US3294834A - Alpha-nor-steroids - Google Patents
Alpha-nor-steroids Download PDFInfo
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- US3294834A US3294834A US288920A US28892063A US3294834A US 3294834 A US3294834 A US 3294834A US 288920 A US288920 A US 288920A US 28892063 A US28892063 A US 28892063A US 3294834 A US3294834 A US 3294834A
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- methyl
- oate
- hydroxy
- pregnene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J61/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by contraction of only one ring by one or two atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Definitions
- the final products of this invention can be represented by the formula CH3 R 4%,
- R" is hydrogen; R is selected from the group consisting of hydrogen, hydroxy and acyloxy and together R and R" is oxo R is selected from the group consisting of hydrogen and acyloxy; and Z is selected from the group consisting of wherein W is selected from the group consisting of hydrogen, acyloxy and halogen (e.g., bromo, chloro, fluoro or iodo).
- R is selected from the group consisting of hydrogen, acyloxy and halogen (e.g., bromo, chloro, fluoro or iodo).
- acyl radicals preferred in the practice of this invention are those from hydrocarbon carboxylic acids of less than 1-0 carbon atoms, as exemplified by the lower alkanoic acids (e.g. acetic, propionic, butyric and tertpentanoic acids), the lower alkenoic acids, the monocyolic aryl carboxylic acids (e.g. benzoic and toluic acids), the monocyclic aryl lower alkanoic acids (e.g. phen-acetic and B-phenylpropionic acids), the cycloalkane carboxylic acids and the cycloalkene carboXylic acids.
- the lower alkanoic acids e.g. acetic, propionic, butyric and tertpentanoic acids
- the monocyolic aryl carboxylic acids e.g. benzoic and toluic acids
- the monocyclic aryl lower alkanoic acids e.g. phen-ace
- a curved line j 1 is employed in the linkage of atoms in a formula, it is meant to denote that the conice nected atom may be either in the alpha or beta position as is determined in the respective compounds.
- the compounds of this invention are physiologically active steroids which possess anti-androgenic activity, i.e., they inhibit the action of androgens, and they are useful in the treatment of such conditions as hyper-androgenic acne.
- the compounds may be formulated for such administration, the concentration and/ or dosage being based on the activity of the particular compound and the requirement of the patient.
- this material may first be converted to the respective B-hydroxy compounds as by treatment with alcoholic alkali metal base such as methanol potassium hydroxide.
- Compounds C and D are then oxidized in the presence of a base, e.g., pyridine, to yield the respective 3ketoA- nor-d -derivatives (Compounds E) and 3-keto-A-nor-A' derivatives (Compounds F) which are new compounds of this invention.
- a base e.g., pyridine
- Compounds E and F are then brominated as by treatment with bromine in an acid medium to yield the 5- bromo A-nor-n -derivatives (Compounds G) and the 5- bromo-A-nor-N-derivatives (Compounds H) which are also new compounds of this invention.
- Compounds I may then be reduced with a reducing agent, such as sodium borohydride to yield the 3-hydroxy- A-nor-A -triene derivatives (Compounds K) which are also new compounds of this invention.
- a reducing agent such as sodium borohydride
- Compounds I may also be further reduced as by treatment with hydrogen in the presence of a catalyst, such as palladium on charcoal to yield the 3-unsubstituted A-nor- A -triene derivatives, which are also new products of this invention.
- a catalyst such as palladium on charcoal
- Example 1 --Methyl 3-h m'roxy-4,4,14-trimefl'1yl-A' Sa-ergOStene-ZI -0ate
- the reaction mixture which solidifies during this period of time is taken up in chloroform and Water, acidified with 4 N hydrochloric acid, and the layers are separated.
- the aqueous phase is extracted with chloroform and the combined chloroform extracts washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The resulting residue is dissolved in 250 ml. of methanol and allowed to crystallize. A first crop of 12 grams and on concentration of the mother liquors a second crop of a 1 gram is obtained.
- the purified methyl 3'B-hydroxy-4A,14-trimethyl-A'L5m-ergostene-2loate has the following properties: M.P. -148, +31 (CHCl ANuiol Analysis.-Calcd. for C H O (486.75): C, 78.96; H, 11.18. Found: C, 78.71; H, 11.22.
- Example 2 Methyl 3,8-hydroxy-4,4,14-trimethyl-A 5 a-EIgOSfEYlB-Z 1 -0ate Following the procedure set forth in Example 1 but substituting an equivalent amount of methyl-3fl-acetoxy-4,4, 14-trimethyl-A -ergostene-2l-oate for 3,B-acetoxy-4,4,14- trirnethyl-N-Soc-ergostene-Zl-oate yields methyl 3fi-hydroxy-4,4, 14-trimethyl-A -5 u-ergOstene-Z l-oate.
- Example 4 Example 4 .4,4,1 4 -trimethy l-A -5 a-pregnene-3 13- 0l-20-0ne Following the procedure set forth in Example 3, but substituting an equivalent amount of 3fi-acetoxy-4,4,14- trimethyl-A' -5a-pregnene-ZO-One for 3fl-acetoxy-4,4,14- trimethy1-A -5wpregnene-ZO-one, there is obtained 4,4,14- trimethyI-A' -Sa-pregnene-35-ol-20-one.
- Example 5 M ethyl A -lan0stene-3fi-0l-21-0ate
- Example 6. Methyl 3-is0propylidene-14-melhyl-A- nor-A 5 a-ergOstene-ZJ -0aze
- Example 7 M ethyl 3-is0 pro py lidene-l 4-methy l-A- nor-A -5a-erg0stene-21-0ate ANu in! max. 1
- Example 8.3-is0pr0pylidene-A-n0r-A -5a-pregnene- 20-one A solution of 100 mg. of 4,4,l4-trimethy1-A -5u-pregnene-3/8-ol-2 0-one in 30 ml. of dry toluene is treated with 100 mg. P01 as described in Example 6. After a total reaction time of 8 minutes the 3-isopropylidene derivative is obtained by crystallization from methanol possessing the following properties: M.P. 13 6-137"; [a] +135 (c. 1.04 in CHC1 Analysis.Calcd. for C H O (340.53): C, 84.64; H, 10.66. Found: C, 84.51; H, 10.48.
- Example 10 Methyl 14-methyl-A-n0r-A -5aergostene-3-0ne'21-0ate
- a solution of 2.5 grams of methyl B-lSOpIOpYlidene-14-methyl-A -5a-ergostene-2l-oate and 850 mg. of pyridine (2 molar equivalents) in 125 ml. of methylene chloride which is immersed in a Dry Ice-acetone bath is passed a stream of oxygen containing 0.00129 mole of ozone/ liter.
- the emerging gas begins to liberate iodine from a potassium iodide trap placed after the reaction vessel and the reaction was stopped.
- Example 11 Methyl-14-methyl-A-nor-A -5oterogstene-S -one-21 -0ate
- Benzene (5000 ml.) elutes the pure methyl 14- methyl-A-nor A -5a-ergostene-3-one-21 oate (128 mg.) which after recrystallization from methanol has the following properties: M.P. 1-02103, [c1 +8 (c. 0.37 in OHCl Nuiol Example 12.14-Methyl-A-n0r-A -5- and 5 p-pregnene-ZO-One A solution of 192 mg. of 3-isQpropylidene-A-nOr-A -Sapregnene-ZO-one and 85 mg. of anhydrous pyridine in 45 ml.
- Example I 3 4-m'e thy l-ZI -acetxy-A -nor- A -m-pregnene-3,2O-di0ne 432 mg. of 3-isopropylidene-14-me-thyl-21-acetoxy-A- nor-Sa-pregnene-ZO-one is ozonized in 40 ml. of methylene chloride and 173 mg. of pyridine as described in 1.25 liters of ozone are required and the ozonide is decomposed by the addition of 1 ml. of acetic acid and 1 g. of zinc dust. The amorphous residue is chromatographed on 20 g. of silica .gel from a solution of '10 ml. of benzene and 30 ml. of hexane. Elution with benzene and chloroform in benzene produces amor- AKBI max.
- Example 14 -14-methy l-A 7z0'r-A -5B-pregnene 210Z3,20-di0ne and 21 -acetate
- the ozonolysis of 1.4 g. of the isopropylidene derivative is carried out exactly as described in theprevious example.
- the crude residue obtained after the decomposition (1.36 g.) is dissolved in 90' ml. of methanol and treated with 15 ml. of 0.7 N KOH. After 30 minutes at room temperature the mixture is neutralized with glacial acetic acid, diluted with water and concentrated in vacuo.
- the mixture is extracted with chloroform and the residue from the chloroform extract (1.083 g.) recrystallized from methanol.
- Example 1 5 .M ethyl 5 a-bromo-I 4-melhyl-A -n0r-A' ergostene-3-0ne-2I-0ate
- a solution of 400 mg. of methyl 14-methyl-A-nor- A' -5a-ergostene-3-one-21-oate in 28 ml. of glacial acetic acid is added at room temperature 0.5 ml. of 6% hydrogen bromide in acetic acid followed immediately thereafter by dropwise addition of 5.15 ml. of a 0.185 molar bromine-sodium acetate solution.
- Example 16 MethyZ-5;S-brom0-14-methyl-A-n0r-A erg0stene-3-0ne-21 -0aterivatives obtained in Example 10 in accordance with the 9 procedures of Examples 15 and 16, there is obtained the 3-keto-5B-bromo-14-methyl-A-nor-A -derivatives thereof.
- Example 1 7.Me thy l-5a-br0m0-14-methyl-A mar-A ergostene-3 --n e-2 1 -0ate A solution of 20 mg. of methyl 14-methyl-A-nor-A a-ergostene-3-one-2l-oate in 2 ml. of glacial acetic acid is brominated with 0.260 m-l. of 0:185 Br M and sodium acetate in acetic acid as described in Example 15. Methyl 5a-bromo-14-methyl-A-nor-A -ergostene-3-one-21 oate is recrystallized from methanol and has the following properties: M.P. 143-144 (dec.), +60 (c. 0.28 in CHCl REE; 5.70 (shoulder) 5.77 1
- Example 1 8.M ethyl 14-methyl-A-n0r-A ergostatriene-S-one-Z] -0ate A solution of 100 mg. of methyl 5a-bromo-14-methyl- A-noraA' -ergostene-3-one-2l-oate and 1.0 g. of lithium bromide in 10 ml. of dimethyl formamide are heated on the steam bath for 2 hours. The mixture is then diluted with water, extracted with chloroform, the chloroform extract washed with water, dried over sodium sulfate and evaporated to dryness in vacuo.
- Example 19 Methyl 1 4-methyl-A mar-A 35,8- erg0striene-3-one-21 -0ate Following the procedure set forth in Example 18, but substituting equivalent amounts of methyl-55-bromo-14- methyl-A-nor-A' -ergostene-3-one-2l-oate and methyl 5abromo-14-methyl-A-nor-A -ergostene-3-one 21 oate for methyl-Sa-bromo-14-methyl-A-nor-A -ergostene 3 one- 21-oate, there is obtained methyl 14 methyl A nor- A -ergostatriene-3-one-2l-oate.
- Example 20 Methyl-14-methyl-A-n0r-A ergostatriene-ZO-one-Zl -0aze A solution of 30 mg. of methyl 5a-bromo-14-methyl-A- nor-A -ergostene-3-one-21-oate in 6 ml. of collidine is refluxed for 2 hours under ablanket of nitrogen. The solution is cooled, diluted with benzene and extracted twice with ice cold 6 N HCl sodium bicarbonate and finally with water. The benzene extract is dried over sodium sulfate and evaporated to dryness in vacuo. The residual oil (24 mg.) crystallizes from methanol and gives 10 10 mg.
- Example 21 M ethyl 14-methyl-A-n0r-A ergosZatriene-ZZ -0ate A suspension of 10 mg. of 10% Pd catalyst on carbon in 5 ml. of alcohol is prereduced with hydrogen (uptake 0.77 ml. in 15 minutes). To this suspension is added 10 mg; of methyl 14-methyl-A-nor-A er'gostatriene-3-one-2l-oate and the hydrogenation continued. Hydrogen uptake ceases after 10 minutes when 1.08 ml. has been absorbed. The mixture is filtered, evaporated to dryness and the residue recrystallized from methanol. There is obtained 9 mg.
- Example 21 treating the 3-keto-14-methyl-A-nor-A -triene derivatives obtained in Example 18 in accordance with the procedures set forth in Example 21 yields the respective 14-methyl-A-nor-A -triene derivatives thereof.
- the ZO-keto group has also been reduced to yield a 20-01 compound. Reoxidation of this compound, as by the well-known treatment with chromium trioxide yields the 20-keto A-nor-pregnatriene derivative of Example 21.
- Example 23 -Me thyl 3 -acet0xy-1 4 -metlzyl-A mar-A (1), -ergostatriene-Z1-0me A solution of 25 mg. of methyl 14-methyl-A-nor- A -ergostatriene-3-ol-21-oate in 1 ml. of pyridine and 0.5 ml. of acetic anhydride is allowed to stand overnight at room temperature. The reagents are removed in vacuo and the residue, consisting of methyl 3-acetoxy- 14-methyl-A-nor-A -ergostatriene-Zl-oate, is recrystallized from methanol.
- Example 16 treating the 3-hydroxy-14-methyl-A-nor- A -triene derivatives obtained in Example 15 according to the procedures of Example 16 yields the respective 3-acetoxy-14-methyl-A-nor-A -triene derivatives thereof.
- Example 24 M ethyl 3-acetoxy-1 4-methyl-A -n0r- A -lan0statriene-21 -0ate Following the procedures set forth in Examples 7, 11, 17, 18, 1'9, 20, 21, 22 and 23 but employing methyl 1 1 acetyl-n -lanostene-Sfi-ol-2l-oate yields methyl 3-acetoxyl4-methyl-A-nor-A -lanostatriene-2l-oate.
- W is selected from the :group consisting of hydrogen, the acyloxy radical of a hydrocarbon carboxylic acid of less than ten carbon atoms and halogen.
- a compound selected from the group consisting of steroid derivatives of the formulae 12 and CHEW i 0 i 3 CH3 wherein W is selected from the group consisting of hydrogen, the acyloxy radical of a hydrocarbon carboxylic acid of less than ten carbon atoms and halogen; and R is as defined in claim 1.
- X is selected from the group consisting of lower alkyl and 0 Bi wherein B is selected from the group consisting of hydroxy and lower alkoxy; Y is iso-alky'l; and R is as defined in claim 1.
Description
United States Patent 6 3,294,334 A-NOR-STEROIDS Josef Fried, Princeton, and David W. Rosenthal, New Brunswick, N.J., assignors, by mesne assignments, to E. R. Squibb & Sons, Inc, New York, N.Y., a corporation of Delaware No Drawing. Filed June 19, 1963, er. No. 288,920 16 Claims. (Cl. 260-468) This invention relates to and has for its objects the provision of new physiologically active steroids, methods for preparing the same and new intermediates useful in said preparation.
The final products of this invention can be represented by the formula CH3 R 4%,,
wherein R" is hydrogen; R is selected from the group consisting of hydrogen, hydroxy and acyloxy and together R and R" is oxo R is selected from the group consisting of hydrogen and acyloxy; and Z is selected from the group consisting of wherein W is selected from the group consisting of hydrogen, acyloxy and halogen (e.g., bromo, chloro, fluoro or iodo).
The acyl radicals preferred in the practice of this invention are those from hydrocarbon carboxylic acids of less than 1-0 carbon atoms, as exemplified by the lower alkanoic acids (e.g. acetic, propionic, butyric and tertpentanoic acids), the lower alkenoic acids, the monocyolic aryl carboxylic acids (e.g. benzoic and toluic acids), the monocyclic aryl lower alkanoic acids (e.g. phen-acetic and B-phenylpropionic acids), the cycloalkane carboxylic acids and the cycloalkene carboXylic acids.
(Whenever in this application and the claims appended hereto a curved line j 1 is employed in the linkage of atoms in a formula, it is meant to denote that the conice nected atom may be either in the alpha or beta position as is determined in the respective compounds.)
The compounds of this invention are physiologically active steroids which possess anti-androgenic activity, i.e., they inhibit the action of androgens, and they are useful in the treatment of such conditions as hyper-androgenic acne. The compounds may be formulated for such administration, the concentration and/ or dosage being based on the activity of the particular compound and the requirement of the patient.
The final products of this invention are prepared by the process of this invention which entails a number of steps beginning with compounds of the following formulae as starting material:
an no CH3 CH3 CH CH3 3fi-hydroXy-21-halo-4,4,14-trirnethyl-A"-pregnene-20-one; 3 B-hydroxy-Zl-halo-4,4,14-trimethyl-A -pregnene-ZO-one; 3fl-hydroxy-16-acetoxy-21-ha-lo-4,4,14-trimethyl-A pregnene-ZO-one; 3 B-hydroxy-16-acetoxy-21-halo-4A,14-trimethyl-A pregnene-ZO-one; 3fi-hydroxy-2v1-acetoxy-4,4,14-trimethy1-A' pregnene- 20-one; 3/3-hydroXy-2'1-acetoxy-4,4,14-trimerhyl-A -pregnene- 20-one; 3 ,S-hydroxy-16,2 1-diaeetoxy-4,4, 14-trimethy1-A' pregnene-ZO-one; 3fl-hydroxy-16,2 1-diacetoXy-4,4,14-trimethyl-A pregnene-ZO-one; 3 B-hydroxy-4,4,14-trimethy1-A -pregnene-20-one; 3,B-hydroxy-4,4,14-trimethyl-M-pregnene-ZO-one; Methy1-3B-hydroxy-A' -eburicene-Z 1oate; Methyl-3fi-hydroXy-M-eburicene-Zl-oate; Methyl-3B-acetOXy-A' -ebuIicene-Zl-oate; Methyl-3 fi-acetoxy-M-eburicene-Z 1 -oate; Methyl-3fi-hydroxy-16-acetoxy-A' -eburicene-21-oate; Methyl-3fi-hydroxy-16a-acetoxy-A -eburicene-2i1-oate; Methyl-3B-hydroXy-A -lanostene-Zl-oate; Methyl-Bfi-acetoxy-Mdanostene-Zl-oate; Methyl-3 fl-hydroxy-A' -lanostene-2 l-oate; A -lanostene-3B-o1; A -lanostene-35-o1.
In addition to the foregoing, starting materials employable in the practice of this invention may also be prepared according to the procedures set forth in copending U.S.
3 applications Serial No. 198,425 filed May 29, 1962, now
US. Patent No. 3,169,957, in the names of Josef Fried- Y and Gerald Krakower and Serial No. 212,154, filed July 24, 1962, now US. Patent No. 3,170,919, in the name of Josef Fried. The steps of this process are generally shown by the following equations, wherein R, R, R" and Z are as hereinbefore defined:
lit a...
C 3 C 3 H3 C 3 In the first step of the process of this invention, the 3B-hydroxy-A or -A starting materials (Compounds A and B), enumerated herein above are reacted with phosphorus pentachloride to yield the respective 3-isopropylisopropylidene A-nor A' derivatives (Compounds D).' In
the event that 3fl-acetoxy A or A -starting materials are employed in the practice of this invention, this material may first be converted to the respective B-hydroxy compounds as by treatment with alcoholic alkali metal base such as methanol potassium hydroxide.
Compounds C and D are then oxidized in the presence of a base, e.g., pyridine, to yield the respective 3ketoA- nor-d -derivatives (Compounds E) and 3-keto-A-nor-A' derivatives (Compounds F) which are new compounds of this invention.
Compounds E and F are then brominated as by treatment with bromine in an acid medium to yield the 5- bromo A-nor-n -derivatives (Compounds G) and the 5- bromo-A-nor-N-derivatives (Compounds H) which are also new compounds of this invention.
Compounds G and H are then dehydrobrominated as by treatment with a dehydrobrominating agent, such as lithium bromide in dimethyl formamide medium, or col- ]idine, to yield the S-keto-A-nor A -triene derivatives (Compounds J) which are new products of this invention.
Compounds I may then be reduced with a reducing agent, such as sodium borohydride to yield the 3-hydroxy- A-nor-A -triene derivatives (Compounds K) which are also new compounds of this invention.
Compounds I may also be further reduced as by treatment with hydrogen in the presence of a catalyst, such as palladium on charcoal to yield the 3-unsubstituted A-nor- A -triene derivatives, which are also new products of this invention.
The invention may be further illustrated by the following examples:
Example 1.--Methyl 3-h m'roxy-4,4,14-trimefl'1yl-A' Sa-ergOStene-ZI -0ate A solution of 17 grams of methyl 3fi-acetoxy-4,4,14- trimethyl-A' -5oc-ergostene-Zl-oate in a mixture of 250 ml. of dioxane and 25 0 m1. of 12% methanolic potassium hydroxide is allowed to stand at room temperature for 18 hours. The reaction mixture, which solidifies during this period of time is taken up in chloroform and Water, acidified with 4 N hydrochloric acid, and the layers are separated. The aqueous phase is extracted with chloroform and the combined chloroform extracts washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The resulting residue is dissolved in 250 ml. of methanol and allowed to crystallize. A first crop of 12 grams and on concentration of the mother liquors a second crop of a 1 gram is obtained. The purified methyl 3'B-hydroxy-4A,14-trimethyl-A'L5m-ergostene-2loate has the following properties: M.P. -148, +31 (CHCl ANuiol Analysis.-Calcd. for C H O (486.75): C, 78.96; H, 11.18. Found: C, 78.71; H, 11.22.
Example 2.Methyl 3,8-hydroxy-4,4,14-trimethyl-A 5 a-EIgOSfEYlB-Z 1 -0ate Following the procedure set forth in Example 1 but substituting an equivalent amount of methyl-3fl-acetoxy-4,4, 14-trimethyl-A -ergostene-2l-oate for 3,B-acetoxy-4,4,14- trirnethyl-N-Soc-ergostene-Zl-oate yields methyl 3fi-hydroxy-4,4, 14-trimethyl-A -5 u-ergOstene-Z l-oate.
Example 3.4,4,14-ZrimethyLA -Sa-pregnene-3/3- 0l-20-0ne in vacuo. The residue (430 mg.) on recrystallization from methanol gives 390 mg. of pure 4,4,14-trimethyl- A -5a-pregnene-3B-ol-ZO-one possessing the following properties, M.P. 253-256"; [:1 -|-.122 (c. 1.2 in chloroform);
Analysis.Calcd. for c m o (358.54): c, 80.39; H, 10.68. Found: c, 80.39; H, 10.62.
Example 4 .4,4,1 4 -trimethy l-A -5 a-pregnene-3 13- 0l-20-0ne Following the procedure set forth in Example 3, but substituting an equivalent amount of 3fi-acetoxy-4,4,14- trimethyl-A' -5a-pregnene-ZO-One for 3fl-acetoxy-4,4,14- trimethy1-A -5wpregnene-ZO-one, there is obtained 4,4,14- trimethyI-A' -Sa-pregnene-35-ol-20-one.
Example 5 .M ethyl A -lan0stene-3fi-0l-21-0ate Example 6.Methyl 3-is0propylidene-14-melhyl-A- nor-A 5 a-ergOstene-ZJ -0aze To a well agitated solution of 2.5 grams of methyl 3,8- hydroxy-4,4,l4-trimethyl-A' Son-ergostene-2l-oate in 350 ml. of dry toluene maintained at 0 is added 2.5 grams of phosphorus pentachloride. Immediately after the addition of the latter, a rapid stream of nitrogen is passed through the suspension and continuted for 20 minutes. At this time 10% potassium carbonate solution is added to the agitated mixture and the temperature allowed to rise to room temperature. The toluene solution is washed again with sodium carbonate and water, dried over p0- tassium carbonate and evaporated to dryness in vacuo. The residue which crystallizes spontaneously is taken up in a small amount of chloroform and diluted with methanol. Crystallization ensues furnishing 2.03 grams of the methyl 3 isopropylidene-14-methyl-A-nor-A -5u-ergostene-Zl-oate. The analytically pure material has the following properties: M.P. 12112l.5, [01],; +18 (chf.),
AnalySis.--CalCd. for C H O C, 81.99; H, 11.18. Found: C, 82.41; H, 11.23.
Similarly, substituting an equivalent amount of any of the 3-hydroxy-A -starting materials set forth hereinabove on pages 3 and 4 of the specification, or which were obtained in Examples 1 to 5, for methyl 35-hydroxy-4,4,l4- trimethyl-A' -Sa-ergostene-Zl-oate yields the corresponding 3 isopropylidene 14-methyl-A-nor-A' -derivatives thereof.
Example 7 .M ethyl 3-is0 pro py lidene-l 4-methy l-A- nor-A -5a-erg0stene-21-0ate ANu in! max. 1
Analysis.Calcd. for 0, 11, 0 0, 81.99; H, 11.18. Found: 0, 81.93; H, 11.25.
Example 8.3-is0pr0pylidene-A-n0r-A -5a-pregnene- 20-one A solution of 100 mg. of 4,4,l4-trimethy1-A -5u-pregnene-3/8-ol-2 0-one in 30 ml. of dry toluene is treated with 100 mg. P01 as described in Example 6. After a total reaction time of 8 minutes the 3-isopropylidene derivative is obtained by crystallization from methanol possessing the following properties: M.P. 13 6-137"; [a] +135 (c. 1.04 in CHC1 Analysis.Calcd. for C H O (340.53): C, 84.64; H, 10.66. Found: C, 84.51; H, 10.48.
A solution of mg. of 4,4,14-trimethyl-A -5a-pregnene-2.1-o1-20-one, 21-acetate in 20 ml. of dry toluene is reacted with PCl at 0 as described in Example 6. On recrystallization from methanol there is obtained 73 mg. of the 3-isopropylidene compound of the following properties: M.P. 172-174; [111 +130 (c. 1.0 in CHCl Analysis.Calcd. for C H O (398.56); C, 78.35; H, 9.61. Found: C, 78.13; H, 9.37.
Similarly, if equivalent amounts of any of the 3-hydroxy-A -starting materials enumerated hereinabove at pages 3 and 4 of the specification or equivalent amounts of any of the 3-hydroxy-A -compounds obtained in Examples 1 to 5 are substituted the respective 3-isoproylidene-14-methyl-A-nor-A -derivatives thereof are obtained.
Example 10.Methyl 14-methyl-A-n0r-A -5aergostene-3-0ne'21-0ate Through a solution of 2.5 grams of methyl B-lSOpIOpYlidene-14-methyl-A -5a-ergostene-2l-oate and 850 mg. of pyridine (2 molar equivalents) in 125 ml. of methylene chloride which is immersed in a Dry Ice-acetone bath is passed a stream of oxygen containing 0.00129 mole of ozone/ liter. When 6.1 liters of this ozone-oxygen mixture has passed through the solution, the emerging gas begins to liberate iodine from a potassium iodide trap placed after the reaction vessel and the reaction was stopped. After warming to 0 3 ml. of glacial acetic acid and 2.5 g. of zinc dust are added with stirring permitting the reaction mixture to reach room temperature. When the ozonide is completely decomposed as indicated by testing with potassium iodide solution (approximately 1 hour) the mixture is filtered, Washed thoroughly with water and the methylene chloride extract dried over sodium sulfate and evaporated to dryness in vacuo. The residue which weighs 2.6 g. is dissolved in methanol from which the desired methyl 14-methyl-A-nor-A -Sa-ergostene-3 -one- 21-oate crystallizes spontaneously. The first crop amounts to 533 mg. melting at 178-1 80" and a second crop mg.) melts at 174-178. The analytically pure material has the following properties: M.P. 179-181", 113
Example 11 .Methyl-14-methyl-A-nor-A -5oterogstene-S -one-21 -0ate A solution of 900 mg. of methyl 3-isopropylidene-14- methyl-A-nor-A -5a-e'rgostene-21-oate and 300 mg. of anhydrous pyridine (2 molar equivalents) in 45 ml. of methylene chloride is ozonized at acetone-Dry Ice temthrough the solution.
Example 12.
perature with a stream of oxygen containing 0.00129 mole/liter until KI-starch solution is blued by the existing gas. This occurs after about 2.59 liters have passed The solution is then allowed to warm to room temperature; 1 ml. of glacial acetic acid and 600 mg. of zinc dust are added with stirring, and the mixture allowed to remain at room temperature until the ozonide is completely decomposed. The mixture is then filtered, thoroughly extracted with water, dried over sodium sulfate and the solvent removed in vacuo. The dried residue (950 mg.) is dissolved in hexane and chromatographed on a column of 40 g. of silica gel. Elution with hexane removes 80 mg. of amorphous material. Benzene (5000 ml.) elutes the pure methyl 14- methyl-A-nor A -5a-ergostene-3-one-21 oate (128 mg.) which after recrystallization from methanol has the following properties: M.P. 1-02103, [c1 +8 (c. 0.37 in OHCl Nuiol Example 12.14-Methyl-A-n0r-A -5- and 5 p-pregnene-ZO-One A solution of 192 mg. of 3-isQpropylidene-A-nOr-A -Sapregnene-ZO-one and 85 mg. of anhydrous pyridine in 45 ml. of methylene chloride is ozonized as described in Example 11 until the exiting gas liberates iodine from a KI-solution. This occurs after 730 mg. of gas has passed through the solution. The solution is then allowed to reach room temperature and 0.3 ml. of glacial acetic acid and 350 mg. of zinc dust are added and the mixture kept stirring until the ozonide is completely decomposed. The mixture is then filtered, thoroughly extracted with water and the methylene chloride extract dried over sodium sulfate and evaporated to dryness in vacuo. The dried residue (190 mg.) is recrystallized from etherhexane and furnishes the essentially pure SIZ-iSOmCI. However, it was preferable to convert the total crude product to the better crystalline SB-isomer as follows: The residue (190 mg.) is dissolved in 9 ml. of methanol and to this is added 1.5 ml. of 0.7 N KOH in methanol. The mixture is allowed to stand at room temperature for 30 minutes, neutralized with glacial acetic acid and after the addition of water extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue (198 mg.) on crystallization from methanol furnishes 81 mg. pure 14-methyl-A-nor-5;3-A -pregnene-3,20- dione of the following properties: M.P. 178-179; [M +273 (c. 0.58 in CHCl max.
Example I 3,-1 4-m'e thy l-ZI -acetxy-A -nor- A -m-pregnene-3,2O-di0ne 432 mg. of 3-isopropylidene-14-me-thyl-21-acetoxy-A- nor-Sa-pregnene-ZO-one is ozonized in 40 ml. of methylene chloride and 173 mg. of pyridine as described in 1.25 liters of ozone are required and the ozonide is decomposed by the addition of 1 ml. of acetic acid and 1 g. of zinc dust. The amorphous residue is chromatographed on 20 g. of silica .gel from a solution of '10 ml. of benzene and 30 ml. of hexane. Elution with benzene and chloroform in benzene produces amor- AKBI max.
Analysis.--Calcd. for C H O (372.49): C, 74.16; H, 8.66. Found: C, 74.09; H, 8.72.
Example 14.-14-methy l-A 7z0'r-A -5B-pregnene 210Z3,20-di0ne and 21 -acetate The ozonolysis of 1.4 g. of the isopropylidene derivative is carried out exactly as described in theprevious example. The crude residue obtained after the decomposition (1.36 g.) is dissolved in 90' ml. of methanol and treated with 15 ml. of 0.7 N KOH. After 30 minutes at room temperature the mixture is neutralized with glacial acetic acid, diluted with water and concentrated in vacuo. The mixture is extracted with chloroform and the residue from the chloroform extract (1.083 g.) recrystallized from methanol. There is obtained 195 mg. of the pure 21-01 possessing the following properties: M.P. 169170 [04 +242 (c. 0.53 in CHCl max KKK 5.70, 5.77;;
Analysis.-Calcd. for C H O (372.49): C, 74.16; H, 8.66. Found: C, 74.18; H, 8.70.
Similarly, treating the 3-isopropylidene-14-methyl-A- nor-A -derivatives which may be obtained in accordance with the procedures of Example 7 according to the procedures set forth in Example 11 there is obtained the respective 3-keto-14-methyl-A-nor-A derivatives thereof.
Example 1 5 .M ethyl 5 a-bromo-I 4-melhyl-A -n0r-A' ergostene-3-0ne-2I-0ate To a solution of 400 mg. of methyl 14-methyl-A-nor- A' -5a-ergostene-3-one-21-oate in 28 ml. of glacial acetic acid is added at room temperature 0.5 ml. of 6% hydrogen bromide in acetic acid followed immediately thereafter by dropwise addition of 5.15 ml. of a 0.185 molar bromine-sodium acetate solution. After 1.5 hours, the mixture is diluted with water, extracted with chloroform and the chloroform extract washed with water, dilute sodium bicarbonate and again with water, dried over sodium s-ulfate and evaporated to dryness in vacuo at a bath temperature not exceeding 30. The resulting residue (503 mg.) on crystallization from methanol yields 146 mg. of methyl 5a-bromo-14-methyl-A-nor-A -ergostene-3-one-21- oate, which after recrystallization has the following properties: M.P. (dec.), +43 (c. 1.66 in CHCl Analysis.Calcd. for C H O Br (520): C, 66.97; H, 8.72; Br, 15.3. Found: C, 66.95; H, 8.28; Br, 15.6.
Similarly, if the 3-keto-14-methyl-A-nor-A -derivatives which may be obtained in accordance with the procedures set forth in Example 10 are treated according to the procedure of Example 15, the respective 3-keto-5a-bromo-14- methyl-A-nor-A' -derivatives thereof are obtained.
Example 16.MethyZ-5;S-brom0-14-methyl-A-n0r-A erg0stene-3-0ne-21 -0aterivatives obtained in Example 10 in accordance with the 9 procedures of Examples 15 and 16, there is obtained the 3-keto-5B-bromo-14-methyl-A-nor-A -derivatives thereof.
Example 1 7.Me thy l-5a-br0m0-14-methyl-A mar-A ergostene-3 --n e-2 1 -0ate A solution of 20 mg. of methyl 14-methyl-A-nor-A a-ergostene-3-one-2l-oate in 2 ml. of glacial acetic acid is brominated with 0.260 m-l. of 0:185 Br M and sodium acetate in acetic acid as described in Example 15. Methyl 5a-bromo-14-methyl-A-nor-A -ergostene-3-one-21 oate is recrystallized from methanol and has the following properties: M.P. 143-144 (dec.), +60 (c. 0.28 in CHCl REE; 5.70 (shoulder) 5.77 1
Analysis.Calcd. for C H O Br (520): C, 66.97; H, 8.72. Found: C, 66.96; H, 8.78.
Similarly, if the 3-keto-14-methyl-A-nor-A -derivatives which may be obtained in accordance with the procedures of Example 15 are treated in accordance with the procedures set forth in Example 17, the 3-keto-5a-bromo-A- nor-A -derivatives thereof are obtained.
Example 1 8.M ethyl 14-methyl-A-n0r-A ergostatriene-S-one-Z] -0ate A solution of 100 mg. of methyl 5a-bromo-14-methyl- A-noraA' -ergostene-3-one-2l-oate and 1.0 g. of lithium bromide in 10 ml. of dimethyl formamide are heated on the steam bath for 2 hours. The mixture is then diluted with water, extracted with chloroform, the chloroform extract washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. Crystallization of the residue from methanol yields the pure methyl 14-methyl- A-nor-A -ergostatriene-3-one-2l-oate of the following properties: M.P. 137-138; [M +11 (c. 1.0 in CHCl x;};-, 217 m (20,000), 261 mp. (10,400), 295 In (2000, plateau); Afif; 5.78, 5.85, 6.29;],
NMR: protons at C and C doublets centered at 2.45
and 2.94 '1'. 1:8 cps. 14-methyl at 8.92.
Analysis.Calcd. for C H O (424.60): C, 79.20; H, 9.5-0. Found: C, 79.24; H, 9.48.
Similarly, treatment of the 3-keto-5a-bromo-14-methyl- A-nor-A -derivatives, which are obtained according to the procedures set forth in Example 15, in accordance with the procedures of Example 18 yields the respective 3-keto-14- methyl-A-nor-A -trieue derivatives thereof.
Example 19.Methyl 1 4-methyl-A mar-A 35,8- erg0striene-3-one-21 -0ate Following the procedure set forth in Example 18, but substituting equivalent amounts of methyl-55-bromo-14- methyl-A-nor-A' -ergostene-3-one-2l-oate and methyl 5abromo-14-methyl-A-nor-A -ergostene-3-one 21 oate for methyl-Sa-bromo-14-methyl-A-nor-A -ergostene 3 one- 21-oate, there is obtained methyl 14 methyl A nor- A -ergostatriene-3-one-2l-oate.
Similarly, if the 3-keto-5fi-bromo-14-methyl-A-nor-N- derivatives, obtained in accordance with Example 16, and the 3-keto-5a-bromo-14-methyl-A-nor-A -derivatives, :obtained in accordance with Example 17, are treated in accordance with the procedures set forth in Example 18, the respective 3-keto-14-methyl-A-nor-A t -triene derivatives thereof are obtained.
Example 20.Methyl-14-methyl-A-n0r-A ergostatriene-ZO-one-Zl -0aze A solution of 30 mg. of methyl 5a-bromo-14-methyl-A- nor-A -ergostene-3-one-21-oate in 6 ml. of collidine is refluxed for 2 hours under ablanket of nitrogen. The solution is cooled, diluted with benzene and extracted twice with ice cold 6 N HCl sodium bicarbonate and finally with water. The benzene extract is dried over sodium sulfate and evaporated to dryness in vacuo. The residual oil (24 mg.) crystallizes from methanol and gives 10 10 mg. of methyl-l4-methyl-A-nor-A -ergostatriene- 20-one-21-oate, crystals melting at 135-137". Prepare: tive thin layer chromatography on activity V alumina gives an additional 4 mg. of material. One recrystallization raises the melting point to 137-138".
Example 21 .M ethyl 14-methyl-A-n0r-A ergosZatriene-ZZ -0ate A suspension of 10 mg. of 10% Pd catalyst on carbon in 5 ml. of alcohol is prereduced with hydrogen (uptake 0.77 ml. in 15 minutes). To this suspension is added 10 mg; of methyl 14-methyl-A-nor-A er'gostatriene-3-one-2l-oate and the hydrogenation continued. Hydrogen uptake ceases after 10 minutes when 1.08 ml. has been absorbed. The mixture is filtered, evaporated to dryness and the residue recrystallized from methanol. There is obtained 9 mg. of the pure methyl 14-methyl-A-nor-A -ergostatriene-2l-oate possessing the following properties: M.P. 88-89 with resolidification and remelting at 101-102"; +6.4 (c. 0.2 in CHCl X 5.78 M22 268 m (820), 273 m (690), 278111;]. (820) NMR: Protons at C and C doublets centered at 2.97 and 3.187, 1:8 cps. I l-methyl at 9. 837.
Analysis.Calcd. for C H O (410.62): C, 81.90; H, 10.31. Found: C, 81.80; H, 10.29.
Similarly, treating the 3-keto-14-methyl-A-nor-A -triene derivatives obtained in Example 18 in accordance with the procedures set forth in Example 21 yields the respective 14-methyl-A-nor-A -triene derivatives thereof. When the pregnene derivatives ofthis invention are treated in accordance with the procedures of Example 21, the ZO-keto group has also been reduced to yield a 20-01 compound. Reoxidation of this compound, as by the well-known treatment with chromium trioxide yields the 20-keto A-nor-pregnatriene derivative of Example 21.
the 3-hydroxy-l4-methyl-A-nor-A -triene derivatives thereof.
Example 23.-Me thyl 3 -acet0xy-1 4 -metlzyl-A mar-A (1), -ergostatriene-Z1-0me A solution of 25 mg. of methyl 14-methyl-A-nor- A -ergostatriene-3-ol-21-oate in 1 ml. of pyridine and 0.5 ml. of acetic anhydride is allowed to stand overnight at room temperature. The reagents are removed in vacuo and the residue, consisting of methyl 3-acetoxy- 14-methyl-A-nor-A -ergostatriene-Zl-oate, is recrystallized from methanol.
Similarly, treating the 3-hydroxy-14-methyl-A-nor- A -triene derivatives obtained in Example 15 according to the procedures of Example 16 yields the respective 3-acetoxy-14-methyl-A-nor-A -triene derivatives thereof.
Example 24 .M ethyl 3-acetoxy-1 4-methyl-A -n0r- A -lan0statriene-21 -0ate Following the procedures set forth in Examples 7, 11, 17, 18, 1'9, 20, 21, 22 and 23 but employing methyl 1 1 acetyl-n -lanostene-Sfi-ol-2l-oate yields methyl 3-acetoxyl4-methyl-A-nor-A -lanostatriene-2l-oate.
Like results are obtained when methyl acetyl-A' -lanostene-3B-ol-2l-oate is substituted for methyl acetyl-A lanostene-35-ol-21-oate. 5
The invention may be variously otherwise embodied within the scope of the appended claims.
What is claimed is:
1. A compound of the formula C wherein Y is iso-alkyl and X is selected from the group consisting of lower alkyl and o B ll wherein B is selected from the group consisting of hydroxy and lower alkoxy; and
omw
wherein W is selected from the :group consisting of hydrogen, the acyloxy radical of a hydrocarbon carboxylic acid of less than ten carbon atoms and halogen.
2. A compound selected from the group consisting of steroid derivatives of the formulae 12 and CHEW i=0 i 3 CH3 wherein W is selected from the group consisting of hydrogen, the acyloxy radical of a hydrocarbon carboxylic acid of less than ten carbon atoms and halogen; and R is as defined in claim 1.
4. A compound selected from the group of steroid derivatives of the formulae MR. al
and
wherein X is selected from the group consisting of lower alkyl and 0 Bi wherein B is selected from the group consisting of hydroxy and lower alkoxy; Y is iso-alky'l; and R is as defined in claim 1.
5. Methyl 3-isopropylidene-14-methyl-A-nor-A' -5aergostene-Zl-oate. 6. Methyl 3-isopropylidene-14-methyl-A-nor-A -5mergostene-Zl-oate. 7. Methyl 14-methyl-A-nor-A -5u-ergostene3-one- 21-oate. 8. Methyl 14-methyl-A-nor-A -5a-ergostene-3-one- 21-oate. 9. Methyl 5u-bromo-l4-methyl-A-nor-A -ergostene- 3-one-21-oate. 10. Methyl 14-methyl-A-nor-A -ergostatriene-3- one-Zl-oate. 11. Methyl 14-methyl-A-nor-A -ergostatriene- 2l-oate. 12. Methyl 14-methyl-A-nor-A -ergostatrieue- 3-ol-21-oate. 13. 14-methyl-A-nor-A -pregnene-3,ZO-dione. 14. l4- methyl-A-nor-A -5fi pregnene-21-ol-3,20-dione ZI-acetate. 15. 3-isopropylidene-l Lmethyl-A-nor-A -5u-pregnene- 20-one. 16. Isopropylidene-l4-methyl-A-nor-A -5a-pregnene- 2l-ol-20-one.
No references cited.
LORRAINE A. WEINBERGER, Primary Examiner.
R. K. JACKSON, Assistant Examiner.
Claims (1)
1. A COMPOUND OF THE FORMULA
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US288920A US3294834A (en) | 1963-06-19 | 1963-06-19 | Alpha-nor-steroids |
| FR987260A FR4073M (en) | 1963-06-19 | 1964-09-07 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US288920A US3294834A (en) | 1963-06-19 | 1963-06-19 | Alpha-nor-steroids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3294834A true US3294834A (en) | 1966-12-27 |
Family
ID=23109235
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US288920A Expired - Lifetime US3294834A (en) | 1963-06-19 | 1963-06-19 | Alpha-nor-steroids |
Country Status (2)
| Country | Link |
|---|---|
| US (1) | US3294834A (en) |
| FR (1) | FR4073M (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3367963A (en) * | 1965-08-30 | 1968-02-06 | Squibb & Sons Inc | 15-oxygenated-delta3-a-norandrostene-2, 17-diones |
| US3484476A (en) * | 1963-09-13 | 1969-12-16 | Squibb & Sons Inc | A-nor steroids |
-
1963
- 1963-06-19 US US288920A patent/US3294834A/en not_active Expired - Lifetime
-
1964
- 1964-09-07 FR FR987260A patent/FR4073M/fr not_active Expired
Non-Patent Citations (1)
| Title |
|---|
| None * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3484476A (en) * | 1963-09-13 | 1969-12-16 | Squibb & Sons Inc | A-nor steroids |
| US3367963A (en) * | 1965-08-30 | 1968-02-06 | Squibb & Sons Inc | 15-oxygenated-delta3-a-norandrostene-2, 17-diones |
| US3375269A (en) * | 1965-08-30 | 1968-03-26 | Squibb & Sons Inc | 16-oxygenated-delta3-a-norandrostene-2, 17-diones |
Also Published As
| Publication number | Publication date |
|---|---|
| FR4073M (en) | 1966-04-12 |
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