AU538905B2

AU538905B2 - Substituted 9,10-anthracene-byshydrazones

Info

Publication number: AU538905B2
Application number: AU60516/80A
Authority: AU
Inventors: Frederick Emil Durr; Keith Chadwick Mudrock
Original assignee: American Cyanamid Co
Current assignee: Wyeth Holdings LLC
Priority date: 1979-05-07
Filing date: 1980-05-05
Publication date: 1984-08-30
Anticipated expiration: 2000-05-05
Also published as: AU6051680A

Description

SUBSTITUTED 9,10-ANTHRACENE-BISHYDRAZONES

This invention relates to new organic compounds and, more particularly, is concerned with novel anthracene-9,10-bis-carbonyl-hydrazones which may be represented by the following general formula:

wherein Z is a moiety of the formulae:

or wherein n is 0, 1, 2 or 3 and R is hydrogen, alkyl having up to 4 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms, phenyl or benzyl; R₁ is hydrogen or alkyl having up to 4 carbon atoms; R₂ is a moiety of the formulae: or

wherein p is 1, 2 or 3, q is 0, 1 or 2, R' is hydrogen or alkyl having up to 4 carbon atoms, R" is alkyl having up to 4 carbon atoms, R₇ is a moiety of the formula:

wherein m is 2, 3, 4 or 5, R₁, R' and R" are as hereinbefore defined and the moiety -NR'R" may be pyrrolidino, piperidino, morpholino or N-methylpiperazino, X is oxo (O=), thioxo (S=) or imino (R'-N= wherein R' is as hereinbefore defined); and R₃, R₄, R₅ and R₆ are each individually selected from the group consisting of hydrogen, halogen (F, Cl, Br, I), hydroxy, nitro, amino, sulfonamido, alkyl having up to 3 carbon atoms and alkoxy having up to 3 carbon atoms. The hydrazono substituents pendant from the anthracene-9,10-bis-carbonyl nuclei may be the same or different and may be in the syn or anti forms. Additionally, where the hydrogen atoms or other substituents at positions 1, 4, 5 and 8 of the anthracene nucleus cause restricted rotation of the bonds extending from C ₉ and C₁₀ of the anthracene nucleus, then the entire units R at the C₉ and C₁₀ positions may be either cis (both extending out from the same face of the anthracene nucleus) or trans (extending out from the opposite faces of the anthracene nucleus). The novel compounds of the present invention are obtainable as yellow crystalline materials having characteristic melting points and absorption spectra and which may be purified by recrystallization from common organic solvents such as lower alkanols, dimethylformamide, tetrahydrofuran, methyl isobutyl ketone, and the like.

The organic bases of this invention form non-toxic acid-addition and quaternary ammonium salts with a variety of pharmacologically acceptable organic and inorganic salt-forming reagents. Thus, acid-addition salts, formed by admixture of the Organic free base with one or more equivalents of an acid, suitably in a neutral solvent, are formed with such acids as sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric, lactic, malic, succinic, tartaric, acetic, benzoic, gluconic, ascorbic, and the like. Quaternary ammonium salts may be formed by reaction of the free bases with one or more equivalents of a variety of organic esters of sulfuric, hydrόhalic and aromatic sulfonic acids. The organic reagents employed for quaternary ammonium salt formation are preferably lower alkyl halides. However, other organic reagents are suitable for quaternary ammonium salt formation, and may be selected from among a diverse class of compounds including benzyl chloride, phenethyl chloride, naphthylmethyl chloride, dimethyl sulfate, methyl benzenesulfonate ethyl toluenesulfonate, allyl chloride, methallyl bromide and crόtyl bromide. For purposes of this invention, the free bases are equivalent to their non-toxic acid-addition and quaternary ammonium salts. The acid-addition and quaternary ammonium salts of theorganic bases of the present invention are, in general, crystalline solids, relatively soluble in water, methanol and ethanol but relatively insoluble in non-polar organic solvents such as diethyl ether, benzene, toluene, and the like. The novel compounds of the present invention possess the property of inhibiting the growth of transplanted mouse tumors as established by the following tests.

Lymphocytic leukemia P388 test The animals used are mice all of one sex, weighing a minimum of 17 g. and all within a 3 gram weight range. There are 5 or 6 animals per test group. The tumor transplant is by intraperitoneal injection of 0.1 ml. or 0.5 ml. of dilute ascitic fluid containing 10 cells of lymphocytic leukemia p388. The test compounds are administered intraperitoneally on days one, 5 and 9 (relative to tumor inoculation) at various doses. The animals are weighed and survivors are reocrded on a regular basis for 30 days. The median survival time and the ratio of survival time for treated (T) /control (C) animals are calculated. The positive control compound is 5-fluorouracil given as a 60 mg./kg. injection. The results of this test with representative compounds of the present invention appear in Table I below. The criterion for efficacy is T/C x 100≥125%

The novel compounds of formula (I) and their pharmacologically acceptable acid-addition and quaternary ammonium salts would be expected to show activity against a broad range of cancer diseases, and especially blood cancer diseases such as leukemia, in standard test animals at doses substantially below toxic levels. The modes contemplated for administration are essentially parenteral and intraperitoneal.

The pharmaceutical compositions can be in forms suitable for injectable use, which forms include sterile aqueous solutions or dispersions and sterile powders for the extemporanous preparation of sterile injectable solutions or dispersions. 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 preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the

like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal gaents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active ingredient or ingredients in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatable with the active ingredient, its use in the present compositions is contemplated. Supplementary active ingredients can also be incorporated into the inventive compositions. It is especially advantageous to formulate compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suited as unitary dosages for the animal subjects to be treated, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the novel dosage unit forms of the invention are dictated by the directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as disclosed in detail in this specification.

The dosage of the principal active ingredient for the treatment of the indicated conditions depends upon the age, weight and condition of the subject being treated; the particular condition and its severity; the particular form of the active ingredient and the route of administration. A daily dose of from about one to about 100 mg./kg. of body weight given singly or in divided doses of up to 5 times a day embraces the effective range for the treatment of most conditions for which the novel compounds are effective and substantially non-toxic. For a 75-kg. subject, this translates into between about 75 and about 7500 mg./day. If the dosage is divided, for example, into 3 individual dosages, these will range from about 25 to about 2500 mg. of the active ingredient. The preferred range is from 2 to about 50 mg./kg. of body weight/day with about 2 to about 30 mg./ kg./day being more preferred.

The principal active ingredient is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically-acceptable carrier in dosage unit form as hereinbefore disclosed. A unit dosage form can, for example, contain the principal active ingre dient in amounts ranging from about 0.1 to about 400 mg., with from about one to about 30 mg. being preferred. Expressed in proportions, the active ingredient is generally present in from about 0.1 to about 400 mg./ml. of carrier. In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.

Regression and palliation of cancers are attained, for example, using intraperitoneal administration. A single intravenous dosage or repeated daily dosages can be administered. Daily dosages up to about 5 or 10 days are often sufficient. It is also possible to dispense one daily dosage or one dose on alternate or less frequent days. As can be seen from the dosage regimens, the amount of principal active ingredient administrated is a sufficient amount to aid regression and palliation of the leukemia or the like, in the absence of excessive deleterious side effects of a cytotoxic nature to the hosts harboring the cancer. As used herein, cancer means blood malignancies such as leukemia, as well as other solid and non-solid malignancies such as the melanocarcinomas, lung carcinomas and mammary tumors. By regression and palliation is meant arresting or retarding the growth of the tumor or other manifestation of the disease compared to the course of the disease in the absence of treatment.

Most of the novel compounds of the present invention may be readily prepared as set forth in the following reaction scheme: wherein Z, R₁, R₂, R₃, R₄, R₅ and R₆ are as hereinabove defined. In accordance with the above reaction scheme, an appropriately substituted 9,10-anthracenedialdehyde or diketone (III) is reacted with a hydrazine derivative of the formula: H₂N-NR₁R₂ to provide the 9,10-anthracene-bis-anthracene-bis-hydrazones (I). The reaction may be carried out in a lower alkanol in the presence of an acid such as hydrochloric, hydriodic or acetic (or glacial acetic acid may be used as the sole solvent) usually at the reflux temperature of the reaction mixture.

The starting 9,10-anthracenedialdehydes and ketones may be obtained commercially or prepared in accordance with any one of the reaction schemes denominated (A) and (B) below wherein R₃, R₄, R₅ and R₆ are as hereinabove defined.

In accordance with the above reaction scheme, the anthracene derivative (IV) suspended in dioxane and concentrated hydrochloric acid and saturated with HCl, is treated with paraformaldehyde at the reflux temperature for 2-6 hours to obtain the 9,10-bis-(chloromethyl) anthracene derivative (V). This 9,10-bis-(chloromethyl) anthracene, suspended in dry dimethyl sulfoxide under nitrogen at room temperature, is treated with sodium in ethanol and worked up as described in the examples to obtain the desired 9,10-anthracene dicarboxaldehyde (VI).

In accordance with the above reaction scheme, the anthracene derivative (IV) is heated with excess vinylene carbonate under reflux for about 20 hours to give the cyclic carbonate (XI). Hydrolysis of the cyclic carbonate (XI) with aqueous-ethanolic potassium hydroxide at 75°C. for about 2 hours produces the diol (XII) which in turn is treated with lead tetraacetate in acetic acid at 35°C. for about 2 hours to give the 9,10-anthracenedicarboxaldehyde (VI).

Certain anthracene bis-hydrazones are more readily prepared by methods other than the general method previously outlined. One of these is outlined as reaction scheme (C) below wherein R₃, R₄, R₅ and R₆ are as .hereinabove defined.

In accordance with the above reaction scheme, a mixture of 9,10-anthracenediacetonitrile derivative (XVI) and a substituted hydrazine hydrochloride, sodium acetate and Raney-nickel in ethanol is reduced with hydrogen until 2 molar equivalents of hydrogen have been absorbed to give the desired anthracene bis-hydrazone (XVII). The novel monohydroxyanthracene-9,10-bis- hydrazones and the dihydroxyanthracene-9,10-bis-hydrazones of the present invention may be prepared as set forth in the reaction scheme (B) after having converted the hydroxy groups to tri methylsilyloxy derivatives, as by treatment with trimethylsilyl chloride in dry tetrahydrofuran in the presence of triethylamine.

The invention is illustrated by the following specific examples. Example 1. 1,1'-[9,10-Anthrylenebis(methylidynenitrilo)]bis-[3- (2-dimethylaminoethyl)guanidine] tetrahydrochloride

A mixture of 3.5 g. of 9,10-anthracenedicarboxaldehyde, 8.3 g. of 1-amino-3-(dimethylaminoethyl)guanidine trihydrochloride, 150 ml. of ethanol and 8 ml. of water is heated under reflux for 2.5 hours, treated with charcoal and filtered. This solution is evaporated to dryness and reevaporated with ethanol. The residue is slurried with hot isopropanol, cooled and filtered to give 9.0 g. of orange solid.

Example 2 9,10-Anthracenedicarboxaldehyde, bis[4-(3-dimethylaminopropyl)-3-thiosemicarbazone] dihydrochloride

A mixture of 2.9 g. of 9,10-anthracenedicarboxaldehyde, 5.0 g. of 4-(3-dimethylaminopropyl)-3-thiosemicarbazide, 100 ml. of ethanol and 12 ml. of 8M ethanolic hydrogen chloride is heated under reflux for 3.5 hours, filtered hot and cooled to give 5.7 g. of orange solid. This is recrystallized from 85 ml. of dimethylformamide to give 4.5 g. of product. After drying at 75°C. in a pistol it has a m.p. of 221-223°C.

Example 3 9 ,10-Anthracenedicarboxaldehyde, bis[4-(3-dimethylaminoethyl)-3-thiosemicarbazone] dihydrobromide

A mixture of 3.5 g. of 9,10-anthracenedicarboxaldehyde, 5.4 g. of 4-(dimethylaminoethyl) thiosemicarbazide, 250 ml. of ethanol and.2 ml. of 48% hydrogen bromide is heated under reflux for 4 hours and filtered hot to give 6.4 g. of solid. This is resuspended in 175 ml. of boiling ethanol and treated with 20 ml. of 48% hydrogen bromide to obtain complete solution. This is cooled, treated with 100 ml. of ether and cooled further to give 3.1 g. of the product in the form of orange-red crystals, m.p. 289-290°C. Example 4 9,10-Anthracenedicarboxaldehyde, bis(4,4-dimethyl-2-imidazolin-2-ylhydrazone) dihydrochloride

A mixture of 2.3.4 g. of 9,10-anthracenedicarboxalde hyde, 4.4 g. of 4,4-dimethylimidazolin-2-ylhydrazine hydrobromide and 50 ml. of n-propanol is boiled for 2 hours. The yellow-orange solid is collected, washed with n-propanol and dried. This hydrobromide salt is dissolved in water and basified with sodium bicarbonate to give a solid which is collected, redissolved in 60 ml. of hot n-propanol and treated with 0.6 ml. of 7N hydrochloric acid in isopropanol and cooled to give 1.2 g. of the title compound, m.p. 310-315°C.

Example 5 9,10-Anthracenedicarboxaldehyde, bis (1,4,5,6-tetrahydro-5,5-dimethyl-2-pyrimidinyl)hydrazone, dihydrochloride A mixture of 0.94 g. of 9,10-anthracenedicarboxalde hyde, 1.7 g. of 5, 5-dimethyl-1,4,5,6-tetrahydropyrimidin-2-ylhydrazine and 50 ml. of n-propanol is heated to boiling for 0.5 hours, then cooled to give 1.7 g. of a yellow crystalline product, m.p. 340°C. (dec).

Example 6 9,10-Anthracenedicarboxaldehyde, bis[4-(2-morpholinoethyl)-3-thiosemicarbazide] dihydrochloride

A mixture of 3.5 g of 1-(2-morpholinoethyl)thio semicarbazide, 1.75 g of 9,10-anthracenedicarboxaldehyde, 250 ml ethanol and 2 ml of concentrated hydrochloric acid is .heated under reflux for 5.5 hours and filtered hot to give 5.5 g of product, m.p. 229-231°C. This is recrystallized from a methanol-water-ether solution to give 5.0 g of orange product: m.p. 235-237°C.

Claims

CLAIMS FOR ALL DESIGNATED COUNTRIES EXCEPT AUSTRIA

1. A compound selected from the group consisting of those of the formula:

wherein Z is a trivalent moiety selected from the group consisting of those of the formulae:

and wherein n is 0, 1, 2 or 3 and R is hydrogen, alkyl having up to 4 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms, phenyl or benzyl; R₁ is selected from the group consisting of hydrogen and alkyl having up to 4 carbon atoms; R₂ is selected from the group consisting of monovalent moieties of the formulae:

and wherein p is 1, 2 or.3, q is 0, 1 or 2, R' is hydrogen or alkyl having up to 4 carbon atoms, R" is alkyl having up to 4 carbon atoms, R₇ is a moiety of the formula:

wherein m is 2, 3, 4 or 5, R₁ , R' and R" are as hereinbefore defined and the moiety -NR'R" may be pyrrolidino, piperidino, morpholino or N-methylpiperazino, X is oxo (O=), thioxo (S=) or imino (R^,-N=) wherein R' is as hereinbefore defined), and R₃, R₄, R₅ and R₆ are each individually selected from the group consisting of hydrogen, halogen (F, CI, Br, I), hydroxy, nitro, amino, sulfonamido, alkyl having up to 3 carbon atoms; and the pharmacologically acceptable acid-addition and quaternary ammonium salts thereof.

2. An acid-addition, salt according to Claim 1, wherein the acid is acetic acid, hydrochloric acid, hydrobromic acid, maleic acid, or gluconic acid.

3. The compound according to Claim 1: 9,10-

-anthracenedicarboxaldehyde, bis (4,4-dimethyl-2-imidazolin-2-ylhydrazone) dihydroehloride.

4. The compound according to Claim 1: 9,10-anthracene-dicarboxaldehyde, bis (1,4,5,6-tetrahydro-5,5-dimethyl-2-pyrimidinyl) hydrazone, dihydroehloride.

5. The compound according to Claim 1: 9,10-anthracenedicarboxaldehyde, bis [4-(3-dimethylaminopropyl) -3-thiosemicarbazone] dihydrochloride.

6. The compound according to Claim 1: 9,10-anthracenedicarboxaldehyde, bis [4-(3-dimethylaminoethyl) -3-thiosemicarbazone] dihydrobromide.

7. The compound according to Claim 1: 9,10-anthracenedicarboxaldehyde, bis [4-(2-morpholinoethyl) -3-thiosemicarbazide] dihydroehloride.

8. The compound according to Claim 1: 1,1'-[9,10-anthrylene bis (methylidynenitrilo)]bis-[3-(2-dimethyl-aminoethyl)quanidine] tetrahydrochloride.

9. A pharmaceutical composition, comprising a compound according to any preceding claim, and a pharmaceutically acceptable carrier or diluent.

CLAIMS 1. A pharmaceutical composition comprising an active compound selected from the group consisting of those of the formula:

wherein Z is a tribalent moiety selected from the group consisting of those of the formulae:

^c and

wherein n is 0, 1, 2 or 3 and R is hydrogen, alkyl having up to 4 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms, phenyl or benzyl; R₁ is selected from the group consisting of hydrogen and alkyl having up to 4 carbon atoims; R₂ is selected from the group consisting of monovalent moieties of the formulae: and

wherein m is 2, 3, 4 or 5, R₁, R' and R" are as hereinbefore defined and the moiety -NR'R"^' may be pyrrolidino, piperidino, morpholino or N-methylpiperazino, X is oxo (O=), thioxo (S=) or imino (R'-N=) wherein R' is as hereinbefore defined), and R₃, R₄, R₅ and R₆ are each individually selected from the group consisting of hydrogen, halogen (F, CI, Br, I), hydroxy, nitro, amino., sulfonamido, alkyl having up to 3 carbon atoms; and the pharmacologically acceptable acid-addition and quaternary ammonium salts thereof; and a pharmaceutically acceptable carrier or diluent.

2. A pharmaceutical composition according to Claim 1, wherein said active compound is 9,10-anthracenedicarboxaldehyde, bis(4,4-dimethyl-2-imidazolin-2-ylhydrazone) dihydroehloride.

3. A pharmaceutical composition according to Claim 1, wherein said active compound is 9, 10-anthracene-dicarboxaldehyde, bis (1,4,5,6-tetrahydro-5,5-dimethyl-2-pyrimidinyl) hydrazone, dihydrochloride.

4. A pharmaceutical composition according to Claim 1, wherein said active compound is 9,10-anthracenedicarboxaldehyde, bis [4-(3-dimethylaminopropyl)-3-thiosemicarbazone] dihydroehloride.

5. A pharmaceutical composition according to Claim 1, wherein said active compound is 9,10-anthracenedicarboxaldehyde, bis [4-(3-dimethylaminoethyl)-3-thiosemicarbazone] dihydrobromide.

6. A pharmaceutical composition according to Claim 1, wherein said active compound is 9,10-antracenedicarboxaldehyde; bis [4-(2-morpholinoethyl)-3-thiosemicarbazide] dihydroehloride.

7. A pharmaceutical composition according to Claim 1, wherein said active compound is 1,1'-[9,10-anthrylene bis(methylidynenitrilo)]bis-[3-(2-dimethyl-aminoethyl)quanidinel tetrahydrochloride.

8. A process for preparing a pharmaceutical composition as. defined in any preceding claim, wherein. said active compound is incorporated with a pharmaceutically acceptable carrier or diluent.

9. A process for preparing a compound of the formula:

wherein Z and R₁-R₆ are as defined in Claim 1, which comprises reacting an appropriately substituted 9,10-anthracenedialdehyde or diketone with a hydrazine derivative of the formula: H₂N-NR₁R₂, wherein R₁ and R₂ are as defined in Claim 1.