US3920703A - D-homosteroid lactones - Google Patents

D-homosteroid lactones Download PDF

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Publication number
US3920703A
US3920703A US508127A US50812774A US3920703A US 3920703 A US3920703 A US 3920703A US 508127 A US508127 A US 508127A US 50812774 A US50812774 A US 50812774A US 3920703 A US3920703 A US 3920703A
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Prior art keywords
homo
lactone
oxo
compound
homosteroid
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Leo Alig
Andor Furst
Peter Keller
Marcel Muller
Ulrich Kerb
Rudolf Wiechert
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F Hoffmann La Roche AG
Hoffmann La Roche Inc
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F Hoffmann La Roche AG
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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
    • 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

Definitions

  • R represents a hydrogen atom or a methyl group when a single bond is I present in the 1,2-position or a methyl group when a double bond is present in the 1,2-position and R represents a hydrogen atom or a mercapto, acylthio or alkylthio group when a single bond is present in the 6,7-position or a hydrogen atom when a double bond is present in the 6,7-position.
  • acyl denotes the residue of a saturated or unsaturated aliphatic carboxylic acid, a
  • cycloaliphatic, an araliphatic or an aromatic carboxylic acid preferably containing up to 15 carbon atoms.
  • acids are formic acid, acetic acid, pivalic acid, propionic acid, butyric acid, caproic acid, oenanthic acid, undecylenic acid, oleic acid, cyclohexylpropionic acid, cyclopentylpropionic acid, phenylacetic acid and benzoic acid.
  • the preferred acyl groups are formic acid, acetic acid, pivalic acid, propionic acid, butyric acid, caproic acid, oenanthic acid, undecylenic acid, oleic acid, cyclohexylpropionic acid, cyclopentylpropionic acid, phenylacetic acid and benzoic acid.
  • the preferred acyl groups are formic acid, acetic acid, pivalic acid, propionic acid, butyric acid, caproic acid,
  • acyl groups containing from 1 m7 carbon atoms.
  • alkyl includes aliphatic, cycloaliphatic and class of D-homosteroids of formula I comprises those in which a double bond is present in the 16,17-position; for example, 7a-acetylthio-3-oxo-D-homo-2l,24 dinor-l7aoz-chola-4,16-diene-23,17a-lactone.
  • Examples of D-homosteroids of formula I in which R represents a hydrogen atom are. 3-oxo-19,21,24-trinor-D-,.
  • the D-homosteroids of formula I hereinbefore are manufactured by a. oxidising the 3-hydroxy-A grouping in a D-homos-' teroid of the general formula 3-oxo-19,21,24-v
  • R represents a methyl group, also to. the ia-keto-A grouping, or
  • oxidation of a D-homosteroid of formula II in ac-' cordance with embodiment a) of the process can be carried out according to the Oppenauer procedure (e.g. by means of aluminium isopropylate), or using an oxidising agent such as chromium trioxide (e.g., Jones reagent), or according to the Pfitzner-Moffatt procedure using dimethyl sulphoxide/dicyclohexylcarbodiimide (the initially obtained A -3-ketone requiring subsequent isomerisation to the A -3-ketone), or using pyridine/sulphur trioxide.
  • an oxidising agent such as chromium trioxide (e.g., Jones reagent)
  • Pfitzner-Moffatt procedure using dimethyl sulphoxide/dicyclohexylcarbodiimide (the initially obtained A -3-ketone requiring subsequent isomerisation to the A -3-ketone), or using pyridine/sulphur
  • the 1,2-dehydrogenation of a D-homosteroid of formula III in accordance with embodiment b) of the process can be carried'out in a manner known per se; for example, in a microbiological manner or using a dehydrogenating agent such as selenium dioxide, 2,3- dichloro-5,6-dicyano-benzoquinone, chloranil, thallium triacetate or lead tetraacetate.
  • Suitable microorganisms for the 1,2-dehydrogenation 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 [F0 3505), Flavobacterium (e.g. F. flavescens IFO 3058), Lactobacillus (e.g.-L. brevis [F0 3345) and Nocardia (e.g. N. opaca ATCC 4276).
  • Pseudomonas e.g. P. aeruginosa [F0 3505
  • Flavobacterium e.g. F. flavescens IFO 3058
  • Lactobacillus e.g.-L. brevis [F0 3345
  • Nocardia e.g. N. opaca ATCC 4276.
  • a -double bond into a 6,7- saturated D-homosteroid of formula 111 can be carried out, for example, using a substituted-benzoquinone such as chloranil [see J. Am. Chem. Soc. 82, 4293 (1960); 81, 5951 (1959)] or using 2,3-dichloro-5,6- dicyano-benzoquinone or using manganese dioxide [see J. Am. Chem. Soc. 75, 5932 (1953)].
  • a substituted-benzoquinone such as chloranil [see J. Am. Chem. Soc. 82, 4293 (1960); 81, 5951 (1959)] or using 2,3-dichloro-5,6- dicyano-benzoquinone or using manganese dioxide [see J. Am. Chem. Soc. 75, 5932 (1953)].
  • a 1,4,6-trisdehydro D-homosteroid can be obtained directly from a 6,7-saturated D-homosteroid of formula III in which R represents a methyl group using 2,3- dichloro-S,6-dicyano-benzoquinone or chloranil.
  • the isomerisation of a D-homosteroid of formula IV in accordance with embodiment c) of the process can be carried out in a manner known per se; for example, by treatment with acidic or basic agents, suitably by warming with mineral acids such as 6-N hydrochloric acid or with an alkali such as aqueous-alcoholic sodium hydroxide or potassium hydroxide at room temperature.
  • the introduction of a substituent denoted by R into a D-homosteroid of formula V in accordance with embodiment d) can be carried out in a manner known per se by reaction with hydrogen sulphide, a mercaptan or a thiocarboxylic acid.
  • the reaction can be carried out in an inert solvent such as an ether (e.g. dioxane or tetrahydrofuran), an alcohol (e.g. methanol or ethanol) or a chlorinated hydrocarbon (e.g. chloroform).
  • the reagent e.g. the thiocarboxylic acid
  • the D-homosteroid starting materials can be prepared as follows:
  • a Grignard compound is prepared from l7aa-ethynyl-3B, 1 7a-dihydroxy-D-homo-androst-5-ene in a manner known per se and is converted into the propiolic acid derivative with carbon dioxide.
  • the sodium salt of the thus-obtained propiolic acid derivative is hydrogenated using palladium-on-carbon in aqueous ethanol until one mol equivalent of hydrogen has been taken up.
  • the resulting acrylic acid derivative lactonises spontaneously and is hydrogenated with the uptake of a second mol equivalent of hydrogen to give a D-homosteroid of formula II in which a single bond is present in the 16,17-position and in which R represents a methyl group.
  • D-homosteroid starting materials of formula II in which a single bond is present in the 16,17-position and in which R represents a hydrogen atom can be prepared as follows:
  • D-homooestrone methyl ether is reduced according to the Birch procedure to give D-homo-2,5( l0)-oestradine-3,17aB-diol-3-methyl ether, this is oxidised (e.g. according to the Pfitzner-Moffatt procedure) to the l7a-ketone and the ketone is reacted with an ethynyl- Grignard compound.
  • Weak acidic hydrolysis thereof e.g.
  • D-homosteroid starting materials which contain a double bond in the 16,17-position are expediently prepared by introducing a C unit at the l7a-position of a D-homo-S, l 6-androstadien-3/3-oll 7a-one (for the preparation of starting materials in which R represents a methyl group) in a manner known per se; for example, by reaction with a Grignard reagent such as or, preferably, with the corresponding lithium compound, converting the protected-aldehyde function into an acid function and lactonising the resulting product by acidification.
  • a Grignard reagent such as or, preferably, with the corresponding lithium compound
  • D-homosteroid starting materials in which a double bond is present in the 16,17-position and in which R represents a hydrogen atom can be prepared by introducing a 16,17-double bond into D-homooestrone methyl ether by bromination and dehydrobromination and then, in a manner analogous to that described earlier, carrying out a Birch reduction on the aromatic ring, oxidising a l7a-hydroxy group, introducing a propionic acid sidechain by means of a Grignard reaction, or condensation with propiolic acid in the presence of potassium hydroxide, lactonising the propionic acid side-chain and hydrolysing the 3-ether group.
  • the D-homosteroids of formula I hereinbefore possess pharmacological activity, their activity on the mineral reserves of the body being of particular interest. They may be used, inter alia, for flushing oedemas which are caused, for example, by heart insufficiencies.
  • the D-homosteroids of formula I hereinbefore may be used as medicaments; for example, in the form of pharmaceutical preparations which contain them in association with a compatible pharmaceutical carrier.
  • This carrier can be an inert organic or inorganic carrier material suitable for enteral, percutaneous or parenteral administration such as, for example, water, gelatine, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkyleneglycols, petroleum jelly and the like.
  • the pharmaceutical preparations can be made up in a solid form (e.g. as tablets, dragees, suppositories or capsules), in a semi-solid form (e.g. as salves) or in a liquid form (e.g.
  • the pharmaceutical preparations may be sterilised and/or may contain adjuvants such as preservatives, stabilisers, wetting agents, emulsifiers, salts for varying the osmotic pressure or buffers.
  • the pharmaceutical preparations may also contain therapeutically valuable substances other than the D-homosteroids provided by the present invention.
  • the pharmaceutical preparations can be prepared in a manner known per se by mixing a D-homosteroid of formula I with non-toxic, solid and/or liquid carrier materials which are customary in pharmaceutical preparations and which are suitable for therapeutic administration (e.g. those carrier materials mentioned hereinbefore) and, if desired, transforming the mixture into the desired pharmaceutical dosage form.
  • the pharmaceutical preparations can be administered in a'dosage range similar to that required for structurally related steroids having a five-membered D-ring.
  • EXAMPLE 1 80 ml of solvent were distilled off while stirring and gassing with argon from a mixture of 12.50 g of 3B- hydroxy-D-homo-2 l ,24-dinorl 7aa-chol-5-ene- 23,17a-lactone, 160 ml of cyclohexanone and 400 ml of toluene. 15.0 g of aluminium tertbutylate were then added and the mixture was heated for 2 hours under reflux and under a water-separator. For the working-up, the mixture was evaporated to a volume of ca 200 ml, poured on to ice-water/dilute hydrochloric acid and extracted with methylene chloride.
  • the starting material was prepared as follows:
  • 3B-Acetoxy-1 7a-ethynyl- 1 7-hydroxy-D-homoandrost-S-ene was converted using, butyl-lithium into the lithium salt which was reacted with carbon dioxide to give 3B,l7aB-dihydroxy-D-homopregn- 5-en-20-yne-2l-carboxylic acid of melting point 194196C; [01],, l23.
  • This acid was catalytically hydrogenated in alkaline solution and, after acidification, yielded 3B-hydroxy-D-homo-21,24- dinor-17aa-chola-5 ,20-diene-23,1 7a-lactone of melting point 205-207C; [01],, 43.
  • This lactone was catalytically hydrogenated using palladium-on-carbon in ethanol to give 3 B-hydroxy-D- homo-21 ,24-dinor-17aa-chol-5-ene-23,l7a-lactone of melting point 240243C [01],, 99 (0 0:1 in dioxane).
  • EXAMPLE 3 A solution of 0.50 g of 3-oxo-l9-nor-D-homo-21,24- dinor-l7aa-chol-5(10)-ene-23,17a-lactone in 50 m1 of dioxane containing 2% HCl was held at room temperature for 2 hours. For the working-up, the mixture was poured on to ice-water and extracted with methylene' chloride. The methylene chloride extract was washed neutral with water, dried over sodium sulphate and evaporated in vacuo.
  • the starting material was prepared as follows:
  • D-homooestrone' methyl ether was reduced according to the Birch procedure and subsequently oxidised according to the Pfitzner-Moffatt procedure to give 3- methoxy-D-homooestra-2 ,5 10 )-dien- 1 7a-one.
  • Partial catalytic hydrogenation of this carboxylic acid in alkaline solution and subsequent treatment with oxalic acid in dioxane yielded 3-oxo-19-nor-D-homo-21,24-dinorl7a0z-chola-5( l0),20-diene-23,17a-lactone which was converted by selective catalytic hydrogenation into 3- oxo-l9-nor-D-homo-21,24-dinor-l7aa-chol- 5(10)-ene-23,17a-lactone.
  • EXAMPLE 4 A solution of 1.0 g of 3-oxo-D-homo-2l,24-dinorl7aa-chola-4,6-diene-23,17a-lactone in 6 ml of thioacetic acid was held at room temperature for 3 hours. The mixture was poured on to ice-water and extracted with ether. The ether extract was washed with dilute sodium hydroxide and water, dried over sodium sulphate and evaporated in vacuo. The residue was chrmatographed over silica gel.
  • EXAMPLE 7 5.0 g of 3B-hydroxy-D-homo-21,24-dinor-l7aachola-5,l6-diene-23,l7a-lactone were dissolved in ml of dimethyl sulphoxide and 25 ml of benzene. 1.2 ml of pyridine and 0.6 ml of trifluoroacetic acid were added while stirring and gassingwith argon. 7.6 g of N,N-dicyclohexylcarbodiimide were then added and the mixture was stirred overnight at room temperature.
  • the starting material was prepared as follows:
  • 3,8-Acetoxy-D-homo-androst-5-en-l 7a-one was brominated with CuBr and, by subsequent treatment with calcium carbonate in dimethylacetamide and acetylation with acetic anhydride/pyridine, converted into 33- acetoxy-D-homoandrosta-S, l 6-dien-l 7a-one.
  • This compound was converted, by treatment with 3B-ethylenedioxy-n-propyl-magnesium bromide and subsequent acetylation, into 3B-acetoxy-l7aa-(3,3'- ethylenedioxa-propyl l 7a-hydroxy-D-homoandrost- 5-ene.
  • EXAMPLE 8 In a manner analogous to that described in Example 5,- from 3B-hydrox y-D-homo-2 l ,24-dinor- 1 7aa-chola- 5,l6-diene-2'3.l7a-lactone there was obtained 3-oxo- D-homo-2 l ,24-dinorl 7aa-chola-4,6, l 6-triene- 23,27a-lactone of melting point 2l42l4.5C.
  • a D-homosteroid of claim 2 wherein a single bond is presentin the 1,2-position and a double bond is present in the 16,17-position.
  • a compound of the formula wherein the broken line in l6,l7-position denotes an optional bond.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Steroid Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US508127A 1973-09-26 1974-09-23 D-homosteroid lactones Expired - Lifetime US3920703A (en)

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JP (1) JPS5058054A (enrdf_load_stackoverflow)
AR (2) AR207230A1 (enrdf_load_stackoverflow)
AT (1) AT337915B (enrdf_load_stackoverflow)
BE (1) BE820303A (enrdf_load_stackoverflow)
CA (1) CA1025435A (enrdf_load_stackoverflow)
CH (1) CH601352A5 (enrdf_load_stackoverflow)
CS (1) CS178930B2 (enrdf_load_stackoverflow)
DD (1) DD115492A5 (enrdf_load_stackoverflow)
DE (1) DE2445783A1 (enrdf_load_stackoverflow)
DK (1) DK135723B (enrdf_load_stackoverflow)
EG (1) EG11189A (enrdf_load_stackoverflow)
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FI (1) FI53709C (enrdf_load_stackoverflow)
FR (1) FR2244497B1 (enrdf_load_stackoverflow)
GB (1) GB1450884A (enrdf_load_stackoverflow)
HU (1) HU172656B (enrdf_load_stackoverflow)
IE (1) IE39913B1 (enrdf_load_stackoverflow)
IL (1) IL45483A (enrdf_load_stackoverflow)
LU (1) LU70980A1 (enrdf_load_stackoverflow)
NL (1) NL7411617A (enrdf_load_stackoverflow)
NO (1) NO140305C (enrdf_load_stackoverflow)
PH (1) PH10616A (enrdf_load_stackoverflow)
PL (2) PL92396B1 (enrdf_load_stackoverflow)
SE (1) SE7411948L (enrdf_load_stackoverflow)
SU (2) SU612637A3 (enrdf_load_stackoverflow)
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4155918A (en) * 1976-10-28 1979-05-22 Hoffmann-La Roche Inc. Novel D-homosteroids
US4202823A (en) * 1977-07-06 1980-05-13 Hoffmann-La Roche Inc. D-Homopregnanes
US4492797A (en) * 1979-02-23 1985-01-08 Hoffmann-La Roche Inc. deA-steroids
US4578475A (en) * 1983-02-11 1986-03-25 Hoffman-La Roche Inc. Novel D-homosteroids

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2652761C2 (de) * 1976-11-16 1985-11-21 Schering AG, 1000 Berlin und 4709 Bergkamen 15,16-Methylen-Spirolactone, Verfahren zu deren Herstellung und diese enthaltende Arzneimittel
AT351191B (de) * 1976-12-20 1979-07-10 Hoffmann La Roche Verfahren zur herstellung von neuen d-homo- steroiden
DE3461090D1 (en) * 1983-02-18 1986-12-04 Schering Ag 11-beta-aryl-estradienes, process for their preparation and pharmaceutical compositions containing them

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3758508A (en) * 1964-09-29 1973-09-11 Hoffmann La Roche Ted derivatives thereof process for the preparation of desaandrostanes pregnanes and unsatura

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3758508A (en) * 1964-09-29 1973-09-11 Hoffmann La Roche Ted derivatives thereof process for the preparation of desaandrostanes pregnanes and unsatura

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4155918A (en) * 1976-10-28 1979-05-22 Hoffmann-La Roche Inc. Novel D-homosteroids
US4202823A (en) * 1977-07-06 1980-05-13 Hoffmann-La Roche Inc. D-Homopregnanes
US4285880A (en) * 1977-07-06 1981-08-25 Hoffmann-La Roche Inc. D-Homopregnanes
US4492797A (en) * 1979-02-23 1985-01-08 Hoffmann-La Roche Inc. deA-steroids
US4578475A (en) * 1983-02-11 1986-03-25 Hoffman-La Roche Inc. Novel D-homosteroids

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ES430369A1 (es) 1976-09-16
AT337915B (de) 1977-07-25
FI276674A7 (enrdf_load_stackoverflow) 1975-03-27
EG11189A (en) 1977-01-31
FI53709B (enrdf_load_stackoverflow) 1978-03-31
NO140305B (no) 1979-04-30
IE39913B1 (en) 1979-01-31
JPS5058054A (enrdf_load_stackoverflow) 1975-05-20
FI53709C (fi) 1978-07-10
CS178930B2 (en) 1977-10-31
GB1450884A (en) 1976-09-29
LU70980A1 (enrdf_load_stackoverflow) 1976-08-19
BE820303A (fr) 1975-03-25
ZA745197B (en) 1975-09-24
DK135723B (da) 1977-06-13
AR207230A1 (es) 1976-09-22
ES437101A1 (es) 1977-01-16
ES437100A1 (es) 1977-01-16
CH601352A5 (enrdf_load_stackoverflow) 1978-07-14
ATA771874A (de) 1976-11-15
AR206632A1 (es) 1976-08-06
DK504574A (enrdf_load_stackoverflow) 1975-06-02
NO140305C (no) 1979-08-08
PL92396B1 (enrdf_load_stackoverflow) 1977-04-30
IL45483A0 (en) 1974-11-29
IE39913L (en) 1975-03-26
FR2244497B1 (enrdf_load_stackoverflow) 1977-11-04
HU172656B (hu) 1978-11-28
SU626706A3 (ru) 1978-09-30
SU612637A3 (ru) 1978-06-25
NL7411617A (nl) 1975-04-01
SE7411948L (sv) 1975-03-27
ES437099A1 (es) 1977-01-16
PH10616A (en) 1977-07-19
CA1025435A (en) 1978-01-31
DK135723C (enrdf_load_stackoverflow) 1977-11-14
DE2445783A1 (de) 1975-04-03
PL94256B1 (enrdf_load_stackoverflow) 1977-07-30
NO743467L (enrdf_load_stackoverflow) 1975-04-28
AU7247974A (en) 1976-02-19
FR2244497A1 (enrdf_load_stackoverflow) 1975-04-18
IL45483A (en) 1977-12-30
DD115492A5 (enrdf_load_stackoverflow) 1975-10-05

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