KR100197162B1 - Platinum(ii) complexes of substituted malonates and preparation method thereof - Google Patents

Abstract

Provided are a novel substituted platinum complex compound of the following general formula (I) having substituted malonic acid as an anionic ligand and a method for producing the same. The compound of the present invention has a lower antitoxicity than the conventional anticancer system and has an excellent anticancer effect.

Description

[Name of invention]

Substituted malonic acid platinum complex and preparation method thereof

Detailed description of the invention

[Purpose of invention]

[Technical field to which the invention belongs and the prior art in that field]

The present invention relates to a platinum complex compound having excellent anticancer effect represented by the following general formula (I) and a method for producing the same.

(Wherein A is a monodentate neutral ligand, ammonia (NH ₃ ), cyclopropylamine (C ₃ H ₅ NH ₂ ), isopropylamine (iso-C ₃ H ₇ NH ₂ ), or in some cases, two Amine chelates with amine groups, such as ethylenediamine (NH ₂ CH ₂ CH ₂ NH ₂ ), trans (±) -1,2-diaminocyclohexane (trans (± -1,2- (NH ₂₎ ) ₂ -cyclo-C ₆ H ₁₀ ), 2,2-dimethyl-1,3-propanediamine (NH ₂ CH ₂ C (CH ₃ ) ₂ CH ₂ NH ₂ ), tetrahydro-4H-pyran-4,4 -Dimethanamine (O- (CH ₂ CH ₂ ) ₂ C (CH ₂ NH ₂ ) ₂ ), 2,2-bis (aminomethyl) -1,3-propanediol (HOCH ₂ ) _2- (C (CH ₂ NH ₂ ) ₂ ) and the like; X represents hydrogen (H-) or fluoro (F-), chloro (Cl-), methoxy (CH ₃ O-), etc. as a substituent of the benzene ring. The positions of the substituents represent 2-, 3- or 4-; Y represents hydrogen (H-), methyl (CH _3- ), ethyl (CH ₃ CH _2- ), allyl (CH ₂ = CHCH _2- ), benzyl _{(C 6 H 5 CH 2 -} ), 2- fluoro-benzyl (2-FC ₆ H ₄ CH _2- ), 3-fluorobenzyl (3-FC ₆ H ₄ CH _2- ), 4-fluorobenzyl (4-FC ₆ H ₄ CH _2- ), 3-methoxybenzyl (3-CH ₃ OC ₆ H ₄ CH _2- ) etc.)

Platinum complex compounds containing these anions have been found to exhibit very good anticancer effects and low toxicity as novel substances.

Among the currently used anticancer drugs, cisplatin, cislatin (cislatin), cis- (NH ₃ ) ₂ PtCl _2, has anticancer effect by B. Rosenberg, Nature, 205, 698 (1965) in 1965. It was officially approved as an anticancer agent by the US FDA in 1979 and is the most effective combination therapy for a wide range of cancers, including testicular cancer, ovarian cancer, bladder cancer, bone marrow cancer, and laryngeal cancer. 835 (1978)). Carboplatin, ie, cis- (NH ₃ ) ₂ Pt (CBDC) (CBDC = 1,1-cyclobutanedicarboxylate, LD50 = 180 mg / kg, MJ Cleare, Biochimie, 60, 835 (1978)) was approved by the FDA in 1989 and started to be used as a second-generation anticancer drug. However, the anticancer effect is significantly lower than that of cisplatin. As a result, there are active researches worldwide on the synthesis and retrieval of third-generation anticancer drugs, which have better anticancer effects and lower toxicity than cisplatin, and these reports cannot be enumerated. In addition to the excellent anticancer effect of cisplatin and low toxicity equivalent to carboplatin, it is also effective against cisplatin or carboplatin-resistant cancer cells, namely cross-resistsnce. It should be absent, and the area of cancer cells treatable should be wider. In addition, since the solubility of the drug in water and the chemical stability must be maintained to satisfy a variety of difficult conditions, currently there are about 10 candidate compounds in clinical trials around the world, but commercialization is not successful.

[Technical problem to be achieved]

Accordingly, the present inventors synthesized a new platinum complex molecule that modified the molecular structure of the anion of the cisplatin molecule as part of a study to develop a new platinum-based anticancer agent having better anticancer effect and lower toxicity than existing cisplatin. The test was conducted. That is, it was observed that the substituted malonic acid including at least one benzyl substituent at the α-position was bonded to platinum, and the introduction of the benzyl substituent into the malonic acid significantly improved the lipophilic properties of the final platinum compounds. In addition, as a result of measuring lipophilic properties of the platinum compounds, the partition coefficient (Partition Coefficient (1-Octanol / Water)) of the platinum complex including one benzyl substituent was 0.1 to 1.0, and two benzyl substituents were used. In the case of including 1.0 to 3.5, it was found that lipophilic properties were greatly improved over the conventional carboplatin (distribution coefficient 0.041). The physiological activity test of these platinum complexes of general formula (I) showed that the toxicity was lower than that of cisplatin and the anticancer effect was much better. In addition, they are excellent in chemical stability and are expected to solve various pharmaceutical problems. As described above, in the case of the platinum complex of substituted malonic acid containing a benzyl substituent, the lipophilic property of the platinum complex is improved, and the concentration of the platinum complex in the target cell is increased because the platinum complex is easily passed through the cell membrane and absorbed into the cell. The anticancer effect is thought to be increased.

[Configuration and Function of Invention]

The present invention will be described in detail as follows. The substituted malonic acid anions which form the core structure of the novel platinum complex compound of general formula (I) having excellent anticancer properties are malonic acid ethyl ester, methyl malonic acid ester, ethyl malonic acid ethyl ester, allyl malonic acid ethyl ester and ethyl benzyl malonic acid ethyl. Esters and the like benzyl chloride (C ₆ H ₅ CH ₂ Cl) and its derivatives, such as 2-fluorobenzylchloride (2-FC ₆ H ₄ CH ₂ Cl), 3-fluorobenzylchloride (3- _{FC 6 H4CH 2 - Cl),} 4- fluoro-benzyl chloride _{(4-FC 6 H 4 CH} 2 Cl), 4- chlorobenzyl chloride _{(4-ClC 6 H 4 CH} 2 Cl), 3- methoxybenzyl chloride ( 3-CH ₃ OC ₆ H ₄ CH ₂ Cl) and the like are reacted under a K ₂ CO ₃ / NaI catalyst in an acetone solvent according to the reference (Org. Syntheses Coll. Vol 3, 705 (1955)). Substituted malonic acid represented by) is obtained.

(Wherein R represents an ethyl group and X and Y are the same as X and Y in general formula (I))

The dicarboxylic acid ester of the general formula (II) obtained above is stirred in an ethanol solvent in the presence of 2.0 to 2.2 equivalents of alkali (KOH or NaOH) at room temperature for 5 to 9 hours, whereby the water-soluble alkali salt of the general formula (III) Precipitates. This salt is filtered off and then used for synthesis of a platinum complex, or the salt is reacted with the same equivalent of barium chloride or calcium chloride to obtain an alkaline earth metal salt of the following general formula (IV). Or stirring the dicarboxylic acid ester of formula (II) in methanol solvent in the presence of 1.0 to 1.2 equivalents of barium hydroxide (Ba (OH) .8H ₂ O) or calcium hydroxide (Ca (OH) ₂ ) for 3-5 hours. After refluxing and cooling to room temperature (25 ° C.), alkaline earth metal salts of general formula (IV) are precipitated directly.

Wherein M (I) is sodium or potassium, M (II) is barium or calcium and X is as defined above)

An alkali metal salt of general formula (III) or an alkaline earth metal salt of general formula (IV) is reacted with a platinum nitrate derivative of general formula (V) or a platinum sulfate derivative of general formula (VI) which is an amine-platinum intermediate, respectively. Prepare the final platinum complex of I).

Wherein A is as defined above.

In the case of an alkali salt of the general formula (III), the aqueous solution of the alkali salt is mixed directly with an aqueous amine-platinum nitrate solution of the general formula (V) or an aqueous amine-platinum sulfate solution of the general formula (VI), and concentrated to give an alkali nitrate. Or the sulfate is dissolved in water and the platinum complex is precipitated by precipitation. Alternatively, when the alkali salt is reacted with the amine-platinum sulfate of general formula (VI) in a methanol solution, insoluble sodium sulfate precipitates, and the filtrate is concentrated to obtain a platinum complex. On the other hand, in the case of alkaline earth metal salt of formula (IV), when the alkaline earth metal salt and amine-platinum sulfate of formula (VI) are reacted in water or a mixed solution of water and methanol, insoluble barium sulfate or calcium sulfate is quantitatively The precipitate is filtered off and the filtrate is simply concentrated, or concentrated and an organic solvent such as acetone or ethyl ether is added to give a pure platinum complex of formula (I) in crystal or powder form.

On the other hand, the platinum nitrate derivative of the general formula (V) is platinum amine iodide and silver nitrate of the general formula (VII), and the platinum sulfate derivative of the general formula (VI) is the amine iodide platinum and sulfuric acid of the general formula (VII) Are prepared according to the known literature (RC Harrison, Inorg. Chimica Acta, 46, L15 (1980)).

Wherein A is as defined above.

Platinum amine iodide in general formula (VII) can be easily obtained by reacting potassium tetrachloride potassium salt with potassium iodide and the corresponding amine compound according to the known literature (M. J. Ceare, Biochimie, 60, 835 (1978)).

Synthesis process of the present invention is represented as follows.

The following examples illustrate the present invention in detail, and the scope of the present invention is not limited to these examples without departing from the scope of the claims.

Elemental analysis of the platinum complexes of the present invention was performed by Perkin Elmer C, H, N analyzer by the characterization center of the present application. Meanwhile, the specimen was made in the form of an infrared absorption spectrum KBr pellet, and then measured between 4000 and 400 cm −1 region by Perkin Elmer 16F PC FT-IR.

Example 1

Preparation of (NH ₃ ) ₂ Pt [(OCC) ₂ C (CH ₂ C ₆ H ₅ ) ₂ ]

(A = NH ₃ ; X = H, Y = CH ₂ C ₆ H ₅ )

Dibenzyl malonic acid ethyl ester ((C ₆ H ₅ CH ₂ ) ₂ C (COOCH ₅ ) ₂ ) 8.51 g (25 mmol) in 50 ml of methanol in barium hydroxide (Ba (OH) ₂ · 8H ₂ O) 9.46 g 100 ml of methanol solution (30 mmol) was added thereto, followed by hydrolysis by reflux with stirring for 4 hours. The reactant was cooled to room temperature (25 ° C.), and the resulting precipitate was filtered, washed twice with methanol and ethyl ether, and then dried under reduced pressure (3 mmHg) to remove barium salt ([(C ₆ H ₅ CH ₂ ) ₂ C (COO ₂ Ba] .2H ₂ O) 10.48 g (92% yield) were obtained.

(NH ₃ ) ₂ obtained by reacting 1.37 g (3.00 mmol) of barium salt thus obtained in 20 ml of water with 1.45 g (3.00 mmol) of amine-platinum intermediate (NH ₃ ) 2 PtI 2 and 0.94 g (3.00 mmol) of Ag ₂ SO _4. PtSO ₄ aqueous solution was slowly added and reacted for 1 hour, and then 100 ml of methanol was added and stirred for 1 hour. The precipitate was filtered off and the filtrate was dried under reduced pressure (3 mmHg) at room temperature to obtain 1.03 g (yield 67.3%) of platinum complex (NH ₃ ) ₂ Pt [(OCC) ₂ C (CH ₂ C ₆ H ₅ ) ₂ ].

Example 2

를 55.6%의 수율로 얻었다.Platinum deposits in the same manner as in Example 1 using the same equivalent of cyclopropylamine instead of ammonia

Was obtained in a yield of 55.6%.

Example 3

Preparation of (iC ₃ H ₇ NH ₂ ) ₂ Pt [(OOC) ₂ C (CH ₂ C ₆ H ₅ ) ₂ ]

(A = iC ₃ H ₇ NH ₂ ; X = H, Y = CH ₂ C ₆ H ₅ )

Platinum complex (iC ₃ H ₇ NH ₂ ) ₂ Pt [(OOC) ₂ C (CH ₂ C ₆ H ₅ ) ₂ ] H ₂ O in the same manner as in Example 1, using the same equivalent of isopropylamine in place of ammonia Was obtained in a yield of 72.5%.

Example 4

의 제조

Manufacture

A platinum complex in the same manner as in Example 1 using the same equivalent of trans (±) -1,2-diaminocyclohexane instead of ammonia

를 80.2%의 수율로 얻었다.

Was obtained in a yield of 80.2%.

Example 5

Preparation of [NH ₂ CH ₂ C (CH ₃ ) ₂ CH ₂ NH ₂ ] Pt [(OOC ₂ C (CH ₂ C ₆ H ₅ ) ₂ ]

(A ₂ = NH ₂ CH ₂ C (CH ₃ ) ₂ CH ₂ NH ₂ ; X = H, Y = CH ₂ C ₆ H ₅ )

A platinum complex {NH ₂ CH ₂ C (CH ₃ ) ₂ CH ₂ NH ₂ ] -Pt [(OCC) in the same manner as in Example 1 using the same equivalent of 2,2-dimethyl-1,3-propanediamine instead of ammonia. ) ₂ C (CH ₂ C ₆ H ₅ ) ₂ ] .H ₂ O was obtained in a yield of 75.8%.

Example 6

Preparation of [(HOCH2) 2C (CH2NH2) 2] Pt [(OOC) 2C (CH2C6H5) 2]

(A2 = (HOCH2) 2C (CH2NH2) 2; X = H, Y == CH2C6H5)

A platinum complex [(HOCH ₂ ) ₂ C (CH ₂ NH ₂ ) ₂ ] Pt [in the same manner as in Example 1 using the same equivalent of 2,2-bis (aminomethyl) -1,3-propanediol instead of ammonia (OOC) ₂ C (CH ₂ C ₆ H ₅ ) ₂ ] .H ₂ O was obtained in a yield of 81.7%.

Example 7

A platinum complex in the same manner as in Example 4 using bis (3-methoxybenzyl) malonic acid ethyl ester instead of dibenzyl malonic acid ethyl ester

를 82.1%의 수율로 얻었다.

Was obtained in a yield of 82.1%.

Example 8

Preparation of [O (CH ₂ CH ₂ ) ₂ C (CH ₂ NH ₂ ) ₂ ] Pt [(OOC) ₂ C (CH ₂ C ₆ H ₄ -3-OCH ₃ ) ₂ ]

(A ₂ = O (CH ₂ CH ₂ ) ₂ C (CH ₂ NH ₂ ); X = OCH ₃ ; Y = CH ₂ C ₆ H ₄ -3-OCH ₃ )

Using the same amount of tetrahydro-4H-pyran-4,4-dimethanamine instead of trans (±) -1,2-diaminocyclohexane in the same manner as in Example 7, the platinum complex [O (CH ₂ CH ₂ ) ₂ C (CH ₂ NH ₂ ) ₂ ] Pt [(OOC) ₂ C (CH ₂ C ₆ H ₄ -3-OCH ₃ ) ₂ ] .2H ₂ O was obtained in a yield of 71.1%.

Example 9

의 제조

Manufacture

A platinum complex in the same manner as in Example 4, using bis (2-fluorobenzyl) malonic acid ethyl ester instead of dibenzyl malonic acid ethyl ester

를 62.1%의 수율로 얻었다.

Was obtained in a yield of 62.1%.

Example 10

의 제조

Manufacture

A platinum complex in the same manner as in Example 4 using bis (3-fluorobenzyl) malonic acid ethyl ester instead of dibenzyl malonic acid ethyl ester

를 58.6%의 수율로 얻었다.

Was obtained in a yield of 58.6%.

Example 11

의 제조

Manufacture

Platinum complexes in the same manner as in Example 4, using bis (4-fluorobenzyl) malonic acid etal ester instead of dibenzyl malonic acid ethyl ester

를 60.5%의 수율로 얻었다.

Was obtained in a yield of 60.5%.

Example 12

의 제조

Manufacture

A platinum complex in the same manner as in Example 4 using benzyl (4-chloro) benzyl malonic acid ethyl ester instead of dibenzyl malonic acid ethyl ester

를 65.6%의 수율로 얻었다.

Was obtained in a yield of 65.6%.

Example 13

의 제조

Manufacture

A platinum complex in the same manner as in Example 4 using benzyl methyl malonic acid ethyl ester instead of dibenzyl malonic acid ethyl ester

를 82.7%의 수율로 얻었다.

Was obtained in a yield of 82.7%.

Example 14

의 제조

Manufacture

A platinum complex in the same manner as in Example 13, using the same equivalent of 2,2-dimethyl-1,3-propanediamine instead of trans (±) -1,2-diaminocyclohexane

를 79.4%의 수율로 얻었다.

Was obtained in a yield of 79.4%.

Example 15

의 제조

Manufacture

A platinum complex in the same manner as in Example 4, using 3-methoxybenzylmethylmalonic acid ethyl ester instead of dibenzyl malonic acid ethyl ester

를 81.7%의 수율로 얻었다.

Was obtained in a yield of 81.7%.

Example 16

의 제조

Manufacture

A platinum complex [NH ₂ CH ₂ C (CH ₃₎ was prepared in the same manner as in Example 15 using the same equivalent of 2,2-dimethyl-1,3-propanediamine instead of trans (±) -1,2-diaminocyclohexane. ) ₂ CH ₂ NH ₂ ] Pt [(OOC) ₂ C (CH ₂ C ₆ H ₄ -4-OCH ₃ ) (CH ₃ )]. 2H ₂ O was obtained in a yield of 83.0%.

Example 17

의 제조

Manufacture

A platinum complex in the same manner as in Example 4, using 4-chlorobenzylmethylmalonic acid ethyl ester instead of dibenzyl malonic acid ethyl ester

를 72.7%의 수율로 얻었다.

Was obtained in a yield of 72.7%.

Example 18

의 제조

Manufacture

A platinum complex in the same manner as in Example 4 using benzyl methyl malonic acid ethyl ester instead of dibenzyl malonic acid ethyl ester

를 83.8%의 수율로 얻었다.

Was obtained in a yield of 83.8%.

Example 19

의 제조

Manufacture

7.26g(25mmol)을 에탄올 50ml에 녹인 용액에 NaOh 2.20g(55mmol)이 녹아 있는 100ml의 에탄올 용액을 가한 후 4시간동안 저으면서 환류하여 가수분해하였다. 반응물을 실온(25℃)으로 식힌 후 생성된 침전물을 여과하여 에탄올, 에틸에테르로 각각 2회씩 세척한 후 감압(3mmHg) 건조하여 나트륨염

7.39g(수율 94%)을 얻었다.Allylbenzyl malonic acid ethyl ester

A solution of 7.26 g (25 mmol) in 50 ml of ethanol was added to 100 ml of ethanol solution in which 2.20 g (55 mmol) of NaOh was dissolved, followed by stirring under reflux for 4 hours to hydrolysis. The reactant was cooled to room temperature (25 ° C.), and the resulting precipitate was filtered, washed twice with ethanol and ethyl ether, and dried under reduced pressure (3 mmHg) to remove sodium salt.

7.39 g (94% yield) were obtained.

;를 0.91g(수율 63.1%) 얻었다.Amine-platinum intermediate _{(NH 3) 2 PtI 2 1.45g} (3.00mmol) and _{Ag 2 SO 4 0.94g (3.00mm ol} ) and the reaction was obtained (NH ₃₎ to obtain a solution in which ₂ were suspended in methanol 50ml PtSO ₄ 0.94 g (3.00 mmol) of sodium allylbenzyl malonate was slowly added to a solution dissolved in 100 ml of methanol, followed by stirring for 2 hours. The precipitate was filtered off, the filtrate was concentrated to 5-7 ml, and ethyl ether was added to give a white crystalline powder. The precipitate was filtered and dried under reduced pressure (3 mmHg) at room temperature to obtain a platinum complex.

0.91g (yield 63.1%) was obtained.

Example 20

의 제조

Manufacture

를 74.1%의 수율로 얻었다.Platinum deposits in the same manner as in Example 19 using the same equivalent of ethylenediamine instead of ammonia

Was obtained in a yield of 74.1%.

Example 21

의 제조

Manufacture

A platinum complex in the same manner as in Example 19 using the same equivalent of trans (±) -1,2-diaminocyclohexane in place of ammonia

를 73.0%의 수율로 얻었다.

Was obtained in a yield of 73.0%.

Example 22

의 제조

Manufacture

A platinum complex in the same manner as in Example 21, using allyl (3-methoxy) benzylmalonic acid ethyl ester instead of allylbenzyl malonic acid ethyl ester

를 74.2%의 수율로 얻었다.

Was obtained in a yield of 74.2%.

Example 23

의 제조

Manufacture

A platinum complex in the same manner as in Example 4 using monobenzyl malonic acid ethyl ester instead of dibenzyl malonic acid ethyl ester

를 87.2%의 수율로 얻었다.

Was obtained in a yield of 87.2%.

[Distribution coefficient test]

The partition coefficient was measured to compare the lipophilic properties of the platinum compound of the present invention. The partition coefficient test was carried out by the standard method (No. 107 Partition Coefficient (1-Octanol / Water) of OECD Guideline for Testing of Chemicals (1981)) and the partition coefficient was calculated as follows.

C _1-octanol : The concentration of platinum complex dissolved in the 1-octanol layer.

C _water : concentration of platinum complex dissolved in the _water layer

The concentration of the platinum complex dissolved in each layer was determined by platinum analysis using Inductively Coupled Plasma-Atomic Emission Spectrometry (ICP-AES), and the results are shown in Table 1. The distribution coefficient of the platinum complexes of the present invention is much larger than the conventional commercialized carboplatin, which means that the lipophilic property is greatly improved.

[Acute Toxicity Test]

As a representative compound of the present invention, the acute toxicity (LD50) of the compounds of Examples 4 and 21 was measured and shown in Table 2 and compared with those of cisplatin.

From the results of Table 2, even the compound of Example 4 of the present invention with the highest toxicity has acute toxicity level twice that of cisplatin, and it can be seen that the toxicity is significantly lower than the existing anticancer drugs.

[Anticancer activity test]

The anticancer activity test for the platinum compound of the present invention was carried out as follows by standard methods (Goldin et al., Europ. J. Cancer. 17, 129 (1981)). 8 rats (BDFI mice), 6 to 8 weeks old, per group, 10 per mouse After implanting mouse leukemia cells L121 0 in dogs, they were dissolved in 0.9% physiological saline of the platinum complex and 10 to 60 mg / kg were injected intraperitoneally on days 1, 5 and 9 as needed. : Increased LIfe Span (%) and 60-day survivors were observed. The results are shown in Table 3.

It can be seen from Table 3 that the anticancer activity of the platinum complexes of the present invention is much superior to conventional commercialized cisplatin or carboplatin.

Claims (6)

Platinum complex compound represented by the following general formula (II).

(Wherein A is a monodentate neutral ligand, ammonia, cyclopropylamine, isopropylamine, or, in some cases, two amine groups in the general formula above form one chelate such as ethylenediamine, trans (±) -1, 2-diaminocyclohexane, 2,2-dimethyl-1,3-propanediamine, tetrahydro-4H-pyran-4,4-dimethanamine, 2,2-bis (aminomethyl) -1,3-propane Diols and the like; X can be hydrogen or fluoro, chloro, methoxy groups, the position can be 2-, 3- or 4- and Y can be hydrogen, methyl, ethyl, allyl, benzyl, 2-fluoro Lobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 3-methoxybenzyl, etc.) A method for producing a platinum complex compound of formula (I), wherein the alkali metal salt of formula (III) and the platinum nitrate derivative of formula (V) are reacted in an aqueous solution at a molar ratio of 1: 1, followed by concentrated precipitation.

Wherein M (I) is sodium or potassium and A, X and Y are as defined in claim 1) The alkali metal salt of formula (III) and the platinum sulfate derivative of formula (VI) are reacted in methanol solution in a 1: 1 molar ratio to filter out the precipitated sodium sulfate, and then the filtrate is simply concentrated, or concentrated and an organic solvent is added. A process for preparing the platinum complex of formula (I).

(Wherein A is as defined in claim 1). The alkaline earth metal salt of general formula (IV) and the platinum sulfate derivative of general formula (VI) are reacted in a mole or a mixed solution of molar and methanol to filter out precipitated barium sulfate or calcium sulfate, and then the filtrate is simply concentrated or concentrated. And then adding an organic solvent to prepare a platinum compound of formula (I).

Wherein M (II) is barium or calcium, and X and Y are as defined in paragraph 1) 4. The process according to claim 3, wherein acetone or ethyl ether is used as the organic solvent. The production method according to claim 4, wherein acetone or ethyl ether is used as the organic solvent.