CA1098127A - 2,6-anthraquinonylene amidines as anti-amebic agents - Google Patents

Abstract

TITLE: 2,6 ANTHRAQUINONYLENE AMIDINES
AS ANTI-AMEBIC AGENTS

ABSTRACT OF THE DISCLOSURE
Novel 2,6 anthraquinonylene amidines that are effective against cecal and hepatic amebic infestations in warm-blooded animals.

Description

,; .
United States Patent No. 3,184,482 discloses a com- ~
pound of the formula: ~ ;

O N=CH-N ^~
R4 î~

wherein Rl and R2 are hydrogen or lower alkyl and R3, R4 and R5 are hydrogen, hydroxy or ~Rl :
-N=CHN \

Utility is described as antibacterial, antiviral, antiprotazoal and anthelmintic.
This invention is concerned with novel compounds of the formula R~ r ~ c/ R2 (1) wherein Rl is selected from the group consisting of hydrogen, alkyl, branched alkyl, cycloalkyl (Cl-C15), heterocyclic, phenyl and substituted phenyl; and R2 and R3 are each hydrogen, phenyl, substituted phenyl, alkyl or branched alkyl, or R2 and R3 taken - 1 - ~

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... ~ , ~ ,. ....

~9~3~27 together with the nitrogen atom to which they are attached form a heterocyclic ring, and pharmaceutically acceptable salts thereof; the method of treating cecal and hepatic amebic infections in warm-blooded animals with said compounds; and their method of preparation.
The compounds of the present invention are normally crystalline solids being soluble in dimethylformamide and di-methylsulfoxide and less soluble in chlorGform, alcohol and .; .
., .

- la -~`

acetone. The salts (mono and di) are readily soluble ln water and less soluble in alcoholO
The compounds of the present invention may be pre-pared according to the following methods:
A) 2,6-Diaminoanthraquinone (1 mole) is reacted with a com-plex formed from phosphorous oxychloride-(1.5 to 3 moles) and an N,N-dialkylamide or N-alkylamide (2 to 6 or more moles) in a solvent such as acetonitrile (at a ratio of about 1-3 liters of solvent per mole of amine) at a temperature of 25 to 70C
for a period of about one to 24 hours.
More specifically, to a solution of the N,N-dialkyl-amide or N-alkylamide in the solvent is added phosphorous oxychloride at -5 to 20C. The resulting mixture is stirred at 0 to room temperature for 30 minutes to 6 hours. The 2,6--diaminoanthraquinone is added and the reaction mixture is stirred at 25 to 70C for one to 24 hours. The reaction mixture is then poured into ice water and basified. The re-sulting crystals are collected by filtration and recyrstallized from an appropriate solvent or mixture of solvents such as chloroform/hexane.
B) 2,6-Diaminoanthraquinone (1 mole) lS reacted with a l-aza-

2-methoxy-1-cycloalkene (2 to 5 or more moles) in a solvent such as dimethylacetamide or dimethylformamide at a ratio of about one liter of solvent per mole of amine and acetic acid at a ratio of about 2 moles per mole of amine at reflux tem-perature for a period of one to 12 hours. The addition of ether to the reaction mixture causes the precipitation of the product which is collected and recrystallized as in (A).
C) 2,6-Diaminoanthraquinone (72 parts) is slurried in 3nO
parts of a triethyl ortho acid and 250 parts of acetic anhyd-ride is added. The mixture is refluxed for one to 8 hours, cooled and the solid product is collected, washed and dried.

- Purification is accomplished by dissolving this crude product .~9~3~Z7 in 1000 parts of chloroform, filtration and concentration of t:he filtrate. Further purification may be realized by re-crystallization from a solvent such as dimethylformamide. A
bis-imino-ether (8 parts) is slurried in 45 parts of an appro-priate amine. One equivalent of glacial acetic acid for eachpart of iminc-ether is added and the slurry is heated in an oil bath at 100-160C for 8 to 24 hours. (The use of a bomb is recommended with low boiling amines.) The reaction mixture is cooled. Products which crystallize are collected ; 10 and recrystallized from a solvent such as methanol, ethanol, methyl cellosolve or dimethylformamide. For products which do not crystallize, the volatiles are removed ln vacuo and the residue is dissolved in methanol. Upon cooling the product crystallizes and is recrystallized from a suitable solvent as abové.
D) Diethyl N,N'-(2,6-anthraquinonylene) di-formimidate is combined with at least 2 molar equivalents of a primary or secondary amine and heated at a temperature of 130-200C
for 2 to 18 hours. The reaction mixture is stripped of vola-tiles under reduced pressure and the pure product is obtained by recrystallization from a suitable solvent.
E) Diaminoanthraquinone is combined with 2 or more molar equivalents of dialkylamide dialkylacetal with or without the corresponding amide as solvent. The mixture is heated at 130-150C for 2 to 66 hours. The reaction mixture is strip-ped of volatiles under reduced pressure. The residue is washed with hexane and the product is obtained by recrystallization from a suitable solvent.
F) Diaminoanthraquinone is combined with 2 or more molar equivalents of an amide. To this mixture is added at least 2 equivalents of an aryl sulfonyl halide. The mixture is heated at below 100C for 2 to 3 hours. Alcohol is added to the reaction mixture. The insoluble salt is collected and ~81Z7 treated with an aqueous base to obtain the free base. Re-crystallization from a suitable solvent gives the purified product.
The compounds of the present invention are active in treating cecal and hepatic amebic infections in warm-blooded animals. Two tests which establish this activity are as follows:
Organism .
The organism used in both tests is the National Institute of Health 200u strain of Entamoeba histolytica.
This strain and an unidentified fecal flora are cultured in Cleveland-Collier~Medium at 37C. This medium consists of a liver infusior. agar base overlaid with a horse serum:saline mixture (1:6) to which is added a few milligrams of sterile rice powder. The amebas are transferred to fresh medium twice weekly.
Cecal Infections in Female Albino Wistar Rats Pooled overlay (0.25 ml) containing large numbers Of amebas is injected into the cecums of anesthetized weanling rats during laparotomy. Treatment is begun on the day after inoculation. The compounds are dissolved or suspended in 0.2~
- aqueous agar and administered once daily, by gavage, for 5 con-secutive days. 5ix days after inoculation of the amebas, the rats are sacrificed and a scraping from the cecal wall of each rat is mixed with a drop of 0.85% saline and examined micro-scopically for amebas. A rat is considered cured if no amebas are seen. The cure or clearance rate (number cured/number treated) for each regimen is calculated and corrected for non-specific curçs observed in the untreated infected controls.
An active dose is the lowest dose, in terms of mg/kg/day, which clears or cures 50% or more of the rats so treated.
The results of typical compounds of the present invention ` appear in the following table together with results obtained .

~98~Z7 using known effective drugs for comparison.
Hepatic Infections in Female Golden Hamsters A piece of ameba-laden absorbable sponge, about 25 millimeters square, is inserted between the middle lobes of the livers of anesthetized hamsters during laparotomy. Un-treated hamsters usually die from the resulting infection about 7 days after inoculation. Treatment is started on the day of inoculation as soon as the hamsters recover from the surgical anesthetic. The test compounds are dissolved or sus-pended in 0.2%-aqueous agar and admlnistered once daily, by gavage, for 5 ccnsecutive days. Effective regimens prevent mortality. Survival rates are corrected for non-specific survival observed in untreated groups. An active dose is the lowest dose, expressed in mg/kg/day, which protects 50%
or more of the hamsters so treated as evidenced by survival 14 days after inoculation. The results of typical compounds of the present invention appear in the following table to-gether with the active dose of known effective drugs for com-parison.

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~9131Z7 The novel 2,6 anthraquinenylene amidines of the present invention are useful for ameliorating cecal and hepatic amebic infections in warm-blooded animals when ad-ministered in amounts ranging from about 0.5 mg. per kg. to about 40 mg. per kg. of body weight per day. A preferred dosage regimen for optimum results would be from about 2 mg.
per kg. to about 29 mg. per kg. Thus, the daily dosage em-ployed for a subject of about 70 kg. of body weight is about 35 mg. to about 2.8 g., and preferably about 140 mg. to about 2.0 g.
- Suitable oral preparations consist, for example, of capsules, tablets, troches, suspensions, syrups and the like.
In the case of tablets the principal active ingredient is mixed with conventional ingredients such as corn starch, lac-tose, sucrose, sorbitol, talc, stearic acid, magnesium stear-ate, dicalcium phosphate, gums or similar materials as non-toxic pharmaceutically acceptable diluents or carriers.
Sustained release formulations are also contemplated by the present invention.
The liquid forms in which the novel compositions of the present invéntion may be incorporated for administration include suitably flavored emulsions with edible oils, such as, cottonseed oil, sesame oil, coconut oil, peanut oil and the like, as well as elixirs and similar pharmaceutical vehicles.
Sterile suspensions or solutions can be prepared for parenteral use. Isotonic preparations containing suitable preservatives are also desirable for in]ectable use.
Example 1 N,N'-(2,6-Anthraquinonylene)-di-formimidic acid diethyl ester A 35.7 g portion of 2,6-diaminoanthraquinone is mixed with 100 ml of triethylorthoformate containing 5 drops of concentrated H2SO4. The mixture is heated to reflux and -- 7 _ ~9~Z7 , the alcohol is removed as it forms over a 2 hour period. The reactlon mixture is cooled to -10C, the solid which forms is col]ected by filtration, washed with 2B alcohol and air dried.
~ecrystallization from dimethylformamide produces brown crys-tals, mp 235-250C.
Example 2 2,6-Bis[(4-methyl-1-piperazinylmethylene)amino]-anthraquinone A 5.25 g portion of N,N'-(2,6-anthraquinonylene)-di-formimidic acid diethyl ester, 4.0 ml of N-methyl pipera-zine and 100 ml of dimethylformamide are heated together on a steam bath overnight. The mixture is cooled, filtered and the solid is washed with dimethylformamide and 2B alcohol and dried ln vacuo at 78C over P2O5 producing an oranye solid, mp 278-281C.
Example 3 N',N"'-(2,6-Anthraquinonylene)bis-N,N-dimethyl formamidine A suspension of 7.15 g of 2,6-diaminoanthraquinone in 17.68 g of N,N-dimethylformamide diethyl acetal is stirred and heated in an oil bath at 150C for 17 hours. The by-product, ethanol, distills out. A 30 ml portion of dimethyl-formamide is added and the hot mixture is filtered. The solid is washed with acetone giving red-brown rods. These rods are recrystallized from 30 ml of dimethylformamide and dried 4 hours at 80C giving a pale yellow solid.
Example 4 N',N"'-(2,6~Anthraquinonylene)bis-N,N-diethyl formamidine A 5.95 g portion of 2,6-diaminoanthraquinone and 14.7 g of diethylformamide dimethyl acetal [prepared as de-scribed by H. Bredereck et al., Chem. Ber. 101, 41-50 (1968)]
are combined and refluxed for 66 hours at 150C in an oil bath.
The reflux condenser is removed and the distillate is allowed to boil off. The remaining volatiles are removed ln vacuo.

- ~639~3~L27 The residue is slurried with 50 ml of hexane, filtered and the solid is washed with hexane and air dried. This solid is extracted with 2 x 100 ml of boiling methanol, fil-tered while hot, the filtrate is cooled to -10C producing a solid which is recovered by filtration and dried ln vacuo over P2O5. This solid is recrystallized from 200 ml of boiling methyl cello-solve, cooled to -10C, filtered and the red solid is dried in vacuo over P2O5, mp 182-184C.
Example 5 N',N"'-(2,6-Anthraquinonylene)bis-N,N-dibutyl formamidine A 50 ml portion of N,N-dibutylformamide and 5.95 g of 2,6-diaminoanthraquinone are combined and 16.9 g of _-toLuene sulfonyl chloride is added. The mixture is heated on a steam bath for 2 1/2 hours. A 150 ml portion of 2B alcohol is added, the mixture is heated to boiling and filtered while hot. The filtrate is c0012d to -10C and a brown solid is recovered and dried at 78~C in vacuo over P2Os. This solid is dissolved in 300 ml of hot water and 20 ml of lN NaOH is added.
The solid which forms is recrystallized from 150 ml of metha-nol (cooled to -10C) and dried at 78C Ln vacuo over P2O5 giving an orange solid, mp 98-100C.
- Example 6 N',N"'-(2,6-Anthraquinonylene)bis-N,N-diethyl acetamidine To a solution of 276.0 g of dried N,N-diethylacet-amide in 800 ml of acetonitrile, which is cooled in an ice-water bath to 5-10C, is added dropwise 87.4 ml of phosphorous oxychloride over a period of 10 to 15 minutes. The ice-water balh is removed and the resulting mixture is stirred at room temperature for one hour. A 95.2 g portion of 2,6-diamino-anthraquinone is added and the resulting mixture is stirred without heating for one hour and then at 60~C for 7 1/2 hours. The mixture is cooled to room temperature and is poured into 1000 ml of ice-water. The aqueous solution is diluted g . . .

~98~Z7 to 3000 ml and is made basic with 5_ sodium hydroxide. The orange-yellow crystals formed are collected by filtration, then the material is washed with water and air dried. The product is dissolved in 450 ml of chloroform, is filtered and is precipitated out with about 400 ml of hexane to give the flnal product as orange crystals, mp 173-175C.
Example 7 N',N"'-(2,6-Anthraquinonylene)bis-N,N~ropyl formamidine A 95.3 g portion of 2,6-diaminoanthraquinone, 260 ml of triethyl orthoformate and 6 drops of concentrated H2SO4 are combined and heated in an Gil bath for 2 hours so that the ethanol is distilled off. A 140 ml portion of triethyl ortho-formate is added and heating at 140C is continued in an oil bath for 6 hours. The mixture is cooled in an ice bath and filtered. The solid is washed twice with ether, dried at 64C
overnight and then at 78C in vacuo over P2O5 giving a brown solid. A 10 g portion of this solid and 50 ml of di-n-propyl-amine are combined and heated with stirring in an oil bath at 140C for 90 minutes. The mixture is allowed to cool overnight and the volatiles are removed in vacuo. The brown solid is recrystallized from 400 ml of 2B alcohol giving an orange solid. This solid is recrystallized from 200 ml of methyl cellosolve (cooled to -10C) giving an orange solid, mp 182-185C.
Example 8 N',N"'-(2,6-Anthraquinonylene)bis-N-octyl-N-methyl formamidine A 10.0 g portion of N,N'-(2,6-anthraquinonylene)-di-formimidic acid diethyl ester and 13.3 g of N-methyl oct-ylamine are combined and heated in an oil bath at 150C for 90 minutes. ~he mixture is cooled and the volatile component is removed ln vacuo. The residue is slurried with two 50 ml portions of hexane, filtered and the orange solid is air dried.
~ 10 --~g~:~Z7 This product is recrystalllzed from a hot mixture of 100 ml of benzene and 200 ml of hexane. Cooling the mixture at 4C
gives the product which is dried at 78C in vacuo over P2O5 yielding an orange solid, mp 81-83C.
Example 9 N',N"'-(2,6-Anthraquinonylene)bis-N,N-diisopropyl formamidine A 5.95 g portion of 2,6-diaminoanthraquinone and 10.0 g of dlisopropylformamide are combined to form a slurry.
To this slurry is added 14.3 g of p-toluenesulfonyl chloride.
The mixture is heated on a steam bath for 2 1/2 hours. A
100 ml portion of 2B alcohol is added and the mixture is re-fluxed for 5 minutes. The mixture is heated to boiling and the solid is recovered by filtration, washed with 2B alcohol and air dried. This solid is slurried in 150 ml of hot water, filtered while hot and the insoluble solid is washed twice with water. The filtrate and washes are treated with excess 10N NaOH to pH 10. The orange precipitate is washed twice with water and air dried. This-solid is recrystallized from 150 ml of 2B alcohol (cooled to -10C) and dried at 78C ln vacuo over P2O5 giving an orange solid, mp 206-208C.
.
- Example 10-N',N"'-(2,6-Anthraquinonylene)bis[N~(p-chlorophenyl)]
formamidine A 10.0 g portion of N,N'-(2,6-anthraquinonylene)--di-formimidic acid diethyl ester and 7.66 g of p-chloroaniline are combined and heated in an oil bath at 160C for 7 hours and then allowed to stand at room temperature. The solid residue is recrystallized from 350 ml of dimethylformamide (cooled to -10C) and dried at 78C in vacuo over P2O5 giving a red solid.

~ 31Z7 Example 11 N',N"!-(2,6-Anthraquinonylene)bis(N-methyl-N-phenyl) formamidine A 10.0 g portion of N,N'-(2,6-anthraquinonylene)-di-formimidic acid diethyl ester and 25 ml of N methylaniline are heated at 140C for 2 hours in an oil bath and then allow-ed to stand at room temperature overnight~ The reaction mix-ture is triturated with two 50 ml portions of hexane and air dried. The orange-brown solid is recrystallized from 200 ml of dimethylformamide cooled to 4C. The solid is recovered by filtration, washed with dimethylformamide and twice with 2B alcohol and dried at 78C ln vacuo over P2O5 giving a dark orange solid, mp 308-312C.
Example 12 2,6-Bis(piperidinomethyleneamino)anthraquinone A mixture of 7.0 g of N,N'-(2,6-anthraquinonylene)-di-formimidic acid diethyl ester and 7.48 g of piperidine is heated in an oil bath at 130-140C for 2 hours and then allow-ed to stand at room temperature overnight. The reaction mix-ture is triturated with two 50 ml portions of hexane and the brown solid is air dried. This solid is recrystallized from 275 ml of boiling methyl cellosolve which is filtered whlle hot and then cooled to 4C. The solid is washed with methyl cellosolve and with 2B alcohol and dried at 78C ln vacuo over P2O5 gi~lng an orange solid, mp 229-233C.
Example 13 N,N'-2,6-Anthraquinonylenedi-acetimidic acid diethyl ester A mixture of 35.7 g of 2,6-diaminoanthraquinone, lOO ml of triethylorthoacetate and 6 drops of concentrated - 30 sulfuric acid is heated for 6 hours in an oil bath at 130C

with a take-off condenser and four inch Vigreux Column. A
5 ml portion of ethyl alcohol is collected, then the mixture is allowed to stir at room temperature overnight. An addi-~9~Z7 tional 60 ml of triethylorthoacetate is added, the mixture is refluxed for 6 hours longer and is allowed to stir overnight at room temperature. The brownish solid collected by filtra-tion is washed with e-ther and dried ln vacuc. A 10 g portion of the above product is recrystallized from 400 ml of methyl cellosolve, the solid is filtered and washed twice with ether and is dried in vacuo at 50C to give orange-tan crystals.
A 1.0 g portion of the brownish solid previously described is recrystallized from 100 ml of dimethylforma~lide to give orange crystals after drying ln vacuo at 50C. The recrystallized materials are combined to give the final pro-duct, mp 195-197C.
Example 14 N',N"'-2,6-Anthraquinonylenebis(N-1,1,3,3-tetra-methylbutyl) formamidine A 95.3 g portion of 2,6-diaminoanthraquinone, 260 ml of triethylorthoformate and 6 drops of concentrated sulfuric acid is combined in a one liter round bottom flask which is fitted with a short Vigreux Column fused to a takeoff con-denser. The flask is heated to reflux in an oil bath so thatethyl alcohol is distilled off. After 2 hours a total of 35 ml of-ethyl alcohol is collected, then 140 ml of triethyl-orthoformate is added to the thickened reaction mixture and heating is continued in an oil bath at 140C. Approximately lOQ ml of distillate is collected over about a 6 hour period at about 80C. The column is then removed and replaced by a takeoff condenser and heating of the oil bath is continued to 165C. An additional 15 ml of distillate is collected at 140C. The flask is removed from the oil bath, cooled in an ice bath and is filtered. The solid is washed twice with ether, pressed dry and dried in a ventilated oven at 64C

overnight. Drying is continued ln vacuo at 78C over phos-phorous pentoxide to give a brown solid, mp 233-280C, iden-~L~39~3~Z7 tified as N,N'-(2,6-anthraquinonylene)-di-formimidic acid diethyl ester.
A slurry of 10 g of the preceding compound and 20 ml of tertiary octylamine in an open flask is heated in an oil bath at 170C. The mixture thickens in about 10 minutes and is mixed periodically with a spatula. A liquid with a boiling point of about 80C is distilled off over a 2 hour period.
The heat is turned off and the mixture is allowed to cool in the oil bath overnlght. The reaction mixture is then slur-ried with hexane and is filtered, this step is repeated andthe dark orange solid is air dried. The product is then extracted with three 1~0 ml portions of boiling benzene and after drying is recrystallized from 100 ml of methyl cellosolve to give an orange-yellow solid, mp 195-198C.
Example 15 2,6-Bis~[1-(4-methyl-1-piperazinyl)ethylidene]-amino}-anthraquinon_ A mixture of 7.5 g of N,N'-2,6-anthraquinonylenedi-acetimidic acid diethyl ester and 40 ml of _-methyl piperizine is heated in an oil bath at 145C with a reflux condenser for 24 hours. The condenser is removed and the mixture is heated for an additional 30 minutes. Upon cooling to room temperature a solid mass is formed which is diluted with 100 ml of diethyl ether and is filtered to gi-~e a tannish solid which is washed with diethyl ether and dried in vacuo. The dried material is recrystallized from 85 ml of dimethyl formamidé
to give yellowish crystals. The product is dried in vacuo at 80C.-Example 16 N',N"'-(2,6-Anthraquinonylene)bis(N,N-dimethyl)acetamidine To a mixture of 5.96 g of 2,6-diaminoanthraquinone and 20 ml of N,N-dimethylacetamide is added 14.3 g of _-toluene sulfonyl chloride. The material is then heated on a steam ~,- . .

~9~
bath for 2 hours with a color change from red to brown. A
100 ml portion of 2B ethyl alcohol is added, the solution is heated to bolling and filtered. The filtrate is cooled at -10C. The solid collected is then washed with 2B alcohol.
The solid is slurried in hot water, filtered while hot, and the insoluble solids washed twice with hot water. The f iltrate and washes are basified with NaOH. The orange solid is dried, recrystallized from 2B alcohol and dried at 78C under vacuum with P2O5, mp 295-330C.
- Example 17 N,N'-2,6-Anthraquinonylenedi-prop onimidic acid diethyl ester A mixture of 7.2 g of 2,6-diaminoanthraquinone, 30 ml of triethylortho propionate and 25 ml of acetic anhydride is refluxed for 2 hours. The mixture is cooled to room tem-perature and a solid is collected by filtration then is washed with diethyl ether and dried ln vacuo. Thé product is recry-stallized from dimethyl formamide to give orange crystals, mp 195-198C.
Example 18 2,6-Bis~[l-(4-methyl-1-piperazinyl)propylidene]-amino~-anthraquinone .
A mixture of 8.12 g of N,N'-2,6-anthraquinonylenedi-propionimidic acid diethyl ester and 40 ml of N-methylpiper-azine is heated in an oil bath at about 140C with a reflux condenser for 20 hours. The condenser is removed and the mix-ture is heated an additional hour, then is concentrated to a thick brown syrup ln vacuo. The syrup is stirred with 125 ml of diethyl ether and the orange brown solid is collected by filtration, washed with ether and dried ln vacuo. The dried material is rècrystallized from 70 ml of dimethylformamide -to give dark yellow crystals, mp 208-210C.

.

~L~98~27 Example 19 2,6-Bis[(l-pi~eridinopropylidene)amino]anthraquinone A mixture of 8.12 g of N,N'-2,6-anthraquinonylenedi-propionimidic acid diethyl ester and 40 ml of piperidine is S heated in an oil bath at 115C with a reflux condenser for 18 hours. The condenser is removed and the mixture is heated an additional hour, then is concentrated in vacuo to a brown syrup. The syrup is then stirred with 100 ml of diethyl ether resulting in a brown solid which is filtered and washed with ether, then dried in vacuo; The dried product is recrystal-lizea from 40 ml of dimethylformamide to give dark yellow crystals,'mp 183-185C.
Example 20 2,6-Bis[(l-piperidinoethylidene)amino]anthraquinone A mixture of 7.56 g of N,N'-2,6-anthraquinonylenedi-acetimidic acid diethyl ester and 40 ml of piperidine is heated in an oil bath at 120C, with a reflux condenser for 20 hours.
The condenser is removed and the mixture heated an additional hour, then is concentrated in vacuo to a dark syrup. The syrup is triturated with 100 ml of diethyl ether, the resulting orange solid is collected by filtration, washed with ether - and is dried ln vacuo. The dried material is recrystallized from 40 ml of dimethylformamide to give yellow crystals, mp 233-235C.
Example 21 2,6-Bis ~[4-(3-dimethylaminopropyl)piperidino]-methylene~amino~ anthraquinone A suspension of 7.0 g of N,N'-(2,6-anthraquinon-ylene)-di-formimidic acid diethyl ester and 15.0 g of 4-(3-dimethylaminopropyl)- piperidine dihydrochloride is heated in an oil bath at 160C for 3 hours in a flask fitted with a short Vigreux Column fused to a take-off condenser, during this time the 78C distillate is allowed to boil off. The 81~7 reaction mixture is allowed to cool in the oil bath then is slurried with hexane and filtered. The solid is dissolved in 100 ml of boiling dimethylformamide and is filtered hot.
I'he resulting filtrate is cooled at -10C and filtered to obtain an orange solid. This solid is recrystallized from 25 ml of me~hyl cellosolve and is filtered hot to clarify.
The filtrate i's cooled at -10C and the orange solid is col-lected. The product is then dried in vacuo at 78C over phosphorous pentoxide to give an orange solid, mp 171-174C.
' Example 22 ' 2,6-Bis[(l-morpholinoethylidene)amino]anthraquinone - A 72 y portion of 2,6-diaminoanthraquinone, 300 ml of triethylorthoacetate and 250 ml of aGetic anhydride are refluxed for 3 hours, cooled in an ice bath and the resulting brownish crystals are collected'by filtration, washed with etherand dried gi-~ing N~Nl-2l6-anthraquinonylenedi-acetimidic acid diethyl ester.
A 7.56 g portion of this imino ether and 40 ml of morpholine are heated in an oil bath at 135C with à reflux condenser for 18 hours. The mixture is cooled in an ice bath.
The brownish crystals are collected by filtration, washed with ether and dried in vacuo. These crystals are slurried in 100 ml of dimethylformamide, heated to boiling and filtered.
The filtrate is stirred in a refrigerator for 3 hours and the yellow-orange crystals are collected by filtration and dried ln vacuo, mp 285-288C. ' .
Example 23 ' 2,6-Bis[(l-morpholinopropylidene)amino]anthraquinone A mixture of 8.12 g of N,N'-2,6-anthraquinonylenedi-propionimidic' acid diethyl ester (Example 17) and 40 ml ofmorpholine are heated in an oil bath with a reflux condenser at 130C for 18 hours. The mixture is then cooled in an ice bath and the dark yellow solid is collected by filtration, - ~9~31;Z7 washed with ether and dried in vacuo at 80C, mp 220-223C.
Example 24 2,6-Bis~[l-(4-methylpiperidino)ethylidene]-amino~anthraquinone A 7.56 g portion of N,N'-2,6-anthraquinonylenedi-acetimidic acid diethyl ester and 40 ml of 4-methylpiperidine are heated in an oil bath at 130C with a reflux condenser for 18 hours. The mixture is cooled in an ice bath, the orange solid is collected by filtration, washed with ether and dried in vacuo at 80C. This solid is recrystallized from 100 ml of methyl cellosolve and the yellow crystals are dried ln vacuo at 80C, mp 200-202C.
Example 25 2,6-Bis'~[1-(4-methylpiperidine)propylidene]-amino}anthraquinone A mixture of 8.12 g of N,N'-2,6-anthraquinonylenedi-propionimidic acid diethyl ester and 40 ml of 4-methylpiperi-dine is heated with a reflux condenser at 130C for 18 hours.
The reaction mixture is cooled in an ice bath and is filtered.
The-filtrate is concentrated in vacuo to a dark brown gum which is taken up in 50 ml of methyl cellosolve with heating.- The solution is stored in a freezer for 2 hours.
The product is collected by filtration and is washed with a small amount of methyl cellosolve then with diethyl ether.
The product is dried in vacuo at 80C to give yellow crystals, mp 150-153C.
Example 26 -N',N"'-2,6-Anthraquinonylenebis(N,N-dipropyl)propionamidine A mixture of 8.12 g of N,N'-2,6-a~thraquinonylenedi-propionimidic acid diethyl ester, 45 ml of di n-propylamine and 2.35 ml of glacial acetic acid is heated at 110C in an oil bath with a reflux condenser for 18 hours. The reaction mixture is cooled to room temperature and is filtered, the ~L~98~Z7 precipitate is washed with diethyl ether. The combined filtrate and washings are concentrated ln vacuo to a dark brown syrup which is taken up in about 50 ml of methyl alcohol and is stored in a freezer overnight.
The product is collected by filtration and is dried in vacuo to give orange crystals, mp 125-128C.
Example 27 N',N'ii-2,6-AnthraquinonylenekistN,N-dibutyl)propionamidine A mixture of 8.12 g of N,N'-2,6-anthraquinonylenedi-propionimidic acid diethyl ester, 50 ml cf di-n-butylamine and 2.35 ml of glacial acetic acid is heated in an oil bath at 150C for 18 hours. The reaction mixture is cooled in an ice bath and diluted with an equal volume of diethyl ether. The resulting reddish-brown solid is collected by filtration, washed with ether and is dried in vacuo. The dried material is taken up in about 40 ml of methanol and allowed to stand in the refrigerator overnight. The solution is filtered and the orange crystals are dried ln vacuo at 80C. The product is recrystallized from 30 ml of 2B ethyl alcohol to give orange crystals, mp 115-117C.
- Example 28 Nl,N"'-2,6-Anthraquinonylenebis(N-butyl-N-methyl)-.
~; propionamidine A mixture of 8.12 g of N,N'-2,6-anthraquinonylenedi-propionimidic acid diethyl ester, 45 ml of N-methyl butylamine and 2.35 ml of acetic acid is heated at 130C in an oil bath with a reflux condenser for 18 hours. The reaction mixture is cooled to room temperature and filtered. The filtrate is concentrated ln vacuo to a dark brown syrup which is taken up in 30 ml of methanol and is stored in a freezer. After 2 hours the orange crystals are filtered and washed with a small amount of methanol and dried ln vacuo. The product is then recrystallized from 30 ml of methanol to give yellow crystals, `
, 1~9~3~Z7 mp 80-82C.
Example 29 2,6~Bis~[(4-methylpiperidino)methylene]amino~anthraquinone A mixture of 6.8 g of N,N'-(2,6-anthraquinonylene)-di-formimidic acid diethyl ester and 8.93 g of 4-methylpiperi-dine is heated in an oil bath at 140C for 2 hours in a flask fitted with a short Vigreux Column fused to a take-off con-denser,- during this time the 78C distillate is allowed to boil off. The reaction mixture is allowed to cool in the oil bath overnight, then is triturated with two 50 ml portions of hexane. The rust brown solid is air dried, recrystallized from 275 ml of boiling methyl cellosolve and filtered hot to clarify. The filtrate is cooled to 4C and the solid is fil-tered and washed with methyl cellosolve followed by 2B ethyl alcohol. The product is dried in vacuo at 78C over phos-phorous pentoxide to give an orange solid, mp 229-233C.
Example 30 2,6-Bis(4,5,6,7-tetrahydro-3H-azepin-2-ylamino)anthraquinone A mixture of 11.9 g of 2,6-diaminoanthraquinone, 28.0 g of 1-aza-2-methoxy-1-cycloheptene and 6.0 g of glacial acetic acid in 50 ml of N,N-dimethylacetamide is heated under reflux in an oil bath for 2 hours. The mixture is cooled to room temperature and lOO ml of diethyl ether is added. The product formed is filtered and is washed copiously with di-methyl sulfoxide, ethyl alcohol and finally ether to give greenish-yellow crystals. This material is dissolved in chloroform and is filtered. The filtrate is evaporated to about 30 ml and the final product i5 precipitated out with ether. Filtration and washing with ether gives orange-yellow crystals, mp 295-298C.

Example 31 N',N"'-2,6-AnthraquinGnylenebis(N,N'-diethyl)-propionamidine A 72 g portion of 2,6-diaminoanthraquinone, 300 ml of triethyl ortho propionate and 250 ml of acetic anhydride are refluxed for 2 hours and then cooled in an ice bath. The reddish-brown solid is collected by filtration, washed with ether and dried. This material is slurried in one liter of chloroform and filtered. The filtrate is treated with acti-vated charcoal, filtered and concentrated in vacuo to theorange solid N,N'-2,6-anthraquinonylenedi-proplonimidic acid diethyl ester.
An 8.12 g portion of the above imino ether, 65 ml of diethyl amine and 2.35 ml of glacial acetic acid are heated in a bomb at 125C for 16 hours. The bomb is cooled in an ice bath and then opened. The reaction mixture is filtered and the filtrate is concentrated in vacuo to a tacky solid. -~
This solid is taken up in 30 ml of methanol with the aid of heat and then stored in a freezer for 2 hours. The orange-yellow crystals which form are collected by filtration, washed-with a small amount of methanol and dried in vacuo.
Thls material is slurried in 50 ml of m~thanol, heated to boiling and the insoluble yellow solid is collected by filtra-tion. This solid is slurried in 50 ml of water and filtered giving a yellow solid which is dried in vacuo at 8QC, mp 147-150C.
Examp]e 32 N',N"'-2,6-Anthraquinonylenebis(N-butyl-N-methyl)-acetamidin_ A mixture of 72 g of 2,6-diaminoanthraquinone, 300 ml of triethyl orthoacetate and 250 ml of acetic anhydride is refluxed for 3 hours, cooled in an ice bath and the brown crystals are collected by filtration, washed with ether and ~(~9~3~2~7 dried. This material is slurried in 800 ml of chloroform, filtered and the filtrate is concentrated ln ~acuo to the orange solid N,N'-2,6-anthraquinonylenedi-acetimidic acid diethyl ester.
A 7.56 g portion of the above imino ether, 45 ml of N-methyl butylamine and 2.35 ml of glacial acetic acid is heated in an oil bath for 17 hours and then filtered. The filtrate is evaporated ln vacuo to a brown gum. This gum is dissolved, with the aid of heat, in 30 ml of methanol and then stored in-a freezer for 2 hours. The orange crystals are collected by filtration, washed with methanol, dried and recrystallized from 30 ml of methanol giving the product as orange crystals, mp 114-116C.
Example 33 N',N"'-2,6-Anthraquinonylenebis(N,N'-dimethyl)-propionamidine To a solution of 24.2 g of N,N-dimethylpropionamide in 200 ml of acetonitrile, which is cooled in an ice-water bath to 5-15C is added dropwise 21.6 ml of phosphorous oxychloride. The resulting mixture is stirred at room tem-perature for 30 minutes, then 23.8 g of 2,6-diaminoanthra-quinone is added and stirring is continued at room temperature for 1~ hours. The mixture is then stirred for 5 hcurs at 60C.
The reaction mixture is poured into one liter of ice-water, is stlrred and is then filtered through a slntered glass funnel. The material retained on the funnel is extracted repeatedly with water and the combined solution of filtrate and extracts is made basic with 5N sodium hydroxide. The oran~e cryytals formed are collected by filtration. The crystalline material is washed with water and air dried. The product is then recrystallized from methyl cellosolve to give orange crystals, mp 206-209C.

lC~9~31Z7 .

Example 34 N',N'''-(2,6-Anthraquinonylene)bis-N,N-diethy~
acetamidine dihydrochloride A portion of N',N"'-(2,6-anthraquinonylene)bis-N,N-diethyl acetamidine is suspended in methyl alcohol and methan-olic HCl is added with stirring until solution is achieved, diethyl ether is added until cloudiness develops. The solution is kept at 0C overnight then is filtered. The precipitate collected is the dihydrochloride salt of N',N' -(2,6-anthra-quinonylene)bis-N,N-diethylacetamidine.
Example 35 2,6-Bis(piperidinomethyleneamino)anthraquinone dihydrochloride trihydrate A 6.1 g portion of 2,6-bis(piperidinomethyleneamino)-anthraquinone, as prepared in Example 12, is slurried in 300 ml of chloroform and is filtered. To the filtrate ls added 10 ml of 4.5_ hydrochloric acid in isopropyl alcohol resulting in formation of a pale orange precipitate which is stored at -10C then is filtered. The collected product is washed on the filter with chloroform and is dried at 78C ln vacuo over phosphorous pentoxide to give a pale orange solid as the tri-hydrate of the dihydrochloride.
Example 36 ., .
;~ N',N"'-2,6-Anthraquinonylenebis(N,N-diethyl)benzamidine To a solution of 75.2 g of diethylamine in 600 ml of diethyl ether is added a solution of 56.3 g of benzoyl chlor-ide in 100 ml of ether. The mixture is stirred at room tem-perature for 2 hours, then 50 ml of water is added in order to dissolve any excess amine and amine hydrochloride. The ether layer is washed with 3 additional portions of water and then is dried over anhydrous sodium sulfate. The ether is removed _ vacuo to give N,N-diethylbenzamide as a colorless oil .

1l;~9131Z7 To a'stirred solution of 23.8 g of the above product in 200 ml of acetonitrile maintained at 5-10C in an ice-water bath is added 36.8 g of phosphorous oxychloride. The ice-water bath is removed and the resulting mixture is stirred at room temperature for one hour. A 23.8 g portion of 2,6-diaminoanthraquinone is then added and the mixture is stirred at 60C for 10 hours. The reaction mixture is then poured into 600 ml of ice-water and made basic wi-th 5N sodium hydrox-,ide solution~ The product is formed as orange crystals which are collected by iltration and are washed with water. The 'product is then recrystallized from chloroform/hexane to give reddish-orange crystals, mp 243-246C.' Example 37 2,6-Bis(~-~iperidinobenzylideneamino)anthraquinone , ,, 15 To a stirred solution of 28.6 g of benzoylpiperidine in 150 ml of acetonitrile maintained at 5-10C in an ice-water bath i- added 18.4 g of phosphorous oxychloride. The , ice-water bath is removed and the resulting mixture is stirred at room temperature for one hour. A 11.9 g portion of 2,6-diaminoanthraquinone is then added and the mixture is stirred ' at 60C for 10 hours. The reaction mixture is then poured - into 500-ml of ice-water and made basic with 5_ sodium hydrox-,' ' ide solution. The product is formed as orange crystals which are collected by filtration and are washed with water. The product is then recrystallized from chloroform/acetone to give ' orange crystals, mp 264-266C.
Example 38 'N',N"'-(2,6-Anthraquinonylene)bis-N-piperidino-N-.
' _-chlorobenzylidene To a stirred solution of 33.55 g of _-chlorobenzoyl piperidine in 100 ml of acetonitrile cooled at 5-15C in an ice-water bath is added 10.8 ml of phosphorous oxychloride over a 30 minute perlod. The ice-water bath is removed' and ;:

~9~

stirring is continued at room temperature for 30 minutes, then 11.9 g of 2,6-diaminoanthraquinone is added and stirring is continued at room temperature for one hour, then at 60C for ~0 hours. The reaction mixture is then cautiously poured into a mixture of 500 ml of ice-water and stirring is continued for one hour gradual1y adding 75 ml of lON sodium hydroxide.
The reddish solid is collected by filtration, is washed with water and is dried in vacuo at 80C. The dried material is slurried in 300 ~1 of chloroform and is filtered. The filtrate is washed 4 times with water, is dried over magnesium sulfate, is filtered and concentrated ln vacuo. The résidue is slur-ried with 50 ml of methyl alcohol and is filtered to collect the orange crystals which are washed with diethyl ether. The product is dried ln v~cuo to give orange crystals, mp 275-277C.
Example 39 N',~"'-(2,6-Anthraquinonylene)bis-N-diethyl-N-p-chlorobenzylidine To a stirred solution of 31.75 g of N,N-diethyl-_-chlorobenzamide in 100 ml of acetonitrile cooled at 5-15C
in an ice-water bath is added 10.8 ml of phosphorous oxy-chloride over a 30 minute period. The ice-water bath is re-moved and stirring is continued at room temperature for 30 minutes, then 11.9 g of 2,6-diaminoanthraquinone is added and stirring is continued at room temperature for one hour, then at 60C for 20 hours. The reaction mixture is then cautiously poured into a mixture of 500 ml of ice-water and stirring is continued for one hour gradually adding 75 ml of lON sodium hydroxide. The red solid is collected by filtration, is washed with water and is dried ln vacuo at 80C. The dried material is slurried in 300 ml of chloroform and is filtered. The filtrate is washed 2 times with water, is dried over magnesium sulfate, is filtered and concentrated in vacuo to a syrup.

1~91~127 This material is slurried with 25 ml of methyl alcohol and the orange-red crystals formed are collected by filtration.
The product is washed with diethyl ether and is dried in vacuo, mp 253-255C.
Example 40 N',N"'-2,6-Anthraquinonylenebis[N-isopropyl acetamidine]
To a solution of 99.2 g of isopropylamine in 600 ml of ether is added 60 g of acetyl c~lloride at -10 in a methanol-ice bath. The reaction mixture is kept at room temperature for 4 hours and then filtered. The fil-trate is concentrated under reduced pr ssure giving an oil. This oil is distilled giving N-isopropyl acetamide as a colorless oil.
A 23.8 g portion of 2,6-diaminoanthraquinone, 36.8 g of pho~phorous oxychloride, 30.3 g o N-isopropyl acetamide and 200 ml of acetonitrile are reacted as de-scribed in Example 1 giving the product as orange crystals mp 264-267C.
Example 41 N',N'"-2,6-Anthraquinonylenebis[N-methyl acetamidine]
A mixture of 21.8 g of N-methyl acetamide, 23.8 g of 2,6-diaminoanthraquinone, 36.8 of phosphorous oxychloride and 200 ml of acetonitrile are reacted as described in Example 1 resulting in a brown crude product as orange crystals, mp 266-269C.
Example 42 N',N"'-2,6-Anthraquinonylenebis~N,N-diethyl acetamidine]
4,4'-methylenebis[3-hydroxy-2-naphthoate -A 4.326 g portion of N',N"'-2,6-anthraquinony-lenebis~N,N-diethyl acetamidine] and 3.884 g of pamoic - -,. . ,:~,, .., . ~ ,.

~9~1~7 acid are dissolved in 20 ml of dimethylformamide and then filetered. Ether is added causing the product to precipi-l:ate as yellow crystals of the pamoate salt, mp 253-255C.
~.
N~,N"'-2,6-Anthraquinonylenebis[N,N-dlmethyl cyclopro-panecarboxamidine To a solution of 300 ml of 40% aqueous dimethyl-amine in 500 ml of ether is added 52.0 g of cyclopropane carboxylic acid chloride in 100 ml of ether dropwise at 10-25C. The mixture is stirred at room temperature for 2 hours. A 50 ml portion of water is added. The ether layer is separated, washed with three 50 ml portions of water, dried over Na2SO4 and filtered. The ether is re-moved and the residue is distilled giving N,N-dimethyl cyclopropanecarboxamide as a colorles~ oil.
A 34.0 g portion of the above product, 23.8 g of 2,6-diaminoanthraquinone, 36.8 g of phosphorous oxy-chloride and 20~ ml of acetonitrile are reacted as de-scribed in Example 1. Recrystallization from 2-methoxy-ethanol giVes the product as orange crystals, mp 241-243C.
Example 44 N',N"'-2,6-Anthraquinonylenebis~N,N-diethyl cyclopro-panecarboxamidine]
A 134 ml portion of' diethylamine in 600 ml of ether and 52.0 g of cyclopropane carboxylic acid chloride are reacted as described in Example 45 giving N,N-diethyl-cyclopropanecarboxamide as a colorless oil.
A 42.4 g portion of the above product, 23.8 g of 2,6-diaminoanthraquinone, 36.8 g of phosphorous oxy-chloride and 200 ml of acetonitrile are reacted as de-~9~3~;27 scribed in Example 1. Recrystallization from 2-methoxy-ethanol gives the product as orange crystals, mp 166-168C.
Example 45 N',N"'-2,6-Anthraquinonylenebis[N,N-dimethyl cyclobutane-carboxamidinel To a solution of 19.1 g of N,N-dimethyl cyclo-butanecarboxylic acid amide in 150 ml of acetonitrile was added 18.4 g of phosphorous oxychloride at 5-10C. The resulting mixture was stirred at room temperature for 1 hour. Then, 11.9 g of 2,6-diaminoanthraquinone was added.
; The mixture was stirred at 60C. for 10 hours, poured into 600 ml of ice-water and then basified with 5N NaOH. Orange ; crystals were collected by filtration and washed with water.The crystals were dissolved in chloroform and filtered.
The chloroform was removed under reduced pressure. Re-crystallization of the residue from methyl cellosolve gave 16.2 g of orange crystals, mp 209-211C.
Example 46 2,6-Bis[(l-methyl-2-pyrrolidinylidene)amino]anthraquinone To a solution of 34.5 g of 1-methyl-2-pyrroli-dinone in 150 ml of CH3CN was added 18.4 g of phosphorous oxychloride at 5-10C. The mixture was stirred at room temperature for 1 hour. To the mixture was added 11.9 g of 2,6-diaminoanthraquinone. The resulting mixture was stirred at 60C for 10 hours, poured into 1000 ml of ice--water and basified with 5N NaOH. Réddish crystals thus obtained were collected by filtration and washed with water. Recrystallization from methyl cellusolve gave 14.0 g of reddish crystals, mp 267-269C.

9~31;27 -`

Example 47 r N',N"'-2,6-Anthraquinonylenebis[N,N,2-trimethyl~ropion-amldlne To a solution of 23.3 g of N,~,2-trimethylpropion-amide in 150 ml of acetonitrite was added 36.8 g of phos-phorous oxychloride at S-10C. The resulting mixture was stirred at room temperature for 1 hour. Tl~en 23.8 g of 2,6-diaminoanthraquinone was added. The mixture was stir-red at 60C. for 10 hours, poured into 600 ml of ice-water and then basified with 5N NaOH. Orange crystals were col-lected by filtration and washed with water. The crystals were dissolved in chloroform and filtered. The chloroform was removed under reduced pressure. Racrystallization of the residue from methyl cellusolve gave 8.0 g of orange crystals, mp 166-168C.
Example 48 N',N"'-2,6-Anthraquinonylenebis[N-ethylacetamidine]
To a solution of 26.1 g of N-ethylacetamide in 200 ml. of acetonitrile was added 36.8 g of phosphorous oxychloride at 5-10~C. The resulting mixture was stirred at room temperature for 1 hour. Then, 23.8 g of 2,6--diaminoanthraquinone was added. The mixture was stirred ; at 60C for 10 hours, poured into 600 ml of ice-water and then basified with 5N NaOH. Orange crystals were collected ~y filtration and washed with water. The orange crystals were dissolved in chloroform and filtered. The chloro-form was removed under reduced pressure. Final recrystal-lization from a CHC13/hexane mixture gave 10;5 g of orange crystals, mp 271-273C.

-- 2g --:~9~ 7 Example 49 N' N"'-2 6-Anthra uinon lenebis[N,N-dieth l]acetamide Y Y
succinate ~ 4.33 g portion of N',N"'-2,6-anthraquinony-lenebis(N,N-diethyl)acetamidine in 100 ml of chloroform and 1.18 g of succinic acid in 100 ml of methanol were mixed. The resulting solution was evaporated under re-duced pressure to dryness. The resulting yield was 5.5 g of orange crystals mp 165-166C.
Example 50 N',N"~-2,6-Anthraquinonylenebis[N,N-dimethyl-3-dimethyl-propionamidine To a solution of 19.4 g of N,N-dimethylpival-amide in 100 ml of acetonitrile was added 18.4 g of phos-phorous oxy¢hloride at 5-15C. over a 30 minute period.
The resulting mixture was stirred at room temperature for 30 minute~, and then heated in an oil bath at 60~C for one hour. Then, 11.9 of 2,6-diaminoanthraquinone was added and the temperature of the oil bath was raised to 78C for 20 hours. Next, the mixture was poured into 500 ml of ice-water. The mixture separated into oil and aqueous phases.
The aqueous phase was decanted from the oil and filtered.
The filtrate was basified with 75 ml of 10N NaOH. Consid-erable solid was precipitated, collected and washed 3 times with water and dried to result in a product with a melting point, 158-160C.
Example 51 N',N"'-2,6-Anthraquinonylenebis[N,N-dimethyl-p-chloro-henzamidine]
To a stirred solution of 27.6 g of N,N-dimethyl--~ass~27 -p-chlorobenzamide in lO0 ml of acetonitrile cooled at 5-15C in an ice-water bath is added 10.8 ml of phosphor-ous oxychloride over a 30 minute period. The ice-water bath is removed and stirring is continued at room temper-ature for 30 minutes, then 11.9 g of 2,6-diaminoanthraquin-one is added and stirring is continued at room temperature for one hour, then at 60C for 20 hours. The reaction mix-ture is then cautiously poured into a mixture of 500 ml of ice-water and stirring is continued for one hour grad-ually adding 75 ml of lON sodium hydroxide. The orange solid is collected by filtration, is washed with water and is dried in vacuo at 80C. The dried material is slurried in 300 ml of chloroform and is filtered. The filtrate is wa~hed 2 time8 wlth water, i~ drled over magnesium sulfate, iQ filtered and concentrated in vacuo to a syrup. Thi~
material is slurried with 25 ml of methyl alcohol and the red crystals formed are collected by filtration. The pro-duct is washed with diethyl ether and is dried ln vacuo, mp 296-298C.

Claims (48)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A method of preparing a 2,6-anthroquinonylamidine of the formula (I) wherein R1 is hydrogen, alkyl, branched alkyl, cycloalkyl (C1-C15) heterocyclic phenyl or substituted phenyl; and R2 and R3 are each hydrogen, phenyl, substituted phenyl, alkyl or branched alkyl, or R2 and R3 taken together with the nitrogen atom to which they are attached form a heterocyclic ring, and pharma-ceutically acceptable salts thereof, which comprises (a) reacting 2,6-diaminoanthraquinone with a complex formed by mixing phosphorous oxychloride and an N,N-dialkylamide or N-alkylamide in an inert solvent at a temperature of about 25° to 70°C for a period of about 1 to 24 hours;
(b) reacting 2,6-diaminoanthraquinone with a 2-methoxy-1-cycloalkene in a dimethylacetamide or dimethylformamide at a reflux temperature for a period of about 1 to 12 hours;
(c) refluxing 2,6-diaminoanthraquinone with triethyl ortho acid and acetic anhydride for a period of about 1 to 8 hours;
(d) combining diethyl N,N'-(2,6-anthraquinonylene)-di-formimidate with a primary or secondary amine and heating at a temperature of about 130°-200°C for about 2 to 18 hours;

(e) combining diaminoanthraquinone with dialkylamide dialkylacetal and heating at about 130°C-10°C for about 2-66 hours; or (f) combining diaminoanthraquinone with an amide and an aryl sulfonyl halide and heated at about 90°C for about 2-3 hours, and, if necessary (g) converting a free base product to a pharmaceut-ically acceptable salt or vice versa.

2. A 2,6-anthraquinonylamidine of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof, when-ever prepared by the method of claim 1, or by an obvious chemical equivalent thereof.

3. A method of preparing N',N'"-2,6-anthraquinonylenebis-[N,N-dimethyl formamidine], which comprises heating 2,6-diamino-anthraquinone with N,N-dimethylformamide diethyl acetal.

4. N',N'"-2,6-Anthraquinonylenebis[N,N-dimethyl form-amidine], whenever prepared by the method of claim 3, or by an obvious chemical equivalent thereof.

5. A method of preparing N',N'"-(2,6-anthraquinonylene) bis-N,N-diethyl acetamidine, which comprises reacting 2,6-di-aminoanthraquinone with the complex formed by mixing phosphorous oxychloride and N,N-diethylacetamide.

6. N',N'"-(2,6-Anthraquinonylene)bis-N,N-diethyl acet-amidine, whenever prepared by the method of claim 5, or by an obvious chemical equivalent thereof.

7. A method of preparing N',N'"-(2,6-anthraquinonylene)-bis-N,N-diisopropyl formamidine, which comprises heating together 2,6-diaminoanthraquinone, diisopropylformamide and p-toluenesulfonyl chloride.

8. N',N'"-(2,6-Anthraquinonylene)bis-N,N-diisopropyl formamidine, whenever prepared by the method of claim 7, or by an obvious chemical equivalent thereof.

9. A method of preparing 2,6-bis-(piperidinomethylene-amino)anthraquinone, which comprises heating together N,N'-(2,6-anthraquinonylene)-di-formimidic acid diethyl ester and piperidine.

10. 2,6-Bis-(piperidinomethyleneamino)anthraquinone, whenever prepared by the method of claim 9, or by an obvious chemical equivalent thereof.

11. A method of preparing N',N'"-(2,6-anthraquinonylene)-bis(N,N-dimethyl)acetamidine, which comprises heating together 2,6-diaminoanthraquinone, N,N-dimethylacetamide and p-toluene-sulfonyl chloride.

12. N',N'"-(2,6-Anthraquinonylene)bis(N,N-dimethyl)-acetamidine, whenever prepared by the method of claim 11, or by an obvious chemical equivalent thereof.

13. A method of preparing 2,6-bis[(1-piperidinopropyli-dene)amino]anthraquinone, which comprises heating together N,N'-(2,6-anthraquinonylenedipropionimidic acid diethyl ester and piperidine.

14. 2,6-Bis[(1-piperidinopropylidene)amino]anthraquinone, whenever prepared by the method of claim 13, or by an obvious chemical equivalent thereof.

15. A method of preparing 2,6-bis[(1-piperidinoethyl-idene)amino]anthraquinone, which comprises heating together N,N'-2,6-anthraquinonylenediacetimidic acid diethyl ester and piperidine.

16. 2,6-Bis[(1-piperidinoethylidene)amino]anthraquinone, whenever prepared by the method of claim 15, or by an obvious chemical equivalent thereof.

17. A method of preparing 2,6-bis[(1-morpholinoethylid-ene)amino]anthraquinone, which comprises refluxing 2,6-diamino-anthraquinone, triethylorthoacetate and acetic anhydride to form N,N'-2,6-anthraquinonylenediacetimidic acid diethyl ether, and reacting this product with morpholine.

18. 2,6-Bis[(1-morpholinoethylidene)amino]anthraquinone, whenever prepared by the method of claim 17, or by an obvious chemical equivalent thereof.

19. A method of preparing 2,6-bis[(1-morpholinopropyl-idene)amino]anthraquinone, which comprises reacting N,N'-2,6-anthraquinonylenedipropionic acid diethyl ester with morpholine.

20. 2,6-Bis[(1-morpholinopropylidene)amino]anthraquinone, whenever prepared by the method of claim 19, or by an obvious chemical equivalent thereof.

21. A method of preparing 2,6-bis[1-(4-methylpiperidino)-ethylidene]amino anthraquinone, which comprises reacting N,N'-2,6-anthraquinonylenediacetimidic acid diethyl ether with 4-methylpiperidine.

22. 2,6-Bis[1-(4-methylpiperidino)ethylidene]amino anthraquinone, whenever prepared by the method of claim 21, or by an obvious chemical equivalent thereof.

23. A method of preparing N',N"'-2,6-anthraquinonylene-bis[N-isopropyl acetamidine], which comprises reacting 2,6-di-aminoanthraquinone, phosphorous oxychloride and N-isopropyl acetamide.

24. N',N'"-2,6-Anthraquinonylenebis[N-isopropyl acetamid-ine], whenever prepared by the method of claim 23, or by an obvious chemical equivalent thereof.

25. A method of preparing N',N'"-2,6-anthraquinonylene-bis[N-methyl acetamidine], which comprises reacting N-methyl acetamide, 2,6-diaminoanthraquinone and phosphorous oxychloride.

26. N',N'"-2,6-Anthraquinonylenebis[N-methyl acetamid-ine], whenever prepared by the method of claim 25, or by an obvious chemical equivalent thereof.

27. A method of preparing N',N'"-2,6-anthraquinonylene-bis[N,N-diethyl cyclopropanecarboxamidine], which comprises reacting N,N-diethyl cyclopropanecarboxamide, phosphorous oxy-chloride and 2,6-diaminoanthraquinone.

28. N',N'"-2,6-Anthraquinonylenebis[N,N-diethyl cyclo-propanecarboxamidine], whenever prepared by the method of claim 27, or by an obvious chemical equivalent thereof.

29. A method of preparing N',N'"-2,6-anthraquinonylene-bis[N,N-dimethyl cyclobutanecarboxamidine], which comprises reacting N,N-dimethyl cyclobutanecarboxylic acid amide with phosphorous oxychloride and then adding 2,6-diaminoanthraquinone.

30. N',N'"-2,6-Anthraquinonylenebis[N,N-dimethyl cyclo-butanecarboxamidine], whenever prepared by the method of claim 29, or by an obvious chemical equivalent thereof.

31. A method of preparing 2,6-bis[(1-methyl-2-pyrrolidin-ylidene)amino]anthraquinone, which comprises reacting 1-methyl-2-pyrrolidinone with phosphorous oxychloride and then adding 2,6-diaminoanthraquinone.

32. 2,6-Bis[(1-methyl-2-pyrrolidinylidene)amino]anthra-quinone, whenever prepared by the method of claim 31, or by an obvious chemical equivalent thereof.

33. A method of preparing N',N'"-2,6-anthraquinonylene-bis[N,N-diethyl acetamidine]-4,4'-methylenebis[3-hydroxy-2-naphthoate], which comprises reacting N',N'"-2,6-anthraquinonyl-ene bis[N,N-diethyl acetamidine] with pamoic acid.

34. N',N'"-2,6-Anthraquinonylenebis[N,N-diethyl acetamid-ine]-4,4'-methylenebis[3-hydroxy-2-naphthoate], whenever pre-pared by the method of claim 33, or by an obvious chemical equivalent thereof.

35. A method of preparing N',N'"-2,6-anthraquinonylene-bis[N,N-dimethyl cyclopropanecarboxamidine], which comprises reacting together N,N-dimethyl cyclopropanecarboxamide, 2,6-diaminoanthraquinone and phosphorous oxychloride.

36. N',N'"-2,6-Anthraquinonylenebis[N,N-dimethyl cyclo-propanecarboxamidine], whenever prepared by the method of claim 35, or by an obvious chemical equivalent thereof.

37. A method of preparing N',N'"-2,6-anthraquinonylene-bis[N,N,2-trimethylpropionamidine], which comprises reacting N,N,2-trimethylpropionamide with phosphorous oxychloride and then adding 2,6-diaminoanthraquinone.

38. N',N'"-2,6-Anthraquinonylenebis[N,N,2-trimethyl-propionamidine], whenever prepared by the method of claim 37, or by an obvious chemical equivalent thereof.

39. A method of preparing N',N'"-2,6-anthraquinonylene-bis[N-ethyl acetamidine], which comprises reacting N-ethyl-acetamide with phosphorous oxychloride and then adding 2,6-di-aminoanthraquinone.

40. N',N'"-2,6-Anthraquinonylenebis[N-ethyl acetamidine], whenever prepared by the method of claim 39, or by an obvious chemical equivalent thereof.

41. A method of preparing N',N'"-2,6-anthraquinonylene-bis[N,N-diethyl acetamidine] succinate, which comprises reacting N',N'"-2,6-anthraquinonylenebis(N,N-diethyl)acetamidine with succinic acid.

42. N',N'"-2,6-Anthraquinonylenebis[N,N-diethyl aceta-midine] succinate, whenever prepared by the method of claim 41, or by an obvious chemical equivalent thereof.

43. A method of preparing N',N'"-2,6-anthraquinonylene-bis[N,N-diethyl acetamidine]dihydrochloride, which comprises reacting N',N'"-2,6-anthraquinonylenebis-N,N-diethyl acetamidine with hydrochloric acid.

44. N',N'"-2,6-Anthraquinonylenebis[N,N-diethyl acetamid-ine]dihydrochloride, whenever prepared by the method of claim 43, or by an obvious chemical equivalent thereof.

45. A method of preparing N',N'"-2,6-anthraquinonylene-bis[N,N-dimethyl propionamidine], which comprises reacting N,N-dimethylpropionamide with phosphorous oxychloride and then adding 2,6-diaminoanthraquinone.

46. N',N'"-2,6-Anthraquinonylenebis[N,N-dimethyl propion-amidine], whenever prepared by the method of claim 45, or by an obvious chemical equivalent thereof.

47. A method of preparing N',N'"-2,6-anthraquinonylene-bis[N,N-dimethyl-p-chlorobenzamidine], which comprises reacting N,N-dimethyl-p-chlorobenzamide with phosphorous oxychloride and then adding 2,6-diaminoanthraquinone.

48. N',N'"-2,6-Anthraquinonylenebis[N,N-dimethyl-p-chlorobenzamidine], whenever prepared by the method of claim 47, or by an obvious chemical equivalent thereof.