DK168333B1 - Analogous Process for Preparation of Anthracene-9,10-Bis-Carbonyl Hydrazones and Derivatives or Salts thereof - Google Patents

Description

in DK 168333 Bl

The present invention relates to an analogous process for the preparation of novel anthracene-9,10-bis-carbonylhydrazones of the general formula R3 ChV r5 ABC (I)

CH i II Æ N-N

V

wherein A, B and C form an anthracene nucleus or a 9,10-dihydroanthracene nucleus, R1 is hydrogen or alkyl of up to 4 carbon atoms, R2 is hydrogen, alkyl of up to 4 carbon atoms, phenyl or a monovalent group of the formula X N- (CH 2) m

II II III

-C-R7 or -C-NH

where m is 2, 3, 4 or 5, R7 means amino, monohydroxyalkylamino having 2-4 carbon atoms and wherein the carbon atom in the α position of the nitrogen atom does not carry a hydroxy group, alkylamino of up to 4 carbon atoms, dialkylamino having up to to 4 carbon atoms per alkyl group, cycloalkylamino of 3-6 carbon atoms, benzylamino, 2-furfurylamino, 3-furfurylamino, α-thenylamino, / 8-thenylamino, α-pyridylmethylamino, ε-pyridylmethylamino, ττ-pyridylmethylamino, indanylamino, X means ox , imino or alkylimino of up to 4 carbon atoms, R3, R4, R5 and R6 each independently represent hydrogen, halogen, alkyl of up to 4 carbon atoms or alkoxy of up to 4 carbon atoms, and R3 and R4 may together with the carbon atoms to which they are attached. is attached, forming a phenyl group, in which case, however, R 1 is hydrogen and R 2 is a group of the formula 2 (CH 2) m

II I

-C-NH

wherein m has the meaning given above, or pharmacologically acceptable acid addition salts or quaternary ammonium salts thereof.

The hydrazino substituents on the anthracene-9,10-bis carbonyl nucleus may be the same or different and may be present in the syn or anti-form. Furthermore, where the hydrogen-10 atoms or other substituents in the 1-, 4-, 5- and 8-positions of the anthracene nucleus cause limited rotation of the bonds of Cg and C1Q in the anthracene nucleus, the entire group R1 can

-CH = N-N

Ni2

in the Cg and C10 positions be either in the cis position (both groups are located on the same side of the anthracene core plane) or trans position (the two groups are located on either side of the anthracene core plane). NMR data for the hydrochloride compound of Example 3 gives strong confirmation of a mixture of rotational isomers at 29 ° C (four peaks for δ 3.02, 3.05, 3.18 and 3.20) but at 85 ° C

the four peaks are fused to a sharp singlet at 25 3.20 (in D 2 O). The quadruplet reappears upon cooling.

By thin layer chromatography at 24 ° C two spots are obtained, which is also the case with the products of Examples 7, 8 and 14. UV absorption data for the products of Examples 3 and 4 indicate that the double bonds close to 30 of the anthracene ring system have been forced out of the plane of this system. .

The analogous method of the present invention is characterized by the method of claim 1.

Preferred compounds prepared by the process of the invention are the compounds of the general formula DK 168333 B1 3 - (cH9) µ in µm

N-NH-C-NH

Sh 5 B {II)

CH

N-NH-C-NH

In N- (CH 2) m where m, R3, R4, R5, R6, A, B and C have the meanings given above, especially the bis- (2-imidazolin-2-ylhydrazone) of 9,10-dihydro -9,10-dianthracenedicarboxaldehyde dihydrochloride, 1,4-dimethyl-9,10-dihydro-9,10-anthracenedicarboxaldehyde dihydrochloride and 1,4-dimethoxy-9,10-dihydro-9,10-dianthracene dicarboxaldehyde.

The compounds prepared are obtained as yellow crystalline products with characteristic melting points and absorption spectra, and they can be purified by recrystallization from conventional organic solvents such as lower alkanols, dimethylformamide, tetrahydrofuran and methyl isobutyl ketone. The organic bases form non-toxic acid addition salts and quaternary ammonium salts with various pharmacologically acceptable organic and inorganic salt-forming reagents. Thus, by mixing the organic free base with one or more equivalents of an acid, conveniently in a neutral solvent, acid addition salts are formed with acids such as sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, sulfamic acid, citric acid, lactic acid, malic acid, succinic acid, acetic acid, benzoic acid, gluconic acid and ascorbic acid. Quaternary ammonium salts can be formed by reacting the free bases with one or more equivalents of various organic esters of sulfuric acid, hydrogen halide acids and aromatic sulfonic acids. The organic reagents used for the formation of the quaternary ammonium salts are preferably lower alkyl halides. However, other organic reagents may also be used for the formation of quaternary ammonium salts, and examples of useful compounds include benzyl chloride, phenylethyl chloride, naphthyl methyl chloride, dimethylsulfate, methylbenzenesulfonate, ethyltoluenesulfonate, allyl chloride, methallyl bromide, For this purpose, the free bases are equivalent to the non-toxic acid addition salts and the quaternary ammonium salts. The acid addition salts and the quaternary ammonium salts of the organic bases 10 are usually crystalline solids which are relatively soluble in water, methanol and ethanol, but highly soluble in nonpolar organic solvents such as diethyl ether, benzene, toluene and the like.

The compounds prepared can be used as I5 antimicrobial agents and have broad spectrum antibacterial activity in vitro against various standard experimental microorganisms determined using the standard agar-plate diffusion assay. In this analysis, the minimum inhibitory concentration (MHC) is determined using 20 double dilutions of the compounds in the agar. One ml of dilution is placed in a sterile Petri dish and 9 ml of nutrient agar are added to each dish.

Five-hour-old excursions of the indicated microorganism -2

Trypticase soy broth is diluted 10 in nutrient substrate.

This dilution of each culture is transferred to the surface of the plates using a Steer apparatus.

After incubation at 37 ° C for 24 hours, the minimum inhibitory concentration is determined as the lowest concentration for the compound, which completely inhibits the macroscopic growth of the organism. The minimum inhibitory concentration for typical examples of the compounds prepared against the listed organisms is given in the following Table I and Table II.

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The antibacterial spectrum expressed at the minimum haem concentration for various typical bacteria is determined using the standard agar dilution plate method for the compounds listed in Table III below. A Steers multiple inoculation apparatus is used with incubation at 37 ° C for 18 hours in Mueller-Ninton agar. The results obtained with 7.12-bis- (2-imidazolin-2-ylhydrazone) benz [a] anthracene-7,12-dicarboxaldehyde dihydrochloride, which is a typical example of the compounds prepared, are set forth in Table III below, expressed by the minimum inhibitory concentration (MHC) in Mg per ml.

Table III

Test organism_MHC_

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 20 _

Furthermore, the compounds prepared are capable of inhibiting the growth of transplanted mouse tumors, as demonstrated by the following tests.

25 Lymphocytic Leukemia P388 Test

As experimental animals, mice of the same sex and with a minimum weight of 17 g are used, all within a weight range of 3 g. experimental group. Tumor transplantation is performed by intraperitoneal injection of 0.1 or 0.5 ml of diluted ascitesg fluid containing 10 cells of lymphocytic leukemia P388. The test compounds are administered intraperitoneally on days 1, 5 and 9 (relative to the tumor inoculation) at various doses. The animals are weighed and the number of surviving 35 animals is recorded regularly over 30 or 60 days.

The average survival time and the ratio of survival time of the treated animals (T) to the survival time of the control animals (C) are calculated. The positive control compound is 5-fluorouracil. The test results are given in Table IV below. The efficiency criterion is T / C x 100 ^ 125%.

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The test method is the same as for the lymphocytic leukemia P388 test, however, the tumor transplant consists in the inoculation of lymphocytic leukemia L1210 at a concentration of 10 ^ cells / mice with an average survival time calculated and the test compound administered only on day 1. The test results obtained with a representative compound are given in the following Table V. The efficiency criterion is T / C x 100 ^ 125%.

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As a test animal, mice (C57BC / 6) of the same sex and with a minimum weight of 17 g are used, all within a weight range of 3 g. experimental group. 1 g melanotic melanoma Bl6 tumor is homogenized in 10 ml of cold balanced saline solution and 0.5 ml of the homogenate is implanted intraperitoneally in each test animal. The test compounds are administered intraperitoneally on days 1 to 9 (relative to the tumor inoculation) at various doses. The animals are weighed and surviving animals are regularly recorded for a period of 60 days.

The mean survival time and the ratio of survival time of treated animals (T) to control animals (C) are calculated. The positive control compound is 5-fluorouracil, which is injected in an amount of 20 mg / kg. The test results are given in the following Table VI. The efficiency criterion is T / C x 100 ^ 125%.

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The compounds of this invention exhibit antibacterial activity upon testing as follows. The antibacterial spectrum expressed at the concentration necessary to inhibit the growth of various typical bacteria is determined in a conventional manner using the agar plate thinner plate. A Steer multiple inoculation apparatus is used with incubation at 37 ° C for 18 hours in Mueller-Ninton agar. The results obtained with typical compounds are given in Table VII below, expressed as 10 at the minimum inhibitory concentration in pg per day. ml.

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The compounds of the formula (I) and the pharmacologically acceptable acid addition salts and quaternary ammonium salts thereof are expected to exhibit efficacy against a wide range of cancerous diseases, especially blood cancer diseases such as leukemia. standard test animals at doses substantially below toxic concentrations.

The intended mode of administration is mainly parenteral and intraperitoneal.

Solutions of the active ingredient in the form of a free base or salt can be produced in water or in water which is suitably mixed with e.g. surfactants. The preferred compound of the laurel (II), where m is 2 and Y means imino, is heavily soluble in water. It can, for example, be converted to an acetate 15 having a pH of aqueous solution of approx. 7.4, which by analysis turns out to contain approx. one acetic acid residue per anthracenkerne. A diacetate having a pH value in aqueous solution of approx. 6.2. The diacetate has a solubility in water of approx. 400 mg per day milliliters of water.

The base or various salts may be made more soluble by the addition of surfactants such as hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof, and in oils. Under conventional conditions of storage and use, these compositions contain a preservative to prevent the growth of microorganisms.

The pharmaceutical compositions may be in forms suitable for injection, e.g. sterile aqueous solutions or dispersions and sterile powders for preparing sterile injectable solutions or dispersions. In all cases, the formulation must be sterile and fluid to the extent that it is readily injectable. The form of preparation must be stable under the conditions of preparation and storage and must be protected against contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or a dispersion medium containing e.g. water, ethanol, polyol, e.g. glycerol, propylene glycol and liquid polyethylene glycol, as well as suitable mixtures thereof, and vegetable oils.

For example, the proper fluidity can be maintained by using a coating, such as lecithin, by adhering to the required particle size in the case of dispersions and by using surfactants. Protection against the effects of microorganisms can be provided by various antibacterial and antifungal agents, e.g.

10 parabens, chlorobutanol, phenol, sorbic acid and thimerosal.

In many cases, it is preferred to add isotonic agents, e.g. sugars or sodium chloride. Prolonged absorption of the injection compositions may be provided using absorption delaying agents, e.g. ammonium monostearate and gelatin.

Sterile injection solutions are prepared by incorporating the active ingredient in the required amount of the appropriate solvent with various of the other ingredients listed above as needed, followed by sterile filtration. Generally, dispersions are prepared by incorporating the various sterile active ingredients into sterile carrier containing the basic dispersion medium and the necessary other ingredients from the above. In the case of sterile powders 25 for preparing sterile injection solutions, the preferred preparation methods are vacuum drying and freeze drying to obtain a powder of the active ingredient plus any additional desired ingredients from a solution previously sterile filtered.

In the context of the present invention, the term "pharmaceutically acceptable carrier" includes, inter alia, all solvents, dispersion media, coating agents, antibacterial agents, antifungal agents, isotonic agents and absorption delay agents. The use of these scoops and agents for pharmaceutically active substances is well known. Apart from such media or agents which are incompatible with the active ingredient, any agent or medium may be used in the subject therapeutic compositions. Additional active ingredients may also be incorporated into the compositions.

It is particularly advantageous to formulate unit dosage form preparations to facilitate administration and to achieve uniform dosage. The unit dosage form here means physically separated units which are suitable as unit dosages for mammals to be treated. Each unit contains a predetermined amount of active substance 10 designed to elicit the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the novel unit dosage forms is dictated by and directly dependent on (a) the unique nature of the active material and the particular therapeutic effect to be achieved, and (b) the limitations necessarily encountered in the art in compounding such active material. for the treatment of diseases in living individuals with a condition of disease in which health is at risk, as described in detail.

The dosage of the main active ingredient to treat the conditions listed depends on the individual's age, weight and condition, the disease state and its severity, and the type of active ingredient and the route of administration concerned. A daily dose of 1 to 100 25 mg / kg body weight given in single or divided doses of up to 5 times a day comprises the effective treatment range for most conditions in which the compounds prepared are effective and substantially non-toxic. For an individual of approx. This means that from 75 to 7500 mg per 75 kg should be given. day. If the amount of active substance is divided up, e.g. in 3 individual doses, these will range from 25 to 2500 mg of active ingredient. The preferred range is from 2 to 50 mg per day. kg body weight per per day, with the most preferred range being from 2 to 30 mg per day. kg body weight per day. 35 35 DK 168333 B1

The essential active ingredient is compounded for convenient and effective administration in an effective amount of a suitable, pharmaceutically acceptable carrier in unit dosage form as described above. A dosage unit form 5 may e.g. contain the essential active ingredient in amounts of from 0.1 to 400 mg, preferably from 1 to 30 mg. In terms of the carrier, this means that the active ingredient is usually present in an amount of from 0.1 to 400 mg per day. ml of carrier. In the case of preparations containing other active ingredients, the dosages are determined taking into account the usual dose and mode of administration of these ingredients.

For example, regression and palliation of cancer are achieved. using intraperitoneal administration.

A single intravenous dose or repeated daily doses may be used. Daily doses of up to 5 or 10 days are often sufficient. It is also possible to distribute 1 daily dose or 1 dose on alternating or fewer days. It is apparent from the dosage regimen that the amount of the major active ingredient administered is a sufficient amount to support regression and palliation of leukemia or the like without the occurrence of exaggerated cytotoxic adverse effects in the subject with cancer. For the purposes of the present invention, cancer is understood to mean malignant blood diseases such as leukemia, as well as other solid and non-solid malignant forms, such as melanocarcinomas, lung carcinomas, and breast tumors.

By regression and palliation is meant locking or diminishing the growth of the tumor or other manifestation of the disease compared to the course of the disease without treatment.

The novel compounds of formula (I) can be readily prepared by the analogous process of this invention in accordance with the following reaction scheme DK 168333 B1 36 N-N -

II

R3 HC = 0 R5 R3 CH R5 ABC _ ^ A I B C J (I) fi 4 / ^^ 'SSS ^ X ^ SN ^' 6

R HC = 0 R R CH D1 R

II

(III) N-N, R 2 where A, B, c, R 1, R 2, R 3, R 4, R 5 and R 6 have the above meanings.

In a variant according to the above reaction scheme, a suitably substituted 9,10-anthracenedialdehyde or diketone (III) is reacted with a hydrazine derivative of the formula 15 H2N-NR1R2 to form the 9,10-anthracene bis-hydrazones (I). The reaction is carried out in a lower alkanol in the presence of an acid such as hydrochloric acid, hydrogen iodide acid or acetic acid (or glacial acetic acid can be used as the sole solvent), usually at the reflux temperature of the reaction mixture.

In another process variant, the compound of formula (III) is reacted with a hydrazine derivative wherein R 2 is -C (SR ') = NR 2 where R 1 is lower alkyl to the compound shown below, which is then reacted with an amine as illustrated in the following: / SR '- HC = NNHC - R3 T ^ NR2 5 (1) + ^ i · 11 ->

ABIC

R * 1 HC = NNHC0 NR2 DK 168333 B1 37 to form a compound of formula (I) wherein R 2 is -C-R 7 or - C - NH, wherein in 5 XN - (CH 2) m X, R 7 and m has the meanings given above.

In accordance with the above reaction scheme, a mixture of the anthracene derivative and 2-2.5 molar equivalents of the amine in a lower alkanol is heated to 50-120 ° C for 2-10 hours to form the desired product.

(2) e3 HC = NNH2 r5 (VYVlcS + CH3S-r2 - (I) R6 HC = NNH2 20 In accordance with a further variant according to the above reaction scheme, an anthracene derivative is heated where R 1 and R 2 represent hydrogen and 2 molar equivalents of methyl-25 thiourea, if desired, in a lower alkanol to 50-120 ° C for 2-10 hours to give the desired product, wherein R 2 has the meaning given above.

The 9,10-anthracenedialdehydes and ketones used as starting materials can be obtained commercially or prepared by any of the methods illustrated in Reaction Schemes (A) and (B) below, wherein A, B, C, R3, R4, R5 and R6 have the above meanings.

38 DK 168333 B1 (A) R3 R5 (IV) \ .r3 \? = C1 r5 / r ch2ci - R4 ciio R6 (VI) 20 In accordance with the above reaction scheme, the anthracene derivative (IV), suspended in dioxane and concentrated hydrochloric acid, is treated and saturated. with HCl # with paraformaldehyde at reflux temperature for 2-6 hours to form the 9,10-bis (chloromethyl) anthracene derivative (V). This 9,10-25 bis (chloromethyl) anthracene, suspended in dry dimethyl sulfoxide under nitrogen at room temperature, is reacted with sodium in ethanol and the reaction mixture worked up as described in the Examples to give the desired 9,10-anthracenedicarboxaldehyde. (WE).

30 35 DK 168333 B1 39 R7 (β) / r3 y / y r5 s R4 R r4 R6 (IV) R (XI)

10 v Å-DH

, CHO ώ5 T, 3 / J-E0

A B C) ^ -: - I O / 1 O I

R4: CHO R4 (XII) rR

(VI) In accordance with the above reaction scheme, the anthracene derivative (IV) is heated with excess vinylene carbonate under reflux for 10-24 hours to form the cyclic carbonate (XI) wherein D and E are 0, S or NH, F is = 0, = S, = NH or cyclohexyl, 7 8 25 and R and R are H, alkyl or aryl. Hydrolysis of the cyclic carbonate (XI) with aqueous ethanolic potassium hydroxide at 70-75 ° C for 1-4 hours gives the diol (XII) which is then reacted with lead tetraacetate in acetic acid at 20-35 ° C for approx. 10 minutes to 2 hours to form the 9,10-30 anthracenedicarboxaldehyde (VI).

Other methods for preparing the dialdehydes used as intermediates are described below.

35 40 DK 168333 B1.? S K5 'R> \ ^ / VR5' Pri '*' (XIII) (XIV)

10 CHO

3 CHO 3 in R CH2 and R CHO (xvi) (XV) 20 In accordance with the above reaction scheme, the anthraquinone (XIII) is reacted with dimethylsulfonium methylide (or dimethyloxosulfonium methylide) in dimethylsulfoxide at 10-40 ° C to give dispiro-25 [oxirane-2.9 l (10 Ή) -anthracene-10 ', 2 "-oxirane] (XIV).

This compound is rearranged with lithium bromide (or lithium perchlorate, boron trifluoride, magnesium bromide, trifluoroacetic acid and methanesulfonic acid) in an organic solvent to form 9-formyl-10-hydroxymethyl anthracene (XV). The 9-Formyl-10-hydroxymethyl anthracene is then oxidized with O-chloroanil (or dichlorodicyano-1,4-benzoquinone, dimethylsulfoxide, diethyl azodicarboxylate, lead tetraacetate, nickel peroxide, manganese oxide, chromium trioxide and selenium oxide) in an organic solution. ° C to form the 9,10-anthracene cendicarboxaldehyde (XIV).

DK 168333 B1 41

ISLAND

HAY

(xiii) - ^ I ft I 1 V

---- XV (XVI) (XVII) In accordance with the above reaction scheme, the anthraquinone of formula (XIII) is reacted with dimethyl sulfoxide dione in dimethyl sulfoxide at. 10-40 ° C to form 9,10-dihydro-9,10- (methanothiomethano) anthracene-9,10-diol-12-oxide (XVII). This compound is reacted with acetic anhydride and then with 88% formic acid to form the 9,10-anthracenedicarboxaldehyde (XVI).

CH3 CKIOCT CK3> 2 r? In Rs s3yvv ^ s A ic 101 lij · 1 -> ^ ΥΜ · - In p6 {CH3 CH (OC ^ CI ^) 2 25 (XVIII) (XIX) 9/10 The dimethyl anthracene (XVIII) in a solution of acetic acid, acetic anhydride and sulfuric acid are cooled to 0-10 ° C and reacted with 2 molar equivalents, chromium trioxide to form the tetraacetate (XIX), which is then hydrolyzed at 20-50 ° C with a sodium carbonate solution to form the dialdehyde (VI).

Other oxidizing agents such as selenium dioxide and cerium ammonium nitrate can be used for the oxidation.

35 42 DK 168333 B1

R

R3 \ j // p5 5 iIV) + fjp _v f © W [o] _ C-R 6 (XX) xo -. / fe. .

* f // rB "r3 '1: * - *

20 R4 V

K .... R4 R6

(XXI). 0 = C-R

(XXII) wherein R is H, alkyl, COOCH 3 or COOH.

In accordance with the above reaction scheme, a mixture of the anthracene and excess acetylene without the use of solvent or with an organic solvent such as xylene is heated to 50-150 ° C for 2-20 hours to form the addition product (XX).

The addition product in a solvent such as ether or dioxane is reacted with osmium tetroxide in the presence of pyridine at 10-60 ° C for 12 hours to 2 days, then reacted with mannitol to form the cis-glycol (XXI). The compound of formula (XXI) ) is then reacted with lead tetraacetate in acetic acid at 20-60 ° C for 1-5 hours to form the dicarbonyl anthracene (XXII). When R is COOH, compounds (XXII) in quinoline or pyridine are heated at 100-180 ° C to form the 9,10-anthracenedicarboxaldehyde (XVI).

The invention is further illustrated by the following examples.

44 DK 168333 B1

Example 1

The bis- (2-imidazolin-2-ylhydrazone) of 9,10-anthracene-dicarboxaldehyde dihydrochloride. The 2-Hydrazino-2-imidazoline monohydrochloride described in U.S. Patent No. 3,931,152 is converted to the dihydrochloride. by treatment with ethanol and concentrated hydrochloric acid. A suspension of 3.46 g of the 2-hydrazino-2-imidazoline dihydrochloride and 2.34 g of 9,10-anthracenedicarboxaldehyde in 100 ml of ethanol is stirred and heated at reflux for 2 hours. The mixture is cooled and the solid is isolated and washed with ethanol to give the desired product in the form of a crystalline, orange solid, m.p. 288-289 ° C (dec.), Yield 97%.

Example 2

Bis (dimethylhydrazone) of 9,10-anthracenedicarboxaldehyde-dihydrochloride; A suspension of 4.68 g of 9,10-anthracenedicarboxaldehyde in 200 ml of ethanol containing 2.40 g of asymmetric dimethylhydrazine and 2 drops of glacial acetic acid is stirred at reflux for 2 hours. The mixture is filtered warm. The desired product is separated from the filtrate in the form of an orange solid with m.p. 177-178 ° C, yield 70%.

Example 3 N, N-Dimethylglycine (9,10-anthrylenedimethylidine) dihydrazide dihydrochloride

A suspension of 4.68 g of 9,10-anthracenedicarboxaldehyde and 6.14 g of N, N-dimethylglycylhydrazide hydrochloride 30 in 200 ml of ethanol is stirred and heated under reflux for 2 hours. After cooling the mixture, the orange solid is isolated and washed twice with ethanol.

A cloudy solution of this solid in 400 ml of hot ethanol is filtered, the filtrate is concentrated to 150 ml and d50 ml of diethyl ether is added. After standing overnight, the orange solid is isolated and washed with acetone. A cloudy solution of this solid in 200 ml of methanol is chromatographed on silica gel and eluted with methanol. The eluate is recommended for 4 hours, during which a small amount of the solid, yellow, free base form is deposited, m.p. 276-279 ° C (dec.) Of the desired product. The filtrate from the yellow solid is evaporated to give an orange solid. A cloudy solution of the orange-colored solid in 150 ml of hot methanol is filtered, concentrated to 50 ml, cooled a bit, inoculated and gradually diluted with 50 ml of diethyl ether. The precipitated solid is filtered off and washed with ethanol to give the desired dihydrochloride product as an orange solid 10, m.p. 277-279 ° C (dec.), Yield 56%.

Example 4 1,1'- [9,10-Anthrylene bis- (methylidynnitrilo)] diguanidine dihydrochloride A suspension of 3.51 g of 9,10-anthracenedicarboxaldehyde οσ 4.08 g of aminoauanidine hydrogen carbonate in a mixture of 100 ml of ethanol and 5.4 ml of 8 N ethanolic hydrochloric acid is stirred and heated under reflux for 2 hours. The mixture is cooled and the solid is isolated, washed four times with cold ethanol and dried to give the desired product in the form of an orange powder with m.p. 298-301 ° C, yield 80%.

Example 5

Bis- (1,4,5,6-tetrahydro-2-pyrimidinylhydrazone) of 9,10-25 -anthracenedicarboxaldehyde dihydrochloride-2-Hydrazino-1,4,5,6-tetrahydropyrimidine mono-hydroiodide, cf. to U.S. Patent No. 3,931,152, is converted to the dihydrochloride by treatment with excess "Dowex-2X8" which is a highly basic anion exchange resin 30 of the hydrochloride form. The aqueous filtrate is acidified with excess concentrated hydrochloric acid to give the dihydrochloride salt. A mixture of 5.61 g of dihydrochloride and 3.51 g of 9,10-anthracenedicarboxaldehyde in 100 ml of ethanol is stirred and heated under reflux for 2 hours, then filtered. From the cooled filtrate, a solid is separated which is isolated and washed three times with ethanol to give the desired product in the form of yellow crystals by snip. 215-230 ° C (dec.). yield is 41%.

Example 6

Bis- (4,5,6,7-tetrahydro-1H-1,3-diazepin-2-ylhydrazone) of 5,10,10-anthracenedicarboxaldehyde dihydroiodide

A mixture of 7.68 g of 2-hydrazino-4,5,6,7-tetrahydro-1H-1,3-diazepine hydroiodide, as described in U.S. Patent No. 3,931,152, 3.51 g. , 10-anthracenedicarboxaldehyde and 7.57 ml of 4 N ethanolic hydrogen iodide acid are reacted analogously to the procedure described in Example 5 to give the desired product in the form of an orange solid, m.p. 301-3Q2 ° C (dec.), Yield 87%.

Example 7 1,11- [9,10-Anthrylene-bis- (nethylidynnitrilo) -bis-3-benzylguanidine dihydroiodide

A mixture of 216 g of thiosemicarbazide and 360 g of iodomethane in 2.4 liters of absolute ethanol is heated under reflux for 2 hours, then cooled overnight, separating colorless crystals of S-methylisothiosemicarbazide hydroiodide. A mixture of 11.65 g of this product and 10.9 ml of benzylamine in 25 ml of absolute ethanol is heated at reflux at 100 ° C for 1 hour. The mixture is cooled and seeded, thereby separating 1-amino-3-benzylguanidine monohydroiodide into form of colorless crystals which are isolated.

A suspension of 2.34 g of 9,10-anthracenedicarboxaldehyde, 5.92 g of 1-amino-3-benzylguanidine magnesium hydroiodide. and 5.8 ml of 3.47 N ethanolic hydrogen iodide acid in 100 ml of ethanol are stirred and refluxed for 2 hours, then the mixture is allowed to cool overnight and the solid is isolated and washed three times with diethyl ether to give the desired product is available in the form of a yellow solid with m.p. 279-282 ° C (decomp.), Yield 70%.

47 DK 168333 B1

Example 8 1,1 '- [9,10-Anthrylene-bis- (methylidynnitrilo)] - bis- (3-cyolohexylguanidine) dihydroiodide

A solution of 2.8 g of 1-amino-3-cyclohexyl guanidine hydroiodide, cf. W.G. Finnegan, R.A. Henry, E. Lisker, J. Org. Chem., 18, 779 (1952), and 2.34 g of anthracene-9,10-dicarboxaldehyde in 200 ml of ethanol and 20 ml of acetic acid are heated under reflux for 18 hours and then filtered hot. The filtrate is evaporated and 5.0 g of an orange solid is obtained. This solid is recrystallized from a mixture of ethanol and ether to give the desired compound, m.p. 300 ° C, yield 53%.

Example 9 Bis- (2-inidazolin-2-ylmethylhydrazone) of 9,10-anthracene-dicarboxaldehyde dihydroiodide

A solution of 48.8 g of 2-methylthio-2-imidazoline hydroiodide and 10.0 g of methyl hydrazine in 200 ml of ethanol is heated under reflux for several hours, clarified, and then cooled to -10 ° C. The precipitated precipitate is isolated, washed with diethyl ether and dried to give 2- (1-methylhydrazino) imidazoline hydroiodide.

A suspension of 5.08 g of 9,10-anthracenedicarbox aldehyde, 10.2 g of 2- (1-methylhydrazino) imidazoline hydroiodide and 12.1 ml of 3.47 N ethanolic hydrogen iodide acid in 135 ml of ethanol is heated under reflux with stirring for 2 hours. The mixture is left to stand overnight and the separated solid is isolated and washed three times with acetone to give the desired product, m.p.

30 298-300 ° C (dec.) Yield 77%.

35 48 DK 168333 B1

Example 10 1,1 '- [9,10-Anthrylene-bis- (methylidynnitrilo)] - * - bis-3-methylguanidine dihydro iodide

A suspension of 3.05 g of 9,10-anthracene-5-dicarboxaldehyde, 5.63 g of 1-amino-3-methylguanidine hydroiodide, cf. Kirsten et al., JACS, 58,800 (1936), and 7 , 50 ml of 3.47 N ethanolic hydrogen iodide acid in 100 ml of ethanol are heated under reflux and stirring for 2 hours, then allowed to cool overnight. The mixture 10 is evaporated to dryness, 40 ml of methanol is added and the mixture is placed in an ice bath for 15 minutes. The separated solid is isolated and washed three times with methanol to give the desired product, m.p.

247-265 ° C (dec.), Yield 44%.

15

Example 11 9.10- Anthracenedicarboxaldehyde bis (thiosemicarbazone)

A mixture of 2.34 g of 9,10-anthracenedicarboxaldehyde and 3.65 g of thiosemicarbazide in 250 ml of absolute ethanol containing 2.0 ml of glacial acetic acid is heated in a steam bath for 24 hours, then the mixture is left to cool and left overnight. .

The solid is isolated, washed with absolute ethanol, dried and recrystallized from aqueous dimethylformamide to give the desired product in the form of orange crystals, m.p. 275-277 ° C, yield 16%.

Example 12 9.10- Anthracenedicarboxaldehyde-disemicarbazone A mixture of 2.34 g of 9,10-anthracenedicarboxaldehyde, 4.46 g of semicarbazide hydrochloride and 5.44 g of sodium acetate in 250 ml of absolute ethanol is heated under reflux for 24 hours, cooled and cooled. recommended at room temperature. The precipitated solid is isolated and recrystallized from a mixture of dimethylformamide and dimethylsulfoxide to give the desired product as yellow crystals, m.p. 300 ° C.

49 DK 168333 B1

Example 13 9.10-Anthracenedicarboxaldehyde bis (methylhydrazone)

A suspension of 4.68 g of 9,10-anthracenedicarboxaldehyde and 1.84 g of methylhydrazine in 200 ml of ethanol containing 2.0 drops of glacial acetic acid is stirred and heated under reflux for 1.5 hours. The mixture is cooled and the solid is isolated and washed with ethanol to give the desired product in the form of orange needles with m.p. 172-174 ° C (dec.), Yield 69%.

10

Example 14 1,1 '- [9,10-Anthrylene-bis- (methylidynitrilo)] -bis-1-methylquanidine dihydrobromide

A mixture of 2.3 g of 9,10-anthracenedicarboxaldehyde, 3.4 g of 1-amino-1-methylguanidine dihydrobromide, 200 ml of ethanol and 1.3 ml of 7.4 N ethanolic hydrobromic acid is heated and stirred at reflux for 17 hours. . The mixture is filtered hot and 4.5 g of product are obtained with m.p. 324-325 ° C (dec.).

20

Example 15 1,1 '- [9,10-Anthrylene-bis- (methylidynitrilo)] bis- [3,3-dimethylcmanidinl-dihydrochloride

A mixture of 4.60 g of 1-amino-3,3-dimethylgyanidine hydroiodide, cf. Finnegan et al., J. Org. Chem., 18, 779 (1953), 2.34 g of 9,10-anthracenedicarboxaldehyde and 5.04 ml of 4 N ethanol isoic hydrogen iodide acid in 100 ml of ethanol are stirred and heated under reflux for 2 hours, then the mixture is left to cool. The separated orange solid is isolated and washed with ethanol to give the desired product, m.p. 320-322 ° C, yield 87%.

Example 16 1,1 '- [9,10-Anthrylene-bis- (methylidynnitrilo)] -bis- [1,3-dimethyl-cruanidine 1-dihydroiodide

A solution of 10.4 g of N, Ν'-dimethylthiourea in 50 ml of ethanol is reacted with 14.5 g of methyl iodide under reflux for 70 minutes. The solution is filtered hot and cooled to give S-methyl-11 N-dimethylisothiourea hydroiodide, m.p. 209-212 "C.

A solution of 17.5 g of S-methyl-Ν, Ν'-dimethylisothiourea hydroiodide in 20 ml of ethanol and 10 ml of water is reacted with 10 ml of hydrazine hydrate under reflux for 20 minutes. The mixture is cooled and the product isolated and washed with a mixture of ethanol and water (2: 1) and with ether, to give 13 g of product. This is recrystallized from 150 ml of boiling ethanol with the addition of water to just complete solution, then cooled to give 1-amino-2,3-dimethylguanidine hydroiodide, m.p. 296-298SC. This salt is reacted analogously to the procedure of Example 14 and after recrystallization from water the desired compound is obtained in the form of an orange solid with m.p. 281-283 ° C, yield 61%.

Example 17 1,1 '- [9,10-Anthrylene-bis- (methylidynitrilo)] bis- [3- (2-hydroxyethyl) -quanidinl-dihydroiodide

A solution of 11.6 g of S-methylthiosemicarbazide hydroiodide and 3.2 ml of ethanolamine in 50 ml of ethanol is heated under reflux on a steam bath for 3 hours. The solution is cooled and treated with 15 ml of 8N ethanolic hydrochloric acid, cooled and diluted with diethyl ether to form a thick, gummy substance. The above liquid is decanted and the residue dissolved in 60 ml of hot ethanol, treated with ca. 1 ml of water and cool. A small amount of solid is filtered off, and the filtrate is added with more ethanolic hydrochloric acid to form a viscous, gummy substance. The supernatant is decanted, the residue of 4.8 g is dissolved in 65 ml of ethanol and reacted with 1.9 g of 9,10-anthracenedicarboxaldehyde under reflux for 2.5 hours. The solution is filtered and cooled to give 1.7 g of product. This product is recrystallized from 15 ml of dimethylformamide to give 1.0 g of product. This product is slurried in 6 ml of methyl cellulose solvent to give 450 mg of an orange crystalline product with m.p. 234-235 ° C.

Example 18 1,1 '- [9,10-Anthrylene-bis- (methylidynnitrilo)] -bis- [3- (2-hydroxy-propyl) -ouanidine-dihydroiodide

A solution of 32.0 g of 1- (2-hydroxypropyl) -imidazole-idin-2-thione and 15 ml of methyl iodide in 250 ml of isopropanol is stirred and refluxed for 4 hours, then cooled to -10 ° C. . The precipitated precipitate is isolated and washed with cold isopropanol and then with diethyl ether to give 1- (2-hydroxypropyl) -2- (methylthio) -2-imide-azoline hydroiodide, m.p. 114-116 ° C. A solution of 30.2 15 g of this salt and 5.2 g of hydrazine hydrate in 200 ml of isopropanol is refluxed for 4 hours, then filtered and cooled to -10 ° C. The precipitate formed is isolated and washed with cold isopropanol and then with ether to give 2-hydrazino-1- (2-hydroxypropyl) -2-imidazoline hydroiodide, m.p. 140-142'C. A mixture of 2.86 g of this salt 1.17 g of 9,10-anthracenedicarboxaldehyde and 2.5 ml of 4 N ethanolic hydrogen iodide acid are reacted analogously to the procedure described in Example 15 to give the desired compound as a yellow solid. with m.p. 249-25 251 ° C (dec.), Yield 47%.

Example 19 1,1 '- [9,10-Anthrylene-bis- (methylidynnitrilo)] - bis- [3- (2-dimethylaminoethyl) -auanidinl-tetrahydroiodide in 2.4 L of absolute ethanol is heated at reflux for 22 hours, then cooled overnight to give colorless crystals of S-methylthiosemicarbazide hydroiodide. A mixture of 11.65 g of this product and 4.41 g of 35 Ν, Ν-dimethylethylenediamine in 25 ml of absolute ethanol is heated at reflux to 100 ° C for 1 hour. The mixture is cooled, diluted with ether and cooled rapidly. The product, 1-amino-3- (2-dimethylaminoethyl) -guanidine hydroiodide, is isolated in the form of a colorless solid. A suspension of 2.34 g of 9,10-anthracenedicarboxaldehyde in 200 ml of absolute ethanol containing 5.46 g of the guanidine salt and 5.8 ml of 3.47 N of ethanolic hydrogen iodide acid are stirred and heated under reflux for 2 hours. The mixture is allowed to cool, finally at 0 ° C, and the desired solid is isolated by filtration.

10

Example 20 1,1 '- [9,10-Anthrylene-bis- (methylidynnitrilo)] - bis- [3- (3-dimethylaminopropyl) -2-ethyl-azuanidine-tetrahydrochloride] 3.82 g of solid (3-dimethylaminopropyl) - Ethylcarbodiimide hydrochloride is gradually added with stirring to an ice-cooled solution of 1.00 g of hydrazine hydrate in 75 ml of water. The mixture is stirred for 1 hour without further cooling, cooled rapidly, made strongly basic by the gradual addition of sodium hydroxide solution, then extracted with ether. The ether phase 20 is dried over magnesium sulfate, filtered and evaporated. A solution of the residue in 100 ml of ethanol is mixed with 3 ml of 8N ethanolic hydrochloric acid and 2.34 g of 9,10-anthracenedicarboxaldehyde, and the resulting suspension is stirred and heated at reflux for 2 hours, then left to cool. The desired product is separated after addition of ether and isolated by filtration.

Example 21 1,1 '- [9,10-Anthrylene-bis- (methylidynnitrilo)] -bis-diguanide-tetrahydrochloride

A suspension of 3.36 g of finely powdered cyanoguanidine in 50 ml of ethanol containing 2.00 g of hydrazine hydrate is stirred and heated on an oil bath at 50 ° C for 5 hours. After the addition of 4.68 g of anthracene-9, 10-dicarboxaldehyde and 15 ml of 8 N 35 ethanolic hydrochloric acid, stirring and heating are continued for 15 hours. After cooling, the separated solid is filtered off and then recrystallized from a mixture of ethanol and water to give the desired product as an orange solid.

Example 22 9,10-Anthracenedicarboxaldehyde-bis- (2-dimethylaminoethyl) -hydrazone

A suspension of 4.68 g of anthracene-9,10-dicarboxaldehyde in 100 ml of ethanol containing 4.13 g of [2- (dimethylamino) -10 ethyl] -hydrazine, cf. Elslager et al., J. Med. Chem. I, 493 (1964), containing two drops of acetic acid, is stirred and heated under reflux for 2 hours. The resulting solution is filtered, concentrated, allowed to cool at 45 ° C, diluted with petroleum ether and then cooled to 5 ° C.

The desired product is excreted in the form of an orange solid which is isolated by filtration.

Example 23 N, NH- [9,10-Anthrylene-bis- (methylidynnitrilo)] -diacetamidine-dihydrochloride

A mixture of 4.68 g of 9,10-anthracenedicarboxaldehyde and 4.38 g of acetimidrazone hydrochloride, cf. Neunhoeffer et al., Ann. 760, 102 (1972), in 100 ml of ethanol containing 5.0 ml of 8 N ethanolic hydrochloric acid is heated under reflux with stirring for 2 hours, after which the mixture is allowed to cool. The separated product is filtered off and washed with cold ethanol to give the desired product in the form of an orange solid.

Example 24 9,10-Anthracenedicarboxaldehyde bis (4,4-dimethylthiosemicarbazone)

A mixture of 2.34 g of 9,10-anthracenedicarboxaldehyde and 3.0 g of 4,4-dimethylthiosemicarbazide in 250 ml of absolute ethanol containing 2.0 ml of glacial acetic acid is heated at reflux for 24 hours, after which the mixture is allowed to cool 54 GB 168333 B1 at room temperature. The crude solid is isolated by filtration to give 1.83 g of orange red crystals, m.p. 241-242 ° C.

Example 25 1,1 · - [9,10-Anthrylene-bis- (ethylidynnitrilo)] - diguanidine dihydrochloride

A suspension of 2.28 g of 9.10-anthracenedicarbonitrile and 5.0 g of methyl magnesium iodide in a solution of 50 ml of ether 10 and 50 ml of toluene is heated at reflux for 8 hours.

The reaction product is isolated, suspended in ether and treated at -10 ° C with a mixture of ice and ammonium chloride. The ether layer is dried over MgSO 4 and saturated with hydrogen chloride to give the bis-ketimine dihydrochloride.

A solution of 3.33 g of bis-ketimine dihydrochlori det, 2.72 g of aminoguanidine hydrogen carbonate and 1.6 g of sodium acetate in 100 ml of ethanol is heated at reflux for 10 hours. The mixture is cooled and filtered to give the desired compound.

20

Example 26

Bis- (2-imidazolin-2-ylhydrazone) of 9,10-anthracenediacetal-dihydro-dihydrochloride

A mixture of 2.56 g of 9.10-anthracenediacetonitrile, cf. J.A.C.S. 77, 2845 (1955), 3.46 g of 2-hydrazino-2-imidazoline dihydrochloride and 1.64 g of sodium acetate in 50 ml of 50% ethanol are reduced in the presence of 12.5 g of Raney nickel until 2 molar equivalents of hydrogen are absorbed. The mixture is heated to boiling and filtered to remove Raney nickel.

The filtrate is evaporated to a small volume and cooled to give the desired product.

Example 27 1,1 '- [2-Methyl-9,10-anthrylene-bis- (methylidynnitrilo)] -dacmanidine dihydrochloride

A suspension of 2.48 g of 2-methyl-9,10-anthracene di-carboxaldehyde (Example 33) and 2.72 g of aminoguanidine hydrogen carbonate in 100 ml of ethanol and 3.6 ml of 8 N ethanolic Hydrochloric acid is heated under stirring and reflux for 2 hours. The mixture is cooled and the desired compound is filtered off.

5

Example 28 1,1 '- [2,3,6,7-Tetramethoxy-9,10-anthrylene-bis- (methylidine nitrilo) 1-diquanidine dihydrochloride

A suspension of 3.54 g of 2,3,6,7-tetramethoxy-9,10-10 anthracenedicarboxaldehyde, cf. 66, 2405n (1967), and 2.72 g of aminoguanidine hydrogen carbonate in 100 ml of ethanol and 3.6 ml of 8 N ethanolic hydrochloric acid are stirred and heated under reflux for 18 hours. The mixture is cooled and the desired compound is filtered, m.p. 314 ° C (dec.), Yield 15 95%.

Example 29 1,1- [2-Ethyl-9,10-anthrylene-bis- (methylidynnitrilo)] - diguanidine dihydrochloride A suspension of 2.72 g of 2-ethyl-9,10-anthracene-dicarboxaldehyde (Example 35) and 2.72 g of aminoguanidine hydrogen carbonate in 100 ml of ethanol and 3.6 ml of 8 N ethanolic hydrochloric acid are stirred and heated at reflux for 2 hours. The mixture is cooled and the desired compound is isolated by filtration.

25

Example 30

Bis- (2-imidazolin-2-ylhydrazone) of 2-chloro-9,10-anthracenedicarboxaldehyde dihydrochloride

A reaction mixture containing 1.34 g of 2-chloro-9,10-anthracenedicarboxaldehyde and 1.73 g of 2-hydrazinoimidazoline dihydrochloride in 80 ml of ethanol is refluxed for 2 hours and the mixture is filtered hot. After cooling, 0.7 g of the desired product is separated from the solution in the form of orange crystals with m.p. > 280eC.

35 56 DK 168333 B1 ✓

Example 31 1,11 - [2,6-Dimethoxy-9 ', 10-anthrylene bis (methylidynitrilo)] - diacmanidine dihydrochloride

A suspension of 2.94 g of 2,6-dimethoxy-9,10-anthracene-dicarboxaldehyde (Example 40) and 2.72 g of aminoguanidine hydrogen carbonate in 100 ml of ethanol and 2.6 ml of 8 N ethanolic hydrochloric acid is stirred. heated under reflux for 2 hours. The mixture is cooled and the desired compound is isolated.

Example 32 2-Chloro-9,10-anthracenedicarboxaldehyde

A solution of 15.0 g of 2-chloranthracene in 60.8 g of vinylene carbonate is heated at reflux for 20 hours.

Excess vinyl carbonate is removed by vacuum distillation.

15

As the residue, a brown solid is obtained which is recrystallized from a mixture of methylene chloride and methanol to give 2-chloro-9,10-dihydro-9,10-ethanoanthracene-11,12-diol-cyclic carbonate, m.p. 200-230 ° C.

A mixture of 12.0 g of this cyclic carbonate 20 and 9.2 g of potassium hydroxide in 100 ml of water and 12 ml of ethanol is heated to 75 ° C for 2 hours. The mixture is evaporated under reduced pressure to a volume of 50 ml, after which 400 ml of water is added. The separated crystalline product is isolated and recrystallized from toluene to give 25 2-chloro-9,10-dihydro-9,10-ethanoanthracene-11,12-diol with m.p. 195-210 ° C.

To a suspension of 2.73 g of this diol in 70 ml of acetic acid at 35 ° C is added potassium, 8.8 g of lead tetraacetate over 5 minutes. The reaction mixture is stirred at 35 ° C for an additional 2 hours and 1.5 g of an orange crystalline mixture is obtained. Evaporation of the mother liquor gives an additional 0.5 g of the compound. The two portions are combined and recrystallized from 50 ml of toluene to give 2-chloro-9,10-anthracenedicarboxaldehyde, m.p. 193-196 ° C, m.p. 195-210 ° C.

Example 33 2-Methyl-9,10-anthracenedicarboxaldehyde 13 g of 2-methylanthracene are converted to 2-methyl-9,10-anthracene-dicarboxaldehyde by analogy to the three-step procedure described for the analogous 2-chloro compound in Example 32, Yield 76%, m.p. 162-164 C.

Example 34 1-Chloro-9,10-anthracenedicarboxaldehyde 10 g of 1-chloroanthracene is converted to 1-chloro-9,10-anthracenedicarboxaldehyde by analogy to the three-step procedure described in Example 32, yield 96%, m.p. 186-189 ° C.

Example 35 2-Ethyl-9,10-anthracenedicarboxaldehyde 14 g of 2-ethylanthracene are converted to 2-ethyl-9,10-anthracenedicarboxaldehyde by analogy to the three-step procedure described in Example 32, yield 25%, m.p. 99-100 ° C.

Example 36 9,10-Bis (chloromethyl) -2-methylanthracene

A mixture of 35 ml of dioxane and 6 ml of concentrated hydrochloric acid is saturated with hydrogen chloride gas. Then 4.5 g of 2-methylanthracene and 3.8 g of 95% paraformaldehyde are added.

The mixture is stirred slowly and heated at reflux under addition of hydrogen chloride gas for 2 hours. The mixture is stirred and heated under reflux for an additional 3 hours, then left at room temperature for 16 hours.

The separated yellow solid is filtered off, washed with 30 dioxane and dried to give the desired compound.

Example 37 2-Methyl-9,10-anthracenedicarboxaldehyde To a stirred suspension of 2.6 g of 9,10-bis- (chloro-35-methyl] -2-methyl-anthracene in 50 ml of dimethylsulfoxide (dried over calcium hydride) under nitrogen at room temperature slowly add a solution prepared by adding 3.0 g of 2-nitropropane to a solution of 0.5 g of sodium in 58 GB 168333 B1

ISLAND

30 ml of ethanol. The color of the reaction mixture gradually changes from yellow to dark orange, and the mixture becomes homogeneous. At this time (2.5-3.0 hours), the mixture is filtered into 200 ml of ice water. The orange precipitate formed is isolated and redissolved in methylene chloride which is then extracted with water. The methylene chloride solution is dried over MgSO 4 and evaporated to dryness to give the desired compound.

Example 38 10 1-Methyl-9,10-anthracenedicarboxaldehyde 4.5 g of 1-methylanthracene is converted to 1-methyl-9,10-anthracenedicarboxaldehyde by analogy to the procedure described in Example 37 for the 2-methyl derivative.

Example 39 2,6-Dihydroxy-9,10-anthracenedicarboxaldehyde

A suspension of 2.4 g (0.01 mole) of 2,6-dihydroxy-anthraquinone in 100 ml of dry tetrahydrofuran containing 2.1 g of triethylamine is reacted with 2.2 g of trimethylsilyl chloride, and the reaction is carried out until the anthraquinone is dissolved.

The triethylamine hydrochloride is filtered off and the residual solution of filtered anthraquinone is used for the subsequent reaction as it is.

In a dry system protected from humidity and under an argon atmosphere, the solution of 0.01 mole of filtered anthraquinone in tetrahydrofuran at room temperature is slowly reacted with a solution of 0.02 mole [α-lithio-α- (N, N-dimethylamino) -methyl] -diphenylphosphine oxide, cf. Peterson, J. Am.

Chem. Soc. 93, 4027 (1971), in anhydrous ether-hexane. The reaction is carried out for 2 hours keeping the temperature at room temperature by means of an ice bath.

The solution of the enamine is hydrolyzed at room temperature by the addition of 20 ml of 90% formic acid solution.

The reaction mixture is filtered, washed with water, dried and 59

ISLAND

is recrystallized from toluene to give 2,6-dihydroxy-9/10-anthracene-dialdehyde.

Using known methods, the 2,6-dihydroxy-9,10-anthracenedicarboxaldehyde can be converted to the 5/6-dialkoxy derivatives.

Example 40 2.6- Dimethoxy-9,10-anthracene-dicarboxaldehyde

A suspension of 2.66 g (0.01 mole) of 2,6-dihydroxy-10 -9,10-anthracenedicarboxaldehyde in 100 ml of toluene is reacted with 0.02 mole of sodium hydride washed in petroleum ether and gently heated with stirring until hydrogen evolution occurs. ceases. The reaction mixture is cooled, then reacted with 2.84 g (0.02 mole) of methyl iodide and stirred at 40 ° C overnight, then refluxed, filtered warm to remove sodium iodide, and then allowed to cool. and crystals of 2,6-dimethoxy-9,10-anthracenedicarboxaldehyde are obtained.

20

Example 41 9,10-Anthracenedicarboxaldehyde

A solution of 2.38 g (0.01 mole) of cis-9,10-25-dihydro-9,10-ethanoanthracene-11,12-diol, cf. Newman et al., J. Am. Chem. Soc., 77, 3789 (1955), in 50 ml of glacial acetic acid is stirred using a magnetic stirrer at 30-35 ° C and 8.9 g (0.02 mol) of lead tetraacetate are added portionwise until iodide starch test paper is obtained. 30 permanent blue color. The reaction mixture is stirred for 2 hours and the orange crystals formed are filtered off and recrystallized from methylene chloride to give 1.5 g (65%) of orange needles with m.p. 245-247 ° C.

35 60 DK 168333 B1

Example 42 1,1'- [9,10-Anthrylene-bis- (methylidene-trilo) -bis- [3-furfurylguanidine] dihydrochloride

A mixture of 1.0 g of 9,10-anthracenedicarboxaldehyde, 2.0 g of 1-amino-3-furylguanidine dihydrochloride and 100 ml of ethanol is heated at reflux for 1.5 hours. The solution is evaporated to a glassy residue which is ground and triturated with diethyl ether to give 2.0 g of an orange powder with m.p. 135-140 ° C (decomp.).

Example 43 1,1'- [9,10-Anthrylene-bis- (methylidynnitrilo)] -bis- [3- (2- -thenyl) -guanidine] dihydrochloride_ A mixture of 2.0 g of 0.96 g of 9,10-anthracenedicarboxaldehyde, 2.0 g of 1-amino-3-thenylguanidine dihydrochloride, 75 ml of ethanol and 0.3 ml of concentrated hydrochloric acid are heated under reflux for 2.5 hours. The solution is cooled and filtered to remove a small amount of solid noise 20 and then evaporated to dryness. The residue is evaporated three times with methanol and dissolved in a small amount of methanol and a large portion of diethyl ether is added to give a gum-like solid. The above liquid is decanted and the residue is slurried with more 25 ether to give a yellow solid in a yield of 2.2 g, m.p. 190-200 ° C (dec.).

Example 44 1,1 '- [9,10-Anthrylene-bis- (methylidynnitrilo)] -bis- [2,3-diisopropylguanidine] dihydroiodide

A mixture of 4.0 g of 1-amino-2,3-diisopropyl-guanidine hydroiodide, 1.6 g of 9,10-anthracenedicarboxaldehyde, 100 ml of ethanol and 2 ml of 4 N ethanolic hydrogen iodide acid is heated at reflux for 4 hours. The mixture is filtered warm to remove a bit of solid and the filtrate is concentrated until an orange crystalline product is obtained. The suspension is cooled and filtered, and 4.4 g of product are obtained with m.p. 278-280 ° C.

Example 45 1,1 '- [9,10-Anthrylene-bis- (methylidynnitrilo)] - bis- [3- (2- 5-indanyl) -guanidine] dihydroiodide

A solution of 1.14 g of 9,10-anthracenedicarboxaldehyde, 3.1 g of 1-amino-3 “(1-indanyl) -guanidine in 50 ml of ethanol containing 3 ml of 4 N ethanolic hydrogen iodide acid is heated under reflux for 3 hours. hours, after which 10 is cooled overnight and 2.3 g of orange crystalline product are obtained with m.p. 262-263 ° C.

Example 26 1,1 '- [9,10-Anthrylene-bis- (methylidynnitrilo)] - bis- [3- (4- 15-pyridylmethyl) -guanidine] -tetrahydroiodide

A mixture of 2.3 g of 9,10-anthracenedicarboxaldehyde, 6.4 g of 1-amino-3- (4-pyridylmethyl) guanidine, 9.0 ml of 4 N hydrogen iodide acid and 100 ml of ethanol is heated at reflux for 3 hours. and cool to give 6.3 g of solid. 3.9 g of the solid are slurried in 160 ml of ethanol, then heated to boiling and water is added dropwise until a solution is formed.

This solution is treated with a bit of "Darco", filtered and cooled to give 2.2 g of product with m.p. 235-240 ° C (dec.).

Example 47 2-Methyl-9,10-anthracenedicarboxaldehyde 2.1 g of an isomeric mixture of 2-methyl-11,12-30-dihydroxy-9,10-ethano-anthracene is dissolved in 45 ml of glacial acetic acid and treated at room temperature with 7 45 g of lead tetraacetate until the iodide starch test is positive. After 2-3 hours at room temperature followed by cooling, orange crystals which are filtered off and recrystallized from methylene chloride-methanol are separated to give 1.1 g of orange crystals with m.p. 162-164 ° C.

62 DK 168333 B1

Example 48

Bis- (2-imidazolin-2-ylhydrazone) of 2-methyl-9,10-anthracenedicarboxaldehyde dihydrochloride monohydrate

A solution of 2.2 g of 2-methyl-9,10-anthracene-5-dicarboxaldehyde in 150 ml of boiling n-propanol is reacted with 3.1 g of 2-imidazolin-2-ylhydrazine. The solution is boiled and concentrated over 2 hours to 100 ml, then filtered and cooled. On standing for a long time, 2.2 g of orange crystals are separated by 10 m.p. 300-302 ° C.

The free base of the above compound can be obtained in the form of red-orange crystals by basifying the mother liquor with aqueous sodium hydrogen carbonate solution, m.p. 295-298 ° C.

15

Example 49 1,4-Dimethoxy-9,10-anthracenedicarboxaldehyde 10 g of an isomeric mixture of 1,4-dimethoxy-11,12-dihydroxy-9,10-ethano-anthracene are dissolved in 150 ml of glacial acetic acid at 50 ° C. and treated portionwise with 30 g of lead tetraacetate. After 2 hours at 50 ° C, the solution is filtered to remove soluble materials and then cooled to separate orange crystals which are filtered off, washed with glacial acetic acid and dried, m.p. 208-212 ° C, dec. 5%.

25

Example 50

Bis - [1,4-dimethoxy-bis- (2-imidazolin-2-ylhydrazone)] of 9,10-anthracenedicarboxaldehyde dihydrochloride

A solution of 1.7 gl, 4-dimethoxy-9,10-anthracenedicarboxaldehyde in 100 ml of n-propanol is reacted with 2.06 g of 2-imidazolin-2-ylhydrazine and boiled for 2 hours while concentrating to 50 ml. The warm solution is filtered to give a yellow solid which is washed with n-propanol and dried, m.p. 300-305 ° C, yield 75%.

35 63 DK 168333 B1

Example 51

Bis- (2-imidazolin-2-ylhydrazone) of 2,6-difluoro-9,10-anthracenedicarboxaldehyde

A suspension of 2.74 g of 2,6-difluoro-9,10-anthracene-dicarboxaldehyde (Example 52) and 3.46 g of 2-hydrazino-2-imide-azoline dihydrochloride in 100 ml of ethanol is stirred and heated at reflux. in 3 hours. The mixture is cooled and the product isolated by filtration, yield 56%, m.p. > 320 "c.

Example 53 2,6-Difluoro-9,10-anthracenedicarboxaldehyde 15 g of 2,6-difluoroanthracene are converted to 2,6-difluoro-9,10-anthracenedicarboxaldehyde using the procedure described in Example 32, eq. 32%, m.p.

240-242 ° C.

Example 53

Bis- (2-imidazolin-2-ylhydrazone) of 2,3-dimethyl-9,10-anthracenecarboxaldehyde A suspension of 2.7 g of 2,3-dimethyl-9,10-anthracendi carboxaldehyde (Example 54) and 3.46 g of 2-hydrazino-2-imidazole-in-dihydrochloride in 100 ml of ethanol is stirred and heated under reflux for 3 hours. The mixture is cooled and the product isolated, yield 93%, m.p. 300-305'C.

25

Example 55 2.3-Dimethyl-9,10-anthracenedicarboxaldehyde 14 g of 2,3-dimethylanthracene is converted to 2,3-dimethyl-9,10-anthracenedicarboxaldehyde using the procedure described in Example 32, eq. 47%. mp. 203-204 "C.

Example 55

Bis- (2-imidazolin-2-ylhydrazone) of 2,6-dichloro-9,10-anthracanedicarboxaldehyde dihydrochloride

A suspension of 3.03 g of 2,6-dichloro-9,10-anthracenedicarboxaldehyde and 3.46 g of 2-hydrazino-2-imidazoline dihydrochloride in 100 ml of ethanol is heated under reflux for 3 hours, then which is cooled to give the desired compound.

Example 56 2,6-Dichloro-9,106 anthracenedicarboxaldehyde

Analogous to the three-step procedure described in Example 32, 18 g of 2,6-dichloro-anthracene-2,6-dichloro-9,10-anthracenedicarboxaldehyde are reacted.

Example 57

Bis- (2-imidazolin-2-ylhydrazone) of 1,4-dimethyl-9,10-anthracenedicarboxaldehyde dihydrochloride

A suspension of 2.6 g, 4-dimethyl-9,10-anthracenedicarboxaldehyde and 3.46 g of 2-hydrazino-2-imidazolin-dihydrochloride in 100 ml of ethanol is heated under reflux for 2 hours and cooled, desired compound is obtained, yield 82%, m.p. 185-190 ° C.

Example 58 1,4-Dimethyl-9,10-anthracenedicarboxaldehyde

Analogous to the three-step procedure described in Example 32, 16 g of 1,4-dimethylanthracene is reacted to give 1,4-dimethyl-9,10-anthracenedicarboxaldehyde, yield 10%, m.p. 158-162 ° C.

25

Example 59 9,10-Dihydro-9,10-anthracenedicarboxaldehyde

A mixture of 21.3 g of vinylene carbonate (redistilled to form a colorless liquid with bp 71-73 ° C, 3.73 kPa) and 4.4 g of dry anthracene are heated at reflux (165-170 ° C) below nitrogen for 20 hours, then the mixture is vacuum distilled (62-64 ° C, 2.27 kPa) and 10.2 g of yellow-brown residue are obtained. This residue is taken up in 100 ml of methylene chloride, treated with charcoal and filtered. The filtrate is treated with 100 ml of methanol and cooled to give colorless crystals of cis-9,10-dihydro-9,10-ethano-anthracene-11, 12-diol, cyclic carbonate, m.p. 260-262 ° C.

65 DK 168333 B1

A mixture of 5.6 g of cis-9,10-dihydro-9,10-ethanoanthracene-11,12'-diol, cyclic carbonate, 4.9 g of potassium hydroxide, 6.4 ml of water and 53 ml of ethanol is stirred at 70 ° C. 75 ° C for 2 hours. The resulting two-phase system is filtered. The filtrate 5 is diluted with twice the volume of water and cooled to give colorless crystals of cis-9,10-dihydro-9,10-ethanoanthracene-11,12-diol with m.p. 202-204 ° C.

A mixture of 2.38 g of cis-9,10-dihydro-9,10-ethanoanthracene-11,12-diol in 40 ml of glacial acetic acid at room temperature is treated portionwise with 4.8 g of lead tetraacetate with stirring for a period of time. 10 minutes. The mixture is cooled to 15 ° C and the solid formed is filtered off, washed once with glacial vinegar and then carefully with water to give the desired product in the form of colorless grains, m.p. 144-146 ° C, yield 94%.

Example 60

Cis-1,4-dimethoxy-9,10-dihydro-9,10-anthracendicarboxaldehyde 1 µl, 4-dimethoxy-9,10-dihydro-9,10-ethano-anthracene-11,12-diol is suspended for 30 minutes. ml of an aqueous solution containing 0.77 g of potassium periodate and 1 ml of ethanol. After stirring at room temperature for 24 hours, the insoluble material is filtered off, washed thoroughly with water and dried to give a yellow product, m.p. 129-132 ° C, yield 28%.

25

Example 61

Bis- (2-imidazolin-2-ylhydrazone) -9,10-dihydro-9,10-anthracene dicarboxaldehyde

A mixture of 2.36 g of 9,10-dihydro-9,10-anthracene

3 O

dicarboxaldehyde and 3.46 g of 2-hydrazinoimidazoline dihydrochloride in 200 ml of n-propanol are boiled on a hot plate for 1 1/2 hours while the volume is concentrated to 100 ml.

The mixture is cooled and left overnight to give a solid, which is isolated by filtration, washed with 35 n-propanol and dried. 0.4 g of this solid is recrystallized from water to give the desired dihydrochloride product in the form of colorless flakes, m.p. 258-262 ° C, yield 13%.

66 DK 168333 B1

Example 62 2-Chloro-9,10-dihyaro-9,10-anthracenedicarboxaldehyde A solution of 15.0 g of 2-chloroanthracene in 60.8 g of vinylene carbonate is refluxed for 20 hours and then vacuum distilled. The residue is recrystallized from a mixture of methylene chloride and methanol to give cis-2-chloro-9,10-dihydro-9,10-ethanoanthracene-11,12-diol, cyclic carbonate in the form of gray crystals, m.p. 200-230 ° C.

A mixture of 12.0 g of cis-2-chloro-9,10-dihydro-9,10-ethanoanthracene-11, 12-diol, cyclic carbonate, 9.2 g of potassium hydroxide, 12 ml of water and 100 ml of ethanol is heated. to 75 ° C for 2 hours, then evaporate in vacuo to 50 ml. The concentrate is diluted with 400 ml of water and the solid formed is filtered off. This solid is recrystallized from toluene, decolorized with a bit of charcoal, and colorless crystals of cis-2-chloro-9,10-dihydro-9,10-ethanoanthracene-11,12-diol are obtained. 195-210 ° C.

To a solution of 2.7 g of cis-2-chloro-9,10- -dihydro-9,10-ethanoanthracene-1,12-diol in 20 ml of acetic acid at room temperature is added portionwise 5.0 g of lead tetraacetate containing 10 % acetic acid. The mixture is stirred for 10 minutes, cooled on an ice-water bath and the 25 crystals formed are filtered off and washed with cold acetic acid to give the desired product in the form of greyish white crystals, m.p. 113-115 ° C yield 33%.

Example 63

2-Chloro-bis- (2-imidazolin-2-ylhydrazone) -9,10-dihydro-9,10-anthracenedicarboxaldehyde dihydrochloride

A reaction mixture containing 0.7 g of 2-chloro-9,10-dihydro-9,10-anthracenedicarboxaldehyde and 0.88 g of 2-hydrazinoimidazoline dihydrochloride in 20 ml of n-propanol is refluxed for 1 hour, 10 ml of the n-propanol is removed through a cooler. The mixture is cooled and ether is added to give the desired product as yellow crystals, m.p. 190 ° C (dec.), Yield 77%.

67 DK 168333 B1

Example 64 1-Chloro-9,10-dihydro-9,10-anthracenedicarboxaldehyde 5 A mixture of 29.5 g of 1-chloranthracene and 126 g of vinyl carbonate is reacted analogously to the procedure described in Example 4 to give yellow-brown crystals of cis- 1-Chloro-9,10-dihydro-9,10-ethanoanthracene-11,12-diol, cyclic carbonate, m.p. 242-250 ° C.

A reaction mixture containing 27.9 g of cis-1-chloro-9,10-dihydro-9,10-ethanoanthracene-11, 12-diol, cyclic carbonate, 21.4 g of potassium hydroxide, 28 ml of water and 230 ml of ethanol is heated. to 75 ° C for 2 hours, then evaporate to a volume of 80 ml. The residue 15 is dissolved in 500 ml of chloroform. The chloroform solution is washed with three times 70 ml of water and stained with charcoal. The chloroform is removed and the yellow residue is dissolved in 150 ml of toluene. On cooling, cis-1-chloro-9,10-dihydro-9,10-ethanoanthracene-11,12-diol is obtained in the form of colorless crystals of m.p. 180-182 ° C.

To a solution of 0.54 g of cis-1-chloro-9,10-dihydro-9,10-ethanoanthracene-11,12-diol in 5 ml of acetic acid at 35 ° C is added portionwise 1.0 g of lead tetraacetate. The mixture is stirred for 10 minutes, cooled in an ice-water bath, and the crystals formed are filtered off and washed with cold acetic acid to give the desired compound as colorless crystals, m.p. 144-146 ° C, dec. 34%.

Example 65 1-Chloro-bis- (2-imidazolin-2-ylhydrazone) -9,10-dihydro-9,10-anthracenedicarboxaldehyde dihydrochloride

A reaction mixture containing 3.7 g of 1-chloro-9,10-dihydro-9,10-anthracenedicarboxaldehyde and 4.64 g of 2-hydrazinoimidazoline dihydrochloride in 100 ml of n-propanol is refluxed for 1 hour, removing approx. 50 ml of n-propanol through the condenser. The mixture is cooled and ether is added to give the desired product as yellow crystals, m.p. 200 ° C (dec.), M.p. 51%.

68 DK 168333 B1

Example 66 2-Methyl-9,10-dihydro-9/10-anthracenedicarboxaldehyde 5 g of 2-methylanthracene in 50 ml of vinylene carbonate is heated at reflux under nitrogen for 20 hours. Excess vinylene carbonate is removed by vacuum distillation (55 ° C, 1.47-1.60 kPa) and the residue is taken up in 100 ml of methylene chloride, filtered and triturated three times with the corresponding volume of methanol. The product, cis-2-methyl - 9,10-dihydro-9,10-ethanoanthracene-11, 12-diol, cyclic carbonate is recovered in the form of its eyesight and anti-forms in the form of cream colored crystals with m.p. 225-227 ° C and 183-185 ° C respectively.

2.8 g of one of the syn and anti forms of cis-2-methyl-9,10-dihydro-9,10-ethanoanthracene-11,12-diol cyclic carbonate (mp 225-227 ° C ) in a mixture of 2.5 g of potassium carbonate, 2.3 ml of water and 27 ml of ethanol is stirred at 70 ° C for 2 hours. The mixture is treated with the 20-fold volume of water to give the corresponding syn or anti-form of cis-2-methyl-9,10-dihydro-9,10-ethanoanthracene-11,12-diol in the form of light yellow crystals with m.p. 227-228 ° C.

7.4 g of the second synthetic anti-form of 25 cis-2-methyl-9,10-dihydro-9,10-ethanoanthracene-11,12-diol, cyclic carbonate, m.p. 183-185 ° C, in a mixture of 6.15 g of potassium hydroxide, 8.1 ml of water and 70 ml of ethanol are reacted as described immediately above to give the corresponding syn or anti-form of cis-2-methyl-30 -9,10-dihydro-9,10-ethanoanthracene-11,12-diol in the form of a cream solid, m.p. 153-156 ° C.

2.5 g of cis-2-methyl-9,10-dihydro-9,10-ethanoanthracene-11,12-diol (prepared above as yellow crystals with mp 227-228 ° C) are suspended in 100 ml of aqueous 33 solution containing 2.14 g of sodium periodate and 1 ml of ethanol. The mixture is stirred at room temperature for 2 hours, after which the solid is filtered off, washed with water and dried to give the desired product as a pale yellow solid, m.p. 125-126 ° C, yield 96%.

69 DK 168333 B1

Example 67 2-Methyl bis (2-imidazolin-2-ylhydrazone) -9,10-dihydro-9,10-anthracenedicarboxaldehyde dihydrochloride

A mixture of 1.9 g of 2-methyl-9,10-dihydro-9,10-anthracenedicarboxaldehyde and 2.63 g of 2-hydrazino-imidazoline dihydrochloride in 150 ml of n-propanol is heated to boiling and concentrated to ca. 50 ml over 10 1-2 hours, then filter hot and then cool. 2-3 ml of acetone and 200 ml of ether are added to form a precipitate which is filtered off and the desired product is obtained in the form of a yellow solid, m.p. 210-220 ° C (dec.), Yield 84%.

15

Example 68 2.3-Dimethyl-9/10-dihydro-9,10-anthracenedicarboxaldehyde

A mixture of 35.4 g of vinylene carbonate and 8.5 g of 2,3-dimethylanthracene, cf. N.G. Jaylord, V. Stepan, 20 Collect. Czeck. Chem. Comm. 39, 1700 (1974), is heated at reflux under nitrogen for 20 hours. The cooled solution is treated with 100 ml of methanol, heated, decolorized with charcoal, filtered and cooled to give 7.1 g of colorless crystals of 2,3-dimethyl-9,10-dihydro-25-9,10-ethanoanthracene-11 , 12-diol, cyclic carbonate, m.p. 207-212 ° C.

A mixture of 6.4 g of 2,3-dimethyl-9,10-dihydro-9,10-ethanoanthracene-11, 12-diol, cyclic carbonate, 5 g of potassium hydroxide, 6.6 ml of water and 60 ml of ethanol is stirred. at room temperature for 56 hours. The resulting precipitate is filtered off, dissolved in glacial acetic acid and precipitated with excess water to give 4.0 g of colorless 2,3-dimethyl-9,10-dihydro-9,10-ethanoanthracene-11,12-diol with m.p. . 240-245 ° C.

A suspension of 0.3 g of 2,3-dimethyl-9,10-35-dihydro-9,10-ethanoanthracene-11, 12-diol in 10 ml of water and 0.1 ml of ethanol is treated with 0.243 g of sodium periodate and stirred at room temperature. 20 ° C for 2.5 hours. The solid formed is filtered off, washed with water and dried to give 0.2 g of 2,3-dimethyl-9,10-dihydro-9,10-anthracenedicarboxaldehyde with m.p. 3-117 ± 1 ° C.

Example 69 2,3-Dimethyl bis- (2-imidazolin-2-ylhydrazone) -9,10-dihydro- -9,10-anthracenedicarboxaldehyde dihydrochloride

A mixture of 0.2 g of 2,3-dimethyl-9,10-dihydro-9,10-anthracenedicarboxaldehyde and 0.3 g of 2-hydrazinoimidazoline dihydrochloride in 30 ml of n-propanol is boiled for 2 hours while mixing concentrated to a volume of 10 ml.

The yellow solution is treated with 0.5 ml of acetone and 20 ml of ether to give a yellow precipitate, which is filtered off, washed with acetone and dried, and 0.15 g of product with m.p. 285-290 ° C.

15

Example 70 1,4-Dimethyl-9,10-dihydro-9,10-anthracenedicarboxaldehyde A mixture of 4.12 g of 1,4-dimethylanthracene and 17.2 g of vinylene carbonate is refluxed under nitrogen 20 for 18 hours, cooled, four volumes are added. methanol, stirred and cooled. The crystals formed are filtered off, washed with methanol and dried to give 5.45 g of colorless 1,4-dimethyl-9,10-dihydro-9,10-ethanoanthracene-11,12-diol, cyclic carbonate, m.p. 225-245 ° C.

A mixture of 4.4 g of 1,4-dimethyl-9,10-dihydro-9,10-ethanoanthracene-11, 12-diol, cyclic carbonate, 3.45 g of potassium hydroxide, 4.5 ml of water and 40 ml ethanol is stirred at 20 ° C for 16 hours. The two-layer mixture is filtered through "Celite" ® and treated with quadruple volume of water, whereby-3Q is obtained 3.8 g of colorless 1,4-dimethyl-9,10-dihydro-9,10-ethanoanthracene-11,12-diol with m.p. 158-160 ° C.

A mixture of 1.5 g, 4-dimethyl-9,10-dihydro-9,10-ethanoanthracene-11, 12-diol and 1.22 g of sodium periodate in 50 ml of water and 1 ml of ethanol is stirred for 2 hours at 20 ° C. ° C.

The resulting solution is filtered, washed with water and dried to give 1.45 g of 1,4-dimethyl-9,10-dihydro-9,10-anthracenedicarboxaldehyde, m.p. 159-160 ° C.

ΙΜΊ ^^ —— ^ 1 - —— 71 DK 168333 B1

Example 71 1,4-Dimethyl bis- (2-imidazolin-2-ylhydrazone) -9,10-dihydro- -9,10-anthracenedicarboxaldehyde dihydrochloride

A mixture of 1,15 g of 1,4-dimethyl-9,10-dihydro-5 -9,10-anthracenedicarboxaldehyde and 1.53 g of 2-hydrazinoimidazoline dihydrochloride in 50 ml of n-propanol is boiled and concentrated to 20 ml over 2 hours. The resulting solution is treated with 1 ml of acetone and 75 ml of ether to give a light yellow precipitate which is filtered off, washed with acetone 10 and dried to give 1.8 g of product with m.p. 230-235 ° C (decomposition).

Example 72

Cis-1,4-dimethoxy-9,10-dihydro-9,10-ethanoanthracene-11, 12-diol, 15 cyclic carbonate, syn- and anti-isomeric 15 g of 1,4-dimethoxyanthracene is refluxed under nitrogen with 55 g of vinylene carbonate for 16 hours. Excess vinylene carbonate is removed under vacuum (55 ° C / L, 60 kPa) and the residue is slurried in chloroform and filtered to give 20 g of a mixture of yellow and colorless crystals.

Boiling this mixture with methylene chloride and filtration yields 10.5 g of colorless crystals with m.p. 283-285 ° C of one of the syn or anti-isomers of the product.

The second syn- or anti-isomer is obtained from the original chloroform filtrate by precipitation with methanol and recrystallization from a mixture of methylene chloride and methanol to give 5 g of colorless crystals with m.p. 255-260 ° C. The two isomers have the same IR spectrum, give correct analysis data and a mixture thereof gives a melting point depression (238-245 ° C).

Example 73

Cis-1,4-dimethoxy-9,10-dihydro-9,10-ethanoanthracene-11,12-diol, syn- and anti-isomeric A mixture of 10.5 g of cis-1,4-dimethoxy-9 , 10- dihydro-9,10-ethanoanthracene-11,12-diol, cyclic carbonate, m.p. 283-285 ° C and 8.5 g of potassium hydroxide, 12 ml of water and 85 ml of ethanol are stirred at room temperature for 16 hours. The solid formed is filtered off, washed with water and dried to give 5.0 g of one of the isomers of the product, snip. 187-188 ° C.

The second syn / anti-isomer is similarly obtained from 4.0 g of the corresponding cyclic carbonate, m.p. 238-245 ° C and 2.1 g of product are obtained with m.p. 183-185 ° C. The two isomeric diols exhibit the same IR spectrum, provide correct analysis and a mixture thereof exhibits a melting point depression, m.p. 155-158 ° C.

10

Example 7 9

Bis- (2-imidazolin-2-ylhydrazone) -1,4-dimethoxy-9,10-dihydro-9,10-anthracenedicarboxaldehyde dihydrochloride

A mixture of 1.5 g of 1,4-dimethoxy-9,10-dihydro-15 -9,10-anthracenedicarboxaldehyde and 1.8 g of 2-hydrazino-2-imidazoline-2-dihydrochloride in 100 ml of n-propanol boil and concentrate to 50 ml over 2 hours. The cloudy solution is clarified by filtration, then basified with saturated sodium hydrogen carbonate solution and diluted with 20 times the triple volume of water to give 1.5 g of the free base as a yellow solid, m.p. 235-240 ° C. The dihydrochloride salt of the product is obtained by dissolving 1 g of the free base in 40 ml of n-propanol and 1 ml of 7 N anhydrous ethanolic hydrochloric acid is added. The solution is concentrated to an oil and recrystallized from n-propanol to give 0.3 g of a colorless dihydrochloride salt, m.p. 250-255 ° C.

Example 75 Bis- (2-imidazolin-2-ylhydrazone) -7,12-dihydro-benz [a] anthracenedicarboxaldehyde 1.43 g of 7,12-dihydro-benz [a] anthracene-7,12 dicarbox aldehyde, cf. Neuman and Din, J. Org. Chem. 36, 966 (1971), dissolved in 100 ml of boiling n-propanol. This solution is treated with 1.73 g of 2-hydrazinoimidazoline dihydrochloride and boiling is continued for 3 hours. The mixture is clarified by hot-filtration. On cooling the filtrate, an orange solid is obtained which is filtered off and washed with n-propanol. The filtrate and n-propanol washings are combined and concentrated to half the volume, diluted to 200 ml with water and made basic with saturated aqueous sodium hydrogen carbonate solution. The rubbery substance formed solidifies and then is washed with water, filtered off, taken up in methanol 5 and precipitated with water to give the desired product in base form with m.p. 190-195 ° C, yield 14%. This base is converted to the dihydrochloride salt by dissolving in n-propanol, adding 6N hydrochloric acid in n-propanol and cooling. The dihydrochloride salt melts at 245-250 ° C, yield 71%.

10

Example 76 5,12-Dihydro-5,12-benz [b] anthracenedicarboxaldehyde

A mixture of 7.0 g of benz [b] anthracene and 26 g of vinylene carbonate is heated at reflux under nitrogen 15 for 20 hours. Excess vinyl carbonate is removed by vacuum distillation (57 ° C / 1.20 kPa) and the residue is taken up in 25 ml of methylene chloride and filtered. The filtrate is treated with twice the volume of methanol and then cooled to form a tan solid and a mother liquor which is set aside. The solid is recrystallized from 60 ml of 1,2-dichloromethane, filtered off, washed with methanol and set aside. The mother liquor is concentrated prior to obtain a gummy solid which is recrystallized from a mixture of methylene chloride and methanol and a gray solid is mixed with the above solid and the mixture is recrystallized from ethyl acetate with charcoal 5,12-dihydro-5,12-ethanobenz [b] anthracene-13,14-diol, cyclic carbonate in the form of colorless rods. A mixture of 1.3 g of the 30 cyclic carbonate, 1.05 g of potassium hydroxide, 1 ml of water and 15 ml of ethanol is stirred at 60-65 ° C for 2 hours. The mixture is diluted with 1-2 volumes of water, filtered and the solid washed with water and dried to give cis-5,12-dihydro-5,12-ethanobenz [b] anthracene-13,14-diol in the form of 35 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 of glacial acetic acid at 20 ° C is added portionwise 4.4 g of lead tetraacetate. The reaction mixture is stirred for 45 minutes.

The slightly purple solid is filtered off, washed with glacial acetic acid and finally with water, then dried and 1.0 g of 5,12-dihydro-5,12-benz [b] anthracene-dicar-boxaldehyde is obtained. with m.p. 170-172 ° C.

Example 77

Bis (2-imidazolin-2-ylhydrazone) -5.12-dihydro-5,12 - benz [b] anthracendicarboxaldehyd dihydrochloride

A mixture of 0.85 g of 5,12-dihydro-5,12-benz [b] -anthracene-dicarboxaldehyde and 1.04 g of 2-hydrazinoimidazoline-10-dihydrochloride in 60 ml of n-propanol is boiled and concentrated to 30 ml. over 2.5 hours. The solution is clarified by filtration and allowed to cool for 48 hours. The resulting dark red crystals of the desired product weigh 0.12 g and melt at 290-295 ° C. More product can be obtained in the form of 15 of the free base by diluting the mother liquor with water and.

then to do basic with sodium hydrogen carbonate solution. The crude product formed is recrystallized from methanol to give 0.15 g of dark red crystals with m.p. 230-233 ° C.

Example 78 7,12-Benz [a] anthracenedicarboxaldehyde.

A mixture of isomers of 7,12-dihydro-7,12-benz [a] anthracenedicarboxaldehyde, cf. Newman & Din, J. Org. Chem. 36, 967 (1971), is suspended in 75 ml of glacial acetic acid, after which 6 g of ferric chloride hexahydrate is added and. Stir at room temperature for 3 hours. A yellow solid is formed which is filtered off, washed with acetic acid and water to give the yellow product, m.p. 197-198 ° C, dec. 75%.

Example 79

Bis - (2-imidazolin-2-ylhydrazone) -7,12-benz [a] -anthracenedi-carboxaldehyde dihydrochloride

A solution of 0.57 g of 7,12-benz [a] anthracenedicarboxaldehyde and 0.70 g of 2-imidazolin-2-ylhydrazine in 50 ml of n-propanol is boiled and concentrated to 20 ml over 3 hours. After cooling for 3 days, the orange powder formed is filtered off, washed with n-propanol and dried to give the product, m.p. 240-245 ° C, yield 53%. The mother liquor is diluted with twice the volume of water and made basic with sodium hydrogen carbonate solution, giving the free base of the product in the form of an orange solid, m.p. 210-215 ° C, yield 30%.

Example 80 5,12-Benz [b] anthracenedicarboxaldehyde

A solution of 5 g of 13,14-dihydroxy-5,12-ethano-benz [b] anthracene in 110 ml of glacial acetic acid is treated with 15.4 g of lead acetate in one portion and stirred at 30-40 ° C for 3 hours.

The formed purple solid is filtered off, washed once with acetic acid and then with water, dried and recrystallized from methylene chloride-methanol to give purple needles, m.p. 215-217 ° C, yield 20%.

Example 81

Bis- (2-imidazolin-2-ylhydrazone) -5,12-benz [b] anthracenedicarboxaldehyde dihydrochloride

A suspension of 1.0 g of 5,12-benz [b] anthracenedicarboxaldehyde and 1.2 g of 2-imidazolin-2-ylhydrazine in 75 ml of n-propanol is boiled and concentrated to 50 ml. The solid formed formed is filtered off from the hot solution, washed with n-propanol to give a purple product with m.p. 320-325 ° C, yield 80%.

25 30 35

Claims (30)

1. Analogous Process for Preparation of Anthracene 9,10-Bis-Carbonyl Hydrazones of General Formula 5 Analogous process according to claim 1, characterized in that the nydrazine is reacted in a lower alkanol solvent in the presence of a catalytic amount of acid at a temperature of 50-125 ° C. The analogous process of claim 1, characterized in that the hydrazine is guanyl hydrazine. 3 CH = 0 -5 R CH = 0 where R3, R4, R5 and R6 as well as rings A, B and C have the meanings given above, are reacted with a hydrazine of the formula R1 / HpN-N 20 \ R | 2 where r ! has the meaning given above and R'2 means R2 as defined above or -C (SR ') = NR2 where R' means lower alkyl and where R'2 means -C (S'R ") = NR2 is reacted with the corresponding amine to give a compound of formula I wherein R 2 is -C-R 7 or -C-NH 1 II IXN - (CH 2) m where X, R 7 and m have the meanings given above, whereupon 35 the product formed when R 1 and R 2 represent hydrogen, if necessary reacted with a compound of the formula H 3 C-S-R 2, wherein R 2 has the meaning given above and / or a compound formed, if desired, is converted to the pharmacological accept -40 table acid addition salt or its quaternary ammonium salt DK 168333 B1 3 CH 5 VvVX A B C Analogue process according to claim 1, characterized in that R1, R3, R4, R5 and R6 are hydrogen and R2 is 10 N (CH2) m -C-NH 15 where m is 2, bis- (2-imidazoline-2 -yl) -hydrazone of 9,10-anthra-cendicarboxaldehyde dihydrochloride. Analogous process according to claim 1, characterized in that R 1 -, R 3, R 4, R 5 and R 6 are hydrogen and R 2 is 20 X in 7 -C-R 7 where X is imino and R 7 is methylamino, 1,1- [9,10-25 anthrylene bis- (methylidynitrilo)] bis-3-methylguanidine dihydroiodide. Analogous process according to claim 1, characterized in that R1, R3, R4, R5 and R6 are hydrogen and R2 is hydrogen. X is 7 -C-R7 where X is methyl imino, R7 is methylamino, 1,1 '- [9,10-anthrylene-bis- (methylidynnitrilo)] -bis- (2,3-dimethyl-guanidine) -dihydroiodid. Analogue process according to claim 1, characterized in that R1, R3, R4, R5 and R6 are hydrogen and R2 is X II-C-R7 where X is imino and R7 is dimethylamino, 1,1'- [1,10-anthrylene-bis- (methylidynnitrilo)] - bis- (3,3-dimethyl-guanidine) - dihydroiodide. An analogous process according to claim 1, characterized in that R1, R3, R4, R5 and R6 are hydrogen, 5 and R2 are XI 7 -C-R7 where X is imino and R7 is hydroxyethylamino, 1,1 * -10 - [9,10-Anthrylene-bis- (methylidynitrilo)] - bis- [3- (2-hydroxyethyl) -guanidine] dihydroiodide. Analogous process according to claim 1, characterized in that R1, R3, R4, R5 and R6 are hydrogen and R2 is hydrogen. X is 7 -C-R7 where X is imino and R7 is 2-furfurylamino, 1,1 '- [9,10-anthrylene-bis- (methylidynnitrilo)] - bis- [3- (2-thienyl) -15 guanidine] dihydrochloride. 10. An analogous process according to claim 1, characterized in that R1, R3, R4, R5 and R6 are hydrogen and R2 is N - (C R * / .hr «s-iT8: v wherein A, B and C form an anthracene nucleus or a 9,10-dihydroanthracene nucleus, R1 is hydrogen or alkyl of up to 15 carbon atoms, R2 is hydrogen, alkyl of up to 15 to 4 carbon atoms, phenyl or a monovalent group of the formula x H- (CH 2) a An analogous process according to claim 1, characterized in that R 1 is methyl, R 3, R 4, R 5 and R 6 are hydrogen and R 2 is N - (CH 2) ® II I -C-NH 35 where m is 2, bis - (2-imidazolin-2-ylmethylhydrazone) of 9,10-anthracenedicarboxaldehyde dihydroiodide. An analogous process according to claim 1, characterized in that R 1, R 3, R 4, R 5 and R 6 are hydrogen and R 2 is X 1 in 7 -C-R 7 where X is imino and R 7 is benzylamino, 1, 1 * - [9,10-5 anthrylene-bis- (methylidynnitrilo)] - bis- (3-benzylguanidine) dihydroiodide. Analogous process according to claim 1, characterized in that R 1, R 3, R 4, R 2 and R 6 are hydrogen and R 2 Analogous process according to claim 1, characterized in that R1, R3, R4, R5 and R6 are hydrogen and R2 is X 15 -C-NH where m is 2, bis- (2-imidazolin-2-ylhydrazone) of 2-methyl-9,10-anthracenedicarboxaldehyde dihydrochloride. An analogous method according to claim 1, characterized in that R1, R3, R4, R5 and R6 are hydrogen and R2 is X17. -C-R7 where X is imino and R7 is 2-thenylamino, 1,1 '- [9,10-anthrylene-bis- (methylidynnitrilo)] - bis- [3- (2-thenyl) -guanidine] - dihydrochloride. X is 7 -C-R7 where X is imino and R7 is amino, 1,1,1 * - [9,10-anthrene-bis- (methylidynnitrilo)] - diguanidine dihydrochloride. Analogous process according to claim 1, characterized in that R1, R3, R4, R5 and R6 are hydrogen and R2 is X in 7 -C-R7 40 where X is imino and R7 is 4-pyridylmethylamino, 1 , 1 '- [9,10-Anthrylene-bis- (methylidynnitrilo)] - bis- [3- (4- Η I - DK 168333 B1 pyridylmethyl) -guanidine] -tetrahydroiodide. Analogous process according to claim 1, characterized in that R 1, R 3, R 4 and R 6 are hydrogen, R 5 is 2-chloro and R 2 is N- (CH 2) m II I -C-NH where m is 2, bis- (2-imidazolin-2-ylhydrazone) of 2-chloro-9,10-anthracenedicarboxaldehyde dihydrochloride. An analogous process according to claim characterized in that R1, R3, R4 and R6 are hydrogen, R5 is 2-methyl and R2 is N- (CH2) rn II I An analogous method according to claim 1, characterized in that R1, R4 and R6 are hydrogen, R3 and Analogous process according to claim 1, characterized in that R 3 and R 4 form a phenyl group with the carbon atoms in ortho and meta position to the anthracene nucleus, R 5 and R 6 are hydrogen and m is 2, bis- (2-imidazolin-2-yl). Hydrazone-7,12-benz [a] anthracenedicarboxaldehyde. R 5 is fluoro and R 2 is N - (CH 2) m -C-NH where m is 2, bis- (2-imidazolin-2-ylhydrazone) of 2,6-difluoro-9,10-anthracenedicarboxaldehyde. II is -C-R7 where X is imino and R7 is cyclohexylamino, 1,1 '- [9,10-anthrylene-bis- (methylidynnitrilo)] - bis- (3-cyclohexyl-guanidine) dihydroiodide. 20. D1 -C-R7 or -C-NH where m is 2, 3, 4 or 5, R7 means amino, monohydroxyalkyl amino of 2-4 carbon atoms and wherein the carbon atom in the α position to the nitrogen atom does not carry a hydroxy group, 25 alkylamino with up to 4 carbon atoms, dialkylamino with up to 4 carbon atoms per alkyl group, cycloalkylamino having 3-6 carbon atoms, benzylamino, 2-furfurylamino, 3-furfurylamino, α-thenylamino, β-thenylamino, α-pyridylmethylamino, 8-pyridylmethylamino, -r-pyridylmethylamino, indanylamino, X means thio, imino or alkylimino having up to 4 carbon atoms, R3, R4, R5 and R6 each independently represent hydrogen, halogen, alkyl of up to 4 carbon atoms or alkoxy of up to 4 carbon atoms, and R3 and R4 may together with the carbon atoms to which they are attached to form a phenyl group, in which case, however, R 1 is hydrogen and R 2 is a group of the formula mi - (CH 2) m II - (CH 2) m II I -C-NH where m has the above or pharmacologically acceptable acid addition salts or quaternary ammonium salts thereof, characterized in that a compound of the formula An analogous process according to claim 1, characterized in that R3 and R4 form a phenyl group with the carbon atoms in the meta and para positions of the anthracene nucleus, R5 and R6 are hydrogen and m is 2, bis- (2-imidazoline-2 ylhydrazone) -5.12-benz [b] anthracendicarboxaldehyd. Analogous process according to claim 1, characterized in that R 3 and R 4 form a phenyl group with the carbon atoms in the ortho and meta positions of the anthracene nucleus, R 5 and R 6 are hydrogen and m is 4, bis- (4,5,6,7 -tetra-40-hydro-1H-1,3-diazeoin-2-ylhydrazone) -7.12-benzananthracene-dicarboxaldehyde. An analogous process according to claim 1, characterized in that R 3 and R 4 form a phenyl group with the carbon atoms in the ortho and meta positions of the 9,10-dihydro-anthracene core, R 5 and R 6 are hydrogen and m is 2, 7,12 -dihydro-bis- (2-imidazolin-2-ylhydrazone) -7,12-benz [a] anthra-cendicarboxaldehyde. Analogous process according to claim 1, characterized in that R3 and R4 form a phenyl group having the carbon atoms in the meta and para positions of the 9,10-dihydro-anthracene nucleus, R5 and R6 are hydrogen and m is 2, 5,12-di -hydro-bis- (2-imidazolin-2-ylhydrazone) -5,12-benz [b] anthracene dicarboxaldehyde. An analogous process according to claim 1, characterized in that R 3 and R 4 form a phenyl group with the carbon atoms in the ortho and meta positions of the 9,10-dihydro-anthracene core, R 5 and R 6 are hydrogen and m is 3, 7, 12-dihydro-bis- (1,3,4,5-tetrahydro-1H-pyrimid-2-ylhydrazone) - 7,12-benz [a] anthracenedicarboxaldehyde. 25. In -C-NH where m is 3, bis- (1,4,5,6-tetrahydro-2-pyrimidin-2-ylhydrazone) of 9,10-anthracenedicarboxaldehyde dihydrochloride. An analogous process according to claims 1-25, characterized in that the compound is formed in the form of the diacetate salt. Analogous process according to claims 1-25, characterized in that the compound is formed in the form of the acetic acid addition salt. An analogous process according to claims 1-25, characterized in that the compound is formed in the form of the hydrochloride addition salt. An analogous process according to claims 1-25, characterized in that the compound is formed in the form of the maleic acid addition acid salt. An analogous process according to claims 1-25, characterized in that the compound is formed in the form of the gluconic acid addition salt. 35 in I -, - - ---