US3138588A - 17-ketals of estrone and derivatives thereof - Google Patents

17-ketals of estrone and derivatives thereof Download PDF

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US3138588A
US3138588A US219135A US21913562A US3138588A US 3138588 A US3138588 A US 3138588A US 219135 A US219135 A US 219135A US 21913562 A US21913562 A US 21913562A US 3138588 A US3138588 A US 3138588A
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estrone
triene
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general

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  • the present invention relates in general to certain new and novel 17-ketals of estrone, 3-substituted ethers and esters thereof, methods of preparing and pharmaceutical preparations containing the same.
  • novel compounds of the invention may be considered by reference to the general structure:
  • R represents a substituent selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, cycloalkyl, lower aralkyl, and acyl
  • W represents a member selected from the group consisting of alkylenedioxyme'thylene, alkylenethioxymethylene and alkylenedithiomethylene, with the provision that when W is alkylenethioxymethylene R must be other than hydrogen; and if alkyl must contain at least 2 carbon atoms therein when W is alkylenedioxymethylene.
  • lower alkyl is intended to refer to those alkyl groups having from 1 to about 20 carbon atoms and more particularly to those having less than 10 carbon atoms.
  • the alkyl group may be normal or branched in structure, although the normal chain is generally preferred. Some examples of these would be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, octyl, dodecyl, and cetyl, to name a few.
  • lower cycloalkyl refers to that substituent wherein the carbon atoms are joined in a carbocyclic ring which is generally 5 or 6 membered, but which may contain a smaller or larger number of carbon atoms subject to the practical limit of stability of such structures.
  • the term lower aralkyl as employed herein refers in general to an alkyl substituted aromatic ring structure, which alkyl group may contain up to about 20 carbon atoms.
  • An example of this type of substituent would be for instance benzyl, phenylethyl, phenylisopropyl, and the like.
  • acyl refers to a substituent derived from a mono-, di-, or poly-carboxylic organic acid which may be saturated or unsaturated. These radicals are, of course, obtained from any suitable organic acid by removal of a hydroxyl group therefrom. Such acyl radicals as the alkanoyl radicals acetyl and propionyl derived from acetic and propionic acids respectively and the aryoyl radical benzoyl derived from benzoic acid would therefore serve as examples of this type of substituent.
  • the ketal substituent present as W in the l7-position of this novel class of compounds is considered to be an essential element of such structures. It is intended by the definition of alkylenedioxymethylene, alkylenethioxymethylene and alkylenedithiomethylene as employed herein to define W to embrace any and all forms of such ketals which can contain up to about 10 carbon atoms but preferably about 2 to 6 carbon atoms therein. These ketals can be of the closed or open chain type, both of which would behave in a similar manner.
  • alkylenethioxymethylene involves those ketal substituents 3,138,588 Patented June 23, 1964 ice.
  • estrone or 3-substituted estrone represented by structure (I) is reacted with a mole equivalent quantity of a suitable ketalizing agent such as an alkylene glycol and acid combination such as p-toluenesulfonic acid or polyphosphoric or the like in an inert solvent at the reflux temperature of the solvent.
  • a suitable ketalizing agent such as an alkylene glycol and acid combination such as p-toluenesulfonic acid or polyphosphoric or the like
  • the corresponding 17-ketal (II) is obtained which is then treated with a suitable alkylating, alkenylating, etc. agent to transform the hydroxy group in the 3-position to a corresponding 3-substituent as above defined for structure (III).
  • the 17-ketone to be ketalized is contacted with the ketal of another carbonyl compound such as the ethylene ketal of acetone, methylethylketone, mesityl oxide or the like in the presence of an acidic catalyst to effect a transfer of the ketal function from the latter compound to the former one.
  • another carbonyl compound such as the ethylene ketal of acetone, methylethylketone, mesityl oxide or the like
  • This reaction may be conducted either in the presence or absence of heating as specific conditions dictate.
  • the present invention also comprehends the preparation of so-called open chain 17-ketals wherein the carbon atoms attached to the oxygen or sulfur atoms are not in fact joined together.
  • the preparation of compounds such as these will become clear to those skilled in the art after consideration of the foregoing disclosure.
  • the compounds of the invention are useful in the field of experimental pharmacology as well as being valuable as intermediates for further steroid synthesis in preparing new steroidal compounds.
  • many of the compounds of the invention have been found to demonstrate high antilipemic properties coupled with low feminizing action.
  • the compounds are useful for their general hormonal effect, particularly in the female.
  • estrogens such as female hypogonadism, amenorrhea, dysmenorrhea, metrorrhagia, ovulation block and contraception, pregnancy maintenance, Mteriosclerosis, osteoporosis, menopausal symptoms, infertility, regulation of water balance, functional uterine bleeding, and the like.
  • novel compounds of the invention when contemplated for use in pharmaceutical products may be employed in combination, if desired, with a large number of compatible diluents, carriers and the like to form a pharmaceutical composition.
  • suitable diluents, carriers and the like may be used where injectables are to be prepared.
  • Glycerine or the like may be used where a syrup is to be used to administer the compound.
  • Carboxymethylcellulose, starches, sugars and the like may be employed where tablets or powders are to be employed as a means of administration.
  • the dosage of the compounds will vary with the severity of the ailment and in general can vary from 0.5 to 100 nag/kilo of body weight per day depending upon the many factors of the case involved.
  • EXAMPLE 2 1 7,1 7-EthyIenethi0xyeszra-1,3,5(10)-Trien-3-Ol Reflux for 4 hours a solution of 10.0 g. (0.037 mole) estrone and 0.6 g. of p-toluenesulfonic acid monohydrate in 10 ml. of 2-mercaptoethanol and 1500 ml. of benzene with continuous separation of water. Cool the solution and wash with an aqueous sodium bicarbonate solution. Dry the organic layer over anhydrous magnesium sulfate and evaporate in vacuo. The crystalline material should Weigh 11.0 g. M.P. 157. Recrystallize from acetonitrile to give material which exhibits M.P.
  • EXAMPLE 3 1 7,1 7-Eethylenethioxy-3 Methoxyestra-I ,3 ,5 (1 0 -T riene
  • EXAMPLE 4 1 7 ,1 7-Etlzyleneditlzi0estra-1,3,5 (10) -Trien-3-Ol Stir and cool to 5 3. mixture of 5.0 g. (0.019 mole) estrone, 5.05 ml. (0.06 mole) of ethanedithiol and ml. chloroform. Slowly bubble hydrogen chloride into this cold mixture for 3.5 hours. During this time, the steroid will gradually dissolve. Evaporate the solution in vacuo. The crystalline material should exhibit M.P. 146.
  • EXAMPLE 6 3-Eth0xy-17,17-Ethylenedioxyestra-1,3,5(10)-Triene Reflux a solution of 700 mg. of the estrone ethyl ether in 70 ml. of benzene containing 120 mg. of p-toluenesulfonic acid monohydrate for 26 hours, and remove water via a Dean-Stark tube. Cool the mixture, wash with saturated sodium bicarbonate solution, then with Water, and evaporate the benzene solution. The residue should weigh 800 mg., M.P. 90-92". Recrystallize from methanol to yield 700 mg. of the ketal, M.P. 92-93;
  • EXAMPLE 9 3-A cetoxy-I 7,1 7-Ethylenedioxyestra-1 ,3,5 (10 -Triene Keep overnight in pyridine (25 cc.) containing acetic anhydride (.35 g.) 17,17-ethylenedioxyestra-1,3,5(10)- trien-3-ol (1 g.), the compound of Example 1. The next day remove the solvent in vacuo and recrystallize the residue from methanol to obtain the 3-acetoxy-17,17- ethylenedioxyestra41,3 ,5 10) -triene.
  • EXAMPLE 12 17,1 7-Ethylenethi0xy-3-Benzy[oxyestra-1,3,5 (10)-Triene Reflux for about 4 hours a solution of 5.0 g. of estrone benzyl ether and 0.3 g. of p-toluenesulfonic acid monohydrate in 5 ml. of 2-mercaptoethanol and 800 ml. of benzene, with continuous separation of water. Cool the solution, wash with an aqueous sodium bicarbonate solution. Dry the organic layer over magnesium sulfate and evaporate in vacuo to obtain the product of this example.
  • R represents a substituent selected from the group consisting of lower alkyl, lower alkenyl, lower cycloalkyl of up to 6 carbon atoms, benzyl, lower alkanoyl and benzoyl; and W represents a member selected from the group consisting of lower alkylenedioxymethylene of up to 6 carbon atoms, lower alkylenedithiomethylene of up to 6 carbon atoms and lower alkylenethioxymethylene of up to 6 carbon atoms, provided that when W is alkylenedioxymethylene R represents a lower alkyl group containing at least 2 carbon atoms.
  • R is lower alkyl and W is ethylenedioxymethylene.
  • R is lower alkenyl and W is ethylenedioxymethylene.
  • R is allyl and W is lower alkylenedioxymethylene of up to 6 carbon atoms.

Description

United States Patent 3,138,588 17-KETALS 0F ESTRONE AND DERIVATIVES THEREOF Herchel Smith, Wayne, Pa., assignor to American Home Products Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Aug. 24, 1962, Ser. No. 219,135 10 Claims. (Cl. 260-239.5)
The present invention relates in general to certain new and novel 17-ketals of estrone, 3-substituted ethers and esters thereof, methods of preparing and pharmaceutical preparations containing the same.
The novel compounds of the invention may be considered by reference to the general structure:
wherein R represents a substituent selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, cycloalkyl, lower aralkyl, and acyl; and W represents a member selected from the group consisting of alkylenedioxyme'thylene, alkylenethioxymethylene and alkylenedithiomethylene, with the provision that when W is alkylenethioxymethylene R must be other than hydrogen; and if alkyl must contain at least 2 carbon atoms therein when W is alkylenedioxymethylene.
In the above definition of the general class of compounds of the invention, the term lower alkyl is intended to refer to those alkyl groups having from 1 to about 20 carbon atoms and more particularly to those having less than 10 carbon atoms. The alkyl group may be normal or branched in structure, although the normal chain is generally preferred. Some examples of these would be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, octyl, dodecyl, and cetyl, to name a few. The term lower cycloalkyl refers to that substituent wherein the carbon atoms are joined in a carbocyclic ring which is generally 5 or 6 membered, but which may contain a smaller or larger number of carbon atoms subject to the practical limit of stability of such structures. The term lower aralkyl as employed herein refers in general to an alkyl substituted aromatic ring structure, which alkyl group may contain up to about 20 carbon atoms. An example of this type of substituent would be for instance benzyl, phenylethyl, phenylisopropyl, and the like. The term acyl as employed herein refers to a substituent derived from a mono-, di-, or poly-carboxylic organic acid which may be saturated or unsaturated. These radicals are, of course, obtained from any suitable organic acid by removal of a hydroxyl group therefrom. Such acyl radicals as the alkanoyl radicals acetyl and propionyl derived from acetic and propionic acids respectively and the aryoyl radical benzoyl derived from benzoic acid would therefore serve as examples of this type of substituent.
The ketal substituent present as W in the l7-position of this novel class of compounds is considered to be an essential element of such structures. It is intended by the definition of alkylenedioxymethylene, alkylenethioxymethylene and alkylenedithiomethylene as employed herein to define W to embrace any and all forms of such ketals which can contain up to about 10 carbon atoms but preferably about 2 to 6 carbon atoms therein. These ketals can be of the closed or open chain type, both of which would behave in a similar manner. The term alkylenethioxymethylene involves those ketal substituents 3,138,588 Patented June 23, 1964 ice.
c we -(U. r ill In the above reaction the known compound estrone (or 3-substituted estrone) represented by structure (I) is reacted with a mole equivalent quantity of a suitable ketalizing agent such as an alkylene glycol and acid combination such as p-toluenesulfonic acid or polyphosphoric or the like in an inert solvent at the reflux temperature of the solvent. The corresponding 17-ketal (II) is obtained which is then treated with a suitable alkylating, alkenylating, etc. agent to transform the hydroxy group in the 3-position to a corresponding 3-substituent as above defined for structure (III).
In this method of preparation in the above reaction schemes where it is desired to prepare the 17-substituted hemithioketal instead of the alkylenedioxy type a reagent such as thioethanol is substituted for alkylene glycol in the ketalizing step of the synthesis. In the same manner where the dithioketal is desired, a reagent such as ethanedithiol is substituted for the alkylene glycol employed in the ketalizing steps. As an alternative and generally more direct method of preparation the 3-ether or ester or estrone is directly ketalized to the 17-ketal in the presence of an inert solvent such as benzene, chloroform, pyridine, etc. at a reaction temperature limited only by the reflux temperature of the solvent over a period of from about 2 to 24 hours duration to complete ketalization In the preparation of the l7-ketals of the invention as illustrated above only one of a plurality of possible methods of ketalization has been disclosed. It should be understood that within the general framework of the invention other alternative means of ketal formation may be employed if desired. For instance the process of 17- ketalization to form these novel compounds may be carried out by an exchange reaction which is known as exchange ketalization. In this method the 17-ketone to be ketalized is contacted with the ketal of another carbonyl compound such as the ethylene ketal of acetone, methylethylketone, mesityl oxide or the like in the presence of an acidic catalyst to effect a transfer of the ketal function from the latter compound to the former one.
This reaction may be conducted either in the presence or absence of heating as specific conditions dictate.
It should further be noted that the present invention also comprehends the preparation of so-called open chain 17-ketals wherein the carbon atoms attached to the oxygen or sulfur atoms are not in fact joined together. However, the preparation of compounds such as these will become clear to those skilled in the art after consideration of the foregoing disclosure.
The compounds of the invention are useful in the field of experimental pharmacology as well as being valuable as intermediates for further steroid synthesis in preparing new steroidal compounds. In addition, many of the compounds of the invention have been found to demonstrate high antilipemic properties coupled with low feminizing action. Also, besides having capacity to regulate blood lipids, the compounds are useful for their general hormonal effect, particularly in the female. Therefore many of the compounds would be expected to exhibit utility in those areas where estrogens are employed, such as female hypogonadism, amenorrhea, dysmenorrhea, metrorrhagia, ovulation block and contraception, pregnancy maintenance, Mteriosclerosis, osteoporosis, menopausal symptoms, infertility, regulation of water balance, functional uterine bleeding, and the like.
The novel compounds of the invention when contemplated for use in pharmaceutical products may be employed in combination, if desired, with a large number of compatible diluents, carriers and the like to form a pharmaceutical composition. Such liquid carriers as mineral oil or a lower aliphatic alcohol may be used where injectables are to be prepared. Glycerine or the like may be used where a syrup is to be used to administer the compound. Carboxymethylcellulose, starches, sugars and the like may be employed where tablets or powders are to be employed as a means of administration. The dosage of the compounds will vary with the severity of the ailment and in general can vary from 0.5 to 100 nag/kilo of body weight per day depending upon the many factors of the case involved.
The invention will be further illustrated by the several following examples of preparation of selected members of the series. It is, of course, to be understood that these examples are purely by way of illustration and are not intended to limit the scope of the invention in any manner. For a legal definition of the proper scope of the invention attention is directed to the several appended claims.
EXAMPLE 1 17,17-Ethylenedixyeslra-1,3,5 (10)-Trien-3-Ol Reflux, while stirring, a mixture of 10.0 g. (0.037 mole) of estrone (I), 56.5 ml. (1.0 mole) ethylene glycol, 1500 ml. benzene and 0.6 g. p-toluenesulfonic acid monohydrate, with continuous separation of water for 4 hours. Cool the mixture, wash with an aqueous sodium bicarbonate solution. Dry the organic layer over anhydrous magnesium sulfate and evaporate in vacuo. Recrystallize the crystalline residue from methanol giving 9.34 g. (80.5%) of the ketal, M.P. 182, [a] =26.2 (C=1% CHCl xiii $9 230 61,. (6=1,820), x 1; 3.02, 3.46, 3.52, 6.13, 6.35, 6.71... The analytical specimen from the same solvent exhibits M.P. 182-185.
Analysis.-Calcd. for C H O C, 76.40; H, 8.34. Found: C, 76.31; H, 8.41.
EXAMPLE 2 1 7,1 7-EthyIenethi0xyeszra-1,3,5(10)-Trien-3-Ol Reflux for 4 hours a solution of 10.0 g. (0.037 mole) estrone and 0.6 g. of p-toluenesulfonic acid monohydrate in 10 ml. of 2-mercaptoethanol and 1500 ml. of benzene with continuous separation of water. Cool the solution and wash with an aqueous sodium bicarbonate solution. Dry the organic layer over anhydrous magnesium sulfate and evaporate in vacuo. The crystalline material should Weigh 11.0 g. M.P. 157. Recrystallize from acetonitrile to give material which exhibits M.P. 162-163, [a] =l.8 (C=1% CHCl Arzalysis.-Calcd. for C H O S: C, 72.69; H, 7.93; S, 9.70. Found: C, 72.17; H, 7.72; S, 9.60.
EXAMPLE 3 1 7,1 7-Eethylenethioxy-3 Methoxyestra-I ,3 ,5 (1 0 -T riene EXAMPLE 4 1 7 ,1 7-Etlzyleneditlzi0estra-1,3,5 (10) -Trien-3-Ol Stir and cool to 5 3. mixture of 5.0 g. (0.019 mole) estrone, 5.05 ml. (0.06 mole) of ethanedithiol and ml. chloroform. Slowly bubble hydrogen chloride into this cold mixture for 3.5 hours. During this time, the steroid will gradually dissolve. Evaporate the solution in vacuo. The crystalline material should exhibit M.P. 146. Recrystallize from carbon tetrachloride to yield 5.0 g. (78%) of the ketal, M.P. ISO-. Purify this material by recrystallizing from a 1:4 ethyl acetatezhexane solution, to yield product which exhibits M.P. -167", [a] =O c=1% CHC1 x55; 3.03, 3.45, 3.53, 6.18, 6.32, 6.63, 7.33, 304..., iifii 280 u E=1.880).
Analysis.Calcd. for C H OS C, 69.32; H, 7.56; S, 18.51. Found: C, 69.33; H, 7.73; S, 18.40.
EXAMPLE 5 1 7,1 7-Etlzylenedfthi0-3-Meth0xyestra-1 ,3,5 (I 0 -Triene Cool a solution of 5.0 g. (0.017 mole) estrone methyl ether, 5.05 ml. (0.06 mole) of ethanedithiol in 20 ml. chloroform to 5. Bubble hydrogen chloride slowly into this cold solution for 3.0 hours. Evaporate the solution in vacuo. The residue, after trituration with petroleum ether, should give 5.0 g. (79%) of the ketal, M.P. 138. The analytical specimen from acetone exhibits M.P. 138- 139; [a] =0 (C=1% CHCl xjZg 230 m (e: 1,905);x, 3.40, 3.53, 6.24, 6.35,
Analysis.Calcd. for C H OS C, 69.95; H, 7.83; S, 17.79. Found: C, 70.15; H, 7.82; S, 17.70.
EXAMPLE 6 3-Eth0xy-17,17-Ethylenedioxyestra-1,3,5(10)-Triene Reflux a solution of 700 mg. of the estrone ethyl ether in 70 ml. of benzene containing 120 mg. of p-toluenesulfonic acid monohydrate for 26 hours, and remove water via a Dean-Stark tube. Cool the mixture, wash with saturated sodium bicarbonate solution, then with Water, and evaporate the benzene solution. The residue should weigh 800 mg., M.P. 90-92". Recrystallize from methanol to yield 700 mg. of the ketal, M.P. 92-93;
[t] +57.4; k 280 mu (e=l,760), 288 me (6: 1,600);
A 3; 3.44, 3.51, 5.24, 5.37 5.57, 5.77 etc.
Analysis.-Calcd. for C H O C, 77.15; H, 8.83. Found: C, 77.30; H, 8.94.
EXAMPLE 7 3-Allyl0xy-17,1 7-Ethylenea'i0xyestra-1,3,5 ()Triene' Treat a solution of 700 mg. of estrone allyl ether [Miescher and Scholz, Helv. Chim. Acta, 20, 1237 (1937)] in 70 ml. of benzene with 120mg. of p4toluenesulfonic acid and 7 ml. of ethylene glycol. Reflux the mixture for hours and remove Water formed during the reaction with a Dean-Stark tube. Wash the reaction mixture twice with saturated sodium bicarbonate solution, then twice with water, and then dry and evaporate the benzene layer. Crystallize the residue from methanol to yield white needles of the ketal as a first crop, 500 mg., M.P. 69-71". Recrystallize from methanol to give the pure sample, M.P. 71-72; [d] k 280 my. (e=1,825);
x55; 3.44, 3.50, 5.05, 6.35, 5.57 etc.
Analysis.Calcd. for (323113003: C, H, 8.53. Found: C, 77.91; H, 8.45.
EXAMPLE 8 3-Cyclopentyloxy-1 7,1 7-Ethylenedi0xyestra-1,3,5 (1 0) Triena Treat a solution of 1.0 g. of estrone cyclopentyl ether in 100 ml. of benzene with 150 mg. of p-toluenesulfonic acid and 9 ml. of ethylene glycol. Reflux for 50 hours, and remove water via a Dean-Stark tube. Wash the mixture with a saturated solution of sodium bicarbonate, then with water. Evaporate the benzene solution and crystallize the residue from methanol to yield 850 mg. of the ketal, M.P. 9799. Recrystallize several times from methanol to obtain the analytical sample, MP. 101- 102.5; h 281 m (e=2,000), 290 (=1,760).
Analysis.-Calcd. for C H O C, 78.49; H, 8.96. Found: C, 78.97; H, 8.90.
EXAMPLE 9 3-A cetoxy-I 7,1 7-Ethylenedioxyestra-1 ,3,5 (10 -Triene Keep overnight in pyridine (25 cc.) containing acetic anhydride (.35 g.) 17,17-ethylenedioxyestra-1,3,5(10)- trien-3-ol (1 g.), the compound of Example 1. The next day remove the solvent in vacuo and recrystallize the residue from methanol to obtain the 3-acetoxy-17,17- ethylenedioxyestra41,3 ,5 10) -triene.
EXAMPLE 10 17,1 7 -Ethylenedioxy-3-Trimethylacetoxyestra-I ,3,5 (10) Triene Keep overnight in pyridine (25 cc.) containing trimethylacetyl chloride (0.6 g.) 17,17-ethylenedioxyestra-1,3,5, (10)-trien-3-ol (1 g.). The next day, add ether, followed by crushed ice. Wash the ether layer with dilute hydrochloric acid, dilute aqueous sodium bicarbonate and water, and then dry. Recrystallize the product from methanol to give 17,17-ethylenedioxy-3-trimethylacetoxyestra-1,3,5 10) -triene.
EXAMPLE 1 l 3-Benzoyloxy-1'7,1 7 -Ethylenedfoxyestra-1 ,3 ,5 (10 -Triene Keep overnight in pyridine (25 cc.) containing benzoyl chloride (1 g.) 17,17-ethylenedioxyestra-1,3,5(10)-trien- 3-01. After 24 hours remove the solvents under vacuum. Dissolve the solids thus recovered in warm acetone, concentrate the solution somewhat, and add hexane slowly until crystallization commences. Recrystallization from methanol gives the product 3-benzoyloxy-17,17-ethylenedioxyestra-1,3,5 10) -triene.
EXAMPLE 12 17,1 7-Ethylenethi0xy-3-Benzy[oxyestra-1,3,5 (10)-Triene Reflux for about 4 hours a solution of 5.0 g. of estrone benzyl ether and 0.3 g. of p-toluenesulfonic acid monohydrate in 5 ml. of 2-mercaptoethanol and 800 ml. of benzene, with continuous separation of water. Cool the solution, wash with an aqueous sodium bicarbonate solution. Dry the organic layer over magnesium sulfate and evaporate in vacuo to obtain the product of this example.
We claim: 1. A compound of the structure:
wherein R represents a substituent selected from the group consisting of lower alkyl, lower alkenyl, lower cycloalkyl of up to 6 carbon atoms, benzyl, lower alkanoyl and benzoyl; and W represents a member selected from the group consisting of lower alkylenedioxymethylene of up to 6 carbon atoms, lower alkylenedithiomethylene of up to 6 carbon atoms and lower alkylenethioxymethylene of up to 6 carbon atoms, provided that when W is alkylenedioxymethylene R represents a lower alkyl group containing at least 2 carbon atoms.
2. A compound according to claim 1 wherein R is lower alkyl and W is ethylenedioxymethylene.
3. A compound according to claim 1 wherein R is lower alkenyl and W is ethylenedioxymethylene.
4. A compound according to claim 1 wherein R is allyl and W is lower alkylenedioxymethylene of up to 6 carbon atoms.
5. 17,17 ethylenedithio 3 methoxyestra 1,3,5(10)- triene.
6. 3-allyloxy-17,17-ethylenedioxyestra-1,3,5 10) -triene.
7. 3-lower alkenyloxy-17,l7-lower alkylenedioxyestra- 1,3,5(10)-triene.
8. 3-lower alkyloxy 17,17 lower alkylenedioxyestra- 1,3,5(10)-triene.
9. 3 -ethoxy-17 17 -ethylenedioxyestra-1,3,5 (10)-triene.
10. 3-lower alkoxy 17 ,17 lower alkylenedithioestra- 1,3,5(l0)-triene.
OTHER REFERENCES Loewenthal: Tetrahedron, vol. 6, June 1959, pp. 269- 303, QD 241 T4.

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WO2004041839A2 (en) * 2002-11-08 2004-05-21 Pantarhei Bioscience B.V. Synthesis of estetrol via estrone derived steroids
WO2004041839A3 (en) * 2002-11-08 2004-07-01 Pantarhei Bioscience Bv Synthesis of estetrol via estrone derived steroids
US20060211669A1 (en) * 2002-11-08 2006-09-21 Verhaar Mark T Synthesis of estetrol via estrone derived steroids
CN100343269C (en) * 2002-11-08 2007-10-17 潘塔希生物科学股份有限公司 Synthesis of estetrol via estrone derived steroids
US10000524B2 (en) 2002-11-08 2018-06-19 Donesta Bioscience B.V. Synthesis of estetrol via estrone derived steroids
US20180265540A1 (en) * 2002-11-08 2018-09-20 Donesta Bioscience B.V. Synthesis of estetrol via estrone derived steroids
US20100048523A1 (en) * 2006-04-07 2010-02-25 Bachman Kurtis E Compounds, Compositions and Methods for Treating Hormone-Dependent Maladies
US11053273B2 (en) 2011-06-01 2021-07-06 Estetra S.P.R.L. Process for the production of estetrol intermediates
US11053274B2 (en) 2011-06-01 2021-07-06 Estetra S.P.R.L. Process for the production of estetrol intermediates
US10844088B2 (en) 2011-07-19 2020-11-24 Estetra Sprl Process for the preparation of estetrol
US10888518B2 (en) 2015-06-18 2021-01-12 Estetra Sprl Orodispersible tablet containing estetrol
US10894014B2 (en) 2015-06-18 2021-01-19 Estetra Sprl Orodispersible tablet containing Estetrol
US11147771B2 (en) 2015-06-18 2021-10-19 Estetra Sprl Orodispersible dosage unit containing an estetrol component
US11793760B2 (en) 2015-06-18 2023-10-24 Estetra Srl Orodispersible dosage unit containing an estetrol component
US11957694B2 (en) 2015-06-18 2024-04-16 Estetra Srl Orodispersible dosage unit containing an estetrol component
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US11896602B2 (en) 2016-08-05 2024-02-13 Estetra Srl Method for preventing pregnancy
US11452733B2 (en) 2018-04-19 2022-09-27 Estetra Sprl Compounds and their uses for alleviating menopause-associated symptoms
US11484539B2 (en) 2018-04-19 2022-11-01 Estetra Sprl Compounds and their uses for alleviating menopause-associated symptoms
US11666585B2 (en) 2018-04-19 2023-06-06 Estetra Srl Compounds and their uses for alleviating menopause-associated symptoms

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