CS202592B2 - Process for preparing derivatives of 9-fluorprednisolone - Google Patents
Process for preparing derivatives of 9-fluorprednisolone Download PDFInfo
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- CS202592B2 CS202592B2 CS791500A CS150079A CS202592B2 CS 202592 B2 CS202592 B2 CS 202592B2 CS 791500 A CS791500 A CS 791500A CS 150079 A CS150079 A CS 150079A CS 202592 B2 CS202592 B2 CS 202592B2
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- CS
- Czechoslovakia
- Prior art keywords
- pregnadien
- dione
- hydroxy
- fluoro
- halide
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- 238000004519 manufacturing process Methods 0.000 title description 4
- -1 trimethylsilyl halide Chemical class 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 7
- 150000002905 orthoesters Chemical class 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 229910052801 chlorine Chemical group 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000000460 chlorine Chemical group 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [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
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 1
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
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- 210000003491 skin Anatomy 0.000 description 6
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- 239000002674 ointment Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010030113 Oedema Diseases 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- DWCSNWXARWMZTG-UHFFFAOYSA-N Trigonegenin A Natural products CC1C(C2(CCC3C4(C)CCC(O)C=C4CCC3C2C2)C)C2OC11CCC(C)CO1 DWCSNWXARWMZTG-UHFFFAOYSA-N 0.000 description 3
- 206010047139 Vasoconstriction Diseases 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- WQLVFSAGQJTQCK-VKROHFNGSA-N diosgenin Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)CC4=CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 WQLVFSAGQJTQCK-VKROHFNGSA-N 0.000 description 3
- WQLVFSAGQJTQCK-UHFFFAOYSA-N diosgenin Natural products CC1C(C2(CCC3C4(C)CCC(O)CC4=CCC3C2C2)C)C2OC11CCC(C)CO1 WQLVFSAGQJTQCK-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
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- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000003470 adrenal cortex hormone Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- RKHQGWMMUURILY-UHRZLXHJSA-N cortivazol Chemical class C([C@H]1[C@@H]2C[C@H]([C@]([C@@]2(C)C[C@H](O)[C@@H]1[C@@]1(C)C2)(O)C(=O)COC(C)=O)C)=C(C)C1=CC1=C2C=NN1C1=CC=CC=C1 RKHQGWMMUURILY-UHRZLXHJSA-N 0.000 description 2
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 2
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 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
- CTIKAHQFRQTTAY-UHFFFAOYSA-N fluoro(trimethyl)silane Chemical compound C[Si](C)(C)F CTIKAHQFRQTTAY-UHFFFAOYSA-N 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ZDYFFPNLCUDFDB-YFWFAHHUSA-N (8s,9s,10r,13s,14s,17s)-17-(2-hydroxyacetyl)-10,13-dimethyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-one Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 ZDYFFPNLCUDFDB-YFWFAHHUSA-N 0.000 description 1
- XYHKNCXZYYTLRG-UHFFFAOYSA-N 1h-imidazole-2-carbaldehyde Chemical compound O=CC1=NC=CN1 XYHKNCXZYYTLRG-UHFFFAOYSA-N 0.000 description 1
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- DNFMJYXRIMLMBZ-UHFFFAOYSA-N Clemizole hydrochloride Chemical compound [Cl-].C1=CC(Cl)=CC=C1CN1C2=CC=CC=C2N=C1C[NH+]1CCCC1 DNFMJYXRIMLMBZ-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012455 Dermatitis exfoliative Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- HHJIUUAMYGBVSD-YTFFSALGSA-N Diflucortolone valerate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)COC(=O)CCCC)[C@@]2(C)C[C@@H]1O HHJIUUAMYGBVSD-YTFFSALGSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 206010061218 Inflammation Diseases 0.000 description 1
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- 241000186359 Mycobacterium Species 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 241000269908 Platichthys flesus Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 208000028004 allergic respiratory disease Diseases 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N beta-methyl-butyric acid Natural products CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
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- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
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- 210000000548 hind-foot Anatomy 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
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- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229960002446 octanoic acid Drugs 0.000 description 1
- BHVICADLOSIXKE-UHFFFAOYSA-N oxaldehydoyl 2-oxoacetate Chemical compound O=CC(=O)OC(=O)C=O BHVICADLOSIXKE-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 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
- 229960005205 prednisolone Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 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
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- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
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- 238000003892 spreading Methods 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
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- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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- Steroid Compounds (AREA)
Description
Vynález se týká způsobu výroby nových derivátů 9-fluorprednisolonu. Dále se zde pojednává o farmaceutických přípravcích, které byto účinné látky obsahují.The present invention relates to a process for the preparation of novel 9-fluorprednisolone derivatives. Further, pharmaceutical preparations containing these active substances are discussed.
9-Fluorprednisolon (9a-fluor-ll/?,17a,21-trihydroxy-l,4-pregnadien-3,20-dion) je znám dlouhou dobu (J. Am. Chem. Soc. 77, 4181, 1955). Tento kortikoid je nevhodný jako účinná látka pro farmaceutické přípravky, které slouží pro lokální ošetřování zánětlivých onemocnění, protože má velmi silné systemické účinky.9-Fluorprednisolone (9α-fluoro-11β, 17α, 21-trihydroxy-1,4-pregnadien-3,20-dione) has been known for a long time (J. Am. Chem. Soc. 77, 4181, 1955). This corticoid is unsuitable as an active ingredient for pharmaceutical preparations which are used for the local treatment of inflammatory diseases because it has very strong systemic effects.
Bylo objeveno, že až dosud neznámé deriváty 9-fluorprednisolonu jsou systemicky pouze slabě účinné, ale při lokálním použití mají překvapivě silný protizánětlivý účinek, který často předčí nejúčinnější kortikoidy komerčně dostupné.It has been discovered that the hitherto unknown 9-fluorprednisolone derivatives are systemically only poorly effective, but have a surprisingly potent anti-inflammatory effect when topically applied, which often outperforms the most potent corticoids commercially available.
Nové deriváty 9-fluorprednisolonu mají obecný vzorec IThe new 9-fluoropredisolone derivatives have the general formula I
kdewhere
Ri představuje alkanoylovou skupinu s 1 až 8 atomy uhlíku nebo benzylovou skupinu aR 1 is C 1 -C 8 alkanoyl or benzyl;
X znamená atom fluoru nebo atom chloru.X represents a fluorine atom or a chlorine atom.
Alkanoylovou skupinu Ri obsahující 1 až 8 atomů uhlíku je třeba rozumět skupinu odvozenou od karboxylových kyselin s otevřeným nebo cyklickým řetězcem, který je přímý nebo rozvětvený, jako například odvozenou od kyseliny máselné, kyseliny isomáselné, kyseliny valerové, kyseliny isovalerové, kyseliny trimethyloctové, kyseliny kapronové, kyseliny terč. butyloctové, kyseliny cyklopentylkarboxylové, kyseliny cyklohexylkarboxylové nebo kyseliny kaprylové, nebo popřípadě od kyseliny mravenčí, kyseliny octové nebo kyseliny propionové.C 1 -C 8 -alkanoyl R 1 is understood to mean a straight or branched chain derivative of carboxylic acids, whether straight or branched, such as, for example, butyric acid, isobutyric acid, valeric acid, isovaleric acid, trimethylacetic acid, caproic acid , tartaric acid. butylacetic acid, cyclopentylcarboxylic acid, cyclohexylcarboxylic acid or caprylic acid, or optionally formic acid, acetic acid or propionic acid.
Zvláště výhodné alkanoylové skupiny Rt jsou takové, které jsou odvozeny od alkankarboxylové kyseliny s až 6 atomy uhlíku.Particularly preferred alkanoyl groups Rt are those derived from an alkanecarboxylic acid having up to 6 carbon atoms.
Deriváty 9-fluorprednisolonu obecného vzorce I s X znamenajícím atom chloru jsou například tyto sloučeniny:9-Fluoropredisolone derivatives of the formula I with X representing chlorine are, for example, the following compounds:
17a-acetoxy-21-chlor-9a-fluor-ll+hydroxy-l,4-pregnadien-3,20-dion,17α-acetoxy-21-chloro-9α-fluoro-11 + hydroxy-1,4-pregnadien-3,20-dione,
21-chlor-9a-fluor-ll,/Ž-hydroxy-17ai-propionyloxy-l,4-pregnadien-3,20-dion,21-chloro-9α-fluoro-11, N-hydroxy-17α-propionyloxy-1,4-pregnadien-3,20-dione,
17a-butyryloxy-21-chlor-9a-fluor-lli(S-hydroxy-l,4-pregnadien-3,20-dion,17α-butyryloxy-21-chloro-9α-fluoro-11 (S-hydroxy-1,4-pregnadien-3,20-dione),
21-chlor-9ai-fluor-llj3-hydroxy-17a-isobutyryloxy-l,4-pregnadien-3,20-dion,21-chloro-9α-fluoro-11β-hydroxy-17α-isobutyryloxy-1,4-pregnadien-3,20-dione,
21-chlor-9a-fluor-ll+hydroxy-17a-valeroxy-l,4-pregnadien-3,20-dion a21-chloro-9α-fluoro-11 + hydroxy-17α-valeroxy-1,4-pregnadien-3,20-dione; and
17ai-benzyloxy-21-chlor-9a-íluor-llj3-hydroxy-l,4-pregnadien-3,20dion.17α-benzyloxy-21-chloro-9α-fluoro-11β-hydroxy-1,4-pregnadien-3,20-dione.
Deriváty 9,21-difluorprednisolonu obecného vzorce I jsou například tyto sloučeniny:9,21-Difluoro-prednisolone derivatives of the formula I are, for example, the following compounds:
17a-acetoxy-9a,21-difluor-ll/3-hydroxy-l,4-pregnadien-3,20-dion,17α-acetoxy-9α, 21-difluoro-11β-hydroxy-1,4-pregnadien-3,20-dione,
9,a,21-difluor-ll(3-hydroxy-17a-propionyloxy-l,4-pregnadien-3,20-dion,9, a, 21-difluoro-11 (3-hydroxy-17α-propionyloxy-1,4-pregnadien-3,20-dione),
17«-butyryloxy-9ia,21-difluor-ll/3-hydroxy-l,4-pregnadien-3,20-dion nebo17'-Butyryloxy-9α, 21-difluoro-11β-hydroxy-1,4-pregnadien-3,20-dione or
9a,21-difluor-ll(ž-hydroxy-17a-isobutyryloxy-l,4-pregnadien-3,20-dion.9α, 21-difluoro-11 (β-hydroxy-17α-isobutyryloxy-1,4-pregnadien-3,20-dione).
Nové deriváty 9-fluorprednisolonu se mohou vyrobit podle o sobě známého způsobu, který spočívá v tom, že se štěpí orthoester obecného vzorce IIThe novel 9-fluorprednisolone derivatives can be prepared according to a method known per se which comprises cleaving the orthoester of the formula II
Rž znamená alkylovou skupinu s 1 až 4 atomy uhlíku aR 2 represents a C 1 -C 4 alkyl group
R3 představuje atom vodíku, alkylovou skupinu nebo cykloalkylovou skupinu s až 7 atomy uhlíku nebo fenylovou skupinu, působením trimethylsilylhalogenidu nebo trifenylmethylhalogenidu.R 3 represents a hydrogen atom, an alkyl or cycloalkyl group of up to 7 carbon atoms, or a phenyl group, by treatment with a trimethylsilyl halide or a triphenylmethyl halide.
Způsob podle vynálezu se provádí za podmínek o sobě známých.The process according to the invention is carried out under conditions known per se.
Štěpení orthoesteru obecného vzorce II se provádí trimethylsilylfluoridem, trimethylsilylchloridem nebo trifenylmethylchloridem s výhodou v inertním rozpouštědle, jako v dipolárním aprotickém rozpouštědle (dimethylformamidu, N-methylpyrrolidonu, dimethylsulfoxidu, hexamethylamidu kyseliny fosforečné a podobně], etheru (diethyletheru, diisopropyletheru, tetrahydrofuranu, dioxanu, glykoldimethy letheru a podobně), chlorovaném uhlovodíku (methylenchloridu, chloroformu, tetrachlorethanu a podobně), uhlovodíku (benzenu, toluenu, cyklohexanu a podobně) nebo směsi těchto rozpouštědel.The cleavage of the orthoester II is carried out with trimethylsilyl fluoride, trimethylsilyl chloride or triphenylmethyl chloride, preferably in an inert solvent such as a dipolar aprotic solvent (dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, hexamethylamphosphoric amide and the like), ether (diethyl ether, dioxoethyl ether, diisopropyl ether, ether and the like), a chlorinated hydrocarbon (methylene chloride, chloroform, carbon tetrachloride and the like), a hydrocarbon (benzene, toluene, cyclohexane and the like) or a mixture of these solvents.
Výchozí sloučeniny pro způsob podle vynálezu se mohou vyrobit jednoduchým způsobem a ve vysokém výtěžku z prednisolonu, který se může sám relativně jednoduše syntetizovat z diosgeninu. Následkem toho je, že se sloučeniny podle vynálezu mohou vyrobit z diosgeninu s relativně nízkými náklady v celkovém výtěžku přibližně 15 %. Naproti tomu je syntéza známých vysoce účinných kortikoidů z diosgeninu podstatně nákladnější a výtěžky nižší (asi 0,5 až 5 °/o). To není bez významu vzhledem k narůstajícím obtížím se získáním vhodných výchozích látek pro syntézy kortikoidů v dostatečném množství a s ohledem na výdaje za účimné látky, které prodražují speciální léčiva obsahující kortikoid.The starting compounds for the process according to the invention can be prepared in a simple manner and in high yield from prednisolone, which itself can be synthesized relatively simply from diosgenin. As a result, the compounds of the invention can be prepared from diosgenin at relatively low cost in an overall yield of about 15%. In contrast, the synthesis of known high-performance corticoids from diosgenin is considerably more expensive and yields lower (about 0.5-5%). This is of no significance in view of the increasing difficulty of obtaining appropriate starting materials for the synthesis of corticoids in sufficient quantities and in view of the cost of the active substances which increase the cost of special corticoid-containing drugs.
Jak již bylo uvedeno, sloučeniny podle vynálezu mají při lokální aplikaci silný protizánětlivý účinek, ale při systemické aplikaci jsou jen slabě účinné.As already mentioned, the compounds of the invention have a strong anti-inflammatory effect when topically applied, but are only weakly effective when administered systemically.
Protizánětlivý účinek se stanoví takto:The anti-inflammatory effect is determined as follows:
Na lidské kůži se vyvolá překrvení tak, že se na zádech dobrovolných pokusných osob mužského a ženského pohlaví rozloží dvacetkrát přes sebe položenými útržky s 2 cm širokým tesafilmem Stratům corneum.Blood on the human skin is induced by spreading on the backs of volunteer male and female test subjects twenty times overlapped pieces of 2 cm wide tesafilm Stratum corneum.
Na označená políčka o velikosti 4 cm2 uvnitř odřené plochy se nanese přibližně 50 mg přípravku ve formě masti.Approximately 50 mg of the ointment preparation is applied to the marked 4 cm 2 patches inside the scuffed area.
Aby se získala srovnatelná výchozí hodnota, použilo se relativních čísel, protože barva neošetřené kůže, stejně jako zčervenání překrvené plochy je u každé osoby odlišné.To obtain a comparable baseline, relative numbers were used because the color of the untreated skin as well as the redness of the bloodied area is different for each person.
Hodnota barvy neošetřené kůže se udává jako 100 a hodnota barvy odřené kůže jako 0.The color value of the untreated skin is given as 100 and the color value of the scuffed skin is 0.
Hodnota barvy kůže, která se zjistila na kůži při vasokonstrikci (100), je poměrným údajem.The skin color value found on the skin during vasoconstriction (100) is a relative value.
Vasokonstrikce malého, středního a vysokého stupně se ohodnotí hodnotou odpovídající 0 až 100.Vasoconstriction of small, medium and high grade is evaluated with a value of 0 to 100.
V následující tabulce jsou uvedeny průměrné hodnoty, které byly zjištěny při zkouškách různých porovnatelných osob a z různých oblastí zad.The following table shows the average values obtained from tests of different comparable persons and from different back areas.
Systemický účinek sloučenin se stanoví pomocí adjuvantového edémového testu takto:The systemic effect of the compounds is determined by the adjuvant edema test as follows:
Krysám SPF o hmotnosti 130 až 150 g se pro dosažení ohniska zánětu injekčně do pravé zadní tlapky vpraví 0,1 ml 0,5% suspenze Mycobacterium butyricum (lze získat od firmy Difco, USA). Před injekcí se změří objem tlapek krys a 24 hodiny po injekci se opět změří objem tlapek, pro stanovení rozsahu „edému. Konečně se krysám orálně aplikuje rozdílné množství testovaných látek. Po dalších 24 hodinách se znovu změří objem tlapky.SPF rats weighing 130-150 g are injected into the right hind paw by injection of 0.1 ml of a 0.5% suspension of Mycobacterium butyricum (available from Difco, USA) to achieve an outbreak of inflammation. Prior to injection, the paw volume of the rats is measured and the paw volume is again measured 24 hours after injection to determine the extent of edema. Finally, different rats were orally administered with different amounts of test substances. After a further 24 hours, the paw volume is measured again.
Ze získaných údajů o objemech tlapek se obvyklým způsobem stanoví množství testované látky, které je potřebné, aby se dosáhlo 50% .zapojení edérnu tlapky.From the paw volume data obtained, the amount of test substance needed to achieve 50% engagement of the edible paw is determined in a conventional manner.
Výsledky získané při uvedených testech jsou uvedeny v následující tabulce.The results obtained in these tests are shown in the following table.
TabulkaTable
Adjuvantový edémový test EDso (mg/kg)Adjuvant edema test ED 50 (mg / kg)
Číslo LátkaNumber Substance
Test vasokonstrikce Koncentrace Výsledky po (%) 4 h 8 hVasoconstriction Test Concentration Results after (%) 4 h 8 h
K podobným výsledkům se dospěje, když se systemický účinek derivátů 9-fluorprednisolonu podle vynálezu stanoví pomocí známého thymolyzového testu nebo známého testu zadržování sodíku a draslíku.Similar results are obtained when the systemic effect of the 9-fluorprednisolone derivatives according to the invention is determined by a known thymolysis test or a known sodium and potassium retention test.
Nové sloučeniny se hodí v kombinaci s nosiči obvyklými v galenické farmacii pro lokální ošetřování kontaktních dermatid, ekzémů různého druhu, neurodermatóz, erythrodermie, popálenin, Pruritis vulvae et ani, trudoviny růžovité, Erythematodes cutaneus, lupénky, liše je plochého a bradavčitého a podobných onemocnění.The novel compounds are useful in combination with carriers customary in galenical pharmacy for the topical treatment of contact dermatides, eczema of various kinds, neurodermatoses, erythrodermia, burns, Pruritis vulvae et ani, rosacea, Erythematodes cutaneus, psoriasis, fox-like and flounder diseases.
Výroba speciálních léčiv se provádí obvyklým způsobem, kdy se účinná látka převede s vhodnými přísadami na požadovanou aplikační formu, jako například na roztoky, lotiony, masti, krémy nebo náplasti. V takto připravených léčivech je koncentrace účinné látky závislá na aplikační formě. U lotionů a mastí se s výhodou používá 0,001 až 1 % koncentrace účinné látky.The manufacture of special medicaments is carried out in the usual manner by converting the active ingredient with suitable additives into the desired dosage form, such as solutions, lotions, ointments, creams or patches. In the medicaments thus prepared, the concentration of active ingredient is dependent on the dosage form. For lotions and ointments, a concentration of active compound of 0.001 to 1% is preferably used.
Kromě toho jsou nové sloučeniny popřípadě vhodné v kombinaci s běžnými nosiči a pomocnými látkami také pro výrobu inhalačních prostředků, které se mohou používat při léčení alergických onemocnění dýchacích cest, jako například bronchlálního astmatu nebo rýmy.In addition, the novel compounds are optionally suitable in combination with conventional carriers and excipients also for the manufacture of inhalants which can be used in the treatment of allergic airway diseases such as bronchial asthma or rhinitis.
Následující příklady slouží k osvětlení vynálezu.The following examples serve to illustrate the invention.
I. Příklad syntézy g 17a,21-(l-ethoxybenzylidendioxy)-9a-fluor-lljS-hydroxy-l^-pregnadien-S^O-dlonu v 40 ml dimethylformamidu se míchá s 4 ml trimethylsilylfluoridu 2 hodiny při teplotě místnosti. Po vysrážení ve vodě a obvyklém zpracování se odpaří ve vakuu. Surový produkt se čistí na 120 g silikagelu methylenchloridem a acetonem při proměnné koncentraci (0 až 10 % acetonu). Výtěžek činí 240 mg 17a-benzyloxy-9a,21-difluor-ll/3hydroxy-l,4-pregnadien-3,20-dionu.I. Example Synthesis of g 17α, 21- (1-ethoxybenzylidenedioxy) -9α-fluoro-11β-hydroxy-1 H -pregnadien-5-O-dlone in 40 ml of dimethylformamide was stirred with 4 ml of trimethylsilyl fluoride for 2 hours at room temperature. After precipitation in water and usual work-up, it is evaporated under vacuum. The crude product is purified on 120 g of silica gel with methylene chloride and acetone at varying concentrations (0-10% acetone). Yield: 240 mg of 17α-benzyloxy-9α, 21-difluoro-11/3-hydroxy-1,4-pregnadien-3,20-dione.
88
II. Farmaceutické přípravky Příklad AII. Pharmaceutical Preparations Example A
Složení mastiOintment composition
0,03 % 9of-fluor-ll/3-hydroxy-17«,21-dipropionyloxy-l,4-pregnadien-3,20-dionu0.03% 9of-fluoro-11β-hydroxy-17,4,2-dipropionyloxy-1,4-pregnadien-3,20-dione
2.50 % Allercurhexachlorofenátu [mikronizovaný, velikost částic asi 8 μτη (Allercur =' zapsaná ochranná známka pro 1-pchlorbenzyl-2-pyrrolidylmethylbenzimidazolj]2.50% Allercurhexachlorophenate [micronized, particle size about 8 μτη (Allercur = 'registered trade mark for 1-pchlorobenzyl-2-pyrrolidylmethylbenzimidazole)]
6,00 % terc.esteru kyseliny orthofosforečné a tetraglykoletheru alkoholu obsaženého ve vosku (Hostaphatu KW 340(R>)6,00% tert-ester of orthophosphoric acid and tetraglycol ether of alcohol contained in wax (Hostaphatu KW 340 (R> )
0,10 % kyseliny sorbové0,10% sorbic acid
10,00 % neutrálního oleje (Migloyol 812(R))10.00% neutral oil (Migloyol 812 (R) )
3.50 % stearylalkoholu3.50% stearyl alcohol
1.50 % vosku z ovčí vlny, bezvodého (DAB 6j1.50% Wax of anhydrous sheep wool (DAB 6j
76,36 % odsolené vody.76.36% desalinated water.
Příklad BExample B
Výroba inhalačního prostředkuManufacture of inhalation agent
1,000 g mikronizovaného 9a-fluor-ll/J-hydroxy-17a,21-dipropionyloxy-l,4-pregnadien-3,20-dionu (průměrná velikost zrna menší než 7 ,«m) se smísí s 39,000 g umleté laktózy.1,000 g of micronized 9α-fluoro-11 H -hydroxy-17α, 21-dipropionyloxy-1,4-pregnadien-3,20-dione (average grain size less than 7 µm) was mixed with 39,000 g of ground lactose.
K inhalacím se používají dávky s 20 mg inhalačního prostředku.Doses with 20 mg of inhalation agent are used for inhalations.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS791500A CS202592B2 (en) | 1977-03-21 | 1979-03-06 | Process for preparing derivatives of 9-fluorprednisolone |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2712862A DE2712862C2 (en) | 1977-03-21 | 1977-03-21 | Derivatives of 9-fluorprednisolone, process for their preparation and pharmaceuticals containing them |
| DE19782809732 DE2809732C2 (en) | 1978-03-03 | 1978-03-03 | Derivatives of 9-fluorprednisolone, process for their production, and pharmaceutical preparations containing these active ingredients |
| CS781785A CS202591B2 (en) | 1977-03-21 | 1978-03-21 | Process for preparing derivatives of 9-fluorprednisolone |
| CS791500A CS202592B2 (en) | 1977-03-21 | 1979-03-06 | Process for preparing derivatives of 9-fluorprednisolone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS202592B2 true CS202592B2 (en) | 1981-01-30 |
Family
ID=27179348
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS791501A CS202593B2 (en) | 1977-03-21 | 1979-03-06 | Process for preparing derivatives of 9-fluorprednisolone |
| CS791500A CS202592B2 (en) | 1977-03-21 | 1979-03-06 | Process for preparing derivatives of 9-fluorprednisolone |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS791501A CS202593B2 (en) | 1977-03-21 | 1979-03-06 | Process for preparing derivatives of 9-fluorprednisolone |
Country Status (1)
| Country | Link |
|---|---|
| CS (2) | CS202593B2 (en) |
-
1979
- 1979-03-06 CS CS791501A patent/CS202593B2/en unknown
- 1979-03-06 CS CS791500A patent/CS202592B2/en unknown
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| Publication number | Publication date |
|---|---|
| CS202593B2 (en) | 1981-01-30 |
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