IE47253B1 - Anthraquinone derivatives - Google Patents

Abstract

The invention pertains to anthraquinone derivatives of the following general formula: the tautomeric forms and the pharmacologically acceptable acid-addition salts thereof, wherein A-B is selected from CH-CH and CH2-CH2; Q is a divalent optionally branched C2-C4 alkylene moiety, wherein R1 and R2 are each individually hydrogen, C1-C4 alkyl monohydroxy C2-C4 alkyl wherein the carbon atom alpha to the nitrogen atom may not bear an hydroxy group, dihydroxy C3-C6 alkyl wherein the carbon atom alpha to the nitrogen atom may not bear an hydroxy group, formyl, C2-C4 alkanoyl trifluoroacetyl and moieties of the formulae: -(CH2)n-CN, -(CH2)n-O-R and wherein n is an integer from 2 to 4, inclusive, R is C1-C4 alkyl and R3 and R4 are each individually hydrogen, C1-C4 alkyl and monohydroxy C2-C4 alkyl wherein the carbon atom alpha to the nitrogen atom may not bear an hydroxy group; and R1 and R2 taken together with their associated N atom and R3 and R4 taken together with their associated N atom is morpholino, thiomorpholino, piperazino, 4-methyl-1 -piperazino or a moiety of the formula: wherein m is an integer from 2 to 6, inclusive; with the proviso that the ratio of the total number of carbon atoms to the sum of the total number of oxygen atoms plus the total number of nitrogen atoms in the side chains at the 1-position and the 4-position may not exceed 4; R5 is hydrogen, hydroxy, chloro and C1-C6 alkanoyloxy; R6 is hydrogen and hydroxy; R7 is hydrogen, hydroxy, chloro, C1-C6 alkanoyloxy and a moiety of the formula wherein R8 and R9 are each individually methyl, ethyl, and beta -hydroxy- ethyl; provided that when R5 is OH then one of R6 and R7 must be H, and when R5 is H then both of R6 and R7 must be H. The above-defined anthraquinone derivatives, many of which are novel per se, have a number of useful properties, including in many cases activity as anti-tumor agents.

Description

This invention relates to new organic compounds, to processes for their preparation, and to pharmaceutical compositions comprising the net/ organic compounds of the invention, and related compounds..

More particularly, according to one aspect, the invention relates to new organic compounds of the following general formula: and the tautomeric forms and the pharmacologically acceptable acidaddition salts thereof, wherein A-B is selected from from those of the formulae: CH CH=CH and CH2-CH2; Q is a divalent moiety selected CH, -ICH.) -, z n 2B5 -CH-CH2-, -CH-CH2-, ?2H5 -CH2-CH-, CH, ^3^3 -CH-CH-, -CH2-CH- , -CH-CH2-CH2-, -cii2-ch-ch2-. and -ch2-ch2 wherein n is an integer from 2 to 4, inclusive; R and R. are X each individually selected from hydrogen, alkyl having from 1 to 4 carbon atoms, monohydroxyalkyl having from 2 to 4 carbon atoms and wherein the carbon atom alpha to the nitrogen atom may not bear an hydroxy group, dihydroxyalkyl having from 3 to 6 carbon atoms and wherein the carbon atom alpha to the nitrogen atom may not bear an hydroxy group, formyl, alkanoyl having from 2 to 4 carbon atoms, trifluoroacetyl and moieties of the formulae: -(αΐ2)η-Ο1 , -(CH2)n-o-R and -(CII2)n-N wherein n is an integer from 2 to 4, inclusive, R is alkyl having from 1 to 4 carbon atoms, and R3 and R4 are each individually selected from hyurogen, alkyl having from to 4 carbon atoms and monohydroxyalkyl having from 2 to 4 carbon atoms and wherein the carbon atom alpha to the nitrogen atom may not bear an hydroxy group; or R^ and R2 taken together with their associated N(itrogen) atom or and R^ taken together with their associated N(itrogen) atom is morpholino, thiomorpholino, piperazino, 4-methy1-1-piperazlno or a moiety of the formula: wherein m is an integer from 2 to 6, inclusive; with the proviso that the ratio of the total number of carbon atoms to the sum of the total number of oxygen atoms plus the total number of nitrogen atoms in the side chains at the 1-position and the 4-position may not exceed 4; R5 is selected from hydrogen, hydroxy, chloro and alkanoyloxy of from 1 to 5 carbon atoms; Rg is selected from hydrogen and hydroxy; Ry is selected from hydrogen, hydroxy, chloro, alkanoyloxy of from 1 to 5 carbon atoms and a moiety of the formula /Rg -NH-CH,CH -N Z J R wherein Rg and Rj are each individually selected from methyl, ethyl, and P -hydroxyethyl; 47853 provided that when Q is -(CHg)- then: a) Rp Rg, Rg, Rg and Ry may not simultaneously be hydrogen; b) when Rg, Rg and Ry are hydrogen R^/Rg cannot be H/monohydroxyalkyl, and: when n is 2 then R-j/Rg cannot be -(CHgJg-O-^Hg^-, H/CHg, or together with their associated nitrogen morpholins, H/Cgl·^. CgHg/CgHg, and when n is 3 R^/Rg cannot be CHg/CHg, -(CHg)g-, or together with their associated nitrogen piperidino; c) when Rg and Ry are hydroxy and Rg is hydrogen and:n is 2 then R-j/Rg may not be CHg/CHg, C^Hg/C^Hg, -(CHg)g-, or together with their associated nitrogen piperidino n is 3 then R^/Rg may not be H/H, CH3/CH3, C3Hy/C3Hy, -(CHgJg-O^CHgJg-, or together with their associated nitrogen morpholino n is 4 then R-j/Rg may not be CgHg/CgHg, C^Hg/C^Hg, -(CHg), or together with their associated nitrogen pyrollidino; d) when Rg is OH then one of Rg and Ry must be H, when Rg is H then both of Rg and Ry must be H; and e) Only one of R^ and Rg may be alkanoyl.

The compounds of the above general formula I wherein A-B is CHg-CHg are generally stable compounds and are known as the leuco forms of the corresponding anthraquinones. These leuco forms are known to exist in their respective tautomeric forms, and all such forms are equivalent for the purposes of the invention.

The leuco forms (herein, leuco bases), and the tautomers thereof may be represented by the following general formula: The compounds are generally obtainable as reddish brown to blue black crystalline materials having characteristic melting points and absorption spectra and which may be purified by leaching with lower alkanols since the free bases are 7 253 for the most part insoluble in water and some of them are insoluble in most organic solvents. The organic bases of this invention (I, II and XXI) form non-toxic addition salts with a variety of pharmacologically acceptable organic and inorganic salt-forming reagents. Thus, acid-addition salts, formed by admixture of the organic free base with 1,2 or up to eight equivalents of an acid, suitably in a neutral solvent, are formed with such acids as sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric, lactic, malic, succinic, tartaric, acetic, benzoic, gluconic, ascorbic, and the like. The preferred acids are hydrochloric and acetic. For purposes of this invention the free bases are equivalent to their non-toxic acid-addition salts. The acid-addition salts of the organic bases of the present invention are, in general, crystalline solids, relatively soluble in water, methanol and ethanol but relatively insoluble in non-polar organic solvents such as diethyl ether, benzene, toluene, and the like.

It will be understood by those skilled in the art that all such salts may be reconverted to their respective free forms represented by formulael, IX and III by methods known to those skilled in the art, and all such salts and free forms are therefore equivalent for purposes of the invention.

A preferred embodiment of the novel compound aspect of the present invention may be represented by the following formula: and the pharmacologically acceptable acid-iiddition salts thereof, wherein A-B and Q are as hereinbefore defined? is hydrogen, alkyl having from 1 to 4 carbon atoms or monobydroxyalkyl having from 2 to 4 carbon atoms and wherein the carbon atom alpha to the nitrogen atom may not bear an hydroxy group; is monohydroxyalkyl having from 2 to 4 carbon atoms and wherein the carbon atom alpha to the nitrogen atom may not bear an hydroxy group, dihydroxyalkyl having from 3 to 6 carbon atoms and wherein the carbon atom alpha to the nitrogen atom may not bear an hydroxy group or a moiety of the formula: (CH2)n-N^3 wherein n, R3 and R^ are as hereinbefore defined; with the proviso that the ratio of the total number of carbon atoms to the sum of the total number of oxygen atoms plus the total number of nitrogen atoms in each of the side chains at the 1-position and the 4-position may not exceed four.

A second preferred embodiment of the novel compound aspect of the present invention may be represented by the following general formula: and the pharmacologically acceptable acid-addition salts thereof, wherein R is hydrogen or alkyl having from 1 to 4 carbon atoms and A-B, n, and Q are as hereinabove defined with the proviso that the ratio of the total number cf carbon atoms to the sum of the t total number of oxygen atoms plus the total number of nitrogen atoms in each of tho side chains at the 1-position and the 4-position may not exceed 4.

A third preferred embodiment of the novel compound aspect of the present invention relates to compounds of the following formula: wherein n, R^, R,> and A-B are as defined above for the first preferred embodiment and the pharmacologically acceptable acid-addition salts thereof.

A fourth preferred embodiment of the novel compound aspect of the present invention relates to compounds of the following formula: wherein is hydrogen or -CI^CHjOH, and the pharmacologically acceptable acid-addition salts thereof. The preferred salts are the hydrochloride and the acetate.

The novel compounds of the present invention represented by formulae I, II and III may be readily 472S3 prepared by a number of processes.

Thus, one process contemplated by the instant invention comprises reacting a compound represented by the following general formula: with a compound of the formula Y[—- Ω3ψ----Z wherein Rg-Ry and Q are as defined hereinabove, one of X and Y is iiR.R.. or NHCOCF, wherein R, and R,, are as defined hereinabove Ιέ 5 I Λ arid the other is selected from OR^, Cl, Br, I, N(R ),, NO2, SO3R1q, SO2RjQ, SOR1(), SR1Q, Ν-., ONO and tetrazolyl, wherein R-^q is selected from hydrogen, alkyl of from 1 to 6 carbon atoms, phenyl, para-tolyl and benzyl; £ and T are different and are chosen from 0 and 1; Z is selected from the group consisting of hydrogen, alkyl of from 1 to 4 carbon atoms, and NRj !'2 wherein R^ and Rg are as defined hereinabove or a group convertible thereto; provided: a) that only X may be NHCOCF^ and only when S is O and Z is not hydrogen or alkyl; b) except as in a), when S is 0, then Rj/R2is JI/H and Z is not hydrogen or alkyl of from 1 to 4 carbon atoms; c) when T is 0 and Y is NR^Rg then Z is hydrogen; d) when T is 0 and X is NR^Rg at leaGt one °f is hydrogen and Z is alkyl of from 1 to 4 carbon atoms; 47353 e) when one of Rj and Ry is chloro or alkanoyloxy then the other is the same and Rg is hydrogen; and f) only one of R^ and Rg may be alkanoyl; and when R5 = Ry = chloro or alkanoyloxy converting them to hydroxy, and when X is NHCOCFg, removing the COCF3 group, and when Z is a group convertible to NR-^Rg effecting its conversion thereto; and, if desired: (i) converting A-B when it is CHg-CHg into CH=CH; and (ii) contacting the product with a pharmacologically acceptable salt-forming agent under salt-forming conditions.

The reaction is preferably carried out by heating the reactants at a temperature of from about 40° to 110°C. for a period of from 2 to 10 hours in a reaction inert solvent such as water, a lower alkanol, for example, methanol, ethanol, propanol, i_-propanol, any of the isomeric butanols and the like, or in an amide solvent such as formamide, dimethyl formamide and the like, or in a solvent such as Ν,Ν,Ν',Ν',- tetramethyl ethylenedlamine or mixtures thereof. The above temperatures, times and solvents and combinations thereof will most normally suffice for carrying out the instant process. Other solvents and reaction parameters may at times be desirable or required and the choice of such additional solvents and reaction parameters is within the skill of the art and are all considered equivalents for the purposes of the instant invention. 7 2 5 3 In most instances, the product will be a solid and will crystallize spontaneously or upon seeding or scratching, from the reaction solvent upon cooling and may be collected by filtration or decantation. In other instances the reaction mixture may be concentrated, for example at elevated temperature under vacuum, and upon cooling the product will crystallize and may be collected by filtration or decantation as above. In certain other instances it may be necessary to evaporate the solvent to dryness in order to collect the product or alternatively to mix or dilute the reaction mixture with another miscible solvent such as water an·’ proceed to collect the product by for example filtration or extraction. Those skilled in the art will be able to choose which procedure to follow and all such procedures are considered equivalent for the purposes of this invention. The product, once collected, may be purified by for example, crystallization, chromatography (thin layer or column) or preferably by leaching with a lower alkanol. Other procedures such as maceration or crushing in a solvent, for example, an organic solvent sucli as ethanol may be utilized and all purification procedures are to be considered as equivalents for purposes of the invention.

Those skilled in the art will recognize that when a product in the leuco form is desired, the tricyclic starting material should be in the leuco form, and care should be taken to protect such materials^ especially when at elevated temperatures (i.e. above room temperature) from oxidizing agents such as, for example oxygen. 47353 Thus, when a leuco product is desired the reaction is normally and efficiently carried out in an atmosphere to the exclusion of air. Thus, the reaction may be carried out in an atmosphere of nitrogen or argon, for 5 example, and this precaution should also be taken during purification procedures especially those requiring elevated temperatures. When an aromatic product is desired and an aromatic starting material is utilized no such precautions are normally necessary.

It is well known in the art that the leuco form may be readily converted to the aromatic form when desired by a variety of methods. Thus, air oxidation is one such method, other methods are treatment with for example, hot nitrobenzene, chloranil, hydrogen peroxide, or sodium perborate. All such methods, and other methods for conversion of the leuco form to the aromatic form, are to be considered equivalents for purposes of the invention.

Those skilled in the art will also understand that when the substituent Z is a group convertible to ,/Rl -Ν' that the said conversion will be able to be readily R2 carried out by obvious procedures, well known to those skilled in the art and within the skill of the art. Conversion of the group Z to Ν 1 by all of these procedures R2 is therefore contemplated by the instant invention and all such procedures are to be considered equivalent for purposes of the instant invention. The preferred procedures contemplat ed by the instant invention for converting the group Z into /R1 -N are exemplified below. It is to be understood that Xr2 . these are merely examples of the said conversion, and arc 30 not intended to delimit the scope of the instant invention.

Other conversion procedures will be known to those skilled in the art and are to be considered full equivalents for the purposes of the instant invention. Thus, when Z 0 I is an aldehyde or ketone group, i.e. -C-R, wherein R is 5 chosen from hydrogen or alkyl, treatment with an amine /R1 of the formula HN wherein R, and R„ are as herein \r2 defined under reducing conditions such as hydrogen with Raney nickel catalyst or sodium borohydride will accomplish the desired conversion.

Also contemplated for Z are moieties of the formula -N 0 ^CIi2>m wherein m is 2 or 3. Treatment of this group with acid, for example aqueous-ethanolic hydrogen chloride at 40-&0°C. for from 1 to 6 hours will convert it to -NH-(CH2 )-011 which is a moiety contemplated by the group -Ν 1 Xr2 Also contemplated for Z are efficient leaving groups, such as Cl, Br, I, para-tosyl, OSC^CH-j and the like. When Z is an above disclosed leaving group or an equivalent, treatment with an amine of the formula HN in for example a lower alkanol solvent will effect \r2 the desired conversion.

Xn addition, when Z is a primary or secondary amine i.e. -NH2 °r -NUR-jj then further alkylation will convert it to the desired group -N agents are known which will readily effect this conversion. Such agents as alkyl halides, alkyl sulfates, substituted Well known alkylating and unsubstituted acrylonitriles, and the like are contemplated, Aldehydes and ketones condensed under reducing conditions may also be utilized.

All such conversions and other conversion procedures are considered equivalents for the purposes of the invention.

A preferred embodiment of the primary process aspect of the present invention may be represented by the following reaction scheme; wherein Rj_, R21 Rg, Rg R? and Q are as hereinabove defined.

In accordance with this reaction scheme, leuco 1,4-dihydroxyanthraquinone (IV) is condensed with an appropriate alkylene diamine (V) in a solvent such as Ν',Ν,Ν’ ,N'-totramethylethylenediaminc, ethanol, water, dimethylformamide, or mixtures thereof 7253 at from about 40“C. to about 60°C. under an atmosphere of nitrogen for several hours to produce the corresponding leuco bases (II). The leuco bases (II) may be readily oxidized to the fully aromatic derivatives (I) by a variety of methods such as air oxidation or treatment with hot nitrobenzene, or treatment with chloranil, hydrogen peroxide, or sodium perborate. The product may then be contacted with a pharmacologically acceptable quaternizing or salt-forming reagent under quaternizing or salt-forming conditions.

A preferred embodiment of this process of the invention may be represented by the following reaction scheme A: wherein R^, U2and Q are as hereinabove defined.

One more preferred embodiment of this process of the invention is represented by the above reaction scheme A wherein U is as hereinabove 7 2 3 3 defined; Κχ is hydrogen or alkyl having from 1 to 4 carbon atoms; is monohydroxyalkyl having from 2 to 4 carbon atoms and wherein the carbon atom alpha to the nitrogen atom may not bear an hydroxy group, dihydroxyalkyl having from 3 to 6 carbon atoms and wherein the carbon atom alpha to the nitrogen atom may not bear an hydroxy group or a moiety of the formula: , -'CH2'n-I\.

R4 wherein n, R and R. are as hereinbefore defined; with the 3 4 proviso that the ratio of the total number of carbon atoms to the sum of the total number of oxygen atoms plus the total number Of nitrogen atoms in each of the side chains at the 1-position and the 4-position may not exceed four, and contacting the product with a pharmacologycallly acceptable acid, preferably acetic or hydrochloric, to prepare the pharmacologically acceptable acid addition salts thereof.

A second more preferred embodiment of this process of the invention is represented by the above reaction scheme A wherein R^ is hydrogen or alkyl having from 1 to 4 carbon atoms and Rg is-(CHg)nOH and n and Q are as hereinabove defined with the proviso that the ratio of the total number of. carbon atoms to the sum of total number of oxygen atoms plus the total number of nitrogen atoms in each of the side chains at the 1-position and the 4-position may not exceed four, and contacting the product with a pharmacologically acceptable acid, preferably acetic or hydrochloric, to prepare the pharmacologically acceptable acid addition salts thereof.

The most preferred embodiment of this process of the invention is represented by the above reaction scheme A wherein Q is -(CH2)n- wherein n is an integer of from 2 to 4, preferably 2, and R^ is hydrogen or -CllgCI^OII and Rg is -CI^CHgOII, and contacting the product with a pharmacologically acceptable acid, preferably acetic or hydrochloric, to prepare the pharmacologically acceptable acid addition salts thereof.

The novel compounds of the invention wherein A-B is 01=01, Rg and Ry are both either hydrogen or as well as compounds of formula (I) to which proviso (e) does not apply, hydroxy, and Hg is hydrogen, may also be prepared by reacting a compound of the formula G with a compound of the formula wherein G is alkanoyloxy of from 1 to 6 carbon atoms, alkoxy of from 1 to 6 carbon atoms, or -N-O-N1 I ' COOK wherein and Rg are as hereinbefore oefined; K is alkyl of from 1 to 6 carbon atoms: L is hydrogen, hydroxy, or ^,R^ NH-Q-N XR, wherein R-| ana Rg are chlorine, or bromine; a) when G is and J is chlorine and the substituent K is removed from the tricyclic product; .- R, b) when G is other than -N-O-N' -1- L is COOK 2 ^1 NH-Q-t^ ' and the cyclized product is aromatized; as hereinbefore defined; and J is hydrogen, provided; -N-Q-N L is hydrogen or hydroxy 'R„ COOK and if desired the product is contacted with a pharmacologically acceptable salt forming reagent. This process is preferably carried out in a reaction inert solvent such as toluene, xylene, or ethanol at a reaction temperature of from 60 to 150°C. preferably in an inert atmosphere such as nitrogen. When required, for example when G is other than XRi SJ-Q-Nj , the tricyclic product is aromatized.

L_. R2 -N I COOK When G is -N-Q- A*1 the substituent K is removed from I COOK 2 the tricylic product by, for example, treatment with aqueous-methanolie acid. Those skilled in the art will recognize that the product obtained after removal of the K substituent is a free carbamic acid which will spontaneously decarboxylate.

An additional method by which the novel compounds of the Invention wherein A-B is CII=CH, Rg and Ry are both either hydrogen or hydroxy, and R. is hydrogen; b may be prepared is as follows; A compound of the formula is reacted with a compound of the formula wherein R-| and Rg are as hereinbefore defined,. R is alkyl of from 1 to 6 carbon atoms or CF,; E and F are both hydrogen or when take.v together form wherein R^ is hydrogen or alkyl of from 1 to 6 carbon carbon atoms; C-D is CH=CH or wherein Y is H or OCII3; provided that when E and F are hydrogen C-D is Ϊ i , and when C-D is CH=CH,E and F form and R,. = R = hydroxy; and hydrolyzing the groups RC'O, and Y when it is OCH^ to convert them respectively to hydrogen and hydroxy; and if desired, contacting the product with a pharmacologically acceptable salt forming reagent.

This reaction is preferably carried out by mixing the reactants in a NaAlCl^(NaCi/AlClj) melt at a temperature from 130 to 200°C. for from 1 to 6 hours. The tricyclic products are subjected to hydrolysis, for example aqueous acid hydrolysis, to remove any protecting groups, and if desired a pharmacologically acceptable salt is prepared.

When the reactants being utilized in the processes of the instant invention comprise certain particular substituents, it has been observed that the process can be made to proceed in a particularly efficient and effective manner by the specific choice of reaction variables such as time, temperature and solvents. These preferred combinations of reactants and reaction variables are exemplified by the below reaction schemes numbered 1-12. It will be appreciated by those skilled in the art that the combinations exemplified by the enumerated schemes are merely preferred combinations and permutations of the processes of the instant invention and are not intended to limit the scope of the invention or the scope of the processes being claimed.

The procedures and preferred combinations taught by reaction schemes 1-12 are merely disclosed for the convenience of those who wish to practice the invention and are not intended to be used to delimit the scope of the invention in any way.

Unless indicated to the contrary, the symbols and definitions utilized in each of schemes 1-12 pertain only to the individual scheme wherein it is being utilized. where Q, an(j are as previously described, X is any good leaving group such as OH, Cl, Br, I, NH?., NO2< SO^Il, §-R10,iTR10'SI1's-R10'ORI0'M3' tetrazolyl, ONO and 0 0 In accordance with the above reaction scheme, an appropriately substituted 9, 10-anthracenediono in either the leuco ?U is H or UH. or aromatic form is reacted with an amine of the structure shown, to give the desired, 1,4-diamino-9,10-anthracenedi.one in either the leuco or aromatic forms. The reaction is carried out in ethanol, propanol, isopropanol or Ν,Ν,Ν',Ν’5 tetramethylethylene diamine under an atmosphere of nitrogen at a temperature of 40° to 100° for 2 to 10 hours. When the product is a leuco compound it is converted to the aromatic form by previously described methods.

R^, R2 and Q are as defined above and R^,, is chloro, or alkanoyl oxy of from 1 to 6 carbon atoms. . 47253 The reaction between lcuco-l,4,5,8-tetra substituted -9,10anthracenedione and the amine is carried out in a lower alkanol at a temperature of 40° to 100° under an atmosphere of nitrogen for a period of 2 to 10 hrs. Disubstituted derivative 1^ is converted to dihydroxy derivative 2_ by either alkaline or acidic hydrolysis using- an ethanol-water solution of either sodium hydroxide or hydrochloric acid. Thinlayer chromatography is used to monitor the reaction so as to control the reaction and avoid hydrolysis of the amino substituents. Again leuco products are converted to the aromatic forms by previously described methods.

The two reactants are mixed in a lower alkanol and heated to 40-90° for 1 to 8 hrs. to give the desired product. When Rj is CFgCO, the latter is removed with aqueous-methanolic potassium carbonate. 4*7233 Q is as previously described R-jj is hydrogen or hyaroxy; R can be lower alkyl, hydroxy lower alkyl or dialky1aminoloweralkyl, Pj may be H or lower alkyl, R„ may be H, lower alkyl or hydroxyloweralkyl. A mixture of the 9,10-anthracenediene and 2 to 3 molar equivalents of the aldehyde or ketone in a lower alkanol is heated to 40° to 100° for 2 to 8 hrs. under reducing conditions such as hydrogen viith Raney nickel or platinum catalysts or sodium borohydride to give the desired 1,4-bis(substi tutedamino) 9,10-anthracenedione.

Where R-jg in hydrogen or hydroxy, Q is as previously described and R is II, lower alkyl or hydroxyloweralkyl.

R is II or lower alkyl.

A mixture of the 9,10-anthracencdione and acrylonitrile 5 in a lower alkanol is heated to GO to 100° for 2 to hrs. to give the desired product.

Bis acetal 1 in aqueous-methanolic acetic acid is warmed 10 to 25° for 0.5 to 3 hours to produce dialdehyde 2. The latter compound in a lower alkanol is treated with 2 to 4 molar equivalents of the amine, R at 40 to 100° for 2 R >» to 10 hours under 1'educing conditions such as hydrogen with Raney nickel or platinum catalysts or sodum borohydride to obtain the desired 1,4-diamino-9,10-anthracenedione.

J?I2 is H, or 0Π, n=l to 3, m=2 or 3. I,euco-l,4-dihydioxy-9,10-anthracencdionc or its aromatic form and amine 5 in a lower alkanol or Ν, K, Ν'-tetramethyl ethylene diamine is heated at 50° to 00° for 2 to 10 hours to produce leuco-1, 4-dinmino-9,10-nnthracencdione C or its aromatic form. . Compound £ is then warmed in aqueous-ethanollc 1!C1 to 4 0 to 00° for 1 to 0 hours to produce the desired 1,4-diamino-9,10-anthracenedione 7.

Compound 6, its preparation from compounds 4 and 5, and its conversion to compound 7, are all novel and form further aspects of j this invention 8.

Where R^g is 11 oj? QH and X is Cl, Br, I, OSOgCgll^' p-CH3, O5O2C1I3. l,4-Diamino-9,10-anthracencdione JL, thionyl chloride and pyridine are mixed in the cold and then heated to 60-110° for Where X is Cl. the solvent (a to 70-100° for product ji, a 1, to 10 hours to produce compound 2 Compound /, the amine ΗΝζ'5^ and lower alkanol) are mixed and heated to 14 hours to give the final 4-diamino~9,lO-anthracenedione.

Where Q and Rj and R2 are as previously described and R3 & R4 arc lower alkyl.

The dihydmaminonapthoquinomcs 1. are prepared according to published procedures (I.S.M. Bloom and G. 0. Dudek, Tetrahedron, 26, 1267(1970)). Reaction of compounds J. with anhydrides in an aprotic solvent in the presence of sodium acetate give the amidestcrs 2 which are then hydrolyzqd with aqueous base to yield the corresponding amide-phenols 2· These amide-phenols are alkylated with alkyl halides or sulfonates in the presence of base to yield the corresponding amide-ethers 2· Hither the >47253 amide-phenols _3 or the amide-ethers 4_ are mixed with maleic anhydride in a NaAlCl^ melt and heated to 130-180° for 1-5 hours to give, after aqueous acid hydrolysis, the desired l,4-diamino-9,10-anthracenediones OSO2CH3, Y is II or 0CII3 and = II or OH.

Diamide 1 in tcluene is treated with Nall and then with araino 2 f°r ont to θ hours at 60 to 110° to give diamide10 diamine 3. The latter compound 3 is mixed with phthalic anhydride £ A1C13 and NaCl and fused at 130-200 for one to 6 hours to give anthraccnodionc !5. Aqueous acidic hydrolysis of 5 then gives the desired 1,4-diamino9,10-anthracenedione 6.

Q, Z, R, and R2 are as previously described, R is lower alkyl.

Diazide 1 is prepared from trans, trans-muconic acid by conventional methods. Diazide 2 and a lower alkanol. in toluene is heated to 70-110° for 2-8 hrs. to give bisurethane 2, Bisurethane 2 is then reacted with an aminoalkyl halide in ether or tetrahydrofuran at 40 to 60° for 2-10 hours in the presence of sodium hydride or other base to give compound 2· The latter compound is then treated with dichloronaphthaquinone 2 i·11 toluene at 60-110° for 1 to 5 hours to give anthracenedione 2 which upon aqueous-methanolic acid hydrolyses gives the desired l,4-diainino-9,10-anthracenedione 6.

Q, R, and R2 are as previously described X=H, Cl or Br, R]2 acyl or OCHg.

Butadiene 1 and diamine 2_ (prepared as described in Tetrahedron, 26, (1970)) in ethanol or toluene at 60 to 150® under nitrogen gives diamine 2- When X is H the conversion of 3 t° £ is accomplished in the same solvent by treating with an dehydrogenation agent such as chloranil. When X is halogen 2 is converted to £ by mild heating in an aqueous-methanolic sodium bicarbonate solution. Mild acid hydrolysis then convert; £ Z=0 aey^L to £ Z=01I.

As has already been indicated, the invention also contemplates conversion of the products into acid-addition salts. Many methods for salt formation are known to those skilled in the art and are to be considered equivalent for purposes of the invention. Thus, for example, the product may be dissolved or suspended in a solvent such as a lower alkanol (e.g. methanol, ethanol, i-propanol) and treated with the salt forming reagent, itself in solution in the same or in a different solvent. Thus, a suspension or solution of the product in ethanol for example may be treated with dilute or concentrated acetic acid, hydrochloric acid or the like, or ethanolic-HCl and the corresponding salt may be collected by for example filtration.

The salt forming reagent may also be added in pure form. Thus, the solution or suspension of the product may be treated with glacial acetic acid or gaseous HCl and the corresponding acid addition salt collected.

The instant invention also contemplates the use of the compounds of formulae 1, 11 and 111, as well as the compounds of these formulae to which provisos (a), (b), (c) and (e) do not apply and the pharmacologically acceptable acid-addition salts of all these compounds, as well as fixtures thereof, as the active ingredients in pharmaceutical therapeutic preparations and compositions.

Preferred therapeutic compositions of this invention inhibit transplanted mouse tumor growth and induce regression and/or palliation of leukemia and related cancers in mammals when administered in amounts ranging from about 5 mg. to about 200 mg. per kilogram of body weigh per day. A preferred dosage regimen for optimum results would be from about 5 mg. to about 50 mg. per kilogram of body weight per day, and such dosage units are employed that a total of from about 350 mg. to about 3.5 grains of the active compound for a subject of about 70 kg. of body weight are administered in a 24-hour period. This dosage regimen may be adjusted to provide the optimum therapeutic response.

For example, several divided doses may be administered or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A decided practical advantage is that the active compound may be administered in any convenient manner such as by the oral. Intravenous, intramuscular, or subcutaneous routes.

The active ingredients may be orally administered, for example, with an inert diluent or with an assimilable edible carrier or they may be enclosed in hard or soft shell gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1¾ of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60¾ of the weight of the unit. The amount of active ingredient in such therapeutically useful compositions in such that a suitable dosage will be ob25 tained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 5 and 200 milligrams of active compound.

The tablets, troches, pills, capsules and the like may also contain the following: A binder sucii as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of Wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liguid carrier. Various other materials may be present as coatings or to otherwise modify tiie physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active ingredients may be incorporated into sustained-release preparations and formulations.

The active ingredients may also be administered parenterally or intraperitoneally. Solutions of the active ingredient as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporanous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringabil·33 472S3 ity exists. It must be stable under the conditions of manu• facture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fung The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the re10 quired particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active ingredient in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a power of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

As used herein, pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatable with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail.

The preferred active ingredients of the therapeutic composition aspect of the present invention may be represented by a compound of the formula: and the pharmacologically acceptable acid-addition salts thereof, wherein A-B, Q, R^ and R2 are as defined above The preferred salts are the hydrochloride, and the acetate.

The more preferred active ingredients of the thera peutic composition aspect of the present invention may be rein presented by a compound of the formula: and the pharmacologically acceptable acid-addition salts thereof, wherein A-Β-, Q and n are as defined above, and R is hydrogen or alkyl of from 1 to 4 carbon atoms. The preferred salts are the hydrochloride and the acetate.

A second more preferred aspect of the therapeutic composition aspect of the present invention may be represented by a compound of the formula: wherein η , R^, R^, and A-B are as defined above and the acid addition salts thereof. The preferred salts are the hydrochloride and the acetate.

The most preferred aspect of the therapeutic composition aspect of the present invention may be represented by a compound of the formula: wherein R^ and Rg are individually chosen from hydrogen and -CH2CH OH and the hydrochloride and acetate salts thereof.

The pharmaceutical compositions of the present invention exhibit useful pharmacological activity.

Regression and palliation of cancers are attained, for example, using oral or injectable modes of administration.

A single oral or intravenous dosage for example or repeated daily dosages can be administered. Daily dosages up to about 5 or 10 days are often sufficient. It is also possible to dispense one daily dosage or one dose on alternate or less frequent days. As can be seen from the dosage regimens, the amount of principal active ingredient administered is a sufficient amount to aid regression and palliation of the leukemia or the like, in the absence of excessive deleterious side effects of a cytotoxic nature to the hosts harboring the cancer. This amount is also referred to herein as the effective amount.

As used herein, cancer disease means blood malignancies such as leukemia, as well as other solid and non-solid malignancies such as the raelanocarcinomas, lung carcinomas, and mammary tumors. By regression and palliation is meant arresting or retarding the growth of the tumor or other manifestation of the disease compared to the course of the disease in the absence of treatment.

Tne novel compounds described heroin are useful as chelating/ complexing or sequestering agents. The complexes formed with polyvalent metal ions are particulc'irly stable and usually soluble in various organic solvents. These properties, of course, render then useful for a variety of purposes wherein metal ion contamination presents a problem; e.g., as stabilizers in various organic systems such as saturated and unsaturated lubricating oils and hydrocarbons, fatty acids and waxes, wherein transition rivatal ion contamination accelerates oxidative deterioration and color formation, They are further useful in analyses of polyvalent metal ions which nay lx? ccmplexcd or extracted by these materials and as metal carriers.

Other uses opuiron to scxiucstcring agent.'; are also apparent for these conr pounds. Tn addition, the leuco bases (II) are useful as .intenurtliales in tlie preptration of the fully aromatic deri vatives (I, wherein Λ-B is Cll Cll).

The novel compounds of the present invention also possess the property of inhibiting the growth of transplanted mouse tumours as established by the following test procedures.

Lymphocyticleukemia P38B test The animals used are DBA/2 mice all of one sex, weighing a minimum of 17 g, and all within a 3 gram weight range. There are 5 or 6 animals per test group. The tumor transplant is by intraperitoneal injection of 0.1 ml. of dilute ascitic fluid containing 106 cells of lymphocytic leukemia P388. The test compounds are administered intraperitoneally on days one, 5 and 9 (relative to tumor inoculation) at various doses. The animals are weighed and survivors are recorded on a regular basis for 30 days. The median survival time and the ratio of survival time for treated (T)/control (C) animals are calculated. The positive control compound is 5-fluorouracil given as a 60-mg./kg. injection. The results of this test with representative compounds of the present invention appear in Table X. The criterion for efficacy is T/C x 100 2 125%.

Dose Median Survival T/C x 100 mg./kg. Time (Days) (Percent) in tn o m ο in o •3' Ol Γ— Κΰ xr co in in ο in ο in o O O O 0 O · 0 Λ r·» W Π in P? o I cn r-l oo co \o n rr*. (\ in m h cm cm cm cm cm o m ο o in ο σ» in o co H cn H rd cm cm cm cm rd Ο O m CM vo CO rd oo o m cm «-ί w H o in cm o co in cm i-f α> a 0 I 1 β o ?->,Ή £ rd ΐ3 >itn χ! π) >1 •Ρ Μ rd X 0)Δ 5>lO 0 +> XJ P β β •ρτι •rd Ctf Ό (U >1 β ,1 c g x: (0 >1 3 •rd -rd rd X 0 « w >1 0 CM | 1 Χ5 Μ e CM CO +ι Ό n -*< *» Φ >< o φ Η gx: ω i c Ή •Η ·Η •Hr-rO υ Ό Ό Λ 0 β <3 1 1 C ·Η Μ CM 00 Μ*-Η 3 3 *—' »- ». ε tr 0 ‘—’in Η h ω ι 1 — id 0 0 •Η r-i ΟΗΛ $4 3 CQ 0 ϋ >ί-Ρ +1 Η β 3Χ β β Ρη Μ* ·Ρ CU -Ρ Π5 0 1 * § ΡΙ (1) ο m rd flj Γ* I rd CM o in o a σ\ cn H Ο O 10 n· in ko φ m CO CM r—( CM I o ο ο ο o in in V · O 0 0 · ro cm r-4 cm cn CM «4 0) 1 0 rd β ίΧ-rd Δ 3 •Ρ σ1 Q) (ΰ 0 Ρ βΧί •rl •Ρ rd β 0 d XJ f n. >i id X 0 0 ε Ρ 1 CM >1 rd ^χ: H •rd (Λ -rd •H ϋ •rd r0 O flj XJ GJ Ρ I co P rd P rd 1 rd P n 0 1 — 0 o p 3 0 0 P 3 -P rd ϋ C x> rd β fn 3 •id β fn o 1 R 0 ί U m X! ft? u. tn TABLE I (continued) Lymphocytic Leukemia P388 Test T/C x 1001 (Percent) 147 126 205 205 , O Ch CO 00 LO id co in lo cm CM id td rd id 205 urvival Days) o © m m © © © o o in in © ο ο ο o m in 0 V 9 β ο o u o u V *» « o o « · 0 · rr cm σ\ ch r- in m cm σ. o co in to cm Ch Ch α φ rd id rd rl id id rd CM id rd id rd id « ε •d -d Ό E*< Φ X • tf φ Λί ω \ o o O O ο ο o in cm O O o o o in CM O O o · © © LO Ο O in CM id 10 O O in CM id LO c cr CM rd CM id CM id ε 1 Φ <0 fi' 1 d 0 Λ fi 0 1 +1 1 -d c o a ~ fi •d Φ C «3 id tf 6 ϋ •d | TO 10 0 ε >i Λ d id fi ιβ χ -P.fi Η 0 Φ -P Λ 3 >1 d 0 fi Ψ> tf λ *σ fi TO Ό Φ TO •Ρ >, •d I fi 0 d Ο) Λ ε >i a Ci •d *d ια x o •d 4J <α rd 0 rd fi I I >< ε 0 «J CM CO Λ ti o efi 1 +1 >, u Ω* >i rd 10 id Φ Λ id Μ X 0) 1 •d •d'd •d 0 0 0 »d r—a 0 Ό τ) 0 5 d (0 Λ 0 a i ) TO 1 *0 d 1 fi d CM CO d CM >1 fi rr *d fi *-* *. fi — Λ 0 κ β 0 i—· in - 0 W -d rd d id TO Φ rd d fi 1 id d •d Ό 0 0 ι — a 0 0 •d ι—ι 0 0 ¢0 f d fi OHO P 3 CQ 0 d fi ι ω 4J H 0 >i C +) rd 1 fi -P id tr *. fi Cm 3 X! -H fi Cn tP -rl fi Cm 0 1 Φ 4J fi O I - § rd TO 0 1 rd | u m id Φ tf a in u in o ο -Ρ Η β Q) σ» en ιη κο CM οο σι Η χη CM cn σκ «η CM id η ο γ* χτ en f CO rd Ο <Λ κο i co CM CM CM 1 KO fc CM rd rd rd Η CM CM rd rd rd rd rl rd rd ο ω X Λ £< — (ΰ > — •Η ω • > >1 Μ (ύ β Ω ο ο ο ο Ο ο Ο Ο Ο Ο o o in m o o in <η σ\ κο ιη r-i σ xr CO Η CO rd O in in in CM Ch Ρ 0) θ'} ί—| f-4 1—1 r-i CM CM CM CM Η rd CM rd rd rd rd rd ιβ e τ) Η 0) a cn ΰ) 44 ϋ) 'Χ ο ο ο ιη ο ο ο o in cm O O o m CM O O 0 · ο ο ιη cm ΚΟ o in cm «-i KO in CM rd KO Ω Cn & CM Η 1—1 I | t 0 rt — β β Η Μ r-l 0 1 0 ><χ: bt! β β -Ρ P-H rd *id •Η β 4J β >1 β β a) cr ft. σ *Η ( —* β ο β rd fc y y 0 κ biP cup Μ 0 β P 0 44 Ρ Μ Ή β 3 s >1« »0 β Ή β Ό α< >ι H i % I ΰ ί 43 rd St Ιί >1 α r-l ·Η 0 X rd X ο fc 0 >t 0 ίΐι 1 I ' fc fc 43 fc CM CO bt P >1 0 »—« ·. cub, α) Ό υ ·—*ιη t 43 r-l EP rd 03 1 •rt •rl *rd •rl ϋ —'Ό Ό Ό nJ ϋ 43 0 β 1 1 β ! 1 β 1 β Μ CM 00 fc cn co fc xr ·η β <—* *. β *—* *> β 0 ·—«in 0 *-*m 0 r-i φ Η Μ 03 t rd fc 03 1 rd fc ί «—« β Ο Ο Ή r-. O 0 »td r-’ 0 0 ΟΗ 0 fc β m o fc β « 0 fc β U >iS +> rd 1 β 44 rd 1 β 44 rd β 43 Μ β xl* -d β &< xj* >rt β Pd β 44 β 0 1 *- S 0 1 fc 6 O 1 J ω π1 U *0 ri flj o m rd fU pm Lymphocytic Leukemia P388 Test Ο Γ* Κ0 Μ* 03 Ο ΙΛ 'tf Ν ΓΝ Η Η Η Η οο m Ό* ΓΟ Γ-t 1—1 r4 Γ4 I—i «—I TO Φ β Ή Ρ £2 Ο ϋ ο ο ο ιη οι ο ο ιη 03 Η 03 ι-Ι I I 0·Η Ρ 3 cu tr 0 Φ β Ρ •ri Χί β -Ρ . to G r4 to XJ X Ρ ο φ Ρ β τι Η >ι το χ2 -I ·Ρ οι το I ω οο •Ρ *> Λ ιη I 1 μ* r— * Ο «Ρ β I «Ρ Ε ϋ <0 Φ β «Ρ β Φ Ν0 ιβ fh β 1 10 ο ο ο ο ο ο σ Ο Ο I ο 1 »0 Ο γο ο οι σ\ σ» ο* ιη ρ ο ο co η co r— w OJ Η Oi oi 03 OJ OJ ΟΙ 03 CM 03 . ο» co ο- id ιη Ο Λ Λ 03 r4 r4 r4 03 ο ιη ο σ ο ο ο ο ο ο ο Ο Ο ο Ο Ο Ο Ο ο ιη σ\ οο m ο 03 σι σ\ ο- ιη η ο ο ο ο- ρ ίο ιη σ» co r4 03 03 OJ 03 ΟΙ 03 03 03 Ρ 03 03 Ρ r4 r4 .-4 Λ Λ CD Ch Ch σ> Μ* in oj ι-4 in ο* ro r4 Ο Ο m ο ο (NWCIHOC Ο Ο Ο Ο ο ο ο ο m oi ο ο VD r4 10 Ο Ο ΙΠ 03 Ρ 03 Ρ 10 1 <- (0 1 (0 0 P t—1 Ρ β G tpXJ •Ρ P β Ρ e β •Ρ β to fO Ν ίΟ r4 >- Φ >1 >; X Ρ X X Ο Φ Φ 0 Ρ P TO Ch Ρ Φ rtf ·Ρ •Ρ ΤΟ >i >1 M Ch >1 X XJ 0 1 Χ3 Ρ ·Ρ ρ to xo TO 1 u ·—*Τθ 1 1 >,00 0 03 CD XJ - P Ρν~' - «-4 •Η 1 in TO •Η ω ιη •Ρ ϋ OJ I >1 ϋ •Ρ I ϋ (Ο (0 Λ <0 Μ I 0 ·Ρ Ρ 1 0 Ρ β 03 q o β •Μ· β β Ο 0 ·» ·Ρ 0 · Η Μ ω ε Ρ Ρ r-t ε ω Ρ Ρ σ ο •rl ίΟ β 0 0 1 (0 β 0 0 Μ β ttrl 0 Ρ □ 0 1-4 0 Ρ β Ρ r4 I Ν β Ρ r4 0 >, C Ρ Ρ β ΙΡ C tu 3λ'·η C tu 0 1 -Ρ β 0 ι Φ Ρ β 0 1 Ο ιη r4 Φ σ υ m J ω tr U ιη continued 47353 Lymphocytic Leukemia P338 Test 47353 TABLE I (continued) Lymphocytic Leukemia P388 Test T/C x 100 (Percent) <<*> Μ* 00 Or A Α ·-1 CO Η PWNMOOH>V£! | ACJCJCJCJCJCJrdrd Λ co CJ d a o r** co ro ^r a O A CJ A I vo CJ CO CJ CJ rd r—J rd rd 159 82 241 218 186 195 182 0Ί A rd rd rt > — •H W > > id rt β Q οοααααοο ιη Ο Α A A © A O 0 © o A o A O A A O O A ω OCslOrdCOOOOKA Μ* στ Ο CO C- A OJ Or CO A rd r- cr. A M4 O rd O rd Γ* β φ ΓΩ Ν Ν Μ r-1 rd rd rd rd CJ A CJ CJ rd rd H rd rd r-! CJ CJ CJ CJ Cd rd rd ό ε Α •rf ·Η ΤΙ Η Φ S A CO A Cl A 01 A CJ Η Α r- A CJ rd A Cl Φ Λί W \ OOOACJAArd Ci α ο Ο Ο O A CJ A CO O o ο σ o a cj a O O 0 · Ο Ο ΙΛ <Ν Η A O OrntNH Ο O A CJ rd Α Φ CJ rd CJ rd CJ rd ε 1 1 Φ rd 0 ·Η >4 id ρ XJ Τ3 0 1 1 >ι — Φ 1 >4 — 0 •Ρ >ird X 0 fi χ o c υ ΟΛΛ 0 β o 0 fi o β >ρΗ ϋ H-H <3 id Ή β β X *Ό 0 ό ε -η π ε ·η ο 0 1 Ρ >,« 3 >ι « 3 α Μ ω π3 ΛΗ 0’ ΛΗ g* g *0 * ΪΗ 1 >i 3 ο >, A X CJ Pl id ΓΊ fii (ί υ X γ—, ·Η 0 X —· -μ χ 1 0 Ό 1 M +J 1 Oi ·Ρ CQ. β n a e ΓΊ —- Η '—•Η Φ ι—f *-* ι rt rd ο rt rd •η ε β W rd •rd ω β >4 •rl *ό ο Ή 1 0 • Η ·Η X □ I— rd β rt X --. 0 rt χ) ε ο rt 1 S*H id ( 0 id M 1 rt id CJ X β 3 3 rd Ό β ' ·Ρ Ο1 n o - >1 >1 0 w Φ rt rd id H S fi rd id rd Qi X< rd id •Η *—» Η 0 0 I d -H 0 0 1 0 -«d 0 0 pq ο χί Μ 3 0 Η Ό id β o s-ι ri id β ι β *μ +> rd ϋ >1 1 4J rd o a ι •P rd -d β C (μ βΧ oo c Ui β M4 β Ui *· £ rt 0 1 φ 4J - o f OJ rd ·. 0 1 rd ίΰ >, ο Α X Φ A u A X H u A Ο σ -μ Η β <ΰ X 0 U U Φ XPU Εη — -4* η ι-ι m m to in u? r-Jcn^or'i^M’fn HNNNr-lr-IrM Ου 1 Η m tn ο ιη ιη ιη ο ο co η ο σ cq φ γCMCMCMCMrHHrHr-1 205 Η β •Η rt ί> >1 μ rt £ Ω in ο in tn ο ο ο o ο m in in ο in in ιη ο ο tn ω CMc\ju?fMcriC7>tom r-f Γ COHOOCOOM^^1 ο α φ ΗΠΝΟΜΗΗΗ Η Η CM CM CM CM »—i r—1 r—I —4 CM β β Ό t· Φ s in CM AO co in cm ιο co tP in cm h m Γ·* in cm η in > Φ X W X ooincMtocoHo ο ο ο σ in ο ο 0 · o in cm ι—ι o in ni H ιο ω σ 6 rH t—l I >1 1 1 h ni Η I 4J M :4 co Λ ** Φ — •μ β Pin fi 0 β β Φ r-. 0 β <ΰ 0 >1 0 c ♦Η >ι α K U-rf Ό X g 0 Ή a •Η 0 ο μ ε σ Μ Μ ο Ό 3 β •Η TJ >Η Η Φ Ν >, Λ >ι£ Ό Η β χ: rH Γ ρ,-Ρ-μ •Η 1 »Η Ή Ν ο c n 0 r4 *0 ϋ — μ 1« 0 Λ 1 fl | fi >ιΗ μ 1 co 14 η ι xr β CM * β *— Κ ο □ 0 «—'m 0 rt I J4 0 γ4 Μ ω ι φ ι—1 Μ μ fl H 0 0 •Η — β 0 Ο fQ 0 >1*0 μ β ffl Ο 0 Μ β r g £ >ι -μ «η 1 fi β 4J rM φ -Η -Η ϋ β fci Μ< ·Η ·Η β ϋι * g fl Ή 0 1 •6 3 0 1 Η 3 I Ο ο m η fl tr Ο ιη Lymphocytic Leukemia P 388 Test 2 S3 +J iSl QJ in »o w r: Λ1 P o O O I m vr CN CO I·' ri r-i Η Η ei co ri ri ri o r— ri ri in ό rl »d in q >« fj fll P r- o\ o cn o o ri r-l ri Ν' ΓΝ ri Η H rl O O ri CT rH ri * os rl '0 w q >1 rj nJ P US (0 N r ( H ri CO Ο CA CN CM r-l ,-l r-l Γ- «.J· O r-i r{ CN CN CN CN CN J O o CN O o ri CN ri CN TABLE I (continued i Q. Ξ >5 o o o ο o oom vo CN r-i o o o ο o ο o m vo CN «-Η ο ο o tn cn ο o ο o m cn > -c o CN r-i f 1 0 I q 0 •H o q ε d ♦P nj ’ri £ ri E nj > nJ ri Λ r-i ΓΗ P >1 x: 0) x: P 0 P q 0) 0 •H o q E q •rl a •ri ε ri ns «Ρ 1 Λ p CN P r-i ri ri φ Φ •ri Pi Φ •rl Ul W •rf •P C ϋ •ri q o rl q ϋ »0 0 nJ Ol 0 nJ Λ 0 nJ ι q P ι q P ι a p CN Ή q CN ·Η q Ν' q q 0 q 0 * q 0 w tr ri i4 ω tr <-i tr ri P •P Of o 2 •H nJ 02 I nJ 0 0 CO P ρ 3 ω P pq 0 P M 3 1 rG P JH ι .£ pri o ,q P ri Ν’ P r· IN *f p cfo q p q ρ q 0 > *- q 0 I ω fi 0 1 ri RJ t) ·Λ r—( nJ Uin p ni t? Ό - TABLE I (continued) Lymphocytic Leukemia P388 Test Compound Dose (tiKj,/‘;g, ) rU-’tl Lull Curvi veil (Day is) T/C x 3 0 0 (Percent) 1,4,5-Tria[(2-amino- 12 15.0 130 ethyl)amino]—2—hy— 6 15.0 130 droxy-anthraqu mono 3 15.0 130 1.5 15.0 130 1,4-Bis [ (2-di:.:et)jyl- 50 18 157 aminoethvi) no] - 25 16 139 ~5,6 ~d i hyd r ox van tl t r it - 12 16 139 quinone Control 0 11.5 S-Kluorouracil 60 19.0 16 5 1., 4-B i ;· ( 3-amino- p rot >y 1ami no)-5, 8 -dihydroxyati thraquinone 25 12 22.0 19.0 183 15« Control 0 12.0 . 5-Flnoroiiraci 1 60 )9.5 162 Lymphocytic leukemia P388 test The procedure used is the same as for the previously described test for lymphocytic leukemia P388 except that the test compounds are administered orally at various doses rather than intraperitoneally. The results of this test with typical compounds of the present invention appear in Table II.

The criterion, for efficacy is T/C x 100 > 125%. 7 2 5 3 η ο Η P fu Xi Ji fi Ή fi •H £ Ό TO C fi fi '0 TO R TO rV. fi TO r-1 υ •H 4J >. .fi fi. {: 47353 Lymphocytic Leukemia L12W test The procedure iu the same aa Lor the Lymphocytic leukemia P388 intraperitoneal test except that the tumor transplant consist?; of lymphocytic leukemia L1210 inoculated 5 at a concentration of 10 cells/mouse with a moan .survival time being calculated. The results wit]; a representative compound of this invention appear in Table Ill below.

Lymphocytic leukemia L1210 'test Melanotic Melanoma 1)16 The animals used are C57BC/6 mice, all of the same sex, weighing a minimum of 17 g. and all within a 3-g„ weight range. There are normally 10 animals per test group. Λ oneg -gram portion of melanotic melanoma B16 tumor is homogenized in ml. of cold balanced salt solution and a 0„5-ml. aliquot of the homogenate is implanted intraperitoneally into each of the test mice. The test compounds are administered intraperitoneally on days one through 9 (relative to tumor inoculation) X0 at various doses. The animals are weighed and survivors are recorded on a regular basis for 60 days. The median survival time and the ratio of survival time for treated (T)/cont.rol (C) animals are calculated. The positive control compound is -fluorouracil given as a 20-mg./kg. injection. The results of this test with representative compounds of the present invention appear in Table IV. The criterion for efficacy is T/C x 100 > 125%. ( 47353 Melanotic Melanoma B16 Test T/C x 100 (Percent) 125 j-4' 1 in r4 <' C* r-4 Μ» CO CO «-4 t-4 n—1 166 cn r·* rin m cn r4 r4 r-4 166 i-4 Rf >i4 (0 > >, 3 Q tn tn 0 0 0 0 0 in 0 m Cfl · • 0 0 • · u • 0 ♦ · · • · 0 ko in CO CM H KD tD CM CM KD KO β QJ CM r4 CM CM CM CM r-4 CM CM CM CM r4 CM « ε Ή Ή Ό Ε-ι QJ a CT OJ 44 in \ O Ο O 0 tn CM Ο O in CM KO Ο O 0 * tn CM in CM «Η CM CM (-4 CM Q th ε QJ I I Φ c z-^ Hf — β 0 r4 P Η O β >1 β I »r4 β «Ρ Λ·Η — β •Η β +) β r4 tr Ό ro φ tr >1 nf -.4 Rf Λ U r-4 P «μ x: 0 X 0) JJ X 0 β JJ 0 β X Μ •Η β β Rf >ιΌ Ό ro nJ Ch •Η 1 β £ >> I χί r-4 J>1 β ro X γ4 ·<4 0 X 0 r4 0 ^(0 P 0 Or >» P 1 P P g •C Ό CM CO >,O 0 -P >1 ·—» ·, D, >, O ro si —'tn r4 I β r-4 •Η -r4 ω Ή r-4 ’«4 •r4 α ό ϋ •Η r—ι O ^(0 0 1 1 Rf Λ 0 Rf 1 1 Rf CM CO P I β P CM 00 P ·» β -Η β β —'in 0 - e 0 <—'in 0 w I rH P r-4 fif QJ r-l M w 1 (-4 P 0 0 1 — β 0 0 -(4 1—· 0 0 ra 0 p β 0 r4 0 fJ 3 « 0 Ρ β I β 4J H 0 >i C «Ρ r-f 1 β •μ Η Μ* -(4 β Ih 3 Si -rl C &4 *3* ·Η β fh u e 0 aj -ρ β 0 1 - ε 0 1 r4 <3 O in u qj tr cj in r4 Rf C> m Melanotic Melanoma B 16 Tp^t T/C x 100 (Percent) 125 LD 1 LO rd 200 LO 1 LO rd r* σ\ r- rd © LO Vp tP rd rd »d rd 166 rd ί>~ •d ω > Λ d to fi a o Ο m o © in tn o in in o in w *-* 0 a 0 · • •00 0 9 o LO LO CM LO LO rd Γ* CO CM LO LD a qj CM td CM cn rd CM cn CM CM CM td CM ιβ B •d *d tl Fh Φ X tf Φ Λί O O W \ 0 · LH O O CM O O O in CM LO CM CM id CM in CM rd CM a h« E Φ Φ , C c 1 0 0 0 ~ fi fi a »d •d >1 fi I fi £ ft tr — O’ rt Φ 0 TO »d TO rd fi Μ M >1 d Sh 0 ft XI Λ Λ ft a 0 -P P 4J Ο-rj C fi Φ fi d fi 0 TO a σ’ T3 £ 1 fi 1 0 TO fi TO S •d >, fi d P Η X Ε X •d Λ Q >1 0 TO 0 £ -P ft -fi u 1 d !3 β E •Ρ Ό CM TJ 1 TO n ai >i — Sh cn ι u B x) id ^rfi rd — Sh rd •d *d •d VJ -d •d W X Ή Ό Ό D •d Ό 0 •H 0 0 1 i TO XI 1 TO Λ d TO d 1 co d f T3 d *— ·» fi tP «. fi ·» Sh fi *—*tn 0 Nin 0 -Xt 0 V) 1 id d id I rd d «d’d H d •d ·-» 0 0 i 1—» 0 0 1 Ό 0 0 CQ 0 d fi 0 0 d fi 0 1 d fi 1 fi •p id U fi -P -d 0 00 •P rd -tf -d C tn 3 -d fi tn fi - β ft - E O 1 Φ £ 0 1 φ in 0 1 rd (0 LL>a ,..-.1¾ g u in .. A. 1 U VI TABLE IV (continued) Melanotic Melanoma ΒΊ6 Test © — © 44 rd β 0 X 0 ιη κο ci co I KO m σκ m cn rd 1 KO 0 H co in 1 cn fc r-orcKo r* © r* in ci ci r- in xp cn cj κο 0 0 CJ Cl rd Cl rd rd rd rd rd rd rd rd rd rd H — rd β Ή V) > >, M n! β tt in 0 in in © 0 m m © © m © 0 tn © © © © ω « « « ci in cn co r- 0 xp 0 κο ci 0 r- 0 xp CJ Cl © ΙΟ Γ*· β ω rd cn m cj rd cn cn m ci cj ci rd cn CJ Cl Cl Cl rd Cl P tl 0 Ξ ti m cj in 0 0 44 • • ω\ © in cj κο © 0 © in ci κο cn © 0 0 in ci κο Ο Ο 0 · tt tn in CJ rd CJ in CJ rd Cl in Cl rd Cl I 1 β 1 β 1 β 0 fc rd fc M fi p >ίΛ — 43 Ή 11 β 44 O P ε c: •id β C fi β β Ν β •rf β rd >f « >1 ε >ι bx fc k β tt Λ O 0 0 Η 0 P M CUM bH *0 0 >0 •rf »0 P3 β ε >i cu>, 44 >< β 1 43 1 Λ 0 43 ο ci .ri rd »rl O-d y* '-Ό ^»0 fiO ε I i I 1 •rf 1 υ Cl co CJ co ε <» υ fc—4 rd · rd β - rd w in •r| w in •rf ι m •rf •rf 1 ϋ □ CJ 1 ϋ 43 r-. β β —-1—» β 1 0 fc ί 0 fc 1 σ fc xP β β -xr β β CJ β β -•rf 0 0 0 rd fc P E 0) rd fc W £ 0 rd fc 1 β β 0 0 J β fi 0 0 •rf β c 0 0 O rd 0 fc β OP 0 M 3 (ΟΡΟ fc β 0 >1 fi 44 H 0 >,e 44 rd 1 >i fi 44 rd β^-Η β fa 0 43-H Cfa xr 43-rf β fa 0 44 β 0 1 QJ P 3 0 1 -Ρ 3 0 1 J® IT U in j « cr Om rd β σ O in TABLE IV (continued) o ο «Ρ rd C 0) * h kJ· 00 Kj· rd in 1 IO moor» >> 1 <*> CM VD M· CM ι—I Γ» r- o tn υ v Xft rd rd rd rd rd rd rd rd CM CM CM Λ Α Λ rd H'- rd ti > — •rd ω > > P ti 3 Q o in in m in O O ο ο in o oo O O W rd 00 O cn > O rd in co Μ· ^kJ* m <*» an me CM CM CM CM rd rd CO rd rd CM CO Π(*) AAA rd CM •rl ‘id Ό F< fl) s tr in in r*<*> 0) X. M\ 0 · ο o in cm io O O CM 10 COrd OO O O O m CM rd CM rd 10 Q σ rd e ti P ~ ti 1 XJ 0 u 0 +> β J3 3 3 •H -3 •rd ti ε β ε > η) ια ti X rd o >,X >, p Xt 0 0) Α Ό +) Ρ Ό y >i fl) Ό -H 5 4) Λ 3 ε ·η X Λ 0 •rl Ό Ο ·Η rd »d ι MAX E ι ¢0 ti l.o o CM - >,co 0 ^tn rd Xi ' M rd W 1 •id ι in τ) •id υ cm r N 0 Λ 0 1 3 ti P --'r-.x: 1 0-P ti P Μ* ·Η 3 NCO 3 . ' ε 0 0 rd ti fl) rd P ra Ε 0 rd p 1 «-> 3 θ 2 •H ffl C0 2 0 >i 0 P 5 m.-) o P 3 υ cu s -P71 1 >,β +! r* 3 0·Η β fa M· XJ ·Ρ β fa fl) p 3 o L *+» 3 ° ' J 0. O’ u m rl HI C u in TABLE IV (continued) Melanotic Melanoma B16 Test T/C X 100 (Percent) *ι· οο σ\ ο4 (ΝΗΟσι rrt rrt ι—1 176 σι oo r- oo γ* ιη γί co r- γο rrt rrt rrt rrt 172 in ro fl· ιη γί r- ο σι γί γη ΓΊ Η ΓΊ rrt 1 Ν Γ- rrt rrt fl > — •rt rt > > μ a β Ω οοιηο ο ο in tn o tn ο ο ιη ο ιη ο ο m ο ιη ω *-* » « ♦ · rrt ο 00 10 Γ- ο σ\ ο o co γί 10 Γ- C0 ΓΊ rrt 10 Γ- 10 Γ* β φ CM CM rrt rrt rrt Γ0 ΓΊ ΓΟ ΓΊ ΓΊ Η ΓΊ ΓΊ ΓΟ ΓΟ ΓΟ ΓΊ rrt ΓΊ β β •rt ‘rt τί μ <ι> a ιη γ* tn r* &) ιη η* ro ose ./k« ο σ tn ΓΊ σ tn γί η Ο Ο ΓΊ «ο ro η σ ο ο σ ΓΊ ΓΊ V0 ΓΟ rrt Ο rrt Ο Ο ΓΊ α σ rrt ε fl μ ^43 0 U | | 1 | fi fi rrt ffl Sa> •rt fl >1 μ X - ε ί>ι •Ρ ,β 0 m fl X β -Ρ μ ι φ rrt 0 Λ β Ό'-’ G >ι μ Ο β >ι 0 0 Λ Ό β >1 Λ β β «Ρ >t β •rt X 1 ·Η «rt Φ 4-ι β g Q ο ε a Β ·Η 0 β Μ -mo1 ·—* »0 α 1 Ό 1 rrt fl ΓΊ CO ε fl1 >1 Ν >|M 0 rrt + jajc rrt *· rrt υ W ·Η •rl W «Ρ -P •rt to in . ·Η •rt »0 ϋ •H ϋ •rt 1 U X) 1 fl Λ — β fl Λ > fl ι ω μ 1 0 >1 μ 1 0 μ μ· «. β fl· fi Κ β fl· β β *·ιη 0 s-rt 0 ο * ·Η 0 rrt I φ rrt μ rrt ε μ rrt μ rrt g φ rrt μ 1 β 0 0 1 βΌ 0 0 1 β C 0 0 Ο 0 0 μ β 0 rrt >, μ β 0 rrt 0 μ β □ β β •Ρ Η U >,J3 Pi-rt ϋ »-*1 μ Ρ rrt β ’rt ·Η β b 3Χ·γΙ Ch fi Λ ·Η β Εμ φ ε β 0 1 φ «Ρ »0 0 1 tl Ρ 3 0 1 3 α ο1 U ιη X) 01 1 Urn pi ω tr ϋ ιη Melanotic Melanoma 816 Test TABLE IV (continued) Melanotic Melanoma ΒΊ6 Test Compound Done (mg . /!;q .) Jiodian Surviv.il (Days) T/C κ 100 (Perce»·,·) 1,4,5-Tris (.(2-nminoethyl) amino]-8-hydroxy-anthraguinone Control 5-Fluorouracil 6 1 0 1 20 26.0 16.0 26.5 163 166 1,4-Bis[2-dimethylaminoothyl)amino]-5,6- -dihydroxyan- thraguinone 50 25 12 6 23 24 23 22.5 153 160 153 150 Control 5-Fluorouracil J 0 20 16.0 26.5 i 166 1,4-His (3-aminopropyTini )-5,8-di hydroxynntlirnguiroiK? 32 6 24.Ο 30.0 )50 187 Control 5-FJuoro.iraci 1 0 20 16.0 26.5 166 7253 Ridgway Osteogenic Sarcoma The animals used are AKDgF^/J mice, all of the same sex, weighing a minimum of 17 g. and all within a three-gram weight range. There are normally 8 animals per test group.

The tumor is administered subcutaneously by trocar as five 2-mm. fragments per mouse. The test compounds are administered intraperitoneally every 4 days for a total of 6 inoculations beginning on day 15 (relative to tumor inoculation) at various doses. The animals are weighed and survivors are 1° recorded on a regular basis for 90 days. The regression of tumors is recorded in all test animals. Table V gives the result of this test with a representative compound of this invention in terms of the percentage of animals showing tumor regression.

/ Ridgway Osteogenic Sarcoma 63 Days After Therapy Stopped T/C (Percent) oo co tn m os Ο © r· CO CN HNH rH oo ο m ΗΗΟ rH rH rH cn rH vo in os oo rH rH rH Median Survival (Days) 44.5 in in • · co cn oo r* p* os r* m in ιη • CN OS VO ιη Ν* Ν' co in cn vo 00 00 pped % Showing 50% Tumor Regression o co in ο o © CN CN csl ο Ο rH ο o > © o in rH rH 7 Days After Therapy Stoi % Inhibition Tumor Growth VO 00 H rH OS cn x 5* vo H Ν’ CO ΙΟ in CN m oom o o os rH rH Tumor I (mm.)2 1189 Nmnoo in vo in r* vo CN 10 N* OS io vo CO Ν’ rH in in os Γ- © Ο Γχ No. Without Tumors/No. Survivors 0/5 I in vo co m vo nnooo vo in vp Η Ο O Ν’ VO fx Ν' VO N* >1 CN Ρ -χ 0 · Bi Ν’ VO r- co cj h* m r* vo oo co co rH CN Ν’ in in m CN OS Ν’ Ν’ OS OS « ti p ti 43 QH rH No. Mice I Per Group1 CO r· co co r> > oo co co CO VO t- tn ΦΛί ωχ 0 · Q CP Β t ο o in cm vo o in cn h rH * in cn vo CN rH in o in * · · rH rH O Compound o Λ Φ ϋ ti Η Ql— ί ι φ •H 1 >1 G Ό 1 -iX 0 1 0 0 o c CNGGUH ’ ·Η ·Η Ό q — ε β χο1 ω ti ti Λ ti Η Η - Η Ρ « tHrH OXJ J X Μ 4J ν· ρ XJ co G Χ φ ρ χ Φ rH g flrtn i . Φ P ti X Φ P P 0 x: P φ -JS Φ G •H P ω •H P 0 G •rH „ > The invention is illustrated by the Examples which follow.

Example 1 Leuco-l,4-bis[(2-dimethylaminoethyl)amino]-5,8-dihydroxy-anthraquinone A reaction mixture comprising 10.58 g. of Ν,Ν5 -dimethylethylenediamine, 60 ml. of Ν,Ν,Ν',N'-tetramethylethylenediamine and 10.96 g. of leuco-1,4,5,8-tetrahydroxyanthraquinone is flushed with nitrogen and stirred under nitrogen for 2 hours while heating with an oil bath kept at 49°-51°C. The mixture is allowed to cool under nitrogen. ]0 The solid is collected and washed with ethanol giving 14.78 g. of the desired product as a dark red-brown solid.

Example 2 1,4-Bis[(2-dimethylaminoethyl) amino]-5,8-dihydroxyanthraguinone A 12.00-g. portion of leuco-l,4-bis[(2-dimethylaminethyl)amino-5,8-dihydroxy-anthraquinone in 100 ml. of nitrobenzene is heated under reflux for 15 minutes and then filtered while hot. The filtrate is reheated to boiling, allowed to cool, and the solid is collected and washed with ethanol giving 8.44 g. of the desired product as blue-black crystals, mp. 236°-238°C.

Example 3 Leuco-l,4-bis(2-7morpholinoethylamino)-5,8-dihydroxyanthraquinone A solution of 15.62 g. of N-(2-aminoethyl)morpholine in 40 ml. of Ν,Ν,Ν*,Ν'-tetramethylethylenediamine is de-aerated by bubbling nitrogen through it for 15 minutes. A 10.97-g. portion of leucopl,4,5,8-tetrahydroxyanthraquinone is added slowly with stirring and the suspension is treated as described in Example 1, giving 18.07 g. of the desired product as an olive solid, mpm 223°-227°C.

Example 4 1,4-Bis(2-morpholinoethylamino)-5,8-dihydroxyanthraquinone A 13.90-g. portion of leuco-1,4-bis(2-morpholinoethylamino)-5,8-dihydroxy-anthraquinone in 100 ml. of nitrobenzene is oxidized as described in Example 2 giving 10.30 g. of the desired product as black rods, mp. 241°-243°C.

Example 5 Leuco-1,4-bis[(2-diethylaminoethyl)amino]-5,8-dihydroxyanthraquinone The procedure of Example 3 is repeated using 13.95 g. of Ν,Ν-diethylethylenediamine in place of the N-(2-aminoethyl)morpholine, giving 13.97 g. of the desired product as a red-brown solid, mp. 182°-185°C.

Example 6 1,4-Bis[(2-diethylaminoethyl)amino]-5,8-dihydroxyanthraquinone A 10.90-g. portion of leuco-1,4-bis[(2-diethylaminoethyl) amino] -5, 8-dihydroxyanthraquinone is oxidized as described in Example 2 giving 6.35 g. of the desired product as blue-black needles, mp. 202°-204°C.

Example 7 Leuco-1,4-bis[2-(1-pyrrolidinyl)ethylamino]-5,8-dihydroxyanthraquinone The procedure of Example 3 is repeated using 12.05 g. of N-2-pyrrolidinoethylamine, in place of the N-(2-aminoethyl)morpholine, and 80 ml. of Ν,Ν,Ν',N*-tetramethylethylenediamine, 47353 giving 13.24 g. of the desired product as a red-brown solid, mp. 180°-185°C.

Example 8 1,4-Bis[2-(1-pyrrolidinyl)ethylamino]-5,8-dihydroxyanthraquinone An 8.61-g. portion of leuco-1,4-bisΓ[2—(1-pyrrolidinyl) ethyl]amino]-5,8-dihydroxyanthraquinone is oxidized as described in Example 2. The reaction mixture is evaporated to dryness and the residue recrystallized from- toluene, giving 5.12 g. of the desired product as blue-black crystals, mp. 193°-196°C. · Example 9 Leuco-1,4-bis[2-(methylamino)ethylaminoI-5,8-dihydroxyanthraquinone The procedure of Example 7 is repeated using 8.90 g. of N-methylethylenediamine in place of the N-2-pyrrolidinoethylamine, giving 13.73-g. of the desired product as a dark green solid, mp. 157°-160°C.

Example 10 Leuco-1,4-bis[(3-dimethylaminopropyl)amino]-5,8-dihydroxyanthraquinone Nitrogen is bubbled through an 80-ml„ portion of dimethylaminopropylamine for 15 minutes. A 10.97-g. portion of leuco-l,4,5,8-tetrahydroanthraquinone is added slowly with stirring. The mixture is heated,under nitrogen at 50°52°C. for 2 hours and then allowed to cool. The solid is collected and washed with cold ethanol giving 5.59-g. of dark, orange-red crystals, mp. 115°-118°C.

Example 11 1,4-Bis f(3-dimethylaminopropyl)amino]-5,8-dihydroxyanthraquinone A suspension of 6.00-g. of leuco-l,4-bis[(3-dimethylaminopropyl)amino)-5,8-dihydroxyanthraquinone in 60 ml. of Ν,Ν,Ν',Ν'-tetramethylethylenediamine is heated on a steam bath under reflux while air is bubbled in for 12 hours. The solution is cooled, producing a solid which is collected and washed twice with heptane and once with petroleum ether. This solid is recrystallized by extracting with 350 ml. of hot heptane, filtering and concentrating to 300 ml. Crystallization and washing with petroleum ether gives 3.72 g. of the desired product as black needles, mp. 154°-157°C.

Example 12 Leuco-1,4-bis(2-aminoethylamino)-5,8-dihydroxyanthraquinone A reaction mixture comprising 10.97-g. of leuco-1,4,5,8-tetrahydroxyanthraquinone in 80 ml. of de-aerated Ν,Ν,Ν',Ν'-tetramethylethylenediamine containing 7.22 g. of ethylenedlamine is heated and stirred under nitrogen at 48°-50°C. for one hour. The mixture is allowed to stand under a slow flow of nitrogen, producing a solid which is collected and washed with ethyl acetate, acetonitrile and petroleum ether giving 13.8 g. of the desired product as a red-black solid.

/ Example 13 Leuco-1,4-bis(3-aminopropylamino)-5,8-dihydroxyanthraquinone A suspension of 10.97 g. of leuco-1,4,5,8-tetrahydroxyanthraquinone in a de-aerated solution of 8.90 g. of 1,3-diaminopropane in 80 ml. of Ν,Ν,Ν',Ν'-tetramethylethylenediamine is stirred and heated at 49°C. for one hour under nitrogen, then allowed to cool. The resulting solid is collected and washed with cold ethanol giving 14.21 g. of the desired product as a black solid.

Example 14 Leuco-1,4-bis(2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone A suspension of 12.5 g„ of 2-(2-aminoethylamino)ethanol in 40 ml. of Ν,Ν,Ν',Ν'-tetramethylethylenediamine is stirred and de-aerated by bubbling nitrogen in for 15 minutes. A 10.97-g. portion of leuco-l,4,5,8-tetrahydroxyanthraquinone is gradually added with stirring. The suspension is heated and stirred under nitrogen in an oil bath at 50°-52°C. for 5 hours. The mixture is allowed to stand and cool under nitro gen for 12 hours. The solid is .collected by decantation, macerated in ethanol, collected and washed with ethanol giving 15.06 g. of the desired product as a green-gray solid, mp. 129°-131°C.

Example 15 Leuco-1,4-bis[2-[di (β-hydroxyethyl)amino]ethylamino]-5,8-dihydroxyanthraquinone A solution of 17.8 g. of ΙΪ,Ν-di (2-hydroxyethyl) ethylenediamine in 100 ml. of methanol is cooled with an ice bath, stirred, cind de-aerated by bubbling in nitrogen for 7C 47233 minutes. A 10.97-gram portion of leuco-l,4,5,8-tetrahydroxyanthraquinone is gradually added with stirring and continued cooling. The suspension is heated and stirred under nitrogen in an oil bath at 50°-52°C. for one hour and the mixture is then allowed to stand and cool under nitrogen overnight. The solid is collected and washed with ethanol giving 14.8 g. of a red-brown solid, m.p. 165°-168<,C.

Example 16 1,4-Bis[2-(methylamino)ethylamino]-5,8-dihydroxyanthraguinone dihydrochloride To a suspension of 11.60 g. (0.03 mole) of leuco-1,4-bis[2-(methylamino)ethylamino]-5,8-dihydroxyanthraquinone in 200 ml. of 2-methoxyethanol was added gradually with stirring 15 ml. of 8N ethanolic hydrogen chloride. The system was chilled with an ice bath and stirred as 7.50 g. (0.0305 mole) of chloranil powder was gradually added. The mixture was stirred overnight at room temperature and diluted with 600 ml. of ether. The solid was collected and washed with tetrahydrofuran. The product (14.16 g.) was recrystallized by dissolving it in 130 ml. of water and adding 650 ml. of acetone to give 13.15 g. of a blue-black solid.

Example 17 1,4-Bis(2-(2-aminoethylamino)ethylamino]-5,8-dihydroxyanthraquinone Following the general procedure of Example 3, a mixture of 10.97-g. of leuco-1,4,5,8-tetrahydroxyanthraquinone, 80 ml. of Ν,Ν,Ν',Ν'-tetramethylethylenediamine and 21.84-g. (0.24 mole) of diethylenetriamine soon gave a thick, ' congealed mass which prevented effective stirring so the 'reaction time was extended to 24 hours. The mixture was ι allowed to cool and the supematent liquid was decanted and discarded. A solution of the congealed mass in 100 ml. of j 5 methanol was filtered, then allowed to oxidize in the air for I four days in a partially covered flask. The gelatinous mass ι which had separated became solid when the oxidation mixture j was agitated with 200 ml. of acetonitrile and then allowed to stand for one hour. After the solid was collected and ί 10 washed first with acetonitrile, then with ether, it amounted to 10.88 g. of a blue-black powder.

Example 18 ; Leuco-1,4-bis(4-aminobutylamino)-5,8-dihydroxy| anthraquinone | 15 Following the general procedure of Example 3 but ! using 45 ml. of 1,4-diaminobutane as the primary amine component, there was obtained 12.20 g. of product as a dull greyj -green solid.

! I J Example 19 Leuco-1,4-bis[2-dimethylaminopropylamino]-5,8-dihydroxyanthraquinone The reaction of 12.26 g. of 2-dimethylaminopropylamine with 10.97 g. of leuco-1,4,5,8-tetrahydroxyanthraquinone in 100 ml. of ethanol for one hour by the procedure of I Example 1 gives 7.29 g. of red-brown crystals.

Example 20 j Leuco-1,4-bis[2-(2-methylaminoethylamino)ethylamino]I -5,8-dihydroxyanthraquinone To a solution of 14.10 g. of 1-methyl diethylenetri30 amine in 50 ml. ,of ethanol and 40 ml. of Ν,Ν,Ν' ,N*-tetramethyl80 ethylenediamine is added 10.97 g. of leuco-1,4,5,8-tetrahydroxyanthraquinone as in Example 1. The mixture is heated at 50° and stirred under nitrogen for one hour, chilled with an ice bath, the solid collected and washed with cold ethanol to give 7.23 g. of green-black crystals, m.p. 108°?-llloC.

Example 21 Leuco-1,4-bis[2-(2-dimethylaminoethylamino)ethylamino 1-5,8-dihydroxyanthraquinone The reaction of N-(dimethylaminoethyl)ethylenediamine with leuco-1,4,5,8-tetrahydroxyanthraquinone by the procedure of Example 20 gives the title compound.

Example 22 Leuco-1,4-bis[2-(l-piperazinyl)ethylamino]-5,8-dihydroxyanthraquinone The procedure of Example 20 applied to 15.50 g. of N-(2-aminoethyl)piperazine gives 3.92 g. of a black powder which does not melt by 350°C. and is discarded. The mother liquor and ethanol washes, on standing and partly evaporating during two weeks in an unstoppered flask, deposit a solid which is collected and washed with ethanol to give 6.19 g. of the title compound as a black'solid, m.p. 200°-203°C.

Example 23 1,4-Bis(2-aminoethylamino)-5,8-dihydroxyanthraquinone dihydrochloride Oxidation with chloranil of 28.25 g. of the product of Example 12 by the procedure of Example 16 gives 29.66 g. of a crude, blue-black solid which is then extracted by stirring for 14 hours with 800 ml. of water. Solids are removed by centrifugation and the supernatent solution freeze-dried, leaving 16.38 g. of a blue-black solid which is unmelted by 350°C.

Example 24 1.4- Bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone Dihydrochloride Chloranil oxidation of 17.86 g. of the product of Example 14 by the procedure of Example 16 gives (without recrystallization) 21.34 g. of blue-black solid, m.p. 203°-205°C.

Example 25 1.4- Bis[2-(2-methylaminoethylamino)ethylamino]-5,8-dihydroxyanthraguinone Tetrahydrochloride The product of Example 20 (11.70 g.) is oxidized with chloranil by the procedure of Example 16, giving 18.03 g. of blue-black solid, m.p. 190°-203°C.

Example 26 1,4-Bis[2~(2-hydroxyethylamino)ethylamino]-5,8dihydroxyanthraquinone In a modification of the synthesis of Example 14 the solvent used is 100 ml. of ethanol. The mother liquor from the leuco product is allowed to stand for two weeks in an unstoppered flask, whereupon the oxidized product separates. It is collec20 ted and washed with ethanol, then recrystallized from ethanol, giving blue-black crystals, m.p. 175°-177°C.

Example 27 Leuco-1,4-bis[3-(2-hydroxyethylamino)-1-propylamino]5,8-dihydroxyanthraquinone The procedure of Example 15 is used with a solution of 14.18 g. of 2-(3-aminopropylamino)ethanol in 100 ml. of ethanol. The resulting solution is filtered and the filtrate diluted with 300 ml. of ether, precipitating the product as a goo.

After decantation of the supematent solution the goo is caused 3° to crystallize by agitating it with 100 ml. of tetrahydrofuran.

Washing with ethanol gives 12.56 g. of green-black solid, m.p. 101°-104°C.

Example 28 1.4- Bis[3-(2-hydroxyethylamino)-1-propylamino]5 5,8-dihydroxyanthraquinone dihydrochloride Oxidation of 9.95 g. of leuco-1,4-bis[3-(2-hydroxyethylamino) propylamino]-5,8-dihydroxyanthraquinone with chlora nil as in Example 16 gives 11.70 g. of a blue solid which does not melt by 350°C.

Example 29 Leuco-1,4-bis[2-(3-hydroxy-l-propylamino)ethylamino]5,8-dihydroxyanthraquinone The procedure of Example 15 is paralleled with 14.18 g of N-(3-hydroxypropyl)ethylenediamine in 100 ml. of ethanol to give 14.63 g. of red-brown crystals, m.p. 58e-60oC.

Example 30 1.4— Bis[2-(3-hydroxy-l-propylamino)ethylamino]5,8-dihydroxyanthraquinone dihydrochloride Chloranil oxidation of 10.77 g. of the product of Example 29 by the procedure of Example 16 yielded 11.64 g. of a dark blue solid, m.p. 210°-216°C.

Example 31 Leuco-1,4-bis[2-(2-hydroxy-1-propylamino)ethylamino]5,8-dihydroxyanthraquinone With 14.18 g. of 1-(2-aminoethylamino)-2-propanol in 100 ml. of ethanol the procedure of Example 15 yields 17.61 g. of green-black crystals, m.p. 50ο-60°α. -47353 Example 32 1,4-Bis[2-(2-hydroxy-l-propylamino)ethylamino]5,g-dihydroxyanthraguinone dihydroehloride A filtered solution of 14.44 g. of leuco-1,4-bis[25 -(2-hydroxy-l-propylamino)ethylamino] -5,8 -dihydroxyanthraquinone in 215 ml. of 2-methoxyethanol is oxidized with 7.65 g. of chlor ' anil by the procedure of Example 16, affording 16.75 g. of purple solid, m.p. 177°-185°C.

Example 33 Eeuco-1,4-bis[2-[2-(2-hydroxyethylamino)ethylamino]ethylamino]-5,8-dihydroxyanthraquinone The procedure of example 15 used with a solution of 17.67 g. of 2-[2-(2-aminoethylamino)ethylamino]ethanol in 100 ml. of methanol gives a solution which is filtered, then diluted - with 300 ml. of ether, precipitating a goo which hardens on standing overnight. Hardening is completed by thorough maceration of the solid in the solvent. The solid is collected and washed with ether, yielding 16.82 g. of a green-black solid.

This solid remains granular if stored at -25°C., but coalesces into a solid cake if stored at 25°C.

Example 34 1,4-Bis[2-[2-(2-hydroxyethylamino)ethylamino]ethylamino]-5,8-dihydroxyanthraquinone tetrahydrochloride Chloranil oxidation of 12.10 g. of the product of Example 33 by the method of Example 16, including three additional washings of the solid with methanol, gives 12.46 g. of dark blue, solid product. 7 2 5 3 Example 35 1,4-Bis[2-(2,3-dihydroxypropylamino)ethylamino]5,8-dihydroxyanthraquinone dihydrochloride By the procedure of Example 15 a solution of 16.10 g. of 3-(2-aminoethylamino)-l,2-propanediol [A. R. Surrey, C. M. Suter and J. S. Buck, J. Am. Chem. Soc., 74, 4102(1952)] in 100 ml. of methanol gives a goo which is separated from solvent by chilling with an ice bath, then decanting. The goo is washed four times by stirring 1.5 hours at 25°'Cwith 100-ml. portions of methanol, chilling with an ice bath, then decanting. A filtered solution of the goo in 280 ml. of 2-methoxyethanol is oxidized with 10.01 g. of chloranil by the method of Example 16. The product is additionally washed with ethanol, giving 15.25 g. of a blue-black solid, m.p. 191°-193°C.

Example 36 Leuco-1,4-bis[2-(1-aziridino)ethylamino]5,8-dihydroxyanthraquinone With 10.33 g. of N-(2-aminoethyl)aziridine in 80 ml. of Ν,Ν,Ν',Ν'-tetramethylethylenediamine the procedure of Example 15 gives a stiff gum. The next day the supernatent solution is discarded, 100 ml. of ether is added and the gum periodically macerated therein for another day, when the gum is mostly hardened. Hardening is completed by maceration during three washings of the solid with ether, giving 17.66 g. of blue-black, granular powder.

Example 37 1,4-Bis[2- (1-aziridino)ethylamino]-5,8-dihydroxyanthraquinone To a suspension of 4.10 g. of the product of Example 36 in 40 ml. of chloroform is added a solution of 1.74 g. of diethyl azodicarboxylate in 25 ml. of chloroform. The mixture is stirred for 20 minutes, the resulting dark blue solution is filtered, and the filtrate is evaporated at<30°. A solution of the residue in 40 ml. of chloroform is stirred five minutes with 2 g. of decolorizing carbon, filtered and washed through with another 25 ml. of chloroform. Addition of 100 ml. of ether to the filtrates precipitates a gum which is eliminated by decantation-filtration. The filtrates deposit crystals which are washed sparingly with acetone. The chloroform-ether mother liquor, chilled at -60°C., deposits a second crop of crystals which is washed with ether and with methanol. A solution of both crops of crystals in 20 ml. of chloroform is stirred with decolorizing carbon, filtered, evaporated at 't25°C. to a volume of 5 ml., diluted with 20 ml. of ether, then chilled at -60°C. The resulting blue-black crystals, washed with ether, amount to 0.64 g., m.p. 168°-170°C. In thin-layer chromatography on silica gel the product is moved as a blue spot by chloroform-triethylamine-methanol, 27/3/1 (ratios by volume).

Example 38 1,4-Bis[2-[2-(1-morpholino)ethylamino]ethylamino]5,8-dihydroxyanthraquinone t'etrahydrochloride -A solution of 20.80 g. of N-(morpholinoethyl)ethylenediamine in 100 ml. of ethanol is used in the procedure of Example 15 to give a solution which is filtered and diluted with 900. ml. of ether, precipitating a goo. The supernatent solution is decanted, the goo dissolved in 175 ml. of 2-methoxyethanol and oxidized with 5.29 g. of chloranil by the method of Example 16, giving 17.7 g. of dark blue solid.

Example 39 Leuco-1,4-Bis[2-(acetamido)ethylamino]5,8-dihydroxyanthraquinone A solution of 12.26 g. of N-acetylethylene diamine in 100 ml. of ethanol in the procedure of Example 15 gives 15.27 g. of dark, red-brown solid, m.p. 125°C.

Example 40 1,4-Bis [2-(acetamido)ethylamino]5,8-dihydroxyanthraquinone A suspension of 11.95 g. of leuco-1,4-bis[2-(acetamido)ethylamino]-5,8-dihydroxyanthraquinone is oxidized with 6.76 g, of chloranil during 61 hours by the method of Example 16, giving a very acidic hydrochloride salt which is converted to the free base by four washings with water. Crystallization from 110 ml. of dimethyl sulfoxide (boiling only 2 minutes and not attempting a hot filtration), then washing with dimethyl sulfoxide and with ethanol gives 7.76 g. of blue-black solid, m.p. 273°-274°C.

Example 41 1,4-Bis[2-[N-(2-hydroxyethyl)triflouroacetamido]ethylamino]-5,8-dihydroxyanthraquinone A suspension of 1.50 g. of 1,4-bis[2-{2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone in 75 ml. of ethyl triflouroacetate and 75 ml. of methanol is stirred for 10 minutes. Evaporation of the resulting solution in vacuo at 30°C. leaves a residue which is washed and macerated with methylene chloride, giving 2.11 g. of blue-black solid, m.p. 162°C.

Example 42 1,4-Bis[2-amino-2-carboxyethylaininol-5,8-dihydroxyanthraquinone . 3/4 HCl To a solution of 6.23 g. of dl-a,β-diaminopropionic acid in 30 ml. of warm water is aided 1.078 g. of lithium hydroxide and 60 ml. of dimethyl sulfoxide. The system is flushed with nitrogen and 4.12 g. of leuco-1,4,5,8-tetrahydroxyanthraquinone is added gradually with stirring. The mixture is stirred and heated with an oil bath at 50°, first for 15 hours under ni10 trogen, then for 21 hours as the initial product is oxidized by bubbling in a stream of air. Thin-layer chromatography on silica gel with methanol-water-concentrated ammonia (25/5/1 by volume) shows all the product spots to be blue when the oxidation is complete. After the mixture is cool the solids are re15 moved by filtration and washed once with dimethyl sulfoxide-water (2/1). Addition of 400 ml. of methanol to the filtrates precipitates a solid which is collected and washed with methanol. Further washing with a total of 13. ml. of 0.01 N aqueous acetic acid dissolves virtually all of the solid. Addition of 3 ml. of concentrated hydrochloric acid to the acetic acid filtrates precipitates a blue-black solid which is washed with acetone to give 0.24 g. of the product. <17253 Example 43 Leuco-1,4-bis[2-(2-methoxyethylamino)ethylamino]5,8-dihydroxyanthraquinone An ethanol solution of N-(2-methoxyethyl)ethylendiamine (U.S. Pat. 3,454,640) reacts in the procedure of Example 15 to give the title compound.

Example 44 1.4- Bis [2- (1,3-oxazolidin-l-yl)ethylamino]-5,8-dihydroxyanthraquinone A solution of 1.62 g. of 37% aqueous formaldehyde solution in 50 ml. of water is stirred overnight with 4.44 g. of 1.4- bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone. The resulting solid is washed with water to give the product, which is a novel compound and thus forms a specific aspect of this invention.

Example 45 1,4-Bis[2-(tetrahydro-1,3-oxazin-l-yl)ethylamino]5,8-dihydroxyanthraquinone A solution of 1.62 ml. of 37% aqueous formaldehyde in ml. of 0.4 N aqueous sodium hydroxide is stirred overnight with 5.45 g. of 1,4-bis[2-(3-hydroxy-l-propylamino)ethylamino]5,8-dihydroxyanthraquinone dihydrochloride. The product is obtained by washing the resulting solid with water. The product is a novel compound and thus forms a specific aspect of this invention.

Example 46 1,4-Bis [2- (1,3-oxazolidin-2-one-l-yl)ethylamino]5,8-dihydroxyanthraquinone A solution of 0.020 g. of sodium in 25 ml. of methanol is stirred and heated under reflux overnight with 75 ml. of diethyl carbonate and 4.44 g. of 1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone. The mixture is allowed to cool. It is stirred with 0.1 ml. of acetic acid, the solid is collected by filtration and washed with methanol to give the product, v/hich is novel and forms a specific aspect of this invention.

Example 47 tetrahydro 1,4-Bis(2- ¢1,3-oxazin-2-one-l-yl)ethylamino]5 5,8-dihydroxyanthraquinone A solution of 0.48 g. of sodium in 25 ml. of methanol is stirred and heated overnight with 75 ml. of diethyl carbonate and 5.45 g. of 1,4-bis[2-(3-hydroxy-1-propylamino)ethylamino]5,8-dihydroxyanthraquinone dihydroehloride. After the mixture cools it is stirred with 0.1 ml. of acetic acid. The solid product is collected by filtration and washed with methanol and then with water. The product is novel and forms a specific aspect of this invention.

Example 48 i 15 1,4-Bis[2-(di(β-hydroxyethyl)amino]ethylamino]- 5, 8-dihydroxyanthraquinone dihydroehloride 5 Chloranil oxidation of 10.77 g. of the product of Ex- ί ample 15 by the method of Example 16 gives 11,64 g. of a dark t j ί ί 20 blue solid, m.p. 216°C. Example 49 Preparation of 50 mg. Tablets Per Tablet Per 10,000 Tablets 0.050 gm. 1,4-bis(3-aminopropylamino)-5,e^SThydroxyanthraquinone .. ......... 500 gm. 25 0.080 gm. Lactose...................... ......... 800 gm. 0.010 gm. Corn Starch (for mix) ........ ......... 100 gm. 0.008 gm. 0.148 gm. Corn Starch (for paste) ...... ......... 75 gm. 1475 gm. 0.002 gm. Magnesium Stearate (1%) ...... ......... 15 gm. 0.150 gm. 1490 gm.

The 1,4-bis(3-aminopropylamino)-5,8-dihydroxyanthraquinone, lactose and corn starch (for mix) are blended together. The corn starch (for paste) is suspended in 600 ml. of water and heated with stirring to form a paste. This paste is then used to granulate the mixed powders. Additional water is used if necessary. The wet granules are passed through a No. 8 hand screen and dried at 120°P. The dry granules are then passed through a No. 16 screen. The mixture is lubricated with 1% magnesium stearate and compressed into tablets in a suitable tableting machine.

Example 50 Preparation of Oral Suspension Ingredient Amount Leuco-1,4-bis(3-aminopropylamino)-5,8-dihydroxyanthraquinone ............ 500 mg.

Sorbitol solution (70% N.F.) .................... 40 ml.

Sodium benzoate ................................. 150 mg.

Saccharin....................................... 10 mg.

Red dye ......................................... 50 mg.

Cherry flavor................................... 50 ml.

Distilled water.. .qs.. .ad........................ 100 ml.

The sorbitol solution is added to 40 ml. of distilled water and the leuco-1,4-bis(3-aminopropylamino)-5,8-dihydroxyanthraquinone is suspended therein. The saccharin, sodium benzoate, flavor and dye are added and dissolved. The volume is adjusted to 100 ml. with distilled water. Each ml. of syrup contains 5 mg. of leuco-1,4-bis(3-aminopropylamino)-5,8-dihydroxyanthraquinone.

Example 51 Preparation of Parenteral Solution In a solution of 700 ml. of propylene glycol and 200 ml. of water for injection is suspended 20.0 grams of 1,4-bis[3-(dimethylamino)propylamino]-5,8-dihydroxyanthraquinone di hydrochloride with stirring. After suspension is complete, 47353 tho pu is adjusted to 5.5 with hydrochloric acid and the volume is made up to 1000 ml. with water for injection. The formulation is sterilized, filled into 5.0 ml. ampoules each containing‘2.0 ml. (representing 40 mg. of drug) and sealed under nitrogen. 7253 Example 52 ffyeparation of 1,4-bi.s(2-dimethylaminoethylamino)anthraquinone Λ mixture of 3 g. of quinizarin, 10 g. of N,N-di5 methylethylcncdiaminc and 17.5 ml. of water is stirred and heated under reflux for 3.5 hours. The mixture is cooled and the solid is collected and washed with water giving 2.96 g. -of the desired product as a dark blue solid, mp. 170°-172°C.

Alternatively, the above product may be prepared by stirring and heating under reflux for 5 hours a mixture of 2.4 g. of quinizarin, 2.62 g. of Ν,Ν-dimethylethylenediamine and 9 ml. of Ν,Ν,Ν1jN'-tetramcthyletbylenediamine. The product is recovered as described above.

Example 53 Preparation of l,4-bis(2-morpho3inoethylamino)anthraquinone A 9.60 g. portion of quinizarin, 46.90 g. of N- {2-aminoethyl)morpholine, and 56 ml. of water are reacted as described in Example 1 giving 9.92 g. of the desired product as a blue-black solid, mp. 158°-159°C.

Example 54 Preparation of 1,4-bis (2-dicthy lamlnoethylaniino) . anthraquinone A mixture of’42 ml. of Ν,Ν,Ν',Ν'-tetramcthylcnodiamine, 17.43 g. of Ν,Ν-diethylethylencdiamine and 12.01 g. of quinizarin is stirred and heated under reflux for 15 hour? The resulting solution is evaporated to dryness and ;i chloroform solution of the residue is filtered through 300 g. of alumina. The blue filtrate is chromatographed on silica gel in a *Nylon film column, developing with a chloroform:methanol (6:1) mixture. The major blue band is cut out and then eluted with a chloroformtmethanol:triethylamine (6:2:1) mixture. The eluate is evaporated. The residue is crystal5 lized from hexane and washed with petroleum ether, giving 1.43 g. of the desired product as blue-black plates, mp. 109 °C.

Example 55 Preparation of leuco-1,4-bis(2-aminoethylarnino)10 anthraquinone Λ 125-rnl. portion of ethylenediamine is de-aerated by bubbling nitrogen through it for 15 minutes. A 12.0-g. portion of leucoguinizarin is added and the mixture is heated with stirring under nitrogen at 50°C. for one hour. The mix15 ture is allowed to cool. The solid is collected and washed successively with ethyl acetate, acetonitrile and petroleum ether, giving 8.07 g. of the desired product as green-gold crystals, mp. 162°-165°C. (dec.) at a heating rate of 9° per minute.

Example 56 Preparation of 1,4-bis(2-aminoethylamino)anthraquinone Air is bubbled into a mixture of 7.0 g. of leuco-1,4-bis(2-aminoethylamino)anthraquinone and 87.5 ml. of ethylenediamine while heating at 50°C. for one hour. The mixture is diluted with 87.5 ml. of acetonitrile, allowed to cool and the solid is collected and washed with acetonitrile giving 5.43 g. of the desired product as a dark blue solid, mp. 170°-171eC.

*Nylon' is a Trade Mark Example 57 ί^!Εί!2ζΐ£ϊ.οι1_ Ίί—2 »4—*J f2- (methyl,imi no) etliy 1 ami no) anthragui none Λ mixture of: 2.4 g. of lcucoquinizarin and 25 g. of de-aerated tl-methylethylenediaminc is heated at 50“c. with stirring tinder nitrogen for one hour. Heating at 50°C. is continued as air is bubbled into the mixture for 40 minutes. The mixture is evaporated to dryness, then re-evaporated twice from 25 ml. portions of ethanol. Crystallization of the residue from ethanol-ether at. -70°C. gives 2.32 g. of crude solid which is recrystaliized twice from carbon tetrachloride giving 1.92 of the desired product as dark blue crystals, mp. 131‘~132f,C.

Example 58 Preparation of 1,4-bis(2-piperidinoethylamino)anthraqninone A mixture of 4.07 g. of quinizarin, 21.74 g. of N-(2-aminoethyl)piperidine and 26 ml. of water is stirred under reflux for 2 hours and then allowed to stand overnight. The gummy solid is collected and washed with water by centrifugation, giving 1.99 g. of blue-black solid. This solid is dissolved in 15 ml. of chloroform and chromatographed by an abbreviated wet-column procedure on 100 g. of alumina, eluting with chloroform. A total of 180 ml. of eluate is collected in eight separate cuts from the time the eluate turns blue until a black band nears the bottom of the column. Cuts 1-6 arc combined and evaporated giving 1.42 g. of blue-black crystals which are recrystaliized from ethanol giving 1.35 g. of the desired product as blue-black needles, mp. 140-141C. Product dried in vacuo at 78C. melted at 156*'-157°C. -154°C.

Example 59 Propara tion of ] eucp --3 _, 4ybi_s( lauHiiSg. ethyl arni no) anthraquinone1 Λ solution of 26.44 g. of N,N-dimethylethylono~ diamine in 75 ml. of Ν,Ν,Ν’,N1-tetrnmethylethylenediaminc is de-aerated by bubbling through Ng for 15 minutes. Then, 12.11 g. of leucoguinizarin is added and the resulting mixture is stirred under Ng while heating at 48°-50DC, for 21 hours. After cooling overnight under nitrogen, the solid is collected by filtration and washed three times by slurrying with acetonitrile and then twice with petroleum ether. There is thus obtained 12.52 g. of dark green crystals, • mp. 15O°-’157°C.; or on the hot stage miscroscope, mp. 153°Example 60 Preparation of 50 mg. Tablets Per 10,000 Tablets Per Tablet 1,4~bisJ2-(methylamino)- .......... 500 gm. ethylamino]anthraquinone Lactose ........................... 800 gm.

Corn Starch (for mix) ............. 100 gm.

Corn Starch (for paste)............ 75 gm. 75' gm.

Magnesium Stearate (15) ........... 15 gm. 0.050 gm 0.080 gm. 0.010 gm. 0.008 gm, 0.148 gm. 0.002 gm. 0.150 gm. 1490 gm. 1,4-bis[2-(methylamino)ethylamino]anthraquinone, lactose and corn starch (for mix) are blended together. The corn starch (for paste) is suspended in 600 ml. of water and heated with stirring to form a paste. This paste is then use. to granulate the mixed powders. Additional water is used if necessary. The wet granules are passed through a No. 8 hand screen and dried at 120*>F. The dry granules are then passed through a No. 16 screen. The mixture is lubricated with 3. magnesium stearate nrd compressed into tablets in a suitable 7 2 5 3 tablet. 1 ng machine.

Example 61 Preparation o f Oral fins pen sion Ingredient Amount Leuco-1,4-bi£{2-aminoethy 1 amino)anthraquinone..... 500 mg.

Sorbitol solution (70% H.P.) ...................... Ίθ mX.

Sodium benzoate................................... 150 mg.

Saccharin ......................................... 10 mg.

. Red dye........................................... 10 mg.

Cherry flavor ..................................... 50 mg.

Distilled water.. .gs·.. .ad.......................... 100 ml.

The sorbitol solution is added to 40 ml. of distilled water and the leuco-1,4-bis(2-aminoethylamino) anthraquinone is suspended therein. The saccharin, sodium benzoate, flavor and dye are added and dissolved. Tlie volume is adjusted to 100 ml. with distilled water. Each ml. of syrup contains 5 mg, of leuco-1,4-bis(2-aminoethylamino)anthraquinone.

Example 62 Preparation of Parenteral Solution In a solution of 700 ml. of propylene glycol and 200 ml. of water for injection is suspended 20.0 grams of 1,4-bis(4-aminobutylamino) anthraquinone with stirring.

After suspension is complete, the ph is adjusted to 5.5 with hydrochloric acid and tlie volume is made up to 1000 ml. with water for injection. The formulation is sterilized, filled into 5.0 ml. ampoules each containing 2.0 ml. (representing 40 mg. of drug) and sealed under nitrogen.

Example 63 Preparation of lcuco-1,4-bi s (3-aminopropylaiiiino) anthraquinone When. 1, 3-propanedi;unine is used instead of ethyl5 enediamine in the procedure of Example 55 the product is the title compound.

Example 64 Preparation of leuco-1,4-bis|2-dimethylamlnopropy1) amino)anthraquinone Using 15.32 g. of 2-dimethylaminopropyl amine instead of Ν,Ν-dimethylethylenediamine in the procedure of Example 59 gives the title compound after a reaction time of one hour at 50°.

Example 65 beuco-l,4-bis [2- (2-methylaminoethylamino) ethylamino) anthraquinone A solution of 14.10 g. (0.12 mole) of 1-rcethyl-diethylenetriamine in 100 ml. of ethanol is de-aersted by bubbling nitrogen through it for 15 minutes; then 9.69 g. (0.04 mole) of leucoquinixarin is added gradually with stirring. The mixture is stirred under nitrogen and heated with an oil bath at 50°C. for 21 hours. The mixture is allowed to cool, the product is collected by filtration and washed with acetonitrile and then with petroleum ether to give the title compound as a dark green solid.

Example 66 Preparation of leuco-1,4,bis(2-methylaminoethylamino)nntliraqui non o To a de-aerated solution of 8.89 a. of N-molhylethylenediamine in 00 ml. of Ν,Ν,Ν',Ν'-totra98 methy)etbyJenediamino is added 9.Gil y. of leueocjuinizarin. Tiic mixLuru in «Lirred and heaLed at 50pC· under nitrogen for one hour, then allowed to cool. The solid is collected, washed with toluene and then with ether, giving 9.0 g. of a green-black solid, m.p. 105p-109°C.

Example 67 1,4,5-Tr'is [ (2-aminoethyl)amino) -8-hydroxy-anthraquinone Λ 100 ml. portion of ethylenediamine is de-aerated by bubbling nitrogen through it for 15 minutes. 7\ 10.97 g. portion of leuco-1,4,5,8-tetrahydroxyanthraquinone is added and the mixture is stirred under nitrogen at 50°-51°C. for one hour. The mixture is cooled and filtered. The unstoppered filtrate is' allowed to cool at 10°C. for 2 hours producing a solid which is collected and washed with ethanol, giving 2.25 g of the desired product as a dark purple solid. 100 Example 68 1,4-Din[(2-dimet)iy laminoethyl) amino J-5,6-di hydroxy-anthraquinone Λ 30 cj. portion of zinc is added portionwise to a boiling mixture of 1.5 liters of glacial acetic acid and 40 ml. of water containing 27.2 g. of l,4,5,6-tetrahydro::yant)ira. quinone. The mixture is boiled for 30 minutes, filtered and the filtrate is cooled. The orange-brown crystals which form are collected giving 19.7 g. of leuco-1,4,5,6-tetrahydrexyanthraquinone, mp. 255°~257°C. Λ 7.9 g. portion of dimethylaminocthylamine in 75 ml of tetramethylethylenediamine is heated to 80°-100°C. and deaerated with nitrogen. This mixture is treated portionwise with 8.22 g. of leuco-1,4,5,6-tetraliydroxyanthraquinone with stirring under nitrogen and heated at 90°-100“0. for 6 hours. The mixture is filtered while hot. The filtrate is cooled to 4°C., treated with ether and after standing 48 hours gives a dark blue gum. Tlie supernatant is decanted, treated with tv.’ic its volume of ether and cooled giving a blue gum. This supernatant is allowed to stand and is then treated with more ether producing 1.5 g. of the desired final product as a blue solid, mp.·. 133°-135°C.

Example 69 1,4,5-Tris ([2- (2-hydroxyethylamino) ethyl 1 aminoj-8-hydroxyanthraquinone The reaction between 2-(2-hydroxycthylamino)ethylamine and leuco-1,4,5,8-tetrahydroxyantbraquinone is carried out as in Example 67 to give the title compound. 101 Example 70 1,4-Bin (3-aminopropyl.'iin-j no) -5 , 8-dihydroxyanthrnnui noni.· Λ suspension of 10.0 g. of leuco-1,4,5,8-tetrahydroxyanthraquinonc in 120 ml. of de-aerated 1,3-diaminopro5 . pane is stirred and heated at 45°C. under nitrogen for one hour and then for 10 minutes as air is bubbled into the suspension. The mixture is then evaporated to dryness and the residue is extracted with 650 ml. of ethiinol in a Soxhlet apparatus for 17 hours. The extract is filtered while hot, concentrated to 95 ml. and then diluted with 900 ml. of diethyl ether. The mixture is cooled and the solid is collected, washed with ethanol-diethyl ether, then diethyl, ether giving the desired product as 9.57 g. of a blue solid, mp. 11.5°-130°C. ' Example 71 Preparation of 50 mg. Tablets Per Tablet Per 10,000 Tablets 0.050 gnu 1,4-bis(3-aminopropylami no)-5,8-dihydroxyanthrnquinono ..... ...... 500 gm. 0.080 0.010 gm. gm. lactose........ . . . ............. ...... 800 Corn Starch (for mix) ........... ...... 100 gm. 0.008 gm. Corn Starch (for paste) ......... ...... 75 gm. 0.143 qm.. 14 75 qm. 0.002 gm. Magnesium Stearate (17.) ......... ...... 15 qm. 25 0.150 gm. 1490 qm. 102 472 5 3 ’ Tho corn starch (for paste) and heated witli stirring to 5 used to granulate the mixed : The l,4-bis(3-atninopropylainino)-5,8-dihydroxyanthra) quinone, lactose and corn stare)) (for mix) are blended toyetlu.-j in suspended in COO in] . of water form ίί paste. This paste is then powders. Additional water is used if necessary. The wet granules are passed through a No. 8 ham; screen and dried at 120°F. The dry granules are then passed witli 12 suitable through a No. 16 screen. 'Die mixture js lubricated magnesium stearate and compressed into tablets in a 10 tableting machine.

Example 72 Preparation of Oral Suspension Ingredient Leuco-1,4-bis (3-ami nopropyl ami, no) -5,8-dihydroxy15 anthraquinone ...................................

Sorbitol solution (70L N.F.) ....................

Sodium benzoate .................................

Saccharin .......................................

Red dye .........................................

Cherry flavor ...................................

Distilled water...qs...ad........................

The sorbitol solution is added to 40 ml. o Amount 500 mg. 0 ml. 150 mg. mg . mg. ml. 100 ml. f distilled water and the leuco-1,4-bis(3-ami nopropylamino)-5,8-dihydroxyanthraqui.none is suspended therein. The saccharin, 25 sodium benzoate, flavor and dye are added and dissolved. 'Die volume is adjusted to 100 ml. with distilled water. Each ml. of syrup contains 5 mg. of leuco-1,4-bis(3-amlnopropylamino)-5,8-dihydroxyanthraquinonc.

Example 73 Preparation of Parenteral Soletion In a solution of 700 ml. of propylene glycol and 200 ml, of water for injection is suspended 20.0 grams of 1,4-bi s (3-.imi nopropylann no) - 5, IJ-diliydi oxy until requi none d i hydrochloride with .stirring. After· suspension is complete, 103 472S3 the plf is adjusted to 5,5 with hydrochloric acid and the vol nine is made up to 1.000 ml. with w.ilei loi injection. Th· formulation is sterilized, filled into 5.0 ml. ampoules pud containing 2.0 ml. (representing 40 mg. of drug) and sealed under nitrogen.

Example 74 1, 4-Bir. [ 2- (2-hydroxyethylamino) ethylamino) -5,8-diliydroxyanthraquinonc disuccinatc .salt A mixture of 222 mg. of 1,4-bis[2-(2-hydroxyethylamino)10 ethylamino)-5,8-dihydroxyanthraquinone, 118 mg. of succinic acid, and 50 ml. of ethanol is heated under reflux for 30 minutes to give the title compound.

Example 75 1,4-Bis[2-(3-hydroxypropylamlno)ethylamino)-5,815 -dihydroxyanthraquinone dimalate salt A mixture of 228 mg. of l,4-bis(2-(3-hydroxyproovlamino)ethylamino)-5,8-dihydroxyanthraquinone, 134 mg. of DL-malic acid, and 50 ml. of ethanol is heated under reflux for 30 minutes to give the title compound.

Example 7,6 1,4-rBis[2-(2-hydroxypropylamino)ethylamino)-5,8-dihydroxyanthraquinone dilactate salt A.mixture of 228 mg. of l,4-bis(2-(2-hydroxypropylami.no)ethylamino)-5,8-dihydroxyanthraquinone, 120 mg. of 80% DL-Jactie acid, and 10 ml. of ethanol is heated on ci steam bath for 10 minutes, cooled, treated with 50 ml. of acetone and cooled to obtain the title compound.

Claims (8)

1. A compound of the formula: the tautomeric forms and the pharmacologically acceptable 5 acid-addition salts thereof, wherein A-B is selected from CH=CH and CHg-CHg! Q is a divalent moiety selected from those of the formulae ^3 -(CK 2 ) n -, -CH-CHg-, ^2¾ 5 -CH-CH 2 -, -CH-CH-, f H 3 -CH-CH - and CH, CHCK, I I 3 I —CHg—CH—, -CH-CH-, CH, I -CH-CHg-CHg-, P>3 -ch 2 -ch 2 -ckwherein n is an integer from 2 to 4, inclusive; R^ and R 2 are each individually selected from hydrogen, alkyl having from 1 to 4 carbon atoms, monohydroxyalkyl having from 2 to 4 carbon atoms and wherein the car15 bon atom alpha to the nitrogen atom may not bear an hydroxy group, dihydroxyalkyl having from 3 to 6 carbon atoms and wherein the carbon atom alpha to the nitrogen atom may not bear an hydroxy group, formyl, alkanoyl having from 2 to 4 carbon atoms, trifluoroacetyl and moieties of the formulae: “(CI1,) -CN, -(CH,) -O-R nnd -(CH,) -N J 2 n fin fin \ D 20 K 4 wherein n is an integer from 2 to 4, inclusive, R is alkyl having from 1 io 4 carbon atoms, and R 3 and R^ are eacii individually selected from hydrogen alkvl having from 1 to 4 carbon atoms and monobydroxyalkyl having from ’ y 105
2. 2. To 4 carbon atoms and wherein the carbon atom alpha to the nitro gen atom may not bear an hydroxy group; or and R 2 takcn to “ gether with their associated N(itrogen) atom and R 3 and R 4 taken together with their associated N(itrogen) atom is morpholino, thiomorpholino, piperazino, 4-methyl-l-pipcrazino or a moiety of the formula: -N (CH 2 ) m wherein m is an integer from 2 to 6, inclusive, provided that the ratio of the total number of carbon atoms to the sum of the total number of oxygen atoms plus the total number of nitrogen atoms in the side chains at the 1-position and the 4-position may not exceed 4; Rg is selected from hydrogen·, hydroxy, chloro and alkanoyloxy of from 1 to 6 carbon atoms. Rg is· selected from hydrogen and hydroxy; R ? is selected from hydrogen, · hydroxy, chloro, alkanoyloxy of from 1 to 6 carbon atoms and a moiety of the formula; -nh-cii 2 ch wherein Rg and Rg are each individually selected from methyl, ethyl and-hydroxyethyl; provided that when Q is -(CH 2 ) n - then: a) Rj, R 2 , R g , Rg and Ry may not simultaneously be hydrogen; b) when R g , Rg and Ry are hydrogen r j/ r 2 cannot be H/nionohydroxyalkyJL, and; 106 when n is 2 then R-j/Rg cannot be -(CHgjg-O-tCHg)^-, H/CHj, Η/CgHg, CgHg/CgHg, or together with their asssociated nitrogen morpholino, and when n is 3 R-j/Rg cannot be CHg/CHg, -(CHg)g-, or together with their associated nitrogen piperidino;
3. 3. The compounds of claim 2 having from 1 to 4 carbon atoms, having from 2 to 4 carbon atoms, 20 3 to 6 carbon atoms or a moiety Ry must be H; and may be alkanoyl. wherein Rg and Ry are hydroxy and wherein Rj is hydrogen or alkyl Rg is monohydroxyalkyl di hydroxyalkyl having from of the formula: -(CH 2 ) n -N Λ 3 β 4. 7 2 5 3 m is 2 or 3; which comprises reacting a compound of the formula: wherein is as defined above, with a compound of the formula: H 2 NCH 2 (CH 2 ) n
4. 4. The compounds of claim 2 from 2 to 4 carbon atoms, and R. 1 to 4 carbon atoms. wherein Rj is monohydroxyalkyl having , is hydrogen or alkyl having from 107 5. Wherein m is as defined above, in a lower alkanol or Ν,Ν,Ν'Ν 1 tetramethyl ethylene diamine at a temperature of from 50° to 90°C. 37. A compound according to Claim 1, substantially as described in any Example herein. 38. A process for preparing a compound according to Claim 1, substant 10 ially as described in any Example herein. 39. A compound whenever prepared by a process according to any one of Claims 10-21 or Claim 38. 40. A composition according to Claim 22, substantially as described in any Example herein. 15 41. The compound 1,4-bis [2-(2-hydroxyethylamino)-ethylamino]-5, 5 yl)ethylamino] -5,8-dihydroxyanthraquinone , and the leuco base and tautomer thereof. 33. A compound selected from 1,4-bis [2-(1,3-oxazolidin-2-one-l yl)ethylamino]-5,8-dihydroxyanthraquinone, and the leuco base and tautomer thereof. 10 34. A compound selected from 1,4-bis [2-(tetrahydro-l,3oxazin-2-one-l-yl)ethylamino] 5,8-dihydroxyanthraquinone, and the leuco base and tautomer thereof. 35. A process for preparing a compound of the formula: 15 wherein R^g is hydrogen or hydroxy, n is 1, 2 or 3 and m is 2 or 3, which comprises treating a compound of the formula: 119 wherein R^, n and m are as hereinbefore defined, with aqueousethanolic HC1 at 40°-80°C for 1-6 hours. 36. A process for the preparation of a compound of the formula the tautomeric forms and the pharmacoligically acceptable acidaddition salts thereof, wherein A- 8 is CH = CH or CHg-CHg, R-| 2 is hydrogen or hydroxy, n is 1, 2 or 3 and 120 5 R-j is hydrogen, and wherein said compound is in the form of the hydrochloride salt. 29. The composition of Claim 27, wherein A-B is CH = CH, and Rj is CHgCHgOH, and wherein said compound is in the form of the acetate salt. 10 30. A compound of the formula: and the tautomeric forms and the pharmacologically acceptable acidaddition salts thereof, wherein A-B is CH = CH or CHg-CHg, Rjg is hydrogen or hydroxy, n is 1, 2 or 3 and m is 2 or 3. 118 31. A compound selected from l,4-biS|2-(l,3-oxazolidin-l-yl)ethylaminoj -5,8-dihydroxyanthraquinone, and the leuco base and tautomer thereof· 32. A compound selected from 1,4-bis [l·-(tetra hydro-1,3-oxazin-l 5 and the tautomeric forms and the pharmacologically acceptable acidaddition salts thereof, wherein A-B is selected from CH = CH and CHg-CHg; Q is a divalent moiety selected from those of the formulae: CHCHCH, CH, | j , J ,' 3 I 3 -(CHg) -, -CH-CHg-, -CHg-CH-, -CH-CH-, ?2 H 5 CgHg CH 3 -CH-CHg-, -CHg-CH-, -CH-CHg-CHg-, CHCH-CHg - CH - CHg- and -CHg- CHg - CH115 . 472S3 wherein n is an integer from 2 to 4, inclusive; R-j and R 2 are each individually selected from hydrogen, alkyl having from 1 to 4 carbon atoms, monohydroxyalkyl having from 2 to 4 carbon atoms and Wherein the carbon atom alpha to the nitrogen atom may not bear an hydroxy group, dihydroxyalkyl having from 3 to 6 carbon atoms and wherein the carbon atom alpha to the nitrogen atom may not bear hydroxy group, formyl, alkanoyl having from 2 to 4 carbon atoms, tri fluoroacetyl and moieties of the formulae: -(CH z ) n -CN, -(CH 2 ) n -0-R and -(CH 2 ) n 10 wherein n is an integer from 2 to 4 inclusive, R is alkyl having from 1 to 4 carbon atoms, and R 3 and R^ are each individually selected from hydrogen, alkyl having from 1 to 4 carbon atoms and monohydroxyalkyl having from 2 to 4 carbon atons and wherein the carbon atom alpha to the nitrogen atom may not bear an hydroxy group; or R-| and R 2 taken 15 together with their associated N(itrogen) atom or R 3 and R^ taken together with their associated M(itrogen) atom is morpholino, thiomorpholino, piperazino, 4-methyl-l-piperazino or a moiety of the formula: Wn> wherein m is an integer from 2 to 6, inclusive, provided that the ratio of the total number of carbon atoms to the sum of the total number 116 of oxygen atoms plus the total number of nitrogen atoms in the side chains at the 1-position and the 4-position may not exceed 4; Rj is selected from hydrogen, hydroxy, chloro or alkanoyloxy of from 1 to 6 carbon atoms; Rg is selected from hydrogen and hydroxy; Ry is selected from chloro or alkanoyloxy of from 1 to 6 carbon atoms; hydrogen, hydroxy and a moiety of the formula R, '9 wherein R g and Rg are each individually selected from methyl, 10 ethyl and g-hydroxyethyl; provided that Q is -(CH 2 ) -: when Rg is OH then one of R g and Ry must be H, and when Rg is H then both of Rg and Ry must be H. 23, The composition of claim 22 wherein Rg and Ry are hydroxy and Rg is hydrogen. 15 24. The composition of Claim 23 wherein R-j is hydrogen or alkyl having from 1 to 4 carbon atoms R 2 is monohydroxyalkyl having from 2 to 4 carbon atoms, dihydroxyalkyl having from 3 to 6 carbon atoms or a moiety of the formula: R. '3 R, ‘4 20 wherein Rg and are as defined in claim 1. 25. The composition of claim 23 wherein R-j is monohydroxyalkyl having from 2 to 4 carbon atoms and R 2 is hydrogen or alkyl having from 1 to 4 carbon atoms. 26. The composition of claim 23 wherein Q is - (CH 2 ) n - and n is an integer of from 2 to 4. 117 27. The composition of Claim 23 wherein Q is -CHgCHgR-| is hydrogen or -CHgCHgOH, and R 2 is -CHgCHgOH. 28. The composition of Claim 27 wherein A-B is CH = CH, and
5. 5. The compounds of Claim 2 wherein Q is - (CHg) n - and n is an integer of from 2 to 4. 5 (c) when Rg and Ry are hydroxy and Rg is hydrogen and: n is 2 then Rj/Rg may not be CHg/CHg, C^Hg/C^Hg, (CHg)gor together with their associated nitrogen piperidino; n is 3 and then Rj/Rg may not be H/H, CHg/CHg, CgHy/CgHy, -(CHgjg-O-iCHgJg- or together with their associated nitrogen morpholino 10 and n is 4 then Rj/Rg may not be CgHg/CgHg, C^Hg/C^Hg, -(CHg)^or together with their associated nitrogen pyrollidino; (d) when Rg is OH then one of R g and Ry must be H, when Rg is H then both of Rg and (e) only one of Rj and R, 15 2. The compounds of Claim 1 Rg i s hydrogen.
6. 6. The compounds of Claim 2 wherein Q is -CHgCHg-, R.j is hydrogen or -CHgCHgOH, and Rg /s -CHgCHgOH, and the 5 pharmacologically acceptable addition salts thereof.
7. 7. The compound of Claim 6 wherein AB is CH = CH, and R-j is hydrogen, in the form of the hydrochloride salt. 8. The compound of Claim 6 wherein A-B is CH = CH, and R-j is -CHgCHgOH in the form of the acetate salt. 10 9. A compound as defined in Claim 1 and specifically identified herein. 10. A process for preparing a compound as defined in Claim 1, which comprises reacting a compound of the formula with a compound of the formula Y - Q -J -Z 108 wherein Rg-Ry and Q are as defined in Claim 1, one of X and Y is NR^ or NHCOCFg wherein and R 2 are as defined in Claim 1 and the other is selected from 0R 10> Cl, Br, 1, N(R 10 ) 2 , NOg, S0 3 R^ 0 , S0 2 R 10 , SOR-jg, SR-jg, Ng, ONO, and tetrazolyl, wherein R^g is selected from hydrogen, alkyl of from 1 to 6 carbon atoms, phenyl, para-tolyl and benzyl; S and T are different are are chosen from 0 and 1, Z is selected from hydrogen, alkyl of from 1 to 4 carbon atoms, and NR-jRg» wherein R-j and R 2 are as defined in claim 1, or a group convertible thereto; provided: a) that only X may be NHCOCFg and only when S is 0 and Z is not hydrogen or alkyl; b) except as in a), when S is 0, then R-j/Rg is H/H and Z is not hydrogen or alkyl of from 1 to 4 carbon atoms; c) when T is 0 and Y is NR-jR-j then Z is hydrogen; d) when T is 0 and X is NR^R 2 at least one of R-|/R 2 is hydrogen and Z is alkyl of from 1 to 4 carbon atoms; e) when one of Rg and Ry is chloro or alkanoyloxy then the other is the same and R g is hydrogen; and f) only one of R-j and R 2 may be alkanoyl; and when Rg = Ry = chloro or alkanoyloxy converting them to hydroxy, and when Z is a group convertible to ΝΡ^ 2 effecting its conversion thereto; and, if desired: converting A-B when it is CH 2 -CH 2 into CH = CH; and contacting the product with a pharmacologically acceptable salt-forming reagent under salt-forming conditions. 11. The process of Claim 9 wherein Rg and Ry are hydroxy and Rg is hydrogen. 109 12. The process of Claim 11 wherein R-j is hydrogen or alkyl having from 1 to 4 carbon atoms, and Rg is monohydroxyalkyl having from 1 to 4 carbon atoms, dihydroxyalkyl having from 3 to 6 carbon atoms or a moiety of the formula: -(CH 2 ) n -fi, wherein R 3 and R^ are as defined in Claim 1. 13. The process of Claim 11 wherein R 1 is monohydroxyalkyl having from 2 to 4 carbon atoms, and Rg is hydrogen or alkyl having from 1 to 4 carbon atoms. 14. The process of Claim 11 wherein Q is -(CHg) n - and n is an integer of from 2 to 4. 15. The process of Claim 11 wherein Q is -CHgCHg-. 16. The process of Claim 15 wherein A-B is CH = CH and R^ is hydrogen, and where'in the compound is recovered in the form of 15 the acetate salt. 17. The process of Claim 15 wherein A-B is CH = CH and R-j is -CHgCHgOH, and wherein the compound is recovered in the form of the acetate salt. 110 18. A process for preparing a compound as defined in Claim 1, wherein Rg and Ry are both hydrogen or hydroxy and Rg is hydrogen, and wherein proviso (e) does not apply, which comprises reacting a compound of the formula with a compound of the formula 111 wherein Q, R-| and Rg are as defined in Claim 1, R is alkyl of from 1 to 6 carbon atoms or CF^; E and F are both hydrogen or when taken together form OR 3 wherein R is hydrogen or alkyl of fran 1 to 6 carbon atans; 3 Y C - D is CH=CH or wherein Y is H or OCH-,; provided that whan E and F are hydrogen C -- D Y 'or., is and when C - D is CH=CfI E and F form and Z is hydroxy; and hydrolysing the the groups RCO, and Y when it is OCH 3 to convert when respectively to hydrogen and hydroxy; ar.d if desired, contacting the product with a pharmacologically acceptable salt forming reagent. 19. The process of claim 17 wherein Z is hydroxy. 112 20. A process for preparing a compound as defined in Claim 1 wherein R g and Ry are both hydrogen or hydroxy and Rg is hydrogen, and wherein proviso (e) does not apply, which comprises reacting a compound of the formula G G with a compound of the formula wherein G is alkanoyloxy of from 1 to 6 carbon atoms, alkoxy of from 1 to 6 carbon atoms, or z Rl - N - Q - N I \ COOK R 2 R-| and R 2 are as defined in C^aim 1, wherein K is an alkyl of from 1 to 6 carbon atoms; L is hydrogen, hydroxy, or 113 NH-Q-N wherein R-| and Rg are as defined in Claim 1 and J is hydrogen, chlorine, or bromine; provided: a) when G is - N-Q-N 1 ^R COOK K 2 L is hydrogen or hydroxy and J is chlorine; b) when G is other than - Ν— 0- N ι \ COOK Rg L is NH - Q - N 10 and the cyclized product is aromatized; and if desired the product is contacted with a pharmacologically acceptable salt forming reagent. 21. The process of Claim 20 wherein Rg and Ry are hydroxy. 114 22. A composition useful for inducing regression/or palliation of cancer diseases in mammals comprising a pharmaceutically acceptable carrier or diluent and a compound selected from those of the formula:
8. 8. -di hydroxyanthraqui none di hydrochlori de.