NO138148B - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE LITHIUM SALT OF 6ALFA-METHYLPREDNISOLONE - Google Patents

PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE LITHIUM SALT OF 6ALFA-METHYLPREDNISOLONE Download PDF

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NO138148B
NO138148B NO2058/73A NO205873A NO138148B NO 138148 B NO138148 B NO 138148B NO 2058/73 A NO2058/73 A NO 2058/73A NO 205873 A NO205873 A NO 205873A NO 138148 B NO138148 B NO 138148B
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methylprednisolone
mixture
preparation
lithium salt
6alfa
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NO138148C (en
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Simone Heurtaux
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Roussel Uclaf
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring

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  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Steroid Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Compositions Of Macromolecular Compounds (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)

Description

Foreliggende oppfinnelse angår en analogifremgangsmåte ved fremstilling av terapeutisk aktivt lithiumsalt av 6a-methyl-prednisolon av generell formel I: The present invention relates to an analogous method for the production of the therapeutically active lithium salt of 6a-methyl-prednisolone of general formula I:

ved hvilken fremgangsmåte et funksjonelt derivat av methansulfon- by which method a functional derivative of methanesulfon-

syre omsettes med 6a-methylprednisolon under dannelse av for- acid reacts with 6a-methylprednisolone with the formation of

bindelsen av generell formel II: the bond of general formula II:

hvilken fremgangsmåte er kjennetegnet ved at den således erholdte forbindelse av formel il omsettes med et dialkalisalt av m-sulfon- which method is characterized by the fact that the thus obtained compound of formula II is reacted with a dialkali salt of m-sulfone

benzoesyre i nærvær av et dialkylamid, og at den erholdte for- benzoic acid in the presence of a dialkylamide, and that it obtained

bindelse føres gjennom en ionebytterharpiks anvendt i syreform, bonding is carried out through an ion exchange resin used in acid form,

hvorefter det erholdte produkt omsettes med lithiumhydroxyd eller lithiumcarbonat under dannelse av produktet av formel I. after which the product obtained is reacted with lithium hydroxide or lithium carbonate to form the product of formula I.

Ved utførelse av fremgangsmåten arbeides det fortrinnsvis When carrying out the procedure, work is preferably done

som følger: as follows:

a) 6a-methylprednisolon løses i pyridin, avkjøles til en temperatur på -10°C hvoretter methansulfonylklorid tilsettes. Blandingen oppvarmes under tilbakeløpskjøling noen minutter, og 21-methylsulfonatet av 6a-methylprednjsolon samles. b) 21-methylsulf onatet av 6a-methylpredndsolon oppvarmes med dinatrium-saltet av metasulfobenzoesyre i nærvær av et dialkylamid slik som • a) 6a-methylprednisolone is dissolved in pyridine, cooled to a temperature at -10°C after which methanesulfonyl chloride is added. The mixture is heated under reflux for a few minutes, and the 21-methylsulfonate of 6α-methylprednisolone is collected. b) The 21-methylsulfonate of 6a-methylprednisolone is heated with the disodium salt of metasulfobenzoic acid in the presence of a dialkylamide such as •

dimethylformamid. 21-metasulfonatriumbenzoatet av 6a-methylprednisolon oppsamles. dimethylformamide. The 21-metasulfonate sodium benzoate of 6α-methylprednisolone is collected.

c) 21-metasulfonatriumbenzoatet av 6a-methylprednisolon suspenderes i vann og det tilsettes en ionebytterharpiks i syreforra. Blandingen c) The 21-metasulphon sodium benzoate of 6a-methylprednisolone is suspended in water and an ion exchange resin is added in acid forra. The mixture

filtreres, og filtratet behandles med lithiumhydroxyd eller lithiumcarbonat hvoretter produktet av formel I oppsamles. is filtered, and the filtrate is treated with lithium hydroxide or lithium carbonate, after which the product of formula I is collected.

Derivatet av generell formel i utviser meget interessante farmakologiske egenskaper, spesielt anti-inflammatoriske. Som følge av disse bemerkelsesverdige egenskaper er forbindelsen av formel I meget anvendbare innen terapien, spesielt ved behandling av inflammatoriske tilstander av reumatisk herkomst eller leddgikt. The derivative of general formula I exhibits very interesting pharmacological properties, especially anti-inflammatory. As a result of these remarkable properties, the compound of formula I is very useful in therapy, especially in the treatment of inflammatory conditions of rheumatic origin or arthritis.

Den anvendte dose varierer alt etter det anvendte produkt, pasient og sykdommens tilstand, og kan være f.eks. 2 til 100 mg pr. dag ved injeksjoner til mennesket. The dose used varies according to the product used, the patient and the condition of the disease, and can be e.g. 2 to 100 mg per day by injection into humans.

Forbindelsen av formel I kan anvendes ved fremstilling av , farmasøytiske komposisjoner inneholdende som aktiv bestanddel av forbindelsen av generell formel I, og i særdeleshet injiserbare vandige løsninger. The compound of formula I can be used in the preparation of pharmaceutical compositions containing as active ingredient the compound of general formula I, and in particular injectable aqueous solutions.

De farmasoytiske komposisjoner kan fremstilles for å administreres ved oral-, parenteral- eller lokal måte. De kan være faste eller flytende, og foreligge som de vanlige .anvendte farmasoytiske former • slik som f.eks. enkle tabletter, eller dragéer, gelatinkapsler, granuler, stikkpiller, injiserbare preparater, pomader, kremer, geler, og de kan fremstilles etter kjente metoder. The pharmaceutical compositions can be prepared to be administered by the oral, parenteral or topical route. They can be solid or liquid, and present as the usual pharmaceutical forms used • such as, for example, simple tablets, or dragées, gelatin capsules, granules, suppositories, injectable preparations, pomades, creams, gels, and they can be prepared by known methods.

Den aktive bestanddeler kan inkorporeres i de vanlige anvendte ekspisienter i de farmasoytiske komposisjoner, slik som talkum, arabisk gummi, lactose, stivelse, magnesiumstearat, kakaosmor, vandige eller ikke vandige bærere, fett av animalsk eller vegetabilsk opprinnelse, paraffiniske derivater, glykoler, diverse fuktemidler, dispergeringsmidler eller emulgeringsmidler og konser-veringsmidler. The active ingredients can be incorporated into the commonly used excipients in the pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous carriers, fats of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents , dispersants or emulsifiers and preservatives.

Det nye derivat av 6a-methylprednisolon av generell formel I utviser viktige, fordelaktige egenskaper. På den ene side er det lett løselige i vann, .men fremfor alt. har dette, samtidig som det bibeholder den farmakologiske aktivitet av kjente og vannloselige 6a-methylpredflso-londerivater" en bedre stabilitet i vandig lbsning sammenlignet med disse-kjente forbindelser. Man har således konstatert at i vandige løsning-er på 1, 5% av 21-metasulfolithiumbenzoat av 6a-methylprednisolon, oppvarmet til 100°C i 6 timer, viser konsentrasjonen av fritt 6a-prednisolon ingen merkbar okning, mens det f.eks. i vandige losninger på 1, 5% av natriumsaltet av hemi-succinatet av 6a-me'thylpredhisolon, oppvarmet under de samme betingelser, observeres en okning i fritt 6a-methylprednisolon på ca. 50%. (Det er å bemerke at de to derivater av 6a-methylprednisolon utviser en aktivitet av samme størrelses-orden) . The new derivative of 6α-methylprednisolone of general formula I exhibits important, advantageous properties. On the one hand, it is easily soluble in water, but above all. this, while retaining the pharmacological activity of known and water-soluble 6α-methylpredazolone derivatives, has a better stability in aqueous solution compared to these known compounds. It has thus been established that in aqueous solution 1.5% of 21 -metasulfolithium benzoate of 6a-methylprednisolone, heated to 100°C for 6 hours, the concentration of free 6a-prednisolone shows no noticeable increase, while, for example, in aqueous solutions of 1.5% of the sodium salt of the hemi-succinate of 6a- methylprednisolone, heated under the same conditions, an increase in free 6a-methylprednisolone of approximately 50% is observed (It should be noted that the two derivatives of 6a-methylprednisolone exhibit an activity of the same order of magnitude).

Dette er årsaken til at man blant de farmasøytiske komposisjoner som taes i betraktning, spesielt foretrekker vandige losninger This is the reason why, among the pharmaceutical compositions that are taken into account, aqueous solutions are particularly preferred

og i særdeleshet injiserbare vandige losninger inneholdende 21-metasulf olithiumbenzoatet av 6a-methylprednisolon. Blant disse skal spesielt nevnes injiserbare vandige losninger'""inneholdende 21-metasulf olithiumbenzoatet av 6a-methylprednisolon, propylenglykol og lithiumbenzoatet. and in particular injectable aqueous solutions containing the 21-metasulf olithium benzoate of 6α-methylprednisolone. Among these, injectable aqueous solutions containing the 21-metasulf olithium benzoate of 6a-methylprednisolone, propylene glycol and the lithium benzoate should be mentioned in particular.

Det etterfølgende eksempel illustrerer oppfinnelsen uten The following example illustrates the invention without

å begrense denne. to limit this.

EKSEMPEL 1 EXAMPLE 1

21- metasulfolithiumbenzoatet av 6q- methylprednisolon: TRINN A: 21- metasulfonatriumbenzoatet av 6q- methylprednisolon The 21- metasulfolithium benzoate of 6q- methylprednisolone: STEP A: The 21- metasulfosodium benzoate of 6q- methylprednisolone

En blanding av 6 g metasulfomononatriumbenzoat og 6 ml vann ble oppvarmet til 90-95°C under omrøring,.hvoretter det ble tilsatt 2, h5 g natriumbicarbonat og deretter 160 ml dime.thylf.ormamid, og destillert under omroring til kokepunktet forble, konstant ved 150-151°C. Suspensjonen ble deretter avkjølt til 95°C, hvoretter det ble tilsatt under nitrogenatmosfære 10 g 21-methylsulfonat av 6a-methylprednisolon og blandingen ble omrbrt i 5 timer ved 95°-100°C. Blandingen ble fordampet til tørrhet under vakuum, residuet ble tatt opp med 30 ml ethanol og fordampet til tørrhet under vakuum. A mixture of 6 g of metasulfomonosodium benzoate and 6 ml of water was heated to 90-95°C with stirring, after which 2.5 g of sodium bicarbonate and then 160 ml of dimethylformamide were added and distilled with stirring until the boiling point remained constant at 150-151°C. The suspension was then cooled to 95°C, after which 10 g of 21-methylsulfonate of 6a-methylprednisolone were added under a nitrogen atmosphere and the mixture was stirred for 5 hours at 95°-100°C. The mixture was evaporated to dryness under vacuum, the residue was taken up with 30 ml of ethanol and evaporated to dryness under vacuum.

Residuet ble tatt opp som pasta i 60 ml ethylacetat og kokt under tilbakelop i 10 min. Blandingen ble sentrifugert, residuet ble vasket med ethylacetat og torket under vakuum. Natriumsaltet ble omkrystallisert på nytt i vann. Etter torking under vakuum ved 50°C, og deretter ved omgivende temperatur, ble det erholdt 10,0<!>+ g 21-metasulfonatriumbenzoat av 6a-methylprednisolon i form av farvelose krystaller som var loselig i methanol, lite loselig i vann og som smeltet ved en temperatur over 260°C. Rotasjons-evnen var [a]^° = + lk9° (c = 1$, methanol). U. V. Spektrum - Methanol; The residue was taken up as a paste in 60 ml of ethyl acetate and boiled under reflux for 10 min. The mixture was centrifuged, the residue was washed with ethyl acetate and dried under vacuum. The sodium salt was recrystallized again in water. After drying under vacuum at 50°C, and then at ambient temperature, 10.0<!>+ g of 21-metasulphon sodium benzoate of 6a-methylprednisolone were obtained in the form of colorless crystals which were soluble in methanol, slightly soluble in water and which melted at a temperature above 260°C. The rotatability was [a]^° = + lk9° (c = 1$, methanol). U. V. Spectrum - Methanol;

Flamme spektrum; Flame spectrum;

Na %■ = U-, 10- hrlh (teoretisk: 3,95) Na %■ = U-, 10- hrlh (theoretical: 3.95)

TRINN 3; 21- metasulfolithiumbenzoat av 6a- methylprednisolc 5 g 21-metasulf onatriumbenzoat av 6ct-methylprednisolon ble suspendert i 125 ml vann, og omrort i noen minutter, hvoretter 25 cm^ aktivert Dowex 50 harpiks i syreform ble tilsatt og blandingen ble omrort i ^0 min. Losningen ble helt over i en kolonne inneholdende STEP 3; 21-metasulfolithium benzoate of 6α-methylprednisolc 5 g of 21-metasulf onate sodium benzoate of 6ct-methylprednisolone was suspended in 125 ml of water, and stirred for a few minutes, after which 25 cm^ of activated Dowex 50 resin in acid form was added and the mixture was stirred for ^0 min . The solution was poured into a column containing

65 ml Dowex 50 harpiks, aktivert og i syreform, og væskene med pH = 1 til pH = 3 ble samlet, hvoretter det ble tilsatt 15,3 ml av en vandig 0,5 N lithiumhydroxydlosning til den erholdte sure fase, og blandinger ble omrort og fordampet til tbrrhet. Residuet ble suspendert i 10 ml n-butanol tilsatt 0,25 ml vann og oppvarmet under omroring til 30°C, hvoretter blandingen ble filtrert, det'klare filtrat ble brakt til en temperatur av 10°C og underkastet krystallisasjon. Blandingen fikk stå over natten ved +5°C og deretter i en time ved 0°C og ble sentrifugert, og bunnfallet vasket med avkjolt n-butanol, torket onde] vakuum og deretter i varmeskap ved 85°C og tilslutt under vakuum, hvorved det ble erholdt 2,35 g metasulfolithiumbenzoat av 6a-methyl-prednisolon i form av farvelose krystaller som er loselig i vann og iuethanol, og som smelter ved en temperatur over 260°C, og hvis rotasjonsevne er: r -,20 -: L(I b = +153°C (c - 1$, methanol).. • • • 65 ml of Dowex 50 resin, activated and in acid form, and the liquids of pH = 1 to pH = 3 were collected, after which 15.3 ml of an aqueous 0.5 N lithium hydroxide solution was added to the obtained acid phase, and mixtures were stirred and evaporated to dryness. The residue was suspended in 10 ml of n-butanol to which was added 0.25 ml of water and heated with stirring to 30°C, after which the mixture was filtered, the clear filtrate was brought to a temperature of 10°C and subjected to crystallization. The mixture was allowed to stand overnight at +5°C and then for one hour at 0°C and was centrifuged, and the precipitate was washed with cooled n-butanol, dried onde] vacuum and then in a heating cabinet at 85°C and finally under vacuum, whereby 2.35 g of metasulfolithium benzoate of 6α-methyl-prednisolone were obtained in the form of colorless crystals which are soluble in water and iuethanol, and which melt at a temperature above 260°C, and whose rotatability is: r -.20 -: L (I b = +153°C (c - 1$, methanol).. • • •

Ana- lvse: Cpgli,C^SLi = 56^,58 Analysis: Cpgli,C^SLi = 56^,58

Beregnet: S % 5,68 Li % 1,23 Calculated: S % 5.68 Li % 1.23

Funnet: 5,6 - 5,8 1,16-1,16 ••'■/ Found: 5.6 - 5.8 1.16-1.16 ••'■/

U. V. Spektrum - Methanol: U. V. Spectrum - Methanol:

Max. ved 235 nm = h28 Max. at 235 nm = h28

Jy 1 cm Cut 1 cm

21-methylsulfonatet av 6a-methylprednisolon kan fremstilles The 21-methylsulfonate of 6α-methylprednisolone can be prepared

som folger: as follows:

10 g 6a-methylprednisolon (3,20-dioxo-6a-methyl lip, 17a-21-trihydroxypregna-1, k-dien) loses i h0 ml pyridin, under omroring, hvoretter blandingen avkjoles til -10°c og det tilsettes U-,% g methansulfonylklorid. Blandingen omrores i en 1 time.dg M-5 min. ved 10 g of 6a-methylprednisolone (3,20-dioxo-6a-methyl lip, 17a-21-trihydroxypregna-1, k-diene) are dissolved in 10 ml of pyridine, with stirring, after which the mixture is cooled to -10°c and U is added -,% g methanesulfonyl chloride. The mixture is stirred for 1 hour.dg M-5 min. by

-10°C, og blandingen helles over i en blanding av 75 g is og- 250-ml -10°C, and the mixture is poured into a mixture of 75 g of ice and 250-ml

av en vandig losning av natriumsulfat til 280 g/l som omrores. i of an aqueous solution of sodium sulphate to 280 g/l which is stirred. in

30 min. Blandingen sentrifugeres, bunnfallet vaskes med. vann inntil fravær av sulfat og torkes under vakuum. 30 min. The mixture is centrifuged, the precipitate is washed with. water until absence of sulfate and dried under vacuum.

11,3 g av residuet oppvarmes under tilbakelopskjoling i 11.3 g of the residue is heated under reflux i

5 min. ved 56 ml 80%-ig ethanol under.omroring, "hvoretter: .temperaturen 5 min. at 56 ml of 80% ethanol with stirring, after which: the temperature

får anta omgivelsestemperatur og blandingen holdes " ved. den temperatur i 30 min. Blandingen sentrifugeres, bunnfallet'.vaskes med 80%- ig ethanol i vann og torkes under vakuum. Det erholdes 10, hh g.21-methylsulfonat av 6a-methylprednisolon. is allowed to assume ambient temperature and the mixture is kept at that temperature for 30 min. The mixture is centrifuged, the precipitate is washed with 80% ethanol in water and dried under vacuum. 10, hh g.21-methylsulfonate of 6a-methylprednisolone is obtained.

Produktet foreligger i form av farvelose krystaller, som er lbselige i aceton og uloselig i vann, og som smelter ved 2<1>+8-2<1>+9<0>C, og hvis rotasjonsevne er: [a]p^_ + 83,5° (c = 1%, aceton). The product is in the form of colorless crystals, which are soluble in acetone and insoluble in water, and which melt at 2<1>+8-2<1>+9<0>C, and whose rotatability is: [a]p^ _ + 83.5° (c = 1%, acetone).

Claims (1)

Analogifremgangsmåte ved fremstiling av terapeutisk aktivt lithiumsalt av 6a-methyl-prednisolon av generell formel I:Analogous process for the preparation of the therapeutically active lithium salt of 6a-methyl-prednisolone of general formula I: ved hvilken fremgangsmåte et funksjonelt derivat av methansulfonsyre omsettes med 6a-methylprednisolon under dannelse av forbindelsen av generell formel II:in which method a functional derivative of methanesulfonic acid is reacted with 6a-methylprednisolone to form the compound of general formula II: karakterisert ved at den således erholdte forbindelse av formel II omsettes med et dialkalisalt av m-sulfonbenzoesyre i nærvær av et dialkylamid, og at den erholdte forbindelse føres gjennom en ionebytterharpiks anvendt i syreform, hvorefter det erholdte produkt omsettes med lithiumhydroxyd eller lithiumcarbonat under dannelse av produktet av formel I.characterized in that the thus obtained compound of formula II is reacted with a dialkali salt of m-sulfonebenzoic acid in the presence of a dialkylamide, and that the obtained compound is passed through an ion exchange resin used in acid form, after which the obtained product is reacted with lithium hydroxide or lithium carbonate to form the product of formula I.
NO2058/73A 1972-05-19 1973-05-18 PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE LITHIUM SALT OF 6ALFA-METHYLPREDNISOLONE NO138148C (en)

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DE2325358B2 (en) 1976-01-29
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NO138148C (en) 1978-07-12
CS165956B2 (en) 1975-12-22
IL42250A (en) 1977-06-30
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AU5590073A (en) 1974-11-21
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JPS5212777B2 (en) 1977-04-09
FR2193576B1 (en) 1975-08-08
DD104787A5 (en) 1974-03-20
FI52588C (en) 1977-10-10

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