JPS62298597A - Cis-platinum(ii) complex containing phospholipid derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R is H or 1-30C aliphatic carboxylic acid residue; A<1> and A<2> are ammine, (substituted) alkylamine, cycloalkylamine or together form a (substituted) bidentate amine]. EXAMPLE:cis-[1-Stearoyl-3-[(2-trimethylammonioethyloxy)(oxido)phosphin yl]tri methylene glycol-2,2-dicarboxylate](diammine)platinum(II) hydrate. USE:An antitumor agent having increased solubility in water and low toxicity. PREPARATION:For example, a compound of formula II (M is alkali metal) [e.g. cis-dinitrato(diammine)platinum(II), etc.] is made to react with a compound of formula III [e.g. 2,2-dicarboxyl-1-stearoyltrimethylene glycol-3-(2- trimethylammonioethyl)phosphate hydrate] in an aqueous solvent preferably at 0 deg.C- room temperature for 1-24hr.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention provides a bonic acid residue with the general formula; A1 and A2 are the same or different and are ammine, optionally substituted alkylamine or cycloalkylamine, or A and A2 together indicate an optionally substituted dish amine. ] This relates to a cis-platinum(II>complex compound represented by the following).

[Prior Art] Since the development of cisplatin, which has an antitumor effect, many studies have been conducted on platinum complex compounds. For example, malonato(1,2-diaminocyclohexane)platinum (ff
) (Mochif;i [(No. 5331648), sulfato(1,2-diaminocyclohexane) platinum (■) (JP-A-54-44620), 1,1-cyclobutane dihydrobonate (diammine) platinum (■) (Bio stain (!3i
ochimic) Volume 60, pp. 835-850, 1
978), 4-carboxyphthalad (1,2-diaminocyclohekiline) platinum (■) (Journal of Clinical Hematology and Oncology) (
J,CI! n, Hematol, Onco1. )
9, pp. 217-234, 1979).

[Problems to be solved by the invention] These platinum complex compounds are being researched with the aim of improving the low water solubility or severe renal toxicity of cisplatin, but the results have not always been satisfactory. Not obtained.

[Means for solving the problem] Under these circumstances, the present inventors conducted extensive research aimed at enhancing antitumor effects, reducing toxicity, and improving water solubility, and as a result, a type of choline-type phospholipid was discovered. It was discovered that a platinum complex compound represented by the general formula [I] into which is introduced has the desired properties, and the present invention was completed.

The compounds of the present invention will be explained in detail below.

As the C1-3o aliphatic carboxylic acid residue in R,
Examples include a C1-3o saturated aliphatic carboxylic acid residue, a C3-3o unsaturated aliphatic carboxylic acid residue, a C2-3o oxyacid residue, or a C2-3o ketoacid residue.

Examples of C1-3o saturated aliphatic carboxylic acid residues include formyl or acetyl, propionyl, butyryl,
Examples include C2-3o alkanoyl groups such as valeryl, hexanoyl, myristoyl, balmitoyl, stearoyl, eicosanoyl, and docorinoyl, and examples of C3-3o unsaturated aliphatic carboxylic acid residues include 9-hexadecenoyl, oleoyl, cis- Examples include C3-3o alkenoyl groups such as 9,cis-12-octadecagenoyl and 9,12.15-octadecatrienoyl.

Examples of C2-3o oxyacid residues include oxyacid residues derived from glycolic acid, lactic acid, α-hydroxylauric acid, α-hydroxymyristic acid, α-hydroxypalmitic acid, etc. Examples of acid residues include 2-30 keto acid residues derived from pyruvic acid, acetoacetic acid, levulinic acid, lycanic acid, and the like.

Examples of the alkylamine in A1 and A2 include C linear or C branched 1-6 3-6 chain alkylamine.

Examples of the C linear alkylamine include methylamine, ethylamine, n-propylamine, n-butylamine, n-amylamine, and n-hexylamine; Examples of the amine include isopropylamine, 5e
Examples include c-butylamine, tert-butylamine, 2-pentylamine, 3-pendelamine, 2-hexylamine, and 3-hexylamine.

Examples of the cycloalkylamines in A'I) and A2 include C3-6 cycloalkylamines, and examples of the C3-6 cycloalkylamines include cyclopropylamine, cyclobutylamine, cyclopendelamine, and cycloalkylamines. can be mentioned.

Examples of the dish amine formed by A1 and A2 together include ethylenediamine, 1,2-diaminocyclopentane, 1,2-diaminocyclobexane, 1-amino-1-aminomethylcyclohexane, 1-amino -2
C linear or cyclic alkyl 2-6 diamines such as -aminomethylcyclohexane, 1,2-bis(amitumedel)cyclohexylline, and 1,1-bis(aminomethyl)cyclohexylamine. The above alkylamines, cycloalkylamines, or rectangular amines include halogen atoms such as fluorine, chlorine, bromine, and iodine; hydroxyl groups: mercapto groups; nitro groups: alkoxy groups such as methoxy, ethoxy, and propoxy; carbamoyloxy One or more groups such as a sulfamoyloxy group, a niamino group, and an azide group may be substituted via a straight 1a or C alkylene chain.

Furthermore, the present invention encompasses geometric isomers and optical isomers of the compound of general formula [I], and necessarily includes all hydrates and crystal forms.

Next, a method for producing the compound of general formula [I] of the present invention will be explained.

The compound of general formula [h] of the present invention can be produced, for example, by the following method.

[■] In formula 1, M represents an alkali metal, R, A1 and A2
has the meaning given above. The reaction between the compound of the general formula [n] and the compound of the general formula [I11] is carried out in an aqueous solvent with O to 100'C1, preferably O'C
- It may be carried out at the lowest temperature for 1 to 24 hours.

The amount of the compound of the general formula [In] to be used is the amount of the compound of the general formula [In].
It is necessary in an amount of 0.5 to 2.0 times the molar amount, preferably equivalent molar amount, to the compound of [n]. Although the initial pH of the reaction mixture is preferably neutral, there is no need to particularly adjust the pH during the reaction.

In addition, when using the free acid in place of the compound of general formula [In], after adding it to an aqueous solvent containing the compound of formula [II]-11, the pH is adjusted with a suitable base, for example, an alkali hydroxide should be adjusted to neutral. If the reaction becomes acidic as the reaction progresses, the same base may be used to maintain I) tl neutral during the reaction.

The target product thus determined can be purified by single or appropriate combinations of operations such as extraction, concentration, recrystallization, and column chromatography.

Further, the compound of general formula [II] can be prepared by a method known per se or a method analogous thereto, for example, in the Journal of Pharmaceutical Sciences (J.

Pharm, Sci.) Volume 65, No. 315~
It can be produced by the method described on page 328, 1976.

The compound of general formula [I[1] can be prepared in-system without isolation and used.

Next, the compound of general formula [I11] can be prepared, for example, by the route described below.

(Margin below) [VI]
[VI] [■] [IX] [In the formula, R has the above-mentioned meaning, R1 represents a protecting group for a carboxyl group; R2 represents a C1-3o aliphatic carboxylic acid residue or a hydroxyl group-protecting group. . ] As the protecting group for the carboxyl group of R1, commonly known ones, such as methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxymethyl, etc.
-xyethoxymethyl, benzyloxymethyl, benzoylmethyl, p-bromobenzoylmethyl, p-methoxybenzoylmethyl, N-phthalimidomethyl, 2,2
．． 2-trichloroethyl, 2-heroethyl, trimethylsilylethyl, methylthioethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(toluenesulfonyl)ethyl, tert-butyl, benzyl, trityl, benzhydryl, 2.4 .6-drimethylbenzyl,
Examples include methoxybenzyl.

Examples of the C1-3o aliphatic carboxylic acid residue of R2 include those similar to the C1-3o aliphatic carboxylic acid residue explained for R, and as the hydroxyl group retention mW, commonly known Optionally substituted alkanoyl groups such as acetyl, propionyl, butyryl, isobutyryl, trichloroacetyl, trifluoroacedel, levulinoyl, phenoxyacetyl, (2,6-dichloro-4-methyl>phenoxyacetyl), benzoyl, Examples include acyl groups such as optionally substituted aroyl groups such as p-chlorobenzoyl; alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl; trityl groups; trialkylsilyl groups such as trimethylsilyl and tert-butyldimethylsilyl. .

Each manufacturing method will be explained in detail below.

(Manufacturing method 1) The reaction between the compound of general formula [IV] and formaldehyde can be performed, for example, as described in Bulletin deux Societies Chimique deux Français (Bj! 1.soc).

Chin, ) Volume 4, pp. 1410-1429, 1
It is carried out by the method described in 937 or a method similar thereto.

(Production method 2) (i) Acylation In the compound of the general formula [v1], the compound in which R2 is a C1-3o aliphatic carboxylic acid residue, the compound of the general formula % formula % or its reactive derivative 1q can be obtained by reacting with a compound of general formula [V].

This reaction is carried out in the presence of a solvent inert to the reaction.

Examples of reactive derivatives of the compound of general formula [X] include those commonly known as reactive derivatives of carboxylic acids, specifically, for example, acid halides; symmetrical acid anhydrides; methanesulfonic acid, 1)-1 toluenesulfonic acid,
Examples include mixed anhydrides of 2,6-dichlorobenzoic acid, trifluoroacetic acid, ethyl carbonate, chlorosulfine, etc.; Shun azide; and acid cyanide.

Furthermore, when the compound of general formula EX] is used as a free compound, it can be carried out in the presence of a suitable condensing agent. Condensing agents that can be used here include N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N
Examples include N,N-disubstituted carbodiimides such as '-morpholinoethylcarbodiimide, N-cyclohexyl-N''-(4-diethylaminocyclohexyl)carbodiimide, and N-ethyl-N-(3-dimethylaminepropyl)carbodiimide. The amount of the condensing agent used is at least equimolar to the compound of general formula [X].

Moreover, this reaction can be carried out in the presence of a base depending on the compound of general formula [X] or its reactive derivative. Examples of the base that can be used here include triethylamine, tripropylamine, tributylamine, N-methylmorpholine, N,N-dimethylaniline, and N.

N-diethylaniline, pyridine, 2,6-lutidine,
Examples include organic bases such as 4-dimethylaminopyridine and inorganic bases such as alkali hydrogen carbonate. The amount of the base used is at least equimolar to the compound of general formula [X].

Further, examples of the inert solvent used in this reaction include tetrahydrofuran, methylene chloride, chloroborum, methanol, ethanol, acetonitrile, and acetone.

In addition, the amount of the compound of general formula [V] to be used is the amount of compound of general formula [X]
of the compound or its reactive derivative.

The reaction temperature and reaction time are not particularly limited, but are appropriately selected depending on the compound of general formula [X] or its reactive derivative.

1i) Protection of hydroxyl group Furthermore, in the compound of the general formula [VI], in the case of a compound in which R2 is a hydroxyl-protecting group, a hydroxyl-protecting group may be introduced into the compound of the general formula [V] according to a conventional method.

(Production method 3) and (Production method 4) Reaction of the compound of general formula [VI] with 2-bromoethylphosphorodichloridate <Production method 3) and general formula [■]
The reaction between the compound and trimethylamine (manufacturing method 4) is
For example, Pharmaceuti force, Acta Helvechi force (Ph
arm, Acta He1v, ) Volume 33, No. 34
9 to 356, 1958, or a method similar thereto.

(Production Method 5) Deprotection Methods for removing the protecting group for the carboxyl group of R and the protecting group for the hydroxyl group of R2 are each commonly used, and are selected as appropriate depending on the type of protecting group. be able to. Further, the protecting groups of R1 and R2 may be removed separately or simultaneously.

After carrying out the reactions of the above production methods 1 to 5, according to the conventional method,
Compounds of general formulas [V] to [IX] can be isolated or prepared from the reaction mixture by extraction, S-condensation, recrystallization, column chromatography, or other operations alone or in an appropriate combination thereof.

(Manufacturing method 6) The compound of general formula [In] is prepared from general formula [IX] in an aqueous solvent.
It can be obtained by adding about twice the molar amount of alkali hydroxide to the compound, or by adjusting the pH to neutral with alkali hydroxide. The reaction temperature is 0° C. to the lowest temperature. The compound of general formula [I[1] can be isolated by distilling off water from the thus obtained aqueous solution of the compound of general formula CIII under normal pressure or reduced pressure or by freeze-drying it. .

Alternatively, from the obtained aqueous solution of the compound of general formula [I[1], the compound of general formula III] can be directly reacted without isolating the compound of general formula [I[1].

The various reaction conditions in the above production are not limited to these, and are appropriately selected depending on the type of reaction reagent and the like.

[Effects of the Invention] Next, the pharmacological effects of representative compounds of the present invention will be described.

Test compound No. 1: cis-[1-heptanoyl-3-[(2-trimethylammonioethyloxy)(oxide)phosphinyl]trimethylene glycol-2,2-dicarboxylate co(trans-dl-1, 2-diaminocyclohexane) platinum (n) hydrate Nα2: cis-[1-
Acetyl-3-[(2-trimethylammonioethyloxy) (oxide)phosphinylcotrimethylene glycol-2,2-dicarboxylate] (trans-d
l-1,2-diaminocyclohexane) platinum (n) hydrate CDDP: Cisplatin A, antitumor effect (a) Cell proliferation inhibitory effect on L-1210 cells Using L-1210 cells in culture, RP the test compound
Contact in MI medium for 48 hours and count the number of viable cells using a Coulter counter.
fi (I C3o) was calculated. The results are shown in Table-1.

Table 1 (b) Effect of L-1210 on ascites cancer when transplanted intraperitoneally. A test compound dissolved or suspended in physiological saline was administered intraorally three times in total on the 1st, 5th, and 9th day after cell transplantation.

CDDP was used as a control compound, and the control group received only physiological saline. Judgment was made based on the average survival days (a
) and the average survival days (b) of the control group to which only physiological saline was administered, the survival rate (ILS>) was calculated according to the following formula.The results are shown in Table 2.

(a)-(b) ILS (%) = X100 (b) Table 2 B. Mouse acute toxicity test Dissolved or suspended in physiological saline to 5 DDY mice (male, 5 weeks old) per group Each test compound was administered once intraperitoneally. On the 144th day after administration, the mice were determined to be alive or dead, and the LD5Q value was calculated. The results are shown in Table-3.

Table 3 From the above results, it can be understood that the compound of general formula [I] of the present invention has excellent antitumor effects and low toxicity.

When the compound of general formula [I] of the present invention is used as a medicine, it can be prepared by itself or mixed with appropriate additives such as pharmaceutically acceptable excipients, carriers, and diluents, and prepared into tablets, capsules, granules, etc. It can be administered orally or parenterally in the form of a powder, injection, or suppository. The dosage is usually about 10 to 500 Ig per day for adults, which is administered once or divided into several doses, and the dosage is appropriately selected depending on age, body weight, and symptoms.

[Example] Next, the present invention will be described with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Note that all solvent mixing ratios are volume ratios.

Moreover, the Rf value of TLC was measured under the following conditions.

TLC: Cellulose N-layer chromatography; manufactured by Merck & Co., Ltd., ART 5718 Developer solvent: 20-butanol: acetic acid: water = 5:1:2 Coloring reagent: Reference example; Dittmer reagent Example: Dittmer? - (Dittmer) reagent and 5% tin chloride 10. IN Hydrochloric Acid Reference Example 1 After dissolving Lyle ester malonic acid dibenzhydryl ester 229 in 100 ml of tetrahydrofuran, 13.9 g of anhydrous potassium carbonate and 15 g of paraformaldehyde were added, and the mixture was stirred at room temperature for 2 hours. Next, insoluble matter was filtered off,
Concentrate the filtrate under reduced pressure.

The obtained concentrated residue is dissolved in 100 d of ethyl acetate and washed twice with 50 d of water. After distilling off the solvent under reduced pressure and dissolving the obtained residue in 50 d of ethanol, 1 d of concentrated hydrochloric acid was added.
．． Add 0d and stir for 5 minutes at room temperature. Then, after distilling off the solvent under reduced pressure, the obtained residue was diluted with methylene chloride 1
Dissolve in 0.00 g of water and wash twice with 50 g of water. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure.

1q of produced product is converted into 200m of carbon tetrachloride! ! Recrystallization with 1 q of 2,2-dimethylolmalonic acid dibenzhydryl ester of colorless needle-like crystals is obtained.

Melting point: 116-118°C IR (KBr) cm-': 3300, 1735.1595.1490.1445.
1220.1130°1090, 1050.790.7
50.69ONMR (CDCl2) δ value: 2.82 (bt, 2M, J=6Hz), 4.18
(d, 4H, J=6Hz).

a, 85 (s, 2N), 7.05-7.55 (m, 20
+l) After dissolving 2.2-dimethylolmalonic acid dibenzhydryl ester 9.609, stearic acid 5.5 (EJ and dimethylaminopyridine 2.36!?) in 100 m of anhydrous methylene chloride, N, N-- Add 4.799 g of dicyclohexylcarbodiimide and stir at room temperature for 1 hour.Then, the precipitate is filtered off, and the filtrate is concentrated under reduced pressure.The obtained concentrated residue is dissolved in 100 d of ethyl acetate, and a small amount of After removing insoluble matter by filtration, the filtrate is washed twice with 20 d of 1N hydrochloric acid and once with 20 d of saturated aqueous sodium bicarbonate solution.After drying over anhydrous magnesium chloride, the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography (manufactured by Merck & Co., Ltd., Art 7734, elution solvent: benzene:ethyl acetate - 0 to 20:1),
Colorless waxy 2-stearoyloxymethyl-2-
Methylolmalonic acid dibenzhydryl ester 5.1g
get.

IR (KBr) cm-1: 3450, 2920.2850.1735.1590.
1490.1450°1220, 1180.1040.
780.760.695N)fR(CDCl2)
δ A direct; 0, 89 (t, 3M, J=5H2),
1.05-1.75 (m, 30H).

2.02 (bt, 2H, J=5112), 4.08 (b
s, 2+1>.

4, 66 (S, 2 old, 6.82 (s, 2 old.

7,05-7.42 (m, 20H) 2-stearoyloxymethyl-2-methylolmalonic acid dibenzhydryl ester 5.00 g and 2,6-lutidine 5.6
After dissolving 213 in anhydrous tetrahydrofuran 40d, 2-bromoethylphosphorodichloridate 3.179
Add. The reaction mixture is stirred IQ at 50'C for 1 hour.

Next, 40 d of water-cooled water was added, and the mixture was stirred at room temperature for 30 minutes. Next, 150 ml of ethyl acetate was added, and the pH was adjusted to 1.0 with 6N hydrochloric acid. Separate the upper layer, add 50% water to it, and adjust to 1) Hl and O with 6N hydrochloric acid. The upper layer was separated, washed with 50 ml of saturated brine, dried over anhydrous magnesium acetate, and the solvent was distilled off under reduced pressure to obtain 2,2-bis(benzhydryloxycarbonyl) as a pale yellow oil. -1-stearoyltrimethylene glycol-
1 portion of 3-(2-bromoethyl) phosphate 6.59. After dissolving this in 50a2 of chloroform, about 10 d of anhydrous trimethylamine is added, and the mixture is allowed to react overnight at room temperature in a sealed tube. Next, the solvent was distilled off under reduced pressure, and 100 ml of chloroform, 100 ml of methanol and 50 ml of water were added to the resulting residue to dissolve it, and the mixture was adjusted to pH 1 with 6N hydrochloric acid.
,O. The lower layer is separated, washed with 20 d of water, and then the solvent is distilled off under reduced pressure.

The obtained pale yellow oil was subjected to column chromatography (Art 7734, manufactured by Merck & Co., Ltd. Elution solvent: Chloroform:
If purified with methanol:water = 65:25:0 to 65:25:4), colorless wax-like 2゜2-bis(benzhydryloxycarbonyl 1-stearoyltrimethylene glycol-3-(2-trimethylammonyl) Oethyl)
Phosphe-1~・hydrate 4, 109 wo'I'
J'le.

IR (KBr) cm-1: 3400, 2920, 2850, 1730, 1
450, 1220, 1080.

1040, 960, 750, 695N) IR (
CDCl2: CD30D=2:1) δ value: 0, 89 (
bt, 3H, J=5Hz), 1.05 ~ 1.75 (
m, 30H).

1, 98 (bt, 2H, J=5Hz), 3.
00(s, 9H).

3, 18 ~3. 50 (ITh, 2N), 3.
60 ~4. 20 (m, 21-1).

4, 25 ~ 4.85 (m, 4H), 6.80 (S, 2
1+).

7, 00 ~7. 50 (m, 20tl)2, 2-
Bis(benzhydryloxycarbonyl)-1-stearoyltrimethylene glycol-3-(2-trimethylammonioethyl)phosphate hydrate 4. oog
After mixing with 2.5 d of anisole, 50 d of trifluoroacetic acid was added under water cooling, and the mixture was stirred at the same temperature for 10 minutes and roughly at the lowest temperature for 30 minutes. Next, the solvent was distilled off under reduced pressure, and 50 parts of diisopropyl ether was added to the obtained oil to solidify it. Filter the solid matter and add 10 mff of acetone.
After washing twice with i and drying, a pale yellow amorphous 2
, 2-dicarboxy-1-stearoyltrimethylene glycol-3-(2-1-limethylammonioethyl)phosphate hydrate 1,869 is obtained.

Melting point: 92°C (decomposed) IR (Br) cm-': 3450, 2920, 2850. 2600-22
00, 1930, 1730.

1460, 1300, 1210, 1160, 1
080, 1035. 97ON)IR (CDCl
2: CD30D=2:1) δ value: 0, 89 (bt, 3
H, J=5Hz), 1.05-1.80 (m, 30t
l).

2, 30 (bt, 2H), 3.22 (s, 9N).

3, 50-3.80 (III, 211), 4.00-
4.70 (m, 6N) Rf value: 0.78 Reference Example 2 In the same manner as Reference Example 1, 1 q of the compound in Table 4 was prepared.

(The following is a blank space) Reference Example 3 2.487 d of 2,2-dimethylolmalonic acid dibenzhydryl ester, 1.399 d of trityl chloride, and 2.02 d of pyridine are dissolved in 14 d of anhydrous tetrahydrofuran and refluxed for 4 hours. Then, after distilling off the solvent under reduced pressure, 40 ml of ethyl acetate and 20 ml of water were added to the evaporated residue. After adjusting the pH to 1.0 with 6N hydrochloric acid,
Separate the organic layer. Pour the obtained organic layer into 10 m of water! ! , 10 d of saturated aqueous sodium bicarbonate solution and 1 d of saturated saline solution
After sequentially washing at 0 m, drying with anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, 2.89 g of 2-trityloxymethyl-2-methylolmalonic acid dibenzhydryl ester was obtained.

(2) 2.2-L bis(penzhydryloxycarbonyl)-1-trityltrimethylene glycol-2-trityloxymethyl-2-methylolmalon dibenzhydryl ester 2.89 cJ, 2-bromoethyl phosphor rhodichloridate 1.893 and 2,6-lutidine 3
．． 2,2-
Bis(benzhydryloxycarbonyl)-1-trityl 1-rimethylene glycol-3-(2-trimethylammonioethyl) phosphate hydrate 1.07y
qru.

IR(Br)c77B-': 3300, 1720.1470.1445.1220.
1070.1040°950, 740.685 NHR (CDCI 3: C1) 30f) ~ 2:1)
δ1 direct: 2.60-3.30 (m, IIH),
3.90 (b, 2N).

4.20-4.90 (m, 4tl), 6.75 (s, 2
11).

6, 80-7.60 (m, 35 old (3) 2,2-dicarboxytrimethylene glyco-2,
2-bis(benzhydryloxycarbonyl)-1-trityltrimethylene glycol-3-(2-trimethylammonioethyl) phosphate hydrate 500m! ?
, Triflu A-acetic acid 5.0m! and anisole 0.5
If the reaction is carried out in the same manner as in Reference Example 1-(4) using d, pale yellowish amorphous 2,2-dicarboxytrimethylene glycol-1-(2-trimethylammonioethyl)bosphate/water is obtained. Take 170 mg of Japanese salt.

IR (Br) cm-1: 3350, 1900.1680.1460.1190.
1025.96ON) IR (C20) δ1 direct: 3, 20 (s, 911), 3.48-3.78 (m
, 2tl).

4.06 (s, 2tl), 4.14-4.48 (m,
LH) Example 1 200 m3 of cis-1-sudearoyl-3-[(2-trimethylammonioethyloxy)(oxide) hostyl trimethylene glycol-2,2-cis-dichlorodiammine platinum (II) was added to 3.0 m3 of water. After suspending the solution in water, 215 ml of silver nitrate is added. This mixture was heated at 60'C for 30
Stir for 1 minute, protected from light. Next, after cooling to the lowest temperature, it was passed through a 0.22 μ membrane filter and 1.0 m of water was passed over the filter. ! By washing with water, a pale yellow and transparent aqueous solution of cis-dinitrato(diammine)platinum (n) is obtained. On the other hand, 2,2-dicarboxy-1-stearoyltrimethylene glycol-3-<2-trimethylammonioethyl) phosphate hydrate 389-3 was dissolved in 5.0 ml of water, and purified with 1N aqueous potassium hydroxide solution.
Adjust to 116-7.

This solution is added to the previously obtained aqueous solution of cis-dinitrato(diammine)platinum (n), and stirred for 204 minutes at the lowest temperature in the dark. Next, 20 parts of chloroform and 20 parts of methanol are added, and after stirring, the lower layer is separated. 5ml water
After washing with water, the solution is concentrated under reduced pressure to about 2 ml to precipitate crystals. The precipitate is collected by filtration, washed sequentially with 2 ml of methanol and 2 ml of diethyl ether, and dried to give a pale yellow amorphous cis-[1-stearoyl-3-[(2
-trimethylammonioethyloxy)(oxide)phosphinylcotrimethyleneglycol-2,2-dicarboxylate] (Diammine)platinum(II>.hydrate) 340 my is obtained.

Melting point: Color starts at 110°C, foams and decomposes at 208°C IR (KBr) (772-1: 3400, 3220.2920.2850.1720.
1620.1460°1380, 1320.1225.
1180.1080.1040.965 NHR (CDC
l2: CD30D=1:1) δ value: 0.88 (bt,
3H, J=5Hz), 1.00-1.90 (m, 30
fl).

2.00-2.60 (b, 2H), 3.35 (bs, 9
H).

3.50 to 3.85 (b, 2H) Rf value: 0.51 Example 2 Cis-1-oleoyl-3-[(2-trimedelammonioethyloxy)(oxide)phos effluent cis- Example 1 Using dichlorodiammine platinum (II>150 mg and 275 mg of 2,2-dicarboxy-1-oleoyltrimethylene glycol-3-'(2-trimethylammonioethyl) phosphate hydrate)
By reacting and treating in the same manner as above, a pale yellow amorphous cis-
[]-]oleoyl-3-C<2-trimethylammonioethyloxy)(oxide)phosphinyl]trimethylene glycol-2,2-dicarboxylate]
(Diammine) Platinum (■) hydrate 180my is 1q.

Melting point: Color starts at 110'C, decomposes at 143°C) IR (KBr) cm-': 3400, 3180.2900.2850.1710.
1600.1440°1350, 1305.1210.
1170.1070.1050.1020.96ONH
R (CDCl2: CD30D=1:1) δ value: 0.8
8. (bt, 3H, J=511z), 1.02-2.
60 (m, 281-1).

3, 55 (bs, 9N), 3.50-3.85
(b, 2tl) 5,10-5.60 (m, 2tl) Rf value: 0.55 Example 3 cis-dichloro(trans-former-1,2-diaminocyclohexane)platinum(II) 150mg and 2.2 -Dicarboxy-1-stearoyltrimethylene glycol-3-(2-trimethylammonioethyl) phosphate hydrate (218 mg) was reacted and treated in the same manner as in Example 1, resulting in a pale yellow amorphous cis-[1 -stearoyl-
3-[(2-trimethylammonioethyloxy) (
oxide) phosphinylcotrimethylene glycol-2
,2-dicarboxylate] (trans-old-1,2j
diaminocyclohexane) platinum (n) hydrate 245
Get mg.

Melting point: Color starts at 170"C and develops at 188°C.
- Bubbling and decomposition IR (KBr) cm-1: 3380, 3200.2900.2850.1720.
1600°1440, 1370.1340.1300.
1220.1160°1070, 1050.1030.
96ONHR (CDCl2: CD30D=1:1)δ
Value: 0, 88 (bt, 3H, J=5Hz), 1.0
0-1.80 (m, 34H).

1.92-2.60 (m, 6H), 2.96-3.4
8 (m, 1111).

3.52-3.85 (m, 2H) If value: 0.91 In the same manner as in Example 3, the compounds shown in Table 5 are obtained.

(Left below) Tsukasa Example 4 Cis-dichloro(trans-old-1,2-diamicycyclohexane)platinum(II) 135m! ? and 2-dicarboxy-1-acetyltrimethylene glycol-3-(
2-trimethylammoniothyl) phosphate hydrate'! 24 tng is reacted in the same manner as in the example. After the reaction is completed, the aqueous liquid is dried under reduced pressure. The obtained residue is extracted with 10 ml of a mixed solvent of chloroform:tanol=1:1.

- Distill the solvent under pressure, add diethyl ether to crystallize, and collect by filtration. Old-1,2-diaminocyclohexa)platinum(II> hydrate 210/1lff
1 time.

Melting point: Starts coloring at 165°C, foams and decomposes at 190'C IR (13r) cm-1: 3400, 3180.2920.2850.1720.
1660.1620°1440, 1370.1310.
1230.1200.1170.1120°1080,
1060.1040.96ONHR (CDCI 3:
CD30D=1:1) δ (direct: 1, OO~2.
60On, 11tl), 3.15~3.50(m,
1111).

3.55-3.90 (m, 2H), 4.00-4.70
(m, 6N) Rf value: 0.44 Example 5 Cis-dichloro(dicyclopentylamine)platinum(II
) 175my and 2,2-dicarboxy-1-stearoyltrimethylene glycol-3-(2-trimethylammonioethyl)phosphate-1~ hydrate 220mg
If the reaction is carried out in the same manner as in Example 1 using dicyclopentylamine) platinum(n) hydrate 235m'j is obtained.

Melting point: Coloring begins at 130'C, foams and decomposes at 143°C IR (Br) cm-1: 3400, 3200.2920.2850.1720.
1600.1450°1360, 1310.1220.
1170.1080.1030.96ONHR(CDC
I3: CD30D=1:1) δ value: 0.89 (bt,
3tl, J=511z), 1.05-2.60(m,
48H).

2.95-3.40 (m, IIH), 3.50-3.8
0(m, 2M) Rf value: 0.78 Example 6 Cis-dichloro(trans-dl-1,2-diaminocyclopentane)platinum (II>100my and 2.2-
Dicarboxy-1-stearoyltrimethylene glycol-3-(2-trimethylammonioethyl) phosphate hydrate When reacted and treated in the same manner as in Example 1 using 151 mFl, a pale yellow amorphous cis- [1-stearoyl-3[(2-trimethylammonioethyloxy)(oxide)small sulfinyl]](+-lance-formerly-1,2-diaminocyclopentane)platinum (II> hydrate 176 #l! Get an F.

Melting point: Color starts at 165°C, foams and decomposes at 189°C IR (KBr)oy+ -1: 3400, 3200.2920.2850.1720.
1610.1460°1360.1300,1220,
1180,1080,1040.97ONHR(CDC
I 3 : CD30D=1:1) δ (direct; 0.
89 (bt, 3H, J=5ilz), 1.00-2.
60 (m, 3811).

2.90~3.40 (m, 1111), 3.50~
3.80 (m, 2H) Rf value: 0.85 Example 7 cis-r1- (2-trimedelammonioethyloxy) (oxide)phosphinylkotrimethys-dichloro(trans-dl-1,2- If 158 m3 of diaminocyclohexane) platinum (II) and 130 mg of 2,2-dicarboxytrimethylene glycol-1-(2-trimethylammonioethyl) phosphate hydrate were reacted and treated in the same manner as in Example 4, Pale yellow amorphous cis-N-(2-1-limethylammonioethyloxy)(oxide)bosphinyl]trimethylene glycol-2,2-dicarboxylate](trans-dl
- 1q of 235my of platinum (n) hydrate (1,2-diaminocyclohexane).

Melting point: Starts coloring at 180'C, foams and decomposes at 204°C IR (KBr) cm-1: 3400-3100.1600.1350.1220°1070.1020.960 N'RR (D20) δ value; 0.90-2.63 (m, 8H), 3.00-3.44
(m, 1lfl).

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R is a hydrogen atom or C_1_~_3_0 aliphatic carboxylic acid residue; A^1 and A^2 are the same or different and are ammine or substituted Alkylamine or cycloalkylamine or A^1 and A
^2 together indicate an optionally substituted bidentate amine. ] A cis-platinum (II) complex compound represented by these.