CA1242697A - GESTAGENICALLY ACTIVE 11.beta.-CHLORO-STEROIDS AND THEIR MANUFACTURE AND USE - Google Patents
GESTAGENICALLY ACTIVE 11.beta.-CHLORO-STEROIDS AND THEIR MANUFACTURE AND USEInfo
- Publication number
- CA1242697A CA1242697A CA000426012A CA426012A CA1242697A CA 1242697 A CA1242697 A CA 1242697A CA 000426012 A CA000426012 A CA 000426012A CA 426012 A CA426012 A CA 426012A CA 1242697 A CA1242697 A CA 1242697A
- Authority
- CA
- Canada
- Prior art keywords
- beta
- chloro
- methyl
- chloroethynyl
- oestren
- 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
Links
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
- C07J1/0051—Estrane derivatives
- C07J1/0081—Substituted in position 17 alfa and 17 beta
-
- 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
- C07J21/005—Ketals
- C07J21/006—Ketals at position 3
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT
Gestagenically active 11.beta.-chloro-steroids and their manufacture and use Novel .OMEGA. of the general formula I
(I) (in which R represents H or acyl) and a process for their manufacture.
The novel compounds have a strong gestagenic action and accordingly may be used as medicaments and contraceptives.
Gestagenically active 11.beta.-chloro-steroids and their manufacture and use Novel .OMEGA. of the general formula I
(I) (in which R represents H or acyl) and a process for their manufacture.
The novel compounds have a strong gestagenic action and accordingly may be used as medicaments and contraceptives.
Description
~ 1 --Gestagenically active ll~-chloro-steroide and their manufacture ~nd use The present invention is concerned with novel 11~-chloro-steroids having a gestagenic action, with a pro-w:~
cess for their manu~acture and~their use as medicaments and contraceptivesO
The present invention provides ll~-chloro-steroids of the general for~ula I
OR
Cl ~ -C-C-Cl ~ (I) in which R represents a hydrogen atom or anacyl group.
The acyl groups represented by ~ may be derived from acids customarily used in steroid chemistry for esterification. Preferred acids are organic carboxylic acids containing up to 15 carbon atoms, especially lo-~er and medium aliphatic carbo~yl.ic acids containing up to 7 carbon atoms~ ~he acids ~ay also be unsatura~, branched or polybaslc 9 or substituted in the customary ~i ~ 2 - .
manner, for e~ample by h~droxyl, ac~lo~, alkoxy, oxo or amino groups or halogen atoms~ A180 suitable are cycloaliphatic, aromatic, mixed aromatic-aliphatic and heterocyclic acids, which may li~e~ise be sub-~tituted in the customary mannerO
The following carboxylic acids may be mentionedby way of e~ample: ~ormlc acid, acetic acid, pro pionic acid, butyric acid, isobut~rlc acid~ valeric acid, i~ovaleric acid, caproic acid 9 oenanthic acid, caprylic acid, pel~rgonic acid, capric acid, undecylic .acid, lsuric acid? tridecylic acid, ~yri~tic acid, pentadecylic acid, trimethylacetic acid, diethylacetic acid 7 tert.-butylacetic acid, ~-cyclopentylpropionic acid, cyclohe~ylacetic acid, cyclohesanecarbo~glic 15 acid9 phenylacetic acid, pheno~yacetlc acid, mono chloroacetic, dichloroacetic and tric~loroacetic acids) aminoacetic acid, dietkylaminoacetic acid9 piperidinoacet~c acid, morpholinoacetic acid, lactic acid, 0-tridecanoyl-glycol~c acid, succinic acid, adipic acid, benzoic acid, nicotinic acid~ i~onico~
.tinic acid and furan-2-carbo~ylic acid.
It i~ a~ready known that 11~ chloro-~teroids have valuable biological propertie~. Dutch published Speci~ication No. 7209299 describes9 ~or e~ample9 11 chloro-17a-ethynyl-18-methyl-~4-oe~trenes which have a ~trong ge~tagenic action.
It ha~ now been found that the corre~ponding 17a-chloroethynyl-compounde of the present inYention oi the general ~ormula I~ which have not previou~ly been known, have a ge~tagenic action which is appro~imatel~
~ time~ stronger than that o~ the 17a-ethy~yl-compound~
known ~rom Dutch Specification No. 7209299.
The gestagenic action of the steroids o~ the pre~ent invention was determined by the cu3tomar~
Clauberg te~t a~er oral.admin~stration to infantile ~emale rabbita.
The mi~imum amount required to produce a po~tive e~ect læ expressed by a McPhail vP1ue o~ 1~50 The results of the test are summarised i~ the ~ollowlng ~able.
~able Compound Dose (mg) McPha~l Chloro-17o-ohloroethynyl- 0.1 3.3 17~-hydro~-18-methyl-~4- 0.03 ~.O
oe~tren-3-one OoOl 1~9 0.00~ 1.2 B ll~-Chloro-17a-ethyn~1-17~- 0.03 2.5 hydroxy-18-methyl-~4-oestren- 0.01 1.4 3-one ~3 1.1 It can be seen from the Table that the thre~hold p~
dose (McPhail 1~5) ~or the gestage~lc action in the ca~e o~ the compound A o~ the pre~ent invention i~
approximately 00003 mg and in the case o~ the known compound ~ approximately 0~01 mg, Compound At ~urthermore, has only a quite minimal 2ndrogenic side e~fect, a~ ~hown by the high com petitio~ factor CF = 15 in the androgen receptor test~
In contrast thereto, compound ~ hich has a compe-tition ~actor oi CF = 6~ ~n the ~ame te~t, still ha~
a weak androgenic action~
~ecau~e o~ their gestagenic 2ctl on9 the compo~ds o~ the general ~ormula I ca~ be u~ed~ for e~ample) in contraceptiva preparations 9 the~e compounds bei~g used as a ge~tagenic component in combination with a hor-mone component hav~ng an oestroge~ic action, for e~ample ethynyl-oe~tradiol, or as the sole active com-ponent. The compounds o~ the general ~ormula I may9 however~ also be used in preparations ~or treating gynaecological disorder~.
The pre~ent invention accordingly also provides -a compou~d of the general form~la I, for use a~ a medicament or a contraceptiveO
The present invention further pro~ide~ a pharma-ceutical preparation ~uitable for such u~e 9 which com~
pri~es a compound of the general .ormula I9 in admi~ture or co~junction with a pharmaceutically sultable carrier.
The preparation may be i~ a ~orm suitable for oral or parenteral administration.
The pharmaceutical preparations may take the cu~tomary medici~al ~orms, and may be manu~actured b~
means o~ methods known Per se, using the additives, carrier~ and taste corrective~ custo~ary in galenical pharmacy. ~or oral administration there come into con-sideration e~pecially tablets, dragées, capsules, pill~, suspensions or solutiona. ~or parenteral admini~tra-tion there come into co~ideration ~olutions, especially oily ~olutions, ~or e~ample ~esame oil or castor oil solutions~ which may, ii desired,,also contain a diluent, for e~ample benzyl benzoate or benzyl alcohol.
~he concentration of the act~ve substance depend o~
the ~orm oi admin~tration. Thus9 for e~ample, ta~let~
~or oral administration pre~erably each contaln 0.01 to 0.5 mg of aeti~e substance and .Qolutions ~or parenteral admini~tration preferably contain 1 to 100 mg o~ active substance per 1 ~1 oY solutionO
The dose o~ a pharmacologically active compound o~ the pre~ent invention may vary accordi~g to the ~orm o~ administration and the purpose of it~ adminis-tration. For example, the dail~ contraceptive dose in the case o~ oral administration to a human female
cess for their manu~acture and~their use as medicaments and contraceptivesO
The present invention provides ll~-chloro-steroids of the general for~ula I
OR
Cl ~ -C-C-Cl ~ (I) in which R represents a hydrogen atom or anacyl group.
The acyl groups represented by ~ may be derived from acids customarily used in steroid chemistry for esterification. Preferred acids are organic carboxylic acids containing up to 15 carbon atoms, especially lo-~er and medium aliphatic carbo~yl.ic acids containing up to 7 carbon atoms~ ~he acids ~ay also be unsatura~, branched or polybaslc 9 or substituted in the customary ~i ~ 2 - .
manner, for e~ample by h~droxyl, ac~lo~, alkoxy, oxo or amino groups or halogen atoms~ A180 suitable are cycloaliphatic, aromatic, mixed aromatic-aliphatic and heterocyclic acids, which may li~e~ise be sub-~tituted in the customary mannerO
The following carboxylic acids may be mentionedby way of e~ample: ~ormlc acid, acetic acid, pro pionic acid, butyric acid, isobut~rlc acid~ valeric acid, i~ovaleric acid, caproic acid 9 oenanthic acid, caprylic acid, pel~rgonic acid, capric acid, undecylic .acid, lsuric acid? tridecylic acid, ~yri~tic acid, pentadecylic acid, trimethylacetic acid, diethylacetic acid 7 tert.-butylacetic acid, ~-cyclopentylpropionic acid, cyclohe~ylacetic acid, cyclohesanecarbo~glic 15 acid9 phenylacetic acid, pheno~yacetlc acid, mono chloroacetic, dichloroacetic and tric~loroacetic acids) aminoacetic acid, dietkylaminoacetic acid9 piperidinoacet~c acid, morpholinoacetic acid, lactic acid, 0-tridecanoyl-glycol~c acid, succinic acid, adipic acid, benzoic acid, nicotinic acid~ i~onico~
.tinic acid and furan-2-carbo~ylic acid.
It i~ a~ready known that 11~ chloro-~teroids have valuable biological propertie~. Dutch published Speci~ication No. 7209299 describes9 ~or e~ample9 11 chloro-17a-ethynyl-18-methyl-~4-oe~trenes which have a ~trong ge~tagenic action.
It ha~ now been found that the corre~ponding 17a-chloroethynyl-compounde of the present inYention oi the general ~ormula I~ which have not previou~ly been known, have a ge~tagenic action which is appro~imatel~
~ time~ stronger than that o~ the 17a-ethy~yl-compound~
known ~rom Dutch Specification No. 7209299.
The gestagenic action of the steroids o~ the pre~ent invention was determined by the cu3tomar~
Clauberg te~t a~er oral.admin~stration to infantile ~emale rabbita.
The mi~imum amount required to produce a po~tive e~ect læ expressed by a McPhail vP1ue o~ 1~50 The results of the test are summarised i~ the ~ollowlng ~able.
~able Compound Dose (mg) McPha~l Chloro-17o-ohloroethynyl- 0.1 3.3 17~-hydro~-18-methyl-~4- 0.03 ~.O
oe~tren-3-one OoOl 1~9 0.00~ 1.2 B ll~-Chloro-17a-ethyn~1-17~- 0.03 2.5 hydroxy-18-methyl-~4-oestren- 0.01 1.4 3-one ~3 1.1 It can be seen from the Table that the thre~hold p~
dose (McPhail 1~5) ~or the gestage~lc action in the ca~e o~ the compound A o~ the pre~ent invention i~
approximately 00003 mg and in the case o~ the known compound ~ approximately 0~01 mg, Compound At ~urthermore, has only a quite minimal 2ndrogenic side e~fect, a~ ~hown by the high com petitio~ factor CF = 15 in the androgen receptor test~
In contrast thereto, compound ~ hich has a compe-tition ~actor oi CF = 6~ ~n the ~ame te~t, still ha~
a weak androgenic action~
~ecau~e o~ their gestagenic 2ctl on9 the compo~ds o~ the general ~ormula I ca~ be u~ed~ for e~ample) in contraceptiva preparations 9 the~e compounds bei~g used as a ge~tagenic component in combination with a hor-mone component hav~ng an oestroge~ic action, for e~ample ethynyl-oe~tradiol, or as the sole active com-ponent. The compounds o~ the general ~ormula I may9 however~ also be used in preparations ~or treating gynaecological disorder~.
The pre~ent invention accordingly also provides -a compou~d of the general form~la I, for use a~ a medicament or a contraceptiveO
The present invention further pro~ide~ a pharma-ceutical preparation ~uitable for such u~e 9 which com~
pri~es a compound of the general .ormula I9 in admi~ture or co~junction with a pharmaceutically sultable carrier.
The preparation may be i~ a ~orm suitable for oral or parenteral administration.
The pharmaceutical preparations may take the cu~tomary medici~al ~orms, and may be manu~actured b~
means o~ methods known Per se, using the additives, carrier~ and taste corrective~ custo~ary in galenical pharmacy. ~or oral administration there come into con-sideration e~pecially tablets, dragées, capsules, pill~, suspensions or solutiona. ~or parenteral admini~tra-tion there come into co~ideration ~olutions, especially oily ~olutions, ~or e~ample ~esame oil or castor oil solutions~ which may, ii desired,,also contain a diluent, for e~ample benzyl benzoate or benzyl alcohol.
~he concentration of the act~ve substance depend o~
the ~orm oi admin~tration. Thus9 for e~ample, ta~let~
~or oral administration pre~erably each contaln 0.01 to 0.5 mg of aeti~e substance and .Qolutions ~or parenteral admini~tration preferably contain 1 to 100 mg o~ active substance per 1 ~1 oY solutionO
The dose o~ a pharmacologically active compound o~ the pre~ent invention may vary accordi~g to the ~orm o~ administration and the purpose of it~ adminis-tration. For example, the dail~ contraceptive dose in the case o~ oral administration to a human female
2~ i~ 0.01 to 0.5 mg of the novel gestagen~ optionall~
combined with 0~01 to 0.0~ mg of ethynyl-oestradiol.
L~
~ .~.
The present invention also include~ within it3 scope a method of contraception, ~herein there ~ 9 ~dmini~tered i~ a contraceptive do~e to a iemale mamQal, ~or e~ample a human ~emale, a compound of the genaral ~ormula I. When the ~emale mammal i~ a human ~emale~ the compound o~ the general formula I may be administered orally in a daily do~e within the r nge of from 0~01 to 0~5 m~. If desired, an oestrogen~
~or e~ample eth~nyl-oe~tradiol, ma~ al80 be admini~-tered in a contraceptive do3e to the ~emale mammal;-when the ~emale mammal iB a huma~ ~emale7 ethynyl-oe~tra-diol ma~ be admini3tered orally in a daily do~e within the ran~e ~i ~rom 0.01 to 0~05 mgO
The pre~ent lnvention ~urther providea a contra-ceptive preparation ~hich comprlses a compound of the general formula I in adml~ture or conjunction with an oe~trogen, for e~ample ethynyl-oe~tradiol~ ~uch a preparation ma~ be in a form ~uitable ior oral ad-mini~tration, for e~ample in unit dosage ~orm con-taining 0.01 to 0.5 mg o~ the compound o~ the general-formula I and Oo Ol to 0.05 mg of ethynyl-oestradiol per dosage unit~
~he present invention further provides a procesa ~or the manufacture of a compound of the general for~ a I 7 wherein a compound of the gene~al formula II
~ ~ ~ (II), Y
in which Y represents P ~ree oxo group or a hydrolgsable protected o~o group, pre~erably a~ acid-hydro-lysable protected o~o group, and ¦i represents a double bond in the 495-, 5,6- or ' ~ 5,10-positio~ or represe~ts two double bonds, o~e e~tending ~rom the ~-position and the other extending from the 5-position9 10 is reacted with an organo~metallic chloroethynyl com-pound to iorm a compound containing a chloroethynyl group in the 17~-poa~tion and a free hydrox~l group in the 17~-position, an~ protected oxo group in the ~-position of t~e resulting compound i~ hydrolysed to form a free oxo group9 and, if desired9 before or after any such hydrolysis9 the 17~-h~droxyl group i9 esterified.
The process o* the present in~ention may be carried out by a method k~own ~er se using an organo-met~llio '~ ~L~
chloroethynyl compound, by reacting the 17-oxo~steroid of the general ~ormula II in a suitable solvent with the organo-metallic chl oroethyn~l compound, The chloroethynyl compound may be formed in situ from 1,2-dichloroethylene and an ethereal alkali metal aIkyl~olution, ~or e~ample an ethereal lithium methyl or lithium butyl ~olution. ~uitable solvents are tetra-hydro~uran and diethyl ether~
A iree ~-keto group is advantageously protected before the chloroethynylation. Together ~ith the double bond(s~ pre6ent i~ ring(s) ~ and/or B, a protected keto group represented b~ Y ~n the compound of the general ~ormula II forms ~uch an arrangement of atom~
that the compound i~ converted by hydrolys~s into a 4~5-un3aturated ketone. In a preferred embodi~ent, the ~-keto group i~ protected by the formation o~ a ketalO The ketal groups may be derived from the al~
cohol~ and thioalcohol6 customarily u~ed to protec~
~ree oxo group6; e~amples uhich may be mentioned are ethylene glycol~ 2,2-dimethyl-1,3-propanediol and ethane-1,2 dithiol. The 3-keto group may, however, al80 be partially protected by the iormation of an enol ether, enol ester or enamine.
The splitting-o~f o~ the ~-keto protective group by hydrolysis, which may be e~fected before or after the possible e~teri~ication in the 17-po~ition, may ?..
_ g ~
~e carried out in accordance with ~ethods known to a person skilled in the art. There may be considered for the hydrolys~ mineral acids, for example per-chloric acid, sulphuric acid or hydrochloric acid, or organic acids, ~or e~ample o~alic acid~ The hydro-ly9i3 i8 pre~erably carried out in an alcoholic 801u-tion or in other polar 301vents, for example acetone, at temperatures of between appro~imately 20 and 100C.
In the case o~ a thioketal protective group, the hydrolysi~ ma~ be carried out in an alcoholic 301u-tion, preferably in water-moist methanol, using methyl iodide9 w~th the addition o~ sodium or pota38ium acetate or ~odium or potas3ium carbonate at tempera-tures between room temperature and the boiling tem-perature o~ the sol~ent.
The optional esteri~icatio~ of the 17~-hydro~yl group may be carried out a~cording to methods custo marily used in steroid chemistrg ~or the esteri~ica-tion o~ tertiary hydroxyl groups. A suitabIe e~teri-fication method which may be mentioned by way of e~ampleiB the reaction o~ the steroids with acid anhydride~
or acid chloriaes in the presence o~ basic catalysts, for example sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, pyridine, lutidine, collidine, triethyl-amine or 4-dimethylaminopyridine~ In accordance wlth ~ 10 --a preferred embcdlment, the e~terificatio~ i~ carried out in the presence o~ pyrldine an~ 4-dimethylamino-pyridine.
Starting compounds of the general formula II
used ~or the pro~es6 of the present invention may be manufactured ~rom ll~-chloro-18-methyl-A4-oestrene-
combined with 0~01 to 0.0~ mg of ethynyl-oestradiol.
L~
~ .~.
The present invention also include~ within it3 scope a method of contraception, ~herein there ~ 9 ~dmini~tered i~ a contraceptive do~e to a iemale mamQal, ~or e~ample a human ~emale, a compound of the genaral ~ormula I. When the ~emale mammal i~ a human ~emale~ the compound o~ the general formula I may be administered orally in a daily do~e within the r nge of from 0~01 to 0~5 m~. If desired, an oestrogen~
~or e~ample eth~nyl-oe~tradiol, ma~ al80 be admini~-tered in a contraceptive do3e to the ~emale mammal;-when the ~emale mammal iB a huma~ ~emale7 ethynyl-oe~tra-diol ma~ be admini3tered orally in a daily do~e within the ran~e ~i ~rom 0.01 to 0~05 mgO
The pre~ent lnvention ~urther providea a contra-ceptive preparation ~hich comprlses a compound of the general formula I in adml~ture or conjunction with an oe~trogen, for e~ample ethynyl-oe~tradiol~ ~uch a preparation ma~ be in a form ~uitable ior oral ad-mini~tration, for e~ample in unit dosage ~orm con-taining 0.01 to 0.5 mg o~ the compound o~ the general-formula I and Oo Ol to 0.05 mg of ethynyl-oestradiol per dosage unit~
~he present invention further provides a procesa ~or the manufacture of a compound of the general for~ a I 7 wherein a compound of the gene~al formula II
~ ~ ~ (II), Y
in which Y represents P ~ree oxo group or a hydrolgsable protected o~o group, pre~erably a~ acid-hydro-lysable protected o~o group, and ¦i represents a double bond in the 495-, 5,6- or ' ~ 5,10-positio~ or represe~ts two double bonds, o~e e~tending ~rom the ~-position and the other extending from the 5-position9 10 is reacted with an organo~metallic chloroethynyl com-pound to iorm a compound containing a chloroethynyl group in the 17~-poa~tion and a free hydrox~l group in the 17~-position, an~ protected oxo group in the ~-position of t~e resulting compound i~ hydrolysed to form a free oxo group9 and, if desired9 before or after any such hydrolysis9 the 17~-h~droxyl group i9 esterified.
The process o* the present in~ention may be carried out by a method k~own ~er se using an organo-met~llio '~ ~L~
chloroethynyl compound, by reacting the 17-oxo~steroid of the general ~ormula II in a suitable solvent with the organo-metallic chl oroethyn~l compound, The chloroethynyl compound may be formed in situ from 1,2-dichloroethylene and an ethereal alkali metal aIkyl~olution, ~or e~ample an ethereal lithium methyl or lithium butyl ~olution. ~uitable solvents are tetra-hydro~uran and diethyl ether~
A iree ~-keto group is advantageously protected before the chloroethynylation. Together ~ith the double bond(s~ pre6ent i~ ring(s) ~ and/or B, a protected keto group represented b~ Y ~n the compound of the general ~ormula II forms ~uch an arrangement of atom~
that the compound i~ converted by hydrolys~s into a 4~5-un3aturated ketone. In a preferred embodi~ent, the ~-keto group i~ protected by the formation o~ a ketalO The ketal groups may be derived from the al~
cohol~ and thioalcohol6 customarily u~ed to protec~
~ree oxo group6; e~amples uhich may be mentioned are ethylene glycol~ 2,2-dimethyl-1,3-propanediol and ethane-1,2 dithiol. The 3-keto group may, however, al80 be partially protected by the iormation of an enol ether, enol ester or enamine.
The splitting-o~f o~ the ~-keto protective group by hydrolysis, which may be e~fected before or after the possible e~teri~ication in the 17-po~ition, may ?..
_ g ~
~e carried out in accordance with ~ethods known to a person skilled in the art. There may be considered for the hydrolys~ mineral acids, for example per-chloric acid, sulphuric acid or hydrochloric acid, or organic acids, ~or e~ample o~alic acid~ The hydro-ly9i3 i8 pre~erably carried out in an alcoholic 801u-tion or in other polar 301vents, for example acetone, at temperatures of between appro~imately 20 and 100C.
In the case o~ a thioketal protective group, the hydrolysi~ ma~ be carried out in an alcoholic 301u-tion, preferably in water-moist methanol, using methyl iodide9 w~th the addition o~ sodium or pota38ium acetate or ~odium or potas3ium carbonate at tempera-tures between room temperature and the boiling tem-perature o~ the sol~ent.
The optional esteri~icatio~ of the 17~-hydro~yl group may be carried out a~cording to methods custo marily used in steroid chemistrg ~or the esteri~ica-tion o~ tertiary hydroxyl groups. A suitabIe e~teri-fication method which may be mentioned by way of e~ampleiB the reaction o~ the steroids with acid anhydride~
or acid chloriaes in the presence o~ basic catalysts, for example sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, pyridine, lutidine, collidine, triethyl-amine or 4-dimethylaminopyridine~ In accordance wlth ~ 10 --a preferred embcdlment, the e~terificatio~ i~ carried out in the presence o~ pyrldine an~ 4-dimethylamino-pyridine.
Starting compounds of the general formula II
used ~or the pro~es6 of the present invention may be manufactured ~rom ll~-chloro-18-methyl-A4-oestrene-
3,17-dione (Dutch Specificatio~ No. 7209299), ~or example by mean3 o~ ketalisation aB follow~:
hloro (2' 2~-dimeth 1trimeth lenediox ~-18-~ ~.3-~ 9 meth~ 5-oestren-17-one 1 g o~ 2,2-dimethyl-1~3-propanediol and 5 mg of ~-tolueneaulphonic acid ~ere added at room temperature to 500 mg of 11~-chloro-18-methy1-~4-oestrene-~,17-dione in 5 ml oY methylene chloride and 0.5 ml o~ o-~ormic acid triethyl ester. ~fter 6 hour~7 the ~holewas diluted with methylene chloride, washed u~til neutral and dried. The crude product wa~ chromato-graphed over silica gel. 300 mg of 11~-chl~ro-3,~
(2',2'-dimethyltrimethyle~edioxy) 18-meth~ 5-oes-tren 17-one having a melting point o~ 161.2C were eluted with acetone/hexane.
The ~ollowing ~xamples illustrate the invention:
~ am~le 1 a) ll~-Chloro-17a-chloroeth~n~ ,3-t ?', 2'-dimeth~l_ trimeth~lenedioxy~-18-methyl-~5-oestren-17~-ol '?d ~3~
21 ml o~ a 5 ~ strength ethereal lithium methyl ~olution were added dropwi~e to 2.8 ml of 192-di-chloroethylene i~ 20 ml of absolute ether while cool-ing with ice/water and introduc~ng argonO ~fter ~0 minutes, 1.2 g o~ chloro-3,3-(2',2'-dimethyl-trimethylenedio~y)-18-methyl-~5-oestren-17-one ~n 5 ml of absolute tetrahydrofuran were added. The whole was stirred at room temperature, a~ter 20 minutes a saturated ammonium chloride ~olutio~ was added, and the whole waa diluted with ether, washed with water and dried. After reorystallizatio~ ~rom acetone/hexane, 1~1 g o~ chloro-17~-chl oroethynyl-3,~-(2',27-dimethyl-trimethylenedioxy~-18-methyl ~5-oe~tren-17~-ol having a melting point o~ 184.2C
were obtained.
b) ll~-Chloro-llo--chloroet~ 17~=h~drox~-18-meth~l-~4-oe~tren-~-one 0.5 ml of ~emi-concentrated hydrochloric acid was added under an argo~ atmosphere ~nd at room tempera-ture to 1.0 g o~ chloro~17a-chloroe~hyny1-3~3-(2',2'-dimethyl-trimethylened~oxy)~18-methyl-~5-oestren-17~-ol in 20 ml of acetone. After 1 hour, the whole was neutral~zed with a ~aHC0~ solution and concentrated in vacuo and the residu~ wa~ di~olved in ethyl acetate, washed with water and dried~ ~fter s37 recrystallization ~rom acetone/heI~ne, the crude pro-duct yielded 4~3 mg of 11~-chloro-17~-chloroethynyl 17~-hydroxy~18-methyl-~4-oestren-3-one having a melt-ing point of 239.2C.
~amPle 2 17B-AcetoYQ~ chloro-17a,-chloroethynyl-18-meth~l-~4-oestren-3-one 300 mg o~ chloro-17~-chloroethynyl-17~-hydro~y-18-methyl-~4-oe~tren-~-one in 4 ml o~ pyrid~ne 10 were stirred at room temperature, with the addition o~ 50 mg o~ 4-dimethylaminopyrid~ne, with 2 m~ o~
acetlc anhydride. A~ter 2 ho~r~ the mi~ture was added to ice/water containing acetic acid~ The product which precipitated was suction-filtered, dissolved in methylene chloride and washed with water. ~ter chromatography of the crude product over ~ilica gel using he~ane/acetone, 190 mg o~ 17~acetox~
chloro-17o-chloroethynyl-18-methyl~4-oestren-3-o~e were obtained in the for~ of a ~oam.
20~ uEeL~_~
_7 meth~ 4_oe~tren-3-one 110 m~ o~ -chloro-17~-chloroethynyl-17~-hydroxy-18-methyl-~4 oestren-~-o~e in 1 ml of pyri-dine were ~tirred at room temperature, with the - 13 ~
addition o~ 100 mg of 4~dimeth~1aminopyridine, with 0.5 ml Or butyric anhydride. A~ter 5 hours the mi~ture was added to ice/water and the product wa~ e~tracted with methylene chloride. ~fter chromatography of the crude product over silica gel using he~ane/acetone, 7~ mg of 17~-butyryloxy~ chloro-17a-chloroethynyl-18-methyl-A4-oestren~3-one were obtained as an oil~
product.
~am~le 4 .
llB-Chloro-lla-chloroeth~ 17~-hePtano~10~-18-meth~ 4-oestren-~-o~e 1.5 ml of oenanthic anhydride and 100 m~ Or 4-dimethylaminopyridine were added at room temperature to 300 ~g of ll~-chl oro-17~-chloroethynyl-17~-hy-dro~y-18-meth~ 4-oe~tren-~-one i~ 3 ml of pyridine.
~fter 24 hour~ the ~olution ~as added to icejwater and the ~hole was extracted with methylene chloride~
hfter chromatography of the crude product over silica gel, 160 mg o~ -chloro-17a-chloroethynyl-17~-hep tanoyloxy-18-methyl-~4-oestren-3-one were obtained i~
the ~orm o~ an oil,
hloro (2' 2~-dimeth 1trimeth lenediox ~-18-~ ~.3-~ 9 meth~ 5-oestren-17-one 1 g o~ 2,2-dimethyl-1~3-propanediol and 5 mg of ~-tolueneaulphonic acid ~ere added at room temperature to 500 mg of 11~-chloro-18-methy1-~4-oestrene-~,17-dione in 5 ml oY methylene chloride and 0.5 ml o~ o-~ormic acid triethyl ester. ~fter 6 hour~7 the ~holewas diluted with methylene chloride, washed u~til neutral and dried. The crude product wa~ chromato-graphed over silica gel. 300 mg of 11~-chl~ro-3,~
(2',2'-dimethyltrimethyle~edioxy) 18-meth~ 5-oes-tren 17-one having a melting point o~ 161.2C were eluted with acetone/hexane.
The ~ollowing ~xamples illustrate the invention:
~ am~le 1 a) ll~-Chloro-17a-chloroeth~n~ ,3-t ?', 2'-dimeth~l_ trimeth~lenedioxy~-18-methyl-~5-oestren-17~-ol '?d ~3~
21 ml o~ a 5 ~ strength ethereal lithium methyl ~olution were added dropwi~e to 2.8 ml of 192-di-chloroethylene i~ 20 ml of absolute ether while cool-ing with ice/water and introduc~ng argonO ~fter ~0 minutes, 1.2 g o~ chloro-3,3-(2',2'-dimethyl-trimethylenedio~y)-18-methyl-~5-oestren-17-one ~n 5 ml of absolute tetrahydrofuran were added. The whole was stirred at room temperature, a~ter 20 minutes a saturated ammonium chloride ~olutio~ was added, and the whole waa diluted with ether, washed with water and dried. After reorystallizatio~ ~rom acetone/hexane, 1~1 g o~ chloro-17~-chl oroethynyl-3,~-(2',27-dimethyl-trimethylenedioxy~-18-methyl ~5-oe~tren-17~-ol having a melting point o~ 184.2C
were obtained.
b) ll~-Chloro-llo--chloroet~ 17~=h~drox~-18-meth~l-~4-oe~tren-~-one 0.5 ml of ~emi-concentrated hydrochloric acid was added under an argo~ atmosphere ~nd at room tempera-ture to 1.0 g o~ chloro~17a-chloroe~hyny1-3~3-(2',2'-dimethyl-trimethylened~oxy)~18-methyl-~5-oestren-17~-ol in 20 ml of acetone. After 1 hour, the whole was neutral~zed with a ~aHC0~ solution and concentrated in vacuo and the residu~ wa~ di~olved in ethyl acetate, washed with water and dried~ ~fter s37 recrystallization ~rom acetone/heI~ne, the crude pro-duct yielded 4~3 mg of 11~-chloro-17~-chloroethynyl 17~-hydroxy~18-methyl-~4-oestren-3-one having a melt-ing point of 239.2C.
~amPle 2 17B-AcetoYQ~ chloro-17a,-chloroethynyl-18-meth~l-~4-oestren-3-one 300 mg o~ chloro-17~-chloroethynyl-17~-hydro~y-18-methyl-~4-oe~tren-~-one in 4 ml o~ pyrid~ne 10 were stirred at room temperature, with the addition o~ 50 mg o~ 4-dimethylaminopyrid~ne, with 2 m~ o~
acetlc anhydride. A~ter 2 ho~r~ the mi~ture was added to ice/water containing acetic acid~ The product which precipitated was suction-filtered, dissolved in methylene chloride and washed with water. ~ter chromatography of the crude product over ~ilica gel using he~ane/acetone, 190 mg o~ 17~acetox~
chloro-17o-chloroethynyl-18-methyl~4-oestren-3-o~e were obtained in the for~ of a ~oam.
20~ uEeL~_~
_7 meth~ 4_oe~tren-3-one 110 m~ o~ -chloro-17~-chloroethynyl-17~-hydroxy-18-methyl-~4 oestren-~-o~e in 1 ml of pyri-dine were ~tirred at room temperature, with the - 13 ~
addition o~ 100 mg of 4~dimeth~1aminopyridine, with 0.5 ml Or butyric anhydride. A~ter 5 hours the mi~ture was added to ice/water and the product wa~ e~tracted with methylene chloride. ~fter chromatography of the crude product over silica gel using he~ane/acetone, 7~ mg of 17~-butyryloxy~ chloro-17a-chloroethynyl-18-methyl-A4-oestren~3-one were obtained as an oil~
product.
~am~le 4 .
llB-Chloro-lla-chloroeth~ 17~-hePtano~10~-18-meth~ 4-oestren-~-o~e 1.5 ml of oenanthic anhydride and 100 m~ Or 4-dimethylaminopyridine were added at room temperature to 300 ~g of ll~-chl oro-17~-chloroethynyl-17~-hy-dro~y-18-meth~ 4-oe~tren-~-one i~ 3 ml of pyridine.
~fter 24 hour~ the ~olution ~as added to icejwater and the ~hole was extracted with methylene chloride~
hfter chromatography of the crude product over silica gel, 160 mg o~ -chloro-17a-chloroethynyl-17~-hep tanoyloxy-18-methyl-~4-oestren-3-one were obtained i~
the ~orm o~ an oil,
Claims (18)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the manufacture of a compound of the general formula I
In which R represents a hydrogen atom or an acyl group having up to 15 carbon atoms, wherein a compound of the general formula II
in which Y represents a free oxo group or a hydrolysable protected oxo group and represents a double bond in the 4,5-, 5,6- or 5,10-position or represents two double bonds, one extending from the 3-position and the other extending from the 5-position, is reacted with an organo-metallic chloroethynyl com-pound to form a compound containing a chloroethynyl group In the 17 ? -position and a free hydroxyl group in the 17 .beta. -position, any protected oxo group In the 3-position of the resulting com-pound is hydrolysed to form a free oxo group, and when required, before or after any such hydrolysis, the 17 .beta.-hydroxy group i s esterified.
In which R represents a hydrogen atom or an acyl group having up to 15 carbon atoms, wherein a compound of the general formula II
in which Y represents a free oxo group or a hydrolysable protected oxo group and represents a double bond in the 4,5-, 5,6- or 5,10-position or represents two double bonds, one extending from the 3-position and the other extending from the 5-position, is reacted with an organo-metallic chloroethynyl com-pound to form a compound containing a chloroethynyl group In the 17 ? -position and a free hydroxyl group in the 17 .beta. -position, any protected oxo group In the 3-position of the resulting com-pound is hydrolysed to form a free oxo group, and when required, before or after any such hydrolysis, the 17 .beta.-hydroxy group i s esterified.
2. An 11 .beta.-chloro-steroid of the general formula in which R represents a hydrogen or an acyl group with up to 15 carbon atoms.
3. A process according to claim 1, in which R is an aliphatic carboxyl group with up to 7 carbon atoms.
4. A compound of formula I given in claim 1, in which R is as claimed in claim 3.
5. A process according to claim 3, in which the aliphatic carboxyl group is saturated.
6. A compound of formula I given in claim 1, in which R is as claimed in claim 5.
7. A process according to claim 1, in which R is hydrogen.
8. A process according to claim 1, which comprises mixing ethereal lithium methyl solution with 1,2-dichloroethylene in absolute ether under argon while cooling, adding to the mix-ture obtained 11 .beta.-chloro-3,3-(2',2'-dimethyltrimethylendl-oxy)-18-methyl-.DELTA. 5-oestren-17-one in absolute tetrahydrofuran at room temperature and treating the 11.beta.-chloro-17?-chloroethynyl-3,3-(2',2'-dimethyl-trimethylen dioxy)-18-methyl-.DELTA.5-oestren-17.beta.-ol obtained in acetone under argon atmosphere at room temperature with semi-concentrated hydrochloric acid.
9. 11.beta.-chloro-17?-chloroethynyl-17.beta.-hydroxy-18-methyl-.DELTA.4-oestren-3-one.
10. A process according to claim 1, in which R Is acetyl.
11. A process according to claim 8, in which the 11.beta.-chloro-17?-chloroethynyl-17.beta.-hydroxy-18-methyl-.DELTA.4-oestren-3-one obtained is stirred in pyridine at room temperature with acetic anhydride In -the presence of 4-dimethyl-aminopyridine.
12. 17.beta.-acetoxy-11.beta.-chloro-17?-chloroethynyl-18-methyl-.DELTA.4-oestren-3-one.
13. A process according to claim 1, in which R Is butyryl.
14. A process according to claim 8, in which the 11.beta.-chloro-17 ?-chloroethynyl-17.beta.-hydroxy-18-methyl-.DELTA.4-oestren-3-one obtained is stirred in pyridine at room temperature with butyric anhydride in the presence of 4-dimethylaminopyridine.
15. 17.beta.-butyryloxy-11 .beta.-chloro-17?-chloroethynyl-18-methyl-.DELTA.4-oestren-3-one.
16. A process according to claim 1, in which R is hep-tanoyl.
17. A process according to claim 8, in which the 11.beta.-chloro-17?-chloroethynyl-17.beta.-hydroxy-18-methyl-.DELTA.4-oestren-3-one obtained is stirred in pyridine at room temperature with oenanthic anhydride In the presence of 4-dimethylaminopyridine.
18. 11.beta.-chloro-17?-chloroethynyl-17.beta.-heptanoyloxy-18-methyl-.DELTA.4-oestren-3-one.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19823214689 DE3214689A1 (en) | 1982-04-16 | 1982-04-16 | 11SS CHLORINE STEROIDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM |
| DEP3214689.2 | 1982-04-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1242697A true CA1242697A (en) | 1988-10-04 |
Family
ID=6161447
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000426012A Expired CA1242697A (en) | 1982-04-16 | 1983-04-15 | GESTAGENICALLY ACTIVE 11.beta.-CHLORO-STEROIDS AND THEIR MANUFACTURE AND USE |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0092173B1 (en) |
| JP (1) | JPS58188899A (en) |
| AT (1) | ATE18407T1 (en) |
| AU (1) | AU555284B2 (en) |
| CA (1) | CA1242697A (en) |
| DD (1) | DD209635A5 (en) |
| DE (2) | DE3214689A1 (en) |
| DK (1) | DK92283A (en) |
| ES (1) | ES520207A0 (en) |
| GR (1) | GR78212B (en) |
| HU (1) | HU186687B (en) |
| ZA (1) | ZA832672B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4232521A1 (en) * | 1992-09-22 | 1994-03-24 | Schering Ag | Progestagenic 4,5; 11,12-estradienes, processes for their preparation, medicaments containing these estradienes and their use for the production of medicaments |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE651797A (en) * | 1962-10-17 | |||
| US3665021A (en) * | 1966-07-29 | 1972-05-23 | Glaxo Lab Ltd | 9alpha-unsubstituted-11beta-chloro-l9 nos-steroids |
| NL7209299A (en) * | 1972-07-01 | 1974-01-03 | Delta-4-3-oxo-11-beta-halo steroids - with hormonal activity |
-
1982
- 1982-04-16 DE DE19823214689 patent/DE3214689A1/en not_active Withdrawn
-
1983
- 1983-02-25 DK DK92283A patent/DK92283A/en not_active Application Discontinuation
- 1983-03-01 ES ES520207A patent/ES520207A0/en active Granted
- 1983-03-16 AU AU12487/83A patent/AU555284B2/en not_active Ceased
- 1983-04-13 JP JP58063807A patent/JPS58188899A/en active Pending
- 1983-04-14 EP EP83103604A patent/EP0092173B1/en not_active Expired
- 1983-04-14 DE DE8383103604T patent/DE3362380D1/en not_active Expired
- 1983-04-14 DD DD83249873A patent/DD209635A5/en unknown
- 1983-04-14 GR GR71089A patent/GR78212B/el unknown
- 1983-04-14 AT AT83103604T patent/ATE18407T1/en not_active IP Right Cessation
- 1983-04-15 HU HU831327A patent/HU186687B/en unknown
- 1983-04-15 ZA ZA832672A patent/ZA832672B/en unknown
- 1983-04-15 CA CA000426012A patent/CA1242697A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| DK92283D0 (en) | 1983-02-25 |
| ZA832672B (en) | 1983-12-28 |
| EP0092173A1 (en) | 1983-10-26 |
| DE3214689A1 (en) | 1983-10-27 |
| ATE18407T1 (en) | 1986-03-15 |
| GR78212B (en) | 1984-09-26 |
| HU186687B (en) | 1985-09-30 |
| ES8401096A1 (en) | 1983-12-01 |
| AU555284B2 (en) | 1986-09-18 |
| ES520207A0 (en) | 1983-12-01 |
| DE3362380D1 (en) | 1986-04-10 |
| AU1248783A (en) | 1983-10-20 |
| DD209635A5 (en) | 1984-05-16 |
| DK92283A (en) | 1983-10-17 |
| JPS58188899A (en) | 1983-11-04 |
| EP0092173B1 (en) | 1986-03-05 |
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