CN104341455A - Ruthenium compound with antitumor activity and preparation method and application thereof - Google Patents

Abstract

Translated fromChinese

本发明公开了一种具有结构式(I)的具有抗肿瘤活性的钌化合物及其制备方法和用途。其化学名称为一氯一(1E，3Z，6E)-1，7-二(3，4-二甲氧基苯基)-4-甲基-1，3，6-庚三烯-3，5-二酮一甲基异丙基苯合钌。其对胃癌SGC-7901细胞株和肝癌BEL-7404细胞株均表现良好的抑制活性，可用于制备治疗癌症的药物，可制成注射剂、片剂、丸剂、胶囊剂、悬浮剂或乳剂的形式使用。本发明所述具有抗肿瘤活性的钌化合物的制备方法简单，原料易得，具有成本低的优势。The invention discloses a ruthenium compound with structural formula (I) and anti-tumor activity as well as its preparation method and application. Its chemical name is monochloro-(1E,3Z,6E)-1,7-bis(3,4-dimethoxyphenyl)-4-methyl-1,3,6-heptatriene-3, 5-Diketone-cymene ruthenium. It has good inhibitory activity on gastric cancer SGC-7901 cell line and liver cancer BEL-7404 cell line, and can be used to prepare drugs for treating cancer, and can be used in the form of injections, tablets, pills, capsules, suspensions or emulsions . The preparation method of the ruthenium compound with anti-tumor activity is simple, the raw materials are easy to obtain, and the cost is low.

Description

A kind of ruthenium compound with anti-tumor activity and its production and use

Technical field

The present invention relates to field of compound preparation, be specifically related to a kind of ruthenium compound with anti-tumor activity and its production and use.

Background technology

At present, cis-platinum has become and has been used for the treatment of cancer one of 3 kinds of medicines the most widely in the world, reaches nearly 500,000,000 dollars in the annual sales amount of the U.S..But the use of cis-platinum also has certain deficiency, it does not have restraining effect to some tumour, and easily and other platinum preparations produce cross resistance.In addition, cis-platinum has multiple side effect, as renal toxicity, peripheral nerve toxicity, bone marrow toxicity, haematics toxicity and emetic etc.Therefore, find efficient, low toxicity and be the study hotspot of researcher always without the new type antineoplastic medicine of cross resistance.

Curcumin chemical compounds is numerous due to its hapto, is easy to form title complex with metal with multiple coordination mode.Recently, because multiple curcumin title complex is found to have wide spectrum pharmacological activity---make one notice as characteristics such as antitumor, anti-inflammatories.With curcumin chemical compounds for main part prepares organometallic ruthenium compound, due to the synergy of metal Ru and curcumin part, its anti-tumor activity can be strengthened.

Summary of the invention

The object of the invention is to the synergistic research according to existing metal Ru and curcumin part, a kind of ruthenium compound with anti-tumor activity and its production and use is provided.

Technical scheme provided by the invention is:

There is a ruthenium compound for anti-tumor activity,

1) this chemical name with the ruthenium compound of anti-tumor activity is chlorine one (1E, 3Z, 6E)-1,7-bis-(3,4-Dimethoxyphenyl)-4-methyl isophthalic acid, and 3,6-heptantriene-3,5-diketone monomethyl isopropyl benzene closes ruthenium;

2) its structural formula is formula (I):

There is a preparation method for the ruthenium compound of anti-tumor activity, wherein, comprise the following steps:

Step one, the hydrate ruthenium trichloride of 0.2-0.5g and the γ-terpinene of 2-6ml are dissolved in 5-15ml dehydrated alcohol, reflux stirs 4-8 hour, standing precipitation obtains the compound with formula (III), and namely dichloride-two-cymene closes two rutheniums (II);

Step 2, take the 3-methyl-2 of 0.05-0.15g, 3 of 4-diacetylmethane, 0.05-0.2g, the boron trioxide of 4-dimethoxy benzaldehyde and 0.02-0.08g is dissolved in 5-15ml dimethyl formamide solution jointly, under nitrogen protection, 70-90 DEG C of reaction is after 4-8 hour, add the hydrochloric acid of 0.1-0.2g, standing precipitation obtains the compound with formula (IV), i.e. (1E, 3Z, 6E)-1,7-bis-(3,4-Dimethoxyphenyl)-3-hydroxy-4-methyl-1,3,6-heptantriene-5-ketone;

Step 3, by (the 1E of 15-25mg, 3Z, 6E)-1,7-bis-(3,4-Dimethoxyphenyl)-3-hydroxy-4-methyl-1, dichloride-two-cymene of 3,6-heptantriene-5-ketone and 28-37mg closes the dehydrated alcohol that two rutheniums (II) are dissolved in 5-12ml, heated and stirred backflow 4-8 hour, react rear and solution evaporation has been remained 1-3ml liquid, add the normal hexane of 25-35ml, separate out red crystals, to obtain final product.

Preferably, described has in the preparation method of the ruthenium compound of anti-tumor activity, and hydrate ruthenium trichloride described in step one is the hydrate ruthenium trichloride of ruthenium weight content 37%; The purity of described γ-terpinene is 95%.

There is a purposes for the ruthenium compound of anti-tumor activity, described in there is anti-tumor activity ruthenium compound for the preparation of the application for the treatment of cancer of the stomach and liver-cancer medicine.

The present invention has following beneficial effect: first, the ruthenium compound with anti-tumor activity of the present invention closes two rutheniums and methyl curcumin compounds, preparation coordination by dichloride-two-cymene, ruthenium compound with methyl has good biocompatibility, effectively can suppress the propagation of cancer of the stomach and liver cancer cell, be 46% to cancer of the stomach and liver cancer cell inhibiting rate, cancer of the stomach and hepatoma cell apoptosis obviously increase.23% is improve relative to its inhibiting rate of Benzazole compounds.Secondly, the ruthenium compound with anti-tumor activity of the present invention can be used for the medicine preparing Therapeutic cancer, and the form that can be made into injection, tablet, pill, capsule, suspension agent or emulsion uses.Finally, the preparation method that the present invention has the ruthenium compound of anti-tumor activity is simple, and raw material is easy to get, and has the advantage that cost is low.

Embodiment

Below in conjunction with embodiment, the present invention is described in further detail, can implement according to this with reference to specification sheets word to make those skilled in the art.

There is a ruthenium compound for anti-tumor activity,

1) this chemical name with the ruthenium compound of anti-tumor activity is chlorine one (1E, 3Z, 6E)-1,7-bis-(3,4-Dimethoxyphenyl)-4-methyl isophthalic acid, and 3,6-heptantriene-3,5-diketone monomethyl isopropyl benzene closes ruthenium;

2) its structural formula is formula (I):

There is a preparation method for the ruthenium compound of anti-tumor activity, wherein, comprise the following steps:

Step one, the γ-terpinene being 95% by the hydrate ruthenium trichloride of 0.2-0.5g ruthenium weight content 37% and 2-6ml purity are dissolved in 5-15ml dehydrated alcohol, put into three-necked bottle, add magneton and carry out magnetic agitation, oil bath is heated, thermostatic control is at 70-90 DEG C, reflux stirs 4-8 hour, and standing precipitation obtains the compound with formula (III), and namely dichloride-two-cymene closes two rutheniums (II);

Step 2, take the 3-methyl-2 of 0.05-0.15g, 3 of 4-diacetylmethane, 0.05-0.2g, the boron trioxide of 4-dimethoxy benzaldehyde and 0.02-0.08g is placed in three-necked bottle, add 5-15ml dimethyl formamide solution again, constantly nitrogen protection is passed in three-necked bottle, react 4-8 hour at 70-90 DEG C after, add the hydrochloric acid of 0.1-0.2g, standing precipitation obtains the compound with formula (IV), i.e. (1E, 3Z, 6E)-1,7-bis-(3,4-Dimethoxyphenyl)-3-hydroxy-4-methyl-1,3,6-heptantriene-5-ketone;

Step 3, by (1E, 3Z, the 6E)-1 of 15-25mg, 7-bis-(3,4-Dimethoxyphenyl) dichloride-two-cymene of-3-hydroxy-4-methyl-1,3,6-heptantriene-5-ketone and 28-37mg closes the dehydrated alcohol that two rutheniums (II) are dissolved in 5-12ml, heated and stirred backflow 4-8 hour, react rear and solution evaporation has been remained 1-3ml liquid, added the normal hexane of 25-35ml, stirred, separate out red crystals, to obtain final product.

There is a purposes for the ruthenium compound of anti-tumor activity, described in there is anti-tumor activity ruthenium compound for the preparation of the application for the treatment of cancer of the stomach and liver-cancer medicine.

Embodiment 1:

There is a ruthenium compound for anti-tumor activity,

A kind of ruthenium compound with anti-tumor activity of the present invention, its chemical name is chlorine one (1E, 3Z, 6E)-1,7-bis-(3,4-Dimethoxyphenyl)-4-methyl isophthalic acid, and 3,6-heptantriene-3,5-diketone monomethyl isopropyl benzene closes ruthenium;

Its physico-chemical property is: red crystals, soluble in water and organic solvent.

The preparation method with the ruthenium compound of anti-tumor activity of the present invention, its concrete steps are as follows:

Step one, the γ-terpinene being 95% by the hydrate ruthenium trichloride of 0.2g ruthenium weight content 37% and 2ml purity are dissolved in 5ml dehydrated alcohol, put into three-necked bottle, add magneton and carry out magnetic agitation, oil bath is heated, thermostatic control is at 70 DEG C, reflux stirs 4 hours, and standing precipitation obtains dichloride-two-cymene and closes two rutheniums (II);

Step 2,3-methyl-2, the 4-diacetylmethane taking 0.05g, the Veratraldehyde of 0.05g and the boron trioxide of 0.02g are placed in three-necked bottle, add 5ml dimethyl formamide solution again, in three-necked bottle, constantly pass into nitrogen protection, react after 4 hours at 70 DEG C, add the hydrochloric acid of 0.1g, standing precipitation obtains (1E, 3Z, 6E)-1,7-bis-(3,4-Dimethoxyphenyl)-3-hydroxy-4-methyl-1,3,6-heptantriene-5-ketone;

Step 3, by (1E, 3Z, the 6E)-1 of 15mg, 7-bis-(3,4-Dimethoxyphenyl) dichloride-two-cymene of-3-hydroxy-4-methyl-1,3,6-heptantriene-5-ketone and 28mg closes the dehydrated alcohol that two rutheniums (II) are dissolved in 5ml, heated and stirred refluxes 4 hours, react rear and solution evaporation has been remained 1ml liquid, added the normal hexane of 25ml, stirred, separate out red crystals, to obtain final product.

Embodiment 2:

There is a ruthenium compound for anti-tumor activity,

A kind of ruthenium compound with anti-tumor activity of the present invention, its chemical name is chlorine one (1E, 3Z, 6E)-1,7-bis-(3,4-Dimethoxyphenyl)-4-methyl isophthalic acid, and 3,6-heptantriene-3,5-diketone monomethyl isopropyl benzene closes ruthenium;

Its physico-chemical property is: red crystals, soluble in water and organic solvent.

The preparation method with the ruthenium compound of anti-tumor activity of the present invention, its concrete steps are as follows:

Step one, the γ-terpinene being 95% by the hydrate ruthenium trichloride of 0.5g ruthenium weight content 37% and 6ml purity are dissolved in 15ml dehydrated alcohol, put into three-necked bottle, add magneton and carry out magnetic agitation, oil bath is heated, thermostatic control is at 90 DEG C, reflux stirs 8 hours, and standing precipitation obtains dichloride-two-cymene and closes two rutheniums (II);

Step 2,3-methyl-2, the 4-diacetylmethane taking 0.15g, the Veratraldehyde of 0.2g and the boron trioxide of 0.08g are placed in three-necked bottle, add 15ml dimethyl formamide solution again, in three-necked bottle, constantly pass into nitrogen protection, react after 8 hours at 90 DEG C, add the hydrochloric acid of 0.2g, standing precipitation obtains (1E, 3Z, 6E)-1,7-bis-(3,4-Dimethoxyphenyl)-3-hydroxy-4-methyl-1,3,6-heptantriene-5-ketone;

Step 3, by (1E, 3Z, the 6E)-1 of 25mg, 7-bis-(3,4-Dimethoxyphenyl) dichloride-two-cymene of-3-hydroxy-4-methyl-1,3,6-heptantriene-5-ketone and 37mg closes the dehydrated alcohol that two rutheniums (II) are dissolved in 12ml, heated and stirred refluxes 8 hours, react rear and solution evaporation has been remained 3ml liquid, added the normal hexane of 35ml, stirred, separate out red crystals, to obtain final product.

Embodiment 3:

There is a ruthenium compound for anti-tumor activity,

A kind of ruthenium compound with anti-tumor activity of the present invention, its chemical name is chlorine one (1E, 3Z, 6E)-1,7-bis-(3,4-Dimethoxyphenyl)-4-methyl isophthalic acid, and 3,6-heptantriene-3,5-diketone monomethyl isopropyl benzene closes ruthenium;

Its physico-chemical property is: red crystals, soluble in water and organic solvent.

The preparation method with the ruthenium compound of anti-tumor activity of the present invention, its concrete steps are as follows:

Step one, the γ-terpinene being 95% by the hydrate ruthenium trichloride of 0.366g ruthenium weight content 37% and 3ml purity are dissolved in 10ml dehydrated alcohol, put into three-necked bottle, add magneton and carry out magnetic agitation, oil bath is heated, thermostatic control is at 80 DEG C, reflux stirs 6 hours, and standing precipitation obtains dichloride-two-cymene and closes two rutheniums (II);

Step 2,3-methyl-2, the 4-diacetylmethane taking 0.095g, the Veratraldehyde of 0.12g and the boron trioxide of 0.07g are placed in three-necked bottle, add 10ml dimethyl formamide solution again, in three-necked bottle, constantly pass into nitrogen protection, react after 6 hours at 80 DEG C, add the hydrochloric acid of 0.146g, standing precipitation obtains (1E, 3Z, 6E)-1,7-bis-(3,4-Dimethoxyphenyl)-3-hydroxy-4-methyl-1,3,6-heptantriene-5-ketone;

Step 3, by (1E, 3Z, the 6E)-1 of 20mg, 7-bis-(3,4-Dimethoxyphenyl) dichloride-two-cymene of-3-hydroxy-4-methyl-1,3,6-heptantriene-5-ketone and 32mg closes the dehydrated alcohol that two rutheniums (II) are dissolved in 8ml, heated and stirred refluxes 6 hours, react rear and solution evaporation has been remained 2ml liquid, added the normal hexane of 30ml, stirred, separate out red crystals, to obtain final product.

Its hydrogen nuclear magnetic resonance modal data is¹h NMR:(ppm, CDCl₃) δ=1.400 (6H, d, J=6.9Hz), 2.350 (3H, s), 2.98 (1H, m, J=6.9Hz), 5.30 (2H, d, J=6.3Hz), 5.57 (2H, d, J=6.3Hz), 2.19 (3H, s), 3.91 (3H, s), 3.93 (3H, s), 3.95 (3H, s), 6.89 (2H, d, J=8.1Hz), 6.99 (2H, d, J=15.3Hz), 7.10 (2H, d, J=1.8Hz), 7.19 (2H, dd, J=8.1Hz, J=1.8Hz), 7.70 (2H, d, J=15.6Hz).

Its pharmaceutical activity and application thereof is further illustrated below by pharmacodynamic experiment.

Experiment one: anti tumor activity in vitro is tested:

Adopt MTT method, carry out vitro cytotoxicity mensuration.The ruthenium compound with anti-tumor activity embodiment 1 obtained and SGC-7901 cell strain and liver cancer BEL-7404 cell strain 72 hours action time respectively, result is as shown in table 1.

Table 1 has the IC of ruthenium compound to tumor cell line of anti-tumor activity₅₀

Cell strain	SGC-7901	BEL-7404
			IC50(umol/mL)	3.0±1.5	3.2±1.7

As shown in Table 1, the ruthenium compound with anti-tumor activity of the present invention shows through anticancer experiment in vitro, acts on after 72 hours, the IC of described SGC-7901 cell strain₅₀be 3.0 ± 1.5, well below the 503nhibiting concentration of conventional Organic metal ruthenium ion pair compound, and the IC of liver cancer BEL-7404 cell strain₅₀reach 3.2 ± 1.7, illustrate that this compound has strong anti-tumor activity.Wherein said IC₅₀for medium effective concentration.The present invention is that the new antitumor drug of research and development provides new thinking.

Although embodiment of the present invention are open as above, but it is not restricted to listed in specification sheets and embodiment utilization, it can be applied to various applicable the field of the invention completely, for those skilled in the art, can easily realize other amendment, therefore do not deviating under the universal that claim and equivalency range limit, the present invention is not limited to specific details.

Claims (5)

1. there is a ruthenium compound for anti-tumor activity, it is characterized in that:

1) this chemical name with the ruthenium compound of anti-tumor activity is chlorine one (1E, 3Z, 6E)-1,7-bis-(3,4-Dimethoxyphenyl)-4-methyl isophthalic acid, and 3,6-heptantriene-3,5-diketone monomethyl isopropyl benzene closes ruthenium;

2) its structural formula is formula (I):

2. there is a preparation method for the ruthenium compound of anti-tumor activity as claimed in claim 1, it is characterized in that, comprise the following steps:

Step one, the hydrate ruthenium trichloride of 0.2-0.5g and the γ-terpinene of 2-6ml are dissolved in 5-15ml dehydrated alcohol, reflux stirs 4-8 hour, standing precipitation obtains the compound with formula (III), and namely dichloride-two-cymene closes two rutheniums (II);

Step 2, take the 3-methyl-2 of 0.05-0.15g, 3 of 4-diacetylmethane, 0.05-0.2g, the boron trioxide of 4-dimethoxy benzaldehyde and 0.02-0.08g is dissolved in 5-15ml dimethyl formamide solution jointly, under nitrogen protection, 70-90 DEG C of reaction is after 4-8 hour, add the hydrochloric acid of 0.1-0.2g, standing precipitation obtains the compound with formula (IV), i.e. (1E, 3Z, 6E)-1,7-bis-(3,4-Dimethoxyphenyl)-3-hydroxy-4-methyl-1,3,6-heptantriene-5-ketone;

Step 3, by (the 1E of 15-25mg, 3Z, 6E)-1,7-bis-(3,4-Dimethoxyphenyl)-3-hydroxy-4-methyl-1, dichloride-two-cymene of 3,6-heptantriene-5-ketone and 28-37mg closes the dehydrated alcohol that two rutheniums (II) are dissolved in 5-12ml, heated and stirred backflow 4-8 hour, react rear and solution evaporation has been remained 1-3ml liquid, add the normal hexane of 25-35ml, separate out red crystals, to obtain final product.

3. the preparation method of tertiary fourth oxygen ethanoyl ruthenium compound as claimed in claim 2, it is characterized in that, hydrate ruthenium trichloride described in step one is the hydrate ruthenium trichloride of ruthenium weight content 30%-40%; The purity of described Y-terpinene is 80%-99%.

4. have the preparation method of the ruthenium compound of anti-tumor activity as claimed in claim 3, it is characterized in that, hydrate ruthenium trichloride described in step one is the hydrate ruthenium trichloride of ruthenium weight content 37%; The purity of described Y-terpinene is 95%.

5. there is a purposes for the ruthenium compound of anti-tumor activity as claimed in claim 1, it is characterized in that, described in there is anti-tumor activity ruthenium compound for the preparation of the application for the treatment of cancer of the stomach and liver-cancer medicine.