US2915434A - 16-fluoro-3-keto-17beta-(beta-hydroxy-propanoyl)-delta4-androstenes and derivatives thereof - Google Patents
16-fluoro-3-keto-17beta-(beta-hydroxy-propanoyl)-delta4-androstenes and derivatives thereof Download PDFInfo
- Publication number
- US2915434A US2915434A US800997A US80099759A US2915434A US 2915434 A US2915434 A US 2915434A US 800997 A US800997 A US 800997A US 80099759 A US80099759 A US 80099759A US 2915434 A US2915434 A US 2915434A
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- United States
- Prior art keywords
- hydroxy
- propanoyl
- fluoro
- androstene
- 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.)
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Definitions
- Starting compounds which are used in the preparation of the valuable compounds of this invention include those having the formulas out/ X wherein .X'and Yhave the-same meaning as above and Z is bromine or iodine.
- the A the A and the A -de- .hydro .analogs of these compounds are also used as starting materials in this invention.
- the steroid compound with the side chain bromohydrin or iodohydrin function is treated with a debrominating or deiodinating agent such as zinc and acetic acid or Raney nickel. It-is preferred to use Raney nickel because of the ease of manipulation and the high yields which can be obtained.
- Suitable solvents for carrying out the reaction with Raney nickel include reaction inert organic solvents such as lower aliphatic oxygenated sol-vents including ethers, alcohols, acids and ketones containing up to five carbon atoms.
- reaction inert organic solvents such as lower aliphatic oxygenated sol-vents including ethers, alcohols, acids and ketones containing up to five carbon atoms.
- .Methanol, ethanol, .propanol, isopropanol, pentanol, acetone, .methyl isopropyl ketone, dioxane, acetic acid and propionic acid are examples of suitable solvents.
- the amount of .Raney nickel used is not critical although to insure the most economical utilization of the steroid. starting material, it is generally preferred to use an excess of this dehalogenating agent. .From four to twenty grams of Raney nickel per gram of steroid starting material has been found to provide suitable yields. The preferred excess, as will be recognized by those skilled in. the art, will depend upon the degree of activity of the Raney nickel. This in turn will depend upon its previous treatment. With Raney nickel which has been washed first with water, then with acetic acid, then with methanol and finally with acetone in accordance with known procedures, it is usually found that from ten to fifteen grams of Raney nickel per gram of steroid leads to excellent yields. However, the Raney nickel can be used without previous treatment or with other known treatments and still function as a dehalogenating agent for the bromohydrin or iodohydrin.
- the duration of the reaction is not critical depending only upon the degree of activity of the. Raney nickel. This degree of activity is readily determined by tests well known to those skilled in the art, and include, for example, the reduction of known compounds requiring varying degrees of reducing activity. Reaction periods as short as five minutes and as long as twenty-four hours have been used. It is, however, generally found that excellent yields can be obtained using a reaction period of from five minutes to two hours.
- the temperature of the reaction should be controlled so that it does not rise above 30 -C.during the reaction period and it is best to carry out the reaction between 0 C. and 15 C.
- the desired product canbe isolated after removalof the Raney nickel by simply evaporating the solvent and purified by recrystallization from a suitable solvent such as ethyl acetate. It can also be purified by trituration with a suitable wash liquid such as ethylacetate or etherethyl acetate.
- the solvent used is alower aliphatic acid or a mixture containing such an acid it maybe desirable to neutralize the acid,,with an alkalinewreagent such as ammonium or sodium hydroxide and to isolate the active compound by extraction from the neutralized aqueous mixture with an organic solvent.
- Suitable extraction solvents include water immiscible lower halogenated alkanes such as ethylene chloride, chloroform and carbon tetrachloride, or ketones such as methyl isobutylketones. The product is isolated from the extraction solvent and purified as described above.
- the biologically active compounds of this invention which, as will be noted, may exist in epimeric forms may be administered alone or in combination with acceptable pharmaceutical carriers, the choice of which is determined by the preferred route of administration, the solubility of the compound and standard pharmaceutical practice.
- the dosage of these compounds is of approximately the same order of magntiude as the dosage of hydrocortisone, and these compounds are useful to treat the types of pathological conditions often treated with hydrocortisone. Because of their great adrenocortical activity it is sometimes possible to use dosages of these compounds which are lower than those of hydrocortisone.
- the compounds may be administered in the form of tablets containing excipients such as starch or milk sugar.
- excipients such as starch or milk sugar.
- Aqueous suspensions and elixirs which may be sweetened or flavored may also be used.
- these therapeutic agents may be prepared in the form of ointments and salves in suitable bases especially non-aqueous petrolatum type bases.
- suitable bases especially non-aqueous petrolatum type bases.
- aqueous suspensions may be employed for intra-articular injection.
- various suspending and wetting agents may be added to the compositions to obtain a suspension not tending to settle out easily or to pack down in the bottle in which it is stored.
- Intramuscular and subcutaneous dosage forms may also be prepared by standard pharmaceutical practice.
- isopropanol was added. (The Raney nickel had been previously washed with water and then with diluted acetic acid to a pH of 7. It was then washed with methanol,
- a compound selected-from the group consisting of X is selected from the*group: consisting of hydrogen, those having theformulas': i j halogen, metho'xy 'an'dle'thoxy; Y is selected from the CH group consisting of keto and B-hydroxyi.
- a pharmaceutical composition comprising a compound as claimed in claim 1 together with a pharmaceuti- Y E I cally acceptable carrier.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Description
'IG-FLUORO '3 KETO -'17 S-(]8-HYDR0XY PROPA- NOYL) A ANDROSTENES AND DERIVATIVES, THEREOF Eugene J. Agnello and Gerald D. Laubach, Jackson Heights, N.Y., assignors to Chas. Pfizer & Co., Inc., Brooklyn, N.Y., a corporation of Delaware No Drawing. Application March 23, 1959 Serial No. 800,997
2 Claims. (Cl. 16777) CH CH3 (EH3 CHzOH CHOH YHz 6 C=O and the A the A and the A dehydro analogs of these compounds wherein Y is selected from the group consisting of keto and fi-hydroxyl and X is selected from the group consisting of hydrogen, halogen atoms, that is, fluorine, chlorine, bromine and iodine and methoxy and ethoxy groups.
Starting compounds which are used in the preparation of the valuable compounds of this invention include those having the formulas out/ X wherein .X'and Yhave the-same meaning as above and Z is bromine or iodine. The A the A and the A -de- .hydro .analogs of these compounds are also used as starting materials in this invention.
2,915,434 i' atented Dec. 1, 1959 The starting compounds are prepared in accordance with copending and concurrently filed patent application Ser. No. 800,996 which describes their preparation from the corresponding epoxide by treatment with hydrogen iodide or hydrogen bromide and subsequent separation of the isomers by chromatography.
For the preparation of the valuable compounds of this invention, the steroid compound with the side chain bromohydrin or iodohydrin function is treated with a debrominating or deiodinating agent such as zinc and acetic acid or Raney nickel. It-is preferred to use Raney nickel because of the ease of manipulation and the high yields which can be obtained.
Suitable solvents for carrying out the reaction with Raney nickel include reaction inert organic solvents such as lower aliphatic oxygenated sol-vents including ethers, alcohols, acids and ketones containing up to five carbon atoms. .Methanol, ethanol, .propanol, isopropanol, pentanol, acetone, .methyl isopropyl ketone, dioxane, acetic acid and propionic acid are examples of suitable solvents.
The use of a mixed solvent such as methanol-acetic acid is sometimes advantageous.
The amount of .Raney nickel used is not critical although to insure the most economical utilization of the steroid. starting material, it is generally preferred to use an excess of this dehalogenating agent. .From four to twenty grams of Raney nickel per gram of steroid starting material has been found to provide suitable yields. The preferred excess, as will be recognized by those skilled in. the art, will depend upon the degree of activity of the Raney nickel. This in turn will depend upon its previous treatment. With Raney nickel which has been washed first with water, then with acetic acid, then with methanol and finally with acetone in accordance with known procedures, it is usually found that from ten to fifteen grams of Raney nickel per gram of steroid leads to excellent yields. However, the Raney nickel can be used without previous treatment or with other known treatments and still function as a dehalogenating agent for the bromohydrin or iodohydrin.
The duration of the reaction is not critical depending only upon the degree of activity of the. Raney nickel. This degree of activity is readily determined by tests well known to those skilled in the art, and include, for example, the reduction of known compounds requiring varying degrees of reducing activity. Reaction periods as short as five minutes and as long as twenty-four hours have been used. It is, however, generally found that excellent yields can be obtained using a reaction period of from five minutes to two hours.
For optimum yields the temperature of the reaction should be controlled so that it does not rise above 30 -C.during the reaction period and it is best to carry out the reaction between 0 C. and 15 C.
Although it is not essential, it is preferred to carry out the reaction in an inert atmosphere such as a nitrogen atmosphere. This assures the most efiicient use of the Raney nickel by minimizing its reaction with atmospheric oxygen.
The desired product canbe isolated after removalof the Raney nickel by simply evaporating the solvent and purified by recrystallization from a suitable solvent such as ethyl acetate. It can also be purified by trituration with a suitable wash liquid such as ethylacetate or etherethyl acetate.
If the solvent used is alower aliphatic acid or a mixture containing such an acid it maybe desirable to neutralize the acid,,with an alkalinewreagent such as ammonium or sodium hydroxide and to isolate the active compound by extraction from the neutralized aqueous mixture with an organic solvent. Suitable extraction solvents include water immiscible lower halogenated alkanes such as ethylene chloride, chloroform and carbon tetrachloride, or ketones such as methyl isobutylketones. The product is isolated from the extraction solvent and purified as described above.
The biologically active compounds of this invention which, as will be noted, may exist in epimeric forms may be administered alone or in combination with acceptable pharmaceutical carriers, the choice of which is determined by the preferred route of administration, the solubility of the compound and standard pharmaceutical practice. In general, the dosage of these compounds is of approximately the same order of magntiude as the dosage of hydrocortisone, and these compounds are useful to treat the types of pathological conditions often treated with hydrocortisone. Because of their great adrenocortical activity it is sometimes possible to use dosages of these compounds which are lower than those of hydrocortisone.
For oral administration the compounds may be administered in the form of tablets containing excipients such as starch or milk sugar. Aqueous suspensions and elixirs which may be sweetened or flavored may also be used. To apply these therapeutic agents topically, they may be prepared in the form of ointments and salves in suitable bases especially non-aqueous petrolatum type bases. For intra-articular injection aqueous suspensions may be employed. In this case various suspending and wetting agents may be added to the compositions to obtain a suspension not tending to settle out easily or to pack down in the bottle in which it is stored. Intramuscular and subcutaneous dosage forms may also be prepared by standard pharmaceutical practice.
The following examples are given solely for the purpose of illustration and are not to be construed as limitations of this invention, many apparent variations of which are possible without departing from the spirit or scope thereof.
EXAMPLE I 16a-flu0r0-17 3(a-hydr0xy-pr0panoyl) -A androstadiene- 113,1 7 oz-diol-3-one A solution containing 500 mg. of 16a-fluoro-17p-(uhydroxy-fi-bromo-propanoyl) A androstadiene 11,3, l7a-diol-3-one in 200 ml. of absolute methanol was cooled to C. and 5 g. of Raney nickel in 50 m1. of
methanol was added. The mixture was stirred for two.
hours, filtered and the methanol removed by evaporation. The residue was triturated with a 1:1 mixture of ethyl acetate and ether. The product was recovered by filtration.
EXAMPLE II 16a-flu0ro-1 7B- B-hydroxy-propan oyl) -A-androstene- 11,8,I7a-di0l-3-0ne A solution containing 500 mg. of 16a-fluoro-17fl-(flhydroxy-B-iodo-propanoyl)-A-androstene-l1 3,170: diol- 3-one in 100 m1. of isopropanol was cooled to 10 C. and
'a mixture containing 4 g. of Raney nickel in 50 ml. of
isopropanol was added. (The Raney nickel had been previously washed with water and then with diluted acetic acid to a pH of 7. It was then washed with methanol,
the methanol removed and the Raney nickel refluxed for drostene-l7a-ol-3,l l-dione 9a-bromo-l 6a-fiuorol 7,9- a-hydroxy-propanoyl -A androstene-l 7a-ol-3, l l-dione 9cc-i0dO-16ct-flUOIO-l7B-( a-hydroxy propanoyl) A androstene-l7u-ol-3,1l-dione 9a-methoxy-l6a-fluoro-l7p-(rz-hydroxy propanoyl) A- androstene-l7a-ol-3,l l-dione 9a-ethoxy-l6a-fiuoro-17 s-(u-hydroxy-propanoyl)-A androstene-l 7oz-0l-3,1 l-dione 16a-fiuoro-17fi-(fl-hydroxy propanoyl) A androstene- 17a-ol-3,1l-dione 9a,16a-difiuoro-17fi-( B-hydroxy-propanoyl) A androstene-l7u--ol-3,11-dione 9a-chloro-l6a-fluoro-17,6-(5-hydroxy-propanoyl)-A androstene-l7a-ol-3,l l-dione 9u-bromo-l6a-fluoro-l7B-(p-hydroxy-propan0yl)-A androstenel7a-ol-3,1l-dione 9a-iodo-l6a-fiuoro-17fi-(B-hydroxy propanoyl) A androstene-17a-ol-3,1l-dione 9a-methoxy-l6a-fiuoro-l 7 3-(B-hydroxy propanoyl) A- androstene-l7a-ol-3J l-dione 9a-ethoxy-l6a-fiuoro-17B-(p-hydroxy-propanoyl)-A androstene-l7a-ol-3,l l-dione 16a-fluoro-l7,9-( 13 hydroxy-propanoyl) A androstene- 11fi,l7a-diol-3-one 9a,l6a-difiuoro-l7fl-(fl-hydroxy propanoyl) A androstene-l lfl,l7u-diol-3-one 9u-chlorol 6a-fiuorol 7,8-( p-hydroxy-propanoyl) -A drostene-l 1,9,17a-diol-3-one 9u-bromo-l6a-fluoro-17B-(fl-hydroxy-propanoyl)-A drostene-l l,8,l7a-diol-3-one 9oc-i0d0-l6a-fluOrO-17fl-( fi-hydroxy propanoyl) A drostene-l 1 [3,17a-di0l-3-OII6 9a-methoxy-16a-fiuoro-17fi-( p-hydroxy propanoyl) androstene-l lB,17oc-diol-3-one 9u-ethoxy-16a-fiuoro-l7B-(p-hydroxy-propanoyD-A drostene-l 16,] 7a-diol-3-one 16oc-fiu0r0-17B-( a-hydroxy-propanoyl) A androstadiene-l lB.17u-diol-3-one 9a,16a-difiuoro-l7/3-(a-hydroxy-propanoyl) A androstadiene--l 5,17 a-diol-3-one 9u-chloro-1 6a-fiuoro-l7/3-( a-hydroxy-propanoyl)-A androstadiene-l1fl,l7u-diol-3-one 9a-blOm0-l6oc-fi1101'O-l7B-(oz hydroxy propanoyl) A androstadiene-11fl,l7a-diol-3-one 9oc-iOd0-16ot-fit10r0-17B-( a-hydroxy-propanoyl) A androstadiene-l 113, 17a-diol-3-one 9a-methoxy-16a-fiuoro-17B-(a-hydroxy-propanoyl) A androstadiene-11B,17a-diol-3-one 9a-ethoxy-16a-fluoro-l7 8-(a-hydroxy propanoyl) A androstadiene-l lfi. 17cz-di0l-3-OH6 16a-fiuoro-17p-(a-hydroxy-propanoyl) A androstadiene- 1711-01-3, 1 l-dione 9a,16a-difll10r0-17/3-( a-hYdIOXY-PI'OPKHOYI) A androstadiene-l7m-ol-3,1 l-dione 9oc-Chl0l'0-16u-fil101'O-1713-(oc hydroxy propanoyl) A androstadiene-l 7a-ol-3,1 l-dione .7 What is claimed is: 5 1 and the A A- and A -dehydro analogs thereof wherein 1. A compound selected-from the group consisting of X is selected from the*group: consisting of hydrogen, those having theformulas': i j halogen, metho'xy 'an'dle'thoxy; Y is selected from the CH group consisting of keto and B-hydroxyi.
CHQOH 5 2. A pharmaceutical composition comprising a compound as claimed in claim 1 together with a pharmaceuti- Y E I cally acceptable carrier. C=O =0 v ---0H .-5 vNo references cited.
Y? F Y Eff F 10 Cris) CH5,"
Claims (2)
1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THE FORMULAS:
2. A PHARMACEUTICAL COMPOSITION COMPRISING A COMPOUND AS CLAIMED IN CLAIM 1 TOGETHER WITH A PHARMACEUTICALLY ACCEPTABLE CARRIER.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US800997A US2915434A (en) | 1959-03-23 | 1959-03-23 | 16-fluoro-3-keto-17beta-(beta-hydroxy-propanoyl)-delta4-androstenes and derivatives thereof |
| BE579476A BE579476A (en) | 1958-06-09 | 1959-06-09 | Improvements to the processes for preparing steroid compounds. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US800997A US2915434A (en) | 1959-03-23 | 1959-03-23 | 16-fluoro-3-keto-17beta-(beta-hydroxy-propanoyl)-delta4-androstenes and derivatives thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US2915434A true US2915434A (en) | 1959-12-01 |
Family
ID=25179925
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US800997A Expired - Lifetime US2915434A (en) | 1958-06-09 | 1959-03-23 | 16-fluoro-3-keto-17beta-(beta-hydroxy-propanoyl)-delta4-androstenes and derivatives thereof |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US2915434A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2980670A (en) * | 1959-11-02 | 1961-04-18 | Pfizer & Co C | Fluorinated corticosteroids |
| US3047594A (en) * | 1960-05-11 | 1962-07-31 | Pfizer & Co C | Preparation of 21-methyl steroids and intermediates |
| US3280159A (en) * | 1961-08-21 | 1966-10-18 | Schering Corp | Process for preparing 21-methyl-20-keto-17alpha, 21-dihydroxy steroids |
-
1959
- 1959-03-23 US US800997A patent/US2915434A/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| None * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2980670A (en) * | 1959-11-02 | 1961-04-18 | Pfizer & Co C | Fluorinated corticosteroids |
| US3047594A (en) * | 1960-05-11 | 1962-07-31 | Pfizer & Co C | Preparation of 21-methyl steroids and intermediates |
| US3280159A (en) * | 1961-08-21 | 1966-10-18 | Schering Corp | Process for preparing 21-methyl-20-keto-17alpha, 21-dihydroxy steroids |
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