GB1593978A - Anti-inflammatory steroids - Google Patents
Anti-inflammatory steroids Download PDFInfo
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- GB1593978A GB1593978A GB54510/76A GB5451076A GB1593978A GB 1593978 A GB1593978 A GB 1593978A GB 54510/76 A GB54510/76 A GB 54510/76A GB 5451076 A GB5451076 A GB 5451076A GB 1593978 A GB1593978 A GB 1593978A
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- Prior art keywords
- prednisolone
- fluoro
- salicylate
- methyl
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—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
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
- C07J5/0069—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
- C07J5/0076—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Pain & Pain Management (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
The novel compounds of the formula I, in which the substituents have the meaning indicated in Patent Claim 1, are prepared by esterifying a compound of the formula II with salicylic acid or acetylsalicylic acid. The novel compounds of the formula I exhibit a high level of antiinflammatory activity when administered topically and/or systemically. <IMAGE>
Description
(54) ANTI-INFLAMMATORY STEROIDS
(71) We, LARK S.P.A. and A. MENARINI S.A.S., respectively of Via
Fabio Filzi 25/A, 20124 Milano, Italy; and Via Sette Santi 3, 50131 Firenze, Italy; both Italian body corporates 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:- The present invention relates to new steroid compounds having high antiinflammatory action, processes for the preparation thereof and to a pharmaceutical composition containing such new steroid compounds.
It is an object of this invention to provide new steroid compounds having particularly high antiinflammatory activity upon topical and/or systemic administration.
According to the present invention there is provided a 21-salicylic acid ester or a 21-acetyl-salicylic acid ester of a steroid of the pregnane series of the general structure:
wherein R is a hydrogen atom or an acetyl group, X is a hydrogen, fluorine or chlorine atom, Y is a hydroxyl group or an oxygen, chlorine or fluorine atom, X' is a hydrogen or halogen atom or a methyl group and Z is a hydrogen atom an methyl group or a hydroxy group or the radical:
where R is as defined above.
Preferred compounds in accordance with the prcsent invention are: 9a-fluoro-prednisalone-21-acetylsalicylate 9-fluoro-prednisolone-2 1 -salicylate 6a,9-difluoroprednisolone-21-acetylsalicylate
6tr,9er-difluoroprednisolone-2 1 -salicylate 6a,9-difluoro-1 6tu-methyl-prednisolone-2 1 acetylsalicylate 6a,9a-difluoro-1 6-methyl -prednisolone-2 1 -salicylate 9n-fluoro- 1 6fr-hydroxy-prednisolone-2 1 -acetylsal icylate 9|cr-fluoro-l6xY-hydroxy-prednisolone-2l-salicylate
6cu-fluoro-l 6n-methyl-prednisolone-2 1-acetylsalicylate
6a-fluoro-l 6y-methyl-prednisolone-2 l-salicylate
6α;-methyl-prednisolone-21-acetylsalicylate
6a-methyl-prednisolone-2 I -salicylate
6GY-methyl-9sr-fluoro-prednisolone-21-acetylsalicylate
6a-methyl-9fr-fluoro-prednisolone-21-salicylate Also in accordance with the present invention, there is provided a process for the preparation of a compound of the general formula I, wherein a compound of the general formula II
in which X, X', Y and Z are as defined in formula (I), is reacted with a suitable
derivative of acetylsalicylic acid.
Typical examples of suitable derivatives of acetylsalicylic acid are the correspond
ing acyl halides such as the chloride, or an activated ester.
The compounds of the present invention may also be prepared by reacting a
compound of the general formula (II) with the free acetylsalicylic acid in the presence
of dicyclohexylcarbodiimide.
Alternatively good results may be achieved by converting the compound of the
general formula (II) into the corresponding 21-mesylate and the latter is reacted in
solution in a polar solvent with an alkali metal salt of acetylsalicylic acid to yield the
desired ester. Upon a mild alkaline hydrolysis of the 21-acetylsalicylic acid ester thus
obtained in nitrogen atmosphere and at room temperature, the corresponding 21-salicylic
acid ester may be prepared and isolated in conventional manner.
The 21-salicylic acid ester of the desired steroid may be directly prepared by
reacting the corresponding 21-mesylate in solution in a polar solvent with an alkali
metal salt of salicylic acid.
Also in accordance with the present invention there is provided a pharmaceutical
composition for topical and/or systemic administration having remarkable anti
inflammatory activity, comprising a compound of the general formula (I) together with
a pharmaceutically acceptable carrier.
Pharmaceutical compositions in accordance with the invention are particularly
useful for the treatment of several inflammatory infections of mucosae and skin such as
rectal or colonic inflammation, congunctivitis or phlogosis of the ear and nose, dermatitis
of various etiology, eczema, psoriasis and allergic infection. They are useful also for
the treatment of internal inflammatory infections, particularly of rheumatoid arthritis
and allergic diseases.
For topical application, the active ingredients of structure (I) can be incorporated
in the usual compatible carriers or excipients for preparing pharmaceutical compositions suitable for topical administration.
Typical examples of said compositions are ointments, lotions, creams, emulsions, drops, sprays and suppositories as are well known in the pharmaceutical art. Ointments may be formulated, for example, both hydrophilic and hydrophobic applications and when lotions are formulated they may comprise aqueous or non-aqueous bases.
lhe pharmaceutical excipients suitable for these formulations are, for example, animal fats, vegetable oils, fatty acids, poly-alkylenc glycols, beeswax, polyesters and the like.
The pharmaceutical compositions according to the present invention may also contain other active ingredients such as preservatives or bacteriostatic agents.
The proportion of active steroid in the pharmaceutical compositions according to the invention, depends on the particular composition and on the inflammatory infection to be cured.
Advantageously the topical compositions will contain the active ingredient in an amount from 0.01% to 5% by weight.
These antiinflammatory topical compositions may be applied to the affected surfaces a few times daily.
If desired, other substances, such as bacteriostatic agents, antibiotics, antimycotic agents and local anesthetics may also be incorporated in these topical antiinflammatory compositions.
For systemic administration, the active ingredient may be incorporated in pharmaceutical compositions for oral or parenteral route. These pharmaceutical compositions may be for example solid or liquid, and be realized in the pharmaceutical forms generally used in human medicine, such as tablets, capsules and granulates, or solutions and suspensions for injectable forms.
The pharmaceutical excipients suitable for these formulations are, for example, talcum, arabic gum, lactose, starch, magnesium stearate and polyethylene glycol.
For systemic administration, the compositions will contain the active ingredient in an amount from 0.5 to 5 mg for dose unit, and the daily doses may vary from 1 to
100 mg.
The following Examples serve to illustrate the invention without limiting same.
EXAMPLE 1.
9a-fluoro-prednisolone-2 1 -acetylsalicylate Into a four-necked flask equipped with stirrer thermometer, dropping funnel and a CaCl2 tube are poured 9a-fluoro-prednisolone (lOg) and a mixture of dry pyridine
(30ml) and dioxane (30ml). After cooling at 50C, 8g of acetylsalicyloylchloride dissolved in 16 ml of dioxane are added dropwise and the mixture is left under stirring
conditions overnight at about 20C. The suspension so obtained is poured onto crushed
ice, the resulting solid collected by filtration, washed with water and dried.
The crude 9,(r-fluoroprednisolone-21-acetylsalicylate so obtained is crystallized
from ethyl acetate.
EXAMPLE 2.
9r-fluoroprednisolone-21-salicylate 9a-fluoroprednisolone-21-acetylsalicylate (10g) in 120 ml of tetrahydrofuran is treated at room temperature tinder a nitrogen stream with 10 ml of 1M methanolic sodium hydroxide. Two hours later the mixture is neutralized, evaporated under vacuum, diluted with methanol and poured into water. The crude 9a-fluoroprednisolone- 21-salicylate is crystallized from ethyl acetate.
EXAMPLE E 3.
9rr-fluoro-prednisolone-21 -salicylate Preparation of the intermediate 9tu-fluoro-prednisolone 21-mesylate
Into a four-necked flask equipped with stirrer, thermometer, dropping funnel and a Ca Cl2 tube are poured 10g of 9(r-fllloro-prednisolone and 20 ml of anhydrous pyridine. The solution was cooled to 5"C, and 6 ml of methanesulfonyl chloride were added dropwise with stirring. The reaction mixture was kept under stirring conditions for a further 6 hours at about OOC, then it was poured onto crushed ice, the resulting solid was filtered, washed with water and dried.
To a suspension of 10 grams of 21-mesylate in 100 ml of dimethylformamide, 15 grams of sodium salicylate were added with stirring at room temperature. The reaction mixture was heated to 1000C with stirring and kept under these conditions for a further 2 hours, then it was poured in 100 ml of cold water. The precipitate was filtered, washed with water and dried.
The crude product recrystallized from acetone gave 7 grams of pure product having the following characteristics: m.p. 209.3"C; razz = + 152.07 (c=1 dioxane)
UV -- Spectnim A", 251 mZt: E 1c/m476.2 IR - Spectnim (Nujol (Trade Mark)) 3290 - 1730 - 1710 - 1670
1660 - 1610 - 1605 - 1580 cm' EXAMPLE 4.
6α,9α-difluoro-16α-methyl-prednisolone-21-salicylate By operating as described in EXAMPLE 3 the 21-salicylic acid ester of 6,r,9R- difluoro-l 6cu-methyl-prcdnisolone (called also flumethasone) was prepared having the following characteristics: m.p. 242.8 C; 131.33C = 131 33 (c=1 dioxane) UV - Spectrum h,,,,, 240 mu; E 1cm = 523.46 EXAMPLE 5.
By operating as described in EXAMPLES 1, 2 and 3 the 21-acetylsalicyclic acid and the 21-salicylic acid esters of the following steroids could be obtained: 6α,9α - difluoroprednisolone, 9α - fluoro - 16α - methyl - prednisolone, 9 < r - fluoro- 16be - hydroxy - prednisolone, 6tr - fluoro - 16a - methyl - prenisolone, 6a - methyl- prednisolone, 6fr - methyl - 9α - fluoro - prednisolone.
EXAMPLE 6.
By operating as described in the previous EXAMPLES also 9α - fluoro - 16ahydroxy - prednisolone 16,21 - disalicylate may be obtained.
EXAMPLE 7.
Biological assays
The topical antiinflammatory activity of 21-salicylic acid esters and of 21-acetylsalicylic acid esters of this invention was determined using the following biological assays: a) Inhibition of cotton pellet-induced granuloma
This test was performed according to Meier, R., Schuler W., Desaulles P.
Experientia vol. 6, 469, 1950.
Male albino rats, Wistar-Morini strain, weighing 150 + 10g are used. Under light ether anesthesia, one cotton pellet introduced subcutaneously on each side of the back through a midline incision. The pellets are cut from dental cotton rolls (No. 1
Johnson & Johnson) and paired to combine a weight of 100 t 1 mg. Before implantation, the pellets are individually soaked in 1% aqueous suspension of carrageenin (Viscarin carrageenin REX 7205, Marine colloids Inc., Rockland, Maine -- USA), dried overnight on filter paper and thereafter autoclaved at 1210C for 1 hr.
The antiinflammatory activity of two compounds of the present invention namely of 9a - fluoro - prednisolone - 21 - salicylate and of 9fr - fluoro - prednisolone - 21acetylsalicylate is compared with that of 9n - fluoro - prednisolone - 21 - acetate.
Scalar doses of the tested compounds dissolved in N,N-dimethyl-formamide are added to each pellet in a volume of 0.2 ml. Pellets which are added 0.2 ml N,Ndimethyl-formamide are used as controls. Pellets are allowed 24 hr to dry in an oven at 60"C. Before implantation the pellets are individually soaked in 0.5% antibiotic
(Combiotic (Trade Mark) Pfizer) solution.
At the end of the test period (8th day after implantation), the animals are killed by CO2 asphyxiation. The pellets with the surrounding granuloma are removed, dried to constant weight at 60 C and weighed.
The amount in excess of 100 mg represents the weight of the granuloma and is expressed in mg/100 g body weight.
The results are reported in the following table
TABLE 1
% inhibition of granuloma formation at the following doses expressed in g/pellet Compound 8 40 9α fluoro prednisolone 21 acetate 9afluoro prednisotone 38.2(15) 43.3 (16) 21 salicylate 9 fluoro prednisolone 21 acetylsalicylate 40.6 (24) 56.4 (33) In parentheses: number of animals.
Statistical evaluation of the data (R. Borth "Simplified Mathematics for Multiple
Bioassays" Acta Endocrinol. 35, 454, 1960) indicates that 9 - fluoro - prednisolone21 - salicylate and 9a - fluoro - prednisolone - 21 - acetylsalicylate are 12 and 22 times as potent at 9a - fluoro - prednisolone 21 - acetate respectively.
b) Inhibition of carrageenin-induced rat paw edema.
Flumethasone salicylate was administered orally suspended in an aqueous vehicle containing NaCI 0.9%, polysorbate 80 0.4%, CMC 0.5% and benzyl alcohol 0.9%.
Male albino rats, Wistar strain, weighing 150-175 g were divided into 4 groups of 10 animals each and fasted overnight before the beginning of the experiments. Immediately before the administration of flumethasone salicylate or the aqueous vehicle, each animal received 5 ml of water by gavage. One hour later, 0.1 ml of 0.5% aqueous suspension of carrageenin (Rex 7205, Marine Colloids Inc., Springfield, N.J. - USA) was injected through a 20 gauge needle into the plantar aponeurosis of the right hind paw according to Winter et al. (P.S.E.B.M., 111, 544, 1962). Foot volume was measured immediately before carrageenin and again 3 hours later by means of a mercury plethysmometer. This was done by immersing the paw of the unanesthetized animal up to the point where mercury was at the level of the lateral malleolus.Increase in paw volume was calculated from the difference of values at 0 and 3 hours after the injection of the phlogistic agent. Data in the accommpanying table indicate that ED50 for flumethasone salicylate is 0.34 mg/Kg.
TABLE 2
Oral activity of flumethasone salicylate in inhibiting carrageenin induced
paw edema in the rat
Increase in paw volume after No. of carrageenin Treatment Dose mg/Kg animals Mean+S.D. % inhibition Aqueous vehicle 10 13.05+1.98 Flumethasone salicylate 0.11 10 8.50+2.25 34.9 Flumethasone salicylate 0.33 - 10 6.30+2.19 51.7 Flumethasone salicylate 1 10 4.95+1.66 62.1 The following EXAMPLES illustrate topical and also systemic formulations
prepared in accordance with the invention.
EXAMPLE 8.
An ointment for topical use is prepared having the following composition:
Components Percent by weight 9-fluoro-prednisolone-21-salicylate 0.250
Benzyl alcohol 0.50
Cetyl alcohol 0.50
Distilled water 5.00
Lanolin 5.00
White soft paraffin to 100 parts w/w
Melt the cetyl and benzyl alcohols and the white soft paraffin at about 700 C, add the 9a - fluoro - prednisolone - 21 - salicylate, then the lanolin previously mixed with the water.
EXAMPLE 9.
An ointment for topical use is prepared having the following composition:
Components Percent by weight A-lmoro-prednisolone-21-salicylate 0.125
Lanolin 24.0
Liquid paraffin 7.0
Neomycin sulfate 0.5
White soft paraffin to 100 parts w/w
Add the 9a - fluoro - prednisolone - 21 - salicylate to the other components previously melted then the antibiotic with stirring.
EXAMPLE 10.
Capsules for oral use are prepared having the following composition:
mg 9a-fluoro-prednisolone-2l-acetylsalicylate 4
Lactose 104
Rice starch 26
Magnesium stearate 16
The 9a - fluoro - prednisolone - 21 - acetylsalicylate and magnesium stearate
were added screened, mixed, together and filled into hard gelatin capsules.
EXAMPLE 11.
Parenteral aqueous suspension having the following composition: 6a,9-difiuoro- 1 6a-methyl-prednisolone-2 t -salicylate Polyethylene glycol 400, U.S.P. 25 Polysorbate 80, U.S.P. 25
Bidistilled water to 2 ml
CLINICAL TRIALS
GENERAL ON TOPICAL ADMINISTRATION
Patients were adult of both sexes. Those eligible for this study were diagnosed
as having skin diseases customarily considered to be steroid-responsive.
The preparations used were: a) Ointment containing 9 - fluoro - prednisolone
21 - salicylate (FPS and b) Ointment containing 9 - fluoro - prednisolone - 21
acetate (FPA).
Each formulation was packaged in identical coded tubes so that the investigators did not know which preparation was being used. Evaluation of the results of the treatment was made in each case while the identity of the agent remained unknown.
In each patient was made use of occlusive dressing.
Patient 1
L.A. Age 50 years -- Housewife.
Affected by a 7 year old bilateral palmo-plantar chronic hyperkeratonic eczema.
Cycles of 3 day medication with 0.125% FPS (right foot) or 0.125% FPA (left foot) started on April 21, 1977.
After 7 days, satisfactory reduction of both erythema and hyperkeratosis of right foot while only slight reduction of erythema of the left one.
After 14 days disappearance of erythema and marked reduction of hyperkeratosis of right foot while barely detectable improvement of the left one.
Patient 2
G.C. Age 55 years -- Housewife.
Affected by a 2 month old bilateral palmo-plantar eczematous hyperkeratonic
dermatitis.
Treatment with 0.125% FPS (right hand and foot) or 0.125% FPA (left hand
and foot) started on June 23, 1977.
After 3 days reduced itching and hyperkeratosis of both right hand and foot while
no detectable improvement of the left ones.
After 6 days decrease of erythema and hyperkeratosis of right hand and foot while
only reduction of itching and erythema of left ones.
Thereafter the patient receives FPS on both sides until complete recovery.
Patient 3
M.G. Age 74 years -- Housewife.
Affected by a long lasting psoriasis with large confluent psoriatic spots on anterior
surface of legs.
Treatment with 0.250 ,s FPS (right leg) or 0.250% FPA (left leg) started on
June 29, 1977.
After 3 days, reduced erythema of the right leg while no detectable improvement of the left one.
After 6 days, further decrease of erythema and almost complete disappearance of desquamation of the right leg while only slight improvement of the left one.
Thereafter the patient receives FPS on both legs until complete recovery.
Patient 4
C.G. Age 29 years -- Worker.
Affected by one year old relapsing nummular eczema of legs, more severe on the left one.
Daily treatment with 0.250% FPS (left leg) or 0.250% FPA (right leg) started on August 12, 1977.
After 7 days decreased itching and erythema on both legs.
After 14 days marked improvement of erythmea and disappearance of desquamation on the left leg while erythema and desquamation, although to a lesser degree, are still present on the right one.
Patient 5 C.G. - Age 46 years -- Businessman.
Affected by a week old erythemato-vescicular eruption with exudate, desquamation and itching, more severe on right forearm.
Daily treatment with 0.0625% FPS (right forearm) or 0.0625% FPA (left forearm) started on August 14, 1977.
After 7 days, decreased itching and disappearance of exudate on both forearms.
Slight decrease of desquamation on the right forearm.
After 14 days, disappearance of itching and vescicles on both forearms.
Disapparance of desquamation on the right forearm and persistenc of it on the left one.
Patient 6
B.G. Age 69 years -- Retired carpenter.
Affected by eczema on both hands.
Daily treatment with 0.250% FPS (right hand) or 0.250% FPA (left hand) started on September 16, 1977.
After 7 days slight improvement on both hands with decreased itching but persistence of desquamation.
After 14 days disappearance of desquamation on right hand and only slight reduction of it on the left one.
WHAT WE CLAIM IS:
1. A 21-salicylic acid ester or a 21-acetylsalicylic acid ester of a steroid of the pregnane series of the general structure:
wherein R is a hydrogen atom or an acetyl group, X is a hydrogen, fluorine or chlorine atom, Y is a hydroxyl group or an oxygen, chlorine or fluorine atom, X' is a hydrogen or halogen atom or a methyl group, and Z is a hydrogen atom or an a-methyl group or a hydroxyl group or the radical:
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (19)
1. A 21-salicylic acid ester or a 21-acetylsalicylic acid ester of a steroid of the pregnane series of the general structure:
wherein R is a hydrogen atom or an acetyl group, X is a hydrogen, fluorine or chlorine atom, Y is a hydroxyl group or an oxygen, chlorine or fluorine atom, X' is a hydrogen or halogen atom or a methyl group, and Z is a hydrogen atom or an a-methyl group or a hydroxyl group or the radical:
where R is as defined above.
2. 9a-Fluoro-prednisolone-21-acetylsalicylate.
3. 9α-Fluoro-prednisolone-21-salicylate.
4. 6a,9a-Difluoroprenisolone-21-acetylsalicylate.
5. 6α,9α-Difluoroprednisolone-21-salicylate.
6. 6a,9a-Difluoro- 16a-methyl-prednisolone-21 -acetylsalicylate .
7. 6α-9α-Difluoro-16α-methyl-prednisolone-21 -salicylate.
8. 91-Fluoro- 16 < r-hydroxy-prednisolone-21 -acetylsalicylate .
9. 9a-Fluoro- 16 < r-hydroxy-prednisolone-21 -salicylate.
10. 6a-Fluoro-1 6a-methyl-prednisolone-2 1 -salicylate.
11. 6a-Fluoro- 16ez-methyl-prednisolone-21 -salicylate .
12. 6a-Methyl-prednisolone-2 1 -acetylsalicylate.
13. 6a-Methyl-prednisolone-21 -salicylate.
14. 6ltz-Methyl-9a-fluoro-prednisolone-21-acetylsalicylate.
15. 6a-Methyl-9 < r-fluoro-prednisolone-21-salicylate.
16. A compound as claimed in any preceding claim, substantially as hereinbefore described and exemplified.
17. A pharmaceutical composition comprising a compound of the general formula (I) together with a pharmaceutically acceptable carrier.
18. A process for the preparation of a compound of the general formula (I), comprising reacting a compound of the general formula II:
in which X, X', Y and Z are as defined in formula (I) with a suitable derivative of acetyl salicylic acid.
19. A process as claimed in claim 18, substantially as hereinbefore described and exemplified.
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB54510/76A GB1593978A (en) | 1976-12-31 | 1976-12-31 | Anti-inflammatory steroids |
FI773929A FI63422C (en) | 1976-12-31 | 1977-12-27 | ANALOGIFOUS FARANDE FOR FRAMSTAELLANDE AV NYA 21-SALICYLSYRAESTRAR OCH 21-ACETYLSALICYLSYRAESTRAR AV STEROIDER UR PREGNANSERIEN |
NL7714482A NL7714482A (en) | 1976-12-31 | 1977-12-28 | MEDICINAL PRODUCT WITH AN ANTI-INFLAMMATORY ACTION BASED ON STEROID DERIVATIVES AND METHOD OF PREPARATION. |
JP15754377A JPS53144561A (en) | 1976-12-31 | 1977-12-28 | Anti inflammatory steroid |
DK581677A DK155673C (en) | 1976-12-31 | 1977-12-28 | ANALOGY PROCEDURE FOR PREPARING ANTI-INFLAMMATORALLY EFFECTIVE 21-SALICYLIC ACID AND 21-ACETYLSALICYLIC ACID ESTERS OF PREGNANCY STEROIDS |
CH1632977A CH633301A5 (en) | 1976-12-31 | 1977-12-30 | Process for preparing novel 21-salicylic acid esters or 21-acetylsalicylic acid esters of steroids of the pregnane series |
NO774525A NO148491C (en) | 1976-12-31 | 1977-12-30 | ANALOGY PROCEDURE FOR THE PREPARATION OF ANTI-INFLAMMATORALLY EFFECTIVE 21-SALICYLIC ACID AND 21-ACETYLSALICYLIC ACID ESTERS OF PREGNANCY STEROIDS |
BE183990A BE862507A (en) | 1976-12-31 | 1977-12-30 | ANTI-INFLAMMATORY STEROIDS |
FR7739817A FR2376160A1 (en) | 1976-12-31 | 1977-12-30 | ANTI-INFLAMMATORY STEROIDS FOR USE AS MEDICINAL PRODUCTS |
SE7714976A SE430607B (en) | 1976-12-31 | 1977-12-30 | ANALOGY PROCEDURE FOR PREPARING NEW 21-SALIEYL ACID ESTERS AND 21-ACETYLSALYYL ACID ESTERS FROM PREGNOMY SERIES |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB54510/76A GB1593978A (en) | 1976-12-31 | 1976-12-31 | Anti-inflammatory steroids |
Publications (1)
Publication Number | Publication Date |
---|---|
GB1593978A true GB1593978A (en) | 1981-07-22 |
Family
ID=10471258
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB54510/76A Expired GB1593978A (en) | 1976-12-31 | 1976-12-31 | Anti-inflammatory steroids |
Country Status (10)
Country | Link |
---|---|
JP (1) | JPS53144561A (en) |
BE (1) | BE862507A (en) |
CH (1) | CH633301A5 (en) |
DK (1) | DK155673C (en) |
FI (1) | FI63422C (en) |
FR (1) | FR2376160A1 (en) |
GB (1) | GB1593978A (en) |
NL (1) | NL7714482A (en) |
NO (1) | NO148491C (en) |
SE (1) | SE430607B (en) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1440063A (en) * | 1972-08-11 | 1976-06-23 | Glaxo Lab Ltd | 17alpha-esters of 17alpha,21-dihydroxy-20-oxo-steroids |
-
1976
- 1976-12-31 GB GB54510/76A patent/GB1593978A/en not_active Expired
-
1977
- 1977-12-27 FI FI773929A patent/FI63422C/en not_active IP Right Cessation
- 1977-12-28 NL NL7714482A patent/NL7714482A/en not_active Application Discontinuation
- 1977-12-28 JP JP15754377A patent/JPS53144561A/en active Granted
- 1977-12-28 DK DK581677A patent/DK155673C/en not_active IP Right Cessation
- 1977-12-30 BE BE183990A patent/BE862507A/en not_active IP Right Cessation
- 1977-12-30 NO NO774525A patent/NO148491C/en unknown
- 1977-12-30 CH CH1632977A patent/CH633301A5/en not_active IP Right Cessation
- 1977-12-30 FR FR7739817A patent/FR2376160A1/en active Granted
- 1977-12-30 SE SE7714976A patent/SE430607B/en unknown
Also Published As
Publication number | Publication date |
---|---|
BE862507A (en) | 1978-04-14 |
NO148491C (en) | 1983-10-19 |
NO148491B (en) | 1983-07-11 |
JPS6220197B2 (en) | 1987-05-06 |
DK155673C (en) | 1989-09-04 |
DK581677A (en) | 1978-07-01 |
FR2376160B1 (en) | 1980-11-14 |
JPS53144561A (en) | 1978-12-15 |
FR2376160A1 (en) | 1978-07-28 |
FI63422C (en) | 1983-06-10 |
SE7714976L (en) | 1978-07-02 |
CH633301A5 (en) | 1982-11-30 |
NL7714482A (en) | 1978-07-04 |
FI63422B (en) | 1983-02-28 |
FI773929A (en) | 1978-07-01 |
DK155673B (en) | 1989-05-01 |
SE430607B (en) | 1983-11-28 |
NO774525L (en) | 1978-07-03 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PS | Patent sealed [section 19, patents act 1949] | ||
PCNP | Patent ceased through non-payment of renewal fee |