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US 5,344,930 AGranted
Fluorine and phosphorous-containing amphiphilic molecules with surfactant properties
AssigneeAlliance Pharmaceutical Corp.
InventorsJean G. Riess, Francois Jeanneaux, Marie-Pierre Krafft, Catherine Santaella, Pierre Vierling
Life of this patent
Estimating the term…
Abstract
Compounds of the general formula: ##STR1## are useful as surfactants in the preparation of fluorocarbon emulsions, which can be used as oxygen-carrying blood substitutes, and for many other therapeutic and diagnostic applications. They are further useful in liposomal formulations which are themselves therapeutic agents or provide a vehicle for such agents.
Claims13
A compound of the general formula:
- ##STR4## wherein:
- m is 0 or 1;
- R.sup.1 represents:
- R.sub.F (CH.sub.2).sub.a --(CH.dbd.CH).sub.b --(CH.sub.2).sub.c --(CH.dbd.CH).sub.d --(CH.sub.2).sub.e --A--;
- R.sub.F --(CH.sub.2).sub.f --OCH.sub.2 CH(CH.sub.2 OH)CH.sub.2 --A--;
- R.sub.F --(CH.sub.2).sub.g --OCH.sub.2 CH(CH.sub.2 OH)--A--;
- wherein --A-- represents --O--, --C(O)O--, --R.sup.6 (R.sup.7)N.sup.+ --, (wherein each of R.sup.6 and R.sup.7 represents C.sub.1 -C.sub.4 alkyl or hydroxyethyl), --(CH.sub.2).sub.n --, wherein n=0 or 1, or
- --C(O)N(R.sup.9)--(CH.sub.2).sub.q --B, wherein q is an integer from 0 to 12,
- B represents --O-- or --C(O)--, and R.sup.9 is hydrogen or R.sup.6, and wherein the sum of a+c+e is from 0 to 11, the sum b+d is from 0 to 12 and each of f and g is from 1 to 12;
- R.sub.F --(CH.sub.2 --CH.sub.2 --O).sub.h --;
- R.sub.F --(CH(CH.sub.3)CH.sub.2 O).sub.h --;
- or
- R.sub.F (--CH.sub.2 --CH.sub.2 --S).sub.h --,
- wherein h is from 1 to 12;
- and
- wherein R.sub.F represents a fluorine -containing moiety having one of the following structures:
- (a) F(CF.sub.2).sub.i --, wherein i is from 2 to 12,
- (b) (CF.sub.3).sub.2 CF(CF.sub.3).sub.j --, wherein j is from 0 to 8,
- (c) R.sub.F 1(CF.sub.2 CF(CF.sub.3)).sub.k --, wherein k is from 1 to 4 , and R.sub.F 1 represents CF.sub.3 --, C.sub.2 F.sub.5 -- or (CF.sub.3).sub.2 CF--,
- (d) R.sub.F 2 (R.sub.F 3)CFO (CF.sub.2 CF.sub.2).sub.l --, wherein l is from 1 to 6 and wherein each of R.sub.F 2 and R.sub.F 3 independently represents CF.sub.3 --, C.sub.2 F.sub.5 --, n--C.sub.3 F.sub.7 -- or CF.sub.3 CF.sub.2 CF(CF.sub.3)-- or R.sub.F 2 and R.sub.F 3 taken together represent --(CF.sub.2).sub.4 -- or --(CF.sub.2).sub.5 --, provided that in compounds of the general formula Ia, when m=0, R.sup.1 is R.sub.F (CH.sub.2).sub.a --(CH.dbd.CH).sub.b --(CH.sub.2).sub.c --(CH.dbd.CH).sub.d --(CH.sub.2).sub.e --A--, wherein --A-- is --(CH.sub.2).sub.n -- and n=0, each of R.sub.F 2 and R.sub.F 3 represents CF.sub.3 --, and l is 1, then the sum of b+d must be 1 or more;
- or
- (e) one of the structures (a) to (d) in which one or more of the fluorine atoms are replaced by one or more hydrogen or bromine atoms and/or at least two chlorine atoms in a proportion such that at least 50% of the atoms bonded to the carbon skeleton of R.sub.F are fluorine atoms, and wherein R.sub.F contains at least 4 fluorine atoms,
- R.sup.2 represents R.sup.1, hydrogen or a group OR,
- wherein R represents a saturated or unsaturated C.sub.1 -C.sub.20 alkyl or C.sub.4 -C.sub.20 acyl;
- and
- when m is 1, R.sup.1 and R.sup.2 may exchange their positions;
- and
- each of X and Y independently represent:
- hydroxyl;
- --OCH.sub.2 CH(OH) CH.sub.2 OH;
- --O(CH.sub.2 CH.sub.2 O).sub.n R.sup.3,
- wherein n is an integer from 1 to 5;
- and
- R.sup.3 represents a hydrogen atom or C.sub.1 -C.sub.4 alkyl group;
- --NR.sup.4 R.sup.5 or N.sup.+ R.sup.4 R.sup.5 R.sup.8,
- wherein each of R.sup.4, R.sup.5 and R.sup.8 independently represents a hydrogen atom;
- a C.sub.1 -C.sub.4 alkyl group;
- --CH.sub.2 CH.sub.2 O(CH.sub.2 CH.sub.2 O).sub.s R.sup.3, wherein s represents an integer of from 1 to 5, or R.sup.4 and R.sup.5 when taken together represent --(CH.sub.2).sub.q wherein q is an integer of from 2 to 5, or when with the nitrogen atom R.sup.4 and R.sup.5 form a morpholino group;
- --O(CH.sub.2).sub.p Z wherein Z represents a 2-aminoacetic acid group, --NR.sup.4 R.sup.5 or --N.sup.+ R.sup.4 R.sup.5 R.sup.8 where R.sup.8 is as defined for R.sup.4 and R.sup.5 above and p is an integer of from 1 to 5;
- with the proviso that X and Y do not both represent hydroxyl;
- further provided for compounds of the general formula Ia, that when m=0 or 1, R.sup.2 is H, and R.sup.1 is R.sub.F (CH.sub.2).sub.a --(CH.dbd.CH).sub.b --(CH.sub.2).sub.c --(CH.dbd.CH).sub.d --A--, in which A is CH.sub.2 or O;
- or, when m=0 and R.sup.1 is R.sub.F --CH.sub.2 --CH.sub.2 --O).sub.h, one of X and Y is not CH.sub.2 CH(OH)CH.sub.2 OH when the other is OH or an ionized form derived from OH.
39 more elements
A compound of the general formula:
- ##STR5## wherein:
- m=0;
- R.sup.1 represents:
- R.sub.F ( CH.sub.2).sub.a --(CH.dbd.CH).sub.b --( CH.sub.2).sub.c --(CH.dbd.CH).sub.d --(CH.sub.2).sub.e --A--;
- R.sub.F --(CH.sub.2).sub.f --OCH.sub.2 CH(CH.sub.2 OH)CH.sub.2 --A--;
- R.sub.F --(CH.sub.2).sub.g --OCH.sub.2 CH(CH.sub.2 OH)--A--;
- wherein --A-- represents --O--, --C(O)O--, --R.sup.6 (R.sup.7)N.sup.+ --, (wherein each of R.sup.6 and R.sup.7 represents C.sub.1 -C.sub.4 alkyl or hydroxyethyl), --(CH.sub.2).sub.n --, wherein n=0 or 1, or --C(O)N(R.sup.9)--(CH.sub.2).sub.q --B,
- wherein q is an integer from 0 to 12;
- B represents --O-- or --C(O)--, and R.sup.9 is hydrogen or R.sup.6 ;
- and wherein the sum of a+c+e is from 0 to 11, the sum b+d is from 0 to 12 and each of f and g is from 1 to 12;
- R.sub.F --(CH.sub.2 --CH.sub.2 --O).sub.l --;
- R.sub.F --(CH(CH.sub.3)CH.sub.2 O).sub.h --;
- or
- R.sub.F (--CH.sub.2 --CH.sub.2 --S).sub.h --,
- wherein h is from 1 to 12;
- and
- wherein R.sub.F is F(CF.sub.2).sub.i --, wherein i is from 2 to 12;
- R.sup.2 represents R.sup.1, hydrogen or a group OR,
- wherein R represents a saturated or unsaturated C.sub.1 -C.sub.20 alkyl or C.sub.4 -C.sub.20 acyl;
- and
- each of X and Y independently represent:
- hydroxyl;
- --OCH.sub.2 CH(OH)CH.sub.2 OH;
- --O(CH.sub.2 CH.sub.2 O).sub.n R.sup.3,
- wherein n is an integer from 1 to 5;
- and
- R.sup.3 represents a hydrogen atom or C.sub.1 -C.sub.4 alkyl group;
- --NR.sup.4 R.sup.5 or N.sup.+ R.sup.4 R.sub.5 R.sup.8,
- wherein each of R.sup.4, R.sup.5 and R.sup.8 independently represents a hydrogen atom;
- a C.sub.1 -C.sub.4 alkyl group;
- --CH.sub.2 CH.sub.2 O(CH.sub.2 CH.sub.2 O).sub.s R.sup.3, wherein s represents an integer of from 1 to 5, or R.sup.4 and R.sup.5 when taken together represent --(CH.sub.2).sub.q wherein q is an integer of from 2 to 5, or when with the nitrogen atom R.sup.4 and R.sup.5 form a morpholino group;
- --O(CH.sub.2).sub.p Z wherein Z represents a 2-aminoacetic acid group, --NR.sup.4 R.sup.5 or --N.sup.+ R.sup.4 R.sup.5 R.sup.8 where R.sup.8 is as defined for R.sup.4 and R.sup.5 above, and p is an integer of from 1 to 5;
- with the proviso that X and Y do not both represent hydroxyl;
- and further provided for compounds of the general formula Ia, that when R.sup.2 is H, and R.sup.1 is R.sub.F (CH.sub.2).sub.a --(CH.dbd.CH).sub.b --(CH.sub.2).sub.c --(CH.dbd.CH).sub.d --A--, in which A is CH.sub.2 or O;
- or, when R.sup.1 is R.sub.F --CH.sub.2 --CH.sub.2 --O).sub.h, one of X and Y is not CH.sub.2 CH (OH)CH.sub.2 OH when the other is OH or an ionized form derived from OH.
32 more elements
A compound of the general formula:
- ##STR6## wherein:
- m=1;
- R.sup.1 and R.sup.2 each represents:
- R.sub.F (CH.sub.2).sub.a --(CH.dbd.CH).sub.b --(CH.sub.2).sub.c --(CH.dbd.CH).sub.d --(CH.sub.2).sub.e --A--;
- R.sub.F --(CH.sub.2).sub.f --OCH.sub.2 CH(CH.sub.2 OH)CH.sub.2 --A--;
- R.sub.F --(CH.sub.2).sub.g --OCH.sub.2 CH(CH.sub.2 OH)--A--;
- wherein --A-- represents --O--, --C(O)O--, --R.sup.6 (R.sup.7)N.sup.+ --, (wherein each of R.sup.6 and R.sup.7 represents C.sub.1 -C.sub.4 alkyl or hydroxyethyl), --(CH.sub.2).sub.n --, wherein n=0 or 1, or --C(O)N(R.sup.9)--(CH.sub.2).sub.q --B, wherein q is an integer from 0 to 12, B represents --O-- or --C(O)--, and R.sup.9 is hydrogen or R.sup.6,
- and wherein the sum of a+c+e is from 0 to 11, the sum b+d is from 0 to 12 and each of f and g is from 1 to 12;
- R.sub.F --(CH.sub.2 --CH.sub.2 --O).sub.h --;
- R.sub.F --(CH(CH.sub.3)CH.sub.2 O).sub.h --;
- R.sub.F (--CH.sub.2 --CH.sub.2 --S).sub.h --,
- wherein h is from 1 to 12;
- and
- wherein R.sub.F represents F(CF.sub.2).sub.i --, wherein i is from 2 to 12;
- and R.sup.2 is the same as R.sup.1 ;
- and
- each of X and Y independently represent:
- hydroxyl;
- --OCH.sub.2 CH(OH)CH.sub.2 OH;
- --O(CH.sub.2 CH.sub.2 O).sub.n R.sup.3,
- wherein n is an integer from 1 to 5;
- and
- R.sup.3 represents a hydrogen atom or C.sub.1 -C.sub.4 alkyl group;
- --NR.sup.4 R.sup.5 or N.sup.+ R.sup.4 R.sup.5 R.sup.8,
- wherein each of R.sup.4, R.sup.5 and R.sup.8 independently represents a hydrogen atom;
- a C.sub.1 -C.sub.4 alkyl group;
- --CH.sub.2 CH.sub.2 O(CH.sub.2 CH.sub.2 O).sub.s R.sup.3, wherein s represents an integer of from 1 to 5, or R.sup.4 and R.sup.5 when taken together represent --(CH.sub.2).sub.q wherein q is an integer of from 2 to 5, or when with the nitrogen atom R.sup.4 and R.sup.5 form a morpholino group;
- --O(CH.sub.2).sub.p Z wherein Z represents a 2-aminoacetic acid group, --NR.sup.4 R.sup.5 or --N.sup.+ R.sup.4 R.sup.5 R.sup.8 where R.sup.8 is as defined for R.sup.4 and R.sup.5 above, and p is an integer of from 1 to 5;
- with the proviso that X and Y do not both represent hydroxyl;
- and further provided for compounds of the general formula Ia, that when R.sup.2 is H, and R.sup.1 is R.sub.F (CH.sub.2).sub.a --(CH.dbd.CH).sub.b --(CH.sub.2).sub.c --(CH.dbd.CH).sub.d --A--, in which A is CH.sub.2 or O;
- one of X and Y is not CH.sub.2 CH(OH)CH.sub.2 OH when the other is 0H or an ionized form derived from OH.
28 more elements
A compound of the general formula:
- ##STR7## wherein:
- m=0 or 1;
- R.sup.1 represents:
- R.sup.1 (CH.sub.2).sub.a --(CH.dbd.CH).sub.b --(CH.sub.2).sub.c --(CH.dbd.CH).sub.d --(CH.sub.2).sub.e --A--;
- R.sub.F --(CH.sub.2).sub.f --OCH.sub.2 CH(CH.sub.2 OH)CH.sub.2 --A--;
- R.sub.F --(CH.sub.2).sub.g --OCH.sub.2 CH(CH.sub.2 OH)--A--;
- wherein --A-- represents --O--, --C(O)O--, --R.sup.6 (R.sup.7)N.sup.+ --, (wherein each of R.sup.6 and R.sup.7 represents C.sub.1 -C.sub.4 alkyl or hydroxyethyl),
- (CH.sub.2).sub.n --, wherein n=0 or 1, or
- --C(O)N(R.sup.9)--(CH.sub.2).sub.q --B, wherein q is an integer from 0 to 12, B represents --O-- or --C(O)--, and R.sup.9 is hydrogen or R.sup.6 ,
- and wherein the sum of a+c+e is from 0 to 11, the sum b+d is from 0 to 12 and each of f and g is from 1 to 12;
- R.sub.F --(CH.sub.2 --CH.sub.2 --O).sub.h --;
- R.sub.F --(CH(CH.sub.3)CH.sub.2 O).sub.h --;
- or
- R.sub.F (--CH.sub.2 --CH.sub.2 --S).sub.h --,
- wherein h is from 1 to 12;
- and
- wherein R.sub.F represents a fluorine-containing moiety having one of the following structures:
- (a) F (CF.sub.2).sub.i --, wherein i is from 2 to 12,
- (b) (CF.sub.3).sub.2 CF(CF.sub.2).sub.j --, wherein j is from 0 to 8,
- (c) R.sub.F 1(CF.sub.2 CF(CF.sub.3)).sub.k --, wherein k is from 1 to 4, and R.sub.F 1 represents CF.sub.3 --, C.sub.2 F.sub.5 -- or (CF.sub.3).sub.2 CF--,
- (d) R.sub.F 2(R.sub.F 3)CFO(CF.sub.2 CF.sub.2).sub.l --, wherein l is from 1 to 6 and wherein each of R.sub.F 2 and R.sub.F 3 independently represents CF.sub.3 --, C.sub.2 F.sub.5 --, n--C.sub.3 F.sub.7 -- or CF.sub.3 CF.sub.2 CF(CF.sub.3)-- or R.sub.F 2 and R.sub.F 3 taken together represent --(CF.sub.2).sub.4 -- or --(CF.sub.2).sub.5 --, provided that in compounds of the general formula of Ia, when m=0, R.sup.2 is H, R.sup.1 is R.sub.F (CH.sub.2).sub.a --(CH.dbd.CH).sub.b --(CH.sub.2).sub.c --(CH.dbd.CH).sub.d --(CH.sub.2).sub.e --A--, wherein --A-- is --(CH.sub.2).sub.n -- and n=0, each of R.sub.F 2 and R.sub.F 3 represents CF.sub.3 --, and l=1, then the sum of b+d must be 1 or more;
- or
- (e) one of the structures (a) to (d) in which one or more of the fluorine atoms are replaced by one or more hydrogen or bromine atoms and/or at least two chlorine atoms in a proportion such that at least 50% of the atoms bonded to the carbon skeleton of R.sub.F are fluorine atoms, and wherein R.sup.F contains at least 4 fluorine atoms;
- R.sup.2 represents R.sup.1, hydrogen or a group OR,
- wherein R represents a saturated or unsaturated C.sub.1 -C.sub.20 alkyl or C.sub.4 -C.sub.20 acyl;
- and
- when m is 1, R.sup.1 and R.sup.2 may exchange their positions;
- and
- each of X and Y independently represent:
- hydroxyl, morpholino, or --O(CH.sub.2 CH.sub.2 0).sub.n R.sup.3,
- wherein n is an integer 1 or 2;
- and
- R.sup.3 represents a methyl group, CH.sub.3 ;
- with the proviso that X and Y do not both represent hydroxyl or an ionized form derived from hydroxyl;
- and further provided for compounds of the general formula Ia, that when m=0 or 1, R.sup.2 is H, and R.sup.1 is R.sub.F (CH.sub.2).sub.a --(CH.dbd.CH).sub.b --(CH.sub.2).sub.c --(CH.dbd.CH).sub.d --A--, in which A is CH.sub.2 or O;
- or, when m=0 and R.sup.1 is R.sub.F --CH.sub.2 --CH.sub.2 --O).sub.h, one of X and Y is not CH.sub.2 CH(OH)CH.sub.2 OH when the other is OH or an ionized form derived from OH.
33 more elements
Dependencies are inferred from the claim text.