IL30547A - 6,9,11-trihalo-16alpha-methyl-pregna-1,4-diene-3,20-diones - Google Patents

Description

The present concerned with new steroids and with their manufacture and particularly the present invention relates to Thus the present invention provides of the general in which represents a hydrogen a lover allanoyl group optionally by an of a lower alkane dicarboxylic acid or an acyl of nitricfsulfuric or phosphoric acid and X and Y each represents a halogen the atomic weight of the halogen atom represented by Y being equal or greater the atomic of the halogen atom represented by The invention also provides a process for the manufacture of an 11 of the general formula wherein 2 halogen atoms are in a known the bond of a corresponding if in the resulting steroid any group is saponified or any group is The Δ used as starting materials in the process according to the present invention may be obtained by the dehydration of the corresponding A possible method o dehydration is by treatment of the with methanesulphonyl chloride in pyridine and is very simply obtained by saponification of corresponding A large number of possible methods are available for the addition of to th Δ for halogens such as chlorine or or compounds of the halogens with one such for chlorine monofluoride or bromine or halogen from polyhalides such for potassium triiodide or iodObenzene may be added directly t double The halogen addition is particularly successful if an agent capable of yielding a positively charge halogen atom and an agent capably of yielding a negatively charged haloge atom are allowed to aot simultaneously on the As agents capable of yielding positive there may be for for example for example or the molecular halogens As agents capable of yielding negative there may be for hydrogen halides and alkali metal for example lithium The addition of halogens to the bond of the steroid always takes place in such a way that the positively charged halogen adds on to the negatively charged halogen adds on to the position of the The molecular weight of the halogen in the never be lower than that of the halogen in the The halogen addition to the bond is preferably carried out at a temperature within the range of from to A free hydroxyl group or an ester group in the can be esterifled or according to a known It to use as mild conditions as possible if good yields are to be In Israel Patent 12621 of Scherbo there is a broad losure of a general class of compounds which formally also includes the novel compounds of the present said disclosure is so broadly worded as to encompass more than compounds and cannot be considered as describing the compounds of the present invention in sufficient manner so that one of ordinary skill in the art through a reading of said patent would constructive of this Moreover there is no teaching or suggestion in said patent that the specific selected compounds of the present invention would possess superior inflammatory Thus it has now been discolvered that the new pounds of the present invention possess an excellent activity in tests on male test persons after local as is shown in Table 1 using as examples of compounds according numbered as compound I and compounds are chosen title structurally analogous compounds more specifically disclosed in said Scherico The test employed to demonstrate the superiority of the compounds according to the present invention was carried out as the Stratum corneum was broken up on the back of test persons years by 20 times pulling a 2 cm wide all the films being taken from the same and a pronounced hyperasmia was Then about 50mg amounts of a ointment base containing respectively or or of the 2 substance being tested were applied on to marked 4 cm areas within the stripped using the same The backs of the test persons were then photographed with a Kodak Colorfilm at definite time In order to assess the hyperasmia and vasoconstriction the color of the dividual areas on the Kodak Colorfilm were converted into luminosity The sections projected from a color ilm through a perforated screen on to an interference filter differed in their A dary electronic amplifier of type IS 9 was used as the brightness indicator and the anode current of the secondary amplifier was measured in order to determine the color In order to determine the which is as a representative syndrome of the tion and which was assessed with regard to commencement of degree o effect and duration of the color value of the untreated and of the treated stripped skin was determined and compared with the color value of the normal with the color value of the normal skin being defined as equal to 100 and the color value of the untreated stripped skin being defined as equal to medium and was rated between 0 and I 0 25 40 50 100 one 0 20 55 75 100 0 15 25 50 90 100 II 5 30 75 95 100 0 15 30 60 85 100 III 15 35 80 100 15 40 75 100 0 30 90 100 IV 6 25 55 100 10 50 75 100 10 40 60 85 100 V 6a 15 45 95 100 15 50 75 100 0 30 55 90 100 VI 10 55 85 100 10 40 75 90 100 VII 15 55 90 100 20 50 80 100 0 35 60 90 100 VIII 10 40 80 100 0 25 50 80 100 IX 15 55 90 100 10 40 90 100 0 25 40 90 100 X 0 0 10 30 30 60 XI 11 0i01 0 20 40 70 90 100 XII 0 0 10 20 20 dione experimental results set out Table 1 clearly that when using the active compounds of the present invention the effect not only starts earlier but the desired effect is reached more rapidly than the hitherto known compound used as a Furthermore the intensity of the new active compounds is higher throughout their action than the case with the substancO Furthermore the produced under the influence f the to the prosent aro in the desired Thus for the carbohydrate metabolism not influenced at all by the compounds according the present or only influenced to a Very slight The effec thus greatly educed as this particularly shown by fact that the concentration sugar is not the glycogen 1 at extremely high The fact that the liver and the transaminases and OPT are only slightly influenced also worth notin The on sodiu potassium and phosphate elimination by of the active compounds according to present is also the present invention further provides ceutlcal preparation which comprise one or more of the in admixture with a ceuticall suitable The new combined with normally used are well suited for the treatmen fo when administered contact eczemas of the most diverse first degree pruritus vulvae et erythematode β when administered acute and chronic asthm and hay following illustrate the ml anhydrous hydrofluoric acid mixed with ml and chloride at g poin and g of sodiuni hydrogen sodium bicarbonate solution wate and and the solvent was evaporated g of melting point to were obtained from chloride at ml an sodium me solution in The mixture was stirred fo room After adding the crystalline precipitate was isolated from n of meltiig point we 6 of melting anhydride under th conditions described in in ml of acetic acid and fo hours at room temperature The mixture was poured water and the precipitated product was filtered off with washed with Example ml o anhydrous hydrofluoric acid with 9 of in ml of acid Was mixed g lithium of and ml with hydrogen The mixture was stirred for hou at into and precipitated product was filtered washed with wate and drie A e from g of me tn oi t odium methylste ions Example of 6 of melting point 162 to poured into extracted methylene and the organic phase washed with sodium bicarbonate carbonate solution and watery dried and concentrated in The was recrystalliaed from Example 18 ml of hydrofluoric ml were mixed for 6 at and poured ntP o 4 of bicarbonate mixture extracted with methylene organic washed hydrPgen sulphite sodium bicarbonate solution and water dried with sodium the evapprated and the residue was of x o melting of point 12 were with were reacted under the conditions described Example The crude product was chroffiatographed silica g ne of melting poin G Example 21 residue was extracted with methylene and th extract washed with sodium dried sulphate and evaporated The residue was o silica of were eluted with d were reacted valeric anhydride Under the conditions described in Example The isolated product twice recrystallleed from 4 40 g of point were Example 25 Composition for an ointmen of Amphocerlne S paraffin liquid DAB 6 g of wate g of perfume oil Ho 6580 Example 26 gelatine methyl supplement mg acid propyl supplement tablets described Examples 29 were manufactured on tablet in the Example 33 of sulphur trloxide was added dropwlse t at to mixture at β was then stirred 1 hour at The adjusted value of hydroxide times The aqueous evaporated vacuo at and the residue material was filtered methanol was o residue ove phosphorus was g of 34 Example wit and then with There g of 35 dissolved 100 ml distilled wate after the Example 36 Composition for nazal drops of and 2g of were dissolved in 100ml of distilled The following example is the experimental proof that in the product of the process can also be an inorganic acid Example 37 6 dione according to example are dissolved in Pyridine and o stirred with ml Hesylchloride for 30 minutes at 0 to 10 The reaction mixture then precipitated in ice water and the precipitated Mesylate is filtered off with and recrystallized from aqueous put g g Mesylate are dissolved in ml Acetone and after addition of g sodium iodide in 115 ml are heated under reflux for 1 After cooling to room temperature the undissolved product is sucked off and the filtrate evaporated in The residue is treated with water and some crystals of sodium thiosulphate and then again sucked In this manner g crude iodo compound are which for purification are twice tallized from aqueous g 166 1 iodo compound is heated under reflux for 2 hours with 50 2 ml phosphoric and 6 ml The reaction mixture is then concentrated under reduced the residue solved in Methanol and the solution adjusted to pH 11 with methanolic sodium The precipitate is filtered off and the filtrate evaporated in vacuo for The residue is dissolved in 5 ml The crude disodium salt is precipitated by addition of This is dissolved in 0 ml of bidistillated the solution is filtrated and the pure filtrate is dried by In insufficientOCRQuality

Claims (1)

1. claim An of the general formula in represents a hydrogen a ower alkanoy group optionally substituted by a chloro an acyl of a lower acid or an acyl of sulfuric or phosphoric acid and X and T each represents a halogen the atomic weight the halogen atom represented by Y being equal or greater the atomic weight of the halogen atom represented by 11 1 23 pregnadi one 14 ene pregnadl one f pregnadl one pregnadi pregnadi one er pregnadi pregnadi A pharmaceutical preparation which comprises an as claimed 1n claim 1n admixture or conjunction a pharmaceutically suitable A pharmaceutical preparation as claimed in claim wherein the preparation contains two or more compounds as claimed in claim A pharmaceutical preparation which comprises the compound claimed in any one of claims 2 to in admixture or conjunction with a tically suitable A pharmaceutical preparation having a composition substantially as described in any one of Examples 25 to 32 A process for the manufacture of an of the general formula in which represents a hydrogen a lower group optionally substituted by a chloro an acyl of a lower alkane dioarboxylic acid or an acy of sulfuric or phosphoric acid and X and Y each represents a halogen the atomic weight of the halogen atom represented by 7 being equal or greater the atomic weight of the halogen atom represented by wherein 2 halogen atoms are in a known to the bondoof a corresponding andi in resulting steroid any group is saponified or any group is A process as claimed in claim wherein the halogen atoms are added to the by of an agent capable of yielding a charged halogen atom and an agent of yielding a negatively charged halogen A process as claimed in claim wherein the agent capable of yielding a ositive chared haloen atom is a molecular haloen a al enac m A process as claimed 1n claim 31 wherein the amlne 1s a A process as claimed claim 31 wherein the 1s a A process as claimed 1n any one of claims 30 to wherein the agent capable of yielding a negatively charged halogen atom 1s a hydrogen hallde or an alkali metal A process as claimed 1n claim wherein the alkali metal hallde 1s a l ithium A process as claimed 1n any one of claims 29 to wherein the addition of the halogen atoms to the bond 1s carried out at a temperature within the range of from about to about A process as claimed In claim and conducted substantially as described 1n any one of Examples 1 to 24 Sodl f pregnadl Sod1 1 chl pregnadl A pharmaceutical preparation having a composition substantial ly as described 1n Example 35 or 36 A process as claimed 1n claim and conducted substantially as described 1n Example 33 or 34 For the Applicants Bregman and insufficientOCRQuality