NO781200L - WATER-SOLUBLE CORTICOIDER. - Google Patents
WATER-SOLUBLE CORTICOIDER.Info
- Publication number
- NO781200L NO781200L NO781200A NO781200A NO781200L NO 781200 L NO781200 L NO 781200L NO 781200 A NO781200 A NO 781200A NO 781200 A NO781200 A NO 781200A NO 781200 L NO781200 L NO 781200L
- Authority
- NO
- Norway
- Prior art keywords
- methyl
- dioxo
- hydroxy
- pregnadien
- fluoro
- Prior art date
Links
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 11
- 229910052708 sodium Inorganic materials 0.000 claims description 11
- 239000011734 sodium Substances 0.000 claims description 11
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 5
- 229940014800 succinic anhydride Drugs 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 239000013543 active substance Substances 0.000 claims description 3
- -1 alkali metal salts Chemical class 0.000 claims description 3
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 2
- 150000001340 alkali metals Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 3
- 239000003470 adrenal cortex hormone Substances 0.000 claims 2
- RKHQGWMMUURILY-UHRZLXHJSA-N cortivazol Chemical compound C([C@H]1[C@@H]2C[C@H]([C@]([C@@]2(C)C[C@H](O)[C@@H]1[C@@]1(C)C2)(O)C(=O)COC(C)=O)C)=C(C)C1=CC1=C2C=NN1C1=CC=CC=C1 RKHQGWMMUURILY-UHRZLXHJSA-N 0.000 claims 2
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 239000003246 corticosteroid Substances 0.000 claims 1
- 229960001334 corticosteroids Drugs 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 230000005587 bubbling Effects 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 208000005374 Poisoning Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 208000005279 Status Asthmaticus Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 235000019621 digestibility Nutrition 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000004992 fission Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- BITYAPCSNKJESK-UHFFFAOYSA-N potassiosodium Chemical compound [Na].[K] BITYAPCSNKJESK-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0007—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa
- C07J5/0023—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa substituted in position 16
- C07J5/003—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group including 16-alkylidene substitutes
- C07J5/0038—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group including 16-alkylidene substitutes by an alkyl group
Description
Oppfinnelsen angår vannoppløselige korticoider som utmerker seg ved et gunstig forhold mellom terapieffekt og toleranse. The invention relates to water-soluble corticoids which are distinguished by a favorable relationship between therapeutic effect and tolerance.
I forhold til tidligere kjente vannoppløselige derivater av korticoider med generell formel II (britisk patentskrift 1.286.093) utmerker de nye korticoider seg ved vesentlig hurtigere virknings-start. In relation to previously known water-soluble derivatives of corticoids with general formula II (British patent document 1,286,093), the new corticoids are distinguished by a significantly faster onset of action.
Den terapeutiske virkning av de nye vannoppløselige korticoider kan f.eks. bekreftes ved hjelp av de kjente endotoxin-sjokkforsøk, eosinofil-forsøk eller adjuvans-ødem-test. For be-stemmelse av uønskede systemiske sidevirkninger og derved toleran-sen for de nye korticoider kan man f.eks. benytte den kjente thy-molysetest, leverglycogenprøven eller natrium-kalium-retensjons-prøven, eller fordøyelighetsprøven. The therapeutic effect of the new water-soluble corticoids can e.g. is confirmed using the known endotoxin shock test, eosinophil test or adjuvant edema test. To determine unwanted systemic side effects and thereby the tolerance for the new corticoids, one can e.g. use the known thymolysis test, the liver glycogen test or the sodium-potassium retention test, or the digestibility test.
De nye vannoppløselige korticoider kan forarbeides på vanlig måte til legemiddelpreparater, idet man tilsetter dem eg-nede tilsetninger, bærere, oppløsningsformidlere, stabilisatorer og smakskorregentia for de ønskede anvendelsesformer, som f.eks. The new water-soluble corticoids can be processed in the usual way into pharmaceutical preparations, by adding suitable additives, carriers, solubilizers, stabilizers and flavor corregents for the desired forms of use, such as e.g.
tabletter, drasjeer, kapsler, oppløsninger osv.tablets, dragees, capsules, solutions, etc.
Således kan man f.eks. fylle angitte mengder av de vann-oppløselige korticoider på ampuller, eventuelt efter tilsetning av vanlige hjelpestoffer og på vanlig måte som tørrstoffer, idet ampullene fortrinnsvis inneholder 10 - 500 mg aktivt stoff. Am-pulleinnholdet blir oppløst i sterilt, destillert vann før bruk. Thus, one can e.g. fill specified quantities of the water-soluble corticoids into ampoules, possibly after adding usual auxiliary substances and in the usual way as dry substances, the ampoules preferably containing 10 - 500 mg of active substance. The ampoule contents are dissolved in sterile, distilled water before use.
Spesialpreparatene kan fortrinnsvis brukes til behandling av akutte truende sykdomstilstander (sjokk efter ulykker, forbrenninger, operasjoner, kretsløpforstyrrelser efter forgift-ninger, hjerteinfarkt, lungeemboli, alvorlige astmaanfall etc). The special preparations can preferably be used for the treatment of acute threatening disease states (shock after accidents, burns, operations, circulatory disorders after poisoning, heart attacks, pulmonary embolism, severe asthma attacks, etc.).
For behandling gir man pasienten, alt efter sykdommens alvor 10 - 1000 mg aktivt stoff intravenøst. For treatment, depending on the severity of the disease, the patient is given 10 - 1000 mg of active substance intravenously.
Fremstillingen av de nye korticoider skjer på en måte som vil være kjent for fagmannen. F.eks. kan man omsette korticoider med generell formel II méd ravsyreanhydrid eller glutarsyreanhydrid i nærvær av baser (som f.eks. pyridin, lutidin, kalium-hydrogencarbonat, natriumcarbonat, kaliumcarbonat, natriumhydroxyd, kaliumhydroxyd etc), og eventuelt overføre de dannede korticoider med generell formel I hvor Y har betydningen hydrogen til salter ved omsetning med alkalimetallhydroxyder, alkalimetallcarbonater, alkalimetallhydrogencarbonater eller alkalimetallalkoholater. The production of the new corticoids takes place in a manner that will be known to the person skilled in the art. E.g. one can react corticoids of general formula II with succinic anhydride or glutaric anhydride in the presence of bases (such as pyridine, lutidine, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc.), and possibly transfer the formed corticoids of general formula I where Y means hydrogen to salts by reaction with alkali metal hydroxides, alkali metal carbonates, alkali metal hydrogen carbonates or alkali metal alcoholates.
Med hjelp av fremgangsmåten ifølge oppfinnelsen kan man f.eks. fremstille: (6a,9a-difluor-lip-hydroxy-16a-methyl-3,20-dioxo-l,4-pregnadien-21-yl)-hemiglutarat, samt dets natrium- eller kaliumsalt såvel som (9a-klor-6a-fluor-113-hydroxy-16a-methyl-3,20-dioxo-1,4-pregnadien-21-yl)-hemiglutarat og dets natrium- og kaliumsalt. With the help of the method according to the invention, one can e.g. prepare: (6a,9a-difluoro-lip-hydroxy-16a-methyl-3,20-dioxo-1,4-pregnadien-21-yl)-hemiglutarate, as well as its sodium or potassium salt as well as (9a-chloro-6a -fluoro-113-hydroxy-16α-methyl-3,20-dioxo-1,4-pregnadien-21-yl)-hemiglutarate and its sodium and potassium salts.
De følgende eksempler belyser fremgangsmåten ifølge oppfinnelsen. The following examples illustrate the method according to the invention.
Eksempel 1Example 1
<a>) 2 g 6a,9a-difluor-lip,21-dihydroxy-16a-methyl-l,4-preg-nadien-3,20-dion oppløses i 10 ml pyridin, 1 g ravsyreanhydrid til-settes og kokes 30 minutter under argoninnbobling. Efter avkjøling røres blandingen ut i isvann, surgjøres med fortynnet svovelsyre, det utfeldte produkt suges fra, vaskes til nøytralitet og tørkes. Efter omkrystallisasjon fra aceton-hexan får man 2,1 g (6a,9a-di-fluor-113-hydroxy-16a-methyl-3,20-dioxo-l,4-pregnadien-21-yl)-hemisuccinat med smeltepunkt 199 - 20l°C. b) 700 mg hemisuccinat innstilles med 10 ml absolutt methanol, og 9,4 ml 0,1 N kaliummethylatoppløsning på pH 8 ved hjelp av et <a>) Dissolve 2 g of 6a,9a-difluoro-lip,21-dihydroxy-16a-methyl-1,4-preg-nadiene-3,20-dione in 10 ml of pyridine, add 1 g of succinic anhydride and boil for 30 minutes under argon bubbling. After cooling, the mixture is stirred into ice water, acidified with dilute sulfuric acid, the precipitated product is sucked off, washed to neutrality and dried. After recrystallization from acetone-hexane, 2.1 g of (6a,9a-di-fluoro-113-hydroxy-16a-methyl-3,20-dioxo-1,4-pregnadien-21-yl)-hemisuccinate with melting point 199 - 20l°C. b) Adjust 700 mg of hemisuccinate with 10 ml of absolute methanol, and 9.4 ml of 0.1 N potassium methylate solution at pH 8 using a
pH-meter. Oppløsningen konsentreres i vakuum og utfelles i 600 ml ether. Det utfeldte kaliumsalt suges fra, vaskes med ether og tør-kes i vakuum over fosforpentoxyd. Man får 670 mg kalium (6a,9a-difluor-113-hydroxy-3,20-dioxo-16a-methyl-l,4-pregnadien-21-yl)-succinat. Smeltepunkt 170 - 180°C, UV: inoo=16600.pH meter. The solution is concentrated in vacuo and precipitated in 600 ml of ether. The precipitated potassium salt is sucked off, washed with ether and dried in vacuum over phosphorus pentoxide. 670 mg of potassium (6α,9α-difluoro-113-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadien-21-yl)-succinate is obtained. Melting point 170 - 180°C, UV: inoo=16600.
c) 650 mg hemisuccinat innstilles i 10 ml absolutt methanol med 11,4 ml 0,1 N natriummethylatoppløsning på pH 8. Oppløsnin-gen konsentreres i vakuum, og røres ut i en blanding av 500 ml ether og 100 ml pentan som holder 3°C. Det utfeldte produkt suges fra og tørkes i vakuum. Man får slik 630 mg natrium (6a,9a-diflu-or-lip^-hydroxy-S , 20-dioxo-l6a-methy 1-1, 4-pregnadien-21-yl)-succinat. Smeltepunkt 175 - 180°C, UV: £23Q = 16500.c) 650 mg of hemisuccinate is placed in 10 ml of absolute methanol with 11.4 ml of 0.1 N sodium methylate solution at pH 8. The solution is concentrated in a vacuum and stirred into a mixture of 500 ml of ether and 100 ml of pentane which maintains 3° C. The precipitated product is sucked off and dried in a vacuum. 630 mg of sodium (6a,9a-diflu-or-lip^-hydroxy-S,20-dioxo-16a-methyl 1-1,4-pregnadien-21-yl)-succinate is thus obtained. Melting point 175 - 180°C, UV: £23Q = 16500.
Eksempel. 2Example. 2
a) 5 g- 6a-fluor-li(3,21-dihydrdxy-16a-methyl-l,4-pregnadien-3,20-dion omsettes i analogi med eksempel la i 25 ml pyridin med 5 g ravsyreanhydrid og opparbeides. Efter omkrystallisasjon fra eddikester får man 5;2 g (6a-fluor-113-hydroxy-16a-methyl-3,20-dioxo-l , 4-pregnadien-21-yl) -hemisuccinat . Smeltepunkt 210-212°C. a) 5 g of 6a-fluoro-li(3,21-dihydroxy-16a-methyl-1,4-pregnadiene-3,20-dione is reacted in analogy with example 1a in 25 ml of pyridine with 5 g of succinic anhydride and worked up. After recrystallization from acetic ester yields 5.2 g of (6a-fluoro-113-hydroxy-16a-methyl-3,20-dioxo-1,4-pregnadien-21-yl)-hemisuccinate.Melting point 210-212°C.
b) .10 g hemisuccinat innstilles i 400 ml absolutt methanol på pH 8 med 17,9 ml 0,1 N natriummethylatoppløsning og utfelles b) 10 g of hemisuccinate is placed in 400 ml of absolute methanol at pH 8 with 17.9 ml of 0.1 N sodium methylate solution and precipitated
som beskrevet under lc). Man får 9,6 g natrium-(6a-fluor-113-hydroxy-16a-methyl-3 , 20-dioxo-l, 4-preg.nadien-21-yl) -succinat. UV: 242<=>1610°- Smeltepunkt 163 - 170°C (spaltning). as described under lc). 9.6 g of sodium (6α-fluoro-113-hydroxy-16α-methyl-3,20-dioxo-1,4-preg.nadien-21-yl)-succinate are obtained. UV: 242<=>1610°- Melting point 163 - 170°C (decomposition).
Eksempel 3Example 3
a) 5 g 6a-fluor-113,21-dihydroxy-16a-methyl-l,4-pregnadien-3,20-dion oppvarmes i 20 ml pyridin med 2 g glutarsyreanhydrid i 4 5 minutter under argonbobling til kokning. Efter avkjøling røres blandingen ut i isvann, surgjøres med fortynnet svovelsyre, det utfeldte produkt filtreres fra, vaskes til nøytralitet og tørkes. Råproduktet ble oppløst i eddikester og rystet med 5 %'s sodaopp-. løsning. Den fraskilte vannfase ble surgjort med saltsyre, ekstra-hert med eddikester, eddikesterekstraktet vasket nøytralt og inn-dampet i vakuum. Man fikk 5,2 g (6a-fluor-ll(3-hydroxy-16a-methyl-3,20-dioxo-l,4-pregnadien-21-yl)-hemiglutarat. Smeltepunkt 171 - 173°C. b) 2,5 g hemiglutarat overføres i analogi med eksempel lc til natriumsalt. Man får 2,4 g natrium(6a-fluor-113-hydroxy-16a-methyl-3 , 20-dioxo-l, 4-pregnadien-21-yl) -glutarat. UV: i 2^-^=16000. Smeltepunkt 167°C (spaltning). a) 5 g of 6a-fluoro-113,21-dihydroxy-16a-methyl-1,4-pregnadiene-3,20-dione are heated in 20 ml of pyridine with 2 g of glutaric anhydride for 45 minutes under argon bubbling until boiling. After cooling, the mixture is stirred into ice water, acidified with dilute sulfuric acid, the precipitated product is filtered off, washed to neutrality and dried. The raw product was dissolved in vinegar and shaken with 5% soda ash. solution. The separated water phase was acidified with hydrochloric acid, extracted with ethyl acetate, the ethyl acetate extract was washed neutral and evaporated in vacuo. 5.2 g of (6a-fluoro-11(3-hydroxy-16a-methyl-3,20-dioxo-1,4-pregnadien-21-yl)-hemiglutarate was obtained. Melting point 171 - 173°C. b) 2 .5 g of hemiglutarate is transferred in analogy to example 1c to the sodium salt. 2.4 g of sodium (6α-fluoro-113-hydroxy-16α-methyl-3,20-dioxo-1,4-pregnadien-21-yl)-glutarate is obtained. UV: i 2^-^=16000. Melting point 167°C (decomposition).
Eksempel 4Example 4
a) lg 6a-fluor-9a-klor-113/21-dihydroxy-16a-methyl-l,4-pregnadien-3,20-dion oppløses i 5 ml pyridin og oppvarmes ved kokning med 0,5 g ravsyreanhydrid i 30 minutter under argonbobling. Efter opparbeidelse som i eksempel la og omkrystallisering fra aceton-eddikester får man 1,23 g (6a-fluor-9a-klor-113-hydroxy-16a-methyl-3,20-dioxo-l,4-preg.nadien-21-yl)-hemisuccinat. Smeltepunkt 249oc (spaltning). b) 700 mg hemisuccinat overføres til natriumsalt med 0,1 N natriummethylatoppløsning i 15 ml methanol. Man får 570 mg natrium- (6a-f luor-9a-klor-ll[3-hydroxy-16a-methyl-3,20-dioxo-l,4-pregna-dien-21-yl)-succinat. Smeltepunkt 165°C. (spaltning). a) lg 6α-fluoro-9α-chloro-113/21-dihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione is dissolved in 5 ml of pyridine and heated by boiling with 0.5 g of succinic anhydride for 30 minutes under argon bubbling. After working up as in example la and recrystallization from acetone-acetic ester, 1.23 g of (6a-fluoro-9a-chloro-113-hydroxy-16a-methyl-3,20-dioxo-1,4-preg.nadiene-21 -yl)-hemisuccinate. Melting point 249oc (decomposition). b) 700 mg of hemisuccinate is transferred to the sodium salt with 0.1 N sodium methylate solution in 15 ml of methanol. 570 mg of sodium (6a-fluoro-9a-chloro-11[3-hydroxy-16a-methyl-3,20-dioxo-1,4-pregna-dien-21-yl)-succinate is obtained. Melting point 165°C. (fission).
Eksempel 5Example 5
På samme måte som i eksempel 3 overføres 6a-fluor-9cc-klor-113,21-dihydroxy-16a-methyl-l,4-pregnadien-3,20-dion i (6a-fluor-9a-klor-llb-hydroxy-16a-methyl-3,20-dioxo-l,4-pregnadien-21-yl)-hemiglutarat. (Smeltepunkt 182 - 183,5°C, spaltning), og dette overføres videre til natrium-(6a-fluor-9a-klor-113-hydroxy-16a-methyl-3 , 20-dioxo-l, 4-preg.nadien-21-yl)-glutarat. Smeltepunkt 124°C (spaltning). In the same way as in Example 3, 6a-fluoro-9cc-chloro-113,21-dihydroxy-16a-methyl-1,4-pregnadiene-3,20-dione is transferred into (6a-fluoro-9a-chloro-11b-hydroxy -16α-methyl-3,20-dioxo-1,4-pregnadien-21-yl)-hemiglutarate. (Melting point 182 - 183.5°C, cleavage), and this is further transferred to sodium (6a-fluoro-9a-chloro-113-hydroxy-16a-methyl-3,20-dioxo-1,4-preg.nadiene -21-yl)-glutarate. Melting point 124°C (decomposition).
Eksempel 6Example 6
l,5.g (6a-fluor-113-hydroxy-16a-methyl-3,20-dioxo-l,4-pregnadien-21-yl)-hemisuccinat og 0,646 g N-methylglucamin ble oppløst i 30 ml dobbeltdestillert vann, og den klare oppløsning frysetørket 24 timer. Man får 2,07 g amorft N-methylglucamin-(6a-fluor-113-hydroxy-16a-methyl-3,20-dioxo-l,4-pregnadien-21-yl)-succinat. 1.5 g of (6α-fluoro-113-hydroxy-16α-methyl-3,20-dioxo-1,4-pregnadien-21-yl)-hemisuccinate and 0.646 g of N-methylglucamine were dissolved in 30 ml of double-distilled water, and the clear solution freeze-dried for 24 hours. 2.07 g of amorphous N-methylglucamine-(6a-fluoro-113-hydroxy-16a-methyl-3,20-dioxo-1,4-pregnadien-21-yl)-succinate are obtained.
Claims (14)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19772715853 DE2715853A1 (en) | 1977-04-06 | 1977-04-06 | WATER-SOLUBLE CORTICOIDS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO781200L true NO781200L (en) | 1978-10-09 |
Family
ID=6005979
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO781200A NO781200L (en) | 1977-04-06 | 1978-04-05 | WATER-SOLUBLE CORTICOIDER. |
Country Status (29)
| Country | Link |
|---|---|
| JP (1) | JPS53149963A (en) |
| AT (1) | ATA239978A (en) |
| AU (1) | AU3481178A (en) |
| BE (1) | BE865760A (en) |
| BG (1) | BG28578A3 (en) |
| CA (1) | CA1113452A (en) |
| CH (1) | CH638537A5 (en) |
| CS (1) | CS198295B2 (en) |
| DD (1) | DD135082A5 (en) |
| DE (1) | DE2715853A1 (en) |
| DK (1) | DK153378A (en) |
| EG (1) | EG13249A (en) |
| ES (1) | ES468572A1 (en) |
| FI (1) | FI781053A (en) |
| FR (1) | FR2386557A1 (en) |
| GB (1) | GB1602266A (en) |
| IE (1) | IE46602B1 (en) |
| IL (1) | IL54443A0 (en) |
| IT (1) | IT1094296B (en) |
| LU (1) | LU79375A1 (en) |
| NL (1) | NL7803188A (en) |
| NO (1) | NO781200L (en) |
| NZ (1) | NZ186745A (en) |
| PL (1) | PL114096B1 (en) |
| PT (1) | PT67872B (en) |
| RO (1) | RO81076A2 (en) |
| SE (1) | SE7803837L (en) |
| SU (1) | SU668611A3 (en) |
| ZA (1) | ZA781977B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4948533A (en) * | 1984-03-28 | 1990-08-14 | The Upjohn Company | 11a-hydroxy steroid diester |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1169444B (en) * | 1961-02-22 | 1964-05-06 | Schering Ag | Process for the preparation of ?-16ª‡-methyl steroids |
| YU34304B (en) * | 1968-08-17 | 1979-04-30 | Schering Ag | Process for preparing corticoid-21-mono-phosphates |
| DK290774A (en) * | 1973-06-08 | 1975-02-03 | Schering Ag |
-
1977
- 1977-04-06 DE DE19772715853 patent/DE2715853A1/en not_active Withdrawn
-
1978
- 1978-03-21 NZ NZ186745A patent/NZ186745A/en unknown
- 1978-03-23 NL NL7803188A patent/NL7803188A/en not_active Application Discontinuation
- 1978-03-29 DD DD78204456A patent/DD135082A5/en unknown
- 1978-03-30 SU SU782595445A patent/SU668611A3/en active
- 1978-03-31 BG BG7839252A patent/BG28578A3/en unknown
- 1978-04-03 CH CH357378A patent/CH638537A5/en not_active IP Right Cessation
- 1978-04-04 LU LU79375A patent/LU79375A1/en unknown
- 1978-04-04 IL IL54443A patent/IL54443A0/en unknown
- 1978-04-04 PL PL1978205800A patent/PL114096B1/en unknown
- 1978-04-04 RO RO7893718A patent/RO81076A2/en unknown
- 1978-04-05 AT AT0239978A patent/ATA239978A/en not_active Application Discontinuation
- 1978-04-05 AU AU34811/78A patent/AU3481178A/en active Pending
- 1978-04-05 IE IE672/78A patent/IE46602B1/en unknown
- 1978-04-05 SE SE7803837A patent/SE7803837L/en unknown
- 1978-04-05 PT PT67872A patent/PT67872B/en unknown
- 1978-04-05 IT IT21995/78A patent/IT1094296B/en active
- 1978-04-05 NO NO781200A patent/NO781200L/en unknown
- 1978-04-05 ES ES468572A patent/ES468572A1/en not_active Expired
- 1978-04-05 EG EG239/78A patent/EG13249A/en active
- 1978-04-05 CA CA300,512A patent/CA1113452A/en not_active Expired
- 1978-04-06 BE BE186622A patent/BE865760A/en not_active IP Right Cessation
- 1978-04-06 JP JP4077278A patent/JPS53149963A/en active Pending
- 1978-04-06 GB GB13527/78A patent/GB1602266A/en not_active Expired
- 1978-04-06 CS CS782252A patent/CS198295B2/en unknown
- 1978-04-06 FR FR7810202A patent/FR2386557A1/en active Granted
- 1978-04-06 ZA ZA00781977A patent/ZA781977B/en unknown
- 1978-04-06 FI FI781053A patent/FI781053A/en not_active Application Discontinuation
- 1978-04-06 DK DK153378A patent/DK153378A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DD135082A5 (en) | 1979-04-11 |
| DE2715853A1 (en) | 1978-10-19 |
| PT67872B (en) | 1979-11-14 |
| IT7821995A0 (en) | 1978-04-05 |
| EG13249A (en) | 1980-12-31 |
| AU3481178A (en) | 1979-10-11 |
| CA1113452A (en) | 1981-12-01 |
| BE865760A (en) | 1978-10-06 |
| NZ186745A (en) | 1980-10-24 |
| IT1094296B (en) | 1985-07-26 |
| SE7803837L (en) | 1978-10-07 |
| IE780672L (en) | 1978-10-06 |
| IE46602B1 (en) | 1983-07-27 |
| RO81076A2 (en) | 1983-02-01 |
| BG28578A3 (en) | 1980-05-15 |
| RO81076B1 (en) | 1983-01-30 |
| CH638537A5 (en) | 1983-09-30 |
| FR2386557B1 (en) | 1980-02-01 |
| ATA239978A (en) | 1981-06-15 |
| NL7803188A (en) | 1978-10-10 |
| FR2386557A1 (en) | 1978-11-03 |
| GB1602266A (en) | 1981-11-11 |
| FI781053A (en) | 1978-10-07 |
| PL205800A1 (en) | 1979-01-29 |
| SU668611A3 (en) | 1979-06-15 |
| DK153378A (en) | 1978-10-07 |
| JPS53149963A (en) | 1978-12-27 |
| PL114096B1 (en) | 1981-01-31 |
| IL54443A0 (en) | 1978-07-31 |
| ES468572A1 (en) | 1978-12-01 |
| PT67872A (en) | 1978-05-01 |
| LU79375A1 (en) | 1978-07-13 |
| CS198295B2 (en) | 1980-05-30 |
| ZA781977B (en) | 1979-03-28 |
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