NO132099B - - Google Patents

Description

In German explanatory document 1,169,444, the production of, among other things, is described. A''" '^-16a-methyl steroids of the formula:

where R and R 2 are hydrogen or halogen, and R 2 is hydrogen or lower acyl.

These compounds have good anti-inflammatory effects, since side effects, such as e.g. the influence of mineral metabolism, despite the mineralocorticoids close structure, is extremely small.

For the practical use of chemical compounds as pharmaceuticals, however, not only the advantages stated above are decisive. Also of particular importance is the duration of action and intensity of action (i.e. the relationship between the dosage on the one hand and the time until the onset of the effect or the onset of the full effect).

In the further development of the investigations according to DAS I.169«444, it has now surprisingly been shown that precisely the 21-acyl esters in which R^ is an acyl group with 7 - 16 carbon atoms in a straight chain or 4 - 16 carbon atoms in a branched chain, are particularly valuable substances as they also have a high intensity of action and a longer duration of action.

The intensity of action was determined by the known Vasoconstriction test on healthy male subjects aged 18 - 38 years. In table 1, the intensity of action of the 21-esters produced according to the invention, e.g. The 21-esters II and III, for example, are placed against the known compounds Ia and Ib for comparison, with t/2 indicating the time at which 50% healing has been achieved with the respective test compound.

Table 1 shows that the new 21-esters produced according to the invention with regard to the onset of action and the intensity of action (t/2) are completely superior to the comparison compounds. For most compounds, this superior result is also achieved with, in some cases, significantly lower dosages.

The duration of action of the new 21-esters was determined on male rats (80 - 100 g), which on the right paw by intraplantar injection with heat-killed and freeze-dried bacteria of the strain Mycobacter-ium butyricum (0.05 ml of a 0.5%-ig suspension in paraffin oil) had caused an oedema. Steroid treatment began 2k hours later. The test compound was used intramuscularly in the form of a castor oil solution. Edema development was followed before and after the steroid treatment by daily volume measurements. In table 2, the superior duration of action of the new 21-esters is demonstrated by, for example, compounds 1-9 compared to the previously known compounds Ia- and Ib-acetate, the end point of the duration of action being determined as the day when there is no longer could be demonstrated any difference between the control and the treated animal group (the stated values are mean values as each animal group comprises 7 - 10 experimental animals).

The present invention therefore relates to analogous processes for the production of the previously undescribed 21-esters of A 1 ' L-16a-methyl steroids of the general formula:

where X is hydrogen or fluorine, and R' is a 7 - 16 carbon atoms containing the straight chain or a 4 - 16 carbon atoms containing branched chain acyl group, by a) a) in the corresponding free 21-alcohols in a manner known per se esterifies the free 21-hydroxyl group with the desired acid,

respectively a reactive derivative thereof, or

b) in a manner known per se, the ^^-doublet bond in the starting steroids transfers the formula:

where R" is hydrogen or R', to the lip-OH-9a-fluorine grouping, and, if in the obtained primary product R• is hydrogen, selectively esterifies the 21-hydroxyl group with the desired acid, respectively a reactive derivative thereof.

The technically simplest preparation method a) starts from the corresponding 21-alcohols (R* = H) in which, in a manner known per se, the free 21-hydroxyl group is selectively esterified with the desired acid

respectively a reactive acid derivative.

However, the new 21-esters where X is fluorine can also be produced according to the invention b) from 9,11-unsaturated compounds of the formula:

where R" is hydrogen or R', converting the A<9>(<H>) double bond to the ultimately desired llp-OH-9a-fluorine grouping in a manner known per se and, in the event that in the obtained primary product R" is hydrogen, the 21-hydroxy group is esterified selectively with the desired acid, or a reactive derivative thereof.

The conversion of the A^(^^-double bond to the ultimately desired 11(3-OH-9a-fluorine grouping preferably takes place by anchoring a hypohalic acid at the 9,11-double bond, e.g. by treatment

with dibromodimethylhydantoin, N-bromo-(resp. chloro)-acetamide or N-bromo-(resp. chloro)-succinimide in the usual way.

The ll(3-OH-9a.-bromo-(or chlorine) grouping is transferred in a manner known per se to the 9,11-oxydo ring, which is then converted with the help of hydrogen fluoride into the ultimately desired lip-OH -9a-fluorine groups-ing .

The A^(<11>) steroids usable as starting material are obtained from

the corresponding saturated lip-hydroxyl compounds. The cleavage of the lip-hydroxyl group takes place by methods known per se, e.g. by treatment with mesyl chloride or also tosyl chloride, a co-present, free 21-hydroxyl group being temporarily protected. The preliminary 21-hydroxyl group protection is omitted when the 21-OH group is already esterified to the ultimately desired acid (R" = R<*>).

Example 1

16α-methyl-6α-fluoro-α<1>'^-pregnadiene-lip,21-diol-3,20-dione-21-oenanthate

2 g of 16a-methyl-6a-fluoro-α<1>'^-pregnadiene-lip,21-diol-3,20-dione is allowed to stand in 8 ml of pyridine with 4 ml of enoanthic anhydride at room temperature. The crystallized enanthate is filtered off with suction and recrystallized several times from methylene chloride-isopropyl ether. Temp. 226 - 227°C. Yield 80% of the theoretical. UV: 2L, 2~1^-2o°-Example 2 l6a-methyl-6a-fluoro-Al'^-pregnadiene-lip,21-diol-3,20-dione-21-t - butyl acetate 1 g l6a-methyl -6a-fluoro-A1,Zf-pregnadiene-lip,21-diol-3,20-dione is stirred in 25 ml of pyridine with 2 ml of t-butylacetyl chloride for 16 hours at -7°C. It is worked up as described in example 12. After recrystallization from isopropyl ether-methylene chloride, 750 mg of 16a-methyl-6a-fluoro-α<1>'^-pregnadiene-lip,21-diol-3,20-dione-21-t-butyl-acetate with melting point 211 - 213 °C.

UV: £2Za= 15,850.

Example 3

16a-methyl-6a-fluoro-A1'^-pregnadiene-lip,21-diol-3,20-dione-21-undecylate 8 g 16a-methyl-6a-fluoro-A<1>'^-pregnadiene-lip, 21-diol-3,20-dione is allowed to stand in 60 ml of pyridine with 13 g of undecyl anhydride for 48 hours at 20°C. After working up as described in Example 8, the impure 16a-methyl-6a-fluoro-α<1>'^-pregnadiene-lip,21-diol-3,20-dione-21-undecylate is triturated with pentane and recrystallized from isopropyl ether.

Temp. 66 - 67°C. Yield 95%.

Ex empe1 4

l6g- methyl- 6g- fluoro- A1 '^- pregnadiene- lip, 21- diol- 3, 2Q- dione- 21- palmitate 1 g l6a-methyl-6a-fluoro- A<1>'^-pregnadiene-llp, 21-diol-3,20-dione is stirred in 20 ml of pyridine with 1 ml of palmitic acid chloride for 48 hours at +7°C and worked up as described in example 8. The 16a-methyl-6a-fluoro-A1,Zf-pregnadiene thus obtained -lip ,21-diol-3,20-dione-21-palmitate is recrystallized from isopropyl ether and melts at 93 - 94°C. Yield 80%.

Example 5

16α-methyl-9α-fluoro-α<1>'^-pregnadiene-lip,21-diol-3,20-dione-21-trimethylacetate

2 g of 16a-methyl-9a-fluoro-α<1>'^-pregnadiene-lip,21-diol-3,20-dione in 20 ml of pyridine are reacted with 2.5 ml of pivalic acid chloride and worked up as described in example 8-

Temp. 205.5 - 206.5°C. Yield 80% of the theoretical.

Example 6

16α-methyl-6α-fluoro-α<1>'^-pregnadiene-1β,21-diol-3,20-dione-21-dimethylacetate

1 g of 16a-methyl-6a-fluoro-A1'^-pregnadiene-lip,21-diol-3,20-dione in 10 ml of pyridine is reacted with 1.2 ml of isobutyric acid chloride and worked up as described in example 8>

Temp. 187 - 188°C. Yield 90% of the theoretical.

UV: £2^2= 15-900.

Example J

16α-methyl-6α-fluoro-α1'^"-pregnadiene-llfB,21-diol-3,20-dione-21-diethylacetate

1 g 16a-methyl-6a-fluoro-Al'^-pregnadiene-11p,21-diol-3,20-dione

is allowed to stand in 5 ml of pyridine with 2.5 ml of diethylacetic anhydride for 20 hours at room temperature and is worked up as described in example 8- After recrystallization from acetic acid ester, 780 mg of 16a-methyl-6a-fluoro-A1,if-pregnadiene- lip ,21-diol-3,20-dione-21-diethyl - acetate with melting point 230 - 233°C.

Example 8

16a-methyl-6a-fluoro-A<1>'^-pregnadiene-lip,21-diol-3,20-dione-21-tri-methylacetate 2 g 16a-methyl-6a-fluoro-A<1>'^ -pregnadiene-lip,21-diol-3,20-dione is stirred in 20 ml of pyridine with 2.5 ml of pivalic acid chloride for 16 hours at +5°C and then poured into ice water. The aspirated precipitate is taken up in acetic acid ester, washed with 1 N sulfuric acid, n/10 caustic soda and water, evaporated and recrystallized from carbon tetrachloride.

Temp. 171 - 173°C. Yield 90% of the theoretical. UV: E 2 Zf 2 =15,600.

Example 9

l6a-methyl-6a-fluor-A1 ,Zf-pregnadiene-llp ,21-diol-3,20-dione-21 -2 ' ,2* - dimethylbutyrate 3 g l6a-methyl-6a-fluor-A1 ,Zf -pregnadiene-ll|3,21-diol-3,20-dione in 75 ml of pyridine at -5°C, 6 ml of 2,2-dimethyl-butyric acid chloride is added and stirred for 16 hours at 4 - 6°C. The preparation takes place as described in example 8. The thus obtained 16α-methyl-6α-fluoro-α1'^-pregnadiene-lip,21-diol-3,20-dione-21-2",2•-dimethylbutyrate is recrystallized from isopropyl ether-methylene chloride and melted at l6l - 163°C.

Yield 85% of the theoretical. UV: E 24l = 1-5-800.

Example 10

6α,9α-difluoro-16α-methyl-1,4-pregnadiene-lip,21-diol-3,20-dione-21-trimethylacetate

Dissolve 200 mg of 6a,9a-difluoro-16a-methyl-1,4-pregnadiene-11(3,21-diol-3,20-dione in 2 ml of pyridine and add 0.25 ml of trimethyl-acetic acid chloride. The solution is allowed to to stand for 16 hours at 0 - 5°C, then stirred for 2 hours at room temperature (approx. 22°C) and then poured into ice water. After 30 minutes of stirring, the precipitated crystals are suctioned off and dissolved again in aqueous acetic acid. the ester solution is washed with 5% acetic acid, with water, with sodium bicarbonate solution and again with water, dried over sodium sulfate and concentrated in vacuo.The precipitated crystallisate is recrystallized from isopropyl ether-methylene chloride.

Yield 185 mg. Temp. 218 - 219°C. UV: t239 ~<1>7-200.

Example 11

6a , 9a-difluoro-:16a-methyl 1-1,4-pregnadiene-llp ,21 -diol-3 ,20-dione-21 - enanthate

Dissolve 400 mg of 6a,9ct-difluoro-16a-methyl-1,4-pregnadiene-11|3,21-diol-3,20-dione in 1.6 ml of pyridine, add 0.8 ml of enoanthic anhydride and get stand for 24 hours at room temperature. The solution is stirred in 20 ml of 8% sulfuric acid at 0°C. The mixture is extracted with methylene chloride. The extract is washed with water, sodium bicarbonate solution and again with water, dried over sodium sulphate and evaporated to dryness in vacuo. The residue obtained is recrystallized from acetone-isopropyl ether.

Temp. 212 - 213 - 214°C. Yield 425 mg. UV: B23y = 16,800.

Example 12

6a,9a-difluoro-16a-methyl-1,4-pregnadiene-11|3,21-diol-3,20-dione-21-undecylate

To a solution of 650 mg of undecyl anhydride in 3 ml of pyridine, 400 mg of 6a,9a-difluoro-16a-methyl-1,4-pregnadiene-11(3,21-diol-3,20-dione is added. The solution is allowed to stand for 48 hours at room temperature and then add approx. 5 ml of water and extract with ether. The extract is washed with 2 N sulfuric acid, with 2 N caustic soda and then with water, dried and evaporated to dryness. The residue is washed with pentane and recrystallized from isopropyl ether.

Temp. 100/101-102°C. Yield 369 mg. UV:£336<=>l6-6o°-

o

Claims (1)

Analogous procedure for the preparation of new, therapeutically active 21-esters of _"'^-16a-methyl steroids of the formula: where X is hydrogen or fluorine, and R' is a 7~16 carbon atoms containing the straight chain or a 4 - 16 carbon atoms containing a branched acyl group, characterized in that a) in the corresponding free 21-alcohols in a manner known per se, the free 21-hydroxyl group is esterified with the desired acid, or a reactive derivative thereof, or b) in a manner known per se, A transfers the <9> ( <H> ) double bond in the starting steroids of the formula: where R" is hydrogen or R', to the 1113-0H - 9a-fluoro grouping, and, if in the obtained primary product R* is hydrogen, selectively esterifies the 21-hydroxyl group with the desired acid, respectively a reactive derivative thereof.