IL45259A - 1,3-dihydroxy-17-oxygenated-8alpha-oestra-1,3,5(10)-triene derivatives - Google Patents
1,3-dihydroxy-17-oxygenated-8alpha-oestra-1,3,5(10)-triene derivativesInfo
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- IL45259A IL45259A IL45259A IL4525974A IL45259A IL 45259 A IL45259 A IL 45259A IL 45259 A IL45259 A IL 45259A IL 4525974 A IL4525974 A IL 4525974A IL 45259 A IL45259 A IL 45259A
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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
- C07J1/0051—Estrane derivatives
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
- C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
- C07J1/0074—Esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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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
- C07J1/0051—Estrane derivatives
- C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J15/00—Stereochemically pure steroids containing carbon, hydrogen, halogen or oxygen having a partially or totally inverted skeleton, e.g. retrosteroids, L-isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0072—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the A ring of the steroid being aromatic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
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Description
(10)5,3,1-mooK-o 8-Όρητη'>3,1 nn in 1 ,3-d1hydro*y-1 -c»y genated-8a-oestra-l ,3,5(10) triene derivatives The present Invention is concerned with 1 ,3-oxygenated 8 -oestratr1enes of the general formula I in which X represents an oxygen atom or the groupl ng R' and R represent a hydrogen atom, an alkanoyl, a methyl-, p-tolyl-, diethylamlno- , 2-propyl- or pi peri di no-sul fonyl , alkyl, cycloalkyl, or tetrah dropyran 1 group, Rg represents a methyl group, and R^ represents a hydrogen atom, or an ethinyl or chloroethi nyl group.
In Israel Patent 25774 which corresponds to Brit. Pat. 1 128 254 and 1n U.S. Patent 3 686 238 there are described compounds similar to those of the present Invention and which differ from the present compounds only by the stereo configuration at the 8-pos1 tion^ said prior art compounds relating to 80-stero1ds as opposed to the 8a-stero1ds of the present Invention.
As shown 1n comparative example 27 hereinafter the 8a-compounds of the present Invention exceed the corresponding 86-sterolds In the dissociation of vaglnotroplc and uterotropic estrogenic effects and the ratio of desired vaglnotroplc activity to undeslred uterotropic activity 1B more pronounced 1n the compounds of the present Invention than 1n the corresponding prior art 83-1somers thereof.
The compounds of the Invention exhibit a favourable dissociated pharmacological activity. Owing to their strong vaginotropic and weak uterotropic action they are more especially suitable for the treatment of women 1n the post-menopause. Thus, they can be used for the treatment of oestrogen-deficiency phenomena, 1n which a centrally controlled action on the uterus Is to be avoided, but an action of the vagina 1s desired. The compounds of the Invention are also useful as Intermediate products for the preparation of pharmacologically valuable steroids.
The favourable oestrogenlc dissociation can be demonstrated, for example, in the sialic add test on the mouse. Thus, the compounds of the Invention exhibit a dissociation quotient which 1s far superior to that of the standard compounds, as 1s shown In Table 1 by way of example with reference to the known oestrogens l7o-eth1nyl-l ,3,5(10)-oestratr1en-3,l78-d1ol (I) and .■»! ,3,5(l0)-oestratr1en-3,l76-d1ol (II) and the new steroids 1 ,3,173-tr1acetoxy-8o-oestra-1 ,3,5(l0)-tr1ene( III) , 1 ,3-d1acetoxy-8a-oestra-1 ,3,5(l0)-tr1en-l73-ol (IV), 1 ,3-d1acetoxy-8o-oestra-l ,3,5(10)-trlen-17-one (Vjj, 1 ,3-d1methoxy-8ct-oestra-l ,3,5(10)-trien-17-one (VI), 1 ,3-d1cyclopentyloxy-8 -oestra-l ,3,5(l0)-tr1en-l7-one (VII), 1 ,3-d1hydroxy-8 -oestra-1 ,3,5(10)-tr1en-l 7-one (VIII), 1 ,3-d1methoxy-l7a-eth1nyl-8ct-oestra-l ,3,5(l0)-tr1en-17B-ol (IX), 1 ,3-d1acetoxy-l7ct-eth1nyl-8ot-oestra-l ,3,5(10) trlen-173-ol (X) and l, -dimetho-qr^«oestra-l,3,5(lO)-trien-17-ol (Xi).
Table 1 No. Name Thr^s ^ld value Dissociation quotient B.C. p.o. e.c. p.o, I 17o-Ethinyl-l,3,5(io)«- oestratrien-3,17P-diol 0.0003 0.01 0.4 0.8 II 1» 3»5( 10 )-0estratrien- 3,17p-diol 0.0005 0.05-0.1 1.0 1.0 IV 1 , 3-Dlacetoxy^6-oestra- 1,3, 5(lO)-trien-17-ol 0.03 7.0 6.0 V 1 , 3-Diaoetoxy^8a«oestra- 1,3,5(l0)-trien-17«>ne 0.03 0.03-0.1 4.0 2.0 VI 1 , 3-Dinethoxy-8a-oe8tra- l,3»5(l0)*trien-17*one 0.1-0.3 2.3 VII 1 , 3-Dicyclopentyloay-^a- oestra-l,3,5(l0)-trien-17-one 2.3 IX 1 , 3-Dlmethozy-17a-ethinyl- 8a-oestra-l,3,5(l0)-trien-17^1 0.1 0.3 3.2 X l,3-W.acetoxy-17-ethlnyl- 8a^estra-l,3,5(l0)-trien*17 l 0.003 0.3 1.8 2.0 XI l,3-Diinet oxy-8a-oestra- l»3,5(l0 trien-17 l 0.1-0.3 0.1 2.5 2.3 The sialio acid test is carried out as follows! - - The mice are ovarectomised. From the 10th day after castration the animals receive the substance to be tested once daily for 3 days.
On the 4th day the animals are killed* The vagina and uterus are immeditely removed by dissection and for hydrolysis weighed in a test tube. '. ¾¾1ΐ1 Determination of the sialic acid is carried Out by the Svemerholm method -(Biochem.Biophys. Acta 24 (1957) 604). The dose-dependent increase in the weights Of the vagina and uterus and also the decrease in content of sialic acid are determined, from which the relative strengths of action of the substance' to be tested as compared with the standard substance, oestradiol (il), are ascertained. The relative activities are expressed as ratios, and give the degree of dissociation Q. For the standard compound, oestradiol, Q is equal to 1. Compounds having A greater than 1 are relatively vaginotropic, and those having Q less than 1 are relatively uterotropic.
The threshold values given in Table 1 were determined by the usual Allen-Doisy test o rats,.
The invention also provides medicinal preparations which contain Sa-oeetratrienes of the general formula I as active substances.
The medicinal preparations are made up in the usual manner by converting the active substances with.the carrier substances, diluents, taste correctives, etc. customary in galenical pharmacy into the desired form of application,, such as tablets, dragees, capsules, solutions, etc. The concentration of the active substance in the medicinal preparations so formulated depends on the form of application. Thus, a tablet preferabl contains 0,01 to 10 mg, and solutions for parenteral administration contain 0.1 to 20 mg per ml of solution.
The iosage of the medicinal preparations of the invention may var^. depending on the form of administration and the particular compound chosen. Moreover, it may vary depending on a particular patient to he treated. In general the compounds of the invention are administered at a concentration that gives effeotive results vithout causing any disadvantageous or harmful side effects. Thus, they are administered, for example, at a dosage within the range of about 0.02 mg to about 20 mg, although in some circumstances charges may be'made, so that a ¾osage exceeding 20 mg, for example, up to 50 mg, may be vised. However, a dosage within the range of about 0.05 mg to about 5 mg is preferably used.
The compounds of the general formula I can be prepared by hydro-genating in a manner in itself known an oestra*oligoene of the general ormula II in which R ., R and X have the meanings given above, and Δ»-»-, B represents a single or double bond, and then optionally, depending on the finally desired meaning of X and RA, reducing the 17-keto group and or splitting off ether or acyl groups and or esterifyin and/or etherifying free hydroxyl groups.
The compounds of the general formula I can also be prepared by 2 oxidising a 3-hydroxy-13-R -ea«-oeetra-l,3,5(l0)-trien-17-one with lead tetracylate, rearranging the reaction product in the presence of a strong acid, and optionally then, depending on the desired meanings of and R1, reducing the 17-keto group and/or splitting off ether or aoyl groups and or esterifying andor etherifying free hdroxyl groups.
The preparation of the new compounds is carried out by methods in themselves known.
The hydrogenation of the oestra-oligo-enes of the formula II may be carried out, for example, by catalytic hydrogenation. As catalysts there come into consideration, inter alia, heavy metal catalysts, such as palladium, optionally distributed on carriers, such as calcium carbonate, active carbon or barium sulphate, o there, may be used Raney nickel* During the hydro-genation an unsaturated hydrocarbon group R 4 optionally present in the I , . molecule may be partially co-hydrogenated. If the finally desired compounds are compounds in which R 4 represents an unsaturated hydrocarbon group, it is of advantage first to carry out the hydrogenation upon compounds of the formula II in which X represents an oxygen atom, and then to carry out the reduction with an organo-metal compound in which the organic residue R 4 is an unsaturated hydrocarbon group.
The oxidation with lead tetracetate and the subsequent rearrangement in the presence of acids is known from the literature in the case of 3-hydroxy-e--oestra-l,3.5(lO)-trieneB, but cannot be applied to the corresponding 3-hydroxy-6a-oestratrienes (Rufer et al., Liebigs Ann. Chem. 732 «•1971- 5)· As opposed to Rufer et al., the reaction can be carried out successfully by effecting the oxidation with a lead tetra-acylate in the usual manner, but interrupting the reaotion after a short time, for example, after three minutes. Then working up and rearrangement follow in the usual manner.
A 17-keto group may subsequently be reduced, for which purpose many methods in themselves known are available.
The reduction can be carried out by reaotion with hydrogen in the presence of one of the usual catalysts, for example, Raney nickel, in ψ& benzene. The hydrogen may also be transferred to the 17-keto group from metal hydrides* As hydrogen donators there are especially preferred complex hydrides, for example, sodium hydrldoborate, lithium hydridoa-luminate, sodium hydridotrimethoxoborate, lithium hydridotri-tert.-buto-xoaluminate, etc.
The reduction can also be carried out by known methods with an 4 organo-metal oompound, in which the organic residue is R , and which may be an alkyl magnesium halide, for example, methyl magnesium bromide or iodide, an alkenyl magnesium andor alkenyl zinc halide, for example, vinyl magnesium bromide or allyl magnesium bromide, an alkinyl magnesium halide such as ethinyl magnesium bromide, propinyl magnesium bromide or propinyl zinc bromide, or an alkali metal acetylide, such as potassium acetylide. The organo-metal compound used as reducing agent may also be formed and brought into reaction, in situ, with the 17-ketone of the formula II. Thus, for example, for reacting organo-metal aUdnyl compounds with the ketone in a suitable solvent an alkine, chloralkine or alkadiine and an alkali metal can be reacted, advantageously in the presence of a tertiary alcohol or ammonia, and optionally under superatmospherlc pressure.
Free hydroxyl groups may subsequently be esterified or etherified. Esteriled or etherified hydroxyl groups may be converted into the free hydroxyl groups.
The acylation in the 1- and 3-position is preferably carried out with pyridine/acld anhydride or pyridine/acid chloride at room temperature. For etherification in the 1-and 3-position alkylating compounds are used, such as, preferably, diazomethane, dialkyl sulphate, cycloalkyl halides and (llhydropyrane.
For esterification of the 17p-hydroxyl group in 1,3-diesters and l,3-cLiether8 the steroid may he reacted for example, with acid anhydride in the presence of strong acids such as para-toluene nulphonic acid, HC10 or pyridine/acid anhydride, at a raised temperature. The last-mentioned methods oan also be used for converting the free trloxy-compound directly into the tiiacylate. The 1- and 3-hydroxyl groups can be liberated from the triacylates by careful partial hydrolysis.
The 1,3-diesters and 1,3-diethers can be converted with dihydro-pyrane in the presence of a strong acid, such as para-toluene sulphonic acid, into the corresponding 17-tetra-hydropyranyl ethers* The etherlfi-cation of the 17-hydroxyl group in the 1,3-diethors of the invention with a alkyl residue is preferably carried out with alkyl halides in liquid ammonia. The two last mentioned methods also enable all the hydrox 1 groups in the hydroxy-compounds of the invention to be etherified in a single operation.
In l,3-diacyl-17-tetraliydropyranyl derivatives the 1- and 3-ΌΗ groups can be liberated by alkaline hydrolysis.
The ether splitting is carried out by methods in themselves known. There may be mentioned, for example, splitting by means of pyridine hydrochloride or pyridine/concentrated hydrochloric acid at a raised temperature (l8O-22O°) or with hydrohallc acids in the presence of lower carboxylic acids at temperatures below 150°C, and the splitting of tetrahydropyranyl ethers is carried out under mild conditions by the addition of acid.
For increasing the yield it may be of advantage to start from compounds in which the hydroxyl groups in 1- and 3-position are ester-ified or etherified. For example, if the ether residues are to be introduced only as Intermediate protected groups, it is of advantage to etherify with dihydropyrane, because, after the reaction, these residues The reduction may also be carried out in a manner such that ester groups present in the starting product remain unchanged.
Alternatively, hydroxy1 groups in the 1- and/or 3-position liberated during the reaction may be selectively reacylated, 3-Hydroxy««8a-oestra-1 ,3»5(lO)-trien-17-ones are known from the literature. The other starting compounds can be prepared, for example* rom 1 ,3-dimethoxy-l ,3,5(10),8,14-oestrapentaen-17-one (A), 1 ,3-di-taethoxy« 17P-acetoxy-1 ,3»5(l0),8,14-oestrapentaene (B) and 1 ,3-
At 1.3-Dimethoxy-l . .5(ΐθ).8.H-oeetrapentaene-l7-one To a suspension of 17 grams of magnesium shavings in 15 ml of absolute tetrahydrofurane are added a trace of iodine and 2 ml of ethyl bromide, and, after heating to 50°C, vinyl chloride is slowly introduced until the temperature falls to room temperature. During the introduction 250 ml of absolute tetrahydrofurane are added dropwise.
Into this vinyl Grignard solution is slowly added dropwise at 20°C. a solution of 52.4 grams o 6,8-dimethoxy-tetralone 84 ml of absolute tetrahydrofurane and 82 ml of absolute benzene, and the whole is allowed to stand overnight in a cooling chamber under nitrogen. After warming to room temperature,- the whole is introduced into a mixture of 84 ml of glacial acetic acid and 350 ml of^ce-^water, stirred for 30 minutes* the aqueous phase is separated off and extracted with benzene. The combined organic extracts are washed neutral with sodium hydrogen carbonate solution and water, and dried. To this solution of the vinyl compound are added 38 grams of 2-methyl<«cyclopentan-dione-(1,3) and 60 mg potassium hydroxide (powdered), the mixture is concentrated to half of its volume, 170 ml of methanol are cautiously added dropwise, and the whole is heated at the boil for three hours under nitrogen. The mixture is allowed to cool to room temperature, diluted with ether, and the excess of 2-methyl-cydopentandione-(1 ,3) Is removed by extraction with a sodium hydroxide solution of 10^ strength. After washing the mixture neutral with water, drying and evaporating, the residue is reorystallised from ethanol. There are obtained 66 grams of 1 ,3-dimethoxy-8,14-3θCO- 1 ,3,5(l0),9(l 1 )^estratetraen-14,17-dione, melting at 87/88-89°C.
A solution of 69 grams of 1 ,3-dimethoxy-8.14-seeo-1 ,3»5(10), 9(11 )-oestratetraen-1 ,17-dione in 940 ml of distilled benzene is mixed with 3 grams of para-toluene sulphonic acid, and the whole is heated at the boil for 20 minutes. After cooling, the mixture is extracted with a cold solution of sodium hydrogen carbonate, washed neutral with water, and dried. By recrystallisation from acetone/hexane over carbon there are obtained 60 grams of rao.- 1,3i-dimethoxy*1,3»5(ΐθ),8,14-oestrapentaen-17-one melting at 120- 121°C. ■ " . _ i .¾-Dimethoxy-173-acetoxy-1.3«5(lO).8.14-oestrapentaene To a solution of 60 grams of rac.-1 ,5-
The following Examples illustrate the invention. The compounds are obtained both in the form of racemates and enwntiomers. It is obvious to a person skilled in the art that the racemates can be split^Lnto the enantiomers by methods of separation such as are ' generally known for the separation of optical antipodes. Thus, the invention includes racemates and enantiomers, Example^ rac-1 ,3^dimethoxy-^o-oestra-1 ,3»5(l0)-trlen-17-one. 0.3 gram of rac.-1 ,3-dimeth0J.y-1 ,3»5(l0),8,14-oestrapentaen- 17-one in 50 ml of tetrahydrofurane is hydrogenated in the presence of 0.1 gram of palladium/CaCO (¾¾ strength) in the course of 3 7 hours at room temperature under a pressure of hydrogen of 50 atmospheres gauge. The catalyst is then filtered off, the filtrate is evaporated, and the residue is recrystallised froin isopropyl ether. There are obtained 40 tag melting at 158-160°C, Sample, ¾ rao.-1 ,3-Dimethoxy-17P-ecetoxy-8o-oestra-1 ,3t5(lO)-triene. (a) 61 grams rac.-1,3Hiimetho--y-17P-aceto-5y-1,3»5(lO),8,14-oestrapentaene in 400 ml of benzene are hydrogenated in the presence of 14 grams of Raney nickel in the course of 17 hours at room temperature under a preseure of hydrogen of 50 atmospheres gauge. The catalyst is then filtered off, the filtrate is evaporated, and the residue is recrystallised from methanol over carbon. There are obtained 50 grams melting at 136-138°C. ( & 100 mg of rac.-1,3-dimethoxy«17P-acetoxy-1 ,3,5(10),8-oestratetraene are hydrogenated in 1.4 ml of distilled tetrahydro-furane over 30 mg of { strength) under atmospheric pressure at room temperature until hydrogen is no longer,absorbed. By filtration and evaporation there are obtained, after reorystallisation from methanol, 44 mg melting at 126/130-131°C.
In an analogous manner there are obtained: rao7.-1 ,3-Dlmetho-fy-17P-ac#toxy-18-methyl-8a-oestra-1 ,3,5(10)-triene and rac.-1 ,3-dimetiioxy-17P-aceto3cy-18-ethyl-eo-oeetra-1 ,3»5(lO)-trlene.
Example 3 rac.-1 ,3.17P^riacetoxy-8a-oestra-1 ,3,5(lO)-triene. Δ mixture of 1 gram of rac. -1 , 3-dimethoxy-17p-acetoxy-8a-oestra-1 ,3,5(lO)-triene and 10 grams of pyridine hydrochloride is heated under nitrogen, while stirring, for 3 hours at 200°C. After cooling, the melt is dissolved in 50 ml of pyridine, and stirred with 5 ml of acetic anhydride for 1 hour at room temperature under nitrogen. After precipitation in ice-water, the precipitate is filtered off and worked up. The crude product is purified by gradient chromatography (methylene chloride/acetone - 9 ♦ 1 ). There are obtained 930 mg melting at 146/147-148°C.
In an analogous manner there are obtained! rac.-1 ,3» 7-Trlacetox-18HDaethyl-8a-^)estra-1 ,3#5(l0)-trlene and rac.^1 , 3, 17|J-trlacetoxy-18-ethyl-e
By using caproic anhydride and caprlic anhydride, respectively, instead of acetic anhydride, there are obtained! rac.«1 ,3.17^ris-hexanoyloxy--ea-oestra-1 ,3»5(l0)-triene and rac.-l ,3,17*-tris-octanoyloxy-ea-oestra-1 ,3#5(l0)-triene.
Example 4 rac.^1 ,3-Dlinethoxy-ea-oestra-1 ,3,5(lO)-trien-17β-ο1. 4.5 grams of rac.-1 ,3-diniethoxy-17P-ecetoxy-8a-oeetra-1 ,3,5(lO)-triene in 100 ml of methanol are hydrolysed with 1 ml of an aqueous solution of potassium carbonate (10# strength) by heating under nitrogen for 1 .5 hours under reflux. After cooling the mixture, it is cautiously neutralised with glacial acetic acid, concentrated to one half of its volume, precipitated in ice-water/faaCl and worked up.; There are obtained 4* 1 grams of crude product. By reoryetallieation To a solution of 60 mg of rac.-1 ,3-dimethoxy-8a-oestra- 1»3i5 lO)-trien-17-one in 3 ml of methanol and 1.0 ml of tetrahydrofurane are slowly added at room temperature 60 mg of NaBH^, and the whole is stirred for 30 minutes under nitrogen at room temperature* The mixture is neutralised vith glacial acetic acid, concentrated, taken up in ether, washed neutral with a saturated solution of sodium chloride, dried and evaporated. The residue is dissolved in 1 ml of pyridine, 0.5 ml of aeetic anhydride is added to the solution, and the solution is mahtalned at 80°C for 1 hour under nitrogen. After cooling, the mixture le introduced into ice- water, the precipitate is filtered off aal taken up in ether. The ethereal solution is washed neutral with a saturated solution of sodium chloride, dried and evaporated. Recrystallisation from methanol over carbon yields 42 mg melting at 131-134°C.
S*amPl 6 rac-1 , 3-Dimethoxy-17a-ethinyl-8a-oestra-1 ,3,5(lO)-trien- 1.2 grams of potassium tert.-butylate (10 mMol), 2.5 ml of tert.-butanol and 20 ml of absolute tetrahydrofurane are intrq&n&pd into an autoclave, scavenged with nitrogen and filled with acetylene to a pressure of 4·5 atmospheres gauge. After 30 minutes, 740 mg of ¾ rac.-1,3-dimethoxy-8a-oestra^ in 5 ml of absolute tetrahydrofurane are introduced, and the mixture is reacted for 45 minutes under acetylene pressure. Precipitation is carried out in 40 ml of dilute sulphuric acid (20$ strength) and ice, the mixture is extracted with methylene chloride, and worked up. The crude product is purified by column chromatography. There are obtained by recrystallisation from hexane/acetone 430 mg melting at 177/178-179°C In A analogous manner, but without tert.-butanol as solvent i the ethinylation, there are obtained: rac.-1 ,3-Diiaetho2cy-18-methyl-17a-ethinyl-8a-oestra-1 ,3,5(lO)-trien-17β-ο1 and rac.-1 ,3niimethoxyTl8^thyl-17o^thinyl-eo-oestra-1 ,3,5(l0)-trlen-17 -ol. Example 7 rac.-1 ,3-Dlacetoxy-8o-oestra-1 ,3»5(10)-trien-17-one.
A mixture of 25 grams of pyridine hydrochloride and 2.5 grams of 1 ,3-dimethoxy-8o-oestra-1 ,3,5(lO)-trien-17-one is heated under nitrogen, while stirring, for 3 hours at 200°C. After cooling, adding 120 ml of pyridine and 1 ml of acetic anhydride, and stirring for 1 hour at room temperature, the solution is introduced into ice-water/NaCl, the whole is stirred for l/2 hour, and the precipitate is filtered off and worked up. The crude product (2.5 grams) is purified by gradient chromatography (60 grams of SiOgt methylene chloride/lO# acetone). After recrystallisation from methanol, there are obtained 710 mg melting at 179-180.5°C.
Example 8 rac.-1 ,3-Placetoxy<-17a-ethinyl-8a-oestra-1,3»5(lO)-trien-*17β-ο1· A mixture of 8.3 grams of potassium tert.-butylate, 2.5 ml of tert.-butanol in 20 ml of absolute tetrahydrofurane is stirred in a roll om) after scavenging with nitrogen, tinder acetylene for 1 hour at room temperature. There are then added 740 mg of rac.-1 ,3-diacetoxy- 8o-oeatra-1 ,3,5(l0)-trien-17-one in 5 ml o absolute tetrahydrofurane, and the whole 1B rolled under acetylene at room temperature for 2 hours. The mixture is introduced into 40 ml of dilute sulphuric acid (20 strength), and the precipitate is filtered off and worked up. The crude product is after-acetylated in 5 ml of pyridine with 2 mg of acetic anhydride. After precipitation with water and working up, the crude product (850 mg) is purified by gradient chromatography (20 grams of SiOg, hexane/25$ acetone). There are obtained 152 mg melting at 154-155°C.
In an analogous manner, but without tert.-butanol as solvent in the ethinylation, there are obtained: rac.-1 ,3-Diacetoxy-18-methyl-17a-ethinyl-ea-oestra-1 ,3,5(lO)-trien- 17β-ο1 and rac.-1 ,3-diacetoxy-18-ethyl-17a-et-inyl-8a«oestra-1 ,3»5(lO)-trien- 17β-ο1.
Example 9 (Opt. active) 1, Diacetoxy-8a-*>estra-1 *3,5(10)-txien-17-one.
To a suspension of 42 grams of '~hydroxy-8a-oestra-1 ,3>5(10)- trien-17-one In 500 ml of glacial acetio acid are added 120 grams of lead tetracetate, the whole is then stirred for 3 minutes at room temperature with the exclusion of moisture, and the mixture is poured Into 600 ml of ice-water. The precipitate is filtered off with suction, washed with water, and the filter residue is taken up in methylene chloride. The product solution is washed neutral with sodium hydrogen carbonate solution and water, dried and concentrated. The concentrate is filtered with methylene chloride over 400 grams of silica gel (+10$ of water). The product-containing fractions are combined and freed from solvent. There are obtained 7 grams of 103aoetoxy-8a-oestra- < , i,4-dien-3, 7-dione is the form of an oil.
To a susperielon of 13.0 grama of ΐόβ-acetoxy-ea-oestra-l ,4-dien-3,17-dione in 125 mlcf acetic anhydride is added dropwise 0*7 ml ofi concentrated sulphuric acid, and the whole is stirred for 3 hours at room temperature, the substance slowly passing into solution.. The mixture is then Introduced into 10 times its quantity of ice^water, to which 7 grams of sodium carbonate is added, the whole Is stirred for 1 hour and then filtered. The washed and dried residue is recrystallleed o from methanol. There are obtained 7 grams melting at 208-211 C. 489° (CHDl c - 0.5).
In an analogous manner there Is obtained: 1 ,3-Diacetoxy-18-n3thyl-80-oeatra^1 t3,5(lO)-trien-17-one.
Example 10 1j 3.17P-Trlacetoxy-8o-«estra-1 , 3» 5(10)-triene.
To a solution of 6 grams of 1,3^acetoxy-8a-oestra-1,3,5(lO)-trien- «>ne in 240 ml of methanol and 100 ml of tetraJiydrofurane are slowly added at room temperature 600 mg of NaBH^, and the whole is stirred for minutes under nitrogen at room temperature. The mixture Is neutralised with glacial acetic acid, and acetylated and worked as In Example 5. Yield: 4.8 grams melting at 149/50-151°C. Ca]jj°- 4.2° (CHClJ, c » 0.5). 1 f 3-Dlacetoxy-17o-ethinyl-*8a-oestra-1 , 3» 5(10)-trien-173-ol.
As in Example 8750 mg of 1 ,3-diacetoxy-8a-oestra-1 ,3# 5(ΐθ)-trlen-1 ©one are ethlnylated and worked up. Yield: 230 mg of a non-oryatalllsing foam. [< °* -33.8° (CHCl^, o - 0.5).
In an analogous manner there is obtained: 1 , 3-vWLacetoxy-l8-anethyl-l 7a«^ethlnyl-8o-oestra-1 , 3» 5 (10)-trlen-17β-ο1.
Example 12 /\ 1 ,3-Bis-cyclopentyloxy-8a-oestra-.1 ,3,5(10)-trien-17β-ο1..
A solution of 850 mg of 8o-oestra-1 ,3,5(lO)-trien-1 ,3ι17β-triol In 30 ml of ethanol is heated under nitrogen with 2.5 ml of cyclopentyl bromide and 2.5 grams of potassium carbonate for 5 hours at the boil. The mixture is then introduced into ice-water, taken up in ether, the organic phase is washed, dried and evaporated. After chromatographic purification over silica gel, there are obtained 365 mg Exampe J,? 1 ,3-Bis-butoxy-8a-oestra-1 ,3,5(10)-trlen-17β-ο1.
In a manner analogous to that in Example 12, 500 mg of 8a-oestra-1,3,5(l0)-trien-1,3,17-triol are reacted with 1.5 ml of n-butyl bromide and worked. There are obtained 230 mg* Exampl 14 1 »31 7P-Tris-tetrahydropyranyloxy-8a-oestra-1 ,3,5(10)-triene.
To a solution of 800 mg of 8a-oestra-1 ,3,5(lO)-trien-1 ,3»17β-triol In 40 ml of absolute benzene are added 1.4 ml of distilled dihydropyrane and 10 mg of para-toluene sulphohic acid. The solution is stirred for 1.5 hours at room temperature, and then washed neutral with sodium hydrogen carbonate solution and water, dried and evaporated There are obtained'700 mg of crude product.
Example 15 1 ,3»17-^rio-hexanoyloxy-8a--0estra-1 ,3f5(l0)-triene.
To a solution of 450 mg of 8a-oestra-1,3»5(lO)-trien-1,3,^-triol in 3 ml of pyridine are added 1.5 ml of caproic anhydride, and the mixture is heated under nitrogen for 5 hours at 90°C. The whole is then poured into ice-water, a little methanol is added, and the mixture is stirred for 1 hour, in order to decompose the excess of anhydride. The product is taken up in ether, and the ethereal solution is washed 1 , -Dimethox -17a^lorethlnl^^estra^1 ,3»5(l0)-trien-17β-ο1, A lithium methyl solution is prepared from 1.39 grams of lithium and 6.9 ml of methyl iodide in 50 ml of absolute ether by heating under reflux (45 minutes under nitrogen). After cooling to 0°C#, there are added dropwise 3.75 ml of dichlorethylene in 15 ml of absolute ether. After stirring for 1.5 hours at room temperature, a solution of 1.3 grams of 1 ,3-dimethoxy-8a-oeBtra-1 ,3,5(lO)-trien-17-one in 50 ml of tetrahydrofurane is added, and the whole is heated at the boil for 1 hour. A saturated solution of sodium chloride is added, while cooling with ice, the mixture is diluted with ether, washed neutral, dried and evaporated. After purification over silica gel there are obtained 475 mg.
Exmple 17 1 ,3-I>iacetoxy-ea- estra-.1 ,3,5(10)-trien-17β<-ο1.
A solution of 1 gram of 1 ,3-diacetoxy-8o-oeetra-1 ,3»5(10)« trien-1 -one in 30 ml of absolute tetrahydrofurane is stirred with 2 grams of lithium tri-1ert.-butoxy-aluminium hydride for 45 minutef, J-while cooling with ice. The mixture is then introduced into ice-water/ NaCl acidified with acetic acid, and extracted with ether. The organic phase is washed neutral, dried and evaporated. The residue (1 gram) is purified by layer chromatography, and, after recrystallisation from hexane/acetone, there are obtained 380 m of 1 ,3-diacetoxy-8a-oestra-1»3.5(l0)-trien-17N>l melting at fl10-211°C, Example 18 . 1 ,3-Bihydroxy-8a-oestra-1 ,?^5(10)-trien-17-one.
To a solution of 3 grams of 1, -diacetoxy-8o-oestra-1,3,5(l0)-trien-17-one in 9 ml of methylene chloride and 18 ml of methanol is added at 0 C under nitrogen 0.23 ml of perchloric acid (70# strength) in 1 ml of methanol, and the mixture is stirred for 3 days at room temperature. The mixture is then diluted with ethyl acetate and washed neutral with saturated sodium chloride solution. After drying and evaporating there are obtained 2.9 grams of 1,3- as an oily substance.
Example 19 1 ,3-Bie-mesyloxy-8a-oestra-1 ,3»5(10)*>trlen-17-one.
To a solution of 1 gram of 1,3-dihydroxy-8a-oestra-1,3,5(l6)-trien-17-one in 14 ml of pyridene are added at 0°C 1.9 ml of methane sulphonic acid chloride, and the whole is stirred for 3 days at 0-10°C. The mixture is then introduced into ice-water (acidified with HDl), filtered, and the residue is dissolved in methylene chloride. After chromatography over SiO^ there are obtained 800 mg Of 1 ,3-bis-oiesyloxy-8a-oestra-1 ,3,5(10)-trien-17-«ne.
Example 20 1 ,3-Bis-mesyloxy-8a-oestra-1 ,3»5(lO)-trien-17β-ο1.
To a solution of 400 mg of 1 ,3-bis-mesyloxy-8o-oestra-1 ,3,5(O)-trien-17-one in 10 ml of absolute tetrahydrofurane are added 800 mg of lithium trl-tert.-butoxy-aluminium hyddide, and the whole is stirred for 60 minutes at 0°C. The mixture is then neutralised with glacial acetic acid and extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated. The crude product so obtained (400 mg) is purified by layer chromatography. There are obtained 320 mg of 1,3-bis-meeyloxy-8-©estra-1,3,5(ld-trien-17-ol# Example 21 1 ,3-Bi8«*iesyloxy-17P-acetoxy-8a-oestra-1 ,3,5(lO)-triene.
To a solution of 200 mg of 1 ,3-bis-mesyloxy-8a-oestra-1 ,3,5(10)- and t¾te whole is allowed to stand for 3 days at room temperature^ The mixture is then introduced into ice-water, extracted with methylene chloride, washed with water, dried and evaporated. The residue (160 mg) is purified by layer chromatography. There are obtained 150 mg of 1 ,3-!-bis-mesyloxy-17-aoetoxy-8a-oestra-1 ,3,5(lO)-triene.
Example 22 1 ,3,17-Tris^esyloxy-17o-ethinyl-8a-oestra-1 ,3,5(lO)-triene.
Acetylene is introduced for 60 minutes at -10°C into a suspension of 1.2 grams of potassium tert.-butylate in 20 ml of, abolute tetra-hydrofurane. Into the suspension of potassium acetylide so obtained is introduced a solution of 400 mg of 1,3-diacetoxy-8a-oestra-1 ,3,5(10)-trien-17-one in 8 ml of absolute tetralaydrofurane. Acetylene is introduoed for a further 1.5 hours at -10°C while stirring, the mixture is then neutralised by the addition of glacial acetic acid, and the mixture is introduced into ice-water and extracted with ether. The ether solution is washed with water, dried and evaporated, The crude product so obtained (250 mg) is dissolved in 5 ml of pyridine, 1 ml of methane sulphonio acid chloride is added at ,0°C, and the whole is stirred for 3 days at 0-O°C, The mixture is then introduced into ice-water (acidified with HCl) , filtered, and the residue is dissolved in methylene chloride. After chromatography over Si02 there are obtained 250 mg of 1 ,3,17β^triβ-mesyloxy-17o-θthinyl-6α-oestra-J,3,5(10)^triene. Exampl f¾ 1 ,3-Bis^(para-tosyloxy)-ea-oestra-1 ,3,5(l0)-trien-17-one.
To a solution of 1 gram of 1 j3«sdihydroxy-8d-oeetra-1 ,3»5(10)-trien-17-one in 14 ml of pyridine are added at 0°G. 2.5 grams of para-toluene sulphonic acid chloride, and the whole is stirred for Example 26 0 To a solution of 900 mg of 1 ,3-d1hydroxy-8a-oestra-1 ,3,5(l0)-tr1en-l 7-one In 45 ml of absolute benzene are added 14 ml of trlethylamlne and, while stirring vigorously 5.4 ml of Isopropyl sulphonlc acid chloride are added. The whole was stirred for 2 days at room temperature, then poured nto Ice, and extracted with ether. The ether phase was washed with water, dried and evaporated. The resulting crude product was purified by chromatography over S 02.
There were obtained 700 mg of 1 ,3-B1s-1sopropylsulphonyloxy-8a-oestra-l ,3,5(10)-tr1en-17-one.
Melting point 134 - 136°C (hexane/acetone) .
Comparative Example 27 The estrogenic dissociation of 1 ,3-D1hydroxy-8a-oestra-1 ,3,5(l0)-tr1en-17-one of Claim 15 of the present application as compared with 1 ,3-D1hydroxy-estra-l ,3,5(10)-tr1ene-17-one disclosed in the Israel Patent 25774 was determined In the sialic add test and by the organ weight of the uterus and vagina on mice.
Female NMR straln mice weighing about 30 g. were ovarlectomlzed. Starting with the 10th day after castration, the animals receive the substance to be tested once dally for 3 days. The dally dose 0.1-10.0 yg (0.1-0.3-1.0-3.0-10.0 yg) was dissolved 1n 0.1 ml castor oil containing a small amount of benzyl benzoate. The solution to be tested was administered subcutaneously to 6 animals per each doses. On the fourth day after the treatments, the animals were sacrificed by decapitation and exsanguinated. Vagina and uterus were Immediately excised and weighed into a test tube for hydrol sis The determination of the sialic add was conducted according to Svennerholm / B ochem. Blophys. Acta 24 (1957) 604/. The Increase In the organ weights of vagina and uterus 1n dependence on the dose, as well as the reduction 1n the sialic add content were determined, deriving therefrom the relative effective strength of the compound to be tested compared to the standard, estradiol.
As parameters of the estrogenic activity, the sialic add concentration and organ weight of the uterus and vagina were employed. Data obtained were subjected to regression analysis to test the regression and Uneallty of a dose-response curve. Relative potencies of an estrogenic compound for 4 parameters, compared with estradiol as a standard, were evaluated by a six-point covarlance analysis.
To see the preferential effect of an estrogen on the uterus or vagina, the relative potencies of the vag no-trophlc effect were divided by those of the uterotrophic effect. The higher 1s the quotient Q, the more vaglno-troph c 1s the estrogen. For the standard compound estradiol , Q s 1.
The Dissociation Quotients of the compounds tested are shown 1n the following table: Compound Dissociation Quotient Q (subcutaneously) 1 ,3-D1hydroxy-8ct-oestra-1 ,3,5(l0)-tr1en-l 7-one 3.2 (Claim 15) 1 ,3-D1hydroxy-oestra-l ,3,5(10) tri en-17-one 1.7 (British Patent 1 ,128,254) 1 ,3-D1 acetoxy-8a-oestra-1 ,3,5(10)-trien-17e-ol 3.2 (Claim 14) 1 ,3-D1 acetoxy-es tra-1 ,3,5(lO)-tr1en-l70-ol 1.5 (US Patent 3 686 238) It can be seen from the Dissociation Quotients of the compound pairs that the claimed 8a-1somers have a surprisingly greater dissociation of estrogenic activities than the corresponding 86 - prior art compounds - 24 c -
Claims (1)
1. WHAT WE CLAIM 1 of the general formula I 1n X represents R 1 and R 3 represent a hydrogen an alkanoyl a R ami or cycloalkyl or tetrahydropyranyl group represents a methyl group and represents a hydrogen or an ethinyl or chloroethlnyi 1 l 1 1 1 orethi nyl 25 1 1 A pharmaceutical preparation which comprises a compound as claimed claim in or conjunction with a pharmaceutically suitable A pharmaceutical preparation which comprises the compound claimed in any one of claims 2 to in admixture or conjunction with a pharmaceutically suitable Process for the manufacture of of the general formula I in which R and X have the meanings given characterised in that in a manner in itself known an of the general formula II in which E and X have the meanings given and represents a single or double is or a is oxidised ith lead and the reaction product is rearranged in the presence of a strong and depending on the finally desired meanings of X and R subsequently the is reduced ether or acyl groups are split off free hydroxyl groups are esteiified or For the Applicants Bregman and Goller 27 insufficientOCRQuality
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2336431A DE2336431C2 (en) | 1973-07-13 | 1973-07-13 | 1.3-oxygenated 8-alpha-estratrienes, processes for their production and pharmaceuticals containing them |
| DE19742426777 DE2426777A1 (en) | 1974-05-31 | 1974-05-31 | 1,3-Oxygenated-8-alpha-oestratrienes for post-menopausal disorders - with vaginotropic, but low uterotrophic activity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL45259A0 IL45259A0 (en) | 1974-10-22 |
| IL45259A true IL45259A (en) | 1977-10-31 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL45259A IL45259A (en) | 1973-07-13 | 1974-07-14 | 1,3-dihydroxy-17-oxygenated-8alpha-oestra-1,3,5(10)-triene derivatives |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS5821639B2 (en) |
| AT (1) | ATA575574A (en) |
| AU (1) | AU477010B2 (en) |
| CA (1) | CA1030951A (en) |
| CH (2) | CH614217A5 (en) |
| CS (2) | CS182260B2 (en) |
| DD (1) | DD114066A5 (en) |
| DK (1) | DK133051C (en) |
| ES (1) | ES428226A1 (en) |
| FI (1) | FI54131C (en) |
| FR (1) | FR2236505B1 (en) |
| GB (1) | GB1479934A (en) |
| HU (1) | HU169791B (en) |
| IE (1) | IE39872B1 (en) |
| IL (1) | IL45259A (en) |
| NO (1) | NO742546L (en) |
| SE (1) | SE7409151L (en) |
| SU (1) | SU626705A3 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2551214C2 (en) * | 1975-11-12 | 1984-07-12 | Schering AG, 1000 Berlin und 4709 Bergkamen | Process for the preparation of 1,3-oxygenated 8α-estatrienes |
| JPS5862734U (en) * | 1981-10-22 | 1983-04-27 | 日工株式会社 | formwork support sabot |
| JPS59146759A (en) * | 1984-01-06 | 1984-08-22 | 株式会社日立製作所 | Automatic screwing device |
| JPS60155376A (en) * | 1984-01-24 | 1985-08-15 | 松下電器産業株式会社 | Nut float detection apparatus |
| DE3710728A1 (en) * | 1987-03-31 | 1988-10-13 | Schering Ag | METHOD FOR PRODUCING 17 (ALPHA) -ETHINYL-17SS-HYDROXY-18-METHYL-4.15-ESTRADIEN-3-ON AND THE NEW INTERMEDIATE PRODUCTS FOR THIS METHOD |
| US6011024A (en) | 1991-08-28 | 2000-01-04 | Imperial College Of Science Technology & Medicine | Steroid sulphatase inhibitors |
| US6476011B1 (en) | 1991-08-28 | 2002-11-05 | Sterix Limited | Methods for introducing an estrogenic compound |
| US6903084B2 (en) | 1991-08-29 | 2005-06-07 | Sterix Limited | Steroid sulphatase inhibitors |
| US7335650B2 (en) | 2000-01-14 | 2008-02-26 | Sterix Limited | Composition |
| GB0020498D0 (en) | 2000-08-18 | 2000-10-11 | Sterix Ltd | Compound |
| RU2679625C1 (en) * | 2018-11-08 | 2019-02-12 | Ильясов Шамиль Сионович | 3-o-sulfamoiloxy-6-oxa-7β-methyl-d-homo-8α-estra-1,3,5(10)-trien-17α-one application for the breast cancer treatment, including the triple negative form, and its production method |
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| US3436411A (en) * | 1967-12-28 | 1969-04-01 | American Home Prod | Process for cleaving an a-ring ether group in 13-alkylgona (and 8-isogona)-1,3,5(10)-trienes and delta-7-,delta-8(9)-,and delta-8(9),14(15)-dehydro derivatives thereof |
-
1974
- 1974-07-09 DK DK368074A patent/DK133051C/en not_active IP Right Cessation
- 1974-07-11 AU AU71123/74A patent/AU477010B2/en not_active Expired
- 1974-07-11 DD DD179870A patent/DD114066A5/xx unknown
- 1974-07-11 SE SE7409151A patent/SE7409151L/en unknown
- 1974-07-11 AT AT575574A patent/ATA575574A/en not_active Application Discontinuation
- 1974-07-11 IE IE1461/74A patent/IE39872B1/en unknown
- 1974-07-12 SU SU742043783A patent/SU626705A3/en active
- 1974-07-12 FI FI2139/74A patent/FI54131C/en active
- 1974-07-12 CH CH1035978A patent/CH614217A5/en not_active IP Right Cessation
- 1974-07-12 CS CS7400004984A patent/CS182260B2/en unknown
- 1974-07-12 CS CS7600001694A patent/CS182300B2/en unknown
- 1974-07-12 CA CA204,667A patent/CA1030951A/en not_active Expired
- 1974-07-12 NO NO742546A patent/NO742546L/no unknown
- 1974-07-12 ES ES428226A patent/ES428226A1/en not_active Expired
- 1974-07-12 JP JP49080116A patent/JPS5821639B2/en not_active Expired
- 1974-07-12 CH CH964674A patent/CH609064A5/en not_active IP Right Cessation
- 1974-07-12 HU HU74@@E480A patent/HU169791B/en unknown
- 1974-07-14 IL IL45259A patent/IL45259A/en unknown
- 1974-07-15 GB GB31241/74A patent/GB1479934A/en not_active Expired
- 1974-07-15 FR FR7424499A patent/FR2236505B1/fr not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| SU626705A3 (en) | 1978-09-30 |
| DK368074A (en) | 1975-03-17 |
| IL45259A0 (en) | 1974-10-22 |
| IE39872B1 (en) | 1979-01-17 |
| DK133051B (en) | 1976-03-15 |
| CS182260B2 (en) | 1978-04-28 |
| NO742546L (en) | 1975-02-10 |
| JPS5032160A (en) | 1975-03-28 |
| CH609064A5 (en) | 1979-02-15 |
| SE7409151L (en) | 1975-01-14 |
| FI54131C (en) | 1978-10-10 |
| FR2236505B1 (en) | 1977-07-08 |
| DD114066A5 (en) | 1975-07-12 |
| IE39872L (en) | 1975-01-13 |
| CA1030951A (en) | 1978-05-09 |
| GB1479934A (en) | 1977-07-13 |
| ES428226A1 (en) | 1976-07-16 |
| AU477010B2 (en) | 1976-10-14 |
| FR2236505A1 (en) | 1975-02-07 |
| FI213974A (en) | 1975-01-14 |
| DK133051C (en) | 1976-08-16 |
| CS182300B2 (en) | 1978-04-28 |
| ATA575574A (en) | 1978-05-15 |
| HU169791B (en) | 1977-01-28 |
| FI54131B (en) | 1978-06-30 |
| JPS5821639B2 (en) | 1983-05-02 |
| CH614217A5 (en) | 1979-11-15 |
| AU7112374A (en) | 1976-01-15 |
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