GB1587033A - Esters of 6-chloro-11,17a,21-trihydroxypregna-1,4,6-triene-3,20-dione - Google Patents

Esters of 6-chloro-11,17a,21-trihydroxypregna-1,4,6-triene-3,20-dione Download PDF

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GB1587033A
GB1587033A GB16281/78A GB1628178A GB1587033A GB 1587033 A GB1587033 A GB 1587033A GB 16281/78 A GB16281/78 A GB 16281/78A GB 1628178 A GB1628178 A GB 1628178A GB 1587033 A GB1587033 A GB 1587033A
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cloprednol
butyryl
triene
dione
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Syntex USA LLC
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    • 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
    • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Description

(54) NEW ESTERS OF B-CHLORO-I1A17t-2 1 TRIHYDROXYPREGNA- 1 ,4,6-TRIENE-3,20-DIONE (71) We, SYNTEX (U.S.A.) INC., a Corporation organised under the laws of the State of Delaware, United States of America, of 3401 Hillview Avenue, Palo Alto, California 94304, United States of America, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to a new class of steroidal anti-inflammatory compounds.More specifically, it relates to certain 17-esters, a 17,21-diester and certain 17,21-orthoesters of cloprednol, (6 - chloro - llp,17a,21 trihydroxypregna - 1,4,6 - triene - 3,20 - dione), and their use as topical antiinflammatories.
Cloprednol and its 21-esters are known compounds as set forth in U.S.
3,232,965 to Ringold and Rosenkranz. The compounds and its 21-esters are generally given orally to aid in reducing the pain of arthritis and other inflammatory conditions. It is generally known that certain 17-esters of pregnadienes can be prepared by forming the 17,21-orthoester of the 17,21-diol and hydrolyzing the orthoester to obtain a 17-acetate. See for example, French Patent 1,469,675; U.S. Patent 3,980,778; and German Patent Application DT 2,055,221.
It has been suggested in a Report dated December 15, 1975 published by Kidder, Peabody and Co. entitled "The Drug Industry -- Hormones: Topical Corticosteroids" that cloprednol might be applied topically and may promise a short-acting steroid molecule that might offer toxicity advantages over older steroids. Unfortunately, cloprednol itself exhibits limited topical, antiinflammatory activities. Although the 21-esters of cloprednol exhibit slightly greater topical anti-inflammatory activity (as estimated by a vasoconstriction assay) than cloprednol and appear to have short half-lives, as does cloprednol, they exhibit substantial systemic activity as measured in small animal assays.It is desirable, of course, to use topical corticosteroids which have a favorable therapeutic ratio of anti-inflammatory systemic activity, i.e. the higher the value of the ratio, the better the compound, assuming the topical activity is in the correct range. Surprisingly, we have now discovered that certain 17-esters, a 17,21-diester and certain 17,21-orthoesters of cloprednol exhibit a more favorable therapeutic ratio of anti-inflammatory (i.e. vasoconstriction) to systemic activity than cloprednol itself or the corresponding 21-esters and that the compounds of this invention are also unexpectedly superior to the heretofore unknown 17-acetate of cloprednol.
The primary aspect of this invention is a compound chosen from those represented by the formula
wherein R is butyryl or benzoyl when R1 is hydrogen or R is butyryl when R' is butyryl, or R1 and R together represent
wherein R2 is propyl or phenyl.
Another aspect of this invention is a topical anti-inflammatory composition which comprises an effective amount of one of the above compounds with a suitable pharmaceutical excipient.
Still another aspect of this invention is a process for treating an inflamed skin condition by contacting the inflamed area with an effective amount of a compound of the invention.
Still another aspect of this invention is a process for preparing the compounds of this invention.
Preferred compounds encompassed by the scope of this invention include the 17-butyrate; the 17-benzoate; and the 17,21-methyl orthobutyrate of cloprednol.
The compounds of this invention are useful for the relief of inflammatory manifestations of corticosteroid responsive dermatoses.
Generally, the inflammatory manifestation in mammals, particularly humans, is combatted by contacting the inflamed area with an effective amount of the novel steroids of this invention, that is an amount which results in improvement of the inflamed condition. Preferably the steroids are first formulated to prepare a suitable pharmaceutical formulation, as discussed hereinafter, which is then placed in contact with the afflicted area. An effective amount will depend upon the particular condition and the animal receiving the treatment, but will vary between 0.0010/, to 10% by weight of the pharmaceutical composition and preferably will be between about 0.01 to 2% by weight of the formulation.Using these levels in the formulation, a therapeutically effective and non-toxic amount, i.e. enough to effect an anti-inflammatory response, but not enough to harm the recipient, is applied to the inflamed area.
The compounds of this invention not only have anti-inflammatory activity but also appear to exhibit a low level of systemic activity, as measured by small animal assays. This allows for the application of an effective amount of the antiinflammatory compounds without an adverse effect on the rest of the animal's system.
The novel steroids of this invention may be formulated with suitable pharmaceutical vehicles known in the art to form particularly effective topical, anti-inflammatory compositions. The rest of the formulated composition will be about 90% w to about 99.999V w, preferably about 98% w to about 99.99, of a suitable excipient which may include a pharmaceutically acceptable solvent and other pharmaceutically acceptable additives to form a topically effective pharmaceutical formulation.
A pharmaceutically acceptable solvent is one which is substantially non-toxic and non-irritating under the conditions used and may be readily formulated into any of the classical drug formulations such as creams, ointments, lotions, gels, or the like. Particularly suitable solvents include water, glycerine, propylene carbonate, and a glycol such as 1,2-propylene diol (i.e. propylene glycol), 1,3propylene diol, polyethylene glycol having a molecular weight of from 100 to 10,000, dipropylene glycol, etc.; and mixture of the aforementioned with each other.
A topical, anti-inflammatory cream may be prepared as a semi-solid emulsion of oil in water or water in oil. A cream base formulation by definition is an emulsion which is a two phase system with one liquid (for example fats or oils) being dispersed as small globules in another substance (e.g., a glycol-water solvent phase) which may be employed as the primary solvent for the novel steroids of this invention. Other than the solvent with the steroids therein, the cream formulation may contain fatty alcohols, surfactants, mineral oil or petrolatum and other typical pharmaceutical adjuvants such as anti-oxidants, antiseptics, or compatible adjuvants. A typical cream base formulation is given in U.S. 3,934,013 to Poulsen and as much of that patent as is pertinent is incorporated herein by reference.
The novel steroids of this invention may also be formulated as ointments. A "classical" ointment is a semi-solid anhydrous composition which may contain mineral oil, white petrolatum, a suitable solvent such as a glycol and may include propylene carbonate and other pharmaceutically suitable additives such as surfactants, for example Span (Trade Mark) and Tween (Trade Mark) or wool fat (lanolin), along with stabilizers such as antioxidants and other adjuvants as mentioned before.
Other suitable ointment base formulations which contain propylene carbonate are described in U.S. Patent 4,017,615 to Shastri et al entitled "Propylene Carbonate Ointment Vehicle" and U.S. 3,924,004 to Chang et al. As much of those patents as is pertinent is incorporated herein by reference.
Suitable solvents, surfactants, stabilizers, etc. are discussed in U.S. 3,934,013 and such discussion is incorporated herein by reference.
A suitable "non-classical" anhydrous, water-washable "ointment type" base is described in U.S. Patent No. 3,592,930 to Katz and Neiman, and as much of that disclosure as is pertinent is incorporated herein by reference.
The fatty alcohols which are suitable have been previously disclosed above in this specification and in U.S. Patent No. 3,592,930. As much of that disclosure as is pertinent is incorporated herein by reference.
Because the compounds of the present invention exhibit anti-inflammatory, antipruritic and vasoconstrictive actions they are indicated for relief of the inflammatory manifestations of corticosteroid-responsive dermatoses. The compounds are contraindicated in vaccinia and varicella, and in those patients with a history of hypersensitivity to components contained in the administered formulations.
As a precaution, the compounds of the present invention should not be used extensively on pregnant patients, in large amounts or for overly prolonged periods of time.
In some instances the administration of the new compounds may lead to certain local adverse reactions such as burning, itching, irritation, dryness, secondary infection, folliculitis, acne from erruptions, hypopigmentation, striae and skin atrophy.
The preferred way of administering the compound is to massage a small amount into the affected area three or four times daily.
The starting compound for the process for preparing the compounds of this invention is, of course, cloprednol. This can be prepared by methods as set forth in U.S. 3,232,965. For example, by following Example 4 of the '965 patent and hydrolyzing the 21-acetate, cloprednol is obtained.
The process for preparing the compounds of this invention comprises reacting cloprednol with trimethyl orthobenzoate or trimethyl orthobutyrate to form the 17a,21-orthoester; hydrolyzing the thus formed 17a,21-orthoester to form the 17a- benzoate or 17a-butyrate; and reacting the 17a-butyrate with a butyric anhydride or acid chloride to form the 17cg,21-dibutyrate according to the following reaction sequence:
wherein R2 is phenyl or propyl.
(1) The first step in the process for preparing the 17a,21-orthoesters of this invention is performed by mixing a substantial molar excessCof the trimethyl orthoester, R2C(OCH3)3, with cloprednol in the presence of a catalytic amount of a suitable acid. The reaction can be carried out neat or in the presence of a suitable solvent. If neat, the excess orthoester acts as a diluting agent to aid in reaction and a molar excess of at least 10 moles of the orthoester per mole of cloprednol is used, preferably about 30 < 0:1. If a solvent is employed a molar excess of less than 10 moles of the orthoester per mole cloprednol is required. Suitable solvents which can be used include inert organic solvents such as benzene, toluene, and the like.
Suitable acid catalysts include p-toluenesulfonic acid (pTSA), sulfuric acid, perchloric acid, methanesulfonic acid, and the like. The reaction takes place at temperatures of about 50"C to about 1500C, preferably at about 110"C to 1200C neat or at the boiling point of the orthoester solvent, whichever is lower. Generally, the reaction goes to completion in less than 5 hours, 1--2 hours being sufficient for the next reaction at 1100--1200C. Once the reaction is completed, the 17a,21orthoester of cloprednol is isolated and purified by using well established means such as extraction, separation, solvent evaporation, recrystallization and thin-layer chromatography (TLC).
(2) Once the l7a,2l-orthoester of cloprednol is obtained it is contacted with a buffered aqueous alcohol solution to hydrolyze the 17(x,21-orthoester and form the 17-ester. A suitable buffering agent is potassium hydrogen phosphate buffer having a pH of 3-3.5. Suitable alcohols include methanol, ethanol, propanol and the like. A mixture of 5-10 parts by volume of the alcohol solvent per part of the aqueous buffer has been found to be suitable. The reaction takes place at temperatures of 20"C to 600 C. At about 25"C the reaction is complete in 24 hours or less. The l7a-ester is then purified by methods well-known in the art, e.g.
extraction, solvent evaporation, crystallization, TLC, etc.
(3) To obtain the 17a,21-butyrate, the 17a-butyrate is reacted with a butyric acid chloride or acid anhydride in a solvent in the presence of an organic base.
Bases which may be used include pyridine, 4- dimethylamino - pyridine, triethylamine and the like, while suitable solvents are chloroform, methylene chloride, benzene and the like. In a preferred procedure, pyridine is used both as the base and the solvent. The acid chloride or anhydride is present in a substantial molar excess such as 5-20 moles of the acid chloride per mole of 17a-ester.
Enough base is used to neutralize the acid formed by the reaction, thus at least one mole of base is needed per mole of 17a-ester. Generally, the reaction takes place readily at temperature of 0--50"C, preferably at about 200C-300C.
The following specific Examples are presented to further illustrate the present invention but are not intended to limit the scope thereof.
EXAMPLE 1 This Example sets forth a method for preparing the 17a,21-ortho esters of cloprednol.
A. Three hundred milligrams (mg) of cloprednol is added to a 50 milliliter (ml) flask along with 5 ml of trimethyl orthobutyrate and fifty mg of dried ptoluenesulfonic acid (pTSA). The mixture is stirred for 1 hour under nitrogen at 120"C in a water bath until the reaction is complete. Fifty ml of ethyl acetate along with 100 ml of water are added to the reaction mixture. After separating the water from the resulting organic phase, the latter is washed with three, 50 ml portions of water. The resulting organic mixture is dried over sodium sulfate, stripped and vacuum dried to give a yellow oil.The material is placed on a 0.75 millimeter (mm) by 1 meter (m) TLC plate and developed three times with a 3% methanol:97% chloroform solvent mixture followed by extraction and crystallization from acetone-hexane to ultimately give 185 mg of approximately 95% pure 6 - chloro llp,17a,21 - trihydroxypregna - 1,4,6 - triene - 3,20 - dione - 17,21 - methyl orthobutyrate, melting point (mp) 120--1220C.
B. Similarly, by following the above procedure but substituting trimethyl orthobenzoate for trimethyl orthobutyrate, the following compound is obtained: 6 - chloro - 11,B,17a,21 - trihydroxypregna - 1,4,6 - triene - 3,20 - dione 17,21 - methyl orthobenzoate, mp 144--1480C (amorphous foam).
EXAMPLE 2 This Example sets forth a method for preparing the 17-esters of cloprednol.
A. One hundred eighty mg of 6 - chloro - 11A,17a,21 - trihydroxypregna1,4,6 - triene - 3,20 - dione 17,21-methyl orthobutyrate as prepared according to Part A of Example 1, 6 ml of methanol and 1 ml of potassium hydrogen phosphate buffer (pH 3.1) are added to a 50 ml flask. The mixture is stirred overnight (approximately 17 hours) at room temperature which results in about 70 /O completion of the reaction. An additional 30 ml of methanol and 5 ml of potassium hydrogen phosphate buffer are added and the mixture is heated to 600C on a hot water bath for about 1 hour to bring the reaction to completion very cleanly.The reaction mixture is partitioned between ethyl acetate and water and the ethyl acetate is removed by vacuum evaporation to give an oil which is then chromatographed on a 0.75 mmxl m TLC plate by developing two times with 3% methanol in chloroform to give 130 mg of 6 - chloro - 11A,17a,21 trihydroxypregna - 1,4,6 - triene - 3,20 - dione 17-butyrate, m.p. 115--120"C (amorphous form).
B. By following the procedure set forth in Part A but substituting the 17,21methyl orthobenzoate obtained according to Part B of Example 1 for the 17cr,21- methyl orthobutyrate the 17-benzoate is obtained, m.p. 244--2480C.
EXAMPLE 3 This Example sets forth a process for preparing the 17cr,21-dibutyrate of cloprednol.
A. Ninety-nine mg of the l7a-butyrate of cloprednol as prepared in Part A of Example 2 above is placed in a suitable flask along with 3 ml of pyridine and 0.2 ml of butyryl chloride and stirred for 2 hours at room temperature. The reaction mixture is then placed in the refrigerator overnight (about 17 hours) after which the reaction is complete. The reaction mixture is poured into dilute aqueous sodium carbonate and extracted with ethyl acetate. The organic phase is washed another time with dilute aqueous sodium carbonate, then four times with water, dried over sodium sulfate and the solvent is removed by vacuum evaporation.The product is purified by chromatography on a 0.75 mmx 1 meter TLC plate developing with 25 /n acetone/75% hexane to afford 80 mg of 6- chloro - ll,l7a,2l trihydroxypregna - 1,4,6 - triene - 3,20 - dione 17,21-dibutyrate, m.p. 129 132"C.
EXAMPLE 4 This Example sets forth data comparing the topical activities of the 17- acetate of cloprednol versus the novel 17-esters, 17,21-dibutyrate and 17,21orthoesters of this invention. The topical anti-inflammatory activity potential for each compound was assayed using a modified Stoughton/McKenzie vasoconstriction assay in humans, a modification of the procedure of McKenzie, S. W.
and Stoughton, R. B. "Method for Comparing Percutaneous Absorption of Steroids" Arc. Dermat. 86, 608 (1962).
Eight normal adult human subjects were treated on each forearm by topical administration with alcoholic solutions containing 1x10-4 and 1x19-5 g/ml of each of the compounds to provide 64 total test sites for each compound in a series (32 for each concentration). Areas of the subjects' forearms were outlined by a rubber stamp grid coated with silicone grease, and 10 lambda are applied per 7x7 mm.
square site. After the preparations have dried, the areas on each forearm are covered with Saran (Trade Mark) wrap and the margins sealed with tape. The occlusive wrap is removed after 18 hours. Twenty-four hours after application, the presence of vasoconstriction is noted by visual examination, and expressed as the number of sites responding (vasoconstriction). The number of sites responding by vasoconstriction is also calculated as a percentage of the total number of sites.
Cloprednol 17-acetate is used as a standard, its activity being indicated as 1.
TABLE I Vasoconstrictive No. Cloprednol Esters Activity I 17-acetate 2 17-butyrate 8 3 17-benzoate 7 4 17,21-dibutyrate 3 5 17,21-methyl orthobutyrate 7 6 17,21-methyl orthobenzoate 3 In order to test the acute toxicity of Compound No. 3, 25 mg/kg of the compound were administered subcutaneously to male Swiss-Webster mice weighing approximately 25 g. During the observation period of 21 days no deaths were observed.
WHAT WE CLAIM IS: 1. A compound chosen from those represented by the formula
wherein R is butyryl or benzoyl when R' is hydrogen or R is butyryl when R' is butyryl, or R and R' taken together represent
**WARNING** end of DESC field may overlap start of CLMS **.

Claims (13)

  1. **WARNING** start of CLMS field may overlap end of DESC **.
    of butyryl chloride and stirred for 2 hours at room temperature. The reaction mixture is then placed in the refrigerator overnight (about 17 hours) after which the reaction is complete. The reaction mixture is poured into dilute aqueous sodium carbonate and extracted with ethyl acetate. The organic phase is washed another time with dilute aqueous sodium carbonate, then four times with water, dried over sodium sulfate and the solvent is removed by vacuum evaporation. The product is purified by chromatography on a 0.75 mmx 1 meter TLC plate developing with 25 /n acetone/75% hexane to afford 80 mg of 6- chloro - ll,l7a,2l trihydroxypregna - 1,4,6 - triene - 3,20 - dione 17,21-dibutyrate, m.p. 129 132"C.
    EXAMPLE 4 This Example sets forth data comparing the topical activities of the 17- acetate of cloprednol versus the novel 17-esters, 17,21-dibutyrate and 17,21orthoesters of this invention. The topical anti-inflammatory activity potential for each compound was assayed using a modified Stoughton/McKenzie vasoconstriction assay in humans, a modification of the procedure of McKenzie, S. W.
    and Stoughton, R. B. "Method for Comparing Percutaneous Absorption of Steroids" Arc. Dermat. 86, 608 (1962).
    Eight normal adult human subjects were treated on each forearm by topical administration with alcoholic solutions containing 1x10-4 and 1x19-5 g/ml of each of the compounds to provide 64 total test sites for each compound in a series (32 for each concentration). Areas of the subjects' forearms were outlined by a rubber stamp grid coated with silicone grease, and 10 lambda are applied per 7x7 mm.
    square site. After the preparations have dried, the areas on each forearm are covered with Saran (Trade Mark) wrap and the margins sealed with tape. The occlusive wrap is removed after 18 hours. Twenty-four hours after application, the presence of vasoconstriction is noted by visual examination, and expressed as the number of sites responding (vasoconstriction). The number of sites responding by vasoconstriction is also calculated as a percentage of the total number of sites.
    Cloprednol 17-acetate is used as a standard, its activity being indicated as 1.
    TABLE I Vasoconstrictive No. Cloprednol Esters Activity I 17-acetate
    2 17-butyrate 8
    3 17-benzoate 7
    4 17,21-dibutyrate 3
    5 17,21-methyl orthobutyrate 7
    6 17,21-methyl orthobenzoate 3 In order to test the acute toxicity of Compound No. 3, 25 mg/kg of the compound were administered subcutaneously to male Swiss-Webster mice weighing approximately 25 g. During the observation period of 21 days no deaths were observed.
    WHAT WE CLAIM IS: 1. A compound chosen from those represented by the formula
    wherein R is butyryl or benzoyl when R' is hydrogen or R is butyryl when R' is butyryl, or R and R' taken together represent
    wherein R2 is propyl or phenyl.
  2. 2. The compound of Claim 1, wherein R' is hydrogen and R is butyryl, 6 chloro - 11p,17a,21 - trihydroxypregna - 1,4,6 - triene - 3,20 - dione 17-butyrate.
  3. 3. The compound of Claim 1, wherein R' is hydrogen and R is benzoyl, 6 chloro - I -llp,17a,21 -trihydroxypregna - 1,4,6 -triene - 3,20 -dione 17-benzoate.
  4. 4. The compound of Claim 1, wherein R and R' are both butyryl, 6 - chloro 11,B,17a,21 - trihydroxypregna - 1,4,6 - triene - 3,20 - dione 17,21-dibutyrate.
  5. 5. The compound of Claim 1, wherein R2 is phenyl, 6 - chloro - 11p,17a,21 trihydroxypregna - 1,4,6 - triene - 3,20 - dione 17,21-methyl orthobenzoate.
  6. 6. The compound of Claim 1, wherein R2 is propyl, 6 - chloro - 1 11p,17a,21 - trihydroxypregna - 1,4,6 - triene - 3,20 - dione 17,21-methyl orthobutyrate.
  7. 7. A topical, pharmaceutical, anti-inflammatory composition which comprises a pharmaceutically acceptable excipient in combination with an effective amount of a compound of Claim 1.
  8. 8. A method of relieving a topical inflammatory condition in non-human mammals which comprises contacting the afflicted area with an effective amount of a compound of Claim 1.
  9. 9. A process for the preparation of a compound represented by the formula
    wherein R is butyryl or benzoyl when R' is hydrogen or R is butyryl when R' is butyryl, or R and R' taken together represent
    wherein R2 is propyl or phenyl, said process comprising one or more of the following steps (a) reacting cloprednol with a trim ethyl orthoester of the formula R2C(OCH3)3, wherein R2 is phenyl or propyl to form the 17,21-methyl orthobenzoate or 17,21-methyl orthobutyrate thereof; (b) hydrolyzing cloprednol 17,21-methyl orthobenzoate or cloprednol 17,21methyl orthobutyrate to cloprednol 17-benzoate or cloprednol 17-butyrate, and (c) converting cloprednol 17-butyrate to cloprednol 17,21-butyrate.
  10. 10. A compound of Claim 1 as exemplified herein.
  11. 11. A process for preparing a compound of Claim 1, substantially as described herein.
  12. 12. A compound of Claim 1 whenever prepared by a process according to Claim 9 or Claim 11.
  13. 13. A pharmaceutical composition comprising a compound of any one of Claims 2 to 6, 10 and 12, with a pharmaceutically acceptable excipient.
GB16281/78A 1977-04-28 1978-05-25 Esters of 6-chloro-11,17a,21-trihydroxypregna-1,4,6-triene-3,20-dione Expired GB1587033A (en)

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DE (1) DE2818319A1 (en)
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IT (1) IT7867960A0 (en)

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US3232965A (en) * 1958-06-20 1966-02-01 Syntex Corp 6-chloro-delta1,4,6-pregnatriene-17alpha, 21-diol-3,20-diones

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JPS53135963A (en) 1978-11-28
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FR2388829A1 (en) 1978-11-24

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