US 5,846,516 A · Perfluoroalkylated amphiphilic phosphorus compounds: preparation and biomedical applications

Abstract

Perfluoroalkylated amphiphilic phosphorus compounds, corresponding to the formulae: ##STR1## wherein V is O or S; R.sup.1, R.sup.2 and R.sup.3 are H or substituted or unsubstituted perfluoroalkylated or hydrocarbon radicals; provided that R.sup.1, R.sup.2 or R.sup.3 is a perfluoroalkylated radical; and Y and Z are radicals which can bear a part derived from a sugar, a polyol, or a hydrophilic polymer such as polyethyleneglycol, a perfluoroalkylated part or a part derived from a pharmaceutically active molecule, and method for their preparation and use. These compounds can be included in preparations, emulsions, dispersions, gels, microemulsions, notably for biomedical uses.

A compound corresponding to one of the general formulae:

##STR10## wherein V is O or S;
--X-- is --O--;
--S--;
or --NR.sup.4 --;
wherein
R.sup.4 is a hydrogen atom;
a linear or branched, saturated or unsaturated C.sub.1 to C.sub.24 hydrocarbon radical;
or R.sub.F (CH.sub.2).sub.a W;
wherein
a is an integer from 0 to 12;
R.sub.F is a fluorinated C.sub.2 to C.sub.23 alkyl radical;
wherein 50 to 100% of the hydrogen atoms have been replaced by fluorine atoms, and R.sub.F can bear other substituents chosen from among Cl and Br, and R.sub.F includes at least 4 fluorine atoms;
and
W is
--(CH.dbd.CH).sub.d --(CH.sub.2).sub.e --(CH.dbd.CH).sub.f --(CH.sub.2).sub.g --;
wherein
d is an integer from 0 to 12;
e is an integer from 0 to 11;
f is an integer from 0 to 12;
g is an integer from 0 to 11;
d+f=0 to 12;
and
e+g=0 to 11;
--OCH.sub.2 CH(CH.sub.2 OH)CH.sub.2 --;
or
--OCH.sub.2 CH(CH.sub.2 OH)--;
and
m is an integer from 1 to 20;
R.sup.1 represents a radical selected from the group consisting of:
R.sub.F ;
R.sub.F --(CH.sub.2).sub.a --W--A--(CH.sub.2).sub.b --;
R.sub.F --(CH.sub.2 CH.sub.2 O).sub.c --CH.sub.2 --;
R.sub.F --(CH(CH.sub.3)CH.sub.2 O).sub.c --CH.sub.2 --;
R.sub.F --(CH.sub.2 CH.sub.2 S).sub.c --CH.sub.2 --;
and
R.sub.F --W--;
wherein
a, R.sub.F and W are as defined above,
b is an integer from 1 to 12;
c is an integer from 1 to 12;
and
A represents
--O--;
--S--;
--OC(O)--;
--C(O)O--;
--(R.sup.5)N--;
or
--(R.sup.5)(R.sup.6)N.sup.+ --;
wherein
R.sup.5 and R.sup.6 represent a hydrogen atom;
a linear or branched, saturated or unsaturated C.sub.1 to C.sub.24 hydrocarbon radical;
the hydroxyethyl radical;
or the R.sub.F (CH.sub.2).sub.a W radical;
wherein
R.sub.F , a, and W are as defined above;
--(CH.sub.2).sub.n --;
wherein n=0 or 1;
--C(O)N(R.sup.5)--(CH.sub.2).sub.s --B--, wherein
R.sup.5 is as defined above;
s=1 to 12;
and
B is --O--;
--OC(O)-- or --C(O)O--;
--C(O)N(R.sup.7)--(CH.sub.2).sub.r -- or --N(R.sup.7)C(O)(CH.sub.2).sub.r --;
wherein
r=1 to 12;
and
R.sup.7 represents a hydrogen atom;
a linear or branched, saturated or unsaturated C.sub.1 to C.sub.24 hydrocarbon radical;
the hydroxyethyl radical;
or
the R.sub.F (CH.sub.2).sub.a --W-- radical;
wherein
R.sub.F, a, and W are as defined above;
R.sup.2 represents
a hydrogen atom;
R.sup.1 --;
R.sub.H --W--A--(CH.sub.2).sub.b --;
R.sub.H --(CH.sub.2 CH.sub.2 O).sub.c --CH.sub.2 --;
R.sub.H --(CH(CH.sub.3)CH.sub.2 O).sub.c --CH.sub.2 --;
or
R.sub.H --(CH.sub.2 CH.sub.2 S).sub.c --CH.sub.2 --;
wherein
R.sub.H represents a hydrogen atom;
or
a linear or branched, saturated or unsaturated C.sub.1 to C.sub.20 hydrocarbon chain;
and
W, A, b and c are as defined above;
R.sup.3 represents a radical selected from the group consisting of:
R.sub.F --;
R.sub.F --(CH.sub.2).sub.a --W--A--;
R.sub.F (CH.sub.2 CH.sub.2 O).sub.c --;
R.sub.F --(CH(CH.sub.3)CH.sub.2 O).sub.c --;
R.sub.F (CH.sub.2 CH.sub.2 S).sub.c --;
R.sub.F --W--;
R.sub.H --W--A--;
R.sub.H (CH.sub.2 CH.sub.2 O).sub.c --;
R.sub.H (CH(CH.sub.3)CH.sub.2 O).sub.c --;
and
R.sub.H (CH.sub.2 CH.sub.2 S).sub.c --;
wherein
R.sub.F, a, W, A, c and R.sub.H are as defined above;
provided that at least one of R.sup.2 and R.sup.3 of formula (Ib) bears the R.sub.F part;
Y represents a radical selected from the group consisting of:
--X.sup.1 (CH.sub.2).sub.a' X.sup.2 (R.sup.8);
and
--X.sup.1 (R.sup.8);
wherein
a' is an integer from 2 to 12;
X.sup.1 and X.sub.2 are independently --O--, --S-- or --N(R.sup.9)--;
wherein
R.sup.9 is a hydrogen atom;
a linear or branched, saturated or unsaturated C.sub.1 to C.sub.24 hydrocarbon;
and
R.sup.8 represents a radical derived from the group consisting of:
a sugar which is a tetrose, pentose, hexose, aminopentose, aminohexose, deoxypentose, deoxyhexose, disaccharide, oligosaccharide;
or a cyclic hexitol, a polyol consisting of the hydrogenated form of a sugar of the tetrose, pentose, hexose, aminopentose, aminohexose, deoxypentose, deoxyhexose, disaccharide or oligosaccharide series;
and
a sugar or polyol as defined above;
wherein one or several hydrogen atoms of the OH polyol or sugar groups have been replaced by an acetyl, benzyl, allyl, benzoyl, trityl, isopropylidene, benzylidene, or cyclohexylidene group;
by a group of formula (CH.sub.2 CH.sub.2 O).sub.p R.sup.9 ;
wherein
p is an integer from 1 to 100;
and
R.sup.9 is as defined above;
or
by an R.sup.1 group as defined above;
##STR11## wherein m and X.sup.1 are as defined above;
R.sup.10 and R.sup.11, which may be identical or different, represent R.sup.2 as defined above;
and
R.sup.12 represents R.sup.3 as defined above;
--OH;
--OM ;
wherein M is an organic or inorganic cation;
--O(CH.sub.2 CH.sub.2 O).sub.p R.sup.9 ;
--O(CH.sub.2 (CH.sub.3)CH.sub.2 O).sub.q R.sup.9 ;
or
--O(CH.sub.2 CH.sub.2 O).sub.q --(CH(CH.sub.3)CH.sub.2 O).sub.q' --(CH.sub.2 CH.sub.2 O).sub.q" R.sup.9 ;
wherein
R.sup.9 is as defined above;
and
p, q, q' and q" are integers from 1 to 100;
and
Z represents a radical selected from the group consisting of:
--X.sup.1 (CH.sub.2).sub.a' --X.sup.2 (R.sup.8);
--X.sup.1 (R.sup.8);
--OH;
--OM;
--O(CH.sub.2 CH.sub.2 O).sub.p R.sup.9 ;
--O(CH(CH.sub.3)CH.sub.2 O).sub.q R.sup.9 ;
--O(CH.sub.2 CH.sub.2 O).sub.q --(CH(CH.sub.3)CH.sub.2 O).sub.q' --(CH.sub.2 CH.sub.2 O).sub.q" --R.sup.9 ;
--OCH.sub.2 CH(OH)CH.sub.2 OH,
--N(R.sup.14)(R.sup.15);
--O(CH.sub.2).sub.d' --W';
and
X.sup.2 R.sup.17 wherein
X.sup.1, X.sup.2, R.sup.8, R.sup.9, a', p, q, q' and q" are as defined above;
R.sup.14 and R.sup.15 are independently a hydrogen atom;
a linear or branched C.sub.1 to C.sub.4 alkyl group;
or (CH.sub.2 CH.sub.2 O).sub.b' R.sup.9, wherein
b' is an integer from 1 to 5;
or
R.sup.14 and R.sup.15 together form --(CH.sub.2).sub.c, wherein c' is an integer from 2 to 5;
or
R.sub.14 and R.sub.15 together form with the nitrogen atom a morpholino group;
W' represents an acetic 2-amino group;
--N(R.sup.14)(R.sup.15) ;
or --N.sup.+ (R.sup.14)(R.sup.15)(R.sup.16);
wherein
R.sup.14 and R.sup.15 are as defined above;
and
R.sup.16 is independently selected from the same group as R.sup.14 or represents a radical derived from an active therapeutic agent;
d' is an integer from 1 to 5;
and
R.sup.17 is a radical derived from a pharmaceutically active molecule;
provided that:
Y and Z do not both represent --OH;
--OM or --O(CH.sub.2 CH.sub.2 O).sub.p R.sup.9 wherein p=1 to 5;
Z does not represent
--OH;
--OM;
--N(R.sup.14)(R.sup.15);
--O--(CH.sub.2).sub.d' --W';
or
--OCH.sub.2 --CH(OH)--CH.sub.2 OH;
when Y is ##STR12## and Z is not --N (R.sup.14)(R.sup.15);
--O--(CH.sub.2)d'--W';
or
--O--CH.sub.2 --(CHOH)--CH.sub.2 OH;
when Y is OH;
OM;
or O(CH.sub.2 CH.sub.2 O).sub.p R.sup.9 wherein p=1 to 5.

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Perfluoroalkylated amphiphilic phosphorus compounds: preparation and biomedical applications

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Perfluoroalkylated amphiphilic phosphorus compounds: preparation and biomedical applications

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Abstract

Claims32