CH621132A5 - Process for the preparation of D-homosteroids - Google Patents
Process for the preparation of D-homosteroids Download PDFInfo
- Publication number
- CH621132A5 CH621132A5 CH1366575A CH1366575A CH621132A5 CH 621132 A5 CH621132 A5 CH 621132A5 CH 1366575 A CH1366575 A CH 1366575A CH 1366575 A CH1366575 A CH 1366575A CH 621132 A5 CH621132 A5 CH 621132A5
- Authority
- CH
- Switzerland
- Prior art keywords
- hydrogen
- chlorine
- formula
- homopregna
- diene
- Prior art date
Links
- 150000000795 D-homosteroids Chemical class 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 title claims description 9
- 238000002360 preparation method Methods 0.000 title claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 29
- 239000001257 hydrogen Substances 0.000 claims abstract description 29
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 17
- 239000000460 chlorine Substances 0.000 claims abstract description 17
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 13
- 239000011737 fluorine Substances 0.000 claims abstract description 13
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 150000002367 halogens Chemical class 0.000 claims abstract description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims abstract description 4
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims abstract 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
- MALIONKMKPITBV-UHFFFAOYSA-N 2-(3-chloro-4-hydroxyphenyl)-n-[2-(4-sulfamoylphenyl)ethyl]acetamide Chemical compound C1=CC(S(=O)(=O)N)=CC=C1CCNC(=O)CC1=CC=C(O)C(Cl)=C1 MALIONKMKPITBV-UHFFFAOYSA-N 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 10
- 230000002124 endocrine Effects 0.000 abstract description 2
- 230000003647 oxidation Effects 0.000 abstract description 2
- 238000007254 oxidation reaction Methods 0.000 abstract description 2
- 150000002431 hydrogen Chemical class 0.000 abstract 4
- 230000000694 effects Effects 0.000 abstract 1
- 229910021653 sulphate ion Inorganic materials 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000001384 succinic acid Substances 0.000 description 3
- -1 unsaturated aliphatic monocarboxylic acid Chemical class 0.000 description 3
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 3
- VOYADQIFGGIKAT-UHFFFAOYSA-N 1,3-dibutyl-4-hydroxy-2,6-dioxopyrimidine-5-carboximidamide Chemical compound CCCCn1c(O)c(C(N)=N)c(=O)n(CCCC)c1=O VOYADQIFGGIKAT-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- QISOBCMNUJQOJU-UHFFFAOYSA-N 4-bromo-1h-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1NN=CC=1Br QISOBCMNUJQOJU-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- ITRJWOMZKQRYTA-RFZYENFJSA-N Cortisone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)CC2=O ITRJWOMZKQRYTA-RFZYENFJSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Natural products OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000003810 Jones reagent Substances 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229960003290 cortisone acetate Drugs 0.000 description 1
- HJZLEGIHUQOJBA-UHFFFAOYSA-N cyclohexane propionic acid Chemical compound OC(=O)CCC1CCCCC1 HJZLEGIHUQOJBA-UHFFFAOYSA-N 0.000 description 1
- CEJLBZWIKQJOAT-UHFFFAOYSA-N dichloroisocyanuric acid Chemical compound ClN1C(=O)NC(=O)N(Cl)C1=O CEJLBZWIKQJOAT-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000002888 oleic acid derivatives Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 150000003628 tricarboxylic acids Chemical class 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
D-Homosteroids with endocrine activity and the formula <IMAGE> in which R<2> is hydrogen or chlorine; R<6> is hydrogen, fluorine, chlorine or methyl; R<9> is hydrogen, fluorine, chlorine or bromine; R<17a> is hydrogen, hydroxyl or acyloxy and R<21> is hydrogen, halogen or a sulphate or phosphate residue, are prepared. They can be obtained by oxidation of corresponding 11-hydroxysteroids. Resulting compounds of the formula I in which R<21> is hydrogen can be halogenated in position 21, and a 17a-acyloxy group in a resulting D-homosteroid of the formula I can be hydrolysed.
Description
Die vorliegende Erfindung betrifft ein Verfahren zur Her
stellung von neuen D-Homosteroiden der Formel
EMI2.1
worin R2 Wasserstoff oder Chlor; Rd Wasserstoff, Fluor, Chlor oder Methyl; R9 Wasserstoff, Fluor, Chlor oder Brom; RI7a Wasserstoff, Hydroxy oder Acyloxy und R21 Wasserstoff, Halogen oder einen Sulfat- oder Phosphatrest darstellen.
Der Ausdruck Halogen umfasst Fluor, Chlor, Brom und Jod. EineAcyloxygruppe kann sich von einer gesättigten oder ungesättigten aliphatischen Monocarbonsäure, einer cycloaliphatischen oder einer aromatischen Monocarbonsäure mit vorzugsweise bis zu 15 C-Atomen ableiten. Beispiele solcher Säuren sind Ameisen-, Essig-, Pivalin-, Propion-, Butter-, Capron-, Önanth-, Undecylen-, Öl-, Cyclopentylpropion-, Cyclohexylpropion-, Phenylessig- und Benzoesäure. Besonders bevorzugt sind C1-7-Alkanoylgruppen. Ein Rest einer Di- oder Tricarbonsäure kann sich z. B. ableiten von der Oxal-, Malon-, Bernstein-, Fumar-, itpfel-, Wein- oder Zitronensäure, vorzugsweise von der Bernsteinsäure. Als wasserlösliche Salze solcher Säurereste kommen vor allem die Alkalisalze wie Na-, K- oder Ammoniumsalze in Frage.
Eine bevorzugte Gruppe von Verbindungen der Formel I sind diejenigen, in denen Rss Wasserstoff oder Methyl, R9 Wasserstoff oder Fluor, Ri7a Hydroxy oder Ct-7-Alkanoyloxy und R21 Halogen darstellen.
Beispiele von Verbindungen der Formel I sind die 21-Phosphate und 21-Sulfate der folgenden D-Homosteroide: 6a-Chloro-17a,21-dihydroxy-D-homopregna-1,4-dien-3,11,20 trion, 6a-Fluoro-17a,21-dihydroxy-D-homopregna-1,4-dien-3,11,20- trion, 17a,21-Dihydroxy-6a-methyl-D-homopregna- 1 4-dien-
3,11,20-trion, 6a-Chloro-9-fluoro-17a,21-dihydroxy-D-homopregna-1,4- dien-3,11,20-trion, 6α,9-Difluoro-17a,21-dihydroxy-D-homopregna-1,4-dien-
3,11,20-trion, 9-Fluoro-17a,21-dihydroxy-6a-methyl-D-homopregna-1,4 dien-3,11,20-trion, 9-Chloro-17a,21-dihydroxy-D-homopregna-1,4-dien-3,11,20- trion, 9-Bromo-17α
;,21-dihydroxy-D-homopregna-1,4-dien-3, 11,20- trion, 9-Chloro-17a,21-dihydroxy-6a-methyl-D-homopregna-1,4 dien-3,11,20-trion, 9-Bromo- 17a,21-dihydroxy-6a-methyl-D-homopregna- 1,4- dien-3,11,20-trion, 9-Chloro-6α-fluoro-17a,21-dihydroxy-D-homopregna-1,4- dien-3,11,20-trion, 9-Bromo-6a-fluoro-17a,21-dihydroxy-D-homopregna-1,4- dien-3,11,20-trion, 21-Hydroxy-D-homopregna-1,4-dien-3, 1 1,20-trion, 9-Fluoro-21-hydroxy-D-homopregna-1,4-dien-3,11,20-trion, 6a-Fluoro-21 -hydroxy-D-homopregna- 1,4-dien-3,1 1,20-trion,
21-Hydroxy-6a-methyl-D-homopregna-1,4-dien-3,11,20-trion, 6y,9-Difluoro-21 -hydroxy-D-homopregna- 11,20 trion, 9-Fluoro-21-hydroxy-6a-methyl-D-homopregna-1,4-dien-
3,11,20-trion, 2-Chloro-17a,21-dihydroxy-D-homopregna-1,4-dien-3,11,20- trion, 2-Chloro-6a-fluoro-17a,21-dihydroxy-D-homopregna-1,4- dien-3,11,20-trion, 2-Chloro-9-fluoro-17a,21-dihydroxy-D-homopregna-1,4- dien-3, 1 1,20-trion, 2-Chloro-17a,21-dihydroxy-6a-methyl-D-homopregna-1,4- dien-3,11,20-trion, 2-Chloro-6a,9-difluoro-17a,21-dihydroxy-D-homopregna-
1,4-dien-3,11,20-trion, 2-Chloro-9-fluoro-17a,21-dihydroxy-6a-methyl-D-homo- pregna-1,4-dien-3,11,20-trion, 2-Chloro-21-hydroxy-D-homopregna-1,4-dien-3,11,20-trion,
2-Chloro-6a-fluoro-21-hydroxy-D-homopregna-1,4-dien-
3,11,20-trion, 2-Chloro-9-fluoro-21-hydroxy-D-homopregna-1,4-dien-
3,11,20-trion, 2-Chloro-21-hydroxy-6a-methyl-D-homopregna-1,4-dien-
3,11,20-trion, 2-Chloro-6a,9-difluoro-21 -hydroxy-D-homopregna-1,4-dien-
3,11,20-trion, 2-Chloro-9-fluoro-21-hydroxy-6a-methyl-D-homopregna-1,4- dien-3,11,20-trion, sowie deren 17a-Ester der Essigsäure, Propionsäure, Buttersäure, Valeriansäure und Bernsteinsäure.
Weitere Beispiele von Verbindungen der Formel I sind: 2,21-Dichloro-17a-hydroxy-D-homopregna-1,4-dien-3,11,20- trion, 21-Chloro-17a-hydroxy-D-homopregna-1,4-dien-3,11,20- trion, 21-Chloro-6a-fluoro-17a-hydroxy-D-homopregna-1,4-dien-
3,11,20-trion, 21-Chloro-17a-hydroxy-6a-methyl-D-homopregna-1,4-dien-
3,11,20-trion, 21-Chloro-9-fluoro-17a-hydroxy-D-homopregna-1,4-dien-
3,11,20-trion, 2,21-Dichloro-6a,9-difluoro-17a-hydroxy-D-homopregna-1,4- dien-3,11,20-trion und deren 17a-Propionate, Acetate, Butyrate und Valerianate.
Die Verbindungen der Formel I können erfindungsgemäss dadurch hergestellt werden, dass man in an sich bekannter Weise in einem D-Homosteroid der Formel
EMI2.2
worin R2, R6, R9, R17a und R21 die oben angegebenen Bedeutungen haben, die 11-Hydroxygruppe oxydiert.
Erwünschtenfalls wird ein erhaltenes D-Homosteroid der Formens
EMI3.1
won.n;R2, RG, RD und Rl7a die oben genannten Bedeutungen haben: in 21-Stellung halogeniert.
Erwünschtenfalls wird eine 17a-Acyloxygruppe in einem D-Homosteroid der Formel I verseift.
Däs: erfindungsgemässe Verfahren der Oxydation der 11 Hydroxygruppe in einer Verbindung II kann z. B. mittels CrOs/Eisessig oder CrO3Pyridin oder Jones' Reagens vorgenommen werden.
Die Halogenierung eines erhaltenen D-Homosteroids in 21-Stellung kann dadurch erfolgen, dass man eine solche Verbindung der Formel I, in der R"1 Wasserstoff ist, gewünsch- tenfalls unter Schutz des 3-Keto-At.4-systems, beispielsweise in Form eines 3-Enaminiumsalzes wie eines 3-Pyrrolidiniumenamins, in saurer Lösung mit elementarem Chlor, Brom oder Jod umsetzt.
Die Verseifung einer Acyloxygruppe in einem Steroid der Formel I kann in an sich bekannter Weise z. B. mit wässrigmethanolischer Kalciumcarbonatlösung bewerkstelligt werden.
Die Ausgangsstoffe können, soweit sie nicht bekannt oder nachstehend beschrieben sind, in Analogie zu bekannten oder in den Beispielen beschriebenen Methoden dargestellt werden.
Verbindungen der Formel II mit einer 11a-Hydroxygrup- pe können aus entsprechenden 11-unsubstituierten Verbindungen mittels Mikroorganismen, die Steroide in 11a-Stellung hydroxylieren, erhalten werden.
Die Verbindungen der Formel I sind endokrin, insbesondere anti-inflammatorisch sehr wirksam. Die hohe Wirksamkeit erscheint überraschend, nachdem bekannt war, dass das D-Homocortisonazetat nur 1/3 bis 1/2 der Hormonaktivität des Cortisonazetats aufweist (J. Am. Chem. Soc. 80, 3398).
Die Verfahrensprodukte können als Heilmittel, z. B. in Form pharmazeutischer Präparate Verwendung finden, welche sie in Mischung mit einem für die enterale, perkutane oder parenterale Applikation geeigneten organischen oder anorganischen inerten Trägermaterial, wie z. B. Wasser, Gelatine, Gummi arabicum, Milchzucker, Stärke, Magnesiumstearat, Talk, pflanzliche Öle, Polyalkylenglykole, Vaseline usw. enthalten. Die pharmazeutischen Präparate können in fester Form, z. B. als Tabletten, Dragees, Suppositorien, Kapseln; in halbfester Form, z. B. als Salben; oder in flüssiger Form, z. B. als Lösungen, Suspensionen-oder Emulsionen, vorliegen. Gegebenenfalls sind sie sterilisiert und bzw. oder enthalten Hilfsstoffe, wie Konservierungs-, Stabilisierungs-, Netz- oder Emulgiermittel, Salze zur Veränderung des osmotischen Druckes oder Puffer.
Sie können auch noch andere therapeutisch wertvolle Stoffe enthalten.
Als Richtlinie für den Dosierbereich topischer Präparate kann etwa 0,01-1 O/o, bei systemischen Präparaten etwa 0,1 bis 10 mg pro Applikationseinheit gelten.
Die Herstellung der Arzneimittel kann in an sich bekannter Weise erfolgen, indem man die Verbindungen der Formel 1 mit zur therapeutischen Verabreichung geeigneten, nichttoxischen, an sich in solchen Präparaten üblichen festen und/ oder flüssigen Trägermaterialien, wie z. B. den vorstehend genannten, vermischt und gegebenenfalls in die gewünschte Form bringt.
In den folgenden Beispielen sind die Temperaturen in Celsiusgraden angegeben.
Beispiel 1
700 mg 9a-Fluor-1 lss, 17a-dihydroxy-D-homopregna-1,4- dien-3,20-dion werden in 70 ml Aceton gelöst. 0,84 ml Jones Reagenz werden zugegeben. Das Gemisch wird 40 Minuten bei Raumtemperatur unter Argon stehengelassen. Nach Zugabe von 5 ml MeOH wird die Lösung im Vakuum eingeengt, mit Methylenchlorid extrahiert, mit Wasser und verdünnter Kochsalzlösung gewaschen, getrocknet und eingedampft. Nach Umkristallisation aus Aceton-Hexan erhält man 610 mg 9a Fluor-17aa-hydroxy-D-homopregna-1,4-dien-3,11,20-trion vom Smp. 252-2530 C, UVe2s6 = 15 200, [a]D + 920 (Dioxan, c = 0,1 0/o).
Beispiel 2
In zu Beispiel 1 analoger Weise wird 21-Chloro-17a-hy droxy-D-homopregna- 1,4-dien-3, 11,20-trion, Smp. 233-2340, [a]D = + 1750 (c = 0,103 0/o in Dioxan), UV: 82sg = 14 950 hergestellt.
The present invention relates to a method for manufacturing
Provision of new D-homosteroids of the formula
EMI2.1
wherein R2 is hydrogen or chlorine; Rd hydrogen, fluorine, chlorine or methyl; R9 is hydrogen, fluorine, chlorine or bromine; RI7a are hydrogen, hydroxy or acyloxy and R21 is hydrogen, halogen or a sulfate or phosphate radical.
The term halogen includes fluorine, chlorine, bromine and iodine. An acyloxy group can be derived from a saturated or unsaturated aliphatic monocarboxylic acid, a cycloaliphatic or an aromatic monocarboxylic acid with preferably up to 15 C atoms. Examples of such acids are formic, acetic, pivalic, propionic, butter, capronic, oenanthic, undecylene, oleic, cyclopentylpropionic, cyclohexylpropionic, phenylacetic and benzoic acid. C1-7 alkanoyl groups are particularly preferred. A residue of a di- or tricarboxylic acid can e.g. B. derived from oxalic, malonic, succinic, fumaric, malic, tartaric or citric acid, preferably from succinic acid. Particularly suitable water-soluble salts of such acid residues are the alkali salts, such as Na, K or ammonium salts.
A preferred group of compounds of the formula I are those in which Rss is hydrogen or methyl, R9 is hydrogen or fluorine, Ri7a hydroxy or Ct-7-alkanoyloxy and R21 is halogen.
Examples of compounds of the formula I are the 21-phosphates and 21-sulfates of the following D-homosteroids: 6a-chloro-17a, 21-dihydroxy-D-homopregna-1,4-diene-3,11,20 trione, 6a- Fluoro-17a, 21-dihydroxy-D-homopregna-1,4-diene-3,11,20-trione, 17a, 21-dihydroxy-6a-methyl-D-homopregna-1 4-diene-
3,11,20-trione, 6a-chloro-9-fluoro-17a, 21-dihydroxy-D-homopregna-1,4-diene-3,11,20-trione, 6α, 9-difluoro-17a, 21 dihydroxy-D-homopregna-1,4-diene
3,11,20-trione, 9-fluoro-17a, 21-dihydroxy-6a-methyl-D-homopregna-1,4-diene-3,11,20-trione, 9-chloro-17a, 21-dihydroxy-D -homopregna-1,4-diene-3,11,20-trione, 9-bromo-17?
;, 21-dihydroxy-D-homopregna-1,4-diene-3, 11,20-trione, 9-chloro-17a, 21-dihydroxy-6a-methyl-D-homopregna-1,4-diene-3,11 , 20-trione, 9-bromo-17a, 21-dihydroxy-6a-methyl-D-homopregna-1,4-diene-3,11,20-trione, 9-chloro-6α-fluoro-17a, 21- dihydroxy-D-homopregna-1,4-diene-3,11,20-trione, 9-bromo-6a-fluoro-17a, 21-dihydroxy-D-homopregna-1,4-diene-3,11,20-trione trion, 21-hydroxy-D-homopregna-1,4-diene-3, 1 1,20-trione, 9-fluoro-21-hydroxy-D-homopregna-1,4-diene-3,11,20-trione , 6a-fluoro-21-hydroxy-D-homopregna-1,4-diene-3.1 1.20-trione,
21-Hydroxy-6a-methyl-D-homopregna-1,4-diene-3,11,20-trione, 6y, 9-difluoro-21-hydroxy-D-homopregna-11,20 trione, 9-fluoro-21 -hydroxy-6a-methyl-D-homopregna-1,4-diene
3,11,20-trione, 2-chloro-17a, 21-dihydroxy-D-homopregna-1,4-diene-3,11,20-trione, 2-chloro-6a-fluoro-17a, 21-dihydroxy- D-homopregna-1,4-diene-3,11,20-trione, 2-chloro-9-fluoro-17a, 21-dihydroxy-D-homopregna-1,4-diene-3, 1 1,20-trione , 2-chloro-17a, 21-dihydroxy-6a-methyl-D-homopregna-1,4-diene-3,11,20-trione, 2-chloro-6a, 9-difluoro-17a, 21-dihydroxy-D -homopregna-
1,4-diene-3,11,20-trione, 2-chloro-9-fluoro-17a, 21-dihydroxy-6a-methyl-D-homopregna-1,4-diene-3,11,20- trion, 2-chloro-21-hydroxy-D-homopregna-1,4-diene-3,11,20-trione,
2-chloro-6a-fluoro-21-hydroxy-D-homopregna-1,4-diene
3,11,20-trione, 2-chloro-9-fluoro-21-hydroxy-D-homopregna-1,4-diene
3,11,20-trione, 2-chloro-21-hydroxy-6a-methyl-D-homopregna-1,4-diene
3,11,20-trione, 2-chloro-6a, 9-difluoro-21-hydroxy-D-homopregna-1,4-diene
3,11,20-trione, 2-chloro-9-fluoro-21-hydroxy-6a-methyl-D-homopregna-1,4-diene-3,11,20-trione, and their 17a esters of acetic acid, Propionic acid, butyric acid, valeric acid and succinic acid.
Further examples of compounds of the formula I are: 2,21-dichloro-17a-hydroxy-D-homopregna-1,4-diene-3,11,20-trione, 21-chloro-17a-hydroxy-D-homopregna-1 , 4-diene-3,11,20-trione, 21-chloro-6a-fluoro-17a-hydroxy-D-homopregna-1,4-diene
3,11,20-trione, 21-chloro-17a-hydroxy-6a-methyl-D-homopregna-1,4-diene
3,11,20-trione, 21-chloro-9-fluoro-17a-hydroxy-D-homopregna-1,4-diene
3,11,20-trione, 2,21-dichloro-6a, 9-difluoro-17a-hydroxy-D-homopregna-1,4-diene-3,11,20-trione and their 17a-propionates, acetates, butyrates and Valerianate.
According to the invention, the compounds of the formula I can be prepared by, in a manner known per se, in a D-homosteroid of the formula
EMI2.2
wherein R2, R6, R9, R17a and R21 have the meanings given above, which oxidizes the 11-hydroxy group.
If desired, an obtained D-homosteroid of molding
EMI3.1
won.n; R2, RG, RD and Rl7a have the meanings given above: halogenated in the 21-position.
If desired, a 17a-acyloxy group is saponified in a D-homosteroid of the formula I.
Däs: inventive method of oxidation of the 11 hydroxy group in a compound II can, for. B. using CrOs / glacial acetic acid or CrO3 pyridine or Jones' reagent.
The halogenation of a D-homosteroid obtained in the 21-position can be carried out by, if desired, protecting such a compound of the formula I in which R "1 is hydrogen, with protection of the 3-keto-At.4 system, for example in Form of a 3-enaminium salt such as a 3-pyrrolidinium enamine, in acidic solution with elemental chlorine, bromine or iodine.
The saponification of an acyloxy group in a steroid of the formula I can be carried out in a manner known per se, for. B. with aqueous methanolic calcium carbonate solution.
Unless they are known or described below, the starting materials can be prepared in analogy to known methods or those described in the examples.
Compounds of the formula II with an 11a-hydroxy group can be obtained from corresponding 11-unsubstituted compounds by means of microorganisms which hydroxylate steroids in the 11a-position.
The compounds of formula I are endocrine, in particular anti-inflammatory, very effective. The high effectiveness appears surprising after it was known that the D-homocortisone acetate has only 1/3 to 1/2 of the hormonal activity of the cortisone acetate (J. Am. Chem. Soc. 80, 3398).
The process products can be used as remedies, e.g. B. in the form of pharmaceutical preparations, which they use in a mixture with an enteral, percutaneous or parenteral application suitable organic or inorganic inert carrier material, such as. B. water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. contain. The pharmaceutical preparations can be in solid form, e.g. B. as tablets, dragees, suppositories, capsules; in semi-solid form, e.g. B. as ointments; or in liquid form, e.g. B. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.
They can also contain other therapeutically valuable substances.
As a guideline for the dosing range of topical preparations, about 0.01-100 / o, for systemic preparations, about 0.1 to 10 mg per application unit.
The pharmaceuticals can be prepared in a manner known per se by the compounds of the formula 1 being suitable with therapeutic, non-toxic solid and / or liquid carrier materials which are customary in such preparations, such as, for. B. the above, mixed and optionally brings into the desired shape.
In the following examples, the temperatures are given in degrees Celsius.
example 1
700 mg of 9a-fluoro-1 lss, 17a-dihydroxy-D-homopregna-1,4-diene-3,20-dione are dissolved in 70 ml of acetone. 0.84 ml Jones reagent are added. The mixture is left under argon at room temperature for 40 minutes. After adding 5 ml of MeOH, the solution is concentrated in vacuo, extracted with methylene chloride, washed with water and dilute sodium chloride solution, dried and evaporated. After recrystallization from acetone-hexane, 610 mg of 9a fluoro-17aa-hydroxy-D-homopregna-1,4-diene-3,11,20-trione of mp 252-2530 C, UVe2s6 = 15,200, [a] D + 920 (dioxane, c = 0.1 0 / o).
Example 2
In a manner analogous to Example 1, 21-chloro-17a-hydroxy-D-homopregna-1,4-diene-3, 11.20-trione, mp. 233-2340, [a] D = + 1750 (c = 0.103 0 / o in dioxane), UV: 82sg = 14 950.
Claims (1)
Priority Applications (23)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1366575A CH621132A5 (en) | 1975-10-22 | 1975-10-22 | Process for the preparation of D-homosteroids |
| NL7611162A NL7611162A (en) | 1975-10-22 | 1976-10-08 | NEW D-HOMOSTEROIDS. |
| US05/731,238 US4137269A (en) | 1975-10-22 | 1976-10-12 | D-homosteroids |
| AU18736/76A AU499324B2 (en) | 1975-10-22 | 1976-10-15 | D-homo pregna 1, 4 diene-3, 11, 20 trione derivatives |
| IL50687A IL50687A0 (en) | 1975-10-22 | 1976-10-15 | New steroids their manufacture and pharmaceutical compositions containing them |
| ZA766167A ZA766167B (en) | 1975-10-22 | 1976-10-15 | Novel steroids |
| NZ182356A NZ182356A (en) | 1975-10-22 | 1976-10-18 | D-homopregna-1,4-diene -3,ii,20-triones |
| DE19762646994 DE2646994A1 (en) | 1975-10-22 | 1976-10-18 | NEW STEROIDS |
| DK472176AA DK140900B (en) | 1975-10-22 | 1976-10-19 | Analogous process for the preparation of D-homopregna-1,4-diene-3,11,20-trions. |
| JP51125058A JPS5251358A (en) | 1975-10-22 | 1976-10-20 | Ddhomosteroid |
| LU76041A LU76041A1 (en) | 1975-10-22 | 1976-10-20 | |
| DD7600195369A DD127910A5 (en) | 1975-10-22 | 1976-10-20 | PROCESS FOR THE PRODUCTION OF NEW STEROIDS |
| GR51977A GR61269B (en) | 1975-10-22 | 1976-10-20 | Preparation process of novel steroids |
| PH19022A PH12987A (en) | 1975-10-22 | 1976-10-20 | D-homosteroid derivatives |
| FR7631696A FR2328455A1 (en) | 1975-10-22 | 1976-10-21 | NEW STEROIDS |
| AT784776A AT352919B (en) | 1975-10-22 | 1976-10-21 | METHOD OF MANUFACTURING NEW D-HOMO-STEROIDS |
| GB43723/76A GB1562119A (en) | 1975-10-22 | 1976-10-21 | D-homo steroids |
| CA263,909A CA1061329A (en) | 1975-10-22 | 1976-10-21 | Steroids |
| BE171678A BE847496A (en) | 1975-10-22 | 1976-10-21 | NEW STEROIDS, |
| ES452574A ES452574A1 (en) | 1975-10-22 | 1976-10-21 | D-homosteroids |
| ES459520A ES459520A1 (en) | 1975-10-22 | 1977-06-06 | A PROCEDURE FOR THE PREPARATION OF D-HOMOSTEROIDS. |
| CH933679A CH621804A5 (en) | 1975-10-22 | 1979-10-17 | Process for the preparation of D-homosteroids |
| CH632080A CH623339A5 (en) | 1975-10-22 | 1980-08-21 | Process for the preparation of D-homosteroids |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1366575A CH621132A5 (en) | 1975-10-22 | 1975-10-22 | Process for the preparation of D-homosteroids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH621132A5 true CH621132A5 (en) | 1981-01-15 |
Family
ID=4394307
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1366575A CH621132A5 (en) | 1975-10-22 | 1975-10-22 | Process for the preparation of D-homosteroids |
| CH933679A CH621804A5 (en) | 1975-10-22 | 1979-10-17 | Process for the preparation of D-homosteroids |
| CH632080A CH623339A5 (en) | 1975-10-22 | 1980-08-21 | Process for the preparation of D-homosteroids |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH933679A CH621804A5 (en) | 1975-10-22 | 1979-10-17 | Process for the preparation of D-homosteroids |
| CH632080A CH623339A5 (en) | 1975-10-22 | 1980-08-21 | Process for the preparation of D-homosteroids |
Country Status (2)
| Country | Link |
|---|---|
| CH (3) | CH621132A5 (en) |
| ZA (1) | ZA766167B (en) |
-
1975
- 1975-10-22 CH CH1366575A patent/CH621132A5/en not_active IP Right Cessation
-
1976
- 1976-10-15 ZA ZA766167A patent/ZA766167B/en unknown
-
1979
- 1979-10-17 CH CH933679A patent/CH621804A5/en not_active IP Right Cessation
-
1980
- 1980-08-21 CH CH632080A patent/CH623339A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CH621804A5 (en) | 1981-02-27 |
| ZA766167B (en) | 1977-09-28 |
| CH623339A5 (en) | 1981-05-29 |
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