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US3020275A - 21-nitrogen substituted steroids of the pregnane series and methods of preparing the same - Google Patents

21-nitrogen substituted steroids of the pregnane series and methods of preparing the same Download PDF

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US3020275A
US3020275A US35388A US3538860A US3020275A US 3020275 A US3020275 A US 3020275A US 35388 A US35388 A US 35388A US 3538860 A US3538860 A US 3538860A US 3020275 A US3020275 A US 3020275A
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dione
acid
dihydroxy
pregnene
fluoro
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US35388A
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Marx Michael
Leland L Smith
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Wyeth Holdings LLC
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American Cyanamid Co
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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
    • 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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Description

This invention relates to new steroid compounds.
More particularly, it relates to Zl-nitrogen derivatives of steroids of the pregnane series and to methods of preparing the same.
In the past, many steroids of the pregnane series having various substituents in the 2l-position have been described such as hydroxy, alkanoyloxy, oxygen, halogen, etc. However, no 21-nitrogen substituted steroids of the pregnane series of our invention have been described.
We have found that compounds having the following structural formula are physiologically active steroids.
wherein 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, Z is a divalent radical selected from the group consisting of O=C'and 0 (non radicals, R is amember of the group consisting of hydrogen and lower alk'yl radicals, R is a member ofthe group consisting of hydrogen, halogen; and loweralkyl radicals R is a member of the group consisting of hydrogen, hydroxyl, fluorine, loweralkyl and lower alkanoyloxy radicals, at least one of the radicals R R and R 'being other than hydrogen, R is a member of the group consisting of hydrogen, hydroxyl, and lower alkanoyloxy radicals; and R and R when taken together form lower alkylidenedioxy and (1-alkoXy)-lower' alkylidenedioxy radicals, R is amember of the group con-' sisting' of amino and lower alkanoylamino radicals, R is hydrogen a'n'dR and R taken together is the radical Patented Feb. 6, 1362 positions comprising pounds as described above with a p ceutically acceptable carrier. 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,
phosphate, acetate, citrate, tartrate, fumarate, gluconate and the like.
The compounds of the present invention can'be' pre pared by the process outlined as follows.
wherein 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.. v
Thereaction, (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. In this reac tion 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. In carrying out the reaction preferably an alkali metal acetate and a catalyst such as a mercurylsalt is also present. Other 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.
When the reaction is complete 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. When 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.
The following examples illustrate the preparation of representative 21-nitrogen substituted steroids of the pregnane series.
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. After stirring for an additional minutes, the 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.
Acetylation of the above product with acetic anhydride and pyridine at room temperature produces the desired 2l-acetylamino compound melting point 263 264 C.
To a stirred solution of milligrams of 9a-fluoro- 1113,17a-dihydroxy-3,20-dioxo-4-pregnen-2l-al 21-oxime, 20 milligrams of sodium acetate, and 5 milligrams of mercuric chloride in a mixture of 6 milliliters of glacial acetic acid and 5 milliliters of acetic anhydride there is added, in small portions over a 30 minute period, 300 milligrams of zinc dust. After stirring for an additional 90 minutes, the reaction mixture is filtered to remove unreacted zinc and insoluble inorganic salts. The filtrate is concentrated to near dryness under reduced pressure and the concentrate thus obtained is diluted with water and extracted with methylene chloride. 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. Approximately 100 milliliters of water are added and refluxing continued for an additional 30 minutes. The precipitated cuprous oxide is removed by filtration, the filtrate diluted with milliliters of water, and the resulting solution concentrated to about 500 milliliters under reduced pressure. The crystal slurry thus produced is allowed to stand for about 16 hours at about 4 C.; then the crystals are removed by filtration and dried to give 2.71 grams of 9m-fiuoro-11p-hydroxy- :,17 u-isopropylidendioxy-3 ,20-dioxo 1,4 pregnadien- 21-al (hydrate) melting point 273-275 C.
A solution of 2.0 grams of 9a-fluoro-11fl-hydroxy- 160:,170; isopropylidenedioxy-3,ZO-dioxo-l, -pregnadien- 5. 21-al and 325 milligrams of hydroxylamine hydrochloride in a mixture of 20 milliliters of pyridine and 20 milliliters of ethanol is heated for about 90 minutes on the steam bath. The reaction mixture is evaporated to about milliliters under reduced pressure and water is added to the concentrate to precipitate the crude product. After Washing several times by decantation with Water, the residue is crystallized from aqueous methanol. 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 A solution of 200 mg. of Qua-fiUOrO-llB-hydlOXy- 1 6u,17a isopropylidenedioxy-3,ZO-dioxo-1,4-pregnadien- 21-al 21-oxime, as prepared in Example 3, 40 mg. of sodium acetate and 10 mg. of mercuric chloride in ml. of glacial acetic acid is treated with 600 mg., of zinc dust added over a period of 15 minutes, at room temperature. 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.
- tta.
infrared-absorption at (KBr) 2.92 4, 3.40 3.85 5.79 6.01 4, 6.16 1 6.23n, 9.40m 1120a, etc.
EXAMPLE 5 Preparation of 21 acelylamino 9oz flu0r0-]1,8-hydr0xy- 1604,] 7w-is0propylidenedioxy-l ,4-pregnadiene-3,20-di0ne A solution of 70' mg; of Z1-amino-9e-fiuoro-11flhydroxy 1641,1706 -isopropylidenedioxy-l,4-pregnadieue- 3 ,20-dione", prepared as in Example 4, in '5 ml. of pyridine and 1 ml. of acetic anhydride is allowed to stand for 18 hours at room temperature. Dilution of the reaction solutiorr with methanol and removal .of the solvents under reduced pressure gives the product, 21-acetylamino-9oe fiuoro l-l'fl-hyd'roxy 16a,l7ot-isopropylidenedioxy 1,4- pregnadieue-3,20'-dione.
EXAMPLE 6 Preparation of 21 acetylamino-9a-fiuorodIfl-hydroxy- 16a,]7a-is0pr0pylidenedioxy-1,4-pregnadiene-3,20-di0ne solution-of 1.5 g. of cupric acetate'monohydrate in IOO ml'. of'hotmethanol-is added to a solution of 1.0 g. of 9a fluoro l1fl,l-7u,21 trihydroxy l6a-inethyl1,4- pregnadiene-3,20-dione in 60 ml; of hot methanol containing 1 ml. of glacial-acetic acid,- and the mixture heated at reflux for minutes.- Refluxing is continued for 30 minutes after addition of 50 ml. of water. The precipitated copper salts are removed by filtration, 50 ml. of water-is addedto the filtrate, and the resulting solution evaporated under reduced pressure until crystallization commenced The-crystallization mixture is aged overrii'ghtin the cold, and the crystals are collected by filtration to give-455 mg. of9a-fluoro-llB,l7a-dihydroxy-16amethyl-3,20-dioxo-1,4 pregnadien-21-alwhich as the hydrate melted at 127-430 C. I
- Preparation of 21-amin0-9a-fln0ro-11BJ 7ot-dihydr0xy- 1out-methyl-1,4-pregnadien-e-3,ZU-dione hydrobromz'de dihydroxyl 6a-methyl-3 ,ZO-dioxol ,4-pregnadien-2 1-211 21- oxirne, as prepared in Example 6 in 20 ml. of propionic' acid is treated with 500 mg. of zinc dust added over 30 minutes at room temperature. Stirring is continued for 30 more minutes, the solids removed by filtration, and the filtrate concentrated to near dryness under reduced pressure. Addition of ethyl acetate produces a crystalline precipitate of zinc pr'opionate, which is filtered oif. The
. filtrates are diluted with anhydrous ether, one and onehalf equivalents of hydrobromic acid are added, and the mixture aged 16 hours at room temperature whereupon the precipitated 2l-amino-9a-fluoro-llfi,l7u-dihydroxy-' 16a-methyl-l,4-prcgnadiene-3,20-dione hydrobromide iscollected by filtration.
EXAMPLE 8 Preparation of 1 7ct-h ydr0-xy-3J 1,20- tri0x0-4-pregnen-2I -al 21 -oxime' A solution of 5 grams of cortisone 21-aldehyde (17ahydroxy-3,ll,20-trioxo-4-pregnen-2l-al) and 1.2 grams of hydroxylamine sulfate in ml. of 50% ethanolic pyr-- idine is heated for one hour on a steam bath. The reaction mixture is then reduced in volume under diminished pressure and water is added to precipitate'the product 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.
EXAMPLE 9 Preparation of 115,17ot-a'ihydr0xy-6a-methyl-3,ZO-dioxo- 1,4-pregnadien-21-al 21 -0xime A heated solution of 27 g. of cupric acetate in 1400 ml. of methanol is added to a heated solution of 20 g; of l1,8,17a,2l-trihydroxy-ot-methyl-l,4-pregnadiene-3,20-
dione in one liter of methanol which contains 20 ml. of
glacial acetic acid. The resulting mixture is refluxed on a steam bath for a half an hour, at which time 800 ml. of water is addedand the heating continued for an ad-' ditional half an hour. The reaction mixture is filtered to remove insoluble inorganic salts and the filtrate is diluted" with 500 ml. of water. The solution obtained is evaporated under reduced pressure to incipient crystallize-- tion and the suspension allowed to stand in mice bath until crystallization is complete. The desired 115,170:- dihydroxy-6a-methyl-3,ZO-dioxo-l,4-pregnadierr- 21 al is filtered, washed with cold water and dried. The aldehyde did not reduce alkaline tetrazolium salts.
A solution of 10' g. of 11B,17a-dihydroxy6a-methyl 3,20-dioxo-1,4-preguadien-21-al as prepared in Example 9 and of 2g. of hydroxylamin'e hydrochloride in 200 mlI of 50% ethanolic pyridine is heated for two hours on a steam bath. The reaction mixture is evaporated under reduced pressure and water is added. The gummy solids produced areseparated'and washed with Water. Crystallization of the 2l-mono-oxime is accomplished from aqueous methanol, and the crystals'are filtered, washed with aqueousmethanol and-dried. The yield is-S'grams'.
The precipitate is washed several times by EXAMPLE 10 Preparation of ZI-amino-I1,8,17a-dihydrxy-6a-methyl- I ,4-pregnadiene-3,20-di0ne hydrochloride A solution of 200 mg. of 11,8,17a-dihydroxy-6a-methyl- 3,20-dioxo-1,4-pregnadien-2l-al 2l-oxime, 40 mg. of sodium acetate, and mg. of mercuric chloride in ml. of glacial acetic acid is prepared. To this solution is added small portions of zinc dust so that 600 mg. of zinc dust is added over 30 minutes. The suspension is well shaken during this time, and is stirred for 90 minutes after zinc addition. The reaction mixture is diluted with diethyl ether and insoluble inorganic materials are filtered. The 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.
EXAMPLE 11 Preparation of steroidal 21 -aldehydes Using the procedures of Examples 1, 3, 5 etc. for the oxidation of the 21-hydroxy-20-ket0steroids to the 20- keto-ZI-aldehydes, the following 21-hydroxy-20-ketosteroids are oxidized and the corresponding ZO-ketone- Ill-aldehyde is recovered:
6a-fluoro-1 1e, l7a-21-trihydroxy-4-pregnene-3,20-dione; fia-chloro-l l5,17a,21-trihydroxy-4-pregnene-3 ,20-dione; 6a-fluoro 17a,21-dihydroxy-4-pregnene-3,1 1,20-trione; 11,9,17a,21-trihydroxy-2a-methyl-4-pregnene-3,20-dione; 1704,2l-dihydroxy-Za-methyl-4-pregnene-3,1 1,20-trione; 17a,2 l-dihydroxy-Z-methy-l-d ,4-pregnadiene 3 ,11,20-trione; 11B,17a,2l-trihydroxy-1,4-pregnadiene-3,20-dione; 17a,21-dihydroxy-1,4-pregnadiene-3,11,20-trione; 11 3,l704,21-trihydroxy-4-pregnene-3 ,ZO-dione; 11 3,l7a,21-trihydroxy-16a-methyl-4-pregnene-3,ZO-dione; 1 1p,17a,21-trihydroxy-16a-methyI-IA- regnadiene- 3,20'dione; 16a-fluoro-1 1e,17a,21-trihydroxy-4-pregnene- 3 ,20-dione; 16a-fluoro-17u,21-dihydroxy-4-pregnene-3 ,1 1,20-trione; lfia-fluoro-l15,21-dihydroxy-4-pregnene-3 ,ZO-dione;
1 1;8,21-dihydroxy-16a-methyl-4-pregnene-3,ZO-dione;
1 118,2 l-dihydroxy-4-pregnene-3 ,ZO-dione;
1 113,21-dihydroxy-6a-methyl-4-pregnene-3,ZO-dione;
9a-fluoro-1 1 18, 16a,17 a,21-tetrahydroxy-4-pregnene- 3,20-dione;
9a-fluoro-11 8,16a,17a,21-tetrahydroxy-1,4-pregnadiene- 3,20-dione;
9a-fluoro-1 1fi,17a,21-trihydroxy-1,4-pregnadiene- 3,20-dione;
9a-fluoro-17a,21-dihydroxy-4-pregnene-3 ,1 1,20-trione;
9a-fluoro-17a,21-dihydroxy-1,4-pregnadiene- 3,11,20-trione;
9a-fluoro-1 15,16a,170:,2l-tetrahydroxy-Z-methyl- 1,4-pregnadiene-3,20-dione;
9a-fluoro-1 119,16a,l7a,2I-tetrahydrOXy-Za-methyl- 4-pregnene-3,20-dione;
6a,9a-difluoro-1 1,3,1711,21-trihydr0xy-4-pregnene- 3,20-dione;
6a,9a-difluoro-11 3,16a,17a,21-tetrahydroxy-4-pregnene- 3,20-dione;
6a,9a-difluoro-1 1,8,170:,21-trihydroxy-1,4-pregnadiene- 3,20-dione;
6a,9a-difluoro-1 15,1611,17a,21-tetrahydroxy-1,4-
pregnadiene-S,20-dione;
9a-chloro-1 1B,16a,17a,21-tetrahydroxy-4-pregnene- 9a-chloro-l 1,8,17a,21-trihydroxy-4-pregnene-3,20-dione;
9a-fluoro-l 1B,16a,17a,21-tetrahydroxy-6a-methyl- 1,4-pregnadiene-3,ZO-dione;
9a-fiuoro-1 13,21-dihydroxy-16a,17a-isopropylidene- Preparation of steroidal ZI-oximes rro=o HC=NOH o=o o=o i it Using the procedures of Examples 1, 3, .6, etc. for the selective formation of the 21-aldehyde oximes from the corresponding 20-keto-21-aldehydes, the 20-ket0-aldehydes prepared as in Example 11 are converted to their 21-oximes as shown above wherein R is a steroid moiety attached at the l7-position.
EXAMPLE 13 Preparation of steroidal amines CH=NOH CHzNHaEKA) Using the procedure of Examples 2, 4, 7, etc. for the reduction of the 21-oximes of steroidal 20-keto-21-aldehydes, the 20-keto-21-aldehyde 21-oximes of Example 12 are reduced to the corresponding 21-aminosteroids. 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. As shown above 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.
EXAMPLE 15 Preparation of 21 butyrylamino-9a-flu0r0-II,B,17a-dihydr0xy-4-pregnene-3,20-di0ne Using the procedure of Example 2 for the preparation of the 21-acetylamino steroid and replacing acetic anhydride with butyric anhydride, the corresponding 21-butyrylamino derivative is formed which is 2l-butyrylamino-9afluoro-l 1p, 17a-dihydroxy-4-pregnene-3,20-dione.
EXAMPLE 16 Preparation of 21-amino-9a-fluoro-11fl-hydr0xy-16a,17misapropylidenedioxy-I,4-pregnadiene-3,20-di0ne hydrachloride A solution of 1.0 g. of 9a-fluoro-11p-hydroxy-16a,17eisopropylideneclioxy 3,20-dioxo-1,4-pregnadien-21-al 21- oxime dissolved in ml. of glacial acetic acid is treated with 2.0 g. of zinc dust, added over a period of 15 minutes at room temperature. The reaction mixture is stirred an additional 45 minutes, then filtered from insolubles. The
9: 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. The 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.
We claim:
1. The compound 21-acetylamino-9m-fluoro-115,17a-dihydroxy-4-pregnene-3,20-dione.
2. The compound 21 amino-9a-fluoro-1lB-hydroxy- 16,17a-isopropylidenedioxy-1,4-pregnadiene-3,20-dione.
3. The compound 21 acetylamino-9a-fluoro-1lB-hydroxy 1601,1711 isopropylidenedioxy 1,4-pregnadiene- 3,20-dione.
propylidenedioxy-3,ZO-dioxo-1,4-pregnadien-2l-al.
5. The compound 9a fluoro-llfl,l7a-dihydroxy-2lpropionylamino-4-pregnene-3,20-dione.
6. The compound 21 butyrylamino-Qa-fluoro-l1 3,170- dihydroxy-4-pregnene-3,20-dione.
7. The compound 9a fluoro-l1,B,l7a-dihydroxy-3,20- dioxo-4-pregnen-2l-al 21-0Xime.
8. The compound 9ot-flI1OI0-1IB-hYdlOXY-lGa, l7a-iS0- propylidenedioxy 3,20 dioxo-1,4-pregnadien-21-al 21- oxime.
9. The compound 9oz fluoro-l1fi,17u-dihydroxy-16umethyl-3,20-dioxo-1,4-pregnadiene-21-al 2l-oxime.
10. 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.
11. A compound selected from the group consisting of:
wherein 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.
12. A compound of the formula:
uni-R (i=0 wherein --C C is a divalent radical selected from the group consisting of --CH CH and -CH'=CH- radicals, 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.
13. A compound of the formula:
wherein C -C is a divalent radical selected from the group consisting of -CH CH and CH'=CH- radicals, 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 References Cited in the file of this patent UNITED STATES PATENTS Agnello et al. Jan. 12, 1960 OTHER REFERENCES Noller: Chemistry of Organic Compounds, 1957, W. B. Sanders Co., Philadelphia, .Pa., pages 210- and 479.
' 'Gilman et 211.: Organic Chemistry, vol. I, second editibn 'April 1953, John Wiley & Sons, New York, N.Y., page 660.
UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,020,275 February 6, 1962 Michael Marx et a1.
It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.
Column 3, line 16, for "to" read of column 5 lines 57 and 58, strike out the italicized heading "Preparation of 2l-acetylamino-9qfluoro-llB-hydroxy16a,l7u-isoprbpylidenedioxy-l,4-pfegnadiene-3,20-dione" and insert instead Preparation of 9q-fluoro-11B,l'la-dihydroxy-la-methyl-3,20- dioxo-l,4-pregnadiene-21-a1 21-0xime in italics.
Signed and sealed this 19th day of June 1962.
(SEAL) Attest:
ERNEST w. swmsa DAVID LADD Attesfing Officer Commissioner of Patents

Claims (1)

11. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF:
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Cited By (9)

* Cited by examiner, † Cited by third party
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US3406189A (en) * 1965-08-12 1968-10-15 American Home Prod Aminopregnanes
US3519659A (en) * 1966-12-09 1970-07-07 Ciba Geigy Corp 6alpha,9alpha-difluoro-16alpha-methyl-prednisolone-21-als
US4076737A (en) * 1975-02-20 1978-02-28 Ciba-Geigy Corporation Aldehydes of the pregnane series and derivatives thereof
JP2011507878A (en) * 2007-12-21 2011-03-10 シェーリング コーポレイション C20-C21 substituted glucocorticoid receptor agonist
EP3538539A2 (en) * 2016-11-08 2019-09-18 Regeneron Pharmaceuticals, Inc. Steroids and protein-conjugates thereof
US11377502B2 (en) 2018-05-09 2022-07-05 Regeneron Pharmaceuticals, Inc. Anti-MSR1 antibodies and methods of use thereof
US11491237B2 (en) 2017-05-18 2022-11-08 Regeneron Pharmaceuticals, Inc. Cyclodextrin protein drug conjugates
US12070506B2 (en) 2018-01-08 2024-08-27 Regeneron Pharmaceuticals, Inc. Steroids and antibody-conjugates thereof
US12134631B2 (en) 2017-11-07 2024-11-05 Regeneron Pharmaceuticals, Inc. Hydrophilic linkers for antibody drug conjugates

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2920999A (en) * 1957-06-07 1960-01-12 Pfizer & Co C 21-nitrogen derivatives of corticosteroids

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2920999A (en) * 1957-06-07 1960-01-12 Pfizer & Co C 21-nitrogen derivatives of corticosteroids

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3406189A (en) * 1965-08-12 1968-10-15 American Home Prod Aminopregnanes
US3519659A (en) * 1966-12-09 1970-07-07 Ciba Geigy Corp 6alpha,9alpha-difluoro-16alpha-methyl-prednisolone-21-als
US3519660A (en) * 1966-12-09 1970-07-07 Ciba Geigy Corp Aldehydes of the pregnane series and derivatives thereof
US4076737A (en) * 1975-02-20 1978-02-28 Ciba-Geigy Corporation Aldehydes of the pregnane series and derivatives thereof
JP2011507878A (en) * 2007-12-21 2011-03-10 シェーリング コーポレイション C20-C21 substituted glucocorticoid receptor agonist
US10711032B2 (en) 2016-11-08 2020-07-14 Regeneron Pharmaceuticals, Inc. Steroids and protein-conjugates thereof
EP3538539A2 (en) * 2016-11-08 2019-09-18 Regeneron Pharmaceuticals, Inc. Steroids and protein-conjugates thereof
US11760775B2 (en) 2016-11-08 2023-09-19 Regeneron Pharmaceuticals, Inc. Steroids and protein-conjugates thereof
US12377159B2 (en) 2016-11-08 2025-08-05 Regeneron Pharmaceuticals, Inc. Steroids and protein-conjugates thereof
EP3538539B1 (en) * 2016-11-08 2025-08-27 Regeneron Pharmaceuticals, Inc. Steroids and protein-conjugates thereof
US11491237B2 (en) 2017-05-18 2022-11-08 Regeneron Pharmaceuticals, Inc. Cyclodextrin protein drug conjugates
US12134631B2 (en) 2017-11-07 2024-11-05 Regeneron Pharmaceuticals, Inc. Hydrophilic linkers for antibody drug conjugates
US12070506B2 (en) 2018-01-08 2024-08-27 Regeneron Pharmaceuticals, Inc. Steroids and antibody-conjugates thereof
US11377502B2 (en) 2018-05-09 2022-07-05 Regeneron Pharmaceuticals, Inc. Anti-MSR1 antibodies and methods of use thereof
US12497460B2 (en) 2018-05-09 2025-12-16 Regeneron Pharmaceuticals, Inc. Anti-MSR1 antibodies and methods of use thereof

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