SE445996B - NEW ATRAKINO DERIVATIVES - Google Patents

Description

7807987-8 taken together with its attached nitrogen atom and R3 and R4 taken together with its attached nitrogen atom is morpholino; R5 is hydrogen or hydroxy; R6 is hydrogen or hydroxy; R7 is hydrogen, hydroxy or a group of the formula: H -NH-cnzcaz-N R where R9 is ß-hydroxyethyl; provided that when Q is -(CH2)n-; a) R R), R5; R and R cannot simultaneously be hydrogen; l' 5 7 and R is hydrogen Rl/R2 cannot be H/mono- b) when R5, R6 7 hydroxyalkyl and A when n is 2 R1/R2 cannot be ~(CH2)2-O-(CH2)2-, H/CH3, H/CZH5 or CZHS/CZHS, and when n is 3 Rl/R2 cannot be CH3/CH3 or -(CH2)5-; c) when R5 and R7 are hydroxy and n is 2, R1/R2 cannot be CH3/CH3, C4H9/C4H9 H/H, CH3/CH3, C3H7/C3H7 or -(CH2)2-O-(CH2)z-; n is 4, R1/R2 cannot be CZHS/C2H5, C4H9/C4H9 or -(CH2)5-; n is 3, R1/R2 cannot be -(CH2)4-: d) when R5 is OH, one of R6 and R7 must be H and when R5 is H, both R6 and R7 must be H; and e) only one of R and R can be alkanoyl. l 2 The compounds of general formula I above, where A-B are CH2- CH2, are usually 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 (here the leuco bases) and the tautomers thereof can be represented by the following general formula: 7807987-8 (II, leuco bases) (III, tautomeric form) The invention also relates to the acid addition salts of the novel compounds of formulae 1, II and III.

The compounds of the invention are generally available as reddish brown to bluish crystalline materials with characteristic melting points and absorption spectra which can be purified by leaching with lower alkanols, since the free bases are mostly insoluble in water and some of them are insoluble in most organic solvents. The organic bases of the invention (I, II and III) form non-toxic addition salts with a variety of pharmacologically acceptable organic and inorganic salt-forming reagents. Thus, acid addition salts, formed by mixing the organic free base with 1, 2 or up to 8 equivalents of an acid, conveniently in a neutral solvent, are formed with such acids as sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, lactic acid, malic acid, succinic acid, tartaric acid, ferric acid, benzoic acid, gluconic acid, ascorbic acid, and the like. Preferred acids are hydrochloric acid and acetic acid. For the purposes of the invention, the free bases are equivalent to their non-toxic acid addition salts. The acid addition salts of the organic bases of the invention are generally crystalline solids which are relatively soluble in water, methanol and ethanol but relatively insoluble in non-polar organic solvents such as diethyl ether, beryllium, toluene and the like.

It will be appreciated by those skilled in the art that all such salts can be converted to their respective free forms, represented by Formulae I, II and III, by methods known to those skilled in the art, and all such salts are therefore equivalent for the purposes of the present invention. The novel compounds of the present invention, represented by Formulae I, II and III, can be readily prepared by the following general procedure. A compound of the formula: is reacted with a compound of the formula wherein one of X and Y is NRIRZ or NHCOCFB and the other is ORm, Cl, Br, I, N(R10)2, NO2. SO3R10, 5021110, SORIO, SRw, NB, ONO or tetrazolyl, wherein R w is hydrogen, alkyl of from 1 to 6 carbon atoms, phenyl, para-tolyl or benzyl; S and T are different and are 0 or 1; Z is hydrogen, alkyl of from 1 to 1 carbon atoms or NR transferable group; provided that: a) only X can be NHCOCFB and only when S is 0 and Z is not IRZ or one of them is hydrogen or alkyl; b) except as in a), when S is 0, then Rl/Rz is 1-1/1-1 and Z is not hydrogen or alkyl of from 1 to 4 carbon atoms; c) when T is 0 and Y is NRIRZ, then Z is hydrogen; d) when T is 0 and X is NRIRZ, then at least one of R l/Rz is hydrogen and Z is alkyl of from 1 to 4 carbon atoms; É. 807987-8 el RÖ is hydrogen and both R5 and R7 are chlorine or alkanoyloxy, which is converted to hydroxy; and f) only one of R1 and R2 can be alkanoyl; and when X is NHCOCF3, removing the COCF3 group, and when Z is a group convertible to NRIR2, carrying out its conversion to this; and, if desired, converting A-B, when CH2-CH2, to CH=CH; and contacting the product with a pharmacologically acceptable salt-forming reagent under salt-forming conditions.

The reaction is preferably carried out by heating the reactants at a temperature of from about 400 to 110°C for about 2 to about 10 hours in a reaction-inert solvent such as water, a lower alkanol, e.g. methanol, ethanol, propanol, n-propane, any of the lower butanols and the like, or in an amide solvent such as formamide, dimethylformamide and the like, or in a solvent such as N,N,N',N'-tetramethylethylenediamine or mixtures thereof. The above temperatures, times and solvents and combinations thereof are generally sufficient to carry out the present process. Other solvents and reaction parameters may sometimes be desirable or necessary, and the selection of such additional solvents and reaction parameters is within the skill of the art and is all considered essential to the present invention. In most cases the product is a solid which crystallizes spontaneously or upon seeding or tearing from the reaction solvent on cooling and can be collected by filtration or decantation. In other cases the reaction mixture can be concentrated, e.g. at elevated temperature under vacuum, and the product crystallizes out on cooling and can be collected by filtration or decantation as above. In some other cases it may be necessary to evaporate the solvent to dryness to collect the product or alternatively to mix or dilute the reaction mixture with another miscible solvent, such as water, and then collect the product by, e.g. filtration or extraction. The skilled artisan can choose which procedure to follow, and all such procedures are considered equivalent for the purposes of the present invention. Once collected the product can be purified by, e.g. crystallization, chromatography (thin layer or column) or preferably by lamination with a lower alkanol. Other methods such as maceration or crushing in a solvent, e.g. an organic solvent such as ethanol, may be used and all purification methods are to be considered equivalent for the purposes of the invention. -7807987-8.

Those skilled in the art will appreciate that when a product is desired in the leuco form, the tricyclic starting material should be in the leuco form and precautions should be taken to protect such materials, particularly at elevated temperatures (i.e. above room temperature), from oxidizing agents such as oxygen. Thus, when a leuco product is desired, the reaction is normally and effectively carried out in an atmosphere to exclude air. Thus, the reaction may be carried out in an atmosphere of nitrogen or argon, and this precaution should also be taken in purification procedures, particularly those requiring elevated temperatures. When an aromatic product is desired and an aromatic starting material is used, no such precautions are normally required.

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

, Those skilled in the art will also recognize that, when the substituent Z is a group transferable to R r -N< I , this transfer can be readily accomplished by R z obvious procedures, which are well known to those skilled in the art and are within the skill of the art. Conversion of the group Z to R -N< 1 by all of these procedures is therefore contemplated by the present invention, and all such procedures are to be considered equivalent for the purposes of the present invention. The preferred procedures contemplated by the present invention for the transfer of the group Z to _N< 1 are exemplified below. Of course, these are only examples of this R transfer and are not intended to limit the scope of the invention.

Other conversion methods are known to those skilled in the art and are to be considered complete equivalents for the purposes of the present invention. Thus, when Z is an aldehyde or ketone group, i.e., -C - R, where R is hydrogen or alkyl, the desired conversion can be accomplished by treatment with an amine of the formula R 1 , wherein R 1 and R 2 are as defined above, under reducing conditions, such as hydrogen with Raney nickel catalyst or sodium borohydride.

"For Z, groups of the formula . /_\ -N O J. <(CH wherein m is 2 or 3, are also contemplated. Treatment of this group with acid, Lex. 2 aqueous-ethanolic hydrogen chloride at 11-O-SOOC for from 1 to 6 hours converts Ri .it to -NH-(CH2)rn-OH, which is a group intended by the group -N \\ R . 2 For Z, effective leaving groups are also contemplated, such as Cl, Br, I, para- tosyl, OSOZCH and the like. When Z is a leaving group as defined above or R / l an equivalent, treatment with an acid of the formula HN\ in R 2 3 Lex. a lower alkanol solvent will effect the desired conversion.

When Z is a primary or secondary amine, i.e. -NHZ or -NHRI So / RI , further alkylation converts it to the desired group -N \ R 2 . Well-known alkylating agents are known which readily effect this conversion.

Such agents as alkyl halides, alkyl sulfates, substituted and unsubstituted acrylonitriles, and the like are contemplated. Aldehydes and ketones condensed under reducing conditions may also be used.

All such transformations and other transformation methods are considered equivalent for the purposes of the invention.

A preferred embodiment of the first process aspect of the present invention can be represented by the following reaction scheme: 7807987-8 /. 1 Nn-Q-N \R2 (I) where R 1, R2, Rj, R7 and Q have the above-given meaning, [according to this reaction scheme, leuco-1Jf-dihydroxyanthraquinone (IV) is condensed with a suitable alkylenediamine (V) in a solvent such as N,N,N',N'-tetramethylethylenediamine, ethanol, water, dimethylformamide, or mixtures thereof at from about 10°C to about 50°C under a nitrogen atmosphere in several stages to produce the corresponding leucobases (II). The leucobases (II) can 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 can then be contacted with a pharmacologically acceptable quaternizing or salt-forming reagent under quaternizing or salt-forming conditions.

A preferred subgeneric embodiment of the first process aspect of the invention can be represented by the following reaction scheme A: Reaction Scheme A where R Rz A more preferred subgeneric embodiment of the first process aspect of the invention is represented by reaction scheme A above wherein Q has the above definition; R1 is hydrogen or alkyl having from 1 to 2 carbon atoms; R2 is monohydroxyalkyl having from 2 to 3 carbon atoms, wherein the carbon atom in the alpha position to the nitrogen atom cannot bear any hydroxy group, dihydroxyalkyl having 3 carbon atoms, wherein the carbon atom in the alpha position to the nitrogen atom cannot bear any hydroxy group, or a group of the formula: / Ra .,(cH2>2 _ N \ Rq where E23 and RLF have the above-given meaning; 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 in the l-position and the L1-position cannot exceed four, and that the product is contacted with a pharmacologically acceptable acid, preferably acetic acid or hydrochloric acid, to produce pharmacologically acceptable acid addition salts thereof.

A second more preferred subgeneric embodiment of the first process aspect of the invention is represented by Reaction Scheme A above, wherein R 1 is hydrogen or alkyl of from 1 to 2 carbon atoms and R 2 is -(CH 2 ) 2 OH and Q has the above definition, 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 in the 1-position and the 1β-position cannot exceed four, and that the product is contacted with a pharmacologically acceptable salt, preferably acetic acid or hydrochloric acid, to produce pharmacologically acceptable acid addition salts thereof. The most preferred subgeneric embodiment of the first process aspect of the invention is represented by Reaction Scheme A above, where Q is -(CH2)n-, wherein n is an integer from Z to 4, preferably 2, and R1 is hydrogen or -CH2CH2OH and R2 is -CH2CH2O1-1, and contacting the product with a pharmacologically acceptable acid, preferably acetic acid or hydrochloric acid to produce pharmacologically acceptable acid addition salts thereof.

The novel compounds of the invention, wherein A-B is CH=CH, R 5 and R 7 are both either hydrogen or hydroxy, and R 6 is hydrogen, can also be prepared by reacting a compound of the formula: G / \ ..-___ _._,______ __.. __... ...v- wf-._......_.._... -_ .. . . ._ _ _.. u.. ._ - V. -_....., .vrf -wv- .\..,. 7807987-8 ll with a compound of the formula L J . \_ f i % a _ J _ L where G is alkanoyloxy having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 l /,/RL carbon atoms, or -N-Q-N \ where K is alkyl having from 1 to 6 carbon atoms; L Cook R2 is hydrogen, hydroxy or _ ten. Wherein -lïx-Q-N/ R / l É NH-Q-N ; and J is hydrogen, chlorine or bromine; R2 provided that: RI a) when G is -N-Q-N \ , then L is hydrogen or hydroxy and J is R Cook 2 chlorine and the substituent K is removed from the tricyclic product; R R l ' 1 b) when G is other than -N-Q-N Z , then L is -NH-Q-N / l \*\R \\R2 Cook 2 and the cyclized product is aromatized; and if desired, reacting the product 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 100°C, preferably in an inert atmosphere such as nitrogen. If necessary, R 1 Lex. when G is other than -N-Q-N \ , the tricyclic product is aromatized and the substituent K is removed from the \ R cook 2 tricyclic product by, for example, treatment with aqueous methanolic acid. Those skilled in the art will recognize that the product obtained after elimination of the K substituent is a free carbamic acid which spontaneously decarboxylates.

A further method by which the novel compounds of the invention can be prepared, wherein A-B is CH=CH, and R? both are either hydrogen or hydroxy, and Rs is hydrogen, are as follows: A compound of the formula Û'_" yzø . O: -is reacted with a compound of the formula where R is alkyl of from 1 to 6 carbon atoms or CF 3 ; E and F are both hydrogen or taken together form - 0R3 \ n . / where RB is hydrogen or alkyl of from 1 to 6 carbon atoms; C-D is CH=CH on Y a. / ~ ' or \ where Y is H or OCHB; 7807987-8 l 3 \ provided that when E and F are hydrogen, then C-D I , and when C-D - / Rs ¶ Y is CH=CH, then E and F form /_ and Rj = R7 = hydroxy; and O RB the groups RCO and Y, when this is OCHB, are hydrolyzed to convert them to hydrogen and hydroxy, respectively; and " if desired, the product is contacted with a pharmacologically acceptable salt-forming reagent.

This reaction is preferably carried out by mixing the reactants in a NaAlCl2 (NaCl/AlCl3) melt at a temperature of from 130 to 200°C for from 1 to 6 hours. The tricyclic products are subjected to hydrolysis, e.g. aqueous acid hydrolysis, to remove all protecting groups, and if desired, a pharmacologically acceptable salt is prepared.

When the reactants used in the processes of the present invention contain certain particular substituents, it has been observed that the process can be made to proceed in a particularly efficient and effective manner by specific selection of reaction variables such as time, temperature and solvent. These preferred combinations of reactants and reaction variables are exemplified by the reaction schemes numbered 1-12 below.

It will be appreciated by those skilled in the art that the combinations exemplified by the listed reaction schemes are only preferred combinations and permutations of the processes of the present invention and are not intended to limit the scope of the invention or the scope of the processes set forth in the claims.

The procedures and preferred combinations taught by Reaction Schemes 1-12 are provided solely for the convenience of those wishing to practice the invention and are not intended to be used to limit the scope of the invention in any way.

Unless otherwise indicated, the symbols and definitions used in each of the reaction schemes 1-12 refer only to the individual reaction scheme in which it is used. » (or leuco form) 7807987-s 14 (or aromatic form) f/ is as previously described, X is any good leaving group O 2 where Q, R 1 and R 11 . such as oH, c1, ar, I, NHZ, Noz, so3a, s-Rwfi-Rlmsiis-RIWORUYNB, o o tetrazolyl, ONO, and Z is H or OH.

According to the above reaction scheme, an appropriately substituted 9,10-anthracenedione in either the leuco or aromatic form is reacted with an amine of the structure shown to give the desired 1,4-diamino-9,10- anthracenedione in either the leuco or aromatic form. The reaction is carried out in ethanol, propanol, isopropanol or N,N,N',N"-tetramethylethylenediamine under a nitrogen atmosphere at a temperature of 40 to 100°C for 2 to 10 hours. When the product is a leuco compound, it is converted to the aromatic form by methods previously described. 7807987-8 15 HO o / H R1, R2 and Q are as defined above and Z is chloro or alkanoyloxy having from 1 to 6 carbon atoms.

The reaction between the leuco-1,4,5,8-tetra-substituted-9,10-anthracenedione and the amine is carried out in a lower alkanol at a temperature of 40 to 100°C under a nitrogen atmosphere for 2 to 10 hours. The disubstituted derivative 1 is converted to the dihydroxy derivative g by either alkaline or acidic hydrolysis using an ethanol/water solution of either sodium hydroxide or hydrochloric acid. Thin layer chromatography is used to follow the reaction, so that the reaction can be controlled and hydrolysis of the amino substituents avoided. Again, the leuco products are converted to the aromatic forms by previously described methods. _* "where Z is H, or OH, Q, R 1 and R z have the above-described meaning, X is Cl, Br, I, O 5 O 2 C 6 H 4 p -Cl-1 3 , OSOBCH B and RB are H or lClCF 3 .

The two reactants are mixed in a lower alkanol and heated to 40- ' 90°C for 1 to 8 hours, which gives the desired product. When R3 is CF3CO, the latter is removed with aqueous-methanolic potassium carbonate. 7807987-8 17 NllQNllRz .l *il \T/ o=cR z o NnQNimZ n T i: NHQNHÉHR [H] R I z 0 NHQNHCHR å.

Q is as previously described, Z is hydrogen or hydroxy, R can be lower alkyl, *hydroxylower alkyl or dialkylaminolower alkyl, R1 can be H or lower alkyl, Rz can be H, lower alkyl or hydroxylower alkyl.

A mixture of the 9,10-anthracenedione and 2 to 3 molar equivalents of the aldehyde or ketone in a lower alkanol is heated to 40 to 1000°C for 2 to 8 hours under reducing conditions such as hydrogen with Raney nickel or platinum catalysts or sodium borohydride to give the desired product (β-bis-substituted-amino)-9,10-anthracenedione. 7807987-8 18 + CH2=C~CN Hgucxxzïacu _ R Z 0 NllQlslCllzCllllCN "2 where Z is hydrogen or hydroxy, Q is as previously described and R is H, lower alkyl ' or hydroxylower alkyl. Rz is H or lower alkyl. A mixture of the 9,10-anthracenedione and acrylonitrile in a lower alkanol is heated to 60 to 1000°C for 2 to 10 hours to give the desired product. 6.

Rl.

NH(cra2)ncH2w< Rz 7aø79s7-s 19 Z is H or OH, n is 1 to 3 and R1 and R2 are as described above.

The bis-acetal _1_ in aqueous methanolic acetic acid is heated to 25°C for 0.5 to 3 hours to produce the dialdehyde. The latter compound in R ~ l a lower alkanol is treated with 2 to 4 molar equivalents of the amine NH R2/"/ at 40 to 1000°C for 2 to 10 hours under reducing conditions such as hydrogen with Raney nickel or platinum catalysts or sodium borohydride to give the desired product 1,4-diammino-9,10-anthracenedione. ,/">~ -N O + n2ncH2(cu2)n"( (Cllzfln A 2 (or aromatic form) Hclizlcflzln N 0 (cazlm _ /\\0 NHcu2(cn2)n Q I lCfizlm' (or aromatic form) _6_ _ HCHZ (CHZ) "NH _(CH2) mOI-l o Nncn2(eá2)nNu(cH2)moH 78Û7987-8 20 Z is H or OH, n=1 to 3, m=2 or 3.

Leuco-1,1s-dihydroxy-9,10-anthracenedione _1_1-_ or its aromatic form and amine 2 in a lower alkanol or N,N,N',N'-tetramethylethylenediamine are heated at 50 to 90°C for 2 to 10 hours to produce leuco-1,4-diamino-9,10-anthracenedione å or its aromatic form. Compound § is then heated in aqueous-ethanolic HCl at #0 to SOOC for 1 to 6 hours to produce the desired product 1,4-diamino-9,10-anthracenedione Z. 8. where Z is H or OH and X is Cl, Br, I, 0SO2C6Hq-p-CH3, OSO2CH3. 1,4-diamino-9,10-anthracenedione i, thionyl chloride and pyridine are mixed in the cold and then heated to 60-110°C for 2 to 10 hours to prepare 7807987-8' 21 R1 compound 2, where X is Cl. Compound 2, the amine HN Z OCh solvent ~ - n R _ _ 2 (a lower alkanol) are mixed and heated to 70-100°C for 2 to 14 hours, giving the final product _3_ , a 1,4-diamino-9,10-anthracenedione. "\\ (n3co)2o 'cH3co2Na 7807987-8 22 where Q and R 1 and R Z are as previously described and RB and R 4 are lower alkyl.

The dihydroaminonaphthoquinones 1 are prepared according to published procedures (1.S.1Vl. Bloom and G.O. Dudek, Tetrahedron, 26, 1267 (1970)). The reaction of the compounds 1 and anhydrides 1 in an aprotic solvent in the presence of sodium acetate gives the amide esters g, which are then hydrolyzed with aqueous base to the corresponding amide-phenols ä. These amide-phenols are alkylated with alkyl halides or sulfonates in the presence of base to the corresponding amide-ethers _41. Either the amide-phenols ä or the amide-ethers 11 are mixed with maleic anhydride in a NaAlClq melt and heated to 130-180°C for 1-5 hours, which after hydrolysis with aqueous acid gives the desired 1,4-diamino-9,10- anthracenediones _5_. 10. u-w-g-š .-š~E-w fflfff"r'- .¥T""_'1_ïr'fIIfI*P'f!" 'Ywäj I' ~1*-"_*^~r .. aat,.>.,....... __ g ___, _ V_(J_ V! _ u _' , , J' 7807987-8 23 where R1 and Rz are as described previously, R is lower alkyl or CF3, n=2 to ll, X is Cl,Br, OSO2C6H4-p-CH3 or OSOZCHB, Y is H or OCHB and Z = H or OH.

The diamide 1 in toluene is treated with NaH and then with the amine 1 for 1 to 5 hours at 60 to 100°C to give the diamide diamine 2. The latter compound 2 is mixed with the phthalic acid anhydride 1, AlCl3 and NaCl and melted at 130-200°C for 1 to 6 hours to give the anthracenedione 2. Aqueous acidic hydrolysis of 5 then gives the desired 1,4-diamino-9,10-anthracenedione 2. 11. on Roocrm I "nl z f 3 í i _ I RoocrfQN\ IICWII! nc=cn Hg-.CHRZ ÜE=CU ï-V _ lïC=lifll ä* HC-aå" | . on Roocrm Rgocl-Qwílïl z R 2 1 _ 2 i i Q, Z, R l and Rz are as previously described, R is lower alkyl.

The diazide _l_ is prepared from transfer-muconic acid by conventional methods. The diazide i and a lower alkanol in toluene are heated to 70-1000C for 2-8 hours to give the bisuretane 2. The bisuretane 2._ is then reacted with an aminoalkyl halide in ether or tetrahydrofuran at 40 to 00C for 2-10 hours in the presence of sodium hydride or other base to give the compound å. The latter compound is then treated with dichloronaphthaquinone g in toluene at 60-1100C for 1 to 5 hours to give the anthracenedione 2, which on hydrolysis with aqueous methanolic acid gives the desired 1,4-diarnino-9,10-anthracenedione Q. ii. _ .R - z Nuqní 1 ne=cu , _ X R2 nc=cn |{ii | R I is 1 and 2 (0) Q, R I and R Z are as previously described, X=H, Cl or Br, Z=Oacyl or OCHB. 7807987-48 25 The butadiene _1_ and the diamine _; (prepared as described in Tetrahedron, ed. (1970)) in ethanol or toluene at 60 to 150°C under nitrogen gives the diamine ed.

When X is H, the conversion of å to 2 is accomplished in the same solvent by treatment with a dehydrogenating agent such as chloranil. When X is halogen, :i is converted to li by gentle heating in an aqueous-methanolic sodium bicarbonate solution. Mild acid hydrolysis then converts the Z=Oacyl in Q to Z=OH.

The invention also relates to the conversion of the products into acid addition salts. Many methods of salt formation are known to those skilled in the art and are to be considered equivalent for the 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, which is itself present in solution in the same or in another solvent. Thus, a suspension or solution of the product in ethanol may, for example, be treated with dilute or concentrated acetic acid, hydrochloric acid or the like, or ethanolic HCl, and the corresponding salt may be collected by Lex. filtration.

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

The present invention also relates to the use of the compounds of formulae I, II and III and the pharmacologically acceptable acid addition salts thereof, as well as mixtures thereof, as the active ingredients in pharmaceutical therapeutic preparations and compositions.

The therapeutic compositions of the invention inhibit the growth of transplanted mouse tumors and cause regression and/or palliation of leukaemia and related cancers in mammals when administered in amounts of from about 5 mg to about 200 mg per kilogram of body weight per day. A preferred dosage regimen for optimum results is likely to be from about 5 mg to about 50 mg per kilogram of body weight per day, using dosage units such that a total of from about 350 mg to about 3.5 g of the active compound is administered to a patient of about 70 kg of body weight during a 24-hour period. This dosage regimen can be adapted to provide the optimum therapeutic response. For example, several divided doses can be administered or the dose can be reduced proportionally as indicated by the needs of the therapeutic situation. A definite practical advantage is that the active compound can be administered by any convenient route, such as, for example, by the oral, intravenous, intramuscular or subcutaneous routes.

The active ingredients may be administered orally, e.g. with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft shelled gelatin capsules, or they may be compressed into tablets, or they may be mixed directly with the dietetic food. For oral therapeutic administration, the active compounds may be mixed with excipients and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% active compound. The percentage in the compositions and preparations may of course be varied and may conveniently be between about 2 to about 60% by weight of the unit. The amount of active ingredient in such therapeutically useful compositions is such that a suitable dosage is obtained. Preferred compositions or formulations of the present invention are formulated so that an oral dosage unit form contains between about 5 and 200 mg of active compound.

The tablets, lozenges, pills, capsules and the like may also contain the following: A binder such 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 flavor. When the dosage unit form is a capsule, it may contain, in addition to substances of the type indicated above, a liquid carrier. Various other substances may be present as coatings or to otherwise modify the physical form of the dosage unit. For example, 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 propyl parabens as preservatives, a coloring agent, and flavoring agents such as cherry or orange flavoring. Of course, any material used in the preparation of a dosage unit form should be pharmaceutically pure and substantially nontoxic 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 in the form of the free base or pharmacologically acceptable salt may be prepared in water, which is suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions may 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.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and fluid to the extent that ready injectability is ensured. It must be stable under the conditions of manufacture and storage and must be protected against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Suitable fluidity may be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size during dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be accomplished by various antibacterial and anti-allergic agents, e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it may be preferable to include isotonic agents, e.g., sugars or sodium chloride. Prolonged absorption of the injectable compositions can be accomplished by the use of absorption-delaying agents in the compositions, e.g., 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 listed above, as required, followed by filtered sterilization. Dispersions are usually prepared by incorporating the various sterilized active ingredients into a sterile vehicle, including all solvents, dispersion media, coatings, containing the basic dispersion medium and the required other ingredients listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile filtered solution thereof.

As used herein, "pharmaceutically acceptable carriers" include 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 where any conventional media or agent is completely incompatible with the active ingredient, its use in the therapeutic grain positions is intended. Grain-coating active ingredients may also be incorporated into the compositions.

It is particularly advantageous to formulate parenteral compositions in -....._-.-_-.-._........ ...V-W 7807987-8 28 dosage unit form for ease of administration and uniform dosage. As used herein, dosage unit form refers to physically discrete units suitable as unitary doses for the mammalian subjects to be treated, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

The specification of the novel dosage unit forms of the invention is dictated by and directly dependent on (a) the unique characteristics of the active ingredient and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the manner of formulating such an active ingredient for the treatment of disease in living subjects with a disease state in which bodily health is impaired as set forth in detail herein.

The active ingredients in the therapeutic composition aspect of the present invention may be represented by a compound selected from the group consisting of those having the formula: tautomeric forms and pharmacologically acceptable acid addition salts thereof, wherein A-B is CH=CH or CH2-CH2; Q is a divalent group having the formula: - hydrogen, alkyl having 1 to 2 members, alkyl having 2 to 3 members, wherein the carbon in the alpha position to the nitrogen atom cannot bear any hydroxy group, dihydroxyalkyl free. 3 alkyl groups, wherein the carbon atom in the alpha position to the nitrogen atom cannot bear any hydroxy group, fornyl, alkanoyl with 2 carbon atoms, trifluoroacetyl or a group of the formula: i 5 z r I r 7807987-8 29 /Rß ~(c'r12)2-ocl1 or -(cH2)2-n 3 p "4 wherein 1:3 wrong; each is vara, mryfl or mmyaroxialiryl rea 2 alkyl groups, wherein the carbon atom in the alpha position to the nitrogen atom cannot bear any lyhydroxy group; and Rl and RZ taken together with their attached nitrogen atom and RB and R4 taken together with their attached nitrogen atom are morpholino; R hydrogen or hydroxy; R is hydrogen or hydroxy; and R7 is 5 6 hydrogen, hydroxy or a group of the formula: H -Nlaaxa a ~N/ 2 2 \ RQ where R9 is β ~hydroxyethyl; provided that when Q is -(CE-I2)n- a) Rl, Rz, RS, R6 and R? cannot simultaneously be hydrogen; b) when RS, RG and R27 are hydrogen, Rl/Rz cannot be H/mmhydroxyalkyl, and when n is 2, Rl/Rz cannot be -(CH2)2-CJ-(CI«I2).¿-, H/CH3, H/C2I-l5 or C2H5/C2H5, and when n is 3, Rl/Rz cannot be CH3/G-I3 or -(CH2) 55-; c) when R 5 and R 7 are hydroxy and n is 2, R 1/R 2 cannot be (CH 3 /CH 3 , CH 9 /CH 4 /CH 9 or -(CH 2 ) 5 -, when n is 3, cannot be H / H, CH 3 /CH 3 , CH 7 /CH 7 or -(CH 2 ) 5 -, not be C 2 H 5 /CH 5 , CH 9 /CH 9 or -(CH 2 ) 4 -; d) when R 6 is OH, the positions of R 6 and R 7 must be H, and when R 6 is fl, both R 6 and R 7 must be H; and e) only one of P 1 and R 2 can be alkylaroyl.

The preferred active ingredients in the therapeutic composition aspect of the present invention may be represented by a compound selected from the group consisting of those having the formula: 7807987-8 30 where A-B, Q, R1 and R2 and pharmacologically acceptable acid addition salts thereof. Preferred salts are as defined above, hydrochloride and acetate. The more preferred active ingredients in the therapeutic composition aspect of the present invention may be represented by a compound selected from the group consisting of those having the formula: NH-Q-N-(CH2)n-OH R NH-Q-¿-(cH2)n-OH where A-B, Q and n are as defined above, and R is hydrogen or alkyl having from 1 to 2 carbon atoms, and pharmacologically acceptable acid addition salts thereof. Preferred salts are hydrochloride and acetate.

A second more preferred aspect of the therapeutic composition aspect of the present invention may be represented by a compound selected from the group consisting of those having the formula: H0 _ NH-(CH )-N/Rl (í 2 n \ Rz 78017987-8 31 where n, R I, R Z and A-B are as defined above, and acid addition salts thereof. Preferred salts are hydrol The most preferred aspect of the therapeutic composition aspect of the present invention may be represented by a compound selected from the group consisting of those having the formula: oii Q lgilcnzciizwl / n "2 \ H 0 Niiciizciizw-Ål Rz where R I and Rz are each hydrogen or -Cl-izCHzOH, and hydrochloride and acetate salts thereof.

The present invention also relates to a method of using the pharmaceutical therapeutic preparations and compositions described above.

Regression and alleviation of cancers is achieved, for example, by the use of oral or injectable routes of administration. For example, a single oral or intravenous dose or repeated daily doses may be administered. Daily doses for up to about 5 or 10 days are often sufficient. It is also possible to administer a daily dose or a dose on alternate or less frequent days. As will be apparent from the dosage regimens, the amount of principal active ingredient administered is a sufficient amount to promote regression and alleviation of leukemia or the like in the absence of excessive deleterious side effects of a cytotoxic nature in the hosts harboring the cancer. This amount is also referred to herein as an effective amount. As used herein, cancer refers to malignant blood diseases such as leukemia, as well as other solid and non-solid malignant tumors such as melanoma, lung carcinoma, and breast tumors. Regression and palliation are intended to arrest or delay the growth of the tumor or other manifestation of the disease compared to the course of the disease in the absence of treatment. 7807987-8 32 The novel compounds described herein are useful as chelating, complexing or sequestering agents. The complexes formed with polyvalent metal ions are particularly stable and usually soluble in various organic solvents. These properties naturally make them useful for a variety of purposes where metal ion contamination is a problem, e.g. as stabilizers in various organic systems such as saturated and unsaturated lubricating oils and hydrocarbons, fatty acids and waxes, where transition metal ion contamination accelerates oxidative degradation and color formation. They are further useful in the analysis of polyvalent metal ions which can be complexed or extracted by these materials and as metal carriers. Other uses common to sequestering agents are also apparent for these compounds. In addition, the leucobases (II) are useful as intermediates in the preparation of the wholly aromatic derivatives (i, where A-B is CH=CH). The novel compounds of the present invention also have the property of inhibiting the growth of transplanted mouse tumors, as determined by the following standard test procedures.

Lymphocytic leukemia P388 test The animals used are DBA/2 mice, all of one sex and weighing at least 17 g, all within a weight range of 3 g. There are 5 or 6 animals per test group. Tumor transplantation is carried out by intraperitoneal injection of 0.1 ml of diluted ascites fluid containing lymphocytic leukemia P388 cells. The test compounds are administered intraperitoneally on days 1, 5 and 9 (relative to tumor inoculation) in various doses. The animals are weighed and surviving animals are recorded on a regular basis for 30 days. The median survival time and survival time ratio of treated (T)/control (CU) animals are calculated. The positive control compound is S-fluorouracil, given as a 60 mg/kg injection. The results of this test with representative compounds of the present invention are given in Table I. The criterion for efficacy is T/C x _l 00 Z 125 96. 7807987-8 mom m.mH om zumhäšosfinm ... m _. m o :oäcox wmfl o.ma mw wfifl oaflfl om w N a o . N H o o .n . cocímopcmnoxoovšàv.. ß m a o .. m .n o o N um nAoEEmïobocnofioëlmvmmnno. Toxauq ß .m N m 0 ma o m :umosooosünn | o 0 m o :obcox »HN m.mfi m mmm o.«N w mmm o.mN NH . _ w m N m . o N mm cocoxmoocm|oxoov>nww| o ß N o . m N o m -w.fiwooosmšoøoooe2à2=oo-~.%moo-o__ o m H o u m .H o m mumozooosfifi I 0 . O H O :Obbüx omfl o.nH maa m v a m . w .P m if fl o _, m H w o mßfl mußfl. Na omfi oomfl mw m w N m .. w N o m :ocEøopcmafixoouæzowàfi.. m o N m _. o N o o -woš:æoàwoooEmofiwëooàmmoñfü 79.35 ficwuoomo . Cmwmvo. .mx\ . .OE wcocoomm oofl N U\B ofzomc>ïow>mnmonwoou moQ Éwfwwmm :coxawg xwïzuowëäq o Aqmmøü. 7807987-3 34 m O N m . mH O w fiumozouozüïw | m ._ m c :oëax w N H o . N H N H m w H o 0 wH m N m m H o 0 mH O m m m H _ o @ w H o o H cocïmhwcmufixoäšnwvl o H m o o N o o N |w.n|NoEEmcawmocwEmšwufifiïwfimmfifia.H m o N m _. m H o w :umhaohozoïn | m _. m o :obcox w N H Q u NH 3 o ß m, H .o ._ m H m N æ m H O _. m H o m , , m ß H o . ßH o o H cocšmhflcmàxoäšzouawfi.. m ß H o _. ß H o o N |NoEERïwuocwëmšwwofiïwwwflnio. ._ åxsmq m o N m ._ m H o m Zumhnoposfinn l m _. m Q Zouwcox m w H o ._ NH o oH cocïmhfcmwflxohux; ß wH o 0 vH Q ON 1:Ywfl|^oEfimHzpwocfiowpoÉxNvflnio.H ._ Écmßcgmo Tmmmš -.mv¥\ - .GE mcficwhom o o H x U\,H_ vchwmcšwtmåwcmouwë won . .. o qfläo H ...Em/ä 7807987-8 N mH m ° m H o m zumosooosflnn I o _» N H o :óäcox o o H . o . 2 .S o _ m N H m . m H m N :ošxmopcmnoxoooænowïw.mv m N H m ._ m H o m .NwcficflïaoomocqcomvfioEoolfiwmñuo.o.

N w H o ._ o N o m numosooosüdå I O . HH O SOHPGOx o. o H o . 3 2 .

H m H o . H N mN m o N o _, m N o m cocšmopcoToxoovxzoïww? m H m o v m o o H |NQEEmhofiufišzvfioooamnflYNNWBÅ,H N w H o . o m, o m :umosooošfin n. O o HH O 295503 m m H o . m H m N m v H o _. m H o m m ß H o . m H o oH :omEnopcm|oxoooš=v..w.n|\wc~com oo ~ o . m N o o N -oàoooooooo.šo-oo-fi moi. 7953 Ccmooono »Lmmmto . mx\ . .mE w o o H x O\B wfimomc>u_..w>ocmwowo.o mOD :Éwomm ñmfioä ~ Aqmmšw 7807987-8 36 o H. H o . H. H o w , HHumhsoho-:Hlw _ .. o . HH o HHohÉox ond o.mH ~.o M o.m«H o.wH m.~H _ o . H o H o . HN m N _ o . m m N o . w N o m n :ocšmopcm o . if N o . if SH -oäzfišåfifw.Woåsfläfiocoëm o . m H o . N _ o oN àåmocflEmoÛmcTNYQwHfiTo.Hloxzoq N w H m . m H o w nomosohosuïw I o . NH o ._ :ohfcox m m H o . o H NH o m H o . m H m N _ m m H o . w H o m o m H o . w H o oH o cccväbcm|oxohu>zool o m H o . w H o o N ..w.n|^oEEmšmohmocHëmlmomwnlo. Toxswq N w H m . m H o o. :oflzohosflå | o ._ N H o HHPScox omfi o.oH NH . m m H o . m .H m N .

N m H o . m N o m _ f cocšmmwcmaflxohvacfiunw. m1 m m H o . m H o o H lNošEm2~$uocHEm|N%fin|o. H -QVEQH _ Gcmuokc Hung- .mx\. mo.. w .. . o o H x U \H vfiwomšwooßšmcmzuwâ m oo :Eoowm 69205 H AHmm/w 730798-7-8 37 m o N. m . m H o m :omhnmhoaflfm a o . m o :obcox m m H o . w H m . NH ß m H o . m H m N w ß H o . m H o m . m m N o . H N o oH cocïmhficmàæokvßzavfw.m1 æ ß o . ß o oN fNocmëmHßmvfißcmnmhwmfianHvawmwmHnuainoxsvH o o N o . o N o m :ummsohosfi-m a o . oH o :oficox oo N o . o N w O . o oH N o . H N m o . o if N o . m N mH . o . o ß N o . ß N m m .o o m N A o . m N A w ß . o o m N A o . m N A m . H o _ o N N o . N N H . m. _ oo N o . o N N . m wÉo3oLv>c=v|coExmhpcmrmxohvßnmv-w m- o m H o . m H. m . N H nflocHEmHÜÅOErcmwfiomxohwßcuNvrNwmmfiïa.H m o N m . m H o m flumåohosfim | o . m o :oäcox N N H o . H H m . N H w H. H o . m H m N m m H o . w H o m ß m H o . m H o o H . . cocmxmäcmffixofiumHswwfmßm| o Q N 0 . m H 0 o N -BEEflärzaococaffius=ïfimzå ä .dšfi .ïcaíckmo . Tmmmvw .Uvç . m5 , w o oH v. U\.H. ufimvmc>øHLu>mcwmcø2 w If :Hcøäm Håïoë m Hama/Ü. 7807987-8 38 HßH o . w H o o w Hwumäzosüm f m . oH o :ohcox wß H . m. w H . wow about m oN m . H N mo . about m oN m . H N mH . o . m o N o . N N etc. o ß m N o . w N mß . o m o N A o . o mA m . H m w N o . m N H . etc. HN o . m N N . w _ v N N m . m N m . N H cocïmäcmàxoovßcww|wâ| _ w HH o . NH m N .N05ëmvßofiocHëmHßpoHxohÉHLINYQmHATo.HnoxsuH H ß H o . m H .o m Hïmäüoaflnm l m . oH o HHobcox N m H o . ß H v o . .o H ßH o . m H m o . o m ß H m . o H mH . o m m H m . m H mm . o oß H m . mH mß . o w H N m . N N m .H .o o H N o . N N H . m omH o . oN N . o N m H o . m H m . N H vïšxohußcwwwcocmxwhpcmåßbšcou» . etc. m m: o -o.màdcwEmHšwHocHëmšpwEvrfifinè._ Ccwuoäc fšmmtv . .mvï . mE wcëmhom ooH x o\.w uflwvmšutwšwcmwuuâ won . . .. oÉå o fimmí. 7807987-8 39 m.om m mH o m :umhshošwïn I o . H H o HHobcox m m H w H w % m . N H m m H _ m ß H o . m H cocmxmhcmuHxQLPHLHHVMMÛNOCHENHÛH» m ß o . m o oH AocHEmïmohmowH|No|w\wHn|a.HuoxsøH m wH m . m H. o w HHUMhDhO-.Hwufi | o . H H o HHobcox w H H o . m H m . H w m H o . m H H . m H m H o . Hmm N. w m ßH o . mH m. NH _ m ß H o . mH m N :ocïmbcmàxøhvæfiwuwfi|fiocHåm . etc. m. 0 m -wrwïcÉflàmëfiümofiïoä7833 m m H m . H. H o m . aumhñosHwÅ .. m . oH o :obcox m m H o . w H o oH w w H o . ß H o o N ß o . w H o o m _ :ocflxmopcmšfiohwëoflvuwfiw o m P o . o m o o w AøcoëwšwsnøcHëmiqommnJo. HpomzoH Qcvuohno _ tmuwvo . muï. UE _ o o H X U\_H_ uñmvmc>mHhw>mcmobw A-WQLOÖ H HHmm/Hh 7807987-8 40 owtob o .Smmmâ o o H o w H . o H. Hmuwhshošwm | o o H o :obcox m ßH m . N. H m m . o m H o . mH m H. . o o m H o q mH mm . H o N N o . NN H . m _. . . omN o.mN Nm . . . uCoHx. o v N o . wN m. NH |9oššn|cocfixmovcfiuïmxohoæsovßo. HNoEEm o N H o . N H m N lïpwHocHêmšaohmlH|Hxo._u.É..Nv|QmHn|o.H . o m H. o . mH o w zumemooaflrfi | o . oH o :oowcox o NH o . NH N . m m m H m . m H m . NH o m H o . m H m N . o m H o . m H o m . . o o _. . o » H o . ßH o oH cocmxmhocflïHxoovmcHunw måšëmšpw o m H o . m H . .o o N _ :ävšëmfišuoxoovboaQoowwxmwfo. H|oxzwH . _ Hmumåhoroïm m: if w šš v N. H o . m H m N m NH o . w H o m . , N mH o . m H o o H co:Emhcmafixoovëmoofwfi..

N m H o . ß H o o N šwoco..EmšfåocmEmr$worHEm|No|N.wEn|o.H ficwuooao Émwmvo , . _.mv_\ . m5, wcqcohom.

O O H N U\..H_ twwmbmc>üffiw>m CMHUQÉ .MOQ . .. 7807987-8 41 O ~ OW ÉUNLD-Ofiåwlfi | o . HH o :obcox v m H o . mH m ß . o ß ßH m . mH m m . H w m H m . mH H . m o m H m . mH m N . m ß ßH m . mH m. NH o o N o . N N m N _ m o m o . H. m about _ _ . . : m w m o . m m o o H :ocšfificmfixokuß.=v|w.mNoc~EmHš.ø ß N H o . w H o o N AošEmfñaPfiTfi |~xox_v>:|mo..Nw$n_|m. ToxnoH wm H o . m H o v HHumäñosflum I o . HH o HHohcox m m H m . H N w ß . o . o o N o . N N m m . H ßNN o . m N H . m mmN o.mN mN.m o . . . 3.33 m ß N A o . o m A m . N H -ohwßfšïcocEE..cmuHxohvßfäwmßwNocHëm ß ß m. . w m N -vsfioc.emqaoa¿åouvaïmwüwwfiï: o w H o ._ w H o v Summshosflnm | o . o H o :otbox if H _ o . m H H . m o w H . o . wH N . m o m H o . m H m . N H m m H m . m H m N o m w H m . m H o m .vïošohvßn o o N o . o N o o H _ :mtwnïcocwxm»PcwàxoovæcmmfmfiNocHëm m m m . m o o N lrâoNocmcäwfifixocfiommocïHonNw.NNwEÉJ ícmuqao »Lmwmto . w¥\ . man wcficwunm o oH x U\H Uïwvmcäwmšmcmwnmrz mOQ owfiomo m .Smmøê 42 7807987-8 mmfi m flw zumosoozflTn :obcox N w .H o . o N etc. w m m H m . flN m . NH m m H m . o N m N _ æfim o . if if , . .cocmxmowcm N o N m . o N o o N -oxooo>.=o-o. Twooofiošpkooosm N o o . o o o N åoâo-Toxo.oš_-No-Nïoo-o.79.33 m m .n , m . Én o v .ömosoosüá I. » Ö . o Én :ošcox w MH o . m .o wo.. . m w ma .o .mon mN . w 2A o . m." m . NH m f.. , m . m." mm o »NN ooN if o. . . »ofišx o mm m . ß N oo .n Lwncwïxoowäàwñflw måorooëmw. o.. :fwf m o o _.. . m N o o N -ošesàooxooo ..-Nwümowo Too ._ oN N m No N oo :ufioäšfio r o m _ o :oficox .nwfl m . what mn . o m wa o . wa if . H .Z m o . m fl . m . m o o N m . m o.. w . w o o N.. m . ma m ,. ma m m N m . H N m N m :ON wvwhOfixOhUäflfiul o. o N o . m m o o .n -cocïoopcmnoxoovšo:Ywfifioflwëmšwm mm m A o . o m A o o N -HošcomâšnfixooooåclüÉowxw floio o Gcwooonc. TmumB .OVQ . mš mcwcwoom o o .n X U\_H vfimtmcšnzow>mcmzflowå wOQ fiwoïooö ~ 44mm <._. 7807987-8 43 mow m.oN oo zumhäosfiln i o Soåcox o va o . wow wow o o na o . wa etc. a m ma m . m a Na . m m wa m . ma mN . o moN m . o N m . Na o oN o .o N mN . . | maN m. aN if | _ l ocäcm > n...officw_w_flwm_wp|zwfiwoh%~rlhww . may máw 23 who. .Ä .vi :übï mm.a m fiw äumhshosüä I Zobcox m ma o . ma mo . o m what o . wa if . a m ...have o . ma Na . m m wa o . m a mN . m moN m . NN m. Nah. a v N m . o N m N . Ehooxopvæåvfl a m N o . N m o m |cocšmhwcm|oxouvæz.UJWÅMNQCMEAW-»ßohaf w a a m . N a o o a åA05Emtfiwoxóovëïmvlmwmmnifl.ä Éøu B m . - . . .

Loa ,vvfl noo\.a. vïwvmfišwofowwfuofwmmwwï Uxßomš wcÉmomm owïoë o 44mm? 44 7807987-8 w m .m m . O N O w ÉUmäÉO-owwlm.

I.Q. O :O-ÖCOX m o N o . m N. m H . o N m N m . m N m m . o m N N m . w N m ß . o N m a o . o N m m . H _ _ www m . % . w wcsxokošfšèocvæhflcm m. ß o . w m . N H åEPAL:å_22osflàwocoem-smsïxo ofm-H ni .no fiomhsoozfiwnn :obcox o m a o . m .n m m . Hmmm Hm . m H N .n . .n o m .n o . m .n m N . m o NH o . wa m . Na o mmfi mf OH MN , Ufiäuflxnvufiuäßflmvüæl o N N o N N o m LSE;m..Ém|oxohušàvxwfi:Nocficmïfiu oNN o . NN ooH . AošëmšwwocoEmtfiwšzürfiflnå._ Ûcwuoäo Émmmvo . muï. .mE .wcflcuhmm v o o H X U\_H_ Ufiwvmšøfihflïmcmdwmwo w OD Aáïoä o »Ümm/É. 7807987-e .fiUfluäuOwåwlh 45 o o N o . o N o N 1 m . oH o :S23 o N H o . m H if m w H o . m H o o .H cøcfixmoflcm m o H o . m H o o N _ m.. .n www m .fi N o . NN o o v AocHEmÉpwocflowooåuwvmfinio H o o H m . o H .o o Houfiâooofin | o .HH o :Pšëo o fio m.ï m? o âšxmrsn.. . _ _ o. . H www o m H o . m H o o N -ÅoooëmïpwoomE2àwE=Yëmoo-o.H Ccwuoä: .öwmv _ ooïëooëofH ooH. what? Hwåïw Hšzmoooš wfiäoon.

, LP/wcmHfiwE _. mvq. mEV won ñwïøä H Hamn/E. 46 .ufo m fl ww Hñooo :unåoošfim HHooÉox H m H o . H.. N N .H .H a H o . H N m N . N w H o . o N o m m yet. o H N o . v N o o H o EEEEEN m _ H www m .w N o . if o o N AoEEmšpwocficmnäßnio.H-oxsuu m ß H o . o H _ o o šäoäšfio n o . HH o HHoLHcox o o H o . .H H o m m LUO m O .m O . N .m O O .n COCMXNuwCM m _ H www ß NH o . H. H o o m :HocHEmffiwocouñwoñnwvwonao.H m oH m . o H _ o o =UE=:.=:A . . 1 o . oH o HHobcox and others. H o . m H o m m :uo o m H o . N H o o H cocšmopcm m J.. .omv oï o¿H . ooN .AOCMfCflfläflmuOfiMEMTAHUMUINVmMDIün.H 7807987-s ïtå o oämšf vsuvesv-s 47 ß d N m . m. H Q m. :ugzošï | o . m o :ohcox m m .m o . ß .fi m m :uo . m m N o . .m m o . H www .u W. N o . N m m H cocïfipcmàocmEmšpøocwEmwfiwëlmvfinla.m m m N O . i, N c w :äääflïn l o . m o :obcox m ß .n m . m Jm ß . etc. 4. m . etc. .n w ß H o . w H m m m H m . m Jr. m m :wo . oo N o . w .m m .m m ~ H www w w o . Nm m N cocfixmhwcmAocmEmïßwocwëmàvflnè._ fiflhob H Émmäh 7807987-8 Compound 1 ,4,5~tris [(2-arn ino- ethylflaminoj-S-hydroxy _ -anthraquinone lßbisßz-dimefyi- aminoety1)amino]~ -Sß-dihydroxyanthra- quinone Control i-Fluoruracil [Jß-bisß-amino- propylamino)-5,8- -dihydroxyanthraquinone Con-mn S-Eluoruracil 48 TABLE 1 (continued) Dose Median- (mg/kg) survival _ (days) 12 15.0 6 15.0 3 15.0 1.5 15.0 50 n 18 25 16 12 . 16 0 11.5 60 19.0 25 22.0 12 19.0 0 12.0 T/C X 100 (percent) 130 130 130 130 157 139 139 16"; 183 158 152 7807987-8 49 Lymphocytic Leukemia P388 Test The procedure used is the same as for the previously described lymphocytic leukemia P388 test except that the test compounds are administered orally at various doses instead of intraperitoneally. The results of this test with typical compounds of the present invention are given in Table 11.

The criterion for the effect is T/C x 100 Z 125 96. 7807987~8 50 a: omfi m2 omfl mwfl m2 of m3 RJ mä mmflficwuoåv ä: u? UZMUCOHTHUQMLwCM flflhßuwwwCwEflfl ÉUNuJhOJTWIfi* odm if flï o QÉ m 0.2 w 92 Nä 0.2 if 0.9 o QÜ Ü QÛ nw. oá: if QÉ if Q: O ¶ 0:3 mm QÉ ow ä: 2: CmwwE må wmv *wmfšwïmšw wåmë -cmnöë w . mon :umhshošmä t. :OPHCOM cccïhmvcmvfixokv>nwulm.nINoEEm .åšboc~Emr3vEMv|N%fln«a.ä XÉUMEJQOU_.H~IW ZOLQEOV~ cocfimhpcmnfixo..všzvàfilßdcfiëmcåv |ocwëmwfiwëmïwvwflnlï ~ -oxzwq zumæfözfwTn .m :obcoz _ cocmšfiwcm .ócfiåmffimxocwEmräwczulwvflnifiÄ wcficuhwm AmcCm.ßm~c~Ewmw~vUmEwxm_ :Bov = .SUQÉ flwwïwwnm :buxafl xmnäuouåëfl 7807987-8 Lymphocytic leukemia Ll2 i O test The procedure is the same as for the ilymphocytic leukemia P388 intraperitoneal test with except that the tumor transplant consists of lyrro-locytic leukemia L12lO inoculated at a concentration of 105 cells/mouse, whereby a mean survival time is calculated. The results with a representative amount for the invention are given in Table III below. _78Û7987-8 52 m 3 w . S ON =ääë=aA | o . w o :obbox m o H q . m N H. q w H o . HH m m ~ :m1 .E ... I . m. m H o N H o m cockmb 3:. mffiwoctcmšflwëfiv Nvwß a H .

Ccmuokä m . m :H man 03 x u? em .å TÉQ _95 wäšom uwfšwïuàfiwuvå mon . .. ÉwToHN HH wëwxsmH xmflñvowëæq _ E HHmm/É. 7807987-8 53 Melanotic melanoma B16 The animals used are C57BC/6 mice, all of the same sex, weighing at least 17 g and all within a 3 gram weight range. There are normally ~ 10 animals per test group. A one-gram portion of melanotic melanoma B16 tumor is hornogenized _in 1_O ml of cold balanced salt solution and a 0.5 ml aliquot of the liorriogenate is implanted intraperitoneally into each of the test mice.

The test compounds are administered intraperitoneally on days 1 to 9 (relative to the tournament inoculation) at various doses. The animals are weighed and surviving animals are recorded on a regular basis for 60 days. The median survival time and the survival time ratio of treated (T)/control (C) animals are calculated. The positive control compound is S-fluorouracil, given as a 20 mg/kg injection. The results of this test with representative compounds of the present invention are given in Table IV.

The criterion for effectiveness is T/C x 100212596.

I 7807987-8 54 .nm .n o _. m N oN zumeäonoïn I m . w H O :Ouurax cocmxmhycménoæššwrwfi.. m3 o _. N N if .mšsmoàvossmååvNmmofiš.#933 q o. No. w N ON =UN=:°..=NA | o . æn o :ohcox N w .n m . m N m o m .n o . n. N w w m n m o w N N .n cocímhpcm|wxohu>swn|wR- mm n m _. N ...N -mšsmerwøcoemäyvsofiwNmwwïwH _ n m .n o . m N o N noumbñosnfn I m n _ O :OLFCOX n. N .n o . n N m o m .n m . n N o . . mm .n o . m N N.n cocšmhocmloxokv>fzv|w n- nmn o . mN mN .Nocïcm Gimo:MEmnÛwEMu-Nwmnnio.nuoxnmq . Bcwufizoo . tmwmvo . moi. m5 w _ o o .n x U\.n. näflåcëwnhušocmovwë , mom cncwhmm äuuïwnm .chocwnmzc ...xmfiocmšê >~ AAMmÉP 7807987-8 55 w m H m . u N o N =um.=.Eo-fi|n | o . w H _ o , :oëax wwfl x WW _ WH :ocEmbcmàxohvšmvàfi: m m m . vw mN |NdcHEmb>wwâ>cwumohb^m|Hvxmfimfinšå mm H m n w N o N zomhshozflun l o . m H o _ HHOHÉox H. .www _ :ocímkwcmvmxohPfwfiïwfilfiocwëm w v H o . m N ow ..-H>«mG>cHvfiot>m|HïfiwwfinTaånoxswH Hömhshošïm H m H o . m w o N .

I m u w H c :obcox _ :ocEmbcmàxohwæcwfiïmü? m NH m . o N o m rNOcHEmA330:fišmwfiofiw|ww~flni~.H _ Ccwucàc Tmmmš . Ux\ . mE .no H X U\m. nfimwæmflhmšwcøHwobz _ mon wcacwäm fimficb >~ HHwm/É. 56 7807987-8 w .w. o.. fimo @ fifiN :umhshosfiå . fiøbcox H v H m _. N N o _ ß w fl m _. m N NH o . m m . m o . ß N m N cocímgwrmàxwhm>cmufw m- ß m .n m . .mm o m A05Emïaoomocfiëwnmvflnifl .Toxawq o w H m . o N o N :umåhoscflln | o ._ wa o :oäcox _ cocoxmhwcmàxohmåcfiuà.Ü o o N o N m N H åwfišmfišwocmEmàwflnioå»oxsma w o .w m . m N o N .zunhzhosflà | o Q w ._.. o :oäcøx . cocšmhpcmlwxohv>zwulw.nu m N ._.. o . o N mN Qd:MEmQÉohQo:@EmvÛoE:Ym%&ni~.H i fiwcmuoLmo . tmwmvo _. mvï .mE _ Q o fi x vä .Émvcwzwohnëwcmovwz but wficäwm omtå >_ .HQMEÉ 7807987-8 :umhshošwïn m m .n o . ß N o w » Q . 3 Q =9Eax m N H o . o N w w m H Q N m ww cocšmhpcmfoxohv>zfivfwä..

WQWHQ w . MM Q m -äfisflawæ.šesàmocmEÅYQQQQTQ._ m ß a o m o . o m Jumäñozflnfiå .. o . ß H o :oäëox H N a m . o N m m N .m o . m N w w fi . WIN" m cocmxmuvcfiwrmxouuæånåfia m o N m . v m o m .fiocoëmïwwfizcwwøhumfifiï Suwæmonïu. fi :oxswq Q Q fl Q . Q m Q N :UQQEQQQQA I O . N. H O . SÖnHCOx w w .m m . m N N . w w m m . m m m . m. ñ cocšmbcmixoašcwvfw*m..

Q Q N Q . Q. Q m N Q . _ . . _ . m f» m . w H o m ...waššmšwuocïcmfßpmënwYmwwonna Toxsmq CcmucQQo Camaro .mvq .UB mcficmhmm O OH ur. U\~f.h UÜwUMC>w~LU>$CMMÛWÜM WOÛ QÉQQV _: »SMEÉ _ 7807987-8 m m a Q . m N o w :UEEQHHA l o . m a O :Opwcøx ß NN o . a. etc. o ß N N A o . w m A ß . o ß N N A o . w m A m . a o ma . m. m N m . _ 0 o a A 0 . m a A w vczxohwaåuèocovæ:=~è.°hvæ=v-w.fi m ß o . aa N a :N05EmïßwaocaëmrapwaxohußsfNïNwwanio.a m ßa o . o m o N . Sumozoosawfn .I O ~ ß .m O . 203.503 m a a m . m a w a N a m . o N m . N a w w a m . w N m N . m wa m . m N if .cocaxmhwzmlmxo..vššïwfi.. o . a N o o a . . . . a. N a |Ho:_Emtaooooo:MEEÉwEaaTNwmanifl Toxsoa Zcwuoä: Émumš . .mx\. m5 wcacwhwm ooa v. U_\B uoävmcïïhu>ocmwvuâ won. 3:0: _: .Smmï 7807937-3 m N H O . m N o m :umšhošïm I m . O EÖHFCOÅ HmH m . m N mH . o w NH o . m N mm . o m ß H o . m m o ß . o mm H o . mmmmm H www m . www w . w vrošohfi;Éwcocoxwbswixoëbšvwfi- mm m . H H m . N H |Noc~EøHñwo^ocHEmHåwEYmwwHnš_H 03 m.. . 3 ON šmåoo=oï | É n Ö .=O.~HCÖX Hm H o . m N w Nm H o . fimwH ww cocfimhwcmåxOpwaczulwfinäcmëm w m H o . __ _, mm m . m o m AXÜAQEEmoHQOMQQmTNYQWÄTo.ToxawH.

Hfiöuohav Émumvo .mz\ .m5 , ooH x U\H nflwwmc>wvmw>mcmmwwffl< mon wcficuëm fimfioö >H wfimmæfl. "7so79s7~so 6G N ß H m . ß N o N HHomosooaHïn ... o omH o HHohÉox N ß H m . ß N ß . o _ m N N o . mm m . H .

MHW. M w w mm cocHxmoflcmuHxooHšzwHvow.nuH-ocwëm m ß H o . w N N H .åfimxocfiEmïpoëvuwwmmnè. H ouoxsuH N ß H m . ß N ON :umszäâa l o . wH oo :obcox ß m H o . N N ß m . o m ß H m . m N m ß . o o ß w H . o . etc. H cocHxmohpcmfflxohuoñnwu|w.nußocoëmrfiw æNH m . oN m. 1 > . | 1. | 1 o m m m . m w ^ocHEmH pfixoovß: NV NNwB :J oxzwq w ß H o . o m o N :omåäšfiw | o ß.H o :ohcox w m o . m H N H m o H m . m H m N _ . _ m H H o . oN if ,. :ooEx movcmnwxoovoncmolæ w- .H N H o o . H N oo H A05Emvßsnofizêmiäwmnxo.H:ovïoq _ Bcuooomo o o fšmmro . .mx\ . mE wcocwšm ooH x UÉ. wtmomfišwïmšocmouwå mon owotooo>o .WEQÉ 7807937-8 O\ (f) <1' V) fl (Û r-l |~| OUH x u\fi šwfiušwcøsvmf/N com cow Na mm om m-~ www ^.mx\.mEv WOÛ ÉUMnDhODÉHIW IOuPCOX _ cocmxmhwcm Åocfiåmfâwoc:oïoëpmvwfinš.fl ZUNfi-ÉODÛIW :OPHGOX :ocämbcm .A05:..mšwwocwëwtfiwåfivnwvwEè"d wcwcvhwm H»>_q4mm<» 62 m 3 o N zufi=ko=zà 1 o :obcox m m H N. o m m. fi m H af ß H m m ß.. J.. m cocïmbcm m m, .n N .n fïcficmflæpmocflëmàvmflniq.~ m w. .m O N Zumunuonflwnn 1 o zobcox m N .n o . N m o ß m .n m . ß N . N .fi ä NM m w f. o.. m N O Q fl -Åocfismqàwocfismævwfinï.#933 78Û7987~8 Ömïoä >~ Aqmm 7807987-8 63 ovfl mwa mom. wflm ßwfi m0 ffißkßmš' f\\D MIOMNN f-(CQ OIOOLÛID Nxømfio oo - o: :umhäošfim :obcox :ocímkpcm A05EmffimocfibmflæwøëlmvmEiflH 43153 >~ AAmm/É. 7807937-8 Association 1,4,5-rr1s[(z- -aminoethylUaminOJ- »Sr-hy-:lroxy-anthraquinone C ontrol S-Flucruracií 1,4-bis[(2-climethylamino'- ethyl)amino]-5,6-clí- hydroxyanthraquinone - Kzontrol â-Fluoruracil lß-bísß-aminopropyl- amíncÛ-ZS-dihydroxy- '-antral Control ' S-Fluorouracil 64 TABLE IV (continued) Dose (rng/kg) Median- ' survival _ (days) 26.0 16.0 26.5 24.0 30.0 T/ C X 100 (percent) 163 166 153 160 153 1650 12.6 150 -187 166 7-807987-8 65 Ridgway sarcoma The animals used are AKDZF 1/ J mice, all of the same sex, weighing less than 1"/ g and all within a 3 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 fourth day for a total of 6 inoculations, starting on day 15 (relative to the turner injection) at various doses. The animals are weighed, and surviving animals are recorded on a regular basis for 90 days. Turner regression is recorded for all test animals. Table 5 gives the results of this test with a representative compound of the invention expressed as the percentage of animals showing tumor regression. ooo oo_ oo oo oo oš oo o oo H3 oo ooo o\o oo. o . oïo ofl . oo ooo ooo.. o oš oo o oá ouëooš o o o o o o o o o oo ïo o o o o oi. oo o oo ooo _o\o om o 3 ooähoooë oï ooo oo oo ooo oš ä. o oo 6 ofi mom o 3 ooo o\o oo o o 6 if o o o o H o o o o o \ o oo o oo -obooåmwmmm mL oo. o eh. ooo o\o oo o oo -oooæäoooeo ooo ooo oo oo ooo oä oo o oo. . .~ooooo.=s_.o_ofl. ooo ooo ooo ooo o\~ oo o ooo -oošåwofnvos R. ooo o ooï ooo oo o o ... oooooflo .

V... .ocwuooav w Äooooumoooo N A .EPC ovcmšoïošm N A .Eoë aozom .öm A . muQ. 95 . . ...ö .Eno of. ox? Bñšš _ . mm o? . If; ...if won ä.. oæošoo. oo »maja -3 umrfio oooE BoÉ ooo osoåom ooæsc z :mamomo m , m cmwwo ommmv mm fö: m: :ommooo cmwow .šwmn o Émowo. 96% www d.

Wed. 7 .

Eovïmo Éw owooo mo» Em > Aqmm/oh 7807987-8 The invention will now be described in more detail in connection with the following specific examples. All temperatures are given in degrees Celsius. äE-'ßlèsli Leuco- lJL-bisÃZælimetvlaniinoethylamino]~5,S-dihydroxy-anthraquinoii A reaction mixture containing 10.58 g of NN-dimethylethylenediamine, 60 ml of 10.96 g of leuco-l,l+,5,8-tetra~ hydroxyanthraquinoii is flushed with nitrogen and stirred under nitrogen for 2 hours under N,N,N',N'--tetramethylethylenediamine and stirring in an oil bath, which is maintained at 49-510. The mixture is allowed to cool under nitrogen. The solid is collected and washed with ethanol, yielding 14.78 g of the desired product as a dark reddish brown solid.

Example 1,1+-bis[(2-dimethylaminoethylamino]-5,8-dihydroxy-anthraquinone A 12.00 g portion of leuco-1,4-bis[(2-dimethylaminoethylamino)-5,8-dihydro-anthraquinone in 100 ml of nitrobenzene is heated under reflux for 15 minutes and then filtered hot. The filtrate is reheated to boiling, allowed to cool, and the solid is collected and washed with ethanol, giving 8.014 g of the desired product as blue-black crystals, m.p. 236-238°. Example 1 Leuco-1,11-bis[(2-dimethylaminoethylamino)-5,8-dihydroxy-anthraquinone [A solution of 15.62 g of N-(2-aminoethylamino)-5,8-dihydroxy-anthraquinone in 40 ml of N,N,N',N'- The tetramethylethylenediammine is deaerated by bubbling nitrogen through it for 15 minutes. A 10.97 g portion of leuco-1,/+,16-tetrahydroxy-anthraquinone is added slowly with stirring, and the suspension is treated as described in Example 1, yielding 18.07 g of the desired product as an olive-colored solid, mp 223-227°.

Example 11 _ 1,11-bis(2-morpholinoethylamino)-5,8-dihydroxy-anthraquinone A 13.90 g portion of leuco-1,11-bis(2-morpholinoethylamino)-5,8-dihydroxy-anthraquinone in 100 ml of nitrobenzene is oxidized as described in Example 2, yielding 10.30 g of the desired product as black rods, mp 2411-2430.

Example 5 Leuco-1,1r-bis(2-diethylaminoethyl)amino]-5,8-dihydroxyanthraquinone The procedure of Example 3 is repeated using 153.95 g of N,N-diethylethylenediamine instead of N'-(2-aminoethyl)morpholine, yielding 13.97 g of the desired product as a reddish brown solid, m.p. 182-1850. 7807987-8 68 æneefi lJL-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, yielding 6.35 g of the desired product as blue-black needles, m.p. 202-201110.

Example 7 Leuco-1,1-bis[2-(1-pyrrolidinyl)ethylamino]-1,8-dihydroxyanthraquinone The procedure of Example 3 is repeated using 12.05 g of N-2-pyrrolidinoethylamine instead of N-(2-aminoethyl)morpholine, and 80 ml of N,N,N',N'-tetramethylethylenediamine, yielding 13.24 g of the desired product as a reddish brown solid, m.p. 180-1850. Example Leuco-1,8-1,8-bis-(methylamino)ethylamino]-5,8-dihydroxyanthraquinone The procedure of Example 7 is repeated using 8.90 g of N-methylethylenediamine instead of N-2-pyrrolidinoethylamine, yielding 13.73 g of the desired product as a dark green solid, m.p. 157-160°.

Example 9_ Leuco-1,4-bis[(3-dimethylaminopropyl)amino]-5,5-dihydroxyanthraquinone Nitrogen is bubbled through an 80 ml portion of dimethylaminopropylamine for 15 minutes. A 10.97 g portion of leuco-1,4,5,8-tetrahydroanthraquinone is added slowly and with stirring. The mixture is heated under nitrogen at 50-520 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 115-1180.

Example 10 L1-bis(3-dimethylaminopropylamino)-5,5-dihydroxyanthraquinone V A suspension of 6.00 g of leuco-1,4-bis(3-dimethylaminopropylamino)-5,5-dihydroxyanthraquinone in 60 ml of N,N,N',Ltetramethylethylenediamine is heated on a steam bath under reflux while air is bubbled in for 12 hours. The solution is cooled, giving a solid which is collected and washed twice with heptane and once with petroleum ether. This solid is recrystallized by extraction with 350 ml of hot heptane, filtration and concentration to 300 ml. 78079087-8 (i 9 Crystallization and washing with petroleum ether give 3.72 g of the desired product as black needles, m.p. 154-1570.

Example 11; Leuco-1,11-his(2-aminoethylamino)-1,1-hydroxyanthraquinone [A reaction mixture containing 10.97 g of leuco-1,11,5,8-tetrahydroxyanthraquinone in 80 ml of deaerated N,N,N',N'-tetramethylethylenediamine, containing 7.22 g of methylenediamine, is heated and stirred under nitrogen at 48-50° in a flask. The mixture is allowed to stand under a slow stream of nitrogen, giving a solid which is collected and washed with ethyl acetate, acetonitrile and petroleum ether, yielding 13.8 g of the desired product as a red-black solid.

Example 12 Leuco-1,11-bis(B-aminopropylamino)-5β-dihydroxyanthraquinone A suspension of 10.97 g leuco-1,1+,5,8-tetrahydroxyanthraquinone in a deaerated solution of 8.903 1β-diaminopropane in 80 ml N-N-N',N'-tetramethylethylenediamine is stirred and heated at 490 for one hour under nitrogen, then allowed to cool. The resulting solid is collected and washed with cold ethanol, yielding 14.21 g of the desired product as a black solid.

Leuco-1,1+-bisÛ-(2-hydroxyethylaminoethylaminof-2S-dihydroxyanthraquinone i A suspension of 12.5 g of 2-(2-aminoethylamino)-ethanol in #0 ml of N,N,NV',N'-tetramethylethylenediamine is stirred and quenched by bubbling in nitrogen for 15 minutes. A 10.97 g portion of leuco-1,1+,5,8-tetrahydroxyanthraquinone is added gradually with stirring. The suspension is heated and stirred under nitrogen in an oil bath at 50-520 for 5 hours. The mixture is allowed to stand and cool under nitrogen 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 greenish-gray solid, m.p. 1294310, Example 14 Leuco-1,4-bis[di(2-hydroxyethylamino]-5,5-dihydroxyanthraquinone A solution of 17.8 g of N,N-di(2-hydroxyethyl)-ethylenediamine in 100 ml of methanol is cooled with an ice bath, stirred and deaerated by bubbling nitrogen for 15 minutes. A 10.97 g portion of leuco-1,4,5-tetrahydroxyanthraquinone is added gradually with stirring and continued cooling. The suspension is heated and stirred under nitrogen in an oil bath at 50-1520 for one hour, and the mixture is then allowed to stand and cool under nitrogen overnight. The solid is collected and washed with ethanol, yielding 14.8 g of a reddish-brown solid, mp 70-165-165°.

.Elicitation of 1-A-bis[2-(methylamino)ethyl]-5,5-dihydroxyanthraquinone dihydrochloride _ To a suspension of 11.60 g (0.03 mol) of leuco-1,1:-bis[2-(methylamino)ethyl]-5,5-dihydroxyanthraquinone in 200 ml of 2-methoxyethanol was gradually added 15 ml of ethanolic 100 ml of hydrogen chloride. The system was cooled with an ice bath and stirred while 7.50 g (0.0305 mol) of 100 ml addition of 650 ml of acetone, which gave 13.15 g of a blue-black solid; Example 16 7 1,4-bis[2-(2-aminoethylamino)ethylamine]-[beta]-dihydroxyanthraquinone According to the general procedure of Example 3, a mixture of 10.97 g of leuco-1,1+,5,8-tetrahydroxyanthraquinone, 80 ml of N,N,1\1', [beta]tetraineethylethylenediamine and 21.84 g (0.24 mol) of diethylenetriamine soon gave a thick solidified mass, which prevented effective stirring, so that the reaction time was extended to 21+ hours. The mixture was allowed to cool, and the supernatant liquid was decanted and discarded. A solution of the solidified mass in 100 ml of methanol was filtered, and then allowed to oxidize in the air for 11 days in a partially covered flask. The gelatinous mass which separated became solid when the oxidation mixture was agitated with 200 ml of acetonitrile and then allowed to stand for one hour. After the solid was collected and washed first with acetonitrile and then with ether, it amounted to 10.88 g of a blue-black powder.

Example 17 Leuco-1,1-bis(1-aminobutylamino)-5,5-dihydroxyanthraquinone Following the general procedure of Example 3 but using #5 ml of 1,5-diaminobutane as the primary amine component, 12.20 g of product was obtained as a dull gray-green solid.

Example 1 Leuco-1,4-bis[2-dimethylaminopropylamino]-5,8-dihydroxyanthraquinone 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 Example 1 gives 7.29 g of reddish brown crystals.

Example 19 Leuco-1,1,5,8-dihydroxyanthraquinone To a solution of 14.10 g of 1-methyl-diethylenetriamine in 50 ml of ethanol and 110 ml of 1,1,5,8-tetrahydro-ethyl ether is added 10.973 g of leuco-1,1,5,8-tetrahydroxyanthraquinone as in Example 1. The mixture is heated at 500 and stirred under reduced pressure for one hour, cooled in an ice bath, and the solid is collected, and washed with cold water, yielding 17.23 g of green-black crystals, solvent. Leuco» 1,11-bis[2-(2-dimethylaminoethylamino)ethylamino]-5,8-dihydroxyanthraquinone Isopropylidenediamine with leuco-1,1+,5,8-tetrahydroanthraquinone by the procedure of Example 20 gives the title compound. .fëïumïål _ '1-.H-bisQ-arryincirrtylairino)-5,8-dihydroxyanthraquinone dihydrochloride Chloranilation of 28.25 g of the product of Example 12 by the procedure of Example 15 gives 29.66 g of a crude, blue-black solid, which is filtered off by stirring for 11+ hours with 300 ml of water. Solids are removed by centrifugation, and the supernatant solution is freeze-dried. leaving 16.38 g of a blue-black solid which is osmili. at ÉUOO. åëetftlf>_ß_l__å2 1J1~bi sÛ-(Z-hydroxyethyl irio)ethyl inof- 5,S-dihydroxyanthraquinone dihydrochloride Chloranil oxidation of 17.86 g of the product of Example 14 by the procedure of Example 15 gives (without recrystallization) 21.34 g of a blue-black solid, m.p. 2o3-2o5°. 1,1L-bis[2-(2-methylaminoethylaminoethylamino]-5,S-dihydroxyanthraquinone tetrahydrochloride The product of Example 19 (11.70 g) is oxidized with chloranil by the procedure of Example 16, yielding 18.03 g of a bluish-black solid, mp 190-203°C. 7807987-"8 w.) k) Example 2._f_l 1ß-bis[2-(1'Z-hydroxyethylamino)ethylamino]-5,S-dihydroxyanthraquinone In a modification of the synthesis in Example 13, the solvent used is ethanol. The leuco product is allowed to stand for two weeks in a stoppered flask, whereupon the oxidized product separates. It is collected and washed in ethanol and then recrystallized from ethanol, giving blue-black crystals. mp. 175-177°.

Example 25 - Lc-tsl-:o-1,fi-bis-[2-hydroxyethylamino]-1-propylamino]-5,5-dihydroxyanthraquinone The method of Example 14 is used with a solution of 10.18 g of 2-13-aminopyrrolarin in 100 ml of ethanol. The resulting solution is filtered, and the filter cake is diluted with 300 ml of ether, whereby the product precipitates as a sticky substance. After decantation of the remaining solution, the sticky substance is caused to crystallize by agitation with 100 ml of tetrahydrofuran.

'Fxšíttrvisig with ethanol gives 12.56 g of greenish-black solid, mp 101-104°.

Example 1,4-bis[3-(2-hydroxyethylamino)propylamino]-5,8-dihydroxyanthraquinone-dihydro- milsil - Oxidation of 9.95 g of leuco-1,4-bis[3-(2-hydroxyethylamino)propylamino]-5,8-dihydroxyanthraquinone with chloranil as in Example 15 gives 11.70 g of a blue solid which does not melt at 350°. Example 27 - ' Leuco-1,1-bis[3-(2-hydroxyethylamino)propylamino]-5,8-dihydroxyanthraquinone The procedure in Example 1.4 is repeated with 14.18 g of N-(3-hydroxypropyl)-ethylamino in 100 ml of ethanol, which gives 14.63 g of reddish brown crystals, m.p. 58-60°C. 1,1;--bis[2- 3-hydroxy-1-propylaminoketylamino]-5β-dihydroxyanthraquinone dihydrochloride Chloranil oxidation of 10.77 g of the product of Example 27 by the procedure of Example 15 gives 11.64 g of a dark blue solid, mp. 210-2169 _ Example 29_ Leuco-1A-bisQ-(2-hydroxy-1-propylaminoketylamino]-1β-dihydroxyanthraquinone Åled 14.18 g of 1ΔZ-aminoethylamino)-2-propanol in 100 ml of ethanol by the procedure of Example 14 gives 17.61 g of greenish-black crystals, mp. 50-600. 7807987-8 73 åêefiflzffiwàl) Eu-biJLfZ-(fš-hydroxy-1-propylaminoketylazrxin]-5,S-dihydroxyanthraquinone-dihydro- lalofošö A filtered solution of 14.04 g leuco-l,ll-bis[2-(2-hydroxy-l~propyl- f axnarioletyflanittfl-l.ßfdihydroxyanthraquinone in 215 ml 2-methoxyethanol is oxidized with 7.65 g chloranil by the procedure of Example 15, giving 16.75 g of a pm purl-lagged solid, mp 177-1850. The reaction mixture of L-[2-(2-hydroxyethylamino)ethylamino)ethylamino]ethylamino-1-bis[2-(2-hydroxyethylamino)ethylamino]ethylamino]-1-dihydroxy- 1-aminomethylethylamino]-1-methylethylamino]-1-methylethylamino]-1-methylethylamino]-1-methylethylamino]-1-methylethylamino]-1-methylethylamino]-1-methylethylamino]-1-methylethylamino]-1-methylethylamino The compound solidifies to a solid cake upon storage at 250. Example 3 3 _ 1,5-bis[2-[2-(2-hydroxyethylaminoethylamino)ethylamino]-5,8-dihydroxyanthraquinone- Chloranil oxidation of 12.10g of the product of Example 31. by the method of Example 15 including three additional washings of the solid with methanol, gives 12.46g of soft solid product. 1,5-bis[2-[2-(2-hydroxyethylaminoethylamino)ethylamino]-5,8-dihydroxyanthraquinone- By the procedure of Example 14, a solution of 16.10g of 3-(2-aminoethylamino)-1,2-propanediol [A. R. Surrey, C. M. Suter, and J. S. Buck, J.

Arn. Chern. Soc., _73, 1102_(195Z}] in 100 ml of methanol a sticky substance, which is separated from the solvent by cooling with an ice bath and then decanting. The sticky substance is washed four times by stirring for one hour at 250 with 100 ml portions of methanol, cooling with an ice bath and then decanting. A filtered solution of the sticky substance in 280 ml of 2-methoxyethanol is oxidized with 10.01 g of chloranil by the method of Example 15.

The product is then washed further with ethanol, which gives 15.25g of a blue-black solid, amp. 1910930. 7807987-8 74 Äléuigel 3-1 V 1,4-bis[2- Z-(1-morpholinolethylaminoethylamino]-5,8-dihydroxyanthraquinone- tetrahydrochloride A solution of 20.80g N-(morpholinolethylaminoethyldiamine) in 100ml ethanol is used in the procedure of Example 14, which gives a solution which is filtered and :ned ml ether, whereby a sticky substance precipitates. The supernatant solution is decanted, the sticky substance is dissolved in 175ml Z-methoxyethanol and oxidized :ned 5.29g chloranil by the method of Example 15, which gives 17.7g dark blue solid.

Leuco-1,1-bis[2-(acetamido)ethylamino]-5,8-dihydroxyanthraquinone _ A suspension of 12.26 g of N-acetylethylenediamine in 100 ml of ethanol by the method of Example 14 gives 15.27 g of dark, reddish-brown solid, m.p. 1250_ 1,1-bis[2-(acetamido)ethylamino]-5,8-dihydroxyanthraquinone A suspension of 11.95 g of leuco-1,1L-bis[2-(acetamido)ethylamino]-5,8-dihydroxyanthraquinone is oxidized with 6.76 g of chloranil for 61 hours by the method of Example 15, giving a very acidic hydrochloride salt, which is converted to the free base by four washes with water. Crystallization from 100 ml of dimethyl sulfoxide (boiling only 2 minutes and no attempt at hot filtration) and then washing with dimethyl sulfoxide and with ethanol gives 7.76 g of blue-black substance. amp. 273-2719.

Example i? A 1',11--bis[2-(2-hydroxyethyl)trifluoroacetamido-ethylamino]-1-dihydroxy- ethanoic acid A suspension of 1.50 g 1,1+-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxy- ethanoic acid in 75 ml ethyl trifluoroacetate and 75 ml methanol is stirred for 10 minutes. Evaporation of the resulting solution in vacuo at 300 leaves a residue which is washed and macerated with methylene chloride to give 2.11 g of a dark solid, m.p. 1620.

EXAMPLE 1,4-bis[2-amino-2-carboxyethylamine-2S-dihydroxyanthraquinone . 3/4 l-lCl To a solution of 6.23 g of dl-ol,β-diaminopropionic acid in 30 ml of hot water are added 1.078 g of lithium hydroxide and 60 ml of dimethylsulphide. The system is flushed with nitrogen and 4.12 g of leul while stirring. The mixture is stirred and heated with an oil bath at 500, first for 15 hours under nitrogen and then for 21 hours, while the starting product 7807987-8 75 is oxidized; by bubbling in a stream of air. Thin layer chromatography on silica gel with methanol/water/conc. ammonia (25/5/1 by volume) shows that all product phases are blue when oxidation is complete. After the mixture has cooled, the solid is removed by filtration and washed once with dimethylsulphide/water (2/1). Addition of 400 ml of methanol to the filtrate precipitates a solid which is collected and washed with methanol. Further washing with a total of 13 ml of 0.01N aqueous acetic acid dissolves practically all of the solid. Addition of 3 ml of conc. hydrochloric acid to the acetic acid filtrate leaves a blue-black solid which is washed with acetone to give 0.24 g of the product. .leflzl-äsij? I_._e_x_l_!¿'_¿_-_ï>,'-_:_-_l_>_i_sP-(LZ-rmethoxyethylaminomethylamino)-5,8-dihydroxyanthraquinone l;a vtanol solution of N-(Z-rrxetoxoethyldiamine (LIS-PS 3,454,61+0) reacts by the method of Example 14 to the title compound. šzsmsl _40 l Jl-tli JZ-[dltß -hydroxyethylamino]ethylaminoj»5,5-dihydroxyanthraquinone-dihydro- chloride Chloranil oxidation of 10.77 g of the product of Example 14 by the method of Example 1 gives 11.6¿l g of a dark blue solid, m.p. 2160. 7807987-8 76 Example _4_í Preparation of 50 mg tablets Per tablet " Per 10,000 tablets 0.050 g l,l:-bis(3-aminopropylamino)~ -ÄS-dihydroxyanthraquinonep 500 g 0.030 g Lactose _ ' son g 0.010 g .Niacin starch (for mix) 100 g Q.0_08_g .Vlaj starch (for paste) _l5_g anus g 1475 g gliegg Ntagensium stearate (l 96) ___1_5__g 0.150 g ~ ' ' V 1-490g IJß-bis(3~aminopropylamino)-Sß-dihydroxyanthraquinone, lactose and rriaisstärkcrlsorx (sor r-riix) hoplaridase. 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 then passed through a No. 8 hand sieve and dried at 490. The dry granules are then passed through a No. 16 sieve.

The mixture is lubricated with 1:96 magnesium stearate and compressed into tablets in a suitable tabletting machine.

Eflëiwslníšš* Preparation of oral suspension ingredient Quantity _ _ Leuco-1ß-bisÜ-aminopropylamino)-5,8- -dihydroxyanthraquinone 500 mg Sorbitol solution (7_0 96 N.F.) 40 ml Sodium berisoate _ 150 mg Saccharin , ' 10 mg Red dye: ' 50 ml _ Cherry flavor _ ' 50 ml Distilled water qs. ad. in 100 ml The sorbitol solution is added to 40 ml of distilled water and the leuco-1ß-bis- I (B-aminopropylaphxind-5,ß-dihydroxyanthraquinone is suspended therein. The saccharin, sodium benzoate, aroma 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-1ßl- I bis(3-aminopropylamino)-5,8-dihydroxyanthraquinone. 7807987-8 77 F1°§:9e1__4 3 Preparation of parenteral solution In a solution of 700 ml of propylene glycol and 200 ml of water for injection, suspe i-is-uis IÉ0.0 g of 1,1+-bis[3(dimethylamino)propylamine]-ZS-dihydroxyanthra- ki- rion~rliliydiol is added to the solution. 5.5 with hydrochloric acid, and the volume is brought to 1000 ml with water for injection. The preparation is sterilized, filled into 5.0 ml ampoules, each containing 2.0 ml (corresponding to 40 mg of drug) and sealed under nitrogen.

L-.Lsfleeiiß Frairstiilirung :tv l,/+~bis(2-dimethylarniinoethylarnino)-anthraquinone A mixture of 3 g quinizarin, 10 g N,N,-dimethylethylenediamine and 17.5 ml water is stirred and heated under reflux for 3 1/2 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. 170-1729 _ Alternatively, the above product can be prepared by stirring and heating under reflux for 5 hours from a mixture of 2.4 g quinizarin, 2.82 g N,N,N',N'-tetramethylethylenediamine. The product is recovered as described above.

Example 4-5 I Preparation of 1,1,9-bis(2-morpholinoethylamino)-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, yielding 9.92 g of the desired product as a blue-black solid, mp 158-1590.

Example 1b Preparation of 1,11-bis(diethylaminoethylamino)anthraquinone A mixture of 42 ml of N,N,N',N'-tetramethylenediamine, 17.43 g of N,N-diethylethylenediamine and 12.01 g of quinizarin is stirred and heated under reflux for 15 hours. The resulting solution is evaporated to dryness, and a chloroform solution of the residue is filtered through 300 µm of alumina. The blue filtrate is chromatographed on silica gel in a Nylon film column, developing with a chloroform-methanol mixture (6:1). The larger blue band is cut out and then eluted with a chloroform/methanol/triethylamine mixture (6:2:1). The eluate is evaporated. The residue is crystallized from hexane and washed with petroleum ether, yielding 1.13 g of the desired product as blue-black plates, m.p. 1090. .7807987-8 78 Éïfíernigel 47 Preparation of leuco-1,4-bis(2-aminoethylamino)-anthraquinone A 125 _ml portion of ethylenediamine is deaerated by bubbling through with nitrogen for 11 minutes. A 12.0 g portion of leucoquinizarin is added, and the mixture is stirred under nitrogen at 500 for 1 hour. The mixture is allowed to cool. The solid is collected and washed successively with ethyl acetate, acetonitrile and petroleum ether, yielding 8.07 g of the desired product as green-gold colored crystals, m.p. 162-1650°C) at a reaction rate of 90°C per minute. Example 48 Preparation of 1,1+-bis(2-aminoethylamino)anthraquinone Air is bubbled into a mixture of 7.0 g of leuco-1,¿+-bis(2-aminoethylamino)anthraquinone and 87.5 ml of ethylenediamine while heating at 50°C for 1 hour. The mixture is diluted with 87.5 ml of acetonitrile, allowed to cool, and the solid is collected and washed with acetonitrile, yielding 5.10 g of the desired product as a dark blue solid, m.p. 170-1710°C.

Example 49 Preparation of 1,4-bis[2-methylamino)ethylamino]anthraquinone A mixture of 2.4 g of leucoquinizarin and 25 g of deaerated N-methylethylenediamin is heated at 50° with stirring and under nitrogen for 1 hour. Heating at 50° is continued, while air is bubbled into the mixture for 40 minutes.

The mixture is evaporated to dryness and then re-evaporated twice from 275 ml portions of ethanol. Crystallization of the residue from ethanol/ether at -70° gives 2.32 g of a solid, which is recrystallized twice from carbon tetrachloride, giving 1.92 g of the desired product as dark blue crystals, m.p. 1329 7807987-3 79 Preparation of leuco-1,/t-bis(2-dimethylaminoethylaminotetraquinone) A solution of 26.41; g of N,N-dimethylethylenediamine in 75 ml of N,N,N',N'-tetramethylethylenediamine is deaerated by bubbling nitrogen through for 15 minutes.

Then 2.1.1 g of leucokinizarin are added and the resulting mixture is stirred under vacuum while heating at IMS-SCO 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. In this way, 12.52 g of dark green crystals are obtained, mp 1561-1570; or on a hot stage microscope, mp 153-1540.

Example 51.

Preparation of 50 mg tablets xg tablet Ber 10,000 tablets in 0.050 g l,2-bis[2-(methylamino)- ethylamino]anthraquinone 500 g 0.050 g Lactose ~ - 800 g 0.010 g :corn starch (for fm) 100 g Qfitlag Corn starch (for paste) lig 0.lli8 y 1475 g Magnesium stearzite ((1 96) __l_§_g 0.1 so g 11:90 g l,li-bis[2-(methylamino)ethylaminoq]anthraquinone, lactose and corn starch (for mix) are mixed 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 the granules are then passed through a No. S hand sieve and dried at 490. The dry granules are then passed through a No. 16 sieve. The mixture is lubricated with 1 96 magnesium stearate and compressed into tablets in a suitable tabletting machine. 7807987-8 80 Example 52 Preparation of oral suspension ingredient ' - Measure Leuco-1,1-bis(2-aminoethylamino)anthraquinone 500 mg _s<>r_biroi-ösning_ (70 9:. N.F.)_ ' 40 ml Sodium benzoate 150 mg Saccharin 10 mg I Red Ärägämn I 10 mg Cherry aroma 50 mg Distilled water q.s. ad. u - 100 ml The sorbitol solution is added to 40 ml of distilled water, and the leuco-1,1-bisQ-aminoethylamino)anthraquinone is suspended therein. The saccharin, sodium benzoate, flavouring and colouring are added and dissolved. The volume is adjusted to 100 ml with distilled water. Each ml of syrup contains 5 mg of leuco-1,#-bis(2-aminoethylamino)anthraquinone.

Example 53 - Preparation of Parenteral Solution In a solution of 700 ml of propylene glycol and 200 ml of water for injection, 20.0 g of 1,11-bis(11-aminobutylaminoanthraquinone are suspended with stirring.

After suspension is completed, the pH is adjusted to 5.5 with hydrochloric acid, and the volume is brought to 1000 ml with water for injection. The preparation is sterilized, filled into 5.0 ml ampoules, each containing 2.0 ml (corresponding to 40 mg of drug) - and sealed under nitrogen.

Example 54 Preparation of leuco-1,1β-bisβ-aminopropylaminoquintraquinone When 1β-propanediamine is used instead of ethylenediamine in the process of Example 47', the title compound is obtained as the product.

Example 55 ' Preparation of leuco-1,11-bis(2-dimethylaminopropylamino)anthraquinone Using 15.32 g of 2-dimethylaminopropylamine instead of N,N-dimethylethylenediamine in the procedure of Example 50 gives the title compound after a reaction time of 1 hour at 500.

-Example 55 '- Leuco-1,11-bis[2-(2-methylaminoethylamino)ethylaminoanthraquinone A solution of 114.10 g (0.12 mol) 1-methyl-diethylenetriamine in 100 ml ethanol is deaerated by bubbling nitrogen through it for 15 minutes, after which 9.69 g (0.01+ mol) leucoquinizarin- is added gradually with stirring. The mixture is stirred under nitrogen and heated on an oil bath at 500 for 21 hours. The mixture is allowed to cool, after which the product is collected by filtration and washed with acetonitrile and then with petroleum ether, giving the title compound as a dark green solid.

Example 57 Preparation of Leuco-1,14-bis(methylaminoethylaminoanthraquinone To a deaerated solution of 8.89 g of N-methylethylenediamine in 30 ml of N,N,N',N'-tetramethylethylenediamine is added 9.68 g of leucoquinizarin. The mixture is stirred and heated at 50° under nitrogen for 1 hour and then allowed to cool. The solid is collected, washed with toluene and then with Et-r, yielding 9.0 g of a greenish-black solid, mp 105-109°. Example 53 1,14-Tris(β-aminoethyl)amino]-8-hydroxy-anthraquinone A 100 ml portion of ethylenediamine is deaerated by bubbling nitrogen through it for 15 minutes. A 10.97 g portion of leuco-1,1,5,8-tetrahydroxy-anthraquinone is added, and the mixture is stirred under nitrogen at 50-510 for 1 hour. The flask is cooled and filtered. The unplugged filtrate is allowed to cool at 10° for 2 hours, giving a solid which is collected and washed with ethanol to give 2.25 g of the desired product as a dark purple solid. Example 59 [1,4-bis[1,4-dimethylaminoethylamino]-5,6-dihydroxy-anthraquinone A 30 g portion of zinc is added portionwise to a boiling mixture of 1.5 l glacial acetic acid and 40 ml water containing 27.2 g 1,4,5,6-tetrahydroxy-anthraquinone. The mixture is boiled for 30 minutes, filtered and the filtrate is cooled. The orange-brown crystals that form are collected and yield 19.7 g of leuco-1,4,5,6-tetrahydroxyanthraquinone, mp 255-257°.

A 7.9 g portion of dimethylaminoethylamine in 75 ml of tetramethylethylenediamine is heated to 80-100° and deaerated with nitrogen. The mixture is treated portionwise with 8.22 g of leuco-1,1+,5,6-tetrahydroxyanthraquinone with stirring and under nitrogen and heated at 90-100° for 6 hours. The mixture is filtered while hot. The filtrate is cooled to ~4°, treated with ether and after standing for 48 hours gives a dark blue gum. The supernatant is decanted, treated with twice its volume of ether and cooled, giving a blue gum.

This supernatant is allowed to stand and then treated with more ether, giving 1.5 g of the desired final product as a blue solid, mp 133-1350. 780798758' 82 Example 60 1A,5-Tris[2-(Z-hydroxyethylamino)ethylamino}-8-hydroxyanthraquinone Reaction of Z-(Z-hydroxyethylamino)ethylamine and leuco-1,1+,5,8-tetrahydroxyanthraquinone is carried out as in Example 53, giving the title compound.

Example 6 l 1,4-bis(3-aminopropylamino)-5,8-dihydroxyanthraquinone A suspension of 10.0 g leuco-1JL,5,S-tetrahydroxyanthraquinone in 120 ml of anhydrous 1J-diaminopropane is stirred and heated at 450 under nitrogen for 1 hour and then for 10 minutes, while air is bubbled into the suspension.

The mixture is then evaporated to dryness and the residue is extracted with 650 ml of ethanol 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 and then with diethyl ether, giving the desired product as 9.57 g of a blue solid, mp 115-130°. Example 6_2 Preparation of 50 ing tablets Per tablet f Per 10,000 tablets 0.050 g l,lt-bis(3-aminopropylamino)- -5,8-dihydroxyanthraquinone 500 g 0.080 g Lactose _ 800 g 0.010 g Cornstarch (for mix) l00 g ïg .Flattened starch (for paste) Äg 0.148 g 1475 g flag .Flattened sodium stearate (11%) _Q_g 0.150 g 1490 g lJß-bisß-aminopropylamino)-5,8-dihydroxyanthraquinone, lactose and the cornstarch (for mix) are mixed together. The cornstarch (for paste) is suspended in 600 ml of water and then heated with stirring so that a paste is formed.

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 sieve and dried at 1499. The dry granules are then passed through a No. 16 sieve. The mixture is lubricated with 1% magnesium stearate and compressed into tablets in a suitable tabletting machine. 7807987-8 83 Example 6__3 Preparation of oral suspension ' Lïïsä Leuco-l,ll-bis(B-aminopropylamino- -5.8~dihydroxyanthraquinone 500 mg Sorbitol solution (70.% N.F.). #0 ml Sodium iberisoate 150 mg Saccharin _ ' 10 mg liquid dye 50 mg Cherry sorbitol 50 ml Distilled water qs. ad. l00 ml Sorbitol solution is added to 40 ml distilled water and leuco-lß-bislB-aminopropylamino)-lâš-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-1,1-bis(B-aminopropylamino)-5,2-dihydroxyanthraquinone.

Example 64 Preparation of Parenteral Solution In a solution of 700 ml propylene glycol and 200 ml water for injection, 20.0 g of 1β-bis(B)-aminopropylamino)-5,8-dihydroxyanthraquinone dihydrochloride are suspended with stirring. After suspension is complete, the pH is adjusted to 5.5 with hydrochloric acid, and the volume is brought to 1000 ml with water for injection.

The preparation is sterilized, filled into 5.0 ml ampoules, each containing 2.0 ml (corresponding to 40 mg of drug) and sealed under nitrogen. i Example 65 1,1+-bis[[*-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone disuccinate salt A mixture of 222 mg of 1J1-bis[Z-(Z-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthral under reflux for 30 minutes, whereby the title compound is obtained. lïiifigLíö 1,4-bis[ 2-(3-hydroxypropylaminoctylamino]-5,8-dihydroxyanthraquinone dimalate- -âfi i A mixture of 228 mg of 1,4-bis[2-(B-hydroxypropylamino)ethylamino]-5,8-dihydroxyanthraquinone, 134 mg DL-malic acid, and 50 ml of ethanol are heated under reflux for 30 minutes to give the title compound. 7807987-8 84 Example 67 1Jl-bis(2-hydroxypropylaminooctylamino)5,3-dihydroxyanthraquinone dilactate salt - _ .

A mixture of 228 mg of 1A-bisβ-(2-hydroxypropylamino)ethylamino]-1S-dihydroxyanthraquinone, 20 mg of 80% DL-lactic acid and 10 ml of ethanol is placed on a steam bath for 10 minutes, cooled, treated with 50 ml of acetone and cooled to give the title compound.

Claims (4)

7. 7807987-8 b '5 CLAIMS 1. Chemical compounds of the formula: tautoxidate phonates and pharmacologically acceptable acid addition salts thereof, wherein AB is CH = CH or' CH 2 -C 12 Q is a divalent group of the formula - (C 12) n -, where n is an integer from 2 to 4; R 1 and R 2 are each hydrogen, alkyl having 1 to 2 carbon atoms, monohydroxyalkyl having 2 to 3 carbon atoms, the carbon dioxide in the alpha position to the nitrogen atom not bearing any hydroxy group, dihydroxyalkyl having 3 carbon atoms, the carbonate in the alpha position to the nitrogen atoxene can not bear any hydroxy group, formyl, alkanoyl. having 2 carbon atoms, triflioraacetyl or a group of the formula: - (CH 2) 2 -OCH 3 or - (CH 2) 2 -N wherein R 3 and R 4 are each hydrogen, methyl or monohydroxyalkyl having 2 lzolate acids, the carbonate being in the alpha position to the nitrogen atom can not support any hydroxy trap; and R1 and R2 taken together with their attached nitrogen and R3 and R4 taken together with their attached nitrogen are morpholino; R 5, is hydrogen or hydroxy; R 5 is hydrogen or hydroxy; and R 7 is hydrogen, hydroxy or a group of the formula: H "NH-GI CH 2 N / 2 2 \ Re where RQ is β-hydroxyxyl; Provided that luir Q is - (cH2) n- a) R 1, R 2, R 5, R 6 and R 7 may not simultaneously be hydrogen; b) when ns, R 6 and R 6 are hydrogen, R 1 / R 2 may not be H / hydroxyalkyl, and when n 2, R 1 / R 2 may not be - (CH 2) 2 - <_) - ((I 6) 2-, H / CH 3, H / C 215 or C 2 H 5 / C 3 F 5, and when n is 3, R 1 / R 2 may not be CH 3 / CH 3 or _ ti; _ c) when H 5 and R 7 are hydroxy and n is 2, R 1 / R 2 may not be CH 3 / CH, C 4 H 9 / C 4 H 9 or - (CH 2) 5 -, when n is Lhkan-R 1 / R 2 may not be H / H, CHB / CHB, C 3 H 7 / C 3 EI 7 or - (CEI 2) 2 -O- (CH 2) 2 -, and when n is 4, R 1 / R 2 may not be C 2 H 5 / C 2 H 5, C 4 H 9 / C 4 H 9 or - (CH 2) 4 -; d) when R 5 is OH, the one of R 6 and R 7 must be H, and when R 5 is H, both H 6 and 12 7 must be H; and e) only one of R 1 and R 2 may be alkanoyl. 2. A compound according to claim 1, characterized in that it is 1,4-b1s-β- (z-hydroxyethylanino) ethylaninqj-sß-ayaharoxy-anthraquinone-ainyarochloria; ' A compound according to claim 1, characterized in that it consists of 1,4-bis- (Z-aminoethylamino) -Sβ-dihydroxyanthraquinone, the leukobase and tautomer thereof and the pharmacologically acceptable acid addition salts thereof. A compound according to claim 1, characterized in that it consists of lul-bis- [Z 2 (Z-hydroxyethylamino) ethyl] amino] -Sß-dihydroxyanthraldnone, the leukobase and tautomer thereof and the pharmacologically acceptable acid addition salts thereof.