IE45877B1 - New derivatives of 9-chloroprednisolone - Google Patents

New derivatives of 9-chloroprednisolone

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Publication number
IE45877B1
IE45877B1 IE2011/77A IE201177A IE45877B1 IE 45877 B1 IE45877 B1 IE 45877B1 IE 2011/77 A IE2011/77 A IE 2011/77A IE 201177 A IE201177 A IE 201177A IE 45877 B1 IE45877 B1 IE 45877B1
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dione
pregnadiene
lip
hydroxy
chloro
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IE2011/77A
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IE45877L (en
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Schering Ag
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Priority claimed from DE2645105A external-priority patent/DE2645105C2/en
Priority claimed from DE19772742982 external-priority patent/DE2742982C2/en
Application filed by Schering Ag filed Critical Schering Ag
Publication of IE45877L publication Critical patent/IE45877L/en
Publication of IE45877B1 publication Critical patent/IE45877B1/en

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    • 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
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
    • C07J7/0085—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21 by an halogen atom

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Derivatives of 9-chloroprednisolone of the formula in which R1 is alkanoyl with 1 to 8 carbon atoms or benzoyl, and X is fluorine, chlorine, hydroxyl, alkanoyloxy with 1 to 8 carbon atoms or benzoyloxy, are prepared. These compounds are obtained by adding HOCl onto the corresponding DELTA <9,11>-prednisolones. The compounds can be used for the treatment of inflammations.

Description

The present invention is concerned with new derivatives of 9-chloroprednisolone, with a process for their manufacture and with pharmaceutical preparations contain ing these active substances. 9 - Ohloroprednisolone (9« - chloro - lip,17«,21 trihydroxy - 4,1*4 - pregnadiene - 3,20 - dione) has been known for a long time (J.Amer.Chem.Soc., 77, 1955, 4181) This corticoid is unsuitable as an active substance in pharmaceutical preparations that are to be used for the topical treatment of inflammatory disorders, as it has very strong systemic effects.
It has now been found that hitherto unknown derivatives of 9-chloroprednisolone are systemically almost inactive, but that in topical use they surprisingly have a strong anti-inflammatory activity, which generally exceeds that of the most active commercial corticoids.
The present invention accordingly provides derivatives of 9-chloroprednisolone of the general formula I in which represents an alkanoyl group containing 1 to 8 carbon atoms or a benzoyl group, and 43877 -3X represents a fluorine atom, a chlorine atom, an alkanoyloxy group containing 1 to 8 carhon atoms or a benzoyloxy group.
As an alkanoyl group represented hy R^ containing 1 to 8 carhon atoms and an alkanoyloxy group represented hy X containing 1 to 8 carhon atoms there is to he understood in each case a group that is derived from a straight-chained or branched fatty acid, for example formic acid, acetic acid, propionic acid, butyric acid, isobutyrie acid, valeric acid, isovaleric aeid, trimethylacetic acid, caproic acid, tert.-butylacetic acid or caprylic acid.
Especially preferred alkanoyl groups represented hy R^ and alkanoyloxy groups represented hy X are those derived from alkane carboxylic acids containing 2 to 6 carhon atoms. 9-chloroprednisolone derivatives of the general formula I in which X represents a chlorine atom or a fluorine atom are, for example those listed in the following Table: TABIE 1 17ot - Acetoxy - 9k, 21 - dichloro - 11(3 - hydroxy - pregnadiene - 3,20 - dione, 9«, 21 - dichloro - lip - hydroxy - 17« "propionyloxy - Δ1’4 ~ pregnadiene - 3,20 - dione, 17«- butyryloxy - 9«,21 - dichloro - lip - hydroxy - - pregnadiene - 3,20 - dione, 9k,21 - dichloro - lip - hydroxy - 17« - iso45877 -4butyryloxy - _ pregnadiene - 3,20 - dione, 17-i. - acetoxy - 9« - chloro - 21 - fluoro - 11/3 hydroxy - 2^’^ ~ pregnadiene - 3,20 - dione, 9ci- chloro - 21 - fluoro - lip - hydroxy - 17w 5 propionyloxy - β/’4 - pregnadiene - 3,20 - dione, 17ot - butyryloxy - 9°t - chloro - 21 - fluoro - 11/3 hydroxy - A^’^ " pregnadiene - 3,20 - dione, 17Λ - benzoyloxy - 9& - chloro - 21 - fluoro - lip hydroxy - A1’^ " pregnadiene - 3,20 - dione, 9 ot - chloro - 21 - fluoro - 11β - hydroxy - 17 isohutyryloxy - - pregnadiene - 3,20 - dione, «,21 - dichloro - lip - hydroxy - 17 - valeryloxy - A1’4 " pregnadiene - 3,20 - dione and 17o( - benzoyloxy - 9«, 21 - dichloro - lip - hydroxy - A1’4 " Pregnadiene - 3,20 - dione. 9-Chloroprednisolone derivatives of the general formula I in which X represents a hydroxyl group can be used as starting materials for the production of 9chloroprednisolone derivatives of the general formula I in which X represents a chlorine atom, and also for the production of 9-chloroprednisolone also for the production of 9-chloroprednisolone derivatives of the general formula I in whioh X represents an alkanoyloxy group. Such 9-chloroprednisolone derivatives of the general formula I in which X represents a hydroxyl group are, for example, those listed in the following Table: TABLE 2 17k.- Acetoxy - 9c<- chloro - lip,21 - dihydroxy 45877 -5- pregnadiene - 3,20 - dione, 9«- chloro - lip,21 - dihydroxy - Πα - propionyloxy - /’4 _ pregnadiene - 3,20 - dione, 17« - butyryloxy - 9« - chloro - lip,21 - dihydroxy - Δ1*4 - pregnadiene - 3,20 - dione, 9a - chloro - lip,21 - dihydroxy - 17a - isobutyryloxy - A1’4' - pregnadiene - 3,20 - dione, Qi — chloro - lip,21 - dihydroxy - 17a - valeryloxy -A1’4 - pregnadiene - 3,20 - dione and 17a - benzoyloxy - 9a- chloro - lip,21 - dihydroxy- pregnadiene - 3,20 - dione.
As 9-chloroprednisolone derivatives of the general formula I in which X represents an alkanoyloxy group or a benzoyloxy group there are preferred those in which the groups represented by and X together contain 3 to 14 carbon atoms. Such chloroprednisolone derivatives are, for example, those listed in the following Table: TABLE 3 17«,21 - Diacetoxy - 9a - chloro lip - hydroxy - pregnadiene - 3,20 - dione, 17a - acetoxy - 9« - chloro - lip - hydroxy - 21 propionyloxy - Δ1’4 " pregnadiene - 3,20 - dione, - acetoxy - 9a - chloro - lip - hydroxy - 17 propionyloxy - 7'^ ~ pregnadiene - 3,20 dione, 17a - acetoxy - 21 - butyryloxy - 9ος - chloro lip - hydroxy - ^’4 - pregnadiene - 3,20-dione, - acetoxy - 17a - butryloxy - 9a - chloro - lip hydroxy - - pregnadiene - 3,20 - dione, 43877 -617 ί - acetoxy - 9« - chloro - lip - hydroxy - 21 isobutyryloxy - Δ1’^ ~ pregnadiene - 3,20 - dione, - acetoxy - 9« - chloro - lip - hydroxy - 17°< isobutyryloxy ~ pregnadiene - 3,20 - dione, 17Λ - acetoxy - 9« - chloro - lip - hydroxy - 21 valeryloxy - Δ1’4 - pregnadiene - 3,20 - dione, - acetoxy - 9« - chloro - lip - hydroxy - 17« valeryloxy - Δ1’^ _ pregnadiene - 3,20 - dione, 17a - aoetoxy - 21 - benzoyloxy - 9 - hydroxy - - pregnadiene - 3,20 - dione, - acetoxy - 17« - benzoyloxy - 9« - chloro - lip - hydroxy - - pregnadiene - 3,20 - dione, 9a- chloro - lip - hydroxy - 17«,21 - dipropionyloxy - ~ pregnadiene - 3,20 - dione, 17« - butyryloxy - 9« - chloro - lip - hydroxy - 21 - propionyloxy - Δ1’4- pregnadiene - 3,20 - dione, - butyryloxy - 9« - chloro - lip - hydroxy - 17« - proprionyloxy - δ1’4 " pregnadiene - 3,20 - dione, 9k- chloro - lip - hydroxy - 17« - isobutyryloxy 21 - propionyloxy - - pregnadiene - 3,20 - dione, 9«- chloro - lip - hydroxy - 21 - isobutyryloxy 17a- proprionyloxy - Δ1’4 - pregnadiene - 3,20 - dione, 9k- chloro - lip - hydroxy - 17k - propionyloxy 21 - valeryloxy - - pregnadiene - 3,20 - dione, 9« - chloro - lip - hydroxy - 21 - propionyloxy 17k - valeryloxy - δ1’4 ~ pregnadiene - 3,20 - dione, 17K - benzoyloxy - 9k - chloro - lip - hydroxy 21 - propionyloxy - δ1’4 - pregnadiene - 3,20 - dione, -721 - benzoyloxy - 9« - chloro - 11/3 - hydroxy 17« - propionyloxy - Δ^’4 " pregnadiene - 3,20 - dione, 17r<,21 - dibutyryloxy - 9% - chloro - 11/3 - hydroxy - Δ1’4 - pregnadiene - 3,20 - dione, 17«' - butyryloxy - 9« - chloro - 11/3 - hydroxy 21 - isobutyryloxy - Δ1’4 " pregnadiene - 3,20 - dione, - butyryloxy - 91’4 pregnadiene - 3,20 - dione, 17a - butyryloxy - 9« - chloro - 11/3 - hydroxy 21 - valeryloxy - Δ?’4 " pregnadiene - 3,20 - dione, - butyryloxy - 91’4 ~ pregnadiene - 3,20 - dione, 17« - benzoyloxy - 21 - butyryloxy - 9« - chloro lip - hydroxy - Δ1’4 " pregnadiene - 3,20 - dione, - benzoyloxy - ΓΗ - butyryloxy - 9« - chlorolip - hydroxy - Δ1’4 - pregnadiene - 3,20 - dione, 9«.- chloro - lip - hydroxy - 17,21 - diisobutyryloxy - Δ1’4 " pregnadiene - 3,20 - dione, 9« - chloro - lip - hydroxy - 17«, 21 - divaleryloxy - /^’4 - pregnadiene - 3,20 - dione.
The new 9-chloroprednisolone derivatives may be prepared by the process of the present invention, as defined below.
The present invention accordingly also provides a process for the manufacture of a compound of the present invention of the genei'al formula I, wherein (a) HOCl is added on at the , -bond of a compound of the general formula II -8CH„X I 2 in whicli R^ and X have the meanings given above, or (b) the epoxide ring of a compound of the general formula III in which R^ and X have the meanings given above, is opened up with hydrogen chloride, or (o) when X represents a fluorine or chlorine atom, an orthoester of the general formula IV in whieh R^ represents a hydrogen atom, an alkyl group containing 1 to 7 carbon a boms or a phenyl group and Rg represents an alkyl group containing 1 to 4 oarbon atoms, S 8 7 7 -9is reacted with trimethylsilyl fluoride or triphenylmethyl fluoride or chloride, or (d) when X represents a chlorine atom, an alkanoyloxy group or benzoyloxy group, a 9-chloro-derivative of the general formula Ia CH.OH ι < in which R^ has the meaning given above, is chlorinated or esterified at the 21-position.
Each of the variants of the process of the present invention may be carried out in a manner known per se.
The process variants (a), (b) and (d) may be carried out under the conditions described in United States Patent Specifications Nos. 3,678,034, 3,718,671 and 3,828,083. The process of the present invention in accordance with process variant (c) may be carried out under the conditions described in United States Patent No. 3,152,154 and in German Offenlegungsschriften Nos. 26 13 875 and 24 36 747.
The starting compounds for the process of the present invention can be prepared, as is known, in a simple manner and in high yields from prednisolone, which itself can be synthesized relatively easily from diosgenin. The consequence of this is that the compounds of the present invention can be prepared from diosgenin 3 8 7 7 -10with relatively little expenditure in a total yield of about 15%. On the other hand, the syntheses of known highly active corticoids from diosgenin are considerably more expensive and the total yields obtained are significantly smaller (about 0.5 to 5%). This is not without importance in view of the increasing difficulties in procuring sufficient quantities of starting materials suitable for the syntheses of corticoids, and having regard to the high costs of the active substances with which medicinal specialities containing corticoids are encumbered.
The compounds of the present invention possess, as has already been stated, a strong anti-inflammatory activity in topical applioation, but they are only very weakly active in systemic application.
The pharmacological properties of the compounds have been determined by the following tests: (A) The inflammation-inhibiting activity in local application to the ears of rats: The substance to be tested was dissolved in an irritant consisting of 4 parts of pyridine, 1 part of distilled water, 5 parts of ether and 10 parts of an ethereal solution of 4% strength of croton oil. Strips of felt, which were attached to the inner sides of a microscope slide forceps, were impregnated with this test solution, and were pressed with light pressure for 15 seconds on' the right ear of male rats weighing 100 to 160 grams. The left ear remained untreated and served S 8 7 7 -11for comparison. Three hours after the application the animals were killed and discs having a sise of 9 mm were stamped out of their ears. The difference in weight between the discs of the right and that of the left ear was a measure of the oedema formed.
The dose of test substance was determined at which after three hours a 50$ inhibition of the formation of oedema was observed.
(B) The inflammation-inhibiting activity in subcutaneous application of the paw of rats: SPP-Hats weighing 130 to 150 grams were injected in the right paw for producing a source of inflammation with 0.1 ml of a suspension of 0.5$ strength of Mycobacterium butyricum (obtainable from the American firm Difko). Before the injection the paw volumes of the rats were measured. 24 Hours after the injection the paw volume was again measured to determine the extent of the oedema. The rats were then injected subcutaneously with various quantities of the test substance dissolved in a mixture of 29$ of benzyl benzoate and 71$ of castor oil. After a further 24 hours the paw volume was again determined.
Control animals were treated in the same manner with the difference that they were injected with a mixture of benzyl benzoate and castor oil free from the test substance.
Prom the paw volumes so obtained was determined in the usual manner the quantities of test substance which 43877 -12was required to produce a 50$ healing of the paw oedema.
(C) The thymolytic effect after oral application: SPP-Rats weighing 70 to 110 grams were adrenalectomized under narcosis produced by ether. Every 6 5 animals formed a test group, each of which received over days a definite quantity of test substance applied -per os. On the fourth day the animals were killed and the weight of their thymus was determined. Control animals were treated in the same manner, but received a mixture of benzyl benzoate and castor oil without the test substance. From the weights of the thymus so obtained was determined in the usual manner the quantity of test substance at which a 50$ thymolysis was observed.
As substances for comparison there were used in these tests the structurally analogous 9-chloroprednisolone and its 21-acetate and also beclomethasone17,21 - dipropionate (9rt - chloro - lip - hydroxy - Ιδρmethyl - 17«,21 - dipropionyloxy - A1’4 - pregnadiene 3,20 - dione.
The results obtained in these tests are given in the following Table: 43877 -153 •rl n s-p r-i (0 o Φ a «ρ (A) Eats (B) Adjuvant d a -p Φ a •d Φ Φ -p o -P fi ra d φ Φ «ρ ? o £ •rl •d fi ft •rt •d ( & o j? i rH ca. rH Φ rH ti i 5 fi *d 5Δ I ΝΛ tt CJ\ «t Φ rH fi rH O I *rl O »d S6 rH CM Λ * O m i i o\ ti ι ra ca. VD Φ rH S i o j? rn ii rH fi rH Φ I ·γΙ ο d 8 i Ά σ\ ι & o £ I oa. φ rH fi rH O I -rt o -d o d> rH CM Λ * o m 1 » o\ fi ι ra H-rt & fr® O fi rH O o d Ν I fi o Φ CM 33 * I rn δ ι S- Q) rH fi J « s?9 p 3 φ So ο Φ «! fi ι ft & o rH & o •rl ft O &.
I rH CM i? o ί ci. i φ &g ?i tt CM o\ * I m S?i o fi rH Φ fc»-H ο d n d g a PQ Φ 1 h- ft -14Similar results are obtained when the pharmacological activity of the 9-chloroprednisolone derivatives of the present invention is determined hy means of the known vasoconstruction test or the known sodium-potassium retention test.
The new compounds of the present invention are suitable In combination with the carrier substances customarily used in, for example, galenical pharmacy for the local treatment of contact dermatitis, eczemas of a very wide variety of types, neurodermatoses, erythrodermia, burns, Pruritis vulvae et ani, Rosacea, Erythematodes cutaneus, Psoriasis, lichen ruber planus et verrucosus and similar skin diseases.
The present invention accordingly further provides a pharmaceutical preparation which comprises a compound of the present invention of the general formula I, in admixture or conjunction with a pharmaceutically suitable carrier. The preparation is advantageously in a form suitable for the topical treatment of inflammations.
The manufacture of the pharmaceutical preparations may be carried out in the usual manner by converting the active substances with suitable additives into the desired form of applioation, for example solutions, lotions, salves, creams or plasters. The concentration of active substance in the pharmaceutical preparations so formulated depends on the form of applioation. In the case of lotions and salves there is preferably used a concentration of active substance within the range of from -150.001% to 1% by weight.
Furthermore, the new compounds of the general formula I are also well suited for the production of inhalent preparations, if desired in combination with the usual carrier substances and auxiliary substances, which preparations can be used for the therapy of allergic disorders of the respiratory system, for example asthma or rhinitis.
The following Examples illustrate the invention. Examples 2 to 11, 13 to 15 and 17 to 41 illustrate the manufacture of the new compounds of the general formula I and Examples 42 and 43 illustrate pharmaceutical preparations containing such compounds. Examples 1, 12 and 16 illustrate the manufacture of starting materials of the general formula I in whioh X represents a hydroxyl group.
Example 1 (a) 5.0 gms of 9«--chloro-lip,174-pregnadiene-3,20-dione were mixed with 500 ml of benzene, 40 ml of dimethylformamide and 500 mg of absolute pyridine tosylate. The mixture was heated, ml of the solvent were distilled off at a bath temperature of 130°0, 60 ml of ortho-benzoic aoid triethyl ester were added and the residual benzene was distilled off during the course of 2-/.- hours. 2.4 ml of pyridine were added to the residue, the mixture was concentrated in vacuo and 17a., 21 - (l-ethoxy-benzylidenedioxy) - 9« -chloro-llp-hydroxy - ^’^-pregnadiene -163,20 - dione was obtained in the form of an oily crude product. (b) The crude product so obtained was mixed with 150 ml of methanol, 54 ml of O.lN-aqueous acetic acid and 6 ml of an O.lN-aqueous solution of sodium acetate and the mixture was heated under reflux for 90 minutes. The reaction mixture was then concentrated in vacuo, water was added to the residue and the mixture was extracted with ethyl acetate. The organic phase was washed with water, concentrated in vacuo, the residue was purified by chromatography over a column of silica gel and reorystallized from acetone-hexane and there were obtained 3.7 gms of 17« - benzoyloxy - 9°t- chloroIl^,21 - dihydroxy - ^’^-pregnadiene - 3,20 - dione melting at 216°C (with decomposition).
Example 2 0.5 gm of 17«. - benzoyloxy - 9« - chloro - lip,21 dihydroxy - ^’^-pregnadiene - 3,20 - dione was stirred for 24 hours at room temperature with 10 ml of formic acid. The reaction mixture was thenpoured into icewater and extracted with diehloromethane, the organic phase was washed, dried over sodium sulphate and concentrated in vacuo and there were obtained 400 mg of 17d - benzoyloxy - 9« -chloro - 21 - formyloxy - lip 25 hydroxy - ^’^"Pregnadiene - 3,20 - dione that solidified in the form of a glassy mass. +53» (chloroform).
Example 3 1.5 gms of 17«- benzoyloxy - 9«. - chloro - lip,214 5 8 7 7 -17dihydroxy - A^’4 " pregnadiene - 3,20 - dione were mixed with 17 ml of pyridine and 8.0 ml of acetic anhydride and the whole wae stirred for one hour at 0°C. The reaction mixture was poured into ice-water, the product that separated was filtered off and dissolved in dichloromethane, and the organic phase was washed, dried with sodium sulphate and concentrated in vacuo. The residue was chromatographed over a column of silica gel with methylene chloride-acetone gradients and recrystallized from acetonehexane and 1.2 gms of 21 - acetoxy 17«. benzoyloxy - 9«· - chloro - lip - hydroxy - A^’4 " pregnadiene - 3,20 - dione melting at 221°C (with decomposition) were obtained.
Example 4 1.5 gms of 17« - benzoyloxy - 9« - chloro - lip,21 dihydroxy - 41’4 - pregnadiene - 3,20 - dione were mixed with 17 ml of pyridine and 8,0 ml of propionic anhydride and the whole was stirred for one hour at 0°C. The reaction mixture was worked up as described in Example 3 and there were obtained 960 mg of 17« - benzoyloxy - 9« chloro - lip - hydroxy - 21 - propionyloxy -A1’4 " pregnadiene - 3,20 - dione melting at 226°C (with decomposition).
Example 5 2.3 gms of 17« - benzoyloxy - 9« - chloro - lip,21 dihydroxy - - pregnadiene - 3,20 - dione were mixed with 50 ml of pyridine and 25 ml of butyric anhydride and the whole was stirred for 16 hours at room temperature. -18The reaction mixture was worked up as described in Example 3 and 2.0 gms of 17« - benzoyloxy - 21 - butyryloxy - 9« - chloro - lip - hydroxy - - pregnadiene 3,20 - dione melting at 226°C (with decomposition) were obtained.
Example 6 2.3 gms of 17« - benzoyloxy - 9 Example 7 2.3 gms of 17« - benzoyloxy - 9« - chloro - lip,21 dihydroxy - - pregnadiene - 3,20 - dione were mixed with 50 ml of pyridine and 25 ml of trimethylacetic anhydride and the whole was stirred for 16 hours at room temperature. The reaction mixture was worked up as described in Example 3 and there were obtained 1.72 gms of 17 λ - benzoyloxy - 9«.- chloro - lip - hydroxy - 21 trimethylacetoxy - - pregnadiene - 3,20 - dione melting at 236°0.
Example 8 2.3 gms of 17oc - benzoyloxy - 9«. - chloro - lip,21 dihydroxy - - pregnadiene - 3,20 - dione were mixed with 50 ml of pyridine and 25 ml of isobutyric anhydride 4S877 -19and the whole was stirred for 16 hours at room temperature. The reaction mixture was worked up as described in Example 3 and 2.1 gms of 17« - benzoyloxy - 9K - chloro - lip hydroxy - 21 - isobutyryloxy - Δ1’4 " pregnadiene - 3,20 dione were obtained in the form of a glassy mass. = +68° (chloroform).
Example 9 2.3 gms of 17« - benzoyloxy - 9«' - chloro - lip,21 dihydroxy - Δ1’4 " pregnadiene - 3,20 - dione were mixed with 50 ml of pyridine and 20 ml of isovaleric acid chloride and the whole was stirred for 2 hours at 0°C.
The reaction mixture was worked up as described in Example 3 and 2.1 gms of 17« - benzoyloxy - 9« - chloro lip - hydroxy - 21 - isovaleryloxy - δ^’4 ~ pregnadiene 3,20 - dione melting at 197°C were obtained.
Example 10 2.3 gms of 17K - benzoyloxy - 9a- chloro - lip,21 dihydroxy - Δ1’4 " pregnadiene - 3,20 - dione were mixed with 50 ml of pyridine and 30 ml of oenanthic anhydride and the whole was stirred for 16 hours at room temperature. The reaction mixture was poured into ice-water and heated and the excess of oenanthic acid was removed by steam distillation. The mixture was extracted with dichloromethane, the organic phase was worked up as described in Example 3 and 2.03 gms of 17« - benzoyloxy - 9« - chloro 21 - heptanoyloxy - lip - hydroxy - Δ.1’4 ~ pregnadiene 3,20 - dione were obtained in the form of an oily product. = +64° (chloroform). -204 5 8 7 7 Example 11 2.3 gms of 17 k. - benzoyloxy - 9K - chloro - lip,21 dihydroxy - - pregnadiene - 3,20 - dione were stirred with 45 ml of pyridine and 1 ml of benzoyl chloride for one hour at room temperature. The reaction mixture was worked up as described in Example 3 and there were obtained 2.5 gms of 17°c,21 - dibenzoyloxy - 9« - chloro lip - hydroxy - - pregnadiene - 3,20 - dione melting at 221°C.
Example 12 (a) Under the conditions described in Example 1(a) 7.5 gms of 9 a - chloro - lip,17ot, 21 - trihydroxy - / ’pregnadiene - 3,20 - dione were reacted with ortho-acetic acid triethyl ester and worked up. There was obtained 17a,21 -(1- ethoxy - ethylidenedioxy) - 9°t- chloro lip - hydroxy - A1’4 - pregnadiene - 3,20 - dione in the form of an oily crude product. (b) The crude product so obtained was reacted under the conditions described in Example 1(b) and worked up, and 5.2 gms of 17«.- acetoxy -9«.- chloro - lip,21 dihydroxy - - pregnadiene - 3,20 - dione melting at 205°C (with decomposition) were obtained.
Example 13 1.0 gm of 17« - acetoxy - 94 - pregnadiene - 3,20 - dione was mixed with 20 ml of pyridine and 5 ml of acetic anhydride and the whole was stirred for one hour at room temperature.
The reaction mixture was then poured into ice-water, the 4S877 -21product that separated was filtered off with suction and dissolved in dichloromethane and the organic phase wae washed and concentrated in vacuo. The residue was recrystallized from acetone-hexane and there were obtained 860 mg of 17«, 21 - diacetoxy -9«.- chloro - lip hydroxy - - pregnadiene - 3,20 - dione melting at 222°C (with decomposition).
Example 14 Under the conditions described in Example 4 1.0 gm of 171’4 - pregnadiene - 3,20 - dione was reacted with propionic anhydride and worked up, and there were obtained 940 mg of 17« - acetoxy - 9« - chloro - lip - hydroxy 21 - propionyloxy - /J’4 " pregnadiene - 3,20 - dione melting at 219°0 (with decomposition).
Example 15 Under the conditions described in Example 6 1.0 gm of 17« - acetoxy - 9« - chloro - lip,21 - dihydroxy Δ1’4 - pregnadiene - 3,20 - dione was reacted with valeric anhydride and worked up, and there were obtained 660 mg of 17« - acetoxy - 9« - chloro - lip - hydroxy 21 - valeryloxy - β1’4 " pregnadiene - 3,20 - dione melting at 220*0 (with decomposition).
Example 16 (a) Under the conditions described in Example 1(a) gms of 9« - chloro - lip,17«,21 - trihydroxy - δ1’4 pregnadiene - 3,20 - dione were reacted with orthopropionic acid triethyl ester and worked up, and 17«,21 45877 -22(l - ethoxy - propylidenedioxy) - 9«- chloro - lip hydroxy - /3’4 - pregnadiene - 3,20 - dione was obtained in the form of a crude product. (b) The crude product so obtained was reacted under 5 the conditions described in Example l(b) and worked up, and there were obtained 2.9 gms of 9Λ - chloro - lip,21 dihydroxy - 17«- propionyloxy - - pregnadiene 3,20 - dione melting at 181°0 (with decomposition).
Example 17 Under the conditions described in Example 2 1.2 gms of 9« - chloro -lip,21 - dihydroxy - 17« - propionyloxy A1’4 - pregnadiene - 3,20 - dione were reacted with formic acid and worked up, and there were obtained 400 mg of oily 9« - chloro - 21 - formyloxy - lip - hydroxy - 17« 15 propionyloxy - A1’4 ~ pregnadiene - 3,20 - dione. [oQ = +67° (chloroform).
Example 18 700 mg of 9« - chloro - lip,21 - dihydroxy - 17« propionyloxy - a1’4 - pregnadiene - 3,20 - dione were reacted with acetic anhydride ae described in Example 3 and worked up and there were obtained 320 mg of 21 acetoxy - 9« - chloro - lip - hydroxy - 17« - propionyloxy - A1,4— pregnadiene - 3,20 - dione melting at 210°0 (with decomposition).
Example 19 700 mg of 9°t- chloro - lip,21 - dihydroxy - 17« propionyloxy - a1’4 " pregnadiene - 3,20 - dione were reacted with propionic anhydride under the conditions 458 77 -23desoribed in Example 4 and worked up, and there were obtained 420 mg of 9« - chloro - lip - hydroxy - 17k,21 dipropionyloxy - Δ1’4 - pregnadiene - 3,20 - dione melting at 215°O (with decomposition).
Example 20 650 mg of 9« - chloro - lip,21 - dihydroxy - 17« propionyloxy - Δ1’4 - pregnadiene - 3,20 - dione were reacted with butyric anhydride under the conditions described in Example 5 and worked up, and there were obtained 360 mg of 21 - butyryloxy - 9«- chloro - lip hydroxy - 17°(- propionyloxy - Δ1’4 ~ pregnadiene - 3,20 dione melting at 208°C (with decomposition).
Example 21 Under the conditions described in Example 6 700 mg of 9« - chloro - lip,21 - dihydroxy - 17a - propionyloxy Δ*'’4 - pregnadiene - 3,20 - dione were reacted with valeric anhydride and worked up, and there were obtained 520 mg of 9« - chloro - lip - hydroxy - 17« - propionyloxy - 21 - valeryloxy - Δ1’4 ~ pregnadiene - 3,20 20 dione melting at 210°C (with decomposition).
Example 22 3.0 gms of 9« - chloro - lip,21 - dihydroxy - 17« η i propionyloxy - δ ~ pregnadiene - 3,20 - dione were mixed with 30 ml of pyridine and 15 ml of caproic anhydride and the whole was stirred for 90 minutes at room temperature. The reaction mixture was worked up as described in Example 3 and there were obtained 2.6 gms of 9 ix - chloro - 21 - hexanoyloxy - lip - hydroxy - 17« 8 77 -24propionyloxy - - pregnadiene - 3,20 - dione.
Example 23 Under the conditions described in Example 10 2.1 gms of 9«- chloro - lip,21 - dihydroxy - 17« - propionyloxy /χ1’^ - pregnadiene - 3,20 - dione were reacted with oenanthic anhydride and worked up, and there were obtained 1.02 gms of 9« - chloro - 21 - heptanoyloxy - lip hydroxy - 17« - propionyloxy - /χ1’^ - pregnadiene - 3,20 dione.
Example 24 Under the conditions described in Example 7 1*4 gms of 9« - chloro - lip,21 - dihydroxy - 17« - propionyloxy- pregnadiene - 3,20 - dione were reacted with trimethylacetic anhydride and worked up, and 670 mg of 9 0(. - chloro - lip - hydroxy - 17« - propionyloxy -21trimethylacetoxy - - pregnadiene - 3,20 - dione were obtained.
Example 25 (a) Under the conditions described in Example 20 gms of lip,17a,21 - trihydroxy - - pregnadiene 3,20 - dione were reacted with butyric anhydride and worked up, and 23.1 gms of 21 - butyryloxy - lip,17« dihydroxy - - pregnadiene - 3,20 - dione were obtained. (b) Into a suspension of 24 gms of eopper-(I) chloride in 480 ml of absolute tetrahydrofuran were introduced dropwise under argon at 0°C 100 ml of an ethereal solution of 5$ strength of lithium methyl. 3 8 7 7 -25The mixture was then cooled to -30°C and a solution of 22.3 gms of 21 - butyryloxy - lip,17« - dihydroxy - Δ^’4pregnadiene - 3,20 - dione in 100 ml tetrahydrofuran was added. The mixture was stirred for 4 hours until the primarily formed lip - hydroxy - 17«,21 - (l-hydroxy butylidenedioxy) - Δ1’4 " pregnadiene - 3,20 - dione had been rearranged. An aqueous solution of ammonium chloride was then added to the reaction mixture, extraction was carried out with methylene chloride, the organic phase was washed and concentrated in vacuo and 20.3 gms of 17ot - butyryloxy - lip,21 - dihydroxy - β1’4 - pregnadiene - 3,20 - dione were obtained in the form of a crude product. (c) Under the conditions described in Example 3 gms of the crude product so obtained were reacted with acetic anhydride and worked up, and there were obtained 14.2 gms of 21 - acetoxy - 17« - butyryloxy - lip hydroxy - Δ1’4 " pregnadiene - 3,20 - dione. (d) 5.4 ml of methane sulphonic acid chloride were introduced dropwise at room temperature into a solution of 10 gms of 21 - acetoxy - 17« - butyryloxy - lip hydroxy - Δ^*4 " pregnadiene - 3,20 - dione in 50 ml of dimethylformamide and 11 ml of pyridine. The reaction mixture was stirred for two hours at 85’C, poured, after cooling, into ice-water and worked up as described in Example 3, and 6.5 gms of 21 - acetoxy - 17« - butyryloxy - δ1’4,9^11^ - pregnatriene- 3,20 - dione were obtained in the form of a crude product. -26(e) 6 gms of the crude product so obtained were suspended in 80 ml of dioxan and 5-6 gms of E-chlorosuccinimide were added. There were then introduced dropwise into the mixture during the course of 10 minutes at 20°0 42 ml of an aqueous solution of 10$ strength of perchloric acid, and the mixture was stirred for 3 hours at 20°C and was then poured into a solution of 2.5 gms of sodium hydrogen sulphite in 400 ml of water. The product that separated was filtered off with suction and worked up as described in Example 3, and 3.1 gms of 21 acetoxy - 17« - butyryloxy - 9« - chloro - lip - hydroxyA1’4 - pregnadiene - 3,20 - dione melting at 215°O were obtained.
Example 26 (a) 9.5 gms of 17« - butyryloxy - lip,21 dihydroxy - a1’4 - pregnadiene - 3,20 - dione prepared as a crude product in accordance with Example 25(b) were reacted under the conditions described in Example 7 with trimethylacetic anhydride and worked up, and 6.3 gms of 17« - butyryloxy - lip - hydroxy - 21 - trimethylacetoxy A1’4 " pregnadiene - 3,20 - dione were obtained. (b) 6.0 gms of 17« - butyryloxy - lip - hydroxy 21 - trimethylacetoxy - a1’4 - pregnadiene - 3,20 - dione were reacted with methane sulphonic acid chloride under the conditions described in Example 25(d) and worked up, and there were obtained 3.4 gms of 17« - butyryloxy 21 - trimethylacetoxy - ^4,9(11) _ pregnatriene - 3,20 · dione in the form of a crude product. 8 7 7 -27(c) 3.0 gms of the crude product so obtained were reacted under the conditions described in Example 25(e) and worked up, and there were obtained 1.1 gms of 17» butyryloxy - 9 « - chloro - lip - hydroxy - 21 - trimethylacetoxy - Δ1’4 - pregnadiene - 3,20 - dione melting at 259°C.
Example 27 (a) 14.1 gms of 17a - butyryloxy - lip,21 dihydroxy - δ'’4 ~ pregnadiene - 3,20 - dione, prepared as a crude product in accordance with Example 25(b), were reacted under the conditions described in Example 10 with oenanthic anhydride and worked up, and there were obtained 8.2 gms of 17« - butyryloxy - 21 heptanoyloxy - lip - hydroxy - Δ1’4 - pregnadiene 3,20 - dione. (b) 7.6 gms of 17« - butyryloxy - 21 - heptanoyloxy - lip - hydroxy - Δ1’4 " pregnadiene - 3,20 - dione were reacted under the conditions described in Example 25(d) and worked up, and 3.9 gms of 17«. - butyryloxy 21 - heptanoyloxy - ^»4,9(11) _ pregnatriene - 3,20 dione were obtained as a crude product. (c) 3 gms of the crude product so obtained were reacted with N-chlorosuccinimide under the conditions described in Example 25(e) and worked up, and 950 mg of 17« - butyryloxy - 9« - chloro - 21 - heptanoyloxy - lip hydroxy - Δ1’4 - pregnadiene - 3,20 - dione were obtained.
Example 28 (a) Under the conditions described in Example 25(b) -2820 gms of lip, 17«. - dihydroxy - 21 - valeryloxy - ^’4 pregnadiene - 3,20 - dione were- reacted with, lithium dimethyl cuprate and worked up, and 18.6 gms of lip,21 dihydroxy - 17« - valeryloxy - β1’4 - pregnadiene 5 3,20 - dione were obtained in the form of a crude product (b) 18 gms of the crude product so obtained were reacted with propionic anhydride under the conditions described in Example 4 and worked up, and 10.8 gms of lip - hydroxy - 21 - propionyloxy - 17«. - valeryloxy 10 Δ^’4 ~ pregnadiene - 3,20 - dione were obtained. (o) 9 gms of lip - hydroxy - 21 - propionyloxy 17«. - valeryloxy - Δ1’4 ~ pregnadiene - 3,20 - dione were reacted with methane sulphonic acid chloride under the conditions described in Example 25(d) and worked up, and 4.9 gms of 21 - propionyloxy - 17« - valeryloxy ^1,4,9(11) _ pregna-triene _ 3,20 - dione were obtained in the form of a crude product. (d) 4.0 gms of the crude product so obtained were reacted under the conditions described in Example 25(e) and worked up, and 1.4 gms of 9θί- chloro - lip hydroxy - 21 - propionyloxy - 17« - valeryloxy pregnadiene - 3,20 - dione were obtained. Melting point: 242°C.
Example 29 (a) 17*2 gms of lip,21 - dihydroxy - 17« - valeryloxy ~ - pregnadiene - >,20 - dione, crude product, were reacted with valeric anhydride under the conditions described in Example 6 and worked up, and there were -29obtained 9.7 gms of lip - hydroxy - 17«,21 - divaleryloxyΔ,1’4 - pregnadiene - 3,20 - dione. (b) 8 gms of 11 p - hydroxy - 17«,21 - divaleryloxyΔ1’4 - pregnadiene - 3,20 - dione were reacted· with methane sulphonic acid chloride under the conditions described in Example 25(d) and worked up, and 4.6 gms of 17«, 21 - divaleryloxy - 4,9(11) _ pregnatriene _ 3,20 - dione were obtained in the form of a crude product. (c) 4.5 gms of the crude product so obtained were reacted under the conditions described in Example 25(e) and worked up, and 1.8 gms of 9« - chloro - lip hydroxy - 17a,21 - divaleryloxy - β1’4 *- pregnadiene 3,20 - dione were obtained. Melting point: 254°0.
Example 30 To 10 ml of hexamethyl-phosphoric acid triamide were added at 0°C 1.3 ml of thionyl chloride and the whole was stirred for 30 minutes. 800 mg of 17« - acetoxy - 9« chloro - lip,21 - dihydroxy - Δ1’4 - pregnadiene - 3,20 dione were then added to the mixture and the whole was stirred for a further 5i hours at 0°C.
The reaction mixture was worked up as described in Example 3 and 540 mg of 17« - acetoxy - 9«,21 - dichloro lip - hydroxy Δ1’4 - pregnadiene - 3,20 - dione melting at 222°C (with decomposition) were obtained.
Example 31 Under the conditions described in Example 30 1.2 gms of 9°i- chloro - lip,21 - dihydroxy - 17« - propionyloxy Δ1’4 ~ pregnadiene - 3,20 - dione were reacted with 877 -30thionyl chloride and worked up, and 860 mg of 9«,21 dichloro - lip - hydroxy - 17« - propionyloxy -A1’4 " pregnadiene - 3,20 - dione melting at 232°C were obtained.
Example 32 Under the conditions described in Example 30 8.5 gms of 17« - benzoyloxy - 9«- chloro - lip,21 - dihydroxy A1’4 - pregnadiene - 3,20 - dione were reacted and worked up, and 4.1 gms of 17« - benzoyloxy - 9«,21 - dichloro lip - hydroxy - - pregnadiene - 3,20 - dione melting at 220°0 were obtained.
Example 33 (a) A suspension of 5.6 gms of 21 - fluoro - 17« hydroxy - a1’4,9^1^ - pregnatriene - 3,20 - dione in ml of diethylene glycol dimethyl ether was stirred with 10 gms of Κ,ΪΤ - dimethylamino - pyridine and 6.4 ml of acetic anhydride for 6.5 hours at 80°C. The reaction mixture was diluted with methylene chloride and washed with 2H-hydrochloric acid. After steam distillation extraction was carried out with methylene chloride, the mixture was dried over sodium sulphate and, after evaporation, 6.7 gms of 17« - acetoxy - 21 - fluoro ^1,4,9(11) _ pregnatriene - 3,20 - dione were isolated. (b) 2 gms of the above crude product were dissolved in 20 ml of dioxan and treated with E-ohlorosuccinimide in a manner analogous to that described in Example 25(e). Purification of the reaction product was carried out over 220 gms of silica gel with a methylene choride-acetone gradient (0 - 10$ of acetone)· The yield was 1.3 gms of -5117 Λ - acetoxy - 9« - chloro - 21 - fluoro - lip hydroxy - Δ1’4- pregnadiene - 3,20 - dione. Melting point: 232°C (with decomposition). 0*3^ = +52° (chloroform). UV: £539 = ^5,100 (methanol).
Example 34 gms of 21 - fluoro - 17« - propionyloxy ^1,4,9(11) _ pregnatriene - 3,20 - dione, prepared in a manner analogous to that described in Example 33(a) from 21 - fluoro - 17« - hydroxy - δ1’4’^11) - pregnatriene 3,20 - dione and propionic anhydride, were reacted with N-chlorosuccinimide under the conditions described in Example 25(e). The crude product was purified over 220 gms of silica gel with a methylene chloride-acetone gradient (0 - 10% of acetone). The yield was 1.24 gms of 9a — chloro - 21 - fluoro - lip - hydroxy - 17« propionyloxy - Δ1’4 " pregnadiene - 3,20 - dione.
Melting point 221°C (with decomposition). («3^ = +48° (chloroform). UV: £239 = -^5,500 (methanol).
Example 35 1.5 gms of 17«- butyryloxy - 21 - fluoro ^-,4,9(11) _ pregnatriene - 3,20 - dione, prepared from 21 - fluoro - 17« - hydroxy - - pregnatriene 3,20 - dione and butyric anhydride in a manner analogous to that described in Example 33(a), were treated with Nchlorosuccinimide in a manner analogous to that described in Example 25(e). Purification of the crude product was carried out over 150 gms of silica gel with methylene chloride-acetone gradient (60 - 10% of acetone). The 46877 -32yield was 840 mg of 17« - butyryloxy - 9«- chloro - 21 fluoro - lip - hydroxy - - pregnadiene - 5,20 dione.
Example 56 1 gm of 17«,21 -(1- ethoxy - benzylidenedioxy) 9a- chloro - lip - hydroxy - Δ1’4 ~ pregnadiene - 5,20 dione prepared in a manner analogous to that described in Example 1(a) was stirred in 40 ml of dimethylformamide with 4 ml of trimethylsilyl fluoride for 2 hours at room temperature. After precipitation in ice-water and the usual working up, evaporation in vacuo was carried out. The crude product was purified over 120 gms of silica gel with a methylene chloride-acetone gradient (0 - 10$ of acetone). The yield was 240 mg of 17« - benzoyloxy 15 9« - chloro - 21 - fluoro - lip - hydroxy - pregnadiene - 5,20 - dione.
Example 57 In a manner analogous to that described in Example 55(a) there were prepared from 5 gms of 21 - fluoro 20 17« - hydroxy - _ pregnatriene - 3,20 - dione and isobutyric anhydride 4.8 gms of 21 - fluoro - 17« isobutyryloxy - ^»4,9(11) _ pregnatriene - 3,20 - dione, whioh were reacted with N-chlorosuocinimide under the conditions described in Example 25(e). The crude product was purified over 350 gms of silica gel with a methylene chloride-acetone gradient (0 - 10$ of acetone). The yield was 3.5 gms of 9a- chloro - 21 - fluoro - lip hydroxy - 17« - isobutyryloxy - /χ1’4 - pregnadiene -554 3 Q γ γ 3,20 - dione.
Example 38 gma of crude 17a,21 -(1- ethoxy - ethylidenedioxy) - 9« - chloro - lip - hydroxy - Δ1’4 - pregnadiene - 3,20 - dione, prepared from 9« - chloroprednisolone and ortho-acetio acid triethyl ester in a manner analogous to that described in Example 1(a), were refluxed under nitrogen for one hour in 30 ml of methylene chloride with 3 gms of triphenyl-methyl chloride. The solvent was distilled off and the residue was purified over 350 gms of silica gel with a methylene chloride-acetone gradient (0 - 15% of acetone). The yield was 1.3 gms of 17« acetoxy - 9«,21 - dichloro - lip - hydroxy - Δ1’4 pregnadiene - 3,20 - dione. Melting point: 222°C (with decomposition). = +124° (pyridine). UV: = ,200 (methanol).
Example 39 gms of crude 17«,21 - (l- ethoxypropylidenedioxy)9» - chloro - lip - hydroxy - Δ1’4 " pregnadiene - 3,20 20 dione, prepared from 9°C- chloroprednisolone and orthopropionic acid triethyl ester in a manner analogous to that described in Example 1(a), were stirred in 50 ml of dimethylformamide with 5 ml of trimethylsilyl chloride for 2 hours at room temperature. After precipitation in ice-water and the usual working up, 1.4 gms of 9«,21 dichloro - lip - hydroxy - 17« - propionyloxy - Δ?’4 pregnadiene - 3,20 - dione were isolated, which were purified hy recrystallization from acetone/hexane. 43S77 -34Melting point: 232°C. +γθ° (chloroform).
UV: S25g = 15,200 (methanol).
EXAMPLE 40 (a) 2 gms of 21 - fluoro - 17 The resulting substance was dissolved in a small amount of pyridine and added to ice-water, and the pyridine was neutralized with dilute hydrochloric acid. After the usual working up 1.6 gms of 21 - fluoro - 17« - isovaleryloxy - ^>4,9(11) _ pregnatriene - 3,20 - dione were isolated. (b) 1 gm of the above crude product was reacted with N-chlorosuccinimide and worked up in a manner analogous to that described in Example 33(b). Purification of the crude product was carried out over 100 gms of silica gel with a methylene chloride-acetone gradient (0 - 100 of acetone). The yield was 580 mg of 9«-25 chloro - 21 - fluoro - lip - hydroxy - 17 Example 41 In a manner analogous to that described in Example 58 7 7 -3533(a) 2 gms of 21 - fluoro - 17« - hydroxy - ^·,4,9(11)_ pregnatriene - 3,20 - dione and trimethylacetic anhydride were reacted together to form 1.6 gms of 21 - fluoro 17« - trimethylacetoxy - ^»4,9(11) _ pregnatriene 3,20 - dione, and the crude product was treated with Nohlorosucoinimide in a manner analogous to that described in Example 33(b). After the usual working up purification of the crude yield was carried out over 150 gms of silica gel with a methylene chlorideacetone gradient (0 10$ of acetone). 810 mg of 9« - chloro - 21 - fluoro lip - hydroxy - 17« - trimethylacetoxy - a1’4 ~ pregnadiene - 3,20 - dione were obtained.
Example 42 The composition of a salve. 0.03$ of 21 - acetoxy - 9« - chloro - lip - hydroxy 17« - propionyloxy - a^’4 - pregnadiene - 3,20 - dione. 2.50$ of Allercur hexachlorophenate, micronized, particle size about 8 μ (Allercur = Trade Mark for 1 - para chloro - benzyl - 2 - pyrrolidyl - methyl benzimidazole) 6.00$ of Hostaphat KW 340 (tertiary ester of O-phosphoric acid and wax alcohol tetra-glycol ether, Hostaphat being a Trade Mark) 16 0.10$ of sorbie acid .00$ of neutral oil (Mlglyol 812, Miglyol being a Trade Mark) 3.50$ of stearyl alcohol 3 8 7 7 -361.50% of wool fat, anhydrous DAB 6 76.36% of desalted water.
DAB 6 is an abbreviation for Deutsches Arzneibuch, 6th edition.
Example 43 The manufacture of an inhalant preparation. 1,000 gm of micronized 21 - acetoxy - 9« - chloro lip - hydroxy - 17 rt - propionyloxy - δ?’4 - pregnadiene 3,20 - dione (average particle size smaller than 7μ) and 39.000 gms of ground lactose were mixed together. A dose of 20 mg of inhalant preparation, per inhalation, ia used.

Claims (47)

1. WHAT WB CLAIM ISs1. A compound of the general formula I in which E-j. represents an alkanoyl group containing 1 to 8 carbon atoms or a benzoyl group, and X represents a fluorine atom, a chlorine atom, an 20 alkanoyloxy group containing 1 to 8 carbon atoms or a benzoyloxy group.
2. A compound as claimed in claim 1, wherein R^ represents an alkanoyl group containing 2 to 6 carbon -37atoms.
3. A compound as claimed in claim 1 or 2, wherein X represents an alkanoyloxy group containing 2 to 6 carbon atoms.
4. Any one of the compounds listed in Table 1 herein.
5. Any one of the compounds listed in Table 3 herein.
6. 17« - Benzoyloxy - 9« - chloro - 21 - formyloxy lip - hydroxy - Δ 1 ’ 4 ~ pregnadiene - 3,20 - dione.
7. 21 - Acetoxy - 17« - benzoyloxy - 9« - chloro lip - hydroxy - Δ*’ 4 - pregnadiene - 3,20 - dione.
8. 17« - Benzoyloxy - 9« - chloro - lip - hydroxy 21 - propionyloxy - Δ 1 ’ 4 “ pregnadiene - 3,20 - dione.
9. 17« - Benzoyloxy - 21 - butyryloxy - 9« chloro - lip - hydroxy - Δ 1 ’ 4 - pregnadiene - 3,20 dione.
10. 17« - Benzoyloxy - 9« - chloro - lip - hydroxy 21 - valeryloxy - Δ 1 ’ 4 “ pregnadiene - 3,20 - dione.
11. 17« - Benzoyloxy - 9« - chloro - lip - hydroxy 21 - trimethylacetoxy - Δ 1 ’ 4 “ pregnadiene - 3,20 - dione.
12. 17« - Benzoyloxy - 9« - chloro - lip - hydroxy 21 - isobutyryloxy - /\ 1,4 - pregnadiene - 3,20 - dione.
13. 17« - Benzoyloxy - 9« - chloro - lip - hydroxy •t J 21 - isovaleryloxy - Δ ’ “ pregnadiene - 3,20 - dione.
14. 17« - Benzoyloxy - 9« - chloro - 21 - heptanoyloxy - lip - hydroxy - δ 1 ’ 4 - pregnadiene - 3,20 - dione.
15. 17«,21 - Dibenzoyloxy - 9«- chloro - lip 4 3 8 7 7 -38hydroxy - - pregnadiene - 3,20 - dione.
16. 17a,21 - Diacetoxy - 9« - chloro - lip hydroxy - ~ pregnadiene - 3,20 - dione.
17. 17« - Acetoxy - 9« - chloro - lip - hydroxy 5 21 - propionyloxy - Δ 1 ’ 4 - pregnadiene - 3,20 - dione.
18. 17« - Acetoxy - 9« - chloro - lip - hydroxy 21 - valeryloxy - - pregnadiene - 3,20 - dione.
19. · 9« - Chloro - 21 - formyloxy - lip - hydroxy 17« - propionyloxy - /χ 1 ’ 4 - pregnadiene - 3,20 - dione. 10 20. 21 - Acetoxy - 9a - chloro - lip - hydroxy 17a - propionyloxy - Δ 1 ’ 4 - pregnadiene - 3,20 - dione. 21. 9a - Chloro - lip - hydroxy - 17a,21 dipropionyloxy - Δ?’ 4 - pregnadiene - 3,20 - dione. 22. 21 - Butyryloxy - 9« - chloro - lip - hydroxy 15 17«- propionyloxy - _ pregnadiene - 3,20 - dione. 23· 9 - 21 - valeryloxy - Δ 1 ’ 4 ~ pregnadiene - 3,20 - dione. 24. 9a - Chloro - 21 - hexanoyloxy - lip - hydroxy 17a - propionyloxy - - pregnadiene - 3,20 - dione.
20. 25. 9a - Chloro - 21 - heptanoyloxy - lip - hydroxy - 17« - propionyloxy - £^ 4 ~ pregnadiene - 3,20 - dione. 26. 9a- Chloro - lip - hydroxy - 17a - propionyloxy - 21 - trimethylacetoxy - Δ^’^ ~ pregnadiene - 3,20 dione.
21. 25 27· 21 - Acetoxy - 17a - butyryloxy - 9a - chloro lip - hydroxy - Δ 1 ’^ -pregnadiene - 3,20 - dione.
22. 28. 17« - Butyryloxy - 9« - chloro - lip - hydroxy 21 - trimethylacetoxy - Δ 1 ’ 4 ~ pregnadiene - 3,20 - dione. -3929. 17ft - Butryloxy - 9« - chloro - 21 - heptanoyloxy - lip - hydroxy - Δ 1 ’ 4 ~ pregnadiene - 3,20 - dione.
23. 30. 9a- Chloro - lip - hydroxy - 21 - propionyloxy 17a - valeryloxy - Δ 1 ’ 4 - pregnadiene - 3,20 - dione.
24. 31. 9 1 ’ 4 ~ pregnadiene - 3,20 - dione.
25. 32. 17« - Acetoxy - 9a, 21 - dichloro - lip - hydroxy - Δ 1 ’ 4 “ pregnadiene - 3,20 - dione.
26. 33. 9ft, 21 - Dichloro - lip - hydroxy - 17« propionyloxy - Δ?’ 4 “ pregnadiene - 3,20 - dione.
27. 34. 17a - Benzoyloxy - 9«,21 - dichloro - lip hydroxy - Δ 1 ’ 4 pregnadiene - 3,20 - dione.
28. 35. 17« - Acetoxy - 9« - chloro - 21 - fluoro lip - hydroxy - Δ 1 ’ 4 ~ pregnadiene - 3,20 - dione.
29. 36. 9« - Chloro - 21 - fluoro - lip - hydroxy 17ft - propionyloxy - Δ 1 ’ 4 - pregnadiene - 3,20 - dione.
30. 37. 17« - Butyryloxy - 9ft - chloro - 21 - fluoro lip - hydroxy - ’ 4 - pregnadiene - 3,20 - dione.
31. 38. 17« - Benzoyloxy - 9a - chloro - 21 - fluorolip - hydroxy - δ>^’ 4 ~ pregnadiene - 3,20 - dione.
32. 39. 9« - Chloro - 21 - fluoro - Up - hydroxy 17 1 ’ 4 “ pregnadiene - 3,20 - dione.
33. 40. 9 ix- Chloro - 21 - fluoro - lip - hydroxy 17« - isovaleryloxy - - pregnadiene - 3,20 - dione.
34. 41· 9 1 ’ 4 - pregnadiene - 3,20 dione.
35. 42. A pharmaceutial preparation which comprises a 4S877 decompound as claimed in claim 1, in admixture or conjunction with a pharmaceutically suitable carrier.
36. 43. A pharmaceutical preparation which comprises a compound as claimed in any one of claims 2 to 5, in 5 admixture or conjunction with a pharmaceutically suitable carrier.
37. 44. A pharmaceutical preparation which comprises the compound claimed in any one of claims 6 to 41, in admixture or conjunction with a pharmaceutically suitable 10 carrier.
38. 45. A preparation as claimed in any one of claims 42 to 44, which is in a form suitable for the topical treatment of inflammations.
39. 46. A preparation as claimed in any one of claims 15 42 to 44, which is in the form of a solution, lotion, salve, cream or plaster.
40. 47. A preparation as claimed in any one of claims 42 to 44, which is in the form of a lotion or salve containing the active substance in an amount within the 20 range of from 0.001$ to 1$ by weight.
41. 48. A preparation as claimed in any one of claims 42 to 44, which is in the form of an inhalant preparation.
42. 49. A pharmaceutical preparation having a composition substantially as described in Example 42 or 43 25 herein.
43. 50. The process for the manufacture of a compound of the general formula I 4 38 7 7 in which R^ represents an alkanoyl group containing 1 to 8 carbon atoms or a benzoyl group, and 5 X represents a fluorine atom, a chlorine atom, an alkanoyloxy group containing 1 to 8 carbon atoms or a benzoyloxy group, wherein (a) HOC1 is added at the A?’ 11 - double bond of a 10 compound of the general formula II in which R^ and X have the meanings given above or (b) the epoxide ring of a compound of the general formula III -4245877 CH„X I 2 (HI) , in which Rj and X have the meanings given above, is opened up with hydrogen chloride, or (c) when X represents a fluorine or chlorine atom, 5 an ortho-ester of the general formula IV in which R^ represents a hydrogen atom, an alkyl group containing 1 to 7 carbon atoms or a phenyl group and R^ represents an alkyl group containing 1 to 4 oarbon atoms, 10 is reacted with trimethylsilyl fluoride or chloride or triphenylmethyl fluoride or chloride, or (d) when X represents a chloride atom, an alkanoyloxy group or a benzoyloxy group, a 9-chloro-derivative of the general formula Ia -43o (la) , in which has the meaning given above, is chlorinated or esterified at the 21-position.
44. 51. A process as claimed in claim 50, conducted 5 substantially as described in any one of Examples 2 to 11, 13 to 15 and 17 to 32 herein.
45. 52. A process as claimed in claim 50, conducted substantially as described in any one of Examples 33, 36, 40 and 41 herein. 10
46. 53. A process as claimed in claim 50, conducted substantially as described in any one of Examples 34, 35 and 37 herein.
47. 54. A process as claimed in claim 50, conducted substantially as described in Example 38 or 39 herein.
IE2011/77A 1976-10-04 1977-10-03 New derivatives of 9-chloroprednisolone IE45877B1 (en)

Applications Claiming Priority (2)

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DE2645105A DE2645105C2 (en) 1976-10-04 1976-10-04 Derivatives of 9-chlorprednisolone, process for their preparation and pharmaceutical preparation containing them
DE19772742982 DE2742982C2 (en) 1977-09-21 1977-09-21 9-chlorprednisolone derivatives, process for their production and pharmaceutical preparation containing them

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FI (1) FI58645C (en)
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US8513247B2 (en) 2010-03-26 2013-08-20 Galderma Laboratories, L.P. Methods and compositions for safe and effective treatment of erythema
PH12014500783A1 (en) 2011-10-19 2014-05-12 Galderma Sa Method of reducing facial flushing associated with systemic use of phosphodiesterase type 5 inhibitors
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IE45877L (en) 1978-04-04
ES462887A1 (en) 1978-12-16
FI58645B (en) 1980-11-28
IL53030A0 (en) 1977-11-30
FR2366313A1 (en) 1978-04-28
ATA703577A (en) 1980-01-15
SU743581A3 (en) 1980-06-25
PT67109B (en) 1979-03-14
NO148597C (en) 1983-11-09
PT67109A (en) 1977-11-01
CH632772A5 (en) 1982-10-29
GR73041B (en) 1984-01-26
JPS6129960B2 (en) 1986-07-10
IL53030A (en) 1982-11-30
HU179593B (en) 1982-11-29
NL7710869A (en) 1978-04-06
CH630098A5 (en) 1982-05-28
AT358202B (en) 1980-08-25
SE431655B (en) 1984-02-20
SU751327A3 (en) 1980-07-23
PL201161A1 (en) 1979-01-29
LU78223A1 (en) 1978-02-01
FI772922A7 (en) 1978-04-05
PL110392B1 (en) 1980-07-31
CH632278A5 (en) 1982-09-30
NO773362L (en) 1978-04-05
IT1113623B (en) 1986-01-20
NO148597B (en) 1983-08-01
FR2366313B1 (en) 1980-02-01
NZ185295A (en) 1980-04-28
FI58645C (en) 1981-03-10
JPS5359654A (en) 1978-05-29
SE7711039L (en) 1978-04-05
GB1594852A (en) 1981-08-05
CH631997A5 (en) 1982-09-15
DK438277A (en) 1978-04-05

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