DE2222491C3 - Pregnan series steroid 21-nitric acid esters, medicaments containing them and processes for the preparation thereof - Google Patents

Description

C ₁ = C ₁₁

\ I

QC ₁

HIg OH

respectively

whereby

HIg means halogen and C _lh —C _{n is} a group of the formulas

16 V ¹⁷ \

H OH (α)

respectively

-Cn-

O O

R ₁ R ₂

whereby

Ri and R2 identical or different substituents, and that are hydrogen or alkyl radicals having 1 to carbon atoms.

2. Medicines, characterized by a content of one or more of the Compounds according to claim 1 as active ingredient or ingredients.

3. Method of making the connection according to claim 1, characterized in that one

a) Steroid 21 alcohols of the pregnancy series of the general my formula

where C9-Cn, C16-Cn, HIg, Ri and R2 as irr Claim 1 are established, esterified in a manner known per se to give steroid 21-nitric acid esters or

b) Steroid 21-nitric acid ester of the Pregnan series « the general formula

H ₂ CO-NO ₂
C = O

wherein C ₉ -Cn, Ci ₆ -Ci ₇ , HIg, Ri and R2 are as defined in claim 1, converted into other steroid 21-nitric acid esters of the general formula I in a manner known per se
and optionally a compound of the formula I in which C ₉ -Ci 1 is a group of the formula

C ₉ C ₁₁

means, reacts with 1,3-dibromo-5,5-dimethylhydantoin.

The invention relates to new stereoid 21-nitric acid esters the Pregnan range, such containing drugs, especially anti-inflammatory, an.tallergic and cardiotropic agents, and a method for making the same.

The known steroid nitric acid esters are easy to prepare and isolate. Because of their persistence (C. D j e r a s s i, Steroid Reactions, pages 75 to 76 [1963]) are they very good for masking hydroxy groups

pen usable. Due to these valuable properties, the nitric acid esters are used in production can be used by other steroid compounds used in therapy, but also have valuable ones themselves pharmacological effects.

For example, from Arzneimittelforschung 19 (1969), pages 684 to 685, and Chemical Abstracts 75 (1971), 77 155 k under various steroid nitric acid esters also known some steroid 21-nitric acid esters

The invention relates to steroid 21-nitric acid esters the pregnancies of the general formula

H ₅ CO-NO,

respectively

C = O

wherein C ₉ -C _{n is} a group of the formulas

H
C ₉ C] ₁

N λ ' \ H /
whereby HIg / \
( -C ₁ , - HIg means halogen. OH respectively H / " and Ci ₆ -Ci _{7 is} a group of the formulas

H OH (*)

-C ₁₇ - ό

whereby

Ri and R2 are identical or different substituents, namely hydrogen or alkyl radicals with 1 to 4 carbon atoms,
represents

Furthermore, according to the invention, medicaments which contain one or more of the above compounds as an active ingredient or ingredients contain or from this or these exist, provided.

This is because the steroid 21-nitric acid esters according to the invention have anti-inflammatory, antiallergic and cardiotropic effects according to the pharmacological investigations by the applicant. A vasodilating effect can also be demonstrated with individual compounds.
The compounds according to the invention are particularly superior with regard to their anti-inflammatory action.

To demonstrate the above, the so-called cotton-wool granuloma test was used for determination the anti-inflammatory effect comparative tests carried out, under the same conditions the compound according to the invention

9 (X- fluoro-11 ß, 16 <x, 17 «, 21 - tetrahydroxy pregna-

1,4-diene-3,20-dione-16,17-acetonide

21 -nitric acid ester

(also triamcinolone acetonide-21-nitric acid ester called)

[Compound of the invention

Example 2] and

9λ- fluoro-11 ß, 16 «, 1 7λ, 2 1 -ietrahydroxy pregna-

1,4-diene-3,20-dione-16,21-disnitric acid ester

(also Triamicinolon-16,21 -disnitric acid ester

called) [reference substance],

a compound structurally closely related to the compounds according to the invention were investigated. the Both compounds showed those listed in Table 1 below with almost the same toxicity anti-inflammatory effects.

Table 1

Vei bond
description

Assignment

Dose anti-inflammatory effects

(Cotton wool granuloma test)

Inhibition in%

9α-fluoro-1 l./i,16a, 17a, 2 l-tetraliy (lioxypregna-1,4-diene-3,20-dione-16,17-acetonide-21-nitric acid ester

9a-Fluor-l l / fJoaJTa ^ l-ietrah
3.20-dione-16.21-disetheric acid ester

according to the invention 1.5 mg 47
Example 2

Comparison substance 4.5 mg 40

This clearly shows that the compound according to the invention is by far superior to the comparison substance in that it shows the higher anti-inflammatory effect of 47% at the much lower dose of 1.5 mg, while the comparison substance itself at a dose of 4.5 mg only shows the has lower anti-inflammatory 40%

Furthermore, 9ß, \\ ß-Epoxy- \ 6ix, \ 7a2i-tnhydTo xypregna-1 ^ -dien- ^ O-dione-16,17-acetonide-21-nitric acid ester (compound of Example 4) was the

Table 2

corresponding free 21-alcohol, namely 90,110-Ep-

oxy-1 6λ, 1 7α, 21 -trihydroxypregna-1,4-diene-3,20-dione-16,17-acetonide, a compound with a known good anti-inflammatory effect, as a reference substance juxtaposed. It was found that the potency in both cases is about the same, However, the compound according to the invention has a significantly better solubility than the comparison substance The results are compiled in Table 2 below

link
description

Assignment

Soluble wedge in g / i oil 25 (

16,17-acetonide-21-nitric acid ester

9.Ä1 Uf-Epoxy-16ff. L 7ff, 21-trihydroxypregna-l

The much better solubility is a major advantage in terms of therapeutic application, because thereby with the compounds according to the invention a lighter and broader therapeutic approach Application is possible

In contrast, the steroid 21-nitric acid esters of the compounds according to the invention described in the literature references A -zneimittelforschung 19 (1969), pages 684 to 685, and Chemical Abstracts 75 (1971), 77 155 k (report from Romanian patent 52 204) are constitutional and also in the direction of action apart. In the publication Arzneimittelforschung 19 (1969), pages 684 to 685, for example, with regard to the steroid 21-nitric acid ester (called 21-nitrates there) [compounds VI and following], when they are discussed on page 685, left column, line Γ. to 18, there is no question of anti-inflammatory effectiveness, only other effects, namely the sodium retention capacity according to the invention 400 500 example 4

Reference substance 100 125

genes, the decrease in Nepalese glycogenesis and the increase in the thymolytic effect as well promoting protein anabolism, despite the fact that for steroid 21-nitric acid esters Different steroid nitric acid esters which have anti-inflammatory effects are indicated. Therefore these are not suitable reference substances.

The steroid 21-nitric acid esters according to the invention are also used can be used for the production of other therapeutically active steroid compounds.

The invention also relates to a process for the preparation of the steroid 21-nitric acid ester according to the invention, which is characterized in that

a) Steroid-21-alcohols of the general pregnancy series formula

40

H ₂ C

C =

wherein C ₉ -Cu, Ci ₆ -C] ₇ , HIg, Ri and R _{2 are} as defined above, are esterified in a manner known per se to give steroid 21-nitric acid esters or

b) Steroid 21-nitric acid ester of the pregnane series of the general formula

H ₇ CO-NO ₂

C = O

wherein G) -Cn, Cib-C17, HIg, Ri and R2 as above are set in a manner known per se in other steroid 21-nitric acid ester of the general Formula I are transferred

and optionally a compound of the formula I in which Cg-Cn is a group of the formula

\ I

means is reacted with 1,3-diprom-5,5-dimethylhydantoin.

The esterification of the steroid 21 alcohol is preferred of the general formula II with a mixture of concentrated nitric acid and acetic anhydride carried out

According to the first embodiment of the method according to the invention, the steroid 21-nitric acid esters for example be prepared so that steroid 21-alcohols of the general formula II in one Solvent in a manner known per se with a mixture of concentrated nitric acid and acetic anhydride are esterified, in such a way that the steroid-21 alcohol-containing solution to cooled mixture of nitric acid and acetic anhydride is added. After the After esterification, the mixture is poured into water and the organic phase until neutral washed and freed from solvent. The steroid 21-nitric acid ester remaining as residue is purified by treatment with solvents and / or by crystallization. As a solvent mainly halogenated hydrocarbons are used. The reaction temperature, in general is around 0 ° C, as well as the amount and the mixing ratio of the nitric acid / acetic anhydride mixture used depend on which steroid 21 alcohol is assumed. The nitric acid and the acetic anhydride are preferably used in excess of the stoichiometric amount used

The reaction can be followed well on thin-layer chromatograms, so that the end point of the Reaction can be precisely determined.

The color of the steroid 21-nitric acid ester obtained in the manner described is pale yellow or greenish. They can be obtained as a crude product in a yield of 85 to 95%. Due to thin layer chromatography Examinations they are uniform and based on analytical examinations the amounts to Purity over 90%.

According to the second embodiment of the method according to the invention, steroid 21-nitric acid esters are used of the general formula I into other compounds according to the invention by reaction routes known per se convicted

If any between carbon atoms 9 and 11 a compound having a double compound, that is to say one in which C9-Cn of the general formula I a group of the formula

\ __ I
C ₉ C ₁₁

means is reacted with 1,3-dibromo-5,5-dimethylhydantoin, becomes a 9a-bromo-1,33-hydroxydcrivat, thus a compound in which Cq-Cn is the general Formula I is a group of the formula

Il

s * V "

Br OH

means received. This bromohydrin can, for example by splitting off hydrogen bromide into an epoxide in a manner known per se, ie a compound in which Cg-Cn is the general ·, Formula I is a group of the formula

C ₁₁

means to be convicted. These epoxides are important intermediates in the manufacture of in Fluorine-containing compounds that are very widely used in therapy. The fluorination with hydrogen fluoride surprisingly chemically peculiar compared to the prior art under particularly favorable conditions, in particular with regard to the outstanding reduction in amount of hydrogen fluoride to be used, one of the most annoying, dangerous and hardest to use handling substances at all.

The invention is explained in more detail with reference to the following examples, which are not to be interpreted as limiting.

example 1

There were 15.7 cm ³ (23.59 g; 0.36 mol) of concentrated nitric acid (specific gravity at least 1.50) with stirring and external cooling at -10 ° C 56.50 cm ³ (61.26 g ; 0.6 mol) acetic anhydride was added dropwise. The temperature was kept at -10 ° C., and 23.59 g (0.06 mol) of 16 ", 17", 21-trihydroxypregna-1,4 dissolved ^{in 354 cm 3 of chloroform were added} , 9 (1 l) -triene-3,20-dione-l 6,17-acetonide was added. The reaction mixture was stirred at this temperature for 30 minutes and then ^{poured into 1500 cm 3 of} ice water. After the aqueous phase had been separated off, it was extracted twice with chloroform, and then the chloroform extracts combined with the chloroform phase were washed until neutral, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure , 17 <x £ l-Trihydroxypregna-l, 4,9 (ll) -triene-3,20-dione-ie.lZ-acetonide ^ l-nitric acid ester obtained. The product was uniform by thin layer chromatography.

Melting point: 163 to 169 ° C (with decomposition).
Yield: 95.5%.

The product recrystallized from a mixture of methyl alcohol and acetone in a ratio of 8: 2 decomposed at 168 ° C
E!:; = 385 (238 to 239 πιμ; C ₂ H ₅ OH).

Molecular formula: C24H29O7N (Molecular weight: 443.48).

Analysis:

Calculated: 0 = 25.25%;
found: 0 = 24.90%.

Characteristic absorption maxima: 5.80 μ, 6.01 μ, 6.08 μ, 6.17 μ, 6.25 μ, 7.80 μ, 9.30 μ, 9.57 μ and 11.80 μ.

Example 2

There were 5.05 cm ³ (7.57 g; 0.12 mol) of concentrated nitric acid (specific gravity of at least 1.50), with stirring and external erfolgendem cooling at - 10 ⁰ C 18,9 cm ³ (20.42 g ; 0.20 mol) of acetic anhydride and then 8.69 g (0.02 mol) of 9a-fluoro-11,16 ", 17 <x, 21-tetrahydroxypregna-1,4-diene-3, suspended ^{in 87 cm 3 of chloroform,} 20-dione-16,17-acetonide was added dropwise. The steroid dissolved in the reaction mixture over the course of 1 to 2 minutes. The reaction mixture was stirred at a temperature of - long stirred for 30 minutes 10 ⁰ C and poured into 250 cm ³ of ice water. The aqueous phase was extracted ^{3 times with 90 cm 3 of chloroform each time.} Otherwise, the procedure indicated in Example 1 was followed. Thus 9.06 g of yellow-white crystalline 9λ- fluoro-11 were ß \ 6α, Ι 7λ obtained 2 1 -tetrahydroxypregna-1,4-diene-3,20-dione-16,17-acetonide-21 -salpetersäureester. The product was uniform by thin layer chromatography.

Melting point: 203 to 214 ° C (with decomposition).

Yield: 94.5%.

The decomposition point of the after repeated recrystallization The white crystalline product obtained from acetone was 2 i 0 ° C.

E \ 1 = 346 (238 to 239 Γημ; C ₂ H ₅ OH).

Molecular formula: CwHjoOeFN (molecular weight: 479.51).

Analysis:

Calculated: F = 3.96%;
found: F = 3.84%.

Characteristic absorption maxima: 3.00 μ, 5.80 μ,

6.00 µ, 6.06 µ, 6.17 µ, 6.25 µ, 7.82 µ, 9.27 µ, 9.46 µ and 11.80 µ.

Example 3

A suspension of 7.17 g (0.02 mol) of 9β, 11β -epoxy-17a, 21-dihydroxypregna-1,4-diene-3,20-dione in 92 cm ^{3 of} chloroform according to Example 2 was reacted. 7.84 g of yellowish-white, oily-crystalline 9β, 1β- epoxy-1 lu.2 1 -dihydroxypregna-1,4-diene-3,20-dione-21 nitric acid ester were obtained.

Yield 95.8%.

By triturating the crude product with 16 cm ^{3 of} ether, 6.42 g of a ^{white crystalline product which melted at 148 to 160 °} C. with decomposition were obtained. The product, which was recrystallized several times from methyl alcohol, decomposed at 165 ° C. and was uniform on thin-layer chromatography.

Ei * - 408 (248 to 249 πιμ; C ₂ H ₅ OH).

Molecular Formula: C21H25O7N (Molecular Weight: 403.42).

Analysis:

Calculated: 0 = 27.76%;
found: 0 = 27.67%.

Characteristic absorption maxima: 3.00 μ, 5.80 μ,

6.01 μ, 6 ,! 1 µ, 625 µ, 730 µ, 11.22 µ and 11.68 µ.

Example 4

lis was a solution of 8.29 g (0.02 mol) of 90.11 / 3-epoxy-16 &, 17α, 21 -trihydroxypregna-M-diene 3,20-dione-16,17-acetonide in 166 cm ^{3 of} chloroform according to Example 2 with nitric acid and acetic anhydride for the reaction; The reaction mixture was ^{stirred at 0 °} C. for 1 hour and worked up in the manner indicated in Example 2. So 9.02 g, ο pale yellow crystalline 9j?, 110-epoxy-16 ", 17a, 21-trihydroxypregna-1,4-diene-3,20-dione-16,17-acetonide-21-nitric acid ester, the was uniform by thin layer chromatography.

Melting point: 145 to 152 ° C (with decomposition).
Yield: 98.1%.

The product, which was recrystallized several times from methyl alcohol, melted at 154 ° C. (with decomposition).
E! I = 357 (247 to 248 IT ^ C ₂ H ₅ OH).
Molecular formula: C24H29O8N (molecular weight 459.48).

Analysis:

Calculated: 0 = 27.86%;
found: 0 = 27.60%.

Characteristic absorption maxima: 5.78 μ, 5.99 μ 6.06 μ, 6.13 μ, 6.23 μ, 7.78 μ, 9.27 μ, 9.62 μ and 11.70 μ.

Example 5

There were 11.0 g (0.025 mol) of the 16 ", 17", 21-trihydroxypregna-1,4,9 (ll) -triene-3 ^ 0-dione-16,17-acetonide-21- prepared according to Example 1 yo nitric acid ester dissolved in 220 cm ^{3 of} tetrahydrofuran. ^{13.5 cm 3} (0.75 mol) of water, 4.5 cm ^: (0.375 mol) of a 60% strength aqueous superchloric acid solution and 5.38 g (0.019 mol) of 1,3-dibromo-5, were added to the solution at room temperature. 5-dimethylhydantoin added. The solution was protected from light and stirred at 20 to 25 ° C. for 1 hour and then poured ^{into a solution of 2.7 g of sodium bisulfite in 1100 cm 3 of water with stirring.} The suspension was _{stirred for 2} hours and then the product was filtered off and washed with water until the reaction was neutral. In this way, 13.30 g of yellowish-brown 9 "-Bromo-l 1 / ?, 16a, 17", 21-tetrahydroxypregna-1,4-diene-3,20-dione-16,17-acetonide-21-nitric acid ester were obtained.

Bromohydrin content: 101.0%.

Melting point: 206 to 214 ° C (with decomposition).

Yield: 98.5%.

The product, recrystallized from a mixture of tetrahydrofuran and diisopropyl ether, melted 202 ° C (with decomposition).

E i? "= 275 (241 to 242 Γημ; C ₂ H ₅ OH).

Molecular formula: C ^ HaoOeBrN (Molecular weight: 540.42).

Analysis:

Calculated: Br = 14.79%;
found: Br = 14.90%.

Characteristic absorption maxima: 2.93 μ, 5.80 μ 6.00 µ, 6.09 µ, 6.15 µ, 6.22 µ, 730 µ, 9.55 µ and 11.70 µ.

Example 6

9.91 g (0.02 mol) dissolved in 100 cm ^{3 of} chloroform 9 "-Bron-II / ?, 16 <x, 17a £ 1-tetrahydroxypregnal, 4-diene-3,20-dione-16,17 -acetonide implemented according to Example 2 So were 8.27 g of 9Ä-bromo-II / ?, 16 ", 17" £ l-tetrahydroxypregna-1,4-diene-3,2 0-dione-l 6,17-acetonide- 21 -

11 12

obtained nitric acid ester. The bromohydrin content of the mixture recrystallizes. It was after the IR and

yellow crystalline product was 101.7%. UV spectra as well as thin-

Melting point: 201-204.5 ° C. layer chromatographic investigations with the

Yield: 76.5%. prepared in the manner described in Example 5

The product was made from a tetrahydrofuran? Product identical,

and diisopropyl ether in a ratio of 1: 1 - decomposition point: 202 ^° C.

Claims (1)

Patent claims: 1. Steroid 21-nitric acid ester of the pregnane series the general formula H ₂ CO-NO ₂ C = O wherein C ₉ -C _{11 is} a group of the formulas H