JPH0236157A - Novel platinum complex and malignant tumor remedy composition - Google Patents

Abstract

NEW MATERIAL:A platinum complex expressed by formula I [X is formula II (R<1> is 1-18C alkyl, 1-18C alkenyl, etc.; R<2> is H or 1-18C alkyl; R<3> is H or 1-3C alkyl or R<2> and R<3> together form 2-7C alkylene; dotted line is single bond or double bond; broken line is conjugated system); steric configuration of 1, 2-diaminocyclohexane is cis.trans-l- or trans-d-; Y is anion]. EXAMPLE:[Pt(Trans-l-1,2-diaminocyclohexane)](3-acetyl-6- methyltetrahydropyran-2,4-dione)2.H2O. USE:A malignant tumor remedy composition having strong antitumor activity and weak toxicity. PREPARATION:A compound expressed by formula III is reacted with a compound expressed by formula IV in the presence of an alkali metal hydroxide or alkaline earth metal hydroxide to provide the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel platinum complex and a composition for treating malignant tumors containing the same as an active ingredient.

[Prior Art] Chemotherapy for malignant tumors has made dramatic progress in recent years with the application of cisdiamine dichlorobratinum (■) (hereinafter abbreviated as CDDP). That is, this is because CDDP has shown remarkable efficacy against genital cancers such as ovarian cancer and testicular cancer, which were previously difficult to treat with chemotherapeutic agents. However, CDDP
has serious side effects such as nephrotoxicity and bone marrow toxicity, which poses problems in clinical use.

On the other hand, especially D L F (dose limiting
Various studies have been carried out to improve nephrotoxicity, which has become a factor in nephrotoxicity.
abbreviated as CBDCA), cis-diammine-〇.

Second generation platinum complexes such as 0'-glycolate platinum (n) were developed (Japanese Patent Application Laid-open No. 154493/1983, etc.).

[Problems to be Solved by the Invention] However, although these compounds have weak nephrotoxicity, their antitumor activity is not as high as that of CDDP.

Therefore, it is desired to develop platinum complexes that have strong antitumor effects (and low toxicity).

An object of the present invention is to provide a novel platinum (I) complex that satisfies both the requirements of having strong antitumor activity and low toxicity, and further to provide a therapeutic agent for malignant tumors that satisfies both of these conditions. It is about providing.

[Means to solve the problem] The above object is achieved by the present invention as described below.

The present invention provides a novel platinum complex represented by (A) below and a composition for treating malignant tumors containing the platinum complex as an active ingredient.

[In formula (A), R1 is an alkyl group having 1 to 18 carbon atoms, an alkenyl group having 1 to 18 carbon atoms, or a group represented by +Z+R4 (Z is -
CH=CH- or an alkylene group having 1 to 5 carbon atoms; R4 is a phenyl group, a hydroxyphenyl group, or a 7-carbon group;
~12 alkoxyphenyl groups, halogenated phenyl groups, nitrophenyl groups, alkoxycarbonylphenyl groups having 8 to 13 carbon atoms, cyclohexyl groups substituted with alkyl groups having 1 to 5 carbon atoms, or groups represented by the following formula. R2 represents a hydrogen atom or an alkyl group having 1 to 18 carbon atoms; R3 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; or R2 and R3 together represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; ~7
The dotted line indicates that it may be a single bond or a double bond; the dashed line indicates a conjugated system), and the configuration of 1.2-diaminocyclohexane is cis-trans-〇- or trans-d and Y represents an anion] The compound (A) of the present invention is a compound of the present invention consisting of 1,2-diaminocyclohexane and a 3-acylpyran-2,4-dione derivative of the following formula (B) (in the formula (B)) R1R and R3 are the same as above)
is the ligand, and the part of formula (B) is the following formula
It is arranged in the form of

R3 This ligand means a conjugated system represented by the following formula.

For example, CHCOO-1C3H7COO-
C1-10 aliphatic carboxylic acid ions such as NO3
-, a halogen ion, or the above formula X, and the like.

The method for producing the compound (A) of the present invention is based on the following reaction formula (
Represented by a), (b) and (c) In the compound (A) of the present invention, in X, R1 is a methyl group, a 2-tetrahydrofurylethyl group, a 2-furylethyl group, a m-hydroxyphenylethyl group. , p-talolophenylethyl group, 3,
Those with 4-methylenedioxyphenylethyl group, those where R2 is a methyl group, and those where R3 is a hydrogen atom are particularly preferred, but are not limited thereto.

Y in the compound (A) of the present invention may be a monovalent anion or a polyvalent anion of divalent or higher valence as long as it is an anion, but a monovalent anion is preferable. Monovalent anion (C) (B) (A)' (D) (B) (A)' (E) (B) (A)' (In each formula, R1, R2, R3 and dotted lines are the same as above. ) The reactions (a) and (b) above are performed using NaOH and KO
Alkali metal hydroxides such as H or Ba(OH)
It can be carried out in the presence of an alkaline earth metal hydroxide such as and Ca (OH)2, but NaOH and KOH are preferably used for the reaction (a), and BaOH and KOH are preferably used for the reaction (a). (OH)2 is preferably used. (
The amount of alkali metal hydroxide or alkaline earth metal hydroxide used in the reaction of (a) is preferably approximately 2 equivalents for the former and approximately equivalent for the latter, and The amount used in is preferably approximately equivalent to that of compound (B).

In addition, a compound in which Y in formula (A) is an anion other than
Alternatively, it can be produced by reacting (E) with an acidic substance equivalent to the anion Y and then reacting with compound (B).

For example, compound (A) when the anion is a monovalent anion
The manufacturing method can be represented by the following reaction formula (d), (e), (e) or (g).

(A) (However, Y in the above formula represents an anion other than X.) The reaction (d) is an equilibrium reaction, and by extracting the generated (B) with a solvent, the target compound (A) can be obtained selectively. H used in the reaction of the above formula (d)
As Y, for example, CH3CO0HSC3H7C00H
aliphatic carboxylic acids having 1 to 10 carbon atoms such as HNO3 or H-Hal (where Hal represents halogen).

Compounds (C) and (D) are raw materials for the synthesis of platinum complexes of the present invention.
) is a known method, for example, Journal of Phar
mechanical 5sciences, 65, 31
5. (197B), it can be easily obtained by reacting silver nitrate or silver sulfate with a compound represented by the following formula (F).

(E) It can be synthesized with

(In the formula, Hal represents a halogen.) The compound of formula (F) has Pt (cis-dach
)Hal, Pt ()lance-α-dach)H
al, Pt () Lance-d-dach) Hal
There are three isomers of 2.

(dach indicates 1,2-diaminocyclohexane.

) Compound (E) is also available from Cancer Treatment
t Reports Vol, 61=p, 1519(1
977), it can be obtained by passing an aqueous solution of compound (C) through a strong anion exchange resin. As a strong anion exchange resin, “Amberlite IRA-4”
00 "Diamond Ion 5A-10A" and the like.

Compound (B) which is another raw material for the platinum complex of the present invention
JP-A-49-5975, Ch Qm I S 1r
yLet,t,ers,1982.1543-154B
The following method described in , represents a halogenated phenyl group, a nitrophenyl group, an alkoxycarbonylphenyl group having 8 to 13 carbon atoms, a cycloalkyl group substituted with an alkyl group having 1 to 5 carbon atoms, and R6 is a cycloalkyl group substituted with an alkyl group having 1 to 5 carbon atoms.
~18 alkyl groups) When a therapeutic agent containing an effective amount of the platinum complex of the present invention is administered in the clinic, it is administered by oral or parenteral routes. Its dosage forms include tablets, sugar-coated tablets, gun powder, capsules, powders,
It includes troches, liquids, suppositories, injections, etc., and these are manufactured by incorporating pharmaceutically acceptable excipients (cxcipients). Examples of excipients include the following.

Lactose, sucrose, glucose, sorbitol, mannitol, potato starch, amylopectin, various other starches, cellulose derivatives (e.g. carboxymethyl cellulose, hydroxyethyl cellulose, etc.), gelatin, magnesium stearate, polyvinyl alcohol calcium, polyethylene glycol wax, gum arabic , talc, titanium dioxide, vegetable oils such as olive oil, peanut oil, and sesame oil, paraffin oil, neutral fat base, ethanol, propylene glycol, physiological saline, sterile water, glycerin, coloring agents, seasonings, thickeners, and stabilizers. ,
Isotonic agents, buffering agents, etc., and other pharmaceutically acceptable excipients.

The therapeutic agent of the present invention contains 0.001 to 8 of the platinum complex of the present invention.
It can be contained in an amount of 5% by weight, preferably 0.005 to 60% by weight.

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

[Examples] Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example 1 (Pt (trans-α-1,2-diaminocyclohexane)] (]3-acetyl-6-methyltitrahydrobilane-24-dione)2 ・R20[Pt (trans-Q-d a ch) (OH ) 2) Aqueous solution 1
0 ml (4.2 mmol) of 3-acetyl-6-methyltitrahydrobilane-2.4-dione 1,
After adding 72 g (10.1 mmol) and stirring at room temperature for 6 hours, the reaction solution was concentrated to dryness at 45-50°C. After washing the obtained solid with ethyl acetate,
It was dried under reduced pressure at 40 to 45°C to obtain 40 g of pale yellow complex 2. (Yield 86%) Melting point, elemental analysis, and IR and NM of this complex
The R spectrum data is shown below.

Melting point: 184-188°C (decomposition) Elemental analysis value: C2. CH as H34N209Pt
N Pt Calculated value (%”) 39.70 5.15 4.2
1 29.31 Actual value (%) 39.3 4.9
4.3 28.0I R (KBr) (cm-1)
3420, 3200, 3080.2980, 2940.

28B0.1700.16B0.1620.1570,
1390, 1290, 1260.10B0.970,7
70'H N M R (d6-DMSO) δ (ppa
+) 4.20 (m, 2H), 3, 55 (S, 6H),
2.1-2.7 (m, toll), 1.5-2.0 (
m, 611), 0.5-2.8 (m, 1OH) The 3-acetyl-6-methyltitrahydropyran-2,4-dione that constitutes the complex has a coordination bond and an anion. The fact that the protons exist in a 1:1 ratio can be seen from the fact that the chemical shifts of the corresponding protons are observed with equal intensity at different positions, as shown in the formula below (I
HNMR1400Mllz, D20).

Example 2 (Pt() lance-α-1,2-diaminocyclohexane)] (]3-acetyl-6-methyl-2H bilane-
2,4(3H)-dione)2 ・H20 In Example 1, 3-acetyl-6-methyltitrahydropyran-2
,4-dione, 1.71 g of dehydroacetic acid (
Using a solution prepared by dissolving 10.1 mmol) in 25 ml of ethanol, 2.40 g of a pale yellow complex was obtained. (Yield 86
%) Melting point, elemental analysis, and IR and -N of this complex
-MR spectrum data is shown below.

Melting point: 191-196℃ (decomposition) Elemental analysis value: CHN as C22HsoN 209 Pt
Pt Calculated value (%) 39.94 4.57 4.23
29.49 Actual value (%) 39.2 4.4 4.
5 30.2I R(KBr)(am-') 3420
．． 3200, 3080, 2940.28B0゜1730
．． 1690.1660.1600,1550°1470
．． 1400.1380,1350. L280゜LL60
．． 1010 1HN MR (d6-DMSO) δ (ppm) 5.
99 (s, LH), 5.39 (S, 1ll), 3.48
(s, 6H), 2.32 (s, 3) 1), 2.25 (s
, 3H), 2.05 (S, 3H), 1.91 (s, 3H)
), 0.5-2.6(m, 1OH) The 3-acetyl-6-methyl-2H-bilane-2,4(3H)-dione that constitutes the complex has a coordinate bond type and an anionic type. The fact that these protons exist in a 1:1 ratio can be seen from the fact that the chemical shifts of the corresponding protons are observed with equal intensity at different positions, as shown in the formula below (I
NMR1400MHz, D20).

Example 3 (Pt(h-lance-α-1,2-diaminocyclohexane)) (3-acetyl-6-methyltitrahydropyran-24-dione) (CH3C0O)/H2O (PtO lance obtained in Example 1) -α-1゜2-diaminocyclohexane)〕 (〕3-acetyl-6-methyltitrahydropyran-24-dione) 2 ・H2
05.57g (8.6+mmol) was dissolved in 100ml of water, and 1.0g of acetic acid was dissolved in 100ml of water. After adding 56 g (25.8 mmol) and stirring at room temperature for 3 hours, the reaction solution was transferred to a separating funnel, and the resulting 3-acetyl-6-methyltitrahydropyran-2,4-dione was mixed with ethyl acetate using 50 ml each time. , extracted four times. Water was distilled off from the remaining aqueous layer under reduced pressure using a rotary evaporator, and the mixture was further dried to dryness under reduced pressure using a vacuum pump. 100 ml of ethyl acetate was added and the product was powdered and washed under cooling at -10°C. The powder was then passed through the mouth and dried to obtain 4.25 g of the complex.

Melting point, elemental analysis, and IR and NM of this complex
The R spectrum data is shown below.

Melting point: 230℃ (unfusible blackening) Elemental analysis value
CHN as Cre H28N 207P t
Pt Calculated value (%) 34.60 5.08 5.04
35.12 Actual value (%) 34.63 5.01
4.97 35.3I R(KBr)(cm') 34
00.2925, 1702, 1560.1440°14
20.1390, 1250, 1075, 1060°63
0.520'HNMR (D20) δ (ppm) 4.56 (m, 1
ll), 2.68-2.31 (m, 4H), 2.2
7 (s, 3tl), 2.08 (21 (), 1.93 (s
, 311), 1.60 (d, 2l-1), 1.38-1
．． 33 (411), 1.25-1.17 (m, 311) One molecule of coordinate bonding 3-acetyl-6-methyl-tetrahydropyran-2,4-dione exists, and one molecule of acetate ion is introduced. What was done is the following formula 'NMR (400MH
z, D20).

e'1i OCCH3(L, 93 fsl l Example 4 [Pt (trans-Q-1,2-diaminocyclohexane)] (]3-acetyl-6-methyl-2Hpyran-2,4(3H)-dione) (CH3COO )・H2O [Pt (trans-α-1゜2-
diaminocyclohexane)] (3-acetyl 6-methyl-2H-pyran 2.4 (3H)-dione)
- Dissolve 3 g (3.5 mmol) of H02 in 40 ml of water, transfer to a branch funnel, and then add 0.0 g of acetic acid. 52g
(8,601 [+101)] and 20ml of ethyl acetate.
Extracted with. The aqueous layer was further extracted twice with 10 ml of ethyl acetate each time. Water was distilled off from the remaining aqueous layer under reduced pressure using a rotary evaporator. The mixture was further dried under reduced pressure with a vacuum pump, 50 ml of ethyl acetate was added, and the product was powdered and washed under cooling at -10°C. The powder was then passed through the mouth and dried to obtain 1.7 g of the complex.

Melting point, elemental analysis, and IR and NM of this complex
The R spectrum data is shown below.

Melting point: 250℃ (unfusible blackening) Elemental analysis value
CHN as C16H26N 207P t
Pt Calculated value (%') 34.72 4.74 5.0B
35.25 Actual value (%) 34.43 4.7
5.21 3B, 4I R (KBr) (cm') 3
400,2925.1720.1B95.1B50゜1
600, L540.1460.1420,1390゜1
340.1160, 1060.1020.1000゜9
70.820.540 1HNMR (D20) δ (ppffl) 8.01 (s
, LH), 2.52-2.48 (2H), 2.41
(s, 3tl), 2.09-1.97 (5H), 1
．． 92 (s, 3tl), 1.61-1.59 (2H)
, IJ4-1.24(2H), 1.21-1.15(2H) Coordinative 3-acetyl-6-methyl-2H-pyran-2,4(3H)-dione is present, and acetic acid The introduction of 1 mole is confirmed by the following 1HMR (400MHz SD
20) Kararekaru.

. ? 0CCI (3L 1.92 (s) 1 Example 5 [Pt (trans-α-1,2-diaminocyclohexane)] (3-acetyl-6-methyltetrahydrobyran-2,4-dione) (C3H7C00) ・H
Butyric acid 0.37 in 100 ml (4.2 mmol) of 2O (Pt(trans-12dach) (OH2)3 aqueous solution
After stirring at room temperature for 2.5 hours, 0.71 g (4,2 mmol) of 3-acetyl-6-methyltitrahydropyran-2,4-dione was added, It took another 2 days to remove the precipitated crystals.
and the P solution was concentrated to dryness. The obtained solid was washed with ethyl acetate and then dried under reduced pressure to obtain 1.70 g of a pale yellow complex. (Yield: 69%) The melting point, elemental analysis, and IR spectrum data of this complex are shown below.

Melting point 201-205℃ (decomposition) Elemental analysis value C18H32N 207P t CH
N Pt Calculated value (%) 37.1 5.53 4.80 3
3.4 Actual value (%”) 36.5 5.1 4.8
32.9I R(KBr')(cm-1) 3430
．． 3190, 3080, 2930, 1890°1570
．． 1390.1260.10B0.970°770.5
20 Example 6 [Pt (trans-〇,-1,2-diaminocyclohexane))(3-(3-(2-tetrahydrofuryl)propionyl)-6-methyltitrahydrobilane-2,4
-dione)2 ・H2O(Pt()' Lance Q d
ach)(OH)2) aqueous solution 100ml (4.2m
mol) of 3-(3-(2-tetrahydrofuryl)propionyl)-6-methyltitrahydropyran-2,4
After adding 2.30 g (9.1+nmol) of -dione and stirring at room temperature for 6 hours, the reaction solution was concentrated to dryness at 45-50°C. After washing the obtained solid with ethyl acetate, it was dried under reduced pressure at 45-50°C to form a white complex 2. 80
I got g. (Yield 80%) Melting point, elemental analysis, IR and NM of this complex
The R spectrum data is shown below.

Melting point: 166-168°C (decomposition) Elemental analysis value: CHN as C3°H58N20□1Pt
Pt Calculated value (%') 46.09 B, 04 3.3
8 23.40 Actual At value (%) 45.7 5.
7 3.5 24. OI R (KI3r) (cm-')
3420, 3150. 3080, 2940, 2860
゜1710.1660.15B0.1400,1340
゜1260.1070 1HN M R (D20,400 MIIz) δ (ppm
) 4.57 (m, 1tl), 4,50 (m,
1ll), 3.90 (Ill, 2H), 3.85 (m,
211), 3.75 (m, 2H), 2.79 (m, 41
1), 2.87 (d, LH), 2.52 (ff1.2H
), 2.42 (d, 2H), 2.38 (m, lID, 2
．． 10 (m, 2H), 2.08 (m, 2H), 1.93
(m, 4H), 178-1.85 (m, 4)l), 1.63 (m, 211), 1.55 (field, 2H), 1.
37 (m, 2H), 1, 39 (d, 310.1.
36 (d, 31), 1.20 (m, 21 () Example 7 Pt () lance-α-dach) So4 aqueous solution 30 ml
(3,2 mmol) to 1.61 g (6°4 mmol) of 3-(3-(2-tetrahydrofuryl)propionyl)-6-methyltitrahydropyran-2,4-dione
) and B a (OH) 2 aqueous solution 150ml (3°2m
a+ol) was added and stirred at room temperature for 24 hours.

After concentrating the reaction solution at 45-50°C, the produced solid (B a S O4) was cooled to 10°C and stripped of P. P
After concentrating the liquid to dryness, it was washed with ethyl acetate and dried under reduced pressure.
1.9 g of a white complex was obtained.

The IR and NMR spectral properties of this complex are shown in Example 6.
The spectrum almost matched that of the complex obtained in .

In addition, the elemental analysis values (%) are C45,8; H5°8; N
3.1; Pt 22.9.

Example 8 (Pt(trans-Q-1,2-diaminocyclohexane'))(3-(3-(2-furyl)propionyl)-
6-methyl-2H-pyran-2,4(3H)-dione)
2 ・H2O [Pt (trans-〇, -dach) (HO)
2) (NO3)2 aqueous solution 25ml (5.3mmo
l) to 3-(3-(2-furyl)propionyl)-6-
Methyl-2H-pyran-2,4(3H)-dione 1°3
0 g (5.2 mmol) in 1N-NaOH aqueous solution 1
A solution of 0.7 ml and 30 ml of ethanol was added, and the mixture was stirred at room temperature for 2 hours. The precipitated crystals were washed one by one with water and ethyl acetate, and then dried under reduced pressure to obtain 0.91 g of a white complex. (Yield 21%) The melting point, elemental analysis values, and IR spectrum data of this complex are shown below.

Melting point 204-207°C (decomposition) Elemental analysis value C3°H36N20. CHN as pt
Pt Calculated value (%) 47.82 4.5L 3.49
24.27 Actual value (%) 47.4 4.4 3
．． 5 24.9I R(KBr)(cm') 3420
．． 31B0.3090,2940.2860゜1?30
,1680.1B60.1550.1420.1180
．． 1010.740 Example 9 (Pt() lance-α-1,2-diaminocyclohexane))(3(3-(m-hydroxyphenyl)propionyl)-6-methyl-2H-pyran-2,4(3H) −
dione)2.H2O[Pt (trans-〇, da
ch) (H20) 2 ) (NO3)2 aqueous solution 20
m1 (2,1ma+ol) with 3-(3-(m-hydroxyphenyl)propionyl)-6-methyl-2H-pyran-2,4(3H)-dione 1. 23g (4,5
mmol) dissolved in 65 ml of methanol and lN
4.3 ml of -NaOH aqueous solution was added, and the mixture was stirred at room temperature for 20 hours.

The reaction solution was concentrated to 38 g, and then added dropwise to 75 ml of water.

A candy-like substance will precipitate, so after removing the supernatant liquid, add 150 ml of water.
Add m1 and stir at room temperature for 2 hours to solidify. The solid was treated with P, washed with ethyl acetate, and dried under reduced pressure to obtain 1.20 g of a pale yellow complex.

(Yield: 65%) The melting point, elemental analysis values, and IR spectrum data of this complex are shown below.

Melting point 179-182°C (decomposition) Elemental analysis value CHN as C36H42N20.1Pt
Pt Calculated value (%) 49.48 4.84 3.21
22.33 Actual value (%”) 49.8 4.7 3
．． 1 21.8I R<KBr)(am') 3400
,3200.3100,294q,,2880°170
0.16B0.1590, 1550, 1460°142
0.12B0.1lB0.1010 Example 10 [:Pt(cis-1,2-diaminocyclohexane)
) (3-(3-(m-hydroxyphenyl)propionyl)-6-methyl-2H-pyran-2゜4 (3H
)-dione)2 ・H20 [Pt(Nsu dach) (K20)2] (N
O0)2 aqueous solution 20ml (4.2mmol) and water 30
After adding m1, 3(3-(m-hydroxyphenyl)
propionyl)-6-methyl-2H-bilane 2,4 (
3H)-dione 2. 30g (8,4[1110of
) dissolved in 8.6 ml of 1N-NaOH aqueous solution and 50 ml of water was added, and the mixture was stirred at room temperature for 2 hours. The precipitated crystals were collected one by one, washed with water and ethyl acetate, and then dried under reduced pressure to obtain 1.80 g of a pale yellow complex. (Yield 49
%) Melting point, elemental analysis values, and IR and NM of this complex
The R spectrum data is shown below.

Melting point 186-190℃ (decomposition) Elemental analysis value CHN as C36H4゜N20□1Pt
Pt Calculated value (%) 49.48 4.84 3.21 2
2.33 Actual value (%) 49.7 4.8 3.2
219I R(K13r)(cm-') 3400,3
200.3100.2940,2860°L730.1
690.1660.1590,1550°1460.1
420.1250, 1160, 1010.780IHN
MR (d6-DMSO) δ (ppm) 9.10 (br, 2H)
, 6.7-7.1 (m, 2H), 8.3-6.8 (m, 6H), 5.81 (s, LH
), 5.32 (s, LH), 3.48 (br, 6
H), 2.3-3.2 (m, 1OH), 1.82-2.0 (m, 6H), 0.5-1.8 (m, 8) 1) Example 11 (Pt (trans -α-1,2-diaminocyclohexane) ) (3-(3-(p-chlorophenyl)propionyl)-6-methyl-2H-pyran-2,4(3H
)-dione)2 ・K20[Pt (trans-(1-
dach) (HO) 2 ) (NO3) 2 aqueous solution 1
5 ml (3,2a+mol) of 3-(3-(p-chlorophenyl)propionyl)6-methyl-2H-bilan-2,4(3H)-dione 2. 12g (7.2m
After adding a solution prepared by dissolving mol) in 200 ml of methanol, 7.2 ml of 1N-NaOH aqueous solution was added, and the mixture was stirred at room temperature for 20 hours. 25 after removing a small amount of sediment from one house
300 ml of water was added and stirred at room temperature for 2 hours. The solid was washed with ethyl acetate and dried under reduced pressure to obtain 1.75 g of a white complex. (Yield 60%) The melting point, elemental analysis values, and IR spectrum data of this complex are shown below.

Melting point 188-192°C (decomposition) Elemental analysis value C36H4oN209C1°Pt as CHN Pt Calculated value (%) 47.48 4.43 3.08 2
1.42 Actual value (%) 47.9 4.3 3.2
20.8IR(KBr)(cm-1) 342rf,
3L60, 3080, 2940.2860°1730.
1690.1B60, 1610.1550°1510.
1490,1420,1090,1010.830 Example 12 (PtO lance-α-1,2-diaminocyclohexane))(3-(3-(3,4-methylenedioxyphenyl)propionyl)-6-methyl-2H -pyran-2,4
(3H)-dione)2 ・In Example 11, 3-
(3-(p-chlorophenyl)propionyl)-6-methyl-2H-bilane-2,4(3H)-dione instead of 3-(3-(3,4-methylenedioxyphenyl)propionyl)-6 -Methyl-2H-pyran-2゜4
(:3H)-dione 2. 21g (7.3mmol
) to obtain 2.25 g of a white complex. (yield 76%
) The melting point, elemental analysis values, and IR spectrum data of this complex are shown below.

Melting point 186-188°C (decomposition) Elemental analysis value CHN as C38H4□N20□3Pt
Pt Calculated value (%) 49.09 4.55 3.01 2
0.98 Actual value (%”) 49.2 4.4 3.2
20.8IR(KBr)(cm-1) 3420,
3180, 3080, 2940.1730°1690.
16B0.1810, 1550.1500°1490,
L420, 1400.1240, 1040.920 Example 13 (Pf (trans α-1,2-diaminocyclohexane)) () 3-acetyltetrahydropyran 2,4-
dione)2 ・H2O 3-acetyltetrahydrobilane-2,4-dione 1.
56 g (10 mmol) was dissolved in 50 ml of ethanol, and (Pt(trans-(1-dach) (OH
)2] 60 ml of aqueous solution (4,0[11[1101)] was added while stirring under water cooling. After leaving it at room temperature for 2 days,
The reaction solution was concentrated to dryness under reduced pressure in a 40°C water bath.

Tetrahydrofuran was added to the obtained solid, which was powdered and washed. After passing through the mouth, dry at room temperature under reduced pressure to obtain pale yellow complex 2.
．． 30 g was obtained (yield 90%).

Melting point, elemental analysis, and IR and NM of this complex
The R spectrum data is shown below.

Melting point: 200℃ (decomposition) Elemental analysis value
CHN P as C20H3ON209 P t
t Calculated value (%) 37.68 4.74 4.39 3
0.60 Actual value (%) 37.69 4.60 4.
46 30.941 R (KL3r) (cm-1) 3
400.30B2, 2940.2368, 168g.

1570.1390.1270.1187,1102°1023.942,915,866.775.719'
HNMR (D20) δ (ppm) 4.29 (t, 21
1), 4.24 (t, 2H), 2.58 (t, 2) 1)
, 2.50-2.47 (m, 4H) , 2.32 (s
, 3H), 2, 57 (s, 311), 2. o7
(d, 2H), 1.63-1.55 (m, 2H),
1.40-LJL(m,2H), 123-1.12([Q,2)1) Example 14 [(Pt(trans-Q-1,2-diaminocyclohexane)] (]3-acetyl-6- Methyl-2H bilane-2,4(3H)-dione) (NO)・H2O [(Pt (trans-〇, -dach) (H2
O) 2) (NO3)2 aqueous solution 30ml (6,3ma
+ol) and dehydroacetic acid2. 12g (12.6mm
A solution prepared by dissolving 12.6 ml of 1N-NaOH aqueous solution was added dropwise while stirring at room temperature. After 20 hours of reaction, two precipitated crystals were collected. After washing with water and ethyl acetate, the mixture was dried under reduced pressure at 40 to 45°C to obtain 2.28 g of a white powdery complex (yield: 65%).

The melting point, elemental analysis values, and IR spectrum data of this complex are shown below.

Melting point 195-198°C (decomposition) Elemental analysis value C14H23N 30 s P t as CH
N Pt Calculated value (%') 30.22 4.17 7.55
3506 Actual value (%) 30.6 3.8 7.4
32.8I R (KBr) (cm-1) 3440,
3200.3100,2940,2860°1760.
1730, 1710.1660.1550°1470.
1430, 1380. Li2O, 1070°1030.
1010.830 Example 15 CD F l 7 'ys (male, 6 weeks old, 1 group 6~
(Using 10 mice) 105 L1210 mouse leukemia cells passaged in DBA/2 mice were intraperitoneally transplanted.

The test drug was intraperitoneally administered three times in total on the 1st day, 5th day, and 98th day from 08 on the day of transplantation. CDD was used as a comparative drug in this experiment.
PSCBDCA was used. Each drug contained 0.05%
It was used by dissolving or suspending it in en80'' solution.Efficacy was determined by T/(1) calculated by the following formula and the number of surviving mice on day 30.

Margin table below (MargAg) (Standard deviation above average) (%) Control BT 8.4±1.0 0/10 Compound of Example 1 5±0°5±1°2±3°0±3°5 ±5°7] 0/6 0/6 0/6 0/6 0/6 0/6 Compound of Example 2 8.7±0.5 13.8±3.6 197±7.5 10.0 ±1.1 6.3±2. 0 2.8±1.6 O/'6 0/6 1/6 0/6 0/6 0/6 DDP 2.5 5.0 7.5 15.2±1.9 181 0/618.
5±6.0 220 1/617.0±2.2
202 0/6 Table L1210-implanted mice with antitumor effect of platinum complex Compound dose (mg/kg) Survival days (standard deviation above the mean) T/C (%) Compound 2 ± 10 8 ± 3 of surviving mice Example 3 .0 0±2.6 0±6.4 2±4.1 7±1,5 0±2.0 0/6 0/6 0/6 2/6 0/6 0/6 0/6 DDP 2 .5 12.0±3.0 143 0/6
5 14.3±2.9 170 0/6
7.5 15.5±2.1 185 0/6
Table L Antitumor action of platinum complex on mice transplanted with 1210 Compounds Dose (ag/kg) Days of survival (standard deviation above the mean) T/C (%) Compound 2 ± 0.4 3 ± 0.8 of surviving mice Example 14 0±8.5 0±6.2 5±1.2 0/6 0/6 2/6 1/6 0/6 0/6 DDP 2.5 10.5±1.8 125 0/6
5 15.5±1.4 185 0/6
7.522.3±3.9 266 1/6 Compound of Example 5 8.8±1°10.2±1°11.8±1°16.3±5°14.2±5°0/ 6 0/6 0/6 0/6 0/6 DDP 2.5 13.0±3.1 153 0/
65 18.2±0.4 214 0
/67.520.2±4.8 238 0/6
BDCA 3±0°3±0°1±1°1±2°1±3°6±0°0/10 0/10 0/10 0/10 0/10 0/10 Example 16 Platinum of the present invention CD complex acute toxicity test in mice
DP was used as a control. The test drug was intraperitoneally administered to Slc:ICR mice (male, 5 weeks old, 6 mice per group). The test drug was dissolved or suspended in a 0.05% "Tween 80" solution. The L Dso value was calculated from the mortality rate 14 days after administration by the Miller Tainter method.

The results are shown in Table 4.

[Effects of the Invention] The platinum complex of the present invention has strong antitumor activity and low toxicity, and is useful as a therapeutic agent for malignant tumors.

Claims (4)

[Claims] (1) A novel platinum complex represented by the following general formula (A). ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (A) [In formula (A), X represents ▲There are mathematical formulas, chemical formulas, tables, etc. group, carbon number 1-18
alkenyl group or group represented by (Z)R^4 (Z
represents -CH=CH- or an alkylene group having 1 to 5 carbon atoms, and R^4 is a phenyl group, hydroxyphenyl group, alkoxyphenyl group having 7 to 12 carbon atoms, halogenated phenyl group, nitrophenyl group, or carbon number An alkoxycarbonylphenyl group having 8 to 13 carbon atoms, a cyclohexyl group substituted with an alkyl group having 1 to 5 carbon atoms, or a group represented by the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc.
R^2 represents a hydrogen atom or an alkyl group having 1 to 18 carbon atoms, and R^3 represents a hydrogen atom or an alkyl group having 1 to 18 carbon atoms. ~3 alkyl group, or R^2 and R^3 together represent an alkylene group having 2 to 7 carbon atoms; the dotted line indicates that it may be a single bond or a double bond; indicates a conjugated system)
, the configuration of 1,2-diaminocyclohexane is cis-,
Represents trans-l- or trans-d-, and Y
indicates an anion] (2) The platinum complex according to claim (1), wherein Y is a monovalent anion. (3) Y is an aliphatic carboxylic acid ion having 1 to 10 carbon atoms,
The platinum complex according to claim 1 or 2, which is an anion selected from the group consisting of NO_3 ion, halogen ion, and X (X is as defined above). (4) A therapeutic composition for malignant tumor containing the platinum complex according to claim (1) as an active ingredient.