US20010039270A1 - Tin polyoxaalkanecarboxylates and compositions containing them - Google Patents

Tin polyoxaalkanecarboxylates and compositions containing them Download PDF

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US20010039270A1
US20010039270A1 US09/770,299 US77029901A US2001039270A1 US 20010039270 A1 US20010039270 A1 US 20010039270A1 US 77029901 A US77029901 A US 77029901A US 2001039270 A1 US2001039270 A1 US 2001039270A1
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Marcel Gielen
Rudolph Willem
Monique Biesemans
Martine Kemmer
Dick de Vos
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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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/22—Tin compounds
    • C07F7/2224—Compounds having one or more tin-oxygen linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • 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.
  • the invention relates to tin polyoxaalkanecarboxylates having the formula
  • 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:
  • 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
  • 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:
  • the condensation can be performed in toluene/ethanol.
  • the water formed during the condensation is eliminated by azeotropic distillation (Dean-Stark funnel)
  • these compounds can also be prepared by a two-step procedure, dibutyltin oxide being first condensed with n-propanol to yield tetrabutyldipropoxydistannoxane:
  • NMR spectra CDCl 3 solutions; 1 H and 13 C chemical shifts ⁇ in ppm vs. TMS, homonuclear coupling constants in Hz, in parentheses; Mössbauer parameters (quadrupole splitting QS, isomers shift IS, and band widths ⁇ 1 and ⁇ 2 ) in mm/s; s: singlet; d: doublet; dd: doublet of doublets; m: complex pattern; t: triplet; tq: triplet of quartets; ⁇ s, 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.
  • 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,
  • 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,
  • 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
  • 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,
  • Compound 11 bis[di-n-butyl(3,6-dioxaheptanoato)tin]oxide, prepared according to method 3,
  • Compound 13 tri-n-butyltin 3,6,9-trioxadecanoate, prepared according to method 2,
  • Compound 14 di-n-butyltin bis (3,6,9-trioxadecanoate), prepared according to method 3,
  • MS: M+K + (m/z 627), 12%; M+Na + , 22%; Mössbauer: QS: 3.77; IS: 1.42; ⁇ 1 : 1.36; ⁇ 2 : 1.18.
  • Compound 15 bis[di-n-butyl(3,6,9-trioxadecanoato)tin]oxide, prepared according to method 3,

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Abstract

Tin polyaalkanecarboxylates having the formula [(R1 pR2 qSn)rOs]t wherein R1 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, R2 is 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=) 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, have anti-tumor activity.

Description

  • The invention relates to novel tin polyoxaalkanecarboxylates and to anti-tumour compositions containing such compounds. [0001]
  • 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. [0002]
  • 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. [0003]
  • More specifically the invention relates to tin polyoxaalkanecarboxylates having the formula[0004]
  • [(R 1 p R 2 q S n)r O s]t
  • wherein [0005]
  • R[0006] 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[0007] 2 is a carboxylic residue selected from:
    Figure US20010039270A1-20011108-C00001
  • and p, q, r, s and t have the following meanings: [0008]
  • p=3, q=1, r=1, s=0 and t=1; [0009]
  • p=2, q=2, r=1, s=0 and t=1; [0010]
  • p=2, q=1, r=2, s=1 and t=2. [0011]
  • According to a preferred embodiment of the invention, represents R[0012] 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 [0013]
    Figure US20010039270A1-20011108-C00002
  • 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: [0014]
  • a) RCOOH+(C[0015] 6H5)3SnOH→(C6H5)3SnOCOR+H2O
  • b) RCOOH+Bu[0016] 3SnOCOCH3→Bu2SnOCOR+CH3COOH
  • c) 2RCOOH+Bu[0017] 2SnO→Bu2Sn(OCOR)2+H2O
  • d) 2RCOOH+2Bu[0018] 2SnO→½{[Bu2(RCOO)Sn]2O}2+H2O
  • Different media and methods can be used to synthesize such derivatives [0019]
  • 1) the condensation can be performed in toluene/ethanol. The water formed during the condensation is eliminated by azeotropic distillation (Dean-Stark funnel) [0020]
  • 2) benzene can be used instead of toluene/ethanol [0021]
  • 3) these compounds can also be prepared by a two-step procedure, dibutyltin oxide being first condensed with n-propanol to yield tetrabutyldipropoxydistannoxane:[0022]
  • 2Bu2SnO+2PrOH→(PrOSnBu2)2O+H2O
  • An a second step, the carboxylic acid is added at room temperature to this tetrabutyldipropoxydistannoxane in the desired molar ratio. [0023]
  • The compounds synthesized by one of these methods were characterized by elemental analysis, [0024] 1H, 13C and 117Sn NMR, electrospray mass spectrometry and 119mSn 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 [0025]
    Figure US20010039270A1-20011108-C00003
    • GENERALITIES AND ABBREVIATIONS
  • NMR spectra: CDCl[0026] 3 solutions; 1H and 13C 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 Γ1 and Γ2) 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 ([0027] 12C, 1H, 16O, 23Na, 39K, 120Sn). Na and/or K are already present in the electrospray mass spectra of the starting carboxylic acids.
  • Charaterization of Compounds 1 to 15 [0028]
  • 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, [0029]
  • 10 h of reflux, recrystallized from diethyl ether/hexane, m.p. 110-1 12° C., yield 98%, elemental analysis: exp. (calc. for C[0030] 35H38SnO8): C: 60.2 (59.60); H: 5.5 (5.43); 1H NMR: 7.7-7.8, m, H(o) & H(5); 7.62, d (4J(1H-1H)=2), H(3); 7.4-7.5, m, H(m) & H(p); 6.91, d (3J(1H-1H)=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); 13C NMR: 172.7, C(7); 152.9, C(1); 148.0, C(2); 138.5, C(i); 137.0, C(o) 2J(117/119Sn—13C)=47/49; 130.2, C(p) 4J(117/119Sn—13C)=13; 129.0, C(m) 3J(117/119Sn—13C)=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); 117Sn NMR: −115.7; electrospray MS: M+K++(m/z=745), 14%; M+Na+, 100%; Mössbauer: QS: 2.26; IS: 0.55; Γ1: 1.34; Γ2: 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, [0031]
  • 4 h of reflux, recryst. hexane/chloroform, m.p. 45-47° C., yield 80%, elemental analysis: exp. (calc. for C[0032] 29H50SnO8.H2O): C: 52.5 (52.50); H: 8.3 (7.90); 1H NMR: 7.63, dd (3J(1H-1H)=8; 4J(1H-1H)=2), H(5); 7.54, d (4J(1H-1H)=2), H(3); 6.82, d (3J(1-1H)=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 (3J(1-1H)=7), H(δ); 13C 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) 2J(117/119Sn—13C)=20; 27.0, C(γ) 3J(117/119Sn—13C)=62/65; 16.6, C(α) 1J(117/119Sn—13C)=341/358; 13.7, C(δ); 117Sn NMR: 108.2; electrospray MS: M+Na+ (m/z=669), 6%; M+H2O+H+, 9%; M+H+, 11%; Mössbauer: QS: 3.40; IS: 1.39; Γ1: 0.72; Γ2: 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, [0033]
  • 6 h of reflux, recryst. hexane/chloroform, m.p. 125-127° C., yield 96%, elemental analysis: exp. (calc. for C[0034] 42H64SnO16): C: 53.5 (53.46); H: 7.1 (6.84); 1H NMR: 7.73, d (3J(1-1H)=8) , H(5); 7.58, s, H(3); 6.86, d (3J(1-1H)=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(l0), 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, (3J(1-1H)=7, 3J(1-1H)=7), H(γ); 0.86, t (3J(1-1H)=7), H(δ); 13C 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) 2J(117/119Sn-13C)=33; 26.3, C(γ) 3J(117/119Sn-13C)=95; 25.4, C(α) 1J(117/119Sn—13C)=569/596; 13.5, C(δ); 117Sn NMR: −156.2; electrospray MS: M+Na+ (m/z 967), 100%; Mössbauer: QS: 3.41; IS: 1.44; ψ1: 10.94; ψ2: 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 [0035]
  • 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[0036] 100H[64Sn4O34): C: 50.0 (50.35); H: 7.1 (6.94); 1H NMR: 7.54, d (3J(1H-1H)=8), H(5); 7.49, s, H(3); 6.84, d (3J(1-1H)=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(8); 13C 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); 117Sn NMR: −213.0 & −217.3; electrospray MS: M/2+K+ (m/z=1233), 11%:; Mössbauer: QS: 3.36; IS: 1.27; Γ1: 0.96; Γ2: 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, [0037]
  • 48 h of reflux, recryst. hexane, m.p.: 130-131° C., yield 95%, elemental analysis: exp. (calc. for C[0038] 33H34SnO7.1 H2O): C: 58.4 (58.34); H: 5.7 (5.35); 1H NMR: 7.7-7.8, m, H(o) & H(5); 7.60, d (4J(1H-1H)=2), H(3); 7.4-7.5, m, H(m) & H(p); 6.82, d (3J(1H-1H)=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; 13C NMR: 172.8, C(7); 153.1, C(1); 148.3, C(2); 138.7, C(i); 136.9, C(o) 2J(117/119Sn—13C)=47/49; 130.1, C(p) 4J(117/119Sn—13C)=13; 128.9, C(m) 3J(117/119Sn—13C)=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); 117Sn NMR: −116.3; electrospray MS: M+K+ (m/z=701, 67%); M+Na+, 73%; Mössbauer: QS: 2.77; IS: 1.23; Γ1: 0.94; Γ2: 0.88.
  • Compound 6: tri-n-butyltin 4,7,10,13,16-pentaoxadicyclo 13.4.0]cosa-1,3 (17),18-triene-1-carboxylate, 20 prepared according to method 2, [0039]
  • 25 h of reflux, Sephadex LH-20, elution with chloroform/methylene chloride, liquid; yield 90%; elemental analysis: exp. (calc. for C[0040] 27H46SnO7.½ H2O): C: 53.1 (53.14); H: 7.8 (7.77); 1H NMR: 7.63, dd (3J(1-1H)=8; 4J(1-1H)=2), H(5); 7.54, d (4J(1H-1H)=2), H(3); 6.82, d (3J(1-1H)=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 (3J(1H-1H)=7), H(δ); 13C 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) 2J(117/119Sn—13C)=20; 27.0, C(γ) 3J(117/119Sn—13C)=62/65; 16.6, C(α) 1J(117/119Sn—13C)=350/362; 13.6, C(δ); 117Sn NMR: 107.4; electrospray MS: M+Na+(m/z=625), 5%; M+NH4 +, 9%; Mössbauer: QS: 3.29; IS: 1.45; Γ1: 0.94; Γ2: 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, [0041]
  • 48 h of reflux, recrystallized from petroleum ether/methylene chloride, m.p.: 130-1329C; yield 98%; elemental analysis: exp. (calc. for C[0042] 38H56SnO14): C: 53.9 (53.35); H: 6.7 (6.60); 1H NMR: 7.74, dd (3J(1-1H)=8, 4J(1-1H)=2), H(5); 7.59, d (4J(1H -1H)=2) , H(3); 6.86, d (3J(1H- 1H)=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 (3J(1H-1H)=7, 3J(1H-1H)=7), H(γ); 0.86, t (3J(1H-1H)=7), H(8); 13C NMR: 175.8, C(7); 153.5, C(l); 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), 2J(117/119Sn—13C)=34; 26.4, C(γ), 3J(117/119Sn—13C)=103; 25.5, C(α), 1J(117/119Sn—13C)=561/588; 13.6, C(δ); 117Sn NMR: −156.8; electrospray MS: M+Na+ (m/z=879), 27%, M+K+, 27%; Mössbauer: QS: 3.28; IS: 1.41; Γ1: 0.92; Γ2: 0.93.
  • Compound 8: triphenyltin 3,6-diheptanoate, prepared according to method 2, [0043]
  • 8 h of reflux, recrystallized from hexane/chloroform, m.p.: 100-102° C., yield 95%, elemental analysis: exp. (calc. for C[0044] 13H24SnO4): C: 57.4 (57.18); H: 4.7 (5.01); 1H 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); 13C NMR: 176.5, C(1); 137.7, C(i); 136.8, C(o) 2J(117/119Sn—13C)=49; 130.2, C(p) 4J(117/119Sn—13C)=13; 128.9, C(m) 3J(117/119Sn—13C)=62/65; 72.0, C(5); 70.6, C(4); 69.0, C(2); 59.0, C(7); 117Sn NMR: −100.0; electrospray MS: M+Na+ (m/z=507), 5%, M+H+, 2%; Mössbauer: QS: 3.60; IS: 1.24; Γ1: 0.85; Γ2: 0.79.
  • Compound 9: tri-n-butyltin 3,6-diheptanoate, prepared according to methode 2, [0045]
  • 8 h of reflux, Sephadex LH-20, elution with methylene chloride, liquid, yield 95% elemental analysis: exp. (calc. for C[0046] 17H36SnO4.½ H2O): C: 47.4 (47.27); H: 8.6 (8.63);; 1H NMR: 4.09, S, H(2); 3.6-3.7, m, H(4); 3.5-3.6, m, H(S); 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 (3J(1-1H)=7), H(δ); 3C NMR: 175.2, C(l); 71.9, C(S); 70.4, C(4); 69.0, C(2); 59.0, C(7); 27.8, C(β) 2J(117/119Sn—13C)=20; 27.1, C(γ) 3J(117/119Sn—13C)=64/67; 16.6, C(α) 1J(117/119Sn—13C)=338/355; 13.7, C(8); 117Sn NMR: 120.7; electrospray MS: M+Na+ (m/z=447), 7%; Mössbauer: QS: 3.81; IS: 1.47; Γ1: 1.15; Γ2: 1.14.
  • Compound 10: di-n-butyltin bis(3,6-diheptanoate), prepared according to method 3, [0047]
  • 12 h of reflux, liquid, yield 98%; elemental analysis: exp. (calc. for C[0048] 18H36SnO8): C: 43.4 (43.31); H: 7.5 (7.27); 1H 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 (3J(1-1H)=7, 3J(1-1H)=7), H(γ); 0.87, t (3J(1H-1H)=7), H(δ); 13C 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) 2J(117/119Sn—13C) 34; 26.3, C(γ) 3J(117/119Sn—13C)=98/102; 25.7, C(α) 1J(117/119Sn—13C)=538/567; 13.4, C(δ); 117Sn NMR: −124.7; electrospray MS: M+Na+ (m/z=523), 77%; M+K+, 13%; Mössbauer: QS: 3.90; IS: 1.44; Γ1: 1.28; Γ2: 1.02.
  • Compound 11: bis[di-n-butyl(3,6-dioxaheptanoato)tin]oxide, prepared according to method 3, [0049]
  • 12 h of reflux, Sephadex LH-20, elution with methylene chloride, liquid, yield 80%; elemental analysis: exp. (calc. for C[0050] 52H108Sn4O18.2H2O): C: 40.7 (40.76); H: 7.2 (7.37); 1H 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, (3J(1H-1H)=7, 3J(1H-1H)=7), H(γ); 0.86, m, H(δ); 13C 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); 117Sn NMR: −204.8 & −215.8; electrospray MS: M/2+Bu2SnOH+(m/z=1001), 40%; Mössbauer: QS: 3.42; IS: 1.34; Γ1: 1.22; Γ2: 1.18.
  • Compound 12: triphenyltin 3,6,9-trioxadecanoate, prepared according to method 2, [0051]
  • 8 h of reflux, recryst. diethyl ether/methylene chloride, m.p.: 109-111° C., yield 92%, elemental analysis: exp. (calc. for C[0052] 25H28SnO5 ): C: 57.1 (56.96); H: 5.4 (5.36);; 1H 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); 13C NMR: 176.4, C(1); 137.8 C(i); 136.9, C(o) 2J(117/119Sn—13C)=47-50; 130.2, C(p) 4J(117/119Sn—13C)=13; 128.9, C(m) 3J(117/119Sn—13C)=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);117Sn NMR: −103.2; electrospray MS: M+K+(m/z=567), 2%; M+Na+, 11%; M+H+, 6%; Mössbauer: QS: 3.44; IS: 1.29; Γ1: 0.91; Γ2: 0.87.
  • Compound 13: tri-n-butyltin 3,6,9-trioxadecanoate, prepared according to method 2, [0053]
  • 8 h of reflux, Sephadex LH-20, elution with methylene chloride, liquid, yield 92%;elemental analysis: exp. (calc. for C[0054] 19H40SnO5.½H20): C: 47.7 (47.94); H: 8.8 (8.68); 1H 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 (3J(1H-1H)=7), H(δ); 13C NMR: 175.1, C(I); 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) 2J(117/119Sn—13C)=20; 27.0, C(γ) 3J(117/119Sn—13C)=63/66; 16.6, C(α) 1J(117/119Sn—13C)=349/355; 13.6, C(δ); 117Sn NMR: 120.7; electrospray MS: M+K+(m/z=507), 18%; M+Na+, 51%; Mössbauer: QS: 3.84; IS: 1.47; γ1: 1.07; Γ2: 1.02.
  • Compound 14: di-n-butyltin bis (3,6,9-trioxadecanoate), prepared according to method 3, [0055]
  • 12 h of reflux, liquid, yield 95%; elemental analysis: exp. (calc. for C[0056] 22H44SnO10 ): C: 44.8 (44.99); H: 7.8 (7.56); 1H 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 (3J(1H-1H)=7, 3J(1H-1H)=7), H(γ); 0.88, t (3J(1H-1H)=7), H(δ); 13C 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), 2J(117/119Sn—13C)=38; 26.3, C(γ), 3J(117/119Sn—13C)=99; 25.6, C(α), 1J(117/119Sn—13C)=540/567; 13.5, C(δ); 117Sn NMR: −124.1; electrospray
  • MS: M+K[0057] +(m/z=627), 12%; M+Na+, 22%; Mössbauer: QS: 3.77; IS: 1.42; Γ1: 1.36; Γ2: 1.18.
  • Compound 15: bis[di-n-butyl(3,6,9-trioxadecanoato)tin]oxide, prepared according to method 3, [0058]
  • 12 h of reflux, Sephadex LH-20, elution with methylene chloride, liquid, elemental analysis: exp. (calc. for C[0059] 60H124Sn4O22.2 H20): C: 42.2 (42.18); H: 7.4 (7.56); yield 80%; 1H 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 (3J(1H-1H)=7, 3J(1H-1H)=7), H(β); 1.4-1.5, m, H(α); 1.27, tq (3J(1-1H)=7, 3J(1H-1H)=7), H(γ); 0.8-0.9, m, H(δ); 13C 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); 117Sn NMR: −204.9 & −217.6; electrospray MS: M/2+Na+ (m/z=861), 10%; M/2+Bu2SnOH+, 33%; Mössbauer: QS: 3.49; IS: 1.32; Γ1: 0.90; Γ2: 0.90.
  • Stability in Water of Organotin Polyoxaalkanenecarboxylates [0060]
  • The stability in the presence of water of four compounds, 6, 8, 9 and 12, was determined. Solutions in CD[0061] 3CD2OD exhibit a single resonance in 117Sn 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 D2O.
  • Antitumour activity of compounds 1 to 15 [0062]
  • The ID[0063] 50 inhibition doses in ng/ml of the tested compounds are given in the table as well as those for some known reference compounds.
    IG-
    MCF-7 EVSA-T WiDr ROV M19 A498 H226
    1 15 12 13 30 16 43 37
    2 35 6 11 30 70 97 100
    3 155 128 781 260 219 282 281
    4 36 46 239 82 68 126 73
    5 <3 <3 <3 <3 <3 <3 <3
    6 <3 <3 <3 <3 <3 <3 <3
    7 273 237 332 321 286 49 854
    8 13 12 34 37 31 32 33
    9 32 40 82 84 90 153 61
    10 60 62 379 128 115 134 161
    11 <3 <3 6 <3 <3 <3 5
    12 9 9 19 33 24 21 25
    13 36 25 40 89 78 93 56
    14 86 66 495 178 167 145 280
    15 <3 <3 3 <3 <3 <3 <3
    cisplatin 699 422 967 169 558 2253 3269
    doxorubicin 10 8 11 60 16 90 199
    etoposide 2594 317 150 580 505 1314 3934
    5-fluoro-uracil 750 475 225 297 442 143 340
    methotrexate 18 5 <3 7 23 37 2287
  • Inhibition doses ID[0064] 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 (3)

1. Tin polyoxaalkanecarboxylates having the formula
[(R1 pR2 qSn)rOs]t
wherein
R1 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,
R2 is a carboxylic residue selected from:
Figure US20010039270A1-20011108-C00004
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.
2. Anti-tumour compositions, containing as an active ingredient one or more tin polyoxaalkanecarboxylates of the formula
R1 3SnR2  (1);R1 2SnR2 2  (2); or{[R1 2R2Sn]2O}2  (3),
wherein R1 and R2 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 R1 represents a phenylgroup or a n-butylgroup.
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