JPS6346064B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel organic compounds, and more specifically to novel anthracene-9,10-bis-carbonyl hydrazones that can be represented by the following general formula, and their pharmacologically acceptable acid addition salts and quaternary Regarding ammonium salts: where A, B and C form an anthracene or 9,10-dihydroanthracene nucleus; R ₁ is hydrogen or an alkyl group having up to 4 carbon atoms; R ₂ is hydrogen, up to 4 carbon atoms Alkyl group or formula having an atom: [Here, m is 2, 3, 4 or 5] is a monovalent group represented by: However, R ₁ and R ₂ are not both hydrogen; R ₃ , R ₄ , R ₅ and R ₆ are each independently selected from hydrogen, halogen, hydroxy group, amino group, alkyl group having up to 4 carbon atoms and alkoxy group having up to 4 carbon atoms; and R ₁ is hydrogen and R ₂ is

[Formula] (where m is as defined above), R ₃ and R ₄ may form a phenyl group together with the carbon atom to which they are bonded. The hydrazino substituents attached to the anthracene-9,10-bis-carbonyl nucleus may be the same or different and may be in the syn or anti form. Furthermore, 1 of the anthracene nucleus,
If the hydrogen atoms or other substituents at positions 4, 5 and 8 restrict the rotation of the bonds extending from C ₉ and C ₁₀ of the anthracene nucleus, all units at C ₉ and C ₁₀ ;

[Formula] may be cis (both extending out from the same side of the anthracene nucleus) or trans (extending from opposite sides of the anthracene nucleus). The nuclear magnetic resonance data of the hydrochloride product of Reference Example A show strong evidence for a mixture of rotamers at 29°C [4-peaks for -N( _CH3 ) ₂ : §3.02, 3.05, 3.18 and 3.20 ], but at 85° C. the four peaks merged into a sharp singlet at 3.20 (in D ₂ O). When cooled, the quartet appears again. Thin layer chromatography at 24°C showed 2 spots, as did the product of Example 7. Ultraviolet absorption data was obtained for the products of Examples 3 and 4, indicating that the double bond closest to the anthracene ring system is pushed out of the plane of the system. The novel compounds of the present invention are obtained as yellow crystals with characteristic melting points and absorption spectra and are purified by recrystallization from common organic solvents such as lower alkanols, dimethylformamide, tetrahydrofuran, methyl isobutyl ketone, etc. can. The organic bases of the present invention form non-toxic acid addition salts and quaternary ammonium salts with a variety of pharmacologically acceptable organic and inorganic salt-forming reagents. Thus, acid addition salts formed by mixing an organic free base with one equivalent or more of an acid, suitably in a neutral solvent, include sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic acids. , formed with acids like citric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, benzoic acid, gluconic acid, ascorbic acid, etc. Quaternary ammonium salts can be formed by reacting the free base with one or more equivalents of various organic esters of sulfuric acid, hydrohalic acid, and aromatic sulfonic acids. The organic reagent used to form the quaternary ammonium salt is preferably a lower alkyl halide. However, other organic reagents are suitable for the formation of quaternary ammonium salts, and include benzyl chloride, phenethyl chloride, naphthylmethyl chloride, dimethyl sulfate, methyl benzenesulfonate,
It may be selected from a variety of compounds including ethyl toluenesulfonate, allyl chloride, methallyl bromide and crotyl bromide. For purposes of this invention, the free base is equivalent to its non-toxic acid addition salts and quaternary ammonium salts. The acid addition salts and quaternary ammonium salts of organic bases of the present invention are generally crystalline solids and are relatively soluble in water, methanol and ethanol, but compared to non-polar organic solvents such as diethyl ether, benzene, toluene, etc. It is insoluble in water. The novel compounds of the present invention are useful antimicrobial agents, having in vitro broad spectrum antibacterial activity against a variety of standard laboratory microorganisms as determined by standard agar well diffusion assays. In this test,
Minimum inhibitory concentrations (MICs) were determined using two-fold dilutions of compounds in agar medium containing nutrients. 1 ml of each dilution was placed in a sterile Petri dish and 9 ml of nutrient-containing agar was added to each dish. The indicated microorganisms were cultured in trypticase soy broth for 5 hours and diluted 1:100 in nutrient broth. Dilutions of each culture were transferred to the surface of the plate using a Steers replicating device.
After 24 hours of incubation at 37°C, the MIC was recorded as the lowest concentration of compound that completely inhibited macroscopic growth of each organism. The MICs of typical compounds of the present invention against living organisms are shown in Tables 1 and 2.

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Table: The antimicrobial spectra for the concentrations required to inhibit the growth of various typical bacteria were determined using standard agar dilution plating techniques for the compounds in Table 3 below. The cells were cultured for 18 hours at 37°C on Mueller-Ninton agar medium using Steers Multiple Inokiura Replicator.
The results for 7,12-bis(2-imidazolin-2-ylhydrazone) dihydrochloride (Example 39) of 7,12-benz[a]anthracenedicarpoxaldehyde (Example 39), a typical compound of the present invention, show that the minimum inhibitory concentration ( MIC) is shown in Table 3 in μ/ml.

Table: The novel compounds of the present invention also have the property of inhibiting the growth of implanted murine tumors as evidenced by the following tests. Lymphocytic Leukemia P388 Study All animals used were of one sex and weighed at least 17 g.
All mice are within the weight range of 3g. There are 5 or 6 animals per test group. Tumor implantation was performed using dilute ascites fluid containing 10 ⁶ cells of lymphocytic leukemia P388.
ml or by intraperitoneal injection of 0.5 ml. Test compounds are administered intraperitoneally on days 1, 5 and 9 (with respect to tumor inoculation) at various doses. Animals are weighed and survival recorded periodically for 30 or 60 days. 50%
Survival times and survival time ratios of treated (T) animals/control (C) animals are calculated. The positive control compound is 5-fluorouracil. The results of this test using representative compounds of the invention are shown in Table 4. The criterion for efficacy is T/C x 100125%.

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[Table] Lymphocytic leukemia L1210 study The mean survival time was calculated when the tumor implant consisted of lymphocytic leukemia L1210 inoculated at a concentration of 10 ⁵ cells/mouse, and the test compound was administered only on day 1. The procedure is similar to the lymphocytic leukemia P388 study. The results of this test using representative compounds of the invention are shown in Table 5. The criterion for efficacy is T/C x 100125%.

[Table] Melasma melanoma B16 The animals used were C57BC/6 mice of the same sex, weighing a minimum of 17 g and all within the 3 g range. There are usually 10 animals per test group. 1 g of melasma melanoma B16 tumor is homogenized in 10 ml of cold buffered saline and 0.5 ml of the homogenate is implanted intraperitoneally into each test mouse. Test compounds are administered intraperitoneally at various doses between days 1 and 9 (regarding tumor inoculation). Weigh animals periodically for 60 days and record survival.
Calculate the 50% survival time and the survival time ratio of treated (T) animals/control animals. Positive control compound is 20mg/Kg
5-fluorouracil given by injection. The results of this test using representative compounds of the present invention are summarized in the sixth section.
Shown in the table. The criteria for determining efficacy is T/C x 100125%
It is.

【table】

Table: The novel compounds of the present invention exhibit antibacterial activity when tested by the following procedure. The antibacterial spectrum, with respect to the concentrations required to inhibit the growth of various typical bacteria, was determined using standard agar dilution plating techniques. The cells were cultured at 37°C for 18 hours on Mueller-Ninton agar medium using a Steers Multiple Inokiura Replicator. Results for typical compounds of the invention are given as minimum inhibitory concentrations in μg/
It is shown in Table 7 in ml.

[Table] The toxicity of the compound of Example 1, which is a representative compound of the present invention, is as follows: Animal administration route LD ₅₀ Male mouse intravenous 105-126 mg/Kg Female mouse intravenous 117〃 Male mouse subcutaneous 225 〃 Female mouse subcutaneously 268 〃 Male rat intravenously 37 〃 Female rat intravenously 42- 50 〃 Male rat subcutaneously 197 〃 Female rat subcutaneously 195 〃 New compound of formula () and its pharmacologically acceptable acid addition salts and fourth Class ammonium salts would be expected to exhibit activity against a wide range of cancer diseases, particularly blood cancers such as leukemia, in standard test animals at doses substantially below toxic levels. The intended modes of administration are parenteral and intraperitoneal in nature. Solutions of the active ingredient as free base or salt can be prepared in water or in water suitably mixed with, for example, a surfactant. formula() Preferred compounds in which m is 2 and Y is an imino group are slightly soluble in water, where R ₃ , R ₄ , R ₅ , R ₆ , A, B and C are as defined above. It can be converted, for example, into the acetate salt, which has a pH of about 7.4 in aqueous solution. It shows approximately one acetate residue per anthracene nucleus in analysis. A diacetate salt having a pH of about 6.2 in aqueous solution can also be prepared. About 450 mg of diacetate is dissolved in water per ml of water. The base or various salts can be made more soluble by adding a surfactant, such as hydroxypropyl cellulose, to the composition. Dispersions can be prepared in glycerin, liquid polyethylene glycols, and mixtures thereof and in oils. Under normal conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms. The pharmaceutical compositions can be in any injectable form, including sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be protected against the contaminating action of microorganisms such as bacteria and fungi. The carrier is, for example, water,
Solvents or dispersion media can include ethanol, polyols (such as glycerin, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the necessary particle size in the case of dispersions, and by the use of surfactants.
Protection against the action of microorganisms can be provided by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenols, sorbic acid, thimerosal, etc. In many cases, it will be preferable to include isotonic agents, such as sugars or sodium chloride. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, such as aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active ingredients in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by hypersterilization. in general,
Dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle that 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 preparation methods are vacuum drying and lyophilization techniques, which yield a powder combining the active ingredient and the desired added ingredients from a previously sterilized solution. As used herein, "pharmacologically acceptable carrier" includes any and all of solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents. is included. The use of such media and reagents for pharmaceutically active substances is well known in the art. Their use in therapeutic compositions is contemplated unless conventional media or reagents are incompatible with the active ingredient.
Supplementary active ingredients can also be incorporated into the compositions of the invention. It is especially advantageous to formulate compositions in dosage unit form for ease of administration and uniformity of dosage. As used herein and in the claims, unit dosage form refers to physically discrete units suitable as a single dose for the animal patient to be treated, each unit containing a pre-designed dose to produce the desired therapeutic effect. Contains the defined amount of active substance together with any necessary pharmaceutical carriers. The specifications for the novel unit dosage form of the present invention are determined by (a) the unique properties of the active agent and the specific therapeutic effect to be achieved, and (b) the physical health, as disclosed in detail herein. The scope inherent in the art of formulating such active substances for the treatment of disease in living patients with the disease state in question is dictated by and directly dependent upon. The use of the main active ingredient for the treatment of the described conditions depends on the age, weight and condition of the patient being treated; the individual condition and its severity; the particular form of the active ingredient and the route of administration. from about 1 to about 100 mg/Kg of body weight given once a day or in up to 5 divided doses.
The daily dosage includes an effective range for treating many conditions for which the new compounds are effective and substantially non-toxic.
For a 75Kg patient, this would be approximately 75 to approximately
Expressed as 7500mg/Kg. If the dose is divided into, for example, three doses, this will amount to about 25 to about 2500 mg of active ingredient. The preferred range is 2 to about 50 mg/body weight
Kg/day, more preferably about 2 to about 30 mg/Kg/day. The principal active ingredient is formulated in unit dosage form as described above for convenient and effective administration of effective amounts. A unit dosage form may contain, for example, from about 0.1 to about 400 mg of the main active ingredient, with about 1 to about 30 mg being preferred. In proportions, the active ingredient is generally present in an amount of about 0.1 to about 400 mg/ml of carrier. In the case of compositions containing auxiliary active ingredients, the dosage is determined with reference to the usual dosages and administration methods of said ingredients. Cancer regression and palliation is achieved, for example, by intraperitoneal administration. Single intravenous administration or repeated daily doses can be applied. Daily administration for up to about 5 or 10 days is often sufficient. It is also possible to administer once daily or every other day or less frequently. As can be seen from the dose regulation, the amount of the main active ingredient administered should be sufficient to aid in the regression and mitigation of leukemia, etc., without undue harmful side effects of cytotoxic nature to the cancer-infested host. be. As used herein, cancer refers to hematological malignancies such as leukemia and other solid and non-solid tumors such as melanoma, lung cancer and breast tumors. Regression and palliation refers to the prevention or delay of tumor growth or other manifestations of the disease compared to the course of the disease without treatment. To further illustrate the preferred use of the compounds in the above applications, the compounds may be formulated with one or more pharmaceutically acceptable carriers, such as solvents, diluents, etc. and tablets, capsules, dispersible powders, granules,
Alternatively, it can be administered orally in the form of a suspension containing, for example, about 0.5-5% suspending agent and an elixir containing, for example, about 20-50% ethanol, or can be administered parenterally in the form of a sterile injectable solution or suspension containing about 0.5-5% suspending agent in an isotonic vehicle. The effective dosage of active ingredient employed will vary depending on the particular compound employed, the mode of administration, and the severity of the condition being treated. However, in general, the compounds of the invention will be administered at a daily dose of about 1 mg to about 10 mg per kg of animal body weight, preferably in divided doses of 2 to 4 times per day or in sustained release form. Satisfactory results are obtained in some cases. Dosage forms suitable for internal use contain about 35-50 mg of active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This mode of administration can be adjusted to provide the optimal therapeutic response. For example, the dosage can be administered in seven divided doses per day, or it can be relatively reduced depending on the exigencies of the therapeutic situation. A clear practical advantage is that these active compounds can be administered orally. Solid carriers include dicalcium phosphate, microcrystalline cellulose and kaolin, and liquid carriers include sterile water, polyethylene glycols, nonionic surfactants and the like and the nature of the active ingredient and as desired. Edible oils such as corn oil, peanut oil and sesame oil are included as appropriate for the particular dosage form. flavoring agents, coloring agents,
Adjuvants commonly used in the manufacture of pharmaceutical compositions may advantageously be included, such as preservatives and antioxidants, such as vitamin E, ascorbic acid, BHT and BHA. Preferred pharmaceutical compositions from the point of view of ease of manufacture and administration are solid compositions, especially tablets and hard-filled or liquid-filled capsules. Formulation example 1 Capsules contain 50 mg of active ingredient and 100 mg of lactose
mg. Formulation Example 2 Tablets usually contain 5-10 mg of active ingredient and dibasic calcium phosphate.
Can be manufactured to contain 200mg. Most of the novel compounds of this invention can be easily prepared as shown in the following reaction scheme: (In the formula, Z is CH, A, B, C, R ₁ , R ₂ ,
R ₃ , R ₄ , R ₅ , R ₆ are the same as defined above) 9,10 appropriately substituted according to the above reaction scheme
-Anthracendialdehyde or diketone ()
is reacted with a hydrazine derivative of the formula: H ₂ N-NR ₁ R ₂ to give 9,10-anthracene-bis-hydrazone (). The reaction is carried out in a lower alkanol in the presence of an acid such as hydrochloric acid, hydroiodic acid or acetic acid (or glacial acetic acid may be used as a sole solvent).
It is usually carried out at the reflux temperature of the reaction mixture. The starting 9,10-anthracene dialdehyde and ketone can be obtained commercially or as follows (A), (B)
It can also be produced by any of the reaction schemes shown in (C) and (C). In the formula, A, B, C, R ₃ , R ₄ ,
R ₅ and R ₆ are as described above. According to the above reaction scheme, an anthracene derivative () suspended in dioxane and concentrated hydrochloric acid and saturated with HCl is treated with paraformaldehyde at reflux temperature for 2 to 6 hours to give a 9,10-bis-(chloromethyl)anthracene derivative (). is obtained.
This 9,10-bis-(chloromethyl)anthracene is suspended in dry dimethyl sulfoxide at room temperature under nitrogen and treated with sodium in ethanol to yield the desired 9,10-anthracene dicarboxaldehyde (). . According to the above reaction scheme, dihydroxyanthraquinone () is treated with trimethylsilyl chloride in the presence of triethylamine in dry tetrahydrofuran to give the trimethylsilyloxy derivative (). The latter compound was then dissolved in tetrahydrofuran and dissolved at room temperature in [α-lithio-
Treatment of α-(N,N-dimethylamino)methyl]diphenylphosphine oxide with an anhydrous diethyl ether-hexane solution gives the bis-enamine (), which without isolation by addition of a 90% formic acid solution. Upon hydrolysis, hydroxy-substituted 9,10-anthracenedicarboxaldehyde () is obtained. According to the above reaction scheme, the anthracene derivative () with excess vinylene carbonate is
Heating under reflux for 10-24 hours yields the cyclic carbonate (XI), where D and E are O, S or
NH, F is =0, =S, =NH or a cyclohexylidene group, and R ₇ and R ₈ are H, an alkyl group or an aryl group. Hydrolysis of the cyclic carbonate (XI) with aqueous ethanolic potassium hydroxide for about 1 to 4 hours at 70-75°C yields the diol (XII), which is then hydrolyzed in acetic acid for about 10 minutes to 2 hours at 20-35°C. Treatment with lead tetraacetate yields 9,10-anthracenedicarboxaldehyde (). Another method for producing the intermediate dialdehyde is as follows. According to the above reaction scheme, anthraquinone ()
When treated with dimethylsulfonium methylide (or dimethyloxosulfonium methylide) in dimethylsulfoxide at 10-40°C, dispiro[oxirane-2,9'(10'H)-anthracene-
10′,2″-oxirane] () is obtained. The latter compound is treated with lithium bromide (or lithium perchlorate, boron trifluoride, magnesium bromide, trifluoroacetic acid and methanesulfonic acid) in an organic solvent. Rearrangement yields 9-formyl-10-hydroxymethylanthracene ().Then, 9-
Formyl-10-hydroxymethylanthracene was dissolved in an organic solvent at 20-100°C with O-chloroanyl (or dichlorodicyano-1,4-benzoquinone, dimethyl sulfoxide, diethyl azodicarboxylate, lead tetraacetate, nickel peroxide, magnesium oxide). , chromium trioxide and selenium oxide) to yield 9,10-anthracenedicarboxaldehyde (). According to the above reaction scheme, when an anthraquinone of formula () is treated with dimethyl sulfoxide anion in dimethyl sulfoxide at 10-40°C, 9,10-
Dihydro-9,10-(methanothiomethano)anthracene-9,10-diol 12-oxide ()
is obtained. Treatment of the latter compound with acetic anhydride followed by 88% formic acid yields 9,10-anthracenedicarboxaldehyde (). 9 in a solution of acetic acid, acetic anhydride and sulfuric acid,
Cooling of 10-dimethylanthracene () to 0-10°C and treatment with 2 molar equivalents of chromium trioxide yields the tetraacetic acid ester (), which is then converted to 20
Hydrolysis with sodium carbonate solution at ~50°C gives the dialdehyde (). Other oxidizing agents such as selenium dioxide and cerium ammonium nitrate may also be used for oxidation. (wherein R is H, an alkyl group or _COOCH3 or COOH) According to the above formula, a mixture of anthracene and excess acetylene is heated to 50-150°C without or with an organic solvent such as xylene. Heating for ~20 hours gives the adduct (). Treatment of the adduct in a solvent such as ether or dioxane with osmium tetroxide in the presence of pyridine at 10-60°C for 12 hours to 2 days followed by mannitol provides the cis-glycol (XI). Compound (XI) is then treated with lead tetraacetate in acetic acid at 20-60°C for 1-5 hours to yield dicarbonylanthracene (XII). R is
When compound [XII] is COOH and is heated at 100-180°C in quinoline or pyridine, 9,10-anthracenedicarboxaldehyde () is obtained. The invention will be explained in more detail with reference to the following specific examples. The structures of the compounds produced in the examples are summarized in the table below.

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[Table] * Unless otherwise specified, the anthracene nucleus is shown. Example 1 Bis(2-imidazolin-2-ylhydrazone) dihydrochloride of 9,10-anthracene dicarboxaldehyde 2-hydrazino described in US Pat. No. 3,931,152 -2-Imidazoline-hydrochloride is converted to dihydrochloride by treatment with ethanol and concentrated hydrochloric acid. 2-hydrazino-2 in 100ml ethanol
A suspension of 3.46 g of imidazoline dihydrochloride and 2.34 g of 9,10-anthracenedicarboxaldehyde is stirred and heated under reflux for 2 hours. The mixture is cooled and the solid collected and washed with ethanol to yield the desired product as a crystalline orange solid, mp 288-289°C.
(decomposition), obtained as Example 2 Bis(dimethylhydrazone) dihydrochloride of 9,10-anthracenedicarboxaldehyde Suspension of 4.68 g of 9,10-anthracenecarboxaldehyde in 200 ml of ethanol containing 2.40 g of unsymmetrical dimethylhydrazine and 2 drops of glacial acetic acid. The suspension is stirred under reflux for 2 hours. Pass the mixture hot. The desired product from the liquid is an orange solid (melting point
177-178℃). Reference example A N,N-dimethylglycine (9,10-anthrylendimethylidine) hydrazide dihydrochloride 4.68 g of 9,10-anthracenedicarboxaldehyde and N,N-dimethylglycyl hydrazide hydrochloride in 200 ml of ethanol The suspension with 6.14 g is stirred and heated under reflux for 2 hours. After the mixture has cooled, the orange solid is collected and washed twice with ethanol. A cloudy solution of this solid in 400 ml of hot methanol is filtered, the liquid is concentrated to 150 ml and 150 ml of diethyl ether is added. Collect the orange solid after standing overnight and wash with acetone. A cloudy solution of this solid in 200 ml of methanol is chromatographed on silica gel, eluting with methanol. The eluate is allowed to stand for 4 hours as a small amount of the free base of the desired product, a solid yellow solid with a melting point of 276 DEG-227 DEG C. (decomposition), precipitates out. Evaporation of the yellow solid gives an orange solid. Hot methanol 150ml
The cloudy orange solid solution is filtered, concentrated to 50 ml, cooled slightly, seeded and gradually diluted with 50 ml of diethyl ether. The solid that separates is collected by filtration and washed with ethanol to give the desired dihydrochloride product as an orange solid with a melting point of 277-279°C (decomposed). Example 3 Bis(1,4,5,6-tetrahydro-2-
pyrimidinylhydrazone) dihydrochloride 2-hydrazino-1,4,5,6-tetrahydropyrimidine monohydriodide (U.S. Pat.
3931152) to the dihydrochloride by treatment with excess Dowex-2x8 (a strongly basic anion exchange resin in the hydrochloride form). Acidification of an aqueous solution with excess concentrated hydrochloric acid produces 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 and then filtered. When the liquid is cooled, a solid precipitates out, which is collected and washed three times with ethanol to give the desired product, a yellow color with a melting point of 215-230°C.
Obtained as a crystal with (decomposition). Example 4 Bis(4,5,6,7-tetrahydro-1H) of 9,10-anthracenedicarboxaldehyde
-1,3-diazepin-2-ylhydrazone)
Dihydriodide 2-hydrazino-4,5,6,7-tetrahydro-1H-1,3-diazepine hydroiodide (US Patent No. 39311152) 7.68g, 9,10
A mixture of 3.51 g of anthracene dicarboxaldehyde and 7.57 ml of 4N ethanolic hydrogen iodide is reacted as in Example 5 to give the desired product as an orange solid with a melting point of 301-302 DEG C. (decomposed). Example 5 Bis(2-imidazolin-2-ylmethylhydrazone) dihydriodide of 9,10-anthracenedicarboxaldehyde 48.8 g of 2-methylthio-2-imidazoline hydroiodide and methyl in 200 ml of ethanol A solution with 10.0 g of hydrazine is heated under reflux for several hours, clarified and then cooled to -10°C. The precipitate was collected, washed with diethyl ether, and dried to give 2-
(1-Methylhydrazino)-imidazoline hydroiodide is obtained. 5.08 g of 9,10-anthracenedicarboxaldehyde, 10.2 g of 2-(1-methylhydrazino)imidazoline hydroiodide in 135 ml of ethanol
and 12.1 ml of 3.47N ethanolic hydrogen iodide is heated under reflux with stirring for 2 hours. The mixture is allowed to stand overnight and the solid is collected and washed three times with acetone to yield a product with the desired melting point of 298-300°C (decomposed). Example 6 9,10-anthracenedicarboxaldehyde bis(methylhydrazone) 9,10-anthracenedicarboxaldehyde in 200 ml of ethanol containing 2.0 drops of glacial acetic acid.
1.5 g of a suspension of 4.68 g and 1.84 g of methylhydrazine
Stir and heat under reflux for an hour. The mixture is cooled and the solid is collected and washed with ethanol to give the desired product as orange needles with a melting point of 172-174°C (decomposed). Example 7 Bis(5-hydroxy-3,4,5,6-tetrahydropyrimidin-2-ylhydrazone) of 9,10-anthracenedicarboxaldehyde
Dihydrobromide A mixture of 26.4 g of hexahydro-4-hydroxypyrimidine-2-thione and 30 ml of ethyl bromide in 250 ml of ethanol is stirred and heated under reflux for 7 hours. Decolorizing charcoal is added, the solution is filtered, cooled and diluted with 1 part of ether. The thick oil separates. Discard the mother liquor and dry the oil in vacuo. residue
22.8g and 100ml of 95% ethanol and hydrazine 5
ml is stirred and heated under reflux for 5 hours with the evolution of ethanethiol. The solution is evaporated to dryness in vacuo and the residue is dissolved in a boiling mixture of 100 ml of isopropanol and 100 ml of methanol. Add decolorizing charcoal and heat the solution to -10°C.
Cool to The resulting precipitate is collected and washed with cold 2-propanol and then with ether. It is then recrystallized using decolorizing charcoal from isopropanol-methanol (1:1) to yield 2-hydrazino-5-hydroxy-3,4,5,6-tetrahydropyrimidine hydrobromide (mp 167-169°C). )
is obtained. 1.19 g of this salt and 1.32 g of 9,10-anthracenedicarboxaldehyde in ethanol
A mixture of 400 ml and 0.95 ml of 7.4N ethanolic hydrogen bromide is reacted as in the previous example to give the desired product as an orange-yellow solid. Example 8 Bis(2-imidazolin-2-ylhydrazone) of 9,10-anthracene diacetaldehyde
Dihydrochloride 9,10-anthracene diacetonitrile in 50 ml of 50% ethanol [JACS 77 , 2845 (1955)]
A mixture of 2.56 g, 2-hydrazino-2-imidazoline dihydrochloride, 3.46 g, and 1.64 g of sodium acetate is reduced in the presence of 1.5 g of Raney-nickel until 2 molar equivalents of hydrogen have been absorbed. Heat the mixture to boiling and strain to remove the Raney-nickel. The liquid is evaporated to a small volume and cooled to yield the desired product. Example 9 2-Chloro-9,10-anthracenedicarboxaldehyde [bis(2-imidazoline-2
-ylhydrazone)] dihydrochloride A reaction mixture in 80 ml of ethanol containing 1.34 g of 2-chloro-9,10-anthracenedicarboxaldehyde and 1.73 g of 2-hydrazinoimidazoline dihydrochloride was refluxed for 2 hours and heated pass Upon cooling, 0.7 g of the desired product precipitates out of the solution as orange crystals (melting point 280 DEG C.). Example 10 Bis(2-imidazoline-
2-ylhydrazone) dihydrochloride 2-hydroxy-9,10 in 100 ml of ethanol
-Anthracendicalboxaldehyde (reference example)
11) A suspension of 2.5 g and 3.46 g of 2-hydrazino-2-imidazoline dihydrochloride is stirred and heated under reflux for 2 hours. The product is collected by cooling the mixture and filtering. Example 11 Bis(2-imidazolin-2-ylhydrazone) dihydrochloride of 1,2-dihydroxy-9,10-anthracenedicarboxaldehyde 1,2-dihydroxy- in 100 ml of ethanol
A suspension of 2.66 g of 9,10-anthracenedicarboxaldehyde (Reference Example 12) and 3.46 g of 2-hydrazino-2-imidazoline dihydrochloride is stirred and heated under reflux for 2 hours. Cool the mixture and collect the product. Example 12 Bis(2-imidazolin-2-ylhydrazone) dihydrochloride of 1,4-dihydroxy-9,10-anthracenedicarboxaldehyde 1,4-dihydroxy- in 100 ml of ethanol
A suspension of 2.66 g of 9,10-anthracenedicarboxaldehyde (Reference Example 13) and 3.46 g of 2-hydrazino-2-imidazoline dihydrochloride is stirred and heated under reflux for 2 hours. Cool the mixture and collect the product. Example 13 Bis(2-imidazoline-2-
(Reference Example 14)
A suspension of 2.5 g and 3.46 g of 2-hydrazino-2-imidazoline dihydrochloride is stirred and heated under reflux for 2 hours. The compound is collected by cooling the mixture and filtering. Reference Example 1 2-Chloro-9,10-anthracenedicarboxaldehyde A solution of 15.0 g of 2-chloroanthracene in 60.8 g of vinylene carbonate is heated under reflux for 20 hours. Excess vinylene carbonate is removed by vacuum distillation. The remaining brown solid was recrystallized from methylene chloride-methanol to give 2-chloro-9,10-
Dihydro-9,10-ethanoanthracene-11,12
- Diols, cyclic carbonates (melting point 200-230
°C) is obtained. 12.0g of this cyclic carbonate and potassium hydroxide
A mixture of 9.2 g 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 and then treated with 400 ml of water. The crystalline product is collected and recrystallized from toluene to give 2-chloro-9,10-dihydro-
9,10-ethanoanthracene-11,12-diol (melting point 195-210°C) is obtained. To a suspension of 2.73 g of this diol in 70 ml of acetic acid at 35° C., 8.8 g of lead tetraacetate are added over a period of 5 minutes. The reaction mixture is stirred for a further 2 hours at 35° C., yielding 1.5 g of orange crystalline compound. Evaporation of the mother liquor yields an additional 0.5 g of compound. Combine these two,
When recrystallized from 50ml of toluene, 2-chloro-9,
10-anthracenedicarboxaldehyde (melting point
193-196℃) is obtained. Reference Example 2 2-Methyl-9,10-anthracenedicarboxaldehyde 13 g of 2-methylanthracene was converted to 2-methyl-9,10-anthracenedicarboxaldehyde by the three-step process described in Reference Example 1 for 2-chloro analogs. be transformed. Reference Example 3 1-Chloro-9,10-anthracenedicarboxaldehyde 15 g of 1-chloroanthracene is converted to 1-chloro-9,10-anthracenedicarboxaldehyde by the three-step process described in Reference Example 1. Reference Example 4 2-Ethyl-9,10-anthracenedicarboxaldehyde 14 g of 2-ethylanthracene is converted to 2-ethyl-9,10-anthracenedicarboxaldehyde using the three-step process described in Reference Example 1. Reference Example 5 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 slowly stirred and heated under reflux while introducing hydrogen chloride gas for 2 hours. The mixture was stirred and heated under reflux for a further 3 hours and then heated to 16
Let stand at room temperature for an hour. The yellow solid is collected by filtration, washed with dioxane, and dried to yield the title compound. Reference Example 6 2-Methyl-9,10-anthracenedicarboxaldehyde 9, stirred at room temperature under nitrogen in 50 ml of dimethyl sulfoxide (dried over calcium hydride)
To a suspension of 2.6 g of 10-bis(chloromethyl)-2-methylanthracene is slowly added a solution prepared by adding 3.0 g of 2-nitropropane to a solution of 0.5 g of sodium in 30 ml of ethanol.
The reaction mixture gradually turns from yellow to dark orange and becomes homogeneous. At this point (2.5-3.0 hours) the mixture is filtered into 200 ml of ice water. The orange precipitate is collected and redissolved in methylene chloride, then it is extracted with water. Dry the methylene chloride solution over _MgSO4 ,
Evaporation to dryness yields the title compound. Reference Example 7 1-Methyl-9,10-anthracene dicarboxaldehyde 1-methylanthracene (4.5 g) was converted into 1-methyl-9,10-anthracene dicarboxaldehyde by the procedure described in 2-methyl derivative.
Converted to 10-anthracenedicarboxaldehyde. Reference Example 8 2,6-Dihydroxy-9,10-anthracenedicarboxaldehyde A suspension of 2.4 g (0.01 mol) of 2,6-dihydroxyanthraquinone in 100 ml of dry tetrahydrofuran containing 2.1 g of triethylamine was mixed with 2.2 g of trimethylsilyl chloride. and allow to react until the anthraquinone is dissolved. Triethylamine hydrochloride is filtered off, and the remaining silated anthraquinone solution is used as it is in the next reaction. In a dry system under an argon atmosphere protected from moisture, a solution of 0.01 mol of the silated anthraquinone in tetrahydrofuran was prepared as [α-lithio-α-(N,N-dimethylamino)methyl] in anhydrous ether-hexane at room temperature. Diphenylphosphine oxide [Peterson, J.Am.Chem.Soc., 93 , 4027
(1971)] gradually treated with a 0.02 molar solution. The reaction is allowed to proceed for 2 hours while maintaining the temperature at room temperature in an ice bath. The solution of enamine is hydrolyzed at room temperature by addition of 20 ml of 90% formic acid solution. The reaction mixture is filtered, washed with water, dried and recrystallized from toluene to yield 2,6-dihydroxy-9,10-anthracene dialdehyde. 2,6-dihydroxy-9, using well-known procedures
10-anthracenedicarboxaldehyde 2,
It can be converted into 6-dialkoxy derivatives and 2,6-diacyloxy derivatives. Reference example 9 2,6-dimethoxy-9,10-anthracenedicarboxaldehyde 2,6-dihydroxy-9, in 100 ml of toluene.
10-anthracenedicarboxaldehyde 2.66g
(0.01 mol) is treated with 0.02 mol of sodium hydride washed with petroleum ether and warmed gently with stirring until hydrogen evolution ceases. The cooled reaction mixture was then mixed with 2.84 g of methyl iodide.
(0.02 mol), stirred overnight at 40°C, then heated to reflux temperature, heated to remove sodium iodide, and allowed to cool to form 2,6-dimethoxy-9,10-anthracenedicarbox. Aldehyde crystals are obtained. Reference example 10 2,6-diacetoxy-9,10-anthracenedicarboxaldehyde 2,6-dihydroxy-9, in 100 ml of hot glacial acetic acid.
10-anthracenedicarboxaldehyde 2.66g
(0.01 mol) solution of acetic anhydride (2.5 g (0.025 mol))
Process with. The mixture is stirred and heated over steam for 1 hour, then allowed to cool to give crystals of 2,6-diacetoxy-9,10-anthracenedicarboxaldehyde. Reference Example 11 2-Hydroxy-9,10-anthracenedicarboxaldehyde A suspension of 2.24 g (0.01 mol) of 2-hydroxyanthraquinone in 100 ml of dry tetrahydrofuran containing 1.05 g (0.01 mol) of triethylamine was mixed with 1.1 g (0.01 mol) of trimethylsilyl chloride. 0.01 mole)
and react until the anthraquinone is dissolved. The triethylamine hydrochloride is filtered off and the remaining silated anthraquinone solution is used as is in the next reaction. In a system similar to that described for the 2,6-dihydroxy analogue, a solution of 0.01 mole of sylated 2-hydroxy-anthraquinone in tetrahydrofuran is gradually treated with a similar solution of 0.01 mole of the lithioanion. The reaction is allowed to proceed for 2 hours at room temperature. This solution of enamine is hydrolyzed at room temperature by addition of 20 ml of 90% formic acid solution. The reaction mixture is filtered, washed with water, dried and recrystallized from toluene to yield 2-hydroxy-9,10-anthracenedicarboxaldehyde. Reference example 12 1,2-dihydroxy-9,10-anthracenedicarboxaldehyde 1,2-dihydroxyanthraquinone 2.4g
Starting from (0.01 mol) and using a three-step procedure similar to that described for the 2,6-dihydroxy analogue, 1,2-dihydroxy-9,10-anthracenedicarboxaldehyde is obtained from toluene as colorless crystals. It will be done. Reference example 13 1,4-dihydroxy-9,10-anthracenedicarboxaldehyde 1,4-dihydroxyanthraquinone 2.4g
Starting from (0.01 mol) and using a three-step procedure similar to that for the 2,6-dihydroxy analogs, 1,4-dihydroxy-9,10-anthracenedicarboxaldehyde is obtained as crystals from toluene. Reference example 14 2-amino-9,10-anthracenedicarboxaldehyde 2-aminoanthraquinone 2.3g (0.01 mol)
Starting from 2-amino-9,10- following the same procedure as described for the 2-hydroxy analogues
Anthracendicalboxaldehyde is obtained. Reference example 15 9,10-anthracenedicarboxaldehyde Cis-9,10-dihydro-9, in 50 ml of glacial acetic acid
10-ethanoanthracene-11,12-diol [Newman et al., J.Am.Chem.Soo., 77 , 3789
(1955)] A solution of 2.38 g (0.01 mol) is stirred magnetically at 30-35°C and treated dropwise with 8.9 g (0.02 mol) of lead tetraacetate or with iodine starch test paper until a blue color persists. The reaction mixture was stirred for 2 hours and the orange crystals so formed were filtered and recrystallized from methylene chloride to give orange needles (melting point 245-247°C).
1.5 g (65%) is obtained. Reference example 16 2-methyl-9,10-anthracenedicarboxaldehyde 2-methyl-11,12-dihydroxy-9,10-
2.1 g of the isomer mixture of ethanoanthracene is dissolved in 45 ml of glacial acetic acid and treated with 7.45 g of lead tetraacetate at room temperature until the iodine starch test is positive.
It was left at room temperature for 2 to 3 hours, then cooled to precipitate orange crystals, which were collected by filtration and recrystallized from methylene chloride-methanol to give orange crystals.
1.1 g is obtained: melts at 162-164°C. Example 14 Bis(2-imidazoline-2-
hydrazone) dihydrochloride hydrate 2-methyl- in 150 ml of boiling n-propanol
9,10-anthracenedicarboxaldehyde
2.2 g of the solution are treated with 3.1 g of 2-imidazolin-2-ylhydrazone. The solution is boiled and concentrated for 2 hours to 100 ml, then filtered and cooled without clarification. If left standing for a long time, orange crystals 2.2
g precipitates, it melts at 300-302℃. The free base of the above product can be obtained as red-orange crystals by basifying the mother liquor with aqueous sodium bicarbonate solution, melting point 295-298°C. Reference example 17 1,4-dimethoxy-9,10-anthracenedicarboxaldehyde 1,4-dimethoxy-11,12-dihydroxy-
10 g of isomer mixture of 9,10-ethanoanthracene
is dissolved in 150 ml of glacial acetic acid at 50°C and treated by adding dropwise 30 g of lead tetraacetate. After 2 hours at 50°C, the solution is filtered to remove insoluble material and upon cooling, orange crystals form which are filtered, washed with glacial acetic acid and dried, melting point 208-212°C. Example 15 Bis[1,4-dimethoxy-bis(2-imidazolin-2-ylhydrazone)] dihydrochloride of 9,10-anthracenedicarboxaldehyde 1,4-dimethoxy-9,10 in 100 ml of n-propanol - A solution of 1.7 g of anthracenedicarboxaldehyde is treated with 2.06 g of 2-imidazolin-2-ylhydrazine and boiled for 2 hours, during which time it is concentrated to 50 ml. Passage of the hot solution yields a yellow solid, which is washed with n-propanol and dried, mp 300-305°C. Example 16 Bis(2-imidozolin-2-ylhydrazone) of 2,6-difluoro-9,10-anthracenedicarboxaldehyde 2,6-difluoro-9, in 100 ml of ethanol,
A suspension of 2.74 g of 10-anthracenedicarboxaldehyde (Reference Example 18) and 3.46 g of 2-hydrazino-2-imidazoline dihydrochloride is stirred and heated under reflux for 3 hours. The mixture is cooled and the product is collected by filtration. Reference Example 18 2,6-difluoro-9,10-anthracene dicarboxaldehyde 15 g of 2,6-difluoroanthracene was converted into 2,6-difluoro-anthracene by the three-step method described in Reference Example 1.
It is converted to 9,10-anthracenedicarboxaldehyde. Example 17 Bis(2-imidazolin-2-ylhydrazone) of 2,3-dimethyl-9,10-anthracenedicarboxaldehyde 2,3-dimethyl-9, in 100 ml of ethanol,
A suspension of 2.7 g of 10-anthracenedicarboxaldehyde (Reference Example 19) and 3.46 g of 2-hydrazino-2-imidazoline dihydrochloride is stirred and heated under reflux for 3 hours. Cool the mixture and collect the product. Reference Example 19 2,3-dimethyl-9,10-anthracene dicarboxaldehyde 14 g of 2,3-dimethylanthracene was converted to 2,3-dimethyl-9,10 by the three-step method described in Reference Example 1.
- Converted to anthracenedicarboxaldehyde. Example 18 Bis(2-imidazolin-2-ylhydrazone) dihydrochloride of 2,6-dichloro-9,10-anthracenedicarboxaldehyde 2,6-dichloro-9,
10-anthracenedicarboxaldehyde 3.03g
and 2-hydrazino-2-imidazoline dihydrochloride
A suspension of 3.46 g is heated under reflux for 3 hours and cooled to give the title compound. Reference Example 20 2,6-dichloro-9,10-anthracene dicarboxaldehyde 18 g of 2,6-dichloroanthracene was converted to 2,6-dichloro-9,10 by the three-step method described in Reference Example 1.
- Converted to anthracenedicarboxaldehyde. Example 19 Bis(2-imidazolin-2-ylhydrazone) dihydrochloride of 1,4-dimethyl-9,10-anthracenedicarboxaldehyde 1,4-dimethyl-9, in 100 ml of ethanol.
10-anthracenedicarboxaldehyde 2.6g
and 2-hydrazino-2-imidazoline dihydrochloride
A suspension of 3.46 g is heated under reflux for 2 hours and cooled to give the title compound. Reference Example 21 1,4-Dimethyl-9,10-anthracene dicarboxaldehyde 16 g of 1,4-dimethylanthracene was converted into 1,4-dimethyl-9,
Converted to 10-anthracenedicarboxaldehyde. Reference example 22 9,10-dihydro-9,10-anthracenedicarboxaldehyde Vinylene carbonate (colorless liquid after redistillation)
A mixture of 21.3 g (71-73 °C, 28 mm, obtained) and 4.4 g of dry anthracene was heated under reflux (165-170 °C) under nitrogen atmosphere for 20 h and then vacuum distilled (62-64 °C, 17 mm ) Then 10.2g of yellowish brown residue
remains. This residue is dissolved in 100 ml of methylene chloride, treated with charcoal and filtered. liquid with methanol
When treated with 100 ml and cooled, colorless crystals of cis-9,10-dihydro-9,10-ethanoanthracene-11,12-diol, cyclic carbonate (melting point
260-262℃) is obtained. Cis-9,10-dihydro-9,10-ethanoanthracene-11,12-diol, cyclic carbonate
A mixture of 5.6 g potassium hydroxide, 4.9 g potassium hydroxide, 6.4 ml water and 53 ml ethanol is stirred for 2 hours at 70-75°C.
The resulting two-layer system is filtered. When the solution is diluted with twice the volume of water and cooled, cis-9,10-dihydro-
Colorless crystals of 9,10-ethanoanthracene-11,12-diol (melting point 202 DEG -204 DEG C.) are formed. 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 while stirring for 10 minutes. do. Mixture 15
Upon cooling to 0.degree. C., the resulting solid is collected by filtration and washed once with glacial acetic acid and then thoroughly with water to give the desired product as colorless particles (melting point 144 DEG-146 DEG C.). Reference example 23 Cis-1,4-dimethoxy-9,10-dihydro-9,10-anthracenedicarboxaldehyde 1,4-dimethoxy-9,10-dihydro-9,
1g of 10-ethanoanthracene-11,12-diol
is suspended in 30 ml of an aqueous solution containing 0.77 g of potassium periodate and 1 ml of ethanol. 24 at room temperature
After stirring for an hour, filter the insoluble material, wash well with water, and dry to produce a yellow product (melting point 129-132
°C) is obtained. Example 20 Bis(2-imidazolin-2-ylhydrazone)-9,10-dihydro-9,10-anthracenedicarboxaldehyde 9,10-dihydro-9,10-anthracenedicarboxaldehyde in 200 ml of n-propanol
2.36g and 2-hydradiimidazoline dihydrochloride 3.46
Boil the mixture with g on a hot plate for 1 1/2 hours and concentrate to a volume of 100 ml. A solid forms when the mixture is cooled and left to stand overnight. Collected through this, n
- Wash with propanol and dry. This solid
Recrystallization of 0.4 g from water gives the desired dihydrochloride product as colorless flakes (mp 258-262°C). Reference Example 24 2-Chloro-9,10-dihydro-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 was recrystallized from methylene chloride-methanol to give cis-2-chloro-9,10-dihydro-9,10-ethanoanthracene-11,12-
Diols and cyclic carbonates are gray crystals (melting point
200-230℃). cis-2-chloro-9,10-dihydro-9,10
-ethanoanthracene-11,12-diol, cyclic carbonate 12.0g, potassium hydroxide 9.2g, water
A mixture of 12 ml and 100 ml of ethanol was heated at 75°C for 2 hours.
Heat it with , then evaporate it in a vacuum to 50ml. The concentrate is diluted with 400 ml of water and the resulting solid is collected by filtration. When this solid was decolorized from toluene with a small amount of charcoal and recrystallized, cis-2-chloro-9,
10-dihydro-9,10-ethanoanthracene-
Colorless crystals of 11,12-diol (melting point 195-210
°C) is obtained. Add a little 5.0 g of lead tetraacetate (containing 10% acetic acid) to a solution of 2.7 g of cis-2-chloro-9,10-dihydro-9,10-ethanoanthracene-11,12-diol in 20 ml of acetic acid at room temperature. Add one by one. mixture
Stir for 10 minutes, cool in an ice-water bath, collect the resulting crystals by filtration and wash with cold acetic acid to give the desired product as off-white crystals (mp 113-115°C). Example 21 2-chloro-bis(2-imidazolin-2-ylhydrazone)-9,10-dihydro-9,10-
Anthracenedicarboxaldehyde dihydrochloride 2-chloro-9,10 in 20 ml n-propanol
The reaction mixture containing 0.7 g of -dihydro-9,10-anthracenedicarboxaldehyde and 0.88 g of 2-hydrazinoimidazoline dihydrochloride is refluxed for 1 hour, during which time about 10 ml of n-prolopanol are removed through a reflux condenser. The mixture is cooled and ether is added to give the desired product as yellow crystals [melting point
190℃ (decomposition)]. Reference Example 25 1-Chloro-9,10-dihydro-9,10-anthracenedicarboxaldehyde When a mixture of 29.5 g of 1-chloroanthracene and 126 g of vinylene carbonate is reacted as described in Reference Example 24, cis-1- Chloro-9,10-dihydro-9,10-ethanoanthracene-11,12-diol, yellowish brown crystals of cyclic carbonate (melting point
242-250℃) is obtained. cis-1-chloro-9,10-dihydro-9,10
-ethanoanthracene-11,12-diol, cyclic carbonate 27.9g, potassium hydroxide 21.4g, water
The reaction mixture containing 28 ml and 230 ml of ethanol was
Heat at 75°C for an hour and then evaporate in vacuo to 80ml. Dissolve the residue in 500 ml of chloroform. Wash the chloroform solution three times with 70 ml of water and decolorize with charcoal. Remove the chloroform and dissolve the yellow residue in 150 ml of toluene. On cooling, the product cis-1-chloro-9,10-dihydro-9,10-ethanoanthracene-11,12-diol is collected as colorless crystals (melting point 180 DEG-182 DEG 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 DEG C. is added portionwise 1.0 g of lead tetraacetate. The mixture was stirred for 10 minutes, cooled in an ice-water bath, and the resulting crystals were collected by filtration and washed with cold acetic acid to give the desired product as colorless crystals (melting point
144-146℃). Example 22 1-chloro-bis(2-imidazolin-2-ylhydrazone)-9,10-dihydro-9,10-
Anthracenedicarboxaldehyde dihydrochloride 1-chloro-9,
The reaction mixture containing 3.7 g of 10-dihydro-9,10-anthracenedicarboxaldehyde and 4.64 g of 2-hydrazinoimidazoline dihydrochloride is refluxed for 1 hour, during which time approximately 50 ml of n-propanol is removed through a reflux condenser. Cool the mixture;
Addition of ether gives the desired product as yellow crystals, melting point 200°C (decomposition). Reference Example 26 2-Methyl-9,10-dihydro-9,10-anthracenedicarboxaldehyde 10 g of 2-methylanthracene in 50 ml of vinylene carbonate are heated under reflux for 20 hours under nitrogen. Excess vinylene carbonate was removed by vacuum distillation (55
The residue is dissolved in 100 ml of methylene chloride, filtered and triturated with three times the amount of methanol. Product, cis-2-methyl-
9,10-dihydro-9,10-ethanoanthracene-11,12-diol, a cyclic carbonate, in its syn and anti forms as cream-colored crystals (melting point 225
-227°C and 183-185°C). Potassium carbonate 2.5g, water 2.3ml and ethanol 27g
2.8 g of cis-2-methyl-9,10-dihydro-9,10-ethanoanthracene-11,12-diol, one of the syn and anti forms of the cyclic carbonate (melting point 225-227 °C) in a mixture of Stir at 70°C for 2 hours. When the mixture is treated with 3 times the amount of water, the corresponding syn or anti form of cis-2-methyl-9,10
-dihydro-9,10-ethanoanthracene-11,
12-diol as pale yellow crystals (melting point 227-228℃)
obtained as. Another syn or anti form of cis-2-methyl-9,10-dihydro-9,10 in a mixture of 6.15 g of potassium hydroxide, 8.1 ml of water and 70 ml of ethanol.
-ethanoanthracene 11,12-diol, 7.4 g of cyclic carbonate (melting point 183-185°C) is reacted as above to give the corresponding syn- or anti-cis-2-methyl 9,10-dihydro-9,10- Ethanoanthracene-11,12-diol is obtained as a cream-colored solid (melting point 153-156°C). cis-2-methyl-9,10-dihydro-9,10
-ethanoanthracene-11,12-diol [obtained above as yellow crystals (melting point 227-228°C)] 2.5 g
2.14g of sodium periodate and 1ml of ethanol
Suspend in 100 ml of an aqueous solution containing The mixture is stirred for 2 hours at room temperature and the solid is collected by filtration, washed with water and dried to give the desired product as a pale yellow solid (mp 125-126°C). Example 23 2-Methyl-bis(2-imidazolin-2-ylhydrazone)-9,10-dihydro-9,10-
Anthracenedicarboxaldehyde dihydrochloride 2-methyl-9 in 150 ml of n-propanol,
A mixture of 1.9 g of 10-dihydro-9,10-anthracenedicarboxaldehyde and 2.63 g of 2-hydrazinoimidazoline dihydrochloride was heated to a boil, concentrated to about 50 ml over 1 to 2 hours, and heated. and cool. 2-3ml of acetone and 200ml of ether
A precipitate is formed, which is collected by filtration and the desired product is a yellow solid [melting point 210-220].
°C (decomposition)]. Reference example 27 2,3-dimethyl-9,10-dihydro-9,10
-Anthracene dicarboxaldehyde 35.4 g vinylene carbonate and 2,3-dimethylanthracene [Jaylord.NG, Stapan, V.,
Collect.Czeck.Chem.Comm. 39 , 1700 (1974)〕8.5
The mixture with g is heated at reflux under nitrogen atmosphere for 20 hours. The cooled solution was treated with 100 ml of methanol, warmed, decolorized with charcoal, filtered and cooled to give 2,3-dimethyl-9,10-dihydro-9,10
-Ethanoanthracene-11,12-diol, colorless crystals of cyclic carbonate (melting point 207-212℃)
7.1g is obtained. 2,3-dimethyl-9,10-dihydro-9,10
-Ethanone anthracene-11,12-diol, cyclic carbonate 6.4g, potassium hydroxide 5g, water
A mixture of 6.6 ml and 60 ml of ethanol is stirred at room temperature for 56 hours. The resulting precipitate is filtered, dissolved in glacial acetic acid, and precipitated with excess water to give colorless 2,3-dimethyl-9,10-dihydro-9,0-ethanoanthracene-11,12-diol (mp 240-245 ℃) is
4.0g obtained. A suspension of 0.3 g of 2,3-dimethyl-9,10-dihydro-9,10-ethanoanthracene-11,12-diol in 10 ml of water and 0.1 ml of ethanol was treated with 0.243 g of sodium periodate. 2.5 hours 20℃
Stir with Strain the resulting solid and wash with water;
Upon drying, 0.2 g of 2,3-dimethyl-9,10-dihydro-9,10-anthracenedicarboxaldehyde (melting point 113-117°C) is obtained. Example 24 2,3-dimethyl-bis(2-imidazoline-
2-ylhydrazone)-9,10-dihydro-9,
10-anthracenedicarboxaldehyde dihydrochloride 2,3-dimethyl- in 30 ml of n-propanol
A mixture of 0.2 g of 9,10-dihydro-9,10-anthracenedicarboxaldehyde and 0.3 g of 2-hydrazinoimidazoline dihydrochloride is boiled for 2 hours, during which time it is concentrated to 10 ml. Treatment of the yellow solution with 0.5 ml of acetone and 20 ml of ether produces a yellow precipitate, which is filtered and washed with acetone.
After drying, 0.15 g of product (melting point 285-290°C) remains. Reference example 28 1,4-dimethyl-9,10-dihydro-9,10
-Anthracene dicarboxaldehyde A mixture of 4.12 g of 1,4-dimethylanthracene and 17.2 g of vinylene carbonate is refluxed for 18 hours under bare atmosphere, cooled, treated with 4 parts of methanol, stirred and cooled. The resulting crystals are filtered, washed with methanol, and dried to yield colorless 1,4-dimethyl-9,10-dihydro-9,10-ethanoanthracene-11,12-diol, cyclic carbonate (melting point 225-245°C) 5.45 g remains. 1,4-dimethyl-9,10-dihydro-9,10
-ethaneanthracene-11,12-diol, cyclic carbonate 4.4g, potassium hydroxide 3.45g, water
A mixture of 4.5 ml and 40 ml of ethanol at 20°C for 16 hours.
Stir with The biphasic mixture was passed through Celite and treated with 4 volumes of water to give colorless 1,4-dimethyl-9,10-dihydro-9,10-ethanoneanthracene-11,12-diol (mp 158-160°C).
3.8g is obtained. A mixture of 1.5 g of 1,4-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 was heated at 20°C for 2 hours. Stir. The resulting solid is filtered, washed with water and dried to give 1,4-dimethyl-9,10-dihydro-9,10
-Anthracendicalboxaldehyde (melting point
159-160℃) 1.45g remains. Example 25 1,4-dimethyl-bis(2-imidazoline-
2-ylhydrazone)-9,10-dihydro-9,
10-anthracenedicarboxaldehyde dihydrochloride 1,4-dimethyl- in 50 ml of n-propanol
A mixture of 1.15 g of 9,10-dihydro-9,10-anthracenedicarboxaldehyde and 1.53 g of 2-hydrazinoimidazoline dihydrochloride was boiled to give 2
Concentrate to 20 ml during the hour. Treatment of the resulting solution with 1 ml of acetone and 75 ml of ether gives rise to a pale yellow precipitate which, when filtered, washed with acetone and dried, yields 1.8 g of product (melting point 230-235°C (decomposed)).
remains. Reference example 29 Cis-1,4-dimethoxy-9,10-dihydro-9,10-ethanoanthracene-11,12-diol, cyclic carbonate, syn and anti isomers 15 g of 1,4-dimethoxyanthracene and 55 g of vinylene carbonate Reflux under nitrogen atmosphere for 16 hours. Excess vinylene carbonate is removed in vacuo (55° C./12 mm) and the residue is slurried in chloroform and filtered to retain 13 g of a mixture of yellow and colorless crystals. The mixture is boiled with methylene chloride and filtered, leaving 10.5 g of colorless crystals of one of the syn or anti isomers of the product (melting point 283-285 DEG C.). The alternative syn or anti isomer is obtained by precipitation with methanol from the original chloroform solution and recrystallized from a mixture of methylene chloride and methanol to give colorless crystals (mp 255-260).
℃) 5 g are obtained. Both isomers exhibit identical infrared spectra (and appear correctly in the analysis) and low melting points (238-245°C). Example 26 Bis(2-imidazolin-2-ylhydrazone)-1,4-dimethoxy-9,10-dihydro-9,10-anthracenedicarboxaldehyde dihydrochloride 1,4-dimethoxy-9,10-anthracenedicarboxaldehyde dihydrochloride in 100 ml of n-propanol 1.5 g of 9,10-dihydro-9,10-anthracenedicarboxaldehyde and 2-hydrazino-
The mixture with 1.8 g of 2-imidazoline dihydrochloride is boiled and concentrated to 50 ml over the course of 2 hours. The cloudy solution was clarified by filtration, then made basic with saturated sodium bicarbonate solution and diluted with 3 volumes of water to give 1.5 g of the free base as a yellow solid, mp 235-240.
℃). The dihydrochloride salt of the product is obtained by dissolving 1 g of the free base in 40 ml of n-propanol and treating with 1 ml of 7N anhydrous hydrochloric acid in ethanol. The solution was concentrated to an oil and recrystallized from n-propanol to give the colorless dihydrochloride (melting point
250-255°C) 0.3g is obtained. Example 27 Bis(2-imidazolin-2-ylhydrazone)-7,12-dihydrobenz[a]anthracenedicarboxaldehyde 7,12-dihydrobenz[a]anthracene-
7,12-dicarboxaldehyde [Neuman &
Din, J.Org.Chem., 36 , 966 (1971)] is dissolved in 100ml of boiling n-propanol. Add this solution to 2-hydrazinoimidazoline dihydrochloride 1.73
g and continue boiling for 3 hours. The mixture is clarified by heating. As the liquid cools, an orange solid forms which is filtered and washed with n-propanol. Combine the solution and n-propanol washing solution, concentrate to 1/2 volume, dilute to 200ml with water,
Make basic with saturated aqueous sodium bicarbonate solution. The resulting cam solid solidifies and is then washed with water, collected by filtration, dissolved in methanol, and precipitated with water to yield the desired product as a base. Melting point 190-195℃. The base is converted to its dihydrochloride salt by dissolving it in n-propanol, treating with 6N hydrochloric acid in n-propanol and cooling. Dihydrochloride melts at 245-250°C. Reference Example 30 5,12-Dihydro-5,12-benz[b]anthracene dicarboxaldehyde A mixture of 7.0 g of benz[b]anthracene and 26 g of vinylene carbonate is heated under reflux for 20 hours under a nitrogen atmosphere. Excess vinylene carbonate is removed by vacuum distillation (57° C./9 mm) and the residue is dissolved in 25 ml of methylene chloride and filtered. 2 liquid
Treatment with twice the volume of methanol and cooling produces a tan solid, and the mother liquor is saved. 1,2 of this solid
- Recrystallize from 60 ml of dichloromethane, collect by filtration, wash with methanol and store. Concentration of the mother liquor (previously saved) gives a gummy solid, which is recrystallized from a mixture of methylene chloride and methanol to give a gray solid, which is combined with said solid and treated with charcoal from ethyl acetate. Recrystallization gives 5,12-dihydro-5,12-ethanobenz[b]anthracene-13,14-diol, a cyclic carbonate, as a colorless rod.
Cyclic carbonate 1.3g, potassium hydroxide 1.05g,
Mixture of 1 ml and 15 ml of ethanol for 2 hours 60-65
Stir at °C. Dilute the mixture with 1-2 volumes of water,
filtrate, wash the solid with water and dry it to give cis-
5,12-dihydro-5,12-ethanobenz[b]
Anthracene-13,14-diol is obtained as a colorless solid. cis-5,12- in 400 ml of glacial acetic acid
Add 4.4 g of lead tetraacetate little by little to a solution of 2.6 g of dihydro-5,12-ethanobenz[b]anthracene-13,14-diol at 20°C. The reaction is stirred for 45 minutes. The pale purple solid was filtered, washed with glacial acetic acid and finally with water, and dried to give 5,12-dihydro-5,
1.0 g of 12-benz[b]anthracenedicarboxaldehyde (melting point 170-172°C) remains. Example 28 Bis(2-imidazolin-2-ylhydrazone)-5,12-dihydro-5,12-benz[b]
Anthracenedicarboxaldehyde dihydrochloride 5,12-dihydro- in 60 ml of n-propanol
A mixture of 0.85 g of 5,12-benz[b]anthracenedicarboxaldehyde and 1.04 g of 2-hydrazinoimidazoline dihydrochloride is boiled and concentrated to 30 ml over the course of 2.5 hours. The solution is clarified by filtration and allowed to cool for 48 hours. 0.12 g of dark red crystals of the resulting product melt at 290-295°C. Further product can be obtained as the free base by diluting the mother liquor with water and making basic with sodium bicarbonate solution. Recrystallization of the resulting crude product from methanol gives 0.15 g of dark red crystals. melting point
230-233℃. Reference example 31 7,12-benz[a]anthracenedicarboxaldehyde 7,12-dihydro-7,12-benz[a]anthracenedicarboxaldehyde [Newman
& Din, J.Org.Chem. 36 , 967 (1971)] is suspended in 75 ml of glacial acetic acid, treated with 6 g of ferric chloride hexahydrate and stirred for 3 hours at room temperature. The remaining yellow solid is filtered and washed with acetic acid and water, leaving a yellow product (mp 197-198°C). Example 29 Bis(2-imidazolin-2-ylhydrazone)-7,12-benz[a]anthracenedicarboxaldehyde dihydrochloride 7,12-benz[a]anthracenedicarboxaldehyde 0.57 in 50 ml of n-propanol
g and 2-imidazolin-2-ylhydrazone 0.70
Boil the solution with g and concentrate to 20 ml over the course of 3 hours. After cooling for 3 days, the resulting orange powder is filtered, washed with n-propanol and dried, leaving the product (mp 240-245°C). The mother liquor is diluted with 2 volumes of water and made basic with sodium bicarbonate solution to give the free base product as an orange solid (mp 210-215
℃). Reference example 32 5,12-benz[b]anthracenedicarboxaldehyde 13,14-dihydroxy-5, in 110 ml of glacial acetic acid
A solution of 5 g of 12-ethanobenz[b]anthracene was treated with 15.4 g of lead tetraacetate at once, and the mixture was heated for 30 to 40 hours.
Stir at °C. The resulting purple solid is filtered, washed once with acetic acid and finally with water, dried and recrystallized from methylene chloride-methanol to give purple needles (melting point 215-217°C). Example 30 Bis(2-imidazolin-2-ylhydrazone)-5,12-benz[b]anthracenedicarboxaldehyde dihydrochloride 1.0 g of 5,12-benz[b]anthracenedicarboxaldehyde in 75 ml of n-propanol
and 2-imidazolin-2-ylhydrazone 1.2g
Boil the suspension and concentrate to 50ml. The resulting solid material is filtered from the hot solution and washed with n-propanol, leaving a purple product (melting point 320-325°C).

Claims (1)

[Claims] 1 Formula: where A, B and C form an anthracene or 9,10-dihydroanthracene nucleus; R ₁ is hydrogen or an alkyl group having up to 4 carbon atoms; R ₂ is hydrogen, up to 4 carbon atoms Alkyl group or formula having an atom: (Here, m is 2, 3, 4 or 5) is a monovalent group represented by; However, R ₁ and R ₂ are not both hydrogen; R ₃ , R ₄ , R ₅ and R ₆ are each independently selected from hydrogen, halogen, hydroxy group, amino group, alkyl group having up to 4 carbon atoms and alkoxy group having up to 4 carbon atoms; and R ₁ is hydrogen and When R ₂ is [Formula] (where m is as described above), R ₃ and R ₄ may form a phenyl group together with the carbon atom to which they are bonded. , and pharmacologically acceptable acid addition salts and quaternary ammonium salts thereof. 2. The compound according to claim 1, which is bis(2-imidazolin-2-ylhydrazone) dihydrochloride of 9,10-anthracenedicarboxaldehyde. 3 9,10-anthracenedicarboxaldehyde bis(1,4,5,6-tetrahydro-2-
The compound according to claim 1, which is pyrimidin-2-ylhydrazone) dihydrochloride. 4. The compound according to claim 1, which is bis(2-imidazolin-2-ylmethylhydrazone) dihydriodide of 9,10-anthracenedicarboxaldehyde. 5 2-chloro-9,10-anthracenedicarboxaldehyde bis(2-imidazoline-2-
2. The compound according to claim 1, which is hydrazone) dihydrochloride. 6 2-chloro-9,10-anthracenedicarboxaldehyde bis(2-imidazoline-2-
2. The compound according to claim 1, which is hydrazone) dihydrochloride. 7. The compound according to claim 1, which is bis(2-imidazolin-2-ylhydrazone) dihydrochloride of 1,4-dihydroxy-9,10-anthracenedicarboxaldehyde. 8. The compound according to claim 1, which is bis(2-imidazolin-2-ylhydrazone) of 2,6-difluoro-9,10-anthracenedicarboxaldehyde. 9. The compound according to claim 1, which is bis(2-imidazolin-2-ylhydrazone)-7,12-benz[a]anthracenedicarboxaldehyde. 10. The compound according to claim 1, which is bis(2-imidazolin-2-ylhydrazone)-5,12-benz[b]anthracenedicarboxaldehyde. 11 Bis(4,5,6,7-tetrahydro-
1H-1,3-diazepin-2-ylhydrazone)
The compound according to claim 1, which is -7,12-benz[a]anthracenedicarboxaldehyde. 12 Bis(1-methyl-1,3,4,5-tetrahydro-1H-2-pyrimidylhydrazone)5,
The compound according to claim 1, which is 12-benz[b]anthracenedicarboxaldehyde. 13 7,12-dihydro-bis(2-imidazolin-2-ylhydrazone)-7,12-benz[a]
The compound according to claim 1, which is anthracene dicarboxaldehyde. 14 5,12-dihydro-bis(2-imidazolin-2-ylhydrazone)-5,12-benz[b]
The compound according to claim 1, which is anthracene dicarboxaldehyde. 15 7,12-dihydro-bis(1,3,4,5
-Tetrahydro-1H-pyrimid-2-ylhydrazone)-7,12-benz[a]anthracenedicarboxaldehyde Claim 1
Compounds described in Section. 16 5,12-dihydro-bis(4,5,6,
7,-tetrahydro-1H-1,3-diazepine-
2-ylhydrazone)-5,12-benz[b]anthracenedicarboxaldehyde. 17. The compound according to claim 2, wherein the compound is in the form of a diacetate salt. 18. The compound according to any one of claims 1 to 16, wherein the compound is in the form of an acetic acid addition salt. 19. The compound according to any one of claims 1 to 16, wherein the compound is in the form of a hydrochloric acid addition salt. 20. The compound according to any one of claims 1 to 16, wherein the compound is in the form of a maleic acid addition salt. 21. The compound according to any one of claims 1 to 16, wherein the compound is in the form of a gluconic acid addition salt. 22 Formula: In the formula, R ₃ , R ₄ , R ₅ and R ₆ are each independently hydrogen, halogen, hydroxy group, amino group, alkyl group having up to 4 carbon atoms and alkoxy group having up to 4 carbon atoms. Also, when R ₁ below is hydrogen and R ₂ below is [Formula] (where m is as above), R ₃ and R ₄ are the carbon atoms to which they are bonded. A compound represented by the formula, which may be taken together to form a phenyl group, is represented by the formula: where R ₁ is hydrogen or an alkyl group with up to 4 carbon atoms; R ₂ is hydrogen, an alkyl group with up to 4 carbon atoms or with the formula: [Here, m is 2, 3, 4 or 5] is a monovalent group represented by, provided that R ₁ and R ₂ are not both hydrogen, reacted with hydrazine represented by And, if desired, a formula characterized by producing pharmacologically acceptable acid addition salts and quaternary ammonium salts thereof: In the formula, A, B, C, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆
is as described above, and a method for producing a pharmacologically acceptable acid addition salt and quaternary ammonium salt thereof. 23. The method of claim 22, wherein hydrazine is reacted in a lower alkanol solvent in the presence of a catalytic amount of acid at a temperature of 50 to 125°C. 24 Formula: where A, B and C form an anthracene or 9,10-dihydroanthracene nucleus; R ₁ is hydrogen or an alkyl group having up to 4 carbon atoms; R ₂ is hydrogen, up to 4 carbon atoms Alkyl group or formula having an atom: (Here, m is 2, 3, 4 or 5) is a monovalent group represented by; However, R ₁ and R ₂ are not both hydrogen; R ₃ , R ₄ , R ₅ and R ₆ are each independently selected from hydrogen, halogen, hydroxy group, amino group, alkyl group having up to 4 carbon atoms and alkoxy group having up to 4 carbon atoms; and R ₁ is hydrogen and When R ₂ is [Formula] (where m is as described above), R ₃ and R ₄ may form a phenyl group together with the carbon atom to which they are bonded. An antibacterial agent characterized by containing a hydrazone compound represented by the following, as well as a pharmacologically acceptable acid addition salt and quaternary ammonium salt thereof as active ingredients. 25 Formula: where A, B and C form an anthracene or 9,10-dihydroanthracene nucleus; R ₁ is hydrogen or an alkyl group having up to 4 carbon atoms; R ₂ ' is of the formula: (Here, m is 2, 3, 4 or 5) is a monovalent group represented by: R ₃ , R ₄ , R ₅ and R ₆ are each independently hydrogen, halogen, hydroxy group, amino group , an alkyl group having up to 4 carbon atoms and an alkoxy group having up to 4 carbon atoms; and R ₁ is hydrogen and R ₂ ' is [Formula] (where m is as defined above) ), R ₃ and R ₄ may form a phenyl group together with the carbon atom to which they are bonded. 1. An antitumor agent characterized by containing an acid addition salt and a quaternary ammonium salt as active ingredients.