J. Org. Chem. 1988,53,5301-5304
5301
Synthesis of 1-Functionalized 5-Methylnaphtho[ 2,3-g]isoquinoline-6,1l-quinones Martine Croisy-Delcey,f Marilys Rautureau,? Christiane Huel,* and Emile Bisagni*pt UA 533 CNRS, Laboratoire d e Synthase Organique, a n d U 219 INSERM-Biophysique, Institut Curie, Section d e Biologie, Bcitiments 110-112,15,rue Georges Clgmenceau, 91405 Orsay, France Received M a y 12, 1988
l-Chloro-5-methylnaphtho[2,3-g]isoquinoline-6,ll-quinones were obtained through two independent pathways: (i) by Diels-Alder reaction of 1-chloro-5-methylbenzo[g]isoquinoline-6,9-quinone with 1,4-diacetoxybutadiene; with 4-acetyl-2-chloro-3-1ithiopyridine ethylene glycol (ii) by condensation of 2-formyl-l,4-dimethoxynaphthalenes ketal and transformation of the resulting key intermediates by a reduction-hydrolysis-cyclization-demethylation-oxidation one-pot process. Whereas 1-substitution of l-chloro-5-methylnaphtho[2,3-g]isoquinoline-6,11quinone itself by amines took place cleanly, the corresponding 10-hydroxy derivative led to complex mixtures.
For the last few years, various studies in our laboratory have been devoted to the synthesis of antitumor drugs derived from polyheterocyclic systems and bearing a [ (dialkylamino)alkyl]aminoside chain.lS2 These chains have been shown to increase strongly the antitumor properties of the corresponding unsubstituted compounds, as demonstrated by the potent activities of 1-[[3-(diethylamino)propyl] amino]-5,11-dimethyl-9-methoxy-6Hpyrido[4,3-b]carbazole (1,BD84),3 which is now under clinical investigation, and lo-[[3-(diethy1amino)propyllamino]-6-methyl-5H-pyrido[3',4':4,5]pyrrolo[ 2,3-g]isoquinoline (2, BD40),4 which has demonstrated high activity /
2
3
'CH~CH,
x&H2cH2cH2N
N
I
H
1
CH,
1 : R=CH,X=C-OCH3 2 : R=H X=N
on numerous experimental tumors5 as well as in various human cancers during phase I clinical trials.6 We have also synthesized and screened various polycyclic quinones, which correspond to general formulas 3,4,798and 5,9respectively.
0
CH,
6
sponding quinone 8 in 93% yield. Diels-Alder addition to this quinone and subsequent of 1,4-dia~etoxybutadiene'~ elimination of acetoxy groups gave 1-chloro-Bmethylnaphtho[2,3-g]isoquinoline-6,1l-quinone9, which reacted with primary amines to provide the corresponding 1-amino derivatives 10 with a 31.5% overall yield. These amines were also obtained in the opposite sequence of steps (Scheme I), with a 36% overall yield. However, applying this pathway to unsymmetrical dienes would probably give the two possible isomers, difficult to separate. In order to easily obtain specifically A ring substituted derivatives, another route to such compounds was then worked out, starting from 2-formyl-l,4-dimethoxynaphthalenes 13. Thus, reaction of 1,4-dimethoxy-2-naphthaldehyde (13a)13with 4-acetyl-2-chloro-3-lithiopyridine ethylene glycol ketal 14'O afforded 4-acetyl-2-chloro-3-[hydroxy[2-(1,4-dimethoxynaphthyl)]methyl]pyridine ethylene glycol ketal (15a). Reduction of this alcohol by triethyl-
w&Jy$ )%P OH
OH
0
0
NHR
OH
OH
0
OH
3
0
4
NHR
HR
0
5
However, all these new products related to mitoxantrone, anthracyclinones, and mimocine were found inactive and our continuing interest in this area led us to design new target molecules related to both compounds 1-2 and 3-4. Thus, maintaining the isoquinoline part of compounds 1 and 2 but replacing their indole (or 5-maindole) nucleus by a quinone system resulted in the general structure 6. In this paper, we describe the two ways that allowed us to prepare such polycyclic derivatives. Cerium ammonium nitrate (CAN) oxidation of 1chloro-5-methyl-6,9-dimethoxybenzo[g]isoquinoline 7,1° performed under the usual conditions," led to the corre-
* To whom correspondance
*
should be adressed. UA 533 CNRS, Laboratoire de Synthsse Organique. U 219 INSERM-Biophysique.
(1) Ducrocq, C.; Bisagni, E.; Rivalle, C.; Lhoste, J.-M., J.Chem. SOC., Perkin Trans- 1 1979, 142. (2) Bisagni, E.; Ducrocq, C.; Lhoste J.-M.; Rivalle, C.; Civier, A. J. Chem. Soc.. Perkin Trans. 1 1979. 1706. (3) Ducrocq, C.; Wendling, F.; Tourbez-Perrin, M.; Rivalle, C.; Tambourin, p.; Pochon, F.; Bisagni, E.; Chermann, J. C. J. Med. Chem. 1980, 23, 1212. (4) Chermann, J. C.; Gruest, J.; Montagnier, L.; Wendling, F.; Tambourin, p.; Perrin, M.; Pochon, F.; Ducrocq, C.; Rivalle, C.; Bisagni, E. C.R. Acad. Sci. Ser. D 1977, 285, 945. (5) Lidereau, R.; Chermann, J. C.; Gruest, J.; Montagnier, L.; Ducrocq, C.; Rivalle, C.; Bisagni, E. Bull. Cancer 1980, 67, 1. (6) Marty, M.; Jasmin, C.; Pouillart, P.; Gisselbrecht, C.; Gouvenia, G.; Magdelainat, H. 17th Annual Meeting of the American Society of Clinical Oncology 1981, C-108. (7) Croisy-Delcey, M.; Bisagni, E. J. Chem. SOC., Chem. Commun. 1984, 897. (8) Croisy-Delcey, M.; Carrez, D.; Bisagni, E. Eur. J.Med. Chem. 1988, 23, 101. (9) Croisy-Delcey,M.; Huel, C.; Bisagni, E. J.Heterocycl. Chem. 1988, 22,661. (10)Bisagni, E.; Rautureau, M.; Croisy-Delcey, M.; Huel, C. Can. J. Chem. 1987,65, 2027. (11)Kubo, A.: Kitahara. Y.: Nakahara, S., Numaka, R. Chem. Pharm. Bull. 1983, 31, 341. (12) Echavarren, A.; Prados, P.; Del Sol, G.; Farina, F. J. Chem. Res. 1981, 3675. (13) Watanabe, M.; Maenosono, H.; Furukawa, S. Chem. Pharm. Bull. 1983, 31, 2662.
0022-3263/88/1953-5301$01.50/00 1988 American Chemical Society
5302 J . Org. Chem., Vol. 53, No. 22, 1988
Croisy-Delcey et al.
Scheme I
\
/
Protocols by F. Lavelle, SociBtB Rhbne Poulenc Santg, Vitry-sur-Seine (L1210 cultured cells and P388 leukemia system). No interesting biological property was detected for these compounds. \
/
/
Experimental Section
-*
All melting points (uncorrected) were determined with a Kofler apparatus. 'H NMR spectra were recorded with a Varian XLlOO 7 8 9 spectrometer. Me,Si was used as internal standard, and chemical OAc shifts are reported on the 6 scale, with peak multiplicities. Elemental analysis were performed by Service Central de MicroNHR analyses du CNRS (91190 Gif-sur-Yvette, France). CAN
