Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J75/00—Processes for the preparation of steroids in general
• • 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
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S424/00—Drug, bio-affecting and body treating compositions
  • Y10S424/13—Burn treatment

Definitions

• This invention relates to new steroid compounds.
• steroids of the pregnane series having various substituents in the 2l-position have been described such as hydroxy, alkanoyloxy, oxygen, halogen, etc.
• no 21-nitrogen substituted steroids of the pregnane series of our invention have been described.
• C -C and C -C are divalent radicals selected from the group consisting of (Fm- 11: and
• radicals X is selected from the group consisting of hydrogen, chlorine, and fluorine atoms
• the invention also includes acid addition salts of the compounds def scribed above, such salts being for example the hydro vchloride, hydrobromide, hydroiodide, nitrate, sulfate,
• the compounds of the present invention can'be' pre pared by the process outlined as follows.
• R is a member of the group consisting of hydrogen, hydroxyl, fluorine, lower alkyl and alkanoyloxy radicals.
• R is a member of the group consisting of hydrogen, hydroxy and allranoyloxy radicals and R plus R when taken together form lower alkylidenedioxy and (l-alkoxy) lower alkylidenedioxy radicals, and R is a member of the group consisting of amino and lower alkanoylamino radicals.
• the first step of the process illustrated above as (A) to (B) can be carried out as described in United States Patent 2,773,078 wherein a 2l-hydroxy steroid of the pregnane series is treated in an alcohol with a copper salt, for example, glacial acetic acid.
• the second step, (B) to (C) can becarried out by the selective formation of the 21-oxime using hydroxylamine or a salt thereof.
• the reactants are generally mixed together at room temperature or below and the reaction mixture is heated to a temperature within the range of 60 C. to C. for a period ranging from 1 hour to about 18 hours.
• the desired product can be obtained from the reactionmixture by methods well known and described in the examples hereinafter..
• reaction (C) to (D), whichis the selective reduc: tion of the 21-oxime to the ZI-amine, is generally accornpanied by the formation of a pharmaceutically acceptable acid addition salt and is performed by employing metallic zinc and acetic acid under mild conditions.
• a temperature within the range of from 0-? to about 50 C. and preferably from 25 C. to 35 C. is used;
• the reaction is completed usually within a period offromabout 10 minutes to minutes.
• an alkali metal acetate and a catalyst such as a mercurylsalt is also present.
• amino derivatives such as 21-alka'noyla'mino' compounds can be prepared essentially inthe' sariie manner w an the 2l-oxirne is selectively treated with an acylatirig ag such as an alka'noic' acid anhydride' in addition" tame conditions for the preparation of the 21-amino compound.
• the desired product in the case of the 21-oxime can be obtained by evaporation of the organic solvent and amine reagent under reduced pressure.
• the product is further purified by crystallization as shown hereinafter in the examples.
• purifying the 2l-amine after the reaction is complete it can be separated from the insolubles byfiltration and neutralized with an alkali metal bicarbonate.
• the product is taken up in a water immiscible organic solvent such as methylene chloride, ether, benzene, etc. After the organic layer is separated it is washed with the alkaline aqueous phase and evaporated to dryness under reduced pressure to produce the desired compound which can be further purified by methods well known in the art.
• the compounds fo the present invention are active glucocorticoids and mineralocorticoids.
• the glucocorticoid activity makes the compounds useful as antiarthritics and in the treatment of burns, skin disorders and similar conditions requiring topical application.
• the mineralocorticoid activity makes the compounds useful in the treatment of edema and other conditions manifested by water in the tissues.
• the acid salts of the present compounds are of particular value with regard to water solubility.
• Compounds such as 21-amino-1Inna-dihydroxy- 6amethyl-1,4-p1egnadiene-3,ZO-diOne hydrochloride are water soluble anti-inflammatory agents useful in the treatment of rheumatoid arthritis.
• the steroids of the present invention can be dispensed in the usual pharmaceutical forms such as tablets, capsules, liquids, suspensions or similar dosage forms. They may be in dosage unit form for single daily therapeutic doses or in small units for multiple doses or in larger units for division into single doses. Obviously, in addition to the therapeutic products, there may be present excipients, binders, fillers and other therapeutically inert ingredients necessary in the compounding of pharmaceutical preparations.
• EXAMPLE 1 A heated solution of 27 grams of cupric acetate in 1400 milliliters of methanol is added to a heated solution of 20 grams of 9rx-fiuoro-l1fi,l7a,2l-trihydroxy-4-pregnene-3,20-dione in 1000 milliliters of methanol containing 20 milliliters of glacial acetic acid and the resulting mixture refluxed for about 30 minutes. Approximately 800 milliliters of water is added and heating continued for an additional 30 minutes. The reaction mixture is then filtered to remove insoluble cuprous oxide, the resulting filtrate diluted with about 400 milliliters of Water, and the resulting solution evaporated under reduced pressure to about 1000 milliliters.
• the crystal slurry thus Produced is allowed to stand for about 16 hours at 4 C., after which time the formed crystals are collected by filtration.
• the yield is 13.1 grams of 9a-fluoro-l1,8,l7a-dihydroxy- 3,20-dioxo-4-pregnen-2l-al (hydrate) Amax, 239 m (6 17,150); infrared bands (in KBr) at 2.88 3.40 5.83 610a, 9.65,u, etc.
• a solution of 1.0 gram of 9a-fiuoro-11/3,17e-dihydi-oxy-3,20-dioxo-4-pregnen-2l-al and 200 milligrams of hydroxylamine hydrochloride in a mixture of 10 milliliters of pyridineand 10 milliliters of ethanol is heated for about 90 minutes on the steam bath.
• the reaction mixture is evaporated under reduced pressure to about milliliters, and water is added in a quantity sufficient to produce a gummy precipitate.
• the solvent mixture is decanted and the residue washed several more times by decantation with water.
• the washed residue is crystah lized from aqueous methanol and the crystals collected by filtration, and dried.
• the yield is 625 milligrams of 9a-fluoro-1MAM-dihydroxy 3,20 dioxo 4 pregnen- Zl-al 2l-oxime melting point 2l0211 G; A 235 HIM (6 25,600); infrared bands (in KBr) at 2.85 1, 3.05n, 3.40 1, 5.881)., 6.16;.L, 6.98 15 9.60M, 112511., etc.
• EXAMPLE 2 Process for the production of ZI-acetyIamino-Qa-fluom- 115,17a-dihydroxy-4-pregnene-3,20-dione To a stirred solution of 100 milligrams of 9oc-fl1101'0- 1 lfi-17a-dihydroxy-3,20-dioxo-4-pregnen-2l-al 21-oxime, 20 milligrams of sodium acetate, and 5 milligrams of mercuric chloride in 10 milliliters of glacial acetic acid there is added, in small portions over 30 minutes, 300 milligrams of zinc dust.
• reaction mixture is diluted with about 150 milliliters of ether and the insoluble inorganic materials filtered oil.
• To the filtrate is added about 1.5 equivalents, based on steroid, of 70 percent aqueous perchloric acid.
• the small quantity of flocculent precipitate which forms is removed by filtration.
• the filtrate is allowed to stand for about 18 hours.
• Thecrystals which form are collected by filtration and air dried.
• the yield is 60 milligrams of 2l-amino-9oc-fiuoro-115,170- dihydroxy-4-pregnene 3,20 dione perchlorate melting point 21l--213 C.
• the methylene chloride extract is washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give a crystalline residue from which is obtained, after two recrystallizations from acetone-petroleum ether, 60 milligrams of 21-acetylamino-9a-fiuoro 11fl,l7oc dihydroxy-4-pregnene-3,ZO-dione.
• a 2371.. (e 16,200); infrared bands (in KBr) at 3.00 2, 3.40s, 5.80n, 6.02 6.54 7.03;/., 9.62 11.27; etc.
• EXAMPLE 3 Process for the production of 9a-fluor0-11fl-hydroxy- 16a,17a-isopropylidenedioxy 3,20 dioxo 1,4 pregnadien-ZI-al 21 -0xime A solution of 4.5 grams of cupric acetate in 300 milliliters of hot methanol is added to a solution of 3.0 grams of 9a-fiuoro-11fi,21 dihydroxy 16cc,17ot isopropylidenedioxy-l ,4-pregnadiene-3,20-dione in 180 milliliters of hot methanol containing 3 milliliters of glacial acetic acid, and the resulting mixture refluxed for about 30 minutes.
• the crystals are collected by filtration and dried to give 1.44 grams of 9a fiuoro-llfi-hydroxy-la,17u-isopropylidenedioxy- 3,20-dioxo-1,4-pregnadien-2l-al 21-oxime having a melting point of 258-260 C. infrared bands (in KBr) at 2.881., 3.95 1 3.4Qu, 3.70M, 5.88M, 6.05/L, 6281.0, 6.90n, 9.48 etc.
• EXAMPLE 4 Preparation of 21-amin0-9a-fln0ro-1Ifl-lzydroxy-I6a, 17ix-isopropylidenedioxy-l,4-pregnadiene-3,20-dione
• the reaction mixture is stirred an additional 15 minutes, then filtered from insolubles.
• the solids are washed with methylene chloride, and the washings and initial filtrate are combined and further diluted with water and the aqueous phase is neutralized with sodium bicarbonate.
• the methylene chloride layer is removed, the aqueous phase re-extracted twice with additional methylene chlo ride, and the combined extracts are washed with saturated aqueous sodium bicarbonate solution.
• the extracts are dried. and evaporated to dryness under reduced pressure giving the product, 2l-amino-9ct-fiuoro-llfi-hydroxy- 160:,1700 isopropylidenedioxy-l,4-pregnadiene-3,20-dione.
• the hydrochloride salt has the following characteristics. h 239n1u.
• EXAMPLE 8 Preparation of 1 7ct-h ydr0-xy-3J 1,20- tri0x0-4-pregnen-2I -al 21 -oxime'
• the oxime is decanted from the solvents, washed with Water, and crystallized from hot aqueousmethanol.
• the crystalline cortisone aldehyde 21-oxime is filtered, washed with small portions of cold aqueous methanol and dried.
• reaction mixture is diluted with diethyl ether and insoluble inorganic materials are filtered.
• ether solution is evaporated to dryness and the residue dried and redissolved in a mixture of absolute ether and ethyl acetate.
• a stream of dry hydrogen chloride gas is passed through the solution until precipitation of the amine hydrochloride salt is complete, at which time the crystalline salt is filtered oil and dried under reduced pressure.
• a wide variety of mineral acids are used for preparation of the aminosteroid salts such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, chloroplatinic acid, etc.; and selected organic acids are also used for salt preparation such as oxalic acid, acetic acid, propionic acid, trichloracetic acid, dichloracetic acid, chloracetic acid, trifiuoroacetic acid, difluoroacetic acid, picric acid, succinic acid, formic acid, methanesulfonic acid, ethanesulfonic acid, etc.
• R is a steroid moiety attached at the 17- position and A is a pharmaceutically accepted acid anion.
• EXAMPLE 14 Preparation of 9a-flu0r0-11,8,17a-dihyaroxy-2l-pr0pi0nylamino-4-pregnene-3,20-di0ne Using the procedure of Example 2 for the preparation of 21-acety1amino steroids except that in place of the acetic anhydride propionic anhydride is used the corresponding 21-propionyl-arnino-steroid, 9a-fiuoro-11B,l7a-dihydroxy- 21-propionylamino-4-pregnene-3,20-dione is obtained.
• filtrate is evaporated. to dryness under" reduced pressure, the residue shaken with water, and the insolubles filtered off.
• the aqueous filtrate is dilutedwith an equal volume. of methanol and this solution is passedth-rough a column containing a strong anion exchange resin of the styrenedivinyl benzene type (which contains quaternary ammonium groups) (such as, for example, Dowex I) in the chloride form.
• the column is further washed with methanol containing 30% water until the amino steroid is completely removed from the resin.
• amino steroid fraction is evaporated under diminished pressure to dryness, and the resulting residue is crystallized from methanol-diethyl ether, yielding crystalline 21-amino-9a-fluoro-11 3-hydroxy 160:,170: isopropylidenedioxy-l,4-pregnadiene- 3,20-dione hydrochloride.
• a process for the production of a member selected from the group consisting of 21-amino and 21-acylamino steroids of the pregnane series which comprises reaction of the corresponding 20,21-dicarbonyl steroid of the pregnane series with a member selected from the group consisting of hydroxylamine and hydroxylamine salts to produce the corresponding 21-oxime, and reacting the oxime with elemental zinc and a member selected from the group consisting of lower aliphatic carboxylic acids and lower aliphatic carboxylic acid-lower aliphatic carboxylic acid anhydride mixtures and recovering said compound therefrom.
• C -C is a divalent radical selected from radicals
• R is selected from the group consisting of hydrogen and lower alkyl radicals
• R is selected from the group consisting of hydrogen, halogen and lower alkyl 7 radicals
• R is selected from the group consisting of hy- 10 drogen,.hydroxyl,,fluo1ine, lower alkyl. and lower alkanoyloxy radicals, at least one-of the radicalsR and R being, other than hydrogen and lower alkyl
• R is selected from the group consisting of hydrogen, liydroxylv and lower alkanoyloxy radicals and R and R? when taken together form a member selected from the group consisting, of lower alkylidenedioxy and- (l-alkoxyj lower alkylidenedioxy radicals and pharmaceutically acceptable acid addition salts.
• X is selected from the group consisting of hydrogen, chlorine and fluorine atoms
• Z is a divalent radical selected from the group consisting of radicals
• R is selected from the group consisting of hy drogen and lower alkyl radicals
• R is selected from the group consisting of hydrogen, halogen and lower alkyl radicals
• R is selected from the group consisting of hydrogen, hydroxyl, fluorine, lower alkyl and lower alkanoyloxy radicals
• R is selected from the group consisting of hydrogen, hydroxyl and lower alkanoyloxy radicals and R and R when taken together form a member selected from the group consisting of lower alkylidenedioxy and (1-alkoxy)-lower alkylidenedioxy radicals and R is a lower alkanoylamino radical.
• X is selected from the group consisting of hydrogen, chlorine and fluorine atoms
• Z is a divalent radical selected from the group consisting of 0-:(3 and 3 radicals
• R is selected from the group consisting of hydrogen and lower alkyl radicals
• R is selected from the group consisting of hydrogen, halogen and lower alkyl radicals
• R is selected from the group consisting of hydrogen, hydroxyl, fluorine, lower alkyl and lower alkanoyloxy radicals
• R is selected from the group consisting of hydrogen, hydroxyl and lower alkanoyloxy radicals and R and R when taken together form a member

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• 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)

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Cited By (8)

Citations (1)

• 1960
  • 1960-06-07 US US35388A patent/US3020275A/en not_active Expired - Lifetime
• 1961
  • 1961-03-10 GB GB8815/61A patent/GB919439A/en not_active Expired
  • 1961-03-14 FR FR855507A patent/FR1010M/fr active Active

Patent Citations (1)

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