EP0000368B1 - D-Homosteroide und solche enthaltende Präparate sowie Verfahren zur Herstellung solcher D-Homosteroide - Google Patents

D-Homosteroide und solche enthaltende Präparate sowie Verfahren zur Herstellung solcher D-Homosteroide Download PDF

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Publication number
EP0000368B1
EP0000368B1 EP78100302A EP78100302A EP0000368B1 EP 0000368 B1 EP0000368 B1 EP 0000368B1 EP 78100302 A EP78100302 A EP 78100302A EP 78100302 A EP78100302 A EP 78100302A EP 0000368 B1 EP0000368 B1 EP 0000368B1
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EP
European Patent Office
Prior art keywords
formula
homosteroid
homosteroids
hydrogen atom
homo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP78100302A
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German (de)
English (en)
French (fr)
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EP0000368A1 (de
Inventor
Andor Dr. Fürst
Peter Dr. Keller
Marcel Dr. Müller
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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Filing date
Publication date
Application filed by F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
Publication of EP0000368A1 publication Critical patent/EP0000368A1/de
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Expired legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics

Definitions

  • the invention relates to new D-homosteroids of the formula wherein the dotted line in the A ring is an optional CC bond; X and Y together are an OC bond or X is hydrogen and Y is hydroxy; R 6 is hydrogen and R 7 is hydrogen or acylthio or R 6 and R 7 together are a C - C bond, and physiologically acceptable salts thereof.
  • the invention further relates to a process for the preparation of the compounds I and pharmaceutical preparations which contain a compound of the formula.
  • 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.
  • acids are formic, acetic, pivalic, propionic, butteric, capronic, oenanthic, undecylene, oleic, cyclohexylpropionic, cyclopentylpropionic, phenylacetic and benzoic acids.
  • Particularly preferred acyl groups are C 1-7 alkanoyl groups, especially actyl.
  • physiologically acceptable salts of the acids of formula I come in particular alkali metal salts, for. B. the Na and K salts and the ammonium salts; and alkaline earth metal salts, e.g. B. the calcium salts into consideration.
  • alkali metal salts for. B. the Na and K salts and the ammonium salts
  • alkaline earth metal salts e.g. B. the calcium salts into consideration.
  • the potassium salts are preferred.
  • the methyl group in the 6-position can be ⁇ - or ⁇ -permanent, the 6 ⁇ -methyl isomers are preferred.
  • a preferred group of compounds of formula 1 are those compounds in which R 7 is acylthio, in particular C 1 7-alkanoylthio.
  • the lactones of the formula are also preferred.
  • the hydrogenation of the 6-methylene group in a D-homosteroid of the formula II according to process variant a) can be carried out in a manner known per se by means of hydrogenation catalysts, for. B. noble metal catalysts, such as palladium.
  • the isomerization of the 6-methylene group to form a 6-methyl- ⁇ 6 group can also in a conventional manner, for. B. be carried out catalytically.
  • isomerization catalysts are, for. B. metal catalysts as used for example in hydrogenations, especially palladium in ethanol.
  • a hydrogen donor, such as cyclohexene, is expediently added as an activator for the catalyst. Undesired side reactions, such as hydrogenations by means of the hydrogen donor, can be avoided by buffering the reaction mixture.
  • 1,2-saturated compounds of the formula I are obtained in which R 6 and R 7 are hydrogen or together are a CC bond.
  • An acylthio substituent R 7 can be introduced into a D-homosteroid of the formula 111 (process variant b) in a manner known per se by treating the steroid with an appropriate thiocarboxylic acid.
  • the reaction can be carried out in an inert solvent such as an ether, e.g. B. dioxane or tetrahydrofuran, or an alcohol such as methanol or ethanol, or in a chlorinated hydrocarbon such as chloroform; the reagent, e.g. B. the thiocarboxylic acid is advantageously used in excess and can serve as a solvent.
  • Process variant b) gives 1,2-saturated D-homosteroids of the formula in which R 6 is hydrogen and R 7 is acylthio.
  • the 1,2-dehydrogenation of a D-homosteroid of the formula IV can be carried out in a manner known per se, for. B. microbiologically or by means of dehydrating agents such as selenium dioxide, 2,3-dichloro-5,6-dicyanobenzoquinone, chloranil, thallium triacetate or lead tetraacetate.
  • Suitable microorganisms for 1,2-dehydrogenation are, for example, schizomycetes, in particular those of the Genera Arthrobacter, e.g. B. A. simplex ATCC 6946; Bacillus, e.g. B. B. lentus ATCC 13805 and B.
  • sphaericus ATCC 7055 Pseudomonas, e.g. B. P. aeruginosa IFO 3505; Flavobacterium, e.g. B. F. flavescens IFO 3058; Lactobacillus, e.g. B. L. brevis IFO 3345 and Nocardia, e.g. B. N. opaca ATCC 4276.
  • a ⁇ 6 double bond can e.g. B. with a 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)].
  • a 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)].
  • the 2,3,6-trisdehydro compound can also be obtained directly with 2,3-dichloro-5,6-dicyanobenzoquinone or chloranil.
  • Process variant c) leads to 4,6-diene, 1,4-diene and 1,4,6-triene-D homosteroids of the formula I.
  • the lactone ring can be split in accordance with process variant d) in a manner known per se, e.g. B. using a base such as potassium or sodium hydroxide in a solvent, e.g. B. an alcohol such as methanol, ethanol or isopropanol, at a temperature between about 0 ° C and the reflux temperature of the reaction mixture, advantageously at about 50 ° C.
  • a base such as potassium or sodium hydroxide
  • a solvent e.g. B. an alcohol such as methanol, ethanol or isopropanol
  • the salts obtained in this way, corresponding to the base used can be acidified, for. B. by means of hydrochloric acid, are converted into the free acids.
  • the latter can be converted into salts by reaction with suitable bases.
  • Process variant d provides compounds of the formula in which X is hydrogen and Y is hydroxy, and their salts.
  • lactonization of a compound of formula VI (variant e) or a salt thereof can be carried out in a manner known per se, e.g. B. using a strong acid, such as hydrochloric acid, sulfuric acid or p-toluenesulfonic acid, in a solvent, e.g. B. water, an alcohol, such as methanol, or mixtures thereof, at a temperature between about -50 ° and 100 ° C, advantageously at room temperature.
  • a strong acid such as hydrochloric acid, sulfuric acid or p-toluenesulfonic acid
  • the oxidation of a compound of formula VII can, according to Oppenauer, e.g. B. by means of aluminum isopropylate, or with oxidizing agents such as chromium trioxide (z. B. Jones'Reagens), or according to Pfitzner-Moffatt using dimethyl sulfoxide / dicyclohexylcarbodiimide (the d 5- 3-ketone initially obtained is then isomerized to the d 4- 3-ketone must), or be carried out using pyridine / S0 3 .
  • oxidizing agents such as chromium trioxide (z. B. Jones'Reagens)
  • Pfitzner-Moffatt using dimethyl sulfoxide / dicyclohexylcarbodiimide (the d 5- 3-ketone initially obtained is then isomerized to the d 4- 3-ketone must), or be carried out using pyridine / S0 3 .
  • the D-homosteroids of the formula and the salts thereof show pharmacological activity. Among other things, they are diuretically effective and are suitable for blocking the action of aldosterone or deoxycorticosterone acetate and can therefore be used, for example, as potassium-sparing diuretics or for flushing out edema. Approximately 0.1 to 10 mg / kg per day can be used as a dosage guideline.
  • D-homosteroids of the formula according to the invention do not contain a methyl radical in the 6-position.
  • the 6-methyl-D-homosteroids according to the invention are known Considerably superior to 6-unsubstituted D-homosteroids.
  • D-homosteroids of the invention have the formula I (compounds A and B in the test report) a stronger potassium p arende diuretic activity than those known from the German Offenlegungsschrift Nr. 2424752 D-homo steroids (compounds C and D).
  • test substance is administered orally to episiotomized and catheterized dogs in a gelatin capsule. Immediately afterwards, animals were injected with 0.5 ⁇ g / kg aldosterone subcutaneously. The urine of the animals is collected over a period of 6 hours. The Na + / K + ratio calculated from the total excretion is obtained as a measure of the aldosterone antagonism.
  • the compounds of formula I and the salts thereof can be used as medicaments, e.g. B. in the form of pharmaceutical preparations are used, which they or their salts in a mixture with a suitable for enteral or parenteral application organic or inorganic inert carrier material, such as. B. water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. contain.
  • the pharmaceutical preparations can be in solid form, e.g. B. as tablets, dragees, suppositories, capsules; or in liquid form, e.g. B. as solutions, suspensions or emulsions.
  • auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances.
  • the pharmaceuticals can be prepared in a manner known per se by combining the compound of the formula with non-toxic, inert, solid and / or liquid carrier materials which are conventional in such preparations and are suitable for therapeutic administration. B. the above, mixed and optionally brings into the desired shape.
  • This compound can also be obtained by acidifying a solution of potassium 17a-hydroxy-6-methyl-3-oxo-D-homo-17a ⁇ -pregna-4,6,16-triene-21-carboxylate with dilute hydrochloric acid.
  • the solution obtained is mixed with 6 ml of glacial acetic acid, poured onto 1000 ml of water and extracted with 3 ⁇ 400 ml of ether-methylene chloride (4: 1). The organic phases are saturated. Washed sodium chloride solution until neutral, dried with magnesium sulfate and evaporated to dryness.
  • the crude product is purified by chromatography on 100 times the amount of silica gel with methylene chloride-acetone (98: 2). The fractions containing the product are pooled and recrystallized from acetone-hexane.
  • the starting material can be prepared as follows: Dimethylsulfoxonium methylide is converted to 17,20-epoxy-3ß-hydroxy-6-methyl-21-norpregn-5 with 3 ⁇ -hydroxy-6-methyl-androst-5-en-17-one in dimethylsulfoxide -en implemented. The latter is opened with ammonia under pressure to give 20-amino-3 ⁇ , 17-dihydroxy-6-methyl-21-norpregn-5-ene.
  • 3ß-hydroxy-6-methyl-D-homoandrost-5-en-17a-one is obtained, which by bromination with copper II-bromide in boiling methanol and subsequent elimination of hydrogen bromide with calcium carbonate in boiling dimethylacetamide over 17x-bromo 3ß-hydroxy-6-methyl-D-homoandrost-5-en-17a-one is converted into 3ß-hydroxy-6-methyl-D-homoandrosta-5,16-dien-17a-one.
  • a lithium Grignard reaction with 3-bromopropionaldehyde dimethylacetal and subsequent acetylation with acetic anhydride pyridine yield 3 ⁇ -acetoxy-21-dimethylacetal-17a-hydroxy-6-methyl-D-homo-17a ⁇ -pregna-5,16-diene.
  • This acetal is split with an aqueous 70% acetic acid solution to the corresponding aldehyde. This cyclizes spontaneously to 3 ⁇ -acetoxy-6-methyl-D-homo-17a ⁇ -pregna-5,16-diene-21, 17a-carbolactol.
  • a tablet for oral administration can have the following composition:
  • a capsule for oral administration can have the following composition:

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Furan Compounds (AREA)
EP78100302A 1977-07-06 1978-07-04 D-Homosteroide und solche enthaltende Präparate sowie Verfahren zur Herstellung solcher D-Homosteroide Expired EP0000368B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
LU77699A LU77699A1 (de) 1977-07-06 1977-07-06 Verfahren zur herstellung von neuen d-homosteroiden
LU77699 1977-07-06

Publications (2)

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EP0000368A1 EP0000368A1 (de) 1979-01-24
EP0000368B1 true EP0000368B1 (de) 1981-04-29

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EP78100302A Expired EP0000368B1 (de) 1977-07-06 1978-07-04 D-Homosteroide und solche enthaltende Präparate sowie Verfahren zur Herstellung solcher D-Homosteroide

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US (2) US4202823A (enrdf_load_stackoverflow)
EP (1) EP0000368B1 (enrdf_load_stackoverflow)
JP (1) JPS5414959A (enrdf_load_stackoverflow)
AU (1) AU3760378A (enrdf_load_stackoverflow)
DE (2) DE2829403A1 (enrdf_load_stackoverflow)
DK (1) DK304778A (enrdf_load_stackoverflow)
ES (1) ES471470A1 (enrdf_load_stackoverflow)
FI (1) FI782137A7 (enrdf_load_stackoverflow)
FR (1) FR2396767A1 (enrdf_load_stackoverflow)
GB (1) GB2000781A (enrdf_load_stackoverflow)
IL (1) IL55049A0 (enrdf_load_stackoverflow)
IT (1) IT1096965B (enrdf_load_stackoverflow)
LU (1) LU77699A1 (enrdf_load_stackoverflow)
NL (1) NL7805939A (enrdf_load_stackoverflow)
NO (1) NO782349L (enrdf_load_stackoverflow)
PT (1) PT68254A (enrdf_load_stackoverflow)
SE (1) SE7807586L (enrdf_load_stackoverflow)
ZA (1) ZA783731B (enrdf_load_stackoverflow)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3766213A (en) * 1966-04-19 1973-10-16 Hoffmann La Roche Retrosteroid a ring formation
CH601352A5 (enrdf_load_stackoverflow) * 1973-09-26 1978-07-14 Hoffmann La Roche
DE2424752A1 (de) * 1974-05-22 1975-12-04 Schering Ag Verfahren zur herstellung von steroidspiro-lactonen
AT351191B (de) 1976-12-20 1979-07-10 Hoffmann La Roche Verfahren zur herstellung von neuen d-homo- steroiden

Also Published As

Publication number Publication date
NL7805939A (nl) 1979-01-09
FR2396767B1 (enrdf_load_stackoverflow) 1980-07-18
DE2829403A1 (de) 1979-01-25
NO782349L (no) 1979-01-09
IL55049A0 (en) 1978-08-31
DK304778A (da) 1979-01-07
EP0000368A1 (de) 1979-01-24
SE7807586L (sv) 1979-01-07
LU77699A1 (de) 1979-03-26
GB2000781A (en) 1979-01-17
ZA783731B (en) 1979-07-25
JPS5414959A (en) 1979-02-03
PT68254A (en) 1978-08-01
FR2396767A1 (fr) 1979-02-02
US4285880A (en) 1981-08-25
US4202823A (en) 1980-05-13
FI782137A7 (fi) 1979-01-07
ES471470A1 (es) 1979-09-16
IT1096965B (it) 1985-08-26
DE2860642D1 (en) 1981-08-06
JPS6160839B2 (enrdf_load_stackoverflow) 1986-12-23
AU3760378A (en) 1980-01-03
IT7825305A0 (it) 1978-07-04

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