CH535223A - (23, 24-bisnor-cholen-22-yl)-guanidines - Google Patents
(23, 24-bisnor-cholen-22-yl)-guanidinesInfo
- Publication number
- CH535223A CH535223A CH792272A CH792272A CH535223A CH 535223 A CH535223 A CH 535223A CH 792272 A CH792272 A CH 792272A CH 792272 A CH792272 A CH 792272A CH 535223 A CH535223 A CH 535223A
- Authority
- CH
- Switzerland
- Prior art keywords
- bisnor
- prepared
- guanidinium
- acid
- acetate
- Prior art date
Links
- 238000000034 method Methods 0.000 claims description 14
- 239000002253 acid Chemical group 0.000 claims description 12
- 150000003431 steroids Chemical class 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical class NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- DXTIKTAIYCJTII-UHFFFAOYSA-N guanidine acetate Chemical compound CC([O-])=O.NC([NH3+])=N DXTIKTAIYCJTII-UHFFFAOYSA-N 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000012458 free base Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000000542 sulfonic acid group Chemical group 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 abstract 1
- 239000004599 antimicrobial Substances 0.000 abstract 1
- 238000010561 standard procedure Methods 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 230000000694 effects Effects 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 230000001717 pathogenic effect Effects 0.000 description 3
- -1 tinctures Substances 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 241000222122 Candida albicans Species 0.000 description 2
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 241001502500 Trichomonadida Species 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 229940095731 candida albicans Drugs 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229960002867 griseofulvin Drugs 0.000 description 2
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 description 2
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 description 2
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 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
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 241001480043 Arthrodermataceae Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 208000003322 Coinfection Diseases 0.000 description 1
- AEMOLEFTQBMNLQ-YMDCURPLSA-N D-galactopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-YMDCURPLSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 208000007163 Dermatomycoses Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 241001480036 Epidermophyton floccosum Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N Gluconic acid Natural products OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 241000893976 Nannizzia gypsea Species 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 208000010195 Onychomycosis Diseases 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 239000005643 Pelargonic acid Substances 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000224527 Trichomonas vaginalis Species 0.000 description 1
- 241000223238 Trichophyton Species 0.000 description 1
- 241001045770 Trichophyton mentagrophytes Species 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- AEMOLEFTQBMNLQ-WAXACMCWSA-N alpha-D-glucuronic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-WAXACMCWSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- SQNGFLZBHUXPNB-UHFFFAOYSA-N benzoic acid;butanedioic acid Chemical compound OC(=O)CCC(O)=O.OC(=O)C1=CC=CC=C1 SQNGFLZBHUXPNB-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000037304 dermatophytes Effects 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229960004198 guanidine Drugs 0.000 description 1
- 229960000789 guanidine hydrochloride Drugs 0.000 description 1
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960000988 nystatin Drugs 0.000 description 1
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic 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
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
(23,24-Bisnor-cholen-22-yl)-guanidines Cmpds. (I) useful as antimicrobial agents (where X is Ch2, or and R is H or acyl; rings A and B cont at least one double bond or C-17 is doubly bonded to C-20) and including the 5 alpha-and 5 beta-isomers and compds. contg. R and S configuration at C-20, are prepd. by standard methods for forming or introducing a gaunidino group in the 22 position.
Description
Die Erfindung betrifft ein Verfahren zur Herstellung ungesättigter 22-Guanidylsteroide der Formel
EMI0001.0000
mit R in der Bedeutung von Wasserstoff oder eines Säu rerestes darstellt und die mindestens eine Doppelbindung in den Ringen A oder B oder zwischen den Kohlenstoff atomen Cl; und C2, enthalten und in denen bei Anwe senheit eines Wasserstoffatoms in 5-Stellung Ring A mit Ring B cis- oder trans-verknüpft ist und die Seitenkette am Kohlenstoffatom C20 R- oder S-konfiguriert sein kann.
Als Säurereste kommen vor allem alle die in Frage, die sich von solchen Säuren ableiten, .die in der Steroid- chemie gebräuchlicherweise für Veresterungen angewandt werden. Bevorzugte Säuren sind solche mit bis zu 15 Kohlenstoffatomen, insbesondere niedere und mittlere aliphatische Carbonsäuren. Weiterhin können die Säuren auch ungesättigt, verzweigt, mehrbasisch oder in üblicher Weise, z.B. durch Hydroxyl-, Aminogruppen oder Ha logenatome, substituiert sein. Geeignet sind auch cycloali- phatische, aromatische, gemicht aromatisch-aliphatische oder heterocyclische Säuren, die ebenfalls in üblicher Weise substituiert sein können.
Als bevorzugte Säuren zur Ausbildung des Säurerestes R seien beispielsweise ge nannt: Essigsäure, Propionsäure, Capronsäure, Önanth- säure, Undecylsäure, -Ölsäure, Trimethylessigsäure, Halo genessigsäure Cyclopentylpropionsäure, Phenylpropion- säure, Phenylessigsäure, Phenoxyessigsäure, Dialkylami- noessigsäure, Piperidinoessigsäure, Bernsteinsäure, Ben zoesäure u.a.
Die erfindungsgemäss herstellbaren Verbindungen können die C=C-Doppelbindung im Steroidmolekül in Form einer Al-, -, A3-, A--, As- oder A7-Doppel- bindung enthalten, was aber nicht ausschliesst, dass auch mehrere Doppelbindungen auftreten wie z.B. als Q3.5-, A13#5\1 '- oder ,1,\',17 \3 '. Zusätzlich können aber auch Doppelbindungen im C- und D-Ring des Ste- roidmoleküls wie z.B. die A511,-, A14(15)- oder A16(17)- Doppelbindung enthalten sein.
Das erfindungsgemässe Verfahren ist dadurch ge kennzeichnet, dass man Verbindungen der Formel
EMI0001.0023
worin Y ein Sulfonsäurerest, St das oben definierte Ste- roidgerüst u. C_" ..... St eine Einfach- oder eine Doppel bindung zwischen dem Kohlenstoffatom C2", und dem Steroidgerüst St bedeuten, mit einem Guanidiniumsalz umsetzt. Gewünschtenfalls können anschliessend aus dem primär entstandenen,Guanidiniumsalz die freie Base nach an sich bekannten Methoden hergestellt und gewünschten falls mit einer beliebigen Säure in ein anderes Salz über führt werden.
Zur Salzbildung sind vor allem anorganische und organische Säuren geeignet. Beispielsweise genannt seien: Salzsäure, Schwefelsäure, Phosphorsäure, Ameisensäure, Essigsäure, Buttersäure, Capronsäure, Oxalsäure, Bern steinsäure, Benzoesäure und insbesondere Gluconsäure, Heptagluconsäure, D-Glucuronsäure, Galacturonsäure, Pelargonsäure und Milchsäure.
Als Sulfonsäurerest in Verbindungen der Formel II kann jeder Sulfonsäurerest verwendet werden, vorzugs weise jedoch der Tosylat- oder der Mesylatrest.
Die neuen ungesättigten 22-Guanidylsteroide sind ge gen Bakterien, Pilze und Trichomonaden wirksam, Insbe sondere zeigen sie gute Wirkung gegen pathogene Hefen und Dermatophyten. wie z.B. Candida albicans, Micro- sporum gypseum, Trichophyton mentagrophytes, Epider- mophyton floccosum und gegen Trichomonaden, wie z.B. Trichomonas vaginalis. Ausserdem sind sie wirksam ge gen gram-positive Bakterien, wie z.B. gegen Staphylococ- cus aureus.
Die erfindungsgemäss herstellbaren Verbindungen sind in ihrer in vitro Wirksamkeit gegen pathogene He fen, wie z.B. gegen Candida albicans, dem bekannten Ny- statin (1) überlegen, wie aus der nachfolgenden Tabelle 1 hervorgeht.
EMI0001.0035
TABELLE <SEP> 1
<tb> Lfd. <SEP> Substanz <SEP> Wirkung <SEP> gegen
<tb> Nr. <SEP> Cand. <SEP> albicans
<tb> I <SEP> Nystatin <SEP> 1
<tb> II <SEP> (3ss-Hydroxy-23,24-bisnor-5- <SEP> 16
<tb> -cholen-22-y1)-guanidinium -acetat
<tb> 111 <SEP> (23,24-Bisnor-5x-chola-2,17[20]- <SEP> 16
<tb> -dien-22-yl)-guanidinium-acetat
<tb> IV <SEP> (23,24-Bisnor-5x-chol-3-en-22- <SEP> 4
<tb> -yl)-guanidinium-acetat Die in der Tabelle 1 enthaltenen Werte wurden im bekannten Röhrchenverdünnungstest erhalten, wobei die Wirkung der Vergleichssubstanz I gleich 1 gesetzt wur de, so dass die Werte aussagen, wieviel man wirksamer die erfindungsgemässen Verbindungen II, III und IV sind.
Ein Beispiel für die gute in vitro Wirksamkeit gegen pathogene Hautpilze, wie z.B. gegen Trichophyton men- tagrophytes, im Vergleich zu dem bekannten Griseofulvin zeigt die nachfolgende Tabelle 2.
EMI0002.0002
TABELLE <SEP> 2
<tb> Lfd. <SEP> Wirkung <SEP> gegen
<tb> Nr. <SEP> Substanz <SEP> Trich.
<tb> mentagrophytes
<tb> V <SEP> Griseofulvin <SEP> 1
<tb> II <SEP> (3ss-Hydroxy-23,24-bisnor-5- <SEP> 4
<tb> -cholen-22-yl)-guanidinium -acetat
<tb> III <SEP> (23,24-Bisnor-5x-chola-2,17(20)- <SEP> 2
<tb> -dien-22-yl)-guanidiniumacetat Die Werte in Tabelle 2 wurden in der gleichen Weise wie die Werte in Tabelle 1 bestimmt.
Die erfindungsgemäss herstellbaren Verbindungen sind bezüglich ihres Wirkungsspektrums somit durch eine erwünscht grosse chemotherapeutische Breite ausge zeichnet.
Die verfahrensgemäss herstellbaren Verbindungen dienen gewöhnlich der äusseren, parenteralen oder oralen Behandlung beispielsweise folgender Erkrankungen: Der- matomykosen, Onychomykosen, Hefeinfektionen des Ga- strointestinal-, Respirations- sowie Urogenitaltraktes und septischer Zustände. Insbesondere sind sie auch wegen ihres Spektrums zur Behandlung von Mischinfektionen gut geeignet. Sie werden dazu in an sich bekannter Weise mit den in der galenischen Pharmazie üblichen Träger substanzen verarbeitet und in die gebräuchlichen Darrei- chungsformnen überführt, wie z.B.
Tabletten, Dragees, Sal ben, Tinkturen, Sprays u.s.w.
Die Herstellung der nicht vorbeschriebenen Ausgangs stoffe erfolgt im allgemeinen in an sich bekannter Weise, indem man z.B. aus einem 20-Ketosteroid mit Aceton- hydridin ein 20-Hydroxy-20-cyansteroid herstellt, aus dem durch Wasserabspaltung beispielsweise mit Phosphoroxy- chlorid in Pyridin die A17(20)- 20-Carbonitrilverbindung entsteht, die mit Lithiumaluminiumhydrid, vorzugsweise in der Siedehitze, reduziert wird.
Das nachfolgende Beiepiel erläutert die Erfindung. Beispiel 0,58 g 50%ige Dispersion von Natriumhydrid in Pa- raffinöl und 1,25 g Guanidinhydrochlorid werden in 40 ml getrocknetem tertiär-Butanol 30 Minuten zum Rückfluss erhitzt, heiss filtriert und sogleich zu einer Lösung von 3,0 g 22-Tosyloxy-23,24-dinor-5α-chol-3-en in 100 ml ab solutem tertiär-Butanol zugetropft. Nach 7stündigem. Er hitzen unter Rückfluss wird das Lösungsmittel im Va kuum vertrieben und der Rückstand wird :mit 40 ml 5%- iger methanolischer KOH versetzt. Nach Verdünnen mit Wasser fällt das freie Guanidin aus, das abgesaugt und rasch getrocknet wird.
Darauf wird es in Methanol auf genommen und mit Eisessig versetzt. Mit Isopropyläther wird das (23,24-Dinor-5α-chol-3-en-22-yl)-guanidinium- acetat vom Schmelzpunkt 198-203 C (Zersetzung) ausge fällt.
The invention relates to a process for the preparation of unsaturated 22-guanidyl steroids of the formula
EMI0001.0000
where R is hydrogen or an acid residue and the at least one double bond in rings A or B or between the carbon atoms is Cl; and C2, and in which, in the presence of a hydrogen atom in the 5-position, ring A is cis- or trans-linked to ring B and the side chain on carbon atom C20 can be R- or S-configured.
Suitable acid residues are above all all those which are derived from acids which are commonly used for esterification in steroid chemistry. Preferred acids are those with up to 15 carbon atoms, in particular lower and medium aliphatic carboxylic acids. Furthermore, the acids can also be unsaturated, branched, polybasic or in the usual way, e.g. be substituted by hydroxyl, amino groups or halogen atoms. Also suitable are cycloaliphatic, aromatic, mixed aromatic-aliphatic or heterocyclic acids, which can likewise be substituted in the usual way.
Preferred acids for the formation of the acid radical R include, for example: acetic acid, propionic acid, caproic acid, enanthic acid, undecylic acid, oleic acid, trimethyl acetic acid, halogen acetic acid, cyclopentylpropionic acid, phenylpropionic acid, phenylacetic acid, phenoxyacetic acid, dialkylamiperic acid, succinic acid, succinic acid Benzoic acid, among others
The compounds that can be prepared according to the invention can contain the C = C double bond in the steroid molecule in the form of an Al, -, A3, A-, As or A7 double bond, but this does not exclude the possibility that several double bonds also occur, e.g. as Q3.5-, A13 # 5 \ 1 '- or, 1, \', 17 \ 3 '. In addition, however, double bonds in the C and D rings of the steroid molecule, e.g. the A511, -, A14 (15) - or A16 (17) - double bond must be included.
The inventive method is characterized in that compounds of the formula
EMI0001.0023
where Y is a sulfonic acid residue, St is the steroid skeleton defined above and. C_ "..... St a single or a double bond between the carbon atom C2" and the steroid structure St mean, with a guanidinium salt. If desired, the free base can then be prepared from the guanidinium salt formed primarily by methods known per se and, if desired, converted into another salt using any acid.
Inorganic and organic acids are particularly suitable for salt formation. Examples include: hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, butyric acid, caproic acid, oxalic acid, succinic acid, benzoic acid and especially gluconic acid, heptagluconic acid, D-glucuronic acid, galacturonic acid, pelargonic acid and lactic acid.
Any sulfonic acid radical can be used as the sulfonic acid radical in compounds of the formula II, but preferably the tosylate or the mesylate radical.
The new unsaturated 22-guanidyl steroids are effective against bacteria, fungi and trichomonads. In particular, they are particularly effective against pathogenic yeasts and dermatophytes. such as. Candida albicans, Microsporum gypseum, Trichophyton mentagrophytes, Epidermophyton floccosum and against Trichomonads, e.g. Trichomonas vaginalis. They are also effective against gram-positive bacteria such as against Staphylococcus aureus.
The compounds which can be prepared according to the invention are effective in their in vitro activity against pathogenic yeasts such as e.g. against Candida albicans, superior to the well-known nastatin (1), as can be seen in Table 1 below.
EMI0001.0035
TABLE <SEP> 1
<tb> Consec. <SEP> substance <SEP> effect <SEP> against
<tb> No. <SEP> Cand. <SEP> albicans
<tb> I <SEP> Nystatin <SEP> 1
<tb> II <SEP> (3ss-Hydroxy-23,24-bisnor-5- <SEP> 16
<tb> -cholen-22-y1) -guanidinium -acetat
<tb> 111 <SEP> (23,24-Bisnor-5x-chola-2,17 [20] - <SEP> 16
<tb> -dien-22-yl) -guanidinium-acetate
<tb> IV <SEP> (23,24-Bisnor-5x-chol-3-en-22- <SEP> 4
<tb> -yl) -guanidinium acetate The values contained in Table 1 were obtained in the known tube dilution test, the effect of the comparative substance I being set equal to 1, so that the values indicate how much more effective the compounds II, III according to the invention can be and IV are.
An example of the good in vitro effectiveness against pathogenic skin fungi, such as against Trichophyton menagrophytes, in comparison to the known griseofulvin, is shown in Table 2 below.
EMI0002.0002
TABLE <SEP> 2
<tb> Consec. <SEP> effect <SEP> against
<tb> No. <SEP> Substance <SEP> Trich.
<tb> mentagrophytes
<tb> V <SEP> Griseofulvin <SEP> 1
<tb> II <SEP> (3ss-Hydroxy-23,24-bisnor-5- <SEP> 4
<tb> -cholen-22-yl) -guanidinium -acetat
<tb> III <SEP> (23,24-Bisnor-5x-chola-2,17 (20) - <SEP> 2
<tb> -dien-22-yl) -guanidinium acetate. The values in Table 2 were determined in the same manner as the values in Table 1.
The compounds which can be prepared according to the invention are thus distinguished in terms of their spectrum of activity by a desired large chemotherapeutic breadth.
The compounds which can be prepared according to the method are usually used for the external, parenteral or oral treatment of the following diseases, for example: dermatomycoses, onychomycoses, yeast infections of the gastrointestinal, respiratory and urogenital tracts and septic conditions. In particular, because of their spectrum, they are also well suited for the treatment of mixed infections. For this purpose, they are processed in a manner known per se with the carrier substances customary in galenic pharmacy and converted into the customary dosage forms, e.g.
Tablets, dragees, ointments, tinctures, sprays, etc.
The starting materials not described above are generally prepared in a manner known per se by e.g. a 20-hydroxy-20-cyansteroid is produced from a 20-ketosteroid with acetone hydride, from which the A17 (20) - 20-carbonitrile compound is formed by splitting off water, for example with phosphorus oxychloride in pyridine, which with lithium aluminum hydride, preferably at boiling point is reduced.
The following example explains the invention. Example 0.58 g of 50% strength dispersion of sodium hydride in paraffin oil and 1.25 g of guanidine hydrochloride are refluxed for 30 minutes in 40 ml of dried tertiary butanol, filtered hot and immediately converted into a solution of 3.0 g of 22-tosyloxy -23,24-dinor-5α-chol-3-ene in 100 ml of absolute tertiary butanol was added dropwise. After 7 hours. After heating under reflux, the solvent is driven off in vacuo and the residue is: 40 ml of 5% strength methanolic KOH are added. After dilution with water, the free guanidine precipitates, which is filtered off with suction and quickly dried.
It is then taken up in methanol and glacial acetic acid is added. The (23,24-dinor-5α-chol-3-en-22-yl) guanidinium acetate with a melting point of 198-203 ° C. (decomposition) is precipitated with isopropyl ether.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19691922457 DE1922457A1 (en) | 1969-04-30 | 1969-04-30 | Unsaturated 22-guanidyl steroids |
| CH630470A CH535752A (en) | 1969-04-30 | 1970-04-27 | Process for the preparation of unsaturated 22-guanidyl steroids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH535223A true CH535223A (en) | 1973-03-31 |
Family
ID=25699331
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH792272A CH535223A (en) | 1969-04-30 | 1970-04-27 | (23, 24-bisnor-cholen-22-yl)-guanidines |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH535223A (en) |
-
1970
- 1970-04-27 CH CH792272A patent/CH535223A/en not_active IP Right Cessation
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