TW201425278A - Platinum (IV) complexes and pharmaceutical composition containing the same - Google Patents

Abstract

The subject of the present invention is to provide a novel platinum (IV) complex characterized by having stronger antitumor activity against malignant tumors and relatively reduced side effects. The solving means is a platinum (IV) complex using cis, cis-spiro[4,4]nonane-1,6-diamine or an optical active diamine thereof as a ligand, particularly a tetravalent platinum dichloromalonate salt complex represented by the formula (G) using (S,S,S)-cis, cis-spiro[4,4]nonane-1,6 diamine as a ligand.

Description

Tetravalent platinum complex and pharmaceutical composition containing the same

The present invention relates to a novel tetravalent platinum complex and a pharmaceutical composition comprising the same as an active ingredient, particularly a therapeutic agent for malignant tumors.

In recent years, malignant tumors have been the leading cause of death, and various anti-tumor substances have been developed for this purpose. Among them, platinum complexes have been found to have anti-tumor effects, and Cisplatin [I], Carboplatin [II], Oxaliplatin [III], etc. have been developed and used for treatment. (For example, refer to Non-Patent Document 1 - Non-Patent Document 3). Further, the applicant of the present application has obtained a novel platinum complex which is a ligand of a spiro[4,4]decane-1,6-diamine as a platinum complex which is found to have an antitumor effect, and It is a registration of Japanese Patent No. 46644425 (Patent Document 1) which is a pharmaceutical composition of an active ingredient.

Prior technical literature Patent literature

Patent Document 1: Japanese Patent No. 4664424

Patent Document 2: US Patent 4,140,707 (February 20, 1979)

Non-patent literature

Non-Patent Document 1: Nature, 1969 222 385-386

Non-Patent Document 2: Cancer Treat Reviews 1985 12 21-33

Non-Patent Document 3: Cancer Letters 1985 27 135-143

However, cisplatin has the following problems: side effects such as nephrotoxicity, hematological toxicity, digestive organ toxicity, and neurotoxicity. Therefore, carboplatin has been developed as a kidney toxicity which reduces cisplatin and increases water solubility, but carboplatin is expensive and its antitumor effect is not necessarily satisfactory. These exhibit anti-tumor activity, and on the other hand, in order to make the specific anti-tumor activity work, it is necessary to give a predetermined amount corresponding to it, and thus there are disadvantages of side effects.

The object of the present invention is to provide a novel tetravalent platinum complex which is tetravalent with cis, cis-spiro[4,4]decane-1,6-diamine and its optically active diamine as a ligand. The platinum complex has a stronger antitumor activity, and the administration amount is a smaller amount, which is effective, and thus the side effects are relatively reduced.

In particular, a novel tetravalent platinum complex is provided which has the following characteristics: (S, S, S)-cis, cis-spiro[4,4]decane-1 represented by the following formula (G) , 6 diamine is a ligand of tetravalent platinum dichloromalonate complex (G), for malignant tumors, especially human lung cancer cells, human gastric cancer cells, human prostate cancer cells, human malignant melanoma cells, humans Bladder cancer cells, human lymphoma cells, and human leukemia cells have strong antitumor activity and relatively reduce side effects.

In order to achieve such a purpose, the malignant tumor agent of the present invention is a tetravalent platinum represented by the following formula: cis, cis-spiro[4,4]decane-1,6-diamine (A) as a ligand. Complex compound.

The present invention is characterized by its optically active substance (S, S, S)-cis, cis-spiro[4,4]decane-1,6-diamine (B) and (R,R,R)-cis, - Spiro[4,4]decane-1,6-diamine (C) is a tetravalent platinum complex of a ligand.

The present invention is a tetravalent platinum complex (D) represented by the following formula, wherein cis, cis-spiro[4,4]nonane-1,6-diamine (A) is a ligand.

In the formula, X and Y and Z are the same or different and each represents a halogen atom or a monovalent anion group containing an acetate group, or Y and Z together represent a divalent residue represented by the formula (b).

Wherein R represents a single bond or a linear or branched divalent hydrocarbon residue having 1 to 6 carbon atoms, and the hydrocarbon residue may have an unsaturated bond, and the hydrocarbon residue may also form a snail. Knot Structure.

The present invention is an optically active substance represented by the following three-dimensional structural formula, that is, (S, S, S)-cis, cis-spiro[4,4]nonane-1,6-diamine (B) is coordinated. a tetravalent platinum complex (E) and a tetravalent group with (R,R,R)-cis,cis-spiro[4,4]decane-1,6-diamine (C) as a ligand Platinum complex (F).

In the formula, X and Y and Z are the same or different and each represents a halogen atom or a monovalent anion group containing an acetate group, or Y and Z together represent a divalent residue represented by the formula (b).

Wherein R represents a single bond or a linear or branched divalent hydrocarbon residue having 1 to 6 carbon atoms, and the hydrocarbon residue may have an unsaturated bond, and the hydrocarbon residue may also form a snail. structure.

The present invention is a tetravalent platinum dichloropropyl group having a (S, S, S)-cis, cis-spiro[4,4]nonane-1,6-diamine as a ligand represented by the following formula (G). Diacid complex.

The present invention is a pharmaceutical composition containing the tetravalent platinum complex of the above formula as an active ingredient.

The present invention relates to a malignant tumor therapeutic agent containing the above-described tetravalent platinum complex of each formula as an active ingredient.

In order to achieve such a purpose, the present inventors have found that a novel platinum (II) complex represented by the following formula (a) with a spiro[4,4]nonane-1,6-diamine as a ligand A pharmaceutical composition containing the compound as an active ingredient is effective for the treatment of malignant tumors, and a patent application has been made (Japanese Patent Application No. 2008-225698).

In the above formula, X and Y are the same or different and each represents a halogen atom, or X and Y together represent a divalent residue represented by the formula (b).

Wherein R represents a single bond or a linear or branched divalent hydrocarbon residue having 1 to 6 carbon atoms, and the hydrocarbon residue may have an unsaturated bond, and the hydrocarbon residue may also form a snail. structure.

Further, it has been clarified that a platinum oxalate complex which is characterized by a cis, cis-spiro[4,4]decane-1,6-diamine as a ligand represented by the following formula (c) ( H) It has strong anti-tumor activity against malignant tumors, especially non-solid tumors such as human lymphoma cells, and relatively reduces side effects.

Cis, cis-spiro[4,4]decane-1,6-diamine has two stereostructures (ie (S, S, S) and (R, R, R)) are present in the form of racemates of the optically active substance. Further, the platinum complex of the optically active diamine was studied in advance of the invention, and a patent application (Japanese Patent Application No. 2009-155399) was obtained, and registration was obtained (Patent Document 1).

As long as the novel tetravalent platinum complex of the present invention is utilized, it can be used for malignant tumors, especially human lung cancer cells, human gastric cancer cells, human prostate cancer cells, human malignant melanoma cells, human bladder cancer cells, human lymphoma cells, A variety of malignant tumors such as human leukemia cells have strong antitumor activity, and the administration amount is smaller in comparison with the previous therapeutic agent for platinum complex malignant tumors, so that side effects are relatively reduced.

Hereinafter, embodiments of the tetravalent platinum complex of the present invention and a therapeutic agent for a malignant tumor comprising the same will be described.

About cis, cis-spiro[4,4]decane-1,6-diamine (A), and its optically active substance (S,S,S)-cis,cis-spiro[4,4]decane -1,6-diamine (B), (R,R,R)-cis,cis-spiro[4,4]decane-1,6-diamine (C), from these two-valent platinum The synthesis of the compounds (H), (I), and (J) has been described in the inventor's patent (Japanese Patent Application No. 2009-155399, International Patent Application No. PCT/JP2009/004077).

The tetravalent platinum complex (D), (E), (F) of the present invention can be applied by a known method, for example, J. Inorg. Biochem. 1996, 61, 291-301., J. Med. Chem. 1997, 40, 112- It is easily obtained by the method described in 116 (reaction formula (i) and reaction formula (ii)).

Although the present complex contains water as a complex, a hydrate is also included in the present invention.

It can be seen that the complex of the present invention can inhibit the proliferation of human lung cancer cells, human gastric cancer cells, human prostate cancer cells, human malignant melanoma cells, human bladder cancer cells, human lymphoma cells, and human leukemia cells at a low concentration, and shows Strong anti-tumor effect. It can be used as a therapeutic agent for malignant tumors.

When a therapeutic agent containing an effective amount of the platinum complex of the present invention is administered clinically, it can be administered by oral or parenteral administration. The dosage form comprises a tablet, a sugar-coated tablet, a pill, a capsule, a powder, a throat, a liquid, a suppository, an injection, and the like, which can be produced by blending an excipient which is pharmaceutically acceptable. As an excipient, the following can be illustrated. Lactose, sucrose, glucose, mountain Pearitol, mannitol, potato starch, amylopectin, various other starches, cellulose derivatives (such as carboxymethyl cellulose, hydroxyethyl cellulose, etc.), gelatin, calcium stearate, magnesium stearate , polyvinyl alcohol, polyethylene glycol wax, gum arabic, talc, titanium dioxide, olive oil, peanut oil, sesame oil and other vegetable oils, paraffin oil, neutral fat base, ethanol, propylene glycol, physiological saline, sterilizing water, glycerin, coloring agent , flavoring agents, thickeners, stabilizers, isotonic agents, buffers, etc., and other pharmaceutically acceptable excipients.

The therapeutic agent of the present invention may contain 0.001 to 85% by weight, preferably 0.005 to 60% by weight, of the platinum complex of the present invention.

The dose of the therapeutic agent of the present invention is mainly determined depending on the symptoms, but is 0.005 to 200 mg per adult body weight per day, preferably 0.01 to 50 mg.

The invention is more specifically illustrated by the following examples.

"Embodiment 1"

Pt(II)((S,S,S)-cis,cis-spiro[4,4]decane 1,6-diamine)malonate complex 0.49 was placed in a 50 ml round bottom flask. g, and adding 22 ml of distilled water and 5.4 ml of 30% hydrogen peroxide water, and heating and stirring at 70 ° C for 2 hours. It was cooled to room temperature and further stirred for 24 hours. The brucite is filtered and washed with water. After the filtrate was concentrated, acetone (200 ml) was added and allowed to stand, and the precipitated solid was filtered, washed with acetone, and dried. It is washed with water, followed by ethanol and further diethyl ether, and dried. 0.48 g of a dihydroxylate of Pt(IV)((S,S,S)-cis,cis-spiro[4,4]decane 1,6-diamine)malonate was obtained. The yield was 93.6%.

0.52 g of this Pt(IV) compound was placed in a 200 ml round bottom flask, to which 98 ml of 0.02 N hydrochloric acid was added and stirred in the dark for 4 days. The brucite is filtered, washed with water and methanol, and the solvent is distilled off.

The residue was dissolved in methanol, and the brucite was filtered again, and methanol was distilled off and dried. Pt(IV) ((S, S, S)-cis, cis-spiro[4,4]decane 1,6-diamine) malonate dichloride (G) 0.33 g was obtained.

The yield was 59.4%.

Elemental analysis values were analyzed for C, H, N, Cl, Pt with C ₁₂ H ₂₀ N ₂ O ₄ Cl ₂ Pt

Calculated values (%) 27.60, 3.86, 5.36, 13.58, 37.4; measured values (%) 26.95, 3.92, 5.16, 13.11, 36.7; IR (KBr): 3177 (NH), 1645 (C=0), 1371 (C) -0)cm ^-1

MS (ESI) m/z 521

From the above results, it was confirmed that the present compound has the chemical structure represented by (Compound 1).

<<Example 2》

Pt(II)((R,R,R)-cis,cis-spiro[4,4]decane 1,6-diamine)malonate complex 1.23 was placed in a 50 ml round bottom flask. g, and adding 18 ml of distilled water and 4.4 ml of 30% hydrogen peroxide water, and heating and stirring at 70 ° C for 2 hours. It was cooled to room temperature and further stirred for 24 hours. The brucite is filtered and washed with water. After concentrating the filtrate, acetone (200 ml) was added and allowed to stand, and the precipitated solid was filtered, washed with acetone and dried. 1.12 g of a dihydroxylate of Pt(IV)((R,R,R)-cis,cis-spiro[4,4]decane 1,6-diamine)malonate was obtained. The yield was 90.0%.

1.04 g of this Pt(IV) compound was placed in a 300 ml round bottom flask, to which 204 ml of 0.02 N hydrochloric acid was added and stirred in the dark for 4 days. The brucite is filtered, washed with water and methanol, and the solvent is distilled off.

The residue was dissolved in methanol, and the brucite was filtered again, and methanol was distilled off and dried. Obtaining optical isomers of Pt(IV)((R,R,R)-cis,cis-spiro[4,4]decane 1,6-diamine)malonate dichloride (G) 0.84 g. The yield was 74.8%.

The results of the IR measurement were consistent with the tetravalent platinum complex of Example 1, and were confirmed as (Compound 2).

Example 3

Pt(II)((S,S,S)-cis,cis-spiro[4,4]decane 1,6-diamine) oxalate complex 1.07 g was placed in a 50 ml round bottom flask. And adding 50 ml of distilled water and 12.4 ml of 30% hydrogen peroxide water, and heating and stirring at 70 ° C for 2 hours. Cool to room temperature and stir for 2 days. The brucite is filtered and washed with water. After concentrating the filtrate, acetone (200 ml) was added and allowed to stand, and the precipitated solid was filtered, washed with acetone and dried. It is dried by washing with water, followed by ethanol and diethyl ether. A 1.15 g of a dihydroxylate of Pt(IV)((S,S,S)-cis,cis-spiro[4,4]decane 1,6-diamine) oxalate was obtained. The yield was 99.6%.

0.88 g of this Pt(IV) compound was placed in a 300 ml round bottom flask, and 165 ml of distilled water and 2.85 ml of 1.2 N hydrochloric acid were added thereto, and stirred in the dark for 3 days. The brucite is filtered, washed with water and methanol, and the solvent is distilled off.

The residue was dissolved in methanol, and the brucite was filtered again, and methanol was distilled off and dried. 0.79 g of Pt(IV)((S,S,S)-cis,cis-spiro[4,4]decane 1,6-diamine) oxalate dichloride was obtained. The yield was 83.1%.

Elemental analysis values were analyzed for C, H, N, Cl, Pt with C ₁₁ H ₁₈ N ₂ O ₄ Cl ₂ Pt

Calculated values (%) 25.99, 3.57, 5.51, 13.95, 38.4; measured values (%) 25.55, 3.65, 5.26, 13.35, 37.9; IR (KBr): 3175 (NH), 1715 (C=0), 1357 (C) -0)cm ^-1

MS (ESI) m/z 507

From the results, it was confirmed that the present compound has the chemical structure represented by (Compound 3).

Example 4

Pt(II)((R,R,R)-cis,cis-spiro[4,4]decane 1,6-diamine) oxalate complex 1.06 g was placed in a 50 ml round bottom flask. And adding 49 ml of distilled water and 12.8 ml of 30% hydrogen peroxide water, and heating and stirring at 70 ° C for 2 hours. Cool to room temperature and stir for 3 days. The brucite is filtered and washed with water. After concentrating the filtrate, acetone (250 ml) was added and allowed to stand, and the precipitated solid was filtered, washed with acetone and dried. 1.11 g of a dihydroxylate of Pt(IV)((R,R,R)-cis,cis-spiro[4,4]decane 1,6-diamine) oxalate was obtained. The yield was 97.3%.

0.92 g of this Pt(IV) compound was placed in a 300 ml round bottom flask, and 190 ml of distilled water, 3.3 ml of 1.2 N hydrochloric acid was added thereto, and stirred in the dark for 3 days. The brucite is filtered, washed with water and methanol, and the solvent is distilled off.

The residue was dissolved in methanol, and the brucite was filtered again, and methanol was distilled off and dried. 0.92 g of Pt(IV)((R,R,R)-cis,cis-spiro[4,4]decane 1,6-diamine) oxalate dichloride was obtained. The yield was 92.4%.

The result of the IR measurement was identical to that of the tetravalent platinum complex of Example 3, and was confirmed to be (Compound 4).

"Embodiment 5"

In a 100 ml round bottom flask, 0.49 g of potassium hexachloroplatinate (IV), 0.24 g of sodium chloride, and 60 ml of distilled water were placed and dissolved. Add (S,S,S)-cis,cis-spiro[4,4]decane-1,6 to the solution. A 10 ml solution of diamine 0.16 g in water. Gradually turbid and precipitated solids. Stir in the dark for 24 hours. It is filtered, washed with water, and dried. Pt(IV)((S,S,S)-cis,cis-spiro[4,4]decane-1,6-diamine) tetrachloride 0.22 g was obtained. The yield was 43.6%.

Elemental analysis values were analyzed for C, H, N, Cl, Pt with C ₉ H ₁₈ N ₂ Cl ₄ Pt

Calculated values (%) 22.01, 3.69, 5.70, 28.87, 39.7; measured values (%) 21.54, 3.58, 5.36, 24.88, 39.2; IR (KBr): 3227 (NH) cm ^-1

MS (ESI) m/z 490

From the results, it was confirmed that the present compound has the chemical structure represented by (Compound 5).

"Embodiment 6"

In the same manner as in Example 5, Pt was obtained from potassium hexachloroplatinate (IV) and (R, R, R)-cis, cis-spiro[4,4]nonane-1,6-diamine 0.16 g. IV) ((R,R,R)-cis,cis-spiro[4,4]decane-1,6-diamine) tetrachloride 0.27 g. The yield was 55.0%.

The results of the IR measurement were identical to those of the tetravalent platinum complex of Example 5, and were confirmed to be (Compound 6).

"Example 7" agent effect test

The test solution was prepared by dissolving (Compound 1) in DMSO (dimethyl sulfoxide) at a concentration of 8 mg/ml.

The test used human lung cancer cells (LU99) and two human gastric cancer cells (KATO). III, MKN-45), human prostate cancer cells (DU145), human malignant melanoma cells (G-361), human bladder cancer cells (T24), two human lymphoma cells (U937, Jurkat E6.1), human Leukemia cells (HL60) are carried out as cancer cells.

The cells were suspended in each medium supplemented with 10% serum and dispensed into 96-well plates. Thereafter, it was cultured overnight at 37 ° C, 5% CO ₂ . The test solution was prepared into various concentrations using a medium, and dispensed into a disk in which cells were seeded in advance. Further, it was cultured for 3 days at 37 ° C in 5% CO ₂ .

The proliferation of the cells after the addition of the drug was measured by the MTS method (Cell Titer 96 Aqueous One Solution Cell Proliferation Assay manufactured by Promega) from the first day to the third day after the administration of the drug.

The inhibition rate (%) of cell proliferation was determined from the measured MTS value by the following formula.

Obstruction rate (%) = (1 - MTS value of the drug addition group / drug not added group MTS value) × 100

The value obtained by the above formula indicates the cell proliferation inhibition rate, and therefore the higher the value, the higher the drug effect. The value of 50 (%) or more is used as a pharmaceutical effect. The results of the cell types with higher effects are shown below.

Compared with Oseliplatin, which has been used as an anticancer agent from the past, it has been confirmed to have a strong effect on human lymphoma cells and human leukemia cells. In particular the amount of cells at low concentrations (5 μ g / ml) higher impede proliferation rate, i.e. less than Orsay force has the effect of platinum.

"Example 8" agent effect test

(Compound 2) was prepared as a test solution, and the cell proliferation inhibition rate was measured by the same method as in Example 7. The results of the cell types with higher effects are shown below.

Compared with Oseliplatin, which has been an anticancer agent since the past, it has been confirmed to have potent effects on human gastric cancer cells, human bladder cancer cells, and human lymphoma cells. In particular, the low cell concentration (5 and 10 μg/ml) has a high cell proliferation inhibition rate, and the effect is less than the amount of Osliplatin.

"Example 9" drug effect test

(Compound 5) was prepared as a test solution, and the cell proliferation inhibition rate was measured by the same method as in Example 7. The results of the cell types with higher effects are shown below.

[table 3]

Compared with Oseliplatin, which has been used as an anticancer agent, it has been confirmed to have potent effects on human lung cancer cells, human gastric cancer cells, human malignant melanoma cells, and human bladder cancer cells. In particular, the low cell concentration (5 and 10 μg/ml) has a high cell proliferation inhibition rate, and the effect is less than the amount of Osliplatin.

"Example 10" agent effect test

(Compound 6) was prepared as a test solution, and the cell proliferation inhibition rate was measured by the same method as in Example 7. The results of the cell types with higher effects are shown below.

Compared with Oseliplatin, which has been used as an anticancer agent from the past, it has been confirmed to have a strong pharmacological effect on human lung cancer cells, human malignant melanoma cells, and human bladder cancer cells. In particular, the low cell concentration (5 and 10 μg/ml) has a high cell proliferation inhibition rate, and the effect is less than the amount of Osliplatin.

Above, according to the results of Embodiments 7 to 10, as long as the novel four of the present invention is utilized The valence platinum complex can be highly resistant to various malignant tumors such as human lung cancer cells, human gastric cancer cells, human prostate cancer cells, human malignant melanoma cells, human bladder cancer cells, human lymphoma cells, and human leukemia cells. Tumor activity, compared with the previous platinum complex tumor malignant therapeutic agent, is less effective in administering the amount, and thus relatively reduces side effects.

[Industrial availability]

As described above, the platinum complex of the present invention has strong antitumor activity and can be used as a therapeutic agent for malignant tumors.

Claims (8)

A tetravalent platinum complex having a cis, cis-spiro[4,4]decane-1,6-diamine (A) as a ligand, represented by the following structural formula, As the tetravalent platinum complex of claim 1 of the patent range, the optically active substance represented by the stereo structure of the following formula is (S, S, S)-cis, cis-spiro[4,4]decane-1. , 6-diamine (B) and (R, R, R)-cis, cis-spiro[4,4]nonane-1,6-diamine (C) are ligands, A tetravalent platinum complex as claimed in claim 1 which is a cis, cis-spiro[4,4]nonane-1,6-diamine (A) represented by the following formula (D). a tetravalent platinum complex which is a ligand, (wherein X and Y and Z are the same or different and each represents a halogen atom or a monovalent anion group containing an acetate group, or Y and Z together represent a divalent residue represented by the formula (b)) (wherein R represents a single bond or a linear or branched divalent hydrocarbon residue having 1 to 6 carbon atoms, and the hydrocarbon residue may have an unsaturated bond, and the hydrocarbon residue may also be formed. Snail structure). For example, the tetravalent platinum complex according to item 2 of the patent application is an optically active substance represented by the following three-dimensional structural formulas (E) and (F), that is, (S, S, S)-cis, cis- Tetravalent platinum complex of spiro[4,4]decane-1,6-diamine (B) as a ligand and (R,R,R)-cis,cis-spiro[4,4]壬a tetravalent platinum complex of alkane-1,6-diamine (C) as a ligand, (wherein X and Y and Z are the same or different and each represents a halogen atom or a monovalent anion group containing an acetate group, or Y and Z together represent a divalent residue represented by the formula (b)) (wherein R represents a single bond or a linear or branched divalent hydrocarbon residue having 1 to 6 carbon atoms, and the hydrocarbon residue may have an unsaturated bond, and the hydrocarbon residue may also be formed. Snail structure). A tetravalent platinum complex according to claim 3 or 4, wherein X is a chlorine atom. The tetravalent platinum complex according to any one of claims 1 to 4, which is represented by the following formula (G) as (S, S, S)-cis, cis-spiro [4, 4] a tetravalent platinum dichloromalonate complex in which decane-1,6-diamine is a ligand and X is a chlorine atom. A pharmaceutical composition comprising the tetravalent platinum complex of any one of claims 1 to 6 as an active ingredient. A therapeutic agent for malignant tumors comprising the tetravalent platinum complex of any one of claims 1 to 6 as an active ingredient.