DE2222491A1 - Steroid 21-nitric acid esters of the Pregnan series, their use and process for producing the same - Google Patents

Description

DR. STEPHAN G. BESZEDES üö6 DACHAU near MÖNCHEN

P.O. Box

PATENT ADVOCATE

AM HEJDEWEG 2

TELEPHONE: DAGHAU 4371

Postal checking account Munich 1368 71 Bank account No. 90 637 at the district and city savings bank Dachau-Indersdorf

P 44-0

Be s reit) u η g .

for patent application

JUDGE GEDSON VEGYESZETI GXAR RlT,

Budapest, Hungarian

concerning

Steroid-21-nitric acid e ster of the Pregnanreih e, their use and process for the production of the same

The invention relates to new steroid 21-nitric acid esters the Pregnanreilie, ih3? e use as medicament, in particular as anti-inflammatory, antiallergic and cardiotropic agents, as well as a method of making the same.

The known steroid nitric acid esters are easy to prepare and isolate. Because of their resistance (G. Djerassi, Steroid Reactions, page 75 to ^r / 6 [1963]) they are very useful for masking hydroxyl groups. Due to these valuable properties, the nitric acid esters are used

209847 / 121.3

Manufacture of other steroid coils used in therapy usable, but also have valuable pharmakolοgi themselves see effects.

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

H ₀ GO- NO

₁ ■ - Ο «means a single or double bond,

C ₉ -

for a group of formulas

, 9 Λ <

HIg OH

- G

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respectively

- G

^C 16 ~ ^C -17

in which

HIg

stands

Halogen and an d ~ or .beta.-hydroxy group or a is in the form of a Esterderivates inaslu.erte oi or ß »hydroxy _v

and

FerineIn's flu

- ^C 16 = ⁰ I ₇ O

16

respectively

O O

CR ₄ R ₅

in which

H, hydrogen, one

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o (~ or ß-methyl radical, a ' o (- or ß-Hydro: xy group or an Λ- or ß-hydroxy group masked in the form of an ester derivative stands,

-z represents a ct-hydroxy group or a cV-hydroxy group masked in the form of an ester derivative and

^ and Rr same or different Substituents, namely hydrogen, alkyl radicals nnfc 1 to 4 carbon atoms or, optionally ring-substituted, phenyl o, the Aralkyl radicals mean

represents.

Furthermore, according to the invention, medicaments which 1 or contain several of the above compounds as an active ingredient or active ingredients or be made from this or these exist, provided.

The steroid 21-nitric acid esters of the invention have namely, according to the applicant's pharmacological studies, anti-inflammatory, antiallergic and cardiotropic effects. A vasodilating effect can also be demonstrated with individual compounds. They are also used to manufacture others therapeutically effective steroid compounds can be used.

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

_ c _ 8 47/1213

2222431

a) 'Steroid-21-alcohols of the pregnancy series of the general ¹ formula

- OK

wherein

, R,

E He fixed- as above. .

¹ P γ ^Λ χ » ^Λ 4

& ^ ~ Τ

_r be placed in. a known manner zti steroid-21-esterified salpetersäiireestern

or

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

209847/1 2.1 3

-O-

wherein

R-

° 9 "° 11 ' ^C 16" ^G 17 R /, and Br as above

> ^j - ⁱ 2'- '3'
are set, can be converted into other steroid 21-nitric acid esters of the general formula I in a manner known per se

and optionally the steroid 21-nitric acid esters obtained are then isolated in a manner known per se.

According to the first embodiment of the method according to the invention, the steroid 21-nitric acid esters can, for example be prepared in such a way that steroid-21-al3iohole of the general formula TI in a solvent is known per se Way be esterified with a mixture of concentrated nitric acid and acetic anhydride, in such a way that the solution containing the steroid 21 alcohol to the cooled mixture of Nitric acid and acetic anhydride is added. After the esterification has ended, the mixture is poured into water and the organic phase washed until neutral and νο; Ί solvent freed. The residue left over Steroid 21-nitric acid ester is made by treating

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with solvents and / or by. Crystallize purified. Mainly halogenated hydrocarbons are used as solvents. The reaction temperature, which is generally around 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. The nitric acid and acetic anhydride are preferably used in excess of the stoichiometric amount.

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 obtained in the described Wdse Steroid 21-nitric acid ester is pale yellow or greenish in color. she can be obtained as a crude product in a yield of 85 to 95%. On the basis of thin-layer chromatographic investigations are they uniform and based on analytical tests the purity is over 90%.

This embodiment of the present invention "method is also suitable for the production of nitric acid diesters, nitric acid triesters, and suitable Salpetersäuretetraestern If, for example, such a compound of general formula II in which Cq -... C ^ a group of the formula ι ΐ ■" ·

- Cq - C _x , ^ - and / or G ^ - C ^ r ₇ a group of the formula ¹ OH.

Il

- C ^ f- - C ^ r ₇ - means or mean, gone out

j IO, i /

OH

nitric acid diesters and / or nitric acid triesters are formed by the esterification taking place in the manner described

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obtain. For example, from Pregna ~ 1,4-diene ~ 11ß, 17v /> 21 ~ -triol-3,20-dione, starting with Pregna-1,4 ~ άΐβη-11β, 17 _Λ , 21-triol--3,20-dione- 11,17,21-nitric acid briester obtained.

According to the second embodiment, the invention Method steroid 21-nitric acid ester are the general Formula I converted into other compounds according to the invention by reaction routes known per se. For example, if a compound having a double bond between the carbon atoms 9 and 11, i.e. one in which Cq - C ^ y, the general formula I a group of the formula

H
I.

^ rCq = C ^ - means with 1,3-bibrom-5 »5-dimethy! hydantoin is implemented, is a 94-bromo-11ß-hydro: xyderivat, so one Compound in which Cq - C ^, ^, of the general formula I a

II
Group of the formula ^ C _Q - 0 _ΛΛ - means obtained. This

r ■ ι

Br OH

Bromohydrin can, for example, by splitting off hydrogen bromide in a manner known per se into an epoxide, that is to say a compound, in various Cq - G ^ of the general formula I

H
I.
a group of the formula ^ Cq- C ^ «* - means to be converted.

These epoxies are important starting materials for the production of the fluorine-containing compounds that are very widely used in therapy.

The invention is not intended to be limiting in light of the following Examples to be understood are explained in more detail.

- 9 -209847 / 1213

example 1

7th

It became 15 »7 cm (23.59 g; 0.36 mole) more concentrated

Nitric acid (specific gravity at least 1.50) below

ο

Stirring and external cooling at -10 g 56.50 cm (61.26 g; 0.6 mol) acetic anhydride was added dropwise. The temperature was kept at -10 ⁰ G and there were 23.59 g (0.06 mol) dissolved in 354 cm ^ chloroform 16c (, 17tff, 21-Trihydroxypregna-1,4,9 (11) -trien-3, 20-dione-16,17-acetonide was added The reaction mixture was at this temperature

7th

Stirred for 30 minutes and then poured into 1,500 cnr ice water poured. After the aqueous phase had been separated off, it was extracted twice with chloroform and then ' the chloroform extracts combined with the chloroform phase washed until neutral, dried over anhydrous sodium sulfate and reduced under reduced pressure to Evaporated dry. Thus 25 / 1-0 g of pale yellow crystalline became 16 ^, 17 <^, 21 ~ Trihydroxypregna-1,4,9 (11) -triene-3,20-dione- ~ 16,17-acetonide-21-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 consisting of methyl alcohol and acetone in a ratio of 8: 2 decomposed at 168 ^° C.

^{up to 259} T ^{; C} 2 ^H 5 ^OH) Molecular formula: Co ^ H ₂ QOr ₇ N (molecular weight: 44-3.48).

Analysis;

calculated: 0 »25.25%; · '

found: 0 = 24.90%.

- 10 -

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- ίο -

Characteristic absorption maxima: 5.80 ρ, 6.01 / u, 6.08 ρ, 6.17 iu, 6.25 jii, 7.80 u, 9.30 ^ u, 9.57 / u and 11.80 | u.

Example 2

It became 5.05 cm ⁵ (7.57 g; 0.12 mole) more concentrated

Nitric acid (specific gravity at least 1.50) below

ο ^y i

Stirring and external cooling at -10 C 18.9 cirr (20.42 g; 0.20 mol) acetic anhydride. And then 8.69 g (0.02 mol) 9p (-Fluor- suspended in 87 C et chloroform) 11 ß, 164.17 <rt, 21-tetrahydroxypregna-1,4-diene-3,20- -dione-16,17-acetonide was added dropwise.The steroid dissolved in the reaction mixture in the course of 1 to 2 minutes stirred for 30 minutes at a 'temperature of from -10 ⁰ C and poured into 250 cmr Eisv / ater. The aqueous

7th

Phase was extracted 3 times with 90 cur chloroform each time. Otherwise, the procedure indicated in Example 1 was followed. Thus 9.06 g of yellow-white crystalline 9 <λ-Έ1υ.οτ- -1iß, 16 (A, 17 (A, 21-tetrahydroxypregna-1,4-diene-3,20-dione-16,17- - »acetonide -21-nitric acid ester obtained The product was uniform in 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.

until
Molecular formula: C ₂₄ H ₅₀ OgFN (molecular weight: 479.51)

- 11 -

209847/1213

Analysis:

calculated: I = 5.96%;
found: 1 = - 3.84%.

Characteristic absorption maxima: 3.00 / u, ·. 5.80 / u, 6.00 u, 6.06 ju, 6.17 yes, 6.25 .u, 7.82 «, 9.27 yes, 9.46 u and 11.80 ia. .

Example 3

There were 2.52 cm ^ (3.78 g; 0.08 mol) of concentrated nitric acid at -10 ⁰ G 9.44 cm ⁵ (10.21 g; 0.10 mol) acetic anhydride and 6.93 g (0, 02 mol) 17 ^, 21-Dihydroxypregn-4-en-3,20-dione suspended in 70 cm of chloroform was added dropwise. The reaction mixture was kept at -10 C for 10 minutes

7th

stirred and then poured into 250 cnr ice water. the aqueous phase was extracted twice with 70 ciir chloroform. The chloroform phases were as described in Example 1 Way worked up. Thus 6.80 g of 17 <7U21-dihydroxypregn-4 ~ -en ~ 3,20-dione-21-nitric acid ester obtained.

Melting point: 154 to 159 C (with decomposition). Yield: 86.8%.

After several recrystallizations from methyl alcohol, a A uniform product with a decomposition point of 159 ° C. was obtained in thin-layer chromatography.

E ^ _n , = 448 (240 to 241 mu; C ₅ H
ι cm ι egg

Molecular formula: Cp ₁₁ Hp ₀ OgN (molecular weight: 391.45).

Analysis:

calculated: 0 = 24.52%;

found: 0 = 24.3E5%. _ 12

• 209847/1213

Characteristic absorption maxima: 2.98 / u, 5 »81 / α, 6.08 ρ, 6.22 u, 7.80 u and 11.75 μ.

Example 4

8.4 cm * (12.6 g; 0.20 moles) were concentrated Nitric acid, 31.1 cm ^ (34.00 g; 0.33 mole) acetic anhydride and 6.93 U (0.02 mol) 17o (, 21-dihydroxypregn-4-ene-3,20-dione reacted according to Example 3 and then the reaction mixture was stirred at 0 C for 2 hours. Furthermore was carried out in the manner indicated in Example 3. So 7.12 g of 17 <A, 21-Dihydroxypregn-4-en-3,20-dione-17,21-di- - (ßnitric acid ester) obtained. The product was on thin layer chromatography uniformly.

Melting point: 127 to 140 ^° C. (with decomposition). Yield: 81.5%

After recrystallization of the crude product from a mixture consisting of methyl alcohol and ether in a ratio of 1: 1 and the subsequent recrystallization from methyl alcohol, the decomposition point was 141 ^° C.

C ₂ H ₅ OH). (Molecular weight: 436.45).

1%
E Υ = 416 (2 ^:
1 cm ^v - 59 to 3 240 nru K ₂ ( Molecular formula: ( '21 ^H 2c 3 ° 8 ^] Analysis: , 33%; calculated: 0 = 29 , 21%. found: 0 = 29

Characteristic absorption maxima: 5j68 / u, 5> 90 u 6.01 IU, 7.69 fu, 7.75 Ri and 11.82 / u.

- 13 209847/1213

Example 5

7.21 g (0.02 mol) of 16 ^ -Methyl-17 ^, 21-dihydroxypregn-4-en-3., 20-dione dissolved ^{in 144.CBr 5 chloroform were reacted according to Example 2.} After working up the product, almost white crystalline 16S-methyl-17iK _i 2'1 ~ dihjdro3cypregn-4 "en-3 _i 20-dione-21-sarpitic ester was obtained. The weight of the product, which was uniform on thin-layer chromatography, was 7 * 4-5 E *

Melting point: 146 to 159 ° C (with decomposition). Yield; 92%. '

The melting point of the product recrystallized several times from methyl alcohol was 156 ^° C. (with decomposition).

Siam formula: Cp2 ^H: 51 ° 6 ^ (molecular weight: 405.48) ,.

Analysis:

calculated: 0 «23.68% y
found: 0 «= 23.87%.

Characteristic absorption maxima: 2.98 p »5 ₅ 80 p, 6.01 p, 6.20 p, 7.80 p and 117OM

Example 6

It was a suspension of 7.17 g (0.02 mol) of J-1,4-diene-3,20-dione in

92 cm ^ chloroform according to Example 2 implemented. So were 7.84 g yellowish-white oily-crystalline 9 /, 11/3-epoxy, , 21-dihydroxypregna ~ 1,4-diene-3,20-dione-21-nitric acid

• - 14 209847/1213

obtained ester.
Yield 95.8;!.

Trituration of the crude product with 16 cnr ether was 6.42 g of an at 148-160 ⁰ C with decomposition melting white crystalline product were obtained. The product, which was recrystallized several times from methyl alcohol, decomposed at 165 '

uniformly"

at 165 C and was on thin layer chromatography

Molecular formula: ^C 21 ^H 25 ° 7 ^N (molecular weight: 403.42).

Analysis:.

calculated; 0 = 27.76%;
found: 0 = 27.67%. ·

Characteristic absorption maxima: 3.00 u, 5.80 u, 6.01p, 6.11 / u, 6.25 to, 7.80 / u, 11.22 η and 11.68 Ai

Example 7 '

A solution of 8.29 g (0.02 mol) of -Epoxy-16p (, 17i ^? I, 21-trihydroxypregna-1,4-diene-3,20-di \ on- -16,17-acetoij .id reacted with nitric acid and acetic anhydride in 166 cmr chloroform according to Example 2. The reaction mixture was stirred for 1 hour at 0 ° C. and worked up in the manner given in Example 2. 9.02 g of pale yellow crystalline 9 ^ , 11 ^ -Epoxy- -16 ^, 17ö (, 21-trihydroxypregna-1,4-diene-3,20-dione-16,17- ~ acetonide-21-nitric acid ester _: the one used in thin-film

- 15 -

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Chromatography was uniform.

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

The process recrystallized several times from methyl alcohol melted at 154 ° C (with decomposition).

4-7 to 2 * ■ , 48). Molecular formula: ' O ₂₄ H ₂₉ O ₈ I. 459 Analysis:· VS mn; C ₂ H ₅ OH). T (molecular weight:

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

Characteristic absorption maxima: 5 »78 Ia ₁ 5» 99 u, 6.06 p, 6.13 ^ u, 6.23 | u, 7> 7 & ν, 9.27yii, 9.62 / u and 11.7OjU.

Example 8

There were nitric acid and acetic anhydride in the. in example 4 specified amounts at -10 ° C for 15 minutes with a suspension of 7.17 g (0.02 mol) 16 (<, 17ii, 21-trihydroxypregna-1,4,9 (11) -triene-3,20-dione implemented according to Example 2 and the reaction mixture was worked up in the manner indicated in Example 2. So it was 8.32 g yellowish white crystalline 16o (, 17i {»21-Trihydroxypregna-1,4,9 (11) -triene-3,20-dione-16,21 -di (.salpet er acid ester) obtain. The product was uniform by thin layer chromatography and contained less than 0.1% di-oil contaminated.

16 ~

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Melting point: 172 to 182 ° G (with decomposition). Yield: 92.8%.

The product recrystallized several times from acetone melted at 174 ^° C. (with decomposition).

Ε * ⁹⁶ ,. ™ = 585 (237 Ms 238 mu; G ₃ H ₁ -OH).

Molecular formula: G ₂₁₁ H ₂ ^ OqN ₂ (molecular weight: 448.42).

Analysis:

calculated: 0 = 32.11%;
found: 0 = 31.96%.

Characteristic absorption maxima: 3 »12 ju, 5» 77 M, 6.01 u, 6.08 ji, 6.12 ju, 6.20 u, 7.22 yu., 7.8 OyU, 8.75 / u,

9.60 Ju, 11.62 u and 14.25 / u.

Example 9

11.0 g (0.025 hol) of the 16c <, 17i (, 21-trihydroxypregna ~ 1,4,9 (11) -triene--3,20-dione-16,17-acetonide-21 Nitric acid ester dissolved in 220 cnr tetrahydrofuran. 13.5 cm ⁵ (0.75 mol) V / water, 4.5 cm ⁵ (0.375 mol) of a 60% aqueous carbonic acid solution and 5.38 S (0.019 mol) 1,3-dibromo-5,5-dimethylhydantoin was added The solution was stirred at 20 to 25 ° C. for 1 hour, protected from light, and then poured into a solution of 2.7 g of sodium bisulfite in 1,100 cnr

Poured 1 water. The suspension was stirred for 1 hour and then the product was filtered off and washed with water until neutral. Thus 6 yellowish brown 9 ^ -Bron-11 _/ 3,16of, 17o (, 21-tetrahydroxypregna-1,4-diene-3,20-dione-16,17-acetonide-21-nitric acid ester were obtained at 13.30.

- 17 -

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Bromhydringehalt: 101 _r E%.

Melting point: 206 to 214 ⁰ G (with decomposition).

Yield; 98.5%. '

The umkri from a mixture of tetrahydrofuran and Biisöpropyläther
| inter decomposition).

Propyl ether recrystallized product melted at 20.2 g

^Ε ίL = 275 (241 to 242 mti; C ₀ H ₁ -OH.).

Molecular formula: C ₂ ^ H ^ ₀ OgBrN (-Molecular weights 540 ^ 2}

Analysis:

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

Characteristic: Absorptionsiüaxiina: 2.93 ^ i 5, ^ 0 6.00 p, 6.09 μ »6.15 p., 6.22 p, 7.80, U ,. 9.55 .ti and 11 * 70 Ji '

Example 1 0

9.916 (0-02 mol) 9 ^ -bromine ~ 11 ^, 16e4.17 (7 (j21-tetrahydroxypregna ~ 1,4-diene--3 »20-dione-16, 17 ~ acetonide converted according to Example 2. Thus 8.27 g of 9 ^ -Brom-11 ₍ 4,16ofii7i (, 21-tetrahydroxypregna-1,4-diene-3,2O-dione-16,17-acetonide ~ 21- The bromohydrin content of the yellow crystalline product was 101.7%.

Melting point: 201 to 204.5 ° C.

Yield: 76.5%. ·.

- 18 -

209847/1213

- Ϊ8 -

The product was made from one of tetrahydrofuran and
Diisopropylatiier in a ratio of 1: 1 existing mixture recrystallized. According to the IR and UV spectra and according to the results of thin-layer chromatographic investigations, it was identical to the product prepared in the manner described in Example 9.
Decomposition point: 202 ⁰ C.

Claims

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Claims (1)

Claims Steroid 21-nitric acid ester of the pregnane series of the general formula H ₂ C - O - NO ₂ wherein C * - C _{2 means} a single or double bond, Cq - C ,, ^ j for a group of formulas ? 9 "° 1 : I. HIg OH ^C \ 9 / ^G
0 - respectively »20 ~ 209847/1213 in which HIg means halogen and R ₁ an (A- or ß-hydroxyl group or a masked in the form of an ester derivative (A- or ß-hydroxyl group, represents. and ^ r ₇ a group of the formulas HH I. " ^C 16 * ^C 17C» " ^C 16" R ₂ ι alternatively - C, - ^ - - C ^ n 0 / C. \ ρ \ / ^R 4 ^E 5 -21 - 209847/121 3 in which R _{2 stands} for hydrogen, a 4- or ß-methyl radical, a ■ $ - or ß-hydroxy group or a iä •. Form of an ester derivates masked όί ^ * or ß ~ Hydrö3cy <~ group stands, R ₅ , an o <-ilydroxy group or an isster derivative in the form of its own • 'masked ö ^ HydröJcy- group darötelXtf E ^ and Re identical or different substituents, and ziwar ViTas « hydrogen, alkyl residues with 1 to 4 carbon lenstoffatöffien or ^ optionally ring-substituted, phenyl or aral kylreste mean depicted. 2.) Medicines, characterized by a content of 1 or more of the compounds according to claim 1 as an active ingredient * or active ingredients. j ■ 5.) Process for the preparation of the compounds according to claim 1, dadurqh marked that one - 22 - 209847/1213 a) Steroid 21 alcohols of the pregnancy series
general formula - OH wherein Claim 1 are set in a manner known per se to steroid 21-nitric acid esters esterified 'or b) Steroid 21-nitric acid ester of the pregnane series of the general formula _v 2098A7 / 1213 worm C ₁ - C ₂ , Cg - G ₁₁ , C ₁₆ - C ₁₇ , HIg, R ₁ , Ep, E,, R ^, and R, - 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 the steroid 21-nitric acid esters obtained then isolated in a manner known per se. M-.) Process according to claim 3 ^a i, characterized in that the esterification of the steroid-21-alcohol of the general formula II is carried out with a mixture of concentrated nitric acid and acetic anhydride. 5.) The method according to claim 3b, characterized in that 'one such a compound of the general formula I, in which Cq - C _{11 is} a group of the formula - 24 - 20984 7/1213 ^ rCq = C ^ - "means, ruifc 1 _$ hydantoin brings about the implementation 209847/1213