GB1594852A - Derivatives of 9-chloroprednisolone - Google Patents
Derivatives of 9-chloroprednisolone Download PDFInfo
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- 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
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- 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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Abstract
Derivatives of 9-chloroprednisolone of the formula <IMAGE> 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
(54) NEW DERIVATIVES OF 9-CHLOROPREDNISOLONE
(71) We, SCHERING AKTIENGESELLSCHAFT, 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 derivatives of 9chloroprednisolone, with a process for their manufacture and with pharmaceutical preparations containing these active substances.
9 - Chloroprednisolone (9a - chloro - 11A,17,21 - trihydroxy - A4 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 9chloroprednisolone 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 9chloroprednisolone of the general formula I
in which
R, represents an alkanoyl group containing 1 to 8 carbon atoms or a benzoyl group, and
X represents a fluorine atom, a chlorine atom, an alkanoyloxy group containing 1 to 8 carbon atoms or a benzoyloxy group.
As an alkanoyl group represented by R1 containing 1 to 8 carbon atoms and an alkanoyloxy group represented by X containing 1 to 8 carbon atoms there is to be understood in each case a group that is derived from a stright-chained or branched fatty acid, for example formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, trimethylacetic acid, caproic acid, tert.-butylacetic acid or caprylic acid.
Especially preferred alkanoyl groups represented by R, and alkanoyloxy groups represented by X are those derived from alkane carboxylic acids containing 2 to 6 carbon 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:
TABLE 1 17α - Acetoxy - 9α,21 - dichloro - 11ss - hydroxy - #1,4 - pregnadiene 3,20 - dione, 9α,21 - dichloro - 11ss - hydroxy - 17α - propionyloxy - #1,4 - pregnadiene 3,20 - dione, 17α - butyryloxy - 9α,21 - dichloro 11ss - hydroxy - #1,4 - pregnadiene 3,20 - dione, 9α,21 - dichloro - 11ss - hydroxy 17 α; - isobutyryloxy - #1,4 - pregnadiene 3,20 - dione, 17α - acetoxy - 9α - chloro - 21 - fluoro - 11ss - hydroxy - #1,4 pregnadiene - 3,20 - dione, 9α - chloro - 21 - fluoro - 11ss - hydroxy - 17α - propionyloxy - #1,4 - pregnadiene - 3,20 - dione,
17a - butyryloxy - 9a - chloro - 21 - fluoro - Ilp - hydroxy - #1,4 pregnadiene - 3,20 - dione, 17α - benzoylxoy - 9α - chloro - 21 - fluoro - 11ss - hydroxy - #1,4 pregnadiene - 3,20 - dione, 9α - chloro - 21 - fluoro - 11ss hydroxy - 17α - isobutyryloxy - #1,4 pregnadiene - 3,20 - dione, 9α,21 - dichloro - 11ss - hydroxy - 17α - valeryloxy - #1,4 - pregnadiene 3,20 - dione and 17α - benzoylxoy - 9α,21 - dichloro - 11ss - hydroxy - #1,4 - 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 9-chloroprednisolone derivatives of the general formula I in which X represents a chlorine atom, and also for the production of 9-chloroprednisolne also for the production of 9-chloroprednisolne derivatives of the general formula I in which X represents an alkanoyloxy or benzoyloxy 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 17α - Acetoxy - 9α - chloro - 11ss,21 - dihydroxy - #1,4 - pregnadiene 3,20 - dione, 9α - chloro - 11ss,21 - dihydroxy - 17α - propionyloxy - #1,4 - pregnadiene 3,20 - dione, 17α - butyryloxy - 9α - chloro - 11ss,21 - dihydroxy - #1,4 - pregnadiene 3,20 - dione, 9α - chloro - 11ss,21 - dihydroxy - 17α - isobutyryloxy - #1,4 - pregnadiene 3,20 - dione, 9α - chloro - 11ss,21 - dihydroxy - 17α - valeryloxy - #1,4 - pregnadiene 3,20 - dione and 17α - benzoyloxy - 9α - chloro - 11ss,21 - dihydroxy - #1,4 - 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 R, and X together contain 3 to 14 carbon atoms.
Such chloroprednisolone derivatives are, for example, those listed in the following
Table:
TABLE 3 17α,21 - Diacetoxy - 9α - chloro - 11ss - hydroxy - #1,4 - pregnadiene 3,20 - dione, 17α - acetoxy - 9α - chloro - 11ss - hydroxy - 21 - propionyloxy - #1,4 pregnadiene - 3,20 - dione,
21 - acetoxy - 9α - chloro - 11ss - hydroxy - 17α propionyloxy - #1,4 pregnadiene - 3,20 - dione, 17α - acetoxy - 21 - butyryloxy - 9α - chloro - 11ss - hydroxy - #1,4 pregnadiene - 3,20 - dione,
21 - acetoxy - 17α - butryloxy - 9α - chloro - 11ss - hydroxy - #1,4 pregnadiene - 3,20 - dione,
17a - acetoxy - 9a - chloro - llp - hydroxy - 21 - isobutyryloxy - A'4 pregnadiene - 3,20 - dione,
21 - acetoxy - 9α - chloro - 11ss - hydroxy - 17α - isobutyryloxy - #1,4 - pregnadiene - 3,20 - dione, 17α - acetoxy - 9α - chloro - 11ss - hydroxy - 21 - valeryloxy - #1,4 pregnadiene - 3,20 - dione,
21 - acetoxy - 9α - chloro - 11ss - hydroxy - 17α - valeryloxy - #1,4 pregnadiene - 3,20 - dione, 17α - acetoxy - 21 - benzoyloxy - 9α - chloro - 11ss - hydroxy - #1,4 pregnadiene - 3,20 - dione,
21 - acetoxy - 17α - benzoyloxy - 9α - chloro - 11ss - hydroxy - #1,4 pregnadiene - 3,20 - dione, 9α - chloro - 11ss - hydroxy - 17α,21 - dipropionyloxy - #1,4 - pregnadiene 3,20 - dione, 17α - butyryloxy - 9α - chloro - 11ss - hydroxy - 21 propionyloxy - #1,4 pregnadiene - 3,20 - dione,
21 - butyryloxy - 9α - chloro - 11ss - hydroxy - 17α - propionyloxy - #1,4 pregnadiene - 3,20 - dione, 9α - chloro - 11ss - hydroxy - 17α - isobutyryloxy - 21 - propionyloxy - #1,4 pregnadiene - 3,20 - dione, 9α - chloro - 11ss - hydroxy - 21 - isobutyryloxy - 17α - propionyloxy - #1,4 pregnadiene - 3,20 - dione, 9α - chloro - 11ss - hydroxy - 17α - propionyloxy - 21 - valeryloxy - #1,4 pregnadiene - 3,20 - dione, 9α - chloro - 11ss - hydroxy - 21 - propionyloxy - 17α - valeryloxy - #1,4 pregnadiene - 3,20 - dione, 17α - benzolyloxy - 9α - chloro - 11ss - hydroxy - 21 - propionyloxy - #1,4 pregnadiene - 3,20 - dione,
21 - benzoyloxy - 9α - chloro - 11ss - hydroxy - 17α - propionyloxy - #1,4 - pregnadiene - 3,20 - dione, 17α,21 - dibutyryloxy - 9α - chloro - 11ss - hydroxy - #1,4 - pregnadiene 3,20 - dione, 17α - butyryloxy - 9α - chloro - 11ss - hydroxy - 21 - isobutyryloxy - #1,4 pregnadiene - 3,20 - dione,
21 - butyryloxy - 9α - chloro - 11ss - hydroxy - 17α - isobutyryloxy - #1,4 pregnadiene - 3,20 - dione, 17α - butyryloxy - 9α - chloro - 11ss - hydroxy - 21 valeryloxy - #1,4 - pregnadiene - 3,20 - dione,
21 - butyryloxy - 9α - chloro - 11ss - hydroxy - 17α - valeryloxy - #1,4 pregnadiene - 3,20 - dione, 17α - benzoyloxy - 21 - butyryloxy - 9α - chloro - 11ss - hydroxy - #1,4 pregnadiene - 3,20 - dione,
21 - benzoyloxy - 17α - butyryloxy - 9α - chloro - 11ss - hydroxy - #1,4 pregnadiene - 3,20 - dione, 9α - chloro - 11ss - hydroxy - 17,21 - diisobutyryloxy - #1,4 - pregnadiene 3,20 - dione, 9α - chloro - 11ss - hydroxg - 17α,21 - divaleryloxy - #1,4 - 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 general formula I, wherein
(a) HOCl is added on at the #9,11-double bond of a 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 Ill
in which R, and X have the meanings given above, is opened up with hydrogen chloride, or
(c) when X represents a fluorine or chlorine atom, an orthoester of the general formula IV
in which R3 represents a hydrogen atom, an alkyl group containing I to 7 carbon atoms or a phenyl group and R2 represents an alkyl group containing 1 to 4 carbon atoms, is reacted with trimethylsilyl fluoride or chloride 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
in which Rl has the meaning given above, is chlorinated or esterified at the 21position.
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 with 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 application, 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 for comparison. Three hours after the application the animals were killed and discs having a size 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 to the paw of
rats:
SPF-Rats weighing 130 to 150 grams were injected in the right rear 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.
From the paw volumes so obtained was determined in the usual manner the quantities of test substance which was required to produce a 50% healing of the paw oedema.
(C) The thymolytic effect after oral application:
SPF-Rats weighing 70 to 110 grams were adrenalectomized under narcosis produced by ether. Every 6 animals formed a test group, each of which received over 3 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 beclomethasone 17,21 - dipropionate (9fez - chloro - l lp - hydroxy - 16p - methyl - 17a,21 dipropionyloxy - A1,4 - pregnadiene - 3,20 - dione.
The results obtained in these tests are given in the following Table: ED50 in mg/kg (A) Rats (B) Adjuvant ear oedema (C) Thymolysis
No. Substance test test test
I 9α-Chloro-11ss,17α,21-trihydroxy-#1,4-pregadiene3,20-dione 1.4 6.3 0.4 II 21-Acetoxy-9α-chloro-11ss,17α-dihydroxy-#1,4pregnadiene-3,20-dione 1.5 6.0 0.6 III 9α-Chloro-11ss-hydrox-16ss-methyl-17α,21-dipropionyloxy-#1,4pregnadiene-3,20-dione 1.4 > 30 2.0 IV 21-Acetoxy-9α-chloro-11ss-hydroxy-17α-propionyloxy-#1,4pregnadiene-3,20-dione 0.026 25 4.8 V 21-Acetoxy-17α-benzoyloxy-9α-chloro-11ss-hydroxy-#1,4pregnadiene-3,20-dione 1.5 > 30 VI 17α-Benzoyloxy-9α;-chloro-11ss-hydroxy-21-propionyloxy-#1,4pregnadiene-3,20-dione 1.5 > 30 Similar results are obtained when the pharmacological activity of the 9chloroprednisolone derivatives of the present invention is determined by means of the known vasoconstriction 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 application, for example solutions, lotions, salves, creams or plasters. The concentration of active substance in the pharmaceutical preparations so formulated depends on the form of application. In the case of lotions and salves there is preferably used a concentration of active substance within the range of from 0.001% 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 bronchial 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 which X represents a hydroxyl group.
Example 1
(a) 5.0 gms of 9cr-chloro-l l,17cr,2l - trihydroxy - å14 - 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, 50 ml of the solvent were distilled off at a bath temperature of 1300C, 60 ml of ortho-benzoic acid triethyl ester were added and the residual benzene was distilled off during the course of 22 hours, 2.4 ml of pyridine were added to the residue, the mixture was concentrated in vacuo and 17α,21 - (1 - ethoxy - benzylidenedioxy) - 9α - chloro - 11ss hydroxy - #1,4 - pregnadiene - 3,20 - 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 0.1N-aqueous acetic acid and 6 ml of an 0.1N-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 recrystallized from acetone-hexane and there were obtained 3.7 gms of 17α - benzoyloxy - 9α - chloro - 11ss,21 - dihydroxy - #1,4 pregnadiene - 3,20 - dione melting at 216 C (with decomposition).
Example 2
0.5 gm of 17cur - benzoyloxy - 9a - chloro - l lp,21 - dihydroxy - å4 pregnadiene - 3,20 - dione was stirred for 24 hours at room temperature with 10 ml of formic acid. The reaction mixture was then poured into ice-water and extracted with dichloromethane, the organic phase was washed, dried over sodium sulphate and concentrated in vacuo and there were obtained 400 mg of 17α - benzoyloxy 9α - chloro - 21 - formyloxy - 11ss - hydroxy - #1,4 - pregnadiene - 3,20 - dione that solidified in the form of a glassy mass. [α]D25=+58 (chloroform).
Example 3
1.5 gms of 17cur - benzoyloxy - 9cr - chloro - llp,21 - dihydroxy - A1,4 pregnadiene - 3,20 - dione were mixed with 17 ml of pyridine and 8.0 ml of acetic anhydride and the whole was stirred for one hour at OOC. 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 - 17α - benzoyloxy - 9α - chloro 11ss - hydroxy - #1,4 - pregnadiene - 3,20 - dione melting at 221 C (with decomposition) were obtained.
Example 4
1.5 gms of 17α - benzoyloxy - 9α - chloro - 11ss,21 - dihydroxy - #1,4 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 17α - benzoyloxy - 9α - chloro - 11ss - hydroxy - 21 - propionyloxy - #1,4 pregnadiene - 3,20 - dione melting at 226 C (with decomposition).
Example 5
2.3 gma of 17α - benzoyloxy - 9α - chloro - 11ss,21 - dihydroxy - #1,4 - 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. The reaction mixture was worked up as described in Example 3 and 2.0 gms of 17α benzoyloxy - 21 - butyryloxy - 9α - chloro - 11ss - hydroxy - #1,4 - pregnadiene 3,20 - dione melting at 226 C (with decomposition) were obtained.
Example 6
2.3 gms of 17α - benzoyloxy - 9α - chloro - 11ss,21 - dihydroxy - #1,4 pregnadiene - 3,20 - dione were mixed with 50 ml of pyridine and 25 ml of valeric 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 1.63 gms of 17α - benzoyloxy - 9α - chloro - 11ss - hydroxy - 21 - valeryloxy #1,4 - pregnadiene - 3,20 - dione melting at 208 C.
Example 7
2.3 gms of 17cr - benzoyloxy - 9a - chloro - llp,21 - dihydroxy - A1,4 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 17α - benzoyloxy - 9α - chloro - l lA - hydroxy 21 - trimethylacetoxy - #1,4 - pregnadiene - 3,20 - dione melting at 236 C.
Example 8
2.3 gms of 17α - benzoyloxy - 9α - chloro - 11ss,21 - dihydroxy - #1,4 pregnadiene - 3,20 - dione - were mixed with 50 ml of pyridine and 25 ml of isobutyric anhydride and 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 17α - benzoyloxy - 9α - chloro - 11ss - hydroxy - 21 - isobutyloxy - #1,4 pregnadiene - 3,20 - dione were obtained in the form of a glassy mass. [α]D25=+68 (chloroform).
Example 9
2.3 gms of 17α - benzoyloxy - 9α - chloro - 11ss,21 - dihydroxy - #1,4 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 17α benzoyloxy - 9α - chloro - 11ss - hydroxy - 21 - isovaleryloxy - #1,4 pregnadiene - 3,20 - dione melting at 197 C were obtained.
Example 10
2.3 gms of 17α - benzoyloxy 9α - chloro - 11ss,21 - dihydroxy - #1,4 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 17cg - benzoyloxy - 9 - chloro - 21 - heptanoyloxy - l 1ss - hydroxy #1,4 - pregnadiene - 3,20 - dione were obtained in the form an oily product, [α]D25+64 (chloroform).
Example 11
2.3 gms of 17α - benzoyloxy - 9α - chloro - 11ss,21 - dihydroxy #1,4 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 descrlbed in Example 3 and there were obtained 2.5 gms of 17α,21 dibenzoyloxy - 9α - chloro - 11ss - hydroxy - #1,4 - pregnadiene - 3,20 - dione melting at 221 C.
Example 12
(a) Under the condistions described in Example 1(a) 7.5 gms of 9α - chloro 11ss,17α,21 - trihydroxy - #1,4 - pregnadiene - 3,20 - dione were reacted with ortho- acetïc acid triethyl ester and worked up. There was obtained 17α,21 - (1 ethoxy - ethylidenedioxy) - 9α - chloro - 11ss - hydroxy - #1,4 - pregadiene 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 17α - acetoxy - 9α - chloro 11ss,21 - dihydroxy - #1,4 - pregnadiene - 3,20 - dione melting 205 C (with decomposition) were obtained.
Example 13
1.0 gm of 17α - acetoxy - 9α - chloro - 11ss,21 - dihydroxy - #1,4 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 product that separated was filtered off with suction and dissolved in dichloromethane and the organic phase was washed and concentrated in vacuo. The residue was recrystallized from acetone-hexane and there were obtained 860 mg of 17α,21 - diacetoxy - 9α chloro - 11ss - hydroxy - #1,4 - pregnadiene - 3,20 - dione melting at 222 C (with decomposition).
Example 14
Under the conditions described in Example 4 1.0 gm of 17α - acetoxy - 9α chloro - 11ss,21 - dihydroxy - #1,4 - pregnadiene - 3,20 - dione was reacted with propionic anhydride and worked up, and there were obtained 940 mg of 17α acetoxy - 9α - chloro - 11ss - hydroxy - 21 - propionyloxy - #1,4 - pregnadiene 3,20 -dione melting at 219 C (with decomposition).
Example 15
Under the conditions described in Example 6 1.0 gm of 17α - acetoxy - 9α chloro - 11ss,21 - dihydroxy - #1,4 - pregnadiene - 3,20 - dione was reacted with valeric anhydride and worked up, and there were obtained 660 mg of 17α acetoxy - 9α - chloro - 11ss - hydroxy - 21 - valeryloxy - #1,4 - pregnadiene 3,20 - dione melting at 220 C (with decomposition).
Example 16
(a) Under the conditions described in Example 1(a) 7 gms of 9α - chloro 11ss, 17α,21 - trihydroxy - #1,4 - pregnadiene - 3,20 - dione were reacted with ortho - propionic acid triethyl ester and worked up, and 17α,21 - (1 - ethoxy propylidenedioxy) - 9α - chloro 11ss - hydroxy - #1,4 - pregnadiene - 3,20 dione was obtained in the form of a crude product.
(b) The crude product so obtained was reacted under the conditions described in Example 1(b) and worked up, and there were obtained 2.9 gms of 9α - chloro 11ss, 21 - dihydroxy - 17α - propionyloxy - #1,4 - pregadiene - 3,20 - dione melting at 181 C (with decomposition).
Example 17
Under the conditions described in Example 2 1,2 gms of 9α - chloro - 11ss,21 dihydroxy - 17α - propionyloxy - #1,4 - pregnadiene - 3,20 - dione were reacted with formic acid and worked up, and there were obtained 400 mg of oily 9α chloro - 21 - formyloxy - 11ss - hydroxy - 17α - propionyloxy - #1,4 pregnadiene - 3,20 - dione, [α]D25=+67 (chloroform).
Example 18
700 mg of 9α - chloro - 11ss,21 - dihydroxy - 17α - propionyloxy - #1,4 pregadiene - 3,20 - dione were reacted with acetic anhydride as described in
Example 3 and worked up ant there were obtained 320 mg of 21 - acetoxy - 9α chloro - 11ss - hydroxy - 17α - propionyloxy - #1,4 - pregnadiene - 3,20 - dione melting at 210 C (with decomposition).
Example 19
700 mg of 9α - chloro - 11ss,21 - dihydroxy - 17α - propionyloxy - #1,4 pregnadiene - 3,20 - dione were reacted with propionic anhydride under the conditions described in Example 4 and worked up, and there were obtained 420 mg of 9α - chloro - 11ss - hydroxy 17α,21 - dipropionyloxy - #1,4 - pregnadiene 3,20 - dione melting at 215 C (with decomposition).
Example 20
650 mg of 9α - chloro - 11ss,21 - dihydroxy - 17α - propionyloxy - #1,4 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 - 9α - chloro - 11ss - hydroxy - 17α - propionyloxy - #1,4 pregnadiene - 3,20 - dione melting at 208 C (with decomposition).
Example 21
Under the conditions described in Example 6 700 mg of 9α - chloro - 11ss,21 dihydroxy, 17α - propionyloxy - #1,4 - pregnadiene - 3,20 - dione were reacted with valeric anhydride and worked up, and there were obtained 520 mg of 9α chloro - 11ss - hydroxy - 17α - propionyloxy - 21 - valeryloxy - #1,4 pregnadiene - 3,20 - dione melting at 210 C (with decomposition).
Example 22
3.0 gms of 9α - chloro - 11ss,21 - dihydroxy - 17α - propionyloxy -#1,4 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 9cr - chloro - 21 - hexanoyloxy - 11ss - hydroxy - 17cr - propionyloxy A1,4 - pregnadiene - 3,20 - dione.
Example 23
Under the conditions described in Example 10 2.1 gms of 9α - chloro
11ss,21 - dihydroxy - 17α - propionyloxy - #1,4 - pregnadiene - 3,20 - dione were reacted with oenanthic anhydride and worked up, and there were obtained 1.02 gms of 9cz - chloro - 21 - heptanoyloxy - 11ss - hydroxy - 17α - propionyloxy #1,4 - pregnadiene - 3,20 - dione.
Example 24
Under the conditions described in Example 7 1.4 gms of 9α - chloro 11ss,21 dihydroxy - 17α - propionyloxy - #1,4 - pregnadiene - 3,20 - dione were reacted with trimethylacetic anhydride and worked up, and 670 mg of 9α - chloro 11ss hydroxy - 17α - propionyloxy - 21 - trimethylacetoxy - #1,4 - pregnadiene 3,20 - dione were obtained.
Example 25 (a) Under the conditions described in Example 20 25 gms of ll,B,17a!,21 trihydroxy - #1,4 - pregnadiene - 3,20 - dione were reacted with butyric anhydride and worked up, and 23.1 gms of 21 - butyryloxy - 11ss,17α - dihydroxy - #1,4 pregnadiene - 3,20 - dione were obtained.
(b) Into a suspension of 24 gms of copper-(I) chloride in 480 ml of absolute tetrahydrofuran were introduced dropwise under argon at 0 C 100 ml of an ethereal soluation of 5% strength of lithium methyl. The mixture was then cooled to -30 C and a solution of 22.3 gms of 21 - butyryloxy - 11ss,17α - dihydroxy - #1,4 pregnadiene - 3,20 - dione in 100 ml of tetrahydrofuran was added. The mixture was stirred for 4 hours until the primarily formed 11ss - hydroxy - 17α,21 - (1 hydroxy - butylidenedioxy) - #1,4 - 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 17a - butyryloxy
11ss,21 - dihydroxy - #1,4 - pregadiene - 3,20 - dione were obtained in the form of a crude product.
(c) Under the conditions described in Example 3 20 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 - 17α - butyryloxy - 11ss - hydroxy - #1,4 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 - 17α - butyryloxy 11ss - hydroxy - #1,4 - 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 - 17a - butyryloxy - AlA,9(1l) - pregnatriene - 3,20 - dione were obtained in the form of a crude product.
(e) 6 gms of the crude product so obtained were suspended in 80 ml of dioxan and 5.6 gms of N-chlorosuccinimide were added. There were then introduced dropwise into the mixture during the course of 10 minutes at 200C 42 ml of an aqueous solution of 10% strength of perchloric acid, and the mixture was stirred for 3 hours at 200C 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 - 17α butyryloxy - 9α - chloro - 11ss - hydroxy - #1,4 - pregnadiene - 3,20 - dione melting at 215 C were obtained.
Example 26
(a) 9.5 gms of 17α - butyryloxy - 11ss,21 - dihydroxy - 1,4 - 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 17α - butyryloxy - 11ss - hydroxy - 21 trimethylacetoxy - #1,4 - pregnadiene - 3,20 - dione - were obtained.
(b) 6.0 gms of 17α - butyryloxy 11ss - hydroxy - 21 - trimethylacetoxy #1,4 - 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 17α - butyryloxy - 21 - trimethylacetoxy #1,4,8(11) - pregnatriene - 3,20 - dione in the form of a crude product.
(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 17cr - butyryloxy - 9cr - chloro - 11/3 - hydroxy - 21 - trimethylacetoxy - å-4 pregnadiene - 3,20 - dione melting at 2590C.
Example 27
(a) 14.1 gms of 17a - butyryloxy - 11p,21 - dihydroxy - år4 - 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 17α - butyryloxy - 21 heptanoyloxy - 11ss - hydroxy - #1,4 - pregnadiene - 3,20 - dione.
(b) 7.6 gms of 17α - butyryloxy - 21 - heptanoyloxy - 11ss - hydroxy - #1,4 pregnadiene - 3,20 - dione were reacted under the conditions described in Example 25(d) and worked up, and 3.9 gms of 17α - butyryloxy - 21 heptanoyloxy - #1,4,8(11) - pregnatriene - 3,20 - dione were obtained as a crude product.
(c) 3 gms of the crude product so obtained were reacted with Nchlorosuccinimide under the conditions described in Example 25(e) and worked up, and 950 mg of 17α - butyryloxy - 9α - chloro - 21 - heptanoyloxy - 11ss hydroxy - #1,4 - pregadiene - 3,20 - dione were obtained.
Example 28
(a) Under the conditions described in Example 25(b) 20 gms of llp,17cr dihydroxy - 21 - valeryloxy - #1,4 - pregnadiene - 3,20 - dione were reacted with lithium dimethyl cuprate and worked up, and 18.6 gms of 11ss,21 - dihydroxy - 17α - valeryloxy - #1,4 - pregnadiene - 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 11ss - hydroxy - 21 - propionyloxy - 17α - valeryloxy - #1,4 pregnadiene - 3,20 - dione were obtained.
(c) 9 gms of 11ss - hydroxy - 21 - propionyloxy - 17α - valeryloxy - #1,4 - 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 - 17α - valerloxy - #1,4,9(11) - pregnatriene - 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 9a - chloro - 11ss hydroxy - 21 - propionyloxy - 17cr - valeryloxy - A1,4 - pregnadiene - 3,20 - dione were obtained. Melting point: 242 C
Example 29
(a) 17.2 gms of 11ss,21 - dihydroxy - 17α - valeryloxy - #1,4 - pregnadiene 3,20 - dione, crude product, were reacted with valeric anhydride under the conditions described in Example 6 and worked up, and there were obtained 9.7 gms of 11ss - hydroxy - 17α,21 - divaleryloxy - #1,4 - pregnadiene - 3,20 - dione.
(b) 8 gms of 11ss - hydroxy - 17α,21 - divaleryloxy - #1,4 - 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 17α,21 divaleryloxy - #1,4,9(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 9α - chloro - 11ss hydroxy - 17α,21 - divaleryloxy - #1,4 - pregnadiene - 3,20 - dione were obtained.
Melting ponit: 254 C.
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 17α acetoxy - 9a - chloro - 11p,21 - dihydroxy - åa4 - pregnadiene - 3,20 - dione were then added to the mixture and the whole was stirred for a further 5 hours at 0 C.
The reaction mixture was worked up as described in Example 3 and 540 mg of 17α - acetoxy - 9α,21 - dichloro - 11ss - hydroxy - #1,4 - 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 9α - chloro
11ss,21 - dihydroxy - 17α - propionyloxy - #1,4 - pregnadiene - 3,20 - dione were reacted with thionyl chloride and worked up, and 860 mg of 9α,21 - dichloro 11,5 - hydroxy - 17cr - 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 17a - benzoyloxy 9α - chloro - 11ss,21 - dihydroxy - #1,4 - pregnadiene - 3,20 - dione were reacted
and worked up, and 4.1 gms of 17α - benzoyloxy - 9α,21 - dichloro - 11ss hydroxy - #1,4 - pregnadiene - 3,20 - dione melting at 2200C were obtained.
Example 33
(a) A suspension of 5.6 gms of 21 - fluoro - 17α - hydroxy - #1,4,8(11) - pregnatriene - 3,20 - dione in 80 ml of diethylene glycol dimethyl ether was stirred with 10 gms of N,N - dimethylamino - pyridine and 6.4 ml of acetic anhydride for 6.5 hours at 800C. The reaction mixture was diluted with methylene chloride and washed with 2N-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 17α - 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 N-chlorosuccinimide 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 chloride-acetone gradient - (0-10% of acetone). The yield was 1.3 gms of 17α - acetoxy - 9α - chloro - 21 - fluoro - 11ss - hydroxy A1,4 - pregnadiene - 3,20 - dione. Melting point: 232 C (with decomposition).
[α]D25=+52 (chloroform). UV: E239=15,100 (methanol).
Example 34
2 gms of 21 - fluoro - 17a - propionyloxy - #1,4,9(11). pregnatriene - 3,20 - dione, prepared in a manner analogous to thal describedin Example 33(a) from 21 fluoro - 17α - - hydroxy - #1,4,9(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 (010% of acetone). The yield was 1.24 gms of 9α - chloro - 21 - fluoro - 11ss - hydroxy - 17α - propionyloxy - #1,4 pregnadiene - 3,20 - dione.Melting point 221 C (with decomposition). [α]D25=+48 (chloroform). UV. #239=15,500 (methanol).
Example 35 1.5 gms of 17α - butyryloxy - 21 - fluoro - #1,4,9(11) - pregnatriene - 3,20 dione, prepared from 21 - fluoro - 17cr - hydroxy - #1,4,9(11) - pregnatriene - 3,20 dione and butyric anhydride in a manner analogous to that described in Example 33(a), were treated with N-chlorosuccinimide 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 a methylene chloride-acetone gradient (60-10% of acetone). The yield was 840 mg of 17cz - butyryloxy - 9a - chloro - 21 - fluoro 11ss - hydroxy - A1,4 - pregnadiene - 3,20 - dione.
Example 36
1 gm of 17α,21 - (1 - ethoxy - benzylidenedioxy) - 9α - chloro - 11ss
hydroxy - #1,4 - pregnadiene - 3,20 - dione prepared in a manner analogous to that described in Example l(a) was stirred in 40 ml of dimethylformamide with 4 ml of trimethylsilyl fluoride for 2 hours at room temperature. After precipitation in icewater 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 (010% of acetone). The yield was 240 mg of 17α - benzoyloxy - 9cr chloro - 21 - fluoro - 11ss - hydroxy - å14 - pregnadiene - 3,20 - dione.
Example 37
In a manner analogous to that described in Example 33(a) there were prepared from 5 gms of 21 - fluoro - 17α - hydroxy - #1,4,9(11) - pregnatriene - 3,20 - dione and isobutyric anhydride 4.8 gms of 21 - fluoro - 17α - isobutyryloxy - #1,4,9(11) pregnatriene - 3,20 - dione, which were reacted with N-chlorosuccinimide 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 (010% of acetone). The yield was 3.5 gms of 9α - chloro - 21 - fluoro - 11ss - hydroxy 17a - isobutyryloxy - åa4 - pregnadiene - 3,20 - dione.
Example 38
5 gms of crude 17α,21 - (I - ethoxy - ethylidenedioxy) - 9a - chloro - 11ss hydroxy - A1,4 - pregnadiene - 3,20 - dione, prepared from 9cr - chloroprednisolone and ortho-acetic 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 17α acetoxy - 9a,21 - dichloro - 11ss - hydroxy - #1,4 - pregnadiene - 3,20 - dione.
Melting point 2220C (with decomposition). [α]D25=+124 (pyridine). UV:
E239= 15,200 (methanol).
Example 39
2 gms of crude 17α,21 - (I - ethoxypropylidenedioxy) - 9α - chloro - lloX hydroxy - #1,4 - pregnadiene - 3,20 - dione, prepared from 9α chloropredisolone and ortho-propionic 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 9a,21 - dichloro - 11ss- hydroxy - 17α - - propionyloxy - #1,4 - pregnadiene - 3,20 - dione were isolated, which were purified by recrystallization from acetone/hexane.Melting point: 232 C. [α]D25=+78 (chloroform). UV: #239=15,200 (methanol).
EXAMPLE 40
(a) 2 gms of 21 - fluoro - 17α - hydroxy - #1,4,9(11) - pregnatriene - 3,20 dione were added to a mixture of 20 ml of isovaleric acid and 8 ml of trifluoroacetic anhydride and then the whole was stirred for 2 hours at 80 C. The whole was then added to warm water in oder to decompose the excess of the anhydride, and then extraction was carried out with methylene chloride. After neutralization with 1% pyridine/water and drying over sodium sulphate evaporation was carried out in vacuo. 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 - 17α - isovaleryloxy - #1,4,9(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 (0-10% of acetone). The yield was 580 mg of 9α - chloro - 21 - fluoro - 11ss - hydroxy - 17α - isovaleryloxy - #1,4 pregnadiene - 3,20 - dione.
Example 41
In a manner analogous to that described in Example 33(a) 2 gms of 21 fluoro - 17α - hydroxy - #1,4,9(11) - pregnatriene - 3,20 - dione and trimethylacetic anhydride were reacted together to form 1.6 gms of 21 - fluoro - 17α - trimethylacetoxy - #1,4,9(11) - pregnatriene - 3,20 - dione, and the crude product was treated with N - chlorosuccinimide 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 metylene chlorideacetone gradient (0-10% of acetone). 810 mg of 9α - chloro - 21 - fluoro - 11ss - hydroxy - 17α trimethylacetoxy - #1,4 - pregnadiene - 3,20 - dione were obtained.
Example 42
The composition of a salve.
0.03% of 21 - acetoxy - 9α - chloro - 11ss - hydroxy - 17α - propionyloxy #1,4 - pregnadiene - 3,20 - dione.
2.50% of Allercur hexachlorophenate, micronized, particle size about 8,u (Allercur=Registered 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 Registered Trade Mark)
16 0.10% of sorbic acid
10.00% of neutral oil (Miglyol 812, Miglyol being a Registered Trade Mark)
3.50% of stearyl alcohol
1.50% 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 - 9α - chloro - 11ss - hydroxy - 17α propionyloxy - #1,4 - pregnadiene - 3,20 - dione (average particle size smaller than 7 ) and 39.000 gms of ground lactose were mixed together. A dose of 20 mg of inhalant preparation, per inhalation, is used.
WHAT WE CLAIM IS:
1. A compound of the general formula I
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (54)
1. A compound of the general formula I
in which
R, represents an alkanoyl group containing 1 to 8 carbon atoms or a benzoyl group, and
X represents a fluorine atom, a chlorine atom, an 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 atoms.
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. 17α - Benzoyloxy - 9α - chloro - 21 - formyloxy - 11ss - hydroxy - #1,4 pregnadiene - 3,20 - dione.
7. 21 - Acetoxy - 17α - benzoyloxy - 9α - chloro - 11ss - hydroxy - #1,4 pregnadiene - 3,20 - dione.
8. 17α - Benzoyloxy - 9α - chloro - 11ss - hydroxy - 21 - propionyloxy #1,4 - pregnadiene - 3,20 - dione.
9. 17α - Benzoyloxy - 21 - butyryloxy - 9α - chloro - 11ss - hydroxy - #1,4 pregnadiene - 3,20 - dione.
10. 17cr - Benzoyloxy - 9a - chloro - 11/3 - hydroxy - 21 - valeryloxy åW4 - pregnadiene - 3,20 - dione.
11. 17α - Benzoyloxy 9α - chloro - 11ss - hydroxy - 21 - trimethylacetoxy #1,4 - pregnadiene - 3,20 - dione.
12. 17α - Benzoyloxy - 9α - chloro - 11ss - hydroxy - 21 - isobutyryloxy #1,4 - pregnadiene - 3,20 - dione.
13. 17α - Benzoyloxy - 9α - chloro - 11ss - hydroxy - 21 - isovaleryloxy #1,4 - pregnadiene - 3,20 - dione.
14. 17α - Benzoyloxy - 9α - chloro - 21 - heptanoyloxy - 11ss - hydroxy #1,4 - pregnadiene - 3,20 - dione.
15. 17α,21 - Dibenzoyloxy - 9α - chloro - 11ss - hydroxy - #1,4 pregnadiene - 3,20 - dione.
16. 17α,21 - Diacetoxy - 9α - chloro - 11ss - hydroxy - #1,4 - pregnadiene 3,20 - dione.
17. 17α - Acetoxy - 9α - chloro - 11ss - hydroxy - 21 - propionyloxy - #1,4 pregnadiene - 3,20 - dione.
18. 17α - Acetoxy - 9α - chloro - 11ss - hydroxy - 21 - valeryloxy - #1,4 pregnadiene - 3,20 - dione.
19. 9a - Chloro - 21 - formyloxy - 11ss - hydroxy - 17α - propionyloxy #1,4 - pregnadiene - 3,20 - dione.
20. 21 - Acetoxy - 9α - chloro - 11ss - hydroxy - 17α - propionyloxy - #1,4 pregnadiene - 3,20 - dione.
21. 9α - Chloro - 11ss - hydroxy - 17α,21 - dipropionyloxy - #1,4 pregnadiene - 3,20 - dione.
22. 21 - Butyryloxy - 9α - chloro - 11ss - hydroxy - 17α - propionyloxy #1,4 - pregnadiene - 3,20 - dione.
23. 9α - Chloro - 11ss - hydroxy 17α - propionyloxy - 21 - valeryloxy #1,4 - pregnadiene - 3,20 - dione.
24. 9α - Chloro - 21 - hexanoyloxy - 11ss - hydroxy - 17α - propionyloxy #1,4 - pregnadiene - 3,20 - dione.
25. 9α - Chloro - 21 - heptanoyloxy - 11ss - hydroxy - 17α - propionyloxy #1,4 - pregnadiene - 3,20 - dione.
26. 9α - Chloro - 11ss - hydroxy - 17α - propionyloxy - 21 trimethylacetoxy - #1,4 - pregnadiene - 3,20 - dione.
27. 21 - Acetoxy - 17α - butyryloxy - 9α - chloro - 11ss - hydroxy - #1,4 pregnadiene - 3,20 - dione.
28. 17α Butyryloxy - 9α - chloro - 11ss - hydroxy - 21 trimethylacetoxy - #1,4 - pregnadiene - 3,20 - dione.
29. 17α - Butryloxy 9α - chloro - 21 - heptanoyloxy - 11ss - hydroxy #1,4 - pregnadiene - 3,20 - dione.
30. 9a - Chloro - 11ss - hydroxy - 21 - propionyloxy - 17cr - valeryloxy #1,4 - pregnadiene - 3,20 - dione.
31. 9α - Chloro - 11ss - hydroxy 17α,21 - divaleryloxy - #1,4 - pregnadiene 3,20 - dione.
32. 17α - Acetoxy - 9α,21 - dichloro - 11ss - hydroxy - #1,4 - pregnadiene 3,20 - dione.
33. 9α,21 - Dichloro - 11ss - hydroxy - 17α - propionyloxy - #1,4 pregnadiene - 3,20 - dione.
34. 17α - Benzoyloxy - 9α,21 - dichloro - 11ss - hydroxy - #1,4 pregnadiene - 3,20 - dione.
35. 17α - Acetoxy - 9α - chloro - 21 - fluoro - 11ss - hydroxy - #1,4 pregnadiene - 3,20 - dione.
36. 9α - Chloro - 21 - fluoro - 11ss - hydroxy - 17α - propionyloxy - #1,4 pregnadiene - 3,20 - dione.
37. 17α - Butyryloxy - 9α - chloro - 21 - fluoro - 11ss - hydroxy - #1,4 pregnadiene - 3,20 - dione.
38. 17α - Benzoyloxy - 9α - chloro - 21 - fluoro - 11ss - hydroxy - #1,4 pregnadiene - 3,20 - dione.
39. 9α - Chloro - 21 - fluoro - 11ss - hydroxy - 17α - isobutyryloxy - #1,4 pregnadiene - 3,20 - dione.
40. 9α - Chloro - 21 - fluoro - 11ss - hydroxy - 17α - isovaleryloxy - #1,4 pregnadiene - 3,20 - dione.
41. 9cr - Chloro - 21 - fluoro - Il,B - hydroxy - 17cr - trimethylacetoxy A1,4 - pregnadiene - 3,20 - dione.
42. A pharmaceutical preparation which comprises a compound as claimed in claim 1, in admixture or conjunction with a pharmaceutically suitable carrier.
43. A pharmaceutical preparation which comprises a compound as claimed in any one of claims 2 to 5, in admixture or conjunction with a pharmaceutically suitable carrier.
44. A pharmaceutical preparation which comprises the compound claimed in any one of claims 6 to 41, in admixture or conjunction with a pharmacutically suitable carrier.
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.
46. A preparation as claimed in any one of claims 42 to 44, which is in the form of a solution, lotion. salve, cream or plaster.
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 range of from 0.001% to 1% by weight.
48. A preparation as claimed in any one of claims 42 to 44, which is in the form of an inhalant preparation.
49. A pharmaceutical preparation having a composition substantially as described in Example 42 or 43 herein.
50. A process for the manufacture of a compound of the general formula I
in which
R, represents an alkanoyl group containing 1 to 8 carbon atoms or a benzoyl group, and
X represents a fluorine atom, a chlorine atom, an alkanoyloxy group containing 1 to 8 carbon atoms or a benzoyloxy group, wherein
(a) HOCI is added at the å9-" - double bond of a 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
in which R, and X have the meanings given above, is opened up with hydrogen chloride, or
(c) when X represents a fluorine or chlorine atom, an ortho-ester of the general formula IV
in which R3 represents a hydrogen atom, an alkyl group containing 1 to 7 carbon atoms or a phenyl group and R2 represents an alkyl group containing 1 to 4 carbon atoms, 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
in which R, has the meaning given above, is chlorinated or esterified at the 21position.
51. A process as claimed in claim 50, conducted substantially as described in any one of Examples 2 to 11, 13 to 15 and 17 to 32 herein.
52. A process as claimed in claim 50, conducted substantially as described in any one of Examples 33, 36, 40 and 41 herein.
53. A process as claimed in claim 50, conducted substantially as described in any one of Examples 34, 35 and 37 herein.
54. A process as claimed in claim 50, conducted substantially as described in
Example 38 or 39 herein.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1594852A true GB1594852A (en) | 1981-08-05 |
Family
ID=25770978
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB40924/77A Expired GB1594852A (en) | 1976-10-04 | 1977-10-03 | Derivatives of 9-chloroprednisolone |
Country Status (21)
| Country | Link |
|---|---|
| JP (1) | JPS5359654A (en) |
| AT (1) | AT358202B (en) |
| CH (4) | CH630098A5 (en) |
| DK (1) | DK438277A (en) |
| ES (1) | ES462887A1 (en) |
| FI (1) | FI58645C (en) |
| FR (1) | FR2366313A1 (en) |
| GB (1) | GB1594852A (en) |
| GR (1) | GR73041B (en) |
| HU (1) | HU179593B (en) |
| IE (1) | IE45877B1 (en) |
| IL (1) | IL53030A (en) |
| IT (1) | IT1113623B (en) |
| LU (1) | LU78223A1 (en) |
| NL (1) | NL7710869A (en) |
| NO (1) | NO148597C (en) |
| NZ (1) | NZ185295A (en) |
| PL (1) | PL110392B1 (en) |
| PT (1) | PT67109B (en) |
| SE (1) | SE431655B (en) |
| SU (2) | SU743581A3 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| US9861631B2 (en) | 2010-03-26 | 2018-01-09 | Galderma Laboratories, L.P. | Methods and compositions for safe and effective treatment of erythema |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2853785A1 (en) * | 1978-12-11 | 1980-06-19 | Schering Ag | NEW PREDNISON DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS AND THE USE THEREOF |
| JPH0374245A (en) * | 1989-08-12 | 1991-03-28 | Mk Seiko Co Ltd | car wash machine |
| CN106632561A (en) * | 2016-12-16 | 2017-05-10 | 广州仁恒医药科技股份有限公司 | Method for preparing difluprednate |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1195748B (en) * | 1961-06-24 | 1965-07-01 | Vismara Francesco Spa | Process for the preparation of 1'-substituted 17alpha, 21- (1'-alkoxy) -methylenedioxysteriodes |
| DE2055221A1 (en) * | 1970-11-10 | 1972-05-18 | Laboratorio Chimico Farmaceutico Dr. P. Blasina S.R.L., Mailand (Italien) | 17-acyloxy-3-keto-pregn-4-enes prepn - by acylating 17-hydroxy steroids in presence ofstannic chloride |
-
1977
- 1977-09-29 NZ NZ185295A patent/NZ185295A/en unknown
- 1977-09-30 PL PL1977201161A patent/PL110392B1/en unknown
- 1977-09-30 IL IL53030A patent/IL53030A/en unknown
- 1977-09-30 CH CH1199177A patent/CH630098A5/en not_active IP Right Cessation
- 1977-10-03 NO NO773362A patent/NO148597C/en unknown
- 1977-10-03 SE SE7711039A patent/SE431655B/en not_active IP Right Cessation
- 1977-10-03 HU HU77SCHE624A patent/HU179593B/en unknown
- 1977-10-03 IE IE2011/77A patent/IE45877B1/en unknown
- 1977-10-03 PT PT67109A patent/PT67109B/en unknown
- 1977-10-03 GB GB40924/77A patent/GB1594852A/en not_active Expired
- 1977-10-03 LU LU78223A patent/LU78223A1/xx unknown
- 1977-10-03 GR GR54473A patent/GR73041B/el unknown
- 1977-10-03 AT AT703577A patent/AT358202B/en not_active IP Right Cessation
- 1977-10-03 IT IT28201/77A patent/IT1113623B/en active
- 1977-10-04 FI FI772922A patent/FI58645C/en not_active IP Right Cessation
- 1977-10-04 DK DK438277A patent/DK438277A/en not_active Application Discontinuation
- 1977-10-04 FR FR7729740A patent/FR2366313A1/en active Granted
- 1977-10-04 SU SU772526300A patent/SU743581A3/en active
- 1977-10-04 NL NL7710869A patent/NL7710869A/en not_active Application Discontinuation
- 1977-10-04 JP JP11940077A patent/JPS5359654A/en active Granted
- 1977-10-04 ES ES462887A patent/ES462887A1/en not_active Expired
-
1978
- 1978-10-13 SU SU782672298A patent/SU751327A3/en active
-
1981
- 1981-09-08 CH CH579281A patent/CH632772A5/en not_active IP Right Cessation
- 1981-09-08 CH CH579481A patent/CH631997A5/en not_active IP Right Cessation
- 1981-09-08 CH CH579381A patent/CH632278A5/en not_active IP Right Cessation
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9861631B2 (en) | 2010-03-26 | 2018-01-09 | Galderma Laboratories, L.P. | Methods and compositions for safe and effective treatment of erythema |
| US9861632B2 (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 |
|---|---|
| FR2366313A1 (en) | 1978-04-28 |
| IT1113623B (en) | 1986-01-20 |
| ATA703577A (en) | 1980-01-15 |
| SE7711039L (en) | 1978-04-05 |
| AT358202B (en) | 1980-08-25 |
| JPS5359654A (en) | 1978-05-29 |
| JPS6129960B2 (en) | 1986-07-10 |
| NL7710869A (en) | 1978-04-06 |
| FI772922A7 (en) | 1978-04-05 |
| CH630098A5 (en) | 1982-05-28 |
| CH632772A5 (en) | 1982-10-29 |
| ES462887A1 (en) | 1978-12-16 |
| FR2366313B1 (en) | 1980-02-01 |
| PL110392B1 (en) | 1980-07-31 |
| FI58645C (en) | 1981-03-10 |
| CH631997A5 (en) | 1982-09-15 |
| NO148597C (en) | 1983-11-09 |
| PL201161A1 (en) | 1979-01-29 |
| PT67109B (en) | 1979-03-14 |
| IE45877L (en) | 1978-04-04 |
| LU78223A1 (en) | 1978-02-01 |
| HU179593B (en) | 1982-11-29 |
| IL53030A0 (en) | 1977-11-30 |
| CH632278A5 (en) | 1982-09-30 |
| IL53030A (en) | 1982-11-30 |
| DK438277A (en) | 1978-04-05 |
| NZ185295A (en) | 1980-04-28 |
| SE431655B (en) | 1984-02-20 |
| SU743581A3 (en) | 1980-06-25 |
| GR73041B (en) | 1984-01-26 |
| IE45877B1 (en) | 1982-12-15 |
| PT67109A (en) | 1977-11-01 |
| FI58645B (en) | 1980-11-28 |
| NO148597B (en) | 1983-08-01 |
| SU751327A3 (en) | 1980-07-23 |
| NO773362L (en) | 1978-04-05 |
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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 |
Effective date: 19941003 |