JPH0269491A - Titanocene (iv) complex compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is lower alkyl; Ar is aryl; n is 0 or 1). EXAMPLE:Bis(alpha-phenylpropionato)titanocene (IV). USE:An antitumor agent. PREPARATION:The objective compound can be produced by reacting a dihalo or dialkyltitanocene (IV) complex of formula II (R<2> is halogen or lower alkyl) with a 2-arylalkanoic acid or 3-aryl-2-oxoalkanoic acid of formula III in an inert solvent (preferably diethyl ether, THF, benzene, etc.) at or below room temperature.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention provides novel titanocene (IV
) concerning complex compounds. More specifically, the present invention provides novel antitumor active titanocene (r
V) Concerning complex compounds.

[Prior art]

In recent years, complex compounds containing transition metals other than platinum, such as titanium, zirconium, hafnium, vanadium, iron, copper, palladium, or gold, have also been found to exhibit antitumor activity, and research is underway to develop them as antitumor agents. [For example, Naturwissensha
ften, 74374 (1987)], especially since it was reported that titanocene, zirconocene and hafnocene dichloride have a growth inhibiting effect on Ehrlich ascites tumors in mice (J, CancerRes, C.
l1n, 0nco1. ．． 96.43 (1980)]
Research has been conducted to develop metallocene complexes with antitumor activity (Chem.

Rev., 87.1137 (1987)].

[Problem that the invention seeks to solve]

However, no metallocene complex compound with sufficiently satisfactory antitumor activity has yet been found, and titanocene dichloride has strong side effects such as hepatotoxicity, as well as low water solubility and low fat solubility. An object of the present invention is to provide a novel titanocene (IV) fit body that has excellent antitumor activity and fewer side effects.

The present inventors have solved the above problems (as a result of intensive studies, 2-7-aryl-alkanoic acid or 3-aryl-
Novel titanocene with 2-oxoalkanoic acid as a ligand (
1'/) The complex compound was successfully synthesized, and this complex became P-3.
It was confirmed that it had a growth inhibiting effect on 88 mouse leukemia cells, and the present invention was completed.

[Means for solving problems]

The present invention provides novel titanocene (IV) iffff gold compounds represented by the following formula: (wherein R1 represents a lower alkyl group, Ar represents an alkyl group, and n is O or 1. It is something to do.

The titanocene (rv
) if body.

As the 2-alkanoic acid as a ligand, 2-
phenylpropionic acid, 2-<4'-)tylphenyl)
Propionic acid, 2-(3'-methylphenyl)propionic acid, 2-(4'-ethylphenyl)propionic acid, 2
-(4'-isopropylphenyl)propionic acid, 2-
(4'-propylphenyl)propionic acid, 2-(4'
-isobutylphenyl) 10 pion 11.2-(2'
4'-dimethylphenyl)propionic acid, 2-(3'
4'-dimethylphenyl)propionic acid, 2-(4'-
Cyclohexylphenyl)propionic acid, 2(4'-methoxyphenyl)propionic acid, 2-(3'-methoxyphenyl)propionic acid, 2-(4'-phenoxyphenyl)propionic M, 2-(3', 4') -dimethoxyphenyl)propionic acid, 2-(3',4'-methylenedioxyphenyl)propionic acid, 2-(4'-chlorophenyl)propionic acid, 2-(4'-fluorophenyl)propionic acid, 2-( 4'-bromophenyl)propion M, 2-(3',4'-dichlorophenyl)propionic acid, 2-(3',4'-difluorophenyl)
Propionic acid, 2(3',5'difluoronoenyl)propionic acid, 2-(4'nitrophenyl)propionic acid, 2-(3'-fluoro-4'-isobutylphenyl)propionic acid, 2-((3'-Fluoro-4'-
phenyl)phenyl)propionic acid, 2-(4'-dimethylaminophenyl)propionic acid, 2-(4'-acetylaminophenyl)propionic acid, 214'-bis(
2#-chloroethyl)aminophenyl)propionic acid,
2-(4'-methoxycarbonylphenyl)propionic acid, 2-(α-naphthyl)propy:t 7 acid, 2-(β
-naphthyl)propionic acid, (+) -2-<6'-
Methoxy-β-naphthyl)propionic acid, 2-(6'-
Methoxy-β-naphthyl)propionic acid, 2-phenylbutanoic acid, 2(4'-methylphenyl)butanoic acid, 2
-(4'ethylphenyl)butanoic acid, 2-(4'-isobutylphenyl)butanoic acid, 2-(3'-methylphenyl)butanoic acid, 2-<4'-methoxyphenyl)butanoic acid, 2-(3' -methoxyphenyl)butanoic acid, 2-(
4'-fluorophenyl)butanoic acid, 2-(3',4'
-dimethoxyphenyl)butanoic acid, 2-phenyl-3-
Methyl butanoic acid and the like can be used.

These 2-arylalkanoic acids can be easily obtained as commercial products, and those with various substituents can be easily synthesized according to known methods (for example, Japanese Patent Publication No. 35068/1983; 53-35067, 58-2934, and JP-A-53-7642).

In addition, the carbon atom at the 2-position of these 2-arylalkanoic acids can be an asymmetric atom, for example (+)
-2-(6'-methoxy-β-naphthyl)propionic acid, in which the 2-position carbon atom is asymmetric (L-configuration), and 2-(6'-methoxy-β-naphthyl)propionic acid, Although there are compounds in which the 2-position carbon is not asymmetric (DL form), any of the L form, 0 form, or DL form can be used as a ligand in the present invention.

Furthermore, as the 3-aryl-2-oxoalkanoic acid as a ligand, 3-phenyl-2-oxobutane
, 3-(4'-methylphenyl)-2-oxobutanoic acid, 3-(4'-ethylphenyl)-2-oxobutanoic acid, 3-(4'-isopropylphenyl)-2-oxobutanoic acid, 3(4' -isobutylphenyl)-2-oxobutanoic acid, 3-(2',4'-dimethylphenyl)-2
-oxobutanoic acid, 3- (3',4'-dimethylphenyl)-2-oxobutanoic acid, 3-(4'cyclohexylphenyl)-2-oxobutanoic acid, 3-(4'-methoxyphenyl)-2- Oxobutanoic acid, 3- (3',
4'-dimethoxyphenyl)-2-oxobutane! ,3
-(4'-chlorophenyl)-2-oxobutanoic acid, 3
-(4'-fluorophenyl)-2-oxobutanoic acid,
3(4'-bromophenyl)-2-oxobutanoic acid, 3
-(3',4'-dichlorophenyl)-2-oxobutanoic acid, 3-(3',4'-difluorophenyl)-2
-Oxobutanoic acid, 3-(3',5'difluorophenyl)-2-oxobutanoic acid, 3-(4'-ditrophenyl)-2-oxobutanoic acid, 3-(4'-dimethylaminophenyl)-2 -oxobutanoic acid, 3-(4'-acetylaminophenyl)-2-oxobutanoic acid, 3-[4
'bis-(2'-chloroethyl)aminophenyl)-2
-Oxobutanoic acid, 3-phenyl-2-oxopenconic acid, 3-(4'-methylphenyl)-2-oxopentanoic acid, 3-(4'-ethylphenyl)-2-oxopentanoic acid, 3-(4' -isobutylphenyl)-2-oxopentane M, 3-(4'-chlorophenyl)-2-oxopencuic acid, 3-(4'-fluorophenyl)-2
-Oxopentanoic acid, 3-(4'-bromophenyl)-
Examples include 2-oxopentanoic acid. These 3-aryl-2-oxoalkanoic acids can be easily synthesized according to known methods (for example, Japanese Patent Publication Nos. 53-35068 and 53-35069, JP-A-53-149970, 56-99445). (see publication).

Titanocene (IV
) The complex compound is a dihalo or dialkyl titanocene (rV) complex represented by the general formula (wherein R'' represents a halogen atom or a lower alkyl group) and a dihalo or dialkyl titanocene (rV) complex represented by the general formula (wherein R'' represents a lower alkyl group, Ar represents an aryl group, and n is 0 or 1).

This reaction is preferably carried out in a suitable solvent. Suitable solvents include chlorine solvents such as methylene chloride, chloroform and carbon tetrachloride, ether solvents such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, benzene, Aromatic solvents such as toluene and xylene,
Alternatively, ethyl acetate can be used, but the reaction can be carried out in any other solvent as long as it does not adversely affect the reaction. Further, in -maximum (2), Rt is a halogen atom, dihalotitanocene (I
V) When using a complex, it can also be carried out in an aqueous solution in which the dihalo complex is easily dissolved.

Further, this reaction can be carried out at a temperature ranging from low temperature to a high temperature that does not decompose the complex, but it is preferably carried out at room temperature or below room temperature in view of a good yield.

In this reaction, 2-arylalkanoic acid or 3-aryl-2-oxoalkanoic acid is titanocene (rV) fi
By using at least twice the molar amount of the t-form (2), titanocene (IV) gold compound) can be obtained with good yield.

Titanocene (r
V) Among the complexes, dichlorotitanocene, which is a dihalo complex, can be easily produced commercially. Further, dialkyl complexes can be produced according to known methods (for example, Ann
, Chin, 654.8 (1962)) as lower alkyl groups, methyl group, ethyl group, propyl group,
Alternatively, those having a butyl group or the like can be used in this reaction.

Typical titanocene (IV) lit gold compounds of the present invention are shown in Table 1.

Table 1 Titanocene (TV) iff compound Table 1 Titanocene (IV) iffff gold compound , for example, bis(β-methyl-β-(p
-cyclohexylphenyl)pyruvato)titanocene(I
V) A concentration of 7.8 μg/ml (7) can inhibit the growth of T-5094 cells.

Hereinafter, the present invention will be explained in more detail with reference to Examples and Test Examples. Further, the melting point, spectral data, etc. of the obtained titanocene (TV) tI compound are shown in Tables 2 and 3.

Example 1 Titanocene dichloride (250at, l, Omm
o l ) was dissolved in water (30 ml), then 2-phenylpropionic acid (600 ml, 4.0 mmol) was added, and the mixture was stirred at room temperature overnight. Methylene chloride was added to this to dissolve the precipitated yellow-orange solid, and 1N aqueous sodium hydroxide solution was added thereto and extracted with methylene chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain an orange oil.
Next, ether was added to precipitate yellow-orange crystals of bis(α-phenylpropionato)titanocene (■) [Compound No. 1], which were separated by filtration, washed with ether, and then dried under reduced pressure. The yield was 21% based on titanocene dichloride.

Example 2 Next, the solvent was distilled off under reduced pressure, ether was added to the obtained orange oil, and the precipitated yellow-orange crystals of bis(α-phenylpropionato) titanocene (■) [Compound No. 1] were separated by filtration. After washing with ether, it was dried under reduced pressure. The yield was 83% based on dimethyltitanocene.

Example 3 2-phenylpropion # (300μ, 2.0mmol
A methylene chloride solution (10 ml) of dimethyl titanocene (210 mg, 1.0 mmol) was added dropwise to a methylene chloride solution (10 ml) of ) under water cooling, and the mixture was stirred for 1 hour, and further stirred for 1 hour at room temperature.

By the same operation as in Example 2, (S)-(+)-2-phenylpropionic acid (300 μ, 2.0 mmol) and dimethyltitanocene (210 Qr1, Ommol) were obtained.
From this, yellow-orange crystals of bisf(S)-(10)-αphenylpropionato)titanocene (■) [Compound No. 2] were obtained. Yield is 88% based on dimethyltitanocene
Met.

2-phenylpropionic acid (300μ, 2.0mmol) and dimethyltitanocene (210μ, 1.Ommol)
Yellow-orange crystals of bis [(11) -(-)-α-phenylpropiona titanocene (■) [Compound No. 3] were obtained. Yield is 84% based on dimethyltitanocene.
%Met.

Example 4 Example 5 By the same operation as in Example 2, (R)-(-)2-(4'
-isobutylphenyl)propionic acid (413w, 2.
Dimethyl titanocene (210 g) was added to 0 mmol of methyl chloride L/7 solution (10 ml).

A methylene chloride solution (10 ml) of 1, Ommol) was added dropwise under water cooling, and the mixture was stirred for 1 hour, and further stirred for 1 hour at room temperature.Next, the solvent was distilled off under reduced pressure, and pentane was added to the resulting orange oil. The precipitated yellow-orange crystals of bis(α-(p-isobutylphenyl)propionato)titanocene (■) [Compound No. 4] were separated by filtration, washed with pentane, and then dried under reduced pressure. The yield was 72% based on dimethyltitanocene.

Example 6 (+) Dimethyltitanocene (210 w
, 1.0 mmo I) in methylene chloride solution (10 ml)
was added dropwise under water cooling, stirred for 1 hour, and further stirred for 1 hour at room temperature.Next, the solvent was distilled off under reduced pressure, and a pentane-ether mixture was added to the obtained orange-yellow oil to precipitate bis(( Yellow crystals of +)-α(6'-methoxy-β-naphthyl)propionato)titanocene (■) [Compound No. 5] were separated by filtration, washed with a pentane-ether mixture, and then dried under reduced pressure. The yield was 85% based on dimethyltitanocene.

Example 7 2-Oxobutanoic acid (623μ, 3.5mmo 1) was added and stirred at room temperature for 1@. Methylene chloride was added to the mixture to dissolve the precipitated yellow-orange solid, and an IN aqueous sodium hydroxide solution was added thereto, followed by extraction with methylene chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain an orange oil.
Next, the ether was processed to produce bis(β-methyl-β
-Phenylpyruva titanocene (■) [Compound No. 6]
Yellow-orange crystals were separated by filtration, washed with ether, and dried under reduced pressure. The yield was 12% based on titanocene dichloride.

Titanocene dichloride (250w, 1.0mm o
1) was dissolved in water (30 ml), and then yellow-orange crystals of 3-F22-Example 8 Product No. 6] were separated by filtration, washed with ether, and then dried under reduced pressure. The yield was 73% based on dimethyltitanocene.

Example 9 3-phenyl-2-oxobutanoic acid (270 ■.

dimethyl titanocene (125+1 g, 0.6 mmol) in methylene chloride solution (10 ml)
A methylene chloride solution (10 ml) was added dropwise under water cooling and stirred for 1 hour, and then roughly stirred at room temperature for 1 hour.
The solvent was distilled off under reduced pressure, and ether was added to the resulting orange oil to precipitate bis(β-methyl-β-phenylpyrubat).
Titanocene (■) [Compound 3-(4'-methylphenyl)
-2-oxobutanoic acid (320w, 1.7mmo I)
A methylene chloride solution (10 ml) of dimethyl titanocene (173 g, 0.8 mmo +) was added to a methylene chloride solution (10 ml) of
7 ml) was added dropwise under water cooling, stirred for 1 hour, and further stirred at room temperature for 1 hour.Then, the solvent was distilled off under reduced pressure, and ether was added to the resulting orange oil to precipitate bis(β-methyl-β- Yellow-orange crystals of <p-methylphenyl)bilbat)titanocene (■) [Compound No. 7] were separated by filtration, washed with ether, and then dried under reduced pressure. The yield was 86% based on dimethyltitanocene.

Example 10 3-(4'-propylphenyl)-2-oxobutane f
Dimethyltitanocene (21
0w, 1.0mmol) of chloride)-F-1/7 solution (
10 ml) was added dropwise under water cooling, and the mixture was stirred for 1 hour and further stirred at room temperature for 1 hour. Next, the solvent was distilled off under reduced pressure, and a pentane-ether mixture was added to the resulting orange oil to precipitate bis(β-methyl-β-(p-propylphenyl)pyruvato)titanocene (■) [Compound No. 8] The yellow-orange crystals were separated by filtration, washed with pentane, and dried under reduced pressure.

The yield was 79% based on dimethyltitanocene.

0CHs Example 11 Yellow-orange crystals of luphenyl)pyruvato)titanocene (■) [Compound No. 9] were separated by filtration, washed with pentane, and then dried under reduced pressure. Yield is 58% based on dimethyltitanocene.
%Met.

Example 12 A solution of 3-(4'-isobutylphenyl)-2-oxobutanoic acid (400 qr, 1.7 mmol) in methylene chloride (10 ml) was added with dimethyltitanocene (180 w, 0.0 ml).
A methylene chloride solution (7 mmol) of 8 mmol was added dropwise under water cooling, stirred for 1 hour, and further stirred at room temperature for 1 hour.Next, the solvent was distilled off under reduced pressure, and pentane was added to the obtained orange oil to precipitate. dimethyltitanocene (190 nr, 1.8 mmol) was added to a methylene chloride solution (10 ml) of bis(β-methyl-β-(p-isobuty3-(4'-sochlorohexylphenyl)-2oxobutanoic acid (470 nr, 1.8 mmol)).
Q+, 0.9 mmol) in methylene chloride solution (lom
+) was added dropwise under water cooling and stirred for 1 hour, and further stirred for 1 hour at room temperature.Next, the solvent was distilled off under reduced pressure, and ether was added to the resulting orange oil to precipitate bis(β-methyl-β Yellow-orange crystals of -(p-cyclohexylphenyl)pyruvato)titanocene (IV) [Compound No. 10] were filtered off, washed with ether, and then dried under reduced pressure. The yield was 78% based on dimethyltitanocene.

Example 13 A solution of 3-(4'-methoxyphenyl)-2-oxobutanoic acid (220w, 1.1 mmo 1) in methylene chloride (
dimethyl titanocene (104■, 0.5m)
A methylene chloride solution (5 ml) of mo+) was added dropwise under water cooling, and the mixture was stirred for 1 hour, and further stirred for 1 hour at room temperature.

Next, the solvent was distilled off under reduced pressure, and a pentane-ether mixture was added to the obtained orange oil to precipitate bis(β-methyl-β-(p-methoxyphenyl)pyruvato)titanocene (■) [Compound No. 11] The yellow-orange crystals were separated by filtration, washed with a pentane-ether mixture, and then dried under reduced pressure. The yield was 82% based on dimethyltitanocene.

Example 14 Fluorophenyl)-2-oxobutane fi(5813
3.0 mmol) was added thereto, and the mixture was stirred at room temperature overnight.

Methylene chloride was added to the mixture to dissolve the precipitated yellow-orange solid, and an IN aqueous sodium hydroxide solution was added thereto, followed by extraction with methylene chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain an orange oil.Next, ether was added to precipitate bis(β-methyl-β-(p-fluorophenyl)pyruvato)titanocene (■) [Compound No. 12 ] Yellow crystals were separated by filtration, washed with ether, and dried under reduced pressure. The yield was 9% based on titanocene dichloride.

Titanocene dichloride (250m, 1.0mm o
I) in water (30 ml), then 3-(4'
EXAMPLE Yellow crystals of phenyl)pyruvato)titanocene(rV)C Compound No. 12] were separated by filtration, washed with ether, and then dried under reduced pressure. The yield was 76% based on dimethyltitanocene.

Dimethyltitanocene (180 g, 0.8
A solution (7 ml) of methylene chloride (mmol 1) in methylene chloride was added dropwise under water cooling, and the mixture was stirred for 1 hour, and further stirred at room temperature for 1 hour.Next, the solvent was distilled off under reduced pressure, and ether was added to the resulting orange oil to precipitate. Bis(β-methyl-β-(p-fluoro pharmacological efficacy test example 1 [Mouse, proliferation inhibitory effect on lymphocytic leukemia cultured cells (P38B)] Mouse, lymphocytic leukemia cultured cells (P2S5), 10
% tallow baby serum supplemented RPAI-1640 culture medium, 5X1
The cells were adjusted to 0' cells/ml and cultured at 37° C. for 48 hours in the presence of the compound of the present invention. The number of floating cells was measured using a Coulter counter, and a dose-response curve was created based on the growth inhibition rate compared to the case without the addition of the compound, TCs. I asked for The results are shown in Table-4.

Although 0.5% or less DMSO coexisted as a solvent for the compound, the growth inhibition rate in the presence of 0.5% DMSO was 10% or less.

Table-4 Mouse leukemia cultured cells of titanocene (■) if compound Growth inhibitory effect of (P-388)

Claims (1)

[Claims] (1) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼-(1) (In the formula, R^1 represents a lower alkyl group, Ar represents an aryl group, and n is 0 or 1.) The titanocene (IV) complex compound shown.