GB959377A - Dioxy steroids and processes for their preparation - Google Patents

Dioxy steroids and processes for their preparation

Info

Publication number
GB959377A
GB959377A GB31484/60A GB3148460A GB959377A GB 959377 A GB959377 A GB 959377A GB 31484/60 A GB31484/60 A GB 31484/60A GB 3148460 A GB3148460 A GB 3148460A GB 959377 A GB959377 A GB 959377A
Authority
GB
United Kingdom
Prior art keywords
compound
dione
treating
acetate
pregnadiene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
GB31484/60A
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Scherico Ltd
Original Assignee
Scherico Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Scherico Ltd filed Critical Scherico Ltd
Publication of GB959377A publication Critical patent/GB959377A/en
Expired legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J21/00Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J5/00Normal 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J75/00Processes for the preparation of steroids in general
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J9/00Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

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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)

Abstract

The invention comprises steroids of the pregnane series having at the 17, 20 and 21 positions the formula: <FORM:0959377/C2/1> wherein R and R1 represent lower alkyl or aralkyl radicals or, taken together with the carbon atom to which they are attached, a cycloaliphatic ring, and B represents hydrogen or an aralkyl, lower alkyl or lower alkanoyl radical, or, taken with the hydrogen atom attached to C21, an aralkylidene or lower alkylidene radical, and the preparation thereof by reacting 17a , 21-dihydroxy-20-keto-21-b steroids, wherein b has the above significance, with compounds of the formula RR1C=Q, wherein R and R1 have the above significance and Q represents O or bis-lower alkoxy, in the presence of a strong acid having a log K of less than 2.25 such as p-toluenesulphonic, sulphuric, hydrochloric and trifluoroacetic acids. By the term "lower" means having not more than 8 carbon atoms. The above process may be modified in that a product obtained having the above general formula wherein B represents hydrogen may be reacted with a lower alkyl halide, or aralkyl halide, formaldehyde, a lower alkyl aldehyde, an aryl substituted aliphatic aldehyde, a lower alkyl ketone, an aryl substituted aliphatic ketone or an ester of a lower alkanoic acid in the presence of a strong base. The steroids having the above formula may contain a hydroxy or keto group or a group convertible to keto by hydrolysis at the 3-position, a dihydroxyacetone side chain at the 17-position, a hydrogen atom or a hydroxy or keto group at the 11-position, halogen at one or more of the positions 2, 4, 6, 9, 11 and 12, a hydroxy group at one or more of the positions 1, 2, 3, 11 and 12, and unsaturation at any of the positions 1, 4, 5, 6, 7 and 9. Preferred steroids have the general formula: <FORM:0959377/C2/2> and the 1, 2-dihydro analogues thereof, wherein Z represents a hydrogen or halogen atom or a methyl group, D represents a hydrogen atom or a lower alkyl or lower alkylidene group, X represents a hydrogen or halogen atom, Y represents a keto, (H,OH), (H,O-Acy) or (H, halogen) group with the proviso that Y is a halogen atom, X is also a halogen atom or X and Y together represent a 9 (11) double bond, and R, R1 and B have the above significance. A product containing a 21-hydroxy group may be esterified to form a 21-ester, an 11a -hydroxy group may be oxidised to the corresponding 11-keto compound, and a product containing a 3-keto group may be reacted with ethylene glycol in the presence of small amounts of p-toluenesulphonic acid to form the corresponding 3-ethylene ketal. A product containing a 9(11)-double bond may be reacted with formic acid, sodium formate and N-chlorosuccinimide to form a 9 a -chloro-11b -formate compound having the structure in the first formula above. Therapeutic compositions useful in the alleviation of burns and the treatment of certain atopic and contact dermatoses and which may be administered topically contain as the active ingredient a steroid having at the 17, 20 and 21-positions the first formula above. 17a , 21- Dihydroxy -20-keto-steroids are prepared by treating the steroids having at the 17, 20 and 21-positions the first formula above with aqueous acid. The product may or may not retain the group represented by the symbol B at the 21-position. corresponding 2a -methyl compound, and treating this compound with refluxing acetic acid. 9a , 11b -Dichloro -16- methylene-1, 4-pregnadiene-17a , 21-diol-3, 20-dione is prepared by treating 16-methyl-5, 16-pregnadiene-3b -ol-20-one with alkaline hydrogen peroxide, acetylating the resulting 16b -methyl-16, 17-oxido -5- pregnene-3b -ol-20-one treating the resulting corresponding 3-acetate with hydrogen bromide to form 16-methylene-5-pregnene-3b , 17a -diol-20-one 3-acetate, treating this compound with bromine, hydrogen bromide and acetic acid to form a 5, 6, 2-tribromo substituted compound, treating this compound with sodium iodide and then potassium acetate to form 16-methylene-5-pregnene-3b , 17a , 21-triol-20-one 3, 21-diacetate, oxidising this compound with a growing culture of Flavobacterium dehydrogenans var. hydrolyticum to form 16-methylene -4- pregnene-17a , 21-diol-3, 20-dione, 11b -hydroxylating this compound with a growing culture of Curvularia lunata to form 16-methylene-hydrocortisone, dehydrogenating this compound with a growing culture of Bacillus sphaericus to form 16-methylene-prednisolone, acetylating this compound to form the corresponding 21-acetate (this compound is also obtainable by 21-acetylating 16-methylene-hydrocortisone and dehydrogenating the resulting 21-acetate with Bacillus sphaericus), treating the 21-acetate with p-toluene sulphonyl chloride and pyridine to form 16-methylene-1, 4, 9 (11)-pregnatriene-17a , 21-diol-3, 20-dione 21-acetate, treating this compound with lithium chloride and N-chlorosuccinimide, and hydrolysing the resulting 9a , 11b -dichloro -16- methylene-1, 4-pregnadiene-17a , 21-diol-3, 20-dione 21-acetate. Prednisolone is prepared by converting pregnane-11b , 17a , 21-triol-3, 20-dione to the corresponding 17a , 21-isopropylidenedioxy by the method referred to in the first paragraph above, brominating the product to form 2, 4-dibromo-17a , 21-isoproylidene-dioxy-pregnane -11b -ol-3, 20-dione, refluxing this compound with dimethyl-formamide to form the corresponding 1, 4-pregnadiene, and hydrolysing the 17a , 21-isopropylidene grouping with refluxing acetic acid. 17a , 21-Dihydroxy -4- pregnene-3, 20-dione is prepared by oxidising the 17a , 21-isopropylidenedioxy derivative of 5(6)-pregnene-3b , 17a , 21-triol-20-one with chromium trioxide in pyridine and cleaning the resulting 17a , 21-isopropylidenedioxy -4- pregnene-3, 20-dione with acetic acid. Cortisone is prepared by oxidising 17a , 21-isopropylidenedioxy -5- pregnene-3b -ol-11, 20-dione with aluminium isopropoxide in cyclohexanone to form 17a , 21-isopropylidenedioxy -4- pregnene-3, 11, 20-trione and cleaning this compound as in the previous paragraph. 2a -Methyl-hydrocortisone is prepared by treating the 17a , 21-isopropylidenedioxy derivative of hydrocortisone with benzaldehyde under alkaline conditions to form 17a , 21-isopropylidenedioxy-21-benxylidene -4- pregnene-11b -ol-3, 20-dione, treating this compound with diethyl oxalate in the presence of sodium methoxide to form the corresponding 2-ethyloxalyl compound, treating this compound with methyl iodide in the presence of potassium t-butoxide to form the resulting 9a , 11b -dichloro -16- methylene-1, 4-pregnadiene-17a , 21-diol-3, 20-dione 21-acetate. 9a -Chloro-1, 4-pregnadiene-11b , 17a , 21-triol-3, 20-dione 11b -formate is prepared by treating 9a -chloro-1, 4-pregnadiene-11b , 17a , 21-triol-3, 20-dione 11b -formate 21-acetate with methanolic perchloric acid. 9a -Chloro-16a -methyl-1,4-pregnadiene-11b , 17a , 21-triol-3, 20-dione 11b -formate is prepared by treating 16a -methyl-1, 4, 9 (11)-pregnadiene-17a , 21-diol-3, 20-dione 21-acetate with formic acid, sodium formate, N-chlorosuccinimide and hydrochloric acid, and treating the resulting 9a -chloro-16a -methyl-1, 4-pregnadiene-11b , 17a , 21-triol-3, 20-dione 11b -formate 21-acetate with methanolic perchloric acid. The corresponding 16b -methyl and 16a -ethyl compounds are prepared by similar methods. Specification 959,378 is referred to.
GB31484/60A 1959-10-12 1960-09-13 Dioxy steroids and processes for their preparation Expired GB959377A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US84559559A 1959-10-12 1959-10-12
US84559459A 1959-10-12 1959-10-12
US84566159A 1959-10-12 1959-10-12

Publications (1)

Publication Number Publication Date
GB959377A true GB959377A (en) 1964-06-03

Family

ID=27420319

Family Applications (2)

Application Number Title Priority Date Filing Date
GB31484/60A Expired GB959377A (en) 1959-10-12 1960-09-13 Dioxy steroids and processes for their preparation
GB15754/63A Expired GB959378A (en) 1959-10-12 1960-09-13 21-substituted 17ª‡, 21-dioxy steroids and processes for their preparation

Family Applications After (1)

Application Number Title Priority Date Filing Date
GB15754/63A Expired GB959378A (en) 1959-10-12 1960-09-13 21-substituted 17ª‡, 21-dioxy steroids and processes for their preparation

Country Status (7)

Country Link
BE (1) BE595971A (en)
CH (1) CH392500A (en)
DE (1) DE1188079B (en)
DK (1) DK108281C (en)
FR (2) FR1428454A (en)
GB (2) GB959377A (en)
NL (1) NL6810178A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4069322A (en) * 1976-10-12 1978-01-17 Interx Research Corporation Pro-drugs for the improved delivery of certain selected anti-inflammatory steroids

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101591482B1 (en) 2008-05-28 2016-02-03 레베라겐 바이오파마 인코포레이티드 - non-hormonal steroid modulators of nf-b for treatment of disease
EP2556083A4 (en) 2010-04-05 2013-12-04 Validus Biopharma Inc Non-hormonal steroid modulators of nf- kappa b for treatment of disease
US10799514B2 (en) 2015-06-29 2020-10-13 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-kappa beta for treatment of disease
US11382922B2 (en) 2019-03-07 2022-07-12 Reveragen Biopharma, Inc. Aqueous oral pharmaceutical suspension compositions

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2866799A (en) * 1957-01-02 1958-12-30 Merck & Co Inc Method for converting a 17-20, 20-21 bismethylenedioxy or a 17-20, 20-21 bis-substituted methylenedioxy steroid of the pregnane series to a 17alpha, 21-dihydroxy-20-ketosteroid of the pregnane series

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4069322A (en) * 1976-10-12 1978-01-17 Interx Research Corporation Pro-drugs for the improved delivery of certain selected anti-inflammatory steroids
DE2745948A1 (en) * 1976-10-12 1978-04-13 Interx Research Corp PRODRUG COMPOUNDS OF STEROIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICINAL PRODUCTS WITH ANTI-INFLAMMATORY EFFECT

Also Published As

Publication number Publication date
DK108281C (en) 1967-11-06
FR957M (en) 1961-11-27
FR1428454A (en) 1966-02-18
BE595971A (en) 1961-02-01
NL6810178A (en) 1968-10-25
CH392500A (en) 1965-05-31
DE1188079B (en) 1965-03-04
GB959378A (en) 1964-06-03

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