Palladium complexes with heterocyclic ligands

FIELD: chemistry of metalloorganic compounds, medicine, oncology.

SUBSTANCE: invention relates to novel chemical compounds, namely, to complexes of palladium with heterocyclic ligands of the general formula (I): wherein R1 means-NH, oxygen atom (O), -CH2; R2 means two hydrogen atoms (2H), O; R3 means hydrogen atom H, CH3, CH2-CH2-NH2,-(CO)-CH3; X means chlorine (Cl), bromine (Br) atom; n = 1; m = 1 if R1 means -NH, O; R2 means 2H; R3 means H, CH3, CH2-CH2-NH2, -(CO)-CH3; n = 2; m = 1 if R1 means O, -CH2; R2 means O, 2H; R3 means H, CH3, -(CO)-CH3; n = 2; m = 3 if R1 means -NH; R2 means 2H; R3 means CH2-CH2-NH2 eliciting pharmacological, in particular, anti-tumor activity. Proposed compounds possess high activity and characterized by reduced toxicity as compared with anti-tumor preparations with platinum complexes.

EFFECT: valuable medicinal properties of complexes.

4 cl, 2 tbl, 10 ex

 

The technical field.

The invention relates to new chemical compounds, in particular palladium complexes with heterocyclic ligands of General formula I

where R1-NH, O, CH2,

R22H, OH,

R3-H, CH3CH2-CH2-NH2, (CO)-CH3,

X is Cl, Br,

n=1, m=1, when R1-NH, O; R2-2N; R3-H, CH3; CH2-CH2-NH2; (CO)-CH3,

n=2, m=1, when R1"Oh, CH2; R2"Oh, 2N; R3-H, CH3, (CO)-CH3,

n=2, m=3, if R1-NH; R2=2N; R3-CH2-CH2-NH2with pharmacological activity.

The prior art.

Known complex compounds of platinum (II)with antitumor activity, such as platinum, cisplatin, carboplatin (Mashkovsky PPM "Drugs", thirteenth edition, Kharkov, Ukraine, publishing house "Torching". 1997, volume II, str-460).

The connection data on the mechanism of close to alkylating compounds, they interact with DNA with formation of inter - and intramolecular crosslinks. The mechanism of antitumor platinum drugs is associated with the ability to bifunctional alkylation of DNA strands, leading to prolonged suppression of the biosynthesis of nucleic acids and cell death.

Known drugs is based platinum highly toxic. Serious side effects of platinum drugs is nephrotoxicity. Other adverse reactions caused by platinum drugs, it should be noted leukopenia, nausea and vomiting.

In addition, because the drugs are very toxic and easily absorbed by the skin and mucous membranes, they are dangerous for people associated with their production. To work with them need rubber gloves and respirators.

And another important disadvantage is the high cost of platinum, which leads to higher prices of medicinal products based on it.

The search for new drugs with high activity and low toxicity based on the platinum group metals is an important task.

Disclosure of inventions

The task of the invention is to expand the Arsenal of chemical compounds acting on a living organism, in particular with antitumor activity with reduced toxicity.

The problem is solved because, according to the invention of a new chemical compound is a palladium complexes with heterocyclic ligands of General formula I:

where R1-NH, O, CH2,

R22H, OH,

R3-H, CH3CH2-CH2-NH2, (CO)-CH3,

X is Cl, Br,

n=1, m=1, when R1-NH, O; R2-2N; R3 -H, CH3; CH2-CH2-NH2,

(CO)-CH3,

n=2, m=1, when R1"Oh, CH2; R2"Oh, 2N; R3-H, CH3, (CO)-CH3,

n=2, m=3, if R1-NH; R2-2N; R3-CH2-CH2-NH2.

According to the invention the new compounds possess, in particular, the high antitumor activity and reduced toxicity. The best variant embodiment of the invention.

The inventive compounds of General formula I represent complexes of palladium cation-anion type, containing the anion [PdCl4]2-.

The method of obtaining compounds consists of two stages.

In the first stage of the organic ligand in solution undergoes protonation halogenation acid. In the second stage protonated ligand in solution is subjected to interaction with the compound of palladium when the stoichiometric ratio of the components at a temperature of 30-80°C, followed by separation of the target product from the solution.

Connections get both in aqueous and non-aqueous environment.

In particular, the following compounds shown in table 1.

Table 1
ConnectionFormulaThe ligand
I[C4H10N2][PdCl 4]Piperazine
II[C5H13N2][PdCl4]N-methylpiperazin
III[C6H13N2O][PdCl4]4-acetylpiperidine
IV[C6H16N3]2[PdCl4]34-AMINOETHYLPIPERAZINE
V[C4H9NO]2[PdCl4]Morpholine
VI[C4H9NO]2[PdBr4]Morpholine
VII[C5H12NO]2[PdCl4]4 methylmorpholin
VIII[C6H12NO2]2[PdCl4]4-acetylmorpholine
IX[C6H15N2O][PdCl4]3·H2O4-aminoacylation
X[C5H9NO]2[PdCl4]·2H2O2-piperidin

The following examples of the preparation of these compounds.

Example 1. Synthesis of compound I

The linkage to 2.29 g (to 11.79 mmol) of uranyl piperazine are dissolved in 13 ml of H2O and acidified with 1.5 ml HCl to pH˜1. A portion of 2.09 g (11,78 mmol) of palladium dichloride is dissolved by heating (˜60° (C) in a mixture of 25 ml of H2O and 3 ml of HCl. Races the thieves merge together and evaporated on a water bath until the onset of crystallization. After cooling, filtered off the crystals formed, is washed with ethanol. Dried in a drying Cabinet at a temperature of 90°and constant pressure. Output 3,68 g, which is 93% of theoretical per introduced into the reaction palladium.

For the composition of C4H10N2PdCl4calculated, %: Pd - 31,63; Cl - 42,16.

Found, %: Pd - 31.90 Beef; Cl - 41,50.

Example 2. Synthesis of compound (II).

A portion of 1.66 g (16.30 mmol) of N-methylpiperazine dissolved in 15 ml of N2O and acidified with 2.5 ml HCl to pH˜1. A portion 2,89 g (16.30 mmol) of palladium dichloride was dissolved under heating in a mixture of 25 ml of N2O and 3 ml of HCl, the solution is filtered, poured to a solution of the ligand and evaporated on a water bath until the onset of crystallization. After cooling, filtered off the precipitated crystals are washed with ethanol. Dried in a drying Cabinet at a temperature of 90°and constant pressure. The output of 4.2 g, which is 74% of theoretical per introduced into the reaction palladium.

For composition With5H13N2PdCl4calculated, %: Pd - 30,36; Cl - 40,42.

Found, %: Pd - 30,90; Cl - 41,10.

Example 3. Synthesis of compound III.

A portion of 1.14 g (1,09 mmol) 4-acetylpiperidine dissolved in 15 ml of acetone and acidified with 0.2 ml HCl for protonation of the ligand. The addition rate of 0.35 g (of 0.91 mmol) benzenetricarboxylate dissolve when heated in 15 ml of acetone, filtered and prili is up to the solution of the ligand. Within 3 hours the mixture was stirred on a magnetic stirrer. The residue is filtered off, washed with acetone, dried in a drying Cabinet at a temperature of 80°and constant pressure. Yield 0.31 g, which is 74% of theoretical calculated on the entered palladium.

For composition With6H13N2OPdCl4calculated, %: Pd - 28,01; Cl - 37,47.

Found, %: Pd - 29,12; Cl - 37,65.

Example 4. Synthesis of compound IV.

A portion of 1.52 g (11,77 mmol) 1-(2-amino-ethyl)piperazine are dissolved in 15 ml of N2O and acidified with 3.5 ml HCl to pH˜1. A portion of 3.13 g (17,65 mmol) of palladium dichloride is dissolved under heating in a mixture of 25 ml of N2O and 4 ml of HCl. The solutions are poured together and evaporated on a water bath at a temperature of 70°before crystallization. After cooling, filtered off the precipitated crystals are washed with ethanol. Dried in a drying Cabinet at a temperature of 80°and constant pressure. The output of 4.38 g, which is 74% of theoretical per introduced into the reaction palladium.

For the composition of C12H32N6Pd3Cl12calculated, %: Pd - 32,16; Cl - 42,16.

Found, %: Pd - 32,64; Cl - 42,80.

Example 5. Synthesis of compound V.

A portion of 1.46 g (Ls 16.80 mmol) of the research is dissolved in 10 ml of N2O and acidified with HCl to pH˜1 (2 ml). The addition of palladium dichloride 1,49 g (8,40 mmol) is dissolved by heating (55-60° (C) in a mixture of 15 ml of N2About 2 ml of HCl filtered and poured to the solution of the research. The resulting mixture was evaporated on a boiling water bath prior to the crystallization, cooled and filtered crystalline precipitate from the mother liquor. Dried in a drying Cabinet at a temperature of 90°at constant pressure to constant weight.

Output 3.1 g, which is 86,8% of theoretical per introduced into the reaction palladium.

For the composition of C8H18N2O2PdCl4calculated, %: Pd - 25,06; Cl - 33,41.

Found, %: Pd - 25,12; Cl - 32,52.

Example 6. Synthesis of compound VI.

A portion of 1.17 g (13,43 mmol) of the research is dissolved in 15 ml of N2O and acidified with HBr to pH˜1 (2,3 ml 46% HBr). A portion of 1.78 g (of 6.71 mmol) PdBr2dissolve by heating (55-60° (C) in a mixture of 20 ml of N2About 2 ml of HBr, the solution is filtered and poured to a solution of the ligand. The mixture is evaporated on a boiling water bath prior to the beginning of crystallization, is cooled, the crystalline precipitate is filtered off, washed with a small amount of ethanol. Dried in a drying Cabinet at 90°and constant pressure to constant weight. The output of 2.68 g, which is 67,5% of theoretical in the calculation introduced in the reaction of palladium. For the composition of C8H18N2O2PdBr4calculated, %: Pd - 17,66; Br - 53,06. Found, %: Pd - 17,63; Br - 54,80.

Example 7. Synthesis of compound VII.

A portion of 1.84 g (18,19 mmol) 4-methylmorpholine dissolved in 20 ml of water and acidified with 2 ml HCl to pH˜1. The nave is of the SSI palladium dichloride of 1.61 g (remaining 9.08 mmol) is dissolved by heating (˜ 60° (C) in a mixture of 15 ml of water and 2 ml of HCl, the solution is filtered and poured to a solution of the ligand. The mixture is evaporated on a boiling water bath to min volume, cooled, separated crystalline precipitate is filtered off, dried in a drying Cabinet at 90°and constant pressure to constant weight. Output 3,44 g, which is 84% of theoretical per introduced into the reaction palladium.

For the composition of C10H24N2O2PdCl4calculated, %: Pd - 23,51; Cl - 31,33.

Found, %: Pd - 23,30; Cl - 31,33.

Example 8. Synthesis of compound VIII.

To button 0.31 g (2,40 mmol) 4-acetylmorpholine in 5 ml of acetone dobavlaut of 0.21 ml of HCl. A portion 0,46 g (1.20 mmol) of benzenetricarboxylate dissolve when heated (˜30° (C) in 15 ml of acetone, filtered and poured to a solution of the ligand. Within 5 hours the mixture is stirred on a magnetic stirrer. The residue is filtered off, washed with acetone, dried in a drying Cabinet at 70°and constant pressure. The yield of 0.47 g, which is 77% of theoretical per introduced into the reaction palladium.

For the composition of C12H24N2O4PdCl4calculated, %: Pd - To 20.91; Cl - of 27.84.

Found, %: Pd - 21,09; Cl - 28,51.

Example 9. Synthesis of compound IX.

A portion of 0.95 g (7,30 mmol) of 4-(2-amino-ethyl)research in 5 ml of N2On acidified with HCl to pH˜1. The addition of palladium dichloride 1.29 g (7,28 mmol) RA is tworay when heated (˜ 60° (C) in a mixture of 15 ml of N2O and 2 ml HCl, filtered and poured to a solution of the ligand. The mixture is evaporated on a water bath at a temperature of 80°s to min volume, cooled, separated crystalline precipitate is filtered from the mother liquor, dried in a drying Cabinet at a temperature of 60°and constant pressure. The output of 1.85 g, which is 66% of theoretical in the calculation introduced in the reaction of palladium. The connection is released in the form of a monohydrate: [C6H16N2O][PdCl4]·N2O.

For the composition of C6H17N2O2PdCl4calculated, %: Pd - 27,53; Cl - 36,69.

Found, %: Pd - 28,16; Cl - 36,60.

Example 10. Synthesis of compound X.

A portion of 1.60 g (16,14 mmol) of 2-piperidone dissolved in 15 ml of N2O and acidified with 2 ml HCl to pH˜1. To this solution is poured hydrochloric acid solution of 1.43 g (8,07 mmol) of palladium dichloride in a mixture of 20 ml of N2O and 3 ml of HCl. The mixture is evaporated on a water bath until the beginning of crystallization, cooled and filtered off the crystals formed. Dried in a drying Cabinet at a temperature of 110°and constant pressure. Output 2,32 g, which is 59% of theoretical per introduced into the reaction palladium.

The compound crystallizes with 2 molecules of water. For the composition of C10H22NO4PdCl4calculated, %: Pd=21,96; Cl=29,96.

Found, %: Pd=21,64; Cl=29,20.

The compounds which was established by the method of IR-spectroscopy.

Infrared spectra were measured in the field 4000-100 cm-1the FTIR spectrometer Nicolet Magna-750 (USA). Spectra in the region of 4000-400 cm-1measured with a resolution of 2 cm-1in tablets with KBr. Spectra in the region 600-100 cm-1obtained with a resolution of 4 cm-1in paste form with vaseline oil.

Conclusions about the structure of the claimed compounds made on the basis of the comparison of the spectra of the complexes with the spectra of free ligands (hyrochloride), and salts containing the anion [PdCl4]2-.

Spectra of compounds V, VII, VIII, IX, X in the field of 2000-400 cm-1similar to spectra of protonated ligands LH+in hydrochloride L.HCl (L - molecule heterocyclic ligand). For compounds I, II, III, IV spectra in this region close to the spectra of the corresponding cations L H22+in dihydrochloride. This clearly indicates that all studied compounds contain protonated ligands as cation. Some of the shifts and splitting of the bands compared to hydrochloride caused by the replacement of the anion. Noticeable changes in the spectra of the complexes compared with hydrochloride are available in the area 4000-2000 cm-1. Most notable is the disappearance of the broad group of strong bands with maxima in the field 2450-2700 cm-1due to the strong hydrogen bonds in the solid hydrochloride. In the complexes of this the system of hydrogen bonds destroyed, and instead of the specified group of bands there is a strong broad band in the region 3000-3100 cm-1stretching vibrations of N+-H. For neutral molecules L absorption in the region above 3000 cm-1no. The appearance in the absorption spectrum in this region confirms the conclusion that the ligand in the palladium complex is present in protonated cationic form.

Low-frequency IR-spectra (500-100 cm-1contain in addition to the bands belonging protonated cation ligand, similar in position to the corresponding bands in hydrochloride two new absorption bands: a strong band in the area 320-335 cm-1and a weaker band around 150-160 cm-1. These bands are characteristic flat square anion [PdCl4]2-and refer, respectively, to the stretching vibrations νPdCl, ν6(E2uand deformation vibrations δPdCl2that ν7(Eu). For comparison, in K2PdCl4the corresponding frequency is equal to 321 and 161 cm-1and in the spectrum with the ionic structure of the complex with ephedrine [C10H16ON]2[PdCl4] they are observed at 323 and 149 cm-1. During the transition from the anion [PdCl4]2-[PdBr4]2-(compound VI) they are shifted to 251 and 126 cm-1that confirms their assignment to fluctuations in allodiploid. We should note, is that for K 2PdBr4these bands lie at 243 and 114 cm-1respectively. The absence of low-frequency spectrum in other bands, which could be attributed to fluctuations in the metal-ligand, is also consistent with the ionic structure. Thus, the IR spectra in the middle and low frequency range clearly show that the compounds have cation-anion structure [LH+]2[PdX42-] (X=Cl, Br) in the case of compounds V-X, [LH22+][PdCl42-] for compounds I-III and [LH3+3]2[PdX42-]3to connect IV (where L is the corresponding complex of the ligand). The conclusion is consistent with data from chemical analyses of the ratio of ligand: metal complexes.

The position of some of the characteristic absorption bands for the proposed compounds are given in table 2.

Table 2

Some characteristic bands (frequencies in cm-1in the IR spectra of compounds
ConnectionFormulaνN+-HνC=OνPdXδPdX
123456
I[C4H10N2][PdCl4]2956 327155
II[C5H13N2][PdCl4]3047334164
III[C6H13N2O][PdCl4]30081622332155
IV[C6H16N3]2[PdCl4]33002322153
V[C4H9NO]2[PdCl4]3086321160
3058
VI[C4H9NO]2[PdBr4]3074249135
3048
VII[C5H12NO]2[PdCl4]3047325154
3013
VIII[C6H12NO2]2[PdCl4 ]30571691323154
IX[C6H15N2O][PdCl4]3000321169
X[C5H9NO]2[PdCl4]31541693323168
3040

Was studied the specific activity of a number of the compounds I, II, V, VI, VII, VIII, IX, X and defined their acute toxicity.

1. The palladium complexes with heterocyclic ligands of General formula I:

where R1- NH, O, CH2;

R2- 2H, O;

R3- H, CH3CH2-CH2-NH2, (CO)-CH3;

X is Cl, Br;

n-1, m=1, when R1- NH, O; R2- 2N; R3- H, CH3; CH2-CH2-NH2; (CO)-CH3;

n=2, m=1, when R1"Oh, CH2; R2"Oh, 2N; R3- H, CH3, (CO)-CH3;

n=2, m=3, if R1- NH; R2- 2N; R3- CH2-CH2-NH2.

2. The palladium complexes with heterocyclic ligands according to claim 1, characterized by the fact that they possess pharmacological activity.

3. The palladium complexes with heterocyclics ligands according to claims 1 and 2, characterized by the fact that they possess antitumor activity.

4. The palladium complexes with heterocyclic ligands according to claims 1-3, characterized by the fact that they crystallize in the anhydrous state or in the form of hydrates.



 

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