GB2023608A - Steroidal[16???,17]cyclohexene and Naphthalene-21-oic Acids and Esters - Google Patents
Steroidal[16???,17]cyclohexene and Naphthalene-21-oic Acids and Esters Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
- C07J13/005—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 16 (17)
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Abstract
Steroids having the formula <IMAGE> and esters thereof, wherein X is hydrogen or halogen; Y is hydrogen, methyl or fluorine; R4 is chlorine, fluorine or hydroxy and R5 is hydrogen or R4 and R5 together are =O; R2 and R3 are each hydrogen, alkyl, phenyl or phenyl substituted with one or more halogen alkyl or alkoxy groups, or R2 and R3 together with the double bond to which they are attached form a benzene ring; R6 and R7 are each hydrogen, alkyl, alkoxy, formyl, <IMAGE> phenyl or cyano and in addition hydroxy, halogen, carboalkoxy and alkylcarbonyl when R2 and R3 are separate, with the proviso that when R6 and R7 are different one of R6 and R7 is hydrogen; R8 is hydrogen or -CH(R9)(R10) wherein R9 and R10 are each hydrogen or alkyl, have anti- inflammatory activity. Preparation (i) from the corresponding 21-ols by oxidation via 20-one-21-als (and/or 21-acetals thereof) and/or 20-hydroxy-21-oic acids (and/or 21-esters thereof); or (ii) from the corresponding ???<16>-21-ols (lacking the fused ring) by oxidation as in process (i) followed by fusing the cyclohexene or tetrahydronaphthalene group into the 16,17-position.
Description
SPECIFICATION
Steroidal[1 6,1 7-b]cyclohexene and
Naphthaleno Derivatives
This invention provides steroids having the formula
and esters thereof, and antiinflammatory pharmaceutical compositions comprising such compounds and a pharmaceutical carrier. In formula I, and throughout the specification, the symbols are as defined below::
X is hydrogen or halogen;
Y is hydrogen, fluorine or methyl;
R4 is chlorine, fluorine or hydroxy and R5 is hydrogen or R4 and R5 together are =0; R2 and R3 are the same or different and are hydrogen, alkyl or aryl or taken together with the double bond to which they are attached, form a benzene ring;
R6 and R7 are the same or different and are hydrogen, alkyl, alkoxy, formyl,
0 alkyl--CC--O-, phenyl or cyano and in addition, hydroxy, halogen, carboalkoxy and alkylcarbonyl when R2 and R3 are separate with the proviso that when R6 and R7 are different, one of the R6 and R7 is hydrogen; and Rg is hydrogen or CH-R9R10 wherein R9 and R10 are the same or different and are hydrogen or alkyl.
The dotted lines in the 1 ,2-position of the steroids of this invention represent the optional presence of ethylenic unsaturation.
The terms "alkyl" and "alkoxY', as used throughout the specification (unless otherwise defined), refer to both straight and branched chain groups having 1 to 6 carbon atoms.
The term "aryl", as used throughout the specification, refers to phenyl or phenyl substituted with one or more halogen, alkyl and alkoxy groups.
The term "halogen", as used throughout the specification, refers to fluorine, chlorine, bromine and iodine.
The esters contemplated are the C1-C10 alkyl, aryl and aralkyl esters.
The steroids of formula I can be prepared from the corresponding 21-hydroxy-steroidal[1 6a,17 b]cyclic-enes having the structural formula
wherein the symbols are as previously defined.
The steroids of formula II are generally known in the art; see for example, Unites States patents 3,927,720 issued February 10, 1 976; 3,994,935 issued November 30, 1976 and 3,944,584 issued March 1 6, 1 976.
A steroid of formula II can be oxidized to the corresponding aldehyde having the formula
using a catalyst such as copper acetate. The reaction can be run in an alcohol solvent.
If the above described oxidation reaction is carried out in the presence of oxygen (e.g., by bubbling air through the reaction mixture), the reaction will generally yield, in addition to a steriodal-21 -aldehyde of formula Ill, the corresponding steroidal-2 1 -acetal formed with the alcohol solvent (R1-OH); i.e., a steroid having the formula
The oxidation reaction will generally be compieted within a relatively short period of time, i.e., about 1 hour.
If the above-described reaction is allowed to proceed for an extended period of time, e.g., more than about 24 hours, the major product will be the 20-hydroxy-21 -carboxylic acid ester having the formula
If water is present as a co-solvent in the oxidation reaction, and the reaction is allowed to proceed for an extended period of time, in addition to the 20-hydroxy-21 -carboxylic acid ester of formula V, the corresponding 20-hydroxy21 -carboxylic acid will be produced: i.e., a steroid having the formula
The steroids of formulas V and VI exist as
mixtures of the 20a- and 20-hydrnxysternids.
Reacting a steroid formulas Ill or IV our a mixture thereof with an inorganic cyanide catalyst, an oxidizing agent, an inert solvent, and alcohol and an organic acid yields the product of formula I.
More specifically, a product of formula I can be obtained by reacting a steroidal-21-aldehyde of formula Ill or the corresponding steroidal-21acetal of formula IV or a mixture thereof with a
mixture of (i) an inorganic cyanide catalyst (e.g., an alkali metal cyanide such as potassium cyanide); (ii) an oxidizing agent, e.g., a heavy metal oxide such as activated manganese dioxide or lead dioxide, (iii) an inert solvent, e.g., a halogenated hydrocarbon solvent such as dichloromethane or chloroform; (iv) a primary or secondary alcohol, R,'--OH (throughout the specification R,' is any primary or secondary R, group); and (v) an acid, e.g., acetic acid, which serves to neutralize the alkali cyanide catalyst.
The products of the above reaction have the formula
The 20o'- and 20-hydrnxysternids of formulas V and VI can be oxidized to obtain the corresponding 20-ketosteroids, having the respective formulas
Exemplary of suitable oxidizing agents are manganese dioxide and chromium dioxide. In the instance wherein the 20- and 20P- hydroxysteroids being oxidized have an 11P- hydroxy substituent, the products of formulas I and VIII will be mixtures of 11p-hydroxy and 11keto steroids.
The esters of formula I can also be prepared by esterification of the corresponding steroidal-21oic acid of formula VIII. (A steroid of formula VIII can be prepared as described above, or alternatively, by saponification of a corresponding steroidal-21-oic acid ester of formula 1.) Still another route for the preparation of the products of formula I wherein R, is a non-tertiary alkyl group of 1 to 10 carbon atoms or aryl is the transesterification of another ester of formula I.
The starting steroid is reacted with the appropriate alcohol in the presence of a basic alkoxide (e.g., sodium ethoxide or aluminum isopropoxide) or, preferably, a source of cyanide ion (e.g., an alkali metal cyanide such as sodium cyanide or potassium cyanide to yield the transesterification product.
The steroids of formula I (including the esters)
may be used as topical antiinflammatory agents which can be used in lieu of known glucocorticoids in the treatment of conditions such as dermititis, psoriasis, sunburn, neurodermatitis, eczema and anogenital pruritus.
The steroids may be administered in a conventional cream, ointment, lotion, or spray in the range of 0.01 to 5.0% by weight, preferably 0.025 to 2.0% by weight.
In an alternative process, steroids of the formula I can be prepared from the corresponding 21 -hydroxy-8'6 steroids having the formula
by first converting the 21 -hydroxy group to a 21 carboxylic acid group and then fusing the cyclohexane and tetrahydronaphthalene groups in the 16,17-position.
The 21-hydroxy-A'6-steroids of formula IX, which form the starting point for the alternate process, or the corresponding 21-acyloxy steroids, are known in the art. The 21 -acyloxy steroids are readily converted to the corresponding 21 -hydroxy steroids using conventional techniques.
A steroid of formula IX can be oxidized to the corresponding aldehyde having the formula
using oxygen (or air) and a catalyst such as copper acetate. The reaction can be run in an alcohol solvent.
If the above described oxidation reaction is carried out in the presence of oxygen (e.g., by bubbling air thrcugh the reaction mixture), the reaction will generally yield, in addition to a steroidal-2 1 -aldehyde of formula X, the corresponding steroidal-2 1 -acetal formed with the alcohol solvent (Ra-OH); i.e., a steroid having the formula
The oxidation reaction will generally be completed within a relatively short peroid of time, i.e., about 1 hour.
If the above described reaction is allowed to proceed for an extended period of time, e.g., more than about 24 hours, the major product will be the 20-hydroxy-21 -carboxylic acid ester having the formula
If water is present as a co-solvent in the oxidation reaction, and the reaction is allowed to proceed for an extended period of time, in addition to the 20-hydroxy-2 1 -carboxylic acid ester of formula Xl, the corresponding 20hydroxy-21-carboxylic acid will be produced; i.e., a steroid having the formula
The steroids of formulas XII and Xlil exist as mixtures of the 20a- and 20ss-hydroxy-steroids.
Reacting a steroid of formulas X or Xl or a mixture thereof with an inorganic cyanide catalyst, an oxidizing agent, an inert solvent, an alcohol and an organic acid yields the product of formula I. A product of formula I can be obtained by reacting a steroidal-2 1 -aldehyde of formula X or the corresponding steroidal-2 1 -acetal of formula Xl or a mixture thereof with a mixture of (i) an inorganic cyanide catalyst (e.g., an alkali metal cyanide such as potassium cyanide); (ii) and oxidizing agent, e.g., a heavy metal oxide such as activated manganese dioxide or lead dioxide; (iii) an inert solvent, e.g., a halogenated hydrocarbon solvent such as dichloromethane or chloroform; (iv) a primary or secondary alcohol, R,'---OH (throughout the specification R,' is any nontertiary R, group); and (v) an acid, e.g., acetic acid, which serves to neutralize the alkali cyanide catalyst. The products of the above reaction have the formula
The 20a- and 20-hydrnxysternids of formulas
XII and XIII can be oxidized to obtain the corresponding 20-ketosteroids, having the respective formulas
and
Exemplary of suitable oxidizing agents are manganese dioxide and chromium dioxide. In the instance wherein the 20n- and 20p- hydroxysteroids being oxidized have an 11,B- hydroxy substituent, the steroids of formulas XV and XVI will be mixtures of 1 1 P-hydroxy and 11-,B keto steroids.
The intermediates of formula XV can also be prepared by esterification of the corresponding steroidal-21-oic acid of formula XVI. (A steroid of formula XV can be prepared as described above, or alternatively, by saponification of a corresponding steroidal-2 1 -oic acid ester of formula XV).
Still another route for the preparation of the intermediates of formula XV wherein R, is a nontertiary group is the transesterification of another ester of formula XIV or XV. The starting steroid is reacted with the appropriate alcohol in the presence of a basic alkoxide (e.g., sodium ethoxide or aluminum isopropoxide), or preferably, a source of cyanide ion (e.g., an alkali metal cyanide such as sodium cyanide or potassium cyanide) to yield the transesterification product.
A steroid of formulas XIV, XV or XVI can be converted to the corresponding product of formula I by reacting it with an benzocyclobutene having the formula
or with a butadiene having the formula
using the Diels-Alder reaction.
In the case of the XVII reactant, the reaction can be run neat or in an inert solvent, e.g., o- dichlorobenzene or diethylbenzene. Preferably the reaction will be run neat, in an inert atmosphere, at temperatures up to the boiling point of the solution. A free radical inhibitor may be added to the mixture.
In the case of the XVI II reactant, the preferred catalysts for the reaction are anhydrous aluminum chloride and anhydrous aluminum bromide. The reaction can be run in an organic solvent, e.g., a halogenated hydrocarbon such as dichloromethane. The above described Diels
Alder reaction is highly selective and takes place exclusively at the double bond in the 16-position, even in the presence of the d' 4-3-keto-function.
In those instances wherein the butadiene is unstable in the presence of a Lewis acid catalyst, the Diels-Alder reaction is run in the presence of a free radical inhibitor at elevated temperatures.
If the steroid of formula XIV, XV or XVI contains an 1 1 P-hydroxy group, it is desirable to first protect the group before running the Diels
Alder reaction. While many means of protecting the 11-functional group will be apparent to a person skilled in the steroid art, one particularly desirable method is the acylation of the group.
The acylation reaction can be run using an acid anhydride, e.g., acetic anhydride in the presence of a Lewis catalyst, e.g., boron trifluoride etherate.
After the Diels-Alder reaction has been run, the protective group can be removed using a conventional technique.
Example 1 9-Fluoro-1',2',3',4'-tetrahydro-11/3-hydroxy- 3,20-dioxopregna-1,4-dieno[16cr,17-b] naphthalene-21-oic acid, methyl ester
9-Fluoro-1 ',2',3',4'-tetrahydro-1 1 /3,21 - dihydroxypregna-l ,4-dienoll 6a,l 7-b] naphthalene-3,20-dione (1.0 g) is dissolved in anhydrous methanol (170 ml) by warming and the solution is cooled to room temperature.
Cupric acetate hydrate (250 mg) is added and under stirring, a slow stream of air is passed into the solution. Within 10 minutes, the starting steroid disappears to give essentially a single less polar material, as judged by thin-layer chromatography (TLC). The methanol is mostly evaporated in vacuo at room temperature; some steroid precipitates out. The concentrate is diluted with water and extracted with chloroform. The chloroform solution is washed with a dilute ammonium chloride solution and water, dried over anhydrous magnesium sulfate and evaporated to leave 0.98 g of 9-fluoro-1 ',Q',3',4'- tetrahydro-11,8-hydroxypregna-1,4- dieno[ 1 6a, 1 7-b]naphthalene-21 -al-3,20-dione.
This material shows a single spot on TLC (chloroform-methanol, 93:7; silica gel) and an IR spectrum consistent with the structure. However, the NMR spectrum shows that it is contaminated with a small amount of the corresponding 21dimethyl acetal.
A mixture of the impure aldehyde (950 mg), anhydrous methanol (50 ml), dry dichloromethane (50 ml), glacial acetic acid (0.9 ml), potassium cyanide (200 mg) and active manganese dioxide (2.1 g) is stirred at room temperature for 10 hours. It is then filtered through a bed of diatomaceous earth. The cake is resuspended in chloroform which is refluxed and filtered again. The fiitrates are combined, washed with a dilute sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate and evaporated to afford 0.86 g of a solid. This is dissolved in a mixture of dichloromethane and methanol. The dichloromethane is removed under reflux to precipitate 675 mg of a solid.This is again subjected to purification as above to afford 630 mg of the title compound, melting point 319-321 C (dec., discoloration starts from about 2600C) with consistent spectral data.
Analysis
Calc'd for C30H33FOs: C, 73.15; H, 6.75; F, 3.86
Found:
C, 72.85; H, 6.95; F, 3,65
Example 2 9-Fluoro-1 ',2',3',4'-tetrahydro-11p-hydroxy- 3.20-dioxopregna-1 .4-dienoll 6cr,l 7-b] naphthalen-21-oic acid, 1 -methylethyl ester
A suspension of 9-fluoro-1 ',2',3',4' tetrahydro-11p-hydroxy-3,20-dioxopregna-1,4- dieno[16a,17-b]naphthalen-21 -oic acid, methyl ester (490 mg., see Example 1) in dry isopropanol (30 ml, freshly distilled from magnesium turnings) containing sodium cyanide (10 mg) is refluxed under an atmosphere of nitrogen for 20 minutes when a clear solution results. A TLC examination at this point shows complete conversion of the starting period into a less polar compound. The mixture is then evaporated in vacuo, the residue is dissolved in chloroform, washed with dilute brine and water, dried over anhydrous magnesium sulfate and evaporated to afford 51 6 mg of the title compound. One crystallization from ethyl acetate affords the analytical specimen of the title compound as colorless needles (410 mg), melting point 269-271 OC (dec., discoloration starts from about 2500 C) with consistent spectral data.
Analysis Calc'd for C32H37FOs: C, 73.82; H, 7.16; F, 3.65
Found:
C, 73.45; H, 7.11; F, 3.47
Example 3 9-Fluoro-1 ',2',3',4'-tetrahydro-11 -hydroxy, 3,20-dicxopregna-1 ,4-dieno[1 6a,1 7-b] naphthalen-21-oic acid, butyl ester 9-Fluoro-1',2',3',4'-tetrahydro-11,B,21- dihydroxypregna-1 ,4-dieno[1 6a,1 7-b] naphthalene-3,20-dione (800 mg) is dissolved in n-butanol (1 50 ml) by warming. The solution is cooled to room temperature, copper acetate hydrate (250 mg) is added and air is bubbled into the solution with stirring for 30 minutes. Most of the n-butanol is then removed by evaporation in vacuo at 40--42 OC. The concentrate is diluted with water and extracted with chloroform.The chloroform extracts are combined, washed with a dilute ammonium chloride solution and water, dried over anhydrous magnesium sulfate and evaporated to afford 850 mg of 9-fluoro- 1 ',2',3',4-tetrahydro-l 1 P-hydroxypregna-l .4- dieno[1 6a, 1 7-b]naphthalene-2 1 -al-3,20-dione.
(This material is characterized spectroscopically.
A TLC examination shows the presence of one major compound, traces of starting material and traces of another impurity, less polar than the starting material, and believed to be 9-fluoro1 ',2',3',4'-tetrahydro-1 1 p-hydroxy-21,21 -di-n butoxy-pregna-1 ,4-dieno[1 6a,1 7-b]naphthalene- 3,20-dione).
The above crude mixture (840 mg) is dissolved in a mixture of dry n-butanol (20 ml) and dichloromethane (50 ml). Acetic acid (0.8 ml), potassium cyanide (200 mg) and active manganese dioxide (2.0 g) are added and the mixture is stirred at room temperature for 60 hours. (A shorter reaction time would be adequate). The mixture is then filtered through a bed of diatomaceous earth. The solids are washed with chloroform, the filtrate and the washings are combined, washed with water, dried over an hydros magnesium sulfate and evaporated to afford the crude product as a gum. From this the major component is isolated by preparative TLC (four, 2.0 mm silica gel plates developed with chloroform-ethyl acetate 1:1) and identifed as the title compound (487 mg).One crystallization from ethyl acetate gives 381 mg of the analytical specimen of the title compound, melting point 245-2460C with consistent spectral data.
Analysis
Calc'd for C33H39FOs: C, 74.13; H, 7.35; F, 3.55
Found:
C, 74.37; H, 7.41; F, 3.46
Example 4 9-Fluoro-1 ',2'.3'.4'-tetrahydro-l 1 -hydroxy- 3,20-dioxopregna-l ,4-dieno[1 6a,l 7-b]
naphthalene-21 -oic acid, 1,1 -dimethylethyl ester
A) 9-Fluoro-1 ',2',3',4'-tetrahydre-1 1 p- hydroxy-3,20-dioxopregna-l ,4-dieno[1 6a,l 7-b]
naphthalene-21 -oic acid
A solution of 9-fluoro-1 ',2',3',4'-tetrahydro 11P-hydroxypregna-l ,4-dieno[1 6a,1 7-b] naphthalene-2 1 -al-3,20-dione (3.0 g see
Example 1 ) in a mixture of dichloromethane (150 ml) and tetrahydrofuran (1 50 ml) containing acetic acid (3.0 ml) and water (4.0 ml) is stirred with activated manganese dioxide (6.0 g) and potassium cyanide (700 mg) for 20 hours. The mixture is then filtered and the solids are washed with warm chloroform-methanol (7:3). The filtrate and the washings are combined and evaporated in vacuo.The residue is washed with water, dried, purified by chromatography, crystallized from methanol-chloroform to afford the title compound, melting point 280-281 OC (dec.).
B) 9-Fluoro-1 ',2',3',4'-tetrahydro-1 1 p- hydroxy-3,20-dioxopregna-l ,4-dieno[1 6a, 17- blnaphthalene-21-oic acid, 1,1 -dimethylethyl ester
To a suspension of 9-fluoro-1 ',2',3',4'- tetrahydro- 11 ,B-hydroxy-3,20-dioxopregna- 1 ,4- dieno[1 6a,1 7-b]naphthalene-2 1 -oic acid (325 mg.) in dry dioxane (60 ml) containing sulfuric acid-phosphoric acid catalyst (0.4 ml.; prepared by the addition of the calculated amount of phosphorous pentoxide to 96% sulfuric acid to react with all of the water) in a pressure reaction vessel is passed a stream of isobutylene (until about 6 ml is added).The reaction vessel is closed and maintained at ambient temperature for 30 hours with stirring. The mixture is poured into a solution of sodium acetate hydrate (5.0 g) in water (500 ml) and extracted successively with chloroform and ethyl acetate. The extracts are washed with brine, combined, dried over anhydrous magnesium sulfate and evaporated.
The residue is purified by chromatography on silica gel to afford 145 mg. of the title compound, melting point 293-2960C (dec., discoloration starts from about 2750C) after crystallization from acetone-hexane.
Example 5 9-Fluoro-1 ',2',3',4'-tetrahydro-1 1 p-hydroxy- 3,20-dioxopregna-1 ,4-dieno[1 6a.l 7- b]naphthalen-21 -cic acid, 2,2-dimethylpropyl ester
A solution of 9-fluoro-1 ',2',3',4'-tetrahydro 11 P-hydroxy-3,20-dioxopregna- 1,4- dieno[l6a,l 7-b]naphthalene-21 -oic acid, methyl ester in dry dioxide (20 ml, distilled over sodium) and dry pyridine (15 ml) is refluxed with neopentyl alcohol (2.2 g) and sodium cyanide (100 mg) under a nitrogen atmosphere for 1 8 hours. The resulting solution is evaporated in vacuo and the residue is dissolved in chloroform.The chloroform solution is washed with dilute sodium chloride solution and water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is dissolved in chloroform-hexane (9:1) and chromatographed on a 35 g-silica gel column.
Elution with chloroform-hexane (9:1) gives 540 mg of material. Crystallization from acetonehexane gives 460 mg of an analytical specimen of the title compound, melting point 329-331 C (dec.).
Analysis
Calc'd for C34H41FOs: C, 74.42; H, 7.53; F, 3.46.
Found:
C, 74.39; H, 7.73; F, 3.37.
Example 6 9-Fluoro-1 1 /3-hydroxy-3,20-dioxopregna-1,$ dieno[1 6a,l 7-d]cyclohexen-21-oic acid, methyl ester
A solution of 1.2 g of 9-fluoro-1 1 ,21 - dihydroxypregna-1 ,4-dieno[1 6a, 1 7- d]cyclohexene-3,20-dione and 300 mg of copper acetate in 1 50 ml of methanol is stirred at room temperature for 1 hour while a stream of air is bubbled through the solution. The solvent is evaporated in vacuo at 300 C. The residue is diluted with water and extracted with chloroform, and then, ethyl acetate. The chloroform solution and ethyl acetate solution are washed with aqueous ammonium chloride solution (10%) :and water, dried over anhydrous sodium sulfate, evaporated in vacuo and combined to give 1.3 g of a solid.The NMR spectrum of the solid shows that it is an approximately equimolar mixture of the 21-aidehyde and 21-dimethylacetal derivatives of the starting steroid.
The solid product of the above reaction (1.3 g) is stirred in a mixture of 50 ml dry methanol and 50 ml dry dichloromethane at room temperature for about 1 6 hours with activated manganese dioxide (2.0 g), glacial acetic acid (1.0 ml) and potassium cyanide (200 mg). The suspension is filtered through a bed of Hyflo and washed with chloroform. The filtrate and washings are combined, washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo to give 1.1 g of a solid. This is dissolved in chloroform and chromatographed on a 35 g-silica gel column. Elution with chloroform gives 930 mg of material.
Crystallization from acetone-hexane gives 650 mg of the title compound, melting point 256- 2580C, with consistent spectra data.
Analysis
Calc'd for C28H3,FOs: C, 70.57; H, 7.06: F, 4.29
Found:
C, 70.66; H, 7.11; F, 4.02
Example 7 9-Fluoro-1 1 -hydrnxy-3,2O-dioxoprngna-1 4 dieno[I 6a,l 7-d]cyclohexen-21 -oic acid, I - methylethyl ester
A solution of 480 mg of 9-fluoro-1 1-hydrnxy- 3,20-dioxopregna- 1 ,4-dieno[1 61 7- d]cyclohexen-21-oic acid, methyl ester (see
Example 1) and 85 mg of sodium cyanide in 65 ml of dry isopropyl alcohol is stirred under a nitrogen atmosphere at 1 000C for about 1 6 hours. The resulting solution is evaporated in vacuo and the residue is dissolved in chloroform and washed with 25 ml of water.The aqueous layer is saturated with sodium chloride and extracted with chloroform. The chloroform solutions are combined, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is dissolved in chloroform-hexane (7:3) and chromatographed on a 25 g-silica gel column. Elution with chloroform-hexane (7:3) gives 370 mg of material. Crystallization from acetone-hexane gives 300 mg of the title compound, melting point 226-2280C, with consistent spectral data.
Analysis
Calc'd for C28H3sFOs: C, 71.46; H, 7.50; F, 4.04
Found:
C, 71.47; H, 7.44; F, 3.82
Example 8 9-Fluoro-l 1 P-hydroxy-3.20-dioxopregna-l .4- dieno[l 6a.l 7-d]cyclohexen91 -oic acid, butyl ester
A mixture of 1.0 g of 9-fluoro-l 1 P,21- dihydroxypregna-1 ,4-dieno[1 6o,1 7- d]cyclohexene-3,20-dione and 250 mg of copper acetate in 50 ml of dichloromethane and 30 ml of n-butanol is stirred at room temperature for 1 hour while a slow stream of air is bubbled through the solution. Since the rate of oxidation is extremely slow, the dichloromethane is evaporated and replaced with 50 ml of n-butanol.
Another 200 mg of copper acetate is added and the reaction is continued for 1.5 hour when the starting material disappears. The solvent is then evaporated in vacuo at 35--400C and the residue is diluted with 200 ml of water and extracted with dichloromethane, and then ethyl acetate. The dichloromethane solution and ethyl acetate solution are washed with ammonium chloride solution (10%) and water, combined, dried over anhydrous sodium sulfate and evaporated in vacuo to give 1.2 g of solid. The NMR spectrum of the solid shows that it is an approximately equimolar mixture of the 21-aldehyde and 21-din-butylacetal derivatives of the starting steroid.
The solid product of the above reaction (1.2 g) is dissolved in 50 ml of dry dichloromethane and 30 ml of dry n-butanol and stirred at room temperature for about 1 6 hours with 2.0 g of activated manganese dioxide, 1.0 ml of glacial acetic acid and 200 mg of potassium cyanide. A dry calcium chloride tube is attached to the fiask to avoid contact with moisture. After 20 hours another 2.0 g of activated manganese dioxide and 200 mg of potassium cyanide are added. The suspension is stirred at room temperature for 7 hours, filtered through a bed of Hyflo, and washed thoroughly with dichloromethane. The filtrate and washings are combined and washed with a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated in vacuo. The title compound in the residue cannot be successfully separated from impurities on precoated silica gel TLC plate.It can, however, be successfully purified on E. Merck precoated silica gel TLC plate (2 mm, 2.5:97.5 methanol-chloroform) to give 400 mg of a foam.
Crystallization from ethyl acetate-hexane gives 330 mg of the title compound, melting point 203-2090C, with consistent spectra data.
Analysis
Calc'd for C29H37FO5:
C, 71.87; H, 7.70; F, 3.92
Found:
C, 71.98; H, 7.73; F, 3.62
Example 9 9-l-luoro-1 I -hydroxy-1 ',2'-dimethyl-3,20- dioxopregna-1,4-dieno[16α,17-d]cyclohexen- 21-oic acid, methyl ester
A solution of 4.9 g of 9-fluoro-11p,21- dihydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4- dieno[16er,17-d]cyclohexene and 1.1 g of copper acetate in 800 ml of methanol is reacted with air following the procedure described in Example 1 (first paragraph) to yield 5.0 g of an approximately equimolar mixture of the 21-aldehyde and 21dimethylacetal derivatives of the starting steroid.
The solid product of the above reaction (4.5 g) is stirred in a mixture of 250 ml dry methanol and 250 ml dry dichloromethane at room temperature for about 16 hours under a nitrogen atmosphere with activated manganese dioxide (7.0 g), glacial acetic acid (4.0 ml) and potassium cyanide (700 mg). The resulting suspension is filtered through a bed of diatomaceous earth and washed with chloroform-methanol (9:1). The filtrate and washings are combined and evaporated in vacuo to give 5.6 g of a solid. This is dissolved in chloroform-hexane (9:1) and chromatographed on a 100 g silica gel column. Eiution with chloroform-hexane (9:1) yields 4.2 g of material, 1.5 g of which is crystallized from acetone-hexane to give 900 mg of an analytical specimen of the title compound, melting point 256-2580C.
Analysis Calc'd for C28H3sFOs C, 71.46; H, 7.50; F, 4.04
Found:
C, 71.38; H, 7.50; F, 3.95
Example 10 9-Fluoro-11ss-hydroxy-1',2'-dimethyl-3,20- dioxopregna-1 ,4dieno[1 6a,1 7-d]cyclohexen- 21-oic acid, ethyl ester
A) 9-Fluoro-1 1 p-hydroxy-1 ',2'-dimethyl-3,20 dioxypregna-l ;4-dieno[l 6a.l 7-d]cyclohexen- 21-oic acid
A solution of 9-fluoro-1 1 -hydroxy-1 ',2'- dimethyl-3,20-dioxopregna-1,4-dieno[16α,17- d]cyclohexen-21-oic acid, methyl ester (2.5 g) in a mixture of methanol (110 ml) and tetrahydrofuran (200 ml) is stirred with a solution of potassium hydroxide (640 mg) in water (10 ml) for 1.0 hour under a nitrogen atmosphere.The reaction mixture is then acidified with 5% hydrochloric acid and is evaporated in vacuo. The resulting slurry is mixed with water and filtered to afford 700 mg of the title compound, melting point 234-2380C.
The filtrate is evaporated in vacuo and washed with chloroform-methanol (4:1). The solvents are evaporated to afford 1.4 g of the hydrated form of the title compound, melting point 215-240 C.
B) 9-Fluoro-1 1 p-hydroxy-1 ',2'-dimethyl-3,20 dioxopregna-1,4-dieno[16α,17-d]cyclohexen- 21-oic acid, ethyl ester
To a suspension of 235 mg of 9-fluoro-11ss- hydroxy-1 ',2'-dimethyl-3,20-dioxopregna-1 ,4- dieno[16α,17-d]cyclohexen-21-oic acid in 5.0 ml of dry dichloromethane is added successively, 0.5 ml of triethylamine and 0.068 ml of pivaloyl chloride. After the resulting solution is stirred at room temperature for 15 minutes, 0.116 ml of absolute ethanol is added. After 3.0 hours, the mixture is acidified with 50% hydrochloric acid, poured into water and extracted with chloroform.
The chloroform extracts are combined, washed with water, dried over anhydrous magnesium sulfate, and evaporated. The residue is subjected to preparative thin-layer chromatography to isolate 97 mg of the title compound, melting point 1 98-2000C.
Example 11 9-Fluoro-1 1 -hydroxy-1 ',2'-dimethyl-3,20- dioxopregna-1,4dieno[16α,17-d]cyclohexen- 21-oic acid, 1,1 -dimethylethyl ester
A solution of 700 mg of 9-fluoro-11ss-hydroxy- 1',2'-dimethyl-3,20-dioxopregna-1,4 dieno[16α,17-d]cyclohexen-21-oic acid (see
Example 1 OA) in 60 ml of dry dioxane containing 12 ml of isobutylene and 0.7 ml of a sulfuric acid/phosphoric acid catalyst (prepared by adding phosphorous pentoxide to 96% sulfuric acid) is maintained in a pressure reaction vessel at room temperature for 24 hours. A stream of dry nitrogen is then passed through the solution to remove the excess isobutylene and the mixture is poured into a saturated sodium bicarbonate solution.The steroid is isolated by extraction with chloroform and the chloroform solution is washed with water, dried over an hydros magnesium sulfate and the solvents are evaporated. The residue (760 mg) is subjected to chromatography on a column of silica gel to isolate 500 mg of the title compound, melting point 209--21 OOC after crystallization from acetone-hexane.
Example 12 9-Fluoro-11 /3-hydroxy-3,20-dioxopregna-1,4- dieno[1 6a,1 7-d]cyclohexen-21 -oic acid, 2,2- dimethylpropyl ester
A solution of 9-fluoro-l 1 P-hydroxy-3,20- dioxopregna-1 ,4-dieno[1 6a,1 7-d]cyclohexen-21 - oic acid, methyl ester (25 mg) in dry dioxane (2.0 ml) containing dry neopentyl alcohol (400 mg) and sodium cyanide (5.0 mg) is refluxed under anhydrous conditions for 2.0 hours. The mixture is then cooled, added to water, and extracted with chloroform. The chloroform extract is washed with water, dried over anhydrous magnesium sulfate, evaporated and the residue is crystallized from ethyl acetate-chloroform to afford 23 mg. of the title compound, melting point 2880C (dec., discoloration starts before melting point).
Example 13 9-Fluoro-1 ',2',3',4'-tetrahydro-1 1 p-hydroxy- 3,20-dioxopregna-1 ,4dieno[1 6a,1 7- bjnaphthalene-21 -oic acid, methyl ester
A) 9-Fluoro-1 1 -hydroxy-3,20-dioxopregna- 1,4,1 6-triene-21 -carboxaldehyde and 9-fluoro 11 p-hydroxy-21 -dimethoxypregna-1,4,16- triene-3,20-dione
A solution of 9-fluoro-1 1 ,21 - dihydroxypregna-1 ,4, 1 6-triene-3,20-dione (1.7 g) is dissolved in methanol (300 ml) by warming and the solution is cooled to room temperature.
Copper acetate (100 mg) is added and a stream of air is passed into the solution under stirring. In about 20 minutes the starting material disappears to give less polar compounds as indicated by thin layer chromatography. The solution is then evaporated in vacuo, the residual solid is washed successively with a dilute ammonium chloride solution and water and is dried to afford an essentially equimoiar mixture (1.9 g) of the title aldehyde (as its hydrate) and the title acetal as indicated by the NMR spectrum. When dried in vacuo (125-1 300C, 0.5 mm of Hg) for 2.0 hours, this material is converted into an essentially equimolar mixture (1.77 g) of the title aldehyde and acetal as shown by NMR and IR spectra.
B) 9-Fluoro-l 1 P-hydroxy-3.20-dioxopregna- 1,4,1 6-trieno-21 -oic acid, methyl ester
To a stirred solution of the mixture of aldehyde and acetal prepared in part A (1.75 g), in a mixture of anhydrous dichloromethane (100 ml) and anhydrous methanol (20 ml) is added successively activated manganese dioxide (4.0 g), potassium cyanide (500 mg) and glacial acetic acid (0.5 ml). In less than 1.0 hour, the starting materials disappear to give essentially a single less polar compound as indicated by thin layer chromatography. The reaction mixture is filtered through a bed of diatomaceous earth and the filter cake is washed with several small portions of a warm mixture of dichloromethane-methanol. Thefiltrate and the washings are combined and evaporated to a solid residue which is washed with water and dried.Crystallization of the resulting material from methanoldichloromethane (with evaporative removal of dichloromethane) yields 1.4 g of the title compound, melting point 284286 C.
C) 9-Fluoro-1 ',2',3',4'-tetrahydro-1 ss- hydroxy-3,20-dioxopregna-1 ,4dieno[1 6a,I 7- b]naphthalene-21-oic acid, methyl ester
A solution of 9-fluoro-11ss-hydroxy-3,20- dioxopregna-1,4,1 6-trieno-21-oic acid, methyl ester (100 mg) in benzocyclobutene (5.0 ml) containing 4,4'-thiobis-6-t-butyl-m-cresol (6.0 mg) is refluxed under an atmosphere of nitrogen for 10 hours; a solid separates from the solution.
The unreacted benzocyclobutene is recovered by vacuum distillation and the pot residue is crystallized from methanol-dichloromethane (by evaporative removal of the dichloromethane) to yield the title compound, melting point 3253260C (discoloration starts from about 2950C).
Example 14 9-Fluoro-l 1 -hydroxy-3,20-dioxopregna- 1,4,16-trieno-21-oic acid
A solution of 9-fluoro-11ss-hydroxy-3,20- dioxopregna-1,4,16-trieno-21-oic acid, methyl ester (100 mg; see Example 1 B) in a mixture of methanol (15 ml) and tetrahydrofuran (15 ml) is stirred with 3M sodium hydroxide (1.0 ml) under a nitrogen atmosphere for 2.0 hours. The mixture is then acidified with 5% hydrochloric acid and evaporated to a residue. The residue is washed with water and crystallized from chloroformmethanol to yield the title compound. This material turns black when heated to 4000 C, but does not melt.
The steroid of this Example can be esterified using conventional techniques and then reacted with a benzocyclobutene as described in Example 1 3C to yield a product of formula I.
Example 15 9-Fluoro-1 1 -hydrnxy-1 ',2'-dimethyl-3,20 dioxopregna-1 ,4dieno [16 , 1 7-d]cyclehexene- 21-oic acid, n-butyl ester
A) 9-Fluoro-11ss-hydroxy-3,20-dioxopregna- 1,4,1 6-triene-21 -carboxaldehyde and 9-fluoro 11 ss-hydroxy-21 -dimethoxypregna-1,4,16- triene-3,20-dione A solution of 9-fluoro-1 1 P,21- dihydroxypregna-1 ,4,1 6-triene-3,20-dione (1.7 g) is dissolved in methanol (300 ml) by warming and the solution is cooled to room temperature.
Copper acetate (100 mg) is added and a stream of air is passed into the solution under stirring In about 20 minutes the starting material disappears to give less polar compounds as indicated by thin layer chromatography. The solution is then evaporated in vacuo, the residual solid is washed successively with a dilute ammonium chloride solution and water and is dried to afford an essentially equimolar mixture (1.9 g) of the title aldehyde (as its hydrate) and the title acetal as indicated by the NMR spectrum. When dried in vacuo (125-130 C, 0.5 mm of Hg) for 2.0 hours, this material is converted into an essentially equimolar mixture (1.77 g) of the title aldehyde and acetal as shown by NMR and IR spectra.
B) 9-Fluoro-11ss-hydroxy-3,20-dioxapregna- 1,4,1 6-trieno-21 -eic acid, methyl ester
To a stirred solution of the mixture of aldehyde and acetal prepared in part A, in a mixture of anhydrous dichloromethane (100 ml) and anhydrous methanol (20 ml) is added successively activated manganese dioxide (4.0 g), potassium cyanide (5Q0 mg) and glacial acetic acid (0.5 ml). In less than 1.0 hour, the starting materials disappear to give essentially a single less polar compound as indicated by thin layer chromatography. The reaction mixture is filtered through a bed of diatomaceous earth and the filter cake is washed with several small portions of a warm mixture of dichloromethane-methanol. The filtrate and the washings are combined and evaporated to a solid residue which is washed with water and dried.Crystallization of the resulting material from methanoldichloromethane (with evaporative removal of dichloromethane) yields 1.4 g of the title compound, melting point 284-286 0C.
C) 11ss-(Acetyloxy)-9-fluoro-3,20-dioxopregna- 1,4,1 6-trieno-21 -oic acid, methyl ester
A solution of 9-fluoro-l 1 P-hydroxy-3,20- dioxopregna-1,4,1 6trieno-21-oic acid, methyl ester (400 mg) in a mixture of glacial acetic acid (9.0 ml) and acetic anhydride (9.0 ml) containing p-toluenesulfonic acid (200 mg) is stirred at room temperature for 24 hours. Sodium acetate (300 mg) is added and the mixture is poured into ice water (200 ml) with stirring. The solid that separates is isolated by filtration, washed with water and dried to yield 400 mg of the title compound that is contaminated with only trace amount impurities as judged by thin layer chromatography. Crystallization of this material from ethyl acetate-hexane yields 350 mg of the title compound, melting point 235-2360C.
D) 11,B-(Acetyloxy)-9-fluoro-1t,2t-dimethyl- 3,20-dioxopregna-1,4-dieno-[16α,17- d]cyclohexen-21-oic acid, methyl ester
To a stirred solution of 11p-(acetyloxy)-9- fluoro-3,20-dioxopregna-1 ,4,1 6-trieno-2 1 -oic acid, methyl ester (320 mg) in anhydrous dichloromethane (25 ml) containing aluminum chloride (100 mg) is added 2,3-dimethyl-1,3- butadiene (0.25 ml). The mixture is stirred at room temperature for 1.5 hour, poured into water and extracted with dichloromethane. The dichloromethane extract is washed with water, dried over anhydrous magnesium sulfate and evaporated to a residue (300 mg). This is subjected to chromatography on a column of silica gel (10 g) to isolate the title compound (265 mg). Crystallization from ethyl acetate-hexane gives needles (160 mg), melting point 1721730C.
E) 9-Fluoro-11 /3-hydroxy-1 ',2'-dimethyl-3,20dioxopregna-1,4-dieno[16α.17-d]cyclohexen- 21-oic acid
A solution of 1 1 P-(acetyloxy)-9-fluoro-l ',2' dimethyl-3,20-dioxopregna-1,4-dieno[16α,17- d]cyclohexen-2 1 -oic acid, methyl ester (235 mg) in a mixture of 90% methanol (100 ml) and tetrahydrofuran (10 ml) containing 3M sodium hydroxide (2.0 ml) is stirred under an atmosphere of nitrogen in a bath at 60-700C for 2-3 hours.
The mixture is acidified with the minimum amount of 5% hydrochloric acid and evaporated in vacuo. The residue is worked up with water and dried to yield 195 mg of the title compound.
Crystallization from a mixture of chloroformmethanol gives the analytical specimen of the title compound, melting point 236-2390C.
F) 9-Fluoro-11,B-hydroxy-1 ',2'-dimethyl-3,20 dioxopregna-1,4dieno[16α,17-d]cyclohexen- 21-oic acid, n-butyl ester To a solution of 9-fluoro-l p-hydroxy-1 ',2'dimethyl-3,20-dioxopregna-1,4-dieno[16α,17- d]cyclohexen-21-oic acid (175 mg) in dichloromethane (40 ml) containing a few drops of methanol is added an excess of an ethereai solution of diazobutane. After 5 minutes, the excess diazobutane is destroyed by the addition of a few drops of acetic acid. The solution is evaporated to dryness and the residue is crystallized from acetone-hexane to yield 127 mg of the title compound melting point 209-211 OC.
Example 16 (11 p, 6p)-9-Fluoro-1 ',2',3',4'-tetrahydro-1 1 hydroxy-3,20-dioxopregna-1,4-dieno[16,17- b]naphthalen-21-oic acid, octyl ester
A solution of 500 mg (0.96 mmole) of (11ss,16α)-9-fluoro-1',2',3',4'-tetra-11-hydroxy3,20-dioxopregna-1 ,4-dieno[1 6,1 7- b]naphthalen-21-oic acid, 1 -methylethyl ester and 40 mg of sodium cyanide in 40 ml of dry octanol-1 (distilled over calcium hydride) was stirred at 1300 under nitrogen atmosphere for 1.5
hour. The resulting solution was evaporated in vacuo. The residue was dissolved in dichloromethane, washed with water, dried over anhydrous Na2SO4 and evaporated in vacuo to give a residue which was dissolved in chloroformhexane (7:3) and chromatographed on a 20 g silica gel column. Elution with chloroform-hexane (7:3) gave 485 mg (97%) of product.
Crystallization from acetone-hexane gave 370 mg (74%) of product, m.p. 215-21 60.
Analysis
Calc'd for C37H47F05: C, 75.22; H, 8.02; F, 3.22
Found:
C, 75.34; H, 8.23; F, 3.21
Claims (39)
1. A steroid having the formula
an ester thereof, or the 1 ,2-dehydro derivative such a steroid or ester, wherein X is hydrogen or halogen; Y is hydrogen, fluorine or methyl; R4 is chlorine, fluorine or hydroxy and R5 is hydrogen or
R4 and R5 together are =0; R2 and R3 are the same or different and are hydrogen, alkyl or aryl, or taken together with the double bond to which they are attached, form a benzene ring; R6 and R7 are the same or different and are hydrogen, alkyl, alkoxy, formyl,
0 alkyl--CC--O-, phenyl or cyano and in addition hydroxy, halogen, carboalkoxy and alkylcarbonyl when R3 and R4 are separate with the proviso that when R8 and R7 are different, one of R6 and R7 is hydrogen;R8 is hydrogen or -CH-R9R10 wherein R9 and R10 are the same or different and are hydrogen or alkyl.
2. A steroid according to claim 1 having the formula
or the 1,2-dehydro derivative thereof, wherein R is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl.
3. A steroid according to claim 1 having the formula
or the 1,2-dehydro derivative thereof, wherein R1 is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl;
X is hydrogen or halogen; Y is hydrogen, fluorine or methyl; R4 is chlorine, fluorine or hydroxy and R5 is hydrogen or R4 and R5 together are =0; R6 and R7 are the same or different and are hydrogen, alkyl, alkoxy, carboalkoxy, formyl,
0 0 alkyl-C-, alkyl-C-O hydroxy, halogen, phenyl or cyano with the proviso that when R6 and R7 are different, one of
R6 and R7 is hydrogen;R8 is hydrogen or-CH- RgRto wherein R9 and R10 are the same or different and are hydrogen or alkyl.
4. A steroid according to claim 1 having the formula
or the 1,2-dehydro derivative thereof, wherein R1 is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl;
R2 and R3 are the same or different and are hydrogen, alkyl or aryl; R4 is hydrogen and RB is hydroxy or together R4 and RB are =0; X is hydrogen or halogen; and y is hydrogen, methyl or fluorine.
5. A steroid according to claim 1 having the formula
or the 12-dehydro derivative thereof, wherein R, is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl;
R2 and R3 are the same or different and are hydrogen, alkyl or aryl; R4 is hydrogen and RB is hydroxy or together R4 and R5 are =0; and Y is hydrogen, methyl or fluorine.
6. A steroid in accordance with any one of claims 1 to 3 wherein X is fluorine.
7. A steroid in accordance with any one of claims 1 to 6 wherein Y is hydrogen.
8. A steroid in accordance with any one of claims 1 to 7 wherein R4 is hydroxy and Rs is hydrogen.
9. A steroid in accordance with any one of claims 1 to 3 wherein R6 and R7 are hydrogen.
10. A steroid in accordance with any one of claims 1 to 3 wherein R8 is hydrogen.
11. A steroid in accordance with any one of claims 1 to 3 wherein R8 is methyl.
12. 9-Fluoro-1 ',2',3',4'-tetrahydro-1 1 p- hydroxy-3,20-dioxopregna-1 ,4-dieno[1 6a,1 7- b]naphthalene-21-oic acid, methyl ester
1 3. 9-Fluoro-1 ',2',3',4'-tetrahydro-1 1 - hydroxy-3,20-dioxopregna-1 ,4-dieno[1 61 7- b]naphthalen-2 1 -oic acid, 1 -methylethyl.
14. 9-Fluoro-1 ',2',3',4'-tetrahydro-1 1 - hydroxy-3,20-dioxopregna-1,4-dieno[16α,17- b]naphthalen-21-oic acid, butyl ester.
15.9-Fluoro-1',2',3',4'-tetrahydro-11ss hydroxy-3,20-dioxopregna-1,4-dieno[16α,17- b] naphthalene-2 1 -oic acid, 1,1-dimethylethyl ester.
1 6. 9-Fluoro-1 ',2',3',4'-tetrahydro-1 1 p hydroxy-3,20-dioxopregna-1 ,4-dieno[1 6a,1 7- b]naphthalen-21-oic acid, 2,2-dimethylpropyl ester.
17. 9-Fluoro-11ss-hydroxy-3,20-dioxopregna- 1,4-dieno[16α,17-d]cyclohexen-21-oic acid, methyl ester.
18. 9-Fluoro-11ss-hydroxy-3,20-dioxopregna- 1,4-dieno[16α,17-d]cyclohexen-21-oic acid, 1 - methylethyl ester.
19. 9-Fluoro-11ss-hydroxy-3,20-dioxopregna- 1,4-dieno[16α,17-d]cyclohexen-21-oic acid, butyl ester.
20. 9-Fluoro-11ss-hydroxy-1',2'-dimethyl- 3,20-dioxopregna-1,4-dieno[16α,17- d]cyclohexen-21-oic acid, methyl ester.
21. 9-Fluoro-11ss-hydroxy-1',2'-dimethyl- 3,20-dioxopregna-1 ,4-dieno[1 6a,1 7- d]cyclohexen-21-oic acid, ethyl ester.
22. 9-Fluoro- 1 1 P-hyd roxy3,20-d ioxopregna- 1,4-dieno[16α,17-d]cyclohexen-21-oic acid, 2,2- dimethylpropyl ester.
23. 9-Fluoro-1 1 p-hydroxy-1 ',2'-dimethyl 3,20-dioxopregna-1 ,4-dieno[1 6a,1 7- d]cyclohexen-21-oic acid, l,l-dimethylethyl ester.
24. A steroid having the formula
or the 1,2-dehydro derivative thereof, wherein X is hydrogen or halogen; Y is hydrogen, fluorine or methyl; R4 is chlorine, fluorine or hydroxy and RB is hydrogen or R4 and RB together are =0; R2 and R3 are the same or different and are hydrogen, alkyl or aryl or taken together with the double bond to which they are attached form a benzene ring; Re and R7 are the same or different and are hydrogen, alkyl, alkoxy, formyl,
0 alkyl-C-O-, phenyl or cyano and in addition, hydroxy, halogen, carboalkoxy and alkylcarbonyl when R2 and R3 are separate, with the proviso that when Re and R7 are different, one of R6 and R7 is hydrogen;; Re is hydrogen or CHRBR10 wherein R9 and R10 are the same or different and are hydrogen or alkyl.
25. A steroid according to claim 24 having the formula
or the 1,2-dehydro derivative thereof, wherein X is hydrogen or halogen; Y is hydrogen, fluorine or methyl; R4 is chlorine, fluorine or hydroxy and RB is hydrogen or R4 and RB together are =0; R6 and R7 are the same or different and are hydrogen, alkyl, alkoxy, carboalkoxy, formyl,
0 0 II If alkyl--CC-, alkyl--CC--O-, hydroxy, halogen, phenyl or cyano with the proviso that when Re and R7 are different, one of Re and R7 is hydrogen;; Re is hydrogen or -CH RgR10 wherein R9 and R10 are the same or different and are hydrogen or alkyl.
26. A steroid according to claim 24 having the formula
27. A steroid according to claim 24 having the formula
28. A steroid having the formula
or the 1,2-dehydro derivative thereof, wherein R, is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl;
X is hydrogen or halogen; Y is hydrogen, fluorine or methyl;R4 is chlorine, fluorine or hydroxy and RB is hydrogen or R4 and RB together are =0; R2 and R3 are the same or different and are hydrogen, alkyl or aryl, or taken together with the double bond to which they are attached form a benzene ring; Re and R7 are the same or different and are hydrogen, alkyl, alkoxy, formyl,
0 alkyl--CC--O-, phenyl or cyano and in addition, hydroxy, halogen, carboalkoxy and alkylcarbonyl when R2 and R3 are separate with the proviso that when RB and R7 are different, one of R6 and R7 is hydrogen;; RB is hydrogen or --CHH-R,R,, wherein R9 and Ro are the same or different and are hydrogen or alkyl.
29. A steroid according to claim 28 having the formula
or the 1,2-dehydro derivative thereof, wherein R1 is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl;
X is hydrogen or halogen; Y is hydrogen, fluorine or methyl; R4 is chlorine, fluorine or hydroxy and RB is hydrogen or R4 and RB together are =0; R6 and R7 are the same or different and are hydrogen, alkyl, alkoxy, carboalkoxy, formyl,
0 0 II II alkyl-C-, al kyl-C-, hydroxy, halogen, phenyl or cyano with the proviso that when R6 and R, are different, one of
R6 and R7 is hydrogen;; RB is hydrogen or (CH-R9-R10 wherein R9 and R10 are the same or different and are hydrogen or alkyl.
30. A steroid according to claim 28 having the formula
or the 1,2-dehydro derivation thereof, wherein R, is alkyl of 1 to 10 carbon atoms, aryi or arylalkyl;
R2 and R3 are the same or different and are hydrogen, alkyl or aryl; R4 is hydrogen and RB is hydroxy or together R4 and RB are =0; and R6 is hydrogen, methyl or fluorine.
31. A steroid according to claim 28 having the formula
32. A steroid having the formula
or
or the 1,2-dehydro derivative thereof, wherein R, is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl;
X is hydrogen or halogen; Y is hydrogen, fluorine or methyl; R4 is chlorine, fluorine or hydroxy and RB is hydrogen or R4 and RB together are =0; R2 and R3 are the same or different and are hydrogen, alkyl or aryl, or taken together with the double bond to which they are attached, form a benzene ring;R6 and R7 are the same or different and are hydrogen, alkyl, alkoxy, formyl,
0 alkyl--CC--O-, phenyl or cyano and in addition, hydroxy, halogen, carboalkoxy and alkylcarbonyl when R2 and R3 are separate with the proviso that when R6 and R7 are different, one of R6 and R7 is hydrogen; RB is hydrogen or -CH-R9R10 wherein R9 and Ro are the same or different and are hydrogen or alkyl.
33. A steroid according to claim 32 having the formula
or
or the 1,2-dehydro derivative thereof, wherein R, is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl;
X is hydrogen or halogen; Y is hydrogen, fluorine or methyl; R4 is chlorine, fluorine or hydroxy and RB is hydrogen or R4 and RB together are =0; R6 and R7 are the same or different and are hydrogen, alkyl, alkoxy, carboalkoxy, formyl,
0 0 II Ij alkyl-C-, alkyl-C-O-, hydroxy, halogen, phenyi or cyano with the proviso that when R6 and R7 are different, one of
R6 and R7 is hydrogen; ; RB is hydrogen or-CH- R,-R,, wherein RB and R10 are the same or different and are hydrogen or alkyl.
34. A steroid according to claim 32 having the formula
or
35. A steroid according to claim 32 having the formula
or
36. A compound according to Claim 1 as named in any of the Examples.
37. An antiinflammatory pharmaceutical composition comprising a compound according to any preceding claim and a pharmaceutical carrier.
38. A composition according to Claim 37 in the form of a topical cream, ointment, lotion or spray.
39. A compound according to any one of
Claims 1 to 36 for use as an antiinflammatory agent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/919,006 US4160772A (en) | 1978-06-26 | 1978-06-26 | Steroidal[16α,17-d]cyclohexene-21-carboxylic acid esters |
| US05/919,020 US4164504A (en) | 1978-06-26 | 1978-06-26 | Steroidal[16α,17-b]naphthaleno-21-carboxylic acid esters |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2023608A true GB2023608A (en) | 1980-01-03 |
| GB2023608B GB2023608B (en) | 1983-04-27 |
Family
ID=27129763
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB7918394A Expired GB2023608B (en) | 1978-06-26 | 1979-05-25 | Steroidal cyclohexene and naphthalene-21-oic acids and esters |
| GB08208035A Expired GB2106116B (en) | 1978-06-26 | 1982-03-19 | Steroidal(16a,17-b)cyclohexene and naphthaleno-21-als and acetals |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08208035A Expired GB2106116B (en) | 1978-06-26 | 1982-03-19 | Steroidal(16a,17-b)cyclohexene and naphthaleno-21-als and acetals |
Country Status (24)
| Country | Link |
|---|---|
| AU (1) | AU524173B2 (en) |
| CA (1) | CA1142916A (en) |
| CH (1) | CH642087A5 (en) |
| CS (2) | CS208160B2 (en) |
| DD (1) | DD144550A5 (en) |
| DE (1) | DE2925552A1 (en) |
| DK (1) | DK267079A (en) |
| ES (2) | ES481875A1 (en) |
| FI (1) | FI791934A (en) |
| FR (1) | FR2429796A1 (en) |
| GB (2) | GB2023608B (en) |
| GR (1) | GR72244B (en) |
| HU (1) | HU180089B (en) |
| IE (1) | IE49178B1 (en) |
| IL (1) | IL57622A (en) |
| IT (1) | IT1162746B (en) |
| LU (1) | LU81420A1 (en) |
| NL (1) | NL7904510A (en) |
| NO (1) | NO792118L (en) |
| NZ (1) | NZ190510A (en) |
| PL (1) | PL216614A1 (en) |
| PT (1) | PT69818A (en) |
| SE (1) | SE7905568L (en) |
| SU (2) | SU946404A3 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4391755A (en) * | 1982-01-18 | 1983-07-05 | E. R. Squibb & Sons, Inc. | Steroid monohydrates, formulations containing same and method |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2924307A (en) * | 1956-09-27 | 1960-02-09 | Gen Motors Corp | Brake adjusting device |
| US3944584A (en) * | 1975-02-03 | 1976-03-16 | E. R. Squibb & Sons, Inc. | Steroidal (16α,17-d)cyclohexenes |
-
1979
- 1979-05-21 NZ NZ190510A patent/NZ190510A/en unknown
- 1979-05-23 CA CA000328182A patent/CA1142916A/en not_active Expired
- 1979-05-25 GB GB7918394A patent/GB2023608B/en not_active Expired
- 1979-05-28 AU AU47481/79A patent/AU524173B2/en not_active Ceased
- 1979-05-29 GR GR59210A patent/GR72244B/el unknown
- 1979-06-07 FR FR7914578A patent/FR2429796A1/en active Granted
- 1979-06-08 NL NL7904510A patent/NL7904510A/en not_active Application Discontinuation
- 1979-06-15 CS CS799420A patent/CS208160B2/en unknown
- 1979-06-15 CS CS794141A patent/CS208159B2/en unknown
- 1979-06-18 FI FI791934A patent/FI791934A/en not_active Application Discontinuation
- 1979-06-22 IL IL57622A patent/IL57622A/en unknown
- 1979-06-25 SU SU792781351A patent/SU946404A3/en active
- 1979-06-25 SE SE7905568A patent/SE7905568L/en not_active Application Discontinuation
- 1979-06-25 NO NO792118A patent/NO792118L/en unknown
- 1979-06-25 IT IT23840/79A patent/IT1162746B/en active
- 1979-06-25 ES ES481875A patent/ES481875A1/en not_active Expired
- 1979-06-25 ES ES481866A patent/ES481866A1/en not_active Expired
- 1979-06-25 HU HU79SU1020A patent/HU180089B/en unknown
- 1979-06-25 LU LU81420A patent/LU81420A1/en unknown
- 1979-06-25 DK DK267079A patent/DK267079A/en not_active Application Discontinuation
- 1979-06-25 CH CH592479A patent/CH642087A5/en not_active IP Right Cessation
- 1979-06-25 DE DE19792925552 patent/DE2925552A1/en not_active Withdrawn
- 1979-06-26 DD DD79213895A patent/DD144550A5/en unknown
- 1979-06-26 PT PT69818A patent/PT69818A/en unknown
- 1979-06-26 PL PL21661479A patent/PL216614A1/xx unknown
- 1979-08-08 IE IE1181/79A patent/IE49178B1/en unknown
-
1980
- 1980-10-23 SU SU802995671A patent/SU1055334A3/en active
-
1982
- 1982-03-19 GB GB08208035A patent/GB2106116B/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| CH642087A5 (en) | 1984-03-30 |
| DK267079A (en) | 1979-12-27 |
| IE791181L (en) | 1979-12-26 |
| PT69818A (en) | 1979-07-01 |
| GB2106116A (en) | 1983-04-07 |
| ES481866A1 (en) | 1980-06-16 |
| IT1162746B (en) | 1987-04-01 |
| IL57622A (en) | 1983-02-23 |
| IT7923840A0 (en) | 1979-06-25 |
| IE49178B1 (en) | 1985-08-21 |
| PL216614A1 (en) | 1980-03-24 |
| CA1142916A (en) | 1983-03-15 |
| HU180089B (en) | 1983-01-28 |
| SU1055334A3 (en) | 1983-11-15 |
| CS208160B2 (en) | 1981-08-31 |
| NL7904510A (en) | 1979-12-28 |
| ES481875A1 (en) | 1980-07-01 |
| CS208159B2 (en) | 1981-08-31 |
| FR2429796A1 (en) | 1980-01-25 |
| DD144550A5 (en) | 1980-10-22 |
| SU946404A3 (en) | 1982-07-23 |
| FI791934A (en) | 1979-12-27 |
| GB2106116B (en) | 1983-08-03 |
| LU81420A1 (en) | 1979-09-12 |
| AU4748179A (en) | 1980-01-03 |
| DE2925552A1 (en) | 1980-01-17 |
| IL57622A0 (en) | 1979-10-31 |
| NO792118L (en) | 1979-12-28 |
| GR72244B (en) | 1983-10-04 |
| NZ190510A (en) | 1982-03-09 |
| GB2023608B (en) | 1983-04-27 |
| SE7905568L (en) | 1979-12-27 |
| AU524173B2 (en) | 1982-09-02 |
| FR2429796B1 (en) | 1983-01-07 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |