AP157A - Novel steroid derivatives. - Google Patents

Abstract

The invention relates to novel

Description

The invention relates to novel Δ -16o<, 17-dihydroxypregnane-16,17-cyclic aldehyde acetal and -cyclic ketone ketal derivatives of general formula (I),

A stands for hydrogen or hydroxyl group;

X stands for hydrogen or halogen with the proviso that if A is hydrogen, then X also means hydrogen;

R stands for hydrogen, benzoyl or C^_galkanoyl group;

2

R and R , which are the same or different, stand for 1 2 hydrogen or a C^^alkyl group; or one of R and R is 1 2 hydrogen and the other is phenyl group; or R and R together form a C^^alkylene group;

--- means a single or double bond between two adjacent carbon atoms, and pharmaceutical compositions containing a physiologically effective dose of these compounds and a process for preparing these compounds and compositions. Furthermore, the invention relates to a method of treatment, which comprises using these compounds or compositions.

The steroid derivatives according to the invention possess highly effective antiinflammatory properties and

AP 0 0 0 1 5 7 therefore they can be used as active ingredients in antiinflammatory compositions.

As used herein: halogen means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine;

C^_galkanoyl means formyl, acetyl, propionyl or any of the various butiryl, valeryl, hexanoyl, heptanoyl or octanoyl groups: in addition to the above groups, acyl involves benzoyl group, too. Cz^alkanoic acids mean acetic, propionic, n- and isobutyric acid.

It was shown by biological investigations carried out as early as in the 50's /3. Am. Chem. Soc. 78 , 1909 (1956)./ that 16<x-hydroxycorticoids have the same or higher antiinflanmatory effects in comparison with those of the native accenal cortex hormones, e.g. hydrocortisone whereas their harmful sodium-retaining (mineralocorticoid) action influencing the electrolyte household of the organism is practically negligible /3. Am. Chem. Soc. 81, 1689 (1959)7The antiinflammatory effect of the corticoid

16<<, 17-cycl ic alcehyde acetals formed from 16o<, 17-dihydroxycorticoids is e . en higher than that of the mother compounds /United States c a t e n t specification No. 3,197,468; and

3. Am. Chem. Set. 80 , 2338 (1958)7- One of these is ( 22RS)-11/3,21-d m;. droxy- 16X, 17-butyl idenedioxypregna* „

1, 4-dien-3,20-d: me (hereinafter: budesonide) a drug used in the therareutical practice /Arzneim.-Forsch. 29,

1687 (1979)7.

Although a number of 16,17-cyclic aldehyde acetals and -cyclic ketone ketals became known in the 14 literature in the course of many years, no & -pregnane derivative has been described.

According to the literature, steroidal 16,17-cyclic aldehyde acetals or ketone ketals can be prepared by reacting the corresponding 16,17-dihydroxycorticoid derivatives with an aldehyde or ketone, respectively, in the presence of an acid catalyst. /German patent specification (DE-PS) No. 1,131,213 and published German patent application (DE-OS) No. 1,118,779; British patent specifications Nos. 916,996 and 933,867; Unites States patent specifications Nos. 3,197,469 and 3,798,216; as well as Hungarian patent specification No. 166,680.7. This reaction is carried out in the presence of a solvent or in an excess of the oxo compound used as reactant.

According to the Hungarian patent specification No. 195,519 cyclic orthoesters of the corresponding 16,17-dihydroxycorticoid derivatives are reacted with oxo compounds .

According to an other aspect of the invention, there is provided a process for the preparation of the new compounds of general formula (I), which comprises

a) reacting a ^-16^, 17-dihydroxypregnane derivative *

of general formula (II), in

Q.

<

(Π) wherein A, X, R and the symbol (bond line) ---- are as defined above, with an oxo compound of general formula (IV), /R’

O=c dv) ^R²

2 wherein R and R are as defined above, in the presence of an acid catalyst;

or

b) reacting a Δ -16<k, 17-dihydroxypregnane cyclic orthoester derivative of general formula (III),

(III) wherein A, X, R and the symbol (bond line) ---- are as defined above and R^ stands for a methyl or ethyl group, with an oxo compound of general formula (IV), (IV) o=c

Ri

R²

2 wherein R and R are as defined above, in the presence of an acid catalyst, then, if desired, hydrolyzing the - 16o(, 17-dihydroxypregnane-16 ,17-cycl ic aldehyde acetal or -cyclic ketone ketal derivatives, respectively, of general formula (I),

(I)

2 wherein A, X, R , R and the symbol (bond line) ---- are as defined above, obtained in process a) or b\ to obtain

Δ -I6o<, I7-dihydroxypregnane-16,17-cyclic aldehyde acetals or -cyclic ketone ketals containing hydrogen as R;

and/or, if desired, acylating the thus obtained compounds of general formula (I), wherein R means hydrogen to obtain compounds of general formula (I),

wherein R represents an acyl group.

(I)

The ^⁴-16oC 17-dihydroxypregnane derivatives of general formula (II)

(II) used as starting substances in the process according to the present invention can be prepared by the permanganate oxidation of the corresponding ^^-pregnane derivatives by using the process described in our Hungarian patent application paralelly filed under

No. 1156/89. The Δ -I6o(, 17-dihydroxypregnane cyclic orthoester derivatives of general formula (III)

can be prepared analoguously as described in the Hungarian patent specification No. 195,519. The oxo compaunds of the general formula (IV) (III) o=c

Ri r2 (IV) used as reactants are known and commercially available ketones and aldehydes.

According to a practical embodiment of process a) of the invention the corresponding oxo compound of general formula (IV) is dissolved in a polar or apolar aprotic solvent. Benzene, tetrahydrofuran, dioxan, ethyl acetate, dichloromethane or acetonitrile and the like may be used for this purpose. An acid catalyst is added to the oxo compound of general formula (IV) dissolved in any of the selected solvents or in a mixture thereof. Suitable acid catalysts are e.g. sulfuric, hydrochloric, perchloric, p-toluene-sulfonic or methanesulfonic acid or an organic acid such as trifluoroacetic acid. The temperature of the reaction mixture is suitably maintaine between 10 °C and 40 °C during the addition and in the course of the reaction. To the reactant prepared as described above, the Δ^-16β<., 17-dihydroxypregnane derivatives of general formula (II) to be transformed are added in a solid form or dissolved suitably in a solvent used for the preparation of the above reactant. The cource of the reaction can be followed by thin layer chromatography (TLC). The formation of the cyclic acetal or ketal usually proceeds within 5 to 120 minutes. After termination of the reaction the mixture is suitably • «· worked up in such a way that aqueous alkaline metal carbonate or hydrogen carbonate solution is added to the reaction mixture in order to neutralize the acid

APO00157 employed as catalyst. The system thus obtained is extracted with a water-immiscible solvent such as ethyl acetate or dichloromethane and after drying the solvent phase and evaporation, the product obtained is recrystallized.

Process b) according to the invention is essentially carried out in the same way as described in process a) apart from the starting substances.

When it is aimed to prepare a derivative containing 10 hydrogen as R from the thus obtained pregnane derivative of general formula (I) containing an acyl group as R, the acyl group can be removed by hydrolysis. This reaction is suitably carried out in such a way that the acyl derivative obtained in the ketal forming reaction is dissolved in a protic water-miscible solvent, suitably in methanol and hydrolyzed by using an aqueous acid or alkali. It is suitable to carry out the hydrolysis by employing acid catalysis; aqueous perchloric acid is preferably be used for this purpose. The hydrolysis of derivatives containing benzoyl group as R may preferably be accomplished by using an aqueous alkaline metal hydroxide solution. The optional subsequent acylation can be carried out in a manner known per se

The Δ^-16<Κ, 17-dihydroxypregnane derivatives of * _e general formula (I)

according to the invention possess valuable glucocorticoid effects.

Two principal (essential) demands are set up against topically used steroid antiinflammatory drugs: a) they 5 should be as active as possible in various animal experiments used for investigating the antiinflammatory action; and b) they should induce the lowest harmful systemic side effect. This latter effect can be well characterized by the thymus weight-decreasing action 10 (involution). The possibly lowest toxicity (i.e the possibly highest LD^g value) is an essential demand for any active agent (drug) used in the therapy.

The tests used for investigation of the antiinflammatory action of the compounds according to the 15 invention are described hereinafter. Budesonide was used as reference drug in these tests.

1) Comparative study on the acute toxicity

Animal groups consisting of 10 CFLP mice or RG Hann

Wistar rats each of both sexes were used. The doses 20 causing the death of 50¾ of the animals (LD^g values) within a 2-week observation period following subcutaneous (s.c.) or oral (p.o.) administration were determined.

AP 0 0 0 1 5 7

2) The croton oil-induced contact dermatitis model /Endocrinology 77 , 625 ( 1965 ); Toxicol. Appl. Pharmacol. 20, 552 ( 1971 )7.

Infantile female rats weighing 45 to 55 g were 5 used. Animals had previously been selected for this test, the ear weight of which increased at least by 100¾ under effect of a treatment with 2¾ croton oil.

The test compounds were dissolved in a 2¾ croton oil mixture in various concentrations and then applied onto the ears of the animals. The control group was treated only with the croton oil inducing inflammation. Six hours after treatment the ears of the animals were cut off and weighed. For evaluation, the diminution of the ear weight increase was expressed as percentage of inhibition, in comparison to the control treated with croton oil only. In the 48th hour the thymi of the animals were excised and the harmful systemic side effect of the test compounds was evaluated by comparing their thymus weight to that of the control animals.

3) The local granuloma sac model /Recent Progr. Hormone Res. 8_, 117 (1953);

Arzneim.-Forsch. 27 , 11 (1977)7This method was used to investigate the anti-exudative action of the topically administered glucocorticoids.

Groups consisting of 10 female RG Hann Wistar rats each weighing 130 to 150 g were used. After shaving the back of the animals 25 ml of air were injected beneath the back skin and 1 ml of 2¾ croton oil inducing inflammation was introduced to the air sac. After 5 days the content of the sac was sucked off and once 3 doses each of the glucocorticoids to be tested or budesonide respectively, in a volume of 0.5 ml suspension in Tween 80 were administered by an injection syringe. On the 10th day following the start of the experiment the animals were sacrificed and the exudate liquid of the sac (expressed as ml) was measured. The percentage of the antiinflammatory effect was calculated based on the decrease in the volume of exudate related to that of the control.

Then, the thymi of the animals were excised and 15 the harmful systemic side effect of the test compounds was calculated as percentage based on the comparison of the thymus weight of animals treated with the test compounds to that of the untreated control group.

A) The experimental asthma model

ZBr. 0. Pharmac. 76, 139 (1982)7

This test was used to investigate the antiasthmatic effect of the test compounds.

It is known that by ovalbumin (0A) treatment an experimental asthma can be induced on guinea-pigs 25 which is accompanied by dyspnoea and causes the death of the animals in severe cases. This test is useful to detect an eventual antiasthmatic effect of the test compounds .

Guinea-pigs of both sexes weighing 300 to 400 g each were used. The experimental animals were sensitized by i.p. ovalbumin (lO^ug of 0A + 100 mg of aluminum hydroxide/animal) and after 30 days they were provoked by the intravenous (i.v.) administration of 100 mg/kg of 0A. Both the test compounds and budesonide used as reference substance were given 50 mg/kg i.p. dose 20 hours before the provocation. The percentage

3* 10 occurance of dyspnoea and the survival were observed.

The above investigations gave the following results (N means the number of animals within one group).

1) Comparative acute toxicity _

Species Sex Route of Budesonide Compound of Compound of admin. LD_sn (mg/kg) Ex. No. 2 Ex. No. 6 _t-0₅₀ (mg/kg) LD₅₀ (mg/kg)

Mouse male s.c. 131.08 584.89 332.82

Mouse male p.o. 1078.82 >4000 2926.07

Mouse female s.c. 109.18 823.14 634.49 ²⁰ Mouse female p.o. 1356.57 >4000 2789.21

Rat male s.c. 59.44 1208.94 161.52

Rat male _ p_:o_L_ _ 3395.89 __ >4000_____>4000

Rat female s.c. 71.50 842.60 163.53

2; Croton oil-induced contact dermatitis

Compound Concentration N Ear weight Inhibition Relative Thymus (/ug/ml) (mg) (\) activity involution

W

Untreated	0	58	76.82+1.1		—
Provoked control	0	58	161.08+2.3	-	-	-
Budesonide	1	28	144.71+2.0	19.43		9.2
Budesonide	10	28	127.78+2.0	39.53	100	3.9
Budesonide	100	28	117.07+2.7	52.24		26.1
Ex. No. 2	1	20	144.60+2.8	19.56		0
Ex. No. 2	10	20	131.10+2.7	35.59	78	0
Ex. No. 2	100	20	118.20+2.2	50.90		9.8
Ex. No. 6	1	20	144.40+3.5	19.80		0
Ex. No. 6	10	20	126.90+2.7	40.57	118	1.7
Ex. No. 6	100	20	115.10+2.6	54.57		0
3) Antiinflammatory	effect on the	loca 1	granuloma	sac

model

AP 0 0 0 1 5 7

Compound	Dose (/ug/sac)	N	Exudate (ml)	Inhibition Relative Thymus
(¾)	activity	involution (%)
Control	0	82	12.73+0.4	-	-	-
Budesonide	0.22	18	6.38+0.4	49.89		0
Budesonide	2.00	19	4.00+0.3	68.58	100	0
3udesonide	18.00	19	1.04+0.5	85.55		24.43
Ex. No. 2	0.22	18	7.47+0.5	41.32		0
Ex. No. 2	2.00	19	5.10+0.4	59.94	62	0
Ex. No. 2	18.00	18	1.36+0.2	89.32		0
Ex .‘No. 6	0.22	17	6.52+0.6	48.79		4.98
Ex. No. 6	2.00	18	5.08+0.4	60.10	71	4.98
Ex. No. 6	18.00	18	1.69+0.3	86.73		6.22

4) The experimental asthma model

Compound	Dyspnoea CO.	Survival (%)
Control	33	66
Budesonide	20	60
Ex. No. 2	14	43
Ex. No. 6	0	100

It is unambiguously evident from the results of the above investigations that the novel Δ^-16<*,1710 dihydroxypregnane derivatives of general formula (I)

according to the invention exert a highly significant local (topical) antiinflammatory and antiasthmatic effect approaching that of the reference drug and both their harmful systemic effect (thymus involution) and toxicity are lower than those of budesonide.

The invention is illustrated in detail by the following non limiting Examples. The ratios defined for the solvent mixtures mean volume ratios.

Example 1

Preparation of lly$,16«<,17,21-tetrahydroxypregna4.14- dien-3,20-dion-16,17-eye 1 ic butyraldehyde acetal

0,4 g (0.951 mmol) of 11/5,16it, 17,21-tetrahydroxypregna-4,14-dien-3,20-dion-21-acetate is dissolved in a mixture containing 0.17 ml (1.90 mmol) of butyraldehyde, ml of acetonitrile and 0.17 ml of 70¾ oerchloric acid. Both the weighing-in and the reaction are carried out under nitrogen. After 10 minutes 4 ml of 5¾ potassium hydrogen carbonate solution are added to the reaction mixture and the neutralized solution is extracted with ethyl acetate. After drying the extract is evaporated under reduced pressure. The oily evaporation residue is dissolved in 6 ml of methanol under nitrogen and after adding 0.4 ml of 60¾ aqueous perchloric acid it is left to stand at room temperature for 10 hours. The mixture is poured into 200 ml of water, the crude product obtained is first recrystallized from a mixture of dichloromethane and n-hexane and then from anhydrous ethanol to obtain 0.35 g (05¾) of the title compound.

According to the HPLC (high performance liquid chromatography) analysis the purity of the above product is 98¾. m.p.: 96-101 °C.

Example 2

Preparation of 11/5,16<<, 17,21-tetrahycJroxypregna1.4.14- trien-3,20-dion-16,17-cyclic butyraldehyde acetal

After weighing in 3.5 ml of 70¾ perchloric acid and

3.5 ml of redistilled butyra ldehyde into 160 ml of acetonitrile under dry nitrogen, 8.00 g (0.0191 mol) of 11/5,16o<, 17,21-tetrahydroxypregna-l, 4, l4-trien-3, 20dion-21-acetate are portionwise added under stirring during 10 minutes. The steroid substance is immediately dissolved. After stirring the solution at room temperature for 30 minutes (the progress of the reaction is observed by using TLC analysis). The reaction mixture is poured into 80 ml of 5% potassium hydrogen carbonate solution and then extracted with 80 ml of ethyl acetate. After washing the extract with water up to neutral and then shaking with concentrated sodium chloride solution it is dried over anhydrous sodium sulfate and evaporated under reduced pressure until it becomes free from the solvent.

After dissolving the evaporation residue in 120 ml of methanol under nitrogen 8 ml of 70% aqueous perchloric acid are dropwise added to the solution. The reaction mixture is stirred at room temperature for 0 hours and then poured into 1600 ml of water. After stirring for 1 hour it is filtered to give 7.95 g (96.59%) of the title compound. This product is purified by suspending in 20 volumes of an 1:5 dichloromethane/n-hexane mixture and recrystallizing from an 1:4 mixture of ethanol and water. In this way a pure title compound is obtained, m.p.: 131-134 °C (decomposition at 205 °C, ζ'ο</πθ= +0.69° (dichloromethane, c = l).

IR spectrum ( V , cm ^): 3420 (-0H), 1722 (20-oxo),

1657 (3-oxo), 1614 and 1598 (C=C).

Example 3

Preparation of 11/¾. 16c<, 17,21-tetrahydroxypregna5 1, 4 , l4-trien-3,20-dion-16,17-cyclic butyraldehyde acetal

0.5 ml of 70¾ perchloric acid and 0.5 ml of redistilled butyraldehyde are added to 20 ml of acetonitrile under dry nitrogen, then 1.00 g of ll/5,16«<,17,21-tetrahydroxypregna-l,4,14-trien-3,20-dione is added in little portions during 10 minutes while stirring. The reaction proceeds within 15 minutes. Then the reaction mixture is poured into 2000 ml of water, stirred for 1 hour and filtered. The crude title product thus obtained is purified as described in the preceding

Example to obtain 1.05 g (91.8¾) of pure title compound,

m.p. : 130-133 °C.

Example 4

Preparation of 11/h, 16o<, 17,21-tetrahydroxypregna 1, 4 , l4-trien-3,20-dion-16,17-cyclic acetaldehyde acetal

After introducing 2.2 ml of 70¾ perchloric acid and 1.3 ml of acetaldehyde into 100 ml of acetonitrile under dry nitrogen, 5.00 g of 11/5,16o<, 17,21-tetrahydroxypregna-1,4,14-trien-3,20-dion-21-acetate are added in several little portions under stirring. The 21-acetoxy derivative of the cyclic acetal is first recovered as described in Example 1 which is then hydrolyzed to give

4.61 g (95.87¾) of the title product, m.p.: 169-173 °C.

AP 0 0 0 1 5 7

Example 5

Preparation of ll/5,16e^,17,21-tetrahydroxypregna1.4.14- trien-3,20-dion-16,17-cyclic benzaldehyde acetal

After introducing 2.2 ml of 70% perchloric acid and 2.4 ml of redistilled benzaldehyde into 100 ml of acetonitrile under dry nitrogen, 5.00g of 11/5,16d, 17,21tetrahydroxypregna-l,4,14-trien-3,20-dion-21-acetate are added in several little portions under stirring. The 21-acetoxy derivative of the cyclic acetal is first recovered as described in Example 1 which is then hydrolyzed to obtain 4.92 g (90.99%) of the title compound, m.p.: 228-233 °C.

Example 6

Preparation of 11β, 16X, 17,21-tetrahydroxypregna1.4.14- trien-3,20-dion-16,17-cyclic isobutyraldehyde aceta1

5.0 g of 11/i, 16«t, 17,21-tetrahydroxypregna-l, 4,14trien-3,20-dion-21-acetate are dissolved in a mixture containing 100 ml of acetonitrile, 2.2 ml of 70% perchloric acid and 2.2 ml of isobutyraldehyde. Both the weighing-in operations and the reaction are carried out under nitrogen.

The 21-acetoxy derivative of the cyclic acetal is first recovered as described in Example 1, then the 21-acetoxy group is hydrolyzed to result in the free hydroxyl group by using aqueous perchloric acid solution to give 4.97 g (96.68%) of the title compound, m.p.:

132-136 °C, /<Χ/θ = +0.607° (dichloromethane, c = l).

IR spectrum ( V , cm ^): 3416 (-0H), 1720 (20-oxo),

1657 (3-oxo), 1618 and 1588.

Example 7

Preparation of 11£, 16ct, 17,21-tetrahydroxypregna1, 4 ,14-1rien-3,20-dion-16,17-cyclic acetonide 21-acetate g (0.0239 mol) of ll_z1j,l6o<,17,21-tetrahydroxypregna1.4.14- trien-3,20-dion-21-acetate are transformed to a paste with 125 ml of acetone under dry nitrogen at room temperature while stirring. Parallelly, 1.6 ml of concentrated sulfuric acid are slowly dropped to 1.0 ml of 70¾ aqueous perchloric acid under cooling and stirring in an other flask. The anhydrous perchloric acid thus prepared is added to the suspension of the steroid in acetone. The steroid is dissolved within about 10 minutes. After stirring for 2 hours the solution is poured into 1000 ml of 2¾ sodium hydrogen carbonate solution, stirred for 1 hour and then the precipitate is recrystallized from acetone to result in 10.01 g (91.41¾) of the title compound, m.p.: 249-261 °C.

Example 8

Preparation of 11/3,16®<, 17,21-tetrahydroxypregna1.4.14- trien-3,20-dion-16,17-cyclic acetonide 2 g (0.0053 mol) of ll/2>, 16ο^ 17,21-tetrahydroxypregna1,4 ,14-trien-3,20-dione are transformed to a paste with 20 ml of acetone under dry nitrogen at room temperature while stirring. To this mixture 1.0 ml of 70¾ aqueous

AP 0 0 0 1 5 7 perchloric acid is added at room temperature under stirring. The reaction proceeds within 30 minutes.

After pouring the reaction mixture into 1000 ml of 2¾ aqueous potassium hydrogen carbonate solution and stirring for 30 minutes, the precipitate is filtered and dried to obtain 2.02 g (91.29¾) of the title substance which is recrystallized from acetone, m.p.: 212-216 °C.

Example 9

Preparation of ll^,16ct,17,21-tetrahydroxypregna1.4.14- trien-3,20-dion-16,17-cyclic acetonide

1.0 g (0.00218 mol) of 11/i, 16c<, 17 , 21-tetrahydroxypregna-l,4,14-trien-3,20-dion-16,17-cyclic acetonide 21-acetate is transformed to a paste with 100 ml of methanol under nitrogen. To this mixture 0.166 g of potassium carbonate dissolved in 1.1 ml of deionized water is added. The solid phase goes into solution within 5 minutes. After 10 minutes the pH value of the solution is adjusted to 6 by adding 1 N hydrochloric acid then the solution is evaporated until it becomes free from solvent. The residue is thoroughly mixed with 100 ml of deionized water, filtered and dried. The product thus obtained is recrystallized from acetone to give 0.79 g (86.98¾) of the title compound, m.p.: 210-215 °C.

Example 10

Preparation of ll/S,16«<,17,21-tetrahydroxypregna1.4.14- trien-3,20-dion-16,17-cyclic acetonide

I

1.0 g (0.00218 mol) of 11^,16^17,21-tetrahydroxypregna-1,4,14-trien-3,20-dion-16,17-cyclic acetonide 21-acetate is dissolved in 200 ml of methanol under nitrogen. After adding 2.0 ml of deionized water and 5 2.0 ml of 60% aqueous perchloric acid the reaction mixture is stirred at room temperature for 48 hours and then evaporated to one tenth of its original volume.

After adding 20 ml of deionized water to the evaporation residue and extracting with dichloromethane, the extract is evaporated to dryness and the residue is recrystallized from ether to give 0.85 g (93.6%) of the title compound, 212-216 °C.

Example 11

Preparation of 11^, 16e<, 17,21-tetrahydroxypregna15 1,4,14-trien-3,20-dion-16,17-cyclic cyclopentanone ketal

After adding 0.44 ml of 70% aqueous perchloric acid and 0.43 ml of cyclopentanone to 20 ml of acetonitrile under nitrogen, 1 g of ll/5,16e<,17,21-tetrahydroxypregna1,4,14-trien-3,20-dion-21-acetate is added to the solution at room temperature. After stirring the reaction mixture for 8 hours the 21-acetate derivative of the cyclic cyclopentanone ketal is first recovered as described in Example 1 which is then hydrolyzed according to Example 9 to obtain 0.50 g (47.3%) of the title compound, m.p.:

AP 0 0 0 1 5 7

Example 12

Preparation of ll/i,16<<,17,21-tetrahydroxypregna1,4 ,14-trien-3,20-dion-16,17-cyclic cyclohexanone ketal

After adding 0.44 ml of 70¾ aqueous perchloric acid 5 and 0.75 ml of cyclohexanone to 20 ml of acetonitrile under nitrogen 1 g of 11/^, 16«^, 17,21-tetrahydroxypregna1,4,14-trien-3,20-dion-21-acetate is added to the above solution at room temperature. After stirring the reaction mixture for 30 minutes the 21-acetate derivative of the cyclic cyclohexanone ketal is first recovered as described in Example 11 which is then hydrolyzed according to Example 9 to obtain 0.75 g (68.74¾) of the title substance, m.p.: 220-223 °C.

Example 13

Preparation of 9<*-f luoro-ll/i,16c<,17,21-tetrahydroxypregna-l,4,14-trien-3,20-dion-16,17-cyclic butyraldehyde acetal

0.3 g (0.69 mmol) of 9<A-f luoro-11/J>, 16«<, 17,21tetrahydroxypregna-1,4,14-trien-3,20-dion-21-acetate is added to a mixture containing 0.13 ml of butyraldehyde, 0.14 ml of 70¾ aqueous perchloric acid and 30 ml of ethyl acetate. The suspension obtained becomes clear within 30 minutes. After stirring for 1 hour the reaction mixture is worked up as described in Example 1 and the

21-acetate derivative of the cyclic butyraldehyde *acetal thus obtained is hydrolyzed by using 0.5 ml of 70¾ aqueous perchloric acid in 5 ml of methanol according to

Example 9. After pouring the reaction mixture into 200 ml of water the precipitate is filtered and dried to obtain 0.24 g (77.9¾) of the title compound, m.p.: 130-136 °C.

Example 14

Preparation of ll/3,16oi,17,21-tetrahydroxypregna1, 4,14-trien-3,20-dion-16 ,17-cyclic butyraldehyde acetal

After dissolving 0.5 g (1.05 mmol) of ethyl ll/i>,16o<,17,21-tetrahydroxypregna-l,4,14-trien-3,20-dion10 16,17-cyclic orthoformate 21-acetate in 50 ml of ethyl acetate under nitrogen, 0.19 ml of redistilled butyraldehyde and then 0.10 ml of 70¾ perchloric acid are added to the above solution. The suspension obtained becomes a clear solution after 2 hours. The reaction is terminated within 3 to 3.5 hours. Subsequently, the reaction mixture is washed first with 30 ml of 5¾ sodium hydrogen carbonate solution and then with distilled water, dried over anhydrous sodium sulfate and evaporated under reduced pressure.

The evaporation residue is dissolved in 10 ml of methanol under nitrogen at room temperature and after adding 0.6 ml of 70¾ aqueous perchloric acid solution, the reaction mixture is left to stand for 12 hours and then dropped into 250 ml of water. After stirring for

1 hour the suspension is filtered and the precipitate is dried. The crude product obtained is first

dichloromethane/n-hexane and then from ethanol to obtain 0.30 g (66.4¾) of the title substance, m.p.: 131-134 °C.

Example 15

Preparation of 11/5,16Λ, 17,21-tetrahydroxypregna5 1,4,14-trien-3,20-dion-16,17-cyclic butyraldehyde acetal

0.19 ml of redistilled butyraldehyde and then 0.10 ml of 70¾ perchloric acid solution are added to 0.5 g (1.05 mmol) of methyl ll/S,16e(,17,21-tetrahydroxypregnal,4,l4-trien-3,20-dion-16,17-cyclic orthoformate

21-acetate dissolved in 50 ml of ethyl acetate under nitrogen. The suspension obtained goes into solution within 2 hours. The reaction proceeds during 3 to 3.5 hours. Subsequently, the reaction mixture is washed with 30 ml of 5¾ sodium hydrogen carbonate solution and then with distilled water, dried over anhydrous sodium sulfate and evaporated under reduced pressure.

After dissolving the evaporation residue in 10 ml of methanol at room temperature under nitrogen, 0.6 ml of 70¾ aqueous perchloric acid solution is added. The reaction mixture is left to stand for 12 hours and then dropped into 250 ml of water. After stirring the suspension for 1 hour, the precipitate is filtered and dried. The crude product thus obtained is first recrystallized from an 1:5 mixture of dichloromethane/n-hexane and then from ethanol to obtain 0.33 g (70.9¾) of the title compound, m.p.: 131-134 °C.

Example 16

Preparation of ll/*>,16o<,17,21-tetrahydroxypregna1,4,14-trien-3,20-dion-16,17-cyclic butyraldehyde acetal

21-butyrate

1.0 g (2.334 mmol) of ll/3,16«<,17,21-tetrahydroxypregna-1,4,14-trien-3,20-dion-16,17-cyclic butyraldehyde acetal (prepared according to Example 2) is dissolved 5 in 15 ml of anhydrous pyridine under dry nitrogen, then 0.77 ml (4.668 mmol) of butyric acid anhydride is added at room temperature. The acylation proceeds within 6 to 8 hours. Then the reaction mixture is poured into 500 ml of water containing 17 ml of concentrated hydrochloric 10 acid, stirred for 1 hour and filtered.The precipitate is recrystallized from ethanol and dried to obtain 1.05 g (90%) of the title product, m.p.: 123-125 °C, with an Rf value of 0.50 (developed with a 70:30:2 mixture of chloroform/ether/methanol).

Exanple 17

Preparation of ll/i,16<*,17,21-tetrahydroxypregna1,4,14-trien-3,20-dion-16,17-cyclic butyraldehyde acetal 21-caproate

1.0 g (2.334 mmol) of 11/5,16o(, 17,21-tetrahydroxy20 pregna-1,4,14-trien-3,20-dion-16,17-cyclic butyraldehyde acetal (prepared according to Example 2) is dissolved in 15 ml of anhydrous pyridine under dry nitrogen and 1.08 ml of caproic acid anhydride are added at room temperature. Further on Example 16 is followed to give 1.05 g (90%) of the title fcompound with an R^ value of 0.47 (developed “ with a 70:30:2 mixture of chloroform/ether/methanol).

Claims (12)

1. Claims jq θ£ performed, i/we declare that i/we claim is;·

   1. Novel Δ, -16<X., 17-dihydroxypregnane-l6,17-cyclic aldehyde acetal and -cyclic ketone ketal derivatives of general formula (I),

   5 wherein

   A stands for hydrogen or hydroxyl group;

   X stands for hydrogen or halogen with the proviso that if A is hydrogen, then X also means hydrogen;

   R stands for hydrogen,benzoyl or C^_galkanoyl group;

   1 2

   10 R and R , which are the same or different, stand for 1 2 hydrogen or a C|_₄alkyl group; or one of R and R is 1 7 hydrogen and the other is phenyl group; or R and R together form a C^^alkylene group;

   — means a single or double bond between two adjacent 15 carbon atoms.
2. 2. A compound selected from the group consisting of ll£,16c£,17,21-tetrahydroxypregna-4,14-dien-3,20-dion16,17-cyclic butyraldehyde acetal;

   ll_/*>,16«Z,17,21-tetrahydroxypregna-l_L4,l4-trien-3,20-dion20 16,17-cyclic butyraldehyde acetal;

   ll/i,16o(, 17,21-tetrahydroxypregna-l,4,14-trien-3,20-dion16,17-cyclic acetaldehyde acetal;

   ll/5,16«<,17,21-tetrahydroxypregna-l,4,l4-trien-3,20-dion16,17-cyclic benzaldehyde acetal;

   11/4,16*·, 17,21-tetrahydroxypregna-1,4,14-trien-3,20-dion16,17-cyclic isobutyraldehyde acetal;

   11/S, 16<<, 17 , 21-tetrahydroxypregna-1,4,14-trien-3,20-dion16,17-cyclic acetonide;

   11/2,I6ik,17,21-tetrahydroxypregna-l,4,l4-trien-3,20-dion16,17-cyclic cyclopentanone ketal;

   1Ιβ,16X, 17,21-tetrahydroxypregna-1,4,14-trien-3,20-dion16,17-cyclic cyclohexanone ketal;

   9o(-f luoro-11/4,16o(,17,21-tetrahydroxypregna-l,4,14-trien3,20-dion-16,17-cyclic butyraldehyde acetal; and 21-acyl derivatives of these compounds.
3. 3. An antiinflammatory pharmaceutical composition, which comprises a therapeutically effective dose 14 of one or more novel A. -16o<, 17-dihydroxypregnane-16,17cyclic aldehyde acetal or -cyclic ketone ketal derivative(s) of general formula (I), wherein A, X, R^,

   R , R and the symbol (bond line) ---- are as defined in claim 1, in admixture with carriers and/or diluting, stabilizing, pH- and osmotic pressure-adjusting agents and formulating additives commonly used in the pharmaceutical industry.
4. 4. A process for the preparation of novel A -16^(.,17dihydroxypregnane-16,17-c^clic aldehyde acetal and -cyclic ketone ketal derivatives of general formula (I),

   AP 0 0 0 1 5 7 ί

   *5«

   A stands for hydrogen or hydroxyl group;

   X stands for hydrogen or halogen with the proviso that if A is hydrogen, then X also means hydrogen;
5. 5 R stands for hydrogen ,benzoy1 or C^ galkanoyl group;

   1 2

   R and R , which are the same or different, stand for 1 7 hydrogen or a C|_₄alkyl group; or one of R and R is 1 7 hydrogen and the other is phenyl group; or R and R together form a C^^alkylene group;

   10 — means a single or double bond between two adjacent carbon atoms, which comprises

   a) reacting a Δ^-Ιόοί, 17-dihydroxypregnane derivative of general formula (II), (II)

   15 wherein A, X, R and the symbol (bond line) ---- are as defined above, with an oxo compound of general (IV) formula (IV), o=c r1

   R²

   1 2 wherein R and R are as defined above, in the presence of an acid catalvst;

   or

   5 b) reacting a Δ^-16ο(, 17-dihydroxypregnane cyclic orthoester derivative of general formula (III), (III)

   APO 00157 wherein A, X, R and the symbol (bond line) ---- are as defined above and R^ stands for a methyl or ethyl group, with an oxo compound of general formula (IV), c=c

   Rl

   R² (IV)

   1 2 wherein R and R are as defined above, in the presence of an acid catalyst,

   1A then, if desired, hydrolyzing the Δ -l6c<,17-dihydroxypregnane-16,17-cyclic aldehyde acetal or -cyclic ketone ketal derivatives respectively, of general formula (I), line) ---b). to are as defined above, obtained in process a) or obtain Δ -16Λ, 17-dihydroxypregnane-16,17-cyclic aldehyde 5 acetals or -cyclic ketone ketals containing hydrogen as R;

   and/or, if desired, acylating the'thus obtained compounds of general formula (I), wherein R means hydrogen to obtain compounds of general formula (I), wherein R represents an acyl group.

   10 5. A process a) as claimed in claim 4, which comprises carrying out the reaction in acetonitrile medium, in the presence of an aqueous perchloric acid solution as acid catalyst.
6. 6. A process a) as claimed in claim 4, which ί *

   - 51 in the presence of an aqueous perchloric acid solution as acid catalyst.
7. 7. A process a) as claimed in claim 4, which comprises carrying out the reaction in ethyl

   5 acetate medium in the presence of an aqueous perchloric acid solution as acid catalyst.
8. 8. A process b) as claimed in claim 4, which comprises carrying out the reaction in ethyl acetate medium in the presence of an aqueous perchloric acid

   10 solution as acid catalyst.
9. 9. A process as claimed in any of claims 4 to 8, which comprises hydrolyzing an obtained Δ^-Ιόοί., 17dihidroxypregnane-16,17-cyclic aldehyde acetal or -cyclic ketone ketal derivative of general formula (I), wherein 1 2

   15 A, X, R , R and the symbol (bond line) ---- are as defined above and R means an acyl group, by using aqueous perchloric acid solution in an aqueous C^_₄alkanol medium.
10. 10. A process as claimed in any of claims 4 to 8, which comprises hydrolyzing an obtained £^-16c<, 1720 dihydroxypregnane-16,17-cyclic aldehyde acetal or -cyclic ketone ketal derivative of general formula (I), wherein 1 2

    A, X, R , R and the symbol (bond line) ---- are as defined above and R means an acyl group, by using an inorganic base in an aqueous C^_₄alkanol medium.

    25
11. 11. A process for the preparation of an antiinflammatory pharmaceutical composition, which comprises mixing as active ingredient one or more

    I S L 0 0 0 dV

    1A novel Δ -16c<, 17-dihydroxypregnane-16,17-cycl ic aldehyde acetal and -cyclic ketone ketal derivative(s ) of general formula (I), wherein A, X, R , R , R and the symbol (bond line) ---- are as de/ined in claim 1,

    5 with carriers, diluting, stabilizing, pH- and osmotic pressure-adjusting agents and formulating additives commonly used in the pharmaceutical industry and transforming them to a pharmaceutical composition.
12. 12. Method for treating mammals including human

    10 suffering from an inflammatory disease, characterized by using a therapeutically effective * 1A amount of a novel Δ -16o(, 17-dihydroxypregnane-16,17-cyclic aldehyde acetal or -cyclic ketone ketal derivative of 1 2 the general formula (I), wherein A, X, R , R , R and