Platinum compounds of malonic acid derivative having leaving group containing amino or alkylamino

Abstract

Disclosed are a class of platinum compounds of malonic acid derivatives having a leaving group containing an amino or alkylamino, and pharmaceutically acceptable salt thereof, preparation method thereof and pharmaceutical composition containing the compounds. Also disclosed are uses of the compounds for treating cell proliferative diseases especially cancers. The platinum compounds of the present invention have high solubility in water, low toxicity and strong anti-tumor effect.

Claims

1. A platinum compound of formula A, ##STR00163## or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein: R.sub.0 may or may not exist; when R.sub.0 exists, it is selected from alkyl, cycloalkyl, alkoxyalkyl, alkylaminoalkyl, heterocyclyl, alkenyl and alkynyl, which are unsubstituted or optionally substituted by halogen, hydroxyl, alkoxy, alkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, and/or aryl, provided that if R.sub.0 contains an unsaturated bond, the atom of the unsaturated bond cannot be directly connected with nitrogen atom, and then formula A is quaternary ammonium compound; while when R.sub.0 does not exist, formula A is a tertiary amine compound; R.sub.1 and R.sub.2 may be the same or different, and are selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, alkylaminoalkyl, heterocyclyl, alkenyl, and alkynyl, which are unsubstituted or optionally substituted by halogen, hydroxyl, alkoxy, alkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, and/or aryl, provided that if R.sub.1 or R.sub.2 contains an unsaturated bond, the atom of the unsaturated bond cannot be directly connected with nitrogen atom; or R.sub.1, R.sub.2 and the nitrogen atom connected with them may together form a closed saturated or unsaturated heterocyclic ring; said ring can be three-membered, four-membered, five-membered, six-membered, seven-membered or eight-membered ring; said ring may be optionally fused with other rings and may be optionally substituted by halogen, hydroxyl, alkoxy, alkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, and/or aryl, provided that the atom connected with said nitrogen atom is a saturated carbon atom; R.sub.3 is C.sub.4 linear alkylene or C.sub.4 cycloalkylene, which can be optionally substituted by one or more alkoxy, hydroxyl, alkyl, halogen, haloalkyl, alkoxyalkyl, and/or heterocyclyl; R.sub.4 and R.sub.5 may be the same or different, and are selected from: hydrogen, hydroxyl, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocyclyl, alkenyl, and alkynyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, alkoxyalkyl, alkylaminoalkyl and heterocyclyl can be unsubstituted or optionally substituted, preferably substituted by halogen, hydroxyl, alkoxy, linear or branched alkyl, alkoxyalkyl, cycloalkyl and/or heterocyclyl; or R.sub.4, R.sub.5 and the atoms connected with them may together form a closed ring, which may be four-membered, five-membered, six-membered, seven-membered or eight-membered ring; said ring may be optionally condensed with other rings and may be optionally substituted.

2. The platinum compound or the pharmaceutical acceptable salt, solvate, stereoisomer, or prodrug thereof according to claim 1, wherein: R.sub.3 is C.sub.4 linear alkylene, which can be optionally substituted by one or more alkoxy, hydroxyl, and/or alkyl, and said alkoxy is selected from: methoxyl, ethoxyl, propoxyl, and isopropoxyl; said alkyl is selected from methyl, ethyl and isopropyl.

3. The platinum compound or the pharmaceutical acceptable salt, solvate, stereoisomer, or prodrug thereof according to claim 1, wherein: R.sub.3 is the C.sub.4 cycloalkylene, which can be optionally substituted by one or more alkoxy, hydroxyl, and/or alkyl, and said alkoxy is selected from methoxyl, ethoxyl, propoxyl, and isopropoxyl; said alkyl is selected from methyl, ethyl, and isopropyl.

4. The platinum compound or the pharmaceutical acceptable salt, solvate, stereoisomer, or prodrug thereof according to claim 1, wherein: R.sub.1 and R.sub.2 are selected independently from hydrogen, methyl, ethyl or propyl; or R.sub.1, R.sub.2 and the atoms connected with them can together form a closed ring; said ring is a pyrrole ring or pyridine ring and can be optionally substituted.

5. The platinum compound or the pharmaceutical acceptable salt, solvate, stereoisomer, or prodrug thereof according to claim 1, wherein the structure thereof is shown in formula C: ##STR00164## and the above structure can be optionally substituted; R.sub.6 is (CH.sub.2).sub.n, wherein n=1-6, preferably 3-5, the most preferably 4, wherein some —CH.sub.2— is optionally substituted by —O—; wherein one or more hydrogens of (CH.sub.2)— are optionally substituted by fluorine, alkyl, hydroxyl, alkoxy, and/or heterocyclyl; R.sub.7 is (CH.sub.2).sub.n, wherein n=0-3, preferably n=0-2; wherein some —CH.sub.2— is optionally substituted by —O—; wherein one or more hydrogens of (CH.sub.2).sub.n are optionally substituted by halogen, alkyl, hydroxyl, hydroxyalkyl, alkoxy, and/or heterocyclyl; R.sub.8 and R.sub.9 are selected from hydrogen, halogen, hydroxyl, hydroxyalkyl, alkyl, alkoxy and heterocyclyl; R.sub.8 and R.sub.9 may be the same or different, preferably hydroxymethyl; R.sub.10 and R.sub.11 are selected from hydrogen, halogen, hydroxyalkyl, alkyl, alkoxy, and heterocyclyl; R.sub.10 and R.sub.11 may be the same or different, preferably hydroxymethyl; R.sub.12 is (CH.sub.2).sub.n, wherein n=2-4; wherein some —CH.sub.2— is optionally substituted by —O—, and one or more hydrogens of (CH.sub.2).sub.n are optionally substituted by halogen, alkyl, hydroxyl, alkoxy and/or heterocyclyl; R.sub.13 is —CH.sub.2— or —O—, preferably —CH.sub.2—; R.sub.14 is selected from hydrogen, halogen, alkyl, alkoxy, heterocyclyl, hydroxyalkyl and hydroxyl; R.sub.14 is preferably hydrogen; R.sub.15 is selected from: (CH.sub.2).sub.n, wherein n=1-3, —CH.sub.2—O—, —O— and —CH.sub.2—O—CH.sub.2—; wherein one or more hydrogens of (CH.sub.2).sub.n are optionally substituted by alkyl, alkoxy, heterocyclyl, hydroxyl, and/or hydroxyalkyl; preferably —CH.sub.2—O—CH.sub.2—.

6. The platinum compound or the pharmaceutical acceptable salt, solvate, stereoisomer, or prodrug thereof according to claim 5, wherein said compound is as shown in the formulae below: ##STR00165## ##STR00166## wherein: R.sub.0 may or may not exist; when R.sub.0 exists, it is selected from alkyl, cycloalkyl, alkoxyalkyl, alkylaminoalkyl, heterocyclyl, alkenyl and alkynyl, which are unsubstituted or optionally substituted by halogen, hydroxyl, alkoxy, alkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, and/or aryl, provided that if R.sub.0 contains an unsaturated bond, the atom of the unsaturated bond cannot be directly connected with nitrogen atom, and then formula A is quaternary ammonium compound; while when R.sub.0 does not exist, formula A is a tertiary amine compound; R.sub.1 and R.sub.2 may be the same or different, and are selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, alkylaminoalkyl, heterocyclyl, alkenyl, and alkynyl, which are unsubstituted or optionally substituted by halogen, hydroxyl, alkoxy, alkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, and/or aryl, provided that if R.sub.1 or R.sub.2 contains an unsaturated bond, the atom of the unsaturated bond cannot be directly connected with nitrogen atom; or R.sub.1, R.sub.2 and the nitrogen atom connected with them may together form a closed saturated or unsaturated heterocyclic ring; said ring can be three-membered, four-membered, five-membered, six-membered, seven-membered or eight-membered ring; said ring may be optionally fused with other rings and may be optionally substituted by halogen, hydroxyl, alkoxy, alkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, and/or aryl, provided that the atom connected with said nitrogen atom is a saturated carbon atom; R.sub.3 is C.sub.4 linear alkylene or C.sub.4 cycloalkylene, which can be optionally substituted by one or more alkoxy, hydroxyl, alkyl, halogen, haloalkyl, alkoxyalkyl, and/or heterocyclyl.

7. The platinum compound or the pharmaceutical acceptable salt, solvate, stereoisomer or prodrug thereof according to claim 1, wherein said compound is selected from the group consisting of: Compound 1: 2-(4-diethylamino butyl)-malonate•cis-diamine platinum (II) acetate; Compound 2: 2-(4-diethylamino butyl)-malonate•cis-(1, 2-ethylenediamine) platinum (II) tosilate; Compound 3: 2-(4-diethylamino butyl)-malonate•cis-(1, 2-trans-cyclohexanediamine) platinum (II) tosilate; Compound 4: 2-(4-(1-piperidyl)-butyl)-malonate•cis-diamine platinum (II) phosphate; Compound 5: 2-(4-(1-tetrahydropyrrolidinyl)-butyl)-malonate•cis-diamine platinum (II) phosphate; Compound 6: 2-(3-dimethylamino cyclobutyl)-malonate•cis-diamine platinum (II) mesylate; Compound 7: 2-(4-di-n-propylamino butyl)-malonate•cis-diamine platinum (II) phosphate; Compound 8: 2-(3-methyl-4-diethylamino butyl)-malonate•cis-diamine platinum (II) acetate; Compound 9: 2-(4-(1-piperidyl)-butyl)-malonate•cis-(1,2-trans-cyclohexanediamine) platinum (II) tosilate; Compound 10: 2-(4-(2-methyl-1-tetrahydropyrrolidinyl)-butyl)-malonate•cis-diamine platinum (II) phosphate; Compound 11: 2-(4-amino butyl)-malonate•cis-(1,2-trans-cyclohexanediamine) platinum (II) phosphate; Compound 12: 2-(4-ethylamino butyl)-malonate•cis-(1, 2-trans-cyclohexanediamine) platinum (II) phosphate; Compound 13: 2-(4-N-methyl-isopropylamino butyl)-malonate•cis-diamine platinum (II) acetate; Compound 14: 2-(4-diethylamino butyl)-malonate•cis-(1, 2-trans-cyclopentanediamine) platinum (II) phosphate; Compound 15: 2-(4-diethylamino butyl)-malonate•cis-(1,2-trans-cyclobutanediamine) platinum (II) succinate; Compound 16: 2-(4-diethylamino butyl)-malonate•cis-(1,2-trans-cyclopropanediamine) platinum (II) phosphate; Compound 17: 2-(4-diethylamino butyl)-malonate•cis-(1,2-ethylenediamine) platinum (II) tosilate; Compound 18: 2-(4-diethylamino butyl)-malonate•cis-(1,3-propanediamine) platinum (II) phosphate; Compound 19: 2-(4-diethylamino butyl)-malonate•cis-(1,4-butanediamine) platinum (II) phosphate; Compound 20: 2-(2-diethylamino butyl)-malonate•cis-1, 2-(1,2-bis hydroxymethyl)-ethylene diamine platinum (II) phosphate; Compound 21: 2-(4-diethylamino butyl)-malonate•cis-1,3-(2,2-hydroxymethyl)-propane diamine platinum (II) phosphate; Compound 22: 2-(4-diethylamino butyl)-malonate•cis-1, 4-(trans-2, 3-cyclobutyl)-butanediamine platinum (II) phosphate; Compound 23: 2-(4-diethylamino butyl)-malonate•cis-(1,4-cyclohexyldiamine) platinum (II) phosphate; Compound 24: 2-(4-diethylamino butyl)-malonate•cis-1,3-(2,2-(4-oxacyclohexyl))-propanediamine platinum (II) phosphate; Compound 25: 2-(4-diethylamino butyl)-malonate•cis-dicyclopentylamine platinum (II) acetate; Compound 26: 2-(4-diethylamino butyl)-malonate•cis-•ammonia•cyclopentylamine platinum (II) acetate; Compound 27: 2-(4-diethylamino butyl)-malonate•cis-•(2-aminomethyl-cyclopentylamine) platinum (II) acetate; Compound 28: 2-(4-diethylamino butyl)-malonate•cis-•ammonia piperidine platinum (II) acetate; and Compound 29: 2-(4-trimethylamino butyl)-malonate-cis-(1, 2-trans-cyclohexanediamine) platinum (II) tosilate.

8. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition according to claim 8, wherein said pharmaceutical composition further comprises one or more of other drugs for the treatment of cancers.

10. A method for preparing the platinum compound according to claim 1, including the following steps: (1) adding potassium chloroplatinite into water and stirring at room temperature to dissolve it, dissolving potassium iodide by water before adding into the above potassium chloroplatinite solution to undergo reaction away from light in water bath under nitrogen charging condition; (2) dissolving R.sub.4NH.sub.2 by water and adding into the reaction solution obtained in (1) before reacting under water bath condition; (3) cooling the above reaction solution below room temperature, dissolving R.sub.5NH.sub.2 by water and then adding to the reaction solution obtained in (2) to undergo reaction under water bath, with a quality of yellow deposit generated; after cooling the reaction solution below room temperature, obtaining diiododiamine platinum (II) through suction filtration and washing; (4) adding Ag.sub.2SO.sub.4 into water and stirring, adding the above diiododiamine platinum (II) into the reaction solution and then adding water to undergo reaction away from light in water bath under nitrogen charging condition, obtaining dihydroldiamine platinum (II) sulfate by suction filtration; (5) placing diethyl malonate and Br—R.sub.3—Br into a flask, adding K.sub.2CO.sub.3 and tetrabutylammonium bromide into the flask and stirring, and then heating the reaction; after removal of solid by suction filtration and washing, combining filtrate, washing the organic layer, drying it, and undergoing reduced pressure distillation of the solvent to collect the distillate; (6) placing 2-Br—R.sub.3-diethyl malonate into a flask, adding anhydrous K.sub.2CO.sub.3 and acetonitrile, and stirring them; adding R.sub.1—NH—R.sub.2 or R.sub.1—N(R.sub.0)—R.sub.2 into the reaction solution, heating the reaction, and removing insoluble substance through filtration; pumping the filtrate to dryness, and then dissolving the residue in organic solvent; obtaining a product through washing with aqueous solution, drying the organic layer, and pumping out the solvent under reduced pressure; and purifying the product; (7) placing the product obtained in (6) into a flask, adding NaOH solution and stirring at room temperature; and (8) after adjusting the product obtained in (7) with acid solution, adding the product obtained in (4), and heating the mixture to obtain the platinum compound of the present invention.

11. The method for preparing the platinum compound according to claim 5 including the following steps: (1) adding potassium chloroplatinite into water and stirring at room temperature to dissolve it, dissolving potassium iodide by water before adding into the above potassium chloroplatinite solution to undergo reaction away from light in water bath under nitrogen charging condition; (2) dissolving bidentate ammonia NH.sub.2—X—NH.sub.2 by water and adding into the reaction solution obtained in (1) before reacting under water bath condition, with a quantity of yellow deposit generated; after cooling the reaction mixture below room temperature, obtaining bidentate diiododiamine platinum (II) through suction filtration and washing; (3) adding Ag.sub.2SO.sub.4 into water and stirring, adding the above diiododiamine platinum (II) into the reaction solution and then adding water to undergo reaction away from light in water bath under nitrogen charging condition, obtaining dihydroldiamine platinum (II) sulfate by suction; (4) placing diethyl malonate and Br—R.sub.3—Br into a flask, adding K.sub.2CO.sub.3 and tetrabutylammonium bromide into the flask and stirring, and then heating the reaction; after removal of solid by suction filtration and washing, combining filtrate, washing the organic layer, drying it, and undergoing reduced pressure distillation of the solvent to collect the distillate; (5) placing 2-Br—R.sub.3-diethyl malonate into a flask, adding anhydrous K.sub.2CO.sub.3 and acetonitrile, and stirring them; adding R.sub.1—NH—R.sub.2 or R.sub.1—N(R.sub.0)—R.sub.2 into the reaction solution, heating the reaction, and removing insoluble substance through filtration; pumping the filtrate to dryness, and then dissolving the residue in organic solvent; obtaining a product through washing with aqueous solution, drying the organic layer, and pumping out the solvent under reduced pressure; and purifying the product; (6) placing the product obtained in (5) into a flask, adding NaOH solution and stirring at room temperature; and; (7) after adjusting the product in (6) with acid solution, adding the product obtained in (3), and heating the mixture to obtain the platinum compound of the present invention.

12. A kit comprising the pharmaceutical composition according to claim 8 or 9 and instructions, wherein said kit further comprises one or more other drugs for the treatment of cancers.

Description

PREFERRED EMBODIMENTS OF THE PRESENT INVENTION

(1) The implementation of the present invention was described by the following examples and test examples in details, but will not limit the present invention in any way. It should be understood by those skilled in the art that any modifications or substitutions of the corresponding technical features according to the instructions of the prior art still belong to the scope claimed by the present invention. The purity of the raw materials used in the present invention is just above chemical purity, which can be purchased commercially. The compounds obtained in the following examples are all in the form of salt, which may be obtained by adding an alkali to adjust pH to obtain a free compound and can be easily converted into other types of organic or inorganic salts by using the method of adding a corresponding acid, which possibly include, but not limited to, nitrate, carbonate, bicarbonate, phosphate, hydrophosphate, dihydric phosphate, sulphate, bisulfate, phosphite, acetate, propionate, isobutyrate, malonate, benzoate, succinate, suberate, fumarate, mandelate, phthalate, benzene sulfonate, tosilate, citrate, tartrate, mesylate, arginine salt, glucuronate or galactose acid salt, etc. This will no longer be illustrated in the following examples one by one. In addition, for the compound having a chiral center, its racemes are generally synthesized by a conventional method, and its optical isomers are obtained by using a conventional resolution method in the art and using a asymmetric synthesis method when synthesizing, these methods are conventional technologies well-known by those skilled in the art.

[Example 1]: 2-(4-diethylaminobutyl)-malonate•cis-diamine platinum (II) acetate

Step 1: 2-(4-bromobutyl)-diethyl malonate

(2) ##STR00010##

(3) 16.06 g (0.1 mol) diethyl malonate and 21.6 g (0.1 mol) 1,4-dibromobutane were placed into a 150 ml three-necked flask, 15.12 g (0.11 mol) K.sub.2CO.sub.3 and 156 mg tetrabutylammonium bromide were added and stirred, the mixture was heated to 65° C.˜85° C. in an oil bath for 16 h 24 h; suction filtration was conducted to remove the solid which was washed with ethyl ether (30 ml×3 times), the filtrate was combined, and the organic layer was washed with water (40 ml×3 times) and then dried over MgSO.sub.4 for 4 h˜8, the solvent was distilled under reduced pressure, and then distilled under reduced pressure using an oil pump, 9.35 g of fraction at 140° C.˜151° C. under the vacuum degree of 7 mmHg was collected, with the yield of 31.69%.

Step 2: diethyl 2-(4-diethylaminobutyl)-malonate

(4) ##STR00011##

(5) 117.9 g (0.4 mol) diethyl 4-bromobutyl-malonate was placed into a three-necked flask, 55.5 g (0.4 mol) anhydrous K.sub.2CO.sub.3 and 500 ml acetonitrile were added and stirred. 73.2 g (1.0 mol) diethylamine was added in the reaction solution, and the mixture was heated to 45° C.˜60° C. in an oil bath to react for 2 h-6 h, the insoluble substance was filtered out, the filtrate was pumped out and then the filtrate was dissolved by adding 1000 ml ethyl acetate and washed with saturated NaCl aqueous solution (250 ml×3 times), and the organic layer was dried over anhydrous MgSO.sub.4 overnight, the solvent was pumped out under reduced pressure using a water pump, to obtain 103.5 g of light yellow, light red, transparent substance which was purified by column chromatography to obtain 48.55 g pure product, with the yield of 42.29%.

Step 3: disodium 2-(4-diethylaminobutyl)-malonate

(6) ##STR00012##

(7) 2M NaOH solution was obtained by dissolving 212.1 mg (5 mmol) NaOH with 2.5 mL water. 575 mg (2 mmol) diethyl 2-(4-diethylaminobutyl)-malonate was placed into a 20 mL three-necked flask, and the above NaOH solution was added thereto, stirring at room temperature for 45 h˜60 h, to obtain a solution of disodium 2-(4-diethylaminobutyl)-malonate.

Step 4: diamine•diiodoplatinum (II)

(8) ##STR00013##

(9) 2.075 g (5 mmol) potassium tetrachloroplatinate (K.sub.2PtCl.sub.4) was added in 50 ml water and dissolved by stirring at room temperature, and 6.640 g (40 mmol) KI was added in the reaction solution after being dissolved with 50 ml water, with the protection of N.sub.2 and away from light, the mixture was heated to 40° C.˜60° C. in a water bath for 0.5 h˜2 h. Then 50 ml ammonia water (containing 5 mmol ammonia) was added in the reaction solution, which was kept under this condition to react for 0.5 h˜2 h. A light yellow solid product was obtained by suction filtration and washed with water (10 ml×3 times) and ethyl ether (10 ml×3 times), to obtain 2.29 g product, with the yield of 95.1%. Elemental analysis: H, 1.24% (theoretical 1.21%), N, 5.56% (theoretical 5.797%).

Step 5: diamine•dihydrated platinum (II) sulphate

(10) ##STR00014##

(11) 625 mg (2 mmol) Ag.sub.2SO.sub.4 was placed in a 100 ml three-necked flask, 30 ml water was added thereto and stirred, and 0.96 g (2 mmol) diamine•diiodoplatinum (II) was added into the reaction solution and then 40 ml water was added to react, with the protection of N.sub.2 and away from light, the mixture was reacted in a water bath at 40° C.˜60° C. for 4 h˜8 h. After removing AgI precipitate by suction filtration, the filtrate was obtained, i.e., the aqueous solution of the product.

Step 6: 2-(4-diethylaminobutyl)-malonate•cis-diamine platinum (II) acetate

(12) ##STR00015##

(13) The pH of disodium [2-(4-diethylaminobutyl)-malonate solution was adjusted to 5˜7 with 1M HAC and then cis-diamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture is heated to 40° C.˜75° C. in a water bath for 4 h-6 h, and the reaction solution was concentrated to a certain volume after suction filtration and stayed, to obtain 130 mg crystalline-type product.

(14) The compound in Example 1 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 28.72% (theoretical 28.82%), H, 5.61% (theoretical 5.46%), N, 8.98% (theoretical 9.17%).

(15) .sup.1HNMR (D.sub.2O) (ppm): δ3.52 (m, 1H), δ2.79-2.67 (b, 4H), δ2.57-2.67 (b, 2H), δ1.80 (m, 2H), δ1.45 (m, 2H), δ1.24 (m, 2H), δ1.05 (t, 6H).

[Example 2]: 2-(4-diethylaminobutyl)-malonate•cis-(1, 2-ethylenediamine) platinum (II) tosilate

(16) Steps 1, 2 and 3 are the same as steps 1, 2, and 3 in [Example 1], respectively.

Step 4: 1, 2-ethanediamine•diiodoplatinum (II)

(17) ##STR00016##

(18) 2.076 g (5 mmol) potassium tetrachloroplatinate (K.sub.2PtCl.sub.4) is added in 50 ml water and dissolved by stirring at room temperature, and 6.64 g (40 mmol) KI is added in the reaction solution after being dissolved with 50 ml water, with the protection of N.sub.2 and away from light, the mixture was heated to 40° C.˜60° C. in a water bath for 0.5 h˜2 h, and then 301 mg (5 mmol) refrigerated 1,2-ethylenediamine (commercially available) was added in the reaction solution after being dissolved with 50 ml water, which was kept under this condition to react for 0.5˜2 h. A yellow solid product is obtained by suction filtration, and washed with water (10 ml×3 times) and ethyl ether (10 ml×3 times), to obtain 2.254 g product, with the yield of 89.8%. Elemental analysis: C, 4.77% (theoretical 4.72%), H, 1.41% (theoretical 1.57%), N, 5.41% (theoretical 5.50%).

Step 5: 1, 2-ethylenediamine•dihydrated platinum (II) sulphate

(19) ##STR00017##

(20) 625 mg (2 mmol) Ag.sub.2SO.sub.4 is placed in a 100 ml three-necked flask, 30 ml water is added thereto and stirred, and 1.020 g (2 mmol) 1, 2-ethylenediamine•diiodoplatinum (II) is added into the reaction solution and then 40 ml water is added to react, with the protection of N.sub.2 and away from light, the mixture is reacted at 40° C.˜60° C. in a water bath for 4 h˜8 h. After removing AgI precipitate by suction filtration, the filtrate was obtained, i.e., the aqueous solution of the product.

Step 6: 2-(4-diethylaminobutyl)-malonate•cis-(1, 2-ethylenediamine) platinum (II) tosilate

(21) ##STR00018##

(22) The pH of disodium 2-(4-diethylaminobutyl)-malonate solution was adjusted to 5˜7 with 1M p-toluenesulfonic acid C.sub.7H.sub.8O.sub.3S, and then 1,2-ethylenediamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜60° C. in a water bath for 4 h-8 h, and the reaction solution was added into 2.5 g silica gel for column chromatography (200-300 meshes), and stirred for 15 min and then pumped to be dryness, the mixture is treated by column chromatography to obtain 138 mg product.

(23) The compound in Example 2 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, phosphate, fumarate, etc. Elemental analysis of the free alkali: C, 32.31% (theoretical 32.23%), H, 5.65% (theoretical 5.58%), N, 8.82% (theoretical 8.68%).

(24) .sup.1HNMR (D.sub.2O) (ppm): δ3.51 (m, 1H), δ2.77-2.67 (br, 4H), δ2.65-2.57 (br, 2H), δ2.25 (br, 4H), δ1.79 (m, 2H), δ1.44 (m, 2H), δ1.23 (m, 2H), δ1.05 (t, 6H).

[Example 3]: 2-(4-diethylaminobutyl)-malonate•cis-(1, 2-trans-cyclohexanediamine) platinum (II) tosilate

(25) Steps 1, 2 and 3 are the same as steps 1, 2 and 3 in [Example 1], respectively.

Step 4: Trans-cyclohexanediamine•diiodoplatinum(II)

(26) ##STR00019##

(27) 2.075 g (5 mmol) potassium tetrachloroplatinate (K.sub.2PtCl.sub.4) was added in 50 ml water and dissolved by stirring at room temperature, and 6.640 g (40 mmol) KI was added in the reaction solution after being dissolved with 50 ml water, with the protection of N.sub.2 and away from light, the mixture was heated to 40° C.˜60° C. in a water bath for 0.5 h˜2 h, and then 571 mg (5 mmol) trans-cyclohexanediamine was added into the reaction solution after being dissolved in 50 ml water, which was kept under this condition to react for 0.5 h˜2. A yellow solid product is obtained by suction filtration and washed with water (10 ml×3 times) and ethyl ether (10 ml×3 times), to obtain 2.709 g product, with the yield of 96.2%. Elemental analysis: C, 12.68% (theoretical 12.80%); H, 2.61% (theoretical 2.51%); N, 4.99% (theoretical 4.98%).

Step 5: trans-1, 2 cyclohexanediamine•dihydrated platinum (II) sulfate

(28) ##STR00020##

(29) 625 mg (2 mmol) Ag.sub.2SO.sub.4 was placed in a 100 ml three-necked flask, 30 ml water was added thereto and stirred, and 1.126 g (2 mmol) trans-cyclohexanediamine•diiodoplatinum (II) was added into the reaction solution and then 40 ml water is added to react, with the protection of N.sub.2 and away from light, the mixture was reacted at 40° C.˜60° C. in a water bath for 4 h˜8 h. After removing AgI precipitate by suction filtration, the filtrate was obtained, i.e., the aqueous solution of the product.

Step 6: 2-(4-diethylaminobutyl)-malonate•cis-(1, 2-trans-cyclohexanediamine) platinum (II) tosilate

(30) ##STR00021##

(31) The pH of disodium [2-(4-diethylaminobutyl)-malonate solution was adjusted to 5˜7 with 1M p-toluenesulfonic acid and then trans-cyclohexanediamine•dihydrated platinum (II) sulphate is poured into the reaction solution, with the protection of N.sub.2, the mixture is heated to 40° C.˜60° C. in a water bath for 4 h-8 h, and the reaction solution was added into 2.5 g silica gel for column chromatography (200-300 meshes) and stirred for 15 min and then pumped to be dryness, the mixture was treated by column chromatography to obtain 157 mg product.

(32) The compound in Example 3 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 37.76% (theoretical 37.92%), H, 6.25% (theoretical 6.13%), N, 7.70% (theoretical 7.81%).

(33) .sup.1HNMR (D.sub.2O) (ppm): δ3.52 (m, 1H), δ2.78-2.65 (br, 4H), δ2.67-2.56 (br, 2H), δ2.05 (br, 2H), δ1.80 (m, 4H), δ1.46 (m, 4H), δ1.25 (m, 4H), δ1.05 (t, 6H), δ1.01 (m, 2H).

[Example 4]: 2-(4-(1-piperidyl)-butyl)-malonate•cis-diamine platinum (II) phosphate

(34) Step 1 is the same as step 1 in [Example 1].

Step 2: diethyl 2-(4-(1-piperidyl)-butyl)-malonate

(35) ##STR00022##

(36) 117.9 g, (0.4 mol) diethyl 4-bromobutyl-malonate was placed into a three-necked flask, 55.5 g (0.4 mol) anhydrous K.sub.2CO.sub.3 and 500 ml acetonitrile were added and stirred. 85.0 g (1.0 mol) piperidine solution was added in the reaction solution, and the mixture was heated to 45° C.˜60° C. in an oil bath to react for 2 h-6 h, the insoluble substance was filtered out, the filtrate was pumped out and then the filtrate was dissolved by adding 1000 ml ethyl acetate and washed with saturated NaCl aqueous solution (250 ml×3 times), and the organic layer was dried over anhydrous MgSO.sub.4 overnight, the solvent was pumped out under reduced pressure using a water pump, to obtain 101.2 g of light yellow, light red, transparent substance which was purified by column chromatography to obtain 36.71 g pure product, with the yield of 30.69%.

Step 3: disodium 2-(4-(1-piperidyl)-butyl)-malonate

(37) ##STR00023##

(38) 2M NaOH solution was obtained by dissolving 212.3 mg (5 mmol) NaOH with 2.5 mL water. 599 mg (2 mmol) diethyl 2-(4-(1-piperidyl)-butyl)-malonate was placed into a 20 mL three-necked flask and the above NaOH solution was added thereto, stirring at room temperature for 45 h˜60 h, to obtain a solution of disodium 2-(4-(1-piperidyl)-butyl)-malonate.

(39) Steps 4, 5 are the same as steps 4, 5 in [Example 1], respectively.

Step 6: 2-(4-(1-piperidyl)-butyl)-malonate-cis-diamine platinum (II) phosphate

(40) ##STR00024##

(41) The pH of disodium 2-(4-(1-piperidyl)-butyl)-malonate solution was adjusted to 5˜7 with 1M H.sub.3PO.sub.4 and then cis-diamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜75° C. in a water bath for 4 h-6 h, and the reaction solution was concentrated to a certain volume after suction filtration and stayed, to obtain 138 mg crystalline-type product.

(42) The compound in Example 4 was soluble in water, the solubility was more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 30.47% (theoretical 30.64%), H, 5.13% (theoretical 5.32%), N, 9.00% (theoretical 8.94%).

(43) .sup.1H NMR (D.sub.2O) (ppm): δ3.61 (t, 1H), δ2.83 (t, 4H), δ2.71 (t, 2H), δ1.84 (m, 2H), δ1.76 (m, 4H), δ1.54 (m, 2H), δ1.42 (m, 2H), δ1.33 (m, 2H).

[Example 5]: 2-(4-(1-tetrahydropyrrolidinyl)-butyl)-malonate•cis-diamine platinum (II) phosphate

(44) Step 1 is the same as step 1 in [Example 1].

Step 2: diethyl 2-(4-(1-tetrahydropyrrolidinyl)-butyl)-malonate

(45) ##STR00025##

(46) 118.1 g, (0.4 mol) diethyl 4-bromobutyl-malonate was placed into a three-necked flask, 55.53 g (0.4 mol) anhydrous K.sub.2CO.sub.3 and 500 ml acetonitrile were added and stirred. 71.2 g (1.0 mol) tetrahydropyrrolidine was added in the reaction solution, and the mixture was heated to 40° C.˜60° C. in an oil bath to react for 2 h-6 h, the insoluble substance was filtered out, the filtrate was pumped out and then the filtrate was dissolved by adding 1000 ml ethyl acetate and washed with saturated NaCl aqueous solution (250 ml×3 times), and the organic layer was dried over anhydrous MgSO.sub.4 overnight, the solvent was pumped out under reduced pressure using a water pump, to obtain 96.4 g of light yellow, light red, transparent substance which was purified by column chromatography to obtain 31.23 g pure product, with the yield of 27.39%.

Step 3: disodium 2-(4-(1-piperidyl)-butyl)-malonate

(47) ##STR00026##

(48) 2M NaOH solution was obtained by dissolving 212.4 mg (5 mmol) NaOH with 2.5 mL water. 545 mg (2 mmol) diethyl 2-(4-(1-tetrahydropyrrolidinyl)-butyl)-malonate was placed into a 20 mL three-necked flask and the above NaOH solution was added thereto, stirring at room temperature for 45 h˜60 h, to obtain a solution of disodium 2-(4-(1-tetrahydropyrrolidinyl)-butyl)-malonate.

(49) Steps 4, 5 are the same as steps 4, 5 in [Example 1], respectively.

Step 6: 2-(4-(1-tetrahydropyrrolidinyl)-butyl)-malonate•cis-diamine platinum (II) phosphate

(50) ##STR00027##

(51) The pH of disodium 2-(4-(1-tetrahydropyrrolidinyl)-butyl)-malonate solution was adjusted to 5˜7 with 1M H.sub.3PO.sub.4 and then cis-diamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜75° C. in a water bath for 4 h-6 h, and the reaction solution was concentrated to a certain volume after suction filtration and stayed, to obtain 128 mg crystalline-type product.

(52) The compound in Example 5 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 28.71% (theoretical 28.95%), H, 4.97% (theoretical 5.04%), N, 9.37% (theoretical 9.21%).

(53) .sup.1HNMR (D.sub.2O) (ppm): δ3.62 (t, 1H), δ2.83 (t, 4H), δ2.72 (t, 2H), δ1.85 (m, 2H), δ1.78 (m, 4H), δ1.51 (m, 2H), δ1.33 (m, 2H).

[Example 6]:2-(3-dimethylaminocyclobutyl)-malonate•cis-diamine platinum (II) mesylate

Step 1: diethyl 2-(3-bromocyclobutyl)-malonate

(54) ##STR00028##

(55) 16.02 g (0.1 mol) diethyl malonate and 21.5 g (0.1 mol) 1, 3-dibromocyclobutyl were placed into a 150 ml three-necked flask, 15.13 g (0.11 mol) K.sub.2CO.sub.3 and 154 mg tetrabutylammonium bromide were added and stirred, the mixture was heated to 65° C.˜85° C. in an oil bath for 16 h˜24 h; suction filtration was conducted to remove the solid which was washed with ethyl ether (30 ml×3 times), the filtrate was combined, and the organic layer was washed with water (40 ml×3 times) and then dried over MgSO.sub.4 for 4˜8 h, the solvent was distilled under reduced pressure, and then distilled under reduced pressure using an oil pump, 9.21 g of fraction at 141° C.˜150° C. under the vacuum degree of 7 mm Hg was collected, with the yield of 31.43%.

Step 2: diethyl 2-(3-dimethylaminocyclobutyl)-malonate

(56) ##STR00029##

(57) 117.21 g, (0.4 mol) diethyl 3-bromocyclobutyl-malonate was placed into a three-necked flask, 55.820 g (0.4 mol) anhydrous K.sub.2CO.sub.3 and 500 ml acetonitrile were added and stirred. 45.2 g (1.0 mol) refrigerated dimethylamine solution was added in the reaction solution, and the mixture was heated to 40° C.˜60° C. in an oil bath to react for 2 h-6 h, the insoluble substance was filtered out, the filtrate was pumped out and then the filtrate was dissolved by adding 1000 ml ethyl acetate and washed with saturated NaCl aqueous solution (250 ml×3 times), and the organic layer was dried over anhydrous MgSO.sub.4 overnight, the solvent was pumped out under reduced pressure using a water pump, to obtain 90.5 g of light yellow, light red, transparent substance which was purified by column chromatography, to obtain 41.3 g pure product, with the yield of 40.18%.

Step 3: disodium 2-(3-dimethylaminocyclobutyl) malonate

(58) ##STR00030##

(59) 2M NaOH solution was obtained by dissolving 213 mg (5 mmol) NaOH with 2.5 mL water, and 514 mg (2 mmol) diethyl 2-(3-dimethylaminocyclobutyl)-malonate was placed into a 20 mL three-necked flask and the above NaOH solution was added thereto, stirring at room temperature for 45 h˜60 h, to obtain a solution of disodium 2-(3-dimethylaminocyclobutyl)-malonate.

(60) Steps 4, 5 are the same as steps 4, 5 in [Example 1], respectively.

Step 6: 2-(3-dimethylaminocyclobutyl)-malonate•cis-diamine platinum (II) mesylate

(61) ##STR00031##

(62) The pH of 2 mmol disodium 2-(3-dimethylaminocyclobutyl) malonate solution was adjusted to 5˜7 with 1M methylsulfonic acid and then cis-diamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜75° C. in a water bath for 4 h-6 h, and the reaction solution was concentrated to a certain volume after suction filtration and stayed, to obtain 143 mg crystalline-type 2-(3-dimethylaminocyclobutyl)-malonate•cis-diamine platinum (II) phosphate.

(63) The compound in Example 6 is soluble in water, the solubility is more than 300 mg/ml. A free compound 2-(3-dimethylaminocyclobutyl)-malonate•cis-diamine platinum (II) could be obtained by adjusting pH with an alkali. Elemental analysis of the free alkali: C, 25.09% (theoretical 25.23%), H, 4.56% (theoretical 4.44%), N, 9.77% (theoretical 9.81%).

(64) .sup.1HNMR (D.sub.2O) (ppm): δ3.61 (d, 1H), δ2.87 (s, 6H), δ2.63 (m, 1H), δ1.73 (dd, 4H), δ1.45 (m, 1H).

[Example 7]: 2-(4-di-n-propylaminobutyl)-malonate•cis-diamine platinum (II) phosphate

(65) Step 1 is the same as step 1 in [Example 1].

Step 2: diethyl 2-(4-di-n-propylaminobutyl)-malonate

(66) ##STR00032##

(67) 118 g (0.4 mol) diethyl 4-bromobutyl-malonate was placed into a three-necked flask, 55.2 g (0.4 mol) anhydrous K.sub.2CO.sub.3 and 500 ml acetonitrile were added and stirred. 101.2 g (1.0 mol) di-n-propylamine was added in the reaction solution, and the mixture was heated to 45° C.˜60° C. in an oil bath to react for 2 h-6 h, the insoluble substance was filtered out, the filtrate was pumped out and then the filtrate was dissolved by adding 1000 ml ethyl acetate and washed with saturated NaCl aqueous solution (250 ml×3 times), and the organic layer was dried over anhydrous MgSO.sub.4 overnight, the solvent was pumped out under reduced pressure using a water pump, to obtain 117.5 g of light yellow, light red, transparent substance which was purified by column chromatography to obtain 49.51 g pure product, with the yield of 39.29%.

Step 3: disodium 2-(4-di-n-propylaminobutyl)-malonate

(68) ##STR00033##

(69) 2M NaOH solution was obtained by dissolving 213 mg (5 mmol) NaOH with 2.5 mL water. 630 mg (2 mmol) diethyl 2-(4-di-n-propylaminobutyl)-malonate was placed into a 20 mL three-necked flask and the above NaOH solution was added thereto, stirring at room temperature for 45 h˜60 h, to obtain a solution of disodium 2-(4-di-n-propylaminobutyl)-malonate.

(70) Steps 4, 5 are the same as steps 4, 5 in [Example 1], respectively.

Step 6: 2-(4-di-n-propylaminebutyl)-malonate•cis-diamine platinum (II) phosphate

(71) The pH of disodium 2-(4-di-n-propylaminobutyl)-malonate solution was adjusted to 5˜7 with 1M H.sub.3PO.sub.4 and then cis-diamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 45° C.˜75° C. in a water bath for 4 h-6 h, and the reaction solution was concentrated to a certain volume after suction filtration and stayed, to obtain 133 mg crystalline-type product.

(72) ##STR00034##

(73) The compound in Example 7 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 32.29% (theoretical 32.10%)); H, 5.72% (theoretical 5.97%); N, 8.59% (theoretical 8.64%).

(74) .sup.1HNMR (D.sub.2O) (ppm): δ3.60 (t, 1H), δ2.77 (t, 4H), δ2.70 (t, 2H), δ1.78 (m, 2H), δ1.44 (m, 2H), δ1.31 (m, 2H), δ1.25 (m, 4H), δ1.05 (t, 6H).

[Example 8]: 2-(3-methyl-4-diethylaminobutyl)-malonate•cis-diamine platinum (II) acetate

Step 1: diethyl 2-(3-methyl-4-bromobutyl)-malonate

(75) ##STR00035##

(76) 16.1 g (0.1 mol) diethyl malonate and 23.0 g (0.1 mol) 2-methyl-1,4-dibromobutane were placed into a 150 ml three-necked flask, 15.3 g (0.11 mol) K.sub.2CO.sub.3 and 155 mg tetrabutylammonium bromide were added and stirred, the mixture was heated to 65° C.˜85° C. in an oil bath for 16 h˜24 h; suction filtration was conducted to remove the solid which was washed with ethyl ether (30 ml×3 times), the filtrate was combined, and the organic layer was washed with water (40 ml×3 times) and then dried over MgSO.sub.4 for 4 h˜8 h, the solvent was distilled under reduced pressure, and then distilled under reduced pressure using an oil pump, 9.65 g of fraction at 145° C.˜156° C. under the vacuum degree of 7 mmHg was collected, with the yield of 31.23%.

Step 2: diethyl 2-(3-methyl-4-diethylaminobutyl)-malonate

(77) ##STR00036##

(78) 123.6 g (0.4 mol) diethyl 3-methyl-4-bromobutyl-malonate was placed into a three-necked flask, 55.6 g (0.4 mol) anhydrous K.sub.2CO.sub.3 and 500 ml acetonitrile were added and stirred. 73.3 g (1.0 mol) diethylamine was added in the reaction solution, and the mixture was heated to 45° C.˜60° C. in an oil bath to react for 2 h-6 h, the insoluble substance was filtered out, the filtrate was pumped out and then the filtrate was dissolved by adding 1000 ml ethyl acetate and washed with saturated NaCl aqueous solution (250 ml×3 times), and the organic layer was dried over anhydrous MgSO.sub.4 overnight, the solvent was pumped out under reduced pressure using a water pump, to obtain 105.7 g of light yellow, light red, transparent substance which was purified by column chromatography, to obtain 49.75 g pure product, with the yield of 41.32%.

Step 3: disodium 2-(3-methyl-4-diethylaminobutyl) malonate

(79) ##STR00037##

(80) 2M NaOH solution was obtained by dissolving 212.1 mg (5 mmol) NaOH with 2.5 mL water. 602 mg (2 mmol) diethyl 2-(4-diethylaminobutyl)-malonate was placed into a 20 mL three-necked flask and the above NaOH solution was added thereto, stirring at room temperature for 45 h˜60 h, to obtain a solution of disodium 2-(4-diethylaminobutyl)-malonate.

(81) Steps 4, 5 are the same as steps 4, 5 in [Example 1], respectively.

Step 6: 2-(3-methyl-4-diethylaminobutyl)-malonate•cis-diamine platinum (II) acetate

(82) ##STR00038##

(83) The pH of disodium [2-(3-methyl-4-diethylaminobutyl)-malonate solution was adjusted to 5˜7 with 1M HAC and then cis-diamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜75° C. in a water bath for 4 h-6 h, and the reaction solution was concentrated to a certain volume after suction filtration and stayed, to obtain 137 mg crystalline-type product.

(84) The compound in Example 8 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 30.71% (theoretical 30.51%), H, 5.63% (theoretical 5.72%), N, 8.99% (theoretical 8.90%).

(85) .sup.1HNMR (D.sub.2O) (ppm): δ3.52 (m, 1H), δ2.79-2.67 (b, 4H), δ2.57-2.67 (b, 2H), δ1.80 (m, 1H), δ1.45 (m, 2H), δ1.25 (m, 2H), δ1.15 (d, 3H), δ1.05 (t, 6H).

[Example 9]: 2-(4-(1-piperidyl)-butyl)-malonate•cis-(1,2-trans-cyclohexanediamine) platinum (II) tosilate

(86) Step 1 is the same as step 1 in [Example 1].

(87) Steps 2, 3 are the same as steps 2, 3 in [Example 4], respectively.

(88) Steps 4, 5 are the same as steps 4, 5 in [Example 3], respectively.

Step 6: 2-(4-(1-piperidyl)-butyl)-malonate•cis-(1,2-trans-cyclohexanediamine) platinum (II) tosilate

(89) ##STR00039##

(90) The pH of disodium 2-(4-(1-piperidyl)-butyl)malonate solution was adjusted to 5˜7 with 1 M p-toluenesulfonic acid and then trans-cyclohexanediamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜60° C. in a water bath for 4 h-8 h, and the reaction solution was added into 2.5 g silica gel for column chromatography (200-300 meshes) and stirred for 15 min and then pumped to be dryness, the mixture was treated by column chromatography to obtain 168 mg product.

(91) The compound in Example 9 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 39.46% (theoretical 39.27%), H, 6.22% (theoretical 6.0%), N, 7.73% (theoretical 7.64%).

(92) .sup.1HNMR (D.sub.2O) (ppm): δ3.52 (m, 1H), δ2.78-2.65 (br, 4H), δ2.67-2.56 (br, 2H), δ2.51 (m, 2H), δ2.02 (m, 4H), δ1.86 (m, 2H), δ1.75 (m, 4H), δ1.45 (m, 2H), δ1.32 (m, 2H), δ1.21 (m, 4H), δ1.11 (t, 2H).

(93) [Example 10]: 2-(4-(2-methyl-1-tetrahydropyrrolidinyl)-butyl)-malonate•cis-diamine platinum (II) phosphate

(94) Step 1 is the same as step 1 in [Example 3].

Step 2: diethyl 2-(4-(2-methyl-1-tetrahydropyrrolidinyl)-butyl)-malonate

(95) ##STR00040##

(96) 118 g (0.4 mol) diethyl 4-bromobutyl-malonate was placed into a three-necked flask, 55.6 g (0.4 mol) anhydrous K.sub.2CO.sub.3 and 500 ml acetonitrile were added and stirred. 85.1 g (1.0 mol) 2-methyl tetrahydropyrrolidine solution was added in the reaction solution (wherein 2-methyl tetrahydropyrrolidine can be racemic, or can be in R-configuration or S-configuration), and the mixture was heated to 40° C.˜60° C. in an oil bath to react for 2 h-6 h, the insoluble substance was filtered out, the filtrate was pumped out and then the filtrate was dissolved by adding 1000 ml ethyl acetate and washed with saturated NaCl aqueous solution (250 ml×3 times), and the organic layer was dried over anhydrous MgSO.sub.4 overnight, the solvent was pumped out under reduced pressure using a water pump, to obtain 110.5 g of light yellow, light red, transparent substance which was purified by column chromatography, to obtain 39.1 g pure product, with the yield of 32.69%.

Step 3: disodium 2-(4-(2 methyl-1-tetrahydropyrrolidinyl)-butyl)-malonate

(97) ##STR00041##

(98) 2M NaOH solution was obtained by dissolving 212.3 mg (5 mmol) NaOH with 2.5 mL water. 598 mg (2 mmol) diethyl 2-(4-(2-methyl-1-tetrahydropyrrolidinyl)-butyl)-malonate was placed into a 20 mL three-necked flask and the above NaOH solution was added thereto, stirring at room temperature for 45 h˜60 h, to obtain a solution of disodium 2-(4-(2-methyl-1-tetrahydropyrrolidinyl)-butyl)-malonate.

(99) Steps 4, 5 are the same as steps 4, 5 in [Example 1], respectively.

Step 6: 2-(4-(2-methyl-1-tetrahydropyrrolidinyl)-butyl)-malonate•cis-diamine platinum (II) phosphate

(100) ##STR00042##

(101) The pH of disodium 2-(4-(2-methyl-1-tetrahydropyrrolidinyl)-butyl)-malonate solution was adjusted to 5˜7 with 1M H.sub.3PO.sub.4 and then cis-diamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜75° C. in a water bath for 4 h-6 h, and the reaction solution was concentrated to a certain volume after suction filtration and stayed, to obtain 128 mg crystalline-type product (which is in racemic configuration, or can be in R-configuration or S-configuration of which the solubility is equivalent to that of the racemic configuration).

(102) The compound in Example 10 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 35.62% (theoretical 35.47%), H, 6.26% (theoretical 6.16%), N, 10.39% (theoretical 10.34%).

(103) .sup.1HNMR (D.sub.2O) (ppm): δ3.61 (t, 1H), δ2.85 (t, 2H), δ2.72 (m, 1H), δ2.61 (t, 2H), δ1.84 (m, 2H), δ1.78 (m, 2H), δ1.67 (m, 2H), δ1.45 (m, 2H), δ1.27 (d, 3H), δ1.12 (m, 2H).

[Example 11]: 2-(4-aminobutyl)-malonate•cis-(1,2-trans-cyclohexanediamine) platinum (II) phosphate

(104) Step 1 is same as step 1 in [Example 1].

Step 2: diethyl 2-(4-aminobutyl)-malonate

(105) ##STR00043##

(106) 118 g (0.4 mol) diethyl 2-bromobutyl-malonate was placed into a three-necked flask, 55 g (0.4 mol) anhydrous K.sub.2CO.sub.3 and 500 ml acetonitrile were added and stirred. Excessive ammonia gas is inlet into the reaction solution, and the mixture was heated to 40° C.˜50° C. in an oil bath to react for 2 h-6 h, the insoluble substance was filtered out, the filtrate was pumped out and then the filtrate was dissolved by adding 1000 ml ethyl acetate and washed with saturated NaCl aqueous solution (250 ml×3 times), and the organic layer was dried over anhydrous MgSO.sub.4 overnight, the solvent was pumped out under reduced pressure using a water pump, to obtain 80.5 g of light yellow, light red, transparent substance which was purified by column chromatography to obtain 36.5 g pure product, with the yield of 39.5%.

Step 3: disodium 2-(4-aminobutyl)-malonate

(107) ##STR00044##

(108) 2M NaOH solution was obtained by dissolving 215 mg (5 mmol) NaOH with 2.5 mL water. 462 mg (2 mmol) diethyl 2-(4-aminobutyl)-malonate was placed into a 20 mL three-necked flask and the above NaOH solution was added thereto, stirring at room temperature for 45 h˜60 h, to obtain a solution of disodium 2-(4-aminobutyl) malonate.

(109) Steps 4, 5 are the same as steps 4, 5 in [Example 3], respectively.

Step 6: 2-(4-aminobutyl)-malonate•cis-(1,2-trans-cyclohexanediamine) platinum (II) phosphate

(110) ##STR00045##

(111) The pH of disodium 2-(4-aminobutyl)-malonate solution was adjusted to 5˜7 with 1M H.sub.3PO.sub.4 and then trans-cyclohexanediamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜60° C. in a water bath for 4 h-8 h, and the reaction solution is added into 2.5 g silica gel for column chromatography (200-300 meshes) and stirred for 15 min and then pumped to be dryness, the mixture is treated by column chromatography to obtain 151 mg product.

(112) The compound in Example 11 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 32.32% (theoretical 32.37%), H, 4.95% (theoretical 5.19%), N, 8.97% (theoretical 8.71%).

(113) .sup.1HNMR (D.sub.2O) (ppm): δ3.61 (t, 1H), δ2.78 (t, 2H), δ2.06 (br, 2H), δ1.81 (m, 2H), δ1.74 (m, 2H), δ1.46 (m, 2H), δ1.33 (m, 2H), δ1.21 (br, 2H), δ1.11 (m, 2H), δ1.01 (m, 2H).

[Example 12]: 2-(4-ethyl aminobutyl)-malonate•cis-(1, 2-trans-cyclohexanediamine) platinum (II) phosphate

(114) Step 1 is the same as step 1 in [Example 1].

Step 2: diethyl 2-(4-ethylaminobutyl)-malonate

(115) ##STR00046##

(116) 118 g (0.4 mol) diethyl 4-bromobutyl-malonate was placed into a three-necked flask, 55.2 g (0.4 mol) anhydrous K.sub.2CO.sub.3 are 500 ml acetonitrile were added and stirred. 45 g (1.0 mol) refrigerated ethylamine was added in the reaction solution, and the mixture was heated to 40° C.˜60° C. in an oil bath to react for 2 h-6 h, the insoluble substance was filtered out, the filtrate was pumped out and then the filtrate was dissolved by adding 1000 ml ethyl acetate and washed with saturated NaCl aqueous solution (250 ml×3 times), and the organic layer was dried over anhydrous MgSO.sub.4 overnight, the solvent was pumped out under reduced pressure using a water pump, to obtain 87.7 g of light yellow, light red, transparent substance which was purified by column chromatography to obtain 38.6 g pure product, with the yield of 37.26%.

Step 3: disodium 2-(4-ethylaminobutyl)-malonate

(117) ##STR00047##

(118) 2M NaOH solution was obtained by dissolving 214 mg (5 mmol) NaOH with 2.5 mL water. 518 mg (2 mmol) diethyl 2-(4-aminobutyl)-malonate was placed into a 20 mL three-necked flask and the above NaOH solution was added thereto, stirring at room temperature for 45 h˜60 h, to obtain a solution of disodium 2-(4-ethylaminobuty)-malonate.

(119) Steps 4, 5 are the same as steps 4, 5 in [Example 3], respectively.

Step 6: 2-(4-ethylaminobutyl)-malonate•cis-(1,2-trans-cyclohexanediamine) platinum (II) phosphate

(120) ##STR00048##

(121) The pH of disodium 2-(4-ethylaminobutyl)-malonate solution was adjusted to 5˜7 with 1M H.sub.3PO.sub.4 and then trans-cyclohexanediamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜60° C. in a water bath for 4 h-8 h, and the reaction solution was added into 2.5 g silica gel for column chromatography (200-300 meshes) and stirred for 15 min and then pumped to be dryness, the mixture is treated by column chromatography to obtain 151 mg product.

(122) The compound in Example 12 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 35.55% (theoretical 35.29%), H, 5.71% (theoretical 5.69%), N, 8.46% (theoretical 8.24%).

(123) .sup.1H NMR (D.sub.2O) (ppm): δ3.61 (t, 1H), δ2.77 (q, 2H), δ2.71 (m, 2H), 2.07 (br, 2H), 1.81 (m, 2H), δ1.71 (m, 2H), 1.46 (m, 2H), 1.35 (m, 2H), 1.26 (m, 2H), 1.17 (br, 2H), δ1.07 (t, 3H) 1.01 (m, 2H).

[Example 13]: 2-[4-(N-methyl-N-isopropylamino)butyl]-malonate•cis diamine platinum (II) acetate

(124) Step 1 is the same as step 1 in [Example 1].

Step 2: diethyl 2-[4-(N-methyl-N-isopropylamino)butyl]-malonate

(125) ##STR00049##

(126) 118.1 g (0.4 mol) diethyl 4-bromobutyl-malonate was placed into a three-necked flask, 55.5 g (0.4 mol) anhydrous K.sub.2CO.sub.3 and 500 ml acetonitrile were added and stirred. 73.1 g (1.0 mol) N-methylisopropylamine was added in the reaction solution, and the mixture was heated to 45° C.˜60° C. in an oil bath to react for 2 h-6 h, the insoluble substance was filtered out, the filtrate was pumped out and then the filtrate was dissolved by adding 1000 ml ethyl acetate and washed with saturated NaCl aqueous solution (250 ml×3 times), and the organic layer was dried over anhydrous MgSO.sub.4 overnight, the solvent was pumped out under reduced pressure using a water pump, to obtain 105.3 g of light yellow, light red, transparent substance which was purified by column chromatography, to obtain 48.54 g pure product, with the yield of 42.28%.

Step 3: disodium 2-[4-(N-methyl-N-isopropylamino)butyl]-malonate

(127) ##STR00050##

(128) 2M NaOH solution was obtained by dissolving 212 mg (5 mmol) NaOH with 2.5 mL water. 576 mg (2 mmol) diethyl 2-[4-(N-methyl-N-isopropylamino)butyl]-malonate was placed into a 20 mL three-necked flask and the above NaOH solution was added thereto, stirring at room temperature for 45 h˜60 h, to obtain a solution of disodium 2-[4-(N-methyl-N-isopropylamino)butyl]-malonate.

(129) Steps 4, 5 are the same as steps 4, 5 in [Example 1], respectively.

Step 6: 2-[4-(N-methyl-N-isopropylamino)butyl]-malonate•cis-diamine platinum (II) acetate

(130) ##STR00051##

(131) The pH of disodium 2-[4-(N-methyl-N-isopropylamino)butyl]-malonate solution was adjusted to 5˜7 with 1M HAC and then cis-diamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture is heated to 40° C.˜75° C. in a water bath for 4 h-6 h, and the reaction solution was concentrated to a certain volume after suction filtration and stayed, to obtain 145 mg crystalline-type product.

(132) The compound in Example 13 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 28.63% (theoretical 28.82%), H, 5.64% (theoretical 5.46%), N, 9.06% (theoretical 9.17%).

(133) .sup.1HNMR (D.sub.2O) (ppm): δ3.51 (m, 1H), δ2.76-2.65 (b, 4H), δ2.65-2.57 (b, 2H), δ1.80 (m, 2H), δ1.45 (m, 2H), δ1.24 (m, 2H), δ1.05 (d, 6H).

[Example 14]: 2-(4-diethylaminobutyl)-malonate•cis-(1,2-trans-cyclopentanediamine) platinum (II) phosphate

(134) Steps 1, 2 and 3 are the same as steps 1, 2, and 3 in [Example 1], respectively.

Synthesis step 4: 1, 2-trans-cyclopentyldiamine

(135) ##STR00052##

(136) 6.81 g (100 mmol) cyclopentene was placed in a 100 ml three-necked flask and dissolved with 30 ml dichloromethane by stirring, and 16.5 g (103 mmol) Br.sub.2 was added dropwise slowly at −5° C.˜10° C., the mixture is stirred for 1 h˜3 h and washed with saturated sodium bicarbonate solution (10 ml×3 times), the organic layer was dried over anhydrous MgSO.sub.4 for 2 h˜3 h, the solvent was pumped out under reduced pressure using a water pump, to obtain 20.56 g 1,2-trans-dibromocyclopentane as a light yellow, transparent substance, with the yield of 90.18%. Elemental analysis: C, 26.51% (theoretical 26.32%), H, 3.62% (theoretical 3.51%).

(137) 11.5 g (50 mmol) 1, 2-trans-dibromocyclopentane was placed into a 100 ml autoclave and 30 ml ethanol solution containing 30% ammonia was added thereto, and the mixture was heated to 40° C.˜60° C. to react for 6 h˜8 h, the solvent was distilled off, to obtain 4.015 g 1,2-trans-cyclopentylamine as a light yellow, transparent substance, with the yield of 79.6%. Elemental analysis: C, 60.21% (theoretical 60%), H, 12.12% (theoretical 12%), N, 28.21% (theoretical 28%).

Step 5: 1,2-trans-cyclopentanediamine•diiodoplatinum (II)

(138) ##STR00053##

(139) 2.073 g (5 mmol) potassium tetrachloroplatinate (K.sub.2PtCl.sub.4) was added in 50 ml water and dissolved by stirring at room temperature, and 6.63 g (40 mmol) KI was added in the reaction solution after being dissolved with 50 ml water, with the protection of N.sub.2 and away from light, the mixture was heated in a water bath to 40° C.˜60° C. for 0.5 h˜2 h. Then 501 mg (5 mmol) 1, 2-trans-cyclopentanediamine was added in the reaction solution after being dissolved with 50 ml water, which was kept under this condition to react for 0.5 h˜2 h. A yellow solid product was obtained by suction filtration and washed with water (10 ml×3 times) and ethyl ether (10 ml×3 times), to obtain 2.561 g product, with the yield of 93.3%. Elemental analysis: C, 10.78% (theoretical 10.93%), H, 2.31% (theoretical 2.19%), N, 4.98% (theoretical 5.10%).

Step 6: 1,2-trans-cyclopentanediamine•dihydrated platinum (II) sulphate

(140) ##STR00054##

(141) 625 mg (2 mmol) Ag.sub.2SO.sub.4 was placed in a 100 ml three-necked flask, 30 ml water was added thereto and stirred, and 1.10 g (2 mmol) 1,2-trans-cyclopentanediamine•diiodoplatinum (II) was added into the reaction solution and then 40 ml water was added to react, with the protection of N.sub.2 and away from light, the mixture was reacted at 40° C.˜60° C. in a water bath for 4 h˜8 h. After removing AgI precipitate by suction filtration, the filtrate was obtained, i.e., the aqueous solution of the product.

Step 7: 2-(4-diethylaminobutyl)-malonate•cis-(1,2-trans-cyclopentanediamine) platinum (II) phosphate

(142) ##STR00055##

(143) The pH of disodium 2-(4-diethylaminobutyl)-malonate solution was adjusted to 5˜7 with 1M H.sub.3PO.sub.4 and then 1,2-trans-cyclohexanediamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜60° C. in a water bath for 4 h-8 h, and the reaction solution was added into 2.5 g silica gel for column chromatography (200-300 meshes) and stirred for 15 min and then pumped to be dryness, the mixture is treated by column chromatography to obtain 153 mg product.

(144) The compound in Example 14 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 36.57% (theoretical 36.64%), H, 5.73% (theoretical 5.92%), N, 8.17% (theoretical 8.02%).

(145) .sup.1HNMR (D.sub.2O) (ppm): δ3.61 (t, 1H), δ2.77 (q, 4H), δ2.68 (t, 2H), δ2.07 (br, 2H), δ1.83 (m, 2H), δ1.72 (m, 2H), δ1.48 (m, 2H), δ1.40 (m, 2H), δ1.17 (m, 2H), δ1.08 (t, 6H), δ1.02 (m, 2H).

[Example 15]: 2-(4-diethylaminobutyl)-malonate•cis-(1,2-trans-cyclobutanediamine) platinum (II) succinate

(146) Steps 1, 2 and 3 are the same as steps 1, 2 and 3 in [Example 1], respectively.

Step 4: 1,2-trans-cyclobutanediamine

(147) ##STR00056##

(148) 5.39 g (100 mmol) cyclobutene was placed in a 100 ml three-necked flask and dissolved with 30 ml dichloromethane by stirring, and 16.5 g (103 mmol) Br.sub.2 was added dropwise slowly at −5° C.˜10° C., the mixture is stirred for 1 h˜3 h, and washed with saturated sodium bicarbonate solution (10 ml×3 times), the organic layer was dried over anhydrous MgSO.sub.4 for 2 h˜3 h, the solvent was pumped out under reduced pressure using a water pump, to obtain 20.37 g 1,2-trans-dibromocyclobutane as a light yellow, transparent substance, with the yield of 95.19%. Elemental analysis: C, 22.53% (theoretical 22.43%), H, 2.61% (theoretical 2.80%).

(149) 10.65 g (50 mmol) 1, 2-trans-dibromocyclobutane was placed into a 100 ml pressure autoclave and 30 ml ethanol solution containing 30% ammonia was added thereto, and the mixture was heated to 40° C.˜60° C. to react for 6 h˜8 h, the solvent was distilled off, to obtain 3.723 g 1,2-trans-cyclobutylamine as a light yellow, transparent substance, with the yield of 86.58%. Elemental analysis: C, 55.57% (theoretical 55.81%); H, 11.90% (theoretical 11.63%); N, 32.17% (theoretical 32.56%).

Step 5: 1,2-trans-cyclobutanediamine•diiodoplatinum (II)

(150) ##STR00057##

(151) 2.075 g (5 mmol) potassium tetrachloroplatinate (K.sub.2PtCl.sub.4) was added in 50 ml water and dissolved by stirring at room temperature, and 6.63 g (40 mmol) KI was added in the reaction solution after being dissolved with 50 ml water, with the protection of N.sub.2 and away from light, the mixture was heated to 40° C.˜60° C. in a water bath for 0.5 h˜2 h. Then 431 mg (5 mmol) 1, 2-trans-cyclobutanediamine was added in the reaction solution after being dissolved with 50 ml water, which was kept under this condition to react for 0.5 h˜2 h. A yellow solid product was obtained by suction filtration and washed with water (10 ml×3 times) and ethyl ether (10 ml×3 times), to obtain 2.429 g product, with the yield of 90.8%.

(152) Elemental analysis: C, 8.75% (theoretical 8.97%), H, 1.91% (theoretical 1.87%), N, 5.98% (theoretical 5.23%).

Step 6: 1,2 trans-cyclobutanediamine•dihydrated platinum (II) sulphate

(153) ##STR00058##

(154) 627 mg (2 mmol) Ag.sub.2SO.sub.4 was placed in a 100 ml three-necked flask, 30 ml water was added thereto and stirred, and 1.07 g (2 mmol) 1,2-trans-cyclobutanediamine•diiodoplatinum (II) was added into the reaction solution and then 40 ml water was added to react, with the protection of N.sub.2 and away from light, the mixture was reacted at 40° C.˜60° C. in a water bath for 4 h˜8 h. After removing AgI precipitate by suction filtration, the filtrate was obtained, i.e., the aqueous solution of the product.

Step 7: 2-(4-diethylaminobutyl)-malonate•cis-(1,2-trans-cyclobutanediamine) platinum (II) succinate

(155) ##STR00059##

(156) The pH of disodium 2-(4-diethylaminobutyl)-malonate solution was adjusted to 5˜7 with 1M succinic acid C.sub.4H.sub.6O.sub.4 and then 1,2-trans-cyclobutanediamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜60° C. in a water bath for 4 h-8 h, and the reaction solution was added into 2.5 g silica gel for column chromatography (200-300 meshes) and stirred for 15 min and then pumped to be dryness, the mixture is treated by column chromatography to obtain 148 mg product.

(157) The compound in Example 15 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 35.57% (theoretical 35.29%), H, 5.65% (theoretical 5.69%), N, 8.38% (theoretical 8.24%).

(158) .sup.1HNMR (D.sub.2O) (ppm): δ3.61 (t, 1H), δ2.78 (q, 4H), δ2.67 (t, 2H), δ2.09 (br, 2H), δ1.82 (m, 2H), δ1.72 (m, 2H), δ1.45 (m, 2H), δ1.38 (m, 2H), δ1.15 (m, 2H), δ1.06 (t, 6H).

[Example 16]: 2-(4-diethylaminobutyl)-malonate•cis-(1, 2-trans-cyclopropanediamine) platinum (II) phosphate

(159) Steps 1, 2 and 3 are the same as steps 1, 2 and 3 in [Example 1], respectively.

Step 4: 1,2-trans-cyclopropanediamine•diiodoplatinum (II)

(160) ##STR00060##

(161) 2.075 g (5 mmol) potassium tetrachloroplatinate (K.sub.2PtCl.sub.4) was added in 50 ml water and dissolved by stirring at room temperature, and 6.63 g (40 mmol) KI was added in the reaction solution after being dissolved with 50 ml water, with the protection of N.sub.2 and away from light, the mixture was heated to 40° C.˜60° C. in a water bath for 0.5 h˜2 h. 361 mg (5 mmol) 1,2-trans-cyclopropanediamine (commercially available) was added in the reaction solution after being dissolved with 50 ml water, which was kept under this condition to react for 0.5 h˜2 h. A yellow solid product was obtained by suction filtration and washed with water (10 ml×3 times) and ethyl ether (10 ml×3 times), to obtain 2.391 g product, with the yield of 91.8%. Elemental analysis: C, 6.97% (theoretical 6.91%), H, 1.41% (theoretical 1.54%), N, 5.47% (theoretical 5.37%).

Step 5: 1,2-trans-cyclopropanediamine•dihydrated platinum (II) sulphate

(162) ##STR00061##

(163) 624 mg (2 mmol) Ag.sub.2SO.sub.4 was placed in a 100 ml three-necked flask, 30 ml water was added thereto and stirred, and 1.04 g (2 mmol) 1,2-trans-cyclopentanediamine•diiodoplatinum (II) was added into the reaction solution and then 40 ml water was added to react, with the protection of N.sub.2 and away from light, the mixture was reacted at 40° C.˜60° C. in a water bath for 4 h˜8 h. After removing AgI precipitate by suction filtration, the filtrate was obtained, i.e., the aqueous solution of the product.

Step 6: 2-(4-diethylaminobutyl)-malonate•cis-(1,2-trans-cyclopropanediamine) platinum (II) phosphate

(164) ##STR00062##

(165) The pH of disodium 2-(4-diethylaminobutyl)-malonate solution was adjusted to 5˜7 with 1M H.sub.3PO.sub.4 and then 1,2-trans-cyclopropanediamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜60° C. in a water bath for 4 h-8 h, and the reaction solution was added into 2.5 g silica gel for column chromatography (200-300 meshes) and stirred for 15 min and then pumped to be dryness, the mixture is treated by column chromatography to obtain 135 mg product.

(166) The compound in Example 16 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 33.63% (theoretical 33.87%), H, 5.32% (theoretical 5.44%), N, 8.59% (theoretical 8.47%).

(167) .sup.1HNMR (D.sub.2O) (ppm): δ3.62 (t, 1H), δ2.79 (q, 4H), δ2.66 (t, 2H), δ2.08 (br, 2H), δ1.82 (m, 2H), δ1.45 (m, 2H), δ1.38 (m, 2H), δ1.15 (m, 2H), δ1.07 (t, 6H).

[Example 17]: 2-(4-diethylaminobutyl)-malonate•cis-(1,2-ethylenediamine) platinum (II) tosilate

(168) Steps 1, 2 and 3 are the same as steps 1, 2 and 3 in [Example 1], respectively.

Step 4: 1, 2-ethylenediamine•diiodoplatinum (II)

(169) ##STR00063##

(170) 2.076 g (5 mmol) potassium tetrachloroplatinate (K.sub.2PtCl.sub.4) was added in 50 ml water and dissolved by stirring at room temperature, and 6.64 g (40 mmol) KI was added in the reaction solution after being dissolved with 50 ml water, with the protection of N.sub.2 and away from light, the mixture was heated to 40° C.˜60° C. in a water bath for 0.5 h˜2 h. Then 301 mg (5 mmol) refrigerated 1, 2-ethylenediamine (commercially available) was added in the reaction solution after being dissolved with 50 ml water, which was kept under this condition to react for 0.5 h˜2 h. A yellow solid product was obtained by suction filtration and washed with water (10 ml×3 times) and ethyl ether (10 ml×3 times), to obtain 2.254 g product, with the yield of 89.8%. Elemental analysis: C, 4.77% (theoretical 4.72%), H, 1.41% (theoretical 1.57%), N, 5.41% (theoretical 5.50%).

Step 5: 1,2-ethylenediamine•dihydrated platinum (II) sulphate

(171) ##STR00064##

(172) 625 mg (2 mmol) Ag.sub.2SO.sub.4 was placed in a 100 ml three-necked flask, 30 ml water was added thereto and stirred, and 1.020 g (2 mmol) 1,2-ethylenediamine•diiodoplatinum (II) was added into the reaction solution and then 40 ml water was added to react, with the protection of N.sub.2 and away from light, the mixture was reacted at 40° C.˜60° C. in a water bath for 4 h˜8 h. After removing AgI precipitate by suction filtration, the filtrate was obtained, i.e., the aqueous solution of the product.

Step 6: 2-(4-diethylaminobutyl)-malonate•cis-(1,2-ethylenediamine) platinum (II) tosilate

(173) ##STR00065##

(174) The pH of disodium 2-(4-diethylaminobutyl)-malonate solution was adjusted to 5˜7 with 1M p-toluenesulfonic acid C.sub.7H.sub.3O.sub.3S and then 1,2-ethylenediamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜60° C. in a water bath for 4 h-8 h, and the reaction solution was added into 2.5 g silica gel for column chromatography (200-300 meshes) and stirred for 15 min and then pumped to be dryness, the mixture is treated by column chromatography to obtain 148 mg product.

(175) The compound in Example 17 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 32.35% (theoretical 32.23%), H, 5.33% (theoretical 5.58%), N, 8.90% (theoretical 8.68%).

(176) .sup.1HNMR (D.sub.2O) (ppm): δ3.63 (t, 1H), δ2.68 (q, 4H), δ2.55 (t, 2H), δ2.31 (t, 4H), δ2.25 (m, 2H), δ1.86 (m, 2H), δ1.12 (m, 2H), δ1.06 (t, 6H).

[Example 18]: 2-(4-diethylaminobutyl)-malonate•cis-(1,3-propanediamine) platinum (II) phosphate

(177) Steps 1, 2 and 3 are the same as steps 1, 2, and 3 in [Example 1], respectively.

Step 4: 1,3-propanediamine•diiodoplatinum (II)

(178) ##STR00066##

(179) 2.073 g (5 mmol) potassium tetrachloroplatinate (K.sub.2PtCl.sub.4) was added in 50 ml water and dissolved by stirring at room temperature, and 6.63 g (40 mmol) KI was added in the reaction solution after being dissolved with 50 ml water, with the protection of N.sub.2 and away from light, the mixture was heated to 40° C.˜60° C. in a water bath for 0.5 h˜2 h. 372 mg (5 mmol) refrigerated 1,3-propanediamine (commercially available) was added in the reaction solution after being dissolved with 50 ml water, which was kept under this condition to react for 0.5 h˜2 h. A yellow solid product was obtained by suction filtration and washed with water (10 ml×3 times) and ethyl ether (10 ml×3 times), to obtain 2.281 g product, with the yield of 87.6%. Elemental analysis: C, 6.77% (theoretical 6.88%), H, 1.79% (theoretical 1.91%), N, 5.43% (theoretical 5.35%).

Step 5: 1,3-propanediamine•dihydrated platinum (II) sulphate

(180) ##STR00067##

(181) 625 mg (2 mmol) Ag.sub.2SO.sub.4 was placed in a 100 ml three-necked flask, 30 ml water was added thereto and stirred, and 1.043 g (2 mmol) 1,2-ethylenediamine•diiodoplatinum (II) was added into the reaction solution and then 40 ml water was added to react, with the protection of N.sub.2 and away from light, the mixture was reacted at 40° C.˜60° C. in a water bath for 4 h˜8 h. After removing AgI precipitate by suction filtration, the filtrate was obtained, i.e., the aqueous solution of the product.

Step 6: 2-(4-diethylaminobutyl)-malonate•cis-(1,3-propanediamine) platinum (II) phosphate

(182) ##STR00068##

(183) The pH of disodium 2-(4-diethylaminobutyl)-malonate solution was adjusted to 5˜7 with 1M H.sub.3PO.sub.4 and then 1,2-ethylenediamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜60° C. in a water bath for 4 h-8 h, and the reaction solution was added into 2.5 g silica gel for column chromatography (200-300 meshes) and stirred for 15 min and then pumped to be dryness, the mixture is treated by column chromatography to obtain 158 mg product.

(184) The compound in Example 18 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 33.94% (theoretical 33.73%, H, 5.66% (theoretical 5.82%), N, 8.58% (theoretical 8.43%).

(185) .sup.1HNMR (D.sub.2O) (ppm): δ3.61 (t, 1H), δ2.67 (q, 4H), δ2.56 (t, 2H), δ2.29 (t, 4H), δ2.21 (m, 2H), δ1.82 (m, 2H), δ1.42 (m, 2H), δ1.21 (m, 2H), δ1.04 (t, 6H).

[Example 19]: 2-(4-diethylaminobutyl)-malonate•cis-(1,4-butanediamine) platinum (II) phosphate

(186) Steps 1, 2 and 3 are the same as steps 1, 2 and 3 in [Example 1], respectively.

Step 4: 1,4-butanediamine•diiodoplatinum (II)

(187) ##STR00069##

(188) 2.071 g (5 mmol) potassium tetrachloroplatinate (K.sub.2PtCl.sub.4) was added in 50 ml water and dissolved by stirring at room temperature, and 6.635 g (40 mmol) KI was added in the reaction solution after being dissolved with 50 ml water, with the protection of N.sub.2 and away from light, the mixture was heated to 40° C.˜60° C. in a water bath for 0.5 h˜2 h. 431 mg (5 mmol) refrigerated 1,3-propanediamine (commercially available) was added in the reaction solution after being dissolved with 50 ml water, which was kept under this condition to react for 0.5 h˜2 h. A yellow solid product was obtained by suction filtration and washed with water (10 ml×3 times) and ethyl ether (10 ml×3 times), to obtain 2.365 g product, with the yield of 88.1%. Elemental analysis: C, 8.69% (theoretical 8.94%), H, 2.39% (theoretical 2.23%), N, 5.44% (theoretical 5.21%).

Step 5: 1,4-butanediamine•dihydrated platinum (II) sulphate

(189) ##STR00070##

(190) 624 mg (2 mmol) Ag.sub.2SO.sub.4 was placed in a 100 ml three-necked flask, 30 ml water was added thereto and stirred, and 1.072 g (2 mmol) 1,2-ethylenediamine•diiodoplatinum (II) was added into the reaction solution and then 40 ml water was added to react, with the protection of N.sub.2 and away from light, the mixture was reacted at 40° C.˜60° C. in a water bath for 4 h˜8 h. After removing AgI precipitate by suction filtration, the filtrate was obtained, i.e., the aqueous solution of the product.

Step 6: 2-(4-diethylaminobutyl)-malonate•cis-(1,4-butanediamine) platinum (II) phosphate

(191) ##STR00071##

(192) The pH of disodium 2-(4-diethylaminobutyl)-malonate solution was adjusted to 5˜7 with 1M H.sub.3PO.sub.4 and then 1,2-ethylenediamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜60° C. in a water bath for 4 h-8 h, and the reaction solution was added into 2.5 g silica gel for column chromatography (200-300 meshes) and stirred for 15 min and then pumped to be dryness, the mixture is treated by column chromatography to obtain 157 mg product.

(193) The compound in Example 19 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 34.95% (theoretical 35.16%), H, 6.02% (theoretical 6.05%), N, 8.13% (theoretical 8.20%).

(194) .sup.1HNMR (D.sub.2O) (ppm): δ3.62 (t, 1H), δ2.66 (q, 4H), δ2.54 (t, 2H), δ2.30 (t, 4H), δ2.20 (m, 2H), δ1.82 (m, 2H), δ1.41 (m, 2H), δ1.23 (m, 4H), δ1.05 (t, 6H).

[Example 20]: 2-(2-diethylaminobutyl)-malonate•cis-1,2-(1,2-dihydroxymethyl)-ethylenediamine platinum (II) phosphate

(195) Steps 1, 2 and 3 are the same as steps 1, 2 and 3 in [Example 1], respectively.

Step 4: 1, 2-(1, 2-dihydroxymethyl)-ethylenediamine•diiodoplatinum (II)

(196) ##STR00072##

(197) 2.073 g (5 mmol) potassium tetrachloroplatinate (K.sub.2PtCl.sub.4) was added in 50 ml water and dissolved by stirring at room temperature, and 6.637 g (40 mmol) KI was added in the reaction solution after being dissolved with 50 ml water, with the protection of N.sub.2 and away from light, the mixture was heated to 40° C.˜60° C. in a water bath for 0.5 h˜2 h. 601 mg (5 mmol) 1, 2-(1, 2-dihydroxymethyl)-ethylenediamine was added in the reaction solution after being dissolved with 50 ml water, which was kept under this condition to react for 0.5 h˜2 h. A yellow solid product was obtained by suction filtration and washed with water (10 ml×3 times) and ethyl ether (10 ml×3 times), to obtain 2.163 g product, with the yield of 79.96%. Elemental analysis: C, 8.65% (theoretical 8.44%), H, 2.39% (theoretical 2.11%), N, 5.03% (theoretical 4.92%).

Step 5: 1, 2-(1,2-dihydroxymethyl)-ethylenediamine•dihydrated platinum (II) sulphate

(198) ##STR00073##

(199) 624 mg (2 mmol) Ag.sub.2SO.sub.4 was placed in a 100 ml three-necked flask, 30 ml water was added thereto and stirred, and 1.138 g (2 mmol) 1,2-(1,2-dihydroxymethyl)-ethylenediamine•diiodoplatinum (II) was added into the reaction solution and then 40 ml water was added to react, with the protection of N.sub.2 and away from light, the mixture was reacted at 40° C.˜60° C. in a water bath for 4 h˜8 h. After removing AgI precipitate by suction filtration, the filtrate was obtained, i.e., the aqueous solution of the product.

Step 6: 2-(4-diethylaminobutyl)-malonate•cis-1,2-(1,2-dihydroxymethyl)-ethylenediamine platinum (II) phosphate

(200) ##STR00074##

(201) The pH of disodium 2-(4-diethylaminobutyl)-malonate solution was adjusted to 5˜7 with 1M H.sub.3PO.sub.4 and then 1,2-(1,2-dihydroxymethyl)-ethylenediamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜60° C. in a water bath for 4 h-8 h, and the reaction solution was added into 2.5 g silica gel for column chromatography (200-300 meshes) and stirred for 15 min and then pumped to be dryness, the mixture is treated by column chromatography to obtain 138 mg product.

(202) The compound in Example 20 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 30.15% (theoretical 30.09%), H, 5.42% (theoretical 5.70%), N, 7.56% (theoretical 7.72%).

(203) .sup.1HNMR (D.sub.2O) (ppm): δ3.88 (d, 4H), δ3.61 (t, 1H), δ3.03 (m, 2H), δ2.77 (q, 4H), δ2.57 (t, 2H), δ2.01 (m, 2H), δ1.45 (m, 2H), δ1.21 (m, 2H), δ1.06 (t, 6H).

[Example 21]: 2-(4-diethylaminobutyl)-malonate•cis-1,3-(2,2-hydroxymethyl)-propanediamine platinum (II) phosphate

(204) Steps 1, 2 and 3 are the same as steps 1, 2 and 3 in [Example 1], respectively.

Step 4: 1,3-(2,2-hydroxymethyl)-propanediamine•diiodoplatinum (II)

(205) ##STR00075##

(206) 2.074 g (5 mmol) potassium tetrachloroplatinate (K.sub.2PtCl.sub.4) was added in 50 ml water and dissolved by stirring at room temperature, and 6.636 g (40 mmol) KI was added in the reaction solution after being dissolved with 50 ml water, with the protection of N.sub.2 and away from light, the mixture was heated to 40° C.˜60° C. in a water bath for 0.5 h˜2 h. 671 mg (5 mmol) 1,3-(2,2-hydroxymethyl)-propanediamine was added in the reaction solution after being dissolved with 50 ml water, which was kept under this condition to react for 0.5 h˜2 h. A yellow solid product was obtained by suction filtration and washed with water (10 ml×3 times) and ethyl ether (10 ml×3 times), to obtain 2.163 g product, with the yield of 79.96%. Elemental analysis: C, 10.37% (theoretical 10.29%); H, 2.49% (theoretical 2.40%), N, 5.01% (theoretical 4.80%).

Step 5: 1,3-(2,2-hydroxymethyl)-propanediamine•dihydrated platinum (II) sulphate

(207) ##STR00076##

(208) 624 mg (2 mmol) Ag.sub.2SO.sub.4 was placed in a 100 ml three-necked flask, 30 ml water was added thereto and stirred, and 1.162 g (2 mmol) 1,3-(2,2-hydroxymethyl)-propanediamine•diiodoplatinum (II) was added into the reaction solution and then 40 ml water was added to react, with the protection of N.sub.2 and away from light, the mixture was reacted at 40° C.˜60° C. in a water bath for 4 h˜8 h. After removing AgI precipitate by suction filtration, the filtrate was obtained, i.e., the aqueous solution of the product.

Step 6: 2-(4-diethylaminobutyl)-malonate•cis-1,3-(2,2-hydroxymethyl)-propanediamine platinum (II) phosphate

(209) ##STR00077##

(210) The pH of disodium 2-(4-diethylaminobutyl)-malonate solution was adjusted to 5˜7 with 1M H.sub.3PO.sub.4 and then 1,3-(2,2-hydroxymethyl)-propanediamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜60° C. in a water bath for 4 h-8 h, and the reaction solution was added into 2.5 g silica gel for column chromatography (200-300 meshes) and stirred for 15 min and then pumped to be dryness, the mixture is treated by column chromatography to obtain 148 mg product.

(211) The compound in Example 21 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 34.48% (theoretical 34.41%), H, 5.80% (theoretical 5.91%), N, 7.49% (theoretical 7.53%).

(212) .sup.1H NMR (D.sub.2O) (ppm): δ3.78 (s, 4H), δ3.61 (t, 1H), δ2.76 (s, 4H), δ2.69 (t, 2H), δ2.56 (q, 4H), δ1.71 (m, 2H), δ1.44 (m, 2H), δ1.22 (m, 2H), δ1.03 (t, 6H).

[Example 22]: 2-(4-diethylaminobutyl)-malonate•cis-1,4-(trans-2,3-cyclobutyl)-butanediamine platinum (II) phosphate

(213) Steps 1, 2 and 3 are the same as steps 1, 2 and 3 in [Example 1], respectively.

Step 4: 2,3-diaminomethylcyclobutane•diiodoplatinum (II)

(214) ##STR00078##

(215) 2.075 g (5 mmol) potassium tetrachloroplatinate (K.sub.2PtCl.sub.4) was added in 50 ml water and dissolved by stirring at room temperature, and 6.64 g (40 mmol) KI was added in the reaction solution after being dissolved with 50 ml water, with the protection of N.sub.2 and away from light, the mixture was heated in to 40° C.˜60° C. a water bath for 0.5 h˜2 h. 571 mg (5 mmol) 1,4-(trans-2,3-cyclobutyl)-butanediamine was added in the reaction solution after being dissolved with 50 ml water, which was kept under this condition to react for 0.5 h˜2 h. A yellow solid product was obtained by suction filtration and washed with water (10 ml×3 times) and ethyl ether (10 ml×3 times), to obtain 2.251 g product, with the yield of 79.96%. Elemental analysis: C, 12.61% (theoretical 12.79%), H, 2.45% (theoretical 2.49%), N, 5.11% (theoretical 4.97%).

Step 5: 2,3-diaminomethylcyclobutane•dihydrated platinum (II) sulphate

(216) ##STR00079##

(217) 625 mg (2 mmol) Ag.sub.2SO.sub.4 was placed in a 100 ml three-necked flask, 30 ml water was added thereto and stirred, and 1.122 g (2 mmol) 2,3-diaminomethylcyclobutane•diiodoplatinum (II) was added into the reaction solution and then 40 ml water was added to react, with the protection of N.sub.2 and away from light, the mixture was reacted in a water bath at 40° C.˜60° C. for 4 h˜8 h. After removing AgI precipitate by suction filtration, the filtrate was obtained, i.e., the aqueous solution of the product.

Step 6: 2-(4-diethylaminobutyl)-malonate•cis 1,4-(trans-2,3-cyclobutyl)-butanediamine platinum (II) phosphate

(218) ##STR00080##

(219) The pH of disodium 2-(2-dimethylaminoethyl)-malonate solution was adjusted to 5˜7 with 1M H.sub.3PO.sub.4 and then 1,4-(trans-2,3-cyclobutyl)-butanediamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜60° C. in a water bath for 4 h-8 h, and the reaction solution was added into 2.5 g silica gel for column chromatography (200-300 meshes) and stirred for 15 min and then pumped to be dryness, the mixture is treated by column chromatography to obtain 147 mg product.

(220) The compound in Example 22 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 37.79% (theoretical 37.92%), H, 6.36% (theoretical 6.13%), N, 7.76% (theoretical 7.81%).

(221) .sup.1HNMR (D.sub.2O) (ppm): δ3.61 (t, 1H), δ2.76 (q, 4H), δ2.71 (t, 2H), δ2.23 (d, 4H), δ1.96 (m, 2H), δ1.71 (m, 2H), δ1.45 (m, 4H), δ1.25 (m, 2H), δ1.13 (m, 2H), δ1.04 (t, 6H)

[Example 23]: 2-(4-diethylaminobutyl)-malonate•cis-1,4-cyclohexanediamine platinum (II) phosphate

(222) Steps 1, 2 and 3 are the same as steps 1, 2 and 3 in [Example 1], respectively.

Step 4: 1,4-cyclohexanediamine•diiodoplatinum (II)

(223) ##STR00081##

(224) 2.071 g (5 mmol) potassium tetrachloroplatinate (K.sub.2PtCl.sub.4) was added in 50 ml water and dissolved by stirring at room temperature, and 6.64 g (40 mmol) KI was added in the reaction solution after being dissolved with 50 ml water, with the protection of N.sub.2 and away from light, the mixture was heated to 40° C.˜60° C. in a water bath for 0.5 h˜2 h. 572 mg (5 mmol) 1, 4-cyclohexanediamine was added in the reaction solution after being dissolved with 50 ml water, which was kept under this condition to react for 0.5 h˜2 h. A yellow solid product was obtained by suction filtration and washed with water (10 ml×3 times) and ethyl ether (10 ml×3 times), to obtain 2.163 g product, with the yield of 76.84%. Elemental analysis: C, 12.74% (theoretical 12.79%), H, 2.45% (theoretical 2.49%), N, 5.17% (theoretical 4.97%).

Step 5: 1,4-cyclohexanediamine•dihydrated platinum (II) sulphate

(225) ##STR00082##

(226) 623 mg (2 mmol) Ag.sub.2SO.sub.4 was placed in a 100 ml three-necked flask, 30 ml water was added thereto and stirred, and 1.125 g (2 mmol) 1,4-cyclohexanediamine•diiodoplatinum (II) was added into the reaction solution and then 40 ml water was added to react, with the protection of N.sub.2 and away from light, the mixture was reacted at 40° C.˜60° C. in a water bath for 4 h˜8 h. After removing AgI precipitate by suction filtration, the filtrate was obtained, i.e., the aqueous solution of the product.

Step 6: 2-(4-diethylaminobutyl)-malonate•cis-1,4-cyclohexanediamine platinum (II) phosphate

(227) ##STR00083##

(228) The pH of disodium 2-(4-diethylaminobutyl)-malonate solution was adjusted to 5˜7 with 1M H.sub.3PO.sub.4 and then 1,4-cyclohexanediamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜60° C. in a water bath for 4 h-8 h, and the reaction solution was added into 2.5 g silica gel for column chromatography (200-300 meshes) and stirred for 15 min and then pumped to be dryness, the mixture is treated by column chromatography to obtain 151 mg product.

(229) The compound in Example 23 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 37.81% (theoretical 37.92%), H, 5.97% (theoretical 6.13%), N, 8.02% (theoretical 7.81%).

(230) .sup.1HNMR (D.sub.2O) (ppm): δ3.61 (t, 1H), δ2.79 (q, 4H), δ2.69 (t, 2H), 2.05 (m, 2H), δ1.81 (m, 2H), δ1.78-1.51 (m, 8H), δ1.41 (m, 2H), δ1.23 (m, 2H), δ1.08 (t, 6H).

[Example 24]: 2-(4-diethylaminobutyl)-malonate•cis-1,3-(2,2-(4-oxacyclohexyl))-propanediamine•platinum (II) phosphate

(231) Step 1, 2 and 3 are same as steps 1, 2 and 3 in [Example 1], respectively.

Step 4: 1,3-(2,2-(4-oxacyclohexyl))-propanediamine•diiodoplatinum (II)

(232) ##STR00084##

(233) 2.071 g (5 mmol) potassium tetrachloroplatinate (K.sub.2PtCl.sub.4) was added in 50 ml water and dissolved by stirring at room temperature, and 6.64 g (40 mmol) KI was added in the reaction solution after being dissolved with 50 ml water, with the protection of N.sub.2 and away from light, the mixture was heated in to 40° C.˜60° C. a water bath for 0.5 h˜2 h. 722 mg (5 mmol) 1,3-(2,2-(4-oxacyclohexyl))-propanediamine was added in the reaction solution after being dissolved with 50 ml water, which was kept under this condition to react for 0.5 h˜2 h. A yellow solid product was obtained by suction filtration and washed with water (10 ml×3 times) and ethyl ether (10 ml×3 times), to obtain 2.547 g product, with the yield of 85.91%. Elemental analysis: C, 14.35% (theoretical 14.17%), H, 2.75% (theoretical 2.70%), N, 4.72% (theoretical 4.72%).

Step 5: 1,3-(2,2-(4-oxacyclohexyl))-propanediamine•dihydrated platinum (II) sulphate

(234) ##STR00085##

(235) 623 mg (2 mmol) Ag.sub.2SO.sub.4 was placed in a 100 ml three-necked flask, 30 ml water was added thereto and stirred, and 1.185 g (2 mmol) 1,3-(2,2-(4-oxacyclohexyl))-propanediamine•diiodoplatinum (II) was added into the reaction solution and then 40 ml water was added to react, with the protection of N.sub.2 and away from light, the mixture was reacted at 40° C.˜60° C. in a water bath for 4 h˜8 h. After removing AgI precipitate by suction filtration, the filtrate was obtained, i.e., the aqueous solution of the product.

Step 6: 2-(4-diethylaminobutyl)-malonate•cis-1,3-(2,2-(4-oxacyclohexyl)-propanediamine•platinum (II) phosphate

(236) ##STR00086##

(237) The pH of disodium 2-(2-diethylaminoethyl)-malonate solution was adjusted to 5˜7 with 1M H.sub.3PO.sub.4 and then 1,3-(2,2-(4-oxacyclohexyl))-propanediamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜60° C. in a water bath for 4 h-8 h, and the reaction solution was added into 2.5 g silica gel for column chromatography (200-300 meshes) and stirred for 15 min and then pumped to be dryness, the mixture is treated by column chromatography to obtain 167 mg product.

(238) The compound in Example 24 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 38.22% (theoretical 38.03%), H, 6.35% (theoretical 6.16%), N, 7.42% (theoretical 7.39%).

(239) .sup.1HNMR (D.sub.2O) (ppm): δ3.71 (t, 4H), δ3.61 (t, 1H), δ2.77 (q, 4H), δ2.69 (t, 2H), δ2.11 (s, 4H), δ1.88 (m, 2H), δ1.51 (t, 4H), δ1.40 (m, 2H), δ1.21 (m, 2H), δ1.03 (t, 6H).

[Example 25]: 2-(4-diethylaminobutyl)-malonate•cis-dicyclopentylamine platinum (II) acetate

(240) Steps 1, 2 and 3 are the same as steps 1, 2 and 3 in [Example 1], respectively.

Step 4: dicyclopentylamine•diiododiamine (II)

(241) ##STR00087##

(242) 2.075 g (5 mmol) potassium tetrachloroplatinate (K.sub.2PtCl.sub.4) was added in 50 ml water and dissolved by stirring at room temperature, and 6.640 g (40 mmol) KI was added in the reaction solution after being dissolved with 50 ml water, with the protection of N.sub.2 and away from light, the mixture was heated in to 40° C.˜60° C. a water bath for 0.5 h˜2 h. 50 ml cyclopropantylamine (containing 5 mmol ammonia) solution was added in the reaction solution, which was kept under this condition to react for 0.5 h˜2 h. A light yellow solid product was obtained by suction filtration and washed with water (10 ml×3 times) and ethyl ether (10 ml×3 times), to obtain 2.903 g product, with the yield of 93.8%. Elemental analysis: C, 19.24% (theoretical 19.39%), H, 3.37% (theoretical 3.55%), N, 6.58% (theoretical 6.79%).

Step 5: dicyclopentylamine•dihydrated platinum (II) sulphate

(243) ##STR00088##

(244) 625 mg (2 mmol) Ag.sub.2SO.sub.4 was placed in a 100 ml three-necked flask, 30 ml water was added thereto and stirred, and 1.238 g (2 mmol) dicyclopentylamine•diiododiamine (II) was added into the reaction solution and then 40 ml water was added to react, with the protection of N.sub.2 and away from light, the mixture was reacted in a water bath at 40° C.˜60° C. for 4 h˜8 h. After removing AgI precipitate by suction filtration, the filtrate was obtained, i.e., the aqueous solution of the product.

Step 6: 2-(4-diethylaminobutyl)-malonate•cis-dicyclopentylamine platinum (II) acetate

(245) ##STR00089##

(246) The pH of disodium 2-(4-diethylaminobutyl)-malonate solution was adjusted to 5˜7 with 1M H.sub.3PO.sub.4 and then cis-diamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜75° C. in a water bath for 4 h-6 h, and the reaction solution was concentrated to a certain volume after suction filtration and stayed, to obtain 165 mg crystalline-type product.

(247) The compound in Example 25 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 42.42% (theoretical 42.42%), H, 6.67% (theoretical 6.90%), N, 7.08% (theoretical 7.07%).

(248) .sup.1HNMR (D.sub.2O) (ppm): δ3.52 (m, 1H), δ2.79 (q, 4H), δ2.67 (m, 2H), δ2.57 (t, 2H), δ2.22 (m, 8H), δ1.80 (m, 2H), δ1.45 (m, 2H), δ1.36 (m, 8H), δ1.24 (m, 2H), δ1.05 (t, 6H).

[Example 26]: 2-(4-diethylaminobutyl)-malonate•cis-ammonia•cyclopentylamine platinum (II) acetate

(249) Steps 1, 2 and 3 are the same as steps 1, 2 and 3 in [Example 1], respectively.

Step 4: ammonia•cyclopentylamine•diiodoplatinum

(250) ##STR00090##

(251) 2.076 g (5 mmol) potassium tetrachloroplatinate (K.sub.2PtCl.sub.4) was added in 50 ml water and dissolved by stirring at room temperature, and 6.65 g (40 mmol) KI was added in the reaction solution after being dissolved with 50 ml water, with the protection of N.sub.2 and away from light, the mixture was heated to 40° C.˜60° C. in a water bath for 0.5 h˜2 h. 25 ml cyclopropantylamine (containing 2.5 mmol ammonia) solution was added in the reaction solution, which was kept under this condition to react for 0.5 h˜2 h, and then 25 ml ammonia water (containing 2.5 mmol ammonia) was added in the reaction solution, which was kept under this condition to react for 0.5 h˜2 h. A light yellow solid product was obtained by suction filtration and washed with water (10 ml×3 times) and ethyl ether (10 ml×3 times), to obtain 2.43 g product, i.e., ammonia•cyclopentylamine•diiodoplatinum (II), with the yield of 88.2%. Elemental analysis: C, 10.76% (theoretical 10.89%), H, 2.31% (theoretical 2.54%), N, 5.18% (theoretical 5.08%).

Step 5: ammonia•cyclopentylamine•dihydrated platinum (II) sulphate

(252) ##STR00091##

(253) 625 mg (2 mmol) Ag.sub.2SO.sub.4 was placed in a 100 ml three-necked flask, 30 ml water was added thereto and stirred, and 1.1 g (2 mmol) ammonia•cyclopentylamine•diiodoplatinum (II) was added into the reaction solution and then 40 ml water was added to react, with the protection of N.sub.2 and away from light, the mixture was reacted at 40° C.˜60° C. in a water bath for 4 h˜8 h. After removing AgI precipitate by suction filtration, the filtrate was obtained, i.e., the aqueous solution of the product.

(254) Step 6: 2-(4-diethylaminobutyl)-malonate•cis-ammonia•cyclopentylamine platinum (II) acetate

(255) ##STR00092##

(256) The pH of disodium 2-(4-diethylaminobutyl)-malonate solution was adjusted to 5˜7 with 1M HAC and then cis-ammonia•cyclopentylamine•diiodoplatinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜75° C. in a water bath for 4 h˜6 h, and the reaction solution was concentrated to a certain volume after suction filtration and stayed, to obtain 156 mg crystalline-type product.

(257) The compound in Example 26 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 36.43% (theoretical 36.50%), H, 6.28% (theoretical 6.27%), N, 7.87% (theoretical 7.99%).

(258) .sup.1HNMR (D.sub.2O) (ppm): δ3.62 (m, 1H), δ2.80 (q, 4H), δ2.67 (m, 1H), δ2.58 (t, 2H), δ2.21 (m, 4H), δ1.80 (m, 2H), 51.45 (m, 2H), δ1.36 (m, 4H), δ1.24 (m, 2H), δ1.05 (t, 6H).

[Example 27]: 2-(4-diethylaminobutyl)-malonate•cis-(2-aminomethyl-cyclopentylamine) platinum (II) acetate

(259) Steps 1, 2 and 3 are the same as steps 1, 2 and 3 in [Example 1], respectively.

Step 4: 2-aminomethyl-cyclopentylamine•diiodoplatinum (II)

(260) ##STR00093##

(261) 2.075 g (5 mmol) potassium tetrachloroplatinate (K.sub.2PtCl.sub.4) was added in 50 ml water and dissolved by stirring at room temperature, and 6.65 g (40 mmol) KI was added in the reaction solution after being dissolved with 50 ml water, with the protection of N.sub.2 and away from light, the mixture was heated in a water bath to 40° C.˜60° C. in a water bath for 0.5 h˜2 h. 50 ml 2-aminomethyl-cyclopentylamine (containing 5 mmol ammonia) solution was added in the reaction solution, which was kept under this condition to react for 0.5 h˜2 h. A light yellow solid product was obtained by suction filtration and washed with water (10 ml×3 times) and ethyl ether (10 ml×3 times), to obtain 2.58 g product, with the yield of 92.31%. Elemental analysis: C, 12.71% (theoretical 12.88%), H, 1.72% (theoretical 1.79%), N, 5.11% (theoretical 5.01%).

Step 5: 2-aminomethyl-cyclopentylamine•dihydrated platinum (II) sulphate

(262) ##STR00094##

(263) 625 mg (2 mmol) Ag.sub.2SO.sub.4 was placed in a 100 ml three-necked flask, 30 ml water was added thereto and stirred, and 1.12 g (2 mmol) 2-aminomethyl-cyclopentylamine•diiodoplatinum (II) was added into the reaction solution and then 40 ml water was added to react, with the protection of N.sub.2 and away from light, the mixture was reacted at 40° C.˜60° C. in a water bath for 4 h˜8 h. After removing AgI precipitate by suction filtration, the filtrate was obtained, i.e., the aqueous solution of the product.

Step 6: 2-(4-diethylaminobutyl)-malonate•cis-(2-aminomethyl-cyclopentylamine) platinum (II) acetate

(264) ##STR00095##

(265) The pH of disodium 2-(4-diethylaminobutyl)-malonate solution was adjusted to 5˜7 with 1M HAC and then cis-2-aminomethyl-cyclopentylamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜75° C. in a water bath for 4 h˜6 h, and the reaction solution was concentrated to a certain volume after suction filtration and stayed, to obtain 147 mg crystalline-type product.

(266) The compound in Example 27 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 37.81% (theoretical 37.92%), H, 6.25% (theoretical 6.13%), N, 7.85% (theoretical 7.81%).

(267) .sup.1HNMR (D.sub.2O) (ppm): δ3.61 (m, 1H), δ2.81 (q, 4H), δ2.69 (m, 1H), δ2.60 (d, 2H), δ2.53 (t, 2H), δ2.31 (m, 1H), δ2.18 (m, 2H), δ1.79 (m, 2H), δ1.45 (m, 2H), δ1.35 (m, 4H), δ1.22 (m, 2H), δ1.03 (t, 6H).

[Example 28]: 2-(4-diethylaminobutyl)-malonate•cis-ammonia•piperidine platinum (II) acetate

(268) Steps 1, 2 and 3 are the same as steps 1, 2 and 3 in [Example 1], respectively.

Step 4: ammonia•piperidine•diiodoplatinum (II)

(269) ##STR00096##

(270) 2.075 g (5 mmol) potassium tetrachloroplatinate (K.sub.2PtCl.sub.4) was added in 50 ml water and dissolved by stirring at room temperature, and 6.65 g (40 mmol) KI was added in the reaction solution after being dissolved with 50 ml water, with the protection of N.sub.2 and away from light, the mixture was heated in a water bath to 40° C.˜60° C. in a water bath for 0.5 h˜2 h. 25 ml piperidine (containing 2.5 mmol ammonia) solution was added in the reaction solution, which was kept under this condition to react for 0.5 h˜2 h. Then 25 ml ammonia water (containing 2.5 mmol ammonia) was added in the reaction solution, which was kept under this condition to react for 0.5 h˜2 h. A light yellow solid product was obtained by suction filtration and washed with water (10 ml×3 times) and ethyl ether (10 ml×3 times), to obtain 2.40 g product, i.e., ammonia•piperidine•diiodoplatinum (II), with the yield of 87.1%. Elemental analysis: C, 10.71% (theoretical 10.89%), H, 2.42% (theoretical 2.54%); N, 5.23% (theoretical 5.08%).

Step 5: ammonia•piperidine•dihydrated platinum (II) sulphate

(271) ##STR00097##

(272) 625 mg (2 mmol) Ag.sub.2SO.sub.4 was placed in a 100 ml three-necked flask, 30 ml water was added thereto and stirred, and 1.09 g (2 mmol) ammonia•piperidine•diiodoplatinum (II) was added into the reaction solution and then 40 ml water was added to react, with the protection of N.sub.2 and away from light, the mixture was reacted at 40° C.˜60° C. in a water bath for 4 h˜8 h. After removing AgI precipitate by suction filtration, the filtrate was obtained, i.e., the aqueous solution of the product.

Step 6: 2-(4-diethylaminobutyl)-malonate•cis-ammonia•piperidine platinum (II) acetate

(273) ##STR00098##

(274) The pH of disodium 2-(4-diethylaminobutyl)-malonate solution was adjusted to 5˜7 with 1M HAC and then cis-ammonia•cyclopentylamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜75° C. in a water bath for 4 h˜6 h, and the reaction solution was concentrated to a certain volume after suction filtration and stayed, to obtain 160 mg crystalline-type product.

(275) The compound in Example 28 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 36.37% (theoretical 36.50%), H, 6.36% (theoretical 6.27%), N, 7.95% (theoretical 7.99%).

(276) .sup.1HNMR (D.sub.2O) (ppm): δ3.61 (m, 1H), δ2.79 (q, 4H), δ2.67 (t, 4H), δ2.58 (t, 2H), δ2.19 (m, 4H), δ1.81 (m, 2H), δ1.40 (m, 2H), δ1.29 (m, 2H), δ1.21 (m, 2H), δ1.03 (t, 6H).

[Example 29]: 2-(4-trimethylaminobutyl)-malonate•cis-(1,2-trans-cyclohexanediamine) platinum(II) tosilate

(277) Step 1 is the same as step 1 in [Example 1], respectively.

Step 2: diethyl 2-(4-trimethylaminobutyl)-malonate

(278) ##STR00099##

(279) 117.9 g, (0.4 mol) diethyl 4-bromobutyl-malonate was placed into a three-necked flask, 55.5 g (0.4 mol) anhydrous K.sub.2CO.sub.3 and 500 ml acetonitrile were added and stirred. 59 g (1.0 mol) trimethylamine was added in the reaction solution, and the mixture was heated to 45° C.˜60° C. in an oil bath to react for 2 h-6 h, the insoluble substance was filtered out, the filtrate was pumped out and then the filtrate was dissolved by adding 1000 ml ethyl acetate and washed with saturated NaCl aqueous solution (250 ml×3 times), and the organic layer was dried over anhydrous MgSO.sub.4 overnight, the solvent was pumped out under reduced pressure using a water pump, to obtain 99.0 g light yellow, light red, transparent substance, and the substance was dissolved with 50 ml water and then 50 g Ag.sub.2O was added thereto, and centrifuged, the supernate fluid was respectively extracted with 300 ml ethyl acetate three times, the extracted solution was combined, and then ethyl acetate was removed by rotary evaporation to obtain 45.6 g product, with the yield of 39.18%.

Step 3: disodium 2-(4-trimethylaminobutyl)-malonate

(280) ##STR00100##

(281) 2M NaOH solution was obtained by dissolving 212 mg (5 mmol) NaOH with 2.5 mL water. 582 mg (2 mmol) diethyl 2-(4-trimethylaminobutyl)-malonate was placed into a 20 mL three-necked flask and the above NaOH solution was added thereto, stirring the mixture at room temperature for 45 h˜60 h, to obtain a solution of disodium 2-(4-trimethylaminobutyl)-malonate.

(282) Steps 4, 5 are the same as steps 4, 5 in [Example 3], respectively.

Step 6: 2-(4-trimethylaminobutyl)-malonate•cis-(1,2-trans-cyclohexanediamine) platinum (II) tosilate

(283) ##STR00101##

(284) The pH of disodium 2-(4-trimethylaminobutyl)-malonate solution was adjusted to 5˜7 with 1 M p-toluenesulfonic acid and then trans-cyclohexanediamine•dihydrated platinum (II) sulphate aqueous solution was poured into the reaction solution, with the protection of N.sub.2, the mixture was heated to 40° C.˜60° C. in a water bath for 4 h-8 h, and the reaction solution was added into 2.5 g silica gel for column chromatography (200-300 meshes) and stirred for 15 min and then pumped to be dryness, the mixture was treated by column chromatography to obtain 150 mg product.

(285) The compound in Example 29 is soluble in water, the solubility is more than 300 mg/ml, and it can be easily converted into other types of organic or inorganic salts by ionization, the organic or inorganic salts may be, but not limited to, sulphate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate, etc. Elemental analysis of the free alkali: C, 35.70% (theoretical 35.42%), H, 6.21% (theoretical 6.09%), N, 7.79% (theoretical 7.75%).

(286) .sup.1HNMR (D.sub.2O) (ppm): δ3.62 (m, 1H), δ2.79 (s, 9H), δ2.65 (m, 2H), δ2.45 (t, 2H), δ1.80 (m, 4H), δ1.46 (m, 4H), δ1.25 (m, 4H), δ1.01 (m, 2H).

Example 30-65

(287) With reference to the above synthesis steps, the compounds in table 1 and table 2 below were produced, and LD.sub.50 and IC.sub.50 of anti-lung cancer A549 were also determined according to the methods of test example 1 and test example 2.

(288) ##STR00102##

(289) —NH.sub.2—R.sub.4 and NH.sub.2—R.sub.5 of formula I of the above structure figure are modified to —R.sub.a and —R.sub.b (see table 1).

(290) Table 1. Synthesized compounds with the structure of formula I, LD.sub.50 value, mass spectra and value of anti-lung cancer A549 thereof.

(291) TABLE-US-00001 TABLE 1 Compounds with formula I structure, their LD.sub.50, mass spectra and IC.sub.50 of anti-lung cancer A549 Mass spec- LD.sub.50 tro- Com- (mmol/ metry IC.sub.50 pound R.sub.1— R.sub.2— —R.sub.3— —R.sub.a —R.sub.b kg) (MS) (mM) 30 C.sub.2H.sub.5— CH.sub.3— 03 —NH.sub.3 —NH.sub.3 0.759 474   0.012 31 C.sub.2H.sub.5— CH.sub.3— 04 05 0.732 554   0.005 32 C.sub.3H.sub.7— C.sub.3H.sub.7— 06 07 0.845 578   0.015 33 08 —C.sub.4H.sub.8— 09 0.826 548   0.007 34 0 CH.sub.3— —C.sub.4H.sub.8— 0.905 552   0.011 35 —C.sub.4H.sub.8— 0.762 534   0.004 36 0.713 584.5 0.007 37 —C.sub.4H.sub.8— 0.825 564   0.009 38 —C.sub.4H.sub.8— 0 0.818 550   0.006 39 —C.sub.4H.sub.8— 0.711 594   0.006 40 C.sub.2H.sub.5— C.sub.2H.sub.5— —C.sub.4H.sub.8— 0.683 570   0.021 41 —C.sub.4H.sub.8— 0.675 598.5 0.013 42 —C.sub.4H.sub.8— 0.826 618   0.005 43 CH.sub.3— —C.sub.4H.sub.8— 0 0.841 564   0.005 44 CH.sub.3— CH.sub.3— —C.sub.4H.sub.8— 0.857 496   0.024 45 CH.sub.3— CH.sub.3— —C.sub.4H.sub.8— 0.834 498   0.031 46 CH.sub.3— CH.sub.3— —C.sub.4H.sub.8— 0.823 468   0.027 47 CH.sub.3— CH.sub.3— —C.sub.4H.sub.8— 0.815 482   0.023 48 CH.sub.3— CH.sub.3— —C.sub.4H.sub.8— 0.831 496   0.031 49 CH.sub.3— CH.sub.3— —C.sub.4H.sub.8— 0.817 510   0.045 50 C.sub.3H.sub.7— C.sub.3H.sub.7— 0.773 592   0.012 51 —C.sub.4H.sub.8— 0 0.654 552   0.026 52 HO—CH2— CH.sub.3— —C.sub.4H.sub.8— —NH.sub.3 0.687 500   0.041 53 CH.sub.3— —C.sub.4H.sub.8— —NH.sub.3 —NH.sub.3 0.874 456   0.054 54 C.sub.2H.sub.5— CH.sub.3— 0.792 540   0.015 55 C.sub.2H.sub.5— C.sub.2H.sub.5— —C.sub.4H.sub.8— 0.852 594   0.061 56 —C.sub.4H.sub.8— 0 0.816 618   0.057 57 CH.sub.3— —C.sub.4H.sub.8— 0.613 586   0.032 58 CH.sub.3— —C.sub.4H.sub.8— 0.607 620.5 0.037 59 CH.sub.3— —C.sub.4H.sub.8— —NH.sub.3 —NH.sub.3 0.598 558.5 0.068 60 C.sub.4H.sub.9— CH.sub.3— —C.sub.4H.sub.8— 0.875 552   0.009 61 CH.sub.3— —C.sub.4H.sub.8— 0.837 552   0.014 62 C.sub.2H.sub.5— C.sub.2H.sub.5— —C.sub.4H.sub.8— —NH.sub.2— CH.sub.2— CH═ CH—CH.sub.3 —NH.sub.2—CH.sub.2—C≡C— CH.sub.2—CH.sub.3 0.796 564   0.023 63 C.sub.2H.sub.5— C.sub.2H.sub.5— —C.sub.4H.sub.8— —NH.sub.2— (CH.sub.2).sub.2— CH.sub.3 0.804 567   0.025 64 C.sub.2H.sub.5— C.sub.2H.sub.5— —C.sub.4H.sub.8— —NH.sub.2— CH.sub.2— —NH.sub.2—CH.sub.2—N— (C.sub.2H.sub.5).sub.2 0.675 587   0.017

(292) ##STR00160##

(293) —NH.sub.2—R.sub.4 and NH.sub.2—R.sub.5 of formula II of the above structure figure are modified to —R.sub.a and —R.sub.b (see table 2).

(294) Table 2. Synthesized compounds with the structure of formula II, LD.sub.50 value, mass spectra and IC.sub.50 value of anti-lung cancer A549 thereof.

(295) TABLE-US-00002 TABLE 2 Compounds with formula II structure, their LD.sub.50, mass spectra and IC.sub.50 of anti-lung cancer A549 Mass LD.sub.50 spectro- com- VALUE ometry IC.sub.50 pound R.sub.0— R.sub.1— R.sub.2— R.sub.3— —Ra —R.sub.b (mmol/kg) (MS) (mM) 65 CH.sub.3— C.sub.4H.sub.9— CH.sub.3— —C.sub.4H.sub.8— 0.615 627 0.016 66 C.sub.2H.sub.5— C.sub.2H.sub.5— C.sub.2H.sub.5— —C.sub.4H.sub.8— —NH.sub.3 —NH.sub.3 0.677 487 0.020 67 C.sub.2H.sub.5— C.sub.2H.sub.5— C.sub.2H.sub.5— —C.sub.4H.sub.8— —NH.sub.2—(CH.sub.2).sub.3—CH.sub.2 —NH.sub.2—(CH.sub.2).sub.3—CH.sub.2 0.802 599 0.027 68 C.sub.2H.sub.5— C.sub.2H.sub.5— C.sub.2H.sub.5— —C.sub.4H.sub.8— 0.714 590 0.019

(296) Phosphates with the molecular number of 1:1 composed of bases and phosphates of the compounds 30-68 in the above examples are all easily dissolved in water, their solubility are more than 300 mg/ml, and pH of the aqueous solution thereof are between 5 and 7.

[Test Example 1]: Acute Toxic Effect of Platinum Complex on Normal Mice

(297) Kunming mice with 4˜6 weeks old and 18 g˜22 g by weight were taken, 50% males and 50% females. The platinum compounds of examples were dissolved with 5% glucose solution, and single intravenous administration (control drugs are carboplatin and cisplatin) was made at the different dosages. The condition of mortality and toxicity were observed after administration. Totally observing for 14 days, LD.sub.50 value was calculated using Bliss method according to the mortality. See Table 3.

(298) TABLE-US-00003 TABLE 3 LD.sub.50 results of intravenous injection of cisplatin, carboplatin and platinum compounds of example in mice: LD.sub.50 vALUE Example LD.sub.50 value Compound (mmol/kg) compound (mg/kg) Cisplatin 0.044 Compound 15 0.872 Carboplatin 0.336 Compound 16 0.767 Compound 1 0.746 Compound 17 0.729 Compound 2 0.797 Compound 18 0.810 Compound 3 0.815 Compound 19 0.767 Compound 4 0.823 Compound 20 0.834 Compound 5 0.845 Compound 21 0.757 Compound 6 0.756 Compound 22 0.779 Compound 7 0.778 Compound 23 0.831 Compound 8 0.801 Compound 24 0.769 Compound 9 0.725 Compound 25 0.722 Compound 10 0.791 Compound 26 0.722 Compound 11 0.803 Compound 27 0.755 Compound 12 0.729 Compound 28 0.725 Compound 13 0.816 Compound 29 0.638 Compound 14 0.866

(299) Conclusion: The acute toxicity of the molar concentration of the compounds of the examples 1-60 is much smaller than that of cisplatin and carboplatin.

(300) [Test Example 2]: Cytotoxcity Effects of the Platinum Compounds on Tumor Cells

(301) The toxic effects of the platinum compounds of examples on tumor cells were observed by applying a MTT colorimetric method. Several kinds of tumor cells in an exponential growth phase were prepared into single cell suspension, inoculated on a 96-well plate with the density of 4×10.sup.4/well, cultivated with a 1640 culture medium containing 10% fetal bovine serum (complete medium) at 37° C. for 24 hours to let cell adherence, and the final culture volume was 100 μl. Cell morphologies were observed after being cultivated for 24 hours. For the dosage of the platinum compounds, since IC.sub.50 values of various cells are different, the following concentrations are determined through a pretest: administering 200 μg/ml, 60 μg/ml, 20 μg/ml, 6 μg/ml, 2 μg/ml, 0.6 μg/ml of cisplatin, 200 μg/ml, 60 μg/ml, 20 μg/ml, 6 μg/ml, 2 μg/ml, 0.6 μg/ml of carboplatin, and appropriately adjusting the dosages of the platinum compounds of the examples depending on the sensitivity to each kind of cells. The results are shown in Table 4-9 below,

(302) TABLE-US-00004 TABLE 4 The cytotoxicity IC.sub.50 of different subjected platinum pharmaceutical compounds to different cells IC.sub.50 (n = 6) of different cell strains to chemotherapeutic drugs IC.sub.50 (mM) Cell trains Carboplatin Cisplatin Compound 1 Compound 2 Compound 3 Compound 4 Breast cancer 0.103 0.012 0.006 0.010 0.007 0.005 MCF-7 Breast cancer 0.255 0.015 0.009 0.015 0.021 0.016 MCF-7 cisplatin resistance strain Lung cancer 0.232 0.016 0.009 0.032 0.008 0.021 A549 Lung cancer 0.055 0.0053 0.003 0.011 0.006 0.008 H292

(303) TABLE-US-00005 TABLE 5 The cytotoxicity IC.sub.50 of different subjected platinum pharmaceutical compounds to different cells IC.sub.50 (n = 6) of different cell strains to chemotherapeutic drugs IC.sub.50 (mM) Cell strains Carboplatin Cisplatin Compound 5 Compound 6 Compound 7 Compound 8 Compound 9 Alveolar 0.037 0.0033 0.002 0.003 0.004 0.005 0.002 Epithelial cells BEAS-2B Lung cancer 0.038 0.045 0.018 0.041 0.021 0.025 0.050 Lewis colon cancer 0.087 0.015 0.009 0.002 0.010 0.016 0.014 SW480 Lung cancer 0.055 0.0053 0.006 0.007 0.004 0.004 0.008 H292

(304) TABLE-US-00006 TABLE 6 The cytotoxicity IC.sub.50 of different subjected platinum pharmaceutical compounds to different cells IC.sub.50 (n = 6) of different cell strains to chemotherapeutic drugs IC.sub.50 (mM) Compound Compound Compound Compound Compound Cell lines Carboplatin Cisplatin 10 11 12 13 14 Alveolar 0.037 0.0033 0.003 0.002 0.008 0.003 0.005 epithelial cells BEAS-2B Lung cancer 0.038 0.045 0.051 0.049 0.018 0.059 0.036 Lewis colon cancer 0.087 0.015 0.013 0.021 0.018 0.015 0.017 SW480 Lung cancer 0.055 0.0053 0.003 0.005 0.006 0.009 0.012 H292

(305) TABLE-US-00007 TABLE 7 The cytotoxicity IC.sub.50 of different subjected platinum pharmaceutical compounds to different cells IC.sub.50 (n = 6) of different cell strains to chemotherapeutic drugs IC.sub.50 (mM) Compound Compound Compound Compound Compound Cell strains Carboplatin Cisplatin 15 16 17 18 19 Testis 0.195 0.00899 0.011 0.010 0.016 0.022 0.013 cell ST gastric cancer 0.625 0.0025 0.003 0.004 0.005 0.002 0.005 MGC803 colon cancer 0.087 0.015 0.018 0.013 0.007 0.014 0.023 SW480 Lung cancer 0.055 0.0053 0.010 0.005 0.004 0.008 0.006 H292

(306) TABLE-US-00008 TABLE 8 The cytotoxicity (IC.sub.50) of different subjected platinum pharmaceutical compounds to different cells IC.sub.50 (n = 6) of differnt cell strains to chemotherapeutic drugs IC.sub.50 (mM) Compound Compound Compound Compound Compound Cell strains Carboplatin Cisplatin 20 21 22 23 24 Testis 0.195 0.00899 0.011 0.013 0.014 0.008 0.006 cell ST gastric cancer 0.625 0.0025 0.004 0.005 0.007 0.005 0.003 MGC803 Esophagus 0.052 0.073 0.017 0.015 0.102 0.066 0.052 cancer ECA109 Lung cancer 0.055 0.0053 0.005 0.012 0.005 0.014 0.003 H292

(307) TABLE-US-00009 TABLE 9 The cytotoxicity IC.sub.50 of different subjected platinum pharmaceutical compounds to different cells IC.sub.50 (n = 6) of different cells strains to chemotherapeutic drugs IC.sub.50 (mM) Compound Compound Compound Compound Compound Cell strains Carboplatin Cisplatin 25 26 27 28 29 Testis cell ST 0.195 0.00899 0.007 0.011 0.013 0.061 0.008 gastric cancer 0.625 0.0025 0.003 0.001 0.005 0.006 0.002 MGC803 Esophagus 0.052 0.073 0.029 0.091 0.054 0.046 0.025 cancer ECA109 Lung cancer 0.055 0.0053 0.006 0.004 0.004 0.011 0.007 H292

(308) As can be seen from Tables 1-2, and 4-9, the compounds of Examples 1-29 have equivalent or stronger cytotoxic effects in vitro with cisplatin, and much stronger than carboplatin.

[Formulation Example 1]: Preparation of Injection

(309) Prescription 1

(310) TABLE-US-00010 The phosphate of the compound in Example 2 10 g Glucose 50 g Adding water for injection to 1000 ml Produced 1000

(311) Process: 10 g tosilate of the compound in Example 2 and 50 g glucose were added into a 2000 ml glassware, and dissolved by adding water for injection to 1000 ml at normal temperature, after filtering with 0.22 μm microporous membrane, the filtrate was charged into 1 ml ampoules to obtain the product with the specification of 10 mg/ml.

(312) Prescription 2

(313) TABLE-US-00011 The mesylate of the compound in Example 6 10 g Glucose 50 g Adding water for injection to 1000 ml Produced 1000

(314) Process: 10 g mesylate of the compound in Example 6, i.e. 10 g mesylate and 50 g glucose were added into a 1000 ml glassware, and dissolved by adding water to 1000 ml for injection at normal temperature, after filtering with 0.22 μm microporous membrane, the filtrate was charged into 2 ml vial to obtain the product with the specification of 10 mg/bottle.

[Formulation Example 2]: Preparation of Freeze-Dried Powder Injection

(315) Prescription 1

(316) TABLE-US-00012 The tosilate of the compound in Example 9 10 g Mannitol 50 g Adding water for injection to 1000 ml Produced 1000

(317) Process: 10 g compound in Example 9 and 50 g Mannitol were added into a 1000 ml glassware, and dissolved by adding water for injection to 1000 ml at normal temperature, after filtering with 0.22 μm microporous membrane, the filtrate was charged into 2 ml vial, 1 ml solution for each bottle, and then freeze-dried to obtain the product with the specification of 10 mg/bottle.

(318) Prescription 2

(319) TABLE-US-00013 The phosphate of the compound in Example 11 20 g Mannitol 50 g Adding water for injection to 1000 ml Produced 1000

(320) Process: 20 g phosphate of the compound in Example 11 and 50 g Mannitol were added into a 1000 ml glassware, and dissolved by adding water for injection to 1000 ml at normal temperature, after filtering with 0.22 μm microporous membrane, the filtrate was charged into 2 ml vial, 1 ml solution for each bottle, and then freeze-dried to obtain the product with the specification of 20 mg/bottle.

(321) Prescription 3

(322) TABLE-US-00014 The acetate of the compound in Example 13 50 g Adding water for injection to 1000 ml Produced 1000

(323) Process: 50 g acetate of the compound in Example 20 was added into a 1000 ml glassware, and dissolved by adding water for injection to 1000 ml at normal temperature, after filtering with 0.22 μm microporous membrane, the filtrate was charged into 2 ml vial, 1 ml solution for each bottle, and then freeze-dried to obtain the product with the specification of 50 mg/bottle.