Tin polyoxaalkanecarboxylates and compositions containing them

Details Tin polyoxaalkanecarboxylates and compositions containing them Tin polyoxaalkanecarboxylates and compositions containing them

2001-01-29

2002-06-18

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C556S106000, C560S186000

Reexamination Certificate

active

06407265

ABSTRACT:

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


REFERENCES:
patent: 5608058 (1997-03-01), Tanaka et al.
patent: 0484596 (1990-11-01), None
patent: 0538517 (1993-04-01), None
patent: 0700921 (1994-09-01), None
“Tin Based Antitumour Drugs”, M. Gielen,Coord. Chem. Rev.,1996.
“Reviews on Silicon, Germanium Tin and Lead Compounds”, G. Atassi, 1985.
“In Vitro Antitumour Activity of Organotin . . . ”, M. Gielen, et al., 1990.
“Comparison of the Sulforhodamine B Protein”, Y.P. Keepers, et al., 1991.
“The Preparation of Organotin Alkoxides”, A. G. Davies, et al., 1991.
“New Colorimetric Cytotoxicity Assay”, P. Skehan, et al., 1989.
“Di-N-Butyltin and Diethyltin Monoflourobenzoates . . . ”, M. Gielen, et al., 1993.

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