CA1105459A - Dihydrobenzanthracene derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
This disclosure describes benzanthracene-5,12(or 7,12)-dicarboxaldehyde-bis-hydrazones and the 5,12(or 7,12)--dihydrobenzanthracene-5,12(or 7,12)-dicarboxaldehyde-bis-hy-drazones useful as antibacterial agents, for inhibiting the growth of transplanted mouse tumors, and for inducing the re-gression and/or pallation of leukemia and related cancers.

Description

Z 1 , J~ B

BRIEF SUMMARY OF T~IE INVENTION
This invention relates to new organic compounds and, more particularly, is concerned with novel benz[a~anthracene--7,12-bis-carbonyl-hydrazones (I), benz~b]~nthracene-5,12- .
-bis-carbonyl-hydra20nes tII), 7,12-dihydrobenz E a]anthracene--7,12-bis-carbonyl-hydrazones (III), ànd 5,12~dihydrobenz~b]-anthracene-5,12-bis-carbonyl-hydrazones tIV) which may be re-presented by the followin~ structural formulae:

~ CH=N-NH-B

(I) CH=N-NH-B

CH-N-NH-B

(II) CH=N-NH-B

(III) H CH=N-NH--B

H CH=N-NH-B

(IV) H CH-N-NH-B

wherein B is a monovalent moiety of the formula:
N - (CH2) n ~ C ~ N-R
wherein n is 2, 3, 4 or 5 and R is hydrogen or alkyl having up to 4 ca-rbon`atoms.
The hydrazino substituents pendant from both the ~ro~
matic form and the dihydro form of the benzanthracene-5,12-(or 7,12)-bls-carbonyl nuclei may be the same or different and may be in the syn or a _ forms. ~dditionally, in the case of the dihydro form, the entire units -C~l=N~NH-B at the 5,12--positions or the 7,12-positions may be èither cis (both ex-tending out from the same face of the anthracene nucleus) or trans ~extending out from the opposite faces of the anthracene nucleus).
A preferred embodiment of the present invention con-sists o~ compounds which may be represented by the following structural formulae:

2) n CH=N- NH~ C - NH
A ~ (V) N ~CH2)n CH=N -NH - C - NH

N- ~(CH2)n H CH=N -NH- C - NH

{ ~ N - (C112)n H CH=N- NH -C - N~l :2 wherein A is a divalent moiety selected from the grouP consisting of those of the formulae:

and n is as hereinabove defined.
In one aspect, the present invention provides a process for the preparation of a compound of the following formulae:

CH=N-NH-B

(I) CH=N-N-NH-B

or ~H=N=NH-B

(II) H=N-NH-B

01`

(III) H CH=N-NH-B

or H CH=N-NH-B
~,~1 H CH=N-NH-B (IV) ,~
i wherein n is 2, 3~ 4 or 5 and R is hydrogen or alkyl having from 1 to 4 carbon atoms, and pharmaceutically acceptable acid addition and quaternary amllonium salts thereof, which comprises (a) where a compound of the formula I is required, reacting a compound of the formula CHO

CHO
with a con~ound of the formula H2N-NH-B, wherein B is a monovalent moiety of the formula N-(GH2)n - C -N - R
wherein n and R are as defined above, or (b) where a con,pound of the formula II is required, reacting a conpound of the formula CHO

CHO
with a compound of the formula H2N-NH-B, wherein B is as defined above, or (c) where a compound of the fornlula III is required, .reacting a compound of the formula ~:`

H GHO
with a compound of the forrnula H2N-NH-B, wherein B is as def.ined above, or ~ ~1 - 3a -., .~ .~

(d) where a compound of the formula IV is required, reacting a cornpound of the formula H CHO

H CHO

with a compound of the formula H2N-NI-I-B, wherein B is as defined above, and where required, converting the resulting product to the pharmaceutically accept-able acid addition or quaternary a~monium salts thereof.

DEr~ILED DESCRI~TION O~ THE IN~TION

The novel compounds of the present invention are obtainable as yellow crystalline materials having characteristic melting points and adsorption spectra and which may be purified by recrystc~llization from common organic solvents such as lower alkanols, dimethylformamide, tetrahydro-furan, methyl l butyl ketone, and the like.
The organic bases of this invention form non-toxic acid-addition and quaternary ammonium salts with a variety of pharmacologically acceptable organic and inorganic salt-forming reagents. Thus, acid-addition salts, formed by admixture of the organic ~ree base with one or more equivalents of an acid, suitably in a neutral solvent, are formed with such acids as sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric~ lactic, ~alic, succinic, tartaric, acetic, benzoic, gluconic, ascorbic, and the like.
Quate~lary c~monium salts may be fo~med by reaction of the free bases with one or more equivalents of a variety of organic esters of sulfuric, hydrohalic and aromatic sulfonic acids. The organic reagents employed for quate m ary ammonium salt formation are preferably lower aIkyl halides. However, other organic reagents are suitable for quatem ary a~rmonium salt formation, and may be - 3b -selected from among a diverse class of compounds including benzyl chloride, phenethyl chloride, naphthylmethyl chloride, dimethyl sulfate, methyl benzenesulfonate, ethyl toluenesul-fonate, allyl chloride, methallyl bromide and crotyl bromide.
For purposes of this invention the free bases are equivalent to their non-toxic acid-addition and quaternary ammonium salts.
The acid-addition and quaternary a~nonium salts of the organic bases of the present invention are, in general, crystalline solids, relatively soluble in water, methanol and ethanol but relatively insoluble in non-polar organic solven~s such as di-ethyl ether, ben~ene, toluene, and the like.
The novel compounds of the present invention are useful as antimicrobial agents and poss ss antibacterial acti-vity in vitro against a variety of standard laboratory micro-organisms. The antibacterial spectrum in terms of the con-centration required to inhibit the growth of various typical bacteria was determined in a standard manner hy the a~ar-dilu-tion streak-plate technique. A Steers multiple inocula repli-cator was used with incubation at 37C. for 1~ hours in Mueller-Ninton agar. The results for 7,12-bis-(2-imidazolin--2-ylhydrazone)benz[a]anthracene-7,12-dicarboxaldehyde dihy-drochloride, a typical compound o~ this invention, are set forth in Table I as the minimal inhibitory concentration (MIC) in micrograms per milliliter.

_ ~ .

5~5~

~ TABLE I
. . . - _ _ Test Organism MIC
. ,,- _ Staphylococcus aureus, OSU 75-2 16 Staphylococcus aureus, Q 74-11 8 .. . ... _. _ ...
Staphylococcus aureus, St. Paul (NYC 78 1) 8 Enterococcus, SM 77-15 8 ...... . ... . . . ................ , ___ The novel compounds of tha present invention also possess the property of inhibiting the growth of transplanted mouse tumors as established by the following teæts.
Lymphocytic leukemia P388 test The animals u-sed are mice all of one sex, weighing a minimum of 17 g. and all within a 3 gram weight range.
There are 5 or ~ animals per tes~ group. The tumor transplant is ~ intraperitoneal injection of 0.1 ml. or 0.5 ml. of di-lute ascitic fluid containing 106 cells of lymphocytic leu-kemia P388. The test compounds are administered intxaperi-toneally on days one, 5 and 9 ~relative to tumor inoculation) at various doses~ The animals are weighed and survivors are recorded on a re~ular basis for 30 days. The median survival time and the ratio of survival time for treated (T)/control (C) animals are calculated~ The positive con~rol compound is 5--fluorouracil given as a 60 mg./kg. injection. The results of this test with representative compounds of the present inven~
tion appear in Table II below. The criterion for e~icacy is T/C x 100i 125~.

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. . . ~ . . .
~o co ul u~ ~I f~ a~ D Ul O O

------ ~ - ------- ~

~ Lr~ ~ ~ co ~ ~ ~ u~ i`
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u~ ~ ~ ~ ~ ~ ~ o o o O ' ~ ~D r~ ,~ o O o ~ ~D
E~ Cl ~

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ts~ Ln N ~9 Ln N ~ /~
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m,Q Ln u a~
__ . . . _ .,_.__._ _ ._ iLl~b~i9 Melanotic Melanoma B16 . . .
The animals used are C57BC/6 mice, all of the same sex, weighing a minimum of 17 g. and all within a 3 g. weight range. There are normally 10 animals per test group. A one--gram portion of melanotic melanoma B16 tumor is homogenized in 10 ml. of cold balanced salt solution and a 0.5 ml. aliquot of the homogenate is implanted intraperitoneally into each of the test mice. The test compounds are administered intraperi-toneally on days one through ~ (relative to tumor inoculation) at various doses~ The animals are weighed and survivors are recorded on a regular basis for 60 days. The median survival time and the ratio of survival time for treated (T)/control ~C) animals are calculated. The positive control compound i5 5--1uorouracil given as a 20 mg./kg. injection. The results of this test with a representative compound of the present in-~ention appear in Table III below. The criterion for effi-cacy is T/C x 100~ 125%.

o~
~:
~ cou~ In x c) o~ oo u~ ~ Ln c~
--- ~
Lr~ o o ~ Lr) rl ~ ~
~1 .--i O 1~ N
~q __.

a) ~ u~
In~ . q .
,~ ~ O C~ o _. .
~ ; ~ `

O N
C ) .

~Q~
O ~ rl N-I h . :~
..
~1 U7 ~ ~ ~
. ~ O I
_ . _ . ~__ The novel compounds of formulae (I-IV) and their pharrnacologically acceptable acid-addition and quaternary ammonium ~alts would be expected to show activity against a broad range of cancer diseases, and especially blood cancer S diseases such as leukemia, in st~ndard test animals at doses substantially below toxic levels. The modes contemplated for administration are essentially parenteral and intraperitoneal.
Solutions of the active ingredient as a free base or salt can be prepared in water or in water suitably mixed with, for example, surfactants such as hydroxypropylcellulose. Disper-sions can also be prepared in glycerol, liquid polyeth~lene glycols, and mixtures thereof and in oils~ Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganismsO
The pharmaceutical compositions can be in forms suit-able for in~ectable use, which forms include sterile aqueous solutions or dispersions and sterile powders or the extempor-anous preparation of sterile injectable solutions or disper-sions. In all cases the form must be sterile and must be fluid to the extent that easy syrinyab:ility exists. It must be stable under the conditions of manufacture and storaye and must be preserved against the conkaminating action of micro-or~anisms such as bacteria and fungiu The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oilsù The propex fluidity can be main-tained, for example, by the use of a coatiny such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention o~ the action of microorganisms can be brought about by various antibacterial and antifungal agents, for ex~nple, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride.
Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delay-ing absorption, for example, aluminum monostearate and gelat.in.
Sterile injectable solutions are prepared by incor-porating the active ingredient or ingredients in the required amount in the appropriate solvent with various of the othe.r ingredients enumerated abover as requi.red, followed by fil-tered sterilization. Generally, dispersions are prepared by incorporating the various sterilized act.ive ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
In the case of sterile powders for the preparation of sterile injectable solutions, the preferred.methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredi.ent plus any additional desired ingredient from a previously sterile-filtered solution thereof.
As used herein, "pharmaceutically acceptable car-rier" includes any and all solvents, dispersion media, coat-ings, antibacterial and antifungal agents, isotonic and ab-sorption delaying agents and the like. ~he use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatable with the active ingredi.ent, its use in the present compositions is contemplated. Supplementary active in~redients can also be incorporated into -the inventive com-positions.
. It is especially advantageous to formulate composi-tions in dosage unit form for ease of administration and uni-formity of dosage. Dosage unit form as used in the specifica-tion and claims herein refers ~o physically discrete units suited as unitary dosages for the animal subjects to be treated, each unit containing a predetermined quantity of ac-tive material calculated to produc~ the desired therapeu-tic effect in association with the required pharmaceutical carrier.
The specification for the novel dosage unit forms of the in-vention axe dictated by and directly dependent Oll (a) the unique characteristi~s of the active material and the particu~
lar therapeutic effect to be achieved, and ~b) the limitations inherent in the art of compounding such an active material Eor the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as disclosed in .
detail in this specification.
The dosage of the principal active ingredient for the treatment of the indicatea conditions depends upon the age, weight and condition of the subject being treated; the particular condition and its se~erity; the particular ~orm of the active ingredient and the route of administration. A
daily dose o~ from about one to about 100 mg./kg. of body weight given singly or in divided doses of up to 5 times a day embraces the effective range for the treatment of most conditions for which the novel compounds are effective and substantially non-toxic. For a 75-kg. suhjectt this trans-lates into between about 75 and about 7500 mg./day. IE the dosage is divided, for example, into 3 individual dosages, these will range from about 25 to about 2500 mg. of the active ingredient. The preferred range is from 2 to about 50 mg./~g.
o bo~y weight/day with about 2 to about 30 mg./kg./day being more preferred.
The principal active ingredient is compounded for S convenient and ef~ective administration in effective amounts with a suitable pharmaceutical~y-acceptable carrier in dosage unit form as hereinbelow disclosed. A unit dosage form can, for example, contain the principal active ingredient in amotlnts r~n~in~ from about 0~1 to ahout 400 mg., with from about one to about 30 mg. being pre~erred. Expressed in proportions, the active ingredient is generally present in from about 0.1 to about 400 mg./ml. of carrier. In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of ad-ministration of the said ingredients~
Regression and palliation of cancers are attained, for example, using intraperitoneal administra~ion. A single intravenous dosage or repeated daily dosages can be adminis-tered. Daily dosages up to about 5 or 10 days are often suf-ficient. It is also possible to dispense one daily closage or one dose on alternate or less frequent days. As can be seen from the dosage regimens, the amount of principal active ingredient administcred is a sufficient amount to aid regres-sion and palliation of the leukemia or the like, in the ab-sence of excessive deleterious side effects of a cytotoxic nature to the hosts harboring the cancer. As used herein, ,cancer means blood malignancies such as leukemia~ as well as other solid and non-solid malignanies such as the melano-carcinomas, lung carcinomas and mammary t,umoxsO By regression and palliatlon is meant arresting or retarding the growth of , - l3 ~

the tumor or other manifestation of the disease compared to the course of the disease in the absence of treatment.
The aromatic benz~nthracene derivatives of the pre-sent invention may be readily prepared as set forth in the following reaction scheme:
o A { ~ ~VII) I (VIII) 1 . ol CH2Cl CH-N(CH3)2 - A ~ ~ { ~ ~ ~J

CH2Cl (IX) / CH-N~CH3)2 (X) - 1 ~//
CH=N-NH~B
CHO

20 A ~ A ~ ~ ~

CHO (XI) CE~N-NII-B (Y, II) wherein A and B are as hereinbefore defined. In accordance with the above reaction scheme, the benzanthracene (VII) is treated with paraformaldehyde at the reflux temperature for .2-6 hours in a solution of dioxane and c~oncO hydrochloric acid which is satur~ted with gaseous HCl to provide the b ---(chloromethyl)benzanthracene (IX). Th.is bis~(chlorometh-yl)benzanthracene, suspended in dry dimethyl sulfoxide under ~s~

nitro~en at room temperature, is treated with ~od.~um in eth~
anol-to provide the intermediate benzanthracene-dicarboxalde-hyde (XI). Alternatively, the benzanthraquinone (VIII) is dis-solved in tetrahydrofuran and treated with an anhydrous di-ethyl ether-hexane solution of ~t-lithio-~-(N,N~dimethyl-amino)methyl]diphenylphosphine oxide at room temperature to provide the bls-enamine (X) which, without isolation, is hy-drolyzed by the addition of a 90% formic acid solution to give the intermediate benzanthracene-dicarboxaldehyde ~XI). Treat-ment of (XI) with a hydrazine derivative of the formula H2N-NH-B then prov.ides the aromatic benzanthracene deriva^
tives (I, II) of the present invention~ This reaction is best carried out in a lower alkanol as solvent in the presence of an acid such as hydrochloric or acetic or glacial acetic acid may be used as the sole solvent) usually at the reflux temperature of the reaction mixture.
The dihydrobenzanthracene derivatives of the presellt invention may be readily prepared as set forth i.n the follo~-ing reaction scheme:

5~ ~o~
/ C=O
_o~

{ ~ ~ - > A { ~ (XII) (VII) H

_ - ~ / CH-OI-3 ~ CH-OH

{ ~ ~ - A { ~ ~ ~

H ' ~ CHO ~XIII) (XIV) ~ \
H CH~N~NH-B

{ , ~ { _ ~ ~ (III, IV) H CH=N-NH-B
CI~O
(XI) \ CH=~I-NH-B

{ ~ (I, II~
CH=N-NH-B
wherein A and B are as hereinbefore defined. In accordance with the above reaction scheme, the benzanthracene ~VII) is heated with excess vinylene carbonate at reflux temperature ~5 under nitrogen for about 10-24 hours. Excess vinylene carbon-ate is removed by vacuum distillation~ The residua is taken .up in methylene chloride, clarified with charcoal, and pre-cipitated with methanol to provide both the s~n and anti forms of the cis-dihydro-ethanobenzanthracene cyclic carbonate (XII).
~lydrolysis of the cyclic carbonate (XII) with aqueous-ethano lic potassium hydro~ide at 70-75C. for ahout 1-4 hours pro-- 16 ~

5~5~

duces both the syn and anti forms of the cis-dihydro-~thano~
benzanthracene diol (XIII) which in turn is treated with lead tetraaceta~e in glacial acetic acid at 20~-35C. for about 10-30 minutes to give the dihydrobenzanthracene-dicarboxalde-hyde (XIV). Alternatively, the diol (XIII) may be suspended in an aqueous solution of either sodium or potassium periodate and stirred at room t~mperature for 24 hours to provide the dicarboxaldehyde (XIV). Either procedure provides the CiS--isomer of the dicarboxaldehyde (XIV) which may be readily converted to the trans ~orm by standard procedures~ Oxida-tion of the dihydrobenzanthracene-dicarboxald~hyde (XIV~ with either ferric chloride in methanol or lead tetraacetate in glacial acetic acid, both at 20-35C. for 1-5 hours, then ~rovides the benzanthracene-dicarboxaldehyde lXI). Treatmen~
of XI and ~IV with a hydrazine derivative of the formula H2N-NE~-~ then provides the novel compounds (I, II, III and IV) of the present invention. This reaction is best carried out in ethanol or n-propanol at the reflux temperature for 1-4 hours in the presence of an acid such as hydrochloric acid or acetic acid.
The invention will b~ described in greater detail in conjunction with the ~ollowing specific examples.
Example 1 Bis(2-imidazolin-2-ylhy~r~ _e ~ dro benz[a]anthra-cene dicarboxaldehyde A 1.43 g. portion of 7,12-dihydro-benzLa~anthracene--7,12-dicarboxaldehyde [Neuman & Din, J~ Org. Chem. 36, 966 (1971)] is dissolved in 100 ml. of boiling n-propanol. This solution is treated with 1.73 g. of 2~hydrazinoimidazoline dihydrochloride and the boiling is continued for 3 hours. The ~ 17 -mixture is clarified b~ filtering while hot. The cooled fil-trate produces an orange solid which is removed by filtration, washing with n-propanol. The combined filtrate and n-propanol washings is concentrated to 1/2 its volume, diluted to 200 ml .
with water and basified with saturated aqueous sodium bicar-bonate solution. The resulting gummy solid hardens and is then washed with water, collected by filtration, taken up in methanol and precipitated with water, giving the desired product as the base, m~p~ 190-195C. This base is converted to its dihydro--chloride salt by dissolving in n-propanol, treating with 61 hydrochloric acid in n-propanol and cooling. The dihydrochlor~
ide salt melts at 245-250C
Example 2 5,12-Dihydro-5,12-benz[b]anthracene dicarboxal~ de A mixture of 7.0 g. of benz[b~dnthracene and 26 g.
of vinylene carbonate is heated at reflux under nitrogen for 20 hours. The excess vinylene carbonate is removed by vacuum dis-tillation (57C./9 mm.) and the residue is taken up in 25 ml.
of methylene chloride and filtered~ The filtrate is txeated with twice its volume of methanol and then cooled, producing a tan solid and a mother liquor which is saved. This solid is re-crystallized from 60 ml. of 1,2-dichloromethane, collected by filtration, washed with methanol and saved. The mother liquox (saved above) is concentrated giving a gummy solid which is re~
2S crystallized from a mixture of methylene chloride and methanol giving a gray solid which is combined with the above solid and recrystallized from ethyl acetate with charcoal treatment giv-ing 5,12-dihydro-5,12-ethanobenz[b]anthracene-13,14~diol, cyc-lic carbonate as colorless rods. A mixture of 1.3 g. of the cyc-lic carbonate, 1.05 g. of potassium hydroxide, one ml. of water 5~

and 15 ml. of ethanol is stirred at 60-65C. for 2 hour~. The mixture is dilutecl with 1-2 volumes of water, filtered and the solid is washed with water and dried giving cis-5,12-dihydro~
-5,12-ethanobenz~b]anthracene-13,14-diol as a colorless solid.
To a solution of 2.6 g. of cis-5,12-dihydro-5,12-ethanobenz[b]-anthracene-13,14-diol in 400 ml. df glacial acetic acid at 20C.
is added portionwise 4.4 g. of lead tetraacetate. The reaction is stirred for 45 minutes. The weakly purple colored solid is filtered off, washed with glacial acetic acid and finally water ~0 and dried leaving 1.0 g. (m.p. 170-172C.) of 5,12-dihydro~-5,12- -benz[b]anthracene dicarboxaldehyde.
Example 3 Bis(2-imidazolin-2-ylhydrazone)--5-l2 dihydro-5,12--benz~b]anthracene dicarboxaldehyde dihydrochloride .. . .. _ .. .. . _ A mixture of 0.85 g. of 5,1~-dihydro-~,12-benz[b]-anthracene dicarboxaldehyde and 1.04 g. of 2-hydrazinoimi-dazo-line dihydrochloxide in 60 ml. of n-propanol is boiled and con-centrated to 30 ml. over the course of 2.5 hours. The solution is clarified by filtration and allowed to cool for 48 hours.
The formed dark red crystals of the desired product weic3h 0.12 g. and melt at 290-295C. More product may be ohtained as the free base by diluting the mother liquor with water and basifying with sodium bicarbonate solution~ l'he formed crude product is recrystallizèd from methanol giving 0.15 g. of dark red crystals melting at 230-233C.
Example 4 7,12-Benz[a~anthracene dicarboxaldehyde A mixture of isomers of 7,12-dihydro~ 7,12-benz[a]-anthracene dicarboxaldehyde [Ne~nan & Din, J. Org. Chem. 36, 967 (1971)] is suspended in 75 ml. of glacial acetic acicl, treat--- 19 - , 5~S~I

ed with 6 g. of ferric chloride hexahydrake and stirred at room temperature for 3 hours. The remaining yellow solid is filtered off, washed with acetic acid and water leaving the yellow product, m.p. 197-1~8C.

~xample 5 Bis(2-imidazolin-2-~lhydrazone)-7,12-benz[a]anthracene dicar-b ldehyde dihydrochloride A solution of 0.57 g. of 7,12-benz[a]anthracene dicarboxaldehyde and 0.70 g. of 2-imida~olin-2-ylhyclrazine in 1~ 50 ml. of n-propanol is boiled and concentrated to 20 ml. over the course o 3 hours. After cooling for 3 days, the formed orange powder is filtered off, washed with _-propanol and dried leaving the product, m.p. 240~245C. Dilution of the mother liquor wi~h two folumes of water and basification with sodium bicarbonate solution gives the free base of the product as an orange solid, m.p. 210~-215C.
Ex~mple 6 5,12-Benz[b]anthracene dicarboxaldeh~de A solution of 5 g. of 13~ dihydroxy-5,12-ethallo~

henz[b~anthracene in 110 ml. of ~lacial acetic acid is treated all at once with 15.4 g. of lead tetraacetate and stirred at 30-40~C. for 3 hours. The formed purple solid is filtered, washed once with a~etic acid, finally with water, dried and re-crystallized from methylene chloride-methanol to give purple needles, m.p. 215-217C.
Example 7 Bis(?-imidazolin-2-ylhydrazone) 5,12 benz[~anthracene dicar-.
boxaldehyde dihydrochlaride A suspension of 1.0 g. of 5,12-benz[b~anthracene dicarboxaldehyde and 1.2 g. of 2-imidazolin-2-ylhydrazine in 75 - 20 ~

~5~5'~

.
ml. of ll-propanol is boiled and concentrated to 50 ml. I~he formed solid material is filtered from the hot solution, washed with n-propanol, retaining the purple colored product, m.p.

3~0-325C.

Claims (20)

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

1. A process for the preparation of a compound of the following formulae:

(I) or (II) wherein n is 2, 3, 4 or 5 and R is hydrogen or alkyl having from 1 to 4 carbon atoms and the pharmaceutically acceptable acid addition and quaternary ammonium salts thereof, which comprises reacting a compound of the following formulae:
(a) or with paraformaldehyde in a solution of dioxane and conc.
HCl which is saturated with gaseous HCl to produce the following compound:

or which is suspended in dry dimethyl sulfoxide under nitrogen atmosphere at room temperature and treated with sodium in ethanol to produce a compound of the following formulae:

or which is reacted with a compound of the following formula: H2N-NH-B, wherein B is a monovalent moiety of the formula:

wherein n is 2, 3, 4 or 5 and R is hydrogen or alkyl having up to 4 carbon atoms; or (b) reacting a benzanthraquinone of the following for-mulae:

or dissolved in tetrahydrofuran with an anhydrous diethyl ether hexane solution of [.alpha.-lithio-.alpha.-(N,N-dimethylamino) methyl] diphenylphosphine oxide at room temperature to produce a compound of the following formulae:

or which is hydrolyzed by the addition of 90% formic acid to give a compound of the following formulae:

or which is reacted with a compound of the following formula:
H2N-NH-B, wherein B is a monovalent moiety of the formula:

wherein n is 2, 3, 4 or 5 and R is hydrogen or alkyl having up to 4 carbon atoms.

2. A compound of the following formulae:

(I) or (II) whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

3. A process for the preparation of bis(2-imidazolin-2-ylhydrazone)-7,12-benz[a]anthracene dicarboxaldehyde which comprises reacting 7,12-benz [a] anthracene dicarboxaldehyde with 2-imidazolin-2-ylhydrazine in n-propanol and isolating the thus formed product.

4. Bis(2-imidazolin-2-ylhydrazone -7,12-benz[a] - anthracene dicarboxaldehyde whenever prepared according to the process of claim 3 or by an obvious chemical equivalent thereof.

5. A process for the preparation of bis(2-imidazolin-2-ylhydrazone)-5, 12-benz[b] anthracene dicarboxaldehyde which comprises reacting 5,12-benz[b]
anthracene dicarboxaldehyde with 2-imidazolin-2-ylhydrazine in n-propanol and isolating the thus formed product.

6. Bis(2-imidazolin-2-ylhydrazone)-5,12-benz[b] anthracene dicarbox-aldehyde whenever prepared according to the process of claim 5 or by an obvious chemical equivalent thereof.

7. A process for the preparation of bis(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-ylhydrazone)-7,12-benz[a]-anthracene dicarboxaldehyde which comprises reacting 7-12-benz[a]-anthracene dicarboxaldehyde with 2-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl) hydrazine in n-propanol and isolating the thus formed product.

8. Bis(4,5,6,7-tetrahydro-lH-1,3-diazepin-2-ylhydrazone)-7,12-benz[a]
anthracene dicarboxaldehyde whenever prepared according to the process of claim 7 or by an obvious chemical equivalent thereof.

9. A process for the preparation of bis(l-methyl-1,3,4,5-tetrahydro-1H-pyrimid-2-ylhydrazone-5,12-benz[b] anthracene dicarboxaldehyde which comprises reacting 5,12-benz[b] anthracene dicarboxyaldehyde with 2-(1-methyl-1,3,4,5-tetrahydro-lH-pyrimid-2-yl) hydrazine in n-propanol and isolating the thus formed product.

10. Bis(l-methyl-1,3,4,5-tetrahydro-lH-pyrimid-2-ylhydrazone-5,12-benz[b] anthracene dicarboxaldehyde whenever prepared according to the process of claim 9 or by an obvious chemical equivalent thereof.

11. A process for the preparation of a compound of the following formulae:

(I) or (II) or (III) or;
(IV) wherein n is 2, 3, 4 or 5 and R is hydrogen or alkyl having from 1 to 4 carbon atoms, and pharmaceutically acceptable acid addition and quaternary ammonium salts thereof, which comprises (a) where a compound of the formula I is required, reacting a compound of the formula with a compound of the formula H2N-NH-B, wherein B is a monovalent moiety of the formula wherein n and R are as defined above, or (b) where a compound of the formula II is required, reacting a compound of the formula with a compound of the formula H2N-NH-B, wherein B is as defined above, or (c) where a compound of the formula III is required, reacting a compound of the formula with a compound of the formula H2N-NII-B, wherein B is as defined above, or (d) where a compound of the formula IV is required, reacting a compound of the formula with a compound of the formula H2N-NH-B, wherein B is as defined above, and where required converting the resulting product to the phramaceutically accept-able acid addition or quaternary arnmonium salts thereof.

12. A compound of the formula I, II, III or IV as defined in claim 11 and pharmaceutically acceptable acid addition and quaternary ammonium salts thereof, whenever prepared by the process of claim 11, or by an obvious chemical equivilent thereof.

13. A process for the preparation of 7, 12-dihydro-bis(2-imidazolin-2-ylhydrazone)-7, 12-benz[a] anthracene dicarboxaldehyde which comprises react-ing 1, 12-dihydro-benz[a] anthracene - 7, 12-dicarboxaldehyde with 2-hydra-zinoimidazoline in n-propanol and isolating the thus formed product.

14. 7,12-dihydro-bis(2-imidazolin-2-ylhydrazone)-7,12-benz[a]
anthracene dicarboxaldehyde whenever prepared by the process of claim 13 or by an obvious chemical equivalent thereof.

15. A process for the preparation of 5, 12-dihydro-bis(2-imidazolin-2-ylhydrazone) -5, 12-benz[b] anthracene dicarboxaldehyde which comprises react-ing 5, 12-dihydro-5, 12-benz [b] anthracene dicarboxaldehyde with 2-hydra-zinoimidazoline in n-propanol and isolating the thus formed product.

16. 5, 12-dihydro-bis(2-imidazolin-2-ylhydrazone)-5,12-benz[b] anthra-cene dicarboxaldehyde whenever prepared by the process of claim 15 or by an obvious chemical equivalent thereof.

17. A process for the preparation of 7,12-dihydro-bis(1,3,4,5-tetrahydro-1H-pyrimid-2-ylhydrazone)-7,12-benz[a] anthracene dicarboxyladehyde which comprises reacting 7,12-dihydro-7,12-benz[a] anthracene dicarboxaldehyde with 2-(1,3,4,5-tetrahydro-IH-pyrimid-2-yl) hydrazine in n-propanol and isolating the thus formed product.

18. 7,12-dihydro-bis(1,3,4,5-tetrahydro-lH-pyrimid-2ylhydrazone)-7,12-benz[a] anthracene dicarboxaldehyde whenever prepared by the process of claim 17 or by an obvious chemical equivalent thereof.

19. A process for the preparation of 5,12-dihydro-bis(4,5,6,7-tetrahydro -lH-1,3-diazepin-2-ylhydrazone)-5,12-benz[b] anthracene dicarboxaldehyde which comprises reacting 5,12-dihydro-5,12-benz[b] anthracene dicarboxaldehyde with 2-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl) hydrazine in n-propanol and isolating the thus formed product.

20. 5,12-dihydro-bis(4,5,6,7-tetrahydro-lH-1,3-diazepin-2ylhydrozone)-5,12-benz[b] anthracene dicarboxaldehyde whenever prepared by the process of claim 19 or by an obvious chemical equivalent thereof.