Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – From carboxylic acid or derivative thereof
Reexamination Certificate
1998-12-22
2001-11-20
Hampton-Hightower, P. (Department: 1711)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
From carboxylic acid or derivative thereof
C528S170000, C528S322000, C528S328000, C528S332000, C528S335000, C528S336000, C528S342000, C424S450000, C554S035000, C554S036000, C554S037000, C554S079000
Reexamination Certificate
active
06320017
ABSTRACT:
FIELD OF THE INVENTION
The present application relates to a series of polyamide oligomers based on &ohgr;-amino (oligoethyleneglycol) alkanoic acid monomers. These compounds can be used as heterobifunctional crosslinkers which can be conjugated to a variety of biomaterials which include, inter alia, proteins, nucleic acids and lipids. Oligomer-lipid conjugates of this invention can be incorporated into liposomes, micelles and other drug delivery systems for a variety of purposes.
BACKGROUND OF THE INVENTION
The pharmacokinetics of liposomal formulations can be improved if the vesicles can be maintained in circulation. An important mechanism for clearance of liposomal formulations is thought to involve the adsorption of proteins onto the liposome surface which mediates subsequent clearance by the cells of the reticuloendothelial system (RES). This clearance may be reduced by the attachment of hydrophilic polymers, such as polyethyleneglycol (PEG), to the liposome surface. These polymers may act in one or both of two ways: (i) they may inhibit or stop protein adsorption on to the liposome's surface, or (ii) they may act as a “steric barrier” to inhibit interactions between the cells involved in clearance and any proteins that might be bound to the liposome surface. The steric barrier effect may also be used to inhibit aggregation in some systems.
PEG-lipid conjugates are used in some commercial liposome formulations to create a steric barrier at the liposome surfaces. PEG is attractive because it is cheap, readily available, non immunogenic and is soluble in all but the most apolar of solvents (see, Torchlin, et al.,
Biochim. Biophys. Acta.,
1195:11-20 (1994); Parr, et al.,
Biochim. Biophys. Acta.,
1195:11-20 (1994); and Woodle, et al.,
Bioconjugate Chem.,
5:493 (1994)). The latter properties allow easy conjugation to a wide range of substrates.
U.S. Pat. No. 5,013,556 and European Patent Applications Nos. 0572 049 A2 and 0 354 855 describe liposomes bearing PEG moieties covalently linked to the external surface. As described therein, the PEG moieties are linked to amino groups in the head group of at least one phospholipid species forming the liposomes.
U.S. Pat. No. 4,426,330 describes phospholipids wherein the polar head group has been modified by covalent attachment of a PEG moiety. European Patent Application No. 0 220 797 A2 describes a process for the preparation of liposomes.
One major drawback of the use of polyethylene glycol is that it exists as a distribution of oligomers with different molecular weights. Further, batch to batch variation can occur. Thus, the properties of the PEG-bound liposomes will vary. What is needed in the art is a specific molecular weight material of defined length to allow selective properties to be imparted to liposomes or other drug delivery systems. The present invention fulfills this and other needs.
SUMMARY OF THE INVENTION
In one aspect, the present invention relates to an intrinsically heterobifunctional polyamide oligomer (PAO) of Formula I:
In Formula I, R is a functional group including, but not limited to, hydrogen, alkyl or acyl. R
1
is a functional group including, but not limited to, hydrogen or alkyl. In an alternative embodiment, R, R
1
and the nitrogen to which they are bound form an azido moiety. R
2
, in Formula I, is a functional group including, but not limited to, hydrogen, optionally substituted alkyl, optionally substituted aryl or the side chain of any natural or synthetic amino acid or amino acid mimetic. R
3
, in Formula I, is a functional group including, but not limited to, halogen, hydroxy, alkoxy, mercapto, hydrazino, amino or NR
4
R
5
, wherein R
4
and R
5
are independently hydrogen or alkyl. In Formula I, the index “n” is an integer having a value ranging from 4 to 80; the index “m” is an integer having a value ranging from 2 to 6; the index “p” is an integer having a value ranging from 1 to 4; and the index “q” is an integer having a value of 0 or 1.
The parentheses between R and R
3
define a monomeric unit. There are “n” monomers in any given compound of Formula I. The values of m, p and q and the definitions of R
1
and R
2
may vary from monomer to monomer for any given value of “n” monomers.
In another aspect, this invention relates to a compound of Formula II:
In Formula II, R
1
is a functional group including, but not limited to, hydrogen or alkyl. A, in Formula II, is a functional group including, but not limited to, hydrogen, alkyl, acyl or a ligand. In an alternative embodiment, R
1
, A, and the nitrogen to which they are bound form an azido moiety. B, in Formula II, is a functional group including, but not limited to, halogen, hydroxy, alkoxy, amino, NR
4
R
5
(wherein R
4
and R
5
are independently hydrogen or alkyl), mercapto, hydrazino, diacylglycerolyl, dialkylglycerolyl, N,N-dialkylamino, 1,2-diacyloxy-3-aminopropane, 1,2-dialkyloxy-3-aminopropane and a ligand. In Formula II, the index “n” is an integer having a value ranging from 4 to 80; the index “m” is an integer having a value ranging from 2 to 6; the index “p” is an integer having a value ranging from 1 to 4; and the index “q” is an integer having a value of 0 or 1. As described above, the parentheses between R and R
3
define a monomeric unit. There are “n” monomers in any given compound of Formula II. The values of m, p and q and the definitions of R
1
and R
2
can vary from monomer to monomer for any given value of “n” monomers.
In yet another aspect, this invention relates to a compound of Formula III:
In Formula III, R is a functional group including, but not limited to, hydrogen, alkyl or aryl. R
1
and R
2
are functional groups which may be the same or different and include, but are not limited to, hydrogen or alkyl. In another embodiment, R, R
1
and the nitrogen to which they are bound form an azido moiety. R
6
and R
7
are functional groups which may be the same or different and include, but are not limited to, hydrogen, optionally substituted alkyl or optionally substituted aryl, wherein the substituents include aryl, amino, carboxyl, thiol or hydroxy groups or the side chain of any natural or synthetic amino acid or amino acid mimetic. The index “v” is an integer having a value ranging from 2 to 40; the indexes “m” and “r” are independently selected and have values ranging from 2 to 6; the indexes “x” and “s” are independently selected and have values ranging from 1 to 4; z and t are independently 0 or 1; and R
3
, in Formula III, is a functional group including, but not limited to, halogen, hydrogen, alkoxy, mercapto, hydrazino, amino or NR
4
R
5
, wherein R
4
and R
5
are independently hydrogen or alkyl. The parenthesis between R and R
3
define a monomeric unit. R
1
, m, R
6
, z, x, r, R
7
and t can be the same or different throughout the series of “v” monomers.
In still yet another aspect, this invention relates to a compound of Formula IV:
In Formula IV, R
1
and R
2
are functional groups which may be the same or different and include, but are not limited to, hydrogen or alkyl. R
6
and R
7
in Formula IV, are functional groups which may be the same or different and include, but are not limited to, hydrogen, optionally substituted alkyl or optionally substituted aryl, wherein the substituents include aryl, amino, carboxyl, thiol or hydroxy groups or the side chain of any natural or synthetic amino acid or amino acid mimetic. The index “v” is an integer having a value ranging from 2 to 40; the indexes “m” and “r” are independently selected and have values ranging from 2 to 6; the indexes “x” and “s” are independently selected and have values ranging from 1 to 4; z and t are independently 0 or 1. A, in Formula IV, is a functional group including, but not limited to, hydrogen, alkyl, acyl or a ligand. In an alternative embodiment, R
1
, A, and the nitrogen to which they are bound form an azido moiety. B, in Formula IV, is a functional group including, but not limited to, halogen, hydroxy, alkoxy, amino, NR
4
R
5
(wherein R
4
and R
5
are independently hydrogen or alkyl), mercapto, hydrazino, d
Hampton-Hightower P.
Inex Pharmaceuticals Corp.
Townsend and Townsend / and Crew LLP
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