Tin polyoxaalkanecarboxylates and compositions containing them

The present application is the Continuation of prior international application PCT/NL98/00429, filed Jul. 29, 1998, which designated the United States, and which international application was published under PCT Article 21 (2)in the English language. The entire contents of said PCT/NL98/00429 are hereby incorporated by reference.

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

[( R 1 p R 2 q Sn) r O s ] t

wherein

R 1 represents C 1 -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=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 O

b) RCOOH+Bu 3 SnOCOCH 3 →Bu 2 SnOCOR+CH 3 COOH

c) 2RCOOH+Bu 2 SnO→Bu 2 Sn(OCOR) 2 +H 2 O

d) 2RCOOH+2Bu 2 SnO→½{[Bu 2 (RCOO)Sn] 2 O} 2 +H 2 O

Different media and methods can be used to synthesize such derivatives

1) the condensation can be performed in toluene/ethanol. 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:

2Bu 2 SnO+2PrOH→(PrOSnBu 2 ) 2 O+H 2 O

In a second step, the carboxylic acid is added at room temperature to this tetrabutyldipropoxydistannoxane in the desired molar ratio.

The compounds synthesized by one of these methods were characterized by elemental analysis, 1 H, 13 C and 117 Sn NMR, electrospray mass spectrometry and 119m Sn Mössbauer 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

NMR spectra: CDCl 3 solutions; 1 H and 13 C chemical shifts δ in ppm vs. TMS, homonuclear coupling constants in Hz, in parentheses; Mössbauer parameters (quadrupole splitting QS, isomers shift IS, and band widths Γ 1 and Γ 2 ) in mm/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-1-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); 1 H NMR: 7.7-7.8, m, H(o) & H(5); 7.62, d ( 4 J( 1 H− 1 H)=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(11), H(14) & H(15); 3.67, ψs, H(12) & H(13); 13 C NMR: 172.7, C(7); 152.9, C(1); 148.0, C(2); 138.5, C(i); 137.0, C(o) 2 J( 117/119 Sn− 13 C)=47/49; 130.2, C(p) 4 J( 117/119 Sn— 13 C)=13; 129.0, C(m) 3 J( 117/119 Sn− 13 C)=61/63; 125.1, C(5); 122.8, C(4); 114.9, 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(11), C(14), C(16) & C(17); 117 Sn NMR: −115.7; electrospray MS: M+K + (m/z=745), 14%; M+Na + , 100%; Mössbauer: QS: 2.26; IS: 0.55; Γ 1 : 1.34; Γ 2 : 1.32.

Compound 2: tri-n-butyltin 4,7,10,13,16,19-hexaoxadicyclo[16.4.0]dicosa-1,3(20),21-triene-1-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 50 SnO 8 .H 2 O): C: 52.5 (52.50); H: 8.3 (7.90); 1 H NMR: 7.63, dd ( 3 J( 1 H− 1 H)=8; 4 J( 1 H− 1 H)=2), H(5); 7.54, d ( 4 J( 1 H− 1 H)=2), H(3); 6.82, d ( 3 J( 1 H− 1 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(11), 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 ( 3 J( 1 H− 1 H)=7), H(δ); 13 C NMR: 171.4, C(7); 152.2, C(1); 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(11), C(14), C(16) & C(17); 27.9, C(β) 2 J( 117/119 Sn− 13 C)=20; 27.0, C(γ) 3 J( 117/119 Sn− 13 C)=62/65; 16.6, C(α) 1 J( 117/119 Sn− 13 C)=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%; Mössbauer: QS: 3.40; IS: 1.39; Γ 1 : 0.72; Γ 2 : 0.85.

Compound 3: di-n-butyltin bis[4,7,10,13,16,19-hexaoxadicyclo[16.4.0]dicosa-1,3(20),21-triene-1-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 SnO 16 ): C: 53.5 (53.46); H: 7.1 (6.84); 1 H NMR: 7.73, d ( 3 J( 1 H− 1 H)=8) , H(5); 7.58, s, H(3); 6.86, d ( 3 J( 1 H− 1 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(11), H(14) & H(15); 3.65, ψs, H(12) & H(13); 1.7-1.8, m, H(β) & H(α); 1.37, tq, ( 3 J( 1 H− 1 H)=7, 3 J( 1 H− 1 H)=7), H(γ); 0.86, t ( 3 J( 1 - 1 H)=7), H(δ); 13 C NMR: 175.7, C(7); 153.3, C(1); 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(11), C(14), C(16) & C(17); 26.7, C(β) 2 J( 117/119 Sn− 13 C)=33; 26.3, C(γ) 3 J( 117/119 Sn− 13 C)=95; 25.4, C(α) 1 J( 117/119 Sn− 13 C)=569/596; 13.5, C(δ); 117 Sn NMR: −156.2; electrospray MS: M+Na + (m/z 967), 100%; Mössbauer: QS: 3.41; IS: 1.44; ψ 1 : 10.94; ψ 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-1-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 100 H 164 Sn 4 O 34 ): C: 50.0 (50.35); H: 7.1 (6.94); 1 H NMR: 7.54, d ( 3 J( 1 H− 1 H)=8), H(5); 7.49, s, H(3); 6.84, d ( 3 J( 1 − 1 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(11), 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(1); 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); 70.6, 70.5, 69.42, 69.35, 69.1 & 68.9, C(8), C(9), C(11), 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); 117 Sn NMR: −213.0 & −217.3; electrospray MS: M/2+K + (m/z=1233), 11%:; Mössbauer: QS: 3.36; IS: 1.27; Γ 1 : 0.96; Γ 2 : 0.99.

Compound 5: triphenyltin 4,7,10,13,16-pentaoxadicyclo[13.4.0]cosa-1,3 (17),18-triene-1-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); 1 H NMR: 7.7-7.8, m, H(o) & H(5); 7.60, d ( 4 J( 1 H− 1 H)=2), H(3); 7.4-7.5, m, H(m) & H(p); 6.82, d ( 3 J( 1 H− 1 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(11), H(12) & H(13);˜2, HOH; 13 C NMR: 172.8, C(7); 153.1, C(1); 148.3, C(2); 138.7, C(i); 136.9, C(o) 2 J( 117/119 Sn− 13 C)=47/49; 130.1, C(p) 4 J( 117/119 Sn— 31 C)=13; 128.9, C(m) 3 J( 117/119 Sn− 13 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(11), C(12) & C(13); 117 Sn NMR: −116.3; electrospray MS: M+K + (m/z=701, 67%); M+Na + , 73%; Mössbauer: QS: 2.77; IS: 1.23; Γ 1 : 0.94; Γ 2 : 0.88.

Compound 6: tri-n-butyltin 4,7,10,13,16-pentaoxadicyclo[13.4.0]cosa-1,3 (17),18-triene-1-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 27 H 46 SnO 7 .½ H 2 O): C: 53.1 (53.14); H: 7.8 (7.77); 1 H NMR: 7.63, dd ( 3 J( 1 H− 1 H)=8; 4 J( 1 H− 1 H)=2), H(5); 7.54, d ( 4 J( 1 H− 1 H)=2), H(3); 6.82, d ( 3 J( 1 H− 1 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(11), 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( 1 H− 1 H)=7), H(δ); 13 C NMR: 171.4, C(7); 152.5, C(1); 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(11), C(12) & C(13); 27.9, C(β) 2 J( 117/119 Sn− 13 C)=20; 27.0, C(γ) 3 J( 117/119 Sn− 13 C)=62/65; 16.6, C(α) 1 J( 117/119 Sn− 13 C)=350/362; 13.6, C(δ); 117 Sn NMR: 107.4; electrospray MS: M+Na +(m/z= 625), 5%; M+NH 4 + , 9%; Mössbauer: QS: 3.29; IS: 1.45; Γ 1 : 0.94; Γ 2 : 0.88.

Compound 7: di-n-butyltin bis[4,7,10,13,16-pentaoxadicyclo[13.4.0]cosa-1,3(17),18-triene-1-carboxylate], prepared according to methode 2,

48 h of reflux, recrystallized from petroleum ether/methylene chloride, m.p.: 130-132° C.; yield 98%; elemental analysis: exp. (calc. for C 38 H 56 SnO 14 ): C: 53.9 (53.35); H: 6.7 (6.60); 1 H NMR: 7.74, dd ( 3 J( 1 H− 1 H)=8, 4 J( 1 H− 1 H)=2), H(5); 7.59, d ( 4 J( 1 H − 1 H)=2) , H(3); 6.86, d ( 3 J( 1 H− 1 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(11), H(12) & H(13); 1.7-1.8, m, H(β) & H(α); 1.38, tq ( 3 J( 1 H− 1 H)=7, 3 J( 1 H− 1 H)=7), H(γ); 0.86, t ( 3 J( 1 H− 1 H)=7), H(δ); 13 C NMR: 175.8, C(7); 153.5, C(1); 148.5, C(2); 125.0, C(5); 122.9, C(4); 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(11), C(12) & C(13); 26.7, C(β), 2 J(117/119Sn− 13 C)=34; 26.4, C(γ), 3 J( 117/119 Sn− 13 C)=103; 25.5, C(α), 1 J( 117/119 Sn— 31 C)=561/588; 13.6, C(δ); 117 Sn NMR: −156.8; electrospray MS: M+Na + (m/z=879), 27%, M+K + , 27%; Mössbauer: QS: 3.28; IS: 1.41; Γ 1 : 0.92; Γ 2 : 0.93.

Compound 8: triphenyltin 3,6-diheptanoate, prepared according to method 2,

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); 1 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(1); 137.7, C(i); 136.8, C(o) 2 J( 117/119 Sn− 13 C)=49; 130.2, C(p) 4 J( 117/119 Sn− 13 C)=13; 128.9, C(m) 3 J( 117/119 Sn− 13 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%; Mössbauer: QS: 3.60; IS: 1.24; Γ 1 : 0.85; Γ 2 : 0.79.

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 .½ H2O): C: 47.4 (47.27); H: 8.6 (8.63);; 1 H 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 ( 3 J( 1 H− 1 H)=7), H(δ); 13 C NMR: 175.2, C(1); 71.9, C(1); 70.4, C(4); 69.0, C(2); 59.0, C(7); 27.8, C(β) 2 J( 117/119 Sn− 13 C)=20; 27.1, C(γ) 3 J( 117/119 Sn− 13 C)=64/67; 16.6, C(α) 1 J( 117/119 Sn− 13 C)=338/355; 13.7, C(8); 117 Sn NMR: 120.7; electrospray MS: M+Na + (m/z=447), 7%; Mössbauer: QS: 3.81; IS: 1.47; Γ 1 : 1.15; Γ 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); 1 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( 1 H− 1 H)=7, 3 J( 1 H− 1 H)=7), H(γ); 0.87, t ( 3 J( 1 H− 1 H)=7), H(δ); 13 C NMR: 178.3, C(1); 71.8, C(5); 70.7, C(4); 68.6, C(2); 59.0, C(7); 26.5, C(β) 2 J( 117/119 Sn− 13 C)=34; 26.3, C(γ) 3 J( 117/119 Sn− 13 C)=98/102; 25.7, C(α) 1 J( 117/119 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%; Mössbauer: QS: 3.90; IS: 1.44; Γ 1 : 1.28; Γ 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 H 108 Sn 4 O 18 .2H 2 O): C: 40.7 (40.76); H: 7.2 (7.37); 1 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, ( 3 J( 1 H− 1 H)=7, 3 J( 1 H− 1 H)=7), H(γ); 0.86, m, H(δ); 13 C NMR: 174.9, C(1); 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); 117 Sn NMR: −204.8 & −215.8; electrospray MS: M/2+Bu 2 SnOH + (m/z=1001), 40%; Mössbauer: QS: 3.42; IS: 1.34; Γ 1 : 1.22; Γ 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);; 1 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(1); 137.8 C(i); 136.9, C(o) 2 J( 117/119 Sn− 13 C)=47-50; 130.2, C(p) 4 J( 117/119 Sn− 13 C)=13; 128.9, C(m) 3 J( 117/119 Sn− 13 C)=63/66; 72.0, C(8); 70.7, 70.7 & 70.5, C(4), C(5) & C(7); 69.0, C(2); 59.0 C(10); 117 Sn NMR: −103.2; electrospray MS: M+K + (m/z=567), 2%; M+Na + , 11%; M+H + , 6%; Mössbauer: QS: 3.44; IS: 1.29; Γ 1 : 0.91; Γ 2 : 0.87.

Compound 13: tri-n-butyltin 3,6,9-trioxadecanoate, prepared 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 .½H 2 O): C: 47.7 (47.94); H: 8.8 (8.68); 1 H NMR: 4.09, s, H(2); 3.6-3.8, m, H(4), H(5) & H(7); 3.5-3.6, m, 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(1); 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( 117/119 Sn− 13 C)=20; 27.0, C(γ) 3 J( 117/119 Sn− 13 C)=63/66; 16.6, C(α) 1 J( 117/119 Sn− 13 C)=349/355; 13.6, C(δ); 117 Sn NMR: 120.7; electrospray MS: M+K + (m/z=507), 18%; M+Na + , 51%; Mössbauer: QS: 3.84; IS: 1.47; γ 1 : 1.07; Γ 2 : 1.02.

Compound 14: di-n-butyltin bis (3,6,9-trioxadecanoate), prepared according to method 3,

12 h of reflux, liquid, yield 95%; elemental analysis: exp. (calc. for C 22 H 44 SnO 10 ): C: 44.8 (44.99); H: 7.8 (7.56); 1 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( 1 H− 1 H)=7), H(γ); 0.88, t ( 3 J( 1 H− 1 H)=7), H(δ); 13 C NMR: 175.8, C(1); 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), 2 J( 117/119 Sn− 13 C)=38; 26.3, C(γ), 3 J( 117/119 Sn− 13 C)=99; 25.6, C(α), 1 J( 117/119 Sn− 13 C)=540/567; 13.5, C(δ); 117 Sn NMR: −124.1; electrospray

MS: M+K + (m/z=627), 12%; M+Na + , 22%; Mössbauer: QS: 3.77; IS: 1.42; Γ 1 : 1.36; Γ 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 Sn4O 22 .2 H 2 O): C: 42.2 (42.18); H: 7.4 (7.56); yield 80%; 1 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 ( 3 J( 1 H− 1 H)=7, 3 J( 1 H− 1 H)=7), H(β); 1.4-1.5, m, H(α); 1.27, tq ( 3 J( 1 H− 1 H)=7, 3 J( 1 H− 1 H)=7), H(γ); 0.8-0.9, m, H(δ); 13 C NMR: 175.1, C(1); 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); 117 Sn NMR: −204.9 & −217.6; electrospray MS: M/2+Na + (m/z=861), 10%; M/2+Bu 2 SnOH + , 33%; Mössbauer: QS: 3.49; IS: 1.32; Γ 1 : 0.90; Γ 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 inhibition 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.