DE3427383A1 - Avarone and avarone derivatives, processes for their preparation, medicaments containing them and their use - Google Patents
Avarone and avarone derivatives, processes for their preparation, medicaments containing them and their useInfo
- Publication number
- DE3427383A1 DE3427383A1 DE19843427383 DE3427383A DE3427383A1 DE 3427383 A1 DE3427383 A1 DE 3427383A1 DE 19843427383 DE19843427383 DE 19843427383 DE 3427383 A DE3427383 A DE 3427383A DE 3427383 A1 DE3427383 A1 DE 3427383A1
- Authority
- DE
- Germany
- Prior art keywords
- avaron
- avarol
- formula
- derivatives
- general formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 239000003814 drug Substances 0.000 title claims 2
- VPRHEJGLNUDEEH-LWILDLIXSA-N 2-[[(1r,2s,4as,8as)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]cyclohexa-2,5-diene-1,4-dione Chemical compound C([C@@]1(C)[C@H]2[C@](C(=CCC2)C)(C)CC[C@@H]1C)C1=CC(=O)C=CC1=O VPRHEJGLNUDEEH-LWILDLIXSA-N 0.000 title abstract description 7
- HFRPPKGMFYMEJZ-UHFFFAOYSA-N Avarone Natural products CC1CCC2(C)C(=CCCC2(C)C1(C)CC3=CC(=O)C=CC3=O)C HFRPPKGMFYMEJZ-UHFFFAOYSA-N 0.000 title abstract description 4
- JSPUCPNQXKTYRO-LWILDLIXSA-N 2-[[(1r,2s,4as,8as)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]benzene-1,4-diol Chemical compound C([C@@]1(C)[C@H]2[C@](C(=CCC2)C)(C)CC[C@@H]1C)C1=CC(O)=CC=C1O JSPUCPNQXKTYRO-LWILDLIXSA-N 0.000 claims abstract description 34
- TXJPJZWNYUQWCP-UHFFFAOYSA-N avarol Natural products CC1CCC2(C)C(=CCCC2(C)C1(C)Cc3cc(O)ccc3O)C TXJPJZWNYUQWCP-UHFFFAOYSA-N 0.000 claims abstract description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 150000007513 acids Chemical class 0.000 claims description 7
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 239000000741 silica gel Substances 0.000 claims description 6
- 229910002027 silica gel Inorganic materials 0.000 claims description 6
- -1 alkylamine hydrochloride Chemical class 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 150000001263 acyl chlorides Chemical class 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 101100037762 Caenorhabditis elegans rnh-2 gene Proteins 0.000 claims description 3
- 208000035473 Communicable disease Diseases 0.000 claims description 3
- 241001483844 Dysidea avara Species 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 4
- 230000000259 anti-tumor effect Effects 0.000 abstract description 4
- 230000000840 anti-viral effect Effects 0.000 abstract description 4
- 238000010171 animal model Methods 0.000 abstract 1
- 230000001857 anti-mycotic effect Effects 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000000394 mitotic effect Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 230000000843 anti-fungal effect Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000010348 incorporation Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 210000004698 lymphocyte Anatomy 0.000 description 3
- 230000029115 microtubule polymerization Effects 0.000 description 3
- AGVBOCPGXNSSLL-NRVXSKMLSA-N 2-[[(1r,2s,4as,8as)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-5-(methylamino)cyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C(NC)=CC(=O)C(C[C@@]2(C)[C@H]3[C@](C(=CCC3)C)(C)CC[C@@H]2C)=C1 AGVBOCPGXNSSLL-NRVXSKMLSA-N 0.000 description 2
- LOWIFWWFLCSJQW-SFPRVHAESA-N 2-[[(1r,2s,4as,8as)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-6-(methylamino)cyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C(NC)=CC(=O)C=C1C[C@@]1(C)[C@H](CCC=C2C)[C@]2(C)CC[C@@H]1C LOWIFWWFLCSJQW-SFPRVHAESA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- 241000257465 Echinoidea Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 238000011785 NMRI mouse Methods 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- JZVUBOIVLRRPJN-GXIQQZJTSA-N [3-[[(1r,2s,4as,8as)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-4-acetyloxyphenyl] acetate Chemical compound C([C@@]1(C)[C@H]2[C@](C(=CCC2)C)(C)CC[C@@H]1C)C1=CC(OC(C)=O)=CC=C1OC(C)=O JZVUBOIVLRRPJN-GXIQQZJTSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- PKHMTIRCAFTBDS-UHFFFAOYSA-N hexanoyl hexanoate Chemical compound CCCCCC(=O)OC(=O)CCCCC PKHMTIRCAFTBDS-UHFFFAOYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 231100000456 subacute toxicity Toxicity 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 229940005605 valeric acid Drugs 0.000 description 2
- WXSTZZVBULFWJM-ZETCQYMHSA-N (2s)-2-(cyclohexa-1,3-dien-1-ylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1=CC=CCC1 WXSTZZVBULFWJM-ZETCQYMHSA-N 0.000 description 1
- 150000005208 1,4-dihydroxybenzenes Chemical class 0.000 description 1
- PGZVFRAEAAXREB-UHFFFAOYSA-N 2,2-dimethylpropanoyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OC(=O)C(C)(C)C PGZVFRAEAAXREB-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- QJHJRWBTIGJOAV-RAKGIWIYSA-N 2-[[(1r,2s,4as,8as)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-5-(ethylamino)cyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C(NCC)=CC(=O)C(C[C@@]2(C)[C@H]3[C@](C(=CCC3)C)(C)CC[C@@H]2C)=C1 QJHJRWBTIGJOAV-RAKGIWIYSA-N 0.000 description 1
- JGXXJNXCKBNCCQ-DQOBCGMHSA-N 2-[[(1r,2s,4as,8as)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-6-(ethylamino)cyclohexa-2,5-diene-1,4-dione Chemical group O=C1C(NCC)=CC(=O)C=C1C[C@@]1(C)[C@H](CCC=C2C)[C@]2(C)CC[C@@H]1C JGXXJNXCKBNCCQ-DQOBCGMHSA-N 0.000 description 1
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- 241000193755 Bacillus cereus Species 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000031404 Chromosome Aberrations Diseases 0.000 description 1
- 108010062580 Concanavalin A Proteins 0.000 description 1
- 230000006820 DNA synthesis Effects 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
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 238000002738 Giemsa staining Methods 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 241000192041 Micrococcus Species 0.000 description 1
- 102000048850 Neoplasm Genes Human genes 0.000 description 1
- 108700019961 Neoplasm Genes Proteins 0.000 description 1
- 241000243142 Porifera Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-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
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-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
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- DPKHZNPWBDQZCN-UHFFFAOYSA-N acridine orange free base Chemical compound C1=CC(N(C)C)=CC2=NC3=CC(N(C)C)=CC=C3C=C21 DPKHZNPWBDQZCN-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000002814 agar dilution Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- DZBUGLKDJFMEHC-UHFFFAOYSA-N benzoquinolinylidene Natural products C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 238000002815 broth microdilution Methods 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
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- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 231100000005 chromosome aberration Toxicity 0.000 description 1
- 230000001332 colony forming effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000002380 cytological effect Effects 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- FDSGHYHRLSWSLQ-UHFFFAOYSA-N dichloromethane;propan-2-one Chemical compound ClCCl.CC(C)=O FDSGHYHRLSWSLQ-UHFFFAOYSA-N 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- XWBDWHCCBGMXKG-UHFFFAOYSA-N ethanamine;hydron;chloride Chemical compound Cl.CCN XWBDWHCCBGMXKG-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- DLDIDQIZPBIVNQ-UHFFFAOYSA-N hydron;2-methylpropan-2-amine;chloride Chemical compound Cl.CC(C)(C)N DLDIDQIZPBIVNQ-UHFFFAOYSA-N 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
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- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 210000004882 non-tumor cell Anatomy 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C50/00—Quinones
- C07C50/02—Quinones with monocyclic quinoid structure
- C07C50/06—Quinones with monocyclic quinoid structure with unsaturation outside the quinoid structure
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
- C07C39/17—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings containing other rings in addition to the six-membered aromatic rings, e.g. cyclohexylphenol
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C46/00—Preparation of quinones
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Avaron und Avaron-Derivate, Verfahren zu ihrer Herstellung, sieAvaron and avaron derivatives, process for their preparation, them
enthaltende Arzneimittel und deren Verwendung Avaron und sein Hydrochinon-Derivat Avarol sind Naturstoffe, 12 die in dem Meeres schwamm Dysidea avara gefunden wurden ) ).Medicinal products containing them and their use Avaron and its hydroquinone derivative Avarol are natural substances 12 found in the marine swam Dysidea avara )).
Die Isolierung dieser Verbindungen gelang aus einem Diethylether-Extrakt mittels Säulenchromatographie an Kieselgel 3) Über biologische Wirkungen war bisher lediglich bekannt, daß Avarol in sehr hoher Konzentration ( 130 M ) Seeigelembryo-3). beeinträchtigt 3 Zellen beeinträchtigt 3). An Derivaten sind in der Literatur u.a. 3'-Methylamino- und 4'-Methylamino-avaron 4) sowie Avarol-dimethylether und Avarol-diacetat 2) beschrieben. Die Methylamino-avarone beeinträchtigen Seeigelembryo-Zellen erst in zehnmal höherer Konzentration in gleicher Weise wie Avarol. Weitere biologische Wirkungen von Avaron-Derivaten waren bisher ebenfalls nicht bekannt.These compounds were isolated from a diethyl ether extract by means of column chromatography on silica gel 3) About biological effects was previously only known that Avarol in very high concentration (130 M) sea urchin embryo-3). affects 3 cells affects 3). In the literature, derivatives include, inter alia 3'-methylamino- and 4'-methylamino-avarone 4) as well as avarol dimethyl ether and avarol diacetate 2). The methylamino-avarones first affect sea urchin embryo cells in ten times higher concentration in the same way as Avarol. More biological Effects of Avaron derivatives were also not known to date.
1) L.Minale, R.Riccio und G.Sodano, Tetrahedron Letters 1974, 3401-3404 2) S.de Rosa, L.Minale, R.Riccio und G.Sodano, J.Chem.Soc.1) L.Minale, R.Riccio and G.Sodano, Tetrahedron Letters 1974, 3401-3404 2) S.de Rosa, L.Minale, R.Riccio and G.Sodano, J.Chem.Soc.
Perkin I,.1408-1414 (1976) 3) L.Cariello, M.de Nicola Giudici und L.Zanetti, Comp.Biochem.Physiol. 65c, 37-41 (1980) 4) G.Cimino, S.de Rosa, S.de Stefano, L.Cariello und L.Zanetti, Experientia 38, 896 (1982) Es wurde nun gefunden, daß Avaron und Avaron-Derivate der allgemeinen Formel I ausgeprägte antitumorale, antibakte- -rielle, antivirale und antimykotische Eigenschaften besitzen, die sie zur Behandlung von Krebs- und Infektionskrankheiten geeignet erscheinen lassen. Perkin I, .1408-1414 (1976) 3) L. Cariello, M.de Nicola Giudici and L. Zanetti, Comp.Biochem.Physiol. 65c, 37-41 (1980) 4) G. Cimino, S.de Rosa, S.de Stefano, L. Cariello and L. Zanetti, Experientia 38, 896 (1982) It has now been found that avaron and avaron derivatives of the general formula I have pronounced antitumoral, antibacterial, antiviral and antifungal properties that they possess seem suitable for the treatment of cancer and infectious diseases.
Gegenstand der Erfindung sind Avaron und Avaron-Derivate der allgemeinen Formel I worin 1. x1 und X2 Oxo bei Doppelbindungen zwischen C-l' und C-6' sowie zwischen C-3' und C-4', R1 Wasserstoff und R2 Alkylamino mit ein, zwei, drei oder vier C-Atomen bedeutet, oder worin 2. X1 und X2 Oxo bei Doppelbindungen zwischen C-1' und C-6' sowie zwischen C-3' und C-4', R¹ Alkylamino mit ein, zwei, drei oder vier C-Atomen und R Wasserstoff bedeutet, oder worin 3. X1 und X2 Hydroxy oder Acyloxy mit 2-6 C-Atomen oder X1 mit X2 Diacyloxy mit 4-6 C-Atomen bei aromatischem Ring und R1 und R2 Wasserstoff bedeutet, sowie die Salze der Alkylamino-avarone mit physiologisch verträglichen Säuren.The invention relates to avaron and avaron derivatives of the general formula I where 1. x1 and X2 oxo in the case of double bonds between Cl 'and C-6' and between C-3 'and C-4', R1 is hydrogen and R2 is alkylamino with one, two, three or four carbon atoms, or where 2 X1 and X2 oxo in the case of double bonds between C-1 'and C-6' and between C-3 'and C-4', R¹ is alkylamino with one, two, three or four carbon atoms and R is hydrogen, or in which 3 X1 and X2 are hydroxy or acyloxy with 2-6 carbon atoms or X1 with X2 are diacyloxy with 4-6 carbon atoms in the case of an aromatic ring and R1 and R2 are hydrogen, as well as the salts of the alkylamino-avarones with physiologically acceptable acids.
Die Verbindungen der Formel I umfassen Avaron und Alkylamino-avarone der Formel I a sowie Avarol und dessen Ester der Formel I b. The compounds of the formula I include avarons and alkylamino-avarones of the formula I a and also avarol and its esters of the formula I b.
Gegenstand der Erfindung ist auch ein Verfahren zur Herstel= lung von Avaron und Avarol, das dadurch gekennzeichnet ist, daß man den zerkleinerten frischen Meeres schwamm Dysidea avara mit Ethylacetat extrahiert, den Extrakt zur Trockne einengt und den Rückstand mit Hilfe geeigneter Lösungsmittel über eine Kieselgelsäule chromatographiert, wobei eine Auftrennung von Avaron und Avarol und damit deren Isolierung erreicht wird.The invention also relates to a method of manufacture of Avaron and Avarol, which is characterized in that the crushed fresh marine sponge Dysidea avara extracted with ethyl acetate to use the extract Dry and concentrate the residue using a suitable solvent over a silica gel column chromatographed, with a separation of Avaron and Avarol and thus their Isolation is achieved.
Gegenstand der Erfindung ist ferner ein Verfahren zur Herstellung von Alkylamino-avaronen der allgemeinen Formel I a mit Ausnahme von 3'-Methylamino- und 4'-Methylamino-avaron, das dadurch gekennzeichnet ist, daß man Avaron mit Alkylamin-hydrochlorid der allgemeinen Formel RNH2 x HC1 umsetzt und die so erhaltenen Verbindungen gewünschtenfalls mit physiologisch verträglichen Säuren in Salze überführt.The invention also relates to a method of production of alkylamino-avarones of the general formula I a with the exception of 3'-methylamino and 4'-methylamino-avarone, which is characterized in that avarone is mixed with alkylamine hydrochloride of the general formula RNH2 x HC1 and the compounds obtained in this way, if desired converted into salts with physiologically compatible acids.
Als Verbindungen der allgemeinen Formel RNH2 x HC1 kommen in Frage Ethyl-, Propyl-, Isopropyl-, n-Butyl-, Isobutyl-und tert.-Butyl-amin-hydrochlorid (Reaktion 1 auf Seite 5 Die Herstellung der Avaron-Derivate der allgemeinen Formel I a durch Einführung des Substituenten -NHR in 3'- bzw.Possible compounds of the general formula RNH2 x HC1 are Ethyl, propyl, isopropyl, n-butyl, isobutyl and tert-butylamine hydrochloride (Reaction 1 on page 5 The preparation of the Avaron derivatives of the general formula I a by introducing the -NHR substituent in 3'- resp.
4'-Stellung ist dadurch gekennzeichnet, daß man die Komponenten in Gegenwart von Pyridin in 50%igem Ethanol miteinander reagieren läßt (G.Cimino, S.de Rosa, S.de Stefano, L.Cariello und L.Zanetti, Experientia 38, 896 (1982)). Die dabei entstehenden Isomerengemische aus 3'- und 4'-Alkylamino-avaronen lassen sich säulenchromatographisch an Kieselgel trennen. Gewünschtenfalls kann man diese Verfahrensprodukte mit physiologisch verträglichen Säuren in ihre Salze überführen. Als solche Säuren eignen sich Chlorwasserstoffsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Weinsäure, Maleinsäure usw.4 'position is characterized by the fact that the components are in Can react with one another in the presence of pyridine in 50% ethanol (G.Cimino, S.de Rosa, S.de Stefano, L. Cariello and L. Zanetti, Experientia 38, 896 (1982)). The one with it Isomer mixtures formed from 3'- and 4'-alkylamino-avarones can be column chromatographed separate on silica gel. If desired, these process products can be treated physiologically compatible acids in their Transfer salts. As such acids suitable are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, Tartaric acid, maleic acid, etc.
Gegenstand der Erfindung ist ferner ein Verfahren zur Herstellung von Avarol-Derivaten der allgemeinen Formel I b, in der R¹ und R² Acyl bedeutet, das dadurch gekennzeichnet ist, daß man Avarol mit einem Acylchlorid der allgemeinen Formel bzw. mit einem Carbonsäureanhydrid der allgemeinen Formel unter Ausnahme von Acetanhydrid am Hydroxyl des C-2' und/oder C-5' acyliert. Hierbei kommen auch Säurechloride oder Säureanhydride zweibasischer Säuren, wie z.B. Bernsteinsäure, in Frage, wobei auf ein Molekül Avarol nur ein Molekül des Derivates der zweibasischen Säure entfällt (Diacyloxy).The invention also relates to a process for the preparation of avarol derivatives of the general formula I b, in which R¹ and R² are acyl, which is characterized in that avarol is mixed with an acyl chloride of the general formula or with a carboxylic anhydride of the general formula with the exception of acetic anhydride on the hydroxyl of C-2 'and / or C-5' acylated. Acid chlorides or acid anhydrides of dibasic acids, such as, for example, succinic acid, are also suitable, with only one molecule of the derivative of the dibasic acid (diacyloxy) being accounted for per molecule of avarol.
Als Verbindungen der allgemeinen Formel kommen beispielsweise in Frage geradkettige Acylchloride wie Acetyl-, Propionyl-, n-Butyryl-, n-Valeroyl- und Capronoyl-chlorid sowie verzweigtkettige Acylchloride wie Isobutyryl-, Isovalerovl-, Ethvl-methvl-acetvl- und Trimethvl-acetvl-chlorid. Als Verbindungen der allgemeinen Formel kommen beispielsweise in Frage geradkettige Säureanhydride wie Propionsäure-, Buttersäure-, Valeriansäure- und Capronsäureanhydrid sowie verzweigtkettige Säureanhydride wie Isobuttersäure-, Valeriansäure-, Ethyl-methyl-essigsäure-und Trimethyl-essigsäure-anhydrid (Reaktion 2 auf Seite 5).As compounds of the general formula For example, straight-chain acyl chlorides such as acetyl, propionyl, n-butyryl, n-valeroyl and capronoyl chloride as well as branched-chain acyl chlorides such as isobutyryl, isovalerovl, ethyl-methyl-acetyl and trimethyl-acetyl chloride come into consideration. As compounds of the general formula For example, straight-chain acid anhydrides such as propionic acid, butyric acid, valeric acid and caproic acid anhydride and branched-chain acid anhydrides such as isobutyric acid, valeric acid, ethyl-methyl-acetic acid and trimethyl-acetic acid anhydride are suitable (reaction 2 on page 5).
Die Herstellung der Avarol-Derivate der allgemeinen Formel I b durch Einführung des Substituenten ist dadurch gekennzeichnet, daß man die Komponenten in Gegenwart von Pyridin miteinander reagieren läßt (S. de Rosa, L.Minale, R.Riccio und G.Sodano, J.Chem.Soc. Perkin I, 1976, 1408-1414; Organikum, VEB Deutscher Verlag der Wissenschaften, 13.Auflage, Berlin 1974, S.441-446).The preparation of the avarol derivatives of the general formula I b by introducing the substituent is characterized in that the components are allowed to react with one another in the presence of pyridine (S. de Rosa, L.Minale, R.Riccio and G.Sodano, J.Chem.Soc. Perkin I, 1976, 1408-1414; Organikum, VEB Deutscher Verlag der Wissenschaften, 13th edition, Berlin 1974, pp 441-446).
Die Verfahrensprodukte lassen sich mit den üblichen Lösungsmitteln, Hilfs- und Trägerstoffen zu Tabletten, Dragees, Kapseln, Tropflösungen, Suppositorien, Injektions und Infusionszubereitungen verarbeiten, um therapeutisch zur peroralen, rektalen oder parenteralen Applikation Verwendung zu finden.The process products can be removed with the usual solvents, Auxiliary and carrier materials for tablets, coated tablets, capsules, drip solutions, suppositories, Process injection and infusion preparations in order to be used therapeutically for peroral, to find rectal or parenteral application use.
Die Verfahrensprodukte der allgemeinen Formel I besitzen wertvolle pharmakologische Eigenschaften. Die Antitumor-Wirkung wurde in vitro am L5178y- und Ll2lo-Mäuselymphomzell system nachgewiesen. Diese Zellen wurden in Suspensionskultur gehalten, wie von uns bereits beschrieben (W.E.G.Müller und R.Zahn, Cancer Res. 39, 1102 (1979)).The process products of the general formula I are valuable pharmacological properties. The anti-tumor effect was demonstrated in vitro on the L5178y- and Ll2lo mouse lymphoma cell system detected. These cells were in suspension culture as already described by us (W.E.G. Müller and R. Zahn, Cancer Res. 39, 1102 (1979)).
Die ED50-Konzentrationen der Verbindungen (Inokulation:
In zytologischen Untersuchungen durch Giemsa-Färbung und Acridin-Orange-Färbung der Mitose-Chromosomen (R.Rigler, Acta Physiol.Scand. 67(supp1.267), 1 (1966)) wurde gefunden, daß die Verfahrensprodukte den Mitoseindex von L5178y-Zellen beeinflussen. Die pharmakologische Wirkung von Avaron und seinen Derivaten ist also die eines Mitosegiftes.In cytological examinations by Giemsa staining and acridine orange staining of the mitotic chromosomes (R. Rigler, Acta Physiol. Scand. 67 (supp1.267), 1 (1966)) found that the products of the process affect the mitotic index of L5178y cells. So the pharmacological effect of Avaron and its derivatives is that of one Mitotic poison.
Auch biochemische Untersuchungen bewiesen diesen Wirkungsmechanismus: Avaron und seine Derivate hemmen die Mikrotubuli-Polymerisation im substöchiometrischen Bereich, wie durch viskosimetrische Untersuchungen, durchgeführt nach S.D.MacLean-Fletcher und T.D.Pollard (J.Cell Biol. 85, 414 -428 (1980)), gezeigt werden konnte. Die Hemmung der Mikrotubuli-Polymerisation erfolgt auf dem Niveau der Protofilament-Elongation. Durch höhere Konzentrationen an Verfahrensprodukten wird neben der Hemmung der Mikrotubuli-Polymerisation während der Mitose-Phase auch die während der anderen Zellzyklus-Phasen gehemmt. Chromosomen-Aberrationen treten nach Gabe von therapeutischen Dosen von Avaron und seinen Derivaten nicht auf.Biochemical studies have also proven this mechanism of action: Avaron and its derivatives inhibit microtubule polymerization at a substoichiometric level Range, as by viscometric studies, carried out according to S.D. MacLean-Fletcher and T.D. Pollard (J. Cell Biol. 85, 414-428 (1980)). The inhibition the microtubule polymerization takes place at the level of protofilament elongation. Higher concentrations of process products not only inhibit microtubule polymerization during the mitotic phase also those during the other cell cycle phases are inhibited. Chromosome aberrations occur after administration of therapeutic doses of Avaron and its derivatives.
Von besonderer Bedeutung für die Verwendung der Verfahrensprodukte zur Chemotherapie von Krebserkrankungen dürfte die Tatsache sein, daß eine zytostatische Wirksamkeit auf nicht-tumorale Zellen in Kultur in therapeutisch anzuwenden-Konzentrationen fehlt. Dieses Ergebnis wurde aus Versuchen mit Lymphozyten-Kulturen gewonnen: Milz-Lymphozyten wurden von sechs Wochen alten NMRI-Mäusen gewonnen; die Erythrozyten wurden aus der Suspension durch Ammoniumchlorid-Behandlung entfernt. Die Milz-Lymphozyten wurden in RPMI 1640-Medium/20 % fötales Kälberserum in einer Dichte von 1,5 x lo' Zellen/ml für 72 Std. in Anwesenheit von 2 pg/ml Concanavalin A gehalten. 18 Std. vor Ende des Versuches wurde C3 -Thymidin hinzugegeben. Bei Inkubation mit lojiN der Verfahrensprodukte wurde keine Beeinträchtigung der DNA-Syntheserate gemessen. In Gegenwart von 15)1M erfolgte eine lediglich 15 %ige Hemmung der Einbaurate von (3H-Thymidin in die DNA.Of particular importance for the use of the process products for cancer chemotherapy is likely to be the fact that a cytostatic Effectiveness on non-tumor cells in culture in therapeutic to apply concentrations is absent. This result was obtained from experiments with lymphocyte cultures recovered: spleen lymphocytes were obtained from six week old NMRI mice; the Erythrocytes were removed from the suspension by treatment with ammonium chloride. The spleen lymphocytes were in RPMI 1640 medium / 20% fetal calf serum in a Density of 1.5 x lo cells / ml for 72 hours in the presence of 2 pg / ml concanavalin A held. C3 thymidine was added 18 hours before the end of the experiment. at Incubation with the products of the process did not affect the rate of DNA synthesis measured. In the presence of 15) 1M, the rate of incorporation was only inhibited by 15% of (3H-thymidine in DNA.
Die Antitumor-Wirkung von Avaron und seinen Derivaten wurde auch am Ganztier in vivo bewiesen. Die Versuchsdurchführung wurde wie früher beschrieben vollzogen (W.E.G.Müller, R.K.The antitumor effects of Avaron and its derivatives were also reported on Whole animal proven in vivo. The experiment was carried out as described earlier completed (W.E.G. Müller, R.K.
Zahn, A.Maidhof, H.C.Schröder, M.Bachmann und H.Umezawa, J.Antibiotics 37, 239 (1984)). NMRI-Mäuse, die mit einem L5178y-Lymphom beimpft worden waren, an diesem Tumor erkrank-.Zahn, A. Maidhof, H.C. Schröder, M.Bachmann and H.Umezawa, J.Antibiotics 37: 239 (1984)). NMRI mice vaccinated with L5178y lymphoma got sick with this tumor.
ten und danach fünf Tage lang z.B. mit 0,3 mg/kg Avaron i.p.and then for five days, e.g. with 0.3 mg / kg Avaron i.p.
pro Tag behandelt wurden1 überlebten unbehandelte Tumormäuse erheblich. Die unbehandelten Tiere waren zu 50 % nach 18 Tagen tot, während 50 % der behandelten Tiere sogar den 26.Tag überlebten.treated per day, 1 untreated tumor mice survived significantly. 50% of the untreated animals were dead after 18 days, while 50% of the treated animals Animals survived even the 26th day.
Die subakute Toxizität von Avaron und seinen Derivaten liegt bei einer fünftägigen i.p.-Behandlung von Mäusen mit Werten zwischen 35 und 75 mg/kg so günstig, daß eine Verwendung der Verfahrensprodukte bei der Chemotherapie von Krebserkrankgen zu erwarten ist.The subacute toxicity of Avaron and its derivatives is one five-day i.p. treatment of mice with values between 35 and 75 mg / kg so favorable, that a use of the process products in the chemotherapy of cancer genes is to be expected.
Die antibakterielle Wirkung von Avaron und seinen Derivaten wurde in in-vitro-Tests etabliert. Sie wurde mit der Agar-Verdünnungsmethode bestimmt (B.E.Scully, K.Jules und H.C.The antibacterial effects of Avaron and its derivatives were made established in in vitro tests. It was determined by the agar dilution method (B.E.Scully, K.Jules and H.C.
Neu, Antimicr.Ag.Chemother. 23, 907 (1983). Die Bakterien -5 wurden in einer Menge von lo colony forming units einge- setzt. Die minimale inhibitorische Konzentration (MIC)wurde z.B. für Avarol mit o,4/1M bei Cocci wie z.B. Micrococcus pyrogenes, mit o9)iM bei gram-negativen Bakterien wie z.B. Escherichia coli und, mit 1,3)1M bei gram-positiven Bakterien wie Bacillus cereus bestimmt. Diese hohe in vitro-Aktivität liegt im Bereich der in vitro-Antitumoraktivität.New, Antimicr.Ag.Chemother. 23: 907 (1983). The bacteria were -5 in a lot of lo colony forming units puts. The minimum inhibitory concentration (MIC) was e.g. for Avarol with 0.4 / 1M for Cocci like e.g. Micrococcus pyrogenes, with o9) iM in gram-negative bacteria such as Escherichia coli and, with 1.3) 1M in gram-positive bacteria such as Bacillus cereus. This high in vitro activity is in the range of the in vitro antitumor activity.
Aufgrund der niedrigen subakuten Toxizität bei Mäusen in vivo ergibt sich ein chemotherapeutischer Index (TI=LD50 bei der Maus dividiert durch die Keimempfindlichkeit) z.B.Due to the low subacute toxicity in mice in vivo a chemotherapeutic index (TI = LD50 in the mouse divided by the sensitivity to germs) e.g.
von Avarol zwischen loo und 140 je nach Mikroorganismus.of Avarol between loo and 140 depending on the microorganism.
Avaron und seine Derivate wirken antiviral in BHK-Zell-Kulturen, die mit Herpes simplex-Virus Typ I oder Typ II infiziert wurden. Die Konzentration an Virus (Multiplizität der Infektiosität) wurde mit o,5 bis 1,5 an "plaque forming units"/Zelle eingestellt. 2 Std. nach Infektion wurden die Kulturen gewaschen und die Verf ahrensprodukte hinzugegeben.Avaron and its derivatives have antiviral effects in BHK cell cultures that contain were infected with herpes simplex virus type I or type II. The focus on Virus (multiplicity of infectivity) was plaque forming with 0.5 to 1.5 units "/ cell. 2 hours after infection, the cultures were washed and the process products are added.
24 Std. p.i, wurde der Virus-Titer (p.f.u./o,2 ml) bestimmt.The virus titer (p.f.u./o.2 ml) was determined 24 hours p.i.
Bei einer Konzentration an z.BX Avarol von 1 P wurde die Typ I-Vermehrung von 9 x 1o4 (Kontrolle) auf 1 x lo (behandelte Kulturen) und die Typ II-Vermehrung von 6 x lo 3 (Kontrolle) auf 7 x lo (behandelte Kulturen) herabgesetzt.At a concentration of e.g. X Avarol of 1 P, the type I propagation became from 9 x 1o4 (control) to 1 x lo (treated cultures) and type II propagation reduced from 6 x lo 3 (control) to 7 x lo (treated cultures).
Die antimykotische Wirkung wurde in vitro mit Saccharomyces cerevisiae nach der Broth Dilution-Methode festgestellt (E.Lennette (ed.), Manual of Clinical Microbiology, ed. by American Society of Microbiology, Washington 1980, S.648-649). Als minimale Hemmkonzentration wurde z.B. für Avarol o,7>iM ermittelt; die 50 °/Oige Hemmkonzentration liegt bei 1, 6jiM.The antifungal effect was determined in vitro with Saccharomyces cerevisiae determined using the broth dilution method (E. Lennette (ed.), Manual of Clinical Microbiology, ed. By American Society of Microbiology, Washington 1980, pp.648-649). The minimum inhibitory concentration found for Avarol, for example, was 0.7> iM; the 50 % Inhibitory concentration is 1.6JM.
Die ausgeprägte antibakteriellle, antivirale und antimykotische Wirksamkeit der Verfahrensprodukte läßt erwarten, daß sie zur Behandlung von Infektionskrankheiten verwendet werden.The pronounced antibacterial, antiviral and antifungal effectiveness the products of the process are expected to be used in the treatment of infectious diseases be used.
Von den nachstehenden Beispielen wurden die Beispiele a'abis 2dnach Reaktion 1 erhalten, während die Beispiele 3 bis 4 nach Reaktion 2 dargestellt wurden. Beispiel 1 betrifft die Herstellung von Avaron und Avarol aus dem Naturprodukt.From the examples below, the examples a'a to 2d to Reaction 1 obtained while Examples 3 to 4 were presented after Reaction 2. Example 1 relates to the production of Avaron and Avarol from the natural product.
Beispiel 1 Avaron und Avarol 3 kg Schwamm werden mit 25o ml Ethylacetat extrahiert, der so gewonnene Extrakt wird über Magnesiumsulfat getrocknet und anschließend filtriert. Das Filtrat wird zur Trockne eingeengt, Der verbleibende Rückstand wird in Benzol aufgenommen und über eine Kieselgel-Säule mit Benzol als Elutionsmittel chromatographiert. Avaron erscheint im Durchlauf, während Avarol auf der Säule verbleibt. Avarol wird mit einem Gemisch Benzol/Ethylacetat (9o:10, V:V) eluiert.Example 1 Avaron and Avarol 3 kg of sponge are mixed with 250 ml of ethyl acetate extracted, the extract obtained in this way is dried over magnesium sulfate and then filtered. The filtrate is concentrated to dryness. The residue that remains is taken up in benzene and passed through a silica gel column with benzene as the eluent chromatographed. Avaron appears in the flow, while Avarol remains on the column. Avarol is eluted with a benzene / ethyl acetate mixture (90:10, V: V).
Das Eluat wird zur Trockne eingeengt und Avarol anschliessend in reiner Form durch Kristallisation aus Dichlormethan-Aceton gewonnen. Avaron wird durch Umkristallisation aus Benzol gereinigt.The eluate is concentrated to dryness and then Avarol in pure Form obtained by crystallization from dichloromethane-acetone. Avaron is going through Purified recrystallization from benzene.
Avaron - Schmp.: Avarol - Schmp.: 148-1500C Beispiel 2 3'-Ethylamino-aVaron und 4'-Ethylamino-avaron a) 2,5 g Ethylaminhydrochlorid und 5 ml Pyridin werden zu einer Lösung von 500 mg Avaron in looo ml 50 °WOigem Ethanol gegeben und nach 20 Std. das Ethanol unter Wasserstrahlpumpenvakuum abdestilliert. Der wäßrige Rückstand wird mit Dichlormethan extrahiert und der eingeengte Dichlormethan-Extakt über eine Kieselgelsäule mit Dichlormethan als Elutionsmittel chromatographiert. Hierbei gelingt die Auftrennung in 3'-Ethylamino- und 4'-Ethylamino-avaron.Avaron - m.p .: Avarol - m.p .: 148-1500C Example 2 3'-Ethylamino-aVaron and 4'-ethylamino-avaron a) 2.5 g of ethylamine hydrochloride and 5 ml of pyridine become added to a solution of 500 mg Avaron in 100 ml 50 ° WOigem ethanol and after The ethanol is distilled off under a water jet pump vacuum for 20 hours. The aqueous residue is extracted with dichloromethane and the concentrated dichloromethane extract over a Chromatographed silica gel column with dichloromethane as the eluent. This succeeds the separation into 3'-ethylamino and 4'-ethylamino-avarone.
In analoger Weise wurden erhalten: b) 3'-Propylamino- und 4'-Propylamino-avaron c) 3'-Isopropylamino- und 4'-Isopropylamino-avaron d) 3' -n-Butyl amino- und 4'-n-Butylamino-avaron Beispiel 3 Avarol-diacetat a) 500 mg Avarol werden in 20 ml absolutem Pyridin gelöst und zur Lösung portionsweise unter Umschütteln 1 g Acetylchlorid hinzugefügt. Es wird in der üblichen Weise aufgearbeitet, zur Trockne eingeengt und der Rückstand mit siedendem Heptan extrahiert. Beim Abkühlen kristallisiert der Ester aus. Er wird aus Hexan umkristallisiert.The following were obtained in an analogous manner: b) 3'-propylamino and 4'-propylamino-avarone c) 3'-Isopropylamino- and 4'-Isopropylamino-avarone d) 3'-n-Butylamino- and 4'-n-Butylamino-avarone example 3 Avarol diacetate a) 500 mg Avarol are dissolved in 20 ml of absolute pyridine and 1 g of acetyl chloride was added in portions to the solution while shaking. It will Worked up in the usual way, evaporated to dryness and the residue with extracted from boiling heptane. The ester crystallizes out on cooling. He will recrystallized from hexane.
Schmp.: 62-64°C In analoger Weise wurden erhalten: b) Avarol-dipropionat c) Avaroldival erianat d) Avarol-ditrimethylacetat Beispiel 4 Avarol-dicapronat a) 300 mg Avarol werden in 25 ml absolutem Pyridin gelöst und zur Lösung portionsweise unter Umschütteln o,6 g Capronsäureanhydrid hinzugefügt. Es wird in der üblichen Weise aufgearbeitet, zur Trockne eingeengt und der Rückstand mit siedendem Heptan extrahiert. Es wird aus Aceton und anschließend aus Hexan umkristallisiert.Melting point: 62-64 ° C. The following were obtained in an analogous manner: b) Avarol dipropionate c) Avaroldival erianat d) Avarol-ditrimethylacetat Example 4 Avarol-dicapronat a) 300 mg of avarol are dissolved in 25 ml of absolute pyridine and added in portions to the solution 0.6 g of caproic anhydride were added while shaking. It will be in the usual Way worked up, evaporated to dryness and the residue with boiling heptane extracted. It is recrystallized from acetone and then from hexane.
In analoger Weise wurden erhalten: b) Avarol-diisovalerianat c) Avarol-di-ethyl-methyl-acetat d) Avarol-succinatThe following were obtained in an analogous manner: b) Avarol diisovalerianate c) Avarol di-ethyl methyl acetate d) Avarol succinate
Claims (6)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19843448313 DE3448313C2 (en) | 1984-07-25 | 1984-07-25 | New avarone and avarol cpds. |
| DE19843427383 DE3427383A1 (en) | 1984-07-25 | 1984-07-25 | Avarone and avarone derivatives, processes for their preparation, medicaments containing them and their use |
| CA000525235A CA1303052C (en) | 1984-07-25 | 1986-12-12 | Avarone and avarol pharmaceutical compositions, and process |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19843427383 DE3427383A1 (en) | 1984-07-25 | 1984-07-25 | Avarone and avarone derivatives, processes for their preparation, medicaments containing them and their use |
| CA000525235A CA1303052C (en) | 1984-07-25 | 1986-12-12 | Avarone and avarol pharmaceutical compositions, and process |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE3427383A1 true DE3427383A1 (en) | 1986-01-30 |
| DE3427383C2 DE3427383C2 (en) | 1993-02-04 |
Family
ID=25671178
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19843427383 Granted DE3427383A1 (en) | 1984-07-25 | 1984-07-25 | Avarone and avarone derivatives, processes for their preparation, medicaments containing them and their use |
Country Status (2)
| Country | Link |
|---|---|
| CA (1) | CA1303052C (en) |
| DE (1) | DE3427383A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0252305A3 (en) * | 1986-06-07 | 1990-09-12 | Merz & Co. GmbH & Co. | Use of avarone and avarol and derivatives thereof for the preparation of a pharmaceutical composition for the control of adult t-cell leukemia/lymphoma |
| EP0252304A3 (en) * | 1986-06-07 | 1990-09-19 | Merz & Co. GmbH & Co. | Use of avarone and avarol and derivatives thereof for the preparation of a pharmaceutical composition for the control of aids and arc |
| WO1997049662A1 (en) * | 1996-06-25 | 1997-12-31 | The University Of Sheffield | Quinone bacterial inhibitors |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109761948B (en) * | 2017-11-09 | 2022-08-09 | 上海交通大学医学院附属仁济医院 | Sponge-derived terpenoid compound Dysiarenone and preparation method and application thereof |
-
1984
- 1984-07-25 DE DE19843427383 patent/DE3427383A1/en active Granted
-
1986
- 1986-12-12 CA CA000525235A patent/CA1303052C/en not_active Expired - Lifetime
Non-Patent Citations (6)
| Title |
|---|
| CA 97 (1982), 21000t * |
| Comp. Biochem. Physiol. 71 B (1982), 281-3 * |
| Experientia 38 (1982), 896 * |
| Fed. Proc. 39 (1980), 26-29 * |
| Tetrahedron Lett, 38 (1974), 3401-04 * |
| Tetrahedron Letters No. 38, 3401-3404, 1974 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0252305A3 (en) * | 1986-06-07 | 1990-09-12 | Merz & Co. GmbH & Co. | Use of avarone and avarol and derivatives thereof for the preparation of a pharmaceutical composition for the control of adult t-cell leukemia/lymphoma |
| EP0252304A3 (en) * | 1986-06-07 | 1990-09-19 | Merz & Co. GmbH & Co. | Use of avarone and avarol and derivatives thereof for the preparation of a pharmaceutical composition for the control of aids and arc |
| WO1997049662A1 (en) * | 1996-06-25 | 1997-12-31 | The University Of Sheffield | Quinone bacterial inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| DE3427383C2 (en) | 1993-02-04 |
| CA1303052C (en) | 1992-06-09 |
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