DE19701664A1 - New derivatives of madura hydroxylactone, process for their preparation and their use - Google Patents

New derivatives of madura hydroxylactone, process for their preparation and their use

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DE19701664A1
DE19701664A1 DE19701664A DE19701664A DE19701664A1 DE 19701664 A1 DE19701664 A1 DE 19701664A1 DE 19701664 A DE19701664 A DE 19701664A DE 19701664 A DE19701664 A DE 19701664A DE 19701664 A1 DE19701664 A1 DE 19701664A1
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substituted
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methyl
alkyl
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Peter Dr Juetten
Winfried Dr Schumann
Lothar Dr Heinisch
Udo Prof Dr Graefe
Walter Dr Werner
Hermann Dr Ulbricht
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Hans Knoell Institut fuer Naturstoffforschung
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Hans Knoell Institut fuer Naturstoffforschung
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Priority to PCT/DE1998/000124 priority patent/WO1998031659A1/en
Publication of DE19701664A1 publication Critical patent/DE19701664A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C337/00—Derivatives of thiocarbonic acids containing functional groups covered by groups C07C333/00 or C07C335/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C337/06—Compounds containing any of the groups, e.g. thiosemicarbazides
    • C07C337/08—Compounds containing any of the groups, e.g. thiosemicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. thiosemicarbazones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/72—Hydrazones
    • C07C251/86—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/48—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom
    • C07C311/49—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/52—Ortho- or ortho- and peri-condensed systems containing five condensed rings

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to imine derivatives of the madurahydroxylacton (3,9,11,14,15-pentahydroxy-7-methoxy-10-methyl-1,8,13-trioxo-1,3,5,6,8 ,13-hexahydronaphthaceno[1,2-f]isobenezofuran), with formula (I), and their pharmaceutically acceptable salts and esters. The invention also relates to a method for their production and pharmaceutical preparations containing these compounds. The compounds, in accordance with the invention, possess a non-steroidal backbone chain, display no estrogenous activity, have in the cell culture only slight cytotoxity, and are characterized in that they have a strong inhibitory effect on microsomal human placenta sulfatase.

Description

Die Erfindung betrifft neue pharmakologisch aktive Derivate des Madurahydroxylactons (3,9,11,14,15-Pentahydroxy-7-methoxy-10-methyl-1,8,13-trioxo-1,3,5,6,8,13-hexahydro­ naphthaceno[1,2-f]isobenzofuran), speziell Iminderivate der Maduransäure (3-Formyl-1,9,11,14- tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo[a]-naphthacen-2- carbonsäure). Sie sind in der endokrinen Therapie von Krebserkrankungen des Menschen, insbesondere zur Bekämpfung hormonabhängiger Tumoren wie Mammakarzinom anwendbar. Die Verbindungen sind für die Herstellung verschiedenster pharmazeutischer Zubereitungen und Applikationsformen geeignet.The invention relates to new pharmacologically active derivatives of madura hydroxylactone (3,9,11,14,15-pentahydroxy-7-methoxy-10-methyl-1,8,13-trioxo-1,3,5,6,8,13-hexahydro naphthaceno [1,2-f] isobenzofuran), especially imine derivatives of maduranic acid (3-formyl-1,9,11,14- tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo [a] -naphthacen-2- carboxylic acid). They are in endocrine therapy for human cancers, especially applicable for combating hormone-dependent tumors such as breast cancer. The Compounds are for the production of various pharmaceutical preparations and Application forms suitable.

Die Verbindungen leiten sich von Madurahydroxylacton ab, welches aus Actinomadura rubra biotechnisch gewinnbar ist (D. Strauß, W. Fleck, D. Tresselt, W. Kochmann, H.-P. Richter, S. Müller, A. Keil, H.-J. Till, P. Scharfenberg, B. Weiher, Patentschrift DD 2 85 614 A5). Die Struktur des Madurahydroxylactons (Formel II) wurde von Paulus und Mitarbeitern aufgeklärt (E.F. Paulus, K. Dornberger, W. Werner, D. Fenske, Acta Cryst. Sect. C 50 (1994) 2064-2067). Madurahydroxylacton gehört zur Klasse der Benzo[a]naphthacenchinone. Die Vertreter dieser Familie zeigen ein breites Spektrum biologischer Wirkungen, die auf verschiedenen Wirkmechanismen beruhen. Insbesondere die Pradimicine (T. Oki in "New Approaches for Antifungal Drugs", Hrsg. P.B. Fernandes, Birkhäuser, Boston, 1992, 64-87) und Benanomicine (H. Yamaguchi, S. Inouye, Y. Orikasa, H. Tohyama, K. Komuro, S. Gomi, S. Ohuchi, T. Matsumoto, M. Yamaguchi, T. Hiratani, K. Uchida, Y. Ohsumi, S. Kondo, T. Takeuchi in "Recent Progress in Antifungal Chemotherapy"; Hrsg. H. Yamaguchi, G.S. Kobayashi, H. Takahashi; Marcel Dekker, New York, 1992, 393-402) sind hierbei als interessante antifungale und antivirale Substanzen bekannt geworden. Darüber hinaus wurden in den letzten Jahren weitere Naturstoffe vom Benzo[a]naphthacenchinon-Typ mit neuen pharmakologischen Wirkungen gefunden, z. B.: die Benastatine (T. Aoyama et al., J. Antibiot. 45 (1992) 1391-1396 und 46 (1993) 712-718) und die Bequinostatine (T. Aoyama et al., J. Antibiot. 46 (1993) 914-920 und T. Yamazaki et al., J. Antbitiot. 46 (1993) 1309-1311, 1993) als Hemmer der Glutathion-S-Transferasen; die ECE- Hemmer WS79089 A, B und C (Y. Tsurumi et al., J. Antibiot. 47 (1994) 619-630 und 48 (1995) 169-174); KS-619-1 ist Inhibitor der Calcium- und Calmodulin-abhängigen cyclischen Nucleotidphosphodiesterase (Y. Matsuda et al., Biochem. Pharmacol. 39 (1990) 841-849), sowie G- 2N und G-2A (R.W. Rickards, J. Antibiot. 42 (1989) 336-339). Madurahydroxylacton selbst besitzt nur ungenügende biologische Wirksamkeit. The compounds are derived from Madurahydroxylacton, which from Actinomadura rubra can be obtained biotechnologically (D. Strauß, W. Fleck, D. Tresselt, W. Kochmann, H.-P. Richter, S. Müller, A. Keil, H.-J. Till, P. Scharfenberg, B. Weiher, patent specification DD 2 85 614 A5). The structure of Madurahydroxylacton (Formula II) was elucidated by Paul and co-workers (E.F. Paulus, K. Dornberger, W. Werner, D. Fenske, Acta Cryst. Sect. C 50 (1994) 2064-2067). Madura hydroxylactone belongs to the class of benzo [a] naphthacene quinones. The representatives of this Family show a wide range of biological effects that affect different Mechanisms of action are based. In particular the Pradimicine (T. Oki in "New Approaches for Antifungal Drugs ", ed. P.B. Fernandes, Birkhauser, Boston, 1992, 64-87) and Benanomicine (H. Yamaguchi, S. Inouye, Y. Orikasa, H. Tohyama, K. Komuro, S. Gomi, S. Ohuchi, T. Matsumoto, M. Yamaguchi, T. Hiratani, K. Uchida, Y. Ohsumi, S. Kondo, T. Takeuchi in "Recent Progress in Antifungal Chemotherapy "; ed. H. Yamaguchi, G.S. Kobayashi, H. Takahashi; Marcel Dekker, New York, 1992, 393-402) are interesting antifungal and antiviral substances known. In addition, other natural products from Benzo [a] naphthacenchinone type with new pharmacological effects found, e.g. E.g .: the Benastatine (T. Aoyama et al., J. Antibiot. 45 (1992) 1391-1396 and 46 (1993) 712-718) and the Bequinostatine (T. Aoyama et al., J. Antibiot. 46 (1993) 914-920 and T. Yamazaki et al., J. Antbitiot. 46 (1993) 1309-1311, 1993) as inhibitors of glutathione S transferases; the ECE Inhibitors WS79089 A, B and C (Y. Tsurumi et al., J. Antibiot. 47 (1994) 619-630 and 48 (1995) 169-174); KS-619-1 is inhibitor of calcium and calmodulin dependent cyclic Nucleotide phosphodiesterase (Y. Matsuda et al., Biochem. Pharmacol. 39 (1990) 841-849), and G- 2N and G-2A (R.W. Rickards, J. Antibiot. 42 (1989) 336-339). Madurahydroxylacton owns insufficient biological effectiveness.  

Die Erfindung dient zur Bereitstellung von substituierten Iminen des Madurahydroxylactons und entsprechenden Salzen sowie zu ihrer Verwendung. Mit den Verbindungen wird angestrebt, die Palette der endokrinen Therapie hormonabhängiger Tumoren durch gezielte Hemmung des für die Estrogenbiosynthese verantwortlichen Enzyms Estronsulfatase zu erweitern. Für die Lösung dieser Aufgabe sind die neuen Verbindungen deshalb von Vorteil, weil sie eine nichtsteroidale Struktur besitzen und keine estrogene Aktivität aufweisen. Die bisher bekannten Hemmer der Steroidsultatase werden meist zu Verbindungen mit hormoneller Aktivität metabolisiert.The invention serves to provide substituted imines of madura hydroxylactone and corresponding salts and their use. With the connections the aim is Range of endocrine therapy of hormone-dependent tumors by targeted inhibition of the for Estrogen biosynthesis responsible for expanding enzyme estrone sulfatase. For solving this The new compounds are advantageous because they have a non-steroidal structure possess and have no estrogenic activity. The previously known inhibitors of steroidultatase are mostly metabolized to compounds with hormonal activity.

Ungefähr 1/3 aller Mammakarzinome beim Menschen sind hormonabhängig. Estrogene, insbesondere 17β-Estradiol, spielen als Hormone eine zentrale Rolle in der Entwicklung und der Unterstützung des Wachstums hormonabhängiger Tumoren (T.R.J. Evans, M.G. Rowlands, S.S. Sahota, R.C. Coombes, J. Steroid Biochem. Mol. Biol. 48 (1994) 563-566). Mamma- und Endometriumkarzinom treten am häufigsten nach der Menopause auf, wenn die Estrogenbildung in den Ovarien zurückgeht. Die Plasmaspiegel an Estron und 17β-Estradiol bei postmenopausalen Frauen sind im allgemeinen sehr niedrig. Auffällig ist aber, daß die Estrogenkonzentrationen in Mammatumor-Geweben im Vergleich zum Plasma um eine Größenordnung höher liegen (L. Duncan, A. Purohit, N.M. Howarth, B.V. Potter, M.J. Reed, Cancer Res. 53 (1993) 298-303). Die erhöhten Tumor-Estrogenkonzentrationen lassen auf eine in situ-Estrogenbildung im Gewebe schließen, die als wesentliche Estrogenquelle bei der Unterstützung des Tumorwachstums in Frage kommt (S.J. Santner, B. Ohlson-Wilhelm, R.J. Santen, Int. J. Cancer 54 (1993) 119-124).About 1/3 of all breast cancers in humans are hormone-dependent. Estrogens, 17β-estradiol in particular, play a central role in the development and development of hormones Supporting the growth of hormone-dependent tumors (T.R.J. Evans, M.G. Rowlands, S.S. Sahota, R.C. Coombes, J. Steroid Biochem. Mol. Biol. 48 (1994) 563-566). Mom and Endometrial cancer is most common after menopause when estrogen production is in the ovaries goes back. Plasma levels of estrone and 17β-estradiol in postmenopausal Women are generally very low. It is striking, however, that the estrogen concentrations in Breast tumor tissues are an order of magnitude higher than plasma (L. Duncan, A. Purohit, N.M. Howarth, B.V. Potter, M.J. Reed, Cancer Res. 53 (1993) 298-303). The heightened Tumor estrogen concentrations suggest in situ tissue estrogen formation, which as an essential source of estrogen to support tumor growth (S.J. Santner, B. Ohlson-Wilhelm, R.J. Santen, Int. J. Cancer 54 (1993) 119-124).

Für die Estrogenbiosynthese im Organismus stehen zwei Hauptwege zur Verfügung, der Momatase- und der Sultataseweg. Bei postmenopausalen Frauen wird die Estrogenbildung unter anderem über den Momataseweg fortgesetzt. Sie verläuft durch periphere Umwandlung von Androstendion zu Estron, vermittelt durch den Enzymkomplex Aromatase (M.J. Reed, Breast Cancer Res. Treat. 30 (1994) 7-17). Aus Estron wird enzymatisch durch 17β-Hydroxysteroid-Dehydrogenase 17β- Estradiol gebildet, der Großteil des Estrons aber durch Sulfotransferase in das Konjugat Estronsulfat umgewandelt (M.J. Reed, Breast Cancer Res. Treat. 30 (1994) 7-17). Estronsulfat ist daher das am reichlichsten im Organismus vorkommende Estrogen.There are two main ways of estrogen biosynthesis in the organism, the and the Sultataseweg. In postmenopausal women, estrogen formation is among other things about continued the Momataseeweg. It runs through peripheral conversion of androstenedione Estron, mediated by the aromatase enzyme complex (M.J. Reed, Breast Cancer Res. Treat. 30 (1994) 7-17). Estrone is converted enzymatically by 17β-hydroxysteroid dehydrogenase 17β- Estradiol formed, but the majority of the estrone by sulfotransferase into the conjugate estrone sulfate (M.J. Reed, Breast Cancer Res. Treat. 30 (1994) 7-17). Estrone sulfate is therefore the most most abundant estrogen in the organism.

Für die intratumorale Estrogenbildung kommt hauptsächlich der sogenannte Sulfataseweg in Frage. Hierbei erfolgt die enzymatische Hydrolyse von Estronsultat durch Estronsulfatase zu Estron, woraus sekundär 17β-Estradiol gebildet wird (M.J. Reed, Breast Cancer Res. Treat. 30 (1994) 7-17). Sultataseaktivität läßt sich in den meisten der bisher untersuchten Mammatumoren nachweisen, Momataseaktivität dagegen nur in etwa 50-60% aller Tumoren (M.J. Reed, Breast Cancer Res. Treat. 30 (1994) 7-17). Quantitativ gesehen überragt die Estronbildung aus Estronsulfat durch Estronsulfatase die Bildung von Androstendion über die Aromatase, so daß dem Sultataseweg ein größeres Gewicht beizumessen ist. Hierfür sprechen ferner: die etwa 10fach höheren Plasmaspiegel von Estronsulfat im Vergleich zum nicht konjugierten Estron und Estradiol (M.J. Reed, A. Purohit, Rev. Endocr. Relat. Cancer 45 (1993 1-12); die bedeutend höhere Plasmahalbwertszeit von Estronsultat (T1/2 = 7.5 h) gegenüber dem freien Estron (T1/2 = 30 min) (M.J. Reed, A. Purohit, Rev. Endocr. Relat. Cancer 45 (1993 1-12); die in vitro nachgewiesene, 1000mal höhere Sulfataseaktivität in Mammatumorgeweben im Vergleich zur Aromataseaktivität (A. Purohit, M.J. Reed, Int. J. Cancer 50 (1992) 901-905). Estronsulfatase nimmt offensichtlich eine Schlüsselstellung in der Regulation der Estrogenbildung in Mammatumoren ein.The so-called sulfatase pathway is primarily suitable for intratumoral estrogen formation. Here, the enzymatic hydrolysis of estrone result by estrone sulfatase to estrone takes place, from which secondary 17β-estradiol is formed (MJ Reed, Breast Cancer Res. Treat. 30 (1994) 7-17). Sultatase activity can be detected in most of the mammary tumors examined to date, but momatase activity only in about 50-60% of all tumors (MJ Reed, Breast Cancer Res. Treat. 30 (1994) 7-17). Seen quantitatively, the formation of estrone from estrone sulfate by estrone sulfatase exceeds the formation of androstenedione over the aromatase, so that the Sultatase pathway has to be given greater weight. This is also supported by: the approximately 10 times higher plasma levels of estrone sulfate compared to non-conjugated estrone and estradiol (MJ Reed, A. Purohit, Rev. Endocr. Relat. Cancer 45 (1993 1-12); the significantly higher plasma half-life of estrone result (T. 1/2 = 7.5 h) compared to the free estrone (T 1/2 = 30 min) (MJ Reed, A. Purohit, Rev. Endocr. Relat. Cancer 45 (1993 1-12); the in vitro proven, 1000 times higher Sulfatase activity in breast tumor tissues compared to aromatase activity (A. Purohit, MJ Reed, Int. J. Cancer 50 (1992) 901-905). Estrone sulfatase obviously plays a key role in the regulation of estrogen formation in breast tumors.

Um die Estrogeneinwirkung auf Gewebe herabzusetzen, richteten sich die meisten Anstrengungen bisher vorrangig auf die Entwicklung spezifischer Momataseinhibitoren. Obgleich solche wirksamen Verbindungen wie Aminoglutethimid und 4-Hydroxyandrostendion die periphere Momatase- Aktivität in vivo größtenteils zu hemmen vermögen, konnten die Plasmakonzentrationen an Estron und Estronsulfat nur zu etwa 50% gesenkt werden (A. Purohit, N.M. Howarth, B.V. Potter, M.J. Reed, J. Steroid Biochem. Mol. Biol. 48 (1994) 523-527). Dies ist für eine therapeutisch brauchbare Senkung des Estronspiegels jedoch unzureichend, und man muß zur Erzielung eines tumoristatischen Effekts weitere Wege der Estronbereitstellung unterbrechen. So erscheint es als möglich, bereits durch alleinige Anwendung von Inhibitoren der Sultatase-Aktivität oder deren Kombination mit Aromatase-Inhibitoren eine effektivere Form der endokrinen Therapie des Mammakarzinoms entwickeln zu können. Steroidsulfatase-Inhibitoren könnten auch bei denjenigen Patienten mit Vorteil eingesetzt werden, deren Tumoren nur eine geringe oder keine Aromataseaktivität aufweisen, oder die gegenüber einem Aromatasehemmer resistent geworden sind.Most efforts have been made to reduce the effects of estrogen on tissues So far primarily on the development of specific Momatase inhibitors. Although such effective Compounds such as aminoglutethimide and 4-hydroxyandrostenedione the peripheral momatase The plasma concentrations of estrone were able to largely inhibit activity in vivo and estrone sulfate can only be reduced by about 50% (A. Purohit, N.M. Howarth, B.V. Potter, M.J. Reed, J. Steroid Biochem. Mol. Biol. 48 (1994) 523-527). This is for a therapeutically useful one Lowering the level of estrone, however, is inadequate and you have to achieve a tumoristatic Effectively interrupt further ways of providing estrone. So it seems possible already by the sole use of inhibitors of sultatase activity or their combination with Aromatase inhibitors are a more effective form of endocrine therapy for breast cancer to be able to develop. Steroid sulfatase inhibitors could also be beneficial in those patients are used whose tumors have little or no aromatase activity, or who have become resistant to an aromatase inhibitor.

Die bekannten Verbindungen mit Steroidsulfatase hemmenden Eigenschaften sind vorwiegend steroidaler und nur wenige nichtsteroidaler Herkunft (H. Birnböck, E. von Angerer, Biochem. Pharmacol. 39 (1990) 1709-1713; N.M. Howarth, A. Purohit, M.J. Reed, B.V. Potter, J. Med. Chem. 37 (1994) 219-221; L.W.L. Woo, A. Purohit, M.J. Reed, B.V.L. Potter, J. Med. Chem. 39 (1996) 1349-1351). Estron-3-O-sulfamat ist der am stärksten bisher bekannte Steroidsulfatseinhibitor (Plazenta, Estronsulfatase, IC50 = 80 nM; N.M. Howarth, A. Purohit, M.J. Reed, B.V. Potter, J. Med. Chem. 37 (1994) 219-221). Estronsulfamat hemmt, wie in vivo- Untersuchungen an der Ratte ergeben haben, sowohl die Estron- als auch die Dehydroepiandrosteron-Sulfataseaktivität (A. Purohlt, G.J. Williams, B.V.L. Potter, M.J. Reed, Eur. J. Endocrinol. 130 Suppl. 2 (1994) 51). Kürzlich wurde jedoch gefunden, daß nach oraler Verabreichung von Estron-3-O-sulfamat bei Ratten unerwartet hohe systemische Estrogenwirkungen bei geringer Leberbelastung beobachtet werden konnten (W. Elger, S. Schwarz, A. Hedden, G. Reddersen, B. Schneider, J. Steroid Biochem. Mol. Biol. 55 (1995) 395-403). Das Interesse muß sich daher in Zukunft gezielt nichtsteroidalen Hemmern zuwenden, deren Metabolite keine hormonelle Aktivität besitzen.The known compounds with steroid sulfatase inhibitory properties are predominantly steroidal and only a few non-steroidal origin (H. Birnböck, E. von Angerer, Biochem. Pharmacol. 39 (1990) 1709-1713; NM Howarth, A. Purohit, MJ Reed, BV Potter, J. Med. Chem. 37 (1994) 219-221; LWL Woo, A. Purohit, MJ Reed, BVL Potter, J. Med. Chem. 39 (1996) 1349-1351). Estrone-3-O-sulfamate is the most widely known steroid sulfate inhibitor (placenta, estrone sulfatase, IC 50 = 80 nM; NM Howarth, A. Purohit, MJ Reed, BV Potter, J. Med. Chem. 37 (1994) 219- 221). Estrone sulfamate inhibits both estrone and dehydroepiandrosterone sulfatase activity (A. Purohlt, GJ Williams, BVL Potter, MJ Reed, Eur. J. Endocrinol. 130 Suppl. 2 (1994 ) 51). However, it has recently been found that, after oral administration of estrone-3-O-sulfamate in rats, unexpectedly high systemic estrogen effects could be observed with low liver stress (W. Elger, S. Schwarz, A. Hedden, G. Reddersen, B. Schneider, J. Steroid Biochem. Mol. Biol. 55 (1995) 395-403). In future, therefore, the interest must specifically turn to non-steroidal inhibitors, the metabolites of which have no hormonal activity.

Die Aufgabe wird erfindungsgemäß gelöst durch die Bereitstellung von neuen Iminderivaten des Madurahydroxylactons, die sich überraschenderweise als wirksame Hemmer der Steroidsulfatase erwiesen.The object is achieved according to the invention by providing new imine derivatives of the Madura hydroxylactones, which surprisingly prove to be effective inhibitors of steroid sulfatase proven.

Die Erfindung betrifft demgemäß Verbindungen der Formel I
The invention accordingly relates to compounds of the formula I.

worin R1 = H bedeutet und
R2 = H, Alkyl oder substituiertes Alkyl, Alkenyl oder substituiertes Alkenyl, Cycloalkyl oder substituiertes Cycloalkyl, Aryl oder substituiertes Aryl, Aralkyl, ein Rest der Formel
-OR5, worin R5 = H, Alkyl oder substituiertes Alkyl, Alkenyl oder substituiertes Alkenyl, Cycloalkyl oder substituiertes Cycloalkyl, Aryl oder substituiertes Aryl, Aralkyl oder Acyl sein können,
-NR6R7, worin R6 und R7 unabhängig voneinander H, Alkyl oder substituiertes Alkyl, Alkenyl oder substituiertes Alkenyl, Cycloalkyl oder substituiertes Cycloalkyl, Aryl oder substituiertes Aryl, Aralkyl, Acyl bedeuten oder zusammen mit dem an sie geknüpften Stickstoffatom einen Ring bilden,
-NR8-C(Z)-NR9R10, worin Z = O, S, NR11 und R8, R9, R10 und R11 unabhängig voneinander H, Alkyl oder substituiertes Alkyl, Alkenyl oder substituiertes Alkenyl, Cycloalkyl oder substituiertes Cycloalkyl, Aryl oder substituiertes Aryl, Aralkyl, Acyl bedeuten, R11 darüber hinaus auch Cyano oder Nitro, R9 und R10 zusammen mit dem an sie geknüpften Stickstoffatom einen Ring bilden können, und
R3 und R4 unabhängig voneinander für Wasserstoff, Alkyl oder Acyl stehen, sowie Salze von Verbindungen der Formel I.where R 1 = H and
R 2 = H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, aralkyl, a radical of the formula
-OR 5 , where R 5 = H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, aralkyl or acyl,
-NR 6 R 7 , wherein R 6 and R 7 independently of one another are H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, aralkyl, acyl or together with the nitrogen atom attached to them a ring form,
-NR 8 -C (Z) -NR 9 R 10 , wherein Z = O, S, NR 11 and R 8 , R 9 , R 10 and R 11 independently of one another H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, aralkyl, acyl, R 11 can also form cyano or nitro, R 9 and R 10 together with the nitrogen atom attached to them can form a ring, and
R 3 and R 4 are independently hydrogen, alkyl or acyl, and salts of compounds of the formula I.

Im Rahmen dieser Erfindung bedeutet Alkyl C1-C18-Alkyl, insbesondere C1-C8, geradkettig oder verzweigtkettig, Alkenyl C1-C8-Alkenyl, Cycloalkyl kann ein mono-, bi- oder tricyclischer gesättigter Kohlenwasserstoffrest sein und bedeutet insbesondere monocyclisches C3-C8-Cycloalkyl, ferner auch 1-Adamantyl, während unter einem Arylrest insbesondere Phenyl oder substituiertes Phenyl verstanden wird. Substituenten solcher Alkyl-, Alkenyl-, Cycloalkyl- oder Arylreste sind z. B. OH, OAlkyl, OAryl, Halogen, Carboxyl, Cyano, Trifluormethyl, Nitro, Dialkylamino, bei Aryl ferner auch Alkyl. Acyl ist im Rahmen dieser Erfindung C1-C8-Alkanoyl, C1-C8-Alkoxycarbonyl, Aroyl, insbesondere Benzoyl- oder substituiertes Benzoyl (worin die Substituenten die gleichen wie bei substituiertem Aryl sind), und gegebenenfalls durch ein oder zwei C1-C4-Alkylreste substituiertes Carbamoyl oder Sulfamoyl, Arylsulfonyl speziell Phenylsulfonyl oder substituiertes Phenylsulfonyl (worin die Substituenten die gleichen wie bei substituiertem Aryl sind). Reste R6 und R7 bzw. R9 und R10, die zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen Ring bilden, sind z. B. C2-C8-Alkylenresten, insbesondere C4-C6-Alkylenreste. Solche Alkylenreste können durch eines oder mehrere, insbesondere eins oder zwei, Heteroatome aus der Gruppe Sauerstoff, Schwefel oder Stickstoff (-NH- oder -NR8-) unterbrochen sein. Salze von Verbindungen der Formel I sind z. B. Alkalimetallsalze, wie z. B. das Natrium- oder Kaliumsalz, oder ein gegebenenfalls substituiertes Ammoniumsalz, wie z. B. Ammonium, Mono-, Di- oder Trialxylammonium oder N-Methyl-D-glucammonium. Im Falle des Vorliegens stereogener C- Atome sind die entsprechenden D- und L-Formen, Enantiomere und Diastereomere sowie Razemate bzw. Enantiomeren- und Diastereomerengemische ebenfalls Gegenstand der Erfindung.In the context of this invention, alkyl means C 1 -C 18 -alkyl, in particular C 1 -C 8 , straight-chain or branched-chain, alkenyl C 1 -C 8 -alkenyl, cycloalkyl can be a mono-, bi- or tricyclic saturated hydrocarbon radical and in particular means monocyclic C 3 -C 8 cycloalkyl, further also 1-adamantyl, while an aryl radical is understood to mean in particular phenyl or substituted phenyl. Substituents of such alkyl, alkenyl, cycloalkyl or aryl radicals are e.g. B. OH, OAlkyl, OAryl, halogen, carboxyl, cyano, trifluoromethyl, nitro, dialkylamino, with aryl also alkyl. In the context of this invention, acyl is C 1 -C 8 alkanoyl, C 1 -C 8 alkoxycarbonyl, aroyl, in particular benzoyl or substituted benzoyl (in which the substituents are the same as in substituted aryl), and optionally by one or two C 1 -C 4 alkyl radicals substituted carbamoyl or sulfamoyl, arylsulfonyl, especially phenylsulfonyl or substituted phenylsulfonyl (in which the substituents are the same as in substituted aryl). R 6 and R 7 or R 9 and R 10 , which together with the nitrogen atom to which they are attached, form a ring are, for. B. C 2 -C 8 alkylene radicals, in particular C 4 -C 6 alkylene radicals. Such alkylene radicals can be interrupted by one or more, in particular one or two, heteroatoms from the group consisting of oxygen, sulfur or nitrogen (-NH- or -NR 8 -). Salts of compounds of formula I are e.g. B. alkali metal salts, such as. B. the sodium or potassium salt, or an optionally substituted ammonium salt, such as. As ammonium, mono-, di- or trialxylammonium or N-methyl-D-glucammonium. If stereogenic C atoms are present, the corresponding D and L forms, enantiomers and diastereomers and racemates or mixtures of enantiomers and diastereomers are likewise the subject of the invention.

Die erfindungsgemäßen Verbindungen werden hergestellt, indem Madurahydroxylacton bzw. Maduransäure (3,9,11,14,15-Pentahydroxy-7-methoxy-10-methyl-1,8,13-trioxo-1,3,5,6,8,13-hexa­ hydronaphthaceno[1,2-f]isobenzofuran) der Formel II
The compounds according to the invention are prepared by Madurahydroxylacton or Maduransäure (3,9,11,14,15-Pentahydroxy-7-methoxy-10-methyl-1,8,13-trioxo-1,3,5,6,8, 13-hexa hydronaphthaceno [1,2-f] isobenzofuran) of the formula II

mit primären Aminoverbindungen der Formel H2N-R2, gegebenenfalls in Form ihrer Salze, umgesetzt werden. Die Reaktion wird unter Verwendung geeigneter Lösungsmittel, z. B. Eisessig, Dioxan oder Tetrahydrofuran, durchgeführt. Die Reaktionstemperatur liegt gewöhnlich zwischen Raumtemperatur und der Siedetemperatur des Lösungsmittels, die Reaktionszeit kann bis zu einigen Stunden betragen.with primary amino compounds of the formula H 2 NR 2 , optionally in the form of their salts. The reaction is carried out using suitable solvents, e.g. B. glacial acetic acid, dioxane or tetrahydrofuran. The reaction temperature is usually between room temperature and the boiling point of the solvent, the reaction time can be up to a few hours.

Erfindungsgemäß hergestellte Verbindungen der Formel I können in an sich bekannter Weise in andere Verbindungen der Formel I überführt werden. So können die erhaltenen Verbindungen der Formel I mit R3 bzw. R4 = H durch Alkylierung oder Acylierung der phenolischen OH-Gruppen in einem zweiten Schritt in O-Alkyl- oder O-Acylderivate, Formel I mit R3 bzw. R4 = Alkyl oder Acyl (z. B. -CO-Alkyl, COO-Alkyl) überführt werden. Dieser Reaktionsschritt wird nach üblichen Methoden der Alkylierung und Acylierung phenolischer OH-Gruppen durchgeführt.Compounds of the formula I prepared according to the invention can be converted into other compounds of the formula I in a manner known per se. Thus, the compounds of formula I obtained with R 3 or R 4 = H by alkylation or acylation of the phenolic OH groups in a second step in O-alkyl or O-acyl derivatives, formula I with R 3 or R 4 = Alkyl or acyl (e.g. -CO-alkyl, COO-alkyl) are transferred. This reaction step is carried out by customary methods of alkylation and acylation of phenolic OH groups.

Die erhaltenen Verbindungen mit R1 = H können nach üblichen Methoden in entsprechende Salze umgewandelt werden, wobei R1 ein Alkalimetallion (z. B. Na⁺, K⁺) oder ein Ammoniumion (NH4⁺, ein Mono-, Di- oder Trialkylammoniumion, z. B. ein Trialkylammoniumion oder ein N-Methyl-D- glucammoniumion) sein kann. Die synthetisierten Verbindungen können mittels üblicher Methoden (z. B. durch Umkristallisation bzw. Säulenchromatographie) gereinigt werden.The compounds obtained with R 1 = H can be converted into corresponding salts by customary methods, where R 1 is an alkali metal ion (for example Na⁺, K⁺) or an ammonium ion (NH 4 ⁺, a mono-, di- or trialkylammonium ion , for example a trialkylammonium ion or an N-methyl-D-glucammonium ion). The synthesized compounds can be purified by means of customary methods (for example by recrystallization or column chromatography).

Die Herstellung des Madurahydroxylactons (Formel II) ist aus der Patentschrift DD 2 85 614 bekannt. Die Ausgangsverbindungen der Formel H2N-R2 sind bekannt oder können nach an sich bekannten Verfahren hergestellt werden.The preparation of the madura hydroxylactone (formula II) is known from the patent specification DD 2 85 614. The starting compounds of the formula H 2 NR 2 are known or can be prepared by processes known per se.

Die erfindungsgemäß hergestellten Verbindungen hemmen die mikrosomale Humanplazenta- Sulfatase. Von besonderer Bedeutung ist, daß die Verbindungen ein nichtsteroidales Grundgerüst besitzen, keine estrogene Aktivität zeigen und in Zellkultur nur eine geringe Cytotoxizität aufweisen.The compounds produced according to the invention inhibit the microsomal human placenta Sulfatase. Of particular importance is that the compounds have a non-steroidal backbone possess no estrogenic activity and have only a low cytotoxicity in cell culture.

Die Verbindungen wurden auf ihre Hemmwirkung (IC50: halbmaximale, hemmende wirksame Konzentration) gegen mikrosomale Humanplazenta-Sulfatase geprüft. Die Ergebnisse der Untersuchungen an repräsentativen Verbindungen der Formel I sind in der Tabelle verzeichnet. Zum Vergleich ist die bekannte, wenn auch strukturell verschiedene Substanz 3-Methyl-1- pentafluorphenylmethyl-6-sulfooxy-2-(4-sulfooxyphenyl)-4-trifluor-methylindol vom Typ des 2- Hydroxyphenylindol-Disulfats mit angegeben (H. Birnböck, E. von Angerer, Biochem. Pharmacol. 11 (1990)1709-1713). Aus den Resultaten geht hervor, daß die erfindungsgemäß dargestellten Substanzen die Hemmwerte der Vergleichssubstanz übertreffen.The compounds were tested for their inhibitory action (IC 50 : half-maximum, inhibitory effective concentration) against microsomal human placenta sulfatase. The results of the tests on representative compounds of the formula I are shown in the table. For comparison, the known, albeit structurally different substance 3-methyl-1-pentafluorophenylmethyl-6-sulfooxy-2- (4-sulfooxyphenyl) -4-trifluoromethylindole of the 2-hydroxyphenylindole disulfate type is also given (H. Birnböck , E. von Angerer, Biochem. Pharmacol. 11 (1990) 1709-1713). The results show that the substances shown according to the invention exceed the inhibitory values of the comparison substance.

Die Verbindungen der Formel I eignen sich auf Grund ihrer Hemmeigenschaften gegenüber Estronsulfatase zur Anwendung in der Therapie hormonabhängiger Krebserkrankungen, insbesondere bei Mammatumoren. Bei solchen Erkrankungen können die Verbindungen der Formel I entweder allein oder mit physiologisch verträglichen Hilfs- oder Trägerstoffen angewandt werden, wobei prinzipiell alle üblichen pharmakologischen Anwendungsformen und physiologisch verträglichen Dosierungen möglich sind.The compounds of the formula I are suitable because of their inhibitory properties Estrone sulfatase for use in the therapy of hormone-dependent cancers, especially with breast tumors. In such diseases, the compounds of formula I can be used either alone or with physiologically compatible auxiliaries or carriers, in principle all the usual pharmacological application forms and physiological tolerable dosages are possible.

Die folgenden Ausführungsbeispiele sollen das Verführen zur Herstellung von Iminderivaten des Madurahydroxylactons näher erläutern, jedoch in keiner Weise einschränken.The following exemplary embodiments are intended to seduce the preparation of imine derivatives of Explain Madura hydroxylactones in more detail, but do not restrict them in any way.

AusführungsbeispieleEmbodiments Darstellung der ThiosemicarbazidePresentation of the thiosemicarbazides

Zu einer Lösung des entsprechenden Isothiocyanats (50 mmol) in Ether (50 ml) tropft man unter Rühren Hydrazinhydrat (100%, 50 mmol). Es setzt eine exotherme Reaktion ein, in deren Verlauf sich erste Kristalle abscheiden. Man kühlt auf 0°C, läßt 1 Std. im Eisbad nachrühren, versetzt mit Petrolether (50 ml) und filtriert das Produkt ab. Das Rohprodukt wird zur Reinigung umkristallisiert.
4-Dodecylthiosemicarbazid, C13H29N3S (259.5), Fp. 69-71°C (EtOH)
4-Cyclopropylthiosemicarbazid, C4H9N3S (131.2), Fp. 94-97°C (EtOH)
4-Cydopentylthiosemicarbazid, C6H13N3S (159.2), Fp. 95-96°C (MeOH-H2O)
4-Cycloheptylthiosemicarbazid, C8H17N3S (187.3), Fp. 129-131°C (EtOH)
4-Cydooctylthiosemicarbazid, C9H19N3S (201.3), Fp. 69-71°C (EtOH)Hydrazine hydrate (100%, 50 mmol) is added dropwise to a solution of the corresponding isothiocyanate (50 mmol) in ether (50 ml) with stirring. An exothermic reaction sets in, in the course of which the first crystals separate out. The mixture is cooled to 0 ° C., left to stir in an ice bath for 1 hour, petroleum ether (50 ml) is added and the product is filtered off. The crude product is recrystallized for cleaning.
4-dodecylthiosemicarbazide, C 13 H 29 N 3 S (259.5), mp 69-71 ° C (EtOH)
4-cyclopropylthiosemicarbazide, C 4 H 9 N 3 S (131.2), mp 94-97 ° C (EtOH)
4-Cydopentylthiosemicarbazid, C 6 H 13 N 3 S (159.2), mp. 95-96 ° C (MeOH-H2O)
4-cycloheptylthiosemicarbazide, C 8 H 17 N 3 S (187.3), mp 129-131 ° C (EtOH)
4-Cydooctylthiosemicarbazid, C 9 H 19 N 3 S (201.3), mp 69-71 ° C (EtOH)

Allgemeine Vorschrift zur Darstellung der Verbindungen 8 bis 27General rule for the representation of connections 8 to 27

Zu einer Lösung von Madurahydroxylacton (0.1 mmol) in Tetrahydrofuran (2 ml) gibt man die entsprechende Aminoverbindung (0.5 mmol) und läßt bis zum vollständigen Umsatz (DC-Kontrolle) rühren. Das Lösungsmittel wird abgezogen und der Rückstand mit Ethanol oder Ether mehrmals ausgezogen, um überschüssiges Reagenz zu entfernen.The solution is added to a solution of madura hydroxylactone (0.1 mmol) in tetrahydrofuran (2 ml) corresponding amino compound (0.5 mmol) and leaves until complete conversion (TLC control) stir. The solvent is removed and the residue with ethanol or ether several times extended to remove excess reagent.

1. Substanz 11. Substance 1

Maduransäure-O-methyloxim (1,9,11,14-Tetrahydroxy-7-methoxy-3-methoxyiminomethyl-10- methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo[a]naphthacen-2-carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 - OCH3, C27H21NO10 (519.5).Maduranic acid-O-methyloxime (1,9,11,14-tetrahydroxy-7-methoxy-3-methoxyiminomethyl-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo [a] naphthacen-2- carboxylic acid), formula I with R 1 = R 3 = R 4 = H, R 2 - OCH 3 , C 27 H 21 NO 10 (519.5).

Ein Gemisch aus Madurahydroxylacton (500 mg; 80%ig), O-Methylhydroxylamin Hydrochlorid (200 mg) und Eisessig (40 ml) wird 30 Min. zum Rückfluß erhitzt. Man läßt über Nacht stehen und saugt die ausgefallenen Kristalle ab (Ausbeute 172 mg), Fp. 267-270°C.
1H-NMR (DMSO-D6): δ (ppm) = 2.05 (s, 3 H, Me-10), 3.79 (s, 3 H, MeO-7), 3.91 (s, 3 H, =NOCH3), 7.22, 7.24 (2 s, 2H, H-4,12), 8.54 (s, 1 H, CH=N), 11.17 (s, 1 H, OH), 13.58 (s, 1 H, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 8.12 (Me-10), 22.35, 28.63 (C-5,6), 60.95, 61.70 (MeO-7, =NOCH3), 170.12 (COOH), 185.47, 187.59 (C-8,13).
FAB-MS (3NBA) m/z = [M + H]⁺: gef. 520.A mixture of madura hydroxylactone (500 mg; 80%), O-methylhydroxylamine hydrochloride (200 mg) and glacial acetic acid (40 ml) is heated to reflux for 30 minutes. The mixture is left to stand overnight and the crystals which have precipitated are filtered off (yield 172 mg), mp. 267-270 ° C.
1 H-NMR (DMSO-D 6 ): δ (ppm) = 2.05 (s, 3 H, Me-10), 3.79 (s, 3 H, MeO-7), 3.91 (s, 3 H, = STILL 3 ), 7.22, 7.24 (2 s, 2H, H-4.12), 8.54 (s, 1 H, CH = N), 11.17 (s, 1 H, OH), 13.58 (s, 1 H, COOH).
13 C-NMR (DMSO-D 6 ): δ (ppm) = 8.12 (Me-10), 22.35, 28.63 (C-5.6), 60.95, 61.70 (MeO-7, = NOCH 3 ), 170.12 (COOH ), 185.47, 187.59 (C-8.13).
FAB-MS (3NBA) m / z = [M + H] ⁺: found 520.

2. Substanz 22. Substance 2

Maduransäure-O-(carboxymethyl)oxim (3-Carboxymethoxyiminomethyl-1,9,11,14-tetra-hydroxy-7- methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo[a]naphthacen-2-carbon-säure), Formel I mit R1 = R3 = R4 = H, R2 = OCH2COOH, C28H21NO12 (563.3).Maduranic acid O- (carboxymethyl) oxime (3-carboxymethoxyiminomethyl-1,9,11,14-tetra-hydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo [a ] naphthacen-2-carbon-acid), formula I with R 1 = R 3 = R 4 = H, R 2 = OCH 2 COOH, C 28 H 21 NO 12 (563.3).

Ein Gemisch aus Madurahydroxylacton (100 mg; 90%ig), O-(Carboxymethyl)hydroxylamin Hydrochlorid (40 mg) und Eisessig (5 ml) wird 3 Std. zum Rückfluß erhitzt. Man läßt über Nacht stehen und saugt die ausgefallenen Kristalle ab (Ausbeute 75 mg), Fp. 255-257°C.
1H-NMR (DMSO-D6): δ (ppm) = 2.10 (s, 3 H, Me-10), 2.8 (br., 4 H, H-5,6), 3.80 (s, 3 H, MeO- 7), 4.70 (s, 2 H, =NOCH2), 7.24, 7.30 (2 s, 2 H, H-4,12), 8.65 (s, 1 H, CH=N), 11.20 (s, 1 H, OH), 13.60 (s, 1 H, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 8.50 (Me-10), 22.20, 29.50 (C-5,6), 61.50 (MeO-7), 70.50 (OCH2COOH), 170.2 (2 x COOH), 185.54, 187.57 (C-8,13).
FAB-MS (3NBA) m/z = [M + H]⁺: gef. 564.A mixture of madura hydroxylactone (100 mg; 90%), O- (carboxymethyl) hydroxylamine hydrochloride (40 mg) and glacial acetic acid (5 ml) is heated to reflux for 3 hours. The mixture is left to stand overnight and the crystals which have precipitated are filtered off (yield 75 mg), mp. 255-257 ° C.
1 H-NMR (DMSO-D 6 ): δ (ppm) = 2.10 (s, 3 H, Me-10), 2.8 (br., 4 H, H-5.6), 3.80 (s, 3 H, MeO- 7), 4.70 (s, 2 H, = NOCH 2 ), 7.24, 7.30 (2 s, 2 H, H-4.12), 8.65 (s, 1 H, CH = N), 11.20 (s, 1 H, OH), 13.60 (s, 1 H, COOH).
13 C-NMR (DMSO-D 6 ): δ (ppm) = 8.50 (Me-10), 22.20, 29.50 (C-5.6), 61.50 (MeO-7), 70.50 (OCH 2 COOH), 170.2 ( 2 x COOH), 185.54, 187.57 (C-8.13).
FAB-MS (3NBA) m / z = [M + H] ⁺: found 564.

3. Substanz 33. Substance 3

Maduransäure-dimethylhydrazon (3-Dimethylhydrazonomethyl-1,9,11,14-tetrahydroxy-7-methoxy- 10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo[a]naphthacen-2-carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 = N(CH3)2, C28H24N2O9 (532.5).Maduranoic acid dimethylhydrazone (3-dimethylhydrazonomethyl-1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo [a] naphthacen-2-carboxylic acid) , Formula I with R 1 = R 3 = R 4 = H, R 2 = N (CH 3 ) 2 , C 28 H 24 N 2 O 9 (532.5).

Zu einer Lösung von Madurahydroxylacton (54 mg 91%ig) in trockenem Tetrahydrofuran (2 ml) gibt man N,N-Dimethylhydrazin (8.4 µl). Die dunkelrote Lösung wird 30 min bei Raumtemperatur gerührt. Man fällt das Produkt mit Petrolether und saugt den dunkelroten Feststoff ab (Ausbeute 58 mg).
1H-NMR (DMSO-D6): δ (ppm) = 2.02 (s, 3 H, Me-10), 2.67, 2.79 (2 x br., 4 H, H-5,6), 2.96 (s, 6 H, NMe2), 3.77 (s, 3H, MeO-7), 7.22,7.30,7.51(3 s, 3H, H-4,12, CH=N), 11.07 (br., 1H, OH), 13.57 (s, 1 H, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 8.12 (Me-10), 22.54, 28.93 (C-5,6), 42.27 (Me2N), 60.92 (MeO-7), 106.33, 114.70 (C-4,12), 109.65, 113.83, 116.75, 117.32, 118.41, 121.63, 130.20, 130.62, 136.57, 143.11, 146.16, 150.84, 155.25, 156.08, 162.01, 162.42 (Cq), 128.86 (CH=N), 170.89 (COOH), 185.41, 187.68 (C-8,13).
FAB-MS (3NBA) [M + H]⁺: m/z = gef. 533.N, N-dimethylhydrazine (8.4 μl) is added to a solution of madura hydroxylactone (54 mg 91%) in dry tetrahydrofuran (2 ml). The dark red solution is stirred for 30 min at room temperature. The product is precipitated with petroleum ether and the dark red solid is filtered off with suction (yield 58 mg).
1 H-NMR (DMSO-D 6 ): δ (ppm) = 2.02 (s, 3 H, Me-10), 2.67, 2.79 (2 x br., 4 H, H-5.6), 2.96 (s , 6 H, NMe2), 3.77 (s, 3H, MeO-7), 7.22.7.30.7.51 (3 s, 3H, H-4.12, CH = N), 11.07 (br., 1H, OH), 13.57 (s, 1H, COOH).
13 C-NMR (DMSO-D 6 ): δ (ppm) = 8.12 (Me-10), 22.54, 28.93 (C-5.6), 42.27 (Me2N), 60.92 (MeO-7), 106.33, 114.70 ( C-4.12), 109.65, 113.83, 116.75, 117.32, 118.41, 121.63, 130.20, 130.62, 136.57, 143.11, 146.16, 150.84, 155.25, 156.08, 162.01, 162.42 (Cq), 128.86 (CH = N), 170.89 (COOH), 185.41, 187.68 (C-8.13).
FAB-MS (3NBA) [M + H] ⁺: m / z = found 533.

4. Substanz 44. Substance 4

Maduransäure-acethydrazon (3-Acethydrazonomethyl-1,9,11,14-tetrahydroxy-7-methoxy-10-methyl- 8,13-dioxo-5,6,8,13-tetrahydrobenzo[a]naphthacen-2-carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 = NHCOCH3, C28H22N2O10 (546.5).Maduranoic acid acethydrazone (3-acethydrazonomethyl-1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo [a] naphthacen-2-carboxylic acid) , Formula I with R 1 = R 3 = R 4 = H, R 2 = NHCOCH 3 , C 28 H 22 N 2 O 10 (546.5).

Zu einer heißen Lösung von Madurahydroxylacton (54 mg, 91%ig) in Eisessig (4 ml) gibt man Acethydrazid (9 mg) und erhitzt 30 min zum Rückfluß. Nach dem Abkühlen filtriert man den roten Feststoff ab und wäscht mit Ether nach (Ausbeute 51 mg, E/Z-Gemisch).
1H-NMR (DMSO-D6): 8 (ppm) = 2.02 (s, 3 H, Me-10), 2.20 (s, 3 H, MeCO), 2.66-2.90 (m, 4 H, H-5,6), 3.77 (s, 3 H, MeO-7), 7.21 (s, 1 H, H-12), 7.34, 7.40 (2 s, 1 H, H-4), 8.30, 8.51(2 s, 1 H, CH-N), 11.12 (br., 1 H, OH), 11.36, 11.53 (2 s, 1 H, OH), 13.53 (s, 1 H, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 8.13 (Me-10), 22.44, 28.76 (C-5,6), 60.99 (MeO-7), 106.39 (C- 12), 115.69, 116.28 (C-4), 109.64, 113.89, 118.32, 118.49, 118.90 119.89, 120.06, 122.15, 129.48, 130.56, 133.67, 134.25, 143.47, 143.93, 146.67, 150.76, 154.66, 155.37, 156.16, 156.35, 162.07, 162.44,165.78, 169.98, 170.32, 171.96, 172.19 (Cq), 140.98 (CH=N), 185.41, 187.70 (C-8,13).Acethydrazide (9 mg) is added to a hot solution of madura hydroxylactone (54 mg, 91%) in glacial acetic acid (4 ml) and the mixture is heated under reflux for 30 min. After cooling, the red solid is filtered off and washed with ether (yield 51 mg, E / Z mixture).
1 H NMR (DMSO-D 6 ): 8 (ppm) = 2.02 (s, 3 H, Me-10), 2.20 (s, 3 H, MeCO), 2.66-2.90 (m, 4 H, H-5 , 6), 3.77 (s, 3 H, MeO-7), 7.21 (s, 1 H, H-12), 7.34, 7.40 (2 s, 1 H, H-4), 8.30, 8.51 (2 s, 1 H, CH-N), 11.12 (br., 1 H, OH), 11.36, 11.53 (2 s, 1 H, OH), 13.53 (s, 1 H, COOH).
13 C-NMR (DMSO-D 6 ): δ (ppm) = 8.13 (Me-10), 22.44, 28.76 (C-5.6), 60.99 (MeO-7), 106.39 (C-12), 115.69, 116.28 (C-4), 109.64, 113.89, 118.32, 118.49, 118.90 119.89, 120.06, 122.15, 129.48, 130.56, 133.67, 134.25, 143.47, 143.93, 146.67, 150.76, 154.66, 155.37, 156.16, 156.35, 162.07, 162.44, 165.78, 169.98, 170.32, 171.96, 172.19 (Cq), 140.98 (CH = N), 185.41, 187.70 (C-8.13).

5. Substanz 55. Substance 5

Maduransäure-benzhydrazon (3-Benzhydrazonomethyl-1,9,11,14-tetrahydroxy-7-methoxy-10- methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo[a]naphthacen-2-carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 = NHCOC6H5, C33H24N2O10 (608.6).Maduranic acid benzhydrazone (3-benzhydrazonomethyl-1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo [a] naphthacen-2-carboxylic acid) , Formula I with R 1 = R 3 = R 4 = H, R 2 = NHCOC 6 H 5 , C 33 H 24 N 2 O 10 (608.6).

Ein Gemisch aus Madurahydroxylacton (610 mg) und Benzhydrazid (140 mg) in Eisessig (20 ml) wird 30 Min. zum Rückfluß erhitzt. Das nach dem Abkühlen ausgefallene Rohprodukt wird mit Tetrahydrofuran-Petrolether umgefällt (Ausbeute 450 mg), Fp. 268-270°C.
1H-NMR (DMSO-D6): δ (ppm) = 2.07 (s, 3 H, Me-10), 2.7 (m, 4 H, H-5,6), 3.80 (s, 3 H, MeO-7), 7.27, 7.48 (2 s, 2 H, H-4,12), 8.91 (2 s, 1 H, CH=N), 11.19 (br., 1 H, OH), 12.08 (s, 1 H, OH), 13.58 (s, 1 H, OH).
13C-NMR (DMSO-D6): δ (ppm) = 8.16 (Me-10), 22.49, 28.84 (C-5,6), 61.01 (MeO-7), 170.13 (COOH), 185.46, 187.70 (C-8,13).
FAB-MS (3NBA) [M + H]⁺: m/z = gef. 609.A mixture of madura hydroxylactone (610 mg) and benzhydrazide (140 mg) in glacial acetic acid (20 ml) is heated to reflux for 30 min. The crude product which has precipitated after cooling is reprecipitated with tetrahydrofuran-petroleum ether (yield 450 mg), mp. 268-270 ° C.
1 H NMR (DMSO-D 6 ): δ (ppm) = 2.07 (s, 3 H, Me-10), 2.7 (m, 4 H, H-5.6), 3.80 (s, 3 H, MeO -7), 7.27, 7.48 (2 s, 2 H, H-4.12), 8.91 (2 s, 1 H, CH = N), 11.19 (br., 1 H, OH), 12.08 (s, 1 H, OH), 13.58 (s, 1H, OH).
13 C-NMR (DMSO-D 6 ): δ (ppm) = 8.16 (Me-10), 22.49, 28.84 (C-5.6), 61.01 (MeO-7), 170.13 (COOH), 185.46, 187.70 ( C-8.13).
FAB-MS (3NBA) [M + H] ⁺: m / z = found 609.

6. Substanz 66. Substance 6

Maduransäure-3,4-dihydroxybenzhydrazon (3-(3,4-Dihydroxybenzliydrazonomethyl)-1,9,11,14- tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo[a]-naphthacen-2- carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 = NHCOC6H3(OH)2, C33H24N2O12 (640.6).Maduranic acid 3,4-dihydroxybenzhydrazone (3- (3,4-dihydroxybenzliydrazonomethyl) -1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13- tetrahydrobenzo [a] -naphthacen-2-carboxylic acid), formula I with R 1 = R 3 = R 4 = H, R 2 = NHCOC 6 H 3 (OH) 2 , C 33 H 24 N 2 O 12 (640.6).

Ein Gemisch aus Madurahydroxylacton (500 mg, 80%ig), 3,4-Dihydroxybenzhydrazid (200 mg) und Eisessig (10 ml) wird 2 h zum Rückfluß erhitzt. Man läßt über Nacht stehen und saugt die ausgefallenen Kristalle ab (Ausbeute 400 mg), Fp. 262-266°C.
1H-NMR (DMSO-D6): δ (ppm) = 2.08 (s, 3 H, Me-10), 2.79 (m, 4 H, H-5,6), 3.80 (s, 3 H, MeO- 7), 6.80, 6.84, 7.28 (3 m, 3 H, Aryl-H), 7.38, 7.47 (2 s, 2 H, H-4,12), 8.83 (s, 1 H, CH=N), 9.50, 9.70 (2 s, 2H, OH, Benzhydrazon), 11.20, 11.80 (2 s, 2H, OH), 13.60 (s, 1 H, COOH.
FAB-MS (3NBA) [M + H]⁺: m/z = gef. 641. A mixture of madura hydroxylactone (500 mg, 80%), 3,4-dihydroxybenzhydrazide (200 mg) and glacial acetic acid (10 ml) is heated to reflux for 2 h. The mixture is left to stand overnight and the crystals which have precipitated are filtered off (yield 400 mg), mp. 262-266 ° C.
1 H NMR (DMSO-D 6 ): δ (ppm) = 2.08 (s, 3 H, Me-10), 2.79 (m, 4 H, H-5.6), 3.80 (s, 3 H, MeO - 7), 6.80, 6.84, 7.28 (3 m, 3 H, aryl-H), 7.38, 7.47 (2 s, 2 H, H-4.12), 8.83 (s, 1 H, CH = N), 9.50, 9.70 (2 s, 2H, OH, benzhydrazone), 11.20, 11.80 (2 s, 2H, OH), 13.60 (s, 1 H, COOH.
FAB-MS (3NBA) [M + H] ⁺: m / z = found 641.

7. Substanz 77. Substance 7

Maduransäure-tosylhydrazon (1,9,11,14-Tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-3- tosylhydrazonomethyl-5,6,8,13-tetrahydrobenzo[a]naphthacen-2-carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 = NHS(O)2C6H4CH3, C33H26N2O11S (658.7).Maduranic acid tosylhydrazone (1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-3-tosylhydrazonomethyl-5,6,8,13-tetrahydrobenzo [a] naphthacen-2-carboxylic acid) , Formula I with R 1 = R 3 = R 4 = H, R 2 = NHS (O) 2 C 6 H 4 CH 3 , C 33 H 26 N 2 O 11 S (658.7).

Ein Gemisch aus Madurahydroxylacton (250 mg, 80%ig), Tosylhydrazid (170 mg) und Eisessig (10 ml) wird 30 Min. zum Rückfluß erhitzt. Die erhaltenen roten Kristalle werden mit heißem Eisessig gewaschen ab (Ausbeute 400 mg), Fp. 262-266°C.
1H-NMR (DMSO-D6): δ (ppm) = 2.10, 2.40 (2 s, 6 H, Me-10, Me-Tosyl), 3.85 (s, 3 H, MeO-7), 7.18, 7.28 (2 s, 2 H, H-4,12), 7.41, 7.46, 7.78, 7.81 (4 m, 4 H, Tosyl-H), 8.91 (s, 1 H, CH=N), 11.19, 11.65 (2 s, 2H, OH), 13.55 (s, 1H, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 8.12 (Me-10), 20.95 (Me, Tosyl), 22.37, 28.79 (C-5,6), 61.01 (MeO-7), 127.14, 129.66 (CH, Tosyl), 146.56 (CH=N), 170.05 (COOH), 185.48, 187.70 (C-8,13).
FAB-MS (3NBA) [M + H]⁺: m/z = gef. 658.A mixture of madura hydroxylactone (250 mg, 80%), tosyl hydrazide (170 mg) and glacial acetic acid (10 ml) is heated to reflux for 30 minutes. The red crystals obtained are washed with hot glacial acetic acid (yield 400 mg), mp. 262-266 ° C.
1 H NMR (DMSO-D 6 ): δ (ppm) = 2.10, 2.40 (2 s, 6 H, Me-10, Me-Tosyl), 3.85 (s, 3 H, MeO-7), 7.18, 7.28 (2 s, 2 H, H-4.12), 7.41, 7.46, 7.78, 7.81 (4 m, 4 H, Tosyl-H), 8.91 (s, 1 H, CH = N), 11.19, 11.65 (2 s, 2H, OH), 13.55 (s, 1H, COOH).
13 C-NMR (DMSO-D 6 ): δ (ppm) = 8.12 (Me-10), 20.95 (Me, Tosyl), 22.37, 28.79 (C-5.6), 61.01 (MeO-7), 127.14, 129.66 (CH, Tosyl), 146.56 (CH = N), 170.05 (COOH), 185.48, 187.70 (C-8.13).
FAB-MS (3NBA) [M + H] ⁺: m / z = found 658.

8. Substanz 88. Substance 8

Maduransäure-semicarbazon (1,9,11,14-Tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-3- semicarbazonomethyl-5,6,8,13-tetrahydrobenzo[a]naphthacen-2-carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 = NHC(O)NH2, C27H21N3O10 (547.5).
1H-NMR (DMSO-D6): δ (ppm) = 2.07 (s, 3 H, Me-10), 2.63-2.86 (m, 4 H, H-5,6), 3.77 (s, 3 H, MeO-7), 7.23, 7.35 (2 d, 2 H, H-4,12), 7.86, 8.28 (2 br. s, 2 H), 8.02 (br., 2 H, NH2), 8.92 (s, 1 H), 10.25 (s, 1 H, NH), 13.63 (s, 1 H, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 8.63 (Me-10), 22.96, 29.22 (C-5,6), 61.53 (MeO-7), 106.86, 116.71 (C-1,12), 110.23, 114.68, 118.89, 119.26, 119.91, 122.58, 130.44, 131.30, 134.66, 143.59, 146.90, 151.31, 155.32, 156.59, 157.07, 162.58, 162.90, 170.57 (Cq), 138.19 (CH=N), 186.06, 188.05 (C-8,13).
FAB-MS (3NBA) [M + H]⁺): m/z = gef. 548.Maduranic acid semicarbazone (1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-3-semicarbazonomethyl-5,6,8,13-tetrahydrobenzo [a] naphthacen-2-carboxylic acid) , Formula I with R 1 = R 3 = R 4 = H, R 2 = NHC (O) NH 2 , C 27 H 21 N 3 O 10 (547.5).
1 H NMR (DMSO-D 6 ): δ (ppm) = 2.07 (s, 3 H, Me-10), 2.63-2.86 (m, 4 H, H-5.6), 3.77 (s, 3 H) , MeO-7), 7.23, 7.35 (2 d, 2 H, H-4.12), 7.86, 8.28 (2 br. S, 2 H), 8.02 (br., 2 H, NH 2 ), 8.92 ( s, 1H), 10.25 (s, 1H, NH), 13.63 (s, 1H, COOH).
13 C NMR (DMSO-D 6 ): δ (ppm) = 8.63 (Me-10), 22.96, 29.22 (C-5.6), 61.53 (MeO-7), 106.86, 116.71 (C-1.12 ), 110.23, 114.68, 118.89, 119.26, 119.91, 122.58, 130.44, 131.30, 134.66, 143.59, 146.90, 151.31, 155.32, 156.59, 157.07, 162.58, 162.90, 170.57 (Cq), 138.19 (CH = N), 186.06, 188.05 (C-8.13).
FAB-MS (3NBA) [M + H] ⁺): m / z = found 548.

9. Substanz 99. Substance 9

Maduransäure-thiosemicarbazon (1,9,11,14-Tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-3- thiosemicarbazonomethyl-5,6,8,13-tetrahydrobenzo[a]naphthacen-2-carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 = NHC(S)NH2, C27H21N3O9S (563.5).
1H-NMR (DMSO-D6): δ (ppm) = 2.06 (s, 3 H, Me-10), 2.67-2.95 (m, 4 H, H-5,6), 3.79 (s, 3 H, MeO 7), 7.27, 7.67 (2 d, 2 H, H-4,12), 7.86, 8.28 (2 br. s, 2 H), 8.42 (s, 1 H, CH N), 11.61 (s, 1 H, =N-NH), 13.56 (s, 1 H, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 8.19 (Me-10), 22.44, 28.68 (C-5,6), 61.07 (MeO-7), 106.38, 116.80 (C-4,12), 109.72, 114.00, 118.43, 119.13, 120.00, 122.18, 129.62, 130.69, 133.48, 143.38, 146.68, 150.81, 154.59, 156.20, 162.11, 162.45, 170.15, 178.24 (Cq), 140.55 (CH=N), 185.53, 187.74 (C-8,13).
FAB-MS (3NBA) [M + H]⁺: m/z = gef. 564.Maduranoic acid thiosemicarbazone (1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-3-thiosemicarbazonomethyl-5,6,8,13-tetrahydrobenzo [a] naphthacen-2-carboxylic acid) , Formula I with R 1 = R 3 = R 4 = H, R 2 = NHC (S) NH 2 , C 27 H 21 N 3 O 9 S (563.5).
1 H NMR (DMSO-D 6 ): δ (ppm) = 2.06 (s, 3 H, Me-10), 2.67-2.95 (m, 4 H, H-5.6), 3.79 (s, 3 H) , MeO 7), 7.27, 7.67 (2 d, 2 H, H-4.12), 7.86, 8.28 (2 br. S, 2 H), 8.42 (s, 1 H, CH N), 11.61 (s, 1 H, = N-NH), 13.56 (s, 1 H, COOH).
13 C NMR (DMSO-D 6 ): δ (ppm) = 8.19 (Me-10), 22.44, 28.68 (C-5.6), 61.07 (MeO-7), 106.38, 116.80 (C-4.12 ), 109.72, 114.00, 118.43, 119.13, 120.00, 122.18, 129.62, 130.69, 133.48, 143.38, 146.68, 150.81, 154.59, 156.20, 162.11, 162.45, 170.15, 178.24 (Cq), 140.55 (CH = N), 185.53, 187.74 (C-8.13).
FAB-MS (3NBA) [M + H] ⁺: m / z = found 564.

10. Substanz 1010. Substance 10

Maduransäure-4-methylthiosemicarbazon (1,9,11,14-Tetrahydroxy-7-methoxy-10-methyl-8,13- dioxo-3-(4-methylthiosemicarbazono)methyl-5,6,8,13-tetrahydrobenzo[a]naphthacen-2-carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 = NHC(S)NHCH3, C28H23N3O9S (577.6).
1H-NMR (DMSO-D6): δ (ppm) = 2.07 (s, 3 H, Me-10), 2.71-2.91 (m, 4 H, H-5,6), 3.05 (d, J = 4.2 Hz, 3 H, NCH3), 3.80 (s, 3 H, MeO-7), 7.27, 7.64 (2 d, 2 H, H-4,12), 8.02 (br. 2 H, NH2), 8.34 15 (br. d, J = 4.2 Hz, 1 H, NH), 8.46 (s, 1 H, CH=N), 11.06 (br., 1 H, OH), 11.58 (s, 1 H, =N-NH), 13.53 (s, 1 H, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 7.99 (Me-10), 22.37, 28.70 (C-5,6), 30.72 (NMe), 60.95 (MeO- 7), 106.32, 116.34 (C-4,12), 109.65, 113.93, 118.40, 118.72, 119.90, 120.07, 129.55, 130.60, 133.77, 140.22, 143.36, 146.45, 150.72, 154.86, 156.09, 161.99, 162.35, 170.02, 177.99 (Cq), 20 140.22 (CH=N), 185.39, 187.62 (C-8,13).
FAB-MS (3NBA) [M + H]⁺: m/z = gef. 578.Maduranic acid 4-methylthiosemicarbazone (1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-3- (4-methylthiosemicarbazono) methyl-5,6,8,13-tetrahydrobenzo [a ] naphthacen-2-carboxylic acid), formula I with R 1 = R 3 = R 4 = H, R 2 = NHC (S) NHCH 3 , C 28 H 23 N 3 O 9 S (577.6).
1 H NMR (DMSO-D 6 ): δ (ppm) = 2.07 (s, 3 H, Me-10), 2.71-2.91 (m, 4 H, H-5.6), 3.05 (d, J = 4.2 Hz, 3 H, NCH 3 ), 3.80 (s, 3 H, MeO-7), 7.27, 7.64 (2 d, 2 H, H-4.12), 8.02 (br. 2 H, NH 2 ), 8.34 15 (br. D, J = 4.2 Hz, 1 H, NH), 8.46 (s, 1 H, CH = N), 11.06 (br., 1 H, OH), 11.58 (s, 1 H, = N -NH), 13.53 (s, 1H, COOH).
13 C-NMR (DMSO-D 6 ): δ (ppm) = 7.99 (Me-10), 22.37, 28.70 (C-5.6), 30.72 (NMe), 60.95 (MeO-7), 106.32, 116.34 ( C-4.12), 109.65, 113.93, 118.40, 118.72, 119.90, 120.07, 129.55, 130.60, 133.77, 140.22, 143.36, 146.45, 150.72, 154.86, 156.09, 161.99, 162.35, 170.02, 177.99 (Cq), 20 140.22 (CH = N), 185.39, 187.62 (C-8.13).
FAB-MS (3NBA) [M + H] ⁺: m / z = found 578.

11. Substanz 1111. Substance 11

Maduransäure-4-propylthiosemicarbazon (1,9,11,14-Tetrahydroxy-7-methoxy-10-methyl-8,13- dioxo-3-(4-propylthiosemicarbazono)methyl-5,6,8,13-tetrahydrobenzo[a]naphthacen-2-carbon­ säure), Formel I mit R1 = R3 = R4 = H, R2 = NHC(S)NH(CH2)2CH3, C30H27N3O9S (605.6).
1H-NMR (DMSO-D6): δ (ppm) = 1.07 (t, 3 H, CH3, Propyl), 1.42-1.67 (m, 2 H, CH2, Propyl), 2.05 (s, 3 H, Me-10), 2.66-2.91 (m, 4 H, H-5,6), 3.78 (s, 3 H, MeO-7), 7.26, 7.55 (2 s, 2 H, H- 4,12), 8.36 (m, 1 H, NH-propyl), 8.45 (s, 1 H, CH=N), 11.58 (s, 1 H, =N-NH), 13.55 (s, 1 H, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 8.23 (Me-10), 11.27 (CH3, Propyl), 22.14, 45.32 ((CH2)2, Propyl), 22.51, 28.87 (C-5,6), 61.13 (MeO-7), 106.44, 116.69 (C-4,12), 109.78, 114.17, 118.52, 119.05, 120.14, 122.24, 129.83, 130.81, 133.78, 143.43, 146.59, 150.84, 151.13, 156.29, 162.17, 162.50, 170.25, 177.19 (Cq), 140.67 (CH=N), 185.62, 187.67 (C-8,13).
FAB-MS (3NBA) [M + H]⁺: m/z = gef. 606. Maduranic acid 4-propylthiosemicarbazone (1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-3- (4-propylthiosemicarbazono) methyl-5,6,8,13-tetrahydrobenzo [a ] naphthacen-2-carbon acid), formula I with R 1 = R 3 = R 4 = H, R 2 = NHC (S) NH (CH 2 ) 2 CH 3 , C 30 H 27 N 3 O 9 S (605.6 ).
1 H NMR (DMSO-D 6 ): δ (ppm) = 1.07 (t, 3 H, CH 3 , propyl), 1.42-1.67 (m, 2 H, CH 2 , propyl), 2.05 (s, 3 H) , Me-10), 2.66-2.91 (m, 4 H, H-5.6), 3.78 (s, 3 H, MeO-7), 7.26, 7.55 (2 s, 2 H, H-4.12) , 8.36 (m, 1 H, NH-propyl), 8.45 (s, 1 H, CH = N), 11.58 (s, 1 H, = N-NH), 13.55 (s, 1 H, COOH).
13 C-NMR (DMSO-D 6 ): δ (ppm) = 8.23 (Me-10), 11.27 (CH 3 , propyl), 22.14, 45.32 ((CH 2 ) 2 , propyl), 22.51, 28.87 (C- 5.6), 61.13 (MeO-7), 106.44, 116.69 (C-4.12), 109.78, 114.17, 118.52, 119.05, 120.14, 122.24, 129.83, 130.81, 133.78, 143.43, 146.59, 150.84, 151.13, 156.29 , 162.17, 162.50, 170.25, 177.19 (Cq), 140.67 (CH = N), 185.62, 187.67 (C-8.13).
FAB-MS (3NBA) [M + H] ⁺: m / z = found 606.

12. Substanz 1212. Substance 12

Maduransäure-4-isopropylthiosemicarbazon (1,9,11,14-Tetrahydroxy-3-(4-isopropylthiosemi­ carbazono)methyl-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo[a]naphthacen-2- carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 = NHC(S)NHCH(CH3)2, C30H27N3O9S (605.6).
1H-NMR (DMSO-D6): δ (ppm) = 1.24 (d, 6 H, (CH3)2, i-Propyl), 2.06 (s, 3 H, Me-10), 2.70-2.94 (m, 4 H, H-5,6), 3.79 (s, 3 H, MeO-7), 4.49 (m, 1 H, CH, i-Propyl), 7.27, 7.49 (2 s, 2 H, H-4,12), 7.89 (d, J = 8.4 Hz, 1 H, NH-propyl), 8.37 (s, 1 H, CH=N), 11.17 (br. s, 1 H, OH), 11.61 (s, 1 H, =N-NH), 13.56 (s, 1 H, OH), 14.5 (s. br., 1 H, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 8.16 (Me-10), 21.88 ((CH3)2, i-Propyl), 22.11, 28.74 (C-5,6), 45.53 (CH, i-Propyl), 61.05 (MeO-7), 106.38, 117.23 (C-4,12), 109.67, 114.04, 118.46, 119.23, 120.09, 122.20, 129.56, 130.65, 133.30, 143.18, 146.63, 150.78, 154.38, 156.12, 162.10, 162.44 (Cq), 170.00 (COOH), 175.92 (C=S), 140.40 (CH=N), 185.49, 187.70 (C-8,13).
FAB-MS (3NBA) [M + H]⁺: m/z = gef. 606.Maduranic acid 4-isopropylthiosemicarbazone (1,9,11,14-tetrahydroxy-3- (4-isopropylthiosemi carbazono) methyl-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo [ a] naphthacen-2-carboxylic acid), formula I with R 1 = R 3 = R 4 = H, R 2 = NHC (S) NHCH (CH 3 ) 2 , C 30 H 27 N 3 O 9 S (605.6).
1 H NMR (DMSO-D 6 ): δ (ppm) = 1.24 (d, 6 H, (CH 3 ) 2 , i-propyl), 2.06 (s, 3 H, Me-10), 2.70-2.94 ( m, 4 H, H-5.6), 3.79 (s, 3 H, MeO-7), 4.49 (m, 1 H, CH, i-propyl), 7.27, 7.49 (2 s, 2 H, H- 4.12), 7.89 (d, J = 8.4 Hz, 1 H, NH-propyl), 8.37 (s, 1 H, CH = N), 11.17 (br. S, 1 H, OH), 11.61 (s, 1 H, = N-NH), 13.56 (s, 1 H, OH), 14.5 (s. Br., 1 H, COOH).
13 C NMR (DMSO-D 6 ): δ (ppm) = 8.16 (Me-10), 21.88 ((CH 3 ) 2 , i-propyl), 22.11, 28.74 (C-5.6), 45.53 (CH , i-Propyl), 61.05 (MeO-7), 106.38, 117.23 (C-4.12), 109.67, 114.04, 118.46, 119.23, 120.09, 122.20, 129.56, 130.65, 133.30, 143.18, 146.63, 150.78, 154.38, 156.12, 162.10, 162.44 (Cq), 170.00 (COOH), 175.92 (C = S), 140.40 (CH = N), 185.49, 187.70 (C-8.13).
FAB-MS (3NBA) [M + H] ⁺: m / z = found 606.

13. Substanz 1313. Substance 13

Maduransäure-4-butylthiosemicarbazon (3-(4-Butylthiosemicarbazono)methyl-1,9,11,14- tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo[a]naphthacen-2- carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 = NHC(S)NH(CH2)3CH3, C31H29N3O9S (619.6).
1H-NMR (DMSO-D6): δ (ppm) = 0.90 (t, 3 H, CH3, Butyl), 1.32 (m, 2 H, CH2, Butyl), 1.58 (m, 2 H, CH2, Buryl), 2.06 (s, 3 H, Me-10), 2.68-2.92 (m, 4 H, H-5,6), 3.56 (dd, J = 13.9/6.6 Hz, CH2- N, Butyl), 3.79 (s, 3 H, MeO-7), 7.27, 7.56 (2 s, 2 H, H-4,12), 8.43 (t, J = 5.7 Hz, 1 H, NH-butyl), 8.44 (s, 1 H, CH=N), 11.58 (s, 1 H, =N-NH), 13.57 (s, 1 H, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 8.28 (Me-10), 13.87 (CH3, Butyl), 19.64, 31.02, 43.37 ((CH2)3, Butyl), 22.53, 28.90 (C-5,6), 61.17 (MeO-7), 106.45, 116.72 (C4,12), 109.82, 114.19, 118.55, 119.07, 120.13, 122.27, 129.84, 130.85, 133.78, 143.45, 146.63, 150.86, 155.08, 156.33, 162.21, 162.53, 170.27, 177.10 (Cq), 140.61 (CH-N), 185.67, 187.73 (C-8,13).
FAB-MS (3NBA) [M + H]⁺: m/z = gef. 620.Maduranic acid 4-butylthiosemicarbazone (3- (4-butylthiosemicarbazono) methyl-1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo [a ] naphthacen-2-carboxylic acid), formula I with R 1 = R 3 = R 4 = H, R 2 = NHC (S) NH (CH 2 ) 3 CH 3 , C 31 H 29 N 3 O 9 S (619.6) .
1 H NMR (DMSO-D 6 ): δ (ppm) = 0.90 (t, 3 H, CH 3 , butyl), 1.32 (m, 2 H, CH 2 , butyl), 1.58 (m, 2 H, CH 2 , Buryl), 2.06 (s, 3 H, Me-10), 2.68-2.92 (m, 4 H, H-5.6), 3.56 (dd, J = 13.9 / 6.6 Hz, CH 2 - N, butyl ), 3.79 (s, 3 H, MeO-7), 7.27, 7.56 (2 s, 2 H, H-4.12), 8.43 (t, J = 5.7 Hz, 1 H, NH-butyl), 8.44 ( s, 1 H, CH = N), 11.58 (s, 1 H, = N-NH), 13.57 (s, 1 H, COOH).
13 C NMR (DMSO-D 6 ): δ (ppm) = 8.28 (Me-10), 13.87 (CH 3 , butyl), 19.64, 31.02, 43.37 ((CH 2 ) 3 , butyl), 22.53, 28.90 ( C-5.6), 61.17 (MeO-7), 106.45, 116.72 (C4.12), 109.82, 114.19, 118.55, 119.07, 120.13, 122.27, 129.84, 130.85, 133.78, 143.45, 146.63, 150.86, 155.08, 156.33 , 162.21, 162.53, 170.27, 177.10 (Cq), 140.61 (CH-N), 185.67, 187.73 (C-8.13).
FAB-MS (3NBA) [M + H] ⁺: m / z = found 620.

14. Substanz 1414. Substance 14

Maduransaure-4-isobutylthiosenucarbazon (1,9,11,14-Tetrahydroxy-3-(4-isobutylthiosemi­ carbazono)methyl-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo[a]naphthacen-2- carbonsäure), Formel I mit R1 = R3 = R4 H, R2 = NHC(S)NHCH(CH3)CH2CH3, C31H29N3O9S (619.6).
1H-NMR (DMSO-D6): δ (ppm) = 0.89 (d, J = 6.7 Hz, 6 H, (CH3)2, Butyl), 2.10 (m, 1 H, CH, Butyl), 2.06 (s, 3 H, Me-10), 2.68-2.93 (m, 4 H, H-5,6), 3.34-3.44 (m, 2 H, CH-N, Butyl), 3.79 (s, 3 H, MeO-7), 7.27, 7.54 (2 s, 2 H, H4,12), 8.32 (m, 1 H, NH-butyl), 8.40 (s, 1 H, CH=N), 11.61 (s, 1 H, =N-NH).
13C-NMR (DMSO-D6): δ (ppm) = 8.29 (Me-10), 20.16 (CH3, Butyl), 22.53, 28.89 (C-5,6), 27.90 (CH, Butyl), 50.92 (CH2, Butyl), 61.19 (MeO-7), 106.48, 117.01 (C-4,12), 109.82, 114.13, 118.62, 119.30, 120.13, 122.28, 129.71, 130.80, 133.55, 143.42, 146.76, 150.90, 154.64, 156.29, 162.22, 162.55, 170.23, 177.47 (Cq), 140.47 (CH=N), 185.65, 187.84 (C-8,13).
FAB-MS (3NBA) [M + H]⁺: m/z = gef. 620.Maduranic acid-4-isobutylthiosenucarbazone (1,9,11,14-tetrahydroxy-3- (4-isobutylthiosemi carbazono) methyl-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo [ a] naphthacen-2-carboxylic acid), formula I with R 1 = R 3 = R 4 H, R 2 = NHC (S) NHCH (CH 3 ) CH 2 CH 3 , C 31 H 29 N 3 O 9 S (619.6 ).
1 H NMR (DMSO-D 6 ): δ (ppm) = 0.89 (d, J = 6.7 Hz, 6 H, (CH 3 ) 2 , butyl), 2.10 (m, 1 H, CH, butyl), 2.06 (s, 3 H, Me-10), 2.68-2.93 (m, 4 H, H-5.6), 3.34-3.44 (m, 2 H, CH-N, butyl), 3.79 (s, 3 H, MeO-7), 7.27, 7.54 (2 s, 2 H, H4.12), 8.32 (m, 1 H, NH-butyl), 8.40 (s, 1 H, CH = N), 11.61 (s, 1 H) , = N-NH).
13 C NMR (DMSO-D 6 ): δ (ppm) = 8.29 (Me-10), 20.16 (CH 3 , butyl), 22.53, 28.89 (C-5.6), 27.90 (CH, butyl), 50.92 (CH 2 , butyl), 61.19 (MeO-7), 106.48, 117.01 (C-4.12), 109.82, 114.13, 118.62, 119.30, 120.13, 122.28, 129.71, 130.80, 133.55, 143.42, 146.76, 150.90, 154.64 , 156.29, 162.22, 162.55, 170.23, 177.47 (Cq), 140.47 (CH = N), 185.65, 187.84 (C-8.13).
FAB-MS (3NBA) [M + H] ⁺: m / z = found 620.

15. Substanz 1515. Substance 15

Maduransäure-4-tert-butylthiosemicarbazon (3-(4-tert-Butylthiosemicarbazono)methyl-1,9,11,14- tetra-hydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo[a]-naphthacen-2- carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 = NHC(S)NHC(CH3)3, C31H29N3O9S (619.6).
1H-NMR (DMSO-D6): δ (ppm) = 1.54 (s, 9 H, (CH3)3, t-Butyl), 2.10 (s, 3 H, Me-10), 2.65-2.94 (m, 4 H, H-5,6), 3.78 (s, 3 H, MeO-7), 7.27, 7.60 (2 s, 2 H, H-4,12), 8.29 (s, 1 H, CH=N), 11.18 (br. s, 1 H, OH), 11.48 (s, 1 H, =N-NH), 13.55 (s, 1 H, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 8.16 (Me-10), 22.41, 28.60 (C-5,6), 28.60 ((CH3)3, t-Buryl), 52.83 (Me3C, t-Butyl), 61.06 (MeO-7), 106.42, 117.83 (C-4,12), 109.69, 114.04, 118.53, 119.63, 120.21, 122.25, 129.49, 130.64, 132.86, 142.98, 146.68, 150.82, 153.93, 156.01, 162.12, 162.45 (Cq), 169.70 (COOH), 175.56 (C=S), 139.69 (CH=N), 185.47, 187.73 (C-8,13).
FAB-MS (3NBA) [M + H]⁺: m/z = gef. 620.Maduranic acid 4-tert-butylthiosemicarbazone (3- (4-tert-butylthiosemicarbazono) methyl-1,9,11,14-tetra-hydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8 , 13-tetrahydrobenzo [a] -naphthacen-2-carboxylic acid), formula I with R 1 = R 3 = R 4 = H, R 2 = NHC (S) NHC (CH 3 ) 3 , C 31 H 29 N 3 O 9 S (619.6).
1 H-NMR (DMSO-D 6 ): δ (ppm) = 1.54 (s, 9 H, (CH 3 ) 3 , t-butyl), 2.10 (s, 3 H, Me-10), 2.65-2.94 ( m, 4 H, H-5.6), 3.78 (s, 3 H, MeO-7), 7.27, 7.60 (2 s, 2 H, H-4.12), 8.29 (s, 1 H, CH = N), 11.18 (br. S, 1 H, OH), 11.48 (s, 1 H, = N-NH), 13.55 (s, 1 H, COOH).
13 C NMR (DMSO-D 6 ): δ (ppm) = 8.16 (Me-10), 22.41, 28.60 (C-5.6), 28.60 ((CH 3 ) 3 , t-buryl), 52.83 (Me 3 C, t-butyl), 61.06 (MeO-7), 106.42, 117.83 (C-4.12), 109.69, 114.04, 118.53, 119.63, 120.21, 122.25, 129.49, 130.64, 132.86, 142.98, 146.68, 150.82, 153.93, 156.01, 162.12, 162.45 (Cq), 169.70 (COOH), 175.56 (C = S), 139.69 (CH = N), 185.47, 187.73 (C-8.13).
FAB-MS (3NBA) [M + H] ⁺: m / z = found 620.

16. Substanz 1616. Substance 16

Maduransäure-4-hexylthiosemicarbazon (3-(4-Hexylthiosemicarbazono)methyl-1,9,11,14-tetra­ hydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo[a]naphthacen-2-carbon-säure), Formel I mit R1 = R3 = R4 = H,R2 = NHC(S)NH(CH2)5CH3, C33H33N3O9S (647.7).
1H-NMR (DMSO-D6): δ (ppm) 0.86 (m, 3 H, CH3, Hexyl), 1.21 1.38 (m, 4 H, (CH2)2, Hexyl), 1.51-1.71 (m, 2H, CH2, Hexyl), 2.06 (s, 3H, Me10), 2.662.99 (m, 4H, H5,6), 3.503.64 (m, 2 H, CH2, Hexyl), 3.79 (s, 3 H, MeO-7), 7.27, 7.59 (2 d, 2 H, H-4,12), 8.35 (m, 1 H, NH-hexyl), 8.42 (s, 1 H, CH-N), 11.14 (br., 1 H, OH), 11.60 (s, 1 H, =N-NH), 13.56 (s, 1 H, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 8.64 (Me-10), 14.35 (CH3, Hexyl), 22.49, 26.46, 29.18, 31.49, 404 ((CH2)5, Hexyl), 22.92, 29.29 (C-5,6), 61.53 (MeO-7), 106.87, 117.12 (C-4,12), 110.19, 114.48, 118.94, 119.50, 120.47, 122.65, 130.65, 131.16, 134.13, 143.85, 147.08, 151.26, 155.23, 156.70, 162.59, 162.93, 170.63, 177.54 (Cq), 140.74 (CH=N),. 185.98, 188.19 (C-8,13).
FAB-MS (3NBA) [M + H]⁺: m/z = gef. 648.Maduranic acid 4-hexylthiosemicarbazone (3- (4-hexylthiosemicarbazono) methyl-1,9,11,14-tetra hydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo [ a] naphthacen-2-carbon-acid), formula I with R 1 = R 3 = R 4 = H, R 2 = NHC (S) NH (CH 2 ) 5 CH 3 , C 33 H 33 N 3 O 9 S (647.7).
1 H NMR (DMSO-D 6 ): δ (ppm) 0.86 (m, 3 H, CH 3 , hexyl), 1.21 1.38 (m, 4 H, (CH 2 ) 2 , hexyl), 1.51-1.71 (m , 2H, CH 2 , hexyl), 2.06 (s, 3H, Me10), 2,662.99 (m, 4H, H5,6), 3,503.64 (m, 2 H, CH 2 , hexyl), 3.79 (s, 3 H, MeO-7), 7.27, 7.59 (2 d, 2 H, H-4.12), 8.35 (m, 1 H, NH-hexyl), 8.42 (s, 1 H, CH-N), 11.14 (br., 1 H, OH), 11.60 (s, 1 H, = N-NH), 13.56 (s, 1 H, COOH).
13 C-NMR (DMSO-D 6 ): δ (ppm) = 8.64 (Me-10), 14.35 (CH 3 , hexyl), 22.49, 26.46, 29.18, 31.49, 404 ((CH 2 ) 5 , hexyl), 22.92, 29.29 (C-5.6), 61.53 (MeO-7), 106.87, 117.12 (C-4.12), 110.19, 114.48, 118.94, 119.50, 120.47, 122.65, 130.65, 131.16, 134.13, 143.85, 147.08 , 151.26, 155.23, 156.70, 162.59, 162.93, 170.63, 177.54 (Cq), 140.74 (CH = N) ,. 185.98, 188.19 (C-8.13).
FAB-MS (3NBA) [M + H] ⁺: m / z = found 648.

17. Substanz 1717. Substance 17

Maduransäure-4-heptylthiosemicarbazon (3-(4-Heptylthiosemicarbazono)methyl-1,9,11,14- tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo[a]naphthacen-2- carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 = NHC(S)NH(CH2)6CH3, C34H35N3O9S (661.7).
1H-NMR (DMSO-D6): δ (ppm) = 0.84 (t, 3 H, CH3, Heptyl), 1.18-1.35 (m, 8 H, (CH2)4, Heptyl), 1.59 (m, 2H, CH2, Heptyl), 2.06 (s, 3H, Me-10), 2.68-2.92 (m, 4H, H-5,6), 3.78 (s, 3 H, MeO-7), 7.27, 7.64 (2 d, 2H, H-4,12), 8.34 (t, J = 6 Hz, 1 H, CNH-heptyl), 8.45 (s, 1 H, CH=N), 11.22 (br., 1 H), 11.57 (s, 1 H, =N-NH), 13.56 (s, 1 H, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 8.27 (Me-10), 14.01 (CH3, Heptyl), 22.12, 26.36, 28.53, 28.84, 31.30, 43.64 ((CH2)6, Heptyl), 22.53, 28.90 (C-5,6), 61.17 (MeO-7), 106.45, 116.65 (C-4,12), 109.81, 114.20, 118.54, 119.05, 120.14, 122.27, 129.86, 130.86, 133.82, 143.45, 146.61, 150.86, 151.17, 156.34, 162.21, 162.53, 170.29, 177.09 (Cq), 140.64 (CH=N), 185.67, 187.71 (C-8,13).
FAB-MS (3NBA) [M + H]⁺P: m/z = gef. 662.Maduranic acid 4-heptylthiosemicarbazone (3- (4-heptylthiosemicarbazono) methyl-1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo [a ] naphthacen-2-carboxylic acid), formula I with R 1 = R 3 = R 4 = H, R 2 = NHC (S) NH (CH 2 ) 6 CH 3 , C 34 H 35 N 3 O 9 S (661.7) .
1 H-NMR (DMSO-D 6 ): δ (ppm) = 0.84 (t, 3 H, CH 3 , heptyl), 1.18-1.35 (m, 8 H, (CH 2 ) 4 , heptyl), 1.59 (m , 2H, CH 2 , heptyl), 2.06 (s, 3H, Me-10), 2.68-2.92 (m, 4H, H-5.6), 3.78 (s, 3 H, MeO-7), 7.27, 7.64 (2 d, 2H, H-4.12), 8.34 (t, J = 6 Hz, 1 H, CNH-heptyl), 8.45 (s, 1 H, CH = N), 11.22 (br., 1 H) , 11.57 (s, 1H, = N-NH), 13.56 (s, 1H, COOH).
13 C-NMR (DMSO-D 6 ): δ (ppm) = 8.27 (Me-10), 14.01 (CH 3 , heptyl), 22.12, 26.36, 28.53, 28.84, 31.30, 43.64 ((CH 2 ) 6 , heptyl ), 22.53, 28.90 (C-5.6), 61.17 (MeO-7), 106.45, 116.65 (C-4.12), 109.81, 114.20, 118.54, 119.05, 120.14, 122.27, 129.86, 130.86, 133.82, 143.45 , 146.61, 150.86, 151.17, 156.34, 162.21, 162.53, 170.29, 177.09 (Cq), 140.64 (CH = N), 185.67, 187.71 (C-8.13).
FAB-MS (3NBA) [M + H] ⁺P: m / z = found 662.

18. Substanz 1818. Substance 18

Maduransäure-4-docecylthiosemicarbazon (3-(4-Doceylthiosemicarbazono)methyl-1,9,11,14-tetra­ hydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo[a]naphthacen-2-carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 = NHC(S)NH(CH2)11CH3, C39H45N3O9S (731.9).
1H-NMR (DMSO-D6): δ (ppm) = 0.81 (m, 3 H, CH3, Dodecyl), 1.14-1.34 (m, 18 H, (CH2)9, Dodecyl), 1.58 (m, 2 H, CH2, Dodecyl), 2.05 (s, 3 H, Me 10), 2.67 2.93 (m, 4 H, H 5,6), 3.78 (s, 3 H, MeO-7), 7.26, 7.58 (2 s, 2 H, H-4,12), 8.43 (dd, J - 5.8/5.6 Hz, 1 H, NH-dodecyl), 8.42 (s, 1 H, CH=N), 11.59 (s, 1 H, =N-NH).
13C-NMR (DMSO-D6): δ (ppm) = 8.27 (Me-10), 13.40 (CH3, Dodecyl), 22.15, 22.53 (C-5 oder C 6), 26.40, 28.79, 28.87, 29.07, 29.13 (C 5,6, CH2, Dodecyl), 31.36, 43.64 (CH2, Dodecyl), 61.16 (MeO 7), 106.48, 116.75 (C-4,12), 109.80, 114.09, 118.61, 119.05, 120.08, 122.27, 129.73, 130.78, 133.75, 143.49, 146.70, 150.88, 154.89, 156.33, 162.21, 162.55, 170.33, 177.10 (Cq), 140.41 (CH-N), 185.62, 187.82 (C-8,13).
FAB-MS (3NBA) [M + H]⁺: m/z = gef. 732. Maduranic acid 4-docecylthiosemicarbazone (3- (4-doceylthiosemicarbazono) methyl-1,9,11,14-tetra hydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo [ a] naphthacen-2-carboxylic acid), formula I with R 1 = R 3 = R 4 = H, R 2 = NHC (S) NH (CH 2 ) 11 CH 3 , C 39 H 45 N 3 O 9 S (731.9 ).
1 H-NMR (DMSO-D 6 ): δ (ppm) = 0.81 (m, 3 H, CH 3 , dodecyl), 1.14-1.34 (m, 18 H, (CH 2 ) 9 , dodecyl), 1.58 (m , 2 H, CH 2 , dodecyl), 2.05 (s, 3 H, Me 10), 2.67 2.93 (m, 4 H, H 5.6), 3.78 (s, 3 H, MeO-7), 7.26, 7.58 (2 s, 2 H, H-4.12), 8.43 (dd, J - 5.8 / 5.6 Hz, 1 H, NH-dodecyl), 8.42 (s, 1 H, CH = N), 11.59 (s, 1 H, = N-NH).
13 C-NMR (DMSO-D 6 ): δ (ppm) = 8.27 (Me-10), 13.40 (CH 3 , dodecyl), 22.15, 22.53 (C-5 or C 6), 26.40, 28.79, 28.87, 29.07 , 29.13 (C 5.6, CH 2 , dodecyl), 31.36, 43.64 (CH 2 , dodecyl), 61.16 (MeO 7), 106.48, 116.75 (C-4.12), 109.80, 114.09, 118.61, 119.05, 120.08 , 122.27, 129.73, 130.78, 133.75, 143.49, 146.70, 150.88, 154.89, 156.33, 162.21, 162.55, 170.33, 177.10 (Cq), 140.41 (CH-N), 185.62, 187.82 (C-8.13).
FAB-MS (3NBA) [M + H] ⁺: m / z = found 732.

19. Substanz 1919. Substance 19

Maduransäure-4-cyclopropylthiosemicarbazon (3-(4-Cyclopropylthiosemicarbazono)methyl- 1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo[a]-naphthacen-2- carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 = NHC(S)NHC3H5, C30H25N3O9S (603.6).
1H-NMR (DMSO-D6): δ (ppm) = 0.69-0.80 (m, 4 H, CH2, Cyclopropyl), 2.04 (s, 3 H, Me-10), 2.65-3.00 (m, 4 H, H-5,6), 3.03-3.14 (m, CH, Cyclopropyl), 3.78 (s, 3 H, MeO-7), 7.24, 7.54 (2 s, 2 H, H-4,12), 8.13 (d, J = 4.0 Hz, 1 H, NH-cyclopropyl), 8.40 (s, 1 H, CH=N), 11.14 (br., 1 H, OH), 11.69 (s, 1 H, =N-NH), 13.54 (s, 1 H, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 6.21 (CH2, Cyclopropyl), 8.13 (Me-10), 22.41, 28.70 (C-5,6), 26.95 (CH-N, Cyclopropyl), 61.02 (MeO-7), 106.37, 117.04 (C-4,12), 109.66, 114.06, 118.41, 119.11, 120.08, 122.16, 129.64, 130.66, 133.45, 143.22, 146.54, 150.75, 154.68, 156.13, 162.08, 162.41, 170.10, 178.62 (Cq), 140.52 (CH=N), 185.46, 187.60 (C-8,13).
FAB-MS (3NBA) [M + H]⁺: m/z = gef. 604.Maduranic acid 4-cyclopropylthiosemicarbazone (3- (4-cyclopropylthiosemicarbazono) methyl-1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo [a ] -naphthacen-2-carboxylic acid), formula I with R 1 = R 3 = R 4 = H, R 2 = NHC (S) NHC 3 H 5 , C 30 H 25 N 3 O 9 S (603.6).
1 H NMR (DMSO-D 6 ): δ (ppm) = 0.69-0.80 (m, 4 H, CH 2 , cyclopropyl), 2.04 (s, 3 H, Me-10), 2.65-3.00 (m, 4 H, H-5.6), 3.03-3.14 (m, CH, cyclopropyl), 3.78 (s, 3 H, MeO-7), 7.24, 7.54 (2 s, 2 H, H-4.12), 8.13 (d, J = 4.0 Hz, 1 H, NH-cyclopropyl), 8.40 (s, 1 H, CH = N), 11.14 (br., 1 H, OH), 11.69 (s, 1 H, = N-NH ), 13.54 (s, 1H, COOH).
13 C-NMR (DMSO-D 6 ): δ (ppm) = 6.21 (CH 2 , cyclopropyl), 8.13 (Me-10), 22.41, 28.70 (C-5.6), 26.95 (CH-N, cyclopropyl) , 61.02 (MeO-7), 106.37, 117.04 (C-4.12), 109.66, 114.06, 118.41, 119.11, 120.08, 122.16, 129.64, 130.66, 133.45, 143.22, 146.54, 150.75, 154.68, 156.13, 162.08, 162.41 , 170.10, 178.62 (Cq), 140.52 (CH = N), 185.46, 187.60 (C-8.13).
FAB-MS (3NBA) [M + H] ⁺: m / z = found 604.

20. Substanz 2020. Substance 20

Maduransäure-4-cyclopentylthiosemicarbazon 3-(4-Cyclopentylthiosemicarbazono)methyl- 1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo[a]-naphthacen-2 carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 = NHC(S)NHC5H9, C32H29N3O9S (631.7).
1H-NMR (DMSO-D6): δ (ppm) = 1.41-1.78 (m, 6 H, CH2, Cyclopenryl), 1.87-2 .09 (m, 2 H, CH2, Cyclopentyl), 2.04 (s, 3 H, Me-10), 2.74-2.92 (m, 4 H, H-5,6), 3.78 (s, 3 H, MeO-7), 4.54-4.66 (m, CH, Cyclopentyl), 7.25, 7.42 (2 s, 2 H, H-4,12), 7.92 (d, J = 8.0 Hz, 1 H, NH-cyclopentyl), 8.32 (s, 1 H,CH=N), 11.15 (br., 1 H, OH), 11.64 (s, 1 H,=N-NH), 13.54 (s, 1 H, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 8.13 (Me-10), 22.41, 28.68 (C-5,6), 23.38, 31.84 (CH2, Cyclopentyl), 55.27 (CH-N, Cyclopropyl), 61.03 (MeO-7), 106.40, 117.67 (C-4,12), 109.65, 114.05, 118.50, 119.59, 120.13, 122.20, 129.49, 130.59, 133.06, 143.00, 146.60, 150.79, 154.00, 156.01, 162.09, 162.43, 169.88, 176.54 (Cq), 140.19 (CH-N), 185.42, 187.70 (C-8,13).
FAB-MS (3NBA) [M + H]⁺: m/z = gef. 632. Maduranic acid 4-cyclopentylthiosemicarbazone 3- (4-cyclopentylthiosemicarbazono) methyl-1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo [a] -naphthacen-2 carboxylic acid), formula I with R 1 = R 3 = R 4 = H, R 2 = NHC (S) NHC 5 H 9 , C 32 H 29 N 3 O 9 S (631.7).
1 H NMR (DMSO-D 6 ): δ (ppm) = 1.41-1.78 (m, 6 H, CH 2 , cyclopenryl), 1.87-2 .09 (m, 2 H, CH 2 , cyclopentyl), 2.04 ( s, 3 H, Me-10), 2.74-2.92 (m, 4 H, H-5.6), 3.78 (s, 3 H, MeO-7), 4.54-4.66 (m, CH, cyclopentyl), 7.25 , 7.42 (2 s, 2 H, H-4.12), 7.92 (d, J = 8.0 Hz, 1 H, NH-cyclopentyl), 8.32 (s, 1 H, CH = N), 11.15 (br., 1 H, OH), 11.64 (s, 1 H, = N-NH), 13.54 (s, 1 H, COOH).
13 C NMR (DMSO-D 6 ): δ (ppm) = 8.13 (Me-10), 22.41, 28.68 (C-5.6), 23.38, 31.84 (CH 2 , cyclopentyl), 55.27 (CH-N, Cyclopropyl), 61.03 (MeO-7), 106.40, 117.67 (C-4.12), 109.65, 114.05, 118.50, 119.59, 120.13, 122.20, 129.49, 130.59, 133.06, 143.00, 146.60, 150.79, 154.00, 156.01, 162.09 , 162.43, 169.88, 176.54 (Cq), 140.19 (CH-N), 185.42, 187.70 (C-8.13).
FAB-MS (3NBA) [M + H] ⁺: m / z = found 632.

21. Substanz 2121. Substance 21

Maduransäure-4-cyclohexylthiosemicarbazon (3-(4-Cyclohexylthiosemicarbazono)methyl-1,9,11,14- tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tettahydrobenzo[a]-naphthacen-2- carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 = NHC(S)NHC6H11, C33H31N3O9S (645.7).
1H-NMR (DMSO-D6): δ (ppm) = 1.11-1.98 (m, 10 H, CH2, cyclohexyl), 2.06 (s, 3 H, Me-10), 2.69-2.91 (m, 4 H, H-5,6), 3.79 (s, 3 H, MeO-7), 4.07-4.25 (m, 1 H, CH, cyclohexyl), 7.26, 7.44 (2 s, 2H, H-4,12), 7.85 (d, J = 8.5 Hz, 1 H, HN-cyclohexyl), 8.39 (s, 1 H, CH=N), 11.50 (s, 1 H, =N- NH), 13.56 (s, 1 H, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 8.15 (Me-10), 22.42, 25.08, 28.74 (CH2, cyclohexyl), 24.76, 31.80 (C-5,6), 52.53 (C-NH, cyclohexyl), 61.05 (MeO-7), 106.36, 117.23 (C-1,12), 109.69, 114.15, 118.41, 119.30, 120.18, 122.20, 129.68, 130.71, 133.32, 143.12, 146.52, 150.75, 154.63, 156.11, 162.01, 162.42, 169.95, 175.85 (Cq), 140.60 (CH=N), 185.52, 187.58 (C-8,13).
FAB-MS (3NBA) m/z = [M + H]⁺: gef. 646.Maduranic acid 4-cyclohexylthiosemicarbazon (3- (4-cyclohexylthiosemicarbazono) methyl-1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tettahydrobenzo [a ] -naphthacen-2-carboxylic acid), formula I with R 1 = R 3 = R 4 = H, R 2 = NHC (S) NHC 6 H 11 , C 33 H 31 N 3 O 9 S (645.7).
1 H NMR (DMSO-D 6 ): δ (ppm) = 1.11-1.98 (m, 10 H, CH 2 , cyclohexyl), 2.06 (s, 3 H, Me-10), 2.69-2.91 (m, 4 H, H-5.6), 3.79 (s, 3 H, MeO-7), 4.07-4.25 (m, 1 H, CH, cyclohexyl), 7.26, 7.44 (2 s, 2H, H-4.12) , 7.85 (d, J = 8.5 Hz, 1 H, HN-cyclohexyl), 8.39 (s, 1 H, CH = N), 11.50 (s, 1 H, = N-NH), 13.56 (s, 1 H, COOH).
13 C-NMR (DMSO-D 6 ): δ (ppm) = 8.15 (Me-10), 22.42, 25.08, 28.74 (CH 2 , cyclohexyl), 24.76, 31.80 (C-5.6), 52.53 (C- NH, cyclohexyl), 61.05 (MeO-7), 106.36, 117.23 (C-1.12), 109.69, 114.15, 118.41, 119.30, 120.18, 122.20, 129.68, 130.71, 133.32, 143.12, 146.52, 150.75, 154.63, 156.11 , 162.01, 162.42, 169.95, 175.85 (Cq), 140.60 (CH = N), 185.52, 187.58 (C-8.13).
FAB-MS (3NBA) m / z = [M + H] ⁺: found 646.

22. Substanz 2222. Substance 22

Maduransäure-4-cycloheptylthiosemicarbazon 3-(4-Cycloheptylthiosemicarbazono)methyl- 1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo[a]-naphthacen-2- carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 = NHC(S)NHC7H13, C34H33N3O9S (659.7).
1H-NMR (DMSO-D6): δ (ppm) = 1.37-1.75 (m, 10 H, CH2, Cycloheptyl), 1.87-2.00 (m, 2 H, CH2, Cycloheptyl), 2.07 (s, 3 H, Me-10), 2.68-2.92 (m, 4 H, H-5,6), 3.80 (s, 3 H, MeO-7), 4.23- 4.43 (m, CH, Cycloheptyl), 7.28, 7.43 (2 s, 2 H, H-4,12), 7.89 (d, J = 8.4 Hz, 1 H, NH- cycloheptyl), 8.35 (s, 1 H, CH=N), 11.16 (br., 1 H, OH), 11.59 (s, 1 H, =N-NH), 13.56 (s, 1 H, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 8.14 (Me-10), 22.39, 28.70 (C-5,6), 23.81, 27.47, 33.84 (CH2, Cycloheptyl), 54.77 (CH N, Cycloheptyl), 61.03 (MeO-7), 106.37, 117.36 (C-4, 12), 109.67, 114.08, 118.44, 119.40, 120.11, 122.19, 129.58, 130.66, 133.19, 143.05, 146.56, 150.76, 154.30, 156.06, 162.09, 162.41 (Cq), 140.27 (CH N), 169.88 (COOH), (C S), 185.48, 187.66 (C 8,13).
FAB-MS (3NBA) [M⁺ + H]: m/z = gef. 660. Maduranic acid 4-cycloheptylthiosemicarbazone 3- (4-cycloheptylthiosemicarbazono) methyl-1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo [a] -naphthacen-2-carboxylic acid), formula I with R 1 = R 3 = R 4 = H, R 2 = NHC (S) NHC 7 H 13 , C 34 H 33 N 3 O 9 S (659.7).
1 H-NMR (DMSO-D 6 ): δ (ppm) = 1.37-1.75 (m, 10 H, CH 2 , cycloheptyl), 1.87-2.00 (m, 2 H, CH 2 , cycloheptyl), 2.07 (s, 3 H, Me-10), 2.68-2.92 (m, 4 H, H-5.6), 3.80 (s, 3 H, MeO-7), 4.23- 4.43 (m, CH, cycloheptyl), 7.28, 7.43 (2 s, 2 H, H-4.12), 7.89 (d, J = 8.4 Hz, 1 H, NH-cycloheptyl), 8.35 (s, 1 H, CH = N), 11.16 (br., 1 H , OH), 11.59 (s, 1H, = N-NH), 13.56 (s, 1H, COOH).
13 C NMR (DMSO-D 6 ): δ (ppm) = 8.14 (Me-10), 22.39, 28.70 (C-5.6), 23.81, 27.47, 33.84 (CH 2 , cycloheptyl), 54.77 (CH N , Cycloheptyl), 61.03 (MeO-7), 106.37, 117.36 (C-4, 12), 109.67, 114.08, 118.44, 119.40, 120.11, 122.19, 129.58, 130.66, 133.19, 143.05, 146.56, 150.76, 154.30, 156.06, 162.09, 162.41 (Cq), 140.27 (CH N), 169.88 (COOH), (CS), 185.48, 187.66 (C 8.13).
FAB-MS (3NBA) [M⁺ + H]: m / z = found 660.

23. Substanz 2323. Substance 23

Maduransäure-4-cyclooctylthiosemicarbazon 3-(4-Cyclooctylthiosemicarbazono)methyl-1,9,11,14- tetrahydroxy-7-methoxy-10-methyl-8,13-dihoxo-5,6,8,13-tetrahydrobenzo[a]-naphthacen-2- carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 = NHC(S)NHC8H17, C35H35N3O9S (673.7).
1H-NMR (3DMSO-D6): δ (ppm) = 1.43-1.88 (m, 14 H, CH2, Cycloocryl), 2.08 (s, 3 H, Me-10), 2.67-2.95 (m, 4 H, H-5,6), 3.81 (s, 3 H, MeO-7), 4.34-4.50 (m, CH, Cyclooctyl), 7.29, 7.42 (2 s, 2 H, H4,12), 7.89 (d, J = 8.4 Hz, 1 H, NH-cyclooctyl), 8.33 (s, 1 H, CH=N), 11.17 (br., 1 H, OH), 11.59 (s, 1 H, =N-NH), 13.57 (br., 1 H, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 8.14 (Me-10), 22.39, 28.70 (C-5,6), 23.55, 26.54, 27.47, 31.79 (CH2, Cyclooctyl), 53.42 (CH-N, Cyclooctyl), 61.04 (MeO-7), 106.38, 117.49 (C-4,12), 109.68, 114.05, 118.48, 119.48, 120.08, 122.19, 129.52, 130.64, 133.11, 143.03, 146.62, 150.79, 154.09, 156.05, 162.10, 162.43 (Cq), 140.13 (CH=N), 169.85 (COOH), 175.63 (C=S), 185.48, 187.73 (C- 8,13).
FAB-MS (3NBA) [M + H]⁺: m/z = gef. 674.Maduranic acid 4-cyclooctylthiosemicarbazone 3- (4-cyclooctylthiosemicarbazono) methyl-1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dihoxo-5,6,8,13-tetrahydrobenzo [a] -naphthacen-2-carboxylic acid), formula I with R 1 = R 3 = R 4 = H, R 2 = NHC (S) NHC 8 H 17 , C 35 H 35 N 3 O 9 S (673.7).
1 H-NMR (3DMSO-D 6 ): δ (ppm) = 1.43-1.88 (m, 14 H, CH 2 , cycloocryl), 2.08 (s, 3 H, Me-10), 2.67-2.95 (m, 4 H, H-5.6), 3.81 (s, 3 H, MeO-7), 4.34-4.50 (m, CH, cyclooctyl), 7.29, 7.42 (2 s, 2 H, H4.12), 7.89 (d , J = 8.4 Hz, 1 H, NH-cyclooctyl), 8.33 (s, 1 H, CH = N), 11.17 (br., 1 H, OH), 11.59 (s, 1 H, = N-NH), 13.57 (br., 1H, COOH).
13 C-NMR (DMSO-D 6 ): δ (ppm) = 8.14 (Me-10), 22.39, 28.70 (C-5.6), 23.55, 26.54, 27.47, 31.79 (CH 2 , cyclooctyl), 53.42 ( CH-N, cyclooctyl), 61.04 (MeO-7), 106.38, 117.49 (C-4.12), 109.68, 114.05, 118.48, 119.48, 120.08, 122.19, 129.52, 130.64, 133.11, 143.03, 146.62, 150.79, 154.09 , 156.05, 162.10, 162.43 (Cq), 140.13 (CH = N), 169.85 (COOH), 175.63 (C = S), 185.48, 187.73 (C- 8.13).
FAB-MS (3NBA) [M + H] ⁺: m / z = found 674.

24. Substanz 2424. Substance 24

Maduransäure-4-(1-adainantyl)thiosemicarbazon (3-[4-(Adamant-1-yl)thiosemicarbazono]-methyl- 1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo-[a]naphthacen-2- carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 = NHC(S)NHC10H15, C37H35N3O9S (697.8).
1H-NMR (DMSO-D6): δ (ppm) = 1.65 (m, 6 H, CH2, Adamantyl), 2.02 (s, 3 H, Me-10), 2.08 (m, 3 H, CH, Adamantyl), 2.28 (m, 6 H, CH2, Adamantyl), 2.61-2.93 (m, 4 H, H-5,6), 3.78 (s, 3 H, MeO-7), 4.54-4.66 (m, CH-N, Adamantyl), 7.22, 7.26 (2 s, 2 H, H-4,12), 7.49 (s, 1 H, NH- adamantyl), 8.28 (s, 1 H, CH=N), 11.14 (br., 1 H, OH), 11.43 (s, 1 H, =N-NH), 13.52 (s, 1 H, OH), 14.6 (s. br., 1 H, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 8.14 (Me-10), 22.43, 28.65 (C-5,6), 29.05 (3 C, CH, Adamantyl), 35.95 (3 C, CH2, Adamantyl), 40.84 (3 C, CH2, Adamantyl), 53.25 (C-N, Adamantyl), 61.03 (MeO-7), 106.45, 117.84 (C-4,12), 109.64, 114.03, 118.56, 119.65, 120.22, 122.24, 129.42, 130.55, 132.83, 143.02, 146.73, 150.82, 153.83, 155.99, 162.11, 162.47, 169.71 (Cq); 139.62 (CH=N), 174.76 (C=S), 185.39, 187.74 (C-8,13).
ES-MS (3NBA) [M - H]⁻: m/z - gef. 696. Maduranic acid 4- (1-adainantyl) thiosemicarbazone (3- [4- (Adamant-1-yl) thiosemicarbazono] methyl-1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13- dioxo-5,6,8,13-tetrahydrobenzo- [a] naphthacen-2-carboxylic acid), formula I with R 1 = R 3 = R 4 = H, R 2 = NHC (S) NHC 10 H 15 , C 37 H 35 N 3 O 9 S (697.8).
1 H-NMR (DMSO-D 6 ): δ (ppm) = 1.65 (m, 6 H, CH 2 , adamantyl), 2.02 (s, 3 H, Me-10), 2.08 (m, 3 H, CH, Adamantyl), 2.28 (m, 6 H, CH 2 , Adamantyl), 2.61-2.93 (m, 4 H, H-5.6), 3.78 (s, 3 H, MeO-7), 4.54-4.66 (m, CH-N, adamantyl), 7.22, 7.26 (2 s, 2 H, H-4.12), 7.49 (s, 1 H, NH-adamantyl), 8.28 (s, 1 H, CH = N), 11.14 ( br., 1 H, OH), 11.43 (s, 1 H, = N-NH), 13.52 (s, 1 H, OH), 14.6 (s. br., 1 H, COOH).
13 C NMR (DMSO-D 6 ): δ (ppm) = 8.14 (Me-10), 22.43, 28.65 (C-5.6), 29.05 (3 C, CH, adamantyl), 35.95 (3 C, CH 2 , adamantyl), 40.84 (3 C, CH 2 , adamantyl), 53.25 (CN, adamantyl), 61.03 (MeO-7), 106.45, 117.84 (C-4.12), 109.64, 114.03, 118.56, 119.65, 120.22 , 122.24, 129.42, 130.55, 132.83, 143.02, 146.73, 150.82, 153.83, 155.99, 162.11, 162.47, 169.71 (Cq); 139.62 (CH = N), 174.76 (C = S), 185.39, 187.74 (C-8.13).
ES-MS (3NBA) [M - H] ⁻: m / z - found 696.

25. Substanz 2525. Substance 25

Maduransäure-1-phenylthiosemicarbazon (1,9,11,14-Tetrahydroxy-7-methoxy-10-methyl-8,13- dioxo-3-(4-phenylthiosemicarbazono)methyl-5,6,8,13-tetrahydrobenzo[a]naphthacen-2-carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 = NHC(S)NHC6H5, C33H25N3O9S (639.6).
1H-NMR (DMSO-d6): δ = 2.05 (s, 3 H, Me-10), 2.70-2.93 (m, 4 H, H-5,6), 3.79 (s, 3 H, MeO-7), 7.06-7.42 (m, 4H), 7.62-7.73 (m, 3 H), 8.53 (s, 1 H), 9.95 (s, 1 H), 11.16 (br., 1 H, OH), 12.02 (s, 1 H, =N-NH), 13.55 (s, 1 H, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 8.17 (Me-10), 22.45, 28.70 (C-5,6), 61.06 (MeO-7), 106.43, 117.33 (C-4,12), 109.70, 114.04, 118.51, 119.31, 120.32, 122.23, 124.23, 128.87, 129.58, 130.66, 133.20, 138.95, 143.36, 146.68, 150.80, 154.57, 156.20, 162.12, 162.47, 170.24, 175.94 (Cq), 123.39 (Cp, Ph), 125.30, 128.15 (Co,m, Ph), 141.20 (CH=N), 185.49, 187.71 (C-8,13).
FAB-MS (3NBA) [M + H]⁺: m/z = gef. 640.Maduranic acid 1-phenylthiosemicarbazone (1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-3- (4-phenylthiosemicarbazono) methyl-5,6,8,13-tetrahydrobenzo [a ] naphthacen-2-carboxylic acid), formula I with R 1 = R 3 = R 4 = H, R 2 = NHC (S) NHC 6 H 5 , C 33 H 25 N 3 O 9 S (639.6).
1 H-NMR (DMSO-d 6 ): δ = 2.05 (s, 3 H, Me-10), 2.70-2.93 (m, 4 H, H-5.6), 3.79 (s, 3 H, MeO- 7), 7.06-7.42 (m, 4H), 7.62-7.73 (m, 3 H), 8.53 (s, 1 H), 9.95 (s, 1 H), 11.16 (br., 1 H, OH), 12.02 (s, 1H, = N-NH), 13.55 (s, 1H, COOH).
13 C NMR (DMSO-D 6 ): δ (ppm) = 8.17 (Me-10), 22.45, 28.70 (C-5.6), 61.06 (MeO-7), 106.43, 117.33 (C-4.12 ), 109.70, 114.04, 118.51, 119.31, 120.32, 122.23, 124.23, 128.87, 129.58, 130.66, 133.20, 138.95, 143.36, 146.68, 150.80, 154.57, 156.20, 162.12, 162.47, 170.24, 175.94 (Cq), 123.39 (Cp , Ph), 125.30, 128.15 (C o, m , Ph), 141.20 (CH = N), 185.49, 187.71 (C-8.13).
FAB-MS (3NBA) [M + H] ⁺: m / z = found 640.

26. Substanz 2626. Substance 26

1,9,11,14-Tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-3-(N-piperidinylthiocarbonyl­ hydrazono)methyl-5,6,8,13-tetrahydrobenzo[a]naphthacen-2-carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 = NHC(S)C5H10N, C32H29N3O9S (631.7).
1H-NMR (DMSO-d6): δ = 1.56-1.69 (m, 6 H, CH2, Piperidinyl), 2.05 (s, 3 H, Me-10), 2.67-2.92 (m, 4 H, H-5,6), 3.78 (s, 3 H, MeO-7), 3.85-3.90 (m, 4 H. Piperidinyl), 7.24, 7.36 (2 s, 2 H, H- 4,12), 8.52 (s, 1 H, CH=N), 11.16, 11.21(2 s, 2H, OH), 13.56 (s, 1 H, =N-NH), 14.3 (s. br., 1 H, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 8.18 (Me-10), 22.47, 28.97 (C-5,6), 23.94, 25.75, 51.06 (CH2, Piperidinyl), 61.03 (MeO-7), 106.37, 115.43 (C-4,12), 109.70, 114.00, 118.43, 118.88, 119.77, 122.15, 129.70, 130.71, 134.42, 146.55, 150.75, 155.24, 156.30, 162.11, 162.44, 170.13, 178.09 (Cq), 143.56 (CH=N), 185.52, 187.65 (C-8,13).
FAB-MS (3NBA) [M + H]⁺: m/z = gef. 632. 1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-3- (N-piperidinylthiocarbonyl hydrazono) methyl-5,6,8,13-tetrahydrobenzo [a] naphthacen-2- carboxylic acid), formula I with R 1 = R 3 = R 4 = H, R 2 = NHC (S) C 5 H 10 N, C 32 H 29 N 3 O 9 S (631.7).
1 H NMR (DMSO-d 6 ): δ = 1.56-1.69 (m, 6 H, CH 2 , piperidinyl), 2.05 (s, 3 H, Me-10), 2.67-2.92 (m, 4 H, H -5.6), 3.78 (s, 3 H, MeO-7), 3.85-3.90 (m, 4 H. Piperidinyl), 7.24, 7.36 (2 s, 2 H, H-4.12), 8.52 (s , 1 H, CH = N), 11.16, 11.21 (2 s, 2H, OH), 13.56 (s, 1 H, = N-NH), 14.3 (s. Br., 1 H, COOH).
13 C-NMR (DMSO-D 6 ): δ (ppm) = 8.18 (Me-10), 22.47, 28.97 (C-5.6), 23.94, 25.75, 51.06 (CH 2 , piperidinyl), 61.03 (MeO- 7), 106.37, 115.43 (C-4.12), 109.70, 114.00, 118.43, 118.88, 119.77, 122.15, 129.70, 130.71, 134.42, 146.55, 150.75, 155.24, 156.30, 162.11, 162.44, 170.13, 178.09 (Cq) , 143.56 (CH = N), 185.52, 187.65 (C-8.13).
FAB-MS (3NBA) [M + H] ⁺: m / z = found 632.

27. Substanz 2727. Substance 27

1,9,11,14-Tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-3-(N-morpholinylthiocarbonyl­ hydrazono)methyl-5,6,8,13-tetrahydrobenzo[a]naphthacen-2-carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 = NHC(S)C4H8NO, C31H27N3O10S (633.6).
1H-NMR (DMSO-d6): δ = 2.04 (s, 3 H, Me-10), 2.68-2.90 (m, 4 H, H-5,6), 3.65-3.70 (m, 4 H, CH2, Morpholinyl), 3.78 (s, 3 H, MeO-7), 3.90-3.95 (m, 4 H, Morpholinyl), 7.24, 7.35 (2 s, 2 H, H-4,12), 8.53 (s, 1 H, CH=N), 11.15, 11.39 (2 s, 2 H, OH), 13.55 (s, 1 H, =N-NH), 14.3 (br., 1 H, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 8.17 (Me-10), 22.45, 28.90 (C-5,6), 50.40, 65.99 (CH2, Morpholinyl), 61.03 (MeO-7), 106.39, 115.70 (C-4,12), 109.68, 113.95, 118.45, 119.00, 119.92, 122.17, 129.58, 130.65, 134.00, 146.64, 150.75, 155.01, 156.27, 162.10, 162.45, 170.06, 180.81 (Cq), 143.59 (CH=N), 185.48, 187.69 (C-8,13).
FAB-MS (3NBA) [M + H]⁺: m/z = gef. 634.1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-3- (N-morpholinylthiocarbonyl hydrazono) methyl-5,6,8,13-tetrahydrobenzo [a] naphthacen-2- carboxylic acid), formula I with R 1 = R 3 = R 4 = H, R 2 = NHC (S) C 4 H 8 NO, C 31 H 27 N 3 O 10 S (633.6).
1 H-NMR (DMSO-d 6 ): δ = 2.04 (s, 3 H, Me-10), 2.68-2.90 (m, 4 H, H-5.6), 3.65-3.70 (m, 4 H, CH 2 , morpholinyl), 3.78 (s, 3 H, MeO-7), 3.90-3.95 (m, 4 H, morpholinyl), 7.24, 7.35 (2 s, 2 H, H-4.12), 8.53 (s , 1 H, CH = N), 11.15, 11.39 (2 s, 2 H, OH), 13.55 (s, 1 H, = N-NH), 14.3 (br., 1 H, COOH).
13 C NMR (DMSO-D 6 ): δ (ppm) = 8.17 (Me-10), 22.45, 28.90 (C-5.6), 50.40, 65.99 (CH 2 , morpholinyl), 61.03 (MeO-7) , 106.39, 115.70 (C-4.12), 109.68, 113.95, 118.45, 119.00, 119.92, 122.17, 129.58, 130.65, 134.00, 146.64, 150.75, 155.01, 156.27, 162.10, 162.45, 170.06, 180.81 (Cq), 143.59 (CH = N), 185.48, 187.69 (C-8.13).
FAB-MS (3NBA) [M + H] ⁺: m / z = found 634.

28. Substanz 2828. Substance 28

Maduransäure-4-allylthiosemicarbazon (3-(4-Allylthiosemicarbazono)methyl-1,9,11,14- tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo[a]naphthacen-2- carbonsäure), Formel I mit R1 = R3 = R4 = H, R2 = NHC(S)NHCH2CH=CH2, C30H25N3O9S (603.6).Maduranic acid 4-allylthiosemicarbazon (3- (4-allylthiosemicarbazono) methyl-1,9,11,14-tetrahydroxy-7-methoxy-10-methyl-8,13-dioxo-5,6,8,13-tetrahydrobenzo [a ] naphthacen-2-carboxylic acid), formula I with R 1 = R 3 = R 4 = H, R 2 = NHC (S) NHCH 2 CH = CH 2 , C 30 H 25 N 3 O 9 S (603.6).

Ein Gemisch aus Madurahydroxylacton (300 mg), 4-Allylthiosemicarbazid (150 mg) und Eisessig (20 ml) wird 30 Min. zum Rückfluß erhitzt. Das nach dem Abkühlen ausgefallene Rohprodukt wird mit Tetrahydrofuran-Petrolether umgefällt (Ausbeute 160 mg).
1H-NMR (DMSO-D6): δ (ppm) = 2.07 (s, 3 H, Me-10), 2.77 (m, 4 H, H-5,6), 3.80 (s, 3 H, MeO- 7), 5.09-5.22 (m, 2 H, =CH2, Allyl), 5.80-6.10 (m, 1 H, HC=C, Allyl), 7.26, 7.59 (2s, 2 H, H- 4,12), 8.57 (s, 1 H, CH=N), 11.16, 11.69, 13.59, 14.08 (4 s, 4H, =N-NH, 2 x OH, COOH).
13C-NMR (DMSO-D6): δ (ppm) = 8.10 (Me-10), 22.37, 28.81 (C-5,6), 46.60 (CH2, Allyl), 61.05 (MeO-7), 106.26, 116.08 (C-4,12), 115.49 (=CH2, Allyl), 134.90 (=CH, Allyl), 141.25 (CH=N), 177.30 (COOH).
FAB-MS (3NBA) [M + H]⁺: m/z = gef. 604. A mixture of madura hydroxylactone (300 mg), 4-allyl thiosemicarbazide (150 mg) and glacial acetic acid (20 ml) is heated to reflux for 30 minutes. The crude product which has precipitated after cooling is reprecipitated with tetrahydrofuran-petroleum ether (yield 160 mg).
1 H NMR (DMSO-D 6 ): δ (ppm) = 2.07 (s, 3 H, Me-10), 2.77 (m, 4 H, H-5.6), 3.80 (s, 3 H, MeO) - 7), 5.09-5.22 (m, 2 H, = CH 2 , allyl), 5.80-6.10 (m, 1 H, HC = C, allyl), 7.26, 7.59 (2s, 2 H, H- 4.12 ), 8.57 (s, 1 H, CH = N), 11.16, 11.69, 13.59, 14.08 (4 s, 4H, = N-NH, 2 x OH, COOH).
13 C NMR (DMSO-D 6 ): δ (ppm) = 8.10 (Me-10), 22.37, 28.81 (C-5.6), 46.60 (CH 2 , allyl), 61.05 (MeO-7), 106.26 , 116.08 (C-4.12), 115.49 (= CH 2 , allyl), 134.90 (= CH, allyl), 141.25 (CH = N), 177.30 (COOH).
FAB-MS (3NBA) [M + H] ⁺: m / z = found 604.

Hemmung der mikrosomalen Humanplazenta-Sulfatase durch Iminderivate des MadurhydroxylactonsInhibition of microsomal human placenta sulfatase by imine derivatives of madurhydroxylactone

Hemmung der mikrosomalen Humanplazenta-Sulfatase durch Iminderivate des MadurhydroxylactonsInhibition of microsomal human placenta sulfatase by imine derivatives of madurhydroxylactone

Claims (6)

1. Verbindungen der Formel I,
worin R1 = H bedeutet und
R2 = H, Alkyl oder substituiertes Alkyl, Alkenyl oder substituiertes Alkenyl, Cycloalkyl oder substituiertes Cycloalkyl, Aryl oder substituiertes Aryl, Aralkyl, ein Rest der Formel
-OR5, worin R5 = H, Alkyl oder substituiertes Alkyl, Alkenyl oder substituiertes Alkenyl, Cycloalkyl oder substituiertes Cycloalkyl, Aryl oder substituiertes Aryl, Aralkyl oder Acyl sein können,
-NR6R7, worin R6 und R7 unabhängig voneinander H, Alkyl oder substituiertes Alkyl, Alkenyl oder substituiertes Alkenyl, Cycloalkyl oder substituiertes Cycloalkyl, Aryl oder substituiertes Aryl, Aralkyl, Acyl bedeuten oder zusammen mit dem an sie geknüpften Stickstoffatom einen Ring bilden,
-NR8-C(Z)-NR9R10, worin Z = O, S, NR11 und R8, R9, R10 und R11 unabhängig voneinander H, Alkyl oder substituiertes Alkyl, Alkenyl oder substituiertes Alkenyl, Cycloalkyl oder substituiertes Cycloalkyl, Aryl oder substituiertes Aryl, Aralkyl, Acyl bedeuten, R11 darüber hinaus auch Cyano oder Nitro, R9 und R10 zusammen mit dem an sie geknüpften Stickstoffatom einen Ring bilden können, und
R3 und R4 unabhängig voneinander für Wasserstoff, Alkyl oder Acyl stehen, sowie Salze von Verbindungen der Formel I.1. Compounds of the formula I
where R 1 = H and
R 2 = H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, aralkyl, a radical of the formula
-OR 5 , where R 5 = H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, aralkyl or acyl,
-NR 6 R 7 , wherein R 6 and R 7 independently of one another are H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, aralkyl, acyl or together with the nitrogen atom attached to them a ring form,
-NR 8 -C (Z) -NR 9 R 10 , wherein Z = O, S, NR 11 and R 8 , R 9 , R 10 and R 11 independently of one another H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, aralkyl, acyl, R 11 can also form cyano or nitro, R 9 and R 10 together with the nitrogen atom attached to them can form a ring, and
R 3 and R 4 are independently hydrogen, alkyl or acyl, and salts of compounds of the formula I. 2. Verbindungen der Formel I gemäß Anspruch 1, worin R1 = H, ein Alkalimetallatom oder ein Ammonium-, insbesondere Trialkylammonium- oder ein N-Methyl-D-glucammoniurnion, bedeutet.2. Compounds of formula I according to claim 1, wherein R 1 = H, an alkali metal atom or an ammonium, in particular trialkylammonium or an N-methyl-D-glucammonium ion. 3. Verbindungen der Formel I gemäß Anspruch 1, worin R2 ein Rest der Formel
-NR6R7 oder -NR8-C(Z)-NR9R10
bedeutet, in dem R6 und R7 bzw. R9 und R10 Alkylen-Reste zusammen mit dem Stickstoffatom, an das sie geknüpft sind, Ringe bilden, die insbesondere 4 bis 6 Ringatome enthalten, wobei die durch die Alkylenreste R6 und R7 bzw. R9 und R10 gebildete Kohlenstoffkette durch eines oder mehrere Heteroatome aus der Gruppe Sauerstoffs Schwefel oder Stickstoff (-NH- oder NR8-) unterbrochen sein kann.3. Compounds of formula I according to claim 1, wherein R 2 is a radical of the formula
-NR 6 R 7 or -NR 8 -C (Z) -NR 9 R 10
means, in which R 6 and R 7 or R 9 and R 10 alkylene radicals together with the nitrogen atom to which they are attached form rings which contain in particular 4 to 6 ring atoms, with the alkylene radicals R 6 and R 7 or R 9 and R 10 formed carbon chain can be interrupted by one or more heteroatoms from the group consisting of oxygen, sulfur or nitrogen (-NH- or NR 8 -). 4. 3-(4-Cydohexylthiosemicarbazono)methyl-1,9,11,14-tetrahydroxy-7-methoxy- 10-methyl- 8,13-dioxo-5,6,8,13-tetrahydrobenzo[a]naphthacen-2-carbonsäure gemäß Anspruch 1.4. 3- (4-Cydohexylthiosemicarbazono) methyl-1,9,11,11,1-tetrahydroxy-7-methoxy-10-methyl 8,13-dioxo-5,6,8,13-tetrahydrobenzo [a] naphthacen-2-carboxylic acid according to claim 1. 5. Verwendung von Verbindungen der Formel I gemäß Anspruch 1 zur Herstellung von Arzneimitteln.5. Use of compounds of formula I according to claim 1 for the preparation of Medicines. 6. Arzneimittel enthaltend eine Verbindung der Formel I gemäß Anspruch 1 zusammen mit einem oder mehreren pharmazeutisch annehmbaren Trägern.6. Medicament containing a compound of formula I according to claim 1 together with one or more pharmaceutically acceptable carriers.
DE19701664A 1997-01-18 1997-01-18 New derivatives of madura hydroxylactone, process for their preparation and their use Withdrawn DE19701664A1 (en)

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PCT/DE1998/000124 WO1998031659A1 (en) 1997-01-18 1998-01-15 Imine derivates of madurahydroylacton, method for their production and pharmaceutical preparations containing these compounds

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