DE2445783A1 - NEW D-HOMOSTEROIDS - Google Patents

Description

The present invention relates to new D-homosteroids the formula

wherein the dashed bonds in 1,2-, 6,7- and 16,17-positions are optional, R ¹⁰ hydrogen or methyl, if one

However, there is a double bond in a 1,2-pitch

7th
only methyl, and R is hydrogen or, if the 6,7-position is saturated, also mercapto, acylthio or alkylthio.

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Green / leu / 3.7.74

The term "acyl" refers to the residue of a saturated or unsaturated aliphatic carboxylic acid, a cycloaliphatic ^ an araliphatic or aromatic carboxylic acid with preferably up to 15 carbon atoms. Examples of such acids are ant, vinegar, pivalic, propionic, butter, capron, oenanth, undecylene, Oil, cyclohexylpropion, cyclopentylpropion, phenyl acetic and benzoic acid. C 1, 1, - acyl groups are particularly preferred. Of the The term "alkyl" is intended to mean aliphatic, cycloaliphatic and araliphatic hydrocarbon radicals with preferably up to to include 8 carbon atoms. Examples of such alkyl groups are methyl, ethyl, propyl, butyl, cyclopentyl, cyclohexyl, benzyl and phenethyl.

Of particular interest are compounds of the formula X. in which R is methyl and furthermore those which are saturated in 1, ^ - uu-J.-lung. Examples of such preferred compounds are 3-0xo ~ D-homo-21,24-dinor-17aa-chola-4,6-diene-23,17a-lactone and Ycx-acetylthio- ^ - oxo-D-homo - ^ l ^^ dinor-lYaa-chol- -4-en-i-23,17a-lactone. Another preferred group of compounds are the compounds of the formula I with a 16,17 double bond, for example 7ct-acetylthio-3-oxo-D-homo-21,24-dinor-17aa-chola-4,16- -dien- 23,17a-lactone. Examples of compounds of the formula I where R ¹⁰ = hydrogen are 3-oxo-19,21,24-trinor-D-homo-17aa-chol-4-en-23,17a-lactone; 3-oxo-19,21,24-trinor-D-homo-17aa-chola-4,6- -diene-23,17a-lactone; 3-oxo-19,21,24-trinor-D-homo-17aα-chola-4,6,16-triene-23,17a-lactone; 3-oxo-19,21,24-trinor-D-homo-17aa- -chola-1,4,6-triene-23,17a-lactone and 7a-acetylthio-3-oxo-19,21,24-trinor -D-homo-17aa-chola-4, 16-diene-23,17a-lactone.

The D-homosteroids of the formula I are according to the invention obtained by one

a) the 3-hydroxy- ^ grouping in a D-homosteroid the formula

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II

αο

where R has the meaning mentioned, ^{oxidizes to the 3-keto-A 4} -, 3-Ke.to- £ ⁴ ' ⁶ - or, if R ^{10 is} methyl, also to the 3-keto & * ^{4 group} , or t >) a D-homosteroid of the formula

III

where R has the meaning mentioned,

dehydrated in 1,2- and / or 6,7-position, in 1,2-position but only when R is methyl, or

c) the 5,10 double bond in a D-homosteroid of the formula

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isomerized into the 4,5-position, or d) a D-homosteroid of the formula

IV

where R has the meaning mentioned,

7 7
with a compound RH, in which R has the meaning mentioned, is reacted and optionally dehydrogenated in the 3f2 position.

The oxidation of a compound of formula II (process variant a) can according to Oppenauer, e.g. by means of Aluminum isopropylate, or with oxidizing agents such as chromium trioxide (e.g. Jones' reagents), or according to Pfitzner-Moffatt by means of dimethyl sulfoxide / dicyclohexylcarbodiimide (where the

5 4

initially obtained Δ -3-ketone subsequently to the A -3-ketone must be isomerized), or by means of pyridine / SO will. When using the above-mentioned oxidizing agents such as Brp / LiBr / LipCO- in dimethylformamide or in the oxidation according to Oppenauer in the presence of benzoquinone, the oxidation gives a 3-keto-Δ grouping. For the Oxidation to a 3-keto-A '' steroid is an example 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ) is suitable.

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The 1,2-dehydrogenation of a D-homosteroid of formula III (Process variant b) can be used in a manner known per se, e.g. carried out microbiologically or by means of dehydrating agents such as selenium dioxide, 2,3-dichloro-5,6-dicyanobenzoquinone, chloranil, thallium triacetate or lead tetraacetate will. Suitable microorganisms for 1,2-dehydration are, for example, schizomycetes, especially those of the Genera Arthrobacter, e.g., A. simplex ATCC 6946; Bacillus, e.g. B. lentus ATCC 13805 and B. sphaericus ATCC 7055; Pseudomonas, e.g. P. aeruginosa IPO 3505; Plavobacterium, e.g., F. flavescens IPO 3058; Lactobacillus, e.g. L. brevis IPO 3345 and Nocardia ,. e.g. N. opaca ATCC 4276.

The introduction of a Δ double bond in a 6,7-saturated D-homosteroid of the formula III can e.g. substituted benzoquinone, such as chloranil [cf. J.Am. Chem. Soc. 82: 4293 (1960); 81, 5951 (1959)] or with 2,3-dichloro-5,6-dicyanobenzoquinone or with manganese dioxide [cf. J. Am. Chem.

Soc. 75, 5932 (1953)].

With 2 _t 3-dichloro-5,6-dicyanobenzoquinone or chloranil, the 1,4,6-trisdehyde compound can be obtained directly from a 6 ^ -saturated D-homosteroid of the formula III, in which R is methyl.

The isomerization of a compound of the formula IV (process variant c) can be carried out in a manner known per se, e.g. by treatment with acidic or basic agents, suitably by heating with mineral acids, such as 6 N hydrochloric acid, or with alkali, such as aqueous-alcoholic Sodium or potassium hydroxide solution at room temperature.

The introduction of the substituent R ^ in a D-homosteroid of formula V (process variant d) can in a manner known per se by treating the steroid with sulfur

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Hydrogen, eLnora mercaptan or a thiocarboxylic acid. The reaction can be carried out in an inert solvent such as an ether, e.g. dioxane or tetrahydrofuran, or an alcohol such as methanol or ethanol, or in a chlorinated hydrocarbon such as chloroform; the reagent, e.g. the thiocarboxylic acid, is expedient used in excess and can serve as a solvent.

The starting compounds can be prepared as follows: A Grignard compound is prepared in a manner known per se from 17aa-ethynyl-5β, lTa-dihydroxy-D-homo-androst-5-ene, and this is converted into the propiolic acid derivative _{with CO 2.} The sodium salt of the propiolic acid derivative thus obtained is hydrogenated with palladium carbon in aqueous ethanol until one molar equivalent of hydrogen is absorbed. The acrylic acid derivative formed lactonizes spontaneously and becomes

hydrogenated with uptake of a second molar equivalent of hydrogen, giving a compound of the formula II which is saturated in the 16,17-position and in which R ^{10 is} methyl. 16,17-saturated starting compounds of the formula II with R = hydrogen can be prepared as follows: D-homo-estrone methyl ether becomes D-homo-2,5 (10) -estradiene-3,17ass-diol-3-methyl ether according to Birch reduced; this is, for example according to Pfitzner-Moffatt, oxidized to the 17a-ketone and the ketone reacted with an ethynyl Grignard compound. Weakly acidic .Hydrolysis, for example with oxalic acid, yields the D-homo-17aa- -äthinyl-17a-hydroxy-5 (10) -estren-3-one, from which by Grignard reaction with COp and hydrogenation as above for the Described 10-methyl compound, the 3- (D-homo-3ß, 17ass-dihydroxy-5 (10) -estren-17aa-yl) -propionic acid lactone is obtained. Oxidation, for example according to Pfitzner-Moffatt, gives 3- (D-homo-17ass-hydroxy-3-oxo-5 (10) -estren-17aa-yl) -propionic acid lactone, ie a 16,17-saturated compound of the formula IV.

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Starting compounds with a 16,17 double bond are conveniently prepared by converting into a D-homo-5,16-androstadien-3β-ol-r7a-one (for the preparation of compounds with R ¹⁰ = methyl) in a manner known per se , ζ .3. by reaction with a Grignard reagent such as BrMg-CH ₂ -CH ₂ -CH ^ _Q _j or, preferably, with the corresponding lithium compound, introduces a U_ unit in the 17a position, converts the protected aldehyde function into an acid function and the reaction product is carried out Acidification lactonized. Analogously, 16,17-unsaturated starting compounds with R = hydrogen can be prepared by introducing a 16,17 double bond into the D-homo-estrone methyl ether by bromination and dehydrobromination and then, in analogy to the reaction sequence described above, a Birch reduction of the aromatic ring, oxidation of the 17a-hydroxy group, introduction of a propionic acid side chain by Grignard reaction or condensation with propiolic acid / KOH, lactonization of the propionic acid side chain and hydrolysis of the 3-ether group.

The compounds of the formulas H-V are new and likewise a subject of the present invention.

D-homosteroids of the formula I are pharmacological Effects, of particular interest is their effect on the kinetic balance of the body. So you can i.a. They are used to flush out edema, e.g. caused by heart failure.

The compounds of the formula I can be used as medicaments, for example in the form of pharmaceutical preparations find which they or their salts in a mixture with a suitable for enteral, percutaneous or parenteral administration organic or inorganic inert carrier material, such as water, gelatin, gum arabic, milk sugar, starch, Magnesium stearate, talc, vegetable oils, polyalkylene glycols, Contains petroleum jelly, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, drage * es, suppositories

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sitoriums, capsules; in semi-solid form, e.g. as Baiben; or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for modification osmotic pressure or buffer. They can also contain other therapeutically valuable substances.

The pharmaceuticals can be prepared in a manner known per se by the compounds of Formula I with non-toxic, inert, per se in such preparations suitable for therapeutic administration conventional solid and / or liquid carrier materials, such as those mentioned above, mixed and optionally in the desired Brings shape.

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example 1

From a mixture of 12.50 g of 3ß-hydroxy-D-homo-21,24-dinor-17aa-chol-5-en-23,17a-lactone, 160 ml of cyclohexanone and 400 ml of toluene, 80 ml ml of solvent is distilled off. Then 15.0 g of aluminum tert-butoxide were added and the mixture was heated under reflux on a water separator for 2 hours. For work-up, the reaction mixture was evaporated to a volume of approx. 200 ml, then poured into ice water / dil. Poured hydrochloric acid and extracted with methylene chloride. The organic extract was washed with water, with Na ₂ SO. dried and evaporated in vacuo. The residue was freed from the solvent and low molecular weight condensation products in a high vacuum at 140 ° and finally chromatographed on silica gel. 10.3 g of pure 3-oxo-D-homo-21,24-dinor-17aoc-chol-4-ene-23,17a-lactone were isolated with methylene chloride / acetone CgSt ^. M.p. 220-221 ° (acetone / isopropyl ether); = 16600, [α] £ ⁵ =

The starting material was prepared as follows:

3ß-Acetoxy-17a-äthinyl-17-hydroxy-D-homo-androst-5-en was converted with butyllithium into the lithium salt, which with CO »to 3ß, 17ass-dihydroxy-D-homo-pregn-5-en- 20-yn-21-carboxylic acid, m.p. 194-196 °, [alri = -123 °, reacted. This acid was catalytically hydrogenated in an alkaline solution and, after acidification, gave 3ß-hydroxy-D-homo-21,24-dinor-17aachola-5,20-diene-23,17a-lactone, melting point 205-207 °, [a] _D = -43 °. Catalytic hydrogenation with Pd / C in ethanol finally led to 3ß-hydroxy-D-homo-21,24-dinor-17aa-chol-5-ene-23,17alactone, m.p. 240-243 °, [a] _D = - 99 ° (c = 0.1 in dioxane).

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Example 2

A solution of 4.0 g of 3-0xo-D-homo-21,24-dinor-17aachol-4-en-23,17a-lactone in 200 ml of dioxane, which contained 6.5 # HCl, was within 3 minutes a solution of 3.1 g of 2,3-dichloro-5,6-dicyano-benzoquinone in 50 ml of dioxane which contained 6.5% HCl was added. The mixture was then stirred for 7 minutes at room temperature, 50 g of NaHCO 3 were added, the mixture was stirred for a further 30 minutes at room temperature and then refluxed for 30 minutes. The mixture was cooled, the precipitate was filtered off and the filtrate was filtered through 100 g of Alox II, eluting with ethyl acetate at the end. The combined filtrates were evaporated in vacuo. The residue was chromatographed on 200 g of silica gel. Pure 3-oxo-D-homo-21,24-dinor-17aα-chola-4,6-diene-23,17a-lactone, mp 242-244 °, was isolated with methylene chloride / aoetone (97: 3); ^ε 284 ^{= 2720} ° »C ^ D ^{= +25} ° ^ ^{C = Ofl in dioxane} ) ·

With methylene chloride / acetone (9il) finally 3-0xo-D-homo-21,24-dinor-17aa-chola-1,4,6-triene-23,17a-lact on eluted from m.p. 179-180 °;

Z ₂₂₂ = 11600, ε ₂₅₅ = 9300, ε ₂₉₈ = 12500, [α] ^ ⁵ = + 15 ° (c = 0.1 in dioxane).

Example 3

A solution of 0.50 g of 3-0xo-19-nor-D-homo-21,24-dinor-17aa-chol-5 (10) -en-23,17a-lactone in 50 ml of dioxane, which contained 2fo HCl , was kept at room temperature for 2 hours. For work-up, it was poured onto ice water and extracted with methylene chloride. The extract was washed neutral with water, with Na ₂ SO. dried and evaporated in vacuo. After recrystallization from acetone / hexane, the residue gave pure 3-0xo-19-nor-D-homo-21,24-dinor-17aa-chol-4-en-23,17a-

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lactone; ε ₂₄₀ = 16800.

The starting material was prepared as follows:

D-homoestrone methyl ether was reduced according to Birch and then oxidized according to Pfitzner-Moffatt to 3-methoxy-D-homoestra-2,5 (10) -dien-r7a-one. Ethynylation with potassium acetylide led to 17aa-ethynyl-17-hydroxy-; 5-methoxy-D-homo-oestra-2,5 (10) -diene, which via the corresponding lithium compound with CO ₂ to 17ass-hydroxy-3-methoxy- 19-nor-D-homo-pregna-2,5 (10) -dien-20a-yn-21-carboxylic acid was converted. Partial catalytic hydrogenation In alkaline solution and subsequent treatment with oxalic acid in dioxane yielded 3-0xo-19-nor-D-homo-21,2 4-dinor-17aa-chola-5 (10), 20-diene-23,17a- lactone, which was converted into 3-0xo-19-nor-D-homo-21,24-dinor-17aa-chol-5 (10) -en-23,17alactone by selective catalytic hydrogenation.

Example 4

A solution of 1.0 g of 3-0xo-D-homo-21,24-dinor-17aoc ~ chola-4,6-diene-23,17a-lactone in 6 ml of thioeaetic acid was kept at room temperature for 3 hours. The reaction mixture was poured onto ice water and extracted with ether. The ether extract was washed with dilute NaOH and water, dried with Na_SO and evaporated in vacuo. The residue was chromatographed on silica gel. The ether / hexane (Itl) eluates provided pure 7a-acetylthio-3-oxo-D-homo-21,24-dinor-17aa-chol-4-ene-23,17a-lactone, m.p. 193-195 ° ( Methanol), ε ^ ₆ = 1900, [α] ^ ⁵ = -26 ° (cs = 0.1 in dioxane).

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_ 12 _

Example 5

1.4 g of 3ß-hydroxy-D-homo-21,24-dinor-17a <z-chol-5-en-23,17a-lactone, 1.8 g of LiBr and 1.8 g of Li ₂ GO were in 30 ml Dimethylformamide is heated to 80 ° and a solution of 1.32 g of bromine in 9.2 ml of dioxane is added over the course of 45 minutes. The mixture was then heated to 80 ° for a further 2 hours. The reaction mixture was poured into water and acidified with acetic acid. The precipitate was filtered off and recrystallized twice from acetone / hexane. Pure 3-0xo-D-homo-21,24-dinor-17aa-chola-4,6-diene-23,17a-lactone with a melting point of 242-244 ° was obtained.

Example 6

1.5 g of 3-oxo-D-homo-21,24-dinor-17aα-chola-4,6-dien-23,17a-lactone were dissolved in 50 ml of tetrahydrofuran containing 2 ° / ₀₀ HCl dissolved. This solution was mixed with 1.2 g of DDQ and stirred for 16 hours at room temperature. Customary work-up gave a product which, after recrystallization from acetone / hexane, was pure 3-oxo-D-homo-21,24-dinor-17aa-cholal, 4,6-triene-23,17a-lactone, melting point 179-180 ° , revealed.

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Example 7

5.0 g of 3β-hydroxy-D-homo-21,24-dinor-17aa-chola-5,16-diene-23,17a-lactone were dissolved in 25 ml of diethyl sulfoxide and 25 ml of benzene. While stirring and gassing with argon, 1.2 ml of pyridine and 0.6 ml of trifluoroacetic acid were added. Then 7.6 g of N, N ¹ -dicyclohexylcarbodiimide were added. It was stirred at room temperature overnight. A mixture of 3.4 g of oxalic acid, 31 ml of methanol and 350 ml of ether was then added to the pale yellowish suspension and the mixture was stirred for a further hour. For work-up, 400 ml of water were added, the mixture was stirred for 15 minutes and then filtered. The piltrate was washed successively with NaHCO, solution and water, with Na ₂ SO. dried and evaporated in vacuo. The crude product was dissolved in 150 ml of acetic acid and 15 ml of 2N hydrochloric acid and kept at room temperature for 1 hour. The reaction solution was then poured into ice water, extracted with methylene chloride and the organic extracts were washed with NapCO solution and water. After drying over Na _? S0. the solvent was evaporated in vacuo and the residue was recrystallized from acetone / hexane. Pure 3-oxo-D-homo-21,24-dinor-17aa-chola-4,16-diene 23,17a-lactone was obtained; E ₃₄₀ = 16650, m.p. 218-219 °.

The starting material was prepared as follows:

3ß-acetoxy-D-homo-androst-5-en-17a-one was with CuBr _? brominated and converted into 3ß-acetoxy-D-homo-androsta-5, 16-dien-17a-one by subsequent treatment with calcium carbonate in dimethylacetamide and acetylation with acetic anhydride-pyridine. This compound was converted to 3ß-acetoxy-17aa- (3 ', 3') -aethylenedioxa-propyl) -17a-hydroxy-D-homo-androst-5-ene by means of 3ß-ethylenedioxy-n-propylmagnesium bromide and subsequent acetylation. Acid saponification of this ethylene ketal, oxidation according to Jones, saponification of the 3ß-acetoxy group with

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K CCL and subsequent treatment with acid led to 3β-Hydroxy-D-homo-21,24-dinor-17aoc-chola-5,16-diene-23,17alactone.

Example 8

In a manner analogous to Example 5, 3ß-hydroxy-D-homo-21,24-dinor-17aa-chola-5,16-diene-23,17a-lactone was obtained the 3-oxo-D-homo-21,24-dinor-17aa-chola-4,6 , l6-triene ~ -23,27a-lactone obtained, M.p. 214-214.50.

Example 9

In an analogous manner to Example 4 was prepared from 6 3-0xo-D-homo-21,24-dinor-chola-17aa "4, l6-triene-23,17a-lactone the 7a-acetylthio -3-0X0-21, 24-dinor-17aa-chola-4, 16 ~ diene-23,17alactone was obtained. M.p. 143-145 ° (except acetone-isopropyl ether); [o] _D = -28 ° (dioxane).

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Claims (17)

Claims .1. Process for the preparation of D-homosteroids of the formula wherein the dashed bonds in 1,2-, 6,7- and 16,17-positions are optional, R is hydrogen or methyl, but only if there is a double bond in the 1,2-position 7th
Methyl, and R hydrogen or, if the 6,7 division is saturated, also mercapto, Represent acylthio or alkylthio, characterized in that one a) the 3-hydroxy- Δ grouping in a D-homosteroid the formula II , 10 wherein R "has the meaning mentioned, 3-keto-Δ '- or, if] represents, also oxidized to the 3-keto-A, '' group, or for 3-keto- ^ A-, 3-keto- Δ ^4> - or, if R ^{10 represents} methyl 5098 U / 1 1 5 5 a D-homo8teroid of the formula III where R has the meaning mentioned, dehydrated in 1,2- and / or 6,7-position, in 1,2-position but only if R is methyl, or c) the 5,10 double bond in a D-homosteroid of the formula IV isomerized into the 4,5-position, or d) a D-homosteroid of the formula 5098U / 1 155 • - 17 - wherein R ^{10 has} the meaning mentioned, with a compound R ⁷ -H, in which R has the meaning mentioned, and optionally dehydrogenated in the 1,3-position. 2. The method according to claim 1, characterized in that that a compound of the formula II in which R is methyl is oxidized to a 3-keto-α or 3-keto <CT 'compound. . 3. The method according to claim Ί, characterized in that a 6,7-saturated compound "of the formula III, in the R represents methyl, dehydrogenated in the 6,7-position. 4. The method according to claim 1, characterized in m a connection of the form!
represents, reacts with thioacetic acid. that a compound of the formula V in which R is methyl 509814/1155 5. Process for the production of pharmaceutical preparations, characterized in that one D-homosteroid of the formula where the dashed bonds in 1,2-, 6,7- and 16,17-positions are optional, R is hydrogen or methyl if there is a double bond in the 1,2-position but only methyl, and R hydrogen or, if the 6,7-position is saturated, also Represent mercapto, acylthio or alkylthio, with non-toxic, inert ones which are suitable for therapeutic administration and which are customary in such preparations mixed solid and / or liquid carriers. 5098U / 1 155 6. Pharmaceutical preparations based on D-homosteroids of the formula wherein the dashed bonds in 1,2-, 6,7- and 16,17-positions are optional, R is hydrogen or methyl if there is a double bond in the 1,2-position but only methyl, and R 'hydrogen or, if the 6,7-position is saturated, also Represent mercapto, acylthio or alkylthio. 7. D-homosteroids of the formula where the dashed bonds in.1,2-, 6.7 and 16.17 pitches are optional, 509814/1155 R is hydrogen or methyl if there is a double bond in the 1,2-position but only methyl, and R 'hydrogen or, if the 6,7-position. is saturated, too Represent mercapto, acyltmo or alkylthio. 8. D-homosteroids according to claim 7, wherein in the formula IR ^{10 is} methyl. 9. D-homosteroids according to claim 8, in which the 1,2-position is saturated and the 16 ; 17-position is unsaturated. 10. 3-0xo-D-homo-21,24-dinor-17aoc-chol-4-eri-23,17a-lactone. 11. S-Oxo-D-homo ^ l ^ -dinor-r / aa-choTa-A, 6-diene-23,17a-lactone. 12. 3-Oxo-19-nor-D-homo-21,24-dinor-17a <x-chol-4-ene-23,17alactone. 13. 7a-Acetylthio-3-oxo-D-homo-21,24-dinor-17aa-chol-4-ene-23 _f 17a-lactone. 14. 3-0xo-D-homo-21,24-dinor-17aa-chola-1,4,6-triene-23,17alactone. 15. 3-0xo-D-homo-21,24-dinor-17aa-chola-4, 16-diene-23,17alactone. 16. 7a-Acetylthio-3-oxo-21,24-dinor-17aa-chola-4,16-diene-23,17a-lactone. 17. 3-0xo-D-homo-21,24-dinor-17aa-chola-4,6,16-triene-23,17alactone. 5098U / 1155