JPS61172894A - (alpha, omega-bis(diphenylphosphino) hydrocarbon) bis ((thiosugar) gold) and bis ((selenosugar) gold) derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel [bis(
a diphenylphosphino)alkyl]histogold derivative and a pharmaceutical composition containing said new derivative, and said derivative by administering m intestinal cell growth-inhibiting amount of said new derivative to a host animal afflicted with said tumor cell. The present invention relates to a method of treating susceptible tumor cells.

BACKGROUND OF THE INVENTION Salaton et al., Journal of Mesointernal Chemistry
d, Chem, ).

15(11), 1095-98 (1972) discloses certain trialkylmonophosphine gold thiosaccharide complexes as anti-arthritic inflammatory agents. Mirabelli et al., Proceedings of the American Association Cancer Research
Proc.

Amer, As5n, Cancer Res, )
, 25.367 (1984), auranofin (
Disclose that certain monophosphine gold(I) thiosaccharide complexes containing auranofin) and related triethylphosphinogold(■) thiolates have significant activity in an intraperitoneal P388 leukemia tumor model. There is. Simon et al. Cancer Research
al, Cancer Res, ).

41.94 (1981) and Mirabelli et al., Cancer Research (Mirabelli et al., C.
Ancer Res, ), 45°32 (1985) discloses that auranofin has significant antitumor effects in animals suffering from P388 leukemia. Duwa et al., JP 58-192893, discloses selenium analogs of auranofin and other related triethylphosphinogold(I) selerates and their use as anti-arthritic agents. Reporting. Struc et al., Journal of Mesointernal Chemistry (Stru
ck et al., J.Med.Chem.)
, 9.414-416 (1966) i;! , discloses the cytotoxic activity of ethylene bis(diphenylphosphine). None of the above-mentioned documents discloses or suggests that the [bis(diphenylphosphino)alkyl]bis-gold(1) thiosugar or selenosugar derivative of the present invention, or the derivative thereof, has tumor cell growth inhibiting activity. .

SUMMARY OF THE INVENTION The present invention provides compounds of the formula: [wherein A is (CH2)n or cisC1(=CH;n
is 1 to 6; 2 and W are the same and mean thiosugar or selenosugar].

The bond of W to the gold atom is via the sulfur atom of thiosugar or the selenium atom of selenosugar.

The present invention also provides lii! ! a tumor cell growth inhibiting amount of the active ingredient 2 and a pharmaceutically acceptable inert carrier or diluent, the composition being effective to inhibit the growth of animal tumor cells susceptible to the active ingredient; The active ingredient has the formula (
The present invention relates to a pharmaceutical composition characterized by being a compound of I).

Another aspect of the invention provides an effective amount of tumor cell growth inhibiting formula (I
A method for inhibiting the growth of animal tumor cells sensitive to the compound of formula (I), which comprises administering the compound of formula (I) to an animal affected by the tumor cell.

DETAILED DESCRIPTION OF THE INVENTION Any 1-thiolibose is represented by the term "thiosaccharide." Examples of such thiosaccharides include 1-thioglucose, 1-thiogalactose, 1-thiomannose,
1-thiolibose, 1-thiomaltose, 1-thiofucose, tetra-O-acetyl-1-thioglucose, tetra-O-acetyl-1-thiomannose, tetra-0
-acetyl-1-thiogalactose, tri-O-acetyl-1-thiolibose, hepta-O-acetyl-1-thiomaltose, tri-O-acetyl-1-thiofucose.

Any non-acetylated 1-selenoaldose is represented by the term "selenosugar". Examples of such seleno sugars include 1-selenoglucose, 1-selenomannose, 1-mole/galactose, 1-selenoribose, 1-
Includes selenomaltose and 1-selenofucose.

Preferred compounds of formula (I) include those where W is 1-thioglucose, 1-thiogalactose and 1-thiomannose. These compounds are preferred because they exhibit particularly effective tumor suppressive activity in a variety of test systems.

All compounds within formula (I) can be prepared by methods available to those skilled in the art. Usually, W is non-acetylated 1-
The formula (which is thioaldose or 1-selenoaldose)
The compound of I) is produced by reacting an appropriate derivative represented by the formula (■): [wherein A has the same meaning as defined above] with an appropriate sodium thiosaccharide or sodium selenothiosaccharide. The desired non-acetylated thiosaccharides or selenosaccharides can be obtained commercially or by methods available to those skilled in the art.

The desired derivative of formula (II) is a derivative of formula (■): [wherein A
has the same meaning as above] is obtained by reacting a suitable diphosphino hydrocarbon represented by directly with chloroauric acid hydrate or with a reduced form of the acid hydrate obtained by treatment with thiodiglycol. I can do it. For example, a solution of thiodiglycol in an inert organic solvent such as methanol or ethanol is reacted with an aqueous solution of chloroauric acid hydrate cooled to a temperature of -10 to 0°C, followed by a mixture of chloroform and methanol. in an inert organic solvent system such as
) for 1-2 hours to obtain the corresponding formula (n
) is obtained. Similarly, chloroauric acid hydrate in an inert organic solvent such as methanol or ethanol can be reacted with a solution of the appropriate compound of formula (11[) for 1 to 2 hours at room temperature to form the corresponding compound of formula (It). get. Formula (II)
The formula (1) required as a starting material for preparing the compound of
1[), all of which are, for example, Massachusetts,
Denver, Strem Chemicals Inc.
It is commercially available from Nvers, Massachusetts).

Compounds of formula (I) in which W is per〇-acetyl thiosugar can be prepared using a suitable derivative of formula (n) and a suitable per〇-acetyl-(thiopseudurea hydrobromide), all of which are commercially available manually. or can be prepared by methods available to those skilled in the art). For example, Durette et al., Carb.
Kes, ), 81.261 (1980).

Alternatively, compounds of formula (I) where W is a non-acetylated thiosaccharide or selenosugar may be treated with a hydrolyzing base such as methanolic ammonia or sodium methoxide in methanol. from the corresponding per--acetyl derivatives to give the desired non-acetylated compounds of formula (I). Suitable per-〇-acetyl sele/sugar starting materials include a suitable derivative of formula (II) and a suitable per-〇-acetyl-(selenopunide urea hydrobromide), all of which are commercially available or can be easily understood by those skilled in the art. (can be manufactured by methods available in
It can be produced by reacting. For example, Doulet et al., Force-Volume Rate Research (C
arb, Res, ), 81.

See 261 (1980).

As mentioned above, compounds of formula (I) have been shown to have tumor cell growth inhibiting activity in various test systems.

The B16 Mouse Melanoma Cell Assay measures the ability of a compound to suppress the clonogenic potential of cells in vitro after 2 hours of exposure to the compound.

The cytotoxic activity of compounds of formula (I) was determined in vitro using B16 melanoma cells according to the method of the present invention.

It was measured with

Using B16 mela/-ma (higher order dislocation subsystem, FIO),
Minimum essential medium supplemented with 10% calf serum and 1% antibiotics was supplied by Grand Island Scientific Company, Grand Island, NY.
and l5land Biological Co.
37 in a humid ink incubator under a 51CO2 atmosphere at Cyland 15land, N, Y, )
were maintained as monolayer cultures at °C. Asynchronous populations of cells were harvested and plated on 60 x 15 JII sterile Petri plates at 5000 cells/plate. The plates were incubated overnight to allow cells to adhere to the plates. Cells were treated with the compounds to be evaluated under sterile conditions and after 2 hours of exposure, the medium was removed by aspiration. After washing the plates once with 5 mg of phosphate buffered saline (PBS), 5 d of fresh medium was added. The plates were incubated at 37° C. in a 2 incubator for 5 days. Viability is measured by the ability of cells to form colonies of 50 cells or more. Colonies are fixed with 0.5% crystal violet in 95% ethanol. Let the plates dry and place them in a Biotron Automatic Counter Riser at New Brunswick Scientific Company, Edgin, Jersey.
Brunswick 5 Scientific Co.
.

Edison, N.J.)). The mean and standard deviation of triplicate samples are determined for each drug concentration. Data are analyzed by plotting the logarithm of the survival function (number of colonies on drug-treated plate/number of colonies on control) versus drug concentration.

Formula in in vitro B16 cytotoxicity determination (
An evaluation of one representative compound of I) is shown in Table 1.

Table 1 AuW AuW Note 3tal Concentration of drug that inhibits the cloning ability of 816 melanoma cells by 50% after 2 hours of contact; drug contact in the presence of 10% fetal bovine serum and another iHvitr
In experiments, Compound No. 1 effectively killed 1(T-29 human colon cancer cells) by contacting with 57 AM IC5o(4-Fe2) for 2 hours.

P388! J lymphocyte leukemia is the most widely used animal tumor model in recent years for screening antitumor agents and for detailed evaluation of active compounds. This tumor system is sensitive to virtually all clinically active antineoplastic drugs, is quantitative, reproducible, amenable to large-scale screening, and has demonstrated activity in animal tumor models. Because it is predictable, it is widely accepted as a material for screening antitumor agents. Drugs that are highly active in intraperitoneal (iP) P388 leukemia are generally active in other tumor models as well. The antitumor activity of compounds of formula (I) is demonstrated in the P388 leukemia mouse model using the following experimental procedure.

106 P388 leukemia cells are intraperitoneally implanted into 86 D 2 F 1 mice. After 24 hours, if the tumor inoculum is found to be free of bacterial contamination (tested by 24 hour incubation in thioglycollate broth), animals are randomly divided into six groups and placed in shoebox cages. The compound to be evaluated is dissolved in a minimal amount of N,N-dimethylacetamide (DMA) or 95% ethanol (depending on solubility). An equivalent volume of saline is added, and once the drug has precipitated out of solution, an equal volume of polyethoxylated castor oil is added, and the saline is diluted until the concentration is such that the desired dose can be administered in 0.5 increments. The final concentration of DMA, ethanol and polyethoxylated castor oil was 10
%. To cover the lid with saline, use saline.
Therefore, as the dose decreases, the proportion of organic solvent in the vehicle also decreases. These vehicles provide soluble formulations (or suspensions). The formulation is prepared immediately before injection. Compounds are administered intraperitoneally from days 1 to 5 (ie, treatment begins 24 hours after tumor inoculation). Each experiment includes 3 groups of 6 animals per group as an untreated control group and a cisplatin positive control group at two dose concentrations. The animals were weighed for each group on days 1, 5, and 9, and the average weight change (ΔW(,) was used as a measure of toxicity. The inoculum titration group consisted of eight mice inoculated intraperitoneally with P388 leukemia cells.

Titer groups are used to calculate cell killing due to drug treatment. Animal mortality is checked daily and the experiment is terminated after 45 days. The endpoint is the median survival time (MST) and the survival rate (ILS), which is the percentage increase in MSr relative to the untreated control group.

Untreated control groups inoculated intraperitoneally with 106 P388 leukemia cells generally survive for a median of 10-11a. If the ILS is 25% or higher, the drug is considered active.

Table A summarizes the evaluation of several compounds of formula (I) in the in vivo P388 model.

%A table AuW AuW 田 (a) Maximum tolerated dose of 86D2F mice (female) when qDx5 was administered intraperitoneally (b) Maximum survival rate of mice inoculated intraperitoneally with P388 leukemia (values separated by slashes represent separate experiments) (01-thioglucose-(oAc)4=tetra-0-
Acetyl-1-thioglucose (number A based on data from separate experiments of dl12)
From the data presented in the table, it can be seen that the compound of formula (I) in v
It was found that intraperitoneal inoculation of P388 leukemic knee tumors had significant antitumor activity in vivo. In particular, compounds nos. 1.22 and 3 have particularly good activity with respect to IL S GC in the P3BB leukemia assay, comparable to the clinically useful anti-tumor agent cisplatin.

Another chemosensitive tumor model is mouse intraperitoneal (i.
p) Inoculated M5076 reticulocyte sarcoma. This B6
In the D2F system, mice (female) were treated with 10% (W:V) M5076 bly 0.5 IR□l prepared from preserved subcutaneous tumors excised approximately 21 days after C57B1/6 donors.
inoculate. Administer the drug intraperitoneally. Daily treatment begins 24 hours after inoculation and continues for 10 days. Due to the slower growth rate of M5076 tumors and the longer survival period of the control group, the administration treatment of M5076 will be longer than that of P2S5. Table 2 shows the antitumor activity of compounds No. 1 and 2 of Table A in the M5Q76 reticulocyte sarcoma tumor model.

Table 2 annotated a) For structure, see Table A (b1 Maximum survival rate of mice intraperitoneally administered with M5076 reticulocyte sarcoma (numbers separated by slashes are from separate experiments) (C) QDXIO peritoneal The cytotoxic activity of Compound No. 1 from Table A, best tolerated by B6D2F mice (female) when administered internally, was evaluated in vivo using B16 melanoma cells. In this system, eight 86D Groups of 2 F1 mice are inoculated intraperitoneally with 10% (W:V) 0.5 shoulder j of B16 melanoma prepared from preserved subcutaneous tumors excised from C67B1/6 donor mice 14-21 days later.

Daily treatment begins 24 hours after tumor implantation and continues daily for 10 days. The route of drug administration is intraperitoneal administration. 60
Monitor mouse survival daily for days. Anti-rm tumor activity is assessed by increase in median survival time. IL of 25% or more
S indicates activity in this tumor system.

A summary of the results of the in vivo intraperitoneal B16 melanoma assay is shown in Table 3.

Note: (a) For the structure, see Table A fbl q D In yet another in vivo tumor model, namely murine 816 melanoma, compounds of Table A were administered intraperitoneally at a treatment schedule of 8.4.2.1 and 0.5 μ/kq. Compound number 1 is 3.4 μM/kQ
The average survival rate (IL) of 32 Hiiragi at the maximum tolerated dose (MTD) of
S) was shown.

Compound No. 1 of Table A may also be further in
Breast cancer 167, a tumor model sensitive to DNA binders and alkylating agents
Tested with C. In this experiment, the tumor was inoculated subcutaneously into C3H mice and the drug was administered on an intermittent treatment schedule, i.e. once every day 1.5.9.13 and 17 days, either intraperitoneally or intravenously. Three weeks after inoculation, tumor size was measured in the mortar, and activity was evaluated based on the degree of tumor growth inhibition. Cisplatin, a drug that generally completely inhibits the growth of mammary adenocarcinoma 16/C, was used as a positive control.

Tumor growth inhibition of greater than 75% indicates activity in this type of animal tumor model. The results of this test are shown in Table 8.

Similarly, compound No. 1 in Table A is further added to ADJ.
- in viv known as PC6 plasmacytoma.

Tested in a tumor model. In this assay, tumor cells are
The cells were subcutaneously subcutaneously carried in ALB/c mice (female), and then collected aseptically on the 21st day and placed in the 11-ink R.
Cut into strips in salt solution. The cells are then uniformly dispersed using a loose-fitting Teflon glass homogenizer, and the cell concentration is adjusted to 4 x 106 viable cells (excluding trypsin blue)/g using a hemocytometer. B A L of a group of 8 animals with a total of 0.5 shoulder/(2X106 cells)
B/c mice (female) are inoculated subcutaneously into the right flank. Tumors are treated by intraperitoneal administration from the first white of the eye on the 10th day, and on the 18th day, the vertical diameter is measured with a caliper to determine the size of the tumor. Tumor volume is calculated as length x width 2 x O15. Generally, 7
Tumor growth inhibition of 5% or more can be said to have significant antitumor activity. The results of this test are shown in Table 6.

Table 6 Note) (a) N, P, = 138 Proportion of mice without obvious tumors in eyes (b) M T V = 18 Mean white of eyes 1] I tumor volume 4
(m13) (C) In other experiments using the same dose and the same treatment schedule, Compound No. 1 inhibited ADJ-PC5 plasma cell raccoon by only 23% (Il). The compositions are characterized in that they consist of a cell growth inhibiting effective amount of a compound of formula (I) and a pharmaceutically acceptable inert carrier or diluent. These compositions are prepared in dosage unit form suitable for parenteral administration. .

Compositions of the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. The composition contains a minimum amount of dimethylacetamide or ethanol,
For example, it may be in the form of a bath solution containing 5% v/v of the active ingredient in peanut oil or normal saline. Polyethoxylated castor oil, e.g. 2-5% V
/V can also be used to solubilize active ingredients. Additionally, the composition can be in the form of a slurry, using, for example, hydroxypropyl cellulose or other suitable suspending agent. As the emulsifier, for example, lecithin can be used. The composition can also be provided in sterile solid form for dissolution in sterile injectable solution immediately prior to use.

The actual preferred dosage of a compound of formula (I) used in the compositions of the invention will vary depending on the compound used, the formulation of the composition, the method of administration, and the site, host, and disease state being treated. The route of administration in the body is based on the formula (I
) should be selected to ensure that the compound contacts the tumor. The optimal dose under given conditions can be determined using known dose determination tests with reference to the experimental data described above. Doses commonly used for parenteral administration are about 5 to about 20 da/ga body surface area per day for 1 to 5 days, repeated 4 times about every 4 weeks.

The method of inhibiting the growth of animal tumor cells sensitive to the compound of formula (I) of the present invention comprises administering to a host animal suffering from the tumor cells an effective amount of the compound of formula (I) for inhibiting tumor cell growth. Become. As noted above, during the treatment period, the active ingredient is administered parenterally in a selected amount between about 300 and about 1000 q.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 μm [1,2-bis(diphenylphosphine/)ethane]
Bis[1-thio β-D-glucopyranosato-5) gold (
1)] 20 μm [1,2-bis(diphenylphosphino)ethane]bis[black cap (1)] Thiodiglycol 11.0.10 in methanol 50d
．． 12.4 g of chlorosaccharide tetrahydrate in 100 mA' of water/150 zl of methanol maintained at 0° C.
(0.03 mol) dropwise over 15 minutes. Zara ζ
After stirring for 15 minutes, chloroform 100#! l! /
6.12.9 (0,015 mol) of 1,2-bis(diphenylphosphino)ethane in 10oIIIe of ethanol (StremChem, Denno, Massachusetts)
icals, Inc., Danvers, Ma.
ssachusetts) manually) to the colorless solution (a precipitate forms immediately after addition). After warming to room temperature (
2 hours), add 0.5e of methanol, collect the product,
Slurry with methylene chloride/ethanol, filter, and dry to yield white product 11,1' (85%). Melting point: 290-292°C.

Other desired derivatives of formula (n) of l,N may also be prepared by using substantially the methods described above and using appropriate ligands of formula (■).

61 μm [1,2-1:”(diphenylphosphino)
ethane]bis[1-thioβ-D-glucohyranosato-
5) Gold (1)] μm[1,2-bis(diphenylphosphine/)ethane]bis[crocodile cap (I')) in 500 g of chloroform/200 g of ethanol at room temperature under an argon atmosphere.
5. O! ! (5.8 mmol) (prepared in the same manner as above A) in 100 ffi of water/3 ethanol
Sodium thioculcose in 00 Re 2.53.7
(11,6 mmol) (Sigma Chemical Company
(obtained from ). After stirring at high speed for 72 hours, the solvent is removed in vacuo. Chromatography of the residue = (
Waters Prep
Solid 3.57. We obtain p(52%).

Melting point 130℃; [α]o (1% methanol) -3,6
゜Example 2 μm 1.2-bis(diphenylphosphino)ethane]bis[(1-thio β-〇-galactopyranosato S)gold(1)] At room temperature under an argon atmosphere, ethanol, Sodium thiogalactose 1.25, p (5,4 mmol) (obtained from Sigma Chemical Company) and μm [1,2
A mixture of -bis(diphenylphosphino)ethane]bis[chrome cap (I)] 2.34JiB 2.72 mmol) (prepared as in Example 1 above) is stirred for 18 hours. The solvent was removed in vacuo and the residue was prepared by high pressure liquid chromatography (f(PLC)) (Waters Pretub 50
0. silica gel, 20% methanol/methylene chloride) to give an oily product, 0.64.9%. Treatment with acetone followed by recrystallization from methanol/ether yields 0.4 g (13%) of amorphous solid product. [α] 0 (1%
methanol) 7 3.9° Example 3 μm [1,2-bis(diphenylphosphino)ethane]
Bis[(2,3,4,6-tetra-0-acetyl-1-
Thio-α-D-mannopyranosato S) Gold(I)] 0.42.9 (3.1 mmol) of potassium carbonate in 10 ml of water was mixed with 0.42.9 (3.1 mmol) of potassium carbonate in 15 ml of water at 0° C. under an argon atmosphere.
- S (2,3,4,6-tetra-0-acetyl α
-D-mannopyranosyl)-2-thiopseudurea hydrobromide 1.35 g (2,77 mmol) (Dourette et al., Carbohydrate Research)
et al., Carb, Res.), 81
．． 261 (1980)). After 15 minutes, ethanol 751 was added, stirred for 10 minutes, and then μm [1,2-bis(diphenylphosphino)ethane]bis[chrome cap (
I)) 1.08 g (1.25 mmol) (Example 1 above)
(prepared in the same manner as above). - After stirring at night, water 150
Add yil, separate the layers, dry the organic layer over magnesium sulfate, filter, and remove the chloroform in vacuo. The residue was recrystallized from ethanol to give 0.87 g of white amorphous solid.
(46%). [α] 0 (1% methanol) +-5
2,1.

Example 4 μm (1,2-bis(diphenylphosphino)ethane)
Bis[1-thio α4-mannopyranosato-S) gold (■
)] μm (1,2-bis(diphenylphosphino)thane)
bis[2,3,4,6-tetra-0-acenal-1-naoD-man/Vilanosato S) gold] 1.0.9 (2,
A mixture of 1 mIJ mol) (prepared by straining as in Example 3 above) and 15 g of concentrated ammonium hydroxide solution in 100 methanol is stirred at room temperature for 18 hours and the solvent is evaporated in vacuo. Add water and methanol and acidify the mixture to pH 4 by adding glacial acetic acid. The solvent is evaporated in vacuo and the residue is washed with water. Chromatography of the residue (silica gel, 30% methanol/methylene chloride)
An oily product is obtained. A white solid is formed upon treatment with acetone, resulting in an amorphous solid product of 0.38. p(4
9%) is obtained. [α]o (1% methanol) 752
．． 2゜Example 5 μm [1,2-bis(diphenylphosphine/)ethane]
bis(2,3,4,6-Citler O-acetyl-1-thio-β-D-glucopyranosato S)gold (μm C1 in 100 ml of chloroform at room temperature under an argon atmosphere,
2-bis(diphenylphosphino)ethane]bis[chloro(I)) 1.0 g (1.16 mmol)
(Prepared in the same manner as in Example 1) was prepared by adding 0.32 g of potassium carbonate (2,3
2 mmol) and 1-β-D-thio2.3.4.6
-tetra-0-acetylglucopyram/-su 0.84.7
(2,32 mmol) (Aldrich-'r', force/
lz-campa=-(Aldrich Cixemic
alCompany) to the solution manually), then chloroform 50tte/ethanol 50ml fM
Jeru.

After stirring for 1 hour, the solvent is evaporated in vacuo, the residue is dissolved in chloroform and washed twice with water, the a-layer is dried over magnesium sulfate, filtered and the solvent is removed in vacuo. The residue was chromatographed (Waters Pretub 500
．． The product 1.6.9 (91
%).

[α) 25 < 1% methanol) -67,6°.

Example 6 μm (1,3-bis(diphenylphosphine/)propane bis[1-thio β-D-glucopyranosato S) gold (1)] in chloroform 75#Ie at room temperature under an argon atmosphere A suspension of 0.55 Ii (0.64 mmol) of μm [1,3-bis(diphenylphosphino)propank bis[black cap (I)] (RKt [prepared in the same manner as in Example 1)] was dissolved in methanol. Thioglucose (manual from Sigma Chemical Company) in 75ml/1oaf of water 0.
3. Add to a rapidly stirred solution of (1,4 mmol).

After 1 hour, the solvent was removed in vacuo, the residue was washed with water, decanted, methanol was added and the precipitate (NaCl
is collected from the ether/methanol solution and ether is added to the solution. - After standing overnight, the product is collected from the ether/methanol solution, washed with ether and dried to give 0.68 g of a white solid. Melting point: 125°C.

Example 7 μm [1,2-bis(diphenylphosphino)ethane]
-bis[1-sere/-β-D-glucopyranosato SE
) Gold (1)] 3, μm [1,2-bis(diphenylphosphine/)ethane]-bis(2,3,4,6-tetra-0-acetyl-
1-Seleno-β-D-glucopyra/Sato5e) Gold (1
)] Potassium carbonate in steamed water 31Le 0.69. p(5,0
A solution of 10 mmol) in water/methanol (1:1)
2-S (2,3,4,6-tetra-0-acetyl-β-D-glucopyranone)-2-selenoin urea hydrobromide in 0d (Wagner et al., Archives de/L/
- Pharmacy - (Wagner et al., Ar
chiv, der Pharmazie), 297
, 461 (1964)) 2.
Stir with a water-cooled solution of 78, p (5,2 mmol). The resulting suspension was dissolved in chloroform at 150 μm.
[1,2-bis(diphenylphosphino)ethane]bis[black cap (I)] (prepared in the same manner as Example 1)
2.16. @ (2.5 mmol) and stir. After 1 hour the chloroform layer is separated and concentrated in vacuo and the residue is flash chromatographed on silica gel (ethyl acetate/chloroform (1:1)) to give 1.4 g of a white amorphous solid. Melting point 110-118"C0 61μmC1,2-his(diphenylphosphine/)ethane-bis[1-sele7-β-D-curcobyranosato-5
e) Gold (■)] μm[1,2-bis(diphenylphosphine/)ethane]bis[2,3,4,6-tetra-0] in anhydrous methanol
-Acetyl-1-seleno-β-D -Curcovira/Sato-3e) Gold(I)) (prepared in the same manner as in 3 above) 710
A mixture of Q(0,44-:IJ mol) and sodium methoxyd 50#I'/(0,92 mmol) is added with the solvent at room temperature until the conversion of the carbohydrate acetate is completed.Then the mixture is Cool, add glacial acetic acid 0.0
Remove excess sodium methoxide from 53ae. The colorless solution is extracted under reduced pressure. The solid residue was washed repeatedly with distilled water, collected and dried in vacuo, leaving a pale yellow substance 3.
Get 9011Q. Melting point 130-135°C.

Implementation F” 8 μm [1,2-bis(diphenylphosphine/)ethanecubisC(2,3,5-tri-O-acetyl)(1-thio D-ribofuranosato S) gold (■)) a, 2,
3.5-1-CoO-acetyl-D-lipofuranonolysothiouronium furomide Trimethylsilyl bromide under alkone atmosphere 4.9.
@(0,032 mmol) in dry methychloride L/73ON
β-D-ribofuranose tetraacetate (Aldrich Chemical Company) in /5.0. p(0,0
16 mol) in a stirred solution (0-5°C). After the addition is complete, the mixture is allowed to warm until 'H-NMR indicates that the conversion of the tetraacetate to triacetylribofuranone rubromide is complete (J.
W Girard, Tetrahedron Letters CJ
,W.

G11lard, Tet, Letters), 2
2,513 (1981)), maintained at room temperature (24
time). The reaction mixture was then concentrated under reduced pressure to a thick oil, and after redissolving the oil in methylene chloride, 2
Time again! m to remove residual trimethylsilyl bromide. Finally, the residue was redissolved in acetone 3 Q at, treated with thiourea 1.22 F (0,016 mol),
Stir at reflux temperature for 0.5 hour. Then cool the mixture and separate the solids. The solid was then washed with cold acetone and
Drying in vacuo yields product 2.7ji. Melting point 128~
130℃. The product is 1t(-α as shown by NMR)
, a mixture of β-anomers (Girard, supra).

63 μm [1,2-bis(diphenylphosphino)ethanecubis[(2,3,5-1-ly0-acetyl)(
1-NaO D-ribofuranosato S) Gold(I)] Potassium carbonate in 3 ml of distilled water 0.76, p (5,
5 mmol) in water/methanol (1:1)
2.3.5-tri-O-acetyl-D- in 100ae
Stir with the cooled solution containing 2.16.7 (5.2 mmol) of ribofuranosylisothiouronium bromide (prepared as above). After the mixture was stirred for 0.5 h under cooling, μm [1
゜2-Bis(diphenylphosphino)ethanecubis [
Black base (I)) (Tested in the same manner as in Example 1!!J
) 2.16, F (2.5 mmol) is rapidly added dropwise. The mixture is then stirred for an additional 2.5 hours, the chloroform layer is separated and concentrated to 70 mW in vacuo. The syrup is dissolved in a gel (Baker F1a5h-Chrom).
(25% methanol/ethyl acetate) to produce product 1.
Obtain 97g. As shown by LH-NMR, the product is a mixture of α,β-amers with α-anomer as a product (J. W. Girard, Tetrahedron Letters (J. W. G11lard, Tet).
, Letters), 22.513 (1981)
).

Example 9 μmEl, 2-bis(diphenylphosphino)ethane CubisC(1-thio〇-ribofura/SatoS) Gold(1
)] μm in anhydrous methanol 50 m/[1,2-bis(diphenylphosphine/)-ethanecubis[(2°3.5-
1-ly-0-acetyl) (1-thio-α, β-I)
IJ Bofuranosato-5) Gold (I)) (Strained as in Example 8) 1. p (0.74 mmol) and sodium methoxide 40MQC (0.74 mmol) are stirred for 20 minutes at room temperature under a dry argon atmosphere. Then,
Ion exchange resin (Biorad
) 50νVX, 8, sulfuric acid form).

The resin is removed and the FQ is evacuated. The oily residue is stirred with water and solidified to give a white powder 480~. melting point 12
2-128℃.

'fdftllfA person SmithKline Beckman Corporation

Claims (14)

[Claims] (1) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, A is (CH_2)_n or cis CH=CH;
n is 1 to 6; and W are the same and mean thiosugar or selenosugar] [bis(diphenylphosphino)alkyl]
Bis-gold [I] compound. (2) W is 1-thioglucose, 1-thiogalactose, 1-thiomannose, 1-thiolibose, 1-thiomaltose, 1-thiofucose, 1-thiolibofuranose, tetra-O-acetyl-1-thioglucose, Tetra-O-acetyl-1-thiomannose, Tetra-O-acetyl-1-galactose, Tri-O-acetyl-1-
Thioribose, hepta-O-acetyl-1-thiomaltose, tri-O-acetyl-1-thiofucose, 1-selenoglucose, 1-selenomannose, 1-selenogalactose, 1-selenoribose, 1-selenomaltose or 1- The compound according to item (1) above, which is selenofucose. (3) The compound according to item (2) above, wherein W is 1-thioglucose, 1-thiogalactose or 1-thiomannose. (4) The compound of item (3) above, wherein A is (CH_2)_2 and W is 1-thioglucose. (5) tumor cell growth inhibiting composition comprising an effective amount of an active ingredient and a pharmaceutically acceptable inert carrier or diluent, the composition being effective in inhibiting the growth of animal tumor cells sensitive to the active ingredient; , the active ingredient has the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, A is (CH_2)_n or cisCH=CH;
n is 1 to 6; and W are the same and mean thiosugar or selenosugar.] A pharmaceutical composition characterized in that it is a compound represented by the following formula. (6) W is 1-thioglucose, 1-thiogalactose, 1-thiomannose, 1-thiolibose, 1-thiomaltose, 1-thiofucose, 1-thiolibofuranose, tetra-O-acetyl-1-thioglucose, Tetra-O-acetyl-1-thiomannose, Tetra-O-acetyl-1-thiogalactose, Tri-O-acetyl-
1-thiolibose, hepta-O-acetyl-1-thiomaltose, tri-O-acetyl-1-thiofucose, 1
- The composition according to item (5), which is selenoglucose, 1-selenomannose, 1-selenogalactose, 1-selenoribose, 1-selenomaltose or 1-selenofucose. (7) The composition according to item (6) above, wherein W is 1-thioglucose, 1-thiogalactose or 1-thiomannose. (8) W is 1-thioglucose and A is (CH_2)
The composition of item (7) above, which is _2. (9) The composition of item (5) above, wherein the composition is in a dosage unit form for parenteral administration. (10) The composition of item (9) above, wherein the parenteral dosage unit is for administration of about 5 to about 20 mg/m^2 body surface area. (11) Formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, A and W have the same meanings as below] and i) appropriate sodium thiosaccharide or react sodium selenothiosaccharide to prepare a compound of formula (I) in which W is a non-acetylated thiosaccharide or a selenosaccharide, or ii) a suitable per-O-acetyl-(thiopseudourea hydrobromide). ) to prepare a compound of formula (I) in which W is an acetylated thiosaccharide, or iii) a suitable per-O-acetyl-(thiopseudurea hydrobromide) or per-O- Acetyl-(selenopseudourea hydrobromide) is reacted to form the formula (I) in which W is an acetylated thiosaccharide or an acetylated selenosugar.
and treating the acetylated reaction product with a hydrolyzing base such as methanolic ammonia or sodium methoxide in methanol, where W is a non-acetylated thiosaccharide or selenosugar. Formula (I) characterized by preparing a compound of formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, A is (CH_2)_n or cisCH=CH;
n is 1 to 6; and W are the same and mean thiosugar or selenosugar] [bis(diphenylphosphino)alkyl]
Method for producing bis-gold[I] compound. (12) W is 1-thioglucose, 1-thiogalactose, 1-thiomannose, 1-thiolibose, 1-thiomaltose, 1-thiofucose, 1-thiolibofuranose, tetra-O-acetyl-1-thioglucose, Tetra-O-acetyl-1-thiomannose, Tetra-O-
Acetyl-1-thiogalactose, tri-O-acetyl-1-thiolibose, hepta-O-acetyl-1-thiomaltose, tri-O-acetyl-1-thiofucose,
The above-mentioned (11
) manufacturing method. (13) The production method according to item (12) above, wherein W is 1-thioglucose, 1-thiogalactose or 1-thiomannose. (14) The production method according to item (13) above, wherein A is (CH_2)_2 and W is 1-thioglucose.