US3758521A - 17a-(5{40 -substituted-5{40 -hydroxy-penta-1{40 , 3{40 -diynyl)-steroids - Google Patents

17a-(5{40 -substituted-5{40 -hydroxy-penta-1{40 , 3{40 -diynyl)-steroids Download PDF

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US3758521A
US3758521A US00037035A US3758521DA US3758521A US 3758521 A US3758521 A US 3758521A US 00037035 A US00037035 A US 00037035A US 3758521D A US3758521D A US 3758521DA US 3758521 A US3758521 A US 3758521A
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hydroxy
oestratrien
mixture
methoxy
pentadiynyl
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C Burgess
P Feather
P Goatly
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BDH Pharmaceuticals Ltd
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    • 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

Definitions

  • ABSTRACT Compounds having sex hormonal activity consisting of steroid compounds processing a l7B-oxygen function and being substituted in the l7a-position by a group of the structure wherein R is selected from the group consisting of carbocyclic aryl, aralkyl, heterocyclic having 5 or 6 members and containing at least one hetero atom selected from O, N and S, alicyclic, alkenyl having two-five carbon atoms and alkyl having one-five carbon atoms;
  • R is selected from the group consisting of hydrogen, carbocyclic aryl, aralkyl, heterocyclic having 5 or 6 membersand containing at least one hetero atom selected from O, N and S, alicyclic, alkenyl having two-five carbon atoms and alkyl having one-five carbon atoms; or
  • R and R together with the carbon atom to which they are attached form an alicyclic ring.
  • the compounds exhibit an unusual separation of oestrogenic and anti-fertility activities (in rats) compared with ethynyl oestradiol.
  • compounds having sex hormonal activity consisting of steroid compounds possessing a l7B-oxygen function and being substituted in the l7a-position by a group of the structure wherein R is a carbocyclic aryl group, an aralkyl group, a heterocyclic group, an alicyclic group, an alkenyl group having two-five carbon atoms or an alkyl group having one-five carbon atoms;
  • R is hydrogen, a carbocyclic aryl group, an aralkyl group, a heterocyclic group, an alicyclic group, an alkenyl group having two-five carbon atoms or an alkyl group having one-five carbon atoms; or
  • R and R together with the carbon atom to which they are attached form an alicyclic ring.
  • steroid is used herein to denote compounds having a nucleus derived from perhydro-l,2- cyclopentenophenanthrene. Since the compounds according to the invention are structurally related to compounds possessing sex hormonal activity they will ordinarily possess an oxygen function, e.g., hydroxy, methoxy or 0x0, at the 3-position; they will ordinarily possess unsaturation in ring A of an olefinic or aromatic character, but may be ring A-saturated; they will ordinarily possess a lower alkyl group at C and may or may not have a methyl group at C These functions are generally found in a variety of sex hormones to a greater or lesser extent although sex hormones devoid of, for example, a 3-oxygen function are known to exist.
  • oxygen function e.g., hydroxy, methoxy or 0x0
  • the compounds according to the invention possess a Yin-oxygen function i.e., a l7B hydroxy group or an ester or ether group thereof, e.g., a lower alkoxy group or a lower alkanoyloxy group.
  • a Yin-oxygen function i.e., a l7B hydroxy group or an ester or ether group thereof, e.g., a lower alkoxy group or a lower alkanoyloxy group.
  • sex hormonal activity activity of an oestrogenic, gestogenic or androgenic nature and includes such activity produced by naturally occurring steroids as well as by steroids not known to exist in .nature.
  • the sex hormonal activity may be directly present in the compound or may be manifested in vivo by biological transformation of the compound.
  • the term also includes activity manifested as anti-hormonal activity although the compounds in question possess some degree of normal hormonal activity e.g., a compound possessing residual oestrogenic activity may function as an ani-oestrogen.
  • R and R may, where their definitions permit, be the same or different.
  • R or R is a carbocyclic aryl group this may be monoor bi-cyclic and when it is bicyclic the rings may be fused.
  • R or R may thus be phenyl, lor 2- naphthyl or 0- or pbiphenylyl.
  • One may use a carbocyclic aryl group in an unsubstituted form or such a group substituted by, for example, one or more fluorine, chlorine or bromine atoms, hydroxy groups, alkyl groups containing one-five carbon atmos, alkoxy groups containing one-five carbon atoms, or trifluoromethyl groups. Examples of such substituted carbocyclic aryl groups include p-tolyl, o-chlorophenyl, oand pmethoxyphenyl.
  • R or R is an aralkyl group
  • the aryl moiety or moieties may be a monoor bi-cyclic carbocylic group, substituted or unsubstituted, as explained above, and the alkyl moiety may contain one-five carbon atoms.
  • Examples of such aralkyl groups include benzyl and phenethyl.
  • R or R is a heterocyclic group it may be a 5-or 6-membered ring containing one or more hetero atoms selected from O, N and S. It may be aromatic or non-aromatic. Examples of such heterocyclic groups include 2- or 3-pyridyl and 2- or 3-thienyl.
  • R or R is an alicyclic group it may be, for ex ample, cyclohexyl or adamantyl, while when R or R is alkenyl it may, for example, be vinyl, propenyl or isopropenyl.
  • R or R is an alkyl group it may eg be a methyl, ethyl, propyl, isopropyl, nor secbutyl or npentyl group.
  • R is preferably a carbocyclic aryl group, a heterocyclic group, an alicyclic group or an alkenyl group.
  • the compounds of the invention may be derived from any l7-keto or l7B-oxygen function-containing steroid compound having sex hormonal activity. In genera], but not exclusively, such compounds will contain unsaturation and/or substitutents in rings A and B.
  • the compounds according to the invention may contain unsaturation as one or more A, A, A A, A A A, A A and A.
  • ring A may be aromatic or may contain A or A unsaturation. Again unsaturation may be present in or shared with rings A and B e.g. as A" or A'' or ring A may be aromatic and ring B may contain 1 or 2 double bonds.
  • Rings A and B may contain one or more substituents selected from acyloxy, alkoxy,alkyl and alkenyl (each containing up to 5 carbon atoms), halogeno, hydroxy and 0x0.
  • substituents selected from acyloxy, alkoxy,alkyl and alkenyl (each containing up to 5 carbon atoms), halogeno, hydroxy and 0x0.
  • One or more of these substitutents may be so chosen that they are metabolised in vivo to give unsaturation.
  • Ring C may be devoid of substituents or may, for example, contain an oxygen or halogen (i.e., chloro or bromo) function at C
  • the compounds according to the invention include l9-nor compounds as well as IO-methyl compounds. They also include l3-methyl, -ethyl and -propyl compounds.
  • the compounds of the invention may, for example, belong to the androstane, l9-norandrostane (or oestrane), l8-methyloestrane or l8-ethyloestrane series.
  • Compounds of the invention which are of particular interest are those which exhibit oestrogenic and/or progestational activity; such compounds may be used in the control of fertility.
  • An important compound according to the invention is 17a-(5-hydroxy-5-methyl-l,3-hexadiynyl)-3- methyoxy-l,3,5( l) -oestratrien-l7B-ol which is a potent oestrogen many times more active than ethynyloestradiol as evidenced by vaginotrophic assay.
  • This compound may be administered at a daily'dosage of from 1 to 10 .g in association with a progestational compound, e.g., megestrol acetate at a daily dosage of from 2 to mg, to women for 21 days during each menstrual cycle for the avoidance of fertility.
  • Compounds of this invention show an unusual separation of oestrogenic and anti-fertility activities in the experimental rat, in comparison with ethynyl oestradiol.
  • the oestrogenic potency determined in the conventional uterotrophic assay, is found to be small relative to the anti-fertility activity.
  • the oestrogenic potency determined in the vaginotrophic assay is significantly greater than in the uterotrophic assay and corresponds more closely to the anti-fertility activity.
  • a sepration of potency between uterotrophic and vaginotrophic assays, relative to ethynyl oestradiol is quite unexpected.
  • a compound which, in the human, showed antifertility activity greater than corresponds to its overall hormonal activity offers advantages in oral contraceptive preparations in terms of decreased side-effects and increased safety, compared with ethynyl oestradiol, at present widely used in such preparations.
  • Important compounds according to the invention by virtue of the separation of their oestrogenic and antifertility activities include a. 17a-(5-hydroxy-5-phenyl-l ,3-pentadiynyl)-3- methoxy-l ,3 ,5( lO)-oestratrien 1 713-01;
  • Compounds according to the invention exhibiting significant anti-fertility activity include .1713 -(5- hydroxy-l,3-hexadiynyl)-4-androsten17B-ol-3-one and l7a (5-hydroxy-5-methyll ,3-hexadiynyl)-4-oestrenl7fl-ol-3-one.
  • the compounds of the invention may be prepared by any suitable method.
  • a further aspect of the invention provides a process for the preparation of said compounds which comprises reacting a mixture of an ethynyl compound R C 5 CH and a haloethylnyl compound R C E CBr wherein one of R, R" is a steroidal moiety to which the ethynyl or haloethynyl group is linked in the a-configuration at the l7-position and the other of R and R is the group wherein R and R have the above-defined meanings in a the presence of a cuprous salt, whilst maintaining said cuprous salt in the reduced state.
  • cuprous salt which is preferably a cuprous halide e.g., cuprous chloride, although other cuprous salts (e.g., the acetate) may be used.
  • cuprous halide e.g., cuprous chloride
  • cuprous salts e.g., the acetate
  • the two ethynyl reactants may be used in approximately equivalent proportions, or one may be in moderate excess. It is desirable to carry out the reacton in the presence of a base to assist the desired reaction and to take up hydrogen bromide.
  • the base is a relatively strong organic base, e.g., a lower alkylamine such as ethylamine or triethylamine it may fulfil both functions; where it is a relatively weak organic base it should be used in association with an inorganic base, e.g., powdered sodium hydroxide or powdered calcium carbonate.
  • a relatively strong organic base e.g., a lower alkylamine such as ethylamine or triethylamine it may fulfil both functions; where it is a relatively weak organic base it should be used in association with an inorganic base, e.g., powdered sodium hydroxide or powdered calcium carbonate.
  • a reducing agent is desirably present in the reaction mixture.
  • a preferred reducing agent is hydroxylamine or a salt thereof. It is advantageous to perform the reaction in an inert atmosphere, e.g., nitrogen.
  • Suitable temperatures for the reaction range between -l0 and 30C, preferably 5 to +5C.
  • reaction medium which should be sufficiently polar to dissolve at least a minor amount of the cuprous salt of the ethynyl compound R -C E CH. It is not necessary for the reactants to be completely in solution but the reaction appears to take place in solution! It is highly desirable for the reaction medium to contain water.
  • Suitable reaction media include lower alcohols (e.g. methanol or ethanol) or their mixtures with dimethylformamide, dimethylacetamide or dimethylsulphoxide, a proportion of water being present.
  • a reagent e.g., potassium cyanide
  • the reaction mixture may be diluted with water and filtered or extracted with a solvent such as ether. Final purification may be by chromatography and/or recrystallisation.
  • the steroid starting material may require protection from any reducing agent present in the reaction mixture. This may be achieved by converting the oxo group into, e.g., an enol ether, enamine, ketal, thioketal or oxime. Conveniently an excess of hydroxylamine may be used as reducing agent, whereby the oxo group is converted into an oxime. Thereafter the oxo group may be regenerated as desired. However, it may be found that an oxo group is not attacked to a sufficient extent to warrant protecting it.
  • Compounds according to the invention containing a 17B-hydroxy group may be prepared by reacting a 17- oxo steroid with a compound of the general formula wherein R and R are as defined above and M is Li, Na, K or Mg Hal (wherein Hal Cl, Br or l),and subsequently regenerating the desired derivative from the resulting complex.
  • M is Na, K or MgHal protection of the OH group of the acetylenic compound, e.g., by prior conversion into a tetrahydropyranyl ether, may be advantageous.
  • the desired derivative is obtained by regeneration from the resulting complex by conventional procedures.
  • a still further method of preparing compounds according to the invention comprises treating a metal derivative (e.g., a Grignard reagent) of a l7q-(buta-l,3- diynyl) steroid compound with an aldehyde or ketone of the general formula RRCO, where R and R are as defined above.
  • a metal derivative e.g., a Grignard reagent
  • compositions according to the invention are intended for administration to both humans and animals.
  • pharmaceutical as used herein to describe compositions and carriers means therefore that these are of use in both human and veterinary medicine.
  • compositions are preferably in the form of dosage units and may be formulated for daily oral administration in such forms as tablets, capsules, sachets etc., either for taking directly or with a draught. Suppositories for rectal absorption may also be employed. Injection preparations may be formulated, preferably for more prolonged action, while implantation pellets may be formulated having the advantage of requiring very infrequent administration.
  • Conventional pharmaceutical excipients for solid preparations may for instance include sugar alcohols, sugars, starch, magnesium stearate, gelatine, polyethylene glycols and suitable colouring agents. Tablets may be coated for protection, colour distinction or elegance by conventional methods such as film coating or sugar or pearl coating. Suppositories may be prepared, using conventional bases such as glyco-gelatine, cocoabutter, or water-dispersible bases with a melting point above body temperature, such as polyglycols.
  • preparations for intramuscular of subcutaneous administration may be prepared in conventional sterile oily, aqueous or emulsion bases, in solution and/or suspension.
  • Vehicles preferably include physiologically acceptable vegetable oils, e.g., arachis oil, fractionated coconut oil; oily esters, e.g., isopropylmyristate; non-aqueous solvents, e.g., propylene glycol; aqueous vehicles such as sterile water or physiological saline; together with suitable formulatory agents such as suspending agents, e.g. aluminium stearate for oily materials, carboxymethyl cellulose for aqueous preparations; physiologically acceptable emulsifying agents,
  • injections may be formulated for immediate use, or as a dry powder for re-constitution before use with a separate vehicle. Unit injections required for prolonged action, e.g., 1 months duration, would naturally contain an increased quantity of active material.
  • Each dosage unit for daily administration to humans preferably contains 1 g to 5 mg active material according to the invention depending on the condition being treated and the potency of the compound.
  • Implantation pellets would in general contain a much higher dosage to cover prolonged activity for preferably several months. implants may be prepared aseptically from sterile material, by fusion or heavy compression, preferably without the addition of other substances.
  • long acting vaginal inserts such as tampons and pessaries, may be prepared in a conventional manner.
  • the dosage required for animal treatment will of course, vary according to the size of the animal.
  • the progestational compounds of the invention may be employed as oral contraceptives, preferably either in daily doses of 0.1 mg to 5 mg on approx. 2l days in each menstrual cycle along or mixed with an oestrogen, e.g., ethynyl oestradiol 0.05 or 0.1 mg.
  • an oestrogen e.g., ethynyl oestradiol 0.05 or 0.1 mg.
  • progestagens may be employed clinically in the following conditions; dysmenorrhoea, functional uterine bleeding, premenstrual tension, diagnosis of pregnancy, and endometriosis.
  • Example 1 17a-(5-Hydroxy-5-phenyl-l ,3-pentadiynyl)-3- methoxy-l ,3,5( l0)-oestratrien- 175-01
  • a solution of ethynyl-phenyl-carbinol (3.4 ml) in N,N-dimethyl-formamide (40 ml) was added to a stirred mixture of cuprous chloride (0.38 g), hydroxylamine hydrochloride (0.86 g), methanol (47 ml), N,N-dimethyl-formamide (80 ml), and aqueous ethylamine (9.7 ml) and the mixture was stirred for 1 hour under nitrogen at room temperature.
  • Example 2 l7a-(5-Hydroxy-5-p-tolyll ,3-pentadiynyl)-3- methoxyl ,3 ,5( l0)'oestratrien- I 73-01
  • Sodium 23 g was added to liquid ammonia (l litre) during passage of a stream of acetylene, to form the mono-sodium derivative of acetylene.
  • p-Tolualdehyde (l20 g) in tetrahydrofuran (500 ml) was added and the mixture stirred under reflux, with continued passage of acetylene, for 3 hours.
  • the ammonia was allowed to evaporate and the residue treated with water, acidified and extracted with ether. Distillation of the ether layer gave ethynyl-p-tolyl-carbinol b.p. 78/0.3mm.
  • Example 3 a Preparation of ethynyl-(2-naphthyl)-carbinol.
  • Ethyl magnesium bromide prepared from ethyl bromide (30.0 g) and magnesium (6.8 g), in tetrahydrofuran (175 ml) was added during 2 hours to a saturated solution of acetylene-in tetrahydrofuran (150 ml). The mixture was stirred for 2 hours during continued passage of acetylene. Z-Naphthaldehyde- (25.0 g) was added and the mixture heated under reflux for 1 hour and allowed to cool. Saturated aqueous ammonium chloride solution (50 ml)v was then added to the mixture which was extracted with ether.
  • Example 4 7a-(5-Hydroxy-5-o-ch1orophenyl-1 ,3-pentadiynyl)-3- methoxy-1,3 ,5(10)-oestratrien-173-ol.
  • Example 5 17a-(5-Hydroxy-5,5-diphenyl-1,3-pentadiynyl)-3- methoxy-l ,3 ,5(10)-oestratrien-173-ol.
  • Example 6 a Preparation 17a-bromoethynyl-63-methyl-5a-androstan-33, 5 ,1 73-triol.
  • Example 7 17a-[5-l-lydroxy-5-( l-naphthyl)-l ,3-pentadiynyl1-3- methoxy l,3,5( l)-oestratrien-l 73-01.
  • Example 8 17a-(5Hydroxyl-S-cyclohexyl-1,3-pentadiynyl)-3- methoxy-1,3 ,5( )-oestratrien- 1 75-01.
  • the precipitate was collected and purified by crystallisation from ether/cyclohexane giving l7a-(5-hydroxy-5-omethoxyphenyl-l,3-pentadiynyl-3methoxy-1,3,5( l0)- oestratrien-l7B-ol, containing cyclohexane of crystallisation, m.p. ill-defined, (a],, 22.5 (C- 0.4 in dioxan), Mm 220mm (6, 20500), 246.2 nm (e. 1950), 277 nm (e, 5400).
  • Example 10 a Preparation of p-biphenylyl-ethynyl-carbinol.
  • Ethyl magnesium bormide prepared from ethyl bromide (12.0 g) and magnesium (2.7 g) in tetrahydrofuran (50 ml) was added during 30 minutes to a saturated solution of acetylene in tetrahydrofuran (60 ml). The mixture was stirred for 1 hour during continued passage of acetylene. A solution of pphenylbenzaldehyde (8.5 g) in tetrahydrofuran (40 ml) was then added and the mixture heated under reflux for 1 hour and allowed to cool. Saturated aqueous ammonium chloride solution (25 ml) was then added and the mixture extracted with ether.
  • Crystallisation from cyclohexane gave l7a-(5-hydroxy- S-p-methoxyphenyl-l,3-pentadiynyl)-3-methoxy- 1,3,5( 10)-oestratrien-l 713-01, containing cyclohexane of crystallisation, m.p. 106C, [Glo -30.5 (C, 0.15 in dioxan); Km. 23 0 rim (a, 22700), 276 nm (e, 4600), 281 nm (e, 4200); M 286.5 nm (e, 3100).
  • Example 12 l7a-(5-l-lydroxy-5-methy1-l ,3-hexadiynyl)-3-methoxy- 1 ,3 ,5( 10 )-oestratrien- 1 73-01
  • a solution of 2-methyl-3-butyn-2-ol (3.00g) in N,N-dimethylformamide (50 ml) was added to a stirred mixture of cuprous chloride (0.43 g), hydroxylamine hydrochloride (1.01g), methanol (52 ml), N,N-dimethylformamide (84 m1), and 70% aqueous ethylamine (13.6 ml), and the mixture was stirred for 1 hour under nitrogen at room temperature.
  • the precipitate was collected a purified by crystallisation from a mixture of di-iso-propyl ether and light petroleum (60-80) and from aqueous methanol, giving 17a-(5-hydroxy-5-methyl-1,3-hexadiynyl)-3- methoxy-l ,3,5( l0)-oestratrien-1 73-01, containing water of crystallisation, m.p. 104C, [ed 53.6 (c, 0.41 in 616x510, Am... 287.7 nm 2000), X 278.5 nm (e, 2200).
  • Example 13 l7a-(5-Hydroxy-5-phenyl-1,3-pentadiyny1)-l,3,5(10)- oestratriene-3 ,17B-diol
  • Silver nitrate (2.00 g) was added to a stirred solution of 3-acetoxy-l7a-ethyny1-1,3 ,5( l0)-oestratrien- 1 75-01 (2.00 g) in a mixture of ethanol (100 ml) and water (30 ml) and the mixture was stirred at room temperature for 35 minutes.
  • N-Bromosuccinimide (2.00 g) was added and the mixture was stirred for 5 minutes and then poured into aqueous sodium bicarbonate solution.
  • Ethynyl-phenyl-carbinol (5.0 ml) was added to a stirred mixture of cuprous chloride (0.60g), hydroxylamine hydrochloride (l.40 g), methanol (70 ml), N,N-dimethylformamide (120 ml) and 70% aqueous ethylamine (14.6 ml) and the mixture was stirred for 1 hour under nitrogen at room temperature. It was then cooled to 0C and 3-acetoxy-l7a-bromoethynyl- 1,3,5(l0)-oestratrien-l7B-ol (10.00g) in N,N-dimethylformamide (130 ml) was added during 1 hour.
  • Example 14 17a-(5-Hydroxy-5-methyl-l,3-hexadiynyl)-1,3,5(10- oestratriene-3 ,1 7fl -diol 2-Methyl-3-butyn-2-ol (0.60 g) in N,N-dimethylformamide (13 ml) was added to a stirred mixture of cuprous chloride (0.1 16 g), hydroxylamine hydrochloride (0.26 g), methanol (14 ml), N,N-dimethylformamide (24 ml) and aqueous ethylamine (3.0 ml) and the mixture was stirred at room temperature for 45 min. and then cooled to 0C.
  • Example 15 l7a-(5-Hydroxy-l ,3-hexadiynyl)-3-methoxy- 1 ,3,5( l0)-oestratrien-1 73-01 55%
  • Aqueous 1-butyn-3-ol (1.30 ml) was added to a stirred mixture of cuprous sulphite (0.10 g), hydroxylamine hydrochloride (0.15 g), methanol 12 ml), water (4 ml), and 70% aqueous ethylamine (3.4 m1) and the mixture was stirred at room temperature under nitrogen for 45 min. and then cooled to 0C.
  • Example 18 l7a-(5-Hydroxy-5 -methyl- 1 ,3-hexadiynyl )-4-oestren- 173-o1-3-0ne 17a-Ethynyl-3-methoxy-3,5-oestradien-173-01 l 3.- 6g.) in N,N-dimethylformamide (340ml.) was added to a stirred mixture of cuprous chloride (l.13g.), hydroxylamine hydrochloride (3.40g.), methanol (142m1.), N,N-dimethylformamide (226.5ml.) and 70% aqueous ethylamine (34ml.) and the mixture was stirred at room temperature under nitrogen for min.
  • cuprous chloride l.13g.
  • hydroxylamine hydrochloride 3.40g.
  • methanol 142m1.
  • N,N-dimethylformamide 226.5ml.
  • Example 19 l7a-( S-Hydroxy-S-methyl-l ,3-hexadiyny1)-5- androstene-33,1 73-diol 17a-Ethynyl-5-androstene-33,l73-diol (7.00g.) in N,N-dirnethylformamide (150m1.) was added to a stirred mixture of cuprous chloride (0.50g.), hydroxylamine hydrochloride (l.00g.),' methanol (6.25ml.), N,N-dimethylformamide (l00ml.) and 70% aqueous ethylamine m1.), and the mixture was stirred under nitrogen while cooling to 0C.
  • a compound having sex hormonal activity selected from the group cnsisting of steroid compounds of the androstane of oestrane series possessing a 173- hydroxy, lower alkoxy or lower alkanoyloxy group and being substituted in the 17oz-position by a group of the structure wherein R is selected from the group consisting of carbocyclic aryl, benzyl, phenethyl, 2-pyridyl, 3-pyridyl, 2- thienyl, 3-thieny1, alicyclic, and alkenyl having 2-5 carbon atoms;
  • R is selected from the group consisting of hydrogen
  • R and R together with the carbon atoms to which they are attached form an alicyclic ring.
  • a compound as defined in claim 1 having an oxygen function at the 3-position.
  • a compound as defined in claim 1 possessing olefinic or aromatic unsatruation in ring A.
  • R or R is selected from the group consisting of phenyl, 1- naphthyl, 2-naphthyl, o-biphenylyl and p-biphenylyl groups, and groups of this character substituted by at least one member selected from the group consisting of fluorine, chlorine, bromine, hydroxy, C -C alkyl, C,-C alkoxy and trifluoromethyl groups.
  • R is selected from the group consisting of cyclohexyl, adamantyl, vinyl, propenyl and isopropenyl;
  • R is selected from the group consisting of cyclohexyl, adamantyl, vinyl, propenyl, isopropenyl, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, and n-pentyl.
  • a compound as defined in claim 1 selected from the group consisting of l7a-(5-hydroxy-5-pehnyl-l ,3-pentadiynyl)-3- methoxyl ,3,5( lO)-oestratrien-173-o1;

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US00037035A 1969-05-16 1970-05-13 17a-(5{40 -substituted-5{40 -hydroxy-penta-1{40 , 3{40 -diynyl)-steroids Expired - Lifetime US3758521A (en)

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GB1427141A (en) * 1972-05-03 1976-03-10 Bdh Pharmaceuticals Ltd 17-alka-1,3-diynyl- steroids
DE2527352A1 (de) * 1975-06-19 1976-12-30 Merck Patent Gmbh Alkin-derivate und verfahren zu ihrer herstellung
US4196215A (en) 1975-06-19 1980-04-01 Merck Patent Gesellschaft Mit Beschraenkter Haftung Alkyne compounds and method of use
JPS60174049U (ja) * 1984-04-18 1985-11-18 和泉電気株式会社 回路遮断器

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Publication number Priority date Publication date Assignee Title
US3164617A (en) * 1962-02-02 1965-01-05 British Drug Houses Ltd 17alpha-butadiynyl-17beta-hydroxy derivatives of perhydrocyclopentenophenanthrene and process for preparation of same
US3463797A (en) * 1966-02-03 1969-08-26 British Drug Houses Ltd Substituted - 17alpha - buta - 1',3'-diynyl-17beta-hydroxy(17beta-alkoxy)-steroids and process for preparation thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3164617A (en) * 1962-02-02 1965-01-05 British Drug Houses Ltd 17alpha-butadiynyl-17beta-hydroxy derivatives of perhydrocyclopentenophenanthrene and process for preparation of same
US3463797A (en) * 1966-02-03 1969-08-26 British Drug Houses Ltd Substituted - 17alpha - buta - 1',3'-diynyl-17beta-hydroxy(17beta-alkoxy)-steroids and process for preparation thereof

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Publication number Publication date
DK129340C (enrdf_load_stackoverflow) 1975-02-17
NL7007153A (enrdf_load_stackoverflow) 1970-11-18
ZA703304B (en) 1971-12-29
GB1307360A (en) 1973-02-21
JPS4842069B1 (enrdf_load_stackoverflow) 1973-12-10
ES379730A1 (es) 1973-01-16
SE374741B (enrdf_load_stackoverflow) 1975-03-17
CA952899A (en) 1974-08-13
IE34171B1 (en) 1975-02-19
FR2051531A1 (enrdf_load_stackoverflow) 1971-04-09
BE750461A (fr) 1970-11-16
DE2023917A1 (de) 1970-11-19
FR2051531B1 (enrdf_load_stackoverflow) 1973-08-10
DK129340B (da) 1974-09-30
IE34171L (en) 1970-11-16

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