DE2004767C3 - Halogen steroids, processes for their production and pharmaceuticals containing them - Google Patents

Description

CH., (Ill)

in which X and Y have the same meaning as in formula I, exchanged for halogen.

wherein Y and Z each represent a halogen atom, and wherein X represents a halogen atom having an atomic weight equal to or less than Y or a hydroxyl group.
2. Process for the preparation of halide d

G
steroids of the general formula

The invention relates to new halogen steroids of the general formula I.

CH ₂ Z

j CH, (I)

wherein Y and Z each represent a halogen atom, and wherein X is a halogen atom with the same or represents a smaller atomic weight than Y or a hydroxyl group, characterized in that that one in a known manner

a) to the I ⁹ "" double bond of a 21-halogen steroid of the general formula II 4 ^r >

CH,

(II)

in which Z has the same meaning as in formula I, halogen or hypohalous acid is added, and. if the ultimately desired process products are 9 \ -fluoro-2-chloro-11 / i-hydroxysteroids are the 9 \ -C'chloro- or bromo-11 / i-hydroxysteroids of formula I into the corresponding 9.11 // epoxy steroids transferred and then opens the epoxy ring with hydrogen fluoride, or

wherein Y and Z each represent a halogen atom, and wherein X represents a halogen atom having the same or represents a smaller atomic weight than Y or a hydroxyl group.

The invention also relates to a method for producing these halogen steroids, characterized in that that one in a known manner

a) to the! '"'" double bond of a halogen chloride of the general formula II

CH ₂ Z

(. '■■ · ■■ o

CH

in which Z has the same meaning as in formula I. Halogen or hypohalous acid added, and, if the ultimately desired process products are c 9 \ -fluoro-2-chloro-1 l / i'-hydroxysteroids, the 9-chloro- or bromine-11 / i-hydroxysteroids of the Formula I into the corresponding 9.1I / J-Fpoxysteroids transferred and then opens the epoxy ring with hydrogen fluoride, or

b) the 21-hydroxyl group of a 21-hydroxysteroids of the general formula III

CH,

(IH)

in which X and Y have the same meaning as in formula I, exchanged for halogen.

For the addition of halogen to the I ⁹ ″ ″ double bond in accordance with process variant a), there are a number of options to choose from. So you can z. B. halogens such as chlorine or bromine, or compounds of the halogens with one another, such as. B. chlorine monofluoride or bromine monochloride, or halogen from polyhalides, such as. B. potassium triiodide or iodobenzene dichloride, attach directly to the double bond.

The halogen addition works particularly well if a positive and a negative halogen are ^{allowed to act on the I 91} "'steroids at the same time. Reagents which contain positive halogen are, for example: halosuecinimides, haloacetamides or the halogens themselves; which supply negative halogen, for example, hydrogen halides and alkali metal halides, in particular lithium halides such as, for example, lithium chloride and lithium bromide, are suitable.

The addition of halogens to the I ¹ "'" double bond of the steroid always takes place in such a way that the positively charged halogen attaches to the 9-position and the negatively charged halogen to the 11-position of the molecule. The atomic weight of the halogen in the 9-position can never be less than that of the halogen in the 11-position because of the known different electronegativity of the halogens. The addition of halogen to the "" double bond is preferably carried out at temperatures between -75 "C and +50" C.

The addition of hypohalous acid onto the r "" double bond of the compounds of the formula II is carried out by the working methods generally known for this. A preferred method is the treatment of the I ⁹ "" double bond, with reagents which, in the presence of water and in the acidic reaction medium, release hypochlorous or non-bromine acid in the course of the reaction, in particular with reagents which form halogen cations, such as. B. Dibromomethylhydantoin, N-haloacylamides, especially N - chloro- or N - bromoacetamide or N - haloacylimides, especially N - bromo- or N-chlorosuccinimide.

If the ultimately desired process products are to be 9-fluorine compounds, the 9-bromo (or chlorine)] 1-hydroxy group is formed in a likewise known manner after halohydrin formation at the 9,1! Double bond , ζ. B. by treatment with basic reagents such as NaOH. KOH, K ₂ CO ,, potassium acetate, pyridine and the like at a preferably elevated reaction temperature, for the 9.11 oxidizing ring

closed, which then by means of hydrofluoric acid into the 11 / i-hydroxy-9 \ -Fluorgruppierung is converted.

The exchange of the 2I-hydroxy group for a Halogen atom according to process variant b) is also carried out according to known working methods.

A preferred method consists in esterifying the 21-hydroxy group with a sulfonic acid, preferably with methanesulfonic acid or p-toluenesulfonic acid, and then replacing the sulfonic acid group with halogen. The 21-hydroxy group is esterified, for example, by allowing a sulfonic acid chloride to act on the compounds of the formula III in the presence of an organic base such as pyridine or in the presence of aqueous alkali. The exchange of the sulfonic acid group for a halogen atom is preferably carried out by treating the 21-sulfonic acid ester with an alkali metal halide, such as, for example, lithium chloride or potassium hydrogen fluoride, in the presence of a polar solvent, such as. B. dimethylformamide, at a reaction temperature of 50 "C to 180 ⁰ C is implemented.

Another one? Method for exchanging the 21-hydroxy group Against a halogen atom is that the compounds of formula III with a common halogenating agents, such as. B. thionyl chloride or methanesulfonic acid chloride. This reaction is preferably carried out with an excess of halogenating agent in the presence of a organic base, such as pyridine, carried out at a reaction temperature below 80 "C.

The new compounds have excellent anti-inflammatory activity in the vasoconstriction test on male test subjects after local application, as shown in the table below using the example of the compounds II to IV according to the invention in comparison with the known 6 \ -Flu- or -11 //, 21-dihydroxy -16 \ - methyl -1,4-pregnadiene-'3,20-dione (I) is shown. This was extremely surprising, since the compounds mentioned by way of example do not contain any free or esterified hydroxyl groups. The vasoconstriction test used for the clinical-experimental evidence of superiority of the compounds according to the invention was carried out as follows: On the back of male test subjects (18 to 38 years of age), the stratum corneum was dismantled by tearing apart 20 times with a 2 cm wide adhesive tape and pronounced hyperemia was produced. Then about 50 mg of a water / oil ointment base were applied to marked 4 cm ² fields within the stripped area with the same application of pressure. each containing 0.1%, 0.01% and 0.001% of the test substance, respectively. The backs of the test persons were then photographed with a Kodak color film at certain time intervals. To assess hyperemia and vasoconstriction, the color of the individual skin areas was converted into brightness values on the Kodak color film. The areas projected by the color film through a pinhole onto an interference filter differ in their brightness. A secondary electron multiplier was used as a brightness indicator and the anode current of the secondary multiplier was measured to determine the color value. To determine the vasoconstriction, which is to be regarded as a representative syndrome of inflammation inhibition and with regard to the onset of action. Efficiency and effectiveness

duration was assessed, the color value is that of the untreated and the treated stripped skin and determined with the color value of the .normal skin compared, the color value of normal skin

Tabel

with = 100 and the color value of the untreated stripped skin with = 0 was determined. Low, moderate and severe vasoconstriction was rated between 0 and 100.

substance

Dose observation time in hours

in %

6 * -Fluoro-11 [12 1 -dihydroxy-16n-methyl-1,4-pregnadiene-3,20-dione

11 6>, 1

ethyl 1,4-pregnadiene-3,20-dione

6 », 1 l / f, 21-trifluor-Z9-dichloro-16 * -methyl-1,4-pregnadiene-3,20-dione

6 _i x, 2 (-Difluoro-2,9, I f // - trichloro-16 * -methy I-1 ^ -p

The test results shown in the table clearly show that when using the invention Active ingredients in addition to the earlier onset of action also the desired maximum effect is reached faster than with the reference substance. In addition, the intensity of action is the new active ingredients during exposure are consistently higher than with the known test substance.

In addition, there are the side effects caused under the influence of the compounds according to the invention desirably low. For example, the carbohydrate metabolism by the invention Connections not at all or only very slightly influenced. The gluconcogcnctic Effect is therefore greatly reduced, which is particularly evident from the fact that the blood sugar concentration is not increased and the liver glycogen does not increase until extremely high doses. Worth mentioning is also the only slight influence on the liver enzymes trvpiophanpyrrolase and the transaminases GOT and GPT. The influence on sodium, Potassium and phosphate excretion under the influence of the active ingredients according to the invention.

The new compounds are - in combination with those commonly used in pharmaceuticals Carriers - ■ well suited for the treatment of z. B. a) locally: contact dermatitis, various eczema Kind, eczema. Erythroderma, 1st degree burns, pruritus vulvac et ani, rosacea, Cutaneous erythematosus. Psoriasis, Liehen ruber planus et verrucosus:

b) Oral: acute and chronic polyarthritis, neurodermatitis, bronchial asthma, hay fever and others.

For the production of the starting products not previously described for the process according to the invention one can, for example, from 6-fluor-2-chloro-21-hydroxy-1 6λ-methyl-1,4,9 (H)-pregnatriene-3,20-dione go out, which can be displayed in the following way.

6 \ - fluoro-11 // - hydroxy-21-acetoxy-16λ -methyll, 4-prgnadiene-3,20-dione is in tetrahydrofuran at -10 C with N-chlorosuccinimide and hydrogen chloride implemented. The 6 \ -fluoro-2-chloro-1! // - hydroxy-21-acetoxy-iox-methyl-M-prgnadiene-3.20-dione is formed (Melting point 207 to 209 C). which one

0.1 5 35 65 100 75 0.01 0 20th 40 50 0.001 0 20th 40 55 0.1 10 25th 60 100 0.01 10 20th 50 100 100 0.01 20th 40 90 100 0.001 10 30th 80 90 100 0.01 10 30th 75 90 0.001 10 20th 60 90

100 100

by heating with methanesulfonyl chloride in pyridine-dimethylformamide in 6A-fluoro-2-chloro-2I-acetoxy-16 \ -methyl-1,4,9 (II) -pregnatriene-3,20-dione (Melting point 161-162 ° C) transferred. To saponify the 21-acetate is then dissolved in methylene chloride and the solution is treated with dilute methanolic Sodium hydroxide solution and receives the 6 \ -Fluoro-2-chloro-21-hy-

jo droxy -16 ^ - methyl -1,4,9 (H) - pregnatrien - 3,20 - dione (melting point 199 to 201 C; [>] i ^! = -5 ";UV:;, _{4 (} = 15700) .

To prepare the starting substances for process variant a), 6-fluoro-2-chloro-21-hydroxy-16λ-methyl-1,4,9 (11) -pregnatriene-3,20-dione can be used, for example, with methanesulfonic acid chloride in pyridine esterifies and receives the 6-fluoro-2-chloro-21-mesyloxy-16-methyl -1,4,9 (11) -prcgnatrinn - 3,20-dione (melting point 197 to 199 'C;|> J " = +8 "; UV:, _{M (J} = 15,600).

The methanesulfonic acid residue of this compound is then replaced in the usual manner by the ultimately desired Halogen atom exchanged, preferably in dimethylformamide or dimethyl sulfoxide with alkali halide.

a; z. B. lithium chloride or lithium bromide (about 1 hour at 100 ° C) or with potassium hydrogen fluoride (8 to 15 hours at about 110 ° C).

To produce the starting substances for process variant b), one can, for example, also

5 (i if 6 \ -Fluoro-2-chloro-21-hydroxy-16 \ -methyl-1,4,9 (11) -pregnadiene-3,20-dione start by proceeding under the reaction conditions already described to the I ⁹ "" double bond of the compound halogen or hypohalogenated acid is added and, if the desired starting products are 9> -fluoro-1 l / <-hydroxysteroids, the corresponding 9-chloro and 9> -bromo-l 1 / f-hydroxysts / oidc is converted into the 9,11 / i-epoxies and then the epoxy ring is opened with hydrogen fluoride.

Example i

A solution of 2.7 g of 6 \, 2l-difluoro-2-chloro-16 \ - methyl - 1,4,9 (11) -pregnatriene - 3,20 - dione (melting point 169 to 171 "C: [>] ir = 4.0. UV:; - ₂₄₅ = 15,400) in 110 ml of dioxane and 27 ml of water, 11 g of N-chlorosuccinimide and 11 ml of 70% perchloric acid are added

b0

stirred in. The precipitated substance is isolated and chromatographed on silica gel. Yield: 487 mg 6, *, 21-difluoro-2,9-dichloro-l! // '- hydroxy-16 \ -methyll, 4-pregnadiene-3,20-dione with a melting point of 238 to 240 ⁰ C (from acetone- Hexane). O] "= + 96 ° (chloroform). UV:. ~ ₂₄₆ = 15,500 (methanol).

Example 2

2.0 g of 6> -fluoro-2,21-dichloro-16A-methyl-1,4,9 (II) -pregnatriene-3,20-dione (melting point 185 to 187 ° C; jVji? = +29 "; UV: F ₂₄₅ = 15,700) are converted into the chlorohydrin as described in Example 1. The crude product, recrystallized from acetone-hexane, gives 1.30 g of ^ -fluoro-2,9,21-trichloro-II / i -hydroxy -16 "- methyl -1.4 - pregnadiene - 3.20 -dione from melting point 238 to 239.5" CO] J ⁵ = + 132 ° (chloroform). UV: F ₂₄₅ = 15,500 (methanol).

Example 3

2.2 g of 6A-fluoro-2,21-dichloro-16A-methyl-l, 4,9 (II) -pregnatriene-3,20-dione, 4.4 g of N-bromosuccinimide and 4.4 ml of 70% strength Perchloric acid in 88 ml of dioxane and 22 ml of water are stirred for 5 hours at room temperature. The reaction product is precipitated with ice water containing sodium sulfite, filtered off with suction, washed, dried and chromatographed on silica gel. 12 to 15% acetone-pentane elute 1.32 g of 6 - »- fluoro-2.21 - dichloro - 9 - bromo -1 l / i - hydroxy - 16λ - methyll, 4-pregnadiene-3,20-dione from the melting point 217 to 219 ° C (from acetone-hexane). O] "= + 117 ° (chloroform). UV: F ₂₄₉ = 14,200 (methanol).

Example 4

11.3 g of 6 »-fluoro-2,21-dichloro-9-bromo-II / i-hydroxy-16λ-methyl-1,4-pregnadiene-3,20-dione and 14.7 g of potassium acetate in 300 ml of ethanol are refluxed for 2 hours. After cooling, water is added, the precipitated product is filtered off with suction, washed, dried and chromatographed on silica gel. 10 to 13% acetone-pentene elute 2.99 g of fe-fluoro-2,21-dichloro-9.1 l / i-epoxy-16a-methyl- / i-pregna-1,4-diene 3,20-dione from melting point 125 to 128 "C (from acetone-hexane). O]" = + 58 ° (chloroform). UV: _.253 = 14,300 (methanol).

Example 5

At = 50 ° C dissolve in a mixture of 10 ml hydrogen fluoride and 10 ml dimethylformamide 3.0 g 6% - fluorine - 2.21 - dichloro - 9.1 l / i - epoxy - 16λ - methyl-9 / i- pregna-l, 4-diene-3,20-dione and left to react for 4 days at 0 ° C. The reaction mixture is stirred into water containing sodium hydrogen carbonate, the precipitated substance is filtered off with suction, dissolved in methylene chloride, the solution is washed with water, dried and evaporated in vacuo. The residue is chromatographed on silica gel. 22-23% acetone-pentane to elute 986 mg of 6 ', 9-difluoro-11 2.21 dichloro / i-hydroxy-1 -methyl 6x -1,4-pregnadiene - 3,20-dione of melting point 182-183 ° C (from diisopropyl ether). O] "= + 100 ° (chloroform). UV: F ₂₄₆ = 14,800 (methanol).

Example 6

6.2 g of 6 *, 21-difluoro-2-chloro-16-k-methyl-1,4,9 (II) -pregnatriene-3,20-dione are - as described in Example 3 - converted into the bromohydrin. The crude product is chromatographed on silica gel. 13 to 18% acetone-pentane to elute 2.30 g of 6- ^ 21-difluoro-2-chloro-9-bromo-l 1 .beta.-hydroxy-16% methyl-1,4-pre Nadien-3,20-dione of melting point 203 to 211 ° C (from acetone-hexane). O] "= + 10 ° (chloroform). UV r _ug = 14,200 (methanol).

Example 7

2.2 g 6, 21-difluoro-2-chloro-9-hrom-II / <-hydroxy 16 \ -methyl-1,4-pregnadiene-3,20-dione are - as described in Example 4 - converted into the epoxide

ίο The crude product is chromatographed on silica gel 8 to 9% acetone-hexane elute 1.02 g 6 \, 21-difluoro 2-chloro-9, ll / i-epoxy-16. \ - methyl-9 / i-pregna -l, 4-diene 3,20-dione from melting point 192 to 194 "C (also acetone-hexane). O]" = + 43 ° (chloroform). UV: / ₂₅ = 14,900 (methanol).

Example 8

950 mg of 6λ, 21-difluoro-2-chloro-9, ll / f-epoxy-16, v methyl-9 / i-pregna-1,4-diene-3,20-dione become - wi <in Example 5 - implemented with hydrogen fluoride. The crude product is recrystallized from acetone-hexar. 316 mg of 6a, 9,21-trifluoro 2-chloro-11 β- hydroxy -1 6λ-methyl -1,4-pregnadiene 3,20-dione with a melting point of 194 to 199 ° C. OP »= + 64 ° ( Chloroform). UV: F ₂₄₆ = 14500 (methanol)

Example 9

4.5 g 6λ, 21 - difluoro - 2 - chloro - 16 * - methyl 1,4,9 (1 l) -pregnatrien-3,20-dione in 225 ml of concentrated acetic acid are mixed with 4.5 g of N-chlorosuccinimide 22.5 g of lithium chloride and 4.5 ml of HCl-saturated dioxane are added and the mixture is 1 hour at room temperature touched. It is poured into water containing sodium sulfite and isolate the precipitated substance. This is chromatographed on silica gel. Yield: 1.96 j 6 \, 21-difluoro-2,9,1 l / I-trichloro-16x-methyl-1,4-pregnadiene-3,20-dione of melting point 243-246 ° C (from methylene chloride-acetone).

O] "= + 137 ° (chloroform). F ₂₄₄ = 15,500 (methanol).

Example 10

A solution of 2.2 g of 6 \, 21-difluoro-2-chloro- (6s-methyl-1,4,9 (II) -pregnatriene-3,20-dione in 4.4 ml of anhydrous hydrogen fluoride, 6.6 ml of tetrahydrofuran and 8.8 ml of methylene chloride are mixed with 4.4 g of N-chlorosuccinimide at −50 ° ^{C. After a reaction time of 16 hours at 0} ° C., the mixture is poured into water containing sodium hydrogen carbonate and sodium sulfite

The substance precipitated in this way is filtered off with suction, dissolved in methylene chloride, the solution is washed with water, dried and concentrated in vacuo. The residue is chromatographed on silica gel. 12-15% acetone-hexane elutes 453 mg of 6λ, 1 l / i, 21-trifluoro-2,9-dichloro- (6λ-methyl-1,4-pregnadiene-3,20-dione, melting point 249-250.5 ° C (from acetone-hexane). O] "= +86" (chloroform). UV: F ₂₄₄ = 15,600 (methanol).

Example 11

2.0 g 6λ - fluoro - 2.21 - dichloro - 16 * - methyl-1,4,9 (1st l) -pregnatrien-3,20-dione - as in example 9 - brought to reaction with N-chlorosuccinimide and lithium chloride. The raw product is chromatographed. Yield 692 mg of 6λ-fluoro-2,9,11 / i, 21-tetrachloro-16 * -methyl-1,4-pregnadiene-3,20-dione of melting point 250-252 "C (from acetone-hexane).

[ _Λ ] ·? = + 142 ° (chloroform). UV: _{> 244} = 15,500 (methanol).

Example 12

2.0 g of 6, λ-fluorine-2.21-dichloro-16χ-methyl-1,4,9 (11) -pregnatriene-3,20-dione are - as described in example 10 - with N-chlorosuccinimide and hydrogen fluoride implemented. The crude product is chromatographed. 8-9% acetone-pentane contains 367 mg fo, ll / i-difluoro-2,9,21-trichloro- (6 \ -methyll, 4-pregnadiene-3,20-dione, melting point 232-237 "C (from Acetone-hexane), [λ] J ⁵ = +103 (chloroform), UV: f _24J = 15,500.

10

at

13th

15th

i play i e1

A solution of 3.0 g of 6i-fluoro-2-chloro-21-acetoxy-16 * -methyl-1,4,9 (.ll) -pregnatriene-3,20-dione in 120 ml of dioxane, 30 ml of water, 12 g of N-chlorosuccinimide and 12 ml of 70% perchloric acid are added and the mixture is stirred one hour at room temperature. It is poured into water containing sodium sulfite, and the precipitated product is sucked off Product off, washed, dried and chromatographed on silica gel. 2.3-4.3% acetone-methylene chloride elute 1.23 g of 6a-fluoro-2,9-dichloro-II / i-hydroxy-21 - acetoxy -16 * - methyl -1,4 - pregnadiene - 3,20 - dione from melting point 120-12TC (from methanol);

[λ] ' _ο ⁵ = + 104 ° (chloroform). UV: ^ ₂₄₆ = 14,800 (methanol).

25th

1.20 g of OA fluorine-dichloro-II / i-hydroxy-l-acetoxy-16A-methyl-1,4-pregnadiene-3,20-dione are dissolved in 25 ml of methylene chloride. 24 ml of methanolic 0.2η potassium hydroxide solution are added and the mixture is stirred for 10 minutes at room temperature under nitrogen. It is diluted with methylene chloride, washed neutral with water, dried and concentrated in vacuo. The residue is chromatographed. 11-13.5% acetone - methylene chloride elute 480 mg 6a-fluoro-2,9 - dichloro -11 ß, 2 1 - dihydroxy -1 6λ - methyl -1,4 - pregnadiene-3,20-dione with a melting point of 249- 250 ⁰ C (from methylene chloride);

Mi ⁵ = + 95 ° (chloroform). UV: ^ ₂₄₅ = 15,200 (methanol).

450 mg of 6A-fluoro-2,9-dichloro-ll / i, 21-dihydroxy-16a-methyl-1,4-pregnadiene-3,20-dione are dissolved in 10 ml of absolute pyridine, and 2 ml of methanesulfonic acid chloride are added to the solution and stored under exclusion of moisture for 16 hours at room temperature. Then it is diluted with methylene chloride, the methylene chloride phase is washed with dilute sulfuric acid and water, dried and concentrated in vacuo. The residue is chromatographed on silica gel and gives 110 mg of 6 \ -fluoro-2,9,21 - trichloro-11 β - hydroxy -1 6λ - methyl -1,4-pregnadiene-3,20-dione of melting point 237-239 ° C (from acetone — hexane), [λ] !? = + 132 ° (chloroform). UV: ^ ₂₄₅ = 15,600 (methanol).

Claims (1)

Patent claims:
I. Halogen steroids of the general formula I CH, (I) 15th b) the 21-hydroxyl group of a 21-hydroxysteroids of the general formula III