Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-11-06
2004-12-07
Tsang, Cecilia J. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S685000, C549S293000, C549S296000, C549S297000, C552S304000, C552S304000, C552S304000
Reexamination Certificate
active
06828347
ABSTRACT:
FIELD OF INVENTION
The present invention relates to a method of regiospecific synthesis of multi-quinone compounds. The invention also relates to novel biquinones and trimeric quinones, particularly those that have antiviral activity.
BACKGROUND OF THE INVENTION
Acquired immune deficiency syndrome (AIDS) is a fatal disease caused by the human immunodeficiency virus (HIV) that afflicts millions of people worldwide. Many current commercially available drugs used to treat HIV act by inhibiting either the enzymes reverse transcriptase or protease. The use of combinations or cocktails of these two classes of drugs has enabled a great number of HIV-infected individuals to keep the virus in check and stay alive. Some patients, however, do not respond to multi-drug therapy, and side effects of several current drugs can be serious. In many cases, HIV develops resistance to existing therapies, and thus there is an urgent need for the continued development of new classes of anti-HIV agents. The seriousness of the AIDS epidemic has resulted in an effort to discover novel HIV inhibitory agents from natural sources as well as man-made drugs.
U.S. Pat. Nos. 5,672,607; 5,783,598; and 5,869,522, all issued to Boyd et al., disclose the isolation of conocurvone from a plant of the genus Conospermum, commonly known as the western Australian smoke bush. The chemical structure of conocurvone was determined to be a trimeric naphthoquinone derivative. The Boyd et al. Patents disclose that conocurvone had been found to inhibit the growth and replication of viruses, and particularly retroviruses such as an HIV.
The Boyd et al. Patents disclose methods of isolating and purifying naturally occurring trimeric naphthoquinone derivatives from plants of the genus Conospermum. In addition, the Boyd et al. Patents disclose synthesizing trimeric naphthoquinones through acid-coupling or base-coupling a 2,3-deoxy-1,4-napthoquinone compound with two other naphthoquinone monomers. The result of this process is a mixture of numerous monomeric naphthoquinone, dimeric naphthoquinone, and trimeric naphthoquinone derivatives. The trimeric naphthoquinone is isolated, purified, and identified by the anti-HIV properties through immunoassay. The Boyd et al. Patents disclose that the naphthoquinone derivatives can be easily distinguished from the monomeric and dimeric naphthoquinones as these compounds were both found to be devoid of antiviral activity. The observed biological activity of conocurvone was thus attributed to the trimeric quinone structure.
Conocurvone and other trimeric quinones may possess a completely novel mechanism of HIV-inhibition by acting against integrase and fusion of HIV to CD4 T-lymphocytes. Therefore, there is a need for methods for synthesis of chemical compounds having a trimeric quinone structure. There is also a need for methods of trimeric quinone synthesis that allow more control over the specific quinone derivatives formed, and provides increased yields of the desired quinone derivatives.
There is a need for a method that can be used to controllably produce various multi-quinone derivatives to facilitate structure-activity-relationship studies that will be crucial to the possible development of new anti-HIV quinone compounds and medicinal compositions. Thus there is a need for dimeric quinone derivatives, and methods to form the dimeric quinone derivatives, which can be used to controllably synthesize trimeric quinone derivatives.
SUMMARY OF THE INVENTION
A general object of the invention is to provide a method for regiospecific synthesis of multi-quinone compounds. A more specific objective of the invention is to overcome one or more of the problems described above. The general object of the invention can be attained, at least in part, through a method for synthesis of a multi-quinone compound including reacting a hydroxyquinone anion with a first quinone possessing a first directing group at a C-2 of the first quinone and a second directing group at a C-3 of the first quinone and obtaining a biquinone having one of the first and second directing groups at a C-3 of a first quinone monomer and a hydroxyl group at a C-3 ′ of a second quinone monomer. One of the first and second directing groups is selected from a group consisting of fluorine, chlorine, bromine, iodine, and a non-halogen, and another of the first and second directing groups is selected from a group consisting of iodine and a non-halogen.
The biquinone can be further reacted in the presence of a base to substitute the hydroxyl group with a different chemical group, such as an alkyl ether, a halogen, an amine, a sulfonate ester, an aryl, a heteroaryl, an aryl ester, an alkyl ester, an alkyl amide, an aryl amide, or a carbamate. The biquinone can also be further reacted with a nucleophile. The nucleophile can substitute for the other of the first and second directing group. The nucleophile, for example, can be an amine analog or a second hydroxyquinone anion. Reacting the biquinone with the second hydroxyquinone anion results in a trimeric quinone. The invention also relates to various biquinone derivatives and trimeric quinone derivatives.
The invention relates to a method for treating a viral infection by administering to a host an antiviral biquinone compound including a first group at a C-3 position and a second group at a C-3′ position. The first group can include a halogen, an ester group, an amide group, a carbamate group, an alkoxyl group, a hydroxyl group, a thiol group, a sulfide group, a primary aliphatic amine, a secondary aliphatic amine, a tertiary aliphatic amine, a cyclic amine, an alkyl, a functionalized alkyl, an alkyne, an alkene, an aryl, or a heteroaryl. The second group can include a halogen, an ester group, an amide group, a carbamate group, an alkoxyl group, a hydroxyl group, a thiol group, a sulfide group, an amine analog, an alkyl, a functionalized alkyl, an alkynyl, an alkenyl, an aryl, or a heteroaryl. Viral infections can also be treated with the trimeric quinones of this invention.
Other objects and advantages will be apparent to those skilled in the art from the following detailed description taken in conjunction with the appended claims.
DESCRIPTION OF PREFERRED EMBODIMENTS
The present invention relates to the development of a method for the regiospecific synthesis of dimeric and trimeric quinone derivatives, also referred to below as biquinones and triquinones respectively. The disclosed method provides control over the placement of functional groups on the carbon atoms of biquinones and trimeric quinones. The invention also relates to new biquinone and trimeric quinone derivatives. The methods and derivatives of this invention facilitate structure-activity-relationship studies that will be crucial to the possible development of new anti-HIV quinone compounds and medicinal compositions.
In one embodiment of this invention, a method for synthesis of a multi-quinone compound includes reacting a hydroxyquinone anion with a first quinone. “Multi-quinone” refers to a chemical compound having more than one quinone monomer. “Quinone” refers to dicarbonyl compounds including two carbonyl groups within a six carbon ring. “Quinone” includes various quinone derivatives including benzoquinone derivatives and naphthoquinone derivatives. The multi-quinone compounds of this invention can include identical quinone monomers or two or more different quinone monomers, such as a biquinone having a benzoquinone monomer bonded to a naphthoquinone monomer.
The first quinone includes at least two directing groups; a first directing group at a carbon-2 (C-2) position of the first quinone and a second directing group at a carbon-3 (C-3). “Carbon-2” or “C-2” refers to one of the six carbon atoms of the quinone core located next to one of the carbons bearing a double bonded oxygen atom (the carbonyl group). “Carbon-3” or “C-3” refers to another of the six carbon atoms of the quinone core next to the C-2 and next to the other carbon bearing a double bonded oxygen atom (the carbonyl group). In one embodiment of t
Emadi Ashkan
Stagliano Kenneth William
Covington Raymond
Illinois Institute of Technology
Pauley Petersen & Erickson
Tsang Cecilia J.
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