JPH0217534B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel organic compounds and methods for their preparation. More specifically, the present invention is based on the following formula () where A-B is selected from the group consisting of CH=CH and _CH2 - _CH2 ; Q is 2 of the formula: -( _CH2 )n-, where n is an integer from 2 to 4; each of R ₁ and R ₂ is hydrogen, an alkyl group having 1 to 4 carbon atoms, having 2 to 4 carbon atoms, and R ₁ and R ₂ are bonded; The carbon atom at the α-position to the nitrogen atom is a monohydroxyalkyl group that does not have a hydroxyl group, and the carbon atom at the α-position to the nitrogen atom has 3 to 6 carbon atoms and to which R ₁ and R ₂ are bonded. Atoms include dihydroxyalkyl groups, acetyl groups, trifluoroacetyl groups that do not have a hydroxyl group and the formulas: -( _CH2 ) ₂ -O- _CH3 and Here, R ₃ and R ₄ are independently hydrogen or methyl, or R ₃ and R ₄ together with the nitrogen atom to which they are bonded are morpholino. or R ₁ and R ₂ together with the nitrogen atom to which they are attached are aziridino, morpholino, piperazino, 4-methyl-1-piperazino, oxazolidino, 1,3-dioxan-2-one or pyrrole. Yes, but a) When n is 2, R ₁ /R ₂ is CH ₃ /
When n is 3 instead of CH ₃ , R ₁ /R ₂ is H/H,
_CH3 / _CH3 , _C3H7 / _{C3H7 or ( -CH2} ) _-2O ( _-CH2
) − ₂ , and when n is 4, R ₁ /R ₂ is
not C ₂ H ₅ /C ₂ H ₅ or (-CH ₂ )- ₄ ; b) only one of R ₁ and R ₂ may be alkanoyl; The present invention relates to a compound selected from acid addition salts thereof. Compounds of the above general formula, where AB is _CH2 - _CH2 , are generally stable compounds and are known as the leuco form of the corresponding anthraquinone. These leuco forms are known to exist in their respective tautomeric forms, and all such forms are equivalents for the purposes of the present invention. The leuco form (leuco base herein) and its tautomers may be represented by the following general formula: The present invention also relates to a process for the preparation of the novel compounds represented by the above formulas and. Accordingly, one method contemplated by the present invention includes the following general formula: The compound represented by the following formula Here, the definitions of Q, R ₁ and R ₂ are the same as above, and the compound represented by is reacted in a tertiary amine solvent, that is, N,N,N',N'-tetramethylethylenediamine, and A compound represented by is produced, and then reacted with chloranil (tetrachloroquinone) if necessary,
Included is a method characterized in that the compound of the above formula () is produced. The invention will now be described in detail. The compound of the present invention is represented by the above general formula (). These compounds can generally be obtained as red and colored to blue-black crystalline materials with characteristic melting points and absorption spectra, with the free base being largely insoluble in water and some in many organic solvents. Therefore, it may be purified by leaching with lower alkanol. The organic base of the present invention (,
and) form non-toxic addition 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 1, 2 or up to 8 equivalents of an acid, preferably in a neutral solvent, include sulfuric, phosphoric, hydrochloric, hydrobromic acids. It is formed with acids like sulfamic acid, citric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, benzoic acid, gluconic acid, ascorbic acid, etc. Preferred acids are hydrochloric acid and acetic acid. For purposes of this invention, free bases are equivalent to their non-toxic acid addition salts. The acid addition salts of organic bases of the present invention are generally crystalline solids that are relatively soluble in water, methanol, and ethanol, but relatively insoluble in nonpolar organic solvents such as diethyl ether, benzene, toluene, and the like. . It is understood that all such salts can be converted back into the respective free forms represented by the formula and by methods known to those skilled in the art, and that all such salts and free forms are therefore equivalent for the purposes of the present invention. This will be understood by those skilled in the art. A preferred embodiment of the novel compound of the present invention has the following general formula: A in the above general formula ().
-B and Q are as above; R ₁ is hydrogen, 1
an alkyl group having ~4 carbon atoms or 2 to 4
R ₂ is a monohydroxyalkyl group containing 2 to 4 carbon atoms and the carbon atom located α to the nitrogen atom does not contain a hydroxyl group; A monohydroxy group that does not contain a hydroxy group, a dihydroxyalkyl group that has 3 to 6 carbon atoms and the carbon atom at the alpha position to the nitrogen atom does not contain a hydroxy group, or a dihydroxyalkyl group that does not contain a hydroxy group: (In the formula, n, R ₃ and R ₄ are as above) (The ratio to the sum of A second preferred embodiment of the novel compound aspect of the present invention has the following general formula: and its pharmacologically acceptable acid addition salts. In the formula, R is hydrogen or an alkyl group having 1 to 4 carbon atoms, and A-B, n and Q
is as described above, and the ratio of the total number of carbon atoms to the sum of the total number of oxygen atoms and the total number of nitrogen atoms in each of the side chains at the 1st and 4th positions does not exceed 4. A third preferred embodiment of the novel compound aspect of the present invention has the following formula: The present invention relates to a compound represented by and a pharmacologically acceptable acid addition salt thereof. where n, R ₁ , R ₂ and AB are as shown in the first preferred embodiment. A fourth preferred embodiment of the novel compound aspect of the present invention has the following formula: The present invention relates to a compound represented by and a pharmaceutically acceptable acid addition salt thereof. In the formula, R ₁ is hydrogen or -CH ₂ CH ₂ OH
It is. Preferred salts are hydrochloride and acetate. The novel compounds of this invention represented by formulas and may be readily prepared by the following general method. The following formula The compound represented by the following formula The following formula is obtained by reacting the compound represented by A compound represented by is produced and then reacted with chloranil (tetrachloroquinone) if necessary. A salt of the compound of formula () above is formed by contacting the compound of formula () above with a pharmacologically acceptable salt-forming reagent under salt-forming conditions. As mentioned above, the initial reaction is N, N, N′,
It is carried out in N'-tetramethylethylenediamine solvent. The reaction temperature is about 40-110℃, for example about 40-60℃
C. and the reaction time is preferably about 2 to about 10 hours. In many cases the product is a solid and may crystallize from the reaction solvent spontaneously or upon cooling by seeding or straining and may be collected by perfusion or decantation. In other examples, the reaction mixture may be concentrated under vacuum at an elevated temperature, for example, and upon cooling the product will crystallize and be collected by filtration or decantation as described above. In other examples, the solvent may be evaporated to dryness or other miscible solvents such as water may be mixed into or diluted with the reaction mixture to collect the product, e.g. by filtration or extraction. It may be necessary to proceed to Those skilled in the art can choose the procedures to follow, and all such procedures are considered equivalent for the purposes of the present invention. Once the product has been collected, it may be purified, for example by crystallization, chromatography (thin layer or column) or leaching, preferably with lower alcohols. Other procedures such as disintegration or crushing in a solvent, eg an organic solvent such as ethanol, may be used and all purification procedures should be considered equivalent for the purposes of the present invention. Those skilled in the art will appreciate that when a product in leuco form is desired, the tricyclic starting material should be in leuco form and that such material, especially at elevated temperatures (i.e. room temperature), can be exposed to oxidizing agents such as oxygen. You will recognize that care should be taken to protect against agents.
Therefore, when a leuco product is desired, the reaction is normally and effectively carried out in an atmosphere excluding air. The reaction may therefore be carried out, for example, in an atmosphere of nitrogen or argon, and this consideration should be taken during purification procedures, especially those requiring high temperatures. Such considerations are usually not necessary when aromatic products are desired and aromatic starting materials are used. It is well known to those skilled in the art that the leuco form can be readily converted to the aromatic form when desired by a variety of methods. According to the invention, such aromatization is carried out by reacting the above product of the first reaction with chloranil (tetrachloroquinone). The reaction scheme of the method of the present invention can be represented by Scheme A below. (wherein R ₁ , R ₂ and Q are as described above) In a more preferred subconcept embodiment of the method of the present invention, Q is as described above, and R ₁ is hydrogen or 1 to 4
a monohydroxyalkyl group in which R ₂ has 2 to 4 carbon atoms and the carbon atom at the alpha position to the nitrogen atom does not contain a hydroxyl group, and 3 to 6 carbon atoms; or a dihydroxyalkyl group in which the carbon atom at the α-position to the nitrogen atom does not contain a hydroxyl group, or the formula:
[Formula] (in which n, R ₃ and R ₄ are as above) (however,
(The ratio of the total number of carbon atoms to the sum of the total number of oxygen atoms and the total number of nitrogen atoms in each of the side chains at the 1st and 4th positions does not exceed 4), and its pharmacology To prepare the above-accepted acid addition salts, the product is contacted with a pharmacologically acceptable acid, preferably acetic acid or hydrochloric acid. A second more preferred embodiment of the process according to the invention is in which R ₁ is hydrogen or an alkyl group having 1 to 4 carbon atoms, R ₂ is -(CH ₂ )nOH, and n and Q are As mentioned above. (However, the ratio of the total number of carbon atoms to the sum of the total number of oxygen atoms and the total number of nitrogen atoms in each of the side chains at the 1st and 4th positions does not exceed 4.) To prepare a pharmaceutically acceptable acid addition salt, the product is contacted with a pharmaceutically acceptable acid, preferably acetic acid or hydrochloric acid. A most preferred sub-embodiment of the process of the invention is in which Q is -( _CH2 )n-, where n is an integer from 2 to 4, preferably 2, and _R1 is hydrogen or -
CH ₂ CH ₂ OH, and R ₂ is -CH ₂ CH ₂ OH, represented by the above reaction scheme A, and in order to produce a pharmacologically acceptable acid addition salt thereof, the product is Contact with an acceptable acid, preferably acetic acid or hydrochloric acid. The novel compounds of the present invention wherein AB is CH=CH also have the formula: Compounds and formulas of: and, if desired, contacting the product with a pharmaceutically acceptable salt-forming reagent. In the formula, G is an alkanoyloxy group of 1 to 6 carbon atoms, an alkoxy group of 1 to 6 carbon atoms, or an alkyl group of 1 to 6 carbon atoms. Yes; L is hydrogen, a hydroxy group, or [formula]; J is hydrogen, chlorine, or bromine; however, when a G is [formula], L is hydrogen or a hydroxy group, and J is chlorine; Substituent K is removed from the tricyclic product; b When G is other than , L is , and the cyclization product is aromatized. This method is preferably carried out in a reaction inert solvent such as toluene, xylene or ethanol.
The reaction temperature is 150° C., preferably in an inert atmosphere such as nitrogen. If necessary, the tricyclic product is aromatized, for example when G is other than [Formula]. When G is [Formula], the substituent K is removed from the tricyclic product, for example by treatment with aqueous methanolic acid. Those skilled in the art will recognize that the product obtained after removing the K substituent is a free carbamic acid that decarboxylates spontaneously. Another method by which the novel compounds of the present invention in which AB is CH=CH can be prepared is as follows: Formula: Compounds and formulas of: and the group RCO and Y are OCH ₃
Y is hydrolyzed to convert it to a hydrogen or hydroxy group, respectively, and the product is contacted with a pharmaceutically acceptable salt-forming agent, if desired. In the formula, R is an alkyl group of 1 to 6 carbon atoms or _CF3
and E and F are both hydrogen or when taken together form [formula] in which R ₃ is hydrogen or an alkyl group of 1 to 6 carbon atoms; C-D is CH=CH or [formula] (wherein Y is H or OCH ₃ ); however, when E and F are hydrogen, CD is [formula] and CD is CH=CH When , E and F form [Formula], and R ₅ =R ₇ =hydroxy group. This reaction preferably converts the reactants into _NaAlCl4
It is carried out by mixing in a (NaCl/AlCl ₃ ) melt at a temperature of 130-200° C. for 1-6 hours. The tricyclic product is hydrolyzed, eg, aqueous oxidative hydrolysis, to remove the protecting groups and, if desired, to prepare a pharmaceutically acceptable salt. It has been recognized that when the reactants utilized in the process of the invention contain certain substituents, the process can be made particularly efficient and effective by specific selection of reaction variables such as time, temperature and solvent. It was done. These preferred combinations of reactants and reaction variables are illustrated by Reaction Schemes 1-12 below.
The combinations illustrated by the listed schemes are merely preferred combinations and arrangements of the methods of the invention;
Those skilled in the art will recognize that they are not intended to limit the scope of the invention or the claimed methods. The procedures and preferred combinations depicted by Schemes 1-12 are disclosed solely for the convenience of those wishing to practice the invention and are in no way to be used to define the scope of the invention. The symbols and definitions used in each of Schemes 1-12 relate only to the particular scheme in which they are used unless indicated in the reaction. In the formula, Q, R ₁ and R ₂ are as described above, and X is
OH, Cl, Br, I, NH ₂ , NO ₂ , SO ₃ H,
[Formula] [Formula], SH, S-R ₁₀ , OR ₁₀ , N ₃ , tetrazolyl, ONO, etc., and Z is H or OH. According to the above reaction scheme, when a suitably substituted 9,10-anthracenedione in the leuco or aromatic form is reacted with an amine of the structure shown, the desired 1,4-diamino-9,10-anthracenedione is converted into the leuco- or aromatic form. or aromatic form. The reaction is carried out in ethanol, propanol, isopropanol or N,N,N',N'-tetramethylethylenediamine at a temperature of 40 to 100° under nitrogen atmosphere for 2 to 10 minutes.
Time is done. When the product is a leuco compound, it is converted to the aromatic form by the methods described above. R ₁ , R ₂ and Q are as described above, and Z is a chloro group or an alkanoyloxy group of 1 to 6 carbon atoms. Leuco 1,4,5,8-tetra-substituted-9,10-
The reaction between the anthracenedione and the amine is carried out in a lower alkanol under a nitrogen atmosphere at a temperature of 40 DEG to 100 DEG for a period of 2 to 10 hours. The disubstituted derivative 1 is converted to the dihydroxy derivative 2 by alkaline or acid hydrolysis using an ethanol-water solution of sodium hydroxide or hydrochloric acid. The reaction is monitored using thin layer chromatography to control the reaction and avoid hydrolysis of the amino substituents. The leuco products can also be converted to the aromatic form by the methods described above. In the formula, Z is H or OH, Q, R ₁ and R ₂ are as described above, and X is Cl, Br, I, OSO ₂ C ₆ H ₄ p
-CH ₃ , OSO ₃ CH ₃ and R ₃ is H or [Formula]. The two reactants are mixed in lower alkanol and 40~
Heating at 90° for 1 to 8 hours yields the desired product. When R ₃ is CF ₃ CO, the latter is removed with aqueous methanolic potassium carbonate. Q is as described above, Z is hydrogen or a hydroxy group, R can be a lower alkyl group, a hydroxy lower alkyl group or a dialkylamino lower alkyl group, and R ₁ is H or a lower alkyl group; and R ₂ may be H, a lower alkyl group or a hydroxy lower alkyl group. A mixture of 9,10-anthracenedione and 2-3 molar equivalents of an aldehyde or ketone in a lower alkanol is heated at 40-100° under reducing conditions such as hydrogen with Raney-nickel catalyst or platinum catalyst or sodium borohydride. Upon heating for a period of time, the desired 1,4-bis(substituted amino)9,10-anthracenedione is formed. In the formula, Z is hydrogen or a hydroxy group, Q is as described above, R is H, a lower alkyl group or a hydroxy lower alkyl group, and R ₂ is H or a lower alkyl group. A mixture of 9,10-anthracenedione and acrylonitrile in a lower alkanol is heated to 60-100° for 2-10 hours to form the desired product. Z is H or OH, n is 1 to 3, and R ₁
and R ₂ are as described above. Bisacetal 1 in aqueous-methanolic acetic acid
When heated to 25° for 0.5 to 3 hours, dialdehyde 2 is produced. The latter compound was reacted with Raney-nickel catalyst or platinum catalyst or sodium borohydride under reducing conditions such as hydrogen in a lower alkanol for 40 to 40 min.
2 to 4 molar equivalents of amine at 100° for 2 to 10 hours,
Treatment with the formula gives the desired 1,4-diamino-9,10-anthracenedione. Z is H or OH, n=1-3, m=2 or 3. Leuco-1,4-dihydroxy-9,10-anthracenedione 4 or its aromatic form and amine 5 are reacted in lower alkanol or N,N,N',N'-tetramethylethylenediamine at 50-90°.
When heated for 10 hours, leuco-1,4-diamino-
9,10-anthracenedione 6 or its aromatic form is produced. Compound 6 was then converted into aqueous ethanolic
Warming at 40-80° in HCl for 1-6 hours yields the desired 1,4-diamino-9,10-anthracenedione 7. In the formula, Z is H or OH, and X is Cl, Br, I,
_{OSO2C6H4p - CH3 , OSO2CH3 .} When 1,4-diamino-9,10-anthracenedione 1, thionyl chloride and pyridine are mixed in the cold and then heated to 60-110° for 2-10 hours, compound 2 is obtained.
(X is Cl) occurs. Compound 2 , the amine [formula] and the solvent (lower alkanol) are mixed and heated at 70-100° for 2-14 hours to obtain the final product 3,1,4-diamino-9,10-anthracenedione. In the formula, Q, R ₁ and R ₂ are as described above, and R ₃ and R ₄ are lower alkyl groups. Dihydroaminonaphthoquinone 1 published procedure [ISMBloom and GODudek,
Tetrahedron, 26, 1267 (1970)]. Reaction of compound 1 with an acid anhydride in the presence of sodium acetate in an aprotic solvent provides the amide ester 2 , which is then hydrolyzed with aqueous base to yield the corresponding amide phenol 3 . Alkylation of this amide phenol with an alkyl halide or alkyl sulfonate in the presence of a base provides the corresponding amide ester 4 .
Amidophenol 3 or amide ester 4
NaAlCl ₄ mixed with maleic anhydride in the melt;
After heating at 130-180° for 1-5 hours, the desired 1,4-diamino-9,10-acetracenedione 5 is obtained after aqueous acid hydrolysis. In the formula, R ₁ and R ₂ are as described above, R is a lower alkyl group or CF ₃ , n = 2 to 4, and X is
Cl, Br, _OSO2C6H4 - _p - _CH3 or _OSO2CH3 , Y is H _{or OCH3 ,} Z= _H or OH
It is. Treatment of diamide 1 in toluene with NaH followed by treatment with amine 2 for 1 to 8 hours at 60-110° yields diamide diamine 3 . The latter compound 3 was mixed with phthalic anhydride 4 , AlCl ₃ and NaCl and 130
Melting at ~200° for 1 to 6 hours produces anthracenedione 5 . Aqueous acid hydrolysis of 5 yields the desired 1,4-diamino-9,10-anthracenedione 6. Q, Z, R ₁ and R ₂ are as described above, and R is a lower alkyl group. Diazide 1 is prepared from trans, trans muconic acid by conventional methods. diazide 1 in toluene
Bis-urethane 2 is produced when the lower alkanol is heated to 70-110° for 2-8 hours. Bisurethane 2 is then dissolved in ether or tetrahydrofuran in the presence of sodium hydride or other base for 40 to
Reaction with aminoalkyl halide for 2-10 hours at 60° produces compound 3 . Subsequent treatment of the latter compound with dichloronaphthoquinone 4 in toluene at 60-110° for 1-5 hours yields anthracenedione 5, which is converted to the desired 1,4-diamino-9,10-anthracene by aqueous methanolic acid hydrolysis. Produces Zeon 6 . Q, R ₁ and R ₂ are as described above, X=Cl or Br, Z=0 acyl or OCH ₃ . Butadiene 1 and diamine 2 [Tetrahedron
26, (1970)] yields diamine 3 in ethanol or toluene under nitrogen at 60-150°. When X is H, conversion of 3 to 4 is accomplished by treatment with a dehydrogenating agent such as chloranil in the same solvent. When X is halogen, 3 is converted to 4 by mild heating in aqueous methanolic sodium bicarbonate solution. Then, by mild acid hydrolysis, 4 Z=O
Convert the acyl to 4 Z=OH. The present invention also contemplates converting the product into an acid addition salt. Many methods of forming salts are known to those skilled in the art and should be considered equivalent for the purposes of the present invention. Thus, for example, the product can be dissolved or suspended in a solvent such as a lower alkanol (e.g. methanol, ethanol, i-propanol) and treated with a salt-forming reagent in its solution in the same solvent or in a different solvent. It's okay. Thus, for example, a suspension or solution of the product in ethanol may be treated with dilute or concentrated acetic acid, hydrochloric acid, etc., or with ethanolic HCl;
The corresponding salt may be collected, for example by filtration. Salt-forming reagents may also be added in pure form. Therefore, a solution or suspension of the product may be treated with glacial acetic acid or gaseous HCl to collect the corresponding acid addition salt. This invention also contemplates the use of compounds of formulas, and their pharmaceutically acceptable acid addition salts, and mixtures thereof, as active ingredients in pharmaceutical therapeutic formulations and compositions. The therapeutic composition of the present invention provides approximately 5 kg of body weight per day.
It inhibits the growth of implanted murine tumors and induces regression and/or alleviation of white plate disease and related cancers in mammals when administered in amounts ranging from ~200 mg. The preferred dosage regimen for optimal results will be from about 5 to about 50 mg per kg of body weight per day. and such dosage unit totals approximately 350mg for a patient weighing approximately 70Kg.
Administration of ~3.5 g of active compound over a 24 hour period is used. This dosage regulation may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered or the dose may be reduced proportionately as indicated by the exigencies of the therapeutic situation. A determined practical advantage is that the active compound can be administered in any convenient manner, such as by oral, intravenous, intramuscular or subcutaneous routes. The active ingredients may be applied orally, for example with an inert diluent or an assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsules, or they may be compressed into tablets. Alternatively, they can be mixed directly into dietary foods. For oral therapeutic administration, the active compound may be mixed with excipients and used as ingestible tablets, lozenges, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. Of course, the proportions of the compositions and formulations may vary; from about 2 to about 60% of the weight of the unit may be convenient. The amount of active ingredient in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions or formulations according to the invention are prepared such that an oral unit dosage form contains about 5 to 200 mg of active compound. Tablets, troches, pills, capsules, etc. may also contain: binders such as tragacanth, acacia, cornstarch or gelatin; excipients such as dibasic calcium phosphate; cornstarch, potato starch. , a disintegrant such as alginic acid, etc.; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or possibly added saccharin, or a flavoring agent such as wintergreen oil or cherries flavor. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. for example,
Tablets, pills or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl or propylparabens as preservatives, a dye, and flavoring, such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form must be pharmaceutically pure and virtually non-toxic in the amounts employed. Additionally, the active ingredients may be incorporated into sustained release formulations and mixtures. The active ingredient may also be administered parenterally or intraperitoneally. Solutions of the active ingredient can be prepared as a free point or as a pharmacologically acceptable salt in water mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also 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. Suitable therapeutic forms for injectable use include 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 can be a solvent or dispersion medium including, for example, water, ethanol, polyols such as glycerin, propylene glycol and liquid polyethylene glycose, 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 is provided by various antibacterial agents,
Antibacterial agents, such as parabens, chlorobutanol,
This can be done using phenol, sorbic acid, thimerosal, etc. In many cases, it will be preferable to include isotonic agents, such as sugars or sodium chloride. Long-term 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 mixing the active ingredients in the required amount in the appropriate solvent with various 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 of the active ingredient and any desired added ingredients from a previously sterilized solution. As used herein, "pharmacologically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antibacterial agents, isotonic agents, absorption delaying agents, and the like. . The use of such media and reagents for pharmaceutically active substances is well known in the art. Its 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. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. As used herein, unit dosage form refers to physically discrete units suitable as a single dose for the mammalian patient to be treated, each unit containing a predetermined amount calculated to produce the desired therapeutic effect. Contains the 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 substance and the specific therapeutic effect to be achieved, and (b) the physical health being impaired, as disclosed in detail herein. The treatment of disease in living patients with certain disease states is dictated by direct reliance on the limitations inherent in the technology of incorporating such active substances. Cancer regression and palliation is achieved using, for example, oral or injectable modes of application. For example, a single oral or intravenous dose or repeated daily doses can be administered. A daily dose is often sufficient for up to about 5 or 10 days. It is also possible to administer once daily or once every other day or less frequently. As can be seen from the dosage regulation, the amount of the main active ingredient administered is sufficient to serve in the regression and mitigation of leukemia, etc., without moderate adverse side effects of cytotoxic nature in the host in which the cancer resides. . This amount is also referred to herein as an effective amount. As used herein, cancer disease 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 disease process without treatment. The novel compounds described herein are useful as chelating agents, complexing agents, or sequestering agents. Complexes formed with polyvalent metal ions are particularly stable and usually stable in various organic solvents. Of course, their properties are suitable for various applications where metal ion contamination poses problems, such as saturated and unsaturated lubricants,
It also makes it useful as a stabilizer in a variety of organic systems, such as hydrocarbons, fatty acids, and waxes, where transition metal ion contamination promotes oxidative degradation and color development. They are also useful in the analysis of polyvalent metal ions that may be complexed or abstracted by these materials, and as metal supports. Other uses common to sequestering agents are also evident for these compounds. Additionally, leuco bases () are useful as intermediates in the preparation of fully aromatic derivatives, where AB is CH=CH. The novel compounds of the present invention also have the property of inhibiting the growth of implanted murine tumors as evidenced by the following standard test procedures. Lymphocytic leukemia P388 test All animals used were of the same sex and weighed at least 17g.
DBA/2 mice with body weights in the g weight range.
There are 5 or 6 animals per test group. Tumor implantation is by intraperitoneal injection of 0.1 ml of dilute ascites fluid containing 10 ⁶ cells of lymphocytic leukemia P388. test compound for 1 day,
Administered intraperitoneally on days 5 and 9 (for tumor inoculation) at various doses. Animals are weighed regularly for 30 days and survival recorded. Calculate the 50% survival time and survival time ratio of treated (T) animals/control (C) animals. The positive control compound is 5-fluorouracil given as a 60 mg/Kg injection. The results of this test using representative compounds of the invention are shown in Table 1. The criterion for effectiveness is T/C x 100125%. [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] *Administered on days 1, 5, and 9
** Lymphocytic Leukemia P388 Study Dosed on Days 1-9 The procedure used was similar to the previous study for lymphocytic leukemia P388, except that the test compound was administered at various doses orally instead of intraperitoneally. The results of this test with typical compounds of the invention are shown in Table 2. The criteria for determining effectiveness is T/C x 100.
≧125%. [Table] *5-Fluorouracil is administered intraperitoneally.
Lymphocytic Leukemia L1210 Study Tumor implants consisted of lymphocytic leukemia L1210 inoculated at a concentration of 10 ⁵ cells/mouse, and the procedure was similar to that of lymphocytic leukemia P388, except for calculating the mean survival time.
It is the same as the abdominal vaginal test. Results for representative compounds of the invention are shown in Table 3. Table: Melanoma B16 All 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 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 regularly for 60 days and record survival. Calculate the 50% survival time and survival time ratio of treated (T) animals/control (C) animals. The positive control compound is 5-fluorouracil given as a 20 mg/Kg injection. The results of this test using representative compounds of the invention are shown in Table 4. The criterion for effectiveness is T/C×100≧125%. [Table] [Table] [Table] [Table] [Table] Ridgway Osteosarcoma The animals used were AKD ₂ F ₁ /J mice of the same sex, weighing at least 17 g and all within the 3 g range. There are usually 8 animals per test group. Tumors are applied subcutaneously via trocar as five 2 mm fragments per mouse. Test compounds are administered intraperitoneally at various doses every 4th day for a total of 6 inoculations starting on day 15 (for tumor inoculation). Weigh animals regularly for 90 days and record survival. Tumor regression is recorded in all test animals. Table 5 shows the results of this study with representative compounds of the invention in terms of the percentage of animals showing tumor regression. TABLE TABLE The invention will be described in more detail in connection with the following specific examples. Example 1 Leuco-1,4-bis[(2-dimethylaminoethyl)amino]-5,8-dihydroxyanthraquinone N,N,-dimethylethylenediamine 10.58 g,
A reaction mixture containing 60 ml of N,N,N',N'-tetramethylethylenediamine and 10.96 g of leuco-1,4,5,8-tetrahydroxyanthraquinone was flushed with nitrogen and heated in an oil bath maintained at 49-51°C. Stir under nitrogen with heating for 2 hours. Allow the mixture to cool under nitrogen. The solid is collected and washed with ethanol to give 14.78 g of the desired product (sintered at 224°C, unmelted at 300°C) as a dark red colored solid. Example 2 1,4-bis[(2-dimethylaminoethyl)
Amino]-5,8-dihydroxyanthraquinone Leuco in 100 ml of nitrobenzene. 1,4-bis[(2-dimethylaminoethyl)amino-5,
12.00 g of 8-dihydroxyanthraquinone are heated under reflux for 15 minutes and then heated. The liquid is heated again to boiling, allowed to cool, and the solid is collected and washed with ethanol to give 8.44 g of the desired product as blue-black crystals, mp 236-238°C. Example 3 Leuco-1,4-bis(2-morpholinoethylamino)-5,8-dihydroxyanthraquinone N-(2-aminoethyl)morpholine in 40 ml of N,N,N',N'-tetramethylethylenediamine 15.62 Degas the solution in g by bubbling nitrogen through it for 15 minutes. Leuko-1, 4, 5, 8
10.97 g of tetrahydroxyanthraquinone are added slowly with stirring and the suspension is treated as described in Example 1 to give 18.07 g of the desired product as an olive solid, mp 223-227°C. Example 4 1.4-bis(2-morpholinoethylamino)-
5,8-Dihydroxyanthraquinone Oxidation of 13.90 g of leuco-1,4-bis(2-morpholinoethylamino)-5,8-dihydroxyanthraquinone in 100 ml of nitrobenzene as described in Example 2 gives 10.30 g of the desired product. Obtained as a black rod, melting point 241-243°C. Example 5 Leuco-1,4-bis[(2-diethylaminoethyl)amino]-5,8-dihydroxyanthraquinone Performed using 13.95 g of N,N-diethylethylenediamine in place of N-(2-aminoethyl)morpholine. Repeating the procedure of Example 3 yields the desired product
13.97g obtained as a red and colored solid, melting point
182-185℃. Example 6 1,4-bis[(2-diethylaminoethyl)
Amino]-5,8-dihydroxyanthraquinone Leuco-1,4-bis[(2-diethylaminoethyl)amino]-5,8-dihydroxyanthraquinone, 10.90 g, is oxidized as described in Example 2 to yield 6.35 g of the desired product. is obtained as blue-black needle-shaped crystals, melting point 202-204℃. Example 7 Leuco-1,4-bis[2-(1-pyrrolidinyl)ethylamino]-5,8-dihydroxyanthraquinone 12.05 g of N-2-pyrrolidinoethylamine and N,
N,N',N'-tetramethylethylenediamine 80
Repeating the procedure of Example 3 using ml gives 13.24 g of the desired product as a red and colored solid, mp 180-185°C. Example 8 1,4-bis[2-(1-pyrrolidinyl)ethylamino]-5,8-dihydroxyanthraquinone Leuco-1,4-bis[[2-(1-pyrrolidinyl)ethyl]amino]-5,8 -8.61 g of dihydroxyanthraquinone are oxidized as described in Example 2. The reaction mixture is evaporated to dryness and the residue is recrystallized from toluene to give 5.12 g of the desired product as blue-black crystals, mp 193-196°C. Example 9 Leuco-1,4-bis[2-(methylamino)
ethylamino]-5,8-dihydroxyanthraquinone N- instead of N-2-pyrrolidinoethylamine
Example 7 using 8.90g of methylethylenediamine
Repeating the procedure gives 13.73 g of the desired product as a dark green solid, mp 157-160°C. Example 10 Leuco-1,4-bis[(3-diethylaminopropyl)amino]-5,8-dihydroxyanthraquinone Add 15 nitrogen to 80 ml of dimethylaminopropylamine
Bubble for a minute. Leuco-1,4,5,8-
Gradually add 10.97 g of tetrahydroanthraquinone with stirring. The mixture is heated at 50-52° C. for 2 hours under nitrogen and then allowed to cool. The solid was collected and washed with cold ethanol to give 5.59 g of dark orange-red crystals.
is obtained, melting point 115-118℃. Example 11 1,4-bis[(3-dimethylaminopropyl)
Leuco-1,4-bis[(3-dimethylaminopropyl)amino]-5,8-dihydroxyanthraquinone in 60 ml of N,N,N',N'-tetramethylethylenediamine 6.00 The suspension of g is heated on a steam bath under reflux and bubbling air for 12 hours. A solid forms as the solution cools, which is collected and washed twice with heptane and once with petroleum ether. This solid is recrystallized by extracting with 350 ml of hot heptane, filtering and concentrating to 300 ml. The desired product crystallizes and is washed with petroleum ether.
3.72g obtained as black needle-shaped crystals, melting point
154-157℃. Example 12 Leuco-1,4-bis(2-aminoethylamino)-5,8-dihydroxyanthraquinone Leuco in 80 ml of degassed N,N,N',N'-tetramethylethylenediamine containing 7.22 g of ethylenediamine. The reaction mixture containing 10.97 g of -1,4,5,8-tetrahydroxyanthraquinone is heated and stirred for 1 hour at 48 DEG-80 DEG C. under nitrogen. The mixture is kept under a slow stream of nitrogen to form a solid which is collected and washed with ethyl acetate, acetonitrile and petroleum ether to give the desired product 13.8
g (does not melt at 350℃, infrared absorption spectrum:
6.34 and 8.20 μm) are obtained as a red-black solid. Example 13 Leuko-1,4-bis(3-aminopropylamino)-5,8-dihydroxyanthraquinone Desorption of 8.90 g of 1,3-diaminopropane in 80 ml of N,N,N',N'-tetramethylethylenediamine A suspension of 10.97 g of leuco-1,4,5,8-tetrahydroxyanthraquinone in an aqueous solution is stirred and heated at 49 DEG C. for 1 hour under nitrogen, then allowed to cool. The resulting solid is collected and washed with cold ethanol to give 14.21 g of the desired product (does not melt at 350° C., infrared absorption spectrum: 6.44 and 8.22 μm) as a black solid. Example 14 Leuco-1,4-bis[2-(2-dihydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone 2-(2 -aminoethylamino) A suspension of 12.5 g of ethanol is stirred and degassed by bubbling nitrogen for 15 minutes. leuco
Gradually add 10.97 g of 1,4,5,8-tetrahydroxyanthraquinone with stirring. The suspension is heated and stirred in an oil bath at 50-52° C. for 5 hours under nitrogen. The mixture is kept cool under nitrogen for 12 hours.
The solid was collected by decantation, disintegrated in ethanol, collected and washed with ethanol to give 15.06 g of the desired product as a gray-green solid, mp 129-131°C. Example 15 Leuco-1,4-bis[2-[di(β-hydroxyethyl)amino]ethylamino]-5,8
-Dihydroxyanthraquinone A solution of 17.8 g of N,N-di(2-hydroxyethyl)ethylenediamine in 100 ml of methanol was cooled with ice, stirred and heated to 15
Degas for a minute. 10.97 g of leuco-1,4,5,8-tetrahydroxyanthraquinone is gradually added with stirring and cooling is continued. The suspension is heated and stirred in an oil bath at 50-52°C under nitrogen for 1 hour, then the mixture is kept under nitrogen overnight to cool. When the solid is collected and washed with ethanol, a red and colored solid 14.8
g, melting point 165-168°C. Example 16 1,4-bis[2-(methylamino)ethylamino]-5,8-dihydroxyanthraquinone dihydrochloride Leuco-1 in 200 ml of 2-methoxyethanol,
4-bis[2-(methylamino)ethylamino]-
5,8-dihydroxyanthraquinone 11.60g
15 ml of 8N ethanolic hydrogen chloride was slowly added to the [0.03 mol) suspension with stirring. The system was cooled in an ice bath, and 7.50 g (0.0305 mol) of chloranil powder was gradually added while stirring. The mixture was stirred at room temperature overnight and diluted with 600 ml of ether. The solid was collected and washed with tetrahydrofuran. The product (14.16 g) was dissolved in 130 ml of water and recrystallized by adding 650 ml of acetone to give a blue-black solid.
13.15 g (does not melt at 350° C., infrared absorption spectrum: 6.20, 6.39, 8.26 and 12.13 μm) was obtained. Example 17 1,4-bis[2-(2-aminoethylamino)
Ethylamino]-5,8-dihydroxyanthraquinone Leuko-1,4, according to the general procedure of Example 3
5,8-tetrahydroxyanthraquinone 10.97
g, N,N,N',N'-tetramethylethylenediamine 80ml and diethylenetriamine 21.84g
(0.24 mol) immediately formed a thick coagulum, which prevented effective stirring, so the reaction time
It was extended to 24 hours. The mixture was allowed to cool and the supernatant was decanted and discarded. A solution of the coagulum in 100 ml of methanol was filtered and then oxidized in air in a partially capped flask for 4 days. The separated gelatinous mass is oxidized with a mixture of acetonitrile and 200%
After stirring with ml and holding for 1 hour, it became solid. Collecting the solid and washing it first with acetonitrile and then with ether yielded 10.88 g of a blue-black powder.
(Does not melt at 350℃, infrared absorption spectrum:
6.21, 6.42 and 8.31μm). Example 18 Leuco-1,4-bis(4-aminobutylamino)-5,8-dihydroxyanthraquinone Following the general procedure of Example 3 and using 45 ml of 1,4-diaminobutane as the primary amine component, the product 12.20 g (does not melt at 350° C., infrared absorption spectrum: 6.31, 8.12 and 12.02 μm) was obtained as a dark gray-green solid. Example 19 Leuco-1,4-bis[2-dimethylaminopropylamino]-5,8-dihydroxyanthraquinone 12.26 g of 2-dimethylaminopropylamine and 10.97 g of leuco-1,4,5,8-tetrahydroxyanthraquinone. When reacted for 1 hour in 100 ml of ethanol according to the procedure of Example 1, 7.29 g of red and colored crystals (blackened at 225°C, did not melt at 350°C,
Infrared absorption spectrum: 6.31, 8.11 and
12.02μm) is obtained. Example 20 Leuco-1,4-bis[2-(2-methyla)
minoethylamino)ethylamino]-5,8-
Dihydroxyanthraquinone Leuko-1,
4,5,8-tetrahydroxyanthraquinone
Add 10.97 g as in Example 1. mixture
Heat at 50 °C, stir for 1 hour under nitrogen, cool in an ice bath, collect the solid and wash with cold ethanol to give 7.23 g of green-black crystals, mp 108-111 °C. Example 21 Leuco-1,4-bis[2-(2-dimethylaminoethylamino)ethylamino]-5,8-
Dihydroxyanthraquinone N-(dimethylaminoethyl)ethylenediamine and leuco-1,4,5,
Reaction with 8-tetrahydroxyanthraquinone yields the subject compounds. Example 22 Leuco-1,4-bis[2-(1-piperazinyl)ethylamino]-5,8-dihydroxyanthraquinone When the procedure of Example 20 is applied to 15.50 g of N-(2-aminoethyl)piperazine, the temperature at 350°C 3.92 g of a black powder that does not melt is produced and is discarded.
The mother liquor and ethanol wash are kept in an open flask for two weeks and partially evaporated to precipitate a solid which is collected and washed with ethanol to give 6.19 g of the title compound as a black solid. melting point
200-203℃. Example 23 1,4-bis(2-aminoethylamino)-5,
8-Dihydroxyanthraquinone dihydrochloride Product of Example 12 by the procedure of Example 16 28.25
When g is oxidized with chloranil, a crude, blue-black solid is obtained.
29.66g was obtained, which was then added with 800ml of water.
Extract by stirring for 14 hours. The solids were removed by centrifugation and the supernatant solution was lyophilized to 350
16.38 g of a blue-black solid remains that does not melt up to . Example 24 1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone dihydrochloride The procedure of Example 16 yields the product of Example 14 17.86
When g is oxidized with chloranil (without recrystallization)
Yields 21.34 g of blue-black solid, melting point 203-205
℃. Example 25 1,4-bis[2-(2-methylaminoethylamino)ethylamino]-5,8-dihydroxyanthraquinone tetrahydrochloride The product of Example 20 (11.70 g) was converted to chloranil by the procedure of Example 16. A blue-black solid when oxidized with
18.30g is obtained. Melting point 190-203℃. Example 26 1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone The solvent used in the modification of the process of Example 14 is 100 ml of ethanol. The mother liquor from the leuco product is held in an uncovered flask for two weeks to separate the oxidized products. It is collected and washed with ethanol, and then recrystallized from ethanol to obtain blue-black crystals, melting point 175-177°C. Example 27 Leuco-1,4-bis[3-(2-hydroxyethyamino)-1-propylamino]-5,8-
Dihydroxyanthraquinone The procedure of Example 15 is used with a solution of 14.18 g of 2-(3-aminopropylamino)ethanol in 100 ml of ethanol. The resulting solution is filtered and the liquid is diluted with 300 ml of ether to precipitate the product as a sticky substance. After decanting the supernatant solution, the sticky substance is stirred with 100 ml of tetrahydrofuran and crystallization occurs. Washing with ethanol yields 12.56 g of a green-black solid, melting point 101~
104℃. Example 28 1,4-bis[3-(2-hydroxyethylamino)-1-propylamino]-5,8-dihydroxyanthraquinone dihydrochloride Leuco-1,4-bis[3-
(2-hydroxyethylamino)propylamino]
Oxidation of 9.95 g of -5,8-dihydroxyanthraquinone with chloranil gives 11.70 g of a blue solid, which does not melt up to 350°C. Example 29 Leuco-1,4-bis[2-(3-hydroxy-1-propylamino)ethylamino]-5,
8-Dihydroxyanthraquinone Example using 14.18 g of N-(3-hydroxypropyl)ethylenediamine in 100 ml of ethanol
If you follow step 15, you will get red and colored crystals 14.63
g, melting point 58-60°C. Example 30 1,4-bis[2-(3-hydroxy-1-propylamino)ethylamino]-5,8-dihydroxyanthraquinone dihydrochloride The procedure of Example 16 yields the product of Example 29 10.77
When g is oxidized with chloranyl, a dark blue solid is obtained.
Yielding 11.64 g, melting point 210-216°C. Example 31 Leuco-1,4-bis[2-(2-hydroxy-1-propylamino)ethylamino]-5,
8-Dihydroxyanthraquinone The procedure of Example 15 includes adding 1-(2
-aminoethylamino)-2-propanol 14.18
Using g gives 17.61 g of green-black crystals, melting point 50-60°C. Example 32 1,4-bis[2-(2-hydroxy-1-propylamino)ethylamino]-5,8-dihydroxyanthraquinone dihydrochloride Leuco-1 in 215 ml of 2-methoxyethanol,
A filtered solution of 14.44 g of 4-bis[2-(2-hydroxy-1-propylamino)ethylamino]-1,4-dihydroxyanthraquinone was used as an example.
Oxidation with 7.65 g of chloranil by procedure 16 gives 16.75 g of a purple solid, melting point 177~
185℃. Example 33 Leuco-1,4-bis[2-[2-(2-hydroxyethylamino)ethylamino]ethylamino]-5,8-dihydroxyanthraquinone The procedure of Example 15 was followed by adding 2-[2] in 100 ml of methanol.
-(2-aminoethylamino)ethylamino] When a solution of 17.67 g of ethanol is used, a solution is formed,
When strained and diluted with 300 ml of ether, a sticky substance precipitates, which hardens when kept overnight. The curing is completed by disintegrating the solid into the solvent. The solid was collected and washed with ether, yielding 16.82 g of a green-black solid (melting point: 75-85°C). This solid remains granular when stored at −25°C, but 25
It becomes a solid cake when stored at °C. Example 34 1,4-bis[2-[2-(2-dihydroxyethylamino)ethylamino]ethylamino]-
5,8-dihydroxyanthraquinone tetrahydrochloride Product of Example 33 by the method of Example 16 12.10
Chloranyl oxidation of g and washing the solid three more times with methanol yielded 12.46 g of a dark blue solid product.
(Melting point: 192℃~202℃, infrared absorption spectrum:
6.21-6.38 and 8.33 μm) are obtained. Example 35 1,4-bis[2-(2,3-dihydroxypropylamino)ethylamino]-5,8-dihydroxyanthraquinone dihydrochloride 3 in 100 ml of methanol by the procedure of Example 15
-(2-aminoethylamino)-1,2-propanediol [AR Surry, CMSuter
and JSBuck), J.Am.Chem.Soc., 74, 4102
(1952)] 16.10 g of the solution yields a sticky substance that is separated from the solvent by cooling in an ice bath and decanting. methanol sticky substance
Wash 4 times by stirring with 100 ml at 25° C. for 1.5 hours, cooling in an ice bath and decanting. A solution of the sticky substance in 280 ml of 2-methoxyethanol is filtered and oxidized with 10.01 g of chloranil according to the method of Example 16. Further washing of the product with ethanol yields 15.25 g of a blue-black solid, mp 191-193°C. Example 36 Leuco-1,4-bis[2-(1-aziridino)
Ethylamino]-5,8-dihydroxyanthraquinone Using 10.33 g of N-(2-aminoethyl)aziridine in 80 ml of N,N,N',N'-tetramethylethylenediamine in the procedure of Example 15 produces a hard gum. The next day, discard the supernatant solution and add 100 ml of ether.
If you add and disintegrate it periodically for another day, the gum will almost harden. While the solid was washed three times with ether, the hardening was completed due to disintegration, resulting in a blue-black granular powder.
17.66 g (melting point: 120-132°C, infrared absorption spectrum: 6.37, 6.89, 8.20 and 12.03 μm) are obtained. Example 37 1,4-bis[2-(1-aziridino)ethylamino]-5,8-dihydroxyanthraquinone 4.10 g of the product of Example 36 in 40 ml of chloroform
A solution of 1.74 g of diethyl azodicarboxylate in 25 ml of chloroform is added to the suspension. The mixture is stirred for 20 minutes, the resulting dark blue solution is filtered and the liquid is evaporated at ≦30°. chloroform residue 40ml
The solution inside was stirred for 5 minutes with 2 g of decolorizing carbon,
Filter and wash with 25 ml of chloroform. Adding 100 ml of ether to the solution precipitates the gum, which is removed by decantation. Crystals will separate from the solution and be washed with a small amount of acetone. -Chloroform cooled to 60℃
A second crystal is precipitated from the ether mother liquor and washed with ether and methanol. Stir the recrystallized solution in 20 ml of chloroform with decolorizing carbon,
Filter, evaporate to a volume of 5 ml at ≦25°C, dilute with 20 ml of ether and then cool to -60°C. When the resulting blue-black crystals are washed with ether, 0.64g
The melting point is 168-170℃. In thin layer chromatography on silica gel, the product was chloroform-triethylamine-methanol 27/3/1
(volume ratio) moves as a blue spot. Example 38 1,4-bis[2-[2-(1-morpholino)ethylamino]ethylamino]-5,8-dihydroxyanthraquinone tetrahydrochloride N-(morpholinoethyl) in 100 ml of ethanol
A solution of 20.80 g of ethylenediamine was used in the procedure of Example 15 to obtain a solution, which was filtered and diluted with ether.
A sticky substance precipitates when diluted with 900 ml. The supernatant solution is decanted, the sticky substance is dissolved in 175 ml of 2-methoxyethanol and oxidized with 5.29 g of chloranil according to the method of Example 16, giving 17.7 g of a dark blue solid (melting point: 265° C.). . Example 39 Leuco-1,4-bis[2-(acetamide)
Ethylamino]-5,8-dihydroxyanthraquinone A solution of 12.26 g of N-acetylethylenediamine in 100 ml of ethanol in the procedure of Example 15 yields 15.27 g of a dark red colored solid, melting point 125°C. Example 40 1,4-bis[2-(acetamido)ethylamino]-5,8-dihydroxyanthraquinone Leuco-1,4-bis[2-(acetamido)
A suspension of 11.95 g of ethylamino]-5,8-dihydroxyanthraquinone was prepared by the method of Example 16.
Oxidation with 6.76 g of chloranil for 61 hours yields the highly acidic hydrochloride salt, which is converted to the free base by washing four times with water. Crystallization from 110 ml of dimethyl sulfonoxide (boiling for 2 minutes without heating), followed by washing with dimethyl sulfoxide and ethanol gives 7.76 g of a blue-black solid, mp 273-274°C. Example 41 1,4-bis[2-[N-hydroxyethyl]
Trifluoroacetamide]ethylamino]-
5,8-dihydroxyanthraquinone ethyl trifluoroacetate 75ml and methanol 75ml
A suspension of 1.50 g of 1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone in ml is stirred for 10 minutes.
The resulting solution is evaporated in vacuo at 30°C, leaving a residue which is washed with methylene chloride and disintegrated to give 2.11 g of a blue-black solid, melting point 162°C. Example 42 1,4-bis[2-amino-2-carboxyethylamino]-5,8-dihydroxyanthraquinone 3/4HCl A solution of 6.23 g of dl-α,β-aminopropionic acid in 30 ml of warm water Add 1.078 g of lithium oxide and 60 ml of dimethyl sulfoxide. The system was flushed with nitrogen and 4.12 g of leuco-1,4,5,8-tetrahydroxyanthraquinone was slowly added with stirring. The mixture is stirred and heated at 50° using an oil bath, first under nitrogen for 15 hours and then for 21 hours while oxidizing the initial product by bubbling air. Methanol-water-concentrated ammonia (by volume)
Thin layer chromatography on silica gel using 25/5/1) shows that the product spots are all blue when oxidation is complete. After cooling the mixture, the solid was removed by filtration and washed once with dimethyl sulfoxide-water (1/2). When 400 ml of methanol is added to the solution, a solid precipitates out, which is collected and washed with methanol. A further wash with a total of 13 ml of 0.01N aqueous acetic acid dissolves virtually all of the solid. When 3 ml of concentrated hydrochloric acid was added to the acetic acid solution, a blue-black solid was precipitated, and when it was washed with acetone, 0.24 g of the product (infrared absorption spectrum:
5.76, 6.21, 6.40, 8.32 and 12.10 μm) are obtained. Example 43 Leuco-1,4-bis[2-(2-methoxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone N-(2-methoxyethyl)ethylenediamine (U.S. Pat. No. 3,454,640) in the procedure of Example 15 The subject compound is obtained by reacting an ethanolic solution of the compound of the present invention. Example 44 1,4-bis[2-(1,3-oxolidine-
1-yl)ethylamino]-5,8-dihydroxyanthraquinone 1.62 g of 37% formaldehyde solution in 50 ml of water
The solution was stirred overnight with 4.44 g of 1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone. When the resulting solid is washed with water, the product (203~
204℃) is obtained. Example 45 1,4-bis[2-(tetrahydro-1,3-
oxazin-1-yl)ethylamino]-5,
8-Dihydroxyanthraquinone A solution of 1.62 ml of 37% aqueous formaldehyde in 50 ml of 0.4N aqueous sodium hydroxide is added to 1,4-bis[2-(3-hydroxy-1-propylamino)ethylamino]-5,8-dihydroxyanthraquinone. Stir overnight with 5.45 g of dihydrochloride. The product is obtained by washing the resulting solid with water. Example 46 1,4-bis[2-(1,3-oxazolidin-2-one-1-yl)ethylamino]-5,
8-Dihydroxyanthraquinone A solution of 0.020 g of sodium in 25 ml of methanol was dissolved in 75 ml of diethyl carbonate and 1,4-bis[2-(2
-hydroxyethylamino)ethylamino]-5,
Stir and heat at reflux overnight with 4.44 g of 8-dihydroxyanthraquinone. Allow the mixture to cool. It is stirred with 0.1 ml of acetic acid and the solid is collected by filtration and washed with methanol to give the product. Example 47 1,4-bis[2-(1,3-oxazine-2
-on-1-yl)ethylamino]-5,8-
Dihydroxyanthraquinone A solution of 0.48 g of sodium in 25 ml of methanol is mixed with 75 ml of diethyl carbonate and 1,4-bis[2-(3-
Hydroxy-1-propylamino)ethylamino-5,8-dihydroxyanthraquinone dihydrochloride
Stir and heat overnight with 5.45g. After the mixture has cooled, it is stirred with 0.1 ml of acetic acid.
The solid product is collected by filtration and washed with methanol and then water. The product exhibits a melting point of 254-256°C. Example 48 1,4-bis[2-[di(β-hydroxyethyl)amino]ethylamino-5,8-dihydroxyanthraquinone diacid hydrochloride acid The product of Example 15 by the method of Example 16 10.77
When g is oxidized with chloranyl, a dark blue solid 11.64
g, melting point 216°C. Reference example 1 Preparation of 50ml tablets 0.050g per 10000 tablets 1,4-bis(3-aminopropylamino)-5,8-dihydroxyanthraquinone...500g 0.080g Lactose...800g 0.010g Cornstarch (for mixing) ...100g 0.008g Cornstarch (for paste)
... 75g 0.148g ...1475g 0.002g Magnesium stearate (1%)
... 15g 0.150g 1490g 1,4-bis(3-aminopropylamino)-
Mix 5,8-dihydroxyanthraquinone, lactose and cornstarch (for blending). Suspend cornstarch (for paste) in 600 ml of water and heat with stirring to form a paste. This paste is then used to granulate the mixed powder. Use more water if necessary. Pass the wet particles through a No. 8 hand screen and dry at 120°C. The dried particles are then passed through a No. 16 sieve. The mixture is lubricated with 1% magnesium stearate and compressed into tablets in a suitable tablet machine. Reference Example 2 Preparation of Oral Suspension Component Amount Leuco-1,4-bis(3-aminopropylamino)-5,8-dihydroxyanthraquinone
...500mg Sorbitol solution (70% NF) ...40ml Sodium benzoate ...150mg Satucalin ...10mg Red dye ...50mg Cheery flavor ...50ml Distilled water ...qs ad ...100ml Add the sorbitol solution to 40ml distilled water Leuco-1,4-bis(3-aminopropylamino)-5,8-dihydroxyanthraquinone is suspended therein. Add saccharin, sodium benzoate, flavor and dye and dissolve. Make up the volume with distilled water
Adjust to 100ml. Each 1ml syrup contains Leuko-1,
4-bis(3-aminopropylamino)-5,8
- Contains 5 mg of dihydroxyanthraquinone. Reference example 3 Preparation of parenteral solution 700ml of propylene glycol and 200ml of water for injection
1,4-bis[3-(dimethylamino)] in solution with
20.0 g of propylamino]-5,8-dihydroxyanthraquinone dihydrochloride is suspended with stirring. After suspension is complete, adjust the pH to 5.5 with hydrochloric acid, and make up the volume to 1000 ml with water for injection. 5.0 to sterilize the formulation and contain 2.0 ml each (equivalent to 40 mg of drug)
Fill into ml ampoules and seal under nitrogen. Example 49 1,4,5-Tris[(2-aminoethyl)amino]-8-hydroxyanthraquinone 100 ml of ethylenediamine are degassed by bubbling nitrogen through it for 15 minutes. leuco
10.97 g of 1,4,5,8-tetrahydroxyanthraquinone was added and the mixture was heated under nitrogen at 50-51°C.
Stir for an hour. Cool and filter the mixture. Cooling the unstoppered liquid at 10°C for 2 hours produces a solid, which is collected and washed with ethanol to yield 2.25 g of the desired product (does not melt up to 360°C, and in 2-methoxyethanol solution, long-wavelength UV absorption peak
Shown at 763 μm. In contrast, 1,4-bis(aminoalkylamino)-5,8-dihydroxy-
Anthraquinone shows a peak around 660 nm. )
is obtained as a dark purple solid. Example 50 1,4-bis[(2-dimethylaminoamino)
Amino-5,6-dihydroxyanthraquinone 30 g of zinc are added in portions to a boiling mixture of 1.5 ml of glacial acetic acid and 40 ml of water containing 27.2 g of 1,4,5,6-tetrahydroxyanthraquinone. Boil the mixture for 30 minutes, strain and cool the liquid. When the orange colored crystals are collected, Leuco-1,
4,5,6-tetrahydroxyanthraquinone
19.7 g is obtained, melting point 255-257°C. 7.9 g of dimethylaminoethylamine in 75 ml of tetramethylethylenediamine are heated to 80-100°C and degassed with nitrogen. This mixture was treated with 8.22 g portions of leuco-1,4,5,6-tetrahydroxyanthraquinone while stirring under nitrogen.
Heat at 100℃ for 6 hours. Heat the mixture.
After cooling the liquor to 4°C, treating with ether and holding for 48 hours, a dark blue gum forms. The supernatant is decanted, treated twice with equal volumes of ether and cooled to yield a blue gum. The supernatant is retained and then further treated with ether to yield 1.5 g of the desired final product as a blue solid, mp 133-135°C. Example 51 1,4,5-Tris{[2-(2-hydroxyethylamino)ethyl]amino}-8-hydroxyanthraquinone 2-(2-hydroxyethylamino)ethylamine and leuco-1,4,5,8 -tetrahydroxyanthraquinone is carried out as in Example 49 to give the subject compound. Example 52 1,4-bis(3-aminopropylamino)-
5,8-Dihydroxyanthraquinone A suspension of 10.0 g of leuco-1,4,5,8-tetrahydroxyanthraquinone in 120 ml of degassed 1,3-diaminopropane was stirred and treated at 45° C. for 1 hour under nitrogen. Then heat for 10 minutes while bubbling air into the suspension. The mixture is then evaporated to dryness and the residue is extracted in a Soxhlet apparatus with 650 ml of ethanol for 17 hours. The extract is filtered hot, concentrated to 95 ml and then diluted with 900 ml of diethyl ether. The mixture is cooled, the solid collected and washed with ethanol-diethyl ether and then diethyl ether to give the desired product as a blue solid, 9.57 g, mp 115-130°C. Reference example 4 Preparation of 50 mg tablets 0.050 g per 10,000 tablets 1,4-bis(3-aminopropylamino)-5,8-dihydroxyanthraquinone ...500 g 0.080 g Lactose ...800 g 0.010 g Cornstarch (for mixing) ...100g 0.008g Cornstarch (for paste)
... 75g 0.148g ...1475g 0.002g Magnesium stearate (1%)
...15g 0.150g 1490g 1,4-bis(3-aminopropylamino)-
Mix 5,8-dihydroxyanthraquinone, lactose and cornstarch (for blending). Suspend cornstarch (for paste) in 600 ml of water and heat with stirring to form a paste. This paste is then used to granulate the mixed powder. Use more water if necessary. Pass the wet particles through a No. 8 hand screen and dry at 120°C. The dried particles are then passed through a No. 16 sieve. The mixture is lubricated with 1% magnesium stearate and compressed into tablets on a suitable tablet machine. Reference Example 5 Preparation of Oral Suspension Component Amount Leuco-1,4-bis(3-aminopropylamino)-5,8-hydroxyanthraquinone
…500mg Sorbitol solution (70% NF) …40ml Sodium benzoate …150mg Saccharin …10mg Red dye …50mg Thierry fragrance …50ml Distilled water…qs ad …100ml Add the sorbitol solution to 40ml of distilled water , in which leuco-1,4-bis(3-aminopropylamino)-5,8-dihydroxyanthraquinone is suspended. Add saccharin, sodium benzoate, flavor and dye and dissolve. Make up the volume with distilled water
Adjust to 100ml. Each 1ml syrup contains Leuko-1,
4-bis(3-aminopropylamino)-5,8
- Contains 5 mg of dihydroxyanthraquinone. Reference example 6 Preparation of parenteral solution Propylene glycol 700ml and water for injection 200ml
20.0 g of 1,4-bis(3-aminopropylamino)-5,8-dihydroxyanthraquinone dihydrochloride is suspended in the solution with stirring. After suspension is complete, adjust the pH to 5.5 with hydrochloric acid, and make up the volume to 1000 ml with water for injection. Sterilize the mixture, 2.0ml each
(equivalent to 40 mg of drug) into a 5.0 ml ampoule and sealed under nitrogen. Example 53 1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone disuccinate 1,4-bis[2-(2-hydroxyethylamino)ethylamino] A mixture of 222 mg of -5,8-dihydroxyanthraquinone, 118 mg of succinic acid and 50 ml of ethanol is heated under reflux for 30 minutes to give the title compound. Example 54 1,4-bis[2-(3-hydroxypropylamino)ethylamino]-5,8-dihydroxyanthraquinone dimalate 1,4-bis[2-(3-hydroxypropylamino)ethylamino] A mixture of 228 mg of -5,8-dihydroxyanthraquinone, 134 mg of DL-malic acid and 50 ml of ethanol is heated under reflux for 30 minutes to give the title compound. Example 55 1,4-bis[2-(2-hydroxypropylamino)ethylamino]-5,8-dihydroxyanthraquinone dilactate 1,4-bis[2-(2-hydroxypropylamino)ethylamino]- A mixture of 228 mg of 5,8-dihydroxyanthraquinone, 120 mg of 80% DL-lactic acid and 10 ml of ethanol is heated on a steam bath for 10 minutes, cooled, treated with 50 ml of acetone, and on cooling yields the subject compound. Example 56 10.97 g (40 mmol) of leucotetrahydroxyanthraquinone were suspended in 300 ml of methanol and argon was bubbled through the suspension for 30 minutes with mechanical stirring. To this was added 12.6 g (120 mmol) of distilled N-(2
-cyanoethyl)-1,2-ethylenediamine is added and the mixture is heated (55-60°C).
and stirred for 12-18 hours. Treat the reddish-brown solution with one tablet of caustic potash and add 55 to 60
Air was bubbled through for 22 hours at °C. A black-blue solid was collected, washed well with methanol and dried.
The crude product was then extracted with refluxing methylene chloride (or chloroform) in a Soxhlet apparatus for 24 hours (until there was no color in the extract). The solvent was removed under reduced pressure and the dark blue product was boiled with approximately 450 ml of methanol, cooled and collected. The material was homogeneous (silica gel GF ₂₄₅
-THF/ _CH3COOH / _H2O -7/3/1). Yield = 12.8g (70%). Melting point: 121-123℃. Elemental analysis, calculated value (C ₂₄ H ₂₆ N ₆ O ₄・0.284H ₂ O)
C=61.64%; H=5.73%; H=17.97%;
O=14.66% Analysis C=61.74%: H=5.65%: N=17.62% Example 57 1,4-bis[2-(methylamino)ethylamino]anthraquinone 10.60 g in 2-methoxyethanol in 200 ml
To a suspension of (0.03 mol) of leuco-1,4-bis[2-(methylamino)ethylamino]anthraquinone, 15 ml of 8N-ethynolic hydrogen chloride was added gradually with stirring. The system was cooled with water, stirred and maintained under nitrogen during the gradual addition of 7.50 g (0.0305 mol) of planil powder. The mixture was stirred at room temperature under nitrogen overnight and
Diluted with 600ml of ether. The solid was collected and washed with ethyl acetate to give the desired product as yellow-green crystals, mp: 162-165°C (dec). Example 58 1.4-bis[(2-dimethylaminoethyl)amino]anthraquinone 12.00 g leuco-in 100 ml nitrobenzene
The 1,4-bis[(2-dimethylaminoethyl)amino]anthraquinone was heated under reflux for 15 minutes and filtered while hot. The liquid was reheated to boiling, cooled, and the solid was collected and washed with ethanol to give the desired product as a black-blue solid. Melting point: 170-172℃. Example 59 1,4-bis[2-(2-hydroxyethylamino)ethylamino]anthraquinone hydrochloride 1 mole of 1,4-bis[2-(hydroxyethylamino)ethylamino]anthraquinone, 8N
A mixture of 4 molar excess of hydrochloric acid and 50 ml of ethanol was heated under reflux for 30 minutes to give the title compound. Melting point: 200° to 203°C.

Claims (1)

[Claims] 1 The following formula () where A-B is selected from the group consisting of CH=CH and _CH2 - _CH2 ; Q is 2 of the formula: -( _CH2 )n-, where n is an integer from 2 to 4; each of R ₁ and R ₂ is hydrogen, an alkyl group having 1 to 4 carbon atoms, having 2 to 4 carbon atoms, and R ₁ and R ₂ are bonded; The carbon atom at the α-position to the nitrogen atom is a monohydroxyalkyl group that does not have a hydroxyl group, and the carbon atom at the α-position to the nitrogen atom has 3 to 6 carbon atoms and to which R ₁ and R ₂ are bonded. Atoms include dihydroxyalkyl groups, acetyl groups, trifluoroacetyl groups that do not have a hydroxyl group and the formulas: -( _CH2 ) ₂ -O- _CH3 and Here, R ₃ and R ₄ are independently hydrogen or methyl, or R ₃ and R ₄ together with the nitrogen atom to which they are bonded are morpholino. or R ₁ and R ₂ together with the nitrogen atom to which they are attached are aziridino, morpholino, piperazino, 4-methyl-1-piperazino, oxazolidino, 1,3-dioxan-2-one or pyrrole. Yes, but a) When n is 2, R ₁ /R ₂ is
Instead of CH ₃ /CH ₃ , when n is 3, R ₁ /R ₂ is H/H, CH ₃ /CH ₃ , C ₃ H ₇ /C ₃ H ₇ or (-CH ₂ )-
₂ O(−CH ₂ )− ₂ , and when n is 4,
R ₁ /R ₂ is not C ₂ H ₅ /C ₂ H ₅ or (-CH ₂ )- ₄ b) Only one of R ₁ and R ₂ can be alkanoyl, the compound represented by, its tautomerism Compounds selected from body and pharmacologically acceptable acid addition salts thereof. 2 R ₁ is hydrogen or an alkyl group having 1 to 4 carbon atoms, and R ₂ is a monohydroxyalkyl group having 2 to 4 carbon atoms, a dihydroxyalkyl group having 3 to 6 carbon atoms, or formula: Here, the definitions of R ₃ and R ₄ are the same as above,
The compound according to claim 2, which is a group represented by: and a pharmacologically acceptable addition salt thereof. 3 R ₁ is a monohydroxyalkyl group having 2 to 4 carbon atoms, and R ₂ is hydrogen or 1 to 4
The compound according to claim 1, which is an alkyl group having 5 carbon atoms, and a pharmacologically acceptable addition salt thereof. 4 Q is -CH ₂ CH ₂ - and R ₁ is hydrogen or -
2. The compound according to claim 1, which is CH ₂ CH ₂ OH and R ₂ is -CH ₂ CH ₂ OH, and a pharmacologically acceptable addition salt thereof. 5. The compound according to claim 4 in the form of a hydrochloride, wherein A-B is CH═CH and R ₁ is hydrogen. 6 A-B is CH=CH and R ₁ is -
5. A compound according to claim 4 in the acetate form which is CH ₂ CH ₂ OH. 7 The following formula () where A-B is selected from the group consisting of CH=CH and _CH2 - _CH2 ; Q is 2 of the formula: -( _CH2 )n-, where n is an integer from 2 to 4; each of R ₁ and R ₂ is hydrogen, an alkyl group having 1 to 4 carbon atoms, having 2 to 4 carbon atoms, and R ₁ and R ₂ are bonded; The carbon atom at the α-position to the nitrogen atom is a monohydroxyalkyl group that does not have a hydroxyl group, and the carbon atom at the α-position to the nitrogen atom has 3 to 6 carbon atoms and to which R ₁ and R ₂ are bonded. Atoms include dihydroxyalkyl groups, acetyl groups, trifluoroacetyl groups that do not have a hydroxyl group and the formulas: -( _CH2 ) ₂ -O- _CH3 and Here, R ₃ and R ₄ are independently hydrogen or methyl, or R ₃ and R ₄ together with the nitrogen atom to which they are bonded are morpholino. or R ₁ and R ₂ together with the nitrogen atom to which they are attached are aziridino, morpholino, piperazino, 4-methyl-1-piperazino, oxazolidino, 1,3-dioxazin-2-one or pyrrole. Yes, but a) When n is 2, R ₁ /R ₂ is
Instead of CH ₃ /CH ₃ , when n is 3, R ₁ /R ₂ is H/H, CH ₃ /CH ₃ , C ₃ H ₇ /C ₃ H ₇ or (-CH ₂ )-
₂ O(−CH ₂ )− ₂ , and when n is 4,
R ₁ /R ₂ is not C ₂ H ₅ /C ₂ H ₅ or (-CH ₂ )- ₄ b) Only one of R ₁ and R ₂ may be alkanoyl, the compound represented by, its tautomerism A method for producing a compound selected from physiologically and pharmacologically acceptable acid addition salts thereof, the method comprising: The compound represented by the following formula Here, the definitions of Q, R ₁ and R ₂ are the same as above, and the compound represented by is reacted in a tertiary amine solvent, that is, N,N,N',N'-tetramethylethylenediamine, and A compound represented by is produced, and then reacted with chloranil (tetrachloroquinone) if necessary,
A method characterized by: producing a compound of the above formula ().