US3749742A - 15alpha,16alpha-methylene steroids and processes for their production and use - Google Patents

15alpha,16alpha-methylene steroids and processes for their production and use Download PDF

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Publication number
US3749742A
US3749742A US00229205A US3749742DA US3749742A US 3749742 A US3749742 A US 3749742A US 00229205 A US00229205 A US 00229205A US 3749742D A US3749742D A US 3749742DA US 3749742 A US3749742 A US 3749742A
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methylene
acid
androsten
hydroxy
compound
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R Wiechert
H Steinbeck
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Bayer Pharma AG
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Schering AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/0065—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by an OH group free esterified or etherified
    • C07J7/0075—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by an OH group free esterified or etherified substituted in position 17 alfa
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C07J53/002—Carbocyclic rings fused
    • C07J53/004—3 membered carbocyclic rings
    • C07J53/008—3 membered carbocyclic rings in position 15/16

Definitions

  • the 15a,l6u-methylene compounds of this invention are steroids of the general Formula I wherein R is a hydrogen atom or saturated or unsaturated alkyl of 1-4 carbon atoms, and physiologically acceptable 17-esters thereof.
  • R can be saturated or unsaturated alkyl of 1-4 carbon atoms, preferably 1-3, more preferably 1-2 carbon atoms, e.g., methyl, ethyl, propyl, butyl, vinyl, allyl, ethinyl, propinyl, etc.
  • esters of physiologically acceptable acids are hydrocarbon carboxylic acids, e.g., of up to 15 carbon "ice atoms, preferably 2 to 11 carbon atoms. These acids can be aliphatic, cycloaliphatic, aromatic, or mixed aromaticaliphatic acids.
  • acids are straight or branched chain alkanoic, e.g., formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, undecyclic acid, trimethylacetic acid, diethylacetic acid, tert.-buty1acetic acid; aralkanoic, e.g., phenylacetic acid; cycloalkanoic, e.g., cyclopentylpropionic acid; and aryl, e.g., benzoic acid.
  • alkanoic e.g., formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, undecyclic acid, trimethylacetic acid, diethylacetic acid, tert.-buty1acetic acid
  • aralkanoic e.g., phenylacetic acid
  • cycloalkanoic e
  • esters described above are esters corresponding to acids bearing one or more simple substituents which do not affect the fundamental character of the steroid.
  • an acid described above can be substituted with halogen, e.g., mono-, dior tri-chloroacetic acid, or any other substituted acid which has been employed to form an ester of a 17-hydroxy steroid, and esters of amino acids, e.g., aminoactic acid, diethylamino-, piperidinoand morpholino-acetic acid, can be used to form water soluble half-esters.
  • esters of the usual inorganic acids such as, for example, sulfuric acid and phosphoric acid which also can be used to produce water soluble esters.
  • the aminoacylates e.g., diethylamino-, piperidino-, and morpholino-acetates
  • their acid addition salts e.g., hydrochloride
  • sulfuric acid esters and phosphoric acid esters and the esters of dibasic organic acids can be converted into their alkali metal, e.g., sodium, salts.
  • the compounds of Formula I and their physiologically acceptable 17-esters possess valuable therapeutic properties, including androgenic activity. They possess high androgenic effectiveness with a favorably differentiated anabolic effect, as evidenced by the experimental data set forth hereinbelow, comparing the activities of 17,8-hydroxy-l5a,16u-methylene-4-androsten-3-one (II) and 17B- acetoxy-15a,16a-methylene-3-androsten-3-one (III) with mesterolone (I) (17p-hydroxy-1u-methyl-5a-androstan-3- one).
  • the experiments were conducted employing the conventional anabolic/androgenic test on juvenile castrated rats (Table 1) and the chicken comb test on oneday-old chickens (Table 2) after oral administration.
  • the compounds of this invention are distinguished in that they produce very minor undesired side effects. Consequently, they can be used, for example, for the treatment of the lessening of male functional power in middle age and old age; cardiac and circulatory disorders; potency disturbances; hypogonadism; convalescence; general exhaustion; chronic infectious diseases, e.g., asthma; cachectic conditions, such as, for example, occurring during radiation therapy; anemias; osteoporosis; chronic diseases of the liver and kidney; muscular dystrophy, etc.
  • the specific drugs are prepared in the usual manner by converting the effective agents, together with pharmaceutically acceptable additives, carriers and flavoring agents, into the desired forms of application, such as tablets, drages, capsules, solutions, ointments, etc.
  • concentration of effective agent in the thus-formulated drugs is dependent on the form of administration.
  • the compounds can be employed in the treatment of aforesaid conditions formulated in conventional pharmaceutically acceptable carriers in the form customarily employed in pharmaceuticals.
  • suitable are tablets, drages, capsules, pills, suspensions and solutions.
  • Suitable excipients for tablets are, for example, lactose, amylose, talc, gelatin, magnesium stearate, and the like.
  • aqueous and oily solutions or suspensions can be employed.
  • the compounds of this invention are formulated so as to provide, for example, 1 to mg. of the effective agent in admixture with 15 mg. to 0.5 mg. of a pharmacologically indifferent excipient, i.e., a pharmaceutically acceptable carrier, per unit dosage, e.g., per tablet.
  • a pharmacologically indifferent excipient i.e., a pharmaceutically acceptable carrier
  • novel la,l6a-methylene steroids of general Formula I and their 17-esters are preferably produced by oxidizing the 3-hydroxy group of a compound of general Formula II Ion, Y l H0 w y wherein R is H or saturated or unsaturated alkyl of 1-4 carbon atoms and R is H or acyl, and
  • a starting compound of Formula H can be oxidized with an aluminum alcoholate in the presence of a ketone.
  • an aluminum alcoholate of a secondary or tertiary alcohol is preferably employed, e.g., aluminum isopropylate, aluminum tert.-butylate and aluminum phenolate, in combination with a lower aliphatic or isocyclic ketone, e.g., acetone, methyl ethyl ketone, cyclopentanone and cyclohexanone.
  • any A -double bond present in the starting material is rearranged into a A -double bond.
  • Starting compounds of Formula II can also be oxidized with chromic acid.
  • chromic acid e.g., acetic acid
  • carboxylic acid e.g., acetic acid
  • oxidation methods can, as is known, also be utilized for the oxidation of the 3-hydroxy group.
  • oxidation methods are: the oxidation with manganese (IV) oxide in an inert solvent, e.g.,
  • the 3-hydroxy group can also be oxidized by a microbiological process, optionally with the simultaneous isomerization of the A -double bond, e.g., fermentation of the starting compound of Formula II with Flavobacterium dehydrogenans under the usual fermentation conditions.
  • the optional esterification of the 17-hydroxy group can be conducted in accordance with the known operating methods.
  • the 17-hydroxy group can be esterified with acid chlorides or acid anhydrides in the presence of an acidic or basic esterification catalyst, e.g., hydrogen chloride, sulfuric acid, p-toluenesulfonic acid, trifiuoroacetic acid, pyridine, collidine and lutidine.
  • an acidic or basic esterification catalyst e.g., hydrogen chloride, sulfuric acid, p-toluenesulfonic acid, trifiuoroacetic acid, pyridine, collidine and lutidine.
  • This esterification takes place at a low temperature, preferably at a starting temperature of --20 C.
  • the esterification can also be conducted at room temperature or at an elevated temperature, e.g., up to C.
  • the starting compounds of general Formula II wherein R is saturated or unsaturated lower alkyl of 14 carbon atoms can be produced preferably by the alkylation of a 3/3-acyloxy-15a,16u-methylene-5-androsten-17-one, e.g., wherein the acyloxy group is that of a hydrocarbon carboxylic acid of 1-8 carbon atoms, e.g., acetic acid, propionic acid, butyric acid, trimethylacetic acid and benzoic acid, with an alkylmagnesium compound.
  • the alkylmagnesium compound means a haloalkylmagnesium compound with a lower saturated or unsaturated alkyl group.
  • This Grignard reaction is, as is known, generally effected in the presence of an ether, e.g., diethyl ether, diisopropyl ether, di-n-butyl ether and tetrahydrofuran.
  • an ether e.g., diethyl ether, diisopropyl ether, di-n-butyl ether and tetrahydrofuran.
  • the metal alkyl compound can also be an alkali acetylide, e.g., lithium, sodium and potassium acetylide.
  • This ethinylation is conventionally conducted in ammonia or in a liquid amine, e.g., ethylene-diamine, or is carried out by reacting the corresponding 17-keto compound with acetylene in the presence of an alcoholate of a tertiary alcohol.
  • the l7a-ethinyl compounds of general Formula II can be converted into the corresponding 17a-vinyl and 17aethyl steroids of Formula II by hydrogenation.
  • This hydrogenation is preferably conducted by reacting the 17a-ethinyl compounds with hydrogen in the presence of a hydrogenation catalyst.
  • suitable hydrogenation catalysts are palladium and platinum oxide catalysts.
  • the alkyl group is stereospecifically introduced at the 17-position with the desired a-configuration.
  • This stereospecific course of the reaction is surprising, since the alkyl residues are introduced in cis-position relationship with respect to the 15a,16a-methylene ring. It would be expected that the methylene group, due to steric hindrance, would hinder introduction of the alkyl groups into the 17OL-POSltlOH, whereby the formation of the isomeric 17,8-alkyl steroids would be favored.
  • this invention relates to a process for the preparation of 15a,16a-methylene steroids of the general Formula Ia wherein R' represents a saturated or unsaturated lower alkyl residue, and R has the values given above, which comprises the steps of reacting a 3B-acyloxy-l5u,16amethylene-S-androsten-l7-one with a metal alkyl compound, alkyl being saturated or unsaturated; and oxidizing, optionally after hydrogenating a 17a-alkinyl group, if present, the B-hydroxy group of the thus-formed compounds of general Formula Ila (H wherein R has the values given above, to a 3-keto group and, optionally thereafter, esterifying a free l7a-hydroxy group, to a l7-ester group.
  • R is a hydrogen atom
  • R is a hydrogen atom
  • a complex metal hydride e.g., sodium borohydride, lithium aluminum hydride and lithium tritert.-butoxyaluminohydride.
  • the 17,8-hydroxy compound is formed stereospecifically. This course of the reduction is surprising, since the thus-introduced hydrogen atom enters at the cis-position with regard to the 15a,160tmethylene group. It would be expected that the methylene group, due to steric hindrance, would make it diflicult to introduce a hydrogen atom in the 170t-POSltlOI1.
  • this invention relates to a process for the production of l5ct,l6a-methylene steroids of the general Formula Ib ICE,
  • R' is a hydrogen atom or acyl, which comprises the steps of reducing 15u,16et-methylene-4-an stene-3,17-dione with a complex metal hydride, and oxidizing the B-hydroxy group of the thus-formed compound of general Formula I-Ib HONN Hb to a 3-keto group and, optionally, thereafter esterifying the free l7B-hydroxy group.
  • novel 3B-acyloxy-l5a,l6a-methylene-5-androsten- 17-ones and the 15a,16a-methylene-4-androstene-3,17- dione which serve as the starting compounds for the above-mentioned processes, can be produced, e.g.
  • Example 1 700 mg. of 15a,16a-methylene-4-androstene-3,l7-dione is mixed with 50 ml. of tetrahydrofuran and 2.75 mg. of lithium tri-tert.-butoxyalanate and agitated at room temerature for one hour. Then, the reaction mixture is poured into ice water, slightly acidified with a mineral acid. The mixture is extracted with methylene chloride, the methylene chloride phase is washed with water, dried, concentrated under vacuum, and 690 mg. of 15u,16a-methylene-4-androstene-3cr,17fl-diol is thus obtained in the form of a crude product.
  • Example 2 350 mg. of 17 3 hydroxy 15a,16a methylene-4- androsten-3-one is mixed with 1.4 ml. of absolute pyridine and 0.7 ml. of propionic anhydride and allowed to stand for two days at room temperature. Thereafter, the reaction mixture is poured into ice water, the precipitate is vacuum-filtered, washed with water, and dried, thus obtaining 370 mg. of 17B-propionyloxy15a,16a-methylene-4- androsten-3-one, M.P. 121-122 C. (from hexane).
  • Example 3 470 mg. of 17/3 hydroxy 150:,1600 methylene-4- androsten-S-one is mixed with 2 ml. of absolute pyridine and 1 ml. of enanthic anhydride and heated for 90 minutes to 125 C. Then, the reaction mixture is poured into water, and the solvent is removed by steam distillation. Thereafter, the aqueous phase is extracted with methylene chloride, the methylene chloride phase is dried, concentrated under vacuum, and 510 mg. of 1713- heptanoyloxy-15a,16a-methylene-4 androsten-3 one is thus obtained in the form of an oil.
  • Example 4 400 mg. of 175 hydroxy 150:,16oc methylene-4- androsten-3-one is dissolved in 2 ml. of absolute pyridine, 1 ml. of capric acid chloride, and 2 ml. of absolute benzene and stored for hours at 5 C. After working up the reaction mixture as described in Example 3, 450 mg. of 17,6-decauoyloxy-15a,16a-methylene-4-androsten- 3-one is obtained as an oil.
  • Example 5 300 mg. of 175 hydroxy 15u,16a methylene-4- androsten-3-one is mixed with 1.5 ml. of absolute pyridine and 0.75 ml. of cyclopentylpropionic anhydride and heated for three hours to 125 C. After the reaction mixture has been worked up as disclosed in Example 3, 320 mg. of 17p-(3'-cyclopentylpropionyloxy)-15a,16a-methylene-4-androsten-3-one is obtained.
  • Example 6 1.0 g. of 3;8-acetoxy-15a,16a-methylene-5-androsten- 17-one is dissolved in 60 ml. of absolute benzene and introduced into a Grignard solution (produced from 1 g. of magnesium filings, 2.97 ml. of methyl iodide, and 40 ml. of absolute ether); the mixture is stirred for four hours at room temperature. Then, the reaction mixture is mixed with saturated ammonium chloride solutions; the aqueous phase is separated and extracted with ether. The combined organic phases are washed with Water, dried, and concentrated, thus obtaining 950 mg. of 17a-methyl- 15a,16a-methylene-5-androsten-3fi,17/3-diol.
  • Example 7 Acetylene is introduced into a Grignard solution (produced from 1.0 g. of magnesium filings, 3.25 ml. of ethyl bromide, and 15 ml. of absolute tetrahydrofuran), cooled to 0 C. Then, this solution is mixed dropwise with a solution of 2 g. of 3fl-acetoxy15a,l6a-methylene-5-androsten- 17-one in 40 ml. of absolute tetrahydrofuran, and the mixture is thereafter agitated for 5 hours at room temperature. After working up the reaction mixture as set forth in Example 6, 1.9 g. of 17a-ethinyl-15a,l6a-methylene- 5-androstene-3[3,17B-diol is obtained.
  • a Grignard solution produced from 1.0 g. of magnesium filings, 3.25 ml. of ethyl bromide, and 15 ml. of absolute tetrahydrofuran
  • Example 8 900 mg. of 170: ethinyl 15a,16a methylene-5- androstene-3p,17B-diol is hydrogenated with 15 ml. of thiophene-free benzene and 900 mg. of palladium catalyst according to Lindlar with 2 equivalents of hydrogen. Then, the catalyst is filtered off, the solution is concentrated to dryness, and the product thus obtained is 170: ethyl methylene-S-androstene-Ilfl,175- diol.
  • a compound of claim 1 wherein R is H. 14.
  • a compound of claim 1 17 8-decanoyloxy-15a,16u- 4.
  • a compound of claim 1 wherein R is a saturated methylene-4-androsten-3-onc. lower 'alkyl group.
  • a compound of claim 1 17p-(3'-cyclopentyl- 5.
  • a compound of claim 1 wherein R is CECH. propionyloxy)-l5a,16u-methylene-4-androsten-3-one.
  • An alkanoic acid ester of claim 1. 5 7.
  • a compound of claim 1 l7fi-acetoxy-15a,l6a- 3318924 5/1967 Georglan 260-4074 methylene-4-androsten-3-0ne.
  • a compound of claim 1 l7fl-propionyloxy-l5a,16w 15 HENRY FRENCH Pnmary Exammer methylene-4-androsten-3-one.
  • U S Cl X R 13 A compound of claim 1, 17fl heptanoyloxy-15a,16amethylene-4-androsten-3-one. 260-3974, 397.5; 424--243 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,749,742 D d July 31, 1973 Inventor(s) Rudolf Wlecherti et all.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
US00229205A 1971-02-24 1972-02-24 15alpha,16alpha-methylene steroids and processes for their production and use Expired - Lifetime US3749742A (en)

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DE2109555A DE2109555C3 (de) 1971-02-24 1971-02-24 Neue 15 a , 16 a -Methylensteroide, diese enthaltende Arzneimittel sowie Verfahren zu ihrei Herstellung

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AT (2) AT323349B (enrdf_load_stackoverflow)
AU (1) AU456892B2 (enrdf_load_stackoverflow)
BE (1) BE779797A (enrdf_load_stackoverflow)
CA (1) CA963000A (enrdf_load_stackoverflow)
CH (1) CH581149A5 (enrdf_load_stackoverflow)
CS (2) CS167346B2 (enrdf_load_stackoverflow)
DD (1) DD96065A5 (enrdf_load_stackoverflow)
DE (1) DE2109555C3 (enrdf_load_stackoverflow)
DK (1) DK130987B (enrdf_load_stackoverflow)
ES (1) ES400056A1 (enrdf_load_stackoverflow)
FI (1) FI49029C (enrdf_load_stackoverflow)
FR (1) FR2126334B1 (enrdf_load_stackoverflow)
GB (1) GB1383334A (enrdf_load_stackoverflow)
HU (1) HU162901B (enrdf_load_stackoverflow)
IE (1) IE36121B1 (enrdf_load_stackoverflow)
IL (1) IL38828A (enrdf_load_stackoverflow)
NL (1) NL7202466A (enrdf_load_stackoverflow)
NO (1) NO135527C (enrdf_load_stackoverflow)
SE (1) SE377338B (enrdf_load_stackoverflow)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USB484068I5 (enrdf_load_stackoverflow) * 1972-02-11 1976-03-02
US4036695A (en) * 1974-11-23 1977-07-19 Schering Aktiengesellschaft Process for the preparation of estrene-3,17-dione derivatives

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102007027635A1 (de) 2007-06-12 2008-12-18 Bayer Schering Pharma Aktiengesellschaft 17ß-Cyano-19-androst-4-en-Derivat, dessen Verwendung und das Derivat enthaltende Arzneimittel
BE1027859B1 (fr) * 2019-12-13 2021-07-14 Georges Debled Hormone stéroïde pour la prévention de maladies associées au vieillissement

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1643005C3 (de) * 1967-02-09 1975-05-22 Schering Ag, 1000 Berlin Und 4619 Bergkamen 15,16beta-Methylen-testosterone, Verfahren zu ihrer Herstellung sowie diese Steroide enthaltende Mittel

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USB484068I5 (enrdf_load_stackoverflow) * 1972-02-11 1976-03-02
US3994937A (en) * 1972-02-11 1976-11-30 Schering Aktiengesellschaft 15α,16α-Methylene-4-estren-17β-ols
US4036695A (en) * 1974-11-23 1977-07-19 Schering Aktiengesellschaft Process for the preparation of estrene-3,17-dione derivatives

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GB1383334A (en) 1974-02-12
DD96065A5 (enrdf_load_stackoverflow) 1973-03-05
DE2109555A1 (de) 1972-09-07
HU162901B (enrdf_load_stackoverflow) 1973-04-28
FI49029B (enrdf_load_stackoverflow) 1974-12-02
DE2109555B2 (de) 1980-03-06
IL38828A0 (en) 1972-04-27
AU456892B2 (en) 1974-12-16
FR2126334A1 (enrdf_load_stackoverflow) 1972-10-06
DK130987B (da) 1975-05-12
CH581149A5 (enrdf_load_stackoverflow) 1976-10-29
NO135527C (enrdf_load_stackoverflow) 1977-04-20
IL38828A (en) 1975-12-31
ES400056A1 (es) 1974-12-16
DE2109555C3 (de) 1980-10-30
FR2126334B1 (enrdf_load_stackoverflow) 1975-03-14
CS167346B2 (enrdf_load_stackoverflow) 1976-04-29
DK130987C (enrdf_load_stackoverflow) 1975-10-06
IE36121L (en) 1972-08-24
CA963000A (en) 1975-02-18
NL7202466A (enrdf_load_stackoverflow) 1972-08-28
SE377338B (enrdf_load_stackoverflow) 1975-06-30
AT323349B (de) 1975-07-10
ZA721052B (en) 1972-10-25
FI49029C (fi) 1975-03-10
AT315393B (de) 1974-05-27
BE779797A (fr) 1972-08-24
NO135527B (enrdf_load_stackoverflow) 1977-01-10
AU3923372A (en) 1973-08-23
CS167345B2 (enrdf_load_stackoverflow) 1976-04-29
IE36121B1 (en) 1976-08-18

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