TIN POLYOXAALKANECARBOXYLATES AND COMPOSITIONS CONTAINING THEM

Abstract: The invention relates to tin polyoxaalkanecarboxylates having the formula [(R<1>pR<2>qSn)rOs]t wherein R<1> represents C1-C6 alkyl, branched or straight, substituted or not by one or more hydroxyl groups or halogen atoms, or a phenyl group, substituted or not by one or more hydroxyl groups or halogen atoms, R<2> is a carboxylic residue selected from (I), (II), (III) or (IV); and p, q, r, s and t have the following meanings: p = 3, q = 1, r = 1, s = 0 and t = 1, p = 2, q = 2, r = 1, s = 0, and t = 1, p = 2, q = 1, r = 2, s = 1 and t = 2, as well as to anti-tumour compositions, containing as an active ingredient one or more of said tin polyoxaalkanecarboxylates.

Description: OLYOXAALKANECARBOXYLATES AND COMPOSITIONS CONTAINING THEM The invention relates to novel tin polyoxaalkanecarboxylates and to anti-tumour compositions containing such compounds . The anti-tumour activity of tin compounds is known; it is also known that the anti-tumour activity of tin compounds could be enhanced by increasing their solubility in water. The invention now provides water-soluble tin compounds which show strong in vitro anti-tumour activities against a broad spectrum of tumours, as appears from the experimental part, disclosed hereinafter. More specifically the invention relates to tin polyoxaalkanecarboxylates having the formula wherein R 1 represents C^C j alkyl, branched or straight, substituted or not by one or more hydroxyl groups or halogen atoms, or a phenyl group, substituted or not by one or more hydroxyl groups or halogen atoms, R 2 is a carboxylic residue selected from: and p, q, r, s and t have the following meanings; p = 3 , -q = 1 , r = 1 , s = 0 and t = 1 ; p = 2, q = 2, r = 1 , s = 0 and t = 1 ; p = 2, q = 1, r = 2, s = 1 and t = 2. According to a preferred embodiment of the invention, represents R 1 a phenyl group or a n-butyl group in a compound having formula (1) , (2) or (3) . The compounds according to the invention can be synthesized by effecting a condensation reaction between a carboxylic acid having formula with triaryltin hydroxide , trialkyltin acetate or dialkyltin oxide , preferably triphenyltin hydroxide , tri -n-butyltin acetate or di-n-butyltin oxide , according to the following reaction schemes : a ) RCOOH + ( C 6 H 5 ) 3 SnOH > ( C 6 H 5 ) 3 SnOCOR + H 2 0 b) RCOOH + Bu 3 SnOCOCH 3 > Bu 2 SnOCOR + CH 3 COOH c ) 2RC00H + Bu 2 SnO > Bu 2 Sn (OCOR) 2 + H 2 0 d) 2RC00H + 2Bu 2 SnO > 1/2 { [Bu 2 (RCOO ) Sn] 2 θ } 2 + H 2 0 Different media and methods can be used to sytithesize such derivatives 1 ) the condensation can be performed in toluene/cthanol. The water formed during the condensation is eliminated by azeotropic distillation (Dean-Stark funnel) 2) benzene can be used instead of toluene/ethanol 3) these compounds can also be prepared by a two-step procedure, dibutyltin oxide being first condensed with n-propanol to yield tetrabutyldipropoxydistannoxane: 2 Bu 2 SnO + 2 PrOH (PrOSnBu 2 ) 2 0 + H 2 0 In a second step, the carboxylic acid is added at room temperature to this tetrabuiyldipropoxydistannoxane in the desired molar ratio. The compounds synthesized by one of these m^nods were characterized by elemental analysis, Η, 1 C and 1 , 7 Sn NMR, electrosp.ray mass spectro etry and , l 9 S n Mossbauer spectroscopy. Chromatography on Sephadex LH-20 proved to be a very efficient method to separate 3 (or 7) from 4 (or 8), or 11, 12, 15 and 16 from the starting carboxylic acid. The structures of the compounds synthesized are depicted below 11 Bu .o. . O. " O. , o ' o' o o * O Bu O 14 15 Generalities and abbreviations NMR spectra: CDC1 3 solutions; 'H and 13 C chemical shifts δ in ppm vs. TMS, homonuclear coupling constants in Hz, in parentheses; Mossbauer parameters (quadrupole splitting QS, isomers shift IS, and band widths T and T 2 ) in mrn/s; s: singlet; d: doublet; dd: doublet of doublets; m: complex pattern; t: triplet; tq: triplet of quartets; ψs, pseudo-singlet. Electrospray mass spectra: positive monoisotopic ions ( 12 C, 1 H, 16 O, 23 Na, 39 K, 120 Sn). Na and/or K are already present in the electrospray mass spectra of the starting carboxylic acids. Charaterization of compounds 1 to 15 Compound 1: triphenyltin 4,7,10,13,16,19- hexaoxadicyclo [16 . 4 . 0] dicosa- 1 , 3 ( 20 ) , 21 -triene- l - carboxylate prepared according to method 1 , 10 h of reflux, recrystallized from diethyl ether/hexane, m.p. 110-112°C, yield 98%, elemental analysis: exp. (calc. for C 35 H 38 SnO 8 ): C: 60.2 (59.60); H: 5.5 (5.43); i H NMR: 7.7-7.8, m, H(o) & H(5); 7.62, d WH-Η) = 2), H(3); 7.4-7.5, m, H(m) & H(p); 6.91, d ( 3 J( 1 H- 1 H) = 9), H(6); 4.1-4.3, m, H(8) & H(17); 3.8-4.0, m, H(9) & H(16); 3.6-3.8, m, H(10), H(l l), H(14) & H(15); 3.67, ψs, H(12) & H(13); 13 C NMR: 172.7, C(7); 152.9, C(l); 148.0, C(2); 138.5, C(i); 137.0, C(o) 2 J( 117/11Q Sn-' 3 C) = 47/49; 130.2, C(p) J( 1 17/1 I9 Sn- 13 C) = 13; 129.0, C(m) 3 J0 I7 ' 119 Sn- 13 C) = 61/63; 125.1, C(5); 122.8, C(4); 1 14.9, C(3); 111.7, C(6); 70.80 & 70.77, C(10) & C(15); 70.71 & 70.66, C(12) & C(13); 70.53, 70.51, 69.4, 69.2, 68.8 & 68.6, C(8), C(9), C(l l), C(14), C(16) & C(17); 117 Sn NMR: -115.7; electrospray MS: M+K + (m z = 745), 14%; M + Na + , 100%; Mossbauer: QS: 2.26; IS: 0.55; I * ,: 1.34; r 2 : 32 - Compound 2 : tri-n-butyltin 4,7,10,13,16,19- hexaoxadicyclo [16.4.0] dicosa-1, 3 (20) , 21-triene-l-carboxylate prepared according to method 1, 4 h of reflux, recryst. hexane/chloroform, m.p. 45-47°C, yield 80%, elemental analysis: exp. (calc. for C 29 H 5 oSnO 8 H 2 O): C: 52.5 (52.50); H: 8.3 (7.90); »H NMR: 7.63, dd ( 3 J( i H- ! H) = 8; 4 j( i H- i H) = 2), H(5); 7.54, d WH-Η) = 2), H(3); 6.82, d WH-Η) = 8), H(6); 4.1-4.3, m, H(8) & H(17); 3.8-4.0, m, H(9) & H(16); 3.6-3.8, m, H(10), H(l l), H(14) & H(15); 3.65, ψs, H(12) & H(13); « 2, HOH; 1.6-1.7, m H(β); 1.2-1.3, m, H(α) & H(γ); 0.89, t WH-'H) = 7), H(δ); 13 C NMR: 171.4, C(7); 152.2, C(l); 148.1, C(2); 125.0, C(4); 124.2, C(5); 115.0, C(3); 112.1, C(6); 70.96 & 70.84, C(10) & C(15); 70.77 & 70.73, C(12) & C(13); 70.66, 70.61, 69.5, 69.4, 68.9 & 68.8, C(8), C(9), C(l l), C(14), C(16) & C(17); 27.9, C(β) 2j ( i i 7/ ι i 9 S n - i 3 C) = 20; 27.0, C(γ) 3J( " 7 /" Q Sn- 13 C) = 62/65; 16.6, C(α) ιj( i i7/ ι i9 Sn . i3 _ 341/358; 13.7, C(δ); 117 Sn NMR: 108.2; electrospray MS: M + Na + (m/z = 669), 6%; M + H 2 O + H + , 9%; M + H + , 11%; Mossbauer: QS: 3.40; IS: 1.39; r,: 0.72; r 2 : 0.85. Compound 3: di-n-butyltin bis [ , 7, 10, 13 , 16 , 19- hexaoxadicyclo [16.4.0] dicosa-1, 3 (20) , 21-triene-l- carboxylate, prepared according to method 1, 6 h of reflux, recryst. hexane/chloroform, m.p. 125-127°C, yield 96%, elemental analysis: exp. (calc. for C 42 H 64 SnOι 6 ): C: 53.5 (53.46); H: 7.1 (6.84); Η NMR: 7.73, d WH-'H) = 8) , H(5); 7.58, s, H(3); 6.86, d (^('H-'H) = 8), H(6); 4.1-4.3, m, H(8) & H(17); 3.8-4.0, m, H(9) & H(16); 3.6-3.8, m, H(10), H(l l), H(14) & H(15); 3.65, ψs, H(12) & H(13); 1.7-1.8, m, H(β) & H(α); 1.37, tq, (3J(1H-1H) = 7, 3 J('H-iH) = 7), H(γ); 0.86, t ( 3 J( i H- i H) = 7), H(δ); 13 C NMR: 175.7, C(7); 153.3, C(l); 148.3, C(2); 124.9, C(5); 122.7, C(4); 115.3, C(3); 112.3, C(6); 70.9, C(10) & C(15); 70.81 & 70.76, C(12) & C(13); 70.73 & 70.67, 69.5, 69.4, 69.2 & 69.0, C(8), C(9), C(l 1), C(14), C(16) & C(17); 26.7, C(β) 2 J( i i7/i i9 Sn - 13 C) = 33; 26.3, C(γ) 3 J( 117 119 Sn- 13 C) = 95; 25.4, C(α) ( n7 , ,9 Sn- 13 C) = 569/596; 13.5, C(δ); 1 I7 Sn NMR: -156.2; electrospray MS: M + Na + (m/z = 967), 100%; Mossbauer: QS: 3.41; IS: 1.44; T,: 10.94; T 2 : 0.94. Compound 4: bis {di-n-butyl- [4 , 7 , 10 , 13 , 16 , 19- hexaoxadicyclo [16.4.0] dicosa-1, 3 (20) , 21-triene-l- carboxylato] tin} oxide, prepared according to method 3 12 h of reflux, Sephadex LH-20, elution with chloroform/methylene chloride; recryst. hexane/chloroform, m.p. 96-98°C, yield 90%, elemental analysis: exp. (calc. for C ] 0 oH 164 Sn 4 O 34 ): C: 50.0 (50.35); H: 7.1 (6.94); Η NMR: 7.54, d WH- i H) = 8), H(5); 7.49, s, H(3); 6.84, d ( 3 J( i H- i H) = 8), H(6); 4.1-4.3, m, o H(8) & H(17); 3.8-4.0, m, H(9) & H(16); 3.6-3.8, m, H(10), H(l l), H(14) & H(15); 3.62, ψs, H(12) & H(13); 1.6-1.8, m, H(β); 1.4-1.6, m, H(α); 1.1-1.4, m, H(γ); 0.7- 0.9, m, H(δ); 13 C NMR: 172.6, C(7); 152.5, C(l); 148.3, C(2); 126.3, C(4); 124.0, C(5); 115.3, C(3); 112.4, C(6); 70.8, C(10) & C(15); 70.7 & 70.6, C(12) & C(13); 5 70.6, 70.5, 69.42, 69.35, 69.1 & 68.9, C(8), C(9), C(l l), C(14), C(16) & C(17); 26.7 & 26.6, C(β); 27.6 & 27.4, C(γ); 29.5 & 28.3, C(α); 13.5 & 13.4, C(δ); H7 Sn NMR: -213.0 & -217.3; electrospray MS: M 2 + K+ (m z = 1233), 11%; Mossbauer: QS: 3.36; IS: 1.27; T,: 0.96; T 2 : 0.99. Compound 5: triphenyltin 4,7,10,13,16- pentaoxadicyclo [13.4.0] cosa-1, 3 (17) , 18-triene-l-carboxylate, prepared according to method 2, 48 h of reflux, recryst. hexane, m.p.: 130-131°C, yield 95%, elemental analysis: exp. (calc. for C 33 H 34 SnO 7 ■ 1 H 2 O): C: 58.4 (58.34); H: 5.7 (5.35); Η NMR: 7.7-7.8, m, H(o) & H(5); 7.60, d (^( I H-Η) = 2), H(3); 7.4-7.5, m, H(m) & H(p); 6.82, d WH-Η) = 8), H(6); 4.1-4.2, m, H(8) & H(15); 3.8-3.9, m, H(9) & H(14); 3.73, ψs, H(10), H(l l), H(12) & H(13); « 2, HOH; 13 C NMR: 172.8, C(7); 153.1, C(l); 148.3, C(2); 138.7, C(i); 136.9, C(o) 2 J( 1 17 119 Sn- 13 C) = 47/49; 130.1, C(p) 4 J( 117/119 Sn- I3 C) = 13; 128.9, C(m) 3 J( 1 I7 119 Sn-' 3 C) = 62/65; 125.2, C(5); 123.3, C(4); 115.7, C(3); 112.1, C(6); 70.95 & 70.92, C(8) & C(15); 70.31 & 70.23, C(9) & C(14); 69.3, 69.2, 69.9 & 68.5, C(10), C(l 1), C(12) & C(13); 117 Sn NMR: -116.3; electrospray MS: M+K+ (m z=701, 67%); M + Na + , 73%; Mossbauer: QS: 2.77; IS: 1.23; r,: 0.94; T 2 : 0.88. Compound 6: tri-n-butyltin 4,7,10,13,16- pentaoxadicyclo [13.4.0] cosa-1, 3 (17) , 18-triene-l-carboxylate, prepared according to method 2, 25 h of reflux, Sephadex LH-20, elution with chloroform/methylene chloride, liquid; yield 90%; elemental analysis: exp. (calc. for C^H^SnO- ? 1/2 H 2 O): C: 53.1 (53.14); H: 7.8 (7.77); Η NMR: 7.63, dd røH-Η) = 8; ^(-H-Η) = 2), H(5); 7.54, d WH-'H) = 2), H(3); 6.82, d ( J('H- i H) = 8), H(6); 4.1-4.2, m, H(8) & H(15); 3.8-3.9, m, H(9) & H(14); 3.73, ψs, H(10), H(l l), H(12) & H(13); 1.6- 1.7, m, H(β); 1.2-1.4, m, H(α) & H(γ); 0.89, t ( 3 J(»H- i H) = 7), H(δ); 13 C NMR: 171.4, C(7); 152.5, C(l); 148.4, C(2); 125.1, C(4); 124.4, C(5); 115.5, C(3); 112.3, C(6); 71.2, C(8) & C(15); 70.57 & 70.52, C(9) & C(14); 69.6, 69.5, 69.1 & 68.9, C(10), C(l l), C(12) & C(13); 27.9, C(β) 2 J( 1 17/ " Sn- 13 C) = 20; 27.0, C(γ) 3 J( 1 I7 1 I9 Sn- 1 C) = 62/65; 16.6, C(α) >J( 1 17 1 19 Sn- 13 C) = 350/362; 13.6, C(δ); 1 I7 Sn NMR: 107.4; electrospray MS: M + Na + (m/z = 625), 5%; M + NH 4 + , 9%; Mossbauer: QS: 3.29; IS: 1.45; r,: 0.94; T 2 : 0.88. Compound 7: di-n-butyltin bis [4 , 7 , 10 , 13 , 16- pentaoxadicyclo [13.4.0] cosa-1, 3 (17) , 18-triene-l- carboxylate] , prepared according to methode 2, m.p.: 130-132°C; yield 98%; elemental analysis: exp. (calc. for C 38 H 56 Sn0 14 ): C: 53.9 (53.35); H: 6.7 (6.60); 'H NMR: 7.74, dd (^('H-'H) = 8, J( i H-»H) = 2), H(5); c 7.59, d ( 4 J( 1 H- 1 H) = 2) , H(3); 6.86, d ( 3 J('H-'H) = 8), H(6); 4.1-4.2, m, H(8) & H(15); 3.8-4.0, m, H(9) & H(14); 3.75, ψs, H(10), H(ll), H(12) & H(13); 1.7-1.8, m, H(β) & H(α); 1.38, tq WH-'H) = 7, 3 J( i H- i H) = 7), H(γ); 0.86, t WH- i H) -= 7), H(δ); 13 C NMR: 175.8, C(7); 153.5, C(l); 148.5, C(2); 125.0, C(5); 122.9, C(4); 0 115.4, C(3); 112.2, C(6); 71.11 & 71.09, C(8) & C(15); 70.39 & 70.31, C(9) & C(14); 69.4, 69.2, 69.0 & 68.6, C(10), C(ll), C(12) & C(13); 26.7, C(β), 2 j( ii7/ ι i9 Sn _ i3 C ) = 34; 26.4, C(γ), 3j i ιτ/ι i9 Sn _i3 C ) = 103; 25.5, C(α), i j( ii7/U9 Sn . i3 C ) _ 561/588; 13.6, C(δ); 117 Sn NMR: -156.8; electrospray MS: M + 5 Na + (m/z = 879), 27%, M + K + , 27%; Mossbauer: QS: 3.28; IS: 1.41; T,: 0.92; T 2 : 0.93. Compound 8 : triphenyltin 3 , 6-diheptanoate, prepared according to method 2, 0 8 h of reflux, recrystallized from hexane/chloroform, m.p.: 100-102°C, yield 95%, elemental analysis: exp. (calc. for C 23 H 24 SnO 4 ): C: 57.4 (57.18); H: 4.7 (5.01); 'H NMR: 7.7-7.8, m. H(o); 7.4-7.5, m, H(m) & H(p); 4.25, s, H(2); 3.7-3.8, m, H(4); 3.5-3.6, m, H(5); 3.35, s, H(7); 13 C NMR: 176.5, C(l); 137.7, C(i); 136.8, 5 C(o) 2 J( 117/119 Sn- I3 C) = 49; 130.2, C(p) 4 J(" 7/ " 9 Sn-' 3 C) = 13; 128.9, C(m) 3 J( 117/ " 9 Sn-' 3 C) = 62/65; 72.0, C(5); 70.6, C(4); 69.0, C(2); 59.0, C(7); 117 Sn NMR: -100.0; electrospray MS: M + Na + (m/z = 507), 5%, M + H + , 2%; Mossbauer: QS: 3.60; IS: 1.24; T,: 0.85; r,: 0.79. 0 " Compound 9 : tri-n-butyltin 3 , 6-diheptanoate , prepared according to methode 2, 8 h of reflux, Sephadex LH-20, elution with methylene chloride, liquid, yield 95% elemental analysis: exp. (calc. for C 17 H 36 SnO 4 • 1/2 H 2 O): C: 47.4 (47.27); H: 8.6 (8.63);; W NMR: 4.09, s, H(2); 3.6-3.7, m, H(4); 3.5-3.6, m, H(5); 3.36, s, H(7); - 2, HOH; 1.5-1.6, m, H(β); 1.2-1.4, m, H(α) & H(γ); 0.88, t ( J( i H- i H) = 7), H(δ); 13 C NMR: 175.2, C(l); 71.9, C(5); 70.4, C(4); 69.0, C(2); 59.0, C(7); 27.8, C(β) 2 J( 1 17/1 1 Sn-' 3 C) = 20; 27.1, C(γ) J( i i '" Sn- 13 C) = 64/67; 16.6, C(α) i j( i i7/i i9 S n- i 3 C) = 338/355; 13.7, C(δ); 117 Sn NMR: 120.7; electrospray MS: M + Na + (m z = 447), 7%; Mossbauer: QS: 3.81; IS: 1.47; T,: 1.15; T 2 : 1.14. Compound 10: di-n-butyltin bis (3 , 6-diheptanoate) , prepared according to method 3 , 12 h of reflux, liquid, yield 98%; elemental analysis: exp. (calc. for C 18 H 36 SnO 8 ): C: 43.4 (43.31); H: 7.5 (7.27); 'H NMR: 4.16, s, H(2); 3.6-3.8, m, H(4); 3.5-3.6, m, H(5); 3.36, s, H(7); 1.6-1.7, m, H(β) & H(α); 1.34, tq ( 3 j( i H-»H) = 7, 3 J( 1 H- 1 H) = 7), H(γ); 0.87, t ( J('H-'H) = 7), H(δ); 13 C NMR: 178.3, C(l); 71.8, C(5); 70.7, C(4); 68.6, C(2); 59.0, C(7); 26.5, C(β) 2 J(" 7 119 Sn- 13 C) = 34; 26.3, C(γ) 3 J( 117 119 Sn- 13 C) = 98/102; 25.7, C(α) 'J( 1 I7 1 19 Sn- 13 C) = 538/567; 13.4, C(δ); 117 Sn NMR: -124.7; electrospray MS: M + Na + (m z = 523), 77%; M + K + , 13%; Mossbauer: QS: 3.90; IS: 1.44; T,: 1.28; T 2 : 1.02. Compound 11 : bis [di -n-butyl ( 3 , 6 -dioxaheptanoato) tin] oxide , prepared according to method 3 , 12 h of reflux, Sephadex LH-20, elution with methylene chloride, liquid, yield 80%; elemental analysis: exp. (calc. for C 52 Hι 08 Sn 4 θ 18 2 H 2 O): C: 40.7 (40.76); H: 7.2 (7.37); >H NMR: 3.95, s, H(2); 3.6-3.7, m, H(4); 3.5-3.6, m, H(5); 3.34, s, H(7); - 2, HOH; 1.5-1.7, m, H(β); 1.3-1.5, m, H(α); 1.30, tq, WH-Η) = 7, 3 J( l H- ! H) = 7), H(γ); 0.86, m, H(δ); 13 C NMR: 174.9, C(l); 71.8, C(5); 70.2, C(4); 69.8, C(2); 58.9, C(7); 27.5 & 27.2, C(β); 26.8 & 26.7, C(γ); 29.0 & 26.3, C(α); 13.57 & 13.55, C(δ); l l7 Sn NMR: -204.8 & -215.8; electrospray MS: M 2 + Bu 2 SnOH + (m/z = 1001), 40%; Mossbauer: QS: 3.42; IS: 1.34; T,: 1.22; T 2 : 1.18. Compound 12 : triphenyltin 3 , 6 , 9-trioxadecanoate, prepared according to method 2, 8 h of reflux, recryst. diethyl ether/methylene chloride, m.p.: 109- 111°C, yield 92%, elemental analysis: exp. (calc. for C 25 H 28 SnO 5 ): C: 57.1 (56.96); H: 5.4 (5.36); ; 'H NMR: 7.7-7.8, m, H(o); 7.4-7.5, m, H(m) & H(p); 4.22, s, H(2); 3.7-3.8, m, H(4); 3.6-3.7, m, H(5); 3.5-3.6, m, H(7); 3.4-3.5, m, H(8); 3.34, s, H(10); 13 C NMR: 176.4, C(l); 137.8 C(i); 136.9, C(o) J( 1 I7 119 Sn- 13 C) = 47-50; 130.2, C(p) J( I I7 119 Sn- 13 C) = 13; 128.9, C(m) 3 J( 117 119 Sn-' 3 C) = 63/66; 72.0, C(8); 5 70.7, 70.7 & 70.5, C(4), C(5) & C(7); 69.0, C(2); 59.0 C(10); I 17 Sn NMR: -103.2; electrospray MS: M + K + (m/z = 567), 2%; M + Na+, 11%; M + H+, 6%; Mossbauer: QS: 3.44; IS: 1.29; T,: 0.91; T 2 : 0.87. Compound 13: tri-n-butyltin 3 , 6 , 9-trioxadecanoate, prepared 10 according to method 2, 8 h of reflux, Sephadex LH-20, elution with methylene chloride, liquid, yield 92%;elemental analysis: exp. (calc. for C 19 H 40 SnO 5 1/2 H 2 O): C: 47.7 (47.94); H: 8.8 (8.68); 'H NMR: 4.09, s, H(2); 3.6-3.8, m, H(4), H(5) & H(7); 3.5-3.6, m, ! 5 H(8); 3.36, s, H(10); - 2, HOH; 1.5-1.7, m, H(β); 1.2-1.4, m, H(α) & H(γ); 0.89, t ( 3 J( 1 H- 1 H) = 7), H(δ); 13 C NMR: 175.1, C(l); 72.0, C(8); 70.6, 70.5 & 70.5, C(4), C(5) & C(7); 69.0, C(2); 58.9, C(10); 27.8, C(β) 2 J( 1 17/1 I 9 Sn- 13 C) = 20; 27.0, C(γ) 3 j( i i7/ ι i9 Sn . i 3 C ) = 63/66; 16.6, C(α) ιj( i i v /i i9 Sn - 13 C) = 349/355; 13.6, C(δ); 1 17 Sn 20 NMR: 120.7; electrospray MS: M + K + (m z = 507), 18%; M + Na + , 51%; Mossbauer: QS: 3.84; IS: 1.47; T,: 1.07; I\: 1.02. Compound 14 : di -n-butyltin bis ( 3 , 6 , 9 -trioxadecanoate ) , prepared according to method 3 , 25 12 h of reflux, liquid, yield 95%; elemental analysis: exp. (calc. for C 22 H 44 SnO, 0 ): C: 44.8 (44.99); H: 7.8 (7.56); 'H NMR: 4.15, s, H(2); 3.6-3.8, m, H(4), H(5) & H(7); 3.5-3.6, m, H(8); 3.35, s, H(10); 0.6-0.8, m, H(β) & H(α); 1.35, tq ( 3 J( 1 H- 1 H) = 7, 3 J('H- i H) = 7), H(γ); 0.88, t ( 3 J('H- i H) = 7), H(δ); ' 3 C NMR: 175.8, C(l); 71.8, C(8); 71.1, 70.6 & 70.4, C(4), C(5) & C(7); 68.7, C(2); 59.0, C(10); 26.6, C(β), J(' 17 " 19 Sn-> 3 C) = 38; 26.3, C(γ), J( 1 17/1 19 Sn- i C) = 99; 25.6, C(α), ■J( 1 17 119 Sn- 13 C) = 540/567; 13.5, C(δ); 117 Sn NMR: -124.1; electrospray 35 MS: M + K + (m/z = 627), 12%; M + Na + , 22%; Mossbauer: QS: 3.77; IS: 1.42; T,: 1.36; r 2 : 1.18. Compound 15: bis [di-n-butyl (3 , 6 , 9-trioxadecanoato) tin] oxide , prepared according to method 3, 12 h of reflux, Sephadex LH-20, elution with methylene chloride, liquid, elemental analysis: exp. (calc. for C 60 H 124 Sn 4 O 22 2 H 2 O): C: 42.2 (42.18); H: 7.4 (7.56); yield 80%; «H NMR: 3.96, s, H(2); 3.6-3.7, m, H(4), H(5) & H(7); 3.5- 3.6, m, H(8); 3.34, s, H(10); « 2, HOH; 1.57, tt ( S J H^H) = 7, 3 J( 1 H- ] H) = 7), H(β); 1.4-1.5, m, H(α); 1.27, tq ( 3 J( 1 H- 1 H) = 7, 3 J( i H- i H) = 7), H(γ); 0.8-0.9, m, H(δ); 13 C NMR: 175.1, C(l); 72.0, C(8); 70.60, 70.55 & 70.4, C(4), C(5) & C(7); 69.9, C(2); 59.0, C(10); 27.6 & 27.3, C(β); 26.9 & 26.7, C(γ); 29.1 & 25.8, C(α); 13.6, C(δ); 1 1 Sn NMR: -204.9 & -217.6; electrospray MS: M/2 + Na + (m/z = 861), 10%; M 2 + Bu2SnOH+, 33%; Mossbauer: QS: 3.49; IS: 1.32; TV 0.90; T 2 : 0.90. Stability in water of organotin polyoxaalkanenecarboxylates The stability in the presence of water of four compounds, 6, 8, 9 and 12, was determined. Solutions in CD 3 CD 2 OD exhibit a single resonance in 117 Sn NMR (at 36.5, -210.7, 27.9 and -212.0 ppm, respectively) that is regularly slightly shifted after the addition of increasing amounts of D 2 O. Antitumour activity of compounds 1 to 15 The ID 50 irihibition doses in ng/ml of the tested compounds are given in the table as well as those for some known reference compounds. Inhibition doses ID 50 in vitro (in ng/ml) against some tumoural cell lines of human origin, two mammary cancers, (MCF-7, EVSA-T) , a colon carcinoma (WiDr) , an ovarian cancer (IGROV) , a melanoma (M19 MEL) , a renal cancer (A 498) and a non small cell lung cancer (H226) of organotin derivatives of carboxybenzocrown and di- or trioxaalkanecarboxylic acids, and of some known reference compounds.

Claims: CLAIMS : 1. Tin polyoxaalkanecarboxylates having the formula wherein R 1 represents C x -C 6 alkyl, branched or straight, substituted or not by one or more hydroxyl groups or halogen atoms, or a phenyl group, substituted or not by one or more hydroxyl groups or halogen atoms, R 2 is a carboxylic residue selected from: and p, q, r, s and t have the following meanings: p = 3, q = l, r = l, s = 0 and t = 1 ; p = 2, q = 2, r = l, s = 0 and t = 1; p = 2, q = 1 , r = 2, s = 1 and t = 2. 2. Anti-tumour compositions, containing as an active ingredient one or more tin polyoxaalkanecarboxylates of the formula R^SnR 2 (1) ; R 1 2 SnR 2 2 (2) ; or { [R 1 2 R 2 Sn] 2 0} 2 (3), wherein R 1 and R 2 have the meanings as defined in claim 1, and a pharmaceutically acceptable carrier. 3. A composition according to claim 2, containing a compound having the formula (1) , (2) or (3) as defined in the claims 1 and 2, wherein R 1 represents a phenylgroup or a n-butylgroup .

Inventors: BIESEMANS MONIQUE, DE VOS DICK, GIELEN MARCEL, KEMMER MARTINE, WILLEM RUDOLPH, BIESEMANS, MONIQUE, DE VOS, DICK, GIELEN, MARCEL, KEMMER, MARTINE, WILLEM, RUDOLPH
Applicants: BIESEMANS MONIQUE, GIELEN MARCEL, KEMMER MARTINE, PHARMACHEMIE BV, VOS DICK DE, WILLEM RUDOLPH, BIESEMANS, MONIQUE, DE VOS, DICK, GIELEN, MARCEL, KEMMER, MARTINE, PHARMACHEMIE B.V., WILLEM, RUDOLPH
Application year: 1998
Main classification: C07F7
IPC codes: A61K33, A61P35, C07F7