NL8203839A - NEW EPOXIDES OF BENZOPHENANTHRIDINE ALKALOIDS, NEW PHARMACEUTICAL PREPARATIONS CONTAINING THESE ALKALOIDS AND METHODS FOR THE PREPARATION OF BOTH THE NEW ALKALOIDS AND THE PHARMACEUTICALS. - Google Patents
NEW EPOXIDES OF BENZOPHENANTHRIDINE ALKALOIDS, NEW PHARMACEUTICAL PREPARATIONS CONTAINING THESE ALKALOIDS AND METHODS FOR THE PREPARATION OF BOTH THE NEW ALKALOIDS AND THE PHARMACEUTICALS. Download PDFInfo
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- NL8203839A NL8203839A NL8203839A NL8203839A NL8203839A NL 8203839 A NL8203839 A NL 8203839A NL 8203839 A NL8203839 A NL 8203839A NL 8203839 A NL8203839 A NL 8203839A NL 8203839 A NL8203839 A NL 8203839A
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- alkaloids
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- new
- epoxides
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- 150000002118 epoxides Chemical class 0.000 title claims description 22
- 238000000034 method Methods 0.000 title claims description 16
- 229930015421 benzophenanthridine alkaloid Natural products 0.000 title claims description 15
- 150000008622 benzophenanthridines Chemical class 0.000 title claims description 14
- 229930013930 alkaloid Natural products 0.000 title claims description 11
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 9
- 239000003814 drug Substances 0.000 title 1
- INVGWHRKADIJHF-UHFFFAOYSA-N Sanguinarin Chemical compound C1=C2OCOC2=CC2=C3[N+](C)=CC4=C(OCO5)C5=CC=C4C3=CC=C21 INVGWHRKADIJHF-UHFFFAOYSA-N 0.000 claims description 25
- 150000001875 compounds Chemical class 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- -1 alkaloid compound Chemical class 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 229910002651 NO3 Inorganic materials 0.000 claims description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 3
- 150000007942 carboxylates Chemical group 0.000 claims description 3
- 238000006735 epoxidation reaction Methods 0.000 claims description 3
- 150000004820 halides Chemical class 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 3
- 239000004593 Epoxy Substances 0.000 claims description 2
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims 2
- 230000000536 complexating effect Effects 0.000 claims 2
- 125000002252 acyl group Chemical group 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims 1
- CUILPNURFADTPE-UHFFFAOYSA-N hypobromous acid Chemical class BrO CUILPNURFADTPE-UHFFFAOYSA-N 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- FCEXWTOTHXCQCQ-UHFFFAOYSA-N Ethoxydihydrosanguinarine Natural products C12=CC=C3OCOC3=C2C(OCC)N(C)C(C2=C3)=C1C=CC2=CC1=C3OCO1 FCEXWTOTHXCQCQ-UHFFFAOYSA-N 0.000 description 13
- 229940084560 sanguinarine Drugs 0.000 description 13
- YZRQUTZNTDAYPJ-UHFFFAOYSA-N sanguinarine pseudobase Natural products C1=C2OCOC2=CC2=C3N(C)C(O)C4=C(OCO5)C5=CC=C4C3=CC=C21 YZRQUTZNTDAYPJ-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 231100000433 cytotoxic Toxicity 0.000 description 4
- 230000001472 cytotoxic effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 244000001385 Sanguinaria canadensis Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- KKMPSGJPCCJYRV-UHFFFAOYSA-N Nitidine Chemical compound C1=C2C3=[N+](C)C=C4C=C(OC)C(OC)=CC4=C3C=CC2=CC2=C1OCO2 KKMPSGJPCCJYRV-UHFFFAOYSA-N 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000000411 inducer Substances 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 238000002211 ultraviolet spectrum Methods 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241001331845 Equus asinus x caballus Species 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 206010023347 Keratoacanthoma Diseases 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- XPDJLGHACUMTKU-UHFFFAOYSA-N benzo[c]phenanthridine Chemical class C1=CC=CC2=CN=C3C4=CC=CC=C4C=CC3=C21 XPDJLGHACUMTKU-UHFFFAOYSA-N 0.000 description 1
- 201000008274 breast adenocarcinoma Diseases 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000007269 dehydrobromination reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 208000002925 dental caries Diseases 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 208000028169 periodontal disease Diseases 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- SLGBZMMZGDRARJ-UHFFFAOYSA-N triphenylene Chemical class C1=CC=C2C3=CC=CC=C3C3=CC=CC=C3C2=C1 SLGBZMMZGDRARJ-UHFFFAOYSA-N 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
*» » J* ' *·* * 823193/vdV/kd* »» J * '* * * 823193 / vdV / kd
Korte aanduiding: Nieuwe epoxyden van benzofenanthridine-alkaloiden, nieuwe farmaceutische preparaten die deze alkaloiden bevatten en werkwijzen. voor de bereiding van zovi/el de nieuwe alkaloiden als de farmaceutische preparaten.Short designation: New epoxides of benzophenanthridine alkaloids, new pharmaceutical preparations containing these alkaloids and methods. for the preparation of as many as the new alkaloids as the pharmaceutical preparations.
De uitvinding heeft betrekking op nieuwe verbindingen met farmaceu-v tische werking, namelijk tegen leukemie, bilbarziosis, Pseudomonas aeruginosa, goedaardige. en kwaadaardige tumoren - zoals granuloma pyogenicum, kerato-acanthoma, basaaUcel carcinoom, geschubde cel carci-5 noom, kwaardaardige melanoma, kaposi's sarcoom en adeno-carcinoom van de borst - alsmede periodontale ziekten en tandcaries.The invention relates to novel compounds with pharmaceutical activity, namely against leukemia, bilbarziosis, Pseudomonas aeruginosa, benign. and malignant tumors - such as granuloma pyogenicum, kerato-acanthoma, basal cell carcinoma, scaly cell carcinoma, malignant melanoma, kaposi's sarcoma and adeno-carcinoma of the breast - as well as periodontal diseases and dental caries.
De uitvinding heeft eveneens betrekking op nieuwe farmaceutische preparaten die deze verbindingen bevatten en op een werkwijze voor de bereiding van deze verbindingen door middel van een chemische epoxy-10 deringsreactie.The invention also relates to new pharmaceutical preparations containing these compounds and to a process for the preparation of these compounds by means of a chemical epoxy reaction.
De nieuwe verbindingen kunnen voorkomen in de vorm van zouten met een zuur met de algemene formules 1 tot 6 van het formuleblad waarin Rp R2» Rp R^ en ^5 een waterstofatoom of alkylgroep voorstellen en X' een halogenide, nitraat, perchloraat, zuursulfaat of carboxylaat- 15 groep, of in de vorm van basen met de formules 7 tot 12- , waarin R^ tot R_ en X" de bovengenoemde betekenis bezitten en R, een waterstofatoom 6 soortgeliike of alkylgroep voorstelt. De meest belangrijke van / verbindingen zijn fagaronine (formula 6a in de zoutvorm en formule 1¾ in basevorm, waarin Rp Rg' en"Rj methylgroepen voorstellen, X“ een chloridegroep is en 20 Rg waterstof en of wel R^ waterstof en R^ methyl of omgekeerd methyl en R^ waterstof is. Deze verbindingen zijn cytotoxisch en werkzaam tegen leukemie P388 in muizen (W.M. Messmer, M. Tin-Wa, H.H.S.The new compounds may exist in the form of salts with an acid of the general formulas 1 to 6 of the formula sheet wherein Rp R 2, Rp R 1 and 5 represent a hydrogen atom or alkyl group and X 'represents a halide, nitrate, perchlorate, acid sulfate or carboxylate group, or in the form of bases of formulas 7 to 12-, wherein R 1 to R 5 and X "have the above meaning and R represents a hydrogen atom 6 like or alkyl group. The most important of compounds are phagaronine (formula 6a in the salt form and formula 1¾ in base form, in which Rp Rg 'and "Rj represent methyl groups, X" is a chloride group and 20 Rg is hydrogen and either R ^ hydrogen and R ^ methyl or reverse methyl and R ^ hydrogen. These compounds are cytotoxic and effective against P388 leukemia in mice (WM Messmer, M. Tin-Wa, HHS
Fong, C. Bevelle, N.R. Farnsworth, D.J, Abraham en J. Trojanek, J.Fong, C. Bevelle, N.R. Farnsworth, D.J, Abraham and J. Trojanek, J.
Pharm. Sci. 61 , 1858 (1972), en nitidine (formule 5a in de vorm van het 25 zout en formule 11a in de vorm van een base, waarin R^ en R^ methylgroepen voorstellen, X" chloride en Rg waterstof is) wordt 00k zeer cytotoxisch en werkzaam geacht tegen leukemie P388 in muizen (M.R. Wall, M.C". Wani, en H.L. Taylor, 162nd National Meesting of the American Chemical Society, Washington D.C. September 1971, Abstracts MEDI 34).Pharm. Sci. 61, 1858 (1972), and nitidine (formula 5a in the form of the salt and formula 11a in the form of a base, wherein R 1 and R 2 represent methyl groups, X "chloride and R 9 is hydrogen) becomes very cytotoxic and considered effective against P388 leukemia in mice (MR Wall, MC ". Wani, and HL Taylor, 162nd National Mast of the American Chemical Society, Washington DC September 1971, Abstracts MEDI 34).
Andere benzo(c)fenanthridine alkaloiden zoals sanguinarine (for-30 mule la in de zoutvorm en formule 7a in de basevorm, waarin R^ is methyl, X” is chloride en Rg is waterstof), in zijn zoutvorm ookwel genoemd 2,3:7,8-bis-methyleen-dioxy-5-methylfenanthridinium chloride, chlerythrine (formule 2a in de zoutvorm en 8a in de basevorm, waarin R^ 8203839 ; > - 2 - R2 en methylgroepen, X“-een chloridegroep en een waterstofatoom voorstelt) 00k we 1 in de zout-'Vorm genoemd 2,3-methyleen-dioxy-5-methyl-7,8-dimethoxyfenanthridinium chloride, die hoe\i/el als cytotoxisch beschou\i/d zijn niet werkzaam tegeileukemie (F.R. Stermitz, N.A. Larson 5 en D.J. Kim, J. Medicinal Chemistry 16 939 (1973)).Other benzo (c) phenanthridine alkaloids such as sanguinarine (for-30 mule 1a in the salt form and formula 7a in the base form, where R 2 is methyl, X ”is chloride and Rg is hydrogen), also referred to in its salt form 2,3: 7,8-bis-methylene-dioxy-5-methylphenanthridinium chloride, chlerythrine (formula 2a in the salt form and 8a in the base form, where R 8203839;> - 2 - R 2 and methyl groups, X 1 - a chloride group and a hydrogen atom We also have 1 in the salt form called 2,3-methylene-dioxy-5-methyl-7,8-dimethoxyphenanthridinium chloride, which are considered to be cytotoxic as cytotoxic (FR Stermitz) , NA Larson 5 and DJ Kim, J. Medicinal Chemistry 16 939 (1973)).
In extracten van planten komen echter werkzame bestanddelen voor zoals "sanguinaria canadensis”, die werkzaam zijn tegen kanker tezamen met andere bestanddelen zoals beschreven in de Portugese octrooiaanvrage 71.727 van Orewa Inc., 10 Bij de onderhavige uitvinding heeft men rekehing gehouden met het feit dat verbindingen met een struktuur sterk overeenkomend met die van benzofenanthridine-alkaloiden, namelijk de benzofenanthrenen, de aromatische polycyclische koolwaterstoffen met dezelfde aromatische ringen als de benzofenenthridinen, die zich onderscheiden van de laatst-15 genoemde door de vervanging van het stikstofatoom door een CH groep, alleen als induceermiddelen voor kanker werken via hun metabolieten waarvan de vorming gepaard gaat met het epoxyderen van de 11, 12 dubbele binding van het zogenaamde K. gebied (D.W. Nebert, R.C. Lewit en 0. Pelkonen, in "Carcinogens Identification and Mechanism of Action” 20 uitgegeven door A.C. Griffin en C.R. Shaw, Raven Press, New York 1979). Dezelfde kanker^-induceermiddelen staan tegelijk 00k bekend als remstoffen voor de carcinogenese, wat op het oog absurd lijkt (L.W. Wattenber in hetzelfde boek), daar zij in een andere fase van de werkwijze werkzaam zijn.Plant extracts, however, contain active ingredients such as "sanguinaria canadensis", which are effective against cancer along with other ingredients as described in Portuguese patent application 71,727 to Orewa Inc., 10 The present invention has taken into account that compounds having a structure very similar to that of benzophenanthridine alkaloids, namely the benzophenanthrenes, the aromatic polycyclic hydrocarbons having the same aromatic rings as the benzophenenthridines, distinguished from the latter by the replacement of the nitrogen atom by a CH group, only if cancer inducers act through their metabolites, the formation of which involves epoxidizing the 11, 12 double bond of the so-called K. region (DW Nebert, RC Lewit and 0. Pelkonen, published in "Carcinogens Identification and Mechanism of Action" 20 by AC Griffin and CR Shaw, Raven Press, New York 1979). The same cancer inducers are at the same time known as inhibitors of carcinogenesis, which appears to be absurd (L.W. Wattenber in the same book), since they are active in a different phase of the process.
25 De onderhavige uitvinding heeft nu betrekking op nieuwe 11, 12- epoxyden van benzofenanthridine-alkaloiden. Bovendien heeft zij betrekking op een werkwijze voor de synthese van deze verbindingen door middel van een keten van reacties in hoofdzaak bestaande uit twee trappen: a) de hydroxybromering door middel van een verbinding die een stikstof-30 broombinding bevat zoals bijvoorbeeld N-broomsuccinimide en b) dehydrobromering die leidt tot het gewenste epoxyde.The present invention now relates to new 11, 12 epoxides of benzophenanthridine alkaloids. In addition, it relates to a process for the synthesis of these compounds by a chain of reactions consisting essentially of two steps: a) the hydroxy bromination by means of a compound containing a nitrogen-bromine bond such as, for example, N-bromosuccinimide and b dehydrobromination leading to the desired epoxide.
Het praktische industrieel belang van- deze werkwijze bestaat in het verkrijgen van nieuwe verbindingen met een farmaceutische werking gelijk aan die van de uitgangsverbindingen voor het oxyderen, doch waar-35 bij deze verbindingen een grotere werkzaamheid bezitten ten gevolge van de metabolische omzetting in cellen waarin zij werkzaam zijn. Bovendien kunnen zij gebruikt worden als tussenprodukten bij de synthese van 8203839 # » - 3 - andere nieuwe verbindingen met farmaceutische werking door opening van de epoxydering.The practical industrial importance of this method consists in obtaining new compounds having a pharmaceutical activity similar to that of the starting compounds for oxidation, but where these compounds have a greater activity due to the metabolic conversion into cells in which they are employed. In addition, they can be used as intermediates in the synthesis of other novel compounds having pharmaceutical activity through epoxidation opening.
Bij de werkwijze ter bereiding van de epoxyden kan men uitgaan van zuivere benzofenenthridineverbindingen of van een mengsel van twee 5 of meer verbindingen, wat belangwekkend is voor zover deze verbindingen voorkomen in extracten van bepaalde planten zoals sanguinaria canadensis, mengseJsvan twee benzofenanthridine-alkaloiden (sanguinarine en chlery-thrine) en het zal duidelijk zijn dat het voordeliger is om de twee alkaloiden gelijktijdig te epoxyderen onder toepassing van een mengsel 10 van de twee epoxyden bij de vervaardiging van farmaceutische preparaten dan eerst de twee alkaloiden te scheiden en een van hen te epoxyderen.The epoxides can be prepared from pure benzophenenthridine compounds or from a mixture of two or more compounds, which is interesting insofar as these compounds are present in extracts of certain plants such as sanguinaria canadensis, mixtures of two benzophenanthridine alkaloids (sanguinarine and chlerythrin) and it will be appreciated that it is more advantageous to epoxidize the two alkaloids simultaneously using a mixture of the two epoxides in the manufacture of pharmaceutical compositions than to first separate the two alkaloids and epoxidize one of them.
Tenslotte dient opgemerkt te worden, dat uitgaande van bepaalde benzofenenthridine-alkaloiden zoals bijvoorbeeld sanguinarine, alsmede uit de epoxyden, soms werkzame farmaceutische preparaten alleen verkre-15 gen kunnen worden als het alkaloid of zijn epoxyde door middel van een metaalzout omgezet wordt in een complex. In het geval van niet-geepoxy-deerde benzofenenthridine-alkabiden is een algemeen bekend feit, in het bijzonder bij sanguinarine sinds 1878 (Amerikaans octrooischrift 209.331 van Littleton Daniel), de tqepassing van dit principe op geepoxydeerde 20 benzofenenthridine verbindingen is echter nieuw.Finally, it should be noted that starting from certain benzophenenthridine alkaloids such as, for example, sanguinarine, as well as from the epoxides, sometimes active pharmaceutical preparations can only be obtained if the alkaloid or its epoxide is converted into a complex by means of a metal salt. In the case of non-epoxidized benzophenenthridine alkabides, it is a well known fact, especially in sanguinarine since 1878 (US Patent 209,331 to Littleton Daniel), however, the application of this principle to epoxidized benzophenenthridine compounds is new.
De volgende voorbeelden lichten de uitvinding toe zonder haar echter te beperken.The following examples illustrate the invention without, however, limiting it.
25 8203839 * · 4 -25 8203839 * 4 -
VOORBEELD IEXAMPLE I
Epoxydering van sanquinarine (base) (2,3;7,8-bis-methyleen~dioxy-6-hydroxy-5-methyl-5,6-dihydrobenzo (c) fenanthridine).Epoxidation of sanquinarine (base) (2,3,7,8-bis-methylene-dioxy-6-hydroxy-5-methyl-5,6-dihydrobenzo (c) phenanthridine).
1. Hydroxybromerinq 5 2 gram sanguinarine worden opgelost in 50 ml tetrahydrofuran en geroerd, de temperatuur ingesteld op 20 °C, 0,2 ml perchloorzuur en 1 g dibromantine toegevoegd waarna 30 minuten geroerd werd. Vervolgens werd 0,5 ml van een 25S5’s waterige natriumbisulfiet-oplossing toegevoegd. De bij deze reaktie gevormde hydroxybroomverbinding wordt niet geisoleerd 10 en direkt onderworpen aan de volgende trap.1. Hydroxybromerin 5 2 grams of sanguinarine are dissolved in 50 ml of tetrahydrofuran and stirred, the temperature adjusted to 20 ° C, 0.2 ml of perchloric acid and 1 g of dibromantine added and stirred for 30 minutes. Then 0.5 ml of a 25S5's aqueous sodium bisulfite solution was added. The hydroxy bromo compound formed in this reaction is not isolated and immediately subjected to the next step.
2. Dehydrobromerinq2. Dehydrobromerinq
Onder handhaven van de temperatuur op 20 °C en onder roeren, wor=s·.-.While maintaining the temperature at 20 ° C and with stirring, = s · .-.
den 2 g: vooraf in 30 ml water opgelost natriumhydroxyde toegevoegd, gevolgd door 3 ml azijnzuur. Alle tetrahydrofuran wordt verdampt en de 15 rest wordt gefiltreerd, gewassen met water, en bij 40 °C gedroogd in vacuo. Men verkrijgt 2 g 2,3:7,8-bis-methyleen-dioxy-6-hydroxy-5-methyl- 5,6-dihydrobenzo (c) fenanthridine 11,12-epoxyde. Smeltpunt 230,5 °C.2 g: added sodium hydroxide previously dissolved in 30 ml of water, followed by 3 ml of acetic acid. All tetrahydrofuran is evaporated and the residue is filtered, washed with water, and dried in vacuo at 40 ° C. 2 g of 2,3: 7,8-bis-methylene-dioxy-6-hydroxy-5-methyl-5,6-dihydrobenzo (c) phenanthridine 11,12-epoxide are obtained. Melting point 230.5 ° C.
UV spectrum in ethanol: max 330, 290, 240 en 220 nm. IR spectrum (inKBr) 2940 (sterk breed) 1765, 1680 ((zwak breed) 1640 (zwak scherp) 20 1520 (middel scherp), 1500, 1490, 1470 (sterk scherp) 1450, 1440, 1420, 1400, 1360, 1340 (zwak scherp), 1250 (sterk scherp), 1260, 1230, 1205, 1180.. (zwak scherp), 1100 (sterk breed), 1005, 980 (zwak scherp), 950 (middel scherp), 930, 890, 880 (zwak scherp), 870 (middel scherp), 860, 850 (zwak scherp), 815 (sterk scherp), 790, 770, 760, 720, 700, 680, 625 25 (zwak scherp), 470 (sterk breed), , NMR spectrum (300 MHz, d£ DMS0-TSS):i 2.759 ( -N-CH-j),6 3.225, 3.372UV spectrum in ethanol: max 330, 290, 240 and 220 nm. IR spectrum (inKBr) 2940 (strong wide) 1765, 1680 ((weak wide) 1640 (weak sharp) 20 1520 (medium sharp), 1500, 1490, 1470 (strong sharp) 1450, 1440, 1420, 1400, 1360, 1340 (weakly sharp), 1250 (strong sharp), 1260, 1230, 1205, 1180 .. (weakly sharp), 1100 (strong wide), 1005, 980 (weakly sharp), 950 (medium sharp), 930, 890, 880 (weakly sharp), 870 (medium sharp), 860, 850 (weakly sharp), 815 (very sharp), 790, 770, 760, 720, 700, 680, 625 25 (weakly sharp), 470 (very wide), , NMR spectrum (300 MHz, d £ DMS0-TSS): i 2.759 (-N-CH-j), 6 3.225, 3.372
Hll;12)^ 5*4°6 (H6)&6.200, 6.259, 6.298 (2x0-CH-0, 2 doubletten respektievelijk gecentreerd bij 6.249 en 6.278) 7.112, 7.136, 7.617, 7.641 (H. . AB systeem gecentreerd bij 7.375; JnD= -7.3 Hz) 7.504, 7,734, 1 Ad 30 8.264 CH9j1Q).Hll; 12) ^ 5 * 4 ° 6 (H6) & 6,200, 6,259, 6,298 (2x0-CH-0, 2 doublets centered at 6,249 and 6,278, respectively) 7,112, 7,136, 7,617, 7,641 (H.. AB system centered at 7,375; JnD = -7.3 Hz) 7.504, 7.734, 1 Ad 30 8.264 CH9]).
VOORBEELD?IIEXAMPLE II
Qmzettinq sanquinarine (base) epoxyde, d.w.z. 2,3:7,8-bis-methyleen-dioxy- 6-6hydroxy-5-methyl-5,6-dihydrobenzo (c) fenanthridine 11,12-epoxyde in het chloride van het sanquinariniumepoxyde, d.w.z. 2,3:7,8-bis-methyleen-35 diQxy-6-hydroxy-5-methyl-5,6-dihydrobenzo (c) fenanthridinium chloride-11, 12-epoxyde.Sanquinarin (base) epoxide, ie, 2,3: 7,8-bis-methylene-dioxy-6-6hydroxy-5-methyl-5,6-dihydrobenzo (c) phenanthridine 11,12-epoxide in the chloride of the sanquinarin epoxide i.e., 2,3: 7,8-bis-methylene-35 di-hydroxy-6-hydroxy-5-methyl-5,6-dihydrobenzo (c) phenanthridinium chloride-11, 12-epoxide.
1 g base wordt opgelost in chloroform of aceton en druppelsgewijs 8203839 - 5 - ' ft - waterig zoutzuur toegevoegd tot een stof met een heldeie oranj e kleur neerslaat. Deze stof wordt afgefiltreerd, gewassen met chloroform en gedroogd in vacuo bij kamertemperatuur. Smeltpunt tussen 300 en 350 °C onder ontleding.1 g of base is dissolved in chloroform or acetone and 8203839 - 5 - aqueous hydrochloric acid is added dropwise to a substance of a bright orange color. This substance is filtered off, washed with chloroform and dried in vacuo at room temperature. Melting point between 300 and 350 ° C with decomposition.
5 VOORBEELD IIIEXAMPLE III
Epoxyderinq van chlerythrine (base) (2,3-methyleendioxy-6-hydroxy~5-methyl-7,8-diinethoxy-5,6-dihydrobenzo (c) fenanthridine).Epoxidizer of chlerythrine (base) (2,3-methylenedioxy-6-hydroxy-5-methyl-7,8-diinethoxy-5,6-dihydrobenzo (c) phenanthridine).
De werkwijze is dezelfde als in voorbeeld I, doch men gaat uit van 2 g chlerythrine (base) in plaats van sanguinarine (base), waarbij 10 men 2 g chlerythrine epoxyde verkrijgt, d.w.z. 2,3-methyleen-dioxy-6-hydroxy-5-methyl-7,8-dimethoxy-5,6-dihydrobenzo (c) fenanthridine 11,12-epoxyde.The procedure is the same as in Example 1, but 2 g of chlerythrine (base) is substituted for sanguinarine (base), whereby 2 g of chlerythrine epoxide is obtained, ie 2,3-methylene-dioxy-6-hydroxy- 5-methyl-7,8-dimethoxy-5,6-dihydrobenzo (c) phenanthridine 11,12-epoxide.
Smeltpunt 250.0 °C. Uv spectrum in ethanol: max. 340, 285, 230 en 210 nm. IR spectrum (in KBr) : 2940 (sterk breed), 1765 (zwak breed), 15 1680 (middel scherp), 1635, 1620, 1565 (zwak breed) 1520 (zu/ak scherp), 1500 (sterk scherp) 1465, 1430, 1400, 1370, 1330, 1310 (zwak scherp) 1275 (sterk scherp), 1220, 1190, 1120 (zwak breed), 1050 (sterk scherp) 1000 (zwak breed), 955 foiddel scherp), 915, 900 (zwak breed), 870 (middel scherp), 840 (zwak breed), 815 (middel scherp), 730, 675, 605, 525 (zwak 20 breed) en 475 (sterk breed).Melting point 250.0 ° C. UV spectrum in ethanol: max. 340, 285, 230 and 210 nm. IR spectrum (in KBr): 2940 (strong wide), 1765 (weak wide), 15 1680 (medium sharp), 1635, 1620, 1565 (weak wide) 1520 (zu / ak sharp), 1500 (strong sharp) 1465, 1430, 1400, 1370, 1330, 1310 (weak sharp) 1275 (strong sharp), 1220, 1190, 1120 (weak wide), 1050 (strong sharp) 1000 (weak wide), 955 medium sharp), 915, 900 (weak wide), 870 (medium sharp), 840 (weak wide), 815 (medium sharp), 730, 675, 605, 525 (weak 20 wide) and 475 (strong wide).
NMR spectrum (300 MHz, dg-DMSO-TSS): 0.868, 1.245, 2.725, 3.176, 3.191, 3,745, 3.779, 3.848, 3.901, 4.191, 5.357, 5.637, 5.646, 5.798, 5.833 5.847, 6.127, 6.151, 6.181, 6.279, 6.303, 7.033, 7.063, 7.347, 7.449, 7.548, 7.582, 7.783, 7.857, 7.881, 7.851.NMR spectrum (300 MHz, dg-DMSO-TSS): 0.868, 1.245, 2.725, 3.176, 3.191, 3.745, 3.779, 3.848, 3.901, 4.191, 5.357, 5.637, 5.646, 5.798, 5.833 5.847, 6.127, 6.151, 6.181, 6,279, 6,303, 7,033, 7,063, 7,347, 7,449, 7,548, 7,582, 7,783, 7,857, 7,881, 7,851.
25 VOORBEELD IVEXAMPLE IV
Bereidinq van een menqsel van sanguinarine (base) en chlerythrine (base) epoxyden uitqaande van een extract van "sanquinaria candensis” dat een menqsel van sanguinarine (base) en chlerythrine (base) bevat.Preparation of a mixture of sanguinarine (base) and chlerythrine (base) epoxides from an extract of "sanquinaria candensis" containing a mixture of sanguinarine (base) and chlerythrine (base).
100 g gedrncgde en gemalen rhizomen van "sanguinaria canadensis" 30 wcrden geextraheerd met 2 porties van 500 ml methylalcchol; de oplossing wcrdt gefiltreerd doer een aluminiumcxydekclcm waarbij de eerste fraktie weggewcrpen wordt, de methylalcchcl afgedampt tot kristallen overvloedig beginnen neer te slaan, die men filtreert en waarbij men 2 g extract verkrijgt. Uit dunne laag chromatografie op silicagel,(10¾ 35 methanol en 90¾ methyleenchloride) blijkt sanguinarine het belangrijkste bestanddeel te zijn gevolgd door chlerythrine. De 2 g extract worden onderworpen aan de bewerkingen als beschreven in voorbeeld I. Men ver- 8203839 9 * » - 6 - krijgt een produkt dat, volgens dunne laag chromatografie en bij ver-gelijking met sanguinarine en chlerythrineepoxyden een mengsel blijkt te zijn waarin sanguinarine-epoxyde overheerst ten opzichte van chlerythri-neepoxyden.100 g of crushed and ground rhizomes of "sanguinaria canadensis" are extracted with 2 portions of 500 ml of methyl alcohol; the solution is filtered through an aluminum oxide coating, the first fraction being discarded, the methyl alcohol evaporated until crystals begin to precipitate abundantly, which are filtered and 2 g of extract are obtained. Thin layer chromatography on silica gel (10¾35 methanol and 90¾ methylene chloride) shows that sanguinarine is the main constituent followed by chlerythrine. The 2 g extract are subjected to the procedures described in Example 1. A product is obtained which, after thin layer chromatography and when compared with sanguinarine and chlerythrine epoxides, is found to be a mixture in which sanguinarine epoxide predominates over chlerythrine epoxides.
5 VOORBEELD VEXAMPLE V
Bereidinq van een farmaceutisch preparaat.Preparation of a pharmaceutical preparation.
Men bereidt een pasta met 45 g zinkchloride, 37 ml gedeioniseerd water, 16 g sanguinarine en 2 g sanguinarine-epoxyde.A paste is prepared with 45 g of zinc chloride, 37 ml of deionized water, 16 g of sanguinarine and 2 g of sanguinarine epoxide.
82038398203839
Claims (14)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PT7376381 | 1981-10-01 | ||
| PT7376381A PT73763B (en) | 1981-10-01 | 1981-10-01 | PROCESS FOR THE PREPARATION OF NOVEL EPOXIDES OF BENZOFENANTRIDINE ALKALOIDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NL8203839A true NL8203839A (en) | 1983-05-02 |
Family
ID=20082989
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NL8203839A NL8203839A (en) | 1981-10-01 | 1982-10-01 | NEW EPOXIDES OF BENZOPHENANTHRIDINE ALKALOIDS, NEW PHARMACEUTICAL PREPARATIONS CONTAINING THESE ALKALOIDS AND METHODS FOR THE PREPARATION OF BOTH THE NEW ALKALOIDS AND THE PHARMACEUTICALS. |
Country Status (6)
| Country | Link |
|---|---|
| BR (1) | BR8205780A (en) |
| DE (1) | DE3236455A1 (en) |
| GB (1) | GB2108955B (en) |
| IN (1) | IN155552B (en) |
| NL (1) | NL8203839A (en) |
| PT (1) | PT73763B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6140328A (en) * | 1997-12-12 | 2000-10-31 | Rutgers, The State University Of New Jersey | Heterocyclic cytotoxic agents |
| US6740650B2 (en) | 1999-10-29 | 2004-05-25 | Rutgers, The State University Of New Jersey | Heterocyclic cytotoxic agents |
| EP1453812B1 (en) | 2001-11-14 | 2008-08-20 | Rutgers, The State University | Cytotoxic agents |
| WO2003051289A2 (en) | 2001-11-14 | 2003-06-26 | Rutgers, The State University | Solubilized topoisomerase poison agents |
| JP4628675B2 (en) | 2001-11-14 | 2011-02-09 | ラトガーズ，ザ ステイト ユニバーシティ | Solubilized topoisomerase poison |
| ATE390923T1 (en) | 2001-11-14 | 2008-04-15 | Univ Rutgers | TOPOISOMERASE TOXICANTS |
| US6992089B2 (en) | 2002-08-09 | 2006-01-31 | Rutgers, The University Of New Jersey | Nitro and amino substituted topoisomerase agents |
| AU2003265405A1 (en) | 2002-08-09 | 2004-02-25 | Edmond J. Lavoie | Nitro and amino substituted heterocycles as topoisomerase i targeting agents |
| US6989387B2 (en) | 2002-08-09 | 2006-01-24 | Rutgers, The State University Of New Jersey | Nitro and amino substituted topoisomerase agents |
| WO2004044174A2 (en) | 2002-11-12 | 2004-05-27 | Rutgers, The State University | Topoisomerase-targeting agents |
| US9562051B2 (en) | 2009-03-06 | 2017-02-07 | Rutgers, The State University Of New Jersey | Methylenedioxybenzo [I] phenanthridine derivatives used to treat cancer |
| WO2010127363A1 (en) | 2009-05-01 | 2010-11-04 | Rutgers, The State University Of New Jersey | Toposiomerase inhibitors |
| US11091498B2 (en) | 2016-04-04 | 2021-08-17 | Rutgers, The State University Of New Jersey | Topoisomerase poisons |
-
1981
- 1981-10-01 PT PT7376381A patent/PT73763B/en not_active IP Right Cessation
-
1982
- 1982-10-01 BR BR8205780A patent/BR8205780A/en unknown
- 1982-10-01 GB GB08228066A patent/GB2108955B/en not_active Expired
- 1982-10-01 NL NL8203839A patent/NL8203839A/en not_active Application Discontinuation
- 1982-10-01 DE DE19823236455 patent/DE3236455A1/en not_active Ceased
- 1982-10-12 IN IN1179/CAL/82A patent/IN155552B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE3236455A1 (en) | 1983-05-05 |
| PT73763B (en) | 1983-10-26 |
| IN155552B (en) | 1985-02-16 |
| PT73763A (en) | 1981-11-01 |
| GB2108955B (en) | 1985-08-21 |
| BR8205780A (en) | 1983-09-06 |
| GB2108955A (en) | 1983-05-25 |
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