BACKGROUND OF THE INVENTION Atherosclerosis is a multifactorial disease characterized by excessive intracellular lipid deposition in macrophages, leading to the formation of foam cells. The accumulation of lipid-loaded foam cells in the subendothelial space leads to formation of fatty steaks, which are the early atherosclerotic lesions.

Oxidative modifications of lipids, specifically low-density lipoprotein, has been implicated as a major process in foam-cellL formation.

Lipoxygenases are nonheme iron-containing enzymes that catalyze the oxygenation of certain polyunsaturated fatty acides such as lipoproteins. Several different lipoxygenase enzymes are lçnown, each having a characteristic oxidation action. One specific lipoxygenase, namely 15-lipoxygenase (15-LO), has been detected in atherosclerotic lesions in mammals, specifically rabbit and man. The enzyme, in addition to its role in oxidative modification of lipoproteins, is important in the inflammatory rection in the atherosclerotic lesion. Indeed, 15-LO has been shown to be induced in humas monocytes by the cytokine IL-4, which is known to be implicated in the inflammatory process.

Inhibitors of 15-LO are especially usefill to prevent and treat inflammatory diseases such as asthma, psoriasis, arthritis, and atherosclerosis. While there are several lipoxygenase enzymes, specific inhibition of 15-LO is important in the inflammatory and atherosclerosis process. A characteristic feature of atherosclerosis is the accumulation of cholesterol ester engorge foam cells. Foam cells are derived from circulating monocytes that invade artery walls in response to hypercholesterolemia, and mature into tissue macrophages. The enzyme 15-LO has been implicated in inflammatory disorders and in the origin and recruitment of foam cells (See Carats, et al., Trends Cardiovasc. Med., 1995; 5 (1) : 29-36). This enzyme is capable of oxidizing esterified polyenoic fatty acids, such as those found in phospholipids. Treatment of experimental animals with antioxidants which reduced hydroperoxides produced by 15-LO has been shown to retard the progression of atherosclerotic lesions. For example, Sendobry, et al., British Journal of PharmacologY, 1997; 120: 1199-1206 show suppression of atherogenesis in rabbits fed a high-fat diet and treated with a 15-LO inhibitor.

THEINVENTIONSUMMARYOF The present invention provides compound shaving the Formula I

each n is independently 0 to 3;

Q is Cl-C6 alkyl, heteroaryl, substituxed heteroaryl,-NR'R', or cycloalkyl; each Rf is independently hydrogen or C1-C6 alkyl; R9 Re is <, C1-C18 alkyl, 7 7 heteroaryl, substituted heteroaryl, naphthyl, benzyl, or dansyl; each of R1,R2,R3,R4,R5,R6,R7,R8,R9,Ra,Rb,Rc, and Rd are independently hydrogen,-OC1-C6 alkyl, -SC1-C6 alkyl, halogen, -OH,-CF3,-NO2,-CN,-CO2H,-OCF3,-CO2C2-C6C1-C6alkyl, -SO3-alkalimetal,-NH2,-NHC1-C6alkyl,alkyl,-SO3H, o o -N (CC1-C6 alkyl) 2,-OCC1-C6 alkyl ? -C02C1-C6 alkyl,-S03H,

-S03 alkali metal,-CN,-CH2-halogen, heteroaryl,aryl,substitutedaryl,cycloalkyl,heteroaryl,substi tuted substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl,benzoyl, 0 ICI CC1-C6 alkyl, 0 0 11 11 -OCEI,-OCC1-C6 alkylX -SO3H,-SO3NR'R',-CHO,-SO2NH2,or -NR'R'; or the pharmaceutically acceptable salts thereof, provided that when Q is not C1-C6 alkyl ; further provided that when X is Y is-NH, Rb is nolt SOH; further provided that when X and Y are Re and Q are mot unsubstituted phenyl; further provided that when Y is Re and Q are not bothprovidedthatwhenYis-SO2NH-orfurther -SO2NC1-C6 alkyl and X is 0 0 11 11 CNH or CNC 1-C6 alkyl, C2 and Re are not both unsubstituted phenyl; further provided that when Y is

0 0 11 11 -CNH or-CNC1-C6 alkyl and X is Re is unsubstituted phenyl di-or tri-substituted phenyl; further provided that when Y is Q is not unsubstituted aryl.

In a preferred embodiment of the compound of Formula I, In another preferred embodiment of the compounds of Formula I, R'is hydrogen or methyl.

In another preferred embodiment of the compound of Formula I, X is-O-.

In another preferred embodiment of the compound of Formula I, X is In another preferred embodiment of the compound of Formula I, R'is hydrogen.

In another preferred embodiment of the compound of Formula I, Rc is -OCH3, halogen,-S-methyl,or-OCF3.-OCH2CH3, In another preferred embodiment of the compound of Formula I9 Y is In another preferred embodiment of the compound of Formula I, X is In another preferred embodiment of the compound of Formula I, Y is

In another preferred embodiment of the compound of Formula I, Rc is hydrogen, hydroxy,-OC1-C6 alkyl, halogen, Cl-C6 alkyl,-SCl-C6 alkyl,-CF3, or-OCF3.

Also provided is a method of treating or preventing atherosclerosis, the method comprising administering to a patient having atherosclerosis or at risk of having atherosclerosis a therapeutically effective amount of a compound of Formula I

each n is independently 0 to 3;

Q is Cl-C6 alkyl, heteroaryl, substituted heteroaryl,-NR'R', or cycloalkyl; each R'is independently hydrogen or C1-C6 alkyl; alkyl, heteroaryl, substituted heteroaryl, naphthyl, benzyl, or dansyl; each ofR1,R2,R3,R4,R5,R7,R8,R9,R10,Ra,Rb,Rc, and Rd are independentlyalkyl,-SC1-C6alkyl,halogen,-OC1-C6 -OH,-CF3,-NO2,-CN,-CO2H,-OCF3,-CO2C1-C6C1-C6alkyl, alkyl,-S03H,-S03-alkali metal,-NH2,-NHCl-C6 alkyl, 0 0 11 11 -N (CC1-C6 alkyl) 2,-OCC1-C6 alkyl, -SO3H,-CO2C1-C6alkyl, -S03 alkali metal,-CN,-CH2-halogen, heteroaryl, substituted heteroaryl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted

heterocycloalkyl, benzol, 0 ICI CC1-C6 alkyl, 0 0 11 11 -OCH,-OCCl-C6 alkyl, -SO3H,-SO3NR'R,-CHO,-SO2NH2,or -NR'R', or the pharmaceutically acceptable salts thereof.

Also provided is a method of treating or preventing inflammation, the method comprising administering to a patient having inflammation or at risk of having inflammation a therapeutically effective amount of a compound of Formula I

each n is independently 0 to 3;

Q is Cl-C6 alkyl, heteroaryl, substituted heteroaryl,-NR'R', or cycloalkyl; each R'is independently hydrogen or C1-C8 alkyl; substitutedalkyl,heteroaryl, heteroaryl, naphthyl, benzyl, or dansyl ; each of R1, R2, R3, R4,R5,R7,R8,R9,R10,Ra,Rb,Rc, and Rd are independently hydrogen,-OC1-C6 alkyl, -SC1-C6 alkyl, halogen, C1-C6alkyl,-OH,-CF3,-NO2,-CN,-CO2H,-OCF3,-CO2C1-C6 alkyl,alkyl,-SO3H,-SO3-alkalimetal,-NH2,-NHC1-C6 0 0 11 11 -N (CCl-C6 alkyl) 2,-OCC1-C6 alkyl, -SO3H,-CO2C1-C6alkyl, -SO3 alkali -CN,-CH2-halogen,

heteroaryl, substituted heteroaryl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted 0 ICI CC1-C6 alkyl, 0 0 11 11 -OCH,-OCC1-C6 alkyl, -SO3H,-SO3NR'R',-CHO,-SO2NH2,or -NR'R', or the pharmaceutically acceptable salts thereof.

The present invention provides a pharmaceutically acceptable composition comprising a compound of Formula I.

Also provided is a method of inhibiting 15-lipoxygenase, the method comprising administering to a patient in need of 15-lipoxygenase inhibition a 15-lipoxygenase inhibiting amount of a compound of Formula I

each n is independently 0 to 3;

Q is Cl-C6 alkyl, heteroaryl, substituted heteroaryi,-R'R', or cycloalkyl; each R'is independently hydrogen or C1-C6 alkyl; heteroaryl,substitutedC1-C18alkyl, heteroaryl, naphthyl, benzyl, or dansyl; each of R1, R2, R3, R4, R57 R6, R7, R8,R9,R10,Ra,Rb,Rc, and Rd are independently hydrogen7-OC1-C6 alkyl,-SC1-C6 alkyl, halogen, Cl-C6 alkyl,alkyl,-OH,-CF3,-NO2,-CN,-CO2H,-OCF3,-CO2C1-C6 heteroaryl, substituted heteroaryl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted 0 ICI CC I-C6 alkyl, 5 10 0 0 11 11 -OCH,-OCC1-C6 alkyl, -SO3H,-SO3NR'R',-CHO,-SO2NH2,or -NR'R', or the pharmaceutically acceptable salts thereof.

Also provided is a method of inhibiting the chemotaxis of monocytes, the method comprising administering to a patient in need of inhibition of chemotaxis of monocytes, a monocyte chemotaxis inhibiting amount of a compound of Formula I

each n is independently 0 to 3;

Q is C1-C6 alkyl, heteroaryl, substituted heteroaryl,-NR'R', or cycloalkyl; each R'is independently hydrogen or G1-C6 alkyl ; C1-Cl8 alkyl, heteroaryl, substituted heteroaryl, naphthyl, benzyl, or dansyl; each of R1,R2,R3,R4,R5,R7,R8, R9, R10, Ra, Rb, RC, and Rd are independently hydrogen,-OCl-C6 alkyl,-SC1-C6 alkyl, halogen, Cl-C6 alkyl,-SO3H,alkyl,-OH,-CF3,-NO2,-CN,-CO2H,-OCF3,-CO2C1-C6 -NH2,-NHC1-C6alkyl,-SO3-alkalimetal, 0 0 11 11 -N (CC1-C6 alkyl) 2,-OCC1-C alkyl.

-CO2C1-C6alkyl,-S03H, -S03 alkali metal,-CN,-CH2-halogen, heteroaryl, substituted heteroaryl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted 0 ICI CC1-C6 alkyl,

0 0 11 11 -OCH,-OCC1-C6 alkyl, -SO3H,-SO3NR'R',-CHO,-SO2NH2,or -NR'R', and the pharmaceutically acceptable salts thereof.

Also provided by the present invention are compound having the Formula 11 wherein Re is phenyl, pyridyl, or substituted phenyl having 1 to 5 substituents selected from halogen, Cl-C6 alkyl, OCl-C6 alkyl,-CF3, or-OH; B is hydrogen, OC1-C6 alkyl, halogen, C1-C6 alkyl,-SC1-C6 alkyl, -OCF3, or-OH; Q is phenyl, pyridyl, or substituted phenyl having from 1 to 5 substituents selected from halogen,-OC-C6 alkyl, oxazolinyl,-CF3, N02, 0 11 -COCl-C6 alkyl, or-Cl-C6 alkyl, acceptable salts thereof.

In a preferred embodiment of the compound of Formula II, B is-OCH3 or -OCF3.

In a preferred embodiment of the compound of Formula II, Re is substitutedphenyl.

In a preferred embodiment of the compound of Formula II,

In a preferred embodiment of the compound of Formula II, B is-OCH3, or-OCF3; Re is substituted phenyl and Y is Also provided are compound shaving the Formula III Re is pyridyl. or phenyl that is substituted with from 1 to 5 substituents selected from halogen,-CF3,-N02, benzoyl,-S03 alkali metal, alkyl,-CN,-COOH,C1-C6alkyl,-OC1-C6 0 11 CCl-C6 alkyl, -OCF3, 0 11 -COC1-C6 alkyi, -SO2NH2, N (CI-C6 alkyl) 2, or -SONH2; B is OC1-C6 alkyl, hydrogen, halogen, or Cl-C6 alkyl; Q is phenyl, pyridyl7 or phenyl substituted with 1 to 5 substituents selected from halogen,-OC1-C6 alkyl, halogen, or C1-C6 alkyl, or the pharmaceutically thereof.salts In a preferred embodiment of the compound of Formula III, Re is substituted phenyl.

In a preferred embodiment of the compound of Formula III, B is-OCH3 or-OCF3, or fluorine.

In a preferred embodiment of the compound of Formula III, In a preferred embodiment of the compound of Formula III, Re is substituted phenyl, B is-OCH3,-OCF3, and Y is Also provided are compound having the Formula IV X is-NHCH2-,-O-, B is-OC1-C6 alkyl, hydrogen, or-OH; Re is phenyl, pyridyl, or phenyl substituted with 1 to 5 substituents selected from halogen,-OC-C6 alkyl,-OH,-NH2,-NHCl-C6 0 11 -N (Cl-C6alkyl) 2, -NO2,-C1-C6 alkyl, naphthyl,-CF3, -OCF3, 0 11 -OCC1C6 alkyl, -CO2C1-C6 alkyl, furyl, CN, phenyl;-CO2H,or

Q is phenyl, pyridyl, or substituted phenyl, wherein the substituted phenyl may contain 1 to 5 substituents selected from those listed for Re, or the pharmaceutically acceptable salts thereof.

In a preferred embodiment of the compound of Formula IV, Re is substituted phenyl.

In a preferred embodiment of the compound of Formula IV, B is-OCH3.

In a preferred embodiment of the compound of Formula IV, X is -NHCH2-.

In a preferred embodiment of the compound of Formula IV, In a preferred embodiment of the compound of Formula IV, Re is substituted phenyl; B is-OCH3; X is-NHCH2-; and Y is Also provided are compounds having, the Formula V B is-OCl-C6 alkyl or halogen; A is phenyl, C1-Clg alkyl, pyridyl ? quinolinyl substituted phenyl, thiazolyl, substituted thiazolyl, substituted pyridyl, substituted quinolinyl, imidazolyl, substituted imidazolyl, naphthyl, substituted naphthyl, benzyl, thienyl, substituted thienyl, isoxazolyl, or substituted isoxazolyl wherein the substituents are selected from halogen, -OC1-C6 alkylX-N02, Cl C6 alkyl,-CF3, -C02H,

-NH2,-NHCl-C6alkyl, -CN, or-CH2-halogen; -CH2NH-, or-NH2CH-, and C is phenyl or substituted phenyl, pyridyl or substituted pyridyl, wherein the substituents are as described for A, or the pharmaceutically acceptable salts thereof In a preferred embodiment ofthe compounds of Formula V, A is C 1-C 1 g alkyl, substituted phenyl, or thienyl.

In a preferred embodiment of the compound of Formula V, B is-OCH3 or halogen.

In a preferred embodiment of the compound of Formula V, In a preferred embodiment of the compound of Formula V, A is C1-C18 alkyl, substituted phenyl or thienyl; B is-OCF3 or halogen; and Also provided is a method of treating or preventing atherosclerosis, the method comprising administering to a patient having atherosclerosis or at risk of having atherosclerosis a therapeutically effective amount of a compound of Formula VI

each R5 is independently hydrogell or C1-C6 alkyl; R1, R2, R3, and R4 are independently hydrogen, -SC1-C6 alkyl,-OCF3, -OH, -NO2,-COOR5,-SO3NR5R5,-CHO,-CF3, -NR5R5,C1-C6alkyl,heteroaryl,substituted-OC1-C6alkyl, heteroaryl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl,ortheheterocycloalkyl,substituted pharmaceutically acceptable salts thereof.

Also provided is a method of treating or preventing inflammation, the method comprising administering to a patient having inflammation or at risk of having inflammation a therapeutically effective amount of a compound of Formula VI each R5 is independently hydrogen or Cl-C6 alkyl; R1, R2, R3, and R4 are independently hydrogen, -SC1-C6 alkyl,-OH, halogen,-CF3,-NO2,-COOR5,-SO3NR5R5,-CHO,-OCF3, -OC1-C6 alkyl, -NR5R5, C1-C6 alkyl, heteroaryl, substituted heteroaryl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl substituted heterocycloalkyl, or the pharmaceutically acceptable salts thereof.

Also provided is a method of inhibiting 15-lipoxygenase, the method comprising administering to a patient in need of 15-lipoxygenase inhibition a 15-lipoxygenase inhibiting amont of a compound of Formula VI each R5 is independently hydrogen or C1-C6 alkyl; R1, R27 R3, and R4 are independently hydrogen,-SC-C6 alkyl,-OH, halogen,-CF3,-NO2,-COOR5,-SO3NR5R5,-CHO,-OCF3, -OC1-C6 alkyl,-NR5R5, Cl 6 alkyl, heteroaryl, substituted heteroaryl, aryly substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, or the pharmaceutically acceptable salts thereof.

Also provided is a method of inhibiting the chemotaxis of monocytes, the method comprising administering to a patient in need of inhibition of chemotaxis of monocytes a chemotaxis inhibiting amount of a compound of Formula VI each R5 is independently hydrogen or C1-C6 alkyl;

RI, R2, R3, and R4 are independently hydrogen,-SCl-C6 alkyl,-OH, halogen,-CF3,-NO2,-COOR5,-SO3NR5R5,-CHO,-OCF3, -OC1-C6 alkyl, NR5R5, C1-C6 alkyl, heteroaryl, substituted heteroaryl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, or the pharmaceutically acceptable salts thereof.

The present invention also provides compound having the Formula VII RZ is phenyl or phenyl substituted with from 1 to 5 substituents selected from halogen or-CF3; or X and RZ are-N (SO2-3, 5-dichSorophenyl) 2, or the pharmaceutically acceptable salts thereof The present invention also provides compound having the Formula VIII

RZ is phenyl, pyridyl, or phenyl substituted with from 1 to 5 substituents wherein the substituents are selected from halogen, pyridyl, or -C02C1-C6 alkyl.

Also provided is a method of treating or preventing atherosclerosis, the method comprising administering to a patient having atherosclerosis or at risk of having atherosclerosis a therapeutically effective amount of a compound of Formula II.

Also provided is a method of treating or preventing inflammation, the method comprising administering to a patient having infíammation or at risk of having inflammation a therapeutically effective amount of a compound of Formula II.

Also provided is a method of inhibiting 15-lipoxygenase, the method comprising administering to a patient in need of 15-lipoxygenase inhibition a 15-lipoxygenase inhibiting amount of a compound of Formula II.

Also provided is a method of inhibiting the chemotaxis of monocytes, the method comprising administering to a patient in need of inhibition of chemotaxis of monocytes a chemotaxis inhibiting amont of a compound of Formula II.

The present invention provides a pharmaceutically acceptable composition comprising a compound of Formula 11.

Also provided is a method of treating or preventing atherosclerosisa the method comprising administering to a patient having atherosclerosis or at risk of having atherosclerosis a therapeutically effective amont of a compound of Formula III.

Also provided is a method of treating or preventing inflammation, the method comprising administering to a patient having inflammation or at risk of having inflammation a therapeutically effective amount of a compound of Formula III.

Also provided is a method of inhibiting 15-lipoxygenase, the method comprising administering to a patient in need of 15-lipoxygenase inhibition a 15-lipoxygenase inhibiting amount of a compound of Formula 111.

Also provided is a method of inhibiting the chemotaxis of monocytes, the method comprising administering to a patient in need of inhibition of chemotaxis of monocytes a chemotaxis inhibiting amount of a compound of Formula III.

The present invention also provides a pharmaceutically acceptable composition comprising a compound of Formula III.

Also provided is a method of treating or preventing atherosclerosis, the method comprising administering to a patient having atherosclerosis or at risk of having atherosclerosis a therapeutically effective amount of a compound of Formula IV.

Also provided is a method of treating or preventing inflammation, the method comprising administering to a patient having inflammation or at risk of having inflammation a therapeutically effective amount of a compound of Formula IV.

Also provided is a method of inhibiting 15-lipoxygenase, the method comprising administering to a patient in need of 15-lipoxygenase inhibition a 15-lipoxygenase inhibiting amont of a compound of Formula IV.

Also provided is a method of inhibiting the chemotaxis of monocytes, the method comprising administering to a patient in need of inhibition of chemotaxis of monocytes a chemotaxis inhibiting amont of a compound of Formula IV.

The present invention provides a pharmaceutically acceptable composition comprising a compound of Formula IV.

Also provided is a method of treating or preventing atherosclerosis, the method comprising administering to a patient having atherosclerosis or at risk of having atherosclerosis a therapeutically effective amount of a compound of Formula V.

Also provided is a method of treating or preventing inflammation, the method comprising administering to a patient having inflammation or at risk of having inflammation a therapeutically effective amount of a compound of Formula V.

Also provided is a method of inhibiting 15-lipoxygenase, the method comprising administering to a patient in need of 15-lipoxygenase inhibition a 15-lipoxygenase inhibiting amount of a compound of Formula V.

Also provided is a method of inhibiting the chemotaxis of monocytes, the method comprising administering to a patient in need of inhibition of chemotaxis of monocytes a chemotaxis inhibiting amount of a compound of Formula V.

The present invention also provides a pharmaceutically acceptable composition comprising a compound of lFormula V Also provided is a method of treating or preventing atherosclerosis, the method comprising administering to a patient having atherosclerosis or at risk of having atherosclerosis a therapeutically effective amount of a compound of Formula VII.

Also provided is a method of treating or preventing inflammation, the method comprising administering to a patient having inflammation or at risk of having inflammation a therapeutically effective amount of a compound of Formula VII.

Also provided is a method of inhibiting 15-lipoxygenase, the method comprising administering to a patient in need of 15-lipoxygenase inhibition a 15-lipoxygenase inhibiting amont of a compound of Formula VII.

Also provided is a method of inhibiting the chemotaxis of monocytes, the method comprising administering to a patient in need of inhibition of chemotaxis of monocytes a chemotaxis inhibiting amount of a compound of Formula VII.

The pressent invention alsc provides a pharmaceutically acceptable composition comprising a compound of Formula VII.

Also provided is a method of treating or preventing atherosclerosis, the method comprising administering to a patient having atherosclerosis or at risk of having atherosclerosis a therapeutically effective amount of a compound of Formula VIII.

Also provided is a method of treating or preventing inflammation, the method comprising administering to a patient having inflammation or at risk of having inflammation a therapeutically effective amount of a compound of Formula VIII.

Also provided is a method of inhibiting 15-lipoxygenase, the method comprising administering to a patient in need of 15-lipoxygenase inhibition a 15-lipoxygenase inhibiting amont of a compound of Formula VIII.

Also provided is a method of inhibiting the chemotaxis of monocytes, the method comprising administering to a patient in need of inhibition of chemotaxis of monocytes a chemotaxis inhibiting amount of a compound of Formula VIII.

The present invention provides a pharmaceutically acceptable composition comprising a compound of Formula VIII.

The present invention provides the compound: 3-Amino-4-methoxy-N- (3,4-dichlorophenyl)-benzamide; 3-(3-Trifluoromethyl-phenylamino)-4-methoxy-N-(4-fluoropheny l)- benzamide, 3- [3- (3, 5-Dichlorophenyl)-thioureido]-4-methoxy-N-phenyl-benzamide; 4- [3- (2-Methoxy-5-phenylcarbamoyl-phenyl)-thioureido]-benzoic acid; 4-Methoxy-N-phenyl-3- (3-pyridin-3-yl-thioureido)-benzamide(3-pyridin-3-yl-thioure ido)-benzamide ; 3-[3-(3,5-Dichlorophenyl)-thioureido]-N-(4-fluorophenyl)-4-m ethoxy- benzamide; 3-(3,5-Dichloro-benzenesulfonylamino)-4-methoxy-N-phenyl-ben zamide; or 3-Methanesulfonylamino-4-methoxy-N- (3,4-dichlorophenyl)-benzamide.

The present invention provides the compounds : 3-Amino-4-methoxy-N- (4-chlorophenyl)-benzamide; 3-Amino-4-methoxy-N- (3 *4-dimethylphenyl)-benzamide(3 *4-dimethylphenyl)-benzamide ; 3-Amino-4-methoxy-N- (4-methylphenyl)-benzamide; 3-Amino-4-methoxy-N-(4-fluorophenyl)-benzamide; 3-Amino-4-fluoro-N-phenyl-benzamide; or 3-Amino-4-ethoxy-N-phenyl-benzamide.

The present invention provides the compound: 3-Amino-4-methoxy-N- (3,5-dimethylphenyl)-benzamide; 3-Amino-4-methoxy-N-(3-chloro-4-methylphenyl)-benzamide; 3-Amino-4-methoxy-N-(2,4-difluorophenyl)-benzamide; 3-Amino-4-methoxy-N-(3,4-difluorophenyl)-benzamide; 3-Amino-4-methoxy-N- (3-chlorophenyl)-benzamide; 3-Amino-4-ethyl-N-phenyl-benzamide; 3-Amino-4-ethyl-N-(3,4-dichlorophenyl)-benzamide; 3-Amino-4-ethyl-N-(3,4-difluorophenyl)-benzamide;or 3-Amino-4-methylsulfanyl-N-phenyl-benzamide.

The present invention provides the compounds: N-(3-Amino-4-methoxyphenyl)-benzamide; 3,4-Dichloro-N-(3-amino-4-fluorophenyl)-benzamide; 3,4-Dichloro-N-(3-amino-4-methoxy-phenyl)-benzamide; 3-Phenylamino-N-phenyl-benzamide; 3-(3,5-Dichloro-phenylamino)-N-phenyl-benzamide; 3-(2-Methoxy-phenylamino)-N-phenyl-benzamide; <BR> <BR> <BR> 4-Methoxy-3-phenylamino-N-phenyl-benzamide;<BR> <BR> <BR> <BR> <BR> 3-(2-Methoxy-phenylamino)-4-methoxy-N-phenyl-benzamide ; or<BR> <BR> <BR> <BR> 3- (3-Trifluoromethyl-phenylamino)-4-methoxy-N-phenyl-benzamide .

The present invention provides the compound: 3- (3-Chloro-phenylamino)-4-methoxy-N-phenyl-benzamide; 3-(3-Methyl-phenylamino)-4-methoxy-N-phenyl-benzamide; 3-(3-Nitro-phenylamino)-4-methoxy-N-phenyl-benzamide ; 3-(4-Methyl-phenylamino)-4-methoxy-N-phenyl-benzamide; 3-(3, 5-Dichloro-phenylamino)-4-rnethoxy-N-phenyl-benzamide ; 3-(3,5-Dimethyl-phenylamino)-4-methoxy-N-phenyl-benzamide; 3-Phenylamino-4-fluoro-N-phenyl-benzamide; 3-Phenylamino-4-methyl-N-phenyl-benzamide;or 3-Phenylamino-4-methoxy-N- (4-fluorophenyl)-benzamide.

The present invention provides the compound: 4-Ethyl-3- (3-trifluoromethyl-phenylamino)-N-phenyl-benzamide; 4-Ethoxy-3-(3-trifluoromethyl-phenylamino)-N-phenyl-benzamid e; 4-Methylsulfanyl-3- (3-trifluoromethyl-phenylamino)-N-phenyl- benzamide; 3- [4- (4,4-Dimethyl-4, 5-dihydro-oxazol-2-yl)-phenylamino]-4-methoxy-N- phenyl-benzamide; <BR> <BR> <BR> 4-Methoxy-3-(3-trifluoromethyl-phenylamino)-N-(3-pyridyl)-be nzamide,<BR> <BR> <BR> <BR> <BR> 4-Methoxy-3-(3, 5-dimethyl-phenylamino)-N-(4-fluorophenyl)-benzamide ; 4-Methoxy-3-(3-trifluoromethyl-phenylamino)-N-(3,4-dichlorop henyl)- benzamide; 4-Methoxy-3-(3-trifluoromethyl-phenylamino)-N-(3,4-difluorop henyl)- benzamide; N- [3- (Phenylamino)-4-methoxy-phenyl]-benzamide; or 3-Benzylamino-4-methoxy-N phenyl-benzamide.

The present invention provides the compound: 3-(3,5-Dichloro-benzylamino)-4-methoxy-N-phenyl-benzamide; <BR> <BR> <BR> 3-(3, 4-Dimethoxy-benzylamino)-4-methoxy-N-phenyl-benzamide ;<BR> <BR> <BR> <BR> <BR> 3-Phenoxy-N-phenyl-benzamide ; 3-Phenoxy-4-methoxy-N-phenyl-benzamide; 3- (Phenylamino)-4-methoxy-benzoic(Phenylamino)-4-methoxy-benzo ic acid, phenyl ester; 4-Hydroxy-3-(3,5-dichloro-phenylamino)-N-phenyl-benzamide; 3- (3, 5-Dichloro-phenylamino)-4-hydroxy-N- (4-methoxyphenyl)- benzamide; 3-(3,5-Dichloro-phenylamino)-4-hydroxy-N-(4-methylphenyl)-be nzamide; or 3- (3, 5-Dichloro-phenylarrxino)-4-hydroxy-N- (3-hydroxy- 4-methoxyphenyl)-benzamide.

The present invention provides the compoundso 3-[3-(3-Chlorophenyl)-thioureido]-4-methoxy-N-phenyl-benzami de; 4-Methoxy-N-phenyl-3-(3-phenyl-thioureido)-benzamide;

4-Methoxy-N-phenyl-3- [3- (4-trifluoromethyl-phenyl)-thioureido]- benzamide; 3- [3- (4-tert-Butyl-phenyl)-thioureido]-4-methoxy-N-phenyl-benzami de; 3- [3-(4-Chlorophenyl)-thioureido]-4-methoxy-N-phenyl-benzamide ; 3-[3-(3-Nitrophenyl)-thioureido]-4-methoxy-N-phenyl-benzamid e; 4-Methoxy-N-phenyl-3- (3-benzoyl-thioureido)-benzamide; 4-Methoxy-N-phenyl-3-[3-(2,3,5,6-tetrafluoro-phenyl)-thioure ido]- benzamide ; 4-Methoxy-N-phenyl-3-(-3-p-tolyl-thioureido)-benzamide;or 3- [3- (3, 5-Dichlorophenyl)-thioureido]-N-phenyl-benzamide.

The present invention provides the compounds: <BR> <BR> <BR> 3- [3- (3, 5-Dichlorophenyl)-thioureido]-4-methyl-N-phenyl-benzamide;&l t;BR> <BR> <BR> <BR> <BR> 3- [3- (3, 4-Dimethoxyphenyl)-thioureido]-4-methoxy-N-phenyl-benzamide; 3- [3- (4-Chloro-3-trifluoromethylphenyl)-thioureido]-4-methoxy-N- phenyl-benzamide; <BR> <BR> <BR> 3- [3- (3-Cyanophenyl)-thioureido]-4-methoxy-N-phenyl-benzamide;< ;BR> <BR> <BR> <BR> <BR> 3- [3- (3-Acetyl-phenyl)-thioureido]-4-methoxy-N-phenyl-benzamide; 3-[3-(4-Chloro-3-nitrophenyl)-thioureido]-4-methoxy-N-phenyl - benzamide; 3-[3-(4-Fluorophenyl)-thioureido]-4-methoxy-N-phenyl-benzami de; 3- [3- (3, 5-Dichlorophenyl)-thioureido]-4-methoxy-N- (4-methoxy-phenyl)- benzamide; or 3- [3- (3,5-Dichlorophenyl)-thioureido]-4-ethoxy-N-phenyl-benzamide .

The present invention provides the compounds: 4-[3-(2-Methoxy-5-phenylcarbamoyl-phenyl)-thioureido]-benzen esulfonic acid ; 4-Methoxy-3- [3- (4-methoxy-phenyl)-thioureido]-N-phenyl-benzamide; 4-Methoxy-N-phenyl-3- [3- (3-trifluoromethyl-phenyl)-thioureido]- benzamide; 3-[3-(3,4-Dichlorophenyl)-thioureido]-4-methoxy-N-phenyl-ben zamide;

1-{3-[3-(3,5-Dichlorophenyl)-thioureido]-4-methoxyphenyl}-3- phenyl- urea; N- {3- [3- (3, 5-Dichlorophenyl)-thioureido]-4-methoxy-phenyll-benzamide; 4-Methoxy-3-[3-(4-nitrophenyl)-thioureido]-N-phenyl-benzamid e; 3- [3- (3, 5-Bis-trifluoromethylphenyl)-thioureido]-4-methoxy-N-phenyl- benzamide; or 4-Methoxy-N-phenyl-3- [3- (4-sulfarnoyl-phenyl)-thioureido]-benzamide.

The present invention provides the compound: N- (4-Chlorophenyl)-3- [3- (3,5-dichlorophenyl)-thioureido]-4-methoxy- benzamide; 3-[3-(4-Dimethylaminophenyl)-thioureido]-4-methoxy-N-phenyl- benzamide; 3-[3-(3,5-Dichlorophenyl)-thioureido]-4-methoxy-N-p-tolyl-be nzamide; 4-Methoxy-N-phenyl-3-(3-m-tolyl-thioureido)-benzamide; 3-[3-(3,5-Dichlorophenyl)-thioureido]-4-fluoro-N-phenyl-benz amide; N- (3,4-Dichlorophenyl)-3- [3-(3, 5-dichlorophenyl)-thioureido]-4-methoxy- benzamide; 4-Methoxy-N-phenyl-3- (3-o-tolyl-thioureido)-benzamide; 3-[3-(3,5-Dimethylphenyl)-thioureido]-4-methoxy-N-phenyl-ben zamide; or 3- [3- (3, 4-Dichlorophenyl)-thioureido]-4-methoxy-N-pyridin-3-yl- benzamide.

The present invention provides the compounds : 5- [3- (3, 5-Dichlorophenyl)-thioureido]-2-fluoro-N-phenyl-benzamide; N-(3,4-Dimethylphenyl)-4-methoxy-3-(3-m-tolyl-thioureido)-be nzamide; N-(3,4-Dimethylphenyl)-4-methoxy-3-(3-m-tolyl-thioureido)-be nzamide; N-(3-Chloro-4-methylphenyl)-3-[3-(3,5-dichlorophenyl)-thiour eido]- 4-methoxy-benzamide; N- (3, 4-Dichlorophenyl)-4-methoxy-3- [3- (4-sulfamoyl-phenyl)- thioureido]-benzamide;

3- [3- (3, 5-Dichlorophenyl)-thioureido]-4-methylsulfanyl-N-phenyl- benzamide; 3- [3- (3, 5-Dichlorophenyl)-thioureidol-N- (3,4-difluoro-phenyl)- 4-methoxy-benzamide; N-(3-Chlorophenyl)-3-[3-(4-fluorophenyl)-thioureido]-4-metho xy- benzamide; 3- [3- (3, 5-Dichlorophenyl)-thioureido]-4-methoxy-N-phenyl- benzenesulfonamide; or 4-Ethyl-N-phenyl-3- [3- (3-trifluoromethylphenyl)-thioureido]-benzamide.

The present invention provides the compound: 4-Ethyl-N-(3, 4-difluorophenyl)-3-C3-(3-triiluoromethyl-phenyl)- thioureido]-benzamide; 3-{3-[2-Methoxy-5-(pyridin-3-ylcarbamoyl)-phenyl]-thioureido }-benzoic acid; 3-[3-(2-Methoxy-5-phenylcarbamoyl-phenyl)-thioureido]-benzoi cacid; 3,4-Dichloro-N- {4-fluoro-3- [3- (3-trifluoromethylphenyl)-thioureido]- phenyl}-benzamide; 3,4-Dichloro-N- f 3- [3- (3,5-dichlorophenyl)-thioureido]- 4-methoxyphenyl}-benzamide, 3-(3,5-Dichloro-benzenesulfonylamino)-4-methoxy-N- (3,4-difluorophenyl)-benzamide; 3-(3,5-Dichloro-benzenesulfonylamino)-4-methoxy-N- (3,4-dichlorophenyl)-benzamide; or 3-Benzenesulfonylamino-4-methoxy-N-phenyl-benzamide.

The present invention provides the compound: 3-(4-Methoxy-benzenesulfonylamino)-4-methoxy-N-phenyl-benzam ide; 3-(3-Nitro-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamid e; 3- (3-Chloro-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide (3-Chloro-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide ; 3-(4-Methyl-benzenesulfonylamino)-4-methoxy-N-phenyl-benzami de; 3- (4-Fluoro-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide ;

3-(4, 5-Dibromo-thiophene 2-sulfonylamino)-4-methoxy-N-phenyl- benzamide; 3-(2-Chloro-benzenesulfonylamino)-4-methoxy-N-phenyl-benzami de; 3- (4-Trifluoromethyl-benzenesulfonylamino)-4-methoxy-N-phenyl- benzamide; 3- (Butane-l-sulfonylamino)-4-methoxy-N-phenyl-benzamide(Butane -l-sulfonylamino)-4-methoxy-N-phenyl-benzamide ; or 3-(Quinoline-8-sulfonylamino)-4-methoxy-N-phenyl-benzamide.

The present invention provides the compounds : 3-(2-Acetylamino-4-methyl-thiazole-5-sulfonylamino)-4-methox y-N- phenyl-benzamide; 3-(2, 5-Dichloro-thiophene-3-sulfonylamino)-4-methoxy-N-phenyl- benzamide; 3- (Naphthalene-1-sulfonylamino)-4-methoxy-N-phenyl-b enzamide(Naphthalene-1-sulfonylamino)-4-methoxy-N-phenyl-b enzamide ; 3-Ethanesulfonylamino-4-methoxy-N-phenyl-benzamide; <BR> <BR> <BR> <BR> 3-Phenylmethanesulfonylamino-4-methoxy-N-phenyl-benzamide;&l t;BR> <BR> <BR> <BR> <BR> <BR> <BR> 3- (3,4-Dichloro-benzenesulfonylamino)-4-methoxy-N-phenyl-benza mide; 3-(2,4-Difluoro-benzenesulfonylamino)-4-methoxy-N-phenyl-ben zamide; 3-(Toluene-3-sulfonylamino)-4-methoxy-N-phenyl-benzamide; 3-(4-Acetylamino-benzenesulfonylamino)-4-methoxy-N-phenyl- benzamide; 3-(Naphthalene-2-sulfonylamino)-4-methoxy-N-phenyl-benzamide ; 3-(1-Methyl-lH-imidazole-4-sulfonylamino)-4-methoxy-N-phenyl - benzamide; 3-(Thiophene-2-sulfonylamino)-4-methoxy-N-phenyl-benzamide; 3-(5-Dimethylamino-naphthalene-1-sulfonylamino)-4-methoxy-N- phenyl- benzamide ; 2-Methoxy-5-phenylcarbamoyl-carbonic acid-phenyl ester phenyl ester; or 4-Hydroxy-3-phenylamino-N-phenyl-benzamide.

The present invention provides the compound : 3-(3-Amino-4-methoxy-benzoylamino)-benzoic acid ethyl ester; 3- (3-Amino-4-methoxy-benzoylamino)-benzoic acid methyl ester;

3,4-Difluoro-N- (3-amino-4-methoxy-phenyl)-benzamide; 3,4-Difluoro-N- (3-amino-4-fluoro-phenyl)-benzamide; 1- (3-Amino-4-methoxy-phenyl)-3- (3,4-dichloro-phenyl)-urea; 3- (4-Fluoro-phenylamino)-4-methoxy-N-phenyl-benzamide(4-Fluoro -phenylamino)-4-methoxy-N-phenyl-benzamide ; or 3-(3,5-Dichloro-phenylamino)-4-methoxy-N-(4-fluoro-phenyl)- benzamide.

The present invention provides the compounds : 3-(4-Fluoro-phenylamino)-4-methoxy-N-(4-fluoro-phenyl)-benza mide; 3- [4-Methoxy-3- (3-trifluoromethyl-phenylamino)-benzoylamino]-benzoic acid methyl ester; 3- [4-Methoxy-3- (3-trifluoromethyl-phenylamino)-benzoylamino]-benzoic acid ethyl ester ; 4-Trifluoromethoxy-3-(3-trifluoromethyl-phenylamino)-N-pheny l- benzamide; 4-Trifluoromethoxy-3-(3-trifluoromethyl-phenylamino)-N-(4-fl uoro- phenyl)-benzamide; 3,4-Dichloro-N- [4-methoxy-3- (3-trifluoromethyl-phenylamino)-phenyl]- benzamide; 3-[3-(2-Methoxy-5-phenylcarbamoyl-phenyl)-thioureido]-benzoi cacid methyl ester; 3-{3-[5-(3,4-Difluoro-phenylcarbamoyl)-2-methoxy-phenyl]-thi oureido}- benzoic acid; 3- [3- (3, 5-Dichloro-phenyl)-thioureido]-4-trifluoromethoxy-N- (4-fluoro- phenyl)-benzamide; or 3- [3- (3-trifluoromethyl-phenyl)-thioureido]-4-trifluoromethoxy-N- (4- fluoro-phenyl)-benzamide.

The present invention provides the compounds : 4- {3- [5- (3, 4-Difluoro-phenylcarbamoyl)-2-methoxy-phenyl]-thioureido)- benzenesulfonic acid; 4-{3-[5-(4-Fluoro-phenylcarbamoyl)-2-methoxy-phenyl]-thioure ido}- benzoic acid;

3- {3- [5-(4-fluoro-phenylcarbamoyl)-2-methoxy-phenyl]-thioureido}- benzoic acid; 4-f 3- [5- (3, 4-Difluoro-benzoylamino)-2-methoxy-phenyl]-thioureido)- benzoic acid; 3- {3- [5- (3, 4-Difluoro-benzoylamino)-2-methoxy-phenyl]-thioureido)- benzoic acid ; N-{3-[3-(3,5-Dichloro-phenyl)-thioureido]-4-fluoro-phenyl}-3 ,4-difluoro- benzamide; 1-(3,4-Dichloro-phenyl)-3-{3-[3-(3,5-dichloro-phenyl)-thiour eido]-4- <BR> <BR> <BR> <BR> methoxy-phenyl}-urea;<BR> <BR> <BR> <BR> <BR> <BR> 3- (3- {5- [3- (3, 4-Dichloro-phenyl)-ureido]-2-methoxy-phenyl)-thioureido)- benzoic acid methyl ester; 3-(3-{5-[3-(3,4-Dichloro-phenyl)-ureido[-2-methoxy-phenyl}-t hioureido)- benzoic acid; or 1-{3-[3-(3,5-Bis-trifluoromethyl-phenyl)-thioureido]-4-metho xy-phenyl}- 3-(3, 4-dichloro-phenyl)-urea.

The present invention provides the compound: 1-{3-[3-(4-chloro-3-nitro-phenyl)-thioureido]-4-methoxy-phen yl}-3-(3,4- dichloro-phenyl)-urea; benzyl3-[3-(3,5-Dichloro-phenyl)-thioureido]-4-methoxy-benzo icacid ester; 3- (Dodecane-1-sulfonylamino)-4-methoxy-N-phenyl-benzamide(Dode cane-1-sulfonylamino)-4-methoxy-N-phenyl-benzamide ; 4-Methoxy-3- (octane-1-sulfonylamino)-N-phenyl-benzamide(octane-1-sulfony lamino)-N-phenyl-benzamide ; 3- (Decane-1-sulfonylamino)-4-methoxy-N-phenyl-benzamide(Decane -1-sulfonylamino)-4-methoxy-N-phenyl-benzamide ; 3- (3-Nitro-benzenesufonylamino)-4-methoxy-N-(3,(3-Nitro-benzen esufonylamino)-4-methoxy-N-(3, 4-difluoro-phenyl)- benzamide; 3,5-Dichloro-N-{5-[3-(3,4-dichloro-phenyl)-ureido]-2-methoxy -phenyl}- benzenesulfonamide; 3-(1-Methylethyl-1-sulfonylamino)-4-methoxy-N-phenyl-benzami de; 4-(2-Methoxy-5-phenylcarbamoyl-phenylsulfamoyl)-benzoic acid; or 3-(Octadecane-1-sulfonylamino)-4-methoxy-N-phenyl-benzamide.

The present invention provides the compound: 3-(3-Amino-benzenesulfonylamino)-4-methoxy-N-(3,4-difluro-ph enyl)- benzamide; 4-Methoxy-3- (4-nitro-benzenesulfonylamino)-N- (3,4-difluoro-phenyl)- benzamide ; 3-(4-Cyano-benzenesulfonylamino)-4methoxy-N-(3,4-difluoro-ph enyl)- benzamide; 4-Methoxy-3- (4-nitro-benzenesulfonylamino)-N-phenyl-benzamide(4-nitro-be nzenesulfonylamino)-N-phenyl-benzamide ; 3-(3-Cyano-benzenesulfonylamino)-4-methoxy-N-(4-fluoro-pheny l)- benzamide; 4-Methoxy-3-(3-nitro-benzenesulfonylamino)-N-(4-fluoro-pheny l)- benzamide; 4-Methoxy-3-(4-nitro-benzenesulfonylamino)-N-(4-fluoro-pheny l)- benzamide; 3- (4-Cyano-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide( 4-Cyano-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide ; 3-(4-Cyano-benzenesulfonylamino)-4-methoxy-N-(4-fluoro-pheny l)- benzamide; or 3- (Dodecane-1-sulfonylamino)-4-methoxy-N-(3,(Dodecane-1-sulfon ylamino)-4-methoxy-N-(3, 4-dichloro-phenyl)- benzamide.

The present invention provides the compound.

3-(3-Cyano-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamid e; 3,4-Dichloro-N- [4-methoxy-3- (4-methoxy-benzenesulfonylamino)- phenyl]-benzamide; 3,4-Dichloro-N- [4-methoxy-3- (toluene-4-sulfonylamino)-phenyl]- benzamide; 3,4-Difluoro-N- [4-methoxy-3- (3-amino-benzenesulfonylamino)-phenyl]- benzamide; 3,4-Difluoro-N- [4-methoxy-3- (4-amino-benzenesulfonylamino)-phenyl]- benzamide; 3,4-Difluoro-N-[4-methoxy-3-(1-dodecane-sulfonylamino)-pheny l]- benzamide;

3,4-Difluoro-N- [4-mexhoxy3- (chloromethy-sulfonylamino)-phenyl]- benzamide; 3,4-Difluro-N-[4-methoxy-3-(4-mitro-benzenesulfonylamino)-ph enyl]- benzamide; 3,4-Difluoro-N- [4-methoxy-3- (3-nitro-benzenesulfonylamino)-phenyl]- benzamide; or 3,4-Difluoro-N- [3- (4-cyano-benzenesulfonylamino)-4-methoxy-phenyl]- benzamide.

The pressent invention provides the compoundso 3,4-Difluoro-N- [3- (3-cyano-benzenesulfonylamino)-4-methoxy-phenyl]- benzamide; 3,4-Difluoro-N-[4-fluoro-3-(thiophene-2-sulfonylamino)-pheny l]- benzamide; Thiophene-2-sulfonic acid {5- [3- (3,4-dichloro-phenyl)-ureido]-2- methoxy-phenyl}-amide; 3-(3, 5-Dichloro-benzenesulionylamino)-4-methoxy-N-phenyl- thiobenzamide; 3,5-Dichloro-N-(2-methoxy-5-phenylaminomethyl-phenyl)- benzenesulfonamide; 3-(3-Hydroxy-benzylamino)-4-methoxy-N-(3, 4-difluoro-phenyl)- benzamide; 3- (4-Diethylamino-benzylamino)-4-methoxy-N-phenyl-benzamide; 3-(3-Fluoro-benzylamino)-4-methoxy-N-(3,4-difluoro-phenyl)-b enzamide; 3-(3-Hydroxy-benzylamino)-4-methoxy-N-phenyl-benzamide;or 4-Methoxy-3- (3-fluoro-benzylamino)-N-phenyl-benzamide.

The present invention provides the compound: 4-Methoxy-3- (3-nitro-benzylamino)-N-phenyl-benzamide; 4-Methoxy-3-(4-methoxy-benzylamino)-N-phenyl-benzamide ; 4-Methoxy-3-[(naphthalen-1-ylmethyl)-amino]-N-phenyl-benzami de; 4-Methoxy-3- (3, $--dimethyl-benzylamino)-N-phenyl-benzamide(3, $--dimethyl-benzylamino)-N-phenyl-benzamide ; 3-(2,3-Difluoro-benzylamino)-4-methoxy-N-phenyl-benzamide;

Acetic acid 4- [ (2-methoxy-5-phenylcarbamoyl-phenylamino)-methyl]- phenyl ester; 4- [ (2-Methoxy-5-phenylcarbamoyl-phenylamino)-methyl]-benzoic acid methyl ester; 3-[(Furan-3-ylmethyl)-amino]-4-methoxy-N-phenyl-benzamide; 4-Methoxy-3- (2-methyl-benzylamino)-N-phenyl-benzamide; or 4-Methoxy-3-(4-fluoro-benzylamino) N phenyl-benzamide.

The present invention provides the compounds : 3-(4-Hydroxy-3-nitro-benzylamino)-4-methoxy-N-phenyl-benzami de; 3-(4-Diethylamino-benzylamino)-4-methoxy-N-3,4-difluoro-phen yl)- benzamide; 3-Benzylamino-4-methoxy-N-(3,4-difluoro-phenyl)-benzamide; 3-(3-Hydroxy-4-nitr-benzylamino)-4-methoxy-N-phenyl-benzamid e; 3- (3-Cyano-benzylamino)-4-methoxy-N-phenyl-benzamide; 3-{[5-(3,4-Difluoro-phenylcarbamoyl)-2-methoxy-phenylamino]- methyl}- benzoic acid; 3-(3-Chloro-benzylamino)-4-methoxy-N-phenyl-benzamide; 3-(4-tert-Butyl-benzylamino(-4-methoxy-N-phenyl-benzamide; 3- (4-Cyano-benzylamino)-4-methoxy-N-phenyl-benzamide; or 4- { [5- (3, 4-Difluoro-phenylcarbamoyl)-2-methoxy-phenylamino]-methyll- benzoicacid.

The present invention provides the compound: 4-Methoxy-3- (4-propoxy-benzylamino)-N-phenyl-benzamide(4-propoxy-benzyla mino)-N-phenyl-benzamide ; 3-[(Biphenyl-4-ylmethyl)-amino]-4-methoxy-N-phenyl-benzamide ; <BR> <BR> <BR> <BR> 4-Methoxy-3-(4-methyl-benzylamino,)-N-phenyl-benzamide ;<BR> <BR> <BR> <BR> <BR> <BR> 4-Methoxy-3-(2-methoxy-benzylamino)-N-phenyl-Denzamide ; 3-(4-Butyl-benzylamino)-4-methoxy-N-phenyl-benzamide; 3-(3-fluoro-benzylamino)-4-methoxy-N-(3,4-dichloro-phenyl)- benzamide; 3- [ (2-Methoxy-5-phenylcarbamoyl-phenylamino)-methyl]-benzoic acid; 3- (3, 4-Dimethyl-benzylamino)-4-methoxy-N-phenyl-benzamide ;

3-(4-Isopropyl-benzylamino)-4-methoxy-N-phenyl-benzamide;or 3,4-Dichloro-N- [3- (3-fluoro-benzylamino)-4-methoxy-phenyl]-benzamide.

The present invention provides the compound: 3,4-Difluoro-N- [3- (3-hydroxy-benzylamino)-4-methoxy-phenyl]- benzamide; 3-{[5-(3,4-Difluoro-benzoylamino)-2-methoxy-phenylamino]-met hyl}- benzoic acid; 3-[3-(3,5-Dichloro-phenyl)-thioureidomethyl]-4-methoxy-N-phe nyl- benzamide; 3-(3,5-Dichloro-benzenesulfonylamino)-4-methoxy-N-phenyl-ben zamide; 3-[(3,5-Dichloro-benzenesulfonylamino)-methyl]-4-methoxy-N-p henyl- benzamide ; 4-Methoxy-3-phenylmethanesulfonylamino-N-phenyl-benzamide; 3-[Bis[(3,5-dichlorophenyl)sulfonyl]amino]-4-methoxy-N-pheny l- benzamide; (2-Methoxy-5-phenylcarbamoyl-phenylcarbamoyl)-acetic acid phenylmethyl ester; 4-Methoxy-N-phenyl-3-[2-(3-trifluoromethyl-phenyl)-ethylamin o0- benzamide; or 4-Methoxy-3- [3- (3-nitro-phenyl)-thioureido]-N-phenyl-benzamide.

The present invention provides the compound: 3- [ (3,5-Dichlorobenzoyl) amino]-4-methyl-N-phenyl-benzamide; 3- [ [ (Cyanoimino) [ (3,5-dichlorophenyl) amino]methyl] amino]-4-methoxy- N-phenyl-benzamide; 3- (2-Hydroxy-2-phenyl-acetylamlno)-4-methoxy-N-phenyl-benzamid e(2-Hydroxy-2-phenyl-acetylamlno)-4-methoxy-N-phenyl-benzami de ; 4-Methoxy-3- [(thiophell-2-yl methyl)-amino]-N-(3,4-difluoro-phenyl)- benzamide; 4-Methoxy-3- [(thiophen-2-ylmethyl)-amino]-N-phenyl-benzamide[(thiophen-2 -ylmethyl)-amino]-N-phenyl-benzamide ; 4-Methoxy-3-[(thiophen-2-ylmethyl)-amino]-N-(4-fluoro-phenyl )- benzamide;

4-Methoxy-3- [ (thiophen-2-ylmethyl)-amino]-N- (3,4-dichloro-phenyl)- benzamide; 4-Methoxy-3-[(thiophen-2-ylmethyl)-amino]-N-pyridin-3-yl-ben zamide; 4-{4-Methoxy-3-[(thiophen-2-ylmethyl)-amino]-benzoylamino}-b enzoic acid ethyl ester ; 3,4-Dichloro-N-{4-methoxy-3-[(thiophen-2-ylmethyl)-amino]-ph enyl}- benzamide; or 3,4-Difluoro-N-{4-methoxy-3-[(thiophen-2-ylmethyl)-amino]-ph enyl}- benzamide.

The present invention provides the compound 3- [ (Benzo [1,3] dioxol-5-ylmethyl)-amino]-4-methoxy-N-phenyl- benzamide; 4-Methoxy0-3-(3,.5-difluoro-benzylamino)-N-phenyl-benzamide; 3-(4-Dimethylamino-benzylamino)-4-methoxy-N-phenyl-benzamide ; 4-Methoxy-3- (3-trifluoromethyl-benzylamino)-N-phenyl-benzamide; 4-Methoxy-3- (2-fluoro-benzylamino)-N-phenyl-benzamide(2-fluoro-benzylami no)-N-phenyl-benzamide ; N- {3- [ (2,3-Dihydro-benzo [1,4] dioxin-6-ylmethyl)-amino]-4-methoxy- phenyl}-benzamide; 3-(4-Hydroxy-benzylamino)-4-methoxy-N-phenyl-benzamide; 4-Methoxy-3-(3-methyl-benzylamino)-N-phenyl-bnenzamide;or 3-(3, 4-Difluoro-benzylamino)-4-methoxy-N-phenyl-benzamide.

The present invention provides the compound: 3- [ (Pyridin-3-ylmethyl)-amino]-4-methoxy-N-phenyl-benzamide; 3-[(Pyridin-3-ylmethyl)-amino]-4-methoxy-N-(3,4-difluoro-phe nyl)- benzamide; 3-[(Pyridin-3-ylmethyl)-amino]-4-methoxy-N-(3,4-dichloro-phe nyl)- benzamide; 4- [(2-Methoxy-5-phenylcarbamoyl-phenylamino)-methyl]-benzoic[( 2-Methoxy-5-phenylcarbamoyl-phenylamino)-methyl]-benzoic acid; 3,4-Dii luoro-N-{ [3-(pyridin-3-ylmethyl)-amino]-4-methoxy-phenyl}- benzamide; or 3- (3-Acetylamino-phenylamino)-4-methoxy-N-phenyl-benzamide.

DETAILED DESCIZIPTION OF THE INVENTION The term"alkyl"means a straight or branche chain hydrocarbon.

Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl, and hexyl. Preferably the alkyl group contains from 1 to 6 carbon atoms.

The term"alkoxy"means an alkyl group attache to an oxygen atom.

Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy, and isobutoxy.

The term "halogen" include chlorine, fluorine, bromine, and iodine.

The term"allçenyl"means a branche or straight chain hydrocarbon shaving one or more carbon-carbon double bond.

"aryl"meansanaromatichydroxarbon.RepresentativeexamplesThete rm of aryl groups include phenyl and naphthyl.

The term"heteroatom"includes oxygen, nitrogen, and sulfura The term "heteroaryl" means an aryl group wherein one or more carbon atom of the aromatic hydrocarbon has been replace with a heteroatom. Examples of heteroaryl radicals inclue, but are not limite to, pyridyl, imidazolyl, pyrrolyl, thienyl, furyl, pyranyl, pyrimidinyl, pyridazinyl, indolyl, quinolyl, naphthyridinyl, and isoxazolyl.

The meansacyclichydroxarbon.Examplesof"cycloalkyl" cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term"substituted"means that the base organic radical has one or more substituents. For example, substituted cyclohexyl means a cyclohexyl radical that has one or more substituents. Substituents inclue, but are not limited to, halogen, -CN,CF3,-NO2,-NH2,-NHC2-C8alkyl,-N(C1-C8alkyl)2,C1-C8alkyl, and-OH.-OC1-C8alkyl, The term"heterocycle"rneans a cycloalkyl group wherein one or more atom is replace with a heteroatom. Examples of heterocycles inclue, but are not limited to, pyrrolidinyl, piperidinyl, and piperazinyl.

The symbol"-"means a bond.

The term"patient"means all animals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, and pigs.

Those skilled in the art are easily able to identify patients having atherosclerosis and inflammation.

A therapeutically effective amount is an amount of a compound of the present invention that when administered to a patient ameliorates a symptom of atherosclerosis or inflammation.

The compound of the pèsent invention can be administered to a patient either alone or as part of a pharmaceutical composition. The compositions can be administered to patients either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracistexnally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments or drops), or as a buccal or nasal spray.

Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or mulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonge absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In suc solid dosage forms, the active compound is

admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extendeurs, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, as for example, , gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders. as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compound, (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tables, and pills, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft-and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.

Solid dosage forms such as tables, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well- known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compound in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compound can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable mulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compoundsF the liquid dosage forms may contain insert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcool, isopropyl alcool, ethyl carbonate, ethyl acetate, benzyl alcool, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcool,

polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compound, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth) or mixtures of these substances, and the like.

Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compound of the present invention with suitable nonirritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax) which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.

Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalant. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention The term"pharmaceutically acceptable salts, esters, amides, and prodrugs" as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compound of the present invention which are, within the scope of sound medical augment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic formes, where possible, of the compound of the invention. The term salts refers to the relatively nontoxic, inorganic and organic acid addition salts of compound of the present invention. These saluts can be prepared in situ during the final isolation and purification of the compound or by separately reacting the purifie compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts

include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactiobionate and laurylsulphonate salts and the like.

These may include cations based on te alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium and amine cations including, but not limited to ammonium, tetramethylammoniurra, tetraethylammonium, methylamine, dimethylamine, trimethylamineX triethylamine, ethylamine, and the like. (See, for example, S. M. Berge, et al., Pharmaceutical Salts, J. Pharm. Sci., 1977; 66: 1-19, which is incorporated herein by reference).

Examples of pharmaceutically acceptable, nontoxic esters of the <BR> <BR> <BR> compound of this invention include C 6 alkyl esters wherein the alkyl group is a straight or branche chain. Acceptable esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. Cl-C4 alkyl esters are preferred. Esters of the compound of the present invention may be prepared according to conventional methods.

Examples of pharmaceutically acceptable, nontoxic amides of the compound of this invention include amides derived from ammonia, primary Cl-C6 alkyl amines and secondary C I-C6 dialkyl amines wherein the alkyl groups are straight or branche chain. In the case of secondary amines the amine may also be in the form of a 5-or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, Cy-C3 alkyl primary amines and C1-C2 dialkyl secondary amines are preferred. Amides of the compound of the invention may be prepared according to conventional methods.

The term"prodrug"refers to compound that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drus as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series, and in Bìoreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

In addition, the compound of the present invention can exist in unsolvated as well as solvate forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvate forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

The compound of the present invention can exist in different stereoisometric forms by virtue of the presence of asymmetric centers in the compound. It is contemplated that all stereoisometric forms of the compound as well as mixtures thereof, including racemic mixtures, form part of this invention.

The compound of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kg, a dosage in the range of about 0. 01 to about 100 mg per kg ou body weight per day is preferable. The specific dosage used, however, can vary. For example, the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to those skilled in the art.

The scope of the present invention inclues compound that are synthesized by standard techniques used organic synthesis and known to those skilled in the art, including combinatorial chemistry, or by biological mechanisms, including digestion and metabolism.

The examples presented below are intended to illustrate particular embodiments of the invention and are not intended to limit the scope of the specification, including the claims, in any way.

EXEMPLES The following abbreviations are used throughout the present application: THF tetrahydrofuran PBS phosphate buffered saline APCI atmosphere pressure chemical ionization

pointm.p.melting CI chemical ionization APODE hydroperoxyoctadecadienoate HODE hydroxyoctadecadienoate Biological Examples Rabbit Reticulocyte 15-LO Assay (h15L0 The present 15-LO assay takes advantage of the ability of 15-LO to oxidize the fatty acid linoleic acid to the hydroperoxy fatty acid 13-(S)HPODE, resulting in the formation of a conjugated diene. The 15-LO inhibitors are incubated with 15-LO enzyme in the presence of linoleic acid substrat. The initial rection is compare to an uninhibited (maximal) rection to yield % inhibition. The 13- (S) BODE produced in the rection is reduced to the more stable corresponding hydroxy fatty acid, 13-hydroxyoctadecadienoate (13-HODE). This prevents artificial nonenzyme lipid peroxidation and product breakdown in the sample. 13-HPODE is quantitated by comparing peak areas of individual samples with those from a standard curve generated using authentic 13-HODE. This assay is performed using 2U of rabbit reticulocyte 15-LO in the presence of 174tM linoleic acide The rection is incubated for 15 minutes at 4°C.

The total rection volume is 100 µL in PBS containing 0.2% Na cholate. The rection is stopped with 100 IL of mobile phase and 10 ZL of triethyl phosphite, which reduces the 13-HPODE to the more stable 13-HODE.

Fifteen-lipoxygenase was obtained from phenylhydrazine-treated rabbits and purifie per the method of Rapport (rapport S. M., Schewe T., Wiesner R., et al. The lipoxygenase of reticulocytes. Purification, characterization, and biological dynamics of the lipoxygenase; its identity with the respiratory inhibitors of the reticulocyte. European Journal of Biochemistry, 1979; 96: 545-561). The following chemicals were purchased and used as received : linoleic acid (NUJCheck Prep), 13-APODE (Biomol Research Labs), sodium cholate (Sigma), trimethyl phosphite (Fluka Chemicals).

Monocyte Recruitment Assay The recruitment or chemotaxis of monocytes was assayed by methods well known to those skilled in the art. In particular, the method set forth in J. Clin.

Invest., 1988; 82: 1853-1863, which is hereby incorporated by reference, was used.

Synthetic Examples The compound of the invention which are diarylamines can be prepared by reacting an aminobenzanilide with an appropriately substituted triarylbismuthine in a solvent such as ether, tetrahydrofuran, dichloromethane, chloroform, or the like. The rection time is 1 hour to 96 hours, generally 4 hours, at a temperature from 20°C to 70°C, preferably 40°C to SO°C, in the presence of an organic base and a chopper salt. The organic base can be chosen from any of a number such as pyridine, DABCO, DBU, trialkylamine, diisopropyl-ethylamine, etc., preferably triethylamine. The chopper salt can be a copper (I) or copper (II) species, or even copper itself, but is preferably copper (II) acetate. The rection requires at least a stoichiometric amount of each of the reagents but they may be employed in large excess; typically an approximately equimolar amount of each is employed. The triarylbismuth reagents may be triaryl Bi (III) or Bi (V) compound, the latter being also the dihalo-or diacyl-species, with the tris (substituted- phenyl) bismuthines being preferred.

The required triarylbismuthines are either commercially available or prepared from commercially available materials using methods known in the literature, for example by reacting a guignard reagent with Bi (III) chloride in TET, Alternatively, the compound of this type can be prepared by the well- known Ullmann rection, in which an amino-benzanilide is reacted with an appropriately substituted aryl halide, such as a bromo-or iodobenzene in the presence of a base such as potassium carbonate or sodium carbonate or an organic base like N-ethylmorpholine, and a copper salt as described above, in a high- boiling solvent such as xylene, toluene, mesitylene, DW, or DMA. The rection is typically carried out at a temperature between 100°C to 200°C, preferably 150°C to 160°C. The concentrations of the reagents is not critical ; typically a 2-to

5-fold excess of the reagents relative to the benzanilide is utilized, and the rection time extends from 3 hours to 5 days, depending on the substitutents present on the aromaticrings.

The aminobenzanilides required are either commercially available or are prepared by methods well-known in the chemical literature.

The thioureas of this invention may be prepared in various ways, all of which are well-known in the art. A convement method of preparing the thioureas in this patent is to react a substituted aminobenzanilide with a substituted phenylisothiocyanate in a nonpolar aprotic solvent such as THF, ethyl acetate, ether, dichloromethane, or dioxane for from about 2 hours to 3 days at from about 0 degrees to about 70 degrees. The resulting product is collecte by filtration or is obtained by concentration of the rection mixture and then collecte by filtration.

Isothiocyanates of various types are well-known and widely available to practitioners of the art.

The sulfonamides of this invention can be prepared using procedures tell- known in the art. In a typical preparation, an aminobenzanilide is reacted with a sulfonyl chloride in equimolar proportions either neat or in a nonreactive organic solvent such as dichloromethane, tetrahydrofuran, toluene, dioxane or the like in the presence of a base such as trialkylamine, pyridine, DABCO, or DBU, over a wide range oftemperatures typically from 0 degrees to about 150 degrees and a time period of 5 minutes to 5 days, followed by a workup procedure well-known to practitioners of the art. The molar ratios of the reactants are not critical but for the compound of this invention equimolar ratios are preferred. Likewise, the sulfonamides of this invention are preferably prepared using pyridine as solvent with a rection time of approximately 3 days at room temperature.

The required sulfonyl chlorides are in general commercially available or are readily prepared by methods well-known in the chemical literature.

STÆTING MATERIALS The benzoic acids, benzaldehydes, and anilines used in the following Examples are obtained from commercial suppliers, for example, Aldrich Chemical Company. 3-Amino-4-methoxy-benzanilide is obtained from Apin or Pfaltz &

Bauer. Triphenylbismuth is obtained from Alfa. The other tris (aryl)-bismuthines are prepared using procedures described in the following references: Tris (2-methoxyphenyl) bismuthine CA 111 (1989): 15411j Tris (3-methylphenyl) bismuthine ibid.

Tris (3-chlorophenyl) bismuthine Synthesis 1994: 775 Tris(3-trifluoromethylphenyl)bismuthineibid.

Tris (4-methylphenyl) bismuthine J. Coord. Chem., 1982; 12 (1): 53-57 Tris [4- (4, 4-dimethyl-2-oxazolino)- International Patent Publication phenyl]-bismuthine Number WO 96/22994, Aug 1, 1996 Tris (3,5-dimethylphenyl) bismuthine Can be prepared in accordance with the procedure set forth in Synthesis, 1994: 775, except using the Grignard reagent as described in J. Organomet Chem., 1994; 468 (1-2): 37 EXAMPLE 1 3-Amino-4-methyl-N-phenyl-benzamide Step A : 4-Methyl-3-nitro-N-phenyl-benzamide Oxalyl chloride (3 mol, 35 mmol) was added dropwise to a stirred solution of 3-nitro-4-methylbenzoic acid (5.0 g, 28 mmol) in a mixture of tetrahydrofuran or dichloromethane (125 mL) and dimethylformamide (1/2 mL) under N2 at ice bath temperature. The mixture was allowed to warm to room temperature. After 1 hour, the solvent was removed by rotary evaporator under reduced pressure. The residue was redissolved in fresh tetrahydrofuran (100 mL) and recooled to ice bath temperature under 1V2 while a solution of aniline (5. 2 g, 56 mmol) in tetrahydrofuran (25 mL) was added dropwise. After 16 hours of stirring at room temperature, the mixture was concentrated to half-volume by rotary evaporator and the residue stirred in water (200 mL). After several hours, the precipitate was

filtered off, rinsed three times with water, and dried to afford the product (6.8 g); m.p. 147-148°C Calculated for C14H12N2O3 : C, 65.62; H, 4.72; N, 10.93.

Found: C, 65.45 ; H, 4.64 ; N, 10.87.

Step B: 3-Amino-4-methyl-N-phenyl-benzamide Raney nickel (1 g) was added to a solution of 3-nitro-4-methyl-N-phenyl- benzamide (6.2 g, 24 mmol) in a mixture of tetrahydrofuran (50 mL) and methanol (100 mL) and shaken at room temperature under an atmosphere of hydrogen, initially at a pressure of 50 psi, until the required amount of hydrogen was taken up. The catalyst was removed by filtration, and the filtrate was stripped of solvent by rotary evaporator. The residue was dried under reduced pressure to afford the pure product (5. 5 g); m. p. 149-151°C.

Calculated for C14Hl4N20 : C, 74.31 ; H, 6.24; N, 12.3 8.

Found: C, 74.09; H, 6.20; N, 12.17.

EXEMPLE 2 3-Amino-4-methoxy-N-(4-chlorophenyl)-benzamide Prepared according to the procedure described for Example 1 using oxalyl chloride (5.5 mL, 63.05 mmol), 4-methoxy-3-nitrobenzoic acid (11.30 g, 57.32 mmol), dimethylformamide (1.0 mL, 1.29 mmol), and 4-chloroaniline (14.6 g, 114 mmol) to afford the product (4.4 g); m. p. 191-192°C.

Calculated for C14Hl3N202Cl : C, 60.77; H, 4.74; N, 10. 12.

Found: C, 60.71; H, 4.67; N, 10.03.

EXAMPLE 3 3-Amino-4-methoxy-N-(4-methoxyphenyl)-henzamide Prepared according to the procedure described for Example 1 using oxalyl chloride (3.0 mL, 34.39 mmol), 4-methoxy-3-nitrobenzoic acid (5.00 g,

25.36 mmol), dimethylformamide (0.5 mL, 6.5 mmol), and 4-methoxyaniline (6.25 g, 50.7 mmol) to afford the product (4.45 g); m. p. 164-167°C.

Calculated for C14H16N2O3: C, 66.16; H, 5.92; N, 10.29.

Found: C, 66.21; H, 5.73; N, 10. 35. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> EXAMPLE 4<BR> <BR> <BR> <BR> <BR> <BR> 3-Amino-4-methoxy-N-(3, 4-dichlorophenyl) benzamide Prepared according to the procedure described for Example 1 using oxalyl chloride (5.0 mL, 57.31 mmol), 3-nitro-4-methoxybenzoic acid (5.04 g, 25.56 mmol), dimethylformamide (0. 5 mLO 6.46 mol), and 3,4-dichloroaniline (8.3 g, 51 mmol) to afford the product (5 45 g); m. p. 179-182°C.

Calculated for C14H12N2O2Cl2: C, 54.04; H, 3.89; N, 9.00.

Found: C, 53.30; H, 3.76; N, 8. 83.

EXILE 5 3-Amino-4-methoxy-N-(3-pyridyl)-benzamide Prepared according to the procedure described for Example 1 using oxalyl chloride (2.0 mL, 22.93 mmol), 4-methoxy-3-nitrobenzoic acid (4.00 g, 20.29 mmol), dimethylformamide (0. 5 mL-6 46 mmol), and 3-aminopyridine (3.83 g, 40.69 mmol) to afford the product (3.98 g); m. p. 193-196°C.

Calculated for C 13H13N3O-0.25 M MeOH: C, 63.33; H, 5.62; N, 16. 73.

Found: C, 63.33; H, 5.41; Nw 16. 88 <BR> <BR> <BR> <BR> <BR> <BR> <BR> EXAMPLE 6<BR> <BR> <BR> <BR> <BR> <BR> 3-tmino-4-methoxy-N- (3, 4-dimethylphenyl)-benzamide Prepared according to the procedure described for Example 1 using oxalyl chloride (3.0 mL, 34.4 mmol), 4-methoxy-3-nitrobenzoic acid (5.00 g, 25.36 mmol), dimethylformamide (1.0 mL, 12.92 mmol), and 3,4-dimethylaniline (6.2 g, 51 mmol) to afford the product (5.99 g); m. p. 138-142°C.

Calculated for C16H18N2°2 : C, 71.09; H, 6.71 ; N, 10.36.

Found: C, 70.63; H, 6.79; N, 10.28.

EXAMPLE7 3-Amino-4-methoxy-N-(4-methylphenyl)-benzamide Oxalyl chloride (5.8 mL, 66.49 mmol) was added dropwise to a solution of 4-methoxy-3-nitrobenzoic acid (13.00 g) 65.94 mmol) and dimethylformamide (1. 5 mL, 1.94 mmol) in tetrahydrofuran (250 mL) at ice bath temperature under a nitrogen atmosphere. The reaction was stirred overnight and allowed to gradually warm to room temperature. The solvent was removed in vacuo. The residue was triturated with hexanes and filtered to obtain 15 68 g of an off-white solid (acid chloride). The acid chloride (5.00 g, 23.19 mmol) was dissolve in tetrahydrofuran (250 mL) and cooled to ice bath temperature under a nitrogen atmosphere while 4-toluidine (14.6 g, 132 mmol) in of tetrahydrofuran (50 mL) was added. The rection was stirred ôvernight and allowed to warm to room temperature. The solvent was concentrated to a volume of 125 mL and diluted with ethyl acetate (125 mL). The organic layer was washed with 1N HCI, 1N NAOS, brine (2 x 40 mL), dried (MgS04), filtered, and evaporated. The solid was triturated with hexanes and collecte by filtration to give 1.23 g of the <BR> <BR> <BR> <BR> nitrobenzamide. The benzamide (lrO6 gX 3.71 mmol) was reduced according to the procedure described for Example 1, Step B to afford the product (0.89 g); m. p.

190-194°C.

Calculated for C15H16N2O2#0.1 M H2O : C, 69.80; H, 6.33; N, 10.68.

Found: C, 69.69; H, 6. 11; N, 10.77.

EXAMPLE 8 3-Amino-4-methoxy-N-(4-fluorophenyl)-benzamide Prepared according to the procedure described for Example 7 using oxalyl chloride (3.0 mL, 34.39 mmol), 4-methoxy-3-nitrobenzoic acid (5.00 g,

25.36 mmol), dimethylformamide (0.5 mL, 6.5 mmol), and 4-fluroaniline (5.0 mL, 52.78 mmol) to afford the product (4e45 g); m. p. 164-167°C.

Calculated for C14Hl3N202F C, 64.61; H, 5.03; N, 10.76.

Found: C, 64. 43; H, 4.95; N, 10.71.

EXAMPLE 9 3-Amino-4-{luoro-N-phenyl-benzamide Step A: 3-Nitro-4-fluoro-N-Phenyl-benzamide Dicyclohexylcarbodiimide (13. 4 g, 65 mmol) was dadded to a mixture of 4-fluoro-3-nitrobenzoic acid (11.21 g 61 mmol), 1-hydroxybenzotriazole hydrate (8.72 g7 65 mol), aniline (6.3 gy 68 mol), and dimethylformamide (200 mL) all at once (exotherm), and the mixture was stirred at room temperature overnight.

The rection mixture was filtered, the solvent was removed by rotary evaporator (70°C), and the residue taken up in ethyl acetate (300 mL). The ethyl acetate solution was washed with water (3 x 200 mol), dried (magnesium sulfate), filtered, and stripped of solvent to leave an orange solid residue. The solid was recrystallized from hexane/ethyl acetate and used without further purification in the next step. Filtration through silica gel, eluting with dichloromethane/methanol 95: 5 afforded an analytical ample9 m. p. 155-157°C.

Calculated for C13HgFN203 C, 60.00; H, 3.49; N, 10.76.

Found: C, 59.94; H, 3.48 ; N, 10. 69.

Step B: 3-Amino-4-fluoro-N-phenyl-benyl-benzamide Zinc dust (14 g) was added to a solution of 4-fluoro-3-nitro-N-phenyl- benzamide (1.99 g, 7.6 mmol) in acetic acid (80 mL) at 0°C. The mixture was stirred and allowed to warm to room temperature. After 4 hours, the mixture was filtered and the residue washed with ethyl acetate. The filtrate and washings were combine and taken to dryness by rotovap and the residue partitioned between ethyl acetate (200 mL) and saturated aqueous NaHC03. The organic layer was washed with saturated brine, dried over MgSO4. filtered, and stripped of solvent.

The residue was triturated in ethyl acetate/hexane and the suspende solid filtered offto afford the product (1.55g); m. p. 167-170°C.

Calculated for C13H112 C, 67. 82; H, 4.82; N, 12. 17.

Found: C, 67.76; H, 4.70; N, 12.06.

EXAMPLE 10 3-Amino-4-ethoxy-N-phenyl-benzamide Step A: 3-Nitro-4-ethoxy-N-phenyl-benzamide 4-Fluoro-3-nitro-N-phenyl-benzamide from Example 9 34(2. g, 9 mmol) was added all at once to a solution prepared by dissolving sodium metal (2.29 g, 100 mmol) in ethanol (100 mol). The rection mixture was stirred 1 hour at room temperature, then citric acid solution (10% aqueous, 4 mL) was added, and the mixture allowed to stand overnight. The rection mixture was then concentrated to dryness and the residue chromatographed on silica gel using hexane/ethyl acetate, 1: 1, as eluant to afford the product as an orange solid (lao9 g); m. p. 189-190°C.

Calculated for C15H14N2O4: C, 62.93; H, 4.93; N, 9.79.

Found: C, 63.09; H, 4.42; N, 9.57.

Step B: 3-Amino-4-ethoxy-N-phenyl-benzamide 4-Ethoxy-3-nitro-N-phenyl-benzamide (0.77 g, 2.7 mmol) was reduced according to the procedure described for Example 9, Step B to afford the product (0.48 g); m. p. 189-190°c.

Calculated for Cl5Hl6N2o2- C, 70.29; H, 6.29; N, 10.93.

Found: C, 70.29; H, 6. 11; N, 10.82.

EXAMPLE11 3-Amino-4-methoxy-N-(3, 5-dimethylphenyl)-henzamide Prepared according to the procédure described for Example 1 using oxalyl chloride (3.0 mL, 4.39 mmol), 4-methoxy-3-nitrobenzoic acid (5.00 g,

25.36 mmol), dimethylformamide (0.5 mL, 6.5 mmol), and 3,5-dimethylaniline (6.4 mL, 51.33 mmol) to afford the product (4e79 g); m. p. 155-162°C.

Calculated for C16H18N2O2: C, 71.09; H, 6.71; N, 10.36.

Found: C, 70. 78; H, 6.90; N, 10.16.

EXAMPLE 12 3-Amino-4-methoxy-N-(3-chloro-4-methylphenyl)-benzamide Prepared according to the procedure described for Example 1 using oxalyl chloride (3.0 mL, 4.39 mmol), 4-methoxy-3-nitrobenzoic acid (5.00 g, 25.36 mmol), DMF (1.0 mI.,, 12.92 mol). and 3-chloro-4-methylaniline (7.0 mL, 57.69 mmol). Chromatography on silica gel in 95: 5 dichloromethane/methanol gave the product, (2.72 g), m. p. 153-157°C.

Calculated for C15H15N2O2Cl: C, 61.97; H, 5.20; N, 9.63.

Found: C, 61.87; H, 5. 15; N, 9.72.

EXAXLE 13 3-Amino-4-chloro-N-phenyl-benzamide Prepared according to the procédure described for Example 1 using oxalyl chloride (2.5 mL, 28.66 mmol), 4-chloro-3-nitrobenzoic acid (4.02 g, 19.94 mmol), DIVIF (1.0 mL, 12. 92 mol), ad aniline (3.6 mL, 39.51 mmol) to afford the product (3.39 g) after trituration in hexane; m. p. 194-197°C after recrystallization from ethyl acetate.

Calculated for C13H11N2OCl: C, 63.29; H, 4.49; N, 11.36.

Found: C, 63.44; H, 4.73; N; 11.31. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> EXAMPLE 1L4<BR> <BR> <BR> <BR> <BR> <BR> 3-Amino-4-methoxy-N-(2, 4-difluorophenyl)-benzamide Prepared according to the procedure described for Example 1 usinez oxalyl chloride (3.0 mL, 34. 39 mmol), 4-methoxy-3-niotrobenzoic acid (5.00 g,

25.36 mol), dé (1.0 mL, 12.92 mol), rand 2,4-difluoroaniline (5.2 mL, 51.07 mmol) to afford the product (6. 07 g), m. p. 166-168°C after trituration in hexane.

Calculated for C14H12N2°2F2 : C, 60.43 ; H, 4.35; N, 10.07.

Found: C, 60.35; H, 4.31; N, 10.01.

EXAMPLE 15 3-Amino-4-methoxy-N-(3, 4-difluorophenyl) benzamide Prepared according to the procedure described for Example 1 using oxalyl chloride (3.0 mL, 34.39 mmol), 4-methoxy-3-nitrobenzoic acid (5.00 g, 25.36 mmol), DMF (1.0 mL. 1292 mmol), and 3,4-difluoroaniline (5.0 mL, 50.42 mmol) to afford the product (6.17 g), m. p. 171-172°C.

Calculated for C14H12N2°2F2 : C, 60.43; H, 4.35; N, 10. 07.

Found: C, 60.45; H, 4.36; N, 10.12.

EXEMPLE 16 3-Amino-4-methoxy-N-(3-chlorophenyl)-benzamide Prepared according tu thé procedure described for Example 1 using oxalyl chloride (3.0 mL, 34.39 mmol), 4-methoxy-3-nitrobenzoic acid (5.00 g, 25.36 mmol), DMF (0.5 mL, 6.46 mol), and 3-chloroaniline (5.4 niL, 51. 05 mmol). The reduction was performed as described but using DMF as the solvent to afford the product (2.29 g) after trituration in hexane; m. p. 144-146°C after recrystallization from ethyl acetate.

Calculated for C14Hl3N202Cl : H,4.74;N,10.12.C,60.77; Found: C, 60.59; H, 4. 61 ; N5 10. 10.

EXAMPLE17 3-Amino-4-ethyl-N-phenyl-benzamide Step A: 3-Nitro-4-ethylbenzoic acid

4-Ethylbenzoic acid (12.0 g, 79.9 mmol) was added portionwise to fuming nitric acid (62 mL) with stirring at room temperature. Following the addition, the mixture was poured into water (500 mL), stirred, and extracted with ethyl acetate (300 mL). Saturated brine (150 mL) was added and the mixture shaken then separated. The organic solution was washed with brine then dried over magnesium sulfate. Filtration, removal of the solvent by rotovap under reduced pressure, and trituration ofthe residue in hexane afforded the product (13.3 g); pure after recrystallization from hexane/ethyl acetate.

Calculated for CgHgN04 : C, 55.39; H, 4.65; N, 7.18.

Found: C, 55.34; H, 4.61; N) 7. 08.

Step B: 3-Nitro-4-ethyl-N-phenyl-benzamide Prepared according to the procedure described for Example 1 using oxalyl chloride (2.0 mL, 22.93 mmol), 3-nitro-4-ethylbenzoic acid (4.00 g, 20.51 mmol), DMF (1.0 mL, 12.92 mol), ans aniline (3.8 mL, 41.70 mmol) to afford the product (4.1 g); m. p. 111-113°C after trituration in hexane.

Calculated for H2O: C, 74.41; H, 6.74; N, 11. 57.

Found: C, 74.26; H, 6. 72; N, 11.40.

EXEMPLE 18 3-Amino-4-ethyl-N-(3s4-dichlorophenyl)-benzamide Prepared according to the procedure described for Example 1 using oxalyl chloride (2.0 mL, 22.93 mmol), 3-nitro-4-ethylbenzoic acid from Example 17, Step A (4.01 g, 20.56 mmol), DMF (1. 0 mL) 12.92 mmol), and 3,4-dichloroaniline (6.64 g, 40.98 mmol) to afford the product (2.1 g): m. p.

115-117°C after chromatorgraphy on silica gel using a 10-25% gradient of ethyl acetate in hexane as the eluant.

Calculated for C15H14Cl2N2O: C, 58.27; H, 4.56; N, 9. 06.

Found: C, 58.10; H, 4.54 ; Ns 9.02

EXAMPLE 19 3-Amino-4-ethyl-N- (3,4-difluorophenyl)-benzamide Prepared according to the procedure described for Example 1 using oxalyl chloride (2.0 rnL, 22.93 mmol), 3-nitro-4-ethylbenzoic acid from Example 17, Step A (3.85 g, 19.74 mmol), DMF (1. 0 mL, 12.92 mmol), and 3, 4-difluoroaniline (4.0 mL, 40.34 mmol) to afford the product (4.9 g); m. p. 108-110°C after trituration in hexane.

Calculated for C15H14N2OF2: C, 65.21; H, 5.11; N, 10.14.

Found: C, 64.89; H, 4.92; N, 9. 97.

EXAMPLE 20 3-Amino-4-methylsulfanyl-N-phenyl-benzamide Step A: 3-Nitro-4-methylsulfanyl-N-phenyl-benzamide 3-Amino-4-chloro-N-phenyl-benzamide from Example 13, Step A (12.06 g, 43.6 mmol) in 100% ethanol was treated with sodium thiomethoxide (3.42 g, 68.5 mmol). The rection mixture was stirred overnight at room temperature then concentrated to dryness. The residue was shaken with a mixture of ethyl acetate (600 mL) and 1N HCl (200 mL), and the insoluble material was collecte by filtration. The resulting solid was washed several times with water then diethyl ether, then dried to affôrd the product (10-8 g); m . p. 219-222°C.

Calculated fôr C14H12N2O3S: C, 58.32; H, 4.20; N, 9.72.

Found: C, 58.06; H, 4.13; N, 9.73.

Step B: 3-Amino-4-methylsulfanyl-N-phenyl-benzamide Prepared according to the procedure described for Example 9, Step B using 4-methylsulfanyl-3-ninto-N-phenyl-benzamide (4.94 g, 17.1 mmol) to give the product (3.72 g); m. p. 143-145°C.

Calculated for C14Hl4N20S-.

C, 65.09; H, 5.46; N) 10.84.

Found: C, 65.17; H, 5.41; N, 10. 78.

EXAMPLE 21<BR> <BR> <BR> <BR> <BR> <BR> <BR> N-(3-Åmino-4-methoxyphenyl) benzamide Step A: N- (3-Nitro-4-fluorophenyl)-benzamide Benzoyl chloride (12 mL, 103 mmol) was added dropwise to 4-fluoro- 3-nitroaniline (15.64 g, 100 mmol) and triethylamine (17 rnL, 122 mmol) in ethyl acetate (400 mL) at room temperature. The reaction mixture was stirred for 2 hours and then allowed to stand overnight. The rection mixture was washed with 10% aqueous citric acid solution (200 mol), saturated aqueous sodium bicarbonate solution (200 mL), and brine (100 mL); dried (magnesium sulfate), filteredv and concentrated tô about 100 mL at which point a solid began to precipitate. The mixture was cooled to zero degrees and the straw-colored solid collecte by filtration to afford the product (21.1 g) in two crops.

Calculated C13H9FN2O3: C, 60.00; H, 3.49; N, 10.76.

Found: C, 60.00; H, 3.27; N, 10.84, Step B: N- (3-Nitro-4-methoxyphenyl)-benzamide Prepared according to the procedure described for Example 10, Step A from N- (4-fluoro-3-nitrophenyl)-benzamide (5.2 g, 20 mmol) and sodium (1.3 g, 57 mmol) using methanol in place of ethanol to afford the product (3.7 g) after chromatography on silica gel in dichloromethanelmethanol 99: 1.

Step C: N- (3-Amino-4-methoxyphenyl)-benzamide Prepared according to the procedure described for Example 9, Step B using N-(4-methoxy-3-nitrophenyl)-benzamide (3.68 g, 13.5 mmol) and zinc dust (20 g) to give the product (2.5 g) after chromatography on silica gel in ethyl acetate/hexane and recrystallization from the same solvent.

Calculated for C14H14N2O2: C, 69.41; H, 5.82; N, 11. 56.

Found: C, 69. 26; H, 5.59; N, 11. 28

EXAMPLE 22 3,4-Dichloro-N-(3-amino-4-fluorophenyl)-benzamide Step A: 3,4-Dichloro-N (3-nitro-4-fluorophenyl)-benzamide 3,4-Dichlorobenzoyl chloride (4.3 g, 20.5 mmol) was added all at once to 4-fluoro-3-nitroaniline (3.14 g, 20.1 mmol) and triethylamine (3 mL, 21.5 mmol) in ethyl acetate (200 mL) at room temperature. The rection mixture was stirred overnight at room temperature then diluted to #500 mL with ethyl acetate. The ethyl acetate was washed successively with 1N HCl (100 mL), saturated sodium bicarbonate (100 mol), and brine (100 mol), then dried (magnesium sulfate), filtered, and stripped of solvent under reduced pressure. Trituration of the residue in hexanes (125 mL) and a few milliliters of ethyl acetate afforded the product by filtration (5.6 g); m. p. 202a204°C.

Step B: 3.4-Diochloro-N-(3-amino-4-fluorophenyl)-benzamide 3,4-Dichloro-N- (3-nitro-4-fluorophenyl)-benzamide from Step A (1.56 g, 4.7 mmol) was reduced according to the procedure described for Example 9, Step B to give the product (1.15 g) m. p. 151-153°C.

Calculated for C13H9Cl2FN2O : C, 52.20; H, 3.03; N, 9.36.

Found: C, 52.15; H. 3.55; N, 9. 20.

EXAMPLE23 3,4-Dichloro-N-(3-amino-4-methoxyphenyl)-benzamide Step A: 3, 4-Dichloro-N-(3-nitro-4-methoxyphenyl)-benzamide Prepared according to the procedure described for Example 10, Step A from 3, 4-dichloro-N-(3-nitro-4-fluorophenyl)-benzamide from Example 22, Step A (5.2 g, 20 mmol) and sodium (1.3 g, 57 mmol) using methanol in place of ethanol to afford the product (5.8 g); m. p. 215-218°C after chromatography on silica gel in dichloromethane/methanol 99: : 1.

Calculated for C14H10Cl2N2O4: C, 49.29; H, 2.95; N, 8. 21.

49.47;H,3.23;N,78.99.Found:C,

Step B: 4-Dichloro-N- (3-amino-4-methoxyphenyl)-benzamide3, Prepared according to the procedure described for Example 9, Step B from 3,4-dichloro-N- (3-nitro-4-methoxyphenyl)-benzamide (3.65 g, 10.7 mmol) to afford the product (1.19 g); no distinct m. p. (gradual decomposition).

Calculated for C14H12Cl2N2°2 : C, 54.04; H, 3.89; N, 9.00.

Found: C, 53.81; H, 4.05; N, 8.54.

EXAMPLE24 1-(3-Amino-4-methoxyphenyl)-3-phenyl-urea Step A: 1-(4-Fluoro-3-nitrophenyl)-3-pllenyll-urea Phenylisocyanate (12. 0 g, 0.1 mol) was added to 4-fluoro-3-nitroaniline (15.6 g9 0.1 mol) in ethyl acetate (400 mL) at room temperature. The rection mixture was stirred overnight, then the volume was reduced to approximately 200 mL and the resulting suspension filtered to afford the product (14.3 g); m. p.

200-202°C. Concentration of the filtrate followed by filtration afforded an additional crop of product (5.4 g) ^ Calculated for C13H10FN3O3: C, 56.73; H, 3.66; N, 15. 27.

Found: C, 56, 74; H, 3.43; N, 15.46.

Step B: 1-(4-Methoxy-3-nitrophenyl)-3-phenyl-urea The product from Step A (5.52 g, 20 mmol) was dissolve in methanol (200 mL) and sodium methoxide in methanol (7.4 mL, 25% w/w) was added.

After standing overnight at room temperature, the rection mixture was concentrated to dryness, taken up in ethyl acetate, washed with 10% citric acid solution then brine, and dried (magnesium sulfate), filtered, and concentrated to dryness. The residue was chromatographed two times on silica gel using ethyl acetate as eluant. The fractions enriched in tlle product were triturated in acetone- ether and the insoluble portion collecte by filtration to afford the product (1.64 g), sufficiently pure for use in the next step.

Step C 1- (3-Amino-4-methoxyphenyl)-3-phenyl-urea Prepared according to the procedure described for Example 9, Step B using the product from Step B above (1.64 g, 5.7 mmol) to give the product (0.715 g) in three crops; m. p. 174-175°C after chromatography on silica gel using a 2-4% gradient of methanol in methylene chloride as eluant, followed by recrystallization from ethyl acetate.

Calculated for C14H15N3O2: C, 65.36; H, 5.88; N, 16.33.

Found. C, 65.15; H, 5.55; N, 16.19.

EXAMPLE 25 3-Phenylamino-N-phenyl-benzamide A mixture of 3-amino-N-phertyl-benzamide (1.5 g, 7.0 mmol), triphenylbismuth (3.7 g, 8.0 mmol), copper (II) acetate (1.3 g, 7.0 mmol), and triethylamine (0.73 g, 7.0 mmol) was stirred under an inert atmosphere in dichloromethane (100 mL) and heated to reflux. After 4 to 24 hours (the rection was monitored for completeness using tlc), the mixture was allowed to cool and was then diluted with additional dichloromethane (200 mL) and stirred into 2N hydrochloric acid (250 mL). After 2 hours, the layers were separated and the organic phase washed successively with 2N HCl, water, 0.5 M aqueous potassium carbonate, water, and saturated aqueous sodium chloride, then dried over MgS04.

The solution was filtered then stripped of solvent under reduced pressure to afford a solid residue which was purifie by chromatography on a column of silica gel in chloroform to give the product (1. 0 g); m. p. 134-135°C after recrystallization from toluene.

Calculated for Cl9H16N2° C, 79.14; H, 5. 59; N, 9.71.

Found: C, 79.17; H, 5.42; N, 9. 63.

EXAMPLE 26 3- (3,5-Dichloro-phenylamino)-N-phenyl-benzamide

A mixture of 3-amino-N-phenyl-benzamide (2.0 g, 9.4 mmol), 3,5-dichloroiodobenzene (2.65 g, 9.7 mmol), N-ethylmorpholine (1. 1 g, 9.5 mmol), and copper (ici) acetate (0.1 g, 0.6 mmol) in N, N-dimethylformamide (6 rnL) was stirred under an inert atmosphere and heated to reflux. After 120 hours, the mixture was allowed to cool and was stirred into water (300 mL) and acidifie with concentrated hydrochloric acid. The mixture was extracted with dichloromethane (300 mL) and the extract separated and washed successively with 2N hydrochloric acid, water, 0. 5 M aqueous potassium carbonate, water, and saturated aqueous sodium chloride, then dried over MgSO4. The solution was filtered and stripped of solvent under reduced pressure to leave a solid residue which was subjected to chromatography on a column of silica gel in chloroform to afford the product (0.1 g); m. p. 164-165°C after recrystallization from ethyl alcool.

Calculated for Cl9Hl4Cl2N20 : C, 63.88; H, 3.95; N, 7.84.

Found: C, 63.64; H, 4.04; N, 7.61.

EXAMPLE 27 3-(2-Methoxy-phenylamino)-Dl-phenyl-benzamide Prepared according to the procedure of Example 25 using 3-amino-N- phenyl-benzamide (0.85 g, 4.0 mmol), tris (2-methoxyphenyl) bismuthine (2.2 g, 4.1 mmol), copper (II) acetate (0.75 g, 4. l mmol), and triethylamine (0.42 g, 4.1 mmol) to give a solid residue which was subjected to chromatography on a column of silica gel in chloroform to afford the product (0.9 g); m. p. 153-154°C after recrystallization from ethanol.

Calculated for C20H18N2O2: C, 75.45; H, 5. 70; N, 8.80.

Found: C, 75.21; H, 5.65; N. 8.72.

EXAMPLE 28 4-Methoxy-3-phenylamino-N-phenyl-henzamide Prepared according to the procedure of Example 25 using 3-amino- 4-methoxy-N-phenyl-benzamide (1.5 g, 6.2 mmol), triphenylbismuth (2.9 g, 6.6 mmol), copper (II) acetate (1.13 g, 6.2 mmol), and triethylamine (0.62 g, 6.2 mmol) to give a solid which was recrystallized from ethanol then subjected to chromatography on a column of silica gel in dichloromethane to afford the product (0.8 g); m. p. 194-195°C after an additional recrystallization from ethyl alcool.

Calculated for C2oHl8N202' C, 75.45 ; H, 5.70 ; N, 8.80.

Found: C, 74.66; H, 5.43 ; N, 8. 67.

EXAMPLE 29 3-(2-methoxy-phenylamino)-4-methoxy-N-phenyl-benzamide Prepared according to the procedure of Example 25 using 3-amino-4-methoxy-N-phenyl-benzamide (0.8 g, 3.2 mmol), tris (2-methoxyphenyl) bismuthine (1.8 g, 3. 4 mmol), copper (II) acetate (0.6 g, 3. 4 mmol), and triethylamine (0.34 g, 3. 4 mmol) to afford the product (0.9 g); m. p. 155-156°C after chromatography on a column of silica gel in chloroform followed by recrystallization from ethanol Calculated for C21H2oN203 : C, 72.40; H, 5.79; N, 8.04.

Found: C, 72.13; H, 5. 73; N, 7, 94.

EXAMPLE 30 3-(3-Trifluoromethyl-phenylamino)-4-methoxy-N-phenyl-benzami de Prepared according to the procedure of Example 25 using 3-amino- 4-methoxy-N-phenyl-benzamide (0.7 g, 2.9 mol), tris (3- trifluoromethylphenyl) bismuthine (2.0 g, 3.1 mmol), copper (Il) acetate (0. 54 g, 3.0 mmol), and triethylamine (0.29 g, 2.9 mmol) to afford the product (oye7 g); m. p. 183-184°C after recrystallization from acetonitrile.

C21H17FN2O2:Calculatedfor C, 65.28 ; H, 4.43 ; N, 7.25.

Found: C, 64.89; H, 4. 13; N, 7.24.

EXAMPLE 31 3-(3-Chloro-phenylamino)-4-methoxy-N-phenyl-benzamide Prepared according to the procedure of Example 25 using 3-amino- 4-methoxy-N-phenyl-benzamide (1.5 g, 6.2 mmol), tris (3-chlorophenyl) bismuthine (3.5 g, 6.4 mmol), copper (II) acetate (1.16 g, 6.4 mmol), and triethylamine (0.65 g, 6.4 mmol) to give a solid which was purifie by chromatography on a column of silica gel in chloroform/ethyl acetate 99: 1 to afford the product (1. 8 g); m. p. 168-170°C after recrystallization from ethanol.

Calculated for C20H17CIN2o2 C, 68.09; H, 4.86; N, 7. 94.

Found C, 67. 91; H, 4.71; N, 7.80 EXAMPLE 32 3-(3-Methyl-phenylamino)-4-methoxy-N-phenyl-benzamide Prepared according to the procedure described for Example 25 using 3-amino-4-methoxy-N-phenyl-benzamide (1.0 g, 4.1 mmol), tris (3-methylphenyl) bismuthine (2.2 g, 4.6 mol), copper (II) acetate (0.8 g, 4.4 mmol), and triethylamine (0.44 g, 4.4 mmol) to afford the product (0.7 g); m. p. 160-161°C after recrystallization from acetonitrile.

Calculated for C21H20N2°2 : C, 75.88; H, 6.06; N, 8. 43.

Found: C, 75. 63; H, 6.11; N, 8.74.

EXAXLE 33 3-(3-Nitro-phenylamino)-=4-methoxy-N-phenyl-benzamide A mixture of 3-amino-4-methoxy-N-phenyl-benzamide (2.0 g, 8 mmol), 1-iodo-3-nitrobenzene (2.5 g, 10 mmol), potassium carbonate (2.8 g, 20 mmol),

and copper (I) iodide (0.4 g, 2 mmol) in mesitylene (20 mL) was stirred under an inert atmosphere and heated to reflux. After 48 hours, the mixture was allowed to cool and was then diluted with tetrahydrofuran (100 rnL) and filtered through Celite. The filtrate was stripped of solvent under reduced pressure to leave an oily residue which was dissolve in ethyl acetate (250 mL) and extracted successively with 2N hydrochloric acid (2 x 200 mL), water, 0.5 M aqueous potassium carbonate, water, and saturated aqueous sodium chloride, then dried over MgS04.

The solution was filtered and the filtrate stripped of solvent under reduced pressure. The resulting residue was subjected to chromatography on a column of silica gel in chloroform to afford the product (0.18 g); m. p. 220-221°C after recrystallization from acetonitrile.

Calculated for C2oHl7N3041 C, 66.11; H, 4.72; N, 11. 56.

Found: C, 65. 81; H, 4. 63; N, 11.47.

EXAMPLE 34 3- (4-Methyl-phenylamino)-4-rraethoxy-Nmphenyl-benzamide Prepared according to the procedure of Example 25 using 3-amino- 4-methoxy-N-phenyl-benzamide (1. 1 g, 4.5 mmol), tris (4-methylphenyl) bismuthine (2.5g, 5.2 mmol), copper (II) acetate (0.82 g, 4.5 mol) ; and triethylamine (0.46 gaz 4.5 mmol) to afford the product (0.8 g); m. p. 187-188°C after recrystallization from acetonitrile then ethyl acetate.

C21H20N2O2:Calculatedfor C, 75.88; H, 6. 06; N, 8.43.

Found: C, 75.57; H, 5 83; N, 8.34, EXAMPLE35 3-(3,5-Dichloro-phenylmino)-4-methoxy-N-phenyl-benzamide Prepared according to the procedure of Example 33 using 3-amino- 4-methoxy-N-phenyl-benzamide (2.0 g, 8.3 mmol), 3,5-dichloroiodobenzene (4.5 g, 16.5 mmol), potassium carbonate (2.9 g, 21.0 mmol), and copper (I) iodide (0.5 g, 2.6 mmol) to give a gummy residue which was subjected to

chromatography on a column of silica gel in dichloromethane to afford the product (0.3 g); m. p. 207-208°C after recrystallization from ethanol.

Calculated or C20H16CI2N2O2?0.2C2H6O: C, 61. 80; H 4.37; N, 7.07.

Found: C, 61.47; H, 4.04; N, 7. 08.

EXAMPLE 3 6 3-(3,5Dimethyl-pheenylamino)-4-methoxy-N-phenyl-benzamide Prepared according to the procedure of Example 25 using 3-amino- 4-methoxy-N-phenyl-benzamide (1.5 g, 6.3 mmol), tris (3,5-dimethylphenyl)- bismuthine (3.3 g, 6.3 mol), copper (II) acetate (1.15 gaz 6.3 mmol), and triethylamine (0.64 g, 6.3 mmol) to afford the product (1.1 g); m. p. 198-199°C after recrystallization from a mixture of dichloromethane and ethyl acetate 10: 1.

Calculated for C22H22N2O2#0.5CH2Cl2: C, 75.52; H, 6.35; N, 7.99.

Found: C, 75.56; H, 6.32; N, 7.92. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> EXAWLE 37<BR> <BR> <BR> <BR> <BR> <BR> 3-Phenylamino-4-fluoro-N-phenyl-benzarnide Prepared according to the procedure of Example 25 using 3-amino- 4-fluoro-N-phenyl-benzamide from Example 9 93(0. g, 4.0 mmol), triphenylbismuth (1.9 g, 4.3 mmol), copper (II) acetate (0.8 g, 4.4 mmol), and triethylamine (0.45 g, 6.3 mmol) to abord the product (0.4 g); m. p. 132-133°C, after chromatography on a column of silica gel in dichloromethane/ethyl acetate 95: 5.

Calculated for C19H15FN2O: C, 74.50; H, 4.94; N, 9.14.

Found: C, 74.21; H, 4.96 ; N, 9.00.

EXÅMPLE 38 3-Phenylamino-4-methyl-N-phenyl-benzamide

Prepared according to the procedure of Example 25 using 3-amino- 4-methyl-benzanilide from Example 1 (1.0 g, 4.4 mmol), triphenylbismuth (2.0 g, 4.5 mmol), copper (II) acetate (0.82 g, 4.5 mol), and triethylamine (0.46 g, 4.5 mmol) to afford the product (0.8); m. p. 119-120'C after chromatography on a column of silica gel in dichloromethane/ethyl acetate 99: 1 and subsequent crystallization from ethanol.

Calculated for C20H18N2O#0.1C2H6O: C, 79.36; H, 6.01; N, 8.98.

Found: C, 79.02; H, 6. 00; N, 9.26.

EXAMPLE 39 3-Phenylamino-4-methoxy-N-(4-fluoropheyl)-benzamide Prepared according to the procedure of Example 25 using 3-amino- 4-methyl-N-(4-fluorophenyl)-benzamide from Example 8 (1.0 g, 3.8 mmol), triphenylbismuth (1. 8 g, 4.1 mol), copper (II) acetate (0.8 g, 4.4 mmol), and triethylamine (0.44 g, 4.4 mmol) to afford the product (0.8 g); m. p. 151-152°C after recrystallization from ethanol.

Calculated for C20H17FN2O2#0.1C2H6O: C, 5.20;N,8.22.H, Found: C, 70 84; H, 5.06; N, 8. 09 <BR> <BR> <BR> <BR> <BR> <BR> EXAWLE 40<BR> <BR> <BR> <BR> <BR> <BR> 3- (3-Trilluoromethyl-phenylamino)-4-methoxy-N- (4-fluorophenyl)- benzamide Prepared according to the procedure of Example 25 using 3-amino- Example8(1.0g,3.8mmol),4-methoxy-N-(4-fluorophenyl)-benzamid efrom tris (3-trifluoromethylphenyl)bismuthine (2.8 g, 4.3 mmol), copper (II) acetate (0.8 g, 4.4 mmol), and triethylamine (0. 44 g, 4.4 mmol) to afford the product (0.9 g); m. p. 163-164°C after recrystallization from acetonitrile.

Calculated for H16F4N2O2: C, 62.38; H, 3.99; N, 6.93.

Found: C, 62.18; H, 4.00; N, 6.84.

EXAMPLE 41 4-Ethyl-3- (3-trifluoromethyl-phenylamino)-N-phenyl-benzamide Prepared according to the procedure of Example 25 using 3-amino-4- ethyl-N-phenyl-benzamide from Example 17 (1.0 g, 4.2 mmol), tris (3- trifluoromethylphenyl) bismuthine (2.9 g, 4.5 mmol), copper (II) acetate (0.8 g, 4.4 mmol), and triethylamine (0.45 g, 4.5 mmol) to give a syrup which was crystallized from ether to afford the produce (0 42 g); m. p. 133-134°C after recrystallization from acetonitrile.

Calculated for C22Hl9F3N2° C, 4.98;N,7.29.H, Found: C, 68.71 ; H. 4.79; N, 7.30.

EXAMPLE 42 4-Ethoxy-3-(3-trifluoromethyl-phenylamino)-N-phenyl-benzamid e Prepared according to the procedure of Example 25 using 3-amino- 4-ethoxy-N-phenyl-benzamide from Example 10 (0.6 g, 2.3 mmol), tris (3-trifluoromethylphenyl) bisrnuthine (1.6 g, 2.5 mol), copper (II) acetate (0.45 g, 2.5 mmol), and triethylamine (0.25 g, 2.5 mmol) to afford the product (0.53 g); m. p. 184-185°C after recrystallization from ethyl alcool.

Calculated for C22H12F3N2O2: C, 65.99; H, 4.78 ; N, 7.00.

Found C, 65.82; H, 4.73; N, 6.92.

EXAMPLE43 <BR> <BR> <BR> <BR> <BR> 4-Methylsulfanyl-3- (3-trifluoromethyl-phenylamino)-N-phenyl-benzamide Prepared according to the procedure of Example 25 using 3-amino- 4-methylsufanyl-N-phenyl-benzamide from Example 20 (0.5 g, 1.9 mmol), tris (3-trifluoromethylphenyl) bismuthine (1, 4 g, 2.1 mmol), copper (II) acetate (0.4 g, 2.2 mmol), and triethylamine (0.21 g, 2.1 mmol) to afford the product (0.25 g); m. p. 169-170°C after recrystallization from acetonitrile.

Calculated for C2lHl7F3N20S : C, 62.68; H, 4.26; N, 6.96.

Found: C, 62.34; H, 4.11; N, 6.87.

EiXAMPLE 44 3- [4- (4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-phenylamino]-4-methox y-N- phenyl-benzamide Prepared according to the procedure of Example 25 using 3-amino- 4-methoxy-N-phenyl-benzamide (1.6 g, 6.6 mmol), tris [4- (4,4-dimethyl- 2-oxazolinyl)-phenyl] bismuthine (4.8 g, 6.6 mmol), copper (II) acetate (1.2 g, 6.6 mmol), and triethylamine (0.67 g, 6. 6 mmol) to afford the product (0.8 g); m. p. 221-222°C after recrystallization from acetonitrile.

Calculated for C25H25N3O3: C, 72.27; H, 6.06 ; N, 10.11.

Found: C, 71.04; H, 5.92 ; N. 9.91.

EXOPLE 45 4-Methoxy-3-(3-trifluoromethyl-phenylamino)-N-(3-pyridyl)-be nzamide Prepared according to the procedure of Example 25 using 3-amino- 4-methoxy-N- (3-pyridyl)-benzamide from(3-pyridyl)-benzamide from Example 5 (1.0 g, 4.1 mmol), tris (3-trifluoromethylphenyl) bismuthine (2.8 gaz 4.3 mmol), copper (ici) acetate (0.8 g, 4.4 mmol), and triethylamine (0.44 g, 4.3 mmol) to afford the product (0.6 g); m. p. 184-185°C after recrystallization from acetonitrile.

Calculated for C20H16F3N3O2: C, 62.01; H, 4.16; N, 10. 85.

Found: C, 61.93 ; H, 4.14; N, 10. 85.

EXAlI'LE 46 4-Methoxy-3-(3,5-dimethyl-phenylamino)-N-(4-fluorophenyl)-be nzamide Prepared according to the procedure of Example 25 using 3-amino- 4-methoxy-N- (4-fluorophenyl)-benzamide(4-fluorophenyl)-benzamide from Example 8 (1.0 g, 3.8 mol) 5 tris (3,5-dimethylphenyl) bismuthine (2. 1 g, 4.0 mol), copper (II) acetate (0.8 g,

4.4 mmol), and triethylamine (0.45 g, 4.4 mmol) to afford the product (0.6 g); m. p. 199-200°C after recrystallization from acetonitrile.

Calculated for C22EI21FN2°2 C, 72.51; H, 5.81; N, 7. 69.

Found: C, 72.32; H, 5.76; N, 7. 60.

EXEMPLE 47 4-Methoxy-3-(3-trifluoromethyl-phenylamino)-N-(3,4-dichlorop henyl)- benzamide Prepared according to the procedure of Example 25 using 3-amino- 4-methoxy-N-(3,4-dichlorophenyl)-benzamide from Example 4 (0. 9 g, 2.9 mmol), tris (3-trifluoromethylphenyl) bismuthine (2.1 g, 3.3 mmol), copper (ici) acetate (0.6 g, 3.3 mmol), and triethylamine (0.34 g, 3.3 mmol) to afford the product (0.4 g); m. p. 154-155°C after recrystallization from ethanol.

Calculated for C2lHl5cl2F3N2o2 C, 55.40; H, 3.32; N, 6.1S Found: C, 55. 21; H, 3.20; N, 5.88.

EXAMPLE48 4-methoxy-3-(3-trifluoromethyl-phenylamino)-N-(3,4-difluorop henyl)- benzamide Prepared according to the procedure of Example 25 using 3-amino- 4-methoxy-N-(3,4-difluorophenyl)-benzamide from Example 15 (1.1 g, 4.0 mmol), tris (3-trifluoromethylphenyl) bismuthine (2.8 g, 4.3 mmol), copper (II) acetate (0.8 g, 4.3 mmol), and triethylamine (0.44 g, 4.3 mmol) to afford the product (1.2 g); m. p. 166-169°C after recrystallization from ethanol.

Calculated for C21H15F5N2O2: C, 5 9.72; H, 3.58; N, 6.63.

Found: C, 59.58 ; H, 3.44; n, 6.44 EXA1\SLE 49 N- [3- (Phenylamino)-4-methoxy-phenyll-benzamide

Prepared according to the procedure of Example 25 using N- (3-amino- 4-methoxyphenyl)-benzamide from Example 21 (1.0 g, 4.1 mmol), triphenylbismuth (2.0 g, 4.5 mmol), copper (II) acetate (0.82 g, 4.5 mmol), and triethylamine (0. 46 g. 4.6 mmol) to affora'the product (0.6 g); m. p. 209-210°C after recrystallization from ethanol.

Calculated for C20H18N2°2: C, 75.45; H, 5.70; N, 8. 80.

Found: C, 75.26; H, 5.75; N, 8.42.

EXAMPLE 50 3-Benzylamino-4-methoxy-N-phenyl-benzamide Benzaldehyde (2.2 g, 21.0 mmol) was added to a stirred solution of 3-amino-4-methoxy-N-phenyl-benzamide (5.0g, 21. 0 mmol) in dichloromethane (250 mL) under an inert atmosphere at room temperature, followed by acetic acid (1.26 g, 21.0 mmol). Aficer 1 hour. sodium triacetoxyborohydride (4.7 g, 21.0 mmol) was added in one portion. After 18 hours, saturated aqueous sodium bicarbonate (200 mL) was added and the mixture stirred for 2 to 3 hours. The layers were separated, the organic phase was washed with water then saturated aqueous sodium chloride, then dried over MgSO4. The solution was filtered and stripped of solvent under reduced pressure to afford the product (6.5 g); m. p.

164-165°C after recrystallization from ethanol.

Calculated for C2lH20N2°2 : C, 75.88; H, 6.06; N, 8.43.

Fonde C, 75.62; H, 6.02; N, 8. 44.

EXAITPLE 51 3-(3,5-Dichloro-benzylamino)-4-methoxy-N-phenyl-benzamide Prepared according to the procedure of Example 50 using 3,5-dichloro- benzaldehyde (0.88 g, 5.0 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (1.22 g, 5.0 mmol), acetic acid (0.24 g, 5.3 mmol), and sodium triacetoxyborohydride (1.12 mmol) to afford the product (0.65 g); m. p. 164-165°C after recrystallization from ethanol.

Calculated for C21H18Cl2N2O2 : C, 62.86; H, 4.52; N, 6.98.

Found: C, 62.58; H, 4.41; N, 6.83.

EXAMPLE 52 3-(3, 4FDimethoxy-benzylamino)-4-1nethoxy-N-phenyl-benzamide Prepared according to the procedure of Example 50 using g,11.6mmol),3-amino-4-methoxy-N-phenyl-3,4-dimethoxybenzalde hyde(1.94 benzamide (2.8 g, 11.6 mmol) acetic acid (0.69 g, 11.5 mmol), and sodium triacetoxyborohydride (2.6 g, 11. 7 mmol) to afford the product (2.9 g); m. p. 187-188°C aflcer recrystallization from ethanol.

Calculated for C23H24N2O4: C, 70. 39 ; H, 6.16; N, 7.14.

Found: C, 70.31; H, 6. 00; N, 7.10.

EXAMPLE 53 3-Phenoxy-N-phenyl-benzamide Prepared according to the procedure of Example 1 Step A using 3-phenoxybenzoic acid (1.2 g, 5.5 mmol), oxalyl chloride (0.55 mL, 6.3 mmol), and aniline (1.0 g, 10.7 mmol) to afford the product (1.5 g); m. p. 111-112°C after recrystallization from ethanol.

Calculated for CCl9H15N°2 C, 78.87; H, 5.23; N, 4. 84.

Found: C, 78.69; H, 5.25; N, 4.82.

EXAMPLE54 3-Phenoxy-4-methoxy-N-phenyl-lbenzamice Step A: 3-Hydroxy-4-methoxybenzoic Acid Methyl Ester A stirred suspension of 3-hydroxy-4-methoxybenzoic acid (6.3 g, 38 mmol) in methanol (200 mL) at ambient temperature was saturated with HCI gas until a solution was obtained. After 16 hours, the mixture was stripped of solvent under reduced pressure to afford the crystalline product (7.1 g); m. p.

64-65°C after chromatography on silica gel eluting with 2.5% methanol in dichloromethane.

Calculated for CgH1004: C, 59.34; H, 5.53.

Found: C, 59.41; H, 5.39.

Step B: 3-Phenoxy-4-methoxybenzoic Acid Methyl Ester Prepared according to the procédure of Example 25 using 3-hydroxy- 4-methoxybenzoic acid methyl ester (1.2 g, 6.6 mmol), triphenylbismuth (3.2 g, 7.3 mol), copper (II) acetate (1. 32 g, 7.3 mmol), and triethylamine (0.73 g, 7.2 mmol) to afford the product (0.9 g); m. p. 61-63°C after trituration in methanol. <BR> <BR> <BR> <BR> <BR> <BR> <P>Step C : 3-Phenoxy-4-methoxybenzoic. Acid<BR> <BR> <BR> <BR> <BR> 3-Phenoxy-4-methoxyberlzoic acid methyl ester (0.8 g. 3.1 mmol) was stirred in a mixture of methanol (8 mL) and 4N potassium hydroxide (10 mL) and heated to refluox. After 2 hours, the mixture was stirred into water (60 mL) and extracted with ether (25 mL). The aqueous solution was stirred and acidifie with 4N HCl, and the resulting precipitate was filtered off, rinsed with water, and dried to afford the product (0.7 g); m. p. 186~187°Ce Calculated fox C4H1204 C, 68.85; H, 4. 95.

Found : C, 68.65; H, 4.74.

Step D: 3-Phenoxy-4-methoxy-N-phenyl-benzamlåe Prepared according to the procedure of Example 1 using 3-phenoxy- 4-methoxybenzoic acid (0.3 g, 1.2 mmol), oxalyl chloride (0.19 g, 1.5 mmol), and aniline (0.22 g, 2.4 mmol) to afford the product (0. 3 g); m. p. 200-201°C after recrystallization from ethanol.

Calculated for C20H17No3: C, 75.22; H, 5.37 ; N, 4.39.

Found: C, 75.01; H, 5.36; N, 4.17.

3-(Phenylamino)-4-methoxybenzoic(Phenylamino)-4-methoxybe nzoic acid, phenyl ester Step A: 3-(Phenylamino)-4-methoxybenzoic acid, methyl ester Prepared according to the procedure of Example 25 using 3-methoxy- 4-aminobenzoic acid methyl ester (1.5 g, 6.9 mol), triphenylbismuth (3.1 g, 7.0 mmol), copper (II) acetate (1.3 g, 7.2 mmol), and triethylamine (0.73 g, 7.2 mmol) to afford the product (1.5 g); m. p. 79-81°C, after recrystallization from ethanol.

Step B : 3-(Phenylamino)-4-methoxybenzoic acid A mixture of 3- (phenylaznino)-4-methoxybenzoic acid, methyl ester (0.4 g, 1.6 mmol), methanol (10 mL), and 4N sodium hydroxide (15 mL) was stirred and heated to reflux. lifter 2 hours, the methanol was removed by rotary evaporator and the residual aqueous suspension stirred and acidified with 4N HCI. The precipitate was filtered off, rinsed with water, and dried to afford the product (0.35 g); m. p. 198-200°C.

Calculated for C14Hl3NO3: C, 69.12; H, 5.39; N, 5.76.

Found: C, 68.27; H, 5.53; N, 5.65.

Step C : 3- (Phenylamino)-4-methoxybenzoic acid, phenyl ester N, N'-Carbonyldiimidazole (0.41 g, 2.5 mmol) was added to a stirred solution of 3- (phenylamino)-4-rrethoxybenzoic acid (0.6 g, 2.5 mmol) in dimethylformamide (15 mL) under an inert atmosphere. After 30 minutes, the solution was heated to 50°C for 1 hour, then phenol (0.24 g, 2.6 mmol) was added followed by diazabicycloundecene (0.40 g, 2.6 mmol) and heating at 50'C was continue for 20 more hours. The mixture was allowed to cool and was then diluted with diethyl ether (100 mL) and washed successively with 2N HCI, water, 0.5NK2CO3, and saturated brine then dried over MgS04. The solvent was removed under reduced pressure, and the residue was chromatographed on a column of silica gel in ethyl acetate to afford the product (0.27 g); m. p. 130-131°C after recrystallization from acetonitrile.

Calculated for C20H17NO3: C, 75.22; H, 5.37; N, 4.39.

Found: C, 74.92; H, 5.51; N, 4.45.

EY-ANTLE 56 4-Hyciroxy-3- (3, 5-dichloro-phenamino)-N-phenyl-benzamide Step A: 3-Amino-4-methoxybenzoic acid methyl ester Concentrated H2S04 (9 mL) was added in portions to a stirred solution of 3-amino-4-methoxybenzoic acid (20.06 g, 110. 4 mmol) in methanol (280 mL).

The mixture was heated to reflux overnight then cooled to room temperature, and the solvent was removed in vacuo. The residue was shaken with 10% aqueous potassium carbonate then extracted with ethyl acetate three times. The combine extracts were washed with saturated sodium bicarbonate, dried (MgS04), filtered, and stripped of solvent under reduced pressure. The residual solid was triturated with hexane and filtered to yield the product (10.82 g); m. p. 75-77°C.

Calculated for C9H11NO3: C, 59.66; H, 6.12; N, 7. 73.

Found: C, 59.93; H, 6.22; N, 7.54. <BR> <BR> <BR> <BR> <BR> <BR> <P>Step B: 2-Acetylamino-4-methoxybenzoic acid methyl ester<BR> <BR> <BR> <BR> <BR> Acetic anhydride (6.5 mL, 68. 80 mmol) was added to a solution of 3-amino-4-methoxybenzoic acid methyl ester (10.58 g, 58.39 mmol) in 200 mL of ethyl acetate. The rection was stirred at room temperature. After 3 days, the mixture was filtered and the filtrante was washed with saturated aqueous sodium bicarbonate until pH = 5, dried (MgSO4), and stripped of solvent under reduced pressure. The residue was triturated with hexane and filtered to afford a tan solid which was combine with the residue remaining in the funnel after the initial filtration and dried to afford the desired product (9.6 g); m. p. 123-126°C.

Calculated for C11H13NO4 : C, 59.19; H, 5.87; N, 6.27.

Found: C, 59.03; H, 5.81; N, 6.23.

Step C: 3-[Acetyl-(3,5-dichlo9rophenyl)-amino]-4-methoxybenzoic acid methylester A mixture of 2-acetylamino-4-methoxybenzoic acid methyl ester (9.58 g, 42.92 mmol), 1-bromo-3,5-dichlorobenzene (28.80 g, 127.48 mmol), copper iodide (2.32 g, 12.18 mmol), and sodium bicarbonate (8.72 g, 103.80 mmol) in of mesitylene (60 mL) was heated to reflux. After 7 days, the mixture was allowed to cool and was diluted with ethyl acétate (300 nif). The resulting solid was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel eluting with hexane/ethyl acetate (9: 1 # 1 : 1) to afford the product (11.6 g); m. p. 100-101°C after trituration in hexane.

Calculated for C17H15Cl2NO4: C, 55.45 ; H, 4.11; N, 3.80.

Found: C, 55.12; H, 3.97; N, 3.73.

Step D: 3-(3,5-Dichlorophenylamino)-4-methoxybenzoic acid methyl ester Concentrated HCI (45 mL) was added to a solution of 3- [acetyl- (3,5- dichlorophenyl)-amino]-4-methoxybenzoic acid methyl ester (11.46 g, 31.12 mmol) in a mixture of tetrahydrofuran (75 mL) and methanol (75 mL). The rection was heated to reflux. ASer 3 days, the solvent was removed in vacuo and the residue was dissolve in ethyl acetate and dried (MgSO4). The ethyl acetate was removed under reduced pressure to give the product (2.4 g); m. p. 134-135°C after chromatography on silica gel in ethyl acétate followed by recrystallization from ether/hexane 1: 9.

Calculated for (C15H13Cl2NO3: C, 55.24; H, 4.02; N, 4.29.

Found: C, 55.20; H, 4.08; N, 4.07.

Step E: 3-(3,5-Dichlorophenylamino)-4-hydroxybenzoic acid A solution of 3-(3,5-dichlorophenylamino)-4-methoxybenzoic acid methyl ester (4.48 g, 13.74 mmol), 100 mL of concentrated HBr, and 60 mL of acetic acid was heated to reflux. After 6 days, the rection was cooled to room temperature

and concentrated aqueous ammonium hydroxide was added in portions until the pH = 4. The mixture was extracted with ethyl acetate three times, and the combine extracts were washed with brine (2x) and H20 (2x) then dried over MgSO4 and stripped of solvent in vacuo. The residue was triturated with 5% ether/hexane, filtered off and dried to afford the product (3.7 g); m. p. 166-167°C.

Calculated for C13H9Cl2NO3-H20: C, 49.39; H, 3. 51 ; N, 4.32.

49.16;H,3.34;N,4.23.Found:C, <BR> <BR> <BR> <BR> <BR> <BR> Step F : 3- (3, 5-Dichloro-phenylamino)-4-hydroxy-N-phenyl-benzamide<BR&g t; <BR> <BR> <BR> <BR> Dicyclohexylcarbodiimide (2 68 g, 12.99 mmol) was added to a solution of 3-(3,5-dichlorophenylamino)-4-hydroxybenzoic acid (3.59 g, 12.05 mmol) and aniline (1. 19 mL, 0613. mmol) in tetrahydrofuran (45 mL) at ice bath temperature.

After 5 days at ambient temperature, the white precipitate was collecte by filtration and washed with ethyl acetate. The filtrate was taken to dryness in vacuo, redissolved in ethyl acetate, and washed successively with H2O, 1N HCI, and brine. The organic layer was dried (MgSO4), filtered, and the solvent removed under reduced pressure. The crude material was chromatographed on silica gel, eluting with 4: 1 hexane/ethyl acetate. The effluent was extracted with 1N NaOH, dried (MgSO4), filtered, and stripped of solvent under reduced pressure. The resulting foam was triturated with hexane to afford the product (1.15 g); m. p. 160-162°C.

Calculated for C19H14N2O2Cl2#0. 25 H20 : C, 60.41; H, 3.87; N, 7. 42.

Found: C, 60.34; H, 3.63; N, 7. 20.

EXEMPLE 57 3-(3,5-Dichloro-phenylamino)-4-hydroxy-N-(4-methoxyphenyl)-b enzamide Prepared according to the procedure described for Example 56, Step F using 3- (3,5-dichloro-phenylamino)-4-hydroxybenzoic acid from Example 56, Step E (0.652 g, 2.19 mmol), 4-anisidine (0.276 g, 2.24 mmol), and 1,3-dicyclohexylcarbodiimide (0. 538 g, 2.61 mmol) to afford the product (0.19 g);

m.p. 186-187°C after chromatography on silica gel using a 20-25% gradient of ethyl acetate in hexane.

C20H16Cl2N2O3#0.5H2O:Calculatedfor C, 58.26; H, 4.16; N, 6.80.

Found: C, 58.17; H, 4.13; N, 6.61.

EXAMPLE58 3- (3, 5-Dichloro-phenylamino)-4-hydroxy-N- (4-methylphenyI)- benzamide Prepared according to the procedure described for Example 56, Step F using 3- (3,5-dichloro-phenylamino)-4-hydroxybenzoic acid from Example 56, Step E (0.365 g, 1.22 mmol), p-toluidine (0.134 g, 1.25 mmol), and 1,3-dicyclohexylcarbodiimide (1.48 mmol) to afford the product (0.34 g); m. p. 179-183°C after chromatography on silica gel using ethyl acetate/hexane 1: 1 followed by trituration in hexane.

Calculated for C20H16Cl2N2O2#0. 25 H20 : C, 61. 31, H, 4.25; N, 7.15.

Found: C, 61. 34; H, 4.48; N, 7. 18.

EXAMPLE 59 3-(3,5-Dichloro-phenylamino)-4-hydroxy-N-(3-hydroxy-4-methox yphenyl)- benzamide Prepared according to the procedure described for Example 56, Step F, with the exception that a catalytic amont of 4-dimethylaminopyridine was added to the rection mixture following the DCC. Thus, 3- (3,5-dichloro- phenylamino-4-hydroxybenzoic acid from Example 56, Step E (0.501 g, 1.68 mmol), 3-hydroxy-4-methoxyaniline (0.234 g, 1.68 mmol), and 1,3-dicyclohexylcarbodiimide (0.416 g, 2.02 lmmol) gave the product (0.06 g); m. p. 170-171°C after chromatography on silica gel using ethyl acetate/hexane 1: 1.

Calculated for C20H16Cl2N2O4#0. 4 H20 : C, 56.32; H, 3.97; N, 6.57.

Found: C, 56.55; H, 4.32; N, 5.98.

EXAMPLE 60 3- [3- (3,5-Dichlorophenyl)-thioureido]-4-methoxy-N-phenyl-benzamid e A mixture of 3-amino-4-methoxy-N-phenyl-benzamide (0.277 g, 1. 14 mmol) and 3,5-dichlorophenyl isothiocyanate (0.238 g, 1.17 mmol) in ethyl acetate (30 mL) was warmed until a solution was obtained, then allowed to stand at room temperature for 3 days. The rection was concentrated until a crystalline obtainedthenallowedtostandovernightatroomtemperature.Theprec ipitatewas solid was collecte by filtration, rinsed with ethyl acetate/hexane, and dried to afford the product (0.423 g); m. p. 195-197°C.

Calculated for C2lHl7Cl2N302S: C9 56. 51; H, 3.84; N, 9. 41.

Found : C, 56.205 H, 3.69; N, 9.28.

EXAMPLE61 3- [3- (3-Chlorophenyl)-thioureidol-4-methoxy-N-phenyl-benzamide Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.218 g, 0.90 mmol) and 3-chlorophenyl isothiocyanate (0.12 niL, 0.92 mmol) to give the product (0.286 g); m. P. 165-168°C.

Calculated for C21H18CIN3O2S: C, 61.23; H, 4.40; N7 10. 20.

Found: C, 61. 01; H, 4. 35; N, 10.15.

EXEMPLE 62 4-Methoxy-N-phenyl-3-(3-phenyl-thioureido)-benzamide Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.245 g, 1.01 mmol) and phenyl isothiocyanate (0.12 mL, 1.00 mmol) to give the product (0.216 g); m.p. 174-176°C.

Calculated for C21H19N3O2S: C, 66. 82; H, 5.07; N, 11.13.

Found: C, 66.34; H, 5. 13; N, 11.04.

EXAMPLE 63 4-Methoxy-N-phenyl-3-[3-(4-trifluoromethyl-phenyl)-thioureid o]-benzamide Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.198 g, 0.82 mmol) and 4- (trifluoromethyl) phenyl isothiocyanate (0.169 g, 0.83 mmol) to give the product (0.306 g); m. p. 194-196°C.

Calculated for C22H18F3N3O2S: C, 59.32; H, 4.07; N, 9.43.

Found: C, 59. 04; H, 4.05; N, 9. 35.

EXAMPLE 64 3-[3-(4-tert-Butyl-phenyl)-thioureido]-4-methoxy-N-phenyl-be nzamide Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0. 216 g, 0.89 mmol) and 4-t- butylphenyl isothiocyanate (0.176 g, 0.92 mmol) to give the product (0.180 g) ; m.p. 198-200°C.

Calculated for C25H27N3O2S # 0.33H2O : C, 68.32; H 6.34; N, 9.56. round: C, 68.22; H 6.49; N, 9. 59.

EXAMPLE 65 3-[3-(4-Chlorophenyl)-thioureido]-4-methoxy-N-phenyl-benzami de Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.243 g, 1.0 mmol) and 4-chlorophenyl isothiocyanate (0.174 g, 1.03 mmol). Trituration in hexanes/ethyl acetate (1: 1) gave the product (0.362 g); m. p. 179-180°C.

Calculated for C21H18CIN3°2S C, 61.23; H, 4.40; N, 10.20, Found: C, 60.94 ; H, 4. 23; N, 10.03.

EXAMPLE 66 3- [3- (3-Nitrophenyl)-thioureidol-4-methoxy-N-phenyl-benzamide Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.243 g, 1.0 mmol) and 3-nitrophenyl isothiocyanate (0.183 g, 1.0 mmol). Trituration in hexanes/ethyl acetate (4: 1) gave the product (0.370 g); m. p. 188-189°C.

Calculated for C21H18N4O4S: C, 59.71 ; H, 4.29; N, 13.26.

Found: C, 58.92; H, 4.23; N, 12.72.

EXEMPLE 67 4-Methoxy-N-phenyl-3-(3-benzoyl-thioureido)-benzamide Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.243 g, 1.0 mmol) and benzoyl isothiocyanate (0.171 g, 1.04 mmol) to afford the product (0.371 g); m.219-222°C.

CI Mass Spectrum: [M + H+] + = 406.

Calculated for C22H19N3o3s C, 65.17 ; H, 4.72; N, 10. 36.

Found: C, 64.98; H, 4.57; N, 10. 26.

EXAMPLE 68 4-Methoxy-N-phenyl-3- [3- (2,3,5, 6-tetrafluoro-phenyl)-thioureido]-benzamide Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl.-benzamide (0.243 g7 1.0 mmol) and 2,3,5,6-tetrafluorophenyl isothiocyanate (0. 224 g, 1.1 mmol) to give the product (0.398 g); m. p. 170-174°C.

Calculated for C21H15F4N3°2S C, 56.12 ; H, 3.36; N, 9. 35.

Found: C, 55.74; H, 3.22; N, 9.19.

EXAMPLE 69 4-Methoxy-N-phenyl-3-(-3-p-tolyl-thioureido)-benzamide Prepared according to the procédure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.243 g, 1.0 mmol) and 4-methylphenyl isothiocyanate (0.205 g, 1.38 mmol). The rection was incomplete after 2 days, so the mixture was diluted to 30 mL with ethyl acetate, and a small additional portion of 4-methylphenyl isothiocyanate was added. The mixture was boiled on a steambath until no solvent remained and the residue triturated in hexanes/ethyl acetate (4: 1) and filtered to afford the product (0.255 g); 156-158°C.p.

Spectrum:[MCIMass + 392.= Calculated for C2SH21N302So0.5 H20: C, 65.97; H, 5.54; N, 10.49.

Found: C, 66.16; H, 5.60; N, 10. 31.

EXAMPLE 70 3-[3-(3,5-Dichlorophenyl)-thioureido]-N-phenyl-benzamide Prepared according to the procedure described for Example 60 using 3-aminobenzanilide (0.213 g, 1.0 mmol) and 3,5-dichlorophenyl isothiocyanate (0.208 g, 1.0 mol). Trituration in ethyl acetate gave the product (0.304 g); m.174-177°C.

APCI Mass Spectrum, M = 416.1.

Calculated for C20H1sCl2N3OS: C, 57.70; H, 3.63; N, 10 09.

Found: C, 58.03; H, 3.57; N, 9.99. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> EXAMPLE 71<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 3- [3- (3, 5-Dichlorophenyl)-thioureidol-4-methyl-N-phenyl-benzamide Prepared according to the procedure described for Example 60 using of 3-amino-4-methyl-N-phenyl-benzamide (, 0.5 g, 2.2 mmol) and 3,5-dichiorophenyl isothiocyanate (0.458 g, 2.2 mmol). Trituration in ethyl acetate afforded the product (0.802 g) in two crops; m. p. 182-184°C.

Calculated for C21Hl7Cl2N3OS: C, 58.61; tI, 3.98; N, 9.76.

Found: C, 58.54; H, 3. 77; N, 9.61.

EXAMPLE 72 3-[3-(3,4-Dimethoxyphenyl)-thioureido]-4-methoxy-N-phenyl-be nzamide A mixture of 3-amino-4-methoxy-N-pllenyl-benzamide (0.972 g, 4.0 mmol), 3,4-dimethoxyphenyl isothiocyanate (0.787 g, 4.0 mmol), and ethyl acetate (25 mL) was heated briefly to 50°C and then allowed to stand overnight at room temperature. The rection mixture was diluted with ethyl acetate (~100 mL), heated to 80°C briefly, then allowed to stand 5 days at room temperature. The precipitate was filtered offto afford the product (0.552 g); m. p. 170-171°C.

Calculated for C23H23N3O4S: C, 63.14; H, 5.30; N, 9. 60 Found: C, 63.02; H, 5.44; N, 9.58.

EXEMPLE 73 3-[3-(4-Chloro-3-trifluoromethylphenyl)-thioureido]-4-methox y-N-phenyl- benzamide Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.0 mmol) and 4-chloro- 3-(trifluoromethyl) phenyl isothiocyanate (0.961 g, 4.0 mmol). Trituration in hexanes/ethyl acetate (3: 2) gave the product (1.91 g); m. p. 172-173°C.

Calculated for C23H17CI2N3°2S: C, 55.06; H, 3.57; N, 8 76 Found: C, 54.88; H, 3.26; N, 8.58.

EXAMPLE 74 3- [3-(3-Cyanophenyl)-thioureido]-4-methoxy-N-phenyl-benzamide Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.0 mmol) and 3-cyanophenyl

isothiocyanate (0.649 g, 4.0 mmol). Trituration in boiling ethyl acetate/dichloromethane (1: 1) gave the product (1.358 g); m. p 183-185°C Calculated C22H18Cl2N4O2S#0.2C4H8O2: C, 65.18; H, 4.70; N, 13.34 Found: C, 64.98; H, 4.80; N, 13.40.

EXAMPLE75 4-[3-(2-Methoxy-5-phenylcarbamoyl-phenyl)-thioureido]-benzoi cacid Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.0 mmol) and 4-carboxyphenyl isothiocyanate (0.722 g, 4.0 mmol) to afford the product (i. 369 g); m. p. 201-202°C.

Calculated for C22H19N3O4S#0. 25 H20: C, 62.03; H, 4.61; N, 9. 87.

Found: C, 61.92; H, 4.73; N, 9.59.

EXÅMPLE 76 3- [3- (3-Aeetyl-phenyl)-thioureido-4-methcaxy-N-phenyl-benzamide Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.971 g, 4.00 mmol) and 3-acetylphenyl isothiocyanate (0. 709 g, 4. 00 mmol) to afford the product m.p.176-177°C.(1.135g); Calculated for C23H21N3O3S: C, 65.85; H, 5. 05 ; Nb 10.02.

Found: C, 65.55; H, 4.93 ; N, 9.83.

EXA1\@LE 77 3-[3-(4-Chloro-3-nitrophenyl)-thioureido]-4-methoxy-N-phenyl -benzamide Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.973 g, 4.00 mmol) and 4-chloro- 3-nitrophenyl isothiocyanate (0.859 g, 4.00 mmol) to afford the product (1.296 g); m. p. 174-1750C.

Calculated for C21Hl7N404ClS: C, 55.20; H, 3.75; N, 12.26.

Found: C, 55.19; H, 3.87; N, 12.29.

EXAMPLE 78 3-[3-(4-Fluorophenyl)-thioureido]-4-methoxy-N-phenyl-benzami de A mixture of 3-amino-4-methoxybenzanilide (0.973 g, 4.00 mmol) in ethyl acetate (75 mL) was heated briefly to ~60°C. The mixture was filtered to clarity and 4-fluorophenyl isothiocyanate (0.49 mL, 4.04 mmol) was added to the filtrate. After 3 days, the mixture was concentrated until a crystalline precipitate was obtained, then allowed to stand several hours at room temperature. Filtration followed by trituration of the collecte solid in ether afforded the product (0,4949 g); m. p. 182-183°C.

Calculated for C21H18N3O2FS: C, 63.78; H, 4.59; N, 10. 63.

Found: C, 63. 72; H, 4. 46; N, 10.45.

EXAMPLE 79 3-[3-(3,5-Dichlorophenyl)-thioureido]-4-methoxy-N-(4-methoxy -phenyl)- benzamide A mixture of 3-amino-4-methoxy-N-(4-methoxyphenyl)-benzamide from Example 3 (0.681 g, 2.50 mmol) in ethyl acetate (80 mL) was heated briefly to 60°C then filtered to clarity and mixed with 3,5-dichlorophenyl isothiocyanate (0.511 g, 2.50 mmol). The rection was allowed to stand for 3 days at room temperature then concentrated to two-thirds volume and allowed to stand overnight. Filtration afforded the product (0.948 g); m. p. 175-182°C.

Calculated for C22H19N3O3Cl2S: C, 55.47; H, 4.02; N, 8.82.

Found: C, 55.42; H, 3.90; N, 8.73.

EXAMPLE 80 3-[3-(3,5-Dichlorophenyl)-thioureido]-4-ethoxy-N-phenyl-benz amide Prepared according to the procedure described for Example 60 using 3-amino-4-ethoxy-N-phenyl-benzamide from Example 10 (0.335 g, 1.30 mmol) and 3,5-dichlorophenyl isothiocyanate (0.266 g, 1.30 mmol) to give the product (0.4609 g); m. p. 201-202°C.

Calculated for C22Hl9N302Cl2S-1/3 H20: C, 56.66; H, 4.25 ; N, 9.01.

Found: C, 56.64; H, 3.98; N, 8.87.

EXAMPLE81 <BR> <BR> <BR> <BR> <BR> 4-Methoxy-N-phenyl-3-(3-pyridin-3-yl-thiollreido)-benzamide& lt;BR> <BR> <BR> <BR> <BR> <BR> Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.00 mmol) and 3-pyridyl isothiocyanate (0.565 g, 4.15 mmol). Trituration in hexanes/ethyl acetate (3: 2) gave the product (1.441 g); m. p. 178-179°C.

Calculated for C2oHl8N402S: C, 63. 47; H, 4.79; N, 14.80.

Found: C, 62.88; H, 4.78; N, 14.65.

EXAMPLE 82 4-[3-(2-Methoxy-5-phenylcarbamoyl-phenyl)-thioureido]-benzen esulfonic Acid Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.00 mmol) and 4-sulfophenyl isothiocyanate sodium salt (1.02 g, 4.0 mmol), except that dimethyl formamide was used as solvent. The dimethyl formamide was removed by rotary evaporator at 60°C to abord the product, m. p. >280°C, aEcer trituration in ethyl acetate.

Calculted for 1.25H2O#0.67DMF# C, 50.16; H, 4.61 ; N, 9.33.

Found: C, 50.21 ; H, 4.32; N, 8. 91.

EXAMPLE 83 4-Methoxy-3-[3-(4-methoxy-phenyl)-thioureido]-N-phenyl-benza mide Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.00 mmol) and 4-methoxyphenyl isothiocyanate (0. 77 g, 5.16 mol), except that after collection of the product obtained upon trituration with hexanes/ethyl acetate, an impurity was present. The impurity was removed by slurrying the solid in dichloromethane/methane 95: 5 followed by filtration to afford the product (0.505 g); m. p. 168-169°C.

Calculated for C22H21N33s: C, 64.85; H, 5.19; N, 10.31.

Found: C, 64.55; H, 5. 17; N, 10.18.

EXAMPLE 84 4-Methoxy-N-phenyl-3-[3-(3-trifluoromethyl-phenyl)-thioureid o]-benzamide Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.00 mmol) and 3-trifluoromethylphenyl isothiocyanate (0.82 g, 4.04 mmol). Trituration in hexanes/ethyl acetate gave the product (1. 12 g) in two crops; m. p. 177-178°C.

Calculated for C22H18O2F3S: C, 59.32; H, 4. 07; N, 9.43.

Found: C, 59.33; H, 3.85; N, 9.37.

EXAMPLE 85 3-[3-(3,4-Dichlorophenyl)-thioureido]-4-methoxy-N-phenyl-ben zamide Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.00 mmol) and 3,4-dichlorophenyl isothiocyanate (0.82 g, 4.02 mmol) to afford the product (1.40 g) in two crops; m. p. 174-175°C Calculated for C21H17N3O2Cl2S: C, 56.51 ; H, 3.84; N, 9.41.

Found: C, 56.54; H, 3.60; N, 9. 36.

EXAMPLE 86 1-{3-[3-(3,5-Dichlorophenyl)-thioureido]-4-methoxyphenyl}-3- kphenyl-urea Prepared according to the procedure described for Example 78 using 1-(4-methoxy-3-aminophenyl)-3-phenyl-urea from Example 24, Step C (0.390 g, 1.52 mmol) and 3,5-dichlorophenyl isothiocyanate (0.311 g, 1.52 mmol).

Filtration without trituration afforded the product (0.5187 g); m. p. 218-219°C.

Calculted for C21H18N4O2Cl2S: C, 54.67; H, 3.93 ; N, 12.14.

Found: C, 54.73; H, 3.95; N, 11. 89.

EDXAMPLE 87 N-{3-[3-(3,5-Dichlorophenyl)-thioureido]-4-methoxy-phenyl}-b enzamide Prepared according to the procedure described for Example 78 using N- (3-mino-4-xnethoxyphenyl)-benzamide from Example 21 (0.88 g, 3.62 mmol) and 3,5-dichlorophenyl isothiocyanate (0.739 g, 3.62 mmol). Filtration without trituration afforded the product (1.31 g); m. p. 194-195°C.

Calculated for C21H17N3O2Cl2S: C, 56. 51; H, 3.84; N, 9.4 1.

Found: C, 56.30; H, 3.74; N, 9.22.

EXAMPLE 88 4-Methoxy-3- [3- (4-nitrophenyl)-thioureidol-N-phenyl-benzamide Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.976 g, 4.02 mmol) and 4-nitrophenyl isothiocyanate (0.723 g, 4.02 mmol) to afford the product (1.39 g) after trituration in ether; m. p. 183-184°C.

Calculated for 1/6EtOAc:# C, 59.53; H, 4.46y N, 12.82.

Found: C, 59. 01 ; H, 4.08; N, 12.71.

EXAMPLE 89 3- [3- (3, 5-Bis-trifluoromethylphenyl)-thioureidol-4-methoxy-N-phenyl- benzamide Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.00 mmol) and 3,5-di (trifluoromethyl) phenyl isothiocyanate (1.08 g, 3.98 mmol) to afford the product (1.076 g); m. p. 192-193°C.

Calculated for C23H17N3O2F6S: C, 53.80; H, 3.34; N, 8.18.

Found: C, 53.71; H, 3.15; N, 8.15.

EXAMPLE 90 4-Methoxy-n-phenyl-3-[3-(4-sulfamoyl-phenyl)-thioureido]-ben zamide@ Prepared according to the procedure described for Example 60 usinez 3-amino-4-methoxy-N-phenyl-benzamide (0.974 g, 4.01 mmol) and 4-isothiocyanatobenzenesulfonamide (0.858 g, 4.00 mmol) to afford the product (0.858 g); m. p. 193-195°C.

Calculated for C21H20N404S2 C, 55.25; H, 4.42; N, 12.27.

Found: C, 54.91; H, 4.34; N, 12.01.

EXAMPLE 91 3-[3-(3,5-Dichlorophenyl)-thioureido]-N-(4-fluorophenyl)-4-m ethoxy- benzamide Prepared according to the procedure described for Exampel 60 using 3-amino-N-(4-fluorophenyl)-4-methoxy-benzamide from Example 8 (0.520 g, 2.00 mmol) and 3,5-dichlorophenyl isothiocyanate (0.409 g, 2.00 mmol).

Filtration afforded the product (0.71 g) in two crops; m. p. 175-178°C.

Calculated for C21H16N3O2Cl2FS: C, 54.32; H, 3. 47; N, 9.05, Found: C, 54.07; H, 3.53; N, 8.88.

EXAMPLE 92 N-(4-Chlorophenyl)-3-[3-(3,5-dichlorophenyl)-thioureido]-4-m ethoxy- benzamide A mixture of 3-amio-N-(4-chlorophenyl)-4-methoxy-benzamide from Example 2 (1.113 g, 4.02 mmol) and 3,5-dichlorophenyl isothiocyanate (0.820 g, 4.02 mmol) in DMF (10 mL) was allowed to stand at room temperature overnight.

The mixture was then diluted with 50 mL lI2O and the precipitate collecte by filtration and dried. Trituration in first ether then ethyl acetate followed by filtration afforded the product (1.19 g); m. pn 180-185°C.

Calculated for C21H16N32C13S: C, 52.46; H, 3.35; N, 8.74.

Found: C, 52.34; H, 3.51; N, 8.92.

EXAMPLE 93 3-[3-(4-Dimethylaminophenyl)-thioureido]-4-methoxy-N-phenyl- benzamide A mixture of 3-amino-4-methoxy-N-phenyl-benzamide (0.975 g, 4.01 mmol), 4-(dimethylamino)phenyl isothiocyanate (0.716 g, 4.00 mmol), and ethyl acetate (20 mL) was allowed to stand at room temperature. After 5 days, the mixture was concentrated to two-thirds volume by rotary evaporator, allowed to stand overnight, then heated to 80 degrees for 4 hours. The precipitate was collecte by filtration and the mother liquor heated to 80 degrees for another 3 hours. More precipitate was collecte by filtration and the mother liquor again heated to 80 degrees and after 7 hours allowed to cool to room temperature overnight. The remaining liquor was concentrated to dryness and the residue triturated in hexanes and the solid filtered off and washed with ethyl acetate.

Combination of all the lots gave the product (0.905 g); m. p. 179-180°C.

Calculated for C23H24N402S-0. 1 M :EtOAc C, 65.46; H, 5.82; N, 13.05.

Found: C, 65.24; H, 5.70; N, 12.86.

EXAMPLE 94<BR> <BR> <BR> <BR> <BR> <BR> <BR> 3- [3- (3, 5-Dichlorophenyl)-thioureidol-4-methoxy-N-p-tolyl-benzamide A suspension of 3-amino-4-methoxy-N-p-tolyl-benzamide from Example 7 (0.515 g, 2.01 mmol) in methylene chloride (75 mL) was heated to the boiling point, then 3,5-dichlorophenyl isothiocyanate (0.411 g, 2.01 mmol) was added, and the rection was allowed to stand at room temperature. Cafter 2 days, the mixture was stripped of solvent at 40°C and the residue triturated in warm methylene chloride. The solid was filtered off, redissolved in methylene chloride/methanol, and filtered to clarity. Evaporation of the solvent afforded the product (0.305 g); m. p. 178-180°C.

Calculated for C22H19N302C1S C, 57.40; H, 4.16; N, 9.13.

Found: C, 56.99; H, 4.11; N, 9.07.

EXAMPLE 95 4-Methoxy-n-phenyl-3-(3-m-tolyl-thioureido)-benzamide Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.973 g, 4.00 mmol) and 3-methylphenyl isothiocyanate (0.55 mL, 4.07 mmol) to afford the product (0.305 g) in two crops; m. p. 168-171°C C22H21N3O2S#0.1MH2O:Calculatedfor C, 67.18; H, 5.43; N, 10.69.

Found: C, 67.00; H, 5.32; N, 10.55. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> EXAMPLE 96<BR> <BR> <BR> <BR> <BR> <BR> 3- [3- (3, 5-Dichlorophenyl)-thioureido-4-fluoro-N-phenyl-benzamide Prepared according to the procedure described for Example 60 using 3-amino-4-fluoro-N-phenyl-berzamide fromExample 9 (0.481 g, 2.09 mmol) and 3,5-dichlorophenyl isothiocyanate (0.427 g, 2.09 mmol). Filtration afforded the product (0.45 g) in two crops; m. p. 173-175°C.

Calculated for C20H14N3OCl2SF: C, 55.31; H, 3.25; N, 9.67.

Found C, 55.21; H, 3.12; N, 9.62.

EXAMPLE 97 N- (3,4-Dichlorophenyl)-3- [3- (3, 5-dichlorophenyl)-thioureido]-4-methoxy- benzamide Prepared according to the procedure described for Example 78 using 3-amino-4-methoxy-N- (3, 4-dichloro-phenyl)-benzamide from Example 4 (0.932 g, 3.00 mmol) and 3, 5-dichlorophenyl isothiocyanate (0.335 g, 1. 64 mmol).

After 2 days, filtration afforded the product (0.426 g); m. p. 189-191°C.

Calculated for C21H15N3O2Cl4S: C, 48.95; H, 2.93; N, 8.16.

Found: C, 48.96; H, 2. 87; N, 8.05.

EXAMPLE 98 4-Methoxy-n-phenyl-3-(3-o-tolyl-thioureido)-benzamide A mixture of 3-amino-4-rnethoxy-N-phenyl-benzamide (0.972 g, 4.00 mmol), 2-methylphenyl isothiocyanate (0.55 mL, 4.11 mmol, and ethyl acetate 20 mL) was allowed to stand at room temperature. After 4 days, the rection was heated to 80°C for 3 hours then allowed to stand at room temperature for an additional 5 days. Filtration afforded the product (0.804 g); m. p.

172-174°C.

Calculated for C22H21N302S : C, 67.50; H, 5 41; N, 10. 73.

Found: C, 66.96; H 47;5. N, 10.56.

EXAMPLE99 3-[3-(3,5-Dimethylphenyl)-thioureido]-4-methoxy-N-phenyl-ben zamide Prepared according to the procedure described for Example 98 using 3-amino-4-methoxy-N-phenyl-benzamide (0.974 g, 4.01 mmol) and

3,5-dimethylphenyl isothiocyanate (0. 66 g, 4.04 mmol) to afford the product (0.42 g); m. p. 203-205°C.

Calculated for C23H23N3O2S: C, 68.12; H, 5. 72; N, 10.36.

Found: C, 67.83; H, 5.66; N, 10.26.

EXAMPLE 100 <BR> <BR> <BR> <BR> 3- [3- (3, 4-Dichlorophenyl)-thioureidol-4-methoxy-N-pyridin-3-yl-benza mide A solution of 3-amino-4-methoxy-N-pyridin-3-yl-benzamide from Example 5 (0.727 g, 2.99 mmol) and 3,5-dichlorophenyl isothiocyanate (0.611 g, 2.99 mmol) in DMF (25 mL) was allowed to stand at room temperature for 3 days. The solvent was removed in vacuo and the residue diluted with water then allowed to stand overnight. The suspende solid was filtered off and triturated successively with ethyl acetate, ether, then boiling methanol to afford the product (0, 57 g); m. p. 17-180°C.

Calculated for C20H16N402Cl2S C, 53.70; H, 3.61; N, 12.53.

Found: C, 53.54; H, 3.52; N, 12. 43.

EXAMPLE 101 5- [3- (3, 5-Dichlorophenyl)-thioureidol-2-fluoro-N-phenyl-benzamide Step A: 5-Amino-2-fluoro-N-phenyl-benzamide Prepared according to the procedure described for Example 1 using oxalyl chloride (3.0 mL, 34.39 mmol), 2-fluoro-5-nitrobenzoic acid (5.00 g, 27.01 mmol), DMF (1.0 mL, 12.92 mmol), and aniline (5.0 mL, 54.88 mmol) to afford the pure product (5.76 g) ; m.p. 120-122°C.

Calculated for C13H11N2OF : C, 67.82 ; H, 4.82; N, 12.17 Found: C, 67.59; H, 4.80; N, 12.08.

Step C: 5-[3-(3,5-Dichlorophenyl)-thioureido]-2-fluoro-N-phenyl-benz amide

Prepared according to the procedure described for Example 60 using 5-amino-2-fluoro-N-phenyl-benzamide (0.920 g, 4.00 mmol) and 3,5-dichlorophenyl isothiocyanate (0.817 g, 4.00 mmol) to afford the product (1.52 g); m. p. 195-196°C.

Calculated for C20H14N3OCl2F: C, 55.31; H, 3.25; N, 9.68.

Found: C, 55.47; H, 3.28; N, 9.43.

EXAWLE 102 N- (3, 4-Dimethylphenyl)-4-methoxy-3- (3-rn-tolyl-thioureido)-benzamide A solution of 3-amino-N- (, 4-dimethylphenyl)-4-methoxy-benzamide from Example 6 (0.541 g, 2.00 mmol) and 3-methylhenyl isothiocyanate (0.28 mL, 2.07 mmol) in ethyl acetate (3S mL) was boiled until nearly all the solvent had evaporated. Filtration after 2 days at room temperature afforded the product (0.44 g) in two crops; m. p. 155-160°C.

Calculated for C24H25N3O2S: C, 68.71; H, 6.01; N, 10.02.

Found C, 68. 11; H, 6.09; N, 9.81.

EXPLE 103 N- (3, 5-Dimethylphenyl)-4-methoxy-3- (3-m-tolyl-thioureido)-benzamide Prepared according to the procedure described for Example 102 using 3-amino-N- (3,5-dimethylphenyl)-4-methoxy-benzamide from Example 11 (0.542 g, 2.01 mmol) and 3-methylphenyl isothiocyanate (0.28 mL, 2. 07 mmol) to afford the product (0. 41 g); m. p. 188-189°C.

Calculated for C24H25N3O2S: C, 68.71; H, 6.01; N, 10.02, Found: C, 68.59; H, 5. 93; N, 9. 85.

EXAMPLE 104 N-(3-Chloro-4-methylphenyl)-3-[3-(3,5-dichlorophenyl)-thiour eido]- 4-methoxy-benzamide A solution of 3-amino-N- (3-chloro-4-methylphenyl)-4-methoxy- benzamide from Example 12 (0. 581 g, 2.00 mmol) and 3,5-dichlorophenyl isothiocyanate (0.409 g, 2.00 mmol) in dichloromethane (40 mL) and DMF (3 mL) was allowed to stand at room temperature. After 16 hours, filtration afforded the product (0.57 g); m. p. 195-196°C.

Calculated for C22H18N3o2Cl3S: C, 53.40; H, 3.67; N, 8.49.

Found: C, 53.13; H, 3.54; N, 8. 37.

EXAMPLE 105 N- (3, 4-Dichlorophenyl)-4-methoxy-3- [3- (4-sulfamoyl-phenyl)-thioureido]- benzamide Prepared according to the procedure described for Example 78 using 3-amino-N-(3,4-dichlorophenyl)-4-methoxy-benzamide from Example 39 (0.622 g, 2.00 mmol) and 4-isothiocyanatobenzenesulfonamide (0.428 g, 2.00 mmol). Filtration without trituration afforded the product (0.714 g); m.p. 190-193°C.

Calculated for C21H18N4O4S2Cl2: C, 48.00; H, 3.45; N, 10.66.

Found: C, 47.86; H, 3.64; N, 10.40.

EXAMPLE 106 3-[3-(3,5-Dichlorophenyl0-thioureido]-4-methylsulfanyl-N-phe nyl-benzamide A solution of 3-amino-N-phenyl-4-methylsulfanyl-benzamide from Example 20 (0.327 g, 1.27 mmol) and 3, 5-a'ichlorophenyl isothiocyanate (0.258 g, 1.26 mmol) in dichloromethane (50 nit) was briefly warmed to 40°C and then allowed to stand at room temperature. Mer 4 days, DMF (5 ml., ) was added and the mixture allowed to stand for 4 hours, then the solvent was removed in vacuo

and the residue mixed with water. Filtration afforded the product (0.3635 g); m. p. 172-175°C after trituration in ether.

Calculated for H2O:# C, 53.50; H, 3.85; N, 8.92.

Found: C, 53.48; H, 3.83; N, 8.86.

EXAMPLE 107 3-[3-(3,5-Dichlorophenyl)-thoureido]-N-(3,4-difluoro-phenyl) -4-methoxy- benzamide Prepared according to the procedure described for Example 60 using Example3-amino-N-(3,4-difluorophenyl)-4-methoxy-benzamidefro m 15 (0.834 g, 3.00 mmol) and 3,5-dichlorophenyl isothiocyanate (0.6124 g, 3.00 mmol) to afford the produit (1.206 g) in 3 cross; m. p. 180-183°C.

Calculated for C2lHl5N302F2Cl2S: C, 52.29; H, 3.13 ; N, 8.71.

Found: C, 52.02; H, 3.07; N, 8.61.

EXÅMPLE 108 N-(3-Chlorophenyl)-3-[3-(4-fluorophenyl)-thioureido]-4-metho xy-benzamide Prepared according to the procedure described for Example 100 using 3-amino-N-(3-chlorophenyl)-4-methoxy-benzamide from Example 16 (0.5545 g, 2.01 mmol) and 4-fluorophenyl isothiocyanate (0.3073 g, 2.01 mmol), and omitting the trituration in methanol to afford the product (0.775 g); m. p.

184-185°C.

Calculated for C2lHl7N302SFCI.

C, 58.67; H, 3.99; N, 9. 77.

Found: C, 58.51 ; H, 3.94; N, 9. 81.

EXAMPLE 109 3-[3-(3,5-Dichlorophenyl)-thioureido]-4-methoxy-N-phenyl- benzenesulfonamide A suspension of 3-amino-4-methoxy N-phenyl-benzenesulfonamide (0.4514 g, 1.62 mmol) in ethyl acetate was heated until a solution was obtained.

3,5-Dichlorophenyl isothiocyanate (0.3310 g, 1.62 mmol) was added and the mixture allowed to stand at room temperature. After 4 days, the rection was concentrated to 1/3 of its original volume and allowed to stand overnight. The solution was concentrated to an oil which was triturated with hexanes and the resulting solid filtered off, dried, and triturated in ether to afford the product (0.2275 g); m. p. 163-165°C.

Calculated for C20H17N303S2Cl2 ^ 0 67 H20: C, 48.58; H, 3.74 ; N, 8.50.

Found: C, 48.54; H, 3.70; N, 8. 21.

EXAMPLE 110 -Ethyl-n-phenyl-3-[3-(3-trifluoromethylphenyl0-thioureido]-b enzamide Prepared according to the procédure described for Example 78 using 3-amino-N-phenyl-4-ethyl-benzamide fromExample 17 (0.961 g, 4.00 mmol) and 3-(trifluormethyl) phenyl isothiocyanate (0. 82 g, 4.04 mol). Filtration without trituration afforded the product (1.4641 g); m. p. 166-167°C.

Calculated for C23H20N3OSF3 # 0. 43 EtOAc : C, 61.68; H, 4.91; N, 8.73.

Found: C, 61.67; H, 4.89; N, 8.73.

EXAMPLE 111 4-Ethyl-N-(3,4-difluorophenyl)-3-[3-(3-trifluoromethyl-pheny l)-thioureido]- benzamide Prepared according to the procedure described for Example 60 using 3-amino-N-3, 4-difluoro-phenyl)-4-ethyl-benzamide from Example 19 (1.5216 g, 5.51 mmol) and 3-(trifuloromethyl)phenyl isothiocyanate (1.12 g, 5.51 mmol) to afford the product (1.78 g); m. p. 169-170°Ce

Calculated for C23H18N3OSF5 # 0. 33 EtOAc: C, 57.44; H, 4.09; N, 8.26.

Found: C, 57.24; H, 3.94; N, 8.36.

EXAMPLE 112 3-{3-[2-Methoxy-5-(pyridiin-3-ylcarbamoyl)-phenyl]-thioureid o}-benzoicacid Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-pyridin-3-yl-benzamide from Example 5 (0.72 g, 3.0 mmol) and 3-carboxyphenyl isothiocyanate (0.53 g, 3. 0 mmol). Trituration in ethyl acetate then hot methanol gave the product (1.0 g); m. p. 191-192°C.

Calculated for C21H18N4O4S # 0. 66 CH30H C, 58.63; H, 4.70; N, 12.62.

Found: C, 58.54; H, 4.32; N, 12.98.

EXAMPLE 113 3-[3-(2-Methoxy-5-phenylcarbamoyl-phenyl)-thioureido]-benzoi cacid A mixture of 4-methoxy-3-amino-N-phenyl-benzamide (0.73 g, 3.0 mmol) and 3-carboxyphenyl isothiocyanate (0.54 g, 3.0 mmol) in ethyl acetate (60 mL) was warmed briefly to 50°C and then allowed to stand overnight at room temperature. The mixture was then rewarmed to 50°C, filtered, and concentrated to dryness. Trituration of the residue in ethyl acetate followed by filtration afforded the product m.p.196-197°C.g); Calculated for C22H19N3O4S : C, 62.69; H, 4.54; N, 9.97.

Found: C, 62.43; H, 4. 55; N, 9.83.

EXAMPLE 114 3,4-Dichloro-N-{4-fluoro-3-[3-(3-trifluoromethylphenyl)-thio ureido]-phenyl}- benzamide Prepared according to the procedure described for Example 60 using 3, 4-dichloro-N-93-amino-4-fluorophenyl)-benzamide from Example 22 (0.69 g,

2. 3 mmol) and 3-trifluoromethylphenyl isothiocyanate (0.47 g, 2.3 mmol) to afford the product (0.532 g); m. p. 172-174°C.

Calculated for C21H13Cl2F4N3OS: C, 50.21; H, 2.61 ; N, 8.37 Found: C, 50.30; H, 2. 63; N, 8.14.

EXAMPLE 115 3,4-Dichloro-N-{3-[3-(3,5-dichlorophenyl)-thioureido]-4-meth oxyphenyl}- benzamide Prepared according to the procedure described for Example 60 using 3, 4-dichloro-N-93-amino-4-methoxyphenyl)-benzamide from Example 23, Step B (0.72 g, 2.3 mmol) and 3,5-dichlorophenyl isothiocyanate (0. 47 g, 2.3 mmol) to afford the product (0.3 g) after chromatogrpahy on silica gel using hexane/ethyl acetate 3: 2 as eluant; m. p. 183-186°C.

Calculated for C21H15C14N302S C, 48.95; H, 2.93; N, 8. 16.

Found: C, 49.16; H, 3.18; N, 8,. 02.

EXAMPLE 116 3-(3,5-dichloro-benzenesulfonylamino)-4-methoxy-N-(3,4-diflu orophenyl)- benzamide A solution of 3-amino-4-methoxy-N-(3, 4-difluorophenyl)-benzamide from Example 15 (0.834 g, 3.00 mmol), 3, 5-dichlorobenzenesulfonyl chloride (0.736 g, 3.00 mmol) and a catalytic amount of 4-dimethylaminopyridine in pyridine (10 mL) was stirred under nitrogen at room temperature. After 16 hours, the solvent was removed in vacuo and the residue shaken with a mixture of ethyl acetate and 1N HCl then filtered. The layers were sequarated and the organic layer washed with brine, dried with MgSO4, concentrated to dryness, triturated in hexanes and filtered to afford a solid which was combine with that obtained in the filtration step to afford the product (1.38 g); m. p. 228-231°C.

Calculated for C20H14Cl2F2N204S C, 49.30; H, 2.90 ; N, 5.75.

Found: C, 48.61; H, 2.97; N, 5.58.

EXAMPLE 117 3-(3,5-Dichloro-benzenesulfonylamino)-4-methoxy-N-(3,4-dichl orophenyl)- benzamide Prepared according to the procedure described for Example 116 using 3-amino-4-methoxy-N-(3,4-dichlorophenyl)-=benzamide from Example 4 (0.932 g, 3.00 mmol), 3,5-dichlorobenzenesulfonyl chloride (0.737 g, 3.00 mmol) and 4-dimethylaminopyridine to afford the product (1. 53 g); m. p. >230°C (dec).

Calculated for C20H14Cl4N2O4S: C, 46.18; H, 2.71; N, 5.38.

Found : C, 47.02; H, 2.82; N, 5.37.

EXÅLE 118 3-(3,5-DIchloro-benzenesulfonylamino)-4-methoxy-n-phenyl-ben zamide Prepared according to the procedure described for Example 116 using 3-amino-4-methoxy-N-phenyl-benzamide (0.7296 g, 3.00 mmol), 3,5-dichlorobenzenesulfonyl chloride (0.7327 g, 3.00 mmol), and 4-dimethylaminopyridine to obtain the produit (1.01 g); m. p. 222-228°C.

Calculated for C20H16N2O4Cl2S: C, 53.23; H, 3. 57; N, 6.21.

Found: C, 53.23; H, 3.51; N, 6.11.

EXAMPLE 119 3-Methanesulfonylamino-4-methoxy-N- (394-dichlorophenyl)-benzamide Prepared according to the procedure described for Example 116 using 3-amino-4-methoxy-N-(3,4-dichlorophenyl)-benzamide from Example 4 (0.6117 g, 1.97 mmol) and methanesulfonic anhydride (0.2505 g, 1.44 mmol) for 7 rays. No product was obtained in the initial filtration step. Trituration in ethyl

acetate/hexane (1: 1) followed by recrystallization from ethyl acetate afforded the product (0.0639 226-228°C.m.p.

Calculated for C15H14N2O4SCl2: C, 46.28; H, 3.63; N, 7. 20.

Found: C, 46. 21; H, 3.66; N, 7.11.

EXAMPLE 120 3-Benzenesulfonylamino-4-mehtoxy-N-phenyl-benzamide A mixture of 3-amino-4-methoxy-N-phenyl-benzamide (0.9726 g, 4.00 mmol), triethylamine (0.56 mL. 4.02 mmol), and benzenesulfonyl chloride (0.51 mL, 4.00 mmol) in ethyl acetate (70 mL) was heated briefly to obtain a solution. The rection was stirred overnight at room temperature under nitrogen.

An additional equivalent of triethylamine and 1/2 equivalent of benzenesulfonyl chloride was added and the mixture heated to 50-60°C. After 7 hours, the solvent was removed in vacuo and the residue dissolve in ethyl acetate and washed with 1N HCl followed by saturated NaHC03. The organic layer was filtered, dried with MgSO4, and stripped of solvent by rotary evaporator. Trituration of the residue in hexane/ethyl acetate (4: 1) afforded the product (0.268 g); m. p.

190-194°C.

Calculated for C20H18N2O4S: C, 4.74;N,7.32.H, Found: C, 62.43; H, 4.86; N, 7.07.

EXAMPLE 121 <BR> <BR> <BR> <BR> 3-(4-Methoxy-benzenesulfonylamino)-4-methoxy-N-phenyl-benzam ide@<BR> <BR> <BR> <BR> <BR> A mixture of 4-methoxbenzenesulfonyl chlorid (2.21 g, 10.0 mmol), 3-amino-4-methoxy-n-phenyl-benzamide 92.43 g, 10.0 mmol) and pyridine (25 rnL) was allowed to stand at room temperature until thin layer chromatography indicated the reaction to be complets The mixture was then partitioned between water (400 mL, l acetate (400 mL). The layers were separated and the organic layer washed with water (2 x 400 rnL), 1N HCL (100 mL), and brine (100 mol), dried (magnesium sulfate), filtered and stripped of

solvent. Trituration of the residue in hexanes/ethyl acetate (1: 1) and filtration afforded the product (3.754 g); m. p. 184-186°C.

Calculated for C21H20N2O5S: C, 61.15 ; H, 4.89; N, 6.79.

Found: C, 61.20; H, 5.03; N, 6.78.

EXAMPLE 122 3-(3-Nitro-benzenesulfonylamino)-4-metholy-N-phenyl-benzamid e Prepared according to the procedure described for Example 121 using 3-nitrobenzenesulfonyl chloride (2.44 g, 10 mmol) and 3-amino-4-methoxy-N- phenyl-benzamide (2.43 g, 10.0 mmol) to afford the product (3.522 g); m.p.208-210°C.

Calculated for C20H17N306S: C, 56.20; H, 4. 01 ; N, 9.83.

Found: C, 56.43; H, 4.10; N, 9.81.

EXAMPLE 123 3-(3-Chloro-benzenesulfonylamino)-4-methoxy-n-phenyl-benzami de Prepared according to the procedure described for Example 121 using 3-chlorobenzenesulfonyl chloride (2.27 g, 10 mmol) and 3-amino-4-methoxy-N- phenyl-benzamide (2.43 g, 10.0 mmol) to afford the product (3.846 g); m.p. 197-199°C.

Calculated for C20H17ClN2O4S: C, 56.20; H, 4.01; N, 9oS3.

Found: C, 56.43; H, 4.10 ; N, 9.81.

EXAMPLE124 3-(4-Methyl-benzenesuflonylamino)-4-methoxy-N-phenyl-benzami de Prepared according to the procedure described for Example 121 using 4-methylbenzenesulfonyl chloride (2.06 g, 10 mmol) and 3-amino-4-methoxy-N- phenyl-benzamide (2.43 g, 10.0 mmol) to afford the product (3. 053 g); m.p. 200-202°C.

Calculated for C21H20N2O4S: C, 63.62; H, 5.08; N, 7.07.

Found: C, 63.43; X, 5.18; N, 6.86.

EXAMPLE 125 3-(4-Fluoro-benzenesulfonylamino)-4-methoxy-N-phenyl-benzami de Prepared according to the procedure described for Example 121 using 4-fluorobenzenesulfonyl chloride (2.14 g, 10 mmol) and 3-amino-4-methoxy-N- phenyl-benzamide (2.43 g, 10.0 mol) tao afford the product (3.522 g); m. p. 209-21 I'C.

Calculated for C20H17FN204S: C, 59.99; H, 4.28 ; N, 7.00 round: C, 59.96; H, 4.24; N, 6.87 EXAMPLE 126 3-(4,5-Dibromothiophene-2-sulfonylamino)-4-methoxy-n-phenyl- benzamide Pyridine (5 mL) was added to a mixture of 3-amino-4-methoxy-N-phenyl- benzamide (0.73 g, 3.0 mmol) and 2,3-dibromothiophene-5-sulfonyl chloride (1.0 g, 3.0 mmol) and stirred under an inert atmosphere at room temperature.

After 20 hours, the mixture was diluted with water (50 mL), acidifie with 4N HCl, and extracted with dichloromethane (2 x 50 mu). The insoluble material was filtered off and rinsed with water. The combine extracts were washed successively with 2N HCl, water, and saturated brine, then dried over MgSO4.

The solvent was removed under reduced pressure and the residue combine with the solid from above to afford the product (0.7 g), m. p. 205-210°C, after recrystallization from ethanol Calculated for C18H14Br2N2O4S2 # 0. 3 EtOH: C, 39.89; H, 2.58; N, 5.00. round: C, 40.26; H, 2.65; N, 5.18.

EXAMPLE 127 3-(2-Chlorobenzenesulfonylamino)-4-methoxy-n-phenyl-benzamid e Pyridine (5 mL) was added to a mixture of 3-amino-4-methoxy-N-phenyl- benzamide (0. 73 g, 3.0 mmol) and 2-chlorobenzenesulfonyl chloride (0.63 g, 3.0 mmol) and stirred under an insert atmosphere at room temperature. After 20 hours, the mixture was diluted with water (50 mL) and acidifie with conc. lHCl. After 2 hours, the mixture was extracted with dichloromethane (2 x 50 mL).

The combine extracts were washed successively with dilute aqueous HCl, water, and sat. brine then dried over MgSO4 and stripped of solvent under reduced pressure to afford the product (1.1 g), m. p. 107-1095C, after trituration in diethyl ether.

Calculated for C20H17ClN2O4S # 0.3 Ether: C, 57.99; H, 4.59; N, 6.38.

Found: C, 57.86; H, 4.65; N, 6.16.

EXAMPLE 128 3-(4-Trifluoromethyl-benzenesulfonylamino)-4-methoxy-n-pheny l- benzamide Pyridine (5 mu) vas added to a mixture of 4-trifluoro- methylbenzenesulfonyl chloride (0 73 g, 3.0 mmol) and 3-amino-4-methoxy-N- phenyl-benzamide (0.73 g, 3. 0 mmol) and stirred at room temperature. After 20 hours, the mixture was added to water (50 mL) acidified with 2N HCI, and stirred for an hour. The precipitate was filtered off, rinsed with water, and dried to afford the product (1.2 g); m. p. 197-198°C.

Calculated for C21H17F3N2O4S: C, 56.00; H, 3.80; N, 6.22.

Fonde C, 56. 01; H, 3.85; N, 6. 12.

EXAMPLE 129 3-(Butane-1-suflonylamino)-4-methoxy-n-phenyl-benzamide Prepared according to the procedure described for Example 128 using 1-butanesulfonhl chloride (0.47 g, 3.0 mol) ad 3-amino-4-methoxy-N-phenyl-

benzamide (0.73 g, 3.0 mmol) to afford the product (1.0 g); m. p. 182-183°C after recrystallization from ethanol.

Calculated for C18H22N2O4S : C, 59.65; H, 6.12; N, 7.73.

Found: C, 59.68; H, 6.09; N, 7.60.

EXAMPLE 130 3-(Quinoline-8-sulfonylamino)-4-methoxy-N-phenyl-benzamide Prepared according to the procedure described for Example 126 using 8-quinolinesulfonyl chloride (0.68 g, 3. 0 mmol) and 3-amino-4-methoxy-N- phenyl-benzamide (0. 73 g, 3.0 mol) po afford the product (1.0 g); m. p.

187-188°C after trituration in diethyl ether and recrystallization from ethanol.

Calculated for C23H19N3o4s C, 63.73; H, 4.42; N, 9.69.

Found: C, 63.68; H, 4. 40; N, 9.66.

EXAMPLE131 3-(2-Acetylamino-4-methylthiazole-5-sulfonylamino)-4-methoxy -N-phenyl- benzamide Prepared according to the procedure described for Example 126 using 2-acetamido-4-methyl-5-thiazolesulfonyl chlorlde (0.76 g, 3. 0 mmol) and 3-amino-4-methoxy-n-phenyl-benzamide (0.73 g, 3.0 mmol) to afford the product (0.7 g); m. p. 260-261°C after trituration in diethyl ether.

Calculated for C2oH2oN405S2: C, 52. 16; H, 4.38; N, 12.17.

Found: C, 52.15; H, 4.26; N, 11.87.

EXAMPLE 132 3-(2,5-Dichlorothiophene-3-sulfonylamino)-4-methoxy-n-phenyl -benzamide Prepared according to the procedure described for Example 127 using 2,5-dichlorothiophene-3-sulfonyl chloride (0.75 g, 3.0 mmol) and 3-amino- 4-methoxy-N-phenyl-benzamide (0.73 g, 3.0 mmol) to afford the product (0.9 g); m.p. 189-190°C.

Calculated for C1gH14C12N204s2e C, 47.27; H, 3.09; N, 6.13.

Found: C, 47.51; H, 3.04; N, 5. 91.

EXAMPLE 133 3-(Naphthalene-1-sulfonylamino)-4-methoxy-N-phenyl-benzamide Prepared according to the procedure described for Example 127 using 1-naphthalenesulfonyl chloride (0.68 g, 3.0 mmol), 3-amino-4-methoxy-N- phenyl-benzamide (0.73 g, 3.0 mmol), and ethyl acetate instead of dichloromethane to afford the product (0.8 g) ; m. p. 212-213°C.

Calculated for C24H20N2o42 C, 66.65; H, 4.66; N, 6.48.

Found: C, 66.48 ; H, 4.75; N, 6.35.

EXAMPLE 134 3-Ethanesulfonylamino-4-methoxy-N-phenyl-benzamide Prepared according to the procedure described for Example 121 using ethanesulfonyl chloride (1.5 mL, 15.8 mmol), 3-amino-4-methoxy-N-phenyl- benzamide (2.43 g, 10 mmol) and pyridine (25 mL) to afford the product (3.023 g); m. p. 175-177°C aEcer trituration in hexanes/ethyl acetate (1: 1).

Calculated for C16H1gN204S: C, 57e47; H, 5. 43; N, 8.38.

Found: C, 57.65; H, 5.37; N, 8.35.

EXAMPLE 13 5 3-Phenylmethanesulfonylamino-4-methoxy-n-phenyl-benzamide Prepared according to the procedure described for Example 121 using benzylsulfonyl chloride (1.90 g, 10 mmol), 3-amino-4-methoxy-N-phenyl- benzamide (2.43 g, 10 mmol), and pyridine (25 mL) to afford the product (2.5 g); m. p. 216-216°C after trituration in hexanes/ethyl acetate (1: 1).

Calculated for C21H20N2O4S2: C, 63.62; H, 5.08 ; N, 7.07.

Found: C, 63. 61 ; H, 5.00; N, 7.00.

EXAMPLE 136 3- (3, 4-Dichloro-benzenesulfonylamino)-4-methozy-N-phenyl-benzamid e Prepared according to the procedure described for Example 121 using 3,4-dichlorobenzenesulfonyl chloride (2. 45 g, 10 mmol), 3-amino-4-methoxy-N- phenyl-benzamide (2.43 g, 10 mmol) ana'pyridine (25 mL) to afford the product (4. 183 g); m. p. 191-193°C after trituration in hexanes/ethyl acetate (1: 1).

Calculated for C20H16Cl2N204S : C, 53.23; H, 3.57; N, 6. 21.

Found: C, 53.30; H, 3.48; N, 6.14.

EXAMPLE 137 3-(2,4-Difluoro-benzenesulfonylamino)-4-methoxy-N-phenyl-ben zamide Prepared according to the procedure described for Example 121 using 2, 4-difluorobenzenesulfonyl chloride (2.19 g, 10 mmol), 3-amino-4-methoxy-N- phenyl-benzamide (2.43 g, 10 mmol), and pyridine (25 mL) to afford the product (3.532 g); m. p. 198-200°C after trituration in hexanes/ethyl acetate (1: 1).

Calculated for C2oHl6F2N204S : C, 57.41; H, 3.85; N, 6. 70.

Found C, 57.52; H, 3.94; N, 6.65.

EXAMPLE 138 3-(Toluene-3-sulfonylamino)-4-methoxy-n-phenyl-benzamide Prepared according to the procedure described for Example 121 using (1.91g,10mmol),3-amino-4-methoxy-N-3-methylbenzenesulfonylch loride phenyl-benzamide (2.43 g, 10 mol), and pyridine (25 mL) to afford the product (3.587 g); m. p. 195-197°C after trituration in hexanes/ethyl acetate (1: 1).

Calculated for C21H20N2O4S: C, 63. 62; H, 5.08; N, 7.07.

Found: C, 63.63; H, 5.14; N, 6.96.

EXAMPLE 139 3-(4-Acetylamino-benzenesuflonylamino)-4-methoxy-N-phenyl-be nzamide Prepared according to the procedure described for Example 121 using (2.33g,10mmol),3-amino-4-methoxy-N-phenyl-N-acetylsufanilylc hloride benzamide (2.43 g, 10 mmol), and pyridine (25 mL) to afford the product (1.80 g); m. p. 250-251 °C after trituration in hexanes/ethyl acetate (1: 1).

Calculated for C22H21N3O5S: C, 60.12; H, 4. 82; N, 9.56. round: C, 60.04; H, 4.90; N, 9.47.

EXAMPLE 140 3-(Naphthalene-2-sulfonylamino)-4-metholy-N-phenyl-benzamide Prepared according to the procedure described for Example 121 using 2-napthalenesulfonyl chloride (2.28 g, 10 mmol), 3-amino-4-methoxy-N-phenyl- benzamide (2.43 g, 10 mmol), and pyridine (25 mL) to afford the product (4.139 g); m. p. 223-225°C after trituration in hexanes/ethyl acetate (1 ; 1).

Calculated for C24H20N3O5S: C, 66.65; H, 4.66; N, 6.48.

Found: C, 66.44; H, 4.55; N, 6.37.

EXEMPLE 141 3-(1-Methyl-1H-imidazole-4-sulfonylamino)-4-methoxy-N-phenyl -benzamide Pyridine (25 mL) was added to a mixture of 3-amino-4-methoxy-N- phenyl-benzamide (2.43 g, 10 mmol) and 1-methylimidazole-4-sulfonyl chloride (1.82 g, 10 mmol) and the mixture agitated then allowed to stand at room temperature. After 4 days, the mixture was partitioned between ethyl acetate (400 mL) and water (400 mol). The insoluble material was collecte by filtration, washed with water, and air dried. The organic extract was washed with water (2 x

400 mL), 1N HCl (100 mL)) and brine (100 mL), then dried over magnesium sulfate, filtered, and stripped of solvent. The residue was combine with the solid obtained above to afford the product (3.07 g); m. p. 250-252°C, after trituration in hexanes/ethyl acetate (1: 1).

Calculated for C18Hl8N405S: C, 55.95; H, 4.70; N, 14.50.

Found C, 55. 99; H, 4.74; N, 14. 53.

EXAWLE 142 3-(Thiophene-2-sulfonylamino)-4-methoxy-N-phenyl-benzamide Prepared according to the procedure described for Example 121 using 2-thiophenesulfonyl chloride (1.82 g, 10 mmol), 3-amino-4-methoxy-N-phenyl- benzamide (2.43 g, 10 mmol), and pyridine (25 mL) to afford the product (3.457 g); m. p. 180-183°C after trituration in hexanes/ethyl acetate (1: 1).

C18H16N2O4S2:Calculatedfor C, 55.65; H, 4.15; N, 7.21.

Found: C, 55. 80; H, 4. 13; N, 7.11.

EXAMPLE 143 3-(5-Dimethylaminonaphthalene-1-sulfonylamino)-4-methoxy-N-p henyl- benzamide Pyridine (5 mL) was added to a mixture of 3-amino-4-methoxy-N-phenyl- benzamide (0.73 g, 3.0 mmol) and dansyl chloride (0.81 g, 3.0 mmol) and stirred under an inert atmosphere at room temperature. Mer 20 hours, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combine extraits were washed with water then saturated brine, then dried over MgSO4 and stripped of solvení under reduced pressure to afford the product m.p.231-232°C.(1.3g); Calculated for C26H25N304S : H,5.30;N,8.84.C,65.67; Found: C, 65.44; H, 5. 29; N, 8.69.

EXAMPLE 144<BR> <BR> <BR> <BR> <BR> <BR> 2-Methoxy-5-phenylcarbamoyl-carbonic acid-phenyl ester phenyl ester A solution of phenyl chlorogformate (0.75 g, 4.8 mmol) in tetrahydrofuran (8 mL) was added dropwise to a stirred solution of 3-hydroxy-4-methoxy-N- phenyl-benzamide (1.1 g, 4.5 mmol) and 1,4-diazabicyclooctane (0.5 g, 4.5 mmol) in tetrahydrofuran (90 niL) under an inert atmosphere at ice bath temperature. The mixture was allowed to warm gradually to room temperature. After 20 hours, additional diazabicyclooctane (0.6 g, 5.3 mmol) and phenyl chloroformate (0.75 g, 4.8 mmol) were added and the mixture heated to reflux. After 20 hours, the mixture was stirred into ice water and extracted with ethyl acetate (2 x 75 mL).

The combine extracts were washed successively with water, ice-cold 1N HCl, 2N K2CO3, and saturated brine then dried over MgSO4. The solvent was removed under reduced pressure and the residue recrystallized from ethanol to afford the product (0.7 g); m. po 152-153°C.

Calculated for C2lHl7NO5: C, 69.41; H, 4.72; N, 3.85.

Found: C, 69. 14; H, 4.59; N, 3.91.

AMPLE 145 4-Hydroxy-3-phenylamino-N-phenyl-benzmaide Boron tribromide-dimethyl sulfide complex (3. 1 g, 9.9 mmol) was added to a stirred suspension of 4-methoxy-3-phenylamino-N-phenyl-benzamide from Example 28 (0.9 g, 2.8 mmol) in 1, 2-dichloroethane (50 mL) under an inert atmosphere, and the mixture heated to reflux. After 1.5 hours, the mixture was allowed to cool and was poured into water (125 mL) and extracted with dichloromethane (2 x 75 mL). The combinez extracts were washed with water, then saturated brine, and dried over MgSOq,. The solvent was removed under reduced pressure and the residue dissolve in ethyl acetate and filtered through a short colurnn of silica gel. The filtrate was stripped of solvant and the residue recrystallized from toluene to afford the product (0.3 g); m. p. 158-159°C.

Calculated for C19H116N2O2: C, 74.98; H, 53.0 ; N, 9.20.

Found: C, 74.48; H, 4.95; N, 8.82.

EXEMPLE 146 (Intermediate) 3-Amino-4-trifluoronaethoxy-N- (4-fluoxo-phenyl)-benzamide Step A: 3-Nitro-4-trifluoromethoxybenzoic Acid A suspension of 4-trifluoromethoxybenzoic acid (TCI, Portland, OR) (1.0 g, 4.9 mmol) in concentrated sulfuric acid (3 mL) was stirred under an inert atmosphere at room temperature until a solution was obtained. Fuming nitric acid (1 mL) was added dropwise. After 20 hours the mixture was poured into water (100 mL) and stirred. After an hour the precipitate was filtered off, rinsed with water and dried to afford the product (0.8 g); m. p. 137-139°C.

Calculated for C8H4F3NO5: C, 38.26; H, 1.61; N, 5.58.

Found: C, 37.89; H, 1.63; N, 5.54.

Step B: 3-Amino-4-trifluoromethoxy-N-(4-tluorophenyl)-benzamide Prepared according to the procedure described for Example 1 using 3-nitro-4-trifluoromethoxybenzoic acid from Step A 1(5. g, 20.5 mol), oxalyl chloride (2.1 mL, 20.5 mmol), and 4-fluoroaniline (Aldrich, Milwaukee, WI) (4.6 g, 41. 1 mmol) to afford the product (5.7g); m. p. 139-140°C.

Calculated for C14H10F4N2°2 : C, 53. 51; H, 3.21; N, 8. 91.

Found: C, 53.34; H, 3.20; N, 8.80. <BR> <BR> <BR> <BR> <BR> <BR> <P> EXAPLE 147 (Intermediate)<BR> <BR> <BR> <BR> <BR> 3-Amino-4-trifluoromethoxy-N-phenyl-benzamide The title compound has been made using the procedure of Example 146, but using 4-trifluoromethoxybenzoic acid and aniline as starting materials, which are commercially available from TCI and Xdrich; m. p. 160-162°C.

EXAMPLE 148 3-(3-Amino-4-methoxy-benzoylamino)-benzoic acid ethyl ester The title compound has been made using the procedure of Example 1, but using 3-amino-4-methoxybenzoic acid and ethyl 3-aminobenzoate as starting materials, which are commercially available from Aldrich; m. p. 144-146°C.

EX-AMPLE 149 3- (3-Amino-4-methoxy-benzoylaanino)-benzoic acid methyl ester Step A: 3-(3-Nitro-4-methoxy-benzoylamino)-benzoic acid methyl ester 4-Methoxy-3-nitrobenzoic acid (5.0 g, 25 mmol) was added to thionyl chloride (20 mL) under an inert atmosphere and stirred and heated to reflux. After 2 hours the mixture was stripper to dryness by rotary evaporator, and 2 portions of benzene were successively mixed with then stripped from the residue to leave a solid. This residue was dissolve in tetrahydrofuran (20 mL) and added dropwise to a stirred solution of methyl 3-aminobenzoate (3.83 g, 25 mmol) and pyridine (2 mL) cooled in an icebath. The mixture was allowed to warm to room temperature following the addition, then the solvent was removed under reduced pressure. The residue was suspende in 1N HCl, stirred, filtered off, and washed successively with IN HCI, 1N NaHCO3 (2X), and water (2X). The resulting solid was boiled briefly in methanol (500 mL)then allowed to cool. Filtration afforded the product (8.0 g) ; m. p. 233-235°C, in sufficient purity for the next step.

STEP B: 3-(3-Amino-4-methoxy-benzoylamino)-benzoic acid methyl ester Raney nickel (1 g) was added to a solution of 3- (3-nitro-4-methoxy- benzoylamino)-benzoic acid methyl ester from Step A (4.0 g, 12 mmol) in dimethylformamide (125 mL) and shaken at room temperature under an atmosphere of hydrogen, initially at a pressure of 50 psi, until the required amount was taken up. The catalyst was removed by filtration and the filtrate was stripped of solvent by rotary evaporator. Recrystallization of the residue from methanol (150 mL) gave the product (2.3 g); m. p. 160-162°C.

Calculated for C16H16N2O4: C, 63.99; H, 5.37; N, 9.33.

Found: C, 63.96 ; H, 5.47; N, 9.29.

EXAMPLE 150 3s4-Difluoro-N-(3-amino-4-methoxy-pherlyl)-benzamide The title compound has been made using the procedure of Example 23, but using 3, 4-difluoro-N-(3-nitro4-fluoro-phenyl)-benzamide from the preparation of Example 151 as a starting material; m.p. 1480-151°C.

EXAMPLE 151 3, 4-Di£Iuoro-N- (3-amino-4-fuoro-phen)-benzamide The title compound has been made using the procedure of Example 22, but using 4-fluoro-3-nitroaniline and 3,4-difluorobenzoyl chloride as starting materials, which are commercially available from Aldrich; m. p. 135-142°C.

EXAMPLE 152 1-(3-Amino-4-methoxy-phenyl)-3-(3,(3-Amino-4-methoxy-phenyl) -3-(3, 4-dichloro-phenyl)-urea The title compound has been made using the procedure of Example 24, but using 3,4-dichlorophenyl isocyanate as a starting material, which is commercially available from Aldrich; m. p. 202-204°C EXEMPLE 153 3-(4-Fluoro-phenylamino)-4-methoxy-N-phenyl-benzamide The title compound has been made using the procedure of Example 25, but using 3-amino-4-metthoxy-N-phenyl benzamide (Aldrich) and tris (4- fluorophenyl) bismuthane as starting materials; m. p. 178-180°C.

EXAMPLE 154 3-(3,5-Dichloro-phenylamino-4-methoxy-N-(4-fluoro-phenyl)-be nzamide Copper (II) acetate (0.5 g, 2.8 mmol) was added to a stirred mixture of 3-amino-4-methoxy-N-(4-fluoro-phenyl)-benzamide from Example 8 (0.7 g, 2.7 mol), 3,5-dichloro-benzene boronic acid (Lancaster Synthesis, Ltd.,

Lancashire, UK) (1.0 g, 5.2 mmol), triethylamine (0.88 g, 8.6 mmol), and ~2 g of ground 4A molecular sieves in dichloromethane (50 mL) and stirred at room temperature in a flask fitted with a drying tube. After 18 hours the mixture was filtered, the residue was rinsed with dichloromethane and the filtrate stripped of solvent under reduced pressure. The residue was chromatographed on a column of silica gel in CHC13/EtOAc (9: 1) to afford a crystalline solid which was triturated in ether, filtered off and dried to afford the product (0.13 g); m. p. 220°C.

Calculated for C20H15C12FN2°2 C, 59.28; H, 3.73; N, 6.91.

Found: C, 58.44; H, 3.69; N, 6.57.

EXÅMPLE 155 3-(4-Fluoro-phenylamino)-4-methoxy-N-(4-fluoro-phenyl)-benza mide The title compound has been made using the procedure of Example 25, but using the title compound of Example 8 as a starting material; m. p. 193-194°C.

EXEMPLE 156 3-[4-Methoxy-3-(3-triflurormethyl-phenylamino)-benzoylamino] -benzoic acid methyl ester The title compound has been made using the procedure of Example 25, but using the title compound of Example 149 as a starting material; m. p. 128-129°C.

EXAMPLE 157 3- [4-Methoxy-3- (3-trifluoromethyl-phenylamino)-benzoylaminol-benzoic acid ethyl ester The title compound has been made using the procedure of Example 25, but using the title compound of Example 148 as a starting material; m. p. 169-170°C.

EXÅMPLE 158 <BR> <BR> <BR> <BR> 4-Trifluoromethoxy-3- (3-trifluoromethyl-phenylamino)-N-phenyl-benzamide The title compound has Ibeen made using the procedure of Example 25, but using the title compound of Example 147 as a starting material ; m. p. 129-130°Ce

EXAMPLE 159<BR> <BR> <BR> <BR> 4-T"rifluoromethoxy-3- (3-trifluoromethylphenylaminoj-N- (4-fluoro-phenyl)- benzamide The title compound has been made using the procedure of Example 25, but using the title compound ofExample 146 as a starting material; m. p. 143-144°C.

EXAMPLE 160 3,4-Dichloro-N-[4-methoxy-3-(3-trifluoromethyl-phenylamino)- phenyl]- benzamide The title compound has been made using the procedure of Example 25, but using the title compound of Example 23 as a starting material; m. p. 151-152°C.

EXEMPLE 161 3- [3- (2-Methoxy-5-phenylcarbamoyl-phenyl)-thioureido]-benzoic acid methyl ester The title compound has been made usinez the procedure of Example 60, but using 3-amino-4-methoxy-N-phenyl benzamide and 3-carbomethoxyphenyl isothiocyanate as starting materials, which are commercially available from Aldrich or Trans World Chemicals, Inc.) GRockville, MD; m. p. 178-180°C.

EXAMPLE 162 3-{3-[5(3,4-Difluoro-phenylcarbamoyl)-2-methoxy-phenyl]-thio ureido}- benzoic acid The title compound has been made using the procedure of Example 113, but using the title compound of Example 15 as a starting material; m. p. 221- <BR> <BR> <BR> 222 C r<BR> <BR> <BR> <BR> <BR> <BR> <BR> EXEMPLE 163 3-[3-(3,5-Dichloro-phenyl)-thioureido]-4-trifluoromethoxy-N- (4-fluoro- phenyl)-benzamide A mixture of 3-amino-4-trifluoromethoxy-N- (4-fluoro-phenyl)-benzamide from Example 146 (0.292 g, 0.92 mmol) and 355-dichloro-phenyl isothiocyanate (Lancaster) (0.191 g, 0.93 mmol) was allowed to stand in ethyl acetate (25 mI.,)

two days at room temperature. Concentration to dryness and trituration with hexanes/ethyl acetate (4: 1) followed by thin layer chromatography revealed no rection had taken place. More 3,5adichlorophenyl isothiocyanate (0.23 g, 1. 13 mmol) was added, and the neat rection mixture was heated on a steam-bath.

Ethyl acetate (25 mL) was added and boiled to dryness. Trituration with hexanes/ethyl acetate (1: 1) gave the product (0.120 g); m. p. 165-166°C.

Calculated for C21H13Cl2F4N3O2S : C, 48.66; H, 2.53 ; N, 8.11.

Found: C, 48.44; H, 2.45; N, 7.89.

EXAMPLE 164 <BR> <BR> <BR> <BR> 3- 3- (3-Trifluoromethyl-phenyl-thioureidol-4-trifluoro-methoxy-N- (4-fluoro- phenyl)-benzamide A mixture of 3-trifluoromethylphenyl isothiocyanate (Trans World) (0.35 g, 1.7 mmol) and 3-amino-4-trifluoromethoxy-N-(4-fluoro-phenyl)- benzamide from Example 146 (0.5 g, 1.6 mmol) in ethyl acetate (25 rnL) was stirred under an inert atmosphere at room temperature for 40 hours then heated to reflux. After 15 hours an additional amount (0.35 g, 1.7 mmol) ofthe isothiocyanate was added and the mixture stirred at room temperaturee After several days the mixture was concentrated on a steambath to a thick oil. Upon cooling the residue partially crystallized, and was triturated in hexane then allowed to stand overnight. Filtration afforded a solid which was chromatographed on silica gel in CHCl3/EtOAc (9: 1) to afford the product (0.39 g); m. p. 153-154°C.

Calculated for C22H14F7N3O2S: C, 51.07; H, 2.73; N, 8. 12.

Found: C, 51. 41; H, 2.97; N, 7.92.

EXANIPLE 165 4-{3-[5-(3,4-Difluoro-phenylcarbamoyl)-2-methoxy-phenyl]-thi oureido}- benzenesulfonic acid, sodium salt

The title compound has been made using the procedure of Example 82, but using the title compound of Example 15 as a starting material; m. p. >280°C.

EXAMPLE 166 4-{3-[5-(4-Fluoro-phenylcarbamoyl)-2-methoxy-phenyl]-thioure ido}-benzoic acid The title compound has been made using the procedure of Example 113, but using the title compound of Example 8 as a starting material; m. p. 203-205°C.

EXÅWLE 167 3-{3-[5-(4-Fluoro-phenylcarbamoyl)-2-methoxy-phenyl]-thioure ido}-benzoic acid The title compound has been made using the procedure of Example 113, <BR> <BR> <BR> but using the title compound of Example 8 as a starting material; m.p. 218-220°C.<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> EXAMPLE 168<BR> <BR> <BR> <BR> <BR> <BR> 4-13- [5- (3, 4-Difluoro-benzoylamino)-2-methoxy-phenyll-thioureidol-benzo ic acid The title compound has been made using the procedure of Example 102, but using the title compound of Example 150 as a starting material; m. p. 200- 203°C.

EXAMPLE 169 <BR> <BR> <BR> <BR> 3-13- [5- (3, 4-Difluoro-benzoylamino)-2-methoxy-phenyll-thioureido)-benzo ic acid The title compound has been made using the procedure of Example 102, but using the title compound of Example 150 as a starting material; m. p. 218- 220°C.

EXAMPLE170 N-{3-[3-(3,5-Dichloro-phenyl)-thioureido]-4-fluoro-phenyl}-3 ,4-difluoro- benzamide

The title compound has been made using the procedure of Example 113, but using the title compound of Example 151 as a starting material; m. p. 197°C.

EXAMPLE 171 <BR> 1- (3, 4-Dichloro-phenyl)-3-13- [3- (3, 5-dichloro-phenyl)-thioureido]-4-methoxy-<BR> phenyl} urea The title compound has been made using the procedure of Example 102, but using the title compound of Example 152 as a starting material; m. p. 202°C.

EXAMPLE 172 3-(3-{5-[3-(3,4-Dichloro-phenyl)-ureido]-2-methoxy-phenyl}-t hioureido)- benzoic acid methyl ester The title compound has been made using the procedure of Example 102, but using the title compound of Example 152 as a starting material; m. p. 193- 194°C.

EXAMPLE 173 3- (3- {5- [3- (3, 4-Dichloro-phenyl)-ureido-2-methogy-phenyl-thioureido)- benzoic acid The title compound has been made using the procedure of Example 102, but using the title compound of Example 152 as a starting material; m. p. 209- 211°C.

EXAMPLE 174 1-{3-[3-(3,5-Bis-trifluoromethyl-phenyl)-thioureido]-4-metho xy-phenyl}-3- (3,4-dichloro-phenyl)-urea The title compound has been made using the procedure of Example 113, but using the title compound of Example 152 as a starting material; m. p. 181°C.

EXAMPLE 175 1-{3-[3-(4-Chloro-3-nitro-phenyl)-thioureido]-4-methoxy-phen yl}-3-3,4- dichloro-phenyl)-urea

The title compound has been made using the procedure of Example 113, but using the title compound of Example 152 as a starting material; m. p. 162- 170°C.

EXAMI'LE 176 <BR> <BR> <BR> <BR> <BR> <BR> 3- [3- (3, 5-Dichloro-phenyl)-thioureidoj-4-methoxy-benzoic acid benzyl ester Step A: 4-Methoxy-3-nitro-benzoic acid benzyl ester The acid chloride prepared as in Example 1, Step A (15.07g, 162 mmol) was dissolve in tetrahydrofuran (150 mL, and 2.0 M benzylmagnesium chloride in tetrahydrofuran was added te thé rapidly stirred solution. Cafter 1 hour the rection was quenched with saturated aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate (700 mL), the layers were separated, the organic layer washed with 1N potassiurri hydroxide and brine, dried (magnesium sulfate), filtered and concentrated to leave an oil. The oil was filtered through silica gel using ethyl acetate as eluant and the nonpolar fractions were chromatographed 2 times on silica gel in hexanes/ethyl acetate, first (1: 1), then (4: 1). Concentration of the eluant followed by trituration with hexanes and a little ethyl acetate afforded the product (1.655 g).

Calculated for C15H13NO5: C ; 62.27; H, 4.56; N, 4.88.

Found: C, 62.15; H, 4.46; N, 4. 75.

Step B: 3-Amino-4-methoxy-benzoic acid benzyl ester The product from Step A (1.52 g, 5.3 mmol) was reacted according to the procedure for Example 9, Step B to give the product (1.05 g) as an oil.

Calculated for C15Hl5NO3 : C, 70.02; H) 5.88; N, 5. 44.

Found: C, 70.22; H, 5.96; N, 5.3 1.

Step C: 3-[3-(3,5-Dichloro-phenyl)-thioureido]-4-methoxy-benzoic acid benzyl ester The product from Step B (0.1405 g, 0fi55 mmol) was reacted according to

the procedure for Example 60 with 3,5-dichlorophenyl isothiocyanate (0.128 g, 0.88 mmol) to give the product (0.214 g); m. p. 144-145°C.

Calculated for C22Hl8Cl2N2o2S: C, 57.27; H, 3.93; N, 6. 07.

Found: C, 57.32; H, 4.09; N, 5.84.

EXAMI'LE 177 3-(Dodecane-1-sulfonylamino)-4-methoxy-N-phenyl-benzamide The title compound has been made using the procedure of Example 126, but using 3-amino-4-methoxy-N-phenyl benzamide and 1-dodecanesulfonyl chloride as starting materials, which are commercially available from Aldrich and Alfa; m. p. 156-157°C.

EXAAVLE 178 4-Methoxy-3-(octane-1-sulfonylamino)-N-phenyl-benzamide The title compound has been made using the procedure of Example 127, but using 3-amino-4-methoxy-N-phenyl benzamide and 1-octanesulfonyl chloride as a starting material, which are commercially available from Aldrich and Lancaster; m. p. 154-155°C.

EXAMPLE179 3- (Decane-1-sulfonylamino)-4-anethoxy-N-pheny-benzamide The title compound has been made using the procedure of Example 128, but using 3-amino-4-methoxy-N-phenyl benzamide and 1-decanesulfonyl chloride as starting materials, which are commercially available from Aldrich and Lancaster; m. p. 160-161°C.

EXAMPLE180 3-(3-Nitro-benzenesufonylamino)-4-methoxy-N-(3,4-difluoro-ph enyl)- benzamide The title compound has been made using the procedure of Example 121, but using the title compound of Example 15 as a starting material; m. p. 220- 222°C.

EXAMPLE 181 3,5-Dichloro-N-{5-[3,(3,4-dichloro-phenyl)-ureido]2-methoxy- phenyl}- benzenesulfonamide The title compound has been made using the procedure of Example 121, but using the title compound of Example 4 as a starting material; m. p. 225-227°C.

EXAMPLE 182 3-(1-Methylethyl-1-sulfonylamino)-4-methoxy-N-phenyl-benzami de The title compound has been made using the procedure of Example 121, but using 3-amino-4-methoxy-N-phenyl benzamide and isopropylsulfonyl chloride as a starting material) which are commercially available from Aldrich; m. p. 135-140°C.

EXANIPLE 183 4- (2-Methoxy-5-phenylearbamoyl-phenyisulfamoyl)-benzoic acid The title compound has been made usinez the procedure of Example 121, but using 3-amino-4-methoxy-N-phenyl benzamide and 4-carboxybenzenesulfonyl chloride as starting materials, which are commercially available from AIdrich; m. p 212-214°C.

EXÅMPLE 184 3-(Octadecane-1-sulfonylamino)-4-methoxy-N-phenyl-benzamide The title compound has been made using the procedure of Example 121, but using 3-amino-4-methoxy-N-phenyl benzamide and 1-octadecanesulfonyl chloride as starting materials, which are commercially available from Aldrich and 154-156°C.Lancaster,m.p.

EXAMPLE 185 3-(3-Amino-benzenesulfonylamino)-4-methoxy-N-(3,4-difluoro-p henyl)- benzamide The title compound has been made using the procedure of Example 9, but using the title compound of Example 180 as a starting material; m. p. 212-214°C.

EXAMPLE 186 4-Methoxy-3-(4-nitro-benzenesulfonylamino)-N-(3,4-difluoro-p henyl)- benzamide The title compound has been made using the procedure of Example 121, but using the title compound of Example 15 as a starting material; m. p. 234- 236°C.

EXAMPLE 187 3-(4-Cyano-benzenesulfoylamino)-4-methoxy-N-(3,4-difluoro-ph enyl)- benzamide The title compound has been made using the procedure of Example 121, but using the titre compound of Example 15 as a starting material; m. p. 228- 230°C.

EXEMPLE 188 4-Methoxy-3-(4-nitro-benzenesulfonylamino)-N-phenyl-benzamid e The title compound has been made using the procedure of Example 121, but using 3-amino-4-methoxy-N-phenyl benzamide and 4-nitrobenzenesulfonyl chloride as starting materials, vvhich are commercially available from Aldrich; m.p. 224-227°C. <BR> <BR> <P> EXAMPLE 189<BR> 3- (3-Cyano-benzenesulfonylamino)-4-methoxy-N- (4-fluoro-phenyl)- benzamide The title compound has been made using the procedure of Example 121, but using the title compound of Example 8 as a starting material; m. p. 221-225°C.

EXAMPLE 190 4-Methoxy-3-(3-nitro-benzenesulfonylamino)-N-(4-fluoro-pheny l)-benzamide The title compound has been made using the procedure of Example 121, but using the title compound of Exampie 8 as a starting material; m. p. 221-240°C.

EXAMPLE 191 <BR> <BR> <BR> <BR> 4-lVIethoxy-3- (4-nitro-benzenesulfonylamino)-N- (4-fluoro-phenyl)-benzamide The title compound has been made usinez the procedure of Example 121, but using the title compound ofExample 8 as a starting material; m. p. 208-211°C.

EXAMPLE 192 3-(4-Cyano-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamid e The title compound has been made using the procedure of Example 121, but using 3-amino-4-methoxy-N-phenyl benzamide and 4-cyanobenzenesulfonyl chloride as starting materials, which are commercially available from Aldrich or Maybridge Chemical Company. Ltd., Cornwall, UK; m. p. 206-208°C.

EXEMPLE 193 3- (4-Cyano-6enzenesulfonylamano)-4-methogy-T- (4-fluoro-phenyl)- benzamide The title compound has been made using the procedure of Example 121, but using the title compound of Example 8 as a starting material; m. p. 131-135°C.

EXAMPLE 194 <BR> <BR> <BR> 3-(Dodecane-1-sulfonylamino)-4-methoxy-N-(3,(Dodecane-1-sulf onylamino)-4-methoxy-N-(3, 4-dichloro-phenyl)-benzamide Pyridine (5 mL) was added to a mixture of 1-dodecane-sulfonyl chloride (Maybridge) (0.8 g, 3.0 mmol) and 3-amino-4-methoxy-N- (3,4-dichloro-phenyl)- benzamide from Example 4 (0.73 g, 3.0 mmol) and stirred at room temperature.

After 5 days the mixture was heated on a steambath for 1.5 hours, allowed to cool, and added to water (150 mL), acidifie with 4N HCI, and stirred for an hour. The precipitate was filtered off, rinsed with water then with ethanol and dried to afford the product (1.3 g); m. p. 151-152°C after recrystallization from ethanol and chromatography on silica gel in CHCl3/EtOAc (9: 1).

Calculated for C26H36Cl2N2O4S: C, 57.45; H, 6.68; N, 5.15.

Found: C, 57.68; H, 6.67; N, 4.90.

EXAMPLE 195<BR> 3-(3-Cyano-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamid e The title compound has been made using the procedure of Example 121, but using 3-amino-4 methoxy-N-phenyl benzamide and 3-cyanobenzenesulfonyl chloride as starting materials, which is commercially available from Aldrich or hIaybridge; m. p. 195-197°C.

EXEMPLE 196 3,4-Dichloro-N-[4-methoxy-3-(4-methoxy-benzenesulfonylamino) -phenyl]- benzamide The title compound has been made using the procedure of Example 121, but using the title compound of Example 23 as a starting material; m. p. 225- 227°C.

EXAMPLE 197 3,4-Dichloro-N- [4-methoxy-3- (toluene-4-sulfonylamino)-phenyll-benzamide The title compound has been made using the procedure of Example 121, but using the title compound of Example 23 as a starting material; m. p. 228- 230°C.

EXAMPLE 198 3,4-Dichloro-N-[4-methoxy-3-(3-amino-benzenesulfonylamino)-p henyl]- benzamide The title compound has been made using the procedure of Example 121/9B, but using the title compound of Example 150 as a starting material; m. p.

205-209°C.

EXAMPLE 199 3,4-Dichloro-N-[4-methoxy-3-(4-amino-benzenesulfonylamino)-p henyl]- benzamide The title compound has been made using the procedure of Example 121/9B, but using the title compound of Example 150 as a starting material; m. p.

229-231°C.

EXAMPLE 200 3,4-Difluoro-N- [4-methoxy-3- (I-dodecane-sulfonylamino)-phenyl]-benzamide The title compound has been made using the procedure of Example 143, but using the title compound of Example 150 as a starting material; m. p. 132°C.

EXAMPLE 201 3,4-Dichloro-N-[4-methoxy-3-(chloromethyl-sufoylamino)-pheny l]- benzamide The title compound has been made using the procédure of Example 143, but using the title compound of Example 150 as a starting material; m. p. 191- 193°C.

EXAMPLE 202 3,4-Difluoro-N- [4-methoxy-3- (4-nitro-benzenesulfonylamino)-phenyl]- benzamide The title compound has been made using the procedure of Example 121, but using the title compound of Example 150 as a starting material; m. p. 231- 249°C.

EXAMPLE 203 3,4-Dichloro-N-[4-methoxy-3-(3-nitro-benzenesulfonylamino)-p henyl]- benzamide The title compound has been made using the procedure of Example 121, but using the title compound of Example 150 as a starting material; m. p. 150- 160°C.

EXEMPLE 204 3,4-Difluoro-N-[3-(4-cyano-benzenesulfonylamino)-4-methoxy-p henyl]- benzamide The title compound has been made using the procedure of Example 121, but using the title compound of Example 150 as a starting material; m. p. 255- 257°C.

EXAMPLE 205 3,4-Difluoro-N-[3-(3-cyano-benzenesulfonylamino)-4-methoxy-p henyl]- benzamide The title compound has been made using the procedure of Example 121, but using the title compound of Example 150 as a starting material; m. p. 212- 214°C.

EXAMPLE206 3,4-Difluoro-N-[4-fluoro-3-(thiphene-2-sulfonylamino)-phenyl ]-benzamide The title compound has been made using the procedure of Example 121, but using the title compound of Example 151 as a starting material; m. p. 202- 203°C.

EXAMPLE 207 Thiophene-2-sulfonic acid {5-[3-(3,4-dichloro-phenyl)-ureido]-2-methoxy- phenyl}-amide The title compound has been made using the procedure of Example 143, but using the title compound of Example 152 as a starting material; m. p. 205- 208°C.

EXAMPLE 208 3-(3,5-Dichloro-benzenesulfonylamino)-4-methoxy-N-phenl-thio benzamide A mixture of 3-(3, 5-dichloro-benzenesulfonylamino)-4-methoxy-N- phenyl-benzamide from Example 118 (3. 61 g, 8. 0 mmol) and Lawesson's reagent (3.57 g, 8.8 mmol) was stirred at room temperature overnight in tetrahydrofuran (250 mL). The rection mixture was warmed tu 50 C for about one hour, then to 65°C for about 4 hours then stirred at room temperature overnight. The mixture was concentrated to dryness and the residue dissolve in ethyl acetate and filtered through silica gel. Concentration of the eluant followed by trituration in hexanes/ethyl acetate (1: 1) afforded the crude product (3.06 g). A portion (0.8 g) of this was chromatographed on silica gel in hexanes/ethyl acetate (1: 1) to afford a pure sample (0.324 g); m. p. 206-208°C.

Calculated for C2oHl6cl2N2o3s2 C, 51.40; H, 3.45; N, 5.99.

Found: C, 51 40; H, 3.66; N, 5.54.

EXAMPLE 209 3,5-Dichloro-2-N-(2-methoxy-5-phenylaminomethyl-phenyl)- benzenesulfonamide A mixture of 3-(3, 5-dichloro-benzenesulfonylamino)-4-methoxy-N- phenyl-thiobenzamide from Example 208 (1. 0 g, 2.1 mmol) and Raney Nickel (21 g) in ethanol (80 mL) was stirred at 50 degrees for 1.5 hours and then for 3 days at room temperature. The rection mixture was filtered through Celite, concentrated to dryness, dissolve in ethyl acetate/methanol/tetrahydrofuran, filtered and concentrated to an Oilo The oil was filtered through silica gel twice, first in hexanes/ethyl acetate (3: then in hexanes/ethyl acetate (85: 15).

Concentration of the eluant followed by trituration in hexanes/ethyl acetate gave the product 8/31/9811/6/98 (0.100 g); m. p. 105-108°C.

Calculated for C20H18Cl2N2O3S: C, 54.93; H, 4.15; N, 6.41.

Found: C, 55.40; H, 4.23; N, 6.30.

EXAMPLE210 3-(3-Hydroxy-benzylamino)-4-methoxy-N-(3,4-difluoro-phenyl)- benzamide The title compound has been made using the procedure of Example 50, but using the title compound ofExample 15 as a starting material; m. p. 160-163°C.

EXAMPLE 211 3-(4-Diethylamino-benzylamino)-4-methoxy-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzaznide and 4-diethylaminobenzaldehyde as starting materials, which are commercialy available from Aldrich; m. p. 180- 181°C.

EXAMPLE 212 3-(3-Fluoro-benzylamino)-4-methoxy-N-(3,4-difluoro-phenyl)-b enzamide The title compound has been made using the procedure of Example 50, but using the title compound of Example 15 as a starting materiall72-174°C.

EXAMPLE 213 3-(3-Hydroxy-benzylamino)-4-methoxy-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 3-hydroxybenzaldehyde as starting materials, which are commercially available from Aldrich; m. p. 168- 170°Cv<BR> <BR> EXAMPLE 214 4-Methoxy-3-(3-fluoro-benzylamino)-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 3-fluorobenzaldehyde as starting materials, which are commercially available front Aldrich; m. p. 137- 140°C.

EXAMPLE 215 4-Methoxy-3-(3-nitro-benzylamino)-N-phenyl-benzamide The title compound has been made usinez the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 3-nitrobenzaldehyde as starting materials, which are commercially available from Aldrich; m. p. 172- 175°C.<BR> <BR> <P> EXAMPLE 216 4-Methoxy-3-(4-methoxy-benzylamino)-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 4-methoxybenzaldehyde as starting materials which are commercially available from Aldrich; m. p. 173- 174°C.

EXAMPLE 217 4-Methoxy-3-[(naphthalen-1-ylmethyl)-amino]-N-phenyl-benzami de The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 1-naphthaldehyde as starting materials, which are commercially available from Aldrich; m. p. 172-174°C EXAMPLE 218 4-Methoxy-3- (3, 5-dimethyl-benzylamino)-1V-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 3,5-dimethylbenzaldehyde as starting materials, which are commercially available from Aldrich or Lancaster; m.p.168-170°C.

EXAMPLE 219 3-(2,3-Difluoro-benzylamino)-4-methoxy-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 2,3-difluorobenzaldehyde as starting materials, which are commercially available from Aldrich; m. p. 134- 135°C.

EXAMPLE 220 Acetic acid 4-1 (2-methoxy-5-phenylcarbamoyl-phenylamino)-methyl]-phenyl ester The title compound has beern made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 4-acetoxybenzaldehyde as starting materials, which are commercially available from Aldrich; m. p. 193- 195°C.

EXAMPLE221 4-[(2-Methoxy-5-phenylcarbamoyl-ophenylamino)-methyl]-benzoi cacid methyl ester The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide or 4-carbomethoxybenzaldehyde

as starting materials, which are commercially available from Aldrich; m. p. 170- 172°C.

EXAMPLE 222 3-[(Furan-3-ylmethyl)-amino]-4-methoxy-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 2-furaldehyde as starting materials, which are commercially available from Aldrich; m. p. 188-190°C.

EXEMPLE 223 4-Methoxy-3-(2-methyl-benzylamino)-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 2-methylbenzaldehyde as starting materials, which are commercially available from Aldrich; m. p. 167- <BR> <BR> <BR> 169°C.<BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> EXÅXLE 224 4-Methoxy-3(4-fluoro-benzylamino)-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 4-fluorobenzaldehyde as starting materials, which are commercially available from Aldrich; m. p. 165- <BR> <BR> <BR> 167°C.<BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> EXAMPLE 225<BR> <BR> <BR> <BR> 3- (4-Hydrogy-3-nitro-benzylamino)-4-methoxy-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 3-nitro-4- hydroxybenzaldehyde as starting materials, which are commercially available from Åldrich ; m. p. 175-176°C.

EXAMPLE 226 3- (4-Diethylamino-benzylamino)-4-methoxy-N- (3,4-difluoro-phenyl)- benzamide

The title compound has been made using the procedure of Example 50, but using the title compound of Example 15 as a starting material ; m. p. 165-167°C.

EXAMPLE 227 3-Benzylamino-4-methogy-N- (3, 4-difluoro-phenyl)-benzamide The title compound has been made using the procedure of Example 50, but using the title compound of Example 15 as a starting material; m. p. 176-178°C.

EXAMPLE 228 3- (3-Hydroxy-4-nitro-benzylamino)-4-methoxy-leT-phenyl-benzami de The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 3-hydroxy-4- nitrobenzaldehyde as starting materials, which are commercially available from Aldrich; m. p. 140-143°C.

EXAMPLE 229 3-(3-Cyano-benzylamino)-4-methoxy-n-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 3-cyanobenzaldehyde as starting materials, which are commercially available from Aldrich; m. p. 172- 174°C e EXAMPLE 230 3-{[5-(3,4-Difluoro-phenylcarbamoyl)-2-methoxy-phenylamio]-m ethyl}- benzoic acid The title compound has been made using the procedure of Example 50, but using the title compound of Example 15 as a starting material; m. p. 240-243°C.

EXAMPLE 231 3-(3-Chloro-benzylamino)-4-methoxy-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 3-chlorobenzaldehyde as

starting materials, which are commercially available from Aldrich; m. p. 203- 205°C.

EXAMPLE 232 3-(4-tert-Butyl-benzylamino)-4-methoxy-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 4-tert-butylbenzaldehyde as starting materials. which are commercially available from Aldrich; m. p. 195- 197°C.

EXAMPLE 233 3- (4-Cyano-benzylamino-4-methoxy-N-phenyl-lbenzamicle The title compound has been made uslng the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 4-cyanobenzaldehyde as starting materials, which are commercially available from Aldrich; m. p. 130- 133°C.

EXEMPLE 234 4-{[5-(3,4-Difluoro-phenylcarbamoyl)-2-methoxy-phenylamno]-m ethyl}- benzoic acid The title compound has been made usinez the procédure of Example 50, but using the title compound of Example 15 as a starting material; m. p. >240°C.

EXAMPLE235 4-Methoxy-3-(4-propoxy-benzylamino)-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 4-n-propoxybenzaldehyde as starting materials, which are commercially available from Aldrich; m. p. 154- 156°C.<BR> <BR> <P> EXAMPLE 236<BR> 3-[(Biphenyl-4-ylmethyl)-amino j-4-methoxy-N-phenyl-benzamide

The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 4-phenylbenzaldehyde as starting materials, which are commercially available from Aldrich; m. p. 222- 223°C.

EXAMPLE237 4-Methoxy-3(3-methyl-benzylamino)-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 4-methylbenzaldehyde as starting materials, which are commercially available from Aldrich ; m. p. 184- 186°C.

EXAMPLE238 4-Methoxy-3-(2-methoxy-benzylamino)-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 2-methoxybenzaldehyde as starting materials, which are commercially available from Aldrich; m. p. 177- 179°C.

EXEMPLE 239 3-(4-Butyl-benzylamino)-4-methoxy-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 4-n-butylbenzaldehyde as starting materials, which are commercially available from Aldrich; m. p. 171- 173°C.

EXÅMPLE 240 3-(3-Fluoro-benzylamino)-4-methoxy-N-(3,4-dichloro-phenyl)-b enzamide The title compound has been made using the procedure of Example 50, but using the title compound of Example 15 as a starting material; m. p. 153-155°C.

EXAMPLE 241 3-[(2-Methoxy-5-phenylcargbamoyl-phenylamino)-methyl]-benzoi dcacid

The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 3-carboxybenzaldehyde as starting materials, which are commercially available from Aldrich; m. p. 210- 212°C.

EXAMPLE 242 3-(3,4-Dimethyl-benzylamino)-4-methoxy-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 3,4-dimethylbenzaldehyde as starting materials, which are commercially available from Aldrich or Maybridge; m.p. 163-1264°C.

EXEMPLE 243 3-*4-(Isopropyl-benzylamino)-4-methoxy-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 4-isopropylbenzaldehyde as starting materials, which are commercially available from Aldrich; m. p. 174- 176°C.

EXEMPLE 244 3,4-Dichloro-N-[3-(3-fluoro-benzylamino)-4-methoxy-phenyl]-b enzamide The title compound has been made using the procedure of Example 50, but casing the title compound of Example 23 as a starting material; m. p. 197-199°C.

EX-ANGLE 245 3,4-Difluoro-N- [3- (3-hydroxy-benzylamino)-4-methoxy-phenyl]-benzamide The title compound has been made using the procedure of Example 50, but using the title compound of Example 15G as a starting material; m. p. 174-176°C.

EXAMPLE246 <BR> <BR> <BR> <BR> 3-1 [5- (3, 4-Difluo ro-benzoylamino)-2-methoxy-phenylamino]-m ethyl)-benzoic acid

The title compound has been made using the procedure of Example 50, but using the title compound of Example 150 as a stalting material; m. p. 218-221°Ce EXAMPLE 247 3- [3- (3, 5-Dichloro-phenyl)-thioureidomethyll-4-methoxy-N-phenyl- benzamide Step A: 4-Methoxy-3-cyanobenzoic Acid A mixture of 4-methoxy-3-cyanomethyl benzoate (Maybridge) (9.94 g, 52 mmol) and IN sodium hydroxide (51 mL) in water (150 mL) was heated briefly to SO°C, then water was added until the solution just became cloudy. After 5 days at room temperature the mixture was stripped of methanol, diluted with water (200 mol), and extracted once with ethyl acetate (discarded). The aqueous solution was acidifie with 1N HCI then extracted with ethyl acetate (400 mL).

The extract was washed with brine, dried over magnesium sulfate, filtered and stripped of solvent. Trituration of the residue in hexanes/ethyl acetate and filtration gave the product (6.79 g).

Calculated C9H7NO3: C, 61.02; H, 3.98; N, 7.91.

Found: C, 61. 10; H, 3.97; N, 7.93.

Step B 4-Methoxy-3-cyano-N-phenyl-benzamide Prepared according to the procedure described for Example 1, Step A using 4-methoxy-3-cyanobenzoic acid from Step A above to afford the product (1.781 g).

Calculated for C15H12N2O2: C, 71.42 ; H, 4.79; N, 11.10.

Found: C, 71.10; H, 4.80; N, 11.02.

Step C: 4-Methoxy-3-aminomethyl-N-phenyl-benzamide The product from Step B above (1.64 g, 6.5 mmol) was exposed to hydrogen gas (46 psi) in the presence of Raney Nickel (2 g) until gas uptake ceased. Concentration of the rection mixture afforded the crude product (1.43 g).

The product was purifie by conversion to its N-t-butyloxy-carbonyl derivative,

prepared as follows. The amine (1.43 g, 5.6 mmol) was treated with di-t- butyldicarbonate (1.68 g, 7.8 mmol) in dioxane/water (1: 1), (110 mL) initially at 50°C. and then at room temperature for 3 days. The dioxane was removed by rotary evaporator and the residue extracted with ethyl acetate (150 mL). The organic extract was washed with 10% citric acid solution (50 mL), sodium bicarbonate solution (100 rnL), and brine (50 mL), then dried over magnesium sulfate, filtered, and stripped of solvent. Trituration of the resulting solid in hexanes containing a few mL of ethyl acetate gave the carbamate (1.61 g). The carbamate (1. 29 g, 3.6 mmol) was dissolve in dichloromethane (50 mL) and hydrogen chloride gas was bubbled in for about 3 minutes. The flask was stoppered and stirred at room temperature for 4 hours. The precipitate was collecte by filtration washed successively with dichloromethane, ether and hexanes to afford the product (1.043 g).

Calculated for C15Hl6N202-HCI: C, 61.54; H. 5.85; N, 9. 57.

Found: C, 60.03; H, 5.76; N, 9.22.

Step D: 3-[3-(3,5-Dichloro-phenyl)-thioureidomethyl]-4-methoxy-N-phe nyl- benzamide A mixture of the product from Step C (0.1585 g, 0.54 mmol), triethylamine (0.5 mL) and 3, 5-dichlorophenyl isothiocyanate (Lancaster) (0.138 g, 0.68 mmol) was heated brieily to 50°C and then allowed to stand at room temperature over-night. The rection mixture was then re-warmed to SO°C, filtered, and concentrated to an oil which was triturated in hexanes/ethyl acetate (2: 1) and filtered through silica gel in ethyl acetate to afford the product (0.067 g); m.p. 208-210°C.

Calculated for C15H16N2O2#HCl: C, 61.54; H, 5.85; N, 9. 57 Found: C, 60.03; H, 5.76; N, 9.22.

EXAMPLE248 3-(3,5-Dichloro-benzenesulfonylamino)-4-methoxy-N-phenyl-ben zamide

The title compound has been made using the procedure of Example 121, but using 3-amino-4-methoxy-N-phenyl benzamide and 3,5- dichlorophenylsulfonyl chloride as starting materials, which are commercially available from Aldrich or Lancaster; m. p. 226-228°C.

EXAMPLE 249 3- [ (3, 5-Dichloro-benzenesulfonylamino)-methyll-4-methoxy-N-phenyl- benzamide The title compound has been made using the procedure of Example 120, but using the title compound of Example 247 as a starting material; mp 203- 206°C.

EXAMPLE 250 44-Methox-3-phenylmethanesulfonylamino-N-phenyl-benzamide The title compound has been made using the procedure of Example 121, but using 3-amino-4-methoxy-N-phenyl benzamide and 3,5- dichlorobenzylsulfonyl chloride as starting materials, which are commercially available from Aldrich or Lancaster; m. p. 2 i4-217°C.

EXAMPLE 251 3- [Bis [(3,5-dichlorophenyl)sulfonyl]amio]-4-methoxy-N-phenyl-benza mide The title compound has been made using the procedure of Example 25, but using 3-amino-4-methoxy-N-phenyl benzamide and 3, 5-dichlorophenylsulfonyl chloride as starting materials, which are commercially available from Aldrich or Lancaster; m. p. 228-231°C.

EXAMPLE252 <BR> <BR> <BR> <BR> (2-Methoxy-5-phenylcarbamoyl-phenylcarbamoyl)-acetic acid phenylmethyl ester Acetoxymandeloyl chloride (1.10 g, 5 mmol) was added to a mixture of 4-methoxy-3-amino-N-phenyl-benzamide (1.24 g, 5mmol) and triethylamine (1.25 mL, 9 mmol) in ethyl acetate (50 mol). The flask was agitated briefly then allowed to stand overnight at room temperature. The rection mixture was diluted

with ethyl acetate (150 mL), washed with aqueous sodium bicarbonate solution (150 mL) then brine (100 mL), dried over magnesium sulfate, and filtered.

Removal of the solvent followed by trituration in hexanes/ethyl acetate (2: 1) gave the product (1.46g.) ; m. p. 168-171°C.

Calculated C24H22N2O5: C, 68.89; H, 5.30; N, 6.69.

Found: C, 68.68; H, 5.14; N, 6.39.

EXAMPLE 253 4-Methoxy-N-phenyl-3-[2-(3-trifluoromethyl-phenyl)-ethylamin o]-benzamide Step A: 4-Methoxy-N-phenyl-3-[2-(3-trifluoromethyl-phenyl)-acetylami no]- benzamide Dicyclohexylcarbodiimide (2.08 g, 10 mmol) was added to a stirred mixture of 4-methoxy-3-amino-N-phenyl-benzamide (2.44 g, 10 mmol) and 3-trifluoromethyl-phenyl-acetic acid (2. 06 g, 10 mmol) in dichloromethane (80 niL) at room temperature followed by 1-hydroxybenzotriazole hydrate (1.36 g, 10 mmol). After overnight stirring the rection mixture was filtered and the solid rinsed with ethyl acetate. The combine organic filtrates were washed with sodium bicarbonate solution (150 mL) then brine (100 mL), dried over magnesium sulfate, filtered, and concentrated. Trituration of the residue with hexanes/ethyl acetate (1: 1) afforded the product (3.023 g).

Calculated for C23H19F3N2O3: C, 64.48; H, 4.47; N, 6.54 Found: C, 64. 46; H, 4.51; N, 6.64.

Step B: 4-Methoxy-N-phenyl-3- [2- (3-trifluoromethyl-phenyl)- thioacetylaminol-benzamide Prepared according to the procedure described for Example 208 using the product from step A above (2.14 g, 5 mmol) and Lawesson's reagent (4.04 g, 10 mmol) to give the product (0.261 g).

Calculated for C23H19F3N2O2S: C, 62. 15; H, 4.31 ; N, 6. 30.

Found: C, 61.82; H, 4.38; N, 6.27.

Step C: 4-Methoxy-N-phenyl-3-[2-(3-trifluoromethyl-phenyl)-ethylamin o]- benzamide Prepared according to the procedure described for Example 209 using the product from Step C above (0. 185 g, 0.42 mmol) and Raney Nickel (5 g) to give the product (0.079 g); m. p. 142-144°C.

Calculated for C23H21F3N2O2: C, 66.66; H, 5.11; N, 6. 76.

Found: C, 66.55; lI, 5.03; N, 6.62.

EXAMPLE 254 4-Methoxy-3- [3- (3-nitro-phenyl)-thioureido-N-phenyl-benzamide The title compound has been made using the procedure of Example 60, but using 3-amino-4-methoxy-N-phenyl benzamide and benzoyl isothiocyanate as starting materials, which are commercially available from Aldrich; m. p. 217- 219°C.

EXEMPLE 255 3- [ (3,5-Dichlorobenzoyl) amino]-4-methyl-N-phenyl-benzamide The title compound has been made using the procedure of Example 252 but using 3-amino-4-methoxy-N-phenyl benzamide and 3,5-dichlorobenzoyl chloride as starting materials, which are commercially available from Aldrich; m.p.202-205°C.

EXAMPLE 256 3-[[(Cyanoimino)[(3,5-dichlorophenyl)amino]methyl]amino]-4-m ethoxy-N- phenyl-benzamide Step A: 3- [3- (3, 5-dichlorophenyl)-thioureido]-4-methoxy-N-phenyl-benzamide from Example 60 (1.83g, 4.1 mmol) was stirred with methyl iodide (2 mL, <BR> <BR> <BR> 32 mmol) in tetrahydro-furan (50 rnL) iSor 2 hours then allowed to stand overnight at room temperature. The precipitate was collecte, washed with tetrahydrofuran

and ether and air-dried to givre te crude product (2.007 g), suitable for use in the next step.

Step B: A mixture of the product from Step A (1.87 g, 4.1 mmol) and cyanamide (Aldrich) (0.199 g, 4.7 mmol) was heated at just below reflux in acetonitrile (50 rnL) under nitrogen. After about 18 hours additional cyanamide (0.23 g) was added. Two hours later more cyanamide (0.39 g) was added followed by isopro- panol (60 mol), and the mixture was heated to reflux. After 18 hours additional cyanamide (0.59 g) was added, and another portion (0.88 g) 18 hours later. About 18 hours after that the mixture was allowed to cool, and the precipitate was filtered off to afford the product (0.361 g), m. p. 225-227°C.

Calculated for C27H17Cl2N5O2 : C, 58.16; H, 3.77; N, 15. 42.

Found: C, 57.92; X, 3.84; N, 15.36.

EY-AWLE 257 3-(2-Eydroxy-2-phenyl-acetylamino)-4-nethoxy-N-phenyl-benzam lde IN Sodium hydroxide (3 mL) was added to (2-methoxy- phenylmethylesterfrom5-phenylcarbamoyl-phenylcarbamoyl)-acet icacid Example 252 (1.29 g, 3. 1 mmol) in methanol (80 rnL) and the rection mixture boiled until most of the solvent was gone. Ådditional 1N sodium hydroxide (4 mL) and methanol (80 mL) were added and the mixture again concentrated to near dryness. Ethyl acetate (100 mL), water (100 mL), and 1N HCl (10 mI., ) were added, the layers separated, the organic layer washed with brine (50 mL), dried over magnesium sulfate, and concentrated to an oil. Trituration in hexanes/ethyl acetate (4: 1) afforded the product (0.826 g); m. p. 173-175°C.

Calculated for C22H20N2°4 C, 70.20; H, 5.36 ; N, 7.44.

Found: C, 69.78; H, 5.12; N, 7. 15.

EXAMPLE258 4-Methoxy-3-[(thiophen-2-ylmethyl)-amino]-N-(3,4-difluoro-ph enyl)- benzamide The title compound has been made using the procedure of Example 50, but using the title compound of Example 15 as a starting material ; m. p. 172-174°C.

EXAMPLE 259 4-Methoxy-3-[(thiophen-2-ylmethyl)-amino]-N-phenyl-benzamide The title compound has been rnade using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 2-thiophenecarboxaldehyde as starting materials, which are commercially available from Aldrich; m. p. 195- 197°C EAMPLE 260 4-Methoxy-3-[(thiophen-2-ylmethyl)-amino]-N-(4-fluoro-phenyl )-benzamide The title compound has been made using the procedure of Example 50, but using the title compound ofExample 8 as a starting material; m. p. 179-181°C.

EXEMPLE 261 4-Methoxy-3-[(thiophen-2-ylmethyl)-amino]-N-(3,4-difluoro-ph enyl)- benzamide The title compound has been made using the procedure of Example 50, but using the title compound of Example 4 as a starting material; m. p. 178-180°C.

EXAMPLE 262 4-M ethoxy-3- [(thiophen-2-ylmethyl)-amino]-N-pyridin-3-yl-benzamide The title compound has been made using the procedure of Example 50, but using the title compound of Example c as a starting material; m. p. 154-155°C.

EXAMPLE 263 3-{4-Methoxy-3-[(thiohen-2-ylmethyl)-amino]-benzoylamino}-be nzoicacid ethyl ester

The title compound has been made using the procedure of Example 50, but using the title compound of Example 148 as a starting material; m. p. 153-155'C.

EXAMPLE 264 3,4-Dichloro-N-{4-methoxy-3-[(thiophen-2-ylmethyl)-amino]-ph enyl}- benzamide The title compound has been made using the procedure of Example 50, but using the title compound of Example 23 as a starting material; m. p. 185-188°C.

EXAMPLE 265 3,4-Difluoro-N-{4-methoxy-3-[(thiophen-2-ylmethyl)-amino]-ph enyl}- benzamide The title compound has been made using the procedure of Example 50, but using the title compound of Example 150 as a starting material; m. p. 187-189°C.

EXEMPLE 266 3- [ (Benzo [1,3] dioxol-5-ylmethyl)-amirno]-4amethoxy-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 3,4- methylenedioxybenzaldehyde as starting materlals, which can be purchased from Aldrich; m. p. 185-187°C.

EXAWLE 267 4-Methoxy-3-(3,5-difluoro-benzylamino)-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 3,5-difluorobenzaldehyde as starting materials, which can be purchased from Aldrich; m. p. 175-177°C.

EXEMPLE 268 3-(4-Dimethylamino-benzylamino)-4-methoxy-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and

4-dimethylaminobenzaldehyde as starting materials, which can be purchased from Aldrich; m. p. 195-197°C.

EXEMPLE 269 4-Methoxy-3-(3-trifluoromethyl benzylamino)-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 3-trifluoromethylbenzaldehyde as starting materials, which can be purchased from 167-171°C.Aldrich;m.p.

EXAMPLE 270 4-Methoxy-3-(2-fluoro-benzylamino)-N-phellyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 2-fluorobenzaldehyde as starting materials, which can be purchased from. Aldrich; m. p. 142-144°C.

EXAMPLE 271 N-{3-[ (2,3-Dihydro-benzo [1,4] dioxin-6-ylmethyl)-aminol-4-methoxy-phenyl)- benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 3.4-ethylenedioxy- benzaldehyde as starting materials, which can be purchased from Aldrich; m. p. 174-175°C.

EXAMPLE 272 3- (4-Hydroxy-benzylamino)-4-methoxy-N-phenyi-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 4-hydroxybenzaldehyde as starting mateIials, which can be purchased frorn Aldrich. m. p. 188-190°C.

EXAMPLE 273 4-Methoxy-3- (3-methyl-benzylamino)-N-phenyl-benzamide

The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 3-methylbenzaldehyde as starting materials, which can be purchased from Aldrich; m. p. 184-185°C.

EXAMPLE 274 3-(3,4-Difluoro-benzylamino)-4-methoxy-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 3,4-difluorobenzaldehyde as starting materials, which can be purchased from Aldrich; m. p. 150-152°C.

The commercial suppliers of the starting materials used to make compound of the present invention are shown below in Table A.

EXANn'LE 275 3-[(Pyridine-3-ylmethyl)-amino]-4-methoxy-N-(3,4-difluoro-ph enyl)- benzamide The title compound has been made using the procedure of Example 50, but using the title compound of Example 15 and pyridine-3-carboxaldehyde, which is available from Aldrich, as starting materials; mp 148-149°C.

EXAMPLE 27O 3-[(Pyriding-3-ylmethyl)-amino]-4-methoxy-N-(3,4-dichloro-ph enyl)- benzamide The title compound has been made using the procedure of Example 50 but using the title compound of Exemple 4 and pyridine-3-carboxaldehyde, which is available from Aldrich, as starting materials; xnp 145-147°C.

EXAMPLE277 3-[(Pyridin-3-ylmethyl)-amino]-4-methoxy-N-phenyl-3-benzamid e The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-benzanilide and pyridine-3-carboxaldehyde, which are available from Aldrich, as starting materials; mp 178-180°C.

EY-ANDLE 278 4-[(2-Methoxy-5-phenylcarbamoyl-phenylamino)-meklthyl]-benzo icacid The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-benzanilide and 4-carboxybenzaldehyde, which are available from Aldrich, as starting materials; mp >240°C.

EAMPLE 279 3,4-Difluoro-N-{[3-(pyridin-3-ylmethyl)-amino]-4-methoxy-phe nyl}- benzamide The title compound has been made using the procedure of Example 50, but using the title compound of Example 150 and pyridine-3-carboxyaldehyde, which is available from Aldrich, as starting materials; mp 177-179°C.

EXEMPLE 280 3-(3-Acdetylamino-phenylamino)-4-methoxy-N-phenyl-benzamide The title compound has been made using the procedure of Example 154, but using 3-amino-4-methoxy-benzanilide, which is available from Aldrich, and 3-acetamidobenzeneboronic acid, which is available from Lancaster, as starting materials; inp 202-2Q3°C.

TABLE A Example Starting Material Supplier Starting Material 146 4-trifluoromethoxybenzoic acid TCI 4-fluoroaniline 147 4-trifluoromethoxybenzoic acid TCI aniline 148 3-amino-4-methoxybenzoic acid Aldrich ethyl 3-aminobenzoate 149 3-amino-4-methoxybenzoic acid Aldrich methyl 3-aminobenzoate 150 * 3,4-difluorobenzoyl chloride 151 4-fluoro-3-nitroaniline Aldrich 3,4-difluorobenzoyl chloride 152 * 3,4-dichlorophenyl isocyanate 153 3-amino-4-methoxy-N-phenyl benzamide Aldrich tris(4-fluorophenyl)bismuthane 154 * 3,5-dichlorbenzeneboronic acid I 155 * tris(4-fluorophenyl)bismuthane 156 * tris(3-trifluoromethylphenyl) bismuthane 157 * tris(3-trifluoromelthylphenyl) bismuthane 158 * tris(3-trifluoromethylphenyl) bismutane TABLE A Example Starting Material Supplier Starting Material 159 * tris(3-trifluoromethylphenyl) bismuthane 160 * 3,4-dichlorobenzoyl chloride 161 3-amino-4-methoxy-N-phenyl benzamide Aldrich 3-carbomethoxyphenyl T@ isothiocyanate 162 * 3-carboxyphenyl isothiocyanate T@ 163 * 3,5-dichlorophenyl L isothiocyanate 164 * 3-trifluoromethylphenyl T@ isothiocyanate 165 * 4-sulfophenyl isothiocyanate sodium salt 166 * 4-carboxyphenyl isothiocyanate T@ 167 * 3-carboxyphenyl isothiocyanate T@ 168 * 4-carboxyphenyl isothiocyanate T@ 169 * 3-carboxyphenyl isothiocyanate T@ TABLE A Example Starting Material Supplier Starting Material 170 * 3,5-dichlorophenyl @ isothiocyanate 171 * 3,5-dichlorophenyl @ isothiocyanate 172 * 3-methoxycarbonylphenyl @ isothiocyanate 173 * 3-carboxyphenyl isothiocyanate T@ 174 * 3,5-bis(trifluoromelthyl)phenyl isothiocyanate 175 * 4-chloro-3-nitrophenyl @ isothiocyanate 176 4-methoxy-3-nitrobenzoic acid Aldrich 3,5-dichlorophenyl @ isothiocyanate 177 3-amino-4-methoxy-N-phenyl benzamide Aldrich 1-dodecanesulfonyl chloride 178 3-amino-4-methoxy-N-phenyl benzamide Aldrich 1-octanesulfonyl chloride @ 179 3-amino-4-methoxy-N-phenyl benzamide Aldrich 1-decanesulfonyl chloride @ TABLE A Example Starting Material Supplier Starting Material 180 * 3-nitrobenzenesulfonyl chloride 181 * 3,5-dichlorobenzenesulfonyl @ chloride 182 3-amino-4-methoxy-N-phenyl benzamide Aldrich isopropylsulfonyl chloride 183 3-amino-4-methoxy-N-phenyl benzamide Aldrich 4-carboxybenzenesulfonyl chloride 184 3-amino-4-methoxy-N-phenyl benzamide Aldrich 1-octadecanesulfonyl chloride I 185 * * 186 * 4-nitrobenzenesulfonyl chloride 187 * 4-cyanobenzenesulfonyl @ chloride 18 3-amino-4-methoxy-N-phenyl benzamidje Aldrich 4-nitjroblenzenesulfonyl chloride 189 * 3-cyanobenzenesulfonyl @ chloride 190 * 3-nitrobenzenesulfonyl chloride 191 * 4-nitrobenzenesulfonyl chloride TABLE A Example Starting Material Supplier Starting Material 192 3-amino-4-methoxy-N-phenyl benzamide Aldrich 4-cyanobenzenesulfonyl @ chloride 193 * 4-cyanobenzenesulfonyl @ chloride 194 * 1-dodecanesulfonyl chloride @ 195 3-amino-4-methoxy-N-phenyl benzamide Aldrich 3-cyanobenzenesulfonyl @ chloride 196 * 4-methoxybenzenesulfonyl chloride 197 * 4-methylbenzenesulfonyl chloride 198 * * 199 * * 200 * 1-dodecanesulfonyl chloride 201 * chloromelthylsulfonyl chloride 202 * 4-nitjrobenzenesulfonyl chloride TABLE A Example Starting Material Supplier Starting Material 203 * 3-nitrobenzenesulfonyl chloride 204 * 4-cyanobenzenesulfonyl @ chloride 205 * 3-cyanobenzenesulfonyl @ chloride 206 * 2-thienylsulfonyl chloride 207 * 2-thienylsulfonyl chloride 208 * 3,4-dichlorobenzenesulfonyl @ chloride 209 * 3,4-dichlorobenzenesulfonyl I chloride 210 * 3-hydroxybenzaldehyde 211 3-amino-4-methoxy-N-phenyl benazmide Aldrich 4-diethylaminobenzaldehyde 212 * 3-fluorobenzaldehyde 213 3-amino-4-methoxy-N-phenyl benazmide Aldrich 3-hydroxybenzaldehyde TABLE A Example Starting Material Supplier Starting Material 214 3-amino-4-methoxy-N-phenyl benazmide Aldrich 3-fluorobenzaldehyde 215 3-amino-4-methoxy-N-phenyl benazmide Aldrich 3-nitrobenzaldehyde 216 3-amino-4-methoxy-N-phenyl benazmide Aldrich 4-methoxybenzaldehyde 217 3-amino-4-methoxy-N-phenyl benazmide Aldrich 1-naphthaldehyde 218 3-amino-4-methoxy-N-phenyl benazmide Aldrich 3,5-dimethylbenzaldehyde I 219 3-amino-4-methoxy-N-phenyl benazmide Aldrich 2,3-difluorobenzaldehyde 220 3-amino-4-methoxy-N-phenyl benazmide Aldrich 4-acetoxybenzaldehyde 221 3-amino-4-methoxy-N-phenyl benazmide Aldrich 4-carbomethoxybenzaldehyde 222 3-amino-4-methoxy-N-phenyl benazmide Aldrich 2-furaldehyde 223 3-amino-4-methoxy-N-phenyl benazmide Aldrich 2-methylbenzaldehyde 224 3-amino-4-methoxy-N-phenyl benazmide Aldrich 4-fluorobenzaldehyde 225 3-amino-4-methoxy-N-phenyl benazmide Aldrich 3-nitro-4-hydroxybenzaldehyde 226 * 4-diethylaminobenzaldehyde 227 * benzaldehyde 228 3-amino-4-methoxy-N-phenyl benazmide Aldrich 3-hydroxy-4-nitrobenzaldehyde 229 3-amino-4-methoxy-N-phenyl benazmide Aldrich 3-cyanobenzaldehyde TABLE A Example Starting Material Supplier Starting Material 230 * 3-carboxybenzaldehyde 231 3-amino-4-methoxy-N-phenyl benzamide Aldrich 3-carboxybenzaldehyde 232 3-amino-4-methoxy-N-phenyl benzamide Aldrich 4-tert-butylbenzaldehyde 233 3-amino-4-methoxy-N-phenyl benzamide Aldrich 4-cyanobenzaldehyde 234 * 4-carboxybenzaldehyde 235 3-amino-4-methoxy-N-phenyl benzamide Aldrich 4-n-propoxybenzaldehyde 236 3-amino-4-methoxy-N-phenyl benzamide Aldrich 4-pheylbenzaldehyde 237 3-amino-4-methoxy-N-phenyl benzamide Aldrich 4-methylbenzaldehyde 238 3-amino-4-methoxy-N-phenyl benzamide Aldrich 2-methoxybenzaldehyde 239 3-amino-4-methoxy-N-phenyl benzamide Aldrich 4-n-butylbenzaldehyde 240 * 3-fluorobenzaldehyde 241 3-amino-4-methoxy-N-phenyl benzamide Aldrich 3-carboxybenzaldehyde 242 3-amino-4-methoxy-N-phenyl benzamide Aldrich 3,4-dimethylbenzaldehyde M 243 3-amino-4-methoxy-N-phenyl benzamide Aldrich 4-isopropylbenzaldehyde 244 * 3-fluorobenzaldehyde 245 * 3-hydroxybenzaldehyde TABLE A Example Starting Material Supplier Starting Material 246 * 3-carboxybenzaldehyde 247 methyl 4-methoxy-3-cyanomethyl Maybridge 3,5-dichlorophenyl L benzoate isothiocyanate 248 3-amino-4-methoxy-N-phenyl benzamide Aldrich 3,5-dichlorophenylsulfonyl L chloride 249 * 3,5-dichlorophenylsulfonyl L chloride 250 3-amino-4-methoxy-N-phenyl benzamide Aldrich 3,5-dichlorobenzylsulfonyl L chloride 251 3-amino-4-methoxy-N-phenyl benzamide Aldrich 3,5-dichlorophenylsulfonyl L chloride 252 3-amino-4-methoxy-N-phenyl benzamide Aldrich O-acetyl mandelic acid chloride 253 3-amino-4-methoxy-N-phenyl benzamide Aldrich 3-trifluoromethylphenyl acetic acid 254 3-amino-4-methoxy-N-phenyl benzamide Aldrich benzoyl isothiocyanate 255 3-amino-4-methoxy-N-phenyl benzamide Aldrich 3,5-dichlorobenzoyl chloride TABLEA Example Starting Material Supplier Starting Material 256 * cyanamide 257 * * 258 * 2-thiophenecarboxaldehyde 259 3-amino-4-methoxy-N-phenyl benzamide Aldrich 2-thiophenecarboxaldehyde 260 * 2-thiophenecarboxaldehyde 261 * 2-thiophenecarboxaldehyde 262 * 2-thiophenecarboxaldehyde 263 * 2-thiophenecarboxaldehyde 264 * 2-thiophenecarboxaldehyde 265 * 2-thiophenecarboxaldehyde 266 3-amino-4-methoxy-N-phenyl benzamide Aldrich 3,4- methylenedioxybenzaldehyde 267 3-amino-4-methoxy-N-phenyl benzamide Aldrich 3,5-difluorobenzaldehyde 268 3-amino-4-methoxy-N-phenyl benzamide Aldrich 4-dimethylaminobenzaldehyde 269 3-amino-4-methoxy-N-phenyl benzamide Aldrich 3-trifluoromethylbenzaldehyde 270 3-amino-4-methoxy-N-phenyl benzamide Aldrich 2-fluorobenzaldehyde TABLE A Example Starting Material Supplier Starting Material 271 3-amino-4-methoxy-N-phenyl benzamide Aldrich 3,4-ethylenedioxybenzaldehyde 272 3-amino-4-methoxy-N-phenyl benzamide Aldrich 4-hydroxybenzaldehyde 273 3-amino-4-methoxy-N-phenyl benzamide Aldrich 3-methylbenzaldehyde 274 3-amino-4-methoxy-N-phenyl benzamide Aldrich 3,4-difluorobenzaldehyde * Synthesis described in the Examples herein Aldrich Chemical Company Inc TCI America<BR> 1001 West Saint Paul Avenue 9211 North Harborgate Street<BR> Milwaukee, WI 53233 Portland, OR 97203<BR> USA USA<BR> Trans World Chemicals, Inc. Lancaster Synthesis Ltd.<BR> <P>14650 Southlawn Lane Eastgate, White Lund<BR> Rockville, MD 20850 Morecambe<BR> USA Lancashire LA3 3DY<BR> UK<BR> Maybridge Chemical Company Ltd.<BR> <P>Trevillett<BR> Tintagel<BR> Cornwall PL34 0HW<BR> UK The results of the assays described above are shown below in Tables 1,2, and 3.

TABLE 1 Example h15LO (ICso nM) or % at 10 ZM 2 290 4 10 5 38 6 79% 7 67% 8 157 9 38% 10 42% 11 390 12 73 14 68% 15 9 16 79 17 65% 182510 19 1100 20 203 21 2130 23 26 TABLE 2 Example h15LO (IC50 nM :) 25 6430 26 1600 27 48% 28 39 29>3000 30 10 31 10 32 23 33 12 34 29 35 7 36 11 37 2940 38 >3000 39 50 40 17 41 65% 42 410 43 73 44 25 45 440 46 20 47 100 48 28 50 846 51 69% 52 62% 53 57% 54 60% 55 54% TABLE 2 <BR> <BR> <BR> <BR> <BR> Example hl5LO (IC50nM) 56 18 57 165 58 80 59 1460 60 8.6 61 11 62 70 63 49 64 41 65 42 66 7 67 10000 68 42 69 32 70 500 71 526 72 56 73 16 74 14.9 75 104 76 48 77 11 78 390 79 127 80 39 81 19 82 124 83 81 84 20 85 20 TABLE 2 Example h15LO (IC50 i) 86 260 87 102 88 33 89 35 90 24 91 8 92 17 93 82 94 42 95 11 96 46 97 19 98 1000 99 11 100 19 101 66% 102 170 104 13 105 14 106 11 107 9 108 34 109 26% 110 290 111 79 112 26 113 52 114 120 115 44 116 20 TABLE 2 Example hl 5LO (IC50 llM) 118 49 119 90 120 40 121 25 122 187 123 31 124 48 125 28 126 48 127 167 128 54 129 79 130 402 131 609 132 lu5 133 58 134 137 135 63 136 48 137 151 138 28 139 104 140 39 141 582 142 12 143 25 144 1190 145 180 146 35.29% 147 37.05% TABLE 2 Example h15LO (IC50 X 148 613 149 330 150 205 151 82.66% 152 57.49% 153 54 154 97.66% 155 94.44% 156 90.33% 157 78.83% 158 48.28% 159 44.58% 160 119 161 22 162 55 163 629 164 1590 165 98.51% 166 98.11% 167 96.22% 168 109 169 246 170 99.53% 171 275 172 89.03% 173 55% 174 53% 175 52% 176 800 177 2 TABLE 2 Example h15LO (IC50M) 178 4 179 7 180 36 181 68 182 232 183 293 184 732 185 99.71% 186 99.35% 187 98.38% 188 97.24% 189 97.17% 190 97.05% 191 96.99% 192 95.56% 193 94.51% 194 93.61% 195 93.07% 196 33 197 36 198 97e77% 199 97.68% 200 96.92% 201 93.97% 202 93.85% 203 92.01% 204 89.54% 205 86.96% 206 45.56% 207 41.59% TABLE 2 Example hl5LO (IC50 nM) 208 98.52% 209 80.94% 210 24 211 69 212 69 213 79 214 89 215 110 216 118.2 217129 218 161 219 166 220 509 221 551 222 591 223 892 224 982 225 97.88% 226 96.21% 227 95.74% 228 92.92% 229 92.70% 230 92.57% 231 224 232 80.36% 233 73.46% 234 71.56% 235 67.26% 236 64.09% 237 64% TABLE 2 Example h15LO (IC50nM) 238 60% 239 58.44% 240 58.09% 241 56.33% 242 50% 243 49.19% 244 86 245 98.02% 246 59.75% 247 40 248 46 249 58 250 63 251 62.01% 252 43% 253 60.56% 254 51% 255 47% 256 45% 257 61% 258 35 259 137 260186 261 98.57% 262 67.58% 263 53.51% 264 37 265 98.89% 266 197 267 198 TABLE 2 Example h15LO (IC50nM) 268 213 269 221 270 241 271 302 272 304 273 385 274 391 275 28 276 52 277 93 278 36% 279 69 280 99% TABLE 3 Monocyte Recna1tment Assay µMExampleED50 28 25% @ 30iM 35 26.3 51 20 56 2.6 60 17.6 65 22.7 66 38% µM30 67 24.1 68 2.3 69 13% µM30

In Vivo Tests-Methods Biochemical Methods The entire descending thoracic aorta was assayed for its cholesteryl ester (CE), free cholesterol, and total phospholipid content. The lipids were extracted in chloroform: methanol (2: 1) by the procedure of Folch, et al. (Folch J., Lees M., Sloane-Stanley G. H., A simple method for the isolation and purification of total lipids from animal tissue, J. Biol. Chern., 19579226 : 497-509) and 300-500 tL of an internal standard, i. e., 200 mg/ml solution of 4-hydroxy-cholesterol in ethyl acetate: acetone (2: 1), was added to the extracts of the thoracic aortic amples.

After extraction, the organic phase vas dried under nitrogen and redissolved in isooctane/tetrahydrofuran (97: 3) The lipid content and composition of the thoracic aorta were measured using an HPLC method.

CytochemicalMethods For histologic evaluation of the aortic arch lesions and for quantification of aortic arch cross-sectional lesion area, a 1 cm segment of the ascending aorta distal to the aortic valves was fixed in 10% neutral buffered formalin for 24 hours.

The vessels were dehydrated, cleared in xylene, and infiltrated with molten paraffin (<60'C) using a Tissue Tek VIP autoprocessor (Miles Scientific, Elkhart, Indiana). The tissue segments were embedded in paraffin and sectioned at 5im with a Reichert-Jung microtome (Baxter, McGraw Park, Illinois). In order to obtain a thorough representation of the histologic appearance of the aortic arch lesions, 3 ribbons of 20 sections each were cute Each ribbon of sections was spaced approximately 100im apart. Three pairs of sections, i. e., 1 pair from each ribbon, were affixed to cleaned 3-aminopropyltriethoxy-silane coated glass slides and stored until stained. The general histologic character was evaluated in Verhoeff s elastica stained sections.

Morphometric Methods The gross extent of atherosclerosis within the aortic arch was measured. In addition, sections of the aortic arch, a site of hypercholesterolemia-induced lesions, stained using the Verhoeff's elastica procedure were used for quantification of lesion cross-sectional. The internal elastic lamina (IEL) was

identifie as a blue-black ring and images of that region were collecte using a digital camera. The area within the IEL was quantifie using the Image Pro Plus image analysis software. The area of the lumen of the aortic arch was also quantifie in a similar fashion. Lesion area was defined as the difference between the area circumscribed by the internal elastic lamina and the lumen area.

Aortic arch lesion extent was also measured. The area distal to the 1 cm segment taken for histologic evaluation to the first intercostal ostia was removed from the animal, opened longitudinally and images of the surface of the vessel was collecte using a digital camera. The lesions were identifie as raised, opaque areas and their area was determinea'using the Image Pro Plus image analysis software. The area of the entire aortic arch was also determined. The percentage of aortic arch covered by atherosclerotic lesions was calculated.

In Vivo Tests n Results Example No. Aortic Årch Åortic Cholesteryl Åortic Arch Cross- (10 mg/kg as Lesion Extent Ester Content Sectional Lesion Area diet admix) (% A from Control) (% A froc Control) (% A from Control) 75-49-28-90 60 +40 +59 +84 4 +20-7-94 91-12 +50-11 100-2 +11 +2 40 +35 +5-6 119 +46 +46-50 NOTE: All vascular efElcacy changes are observe in the absence of changes in plasma cholesterol levels.

Experimental Design : Rabbits were fed a 0.25% cholesterol, 3% peanut oil, 3% coconut oil diet with or without 10 mg/kg of the compound noted above for 12weeks.