3-one- 3-monoethylene ketal (4 go) in pyridine (Pisher reagent grade; 60 ml.) was treated with excess of nitrosylchloride at ca. 5° until the solution became reddish brown,, Dilution with ice-water, extraction with methylene dichloride and evaporation of the solvent in vacuo at ca. 45° (bath-temperature) gave the crude 11β, 173-bis-nitrito compound^ which without further purification was refluxed with methanol for ca, 1 hour. The course of the reaction could be best followed by disappearance of the starting material by TLC (Thin Layer Chromatographyl) . The 11-nitrite group mostly survived such solvolysis. Evaporation of the solvent in vacuo at ca. 45° (bath-temperature ) gave a crude crystalline residue . Chromatography of the same in methylene dichloride over neutral alumina (20 g„) and elution with the same solvent (ca, 125 ml.) gave the crystalline 11-mononitrite , which was triturated with large excess of hexane and set aside in the cold. Filtration gave the desired crystalline 11-mononitrite (3°6 g. , 83°5 ) m.p. 168 - 174° o Recrystallization from methylene dichloride gave prisms, m.p. 171 - 174° , ^J^'5°- 81038° (c 0,98 in chloroform) μ! IH?clΞ-3C 3550(s), 3360(m)? I640(vs) and I600(m) cm,"*1 Analo Oalcd. for C^H^O^s 0, 68,80; H, 7 = 78; 0, 19.93; N, 3.49. monoethylene ketal. (i) A solution of the 11-mononitrite prepared in d) above (1.2 g.) in dry benzene (170 ml.) was irradiated at 6 - 10° (bath-temperature) with a 200 watt mercury arc lamp for 57 minutes (disappearance of the nitrite spot on TLC) in a pyrex vessel.

After evaporation of the solvent under reduced pressure , the residue was chromatographed over neutral alumina (28 g.).

Elution with methylene dichloride containing increasing proport-ions of methanol gave the following compounds in order of ease of elution; (I) 17a~ethynyl-androst-5-ene-17P-ol-3»ll-dione-3-monoethylene ketal (140 mg.); (II) 17a-ethynyl-androst-5-ene-113,173-diol-3-one-3-monoethylene ketal (35 mg„); (III) trace oil fractions consisting mainly of 11-alcohol 19-oxime and some compound of intermediate polarity; (IV) the desired 19-oxime (437 mgo, 36.4$) m.p. 215 - 220° as a white powder. Recrystalli-zation (with difficulty) from methylene dichloride hexane gave micro crystals, m.p. 224 - 227°; Ζ~α_¾6 * (° °°487 in dioxane) 3510(vs), 3360(vs), 1650(vw), 1095(vs) cm,"1 Anal, Calcd. for 0, 68.98; H, 7.55; 0, 19.98; N, 3.50.

Pound? C, 68.53; Hf 7.62; 0, 20.27; N, 3.61. (ii) A solution of the 11-mononitrite prepared in Example 1 (4 g.) in dry benzene (750 ml.) was photolyzed as in (a) above with a 550 watt lamp for 36 minutes, during which time the reaction was virtually complete (TLC). After evaporation of the solvent, the light-brown residue was dissolved in methylene dichlo ride (40 ml.), seeded with 19-oxime (from the previous batch) and allowed to stand overnight at room temperature. Crystallizat-ion ensued in ca, 30 minutes. The white ppt. was filtered off, washed with methylene dichloride (ca. 20 ml.) and dried in air. This still contained some less polar impurities (TLC) and was ··*- . hence warmed with methylene dichloride (25 ml.) to give a suspension and filtered after letting it stand overnight at room temperature . The residue (1,88 o , 47$) s m.p, 215-222° , - 152.6° (c 0.51 in dioxane), was almost pure 19-oxime as shown by TLC.

Its infra-red spectrum was almost identical with that of the analytical specimen. (f ) 17a-Ethynyl-19-oxo-androst-5-ene-ll3,173-diol-3-one-3-monoethylene ketal-ll819-hemiacetal The 19-oximino compound produced in (e) above (1.13 g.) in glacial acetic acid (79 ml.) and water (40 ml.) was treated with sodium nitrite crystals (2.8 g.) and kept at room temperature for ca. 15 min. The crude crystalline product obtained on dilution with water and extraction with methylene chloride, was dissolved in methanol (45 ml.) and treated with methanolic sodium hydroxide (68 ml., 10$) at R.T. After 3 hrs. the reaction product was neutralized with dilute hydrochloric acid and the solvents removed in vacuo . Trituration with water gave prisms (855 mg., 78.3$), m.p. 270 - 274° . After crystallization from f— -»23 methanol-methylene chloride,, this had m.p. 272 - 277°. L α_/υ + 12.5 (c 0.74 in dioxan) ; 3670(vs), 3360(s), 2130(vw), I660(w), 1110(a) cm."1 Anal. Oalcd. for ^^ fl^ i 0, 71.45; H, 7.82? 0, 20.69° Found! 0, 71.45; H, 7.69; 0, 20.80. (g) 17a-Ethynyl-19-oxo-androst-4-ene-lie.17g-diol-3-one-ll .19-hemiace al The above ketal (1.2 g.) was taken up in dioxan (77 ml.) containing aqueous hydrochloric acid (8.1 ml., IN) and left at R.T. for ca. 24 nr. Dilution with saturated brine, extraction into methylene chloride and crystallization from benzene-hexane gave the crude compound (916 mg. , 80$) as amorphous powder, m.p. 115 - 130°, λ„ον 246 πιμ (ε 10,500). TLC analysis (silica gel plate impregnated with fluorescein, 6$ methanol in methylene chloride, developed with phosphomolybdic acid). showed a slight non-U.V.-absorbing Δ -3-ketone just ahead of the U.V.-absorbing spot corresponding to the desired Δ^-3-ketone . Purification was difficult to effect by crystallization,, However 9 an analytical sample (benzene-hexane ) had m.p. 120 - 132° , a_ ^ + 110.1° (c 0.445) s \max 247 m (ε 11,000) .

Anal. Calcd. for σ21Η26048 C, 73.65; H, 7.67; 0, 18.69.

Pounds 0, 73.54; H, 7.80; 0, 18.58.

The presence of unconjugated ketone does not effect the biological activity and the crude product described above may be used directly in medical applications.

Example 2 ethylene (a) ΙΙβ-NitroBylprogesterone 3> 20-Bisjyetal .

Excess nitrosyl chloride was passed through a solution of 4 g. of Ιΐβ-hydroxyprogesterone 3 , 20-bisketal in 40 ml. of pyridine at 4° . Ice was added, followed by water, to precipitate the crude nitrite. The product was crystallized from hexane; m.p. 130 - 134°. C^j^" + 5°. This compound was unstable and satisfactory analytical data were not obtained; „αΎ IIIc-Λ- 2996(s), 1625(a), 1600(m) cm."1 (0N0): yield 7796. ethylene (b) 19-0ximino-113-hydrox,yprogesterone 3 » 20-Bisketal A solution of 10 g. of nitrite from (a) above in 300 ml. of toluene was irradiated for 1.5 hr. using a 200-w. mercury vapor lamp. The toluene was removed under reduced pressure; the derived 19-oxime was precipitated with ethyl acetate and recry-stallized from the same solvent; m.p. 263 - 265°; -23°; 3300(s), (OH), 2995(s), 1650(w) cm."1 (C=N); yield 18 .

Anal. Calcd. for C^H^NOg s C, 67.39; H, 7«92 j N, 3.14.

Found $ C, 67.22; H, 8.14; N, 3.16. (c) llg19-Hemiaoetal of llg-Hydroxy-19-oxoprogesterone 3»20- Diske To 40 ml„ of cold glacial acetic acid was added 2 g. of sodium nitrite followed by the mother liquors from (b) containing the 19-oxime. The mixture was stirred for 2.5 min. at 5°. After the usual work-upy the resulting oil was taken up in 30 ml, of Vfo methanol-sodium hydroxide . Upon standing, the product crystallized from the reaction mixture; m.p. (recrystallized from methanol) 245 - 256°; £~ Anal. Calcd. for ¾Η36°6 ! °' 69β42' H» 8·39.

Found ί 68.92; H, 8.46. (d) 11 ,19-Hemiacetal of 113-Hydroxy-19-oxoprogesterone and Its A 596 Isomer A suspension of 115 mg. of the 11,19-hemiacetal bisketal from (c) above in 4.5 ml. of acetone and 1.25 ml. of water containing 0o05 ml. of concentrated sulphuric acid was heated under reflux for 15 min. to effect solution and allowed to stand at room temperature for an additional 30 min. After the usual work-up, a mixture of the products was obtained from methanol; m.p. 210 - 222% £"oj^4 + 227°; λ^Η 246 ιημ (ε 7800); 3600(s) (OH), 3000(s)s 1715(B) (20-0=0), 1693(e) (β,Υ-unsaturated 0=0) , 1660(a), 16l0(m) cm."1 (C=0-C=0); yield 99$.

Anal. Oalcd, for ^21E28° ° 0> 75e25; H» 8el9- Founds 0, 72.94; H, 9.05.

On treatment with HC1 in aqueous dioxane, the above mixture was converted to nearly pure Δ^-3-keto compound.

Example 3 19-Fluoro-pregn-4--en~3 20-dione-I13819-oxide 113-Hydroxy-19-oxo»-pregn-4-en-3s 20-dione-113,19-hemiacetal (612 mg. , 1.78 mM„) is dissolved in a mixture of 3.1 g. HF and 6 ml. tetrahydrofuran-chloroform (3sl) at -20° and stirred for tetrahydrofuran, poured into ice-cold NaHCO^ solution ( a. 500 mle) and extracted with chloroform. The chloroform extracts are washed with more NaHOO-j solution and water ? dried over anhydrous NagSO^, and evaporated. The resulting material is crystallized and recrystallized from methylene chloride-ether to give 446 mg. (1.29 mM, 72?6) of the compound, m.p. 183 - 4°, T^/)0'8 + 255.0° (c = 1.153) (Chloroform) Anal. Calcd. for C21H27F03; C, 72.80; H, 7.86; FP 5.48$.

Found*. C, 72.78; H, 7.76; F, 5.38$.

Example 4 andros t 17a-Eth,ynyl-173-hydroxy-19-fluoro-p¾a.ff]a-4-en-3-one-113,19-oxide andros t 113-Hydroxy-17a-ethynyl-173-hydroxy-19-oxo-pp»g»-4-en-3-one-113,19-hemiacetal (116 mg. , 0.340 mM,) is heated with 1.7 g. HF and 3.5 ml. THF-Chloroform (3*1) and worked up as described in Example 3» The resulting colourless oil is subjected to chromatography over a short column of neutral alumina (5 g., Grade. 3). After removal of some unpolar impurities with 30 ml. CHgClgp the compound is eluted by 50 ml. chloroform; yield, 60 mg. (0.173 mM.

Anal. Calcd. for 021Η25ΙΌ3ί C, 73.23; H, 7.33; F, 5. 0$.

Found! C, 73.29? H, 7.52; F, 5.33$.

Example 5 19-Fluoro-pregn-4-en-5 « 20-dione-63 , 19-oxide (a) The oxime of 33~acetoxy-5a-bromo-63-hydroxy-19-oxo-pregnan- 20-one (4.60 g. = 9.50 mM. ) is dissolved in 200 ml. glacial acetic acid. The mixture is stirred, and 135 ml. H20 and one-third of a total amount of 50 g. NaN02 is added. The remaining NaltfOg is added in two portions at intervals of approximately 20 minutes. After addition of the last portion of NaN02, the mixture is stirred for another hour. It is then poured into 3 1. HgO and stirred until the cloudy precipitate can be filtered off.

It is washed free from acetic acid and dissolved in methylene evaporated, and the residue is crystallized from methylene chloride-hexane. Yield J 3.07 g. (6.58 mM. , 69) of 33-acetoxy-5a-bromo-63-hydroxy-19-oxo-pregnan-20-one-6 , 19-hemiacetal .

Anal. Calcdo for C^H^B O^ C, 58.85? H, 7.09; 0, 17o04; Br, 17.02$.

Found! C, 59.03; H, 7.29; 0, 17.21; Br. 16.92 . (b) The hemiacetal from (a) above (2.14 g., 4.82 mM,) is treated with 7.0 o HF in 14 ml. chloroform-tetrahydrofuran (1.3) mixture and worked up as described in Example 3. The crude material is crystallized from ether-hexane . Yield: 1.39 g. (3.10 mM. , 64$) of 33-acetoxy-5a-bromo--6^ ¾Kfa? ¾?^19- luoro-pregnan-20-one-63 ,19-oxide , m,p. 193 - 5°.

Anal. Calcd. for G^H^Br O^? 0, 58.60; H, 6.84; F, 4.03; Br, 16.95$.

Founds C, 58.81; H, 7.02; F, 4.20; Br, 17.10$. (c) The acetoxy fluoride from (b) above (757 mg., 1.61 mM.) is dissolved in 12 ml. tetrahydrofuran and 12 ml. methanol.

Sixteen ml, of a 0.1 M KgCO-j solution in aqueous MeOH is added and the mixture is heated to reflux for 15 minutes, then poured into saturated NH^Gl solution, and extracted with chloroform.

The chloroform solution is washed with water, dried, and evaporated to give 604 mg. (1.40 mM. , 88$) of 33-hydroxy-5a-bromo-19-fluoro-pregnan-20-one-63»19-oxide8 m,p, 184-6°, Anal. Calcd. for 0, 58.73; H, 7.04; Br, 18.61; F, 4.43$.

Founds 0, 58,79; Hr 7.24; Br, 18.47; F, 4.69$. (d) The hydroxy compound from (c) above (450 mg., 1.05 mM.) is dissolved in 25 ml, acetone and oxidized at 0° with 2.5 ml. 8 N Jones' Reagent for 3 minutes. Excess oxidant is destroyed with 25 ml, methanol (stirring for 10 minutes at 0°), Then the reaction mixture is poured into saturated NaHOO^ solution and extracted with chloroform. The chloroform solution is washed twice with water, dried over anhydrous Na2S0^, and evaporated. The crude material is dissolved in 10 ml. dimethyl formamide, and 15 ml. of a solution of 5 g. potassium acetate in 100 ml. 90$ dimethyl formamide: 10$ water is added. The mixture is heated on a steam bath for 10 minutes, poured into water (500 ml.), and extracted five times with ether. The ethereal solution is thoroughly washed with water to remove all of the dimethyl formamide and then dried (lite^SO^) and evaporated. The resulting gum crystallizes from etherhexane to give 263 mg. (0.71 mM. , 68$) of 19-fluoro-pregn-4-en-3,20-dione-63,19-oxide, m.p. 146 - 147°.

Anal. Calcd. for C21H27F05: C, 72.80; H, 7.86; P, 5.48$.

Pound: C, 72.77; H, 7.89; P, 5.31$.

Exampcle —6 et. ,hyl,ene ( ) 21-Ρθ8θχ.νοοΓΪϊαο1-3< 20-bis etal-113-nitrite 21-deoxycor tisol-3, 20-bisethyleneketa I (i) The -al-ooho-l- (5.3 g.) in pyridine (80 cc.) was treated (with occasional cooling in a water-ice bath) with an excess of N0C1. The solution was diluted to about 500 cc. with ice water and refrigerated overnight. The solution was filtered and washed with water yielding 5.3 g. (air dried) (95$) of white solid. T.l.c, (benzene-EtOAc 1:1) showed one major spot midway in polarity between starting alcohol and minor impurity, probably "dinitrite," ^ m o 3500(s), 3300(w), I670(w) , I625(vs), and 1590(m) cm. . (ii) When the partially gummy nitrite does not solidify after refrigeration, it is extracted into MegOlg* which is washed with water, dried, and evaporated. It is then treated in boiling methanol (50 to 100 cc./g.) for 20 minutes. T.l.c. (benzene-EtOAc 1:1) shows the product to be virtually pure nitrite, which may be crystallized (one experiment yielded 76$ crystalline nitrite) or used directly after evaporation of the methanol. . . ethylene (b) 19-0ximino-21-deaox.voortisol-3.20-biajcetal The nitrite from part (a) (i) above (5.3 g.) was dried and photolyzed in toluene (about 500 c.c.) containing pyridine- (0,8 oc, approximately 1 mole) using a 500-watt lamp for 40 minutes. The pale green precipitate was filtered. The weight of the air-dried sample was 3 g. (56$), m.p. 239 - 53° C, ) 3600(vs), 3400(vs) cm."1. ethylene (c) The 11,19-Hemiacetal of 21-Desoxycortisol-3 20-Bisketal The oxime from (b) above (500 mg.) in acetic acid (50 cc.) was treated with NaNOg (500 mg.) by swirling the solution at room temperature for five minutes. Water was added. The produce was extracted with Me2Cl2» which was washed with water and sodium bicarbonate solution, dried, and evaporated. The residue was then treated with 1$ NaOH in MeOH (10 cc.) at room temperature for three hours. Water was added. The precipitate was filtered and air dried to give 347 mg. (72$) of material which gave one spot on t.l.c. (benzene-EtOAc 1:1), m.p. 281 - 95°C.,) mK:aBxr, 3600(vs) cm -1 (d) The 11 , 19-Hemiacetal of 21-Desoxycortisol ethylene The bisietal from (c) above ( 150 mg.) was treated with acetone ( 6 cc), water ( 2 oc), and cone. HgSO^ ( 0.07 cc.) at reflux for one hour. Some of the acetone was evaporated in vacuo . Water and NaCl were added. The precipitate, when filtered and air dried, weighed 80 mg. ( 67 ) , m.p. ( 191 ) 197 - 208°C., ) fflcl-X. o 3650 , 3550 (double peak-vs), 3300 (vs), 1700(vs), 1660 ( shoulder-vs) , 1600(vs), and 1640(m) cm."1. (e) 21-Desoxycortisol-ll.19-hemiacetal acetate The 11 , 19-hemiacetal of 21-desoxycortisol prepared in (d) above ( 100 mg.) was dissolved in pyridine ( 1 .5 c.c) and acetic anhydride ( 4 o.c) added. The mixture was allowed to stand for 4 hours and worked up in the usual way to yield the desired acetate (80 mg.), m.p. 240 - 244* 0. , "α-7ϋ° + 55o5°e Analysis. Calculated'. C 68.6$ H 7. $ Found? 0 68 .8$ H 7 o 7$

Claims (1)

1. CLAIMED A pharmaceutical comprising compounds of the wherein Y is a keto a keto hydroxy or an hydroxy or is an atom which is joined to the 6 or halogen or tosyl o represents a joined to the is a group where is a hydrogen or halogen and 2 is a hydrogen atom or hydroxy or acyloxy group or is a hydroxy group and fi is an aliphatic hydrocarbon group which if carry one or more halogen atoms as substituents and and thereof9 together with a pharmaceutically Steroid hemiacetals of the skeletal formula where Y is a a hydroxy or acyloxy is is an oxygen atom which is to the or is a group where X is a hydrogen and is hydrogen or hydroxy or acyloxy group or is a hydroxy group and ethynyl which or more aliphatic hydrocarbon substituents of up 6 carbon atoms as the molecular weight of the steroid being at least when 2 is hydrogen and is a halogen or represents a bond joined to the and Compounds claimed in Claim 2 in which is a group where X is a and is a hydrogen atom or an acyloxy grou or R 1 is a hydroxy group and R 2 is an ethynyl R is a divalent oxygen atom joined 3 to the Z is fluorine and R represents a bond joined to the 2 Compounds as claimed in Claim 2 wherein R is a lower aliphatic acyloxy group having carbon atoms or a phosphate ester 2 Compounds as claimed in Claim in which R is an acetoxy or propionoxy Compounds as claimed any of Claims 2 to 3 in which R2 an ethynyl 9 3 and its Compounds as claimed in Claim 2 substantially as herein defined and with reference to any of the A process for the preparation of compounds as claimed in Claim 2 including the step of reacting a compound o the skeletal formula H V 27072 R R and R have the meanings given in Claim 2 and one group R hydrogen while the other is a hydroxyl in form where Y is a with a nitrosofluorinating agent or a nitrosylating agent in the presence of fluoride ions to give a compound wherein X is 13 A process as claimed in Claim 12 in which the ketone protected form of the compound of formula II is the l A process as claimed in Claims 12 and 13 which in the compound of formula II is and the group is protected in the form of a A process as claimed in any Claims 12 to in the agent is nitrosyl fluoride or nitrosyl A process as claimed in any of Claims 12 to in which the nitrosylating agent nitrosyl chloride or nitrosyl A process as claimed in any of Claims 12 to 16 in which the protected ketone group is converted to a ketone A process as claimed in Claim 17 in which the protected ketone group is an ethylene ketal and is su hydrolysed with mineral acid or is an acyloxy group and is subsequently hydrolysed with mineral acid to a group which is then oxidized with a reagent serving to oxidise a secondary alcohol group to a keto A process as claimed in Claim 18 in which said hydro yl group is oxidized with chromic A process for the production of compounds as claimed in Claim 2 in which a corresponding compound in which Z is a group is reacted with hydrogen flyorlde in an inert if desired after conversion of the hydroxyl group to a carboxylic acyloxy to a A process for the preparation of compounds as claimed in Claim which a corresponding compound in which Z is a hydroxyl group is converted into a corresponding compound having a reactive ester group at the followed by reaction fluoride ions to replace said reactive esters grou s by a fluorine A process as claimed in any of Claims 12 to 21 t in which the oxime of formula II used as starting is prepared by photolysis of a nitrite of the skeletal formula and Y have the meansings given in Claim in ketone protected by irradiation with UV light of a wavelength absorbed by nitrite process as claimed in Claim 22 in which the nitrite starting compound is prepared by nitrosylation of the corresponding A process as claimed in Claim in which the hydroxy compound used as starting material is prepared by reduction of the corresponding A process as defined in Claim 12 substantially as herein defined and with reference to any of the A process as claimed in Claim 12 substantially as herein described with reference to any of the fiompositions as claimed in Claim 1 in dosage unit Compositions as claimed in Claim 1 in which each dosage unit contains to 100 mg active Compositions as claimed in Claim 1 in which each dosage unit contains to mg active Compositions as claimed in any of Claims 1 and 27 to 30 in a form adapted for oral Compositions as claimed in Claim 31 in the form capsules or coated Compositions as claimed in Claim 27 in the form of syrupst elixirs or 3 Compositions as in any of Claims 27 to 33 in which the carrier or exclpients are in solid form or are sterile liquids or liquids containing one or more or preseriating Compositions as claimed in any of Claims 27 to containing a diuretic a minor proportion of an oestrogenic or enie Compositions as claimed in any of Claims 1 and 27 to 35 in which the active compound is a compound as Claimed in Claim 2 ATTORNEYS FOR APPLICANTS insufficientOCRQuality