Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ketone doai
Reexamination Certificate
2001-09-27
2003-07-22
Pryor, Alton N. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ketone doai
C514S680000, C552S289000, C552S290000
Reexamination Certificate
active
06596774
ABSTRACT:
BACKGROUND OF THE INVENTION
Field of the invention. The synthesis of a series of 1,5-dichloro-9(10H)-anthracenones bearing O-linked and N-linked substituents in the 10-position are described. These compounds were evaluated for their ability to inhibit the growth of the tumor, and lipid peroxidation in model membranes.
Description of the prior art. Anthracenone derivatives display potent and selective antitumor activity, but their mechanism of action is not clearly established yet. Despite structural similarities between the substitutents anthracenone nucleus and molecules possessing known antitumor activity, antiproliferative, antipsoriatic, antiinflammatory, or antioxidant activity, these agents form a distinct mechanictic class. Perry P. J., et al., J. Med. Chem., vol. 41, pp. 3253-3260, 4873-4884 (1998); Perry P. J., et al., J. Med. Chem., vol. 42, pp. 2679-2684 (1999). Anthracene and anthracenone derivatives have been the subject of extensive research mainly due to their well-recognized biological importance and the significant biological applications. Although potential drug targets only present in cancerous cells have surfaced, the design of a drug which is selectively toxic to a tumor and not to the host organism is still very difficult have reported by Krapcho A. P., et al., J. Med. Chem., vol. 41, pp. 5429-5444 (1998).
We have previously shown that 9-acyloxy 1,5-dichloroanthracenes at WO 0061536 and 9-acyloxy 1,8-dichloroanthracenes on Chem. Pharm. Bull., vol. 49(8), pp. 969-973(2001). In the previous papers, we described the synthesis, biological evaluation and structure-activity relationships for 9-acyloxy derivatives. In order to provide further insight into anthracene and anthracenone pharmacophore, the involvement of free radicals and antiproliferative activity, we examined the effects of introducing electron-donating 10-oxy and 10-N substituents to see where replacement of the electron-withdrawing carbonyl of the earlier series can provide analogs with both potent antioxidant and antiproliferative activities. Despite the extensive and long-standing therapeutic utilization of anthracenones, their mechanism of action is still uncertain. A large body of evidence is consistent with a fundamental role of oxygen radicals in the induction of skin inflammation by anthracenes of Müller K., Biochem. Pharmacol., vol. 53, pp. 1215-1221 (1997).
The mode of action of anthracenones leads to the conclusion that no single mechanism is predominantly operative and oxygen radicals play a crucial role in the proinflammatory action. As noted above, cancer is typically characterized by hyperproliferative component. There is thus a continuing need for effective compounds that address these aspects of cancer disease. To gain a wider understanding of the involvement of radicals in the action of anthracenone-derived agents, several related compounds bearing selected characteristic functional groups were designed. The approach was to develop structure-activity relationships (SARs) of 9(10H)-anthracenone analogs with redox-active centers attached to the anthraquinone skeleton through spacer side chains at position 10, together with substituents with DNA-binding affinity. This paper describes the design and synthesis of anthracenones that incorporate in their structure a potential antioxidant component and the results of relevant biologic studies.
SUMMARY OF THE INVENTION
The present invention is described the novel 1,5-dichloro-9(10H)-anthracenones bearing O-linked and N-linked substituents compounds and analogs thereof having therapeutic utility with respect to tumor conditions or antioxidant activity. In particular, many of the improved anthracenone compounds provided for according to the practice of the invention are effective at low concentrations for treatment of patients suffering from tumor conditions or antioxidant activity.
Accordingly, in one embodiment of the invention, there is provided an anthracene compound according to formula 3 as defined below and shown in
FIG. 1
, said compound containing substituent R
1
, wherein R
1
represents oxygen, nitrogen. The substituent R
2
, wherein R
2
represents a branched or straight chain alkyl group having from 1 to 4 carbon atoms, said alkyl group being substituted with at least one substituent selected from the group consisting of a carboxyl, hydrogen, substituted phenyl, benzyl and substituted benzyl groups or a substituted phenyl group.
Still other objects and advantages of the present invention will become readily apparent to those skilled in this art from the following detailed description wherein I have shown and described only the preferred embodiment of the invention, simply by way of illustration of the best mode contemplated by carrying out my invention. As will be realized, the invention is capable of modification in various obvious respects all without departing from the invention. Accordingly, the drawings and description of the preferred embodiment are to be regarded as illustrative in nature, and not as restrictive.
REFERENCES:
Beilstein Record 3388717; Feb. 15, 1990.*
Beilstein Record 3414294; Feb. 15, 1990.*
Beilstein Record 3458641; Feb. 15, 1990.*
Haung et al., Studies on anthracenes, Chemical & Pharmaceutical Bulletin, 2001, 49(10), 1288-91.*
Cook et al, Recl. Trav. Chim. Pays-Bas, 44, 1925, 897.*
Barnett et al, Chem.Ber., 62, 1929.*
Preparation of Anthraquinones From 10-Hydroxy-9Anthracenecarbonitriles Obtained From a Novel Aryne Annulation Reaction, Bhawal, et al, J. Org. Chem, vol. 56, No. 8, 1991, pp. 2846-2849.
Studies Related to the Conversion of 9,10-Anthraquinones to Anthracenes, Criswell, et al, J. Org. Chem, vol. 39, No. 6, 1974, pp. 770-774.
Synthesis and Antitumor Evaluation of 2,5-Disubstituted-Indazolo[4,3-GH]Isoqunolin-6(2H)-Ones (9-Aza-Anthrapyrazoles), Krapcho, et al, J. Med. Chem. 1998 41, 5429-5444.
Antipsoriatic and Proinflammatory Action of Anthralin—Implication for the Role of Oxygen Radicals, Klaus Muller, Biochemical Pharmacology, vol. 53, pp. 1215-1221, 1997.
Antipsoriatic Anthrones With Modulated Redox Properties. 3. 10-Thio-Substituted 1,8-Dihydroxy-9(10H)-Anthracenones as Inhibitors or Keratinocyte Growth, 5-Lipoxygenase, and the Formation of 12(2)-Hete in Mouse Epidermis, Muller, et al, Journal of Medicinal Chemistry, vol. 39, No. 16, pp. 3132-3138.
Syntheses of Anthracenones. 1. Sodium Dithionite Reduction of Peri-Substituted Anthracenediones, J. Org. Chem, 1996, 61, 2853-2856.
Conversion of Alkoxy-9,10-Anthraquinones to Alkoxyanthracenes, Shyamasundar, et al, J. Org. Chem, 1981, 46, 809-811.
Lithium Aluminum Hydride Reduction of Peri-Alkoxy-9,10-Anthraquinones, Shyamasudar, et al, J. Org. Chem, 1981, 46, 1552-1557.
N-Allylsecoboldine as a Novel Antioxidant Against Peroxidative Damage, Teng, et al, European Journal of Pharmacology 303, 1996, 129-139.
Studies on Anthracenes. 3. Synthesis, Lipid Peroxidation and Cytotoxic Evaluation of 10-Substituted 1,5-Dichloro-9(10H)-Anthroacenone Derivatives, Huang, et al, Chem. Pharm. Bull. 49, No. 10, 2001 Pharmaceutical Society of Japan.
Studies on Anthracenes. 1. Human Telemerase Inhibition and Lipid Peroxidation of 9-Acyloxy 1,5-Dichloroanthracene Derivatives, Huang, et al, Chem. Pharm. Bull. 49(8) 969-973, 2001 Pharmaceutical Society of Japan.
Dykas Frank J.
Nipper Stephen M.
Pryor Alton N.
Shaver Robert L.
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