JP2737240B2 - Novel platinum complex and tumor therapeutic composition - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel platinum complex and a tumor therapeutic composition containing the same as an active ingredient.

[Related Art] In recent years, tumor chemotherapy has made remarkable progress by applying cisdiamminedichloroplatinum (II) (hereinafter abbreviated as CDDP). That is, CDDP showed a remarkable effect on genital cancers such as ovarian cancer and testicular cancer, which had been difficult to treat with chemotherapeutic agents until then. However, CDDP has serious side effects such as nephrotoxicity and bone marrow toxicity, which is a problem in clinical effects.

On the other hand, various studies have been carried out to improve nephrotoxicity, which is a limiting factor (DLF).
Second-generation platinum complexes such as diammine-1,1-cyclobutanedicarboxylate platinum (II) (hereinafter abbreviated as CBDCA) and cis-diammine-0,0'-glycolate platinum (II) have been developed. JP-A-56-154493, etc.).

[Problems to be Solved by the Invention] However, although these compounds have weak nephrotoxicity, their antitumor activity is not as high as CDDP. Therefore, development of a platinum complex having a strong antitumor effect and a low toxicity has been desired.

An object of the present invention is to provide a novel platinum (II) complex which has both strong antitumor activity and low toxicity, and further provides a tumor therapeutic agent which satisfies both conditions. It is in.

[Means for Solving the Problems] The above object is achieved by the present invention described below. That is, the present invention provides a novel platinum complex represented by the following general formula (I) and a tumor therapeutic agent composition containing the platinum complex as an active ingredient.

[Wherein, R ¹ represents a hydrogen atom or an alkyl group having 4 or less carbon atoms, and R ² represents a hydrocarbon group having 18 or less carbon atoms, or a group having 3 to 10 carbon atoms to which a carboxyl group or a salt thereof is bonded. ), The configuration of 1,2-diaminocyclohexane is cis-, trans-l- or trans-d-
The hydrocarbon group having 18 or less carbon atoms is an alkyl group, an alkenyl group, a cycloalkyl group, an aryl group and the like, and specifically, for example, methyl, ethyl, propyl, butyl,
Pentyl, hexyl, And the like, but are not limited thereto.

R ¹ includes a hydrogen atom, a methyl group, an ethyl group and the like.

R ¹ is bonded to R ² to form — (CH ₂ ) ₄ — and — (CH ₂ ) ₅
A group may be formed;

Further, the group having 3 to 10 carbon atoms to which a carboxyl group or a salt thereof is bonded is a group in which a carboxyl group or a salt thereof is bonded to an alkyl group, an alkenyl group, a cycloalkyl group, an aryl group, and the like. Is, for example, And the like.

Examples of the salt of the carboxyl group include a sodium salt, a potassium salt, an N-methylglucamine salt, an ammonium salt and the like.

Compound (I) of the present invention comprises 1,2-diaminocyclohexane and the following general formula (III) [Wherein, R ¹ and R ² are the same as those described above].

The α, γ-dioxocarboxylic acid of the general formula (III) is in equilibrium with the tautomeric enol form (V) as shown in the following formula: [R ¹ and R ² in the formula (V) are the same as described above] The complex of the present invention is a compound in which two acidic protons are removed from the enolized form (V) and coordinated to divalent platinum. It is.

The compound (I) of the present invention is represented by the following reaction formulas (1) and (2)
Can be obtained by

[X in the above formula (IV) represents NO ₃ or 1 / 2SO ₄ ] As the alkali, caustic soda, caustic potash, sodium carbonate, sodium hydrogen carbonate and the like are preferably used.

The reaction of (1) and (2) can be carried out by stirring at 0 to 80 ° C, preferably 0 ° C to room temperature in an aqueous solution or a mixed solvent of an aqueous solution and a water-soluble solvent (such as methanol, ethanol, and tetrahydrofuran) for 1 to 24 hours Good.

The α, γ-diketocarboxylic acid of the formula (III) is generally used in an amount of 0.5 to 2 mol, preferably equimolar, based on the platinum complex raw material.

The compound (I) of the present invention obtained by reacting in an aqueous solution or a water-containing solvent may be an aquo complex coordinated with water, and the aquo complex is also included in the compound of the present invention.

Among the complexes of the present invention, the complex in which R ^{2 of} the ligand is a hydrocarbon group to which a carboxyl group is bonded and the carboxyl group is a salt is a complex in which R ² corresponds to a hydrocarbon group to which a carboxyl group is bonded. It can be obtained in good yield by reacting with a base in a methanol solvent.

The platinum compound of the general formula (IV), which is a raw material for synthesizing the platinum complex of the present invention, can be prepared by a known method, for example, Journal of Pharmaceuticals.
It can be easily obtained by applying silver nitrate or silver sulfate to a compound represented by the following formula (VI) by applying the method described in tical Science, 65 , 315 (1976).

[Wherein Hal represents a halogen] The compound of the formula (VI) has (cis-dach) PtHa according to the stereostructure of 1,2-diaminocyclohexane used.
l ₂ , (trans-l-dach) PtHal ₂ , (trans-d-
dach) There are three isomers of PtHal ₂ (dach is 1,2-
Diaminocyclohexane).

The platinum compound of the formula (II) Can be obtained by a known method in which an aqueous solution of is passed through a strong ion exchange resin.

Α, γ-dioxocarboxylic acid [compound (III)], which is another raw material of the platinum complex of the present invention, is synthesized by a general reaction represented by the following formula.

[In the above formula, R ¹ and R ² are the same as above.] When a therapeutic agent containing an effective amount of the platinum complex of the present invention is clinically administered, it is administered by an oral or parenteral route. Its dosage forms include tablets, dragees, pills, capsules, powders, troches, solutions, suppositories, injections, etc., which are prepared by incorporating a pharmaceutically acceptable excipient. Is done.

The following can be exemplified as the excipient. Lactose, sucrose, glucose, sorbitol, mannitol, potato starch, amylopectin, other various starches, cellulose derivatives (eg, carboxymethyl cellulose, hydroxyethyl cellulose, etc.), gelatin, magnesium stearate, polyvinyl alcohol, calcium stearate, polyethylene glycol wax Vegetable oils such as gum arabic, talc, titanium dioxide, olive oil, peanut oil, gum oil, paraffin oil, neutral fat base, ethanol, propylene glycol, saline, sterile water, glycerin, coloring agents, seasonings, and thickeners Agents, stabilizers, isotonic agents, buffering agents, etc.
And other pharmaceutically acceptable excipients.

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

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

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples.

Reference Example 1 Synthesis of ethyl 4-acetylphenoxyacetic acid 3.24 g of sodium hydride (oily, content 60%) was added to 60 ml of dimethylformamide, and the mixture was cooled with ice.

10.0 g (73.4 mmol) of p-hydroxyacetophenone are added in small portions, and then the mixture is returned to room temperature and stirred. 9.0 ml (80.7 mmol) of ethyl bromoacetate is slowly added dropwise, and the mixture is heated at 80 ° C. for 2 hours.

Neutralize the reaction solvent with dilute hydrochloric acid and extract with ethyl acetate.
The organic layer is washed with water and saturated saline and dried over anhydrous magnesium sulfate.

The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 15.36 g (94% yield) of a colorless oil. ¹ H-NMR (90 MHz, CDCl ₃ ) ppm: 7.94 (d, J = 8.9 Hz, 2H), 6.94 (d, J = 9 Hz, 2H), 4.68
(S, H), 4.27 (q, J = 7.4Hz, 2H), 2.55 (S, 3H), 1.29
(T, J = 6.9 Hz, 3H) Reference Example 2 4- (3-carbomethoxy-1,3-dioxopropyl)
Synthesis of methyl phenoxyacetic acid 13.4 g of sodium methoxide in 240 ml of anhydrous methanol
(0.248 mol) and stir at room temperature.

36.9 g (0.166 mmol) of 4-acetylphenoxyacetic acid ethyl ester and dimethyl oxalate 23.5
g (0.199 mmol) is added slowly, and the mixture is directly heated at 60 ° C. for 3.5 hours, and then stirred at room temperature for 10 hours.

The methanol is distilled off under reduced pressure, diluted hydrochloric acid is added, and the aqueous layer is extracted with ethyl acetate. The organic layer is washed with water and saturated saline and dried over anhydrous magnesium sulfate.

After concentration of the solvent, the crude product is recrystallized from benzene.
33.3 g (68% yield) of pale yellow needles were obtained.

Melting point: 117.8-118.4 ° C IR (KBr disc) cm ^-1 : 2950, 1755, 1730, 1600, 1260, 1168, 1110, 1081, 84
0, 778 ¹ H-NMR (90 MHz, CDCl ₃ ) ppm: 15.33 (brs, 1H), 8.00 (d, J = 9 Hz, 2H), 7.03 (S, 1
H), 6.98 (d, J = 9HZ, 2H), 4.73 (S, 2H), 3.94 (S, 3
H), 3.83 (S, 3H) Reference Example 3 Synthesis of 4- (3-carboxy-1,3-dioxopropyl) phenoxyacetic acid 4- (3-carbomethoxy-1,3-dioxopropyl) phenoxyacetic Acid methyl ester 821m
g is added to 50 ml of methanol and stirred at room temperature. This is 1N
-Add 12 ml of aqueous sodium hydroxide solution and stir for 3 hours.

The resulting insolubles were separated and washed with methanol. The insolubles were added to 20 ml of water, and 12 ml of 1N hydrochloric acid was further added.

Extract with ethyl acetate and wash the organic layer 5 times with water. After drying over anhydrous sodium sulfate, the solvent was concentrated to dryness and washed with benzene to obtain 646 mg (87.0% yield) of pale yellow crystals.

Melting point: 178.0-179.7 ℃ (decomposition) Colored at 120 ℃ IR (KBr disc) cm ^-1 : 3530, 2920, 2780, 2580, 1733, 1598, 1245, 1178, 11
13, 822, 778 ¹ H-NMR (90 MHz, CD ₃ OD) ppm: 8.03 (d, J = 9.3 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H), 4.79
(S, 2H) Example 1 810 mg (6.2 mmol) of 2,4-dioxopentanoic acid was dissolved in 50 ml of tetrahydrofuran, and 523 mg of sodium hydrogen carbonate was dissolved.
(6.2 mmol) and cooled on ice.

To this, 81 ml of an aqueous solution containing 2.69 g (6.2 mmol) of dinitrat (trans-1-1,2-diaminocyclohexane) platinum (II) is slowly dropped, and after dropping, the mixture is returned to room temperature and stirred for 12 hours.

The solvent is distilled off and methanol is added to separate insolubles. After the solution was distilled off under reduced pressure, the solution was reprecipitated with ethanol-ethyl acetate, and the precipitate was washed with tetrahydrofuran. The precipitate is dissolved in a mixed solvent of methanol and water, and methanol is distilled off under reduced pressure. The resulting precipitate was collected and dried under reduced pressure to obtain 1.5 g of a pale yellow solid (yield 53%).

Mp: 230.0 to 231.8 ° C. ^{(decomposition) IR (KBr disc) cm -1} : 3430,3200,2940,1565,1380,1165 1 H-NMR (400MHz, D 2 O) ppm: 6.30 (1H, S), 5.82 (2H, dd, J = 9.2,35.2Hz), 2.52 (2
H, m), 2.04 (2H, d, J = 12.2Hz), 1.93 (3H, S), 1.56
(2H, m), 1.33 (2H, m), 1.15 (2H, m) Example 2 688 mg (4.4 mmol) of 2,4-dioxoheptanoic acid was dissolved in 56 ml of tetrahydrofuran, and 365 mg of sodium hydrogen carbonate was dissolved.
(4.4 mmol) and cooled on ice.

56 ml of an aqueous solution containing 1.82 g of dinitrat (trans-1-diaminocyclohexane) platinum (II) is slowly added dropwise thereto. After the addition, the mixture is returned to room temperature and stirred for 12 hours.

By treating in the same manner as in Example 1, the desired product was obtained as 1.17 g (55% yield) of a pale yellow solid.

Melting point: 230.8-233.9 ° C (decomposition) IR (KBr disc) cm ^-1 : 3400, 3180, 3050, 2930, 1620, 1545, 1505, 1380, 10
60, 800 ¹ H-NMR (400 MHz, D ₂ O) ppm: 6.27 (1 H, S), 5.83 (2 H, dd, J = 9.2, 36 Hz), 5.27 (2H,
brs), 2.53 (2H, m), 2.21 (2H, t, J = 7.2Hz), 2.04
(2H, brd, J = 11.6Hz), 1.56 (4H, m), 1.32 (2H, m),
1.14 (2H, m), 0.86 (3H, t, J = 7.3Hz) Example 3 950 mg (4.43 mmol) of ethyl 2,4-dioxodecanoate is dissolved in 70 ml of tetrahydrofuran and cooled with ice.

An aqueous solution containing dihydroxy (trans-1-diaminocyclohexane) platinum (II) (concentration 6.72 × 10 ⁻² mm
ol / ml) 60 ml (4.03 mmol) was added dropwise and stirred for 12 hours.

The tetrahydrofuran is distilled off under reduced pressure, and the aqueous layer is washed with ethyl acetate. The aqueous layer is concentrated to about 10 ml and cooled on ice. The resulting precipitate is removed, washed once with ice water, and dried under reduced pressure. 1.00 g (49% yield) of a pale yellow solid was obtained.

Melting point: 229.1-238.0 ° C. (decomposition) ¹ H-NMR (400 MHz, CD ₃ OD) ppm: 6.21 (1 H, S), 2.44 (2 H, m), 2.20 (2 H, t, J = 8.0 H)
z), 2.03 (2H, m), 1.58 (4H, m), 1.32 (10H, m), 0.
89 (3H, t, J = 7.0Hz) IR (KBr disc) cm ^-1 : 2936, 1620, 1560, 1320 Example 4 513 mg of 2,4-dioxooctanedicarboxylic acid (2.54 mmo
l) is dissolved in 38 ml of tetrahydrofuran and cooled with ice.

An aqueous solution containing dihydroxy (trans-1-diaminocyclohexane) platinum (II) (concentration 6.72 × 10 ⁻² mm
ol / ml) 38 ml (2.55 mmol) is slowly added dropwise.
Return to room temperature and stir for 12 hours.

The solvent is distilled off under reduced pressure, and the residue is reprecipitated with methanol-ethyl acetate. Further, the precipitate was reprecipitated from water-acetone to obtain 1.43 mg (yield: 48%) of the desired product as a pale yellow solid.

mp: 238.5-246.8 ℃ (decomposition, coloring at 220 ℃) IR (KBr disc) cm ^-1 : 3492, 2944, 1709, 1620, 1535, 1431, 1336, 1220, 10
38 Example 5 8.18 g (30.7 mmol) of 4- (3-carboxy-1,3-dioxopropyl) phenoxyacetic acid and sodium hydrogen carbonate
2.58 g (30.7 mmol) in tetrahydrofuran-water (10: 1) 4
Add to 40 ml and cool on ice.

To this, 400 ml of an aqueous solution containing 13.29 g (30.7 mmol) of dinitrat (trans-1-1,2-diaminocyclohexane) platinum (II) is added dropwise over 1.5 hours. Immediately after the dropwise addition, the temperature is returned to room temperature and stirred for 12 hours.

The tetrahydrofuran is distilled off under reduced pressure, and the precipitated yellow solid is separated and washed with water. 400 ml of methanol in the precipitate
After removing insolubles, the solution is concentrated to about 50 ml and reprecipitated by adding ethyl acetate. The precipitate was washed with tetrahydrofuran and dried to obtain 9.20 g (yield 51%) of the desired complex.

Melting point: 229.2-249.2 ℃ (decomposes, colored at 190 ℃) IR (KBr, disc) cm ^-1 : 3400, 3200, 2930, 1600, 1579, 1538, 1498, 1380, 12
^{50,1225,1177,1060 1 H-NMR (400MHz,} CD 3 OD) ppm: 7.94 (2H, d, J = 9.3Hz), 6.96 (2H, d, J = 9.3Hz), 6.94
(1H, S), 6.33 (1H, brd), 6.05 (1H, brd), 5.71 (2
H, brddt), 2.50 (2H, m), 2.10 (2H, m), 1.65 (2H, br
d), 1.41 (2H, m), 1.25 (2H, m) 615 mg of the platinum complex compound obtained in Example 5 (1.04 mmo
l) is dissolved in 60 ml of methanol, and 56 mg (1.04 mmol) of sodium methoxide is added thereto, followed by stirring at room temperature for 30 minutes.

The solvent is concentrated to 10 ml, and tetrahydrofuran is added for precipitation. Separate the precipitate and wash with tetrahydrofuran. After drying, 606 mg (95% yield) of pale yellow crystals were obtained.

Melting point: 261.0-266.2 ° C (decomposed, colored at 230 ° C) IR (KBr disc) cm ^-1 : 3410, 3160, 2940, 1610, 1543, 1500, 1420, 1360, 12
45, 1185, 1050, 840, 800 ¹ H-NMR (400 MHz, D ₂ O) ppm: 7.81 (2H, d, J = 8.9 Hz), 6.91 (2H, d, J = 8.9 Hz), 6.87
(1H, S), 5.76 (2H, dd, J = 68.7,8), 5.09 (2H, m),
4.54 (2H,) S, 2.51 (2H, brs), 2.08 (2H, brs), 1.6
1 (2H, m), 1.34 (2H, m), 1.23 (2H, m) Example 7 295 mg (0.5 mmol) of the platinum complex compound obtained in Example 5
Was dissolved in methanol in 20 ml, and N-methyl-D-
Add 97 mg (0.5 mmol) of glucamine and stir at room temperature for 30 minutes.

The solvent is concentrated to 5 ml, and tetrahydrofuran is added for precipitation. Separate the precipitate and wash with tetrahydrofuran. After drying, 360 mg (92% yield) of pale yellow crystals were obtained.

Melting point: 165.4-193.1 ° C. (decomposition) ¹ H-NMR (400 MHz, D ₂ O) ppm: 7.79 (2H, d, J = 8.9 Hz), 6.87 (2H, d, J = 8.9 Hz), 6.84
(1H, S), 5.76 (2H, dd, J = 70.2,8.0Hz), 5.10 (2H,
m), 4.48 (2H, S) IR (KBr disc) cm ^-1 : 3060, 1547, 1386, 1249 Example 8 1.33 g (5.0 mmol) of 3- (3-carboxy-1,3-dioxopropyl) phenoxyacetic acid was added to tetrahydrofuran 70
Dissolve in ml and cool on ice.

To this, 74 ml of an aqueous solution containing 1.71 g (5.0 mmol) of dihydroxy (trans-1-diaminohexane) platinum (II) is added dropwise, followed by stirring at room temperature for 12 hours.

The solvent is distilled off, and the residue is dissolved in methanol to separate insolubles. After concentrating the liquid to dryness, the residue was treated with methanol-
Reprecipitate with ethyl acetate and wash the precipitate with tetrahydrofuran. After drying, 1.18 g (40% yield) of a pale yellow complex was obtained.

Melting point: 231.7-246.2 ° C (decomposition) IR (KBr disc) cm ^-1 : 2936, 1620, 1560, 1510, 1342 Example 9 Dissolve 851 mg (5.0 mmol) of 4- (1-methylcyclopropyl) -2,4-dioxobutanoic acid in 60 ml of methanol,
840 ml (10.0 mmol) of sodium hydrogen carbonate are added, and the mixture is cooled with ice.

An aqueous solution (59 ml) containing 2.15 g (5.0 mmol) of dinitrat (trans-1-1,2-diaminocyclohexane) platinum (II) is slowly added dropwise thereto, and then the mixture is returned to room temperature and stirred for 12 hours.

The solvent is distilled off and methanol is added to separate insolubles. The solution is concentrated, the residue is reprecipitated with methanol-ethyl acetate, and the precipitate is washed with ice water. After drying, pale yellow crystals were obtained. Yield 1.40 g (56.5%).

Melting point: 249.8-257.1 ° C (decomposition) IR (KBr disc) cm ^-1 : 3400, 3170, 3080, 2940, 1620, 1545, 1510, 1350, 11
60, 810 ¹ H-NMR (400 MHz, D ₂ O) ppm: 6.30 (1 H, S), 2.50 (2 H, m), 2.06 (2 H, m), 1.58 (2
H, m), 1.31 (3H, S), 1.31 (2H, m), 1.25 (2H, m),
1.16 (2H, m), 0.82 (2H, m) Example 10 In this example, the antitumor activity of the compound of the present invention was previously known.
Shown in comparison with CDDP or CBDCA.

CDF ₁ mouse (male, 6 weeks old, using 6 to 10 mice per group) L1210 1 mouse leukemia cell passaged intraperitoneally with DBA / 2 mouse
× 10 ⁵ were transplanted. The first day, 5
The test drug was administered intraperitoneally a total of three times on days 9 and. Each drug was used after being dissolved or suspended in a 0.05% “Tween 80” solution. Determination of the antitumor effect of the platinum complex on L1210-transplanted mice was determined by the following formula, T / C value and 3
Performed by the number of surviving mice on day 0.

The results are shown in Tables 1 to 5.

Example 11 In this example, the antitumor activity of the compound of the present invention was determined by a known method.
Shown in comparison with CDDP or CBDCA.

CDF ₁ mouse (male, 6 weeks old, using 6 to 10 mice per group) L1210 1 mouse leukemia cell passaged intraperitoneally with DBA / 2 mouse
× 10 ⁵ were transplanted. The test drug was intraperitoneally administered five times in total on day 1, day 2, day 3, day 4, and day 5, with the transplantation day as day 0. Each drug was used after being dissolved in a 0.05% “Tween 80” solution. The antitumor effect of the platinum complex on the L1210-transplanted mouse was determined in the same manner as in Example 10.

 The results are shown in Table-6.

Example 12 An acute toxicity test was performed on a compound of the present invention using CDDP in mice. Slc: ICR mouse (male, 5 weeks old)
The test drug was administered intraperitoneally in the test. The test drug is 0.05% “Twee
n 80 "was used by dissolving or suspending in the solution. was calculated LD ₅₀ values from day 14 mortality after administration.

 The results are shown in Table-7.

[Effect of the Invention] The compound of the present invention has strong antitumor activity and low toxicity, and is useful as an antitumor therapeutic agent.

Claims (4)

(57) [Claims] 1. A compound represented by the following general formula (I) [Wherein, R ¹ represents a hydrogen atom or an alkyl group having 4 or less carbon atoms, and R ² represents a hydrocarbon group having 18 or less carbon atoms, or a group having 3 to 10 carbon atoms to which a carboxyl group or a salt thereof is bonded. ), And the configuration of 1,2-diaminocyclohexane is cis-, trans-l- or trans-d-]. 2. A tumor therapeutic composition comprising the platinum complex according to claim 1 as an active ingredient. 3. The following formula (II) And a platinum compound represented by the following general formula (III) [Wherein, R ¹ represents a hydrogen atom or an alkyl group having 4 or less carbon atoms, and R ² represents a hydrocarbon group having 18 or less carbon atoms, or a group having 3 to 10 carbon atoms to which a carboxyl group or a salt thereof is bonded. A tumor therapeutic agent composition comprising, as an active ingredient, a platinum complex obtained by reacting α, γ-dioxocarboxylic acid represented by the following formula: 4. The following general formula (IV) [Wherein X represents NO ₃ or 1 / 2SO ₄ ] and a platinum compound represented by the following general formula (III) [Wherein, R ¹ represents a hydrogen atom or an alkyl group having 4 or less carbon atoms, and R ² represents a hydrocarbon group having 18 or less carbon atoms, or a group having 3 to 10 carbon atoms to which a carboxyl group or a salt thereof is bonded. A tumor therapeutic agent composition comprising, as an active ingredient, a platinum complex obtained by reacting α, γ-dioxocarboxylic acid represented by the following formula in the presence of an alkali.