Novel organo-tin compounds having anti-tumour activity and anti-tumour compositions

Abstract: The invention relates to anti-tumour compositions containing as an active ingredient one or more compounds of the formula Ar₃Sn-O-C(O)-C₆H₂XYZ wherein X and Y are each H, OH, halogen or alkyl; and Z is halogen, amino, alkoxy, acyloxy, sulphonic acid or alkyl. A number of these compounds are novel compounds.

Description: This invention relates to novel organo-tin compounds have anti-tumour activity and to anti-tumour compositions or to a process for preparing these compositions. In addition to platinum compounds, such as cis-platin, cis-(NH₃)₂Cl₂Pt, also organo-tin compounds are known anti-tumour drugs. An article by W.D. Honnick and J.J. Zuckermann, Inorg. Chem. 18 , 1979, 1437-1443, "The Synthetis of Tin (IV)-Oxygen and Sulfur Heterocycles and their transformation to Tin (II) Analogues" describes a number of diorgano-tin compounds have anti-tumour activities, for instance (A di-organo-tin compound is defined herein as a tin compound wherein two organic groups are bound directly to a Sn atom via carbon atoms). In an article by V.L. Narayanan in "Structure-Activity Relationships of Anti-Tumour Agents", ed. D.N. Reinhoudt, T.A. Connors, H.M. Pinedo and K.W. van de Poll, Martinus Nijhoff, 1983, p. 16-33, it is reported that of 129 di-organo-tin compounds tested against P388 leukemia, 48% were fond active, whereas of 132 tri-organo-tin compounds only 9% were found active. The present invention provides anti-tumour compositions, containing as an active ingredient one or more compounds of the formula: Ar₃Sn-O-C(O)-C₆H₂XYZ wherein Ar is substituted or unsubstituted phenyl; X and Y are each H, OH, halogen or alkyl; and Z is halogen, amino, alkyl, acyloxy, sulphonic acid or alkyl. Molloy et al, J.Chem.Soc. Dalton Trans. (1988), 1259-1266, disclose compounds of the formula (C₆H₅)₃ Sn OC(O)C₆ H 5-n X n wherein X = 2-NH₂, 2-CH₃, 2-OCH₃, 2-F, -3F, -4F, 2-Cl, 3-Cl, 4-Cl, 2-Br, 2-I (n=1) and 2,5-Cl₂, 3,4-Cl₂, 3,5-Cl₂, 2,4-Cl₂ (n=2). This article does not mention any pharmacological activity for these and related compounds. EP-A-119419 discloses the compound (C₆H₅)₃Sn-O-C(O)-C₆H₅OCOCH₃ wherein the acetyl group is at the 2-position as a biocidal compound; a pharmacological activity is not mentioned. US-A-4 043 949 concerns the use of triphenyltin-3-amino-2,5-dichlorobenzoate and other organotin-compounds as catalysts for the preparation of polyurethane foams. Preferably, the alkyl group is isopropyl. The present compounds can be prepared by reacting triphenyltin hydroxide with XYZC₆H₂COOH at elevated temperature. Preparation In all preparations, 2 g (5.4 mmol) of triphenyltin hydroxide was added to a solution of 5.4 mmol XYZC₆H₂COOH in a mixture of 150 ml of toluene and 50 ml of ethanol. This mixture is heated at reflux for 6 hours; first the ternary azeotrope water/toluene/ethanol is distilled off using a Dean-Stark funnel, followed by half of the remaining solvent. The obtained solution is evaporated under vacuum. An oily compound is obtained; this material is crystallized from ethanol or from CH₂Cl₂/petroleum ether. The follows compounds were prepared: Triphenyltin ortho-methoxybenzoate, compound 1 recrystallized from ethanol; m.p.: 102-103°C; yield: 68%; Rf on Polygram® SIL G/UV₂₅₄ TLC plates from Macherey-Nagel+CO, elution with cyclohexane/dioxane 1/1:0.80; Mössbauer parameters (in mm/s: quadrupole splitting QS:2.33, isomer shift IS: 1.22, band widths Γ₁ & Γ₂: 0.92 & 0.90; ¹H NMR (CDCl₃) parameters (proton number: multiplicity, chemical shift in ppm [coupling constants in Hz]: H-3: d, 6.94 [8]; H-4: dd, 6.95 [7, 7]; H-5: hidden under the sighals of meta and para protons; H-6: dd, 7.98 [8, 2]; ortho-H: m: 7.78 - 7.82; meta- & para-H: m: 7.39 - 7.46; CH₃O: s, 3.88. Triphenyltin para-fluorbenzoate, compound 2 recrystallized from ethanol; m.p.: 86-87°C; yield: 24%; Rf on Polygram® SIL G/UV₂₅₄ TLC plates, elution with petroleum ether/acetic acid 6/1:0.51; Mössbauer parameters (in mm/s): QS:2.54, IS: 1.27, Γ₁ & Γ₂: 0.85 & 0.86; ¹H NMR (CDCl₃) parameters: H-2 & H-6: dd, 8.14 [9, 6]; H-3 & H-5: dd, 7.05 [9, 9]; ortho-H: m: 7.76-7.81; meta- & para-H: m:7.45-7.51. Triphenyltin 3,5-difluorobenzoate, compound 3 recrystallized from ethanol; m.p.: 121-122°C; yield: 30%; Rf on Polygram R SIL G/UV₂₅₄ TLC plates, elution with cyclohexane/dioxane 1/1:0.53; Mössbauer parameters (in mm/s): QS:2.61, IS: 1.26, Γ₁ & Γ₂: 0.90 & 0.89; ¹H NMR (CDCl₃) parameters: H-2 & H-6: dd, 7.62 [8, 2] ; The present invention also provides novel compounds of the formula Ar₃Sn-O-C(O)-C₆H₂YXZ wherein Ar is defined in claim 1; X and Y are each H, OH, halogen or alkyl; and Z is halogen, amino, alkoxy, acyloxy, sulphonic acid or alkyl; with the proviso that: a) when Z is alkoxy; acyloxy; alkyl, X and Y are not both H b) when Z is amino, X and Y are not both H or chloro and c) when Z is halogen and one of X and Y is H or halogen, the other one of X and Y is not H. H-4: tt, 6.94 [9, 2]; ortho-H: m: 7.76 - 7.82; meta- & para-H: m: 7.45-7.51. Triphenyl acetylsalicylate, compound 4 recrystallized from CH₂Cl₂/petroleum ether; m.p.: 110-111°C; yield: 85%; Rf on Polygram® SIL G/UV₂₅₄ TLC plates, elution with cyclohexane/dioxane 1/1: 0.85; Mössbauer parameters (in mm/s): QS: 2.54, IS: 1.27, Γ₁ & Γ₂: 0.86 & 0.89; ¹H NMR (CDCl₃) parameters: CH₃:s: 2.04; H-3: dd: 7.04 [8, 1]; H-4: ddd: 7.23 [8, 8, 1]; H-6: dd: 8.11 [8,2]; ortho-H: m: 7.64-7.90 [³J(Sn-H)=60]; H-5, meta- & para-H: m:7.35-7.50. Triphenyltin 5-chlorosalicylate, compound 5 recrystallized from CH₂Cl₂/petroleum ether; m.p.: 122-123°C; yield: 75%; Rf on Polygram® SIL G/UV₂₅₄ TLC plates, elution with cyclohexane/dioxane 1/1: 0.76; Mössbauer parameters (in mm/s): QS: 2.79, IS: 1.32, Γ₁ & Γ₂: 0.90 & 0.89, ¹H NMR (CDCl₃) parameters: H-3: d: 6.88 [9]; H-6: d: 7.94 [2]; ortho-H: m: 7.65-7.90 [³J(Sn-H) = 64]; H-4 meta- & para-H: m: 7.45-7.53; OH: bs: 11.06. Triphenyltin 5-aminosalicylate, compound 6 recrystallized from CH₂Cl₂/petroleum ether; m.p.: 145-146°C; yield: 78%; Rf on Polygram® SIL G/UV₂₅₄ TLC plates, elution with cyclohexane/dioxane 1/1: 0.73; Mössbauer parameters (in mm/s): QS: 3.10, IS: 1.30, Γ¹ & Γ₂: 0.90 & 0.89; ¹H NMR (CDCl₃) parameters H-3 & H-4: AB part of an ABX system with √ A =6.75, √ B 6.79, J AB =9, J AX =nv and J BX =2; H-6: d:7.292 [2]; ortho-H:m:7.64 - 7.90 [³J(Sn-H)=54];meta- & para-H: m:7.40 -7.50; NH₂: m: 2.71-3.42; ¹³C NMR (CDCl₃): ipso-C: 137.7 [¹J(Sn-C)=630]; ortho-C: 136.7 [²J(Sn-C)=47]; meta- C: 128.9 [³J(Sn-C)=64]; para-C: 130.3; C-1: 113.1;C-2: 154.8; C-3: 116.5; C-4: 124.0; C-5: 137.9; C-6: 117.6; CO: 174.8; ¹¹⁹Sn NMR (CDCl₃): -116.1. Triphenyltin 5-methoxysalicylate, compound 7 recrystallized from CH₂Cl₂/petroleum ether; m.p.: 137-138°C; yield: 72% Rf on Polygram® SIL G/UV₂₅₄ TLC plates, elution with cyclohexane/dioxane 1/1:0.97; Mössbauer parameters (in mm/s): QS: 2.75, IS: 1.28 Γ₁ & Γ₂: 0.91 & 0.90; ¹H NMR (CDCl₃) parameters: CH₃O: s: 3.74; H-3: d: 6.864 [9]; H-4: dd: 7.024 [9.3]; ortho-H: m: 7.65-7.91 [³J(Sn-H) s 63]; H-6, meta- & para-H: m: 7.42-7.53; OH: bs: 4.5; ¹³C NMR (CDCl₃): CH₃O: 55.8; ipso-C: 137.9 [¹J(Sn-C) = 632]; ortho-C: 136.7 [²J(Sn-C) = 47]; meta-C: 128.9 [³J(Sn-C) = 62]; para-C: 130.3; C-1: 114.0; C-2: 156.0; C-3: 118.0; C-4: 123.5; C-5: 151.8; C-6: 113.1; CO: 174.7; ¹¹⁹Sn NMR (CDCl₃): -97.6 Triphenyltin 5-hydroxysulfonylsalicylate, compound 8 recrystallized from ethanol; m.p.: >350°C; yield: 76%; Rf on Polygram® SIL G/UV₂₅₄ TLC plates, elution with ethanol: 0.88; ¹H NMR (DMSO-d₆) parameters: H-3: d: 6.818 (8); H-6: d: 8.105 [2]; ortho-H: d: 7.771 (7) [³J(Sn-H) = 106]; H-4, meta- & para-H: m: 7.34-7.46; OH: bs: 11.6, SO₃H: 3.39 - 3.47; ¹³C NMR (DMSO-d₆): ipso-C: 144.6; ortho-C: 139.5; meta-C: 133.6; para-C: 134.3; C-1: 118.3; C-2: 165.8; C-3: 121.2; C-4: 137.5; C-5: 152.9; C-6: 132.7; CO: 179.3; ¹¹⁹Sn NMR (DMSO-d₆): -276.7 Triphenyltin 3,5-di-isopropylsalicylate, compound 9 recrystallized from ethanol; m.p.: 150-151°C; yield: 90%; Rf on Polygram® SIL G/UV₂₅₄ TLC plates, elution with cyclohexane/dioxane 1/1: 0.78; m.p. > 350°C; yield 76%; Rf on Polygram R SIL G/UV₂₅₄ TLC plates, elution with ethanol: 0.88; Mössbauer parameters (in mm/s): QS: 2.56, IS: 1.28, Γ₁ & Γ₂: 0.86 & 0.92; ¹H NMR (CDCl₃) parameters: 3-i-Pr: CH: sept: 3.344 [7]; CH₃: sept: 1.231 [7]; 5-i-Pr: CH: sept: 2.843 [7]; CH₃: sept: 1.220 [7]; H-4: d: 7.236 [2]; H-6; d: 7.715 [2]; ortho-H: m: 7.67 - 7.91 [³J(Sn-H) = 59]; meta- & para-H: m: 7.40 - 7.49; OH: bs: 11.3; ¹³C NMR (CDCl₃): 3-i-Pr; CH₃: 24.1; CH: 33.4; 5-i-Pr: CH₃: 22.4; CH: 26.9; ipso-C: 137.9 [¹J( 119/117 Sn-¹³C) = 648/618]; ortho-C: 138.0 [²J(Sn-C) = 48]; meta-C: 128.9 [³J(Sn-C) = 64]; para-C: 130.3 [⁴J(Sn-C) = 13]; C-1: 112.1; C-2: 157.4; C-3: 136.2; C-4: 130.6; C-5: 138.6; C-6: 125.9; CO: 175.7; ¹¹⁹Sn NMR (CDCl₃): -101.4 The above compounds were tested in vitro against the following human tumour cell lines: MCF-7 mammary carcinoma (M cells) WiDr colon tumour cells (W cells) The tests were carried out according to the method of R. van Lambalgen and P. Lelieveld, the PIT method: an automated in vitro technique for drug toxicity testing. Invest. New Drug 5 , 161-165 (1987). The ID₅₀ values in ng/ml for the above nine compounds and for two known compound (compounds 9 and 10) were determined according to the above-mentioned procedure. The ID₅₀ value is the amount which inhibits 50% of the cell growth. The results are shown in the following Table. (C₆H₅)₃Sn-O-C(O)-C₆H₂XYZ From the above results it can be seen that the present tri-organo-tin compounds exhibit excellent ID₅₀ values which are considerably higher than the ID₅₀ values of the known compounds which were tested for comparative purposes.

Claims: Claims for the following Contracting States : DE, GB, FR, IT, NL, SE, CH, LI, BE, AT, LU, DK Anti-tumour compositions, containing as an active ingredient one or more compounds of the formula Ar₃Sn-O-C(O)-C₆H₂YXZ wherein Ar is a substituted or unsubstituted phenyl group; X and Y are each H, OH, halogen or alkyl; and Z is halogen, amino, alkoxy, acyloxy, sulphonic acid or alkyl. Compounds of the formula Ar₃Sn-O-C(O)-C₆H₂YXZ wherein Ar is defined in claim 1; X and Y are each H, OH, halogen or alkyl; and Z is halogen, amino, alkoxy, acyloxy, sulphonic acid or alkyl with the proviso that a) when Z is alkoxy, acyloxy or alkyl, X and Y are not both H; b) when Z is amino, X and Y are not both H or chloro; and c) when Z is halogen and one of X and Y is H or halogen, the other one of X and Y is not H. Claim for the following Contracting States : ES, GR A process for preparing anti-tumour compositions, characterized by combining as an active ingredient one ore more compounds of the formula Ar₃Sn-O-C(O)-C₆H₂XYZ wherein Ar is a substituted or unsubstituted phenyl group; X and Y are each H, OH, halogen or alkyl; and Z is halogen, amino, alkoxy, acyloxy, sulphonic acid or alkyl; with a carrier or diluent for said active ingredient.

Inventors: BOUAELAM MOHAMMAD, EL KHLOUFI ABDELAZIZ, GIELEN MARCEL, VOS DIRK DE, WILLEM RUDOLPH, BOUAELAM, MOHAMMAD, VRIJE UNIVERSITEIT BRUSSEL, DE VOS, DIRK, EL KHLOUFI, ABDELAZIZ, VRIJE UNIVERSITEIT BRUSSEL, GIELEN, MARCEL, WILLEM, RUDOLPH, Bouälam, Mohammad, Vrije Universiteit Brussel
Applicants: PHARMACHEMIE BV, PHARMACHEMIE B.V.
Application year: 1991
Main classification: C07F7
IPC codes: C07F7, A61P35, A61K31