GB1589585A - 12a-halocorticoids - Google Patents
12a-halocorticoids Download PDFInfo
- Publication number
- GB1589585A GB1589585A GB28994/77A GB2899477A GB1589585A GB 1589585 A GB1589585 A GB 1589585A GB 28994/77 A GB28994/77 A GB 28994/77A GB 2899477 A GB2899477 A GB 2899477A GB 1589585 A GB1589585 A GB 1589585A
- Authority
- GB
- United Kingdom
- Prior art keywords
- compound
- methyl
- dione
- general formula
- pregnadiene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
-
- 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
- C07J5/0007—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 not substituted in position 17 alfa
- C07J5/0023—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 not substituted in position 17 alfa substituted in position 16
- C07J5/003—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 not substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group including 16-alkylidene substitutes
- C07J5/0038—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 not substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group including 16-alkylidene substitutes by an alkyl group
Abstract
Corticoids of the formula <IMAGE> in which X is fluorine, chlorine or bromine R1 is hydrogen, hydroxyl or acyloxy and R2 is a free or esterified hydroxyl group, are prepared. These compounds are obtained by opening the epoxide ring present in the 11 beta , 12 beta position in appropriate starting compounds using hydrohalic acid. The resulting compounds can be used as antiinflammatory agents.
Description
(54) NEW 12c(-HALO-CORTICOIDS (71) We, SCHERING AKTIF.NGESELLSCHAFT, a Body Corporate organised according to the laws of the Federal Republic of Germany, of Berlin and Bergkamen, the Federal Republic of Germany, 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 is concerned with new 12R-halo-corticoids, with their manufacture and with pharmaceutical preparations containing the 12n-halo-corticoids as active substances.
The present invention provides compounds of the general formula I
in which
X represents a fluorine, chlorine or bromine atom,
R1 represents a hydrogen atom a hvdroxyl group or an acyloxy group and
R2 represents a free or esterified hydroxyl group.
The new corticoids of the general formula I are pharmacologically active substances, which are especially distinguished by having in tonical use a good antiinflammatory activity and causing onlv slight systemic side effects.
The inception and duration of the action of the new corticoids and also their solubilitv in physiologically tolerable solvents are, as is also the case with known corticoids, especially dependent on whether, and if so with what acid, a hydroxyl group in the 17- and/or 21-position(s) is esterified.
As esterified 21-hydroxyl groups represented by R there come into consideration preferably acyloxy groups derived from carboxylic acids containing 1 to 16 carbon atoms, and also acyl groups obtainable from oxygen-containing inorganic acids by the removal of a hydroxyl group, for example sulphate groups or phosphate groups.
Suitable acyloxy groups are, for example, those derived from straight chain or branched, saturated or unsaturated aliphatic mono- or di-carboxylic acids, which may be substituted in the usual manner, for example by hydroxyl groups, amino groups or halogen atoms.
Furthermore, there are suitable as acyloxy groups also groups of cycloaliphatic, aromatic, mixed aromatic-aliphatic or heterocyclic acids, which may also be substituted in the usual manner. As suitable acyloxy groups there may be mentioned, for example, formyloxy, acetoxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, octanoyloxy, undecanoyloxy, dimethylacetoxy, trimethylacetoy, diethylacetoxy, tert.butylacetoxy, benzoyloxy, phenacetyloxy, cyclopentylpropionyloxy, hydroxyacetoxy, monochloracetoxy, dichloracetoxy and trichloracetoxy groups, and also dimethylaminoacetoxy, trimethylaminoacetoxy, diethylaminoacetoxy, piperidinoacetoxy, nicotinoyloxy, carboxypropionyloxy and carboxypentanoyloxy groups.
For preparing water-soluble active substances the 21-acyloxy-compounds containing a basic nitrogen group in the acyl group may be converted into the corresponding acid addition salts, for example the hydrochlorides, hydrobromides, sulphates, phosphates, oxalates, tartrates or maleates. Furthermore, the 21-dicarboxylic acid monoesters, and also the sulphuric acid and phosphoric acid esters, may be converted for increasing the solubility in water into their alkali salts, for example the sodium or potassium salts.
Especially preferred esterified hydroxyl groups represented by R2 are acyloxy groups derived from carboxylic acids containing 1 to 8 carbon atoms.
As esterified 17-positioned hydroxyl groups represented by R1 there come into consideration acyloxy groups derived from carboxylic acids that preferably contain 1 to 8 carbon atoms. Especially suitable acyloxy groups are alkanoyloxy groups, for example an acetoxy, propionyloxy, butyryloxy, pentanoyloxy or hexanoyloxy group.
The present invention also provides a process for the manufacture of the new corticoids of the general formula I, wherein the epoxide ring in a compound of the general formula II
in which R1 and R2 have the meanings given above, is opened with hydrogen fluoride,
chloride or bromide, respectively, and, if desired, in the resulting compound any ester
group is hydrolysed and/or any free hydroxyl group is esterified.
The opening of the epoxide ring in the process of the present invention is carried
out in the presence of an inert solvent capable of absorbing a hydrogen halide. Suitable
solvents are, for example, lower alcohols, for example methanol, ethanol or isopropanol, ethers, for example diethyl ether, glycol monoinethyl ether, dioxan or tetrahydrofuran, chlorohydrocarbons, for example dichloromethane, chloroform or tetrachlorethylene, dipolar aprotic solvents, for example dimethylformamide, or hexamethyl-phosphoric acid triamide or mixtures of these solvents. The reaction is preferably carried out at
a reaction temperature of --50"C. to +5O0C.
The optional subsequent hydrolysis of acyloxy groups present in the 17- and/or
21-position(s) is carried out by the usual methods, for example, by reaction of the
esters in aqueous or alcoholic solutions or mixtures of solvents in the presence of
strong acids, for example sulphuric acid, hydrochloric acid, para-toluene sulphonic
acid or trifluoracetic acid, or by reaction of the esters in aqueous or alcoholic solutions or mixtures of solvents in the presence of alkali alcoholates, alkali hydroxides or alkali carbonates.
If the hydrolysis is carried out under mild conditions it is possible to hydrolyse the 17a,21-diacyloxy-steroids of the general formula I selectively to form the 21 hydroxy-1 7a-acyloxy-steroids.
An optional subsequent esterification of free hydroxyl groups in the 17- and/or 21-position(s) is likewise carried out by methods known per se. Thus, for example, the hydroxy-steroids may be esterified with acyl chlorides or acyl anhydrides in the presence of acids, for example hydrochloric acid, para-toluene sulphonic acid or trifluoroacetic acid. or in the presence of bases, for example potassium carbonate, pyndme, collidine or para-dimethylaminopyridine. On the other hand, it is possible to esterify the hydroxy-compounds with carboxylic acids in the presence of trifluoracetic anhydride. When these esterifications are carried out under mild conditions, as is known, only the primary hydroxyl groups (in the 21-position) are esterified, whereas an optionally present tertiary hydroxyl group (in the 17a-position) is not reacted.
The alkali sulphates of the 21-monosulphuric acid esters can be prepared from
the 21-hydroxy-compounds of the general formula I in a manner known per se, for
example, by reacting the 21-hydroxy-compounds with sulphur trioxide in pyridine,
and converting the sulphuric acid esters so obtained by treatment with alkali bases
into the alkali salts.
As already mentioned, the new corticoids are distinguished in topical use by a good anti-inflammatory activity. Thus, for example, (,12a-difluorow ,21-dihydroxy- 16lsg-methyl-' 4-pregnadiene-3,20-dione exhibits in the vasoconstriction test an equally
good anti-inflammatory activity as the known 6an9la-difluorO-llJBn21-dihydroxy-l6a methyl-al4-pregnadiene-3,20-dione (German Patent No. 1,211,194).
The vasoconstriction test was carried out as follows:
On the backs of voluntary test persons the Stratum corneum was broken up by
twenty times tearing off a Tesa film (that is a transparent gummed tape) that had
been applied to it, all the films having been applied and torn off from the same place,
whereby a pronounced hyperaemia was produced. Within the stripped regions was
applied to each of marked areas 4 cm2 in size 50 mg amounts of a salve, which con
tained 0.1% and 0.01% by weight, respectively, of the substance to be tested or of
the reference substance in a water-oil base. 1, 2, 3 and 4 hours after the application
the extent of the vasoconstriction was determined.
In systemic application the new corticoids are considerably weaker in action than
the structurally analogous known 9.a-halcgeno-corticoids. Thus, for example, 6a,12a- difluoro-11US,21-dihydroxy-16-methyl-l -pregnadiene-3,20-dione exhibits in the
adjuvant oedema test an activity five times weaker than that of 6n,9cu-difluoro-l lp,21- dihydroxy- 161or-methyl-A14-pregnadiene-3,20-dione.
The adjuvant oedema test was carried out as follows:
SPF-Rats weighing 130 to 150 gms were injected, in order to produce a source
of inflammation, in the rear right hand paw with 0.1 ml of a suspension (obtainable
from the American firm Difko) of 0.5% strength of Mycobactenum butyricum.
Before the injection the volumes of the paws of the rats were measured. 24 Hours
after the injection the volumes of the paws were again measured in order 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 24 hours the volumes of the paws were again measured.
The control animals were treated in the same manner, but with the difference
that they were injected with a benzyl benzoate-castor oil mixture free from the test
substance. From the paw volumes so obtained the oedema-inhibiting action was calcu
lated as a percentage in the usual manner.
The highly active corticoids hitherto used for the treatment of skin inflamma
tions have, in addition to the topical action, always a pronounced systemic action.
These corticoids, even in topical application, are able, owing to absorption. by the
inflamed skin or owing to skin damage, to enter the blood stream where as hormone
active substances they influence the functions of the body in various ways.
In the case of the topically highly active, but systemically little active, compounds
of the present invention the above disadvantage is diminished. They are therefore very
well suited for the local treatment of inflammations.
The new compounds of the present invention are suitable in combination with the
carriers customarily used in, for example, galenical pharmacy for the local treatment
of contact dermatitis, eczemas of very many types, neurodermatitis, erythrodermia,
burns, Pruritis vulvae et ani, rosacea, Erythematodes cutaneus, psoriasis, Lichen ruber
planus et verrucosus and similar skin diseases.
Furthermore, the corticoids of the present invention are also suitable for the
treatment of allergic diseases of the respiratory system, for example rhinitis or bronchial
asthma.
The present invention accordingly further provides a pharmaceutical preparation
which comprises a compound of the general formula I, in admixture or conjunction
with a pharmaceutically suitable carrier. The preparation may be in a form suitable
for local application.
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 forms of application, for example solutions, lotions, salves, creams, plasters
or inhalant preparations. The concentration of active substance in the pharmaceutical
preparations so formulated depends on the form of application. In the case of lotions
and salves it is preferable to use a concentration of active substance of 0.001% to 2%
by weight.
The starting compounds of the general formula II used for the process of the present invention may be prepared by methods that are generally known to the expert and are illustrated by way of example for typical representatives in the Examples below.
The following Examples illustrate the invention. Examples 4 to 7 and 10 describe the preparation of compounds of the general formula I and Examples 1 to 3, 8 and 9 describe the preparation of intermediates.
Example 1.
300 Gms of 65 - fluoro - 11, - hydroxy - 16 methyl - 21 - valeryloxy 4-pregnadiene-3,20-dione in 1500 ml of hexamethyl-phosphoric acid triamide were stirred with 500 gms of methyl-triphenoxy-phosphonium iodide for 1 hour at a 900 C.
internal temperature in an atmosphere of argon. After cooling, the solution was introduced into 10 litres of an ice-cold solution of 5% strength of potassium hydroxide, and the precipitated product was filtered off with suction and taken up in ethyl acetate.
The ethyl acetate extract was washed with water and evaporated in vacuo. From the crude product so obtained, which acccrding to the NMR-spectrum contained 70% of 6tz - fluoro - 16 - methyl - 21 - valeryloxy - Al,4,9(11) ~ pregnatriene - 3,20 - dione and 30% of 6α - fluoro - 16α - methyl - 21 - valeryloxy - Al,4,11 - pregnatriene 3,20-dione, the latter was separated by fractional crystallization from methanol, and 49.4 gms of pure product melting at 96-970C. were obtained.
Example 2.
40 Gms of 645 - fluoro - 16 - methyl - 21 - valeryloxy - A141l - pregnatriene-3,20-dione were dissolved in 800 ml of dimethylformamide, the solution was cooled to - 100C., 20 gms of N-bromosuccinimide were added, and 90 ml of 1N- perchloric acid were added dropwise. The solution was maintained at + 20C. for 18 hours, and was then stirred into 8 litres of ice-water, to which had been added 20 gms of sodium hydrogen sulphite and 30 gms of sodium acetate. The precipitated product was filtered off with suction, then taken up in methylene chloride, and the methylene chloride solution was washed with water. The solution was concentrated to a volume of 300 ml and pentane was added.The 12α-bromo-6α-fluoro-11ss-formyloxy-16α- methyl-21-valeryloxy-#1,4-pregnadiene-3,20-dione (39.7 gms) that crystallized out was filtered off with suction, and again recrystallized from methanol.
Melting point: 177-1780C.
Example 3.
26 Gms of 12 - bromo - 6a - fluoro - 11ss - formyloxy - 162 - methyl - 21- valeryloxy-#1,4-Dregnadiene-3.20-dione in 500 ml of ethanol were heated under reflux for 2 hours with 30 gms of potassium acetate. After cooling, the solution was precipitated in ice-water, and the product was filtered off with suction, washed with
water and dried. After recrystallization from acetone/hexane 18.5 gms of 6a-fluoro- 11,12ss - epoxy - 16α - methyl - 21 - valeryloxy - A1 & - pregnadiene - 3,20 - dione
melting at 163-1660C. were obtained.
Example 4.
To a solution of 34 ml of hydrogen fluoride, 165 ml of chloroform and 17 ml of ethanol was added dropwise at -20 C. a solution of 16.4 gms of 6a-fluoro-11,12jB- epoxy - 16a - methyl - 21 - valeryloxy - A14 - pregnadiene - 3,20 - dione in 165 ml of chloroform, and the mixture was stirred for 2 hours at 030 C. The solution was poured into ice-water containing potassium bicarbonate, and the precipitated product was filtered off with suction, washed with water and dried. After chromatography over silica gel and recrystallization from methanol 13.1 gms of 6a,12o-difluoro- 11ss - hydroxy - 16ce - methyl - 21 - valeryloxy - A1,4 ~ pregnadiene - 3,20 - dione melting at 207.3-2090C. were obtained
Example 5.
3.2 Gms of 6a,12e - difluoro - ll,B - hydroxy - 16a - methyl - 21 - valeryloxy #1,4-pregnadiene-3,20-dione were dissolved in 25 ml of methylene chloride and 25 ml of methanol, the solution was cooled to 0 C., and a solution of 180 mg of potassium hydroxide in 5 ml of methanol was added while gassing with argon. The solution was stirred for 3 hours at 0-30C., neutralized with glacial actic acid and concentrated in vacuo, and the residue was taken up in methylene chloride.The methylene chloride phase was washed until neutral with water, then evaporated in vacuo, and the residue was crystallized from acetone-hexane. 2.35 Gms of 6α,12α-difluoro-11ss,21-dihydroxy- 16α-methyl-#1,4-pregnadiene-3,20-dione melting at 251 C. (with decomposition) were obtained.
Example 6.
1.8 Gms of 6α - fluoro - 11ss,12ss - epoxy - 16α - methyl - 21 - valeryloxy alg4-pregnadiene-3,20-dione were dissolved in 60 ml of methylene chloride and cooled to --5"C. Into this solution dry hydrogen chloride was introduced during the course of 15 minutes in such a manner that the temperature did not exceed +5 C. The mixture was further stirred for 1 hour at 0 to +2 C., diluted with methylene chloride and washed until neutral with water.After evaporation in vacno and crystallization from acetone-hexane 12α - chloro - 6α - fluoro - 11 - hydroxy - 16α - methyl 21-valeryloxy-#1,4-pregnadiene-3,20-dione was obtained.
Example 7.
10 Gms of 6a,12a - difluoro - 11l,21 - dihydroxy - 16a - methyl A1" pregnadiene-3,20-dione were stirred in 32 ml of pyridine and 16 ml of acetic anhydride for 90 minutes at 0 to 5 C. The mixture was then poured into ice water, and the precipitated product was filtered off with suction, washed with water and dried. After recrystallization from acetone - hexane 21 - acetoxy - 6α,12α - difluoro - llss- hydroxy - 16α - methyl - #1,4 - pregnadiene - 3,20 - dione melting at 297-2980C.
was obtained.
Example 8.
2 Gms of 65 - fluoro - llss,12ss - epoxy - 16os - methyl - 21 - valeryloxy- #1,4-pregnadiene-3,20-dione were dissolved in 20 ml of methylene chloride and 20 ml of methanol, the solution was cooled to 0 to 50C., and while gassing with argon a solution of 1SO mg of potassium hydroxide in 6 ml of methanol was added. The solution was stirred for 90 minutes at 0-30C. neutralized with acetic acid, evaporated in vacua and worked up.After recrystallization from acetone/hexane 1.5 gms of 6afluoro - lljss,12ss - epoxy - 21 - hydroxy - 16tx - methyl #1,4 - pregnadiene - 3,20- dione melting at 162-165 C. were obtained.
Example 9.
1.5 Gms of 6a - fluoro - 11Th12fl - epoxy - 21 - hydroxy - 16e - methyl- Als4-pregnadiene-3,20-dione in 6 ml of pyridine were stirred with 3 ml of acetic anhydride for 18 hours at 20 C. Precipitation in ice-water was then carried out, and the product was filtered off with suction, washed with water and dried. After crystallization from acetone/hexane 1.5 gms of 21-acetoxy-6α-fluoro-11ss,12ss-epoxy-16α- methyl-#1,4-pregnadiene-3,20-dione melting at 213.3-216.5 0C. were obtained.
Example 10.
1.4 Gms of 21 - acetoxy - 6α - fluoro - 11ss,12ss - epoxy - 16 - methyl- #1,4-pregnadiene-3,20-dione were dissolved in 22 ml of chloroform, 22 ml of a chloroform solution saturated with hydrogen chloride were added, and the mixture was stirred at OOC. for 10 minutes. Then the mixture was diluted with chloroform, washed with water and evaporated in vacua. After crystallization from methylene chloride, methanol and ethyl acetate 1.38 gms of 21-acetoxy-12α-chloro-6α-fluoro-11ss-hydroxy- 16α-methyl-#1,4-pregnadiene-3,20-dione melting at 305 C. (with decomposition) were obtained.
Example 11.
The composition of a salve:
0.1% of 6a,12tr - difluoro - 11ss - hydroxy - 16a - methyl - 21 - pentanoyloxy 14-pregnadiene-3,20-dione 2.5% of "Allercur" hexachlorophenate, micronized, particle size about 8 ("Aller
cur" is a Registered Trade Mark for 1 -para-chlorobenzyl-2-pyrrolidyl-methyl- benzimidazole) 6.0 , of "Hostaphat" KW 340 - "Hostaphat" being a Registered Trade Mark
(teriary ester of O-phosphoric acid and wax alcohol tetraglycol ether)
0.1% of sorbic acid 10.0% of neutral oil ("Migloyol" 812 - "Migloyol" being a Registered Trade Mark) 3.5% of stearyl alcohol 1.5% of wool fat, anhydrous DAB 6 76.3% of desalted water.
"DAB 6" is an abbreviation for Deutsches Arzneibuch, 6th edition.
Claims (24)
1. A compound of the general formula I
in which
X represents a fluorine, chlorine or bromine atom,
R1 represents a hydrogen atom, a hydroxyl group or an acyloxy group and
R2 represents a free or esterified hydroxyl group.
2. A compound as claimed in claim 1, wherein R, represents an acyloxy group derived from a carboxylic acid containing 1 to 16 carbon atoms.
3. A compound as claimed in claim 2, wherein R2 represents an acyloxy group derived from a carboxylic acid containing 1 to 8 carbon atoms.
4. A compound as claimed in claim 1, wherein R, represents a sulphate or phosphate group.
5. A compound as claimed in any one of claims 1 to 4, wherein R1 represents an acyloxy group derived from a carboxylic acid containing 1 to 8 carbon atoms.
6. A compound as claimed in any one of claims 1 to 5, wherein R1 represents an alkanoyloxy group.
7. 6a,12a - Difluoro - llss,21 - dihydroxy - 16a - methyl - Al,4 - pregnadiene
3,20-dione.
8. 6a,12 - Difluoro - llss - hydroxy - 16a - methyl - 21 - valeryloxy - A1s4 pregnadiene-3 ,20-dione.
9. 21 - Acetoxy - 6α,12α - difluoro - 11ss - hydroxy - 16α - methyl - #1,4- pregnadiene-3,20-dione.
10. 122 - Chloro - 6o - fluoro - iip - hydroxy - 16a - methyl - 21 - valeryloxy #1,4-pregnadiene-3,20-dione.
11. 21 - Acetoxy - 12 - chloro - 6,sr - fluoro - lift - hydroxy - 16a - methyl- #1,4-pregnadiene-3,20-dione.
12. A process for the manufacture of a compound of the general formula I
in which
X represents a fluorine, chlorine or bromine atom,
R1 represents a hydrogen atom, a hydroxyl group or an acyloxy group and
R2 represents a free or esterified hydroxy group, wherein the epoxide ring in a com
pound of the general formula II
in which Rl and R2 have the meanings given above, is opened with hydrogen fluoride, chloride or bromide, respectively, and, if desired, in the resulting compound any ester group is hydrolysed and/or any free hydroxyl group is esterified.
13. A process as claimed in claim 12, conducted substantially as described herein.
14. A process for the manufacture of a compound of the general formula I given in claim 1, in which X, R1 and R2 have the meanings given in claim 1, conducted substantially as described in any of Examples 4, 5, 6 and 7 herein.
1S. A process for the manufacture of a compound of the general formula I given in claim 1, in which X, Rl and R2 have the meanings given in claim 1, conducted substantially as described in Examples 1 to 4 herein.
16. A process for the manufacture of a compound of the general formula I given in claim 1, in which X, Rl and R2 have the meanings given in claim 1, conducted substantially as described in Example 10 herein.
17. A process for the manufacture of a comnound of the general formula I given in claim 1, in which X, R, and R. have the meanings given in claim 1, conducted substantially as described in Examples 1 to 3 and 8 to 10 herein.
18. A pharmaceutical preparation which comprises a compound as claimed in claim 1, in admixture or conjunction with a pharmaceutically suitable carrier.
19. A pharmaceutical preparation which comprises a compound as claimed in any one of claims 2 to 6, in admixture or conjunction with a pharmaceutically suitable carrier.
20. A pharmaceutical preparation which comprises the compound claimed in any one of claims 7 to 11, in admixture or conjunction with a pharmaceutically suitable carrier.
21. A preparation as claimed in any one of claims 18 to 20, which is in a form suitable for local application.
22. A prenaration as claimed in any one of claims 18 to 20, which is in the form of a solution, lotion. salve, cream, plaster or inhalant preparation.
23. A preparation as claimed in any one of claims 18 to 20. which is in the form of a lotion or salve containing 0.001 to 2% bv weight of active substance.
24. A preparation as claimed in claim 18, having a composition substantially as described in Example 11 herein.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2632678A DE2632678C2 (en) | 1976-07-16 | 1976-07-16 | 6α-Fluoro-12α-Halo-Corticoids and Process for Their Preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1589585A true GB1589585A (en) | 1981-05-13 |
Family
ID=5983515
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB28994/77A Expired GB1589585A (en) | 1976-07-16 | 1977-07-11 | 12a-halocorticoids |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS5315361A (en) |
| AT (1) | AT355743B (en) |
| BE (1) | BE856862A (en) |
| CH (1) | CH627191A5 (en) |
| DE (1) | DE2632678C2 (en) |
| DK (1) | DK323877A (en) |
| FR (1) | FR2358421A1 (en) |
| GB (1) | GB1589585A (en) |
| IT (1) | IT1125789B (en) |
| LU (1) | LU77768A1 (en) |
| NL (1) | NL7707920A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2244000A (en) * | 1990-05-18 | 1991-11-20 | Teasdale S | Mattress |
| US9744168B2 (en) | 2011-10-19 | 2017-08-29 | Galderma Laboratories, Inc. | Method of reducing facial flushing associated with systemic use of phosphodiesterase type 5 inhibitors |
| US9861632B2 (en) | 2010-03-26 | 2018-01-09 | Galderma Laboratories, L.P. | Methods and compositions for safe and effective treatment of erythema |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3053837A (en) * | 1958-10-01 | 1962-09-11 | Olin Mathieson | 16, 17-acetal and ketal derivatives of 6alpha, 12alpha-dihalo-16alpha, 17alpha-dihydroxy steroids of the pregnane series; and intermediates therefor |
| GB1174780A (en) * | 1965-12-22 | 1969-12-17 | Squibb & Sons Inc | 01beta-Hydroxy-12alpha-Bromo-16alpha-Methyl-5beta-Pregnanes |
-
1976
- 1976-07-16 DE DE2632678A patent/DE2632678C2/en not_active Expired
-
1977
- 1977-07-11 GB GB28994/77A patent/GB1589585A/en not_active Expired
- 1977-07-12 CH CH861277A patent/CH627191A5/en not_active IP Right Cessation
- 1977-07-13 AT AT504777A patent/AT355743B/en not_active IP Right Cessation
- 1977-07-14 LU LU77768A patent/LU77768A1/xx unknown
- 1977-07-15 JP JP8493377A patent/JPS5315361A/en active Pending
- 1977-07-15 DK DK323877A patent/DK323877A/en not_active Application Discontinuation
- 1977-07-15 BE BE179386A patent/BE856862A/en unknown
- 1977-07-15 NL NL7707920A patent/NL7707920A/en not_active Application Discontinuation
- 1977-07-15 IT IT25805/77A patent/IT1125789B/en active
- 1977-07-18 FR FR7721933A patent/FR2358421A1/en active Granted
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2244000A (en) * | 1990-05-18 | 1991-11-20 | Teasdale S | Mattress |
| US9861632B2 (en) | 2010-03-26 | 2018-01-09 | Galderma Laboratories, L.P. | Methods and compositions for safe and effective treatment of erythema |
| US9861631B2 (en) | 2010-03-26 | 2018-01-09 | Galderma Laboratories, L.P. | Methods and compositions for safe and effective treatment of erythema |
| US9744168B2 (en) | 2011-10-19 | 2017-08-29 | Galderma Laboratories, Inc. | Method of reducing facial flushing associated with systemic use of phosphodiesterase type 5 inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| ATA504777A (en) | 1979-08-15 |
| DE2632678A1 (en) | 1978-01-26 |
| DE2632678C2 (en) | 1986-02-27 |
| JPS5315361A (en) | 1978-02-13 |
| AT355743B (en) | 1980-03-25 |
| BE856862A (en) | 1978-01-16 |
| LU77768A1 (en) | 1977-10-17 |
| NL7707920A (en) | 1978-01-18 |
| FR2358421B1 (en) | 1979-05-11 |
| CH627191A5 (en) | 1981-12-31 |
| FR2358421A1 (en) | 1978-02-10 |
| IT1125789B (en) | 1986-05-14 |
| DK323877A (en) | 1978-01-17 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed | ||
| PCNP | Patent ceased through non-payment of renewal fee |