Clinical studies using mitoxantrone, an anthraquinone, were begun in the United States in 1979. Subsequent phase II and III trials have shown that mitoxantrone has significant clinical activity in patients with breast cancer, acute leukemia, and lymphoma. The drug has antiviral, antibacterial, antiprotozoal, immunomodulating, and antineoplastic properties and is mutagenic in some animal systems. Its mechanism of action seems to involve both DNA intercalation and nonintercalative electrostatic interactions. The dose-limiting toxicity is myelosuppression when the drug is given on a single-dose, every-3-week schedule and mucositis when it is given daily for 5 days. Other toxicities include gastrointestinal and cardiac effects, the gastrointestinal toxicity being less severe and less frequent than that with the anthracycline anticancer drugs. Because of its low incidence of serious toxicities and effectiveness in treating certain solid tumors and leukemias, mitoxantrone is a promising new agent in the treatment of cancer.

Mitoxantrone: a new anticancer drug with significant clinical activity.

Imidazoquinoline and tetrahydroimidazoquinoline compounds that contain sulfonamide or sulfonamide functionality at the 1-position are useful as immune response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.

Sulfonamide and sulfamide substituted imidazoquinolines

Imidazoquinoline and tetrahydroimidazoquinoline compounds that contain amide functionality at the 1-position are useful as immune response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.

Amide substituted imidazoquinolines

Imidazoquinoline and tetrahydroimidazoquinoline compounds that contain thioether functionality at the 1-position are useful as immune response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.

Thioether substituted imidazoquinolines

Imidazoquinoline and tetrahydroimidazoquinoline compounds that contain ether and aryl or alkenyl functionality at the 1-position are useful as immune response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.

Aryl ether substituted imidazoquinolines

Bis-basic-substituted polycyclic aromatic compounds. A new class of antiviral agents. 2. Tilorone and related bis-basic ethers of fluorenone, fluorenol, and fluorene.

A series of bisalkamine esters, bis-basic ethers, and bis-basic ketones of carbazole, N-ethylcarbazole, dibenzofuran, and dibenzothiophene was synthesized and evaluated for antiviral activity. The series also included two bis-basic alkanes of N-ethylcarbazole and one bis-basic carboxamide of dibenzofuran. Structure-activity relationships indicated that within the carbazole and N-ethylcarbazole series the bisalkamine esters gave the most active derivatives while the bis-basic ketone derivatives of dibenzofuran and dibenzothiophene afforded the more potent compounds within the respective series. The [6,5,6]heterocyclic nuclei were compared with the [6,5,6] aromatic nuclei (fluroene and fluoren-9-one) including tilorone with respect to antiviral activity against encephalomyocarditis (EMC) virus. Maximum activity was associated with the bis-basic ketone side chain and fluoren-9-one nucleus.

Bis-basic-substituted polycyclic aromatic compounds. A new class of antiviral agents. 8. Bis-basic derivatives of carbazole, dibenzofuran, and dibenzothiophene.

Novel pharmaceutical compositions containing bis-basic ethers and thioethers of fluorenone and fluorene selected from a base of the formula WHEREIN: Z is oxygen or H2; each Y is oxygen or sulfur; and each X is A. the group WHEREIN A is alkylene of two to about eight carbon atoms and separates the amino nitrogen thereof and Y by an alkylene chain of at least two carbon atoms, each R and R1 is hydrogen, (lower)alkyl, cycloalkyl of three to six ring carbon atoms, alkenyl of three to six carbon atoms having the vinyl unsaturation in other than the 1-position of the alkenyl group, or each set of R and R1 taken together with the nitrogen to which they are attached is pyrrolidino, piperidino, N(lower)alkylpiperazino, or morpholino; or B. the group WHEREIN N IS AN INTEGER OF 0 TO 2, M IS 1 OR 2 AND R2 is hydrogen, (lower)alkyl, or alkenyl of three to six carbon atoms having the vinyl unsaturation in other than the 1-position of the alkenyl group; or a pharmaceutically acceptable acid addition salt of said base. These compositions can be used as pharmaceuticals for preventing or inhibiting a viral infection.

Treating viral infections with bis-basic ethers and thioethers of fluorenone and fluorene and pharmaceutical compositons of the same

Bis-basic-substituted polycyclic aromatic compounds. A new class of antiviral agents. 5. Bis-basic ethers of anthraquinone and bisalkamine esters of anthraquinonedicarboxylic acids.

Robert W. Fleming

Papers

Bis-basic-substituted polycyclic aromatic compounds. A new class of antiviral agents. 2. Tilorone and related bis-basic ethers of fluorenone, fluorenol, and fluorene.

Bis-basic-substituted polycyclic aromatic compounds. A new class of antiviral agents. 8. Bis-basic derivatives of carbazole, dibenzofuran, and dibenzothiophene.

Treating viral infections with bis-basic ethers and thioethers of fluorenone and fluorene and pharmaceutical compositons of the same

Bis-basic-substituted polycyclic aromatic compounds. A new class of antiviral agents. 5. Bis-basic ethers of anthraquinone and bisalkamine esters of anthraquinonedicarboxylic acids.

Bis-basic-substituted polycyclic aromatic compounds. A new class of antiviral agents. 3. 2,7-Bis(aminoacyl)fluorenes and -fluorenones.