DE2222491B2 - STEROID-21 NITRIC ACID ESTERS OF THE PREGN SERIES, MEDICINAL PRODUCTS CONTAINING SUCH, AND METHOD FOR MANUFACTURING THE SAME - Google Patents

Description

. C X

wherein C, C _{11 represent} a group of the formulas

.QC ₁₁ -

HIg OH

respectively

CC ₁₁ -

whereby

HIg halogen means

and C _n , C _{17 is} a group of the formulas

H OH («)

respectively

YlI) γ Π

O ()

/ \
R ₁ R ₂

whereby

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

represents.

2. Medicines, characterized by a hold on one or more of the Compounds according to claim I as active air or active ingredients.

i. Process / for making the connections according to claim!, characterized in that dal.l man

a) Steroid-21 alcohols of the l'ivg nan series of the general l-ormel

IIX Oll

C O

C,

C,

wherein C ₄ -Cn, Ck ₁ -Ci ₇ , HIg, Ri and R _{2 are} as defined in claim 1, esterified in a manner known per se to give steroid 21-nitric acid esters or

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

H ₁ CC) -NO ₁

C,

C = O

/ C _x

¹⁷ C

wherein Cq-Cn, Ck, -O7, 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 1 -C 1 is a group of the formula

QC ₁₁ -

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

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

The known Stcroidsalpctcrsäurccstcr are easy to prepare and isolate. Because of their persistence (C. Djerassi, Steroid Reactions, pages 75 to 76 [1963]) they are very good for masking hydroxy groups

pen usable. Because of these few full oil properties are the nitric acid esters / for the production of other sumid compounds used in therapy usable, but also have valuable pharmacological effects themselves.

From drug research 19 (1% 9), page 684 to 685, and Chemical Abstracts 75 (1971), 77 155 k among various Sleroidsalpelersaureesiern also some Known steroid 21-nitric acid ester.

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

H ₁ CO NO,

!
I.

ν V-

wherein C, C ₁₁ door is a group of the formulas

FI

C ₄ -C _n HIg OH

respectively

whereby

HIg halogen means

and Ci6 - Ci _{7 is} a group of the formulas

I /

H OH (λ)

Kvieliimuswvisc

O O

R,

R ₁

whereby

Ri and R _{2 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.

The steroid 21-nitric acid esters according to the invention have namely after the pharmacological Investigations by the applicant on anti-inflammatory, antiallergic and cardiotropic effects. at A vasodilating effect can also be demonstrated for individual compounds.

• The compounds according to the invention are in particular with regard to their anti-inflammatory action think.

To demonstrate the above, the so-called Waite granuloma test was used to determine the anti-inflammatory effect comparative tests carried out, with the same conditions compound according to the invention

9a-fluoro-1 Ij9,16 <x, 17a, 2l-tetrahydroxypregna-

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

[Compound of the invention

Example 2] and

9 "-Fluoro-1, 3, 16", 17 ", 21-tetrahydroxypregna- ^4S 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 the toxicity compiled in Table 1 below, with almost the same toxicity anti-inflammatory effects.

Tabel

link
description

9ff-Fluor-1 \ ß, \ ba, 17fl \ 2i-tetrahydroxypregna-i, 4-diene-3,20-dione-16,17-acetonide-21 -nitric acid ester

9 tf-fluorine-1 l / U 6 «, 17 a, 2 1 -tctrahydroxypregna-1,4-diene-3.20-cl ion-16,21-disnitric acid ester

Assignment

Dose of inflammatory

hcmmcndc Wirkuni

(Watle Granuloma Test)

Inhibition in%

1.5 mg 47 according to the invention

Example 2

Comparison substance 4.5 mg 40

This clearly shows that the invention Connection of the Veigleichssubsian / by far is superior in that the much lower dose of 1.5 mg provides the higher anti-inflammatory properties of 47% shows, while the livestock subsum / self in a dose of 4.5 mg ιίιγ the lower inflammation inhibition of 40% has.

Furthermore, 9 / i, l / i-epoxy-16nt, 17 «, 21-trihydroxypregna-1,4-diene-3,2u-dione-16,17-iicclonid-21 nitric acid ester (compound of Example 4) dem

Table 2

link
lic / cichnung

^l ) ß, 1 1 // - Epoxy-16 ^, 17 if, 21-tri hydroxy pregna-l, 4-die n-3,2 () - d ion-16,17-acetonid-2 1-sal pe Ie! Acid esters

9 / i, 11 // - Epoxy-I6i /. 17 ^, 2 l-tiiiiydroxyprcgna-l, 4-diene-3,2 () -dione-16,17-ncetonide

corresponding free 21-alcohol, namely ^c / i, l I / M-Ipoxy-lb, v, I 7i \, 21-trihydronypregn; i-1,4-dien-i, 2 () - dione 16,17! -acetonide, a compound with a known good anti-inflammatory effect, as a comparative substance / compared. It was found that the strengths of action in both grooves are approximately the same, but that the compound according to the invention has a significantly better solubility than the comparison substance /. The results are compiled in Table 2 below.

/ uorcliuing

Solubility in μ / 1 0 (25 (

L'illndiingsgemäl.lcs
Example 4

Consumption Substance /

400

1 (1 (1

500

125

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 therapeuti- ^ s see application is possible.

In contrast, those in the literature references Arzneimittelforschung 19 (1969), pages 684 to 685, and Chemical Abstracts 75 (1971), 77 155 k (report from the Romanian patent specification 52 204) described Ste-; o roid-21-nitric acid ester of the compounds according to the invention constitutionally and also in the Direction of action apart. For example, in the publication Arzneimittelforschung 19 (1969), pages 684 to 685 just re the steroid 21-nitric acid ester? s (called 21-nitrates there) [compounds VI and following], when they are discussed on page 685, left Column, lines 11 to 18, there is no question of anti-inflammatory activity, only of others Effects, namely the natural retention capacity, the reduction of the hepatic glycogenesis and the increase in the thymolytic effect as well as the promotion of protein anabolism, and dins in spite of it the fact that for steroid 21-nitric acid esters Different steroid nitric acid cster which has anti-inflammatory effects is indicated. Therefore these are not suitable comparison 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

H ₁ C-OH

C = O

(H)

wherein C9-Cn, Cu, -Cw, HIg, R | and R2 as above are set to be esterified in a manner known per se to give steroid 21-nitric acid esters or

b) Steroid 21-nitric acid ester
the general formula

the Pregnan series

H ₂ CO-NO ₁ C = O

in which C ₄ -Cn, Cn, —Ci ₇ , HIg, Ri and R2 are defined as above, are converted into other steroid 21-nitric acid esters of the general formula I in a manner known per se

and optionally a compound of formula 1 which Cq-Cn is a group of the formula

Il

C _n

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

The esterification of the Stcroid-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 process according to the invention, the steroid-21-nitric acid esters can be prepared, for example, in such a way that steroid-21-alcohols of the general formula II are esterified in a solvent in a manner known per se with a mixture of concentrated nitric acid and acetic anhydride, namely in such a way that the solution containing the steroid 21 alcohol is added to the cooled mixture of nitric acid and acetic anhydride. After the esterification has ended, the mixture is poured into water and the organic phase is washed until the reaction is neutral and the solvent is removed. The steroid 21-nitric acid ester remaining as residue is purified by treatment with solvents and / or by crystallization. Mainly halogenated hydrocarbons are used as solvents. The reaction temperature, which is generally around 0 ⁰ C, and the amount and the mixing ratio of the nitric acid / acetic anhydride mixture used depend on which steroid-21-alcohol is used stoichiomelric 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 Stcroid-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 Purity over 90%.

According to the second embodiment of the fiction According to the method, steroid 21-nitric acid esters of the general formula I are based on known ones Reaction pathways converted into other compounds according to the invention.

If a compound having a double bond between the carbon atoms 9 and 1 I, that is one in which Ci-C'n tier general formula I a group of the formula

Il

C,

with IJ-Dihiom ^r ), ^r > dimethvlhydaNUiiii

is set, a 9a-bromo-l 1/3-hydroxyderivat, ie a compound in which C ₄ -Cn of the general formula I is a group of the formula

/ ϊ r

Br OH

means received. This bromohydrin can, for example, by splitting off hydrogen bromide into an epoxide in a manner known _{per se, that is to say a compound in which C 4} -Cn of the general formula I is a group of the formula

Il

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

is to be.

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

B c i s ρ i c I 1

There were 15.7 cm ¹ (23.59 g, 0.36 mol) of concentrated nitric acid (specific gravity of at least 1.50), with stirring and external erfolgendem cooling at - 10 ⁰ C 56.50 cm ¹ (61.26 g ; 0.6 mol) acetic anhydride was added dropwise. The temperature was kept at -10 "C, and there were 23.59 g (0.06 mol) of ^{leiX dissolved in 354 cm!} Of chloroform. ^ A ^ l-Trihydroxyprcgna-1,4,9 (1 l) -triene- 3,20-dione-16,17-acetonide was added The reaction mixture was stirred at this temperature for 30 minutes and then ^{poured into 1500 cm 1 of} ice water the chloroform extracts combined of the chloroform phase were washed until neutral, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. triun-j, 20-dione-16,17-acetonide-2l-nitric acid ester.1); The product was uniform on thin-sight chromatography.

Melting point: lh.i to lh ^l ) "('(iinkT /er.setzimg).

Bulge: 95.5%.

Consisting of a catalyzed from Mulhylakohol and acetone in a ratio of 8 .2 bustehundun mixture iimknslalli product decomposed at l (i8 "C.

F,! ;, = JH!: I (2: 38 to 2: i ^l ) ni | i; C, ||, ₁ () ||).

Molecular formula:
443.48).

Analysis:

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

C24H24O7N (Molecular Weight:

found: 0 = 24.90%.

Characteristic absorption maxima: 5.80 μ, 6, (
6.08µ, 6.17µ, 6.25µ, 7.80µ, 9.30µ, 9.57µ and 11.80µ.

L, 6.01 μ,

Example 2

There were 5.05 cm ^J (7.57 g; 0.12 mol) of concentrated nitric acid (specific gravity of at least 1.50), with stirring and external erfolgendem cooling at - 1O ⁰ C 18.9 cm ¹ (20.42 g ; 0.20 mol) of acetic anhydride and then 8.69 g (0.02 mol) of 9 <x -fluoro-1 l / 3.16a, 17a, 21-telrahydroxypregna-1 ^ -diene-S suspended ^{in 87 cm 3 of chloroform} ^ O-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 - stirred for 30 Minutes 10 ⁰ C and 250 'cm of ice-water poured. 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 white, crystalline 9 <x -fluoro-1, 3, 16 ", 17a, 21-tetrahydroxypregna-1, 4-diene-3,20-dione-16,17-acetonide-21-nitric acid ester were obtained. The product was uniform by thin layer chromatography.

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

Yield: 94.5%.

The decomposition point of the white crystalline product obtained after repeated recrystallization from acetone was 210 ^° C.

E, ':;"= 346 (238 to 239 ηιμ; C ₂ H ₁ OH).

Molecular formula: Ci ₄ H) OOkFN (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) 9β, \ l / J-Epoxy-Woc ^ i-dihydroxyprcgna-M-diene ^ O-dione in 92 cm 'chloroform according to Example 2 was implemented. Thus 7.84 g of yellowish-white, oily-crystalline 9 / J, 11 / J-iipoxy-17 ", 2l-dihydroxypregna-1,4-diene-3,20-dione-2lsalpier acid ester were obtained.

Yield 95.8%.

By rubbing the crude product with 16 cm of ether 6.42 g of one were obtained at 148 to 16 () "C with decomposition obtained melting white crystalline product. Which recrystallized several times from methyl alcohol Product decomposed at 165 "C and was uniform on dune herd thromatographic.

E 1 ■; "= 408 (248 to 249 ηιμ; C..11-, 011).

Molecular Formula: Cill ^ OfN (Molecular Weight: 403.42).

Analysis:

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

(Harakleristic absorption number: 3.00 μ, ^Γ >, Κ0 μ,

6.01 µ, 6.11 µ, 6.25 µ, 7.80 µ, I 1.22 µ and I 1.68 µ.

Example 4

A solution of 8.29 g (0.02 MoF 9ß, 11 ß- Epoxy-16 «, 17 <x, 21 -t rihydroxy pregna-1,4-diene-3,20-dione-16,17- acetonide in 166 cm 'chloroform with nitric acid and acetic anhydride according to Example 2. The reaction mixture was stirred for 1 hour at 0 ° C. and worked up in the manner indicated in Example 6. Thus 9.02 g of pale yellow crystalline 9jJ, llj3-epoxy were obtained -16 «, 17a, 21-trihydroxypregna-1 ^ -dien ^ O-dione-16,17-acetonide-21 -nitric acid ester, which was uniform in 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!.;. = 357 (247 to 248nHi; C> H-, OH).

Molecular formula: Ci ₄ Hj ₁ ) OsN (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 I 1.70 μ.

Example 5

There were 11.0 g (0.025 mol) of the 16 ", 17 <x, 21-trihydroxypregna-1,4,9 (l 1) triene-3,20-dione-16,17-acetonide-21 prepared according to Example 1 ο 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% aqueous solution of excess chloric acid and 5.38 g (0.019 mol) of!, S-dibromine were added to the solution at room temperature. SS-dimethylhydantoin added. The solution was protected from light and stirred at 20 to 25 ° C. for an 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 3} hours, and then the product was filtered off and washed with water until the reaction was neutral. 13.30 g of yellowish-brown 9, x-bromine-1 , 16a, 17 ", 21-tetrahydro-

xypregna-1 ^ -dien ^ O-dione-16,17-acetonide-21-sal-4S obtained pitric acid ester.

Bromohydrin content: 101.0%.

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

Yield: 98.5%.

The from a mixture of tetrahydrofuran unc si. Diisopropyl ether recrystallized product melted 202 "C (with decomposition).

EJ ₁₁₁ = 275 (241 to 242 ηιμ; CI 1, Ol I).

Molecular formula: C.,., 11 "> O _H DrN (molecular weight 540.42).

^ Analysis:

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

Characteristic absorption maxima: 2.93 μ, 5, KO μ ι .., 6.00 μ, 6.09 μ, 6.1. '; µ, 6.22 µ, 7.80 µ, 9.55 µ and 11.70 µ.

Example 6

It diaper) 9.41 μ (0.02 mol) in 100 cm ^{1 of} chloroform

1, s dissolved 9 <\ - llron-l l / <, l6 (\, l7 <\, 21-tetrahydroxypregna-

1,4-ilien- J, 20-clion-16,17-acetonide me Example 2 iiinge-

selzl. Thus 8.27 g 9, \ - Bmm-l I //. 1 fo / x.l7rx.21-tctrii-

liydn) xyptegna-l, 4-diene-3,20-dionl6.l7-acLMonid-2l-

obtained nitric acid ester. The bromohydrin content of the yellow crystalline product was 101.7%.

Melting point: 201 to 204.5 ⁰ C.

Yield: 76.5%.

The product would consist of a 1: 1 ratio of tetrahydrofuran and diisopropyl ether

the mixture recrystallized. According to the IR UV spectra and according to the results of layer chromatographic investigations, it was identical to the product prepared in the manner described in Example 5.
Decomposition point: 202 ⁰ C.

Claims (1)

22 22 49! Patent claims: 1. Steroid ^ l-nitric acid ester of the Pregnan series the general formula NO, C O