JPH01123803A - Novel complex, its production and carcinostatic agent having said complex as effective component - Google Patents

Abstract

PURPOSE:To obtain a complex useful as a water-soluble carcinostatic agent having few side effects and a wide carcinostatic spectrum, by substituting specified platinum- containing groups for part of the hydrogen atoms of the OH groups of dextran. CONSTITUTION:Activated dextran derived by substituting -RSO3H groups (wherein R is a bivalent hydrocarbon group) for part of the hydrogen atoms of the OH groups of dextran is reacted with a cis platinum (II) complex of formula I (wherein L<1-2> are each an amine, a monodentate amine or they may be combined together to form a bidentate amine), X<1-2> are each a nitrato ligand, a hydroxo ligand or they may be combined together to form a sulfato ligand) to obtain dextran in which part of the RSO3H groups are replaced by formula II or III (wherein X<3> is a nitrato ligand, a hydroxo ligand or the sulfato group remaining after either of X<1-2> is bound to the activated dextran) and/or its salt. It desired, the product may be reacted with a compound which can form an anion (e.g., NaOH) to convert the X<3> group into a different anionic group. Namely, dextran in which part of the hydrogen atoms of the OH groups are replaced by -RSO3H and groups of formula IV or V (wherein Y is an anionic ligand containing X<3>) or its pharmacologically acceptable salt is obtained.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel complex, in particular cis-platinum (II).
) relates to a water-soluble polymeric complex bound to a complex.

The present invention also relates to a method for producing the above-mentioned complex, and further relates to an anticancer agent containing the complex as an active ingredient.

Prior Art In 1969 Rosenberg (B.
g) et al., the platinum complex cis-dichlorodiammine platinum (n) (- role name: cisplatin) was used to treat tumor sarcoma 1.
Since it was discovered that Sarcom 8180 has an anticancer effect on Sarcom 8180, research and development on cancer chemistry methods using platinum complexes have been actively conducted in various countries, and platinum complexes have been shown to have a wide anticancer effect. It has been attracting attention as a unique anticancer agent with the following properties. However, cisplatin has extremely strong nephrotoxicity, and due to its cumulative nature, it can cause gastrointestinal disorders, decreased bone marrow function, hearing loss, etc. Furthermore, when administered, it can cause severe nausea and vomiting, causing patients to It is said that it causes more pain than one can imagine.

Also, cisplatin has a solubility in water of only 1 rq.
/ l rug, making it difficult to formulate into a therapeutically effective dosage form. Despite these shortcomings, cisplatin is currently indispensable in the treatment of diseases such as disc ulcers, ovarian tumors, bladder cancer, and head and neck cancer, although of course there are significant limitations to its use. ing. Also, cis-dichloro(1,2-diaminonechlorohexane)
Platinum (■), cis-dichloro(2-aminomethylpyridine) Platinum(II), cis-dichloroplatinum(n) complexes known to have anticancer effects, such as cis-dichlorobis(cyclopentylamine)platinum(n) is less soluble in water than cisplatin. Therefore, many studies have been conducted in various countries to find platinum complex-based cancer drugs that eliminate the drawbacks of these cis-dichloroplatinum (If) complexes. Latodiammine platinum (n) (generic name: carboplaten), cis-dichloro-trans-dihydroquinbis(ingloviramine) platinum (F/), R-t
, i-cyclobutanedicarboxylate(2-aminomethylpyrrolidine)platinum(II), (glycorado-0,0)
- Diammineplatinum (It), i.

1-cyclobutanedicarboxylate (2-methyl-1,
4-butanediamine) platinum (■), oxalad (IR,
2R-7 chlorohexanediamine) platinum(II), etc. were developed.

In addition, the molecular weight s of polyamino acids, anionic polysaccharides, etc.
, ooo ~ 60,000 and a platinum complex or palladium complex is reported to be suitable for the treatment of tumors and the treatment and prevention of trypanome infections (Japanese Patent Application Laid-Open No. 1983-1973). (See Publication No. 116221). Furthermore, carboxymethyl dextrans has been reported to be a complex of poly-L-glutamic acid and cisplatin or cisdiamine aqua platinum (II) nitrate, and a complex of a polymer with trimellitic acid ester bonded and a platinum complex ( Cancer Bioc
hem, Biophys.

Eng., 277-287, 289-298 (1986); and UKPatent Application GB
2168063A].

Problems to be Solved by the Invention The various platinum complexes described above are far from satisfactory in terms of reduction of side effects, range of application, solubility in water, and the like. Thus, it is difficult to see the creation of new regulated cancer drugs that overcome various drawbacks from low-molecular platinum complexes.

Furthermore, the above compositions are not satisfactory in terms of anticancer activity, toxicity, or solubility in water.

Therefore, one of the objects of the present invention is to provide a new water-soluble compound that has fewer side effects, a broader anticancer spectrum, and excellent anticancer activity than conventional platinum complex anticancer agents. Another object of the present invention is to provide a method for producing the novel compound. Furthermore, another object of the present invention is to provide the use of the novel compound as an anticancer agent.

Means for Solving the Problems According to the present invention, the above object is achieved by (1) hydrogen atoms of the hydroxyl group partially representing the general formula (wherein Ll and L2 each represent ammine or monodentate amine, or - (together represent a bidentate amine, Y represents an anionic ligand, and R represents a divalent hydrocarbon group), and is partially substituted with a group represented by the general formula % formula % () (wherein R is as defined above) Dextran or a pharmacologically acceptable salt thereof [hereinafter, these compounds are referred to as complexes], (1) The hydrogen atom of the hydroxyl group is partially represented by the general formula (II
Dextran substituted with a group represented by I) has the general formula (I, 1 and L2 are as defined above, and X
The hydrogen atom of the hydroxyl group is reacted with a 7s platinum (It) complex represented by 1 and nidrado or hydroquine, respectively, or together sulfato. is partially general, with the formula (where Ll, L2 and R are as defined above)
3 represents a nidrado ligand or a hydroxo ligand, or represents a residual sulfato ligand resulting from binding of either Xl or X2 with activated dextran) , and partially replaced by the general formula (
By obtaining dextran and/or a salt thereof substituted with a group represented by DI), and then optionally reacting the obtained dextran and/or salt thereof with a compound that produces an anion, a hydroquinyl group can be obtained. hydrogen atoms are partially substituted with a group represented by the general formula (in which LL, L2 and R are as defined above, and X4 represents an anionic ligand), and General formula (
A method for producing the above-mentioned complex, characterized by obtaining dextran and/or a salt thereof substituted with a group represented by I [I), and (1) providing an anticancer agent containing the complex as an active ingredient. achieved.

Ll and L2 in the above formula will be explained in detail. Monodentate amines represented by Ll and L2 include n-propylamine, n-butylamine, n-hexylamine,
Examples include n-octylamine, impentylamine, impentylamine, oxo-2-aminoturbonone, cyclopropylamine, ncrobutylamine, cyclopentylamine, cyclohexylamine, cyclohebutylamine, aniline, alanine, glycine, and the like. Also L
The bidentate amines formed by l and L2 together include 1,2-diaminocyclopentane, 1,2-diaminocyclohexane, 1,2-diaminocyclohebutane,
1.2-diaminoadamantane, 1-amino-1-aminemethylcyclohexane, 1-amino-1-aminemethylcyclopentane, 1-amino-1-aminomethylcyclooctane, 1-amino-2-aminemethylcyclohexane, 1 -amino-2-aminomethyl-3,3,5-trimethylunclobencune, 1,1-di(aminomethyl)
Cyclohexane, 1,2-diaminoadamantane, diΦ
-2,3-diaminobicyclo(2,2,1)hebutane, 0-phenylenediamine, ethylenediamine,
1.2-dicarboxyethylenediamine, 1,2-bis(4-hydroxyphenyl)ethylenediamine, 1,2
- His(3,4-dimethquinphenyl)ethylenediamine, 1,2-bis(4-methoxyphenyl)ethylenediamine, N,N'-dimethylethylenediamine, N,
N'-) Inbutylpropane, 1,2-diamino-2-methylbutane, 1,2-
Diamino-2-ethylbutane, 1,3-diaminopropane, 1,3-diaminopentane, 2,4-diaminopentane, 1,3-diamino-1,3-diphenylpropane, 1,3-diamino-2-methyl- 2-ethylpropane, 2-m+-1,4-butanediamine, 1,3-diamino-2,2-dibenzylpropane, S-stilbendiamine, 2-aminomethylpyridine, 2-(1-aminoethyl) Pyridine, 2-(methylaminomethyl)pyridine, 2-aminomethylpiperidine, N-(2-aminoethyl)piperidine, 2-aminomethylpyrrolidine, 2-
Examples include (1-aminoethyl)pyrrolidine, N-ethyl-2-aminomethylpyrrolidine, and N-(2-aminoethyl)pyrrolidine. In addition, these bidentate amines include geometric isomers or optical isomers if such isomers exist. The anionic ligands represented by Y and X4 include hydroxo, nidrado, nitro, sulfato, ethylsulfato, sulfite, chloro, bromo, iodo, carbonato, hydrogencarbonate, phosphato, methylphosphonate, borate, tetraborate, butylboronate. , sulfamad, promado, chromato, manganate, methanesulfonate, acetate, monopromoacetate, monochloroacetate, acetoacetate% birubat, lactate, glucuronate, gluconate, oxalad,
Examples include maronato, succinato, and benzonato.

Examples of pharmacologically acceptable salts contained in the complex of the present invention include salts of alkali metals such as sodium and calicum; salts of alkaline earth metals such as calcium and barium; ammonium salts; Examples include salts of tertiary amines such as n-butylamine.

The composite of the present invention can be produced, for example, by the method described above, and this method can be schematically expressed in the following reaction formula 9. Note that dextran is represented by 1Dex-OH, and dextran is activated by partially substituting the hydrogen atom of the hydroxyl group of dextran with a group represented by the general formula (1 [1)] (hereinafter referred to as dextran). This is called activated dextran) is ρex -0-R
-3OsH.

1Dex-OH activated IDex-0-R-8O3H"'
---〇(It-1) (I-2) (It-2) In the above formula, Ll, L2, R, X", X2, X3 and X
4 corresponds to the above definition. - Monka (1-1) and -
Mon'a (n-1) respectively indicates a complex of the present invention obtained by partially reacting activated dextran with a cis platinum (II) complex represented by the general formula (It/), and - Mon'a (
1-2) and -Momona (II-2') are respectively -Momona (II-2')
1-1) and the complex of the present invention, which were obtained by subjecting the complex represented by Monkei (, 11-1) to ligand conversion as necessary. Note that -Momona (n-1) and -Momona (If-2) each indicate a complex that is thought to be produced by using water during the reaction or during the separation and purification described below. The binding moiety of platinum pt to activated dextran is represented by -3Oa-Pt.

The above method will now be explained in detail. The reaction between the activated dextran and the cis platinum (n) complex represented by the general formula (■) is usually preferably carried out in an aqueous solvent.

Further, the reaction is usually carried out at room temperature, but it can also be carried out by heating up to about 80°C in order to increase the reaction efficiency. The reaction time varies depending on the reaction temperature set, but is from several hours to two days. Activated dextran and cis platinum(II)
The amount of the complex to be charged is an arbitrary ratio depending on the degree of activation of dextran, the molecular weight of the cis platinum (II) complex, the administration form of the target complex as an anticancer drug, etc.
Typically, the weight ratio of activated dextran/cis platinum(n) complex ranges from about 110.05 to about 1/3. As the amount of cis platinum (n) complex charged increases, the platinum content bound to activated dextran increases. The reaction solution of the activated dextran thus obtained and the cis platinum (U) complex represented by the general formula (IV) is directly subjected to the separation and purification operations described below to obtain the desired complex. Obtainable. If necessary, to convert the ligand of the cis platinum(n) complex bound to the activated dextran, an anion-forming compound is added to the reaction solution obtained by the above method. The complex obtained by adding or separating from the reaction solution may be dissolved in an aqueous solvent, the anion-generating compound may be added to the solution, and the mixture may be stirred at room temperature for several hours to one day. Compounds that generate anions include, for example, bicarbonate, carbonic acid, boric acid, sulfurous acid, nitrous acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, bromic acid, hydrobromic acid, hydrogen iodide, chromic acid, and manganic acid. , alkali metal salts, alkaline earth gold salts or ammonium salts of inorganic acids such as tetraboric acid, or acetic acid, bromoacetic acid, chloroacetic acid, succinic acid, maleic acid, malonic acid, oxalic acid, benzoic acid,
Examples include alkali metal salts, alkaline earth metal salts, or ammonium salts of organic acids such as glucuronic acid, gluconic acid, pyruvic acid, lactic acid, acetoacetic acid, methanesulfonic acid, ethyl sulfate, methanephosphonic acid, butylboric acid, and sulfamic acid. Among them, representative compounds include sodium bicarbonate, ammonium bicarbonate, sodium chloride,
Potassium bromide, sodium acetate, sodium glucuronate, sodium pyruvate, sodium monochloroacetate, etc. can be listed. Examples of compounds that generate hydroxy anions include barium hydroxide, potassium hydroxide, sodium hydroxide, ammonia water, and the like. The amount of the above-mentioned anion-generating compound to be added varies depending on the type of activated dextran used and the anion-generating compound, but approximately Equimolar to about 20 times the molar amount. The treatment time for anion-ligand conversion varies depending on the type and amount of the anion-generating compound, but ranges from several minutes to about 10 hours. This treatment may cause cleavage of the 7 bond in -3O3-Pt, the bonding portion of platinum pt to activated dextran, so the treatment time ranges from several minutes to about 2
time is preferable.

The fraction of the complex from the reaction solution thus obtained
The purification operation will be explained next. Dialyze low-molecular substances such as unreacted cis-platinum (It) complex or excess of the anion-generating compound added for ligand conversion from the reaction solution.
It is removed by operations such as gel filtration, reprecipitation, and ultrafiltration. The complex solution obtained by this operation is appropriately concentrated, and the concentrated solution is reprecipitated using methanol, inpropatol, or a mixed solvent thereof, or the complex solution is freeze-dried as it is. The body can be obtained as a solid product. In the dialysis, ultrafiltration and gel filtration described above, water is used as a solvent or eluent.

The complex of the present invention obtained in this way has an anionic ligand or its aqua type ligand as a ligand as explained above, but these ligands are 1a! in the same molecule. There is no need to be similar.

The complexes of the present invention also include those having partially different ligands.

The complex of the present invention usually contains platinum atoms in a range of about 0.1 to 20% by weight, depending on the type of activated dextran. Complexes with a platinum atom content in the range of approximately 1 to 15% by weight are preferred as complexes in which the intended pharmacological action of the complex is fully expressed, and which is sufficiently soluble in water and can be easily administered to the living body. is preferable, and more preferably the content is about 3 to 10% by weight.
Preferably, the range is . The content of platinum atoms in the complex is determined by atomic absorption spectroscopy.

The composite of the present invention has molecules i (weight average molecular weight) of approximately several thousand to one million. The complex is appropriately selected from those having a molecular weight within the above range depending on the purpose of use. When the complex is administered locally to a tumor tissue or into its feeding artery, it is preferable that the complex dissolves in a solvent, has an appropriate viscosity, and is easily retained locally, and has a molecular weight of 10
It is appropriate that it is within the range of 300,000 to 800,000, and 300,000 to 800,000.
It is preferably within the range of 600,000. In addition, when administering the complex intravenously, the molecular weight of the complex should be within the range of 10,000 to 300,000 in order to maintain an appropriate blood concentration of the complex and reduce its accumulation in the body. It is appropriate that the number is within the range of 30,000 to 200,000, and it is preferably within the range of 60,000 to 200,000.
It is particularly preferable that the number is within the range of 10,000 to 150,000. Many of the known platinum complex anticancer substances are poorly soluble in water, but when the complex of the present invention is simply used as a low toxicity anticancer substance soluble in water, the complex of seven It is sufficient for the molecular weight to be in the range of several thousand to ten thousand.

The cis platinum (II) complex represented by the general formula (■) can be produced by a conventional method. That is, the general formula (in the formula
L! and L2 are as defined above. ) By reacting the cis-dichloroplatinum complex represented by 2 equivalents of silver nitrate, a nidorado platinum complex in which Xl and X2 are both nidorado ligands in the general formula (IV) can be obtained. This reaction is usually carried out in an aqueous medium at a temperature ranging from room temperature to about 80°C.

Thereafter, the silver chloride precipitate deposited from the reaction solution is removed, and the resulting aqueous solution can be used as it is in the reaction for producing the composite of the present invention. Note that this aqueous solution is acidic, and if necessary, it can be prepared with aqueous ammonia or aqueous sodium hydroxide solution and then subjected to the reaction for producing a composite. Furthermore, by distilling off water under reduced pressure from the aqueous solution from which the silver chloride precipitate has been removed, the nidorado-platinum complex can be isolated and obtained as crystals. In this case, the resulting nidradoplatinum complex has two molecules of water of crystallization.

The aqueous solution of the Nidorado platinum complex obtained by the above method was treated with an anion exchange resin, such as Diaion 5A-1OA.
By passing it through Amberlite IRA-400, DOWEX I, etc.,
An alkaline aqueous solution of a hydroquine platinum complex in which both are hydroquine ligands is obtained. Hydroquine platinum complex is very unstable when isolated as a solid;
The aqueous solution is subjected to the reaction for producing the complex of the present invention.

In addition, by reacting 1 equivalent of silver sulfate with the cis-dichloroplatinum complex shown by -Momona (V) in an aqueous solvent and removing the silver chloride produced from the reaction solution, -Momona (IV) An aqueous solution of a sulfatoplatinum complex is obtained in which Xl and X2 together represent a sulfato ligand. The aqueous solution of the hydroquine platinum complex can also be obtained by adding barium hydroxide to this aqueous solution and reacting it, and removing the precipitate of barium sulfate produced from the reaction solution.

Dextran is produced from sucrose through the action of dextran saccharase possessed by microorganisms.
It is a polysaccharide with a chemical structure mainly composed of α-1,6-D-gelcondo bonds, which is obtained by removing fructose from sucrose and bonding only glucose in large numbers. Dextran hydrolyzate is easily soluble in water and is used as a plasma substitute. Furthermore, dextran is easily decomposed into glucose by dextranase, which is widely distributed in living organisms.

Activated dextran can be obtained by reacting dextran with a salt of a sulfonic acid having a halogen atom represented by the general formula % (in which R is as defined above and 2 represents 10 gen atoms). It can be manufactured by

- The sulfonic acids having a halogen atom represented by the symbol (Vl) include aliphatic sulfonic acids represented by the following general formula (■-1) and aromatic sulfonic acids represented by the symbol (■-2) .

Z-CmH2m-8OsH(Vi-1)Z-CnH2n
GSO3H(■-2) However, in the above formula, Z is as defined above, m represents an integer of 1 to 8, and n represents an integer of 0 to 4. Typical examples of sulfonic acid salts containing halogen atoms include:
Examples include 2-chloroethanesulfonic acid sodium salt, 2-chloroethanesulfonic acid potassium salt, 2-bromoethanesulfonic acid sodium salt, 4-chlorobutanesulfonic acid sodium salt, and p-bromomethylbenzenesulfonic acid sodium salt. . The reaction is water, Impropatool,
Sodium hydroxide, aqueous potassium dispersion, potassium carbonate, 1,8-diazabicyclo[5,4,,0] in a solvent such as N,N-dimethylformamide or dimethylsulfoquine.
It is carried out in the presence of a dehydrogenating agent such as -7-undecene. The reaction is carried out at room temperature or under heating up to about 120° C., depending on the reaction temperature, for several hours to one day. This method depends on the type of sulfonic acid salt used as the raw material, but usually the sulfonic acid salt and dextran are mixed in an aqueous sodium hydroxide solution under a nitrogen atmosphere for about 100 to
Good results are obtained by carrying out the reaction at a temperature of 110 DEG C. for about 2 to 6 hours with stirring. The number of moles of the raw material sulfonic acid salt charged to the monosaccharide unit of dextran varies depending on the reaction conditions, but is in the range of about 0.5 to 7 moles. The desired activated dextran can be obtained by subjecting the reaction solution thus obtained to operations such as reprecipitation, ultrafiltration, gel filtration, and dialysis.

Activated dextran can also be produced by reacting dextran with propane sultone in a conventional manner.

The complex of the present invention has both the strong anticancer activity derived from the cis platinum (n) complex represented by the general formula (If/) and the properties possessed by activated dextran, and also has the hydrogen atom of the hydroxyl group of dextran. Because it is a complex based on the bonding mode of dextran activated by partially substituting with a group represented by the general formula (III) and a cis platinum (II) complex, it has the following excellent characteristics. have That is, the complex of the present invention comprises a water-soluble activated dextran and a cis platinum(II) complex as described above.
Since it has a bonded structure in the form of Dex-0-R-8Os-PtO, it is easily soluble in water and there are no restrictions on the method of administration. The platinum complex is gradually released in the form of active species from the complex of the present invention administered into the body, its effective concentration in the blood is maintained for a long time, and the toxicity is reduced. The therapeutic index of the complex is significantly improved. Furthermore, the complex of the present invention significantly improves nephrotoxicity induced by cisplatin and thrombocytopenia induced by carpoplatin. Furthermore, since solid tumors have properties such as angiogenesis, high vascular permeability, and leakage from blood vessels, the complex of the present invention easily accumulates within tumors and has little effect on normal tissues. Furthermore, the complex of the present invention does not cause association or crystallization and remains in the blood circulation system for a certain period of time, after which the dextran is metabolically decomposed in the body and excreted by the kidneys, so that it does not accumulate in body tissues. Furthermore, the complex of the present invention exhibits lymphatic migration properties and is also effective in treating cancer that has metastasized to the lymphatic system. Therefore, the complex of the present invention has an expanded or changed anticancer spectrum compared to existing low-molecular-weight platinum complex anticancer agents,
It has enhanced anticancer activity without causing serious side effects.

Hereinafter, a test of the anticancer effect of the complex of the present invention and cisplatin used as a control drug on experimental mouse tumors and the results thereof will be shown.

Anticancer activity against leukemia L1210 in test example mice CDF1 mice (6 weeks old, male, 6 mice/group) were intraperitoneally transplanted with 10 L1210g5 cells/mouse, and then the test drug was administered on the 18th and 58th day. was dissolved in distilled water for injection and administered through the tail vein. Cisplatin, a control drug, was dissolved in an aqueous les mannitol solution and administered. The anticancer effect was determined by the ratio T/C (%) of the survival days of the treated group to the survival days of the untreated group. The survival period for the untreated group was approximately 8 days (mean su
rvivaltime). These results are shown in Table 1.

As is clear from Table 1, which shows that 3 or more mice died due to toxicity within 5 days after transplantation, the complex of the present invention exhibited significant anticancer activity. , shows clearly superior therapeutic activity compared to the control drug cisplatin. Moreover, the uninvented complex was water-soluble, and there were no problems with the administration form. The composites obtained in Comparative Examples 1 and 2 also had less satisfactory anticancer activity than the composites of the present invention. Furthermore, the complex obtained in Comparative Example 2 exhibited strong toxicity.

The complex of the present invention is useful as a therapeutic agent for cancer in mammals such as humans, horses, cows, pigs, dogs, mice, rats, and guinea pigs.

The complex of the present invention can release anticancer active species of a low-molecular platinum complex even under mild conditions, for example, the monochloride or dichloride of the corresponding platinum complex can be released by the action with salt in the body. The release of active species is expected. However, when considering interactions with various biological components in vivo, the cleavage of this complex is not simple, and the complex of the present invention is compared to known low-molecular-weight platinum complex anticancer substances. As mentioned above, it has various characteristics and can be used as an excellent new polymer anticancer agent.

The effective dosage of the complex of the present invention is based on the platinum content in the complex,
The method of administration, the symptoms of the patient to whom it should be administered, the nature of the cancer to be treated,
It can vary widely depending on body weight, age, gender, and the judgment of the treating physician. For humans, the dose of the complex can generally range from about 0.3 to 20 2 /day, and this dose can be administered once a day or in divided doses.

The complex of the present invention can be administered orally or parenterally to mammals such as humans, horses, cows, pigs, dogs, mice, rats, guinea pigs, etc., although treatment by parenteral administration is usually preferred. . The complex of the present invention can be dissolved or suspended in a suitable injection solvent, such as distilled water for injection, 1H sodium bicarbonate solution, 5% glucose aqueous solution, ethanol water, glycerin water, propylene glycol water, etc., and can be injected intravenously or intramuscularly. ,
Administering by subcutaneous injection or infusion gives good results. In addition, if necessary, it can be injected into an artery or into a cancerous area. In the latter case, since the complex of the present invention is a polymeric substance, it tends to stay locally, and the active species are gradually released from the complex over a long period of time, and the excellent anticancer effect of the complex of the present invention is enhanced. Demonstrated.

Therefore, the present invention also includes anticancer agents containing at least one type of complex as an active ingredient.

The complexes of the invention can also be used in combination with one or more other anticancer agents and may also be combined with various buffering agents, local anesthetics, hypnotics, analgesics, etc. to impart the desired pharmacological properties. It can also be prepared in combination with drugs such as drugs. Although the complex of the present invention can be encapsulated in an ampoule as a solution or suspension, it is preferably stored in an ampoule or a vial as a powder or lyophilized product and reconstituted as needed before use.

EXAMPLES The present invention will be specifically explained below using examples. Note that the present invention is not limited to these Examples.

Reference Example 1 Dextran 70 (average molecular weight as described in the Japanese Pharmacopoeia: approximately 70,000) 2.01 was mixed with sodium hydroxide 4. Oi water 8
After adding it to the solution obtained by dissolving it in - and dissolving it by heating, it was stirred at room temperature overnight. Approximately 40 d of ingropanol was added to the resulting solution and heated under reflux for 1.5 hours. next,
While keeping this mixture at a temperature of 70 to 8°C, add 2-chloroethanesulfonic acid sodium salt to this mixture.
Add 3.3f of hydrate in several portions over 2 hours,
After heating under reflux for an additional 4 hours, the reactor was heated overnight. Thereafter, the reaction solution was reprecipitated using about 3 tons of methanol. The obtained precipitate was dissolved in about 200M water, and filtered using an ultrafiltration membrane (manufactured by Sartorius, molecular weight cutoff: 20,000).
Filtered for 0 hours. Next, the filtered liquid was freeze-dried to obtain 1.81 sulfoethyldextran sodium salt.

Reference Example 2 1.61 sulfoethyl dextran sodium salt was obtained in the same manner as in Reference Example 1 except that Dextran 40 (average molecular weight as described in the Japanese Pharmacopoeia: approximately 40,000) was used instead of Dextran 7o.

Reference Example 3 15.0 Or of potassium platinum chloride was dissolved in 160 d of water, and trans-1,2-diaminocyclohexane (hereinafter, this compound is abbreviated as DACH; A
ldrich Chemical Co.) 4.20
f to water 201El! The solution obtained by dissolving in was added and stirred at room temperature for 1 day. The precipitated crystals were collected by filtration and recrystallized with about 251 O, IN hydrochloric acid to give cis-dichloro(DACH) platinum (I
I) was obtained at 8.80F.

Nsu dichloro (DACH) obtained by the above method
Platinum(II) 388 rIq (1,02 mmole)
Silver nitrate 340* (2,OO
mmole) in 3 yLt of water was added and stirred at about 60° C. for 40 minutes in a system disconnected from light, and then stirred overnight at room temperature. Thereafter, the silver chloride precipitate precipitated from the antiseptic solution was removed by filtration to obtain an aqueous solution of cis-dinitrato (DACH) platinum (I[) as a filtrate.

Reference example 4 Potassium chloride platinum 15.0 (M' is water 180yx
15.001 of ammonium chloride in this solution.
was added and stirred. To the obtained solution, 28.0 m/3N aqueous ammonia was added, and the mixture was stirred for 5 days at a temperature of 3° C. or lower in a system shielded from light. The precipitated crystals were collected by filtration, and the resulting crystals were dissolved in N,N-dimethylformamide 5
00 resistance, and insoluble matter was removed by filtration. Next, methanol 1t11:IK was added dropwise to the filtrate, and the mixture was stirred at room temperature for 2 hours. The precipitated crystals were collected by filtration and 0. By recrystallizing with 430 d of IN hydrochloric acid, 6.13 f of Nsu dichlorodiammine platinum (It) was obtained as yellow crystals.

Silver nitrate 136''P (0,80
mmole ) in water 3#! / and stirred for 1 hour at about 60°C in a system shielded from light.
It was then stirred at room temperature overnight. Thereafter, the silver chloride precipitate precipitated from the reaction solution was removed by filtration to obtain an aqueous solution of cysudinitocytodiammine platinum (It) as a filtrate.

Reference Example 5 6.23 F of potassium platinum chloride was dissolved in 65 rttl of water, and 1.80 F of 2-aminomethylpyridine was added to this solution.
A solution obtained by dissolving r in 10 wl of water was added, and the mixture was stirred at room temperature for 1 day. The precipitated crystals are removed by filtration,
After washing with water and drying, cis-dichloro(2-aminomethylpyridine)platinum (n
) was obtained at 4.39F.

Cis-dichloro(2-aminomethylpyridine)platinum (It) obtained by the above method 194■ (0.52m
136 silver nitrate into a mixture of 5 ml of water
A solution obtained by dissolving 1 F (0.80 mmole) in two glasses of water was added, and the mixture was heated at approximately 60°C in a system shielded from light.
Stirred for 0 min and then at room temperature overnight. Thereafter, the silver chloride precipitate precipitated from the reaction solution was removed by filtration to obtain an aqueous solution of cis-dinitrato(2-aminomethylpyridine)platinum(II) as a filtrate.

Reference Example 6 10.00 f of potassium chloroplatinate was dissolved in 60 d of water, and 4.202 g of cyclopentylamine was added to 4 g of water in this solution.
A solution obtained by dissolving in Ogo was added, and the mixture was stirred at room temperature for 6 hours. The precipitated crystals were collected by filtration and washed successively with concentrated hydrochloric acid, water, methanol, acetone and diethyl ether. Next, the obtained crystals were dissolved in 50 d of N,N-dimethylformamide, and 0.5 d of N-hydrochloric acid was added to this solution.
Added Go.

The precipitated crystals were collected by filtration and washed sequentially with water and methanol to obtain 2.0% of cis-dichlorobis(cyclopentylamine)platinum (U) as pale yellow crystals.
I got 29.

Cis-dichlorobis(cyclopentylamine)platinum (n) obtained by the above method 178■ (0.41mm
ole) and water, add 13611q silver nitrate to the mixture.
(0.80 mmole) in 2 d of water was added, stirred at about 60° C. for 1 hour in a system shielded from light, and then stirred at room temperature for 1 day. Thereafter, the silver chloride precipitate precipitated from the reaction solution was removed by filtration to obtain an aqueous solution of cis-dichlorobis(cyclobentylbane)platinum(II) as a filtrate.

Reference Example 7 Cis-dichlorobis(cyclohexylamine)platinum(II)'&2.06y was obtained in the same manner as in Reference Example 6 except that cyclohexylamine 4.9 (M') was used instead of cyclopentylamine 4.202.

Then, according to the same method as in Reference Example 6, 7-dichlorobis(cyclohexylamine)platinum(II)
241 ”P (0.52 mmole) and silver nitrate 136
m? (0.80 mmole), an aqueous solution of nitratebis(cyclohexylamine)platinum (It) was obtained.

Example 1 Dissolve 1000++v of sulfoethyldextran sodium salt obtained in Reference Example 1 in 30+l/water, add the aqueous solution of cis-dinitrato (DACH) platinum (n) obtained in Reference Example 3 to this solution, and protect from light. The mixture was stirred overnight at room temperature. The reaction solution was filtered through a dialysis membrane (tube size 30
/32, Union Carbide Corp.

fM) for 2 days, the dialyzed solution was filtered to remove a small amount of suspended matter, and the filtrate was freeze-dried. Cis-nidorado and its aqua form (L
) ACH) Platinum(II)-sulfoethyldextran complex [cis-nidorado CD in sulfoethyldextran
ACH) platinum(II)- and its aqua form (iJACH
) Represents a complex in which platinum(II)- is partially bound.

- Ll and L2 together represent trans-1,2-diaminocyclohexane in the pattern hole (1-1),
X3 represents a nidorado ligand, and 1Dex-0-R
a complex in which -8OaH represents sulfoethyldextran, and - in the crest (n-1), Ll and L2 together represent trans-1,2-diaminocyclohexane, and X3 represents a nidrado ligand, and ρex-
0-R-8OsH corresponds to a complex representing sulfoethyldextran. The same applies hereinafter in this specification. ] got 990 ki.

The platinum content of this composite was 8.4% by weight and the sulfur content was 2.9% by weight. The infrared absorption spectrum (FT-IR) of this composite is shown in FIG.

Examples 2 to 6 Sulfoethyldext 2 obtained in the reference examples shown in Table 2
400 IIv of sodium salt was dissolved in 12d of water. An aqueous solution of the platinum complex obtained in the reference example shown in Table 2 was added to this solution, and the mixture was stirred overnight at room temperature in a system shielded from light.

The subsequent treatments were carried out in the same manner as in Example 1 to obtain corresponding composites. These results are shown in Table 2. The infrared absorption spectra (FT-IR) of the composites obtained in Examples 2 to 5 are shown in FIGS. 2 to 5, respectively.

Example 7 1200 μl of sulfoethyldextran sodium salt obtained in the same manner as in Reference Example 1 was dissolved in 40 mj of water. To this solution was added an aqueous solution of DACH platinum(II) obtained in the same manner as in Reference Example 3, and the mixture was stirred overnight at room temperature in a system shielded from light. 330 η of sodium bicarbonate as an anion-generating compound was added to the resulting reaction solution, and the mixture was stirred at room temperature overnight. After that, the precipitate precipitated from the reaction solution was separated and removed using a centrifuge, and gel filtration (filling agent: 5 eph
adex G-25+manufactured by Pharmacia; eluent: distilled water), and the effluent of the high molecular weight fraction was collected and freeze-dried to obtain cis-hydrogen hydroxide and its aqua W (DACH) platinum (I[)- 1190η of a sulfoethyldextran complex was obtained. The platinum content of this composite was 3.3% by weight and the sulfur content was 3.2% by weight. Infrared absorption spectrum (FT-I) of this complex
R) is shown in FIG.

Comparative Example 1 Dextran 705. Or 30% sodium hydroxide aqueous solution 251! J was heated and dissolved. 70% of the resulting solution
6. Add monochloroacetic acid to this solution while keeping the temperature at ~80°C. Of was added in several portions and stirred for 4 hours. Next, the reaction solution was reprecipitated using about 5 tons of methanol. The obtained precipitate was dissolved in about 30 g of water, and reprecipitation was repeated using about 5 tons of methanol for this solution.

Next, the precipitate was dissolved in about 500 d of water and filtered through a dialysis membrane (tube size 30/32. Union Carbide
Corp.) for 2 days, and the dialyzed solution was freeze-dried to obtain 4.71 carboxymethyl dextran sodium salt.

Obtained carboxymethyl dextran sodium salt 4
00119 was dissolved in water 12-, and an aqueous solution of cysudinitratodiamine platinum (If) obtained in the same manner as in Reference Example 4 was added to this solution to prepare a system shielded from light.
The mixture was stirred overnight at room temperature. The reaction solution was filtered through a dialysis membrane (tube size 18/32.Union Carbide Corp.
Cis-nidorado and its aqua-type diammineplatinum(■)-calhoki/methyldextran complex 3709 were obtained by dialysis for 2 days using a dialysis solution (manufactured by , Co., Ltd.) and freeze-drying the dialyzed solution. The platinum content of this complex is 11.
It was 0% by weight.

Comparative Example 2 Dextran sulfate sodium salt (manufactured by Sigma, molecular weight approximately 5 Ooo) iooo II9 was dissolved in 40 aff of water, and the resulting solution was added with platinum (DACH) obtained in the same manner as in Reference Example 3. Add an aqueous solution of
Stir overnight at room temperature in a system protected from light.

The reaction solution was filtered through a dialysis membrane (tube size 30/32, Unio
11801q of cis-nidorado and its aqua form (DACH) platinum(n)-dextran sulfate complex were obtained by dialysis for one day using NCarbide Corp. and freeze-drying the non-dialysed solution. The platinum content of this composite is 8.8% by weight and the sulfur content is 13.0wt.
It was s.

When the thus obtained composite was stored at room temperature for a long time, it became a brown candy-like substance and lacked stability.

Comparative Example 3 Carboquine methylcellulose sodium salt was synthesized in a manner similar to that described on page 216 of Polymer Chemistry Experimental Methods (translated by Yoshio Iwakura, supervised by Asakura Shoten, published in 1962). That is, powdered cellulose 15. Of Improper Tools 40
0.0 g and stirred vigorously under nitrogen atmosphere, then 30 g.
An aqueous sodium hydroxide solution 502 was added over a period of 15 minutes, and the mixture was stirred for an additional 30 minutes. Add 17.5 y of monochloric acid to the reaction mixture and add 50 y of inpropanol.
The resulting solution was added over a period of 30 minutes and then stirred for 4 hours at a temperature of about 60°C.

The reaction mixture was neutralized with glacial acetic acid using phenolphthalein as an indicator, and then filtered. The solid product obtained was dispersed in 400 ml of 80% aqueous methanol at a temperature of about 60°C, then filtered off and washed with methanol containing a small amount of water. This operation of dispersion in water-containing methanol, filtration, and washing was repeated three times, finally washed with pure methanol, and then dried under reduced pressure at a temperature of about 50°C to obtain a powder of carboxymethyl cellulose sodium salt at 22°C. I got .8r.

The carboxymethylcellulose sodium salt powder iooowq thus obtained was dissolved in water 6014,
An aqueous solution of cis-dinitrato (DACH) platinum (n) obtained in the same manner as in Reference Example 3 was added dropwise to the resulting solution while stirring at room temperature, but the reaction solution completely gelled before the dropwise addition was completed. The desired water-soluble complex could not be obtained.

Furthermore, in the synthesis of carboxymethyl cellulose sodium salt described above, when the amount of monochloroacetic acid charged was halved to reduce the degree of substitution of the carboxyl methyl group, only about half of the resulting product was soluble in water. Ta.

Effects of the Invention The complex provided by the present invention is water-soluble and, as is clear from the results of the above tests, has excellent anti-cancer effects and low toxicity. Furthermore, an anticancer agent containing the complex as an active ingredient effectively exhibits the excellent anticancer effect of the complex.

[Brief explanation of the drawing]

1 to 6 show infrared absorption spectra (FT-IR) of the composites obtained in Examples 1 to 5 and 7, respectively. In these figures, the horizontal axis represents the wave number (1), and the vertical axis represents the transmittance (%). Patent applicant RiRa Shi Co., Ltd.

Claims (1)

[Claims] 1. The hydrogen atom of the hydroxyl group is partially represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, L^1 and L^ 2 each represents an ammine or a monodentate amine, or together represent a di-coordinated amine, Y represents an anionic ligand, and R represents a divalent hydrocarbon group) Dextran which is substituted and partially substituted with a group represented by the general formula -R-SO_3H (wherein R is as defined above) or a pharmacologically acceptable salt thereof. 2. The hydrogen atom of the hydroxyl group partially has the general formula -R-
SO_3H (In the formula, R represents a divalent hydrocarbon group) There are general formulas, chemical formulas, tables, etc. for dextran substituted with a group represented by the formula ▼ (In the formula, L^1 and L^2 each represents an ammine or a monodentate amine or together represent a bidentate amine; cis platinum (representing a sulfate ligand)
II) By reacting the complex, the hydrogen atoms of the hydroxyl group partially form the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, L^1, L ^2 and R are as defined above, and X^3 represents a nitrato-ligand or a hydroxo-ligand, or one of X^1 and X^2 is bound to activated dextran. (representing the resulting remaining sulfato ligand) and partially substituted with a group of the general formula -R-SO_3H (wherein R is as defined above) By obtaining dextran and/or its salt, and then optionally reacting the obtained dextran and/or its salt with a compound that generates an anion, the hydrogen atoms of the hydroxyl group partially form the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, L^1, L^2 and R are as defined above, and X^4 is an anionic ligand. Dextran and/or salts thereof, which are substituted with a group represented by the following formula and partially substituted with a group represented by the general formula -R-SO_3H (wherein R is as defined above) Characterized by the fact that the hydrogen atom of the hydroxyl group partially has the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, L^1, L^ 2 and R are as defined above, Y represents an anionic ligand) and partially substituted with a group represented by the general formula -R-SO_3H (wherein R is as defined above) ) A method for producing dextran and/or a pharmacologically acceptable salt thereof substituted with a group represented by the following. 3. The hydrogen atom of the hydroxyl group is partially represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, L^1 and L^2 are ammine or monodentate, respectively) represents a coordinating amine or together represent a bidentate amine, Y represents an anionic ligand, R represents a divalent hydrocarbon group), and An anticancer agent containing as an active ingredient dextran partially substituted with a group represented by the general formula -R-SO_3H (wherein R is as defined above) or a pharmacologically acceptable salt thereof.