CS198295B2 - Method of producing water soluble corticoides - Google Patents

Abstract

Novel, water-soluble corticoids have the following formula <IMAGE> in which n denotes the figures 2 or 3, X denotes hydrogen, fluorine or chlorine and Y denotes hydrogen, an alkali metal atom or the N-methylglucamine radical. The compounds of the formula I are obtained by partially esterifying a corresponding 21-hydroxycorticoid with succinic anhydride or glutaric anhydride. Medicaments which contain a compound of the formula I as the active compound component can be used for the treatment of shock after an accident, burns, operation wounds, circulatory failure after intoxications, cardiac infarcts, pulmonary embolism and asthma.

Description

(54) A process for the production of water-soluble corticoids

The present invention relates to a process for the preparation of water-soluble corticoids, which, in general, means

These

a hydrogen atom, a fluorine atom or an alkali (I) chlorine and metal atom, or an N-ethylglucaine residue., the compounds are prepared by a corticoid of formula II

(II) where

X is as defined above, partially esterified in a known manner with succinic anhydride or glutaric anhydride, and the corticosteroids of formula I where Y is hydrogen and X and are as defined above are converted to their alkali metal or N-methylglucamine salts salts.

Particularly important compounds which can be prepared by the process according to the invention are: on the tri- (6,9,9-difluoro-1 H -hydroxy-16,6-methyl-1,20,20-dioxo-1,4-methyl-4-oxo-1,4-difluoro-1 H- pregnadien-21-yl / succinate, on trii [6- (4-fluoro-11) -hydroxy-16-methyl-1,20,20-dioxo-1,4-pregnadien-21-yl] succinate sodium (6'-fluoro-11'-hydroxy-16'-methyl-3,20,20-dioxo-1,4-pregnadien-21-yl) glutarate, sodium (9'-chloro-fluoro-fluorine) -1,13-Hydroxy-16-methyl-1-3,20-dioxo-1,4-pregnadien-21-yl] succinate, potassium- [6,9-9-difluoro- 11,13-Hydroxy-1,6-methyl-1,3,20-dioxo-1,4-piperidin-2-yl-succinate (6oC, 9'-fluorophen-1) 1/3-Hydroxy-16,6-methyl-1,3,20-dioxo-1,4-piperidin-2-yl-gamma succinate, 6H-fluoro-11'-hydroxy -1,6 (4-ethoxy-1,3,20-dioxo-1,4-pregnadien-21-yl) hemisuccinate, (6 ') -fluoro-11'-hydroxy-16'-hydroxy-1'-hydroxy 3,20-dio xo-1,4-pregnadien-21 -у 1 / hemiglu tate,

Z9dr-Chloro-6 (* -fluoro-11/3-hydroxy-16 *) - methyls 1-3,20-dioxo-1,4-pregnadien-21-yl (game succinate, sodium) 9-chloro-6-fluoro-11/3-hydroxy-1α-methyl-3, 20-dioxo-1,4-pregnadien-2'-yl / glutarate and N-methylglucamine / 6 < 5 &gt; -fluoro-11 (3-Hydroxy-16? -Methyl-3,20-dioxo-1,4-propyladien-21-yl) succinate

The novel water-soluble corticoids are characterized by a favorable ratio between therapeutic effect and tolerability. Compared to the previously known water-soluble corticoid derivatives of the general formula II (British Patent No. 1 286 093), the new corticoids are characterized by a much faster onset of action.

The therapeutic effect of the novel water-soluble corticoids can be determined, for example, by the known endotoxin shock, eosinophil assay or adjuvant-edema assay. For example, a thymolysis test, a liver glycogen test or a sodium and potassium retention test, or a tolerance test may be used to determine undesirable systemic side effects and thus tolerance of new corticoids.

The novel water-soluble corticoids can be formulated in conventional manner into special medicaments by converting them, optionally with suitable additives, carriers, solubilizers, stabilizers and flavoring agents, into the desired dosage forms such as tablets, dragees, capsules, solutions and the like.

For example, a certain amount of water-soluble corticoids, optionally after addition of conventional excipients under the usual pharmaceutical conditions, can be filled as dry substances into ampoules, preferably containing 10 to 500 mg of active ingredient. The contents of the ampoule are dissolved in sterile distilled water prior to administration.

The special medicaments can be advantageously used for the treatment of acute dangerous disease states (nerve shock after injury, burns, surgery, blood circulation poisoning failure, heart attack, pulmonary embolism, severe asthma attacks and the like).

Depending on the severity of the disease state, preferably 10 to 1000 mg of active ingredient are administered intravenously for the treatment of patients.

The production of new corticoids takes place in a manner well known to those skilled in the art. Thus, for example, corticosteroids of formula II are reacted with succinic anhydride or glutaric anhydride in the presence of a base such as pyridine, lutidine, potassium bicarbonate, sodium or potassium carbonate, sodium or potassium hydroxide, and the like, and optionally formed corticoids of formula I wherein Y is hydrogen are converted to their 3αs by reaction with alkali metal hydroxides, carbonates, acid carbonates or alcoholates.

For example, the following compounds can be produced by the process of the invention:

(6-ethoxy-9-difluoro-11/3-hydroxy-16eC-methyl 1-3, 20-dioxin-1,4-pregnadien-21-ou) hemiglutarate as well as its sodium and potassium salt as well as (9x) -chloro-6cO-fluoro-11/3-hydroxy-16-methyl-3,20,20-dioxo-1,4-pentadien-21-one / hemiglutate and its sodium or potassium salt.

The following examples serve to illustrate the process of the invention.

EXAMPLE 1 a (2 g of 6), 99-difluoro-11 (3,21-dihydroxy-16-methyl-1,4-pregnadien-3,20-dione) is dissolved in 10 ml of pyridine, 1 g of succinic anhydride is added and heated to boiling under argon for 30 minutes. After cooling, it is stirred in ice water, acidified with dilute sulfuric acid, the precipitated product is filtered off with suction, washed neutral and dried. Recrystallization from mixtures of acetone and hexane gave 2.1 g (6 ', 9'-di-fluoro-11) of myroxy-16-methyl-1, 20, 20-disxo-1,4-propyl-21-yl). melting point 199 DEG-201 DEG.

(b) 700 mg of hemisuccinate in 10 ml of absolute methanol are treated with 9.4 ml of a 0.1 N potassium melate solution to pH 8 using a pH of ether. The solution is concentrated in vacuo and precipitated in 600 ml of ether. The precipitated potassium salt was washed with ether and dried in vacuo over phosphorus pentoxide. 670 mg of potassium (6 ', 9'-difluoro-11,13-hydroxy-3,2,20-dioxo-1,16-methyl-1-1,4-priadiadil-21-yl) -tincinate are obtained. Melting point ^: 170-180 ° C.

c / 650 mg of gaming quinate is made up to pH 8 in 10 ml of absolute methanol with 11.4 ml of 0.1 N sodium methoxide solution. The solution is evaporated in vacuo and stirred in a mixture cooled to +3 ° C. which consists of 500 ml of ether and 100 ml of pentane. The precipitated product is filtered off with suction and dried under vacuum. There was thus obtained 630 mg of sodium (9M) -difluoro-11 (5-hydroxy-3,20-dioxo-1 H) -methyl-1 H -pregnadien-21-γ S -tetrate. Tep ^ ta 'point 175 DEG -180 DEG C. UV: 238 ^ 500Příklad2 and / 5g / ffut CV-s-11β, 21-dihydmsxy ~ 1 / a · ^t -шelyS 1,4-3,20-prlgnadiln The dione was reacted in 25 ml of pyridine with 5 g of succinic anhydride analogously to Example 1a and the same was worked up. After recrystallization from ethyl acetate, 5.2 g of (R) -dioxo-11,6-methoxy-3,20-dioxo-1,1'-p-g-dim-2-ol was obtained. -yl / hemi-succinate. Mp 210-212 ° C.

(b) 10 g of hemisuccinate are treated in 400 ml of absolute ground with. 17.9 ml of a 0.1 N sodium metasulfate solution to pH 8 and precipitated under the conditions described in Example 1c. There was thus obtained 9.6 g of Μ (ύύύ // / Ι «« «« f f lu f-f f f f f f f f f f f f f f f f f f f f f f f f f f,20,20,20,20,20,20,20 s simimimimimimim). Melting point: 163 DEG-170 DEG C. (decomposition).

EXAMPLE 3 / 5g 6 <^ flusr-1 1/3, 21-dihydroxy-l 6 <ι ^ - ^^ ιγΧι-1 _{and 4-3-prlgnjdiln>} 20-dione are refluxed in 20 ml pyridine with 2 g glutaric anhydride 45 min under argon. After cooling, it is stirred in ice water, diluted with sulfuric acid, filtered off with suction, washed until neutral and dried. The crude product is dissolved in ethyl acetate and shaken with 5% sodium carbonate. The separated aqueous phase was acidified with hydrochloric acid, extracted with ethyl acetate, and the extract was washed to neutralize the reaction. and evaporated in vacuo. There was thus obtained 5.2 g (G.fluoro-11A-hydroxy-1S-3.20-dioxo-1,4-pregnadien-21 melting point ^{) 71} . ^{to 173} ° C.

b) 2.5 g of the magnesium glutarate are converted analogously to Example 1c into the sodium salt. 2.4 g of loro-l-1,3-ydox y-l-6-methyl-3,20-disxo-1,4-trifluoromethyl-21-slgl-butyrate are obtained.

Mp 167 ° C (decomposition).

EXAMPLE 4 a / 1 g of 6-fluoro-9-chloro-11,3,21-dihydroxy-16-methyl-1,4-propyl-2,4-dione is heated. to boiling point in 5 ml of pyridine with 0.5 g of succinic anhydride for 30 minutes under an argon atmosphere. After work-up as described in Example 1a and recrystallization from acetone / sweeten, 1.23 g (69%) -904-: 1101 11/3-hexroxx-16-a-6 is obtained. 1- (1, 3, 20-dioxo-1 H -pregnadil-21 1-hexyl acetate). 249 ° C (dec.).

(b) 700 mg of hemisuccinate is converted into sodium salt in 0.1 ml of sodium neeylate solution in 15 ml of methanol. 570 mg of sodium (6/1, 000, 9'-chloro-11'-hydroxydoxy-1'-methyl-1-3,20-dioxo-1,4-l'-fluoroyl-21-χ1) are obtained. She's here. Melting point 165 ° C (decomposition),

98295

Example 5

Analogously to that described in Example 3, 8e, 60-fluoro-9d-chloro-11β, 3,22-dihydroxy-16α-methyl-1,4-pregnadiene-3 _t- 20-dione is converted to β-6. N- (3-hydroxy-1,3-dioxo-1,4,20-dioxo-1,4-pregaacetic acid) -21-l (h-miglutarate) m.p. up to 183.5 ° C, decomposition and this is further reacted with sodium (6-furr-96-) -chloro-11 H-dd> rχ-1 6 <^ / ^ t у ^ з ^ О ^ ^^ о-,, 4 (pregnadien) (21) yl] glutarate. 124 ° C / dec.

EXAMPLE 6 5 g of (6A-fluoro-11) -hydroxy-16-methyl-5-O-dloxo-1,4-pregnadien-21-ylhexidine and 0.646 g of N The glucyllucine is dissolved in 30 ml of double-white water and the clear solution is freeze dried for 24 hours. There was thus obtained 2.07 g of ammonium N-ethylglucaine (4-fluoro-1/33-hydroxy-16-methyl-3,20-drxxo-1,4-propylamino-21-yl) hexanate. .

Claims (2)

SUBJECT OF THE INVENTION A process for the preparation of water-soluble corticoids of the general formula I wherein n is the number 2 or 3, X stands for Y represents a hydrogen atom, a hydrogen atom, a fluorine atom or an alkali metal atom of chlorine and (I), or an N-methylglucamine residue, characterized in that the corticoid of the formula II wherein: X is as hereinbefore defined, partially esterified with succinic anhydride or glutaric anhydride and any cortices of formula I where Y is hydrogen and X and mm are converted to their salts with an alkali metal or N-methylglucamine salt. 2. The process of item 1 for producing compounds of formula Ia wherein X and n have the meanings given in 1 and are hydrogen or an alkali metal (Ia), characterized in that the corticoid of the formula II CH? OH 1 oo JL _Z ^CH 3 XT F where X is as defined above, partially esterified with succinic anhydride or glutaric anhydride, and the optionally formed corticoids of formula Ia wherein Y is hydrogen and X and n are as defined above are converted to their alkali metal salts.