WO1998039287A1

WO1998039287A1 - Benzanthrone compounds and antiviral uses thereof

Info

Publication number: WO1998039287A1
Application number: PCT/US1998/004140
Authority: WO
Inventors: Michael R. Johnson; Myung-Chol Kang; Alexei G. Nemazany; Kenner C. Rice
Original assignee: Trimeris Inc; US Department of Health and Human Services
Current assignee: Trimeris Inc; US Department of Health and Human Services
Priority date: 1997-03-05
Filing date: 1998-03-04
Publication date: 1998-09-11
Anticipated expiration: 1999-09-05
Also published as: AU6680998A; EP1021397A4; EP1021397A1; AR012553A1

Abstract

The present invention relates to benzanthrones and benzanthrone derivatives having antiviral properties and to antiviral compositions that include at least one benzanthrone or benzanthrone derivative having antiviral properties. Benzanthrones and benzanthrone derivatives having antiviral properties include 7H-benz[de]anthracen-7-ones, azabenzanthrones, and 7H-benz[de]anthracenes. In addition, the invention relates to a method for the treatment of viral infections with a pharmaceutical composition that includes at least one benzanthrone or benzanthrone derivative having antiviral properties.

Description

BENZANTHRONE COMPOUNDS AND ANTIVIRAL USES THEREOF

Field of the Invention The present invention relates to benzanthrones and derivatives thereof having antiviral activity, and to the use of benzanthrones and benzanthrone derivatives as inhibitors of membrane fusion associated events, such as viral transmission.

Background of the Invention By the age of three, virtually every child in America has had at least one respiratory infection caused by respiratory syncytial virus ("RSV") . Of the eight million children under the age of five infected by RSV in the United States each year, approximately 5,000 die, another 100,000 are hospitalized, and 2.4 million are treated by a physician.

The availability of effective treatments for RSV infections is limited. A typical treatment for an RSV infection involves the administration of ribavirin

(Virazole^®) as an aerosol, which can reduce the severity of lower respiratory infections. However, ribavirin has a low level of efficacy, as well as a variety of undesirable side effects. The treatment of RSV infections with ribavirin is described by C.B. Hall et al., Journal of the American Medical Association, 1983, 249, 2666-2670.

Therefore, a need exists for an effective treatment of RSV infections having high potency, low toxicity, and few side effects. The present invention provides such a treatment.

Summary of the Invention

The present invention is directed to benzanthrone and benzanthrone derivative compositions having antiviral activity and to pharmaceutical compositions for the treatment of a viral infection, which comprise a therapeutically effective amount of at least one benzanthrone or benzanthrone derivative. Preferred benzanthrones and benzanthrone derivatives include 7H-benz [de]anthracen-7-ones and salts thereof of formula,

azabenzanthrones and salts thereof of formula II,

or formula III,

H-benz[de] anthracenes and salts thereof of formula IV,

or V,

and derivatives thereof, where

R_lf R₂, and R₃, are the same or different, and are individually selected from the group consisting of hydrogen, halide, alkyl, nitrile, nitro, alkanoly, benzyl, benzoly, hydroxyl, methylenedioxy, ethylenedioxy, dialkyamino, and cyclic amino;

R₄ is selected from the group consisting of hydrogen, alkyl, benzyl, benzoly;

R₅ and R₆ are hydrogen or alkyl having one to four carbon atoms, or form a 5- or 6-membered heterocyclic ring with the nitrogen to which they are attached, where the 5- or 6-membered heterocyclic ring is selected from the group consisting of piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino having from one to four carbon atoms in the alkyl group; and

X and Y are selected from the group consisting of carbon, nitrogen and oxygen. Preferred antiviral compositions include those containing a 3-substituted benzanthrone or salt thereof of formula

wherein Ri is selected from the group consisting of alkyl and aryl sulfonamide, such as CONHS0₂CH₃, tetrazole, natural and synthetic carbonyl amino acids, such as CO-glycine, CO-asparagine, CO-arginine, CO-tryptophan, CO-leucine, and CO-proline, carbonyl-N-methylpiperazine, amide, halide, hydroxymethyl, methoxymethyl, and carboxylic acids, and those compositions that contain a 3 , 9-disubstituted benzanthrone or salt thereof of formula

or a derivative thereof, wherein R_x and R₂ are the same or different, and are individually selected from the group consisting of alkyl and aryl sulfonamide, such as CONHS0₂CH₃, tetrazole, natural and synthetic carbonyl amino acids, such as CO-glycine, CO-asparagine, CO-arginine, CO-tryptophan, CO-N-methylpiperazine, CO-leucine, and CO-proline, carbonyl-N-methylpiperazine, amide, halide, hydroxymethyl, and carboxylic acid, including CONH2 , CN, Br, C0₂H, and C0₂Na. Preferred 3,9-disubstituted benzanthrones and salts include those where R₁=R₂=CO-N-methylpiperazine, R₁=R₂=CONH₂, R_X=CN and R₂=CONH₂, R₁=CONH₂ and R₂=Br, R_x=C0₂H and R₂=Br, or R_L=C0₂Na and R₂=Br. The most prefered 3-substituted benzanthrones and salts are of formula

and

and the most preferred 3,9-disubstituted benzanthrones and salts are of formula

The invention also relates to a method for the treatment of a viral infection, which comprises administering to a patient having a viral infection a therapeutically effective amount of an antiviral composition comprising at least one of benzanthrone or benzanthrone derivative, where the benzanthrone or benzanthrone is preferably a 7H-benz[de]anthracen-7-one, an azabenzanthrone, a 7H-benz[de] anthracene, or a derivative thereof, as described above. The method of the invention typically comprises mixing the benzanthrone or benzanthrone derivative with a pharmaceutically suitable carrier to facilitate the administration of the antiviral composition. Preferably the benzanthrone and benzanthrone derivative compositions are used to treat RSV infections.

Detailed Description of the Invention The present invention is directed to compositions comprising benzanthrones and benzanthrone derivatives having antiviral activity, and to a method of treating viral infections, in particular, RSV infections, with compositions comprising benzanthrones and benzanthrone derivatives.

Benzanthrones having antiviral activity include 7H-benz [de] anthracene-7-ones of formula I,

azabenzanthrones of formula II,

or III,

7H-benz [de] anthracenes of formula IV,

and formula V,

and derivative thereof, where

R_lf located at one of positions C₈ to C_llf R₂, located at one of positions C_x to C₃, and R₃, located at one of positions C₄ to C₆, are the same or different, and are individually selected from the group consisting of hydrogen, halide, alkyl, nitrile, nitro, alkanoly, benzyl, benzoly, hydroxy1, methylenedioxy, ethylenedioxy, dialkyamino, and cyclic amino;

R₄ is selected from the group consisting of hydrogen, alkyl, benzyl, benzoly;

R₅ and R₆ when taken individually are selected from the group consisting of hydrogen and alkyl having one to four carbon atoms, or may form a 5- or 6-membered heterocyclic ring with the nitrogen to which they are attached, where the 5- or 6-membered heterocyclic ring is selected from the group consisting of piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino having from one to four carbon atoms in the alkyl group; and

X and Y are selected from the group consisting of carbon, nitrogen and oxygen.

For the treatment of a patient having a viral infection, e.g., an RSV infection, a composition comprising at least one benzanthrone or benzanthrone derivative having antiviral activity may be administered to the patient by any means known in the art. To facilitate the administration, the benzanthrone composition may be mixed with a suitable pharmaceutical carrier. Benzanthrones and benzanthrone derivatives may be tested for anti-RSV activity by a variety of methods known in the art. For example, benzanthrones and benzanthrone derivatives may be tested for the ability to disrupt the ability of HEp2 cells acutely infected with RSV (i.e. , cells which are infected with a multiplicity of infection of greater than 2) to fuse and cause syncytial formation on a monolayer of an uninfected line of Hep-2 cells. The lower the observed level of fusion, the greater the antiviral activity of the benzanthrone or benzanthrone derivative is determined to be.

Uninfected confluent monolayers of Hep-2 cells are grown in microtiter wells in 3% EMEM (Eagle Minimum Essential Medium w/o L-glutamine [Bio hittaker Cat. No. 12-125F] , with fetal bovine serum [FBS; which had been heat inactivated for 30 minutes at 56°C; Bio Whittaker Cat. No. 14-501F) supplemented at 3%, antibiotics (penicillin/streptomycin; Bio Whittaker Cat. No. 17-602E) added at 1%, and glutamine added at 1%. To prepare Hep2 cells for addition to uninfected cells, cultures of acutely infected Hep2 cells are washed with DPBS (Dulbecco's Phosphate Buffered Saline w/o calcium or magnesium; Bio Whittaker Cat. No. 17-512F) , and cell monolayers are removed with Versene (1:5000; Gibco Life Technologies Cat. No. 15040-017) . The cells are spun 10 minutes, and resuspended in 3% FBS. Cell counts are performed using a hemacytometer. Persistent cells are added to the uninfected Hep-2 cells.

The antiviral assay may be conducted by, first, removing all media from the wells containing uninfected Hep-2 cells, then adding a benzanthrone or benzanthrone derivative and 100 acutely RSV-infected Hep2 cells per well. Wells are then incubated at 37°C for 48 hours.

After incubation, cells in control wells are checked for fusion centers, media is removed from the wells, followed by addition, to each well, of either Crystal Violet stain or XTT. With regard to Crystal Violet, approximately 50μl 0.25% Crystal Violet stain in methanol are added to each well. The wells are rinsed immediately, to remove excess stain, and allowed to dry. The number of syncytia per well are then counted, using a dissecting microscope. With regard to XTT (2, 3-bis[2-Methoxy-4-nitro-5- sulfophenyl]-2H-tetrazolium-5-carboxyanilide inner salt) , 50μl XTT (lmg/ml in RPMI buffered with lOO M HEPES, pH 7.2-7.4, plus 5% DMSO) are added to each well. The OD_450/690 is measured (after blanking against growth medium without cells or reagents, and against reagents) according to standard procedures.

Anti-RSV activity cε_n also be assayed in vivo via well known mouse models. For example, RSV can be administered intranasally to mice of various inbred strains. Virus replicates in lungs of all strains, but the highest titers are obtained in P/N, C57L/N and DBA/2N mice. Infection of BALB/c mice produces an asymptomatic bronchiolitis characterized by lymphocytic infiltrates and pulmonary virus titers of 10⁴ to 10⁵ pfu/g of lung tissue (Taylor, G. et al. , 1984, Infect. Immun. 43:649-655) .

Cotton rat models of RSV are also well known. Virus replicates to high titer in the nose and lungs of the cotton rat but produces few if any signs of inflammation.

Examples

The following non-limiting examples are merely illustrative of the preferred embodiments of the present invention, and are not to be construed as limiting the invention, the scope of which is defined by the appended claims.

Benzanthrones and benzanthrone derivatives may be prepared from readily available starting materials. For example, to prepare 3-substituted benzanthrones, 3-bromobenzanthrone is treated with CuCN to provide 3-cyanobenzanthrone. The 3-cyanobenzanthrone is then hydrolyzed with sodium hydroxide to yield 3-carboxylic benzanthrone. The 3-substituted amides of benzanthrones are prepared by reacting 3-carboxylic benzanthrones with thionyl chloride to yield the acid chloride followed by substitution with corresponding amines.

To prepare amino acid derivatives of 3-carbonybenzanthrones, a mixture of the acyl chloride of benzanthrone-3-carboxylic acid (1 mmol) , a suitable amino derivative (1.1 mmol), such as , e.g., aspartic acid or DL-leucine, and potassium carbonate (3 mmol) (freshly tempered at 200°C for 36 hours at reduce pressure, and ground before use) in 50 ml of anhydrous 1,4-dioxane is stirred at reflux temperature, i.e., 102 to 105°C, for 4 hours. After cooling, the solvent is removed under reduced pressure in a rotary evaporator, and 25 ml of water is added. The reaction mixture is then neutralized to a pH of 6 to 7 by the addition of acetic acid. The resulting precipitate is then collected by filtration, washed with 5 ml of cold water, dried, and recrystaUized from nitromethane. Yields range from about 36 to about 47 percent.

The 3-tetrazole and methane sulfonamide derivatives of benzanthrones are prepared from a mixture of the acyl chloride of benzanthrone-3-carboxylic acid (1 mmol) and a suitable amino derivative (1.1 mmol), such as , e.g., lH-tetrazole or methane sulfonamide, in 40 ml of anhydrous pyridine, which is stirred at reflux temperature, i.e., 115 to 117 °C for 3 hours. After cooling, the is pyridine removed under reduced pressure in a rotary evaporator, and 40 ml of water is added. The resulting precipitate is then collected by filtration, washed with 10 ml of cold water, dried, and recrystaUized from nitromethane. Yields range from about 57 to about 61 percent.

The 3,9-substituted benzanthrones are prepared from a mixture of the acyl chloride of benzanthrone-3 ,9-dicarboxylic acid (1 mmol), a suitable amine, such as, e.g., 0.1 mol ammonium hydroxide or 2.4 mmol N-methyl piperazine, and potassium carbonate (freshly tempered at 200°C for 36 hours at reduce pressure, and ground before use) in 50 ml of anhydrous 1,4-dioxane, which is stirred at reflux temperature, i.e., 102 to 105°C, for 3.5 hours. After cooling, the solvent is removed under reduced pressure in a rotary evaporator, and 25 ml of water is added.

The resulting precipitate is then collected by filtration, 5 washed with 5 ml of cold water, dried, and recrystaUized from N,N-dimethylformamide. Yields range from about 33 to about 42 percent.

The antiviral properties of a number of benzanthrone compositions were determined by tests using 0 ELISA (Enzyme-linked Immunosorbent Assay) , RSV plaque reduction assay, and RSV infectious center assay.

Cytotoxicity was determined by test using XTT

(2 , 3-bis [2-methoxy-4-nitro-5-sulfophenyl] -2H-tetrazolium-

5-carboxanilide inner salt) assay. Results of the tests of 5 the indicated compositions are provided below as percent inhibition for ELISA assay, and EC₅₀ (ug/ l) .

3-Substituted Benzanthrones and Their Salts

Structures EC (uα/ l

R=

™ ^H 0.86

³⁰ Br 0.71

I 0.36

CN 0.1

C0₂H 0.45

C0₂Na 2.7

CO-N-methlypiperaz ine 1.0

CONH(CH₂)₃CH₃ 3.4

35 CO-N-morpholine 1.48

C0NH₂ 0.04

C0NHCH₃ 0.44

CO-N-piperidine 2.7 CONHCH₂CH₂-Ph-m-OCH₃ 1.36

CONH(CH₂)₃C0₂H 0. 47

C0NEt₂ 1. 46

COOCH₃ 0. 17

CONHCH (CH₃)Ph 1. 8

CONH-c-NCOCH₂C (CH₃) ₂CH₂C0 0. .95

CONH (CH₂) ₃-Imidazole 1. 3

C00(CH₂)₂0Et 0. ,9

CONH-2-pyridine 1. ,8

CONHOCH₃ 0. .7

CONHCH ( CH₃ ) CH₂C0₂H 1. .0

C0NHNHC0₂CH₃ 3. .4

C0NHCH₂CH₂-2 -pyridine 0. .8

C0NHS0₂CH₃ 0. .3

Tetrazole 1, .0

CO-glycine 16

CO-asparagine 42

CO-arginine 2. .5

CO-tryptophan 9, .3

CO-leucine 0, .6

CO-proline 2, .2

3 , 9-Disubstituted Benzanthrones

Structures EC. (u /ml)

R_x=R₂=Br 18.5

R_X=R₂=CN 1.3

R_X=H, R₂=S0₃Na 4.4

R_x=Br, R₂=S0₃Na 0.56

R₁=R₂=C0₂H 70

R₁=R₂=C0₂Na 35

R₁=R₂=CO-N-methylpiperazine 0.03 R₁=R₂=C0NH₂ 0.04

R_X=CN, R₂=C0NH₂ 0.23 R₁=CONH₂, R₂=Br 0.03 R^CO^, R₂=Br 0.2 R₁=C0₂Na, R₂=Br 0.6 3-Azabenzanthrones and Their Salts

Structures EC-_n (uα/ml.

R^N-pyridinium salt , R₂=H 18 R_X=NH₂ , R₂=H 0.08 R₁=NHCOCH₃ , R₂=H 15 R^NHCOPh , R₂=H 57

Pyridylbenzanthrone and Its Salts

Structures EC₅ (uα/ml)

R=H 0.03

The preparation and analysis of various compounds useful in the present invention are provided in the following examples. EXAMPLE 1

3-Methoxy-benz (de) anthracen-7-one

A suspension of 3-bromo-benz (de)anthracen-7-one (1.0 g, 0.3 mmol) in 100 ml of methyl alcohol and potassium hydroxide (1.68 g, 3 mmol) was stirred at the reflux temperature for 96 hours. After cooling the methyl alcohol was removed under reduced pressure, 100 ml of water was added, and the resulting mixture was neutralized by the addition of glacial acetic acid. The precipitate was collected by filtration, washed in 25 ml of water, recrystaUized from nitromethane, and dried.

Yield = 0.54 g (90%). C₁₈H₁₂0₂ m/z - 260 (m⁺) IR (KBr): 2844, 1734, 1652, 1579, 1285, 746 cm^"1.

^XH NMR (300 MHz, DMSO-d₆, TMS): <S (ppm) 4.12 (s, 3H, 0-CH3), 7.27 (d, IH, J=8.0 Hz), 7.57 (dd, IH, J=8.0, 1.5 Hz), 7.80-7.93 (m. 3H) , 8.32 (dd, IH, J=8.0, 1.0 Hz), 8.53 (d, IH, J=8.5 Hz), 8.66-8.73 (m, 2H) .

EXAMPLE 2

3-Cyano-benz (de) anthracene-7-one

A suspension of 3-bromo-benz (de) anthracene-7-one (2.0 g, 0.65 mmol) in phenylacetonitrile (30 ml) with cuprous cyanide

(1.0 g, 1.1 mmol) was heated at 265 °C for 7.5 hours, and cooled to 0°C. The separated solid was collected, washed with 2-propanol (50 ml) , repeatedly boiled with dilute nitric acid (200 ml) to remove copper salts, washed with 100 ml of water, recrystaUized from glacial acetic acid and nitrobenzene, and dried.

Yield = 1 . 27g ( 77% ) . C_ιaH₉N0₂ m/ z - 255 (m⁺)

IR (KBr): 3485, 2223, 1660, 1326, 780 cm^-1. *H NMR(300 MHz, DMSO-d₆, TMS): δ (ppm) 7.74 (t, IH, J=8.0 Hz),

7.92 (t, IH, J=8.0 Hz), 8.13 (dd, IH, J=8.0 , 1.0 Hz), 8.38 (d, IH, J=8.0 Hz), 8.48 (d, IH, J=8.0 Hz), 8.55 (d, IH, J=8.0 Hz), 8.65-8.71 (m, 2H) , 8.84 (d, IH, J=8.0 Hz).

EXAMPLE 3

Benz (de) anthracene-7-one-3-carboxylic acid

A mixture of 3-cyano-benz (de) anthracene-7-one (3.0 g,

1.2 mmol), glacial acetic acid (60 ml), and 50% sulfuric acid

(48 ml) was stirred at the reflux temperature of 150°C for 16 hours. The reaction mixture was cooled to 60°C, and treated with sodium nitrite (1.69 g, 2.54 mmol) over a 1 hour period with rapid stirring to decompose any amide. After cooling the reaction mixture to 0°C, the carboxylic acid was precipitated with water (250 ml) , recrystaUized from glacial acetic acid and nitrobenzene, and dried to give a 2.65 g

(82%) yield of the compound in the form of pale lemon-yellow needles . C₁₈H₁₀O₃ m/z - 274 (m⁺)

IR (KBr): 3274, 1687, 1668, 1512, 1276, 758 cm^'1. ^XH NMR( 300 MHz, DMSO-d₆, TMS): δ (ppm) 7.72 (dd, IH, J=8.0, 1.0 Hz), 7.90 (dd, IH, J=8.0 , 1.0 Hz), 8.02 (dd, IH, J=8.0 , 1.0 Hz), 8.37 (dd, 2H, J=8.0 , 1.5 Hz), 8.66 - 8.71 (m, 2H) , 8.45 (d, IH, J=8.0 Hz), 9.35 (d, IH, J=8.0 Hz) . The conversion to the sodium salt of 7-oxo-benz (de) anthracene-3-carboxylic acid yielded a yellow solid, which was recrystaUized from water to provide an analytical sample, mp >360°C Analysis: Cal. for C₁₃H₉0₃Na x 1.5 H₂0: C, 66.87; H, 3.74%. Found: C, 66.61; H, 3.585. m/z - 296 (m⁺)

IR (KBr): 3502, 1652, 1600, 1558, 1378, 1279, 771 cm^"1. ^XH NMR ( 300 MHz, DMS0-d6, TMS): δ (ppm) 7.645 (t, IH, J=8.0 Hz), 7.832 (dt, IH, J=8.0, 1.5 Hz), 7.858 (dt, IH, J=8.0, 1.5 Hz), 7.93 (d, IH, J=8.0 Hz) , 8.34 (dd, IH, J=8.0, 1.0 Hz), 8.59 (dd, IH, J=8.0, 1.0 Hz), 8.62 (d, IH, J=8.0 Hz), 8.69 (d, IH, J=8.0 Hz), 9.50 (dd, IH, J=8.0 , 1.5 Hz) .

EXAMPLE 4

7-Oxo-benz (de) anthracene-3-carbonyl chloride A suspension of 7-oxo-benz (de) ahthracene-3-carboxylic acid (2.7 g, 1 mmol) in benzene (70 ml) with thionyl chloride (3.6 ml, 5 mmol) and one drop of N,N-dimethylformamide was heated at the reflux temperature of 95°C for 5 hours. After cooling, the solvent was removed under reduced pressure, added benzene was added in three 25 ml aliquots and removed, and 70 ml of hexane was added. The precipitate was collected by filtration, washed with 20 ml of hexane, and dried. Yield = 2.81 g (96.2%), yellow needles. C₁₈H₉0₂C1 m/z - 292 (m*)

EXAMPLE 5

3-Hydroxymethyl-benz (de) anthracene-7-one

A mixture of 7-oxo-benz (de) anthracene-3-carbonyl chloride (2.93 g, 1 mmol), ethyl acetate (400 ml), and sodium borohydride (1.89 g, 5 mmol) was stirred at room temperature for 24 hours. Then 30 ml of 5% hydrochloric acid was added. The product was separated with ethyl acetate, washed with water, dried with sodium sulfate, and the solvent was removed under the reduced pressure.

Yield = 1.1 g(42%). RecrystaUized from nitromethane.

^C18^H12°2 m/z - 260 (irT)

IR (KBr): 3280, 1684, 1648, 1559, 1280, 1017, 774 cm^"1.

^XH NMR (300 MHz, DMSO-d6, TMS): δ (ppm) 5.12 (d, 2H, -CH₂-,

J=7.0 Hz), 5.57 (m, IH -OH), 7.64 (t, IH, J=8.0 Hz),

7.836-7.956 (m, 3H) , 8.34 (dd, IH, J=8.0 , 1.0 Hz), 8.61-8.67 (m, 3H) , 8.75 ( d, IH, J=8.0 Hz), p 199°C Analysis : Calcd . for C₁₈H₁₂0₂ x 0 . 1 H₂0 : C , 82 . 48 ; H , 4 . 62 % . Found : C , 82 . 39 ; H , 4 . 71 % .

EXAMPLE 6

3-Methyl-benz (de) anthracene-7-one and α-[7-oxo-benz (de) anthracen-3-yl] -methyl acetate

A mixture of 3-hydroxymethyl-benz (de) anthracene-7-one (0.26 g, 0.1 mmol), N,N, -dimethylformamide (40 ml), potassium carbonate (0.414 g, 0.3 mmol) and bromomethyl acetate (0.23g, 0.15 mmol) was stirred at 160°C for 4 hours. After cooling the reaction mixture, N,N, -dimethylformamide was removed under reduced pressure, water (25 ml) was added. The precipitate was collected by filtration, washed with water (15 ml), and dried. Yield = 0.l4g (57%).

The sample was further purified with thin layer chromatography (TLC) on silica gel GF (2000 mic) using hexane/ethyl acetate (8:2) as eluant to give the 3-methyl-benz (de) anthracene-7-one and 7-oxo-[benz (de) anthracene-3-yl] methyl acetate. 3-Methyl-benz (de) anthracene-7-one: C_1BH₁₂0 m/z - 244 (m*)

IR (KBr): 3128, 1646, 1580, 1277, 772 cm"¹. ^XH NMR (300 MHz, CDC1₃, TMS): δ (ppm) 2.82 (s, 3H, CH₃-) , 7.53 (dt, 2H, J=8.0 , 1.5 Hz), 7.74 (dd, IH, J=8.0, 1.0 Hz), 7.82 (t, IH, J=8.0), 8.31-8.37 ( , 2H) , 8.46 (d, IH, J=8.0 Hz), 8.5 (dd, IH, J=8.0, 1.0 Hz), 8.8 (d, IH, J=8.0 Hz) .

7-Oxo- [ benz (de) anthracene-3 -yl] methyl acetate C₂₀H₁₄O₃ m/ z - 302 (m⁺)

IR (KBr): 3388, 1739, 1658, 1299, 1046, 776 cm^"1.

^XH NMR (300 MHz, CDC1₃, TMS): δ (ppm) 2.14 (s, 3H, -CH₃) , 5.62

(s, 2H, -CH₂-) , 7.55 (t, IH, J=8.0 Hz), 7.69-7.84 (m, 3H) , 8.25-8.39 (m, 3H) , 8.47 (dd, IH, J=8.0, 1.0), 8.75 (d, IH,

J=8.0) . EXAMPLE 7

3-Chloromethyl-benz (de) anthracene-7-one

A mixture of 3-hydroxymethyl-benz (de) anthracene-7-one (O.lg, 0.04 mmol), benzene (60 ml), thionyl chloride (0.05 ml,

0.07 mmol), and one drop of pyridine was stirred at the reflux temperature for 4 hours. After cooling, the solvent was removed under the reduced pressure, 2 15 ml aliquots of benzene were added and removed, and water (15 ml) was added. The precipitate was collected by filtration, washed with water (10 ml) , recrystaUized from nitromethane, and dried.

Yield = 0.09g (85%), C₁₈H_uOCl m/z - 278 (m^*)

IR (KBr): 3032, 1652, 1529, 1456, 961, 773, 703 cm^"1. ^XH NMR (300 MHz, DMSO-d₆ , TMS): δ (ppm) 5.42 (s, 2H, -CH₂-) ,

7.67 (dt, IH, J=8.0, 1.5 Hz), 7.86-8.04 (m, 3H) , 8.35 (dd,

IH, J=8.0, 1.0 Hz), 8.63-8.78 (m, 4H) .

EXAMPLE 8

3- (4-Methylpiperazinyl)methyl-benz (de) anthracene-7-one A solution of 3-chloromethyl-benz (de) anthracene-7-one (0.05 g, 0.018 mmol) in 1,4-dioxane (70 ml) with N-methylpiperazine (0.02 g, 0.02 mmol) and potassium carbonate (0.07 g, 0.05 mmol) was stirred at 105°C for 3 hours. After cooling, the solvent was removed under the reduced pressure, water (10 ml) was added, and the precipitate was collected by filtration, washed with water, recrystaUized from nitromethane, and dried, producing yellow crystals. Yield = 0.041g, (68%), C₂₃H₂₂ N₂0 m/z - 342 (n^*)

IR (KBr): 2935, 2433, 2363, 1647, 1576, 776, 697 cm^"1. ^XH NMR (300 MHZ, DMSO-d₆, TMS): δ (ppm) 2.14 (s, 3H, N-CH₃) , 2.31-2.45 ( , 8H, aliphatic), 4.00 (s, 2H, -CH₂-) , 7.64 (t, IH, J=8.0 Hz), 7.74 (d, IH, J=6.0 Hz), 7.85-7.96 (m, 2H) ,

8.34 (dd, IH, J=8.0, 1.0 Hz), 8.61-8.73 (m, 3H) , 8.83 (d, IH, J=7.0 Hz) . Conversion to the hydrochloride yielded a yellow solid: C₂₃H₂₃C1N₂0 m/z - 342 (m⁺ -36)

IR (KBr): 2903, 2334, 1648, 1559, 1419, 1279, 851, 754 cm^"1.

EXAMPLE 9

3-Methoxymethyl-benz (de) anthracene-7-one

A mixture of 3-chloromethyl-benz (de) anthracene (0.278 g, 0.1 mmol), methyl alcohol (60 ml), and potassium hydroxide (1.12 g, 0.2 mmol) was stirred at reflux temperature for 4 hours. After cooling, the solvent was removed under reduced pressure, water (15 ml) was added, and the reaction mixture was neutralized with acetic acid (pH=7) . The precipitate was filtered, washed with water, and dried.

Yield = O.llg (40%). Further purification with TLC on silica gel GF (1000 mic) using chloroform/methyl alcohol (9:1) as eluant was performed to give the analytically pure compound. C₁₉H₁₄0₂ m/z - 274 (m^*)

IR (KBr) : 3649, 2807, 1653, 1576, 778, 749 cm¹. ^XH NMR (300 MHz, DMSO-d₆ , TMS): δ (ppm) 3.43 (s, 3H, 0-CH₃) , 5.00 (s, 2H, -CH₂-) , 7.65 (t, IH, J=8.0, 1.5 Hz) , 7.80-7.94 (m, 4H.), 8.35 (dd, IH, J=8.0, 1.0 Hz) , 8.59-8.67 ( , 2H) , 8.73 (d, IH, J=8.0 Hz) .

3-{ [2- (2-Pyrrolidinylethoxy) ethoxy]methyl}-benz (de) anthracene-7-one was also prepared in a similar manner from 3-chloromethyl-benz (de) anthracene-7-one, and purified with TLC on silica gel GF (1000 mic) using benzene as the eluant to give the analytically pure compound. C_2e ^H ₂₇ ^N0 ₃ m/z - 401 (m⁺)

IR (KBr): 3649, 2963, 1646, 1559, 1386, 1323, 1277, 1006, 772, 695 cm^"1. ^:H NMR (300 MHz, DMSO-d₆, TMS): 5 (ppm) 1.69-1.77 ( , 2H) , 2.58-2.62 (t, 2H, J=4.0 Hz), 3.47-3.59 (m, 4H) , 4.2 (d, 2H, J=6.0 Hz, -CH₂-) , 7.66-7.77 (m, 2H) , 7.92 (t, IH, J=8.0 Hz), 8.01 (t, IH, J=8.0 Hz), 8.40 (dd, IH, J=8.0 , 1.0 Hz), 8.67 (d, 2H, J=8.0 Hz), 8.74 (d, 2h, J=8.0 Hz).

EXAMPLE 10

3- (4-Methylpiperazinyl) carbonyl-benz (de) anthracene-7-one A mixture of the 7-oxo-benz (de) anthracene-3-carbonyl chloride (0.293 g, 0.1 mmol), 1,4-dioxane (40 ml), 1-methylpiperazine (0.15 g, 0.15 mmol), and potassium carbonate (freshly tempered at 200°C for 36 hours at reduced pressure, and ground before use) (0.345 g, 0.25 mmol) was stirred at 80°C for 2.5 hours. After cooling, the solvent was removed under reduced pressure, water (30 ml) was added, and the reaction mixture was neutralized to a pH of 6 to 7 with acetic acid. The precipitate was collected with filtration, washed with cold water (15 ml) , recrystaUized from nitromethane, and dried.

Yield = 0.18g (51%). C₂₃H₂₀N₂O₂ m/z-356 (m⁺) IR (KBr):3335, 2802, 1645, 1622, 1447, 1273, 755 cm^"1.

^XH NMR (300 MHz, DMSO-d₆, TMS): δ (ppm) 2.12 - 2.14 (m, 2H) , 2.205(s, 3H, N-CH₃) , 3.14 - 3.33 (m, 2H) , 3.76 - 3.88 (m, 4H) , 7.69 (t, IH, J=8.0, 1.5 Hz) , 7.75 (dd, IH, J=8.0, 1.0 Hz) , 7.911 (dt, IH, J=8.0, 1.0 Hz) ,7.99 (t, IH, J=8.0 , 1.5 Hz), 8.28 (dd, IH, J=8.0, 1.0 Hz) , 8.37 (dd, IH, J=8.0 , 1.0 Hz), 8.68 (dt, 2H, J=9.5, 1.5 Hz), 8.83 (d, IH, J=8.0 , 1.0 Hz) , mp 222 °C dec.

Analysis: Calcd. for C₂₃H₂₀N₂O₂ x 0.2 H₂0: C, 76.73; H, 5.60; N, 7.74 %. Found: C,76.87; H, 5.90; N, 7.52 %.

Conversion to the hydrochloride yielded a yellow solid.

C₂₃H₂₁C1N₂0₂

^XH NMR (300 MHz, DMSO-d₆, TMS) : 5 (ppm) 2.80 (s, 3H, N-CH₃) ,

3.21 - 3.52 (m, 4H) , 4.76 - 4.79 (m, 2H) , 7.70 (t, IH, J=8.0 Hz), 7.85 (dd, IH, J=8.0 , 1.0 Hz), 7.92 (dt, 2H, J=8.0, 1.5 Hz), 7.99 (dt, IH, J=8.0, 1.5 Hz) , 8.38 (dd, IH, J=8.0, 1.0 Hz) , 8.71 (dd, 2H, J=8.0, 1.5 Hz) , 8.87 (d, IH, J=8.0 Hz) .

EXAMPLE 11

The following compounds were prepared from the appropriate reactants using the procedure of Example 10.

The compounds prepared in Example 11 are provided in the accompanying Table.

23

SUBSTITUTE SHEET (RULE iβ - [ (7-0xo-benz (de) anthracen-3-yl) carbonylamino] -propane-1, 3- dicarboxylic acid sodium salt was prepared from the appropriate reactants following the procedure of Example 10 with using dry sodium carbonate. An analysis of several of the compounds produced in Example 11 is set forth below. R = C0NH₂, mp 293 °C.

Analysis: Calcd. for C₁₈H₁₁N0₂ x 0.1 H₂0: C, 78.58; H, 4.03; N, 5.04 %. Found: C, 78.51; H, 4.21; N, 5.28 %.

R=CONH(CH₂)₃CH₃, mp 192 °C.

Analysis: Calcd. for C₂₂H₁₉N0₂: C, 80.21; H, 5.81; N, 4.25 %.

Found: C, 80.13; H, 5.83; N, 4.23 %.

R=CONHCH₂CH₂-Ph-m-OCH₃ , mp 171 °C.

Analysis: Calcd. for C₂-H₂₁N0₃: C, 79.58; H, 5.20; N, 3.44 %. Found: C, 79.41; H, 5.23; N, 3.40 %.

R=CONHCH(CH₃)Ph, mp 224 °C. Analysis: Calcd. for C₂₆H₁₉N0₂: C, 82.73; H, 5.07; N, 3.71 %. Found: C, 82.46; H, 5.12; N, 3.68 %.

R=CONHCH(COOH)CH₂CH(CH₃)₂, mp 158 to 164 °C.

Analysis: Calcd. for C₂₄H₂₁N0₄ x 0.2 H₂0: C, 73.72; H, 5.41; N, 3.58 %. Found: C, 73.54; H, 5.44; N, 3.60 %.

R=CONHCH(COOCH₃)CH₂-3-indole, mp 138 to 141°C.

Analysis: Calcd. for C₃₀H₂₂N₂O₄ x 0.2 H₂0: C, 75.36; H, 4.63; N, 5.86 %. Found: C, 75.20; H, 4.59; N, 5.87 %.

EXAMPLE 12

3- (2H-2, 3 , 4 ,5-Tetrazolyl) carbonyl-benz (de) anthracene-7-one A mixture of 7-oxo-benz (de) anthracene-3-carbonyl chloride (0.293 g, 0.1 mmol), lH-tetrazole (0.077g, 0.11 mmol), and dry pyridine (40 ml) was stirred at the reflux temperature (115°C) for 3 hours. After cooling, the pyridine was removed under reduced pressure, water (40 ml) was added, and the precipitate was collected by filtration, washed with cold water (10 ml) , recrystaUized from nitromethane, and dried. Yield = 0.186g (57%). C₁₉H₁₀N₄O₂ m/z - 326 (m⁺)

IR (KBr): 3097, 1651, 1595, 1281, 781 cm"¹. ^λH NMR (300 MHz, DMS0-d₆, TMS): 5 (ppm) 7.72 (t, IH, J=8.0 Hz), 7.92 (t, IH, J=8.0 Hz), 8.08 (t, IH. , J=8.0), 8.34 -8.42 (m, 2H) , 8.65 - 8.73 (m, 3H) , 8.89 (d, IH, J=8.0 Hz), 9.57 (dd, IH, J=8.0, 1.0 Hz) .

EXAMPLE 13

N-(Methylsulfonyl) -[7-oxo-benz (de) anthracen-3yl) formamide was prepared using the procedure of Example 12 from 7-oxo-benz (de) anthracene-3-carbonyl chloride, and recrystaUized from nitromethane. Yield=0.214 g (61%). C₁₉H₁₃N0₄S m/z - 351 (m⁺)

'H NMR (300 M z, DMSO-d₆, TMS): δ (ppm) 3.74 (s, 3H, CH3 ) , 7.68 (t, IH, J=8.0 Hz), 7.88 (dt, 2H, J=12.0, 1.5 Hz), 8.10 (d, IH, J=8.0 Hz), 8.39 (d, IH, J=8.0 Hz), 8.45 (d, IH, J=8.0 Hz), 8.54 (d, IH, J=8.0 Hz), 8.79 (d, IH, J=8.0 Hz), 8.84 (d, IH, J=8.0 Hz).

N-[ (4-Methylphenyl) sulfonul] -[7-oxo-benz (de) anthracen-3-yl] formamide was prepared in a similar manner from

7-oxo-benz (de) anthracene-3-carbonyl chloride, and recrystaUized from nitromethane.

Yield=0.31 g (72.5%). C₂₅H₁₇N0₄S m/z - 427 (m⁺)

IR(KBr): 3195, 1698, 1630, 1574, 1430, 1347, 1159, 1057, 781,

547 cm^"1. ^λE NMR (300 Mhz, DMSO-d₆, TMS): δ (ppm) 2.46 (s, 3H, -CH₃) ,

7.54 (d, 2H, J=8.0 Hz), 7.71 (t, IH, J=8.0 Hz), 7.88 - 8.03 (m, 5H) , 8.32 - 8.36 (m, 2H) , 8.66 (dt, 2H, J=12.0, 1.5 Hz), 8.82 (d, IH, J=8.0 HzO.

Example 14

5

7-Oxo-benz (de)anthracene-9-sulfonic acid, sodium salt A mixture of benz (de) anthracene-7-one (25 g, 0.109 mol) and fuming sulfuric acid (5% of S0₃) (250 g) was heated at 145 to 150°C for 2 hours, cooled, and poured into ice (600 g) . 0 Unreacted benz (de)ahtracene-7-one was removed with filtration, and sodium carbonate (750 g) was added with stirring at 80°C. The reaction mixture was made up to 51 by the addition of a saturated salt solution, boiled, and allowed to cool. The crystalline sodium salt of the 5 sulphonic acid (37 g) separated, and was collected, washed with salt solution, and purified with four recrystallizations from hot water from which it separated as a green-yellow crystalline powder. Yield = 5 g (14%) . C₁₇H₉Na0₄S 0 m/z - 332 (m⁺)

IR (KBr): 3446, 1648, 1597, 1195, 1042, 632 cm^"1.

^XH NMR (300 MHz, DMSO-d₆, TMS): δ (ppm) 7.66 (t, IH,

J=8.0 Hz), 7.82-7.96 (m, 2H) , 8.04 (dd, IH, J=8.0, 1.0 Hz),

8.26 (d, IH, J=6.0 Hz), 8.51 (d, IH, J=6.0 Hz), 8.59-8.81 (m, 5 2H) , 9.39 (dd, IH, J=7.0 , 1.0 Hz).

EXAMPLE 15

3-Nitro-benz (de) anthracene-7-one

30 88% nitric acid (2.7 ml, 5.6 mmol) was added dropwise to a solution of benz (de) anthracene-7-one (lOg, 4.35 mmol) in nitrobenzene (80 ml) at 18 to 20°C. The reaction mixture was stirred at 50°C for 3 hours, and the yellow precipitate was filtered off, washed with nitrobenzene, reczystallized with

35 chlorobenzene, and dried.

Yield = 8 . 4 g ( 70%) . C₁₇H₉N0₃ m/ z - 275 ( *) IR (KBr): 1684, 1540, 1456, 1305, 777 cm^"1. ^XH NMR (300 MHz, DMSO-d₆, TMS): δ (ppm) 7.75 (t, IH, J=8.0 Hz), 7.93 (dt, IH, J=8.0 , 1.0 Hz), 8.09 (dt, IH, J=8.0, 1.0 Hz), 8.33 (dd, IH, J=8.0, 1.0 Hz), 8.49 (d, IH, J=8.0 Hz), 8.65 (d, IH, J=8.0 Hz), 8.69 (d, IH, J=8.0 Hz), 8.78 (d, IH, J=8.0 Hz), 8.87 (d, IH, J=8.0 Hz),

EXAMPLE 16

3-Amino-benz (de) anthracene-7-one

3-nitro-benz (de) anthracene-7-one (6 g, 2.1 mmol) was added to an aqueous solution of sodium sulfide (10 g, 4.2 mmol) in water (50 ml) . The resulting suspension was stirred initially at 18 at 20°C for 1.5 hours and then at boiling point for 4 hours. The red precipitate was filtered from the hot reaction mixture, and washed on a filter to a neutral reaction (pH=7) with water, recrystaUized from chlorobenzene, and dried to provide the compound in the form of yellow needles. Yield = 4.3 g (83.5%). C^H^NO m/z - 245 (m⁺)

IR (KBr): 2808, 1734, 1636, 1559, 1316, 773 cm¹. ^:H NMR (300 MHz, DMSO-d₆, TMS): ό^" (ppm) 6.90 ( , 2H, - NH₂) , 7.42 (t, 2H, J=8.0 Hz), 7.71-7.80 (m, 2H) , 8.28 (dd, IH, J=8.0, 1.0 Hz), 8.40 (d, IH, J=8.0 Hz), 8.48 (d, IH,

J=8.0 Hz), 8.67 (d, IH, J=8.0 Hz), 8.74 (d, IH, J=8.0 Hz).

EXAMPLE 17

3-Iodo-benz (de)anthracene-7-one

Sodium nitrite (0.14 g, 0.2 mmol) was added to a solution of 3-amino-benz (de) anthracene-7-one (0.25 g, 0.1 mmol) in 96% sulfuric acid (10 g) , and stirred at 5°C at 5°C for 0.5 hour. A mixture of water (50 ml) and ice (50 g) was then added. A solution of sodium iodide (0.6 g, 0.4 mmol) in water (5 ml) was added to the stirred red reaction mixture, which was heated at 35 to 40°C for 1 hour. The mixture was cooled, and the precipitate was filtered off, washed with water, recrystaUized from chlorobenzene, and dried, providing yellow crystals. Yield = 0.14 g (57%). C₁₇H₉IO m/z - 356 (nC)

^XH NMR (300 MHz, DMSO-d₆, TMS): δ (ppm) 7.66 (t, IH, J=8.0 , 1.5 Hz), 7.86 (dt, IH, J=8.0, 1.5 Hz), 7.98 (t, IH, J=8.0, 1.5 Hz), 8.32 (dd, IH, J=8.0, 1.0 Hz), 8.39 (d, IH, J=8.0 Hz), 8.45 (d, IH, J=8.0 Hz), 8.49 (dd, IH, J=8.0, 1.0 Hz), 8.58 (d, IH, J=8.0 Hz) , 8.67 (dd, IH, J=8.0 , 1.0 Hz)

EXAMPLE 18

N- (7-Oxo-benz (de) anthracen-3-yl) -ethanamide 3-Amino-benz (de) anthracene (2.4 g, 1.0 mmol) was dissolved in boiling glacial acetic acid (70 ml) , and a solution of acetic anhydride (7 ml, 7.4 mmol) was added to the resulting mixture, which was boiled for 1 hour. After cooling, the acetic acid was removed under the reduced pressure, water (50 ml) was added, and the precipitate was collected by filtration, washed with acetone, recrystaUized from N,N-dimethylformamide, and dried. Yield = 1.17 g (45%). C₁₉H₁₃N0₂ m/z - 287 (irT) IR (KBr): 3265, 1683, 1657, 1539, 1306, 779 cm^"1.

^XH NMR (300 MHz, DMSO-d₆, TMS): 5 (ppm) 2.27 (s, 3H, -CH₃) , 7.62 (t, IH, J=8.0 Hz), 7.87 (dt, IH, J=8.0, 1.0 Hz), 7.96 (t, IH, J=8.0 Hz), 8.13 (d, IH, J=8.0 Hz), 8.34 (dd, IH, J=8.0, 1.0 Hz). 8.59 (dd, IH, J=8.0, 1.0 Hz), 8.70-8.78 (m, 3H) , 10.30 (s, IH, -NH-) .

EXAMPLE 19

3-[ (Diethyloxyphosphinyl) methyl] amino-benz (de) anthracene-7-on e

Diethylhydrogen phoshite (1.38 g, 1.0 mmol) and paraformaldehyde (0.3 g) were added To a solution of 3-amino-benz (de) anthracene-7-one (2.45 g, 1.0 mmol) in 1.4-dioxane (200 ml). The reaction mixture was boiled for 4 hours. After cooling, 1,4-dioxane was distilled off, and the residue was dissolved in chloroform, filtered, and dried by 5 evaporation.

Yield = 1.5 g (42.8%). C₂₂H₂₂N0₄P m/z - 395 (m⁺) , m. p. 149°C.

EXAMPLE 20 0

9-Bromo-3-cyano-benz (de) ahthracene-7-one

Bromine (1.0 g, 0.63 mmol) was added to a well stirred suspension of 3-cyano-benz (de) anthracene-7-one (0.51 g,

0.2 mmol) in water (100 ml) at 30 - 40°C, and the resulting 5 reaction mixture was heated at 70°C for 170 hours. After cooling, the precipitate was collected by filtration, washed with water recrystaUized from nitrobenzene, and dried.

Yield = 0.48 g (71.6%). C₁₈H₈BrNO m/z - 335 (m⁺) 0 ^XH NMR (300 MHz, DMSO-d₆, TMS): <S (ppm) 8.08 (dd, IH, J=8.0,

1.0 Hz), 8.14 (d, IH, J=8.0 Hz), 8.38 (d, IH, J=8.0 Hz), 8.40 (d, IH, J=8.0 Hz), 8.58 (dd, IH, J=8.0 , 1.0 Hz), 8.63 (d, IH,

J=8.0 Hz), 8.71 (dd, IH, J=8.0, 1.0 Hz), 8.86 (dd, 2H, J=8.0,

1.5 Hz) 25

EXAMPLE 21

3 , 9-Dibromo-benz (de) anthracene-7-one was synthesized from the bromination reaction of 3-bromo-benz (de) anthracene-7-one for 30 18 hours using the same procedure used for Example 20. The product was recrystaUized from nitrobenzene in the form of yellow needles.

Yield = 3.4 g (87.6%), C₁₇H₈Br₂0 m/z - 388 (m^*) 35 IR (KBr): 1644, 1561, 1373, 1079, 823 cm^"1. ^XH NMR (300 MHz, DMSO-d₆ , TMS): δ (ppm) 8.02 (dt, IH, J=8.0, 1.0 Hz), 8.12 (d, IH, J=8.0 Hz), 8.31 (d, IH, J=8.0 Hz) , 8.50 (d, IH, J=8.0 Hz), 8.55-8.66 (m, 4H) . mp 246°C Analysis: Calcd. for C₁₇H₈Br₂0 : C, 52.61; H, 2.08 %. Found: C, 52.71; H,2.08 %.

The 9-Bromo-7-oxo-benz (de) anthracene-3-carboxamide was prepared from 7-oxo-benz (de)anthracene-3-carboxamide using the bromination reaction procedure of Example 20 for 48 hours with recrystallization from nitrobenzene.

Yield = 0.36 g (47%). C₁₈H₁₀BrNO₂ m/z - 351 (m⁺-l)

^XH NMR (300 MHz, DMSO-d₆ , TMS) : <S (ppm) 7.87 (s, IH) , 7.91-8.00 (m, 3H) , 8.07 (dd, IH, J=8.0 , 1.0 Hz) , 8.27 (s,

IH) , 8.41 (d, IH, J=8.0 Hz) , 8.64 (d, IH, J=8.0 Hz) , 8.68 (dd, IH, J=8.0, 1.0 Hz), 8.83 (d, 2H, J=8.0 Hz) .

EXAMPLE 22

9-Bromo-7-oxo-benz (de) anthracene-3-carboxylic acid was prepared from 9-bromo-3-cyano-benz (de) anthracene-7-one following the hydrolysis reaction procedure of Example 3 for

48 hours with recrystallization from glacial acetic acid. Yield = 0.27 g (77%). C₁₈H₉Br0₃ m/z - 354 (m⁺+l)

Conversion to the sodium salt of

9-bromo-7-oxo-benz (de) anthracene-3-carboxylic acid yielded a yellow powder. C₁₈H₈BrNa0₃

EXAMPLE 23

9-Bromo-7-oxo-benz (de) anthracene-3-carbonyl chloride was prepared from 9-bromo-7-oxo-benz (de) anthracene-3-carboxylic acid using the same procedure as used in the Example 4 with recrystallization from m-xylene. Yield=0.97g (82%). C₁₈H₈BrCl0₂ m/z - 371 (m^*) .

EXAMPLE 24

9-Bromo-3-hydroxymethyl-benz (de) anthracene-7-one was prepared from 9-bromo-7-oxo-benz (de) anthracene-3-carbonyl chloride using the procedure of Example 5 for 32 hours with further purification with TLC on silica gel GF (1000 mic) using chloroform/methanol (9:1) as the eluant. Yield = 0.15 g (45.5%). C₁₈H Br0₂ m/z - 338 (m⁺-l)

IR (KBr): 3488, 1643, 1575, 1375, 1302, 1055, 815 cm"¹. ^XH NMR (300 MHz, DMS0-d₆, TMS): 5 (ppm) 5.12 (d, 2H, J=4.0 Hz, -CH₂-) , 5.60 (m, IH. -OH), 7.86 (d, IH, J=6.0 Hz), 7.95 (t, IH, J=8.0 Hz), 8.04 (dd, IH, J=8.0 , 1.0 Hz), 8.40 (d, IH, J=8.0 Hz), 8.60 (d, IH, J=8.0 Hz),, 8.64-8.68 (m, 2H) , 8.78 (d, IH, J=8.0 Hz) .

EXAMPLE 25

3-Bromo-7-oxo-benz (de) anthracene-9-sulfonic acid sodium salt was prepared from 3-bromo-benz (de) anthracene-7-one using the same procedure used for Example 14 with recrystallization from aqueous ethyl alcohol. Yield = 3.67 g (23.5%) C₁₇H₈Br0₄SNa m/z - 411 (m⁺)

IR (KBr): 3446, 1650, 1501, 1198, 1046, 825, 627 cm^"1. ^lK NMR (300 MHz, DMS0-d₆, TMS): δ (ppm) 8.02-8.07 (m, 3H) , 8.16 (d, IH, J=8.0 Hz), 8.56-8.65 (m, 3H) , 8.73 (dd, IH, J=8.0, 1.0 Hz) .

EXAMPLE 26

3-Bromo-6- (2-pyridilamido) -benz (de) anthracene-7-one 3-Bromo-benz (de)anthracene-7one (0.3g, 0.1 mmole) was added to a stirred mixture of the 2-aminopyridine (0.282g, 0.3 mmole) in dry methyl syIfoxide (30 ml) and powdered potassium hydroxide (1.4g, 2.5 mmole). The reaction mixture was stirred at room temperature for 16 hours, diluted with ice-cold water (100 ml) , and adjusted to a pH of 4 to 5 using hydrochloric acid (35%) . The product was separated, filtared, washed with water, dried, and purified using TLC on silica gel GF (2000 mic.) with benzene/ethyl acetate (8:2) as the eluant.

Yield= 0.27g (67.5%). C₂₂H₁₃BrN₂0 m/z - 401 (m⁺) IR(KBr): 3389, 2955, 1648, 1559, 1457, 1296, 1147 cm"¹. H NMR (300 Mhz, DMSO-d6 , TMS): δ (ppm) 7.21 (t, IH, J=8.0 Hz), 7.35 (d, IH, J=8.0 Hz), 7.69 (d, IH, J=8.0 Hz), 7.71 (d, IH, J=8.0 Hz), 7.90-7.98 (m, 3H) , 8.49(dd, IH, J=8.0, 1.0 Hz), 8.53 (dd, IH, J=8.0 , 1.0 Hz) , 8.68 (d, IH, J=8.0 Hz), 8.70 (d, IH, J=8.0 Hz), 9.246 (dd, IH, J=8.0, 1.0 Hz), 14.33 (s, IH, N-H) .

EXAMPLE 27

3 , 9-Dicyano-benz (de) ahtracene-7-one was prepared from

3 ,9-dibromo-benz (de) ahthracene-7-one using the procedure of Example 2 with recrystallization from nitrobenzene. Yield = 0.15 g (53.6%). C₁₉H₈N₂0 m/z - 280 (m^*) IR (KBr): 3070, 2227, 1659, 1577, 1381, 779 cm^"1.

'H NMR (300 MHz, DMSO-d₆ , TMS): <5 (ppm) 8.09 (t, IH, J=8.0 Hz), 8.27 (dd, IH, J=8.0 , 1.0 Hz) , 8.39 (d, IH, J=8.0 Hz), 8.51-8.56 (m, 2H) , 8.64 (dd, IH, J=8.0, 1.0 Hz), 8.77 (d, IH, J=8.0 Hz), 8.86 (d, IH, J=8.0 Hz).

EXAMPLE 28

3,9-Di-(2H-2,3,4,5-tetrazolyl) -benz (de) anthracene-7-one A suspension of 3 , 9-dicyano-benz (de) anthracene-7-one (0.28 g, 0.1 mmol), sodium azide (0.65 g, 1.0 mmol), ammonium chloride (0.54 g, 1.0 mmol) in fresh distilled anhydrous N,N-dimethyIformamide was stirred at 100°C for 48 hours. After cooling, the solvent was removed under reduced pressure, and water (15 ml) was added. The precipitate was collected by filtration, washed with water (10 ml) , recrystaUized from N,N-dimethyIformamide, and dried. Yield = 0.15 g (41.6%). C₁₉H₁₀N₈O m/z - 366 (m⁺)

IR (KBr): 3528, 3424, 3027, 1653, 1570, 1384, 1311, 1027, 842, 742 cm^-1.

^XH NMR (300 MHz, DMSO-d₆, TMS): δ (ppm) 8.00 (dd, IH, J=8.0, 1.0 Hz), 8.08 (dd, IH, J=8.0, 1.0 Hz), 8.37 (dd, IH, J=8.0, 1.0 Hz), 8.44 (dd, IH, J=8.0, 1.0 Hz), 8. 52 (dt, IH, J=8.0, 1.0 Hz), 8.70 (dt, IH, J=8.0, 1.0 Hz), 8.80 (dd, IH, J=8.0 , 1.5 Hz), 8.92 (dt, IH, J=8.0 , 1.0 Hz), 9.54 (d, 2H, -NH-) .

EXAMPLE 29

7-Oxo-benz (de) anthracene-3 , 9-carboxylic acid prepared from

3 , 9-dicyano-benz (de) anthracene-7-one with the of hydrolysis reaction of Example 3 for a period of 48 hours with recrystallization from glacial acetic acid and nitrobenzene.

Yield = 0 . 21 g ( 66% ) . C₁₉H₁₀O_s m/ z - 317 (m⁺-l)

IR (KBr): 3467, 3151, 1698, 1651, 1604, 1580, 1280, 780 cm^"1.

^XH NMR (300 MHz, DMSO-d₆, TMS): δ (ppm) 7.97 (t, IH, J=8.0 Hz), 8.05 (t, IH, J=8.0 Hz), 8.31 (d, IH, J=8.0 Hz),

8.47 (dd, IH, J=8.0, 1.0 Hz), 8.61-8.80 ( , 4H) .

Conversion to the sodium salt of

7-oxo-benz (de) anthracene-3 , 9-dicarboxylic acid yielded a yellow powder . C₁₉H₈0₅Na₂

IR (KBr) : 3538 - 3082 , 1697 , 1654 , 1601 , 1509 , 1335 , 1278 ,

784 cm -ι EXAMPLE 30

3 ,9-Di- [benz (de) anthracene-7-one] carbonyl chloride was prepared from 7-oxo-benz (de) anthracene-3,9-dicarboxylic acid using the procedure of Example 4 with recrystallization from benzene.

Yield = 2.0 g (88.5%). C₁₉H₈C1₂0₃ m/z - 355 (m⁺)

EXAMPLE 31

3 , 9-Di- (hydroxymethyl) -benz (de) ahthracene-7-one was synthesized from 3 , 9-di- [benz (de) anthracene-7-one] carbonyl chloride using the procedure of Example 5 and further purification with TLC on silica gel GF (1000 mic) using chloroform/methanol (9:1) as the eluant to give the analytically pure compound.

Yield = 0.17 g (58.6%) . C₁₉H₁₄0₃ m/z - 290 (m⁺) IR (KBr) : 3297, 2991, 1650, 1575, 1-49, 780 cm^"1.

^XH NMR (300 MHz, DMS0-d₆, TMS) : δ (ppm) 4.68 (d, 2H, -CH₂-,

J=4.0 Hz) , 5.12 (d, 2H, -CH₂-, J=4.0 Hz), 5.45-5.46 (m, IH,

-OH), 5.55-5.56 (m, IH, -OH), 7.80 (dd, IH, J=8.0, 1.0 Hz),

7.84 (d, IH, J=8.0 Hz) , 7.93 (t, IH, J=8.0 Hz) , 8.31 (s, IH) , 8.59 (d, IH, J=8.0 Hz) , 8.63 (dd, IH, J=8.0 , 1.0 Hz) , 8.66

(dd, IH, J=8.0, 1.0 Hz), 8.74 (dd, IH, J=8.0 Hz) . mp 167 °C dec.

Analysis: Calcd. for C₁₉H₁₄0₃ x 0.2 H₂0: C, 77.64; H, 4.80 %.

Found: C, 77.49; H, 4.84 %.

EXAMPLE 32

3, 9-Di- [7-oxo-benz (de) anthracenyl] carbamide have been prepared from 3 , 9-di- [benz (de) anthracene-7-one]carbonyl chloride with the procedure of Example 10 with recrystallization from N,N, -dimethylformamide. Yield = 0.1 g (33%). C₁₉H₁₂N₂0₃ m/z - 316 (irT)

^XH NMR (300 MHz, DMSO-d₆, TMS): δ (ppm) 7.61 (d, IH, J=8.0 Hz), 7.88-7.96 (m, 2H) , 8.07-8.09 (m, IH) , 8.28-8.41 (m, 3H) , 8.5 (dd, IH, J=8.0, 1.0 Hz), 8.667 (dt, IH, J=8.0, 1.5 Hz), 8.73-8.85 (m, 2H) .

EXAMPLE 33

3 , 9-Di- (4-methylpiperazinyl) carbonyl-benz (de) anthracene-7-one was prepared from 3 ,9-di- [benz (de) anthracene-7-one] -carbonyl chloride with the procedure of Example 10 with recrystallization from N,N-dimethylformamide.

Yield = 0.2 g (42%). C₂₉H₃₀N₄O₃ m/z - 482 (m⁺) ^XH NMR (300 MHz, DMSO-d₆, TMS): δ (ppm) 1.75 (s, 6H, CH₃) ,

2.13-2.43 (m, 8H) , 3.42-3.45 (m, 4H) , 3.67-3.69 (m, 4H) , 7.92

(d, IH, J=8.0 Hz), 8.13 (t, IH, J=8.0 Hz), 8.28 (t, IH,

J=8.0 Hz), 8.44 (d, IH, J=8.0 Hz), 8.58 (d, IH, J=8.0 Hz),

8.71-8.74 (m, 2H) , 8.83 (m, IH) .

EXAMPLE 34

N-[ (Methylsulfonyl) -9- (methylsulfonyl) carbamoyl-7-oxobenz (de) anthracen-3-yl] formamide was prepared from 3 , 9-di- [benz (de) anthracene-7-one] carbonyl chloride with the procedure of Example 12 with recrystallization from nitromethane.

Yield = 0.26 g (55%) . C₂₁H₁₆N₂0₇S₂ m/z - 472 (m⁺) IR (KBr) : 3628-3026, 1715, 1699, 1603, 1471, 1383, 1157, 886,

783, 520 cm^"1.

^XH NMR (300 MHz, DMSO-d_s, TMS) : δ (ppm) 3.44 (s, 3H, CH₃) ,

3.55 (s, 3H, CH₃) , 8.06 (t, IH, J=8.0 Hz), 8.10 (t, IH,

J=8.0 Hz) , 8.39 (d, IH, J=8.0 Hz), 8.72 (d, IH, J=8.0 Hz), 8.75 (d, IH, J=8.0 Hz), 8.87 (d, IH, J=8.0 Hz) , 8.92 (d, IH,

J=8.0 Hz), 8.97 (d, IH, J=8.0 Hz). EXAMPLE 35

7H-Benz (de) anthracene

A mixture of benz (de) anthracene-7-one (0.5 g, 0.22 mmol), 2-propanol (80 ml), and aluminum isopropoxide (4.4 g,

2.2 mmol) was heated at 85°C for 20 hours. After cooling, the solvent was removed under the reduced pressure, water (100 ml) was added, and the reaction mixture was acidified with dilute sulfuric acid (pH=l) . The product was then extracted with boiling benzene (100 ml) , the organic layer was dried with Na₂S0₄ , and the solvent was evaporated to give the compound, which was purified with TLC on silica gel GF (2000 mic) using hexane as the eluant. Yield = 0.35 g (74 %) . C₁₇H₁₂ m/z- 215 (m^*-l)

IR (KBr): 2986, 1559, 815, 750 cm^"1.

^XH NMR (300 MHz, CDC1₃, TMS): δ (ppm) 4.48 (s, 2H, -CH₂-) , 7.27 (d, IH, J=8.0, Hz), 7.32-7.51 (m, 5H) , 7.67 (d, IH, J=8.0 Hz), 7.71 (d, IH, J=8.0 Hz), 8.00 (d, IH, J=8.0 Hz), 8.03 (d, IH, J=8.0 Hz), mp 74 °C

Analysis: Calcd. for C₁₇H₁₂: C, 94.40; H, 5.59 %. Found: C, 94.17; H, 5.55 %.

Similarly, the following compounds were prepared from the appropriate reactants:

3-Bromo-7H-benz (de) anthracene. Purification was achieved via

TLC on silica gel GF (2000 mic) using hexane as the eluant. Yield = 1.2 g (81 %) . C₁₇H_xlBr m/z- 295 (m^*)

IR (KBr): 3486, 1490, 1380, 1250, 832, 772 cm^"1.

^XH NMR (300 MHz, CDC1₃, TMS): δ (ppm) 4.57 (s, 2H, -CH₂-) ,

7.31-7.33 (m, 2H) , 7.44 (dd, IH, J=8.0, 1.0 Hz), 7.55 (t, IH, J=8.0 Hz), 7.78 (d, IH, J=8.0 Hz), 7.85 (d, IH, J=8.0 Hz),

8.00 (dd, 2H, J=8.0, 1.5 Hz), 8.07 (d, IH, J=8.0 Hz). mp 113°C Analysis: Calcd. for C^H^Br x 1.5 H₂0: C, 63.77; H, 3.44 %. Found: C, 63.61; H, 3.29 %.

3-Cyano-7H-benz (de) anthracene. Purification was achieved via TLC on silica gel GF (2000 mic) using benzene/petroleum ether (1:1) as the eluant. Yield = 0.16 g (66 %).C₁₈H₁₁N m/z- 240 (m⁺-l) IR (KBr): 2218, 1559, 773 cm^"1. ^XH NMR (300 MHz, CDC1₃, TMS): δ (ppm) 4.60 (s, 2H, -CH₂-) ,

7.37-7.39 (m, 3H) , 7.51 (dd, IH, J=8.0, 1.0 Hz), 7.64 (t, IH, J=8.0 Hz), 7.90 (d, IH, J=8.0 Hz), 8.01 (d, IH, J=8.0 Hz), 8.03 (d, IH, J=8.0 Hz), 8.07 (d, IH, J=8.0 Hz).

7H-Benz (de) anthracene-3-carboxylic acid

Yield = 0. 15 g (57%) . RecrystaUized from toluene . C₁₈H₁₂0₂ m/ z- 260 (m⁺)

IR (KBr): 3385, 1684, 1517, 771 cm^"1. ^lH NMR (300 MHz, DMSO-d₆, TMS): δ (ppm) 4.61 (s, 2H, -CH₂-) , 7.37-7.44 (m, 2H) , 7.53 (dd, IH, J=8.0 , 1.0 Hz), 7.64 (d, IH,

J=8.0 Hz), 8.16-8.23 (m, 2H) , 8.68 (d, IH, J=8.0 Hz), 8.77

(dd, IH, J=8.0, 1.0 Hz), 9.36 (dd, IH, J=8.0 , 1.0 Hz) .

Conversion to the sodium salt of 7H-benz (de) anthracene-3-carboxylic acid and recrystaUized from water to give analytical sample. C^H^O^a ^XH NMR (300 MHz, DMSO-d₆, TMS): δ (ppm) 4.52 (s, 2H, -CH₂-) , 7.25-7.42 (m, 5H) , 7.75 (d, IH, J=8.0 Hz), 8.03 (d, IH, J=8.0 Hz), 8.09 (dd, IH, J=8.0, 1.0 Hz), 8.82 (d, IH, J=8.0 Hz) .

3-Hydroxymethyl-7H-benz (de) anthracene. Purification was achieved via TLC on silica gel GF (2000 mic) using hexane/ethyl acetate (1:1) as the eluant. Yield = 0.11 g (44.7 %) . C₁₈H₁₄0 m/z- 246 (m⁺) IR (KBr): 2923, 1576, 1456, 1094, 772 cm^"1. ^XH NMR (300 MHz, CDC1₃, TMS): <S (ppm) 4.56 (s, 2H, -CH₂-) , 7.25 (d, IH, J=8.0 Hz), 7.28 (d, IH, J=8.0 Hz), 7.30 (dd, IH, J=8.0, 1.0 Hz), 7.34 (d, IH, J=8.0 Hz), 7.39 (dd, IH, J=8.0, 1.0 Hz), 7.48 (d, IH, J=8.0 Hz), 7.80 (d, IH, J=8.0 Hz), 7.91 (d, IH, J=8.0 Hz), 8.01 (d, IH, J=8.0 Hz) .

EXAMPLE 36

7-Methyl-benz (de) anthracen-7-ol Benz (de) anthracene-7-one (5.0 g, 2.2 mmol) was dissolved in dry ether (120 ml). Excess of methyllithium (1.4 M solution in diethyl ether) (50 ml) was added using a hypodermic syringe, and the reaction mixture was stirred overnight at room temperature under an argon atmosphere. The lithium salt of the alcohol was hydrolyzed by dropwise addition of water (50 ml) using a dropping funnel. The alcohol was extracted with ether, and the combined ether extract was dried over Na₂S0₄. Evaporation of ether yielded the compound, which was recrystaUized from carbon tetrachloride. Yield = 4.4 g, (76%). C₁₈H₁₄0 m/z- 246 (m⁺)

IR (KBr): 3282, 1559, 1081, 761 cm^"1.

^:H NMR (300 MHz, DMSO-d₆ , TMS): δ (ppm) 1.46 (s, 3H, -CH₃) , 6.08 (s, IH, -OH), 7.39-7.44 (m, 2H) , 7.61 (t, IH, J=8.0 Hz), 7.64 (t, IH, J=8.0 Hz) , 7.87 (d, IH, J=8.0 Hz), 7.89 (d, IH, J=8.0 Hz), 7.92 (d, IH, J=8.0 Hz), 7.97 (dd, IH, J=8.0 , 1.0 Hz), 8.20 (dd, IH, J=8.0 , 1.0 Hz), 8.29 (d, IH, J=8.0 Hz) .

EXAMPLE 37

7-Methylene-benz (de) anthracene

Sulfuric acid (10%, 50 ml) was added to a solution of 7-methyl-benz (de) anthracen-7-ol (2.5 g, 1.0 mmol) in ether (125 ml) . The reaction mixture was stirred overnight, and the precipitated solid was filtered, washed with water to remove sulfuric acid, recrystaUized from carbon tetrachloride and absolute ethyl alcohol, and dried. Yield = 1.85 g (81%).C₁₈H₁₂ m/z- 228 (in^*) IR (KBr): 3022, 1576, 778, 749 cm^"1.

^XH NMR (300 MHz, DMSO-d₆ , TMS): δ (ppm) 5.32 (dd, IH, J=6.0, 3.0 Hz, =CH₂) , 5.49 (dd, IH, J=6.0, 3.0 Hz, =CH₂) , 7.09 (dt, IH, J=8.0 Hz), 7.53 (t, IH, J=8.0 Hz), 7.65 (t, IH, J=8.0 Hz), 7.75 (t, IH, J=8.0 Hz), 7.78 (t IH, J=8.0 Hz), 7.96 (t, IH, J=8.0 Hz) , 8.24 (dt, IH, J=8.0, 1.5 Hz) , 8.31 (d, IH, J=8.0 Hz), 8.42 (d, IH, J=8.0 Hz), 8.76 (dd, IH, J=8.0, 1.0 Hz), 8.92 (dd, IH, J=8.0 , 1.0 Hz).

EXAMPLE 38

7-Hydroxyimino-benz (de) anthracene

A mixture of benz (de) anthracene (2.5 g, 1.09 mmol), hydroxylamine hydrochloride (12 g, 17.4 mmol) in dry pyridine

(60 ml) was heated at 115°C for 70 to 90 hours. Most of the pyridine was distilled off, and the residue was poured into water (40 ml) , and extracted with 3 70 ml aliquots of ether, and dried over Na₂S0₄, followed by evaporation. The product was further purified via TLC on silica gel GF (2000 mic) using benzene as the eluant. Yield = 1.87 g (70 %) . C₁₇H N0 m/z- 245 (m^*)

IR (KBr): 3304, 1559, 1368, 980, 742 cm^"1.

^XH NMR (300 MHz, DMSO-d₆, TMS): δ (ppm) 7.48 (dd, IH, J=8.0, 1.5 Hz), 7.58 (t, IH, J=8.0 Hz) , 7.69 (dd, IH, J=8.0 , 1.0 Hz), 7.76 (dd, IH, J=8.0 , 1.0 Hz), 8.01 (d, IH,

J=8.0 Hz), 8.12 (d, IH, J=8.0 Hz), 8.24 (d, IH, J=8.0 Hz), 8.37 (d, IH, J=8.0 Hz), 8.38 (d, IH, J=8.0 Hz), 9.34 (d, IH, J=8.0 Hz), 12.48 (s, IH, =N-0H) .

The following compounds were similarly prepared from the appropriate starting materials: 3-Bromo-7-hydroxyimino-benz (de) anthracene. RecrystaUized from toluene with charcoal. Yield = 2.1 g (65%). C₁₇H₁₀BrNO m/z- 325 (m*+l) IR (KBr): 3380, 1559, 1334, 1052, 947, 743 cm^"1.

^XH NMR (300 MHz, DMSO-d₆, TMS): δ (ppm) 7.49 (dt, IH, J=8.0, 1.0 Hz), 7.57 (dt, IH, J=8.0, 1.0 Hz), 7.89 (t, IH, J=8.0 Hz), 8.05 (d, IH, J=8.0 Hz), 8.22 (dd, IH, J=8.0, 1.0 Hz), 8.34 (d, IH, J=8.0 Hz), 8.36 (dd, IH, J=8.0 , 1,0 Hz), 9.40 (d, IH, J=8.0 Hz), 14.28 (s, IH, =N-OH) .

3-Carboxamido-7-hydroxyimino-benz (de) anthracene.

Purification was achieved via TLC on silica gel GF (2000 mic) using hexane/ethyl acetate (1:1) as the eluant. Yield = 1.91 g (70%) .C₁₈H₁₁N0₂ m/z- 273 ( ^*)

IR (KBr): 2953, 1559, 1374, 931, 763 cm^"1.

^XH NMR (300 MHz, DMSO-d₆ , TMS): δ (ppm) 6.23 (s, 2H) , 6.80

(dd, IH, J=8.0, 1.5 Hz), 7.24 (t, IH, J=8.0 Hz), 7.41 (dt, IH, J=8.0, 1.5 HZ), 7.57 (t, IH, J=8.0 Hz) , 8.07-8.18 (m,

3H) , 8.90 (d, IH, J=8.0 Hz), 9.25 (dd, IH, J=8.0, 1.0 Hz),

12.07 (s, IH, =N-OH) .

EXAMPLE 39

1- [2 , 7-Dioxo-2 , 7-dihydro-3H-naphtho (1,2, 3-de) quinolin-1-yl ] pyridinium chloride

N-(9, 10-Dioxoanthryl) -2-N-chloroethanamide was produced by adding chloroacetyl chloride (5 g, 4.46 mmol) to 1-aminoantraquinone (5 g, 2.25 mmol) in dry benzene (100 ml), and heating the reaction mixture at 90°C for 1.5 hours.

After cooling to 10 °C the precipitate was collected by filtration, washed with benzene, anhydrous ether, recrystaUized from nitromethane, and dried. Yield = 6.23 g (95 %) . C₁₆H₁₀ClNO₃ m/z - 299 (m^*) ^XH NMR (300 MHz, DMSO-d₆ , TMS): δ (ppm) 4.59 (s, 2H, -CH₂-C1) , 7.92-8.03 (m, 4H) , 8.19 (dd, IH, J=8.0, 1.0 Hz), 8.26 (dd, IH, J=8.0, 1.0 Hz), 9.03 (dd, IH, J=8.0, 1.0 Hz). A suspension of the N-(9, 10-dioxoanthryl) -2-chloroethanamide 5 (2.5 g, 0.84 mmol) in dry pyridine (50 ml) was stirred at 120°C for 1 hour. After cooling to 0°C, the precipitate was collected by filtration, washed with benzene and ether, recrystaUized from water, and dried, yielding 1- [2 , 7-Dioxo-2 , 7-dihydro-3H-naphtho (1,2, 3-de) quinolin-1-yl] 0 pyridinium chloride.

Yield = 2.83 g (93.7%) . C₂₁H₁₃C1N₂0₂ m/z- 325 (m⁺-35)

IR (KBr): 3412, 3012, 1662, 1621, 1593, 1469, 1336, 1280,

700 cm^"1. 5 ^XH NMR (300 MHz, DMSO-d₆, TMS): δ (ppm) 6.31 (d, IH,

J=8.0 Hz), 7.53 (dd, IH, J=8.0 , 1.0 Hz), 7.58 (dd, IH, J=8.0,

1.0 Hz), 7.79 (t, IH, J=8.0 Hz), 7.91 (dd, IH, J=8.0,

1.0 Hz), 8.00 (t, IH, J=8.0 Hz), 8.24 (dd, IH, J=8.0,

1.0 Hz), 8.40 (dd, IH, J=8.0 , 1.0 Hz), 8.48 (d, IH, J=8.0 Hz), 0 8.55 (d, IH, J=8.0 Hz), 9.04 (t, IH, J=8.0 Hz), 9.39 (d, IH, J=8.0 Hz) .

1- [Bromo-5-methyl-2 , 7-dioxo-2 , 7-dihydro-3H-naphtho (1,2, 3-de) quinolin-1-yl]pyridinium chloride was prepared in a similar 5 manner using recrystaUized from water from

3-bromo-6 (2-pyridylamido) -benz (de) anthracene-7-one.

Yield = 0.83g (86%). C₂₂H₁₄BrClN₂0₂ m/z- 418 (m⁺-35)

IR (KBr): 3508, 3037, 1683, 1646, 1463, 1244, 1070, 707,

30 628 cm^"1.

^XH NMR (300 MHz, DMSO-d₆ , TMS) : δ (ppm) 2.66 (s, 3H, CH₃) , 6.40 (d, IH, J=8.0, Hz), 7.50 (dt, IH, J=8.0 , 1.0 Hz), 7.74 (t, IH, J=8.0 Hz) , 8.14 (s, IH, N-H) , 8.25 (dd, IH, J=8.0 , 1.0 Hz) , 8.51 (t, IH, J=8.0 Hz) , 9.01 (t, IH, J=8.0 Hz), 9.40

35 (d, IH, J=8.0 Hz) . l-[3-Methyl-3H-2,7-dioxo-2,7-dihydronaphtho(1,2, 3-de) ] pyridinium chloride have been prepared in a similar manner from N- (9 , 10-dioxoanthryl) -2-chloro-N-methylethanamide, and recrystaUized from water. Yield = 3.12g (83 %) . C₂₂H₁₅C1N₂0₂ m/z- 339 (m⁺-35)

^XH NMR (300 MHz, DMSO-d₆ , TMS): δ (ppm) 3.90 (s, 3H, N-CH₃) , 6.32 (d, IH, J=8.0, Hz), 7.55 (dt, IH, J=8.0, 1.0 Hz) , 7.78 (dt, IH, J=8.0, 1.0 Hz), 8.13 (t, IH, J=8.0 Hz) , 8.22 (d, IH, J=8.0 Hz), 8.32 (dd, IH, J=8.0, 1.0 Hz) , 8.40 (dd, IH, J=8.0, 1.0 Hz), 8.52 (d, IH, J=8.0 Hz) , 8.55 (d, IH, J=8.0 Hz), 9.04 (t, IH, J=8.0 Hz), 9.38 (d, IH, J=8.0 Hz), 9.40 (d, IH, J=8.0 Hz) .

EXAMPLE 40

1- (4-Methylpiperazin-l-yl) -3-methyl-3H-naphtho (1, 2 , 3-de) quinoline-2 , 7-dione

A suspension of N- (9 , 10-dioxoanthryl) -2-chloro-N- methylethanamide (0.78 g, 0.25 mmol) in 1-methylpiperazine (10 ml) was stirred at 125°C for 2 hours. After cooling to 0°C, the precipitate was collected by filtration, washed with benzene and ether, recrystaUized from nitromethane, and dried. Yield = 0.32 g (36%). C₂₂H₂₁N₃0₂ m/z- 359 (m⁺)

^XH NMR (300 MHz, DMS0-d₆ , TMS): δ (ppm) 3.90 (s, 3H, N-CH₃) , 6.32 (d, IH, J=8.0 Hz), 7.55 (dt, IH, J=8.0, 1.0 Hz), 7.78 (dt, IH, J=8.0, 1.0 Hz), 8.13 (t, IH, J=8.0 Hz) , 8.22 (dd, IH, J=8.0, 1.0 Hz), 8.32 (dd, IH, J=8.0, 1.0 Hz), 8.40 (dd, IH, J=8.0, 1.0 Hz), 8.52 (d, IH, J=8.0 Hz), 8.55 (d, IH, J=8.0 Hz), 9.04 (t, IH, J=8.0 Hz), 9.38 (d, IH, J=8.0 Hz), 9.40 (d, IH, J=8.0 Hz) .

Conversion to the hydrochloride yielded l- [ (4-methylpiperazin-l-yl) ] -3-methyl-3H-naphtho ( l , 2 , 3-de) quinoline-2 , 7-dione hydrochloride . C₂₂H₂₂ClN₃θ₂ IR (KBr): 2826, 1675, 1656, 1559, 1315, 1132, 976, 812, 713 cm^"1.

^XH NMR (300 MHz, DMSO-d₆, TMS): 5 (ppm) 1.86-2.01 (m, 6H) , 2.58 (d, IH, J=8.0 Hz), 2.80 (d, IH, J=8.0 Hz), 3.15 (s, 6H, N-CH₃) , 7.84 (dd, IH, J=8.0 , 1.0 Hz) , 7.90-7.93 (m, 3H) , 8.18

(dd, IH, J=8.0, 1.0 Hz), 8.21 (dd, IH, J=8.0, 1.0 Hz), 8.28

(dd, IH, J=8.0, 1.0 Hz) .

EXAMPLE 41

3H-Naphtho (1,2, 3-de) quinoline-2 , 7-dione

A suspension of l-[2 , 7-dioxo-2 , 7-dihydro-3H-naphtho (1, 2 , 3-de) quinolin-1-yl] -pyridinium chloride (0.5 g, 0.14 mmol) in N,N-dimethylaniline was stirred at 220°C for 16 hours. After cooling, the precipitate was collected by filtration, washed with 2-propanol and ether, recrystaUized from N,N-dimethyIformamide with charcoal, and dried. Yield = 0.11 g (32.3%). C₁₆H₉N0₂ m/z- 247 (m^*) IR (KBr): 3051, 2847, 1660, 1565, 1379, 1244, 779 cm^"1.

^XH NMR (300 MHz, DMSO-d_s, TMS): δ (ppm) 7.72 (dd, IH, J=8.0 , 1.0 Hz), 7.75 (s, IH, N-H) , 7.79 (dd, IH, J=8.0 , 1.0 Hz), 7.84 (s, IH) , 7.92-7.85 (m, 2H0, 8.06 (dd, IH, J=8.0 , 1.0 Hz), 8.32 (d, IH, J=8.0 Hz), 8.60 (d, IH, J=8.0 Hz). mp > 340°C

6-Bromo-4-methyl-3H-naphtho(l, 2, 3-de)quinoline-2 ,7-dione was prepared similarly from l-[6-bromo-5-methyl-2, 7-dioxo-

2, 7-dihydro-3H-naphtho(1,2, 3-de) ]pyridinium chloride, and recrystaUized from N,N-dimethyIformamide with charcoal.

Yield = 0.27 g (79 %) . C₁₇H₁₀BrNO₂ m/z- 340 (m^*)

IR (KBr): 3032, 1683, 1647, 1558, 1282, 755 cm^"1.

^XH NMR (300 MHz, DMSO-d₆ , TMS): δ (ppm) 2.57 (s, 3H, CH₃) , 6.64 (m, IH) , 7.12 (t, IH, J=8.0 Hz), 7.52 (s, IH) , 7.68-7.85

(m, 2H) , 8.54 (d, IH, J=8.0 Hz), 11.40 (s, IH, N-H). EXAMPLE 42

3-Methyl-3H-naphtho (1,2, 3-de) quinoline-2 , 7-dione 3H-Naphtho(l,2,3-de)quinoline-2,7-dione (0.49 g, 0.2 mmol) was heated with excess of dimethyl sulfate (10 ml) at 145°C for 2 hours. After cooling, the reaction mixture was diluted with benzene (50 ml) , and the precipitate was collected by filtration, washed with benzene, boiled in 2-propanol and filtered off after cooling, recrystaUized from 2-propanol with charcoal, and dried.

Yield = 0.31 g (59.6%). C₁₇H₁₁N0₂ m/z - 261 (itT)

EXAMPLE 43

2-Chloro-naphtho (1 , 2 , 3-de) quinoline-7-one A suspension of 3H-naphtho (1,2, 3-de) quinoline-2 ,7-dione (1.0 g, 0.4 mmol) in phosphorus oxychloride (15 ml) was heated at 105°C for 5 hours. After cooling, the dark reaction mixture was poured into ice (100 g) , and the precipitate, was filtered off, washed with hot water (150 ml) , recrystaUized from m-xylene, and dried. Yield = 0.93 g (87.7%). C₁₆H₈C1N0 m/z - 265 (m^*)

EXAMPLE 44

l-Amino-3H-naphtho (1,2, 3-de) quinoline-2 , 7-dione

A suspension of l-[2 ,7-dioxo-2 ,7-dihydro-3H-naphtho (1,2, 3-de)quinolin-l-yl]pyridinium chloride (3.61 g, 1.0 mmol) in aniline (17 ml) was heated at 190°C for 5 minutes to 1.5 hours. After cooling, methanol (40 ml) was added, and the precipitate was collected by filtration, washed with methanol, recrystaUized from N,N-dimethylformamide with charcoal, and dried. Yield = 2.41 g (92%). C₁₆H₁₀N₂O₂ m/z- 262 (m⁺) IR (KBr) : 3320, 2881, 1674, 1637, 1546, 1349, 758 cm^"1.

^XH NMR (300 MHz, DMSO-d₆, TMS): δ (ppm) 7.25 (s, 2H, NH₂) ,

7.52 (d, IH, J=8.0 Hz), 7.55 (d, IH, J=8.0 Hz) , 7.60 (t, IH,

J=8.0 Hz) , 7.64 (s, IH, N-H), 7.85 (dt, IH, J=8.0, 1.0 Hz) , 8.11 (dd, IH, J=8.0, 1.0 Hz) , 8.41 (dd, IH, J=8.0, 1.0 Hz),

8.62 (d, IH, J=8.0 Hz) . mp >350°C

Analysis: Calcd. for C₁₆H₁₀N₂O₂: C, 73.27; H, 3.84; N, 10.68 %.

Found: C, 73.05; H, 3.87; N, 10.69 %.

l-Amino-3-methyl-3H-naphtho (1, 2 , 3-de) quinoline-2 , 7-dione was similarly prepared from l-[3-methyl-3H-2 ,7-dioxo-

2,7-dihydro-naphtho(l,2,3-de) ]pyridinium chloride, and recrystaUized from N,N-dimethy If ormamide with charcoal. Yield = 0.27 g (39%). C₁₇H₁₂N₂0₂ m/z- 276 (m⁺)

IR (KBr) : 3322, 1653, 1648, 1593, 1337, 985, 759 cm^'1.

^XH NMR (300 MHz, DMSO-d₆, TMS) : δ (ppm) 3.84 (s, 3H, N-CH₃) ,

7.33 (s, 2H, -NH₂) , 7.57 (dd, IH, J=8.0, 1.0 Hz) , 7.61 (dd, IH, J=8.0, 1.0 Hz), 7.83 (dd, IH, J=8.0 , 1.0 Hz) , 7.87 (dd,

IH, J=8.0, 1.0 Hz), 8.19 (dd, IH, J=8.0 , 1.0 Hz), 8.39 (dd,

IH, J=8.0, 1.0 Hz) , 8.62 (d, IH, J=8.0 Hz) . mp 259°C.

Analysis: Calcd. for C₁₇H₁₂N₂0₂ x 0.1 H₂0: C, 73.42; H, 4.35; N, 10.07 %. Found; C, 73.33; H, 4.41; N,9.98 %.

l-Amino-6-bromo-4-methyl-3H-naphtho(l,2 , 3-de) quinolin-2 , 7- dione was similarly prepared from l-[6-bromo-5-methyl-2 ,7- dioxo-2 , 7-dihydro-3H-naphtho (1,2, 3-de) pyridinium chloride, and recrystaUized from N,N-dimethyIformamide with charcoal.

Yield = 0.31 g (87%). C₁₇H BrN₂0₂ m/z- 356 (m⁺+l)

IR (KBr): 3434, 3334, 3170, 1670, 1646, 1584, 1335, 1038,

625 cm^"1. ^XH NMR (300 MHz, DMSO-d₆, TMS): δ (ppm) 2.55 (s, 3H, -CH3),

7.29 (s, 2H, -NH2), 7.55 (d, IH, J=8.0 Hz), 7.60 (d, IH, J=8.0 Hz), 7.79 (dt, IH, J=8.0, 1.0 Hz), 8.23 (dd, IH, J=8.0, 1.0 Hz), 8.55 (d, IH, J=8.0 Hz).

Example 45

2 , 7-Dioxo-4-methyl-l-trimethylamino-3-H-naphtho (1,2, 3-de) quinolinium 4-methylbenzosulfonoate A mixture of l-amino-3-methyl-3H-naphtho(l, 2, 3-de) quinoline-2,7-dione (0.276 g, 0.1 mmol) and methyl p-tolyenesulfonate (3.0 g, 1.6 mmol) was heated at 135°C for 1.5 hours. After cooling, dry ether (150 ml) was added, and the precipitate was collected by filtration, washed with dry ether, recrystaUized from 2-propanol, and dried. Yield = 0.27 g (55%). C₂₇H₂₆N₂0₅S m/z- 319 (m⁺-171)

IR (KBr): 3502, 2987, 1683, 1668, 1559, 1320, 1202, 1050, 804, 693, 569 cm^"1.

^XH NMR (300 MHz, DMSO-d₆, TMS): δ (ppm) 2.27 (s, 3H, C₆H₄-CH₃) , 3.94 (s, 3H, N-CH₃) , 4.97 (s, 9H, N-CH₃)₃), 7.09 (d, IH, J=8.0 Hz), 7.44 (d, IH, J=8.0 Hz), 8.14 (t, IH, J=8.0 Hz), 8.24 (d, IH, J=8.0 Hz), 8.36 (d, IH, J=8.0 Hz), 8.52 (t, IH, J=8.0 Hz), 9.02 (d, IH, J=8.0 Hz), 9.18 (d, IH, J=8.0 Hz), 10.51 (d, IH, J=8.0 Hz) .

EXAMPLE 46

l-Acetamido-3H-naphtho (1,2, 3-de) quinoline-2 , 7-dione 2-Methyl-naphtho (1, 2 , 3-de) oxazole[5, 4-b]quinolin-8-one was produced from a suspension of l-amino-3H-naphtho(l, 2 , 3-de) quinoline-2,7-dione (0.13 g, 0.05 mmol) in acetic anhydride (2 ml) . The suspension was refluxed for 2 hours, cooled and precipitate was collected by filtration, washed with 2-propanol and ether, and recrystaUized from glacial acetic acid and N,N-dimethylformamide with charcoal. Yield = 0.091 g (6 3%). C₁₈H₁₀N₂O₂

IR (KBr): 1674, 1648, 1581, 1297, 737 cm^"1. ^XH NMR (300 MHz, CF₃C0₂D, TMS): δ (ppm) 3.04 (s, 3H, -CH₃) 8.01 (t, IH, J=8.0 Hz), 8.13 (t, IH, J=8.0 Hz), 8.39 (t, IH, J=8.0 Hz), 8.66 (d, IH, J=6.5 Hz), 8.67 (d, IH, J=8.0 Hz), 9.07 (d, IH, J=8.0 Hz), 10.00 (d, IH, J=8.0 Hz) . The 2-Methyl-naphtho(l,2,3-de)oxazole[5,4-b]quinolin-8-one product (0.14 g, 0.05 mmol) was dissolved with refluxing in aqueous 1.4-dioxane (1:1) (30 ml), and hydrochloric acid (35 %) (1.0 ml) was added. The reaction mixture was cooled, and neutralized with a solution of sodium bicarbonate. The precipitate was removed by filtration, washed with

2-propanol, recrystaUized from a mixture of acetic acid and water (1:1) with charcoal, and dried, yielding l-Acetamido-3H-naphtho (1,2, 3-de) quinoline-2 , 7-dione . Yield = 0.08 g (53%). C_lθH₁₂N₂θ₃ IR (KBr): 3294, 2825, 1690, 1653, 1558, 1478, 1244, 926, 764 cm^"1.

^XH NMR (300 MHz, DMSO-d₆ , TMS): 5 (ppm) 2.16 (s, 3H, CH3), 7.65-7.82 (m, 5H) , 8.10 (d, IH, J=8.0 Hz), 8.29 (d, IH, J=8.0 Hz), 10.14 (s, IH) .

EXAMPLE 47

l-Benzamide-3H-naphtho (1, 2 , 3-de) quinoline-2 , 7-dione

2-Pheny1-naphtho (1,2,3-de) oxazole [ 5 , 4-b] quinolin-8-one was prepared from a suspension of l-amino-3H-naphtho (1, 2 , 3-de) quinoline-2,7-dione (0.262 g, 0.1 mmol) in the benzoyl chloride (15 ml) by heating the suspension at 110°C for 1 hour. After cooling the precipitate was filtered and washed with 2-propanol and ether, and recrystaUized from N,N-dimethyIformamide with charcoal. Yield = 0.27 g (78 %) . C₂₃H₁₂N₂0₂ IR (KBr): 1660, 1544, 1267, 1025, 699 cm^"1. 'H NMR (300 MHz, CF₃C0₂D, TMS): δ (ppm) 7.74 (d, IH, J=6.0 Hz), 7.78 (d, IH, J=6.0 Hz), 7.87 (t, IH, J=8.0 Hz), 8.03 (t, IH, J=8.0 Hz) , 8.19 (t, IH, J=8.0 Hz), 8.39 (t, IH, J=8.0 Hz), 8.53 (d, IH, J=6.5 Hz), 8.55 (d, IH, J=6.5 Hz), 8.68 (d, IH, J=6.5 Hz), 8.71 (d, IH, J=6.5 Hz), 9.10 (dd, IH, J=6.5, 1.0 Hz), 10.15 (t, IH, J=8.0 Hz).

The 2-Phenyl-naphtho (1,2, 3-de) oxazole [5 , 4-b] quinolin-8-one product (0.17 g, 0.05 mmol) was dissolved with refluxing in aqueous 1.4-dioxane (1:1) (30 ml), and sodium hydroxide solution (40%) (0.5 ml) was added to the solution. The mixture was cooled, neutralized with sulfuric acid and filtered. The solid was washed with water and 2-propanol, recrystaUized from mixture acetic acid/water (3:1), and dried, yielding l-Benzamide-3H-naphtho(l, 2 ,3-de) quinoline-2 , 7-dione. Yield = 0.11 g (60%). C₂₃H₁₄N₂0₃

IR (KBr): 3504, 3327, 2828, 1689, 1649, 1558, 1263, 926, 785 cm^"1. ^:H NMR (300 MHz, DMSO-d₆ , TMS): δ (ppm) 7.57-7.84 (m, 6H) , 7.82 (t, IH, J=8.0 Hz), 8.08 (d, IH, J=8.0 Hz), 8.14 (d, IH, J=8.0 Hz), 8.34 (d, IH, J=8.0 Hz), 8.72 (d, IH, J=8.0 Hz), 10.29 (s, IH) .

The molecular binding and antiviral activity of the benzanthrone class of molecules and a benzanthrone series structure activity relationship chart are provided in the tables below.

Molecular Binding and Antiviral Activity of the Benzanthrone Class of Molecules

5

n

25

25

3B

10 n

15

20

25

3B

25

3B

5

5

B

25

5

5

B

25

5

B

While it is apparent that the invention disclosed herein is well calculated to fulfill the objects stated above, it will be appreciated that numerous modifications and embodiments may be devised by those skilled in the art. Therefore, it is intended that the appended claims cover all such modifications and embodiments that fall within the true spirit and scope of the present invention.

Claims

THE CLAIMSWe claim:

1. A composition having antiviral properties, which comprises a 7H-benz[de] anthracene or salt thereof of for ula

and

and derivatives thereof, where

R_lf R₂, and R₃, are the same or different, and are individually selected from the group consisting of hydrogen, halide, alkyl, nitrile, nitro, alkanoly, benzyl, benzoly, hydroxy1, methylenedioxy, ethylenedioxy, dialkyamino, and cyclic amino;

R₄ is selected from the group consisting of hydrogen, alkyl, benzyl, benzoly; R₅ and R₆ are hydrogen or alkyl having one to four carbon atoms, or form a 5- or 6-membered heterocyclic ring with the nitrogen to which they are attached, where the 5- or 6-membered heterocyclic ring is selected from the group consisting of piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino having from one to four carbon atoms in the alkyl group; and X and Y are selected from the group consisting of carbon, nitrogen and oxygen.

2. A pharmaceutical composition for the treatment of a viral infection, which comprises a therapeutically effective amount of at least one benzanthrone or benzanthrone derivative of a 7H-benz[de]anthracen-7-one or salt thereof of formula

an azabenzanthrone or salt thereof of formula II,

or III ,

III

a 7H-benz[de] anthracene or salt thereof of formula IV,

or V,

or a derivative thereof, where R_lf R₂, and R₃, are the same or different, and are individually selected from the group consisting of hydrogen, halide, alkyl, nitrile, nitro, alkanoly, benzyl, benzoly, hydroxy1, methylenedioxy, ethylenedioxy, dialkyamino, and cyclic amino;

R₄ is selected from the group consisting of hydrogen, alkyl, benzyl, benzoly; R₅ and R₆ are hydrogen or alkyl having one to four carbon atoms, or form a 5- or 6-membered heterocyclic ring with the nitrogen to which they are attached, where the 5- or 6-membered heterocyclic ring is selected from the group consisting of piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino having from one to four carbon atoms in the alkyl group; and

X and Y are selected from the group consisting of carbon, nitrogen and oxygen.

3. The pharmaceutical composition of claim 2, further comprising a pharmaceutically suitable carrier.

4. A method for the treatment of a viral infection, which comprises administering to a patient having a viral infection a therapeutically effective amount of an antiviral composition comprising at least one of benzanthrone or benzanthrone derivative of a 7H-benz [de]anthracen-7-one of formula

an azabenzanthrone of formula II,

or III,

a 7H-benz [de] anthracene of formula IV,

or V,

or a derivative thereof, where

R₄ is selected from the group consisting of hydrogen, alkyl, benzyl, benzoly;

X and Y are selected from the group consisting of carbon, nitrogen and oxygen.

5. The method of claim 4, further comprising mixing the benzanthrone or benzanthrone derivative with a pharmaceutically suitable carrier to facilitate the administration of the antiviral composition.

6. The method of claim 4, wherein the viral infection is an RSV infection.

7. A composition having antiviral properties, which comprises a 3-substituted benzanthrone or salt thereof of formula

wherein R_x is selected from the group consisting of alkyl and aryl sulfonamide, tetrazole, natural and synthetic carbonyl amino acids, carbonyl-N-methylpiperazine, amide, halide, hydroxymethyl, methoxymethyl, and carboxylic acid.

8. The composition of claim 7, wherein R_x is selected from the group consisting of CONHS0₂CH₃, tetrazole, CO-glycine, CO-asparagine, CO-arginine, CO-tryptophan, CO-leucine, and CO-proline.

9. The composition of claim 7, wherein the 3-substituted benzanthrone or salt thereof is of the formula

or

10. A composition having antiviral properties, which comprises a 3,9-disubstituted benzanthrone or salt thereof of formula

or a derivative thereof, wherein R_x and R₂ are the same or different, and are individually selected from the group consisting of alkyl and aryl sulfonamide, tetrzaole, natural and synthetic carbonyl amino acids, carbonyl-N-methylpiperazine, amide, halide, hydroxymethyl, and carboxylic acid.

11. The composition of claim 9, wherein R_x is selected from the group consisting of CONHS0₂CH₃, tetrazole, CO-glycine, CO-asparagine, CO-arginine, CO-tryptophan, CO-leucine, and CO-proline, and R₂ is selected from the group consisting of be CONHS0₂CH₃, tetrazole, CO-glycine, CO-asparagine, CO-arginine, CO-tryptophan, CO-leucine, CO-proline, CO-N-methylpiperazine, C0NH₂, CN, Br, C0₂H, and C0₂Na.

12. The composition of claim 9, wherein R₂ is selected from the group consisting of CONHS0₂CH₃, tetrazole, CO-glycine, CO-asparagine, CO-arginine, CO-tryptophan, CO-leucine, and CO-proline, and R_x is selected from the group consisting of be CONHS0₂CH₃, tetrazole, CO-glycine, CO-asparagine, CO-arginine, CO-tryptophan, CO-leucine, CO-proline, CO-N-methylpiperazine, CONH₂, CN, Br, C0₂H, and C0₂Na .

13. The composition of claim 9, wherein

R₁=R₂=CO-N-methylpiperazine, R₁=R₂=CONH₂, R_X=CN and R₂=CONH₂, R_j=C0NH₂ and R₂=Br, R₁=C0₂H and R₂=Br, or R₁=C0₂Na and R₂=Br.

14. The composition of claim 9, wherein the 3 , 9-disubstituted benzanthrone or salt thereof is of the formula