Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Chemical aftertreatment – e.g. – acylation – methylation – etc.
Reexamination Certificate
2002-05-07
2004-04-27
Russel, Jeffrey E. (Department: 1654)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Chemical aftertreatment, e.g., acylation, methylation, etc.
C424S009340, C424S178100, C514S002600, C514S04400A, C530S300000, C530S350000, C530S391100, C530S402000, C530S409000, C530S410000, C536S023100
Reexamination Certificate
active
06727347
ABSTRACT:
Subject of the present invention is the preparation of polycation based bioconjugates that are suitable for transporting active substances of different type within the body, that is for functioning as carriers.
New polycation bioconjugates according to the invention are prepared by coupling [(k)Mx] and/or [(i)Mx] molecules, bearing functional groups appropriate for conjugation—which may either be identical ones or of (two or more i.e. “x”) different kind—to a given representative of isopolypeptide polycations, having free &agr;-amino groups, as carrier molecules, by chemical bonds; and the bioconjugates synthetized this way can be described by the general formula (I):
and within the polycation bioconjugatis there are isopolypeptide polycation carrier molecules (further on: carrier molecules), having free &agr;-amino groups, that can be described by the general formula (I/a):
and in each carrier molecule of general formula (I/a) there are monomeres of the same configuration (i.e. either D-, or L-), and the individual monomeres are not linked together by their amino groups in the &agr;-positions, but by their in other amino groups (i.e. in &bgr;-, &ggr;-, &dgr;-, &egr; etc.) positions, according to the value of “m”, and their structures are therefore divergent from those of the polypeptides build up by customary &agr;-amino-peptide bonds, generally occurring in mammal organisms;
wherein:
“r” is a mean value between 20 and 400;
“m”=0, 1, 2, 3, . . . k;
“[(k)Mx]” designates enhancer molecules and/or connecting molecules conjugated by covalent (═k) bonds to the isopolypeptide polycation carrier molecule, and
“[(i)Mx]” designates enhancer molecules conjugated by ionic (═i) bonds to the isopolypeptide polycation carrier molecule, whereas the said enhancer molecules and connecting molecules having appropriate functional groups for conjugation may either be identical ones or of (two or more i.e. “x”) different kind and the enhancer molecules can be conjugated
directly and/or
indirectly through a connecting molecule,
and further the joint occurrence of [(k)Mx] and [(i)Mx] within the same polycation bioconjugate is symbolized by [(k/i)Mx]. On the basis of the general formula (I) of the new polycation bioconjugates according to the invention further molecules of general formulae (II), (III), (IV), (VI), (VII), (IX), (X), (XI) and of schematic formulae (V), (VIII), (IX/a), (X/a), (XI/a) can be derived.
In case the [Ex
i
] enhancer molecules—which may either be identical ones or of (two or more i.e. “x”) different kind—are directly conjugated to a given representative of carrier molecules of general formula (I/a), by covalent bonds, then:
[(
k
)
Mx]=[Ex
i
]
p1
,
and the new polycation bioconjugates are being described by the general formula (II):
In case the [(−)Cx
j
] connecting molecules of exclusively anionic character—which may either be identical ones or of (two or more i.e. “x”) different kind—are conjugated to a given representative of carrier molecules of general formula (I/a), by covalent bonds, an additional possibility arises to establish ionic bonds with cations—which may either be identical ones or of (two or more i.e. “x”) different kind—and then:
[(
k
)
Mx]=
[(−)
Cx
j
]
p2
,
and the new conjugates are being described by the general formula (III):
In case the [Ex
ek
] enhancer molecules—which may either be identical ones or of (two or more i.e. “x”) different kind—are indirectly conjugated by covalent bonds to a given representative of carrier molecules of general formula (I/a), through [Cx
ck
] connecting molecules—which may also be either identical ones or of (two or more i.e. “x”) different kind—then:
[(
k
)
Mx]=[Cx
ck
−Ex
ek
]
p3
,
and the new polycation bioconjugates are being described by the general formula (IV):
In the case when [Ex
i
] and/or [Cx
ck
−Ex
ek
] enhancer molecules and/or [(−)Cx
j
] connecting molecules of anionic character are also conjugated to a given representative of carrier molecules of general formula (I/a), and furthermore from among “p
1
, p
2
and p
3
” the value of at least two are greater than 0, then:
[(
k
)
Mx]=[Ex
i
]
p1
+[Cx
ck
−Ex
ek
]
p3
+[(−)
Cx
j
]
p2
,
and the new polycation bioconjugates are being described by the schematic formula (V):
wherein:
“Ex” in [Ex
i
]
p1
designates the Ex enhancer molecules of different (“x”) kind conjugated directly to a given representative of carrier molecules of general formula (I/a), by covalent bonds, and
“i” indicates whether the Ex enhancer molecules, conjugated to the given carrier molecule by covalent bonds, are identical ones (i=1), or they are of different kind, of number “i” (i=2, 3, . . . “x” kind); and
“(−)Cx” in [(−)Cx
j
]
p2
designates (−)Cx connecting molecules of exclusively anionic character, of different (“x”) kind conjugated to a given representative of carrier molecules of general formula (I/a) by covalent bonds, in order to make it capable for establishing ionic bonds with cations, and
“j” indicates whether the (−)Cx connecting molecules, conjugated to the given carrier molecule by covalent bonds, are identical ones (j=1), or they are of different kind, of number “j” (j=2, 3, . . . “x”); and “Cx−Ex” in [Cx
ck
−Ex
ek
]
p3
designates the Ex enhancer molecules of different (“x”) kind, conjugated by covalent bonds indirectly, through Cx connecting molecules of different (“x”) kind, and these Cx molecules are also conjugated by covalent bonds to a given representative of carrier molecules of general formula (I/a), and
“ck” indicates whether the Cx connecting molecules, conjugated to a given carrier molecule by covalent bonds, are identical ones (ck=1), or they are of different kind, of the number “ck” (ck=2, 3, . . . “x”), and these Cx connecting molecules—practically depending on the structure of the Ex enhancer molecules—may be neutral and/or of anionic and/or of cationic character,
“ck” indicates whether the Ex enhancer molecules, conjugated to a given carrier molecule indirectly through “Cx” connecting molecules by covalent bonds, are identical ones (ek=1), or they are of different kind, of the number “ck” (ek=2, 3, . . . “x”).
Furthermore the degree of saturation in % of a given representative of carrier moleculea of general formula (I/a) by [Ex
i
]
p1
and/or [Cx
ck
−Ex
ek
]
p3
enhancer molecules and/or [(−)Cx
j
]
p2
connecting molecules are given by the different values of “p
1
, p
2
and p
3
”, whereas the summarized value of “p
1
+p
2
+p
3
” within one given polycation bioconjugate is >0 and ≦100; whereby the ratio between the free (not involved in peptide bonds) and bound NH
2
-groups is determined, which in turn influences the charge and the cationic character of the polycation bioconjugates; and thus
“p
1
” indicates a degree of saturation in % of a carrier molecule of general formula (I/a) with [Ex
i
] enhancer molecules,
“p
2
” indicates a degree of saturation in % of a carrier molecule of general formula (I/a) with [(−)Cx
j
] connecting molecules of exclusively anionic character,
“p
3
” indicates a degree of saturation in % of a carrier molecule of general formula (I/a) with [Cx
ck
−Ex
ek
] enhancer molecules which are bound to connecting molecules,
and on the basis of the above, in the schematic formula (V) “p
1
+p
2
+p
3
”>0 and ≦100, and from among “p
1
, p
2
and p
3
” the value of at least two are greater than 0; further in a given polycation bioconjugate, the Ex molecules in [Ex
i
] and the (−)Cx molecules in [(−)Cx
j
] are not necessarily identical with those E
Covington & Burling
Reister Andrea G.
Russel Jeffrey E.
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