WO1995014703A1 - Triorganophosphinegold (i) thionucleobases with anti-tumor activity - Google Patents

Triorganophosphinegold (i) thionucleobases with anti-tumor activity Download PDF

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WO1995014703A1
WO1995014703A1 PCT/AU1994/000725 AU9400725W WO9514703A1 WO 1995014703 A1 WO1995014703 A1 WO 1995014703A1 AU 9400725 W AU9400725 W AU 9400725W WO 9514703 A1 WO9514703 A1 WO 9514703A1
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same
compound
pharmaceutical
pharmaceutical composition
phenyl
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PCT/AU1994/000725
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French (fr)
Inventor
Edward R. T. Tiekink
Lorraine K. Webster
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Luminis Pty. Ltd.
Peter Maccallum Cancer Institute
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Priority to AU10593/95A priority Critical patent/AU1059395A/en
Publication of WO1995014703A1 publication Critical patent/WO1995014703A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3

Definitions

  • This invention relates to triorganophosphinegold (I) thionucleobases with useful pharmaceutical effects.
  • the compounds of this invention have been found to have anti-tumor activity as evidenced by tests performed in vitro and in vivo.
  • the invention also relates to a method for treating tumors by administering therapeutic amounts of such compounds.
  • R, R' and R" are alkyl or aryl compounds and R x is a heterocyclic compound and wherein R x contains a C-N chromophore bonded to S to form an S-C-N chromophore.
  • Preferred compounds of this invention are those of the general formula R3PAuSR x with R is Ethyl (Et), Phenyl (Ph) or Cyclohexyl (Cy) and R x is pyridine, pyrimidine, thiouracil, thioguanine, mercaptopurine or derivatives of these such as 5-carboxy-2-thiouracil, 6-methyl-2-thiouracil or n-propyl-thiouracil.
  • the inventors theorise that the P-Au-S chromophore is the active element of these compounds and the ligands effect the variation in activity and toxicity.
  • the forming of an S-C-N chromophore where the C-N is part of a heterocyclic structure results in enhanced pharmaceutical efficacy compared to known compounds with the P-Au-S chromophore.
  • Some anti-tumor complexes containing gold (I) are known.
  • Auranofin, (1- thio- ⁇ -D-gluco-pyranose 2, 3, 4, 6-tetraacetato-£)(triethylphosphine)gold(I) is known as a treatment for rheumatoid arthritis but has also been tested as an anti-tumor agent. It has been shown by Simon et al Cancer Res. 45, 32-39, 1985 to have a significant antileukemic effect in P388 grafted mice. The in vitro and in vivo anti-tumor activity of a number of gold (I) coordination complexes has been examined by Mirabelli et al J.Med. Chem. 29, 218-233, 1986. United States patent number 5037812 claims pharmaceutical compositions of tumor cell growth-inhibiting amounts of gold (I) coordination complexes but does not disclose the compounds of the present invention.
  • composition having anti-tumor activity which comprises an effective anti-tumor active ingredient, in unit dosage form, and a pharmaceutical carrier or diluent wherein the active ingredient comprises a compound containing the chromophore P-Au-S and of the general formula
  • R, R' and R" are alkyl or aryl and R x is a heterocyclic compound and wherein R x contains a C-N chromophore bonded to S to form an S-C- N chromophore.
  • the invention resides in a pharmaceutical composition having anti-tumor activity which comprises an effective anti-tumor active ingredient, in unit dosage form, and a pharmaceutical carrier or diluent wherein the active ingredient comprises a compound containing the chromophore P-Au-S and of the general formula
  • R, R' and R" are alkyl or aryl and SR X is a thionucleobase containing the S-C-N chromophore where C-N is part of a six member ring. .
  • the invention resides in a pharmaceutical composition having anti-tumor activity which comprises an effective anti- tumor active ingredient, in unit dosage form, and a pharmaceutical carrier or diluent wherein the active ingredient comprises a compound containing the chromophore P-Au-S and of the general formula
  • R, R' and R" are Et, Ph or Cy and R x is pyridine, pyrimidine, thiouracil, thioguanine, mercaptopurine or derivatives of these.
  • the invention can be said to reside in a method of inhibiting tumor cell growth in animals comprising the steps of administering to an animal afflicted with tumor cells a pharmaceutically acceptable tumor cell growth inhibiting amount of a compound of the general formula
  • R, R' and R" are alkyl or aryl and R x is a heterocyclic compound and wherein R x contains a C-N chromophore bonded to S to form an S-C- N chromophore.
  • the compound is administered with a pharmaceutically acceptable carrier or diluent.
  • R, R' and R" are alkyl or aryl and R x is a heterocyclic compound and wherein R x contains a C-N chromophore bonded to S to form an S-C- N chromophore.
  • FIG 1 shows the molecular structure and crystallographic numbering scheme employed for the complex (6-n-propyl-2-thiouracilato) tricyclohexylphosphine gold (I).
  • triorganophosphine gold (I) compounds of this invention can be prepared by methods available to a person skilled in the art and following the procedures of Harker et al Inorg. Chim. Acta 181, 23 1991.
  • R3PAUCI salts were prepared according to the procedures of Al-Saady etal. Inorg. Synth. 23, 191 1985. All starting materials are commercially available. Analytical grade reagents were used without further purification.
  • Ph3PAu(2-pymS) pale 86.4 196-197 yellow
  • Ph3PAu(6-MP) pale 93.7 254-255 yellow
  • the crystal structure of (6-n-propyl-2-thiouracilato) tricyclohexylphosphine gold (I) has been determined at room temperature and is depicted in FIG 1.
  • the Au atom is linearly coordinated with the P and S atoms at an angle of 177.6(1)°.
  • FaDu human squamous carcinoma of the pharynx
  • SKOV-3 human ovarian carcinoma
  • the FaDu human squamous carcinoma cell line was maintained in RPMI 1640 plus 10% fetal calf serum.
  • the SKOV-3 human ovarian carcinoma cell line was maintained in ⁇ -MEM plus 15% fetal calf serum.
  • 5xl0 3 exponentially growing SKOV-3 cells or lxlO exponentially growing FaDu cells in lOO ⁇ l medium were allowed to adhere in 96-well culture plates for 12 to 16 hours at 37°C in a humidified incubator gassed with 5% C ⁇ 2/95% air.
  • results of growth inhibition testing of the phosphinegold(I) thionucleobase complexes are summarised in Table 2.
  • the activity of the free thionucleobases is included for comparison.
  • the only metal- containing anticancer drugs in common use are cisplatin and carboplatin, their IDso's are also included for comparison.
  • the results listed in Table 2 are reported as the mean ⁇ standard deviation and in most cases are the average of at least three assays.
  • Table 2 also includes a toxicity score. Toxicity was determined from tests on Dark Agouti rats and is defined as causing greater weight loss (>10 g/15 days) than untreated controls at a dose of 10 mg Au/Kg.
  • compositions of the present invention will vary according to the particular complex being used, the particular composition formulated, the mode of administration and the particular site, host and tumor being treated.
  • Optimal dosages for a given set of conditions can be determined by those skilled in the art using conventional dosage determination tests in the light of the experimental data disclosed herein.
  • the compounds will generally be administered with an inert pharmaceutical carrier or diluent.
  • the carrier can be selected from a range of commercially available carriers having minimal or benign toxicity.
  • the pharmaceutical suitability of a particular carrier or diluent can be determined by conventional techniques known to those skilled in the art.
  • Preferred carriers include :
  • dispersions in dermo-compatible non-aqueous solvent systems e.g. dmso.glycerol (4:1 v/v) or ethanol:propan-l,2-diol (2:1 v/v)
  • dmso.glycerol 4:1 v/v
  • ethanol:propan-l,2-diol 2:1 v/v
  • hydroxypropylcellulose Kerel
  • CMC carboxymethylcellulose
  • PEG polyethyleneglycol
  • One or more of the compounds may be suitable for suspension by sonification in arachis oil.
  • the gold complexes of the present invention show a greater activity and reduced toxicity compared to the existing anti-tumor drugs in all cases.
  • EXAMPLE 8a Preparation of [Et3PAu(6-MP)].

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Pharmaceutical compounds having anti-tumour activity wherein the active ingredient comprises a triorganophosphinegold (I) thionucleobase of the general formula: R3PAuSRx, wherein R is alkyl or aryl and wherein Rx is a heterocyclic compound containing a C-N chromophore bonded to S. Also a method of inhibiting tumour cell growth in animals by administering a tumour cell growth inhibiting amount of a triorganophosphinegold (I) thionucleobase with a pharmaceutically acceptable carrier or diluent.

Description

TRIORGANOPHOSPHINEGOLD (I) THIONUCLEOBASES WITH ANTI-TUMOR ACTIVITY
This invention relates to triorganophosphinegold (I) thionucleobases with useful pharmaceutical effects. In particular the compounds of this invention have been found to have anti-tumor activity as evidenced by tests performed in vitro and in vivo. The invention also relates to a method for treating tumors by administering therapeutic amounts of such compounds.
BACKGROUND ART
The compounds of this invention have the general formula R
I
R'— P— Au— S— Rx
I R" where R, R' and R" are alkyl or aryl compounds and Rx is a heterocyclic compound and wherein Rx contains a C-N chromophore bonded to S to form an S-C-N chromophore.
Preferred compounds of this invention are those of the general formula R3PAuSRx with R is Ethyl (Et), Phenyl (Ph) or Cyclohexyl (Cy) and Rx is pyridine, pyrimidine, thiouracil, thioguanine, mercaptopurine or derivatives of these such as 5-carboxy-2-thiouracil, 6-methyl-2-thiouracil or n-propyl-thiouracil.
The inventors theorise that the P-Au-S chromophore is the active element of these compounds and the ligands effect the variation in activity and toxicity. The forming of an S-C-N chromophore where the C-N is part of a heterocyclic structure results in enhanced pharmaceutical efficacy compared to known compounds with the P-Au-S chromophore.
Some anti-tumor complexes containing gold (I) are known. Auranofin, (1- thio-β-D-gluco-pyranose 2, 3, 4, 6-tetraacetato-£)(triethylphosphine)gold(I), is known as a treatment for rheumatoid arthritis but has also been tested as an anti-tumor agent. It has been shown by Simon et al Cancer Res. 45, 32-39, 1985 to have a significant antileukemic effect in P388 grafted mice. The in vitro and in vivo anti-tumor activity of a number of gold (I) coordination complexes has been examined by Mirabelli et al J.Med. Chem. 29, 218-233, 1986. United States patent number 5037812 claims pharmaceutical compositions of tumor cell growth-inhibiting amounts of gold (I) coordination complexes but does not disclose the compounds of the present invention.
The anti-tumor activity of related compounds with the P-Au-S-C-N chromophore has been suggested in three publications of which the inventor is aware but none of the publications disclose the anti-tumor activity of the pharmaceutical compositions of the present invention. Aritzi et al Anticancer Res. 11, 625-628, 1991 have discussed the effect of [8- thiotheophyllinato] [triphenylphosphine] gold(I) on Friend leukemia cells. Agrawal et al Proc. Am. Assoc. Can. Res. 18, 28 1978 has reported antineoplastic activity against P388 leukemia in mice for 2-thiouracil, 6- mercaptopurine and thymidine derivatives of triphenylphosphine gold. The report identified the thymidine derivative as being the most active and the 2-thiouracil derivative as being inactive. The activity of the 6- mercaptopurine derivative is not specifically mentioned. Stocco et al Inorg. Chim. Acta 209 129-135 1993 has reported potential anti-tumor activity for a class of bifunctional compounds including dithiouracil, thiouguanine and dithioxanthine derivatives of trialkylphosphine and triarylphosphine. The reported compounds differ from the present invention as they are all binuclear.
SUMMARY OF THE INVENTION
In one form of the invention although it need not be the only or indeed the broadest form there is proposed a pharmaceutical composition having anti-tumor activity which comprises an effective anti-tumor active ingredient, in unit dosage form, and a pharmaceutical carrier or diluent wherein the active ingredient comprises a compound containing the chromophore P-Au-S and of the general formula
R
I
R'— P— Au— S— Rx
I R" where R, R' and R" are alkyl or aryl and Rx is a heterocyclic compound and wherein Rx contains a C-N chromophore bonded to S to form an S-C- N chromophore. In a further form the invention resides in a pharmaceutical composition having anti-tumor activity which comprises an effective anti-tumor active ingredient, in unit dosage form, and a pharmaceutical carrier or diluent wherein the active ingredient comprises a compound containing the chromophore P-Au-S and of the general formula
R
I
R'— P— Au— S— R
I R" where R, R' and R" are alkyl or aryl and SRX is a thionucleobase containing the S-C-N chromophore where C-N is part of a six member ring. .
In a still further form the invention resides in a pharmaceutical composition having anti-tumor activity which comprises an effective anti- tumor active ingredient, in unit dosage form, and a pharmaceutical carrier or diluent wherein the active ingredient comprises a compound containing the chromophore P-Au-S and of the general formula
R
I
R — P— Au— S— Rx
I R" where R, R' and R" are Et, Ph or Cy and Rx is pyridine, pyrimidine, thiouracil, thioguanine, mercaptopurine or derivatives of these.
In a yet further form the invention can be said to reside in a method of inhibiting tumor cell growth in animals comprising the steps of administering to an animal afflicted with tumor cells a pharmaceutically acceptable tumor cell growth inhibiting amount of a compound of the general formula
R
I
R'— P— Au— S— Rx
I R" where R, R' and R" are alkyl or aryl and Rx is a heterocyclic compound and wherein Rx contains a C-N chromophore bonded to S to form an S-C- N chromophore. In preference the compound is administered with a pharmaceutically acceptable carrier or diluent.
In another form the invention resides in a pharmaceutical compound of the general formula
R
I
R'— P— Au— S— Rx
I R" where R, R' and R" are alkyl or aryl and Rx is a heterocyclic compound and wherein Rx contains a C-N chromophore bonded to S to form an S-C- N chromophore.
The invention should not be understood as being limited to the above list of possibilities for R, R1 and R". Other possibilities include p_-tol, m-tol, p»- tol, methyl, phenyl fluoride, tolyl fluoride etc.
BRIEF DESCRIPTION OF THE DRAWING
FIG 1 shows the molecular structure and crystallographic numbering scheme employed for the complex (6-n-propyl-2-thiouracilato) tricyclohexylphosphine gold (I).
DETAILED DESCRIPTION OF THE INVENTION
The triorganophosphine gold (I) compounds of this invention can be prepared by methods available to a person skilled in the art and following the procedures of Harker et al Inorg. Chim. Acta 181, 23 1991. R3PAUCI salts were prepared according to the procedures of Al-Saady etal. Inorg. Synth. 23, 191 1985. All starting materials are commercially available. Analytical grade reagents were used without further purification.
Generally, synthesis of the triorganophosphine gold (I) complexes involved the reaction of the phosphinegold(I) precursor with an appropriate quantity of thionucleobase in the presence of base (KOH) in ethanolic solution. After stirring the mixture for approximately 1 hour, the solution was allowed to stand until the solvent evaporated; the solid residue was recrystallized from acetone, ethanol or dichloromethane. Physical data for a number of compounds of the general formula R3PAuSRx is presented in Table 1. TABLE 1
Yield Melting
Complex Colour (%) Point (°C)
Et3PAu(2-pyS) pale 88.2 77-78 yellow
Cy3PAu(2-pyS) pale 69.8 162-163 green
Ph3PAu(2-pyS) yellow 96.3 193-194
Et3PAu(2-pymS) oily 60.0 - green
Cy3PAu(2-pymS) pale 68.5 174-175 brown
Ph3PAu(2-pymS) pale 86.4 196-197 yellow
Et3PAu(5-carboxy-2-TU) pale 59.1 103-104 yellow
Cy3PAu(5<arboxy-2-TU) white 80.4 198-199
Ph3PAu(5-carboxy-2-TU) white 83.5 136-137
Et3PAu(6-Me-2-TU) white 75.0 193-194
Cy3PAu(6-Me-2-TU) white 70.7 185-186
Ph3PAu(6-Me-2-TU) pale 76.7 239-240 yellow
Et3PAu(6-n-propyl-2-TU) white 99.4 139-141
Cy3PAu(6-n-propyl-2-TU) white 86.6 195-196
Ph3PAu(6-n-propyl-2-TU) white 63.1 215-216
Et3PAu(2-NH2-6-MP) pale 58.7 241-242 green
Cy3PAu(2-NH2-6-MP) pale 81.8 170-171 yellow
Ph3PAu(2-NH2-6-MP) white 59.2 238-239
Et3PAu(6-MP) pale 99.2 102-103 yellow
Cy3PAu(6-MP) pale 93.2 139-140 yellow
Ph3PAu(6-MP) pale 93.7 254-255 yellow The crystal structure of (6-n-propyl-2-thiouracilato) tricyclohexylphosphine gold (I) has been determined at room temperature and is depicted in FIG 1. The crystals are monoclinic, space group P2ι/c with unit cell dimensions a=9.539(2), b=16.452(4), c=16.880(2) A, β=95.37(2)°, Z=4 and Dχ=1.628 Mg m"3. The structure was solved by direct-methods and refined by a full- matrix least-squares procedure based on F using the teXsan structure analysis package from Molecular Structure Corporation to final R=0.043 using 3695 reflections. The Au atom is linearly coordinated with the P and S atoms at an angle of 177.6(1)°.
The structure shown in FIG 1 and described above is representative of the compounds of the present invention.
Screening for anti-tumor activity was performed by examining the response to the complexes of L1210 mouse leukemia cells grown as suspension cultures in Eagle's Minimum Essential Medium plus 1% glutamine and 10% fetal calf serum. The compounds were dissolved in DMSO at 10 concentrations over a 3-log range, with a final maximum DMSO concentration in the medium of 0.5%. Growth inhibition was tested by incubation of log-phase cells at 37"C in a humidified incubator gassed with 10% Cθ2/90% air for 48 h in the presence of the compound. Cells were then counted using a Coulter counter, and the ID50 in μmol dm"3, or dose causing 50% inhibition of cell growth, was determined from the curve of percentage growth versus dose. Control culture exposed to only the vehicle were the reference for 100% growth in each test.
Some of the compounds were also tested against the human tumor lines FaDu (human squamous carcinoma of the pharynx) and SKOV-3 (human ovarian carcinoma). The FaDu human squamous carcinoma cell line was maintained in RPMI 1640 plus 10% fetal calf serum. The SKOV-3 human ovarian carcinoma cell line was maintained in α-MEM plus 15% fetal calf serum. For the growth inhibition studies, 5xl03 exponentially growing SKOV-3 cells or lxlO exponentially growing FaDu cells in lOOμl medium were allowed to adhere in 96-well culture plates for 12 to 16 hours at 37°C in a humidified incubator gassed with 5% Cθ2/95% air. Compounds were dissolved in DMSO and diluted in medium to 10 concentrations over a 4- log range, and lOOμl of each compound solution was added to 5 wells, at a maximum final DMSO concentration of 0.5%. Controls included 5 replicates of 0.5% DMSO, as well as 0.9% NaCl blanks. Cells were incubated with the compounds for a further 72 hours, after which viable cells in each well were measured using the sulforhodamine B (SRB) assay method that measures cellular protein content. Briefly, cells were fixed with trichloracetic acid and stained with SRB. Unbound dye was removed by washing with acetic acid, protein-bound dye was solubilized with Tris base, and the optical density was read at 550 nm using an automated plate reader. The percentage growth and the IC50 were calculated graphically, as previously.
TABLE 2
Complex Toxicity Anti-Tumor Potency L1210 FaDu SKOV-3 cisplatin 4+ 0.6 6.1 3.0 carboplatin 3+ 12
2-TU 3+ >100
6-MPH + 0.310 ± 0.133 >5 >100
6-TG 4+ 0.096 ± 0.022 >2 >20
Ph3PAuCl 0.40 0.10
Et3PAu(2-TU) 0.086 ± 0.082
Cy3PAu(2-TU) 2+ 0.115 ± 0.020
Ph3PAu(2-TU) 0.131 ± 0.072
Et3PAu(6-TG) + 0.041 ± 0.013
Cy3PAu(6-TG) + 0.084 ± 0.030
Ph3PAu(6-TG) 2+ 0.052 ± 0.017 0.39 ± 0.38 0.24
Et3PAu(6-MP) . 0.094 ± 0.051
Cy3PAu(6-MP) + . 0.079 ± 0.028
Ph3PAu(6-MP) + 0.083 ± 0.048 0.25 ± 0.28 0.135
The results of growth inhibition testing of the phosphinegold(I) thionucleobase complexes are summarised in Table 2. The activity of the free thionucleobases is included for comparison. The only metal- containing anticancer drugs in common use are cisplatin and carboplatin, their IDso's are also included for comparison. The results listed in Table 2 are reported as the mean ± standard deviation and in most cases are the average of at least three assays.
Table 2 also includes a toxicity score. Toxicity was determined from tests on Dark Agouti rats and is defined as causing greater weight loss (>10 g/15 days) than untreated controls at a dose of 10 mg Au/Kg.
In vivo testing of some of the compounds in female Balb/c mice has also been conducted. The results of the in vivo testing are summarised in Table 3. Compounds were dissolved in DMSO and injected intraperitoneally at 2.5 ml/kg. MTD (maximum tolerated dose) indicates the dose where no death occurs and maximum weight loss is less than 20 %. For anti-tumor studies, ADJ/PC6 plasmacytoma cells were used. The tumor grows as a subcutaneous mass following passage of pieces measuring 1 mm3 into the flank. On day 21 after inoculation of the tumor, a single intraperitoneal MTD dose of the compound is given. Controls receive the vehicle (DMSO). The positive (known active) control was cisplatin in saline. Ten days later, the animals are sacrificed and the tumor is dissected and weighed. The mean weight of the treated group is compared to the vehicle control group.
TABLE 3
Figure imgf000010_0001
It will be appreciated that the preferred dosages of the compounds used in the compositions of the present invention will vary according to the particular complex being used, the particular composition formulated, the mode of administration and the particular site, host and tumor being treated. Optimal dosages for a given set of conditions can be determined by those skilled in the art using conventional dosage determination tests in the light of the experimental data disclosed herein.
Furthermore, it will be evident to those skilled in the art that the compounds will generally be administered with an inert pharmaceutical carrier or diluent. The carrier can be selected from a range of commercially available carriers having minimal or benign toxicity. The pharmaceutical suitability of a particular carrier or diluent can be determined by conventional techniques known to those skilled in the art.
Preferred carriers include :
(i) dispersions in dermo-compatible non-aqueous solvent systems, e.g. dmso.glycerol (4:1 v/v) or ethanol:propan-l,2-diol (2:1 v/v), for dermal applications of those complexes found to be effective by transcutaneous delivery.
(ii) as dispersions in saline emulsifier solutions, e.g. with 0.02% Tween-
20 in 0.15 M sodium chloride, for subcutaneous or intramuscular administration.
(iii) as dispersions in aqueous emulsifiers for oral administration of those complexes found to be orally effective.
Other specific carriers may include hydroxypropylcellulose (Klucel), carboxymethylcellulose (CMC) or 50% polyethyleneglycol (PEG) 400 in distlled water. One or more of the compounds may be suitable for suspension by sonification in arachis oil.
The gold complexes of the present invention show a greater activity and reduced toxicity compared to the existing anti-tumor drugs in all cases.
The following examples illustrate the preparation of compounds of the present invention and as such are not to be construed as limiting the scope thereof. All temperatures are in degrees Celsius. EXAMPLE la : Preparation of [Et3PAu(2-pyS)].
Figure imgf000012_0001
To a stirred ethanolic solution (ca 30 cm3) of [Et3PAuCl] (0.200 g, 0.571 mmol) and 2-mercaptopyridine (0.063 g, 0.571 mmol) aqueous potassium hydroxide (0.200 mol dm"3, 0.571 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from a small quantity of 1:1 ethanol / dichloromethane to give a pale yellow microcrystalline product. Yield = 0.214 g; % yield = 88.2%; m.p. (dec.) = 77 - 78° C.
EXAMPLE lb : Preparation of [Cycl3PAu(2-pyS)].
To a stirred ethanolic solution (ca 30 cm3) of [CycbPAuCl] (0.200 g, 0.390 mmol) and 2-mercaptopyridine (0.043 g, 0.390 mmol) aqueous potassium hydroxide (0.200 mol dm"3, 0.390 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from a small quantity of 1:1 ethanol / dichloromethane to give a pale green microcrystalline product. Yield = 0.160 g; % yield = 69.8%; m.p. (dec.) = 162 - 163° C. EXAMPLE lc : Preparation of [Ph3PAu(2-pyS)].
To a stirred ethanolic solution (ca 30 cm3) of [PI13PAUCI] (0.200 g, 0.405 mmol) and 2-mercaptopyridine (0.045 g, 0.405 mmol) aqueous potassium hydroxide (0.200 mol dm"3, 0.405 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from a small quantity of 1:1 ethanol / dichloromethane to give a yellow microcrystalline product. Yield = 0.222 g; % yield = 96.3%; m.p. (dec.) = 193 - 194° C.
EXAMPLE 2a : Preparation of [Et3PAu(2-pymS)].
Figure imgf000013_0001
To a stirred ethanolic solution (ca 30 cm3) of [Et3PAuCl] (0.200 g, 0.571 mmol) and 2-mercaptopyrimidine (0.064 g, 0.571 mmol) aqueous potassium hydroxide (0.200 mol dm"3, 0.571 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from a small quantity of 1:1 ethanol / dichloromethane to give a green oily product. Yield = 0.146 g; % yield = 60.0%. EXAMPLE 2b : Preparation of [Cycl3PAu(2-pymS)].
To a stirred ethanolic solution (ca 30 cm3) of [CycbPAuCl] (0.200 g, 0.390 mmol) and 2-mercaptopyrimidine (0.044 g, 0.390 mmol) aqueous potassium hydroxide (0.200 mol dm"3, 0.390 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from a small quantity of 1:1 ethanol / dichloromethane to give a pale brown microcrystalline product. Yield = 0.157 g; % yield = 68.5%; m.p. (dec.) = 174 - 175° C.
EXAMPLE 2c : Preparation of [Ph3PAu(2-pymS)].
To a stirred ethanolic solution (ca 30 cm3) of [PhaPAuCl] (0.200 g, 0.405 mmol) and 2-mercaptopyrimidine (0.045 g, 0.405 mmol) aqueous potassium hydroxide (0.200 mol dm"3, 0.405 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from a small quantity of 1:1 ethanol / dichloromethane to give a pale yellow microcrystalline product. Yield = 0.199 g; % yield = 86.4%; m.p. (dec.) = 196 - 197° C.
EXAMPLE 3a : Preparation of [Et3PAu(2-TU)].
Figure imgf000014_0001
To a stirred ethanolic solution (ca 30 cm3) of [Et3PAuCl] (0.200 g, 0.571 mmol) and 2-thiouracil (0.073 g, 0.571 mmol) aqueous potassium hydroxide (0.200 mol dm"3, 0.571 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from a small quantity of 1:1 ethanol / dichloromethane to give a white microcrystalline product. Yield = 0.224 g; % yield = 88.8%; m.p. (dec.) = 129 - 130° C.
EXAMPLE 3b : Preparation of [Cy3PAu(2-TU)].
To a stirred ethanolic solution (ca 30 cm3) of [Cycl3PAuCl] (0.200 g, 0.390 mmol) and 2-thiouracil (0.050 g, 0.390 mmol) aqueous potassium hydroxide (0.200 mol dm"3, 0.390 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from a small quantity of 1:1 ethanol / dichloromethane to give a white microcrystalline product. Yield = 0.217 g; % yield = 92.1%; m.p. (dec.) = 205 - 206° C.
EXAMPLE 3c : Preparation of [Ph3PAu(2-TU)].
To a stirred ethanolic solution (ca 30 cm3) of [Pfi3PAuCl] (0.200 g, 0.405 mmol) and 2-thiouracil (0.051 g, 0.405 mmol) aqueous potassium hydroxide (0.200 mol dm"3, 0.405 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from a small, quantity of 1:1 ethanol / dichloromethane to give a pale brown microcrystalline product. Yield = 0.182 g; % yield = 76.9%; m.p. (dec.) = 196 197° C.
EXAMPLE 4a : Preparation of [Et3PAu(5-carboxy-2-TU)].
Figure imgf000016_0001
To a stirred ethanolic solution (ca 30 cm3) of [Et3PAuCl] (0.200 g, 0.571 mmol) and 5-carboxy-2-thiouracil (0.098 g, 0.571 mmol) aqueous potassium hydroxide (0.200 mol dm"3, 0.571 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from a small quantity of 1:1 ethanol / dichloromethane to give a pale yellow microcrystalline product. Yield = 0.164 g; % yield = 59.1%; m.p. (dec.) = 103 - 104° C.
EXAMPLE 4b : Preparation of [Cycl3PAu(5-carboxy-2-TU)].
To a stirred ethanolic solution (ca 30 cm3) of [CyckPAuCl] (0.200 g, 0.390 mmol) and 5-carboxy-2-thiouracil (0.067 g, 0.390 mmol) aqueous potassium hydroxide (0.200 mol dm"3, 0.390 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from a small quantity of 1:1 ethanol / dichloromethane to give a white microcrystalline product. Yield = 0.203 g; % yield = 80.4%; m.p. (dec.) = 198 - 199° C.
EXAMPLE 4c : Preparation of [Ph3PAu(5-carboxy-2-TU)].
To a stirred ethanolic solution (ca 30 cm3) of [PI13PAUCI] (0.200 g, 0.405 mmol) and 5-carboxy-2-thiouracil (0.070 g, 0.405 mmol) aqueous potassium hydroxide (0.200 mol dm"3, 0.405 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from a small quantity of 1:1 ethanol / dichloromethane to give a white microcrystalline product. Yield = 0.213 g; % yield = 83.5%; m.p. (dec.) = 136 - 137° C.
EXAMPLE 5a : Preparation of [Et3PAu(6-Me-2-TU)].
Figure imgf000017_0001
To a stirred ethanolic solution (ca 30 cm3) of [Et3PAuCl] (0.200 g, 0.571 mmol) and 6-methyl-2-thiouracil (0.081 g, 0.571 mmol) aqueous potassium hydroxide (0.200 mol dm"3, 0.571 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from a small quantity of 1:1 ethanol / dichloromethane to give a white microcrystalline product. Yield = 0.195 g; % yield = 75.0%; m.p. (dec.) = 193 - 194° C. EXAMPLE 5b : Preparation of [Cyd3PAu(6-Me-2-TU)].
To a stirred ethanolic solution (ca 30 cm3) of [CycbPAuCl] (0.200 g, 0.390 mmol) and 6-methyl-2-thiouracil (0.055 g, 0.390 mmol) aqueous potassium hydroxide (0.200 mol dm"3, 0.390 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from a small quantity of 1:1 ethanol / dichloromethane to give a white microcrystalline product. Yield = 0.171 g; % yield = 70.7%; m.p. (dec.) = (185 - 186)° C.
EXAMPLE 5c : Preparation of [Ph3PAu(6-Me-2-TU)].
To a stirred ethanolic solution (ca 30 cm3) of [PI13PAUCI] (0.200 g, 0.405 mmol) and 6-methyl-2-thiouracil (0.058 g, 0.405 mmol) aqueous potassium hydroxide (0.200 mol dm"3, 0.405 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from a small quantity of 1:1 ethanol / dichloromethane to give a pale yellow microcrystalline product. Yield = 0.186 g; % yield = 76.7%; m.p. (dec.) = 239 - 240° C.
EXAMPLE 6a : Preparation of [Et3PAu(6-n-propyl-2-TU)].
Figure imgf000018_0001
To a stirred ethanolic solution (ca 30 cm3) of [Et3PAuCl] (0.200 g, 0.571 mmol) and 6-n-propyl-2-thiouracil (0.097 g, 0.571 mmol) aqueous potassium hydroxide (0.200 mol dm"3, 0.571 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from -a small quantity of 1:1 ethanol / dichloromethane to give a white microcrystalline product. Yield = 0.275 g; % yield = 99.4%; m.p. (dec.) = 139 - 141° C.
EXAMPLE 6b : Preparation of [Cycl3PAu(6-n-propyl-2-TU)].
To a stirred ethanolic solution (ca 30 cm3) of [Cyc PAuCl] (0.200 g, 0.390 mmol) and 6-n-propyl-2-thiouracil (0.066 g, 0.390 mmol) aqueous potassium hydroxide (0.200 mol dm"3, 0.390 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from "a small quantity of 1:1 ethanol / dichloromethane to give a white microcrystalline product. Yield = 0.218 g; % yield = 86.6%; m.p. (dec.) = 195 - 196° C.
EXAMPLE 6c : Preparation of [Ph3PAu(6-n-propyl-2-TU)].
To a stirred ethanolic solution (ca 30 cm3) of [PhsPAuCl] (0.200 g, 0.405 mmol) and 6-n-propyl-2-thiouracil (0.069 g, 0.405 mmol) aqueous potassium hydroxide (0.200 mol dm"3, 0.405 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from a small quantity of 1:1 ethanol / dichloromethane to give a white microcrystalline product. Yield = 0.160 g; % yield = 63.1%; m.p. (dec.) = 215 - 216° C.
EXAMPLE 7a : Preparation of [Et3PAu(6-TG)].
Figure imgf000020_0001
To a stirred ethanolic solution (ca 30 cm3) of [Et3PAuCl] (0.200 g, 0.571 mmol) and 2-amino-6-mercaptopurine (0.095 g, 0.571 mmol) aqueous potassium hydroxide (0.200 mol dm"3, 0.571 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from a small quantity of 1:1 ethanol / dichloromethane to give a pale green microcrystalline product. Yield = 0.161 g; % yield = 58.7%; m.p. (dec.) = 241 - 242° C.
EXAMPLE 7b : Preparation of [Cycl3PAu(6-TG)].
To a stirred ethanolic solution (ca 30 cm3) of [CycbPAuCl] (0.200 g, 0.390 mmol) and 2-amino-6-mercaptopurine (0.065 g, 0.390 mmol) aqueous potassium hydroxide (0.200 mol dm"3, 0.390 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from a small quantity of 1:1 ethanol / dichloromethane to give a pale yellow microcrystalline product. Yield = 0.204 g; % yield = 81.8%; m.p. (dec.) = 170 - 171° C.
EXAMPLE 7c : Preparation of [Ph3PAu(6-TG)].
To a stirred ethanolic solution (ca 30 cm3) of [PI13PAUCI] (0.200 g, 0.405 mmol) and 2-amino-6-mercaptopurine (0.068 g, 0.405 mmol) aqueous potassium hydroxide (0.200 mol dm"3, 0.405 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from a small quantity of 1:1 ethanol / dichloromethane to give a white microcrystalline product. Yield = 0.150 g; % yield = 59.2%; m.p. (dec.) = 238 - 239° C.
EXAMPLE 8a : Preparation of [Et3PAu(6-MP)].
Figure imgf000021_0001
To a stirred ethanolic solution (ca 30 cm3) of [Et3PAuCl] (0.200 g, 0.571 mmol) and 6-mercaptopurine (0.091 g, 0.571 mmol) aqueous potassium hydroxide (0.200 mol dm-3, 0.571 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from a small quantity of 1:1 ethanol / dichloromethane to give a pale yellow microcrystalline product. Yield = 0.264 g; % yield = 99.2%; m.p. (dec.) = 102 - 103° C. EXAMPLE 8b : Preparation of [Cycl3PAu(6-MP)].
To a stirred ethanolic solution (ca 30 cm3) of [CycbPAuCl] (0.200 g, 0.390 mmol) and 6-mercaptopurine (0.059 g, 0.390 mmol) aqueous potassium hydroxide (0.200 mol dm"3, 0.390 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from a small quantity of 1:1 ethanol / dichloromethane to give a light yellow microcrystalline product. Yield = 0.228 g; % yield = 93.2%; m.p. (dec.) = 139 - 140° C.
EXAMPLE 8c : Preparation of [Ph3PAu(6-MP)].
To a stirred ethanolic solution (ca 30 cm3) of [PI 3PAUCI] (0.200 g, 0.405 mmol) and 6-mercaptopurine (0.062 g, 0.405 mmol) aqueous potassium hydroxide (0.200 mol dm"3, 0.405 mmol) was added dropwise over a few minutes. After 15 min of stirring, a pale yellow solid started to form in the clear solution. The solution was left to stir for a further 1 h, then left in a fumehood until the solvent evaporated. The solid residue was dissolved with stirring into boiling acetone (ca 100 cm3), then vacuum filtered to remove undissolved solids. The filtrate was left to stand until the acetone evaporated, and the off-white product was recrystallized twice from a small quantity of 1:1 ethanol / dichloromethane to give a pale yellow microcrystalline product. Yield = 0.231 g; % yield = 93.7%; m.p. (dec.) = 254 - 255° C.

Claims

1. A pharmaceutical composition having anti-tumor activity which comprises an effective anti-tumor active ingredient, in unit dosage form, and a pharmaceutical carrier or diluent wherein the active ingredient comprises a compound containing the chromophore P-Au-S and of the general formula
R
I
R'— P— Au— S— Rx
I R" where R, R' and R" are alkyl or aryl and Rx is a heterocyclic compound and wherein Rx contains a C-N chromophore bonded to S to form an S-C- N chromophore.
2. * A pharmaceutical composition having anti-tumor activity which comprises an effective anti-tumor active ingredient, in unit dosage form, and a pharmaceutical carrier or diluent wherein the active ingredient comprises a compound containing the chromophore P-Au-S and of the general formula
R
I
R'— P— Au— S— R
I R" where R, R' and R" are alkyl or aryl and SRx is a thionucleobase containing the S-C-N chromophore where C-N is part of a six member ring.
3. The pharmaceutical composition of claim 2 wherein R, R' and R" are chosen from Et, Ph, Cy, Q-tol, m-tol, p-tol, methyl, phenyl fluoride, tolyl fluoride.
4. The pharmaceutical composition of claim 2 wherein SRX is chosen from pyridine, pyrimidine, thiouracil, thioguanine, mercaptopurine or derivatives of these.
5. The pharmaceutical composition of claim 2 wherein R, R', and R" are the same and are Ethyl and SRX is pyridine.
6. The pharmaceutical composition of claim 2 wherein R, R', and R" are the same and are Phenyl and SRX is pyridine.
7. The pharmaceutical composition of claim 2 wherein R, R', and R" are the same and are Cyclohexyl and SRX is pyridine.
8. The pharmaceutical composition of claim 2 wherein R, R', and R" are the same and are Ethyl and SRX is pyrimidine.
9. The pharmaceutical composition of claim 2 wherein R, R', and R" are the same and are Phenyl and SRX is pyrimidine.
10. The pharmaceutical composition of claim 2 wherein R, R', and R" are the same and are Cyclohexyl and SRX is pyrimidine.
11. The pharmaceutical composition of claim 2 wherein R, R', and R" are the same and are Ethyl and SRX is thiouracil.
12. The pharmaceutical composition of claim 2 wherein R, R', and R" are the same and are Phenyl and SRX is thiouracil.
13. The pharmaceutical composition of claim 2 wherein R, R', and R" are the same and are Cyclohexyl and SRX is thiouracil.
14. • The pharmaceutical composition of claim 2 wherein R, R', and R" are the same and are Ethyl and SRX is thioguanine.
15. The pharmaceutical composition of claim 2 wherein R, R', and R" are the same and are Phenyl and SRX is thioguanine.
16. The pharmaceutical composition of claim 2 wherein R, R', and R" are the same and are Cyclohexyl and SRX is thioguanine.
17. The pharmaceutical composition of claim 2 wherein R, R', and R" are the same and are Ethyl and SRX is mercaptopurine.
18. The pharmaceutical composition of claim 2 wherein R, R', and R" are the same and are Phenyl and SRX is mercaptopurine.
19. The pharmaceutical composition of claim 2 wherein R, R', and R" are the same and are Cyclohexyl and SRX is mercaptopurine.
20. A method of inhibiting tumor cell growth in animals comprising the steps of administering to an animal afflicted with tumor cells a pharmaceutically acceptable tumor cell growth inhibiting amount of a compound of the general formula
R
I
R'— P— Au— S— Rx
I R" where R, R' and R" are alkyl or aryl and Rx is a heterocyclic compound and wherein Rx contains a C-N chromophore bonded to S to form an S-C- N chromophore.
21. A method of inhibiting tumor cell growth in animals comprising the steps of administering to an animal afflicted with tumor cells a pharmaceutically acceptable tumor cell growth inhibiting amount of a compound of the general formula
R
I
R'— P— Au— S— Rx
I R" where R, R' and R" are alkyl or aryl and SRx is a thionucleobase containing the S-C-N chromophore where C-N is part of a six member ring.
22. The method of claim 21 wherein the compound is administered with a pharmaceutically acceptable carrier or diluent.
23. The method of claim 21 wherein R, R' and R" are chosen from Et, Ph, Cy, p_-tol, m-tol, μ-tol, methyl, phenyl fluoride, tolyl fluoride.
24. The method of claim 21 wherein SRX is chosen from pyridine, pyrimidine, thiouracil, thioguanine, mercaptopurine or derivatives of these.
25. The method of claim 21 wherein R, R' and R" are chosen from Et, Ph, Cy, Q-tol, m-tol, £-tol, methyl, phenyl fluoride, tolyl fluoride, SRX is chosen from pyridine, pyrimidine, thiouracil, thioguanine, mercaptopurine or derivatives of these and the compound is administered with a pharmaceutically acceptable carrier or diluent.
26. A pharmaceutical compound of the general formula
R
I
R'— P— Au— S— Rx
I R" where R, R' and R" are alkyl or aryl and Rx is a heterocyclic compound and wherein Rx contains a C-N chromophore bonded to S to form an S-C- N chromophore.
27. A pharmaceutical compound of the general formula
R
I
R'— P— Au— S— Rx
I R" where R, R' and R" are alkyl or aryl and SRX is a thionucleobase containing the S-C-N chromophore where C-N is part of a six member ring.
28. The pharmaceutical compound of claim 27 wherein R, R' and R" are chosen from Et, Ph, Cy, Q-tol, m-tol, g-tol, methyl, phenyl fluoride, tolyl fluoride.
29. The pharmaceutical compound of claim 27 wherein SRX is chosen from pyridine, pyrimidine, thiouracil, thioguanine, mercaptopurine or derivatives of these.
30. The pharmaceutical compound of claim 27 wherein R, R', and R" are the same and are Ethyl and SRX is pyridine.
31. The pharmaceutical compound of claim 27 wherein R, R', and R" are the same and are Phenyl and SRX is pyridine.
32. The pharmaceutical compound of claim 27 wherein R, R', and R" are the same and are Cyclohexyl and SRX is pyridine.
33. The pharmaceutical compound of claim 27 wherein R, R', and R" are the same and are Ethyl and SRX is pyrimidine.
34. The pharmaceutical compound of claim 27 wherein R, R', and R" are the same and are Phenyl and SRX is pyrimidine.
35. The pharmaceutical compound of claim 27 wherein R, R', and R" are the same and are Cyclohexyl and SRX is pyrimidine.
36. * The pharmaceutical compound of claim 27 wherein R, R', and R" are the same and are Ethyl and SRX is thiouracil.
37. The pharmaceutical compound of claim 27 wherein R, R', and R" are the same and are Phenyl and SRX is thiouracil.
38. The pharmaceutical compound of claim 27 wherein R, R', and R" are the same and are Cyclohexyl and SRX is thiouracil.
39. The pharmaceutical compound of claim 27 wherein R, R', and R" are the same and are Ethyl and SRX is thioguanine .
40. The pharmaceutical compound of claim 27 wherein R, R', and R" are the same and are Phenyl and SRX is thioguanine.
41. The pharmaceutical compound of claim 27 wherein R, R', and R" are the same and are Cyclohexyl and SRX is thioguanine.
42. The pharmaceutical compound of claim 27 wherein R, R', and R" are the same and are Ethyl and SRX is mercaptopurine.
43. The pharmaceutical compound of claim 27 wherein R, R', and R" are the same and are Phenyl and SRX is mercaptopurine.
44. The pharmaceutical compound of claim 27 wherein R, R', and R" are the same and are Cyclohexyl and SRX is mercaptopurine.
PCT/AU1994/000725 1993-11-24 1994-11-23 Triorganophosphinegold (i) thionucleobases with anti-tumor activity WO1995014703A1 (en)

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Publication number Priority date Publication date Assignee Title
CN106459116A (en) * 2014-05-28 2017-02-22 奥斯弗伦里克斯有限公司 Gold (I)-phosphine compounds as anti-bacterial agents
CN106573944A (en) * 2014-05-28 2017-04-19 奥斯弗伦里克斯有限公司 Gold (I)-phosphine compounds as anti-bacterial agents
JP2017519817A (en) * 2014-05-28 2017-07-20 オースフェリクス・リミテッドＡｕｓｐｈｅｒｉｘ Ｌｉｍｉｔｅｄ Gold (I) -phosphine compounds as antibacterial agents

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