NO137321B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 3-OXO-17ALFA-ACYLOXYANDROST-4-EN-17BETA-CARBOXYLIC ACID ESTERS - Google Patents
ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 3-OXO-17ALFA-ACYLOXYANDROST-4-EN-17BETA-CARBOXYLIC ACID ESTERS Download PDFInfo
- Publication number
- NO137321B NO137321B NO111/72A NO11172A NO137321B NO 137321 B NO137321 B NO 137321B NO 111/72 A NO111/72 A NO 111/72A NO 11172 A NO11172 A NO 11172A NO 137321 B NO137321 B NO 137321B
- Authority
- NO
- Norway
- Prior art keywords
- group
- methyl
- hydroxy
- compound
- formula
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 230000001225 therapeutic effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 85
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 44
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 125000004432 carbon atom Chemical group C* 0.000 claims description 25
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 229910052801 chlorine Inorganic materials 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 10
- 125000001153 fluoro group Chemical group F* 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000004423 acyloxy group Chemical group 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 7
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 5
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 76
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- 230000003110 anti-inflammatory effect Effects 0.000 description 29
- 239000007858 starting material Substances 0.000 description 29
- 239000000203 mixture Substances 0.000 description 28
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 25
- 239000002904 solvent Substances 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 20
- 238000004519 manufacturing process Methods 0.000 description 20
- 239000000047 product Substances 0.000 description 17
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 230000000694 effects Effects 0.000 description 13
- -1 steroid compounds Chemical class 0.000 description 13
- 150000003431 steroids Chemical class 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 238000002425 crystallisation Methods 0.000 description 11
- 230000008025 crystallization Effects 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 238000001953 recrystallisation Methods 0.000 description 11
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- 150000001441 androstanes Chemical class 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 9
- 230000008020 evaporation Effects 0.000 description 9
- 239000003862 glucocorticoid Substances 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 8
- 229940117975 chromium trioxide Drugs 0.000 description 8
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 8
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 150000008064 anhydrides Chemical class 0.000 description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 7
- 150000004702 methyl esters Chemical class 0.000 description 7
- 238000012746 preparative thin layer chromatography Methods 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 5
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 239000002395 mineralocorticoid Substances 0.000 description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- JWMFYGXQPXQEEM-NUNROCCHSA-N 5β-pregnane Chemical compound C([C@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](CC)[C@@]2(C)CC1 JWMFYGXQPXQEEM-NUNROCCHSA-N 0.000 description 3
- 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 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003377 acid catalyst Substances 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000003797 solvolysis reaction Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 2
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 2
- QZLYKIGBANMMBK-UGCZWRCOSA-N 5α-Androstane Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CCC[C@@]2(C)CC1 QZLYKIGBANMMBK-UGCZWRCOSA-N 0.000 description 2
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 2
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 229960004544 cortisone Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 150000002366 halogen compounds Chemical class 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000002798 polar solvent 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
- JWMFYGXQPXQEEM-WZBAXQLOSA-N pregnane Chemical class C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](CC)[C@@]1(C)CC2 JWMFYGXQPXQEEM-WZBAXQLOSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- 239000011343 solid material Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- GIXAVGROVIRVPE-UHFFFAOYSA-N 1-fluoro-4-[4-(4-pentylcyclohexyl)phenyl]benzene Chemical compound C1CC(CCCCC)CCC1C1=CC=C(C=2C=CC(F)=CC=2)C=C1 GIXAVGROVIRVPE-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- WXHLLJAMBQLULT-UHFFFAOYSA-N 2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-n-(2-methyl-6-sulfanylphenyl)-1,3-thiazole-5-carboxamide;hydrate Chemical compound O.C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1S WXHLLJAMBQLULT-UHFFFAOYSA-N 0.000 description 1
- QSECPQCFCWVBKM-UHFFFAOYSA-N 2-iodoethanol Chemical compound OCCI QSECPQCFCWVBKM-UHFFFAOYSA-N 0.000 description 1
- DFGKGUXTPFWHIX-UHFFFAOYSA-N 6-[2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]acetyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)C1=CC2=C(NC(O2)=O)C=C1 DFGKGUXTPFWHIX-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 235000003911 Arachis Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BMTAFVWTTFSTOG-UHFFFAOYSA-N Butylate Chemical group CCSC(=O)N(CC(C)C)CC(C)C BMTAFVWTTFSTOG-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000001780 adrenocortical effect Effects 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 239000000538 analytical sample Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical class [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 229960002242 chlorocresol Drugs 0.000 description 1
- SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000005332 diethylamines Chemical class 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- 230000006203 ethylation Effects 0.000 description 1
- 238000006200 ethylation reaction Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000009905 homogeneous catalytic hydrogenation reaction Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000001151 other effect Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 150000003128 pregnanes Chemical class 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000006207 propylation Effects 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 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
- 238000010992 reflux Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- QBERHIJABFXGRZ-UHFFFAOYSA-M rhodium;triphenylphosphane;chloride Chemical compound [Cl-].[Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QBERHIJABFXGRZ-UHFFFAOYSA-M 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- PNYYBUOBTVHFDN-UHFFFAOYSA-N sodium bismuthate Chemical compound [Na+].[O-][Bi](=O)=O PNYYBUOBTVHFDN-UHFFFAOYSA-N 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Classifications
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
- C07J3/005—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom the carbon atom being part of a carboxylic function
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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Abstract
Analogifremgangsmåte for fremstilling av terapeutisk aktive 3-okso-17a-acyloksyandrost-4-en-17S-karbok-sylsyreestere.Analogous process for the preparation of therapeutically active 3-oxo-17a-acyloxyandrost-4-ene-17S-carboxylic acid esters.
Description
Denne oppfinnelse angår fremstilling av steroidforbin-delser med anti-inflammatoriske egenskaper. This invention relates to the production of steroid compounds with anti-inflammatory properties.
Etter oppdagelsen av kortison er det fremstilt en rekke forbindelser med analog struktur og med anti-inflammatoriske egenskaper, og slike forbindelser har generelt vært av pregnan-serien. After the discovery of cortisone, a number of compounds with analogous structure and with anti-inflammatory properties have been prepared, and such compounds have generally been of the pregnan series.
Anti-inflammatoriske steroider har funnet omfattende anvendelse innen medisinen, og i de senere år har stor oppmerk-somhet vært rettet mot forbindelser som har høy anti-inflammatorisk virkning ved lokal administrering. Anti-inflammatory steroids have found extensive use in medicine, and in recent years much attention has been directed towards compounds that have a high anti-inflammatory effect when administered locally.
Ettersom de anti-inflammatoriske steroider av pregnan-serien som hittil er beskrevet, generelt er analoge med kortison, har de i større eller mindre grad tendens til å utøve den fysiologiske virkning av det naturlige hormon, og i tillegg til anti-inflammatorisk virkning har de således andre virkninger i likhet med kortisonlignende forbindelser. De fysiologiske virkninger av de anti-inflammatoriske steroider av pregnantypen kan generelt klassifiseres som glukokortikoid og mineralokortikoid virkning, idet den anti-inflammatoriske virkning i det minste inntil den senere tid har vært ansett som en glukokortikoid virkning. Glukokortikoide virkninger omfatter også generell forstyrrelse av kroppens stoffskifte og kan være meget uønsket. Mineralokortikoid-virkninger omfatter forstyrrelse av salt- og vannbalansen i kroppen, og forbindelser som har markert mineralokortikoid virkning, vil sannsynligvis gi uønskede virkninger ved administrering. As the anti-inflammatory steroids of the pregnan series described so far are generally analogous to cortisone, they tend to a greater or lesser extent to exert the physiological action of the natural hormone, and in addition to anti-inflammatory action they have thus other effects similar to cortisone-like compounds. The physiological effects of the anti-inflammatory steroids of the pregnane type can generally be classified as glucocorticoid and mineralocorticoid effects, the anti-inflammatory effect being at least until recently considered a glucocorticoid effect. Glucocorticoid effects also include general disruption of the body's metabolism and can be very undesirable. Mineralocorticoid effects include disruption of salt and water balance in the body, and compounds that have marked mineralocorticoid effects are likely to produce undesirable effects when administered.
Selv ved lokal administrering av anti-inflammatoriske steroider er det en risiko for at steroidet kan absorberes inn i systemet gjennom huden, med påfølgende utvikling av uønskede bivirkninger. Even with local administration of anti-inflammatory steroids, there is a risk that the steroid can be absorbed into the system through the skin, with subsequent development of unwanted side effects.
Det er således et generelt ønske å finne frem til et anti-inflammatorisk steroid som har høy anti-inflammatorisk virkning, There is thus a general desire to find an anti-inflammatory steroid that has a high anti-inflammatory effect,
men for hvilket de uønskede virkninger, av enten mineralokortikoid eller glukokortikoid natur, er redusert. but for which the undesirable effects, of either a mineralocorticoid or glucocorticoid nature, are reduced.
Vi har nu funnet at visse nye steroider av androstanserien er i besittelse av en markert anti-inflammatorisk virkning, våre forsøk tyder videre på at generelt er forholdet mellom anti-inflammatorisk virkning og uønsket kortisonlignende virkning i de nye forbindelser generelt godt. We have now found that certain new steroids of the androstane series possess a marked anti-inflammatory effect, our experiments further indicate that in general the relationship between anti-inflammatory effect and unwanted cortisone-like effect in the new compounds is generally good.
Steroidforbindelsene som fremstilles i henhold til oppfinnelsen er forbindelser med den generelle formel: The steroid compounds produced according to the invention are compounds with the general formula:
hvor a) X betyr et hydrogen-, klor- eller fluoratom; where a) X means a hydrogen, chlorine or fluorine atom;
betyr en hydroksygruppe i j3-konfigurasjon eller (når X betyr et kloratom) kan også bety et kloratom i means a hydroxy group in j3 configuration or (when X means a chlorine atom) can also mean a chlorine atom in
|3-konf iguras jon; |3-conf igura ion;
1*2 betyr et hydrogenatom, en metylengruppe eller en metylgruppe (i enten a- eller (3-konf iguras jon); 1*2 means a hydrogen atom, a methylene group or a methyl group (in either α- or (3-configuration);
R, betyr et hydrogenatom, en alkylgruppe inneholdende R, means a hydrogen atom, an alkyl group containing
1 til 3 karbonatomer eller en fenylgruppe; R^ betyr en alkylgruppe med 1-4 karbonatomer;. en alkylgruppe med 1-4 karbonatomer substituert med minst ett halogenatom eller minst én alkoksykarbonylgruppe med. 1-4 karbonatomer i alkoksydelen; eller en (C^-C^) lavere .alkylgruppe substituert med en acyloksygruppe med 2-5 karbonatomer; og betyr en enkelt- eller dobbeltbinding, med den: unntagelse at R^ ikke er en n-propyl-, isopropyl- eller n-butylgruppe, med mindre én eller flere av gruppene X, R2 og R., er annet enn et hydrogenatom, og/eller 1 to 3 carbon atoms or a phenyl group; R 1 means an alkyl group with 1-4 carbon atoms; an alkyl group with 1-4 carbon atoms substituted with at least one halogen atom or at least one alkoxycarbonyl group with. 1-4 carbon atoms in the alkoxy part; or a (C₁-C₁) lower alkyl group substituted with an acyloxy group of 2-5 carbon atoms; and means a single or double bond, with the exception that R^ is not an n-propyl, isopropyl or n-butyl group, unless one or more of the groups X, R 2 and R , is other than a hydrogen atom, and /or
betyr en dobbeltbinding; eller means a double bond; or
b) X betyr et klor- eller fluoratom; b) X represents a chlorine or fluorine atom;
R^ betyr en oksogruppe; R 1 means an oxo group;
R2 betyr et hydrogenatom, en metylengruppe eller en metylgruppe (i enten a- eller &-konfigurasjon); R 2 means a hydrogen atom, a methylene group or a methyl group (in either α- or β-configuration);
R^ betyr en metyl- eller etylgruppe; R 1 represents a methyl or ethyl group;
R 4 betyr en alkylgruppe med 1-4 karbonatomer; en alkylgruppe med 1-4 karbonatomer substituert med minst ett halogenatom eller minst én alkoksykarbonylgruppe med 1-4 karbonatomer i alkoksydelen; eller en(C2_^) lavere alkylgruppe substituert med en acyloksygruppe med 2-5 karbonatomer; og R 4 means an alkyl group with 1-4 carbon atoms; an alkyl group with 1-4 carbon atoms substituted by at least one halogen atom or at least one alkoxycarbonyl group with 1-4 carbon atoms in the alkoxy part; or a (C2_^) lower alkyl group substituted with an acyloxy group of 2-5 carbon atoms; and
betyr en enkelt- eller dobbeltbinding. means a single or double bond.
De nye androstanforbindelser har anti-inflammatorisk virkning ved lokal og innvendig administrering, og den anti-inflammatoriske aktivitet av forbindelsene ved lokal administrering er generelt høy. The new androstane compounds have anti-inflammatory action when administered locally and internally, and the anti-inflammatory activity of the compounds when administered locally is generally high.
Generelt er gruppen R^ i formel .1 fortrinnsvis en alkylgruppe inneholdende opptil 3 karbonatomer/ dvs. en metyl-, etyl-, n-propyl- eller isopropylgruppe. I forbindelser hvor R^ betyr et hydrogenatom, betyr R^ fortrinnsvis en metylgruppe. In general, the group R 1 in formula 1 is preferably an alkyl group containing up to 3 carbon atoms, i.e. a methyl, ethyl, n-propyl or isopropyl group. In compounds where R₂ means a hydrogen atom, R₂ preferably means a methyl group.
Gruppen R^ i formel I er fortrinnsvis en metyl-, etyl-eller propylgruppe. The group R 1 in formula I is preferably a methyl, ethyl or propyl group.
Når det gjelder de mulige substituenter på den lavere alkylgruppe, er halogenatomet fortrinnsvis et fluor-, klor- eller bromatom, den lavere (C2_5) acyloksygruppe er fortrinnsvis en acetoksygruppe, og alkoksykarbonylgruppen (hvor alkoksygruppen inneholder 1-4 karbonatomer) er hensiktsmessig en metoksykarbonyl-gruppe. As for the possible substituents on the lower alkyl group, the halogen atom is preferably a fluorine, chlorine or bromine atom, the lower (C2_5) acyloxy group is preferably an acetoxy group, and the alkoxycarbonyl group (where the alkoxy group contains 1-4 carbon atoms) is conveniently a methoxycarbonyl- group.
Generelt foretrekkes forbindelser med formel I hvor 5^ betyr en fi-hydroksygruppe. Generelt foretrekkes også forbindelser med formel I hvor R2 betyr en metylgruppe i p-konfigurasjon p.g.a. deres høye lokale anti-inflammatoriske virkning. In general, compounds of formula I are preferred where 5^ means a 1-hydroxy group. In general, compounds of formula I where R 2 means a methyl group in p-configuration are also preferred because their high local anti-inflammatory effect.
En foretrukket klasse forbindelser med formel I med A preferred class of compounds of formula I with
særlig god lokal anti-inflammatorisk virkning og med et gunstig forhold mellom lokal anti-inflammatorisk virkning og glukokortikoid virkning, er de forbindelser hvor X betyr et klor- eller fluoratom, (fortrinnsvis et fluoratom) , R., betyr en /3-hydroksygruppe, R2 betyr en metylgruppe (fortrinnsvis i /3-konf iguras jon) , R^ betyr en metyl-, etyl- eller n-propylgruppe, R^ betyr en metylgruppe, og betyr en dobbeltbinding. En annen foretrukket klasse forbindelser med formel I som også har god lokal anti-inflammatorisk virkning med et gunstig forhold mellom lokal anti-inflammatorisk virkning og glukokortikoid virkning, er de hvor X betyr et fluor-eller kloratom (fortrinnsvis et fluoratom), R^ betyr en ketogruppe, R2 betyr en metylgruppe i ^-konfigurasjon, R3 betyr en metyl- particularly good local anti-inflammatory action and with a favorable relationship between local anti-inflammatory action and glucocorticoid action, are those compounds where X means a chlorine or fluorine atom, (preferably a fluorine atom), R., means a /3-hydroxy group, R 2 means a methyl group (preferably in the /3 configuration), R 2 means a methyl, ethyl or n-propyl group, R 2 means a methyl group, and means a double bond. Another preferred class of compounds of formula I which also have good local anti-inflammatory action with a favorable ratio between local anti-inflammatory action and glucocorticoid action are those where X means a fluorine or chlorine atom (preferably a fluorine atom), R^ means a keto group, R2 means a methyl group in ^-configuration, R3 means a methyl-
eller etylgruppe, R^ betyr en metylgruppe og betyr en dobbeltbinding. or ethyl group, R 1 means a methyl group and means a double bond.
En ytterligere foretrukket klasse forbindelser med formel I med høy lokal anti-inflammatorisk aktivitet er de hvor X betyr et fluor- eller kloratom (fortrinnsvis et fluoratom), R^ betyr en /3-hydroksygruppe, R2 betyr en metylengruppe, R^ betyr en metyl-, etyl-, n-propyl- eller isopropylgruppe, R^ betyr en metyl- eller etylgruppe (fortrinnsvis en metylgruppe), og betyr fortrinnsvis en dobbeltbinding. A further preferred class of compounds of formula I with high local anti-inflammatory activity are those where X means a fluorine or chlorine atom (preferably a fluorine atom), R^ means a β-hydroxy group, R2 means a methylene group, R^ means a methyl -, ethyl, n-propyl or isopropyl group, R 1 means a methyl or ethyl group (preferably a methyl group), and preferably means a double bond.
4 4
En foretrukket klasse A forbindelser med formel I A preferred class A compounds of formula I
(dvs. forbindelser hvor betyr en enkeltbinding) med særlig god lokal anti-inflammatorisk aktivitet og gunstig forhold for lokal anti-inflammatorisk aktivitet til glukokortikoid aktivitet, (i.e. compounds where means a single bond) with particularly good local anti-inflammatory activity and a favorable ratio of local anti-inflammatory activity to glucocorticoid activity,
er de hvor X betyr et fluor- eller kloratom (fortrinnsvis et fluoratom) , R^ betyr en /3-hydroksygruppe, R2 betyr en metylgruppe (fortrinnsvis i /3-konf iguras j on) , R^ betyr en metyl-, etyl- eller n-propylgruppe, og R4 betyr en metyl- eller etylgruppe (fortrinnsvis en metylgruppe). ' are those where X means a fluorine or chlorine atom (preferably a fluorine atom), R^ means a /3-hydroxy group, R2 means a methyl group (preferably in the /3 configuration), R^ means a methyl-, ethyl- or n-propyl group, and R 4 means a methyl or ethyl group (preferably a methyl group). '
En ytterligere klasse forbindelser med formel I som har A further class of compounds of formula I which have
god lokal anti-inflammatorisk aktivitet, er de hvor X betyr et hydrogenatom, R.^ betyr .en /3-hydroksygruppe og R2 betyr fortrinnsvis et hydrogenatom eller en metylgruppe (særlig i /3-konfigurasjon) , good local anti-inflammatory activity, are those where X means a hydrogen atom, R.^ means a /3-hydroxy group and R2 preferably means a hydrogen atom or a methyl group (especially in /3-configuration),
betyr fortrinnsvis en alkylgruppe inneholdende 1, 2 eller 3 karbonatomer, R^ betyr fortrinnsvis en lavere alkylgruppe (f.eks. preferably means an alkyl group containing 1, 2 or 3 carbon atoms, R^ preferably means a lower alkyl group (e.g.
en metylgruppe), o<g>'^rrr betyr fortrinnsvis en dobbeltbinding. a methyl group), o<g>'^rrr preferably means a double bond.
De forbindelser av denne klasse hvor R0 betyr en metylgruppe i /3-konf iguras jon, er funnet å være i besittelse av særlig høy, The compounds of this class where R0 means a methyl group in the /3 configuration have been found to possess particularly high,
lokal anti-inflammatorisk aktivitet. local anti-inflammatory activity.
En annen klasse forbindelser med formel I "som har særlig god lokal anti-inflammatorisk aktivitet og et godt forhold for lokal anti-inflammatorisk aktivitet til glukokortikoid aktivitet, er de hvor X dg R^ betyr kloratomer, R^ betyr en metylgruppe, fortrinnsvis i a-konfigurasjon, R^ betyr en metyl- eller etyl-. gruppe, R^ betyr en metyl- eller etylgruppe og betyr fortrinnsvis en dobbeltbinding. Another class of compounds of formula I "which have particularly good local anti-inflammatory activity and a good ratio of local anti-inflammatory activity to glucocorticoid activity are those where X dg R^ means chlorine atoms, R^ means a methyl group, preferably in a -configuration, R₂ means a methyl or ethyl group, R₂ means a methyl or ethyl group and preferably means a double bond.
Individuelle, foretrukne androstaner som er funnet å ha særlig god lokal anti-inflammatorisk aktivitet med generelt lave verdier for glukokortikoid aktivitet, omfatter: metyl-17a-acetoksy-9a-fluor-ll/3-hydroksy-16/3-metyl-3-okso-androsta-1,4-dien-17/3-karboksylat metyl-9a-f luor-ll/3-hydroksy-16/3-metyl-3-okso-17o!-propionyloksyandrosta-1,4-dien-17/3-karboksylat, metyl-17a-butyryloksy-9a-f luor-ll/3-hydroksy-16/3-metyl-3-oksoandrosta-1,4-dien-17/3-karboksylat, metyl-17a-acetoksy-9a-fluor-ll/3-hydroksy-16a-metyl-3-oksoandrosta-1,4-dien-17/3-karboksylat, metyl-9a-fluor-ll/3-hydroksy-16a-metyl-3-okso-17a;-propionyloksyandrosta-1,4-dien-17/3-karboksylat, metyl -17 a-butyry 1 ok sy- 9 a- fluor-11 j3 -hydr ok sy-16 a-me ty 1 - 3 - oks o-androsta-1, 4-dien-17/3-karboksylat, metyl-9a-f luor-ll/3-hydroksy-16-metylen-3-okso-17o!-propionyloksyandrosta-1, 4-dien-17/3-karboksylat, metyl-9a!-f luor-ll/3-hydroksy-16/3-metyl-3-okso-17o!-propionyloksyandrost-4-en-17/3-karboksylat, metyl-17o!-acetoksy-9Q!-f luor-16/3-metyl-3 ,11-dioksoandrosta-l, 4-dien-17/3-karboksylat, etyl-9a-fluor-ll/3-hydroksy-16/3-metyl-3-okso-17o;-propionyloksyandrosta-1,4-dien-17/3-karboksylat, metyl-17a-acetoksy-9o!, ll/3-diklor-16o!-metyl-3-okso-androsta-l, 4-dien-17/3-karboksylat, metyl-9a-fluor-ll/3-hydroksy-17a!-isobutyryloksy-16-metylen-3-oksoandrosta-1,4-dien-17/3-karboksylat, Individual preferred androstanes which have been found to have particularly good local anti-inflammatory activity with generally low values of glucocorticoid activity include: methyl-17α-acetoxy-9α-fluoro-11/3-hydroxy-16/3-methyl-3- oxo-androsta-1,4-diene-17/3-carboxylate methyl-9α-fluoro-1/3-hydroxy-16/3-methyl-3-oxo-17o!-propionyloxyandrosta-1,4-diene-17 /3-carboxylate, methyl 17a-butyryloxy-9a-fluoro-11/3-hydroxy-16/3-methyl-3-oxoandrosta-1,4-diene-17/3-carboxylate, methyl 17a-acetoxy- 9a-fluoro-1/3-hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17/3-carboxylate, methyl 9a-fluoro-1/3-hydroxy-16a-methyl-3-oxo- 17a;-propionyloxyandrosta-1,4-diene-17/3-carboxylate, methyl -17 a-butyry 1 ok sy- 9 a- fluoro-11 j3 -hydr ok sy-16 a-me ty 1 - 3 - ox o -androsta-1, 4-diene-17/3-carboxylate, methyl-9a-fluoro-11/3-hydroxy-16-methylene-3-oxo-17o!-propionyloxyandrosta-1, 4-diene-17/3 -carboxylate, methyl 9α!-fluoro-11/3-hydroxy-16/3-methyl-3-oxo-17o!-propionyloxyandrost-4-ene-17/3-carboxylate, methyl 17o!-acetoxy-9 Q1-fluoro-16/3-methyl-3,11-dioxoandrosta-1, 4-diene-17/3-carboxylate, ethyl 9a-fluoro-11/3-hydroxy-16/3-methyl-3- oxo-17o;-propionyloxyandrosta-1,4-diene-17/3-carboxylate, methyl-17a-acetoxy-9o!, 11/3-dichloro-16o!-methyl-3-oxo-androsta-1,4-diene -17/3-carboxylate, methyl 9α-fluoro-11/3-hydroxy-17α!-isobutyryloxy-16-methylene-3-oxoandrosta-1,4-diene-17/3-carboxylate,
etyl-9o!-fluor-ll/3-hydroksy-17Q!-isobutyryloksy-16-metylen-3-oksoandrosta-1, 4-dien-17/3-karboksylat, og ethyl 90-fluoro-11/3-hydroxy-17Q1-isobutyryloxy-16-methylene-3-oxoandrosta-1,4-diene-17/3-carboxylate, and
metyl-ll/3-hydroksy-16/3-metyl-3-okso-17a!-propionyloksyandrosta-l, 4-dien-17/3-karboksylat. methyl 11/3-hydroxy-16/3-methyl-3-oxo-17α!-propionyloxyandrosta-1, 4-diene-17/3-carboxylate.
U.S.-patent 3 636 010 angår visse androstanforbindelser som har en fri eller forestret karboksylgruppe i 173-stilling og en fri eller forestret hydroksygruppe i 17a-stilling slik som angitt i formel I i patentets hovedkrav. Forbindelsene med formel I i patentet kjennetegnes blant annet ved et fluoratom i 6-stilling, mens forbindelsene fremstilt ifølge foreliggende oppfinnelse er usubstituert i denne stilling. Forbindelsene som fremstilles ifølge oppfinnelsen, adskiller seg således klart fra forbindelsene ifølge patentet. En ytterligere forskjell vil fremgå ved en nærmere gjennom-gåelse av patentet. Selv om krav 1 i patentet omfatter forbindelser hvor R 2 betyr en forestret hydroksygruppe i 17a-stilling, er det ingen eksempler i beskrivelsen på fremstilling av slike forbindelser. Forbindelsene som fremstilles ifølge foreliggende oppfinnelse, inneholder derimot nødvendig-vis en estergruppe i 17a-stilling. Den foretrukne forbindelse ifølge patentet (spalte 2, linje 23) er en 17a-hydroksy-forbindelse, i likhet med alle de andre spesielt beskrevne forbindelser i patentet. U.S. Patent 3,636,010 relates to certain androstane compounds having a free or esterified carboxyl group in the 173-position and a free or esterified hydroxy group in the 17a-position as set forth in formula I of the main claims of the patent. The compounds with formula I in the patent are characterized, among other things, by a fluorine atom in the 6-position, while the compounds produced according to the present invention are unsubstituted in this position. The compounds produced according to the invention thus clearly differ from the compounds according to the patent. A further difference will be apparent from a closer review of the patent. Although claim 1 in the patent includes compounds where R 2 means an esterified hydroxy group in the 17a position, there are no examples in the description of the preparation of such compounds. The compounds produced according to the present invention, on the other hand, necessarily contain an ester group in the 17a position. The preferred compound according to the patent (column 2, line 23) is a 17a-hydroxy compound, like all the other specifically described compounds in the patent.
Vi har undersøkt den ovennevnte foretrukne forbindelse ifølge U.S.-patentet for å bestemme forbindelsens lokale anti-inflammatoriske virkning sammenlignet med virk-ningen av forbindelsene fremstilt ifølge oppfinnelsen. De forbindelser fremstilt ifølge oppfinnelsen som strukturmessig kommer nærmest den foretrukne forbindelse ifølge patentet, er de tilsvarende 6-hydrogen-analoger med en acetat-, propionat-eller butylatgruppe i 17a-stilling, og disse forbindelser er beskrevet i henholdsvis eksempel 20, 21 og 22. We have examined the above preferred compound according to the U.S. patent to determine the local anti-inflammatory action of the compound compared to the action of the compounds prepared according to the invention. The compounds produced according to the invention which structurally come closest to the preferred compound according to the patent are the corresponding 6-hydrogen analogues with an acetate, propionate or butylate group in the 17a position, and these compounds are described in examples 20, 21 and 22 respectively .
Virkningene av forbindelsene ble målt under anvendelse av den velkjente McKenzie flekkprøve som representerer et verdifullt kriterium på klinisk lokal anti-inflammatorisk virkning for et gitt steroid. Ved dette forsøk ble det funnet at 17-acetatet, -propionatet og -butylatet fremstilt.ifølge oppfinnelsen som angitt ovenfor, var henholdsvis 3.0, 20 og 45 ganger så aktiv som den foretrukne forbindelse ifølge.U.S.-patentet. The effects of the compounds were measured using the well-known McKenzie spot test which represents a valuable criterion of clinical local anti-inflammatory action for a given steroid. In this experiment it was found that the 17-acetate, -propionate and -butylate produced according to the invention as set forth above were respectively 3.0, 20 and 45 times as active as the preferred compound according to the U.S. patent.
Farmasøytiske preparater som er egnet til bruk ved behandling av inflammasjoner, omfatter minst én androstan-forbindelse med formel I, sammen med ett eller flere farma-søy.tiske bæremidler eller eksipienser. Slike preparater kan være i former som er egnet for lokal eller innvendig administrering. Pharmaceutical preparations which are suitable for use in the treatment of inflammations comprise at least one androstane compound of formula I, together with one or more pharmaceutical carriers or excipients. Such preparations may be in forms suitable for local or internal administration.
For parenteral.administrering kan forbindelsene innføres i sterile, vandige eller oljeaktige bæremidler,. hensiktsmessig oljeaktige bæremidler så som arachisolje, oliven-olje osv. For parenteral administration, the compounds can be introduced into sterile, aqueous or oily carriers. suitably oily carriers such as arachis oil, olive oil, etc.
Foretrukne preparatformer for innvendig administrering er enhetsdoseformer, dvs. preparater i enhetsform, hvor hver.enhet inneholder en ønsket dose av det aktive steroid. Slike enhetsdoseformer inneholder fra 0,05 til 2,0 mg, fortrinnsvis fra 0,25 til 1,0 mg av det aktive steroid. . Forbindelser fremstilt i henhold til oppfinnelsen kan generelt gis ved innvendig administrering i de tilfeller hvor systemisk adreno-kortikal behandling ønskes. Preferred preparation forms for internal administration are unit dosage forms, i.e. preparations in unit form, where each unit contains a desired dose of the active steroid. Such unit dosage forms contain from 0.05 to 2.0 mg, preferably from 0.25 to 1.0 mg, of the active steroid. . Compounds produced according to the invention can generally be given by internal administration in cases where systemic adreno-cortical treatment is desired.
Preparater for innvendig administrering inneholder generelt fra 0,01 til 5,0% av den aktive bestanddel, avhengig av den aktuelle type. Den daglige dose kan variere fra 0,05 til 10,0 mg avhengig av den lidelse som behandles og den ønskede behandlingsvarighet. Preparations for internal administration generally contain from 0.01 to 5.0% of the active ingredient, depending on the type in question. The daily dose may vary from 0.05 to 10.0 mg depending on the disorder being treated and the desired duration of treatment.
Preparatene kan også inneholde ett eller flere kon-serveringsmidler eller bakteriostatiske midler, f.eks. metyl-hydroksybenzoat, propylhydroksybenzoat, klorkresol eller benzalkoniumklorider. Preparatene kan også inneholde andre aktive bestanddeler så som antimikrobielle midler, særlig antibiotika The preparations may also contain one or more preservatives or bacteriostatic agents, e.g. methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol or benzalkonium chlorides. The preparations may also contain other active ingredients such as antimicrobial agents, especially antibiotics
så som neomycin. such as neomycin.
Forbindelsene med formel I fremstilles i henhold til oppfinnelsen ved forestring av en tilsvarende 17a-monoester-17/3-karboksylsyre (eller funksjonell ekvivalent derav) eller 17a-hydroksy-17/3-karboksylat for å danne den tilsvarende forbindelse med formel I. The compounds of formula I are prepared according to the invention by esterification of a corresponding 17a-monoester-17/3-carboxylic acid (or functional equivalent thereof) or 17a-hydroxy-17/3-carboxylate to form the corresponding compound of formula I.
Som kjent er det ofte hensiktsmessig å innføre de ønskede substituenter i 17a- og 17/3-stillingene på et mellomliggende trinn ved fremstillingen av den ønskede sluttforbindelse, idet én eller flere andre substituenter (eller umettethet) innføres på et senere trinn. For fremstilling av 11-okso-forbindelser er det f.eks. mulig å først fremstille en 11/3-hydroksyforbindelse med den ønskede 17a-acyloksygruppe og den ønskede 17/3-karboksylatester-gruppe, og deretter oksydere 11/3-hydroksygruppen. Andre tilfeller hvor de ønskede substituenter kan innføres før den endelige inn-føring av de øvrige substituenter i de ønskede androstanmolekyl omfatter f. eks. fremstilling av A^'^' eller ring A umettede forbindelser med de ønskede 17a-acyloksy- og 17/3-karboksylatester-grupper, idet bearbeidelsen av ringene A, B og C deretter fullføres på vanlig måte. As is known, it is often appropriate to introduce the desired substituents in the 17a and 17/3 positions at an intermediate stage in the preparation of the desired final compound, with one or more other substituents (or unsaturation) being introduced at a later stage. For the production of 11-oxo compounds, there is e.g. possible to first prepare a 11/3-hydroxy compound with the desired 17a-acyloxy group and the desired 17/3-carboxylate ester group, and then oxidize the 11/3-hydroxy group. Other cases where the desired substituents can be introduced before the final introduction of the other substituents in the desired androstane molecule include e.g. preparation of A^'^' or ring A unsaturated compounds with the desired 17α-acyloxy and 17/3-carboxylate ester groups, the processing of rings A, B and C then being completed in the usual manner.
Innføring av de karakteristiske 17-substituenter i de nye androstanforbindelser kan hensiktsmessig gjøres fra pregnan-forbindelser feom har den følgende delformel i 17-stilling: Introduction of the characteristic 17-substituents in the new androstane compounds can conveniently be done from pregnane compounds which have the following partial formula in the 17-position:
ved oksydasjon på kjent måte for å danne en tilsvarende androstan 17j3-karboksylsyre som deretter kan forestres. 17a-hydroksygruppen kan forestres eller omdannes funksjonelt på annen måte før oksydasjonen og deretter eventuelt regenereres eller omdannes til en forskjellig 17a-acyloksygruppe. by oxidation in a known manner to form a corresponding androstane 17j3-carboxylic acid which can then be esterified. The 17a-hydroxy group can be esterified or functionally converted in another way before the oxidation and then possibly regenerated or converted into a different 17a-acyloxy group.
Den oksydative fjernelse av 21-karbonatomet i pregnan-utgangsmaterialet kan f.eks. utføres med perjodsyre, i et opp-løsningsmiddelmedium og fortrinnsvis ved romtemperatur. Alternativt kan natriumvismutat anvendes for å frembringe den ønskede oksydative fjernelse av 21-karbonatomet i en 17a-acyloksy-pregnan-forbindelse. The oxidative removal of the 21-carbon atom in the pregnane starting material can e.g. is carried out with periodic acid, in a solvent medium and preferably at room temperature. Alternatively, sodium bismuthate can be used to produce the desired oxidative removal of the 21-carbon atom in a 17a-acyloxy-pregnan compound.
Hvis pregnan-utgangsforbindelsen skulle inneholde en substituent som påvirkes av den ovenfor beskrevne oksydasjon, bør en slik gruppe beskyttes på passende måte. If the starting pregnane compound should contain a substituent affected by the above-described oxidation, such a group should be suitably protected.
17/3-karboksylsyre-utgangsforbindelsen for. forbindelsene The 17/3-carboxylic acid starting compound for. the connections
med formel I kan forestres på kjent måte for å danne de nye 17/S-karboksyiatestere. For å fremstille en., lavere alkylester kan f.eks. 17/3-karboksylsyren omsettes, med et passende diazoalkan,. f.eks. diazometan, idet omsetningen, fortrinnsvis utføres i et oppløsningsmiddel, f.eks. eter, tetrahydrofuran eller metanol, og ved en lav temperatur, fortrinnsvis ved -5 til +30°C. Alternativt kan 17/3-karboksylsyren omsettes med et passende O-alkyl-N jN^-dicyklohéksyl-isour instof f,. f.eks. O-t-butyl-N,N^-dicykloheksyl-isourinstof f , fortrinnsvis i et aprotisk oppløsningsmiddel så som etylacetat, og hensiktsmessig ved en temperatur på 25-lOO°C. with formula I can be esterified in a known manner to form the new 17/S-carboxy esters. To prepare a lower alkyl ester, e.g. The 17/3-carboxylic acid is reacted with a suitable diazoalkane. e.g. diazomethane, the reaction preferably being carried out in a solvent, e.g. ether, tetrahydrofuran or methanol, and at a low temperature, preferably at -5 to +30°C. Alternatively, the 17/3-carboxylic acid can be reacted with a suitable O-alkyl-N jN^-dicyclohexyl-isour instof f,. e.g. O-t-butyl-N,N^-dicyclohexyl-isourea, preferably in an aprotic solvent such as ethyl acetate, and conveniently at a temperature of 25-100°C.
Et salt av 17/3-karboksylsyre-utgangsmaterialet, f. eks. et alkali-metallsalt så som litium-, natrium- eller kaliumsaltet eller kvartært ammoniumsalt, så som trietylammonium- eller tetrabutyl-ammoniumsaltet, kan alternativt omsettes med et passende alkyleringsmiddel, f.eks. et alkylhalogenid så som jodidet eller et dialkyl-sulfat, så som dimetylsulfat, fortrinnsvis i et polart oppløsnings-middel så som aceton, metyletylketon eller dimetylformamid, hensiktsmessig ved en temperatur i området 25-lOO°C. Omsetningen med et alkylhalogenid kan fortrinnsvis anvendes til å fremstille etyl- og propyl-17/3-karboksylatestrene og høyere alkylestere. A salt of the 17/3-carboxylic acid starting material, e.g. an alkali metal salt such as the lithium, sodium or potassium salt or quaternary ammonium salt such as the triethylammonium or tetrabutylammonium salt may alternatively be reacted with a suitable alkylating agent, e.g. an alkyl halide such as the iodide or a dialkyl sulphate such as dimethyl sulphate, preferably in a polar solvent such as acetone, methyl ethyl ketone or dimethylformamide, suitably at a temperature in the range of 25-100°C. The reaction with an alkyl halide can preferably be used to prepare the ethyl and propyl-17/3-carboxylate esters and higher alkyl esters.
Alternativt kan 17a-hydroksy-17/3-karboksylsyre-utgangs-forbindelsene for forbindelsene med formel I forestres på kjent måte for å danne de tilsvarende 17a-hydroksy-17/3-karboksylatestere. F.eks. kan 17|3-karboksylsyren omsettes med et diazoalkan eller et O-alkyl-dicykloheksyl-isourinstoff, eller et salt av 17/3-karboksylsyren kan omsettes med et alkyleringsmiddel som beskrevet ovenfor for fremstilling av 17£-karboksylatestrene. 17a-hydroksy-17/3-karboksylatestrene kan deretter forestres videre på kjent måte for å danne de nye forbindelser med formel I. Alternatively, the 17α-hydroxy-17/3-carboxylic acid starting compounds for the compounds of formula I can be esterified in a known manner to form the corresponding 17α-hydroxy-17/3-carboxylic esters. E.g. the 17/3-carboxylic acid can be reacted with a diazoalkane or an O-alkyl-dicyclohexyl isourea, or a salt of the 17/3-carboxylic acid can be reacted with an alkylating agent as described above to produce the 17£-carboxylate esters. The 17a-hydroxy-17/3-carboxylate esters can then be further esterified in a known manner to form the new compounds of formula I.
Forestringen av 17o!-hydroksygruppen ved den ovenfor beskrevne fremstilling av de nye androstanforbindelser kan utføres på kjent måte, f.eks. ved omsetning av 17a-hydroksy-utgangsforbindelsen med en passende karboksylsyre, hensiktsmessig i nærvær av trifluoreddiksyreanhydrid og fortrinnsvis i nærvær av en syrekatalysator, f.eks. p-toluensulfonsyre eller sulfosalicylsyre. The esterification of the 17o!-hydroxy group in the preparation of the new androstane compounds described above can be carried out in a known manner, e.g. by reacting the 17a-hydroxy starting compound with a suitable carboxylic acid, conveniently in the presence of trifluoroacetic anhydride and preferably in the presence of an acid catalyst, e.g. p-toluenesulfonic acid or sulfosalicylic acid.
Omsetningen utføres hensiktsmessig i et organisk medium The reaction is suitably carried out in an organic medium
så som benzen, metylenklorid eller et overskudd av den anvendte karboksylsyre, og omsetningen utføres hensiktsmessig ved en temperatur på 20-100°C. such as benzene, methylene chloride or an excess of the carboxylic acid used, and the reaction is conveniently carried out at a temperature of 20-100°C.
Alternativt kan 17a-hydroksygruppen forestres ved at 17a-hydroksy-utgangsforbindelsen omsettes med det passende syre-anhydrid eller syreklorid, eventuelt i nærvær av ikke-hydroksyl-holdige oppløsningsmidler, f.eks. kloroform, metylenklorid eller benzen, og fortrinnsvis i nærvær av en sterk syrekatalysator, Alternatively, the 17a-hydroxy group can be esterified by reacting the 17a-hydroxy starting compound with the appropriate acid anhydride or acid chloride, possibly in the presence of non-hydroxyl-containing solvents, e.g. chloroform, methylene chloride or benzene, and preferably in the presence of a strong acid catalyst,
f.eks. perklorsyre, p-toluensulfonsyre eller en sterkt sur katiqne^-bytterharpiks, f.eks. "Amberlite IR 120" h idet omsetningen hensiktsmessig utføres ved en temperatur fra 25 - 100°C. e.g. perchloric acid, p-toluenesulfonic acid or a strongly acidic cation exchange resin, e.g. "Amberlite IR 120" h as the reaction is suitably carried out at a temperature from 25 - 100°C.
For fremstilling av 17a-estrene av 17/3-karboksylsyrene som kan anvendes ved fremstillingen av de nye forbindelser, foretrekkes det ofte å behandle 17a-hydroksy-utgangsforbindelsen med det passende karboksylsyreanhydrid for å få 17a-esteren av det blandede anhydrid av androstan-17/3-karboksylsyren og karboksylsyren i utgangsanhydridet, idet denne omsetning hensiktsmessig utføres ved forhøyet temperatur, hvoretter det resulterende anhydrid solvolyseres under sure betingelser (f.eks. under anvendelse av vandig eddiksyre) eller under basiske betingelser (f.eks. under anvendelse av vandig pyridin eller et sekundært amin så som dietylamin i aceton). For the preparation of the 17a-esters of the 17/3-carboxylic acids which can be used in the preparation of the new compounds, it is often preferred to treat the 17a-hydroxy starting compound with the appropriate carboxylic acid anhydride to obtain the 17a-ester of the mixed anhydride of androstane-17 the /3-carboxylic acid and the carboxylic acid in the starting anhydride, this reaction being conveniently carried out at an elevated temperature, after which the resulting anhydride is solvolysed under acidic conditions (e.g. using aqueous acetic acid) or under basic conditions (e.g. using aqueous pyridine or a secondary amine such as diethylamine in acetone).
Alternativt kan 17o;-hydroksy-utgangsf orbindelsen behandles med det passende karboksylsyreklorid, fortrinnsvis i et oppløsnings-middel så som ét halogenert hydrokarbon, f . eks. metylenklorid, og hensiktsmessig i nærvær av en base så som trietylamin, fortrinnsvis ved en lav temperatur, f.eks. 0°C. Alternatively, the 17o;-hydroxy starting compound can be treated with the appropriate carboxylic acid chloride, preferably in a solvent such as a halogenated hydrocarbon, e.g. e.g. methylene chloride, and suitably in the presence of a base such as triethylamine, preferably at a low temperature, e.g. 0°C.
Forbindelser hvor 11-stillingen inneholder en ketogruppe, kan f. eks. fremstilles ved oksydasjon av en tilsvarende 11/3-hydroksyforbindelse, f.eks. ved hjelp av kromtrioksyd, hensiktsmessig i et inert oppløsningsmiddel så som aceton, fortrinnsvis i nærvær av svovelsyre. Alternativt kan man anvende kromtrioksyd i nærvær av pyridin. Compounds where the 11-position contains a keto group can e.g. is produced by oxidation of a corresponding 11/3-hydroxy compound, e.g. using chromium trioxide, conveniently in an inert solvent such as acetone, preferably in the presence of sulfuric acid. Alternatively, chromium trioxide can be used in the presence of pyridine.
Den ovenfor beskrevne oksydasjon av en 11/3-hydroksygruppe til en 11-ketogruppe kan utføres på et hvilket som helst passende trinn ved syntesen av androstanforbindelsene, f.eks. før eller etter den oksydative fjernelse av 21-karbonatomet i det ovennevnte pregnan-utgangsmateriale eller forestringen av 17a-hydroksygruppen. The above described oxidation of a 11/3-hydroxy group to a 11-keto group can be carried out at any suitable step in the synthesis of the androstane compounds, e.g. before or after the oxidative removal of the 21-carbon atom in the above pregnane starting material or the esterification of the 17a-hydroxy group.
De forbindelser med formel I hvor R4 betyr en lavere alkylgruppe substituert med minst ett halogenatom eller en lavere alkoksykarbonylgruppe; eller en lavere alkylgruppe substituert med en lavere acyloksygruppe, kan f.eks. fremstilles ved at et salt av 17/3-karboksylsyre-utgahgsforbindelsen omsettes med en passende halogenforbindelse som tjener til å innføre den ønskede gruppe R. i forbindelsen med formel I. The compounds of formula I where R 4 means a lower alkyl group substituted by at least one halogen atom or a lower alkoxycarbonyl group; or a lower alkyl group substituted with a lower acyloxy group, can e.g. is prepared by reacting a salt of the 17/3-carboxylic acid starting compound with a suitable halogen compound which serves to introduce the desired group R. into the compound of formula I.
Som saltet av 17/3-karboksylsyre-utgangsforbindelsen anvendes hensiktsmessig et alkalimetall- f.eks. litium-, natrium-eller kalium-salt eller et kvartært ammoniumsalt så som et trietylammonium- eller tetrabutylammoniumsalt, hensiktsmessig i et polart oppløsningsmiddel så som aceton, metyletylketon eller dimetylformamid. As the salt of the 17/3-carboxylic acid starting compound, an alkali metal is suitably used, e.g. lithium, sodium or potassium salt or a quaternary ammonium salt such as a triethylammonium or tetrabutylammonium salt, suitably in a polar solvent such as acetone, methyl ethyl ketone or dimethylformamide.
De substituerte lavere alkylgrupper betegnet med R^ i formel I kan eventuelt modifiseres på passende måte etter vanlige metoder. The substituted lower alkyl groups denoted by R₂ in formula I can optionally be modified in a suitable manner by usual methods.
Når R4 i formel I betyr en alkylgruppe substituert med en lavere alkoksykarbonylgruppe, kan således den resulterende forbindelse eventuelt omdannes til en forbindelse hvor R^ betyr en alkylgruppe med en forskjellig alkoksykarbonylsubstituent ved esterveksling, f.eks. ved behandling med metanol i nærvær av en syrekatalysator så som perklorsyre, for å omdanne en etoksykarbonyl-forbindelse til den tilsvarende metoksykarbonylforbindelse. When R 4 in formula I means an alkyl group substituted with a lower alkoxycarbonyl group, the resulting compound can thus optionally be converted into a compound where R 4 means an alkyl group with a different alkoxycarbonyl substituent by ester exchange, e.g. by treatment with methanol in the presence of an acid catalyst such as perchloric acid, to convert an ethoxycarbonyl compound to the corresponding methoxycarbonyl compound.
Den ovenfor beskrevne omsetning av saltet av en 17/3-karboksylsyre med en halogenforbindelse kan dessuten anvendes til å fremstille forbindelser av den type med formel I hvor R^ betyr en lavere alkylgruppe inneholdende minst to karbonatomer substituert med en hydroksygruppe (på annet sted enn i a-stilling), hvilke forbindelser kan omdannes til de tilsvarende halogensubstituerte forbindelser via de tilsvarende sulfonyloksyalkyl- f.eks. metyloksyalkyl-derivater, idet slik omdannelse kan utføres på vanlig måte. The above-described reaction of the salt of a 17/3-carboxylic acid with a halogen compound can also be used to prepare compounds of the type with formula I where R^ means a lower alkyl group containing at least two carbon atoms substituted with a hydroxy group (at a place other than in a-position), which compounds can be converted into the corresponding halogen-substituted compounds via the corresponding sulfonyloxyalkyl, e.g. methyloxyalkyl derivatives, as such conversion can be carried out in the usual way.
Sulfonyloksyalkylforbindelsen kan således hensiktsmessig omsettes med et alkalimetall-, jordalkalimetall- eller kvartært ammoniumhalogenid, fortrinnsvis litiumklorid, hensiktsmessig i et oppløsningsmiddel som f.eks. inneholder aceton, dimetylformamid eller etanol. The sulfonyloxyalkyl compound can thus suitably be reacted with an alkali metal, alkaline earth metal or quaternary ammonium halide, preferably lithium chloride, suitably in a solvent such as e.g. contains acetone, dimethylformamide or ethanol.
Alternativt kan de ovennevnte hydroksyalkylderivater acyleres, f.eks. med det passende karboksylsyreklorid eller -anhydrid, for å danne forbindelser med formel I hvor R4 betyr en fc2_4) alkylgruppe substituert med en lavere acyloksygruppe. Alternatively, the above-mentioned hydroxyalkyl derivatives can be acylated, e.g. with the appropriate carboxylic acid chloride or anhydride, to form compounds of formula I wherein R 4 means a fc 2-4 ) alkyl group substituted with a lower acyloxy group.
Forbindelser med formel I hvor R4 betyr en lavere alkylgruppe substituert med et halogenatom ved karbonatomet bundet til oksygenatomet i 17/3-karboksylatet, kan f.eks. fremstilles ved at 17/3-karboksylsyre-utgangsforbindelsen omsettes med et passende aldehyd i nærvær av en hydrogenhalogensyre. Omsetningen kan hensiktsmessig utføres i nærvær av en katalysator, f.eks. sink-klorid. Compounds of formula I where R4 means a lower alkyl group substituted with a halogen atom at the carbon atom bound to the oxygen atom in the 17/3-carboxylate, can e.g. is prepared by reacting the 17/3-carboxylic acid starting compound with a suitable aldehyde in the presence of a hydrohalic acid. The reaction can conveniently be carried out in the presence of a catalyst, e.g. zinc chloride.
A 4 forbindelsene med formel I kan hensiktsmessig frem- A 4 the compounds of formula I can suitably be prepared
1 4 1 4
stilles ved delvis reduksjon av den tilsvarende A ' forbindelse, f.eks. ved hydrogenering under anvendelse av en palladiumkatalysator, hensiktsmessig i et oppløsningsmiddel, f.eks. etylacetat, eller ved homogen hydrogenering under anvendelse av f.eks. tris(trifenyl-fosfin)rodiumklorid, hensiktsmessig i et oppløsningsmiddel så som benzen, eller ved utvekslingshydrogenering under anvendelse av f.eks. cykloheksen i nærvær av en palladiumkatalysator i et oppløsningsmiddel, f.eks. etanol, fortrinnsvis under tilbakeløps-kj øling. is provided by partial reduction of the corresponding A ' compound, e.g. by hydrogenation using a palladium catalyst, suitably in a solvent, e.g. ethyl acetate, or by homogeneous hydrogenation using e.g. tris(triphenyl-phosphine)rhodium chloride, suitably in a solvent such as benzene, or by exchange hydrogenation using e.g. cyclohexene in the presence of a palladium catalyst in a solvent, e.g. ethanol, preferably under reflux cooling.
Det skal legges merke til at androstanforbindelser svarende til de nye 17o;-acyloksyforbindelser av androstanserien med formel I, men som har en fri hydroksygruppe i 17-stilling i Q!-konfigurasjon, er nye forbindelser, bortsett fra de forbindelser hvor X og R ? begge er hydrogen, R^ er en metylgruppe, er en enkeltbinding og R^ er en /3-hydroksy- eller oksogruppe. Disse nye forbindelser er nyttige mellomprodukter for fremstilling av de It should be noted that androstane compounds corresponding to the new 17o;-acyloxy compounds of the androstane series of formula I, but having a free hydroxy group in the 17-position in the Q! configuration, are new compounds, except for those compounds where X and R ? both are hydrogen, R^ is a methyl group, is a single bond and R^ is a /3-hydroxy or oxo group. These new compounds are useful intermediates for their preparation
nye 17a-acyloksyforbindelser. new 17a-acyloxy compds.
Andre nye androstanforbindelser som er nyttige som mellomprodukter ved fremstilling av forbindelsene med den generelle formel I, omfatter 17/3-karboksylsyre-utgangsforbindelsene for slike forbindelser, og deres anhydrider, f.eks. deres blandede anhydrider med lavere alkansyrer, særlig lavere alkansyrer så som eddiksyre og propionsyre. Other novel androstane compounds useful as intermediates in the preparation of the compounds of general formula I include the 17/3-carboxylic acid parent compounds of such compounds, and their anhydrides, e.g. their mixed anhydrides with lower alkanoic acids, especially lower alkanoic acids such as acetic acid and propionic acid.
De følgende eksempler skal tjene til å illustrere oppfinnelsen ytterligere. The following examples shall serve to further illustrate the invention.
I eksemplene 1 - 38 er fremstillingen av forbindelsene beskrevet med henvisning til de følgende generelle fremstillings-måter A til F, idet detaljene for forbindelsen fremstilt i hvert tilfelle og dens fysikalske konstanter er gitt i de etterfølgende tabeller. Av disse eksempler angår 1-4, 16, 18, 19, 24-26 og In Examples 1 - 38, the preparation of the compounds is described with reference to the following general methods of preparation A to F, the details of the compound prepared in each case and its physical constants being given in the subsequent tables. Of these examples, 1-4, 16, 18, 19, 24-26 and
35-36 fremstilling av utgangsmaterialer. 35-36 production of starting materials.
Metode A Fremstilling av androstan- 17/ 3- karboksylsyrer Method A Production of androstane-17/3-carboxylic acids
En oppløsning av 20-keto-2i^nydroksy-pregriansterbidet A solution of the 20-keto-2n-hydroxy-pregriansterbide
(1 del) i metanol (50 deler vekt/volum) ble behandlet med en oppløsning, av perjodsyre (1,5 deler, vekt/vekt) i vann (10 deler vekt/volum) ved.romtemperatur inntil omsetningen ble bedømt å være fullstendig (tynnsjiktkromatografi).. Mesteparten.av metanolen- (1 part) in methanol (50 parts w/v) was treated with a solution of periodic acid (1.5 parts, w/v) in water (10 parts w/v) at room temperature until the reaction was judged to be complete (thin-layer chromatography).. Most.of the methanol-
ble avdampet, og. etter tilsetning av vann ble det faste 17/3-karboksylsyre-steroid fjernet ved-filtrering og renset ved krystallisasjon. was evaporated, and. after addition of water, the solid 17/3-carboxylic acid steroid was removed by filtration and purified by crystallization.
Metode B Method B
Metylering av androstan- 17/ 3- karboksylsyrér. Methylation of androstane-17/3-carboxylic acid.
Androstan-17/3-karboksylsyren (1 del) ble oppløst i metanol (62-75 deler vekt/volum) og behandlet ved 0°C med en eteroppløsning av diazometan inntil en gul farge holdt seg, og omsetningen ble funnet å være fullstendig ved tynnskiktkromatografi. Etter ødeleggelse av overskudd av diazometan med noen få dråper eddiksyre ble reaksjonsblandingen inndampet til tørrhet i vakuum, og residuet ble renset ved krystallisasjon. The androstane-17/3-carboxylic acid (1 part) was dissolved in methanol (62-75 parts w/v) and treated at 0°C with an ether solution of diazomethane until a yellow color remained, and the reaction was found to be complete at thin layer chromatography. After destroying excess diazomethane with a few drops of acetic acid, the reaction mixture was evaporated to dryness in vacuo and the residue was purified by crystallization.
Metode C Method C
Etylering og propylering av androstan- 17/ 3- karboksylsyrer. Ethylation and propylation of androstane-17/3-carboxylic acids.
Androstan-17/3-karboksylsyren (1 del) i aceton (100 deler vekt/volum) ble behandlet med trietylamin (1,2-5,0 ekvivalenter basert på steroidet) og deretter etyl- eller propyljodid The androstane-17/3-carboxylic acid (1 part) in acetone (100 parts w/v) was treated with triethylamine (1.2-5.0 equivalents based on the steroid) and then ethyl or propyl iodide
(5 ekvivalenter basert på steroidet). Blandingen ble tilbakeløps-behandlet inntil tynnskiktkromatografi viste at omsetningen var fullstendig. Mesteparten av oppløsningsmidlet ble fjernet i vakuum, og residuet ble fortynnet med vann for å gi produktet som ble fjernet ved filtrering og renset ved krystallisasjon. (5 equivalents based on the steroid). The mixture was refluxed until thin-layer chromatography showed that the reaction was complete. Most of the solvent was removed in vacuo and the residue was diluted with water to give the product which was removed by filtration and purified by crystallization.
Metode D Method D
Fremstilling av C- 17- estere ved acylering av 17a- hydroksy- androstan-17/ 3- karboksylater. Production of C-17-esters by acylation of 17a-hydroxyandrostane-17/3-carboxylates.
17a-hydroksy-17/3-karboksylatet (1 del) ble blandet med den passende alifatiske karboksylsyre (10 deler vekt/volum), trifluoreddiksyreanhydrid (1-2,4 deler vekt/volum) og toluen-p-sulfonsyre (0,005-0,03 del vekt/vekt tilsatt som en vannfri oppløsning i klorform), og blandingen ble oppvarmet i et oljebad ved 80°C inntil omsetningen ble bedømt å være fullstendig ved tynnskiktkromatografi. Den avkjølte reaksjonsblanding ble hellet i overskudd av fortynnet The 17α-hydroxy-17/3-carboxylate (1 part) was mixed with the appropriate aliphatic carboxylic acid (10 parts w/v), trifluoroacetic anhydride (1-2.4 parts w/v) and toluene-p-sulfonic acid (0.005-0 .03 part w/w added as an anhydrous solution in chlorine form), and the mixture was heated in an oil bath at 80°C until the reaction was judged to be complete by thin layer chromatography. The cooled reaction mixture was poured into an excess of dilute
natriumbikarbonatoppløsning og omrørt inntil alt overskudd av anhydrid var spaltet. Det utfelte produkt ble fjernet ved filtrering og renset ved krystallisasjon. sodium bicarbonate solution and stirred until all excess anhydride was decomposed. The precipitated product was removed by filtration and purified by crystallization.
Metode E Method E
17a-hydroksy-17/3-karboksylatet (1 del) i den passende alifatiske karboksylsyre ( ca. -20 deler vekt/volum) ble behandlet med trifluoreddiksyreanhydrid (5 deler vekt/volum) og toluen-p-sulfonsyre (ca. 6 mg som vannfri oppløsning i kloroform), og blandingen ble holdt ved romtemperatur inntil omsetningen ble bedømt å være fullstendig (tynnskiktkromatografi). Blandingen ble hellet i fortynnet natriumbikarbonatoppløsning, og det utfelte produkt ble fjernet ved filtrering, tørret og omkrystallisert. The 17α-hydroxy-17/3-carboxylate (1 part) in the appropriate aliphatic carboxylic acid (about 20 parts w/v) was treated with trifluoroacetic anhydride (5 parts w/v) and toluene-p-sulfonic acid (about 6 mg as anhydrous solution in chloroform), and the mixture was kept at room temperature until the reaction was judged to be complete (thin layer chromatography). The mixture was poured into dilute sodium bicarbonate solution and the precipitated product was removed by filtration, dried and recrystallized.
Metode F Method F
Oksydasjon av 11/ 3- hydroksysteroider til 11- ketoner. Oxidation of 11/ 3- hydroxysteroids to 11- ketones.
11/3-hydroksysteroidet (1 del) ble oppløst i aceton The 11/3-hydroxysteroid (1 part) was dissolved in acetone
(25-150 deler vekt/volum), avkjølt i et isbad, og en oppløsning av kromtrioksyd (fremstilt ved tilsetning av konsentrert svovelsyre (53,3 ml) til kromtrioksyd (66,7 g) i vann og fortynning opp til 250 ml ved tilsetning av vann) (1,6-2,08 ekvivalenter) ble tilsatt. Da omsetningen ved tynnskiktkromatografi ble bedømt å være fullstendig, ble blandingen fortynnet med eter eller eter og etylacetat og vasket omhyggelig med vann. Avdampning av oppløsningsmidlet ga det urensede 11-keton som ble renset ved krystallisasjon. (25-150 parts w/v), cooled in an ice bath, and a solution of chromium trioxide (prepared by adding concentrated sulfuric acid (53.3 ml) to chromium trioxide (66.7 g) in water and diluting up to 250 ml at addition of water) (1.6-2.08 equivalents) was added. When the reaction was judged to be complete by thin layer chromatography, the mixture was diluted with ether or ether and ethyl acetate and washed thoroughly with water. Evaporation of the solvent gave the crude 11-ketone which was purified by crystallization.
Eksempel 39 (fremstilling av utgangsmateriale) Example 39 (production of starting material)
Metyl- 9a- fluor^ llff, 17a- dihydroksy- 16/ 3- metyl- 3- okso- androsta- l, 4-dien- 17/ 3- karboksylat Methyl- 9a- fluoro^ llff, 17a- dihydroxy- 16/ 3- methyl- 3- oxo-androstal- l, 4-diene- 17/ 3- carboxylate
Metyljodid (12 ml) ble satt til en oppløsning av 9a-fluor-11/3,17a-dihydroksy-16/3-metyl-3-okso-androsta-l, 4-dien-17j3-karboksylsyre (10,045 g) i aceton (500 ml) inneholdende trietylamin (4,6 ml), og blandingen ble tilbakeløpsbehandlet, idet mer metyljodid (6 ml) ble tilsatt etter 4 timer. Etter 5,25 timer ble mesteparten av oppløsningsmidlet avdampet i vakuum, og residuet ble fortynnet med natriumbikarbonatoppløsning. Det utfelte, faste materiale ble fjernet ved filtrering og ble etter tørring filtrert gjennom en kort plugg av grad III nøytralt aluminiumoksyd i etylacetat inneholdende litt metanol. Inndampning av eluatet ga metyl-9a-f luor-11/3,17a-dihydroksy-16/3-metyl-3-okso-androsta-l, 4-dien-17/3-karboksylat med infrarøde og kj ernemagnetiske spektra svarende til hva man fikk for metylesteren fremstilt med diazometan. Methyl iodide (12 ml) was added to a solution of 9a-fluoro-11/3,17a-dihydroxy-16/3-methyl-3-oxo-androsta-1,4-diene-17j3-carboxylic acid (10.045 g) in acetone (500 mL) containing triethylamine (4.6 mL), and the mixture was refluxed, with more methyl iodide (6 mL) being added after 4 h. After 5.25 hours, most of the solvent was evaporated in vacuo and the residue was diluted with sodium bicarbonate solution. The precipitated solid material was removed by filtration and, after drying, was filtered through a short plug of grade III neutral alumina in ethyl acetate containing a little methanol. Evaporation of the eluate gave methyl 9a-fluoro-11/3,17a-dihydroxy-16/3-methyl-3-oxo-androstal-1,4-diene-17/3-carboxylate with infrared and nuclear magnetic spectra corresponding to what was obtained for the methyl ester prepared with diazomethane.
Eksempel 40 (fremstilling av utgangsmateriale) Example 40 (production of starting material)
17a- acetoksy- 9o!- fluor- ll/ 3- hydroksy- 16j3- metyl- 3- oksoandrosta- l, 4-dien- 17/ 3- karboksyl- eddiksyre. 17a- acetoxy- 9o!- fluoro- 11/ 3- hydroxy- 16j3- methyl- 3- oxoandrostal- 1, 4-diene- 17/ 3- carboxylic- acetic acid.
9a-fluor-ll/3,17a-dihydroksy-16/3-metyl-3-oksoandrosta-l, 4-dien-17/3-karboksylsyre (1 g) ble suspendert i eddiksyreanhydrid 9α-Fluoro-11/3,17α-dihydroxy-16/3-methyl-3-oxoandrosta-1,4-diene-17/3-carboxylic acid (1 g) was suspended in acetic anhydride
(15 ml) og oppvarmet på dampbad i 45 minutter og deretter ved 115°C (15 ml) and heated on a steam bath for 45 minutes and then at 115°C
i 1 time, i løpet av hvilken tid alt steroidet var oppløst. Blandingen ble avkjølt, og de utfelte materialer ble fjernet ved filtrering og omkrystallisert fra aceton-heksan for å gi 17a-acetoksy-9a-f luor-ll/3-hydroksy-16/3-metyl-3-oksoandrosta-l, 4-dien-17/3-karboksyl-eddiksyre-anhydrid, sm.p. 218-220°C, [ a] Q +42,4° for 1 hour, during which time all the steroid had dissolved. The mixture was cooled, and the precipitates were removed by filtration and recrystallized from acetone-hexane to give 17α-acetoxy-9α-fluoro-11/3-hydroxy-16/3-methyl-3-oxoandrosta-1,4- diene-17/3-carboxylic acid anhydride, m.p. 218-220°C, [ a ] Q +42.4°
(c 0,8, dioksan), Xmaks 238 nm (£ 15.900) (c 0.8, dioxane), Xmax 238 nm (£15,900)
(Funnet: C 64,65, H 6,5. C25H31F07 krever C 64,9, H 6,7%). (Found: C 64.65, H 6.5. C 25 H 31 F 07 requires C 64.9, H 6.7%).
Eksempel 41 (fremstilling av utgangsmateriale) Example 41 (production of starting material)
17a- acetoksy- 9a- fluor- ll/ 3- hydroksy- 16/ 3- metyl- 3- oksoandrosta- l, 4-dien- 17/ 3- karboksylsyre (1) 17a-acetoksy-9a-fluor-ll/3-hydroksy-16/3-metyl-3-oksoandrosta-1, 4-dien-17/3-karboksyl-eddiksyre-anhydrid (5 30 mg) ble oppløst i eddiksyre (100 ml), og vann (50 ml) ble tilsatt, og blandingen ble holdt ved romtemperatur inntil omsetningen var fullstendig (45 minutter). Inndampning i vakuum ga produktet, 17a- acetoxy- 9a- fluoro- ll/ 3- hydroxy- 16/ 3- methyl- 3- oxoandrostal- 1, 4-diene- 17/ 3- carboxylic acid (1) 17a-acetoxy-9a- fluoro- ll/3- Hydroxy-16/3-methyl-3-oxoandrosta-1,4-diene-17/3-carboxylic acetic anhydride (5 30 mg) was dissolved in acetic acid (100 ml), and water (50 ml) was added, and the mixture was kept at room temperature until the reaction was complete (45 minutes). Evaporation in vacuo gave the product,
som etter krystallisasjon fra aceton-petroleter ga 17a-acetoksy-9a!-f luor-ll/3-hydroksy-16/3-metyl-3-oksoandrosta-l, 4-dien-17/3-karboksylsyre, sm.p. 212-214°C, la] +22,2° (c 0,8, dioksan), *maks#239 nm which after crystallization from acetone-petroleum ether gave 17α-acetoxy-9α!-fluoro-11/3-hydroxy-16/3-methyl-3-oxoandrosta-1,4-diene-17/3-carboxylic acid, m.p. 212-214°C, la] +22.2° (c 0.8, dioxane), *max#239 nm
(£ 14.700) (Funnet: C 64,1, H 7,1. C23H29F°6 krever C 64,3, (£ 14,700) (Found: C 64.1, H 7.1. C23H29F°6 requires C 64.3,
H 7,05%). (2) 17a-acetoksy-9a-f luor-lli3-hydroksy-16/3-metyl-3-oksoandrosta-1, 4-dien-17/3-karboksyl-eddiksyre-anhydrid (57 mg) ble oppløst i 50% vannfri pyridin (8 ml) og holdt ved romtemperatur i 45 minutter. Avdampning av oppløsningsmidlet ga et fast stoff hvis infrarøde og kjernemagnetiske spektra var lik de man fikk for materialet fremstilt i (1) ovenfor. H 7.05%). (2) 17α-acetoxy-9α-fluoro-lli3-hydroxy-16/3-methyl-3-oxoandrosta-1,4-diene-17/3-carboxylic acetic anhydride (57 mg) was dissolved in 50% anhydrous pyridine (8 ml) and kept at room temperature for 45 minutes. Evaporation of the solvent gave a solid whose infrared and nuclear magnetic spectra were similar to those obtained for the material prepared in (1) above.
Eksempel 42 (fremstilling av utgangsmateriale) Example 42 (production of starting material)
9a- fluor- llj3- hydroksy- 16/ 3- metyl- 3- okso- 17a- propionyloksy- androsta-1, 4- dien- 17j3- karboksyl- propionsyre- anhydrid. 9a- fluoro- llj3- hydroxy- 16/ 3- methyl- 3- oxo- 17a- propionyloxy-androsta-1, 4- diene- 17j3- carboxylic- propionic anhydride.
9a-f luor-11/3,17a-dihydroksy-16/3-metyl-3-oksoandrosta-l, 4-dien-17/3-karboksylsyre (1 g) ble suspendert i propionsyreanhydrid (15 ml) og oppvarmet i et oljebad ved 115° i 15 minutter, i løpet av hvilken tid steroidet ble oppløst. Reaksjonsblandingen ble fortynnet med petroleter (100 ml) for å gi et hvitt, krystallinsk, fast stoff som ble fjernet ved filtrering og tørret. Omkrystallisasjon fra aceton-heksan ga 9a-fluor-ll/3-hydroksy-16/3-metyl-3-okso-17a-propionyloksy-androsta-l, 4-dien-17i3-karboksyl-propionsyreanhydrid, sm.p. 180-182°, [ a]^ + 50,5° (c 0,7, dioksan) Xmaks 238 nm (t 15.700) (Funnet: C 66,4, H <7,1>. C27H35FO? krever C 66,1, H 7,2%), 9α-fluoro-11/3,17α-dihydroxy-16/3-methyl-3-oxoandrosta-1,4-diene-17/3-carboxylic acid (1 g) was suspended in propionic anhydride (15 mL) and heated in a oil bath at 115° for 15 minutes, during which time the steroid dissolved. The reaction mixture was diluted with petroleum ether (100 mL) to give a white crystalline solid which was removed by filtration and dried. Recrystallization from acetone-hexane gave 9a-fluoro-11/3-hydroxy-16/3-methyl-3-oxo-17a-propionyloxy-androsta-1,4-diene-17i3-carboxylic-propionic anhydride, m.p. 180-182°, [ a]^ + 50.5° (c 0.7, dioxane) Xmax 238 nm (t 15,700) (Found: C 66.4, H <7.1>. C27H35FO? requires C 66, 1, H 7.2%),
Eksempel 43 (fremstilling av utgangsmateriale) Example 43 (production of starting material)
9a- fluor- ll/ 3- hydroksy- 16ff- metyl- 3- okso- 17a- propionyloksy- androsta-1, 4- dien- 17/ 3- karboksylsyre 9a- fluoro- ll/ 3- hydroxy- 16ff- methyl- 3- oxo- 17a- propionyloxy- androsta-1, 4- diene- 17/ 3- carboxylic acid
(1) 9a-fluor-lli3-hydroksy-16j3-metyl-3-okso-17a-propionyloksyandrosta-1,4-dien-17/3-karboksyl-propionsyre-anhydrid (1) 9a-fluoro-lli3-hydroxy-16j3-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17/3-carboxylic-propionic anhydride
(342 mg) ble oppløst i eddiksyre (25 ml) og vann (15 ml) ble tilsatt, og blandingen ble holdt ved romtemperatur inntil omsetningen ble funnet å være fullstendig (tynnskiktkromatografi). Avdampning av mesteparten av oppløsningsmidlet og fortynning med vann ga produktet som ble omkrystallisert fra aceton-heksan for å gi 9a-fluor-ll/3-hydroksy-16/3-metyl-3-okso-17a-propionyloksyandrosta-l, 4-dien-17/3-karboksylsyre, sm.p. 188-190°, Xmaks 239 nm (t 15.600) (342 mg) was dissolved in acetic acid (25 ml) and water (15 ml) was added and the mixture was kept at room temperature until the reaction was found to be complete (thin layer chromatography). Evaporation of most of the solvent and dilution with water gave the product which was recrystallized from acetone-hexane to give 9α-fluoro-11/3-hydroxy-16/3-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene -17/3-carboxylic acid, m.p. 188-190°, Xmax 239 nm (t 15,600)
(Funnet: C 65,1, H 7,5. C^H^FOg.Me^O krever C 65,8, H 7,6%). (Found: C 65.1, H 7.5. C^H^FOg.Me^O requires C 65.8, H 7.6%).
(2) 9a-f luor-ll/3-hydroksy-16/3-metyl-3-okso-17a-propionyloksyandrosta-1, 4-dien-17/3-karboksyl-propionsyre-anhydrid (6, 93 g) (2) 9α-fluoro-11/3-hydroxy-16/3-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17/3-carboxylic-propionic anhydride (6.93 g)
i aceton (150 ml) ble behandlet med dietylamin (5 ml), og blandingen ble holdt ved romtemperatur i ca. 1/2 time. Oppløsningsmidlet ble avdampet i vakuum, og residuet ble oppløst i vann, surgjort og ekstrahert med etylacetat. Det vaskede, organiske lag ble inndampet in acetone (150 ml) was treated with diethylamine (5 ml), and the mixture was kept at room temperature for approx. 1/2 hour. The solvent was evaporated in vacuo and the residue was dissolved in water, acidified and extracted with ethyl acetate. The washed organic layer was evaporated
i vakuum for å gi et fast stoff som ble utgnidd med eter for å gi 9a- fluor-ll/3-hydroksy-16/3-metyl-3-okso-17o!-propionyloksy-androsta-1,4-dien-17/3-karboksylsyre. in vacuo to give a solid which was triturated with ether to give 9α-fluoro-1/3-hydroxy-16/3-methyl-3-oxo-17o!-propionyloxy-androsta-1,4-diene-17 /3-carboxylic acid.
Eksempel 44 Example 44
Metyl- 9g?- f luor- 16- metylen- 3 , ll- diokso- 17af- propionyloksyandrosta- l, 4-dien- 17/ 3- karboksylat Methyl- 9g?- fluoro- 16- methylene- 3 , ll- dioxo- 17af- propionyloxyandrostal- 1, 4-diene- 17/ 3- carboxylate
Metyl-9c^-fluor-ll/3-hydroksy-16-metylen-3-okso-17d!-propionyloksyandrosta-1,4-dien-17/3-karboksylat (204 mg) i aceton Methyl 9c-fluoro-11/3-hydroxy-16-methylene-3-oxo-17d1-propionyloxyandrosta-1,4-diene-17/3-carboxylate (204 mg) in acetone
(4 ml) ble behandlet ved romtemperatur med en oppløsning av kromtrioksyd [0,23 ml; fremstilt ved tilsetning av konsentrert svovelsyre (53,3 ml) til kromtrioksyd (66,7 g) i vann og fortynning til 250 nil med vann] . Etter 30 minutter ble reaksjonsblandingen fortynnet med eter og vasket suksessivt med vann, natriumbikarbonat-oppløsning og vann. Den tørrede eteroppløsning ble inndampet i vakuum, og residuet ble omkrystallisert fra metanol for å gi den i tittelen angitte forbindelse, sm.p. 194-195°, IcdD -37,8° (4 ml) was treated at room temperature with a solution of chromium trioxide [0.23 ml; prepared by adding concentrated sulfuric acid (53.3 ml) to chromium trioxide (66.7 g) in water and diluting to 250 nil with water] . After 30 minutes, the reaction mixture was diluted with ether and washed successively with water, sodium bicarbonate solution and water. The dried ether solution was evaporated in vacuo and the residue recrystallized from methanol to give the title compound, m.p. 194-195°, IcdD -37.8°
(c 1,06, dioksån) , X iUa.v .K S •234,5 nm (£, 15.800), (Funnet: C 67,3, (c 1.06, dioxane) , X iUa.v .K S •234.5 nm (£, 15,800), (Found: C 67.3,
H 6,7. C25H29F06 krever C 67,55, H 6,58%). H 6.7. C25H29F06 requires C 67.55, H 6.58%).
Eksempel 45 Example 45
Metyl- 17a- benzoyloksy- 9a- fluor- ll/ 3- hydroksy- 16/ 3- metyl- 3- okso- andros ta-1, 4- dien- 17/ 3- karboksylat. Methyl- 17a- benzoyloxy- 9a- fluoro- ll/ 3- hydroxy- 16/ 3- methyl- 3- oxo-androsta-1, 4- diene- 17/ 3- carboxylate.
En suspensjon av metyl-9a-f luor-11/3,17a-dihydroksy-16j3-metylandrosta-1,4-dien-17/3-karboksylat (439 mg) i metylenklorid A suspension of methyl 9a-fluoro-11/3,17a-dihydroxy-16j3-methylandrosta-1,4-diene-17/3-carboxylate (439 mg) in methylene chloride
(15 ml) ble behandlet med benzoesyre (573 mg), trifluoreddiksyreanhydrid (0,6 ml) og toluen-p-sulfonsyre (12 mg), og blandingen ble omrørt ved 80°. Etter 48 timer ble blandingen avkjølt og fortynnet med metylenklorid, og oppløsningen ble vasket med natriumbikarbonat og vann. Inndampning av den tørrede, organiske oppløsning ga et residuum som ble renset ved preparativ tynnskiktkromatografi og krystallisasjon fra metanol for å gi det i tittelen angitte benzoat med sm.p. 166-168°, [ a] D +3,3° (c 1,09, dioksan). Xmaks 232 nm (15 ml) was treated with benzoic acid (573 mg), trifluoroacetic anhydride (0.6 ml) and toluene-p-sulfonic acid (12 mg), and the mixture was stirred at 80°. After 48 hours, the mixture was cooled and diluted with methylene chloride, and the solution was washed with sodium bicarbonate and water. Evaporation of the dried organic solution gave a residue which was purified by preparative thin layer chromatography and crystallization from methanol to give the title benzoate of m.p. 166-168°, [α] D +3.3° (c 1.09, dioxane). Xmax 232 nm
(£, 27.800). (Funnet: C 70,0, H 6,6. C29H33F06 krever C 70,14, (£, 27,800). (Found: C 70.0, H 6.6. C29H33F06 requires C 70.14,
H 6,7%) . H 6.7%) .
Eksempel 46 Example 46
Metyl- 9a- fluor- ll/ 3- hydroksy- 16/ 3- metyl- 3- okso- 17a- propionyloksyandrost- 4- en- 17/ 3- karboksylat. Methyl- 9a- fluoro- ll/ 3- hydroxy- 16/ 3- methyl- 3- oxo- 17a- propionyloxyandrost- 4- en- 17/ 3- carboxylate.
En oppløsning av metyl-9a-fluor-llj8-hydroksy-16/3-metyl-3-okso-17a-propionyloksyandrosta-l, 4-di en-17/3-karboksyl at (454 mg) i etanol (45 ml) ble behandlet med 5% palladium-trekull (453 mg) og cykloheksen (0,9 ml), og blandingen ble tilbakeløpsbehandlet i 15 minutter. Filtrering av den avkjølte blanding og avdampning av oppløsningsmidlet i vakuum ga et skum som etter rensning ved preparativ tynnskiktkromatografi og krystallisasjon fra aceton-petroleter ga den i tittelen angitte forbindelse, sm.p. 204-208°. A solution of methyl-9a-fluoro-llj8-hydroxy-16/3-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17/3-carboxyl at (454 mg) in ethanol (45 ml) was treated with 5% palladium-charcoal (453 mg) and cyclohexene (0.9 mL), and the mixture was refluxed for 15 minutes. Filtration of the cooled mixture and evaporation of the solvent in vacuo gave a foam which, after purification by preparative thin layer chromatography and crystallization from acetone-petroleum ether, gave the title compound, m.p. 204-208°.
"Snaks 237,5 nm (£ 15.400) (Funnet: C 66,8, H 7,8. C25H35F06"Snaks 237.5 nm (£15,400) (Found: C 66.8, H 7.8. C25H35F06
krever C 66,65, H 7,8%). t. requires C 66.65, H 7.8%). t.
Eksempel 47 Example 47
Metyl- 9a?- fluor- 16j3- metyl- 3 , ll- diokso- 17 a - propionyloksy- androst- 4- en-17/ 3- karboksylat. Methyl- 9a?- fluoro- 16j3- methyl- 3 , ll- dioxo- 17 a - propionyloxy- androst- 4- en-17/ 3- carboxylate.
En oppløsning av metyl-9o!-fluor-ll/3-hydroksy-16/3-metyl-3-okso-17a-propionyloksyandrost-4-en-17/3-karboksylat (100 mg) i aceton (7 ml) ble behandlet, ved 0°C, med en oppløsning av kromtrioksyd [0,09 ml; fremstilt ved tilsetning av konsentrert svovel- A solution of methyl 90-fluoro-11/3-hydroxy-16/3-methyl-3-oxo-17a-propionyloxyandrost-4-ene-17/3-carboxylate (100 mg) in acetone (7 ml) was treated, at 0°C, with a solution of chromium trioxide [0.09 ml; produced by adding concentrated sulphur-
syre (53,3 ml) til kromtrioksyd (66,7 g) i vann og fortynning opp til 250 ml med vann]. Etter 1,25 timer ble blandingen fortynnet med eter og etylacetat og vasket omhyggelig'' med vann. Avdampning av det organiske oppløsningsmiddel ga deretter et hvitt, fast stoff som ble krystallisert fra aceton-petroleter for å gi den i tittelen angitte forbindelse, sm.p. 218-220°C etter forutgående mykning, . Vaks 234 nm ^£ 16.000) (Funnet: C 66,55, H 7,<4.> C^H^FOg krever acid (53.3 ml) to chromium trioxide (66.7 g) in water and diluting up to 250 ml with water]. After 1.25 hours, the mixture was diluted with ether and ethyl acetate and washed thoroughly with water. Evaporation of the organic solvent then gave a white solid which was crystallized from acetone-petroleum ether to give the title compound, m.p. 218-220°C after prior softening, . Wax 234 nm ^£ 16,000) (Found: C 66.55, H 7.<4.> C^H^FOg requires
C 66,95, H 7,4%). C 66.95, H 7.4%).
Eksempel 48 Example 48
Metyl- 17af- acetoksy- llj3- hydroksy- 3- oksoandrosta- l, 4- dien- 17/ 3- karboksylat Methyl- 17af- acetoxy- llj3- hydroxy- 3- oxoandrostal, 4- diene- 17/ 3- carboxylate
Perjodsyre (14,163 g) i vann (80 ml) ble satt til en opp-løsning av prednisolon (8,286 g) i metanol (800 ml), og den resulterende blanding ble holdt ved romtemperatur. Etter 1 time ble mesteparten av metanolen avdampet i vakuum, residuet ble for- Periodic acid (14.163 g) in water (80 ml) was added to a solution of prednisolone (8.286 g) in methanol (800 ml) and the resulting mixture was kept at room temperature. After 1 hour, most of the methanol was evaporated in vacuo, the residue was
tynnet med vann, og den krystallinske 11/3,17o;-dihydroksy-3-oksoandrosta-1, 4-dien-17/3-karboksylsyre ble fjernet ved filtrering. Den analytiske prøve som ble krystallisert fra fuktig aceton og petroleter, hadde sm.p. 264-266° (Funnet: C 69,2, H 7,4. <C>20<H>26°5 krever C 69,3, H 7,5%) . diluted with water, and the crystalline 11/3,17o;-dihydroxy-3-oxoandrosta-1,4-diene-17/3-carboxylic acid was removed by filtration. The analytical sample, which was crystallized from moist acetone and petroleum ether, had m.p. 264-266° (Found: C 69.2, H 7.4. <C>20<H>26°5 requires C 69.3, H 7.5%) .
Den ovenstående karboksylsyre (3,6 g) i metanol (200 ml) ble behandlet ved 0°C med en eteroppløsning av diazometan inntil blandingen var gul. Avdampning av mesteparten av det organiske oppløsningsmiddel i vakuum og fortynning av residuet med vann ga krystallinsk metyl-11/3,17a-dihydroksy-3-oksoandrosta-l, 4-dien-17/3-karboksylat, sm.p. 203-206°c. En prøve krystallisert fra aceton- The above carboxylic acid (3.6 g) in methanol (200 ml) was treated at 0°C with an ether solution of diazomethane until the mixture was yellow. Evaporation of most of the organic solvent in vacuo and dilution of the residue with water gave crystalline methyl 11/3,17α-dihydroxy-3-oxoandrosta-1,4-diene-17/3-carboxylate, m.p. 203-206°c. A sample crystallized from acetone-
heksan hadde sm.p. 202-205°, [a]D + 59,6° (c 0,8, dioksan), hexane had m.p. 202-205°, [α]D + 59.6° (c 0.8, dioxane),
^maks. 242, 5 nm (£ 15.100) (Funnet: C 70,0, H 7,9. C21H2<g0>5 krever C 69,98, H 7,83%). ^max. 242.5 nm (£15,100) (Found: C 70.0, H 7.9. C21H2<g0>5 requires C 69.98, H 7.83%).
Den ovenstående metylester (464 mg) i eddiksyre (5 ml) ble behandlet med trifluoreddiksyreanhydrid (1 ml), og blandingen ble omrørt ved romtemperatur. Etter 1 time ble toluen-p-sulfonsyre (7 mg) tilsatt, og blandingen ble holdt ved romtemperatur i ytterligere 2,5 timer. Fortynning av oppløsningen med natrium-bikarbonatoppløsning ga et bunnfall som ble fjernet ved filtrering og renset ved preparativ tynnskiktkromatografi og krystallisasjon for å gi den i tittelen angitte forbindelse med sm.p. 284-286°C, la] D + 8,9° (C 0,7, dioksan), "Xmaks 243 nm (£15.000). The above methyl ester (464 mg) in acetic acid (5 mL) was treated with trifluoroacetic anhydride (1 mL), and the mixture was stirred at room temperature. After 1 hour, toluene-p-sulfonic acid (7 mg) was added and the mixture was kept at room temperature for another 2.5 hours. Dilution of the solution with sodium bicarbonate solution gave a precipitate which was removed by filtration and purified by preparative thin layer chromatography and crystallization to give the title compound of m.p. 284-286°C, la] D + 8.9° (C 0.7, dioxane), "Xmax 243 nm (£15,000).
(Funnet: C 68,6, H 7,6. c23H3o°6 krever C 68,65, H 7,5%). (Found: C 68.6, H 7.6. c23H3o°6 requires C 68.65, H 7.5%).
Eksempel 49 Example 49
Metyl- 9a- fluor- llff , 17Q?- dihydroksy- 16/ 3- metyl- 3- oksoandrosta- l, 4-dien- 17/ 3- karboksylat Methyl- 9a- fluoro- llff, 17Q?- dihydroxy- 16/ 3- methyl- 3- oxoandrostal- l, 4-diene- 17/ 3- carboxylate
En oppløsning av natrium-9a-f luor-11/3 ,17a-dihydroksy-16i3-metyl-3-oksoandrosta-l, 4-dien-17j3-karboksylat [fremstilt ved titrering av en oppløsning av 9a-fluor-ll/3,17a-dihydroksy-16/3-metyl-3-oksoandrosta-l, 4-dien-17/3-karboksylsyre (103 mg) i metanol (20 ml) med vandig-metanolisk N natriumhydroksydoppløsning til pH 8,3] ble behandlet med metyljodid (0,085 ml), og blandingen ble tilbakeløpsbehandlet. Etter 16 timer ble oppløsningsmidlet A solution of sodium 9a-fluoro-11/3,17a-dihydroxy-16i3-methyl-3-oxoandrosta-1,4-diene-17j3-carboxylate [prepared by titrating a solution of 9a-fluoro-11/3 ,17α-dihydroxy-16/3-methyl-3-oxoandrostal-1,4-diene-17/3-carboxylic acid (103 mg) in methanol (20 mL) with aqueous-methanolic N sodium hydroxide solution to pH 8.3] was treated with methyl iodide (0.085 mL), and the mixture was refluxed. After 16 hours, the solvent was
avdampet i vakuum, residuet ble utgnidd med vann, og det uoppløselige materiale ble fjernet ved filtrering. evaporated in vacuo, the residue triturated with water, and the insoluble material removed by filtration.
Det kjernemagnetiske resonansspektrum for dette materiale i (CD-J-SO viste metylsignaler ved f 6,36, 8,47, 8,84 og 8,92 som følge av den i tittelen angitte forbindelse. The nuclear magnetic resonance spectrum for this material in (CD-J-SO) showed methyl signals at f 6.36, 8.47, 8.84 and 8.92 due to the title compound.
Eksempel 50 (fremstilling av utgangsmateriale) Example 50 (production of starting material)
2 ' - hydroksyetyl- 9o?- f luor- liP- hvdroksv- 16B- metyl- 3- okso- 17a- propionvl-oksy andros ta- 1, 4- dien- 17B- karboksylat 2' - hydroxyethyl- 9o?- fluoro- liP- hvdroxv- 16B- methyl- 3- oxo- 17a- propionvl-oxyandrosta- 1, 4- diene- 17B- carboxylate
En oppløsning av 9a;-fluor-lli3-hydroksy-16/3-metyl-3-okso-17a-propionyloksy-androsta-l, 4-dien-17/?-karboksylsyre (200 mg) i aceton (20 ml) ble behandlet med redestillert trietylamin (0,38 ml) og 2-jodetanol (0,36 ml), og blandingen ble tilbakeløpsbehandlet ! i 20 timer, og omsetningen ble da funnet å være fullstendig (tynnskiktkromatografi). Mesteparten av oppløsningsmidlet ble fjernet i vakuum, og vann (45 ml) ble tilsatt for å gi produktet som ble omkrystallisert, først fra metanol og deretter fra aceton for A solution of 9α;-fluoro-lli3-hydroxy-16β-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carboxylic acid (200 mg) in acetone (20 ml) was treated with redistilled triethylamine (0.38 mL) and 2-iodoethanol (0.36 mL), and the mixture was refluxed ! for 20 hours, and the conversion was then found to be complete (thin-layer chromatography). Most of the solvent was removed in vacuo and water (45 mL) was added to give the product which was recrystallized first from methanol and then from acetone for
å gi den i tittelen angitte forbindelse, sm.p. 171-173°, to give the compound indicated in the title, sm.p. 171-173°,
39,7° (c 0,99, dioksan), X. , 237,5 nm (fc 15.650). 39.7° (c 0.99, dioxane), X. , 237.5 nm (fc 15,650).
XJ IU9.K. S • XJ IU9.K. S •
(Funnet: C 64,95, H 7,2. C»,HocF0_ krever C 65,3, H 7,4%). (Found: C 64.95, H 7.2. C»,HocF0_ requires C 65.3, H 7.4%).
Eksempel 51 (fremstilling av utgangsmateriale) Example 51 (production of starting material)
2 ' - metansulf onyloksyetyl- 9o!- f luor- ll/ 3- hydroksv- 16/ 3- metyl- 3- okso-17o;- propionyloksyandrosta- l, 4- dien- 17/ 3- karboksylat 2' - methanesulfonyloxyethyl- 9o!- fluoro- 11/ 3- hydroxy- 16/ 3- methyl- 3- oxo-17o;- propionyloxyandrostal- 1, 4- diene- 17/ 3- carboxylate
En oppløsning av 2 ' -hydroksyetyl-9o!-f luor-ll/3-hydroksy-16/3-metyl-3-okso-17o!-propionyloksyandrosta-l, 4-dien-17/3-karboksylat (240 mg) i tørr pyridin (1 ml) ble behandlet dråpevis ved -1 til A solution of 2'-hydroxyethyl-9o!-fluoro-11/3-hydroxy-16/3-methyl-3-oxo-17o!-propionyloxyandrosta-1, 4-diene-17/3-carboxylate (240 mg) in dry pyridine (1 ml) was treated dropwise at -1 to
-10°C med redestillert metansulfonylklorid (0,2 ml). Etter 40 -10°C with redistilled methanesulfonyl chloride (0.2 ml). After 40
minutter ble blandingen hellet i 2N svovelsyre (8 ml) og utgnidd for å gi et fast stoff som ble renset ved preparativ tynnskikt-kromatograf i og omkrystallisasjon fra metanol for å gi den i tittelen angitte forbindelse med sm.p. 129-131°, x ^ 238 nm (£ 15.850) (Funnet: C 58,5, H 6,7. C27H3?FOgS krever C 58,3, minutes, the mixture was poured into 2N sulfuric acid (8 ml) and triturated to give a solid which was purified by preparative thin layer chromatography and recrystallization from methanol to give the title compound of m.p. 129-131°, x ^ 238 nm (£ 15,850) (Found: C 58.5, H 6.7. C27H3?FOgS requires C 58.3,
H 6,7%) . H 6.7%) .
Eksempel 52 Example 52
2 ' - kloretyl- 9o!- fluor- llj3- hydroksy- 16) 3- metyl- 3- okso- 17a- propionyloksyandrosta- 1, 4- dien- 17/ 3- karboksylat 2' - chloroethyl- 9o!- fluoro- llj3- hydroxy- 16) 3- methyl- 3- oxo- 17a- propionyloxyandrosta- 1, 4- diene- 17/ 3- carboxylate
En blanding av 2 '-metansulf onyloksyetyl-9o!-f luor-11/3-hydroksy-3-okso-17a-propionyloksyandrosta-l, 4-dien-l7/3-karboksylåt (223 mg) og tørt litiumklorid (170 mg) i aceton (9 ml) ble tilbake-løpsbehandlet i 22 timer. Etter fjernelse av oppløsningsmidlet i vakuum ble residuet utgnidd med vann for å gi et fast stoff som ble renset ved preparativ tynnskiktkromatografi og krystallisasjon fra A mixture of 2'-methanesulfonyloxyethyl-9o!-fluoro-11/3-hydroxy-3-oxo-17a-propionyloxyandrosta-1,4-diene-17/3-carboxylate (223 mg) and dry lithium chloride (170 mg ) in acetone (9 mL) was refluxed for 22 h. After removal of the solvent in vacuo, the residue was triturated with water to give a solid which was purified by preparative thin layer chromatography and crystallization from
eter for å gi den i tittelen angitte kloretylester,. sm.p. 194-196°C, la] + 43,4° (c 0,99, dioksan), Xmaks 237 nm .(£. 15.800). ether to give the title chloroethyl ester,. sm.p. 194-196°C, la] + 43.4° (c 0.99, dioxane), Xmax 237 nm .(£. 15,800).
(Funnet: C 62,9, H 6,9, Cl 7,<0.> C26H34ClF06 krever C 62,8, (Found: C 62.9, H 6.9, Cl 7.<0.> C26H34ClF06 requires C 62.8,
H 6,9, Cl 7,1%) . H 6.9, Cl 7.1%) .
Eksempel 5 3 Example 5 3
2 ' - brometyl- 9a- fluor- ll/ 3- hydroksy- 16/ 3- metyl- 3- okso- 17Q!- propionyloksyandrosta- 1, 4- dien- 17/ 3- karboksylat 2' - bromomethyl- 9a- fluoro- ll/ 3- hydroxy- 16/ 3- methyl- 3- oxo- 17Q!- propionyloxyandrosta- 1, 4- diene- 17/ 3- carboxylate
Behandling av 2 1-metansulfonyloksyetyl-9o!-fluor-11/3-hydroksy-3-okso-17o!-propionyloksyandrosta-l, 4-dien-17/3-karboksylat (222 mg) med tørt litiumbromid (348 mg) i aceton (9 ml) i 2 timer fulgt av bearbeidelse som beskrevet i eksempel 52, med rensning fra eter ga den i tittelen angitte brometylester, sm.p. 182-184,5°C , mykning over 122°C la] + 38,8° (c 1,02, dioksan), Xmaks 237,5 nm (£.16.000). (Funnet: C 57,9, H 6,3, Br 14,6. C26H34BrF06 krever C 57,7, H 6,3, Br 14,8%). Treatment of 2 1-methanesulfonyloxyethyl-9o!-fluoro-11/3-hydroxy-3-oxo-17o!-propionyloxyandrosta-1,4-diene-17/3-carboxylate (222 mg) with dry lithium bromide (348 mg) in acetone (9 ml) for 2 hours followed by work-up as described in Example 52, with purification from ether gave the title bromomethyl ester, m.p. 182-184.5°C , softening above 122°C la] + 38.8° (c 1.02, dioxane), Xmax 237.5 nm (£.16,000). (Found: C 57.9, H 6.3, Br 14.6. C26H34BrF06 requires C 57.7, H 6.3, Br 14.8%).
Eksempel 54 (fremstilling av utgangsmateriale) Example 54 (production of starting material)
9o?- klor- ll73, 17a- dihydroksy- 16/ 3- metyl- 3- oksoandrosta- l, 4- dien- 17/ 3-karboksylsyre 9o?- chloro- ll73, 17a- dihydroxy- 16/ 3- methyl- 3- oxoandrostal- 4- diene- 17/ 3- carboxylic acid
Behandling av 9a-klor-ll/3 ,17a-21-trihydroksy-16/3-metyl-pregna-1,4-dien-3,20-dion ved fremgangsmåten beskrevet i metode A, ga etter omkrystallisasjon fra aceton-etanol-bensin den i tittelen angitte karboksylsyre, sm.p. 247-249°C, [ a] + 93,0° (c 0,7, dioksan), Xmaks 238'5 nm ( t 14.300). (Funnet: C 63,3, H 7,1. Treatment of 9a-chloro-11/3,17a-21-trihydroxy-16/3-methyl-pregna-1,4-diene-3,20-dione by the procedure described in method A gave, after recrystallization from acetone-ethanol- petrol the carboxylic acid stated in the title, m.p. 247-249°C, [ a] + 93.0° (c 0.7, dioxane), Xmax 238'5 nm ( t 14,300). (Found: C 63.3, H 7.1.
C2lH27Cl04 krever c 63., 85, H 6,9%). C2lH27Cl04 requires c 63., 85, H 6.9%).
Eksempel 55 (fremstilling av utgangsmateriale) Example 55 (production of starting material)
9a- klor, -. ll. / 3- h, ydroksy- 16j3- metyl- 3- okso- 17Q!- propionyloksyandrosta--i 1, 4- dien- 17/ 3- karboksylsyre. En blanding av 9a-klor-llB-, 17a-dihydroksy-16B-metyl-3-okso-androsta-l,4-dien-17B~karboksylsyre (1,42 g) og trietylamin (1,66 ml) i tørr metylenklorid (35 ml) ble omrørt 9a- chlorine, -. ll. / 3- h, ydroxy- 16j3- methyl- 3- oxo- 17Q!- propionyloxyandrosta--i 1, 4- diene- 17/ 3- carboxylic acid. A mixture of 9α-chloro-11B-,17α-dihydroxy-16B-methyl-3-oxo-androsta-1,4-diene-17B-carboxylic acid (1.42 g) and triethylamine (1.66 ml) in dry methylene chloride (35 ml) was stirred
ved 0°C og behandlet dråpevis med propionylklorid (1,32 ml). Etter 35 minutter ved 0°C ble oppløsningen fortynnet med metylenklorid, vasket suksessivt med 3% natriumbikarbonatoppløsning, Nsaltsyre og vann, og etter tørring (magnesiumsulfat) ble oppløsningsmidlet fjernet i vakuum for å gi et fargeløst, krystallinsk, fast stoff. at 0°C and treated dropwise with propionyl chloride (1.32 mL). After 35 minutes at 0°C, the solution was diluted with methylene chloride, washed successively with 3% sodium bicarbonate solution, N hydrochloric acid and water, and after drying (magnesium sulfate) the solvent was removed in vacuo to give a colorless crystalline solid.
Dette faste stoff ble oppløst i aceton (40 ml) og behandlet med redestillert dietylamin (1,3 ml); konsentrering i vakuum ga det krystallinske dietylaminsalt som ble oppsamlet, tørret, oppløst This solid was dissolved in acetone (40 mL) and treated with redistilled diethylamine (1.3 mL); concentration in vacuo gave the crystalline diethylamine salt which was collected, dried, dissolved
i vann, og oppløsningen ble surgjort med 2N saltsyre. Produktet ble ekstrahert med etylacetat, og oppløsningsmidlet ble fjernet for å gi krystallinsk 9a-klor-ll/3-hydroksy-16/3-metyl-3-okso-17a!-propionyloksyandrosta-1, 4-dien-17i3-karboksylsyre (1,49 g), sm.p. 187-188°C (spaltn.)., [a]D + 52,0° (c 0,95, dioksan), in water, and the solution was acidified with 2N hydrochloric acid. The product was extracted with ethyl acetate and the solvent removed to give crystalline 9α-chloro-11/3-hydroxy-16/3-methyl-3-oxo-17α1-propionyloxyandrosta-1,4-diene-1713-carboxylic acid (1 .49 g), m.p. 187-188°C (dec.), [α]D + 52.0° (c 0.95, dioxane),
X n 238 nm {eY/o 315) . 'inaks. lem. j Eksempel 56 X n 238 nm (eY/o 315). 'inaks. limb. j Example 56
Metyl- 9a- klor- ll| 3- hydroksy- 16| 6- metyl- 3- okso- 17Q;- propionyloksyandrosta- 1, 4- dien- 17j3- karboksylat Methyl- 9a- chloro- ll| 3- hydroxy- 16| 6- methyl- 3- oxo- 17Q;- propionyloxyandrosta- 1, 4- diene- 17j3- carboxylate
En oppløsning av 9a-klor-ll/3-hydroksy-16/3-metyl-3-okso-17a-propionyloksyandrosta-l, 4-dien-17j3-karboksylsyre (501 mg) i aceton (20 ml) ble avkjølt i is og behandlet med en eteroppløsning av diazometan i henhold til metode B. Etter å ha vært underkastet kromatografi på silikagel ble produktet omkrystallisert fra A solution of 9a-chloro-11/3-hydroxy-16/3-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17j3-carboxylic acid (501 mg) in acetone (20 ml) was cooled in ice and treated with an ether solution of diazomethane according to method B. After being subjected to chromatography on silica gel, the product was recrystallized from
metanol for å gi den i tittelen angitte metylester, sm.p. 214-217°C (spaltn.), [ a] + 60,3° (c 0,97, dioksan), Xmaks 237 nm (£.15.700). methanol to give the title methyl ester, m.p. 214-217°C (dec.), [ a] + 60.3° (c 0.97, dioxane), Xmax 237 nm (£.15,700).
(Funnet: C 64,5, H 7,2, Cl 7,5. C25H33C106 krever C 64,6, (Found: C 64.5, H 7.2, Cl 7.5. C25H33C106 requires C 64.6,
H 7,15, Cl 7,6%) . H 7.15, Cl 7.6%) .
Eksempel 57 (fremstilling av utgangsmateriale) Example 57 (production of starting material)
11/ 3, 17a- dihydroksy- 16/ 3- metyl- 3- oksoandrosta- l, 4- dien- 17/ 3-karboksylsyre 11/ 3, 17a- dihydroxy- 16/ 3- methyl- 3- oxoandrostal, 4- diene- 17/ 3- carboxylic acid
En oppløsning av 11/3,17a, 21-trihydroksy-16/3-metylpregna-1,4-dien-3,20-dion (640 mg) i dioksan (28 ml) ble omrørt og behandlet med en oppløsning av perjodsyre (1,76 g) i vann (14 ml). Etter 40 minutter ble oppløsningen fortynnet med vann (14 ml) og konsentrert i vakuum. Det krystallinske produkt (579 mg) ble omkrystallisert fra aceton for å gi den i tittelen angitte syre, A solution of 11/3,17a,21-trihydroxy-16/3-methylpregna-1,4-diene-3,20-dione (640 mg) in dioxane (28 mL) was stirred and treated with a solution of periodic acid ( 1.76 g) in water (14 ml). After 40 minutes, the solution was diluted with water (14 mL) and concentrated in vacuo. The crystalline product (579 mg) was recrystallized from acetone to give the title acid,
sm.p. 226-229°C (spaltn.), [ a] + 78,0° (c 0,50, dimetylsulfoksyd), Xmaks 242 nm (fc 14.850), (Funnet: C 70,1, H 8,<0.> c2iH28°5 krever sm.p. 226-229°C (dec.), [ a] + 78.0° (c 0.50, dimethylsulfoxide), Xmax 242 nm (fc 14.850), (Found: C 70.1, H 8.<0.> c2iH28°5 requires
C 70,0, H 7,8%) . C 70.0, H 7.8%).
Eksempel 58 (fremstilling av utgangsmateriale) Example 58 (production of starting material)
ll/ 3- hydroksy- 16/ 3- metyl- 3- okso- 17a- propionyloksyandrosta- l, 4- dien-17/ 3- karboksylsyre ll/ 3- hydroxy- 16/ 3- methyl- 3- oxo- 17a- propionyloxyandrostal- l, 4- diene-17/ 3- carboxylic acid
Behandling av 11/3,17a-dihydroksy-16/3-metyl-3-okso-andros.ta-1,4-dien-17/3-karboksylsyre (310 mg) med propionylklorid (0,269 ml) fulgt av solvolyse av det resulterende produkt med dietylamin ved metoden beskrevet i eksempel 55, ga krystallinsk ll/3-hydroksy-16/3-metyl-3-okso-17a-propionylqksyandrosta-l, 4-dien-17/3-karboksylsyre, sm.p. 202-205°C (spaltn.), [ a] + 24,4° (c 0,97, dioksan), Treatment of 11/3,17α-dihydroxy-16/3-methyl-3-oxo-andros.ta-1,4-diene-17/3-carboxylic acid (310 mg) with propionyl chloride (0.269 ml) followed by solvolysis of the resulting product with diethylamine by the method described in Example 55 gave crystalline 11/3-hydroxy-16/3-methyl-3-oxo-17a-propionylqxyandrosta-1,4-diene-17/3-carboxylic acid, m.p. 202-205°C (dec.), [ a] + 24.4° (c 0.97, dioxane),
^maks. 242'5 nm (£ 14-820)- ^max. 242'5 nm (£14-820)-
Eksempel 59 Example 59
Metyl- ll| 3- hvdroksy- 16j3- metyl- 3- okso- 17a- propionyloksyandrosta- l, 4-dien- 17/ 3- karboksylat Methyl- ll| 3- hydroxy- 16j3- methyl- 3- oxo- 17a- propionyloxyandrostal, 4-diene- 17/ 3- carboxylate
En suspensjon av ll/3-hydroksy-16/3-metyl-3-okso-17a-propionyloksyandrosta-1, 4-dien-17/3-karboksylsyre (250 mg) i aceton (10 ml) ble avkjølt til 0°C og behandlet med en eter-oppløsning av diazometan i henhold til metode B. Etter å ha vært underkastet preparativ tynnskiktkromatografi på silikagel ble produktet krystallisert fra metanol for å gi den i tittelen angitte metylester, sm.p. 223-226°C, [a]D+45,4° (c 0,98, dioksan), A suspension of 11/3-hydroxy-16/3-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17/3-carboxylic acid (250 mg) in acetone (10 ml) was cooled to 0°C and treated with an ether solution of diazomethane according to method B. After being subjected to preparative thin layer chromatography on silica gel, the product was crystallized from methanol to give the title methyl ester, m.p. 223-226°C, [α]D+45.4° (c 0.98, dioxane),
Xmaks 242 nm (t 14.820). (Funnet: C 69,4, H 7,<9.><C>25<H>34°6 krever C 69,7, H 8,0%). Xmax 242 nm (t 14,820). (Found: C 69.4, H 7.<9.><C>25<H>34°6 requires C 69.7, H 8.0%).
Eksempel 60 Example 60
t- butyl- 9a- fluor- ll/ 3- hydroksy- 16/ 3- metyl- 3- okso- 17a!- propionyloksyandrosta- 1, 4- dien- 17/ 3- karboksylat t- butyl- 9a- fluoro- ll/ 3- hydroxy- 16/ 3- methyl- 3- oxo- 17a!- propionyloxyandrosta- 1, 4- diene- 17/ 3- carboxylate
En suspensjon av 9a-fluor-ll/3-hydroksy-16/3-metyl-3-okso-17a-propionyloksyandrosta-l, 4-dien-17/3-karboksylsyre (400 mg) i etylacetat (5 ml) ble behandlet med 0-t-butyl-N,N'-dicykloheksyl-isourinstoff (1,14 g) og blandingen ble tilbakeløpsbehandlet i 10 1/4 time. 2N saltsyre ble tilsatt, og blandingen ble omhyggelig omrørt. Fast materiale ble fjernet og vasket omhyggelig med etyl-- acetat og vann. De samlede etylacetatoppløsninger ble vasket med mettet natriumbikarbonatoppløsning og vann, tørret over magnesiumsulfat, og oppløsningsmidlet ble fjernet i vakuum. Det resulterende produkt (398 mg) ble renset ved kromatografi på silikagel og krystallisert først fra aceton-bensin og deretter fra metanol for å gi den i tittelen angitte t-butylester, sm.p. 200-207°C, A suspension of 9α-fluoro-17/3-hydroxy-16/3-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17/3-carboxylic acid (400 mg) in ethyl acetate (5 ml) was treated with 0-t-butyl-N,N'-dicyclohexyl-isourea (1.14 g) and the mixture was refluxed for 10 1/4 hrs. 2N hydrochloric acid was added and the mixture was carefully stirred. Solid material was removed and washed carefully with ethyl acetate and water. The combined ethyl acetate solutions were washed with saturated sodium bicarbonate solution and water, dried over magnesium sulfate, and the solvent was removed in vacuo. The resulting product (398 mg) was purified by chromatography on silica gel and crystallized first from acetone-petrol and then from methanol to give the title t-butyl ester, m.p. 200-207°C,
■ la]- + 35,2° (c 0,95, dioksan), *maks 238-238,5 nm ( £, 14.600), (Funnet: C 68,8, H 8,1. C28H39F06 krever C 68,55, H 8,0%). ■ la]- + 35.2° (c 0.95, dioxane), *max 238-238.5 nm ( £, 14,600), (Found: C 68.8, H 8.1. C28H39F06 requires C 68, 55, H 8.0%).
Eksempel 61 (fremstilling av utgangsmateriale) Example 61 (production of starting material)
11/ 3, 17a?- dihydroksy- 3- okso- androst- 4- en- 17j3- karboksylsyre 11/ 3, 17a?- dihydroxy- 3- oxo- androst- 4- en- 17j3- carboxylic acid
Omsetning av 11/3,17a, 21-trihydrbksypregn-4-en-3 , 20-dion Turnover of 11/3,17a,21-trihydrbxypregn-4-en-3,20-dione
(5,0 g) med perjodsyre i henhold til metode A ga et urenset produkt som ble fordelt mellom etylacetat og mettet natriumbikarbonat. Den vandige fase ble fraskilt og surgjort med for- (5.0 g) with periodic acid according to method A gave an impure product which was partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous phase was separated and acidified with
tynnet svovelsyre, og det resulterende bunnfall ble oppsamlet, dilute sulfuric acid, and the resulting precipitate was collected,
vasket med vann og tørret i vakuum. Omkrystallisasjon fra metanol ga den i tittelen angitte syre, sm.p. 235-239°C (spaltn.) washed with water and dried in vacuum. Recrystallization from methanol gave the title acid, m.p. 235-239°C (dec.)
[al + 123,5° (c 0,57, dioksan), X , 241,5 nm (£15.650). [al + 123.5° (c 0.57, dioxane), X , 241.5 nm (£15,650).
jj rricLKs • jj rricLKs •
(Funnet: C 68,4, H 7,8. c2oH28°5 krever C 68,9, H 8,1%). (Found: C 68.4, H 7.8. c2oH28°5 requires C 68.9, H 8.1%).
Eksempel 62 (fremstilling av utgangsmateriale) Example 62 (production of starting material)
17a- butyryloksy- ll/ 3- hydroksy- 3- oksoandrost- 4- en- 17/ 3- karboksylsyre 17a- butyryloxy- ll/ 3- hydroxy- 3- oxoandrost- 4- en- 17/ 3- carboxylic acid
11/3,17a-dihydroksy-3-oksoandrost-4-en-17/3-karboksylsyre 11/3,17α-dihydroxy-3-oxoandrost-4-ene-17/3-carboxylic acid
(1,5 g) ble behandlet med n-butyrylklorid (3,0 ml), og produktet ble solvolysert med dietylamin ved metoden beskrevet i eksempel 55 (1.5 g) was treated with n-butyryl chloride (3.0 ml), and the product was solvolyzed with diethylamine by the method described in Example 55
for å gi, etter omkrystallisasjon fra metanol, 17a-butyryloksy-ll/?-hydroksy-3-oksoandrost-4-en-17/8-karboksylsyre, sm.p. 222-223°C (spaltn.), la] + 45,1° (c 0,98, dioksa<n>), X-maks 240 nm (£ 16.300). to give, after recrystallization from methanol, 17a-butyryloxy-11/?-hydroxy-3-oxoandrost-4-ene-17/8-carboxylic acid, m.p. 222-223°C (dec.), la] + 45.1° (c 0.98, dioxa<n>), X-max 240 nm (£ 16,300).
(Funnet: C 68,3, H 8,2. C24H34<0>6 krever C 68,9, H 8,2%). (Found: C 68.3, H 8.2. C 24 H 34<0>6 requires C 68.9, H 8.2%).
Eksempel 63 Example 63
Metvl- 17a- butyryloksy- ll/ 3- hydroksy- 3- oksoandrost- 4- en- 17/ 3-karboksyl at Metvl- 17a- butyryloxy- ll/ 3- hydroxy- 3- oxoandrost- 4- en- 17/ 3-carboxyl at
Behandling av 17a-butyryloksy-ll/3-hydroksy-3-okso-androst-4-en-17/3-karboksylsyre (400 mg) i metanol (40 ml) med eterisk diazometan i henhold til metode B ga, etter omkrystallisasjon fra metanol, den i tittelen angitte metylester, sm.p. 162-165°C, Treatment of 17α-butyryloxy-11/3-hydroxy-3-oxo-androst-4-ene-17/3-carboxylic acid (400 mg) in methanol (40 ml) with ethereal diazomethane according to method B gave, after recrystallization from methanol, the methyl ester indicated in the title, m.p. 162-165°C,
la] D + 49,4° (c 0,71, dioksan), Xmaks> 240 nm (L 16.550). la] D + 49.4° (c 0.71, dioxane), Xmax > 240 nm (L 16,550).
(Funnet: C 69,05, H 8,3. C25H3606 krever C 69,4, H 8,4%). (Found: C 69.05, H 8.3. C 25 H 36 O 6 requires C 69.4, H 8.4%).
Eksempel 64 (fremstilling av utgangsmateriale) Example 64 (production of starting material)
ll/ 3- hydroksy- 3- okso- 17Q!- propionyloks yan dros t- 4- en- 17/ 3- karboksylsyre ll/ 3- hydroxy- 3- oxo- 17Q!- propionylox yan dros t- 4- en- 17/ 3- carboxylic acid
Behandling av 11/3,17a-dihydroksy-3-oksoandrost-4-en-17/3-karboksylsyre (3,0 g) med propionylklorid (2,7 ml) og solvolyse av produktet med dietylamin (3,25 ml) ved fremgangsmåten beskrevet i eksempel 55 ga etter omkrystallisas jon fra aceton-bensin 11)3-hydroksy-3-okso-17o!-propionyloksy- andros t-4-en-17/3 -karboksyl syre, sm.p. 225-226°C (spaltn.), [ a] + 46,2° (c 0,98, dioksan), Treatment of 11/3,17α-dihydroxy-3-oxoandrost-4-ene-17/3-carboxylic acid (3.0 g) with propionyl chloride (2.7 mL) and solvolysis of the product with diethylamine (3.25 mL) at the method described in example 55 gave after recrystallization from acetone-gasoline 11)3-hydroxy-3-oxo-17o!-propionyloxy- andros t-4-ene-17/3-carboxylic acid, m.p. 225-226°C (dec.), [ a] + 46.2° (c 0.98, dioxane),
\maks 240,5 nm ( t 15.500). (Funnet: C 67,1, H 7,8. C23H32°6" 1// 2H2° krever C 66,8, H 7,8%)-. \max 240.5 nm (t 15,500). (Found: C 67.1, H 7.8. C23H32°6" 1// 2H2° requires C 66.8, H 7.8%)-.
Eksempel 65 Example 65
Metyl- ll/ 3- hydroksy- 3- okso- 17o!- propionyloksyandrost- 4- en- 17/ 3-karboksylat Methyl- ll/ 3- hydroxy- 3- oxo- 17o!- propionyloxyandrost- 4- en- 17/ 3-carboxylate
Behandling av ll./3-hydroksy-3-okso-17o;-propionyloksyandrost-4-en-17/3-karboksylsyre (2,5 g) i metanol (400 ml) med eterisk diazometan i henhold til metode B ga et urenset produkt; Treatment of 11/3-hydroxy-3-oxo-17o;-propionyloxyandrost-4-ene-17/3-carboxylic acid (2.5 g) in methanol (400 ml) with ethereal diazomethane according to method B gave an impure product;
kromatografi av del på kiselsyre ga etter omkrystallisasjon fra metanol den i tittelen angitte metylester, sm.p. 176-178°C, chromatography of part on silicic acid gave, after recrystallization from methanol, the methyl ester indicated in the title, m.p. 176-178°C,
[ a] + 51,1° (c 0,59, dioksan), Xmaks 240 nm (£15.800). [ a] + 51.1° (c 0.59, dioxane), Xmax 240 nm (£15,800).
(Funnet: C 68,9, H 8,3. <C>24<H>34°6 krever c 68-9, H 8,2%) . (Found: C 68.9, H 8.3. <C>24<H>34°6 requires c 68-9, H 8.2%) .
Eksempel 66 (fremstilling av utgangsmateriale) Example 66 (production of starting material)
17a- acetoksy- ll/ 3- hydroksy- 3- oksoandrost- 4- en- 17/ 3- karboksylsyre 17a- acetoxy- ll/ 3- hydroxy- 3- oxoandrost- 4- en- 17/ 3- carboxylic acid
Omsetning av 11/3,17a-dihydroksy-3-oksoandrost-4-en-17/3-karboksylsyre (3,0 g) med acetylklorid (2,2 ml) og solvolyse av produktet med dietylamin (3,0 ml) ved fremgangsmåten beskrevet i eksempel 55 ga, etter kromatografi på silikagel og omkrystallisasjon fra aceton-bensin, den i tittelen angitte 17/3-karboksylsyre, Reaction of 11/3,17α-dihydroxy-3-oxoandrost-4-ene-17/3-carboxylic acid (3.0 g) with acetyl chloride (2.2 ml) and solvolysis of the product with diethylamine (3.0 ml) at the method described in example 55 gave, after chromatography on silica gel and recrystallization from acetone-gasoline, the 17/3-carboxylic acid stated in the title,
sm.p. 161-167°C, la]^ D + 42,8° (c 0,25, dioksan), X ma. Ks. 241 nm (£ 14.550). (Funnet: C 64,6, H 7,5. C22H30°6 krever c 64'7' H 7 - 9%) • sm.p. 161-167°C, la]^ D + 42.8° (c 0.25, dioxane), X ma. Ks. 241nm (£14,550). (Found: C 64.6, H 7.5. C22H30°6 requires c 64'7' H 7 - 9%) •
Eksempel 67 Example 67
Metyl- 17a- acetoksy- ll/ 3- hvdroksy- 3- oksoandrost- 4- en- 17/ 3- karboksylat Methyl- 17a- acetoxy- ll/ 3- hydroxy- 3- oxoandrost- 4- en- 17/ 3- carboxylate
Omsetning av 17a-acetoksy-ll/3-hydroksy-3-oksoandrost-4-en-17/3-karboksylsyre (2,3 g) i metanol (368 ml) med eterisk diazometan i henhold til metode B ga etter omkrystallisasjon fra metanol den Reaction of 17α-acetoxy-11/3-hydroxy-3-oxoandrost-4-ene-17/3-carboxylic acid (2.3 g) in methanol (368 ml) with ethereal diazomethane according to method B gave after recrystallization from methanol it
i tittelen angitte metylester, sm.p. 250-252°C, t«lD + 54,4° methyl ester indicated in the title, m.p. 250-252°C, t«lD + 54.4°
(c 0,61, dioksan) Xmaks 240 nm (£,15.350). (Funnet: C 67,9, (c 0.61, dioxane) Xmax 240 nm (£,15,350). (Found: C 67.9,
H 8,<0.> C_oH-„0c krever C 68,3, H 8,0%). H 8.<0.> C_oH-„0c requires C 68.3, H 8.0%).
Eksempel 68 . Example 68 .
2 1 - acetoksyetvl- 9o?- f luor- llj3- hydroksy- 16/ 3- metyl- 3- okso- 17o?-propionyloksyandrosta- 1, 4- dien- 17/ 3- karboksylat 2 1 - acetoxyetvl- 9o?- fluoro- llj3- hydroxy- 16/ 3- methyl- 3- oxo- 17o?- propionyloxyandrosta- 1, 4- diene- 17/ 3- carboxylate
En oppløsning av 2 ' -hydroksyetyl-9a-f luor-llj3-hydroksy-16/3-metyl-3-okso-17o!-propionyloksyandrosta-l, 4-dien-17/3-karboksylat (300 mg) i tørr pyridin (6 ml) ble behandlet med eddiksyreanhydrid (0,6 ml). Etter å ha vært holdt ved romtemperatur i 2 3/4 time ble blandingen hellet i godt omrørt N svovelsyre for å gi et farge-løst, fast stoff (311 mg) som ble renset ved preparativ tynnskikt-kromatograf i på silikagel. To omkrystallisasjoner fra aceton ga fargeløse krystaller av den i tittelen angitte etoksyetylester, A solution of 2'-hydroxyethyl-9α-fluoro-113-hydroxy-16/3-methyl-3-oxo-170!-propionyloxyandrosta-1,4-diene-17/3-carboxylate (300 mg) in dry pyridine (6 ml) was treated with acetic anhydride (0.6 ml). After standing at room temperature for 2 3/4 hours, the mixture was poured into well-stirred N sulfuric acid to give a colorless solid (311 mg) which was purified by preparative thin layer chromatography on silica gel. Two recrystallizations from acetone gave colorless crystals of the title ethoxyethyl ester,
sm.p. 156-158°C, [ a] D _ + 31,9° (c 0,98, dioksan), X mak, s. 237 nm ( £ 15.800). (Funnet: C 64,6, H 7,<3.> C^H^FOg krever C 64,6, sm.p. 156-158°C, [ a] D _ + 31.9° (c 0.98, dioxane), X mak, p. 237 nm ( £ 15,800). (Found: C 64.6, H 7.<3.> C^H^FOg requires C 64.6,
H 7, 2%). H 7.2%).
Eksempel 69 Example 69
Metyl- lip- hydroksy- 16p- metyl- 3- okso- 17a- propionyloksy- androst-4- en- 17 3- karboksylat Methyl- lip- hydroxy- 16p- methyl- 3- oxo- 17a- propionyloxy- androst-4- ene- 17 3- carboxylate
5% Pd/C (50mg) i etylacetat (30 ml), vann (6,02 ml) og pyridin (20^ul) ble forhåndsredusert. Metyl-llp-hydroksy-16p-metyl-3-okso-17o-propionyloksyandrosta-l,4-dien-17p-karboksylat (1,1 g) oppløst i etylacetat (130 ml) ble tilsatt, og blandingen ble hydrogenert inntil tynnsjiktkromatografi viste fullstendig fravær av utgangsmateriale (86 ml). Katalysatoren ble frafiltrert 5% Pd/C (50mg) in ethyl acetate (30ml), water (6.02ml) and pyridine (20µl) was pre-reduced. Methyl 11β-hydroxy-16β-methyl-3-oxo-17o-propionyloxyandrosta-1,4-diene-17β-carboxylate (1.1 g) dissolved in ethyl acetate (130 mL) was added and the mixture was hydrogenated until thin layer chromatography showed complete absence of starting material (86 ml). The catalyst was filtered off
gjennom.kiselgur, og oppløsningsmiddelet ble avdampet. Preparativ tykksjiktkromatografi under anvendelse av etylacetat-kloroform 1:7 som oppløsningsmiddel og eluering med etylacetat fulgt av krystallisasjon fra vandig metanol gav den i tittelen angitte forbindelse (150 mg) sm.p. 184-186°C, [<z]D + 72° (C, 0,18 dioksan), through diatomaceous earth, and the solvent was evaporated. Preparative thick layer chromatography using ethyl acetate-chloroform 1:7 as solvent and elution with ethyl acetate followed by crystallization from aqueous methanol afforded the title compound (150 mg) m.p. 184-186°C, [<z]D + 72° (C, 0.18 dioxane),
X (EtoH) 241,5 nm, (e 15.800). X (EtoH) 241.5 nm, (e 15,800).
max max
\ \
Claims (1)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB278771A GB1384372A (en) | 1971-01-20 | 1971-01-20 | Dereivatives of 17alpha-hydroxyandrost-4-ene-17beta-carboxylic acids |
Publications (2)
Publication Number | Publication Date |
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NO137321B true NO137321B (en) | 1977-10-31 |
NO137321C NO137321C (en) | 1978-02-08 |
Family
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Application Number | Title | Priority Date | Filing Date |
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NO111/72A NO137321C (en) | 1971-01-20 | 1972-01-19 | ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 3-OXO-17ALFA-ACYLOXYANDROST-4-EN-17BETA-CARBOXYLIC ACID ESTERS |
Country Status (17)
Country | Link |
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JP (1) | JPS5611720B1 (en) |
AU (1) | AU473868B2 (en) |
BE (1) | BE778285A (en) |
CA (1) | CA1003820A (en) |
CH (1) | CH602786A5 (en) |
DE (1) | DE2202691A1 (en) |
DK (1) | DK132894C (en) |
ES (1) | ES399057A1 (en) |
FR (1) | FR2122539B1 (en) |
GB (1) | GB1384372A (en) |
HK (1) | HK34278A (en) |
IE (1) | IE36000B1 (en) |
IL (1) | IL38589A (en) |
NL (1) | NL172511C (en) |
NO (1) | NO137321C (en) |
SE (1) | SE383522B (en) |
ZA (1) | ZA72401B (en) |
Families Citing this family (35)
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GB1438940A (en) * | 1972-07-19 | 1976-06-09 | Glaxo Lab Ltd | 17beta-haloalkoxycarbonyl-17alpha-oxysteroids |
DE2365102C2 (en) * | 1973-12-21 | 1982-12-02 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | New pregnanic acid derivatives |
DE2444618C2 (en) * | 1974-09-16 | 1984-01-19 | Schering AG, 1000 Berlin und 4709 Bergkamen | New Pregnan-21-Acid-Derivatives |
DE2319479C2 (en) * | 1973-04-14 | 1982-10-28 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | Pregnanic acid derivatives, processes for their production and pharmaceutical preparations containing them |
GB1514476A (en) * | 1974-08-30 | 1978-06-14 | Glaxo Lab Ltd | Alkyl and haloalkyl androst-4-ene and androsta-1,4-diene-17beta-carboxylates |
SE427276B (en) * | 1975-04-03 | 1983-03-21 | Hoffmann La Roche | PROCEDURE FOR PREPARING D-HOMOSTEROIDS |
CH628355A5 (en) * | 1976-02-24 | 1982-02-26 | Ciba Geigy Ag | METHOD FOR PRODUCING NEW ANDROSTADIEN-17BETA-CARBONIC ACIDS AND THEIR ESTERS AND SALTS. |
IT1114534B (en) * | 1978-02-08 | 1986-01-27 | Glaxo Group Ltd | ANTI-INFLAMMATORY STEROID OF THE ANDROSTANE SERIES COMPOSITIONS THAT CONTAIN IT AND PROCEDURE TO PRODUCE IT |
CA1138857A (en) * | 1979-01-24 | 1983-01-04 | Leo Alig | D-homosteroids |
SE449106B (en) * | 1980-07-10 | 1987-04-06 | Otsuka Pharma Co Ltd | STEROID WITH ANTI-INFLAMMATORY EFFECT AND COMPOSITION CONTAINING THIS |
JPS59139315A (en) * | 1983-01-31 | 1984-08-10 | Taisho Pharmaceut Co Ltd | Cream agent |
US4607028A (en) * | 1983-08-18 | 1986-08-19 | Ciba-Geigy Corporation | Novel carboxylic acid esters |
US5981517A (en) * | 1996-05-09 | 1999-11-09 | Soft Drugs, Inc. | Androstene derivatives |
GB0015876D0 (en) | 2000-06-28 | 2000-08-23 | Novartis Ag | Organic compounds |
US6858596B2 (en) | 2000-08-05 | 2005-02-22 | Smithkline Beecham Corporation | Formulation containing anti-inflammatory androstane derivative |
US6858593B2 (en) | 2000-08-05 | 2005-02-22 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
CA2417825C (en) | 2000-08-05 | 2008-07-22 | Glaxo Group Limited | 6.alpha., 9.alpha.-difluoro-17.alpha.-`(2-furanylcarboxyl)oxy!-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-androst-1,4,-diene-17-carbothioic acid s-fluoromethyl ester as an anti-inflammatory agent |
US6759398B2 (en) | 2000-08-05 | 2004-07-06 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative |
GB0019172D0 (en) | 2000-08-05 | 2000-09-27 | Glaxo Group Ltd | Novel compounds |
US6777399B2 (en) | 2000-08-05 | 2004-08-17 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
US6787532B2 (en) | 2000-08-05 | 2004-09-07 | Smithkline Beecham Corporation | Formulation containing anti-inflammatory androstane derivatives |
US6750210B2 (en) | 2000-08-05 | 2004-06-15 | Smithkline Beecham Corporation | Formulation containing novel anti-inflammatory androstane derivative |
US6777400B2 (en) | 2000-08-05 | 2004-08-17 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
UA77656C2 (en) | 2001-04-07 | 2007-01-15 | Glaxo Group Ltd | S-fluoromethyl ester of 6-alpha, 9-alpha-difluoro-17-alpha-[(2-furanylcarbonyl)oxy]-11-beta-hydroxy-16- alpha-methyl-3-oxoandrosta-1,4-dien-17-beta-carbothioacid as anti-inflammatory agent |
US7291608B2 (en) | 2001-04-30 | 2007-11-06 | Glaxo Group Limited | Anti-inflammatory 17.β.-carbothioate ester derivatives of androstane with a cyclic ester group in position 17.α |
GB2389530B (en) | 2002-06-14 | 2007-01-10 | Cipla Ltd | Pharmaceutical compositions |
WO2004112800A1 (en) | 2003-06-19 | 2004-12-29 | Bodor Nicholas S | Enhancement of activity and/or duration of action of selected anti-inflammatory steroids |
JP4893305B2 (en) | 2003-06-19 | 2012-03-07 | ボーダー、ニコラス・エス | Enhancement of the activity and / or duration of action of soft anti-inflammatory steroids for topical or other topical administration |
GB0316290D0 (en) | 2003-07-11 | 2003-08-13 | Glaxo Group Ltd | Novel compounds |
EP1841780B1 (en) | 2005-01-10 | 2011-07-27 | Glaxo Group Limited | Androstane 17-alpha-carbonate derivatives for use in the treatment of allergic and inflammatory conditions |
US7687484B2 (en) | 2006-05-25 | 2010-03-30 | Bodor Nicholas S | Transporter enhanced corticosteroid activity |
US7691811B2 (en) | 2006-05-25 | 2010-04-06 | Bodor Nicholas S | Transporter-enhanced corticosteroid activity and methods and compositions for treating dry eye |
DE102010029875A1 (en) | 2010-06-09 | 2011-12-15 | Bayer Schering Pharma Aktiengesellschaft | Preparing 1,4-pregna-dienoic acid derivatives, comprises oxidizing 20-oxo-steroid derivatives to 20-hydroxysteroid derivatives in the presence of copper(II) salts with hydroxyalkyl, and oxidizing the 20-oxo-steroid derivatives |
DE102010029877A1 (en) | 2010-06-09 | 2011-12-15 | Bayer Schering Pharma Aktiengesellschaft | Preparing 1,4-pregna-dienoic acid derivative from 20-hydroxysteroid derivative by Swern oxidation, comprises adding 20-hydroxysteroid derivative in mixture of e.g. secondary amine and dimethylsulfoxide, and adding chlorosulfonic acid |
US8835410B2 (en) | 2011-05-10 | 2014-09-16 | Bodor Laboratories, Inc. | Treatment of eyelid dermatitis |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US3636010A (en) * | 1968-12-23 | 1972-01-18 | Ciba Geigy Corp | Esters of steroid-17-carboxylic acids |
-
1971
- 1971-01-20 GB GB278771A patent/GB1384372A/en not_active Expired
-
1972
- 1972-01-19 IL IL38589A patent/IL38589A/en unknown
- 1972-01-19 NO NO111/72A patent/NO137321C/en unknown
- 1972-01-20 NL NLAANVRAGE7200818,A patent/NL172511C/en not_active IP Right Cessation
- 1972-01-20 FR FR7201852A patent/FR2122539B1/fr not_active Expired
- 1972-01-20 CA CA132,814A patent/CA1003820A/en not_active Expired
- 1972-01-20 IE IE82/72A patent/IE36000B1/en unknown
- 1972-01-20 CH CH84372A patent/CH602786A5/xx not_active IP Right Cessation
- 1972-01-20 DK DK29672*#A patent/DK132894C/en active
- 1972-01-20 ES ES399057A patent/ES399057A1/en not_active Expired
- 1972-01-20 DE DE19722202691 patent/DE2202691A1/en not_active Ceased
- 1972-01-20 ZA ZA720401A patent/ZA72401B/en unknown
- 1972-01-20 AU AU38110/72A patent/AU473868B2/en not_active Expired
- 1972-01-20 BE BE778285A patent/BE778285A/en not_active IP Right Cessation
- 1972-01-20 JP JP735572A patent/JPS5611720B1/ja active Pending
- 1972-01-20 SE SE7200662A patent/SE383522B/en unknown
-
1978
- 1978-06-29 HK HK342/78A patent/HK34278A/en unknown
Also Published As
Publication number | Publication date |
---|---|
SE383522B (en) | 1976-03-15 |
NO137321C (en) | 1978-02-08 |
IE36000L (en) | 1972-07-20 |
GB1384372A (en) | 1975-02-19 |
NL172511C (en) | 1983-09-16 |
AU3811072A (en) | 1973-07-26 |
BE778285A (en) | 1972-07-20 |
JPS5611720B1 (en) | 1981-03-16 |
DE2202691A1 (en) | 1972-08-03 |
ES399057A1 (en) | 1974-11-01 |
CA1003820A (en) | 1977-01-18 |
CH602786A5 (en) | 1978-08-15 |
IL38589A (en) | 1976-06-30 |
NL7200818A (en) | 1972-07-24 |
NL172511B (en) | 1983-04-18 |
ZA72401B (en) | 1973-09-26 |
DK132894B (en) | 1976-02-23 |
FR2122539B1 (en) | 1975-11-28 |
FR2122539A1 (en) | 1972-09-01 |
HK34278A (en) | 1978-07-07 |
IL38589A0 (en) | 1972-03-28 |
IE36000B1 (en) | 1976-07-21 |
AU473868B2 (en) | 1976-07-08 |
DK132894C (en) | 1976-07-26 |
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