JPH0152365B2 - - Google Patents

Description

[Detailed description of the invention] The present invention effectively utilizes novel anthraquinone compounds.
The present invention relates to an anticancer agent as a component. More specifically, the present invention includes: formula: During the ceremony, A-B is CH=CH and CH₂−CH₂A group consisting of more
selected; Q is the formula: (In the formula, n is an integer from 2 to 4) A divalent group selected from the group consisting of
And; R₁and R₂each of hydrogen, 1 to 4 carbons
an alkyl group having 2 to 4 carbon atoms
Has and R₁and R₂For the nitrogen atom to which
The carbon atom at the α position is a model that does not have a hydroxyl group.
hydroxyalkyl group, containing 3 to 6 carbon atoms
Has and R₁and R₂For the nitrogen atom to which
The carbon atom at the α position is a dicarbonate that does not have a hydroxyl group.
Hydroxyalkyl group and formula: (In the formula, n is an integer from 2 to 4, and R₃and R_FourNoso
each of hydrogen and atom having 1 to 4 carbon atoms
(independently selected from the group consisting of independently selected from the group consisting of the groups represented by;
Or R₁and R₂is the nitrogen they are bonded to.
Together with the elementary atoms, and R₃and R_FourHaso
Together with the nitrogen atom to which they are bonded, the mole
phorino group or formula: (In the formula, m is an integer from 2 to 6) (However, the side chains at the 1st and 4th positions
total number of carbon atoms versus total number of oxygen atoms and nitrogen in
(the ratio of the sum to the total number of atoms does not exceed 4); R_Fiveis selected from the group consisting of hydrogen and hydroxy groups.
Bare; R₆is selected from the group consisting of hydrogen and hydroxy groups.
Bare; R₇is hydrogen, hydroxy group and -NH-
CH₂CH₂N.H.₂selected from the group consisting of the groups represented by
be; however, R_FiveWhen is OH, R₆and R₇
one of must be H and R_Fiveis H
R when₆and R₇must both be H
do not have, The compound represented by, its tautomeric form and pharmacological
Compounds selected from the group consisting of acceptable acid addition salts
It is an anticancer agent characterized by having a substance as an active ingredient.
Ru. A-B is CH₂−CH₂A compound of the above general formula that is
substances are generally stable compounds, and the corresponding ant
It is known as the leuco form of laquinone. these
Leuco forms exist in each tautomeric form
This is well known, and all such forms are
equivalent for the purposes of the present invention. Leuco form (honmei)
Leuco base) and its tautomer are as follows:
It can also be expressed as a general formula: The above novel compounds generally have characteristic melting points and
Red and colored to blue-black crystals with a concentrated spectrum
It can be obtained as a crystalline substance, with the free base being mostly
It is insoluble in water and its slightly many organic solvents
It is leached with lower alkanol because it is insoluble in
It may also be purified. Organic base of the invention
(, and) are various pharmacologically acceptable organic
and non-toxic addition salts with inorganic salt-forming reagents.
Ru. Therefore, 1 equivalent, 2 equivalents or
up to 8 equivalents of acid, preferably in a neutral solvent.
Acid addition salts formed by combining sulfuric acid,
acid, hydrochloric acid, hydrobromic acid, sulfamic acid,
acid, lactic acid, malic acid, succinic acid, tartaric acid, vinegar
acids, benzoic acid, gluconic acid, ascorbic acid, etc.
Formed with acids such as Preferred acids are hydrochloric acid and
It is acetic acid. For the purposes of this invention, free bases are
is equivalent to the non-toxic acid addition salt of Organic salt of the invention
Acid addition salts of groups are generally crystalline solids that can be dissolved in water, methane, etc.
relatively soluble in alcohol and ethanol;
Like ethyl ether, benzene, toluene etc.
Relatively insoluble in non-polar presolvents. All such salts can be prepared by methods known to those skilled in the art.
and the respective play shown by
be able to convert back into a detached form, and therefore such
All salts and free forms are equivalent for the purposes of this invention.
It will be understood by those skilled in the art that Preferred embodiments of the novel compound aspect of the invention
The following general formula: and its pharmacologically acceptable acid addition salts.
You can ignore it. In the formula, A-B and Q are as above
And; R₁is hydrogen, has 1 to 4 carbon atoms
alkyl group having 2 to 4 carbon atoms or nitrogen
The carbon atom at the α position does not contain a hydroxyl group.
is a monohydroxyalkyl group; R₂is 2~
A carbon atom that has 4 carbon atoms and is located α to the nitrogen atom
is a monohydroxy group that does not contain a hydroxy group, 3
~6 carbon atoms and a carbon atom at α position to the nitrogen atom
The child is a dihydroxyalkyl group that does not contain a hydroxyl group.
Group or formula: (In the formula, n, R₃and R_Fouris as above) (However, the 1st and 4th place
Total number of oxygen atoms in each side chain
The ratio of the total number of children to the sum of the total number of nitrogen atoms is 4
). Second preferred embodiment of the novel compound aspect of the present invention
The embodiment has the following general formula: and its pharmacologically acceptable acid addition salts.
You may do so. In the formula, R is hydrogen or 1 to 4 carbon atoms
an alkyl group having children AB, n and Q
is as above, and each of the 1st and 4th place
The total number of oxygen atoms and the total number of carbon atoms in the side chain
The ratio to the sum of the total number of nitrogen atoms does not exceed 4.
stomach. Third preferred embodiment of the novel compound aspect of the present invention
The implementation is as follows: Compounds represented by and their pharmacologically acceptable acidification
Regarding salting. In the formula, n, R₁,R₂and A-B is
As shown in the first preferred embodiment. Fourth preferred embodiment of the novel compound aspect of the present invention
The implementation is as follows: Compounds shown in and their pharmaceutically acceptable acidification
Regarding salting. R in the formula₁is hydrogen or -CH₂CH₂OH
It is. Preferred salts are hydrochloride and acetate. The novelty of the present invention is represented by the formula, and
The compound is easily prepared by the following general method.
Will. formula: Compound and formula shown by: Y-[Q-]_TZ React with the compound shown by R_Five=R₇= black
When it is a group or an alkanoyloxy group, it is
Converted to hydroxy group, X is NHCOCF₃That is
COCF₃group is removed and Z becomes NR₁R₂In conversion to
When it is a group that can be converted into a
If so, A-B is CH₂−CH₂when it is
The product is converted to CH−CK under salt-forming conditions.
with a pharmacologically acceptable salt-forming reagent. formula
During ~ One of X and Y is NR₁R₂or NHCOCF₃And
and the other is OR_Ten, Cl, Br, I, N(R_Ten)₂, NO₂,
S.O.₃R_Ten, S.O.₂R_Ten,SOR_Ten, S.R._Ten,N₃, ONO and
and tetrazolyl (in the formula R_Tenis hydrogen, 1 to 6 carbons
Subatomic alkyl group, phenyl group, p-tolyl group
and benzyl group)
selected from the group; S and T are different and selected from 0 and 1; Z is hydrogen, an alkyl group of 1 to 4 carbon atoms, and
NR₁R₂is from the group consisting of groups that can be converted into
selected; however, (a) Only X is NHCOCF₃It is okay to be, and
Z is hydrogen or an alkyl group only when S is 0
isn't it, (b) Otherwise, if S is 0, then R₁/R₂
is H/H, and Z is hydrogen or 1 to 4 alkyl
Not a kill group, (c) T is 0 and Y is NR₁R₂When Z
is hydrogen, (d) T is 0 and X is NR₁R₂when
R₁/R₂at least one is hydrogen and Z is 1
~4 hydrocarbon alkyl groups, (e)R_Fiveand R₇one of them is a chloro group or an alkanoyl group
When it is a group, the other one is the same.
R, R₆is hydrogen, (f)R₁and R₂only one of them is an alkanoyl group
It's good to wear. The reaction is preferably carried out with water, lower alkanols, e.g.
methanol, ethanol, propanol, i-
Propanol, any isomeric butanol, etc.
in a reaction-inert solvent such as
Amide solvents such as dimethylformamide, dimethylformamide, etc.
in medium or N,N,N',N'-tetramethyl
Solvents such as ethylenediamine or mixtures thereof
For about 2 to about 10 hours at a temperature of about 40 to 110℃ in a container.
This is done by heating the reactants. above
Temperature, time and solvent and combinations thereof
Most will be sufficient to carry out the method. other solvents
and reaction parameters are sometimes desirable or necessary.
Although there may be other solvents such as
The selection of response parameters is within the scope of technology and is beyond the scope of this project.
All appear to be equal for the purpose of light. Products are often solids and are found in nature
Or, if you add crystal seeds or strain them, they will react when cooled.
Crystallized from solvent and per- or decantated
You may collect more. In other examples, the reaction mixture
may be concentrated, e.g. under vacuum at elevated temperature, and
When cooled, the product crystallizes, as described above.
may be collected by filtration or decantation.
cormorant. In other examples, a solvent may be used to collect the product.
Evaporating the medium to dryness or other miscible media such as water
The solvent is mixed into or diluted with the reaction mixture, e.g.
Proceed to collect the product, e.g. by filtration or extraction.
may be necessary. A person skilled in the art should follow the steps
all such steps are
are considered equivalent for the purpose of the present invention.
Ru. If the product is collected, e.g. crystallization, chroma
(thin layer or column) or preferably
can be purified by leaching with lower alcohols.
good. solvents, e.g. organic solvents like ethanol
Other procedures such as disintegration or crushing may also be used.
and purification procedures are all suitable for the purpose of the present invention.
should be considered equal. Those skilled in the art will understand that when a leuco form of the product is desired, the tricyclic
The starting material should be in leuco form and its
such substances, especially at high temperatures (i.e. room temperature).
Protected against oxidizing agents such as oxygen when
You will recognize that you should be careful to protect yourself.
Therefore, when a leuco product is desired, the reaction is normal.
The process is carried out in an atmosphere that effectively excludes air.
Ru. Therefore, the reaction can be carried out under conditions such as nitrogen or argon.
It may be carried out in an atmosphere, and the purification procedure, especially
This consideration should be made during procedures requiring high temperatures.
be. Desiring an aromatic product and using an aromatic starting material
Such consideration is usually not necessary when
stomach. When desired, the leuco form can be accommodated by various methods.
It is well known to those skilled in the art that it can be easily converted into aromatic forms.
It is. Therefore, air oxidation is one such method.
and other methods, e.g. hot nitrobenzene
chloranil, hydrogen peroxide or sodium perborate
Treat with lium. All such methods,
Other methods of converting the leuco and leuco forms to aromatic forms are
should be considered equivalent for the purpose of the present invention.
Ru. A person skilled in the art will also understand that substituent Z can be converted to The above conversions are well known to those skilled in the art when
can be easily performed using self-evident procedures within the technology.
You will understand that you can. Therefore this
Convert the group Z to [Formula] using all the steps of It is intended by the present invention to make such
All procedures are equivalent for the purposes of the invention.
You should think about it. Convert group Z to [formula] Therefore, the preferred procedure contemplated by the present invention is as follows:
Illustrated. These are just examples of said transformations.
It is understood that this does not define the scope of the invention.
should be understood. Other conversion procedures are known to those skilled in the art.
and is considered to be completely equivalent for the purpose of the present invention.
should be Therefore, Z is an aldehyde group or
Ton group, that is, [Formula] (wherein R is hydrogen or selected from alkyl groups)
[Formula] (R in the formula₁and R₂is as above) Rani-Nitz under reducing conditions such as hydrogen with an amine of
treated with Kell catalyst or sodium borohydride.
If controlled, the desired conversion will be achieved. For Z the formula: (In the formula, m is 2 or 3) Also contemplated are components shown in . This group is an acid,
For example, with aqueous ethanolic hydrogen chloride at 40-80℃
When treated for ~6 hours, it becomes -NH-(CH₂)m-
converted to OH, which is intended by the group [formula]. It is an ingredient that is Similarly, Z includes Cl, Br, I, p-tosyl,
O.S.O.₂CH₃Valid residual groups such as
Ru. When Z is the above-mentioned residual group or equivalent
An amine of the formula, [formula], such as a lower alkano Treatment in a cool solvent will result in the desired conversion.
Dew. Furthermore, Z is a primary amine or a secondary amine, i.e.
Chi-NH₂or −NHR₁When , further
When alkylated, it becomes the desired group, [formula] It will be transformed. A well-known alkylating agent is this
It is known that conversion easily occurs. Halogen
Alkyl nitrides, alkyl sulfates, substituted and unsubstituted alkyl
Reagents such as crylonitrile and the like are contemplated.
Aldehydes and ketones condensed under reducing conditions are also
You can also use it. All such conversions and other conversion procedures are
considered to be equivalent for the purposes of the present invention. Preferred embodiments of the first method aspect of the invention
may be represented by the following diagram. (R in the formula₁,R₂,R_Five,R₆,R₇and Q as above
) According to this reaction scheme, leuco 1,4 dihydro
xyanthraquinone () to N, N, N', N'-
Tetramethylethylenediamine, ethanol, diamine
Solvents such as methylformamide or mixtures thereof
In a nitrogen atmosphere at about 40 to about 60℃ for several hours.
The corresponding compound is condensed with alkylene diamine ().
Generate icobase (). Leuco base ()
air oxidation or thermal nitrobenzene treatment or
Loranil, hydrogen peroxide or sodium perborate
fully aromatic by various methods such as treatment with
It will be easily oxidized to the derivative (). next
to quaternize or salt-form the product under pharmacologically acceptable conditions.
Even if it comes into contact with a quaternizing agent or a salt-forming agent that is
good. Preferred subconcepts of the first method aspect of the invention
An embodiment of is also represented by the following reaction scheme A.
good: (R in the formula₁,R₂and Q are as above) A more preferred subsection of the aspect of the first method of the present invention
An embodiment of the concept is where Q is as above and R₁but
hydrogen or an alkyl group having 1 to 4 carbon atoms
and R₂has 2 to 4 carbon atoms and is a nitrogen source
A model whose α-position carbon atom does not contain a hydroxyl group
hydroxyalkyl group, containing 3 to 6 carbon atoms
The carbon atom at the alpha position to the nitrogen atom has a hydroxyl group.
Dihydroxyalkyl group not containing or formula:
[Formula] (In the formula, n, R₃and R_Fouris mentioned above (as shown in the following) (however,
Carbon atoms in each side chain at position 1 and position 4
The sum of the total number of oxygen atoms and the total number of nitrogen atoms in
According to the above reaction scheme A)
and its pharmacologically acceptable acid addition.
To produce salts, the product must be made pharmacologically acceptable.
with an acid, preferably acetic acid or hydrochloric acid. A second more preferred aspect of the first method of the present invention
The implementation of the subconcept is R₁is hydrogen or 1 to 4
is an alkyl group having carbon atoms of R₂Ga-
(CH₂) nOH, where n and Q are as above.
(However, if the side chains at positions 1 and 4 are
total number of carbon atoms, total number of oxygen atoms and nitrogen atoms
(the ratio to the sum of the total number does not exceed 4)
It is expressed by the chemical formula and its pharmacologically acceptable
To produce acid addition salts, the product can be used as a drug.
Contact with a theoretically acceptable acid, preferably acetic acid or hydrochloric acid.
Let me touch it. The most preferred subdivision of the first method aspect of the invention
An embodiment of the concept is that Q is −(CH₂)_o-(in the formula, n is 2~
an integer of 4, preferably 2), and R₁
is hydrogen or -CH₂CH₂OH and R₂Ga-
CH₂CH₂Represented by reaction scheme A above, which is OH
and produce its pharmacologically acceptable acid addition salts.
The product can be treated with a pharmacologically acceptable acid, preferably
Preferably, contact with acetic acid or hydrochloric acid. A-B is CH=CH, and R_Fiveand R₇together
hydrogen or hydroxy group, R₆is hydrogen The novel compounds of the invention also have the formula: Compounds and formulas of: and if desired, the product can be used pharmacologically.
produced by contacting with an acceptable salt-forming reagent.
You can also build it. During the ceremony, G is alkanoyloxy of 1 to 6 carbon atoms
group, alkoxy group of 1 to 6 carbon atoms or
[Formula] (where K is 1 to 6 carbon atoms ); L is hydrogen, hydro
is a xy group or [formula]; J is hydrogen, Chlorine or bromine; however, (a) When G is [formula], L is water or a hydroxy group, J is chlorine,
substituent K is removed from the tricyclic product; (b) When G is other than [formula], L is [formula] and the cyclization product is aromatic become a tribe. This method preferably uses toluene, xylene or
60 ~ in a reaction inert solvent like ethanol
At a reaction temperature of 150°C, preferably an inorganic gas such as nitrogen is used.
It is carried out in an active atmosphere. when it is necessary
For example, when G is other than [expression] The tricyclic product is aromatized. G is
[Formula] When the substituent K is, e.g. for example by treatment with aqueous ethanolic acid.
removed from the cyclic product. Those skilled in the art can define the K substituent as
The product obtained after removal is free carbamic acid
and allow it to decarboxylate naturally.
Dew. A-B is CH=CH, and R_Fiveand R₇together
hydrogen or hydroxy group, R₆is hydrogen
Other methods by which the novel compounds of the invention may be prepared include:
It is as follows: formula: Compounds and formulas of: and the group RCO and Y are OCH₃
When Y is hydrolyzed to produce hydrogen or
conversion to hydroxy groups and pharmacological use of the product if desired.
contact with an acceptable salt forming agent. During the ceremony, R is an alkyl group of 1 to 6 carbon atoms or CF₃in
can be; E and F are both hydrogen or together
When [formula] (in the formula R₃is hydrogen or 1 to 6 is an alkyl group of carbon atoms); CD is CH=CH or [Formula] (where Y is H or OCH₃is); however, When E and F are hydrogen, C-D is
[Formula] and when CD is CH=CH , E and F form [formula], and R_Five=R₇＝Hi It is a droxy group. This reaction preferably uses reactants as NaAlCl_Four
(NaCl/AlCl₃) at a temperature of 130-200 °C in the melt
This is done by mixing for 1 to 6 hours. three rings
The formula product can be hydrolyzed, e.g. by aqueous acid hydrolysis.
to remove the protecting group and, if desired, to remove a pharmacologically acceptable
Manufacture salt. The specific location of the reactants utilized in the method of the invention
When substituents are involved, the method may be modified by time, temperature and
Particularly effective due to specific selection of reaction variables such as solvent
It has been recognized that progress can be made efficiently and effectively.
It was. These preferred sets of reactants and reaction variables
The combination is illustrated by Reaction Schemes 1-12 below.
The combinations illustrated by the recited schemes are of the invention.
is merely a preferred combination or arrangement of the methods of
Limiting the scope of the invention or the claimed method
Those skilled in the art will recognize that this is not the case.
Dew. The procedures and preferences illustrated by Reaction Schemes 1 to 12
The new combinations are for the convenience of those who wish to practice the invention.
The scope of the invention is in no way defined.
It is not intended to be used for The symbols and definitions used in each of diagrams 1 to 12 are
Individual figures in which they are used unless indicated to the contrary
Concerning expressions only. In the formula, Q, R and R₂is as above, and X is
OH, Cl, Br, I, NH₂, NO₂, S.O.₃H,
[Formula] [Formula] SH, S-R_Ten,OR_Ten,N₃, It is a group that remains well, such as tetrazolyl and ONO,
Z is H or OH. According to the above reaction scheme, leuco form or aromatic
9,10-anthracendio with appropriate substitutions in the form
When reacting with an amine of the structure shown, the desired
1,4-diamino-9,10-anthracenedione
is obtained in leuco or aromatic form. The reaction is
Ethanol, propanol, isopropanol or
is N,N,N',N'-tetramethylethylenedia
2 to 10 minutes at a temperature of 40 to 100° under a nitrogen atmosphere in a
Time is done. If the product is a leuco compound
It can then be converted into aromatic form by the method described above.
converted into. R₁,R₂and Q are as above, and Z is black.
or alkanoyloxy of 1 to 6 carbon atoms
It is a group. Leuco 1,4,5,8-tetra-substituted-9,10-
The reaction between anthracenedione and amine is a low
Temperature of 40-100° under nitrogen atmosphere in alkanol
It takes place for 2 to 10 hours. Disubstituted derivative1teeth
Ethanol-aqueous solution of sodium hydroxide or hydrochloric acid
by alkaline hydrolysis or acid hydrolysis using
dihydroxy derivative2converted into. control the reaction
A thin layer of cream is added to avoid hydrolysis of the amino substituent.
Monitor the reaction using chromatography. Also
The leuco product is converted into aromatic form by the method previously described.
converted into. In the formula, Z is H or OH, Q, R₁and R₂is before
As shown below, X is Cl, Br, I, OSO₂C₆H_Fourp
−CH₃, O.S.O.₃CH₃Deriri, R₃is H or [formula] It is. The two reactants are mixed in lower alkanol and 40~
Heating at 90° for 1 to 8 hours produces the desired product.
Ru. R₃is CF₃When CO, the latter is converted into aqueous methane.
Remove with nordic potassium carbonate. Q is as above and Z is hydrogen or hydroxy
R is a lower alkyl group, hydroxy lower
alkyl group or dialkylamino lower alkyl group
can be a group, R₁is H or lower alkyl
It may be a group, R₂is H, lower alkyl group or
may be a hydroxy lower alkyl group. 2 to 3 molar equivalents of 9,10-anthracenedione
of aldehydes or ketones in lower alkanols
The mixture is subjected to Rani-Nitzke under reducing conditions such as hydrogen.
catalyst or platinum catalyst or sodium borohydride
When heated for 2 to 8 hours at 40 to 100 degrees with
Desired 1,4-bis(substituted amino)9,10-antho
Lasendion occurs. In the formula, Z is hydrogen or a hydroxy group, and Q is
As shown below, R is H, lower alkyl group or hydrogen
droxy lower alkyl group, R₂is H or low
It is a class alkyl group. 9,10-anthracenedione and acrylonito
Mixture of lyl in lower alkanol to 60-100°
Heating for 2-10 hours yields the desired product. Z is H or OH, n is 1 to 3, and R₁
and R₂is as described above. Bisacetal in aqueous-methanolic acetic acid1
When heated to 25° for 0.5 to 3 hours, dialdehyde2but
arise. The latter compound was dissolved in water in a lower alkanol.
Raney-nickel catalyst or
40~ with platinum catalyst or sodium borohydride
2 to 4 molar equivalents of amine for 2 to 10 hours at 100°
When treated with [Formula], the desired 1,4-diamino -9,10-anthracenedione is obtained. Z is H or OH, n=1-3, m=2 or
is 3. Leuco-1,4-dihydroxy-9,10-an
trasendion4or its aromatic forms and amines
5 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, Fr, 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-anthracenedione 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=Oacyl 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=0
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 test agent in its own solution in the same solvent or in a different solvent. You may do so. 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, and the corresponding salts may be collected, for example by filtration. good. 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 mouse tumors and induces regression and/or alleviation of leukemia 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 and 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 formulations. The active ingredient may also be administered parenterally or intraperitoneally. Solutions of the active ingredient as the free base or pharmaceutically acceptable salt in water suitably mixed with a surfactant such as hydroxypropyl cellulose can be prepared. 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. Therapeutic forms suitable 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 glycol, suitable mixtures thereof, and vegetable oils.
Proper fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the necessary particle size in the case of dispersions, and by the use of surfactants. Protection against the action of microorganisms can be provided by various antibacterial and antibacterial agents, such as parabens, chlorobutanol, phenols, sorbic acid, thimerosal, etc. In many cases, it will be preferable to include isotonic agents, such as sugars or sodium chloride. 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. The present invention also contemplates methods of using the pharmaceutical therapeutic formulations and compositions described above. 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 give once daily or once every other day or on fewer days. As can be seen from the dose regulation, the amount of the main active ingredient administered is sufficient to serve in the regression and mitigation of leukemia, etc., without undue 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. Aspects of the method of the invention include the formula: regression of a cancer disease in a mammal, the method comprising orally or parenterally administering to the mammal an effective amount of a compound selected from the group consisting of: (or) methods of inducing relaxation. 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 extracted 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] Lymphocytic Leukemia P388 Study The test compound was administered orally instead of intraperitoneally at various doses. The procedure used was similar to the previous study for lymphocytic leukemia P388, except that 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] Lymphocytic leukemia L1210 study The tumor transplant 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 similar to the intraperitoneal 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. Positive control compound is 20
5-Fluorouracil given as mg/Kg injection. The results of this test using representative compounds of the invention are shown in Table 4. The criteria for determining 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 fourth day for a total of six 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 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-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. Melting point 236-238℃. 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-morpholinoethylamine)-5,8-dihydroxyanthraquinone in 100 ml of nitrobenzene as described in Example 2 yields 10.30 g of the desired product. Obtained as a black rod. Melting point 241-243℃. 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. Melting point 180-185℃. 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. Melting point 157-160℃. Example 10 Leuco-1,4-bis[(3-dimethylaminopropyl)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 for 12 hours with air bubbling. 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 48-50 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-hydroxyethylamino)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 under nitrogen for 5 hours. The mixture is kept cool under nitrogen for 12 hours. The solid is 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.
Melting point 129-131℃. 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
(0.03 mol) was slowly added with stirring to 15 ml of 8N ethanolic hydrogen chloride. 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: 620, 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 8.31 μm). Example 18 Leuco-1,4-bis(4-aminobutylamino)-5,8-dihydroxyanthraquinone Following the general procedure of Example 3 but using 45 ml of 1,4-diaminobutane as the primary amine component the product 12.20 g (unmelted at 350° C., infrared absorption spectra: 6.31, 8.12, and 12.02 μm) were 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 12.02μ
m) is obtained. Example 20 Leuco-1,4-bis[2-(2-methylaminoethylamino)ethylamino]-5,8-dihydroxyanthraquinone in 50 ml of ethanol and 40 ml of N,N,N',N'-tetramethylethylenediamine. Leuko-1 in a solution of 14.10 g of 1-methyldiethylenetriamine,
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 washings are kept in an open flask for two weeks and partially evaporated to precipitate a solid, which is collected and washed with ethanol to yield 6.19 g of the subject 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, which 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 treated with chloranil by the procedure of Example 16. Blue-black solid when oxidized
18.03 g is obtained, melting point 190-203°C. 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-hydroxyethylamine)-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 gives 12.56 g of a green-black solid. Melting point 101~
104°C Example 28 1,4-bis[3-(2-hydroxyethylamino)-1-propylamino]-5,8-dihydroxyanthraquinone dihydrochloride Leuco-1,4-bis[3-(2-hydroxyethylamino)-1-propylamino]-5,8-dihydroxyanthraquinone dihydrochloride as in Example 16 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 is obtained. Point 58-60℃. 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 out, which hardens when kept overnight.
The curing is completed by disintegrating the solid into the solvent. Collecting the solid and washing with ether yields 16.82 g of a green-black solid (melting point: 75 DEG -85 DEG C.). . This solid remains granular when stored at -25°C, but
It becomes a solid cake when stored at 25°C. Example 34 1,4-bis[2-[2-(2-hydroxyethylamino)ethylamino]ethylamino]-5,
8-Dihydroxyanthraquinone tetrahydrochloride Product of Example 33 12.10 by the method of Example 16
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: 119° to 202°C, 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, which 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° 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-dihydroxyanthraquino Using the procedure of Example 15 and using 10.33 g of N-(2-aminoethyl))aziridine in 80 ml of N,N,N',N'-tetramethylethylenediamine, a hard gum was obtained. occurs. The next day, discard the supernatant solution and dilute with 100% ether.
ml 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) is 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 60Kg−
A second crystal is precipitated from the ether mother liquor and washed with ether and methanol. A solution of both crystals in 20 ml of chloroform was stirred 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. The resulting blue-black crystals weigh 0.64 g and are washed with ether, melting point 168-170°C. In thin layer chromatography on silica gel, the product migrates as a blue spot with chloroform-triethylamine-methanol 27/31/1 (volume ratio). 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 sulfoxide (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-(2-hydroxyethyl)trifluoroacetamide]ethylamino]-5,8-dihydroxyanthraquinone 75 ml of ethyl trifluoroacetate and 75 ml of methanol
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℃. Example 42 1,4-bis[2-amino-2-carboxyethylamino]-5,8-dihydroxyanthraquinone 3/4HCl A solution of 6.23 g of dl-α,β-diaminopropionic acid in 30 ml of warm water was hydroxylated. Add 1.078 g of lithium 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 the oxidation is complete. After cooling the mixture, the solids were removed by filtration and washed once with dimethyl sulfoxide-water (2/1). When 400ml of methanol was added to the liquid, solids precipitated.
It 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 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-oxazolidin-1-yl)ethylamino]-5,8-dihydroxyanthraquinone 1.62 g of 37% formaldehyde aqueous 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 is mixed with 75 ml of diethyl carbonate and 1,4-bis[2-(2
-hydroxyethylamino)ethylamino]-5,
Stir and heat under 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-
Stir and heat overnight with 5.45 g of hydroxy-1-propylamino)ethylamino]-5,8-dihydroxyanthraquinone dihydrochloride. 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 dihydrochloride Product of Example 15 10.77 by the method of Example 16
When g is oxidized with chloranyl, a dark blue solid 11.64
g, melting point 216°C. Example 49 [Table] 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. Example 50 Preparation of oral suspension Ingredient amounts Leuco-1,4-bis(3-aminopropylamino)-5,8-dihydroxyanthraquinone 500mg Sorbitol solution (70% NF) 40ml Sodium benzoate 150mg Satucalin 10mg Red dye 50mg Thierry flavor 50ml Distilled water...qs ad 100ml Add the sorbitol solution to 40ml of distilled water and suspend leuco-1,4-bis(3-aminopropylamino)-5,8-dihydroxyanthraquinone. 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. Example 51 Preparation of parenteral solution 700 ml of propylene glycol and 200 ml 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 52 Preparation of 1,4-bis(2-dimethylaminoethylamino)anthraquinone A mixture of 3 g of quinizarin, 10 g of N,N-dimethylethylenediamine and 17.5 ml of water is stirred and heated under reflux for 3.5 hours. The mixture is cooled and the solid collected and washed with water to give 2.96 g of the desired product as a dark blue solid, mp 170-172°C. Alternatively, quinizarin 2.4 g, N,N-dimethylethylenediamine 2.82 g and N,N,N′,
The above product may be prepared by heating a mixture of 9 ml of N'-tetramethylethylenediamine under reflux with stirring for 5 hours. The product is recovered as described above. Example 53 1,4-bis(2-morpholinoethylamino)
Production of anthraquinone Quinizarin 9.60g, N-(2-aminoethyl)
46.90 g of morpholine and 56 ml of water are reacted as described in Example 52 to give 9.92 g of the desired product as a blue-black solid, mp 158-159°C. Example 54 Production of 1,4-bis(2-diethylaminoethylamino)anthraquinone N,N,N',N'-tetramethylethylenediamine 42ml, N,N-diethylethylenediamine
A mixture of 17.43 g and 12.01 g of quinizarin is stirred and heated under reflux for 15 hours. The resulting solution was evaporated to dryness, and the remaining chloroform solution was washed with alumina.
Pass through 300g. The blue liquid is chromatographed on silica gel in a nylon film column and developed with a chloroform:methanol (6:1) mixture. The main blue band is cut out and then eluted with a chloroform:methanol:triethylamine (6:2:1) mixture. Evaporate the eluate. Crystallization of the residue from hexane and washing with petroleum ether gives 1.43 g of the desired product as blue-black platelets, mp 109°C. Example 55 Preparation of leuco-1,4-bis(2-aminoethylamino)anthraquinone 125 ml of ethylenediamine are degassed by bubbling with nitrogen for 15 minutes. 12.0 g of leucoquinizarin are added and the mixture is heated at 50° C. for 1 hour with stirring under nitrogen. Allow the mixture to cool. The solid was collected and washed sequentially with ethyl acetate, acetonitrile and petroleum ether to give 8.07 g of the desired product as green-gold crystals, melting at a heating rate of 9°/min.
~165°C (decomposition) Example 56 Production of 1,4-bis(2-aminoethylamino)anthraquinone 7.0 g of leuco-1,4-bis(2-aminoethylamino)anthraquinone and ethylenediamine
Bubble air through 87.5 ml of the mixture for 1 hour while heating to 50°C. Acetonitrile mixture 87.5
ml, allowed to cool, collected the solid and washed with acetonitrile to give 5.43 g of the desired product as a dark solid, mp 170-171°C. Example 57 Preparation of 1,4-bis[2-(methylamino)ethylamino]anthraquinone A mixture of 2.4 g of leucoquinizarin and 25 g of degassed N-methylethylenediamine is heated at 50° C. with stirring under nitrogen for 1 hour. . aerate the mixture
Continue heating at 50°C with bubbling for 40 minutes.
The mixture is evaporated to dryness and then again twice from 25 ml of ethanol. Crystallization of the residue at −70 °C from ethanol-ether yields a crude solid 2.32
g is obtained, which is recrystallized twice from carbon tetrachloride to give 1.92 g of the desired product as dark blue crystals, mp 131-132°C. Example 58 1,4-bis(2-piperidinoethylamino)
Production of anthraquinone Quinizarin 4.07g, N-(2-aminoethyl)
A mixture of 21.74 g piperidine and 26 ml water is stirred under reflux for 2 hours and then kept overnight. The gummy solid is collected and washed with water by centrifugation to yield 1.99 g of a blue-black solid. This solid is dissolved in 15 ml of chloroform and chromatographed on 100 g of alumina using a relatively short wet column procedure, eluting with chloroform. Total eluate 180ml
Collect into 8 individual cuts from when the eluate turns blue until the black band approaches the bottom of the column. Evaporation of Cuts 1 to 6 together gives 1.42 g of blue-black crystals, which are recrystallized from ethanol to give 1.35 g of the desired product as blue-black needles, mp 140-141°C. Dry the product in vacuo at 78°C, melt at 156-157°C. Example 59 Preparation of leuco-1,4-bis(2-dimethylaminoethylamino)anthraquinone N,N-dimethylethylenediamine in 75 ml of N,N,N',N'-tetramethylethylenediamine
Degas the 26.44 g solution by bubbling N ₂ for 15 minutes. Next, 12.11 g of leucoquinizarin was added,
While heating the resulting mixture to 48-50 °C under nitrogen
Stir for 21 hours. After cooling overnight under nitrogen, the solids are collected by filtration and washed by slurrying three times with acetonitrile and then twice with petroleum ether. 12.52g of dark green crystals
obtained, melting point 150-157°C; or melting point 153-154°C on a hot stage microscope. Example 60 [Table] [Table] Mix 1,4-bis[2-(methylamino)ethylamino]anthraquinone, lactose and corn starch (for mixing). 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. Example 61 Preparation of oral suspension Quantity of ingredients Leuco-1,4-bis(2-aminoethylamino)anthraquinone 500mg Sorbitol solution (70% NF) 40ml Sodium benzoate 150mg Satucalin 10mg Red dye 10mg Thierry flavor 50mg Distilled water ...qs.ad. Add 100 ml of sorbitol solution to 40 ml of distilled water, and suspend leuco-1,4-bis(2-aminoethylamino)anthraquinone therein. Satukarin,
Add sodium benzoate, flavor and dye and dissolve. Adjust the volume to 100 ml with distilled water. Each ml of syrup contains 5 mg of leuco-1,4-bis(2-aminoethylamino)anthraquinone. Example 62 Preparation of parenteral solution 700 ml propylene glycol and 200 ml water for injection
20.0 g of 1,4-bis(4-aminobutylamino)anthraquinone is suspended in the solution with stirring. After suspending, adjust the pH to 5.5 with hydrochloric acid,
Bring 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 63 Preparation of leuco-1,4-bis(3-aminopropylamino)anthraquinone When 1,3-propanediamine is substituted for ethylenediamine in the procedure of Example 55, the product is the subject compound. Example 64 Preparation of leuco-1,4-bis[(2-dimethylaminopropyl)amino]anthraquinone When 15.32 g of 2-dimethylaminopropylamine is used in place of N,N-dimethylethylenediamine in the procedure of Example 59, 50 The title compound is obtained after a reaction time of 1 hour at .degree. Example 65 Leuco-1,4-bis[2-(2-methylaminoethylamino)ethylamino]anthraquinone A solution of 14.10 g (0.12 mol) of 1-methyldiethylenetriamine in 100 ml of ethanol is added to
Degas by bubbling nitrogen for a minute and then slowly add 9.69 g (0.04 mol) of leucoquinizarin with stirring. The mixture is stirred under nitrogen and heated using an oil bath at 50° C. for 21 hours. The mixture is allowed to cool and the product is collected by filtration and washed with acetonitrile and then petroleum ether to give the title compound as a dark green solid. Example 66 Preparation of leuco-1,4-bis(2-methylaminoethylamino)anthraquinone 8.89 g of N-methylethylenediamine in 80 ml of N,N,N',N'-tetramethylethylenediamine
Degas the solution (see Example 59) and add 9.68 g of leucoquinizarin. Stir the mixture and place under nitrogen
Heat at 50°C for 1 hour and then allow to cool. The solid was collected and washed with toluene and then ether to give 9.0 g of a green-black solid, mp 105-109°C. Example 67 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 produced a solid, which was collected and washed with ethanol, yielding 2.25 g of the desired product (does not melt up to 360°C, and in 2-methoxyethanol solution at long wavelengths (1,4-bis(aminoalkylamino)-5,8-dihydroxy-anthraquinone shows a peak around 660 nm.) is obtained as a dark purple solid. Example 68 1,4-bis[(2-dimethylaminoethyl)
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 69 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 67 to give the subject compound. Example 70 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 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 was filtered hot, concentrated to 95 ml and then diluted with diethyl ether.
Dilute with 900ml. 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. Example 71 [Table] 1,4-bis(3-aminopropylamino)-
Mix 5,8-dihydroxyanthraquinone, lactose and cornstarch (for blending). Suspend cornstarch (for paste) in 600ml 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. Example 72 Preparation of oral suspension Quantity of ingredients Leuco-1,4-bis(3-aminopropylamino)-5,8-hydroxyanthraquinone 500mg Sorbitol solution (70% NF) 40ml Sodium benzoate 150mg Satucalin 10mg Red dye 50 mg Thierry fragrance 50 ml distilled water...qs ad 100 ml Add the sorbitol solution to 40 ml of distilled water, and suspend leuco-1,4-bis(3-aminopropylamino)-5,8-dihydroxyanthraquinone therein. Add saccharin, sodium benzoate, flavor and dye and dissolve. Volume 100 with distilled water
Adjust to ml. Each 1ml syrup contains Leuko-1,4
-bis(3-aminopropylamino)-5,8-
Contains 5mg of dihydroxyanthrquinone. Example 73 Preparation of parenteral solution 700 ml propylene glycol and 200 ml water for injection
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 formulation, 2.0ml each
(equivalent to 40 mg of drug) into a 5.0 ml ampoule and sealed under nitrogen. Example 74 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 75 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 mg of ethanol is heated under reflux for 30 minutes to give the title compound. Example 76 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 cooled to give the title compound. Example 77 10.97 g (40 mmol) of leucotetrahydroxyanthraquinone were suspended in 300 ml of methanol and argon was bubbled through the suspension with stirring in the machine for 30 minutes. 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 ₂₅₄
-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%; N=17.97%; O=
14.66% Analysis C = 61.74%: H = 5.65%: N = 17.62% Example 78 1,4-bis[2-(merthiamino)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 79 1,4-bis[(2-dimethylaminoethyl)
Amino]Anthraquinone 12.00g Leuco in 100ml 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 80 1,4-bis[2-(2-hydroxyethylamino)ethylamino]anthraquinone hydrochloride 1 mole of 1,4-bis[2-(2-hydroxyethylamino)ethylamino]anthraquinone,
A mixture of 4 molar excess of 8N 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. Example 81 The LD ₅₀ value of 1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone is as follows. Intravenous injection Mouse (male) LD ₅₀ = 11.3mg/Kg Mouse (female) LD ₅₀ = 9.7mg/Kg Intravenous injection Rat (male) LD ₅₀ = 5.3mg/Kg Rat (female) LD ₅₀ = 7.1mg/Kg Intraperitoneal Administration mouse (male) LD ₅₀ = 16.6 mg/Kg Mouse (female) LD ₅₀ = 19.7 mg/Kg

Claims (1)

[Claims] 1 Formula: where A-B is selected from the group consisting of CH=CH and _CH2 - _CH2 ; Q is of the formula: (in the formula, n is an integer of 2 to 4); each of R ₁ and R ₂ is hydrogen, an alkyl group having 1 to 4 carbon atoms; monohydroxyalkyl group, having 2 to 4 carbon atoms and having no hydroxyl group on the carbon atom α to the nitrogen atom to which R ₁ and R ₂ are bonded, 3 to 6 carbon atoms A dihydroxyalkyl group that has an atom and does not have a hydroxyl group on the carbon atom α to the nitrogen atom to which R ₁ and R ₂ are bonded, and a dihydroxyalkyl group with the formula: (where n is an integer from 2 to 4, and each of R ₃ and R ₄ is independently selected from the group consisting of hydrogen and an alkyl group having 1 to 4 carbon atoms) Is it independently selected from;
Alternatively, R ₁ and R ₂ together with the nitrogen atom to which they are attached, and R ₃ and R ₄ together with the nitrogen atom to which they are attached, form a morpholino group or the formula: (In the formula, m is an integer from 2 to 6) (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 the side chains at the 1st and 4th positions is R ₅ is selected from the group consisting of hydrogen and hydroxy groups; R ₆ is selected from the group consisting of hydrogen and hydroxy groups; R ₇ is hydrogen, hydroxy groups and -NH-
selected from the group consisting of CH ₂ CH ₂ NH ₂ ; provided that when R ₅ is OH, R ₆ and R ₇
one of them must be H, and when R ₅ is H, both R ₆ and R ₇ must be H. An anticancer agent characterized by containing as an active ingredient a compound selected from the group consisting of salts. 2 Claim 1 whose active ingredient is a compound in which R ₅ and R ₇ are hydroxy groups and R ₆ is hydrogen
The anticancer agent described in Section 1. 3 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: Claim 2 whose active ingredient is a compound represented by the group represented by or a pharmacologically acceptable addition salt thereof
The anticancer agent described in Section 1. 4 R ₁ is a monohydroxyalkyl group having 2 to 4 carbon atoms, and R ₂ is hydrogen or 1 to 4
3. The anticancer agent according to claim 2, which contains as an active ingredient a compound which is an alkyl group having 5 carbon atoms or a pharmacologically acceptable addition salt thereof. 5. The anticancer agent according to claim 2, wherein the active ingredient is a compound in which Q is -( _CH2 )n-, and n is an integer of 2 to 4, or a pharmacologically acceptable addition salt thereof. 6 Q is -(CH ₂ ) n-, and R ₁ is hydrogen or -
The anticancer agent according to claim ₂ , which contains as an active ingredient a compound or a pharmacologically acceptable addition salt thereof, which is CH 2 CH ₂ OH and R ₂ is -CH ₂ CH ₂ OH. 7 A-B is CH=CH and R ₁ is hydrogen,
The anticancer agent according to claim 6, which contains a compound in the form of a hydrochloride as an active ingredient. 8 A-B is CH=CH and R ₁ is CH ₂ CH ₂ OH
The anticancer agent according to claim 6, which contains an acetate form of the compound as an active ingredient. 9 The following formula A compound selected from 1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone, its leuco base and its tautomer, and its pharmacologically acceptable acid addition salts The anticancer agent according to claim 1, which contains as an active ingredient. 10 The following formula The anticancer agent according to claim 1, which contains as an active ingredient a compound selected from the leuco base, its tautomer, and a pharmacologically acceptable acid addition salt thereof. 11. Claims 1 to 1, useful for inducing regression or alleviation of cancer diseases in mammals, in the form of unit dosage forms containing from about 1 to about 2 mg per kg of body weight of the active ingredient per daily dose unit. The anticancer agent according to any one of Item 10.