DE2307795C3 - 11 beta 17alpha, 21 trihydroxy-6 - Google Patents

Description

C-CH ₂ -OC = O

wherein R represents a hydrogen atom or an alkali metal atom.

2. Process for the preparation of the compounds according to claim 1, characterized in that the 21-mesylate of the formula III

-C-CH ₂ -O-SO ₂ -CH ₃ O

CH,

CH ₃

(III)

reacted with a double salt of m-sulfobenzoic acid in the presence of a dialkylamine and then the compound obtained via an ion exchange resin used in acidic form conducts, a compound of the formula I being obtained in which R represents a hydrogen atom, and optionally reacting this compound with an alkali metal hydroxide, a Compound of formula I is obtained, wherein R represents an alkali metal atom.

3. Pharmaceutical compositions, characterized in that they are effective Basic constituent contain at least one compound of formula 1 according to claim 1.

[3,2-c] pyrazolo-21-m-sulfobenzoate of the general formula

-C-CH ₂ -OC = O

wherein R represents a hydrogen atom or an alkali metal atom.

The invention also relates to a process for preparing a compound of general zo position Forme] I, which is characterized in that a compound of formula III

"_Y rr C-CH ₂ -O-SO ₂ -CH ₃

(III)

with a double salt of m-sulfobenzoic acid in the presence a dialkylamine and then the product obtained via an ion exchange resin conducts, which is used in acidic form, giving the product of general formula I, wherein R represents a hydrogen atom, and optionally this compound with an alkali metal hydroxide reacted to obtain the compound of the general formula I, wherein R represents an alkali metal atom.

The compound of the formula III, the 21-mesylate, is obtained in a known manner by a functional derivative of methanesulfonic acid with 11, ϊ, 17α, 21 - trihydroxy - 6,16 «- dimethyl - 2,4,6-pregnatriene - 20 - one - 2 '- phenal [3.2 - c] pyrazole of the formula II

CH ₁

C-CH ₂ OH

(H)

The invention relates to a 11 / 3,17a, 2t-trihydroxy-6,1 6a -dimethyl-2,4,6-pregnatriene-20-one-2'-phenyl-converted.

The invention also relates to pharmaceutical compositions which are characterized in that

that they contain at least one compound of formula 1 according to claim 1 as an effective basic ingredient contain.

In the process according to the invention for the preparation of the derivatives of the general formula 1 works one preferably as follows:

The compound of the formula JU is left at a temperature of about 95 ° C. with the sodium m-sulfobenzoate react in the presence of dimethylformamide and then pass the product obtained via an ion exchange resin (acidic form) to obtain the compound of general formula I, wherein R represents a hydrogen atom.

If so desired, the compound of the general formula I in which R is obtained is used Represents hydrogen atom, with sodium hydroxide to form the compound of general formula 1 um, wherein R represents a matrium atom. Likewise, if so desired, the connection is made of the general formula I, in which R represents a hydrogen atom, with other alkali metal hydroxides, like those of lithium or potassium.

The derivatives of the general formula I have very interesting pharmacological, especially anti-inflammatory Properties. In particular, it has been found, for example, that the connection of the general formula I, in which R represents a hydrogen atom, has a duration of action that is im Comparison with that of the esters of the same alcohol, i.e. H. des 11 / ί, 17α ^ 1 - trihydroxy - 6,16a - dimethyl-2,4,6 - pregnatrien - 20- on - 2 '- phenal [3,2 - c] pyrazole, surprisingly is considerably elongated.

Such esters are in the French patent 14 82 808.

Clinical studies have shown the compounds to be of considerable efficacy, particularly in the Treatment of asthmatic conditions, confirmed. You have such a regular and long-lasting one Effect of the 21-m-sulfobenzoate of the formula I (R = H) found, whereas certain known derivatives are not very effective.

Due to their remarkable pharmacological properties, especially anti-inflammatory, the compounds of general formula I are very useful for therapeutic purposes. she can be used, for example, in humans for the treatment of acute or chronic rheumatic diseases, used in inflammatory dermatoses, asthma and viral hepatitis will.

The usual dose depends on the particular disease, the product used, the treated Patient and route of administration. You can for example from 0.1 mg to 10 mg per Day in humans by the intramuscular route.

The compounds of general formula 1 can be incorporated into pharmaceutical compositions intended for oral, parenteral or topical use. This pharmaceutical Compositions can for example in solid or liquid foito or in usually in forms used in human medicine, such as simple tablets or dragees, Capsules, granules, solutions, suspensions, syrups, suppositories, various injectable preparations, such as solutions, suspensions, sterile ones for immediate preparation and administration Powders, ointments, creams, gels and aerosols. They are made according to the usual pharmacotechnical Methods made. The active ingredient or ingredients can usually be found in excipients used in pharmaceutical compositions, such as talc, gum arabic, Lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous carriers,

ίο greasy animal or vegetable-based bases, paraffin derivatives, glycols, various wetting agents, dispersants, emulsifiers and preservatives.
The following examples serve to illustrate the invention without restricting it.

example 1

11 / ϊ, 17α, 21 -Trihydroxy-o.Ioa-dimethyl ^ .o / regnatrien-20-one-2'-phenyl [3,2-c] -pyrazolo-21-m-: 5ulfobenzoate (acidic form, R = H):

A: Preparation of the 21-mesylate des II / ?, 17u, 2i-trihydroxy - 6,16a - dimethyl - 2,4,6 - pregnalrien - 20 - one-2'-pheny! [3,2-cjpyrazoles

Dissolve 10.33 g (0.0212MoI) 11 / U 7u, 21-trihydroxy-6,16a-dimethyl-2,4,6-pregnatriene-20-one-2'-phenyl [3,2-c] pyrazole in 60 ml of methylethylpyridine and stir for about 10 minutes at a temperature of + 24 ⁰ C.

3.3 ml (0.0424 mol) of methanesulphonyl chloride are introduced into the resulting solution for about 5 minutes one.

Increasing the temperature of +24 ⁰ C to + 28 ° C for 10 minutes, then cooled to + 10 ⁰ C ± 2 ° C in an ice bath, and this temperature retains 1 hour.

The solution is then poured into one of 250 ml of distilled water and 40 ml of concentrated hydrochloric acid mixture formed. The mixture is stirred for 2 hours and then the pH is adjusted to 1.

It is extracted with ethyl acetate, washed with water until pH = 4-5, dried over sodium sulphate and dried concentrated to dryness in vacuo.

An amorphous product is obtained, which is obtained by chromatography on silica and eluting with a mixture of ethyl acetate (4) benzene (6). 7.7 g of a white amorphous product are isolated, which is recrystallized from a mixture of acetone-water (1/1).

After suctioning off, washing and drying, 6.56 g (55% yield) of the 21-Mi: sylate des 11 ß, 17a, 21-trihydroxy-6,16a-dimethyl-2,4,6-pregnatriene-20- on-2'-phenyI [3,2-c] pyrazole in the form of a white crystalline product which is soluble in ethanol, chloroform, acetone and ethyl acetate and is insoluble in water and melts at 195 ° C. [u]? = +1.5 ± 1 ° (c = 0.65%, chloroform).

B: 110, 7a, 2- trihydroxy-6,16 "-dimethyl · 2,4,6-pregnatrien-20-one-: i'-phenyl [3,2-c] pyrazolo-21-m-

sulfobenzoate (acidic form, R = H)

The mixture is warmed to 3 f »(0.0132 mol) monosodium m-sulfobenzoate in 3 ml of distilled water to 90 to 95 ° C and add 1.03 g (0.0123 mol) of sodium bicarbonate and stir for 10 minutes. 100 ml of dimethylformamide are then added to the solution and the mixture is distilled to remove all water. The mixture is cooled to 95 ° C. and all at once 5 g (0.0088 mol) of des

21-mesylate des II / J, 17a, 21-trihydroxy-6,1Ou-dimethyl-2,4,6-pregnatriene-20-one-2'phenyl [3,2-c] -pyraiols. The mixture is stirred for 5 hours at 95 ° C. under a stream of nitrogen. It is concentrated to dryness in vacuo, and the residue is taken up in 100 ml of an ethanolic solution containing 50% water. The solution obtained is then passed over an acidic ion exchange resin of the Dowex 50 H® type. Collecting the eluate and distributes the alcohol by distillation in vacuo (12 mm Hg, temperature <50 ⁰ C), kiiistaUistert The acid and is filtered off and washed four times with distilled water. After a second pass over ion exchange resin, followed by distillation in vacuo, a cream-colored solid product is obtained which is dissolved in 60 ml of acetone. 60 ml of water are then added and the solution is concentrated. The crystals formed are filtered off with suction and washed with a mixture of acetone (15) and water (60). The product obtained is redissolved in 70 ml of acetone and treated with 60 ml of water, whereupon the solution is concentrated. The crystals formed are acidified and washed with a mixture of acetone (25) and water (60).

A crude product is obtained which is recrystallized from a mixture of acetone and water (1/1). After concentrating, the crystals formed are suctioned off and mixed with a mixture of Acetone (15) and water (50).

After drying in vacuo, 4.05 g of 11 ß, 17a, 21-trihydroxy-6,16a-dimethyl-2,4,6-pregnatriene-20-one-2'-phenyl [3.2-c] pyrazolo- 21-msulfobenzoate in an amount of 68.5% in the form of fine needles that melt at 280 ° C. The compound is soluble in a mixture of water-acetone and water-ethanol and is sparingly soluble in acetone, water, ethanol, [a] i? = + 103 ° ± 2 ° (c = 1%, ethanol with 50% water).

Analysis: C ₃₇ H ₄₀ O ₈ N ₂ S = 672.78

Calculated ... C 66.05, H 5.99, N 4.17, S 4.77%;
found .... C 65.8, H 6.3, N 4.0, S 4.6%.

B e i s ρ i e 1 2

^^ yyy

2,4,6-pregnatrien-20-one-2'-phenyl [3,2-c] pyrazolo-

21-m-sodium sulfobenzoate (R = Na)

1.6 g (0.00238 mol) of the 11 / ?, 17 ", 21-trihydroxy are added - 6,16a - dimethyl - 2,4,6 -ρ regnatriene - 20 - one-2'-phenyl [3,2-c] pyrazole-21-m-sulphene benzoate in a solution consisting of 23.8 ml of 0.1 N sodium hydroxide and 137 ml of distilled water. You let them Warm mixture slightly to get a clear solution

s, and then adjusts the pH to 7.3 Addition of small amounts of the free 1 l / ?, 17u, 21-trihydroxy - 6.16u - dimethyl - 2,4,6 - pregnatriene - 20 - on-

2'-phenyl [3,2-c] pyrazolo-21 -m-sulfobenzoate.

The solution is filtered and the obtained lyophilized Filtrate. 1.61 g (97.5% yield) of the 1 l / f, 7 ", 21-trihydroxy-6,16a-dimethyl-2,4,6-pregnatrien-20-one-2'-phenyl [ 3,2-c] pyrazolo-21-m- sodium sulfobenzoate in the form of a pale yellow powder which is soluble in water.

Analysis: C ₃₇ H ₃₉ O ₈ N ₂ NaS = 694.77

Calculated ... C 58, H 6.14, N 3.63, Na 3.01

S 4.2%;

found ... C 58.5, H 6.2, N 3.8, Na 3.1,
S 4.1%.

UV spectrum - ethanol:

max. 228 nm
max. 282 nm
max. 314 mn

Ej * = 300
El * = 242
E | * = 273

= 18,900

Nujol:

1R spectrum

Ketone at 1715 cm "" ¹ ,
1594 and 1499 cm " ¹ .

C = C aromatic at

Preparation of pharmaceutical compositions:

A) Injectable preparations are made with the following composition:

11β, \ 7u, 21-trihydroxy-6,16a-dimethyl-2,4,6-pregnatrien-20-one-2'-phenyl- [3,2-c] pyrazolo-21-m-sulfobenzoate in

acidic form 3 mg

Carrier ad 2 cm ³

B) Tablets of the following formulation are produced:

1Ϊ ß, 17a, 21 -Trihydroxy-6,16a-dimethyl-

2,4,6-pregnatrien-20-one-2'-phenyl-

[3,2-c] pyrazolo-21-m-sodium sulfo-

benzoate 1 mg

Carrier in sufficient shape for
a pill

(Carrier: lactose, starch, talc, magnesium stearate)

Claims (1)

A \ Patent claims: f 1. 11 | ϊ, 17α, 21-trihydroxy-6,16α-dimethyl 2,4,6-pregnatrien-20-one-2'-phenyl [3,2-c] pyrazolo 2.1-m-sulfobenzoate of the general formula CH ₃