Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-09-08
2003-03-11
Fonda, Kathleen K. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S053000, C536S017200, C536S017900, C536S029100
Reexamination Certificate
active
06531454
ABSTRACT:
TECHNICAL FIELD
The present invention relates to certain sugars. More specifically, this invention provides glycosylated polyamine compounds, methods for their synthesis, characterization, their use as ligands in preparing metal complexes for developing analytical methodology, and their pharmaceutical uses, for example, as antitumor agents or modulators of estrogen receptor activity.
BACKGROUND OF THE INVENTION
Glycosylated amines, also variously known as N-glycosides, glycosylamines, or aminoglycosides, are formed by reacting a carbonyl containing sugar molecule with an amine. Glycosylated amines are known in the fields of polymer chemistry, and cosmetics. For example, glycosylated amines from primary amines of intermediate molecular weight have been reported to be good wetting agents. Mitts, E. and Hixon, R. M.,
J. Am. Chem. Soc.,
66: 483 (1944). Glycosylated amines as a class have been reported as components for detergents and cosmetics, surfactants, polymers, sweeteners and as liquid crystalline compounds. Lammers, et al.,
Tetrahedron,
59: 8103 (1994). Glycosylamines also have been used in kraft pulping liquor in the wood processing industry. MacLeod, J. M.,
Carbohydrate Res.,
75: 71 (1979).
Glycosylated amines also play a vital role at the cellular level, because they are essential components of nucleic acids, wherein the ring nitrogen atoms of purine or pyrimidine bases form N-glycosyl linkages with carbon atom 1 of D-ribose or 2-deoxy-D-ribose, which are incorporated into ribonucleic acid (RNA) and deoxyribonucleic acid (DNA), respectively. While the physiological functions of some of the glycosylated amines appear to have been examined, their potential as pharmacological agents has not been fully explored.
Lammers et al. supra, have disclosed the preparation of mono- and diglycosylamines, wherein the amine and the saccharide were mixed in water under reductive amination conditions. However the yields were poor. Mitts et al. supra, reported the preparation of N,N′-propylenediglucamine by refluxing glucose with propylenediamine in methanol followed by reduction over activated Raney Nickel and at high pressures and temperatures. The yield appeared to be very low in this case also because it was reported that only a very small amount of the reduced compound was isolated. Mitts et al. further disclosed that attempts to isolate and characterize the condensation products of amines such as isopropylamine, 2-aminooctane, and propylenediamine with glucose were not successful. Accordingly, there exists a need for a synthetic procedure to prepare glycosylated amines and glycosylated polyamines comprising a variety of sugars and amines.
Many analytical techniques have been developed to characterize glycosylamines. Only recently, however, has the research focussed on investigation of linkage information of metal cationized oligosaccharides by mass spectrometry (MS) and tandem mass spectrometry (MS
n
). Asam, M. R. and Glish, G. L.,
J. Am. Soc. Mass Spectrom.,
8: 987 (1998); Weiskopf, et al.
Rapid Com. Mass Spec.,
11: 1493 (1997); Hofineister, et al.,
J. Am. Chem. Soc.,
113: 5964 (1991); and Fura, A. and Leary, J. A.,
Anal. Chem.,
65: 2805 (1993).
Mass spectrometry is not a tool traditionally used to distinguish stereoisomers. However, the stereochemistry of individual monosaccharides as well as &agr; versus &bgr; configuration of glycosidic bonds in disaccharides can be determined by MS
n
. See for example, Gaucher, S. P. and Leary, J. A.,
Anal. Chem.,
70: 3009 (1998); Smith, et al.
J. Org. Chem.,
62: 2152 (1997). This method involves cationizing the saccharide using a metal-ligand system such as Zn(diethylenetriamine)
2
Cl
2
or Ni(1,3-diaminopropane)
3
Cl
2
, by allowing metal N-glycoside complexes to form in solution. Yano, S.,
Coord. Chem. Rev.,
92: 113 (1988); and Yano, et al.
J. Chem. Soc., Dalton Trans.,
1699 (1993). The complexes are then transferred from solution to the gas phase by electrospray ionization (ESI) or fast atom bombardment (FAB) and analyzed by tandem mass spectrometry (MS/MS). See for example, Gaucher and Leary, supra; Smith and Leary, supra; and Smith, et al., supra. The axial versus equatorial stereochemistry of the C2 and C4 hydroxyl groups could be differentiated by the cross ring cleavage patterns observed in the gas phase.
In the above-described mass spectrometric procedures, it is time consuming to screen the efficacy of different metals for a given saccharide or ligand because each individual metal-ligand complex requires synthesis a priori. Accordingly, methods for rapid synthesis of metal-ligand complexes are needed so that the metal-ligand complexes so formed can be readily analyzed upon their synthesis.
All literature references, patents, and patent applications cited in this specification are hereby incorporated by reference in their entirety.
DISCLOSURE OF THE INVENTION
The present invention discloses glycosylated polyamines, methods for their preparation and use, and pharmaceutically acceptable compositions comprising gylcosylated polyamines. Glycosylated polyamines, in one embodiment, are prepared from two or more saccharides and a polyamine. In one embodiment, the glycosylated polyamine compound has the following formula (Formula I):
R
1
—Z—R
2
(Formula I)
wherein:
each of R
1
and R
2
is independently a monosaccharide residue or an oligosaccharide residue; Z is an aliphatic polyamino linker that is the residue of an aliphatic polyamine comprising at least two amino groups, each of which is independently a primary or secondary amino group; and each of R
1
and R
2
is linked through its anomeric carbon at its 1 position to a different amino group of the aliphatic polyamino linker to form a glycosidic bond;
provided that when each of R
1
and R
2
is the same and is a glucose, galactose, mannose, or cellobiose residue, Z is the residue of an aliphatic polyamine other than ethylenediamine or diaminopropane;
and pharmaceutically acceptable salts, prodrugs and derivatives thereof.
In one embodiment, each of R
1
and R
2
of Formula I is an oligosaccharide residue. In another embodiment, at least one of R
1
and R
2
has a group other than hydrogen in equatorial conformation at the C2 position that is adjacent to the anomeric carbon atom linked to the aliphatic polyamine.
In a further embodiment, the group in equatorial conformation at C2 position is a hydroxy, alkoxy, halo, lower alkyl, amino, N-acetyl, N-alkyl, N-hydroxy, N-alkoxy, aminothiol, amino alcohol, spermine, or nitro group, and optionally a hydrogen in the axial conformation.
In one embodiment of Formula I, R
1
is a monosaccharide residue and R
2
is an oligosaccharide residue. In another embodiment, each of R
1
and R
2
of Formula I is a monosaccharide residue. In yet another embodiment, each of R
1
and R
2
of Formula I is a hexose residue. In a further embodiment, each of the hexose residues is independently substituted by one or more of the following groups: a lower alkyl, lower alkoxy, acyl, carboxy, carboxyamino, amino, acetamido, halo, thio, or nitro; provided that the anomeric carbon has a free hydroxyl group to form a glycosidic linkage with the aliphatic polyamino linker.
In one embodiment, at least one of R
1
and R
2
has a group other than hydrogen in equatorial conformation at the C2 position that is adjacent to the anomeric carbon atom linked to the aliphatic polyamine. In another embodiment, the group in equatorial conformation at C2 position is a hydroxy, alkoxy, halo, lower alkyl, amino, N-acetyl, N-alkyl, N-hydroxy, N-alkoxy, or nitro group, and optionally a hydrogen in the axial conformation.
In one embodiment, the aliphatic polyamino linker of Formula I is a residue of diethylenetriamine. In a further embodiment, the diethylenetriamine residue is substituted by one or more the following groups: lower alkyl, hydroxy, lower alkoxy, amino, acyl, acetamido, halo, or nitro; provided that there is at least one amino group per each saccharide residue to form a glycosidic linkage.
Another embodiment presents a compound of Formul
Gaucher Sara P.
Leary Julie A.
Pedersen Steven F.
Fonda Kathleen K.
Maier Leigh C.
The Regents of the University of California
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