Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
• • 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
  • C07J7/001—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 a keto group
  • C07J7/0015—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 a keto group not substituted in position 17 alfa
  • C07J7/002—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 a keto group not substituted in position 17 alfa not substituted in position 16
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
  • C07J1/0051—Estrane derivatives
  • C07J1/0055—Estrane derivatives not substituted in position 17

Definitions

• the present invention relates to the field of steroid chemistry and in particular to 6-methylated estrogenic steroid derivatives.
• A represents hydrogen or a lower oxoalkyl radical
• B represents hydrogen or a lower oxoalkyl radical or else A is a free or esterified hydroxyl and B is a lower alkyl radical or a lower alkynyl radical
• R 1 represents hydrogen or a lower alkyl radical, and in particular 6-methyl 3,20-dioxo 19-nor pregna 4,6-diene.
• R 2 is a lower alkyl radical having from 1 to 4 carbon atoms
• R 3 is hydrogen, hydroxyl or an OR 5 group in which R 5 is an acyl residue derived from an organic carboxylic, aliphatic or aromatic acid having from 1 to 10 atoms
• R 1 represents hydrogen or a lower alkyl radical
• R 4 represents hydrogen or an acyl residue of an aliphatic or aromatic organic carboxylic acid having from 1 to 10 carbon atoms, and in particular 17 ⁇ -acetoxy 17ot-ethynyl 6-methyl 3-oxo estra
• R 3 represents the acyl residue of an organic carboxylic acid, aliphatic or aromatic, having from 1 to 10 carbon atoms.
• the invention relates to a process for obtaining 3-oxo 6-methyl extra 4,6-diene of formula I A which consists in starting from 3-oxo estra 4-ene to subject the latter to the action of an agent etherifying in an acid medium to form a 3-alkoxy estra 3,5-diene, which is formulated into 3-alkoxy 6-formyl estra 3,5-diene, reduced this by means of a mixed alkali metal hydride to 3-alkoxy 6-hydroxymethyl estra 3,5-diene, dehydrates the latter by treatment in an acid medium to form a 3-oxo 6-methylene estra 4-ene which is isomerized to 3-oxo 6-methyl estra 4, 6-diene by heating in the presence of an isomerization catalyst.
• the invention relates to a process for obtaining 3,20-dioxo 6-methyl 19-nor pregna 4,6-diene of formula I B which consists in subjecting a 3,20-dioxo 19-nor pregna 4-ene to the action of an etherification agent in an acid medium to obtain a 3-alkoxy 20-oxo 19-nor pregna 3,5-diene, treat the latter with a formylating agent to obtain a 3- 6-formyl alkoxy 20-oxo 19-nor pregna 3,5-diene which is reduced to 3-alkxy 6-hydroxymethyl 20-oxo 19-nor pregna 3,5-diene which is reduced to 3-alkoxy 6 -hydroxymethyl 20-oxo 19-nor pregna 3,5-diene by a mixed hydride of alkali metal, dehydrates the latter in an acid medium to form the 3,20-dioxo 6-methylene 19-nor pregna 4-ene which is isomerized to 3.20-dioxo 6-methyl 19
• the invention relates to a process for obtaining 17 ⁇ -acyloxy or 17 ⁇ -hydroxy 17 ⁇ -alkynyl 6-methyl estra 4,6-dienes of general formula I D which consists in subjecting a 3-alkoxy 17-oxo 19 -nor estra 3,5-diene to the action of an etherifying agent to form a 3-alkoxy 17-oxo 19-nor estra 3,5-diene then to a formylating agent under the reaction conditions of Vilsmeier-Hack to form a 3-alkoxy 6-formyl 17-oxo estra 3,5-diene, which is reduced by the action of a mixed alkali metal hydride to the corresponding 6-hydroxymethylated derivative, treats the latter with an aqueous solution of strong acid mineral, to form 3-oxo 6-methylene 17 ⁇ -hydroxy estra 4-ene, isomerizes the latter by heating with an isomerization agent, a 3-oxo 6-methyl 17 ⁇ -hydroxy estra 4, 6-diene which is
• the same compounds can also be obtained by a process which consists in subjecting a 3-oxo 6-methylene 17 ⁇ -acyloxy 17 ⁇ -alkynyl estra 4-ene to the action of an isomerization agent and forming a 3-oxo 6- methyl 17 ⁇ -acyloxy 17 ⁇ -alkynyl estra 4,6-diene.
• the compounds of formula I D can also be obtained according to the invention by a process which consists in subjecting a 17 ⁇ -acyloxy 17 ⁇ -ethynyl 3-oxo estra 4-ene to the action of an agent etherification in an acid medium to obtain a 3-alkyloxy 17 ⁇ -acyloxy 17 ⁇ -ethynyl estra 3,5-diene, treats it with a formylation reagent under the conditions of the Vilsmeier-Hack reaction to form the derivative 6 -formylated which is reduced by means of a mixed hydride of alkali metal to 6-hydroxymethyl derivative, dehydrates the latter in an acid medium to form a 3-oxo 6-methylene 17 ⁇ -acyloxy 17 ⁇ -ethynyl estra 4-ene then isomerized this in the presence of a 3-oxo 6-methyl 17 ⁇ -acyloxy 17 ⁇ -ethynyl estra 4,6-diene isomerization catalyst.
• the invention further extends to obtaining 3,17-dioxo 6-methyl estra 4,6-diene of formula I E by a process which consists in subjecting 3,17-dioxo estra 4-ene to an etherification reagent in an acid medium to form a 3-alkoxy 17-oxo estra 3,5-diene, treats this with a formylation reagent to form 3-alkoxy 17-oxo 6-formyl estra 3,5-diene, reduced this by a mixed hydride of alkali metal to 3-alkoxy 6-hydroxymethyl 17 ⁇ -hydroxy estra 3,5-diene which is dehydrated in an acid medium to 3-oxo 6-methylene 17 ⁇ - hydroxy estra 4-ene, isomerizes it with an isomerization catalyst into 6-methyl 3-oxo 17-hydroxy estra 4,6-diene then if desired reoxides the latter with a metal oxidant to form 3,17-dioxo 6-methyl estra 4,6-diene or else subjects
• the compounds of general formula I are presented for therapeutic purposes in one of the forms which are suitable for parenteral, oral, rectal, percutaneous or permucosal administration.
• the compounds of general formula I are above all precious synthesis intermediates, which allow access to pharmacologically active 6-methyl 19-nor pregna 4,6-dienes such as 17ot-acetpxy 6-methyl 3,20-dioxo 19- nor pregna 4,6-diene, 6-17 ⁇ -dimethyl 3,20-dioxo 19-nor pregna 4,6-diene, 6-17 ⁇ , 21-trimethyl 3,20-dioxo 19-nor pregna 4,6-diene, the gestational and progestomimetic properties of which have already been described (cf. French patent application No. 89.04910 in the name of the applicant and French patent 2,271,833).
• the compounds of general formula I D are converted by hydration then by alkylation to 6-methyl 17 ⁇ -alkyl 3.20-dioxo 19-nor estra 4,6-dienes.
• the 17-oxo 6-methyl estra 4,6-dienes or the estra 4,6-dienes of general formula I E after oxidation are converted by a triphenylethylphosphonium halide to the 17-ethylidenene derivative which by bis-hydroxylation by means of Osmium tetroxide and triethylamine or morpholine N-oxide hydroperoxide leads to 17ot-hydroxy 3.20-dioxo 6-methyl 19-nor pregna 4,6-diene.
• 3,17-dioxo 6-methyl estra 4,6-diene is a synthetic intermediate which allows either by reaction with an alkyl magnesium salt to form a derivative 17 ⁇ -hydroxy 17 ⁇ -alkylated, or by reaction with a salt d 'alkyl triphenyl phosphonium to form an alkylidene derivative which is oxidized to 17 ⁇ -hydroxy derivative 19-nor pregna 20-one, or again by reaction with a metallic acetylide to form a 17 ⁇ -hydroxy derivative 17 ⁇ -ethynylated.
• 17 ⁇ -acyloxy 17 ⁇ -ethynyl 6-methyl estradien-4,6 are useful raw materials for preparing 6,17 ⁇ -dimethyl 19-nor 20-keto pregnadi ⁇ nes-4,6 according to a process which consists in subjecting the derivative 17 ⁇ - 17 ⁇ -ethynylated acyloxy to a hydration reaction in the presence of a mercuric salt and then to treat the 20-keto 17 ⁇ -acyloxy 19-nor pregnane obtained, to the action of a methylating agent after reduction with a metal to form a 17 ⁇ -methyl 20-keto 19-nor pregnanic derivative.
• the dry extract After purification by chomatography on a silica column for chomatography, with elution with Toluene, the dry extract delivers 450 mg of white crystals of 17 ⁇ -ethynyl 17-3-hydroxy 6-methyl estra 4,6-diene.
• Formulation of the Stage I product provides 99% of 6-formylated product, the UV spectrum of which indicates a maximum at 325 nm
• the 6-hydroxy methyl derivative was dehydrated with 2N sulfuric acid in an eth.anol / dimethyl formamide mixture. 84% of crude product is collected.
• the IR spectrum indicates a total absence of band at 3400 cm -1 , the UV spectrum shows a maximum absorption at 263 nm.
• the mixture is brought to reflux for 4 hours, the solvent is evaporated to dryness and the residue is taken up in 50 ml of Toluene and then 1.4 g of potassium terbutylate are added. The mixture is brought to reflux again for 24 h.
• the ether enolization stage is carried out starting from 15 g of 3-oxo estra 4-ene in 39 ml of ethanol and 20 ml of ethyl orthoformate in the presence of 0.06 g of p.toluene acid sulfonic then at the end of 0.8 ml of triethylamine.
• the formylation is carried out with the Vilsmeier reagent (DMP 6 ml, POC131.4 ml) introduced at 0 ° C, under inert gas to a solution of 2 g of 3-ethoxy estra 3,5-diene, in 14 ml DMF. After 15 min, 20 ml of aqueous potassium acetate solution are added, stirring 30 min before filtering to recover 0.9 g (41%) of 3-ethoxy 6-formyl estra 3,5-diene.
• UV: ⁇ max 325 nm ⁇ 14.245
• the mixture of the two alkoxylated products is hydrolyzed with 36 ml of a sulfuric acid solution (2N) in 40 min followed by the addition of 20 ml of an aqueous solution of potassium carbonate (0.44 g / ml) , the 3-ceto 6-methylenic derivative is obtained.
• the isomerization of 5 g of 6-methylenic product is carried out with 125 ml of methanol, 2.5 g of paladiated charcoal and 30 minutes of reflux.
• the product obtained is chromatographed with methylene chloride on 150 g of silica to obtain 2 g (40%) of 6-methylated derivative which is crystallized from methanol.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Steroid Compounds (AREA)

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• 1989
  • 1989-05-24 FR FR8906790A patent/FR2647452A1/fr active Pending
• 1990
  • 1990-05-21 MA MA22117A patent/MA21851A1/fr unknown
  • 1990-05-23 JP JP2508397A patent/JPH04503362A/ja active Pending
  • 1990-05-23 GR GR900100394A patent/GR900100394A/el unknown
  • 1990-05-23 AU AU57426/90A patent/AU643218B2/en not_active Ceased
  • 1990-05-23 TN TNTNSN90066A patent/TNSN90066A1/fr unknown
  • 1990-05-23 HU HU905221A patent/HU209590B/hu not_active IP Right Cessation
  • 1990-05-23 PT PT94134A patent/PT94134A/pt not_active Application Discontinuation
  • 1990-05-23 EP EP19900908555 patent/EP0431107A1/de not_active Withdrawn
  • 1990-05-23 WO PCT/FR1990/000363 patent/WO1990015067A2/fr not_active Application Discontinuation
• 1991
  • 1991-01-23 FI FI910351A patent/FI910351A0/fi not_active Application Discontinuation
  • 1991-01-23 KR KR1019910700091A patent/KR920701231A/ko not_active Application Discontinuation

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