CA1064476A - Steroids and process for preparing the same - Google Patents
Steroids and process for preparing the sameInfo
- Publication number
- CA1064476A CA1064476A CA219,681A CA219681A CA1064476A CA 1064476 A CA1064476 A CA 1064476A CA 219681 A CA219681 A CA 219681A CA 1064476 A CA1064476 A CA 1064476A
- Authority
- CA
- Canada
- Prior art keywords
- alpha
- beta
- bromo
- pregna
- dione
- 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
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Classifications
-
- 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
- C07J5/0046—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 substituted in position 17 alfa
- C07J5/0053—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 substituted in position 17 alfa not substituted in position 16
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- C07J5/0046—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 substituted in position 17 alfa
- C07J5/0061—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 substituted in position 17 alfa substituted in position 16
- C07J5/0069—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 substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
- C07J5/0076—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 substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
-
- 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
- C07J5/0046—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 substituted in position 17 alfa
- C07J5/0061—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 substituted in position 17 alfa substituted in position 16
- C07J5/0092—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 substituted in position 17 alfa substituted in position 16 by an OH group free esterified or etherified
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/0026—Oxygen-containing hetero ring cyclic ketals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/0026—Oxygen-containing hetero ring cyclic ketals
- C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Pain & Pain Management (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A B S T R A C T
There is disclosed compounds having the general formula:
There is disclosed compounds having the general formula:
Description
10644~6 -The present invention relates to a new class of steroids having good anti-inflammatory activity, to processes of making them and to pharmaceutical compositions containing them.
Many steroids having anti-inflammatory activity upon topical and/or systemic administration are known and some of them have quite satisfactory anti-inflammatory activity.
Unfortunately they all tend to give undesired side effects.
I For instance they may disturb the mineral balance in the ;; 10 subject to which they are administered, for example they may reduce the potassium and/or sodium balance, and they may ,l affect adversely the adrenals function.
Accordingly their application has to be conducted with caution.
It has been our object to produce novel steroids l that have very good anti-inflammatory activity, preferably , I
~, higher than that of most or all known steroids, and which have i very low or no side effects, preferably when measured in abso-,~¦ lute terms but in particular when measured as the therapeutic ratio, i.e. the ratio of the active dose that is required to ~¦ achieve the desired anti-inflammatory activity to the minimum dose that incurs undesired side effects.
, ., We have now found that 2-bromo-6~-fluoro-pregna-1,4-diene-3,20-diones have high anti-inflammatory activity and at the same avoid completely or at least minimize the undesirable side effects of known steroid compounds. The preferred novel compounds of the invention have the general formula: ;
, ..-.
,., ~L
. -- 1 -- ~
.
: ' : ,.: -: - . ' : , .
. . .
.
~64476 1 2Rl = ~ 3 Br ~
(A) F
- wherein X represents Br, Cl, or OQ;
Y represents Br, Cl, F or H;
Rl represents OQ;
~ R~ represents OQ;
;~ R3 represents H, ~OQ, ~CH3 or ~CH3; and the radicals Q, which may be the same or different, are selected from H and acyl radicals, or the groups OQ in the 16 and 17-positions or in the 17 and 21-positions may together form a cyclic ketal, cyclic acetal or cyclic alkyl orthoester, and pharmaceutically acceptable salts or esters with those compounds wherein at least one radical Q is a polycarboxylic or an inorganic acid radical. The salts are preferably water soluble and are preferably with an alkali metal, for example sodium or potassium. The esters are preferably with an aliphatic, aryl, arylaliphatic or cycloaliphatic group. The OQ group of Rl can be also an alkyl orthoester.
Typical values of aliphatic radicals suitable as the ~ esterifying radical in a dicarboxylic acyl group are alkyl, ; 20 preferably containing up to 7 carbon atoms, and alkenyl. Par-ticularly preferred are alkyl containing up to 4 carbon atoms, especially methyl, ethyl and propyl. Typical cycloaliphatic are cycloalkyl radicals containing 5 to 8 carbon atoms, for example cyclopentyl and cyclohexyl. Typical arylaliphatic
Many steroids having anti-inflammatory activity upon topical and/or systemic administration are known and some of them have quite satisfactory anti-inflammatory activity.
Unfortunately they all tend to give undesired side effects.
I For instance they may disturb the mineral balance in the ;; 10 subject to which they are administered, for example they may reduce the potassium and/or sodium balance, and they may ,l affect adversely the adrenals function.
Accordingly their application has to be conducted with caution.
It has been our object to produce novel steroids l that have very good anti-inflammatory activity, preferably , I
~, higher than that of most or all known steroids, and which have i very low or no side effects, preferably when measured in abso-,~¦ lute terms but in particular when measured as the therapeutic ratio, i.e. the ratio of the active dose that is required to ~¦ achieve the desired anti-inflammatory activity to the minimum dose that incurs undesired side effects.
, ., We have now found that 2-bromo-6~-fluoro-pregna-1,4-diene-3,20-diones have high anti-inflammatory activity and at the same avoid completely or at least minimize the undesirable side effects of known steroid compounds. The preferred novel compounds of the invention have the general formula: ;
, ..-.
,., ~L
. -- 1 -- ~
.
: ' : ,.: -: - . ' : , .
. . .
.
~64476 1 2Rl = ~ 3 Br ~
(A) F
- wherein X represents Br, Cl, or OQ;
Y represents Br, Cl, F or H;
Rl represents OQ;
~ R~ represents OQ;
;~ R3 represents H, ~OQ, ~CH3 or ~CH3; and the radicals Q, which may be the same or different, are selected from H and acyl radicals, or the groups OQ in the 16 and 17-positions or in the 17 and 21-positions may together form a cyclic ketal, cyclic acetal or cyclic alkyl orthoester, and pharmaceutically acceptable salts or esters with those compounds wherein at least one radical Q is a polycarboxylic or an inorganic acid radical. The salts are preferably water soluble and are preferably with an alkali metal, for example sodium or potassium. The esters are preferably with an aliphatic, aryl, arylaliphatic or cycloaliphatic group. The OQ group of Rl can be also an alkyl orthoester.
Typical values of aliphatic radicals suitable as the ~ esterifying radical in a dicarboxylic acyl group are alkyl, ; 20 preferably containing up to 7 carbon atoms, and alkenyl. Par-ticularly preferred are alkyl containing up to 4 carbon atoms, especially methyl, ethyl and propyl. Typical cycloaliphatic are cycloalkyl radicals containing 5 to 8 carbon atoms, for example cyclopentyl and cyclohexyl. Typical arylaliphatic
- 2 -.
' , :1064476 .
radicals are phenyl alkyl radicals, for example where alkyl is as described above, for instance benzyl. Typical aryl radi-cals are those containing a phenyl ring, for example unsubsti-tuted phenyl.
When Q is acyl, OQ thus being an ester radical, Q
may be the radical of an inorganic acid, for example sulphuric . acid or phosphoric acid, or an organic acid, for example a sulphonic acid or a carboxylic acid, including aliphatic, ~ -:- .
~ alicyclic, aromatic, arylaliphatic and heterocyclic carboxylic ... .
acids, including carboxylic acids such as thiocarboxylic acids and amino carboxylic acids. Preferred carboxylic acids are formic acid, acetic acid, chloroacetic acid, trifluoroacetic .
acid, propionic acid, butyric acid, valeric acid, trimethyl-acetic acid, diethylacetic acid, caproic acid, crotonic acid, enanthic acid, caprylic acid, capric acid, palmitic acid, undecanic acid, undecylenic acid, oxalic acid, succinic acid, glutaric acid, pimelic acid, tartaric acid, maleic acid, lactic acid, carbamic acid, glycine, alkoxy carboxylic acids, hexahydrobenzoic acid, cyclopentylpropionic acids, cyclohexyl-acetic acid, cyclohexylbutyric acids, benzoic acid, phthalic -~
acid, phenylacetic acid, phenylpropionic acids, furane-2-carboxylic acid, nicotinic acid and isonicotinic acid. Pre-ferred sulphonic acids are methanesulphonic acid and toluene-.
sulphonic acid.
Particularly preferred acyl radicals are those derived from acetic acid, trimethylacetic acid, propionic acid ~-phenylpropionic acid, a-phenylpropionic acid, valeric acid and dicarboxylic acids, for example succinic acid.
It is often preferred that in Rl Q shall be an acyl 3Q group as described above, particularly the preferred carbox-ylic acyl groups as described above, since 21-esters have .;
' , :1064476 .
radicals are phenyl alkyl radicals, for example where alkyl is as described above, for instance benzyl. Typical aryl radi-cals are those containing a phenyl ring, for example unsubsti-tuted phenyl.
When Q is acyl, OQ thus being an ester radical, Q
may be the radical of an inorganic acid, for example sulphuric . acid or phosphoric acid, or an organic acid, for example a sulphonic acid or a carboxylic acid, including aliphatic, ~ -:- .
~ alicyclic, aromatic, arylaliphatic and heterocyclic carboxylic ... .
acids, including carboxylic acids such as thiocarboxylic acids and amino carboxylic acids. Preferred carboxylic acids are formic acid, acetic acid, chloroacetic acid, trifluoroacetic .
acid, propionic acid, butyric acid, valeric acid, trimethyl-acetic acid, diethylacetic acid, caproic acid, crotonic acid, enanthic acid, caprylic acid, capric acid, palmitic acid, undecanic acid, undecylenic acid, oxalic acid, succinic acid, glutaric acid, pimelic acid, tartaric acid, maleic acid, lactic acid, carbamic acid, glycine, alkoxy carboxylic acids, hexahydrobenzoic acid, cyclopentylpropionic acids, cyclohexyl-acetic acid, cyclohexylbutyric acids, benzoic acid, phthalic -~
acid, phenylacetic acid, phenylpropionic acids, furane-2-carboxylic acid, nicotinic acid and isonicotinic acid. Pre-ferred sulphonic acids are methanesulphonic acid and toluene-.
sulphonic acid.
Particularly preferred acyl radicals are those derived from acetic acid, trimethylacetic acid, propionic acid ~-phenylpropionic acid, a-phenylpropionic acid, valeric acid and dicarboxylic acids, for example succinic acid.
It is often preferred that in Rl Q shall be an acyl 3Q group as described above, particularly the preferred carbox-ylic acyl groups as described above, since 21-esters have .;
- 3 -, .
- ~ , . .
.
- - `
particularly good biological activity. It is often preferred that when X represents OQ, Q shall be hydrogen.
Any convenient cyclic ketals or cyclic acetals may be formed at the 16,17 or 17,21-positions but are preferably acetonides or 17,21-methylene dioxy derivatives. Suitable cyclic orthoesters that may be formed at these positions include the 17,21-methylorthoacetate, the 17,21-ethylortho-propionate, the 17,21-methylorthobenzoate and the 17,21-methylorthovalerate.
10 One preferred class of compounds of the invention are those wherein R3 represents H or ~OQ, especially OH. An-other preferred class of compounds of the invention are those ; wherein R3 represents ~ or ~-methyl, most preferably ~-methyl.
It is often preferred that Y should be halogen. X
can also be halogen and thus some preferred compounds of the invention have both X and Y representing halogen, usually both ~; representing chlorine or both representing bromine. However, it is generally preferred that Y shall represent halogen and X
shall represent OQ, preferably OH. Preferred values of Y are ..~
bromine and, especially, fluorine. Thus particularly pre-ferred compounds of the invention are 9-~-halo (especially fluoro) ll-~-hydroxy compounds.
It is of course already well known to make pregna-1,4-diene-3,20-dione compounds. It is also known to produce a -; few 2-bromo steroids. Further, it is well known to make 6-~-; fluoro steroids. There have been some references to the pro-; duction of 6-~-fluoro steroids in the literature but it seems to have been considered generally in the art that 6-~-fluoro - steroids are inferior pharmaceutically to 6-~-fluoro steroids.
The combination of 2-bromo with 6-~-fluoro in pregna-1,4-diene-3,20-diones appears to be new and gives good anti-- ~' : . . , - .
. . .
; ~
inflammatory activity with low or negligible side effects as :,....................................................................... .
` discussed above.
~ The novel compounds of the invention have good anti--; inflammatory activity. This activity can be exhibited upon conventional methods of administration, for example topically and systemically. Some compounds give best results topically while others give best results systemically, for instance when ; taken orally as is preferred. Because of the very high activity possessed by preferred compounds of the invention lower dosages can be used than are useful with known anti-inflammatory steroids; even at conventional dosages preferred ` compounds of the invention have much less, and generally no ;
side effects compared with known anti-inflammatory steroids.
The compounds of the invention are useful for treatment of a wide variety of inflammatory conditions, for ;J example in the treatment of inflammatory conditions of the skin, eyes and ears of humans and of valuable domestic -animals, as well as contact dermatitis and other allergic -reactions and also possess valuable antirheumatoid arthritic .. . .
~~ 20 properties.
I; Therapeutic compositions of the invention comprise a compound of the invention together with a pharmaceutically s acceptable liquid or solid carrier. Any therapeutically acceptable and effective concentration of the compound in the composition may be used. Any suitable composition may be ;,; prepared, according to the chosen manner of administration.
;. ; , Suitable compositions include pills, tablets, capsules, solutions, syrups or elixirs for oral use, liquid forms of the ~ -types used to make injectable compositions of the natural and ` 30 synthetic cortical steroid hormones, and topical compositions, ; for example in the form of ointments, creams and lotions.
'.', ;, ... .. .. . . ... . .. . . . . . . .. .
.,, 1(364476 The compositions may also include coacting anti-biotics, germicides or other materials forming advantageous combination therewith.
The local anti-inflammatory activity has been evalu-ated in rats by the cotton-pellet induced granuloma test, applying the compound directly to the pellet.
All the new compounds of the present invention show a remarkable anti-inflammatory activity without undesirable side effects on the thymus and on the body weight increase even at very high concentrations (40 micrograms/pellet).
The most active compounds inhibit the cotton-pellet induced granuloma at doses as low as 0.002 - 0.1 micrograms~
pellet whereas fluocinolone-16,17-acetonide evokes the same ; effect at a dose of 0.5 - 2 micrograms/pellet. Other compounds of the present invention are active at doses ranging - , from 0.1 to 2 micrograms/pellet whereas betamethasone 17-valerate is active at a dose of 5 - 20 micrograms/pellet.
Some other compounds of the present invention display activity at doses higher than 2 micrograms/pellet. Hydrocortisone acetate shows the same activity at about 100 - 200 micrograms/
pellet.
The systemic anti-inflammatory activity has been evaluated in rats by the cotton-pellet induced granuloma test, giving the compounds orally for 8 days. The most active compounds show activity at doses ranging from 0.01 to 0.1 mg/kg b.w. In the same experimental conditions betamethasone (alcohol or phosphate) shows activity at doses of about 0.05 -0.1 mg/kg b.w. while hydrocortisone acetate and methylpredni-solone are active at doses ranging from 10 to 50 mg/kg b.w.
Most of the compounds of the present invention have, on this test, no inhibiting action on adrenals weight and a thymolitic . ~ . :
or body weight reducing activity lower than that displayed by the most active already known steroids.
The compounds of the invention can be made by various processes including the following:-1. Compounds where Rl and R2 are as defined previously, R3 is hydrogen or ~ or ~-methyl or ~OQ (preferably OH), X is OQ
(preferably OH) and Y is Br can be made by dissolving the corresponding 9,11-unsaturated compound in an organic solvent such as methylene chloride, tertiary butyl alcohol, dioxane, tetrahydrofurane, tertiary amyl alcohol or the like, and by reacting this at room temperature with an hypobromous acid releasing agent, which includes N-bromoacetamide, N-bromo-succinimide, 1,3-dibromo-5,5-dimethyl-hydantoin or the like, in the presence of an acid such as perchloric acid, diluted sulfuric acid and the like. Normally the bromination is con-ducted at room temperature, between fifteen and thirty degrees centigrade. The reaction period may vary from about five minutes to one hour. At the conclusion of the desired reaction the excess hypobromous acid is destroyed by the addition of sulfites or hydrosulfites, sodium sulfite being normally employed. The resulting compound can be isolated from the reaction mixture by adding an excess of water and extracting the product with organic solvents or by recovering the precipitated compound by filtration.
2. Compounds in which Rl and R2 are as defined above, R3 is hydrogen or ~ or ~-methyl or ~OQ (preferably OH) and X and Y
are both bromine or both chlorine can be made by reacting the corresponding 9,11-unsaturated compound with a chlorinating or - brominating agent. Suitable agents are N-chlorosuccinimide, N-bromosuccinimide, N-chlorophthalimide, N-bromoacetamide, N-chloroacetamide or the like. The reaction is preferably - .- . : , - . .. .: , , ~
---~
conducted in an organic solvent such as lower aliphatic carboxylic acids, for example glacial acetic acid, diethyl-acetic acid, propionic acid or butyric acid, or in ether solvents, for example tetrahydrofurane or dioxane, or in halogen solvents for example methylene chloride or chloroform, or in a mixture of these solvents. The reaction is carried out at temperature of 0 to 50C, preferably ambient tempera-ture in the presence of halogen-anions such as chloro or bromo in the form of corresponding alkali halides, preferably - 10 potassium or lithium chloride.
3. Compounds where Rl and R2 are as defined above, R3 is hydrogen or ~ or ~-methyl or ~OQ (preferably OH), X is OQ, preferably OH, and Y is halogen (preferably F and Cl) can be made by reacting the corresponding 9,11-epoxide ~for instance prepared by dehydrobromination with an alkaline carbonate ,:
- solution of the 9-bromo-11-hydroxy compound prepared as .~
described abovel with hydrogen halide, namely HF or HCl. This may be generated in sit~ but preferably is introduced as aqueous solution. The steroid is first dissolved in an 2U organic solvent such as tetrahydrofurane, methylene chloride -~ and the like. The halogenation reaction is operative at room ~; temperature but is preferably conducted at lower temperatures, ~` ;. :.
such as zero to minus eighty degrees centigrade, with continu-ous stirring. After the reaction is completed, the mixture is ~;~ poured into water and neutralized with diluted base, such as diluted sodium or potassium hydroxide, or a bicarbonate such `~ as sodium bicarbonate, potassium bicarbonate or the like. The ~ reaction mixture is then extracted in the usual manner, such : ~ .
;~ as with methylene chloride, and the resulting compound is recovered in a purified form by recrystallization or chroma-tography. -.
, :' .. ., . ~, . . -, .... ... . .
10644~6
- ~ , . .
.
- - `
particularly good biological activity. It is often preferred that when X represents OQ, Q shall be hydrogen.
Any convenient cyclic ketals or cyclic acetals may be formed at the 16,17 or 17,21-positions but are preferably acetonides or 17,21-methylene dioxy derivatives. Suitable cyclic orthoesters that may be formed at these positions include the 17,21-methylorthoacetate, the 17,21-ethylortho-propionate, the 17,21-methylorthobenzoate and the 17,21-methylorthovalerate.
10 One preferred class of compounds of the invention are those wherein R3 represents H or ~OQ, especially OH. An-other preferred class of compounds of the invention are those ; wherein R3 represents ~ or ~-methyl, most preferably ~-methyl.
It is often preferred that Y should be halogen. X
can also be halogen and thus some preferred compounds of the invention have both X and Y representing halogen, usually both ~; representing chlorine or both representing bromine. However, it is generally preferred that Y shall represent halogen and X
shall represent OQ, preferably OH. Preferred values of Y are ..~
bromine and, especially, fluorine. Thus particularly pre-ferred compounds of the invention are 9-~-halo (especially fluoro) ll-~-hydroxy compounds.
It is of course already well known to make pregna-1,4-diene-3,20-dione compounds. It is also known to produce a -; few 2-bromo steroids. Further, it is well known to make 6-~-; fluoro steroids. There have been some references to the pro-; duction of 6-~-fluoro steroids in the literature but it seems to have been considered generally in the art that 6-~-fluoro - steroids are inferior pharmaceutically to 6-~-fluoro steroids.
The combination of 2-bromo with 6-~-fluoro in pregna-1,4-diene-3,20-diones appears to be new and gives good anti-- ~' : . . , - .
. . .
; ~
inflammatory activity with low or negligible side effects as :,....................................................................... .
` discussed above.
~ The novel compounds of the invention have good anti--; inflammatory activity. This activity can be exhibited upon conventional methods of administration, for example topically and systemically. Some compounds give best results topically while others give best results systemically, for instance when ; taken orally as is preferred. Because of the very high activity possessed by preferred compounds of the invention lower dosages can be used than are useful with known anti-inflammatory steroids; even at conventional dosages preferred ` compounds of the invention have much less, and generally no ;
side effects compared with known anti-inflammatory steroids.
The compounds of the invention are useful for treatment of a wide variety of inflammatory conditions, for ;J example in the treatment of inflammatory conditions of the skin, eyes and ears of humans and of valuable domestic -animals, as well as contact dermatitis and other allergic -reactions and also possess valuable antirheumatoid arthritic .. . .
~~ 20 properties.
I; Therapeutic compositions of the invention comprise a compound of the invention together with a pharmaceutically s acceptable liquid or solid carrier. Any therapeutically acceptable and effective concentration of the compound in the composition may be used. Any suitable composition may be ;,; prepared, according to the chosen manner of administration.
;. ; , Suitable compositions include pills, tablets, capsules, solutions, syrups or elixirs for oral use, liquid forms of the ~ -types used to make injectable compositions of the natural and ` 30 synthetic cortical steroid hormones, and topical compositions, ; for example in the form of ointments, creams and lotions.
'.', ;, ... .. .. . . ... . .. . . . . . . .. .
.,, 1(364476 The compositions may also include coacting anti-biotics, germicides or other materials forming advantageous combination therewith.
The local anti-inflammatory activity has been evalu-ated in rats by the cotton-pellet induced granuloma test, applying the compound directly to the pellet.
All the new compounds of the present invention show a remarkable anti-inflammatory activity without undesirable side effects on the thymus and on the body weight increase even at very high concentrations (40 micrograms/pellet).
The most active compounds inhibit the cotton-pellet induced granuloma at doses as low as 0.002 - 0.1 micrograms~
pellet whereas fluocinolone-16,17-acetonide evokes the same ; effect at a dose of 0.5 - 2 micrograms/pellet. Other compounds of the present invention are active at doses ranging - , from 0.1 to 2 micrograms/pellet whereas betamethasone 17-valerate is active at a dose of 5 - 20 micrograms/pellet.
Some other compounds of the present invention display activity at doses higher than 2 micrograms/pellet. Hydrocortisone acetate shows the same activity at about 100 - 200 micrograms/
pellet.
The systemic anti-inflammatory activity has been evaluated in rats by the cotton-pellet induced granuloma test, giving the compounds orally for 8 days. The most active compounds show activity at doses ranging from 0.01 to 0.1 mg/kg b.w. In the same experimental conditions betamethasone (alcohol or phosphate) shows activity at doses of about 0.05 -0.1 mg/kg b.w. while hydrocortisone acetate and methylpredni-solone are active at doses ranging from 10 to 50 mg/kg b.w.
Most of the compounds of the present invention have, on this test, no inhibiting action on adrenals weight and a thymolitic . ~ . :
or body weight reducing activity lower than that displayed by the most active already known steroids.
The compounds of the invention can be made by various processes including the following:-1. Compounds where Rl and R2 are as defined previously, R3 is hydrogen or ~ or ~-methyl or ~OQ (preferably OH), X is OQ
(preferably OH) and Y is Br can be made by dissolving the corresponding 9,11-unsaturated compound in an organic solvent such as methylene chloride, tertiary butyl alcohol, dioxane, tetrahydrofurane, tertiary amyl alcohol or the like, and by reacting this at room temperature with an hypobromous acid releasing agent, which includes N-bromoacetamide, N-bromo-succinimide, 1,3-dibromo-5,5-dimethyl-hydantoin or the like, in the presence of an acid such as perchloric acid, diluted sulfuric acid and the like. Normally the bromination is con-ducted at room temperature, between fifteen and thirty degrees centigrade. The reaction period may vary from about five minutes to one hour. At the conclusion of the desired reaction the excess hypobromous acid is destroyed by the addition of sulfites or hydrosulfites, sodium sulfite being normally employed. The resulting compound can be isolated from the reaction mixture by adding an excess of water and extracting the product with organic solvents or by recovering the precipitated compound by filtration.
2. Compounds in which Rl and R2 are as defined above, R3 is hydrogen or ~ or ~-methyl or ~OQ (preferably OH) and X and Y
are both bromine or both chlorine can be made by reacting the corresponding 9,11-unsaturated compound with a chlorinating or - brominating agent. Suitable agents are N-chlorosuccinimide, N-bromosuccinimide, N-chlorophthalimide, N-bromoacetamide, N-chloroacetamide or the like. The reaction is preferably - .- . : , - . .. .: , , ~
---~
conducted in an organic solvent such as lower aliphatic carboxylic acids, for example glacial acetic acid, diethyl-acetic acid, propionic acid or butyric acid, or in ether solvents, for example tetrahydrofurane or dioxane, or in halogen solvents for example methylene chloride or chloroform, or in a mixture of these solvents. The reaction is carried out at temperature of 0 to 50C, preferably ambient tempera-ture in the presence of halogen-anions such as chloro or bromo in the form of corresponding alkali halides, preferably - 10 potassium or lithium chloride.
3. Compounds where Rl and R2 are as defined above, R3 is hydrogen or ~ or ~-methyl or ~OQ (preferably OH), X is OQ, preferably OH, and Y is halogen (preferably F and Cl) can be made by reacting the corresponding 9,11-epoxide ~for instance prepared by dehydrobromination with an alkaline carbonate ,:
- solution of the 9-bromo-11-hydroxy compound prepared as .~
described abovel with hydrogen halide, namely HF or HCl. This may be generated in sit~ but preferably is introduced as aqueous solution. The steroid is first dissolved in an 2U organic solvent such as tetrahydrofurane, methylene chloride -~ and the like. The halogenation reaction is operative at room ~; temperature but is preferably conducted at lower temperatures, ~` ;. :.
such as zero to minus eighty degrees centigrade, with continu-ous stirring. After the reaction is completed, the mixture is ~;~ poured into water and neutralized with diluted base, such as diluted sodium or potassium hydroxide, or a bicarbonate such `~ as sodium bicarbonate, potassium bicarbonate or the like. The ~ reaction mixture is then extracted in the usual manner, such : ~ .
;~ as with methylene chloride, and the resulting compound is recovered in a purified form by recrystallization or chroma-tography. -.
, :' .. ., . ~, . . -, .... ... . .
10644~6
4. Compounds in which Rl, X and Y are all as defined for : -Formula A, and R2 and R3 are both OH may be made by oxidizing the corresponding 16,17-unsaturated compound. Any oxidizing agents known for oxidizing a double bond in a steroid to pro-duce a dihydroxy compound can be used, for example potassium permanganate. The reaction is preferably conducted in an acidic aqueous organic solution such as glacial acetic acid or formic acid in aqueous acetone at a temperature of -20 to +50C. The reaction may be terminated by adding a reducing agent, such as sodium sulphite.
S. Any compound of the invention in which any or all of X, Rl, R2 or R3 represent OQ where Q is H can be made by hydro-lyzing the corresponding compound where Q is acyl. Hydrolysis can be conducted under acidic conditions, for example in the presence of an acid such as hydrochloric acid, or under alka-line conditions, for example in the presence of an alkali such as sodium hydroxide or sodium carbonate, in an aqueous, organic or aqueous organic solvent, for example a lower alco-hol, at temperature of 0 to 100C, preferably under reflux.
Acetates in ll-position usually are extremely resistant to hydrolysis. -6. Any compound of the invention in which one or more of X, Rl, R2 and R3 represents OQ where Q is an acyl radical can be made by esterifying the corresponding compound in which Q
represents hydrogen. Esterification can be conducted by reaction with the appropriate acid halide or acid anhydride in pyridine or other suitable organic solvent, preferably a basic solvent. The reaction is best conducted in organic solvent at ~,, - . .
- temperatures of 0 to 100C preferably under reflux. This process is best carried out on the 16 or 21-positions, the ; hydroxy group in the 11 and 17-positions usually remaining : ~ ~ 9 ~ ' ' , :
.. , ~ , .
''s' ';, . ' . . : ~ , , , , , . . : -, ~ ,. :.
- ~- , , . . . : ~ . : . . : . : . . .
::: . , : - .
~064476 unchanged during the reaction. The 17 and ll-positions require acid anhydrides with mineral acids as catalyst. The 17-monoesters are prepared by a mineral or organic acid hydrolysis of cyclic 17,21-alkyl orthoesters. The cyclic 17,21-alkyl orthoesters are prepared from the corresponding 17,21-dihydroxy by exchange reaction with trimethyl ortho-esters in the presence of an acid catalyst. The orthoesteri-fication steps is carried out at temperature ranging from 60 to 130C and preferably around 100-110C for a period of 4-24 hours. The orthoesters thus obtained are then hydrolyzed with a mineral or organic acid to give the 17-monoesters. The cyclic 16,17-alkyl orthoesters are also prepared from the corresponding diols with trimethylorthoesters in the presence of an acid catalyst. The orthoesterification step is carried - out at temperature ranging from 20 to 30C for a period of 1-2 hours.
7. Compounds of the invention in which OQ in the 16 and 17-positions or in the 17 and 21-positions represent a cyclic acetal or a cyclic ketal can be made by treating a suspension - 20 or solution of the corresponding diols in the desired aldehyde or ketone (or an organic solvent, if the aldehyde or ketone is a solid) with an acid catalyst (e.g., perchloric acid, p-toluene sulfonic acid and hydrochloric acid), neutralizing the acid and recovering the cyclic acetal or ketal derivative formed. The reaction is preferably carried out at a tempera-ture within the range from about 15 to 60C. It is usually completed within a period from about one hour to eighteen hours. The 17,21-cyclic acetals and ketals are prepared by an acid catalyzed interchange reaction between the corresponding diols and lower alkyl acetals of aliphatic, cycloaliphatic or arylaliphatic aldehydes or ketones. The reaction is best ., ' - 10 --: :
~ .
conducted in organic solvent at temperatures from 20 to 100C
preferably under reflux.
- The 16,17-unsaturated compound described above as the starting material for the production of the 16,17-dihydroxy compound may be made by dehydration of the corre- ~:
sponding 17-hydroxy compound in which R3 is H so that all the processes described above can be considered to start from the 9,11-unsaturated compound wherein R3 is hydrogen or methyl.
We show in Figure 1 a suitable reaction scheme for making these compounds, having Formula VIII, starting from the known compound I.
.. '~
:'' ., ' ~
. . .
~.
:
;~ - 11 -i , '.
, .
106447~;
FIGURE I
CIH20AC CH20Ac CH20Ac CO CO CO
~/ 3~R3 C ~ CH 2U~J
II III
., / ~
/
~/ ' f 2 CIH20Ac CIH20Ac CO CO CO
HO~ ~J~R3 HO-~ ~R3 MSO--~
~R3 ~~ Br., ~r., ~~
`' 0~ ~J ~ '' ~ F HO F ' ~:
`.:` IV V VI :
.,' ~::
,., ~ ~
;': ' . ., T fH 20AC CH 20AC
. CO C~) CO
~R3 MSO."~R MSO~ /~
Br~Br~ 3r-"~
~,''' 0~ ~ ~/ '':,', F F ACO F
VIII VII bi6 VII
- , . . . ` , `: ' `, , ~
~)64476 ::.
A suitable way of carrying out the reaction scheme in Fig. 1 is now described. In this the known starting material 11~,17~,21-trihydroxy-pregn-4-ene-3,20-dione-21-acetate (I) or its known 16~ or 16~-methyl analogue, is first ketalized to produce the 3-ketal (II). Ethylene glycol, in the presence of p-toluenesulfonic acid or pyridine hydro-chloride, is the preferred ketalizing agent. Formation of the ketal is accompanied by migration of the double bound from the 4,5 to the 5,6-position.
The epoxidation of the 5(6) double bound of the compound II with a peracid (perbenzoic or mono perphthalic acid or other known epoxidizing agents) produces the corre-sponding 5~,6~-epoxide (III). A mixture of both the ~ and ~-epoxides is produced in this epoxidation reaction, and the mixture can be separated by crystallization. The ~-epoxide III is employed in the next step, which is an epoxide opening reaction in which the 11~,17~,21-trihydroxy-3,3-ethylenedioxy--: 5~,6~-oxido-pregnane-20-one-21-acetate (III) is reacted with ;
hydrofluoric acid to produce the corresponding 6~-fluoro-5~, 11~,17~,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (IV).
The buffered bromination of the compound IV stops to the 2a-bromo-6~-fluoro-5~ ,17~,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (V).
ddition of methanesulphonyl chloride to the compound V produces the 2a-bromo-6~-fluoro-5~ ,17~,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-21-acetate (VI).
Treatment of the mesylate VI with acetic anhydride and perchloric acid produces the 2~-bromo-6~-fluoro-5~,11~, 17~,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-5,17,21-triacetate (VII), which is converted, by bromination in acetic acid containing potassium or sodium acetate as the base, into ~C~64476 2,2-dibromo-6~-fluoro-11~,17~,21-trihydroxy-pregn-4-ene-3,20-dione-ll-mesylate-17,21-diacetate (VII bis).
The combination of certain metal halides, particu-larly lithium chloride and bromine in hot dimethylformamide, is particularly effective in dehydrobromination of compound VII bis to the corresponding triene VIII, 2-bromo-6~-fluoro-17~,21-dihydroxy-pregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate. Other amide solvents, such as dimethyl-acetamide and N-formylpiperidine can be used in place of dimethyl-- 10 formamide. A modification involves the use of an excess of lithium carbonate in dimethylformamide.
A particularly important step in this scheme is the formation of the compound of formula V. Accordingly a further feature of the invention resides in the bromination of compounds of formula IV, as well as the 11 and/or 17-esters and/or 21-hydroxy derivatives to produce the corresponding 2~-` bromo compounds. The introduction of the 2~-bromo compound at this stage appears to fix the configuration of the 6~-fluoro group so that it is stable during the subsequent reactions in the steroid molecule.
Compounds of formula V, as well as the 11 and/or 17-esters and/or 21-hydroxy analogues are novel compounds, as also are compounds of each of formulae II to VIII inclusive.
' ':
:: ' .' .
' . .
. - .,, -: , . :: .
.~ ' , ... . . . . .. . .
:. , . , . . . : :
`` 1064476 Convenient ways of carrying out the processes 1 to 7 listed above are shown in the reaction scheme in Fig. 2.
FIGURE II
fH2AC CH20Ac fH2AC
CO CO CO
~ HO ~ 3 ~ AR3 Br ~ ~ Br ~ ~ Br ¦ ¦ < ¦ Br¦ C
0~ ~ 0~ ~/ 0~ ~ .
¦ X ¦ IX ¦ VIII
: F F F
', \
\ fH2AC \ ~ fH2Rl \ CO CO
H ~r~_R3 Cl~ R3 r ~
. XIII XII
.. F F
'.
fH2Rl fH2R1 7 2 1 .", \ / CO CO CO
'~ HO ~ ~ ~ 3 ~ HO ~ ~OH
~ Br ~ Br ~/ ~ Br ~
~ o~5~ >oJ~J >O~J
XI when XI biS / I XVII
~,' / I
f 2 1 / ~ f 2 1 co L~ co ' HO ~ ..H,R3HO ~ O - C ~ R4 Br ~ Br ~
,:' 0~ 0~
¦ XVIII ¦ XIX
F F
~064476 .:
The reaction of the compound VIII with hypobromous acid produces the corresponding 9a-bromo compound IX. When this 9~-bromo compound is reacted with potassium carbonate in acetone the 9~ -oxido compound X is obtained. Reaction of the latter compound with hydrofluoric acid affords 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XI, Rl = R2 ~ OCOCH3) which upon hydrolysis is converted into the corresponding free alcohol ; XIa, (XI, Rl = R2 = OH). In similar manner reaction of compound X with hydrochloric acid yields the ll-hydroxy-9~
chloro analogue. This reaction with the hydrochloric acid is particularly convenient when R3 represents methyl. ~ -The fluorine atom at the 6~-position of the compound XI (Rl = R2 ~ OCOCH3) is considered to be in the stable con-figuration on the basis of the following observation.
Attempts to isomerize 2-bromo-6~,9~-fluoro-11~,17~, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate ; -; tXI, R1 = R2 = OCOCH3) with dry hydrochloric acid in chloro-form at 0C for 2 hrs. do not alter the optical rotatory dis-persion curve of the crude product. Recrystallization affords pure product identical in all aspects to the starting sample ~; XI (R1 = R2 = OCOCH3). Reaction of compound X with hydro-chloric acid affords 2-bromo-6~-fluoro-9~-chloro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XIII).
The triene VIII is reacted with N-chlorosuccinimide to obtain the 2-bromo-6~-fluoro-9a,11~-dichloro-17~,21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XII, Rl = R2 ~ OCOCH3) which upon hydrolysis is converted into the corresponding free alcohol XIIa (XII, Rl = R2 = OH).
- 30 Similarly, the triene VIII can be reacted with N-bromo succinimide to produce the corresponding 9 ,', - . - , ., . , ,. . - .~ -. . .. . . :
":- ;
dibromo compound XII, especially when R3 represents methyl.
When the compound XI (where Rl = R2 ' OCOCH3 and R3 ~ H~ is reacted with potassium acetate in hot dimethylformamide the 2-bromo~6~,9a-difluoro-11~,21-dihydroxy-pregna-1,4,16-triene-21-acetate (XI bis, Rl - OCOCH3) is obtained. The compound XI
bis (Rl = OCOCH3) is then oxidated with potassium permanganate to produce the corresponding 2-bromo-6~,9a-difluoro-11~,16a, 17a,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-21-acetate (XVII, Rl = OCOCH3) which upon hydrolysis is converted into the corresponding free alcohol XVIIa (XVII, Rl = OH).
Esterification of the hydroxyl function at the 21- ~ -position is conveniently effected with a lower fatty acid anhydride, such as acetic anhydride, or preferably with a ~;; . .
~i lower aliphatic acid chloride such as acetic acid chloride in -.
presence of pyridine, which simultaneously serves as solvent.
The 17a-esters are prepared by treatment of the corresponding 17a,21-diols with a lower alkyl orthoesters in the presence of ~-- an acid catalyst followed by acid hydrolysis of the resulting 17a,21-orthoester (a mixture of two epimeric orthoesters).
The esterification of the hydroxyl function at the 21-position can also be achieved by trans-esterification of the corre-sponding 17a-esters. Treatment of the corresponding 17a,21-diols with 2,2-dimethoxy-propane in presence of p-toluene- ;
; sulfonic acid produces the 17,21-acetonides. Treatment of the compounds XVII with acetone and perchloric acid produces the 16,17-acetonides XVIII. The esterification of the hydroxyl function at the 16-position of the compounds XVII is effected with a lower fatty acid anhydride in presence of pyridine ~-~ which simultaneously serves as solvent.
~ 3~ We list below particularly preferred compounds of : ' the invention and for convenience here and in the Examples . '; , .
: .
:~064476 denote after the compounds a number corresponding to the number of the formula in the figures. In view of the large number of subscripts necessary for formula XI we use two .; :
systems of nomenclature. The compounds in which R3 is hydrogen or hydroxy are numbered by reference to the formulae numbering appearing in Figs. 1 and 2. The compound in which R3 is ~ or ~-methyl have a different system of numbering in which 10 corresponds to formula IX, 11 corresponds to formula X and 12 corresponds to formulae XI, XII and XIII.
10 2,9~-dibromo-6~-fluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (IX) 2-bromo-6~,9~-difluoro~ ,17~,21-trihydroxv-pregna-1,4-diene-3,20-dione-17,21-diacetate (XI) 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20~dione-17,21-acetonide (XIb) 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-acetate (XIc) 20 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-propionate (XId) 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-valerate (XIe) 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-pivalate (XIf) 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-terbutylacetate (XIg) 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-enantate (XIh) 30 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate (XIi) . . ~
.
: 2-bromo-6~,9a-difluoro~ 17a~21~trihydroxy-pregna~1~4~diene~- .
3,20-dione-17-valerate (XIl) - .
2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna~1~4 diene-~: 3,20-dione-17-valerate-21-acetate (XIm 2-bromo-6~,9a-difluoro~ ,17a,21-trihydroxy-pregna lr4.diene~
3,20-dione-17-acetate (XIn~
~ ~ 2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna~1~4~diene- ~-`-~. 3,20-dione-17-acetate-21-valerate (XIo~ - :
. ..................................................................... ~
2-bromo-6~,9a-difluoro~ ,17a,21-trihydroxy-pregna-1~4-diene-.- 10 3,20-dione-17-propionate (XIpl ~:: 2-bromo-6~,9-difluoro-11~,17a,21-trihydroxy-pregna^1,4-diene-`~ 3,2Q-dione-17-benzoate (XIq) 2-bromo-6~-fluoro-9~ -dichloro-17a,21-dihydroxy~pregna-1,4-' diene-3,20-dione-17,21-diacetate (XII) 2-bromo-6~-fluoro-9~ -dichloro--17a,21-dihydroxy-pregna-1,4-diene-3,20-dione (XIIa~ ~:
~ 2-bromo-6,~-fluoro-9a,11,B-dichloro-17a,21-dihydroxy-pregna-1,4 .~ diene-3,20-dione-17-acetate (XIIb) : -2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4- :
., ~
20 diene-3,20-dione-21-acetate (XIIc) 2-bromo-6~,9a-difluoro-11~,16a,17a,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-21-acetate (XVII) : 2-bromo-6~,9a-difluoro-11~,16a,17a,21-tetrahydroxy-pregna-1,4--: ~
~ diene-3,20-dione (XVIIa) :~ 2-bromo-6~,9a-difluoro-11~,16,17a,21-tetrahydroxy-pregna-1,4-~. diene-3,20-dione-16,21-diacetate (XVIII) :~
,;~ 2-bromo-6~,9a-difluoro-11~,16a,17a,21-tetrahydroxy-pregna-1,4-..
:- diene-3,20-dione-16,17-acetonide-21-acetate (XIX) :~ 2-bromo-6~,9a-difluoro-11~,16a,17a,21-tetrahydroxy-pregna-1,4-~ 30 diene-3,20-dione-16,17-acetonide (XIXa) ..4.
2-bromo-6~-fluoro-9a-chloro~ ,17a,21-trihydroxy-pregna-1,4-~. , - : ~ , . ' .
~ 1064476 . diene-3,20-dione-17,21-diacetate (XXIII) 16~-methyl-2,9a-dibromo-6~-fluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione~17,21-diacetate (10 a) - 16~-methyl-2,9a-dibromo-6~-fluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (10 b) -~
16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-; pregna-1,4-diene-3,20-dione-17,21-diacetate (12 a) ~:
16~-methyl-2-bromo-6~,9~-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (12 b) : 10 16a-methyl-2-bromo-6~-fluoro-9~-chloro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (12 c) 16~-methyl-2-bromo-6~ fluoro-9a-chloro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (12 d) 16a-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (12 e) 16~-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (12 f) 16a-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) . 20 16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 h) 16a-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione (12 i) 16~-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna~l,4-diene-3,20-dione (12 j) 16a-methyl-2-bromo-6~,9a-difluoro-11~,17~,21-trihydroxy-' pregna-1,4-diene-3,20-dione-21-acetate (12 k) -:~ 16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-acetate (12 1) 16a-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-propionate (12 m) : .
:
:
.
.
16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-: pregna-1,4-diene-3,20-dione-21-propionate (12 n) ~ ~ .
16a-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-~- pregna-1,4-diene-3,20-dione-21-acetate (12 o) 16~-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17~,21-dihydroxy-~ pregna-1,4-diene-3,20-dione-21-acetate (12 p) ;` 16a-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate (12 q) ~,.
16a-methyl-2-bromo-6~,9~-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (12 r) ~:
16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy- ~ ~.
pregna-1,4-diene-3,20-dione-17-valerate (12 s) ~:. 16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-. pregna-1,4-diene-3,20-dione-17-acetate (12 t) :. , 16a-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-:' pregna-1,4-diene-3,20-dione-17-acetate (12 u) . ',j ~-, 16~-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (12 v) 16a-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-... .
pregna-1,4-diene-3,20-dione-17,21-acetonide (12 w) 16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-acetonide (12 z) 16a-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-:
:~ pregna-1,4-diene-3,20-dione-21-valerate (12 aa) 16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-valerate (12 ab) i 16a-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-; pregna-1,4-diene-3,20-dione-21-pivalate (12 ac) 16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-- : 30 pregna-1,4-diene-3,20-dione-21-pivalate (12 ad) : ~ 16a-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-"
- . : ' :
pregna-1,4-diene-3,20-dione-21-benzoate (12 ae) 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate (12 af~
16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-propionate (12 ag) 16~-methyl-2-bromo-6~,9a-difluoro-11~,17~,21-trihydroxy-- pregna-1,4-diene-3,20-dione-17-benzoate (12 ah) Compounds particularly preferred for topical administration are XI and XId, e, f, i, m, p and q, and compounds 12 k, i and o. Compounds that are particularly suitable for systemic administration, and also for topical and systemic administration, are XIa, c and e and XIX and 12 g and k, and XIn is also very useful for systemic administration.
Particularly preferred compounds of the invention are XI and XIa.
The following are some Examples of the invention:
A mixture of 8 g. of 11~,17~,21-trihydroxy-pregn-4-- ene-3,20-dione-21-acetate (I), 200 ml. of benzene, 80 ml. of i ;
; 20 ethylene glycol and 4.8 g. of pyridine hydrochloride was refulxed under stirring for 8 hr. in a water separator. After ` reaction was completed 200 ml~ of 5~ sodium bicarbonate aque-ous solution were added. The mixture was further concentrated until crystals appeared and then poured into cold water. The resulting precipitate was removed by filtration, washed neutral with water and dried. Crystallization of the residue from chloroform and ethyl ether gave 6 g. of 11~,17~,21-tri-hydroxy-3,3-ethylene-dioxy-pregn-5-ene-20-one-21-acetate (II).
IR(KBr) 3565, 3540, 3450 (broad), 1755, 1730, 1220 cm 1 Analysis: Calcd. for C25H36O7 (percent) C 66,94; H 8,09.
Found (percent) C 67,07; H 8,15.
:
1~)64476 ;~; A solution of permonophthalic acid (8 g.~ in ether (60 ml.) was added over 1.5 hr. to a solution of 6 g. of 11~, 17~,21-trihydroxy-3,3-ethylene-dioxy-pregn-5-ene-20-one-21-acetate (II) in chloroform (200 ml.) at -30C. After keeping at -30C for 3 hrs. the organic phase was washed acid free - with 5% sodium bicarbonate aqueous solution. The solution was then washed with water, dried and evaporated to a residue which by crystallization from methanol gave 4.5 g. of 11~,17~, 10 21-trihydroxy~3,3-ethylene-dioxy-5~,6~-oxido-pregnane-20-one-21-acetate (III).
IR(KBr) 3585, 3540, 3485 (broad), 1760, 1732, 1230 cm Analysis: Calcd. for C25H36O8 (percent) C 64,63; H 7,81 Found (percent) C 64,78; H 7,82.
4,5 g. of 11~,17~,21-trihydroxy-3,3-ethylene-dioxy-
S. Any compound of the invention in which any or all of X, Rl, R2 or R3 represent OQ where Q is H can be made by hydro-lyzing the corresponding compound where Q is acyl. Hydrolysis can be conducted under acidic conditions, for example in the presence of an acid such as hydrochloric acid, or under alka-line conditions, for example in the presence of an alkali such as sodium hydroxide or sodium carbonate, in an aqueous, organic or aqueous organic solvent, for example a lower alco-hol, at temperature of 0 to 100C, preferably under reflux.
Acetates in ll-position usually are extremely resistant to hydrolysis. -6. Any compound of the invention in which one or more of X, Rl, R2 and R3 represents OQ where Q is an acyl radical can be made by esterifying the corresponding compound in which Q
represents hydrogen. Esterification can be conducted by reaction with the appropriate acid halide or acid anhydride in pyridine or other suitable organic solvent, preferably a basic solvent. The reaction is best conducted in organic solvent at ~,, - . .
- temperatures of 0 to 100C preferably under reflux. This process is best carried out on the 16 or 21-positions, the ; hydroxy group in the 11 and 17-positions usually remaining : ~ ~ 9 ~ ' ' , :
.. , ~ , .
''s' ';, . ' . . : ~ , , , , , . . : -, ~ ,. :.
- ~- , , . . . : ~ . : . . : . : . . .
::: . , : - .
~064476 unchanged during the reaction. The 17 and ll-positions require acid anhydrides with mineral acids as catalyst. The 17-monoesters are prepared by a mineral or organic acid hydrolysis of cyclic 17,21-alkyl orthoesters. The cyclic 17,21-alkyl orthoesters are prepared from the corresponding 17,21-dihydroxy by exchange reaction with trimethyl ortho-esters in the presence of an acid catalyst. The orthoesteri-fication steps is carried out at temperature ranging from 60 to 130C and preferably around 100-110C for a period of 4-24 hours. The orthoesters thus obtained are then hydrolyzed with a mineral or organic acid to give the 17-monoesters. The cyclic 16,17-alkyl orthoesters are also prepared from the corresponding diols with trimethylorthoesters in the presence of an acid catalyst. The orthoesterification step is carried - out at temperature ranging from 20 to 30C for a period of 1-2 hours.
7. Compounds of the invention in which OQ in the 16 and 17-positions or in the 17 and 21-positions represent a cyclic acetal or a cyclic ketal can be made by treating a suspension - 20 or solution of the corresponding diols in the desired aldehyde or ketone (or an organic solvent, if the aldehyde or ketone is a solid) with an acid catalyst (e.g., perchloric acid, p-toluene sulfonic acid and hydrochloric acid), neutralizing the acid and recovering the cyclic acetal or ketal derivative formed. The reaction is preferably carried out at a tempera-ture within the range from about 15 to 60C. It is usually completed within a period from about one hour to eighteen hours. The 17,21-cyclic acetals and ketals are prepared by an acid catalyzed interchange reaction between the corresponding diols and lower alkyl acetals of aliphatic, cycloaliphatic or arylaliphatic aldehydes or ketones. The reaction is best ., ' - 10 --: :
~ .
conducted in organic solvent at temperatures from 20 to 100C
preferably under reflux.
- The 16,17-unsaturated compound described above as the starting material for the production of the 16,17-dihydroxy compound may be made by dehydration of the corre- ~:
sponding 17-hydroxy compound in which R3 is H so that all the processes described above can be considered to start from the 9,11-unsaturated compound wherein R3 is hydrogen or methyl.
We show in Figure 1 a suitable reaction scheme for making these compounds, having Formula VIII, starting from the known compound I.
.. '~
:'' ., ' ~
. . .
~.
:
;~ - 11 -i , '.
, .
106447~;
FIGURE I
CIH20AC CH20Ac CH20Ac CO CO CO
~/ 3~R3 C ~ CH 2U~J
II III
., / ~
/
~/ ' f 2 CIH20Ac CIH20Ac CO CO CO
HO~ ~J~R3 HO-~ ~R3 MSO--~
~R3 ~~ Br., ~r., ~~
`' 0~ ~J ~ '' ~ F HO F ' ~:
`.:` IV V VI :
.,' ~::
,., ~ ~
;': ' . ., T fH 20AC CH 20AC
. CO C~) CO
~R3 MSO."~R MSO~ /~
Br~Br~ 3r-"~
~,''' 0~ ~ ~/ '':,', F F ACO F
VIII VII bi6 VII
- , . . . ` , `: ' `, , ~
~)64476 ::.
A suitable way of carrying out the reaction scheme in Fig. 1 is now described. In this the known starting material 11~,17~,21-trihydroxy-pregn-4-ene-3,20-dione-21-acetate (I) or its known 16~ or 16~-methyl analogue, is first ketalized to produce the 3-ketal (II). Ethylene glycol, in the presence of p-toluenesulfonic acid or pyridine hydro-chloride, is the preferred ketalizing agent. Formation of the ketal is accompanied by migration of the double bound from the 4,5 to the 5,6-position.
The epoxidation of the 5(6) double bound of the compound II with a peracid (perbenzoic or mono perphthalic acid or other known epoxidizing agents) produces the corre-sponding 5~,6~-epoxide (III). A mixture of both the ~ and ~-epoxides is produced in this epoxidation reaction, and the mixture can be separated by crystallization. The ~-epoxide III is employed in the next step, which is an epoxide opening reaction in which the 11~,17~,21-trihydroxy-3,3-ethylenedioxy--: 5~,6~-oxido-pregnane-20-one-21-acetate (III) is reacted with ;
hydrofluoric acid to produce the corresponding 6~-fluoro-5~, 11~,17~,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (IV).
The buffered bromination of the compound IV stops to the 2a-bromo-6~-fluoro-5~ ,17~,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (V).
ddition of methanesulphonyl chloride to the compound V produces the 2a-bromo-6~-fluoro-5~ ,17~,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-21-acetate (VI).
Treatment of the mesylate VI with acetic anhydride and perchloric acid produces the 2~-bromo-6~-fluoro-5~,11~, 17~,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-5,17,21-triacetate (VII), which is converted, by bromination in acetic acid containing potassium or sodium acetate as the base, into ~C~64476 2,2-dibromo-6~-fluoro-11~,17~,21-trihydroxy-pregn-4-ene-3,20-dione-ll-mesylate-17,21-diacetate (VII bis).
The combination of certain metal halides, particu-larly lithium chloride and bromine in hot dimethylformamide, is particularly effective in dehydrobromination of compound VII bis to the corresponding triene VIII, 2-bromo-6~-fluoro-17~,21-dihydroxy-pregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate. Other amide solvents, such as dimethyl-acetamide and N-formylpiperidine can be used in place of dimethyl-- 10 formamide. A modification involves the use of an excess of lithium carbonate in dimethylformamide.
A particularly important step in this scheme is the formation of the compound of formula V. Accordingly a further feature of the invention resides in the bromination of compounds of formula IV, as well as the 11 and/or 17-esters and/or 21-hydroxy derivatives to produce the corresponding 2~-` bromo compounds. The introduction of the 2~-bromo compound at this stage appears to fix the configuration of the 6~-fluoro group so that it is stable during the subsequent reactions in the steroid molecule.
Compounds of formula V, as well as the 11 and/or 17-esters and/or 21-hydroxy analogues are novel compounds, as also are compounds of each of formulae II to VIII inclusive.
' ':
:: ' .' .
' . .
. - .,, -: , . :: .
.~ ' , ... . . . . .. . .
:. , . , . . . : :
`` 1064476 Convenient ways of carrying out the processes 1 to 7 listed above are shown in the reaction scheme in Fig. 2.
FIGURE II
fH2AC CH20Ac fH2AC
CO CO CO
~ HO ~ 3 ~ AR3 Br ~ ~ Br ~ ~ Br ¦ ¦ < ¦ Br¦ C
0~ ~ 0~ ~/ 0~ ~ .
¦ X ¦ IX ¦ VIII
: F F F
', \
\ fH2AC \ ~ fH2Rl \ CO CO
H ~r~_R3 Cl~ R3 r ~
. XIII XII
.. F F
'.
fH2Rl fH2R1 7 2 1 .", \ / CO CO CO
'~ HO ~ ~ ~ 3 ~ HO ~ ~OH
~ Br ~ Br ~/ ~ Br ~
~ o~5~ >oJ~J >O~J
XI when XI biS / I XVII
~,' / I
f 2 1 / ~ f 2 1 co L~ co ' HO ~ ..H,R3HO ~ O - C ~ R4 Br ~ Br ~
,:' 0~ 0~
¦ XVIII ¦ XIX
F F
~064476 .:
The reaction of the compound VIII with hypobromous acid produces the corresponding 9a-bromo compound IX. When this 9~-bromo compound is reacted with potassium carbonate in acetone the 9~ -oxido compound X is obtained. Reaction of the latter compound with hydrofluoric acid affords 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XI, Rl = R2 ~ OCOCH3) which upon hydrolysis is converted into the corresponding free alcohol ; XIa, (XI, Rl = R2 = OH). In similar manner reaction of compound X with hydrochloric acid yields the ll-hydroxy-9~
chloro analogue. This reaction with the hydrochloric acid is particularly convenient when R3 represents methyl. ~ -The fluorine atom at the 6~-position of the compound XI (Rl = R2 ~ OCOCH3) is considered to be in the stable con-figuration on the basis of the following observation.
Attempts to isomerize 2-bromo-6~,9~-fluoro-11~,17~, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate ; -; tXI, R1 = R2 = OCOCH3) with dry hydrochloric acid in chloro-form at 0C for 2 hrs. do not alter the optical rotatory dis-persion curve of the crude product. Recrystallization affords pure product identical in all aspects to the starting sample ~; XI (R1 = R2 = OCOCH3). Reaction of compound X with hydro-chloric acid affords 2-bromo-6~-fluoro-9~-chloro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XIII).
The triene VIII is reacted with N-chlorosuccinimide to obtain the 2-bromo-6~-fluoro-9a,11~-dichloro-17~,21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XII, Rl = R2 ~ OCOCH3) which upon hydrolysis is converted into the corresponding free alcohol XIIa (XII, Rl = R2 = OH).
- 30 Similarly, the triene VIII can be reacted with N-bromo succinimide to produce the corresponding 9 ,', - . - , ., . , ,. . - .~ -. . .. . . :
":- ;
dibromo compound XII, especially when R3 represents methyl.
When the compound XI (where Rl = R2 ' OCOCH3 and R3 ~ H~ is reacted with potassium acetate in hot dimethylformamide the 2-bromo~6~,9a-difluoro-11~,21-dihydroxy-pregna-1,4,16-triene-21-acetate (XI bis, Rl - OCOCH3) is obtained. The compound XI
bis (Rl = OCOCH3) is then oxidated with potassium permanganate to produce the corresponding 2-bromo-6~,9a-difluoro-11~,16a, 17a,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-21-acetate (XVII, Rl = OCOCH3) which upon hydrolysis is converted into the corresponding free alcohol XVIIa (XVII, Rl = OH).
Esterification of the hydroxyl function at the 21- ~ -position is conveniently effected with a lower fatty acid anhydride, such as acetic anhydride, or preferably with a ~;; . .
~i lower aliphatic acid chloride such as acetic acid chloride in -.
presence of pyridine, which simultaneously serves as solvent.
The 17a-esters are prepared by treatment of the corresponding 17a,21-diols with a lower alkyl orthoesters in the presence of ~-- an acid catalyst followed by acid hydrolysis of the resulting 17a,21-orthoester (a mixture of two epimeric orthoesters).
The esterification of the hydroxyl function at the 21-position can also be achieved by trans-esterification of the corre-sponding 17a-esters. Treatment of the corresponding 17a,21-diols with 2,2-dimethoxy-propane in presence of p-toluene- ;
; sulfonic acid produces the 17,21-acetonides. Treatment of the compounds XVII with acetone and perchloric acid produces the 16,17-acetonides XVIII. The esterification of the hydroxyl function at the 16-position of the compounds XVII is effected with a lower fatty acid anhydride in presence of pyridine ~-~ which simultaneously serves as solvent.
~ 3~ We list below particularly preferred compounds of : ' the invention and for convenience here and in the Examples . '; , .
: .
:~064476 denote after the compounds a number corresponding to the number of the formula in the figures. In view of the large number of subscripts necessary for formula XI we use two .; :
systems of nomenclature. The compounds in which R3 is hydrogen or hydroxy are numbered by reference to the formulae numbering appearing in Figs. 1 and 2. The compound in which R3 is ~ or ~-methyl have a different system of numbering in which 10 corresponds to formula IX, 11 corresponds to formula X and 12 corresponds to formulae XI, XII and XIII.
10 2,9~-dibromo-6~-fluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (IX) 2-bromo-6~,9~-difluoro~ ,17~,21-trihydroxv-pregna-1,4-diene-3,20-dione-17,21-diacetate (XI) 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20~dione-17,21-acetonide (XIb) 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-acetate (XIc) 20 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-propionate (XId) 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-valerate (XIe) 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-pivalate (XIf) 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-terbutylacetate (XIg) 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-enantate (XIh) 30 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate (XIi) . . ~
.
: 2-bromo-6~,9a-difluoro~ 17a~21~trihydroxy-pregna~1~4~diene~- .
3,20-dione-17-valerate (XIl) - .
2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna~1~4 diene-~: 3,20-dione-17-valerate-21-acetate (XIm 2-bromo-6~,9a-difluoro~ ,17a,21-trihydroxy-pregna lr4.diene~
3,20-dione-17-acetate (XIn~
~ ~ 2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna~1~4~diene- ~-`-~. 3,20-dione-17-acetate-21-valerate (XIo~ - :
. ..................................................................... ~
2-bromo-6~,9a-difluoro~ ,17a,21-trihydroxy-pregna-1~4-diene-.- 10 3,20-dione-17-propionate (XIpl ~:: 2-bromo-6~,9-difluoro-11~,17a,21-trihydroxy-pregna^1,4-diene-`~ 3,2Q-dione-17-benzoate (XIq) 2-bromo-6~-fluoro-9~ -dichloro-17a,21-dihydroxy~pregna-1,4-' diene-3,20-dione-17,21-diacetate (XII) 2-bromo-6~-fluoro-9~ -dichloro--17a,21-dihydroxy-pregna-1,4-diene-3,20-dione (XIIa~ ~:
~ 2-bromo-6,~-fluoro-9a,11,B-dichloro-17a,21-dihydroxy-pregna-1,4 .~ diene-3,20-dione-17-acetate (XIIb) : -2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4- :
., ~
20 diene-3,20-dione-21-acetate (XIIc) 2-bromo-6~,9a-difluoro-11~,16a,17a,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-21-acetate (XVII) : 2-bromo-6~,9a-difluoro-11~,16a,17a,21-tetrahydroxy-pregna-1,4--: ~
~ diene-3,20-dione (XVIIa) :~ 2-bromo-6~,9a-difluoro-11~,16,17a,21-tetrahydroxy-pregna-1,4-~. diene-3,20-dione-16,21-diacetate (XVIII) :~
,;~ 2-bromo-6~,9a-difluoro-11~,16a,17a,21-tetrahydroxy-pregna-1,4-..
:- diene-3,20-dione-16,17-acetonide-21-acetate (XIX) :~ 2-bromo-6~,9a-difluoro-11~,16a,17a,21-tetrahydroxy-pregna-1,4-~ 30 diene-3,20-dione-16,17-acetonide (XIXa) ..4.
2-bromo-6~-fluoro-9a-chloro~ ,17a,21-trihydroxy-pregna-1,4-~. , - : ~ , . ' .
~ 1064476 . diene-3,20-dione-17,21-diacetate (XXIII) 16~-methyl-2,9a-dibromo-6~-fluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione~17,21-diacetate (10 a) - 16~-methyl-2,9a-dibromo-6~-fluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (10 b) -~
16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-; pregna-1,4-diene-3,20-dione-17,21-diacetate (12 a) ~:
16~-methyl-2-bromo-6~,9~-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (12 b) : 10 16a-methyl-2-bromo-6~-fluoro-9~-chloro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (12 c) 16~-methyl-2-bromo-6~ fluoro-9a-chloro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (12 d) 16a-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (12 e) 16~-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (12 f) 16a-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) . 20 16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 h) 16a-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione (12 i) 16~-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna~l,4-diene-3,20-dione (12 j) 16a-methyl-2-bromo-6~,9a-difluoro-11~,17~,21-trihydroxy-' pregna-1,4-diene-3,20-dione-21-acetate (12 k) -:~ 16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-acetate (12 1) 16a-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-propionate (12 m) : .
:
:
.
.
16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-: pregna-1,4-diene-3,20-dione-21-propionate (12 n) ~ ~ .
16a-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-~- pregna-1,4-diene-3,20-dione-21-acetate (12 o) 16~-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17~,21-dihydroxy-~ pregna-1,4-diene-3,20-dione-21-acetate (12 p) ;` 16a-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate (12 q) ~,.
16a-methyl-2-bromo-6~,9~-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (12 r) ~:
16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy- ~ ~.
pregna-1,4-diene-3,20-dione-17-valerate (12 s) ~:. 16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-. pregna-1,4-diene-3,20-dione-17-acetate (12 t) :. , 16a-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-:' pregna-1,4-diene-3,20-dione-17-acetate (12 u) . ',j ~-, 16~-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (12 v) 16a-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-... .
pregna-1,4-diene-3,20-dione-17,21-acetonide (12 w) 16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-acetonide (12 z) 16a-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-:
:~ pregna-1,4-diene-3,20-dione-21-valerate (12 aa) 16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-valerate (12 ab) i 16a-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-; pregna-1,4-diene-3,20-dione-21-pivalate (12 ac) 16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-- : 30 pregna-1,4-diene-3,20-dione-21-pivalate (12 ad) : ~ 16a-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-"
- . : ' :
pregna-1,4-diene-3,20-dione-21-benzoate (12 ae) 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate (12 af~
16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-propionate (12 ag) 16~-methyl-2-bromo-6~,9a-difluoro-11~,17~,21-trihydroxy-- pregna-1,4-diene-3,20-dione-17-benzoate (12 ah) Compounds particularly preferred for topical administration are XI and XId, e, f, i, m, p and q, and compounds 12 k, i and o. Compounds that are particularly suitable for systemic administration, and also for topical and systemic administration, are XIa, c and e and XIX and 12 g and k, and XIn is also very useful for systemic administration.
Particularly preferred compounds of the invention are XI and XIa.
The following are some Examples of the invention:
A mixture of 8 g. of 11~,17~,21-trihydroxy-pregn-4-- ene-3,20-dione-21-acetate (I), 200 ml. of benzene, 80 ml. of i ;
; 20 ethylene glycol and 4.8 g. of pyridine hydrochloride was refulxed under stirring for 8 hr. in a water separator. After ` reaction was completed 200 ml~ of 5~ sodium bicarbonate aque-ous solution were added. The mixture was further concentrated until crystals appeared and then poured into cold water. The resulting precipitate was removed by filtration, washed neutral with water and dried. Crystallization of the residue from chloroform and ethyl ether gave 6 g. of 11~,17~,21-tri-hydroxy-3,3-ethylene-dioxy-pregn-5-ene-20-one-21-acetate (II).
IR(KBr) 3565, 3540, 3450 (broad), 1755, 1730, 1220 cm 1 Analysis: Calcd. for C25H36O7 (percent) C 66,94; H 8,09.
Found (percent) C 67,07; H 8,15.
:
1~)64476 ;~; A solution of permonophthalic acid (8 g.~ in ether (60 ml.) was added over 1.5 hr. to a solution of 6 g. of 11~, 17~,21-trihydroxy-3,3-ethylene-dioxy-pregn-5-ene-20-one-21-acetate (II) in chloroform (200 ml.) at -30C. After keeping at -30C for 3 hrs. the organic phase was washed acid free - with 5% sodium bicarbonate aqueous solution. The solution was then washed with water, dried and evaporated to a residue which by crystallization from methanol gave 4.5 g. of 11~,17~, 10 21-trihydroxy~3,3-ethylene-dioxy-5~,6~-oxido-pregnane-20-one-21-acetate (III).
IR(KBr) 3585, 3540, 3485 (broad), 1760, 1732, 1230 cm Analysis: Calcd. for C25H36O8 (percent) C 64,63; H 7,81 Found (percent) C 64,78; H 7,82.
4,5 g. of 11~,17~,21-trihydroxy-3,3-ethylene-dioxy-
5~,6~-oxido-pregnane-20-one-21-acetate (III) were added over a period of about 1.5 hr. under stirring to 45 ml. of a cooled (-65C) 70% hydrofluoric acid aqueous solution. After 20 addition was completed the solution was stirred for 0.5 hr. at -60C and then poured into water (650 ml.). The solid was ! dissolved in ethyl acetate (400 ml.), the solution was washed with sodium bicarbonate aqueous solution until it was acid free and then washed neutral with water and finally dried over sodium sulphate. Removal of the solvent afforded a crude product M.P. 198-201C. One crystallization from acetone-light petroleum afforded 3 g. of 6~-fluoro-5~ ,17~,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (IV) M.P. 205-7C.
t ~ ~D + 36 (C 1.0 in dioxane) 30 ~ max (methanol) 290 m~ (~ lQ4~
IR(KBr) 3640, 3440 (broad~, 1745, 1730, 17Q5, 1230 cm 1.
Analysis: Calcd. for C23H33FO7 (percent) C 62,71; H 7,55;
F 4,31.
Found (percent) C 62,82; H 7,52; F 4,45.
When the crude product was purified by column chromatography on FLORISIL (Registered Trade Mark) (ratio 1:50) with chloroform-methanol (99:1) as eluant, the 6~-; fluoro-5~ ,17~,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (IV) was characterized by M.P. 223-4C.
A max (methanol) 290 m~ (~ 97) ~ ~D0 + 51 (C 1.0 in chloroform).
A mixture of 2 g. of sodium acetate and 10 g. of 6~-fluoro-5a,11~,17~,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (IV) dissolved in 100 ml. of dioxane was stirred at 25-30C while a solution of 4 g. of bromine in 50 ml. of dioxane was added dropwise over a period of about 2-3 min.
After addition of bromine was completed the mixture of reaction was poured into 1500 ml. of a cold 5% sodium chloride aqueous solution. After stirring for 1 hr., 8.5 g. of a white crystalline product was collected by filtration, washed with water and dried. Crystallization from acetone-methanol-chloroform (1:10:20) gave about 6 g. of 2~-bromo-6~-fluoro-5~ ,17~,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (V) characterized by M.P. 139-140C (decomposition).
~D ~ 49 (C 1.0 in dioxane) -~ max (methanol) 288 m~ (~ 124) IR(KBr) 3530, 3430, 3250 (broad), 1760, 1720, 1220 cm 1.
Analysis: Calcd. for C23H32BrFO7 (percent) C 53,18; H 6,20;
Br 15,38; F 3,65.
Found (percent) C 52,93; H 6,36; Br 15,59; F 3,44.
- . . - . : -.
.~
:
`~
` ~L064476 A solution of 10 g. of 2~-bromo-6~-fluoro-5~,11~, 17~,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (V) in 50 ml. of pyridine was stirred at -5C while dropwise adding 8 g.
of methane sulfonylchloride over a period of about 15 min.
After addition was completed the mixture was stirred for 1.5 hr. maintaining the temperature at about 0C, then poured into 400 ml. of cold water and 200 ml. of dichloroethane. The mixture was acidified at pH 3.5 with an 4N sulphoric acid solution and stirred for 1 hr. The product was collected by filtration, washed with water and dried giving 9 g. of 2~-bromo-6~-fluoro-5~ ,17~,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-21-acetate (VI). Crystallization from ben~ene gave a white solid characterized by M.P. 122-3C
(decomposition).
~D + 47 (C 1.0 in dioxane) max (ethanol) 288 m~ (~ 119) IR(KBr) 3560, 3520 (broad), 1730 (broad), 1330, 1230, 1170 cm ~ 20 Analysis: Calcd. for C24H34BrFOgS (percent) C 48,24; H 5,73;
- Br 13,37; F 3,17; S 5,36.
Found (percent) C 48,44; H 5,60; Br 13,52; F 3,06;
5,45.
- 10 g. of 2~-bromo-6~-fluoro-5~ ,17~,21-tetra-hydroxy-pregnane-3,20-dione-11-mesylate-21-acetate (VI) were added to a solution of 75 ml. of acetic anhydride and 0.5 ml.
of 70~ perchloric acid in 450 ml. of ethyl acetate. The mixture was kept at 30C for 0.5 hr. and washed successively - 30 with 5~ sodium bicarbonate aqueous solution. The ethyl acetate solution after anhydrification on sodium sulphate was evaporated to dryness under vacuum. Crystallization of the residue from methanol gave about 9 g. of 2a-bromo-6~-fluoro-5a,11a,17a,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-5,17,21-triacetate (VII) characterized by M.P. 131-2C
(decomposition).
~ D -11,7 (C 1.0 in chloroform) ~ max (methanol) 285 m~ (~ 104) IR(KBr) 1740 (broad), 1370, 1230 (broad), 1170 cm 1.
.
NMR (CDC13 - TMS) Hz at 60 mHz 355, 307 (doublet of triplets, 1, C-6 H) 304-290 (m, 2, C-2 H and C-ll H) 300, 284, 278, 262 (doublet of doublets, 2, -CH2OAc) 224, 210 (d, 1, C-4 Ha) 184 (S, 3, OSO2CH3) 124 (S, 6, 20Ac) 120 (S, 3, OAc) 94, 90 (d, 3, 19 CH3 split by 6~F) 48 (S, 3, 18 CH3).
; Analysis: Calcd. for C28H38BrFOllS (percent) C 49,34; H 5,62;
Br 11,72; F 2,79; S 4,70 Found (percent) C 49,13; H 5,43; Br 12,03; F 2,65;
S 4,57.
t ~ ~D + 36 (C 1.0 in dioxane) 30 ~ max (methanol) 290 m~ (~ lQ4~
IR(KBr) 3640, 3440 (broad~, 1745, 1730, 17Q5, 1230 cm 1.
Analysis: Calcd. for C23H33FO7 (percent) C 62,71; H 7,55;
F 4,31.
Found (percent) C 62,82; H 7,52; F 4,45.
When the crude product was purified by column chromatography on FLORISIL (Registered Trade Mark) (ratio 1:50) with chloroform-methanol (99:1) as eluant, the 6~-; fluoro-5~ ,17~,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (IV) was characterized by M.P. 223-4C.
A max (methanol) 290 m~ (~ 97) ~ ~D0 + 51 (C 1.0 in chloroform).
A mixture of 2 g. of sodium acetate and 10 g. of 6~-fluoro-5a,11~,17~,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (IV) dissolved in 100 ml. of dioxane was stirred at 25-30C while a solution of 4 g. of bromine in 50 ml. of dioxane was added dropwise over a period of about 2-3 min.
After addition of bromine was completed the mixture of reaction was poured into 1500 ml. of a cold 5% sodium chloride aqueous solution. After stirring for 1 hr., 8.5 g. of a white crystalline product was collected by filtration, washed with water and dried. Crystallization from acetone-methanol-chloroform (1:10:20) gave about 6 g. of 2~-bromo-6~-fluoro-5~ ,17~,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (V) characterized by M.P. 139-140C (decomposition).
~D ~ 49 (C 1.0 in dioxane) -~ max (methanol) 288 m~ (~ 124) IR(KBr) 3530, 3430, 3250 (broad), 1760, 1720, 1220 cm 1.
Analysis: Calcd. for C23H32BrFO7 (percent) C 53,18; H 6,20;
Br 15,38; F 3,65.
Found (percent) C 52,93; H 6,36; Br 15,59; F 3,44.
- . . - . : -.
.~
:
`~
` ~L064476 A solution of 10 g. of 2~-bromo-6~-fluoro-5~,11~, 17~,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (V) in 50 ml. of pyridine was stirred at -5C while dropwise adding 8 g.
of methane sulfonylchloride over a period of about 15 min.
After addition was completed the mixture was stirred for 1.5 hr. maintaining the temperature at about 0C, then poured into 400 ml. of cold water and 200 ml. of dichloroethane. The mixture was acidified at pH 3.5 with an 4N sulphoric acid solution and stirred for 1 hr. The product was collected by filtration, washed with water and dried giving 9 g. of 2~-bromo-6~-fluoro-5~ ,17~,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-21-acetate (VI). Crystallization from ben~ene gave a white solid characterized by M.P. 122-3C
(decomposition).
~D + 47 (C 1.0 in dioxane) max (ethanol) 288 m~ (~ 119) IR(KBr) 3560, 3520 (broad), 1730 (broad), 1330, 1230, 1170 cm ~ 20 Analysis: Calcd. for C24H34BrFOgS (percent) C 48,24; H 5,73;
- Br 13,37; F 3,17; S 5,36.
Found (percent) C 48,44; H 5,60; Br 13,52; F 3,06;
5,45.
- 10 g. of 2~-bromo-6~-fluoro-5~ ,17~,21-tetra-hydroxy-pregnane-3,20-dione-11-mesylate-21-acetate (VI) were added to a solution of 75 ml. of acetic anhydride and 0.5 ml.
of 70~ perchloric acid in 450 ml. of ethyl acetate. The mixture was kept at 30C for 0.5 hr. and washed successively - 30 with 5~ sodium bicarbonate aqueous solution. The ethyl acetate solution after anhydrification on sodium sulphate was evaporated to dryness under vacuum. Crystallization of the residue from methanol gave about 9 g. of 2a-bromo-6~-fluoro-5a,11a,17a,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-5,17,21-triacetate (VII) characterized by M.P. 131-2C
(decomposition).
~ D -11,7 (C 1.0 in chloroform) ~ max (methanol) 285 m~ (~ 104) IR(KBr) 1740 (broad), 1370, 1230 (broad), 1170 cm 1.
.
NMR (CDC13 - TMS) Hz at 60 mHz 355, 307 (doublet of triplets, 1, C-6 H) 304-290 (m, 2, C-2 H and C-ll H) 300, 284, 278, 262 (doublet of doublets, 2, -CH2OAc) 224, 210 (d, 1, C-4 Ha) 184 (S, 3, OSO2CH3) 124 (S, 6, 20Ac) 120 (S, 3, OAc) 94, 90 (d, 3, 19 CH3 split by 6~F) 48 (S, 3, 18 CH3).
; Analysis: Calcd. for C28H38BrFOllS (percent) C 49,34; H 5,62;
Br 11,72; F 2,79; S 4,70 Found (percent) C 49,13; H 5,43; Br 12,03; F 2,65;
S 4,57.
6.8 g. of 2a-bromo-6~-fluoro-5a,11a,17a,21-tetra-hydroxy-pregnane-3,20-dione-11-mesylate-5,17,21-triacetate ` (VII) were dissolved in 330 ml. of anhydrous acetic acid at - 90C on the steam-bath. A solution of sodium acetate (15.3 g.
dried at 100C) in acetic acid (60 ml.) at 90C was added, followed immediately by 1.75 g. of bromine in acetic acid (25 ml.), added in one lot. Heating at 90C was continued until the bromine colour disappeared (about 3 min. in all).
The solution was then cooled as rapidly as possible to room temperature and poured in cold water. The solid was collected by filtration, washed thoroughly with water and dried to a constant weight, giving about 6.5 g. of VII bis (2,2-dibromo-6~-fluoro-lla,17a,21-trihydroxy-pregn-4-ene-3,20-dione-11-' ~
. .
mesylate-17,21-diacetate). Crystallization from methanol gave a white solid characterized by M.P. 140-2C (decomposition).
~ max (methanol) 242-3 m~ ( 10000) IR(KBr) 1745, 1730, 1697, 1625, 1340, 1230, 1170 cm 1.
~D -18 (C 1.0 in chloroform) NMR (CDC13 - TMS) Hz at 60 mHz 362, 358 (d, 1, C-4 H) 328, 278 (doublet of triplets, 1, C-6 H) 320-290 (m, 1, C-ll H) 302, 286, 280, 264 (doublet of doublets, 2, -CH2OAc) 228, 212, 204, 188 (doublet of doublets, 2, C-l H~ and H~) 190 (S, 3, -OSO2CH3) 130 (S, 3, OAc) 128 (S, 3, OAc) 108, 104 (d, 3, 19 CH3 split by 6~F) 52 (S, 3, 18 CH3).
Analysis: Calcd. for C26H33Br2FOgS (percent) C 44,58; H 4,75;
Br 22,82; F 2,71; S 4,58 Found (percentl C 44,63; H 4,81; Br 22,69; F 2,84;
S 4,38.
dried at 100C) in acetic acid (60 ml.) at 90C was added, followed immediately by 1.75 g. of bromine in acetic acid (25 ml.), added in one lot. Heating at 90C was continued until the bromine colour disappeared (about 3 min. in all).
The solution was then cooled as rapidly as possible to room temperature and poured in cold water. The solid was collected by filtration, washed thoroughly with water and dried to a constant weight, giving about 6.5 g. of VII bis (2,2-dibromo-6~-fluoro-lla,17a,21-trihydroxy-pregn-4-ene-3,20-dione-11-' ~
. .
mesylate-17,21-diacetate). Crystallization from methanol gave a white solid characterized by M.P. 140-2C (decomposition).
~ max (methanol) 242-3 m~ ( 10000) IR(KBr) 1745, 1730, 1697, 1625, 1340, 1230, 1170 cm 1.
~D -18 (C 1.0 in chloroform) NMR (CDC13 - TMS) Hz at 60 mHz 362, 358 (d, 1, C-4 H) 328, 278 (doublet of triplets, 1, C-6 H) 320-290 (m, 1, C-ll H) 302, 286, 280, 264 (doublet of doublets, 2, -CH2OAc) 228, 212, 204, 188 (doublet of doublets, 2, C-l H~ and H~) 190 (S, 3, -OSO2CH3) 130 (S, 3, OAc) 128 (S, 3, OAc) 108, 104 (d, 3, 19 CH3 split by 6~F) 52 (S, 3, 18 CH3).
Analysis: Calcd. for C26H33Br2FOgS (percent) C 44,58; H 4,75;
Br 22,82; F 2,71; S 4,58 Found (percentl C 44,63; H 4,81; Br 22,69; F 2,84;
S 4,38.
7 g. of 2,2-dibromo-6~-fluoro-11~,17~,21-trihydroxy-pregn-4-ene-3,20-dione-11-mesylate-17,21-diacetate (VII bis) were added, in one portion, to a mixture of 70 ml. of dimethylformamide, 14 g. of lithium carbonate and 7 g. of lithium bromide under stirring at 100C. The reaction mixture was then refluxed at 130C under nitrogen for 0.5 hr., cooled and poured into cold water. The precipitate was filtered off, washed with water and dried. Crystallization of the residue from acetone gave 4.8 g. of 2-bromo-63-fluoro-17~,21-dihydroxy-pregna-1,4,9(111-triene-3,20-dione-17,21-diacetate (VIII) characterized by M.P. 270-1C (decomposition).
C ~D -88,5 (C 1.0 in chloroform) ; ~ max (methanol) 246-7 m~ (~ 12750) 30 IR(KBr) 1740 (broad), 1675, 1645, 1600, 1230 cm 1.
NMR (CDC13 - TMS) Hz at 60 mHz 452 (S, 1, C-1 H) 376, 372 .," ' ~ (d, 1, C-4 H) 342-332 (m, 1, C-ll H) 334, 286 (doublet of . . .
triplets, 1, C-6 H) 302, 284, 280, 262 (doublet of doublets, ~ 2, CH2OAc) 130 (S, 3, OAc) 123 (S, 3, OAc) 94, 92 (d, 3, 19 ; CH3 split by 6~F) 45 (S, 3, 18 CH3).
Analysis: Calcd. for C25H28BrFO6 (percent) C 57,37; H 5,39;
sr 15,27; F 3,63.
... .- ~
Found (percent) C 57,53; H 5,61; Br 15,03; F 3,71.
-~ EXAMPLE 9 :.
7.1 g. of 1,3-dibromo-5,5-dimethyl-hydantoin were added in the dark at room temperature under stirring over a period of 0.5 hr. to a suspension of 10 g. of 2-bromo-6~-fluoro-17~,21-dihydroxy-pregna-1,4,9(11)-triene-3,20-dione-~ ~.
17,21-diacetate (VIII) in 200 ml. of tetrahydrofurane and 1 g.
of 70% perchloric acid in 10 ml. of water. During the addition the suspension began to thin and after a total ::
reaction time of 45 min. all the starting material was dis-solved. After an additional 2 hr., 10~ sodium sulfite aqueous solution was added under stirring until KJ-starch paper was no longer blued. The solution was slowly poured into 1000 ml.
cold water. The product (IX) was filtered and utilized moist in the next reaction. Analytically pure 2,9~-dibromo-6~-~''':~.! , , !
I fluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-,, :
17,21-diacetate (IX) was obtained by additional crystalli-;~ zation from acetone-hexane. It was dried in vacuo at room temperature M.P. 208-10C (decomposition).
~ . , - .
~D -18,2 (C 1.0 in chloroform) ~ ~ max (methanol) 248 m~ (s 10250) ;~ IR(KBr) 3520, 1755, 1740, 1710, 1675, 1640, 1605, 1230 cm 1.
. ~ ....
~ Analysis: Calcd. for C25H29Br2FO7 (percent) C 48,41; H 4,71;
`~- 3Q Br 25,76; F 3,06 Found (percent) C 48,74; H 4,65; Br 25,60; F 3,31.
': ~
.
,.,' ~ '~
,'.:. ~ , . ', ' ,~, . . .
. , .
:~ 1064476 ..
40 ml. of a 14~ potassium carbonate aqueou~ solution were added over a period of 20 min. at 20C under stirring to the solution of the moist product (IX) 2,9~-dibromo-6~-fluoro-,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-di-.",6 acetate (obtained in Example 9 from 10 g. of the product VIII) in 200 ml. of acetone. The solution was stirred for 4 hr.
~` Ice water was added under stirring, upon which crystallization occurs rapidly. The product 2-bromo-6~-fluoro-17~,21-dihydroxy-9~ -oxido-pregna-1,4-diene-3,20-dione-17,21-diacetate (X) was filtered, washed with water, dried and characterized by M.P. 241-2C (decomposition), raised by crystallization from benzene-cyclohexane to 248-9C.
; ~ ~D -88,4 (C 0.5 in chloroform) ~ IR(KBr) 1755, 1740 (broad), 1670, 1640, 1600, 1230 (broad) ~ --1 -~ cm Analysis: Calcd. for C25H28srFo7 (percent) C 55,67; H 5,23;
Br 14,81; F 3,52.
Found (percent) C 55,80; H 5,15; Br 14,72; F 3,45.
~ ~ 100 ml. of a 7Q% hydrofluoric acid aqueous solution ;~ were cooled to -10C in a polyethylene flask equipped with ~ .
electromagnetic stirrer. 10 g. of 2-bromo-6~-fluoro-17~,21-dihydroxy-9~ -oxido-pregna-1,4-diene-3,20-dione-17,21-diacetate (X) were added under stirring during 15 min. After 0.5 hr. the reaction mixture was precipitated in water and ammonia. The solid was collected by filtration, washed with water and dried to a constant weight, giving about 9.5 g. of . .
2-bromo-6~,9~-difluoro~ ,17~,21-trihydroxy-pregna-1,4-diene-;- 30 3,20-dione-17,21-diacetate (XI) (Rl = R2 = OCOCH3). Crystal-~ lization from benzene gave 7 g. of pure product, homogeneous - .:
~ .
~ '. - , ', . ''' '., - . .' ~ . .-10~4476 by TLC on silica gel (6:3:2 CHC13-acetone-cyclohexane). M.P.
290-2C (decomposition).
~D -36 (C 1.0 in chloroform) ~ max (methanol) 246 m~ ( 12500) IR(KBr) 3520, 1758, 1733, 1705, 1680, 1650, 1610, 1235 cm NMR (dimethyl-d6 sulfoxide-TMS) Hz at 60 mHz 471 (S, 1, C-l H) 393, 389 (d, 1, C-4 H) 350, 300 (doublet of triplets, 1, - C-6 H) 341, 335 (d, 1, C-ll OH) 289 (S, 2, CH2OAc) 270-240 (m, 1, C-ll H) 127 (S, 3, OAc) 122 (S, 3, OAc) 99, 96 (d, 3, 19 CH3 split by 6~F) 56 (S, 3, 18 CH3).
M.S. (70 e.v., ion source temperature 210C, direct sample - introduction) ions at m/e 558/560 (M+, C25H29BrF2O7), 540/542, 538/540, 518/520, 498/500, 483/485, 478/480, 458/460, 397/399, 377/379, 359/361, 357/359, 339/341, 317/319, 315/317, 299/301, 278, 217/219, 212/214, 199/201, 165, 147, 139, 121, 109, 101, 91, 79, 73 (base peak), 69, 60, 55.
Analysis: Calcd. for C25H29BrF2O7 (percent) C 53,67; H 5,22;
F 6,79; Br 14,28.
Found (percent) C 53,27; H 5,22; F 6,80; Br 14,32.
~- 20 EXAMPLE 12 A suspension of 10 g. of 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XI) (Rl - R2 = OCOCH3) in 200 ml. of 1% potassium hydroxide methanolic solution was stirred under nitrogen at 0C for 3 hrs. Addition of cold water, elimination of methanol i~ vacuo, acidification with acetic acid and fil-tration gave 7 g. of 2-bromo-6~,9~-difluoro-11~,17~,21-tri-hydroxy-pregna-1,4-diene-3,2~-dione (XIa) (XI, Rl = R2 = OH).
M.P. 223-227C (decomposition), raised by crystallization from dichloroethane to 228-230C.
~D -5.6 (C 1.0 in dioxane) -- . : . .
' ' ' ~ , . ~ , :' . :' ' max (methanol) 246 m~ (~ 11700) IR(KBr) 3430 (broad), 1715, 1670, 1645, 1600 cm 1.
NMR (dimethyl-d6 sulfoxide-TMS) ~Iz at 60 mHz 470 (S, 1, C-l H) 392, 388 (d, 1, C-4 H) 348, 298 (doublet of triplets, 1, C-6 H) 327, 322 (d, 1, C-ll OH) 316 (S, 1, C-17 OH) 280, 276, 270, 266, 261, 257, 250, 246 (octuplet which becomes a quartet by deuterium exchange, 2, COCH2OH) 99, 96 (d, 3, 19 CH3 split by 6~F) 48 (S, 3, 18 CH3).
M.S. (70 e.v., ion source temperature 210C, direct sample introduction) ions at m/e 474/476 (M+, C21H25BrF2O5) 456/458, 444/446, 427/429, 414/416, 394/396, 379/381, 359/361, 317/319, 315/317, 219/221, 217/219 (base peak), 212/214, 199/201, 139, 109, 95, 67, 55.
Analysis: Calcd. for C21H25BrF2O5 (percent) C 53,06; H 5,30;
Br 16,81; F 7,99 Found (percent) C 53,15; H 5,30; Br 16,73; F 8.05.
To a solution of 10 g. of 2-bromo-6~-fluoro-17a,21-dihydroxy-pregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate (VII) and 40 g. lithium chloride in 200 ml. of glacial acetic acid were added at 20C under stirring 5 g. of N-chloro-succinimide. The mixture was kept at 20C and stirred while dropwise adding 10 ml. of a 12~ hydrochloric acid tetrahydro-furane solution over a period of about 10 min. ~fter 3.5 hrs.
the reaction mixture was poured into cold water, the solid collected by filtration, washed with water and dried, giving 6 g. of pure product 2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XII) (Rl = R2 = OCOCH3). M.P. 244-6C (decomp.).
~ ~D -2.5 (C 1.0 in chloroform) ~ IR(KBr) 1753, 1740~ 1672, 1645; 1602, 1230 cm 1.
:'' , . " . . :
.
, ;. -- . , : .
`- 1064476 .
; NMR (dimethyl-d6 sulfoxide-TMS) Hz at 60 mHz 465 (S, 1, C-l H) ~ -, 394, 390 (d, 1, C-4 H) 350, 300 (doublet of triplets, 1, :- C-6 H) 320-305 (m, 1, C-ll H) 289 (S, 2, CH2OAc) 127 (S, 3, OAc) 122 (S, 3, OAc) 110, 106 (d, 3, 19 CH3 split by 6~F) 61 (S, 3, 18 CH3).
Analysis: Calcd. for C25H28BrC12FO6 (percent) C 50,27;
:.,~ , .
` H 4,72; F 3,18; Cl 11,87; Br 13,38 ~ Found (percent) C 50,55; H 4,81; F 3,25 Cl 12,05;
,,,~" ~
Br 13,67.
~; 10 ~ max (methanol) 245-6 m~ ( 12280).
-. :.' Using the general procedure of Example 12 the 2- ~
,: . .
bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4- -~
diene-3,20-dione-17,21-diacetate (XII) (Rl = R2 = OCOCH3) was .
; converted to 2-bromo-6~-fluoro-9~ -dichloro-17~,21-dihydroxy-pregna-1,4-diene-3,20-dione XIIa (XII, Rl - R2 = OH) M.P. 185-7C (decomposition).
.
max (methanol) 245 m~ (~ 12000) ~D ~ 34 (C 0.7 in chloroform) IR(KBr) 3450 (broad), 1715, 1675, 1645, 1605 cm 1.
Analysis: Calcd. for C21H24BrC12FO4 ~ercent) C 49~43 H 4,74, F 3,72~ Cl 13,9Q, Br 15,66 "r ' Found (percent~ C 49,78, F 3~7Qi Cl 14,Q7, Br 15,75; H 4,76.
., :
`~ A mixture of 7 g. of 2-bromo-6~,9a-difluoro~ ,17~, ~ 21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XI) -~ Rl = R2 = OCOCH3), 70 ml. of dimethylformamide and 3.5 g. of ;~ anhydrous potassium acetate was refluxed at 120C under nitro-gen for 0.5 hr. The reaction mixture was then cooled and poured into cold water. The precipitate was filtered off, ' . .
~064476 washed with water, dried. Crystallization of the residue from acetone-hexane gave 5 g. of 2-bromo-6~,9~-difluoro~ ,21-dihydroxy-pregna-1,4,16-triene-3,20-dione-21-acetate (XI bis) (Rl = OCOCH3) characterized by M.P. 257-8C (decomposition).
~D ~ 24 (C 1.0 in chloroform) IR(KBr) 3520, 1730, 1680, 1640, 1600, 1588, 1220 cm 1.
~ max (methanol) 242-3 m~ (~ 21500) Analysis: Calcd. for C23H25BrF2O5 (percent) C 55,32; H 5,04;
Br 16,00; F 7,61;
Found (percent) C 55,21; H 4,89; Br 16,25; F 7,49.
A solution of potassium permanganate (3.5 g.) in acetone (75 ~1.) and water (25 ml.) was added, in one portion, at -5C to a solution of 5 g. of 2-bromo-6~,9~-difluoro-11~,21-dihydroxy-pregna-1,4,16-triene-3,20-dione-21-acetate (XI bis) (Rl = OCOCH3) in acetone (150 ml.) and formic acid (1.7 ml.). The mixture of reaction was stirred for 5 min. at -5C and then 50 ml. of 10% Na2SO3 aqueous solution were added. The mixture was filtered through Celite (Trade Mark) and the pale yellow filtrate concentrated i~ va~uo and poured into cold water. The solid filtered after crystallization ~ from acetone-hexane yielded 4.5 g. of 2-bromo-6~,9~-difluoro-; 11~,16~,17~,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-21-acetate (XVII) (Rl = OCOCH3) characterized by M.P. 225-7 C
(decomposition).
~D -16 (C 1.0 in dioxane) max (methanol) 245-6 m~ (~ 12000) .~
IR(KBr) 3440 (broad), 1745, 1732, 1672, 1645, 1605, 1230 cm 1 NMR (dimethyl-d6 sulfoxide-TMS) Hz at 60 mHz 472 (S, 1, C-l H) - 30 392, 388 (d, 1, C-4 H) 348, 298 (doublet of triplets, 1, ~l C-6 H) 337, 332 (d, 1, C-ll OH) 328, 323 (d, 1, C-16 OH) 312, .
- . .
' '': ; ~ .. ': ' . ~ .
296, 292, 276 (doublet of doublets 2, CH2OAc) 290 (S, 1, C-17 OH) 290-280 (m, 1, C-16 H) 265-240 (m, 1, C-ll H) 126 (S, 3, OAc) 98, 95 (d, 3, 19 CH3 split by 6~F) 52 (S, 3, 18 CH3). `
Analysis: Calcd. for C23H27BrF2O7 (percent) C 51,79; H 5,10;
F 7,12; Br 14,98 Found (percent) C 52,05; H 5.02; F 7.25; Br 16,18.
:~ .
Using the general procedure of Example 12 the 2- ~ `
bromo-6~,9~-difluoro-11~,16~,17~,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-21-acetate (XVII) (Rl = OCOCH3) was converted to 2-bromo-6~,9a-difluoro-11~,16~,17~,21-tetrahydroxy-pregna- -~
1,4-diene-3,20-dione (XVIIa) (XVII Rl = OH). M.P. 208-10C
(decomposition).
.
IR(KBr) 3460 (broad), 171S, 1670, 1645, 160S cm 1. ~~
Analysis: Calcd. for C21H25BrF2O6 (percent) C 51,33; H 5,13;
Br 16,26; F 7,37 Found (percent) C 51,51; H 5,10; Br 16,15; F 7,81.
~D ~30 (C 1.0 in dioxane) :! A max (methanol) 246-7 m~ (~ 1140Q).
: 1 , A solution of 5 g. of 2-bromo-6~,9~-difluoro-11~, : :
n 17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, , . .
Rl = R2 = OH) in 10 ml. of dimethylformamide and 37 ml. of 2,2-dimethoxypropane with 0.025 g. of p-toluenesulfonic acid was heated for 6 hrs. at 115C. The reaction mixture was ~ cooled, poured in 10% sodium bicarbonate aqueous solution and --i chloroform. The chloroform solution was then washed with ~ water, dried and evaporated to a residue which by crystalli--,~ zation from acetone gave 4 g. of 2-bromo-6~,9~-difluoro-11~, 17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-acetonide (XIb) characterized by M.P. 230-1C (decomposition).
. .
~ - 34 -.. . .
, :, . . .. ..
,, . :
r~ ,~
~Q64476 ~D -1 (C 1.0 in chloroform) max (methanol) 245-6 m~ ( 12100) IR (KBr) 3440 (broad), 1720, 1670, 1645, 1600 cm 1 Analysis: Calcd. for C24H29BrF2O5 (percent) C 55,93; H 5,67;
Br 15,50; F 7, 37 Found (percent) C 56,07; H 5,72; Br 15,37; F 7,50.
2.5 ml. of 70% perchloric acid were added under stirring at 15C to a suspension of 10 g. of 2-bromo-6~,9~-difluoro-11~,16~,17~,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-21-acetate (XVII) (Rl = OCOCH3) in 400 ml. of acetone.
The solution was stirred at 15C for 50 min. and 5 g. of sodium bicarbonate were added. The mixture was stirred for 10 min. and then filtered. The acetone solution was evapo-rated to dryness in vacuo at 60C. The solid residue was crystallized from ethylacetate-light petroleum giving 6 g. of pure 2-bromo-6~,9~-difluoro 11~,16a,17~,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-21-acetate-16,17-acetonide (XIX) (Rl = OCOCH3, R4 = R5 = CH3).
20 IR(KBr) 3560, 3480, 3430, 1755, 1730, 1670, 1645, 1600, 1225 ~- cm Analysis: Calcd. for C26H31BrF2O7 (percent) C 54,46, H 5,45;
^~ Br 13,93; F 6,62 ;~ Found (percent) C 54,65; H 5,57; Br 13,85; F 6,47.
~D + 8 (C 1.0 in chloroform) max (methanol) 246 m~ (E 11550).
5 ml. of acetic anhydride were dropwise added to a mixture of 50 ml. of pyridine and 10 g. of 2-bromo-6~,9~-30 difluoro~ ,16~,17~,21-tetrahydroxy-pregna-1,4-diene-3,20-lr' dione-21-acetate (X~II) (R1 = OCOCH3). The mixture was kept ' ~
.
.. : :
, ,. ~ . , . .: : , . .
,' ~
at room temperature for 1.5 hr. and then poured under vigorous stirring into 500 ml. of cold water. After about 0.5 hr. the solid was collected by filtration, washed thoroughly with cold water, dried to a constant weight, giving about 9.5 g. of ;
2-bromo-68,9~-difluoro-11~,16~,17~,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-16,21-diacetate (XVIII) Rl = R3 = OCOCH3), crystallized by methanol-water.
- IR(KBr) 3570, 3500 (broad) 1760, 1735 (broad), 1670, 1645, 1605, 1240 (broad) cm 1 Analysis: Calcd. for C25H29BrF2O8 (percent) C 52,18; H 5.08;
Br 13,89; F 6,60 Found (percent) C 52,07; H 5,10; Br 14,07; F 6,70.
M.P. 238-40 C (decomposition) r~D ~49 4 (C 1.0 in chloroform) max (methanol) 246 m~ (s 11900).
5 g. of 2-bromo-6~,9~-difluoro-11~,17~,21-tri-hydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, Rl = R2 = OH) were dissolved in 50 ml. of pyridine containing 25 ml. of acetic anhydride and kept at room temperature for 12 hrs.
Addition'of ice water afforded a product which was extracted with chloroform. The chloroform solution was washed with ;~ water, 2N HCl, 5% sodium bicarbonate solution and water.
., .
- After drying (Na2SO4) and removal of the solvent in vacuo the ` residue was crystallized from acetone-hexane to gave 2-bromo-:
6~,9~-difluoro-113,17~,21-trihydroxy-pregna-1,4-diene-21-acetate (XIc) (XI, Rl = OCOCH3, R2 = OH) characterized by M.P.
~- ` 194-6C (decomposition).
~D + 12 (C 1.0 in chloroform) ~` ~ 30 ~ max (methanol) 246 m~ (~ 11800) ~; IR(CHC13) 3620, 3500 (broad), 1745, 1730, 1672, 1645, 1605, ,~~ ,. '.
.
` ~
~6)64476 1230 (broad) cm 1 Analysis: Calcd. for C23H27BrF2O6 (percent) C 53,39; H 5,26;
Br 15,44; F 7,34 Found (percent) C 53,51; H 5,21; Br 15,70; F 7,28.
Using the general procedure of Example 21, the 2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene--~ 3,20-dione (XIa) (XI, Rl = R2 = OH) was converted to 2-bromo-6~,9~-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-propionate (XId) (XI, Rl = OCOCH2CH3, R2 = OH) by reaction with propionic anhydride. M.P. 180-3C (decompo-- sition) ~D ~ 22 (C 1.0 in chloroform) max (methanol) 246 m~ ( 10900) IR(CHC13) 3610, 3500 (broad), 1740, 1728, 1672, 1645, 1605, 1220 cm 1.
Analysis: Calcd. for C24H29BrF2O6 (percent) C 54,25; H 5,50;
Br 15,04; F 7,15 Found (percent) C 54,09; H 5,60; Br 14,92; F 7,05.
Using the general procedure of Example 21, the 2-bromo-6~,9a-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, Rl = R2 = OH) was converted to 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-valerate (XIe) (XI, Rl = OCO(CH2)3CH3, R2 = OH) by reaction with valeric anhydride. M.P. 155-7C (decomposition) ; ~ ~D ~ 27 (C 1.0 in chloroform) ~ max (methanol) 246 m~ (~ 11600) IR(KBr) 3500 (broad), 1740, 1720, 1670, 1640, 1600, 1230 3a (broad) cm 1.
Analysis: Calcd. for C26H33BrF2O6 (percent) C 55,82; H 5,94;
.' ,. . .
' ' ' . : . . : ~
': ~ , ' ' : ' ' . ' ' ~ . ': ' ' Br 14,28; F 6,79 Found (percent) C 55,70; H 5,91; Br 14,35; F 6,87.
Using the general procedure of Example 21, the ~- 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, Rl = R2 = OH) was converted to 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-- dione-21-pivalate (XIf) (XI, Rl = OCOC(CH3)3, R2 = OH) by M.P.
224-6C (decomposition) ~ ~D t 22 (C 1.0 in chloroform) ~, , .
max (methanol) 245-6 m~ (~ 10900) ~; IR(KBr) 3470 (broad), 1740, 1730, 1665, 1640, 1600, 1220 cm . .
Analysis: Calcd. for C26H33BrF2O6 (percent) C 55,82; H 5,94;
Br 14,28; F 6,79 Found (percent) C 55,75; H 5,88; Br 14,07; F 6,65.
3 g. of 2-bromo-6~,9~-difluoro-11~,17~,21-tri-hydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, Rl = R2 = OH) were dlssolved in 30 ml. of pyridine containing 1 ml. of terbutylacetic acid chloride and kept at room temperature for 16 hrs. Addition of ice water afforded a product which was extracted with chloroform. The chloroform solution was washed :
(Na2SO4) and removal of the solvent in vacuo, the residue was crystallized from acetone-hexane to give 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-; terbutylacetate (XIg) (XI, Rl = OCOCH2C(CH3)3, R2 = OH). M.P.
198-200C (decomposition) ~D + 25 tC 1.0 in chloroform) ~ max (methanol) 245-6 m~ (~ 10900) IR(KBr) 3490 (broad), 1735 (broad), 1670, 1640, 1600, 1230 cm 4 .~
~ 1064476 Analysis: Calcd. for C27H35BrF2O6 (percent) C 56,55; H 6,15;
Br 13,93; F 6,62 Found (percent) C 56,71; H 6,02; Br 13,85; F 6,75.
Using the general procedure of Example 25 the 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene~
3,20-dione (XIa) (XI, Rl = R2 = OH) was converted to 2-bromo-6~,9~-difluoro~ ,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-enantate (XIh) (XI, Rl = OCO(CH2)5CH3, R2 = OH) by reaction with enanthic acid chloride. M.P. 173-5C (decompo-sition) ~D + 28 (C 1.0 in chloroform) ~ max (methanol) 245-6 m~ ( 11500) IR(KBr) 3500 (broad), 1735 (broad), 1670, 1640, 1600, 1230 ~ (broad) cm 1 ; Analysis: Calcd. for C28H37BrF2O6 (percent) C 57,24; H 6,35;
Br 13,60; F 6,47 Found (percent) C 57,31; H 6,30; Br 13,72; F 6,29.
Using the general procedure of Example 21 the 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, Rl = R2 ~ OH) was converted to 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate (XIi) (XI, Rl = OCOC6H5, R2 ~ OH), by reaction with benzoic anhydride. M.P. 209-10C (decompo-sition) ~D + 93 (C 1.0 in chloroform) max (methanol) 233-4 m~ ( 22000) IR(KBr) 3600, 3420 (broad), 1725, 1710, 1670, 1640, 1600 cm 1.
Analysis: Calcd. for C28H29BrF2O6 (percent) C 58,04; H 5,04;
Br 13,79; F 6,56 _ 39 _ ~064476 .. .
Found (percent) C 58,21; H 4,93; Br 13,68; F 6,39.
A mixture of 5 g. of 2-bromo-6~,9~-difluoro-11~, 17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, Rl = R2 = OH), 5 ml. of methylorthovalerate and 0.020 g. of p-toluene sulfonic acid in 15 ml. of dimethylformamide was maintained for 4 hrs. under nitrogen at 115C. Then the mixture was neutralized by pyridine and concentrated under vacuum to dryness. Purification by column chromatography on FLORISIL (Registered Trade Mark) (ratio 1:30) with benzene-chloroform (8:2) as eluant, gave 3.5 g. of 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-(1'-methoxy)-n-pentylidenedioxy, which without further purification was suspended in 25 ml. of methanol and 3 ml. lN
hydrochloric acid aqueous solution, heated on water bath at 40-50C. After complete solubilization of the product, the mixture was concentrated under vacuum. The insoluble product was filtered off, washed with water and then dried. The 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate (XIl) (XI, Rl = OH, R2 = OCO(CH2)3CH3) ~- thus obtained was crystallized from acetone-hexane and charac-terized by M.P. 201-3C (decomposition) ~D ~74 (C 1.0 in chloroform) max (methanol) 246 m~ (~ 12600) IR(Ksr) 3500 (broad), 1730, 1715, 1670, 1645, 1600 cm Analysis: Calcd. for C26H33BrF2O6 (percent) C 55,82; H 5,94;
~3r 14,28; F 6,79 Found (percent) C 55,91; H 6,07; Br 14,27; F 6,72.
Using the general procedure of Example 21 the 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate (XIl) (XI, R1 = OH, R2 = OCO(CH2)3CH3) was converted to 2-bromo-6~,9a-difluoro~ ,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate-21-acetate (XIm) (XI, Rl = OCOCH3, R2 = O(CH2)3CH3) by reaction with acetic anhydride. The product was crystallized from acetone-hexane.
The crystals showed at 125C a transaction from the low melting form II to the form I melting 173-5 C (decomposition).
~D -25 (C 1.0 in chloroform) ~ max (methanol) 245-6 m~ ( 11400) IR(KBr) 3500 (broad), 1735 (broad), 1672, 1645, 1605, 1230 (broad) cm 1.
Analysis: Calcd. for C28H35BrF2O7 (percent) C 55,91; H 5,86;
Br 13,28; F 6,32 Found (percent) C 56,03; H 5,81; Br 13,07; F 6,28.
_AMPLE 30 Using the general procedure of Example 28 the 2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, Rl = R2 = OH) was converted to 2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (XIn) (XI, Rl = OH, R2 = OCOCH3) by reaction with ethylorthoacetate followed by acid hydrolysis of the resulting 17,21-orthoacetate. The product was crystallized from acetone-hexane. M.P. 230-2C (decomposition) ~ ~D -75,8 (C 1.0 in chloroform) ;- ~ max (methanol) 245 m~ ( 11700) IR(KBr) 3500, 3420, 1730, 1720, 1675, 1640, 1610, 1220 cm 1.
.~
Analysis: Calcd. for C23H27BrF2O6 (percent) C 53,40; H 5,26;
Br 15,44; F 7,34 Found (percent) C 53,52; H 5,32; Br 15,52; F 7,27.
Using the general procedure of Example 21 the , ,- ~ , . :
.: . , 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (XIm) (XI, Rl = OH, R2 = OCOCH3) was ~ converted to 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy--~ pregna-1,4-diene-3,20-dione-17-acetate-21-valerate (XIo) ` (XI, Rl = OCO(CH2)3CH3, R2 = OCOCH3) by reaction with valeric anhydride. The product was crystallized from acetone-hexane.
M.P. 159-60C (decomposition) ~/D ~37 (C 1.0 in chloroform) A max (methanol) 246-7 m~ ( 11750) 10 IR(KBr) 3660, 3520, 3380, 1730 (broad), 1675, 1640, 1600, 1240 - cm Analysis: Calcd. for C28H35BrF2O7 (percent) C 55,91; H 5,86;
Br 13,28; F 6,32 ; Found (percent) C 56,07; H 5,73; Br 13,21; F 6,55.
~' Using the general procedure of Example 28 the 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-:
; 3,20-dione (XIa) (XI, Rl = R2 = OH) was converted to 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-~;~ 20 dione-17-propionate (XIp) (XI, Rl = OH, R2 = OCOCH2CH3) by reaction with ethylorthopropionate followed by acid hydrolysis of the resulting 17,21-orthopropionate. The product was crystallized by acetone-hexane. M.P. 215-7C (decomposition) ~' A max (methanol) 245-6 m~ (E 12300) ~ ~D ~75 (C 1.0 in chloroform) - ~ IR(KBr) 3500, 3420, 1730, 1712, 1675, 1640, 1605, 1200 cm 1.
Analysis: Calcd. for C24H29BrF2O6 (percent) C 54,24; H 5,50;
Br 15,04; F 7,15 Found (percent) C 54,20; H 5,52; Br 14,79; F 6,97.
Using the general procedure of Example 28 the :
:
1064476 ~ ~
2-bromo-6~,9~-difluoro~ ,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, R1 = R2 = OH) was converted to 2-bromo-6~,9~-difluoro~ ,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-benzoate (XIq) (XIt Rl = OH, R2 OCOC6H5) by reaction with ethylorthobenzoate followed by acid hydrolysis of the resulting 17,21-orthobenzoate. The product was crystallized by acetone-hexane. M.P. 241-3C (decomposition) ~D -103 (C 1.0 in chloroform) ~ max (methanol) 234-5 m~ (~ 23500) IR(KBr) 3520, 3430, 1730, 1700, 1680, 1645, 1610 cm 1 Analysis: Calcd. for C28H2gBrF2O6 (percent) C 58,04; H 5,04;
; Br 13,79; F 6,56 Found (percent) C 58,12; H 4,95; Br 13,62; F 6,50.
Using the general procedure of Example 28 the 2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione (XIIa) (XII, Rl = R2 = OH) was converted to .
2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (XIIb) (XII, Rl = R2 = OCOCH3) by ~`- 20 reaction with ethylorthoacetate followed by acid hydrolysis of the resulting 17,21-orthoacetate. The product was crystal-lized by acetone-hexane. M.P. 193-4C (decomposition) ~D -32 (C 1.0 in chloroform) max (methanol) 245 m~ (~ 11700) IR(KBr) 3500, 1730 (broad), 1705, 1680, 1650, 1605, 1240 ~` (broad) cm 1.
! ',: ' . ~ :.
~ Analysis: Calcd. for C23H26BrC12FO5 (percent) C 50,02;
~ ......................................................................... .
~ H 4,74; Br 14,47; Cl 12,84; F 3,44 ., .
Found (percent) C 50,11; H 4,82; Br 14,35;
Cl 13,03; F 3,32.
.
.:~
~ 43 ~
.
. ' , - - - .. : .: . . . . . :~ : .
. . .. . ~ . . ~ .
.
. . .
Using the general procedure of Example 21 the 2-bromo-6~-fluoro-9~ -dichloro-17~,21-dihydroxy-pregna~1,4-diene-3,20-dione (XIIa) (XII, Rl = R2 = OH) was converted to 2-bromo-6~-fluoro-9~ -dichloro-17~,21-dihydroxy-pregna-1,4-diene-3,20-dione-21-acetate (XIIc) (XII, Rl = OCOCH3, R2 = OH) by reaction with acetic anhydride. The product was crystal-lized from benzene-light petroleum. M.P. 202-4C (decompo-sition) ~ ~D + 49 (C 1.0 in chloroform) - ~ max (methanol) 245 m~ ( 11800) IR(KBr) 3470, 1750, 1730, 1668, 1640, 1600, 1230 cm 1.
Analysis: Calcd. for C23H26FC12BrO5 (percent) C 50,02;
H 4,74; Br 14,47; Cl 12,84; F 3,44 Found (percent) C 50,21; H 4,63; Br 14,41;
Cl 12,79; F 3,38.
_AMPLE 36 Using the general procedure of Example 19 the 2-bromo-6~,9~-difluoro~ ,16~,17~,21-tetrahydroxy-pregna-1,4-- 2Q diene-3,20-dione (XVIIa) (XVII, Rl = OH) was con~erted into 2-bromo-6~,9~-difluoro-11~,16~,17~,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-16,17-acetonide (XIXa) (XIX, Rl = OH, R4 = R5 = CH3) crystallized from acetone-hexane. M.P. 221-3C
(decomposition) ~20 + 9 (C 1 0 in chloroform) ~ max (methanol) 246 m~ (~ 11950) IR(KRb) 3500, 3280, 1730, 1670, 1645, 1605 cm 1.
Analysis: Calcd. for C24H29BrF2O6 (percentl C 54,25; H 5,50;
Br 15,04; F 7,15 Found (percent) C 54,37; H 5,42; Br 14,95; F 7,10.
50 ml. of hydrochloric acid were added at 0C over a period of 30 min. to a suspension of 5 g. of 2-bromo-6~-fluoro-17~,21-dihydroxy-9~ oxido-pregna-1,4-diene-3,20-dione-17,21-diacetate (X) in 30 ml. of acetone. The mixture was held at 0C under stirring for 6 hrs. and then the pre-cipitated 2-bromo-6~-fluoro-9~-chloro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XXIII) was recovered by filtration, washed repeatedly with water, dried 10 and crystallized by acetone-hexane. M.P. 258-60C (decompo-; sition) ~20 -22 (C 1.0 in chloroform) max (methanol) 246 m~ ( 11100) IR(KBr) 3440 (broad), 3350, 1753, 1740, 17Q5, 1675, 1600, 1230 ~ l , , Analysis: Calcd. for C25H29BrClFO7 (percent~ C 52,14; H 5,Q8; -~
Br 13,88; Cl 6,16; F 3,30 Found (percent) C 52,34; H 5,02; Br 13,72; Cl 6,22; -F 3,25.
A mixture of 4.1 g. of 16~-methyl-11~,17~,21-tri-hydroxy-pregn-4-ene-3,20-dione-21-acetate (Ia) (R3 = ~CH3), 110 ml. of benzene, 41 ml. of ethylene glycol and 2.45 g. of ~ pyridine hydrochloride was refluxed under stirring for 8 hrs.
- in a water separator. After the reaction was completed 100 ml.
of 5% sodium bicarbonate aqueous solution were added. The mixture was further concentrated until crystals appeared and then poured into cold water. The resulting precipitate was removed by filtration, washed neutral with water and dried.
30 Crystallization of the residue gave 3.7 g. of 16~-methyl-11~, 17~,21-trihydroxy-3,3-ethylene-dioxy-pregn-5-ene-20-one-21-, acetate (IIa) (R3 = ~CH3) characterized by M.P. 214-6C.
max (methanol) 292 m~ (~ 110) ~20 ~ 1 (C 1.0 in chloroform) IRtKBr) 3480 (broad~, 1755, 1730, 1230 cm Analysis: Calcd. for C26H38O7 (percent) C 67,51; H 8,28 Found (percent) C 67,68; H 8,35.
Using the general procedure of Example 38 the 16~-methyl~ ,17~,21-trihydroxy-pregn-4-ene-3,20-dione-21-acetate (Ib) (R3 = ~CH3) was converted into 16~-methyl-11 , 17~,21-trihydroxy-3,3-ethylene-dioxy-pregn-5-ene-20-one-21-acetate (IIb) (R3 = ~CH3), characterized by M.P. 214-6 C.
" ~ max (methanol) 292 m~ (~ 130) ~D ~ 36 (C 1.0 in chloroform) IR(KBr) 3525 (broad), 1755, 1730, 1230 cm 1.
Analysis: Calcd. for C26H38O7 (percent) C 67,51; H 8,28 Found (percent) C 67,57; H 8,15.
A solution of monoperphthalic acid (21 g.) in ether (120 ml.) was added over 1.5 hr. to a solution of 15 g. of 16~-methyl-11~,17~,21-trihydroxy-3,3-ethylene-dioxy-pregn-5-ene-20-one-21-acetate (IIa) (R3 = ~CH3) in chloroform (500 ml.) at -30C. After keeping at -30C for 3 hrs. the organic phase was washed acid free with 5~ sodium bicarbonate aqueous solution. The solution was then washed with water, dried and evaporated to a residue which by crystallization from methanol gave 12 g. of 16~-methyl-11~,17~,21-trihydroxy-3,3-ethylene-dioxy-5~,6~-oxido-pregnane-20-one-21-acetate (IIIa) (R3 = ~CH3) characterized by IR(KBr) 3600, 3520, 1755, 1725, 1235 cm 1.
Analysis: Calcd. for C26H38O8 (percent) C 65,25; H 8,00 .
~064476 Found (percent) C 65,20; H 7,92.
Using the general procedure of Example 40 the 16~-methyl~ ,17~,21-trihydroxy-3,3-ethylene-dioxy-pregn~5-ene-20-one-21-acetate (IIb) (R3 = ~CH3) was converted into 16~
methyl-11~,17~,21-trihydroxy-3,3-ethylene-dioxy-5~,6~-oxido-pregnane-20-one-21-acetate (IIIb) (R3 = ~CH3) characterized by IR(KBr) 3550, 3450 (broad), 1740, 1728, 1235 cm 1 Analysis: Calcd. for C26H38O8 (percent) C 65,25; H 8,00 Found (percent) C 65,37; H 8,08.
4.5 g. of 16~-CH3-11~,17~,21-trihydroxy-3,3-ethylene-dioxy-5a,6~-oxido-pregnane-20-one-21-acetate (IIIa) (R3 = ~CH3) were added over a period of about 1.5 hr. under ` stirring to 45 ml. of a cooled (-65C) 70% hydrofluoric acid , :: .
aqueous solution. After addition was completed the solution was stirred for 0.5 hr. at -60C. and then poured into water (650 ml.). The solid was dissolved in ethyl acetate (400 ml.), the solution was washed with sodium bicarbonate aqueous solution until it was acid free and then washed neutral with water andfinally dried over sodium sulphate. Removal of the solvent afforded a crude product which by one crystallization from acetone-hexane afforded 3.2 g. of 16~-methyl-6~-fluoro-5~ ,17~,21-tetrahydroxy-pregnane-3,2Q-dione-21-acetate (IVa) (R3 = ~CH3) characterized by M.P. 218-20 C.
max (methanol) 290 m~ (~ 90) ~D ~ 21 (C 1.0 in chloroform) IR(KBr) 3640, 3560, 3450 (broad), 1740, 1730, 1710, 1230 cm 1.
Analysis: Calcd. for C24H35FO7 (percent) C 63,42; H 7,76;
F 4,18 Found (percent) C 63,50; H 7,65; F 4,15.
.
' :, .' ' . , Using the general procedure of Example 42 the 16~-methyl-11~,17~,21-trihydroxy-3,3-ethylene-dioxy-5~,6~-oxido-pregnane-20-one-21-acetate (IIIb) (R3 = ~CH3) was converted into 16~-methyl-6~-fluoro-5a,11~,17~,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (IVb) (R3 = ~CH3) M.P. 220-2 C.
~ ~20 + 54 (C 1.0 in chloroform) i ~ max (methanol) 292 m~ (~ 98) IR(KBr) 3640, 3460 (broad), 1750, 1730, 1705, 1235 cm Analysis: Calcd. for C24H35FO7 (percent) C 63,42; H 7,76;
F 4,18 Found (percent) C 63,31; H 7,62; F 4,02.
A mixture of 2 g. of sodium acetate and 10 g. of 16~-methyl-6~-fluoro-5~ ,17a,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (IVa~ (R3 = ~CH3) dissolved in 100 ml. of dioxane was stirred at 25-30C while a solution of 4 g. of bromine in 50 ml. of dioxane was added dropwise over a period of about 2-3 min. After addition of bromine was completed the mixture of reaction was poured into 1500 ml. of a cold 5~
sodium chloride aqueous solution. After stirring for 1 hr., a white crystalline product was collected by filtration, washed with water and dried, 16~-methyl-2~-bromo-6~-fluoro-5~,11~, 17~,21-tetrahydroxy-pregnane-3,20~dione-21-acetate (Va) (R3 ~ ~CH3). Crystallization from acetone-hexane gave about 7 g. of white solid characterized by M.P. 137-8C (decompo-sition).
~20 + 27 (C 1.0 in dioxane) ~: ~ max (methanol) 288 m~ (s 112) IR(KBr) 3640, 3560, 3470 (broad), 1730 (broad), 1230 (broad) cm r - ~
11)64476 Analysis: Calcd. for C24H34srFO7 (percent) C 54,04; H 6,42 Br 14,98; F 3,56 Found (percent) C 54,23; H 6,46; Br 14,81; F 3,57.
Using the general procedure of Example 4~ the 16~-. methyl-6~-fluoro-5c~,llcl,17cc-21-tetrahydroxy-pregnane-3,2a- dione-21-acetate (IVb) R3 = ~CH3) was converted into 16~-methyl-2~-bromo-6~-fluoro-5~ ,17a,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (Vb) R3 = ~CH3) ~ ~20 + 68 (C 1 0 in dioxane) max (methanol) 292 m~ (~ 123) IR(KBr) 3640, 3460, 3420, 1745, 1735 (broad~, 1230 cm 1 Analysis: Calcd. for C24H34BrFO7 (percent) C 54,04; H 6,42;
Br 14,98; F 3,56 Found (percent) C 54,24; H 6,48; Br 14,75; F 3,48.
EXAMPLE 46 ;
A solution of 10 g. of 16~-CH3-2~-bromo-b~-fluoro-5~ ,17~,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (Va) (R3 = ~CH3) in 50 ml. of pyridine was stirred at -5C while dropwise adding 8 g. of methane sulfonyl chloride over a period of about 15 min. After addition was completed the mixture was stirred for 1.5 hr. maintaining the temperature at about 0C, then poured into 400 ml. of cold water and 200 ml.
of dichloroethane. The mixture was acidified at pH 3.5 with 4N sulphuric acid solution and stirred for 1 hr. The di-- chloroethane layer was separated, the aqueous portion extract-ed once with 200 ml. of dichloroethane and the combinated organic extracts washed neutral with water, dried and concen-.~
trated to dryness under vacuum at 60C. The yellow oily residue by crystallization from benzene-hexane gave 16~-methyl-2a-bromo-6~-fluoro-5~ ,17~,21-tetrahydroxy-pregnane-:: :
.
3,20-dione-11-mesylate-21-acetate (VIa) (R3 = ~CH3) ~20 + 30 (C 1.0 in dioxane) max (methanol) 288 m~ ( 110) IR(KBr) 3520 (broad), 1730 (broad), 1330, 1230, 1170 cm 1 Analysis: Calcd. for C25H36BrFOgS (percent) C 49,10; H 5,93;
Br 13,07; F 3,11 Found (percent) C 48,85; H 5,81; Br 13,23; F 3,20.
Using the general procedure of Example 46 the 16~-methyl-2~-bromo-6~-fluoro-5~ l7~l2l-tetrahydroxy-pregnane-3,20-dione-21-acetate (Vb) (R3 = ~CH3) was converted ~nto 16~-methyl-2~-bromo-6~-fluoro-5~ ,17~,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-21-acetate (VIb) (R3 = ~CH3). M.P.
148-50C (decomposition).
~D + 60 (C 1.0 in dioxane) ~ max (methanol) 292 m~ (~ 99) IR(KBr) 3660, 3520 (broad), 3370 (broad), 1740, 1725, 1330, 1230, 1170 cm 1.
Analysis: Calcd. for C25H36BrFOgS (percent) C 49,10; H 5,93;
Br 13,07; F 3,11 Found (percent) C 49,23i H 5,89, Br 13,25; F 2,98.
10 g. of 16~-methyl-2~-bromo-6~-fluoro-5~ ,17~, 21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-21-acetate (VIa) (R3 = ~CH3) were added to a solution of 75 ml. of acetic anhydride and 0.5 ml. of 70% perchloric acid in 450 ml. of ethyl acetate. The mixture was kept at 30C for 0.5 hr. and washed successively with 5% sodium bicarbonate aqueous solution. The ethyl acetate solution after anhydrification on sodium sulphate was evaporated to dryness under vacuum.
. .
` Crystallization of the residue from methanol gave about 9 g.
. -. .
. .
- . : .
of 16~-methyl-2a-bromo-6~-fluoro-5~ ,17~,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-5,17,21-triacetate (VIIIa) (R3 = ~CH3) characterized by M.P. 136-8C (decomposition).
~ ~20 _3 (C 1.0 in chloroform) -~ IR(KBr) 1745 (broad), 1365, 1220 (broad), 1170 cm 1... . .
Analysis: Calcd. for C29H40BrFOllS (percent) C 50,07; H 5,80;
~-~ Br 11,49; F 2,73.
....
Found (percent) C 50,25; H S,92; Br 11,35; F 2,66. -~; 10 Using the general procedure of Example 48 the 16~-methyl-2~-bromo-6~-fluoro-5~ ,17a,~1-tetrahydroxy-pregnane- -~
.,; ~ . :, 3,20-dione-11-mesylate-21-acetate (VIb) (R3 = ~CH3) was converted into 16~-methyl-2~-bromo-6~-fluoro-5~ ,17~,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-5,17,21-tri-.~ . .
acetate (VIIIb) (R3 ~ ~CH3) characterized by M.P. 131-2C
' (decomposition).
~20 ~ 27 (C 1.0 in chloroform) ' IR(KBr) 1750 (broad), 1370, 1220 (broad), 1170 cm 1.
, . I ::
Analysis: Calcd. for C29H40BrFOllS (percent) C 50,07; H 5,80;
Br 11,49; F 2,73 ;
;~ Found (percent~ C 50,15; H 5,72; Br 11,55; F 2,82.
-- .
,~- 6.9 g. of 16~-methyl-2~-bromo-6~-fluoro-5a,11~,17, 21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-5,17,21-tri-acetate (VIIa) (R3 = ~CH3) were dissolved in 320 ml. of anhydrous acetic acid at 90C on the steam bath. A solution of sodium acetate (15 g. dried at 100C) in acetic acid (60 ml.) at 90C was added, followed immediately by 1.80 g. of bromine in acetic acid (25 ml.), added in one lot. Heating at 90C was continued until the bromine colour disappeared (about 5 min. in all). The solution was then cooled as rapidly as , ,. : :
.',~ - .
possible to room temperature and poured in cold water. The solid was collected by filtration, washed thoroughly with water and dried to a constant weight, giving about 7 g. of 16~-methyl-2,2-dibromo-6~-fluoro-11~,17~,21-trihydroxy-pregn-4-ene-3,20-dione-11-mesylate-17,21-diacetate (VIIa bis) (R3 = ~CH3). M.P. 135-7C (decomposition).
~20 -20 (C 1.0 in chloroform) max (methanol) 242-3 m~ (~ 10700) IR(KBr) 1745, 1730, 1698, 1620, 1330, 1220, 1170 cm 1.
- 10 Analysis: Calcd. for C27H35Br2FOgS (percent) C 45,39; H 4,94;
- Br 22,37; F 2,66 Found (percent) C 45,62; H 5,05; Br 22,23; F 2,55.
;~ Using the general procedure of Example 50 the 16~-methyl-2~-bromo-6~-fluoro-lla,17~,21-trihydroxy-pregnane-3,20-dione-ll-mesylate-5,17,21-triacetate (VIIb) (R3 = ~CH3) was . ,: .
converted into 16~-methyl-2,2-dibromo-6~-fluoro-11~,17~,21-,: :
trihydroxy-pregn-4-ene-3,20-dione-11-mesylate-17,21-diacetate (VIIb bis) (R3 = ~CH3). M.P. 141-2C (decomposition).
` 20 ~/,20 + 12 (C 1.0 in chloroform) max (methanol) 243 m~ (~ 10600) IR(KBr) 1745, 1730, 1696, 1625, 1330, 1220, 1170 cm 1.
., .
Analysis: Calcd. for C27H35Br2FOgS (percent) C 45,39, H 4,94;
Br 22,37; F 2,66 Found (percent~ C 45,51; H 4,88; Br 22,48; F 2,52. -~ -; 6 g. of 16~-methyl-2,2-dibromo-6~-fluoro~ ,17~,21-trihydroxy-pregn-4-ene-3,20-dione-11-mesylate-17,21-diacetate (VIIa bis) (R3 = ~CH3) were added in one portion to a mixture of 60 ml. of dimethylformamide, 12 g. of lithium carbonate and 6 g. of lithium bromide under stirring at 100C. The reaction .. . .
~.
' - . .: :. .: . . . . .
~064476 . . .
mixture was then refluxed at 130C under nitrogen for 0.5 hr., cooled and poured into cold water. The precipitate was filtered off, washed with water and dried. Crystallization of the residue from acetone-hexane gave 3.5 g. of 16a-methyl-2-bromo-6~-fluoro-17~,21-dihydroxy-pregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate (VIIIa) (R3 = 16~CH3) characterized by ~20 -84 (C 1.0 in chloroform) ~ max (methanol) 246-7 m~ ( 12900) IR(KBr) 1745, 1730, 1680, 1605, 1230 cm 1.
Analysis: Calcd. for C26H30BrFO6 (percent) C 58,11; H 5,63;
Br 14,87; F 3,53 Found (percent) C 58,07; H 5,69; Br 14,79; F 3,47.
Using the general procedure of Example 52 the 16~-methyl-2,2-dibromo-6~-fluoro-11~,17~,21-trihydroxy-pregn-4-ene-3,20-dione-11-mesylate-17,21-diacetate (VIIb bis) " . :
`- (R3 = ~CH3) was converted into 16~-methyl-2-bromo-6~-fluoro-17~,21-dihydroxy-pregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate (VIIIb) (R3 = ~CH3) characterized by ~ ~D0 -66 (C 1.0 in chloroform) max (methanol) 246 m~ (~ 12430) ;: ~
IR(KBr) 1760, 1740 (broad), 1670, 1600, 1235 cm 1.
NMR (CDC13-TMS) Hz at 60 mHz 454 (S, 1, C-l H) 376, 372 (d, 1, ; C-4 H) 342, 288 (doublet of triplets, 1, C-6 H) 340-330 (m, 1, C-ll H) 298, 282, 266, 250 (doublet of doublets, 2, CH2OAc) . 130 (S, 3, OAc) 126 (S, 3, OAc) 96, 94 (d, 3, 19 CH3 split by ~ 6~F) 85, 78 (d, 3, C-16 ~CH3) 46 (S, 3, 18 CH3) - Analysis: Calcd. for C26H30BrFO6 (percent) C 58,11; H 5,63;
~: Br 14,87; F 3,53 '~ 30 Found (percent) C 58,20; H 5,71; Br 14,92; F 3,47.
~:
, .- , :
/
, .
~064476 EXAMPL~ 54
C ~D -88,5 (C 1.0 in chloroform) ; ~ max (methanol) 246-7 m~ (~ 12750) 30 IR(KBr) 1740 (broad), 1675, 1645, 1600, 1230 cm 1.
NMR (CDC13 - TMS) Hz at 60 mHz 452 (S, 1, C-1 H) 376, 372 .," ' ~ (d, 1, C-4 H) 342-332 (m, 1, C-ll H) 334, 286 (doublet of . . .
triplets, 1, C-6 H) 302, 284, 280, 262 (doublet of doublets, ~ 2, CH2OAc) 130 (S, 3, OAc) 123 (S, 3, OAc) 94, 92 (d, 3, 19 ; CH3 split by 6~F) 45 (S, 3, 18 CH3).
Analysis: Calcd. for C25H28BrFO6 (percent) C 57,37; H 5,39;
sr 15,27; F 3,63.
... .- ~
Found (percent) C 57,53; H 5,61; Br 15,03; F 3,71.
-~ EXAMPLE 9 :.
7.1 g. of 1,3-dibromo-5,5-dimethyl-hydantoin were added in the dark at room temperature under stirring over a period of 0.5 hr. to a suspension of 10 g. of 2-bromo-6~-fluoro-17~,21-dihydroxy-pregna-1,4,9(11)-triene-3,20-dione-~ ~.
17,21-diacetate (VIII) in 200 ml. of tetrahydrofurane and 1 g.
of 70% perchloric acid in 10 ml. of water. During the addition the suspension began to thin and after a total ::
reaction time of 45 min. all the starting material was dis-solved. After an additional 2 hr., 10~ sodium sulfite aqueous solution was added under stirring until KJ-starch paper was no longer blued. The solution was slowly poured into 1000 ml.
cold water. The product (IX) was filtered and utilized moist in the next reaction. Analytically pure 2,9~-dibromo-6~-~''':~.! , , !
I fluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-,, :
17,21-diacetate (IX) was obtained by additional crystalli-;~ zation from acetone-hexane. It was dried in vacuo at room temperature M.P. 208-10C (decomposition).
~ . , - .
~D -18,2 (C 1.0 in chloroform) ~ ~ max (methanol) 248 m~ (s 10250) ;~ IR(KBr) 3520, 1755, 1740, 1710, 1675, 1640, 1605, 1230 cm 1.
. ~ ....
~ Analysis: Calcd. for C25H29Br2FO7 (percent) C 48,41; H 4,71;
`~- 3Q Br 25,76; F 3,06 Found (percent) C 48,74; H 4,65; Br 25,60; F 3,31.
': ~
.
,.,' ~ '~
,'.:. ~ , . ', ' ,~, . . .
. , .
:~ 1064476 ..
40 ml. of a 14~ potassium carbonate aqueou~ solution were added over a period of 20 min. at 20C under stirring to the solution of the moist product (IX) 2,9~-dibromo-6~-fluoro-,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-di-.",6 acetate (obtained in Example 9 from 10 g. of the product VIII) in 200 ml. of acetone. The solution was stirred for 4 hr.
~` Ice water was added under stirring, upon which crystallization occurs rapidly. The product 2-bromo-6~-fluoro-17~,21-dihydroxy-9~ -oxido-pregna-1,4-diene-3,20-dione-17,21-diacetate (X) was filtered, washed with water, dried and characterized by M.P. 241-2C (decomposition), raised by crystallization from benzene-cyclohexane to 248-9C.
; ~ ~D -88,4 (C 0.5 in chloroform) ~ IR(KBr) 1755, 1740 (broad), 1670, 1640, 1600, 1230 (broad) ~ --1 -~ cm Analysis: Calcd. for C25H28srFo7 (percent) C 55,67; H 5,23;
Br 14,81; F 3,52.
Found (percent) C 55,80; H 5,15; Br 14,72; F 3,45.
~ ~ 100 ml. of a 7Q% hydrofluoric acid aqueous solution ;~ were cooled to -10C in a polyethylene flask equipped with ~ .
electromagnetic stirrer. 10 g. of 2-bromo-6~-fluoro-17~,21-dihydroxy-9~ -oxido-pregna-1,4-diene-3,20-dione-17,21-diacetate (X) were added under stirring during 15 min. After 0.5 hr. the reaction mixture was precipitated in water and ammonia. The solid was collected by filtration, washed with water and dried to a constant weight, giving about 9.5 g. of . .
2-bromo-6~,9~-difluoro~ ,17~,21-trihydroxy-pregna-1,4-diene-;- 30 3,20-dione-17,21-diacetate (XI) (Rl = R2 = OCOCH3). Crystal-~ lization from benzene gave 7 g. of pure product, homogeneous - .:
~ .
~ '. - , ', . ''' '., - . .' ~ . .-10~4476 by TLC on silica gel (6:3:2 CHC13-acetone-cyclohexane). M.P.
290-2C (decomposition).
~D -36 (C 1.0 in chloroform) ~ max (methanol) 246 m~ ( 12500) IR(KBr) 3520, 1758, 1733, 1705, 1680, 1650, 1610, 1235 cm NMR (dimethyl-d6 sulfoxide-TMS) Hz at 60 mHz 471 (S, 1, C-l H) 393, 389 (d, 1, C-4 H) 350, 300 (doublet of triplets, 1, - C-6 H) 341, 335 (d, 1, C-ll OH) 289 (S, 2, CH2OAc) 270-240 (m, 1, C-ll H) 127 (S, 3, OAc) 122 (S, 3, OAc) 99, 96 (d, 3, 19 CH3 split by 6~F) 56 (S, 3, 18 CH3).
M.S. (70 e.v., ion source temperature 210C, direct sample - introduction) ions at m/e 558/560 (M+, C25H29BrF2O7), 540/542, 538/540, 518/520, 498/500, 483/485, 478/480, 458/460, 397/399, 377/379, 359/361, 357/359, 339/341, 317/319, 315/317, 299/301, 278, 217/219, 212/214, 199/201, 165, 147, 139, 121, 109, 101, 91, 79, 73 (base peak), 69, 60, 55.
Analysis: Calcd. for C25H29BrF2O7 (percent) C 53,67; H 5,22;
F 6,79; Br 14,28.
Found (percent) C 53,27; H 5,22; F 6,80; Br 14,32.
~- 20 EXAMPLE 12 A suspension of 10 g. of 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XI) (Rl - R2 = OCOCH3) in 200 ml. of 1% potassium hydroxide methanolic solution was stirred under nitrogen at 0C for 3 hrs. Addition of cold water, elimination of methanol i~ vacuo, acidification with acetic acid and fil-tration gave 7 g. of 2-bromo-6~,9~-difluoro-11~,17~,21-tri-hydroxy-pregna-1,4-diene-3,2~-dione (XIa) (XI, Rl = R2 = OH).
M.P. 223-227C (decomposition), raised by crystallization from dichloroethane to 228-230C.
~D -5.6 (C 1.0 in dioxane) -- . : . .
' ' ' ~ , . ~ , :' . :' ' max (methanol) 246 m~ (~ 11700) IR(KBr) 3430 (broad), 1715, 1670, 1645, 1600 cm 1.
NMR (dimethyl-d6 sulfoxide-TMS) ~Iz at 60 mHz 470 (S, 1, C-l H) 392, 388 (d, 1, C-4 H) 348, 298 (doublet of triplets, 1, C-6 H) 327, 322 (d, 1, C-ll OH) 316 (S, 1, C-17 OH) 280, 276, 270, 266, 261, 257, 250, 246 (octuplet which becomes a quartet by deuterium exchange, 2, COCH2OH) 99, 96 (d, 3, 19 CH3 split by 6~F) 48 (S, 3, 18 CH3).
M.S. (70 e.v., ion source temperature 210C, direct sample introduction) ions at m/e 474/476 (M+, C21H25BrF2O5) 456/458, 444/446, 427/429, 414/416, 394/396, 379/381, 359/361, 317/319, 315/317, 219/221, 217/219 (base peak), 212/214, 199/201, 139, 109, 95, 67, 55.
Analysis: Calcd. for C21H25BrF2O5 (percent) C 53,06; H 5,30;
Br 16,81; F 7,99 Found (percent) C 53,15; H 5,30; Br 16,73; F 8.05.
To a solution of 10 g. of 2-bromo-6~-fluoro-17a,21-dihydroxy-pregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate (VII) and 40 g. lithium chloride in 200 ml. of glacial acetic acid were added at 20C under stirring 5 g. of N-chloro-succinimide. The mixture was kept at 20C and stirred while dropwise adding 10 ml. of a 12~ hydrochloric acid tetrahydro-furane solution over a period of about 10 min. ~fter 3.5 hrs.
the reaction mixture was poured into cold water, the solid collected by filtration, washed with water and dried, giving 6 g. of pure product 2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XII) (Rl = R2 = OCOCH3). M.P. 244-6C (decomp.).
~ ~D -2.5 (C 1.0 in chloroform) ~ IR(KBr) 1753, 1740~ 1672, 1645; 1602, 1230 cm 1.
:'' , . " . . :
.
, ;. -- . , : .
`- 1064476 .
; NMR (dimethyl-d6 sulfoxide-TMS) Hz at 60 mHz 465 (S, 1, C-l H) ~ -, 394, 390 (d, 1, C-4 H) 350, 300 (doublet of triplets, 1, :- C-6 H) 320-305 (m, 1, C-ll H) 289 (S, 2, CH2OAc) 127 (S, 3, OAc) 122 (S, 3, OAc) 110, 106 (d, 3, 19 CH3 split by 6~F) 61 (S, 3, 18 CH3).
Analysis: Calcd. for C25H28BrC12FO6 (percent) C 50,27;
:.,~ , .
` H 4,72; F 3,18; Cl 11,87; Br 13,38 ~ Found (percent) C 50,55; H 4,81; F 3,25 Cl 12,05;
,,,~" ~
Br 13,67.
~; 10 ~ max (methanol) 245-6 m~ ( 12280).
-. :.' Using the general procedure of Example 12 the 2- ~
,: . .
bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4- -~
diene-3,20-dione-17,21-diacetate (XII) (Rl = R2 = OCOCH3) was .
; converted to 2-bromo-6~-fluoro-9~ -dichloro-17~,21-dihydroxy-pregna-1,4-diene-3,20-dione XIIa (XII, Rl - R2 = OH) M.P. 185-7C (decomposition).
.
max (methanol) 245 m~ (~ 12000) ~D ~ 34 (C 0.7 in chloroform) IR(KBr) 3450 (broad), 1715, 1675, 1645, 1605 cm 1.
Analysis: Calcd. for C21H24BrC12FO4 ~ercent) C 49~43 H 4,74, F 3,72~ Cl 13,9Q, Br 15,66 "r ' Found (percent~ C 49,78, F 3~7Qi Cl 14,Q7, Br 15,75; H 4,76.
., :
`~ A mixture of 7 g. of 2-bromo-6~,9a-difluoro~ ,17~, ~ 21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XI) -~ Rl = R2 = OCOCH3), 70 ml. of dimethylformamide and 3.5 g. of ;~ anhydrous potassium acetate was refluxed at 120C under nitro-gen for 0.5 hr. The reaction mixture was then cooled and poured into cold water. The precipitate was filtered off, ' . .
~064476 washed with water, dried. Crystallization of the residue from acetone-hexane gave 5 g. of 2-bromo-6~,9~-difluoro~ ,21-dihydroxy-pregna-1,4,16-triene-3,20-dione-21-acetate (XI bis) (Rl = OCOCH3) characterized by M.P. 257-8C (decomposition).
~D ~ 24 (C 1.0 in chloroform) IR(KBr) 3520, 1730, 1680, 1640, 1600, 1588, 1220 cm 1.
~ max (methanol) 242-3 m~ (~ 21500) Analysis: Calcd. for C23H25BrF2O5 (percent) C 55,32; H 5,04;
Br 16,00; F 7,61;
Found (percent) C 55,21; H 4,89; Br 16,25; F 7,49.
A solution of potassium permanganate (3.5 g.) in acetone (75 ~1.) and water (25 ml.) was added, in one portion, at -5C to a solution of 5 g. of 2-bromo-6~,9~-difluoro-11~,21-dihydroxy-pregna-1,4,16-triene-3,20-dione-21-acetate (XI bis) (Rl = OCOCH3) in acetone (150 ml.) and formic acid (1.7 ml.). The mixture of reaction was stirred for 5 min. at -5C and then 50 ml. of 10% Na2SO3 aqueous solution were added. The mixture was filtered through Celite (Trade Mark) and the pale yellow filtrate concentrated i~ va~uo and poured into cold water. The solid filtered after crystallization ~ from acetone-hexane yielded 4.5 g. of 2-bromo-6~,9~-difluoro-; 11~,16~,17~,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-21-acetate (XVII) (Rl = OCOCH3) characterized by M.P. 225-7 C
(decomposition).
~D -16 (C 1.0 in dioxane) max (methanol) 245-6 m~ (~ 12000) .~
IR(KBr) 3440 (broad), 1745, 1732, 1672, 1645, 1605, 1230 cm 1 NMR (dimethyl-d6 sulfoxide-TMS) Hz at 60 mHz 472 (S, 1, C-l H) - 30 392, 388 (d, 1, C-4 H) 348, 298 (doublet of triplets, 1, ~l C-6 H) 337, 332 (d, 1, C-ll OH) 328, 323 (d, 1, C-16 OH) 312, .
- . .
' '': ; ~ .. ': ' . ~ .
296, 292, 276 (doublet of doublets 2, CH2OAc) 290 (S, 1, C-17 OH) 290-280 (m, 1, C-16 H) 265-240 (m, 1, C-ll H) 126 (S, 3, OAc) 98, 95 (d, 3, 19 CH3 split by 6~F) 52 (S, 3, 18 CH3). `
Analysis: Calcd. for C23H27BrF2O7 (percent) C 51,79; H 5,10;
F 7,12; Br 14,98 Found (percent) C 52,05; H 5.02; F 7.25; Br 16,18.
:~ .
Using the general procedure of Example 12 the 2- ~ `
bromo-6~,9~-difluoro-11~,16~,17~,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-21-acetate (XVII) (Rl = OCOCH3) was converted to 2-bromo-6~,9a-difluoro-11~,16~,17~,21-tetrahydroxy-pregna- -~
1,4-diene-3,20-dione (XVIIa) (XVII Rl = OH). M.P. 208-10C
(decomposition).
.
IR(KBr) 3460 (broad), 171S, 1670, 1645, 160S cm 1. ~~
Analysis: Calcd. for C21H25BrF2O6 (percent) C 51,33; H 5,13;
Br 16,26; F 7,37 Found (percent) C 51,51; H 5,10; Br 16,15; F 7,81.
~D ~30 (C 1.0 in dioxane) :! A max (methanol) 246-7 m~ (~ 1140Q).
: 1 , A solution of 5 g. of 2-bromo-6~,9~-difluoro-11~, : :
n 17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, , . .
Rl = R2 = OH) in 10 ml. of dimethylformamide and 37 ml. of 2,2-dimethoxypropane with 0.025 g. of p-toluenesulfonic acid was heated for 6 hrs. at 115C. The reaction mixture was ~ cooled, poured in 10% sodium bicarbonate aqueous solution and --i chloroform. The chloroform solution was then washed with ~ water, dried and evaporated to a residue which by crystalli--,~ zation from acetone gave 4 g. of 2-bromo-6~,9~-difluoro-11~, 17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-acetonide (XIb) characterized by M.P. 230-1C (decomposition).
. .
~ - 34 -.. . .
, :, . . .. ..
,, . :
r~ ,~
~Q64476 ~D -1 (C 1.0 in chloroform) max (methanol) 245-6 m~ ( 12100) IR (KBr) 3440 (broad), 1720, 1670, 1645, 1600 cm 1 Analysis: Calcd. for C24H29BrF2O5 (percent) C 55,93; H 5,67;
Br 15,50; F 7, 37 Found (percent) C 56,07; H 5,72; Br 15,37; F 7,50.
2.5 ml. of 70% perchloric acid were added under stirring at 15C to a suspension of 10 g. of 2-bromo-6~,9~-difluoro-11~,16~,17~,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-21-acetate (XVII) (Rl = OCOCH3) in 400 ml. of acetone.
The solution was stirred at 15C for 50 min. and 5 g. of sodium bicarbonate were added. The mixture was stirred for 10 min. and then filtered. The acetone solution was evapo-rated to dryness in vacuo at 60C. The solid residue was crystallized from ethylacetate-light petroleum giving 6 g. of pure 2-bromo-6~,9~-difluoro 11~,16a,17~,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-21-acetate-16,17-acetonide (XIX) (Rl = OCOCH3, R4 = R5 = CH3).
20 IR(KBr) 3560, 3480, 3430, 1755, 1730, 1670, 1645, 1600, 1225 ~- cm Analysis: Calcd. for C26H31BrF2O7 (percent) C 54,46, H 5,45;
^~ Br 13,93; F 6,62 ;~ Found (percent) C 54,65; H 5,57; Br 13,85; F 6,47.
~D + 8 (C 1.0 in chloroform) max (methanol) 246 m~ (E 11550).
5 ml. of acetic anhydride were dropwise added to a mixture of 50 ml. of pyridine and 10 g. of 2-bromo-6~,9~-30 difluoro~ ,16~,17~,21-tetrahydroxy-pregna-1,4-diene-3,20-lr' dione-21-acetate (X~II) (R1 = OCOCH3). The mixture was kept ' ~
.
.. : :
, ,. ~ . , . .: : , . .
,' ~
at room temperature for 1.5 hr. and then poured under vigorous stirring into 500 ml. of cold water. After about 0.5 hr. the solid was collected by filtration, washed thoroughly with cold water, dried to a constant weight, giving about 9.5 g. of ;
2-bromo-68,9~-difluoro-11~,16~,17~,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-16,21-diacetate (XVIII) Rl = R3 = OCOCH3), crystallized by methanol-water.
- IR(KBr) 3570, 3500 (broad) 1760, 1735 (broad), 1670, 1645, 1605, 1240 (broad) cm 1 Analysis: Calcd. for C25H29BrF2O8 (percent) C 52,18; H 5.08;
Br 13,89; F 6,60 Found (percent) C 52,07; H 5,10; Br 14,07; F 6,70.
M.P. 238-40 C (decomposition) r~D ~49 4 (C 1.0 in chloroform) max (methanol) 246 m~ (s 11900).
5 g. of 2-bromo-6~,9~-difluoro-11~,17~,21-tri-hydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, Rl = R2 = OH) were dissolved in 50 ml. of pyridine containing 25 ml. of acetic anhydride and kept at room temperature for 12 hrs.
Addition'of ice water afforded a product which was extracted with chloroform. The chloroform solution was washed with ;~ water, 2N HCl, 5% sodium bicarbonate solution and water.
., .
- After drying (Na2SO4) and removal of the solvent in vacuo the ` residue was crystallized from acetone-hexane to gave 2-bromo-:
6~,9~-difluoro-113,17~,21-trihydroxy-pregna-1,4-diene-21-acetate (XIc) (XI, Rl = OCOCH3, R2 = OH) characterized by M.P.
~- ` 194-6C (decomposition).
~D + 12 (C 1.0 in chloroform) ~` ~ 30 ~ max (methanol) 246 m~ (~ 11800) ~; IR(CHC13) 3620, 3500 (broad), 1745, 1730, 1672, 1645, 1605, ,~~ ,. '.
.
` ~
~6)64476 1230 (broad) cm 1 Analysis: Calcd. for C23H27BrF2O6 (percent) C 53,39; H 5,26;
Br 15,44; F 7,34 Found (percent) C 53,51; H 5,21; Br 15,70; F 7,28.
Using the general procedure of Example 21, the 2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene--~ 3,20-dione (XIa) (XI, Rl = R2 = OH) was converted to 2-bromo-6~,9~-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-propionate (XId) (XI, Rl = OCOCH2CH3, R2 = OH) by reaction with propionic anhydride. M.P. 180-3C (decompo-- sition) ~D ~ 22 (C 1.0 in chloroform) max (methanol) 246 m~ ( 10900) IR(CHC13) 3610, 3500 (broad), 1740, 1728, 1672, 1645, 1605, 1220 cm 1.
Analysis: Calcd. for C24H29BrF2O6 (percent) C 54,25; H 5,50;
Br 15,04; F 7,15 Found (percent) C 54,09; H 5,60; Br 14,92; F 7,05.
Using the general procedure of Example 21, the 2-bromo-6~,9a-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, Rl = R2 = OH) was converted to 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-valerate (XIe) (XI, Rl = OCO(CH2)3CH3, R2 = OH) by reaction with valeric anhydride. M.P. 155-7C (decomposition) ; ~ ~D ~ 27 (C 1.0 in chloroform) ~ max (methanol) 246 m~ (~ 11600) IR(KBr) 3500 (broad), 1740, 1720, 1670, 1640, 1600, 1230 3a (broad) cm 1.
Analysis: Calcd. for C26H33BrF2O6 (percent) C 55,82; H 5,94;
.' ,. . .
' ' ' . : . . : ~
': ~ , ' ' : ' ' . ' ' ~ . ': ' ' Br 14,28; F 6,79 Found (percent) C 55,70; H 5,91; Br 14,35; F 6,87.
Using the general procedure of Example 21, the ~- 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, Rl = R2 = OH) was converted to 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-- dione-21-pivalate (XIf) (XI, Rl = OCOC(CH3)3, R2 = OH) by M.P.
224-6C (decomposition) ~ ~D t 22 (C 1.0 in chloroform) ~, , .
max (methanol) 245-6 m~ (~ 10900) ~; IR(KBr) 3470 (broad), 1740, 1730, 1665, 1640, 1600, 1220 cm . .
Analysis: Calcd. for C26H33BrF2O6 (percent) C 55,82; H 5,94;
Br 14,28; F 6,79 Found (percent) C 55,75; H 5,88; Br 14,07; F 6,65.
3 g. of 2-bromo-6~,9~-difluoro-11~,17~,21-tri-hydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, Rl = R2 = OH) were dlssolved in 30 ml. of pyridine containing 1 ml. of terbutylacetic acid chloride and kept at room temperature for 16 hrs. Addition of ice water afforded a product which was extracted with chloroform. The chloroform solution was washed :
(Na2SO4) and removal of the solvent in vacuo, the residue was crystallized from acetone-hexane to give 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-; terbutylacetate (XIg) (XI, Rl = OCOCH2C(CH3)3, R2 = OH). M.P.
198-200C (decomposition) ~D + 25 tC 1.0 in chloroform) ~ max (methanol) 245-6 m~ (~ 10900) IR(KBr) 3490 (broad), 1735 (broad), 1670, 1640, 1600, 1230 cm 4 .~
~ 1064476 Analysis: Calcd. for C27H35BrF2O6 (percent) C 56,55; H 6,15;
Br 13,93; F 6,62 Found (percent) C 56,71; H 6,02; Br 13,85; F 6,75.
Using the general procedure of Example 25 the 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene~
3,20-dione (XIa) (XI, Rl = R2 = OH) was converted to 2-bromo-6~,9~-difluoro~ ,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-enantate (XIh) (XI, Rl = OCO(CH2)5CH3, R2 = OH) by reaction with enanthic acid chloride. M.P. 173-5C (decompo-sition) ~D + 28 (C 1.0 in chloroform) ~ max (methanol) 245-6 m~ ( 11500) IR(KBr) 3500 (broad), 1735 (broad), 1670, 1640, 1600, 1230 ~ (broad) cm 1 ; Analysis: Calcd. for C28H37BrF2O6 (percent) C 57,24; H 6,35;
Br 13,60; F 6,47 Found (percent) C 57,31; H 6,30; Br 13,72; F 6,29.
Using the general procedure of Example 21 the 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, Rl = R2 ~ OH) was converted to 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate (XIi) (XI, Rl = OCOC6H5, R2 ~ OH), by reaction with benzoic anhydride. M.P. 209-10C (decompo-sition) ~D + 93 (C 1.0 in chloroform) max (methanol) 233-4 m~ ( 22000) IR(KBr) 3600, 3420 (broad), 1725, 1710, 1670, 1640, 1600 cm 1.
Analysis: Calcd. for C28H29BrF2O6 (percent) C 58,04; H 5,04;
Br 13,79; F 6,56 _ 39 _ ~064476 .. .
Found (percent) C 58,21; H 4,93; Br 13,68; F 6,39.
A mixture of 5 g. of 2-bromo-6~,9~-difluoro-11~, 17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, Rl = R2 = OH), 5 ml. of methylorthovalerate and 0.020 g. of p-toluene sulfonic acid in 15 ml. of dimethylformamide was maintained for 4 hrs. under nitrogen at 115C. Then the mixture was neutralized by pyridine and concentrated under vacuum to dryness. Purification by column chromatography on FLORISIL (Registered Trade Mark) (ratio 1:30) with benzene-chloroform (8:2) as eluant, gave 3.5 g. of 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-(1'-methoxy)-n-pentylidenedioxy, which without further purification was suspended in 25 ml. of methanol and 3 ml. lN
hydrochloric acid aqueous solution, heated on water bath at 40-50C. After complete solubilization of the product, the mixture was concentrated under vacuum. The insoluble product was filtered off, washed with water and then dried. The 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate (XIl) (XI, Rl = OH, R2 = OCO(CH2)3CH3) ~- thus obtained was crystallized from acetone-hexane and charac-terized by M.P. 201-3C (decomposition) ~D ~74 (C 1.0 in chloroform) max (methanol) 246 m~ (~ 12600) IR(Ksr) 3500 (broad), 1730, 1715, 1670, 1645, 1600 cm Analysis: Calcd. for C26H33BrF2O6 (percent) C 55,82; H 5,94;
~3r 14,28; F 6,79 Found (percent) C 55,91; H 6,07; Br 14,27; F 6,72.
Using the general procedure of Example 21 the 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate (XIl) (XI, R1 = OH, R2 = OCO(CH2)3CH3) was converted to 2-bromo-6~,9a-difluoro~ ,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate-21-acetate (XIm) (XI, Rl = OCOCH3, R2 = O(CH2)3CH3) by reaction with acetic anhydride. The product was crystallized from acetone-hexane.
The crystals showed at 125C a transaction from the low melting form II to the form I melting 173-5 C (decomposition).
~D -25 (C 1.0 in chloroform) ~ max (methanol) 245-6 m~ ( 11400) IR(KBr) 3500 (broad), 1735 (broad), 1672, 1645, 1605, 1230 (broad) cm 1.
Analysis: Calcd. for C28H35BrF2O7 (percent) C 55,91; H 5,86;
Br 13,28; F 6,32 Found (percent) C 56,03; H 5,81; Br 13,07; F 6,28.
_AMPLE 30 Using the general procedure of Example 28 the 2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, Rl = R2 = OH) was converted to 2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (XIn) (XI, Rl = OH, R2 = OCOCH3) by reaction with ethylorthoacetate followed by acid hydrolysis of the resulting 17,21-orthoacetate. The product was crystallized from acetone-hexane. M.P. 230-2C (decomposition) ~ ~D -75,8 (C 1.0 in chloroform) ;- ~ max (methanol) 245 m~ ( 11700) IR(KBr) 3500, 3420, 1730, 1720, 1675, 1640, 1610, 1220 cm 1.
.~
Analysis: Calcd. for C23H27BrF2O6 (percent) C 53,40; H 5,26;
Br 15,44; F 7,34 Found (percent) C 53,52; H 5,32; Br 15,52; F 7,27.
Using the general procedure of Example 21 the , ,- ~ , . :
.: . , 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (XIm) (XI, Rl = OH, R2 = OCOCH3) was ~ converted to 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy--~ pregna-1,4-diene-3,20-dione-17-acetate-21-valerate (XIo) ` (XI, Rl = OCO(CH2)3CH3, R2 = OCOCH3) by reaction with valeric anhydride. The product was crystallized from acetone-hexane.
M.P. 159-60C (decomposition) ~/D ~37 (C 1.0 in chloroform) A max (methanol) 246-7 m~ ( 11750) 10 IR(KBr) 3660, 3520, 3380, 1730 (broad), 1675, 1640, 1600, 1240 - cm Analysis: Calcd. for C28H35BrF2O7 (percent) C 55,91; H 5,86;
Br 13,28; F 6,32 ; Found (percent) C 56,07; H 5,73; Br 13,21; F 6,55.
~' Using the general procedure of Example 28 the 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-:
; 3,20-dione (XIa) (XI, Rl = R2 = OH) was converted to 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-~;~ 20 dione-17-propionate (XIp) (XI, Rl = OH, R2 = OCOCH2CH3) by reaction with ethylorthopropionate followed by acid hydrolysis of the resulting 17,21-orthopropionate. The product was crystallized by acetone-hexane. M.P. 215-7C (decomposition) ~' A max (methanol) 245-6 m~ (E 12300) ~ ~D ~75 (C 1.0 in chloroform) - ~ IR(KBr) 3500, 3420, 1730, 1712, 1675, 1640, 1605, 1200 cm 1.
Analysis: Calcd. for C24H29BrF2O6 (percent) C 54,24; H 5,50;
Br 15,04; F 7,15 Found (percent) C 54,20; H 5,52; Br 14,79; F 6,97.
Using the general procedure of Example 28 the :
:
1064476 ~ ~
2-bromo-6~,9~-difluoro~ ,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, R1 = R2 = OH) was converted to 2-bromo-6~,9~-difluoro~ ,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-benzoate (XIq) (XIt Rl = OH, R2 OCOC6H5) by reaction with ethylorthobenzoate followed by acid hydrolysis of the resulting 17,21-orthobenzoate. The product was crystallized by acetone-hexane. M.P. 241-3C (decomposition) ~D -103 (C 1.0 in chloroform) ~ max (methanol) 234-5 m~ (~ 23500) IR(KBr) 3520, 3430, 1730, 1700, 1680, 1645, 1610 cm 1 Analysis: Calcd. for C28H2gBrF2O6 (percent) C 58,04; H 5,04;
; Br 13,79; F 6,56 Found (percent) C 58,12; H 4,95; Br 13,62; F 6,50.
Using the general procedure of Example 28 the 2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione (XIIa) (XII, Rl = R2 = OH) was converted to .
2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (XIIb) (XII, Rl = R2 = OCOCH3) by ~`- 20 reaction with ethylorthoacetate followed by acid hydrolysis of the resulting 17,21-orthoacetate. The product was crystal-lized by acetone-hexane. M.P. 193-4C (decomposition) ~D -32 (C 1.0 in chloroform) max (methanol) 245 m~ (~ 11700) IR(KBr) 3500, 1730 (broad), 1705, 1680, 1650, 1605, 1240 ~` (broad) cm 1.
! ',: ' . ~ :.
~ Analysis: Calcd. for C23H26BrC12FO5 (percent) C 50,02;
~ ......................................................................... .
~ H 4,74; Br 14,47; Cl 12,84; F 3,44 ., .
Found (percent) C 50,11; H 4,82; Br 14,35;
Cl 13,03; F 3,32.
.
.:~
~ 43 ~
.
. ' , - - - .. : .: . . . . . :~ : .
. . .. . ~ . . ~ .
.
. . .
Using the general procedure of Example 21 the 2-bromo-6~-fluoro-9~ -dichloro-17~,21-dihydroxy-pregna~1,4-diene-3,20-dione (XIIa) (XII, Rl = R2 = OH) was converted to 2-bromo-6~-fluoro-9~ -dichloro-17~,21-dihydroxy-pregna-1,4-diene-3,20-dione-21-acetate (XIIc) (XII, Rl = OCOCH3, R2 = OH) by reaction with acetic anhydride. The product was crystal-lized from benzene-light petroleum. M.P. 202-4C (decompo-sition) ~ ~D + 49 (C 1.0 in chloroform) - ~ max (methanol) 245 m~ ( 11800) IR(KBr) 3470, 1750, 1730, 1668, 1640, 1600, 1230 cm 1.
Analysis: Calcd. for C23H26FC12BrO5 (percent) C 50,02;
H 4,74; Br 14,47; Cl 12,84; F 3,44 Found (percent) C 50,21; H 4,63; Br 14,41;
Cl 12,79; F 3,38.
_AMPLE 36 Using the general procedure of Example 19 the 2-bromo-6~,9~-difluoro~ ,16~,17~,21-tetrahydroxy-pregna-1,4-- 2Q diene-3,20-dione (XVIIa) (XVII, Rl = OH) was con~erted into 2-bromo-6~,9~-difluoro-11~,16~,17~,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-16,17-acetonide (XIXa) (XIX, Rl = OH, R4 = R5 = CH3) crystallized from acetone-hexane. M.P. 221-3C
(decomposition) ~20 + 9 (C 1 0 in chloroform) ~ max (methanol) 246 m~ (~ 11950) IR(KRb) 3500, 3280, 1730, 1670, 1645, 1605 cm 1.
Analysis: Calcd. for C24H29BrF2O6 (percentl C 54,25; H 5,50;
Br 15,04; F 7,15 Found (percent) C 54,37; H 5,42; Br 14,95; F 7,10.
50 ml. of hydrochloric acid were added at 0C over a period of 30 min. to a suspension of 5 g. of 2-bromo-6~-fluoro-17~,21-dihydroxy-9~ oxido-pregna-1,4-diene-3,20-dione-17,21-diacetate (X) in 30 ml. of acetone. The mixture was held at 0C under stirring for 6 hrs. and then the pre-cipitated 2-bromo-6~-fluoro-9~-chloro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XXIII) was recovered by filtration, washed repeatedly with water, dried 10 and crystallized by acetone-hexane. M.P. 258-60C (decompo-; sition) ~20 -22 (C 1.0 in chloroform) max (methanol) 246 m~ ( 11100) IR(KBr) 3440 (broad), 3350, 1753, 1740, 17Q5, 1675, 1600, 1230 ~ l , , Analysis: Calcd. for C25H29BrClFO7 (percent~ C 52,14; H 5,Q8; -~
Br 13,88; Cl 6,16; F 3,30 Found (percent) C 52,34; H 5,02; Br 13,72; Cl 6,22; -F 3,25.
A mixture of 4.1 g. of 16~-methyl-11~,17~,21-tri-hydroxy-pregn-4-ene-3,20-dione-21-acetate (Ia) (R3 = ~CH3), 110 ml. of benzene, 41 ml. of ethylene glycol and 2.45 g. of ~ pyridine hydrochloride was refluxed under stirring for 8 hrs.
- in a water separator. After the reaction was completed 100 ml.
of 5% sodium bicarbonate aqueous solution were added. The mixture was further concentrated until crystals appeared and then poured into cold water. The resulting precipitate was removed by filtration, washed neutral with water and dried.
30 Crystallization of the residue gave 3.7 g. of 16~-methyl-11~, 17~,21-trihydroxy-3,3-ethylene-dioxy-pregn-5-ene-20-one-21-, acetate (IIa) (R3 = ~CH3) characterized by M.P. 214-6C.
max (methanol) 292 m~ (~ 110) ~20 ~ 1 (C 1.0 in chloroform) IRtKBr) 3480 (broad~, 1755, 1730, 1230 cm Analysis: Calcd. for C26H38O7 (percent) C 67,51; H 8,28 Found (percent) C 67,68; H 8,35.
Using the general procedure of Example 38 the 16~-methyl~ ,17~,21-trihydroxy-pregn-4-ene-3,20-dione-21-acetate (Ib) (R3 = ~CH3) was converted into 16~-methyl-11 , 17~,21-trihydroxy-3,3-ethylene-dioxy-pregn-5-ene-20-one-21-acetate (IIb) (R3 = ~CH3), characterized by M.P. 214-6 C.
" ~ max (methanol) 292 m~ (~ 130) ~D ~ 36 (C 1.0 in chloroform) IR(KBr) 3525 (broad), 1755, 1730, 1230 cm 1.
Analysis: Calcd. for C26H38O7 (percent) C 67,51; H 8,28 Found (percent) C 67,57; H 8,15.
A solution of monoperphthalic acid (21 g.) in ether (120 ml.) was added over 1.5 hr. to a solution of 15 g. of 16~-methyl-11~,17~,21-trihydroxy-3,3-ethylene-dioxy-pregn-5-ene-20-one-21-acetate (IIa) (R3 = ~CH3) in chloroform (500 ml.) at -30C. After keeping at -30C for 3 hrs. the organic phase was washed acid free with 5~ sodium bicarbonate aqueous solution. The solution was then washed with water, dried and evaporated to a residue which by crystallization from methanol gave 12 g. of 16~-methyl-11~,17~,21-trihydroxy-3,3-ethylene-dioxy-5~,6~-oxido-pregnane-20-one-21-acetate (IIIa) (R3 = ~CH3) characterized by IR(KBr) 3600, 3520, 1755, 1725, 1235 cm 1.
Analysis: Calcd. for C26H38O8 (percent) C 65,25; H 8,00 .
~064476 Found (percent) C 65,20; H 7,92.
Using the general procedure of Example 40 the 16~-methyl~ ,17~,21-trihydroxy-3,3-ethylene-dioxy-pregn~5-ene-20-one-21-acetate (IIb) (R3 = ~CH3) was converted into 16~
methyl-11~,17~,21-trihydroxy-3,3-ethylene-dioxy-5~,6~-oxido-pregnane-20-one-21-acetate (IIIb) (R3 = ~CH3) characterized by IR(KBr) 3550, 3450 (broad), 1740, 1728, 1235 cm 1 Analysis: Calcd. for C26H38O8 (percent) C 65,25; H 8,00 Found (percent) C 65,37; H 8,08.
4.5 g. of 16~-CH3-11~,17~,21-trihydroxy-3,3-ethylene-dioxy-5a,6~-oxido-pregnane-20-one-21-acetate (IIIa) (R3 = ~CH3) were added over a period of about 1.5 hr. under ` stirring to 45 ml. of a cooled (-65C) 70% hydrofluoric acid , :: .
aqueous solution. After addition was completed the solution was stirred for 0.5 hr. at -60C. and then poured into water (650 ml.). The solid was dissolved in ethyl acetate (400 ml.), the solution was washed with sodium bicarbonate aqueous solution until it was acid free and then washed neutral with water andfinally dried over sodium sulphate. Removal of the solvent afforded a crude product which by one crystallization from acetone-hexane afforded 3.2 g. of 16~-methyl-6~-fluoro-5~ ,17~,21-tetrahydroxy-pregnane-3,2Q-dione-21-acetate (IVa) (R3 = ~CH3) characterized by M.P. 218-20 C.
max (methanol) 290 m~ (~ 90) ~D ~ 21 (C 1.0 in chloroform) IR(KBr) 3640, 3560, 3450 (broad), 1740, 1730, 1710, 1230 cm 1.
Analysis: Calcd. for C24H35FO7 (percent) C 63,42; H 7,76;
F 4,18 Found (percent) C 63,50; H 7,65; F 4,15.
.
' :, .' ' . , Using the general procedure of Example 42 the 16~-methyl-11~,17~,21-trihydroxy-3,3-ethylene-dioxy-5~,6~-oxido-pregnane-20-one-21-acetate (IIIb) (R3 = ~CH3) was converted into 16~-methyl-6~-fluoro-5a,11~,17~,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (IVb) (R3 = ~CH3) M.P. 220-2 C.
~ ~20 + 54 (C 1.0 in chloroform) i ~ max (methanol) 292 m~ (~ 98) IR(KBr) 3640, 3460 (broad), 1750, 1730, 1705, 1235 cm Analysis: Calcd. for C24H35FO7 (percent) C 63,42; H 7,76;
F 4,18 Found (percent) C 63,31; H 7,62; F 4,02.
A mixture of 2 g. of sodium acetate and 10 g. of 16~-methyl-6~-fluoro-5~ ,17a,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (IVa~ (R3 = ~CH3) dissolved in 100 ml. of dioxane was stirred at 25-30C while a solution of 4 g. of bromine in 50 ml. of dioxane was added dropwise over a period of about 2-3 min. After addition of bromine was completed the mixture of reaction was poured into 1500 ml. of a cold 5~
sodium chloride aqueous solution. After stirring for 1 hr., a white crystalline product was collected by filtration, washed with water and dried, 16~-methyl-2~-bromo-6~-fluoro-5~,11~, 17~,21-tetrahydroxy-pregnane-3,20~dione-21-acetate (Va) (R3 ~ ~CH3). Crystallization from acetone-hexane gave about 7 g. of white solid characterized by M.P. 137-8C (decompo-sition).
~20 + 27 (C 1.0 in dioxane) ~: ~ max (methanol) 288 m~ (s 112) IR(KBr) 3640, 3560, 3470 (broad), 1730 (broad), 1230 (broad) cm r - ~
11)64476 Analysis: Calcd. for C24H34srFO7 (percent) C 54,04; H 6,42 Br 14,98; F 3,56 Found (percent) C 54,23; H 6,46; Br 14,81; F 3,57.
Using the general procedure of Example 4~ the 16~-. methyl-6~-fluoro-5c~,llcl,17cc-21-tetrahydroxy-pregnane-3,2a- dione-21-acetate (IVb) R3 = ~CH3) was converted into 16~-methyl-2~-bromo-6~-fluoro-5~ ,17a,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (Vb) R3 = ~CH3) ~ ~20 + 68 (C 1 0 in dioxane) max (methanol) 292 m~ (~ 123) IR(KBr) 3640, 3460, 3420, 1745, 1735 (broad~, 1230 cm 1 Analysis: Calcd. for C24H34BrFO7 (percent) C 54,04; H 6,42;
Br 14,98; F 3,56 Found (percent) C 54,24; H 6,48; Br 14,75; F 3,48.
EXAMPLE 46 ;
A solution of 10 g. of 16~-CH3-2~-bromo-b~-fluoro-5~ ,17~,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (Va) (R3 = ~CH3) in 50 ml. of pyridine was stirred at -5C while dropwise adding 8 g. of methane sulfonyl chloride over a period of about 15 min. After addition was completed the mixture was stirred for 1.5 hr. maintaining the temperature at about 0C, then poured into 400 ml. of cold water and 200 ml.
of dichloroethane. The mixture was acidified at pH 3.5 with 4N sulphuric acid solution and stirred for 1 hr. The di-- chloroethane layer was separated, the aqueous portion extract-ed once with 200 ml. of dichloroethane and the combinated organic extracts washed neutral with water, dried and concen-.~
trated to dryness under vacuum at 60C. The yellow oily residue by crystallization from benzene-hexane gave 16~-methyl-2a-bromo-6~-fluoro-5~ ,17~,21-tetrahydroxy-pregnane-:: :
.
3,20-dione-11-mesylate-21-acetate (VIa) (R3 = ~CH3) ~20 + 30 (C 1.0 in dioxane) max (methanol) 288 m~ ( 110) IR(KBr) 3520 (broad), 1730 (broad), 1330, 1230, 1170 cm 1 Analysis: Calcd. for C25H36BrFOgS (percent) C 49,10; H 5,93;
Br 13,07; F 3,11 Found (percent) C 48,85; H 5,81; Br 13,23; F 3,20.
Using the general procedure of Example 46 the 16~-methyl-2~-bromo-6~-fluoro-5~ l7~l2l-tetrahydroxy-pregnane-3,20-dione-21-acetate (Vb) (R3 = ~CH3) was converted ~nto 16~-methyl-2~-bromo-6~-fluoro-5~ ,17~,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-21-acetate (VIb) (R3 = ~CH3). M.P.
148-50C (decomposition).
~D + 60 (C 1.0 in dioxane) ~ max (methanol) 292 m~ (~ 99) IR(KBr) 3660, 3520 (broad), 3370 (broad), 1740, 1725, 1330, 1230, 1170 cm 1.
Analysis: Calcd. for C25H36BrFOgS (percent) C 49,10; H 5,93;
Br 13,07; F 3,11 Found (percent) C 49,23i H 5,89, Br 13,25; F 2,98.
10 g. of 16~-methyl-2~-bromo-6~-fluoro-5~ ,17~, 21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-21-acetate (VIa) (R3 = ~CH3) were added to a solution of 75 ml. of acetic anhydride and 0.5 ml. of 70% perchloric acid in 450 ml. of ethyl acetate. The mixture was kept at 30C for 0.5 hr. and washed successively with 5% sodium bicarbonate aqueous solution. The ethyl acetate solution after anhydrification on sodium sulphate was evaporated to dryness under vacuum.
. .
` Crystallization of the residue from methanol gave about 9 g.
. -. .
. .
- . : .
of 16~-methyl-2a-bromo-6~-fluoro-5~ ,17~,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-5,17,21-triacetate (VIIIa) (R3 = ~CH3) characterized by M.P. 136-8C (decomposition).
~ ~20 _3 (C 1.0 in chloroform) -~ IR(KBr) 1745 (broad), 1365, 1220 (broad), 1170 cm 1... . .
Analysis: Calcd. for C29H40BrFOllS (percent) C 50,07; H 5,80;
~-~ Br 11,49; F 2,73.
....
Found (percent) C 50,25; H S,92; Br 11,35; F 2,66. -~; 10 Using the general procedure of Example 48 the 16~-methyl-2~-bromo-6~-fluoro-5~ ,17a,~1-tetrahydroxy-pregnane- -~
.,; ~ . :, 3,20-dione-11-mesylate-21-acetate (VIb) (R3 = ~CH3) was converted into 16~-methyl-2~-bromo-6~-fluoro-5~ ,17~,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-5,17,21-tri-.~ . .
acetate (VIIIb) (R3 ~ ~CH3) characterized by M.P. 131-2C
' (decomposition).
~20 ~ 27 (C 1.0 in chloroform) ' IR(KBr) 1750 (broad), 1370, 1220 (broad), 1170 cm 1.
, . I ::
Analysis: Calcd. for C29H40BrFOllS (percent) C 50,07; H 5,80;
Br 11,49; F 2,73 ;
;~ Found (percent~ C 50,15; H 5,72; Br 11,55; F 2,82.
-- .
,~- 6.9 g. of 16~-methyl-2~-bromo-6~-fluoro-5a,11~,17, 21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-5,17,21-tri-acetate (VIIa) (R3 = ~CH3) were dissolved in 320 ml. of anhydrous acetic acid at 90C on the steam bath. A solution of sodium acetate (15 g. dried at 100C) in acetic acid (60 ml.) at 90C was added, followed immediately by 1.80 g. of bromine in acetic acid (25 ml.), added in one lot. Heating at 90C was continued until the bromine colour disappeared (about 5 min. in all). The solution was then cooled as rapidly as , ,. : :
.',~ - .
possible to room temperature and poured in cold water. The solid was collected by filtration, washed thoroughly with water and dried to a constant weight, giving about 7 g. of 16~-methyl-2,2-dibromo-6~-fluoro-11~,17~,21-trihydroxy-pregn-4-ene-3,20-dione-11-mesylate-17,21-diacetate (VIIa bis) (R3 = ~CH3). M.P. 135-7C (decomposition).
~20 -20 (C 1.0 in chloroform) max (methanol) 242-3 m~ (~ 10700) IR(KBr) 1745, 1730, 1698, 1620, 1330, 1220, 1170 cm 1.
- 10 Analysis: Calcd. for C27H35Br2FOgS (percent) C 45,39; H 4,94;
- Br 22,37; F 2,66 Found (percent) C 45,62; H 5,05; Br 22,23; F 2,55.
;~ Using the general procedure of Example 50 the 16~-methyl-2~-bromo-6~-fluoro-lla,17~,21-trihydroxy-pregnane-3,20-dione-ll-mesylate-5,17,21-triacetate (VIIb) (R3 = ~CH3) was . ,: .
converted into 16~-methyl-2,2-dibromo-6~-fluoro-11~,17~,21-,: :
trihydroxy-pregn-4-ene-3,20-dione-11-mesylate-17,21-diacetate (VIIb bis) (R3 = ~CH3). M.P. 141-2C (decomposition).
` 20 ~/,20 + 12 (C 1.0 in chloroform) max (methanol) 243 m~ (~ 10600) IR(KBr) 1745, 1730, 1696, 1625, 1330, 1220, 1170 cm 1.
., .
Analysis: Calcd. for C27H35Br2FOgS (percent) C 45,39, H 4,94;
Br 22,37; F 2,66 Found (percent~ C 45,51; H 4,88; Br 22,48; F 2,52. -~ -; 6 g. of 16~-methyl-2,2-dibromo-6~-fluoro~ ,17~,21-trihydroxy-pregn-4-ene-3,20-dione-11-mesylate-17,21-diacetate (VIIa bis) (R3 = ~CH3) were added in one portion to a mixture of 60 ml. of dimethylformamide, 12 g. of lithium carbonate and 6 g. of lithium bromide under stirring at 100C. The reaction .. . .
~.
' - . .: :. .: . . . . .
~064476 . . .
mixture was then refluxed at 130C under nitrogen for 0.5 hr., cooled and poured into cold water. The precipitate was filtered off, washed with water and dried. Crystallization of the residue from acetone-hexane gave 3.5 g. of 16a-methyl-2-bromo-6~-fluoro-17~,21-dihydroxy-pregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate (VIIIa) (R3 = 16~CH3) characterized by ~20 -84 (C 1.0 in chloroform) ~ max (methanol) 246-7 m~ ( 12900) IR(KBr) 1745, 1730, 1680, 1605, 1230 cm 1.
Analysis: Calcd. for C26H30BrFO6 (percent) C 58,11; H 5,63;
Br 14,87; F 3,53 Found (percent) C 58,07; H 5,69; Br 14,79; F 3,47.
Using the general procedure of Example 52 the 16~-methyl-2,2-dibromo-6~-fluoro-11~,17~,21-trihydroxy-pregn-4-ene-3,20-dione-11-mesylate-17,21-diacetate (VIIb bis) " . :
`- (R3 = ~CH3) was converted into 16~-methyl-2-bromo-6~-fluoro-17~,21-dihydroxy-pregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate (VIIIb) (R3 = ~CH3) characterized by ~ ~D0 -66 (C 1.0 in chloroform) max (methanol) 246 m~ (~ 12430) ;: ~
IR(KBr) 1760, 1740 (broad), 1670, 1600, 1235 cm 1.
NMR (CDC13-TMS) Hz at 60 mHz 454 (S, 1, C-l H) 376, 372 (d, 1, ; C-4 H) 342, 288 (doublet of triplets, 1, C-6 H) 340-330 (m, 1, C-ll H) 298, 282, 266, 250 (doublet of doublets, 2, CH2OAc) . 130 (S, 3, OAc) 126 (S, 3, OAc) 96, 94 (d, 3, 19 CH3 split by ~ 6~F) 85, 78 (d, 3, C-16 ~CH3) 46 (S, 3, 18 CH3) - Analysis: Calcd. for C26H30BrFO6 (percent) C 58,11; H 5,63;
~: Br 14,87; F 3,53 '~ 30 Found (percent) C 58,20; H 5,71; Br 14,92; F 3,47.
~:
, .- , :
/
, .
~064476 EXAMPL~ 54
8.5 g. of 1,3-dibromo-5,5-dimethyl-hydantoin were added in the dark at 15C under stirring over a period of 0.5 hr. to a suspension of 11 g. of 16a-methyl-2-bromo-6~-fluoro-17~,21-dihydroxy-pregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate (VIIIa) (R3 = ~CH3) in 250 ml. of tetrahydrofurane and 1.1 g. of 70% perchloric acid in 11 ml. of water. During the addition the suspension began to thin and after a total reaction time of 45 min. all the starting material was dis-solved. After an additional 2 hrs., 10% sodium sulfite a~ue-ous solution was added under stirring until KJ-starch paper was no longer blued. The solution was slowly poured into 1000 ml. cold water, then filtered and utilized moist in the next reaction. The 16~-methyl-2,9~-dibromo-6~-fluoro-11~,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (10 a) (R3 - ~CH3) was filtered and utilized moist in the next reaction. Analytically pure (10 a) was obtained by crystalli-zation from acetone-hexane. M.P. 205-7C (decomposition).
IR(KBr) 3470, 1760, 1730, 1670, 1640, 1610, 1230 cm 1 Analysis: Calcd. for C26H31Br2FO7 (percent) C 49,23; H 4,93;
Br 25,19; F 2,99 Found (percent) C 49,31; H 5,05; Br 25,35; F 3,10. -Using the general procedure of Example 54 the 16~-methyl-2-bromo-6~-fluoro-17~,21-dihydroxy-pregna-1,4,9(11)-(:
triene-3,20-dione-17,21-diacetate (VIIIb) (R3 = ~CH3) was converted into 16~-methyl-2,9~-dibromo-6~-fluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (10 b) (R3 = ~CH3) characterized by M.P. 207-9C (decomposition).
IR(KBr) 3500 (broad), 1740, 1725, 1675, 1645, 1600, 1235 cm 1.
Analysis: Calcd. for C26H31Br2FO7 (percent) C 49,23; H 4,93;
::
~, Br 25,19; F 2,99 Found (percent) C 49,37; H S,10; Br 24,95; F 2,91.
However, the product (10 b) was filtered and util-ized moist in the next reaction.
50 ml. of a 14% potassium carbonate aqueous solution were added over a period of 20 min. at 20C under stirring to the solution of the moist product (10 a) (R3 = ~CH3) 16~-methyl-2,9~-dibromo-6~-fluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate obtained in Example 54 from 11 g. of the product (VIIIa) (R3 = ~CH3) in 220 ml. of acetone. The solution was stirred for 3.5 hrs. Ice water was added under stirring, upon which crystallization occurs rapidly. The product 16~-methyl-2-bromo-6~-fluoro-17~,21-dihydroxy-9~ -oxido-pregna-1,4-diene-3,20-dione-17,21-diacetate (11 a) (R3 = ~CH3) was filtered, washed with water, dried and characterized by M.P. 232-4C (decomposition).
` ~ ~20 -96 (C 1.0 in chloroform) IR(KBr) 1755, 1735, 1675, 1645, 1610, 1235 cm 1.
Analysis: Calcd. for C26H30BrF07 (percent) C 56,43; H 5,46;
Br 14,44; F 3,43 Found (percent) C 56,61; H 5,32; Br 14,27; F 3,52.
~ Using the general procedure of Example 56 the 16~-s``i methyl-2~9~-dibromo-6~-fluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (10 b) (R3 = ~CH3) was ;~l converted into 16~-methyl-2-bromo-6~-fluoro-17~,21-dihydroxy-
IR(KBr) 3470, 1760, 1730, 1670, 1640, 1610, 1230 cm 1 Analysis: Calcd. for C26H31Br2FO7 (percent) C 49,23; H 4,93;
Br 25,19; F 2,99 Found (percent) C 49,31; H 5,05; Br 25,35; F 3,10. -Using the general procedure of Example 54 the 16~-methyl-2-bromo-6~-fluoro-17~,21-dihydroxy-pregna-1,4,9(11)-(:
triene-3,20-dione-17,21-diacetate (VIIIb) (R3 = ~CH3) was converted into 16~-methyl-2,9~-dibromo-6~-fluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (10 b) (R3 = ~CH3) characterized by M.P. 207-9C (decomposition).
IR(KBr) 3500 (broad), 1740, 1725, 1675, 1645, 1600, 1235 cm 1.
Analysis: Calcd. for C26H31Br2FO7 (percent) C 49,23; H 4,93;
::
~, Br 25,19; F 2,99 Found (percent) C 49,37; H S,10; Br 24,95; F 2,91.
However, the product (10 b) was filtered and util-ized moist in the next reaction.
50 ml. of a 14% potassium carbonate aqueous solution were added over a period of 20 min. at 20C under stirring to the solution of the moist product (10 a) (R3 = ~CH3) 16~-methyl-2,9~-dibromo-6~-fluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate obtained in Example 54 from 11 g. of the product (VIIIa) (R3 = ~CH3) in 220 ml. of acetone. The solution was stirred for 3.5 hrs. Ice water was added under stirring, upon which crystallization occurs rapidly. The product 16~-methyl-2-bromo-6~-fluoro-17~,21-dihydroxy-9~ -oxido-pregna-1,4-diene-3,20-dione-17,21-diacetate (11 a) (R3 = ~CH3) was filtered, washed with water, dried and characterized by M.P. 232-4C (decomposition).
` ~ ~20 -96 (C 1.0 in chloroform) IR(KBr) 1755, 1735, 1675, 1645, 1610, 1235 cm 1.
Analysis: Calcd. for C26H30BrF07 (percent) C 56,43; H 5,46;
Br 14,44; F 3,43 Found (percent) C 56,61; H 5,32; Br 14,27; F 3,52.
~ Using the general procedure of Example 56 the 16~-s``i methyl-2~9~-dibromo-6~-fluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (10 b) (R3 = ~CH3) was ;~l converted into 16~-methyl-2-bromo-6~-fluoro-17~,21-dihydroxy-
9~ -oxido-pregna-1,4-diene-3,20-dione-17,21-diacetate (11 b) (R3 = ~CH3) characterized by M.P. 234-5C (decompo-sition).
~ -53 (C 1.0 in chloroform) -- .
: ' ' , ' IR(KBr) 1755, 1730, 1675, 1645, 1610, 1240 cm Analysis: Calcd. for C26H30BrFO7 (percent) C 56,43; H 5,46;
Br 14,44; F 3,43 Found (percent) C 5629; ~ 5,32; sr 14,57; H 3,37.
50 ml. of a 70% hydrofluoric acid aqueous solution were cooled to -10C in a polyethylene flask equipped with electromagnetic stirrer. 3.7 g. of 16~-methyl-2-bromo-6~-fluoro-17~,21-dihydroxy-9~ -oxido-pregna-1,4-diene-3,20-
~ -53 (C 1.0 in chloroform) -- .
: ' ' , ' IR(KBr) 1755, 1730, 1675, 1645, 1610, 1240 cm Analysis: Calcd. for C26H30BrFO7 (percent) C 56,43; H 5,46;
Br 14,44; F 3,43 Found (percent) C 5629; ~ 5,32; sr 14,57; H 3,37.
50 ml. of a 70% hydrofluoric acid aqueous solution were cooled to -10C in a polyethylene flask equipped with electromagnetic stirrer. 3.7 g. of 16~-methyl-2-bromo-6~-fluoro-17~,21-dihydroxy-9~ -oxido-pregna-1,4-diene-3,20-
10 dione-17,21-diacetate (11 a) (R3 = ~CH3) were added under stirring during 15 min. After 1.5 hr. the reaction mixture was precipitated in water and ammonia. The solid was col-lected by filtration, washed with water and dried to a constant weight, giving about 3.5 g. of 16a-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (12 a) (X = OH, Y = F, Rl = R2 = OCOCH3, ~; R3 = CH3). Crystallization from benzene-n-hexane gave 3 g. -of pure product characterized by M.P. 288-9C (decomposition).
~ ~20 _47 (C 1.0 in chloroform) 20 ~ max (methanol) 246 m~ ( 12100) IR(KBr) 3500, 1760, 1730, 1710, 1680, 1640, 1610, 1230 cm 1.
Analysis: Calcd. for C26H31BrF2O7 (percent) C 54,46; H 5,45;
Br 13,93; F 6,63 Found (percent) C 54,58; H 5,37; Br 13,80; F 6,75.
Using the general procedure of Example 58 the 16~-; methyl-2-bromo-6~-fluoro-17~,21-dihydroxy 9~ ~oxido-pregna-1,4-diene-3,20-dione-17,21-diacetate (11 b) (R3 = ~CH3) was converted into 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-30 trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (12 b) (X - OH, Y = F, Rl = R2 = OCOCH3, R3 = ~CH3), characterized by ,, ' ~ ,: : ' . ',' :
~L064476 0 -13 (C 1.0 in chloroform) ~ max (methanol) 246 m~ (~ 12000) IR(KBr) 3480, 1755, 1740, 1725, 1678, 1645, 1600, 1235 cm 1.
Analysis: Calcd. for C26H31BrF2O7 (percent) C 54,46; H 5,45;
Br 13,93; F 6,63 Found (percent) C 54,65; H 5,38; Br 14,10; F 6,75.
50 ml. of hydrochloric acid were added at 0C over a period of 40 min. to a solution of 5 g. of 16a-methyl-2-bromo-6~-fluoro-17~,21-dihydroxy-9~ -oxido-pregna-1,4-diene-3,20-dione-17,21-diacetate (11 a) (R3 = aCH3) in 30 ml. of acetone.
The mixture was held at 0C with stirring for about 2.5 hrs.
and then the precipitate of 16a-methyl-2-bromo-6~-fluoro-9a-chloro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (12 c) (X = OH, Y = Cl, R3 = ~CH3, Rl = R2 = OCOCH3) was recovered by filtration, washed repeatedly with water and dried (4.9 g.). The solid was crystallized from acetone-hexane and characterized by M.~. 245-6C (decomposition).
max (methanol) 246 m~ (~ 12000) ~ ~20 _34 (C 1.0 in chloroform) IR(KBr) 3460, 1757, 1730, 1710, 1678, 1645, 1608, 1230 cm ~- Analysis: Calcd. for C26H31BrClFO7 (percent) C 52,94; H 5,30;
Br 13,54; Cl 6,01; F 3,22 Found (percent) C 53,12; H 5,37; Br 13,71; Cl 6,12;
F 3,14.
Using the general procedure of Example 60 the 16~
methyl-2-bromo-6~-fluoro-17a,21-dihydroxy-9~ oxido-1,4-diene-3,20-dione-17,21-diacetate (11 b) (R3 = ~CH3) was converted into 16~-methyl-2-bromo-6~-fluoro-9a-chloro-11~,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate . .
(12 d) (X = OH, Y = Cl, R1 = R2 = OCOCH3, R3 = ~CH3) charac-terized by M.P. 250-1C (decomposition).
max (methanol) 246 m~ (E 12150) ~20 + 2 (C 1.0 in chloroform) IR(KBr) 3480, 1740 (broad), 1723, 1675, 1645, 1600, 1235 cm 1.
Analysis: Calcd. for C26H31BrClFO7 (percent) C 52,94; H 5,30;
Br 13,54; Cl 6,01; F 3,22 Found (percent) C 52,73; H 5,32; Br 13,60; C1 6,15;
F 3,31.
To a solution of 10 g. of 16a-methyl-2-bromo-6~-fluoro-17a,21-dihydroxy-pregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate (IXa) (R3 = aCH3) and 40 g. lithium chloride in 200 ml. of glacial acetic acid were added at 20C under stirring 5 g. of N-chlorosuccinimide. The mixture was kept at 20C and stirred while dropwise adding 10 ml. of a 12% hydro-chloric acid tetrahydrofurane solution over a period of about 10 min. After 3.5 hrs. the reaction mixture was poured into cold water, the solid was collected by filtration, washed with water and dried, giving 7.5 g. of pure product 16a-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (12 e) (X = Y = Cl, Rl ~ R2 = OCOCH3, R3 = aCH3) characterized by M.P. 253-5C
(decomposition).
; ~ ~D -10 (C 1.0 in chloroform) - ~ max (methanol) 245 m~ (~ 12350) IR(KBr) 1745, 1730, 1670, 1645, 1605, 1235 cm 1.
NMR (dimethyl-d6 sulfoxide-TMS) Hz at 60 mHz 464 (S, 1, C-l H) ; 393, 398 (d, 1, C-4 H) 346, 296 (doublet of triplets, 1, C-6 H) 318-304 (m, 1, C-ll H) 309, 293, 288, 272 (doublet of doublets, 2, CH2OAc) 125 (S, 1, OAc) 123 (S, 1, OAc) 108, 104 .
- . ,'~ ' , ' .
.
.
(d, 3, 19 CH3 split by 6~F) 65 (S, 3, 18 CH3) 58, 51 (d, 3, 16~CH3) Analysis: Calcd. for C26H30BrC12FO6 (percent) C 51,33;
H 4,97; Br 13,14; Cl 11,66; F 3,12 - Found (percent) C 51,45; H 5,07; Br 13,04;
Cl 11,81; F 3,19.
Using the general procedure of Example 62 the 16~-methyl-2-bromo-6~-fluoro-17~,21-dihydroxy-pregna-1,4,9(11)- ~-10 triene-3,20-dione-17,21-diacetate (IXb) 9R3 = ~CH3) was converted into 16~-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17~,21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate - (12 f) (Rl = R2 = OCOCH3, R3 = ~CH3, X = Y = Cl) characterized j~ by M.P. 224-6C (decomposition).
~20 + 21 (C 1.0 in chloroform) IR(KBr) 1750, 1730, 1675, 1605, 1230 cm NMR (dimethyl-d6 sulfoxide-TMS) Hz at 60 mHz 465 (S, 1, C-l H) 394, 390 (d, 1, C-4 H) 348, 298 (doublet of triplets, 1, C-6 H) 320-305 (m, 1, C~ll H) 295, 279, 270, 254 (doublet of 20 doublets, 2, CH2OAc) 126 (S, 6, 2xOAc) 109, 105 (d, 3, 19 CH3 ~-~ split by 6~F) 78, 72 (d, 3, 16~CH3) 58 (S, 3, 18 CH3) Analysis: Calcd. for C26H30BrC12FO6 (percent) C 51,33;
H 4,97; Br 13,14; C1 11,66; F 3,12 Found (percent) C 51,55; H 4,82; Br 12,98;
Cl 11,65; F 3,12.
; EXAMPLE 64 . ~
A suspension of 5.2 g. of 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-: ~
17,21-diacetate (12 a) (X = OH, Y = F, R3 = ~CH3, Rl = R2 =
30 OCOCH3) in 120 ml. of 1% potassium hydroxide methanolic so-lution was stirred under nitrogen at 0C for 3 hrs. Addition , , 1~64476 of cold water, elimination of methanol in vae~o, acidification with acetic acid and filtration gave 4 g. of 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) (X = OH, Y ~ F, Rl = R2 = OH, R3 ~CH3).
~ ~ ~20 -24 (C 1.0 in chloroform) - ~ max (methanol) 245-6 m~ (s 12250) IR(KBr) 3460 (broad), 1710, 1665, 1640, 1603 cm 1.
NMR (dimethyl-d6 sulfoxide-TMS) Hz at 60 mHz 466 (S, 1, C-l H) 388, 384 (d, 1, C-4 H) 345, 295 (doublet of triplets, 1, C-6 H) 318-314 (d, 1, C-ll OH) 296 (S, 1, C-17 OH) 280-225 (multiplet which becomes a quartet by deuterium exchange, 2, COCH2OH) 96, 94 (d, 3, 19 CH3 split by 6~F) 54 (S, 3, 18 CH3) ~ ;
54, 44 (d, 3, C-16~CH3) Analysis: Calcd. for C22H27BrF2O5 (percent) C 53,99; H 5,56;
Br 16,33; F 7,76 Found (percent) C 54,10; H 5,70; Br 16,41; F 7,85.
Using the general procedure of Example 64 the 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-20 1,4-diene-3,20-dione-17,21-diacetate (12 b) (X = OH, Y = F, Rl = R2 = OCOCH3, R3 = ~CH3) was converted into 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 h) ~X = OH, Y = F, Rl = R2 = OH, R3 = ~CH3) M.P. 216-7C (decomposition).
~D + 11 (C 1.0 in chloroform) ~ max (methanol) 246 m~ (~ 10900) - IR(KBr) 3440 (broad), 1715, 1665, 1640, 1600 cm NMR (dimethyl-d6 sulfoxide-TMS) Hz at 60 mHz 472 (S, 1, C-l H) 388, 384 (d, 1, C-4 H) 346, 296 (doublet of triplets, 1, ~ -30 C-6 H) 339-334 (m, 1, C-ll OH) 315 (S, 1, C-17 OH) 280-240 (multiplet which becomes a quartet by deuterium exchange, 2, .: , .: :
- : , .
, ,:
:
COCH2OH) 96,94 (d, 3, 19 CH3 split by 6~F) 65, 58 (d, 3, C-16~CH3) 58 (S, 3, 18 CH3) Analysis: Calcd. for c22H27srF2o5 (percent) C 53,99; H 5,56;
Br 16,33; F 7.76 Found (percent) C 53,75; H 5,45; Br 16,41; F 7,87.
Using the general procedure of Example 64 the 16~-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17~,21-dihydroxy-`~ pregna-1,4-diene-3,20-dione-17,21-diacetate (12 e) Rl ~ R2 =
10 OCOCH3, R3 = ~CH3, X = Y ~ Cl) was converted into 16~-methyl-2-bromo-6~-fluoro-9~ -dichloro-17~,21-dihydroxy-pregna-1,4-; diene-3,20-dione (12 i) (Rl = R2 = OH, R3 - ~CH3, x = Y = Cl).
The product was crystallized from acetone-hexane. M.P.
216-8C.
~D ~ 21 (C 1.0 in chloroform) IR(RBr) 3640, 3500, 3400, 1705, 1665, 1642, 1605 cm 1.
Analysis: Calcd. for C22H26BrC12FO4 (percent) C 50,40;
H 4,99; Br 15,24; Cl 13,52; F 3,62 Found (percent) C 50,63; H 5,12; Br 15,34;
- 20 Cl 13,68; F 3,61.
Using the general procedure of Example 66 the 16~-methyl-2-bromo-6~-fluoro-9~ -dichloro-17~,21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (12 d) (Rl = R2 =
OCOCH3, R3 = ~CH3, X = Y = Cl) was converted into 16~-methyl-2-bromo-6~-fluoro-9~ -dichloro-17~,21-dihydroxy-pregna-1,4-diene-3,20-dione (12 j) (Rl = R2 = OH, R3 ~ ~CH3, X - Y = Cl).
~ ~ 51 (C 1.0 in chloroform) ~ max (methanol) 245-6 m~ (~ 11500) 30 IR(KBr) 3600, 3480, 3360, 1710, 1665, 1645, 1610 cm 1.
Analysis: Calcd. for C22H26BrC12FO4 (percent) C 50,40;
j.l ; 1064476 .
H 4,99; Br 15,24; Cl 13,52; F 3,62 Found (percent) C 50,35; H 4,81; Br 15,20;
Cl 13,31; F 3,68.
7 g. of 16~-methyl-2-bromo-6~,9~-difluoro~ ,17~, 21-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) (Rl = R2 = OH, R3 = aCH3, X = OH, Y = F) were dissolved in 70 ml. of pyridine containing 35 ml. of acetic anhydride and kept at room temper- 3 ature for 12 hrs. Addition of ice water afforded a product 10 which was extracted with chloroform. The chloroform solution was washed with water, HCl 2N, 5% sodium bicarbonate solution and water. After drying (Na2SO4) and removal of the solvent in vacuo the residue was crystallized from acetone-hexane to give 6.7 g~ of 16~-methyl-2-bromo-6~,9~-difluoro~ ,17~,21-trihydroxy-pregna-1,4-diene-21-acetate (12 k) (Rl = OCOCH3, R2 = OH, X = OH, Y = F, R3 = ~CH3) M-P- 229-31C.
~20 -6 (C 1.0 in chloroform) max (methanol) 246 m~ ( 11300) IR(KBr) 3520 (broad), 1740, 1720, 1665, 1640, 1605, 1230 cm 20 Analysis: Calcd. for C24H29BrF2O6 (percent) C 54,25; H 5,50;
Br 15,04; F 7,15 Found (percent) C 54,41; H 5,60; Br 14,95; F 7, 12.
Using the general procedure of Example 68 the 16~- -methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20 dione (12 h) (Rl = R2 = OH~ R3 = ~CH3~ X = OH~
Y = F) was converted into 16~-methyl-2-bromo-6~,9~-difluoro-
~ ~20 _47 (C 1.0 in chloroform) 20 ~ max (methanol) 246 m~ ( 12100) IR(KBr) 3500, 1760, 1730, 1710, 1680, 1640, 1610, 1230 cm 1.
Analysis: Calcd. for C26H31BrF2O7 (percent) C 54,46; H 5,45;
Br 13,93; F 6,63 Found (percent) C 54,58; H 5,37; Br 13,80; F 6,75.
Using the general procedure of Example 58 the 16~-; methyl-2-bromo-6~-fluoro-17~,21-dihydroxy 9~ ~oxido-pregna-1,4-diene-3,20-dione-17,21-diacetate (11 b) (R3 = ~CH3) was converted into 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-30 trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (12 b) (X - OH, Y = F, Rl = R2 = OCOCH3, R3 = ~CH3), characterized by ,, ' ~ ,: : ' . ',' :
~L064476 0 -13 (C 1.0 in chloroform) ~ max (methanol) 246 m~ (~ 12000) IR(KBr) 3480, 1755, 1740, 1725, 1678, 1645, 1600, 1235 cm 1.
Analysis: Calcd. for C26H31BrF2O7 (percent) C 54,46; H 5,45;
Br 13,93; F 6,63 Found (percent) C 54,65; H 5,38; Br 14,10; F 6,75.
50 ml. of hydrochloric acid were added at 0C over a period of 40 min. to a solution of 5 g. of 16a-methyl-2-bromo-6~-fluoro-17~,21-dihydroxy-9~ -oxido-pregna-1,4-diene-3,20-dione-17,21-diacetate (11 a) (R3 = aCH3) in 30 ml. of acetone.
The mixture was held at 0C with stirring for about 2.5 hrs.
and then the precipitate of 16a-methyl-2-bromo-6~-fluoro-9a-chloro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (12 c) (X = OH, Y = Cl, R3 = ~CH3, Rl = R2 = OCOCH3) was recovered by filtration, washed repeatedly with water and dried (4.9 g.). The solid was crystallized from acetone-hexane and characterized by M.~. 245-6C (decomposition).
max (methanol) 246 m~ (~ 12000) ~ ~20 _34 (C 1.0 in chloroform) IR(KBr) 3460, 1757, 1730, 1710, 1678, 1645, 1608, 1230 cm ~- Analysis: Calcd. for C26H31BrClFO7 (percent) C 52,94; H 5,30;
Br 13,54; Cl 6,01; F 3,22 Found (percent) C 53,12; H 5,37; Br 13,71; Cl 6,12;
F 3,14.
Using the general procedure of Example 60 the 16~
methyl-2-bromo-6~-fluoro-17a,21-dihydroxy-9~ oxido-1,4-diene-3,20-dione-17,21-diacetate (11 b) (R3 = ~CH3) was converted into 16~-methyl-2-bromo-6~-fluoro-9a-chloro-11~,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate . .
(12 d) (X = OH, Y = Cl, R1 = R2 = OCOCH3, R3 = ~CH3) charac-terized by M.P. 250-1C (decomposition).
max (methanol) 246 m~ (E 12150) ~20 + 2 (C 1.0 in chloroform) IR(KBr) 3480, 1740 (broad), 1723, 1675, 1645, 1600, 1235 cm 1.
Analysis: Calcd. for C26H31BrClFO7 (percent) C 52,94; H 5,30;
Br 13,54; Cl 6,01; F 3,22 Found (percent) C 52,73; H 5,32; Br 13,60; C1 6,15;
F 3,31.
To a solution of 10 g. of 16a-methyl-2-bromo-6~-fluoro-17a,21-dihydroxy-pregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate (IXa) (R3 = aCH3) and 40 g. lithium chloride in 200 ml. of glacial acetic acid were added at 20C under stirring 5 g. of N-chlorosuccinimide. The mixture was kept at 20C and stirred while dropwise adding 10 ml. of a 12% hydro-chloric acid tetrahydrofurane solution over a period of about 10 min. After 3.5 hrs. the reaction mixture was poured into cold water, the solid was collected by filtration, washed with water and dried, giving 7.5 g. of pure product 16a-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (12 e) (X = Y = Cl, Rl ~ R2 = OCOCH3, R3 = aCH3) characterized by M.P. 253-5C
(decomposition).
; ~ ~D -10 (C 1.0 in chloroform) - ~ max (methanol) 245 m~ (~ 12350) IR(KBr) 1745, 1730, 1670, 1645, 1605, 1235 cm 1.
NMR (dimethyl-d6 sulfoxide-TMS) Hz at 60 mHz 464 (S, 1, C-l H) ; 393, 398 (d, 1, C-4 H) 346, 296 (doublet of triplets, 1, C-6 H) 318-304 (m, 1, C-ll H) 309, 293, 288, 272 (doublet of doublets, 2, CH2OAc) 125 (S, 1, OAc) 123 (S, 1, OAc) 108, 104 .
- . ,'~ ' , ' .
.
.
(d, 3, 19 CH3 split by 6~F) 65 (S, 3, 18 CH3) 58, 51 (d, 3, 16~CH3) Analysis: Calcd. for C26H30BrC12FO6 (percent) C 51,33;
H 4,97; Br 13,14; Cl 11,66; F 3,12 - Found (percent) C 51,45; H 5,07; Br 13,04;
Cl 11,81; F 3,19.
Using the general procedure of Example 62 the 16~-methyl-2-bromo-6~-fluoro-17~,21-dihydroxy-pregna-1,4,9(11)- ~-10 triene-3,20-dione-17,21-diacetate (IXb) 9R3 = ~CH3) was converted into 16~-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17~,21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate - (12 f) (Rl = R2 = OCOCH3, R3 = ~CH3, X = Y = Cl) characterized j~ by M.P. 224-6C (decomposition).
~20 + 21 (C 1.0 in chloroform) IR(KBr) 1750, 1730, 1675, 1605, 1230 cm NMR (dimethyl-d6 sulfoxide-TMS) Hz at 60 mHz 465 (S, 1, C-l H) 394, 390 (d, 1, C-4 H) 348, 298 (doublet of triplets, 1, C-6 H) 320-305 (m, 1, C~ll H) 295, 279, 270, 254 (doublet of 20 doublets, 2, CH2OAc) 126 (S, 6, 2xOAc) 109, 105 (d, 3, 19 CH3 ~-~ split by 6~F) 78, 72 (d, 3, 16~CH3) 58 (S, 3, 18 CH3) Analysis: Calcd. for C26H30BrC12FO6 (percent) C 51,33;
H 4,97; Br 13,14; C1 11,66; F 3,12 Found (percent) C 51,55; H 4,82; Br 12,98;
Cl 11,65; F 3,12.
; EXAMPLE 64 . ~
A suspension of 5.2 g. of 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-: ~
17,21-diacetate (12 a) (X = OH, Y = F, R3 = ~CH3, Rl = R2 =
30 OCOCH3) in 120 ml. of 1% potassium hydroxide methanolic so-lution was stirred under nitrogen at 0C for 3 hrs. Addition , , 1~64476 of cold water, elimination of methanol in vae~o, acidification with acetic acid and filtration gave 4 g. of 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) (X = OH, Y ~ F, Rl = R2 = OH, R3 ~CH3).
~ ~ ~20 -24 (C 1.0 in chloroform) - ~ max (methanol) 245-6 m~ (s 12250) IR(KBr) 3460 (broad), 1710, 1665, 1640, 1603 cm 1.
NMR (dimethyl-d6 sulfoxide-TMS) Hz at 60 mHz 466 (S, 1, C-l H) 388, 384 (d, 1, C-4 H) 345, 295 (doublet of triplets, 1, C-6 H) 318-314 (d, 1, C-ll OH) 296 (S, 1, C-17 OH) 280-225 (multiplet which becomes a quartet by deuterium exchange, 2, COCH2OH) 96, 94 (d, 3, 19 CH3 split by 6~F) 54 (S, 3, 18 CH3) ~ ;
54, 44 (d, 3, C-16~CH3) Analysis: Calcd. for C22H27BrF2O5 (percent) C 53,99; H 5,56;
Br 16,33; F 7,76 Found (percent) C 54,10; H 5,70; Br 16,41; F 7,85.
Using the general procedure of Example 64 the 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-20 1,4-diene-3,20-dione-17,21-diacetate (12 b) (X = OH, Y = F, Rl = R2 = OCOCH3, R3 = ~CH3) was converted into 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 h) ~X = OH, Y = F, Rl = R2 = OH, R3 = ~CH3) M.P. 216-7C (decomposition).
~D + 11 (C 1.0 in chloroform) ~ max (methanol) 246 m~ (~ 10900) - IR(KBr) 3440 (broad), 1715, 1665, 1640, 1600 cm NMR (dimethyl-d6 sulfoxide-TMS) Hz at 60 mHz 472 (S, 1, C-l H) 388, 384 (d, 1, C-4 H) 346, 296 (doublet of triplets, 1, ~ -30 C-6 H) 339-334 (m, 1, C-ll OH) 315 (S, 1, C-17 OH) 280-240 (multiplet which becomes a quartet by deuterium exchange, 2, .: , .: :
- : , .
, ,:
:
COCH2OH) 96,94 (d, 3, 19 CH3 split by 6~F) 65, 58 (d, 3, C-16~CH3) 58 (S, 3, 18 CH3) Analysis: Calcd. for c22H27srF2o5 (percent) C 53,99; H 5,56;
Br 16,33; F 7.76 Found (percent) C 53,75; H 5,45; Br 16,41; F 7,87.
Using the general procedure of Example 64 the 16~-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17~,21-dihydroxy-`~ pregna-1,4-diene-3,20-dione-17,21-diacetate (12 e) Rl ~ R2 =
10 OCOCH3, R3 = ~CH3, X = Y ~ Cl) was converted into 16~-methyl-2-bromo-6~-fluoro-9~ -dichloro-17~,21-dihydroxy-pregna-1,4-; diene-3,20-dione (12 i) (Rl = R2 = OH, R3 - ~CH3, x = Y = Cl).
The product was crystallized from acetone-hexane. M.P.
216-8C.
~D ~ 21 (C 1.0 in chloroform) IR(RBr) 3640, 3500, 3400, 1705, 1665, 1642, 1605 cm 1.
Analysis: Calcd. for C22H26BrC12FO4 (percent) C 50,40;
H 4,99; Br 15,24; Cl 13,52; F 3,62 Found (percent) C 50,63; H 5,12; Br 15,34;
- 20 Cl 13,68; F 3,61.
Using the general procedure of Example 66 the 16~-methyl-2-bromo-6~-fluoro-9~ -dichloro-17~,21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (12 d) (Rl = R2 =
OCOCH3, R3 = ~CH3, X = Y = Cl) was converted into 16~-methyl-2-bromo-6~-fluoro-9~ -dichloro-17~,21-dihydroxy-pregna-1,4-diene-3,20-dione (12 j) (Rl = R2 = OH, R3 ~ ~CH3, X - Y = Cl).
~ ~ 51 (C 1.0 in chloroform) ~ max (methanol) 245-6 m~ (~ 11500) 30 IR(KBr) 3600, 3480, 3360, 1710, 1665, 1645, 1610 cm 1.
Analysis: Calcd. for C22H26BrC12FO4 (percent) C 50,40;
j.l ; 1064476 .
H 4,99; Br 15,24; Cl 13,52; F 3,62 Found (percent) C 50,35; H 4,81; Br 15,20;
Cl 13,31; F 3,68.
7 g. of 16~-methyl-2-bromo-6~,9~-difluoro~ ,17~, 21-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) (Rl = R2 = OH, R3 = aCH3, X = OH, Y = F) were dissolved in 70 ml. of pyridine containing 35 ml. of acetic anhydride and kept at room temper- 3 ature for 12 hrs. Addition of ice water afforded a product 10 which was extracted with chloroform. The chloroform solution was washed with water, HCl 2N, 5% sodium bicarbonate solution and water. After drying (Na2SO4) and removal of the solvent in vacuo the residue was crystallized from acetone-hexane to give 6.7 g~ of 16~-methyl-2-bromo-6~,9~-difluoro~ ,17~,21-trihydroxy-pregna-1,4-diene-21-acetate (12 k) (Rl = OCOCH3, R2 = OH, X = OH, Y = F, R3 = ~CH3) M-P- 229-31C.
~20 -6 (C 1.0 in chloroform) max (methanol) 246 m~ ( 11300) IR(KBr) 3520 (broad), 1740, 1720, 1665, 1640, 1605, 1230 cm 20 Analysis: Calcd. for C24H29BrF2O6 (percent) C 54,25; H 5,50;
Br 15,04; F 7,15 Found (percent) C 54,41; H 5,60; Br 14,95; F 7, 12.
Using the general procedure of Example 68 the 16~- -methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20 dione (12 h) (Rl = R2 = OH~ R3 = ~CH3~ X = OH~
Y = F) was converted into 16~-methyl-2-bromo-6~,9~-difluoro-
- 11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-acetate (12 1) (Rl = OCOCH3, R3 = OH, X = OH, Y = F, R3 = ~CH3) M.P.
30 2l6-8oc.
~D ~ 25 (C 1.0 in chloroform) ..
. . . . . . . . . .
10644'76 ~ max (methanol) 245-6 m~ (E 11500) IR(KBr) 3500 (broad), 1745, 1720, 1675, 1645, 1610, 1230 cm .
Analysis: Calcd. for C24H29BrF2O6 (percent) C 54,25; H 5,50;
Br 15,04; F 7,15 Found (percent) C 54,45; H 5,38; Br 15,11; F 7,08.
Using the general procedure of Example 68 the 16a- -- methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) (Rl = R2 = OH~ R3 = aCH3, X = OH~
Y = F) was converted into 16a-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dlone-21-propio-nate (12 m) (Rl = OCOCH2CH3, R2 = OH, R3 = aCH3, X = OH, - Y = F) by reaction with propionic anhydride.
~20 + 4 (C 1.0 in chloroform) max (methanol) 246 m~ (E 10800) ~ IR(KBr) 3520 (broad), 1740, 1728, 1672, 1645, 1605, 1225 cm 1.
; Analysis: Calcd. for C25H31BrF2O6 (percent) C 55,05; H 5,73;
Br 14,65; F 6,97 Found (percent) C 55,25; H 5,62; Br 14,55; F 7,07.
Using the general procedure of Example 68 the 16~-~, methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-- 1,4-diene-3,20-dione (12 h) (Rl = R2 ~ OH, R3 = ~CH3, X = OH, Y = F) was converted into 16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-propio-nate (12 n) (Rl = OCOCH2CH3, R2 = OH, R3 = ~CH3, X - OH, Y = F) by reaction with propionic anhydride.
~20 ~ 27 (C 1.0 in chloroform) max (methanol) 246 m~ (E 11000) IR(KBr) 3500 (broad), 1745, 1730, 1670, 1645, 1605, 1220 cm , .
Analysis: Calcd. for C25H31BrF2O6 (percent) C 55,05; H 5,73;
:
.,- ''~
Br 14,65; F 6,97 Found (percent) C 55,10; H 5,72; Br 14,85 F 7,08.
Using the general procedure of Example 68 the 16~-methyl-2-bromo-6~-fluoro-9~ dichloro-17~,21-dihydroxy-pregna-1,4-diene-3,20-dione (12 i) (Rl = R2 = OH, R3 = ~CH3, X - Y = Cl) was converted into 16~-methyl-2-bromo-6~-fluoro-; 9~ -dichloro-17~,21-dihydroxy-pregna-1,4-diene-3,20-dione-21-acetate (12 o) (Rl = OCOCH3, R2 = OH, R3 = ~CH3, X = Y =
Cl). The product was crystallized from methanol. The crystals showed at 158C a transaction from the low melting form II to the form I melting 237-8C (decomp.).
C~DO + 32 (C 1.0 in chloroform) max (methanol) 246 m~ ( 11550) IR(KBr) 3550, 3460, 3340, 1755, 1730, 1673, 1635, 1605, 1230 cm-l Analysis: Calcd. for C24H28BrC12FO5 (percent) C 50,90;
H 4,98; Br 14,11; Cl 12,52; F 3,35 Found (percent) C 51,12; H 5,05; Br 13,98;
Cl 12,40; F 3,28.
~ - :
Using the general procedure of Example 68 the 16~-- methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17~,21-dihydroxy-pregna-1,4-diene-3,20-dione (12 j) (Rl = R2 = OH, R3 = ~CH3, X = Y = Cl) was converted into 16~-methyl-2-bromo-6~-fluoro-9~ -dichloro-17~,21-dihydroxy-pregna-1,4-diene-3,20-dione-21-acetate (12 p) (Rl = OCOCH3, R2 = OH, R3 = ~CH3, X = Y = -Cl).
~D ~ 61 (C 1.0 in chloroform) 30 ~ max (methanol) 245-6 m~ (~ 11000) IR(KBR) 3500 (broad), 1750, 1730, 1675, 1645, 1605, 1230 cm ~ . .
.: . ' :.' . : : , :
106447~;
Analysis: Calcd. for C24H28BrC12FO5 (percent) C 50,90;
H 4,98; Br 14,11; C1 12,52; F 3,35 Found (percent) C 51,12; H 4,88; Br 13,95;
Cl 12,41; F 3,28.
EXAMPLE 74 ~-A mixture of 5 g. of 16~-methyl-2-bromo-6~,9~- -difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione g) (Rl R2 OH, R3 = ~CH3, X = OH, Y = F) 5 ml of dimethylformamide was maintained for 4 hrs. under nitrogen at 115C. Then the mixture was neutralized by pyridine and concentrated under vacuum to dryness. Purification by column chromatography on F~ORISIL (Registered Trade Mark) (ratio 1:150) with benzene-chloroform (1:1) as eluant, gave 4 g. of 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-(1'-methoxy)-n-pentylidene-dioxy which, without further purification, was suspended in 25 ml. of methanol and 3 ml. lN hydrochloric acid aqueous solution, heated on water bath at 40-50C. After complete solubilization of the product, the mixture was concentrated under vacuum. The insoluble product was filtered off, washed with water and then dried. The 16~-methyl-2-bromo-6~,9~-:, 1, .
difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate (12 q) (Z = H, Rl = OH, R2 = OCOCH2)3CH3, R3 = H, X = OH, Y = F) thus obtained was characterized by ~20 -92 (C 1.0 in chloroform) max (methanol) 246 m~ (E 12300) IR(KBr) 3500 (broad), 1730, 1715, 1672, 1640, 1605 cm Analysis: Calcd. for C27H35BrF2O6 (percent) C 56,55; H 6,15;
Br 13,93; F 6,63 Found (percent) C 56,67; H 6,05; Br 14,12; F 6,75.
, ~,. .
. .
Using the general procedure of Example 74 the 16~-~; methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) (Rl ~ R2 = OH, R3 aCH3, X OH, Y = F) was converted into 16~-methyl-2-bromo-6~,9~-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (12 r) (Rl = OH, R2 = OCOCH3, R3 = ~CH3, X = OH, Y - Z) M.P.
212-4C (decomposition).
~20 -91 (C 1.0 in chloroform) ~ max (methanol) 245-6 m~ (~ 12100) IR(KBr) 3450 (broad), 1725, 1710, 1680, 1640, 1610, 1250 cm .
Analysis: Calcd. for C24H29BrF2O6 (percent) C 54,25; H 5,50;
Br 15,04; F 7,15 Found (percent) C 54,48; H 5,57; Br 15,18; F 7,20.
Using the general procedure of Example 74 the 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 h) (Rl = R2 = OH, R3 = ~CH3, X = OH, = F) was converted into 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate (12 s) (Rl = OH, R2 = OCO(CH2)3CH3, R3 = ~CH3, X = OH, Y = Z).
~20 -60 (C 1.0 in chloroform) ,.. ~ .
~ max (methanol) 246 m~ (~ 12000) `~
:~; . . - 1 -; IR(KBr) 3480 (broad), 1730, 1710, 1675, 1640, 1610 cm Analysis: Calcd. for C27H35BrF2O6 (percent) C 56,55; H 6,15;
` Br 13,93; F 6,63 Found (percent) C 56,80; H 6,08; Br 13,83; F 6,75.
Using the general procedure of Example 74 the 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 h) (Rl = R2 = OH, R3 = ~CH3, X = OH, ~.
.. ',, , ' ~ , ' ,' ` :, ~: 106~476 Y = F) was converted into 16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (12 t) (Rl = OH, R2 = OCOCH3, R3 = ~CH3, X = OH, Y = Z). M.P.
227-8C (decomposition).
A max (methanol) 246 m~ (E 11100) IR(KBr) 3500 (broad), 1670, 1642, 1605, 1230 cm 1.
Analysis: Calcd. for C24H29BrF2O6 (percent) C 54,25; H 5,50;
- Br 15,04; F 7,15 Found (percent) C 53,97; H 5,61; Br 15,24; F 7,27.
Using the general procedure of Example 74 the 16a-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione (12 i) (Rl = R2 = OH, R3 = aCH3, `~ X = Y = Cl) was converted into 16a-methyl-2-bromo-6~-fluoro-9~ -dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione-, ~k, 17-acetate (12 u) (Rl = OH, R2 = OCOCH3, R3 = aCH3, X = Y =
Cl). M.P. 245-7C (decomposition).
~20 _43 (C 1.0 in chloroform) A max (methanol) 245 m~ (E 11750) IR(KBr) 3500, 1720, 1710, 1675, 1640, 1607 cm .~
Analysis: Calcd. for C24H28BrC12FO5 (percent) C 50,90;
H 4,98; Br 14,11; Cl 12,52; F 3,35 Found (percent) C 51,12; H 5,07; Br 13,97;
Cl 12,30; F 3,27.
-~ EXAMPLE 79 Using the general procedure of Example 74 the 16~-- methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione (12 h) (Rl = OH, R2 = OCOCH3, R3 = ~CH3, X = Y = Cl) was converted into 16~-methyl-2-bromo-30 6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (12 v) (Rl = OH, R2 = OCOCH3, R3 = ~CH3, X = Y = Cl).
0 -12 (C 1.0 in chloroform) max (methanol) 246 m~ (~ 11600) IR(KBr) 3500 tbroad), 1720, 1710, 1670, 1645, 1605 cm 1.
Analysis: Calcd. for C24H28BrC12FO5 (percent) C 50,90;
H 4,98; Br 14,11; Cl 12,52; F 3,35 Found (percent) C 51,15; H 5,19; sr 14,05;
Cl 12,47; F 3,28. ~-A solution of 6 g. of 16a-methyl-2-bromo-6~,9a-; difluoro~ ,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione . , .
- (12 g) (Rl = R2 = OH, R3 = ~CH3) in 12 ml. of dimethyl-formamide and 40 ml. of 2,2-dimethoxypropane with 0.030 g. of p-toluenesulfonic acid was heated for 5 hrs. at 115C. The ; reaction mixture was cooled, poured in 10% sodium bicarbonate aqueous solution and chloroform. The chloroform solution was ., .
then washed with waterj dried and evaporated to a residue which by crystallization from acetone-hexane gave 5 g. of 16-methyl-2-bromo-6~,9-difluoro-11~,17a,21-trihydroxy-pregna-20 1,4-diene-3,20-dione-17,21-acetonide (12 w) characterized by 20 -18 (C 1.0 in chloroform) max (methanol) 246 m~ (~ 11950) IR(KBr) 3480 (broad), 1725, 1678, 1645, 1605 cm 1.
Analysis: Calcd. for Cz5H31BrF2O5 (percent) C 56,72; H 5,90;
.. . ..
Br 15,09; F 7,18 Found ~percent) C 56,90; H 6,08; Br 15,25; F 7,27.
Using the general procedure of Example 80 the 16~-; methyl-2-bromo-6~,9a-difluoro-11~,17~,21-trihydroxy-pregna-30 1,4-diene-3,20-dione (12 h) (Rl = R2 = OH, R3 = ~CH3, X = OH, Y = F) was converted into 16~-methyl-2-bromo-6~,9a-difluoro-, . .
: .,, . ~ . ~ . ' ." , 11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-acetonide (12 z) characterized by -- ~ ~20 t 14 (C 1.0 in chloroform) ~ max (methanol) 246 m~ (~ 12000) IR(KBr) 3475 (broad), 1720, 1675, 1640, 1605 cm 1.
Analysis: Calcd. for C25H31BrF2O5 (percent) C 56,72; H 5,90;
Br 15,09; F 7,18 Found (percent) C 56,91; H 5,73; Br 14,89; F 7,12. -Using the general procedure of Example 68 the 16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-- 1,4-diene-3,20-dione (12 g) (Rl = R2 = OH, R3 = CH3~ X = OH~
Y = F) was converted into 16a-methyl-2-bromo-6~,9a-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-valerate (12 aa) (Rl = OCO(CH2)3CH3, R2 = OH, R3 = aCH3, X = OH, Y = F) by reaction with valeric anhydride.
~20 ~ 10 (C 1.0 in chloroform) A max (methanol) 246 m~ ( 11700) IR(KBr) 3500 (broad), 1740, 1725, 1670, 1640, 1605, 1230 cm 20 Analysis: Calcd. for C27H35BrF2O6 (percent) C 56,55; H 6,15;
Br 13,93; F 6,62 .
,~
Found (percent) C 56,48; H 6,21; Br 14,05; F 6,55.
- Using the general procedure of Example 68 the 16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 h) (Rl = R2 = OH, R3 = ~CH3, X = OH, Y = F) was converted into 16~-methyl-2-bromo-6~,9a-difluoro-,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-valerate ) (Rl OCO(CH2)3CH3, R2 ~ OH, R3 = ~CH , X = OH Y - F) ; 30 by reaction with valeric anhydride.
~ ~ ~D0 ~ 39 (C 1.0 in chloroform) .; `
,: :
-, ~.
: ' ., ' , . . .~., . ~ , : . .
., :
~ max (methanol 246 m~ ( 11800) IR(KBr) 3520 (broad), 1745, 1730, 1670, 1645, 1605, 1230 cm 1.
Analysis: Calcd. for C27H35BrF2O6 (percent) C 56,55; H 6,15;
Br 13,93; F 6,62 Found (percent) C 56,61; H 6,05; Br 13,89; F 6,70.
Using the general procedure of Example 68 the 16~-methyl-2-bromo-6~,9~-difluoro~ ,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) (Rl = R2 = OH, R3 ~CH3, X OH, 10 Y = F) was converted into 16~-methyl-2-bromo-6~,9~-difluoro- ;
11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-pivalate (12 ac) (Rl = OCOC(CH3)3, R2 = OH, R3 = ~CH3, X = OH, Y = F) by reaction with pivalic anhydride.
~20 + 5 (C 1.0 in chloroform) max (methanol) 245-6 m~ ( 10850) IR(KBr) 3480 (broad), 1740, 1730, 1670, 1645, 1605, 1225 cm Analysis: Calcd. for C27H35BrF2O6 (percent) C 56,55; H 6,15;
Br 13,93; F 6,62 Found (percent) C 56,60; H 6,12; Br 13,95; F 6,55.
EXAMPLE 85 ~;~
Using the general procedure of Example 68 the 16~- -methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 h) (Rl = R2 = OH, R3 = ~CH3, X OH, Y = F) was converted into 16~-methyl-2-bromo-6~,9~-difluoro-,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-pivalate (12 ad) (Rl = OCOC(CH3)3, R2 = OH, R3 = ~CH3, X = OH, Y = F) by reaction with pivalic anhydride.
~D + 36 (C 1.0 in chloroform) max (methanol) 245-6 m~ ( 11000) 30 IR(KBr) 3490 (broad), 1740, 1730, 1670, 1640, 1600, 1230 cm 1.
Analysis: Calcd. for C27H35BrF2O6 (percent) C 56,55; H 6,15;
~ :' '; ' . - . .
. .
Br 13,93; F 6,62 Found (percent) C 56,70; H 6,23; Br 14,08; F 6,75.
Using the general procedure of Example 68 the 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) (Rl = R2 = OH, R3 ~CH3, X OH, Y = F) was converted into 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate
30 2l6-8oc.
~D ~ 25 (C 1.0 in chloroform) ..
. . . . . . . . . .
10644'76 ~ max (methanol) 245-6 m~ (E 11500) IR(KBr) 3500 (broad), 1745, 1720, 1675, 1645, 1610, 1230 cm .
Analysis: Calcd. for C24H29BrF2O6 (percent) C 54,25; H 5,50;
Br 15,04; F 7,15 Found (percent) C 54,45; H 5,38; Br 15,11; F 7,08.
Using the general procedure of Example 68 the 16a- -- methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) (Rl = R2 = OH~ R3 = aCH3, X = OH~
Y = F) was converted into 16a-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dlone-21-propio-nate (12 m) (Rl = OCOCH2CH3, R2 = OH, R3 = aCH3, X = OH, - Y = F) by reaction with propionic anhydride.
~20 + 4 (C 1.0 in chloroform) max (methanol) 246 m~ (E 10800) ~ IR(KBr) 3520 (broad), 1740, 1728, 1672, 1645, 1605, 1225 cm 1.
; Analysis: Calcd. for C25H31BrF2O6 (percent) C 55,05; H 5,73;
Br 14,65; F 6,97 Found (percent) C 55,25; H 5,62; Br 14,55; F 7,07.
Using the general procedure of Example 68 the 16~-~, methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-- 1,4-diene-3,20-dione (12 h) (Rl = R2 ~ OH, R3 = ~CH3, X = OH, Y = F) was converted into 16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-propio-nate (12 n) (Rl = OCOCH2CH3, R2 = OH, R3 = ~CH3, X - OH, Y = F) by reaction with propionic anhydride.
~20 ~ 27 (C 1.0 in chloroform) max (methanol) 246 m~ (E 11000) IR(KBr) 3500 (broad), 1745, 1730, 1670, 1645, 1605, 1220 cm , .
Analysis: Calcd. for C25H31BrF2O6 (percent) C 55,05; H 5,73;
:
.,- ''~
Br 14,65; F 6,97 Found (percent) C 55,10; H 5,72; Br 14,85 F 7,08.
Using the general procedure of Example 68 the 16~-methyl-2-bromo-6~-fluoro-9~ dichloro-17~,21-dihydroxy-pregna-1,4-diene-3,20-dione (12 i) (Rl = R2 = OH, R3 = ~CH3, X - Y = Cl) was converted into 16~-methyl-2-bromo-6~-fluoro-; 9~ -dichloro-17~,21-dihydroxy-pregna-1,4-diene-3,20-dione-21-acetate (12 o) (Rl = OCOCH3, R2 = OH, R3 = ~CH3, X = Y =
Cl). The product was crystallized from methanol. The crystals showed at 158C a transaction from the low melting form II to the form I melting 237-8C (decomp.).
C~DO + 32 (C 1.0 in chloroform) max (methanol) 246 m~ ( 11550) IR(KBr) 3550, 3460, 3340, 1755, 1730, 1673, 1635, 1605, 1230 cm-l Analysis: Calcd. for C24H28BrC12FO5 (percent) C 50,90;
H 4,98; Br 14,11; Cl 12,52; F 3,35 Found (percent) C 51,12; H 5,05; Br 13,98;
Cl 12,40; F 3,28.
~ - :
Using the general procedure of Example 68 the 16~-- methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17~,21-dihydroxy-pregna-1,4-diene-3,20-dione (12 j) (Rl = R2 = OH, R3 = ~CH3, X = Y = Cl) was converted into 16~-methyl-2-bromo-6~-fluoro-9~ -dichloro-17~,21-dihydroxy-pregna-1,4-diene-3,20-dione-21-acetate (12 p) (Rl = OCOCH3, R2 = OH, R3 = ~CH3, X = Y = -Cl).
~D ~ 61 (C 1.0 in chloroform) 30 ~ max (methanol) 245-6 m~ (~ 11000) IR(KBR) 3500 (broad), 1750, 1730, 1675, 1645, 1605, 1230 cm ~ . .
.: . ' :.' . : : , :
106447~;
Analysis: Calcd. for C24H28BrC12FO5 (percent) C 50,90;
H 4,98; Br 14,11; C1 12,52; F 3,35 Found (percent) C 51,12; H 4,88; Br 13,95;
Cl 12,41; F 3,28.
EXAMPLE 74 ~-A mixture of 5 g. of 16~-methyl-2-bromo-6~,9~- -difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione g) (Rl R2 OH, R3 = ~CH3, X = OH, Y = F) 5 ml of dimethylformamide was maintained for 4 hrs. under nitrogen at 115C. Then the mixture was neutralized by pyridine and concentrated under vacuum to dryness. Purification by column chromatography on F~ORISIL (Registered Trade Mark) (ratio 1:150) with benzene-chloroform (1:1) as eluant, gave 4 g. of 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-(1'-methoxy)-n-pentylidene-dioxy which, without further purification, was suspended in 25 ml. of methanol and 3 ml. lN hydrochloric acid aqueous solution, heated on water bath at 40-50C. After complete solubilization of the product, the mixture was concentrated under vacuum. The insoluble product was filtered off, washed with water and then dried. The 16~-methyl-2-bromo-6~,9~-:, 1, .
difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate (12 q) (Z = H, Rl = OH, R2 = OCOCH2)3CH3, R3 = H, X = OH, Y = F) thus obtained was characterized by ~20 -92 (C 1.0 in chloroform) max (methanol) 246 m~ (E 12300) IR(KBr) 3500 (broad), 1730, 1715, 1672, 1640, 1605 cm Analysis: Calcd. for C27H35BrF2O6 (percent) C 56,55; H 6,15;
Br 13,93; F 6,63 Found (percent) C 56,67; H 6,05; Br 14,12; F 6,75.
, ~,. .
. .
Using the general procedure of Example 74 the 16~-~; methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) (Rl ~ R2 = OH, R3 aCH3, X OH, Y = F) was converted into 16~-methyl-2-bromo-6~,9~-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (12 r) (Rl = OH, R2 = OCOCH3, R3 = ~CH3, X = OH, Y - Z) M.P.
212-4C (decomposition).
~20 -91 (C 1.0 in chloroform) ~ max (methanol) 245-6 m~ (~ 12100) IR(KBr) 3450 (broad), 1725, 1710, 1680, 1640, 1610, 1250 cm .
Analysis: Calcd. for C24H29BrF2O6 (percent) C 54,25; H 5,50;
Br 15,04; F 7,15 Found (percent) C 54,48; H 5,57; Br 15,18; F 7,20.
Using the general procedure of Example 74 the 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 h) (Rl = R2 = OH, R3 = ~CH3, X = OH, = F) was converted into 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate (12 s) (Rl = OH, R2 = OCO(CH2)3CH3, R3 = ~CH3, X = OH, Y = Z).
~20 -60 (C 1.0 in chloroform) ,.. ~ .
~ max (methanol) 246 m~ (~ 12000) `~
:~; . . - 1 -; IR(KBr) 3480 (broad), 1730, 1710, 1675, 1640, 1610 cm Analysis: Calcd. for C27H35BrF2O6 (percent) C 56,55; H 6,15;
` Br 13,93; F 6,63 Found (percent) C 56,80; H 6,08; Br 13,83; F 6,75.
Using the general procedure of Example 74 the 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 h) (Rl = R2 = OH, R3 = ~CH3, X = OH, ~.
.. ',, , ' ~ , ' ,' ` :, ~: 106~476 Y = F) was converted into 16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (12 t) (Rl = OH, R2 = OCOCH3, R3 = ~CH3, X = OH, Y = Z). M.P.
227-8C (decomposition).
A max (methanol) 246 m~ (E 11100) IR(KBr) 3500 (broad), 1670, 1642, 1605, 1230 cm 1.
Analysis: Calcd. for C24H29BrF2O6 (percent) C 54,25; H 5,50;
- Br 15,04; F 7,15 Found (percent) C 53,97; H 5,61; Br 15,24; F 7,27.
Using the general procedure of Example 74 the 16a-methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione (12 i) (Rl = R2 = OH, R3 = aCH3, `~ X = Y = Cl) was converted into 16a-methyl-2-bromo-6~-fluoro-9~ -dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione-, ~k, 17-acetate (12 u) (Rl = OH, R2 = OCOCH3, R3 = aCH3, X = Y =
Cl). M.P. 245-7C (decomposition).
~20 _43 (C 1.0 in chloroform) A max (methanol) 245 m~ (E 11750) IR(KBr) 3500, 1720, 1710, 1675, 1640, 1607 cm .~
Analysis: Calcd. for C24H28BrC12FO5 (percent) C 50,90;
H 4,98; Br 14,11; Cl 12,52; F 3,35 Found (percent) C 51,12; H 5,07; Br 13,97;
Cl 12,30; F 3,27.
-~ EXAMPLE 79 Using the general procedure of Example 74 the 16~-- methyl-2-bromo-6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione (12 h) (Rl = OH, R2 = OCOCH3, R3 = ~CH3, X = Y = Cl) was converted into 16~-methyl-2-bromo-30 6~-fluoro-9a,11~-dichloro-17a,21-dihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (12 v) (Rl = OH, R2 = OCOCH3, R3 = ~CH3, X = Y = Cl).
0 -12 (C 1.0 in chloroform) max (methanol) 246 m~ (~ 11600) IR(KBr) 3500 tbroad), 1720, 1710, 1670, 1645, 1605 cm 1.
Analysis: Calcd. for C24H28BrC12FO5 (percent) C 50,90;
H 4,98; Br 14,11; Cl 12,52; F 3,35 Found (percent) C 51,15; H 5,19; sr 14,05;
Cl 12,47; F 3,28. ~-A solution of 6 g. of 16a-methyl-2-bromo-6~,9a-; difluoro~ ,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione . , .
- (12 g) (Rl = R2 = OH, R3 = ~CH3) in 12 ml. of dimethyl-formamide and 40 ml. of 2,2-dimethoxypropane with 0.030 g. of p-toluenesulfonic acid was heated for 5 hrs. at 115C. The ; reaction mixture was cooled, poured in 10% sodium bicarbonate aqueous solution and chloroform. The chloroform solution was ., .
then washed with waterj dried and evaporated to a residue which by crystallization from acetone-hexane gave 5 g. of 16-methyl-2-bromo-6~,9-difluoro-11~,17a,21-trihydroxy-pregna-20 1,4-diene-3,20-dione-17,21-acetonide (12 w) characterized by 20 -18 (C 1.0 in chloroform) max (methanol) 246 m~ (~ 11950) IR(KBr) 3480 (broad), 1725, 1678, 1645, 1605 cm 1.
Analysis: Calcd. for Cz5H31BrF2O5 (percent) C 56,72; H 5,90;
.. . ..
Br 15,09; F 7,18 Found ~percent) C 56,90; H 6,08; Br 15,25; F 7,27.
Using the general procedure of Example 80 the 16~-; methyl-2-bromo-6~,9a-difluoro-11~,17~,21-trihydroxy-pregna-30 1,4-diene-3,20-dione (12 h) (Rl = R2 = OH, R3 = ~CH3, X = OH, Y = F) was converted into 16~-methyl-2-bromo-6~,9a-difluoro-, . .
: .,, . ~ . ~ . ' ." , 11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-acetonide (12 z) characterized by -- ~ ~20 t 14 (C 1.0 in chloroform) ~ max (methanol) 246 m~ (~ 12000) IR(KBr) 3475 (broad), 1720, 1675, 1640, 1605 cm 1.
Analysis: Calcd. for C25H31BrF2O5 (percent) C 56,72; H 5,90;
Br 15,09; F 7,18 Found (percent) C 56,91; H 5,73; Br 14,89; F 7,12. -Using the general procedure of Example 68 the 16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-- 1,4-diene-3,20-dione (12 g) (Rl = R2 = OH, R3 = CH3~ X = OH~
Y = F) was converted into 16a-methyl-2-bromo-6~,9a-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-valerate (12 aa) (Rl = OCO(CH2)3CH3, R2 = OH, R3 = aCH3, X = OH, Y = F) by reaction with valeric anhydride.
~20 ~ 10 (C 1.0 in chloroform) A max (methanol) 246 m~ ( 11700) IR(KBr) 3500 (broad), 1740, 1725, 1670, 1640, 1605, 1230 cm 20 Analysis: Calcd. for C27H35BrF2O6 (percent) C 56,55; H 6,15;
Br 13,93; F 6,62 .
,~
Found (percent) C 56,48; H 6,21; Br 14,05; F 6,55.
- Using the general procedure of Example 68 the 16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 h) (Rl = R2 = OH, R3 = ~CH3, X = OH, Y = F) was converted into 16~-methyl-2-bromo-6~,9a-difluoro-,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-valerate ) (Rl OCO(CH2)3CH3, R2 ~ OH, R3 = ~CH , X = OH Y - F) ; 30 by reaction with valeric anhydride.
~ ~ ~D0 ~ 39 (C 1.0 in chloroform) .; `
,: :
-, ~.
: ' ., ' , . . .~., . ~ , : . .
., :
~ max (methanol 246 m~ ( 11800) IR(KBr) 3520 (broad), 1745, 1730, 1670, 1645, 1605, 1230 cm 1.
Analysis: Calcd. for C27H35BrF2O6 (percent) C 56,55; H 6,15;
Br 13,93; F 6,62 Found (percent) C 56,61; H 6,05; Br 13,89; F 6,70.
Using the general procedure of Example 68 the 16~-methyl-2-bromo-6~,9~-difluoro~ ,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) (Rl = R2 = OH, R3 ~CH3, X OH, 10 Y = F) was converted into 16~-methyl-2-bromo-6~,9~-difluoro- ;
11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-pivalate (12 ac) (Rl = OCOC(CH3)3, R2 = OH, R3 = ~CH3, X = OH, Y = F) by reaction with pivalic anhydride.
~20 + 5 (C 1.0 in chloroform) max (methanol) 245-6 m~ ( 10850) IR(KBr) 3480 (broad), 1740, 1730, 1670, 1645, 1605, 1225 cm Analysis: Calcd. for C27H35BrF2O6 (percent) C 56,55; H 6,15;
Br 13,93; F 6,62 Found (percent) C 56,60; H 6,12; Br 13,95; F 6,55.
EXAMPLE 85 ~;~
Using the general procedure of Example 68 the 16~- -methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 h) (Rl = R2 = OH, R3 = ~CH3, X OH, Y = F) was converted into 16~-methyl-2-bromo-6~,9~-difluoro-,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-pivalate (12 ad) (Rl = OCOC(CH3)3, R2 = OH, R3 = ~CH3, X = OH, Y = F) by reaction with pivalic anhydride.
~D + 36 (C 1.0 in chloroform) max (methanol) 245-6 m~ ( 11000) 30 IR(KBr) 3490 (broad), 1740, 1730, 1670, 1640, 1600, 1230 cm 1.
Analysis: Calcd. for C27H35BrF2O6 (percent) C 56,55; H 6,15;
~ :' '; ' . - . .
. .
Br 13,93; F 6,62 Found (percent) C 56,70; H 6,23; Br 14,08; F 6,75.
Using the general procedure of Example 68 the 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) (Rl = R2 = OH, R3 ~CH3, X OH, Y = F) was converted into 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate
12 ae) (Rl = OCOC6H5, R2 = OH~ R3 = ~CH3~ X = OH~ Y = F) by - 10 reaction with benzoic anhydride ; ~ ~D ~ 75 (C 1.0 in chloroform) ~ max (methanol) 234 m~ ( 22500) IR(KBr) 3600, 3430 (broad), 1730, 1710, 1670, 1645, 1605 cm Analysis: Calcd. for C29H31BrF2O6 (percent) C 58,69; H 5,26;
Br 13,46; F 6,40 Found (percent) C 58,85; H 5,35; Br 13,37; F 6,30.
Using the general procedure of Example 68 the 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-20 1,4-diene-3,20-dione (12 h) (Rl = R2 = OH, R3 = ~CH3, X = OH~
Y = F) was converted into 16~-methyl-2-bromo-6~,9~-difluoro-,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate (12 af) (R1 = OCOC6H5, R2 = OH, R3 = ~CH3, X = OH, Y = F) by reaction with benzoic anhydride.
~ ~ ~D0 + 106 (C 1.0 in chloroform) ;; ~ max (methanol) 234 m~ (~ 22700) - IR(KBr) 3580, 3420 (broad), 1725, 1710, 1670, 1640, 1600 cm Analysis: Calcd. for C29H31BrF2O6 (percent) C 58,69; H 5,26;
Br 13,46; F 6,40 - 30 Found (percent) C 58,78; H 5,15; Br 13,27; F 6,25.
.
; 71 ~ . . - - . . , ' .; , ,. . . ~ . : . : : ' .
.
: , . .
~064476 ~ ,.
.
Using the general procedure of Example 74 the 16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) (Rl = R2 = OH~ R3 = aCH3, X = OH~
Y = F) was converted into 16a-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-propio-nate (12 ag) (Rl = OH, R2 = OCOCH2CH3, R3 = aCH3, X = OH, .b;, Y = F).
~ ~20 -92 (C 1.0 in chloroform) ;
~ max (methanol) 246 m~ (~ 12100) IR(KBr) 3500, 3430, 1730, 1710, 1675, 1645, 1605 cm Analysis: Calcd. for C25H31BrF2O6 (percent) C 55,05; H 5,73;
Br 14,65; F 6,97 , .. .
Found (percent) C 55,15; H 5,68; Br 14,47; F 7,02. -Using the general procedure of Example 74 the 16a-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-. :
1,4-diene-3,20-dione (12 g) (Rl = R2 = OH~ R3 = aCH3, X = OH~
~- Y = F) was converted into 16a-methyl-2-bromo-6~,9a-difluoro-'~' ';
11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-benzoate ~ ~ (12 ah) (Rl = OH, R2 = OCOC6H5, R3 = aCH3, X = OH, Y = F)-`~ ~ ~20 -120 (C 1.0 in chloroform) max (methanol) 234 m~ (~ 23000) IR(KBr) 3490, 3420, 1730, 1710, 1678, 1645, 1605 cm Analysis: Calcd. for C29H31BrF2O6 (percent) C 58,69; H 5,26;
Br 13,46; F 6,40 Found (percent) C 58,75; H 5,18; Br 13,35; F 6,30.
~; EXAMPLE 90 Topical cream formulations containing variable per-centages of 2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XI).
r. .` : :
' ' ' s, . . .
;''" . '' ' '"'' '.'''; ',","'" ' '' ;''',,' '''''~' ''. "' ''' ; ;' '' ';;
/~ -~064476 . . .
Ingredients Percent range (w/w) :
2-bromo-6~,9~-difluoro-11~,17a,21 trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate 0.005-0.5 Cetostearyl alcohol 5-20 Polysorbate 60 1-5 Polysorbate 80 1-5 Isopropyl miristate 5-15 Gliceryl monostearate 1-5 Sorbitol solution 1-10 Preservatives 0.2-0.5 Distilled water q.s. ad 100 The ingredients are mixed in a conventional manner for preparing a pharmaceutical topical cream. If desired, an antibacterial component such as neomycin may be added to the formulation in amount ranging from 0.1% to 3%.
Topical ointment formulations containing variable percentages of 2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XI).
Ingredients Percent range (w/w) 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate 0.005-0.5 White petrolatum q.s. ad 100 The ingredients are blended in a conventional manner providing a colorless topical ointment. If desired, an anti-bacterial component such as neomycin may be added to the formulation in amount ranging from 0.1% to 3%.
^~ 30 EXAMPLE 92 Topical gel formulations containing variable per-centages of 2-bromo-6~,9a-difluoro-11~,17~,21-trihydroxy- ~-~
pregna-1,4-diene-3,20-dione-17,21-diacetate (XI).
~ ^~
-Ingredients Perceht range (w/w) - 2-bromo-6~,9~-difluoro-11~,17~,21-`~ trihydroxy-pregna-1,4-diene-3,20 dione-17,21-diacetate 0.005-05 Carbopol~ 934 0.5-2.5 Di-isopropanolamine 0.2-1 Propylene glycol 5-50 Polysorbate 80 0.5-5 Potassium sorbate 0.05-0.25 10 Distilled water q.s. ad 100 The ingredients are mixed in a conventional manner for preparing a pharmaceutical topical gel.
Topical lotion formulations containing variable per-centages of 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XI).
Ingredients Percent range (w/w) 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-20 dione-17,21-diacetate 0.005-0.5 Propylene glycol 5-35 ~ Cetostearyl alcohol 0.5-2 - Isopropyl miristate 0.5-2 Eumulgin C-700 0.25-1 Potassium sorbate 0.05-0.25 Distilled water q.s. ad 100 ~,,.
~~ The ingredients are mixed in a conventional manner providing a topical lotion. If desired, an antibacterial ~` component such as neomycin may be added to the formulation in . ,~ ................................................................... .
:: 30 amount ranging from 0.1% to 3~. -.
~ . :
Ophthalmic (otic) ointment containing variable per-centages of 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-.' 4 . . .
-- , - ~ , ,, . . ,, . : .
' ,'' : ~ . ' ~ ' ' ' ,'' , ` . ' .
- '~
-pregna-1,4-diene-3,20-dione-17,21-diacetate (XI).
Ingredients Percent range (w/w) 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate 0.005-0.5 Mineral oil 1-10 White petrolatum q.s. ad 100 Ingredients are blended in a conventional manner providing an ophthalmic or otic preparation. If an anti-bacterial ingredient is desired, neomycin may be added as the micronized sulfate salt.
Tablets containing variable amount of 2-bromo-6~,9~-- difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa).
Ingredients Amount in mg per 200 mg tablet 2-bromo-6~,9~-difluoro-11~,17~,21-` trihydroxy-pregna-1,4-diene-3,20-dione 1-50 20 Starch 99_75 Lactose 90-65 Talc 8 Magnesium stearate 2 The active compound, starch and lactose are blended and compressed into slugs which are then granulated. Talc and magnesium stearate are added to the granulated mixture which !, iS compressed into tablets weighing 0.200 g. Each tablet contains 1-50 mg of active compound.
; EXAMPLE 96 Oral suspension containing variable amount of 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-acetate (XIc).
., .
- 75 - ~
Ingredients 100 ml of suspension (w/v) 2-bromo-6~,9~-difluoro-113,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-acetate 0.010-0.5 Tragacanth gum 0-3 Glycerol 3 Tween 80 0.1 ~-Sucrose 50 Methylparaben 0.15 10 Propylparaben 0 05 Elavours and colours 9.5 Distilled water q.s. ad 100 The ingredients are mixed in a conventional manner - to provide a flavoured suspension.
. Suspension for injections containing variable amount of 2-bromo-6~,9~-difluoro~ ,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-acetate (XIc).
Ingredients 100 ml of suspension (w/v) 20 2-bromo-6~,9~-difluoro-11~,17~,21 trihydroxy-pregna-1,4-diene-3,20-. dione-21-acetate 0.5-10 -` Sodium CMC 0.75 Sodium chloride 0.65 Polysorbate 80 0.04 Benzyl alcohol 0.9 Distilled water q.s. ad 100 The ingredients are mixed in a conventional manner . to provide a sterile suspension of the active compound in very fine particles.
Compositions of all the other compounds of the invention, and in particular those named specifically above, may be made by replacing the active ingredients in each of Examples 91 to 97 with any one of the other named compounds.
., .
.: . .
Br 13,46; F 6,40 Found (percent) C 58,85; H 5,35; Br 13,37; F 6,30.
Using the general procedure of Example 68 the 16~-methyl-2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-20 1,4-diene-3,20-dione (12 h) (Rl = R2 = OH, R3 = ~CH3, X = OH~
Y = F) was converted into 16~-methyl-2-bromo-6~,9~-difluoro-,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate (12 af) (R1 = OCOC6H5, R2 = OH, R3 = ~CH3, X = OH, Y = F) by reaction with benzoic anhydride.
~ ~ ~D0 + 106 (C 1.0 in chloroform) ;; ~ max (methanol) 234 m~ (~ 22700) - IR(KBr) 3580, 3420 (broad), 1725, 1710, 1670, 1640, 1600 cm Analysis: Calcd. for C29H31BrF2O6 (percent) C 58,69; H 5,26;
Br 13,46; F 6,40 - 30 Found (percent) C 58,78; H 5,15; Br 13,27; F 6,25.
.
; 71 ~ . . - - . . , ' .; , ,. . . ~ . : . : : ' .
.
: , . .
~064476 ~ ,.
.
Using the general procedure of Example 74 the 16~-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) (Rl = R2 = OH~ R3 = aCH3, X = OH~
Y = F) was converted into 16a-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-propio-nate (12 ag) (Rl = OH, R2 = OCOCH2CH3, R3 = aCH3, X = OH, .b;, Y = F).
~ ~20 -92 (C 1.0 in chloroform) ;
~ max (methanol) 246 m~ (~ 12100) IR(KBr) 3500, 3430, 1730, 1710, 1675, 1645, 1605 cm Analysis: Calcd. for C25H31BrF2O6 (percent) C 55,05; H 5,73;
Br 14,65; F 6,97 , .. .
Found (percent) C 55,15; H 5,68; Br 14,47; F 7,02. -Using the general procedure of Example 74 the 16a-methyl-2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-. :
1,4-diene-3,20-dione (12 g) (Rl = R2 = OH~ R3 = aCH3, X = OH~
~- Y = F) was converted into 16a-methyl-2-bromo-6~,9a-difluoro-'~' ';
11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-benzoate ~ ~ (12 ah) (Rl = OH, R2 = OCOC6H5, R3 = aCH3, X = OH, Y = F)-`~ ~ ~20 -120 (C 1.0 in chloroform) max (methanol) 234 m~ (~ 23000) IR(KBr) 3490, 3420, 1730, 1710, 1678, 1645, 1605 cm Analysis: Calcd. for C29H31BrF2O6 (percent) C 58,69; H 5,26;
Br 13,46; F 6,40 Found (percent) C 58,75; H 5,18; Br 13,35; F 6,30.
~; EXAMPLE 90 Topical cream formulations containing variable per-centages of 2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XI).
r. .` : :
' ' ' s, . . .
;''" . '' ' '"'' '.'''; ',","'" ' '' ;''',,' '''''~' ''. "' ''' ; ;' '' ';;
/~ -~064476 . . .
Ingredients Percent range (w/w) :
2-bromo-6~,9~-difluoro-11~,17a,21 trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate 0.005-0.5 Cetostearyl alcohol 5-20 Polysorbate 60 1-5 Polysorbate 80 1-5 Isopropyl miristate 5-15 Gliceryl monostearate 1-5 Sorbitol solution 1-10 Preservatives 0.2-0.5 Distilled water q.s. ad 100 The ingredients are mixed in a conventional manner for preparing a pharmaceutical topical cream. If desired, an antibacterial component such as neomycin may be added to the formulation in amount ranging from 0.1% to 3%.
Topical ointment formulations containing variable percentages of 2-bromo-6~,9a-difluoro-11~,17a,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XI).
Ingredients Percent range (w/w) 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate 0.005-0.5 White petrolatum q.s. ad 100 The ingredients are blended in a conventional manner providing a colorless topical ointment. If desired, an anti-bacterial component such as neomycin may be added to the formulation in amount ranging from 0.1% to 3%.
^~ 30 EXAMPLE 92 Topical gel formulations containing variable per-centages of 2-bromo-6~,9a-difluoro-11~,17~,21-trihydroxy- ~-~
pregna-1,4-diene-3,20-dione-17,21-diacetate (XI).
~ ^~
-Ingredients Perceht range (w/w) - 2-bromo-6~,9~-difluoro-11~,17~,21-`~ trihydroxy-pregna-1,4-diene-3,20 dione-17,21-diacetate 0.005-05 Carbopol~ 934 0.5-2.5 Di-isopropanolamine 0.2-1 Propylene glycol 5-50 Polysorbate 80 0.5-5 Potassium sorbate 0.05-0.25 10 Distilled water q.s. ad 100 The ingredients are mixed in a conventional manner for preparing a pharmaceutical topical gel.
Topical lotion formulations containing variable per-centages of 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XI).
Ingredients Percent range (w/w) 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-20 dione-17,21-diacetate 0.005-0.5 Propylene glycol 5-35 ~ Cetostearyl alcohol 0.5-2 - Isopropyl miristate 0.5-2 Eumulgin C-700 0.25-1 Potassium sorbate 0.05-0.25 Distilled water q.s. ad 100 ~,,.
~~ The ingredients are mixed in a conventional manner providing a topical lotion. If desired, an antibacterial ~` component such as neomycin may be added to the formulation in . ,~ ................................................................... .
:: 30 amount ranging from 0.1% to 3~. -.
~ . :
Ophthalmic (otic) ointment containing variable per-centages of 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-.' 4 . . .
-- , - ~ , ,, . . ,, . : .
' ,'' : ~ . ' ~ ' ' ' ,'' , ` . ' .
- '~
-pregna-1,4-diene-3,20-dione-17,21-diacetate (XI).
Ingredients Percent range (w/w) 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate 0.005-0.5 Mineral oil 1-10 White petrolatum q.s. ad 100 Ingredients are blended in a conventional manner providing an ophthalmic or otic preparation. If an anti-bacterial ingredient is desired, neomycin may be added as the micronized sulfate salt.
Tablets containing variable amount of 2-bromo-6~,9~-- difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa).
Ingredients Amount in mg per 200 mg tablet 2-bromo-6~,9~-difluoro-11~,17~,21-` trihydroxy-pregna-1,4-diene-3,20-dione 1-50 20 Starch 99_75 Lactose 90-65 Talc 8 Magnesium stearate 2 The active compound, starch and lactose are blended and compressed into slugs which are then granulated. Talc and magnesium stearate are added to the granulated mixture which !, iS compressed into tablets weighing 0.200 g. Each tablet contains 1-50 mg of active compound.
; EXAMPLE 96 Oral suspension containing variable amount of 2-bromo-6~,9~-difluoro-11~,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-acetate (XIc).
., .
- 75 - ~
Ingredients 100 ml of suspension (w/v) 2-bromo-6~,9~-difluoro-113,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-acetate 0.010-0.5 Tragacanth gum 0-3 Glycerol 3 Tween 80 0.1 ~-Sucrose 50 Methylparaben 0.15 10 Propylparaben 0 05 Elavours and colours 9.5 Distilled water q.s. ad 100 The ingredients are mixed in a conventional manner - to provide a flavoured suspension.
. Suspension for injections containing variable amount of 2-bromo-6~,9~-difluoro~ ,17~,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-acetate (XIc).
Ingredients 100 ml of suspension (w/v) 20 2-bromo-6~,9~-difluoro-11~,17~,21 trihydroxy-pregna-1,4-diene-3,20-. dione-21-acetate 0.5-10 -` Sodium CMC 0.75 Sodium chloride 0.65 Polysorbate 80 0.04 Benzyl alcohol 0.9 Distilled water q.s. ad 100 The ingredients are mixed in a conventional manner . to provide a sterile suspension of the active compound in very fine particles.
Compositions of all the other compounds of the invention, and in particular those named specifically above, may be made by replacing the active ingredients in each of Examples 91 to 97 with any one of the other named compounds.
., .
.: . .
Claims (34)
1. Process for the preparation of pregnadiene 1,4-derivatives of the general formula:
wherein:
R1 is OQ;
R2 is OQ;
R3 is H or .alpha.OQ;
where Q stands for H or an acyl radical having 2 to 8 carbon atoms and selected from alkyl or phenylloweralkyl;
R1 and R2 or R2 and R3 may be joined together to form a 17,21- or 16,17-cyclic acetal or ketal of the formula:
where R4 and R5 stand for lower alkyl, which comprises, A. when Q is other than H and R3 is H: fluorinating a compound of the formula:
wherein Q is an acyl radical as defined above;
B. when Q is H and R3 is H: hydrolyzing the product obtained in Step A;
C. when R1 and R2 stand for a 17,21-cyclic acetal or ketal as defined above: reacting in the presence of an acid cata-lyst a compound of the formula:
with a compound of the formula:
wherein alk., R4 and R5 stand for loweralkyl;
D. when R2 and R3 stand for a 16,17-cyclic acetal or ketal as defined above: reacting in the presence of an acid catalyst a compound of the formula:
with a compound of the formula:
wherein alk., R4 and R5 stand for loweralkyl and Q stands for an acyl radical having 2 to 8 carbon atoms and selected from alkyl or phenyl loweralkyl;
E. when R1 is OQ and Q is acyl, R2 is OH and R3 is H:
acylating a compound of the formula:
F. when R1 is OH, R2 is OH and R3 is H: reacting a compound of the formula:
with a loweralkyl orthoester in the presence of an acid catalyst and hydrolyzing the intermediate thus obtained;
G. when R1 is OQ and Q is acyl, R2 is OQ wherein Q is an acyl different from the acyl of Q in R1, the Q in R1 and R3 is H: acylating a compound of the formula:
H. when R1 is OQ and Q is acyl, R2 is OQ wherein Q is an acyl different from the acyl of Q in R1, R3 is H: acylating a compound of the formula:
wherein:
R1 is OQ;
R2 is OQ;
R3 is H or .alpha.OQ;
where Q stands for H or an acyl radical having 2 to 8 carbon atoms and selected from alkyl or phenylloweralkyl;
R1 and R2 or R2 and R3 may be joined together to form a 17,21- or 16,17-cyclic acetal or ketal of the formula:
where R4 and R5 stand for lower alkyl, which comprises, A. when Q is other than H and R3 is H: fluorinating a compound of the formula:
wherein Q is an acyl radical as defined above;
B. when Q is H and R3 is H: hydrolyzing the product obtained in Step A;
C. when R1 and R2 stand for a 17,21-cyclic acetal or ketal as defined above: reacting in the presence of an acid cata-lyst a compound of the formula:
with a compound of the formula:
wherein alk., R4 and R5 stand for loweralkyl;
D. when R2 and R3 stand for a 16,17-cyclic acetal or ketal as defined above: reacting in the presence of an acid catalyst a compound of the formula:
with a compound of the formula:
wherein alk., R4 and R5 stand for loweralkyl and Q stands for an acyl radical having 2 to 8 carbon atoms and selected from alkyl or phenyl loweralkyl;
E. when R1 is OQ and Q is acyl, R2 is OH and R3 is H:
acylating a compound of the formula:
F. when R1 is OH, R2 is OH and R3 is H: reacting a compound of the formula:
with a loweralkyl orthoester in the presence of an acid catalyst and hydrolyzing the intermediate thus obtained;
G. when R1 is OQ and Q is acyl, R2 is OQ wherein Q is an acyl different from the acyl of Q in R1, the Q in R1 and R3 is H: acylating a compound of the formula:
H. when R1 is OQ and Q is acyl, R2 is OQ wherein Q is an acyl different from the acyl of Q in R1, R3 is H: acylating a compound of the formula:
2. The process of Claim 1, wherein 2-bromo-6.beta.-fluoro-17.alpha.,21-dihydroxy-9.beta.,11.beta.-oxido-pregna-1,4-diene-3,20-dione-17,21-diacetate is fluorinated to provide the 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate.
3. The process of Claim 1, wherein 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate is hydrolyzed to provide the 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione.
4. The process of Claim 1, wherein 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione is reacted with the 2,2-dimethoxypropane in the presence of an acid catalyst to provide the 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-acetonide.
5. The process of Claim 1, wherein 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione is acetylated to provide the 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-21-acetate.
6. The process of Claim 1, wherein 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione is reacted with propionic anhydride to provide the 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-propionate.
7. The process of Claim 1, wherein 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione is reacted with valeric anhydride to provide the 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-valerate.
8. The process of Claim 1, wherein 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione is reacted with pivalic anhydride to provide the 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-pivalate.
9. The process of Claim 1, wherein 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione is reacted with tertiarybutylacetic acid chloride to provide the 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-tertiarybutylacetate.
10. The process of Claim 1, wherein 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione is reacted with enanthic acid chloride to provide the 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-enanthate.
11. The process of Claim 1, wherein 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione is reacted with benzoic anhydride to provide the 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate.
12. The process of Claim 1, wherein 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione is reacted with methylorthovalerate in the presence of an acid catalyst and hydrolyzing the 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-(1'-methoxy)-n-pentylidenedioxy thus obtained to yield the 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate.
13. The process of Claim 1, wherein 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate is reacted with valeric anhydride to provide the 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate-21-valerate.
14. The process of Claim 1, wherein 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione is reacted with ethylorthopropionate and the reaction product thus obtained is subjected to acid hydrolysis to provide the 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-propionate.
15. The process of Claim 1, wherein 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione is reacted with ethylorthobenzoate in the presence of an acid catalyst and the reaction product thus obtained is subjected to acid hydrolysis to provide the 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha., 21-trihydroxy-pregna-1,4-diene-3,20-dione-17-benzoate.
16. The process of Claim 1, wherein 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate is reacted with acetic anhydride to provide the 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate-21-acetate.
17. The process of Claim 1, wherein 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione is reacted with ethylorthoacetate and hydrolyzing the 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-orthoacetate thus obtained to provide the 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate.
18. The pregnadiene 1,4-derivatives of the general formula:
wherein:
R1 is OQ;
R2 is OQ;
R3 is H or .alpha.OQ;
where Q stands for H or an acyl radical having 2 to 8 carbon atoms and selected from alkyl or phenylloweralkyl;
R1 and R2 or R2 and R3 may be joined together to form a 17,21- or 16,17-cyclic acetal or ketal of the formula:
where R4 and R5 stand for lower alkyl, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.
wherein:
R1 is OQ;
R2 is OQ;
R3 is H or .alpha.OQ;
where Q stands for H or an acyl radical having 2 to 8 carbon atoms and selected from alkyl or phenylloweralkyl;
R1 and R2 or R2 and R3 may be joined together to form a 17,21- or 16,17-cyclic acetal or ketal of the formula:
where R4 and R5 stand for lower alkyl, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.
19. The 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate, when prepared by the process defined in Claim 2 or by an obvious chemical equivalent.
20. The 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione, when prepared by the process defined in Claim 3 or by an obvious chemical equivalent.
21. The 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-17,21-acetonide, when prepared by the process defined in Claim 4 or by an obvious chemical equivalent.
22. The 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-21-acetate, when prepared by the process defined in Claim 5 or by an obvious chemical equivalent.
23. The 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-21-propionate, when prepared by the process defined in Claim 6 or by an obvious chemical equivalent.
24. The 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-21-valerate, when prepared by the process defined in Claim 7 or by an obvious chemical equivalent.
25. The 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-pivalate, when prepared by the process defined in Claim 8 or by an obvious chemical equiva-lent.
26. The 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-tertiarybutylacetate, when prepared by the process defined in Claim 9 or by an obvious chemical equivalent.
27. The 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-enanthate, when prepared by the process defined in Claim 10 or by an obvious chemical equiva-lent.
28. The 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate, when prepared by the process defined in Claim 11 or by an obvious chemical equiva-lent.
29. The 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate, when prepared by the process defined in Claim 12 or by an obvious chemical equiva-lent.
30. The 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate-21-valerate, when prepared by the process defined in Claim 13 or by an obvious chemical equivalent.
31. The 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-propionate, when prepared by the process defined in Claim 14 or by an obvious chemical equiva-lent.
32. The 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-benzoate, when prepared by the process defined in Claim 15 or by an obvious chemical equiva-lent.
33. The 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate, when prepared by the process defined in Claim 17 or by an obvious chemical equiva-lent.
34. The 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate-21-acetate, when prepared by the process defined in Claim 16 or by an obvious chemical equivalent.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8928/74A GB1499822A (en) | 1974-02-27 | 1974-02-27 | 2-bromo-6beta-fluoropregna-1,4-diene-3,20-diones |
| GB2998474 | 1974-07-05 | ||
| GB3294574 | 1974-07-25 | ||
| GB4998274 | 1974-11-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1064476A true CA1064476A (en) | 1979-10-16 |
Family
ID=27447687
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA219,681A Expired CA1064476A (en) | 1974-02-27 | 1975-02-10 | Steroids and process for preparing the same |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS5614677B2 (en) |
| AR (1) | AR218601A1 (en) |
| BE (1) | BE826030A (en) |
| CA (1) | CA1064476A (en) |
| CH (1) | CH608243A5 (en) |
| DE (3) | DE2508136C3 (en) |
| DK (1) | DK144068C (en) |
| ES (3) | ES435067A1 (en) |
| FI (1) | FI56188C (en) |
| FR (1) | FR2261776B1 (en) |
| GB (1) | GB1499822A (en) |
| IE (1) | IE42112B1 (en) |
| LU (1) | LU71908A1 (en) |
| NO (1) | NO144527C (en) |
| NZ (1) | NZ176716A (en) |
| RO (1) | RO78881A (en) |
| SE (1) | SE410736B (en) |
| YU (3) | YU108381A (en) |
-
1974
- 1974-02-27 GB GB8928/74A patent/GB1499822A/en not_active Expired
-
1975
- 1975-02-10 CA CA219,681A patent/CA1064476A/en not_active Expired
- 1975-02-14 FR FR7504616A patent/FR2261776B1/fr not_active Expired
- 1975-02-19 DK DK61575A patent/DK144068C/en not_active IP Right Cessation
- 1975-02-20 NZ NZ176716A patent/NZ176716A/en unknown
- 1975-02-24 AR AR257732A patent/AR218601A1/en active
- 1975-02-24 IE IE379/75A patent/IE42112B1/en unknown
- 1975-02-25 LU LU71908A patent/LU71908A1/xx unknown
- 1975-02-25 ES ES435067A patent/ES435067A1/en not_active Expired
- 1975-02-25 CH CH232575A patent/CH608243A5/en not_active IP Right Cessation
- 1975-02-25 FI FI750537A patent/FI56188C/en not_active IP Right Cessation
- 1975-02-25 DE DE2508136A patent/DE2508136C3/en not_active Expired
- 1975-02-25 NO NO750633A patent/NO144527C/en unknown
- 1975-02-26 SE SE7502146A patent/SE410736B/en unknown
- 1975-02-26 BE BE153787A patent/BE826030A/en not_active IP Right Cessation
- 1975-02-26 JP JP2298075A patent/JPS5614677B2/ja not_active Expired
- 1975-02-26 RO RO7581496A patent/RO78881A/en unknown
- 1975-07-25 DE DE2533377A patent/DE2533377C3/en not_active Expired
- 1975-07-25 DE DE2533323A patent/DE2533323C3/en not_active Expired
-
1977
- 1977-02-15 ES ES455934A patent/ES455934A1/en not_active Expired
- 1977-02-15 ES ES455933A patent/ES455933A1/en not_active Expired
-
1981
- 1981-04-27 YU YU01083/81A patent/YU108381A/en unknown
- 1981-04-27 YU YU01082/81A patent/YU108281A/en unknown
- 1981-04-27 YU YU01084/81A patent/YU108481A/en unknown
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