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 are morpholino; R 5 is hydrogen or hydroxy; R 6 is hydrogen or hydroxy; R 7 is hydrogen, hydroxy or a group of the formula: H -NH-cnzcaz-N R where R 9 is β-hydroxyethyl; provided by? when Q is - (CH 2) n -; a) R 1 is R 1, R 5; R and R do not simultaneously be hydrogen; 17 and R is hydrogen, R 1 / R 2 can not be H / mono- b) when R 5, R 6 is hydroxyalkyl and A when n is 2, R 1 / R 2 can not be ~ (CH 2) 2 -O- (CH 2) 2 -, H / CH 3, H / C 2 H 5 or C 2 H 5 / C 2 H 5, and when n is 3, R 1 / R 2 cannot be CH 3 / CH 3 or - (CH 2) 5 -; c) when R 5 and R 7 are hydroxy and n is 2, R 1 / R 2 cannot be CH 3 / CH 3, C 4 H 9 / C 4 H 9 Be H / H, CH 3 / CH 3, C 3 H 7 / C 3 H 7 or - (CH 2) 2 -O- (CH 2) 2 -; n is 4, R 1 / R 2 cannot be C 2 H 5 / C 2 H 5, C 4 H 9 / C 4 H 9 or or - (CH 2) 5 -; n is 3, R 1 / R 2 cannot - (CH 2) 4 -: d) when R 5 is OH, one of R 6 and R 7 must be H and when R 5 is H, both R 6 and R 7 must be H; and e) only one of R and R may be alkanoyl. The compounds of general formula I above, where A-B is CH 2 -CH 2, are usually stable compounds and are known as the leukoforms of the corresponding anthraquinones. These leukoforms are known to exist in their respective tautomeric forms, and all such forms are equivalent for the purposes of the invention. The leukoforms (here the leukobases) and the tautomers thereof can be represented by the following general formula: 7807987-8 (II, leukobases) (III, tautomeric form) The invention also relates to the acid addition salts of the new compounds of formulas 1, II and III.

The compounds of the invention can generally be obtained from reddish brown to blue-black crystalline materials with characteristic melting points and absorption spectra which can be purified by leaching with lower alkanols, since the free bases are largely 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, suitably in a neutral solvent, are formed from such acids as sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, sulfarric acid, citric acid, lactic acid , malic acid, succinic acid, tartaric acid, hereditary 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 usually crystalline solids which are relatively soluble in water, methanol and ethanol but relatively insoluble in non-polar organic solvents such as diethyl ether. beriseri, toluene and the like.

It will be appreciated by those skilled in the art that all such salts may be converted into their respective free forms, which are represented by formulas I, II and III, the methods known to those skilled in the art, and all such free radicals are therefore equivalent to the purposes of the novel teachings. of the present invention corresponding to formulas I, II and III, can be readily prepared by the following general procedure. In A compound of the formula: Ü: NH-ois x R r 1 s \\ // A \ \\\ 7 o [ziH-Qiš-qr is reacted with a compound of the formula Vf * _ q? Z where one of X and Y is NRIRZ or NHCOCFB and the other is ORm, Cl, Br, I, N (R10) 2, NO2. SO 3 R 10, 5021110, SORIO, SRw, NB, ONO or tetrazolyl, wherein R w is hydrogen, alkyl having from 1 to 10 carbon atoms, phenyl, para-tolyl or benzyl; S and T are different and are 0 or 1; Z is hydrogen, alkyl having 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 thereof is hydrogen or alkyl; b) except as in a), when S is 0, then R 1 / R 2 is 1-1 / 1-I and Z is not hydrogen or alkyl having from 1 to 4 carbon atria; c) when T is 0 and Y is NRIRZ, then Z is hydrogen; d) when T is 0 and X is NR IR 2, then at least one of R 1 / R 2 is hydrogen and Z is alkyl having from 1 to 4 carbon atoms; 807987-8 or R 5 is hydrogen and both R 5 and R 7 are chlorine or alkanoyloxy, which are converted to hydroxy; and f) only one of R 1 and R 2 may be alkanoyl; and when X is NHCOCF3, it removes the COCF3 group, and when Z is a group transferable to NRIRZ, performs its conversion therein; and, if desired, convert A-B, when CH 2 -CH 2, to CH = CH; and for the product in contact 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 10 ° C for about 2 to about 10 hours in a reaction inert solvent such as water, a lower alkanol, e.g. methanol, ethanol or propanol, i-propanoh any of the lower butanol and the like, or in an arnide solubilizer 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 for the most part sufficient to carry out the present process. Other solvents and reaction parameters may sometimes be desirable or, if necessary, and the choice of such additional solvents and reaction parameters is within the skill of the art and are all considered to be equivalent values within the scope of the present invention. In most cases the product is a solid which crystallizes spontaneously or upon seeding or tearing out of the reaction solvent on cooling and can be collected by filtration or decantation. In other cases the reaction mixture may be concentrated, e.g. at elevated temperature under vacuum, and the product crystallizes 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 mix or dilute the reaction mixture with another miscible solvents, such as water, and then collect the product through Lex. filtration or extraction. Those skilled in the art can choose which method to follow, and all such methods are considered equivalent for the purposes of the present invention. Once the product has been collected, it can be purified by e.g. crystallization, chroniatography (thin layer or column) or preferably by lacquinization with a lower alkanol. Other processes such as maceration or crushing in a solvent, e.g. an organic solvent such as ethanol, can be used and all purification procedures are to be considered as equivalents for the purposes of the invention. -7807987-8.

Those skilled in the art will recognize that when a product is desired in leukoform, the tricyclic starting material should be present in the leukoform and measures should be taken to protect such materials, especially at elevated temperatures (ie, above room temperature), from oxidizing agents such as t .ex. oxygen. Thus, when a leukoproduct is desired, the reaction is normally and efficiently carried out in an air exclusion atmosphere. Thus, the reaction can be carried out in an atmosphere of nitrogen or argon, and this precaution should also be taken in purification procedures, especially 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 leukoform, when desired, can be easily transferred to the aromatic form by a variety of methods. Thus, air oxidation is one such method, and other methods are medtex treatment. hot nitrobenzene, chloranil, hydrogen peroxide or sodium perborate. All such methods, and other methods for transferring the leukoform to the aromatic form, are to be considered as equivalents 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 1 -N <I, this transfer can be readily accomplished by R 2 obvious methods 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 methods is therefore contemplated by the present invention, and all such methods are to be considered equivalent to the objects of the present invention. The preferred methods contemplated by the present invention for transferring the group Z to _N <1 are exemplified below. Of course, these are merely examples of this invention 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 as complete equivalents for the purposes of the present invention. Thus, when Z is an aldehyde or ketone group, i.e. -C - R, or R 2 is hydrogen or alkyl, the desired conversion can be achieved by treatment with an amine of the formula in R 1, wherein R 1 and R 2 have the above definition, under R 2 7807987-8 reducing conditions, such as hydrogen with Raney nickel catalyst or sodium borohydride.

For Z are also groups of the formula. / _ \ -NO J. <(CH wherein m is 2 or 3, intended. Treatment of this group with acid, Lex. 2 aqueous-ethanolic hydrochloric acid at 11-O-SOOC in from 1 to 6 hours, R 1 converts it to -NH- (CH 2) r n -OH, which is a group intended for the group -N 2 R 2. For Z, it also means effective leaving groups, such as Cl, Br, I, para- tosyl, OSOZCH, etc. When Z is an above leaving group or R / 1 an equivalent, treatment with an amine of the formula HN 2 in R 2 Lex a lower alkanol solvent achieves the desired conversion.

When Z is a primary or secondary amine, i.e. -NHZ or -NHRI So / RI further transfers alkylation to the desired group -N \ R. 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 can also be used.

All such conversions and other conversion procedures are considered to be the "equivalents" of the objects of the invention.

A preferred embodiment of the first process aspect of the present invention may be represented by the following reaction scheme: 7807987-8 /. Nn-QN \ R2 (I) where R 1, R 2, R 2, R 6, R 7 and Q have the meaning given above, [according to this reaction scheme, leuko-1H-dihydroxyanthraquinone (IV) is condensed with a suitable alkylenediamine (V) 1 a solvent such as N, N, N ', N'-tetramethylethylenediamine, ethanol, water, dimethylformamide, or mixtures thereof at from about uo ° c now about so ° c under a nitrogen atmosphere in several belts to produce the corresponding leukobases (II) . The leukobases (II) can be easily oxidized to the fully aromatic derivatives (1) by a variety of methods such as air oxidation or treatment with hot nitrobenzene, or treatment 7807987-8 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 may be represented by the following reaction scheme A: Reaction Scheme A wherein R R 2 is a more preferred subgeneric embodiment of the first process 1, and Q has the meaning given above. the aspect of the invention is represented by the above reaction scheme wherein Q has the above definition; R 1 is hydrogen or alkyl having from 1 to 2 carbon atoms; R 2 is monohydroxyalkyl having from 2 to 3 carbon atoms, wherein the carbon atom in the alpha position to the nitrogen atom can not bear any hydroxy group, dihydroxyalkyl having 3 carbon atoms, the carbon atom in the alpha position to the nitrogen atom not bearing any hydroxy group, or a group of the formula: / Ra., (cH2> 2 _ N \ Rq where E23 and RLF have the meaning given above; provided that the ratio between the total number of carbon atoms and 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 Lil-position can not exceed four, and that the product is brought into contact 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 the reaction scheme A above, wherein R 1 is hydrogen or alkyl having 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 between the total number of carbon atoms and 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 lß-position can not exceed four, and that the product is brought into contact with a pharmacologically acceptable salt, preferably acetic acid or hydrochloric acid, for the preparation of pharmacologically acceptable acid addition salts thereof. The most preferred subgeneric embodiment of the first process aspect of the invention is represented by the reaction scheme A above, wherein Q is - (CH 2) n -, wherein n is an integer from Z to 4, preferably 2, and R 1 is hydrogen or -CH 2 CH 2 OH and R 2 is -CH 2 CH 2 OI-1, 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.

The novel compounds of the invention, where AB 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 II with a compound of formula L 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 tin. Näfoär -lïx-Q-N / R / l É NH-Q-N; and J is hydrogen, chlorine or bromine; R 2 provided that: R 1 a) when G is -N-Q-N 2, 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 1 '1 b) when G is other than -N-Q-N Z, then L is -NH-Q-N / 1 \ * \ R \\ R2 Cook 2 and the cyclized product is flavored; 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 IBOOC, preferably in an inert atmosphere such as nitrogen. If necessary, R 1 Lex. when G is other than -N-Q-N \, the tricyclic product Cook 2 R1 is aromatized, the substituent K is removed from the \ R cook 2 tricyclic product by e.g. treatment with aqueous-methanolic 7807987-s 12 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 new compounds of the invention can be prepared, wherein A-B is CH = CH, 125 and R? both are either hydrogen or hydroxy, and R 5 is hydrogen, are as follows: A compound of the formula Û 2+ is reacted with a compound of the formula wherein R is alkyl of from 1 to 6 carbon atoms or CF 3; F both are hydrogen or taken together form -OR 3 \ n. / Where RB is hydrogen or alkyl having from 1 to 6 carbon atoms; CD is CH = CH on Y a. / ~ 'Or \ where Y is H or OCHB; 7807987- Provided that when E and F are hydrogen, then CD is I, and when CD - / Rs ¶ Y is CH = CH, then E and F / _ and Rj = R7 = hydroxy, and O RB is hydrolyzed the groups RCO and Y, when this is OCHB, to convert them to hydrogen and hydroxy, respectively; and "if desired for the product in contact with a pharmacologically acceptable salt-forming reagent.

This reaction is preferably carried out by mixing the reactants in a NaAlCl 2 (NaCl / AlCl 3) melt at a temperature of from 130 to 100 ° 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 carried out in a particularly efficient and effective manner by specifically selecting reaction variables such as time, temperature and solvent. These preferred combinations of reactants and reaction variables are exemplified by the following reaction schemes numbered 1-12.

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

The methods and preferred combinations taught by Reaction Schemes 1-12 are set forth only to facilitate those wishing to practice the invention and are not intended to be used in any way to limit the scope of the invention.

Unless otherwise indicated, the symbols and definitions used in each of Reaction Schemes 1-12 refer only to the individual reaction scheme in which it is used. »(Or leukoform) 7807987-s 14 (or aromatic form) f / is as previously described, X is some good leaving group O 2 where Q, R 1 and R II. such as oH, c1, ar, I, NH2, 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 leuko- or aromatic form is reacted with an amine of the structure shown to give the desired 1,4-diamino-9,10-anthracenedione in either leuko- - 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. The form by previously described methods HO, O / H R 1, R 2 and Q have the above definition and Z is chlorine or alkanoyloxy having from 1 to 6 carbon atoms.

The reaction between leuko-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 acid hydrolysis using an ethanol / water solution of either sodium hydroxide or hydrochloric acid. Thin layer chromatography is used to monitor the reaction so that the reaction can be controlled and hydrolysis of the amino substituents avoided. Again, leuko-products are converted to the aromatic forms by previously described methods. Where Z is H, or OH, Q, R 1 and R 2 have the meaning given above, X is Cl, Br, I, O 5 O 2 C 6 H 4 P -Cl 13, OSOBCHB and RB is H or 1ClCl 3.

The two reactants are mixed in a lower alkanol and heated to 40-90 ° C for 1 to 8 hours to give 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 may be lower alkyl, hydroxy lower alkyl or dialkylamino lower alkyl R 1 may be H or lower alkyl, R 2 may be H, lower alkyl or hydroxy lower 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 100 ° 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-anthracendione. 7807987-8 18 + CH 2 = C 1 -C 6 Hgucxxzïacu _ R Z 0 N11QlslCllzCllllCN „2 where Z is hydrogen or hydroxy, Q is as previously described and R is H, lower alkyl 'or hydroxy lower alkyl. R 2 is H or lower alkyl. A mixture of the 9,10-anthracenedione and acrylonitrile in a lower alkarol is heated to 60 to 100 ° 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 RI and RZ 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 ~ 1 a lower alkanol is treated with 2 to 4 mill equivalents of the amine NH to 100 DEG 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-diamino-9,10-anthracenedione. , / ”> ~ -NO + n2ncH2 (cu2) n“ ((Cllz fl n A 2 (or aromatic form) Hclizlc fl zln N 0 (cazlm _ / \\ 0 NHcu2 (cn2) n QI lC fi zlm '(or aromatic form) _6_ _ HCHZ (CH 2) n NH - (CH 2) m OI-10 Nncn 2 (e 2) nNu (cH 2) mo H 78Û7987-8 Z is H or OH, n = 1 to 3, m = 2 or 3.

Leuko-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 for the preparation of leuko-1,4-diamino-9,10-anthracenedione or its aromatic form. Compound § is then heated in aqueous ethanolic HCl to # 0 to SOOC for 1 to 5 hours to prepare the desired product 1,4-diamino-9,10-anthracenedione Z. 8. where Z is H or OH and X is Cl , Br, I, SO 2 CO 6 Hq-p-CH 3, OSO 2 CH 3. 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 compound 2, where X is Cl. Compound 2, the amine HN 2 AND the solvent (R 2) (a lower alkanol) are mixed and heated to 70-100 ° C for 2 to 14 hours to give the final product 3, a 1,4-diamino-9, 10 -antracendion. Where Q and R 1 and R 2 are as previously described and R 8 and R 4 are lower alkyl.

The dihydroaminonaphthoquinones 1 are prepared according to published procedures (1S1Vl. Bloom and G.O. Dudek, Tetrahedron, 26, 1267 (1970)). The reaction between the compounds 1 and anhydrides 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. These amide phenols are alkylated with alkyl dialogues or sulfonates in the presence of a base to the corresponding amide _41. Either the amide phenols α or the amide ethers 11 are mixed with maleic anhydride in a NaAlCl 2 melt and heated to 130-180 ° C for 1-5 hours, which after hydrolysis with aqueous acid gives the desired 1,4-diamino- 9, l0- anthracenedionene _5_. 10. uwg-š.-Š ~ Ew fflfff “r'-. ¥ T" "_ '1_ïr'fIIfI * P'f!“' Ywäj I '~ 1 * - "_ * ^ ~ r .. aat ,. >., ....... __ g ___, _ V_ (J_ V! _ u _ ',, J' 7807987-8 23 where R 1 and R 2 are as previously described, R is lower alkyl or CF 3, n = 2 to 11, X is Cl, Br, OSO2C6H4-p-CH3 or OSOZCHB, Y is H or OCHB and Z = H or OH.

The diamide in toluene is treated with NaH and then with the amine g for 1 to 5 hours at 60 to 100 DEG C. to give the diamide diamine. The latter compound 2 is mixed with the phthalic anhydride g, AlCl3 and NaCl and melted at 130 DEG-200 DEG C. for 1 hour. to 6 hours, giving the anthracenedione 2. Aqueous acid hydrolysis of _5_ then gives the desired 1,4-diamino-9,10-anthracenedione §_. 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 "|. ons noocrm Rgocl-Qwílïl z R 2 1 _ 2 ii Q, Z, R 1 and Rz are as previously described, R is lower alkyl.

The diazide is produced from trans-muconic acid by conventional methods. The diazide and a lower alkanol in toluene are heated to 70 DEG-100 DEG C. for 2-8 hours to give bisurethane 2. Bisurethane 2. is then reacted with an aminoalkyl halide in ether or tetrahydrouran at 40 DEG to GOOC for 2 to 10 hours in the presence of sodium hydride. or other base to give the compound å. The latter compound is then treated with dichloronaphthakinone g in toluene at 0 DEG-110 DEG C. for 5 hours to give the anthracenedione 2, which on hydrolysis with aqueous methanolic acid gives the desired 1,4-diarnino- 9, 10-anthracendionene Q. ii. _ .R - z Nuqní 1 ne = cu, _ X R2 nc = cn | {ii | R 1 is 2 (0) Q, R 1 and R 2 are as previously described, X = H, Cl or Br, Z = Oacyl or OCHB. 7807987-48 Butadiene _1_ and diamine _; (prepared as described in Tetrahedron, ä. (1970)) in ethanol or toluene at 60 to 150 ° C under nitrogen gives the diamine ä.

When X is H, the conversion of y to 2 in the same solvent is effected by treatment. a dehydrogenation agent such as chloranil. When X is halogen, it is converted to 1 L by gentle heating in an aqueous-methanolic sodium bicarbonate solution. Mild acid hydrolysis then transfers Z = Oacyl in Q to Z = OH.

The invention also relates to the transfer of the products to 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 (eg methanol, ethanol, i-propanol) and treated with the salt-forming reagent which itself is in solution in the same or in another solvent. Thus, a suspension or solution of the product in ethanol can e.g. treated with dilute or concentrated acetic acid, hydrochloric acid or the like, or ethanolic HCl, and the corresponding salt can 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 formulas 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 alleviation of leukemia and related cancers in mammals when administered in amounts from about 5 mg to about 200 mg per kilogram of body weight per day. A preferred dosage regimen for optimal results should be from about 5 mg to about 50 mg per kilogram of body weight per day, and such dosage units are used 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 body weight over a 24-hour period. This dosing regimen can be adapted to provide optimal therapeutic response. For example, several divided doses may be administered or the dose may be reduced proportionately to the extent indicated by the needs of the therapeutic situation. A definite practical advantage is that the active compound can be administered in any suitable manner, such as e.g. orally, intravenously, intramuscularly or subcutaneously.

The active ingredients can be administered orally, Lex. with an inert diluent or with an assimilable edible carrier, or they can be enclosed in hard or soft shell gelatin capsules, or they can be compressed into tablets, or they can be mixed directly with the dietary food. For oral therapeutic administration, the active compounds may be mixed with excipients and used in the form of ingestible tablets, oral tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of the active compound. The percentage in the compositions and preparations may, of course, be varied and may suitably be between about 2 to about 60 96 by weight of the unit. The amount of active ingredient in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions or preparations according to 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 disintegrant 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, wintergreen oil or cherry aroma. When the dosage unit form is a capsule, it may contain, in addition to substances of the above type, 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 a preservative, a coloring and flavoring agent such as cherry or orange flavor. Of course, any substance used in the manufacture of a dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts used. In addition, the active ingredients can be incorporated into preparations and preparations with sustained release.

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

Forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the immediate preparation of sterile solution for injection or dispersion. In all cases, the form must be sterile and fluid to the extent that easy injectability exists. It must be stable under the conditions of manufacture and storage and must be protected against the contaminating action of micro-organisms such as bacteria and fungi. The carrier can be a solvent or a dispersion medium, which contains e.g. water, ethanol, polyol (Lex. glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Appropriate fluidity can be maintained e.g. by using a coating such as lecithin, by maintaining the required particle size during dispersion and by using surfactants. The prevention of the action of microorganisms can be accomplished with various antibacterial and antiviral agents, Lex. 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 may be brought about 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 into the appropriate solvent with various of the other ingredients listed above, as needed, 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 of those listed above. with sterile powders for the preparation of sterile injectable solutions, preferred methods of preparation are vacuum drying and lyophilization techniques, which give 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 pharmaceutically active substances is well known in the art. Except when each conventional medium or agent is completely incompatible with the active ingredient, its use in the therapeutic grain positions is intended. Grain-plating active ingredients can also be incorporated into the compositions.

It is particularly advantageous to prepare parenteral compositions in dosage unit form for ease of administration and uniform dosing. As used herein, the dosage unit form refers to physically different units suitable as unitary dosages for the mammalian patients to be treated, each unit containing a predetermined amount of active substance which is 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 depends directly on (a) the unique characteristics of the active substance and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the composition of such an active substance. treatment of disease in living objects with a disease state, in which the health of the body deteriorates as stated in detail here.

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 CH 2 -CH 2; Q is a divalent group of the formula: - hydrogen, alkyl of 1 to 2 radicals, mmhymmalkyl of 2 fines 3, whereby the carbonate in the alpha position to the nitrogen atom can not support any hydroxy group, dihydroxyalkyl peace. 3 carbon oxides, whereby the carbon atom in the alpha position to the nitrogen atoms can not carry any hydrogen element, formyl, alkanoyl having 2 carbon atoms, trifluoroacetyl or a group down the form: i 5 zr I r 7807987-8 29 / Rß ~ (c'r12) 2- ocl1 or - (cH2) 2-n 3 p “4 wherein 1: 3 wrong; each is a product, mryfl or methyroxyalkiryl rea 2 carbonates, the carbonate in the alpha position of the nitrogen ether not being able to support a hydroxy group; and R1 and RZ taken together with their connected nitrogen and RB and R4 taken with their connected nitrogen are marfolino; R is hydrogen or hydroxy; R is hydrogen or hydroxy; and R 7 is hydrogen, hyxyxy or a group having the phonrel: H -Naaxa a ~ N / 2 2 \ RQ where R 9 is ß-hydroxyethyl; provided that when Q is - (CE-I2) n- a) can R 1, R 2, R 5, R 6 and R? not at the same time be hydrogen; b) when R 5, R 9 and 127 are hydrogen, R 1 / R 2 may not be H / mmhydroxyalkyl, and when 2 is, R 1 / R 2 may not be - (CH 2) 2 -CJ- (CI (I 2). / CH 3, H / C 21 -15 or C 2 H 5 / C 2 H 5, and when n is 3, R 1 / R 2 may not be CH 3 / G-13 or - (CH 2) 55 -; c) when R 5 and R 7 are hydroxy and n is 2, R 1 / R 2 can not be (i 1 -13 / Cl 13, C 4 H 9 / C 4 IlI 9 or - (ClI 2) 5 -, when n is 3, can not be H / H, CH 3 / CH 3, C 3 H 7 / C 3 H 7 or - (do not be C 2 H 5 / C 2 H 5, C 4 H 9 / C 4 H 9 or - (CIPI 2) 4 -; d) when R 5 is OH, most of the R 6 and R 7 are H, and when R is H, both R 6 and R 7 must be H; and e) only one of P 1 and R 2 may be aalkarioyl.

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 of the formula: wherein A-B, Q, R 1 and R 2 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 of the formula: NH-QN- (CH2) n-OH R NH-Q-¿- (cH2) n -OH where AB, Q and n have the above definition, 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 of the formula: H 2 -NH- (CH) -N / R 1 (H 2 N 2 R 7 78017987-8 Wherein n, R 1, R 2 and AB have the above definition, and acid addition salts thereof Preferred salts are hydrole The most preferred aspect of the therapeutic composition aspect of the present invention may be represented by a compound selected from a group consisting of such of the formula: wherein the R 1 and R 2 are each hydrogen or -Cl-1zCH 2 OH, 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 relief of cancers is achieved e.g. by using 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 dispense a daily dose or a dose alternating or less frequent days. As can be seen from the dosage regimens, the amount of the main active ingredient administered is a sufficient amount to promote the regression and alleviation of leukemia or the like in the absence of excessively harmful side effects of a cytotoxic nature in the hosts harboring the cancer. This quantity is also called the effective quantity here. As used herein, cancer refers to malignant blood diseases such as leukemia, as well as other solid and non-solid malignant tumors such as melanocarcinoma, lung carcinoma and breast tumors. By regression and relief is meant that the growth of the tumor or other manifestation of the disease is stopped or delayed compared with 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 I 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 from these materials and as metal carriers. Other uses common to sequestrants are also apparent to these compounds. In addition, the leukobases (II) are useful as intermediates in the preparation of the fully 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 found by the following standard test procedures.

Lymphocytic leukemia P388 test The animals used are DBA / 2 mice, all of which are of one sex and weigh at least 17 g, all of which are within a weight range of 3 g. There are 5 or 6 animals per test group. The tumor transplantation is by intraperitoneal injection of 0.1 ml of diluted ascites fluid, which contains lymphocytic leukemia cells P388. The test compounds are administered intraperitoneally on days 1, 5 and 9 (relative to the tumor inoculation) in different doses. The animals are weighed and surviving animals are registered on a regular basis for 30 days. The median survival time and the survival time ratio of treated (T) / control (CU animals) are calculated. 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 set forth in Table I. The criterion for effect is T / C x _l 00 Z 125 96. 7807987-8 para m.mH om zumhäšos fi nm ... m _. Mo: oäcox wm fl o.ma mw w fifl oa flfl om w N ao. NH oo .n .cocímopcmnoxoovšàv .. ß mao .. m .noo N um nAoEEmïobocno fi oëlmvmmnno. Toxauq ß .m N m 0 ma om: umosooosünn | o 0 mo: obcox »HN m.m fi m mmm o.« N w mmm o.mN NH. _ wm N m. o N mm cocoxmoocm | oxoov> nww | o ß N o. m N om -w. fi wooosmšoøoooe2à2 = oo- ~.% moo-o__ om H oum .H om mumozooos fifi I 0. OHO: Obbüx om fl o .nH maa mvam. w .P m om fl o _, m H wo mß fl muß fl. Na om fi oom fl mw mw N m .. w N om: ocEøopcma fi xoouæzowà fi .. mo N m _. o N oo -woš: æoàwoooEmo fi wëooàmmoñfü 79. .Cmwmvo. .Mx \. .OE wcocoomm oo fl NU \ B ofzomc> ïow> mnmonwoou moQ Éwfwwmm: coxawg xw ïzuowëäq o Aqmmøü. 7807987-3 34 m O N m. mH O w fi umozouozüïw | m ._ m c: oogax 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 cocïmhwcmu fi xoäšnwvl o H m o o N o o N | w.n | NoEEmcawmocwEmšwu fifi ïw fi mm fifi a.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 cocšmh fl cmàxoäšzouaw fi .. m ß H o _. ß H o o N | NoEERïwuocwëmšwwo fi ïwww fl nio. ._ åxsmq m o N m ._ m H o m Zumhnopos fi nn l m _. m Q Zouwcox m w H o ._ NH o oH cocïmhfcmw fl xohux; ß wH o 0 vH Q ON 1: Yw fl | ^ oE fi mHzpwoc fi owpoÉxNv fl nio.H ._ Écmßcgmo Tmmmš -.mv ¥ \ - .GE mc fi cwhom o o H x U \, H_ vchwmcšwtmåwcmouwë won. .. o q fl äo H ... Em / ä 7807987-8 N mH m ° m H o m zumosooos fl nn 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 .Nwc fi c fl ïaoomocqcomv fi oEool fi wmñuo.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 | NQEEmho fi u fi šzv fi oooamn fl YNNWBÅ, H N w H o. o m, o m: umosoooš fi n 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 w fi momc> u _ .. w> ocmwowo.o mOD: Éwomm ñm fi oä ~ 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 oH o. HN m N _ o. m m N o. w N o m n: ocšmopcm o. om N o. om SH -oäz fi šå fi fw.Woås fl ä fi ocoëm o. m H o. N _ o oN àåmoc fl EmoÛmcTNYQwH fi To.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 .: o fl zohos fl å | o ._ N H o HHPScox om fi o.oH NH. m m H o. m .H m N.

N m H o. m N o m _ f cocšmmwcma fl xohvac fi unw. m1 m m H o. m H o o H lNošEm2 ~ $ uocHEm | N% fi n | o. H -QVEQH _ Gcmuokc Hung- .mx \. mo .. w ... o o H x U \ H v fi womšwooßšmcmzuwâ m oo: Eoowm 69205 H AHmm / w 730798-7-8 37 m o N. m. m H o m: omhnmhoa fl fm 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 cocïmh fi cmàæokvßzavfw.m1 æ ß o. ß o oN fNocmëmHßmv fi ßcmnmhwm fi anHvawmwmHnuainoxsvH o o N o. o N o m: ummsohos fi- m a o. oH o: o fi cox oo N o. o N w O. o oH N o. H N m o. o om 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 n fl ocHEmHÜÅOErcmw fi omxohwßcuNvrNwmm fi ïa.H m o N m. m H o m fl umåohos fi m | 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 oH. . cocmxmäcmf fi xo fi umHswwfmßm | o Q N 0. m H 0 o N -BEE fl ärzaococaf fi us = ï fi mzå ä .dš fi .ïcaíckmo. Tmmmvw .Uvç. m5, w o oH v. U \ .H. u fi mvmc> øHLu> mcwmcø2 w About: 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. wo. o m oN m. H N mo. o m oN m. H N mH. o. m o N o. N N mm. 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. m m HN o. m N N. w _ v N N m. m N m. N H cocïmäcmàxoovßcww | wâ | _ w HH o. NH m N .N05ëmvßo fi ocHëmHßpoHxohÉHLINYQmHATo.HnoxsuH H ß H o. m H .o m Hïmäüoa fl nm 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 ». m m o. m m: o -o.màdcwEmHšwHocHëmšpwEvr fifi nè._ Ccwuoäc fšmmtv. .mvï. mE wcëmhom ooH x o \ .w u fl wvmšutwšwcmwuuâ won. . .. oÉå o fi mmí. 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-.Hwu fi | 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. Hm N. w m ßH o. mH m. NH _ m ß H o. mH m N: ocïmbcmàxøhvæ fi wuw fi | fi ocHåm. m m o. m. 0 m -wrwïcÉ fl àmë fi ümo fi ïoä7833 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 _: oc fl xmopcmš fi ohwëo fl vuw fi w 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 | coc fi xmovc fi uïmxohoæsovßo. HNoEEm o N H o. N H m N lïpwHocHêmšaohmlH | Hxo._u.É..Nv | QmHn | o.H. o m H. o. mH o w zumemooa fl r fi | 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 cocmxmhoc fl ïHxoovmcHunw måšëmšpw o m H o. m H. .o o N _: ävšëm fi šuoxoovboaQoowwxmwfo. H | oxzwH. _ Hmumåhoroïm m: om 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: Emhcma fi xoovëmoofw fi ..

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

O O H N U \ .. H_ twwmbmc> üf fi w> m CMHUQÉ .MOQ. .. 7807987-8 41 O ~ OW ÉUNLD-O fi åwl fi | 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 om _ _. . : m w m o. m m o o H: ocš fifi cm fi xokuß. = v | w.mNoc ~ EmHš.ø ß N H o. w H o o N AošEmfñaP fi T fi | ~ xox_v>: | mo..Nw $ n_ | m. ToxnoH wm H o. m H o v HHumäños fl um 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 -vs fi oc.emqaoa¿åouvaïmwüww fi ï: o w H o ._ w H o v Summshos fl nm | o. o H o: otbox om 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 »Pcwàxoovæcmmfm fi NocHëm m m m. m o o N lrâoNocmcäw fifi xoc fi ommocïHonNw.NNwEÉJ ícmuqao »Lmwmto. w ¥ \. man wc fi cwunm o oH x U \ H Uïwvmcäwmšmcmwnmrz mOQ ow fi omo m .Smmøê 42 7807987-8 mm fi m fl w zumosooz fl Tn: obcox N w .H o. o N mm. w m m H m. fl N m. NH m m H m. o N m N _ æ fi m o. if if , . .cocmxmowcm N o N m. o N o o N -oxooo>. = o-o. Twooo fi ošpkooosm 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 om o. . »O fi šx o mm m. ß N oo .n Lwncwïxoowäàwñ fl w måorooëmw. o ..: fwf m o o _ ... m N o o N -ošesàooxooo ..- Nwümowo Too ._ oN N m No N oo: u fi oäš fi o r o m _ o: o fi cox .nw fl m. va mn. o m wa o. wa om. H .Z m o. m fl .m. m o oN m. m o .. w. w o o N .. m. ma m,. ma m m N m. H N m N m: ON wvwhO fi xOhUä flfi ul o. O N o. m m o o .n -cocïoopcmnoxoovšo: Yw fifi o fl wëmšwm mm m A o. o m A o o N -Hošcomâšn fi xooooåclüÉowxw fl oio o Gcwooonc. TmumB .OVQ. mš mcwcwoom o o .n X U \ _H v fi mtmcšnzow> mcmz fl owå wOQ fi woïooö ~ 44mm <._. 7807987-8 43 mow m.oN oo zumhäos fi ln i o Soåcox o va o. wa wo. o o na o. wa mm. 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 om | _ l ocäcm> n ... of fi cw_w_ fl wm_wp | zw fi woh% ~ rlhww. må máw 23 who. .Ä .vi: übï mm.a m fi w äumhshosüä I Zobcox m ma o. ma mo. o m va o. wa om. a m ... ha o. ma Na. m m wa o. m a mN. m moN m. NN m. Na. a v N m. o N m N. Ehooxopvæåv fl a m N o. N m o m | cocšmhwcm | oxouvæz.UJWÅMNQCMEAW- »ßohaf w a a m. N a o o a åA05Emt fi woxóovëïmvlmwmmni fl. Ä Éøu B m. -. . .

Loa, vv fl noo \ .a. vïwvm fi šwofowwfuofwmmwwï 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. fi%. w wcsxokošfšèocvæh fl cm m. ß o. w m. N H åEPAL: å_22os fl àwocoem-smsïxo ofm-H ni .no fi omhsooz fi wnn: obcox o m a o. m .n m m. H m m H m. m H N .n. .n o m .n o. m .n m N. m o NH o. wa m. Na o mm fi mf OH MN, U fi äu fl xnvu fi uäß fl mvüæl o N N o N N o m LSE; m..Ém | oxohušàvxw fi: Noc fi cmï fi u oNN o. NN ooH. AošëmšwwocoEmt fi wšzür fifl nå._ Ûcwuoäo Émmmvo. muï. .mE .wc fl cuhmm v o o H X U \ _H_ U fi wvmšø fi h fl ïmcmdwmwo w OD Aáïoä o »Ümm / É. 7807987-e .fi U fl uäuOwåwlh 45 o o N o. o N o N 1 m. oH o: S23 o N H o. m H om m w H o. m H o o .H cøc fi xmo fl cm m o H o. m H o o N _ m .. .n www m .fi N o. NN o o v AocHEmÉpwoc fl owooåuwvm fi nio H o o H m. o H .o o Hou fi âooo fi n | o .HH o: Pšëo o fi o 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. x u? Hwåïw Hšzmoooš w fi äoon.

, LP / wcmH fi wE _. mvq. mEV won ñwïøä H Hamn / E. 46 .ufo m fl ww Hñooo: unåooš fi m 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 än. o H N o. v N o o H o EEEEEN m _ H www m .w N o. om o o N AoEEmšpwoc fi cmnäßnio.H-oxsuu m ß H o. o H _ o o šäoäš fi o 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: HocHEmf fi wocouñwoñnwvwonao.H m oH m. o H _ o o = UE =:. =: A. . 1 o. oH o HHobcox o m. 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 .AOCMfC flfl ä fl muO fi MEMTAHUMUINVmMDIün.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 cocï fi pcmàocmEmšpøocwEmw fi wëlmv fi nla.m m m N O. i, N c w: äää fl ïn l o. m o: obcox m ß .n m. m Jm ß. o m m 4. m. m fl m. .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 coc fi xmhwcmAocmEmïßwocwëmàv fl nè._ fifl hob H Émmäh 7807987-8 Compound 1, 4,5 ~ tris [(2-arn ino- ethyl fl aminoj-S-hydroxy _ -anthraquinone lßbisßz-dimefyi- hydroxyantra] amino] Control i-Fluoruracil [β-bisβ-amino-propylamino] -5,8--dihydroxyanthraquinone Con-mn S-Fluoruracil 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 / CX 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 test for lyophilic leukemia P388 except that the test compounds are administered orally in different doses instead of intraperitoneally, the results of this test with typical compounds of the present invention are given in Table II.

The criterion for effect is T / C x 100 Z 125 96. 7807987 ~ 8 50 a: om fi m2 om fl mw fl m2 of m3 RJ mä mm flfi cwuoåv ä: u? UZMUCOHTHUQMLwCM flfl hßuwwwCwE flfl ÉUNuJhOJTWI fi * odm om fl ï o QÉ m 0.2 w 92 Nä 0.2 om 0.9 o QÜ Ü QÛ nw. oá: om QÉ om Q: O ¶ 0: 3 mm QÉ ow ä: 2: CmwwE må wmv * wmfšwïmšw wåmë -cmnöë w. mon: umhshošmä t.: OPHCOM cccïmhvcmv fi xokv> nwulm.nINoEEm .åšboc ~ Emr3vEMv | N% fl n «A.A. XÉUMEJQOU_.H ~ IW ZOLQEOV ~ coc fi mhpcmn fi xo..všzvà fi lßdc fi ëmcåv | ocwëmw fi wëmïwvw al NLI ~ -oxzwq zumæfözfwTn .m: obcoz _ cocmš fi WCM .óc fi AMF fi mxocwEmräwczulwv al you FI A toilet fi cuhwm AmcCm.ßm ~ c ~ Ewmw ~ vUmEwxm_: Bov = .SUQÉ fl wwïwwnm: buxa fl xmnäuouåë fl 7807987-8 Lymicocytic leukemia Ll2 in O-test L1210 inoculated at a concentration of 105 cells / mouse, calculating a mean survival time. The results with a representative embodiment of the invention are set forth 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 :. mf fi woctcmš fl wë fi v Nvwß a H.

Ccmuokä m. m: H man 03 x u? em .å TÉQ _95 wäšom uwfšwïuà fi wuvå mon. .. ÉwToHN HH wëwxsmH xm fl ñvowëæq _ E HHmm / É. 7807987-8 53 Nelanotic 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. It is normally ~ l0 animals per cheese group. A one-grain aliquot of melanotic rnelanom Blé tumor is hornogenized in 10 ml of cold balanced saline and a 0.5 ml aliquot of the liorriogenate is implanted intraperitoneally in each of the test mice.

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

The criterion for effect is T / C x 100212596.

I 7807987-8 54 .nm .n o _. m N oN zumeäonoïn I m. w H O: Ouurax cocmxmhycménoæššwrw fi .. m3 o _. N N om .mšsmoàvossmååvNmmo fi š. # 933 q o. N o. 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 -mšsmerwøcoemäyvso fi wNmwwïwH _ 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. Bcwu fi zoo. tmwmvo. moï. m5 w _ o o .n x U \ .n. nä fl åcëwnhušocmovwë, mom cncwhmm äuuïwnm .chocwnmzc ... xm fi ocmšê> ~ AAMmÉP 7807987-8 55 w m H m. u N o N = um. =. Eo- fi | n | o. w H _ o,: oogax ww fl x WW _ WH: ocEmbcmàxohvšmvà fi: m m m. vw mN | NdcHEmb> wwâ> cwumohb ^ m | Hvxm fi m fi nšå mm H m n w N o N zomhshoz fl un l o. m H o _ HHOHÉox H. .www _: ocímkwcmvmxohPfw fi ïw fi l fi ocwëm w v H o. m N ow ..- H> «mG> cHv fi ot> m | Hï fi ww fi nTaånoxswH Hömhshošïm H m H o. m w o N.

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MHW. M w w mm cocHxmo fl cmuHxooHšzwHvow.nuH-ocwëm m ß H o. w N N H .å fi mxoc fi Emïpoëvuwwmmnè. 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. o m m. H cocHxmohpcmf fl xohuoñnwu | w.nußocoëmr fi w æNH m. oN m. 1>. | 1. | 1 o m m m. m w ^ ocHEmH p fi xoovß: NV NNwB: J oxzwq w ß H o. o m o N: omåäš fi w | 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 om,. : ooEx movcmnwxoovoncmolæ w- .H N H o o. H N oo H A05Emvßsno fi zêmiäwmnxo.H: ovïoq _ Bcuooomo o o fšmmro. .mx \. mE wcocwšm ooH x UÉ. wtmom fi šwïmšocmouwå mon owotooo> o .WEQÉ 7807937-8 O \ (f) <1 'V) fl (Û rl | ~ | OUH xu \ fi šw fi ušwcøsvmf / N com cow Na mm om m- ~ www ^ .mx \ .mEv WOÛ ÉUMnDhODÉHIW IOuPCOX _ cocmxmhwcm Åoc fi åmfâwoc: oïoëpmvw fi nš. m. fi m H af ß H mm ß .. J .. m cocïmbcm mm, .n N .n fïc fi cm fl æpmoc fl ëmàvm fl niq. ~ m w. .m ON Zumunuon fl wnn 1 o zobcox m N .no. N mo ß m .nm. ß N. N .fi ä NM mw fo. M NOQ fl -Åoc fi smqàwoc fi smævw fi nï. # 933 78Û7987 ~ 8 Ömïoä> ~ Aqmm 7807987-8 63 ov fl mwa mom. W fl m ßw fi m0 f fi ßkßmš 'N oO D F \. - o:: umhäoš fi m: obcox: ocímkpcm A05Emf fi moc fi bm fl æwøëlmvmEi fl H 43153> ~ AAmm / É. 7807937-8 Förening 1,4,5-rr1s [(z- -aminoetyUaminOJ- »Sr-hyr-sacri: lr , 4-bis [(2-climethylamino'-ethyl) amino] -5,6-cli-hydroxyanthraquinone - Kzontroll â-Fluoruracil lß-bis-aminopropyl-amincÛ-ZS-dihydroxy- '-antral control' S-Fluoruracil 64 TABLE IV (f locality) Dose (rng / kg) Median survival _ (days) 26.0 16.0 26.5 24.0 30.0 T / CX 100 (percent) 163 166 153 160 153 1650 12.6 150 -187 166 7-807987-8 65 Ridgwavjgíiïåoggnt sarcoma The animals used are AKDZF 1 / J-rnöss, all of the same sex, weighing niinsr 1 "/ g and all within a 3 gram weight range. There are normally 8 'animals per test group. The tumor is administered subcutaneously with trocar as five 2 mm fragments per mouse. The test compounds are administered intraperitoneally every four days in a total of 6 inoculations, starting on day 15 (relative to the tournament renal run) in different doses. The animals are weighed, and surviving animals are registered on a regular basis for 90 days. The turner regression is registered for all experimental animals. Table 5 indicates the result of this test with a representative compound of the invention expressed in the percentage of animals showing tumor regression. ooo oo_ oo oo oo oo oš oo o oo H3 oo ooo ooo o o \ o oo. o. oïo o fl. oo ooo ooo .. o oš oo o oá ouëooš o o o o o o o o o o o o ïo o 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 o fi mom o 3 ooo o \ o oo o o 6 om o o o o H o o o o o \ o oo o oo -obooåmwmmm mL oo. o ä. ooo o \ o oo o oo -oooæäoooeo ooo ooo oo oo oo ooo oä oo o oo. . . ~ ooooo. = s_.o_o fl. ooo oo oo oo oo oo. o \ ~ oo o ooo -oošåwofnvos R. ooo o ooï ooo oo o o o ... ooooo fl o.

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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. A-mixture of reaction containing 10.58 g of NN-dimethylethylenediamine, 60 ml of 10.96 g of leuko-1,1 +, 5,8-tetrahydroxyanthraquinori spools nitrogen and stirred under nitrogen for 2 hours under N, N, N ', N' - tetramethylethylenediamine and stirring in an oil bath maintained at 49-510. The mixture is allowed to cool under nitrogen. The solid is collected and washed with ethanol to give 14.78 g of the desired product as a dark red-brown solid.

Example 1,1 + -bisLf (2-dimethylaminoethylamino] -Sβ-dihydroxy-anthraquinone A 12.00 g portion of leuko-1,4-bis [(2-dimethylaminethysamine-δ-5,8-dihydrozri-anthraquinone in 100 ml nitrobenzene) 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 to give 8.014 g of the desired product as blue-black crystals, mp 236-2380 Leuko-11,11bis2-morpholinoethylaminofl-5,8-dihydroxyanthraquinone [A solution of 15.62 g of N- (2-aminoethyl] nororpholine in 40 ml of N, N, N ', N'-tetranethylethylenediarriine is deaerated by bubbling nitrogen through it for 15 minutes A 10.97 g portion of leuko-1, + +, Laš-tetrahydroxy-anthraquinone is added slowly with stirring, and the suspension is treated as described in Example 1 to give 18.07 g of the desired the product as an olivine solid, mp 223-2270.

Example 11,11,11-Bis (2-chloropholinoethylamino) -5,5-dihydroxyanthraquinone A 13.90 g portion of leuko-1β-bis-morioinoethylamino) -5,8-dihydroxyanthraquinone 100 ml of nitrobenzene is oxidized as described in Example 2 to give 10.30 g of the desired product as black bars, m.p. 2411-2430.

Example 5 Leuko-1,1'-bis (2-z-diethylaminoethyl) amino] -S, β-dihydroxyanthraquinone The loss in Example 3 is repeated using 153.95 g of N, N-diethylethylenediamine instead of N '- (Z-aminoethylD-morpholine to give 13.97 g of the desired product as a red-brown solid, mp 182-1850, 7807987-8 68 eeneJ1-bRsÄZ-diethylaminoethylamino] -5, êš-dihydroxyanthraquinone A 10.90 g portion of leuko-1,4 -biso-diethylaminoethyl) amino] -5,8-dihydroxyanthralcinone is oxidized as described in Example 2 to give 6.35 g of the desired product as blue-black needles, m.p. 202-201110.

Example 7 Leuko- [1-bis [2- (1-pyrrolidinyl) ethylamino] -1β-dihydroxyanthraquinone in The procedure of Example 3 is repeated using 12.05 g of N-2-pyrrolidinoethylarnin instead of N- (Z-aminoethylethyl). morpholine, and 80 ml of N, N, N ', N'-tetramethylalkylamine to give 13.24 g of the desired product as a reddish-brown substance, mp 180-1850.Esesipslå Leuko-1, Aß-bisß- (methylamino ) ethylamino] -5,8-dihydroxyanthraquinone The procedure of Example 7 is repeated using 8.90 g of N-methylethylenediamine instead of NZ-pyrrolidinoethylamine to give 13.73 g of the desired product as a dark green solid, m.p. l60 °.

Example 9 (Leuko-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 leuko-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 to give 5.59 g of dark orange-red crystals, m.p. 115-1180.

Example 10 LLI-biSZIiB-dimethylaminopropylamino] -5,5-dihydroxyanthraquinone V A suspension of 6.00 g of leuko-1,4-bis-3-dimethylaminopropylaminof5-5-dihydroxyanthraquinone in 60 ml of N, N, N ', L-tetramethylasethylene diamine , while air is bubbled for 12 hours. The solution is cooled to give 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 (in 9 Crystallization and washing with petroleum ether gives 3.72 g of the desired product as black needles, m.p. 154-1570).

Example 11; Leuko-1,1'i-his (2-aminoethylamine-if-β-clihydroxyanthraquinone [In reaction mixture containing 10.97 g of 1euko-1,1,1,5,8-tetrahydroxyanthraquinrine in 80 ml of deaerated N, N, N ', N'- The tetramethylethylenediamine, which contains 7.22 g of methylenediamine, is heated and stirred under nitrogen at 48 DEG-500 DEG C. in a medium, the solution being allowed to stand under a slow stream of nitrogen to give a solid which is collected and washed with ethyl acetate, acetonitrile and petroleum ethers. 13.8 g of the desired product as a red-black solid.

Example 12 Leuko-1,11-bis (β-aminopropylamino) -5β-dihydroxyanthraquinone A suspension of 1.097 g of leuko-1,1 +, 5,8-tetrahydroxyanthraquinone in a deaerated solution of 8,903 μS-diaminopropane in 80 ml NN-N The N '-tetramethylethyleneamine 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 to give 14.21 g of the desired product as a black solid.

Leuko-1,1 + -bisÛ- (Z-hydroxyethylaminolethylamino) or ZS-dihydroxyanthraquinone in A suspension of 12.5 g of 2- (2-aminoethylamino) -ethanol in # 0 ml of N, N, NV ', N'-tetrarmethylethylenediamine tubes and A 10.97 g portion of leuko-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 to give 15.06 g of the desired product as a green-gray solid, mp 1294310, Example 14 Leuko-1, êl-bis fl- [di (hydroxyethyl] amino] ethylamino] -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 leuko-1,4,5ß-tetrahydroxyanthraquinone is added gradually with stirring and continued that 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 to give 14.8 g of a red-brown solid, m.p. 7so79s7 ~ s 70 - 165-i6s °.

.Elílzlššçklfi 1A-bisß- (zneßuninocatylarnincJ- fi, S-dihydroxyanthraquinone dihydrochloride _ Till a suspension of 11.60 g (0.03 mol) leuko-1,1: -bis [2- (methylamino) -ethylaztiiriojf-5. S-Clihydroxyanthraquinone in 200 ml of Z-methoxyethanol was gradually added while stirring with 15 ml of SN ethereal hydrochloric acid. room temperature and diluted with 600 ml of ether. The solid was collected and washed with tetrahydrofuran. The product (11.6 g) was recrystallized by dissolving it in 130 ml of water and adding 650 ml of acetone to give 13 ml. Example 16 7 1,4-bis [2- (2-aminoethylamino) ethylamineQY-, S-dihydroxyanthraquinone According to the general procedure of Example 3, a mixture of 10.97 g of leuko-1 , 1 +, 5,8-tetrahydroxyanthraquinone, 80 ml of N, N, 11 ', tetraethylethylethylenediamine and 21.84 g (024 mol) of diethylenetriamine soon a thick solidified mass, which prevented efficient stirring, so that the reaction time was extended to 21+ hours. The mixture was allowed to cool, and the supernatant was decanted and discarded. A solution of the solidified mass in 100 ml of methanol was filtered, and then allowed to oxidize in air for 1 day 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 Leuko-11β-bisGi-aminobutylamino) -5,5-dihydroxyanthraquinone Following the general procedure of Example 3 but using # 5 ml of β-diaminobutane as the primary amine component, 12.20 g of product was obtained as a dull gray-green solid. substance.

Examples of Leuko-1,4-bis [2-dimethylaminopropylamino] -5,8-dihydroxyanthraquinone Reaction of 12.26 g of Z-dimethylaminopropylamine with 10.97 g of leuko-1,4,5,8-tetrahydroxyanthraquinone in 100 ml of ethanol in a hour by the procedure of Example 1 gives 7.29 g of reddish brown crystals.

Example 19 Leuko-1H: -bis [2- (2-methylaminoethylamino) ethylamine] -5,8-dihydroxyanthraquinone To a solution of 14.10 g of 1-methyl-diethylenetriamine in 50 ml of ethanol and 7807987-8 '31 110 ml of 1 \ '. \' ,. The tetrasetriethylethylertfliaxriiii is set to 10,973; leuko-1,11,8,8,8-tetrahydroxyzizethracirion as in Example 1. The iandland ring is tipped at 500 and stirred ui-dei irl-Lite for one hour, cooled: down an ice bath, and the solid up-paarnia., and h washed: down cold wt-uiol, which gear 17.23 g green-black crystals, los-iir ”. šïsmtßsLjåil Leuko »1, ll-bis [2- (Z-dirrietylarminoethylethylino) ethylamino] -5, S-dihydroxyanthraquinone Onisoating of N- (dimethylamirloethyl] ethylenediamine with leuko-1,1 +, 5,8-tetrttšiydrosiantraquinone example. Phenium (1- (1H-bisQ-arriincyrethyl) amino) -5,8-dihydroxyanthraquinone dihydrochloride Chloranil addition 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. substance, which the sofa f-xzrt-tlitaras by stirring for 11+ hours tried 300 ml of water. Solids are removed by centrifugation and the supernatant solution is lyophilized. whereby: nan remains 16.38 g of a bluish black solid which is osmlili. at ÉUOO. [3-S] dihydroxyanthraquinone dihydrochloride Chloraniloxidation of 17.86 g of the product of Example 14 by the procedure of Example 15 gives (without recrystallization) 21.34 g blue-black solid subs-rank, m.p. 2o3-2o5 °. 1,1L-bis [2- (2-methylaminoethylaminolethylarino] -5,5-dihydroxyanthraquinone tetrahydrochloride The product of Example 19 (11.7 g) is oxidized with chloranil by the procedure of Example 16 to give 18.03 g of a bluish black solid, mp 190-203 ". 7807987-" 8 w.) k) Example? (1β-bisfZ-1'Z-hydroxyethylamino) ethylamino] -5,5S-dihyciroxyanthraquinone In a modification of the synthesis of Example 13 is the solution used .rnc-rl -i lÛC nl ethanol. The ivloder liquor from the leukoproduct is steeled for two weeks in a flask uL-an stopper, after which the oxyclated procluist separates. It is collected and washed in ethanol and then recrystallized from ethanol to give blue-black crystals. mp. 175-177 °.

Exerngiel 25-Lc-tsl-: ol, fi-bšsfß- (Z-hydroxyethylamino: 101-1-propylnirlo] -5, S-dihydroxyanthraquinone The procedure of Example 14 is used with a solution of 10.18 g of 2-13-arnitine. The resulting solution is filtered, and the filtrate is diluted with 300 ml of ether, the product precipitating as a sticky substance. After decantation of the lower solution, the sticky acid is caused to crystallize by agitation with 100 ml tetrahydrofuran.

'Fxšíttrwisig with ethanol gives 12.56 g of greenish-black solid, m.p. 101-1040.

Example 1, # - BisÛ- (Z-hydroxyethylamino fi-1-propylamino] -5,5-dihydroxyanthraquinone dihydromylsil - Oxidation of 9.95 g of leuko-1,4-bis [3- (2-hydroxyethylamino) propylamino ] ~, Sëdinydroxyanthraquinone with chloranil as in Example 15 gives 11.70 g of a blue solid which does not melt at 3500. es xesripel 27 _ 'Leuko-í, ll-lyis fl- (B-hydroxy-1-propylarnin fl ethylamino] -5 .8-Dihydroxyanthraquinone The procedure of Example 1.4 is repeated with 14.18 g of N- (3-hydroxypropyl) -ethylleridiarine in 100 ml of ethanol to give 14.63 g of red-brown crystals, mp 58-50 ° C. -bis [2- [3-hydroxy-1-propylaminoketylamino] -5β-dihydroxyanthraquinone dinhydrochloride 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, m.p. 210-2169 Example 29 Leuko-1A-bisQ- (Z-hydroxy-1-propylaminoctylamine) -α, š-dihydroxyanthraquinorole Aled 14.18 g of 1αZ-arninoethyllainino) -2-propanol in 100 ml of ethanol gives the procedure of Example 14 17.61 g of green-black crystals, mp 50-600. 7807987-8 73 .mu.l of zifiwal) Eu-biJLfZ- (β-hydroxy-1-propylaminoketylazarxine] -5,5-dihydroxyanthraquinone-dihydrolalophosphate A filtered solution of 14.04 g of leuko-1,11-bis [2- (2-hydroxy-1 propyl-phaxnarioletyflantine fl-1,6-dihydroxyanthraquinone in 215 ml of Z-methoxyethanol is oxidized: 7.65 g of chloranil by the procedure of Example 15 to give 16.75 g of a purified solid, m.p. 177-1850. fås-.L-.fizetil i L. <= uko-l_.1 + «bis ['2- [Z- (2-hydroxyethylamino) ethylarrlino] ethylartiinc fl- iß-dihydroxy- êf-ilgtki fi f-f- l-'iïr The proportion used in Example 14 was used in a solution of 17.67 g of 2- [2- (2-an-within; 'Liminoxytylarinojetanol | 100 ml of methanix) gives a solution which is filtered and then diluted with 300 ml of ether to give a sticky substance. precipitates, when allowed to stand overnight. The curing is completed by thorough insertion of the solid into the solvent. The solid is collected and washed with ether to give 16,82 g of a green-black charge substance. This solid remains granular. when stored at -25 DEG C., the solids form into a solid cake when stored at 250 DEG C. Gel 3 3 _ 1, 1-bis [2- [2- (Z-hydroxyethylamino] ethylamino] ethylamino] ~ 5,8-dihydroxyanthraquinone- Làlíëhxslrßßle Chloraniloxidation of 12 g of the product of Example 31 by the methylene of Example 15 including three additional washes of the solid with methanol gives 12.46 g of ast product. [11 - bis fi- (Z, B-dihydroxypropylamino) ethylamino] -5,8-dihydroxyanthraquinone-E1l1d._f ° _l \ i9Li_d_ By the procedure of Example 14 gives a solution of 16,10g of 3- (2-aminoethylaritino) -1 2-propanediol [A. R. Surrey, C. M. Suter, and J. S. Buck, J.

Arn. Chern. Soc., 73, IIIO 2 - (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 10 hours 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-methoxyethane is oxidized with 10.01 g of chloroanil by the method of Example 5.

The product is then further washed with ethanol to give 1.55g of a bluish black charge substance, amp. 1910930. 7807987-8 74 âugeugel 3-1 V 1,4-bis [2- Z- (1-morpholinolethylaminojetylamino] -5,8-dihydroxyanthraquinone tetrahydrochloride A solution of 20.80 g of N- (rnorpholinoethyldethylenediamine in 100 ml of ethanol is used in the procedure of Example 14 to give a solution which is filtered and: 1 ml of ether, precipitating a sticky substance, decanting the supernatant solution, dissolving the sticky substance in 175 ml of Z-methoxyethanol and oxidizing: 5,29 g chloranil by the method of Example 15 to give 17.7 g of a dark blue solid.

Leuko-1H-bisQ- (acetaridolethylamino] -5,8-dihydroxyanthraquinone A solution of 12.26 g of N-acetylethylenediamine in 100 ml of ethanol in the procedure of Example 14 gives 15.27 g of a dark red-brown solid, mp 1,250 l. β-bisβ- (acetamido) ethylamino-S, S-dihydrexiantraquinone A suspension of 11,95 g of leuko-1,1L-bis [2- (acetamido) -ethylamino] -5,8-dihydroxyanthraquinone is oxidized with 6.76 g of chloranil for 61 hours using the method of Example 15 to give a very acidic hydrochloric acid salt, which is transferred to the free base by four washes with water, crystallization from 100 ml of dimethyl sulphoxide (boiling for only 2 minutes and no attempt at hot filtration) and then washing with dimethyl sulphoxide and with ethanol gives 7.76 g of blue-black substance: amp. 273-2719.

Example i? A 1 ', 11-bis-N-N- (Z-hydroxyethyl) trifluoroacetamido] -ethylamino] -lase-dihydroxy-ethanoic acid - A suspension of 1,50 g, 1 + -bis [2- (2-hydroxyethylamino) ethylamino] - 5 8-Dihydroxyanthraquinone in 75 ml of ethyl tritluoroacetate and 75 ml of methanol are 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 2.1 g of blue-black solid, m.p. 1620

Example 1 is 1,4-bis [2-amino-Z-carboxyethylamine-ZS-dihydroxyanthraquinone. 3/4 l-1Cl To a solution of 6.23 g of dl-10, β-diaminopropionic acid in 30 ml of hot water is added 1.078 g of lithium hydroxide and 60 ml of dimethylsulioxide. The system is purged with nitrogen and 4.12 g of leul while stirring. the landing is stirred and tipped with an oil bath at 500, first for 15 hours under nitrogen and then for 1 hour, while the starting material is oxidized; by bubbling in an air tube. Thin layer chromatography on silica gel: down .netanol / water / concentrated ammonia (25/5/1 by volume) shows that all product flasks are blue when oxidatlonezl is complete. After the mixture has cooled, the solid is removed by filtration and washed once. Addition of 400 ml of methanol to the filtrates precipitates a solid which is collected and washed with methanol Further washing with a total of 13 ml of 0,01N aqueous acetic acid dissolves practically: 11 l of solids. 3 ml of concentrated hydrochloric acid to the acetic acid The filtrate gives a bluish-black solid, which is washed with acetone to give 0.24 g of the product [.lëe fl zl-äsij? I _._ e_x_l_! ¿'_¿ _-_ ï>,' - (1- (3-Hydroxyanthraquinolothylamino) -5,8-dihydroxyanthraquinone (N) (Z-methoxyethylethethylenediarnix (LIS-PS 3,454.61 + 0) reacts in the procedure of Example 14 to give the title compound. šzsmsl _40 l Jl-tli JZ- [dltß -hydroxyethylamino] ethylaminoj »5, S-dihydroxyanthraclnone-dihy hydrochloride Chlorine anoxidation of 10.77 g of the product of Example 14 by the method of Exemgat-l lieger ll, 6¿l g of a dark blue solid, m.p. 2160. 7807987-8 76 Example 4 Preparation of 50 mg tablets Per tablet Per 10,000 tablets 0.050 g / l: -bis (3-aminopropylamino) -α-dihydroxyanthraquinone 500 g 0.030 g Lactose son g 0.010 g Niais starch (for mix) 100 g Q, 0_08_g. Vlajs starch (for pasta) _l5_g anus g 1475 g gligäg Ntagnesium stearate (l 96) ___1_5__g 0,150 g ~ '' V 1-490g IJß-bis (3 ~ aminopropylamino) -Sß-dihydroxyantraquinone The corn starch (for pasta) 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 is then passed through a No. 8 hand screen and dried at 490. The dry granules are then passed through a No. 16 screen.

The mixture is lubricated with 96 g of magnesium stearate and compressed into tablets in a suitable tableting machine.

* Preparation of oral suspension ingredient Quantity _ - Leuko-1β-bisU-aminopropylamino) -5,8--dihydroxyanthraquinone 500 mg Sorbitol solution (7_0 96 NF) 40 ml Sodium berisoate _ 150 mg Saccharin, 10 mg Red dye: 50 ml _ Cherry aroma _ '50 ml Distilled water qs. A.D. in 100 ml of the sorbitol solution is added to 40 ml of distilled water and the leuko-1β-bis- (B-arininopropylafraxind-5, β-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 leuko-β1- I bis (3-aminopropylamino) -5,8-dihydroxyanthraquinone 7807987-8 77 F1 ° §: 9e1__4 3 Release of parenteral solution In a solution of 700 ml of propylene glycol and 200 ml of water for injection sus-i-is-uis IÉ0,0 gl, l + -bis [3 (dimethylamino) propylamine] -ZS-dihydroxyanthracionionurilyl diol p-1-xphosphine to 5.5 with hydrochloric acid, and the volume is brought to 1000 ml with water The formulation is sterilized, filled into 5.0 ml ampoules, each containing 2.0 ml (equivalent to 40 mg of medicinal product) and sealed under nitrogen.

L-.Lsf fl eeiiß Frairstiilirung: tv l, / + ~ bis (2-dimethylaminoethylamino) -anthraquinone A mixture of 3 g quinizarine, 10 g N, N, -dimethylethylenediamine and 17.5 ml water is stirred and heated under reflux in 3 L / 2 hours. The mixture is cooled, and the solid is collected and washed with water to give 2.96 g of the desired product as a dark blue solid, m.p. Alternatively, the above product can be prepared by stirring and heating under reflux for 5 hours from a mixture of 2.4 g of quinizarine, 2.82 g of NN-dimethylethylenediamine and 9 ml of N, N, N ', N'- tetrarethylethylenediamine. The product is recovered as described above.

Example 4_5 I Preparation of 1,9,9-bis (2-morpholinoethylamino) -anthraquinone A 9.60 g portion of quinizarine, 46.90 g of N- (Z-aminoethyl morpholine and 56 ml of water are reacted as described in Example 1 to give 9 92 g of the desired product are a blue-black solid, mp 158-1590.

Example F in Preparation of 1,1'-bis (fi-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 quinizarine is stirred and heated under refill for 15 hours. The resulting solution is evaporated to dryness, and a chloroform solution of the residue is filtered through 300 Å of alumina. The blue filtrate is chromatographed on silica gel in a Nylon film column, developing with a chloroorm-methanol mixture (6: 1). The larger blue band is cut out and then eluted with a chloroform / methanol / triethylamine mixture I (6: 2: 1). The eluate is evaporated. The residue is crystallized from hexane and washed with petrolc crucibles to give 1.1 .mu.g of the desired product as blue-black plates, m.p. 1090. .7807987-8 78 Éifíernigel 47 Preparation of Leuco-1,4-bis (2-aminoethylamino) -anthraquinone A 125 ml portion of ethylenediamine is deaerated by bubbling nitrogen for 1 minute. A 1.2 g portion of leukokinizarine is added, and the mixture is> 1i-i1cf, .- i :; while stirring under nitrogen at 500 for 1 hour. the landing is allowed to cool. The solid is collected and washed successively with ethyl acetate, acetonitrile and petroleum ether to give 8.07 g of the desired product as a green-gold crystalline crystalline melt (162-1650 ml) at a rate of 90 g per minute. Example 48 IF Preparation of 1,1 + -bis (2-aminoethylaminol-anthraquinone Air is bubbled into a mixture of 7.0 g of leuko-1,1 + -bis (2-aminoethylamino) anthraquinone and 87.5- ml The mixture is diluted with 87.5 ml of acetonitrile, allowed to cool, and the solid is collected and washed with acetonitrile to give 5.10 g of the desired product as a dark blue solid, m.p. 1710

Example 49 Preparation of 1,4-bis [2-methylamino) ethylamino] -anthraquinone A mixture of 2.4 g of leukokinizarin and 25 g of deaerated N-methylethylenediarnine is heated at 500 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 crude solid, which is recrystallized twice from carbon tetrachloride to give 1.92 g of the desired product as dark blue crystals, m.p. 139 7807987-3 79 Inventive preparation of leuko-1,1-bis (2-dimethylamirioethylaminoanthraquinone A solution of 26.41 g of N, N-dimethylethylenediamine in 75 ml of N, N, N ', N'-te * Ramethylethylenediamine is deaerated by bubbling nitrogen for 15 minutes.

Then 2.1 g of leukokinizarin are added and the resulting mixture is stirred under nitrogen while heating at IMS-SCO for 2 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 you get l2.52g dark green crystals, m.p. 1561-1570; or on a microscope with a hot slide, m.p. 153-1540.

Example 51.

Preparation of 50 mg tablets times tablet Ber 10,000 tablets in 0.050 g, 2-bis [2- (methylamino) -ethylarinoinoanthraquinone 500 g 0.0S0 f: Lactose ~ - 800 g 0.010 g: maize starch (for fm) 100 g Q fi low Maize starch (for pasta) lig 0, lli8 y 1475 g Magnesium stearzite ((1 96) __l_§_g 0.1 so g 11:90 gl, li-bis [2- (methylamino) ethylamineq] anthraquinone, lactose and maize starch (for The corn starch (for pasta) 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 hand sieve No. 5 and dried at 490. The dry granules are then passed through a sieve No. 16. The mixture is lubricated with 96 g of magnesium stearate and compressed into tablets in a suitable tableting machine 7807987-8 80 Example 52 Preparation of oral suspension ingredient '- Måügd Leuko- 1,1-bis (2-aminoethylamino) anthraquinone 500 mg _s <> r_biroi-iosin ng_ (70 9 :. N.F.) _ '40 m1 Sodium benzoate 150 mg Saccharin 10 mg I Red nutrient I 10 mg Cherry aroma 50 mg Distilled water q.s. A.D. u - 100 ml of the sorbitol solution is added to 40 ml of distilled water, and leuko-IJL-bisQ-arninoethylamino) anthraquinone is suspended therein. The saccharin, sodium benzoate, flavor and color are added and dissolved. Adjust the volume to 100 ml with distilled water. Each ml of syrup contains 5 mg of leuko-1,1-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 1,1-li-bis (li-aminobutylaminoanthraquinone are suspended with stirring.

After completion of the suspension, the arrow value 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 (equivalent to 40 mg of drug) - and sealed under nitrogen.

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

Example 55 'Preparation of leukol-1,1-bis (2-dimethylaminopropylamino) anthraquinone The use of 15.32 g of Z-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 '- Leuko-1,1'-bis [2- (2-methylaminoethylamino) ethylamino] anthraquinone A solution of 114.10 g (0.2 mol) of 1-methyl-diethylenetriamine in 100 ml of ethanol is deaerated through. bubbling nitrogen through it for 15 minutes, after which 9.69 g (0.0l + mol) of leukokinizarin is added gradually with stirring. 7807987-8 81 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 to give the title compound as a dark green solid.

Example 57 Preparation of leuco-1,1kbisQ-methylaminoethylaminolanthraquinone 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 leukokinizarin. The mixture is stirred and heated at 500 under nitrogen for 1 hour and then allowed to cool. The solid is collected, washed with toluene and then with etc. to give 9.0 g of a green-black solid, m.p. 105-1090. Example 53 1,1,4-Tris (aminoethyl) amino] -8-hydroxyanthraquinone A 10 ml portion of ethylenediamine is deaerated by bubbling nitrogen through it for 15 minutes. A 10.97 g portion of leuko-1,1,5,8,8-tetrahydroxyanthraquinone is added, and. the mixture is stirred under nitrogen at 50-510 for 1 hour. ßlanclningori 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 [bis-bis-1-dimethylaminoethyl] amino] -5,6-dihydroxyanthraquinone A 30 g portion of zinc is added portionwise to a boiling mixture of 1.51 glacial acetic acid and 40 ml of water containing 27.2 g of 1,5,5 g. tetrahydroxyanthraquinone. The mixture is boiled for 30 minutes, filtered and the filtrate is cooled. The orange-brown crystals which form are collected to give 19.7 g of leuko-1,4,5,6-tetrahydroxyanthraquinone, m.p. 255-257 °.

A 7.9 g portion of dimethylaminoethylamine in 75 ml of tetramethylethylenediamine is heated to 80-1000 and deaerated with nitrogen. The mixture is treated portionwise with 8.22 g of leuko-1,1 +, 5,6-tetrahydroxyanthraquinone with stirring and under nitrogen and heated at 90-100 ° for 6 hours while the mixture is filtered while hot. The filtrate is cooled to 44 °, treated with ether and gives a dark blue gum after standing for 48 hours. The supernatant is decanted, treated with twice its volume of ether and cooled to give a blue gum.

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

Example 6 1 1,4-Bis (3-aminopropylamino) -5,8-dihydroxyanthraquinone A suspension of 10.0 g of leuko-1HL, 5,5-tetrahydroxyanthraquinone in 120 ml of derivative 1J-diaminopropane is stirred and heated at 450 DEG. under nitrogen in l-tin and then for - l0 minutes, while air is bubbled- in the suspension.

The mixture is then evaporated to dryness and the residue is extracted with 650 ml of ethanol in a Soxhle 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 to give the desired product as 9.57 g of a blue solid, m.p. 115-1300. Example 6_2 Preparation of 50 ing tablets Per tablet f Per 10,000 tablets 0.050 g, lt-bis (3-aminopropylamino) -5,5-dihydroxyanthraquinone 500 g 0.080 g Lactose 800 g 0.010 g Maize starch (for mix) 100 g Vlajs starch (for pasta) Own 0.148 g 1475 g fl low .Vlagnesium stearate (11%) _Q_g 0.150 g 1490 g lJß-bis-aminopropylamino) -5,8-dihydroxyanthraquinone, lactose and corn starch (for mix) are mixed together. The corn starch (for pasta) is suspended in 600 ml of water and then heated with stirring to form a paste.

This paste is then used to granulate the mixed powders. Additional water is used if required. 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 96 g of magnesium stearate and compressed into tablets in a suitable tabletting machine. 7807987-8 83 Example Gel 6__3 Preparation of oral suspension 'Lïïsä Leuko-1,11-bis (β-aminopropylamino--5,8-dihydroxyarthraquinone 500 mg Sorbitol solution (70% NF) # 0 ml Sodium iberisoate 150 mg Saccharin _' 10 mg of light dye 50 mg Cherry broth 50 ml of distilled water and, to date, 100 ml of the sorbitol solution are added to 40 ml of distilled water and leuco-1β-bislB-aminopropylamino) -i-dihydroxyanthraquinone is suspended therein. The saccharin, sodium benzoate, flavor and color are added and dissolved. The volume is adjusted to 100 ml with distilled water.- Each ml of syrup contains 5 mg of leuko-11β-bis (β-aminopropylamino) -Sβ-dihydroxyanthraquinone.

Example 64 Preparation of parenteral solution In a solution of 700 ml of propylene glycol and 200 ml of water for injection, 20.0 g of 1β-bisB-aminopropylamino) -5,8-dihydroxyanthraquinone dihydrochloride are suspended with stirring. After completion of the suspension, 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 (equivalent to 40 mg of drug) and sealed under nitrogen. In Example 65 l, 1 + -bis ['* - (2-hydroxyethylamino) ethylamino] -5, S -dihydroxyanthraquinone disuccinate salt A mixture of 222 mg of 1,1-bis [Z- (Z-hydroxyethylamino) ethylamino] -5,8-dihydroxyanthral under reflux for 30 minutes to give the title compound. 2- (3-hydroxypropylaminoctylamino] -5,5-dihydroxyanthraquinone dimalate - a mixture of 228 mg of 1,4-bis [2- (B-hydroxypropylamino) ethylamine] -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 Gel 67 1β-bis- (Z-hydroxypropylaminoctylamines) 5,3-dihydroxyanthraquinone dilactate salt.

A mixture of 228 mg of 1A-bis- (Z-hydroxypropylamino) ethylamino] -1S-dihydroxyanthraquinone, 20 mg of 80% of DL-lactic acid and 10 ml of ethanol is charged to a steam bath for 10 minutes, cooled, treated with 50 ml 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.