Multicyclic aromatic compounds and uses thereof

Details Multicyclic aromatic compounds and uses thereof Multicyclic aromatic compounds and uses thereof

2000-08-10

2003-02-25

Aulakh, Charanjit S. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C544S310000, C544S323000, C546S041000, C546S036000, C252S301250, C252S700000

Reexamination Certificate

active

06525200

ABSTRACT:

The present invention relates to multicyclic aromatic compounds, and more particularly to multicyclic aromatic compounds useful as complexing agents.
BACKGROUND OF THE INVENTION
Small biological molecules such as urea, guanidine, their derivatives and their acid addition salts are present in human bodily fluids, such as serum and urine, where they can serve as indications of various disorders. For example, the concentration of urea in blood serum is used as an indication of renal dysfunction, such as uremia, and defects in nitrogen metabolism; see for example, (Wright, “Maintenance Hemodialysis”, G. K. Hall: Boston (1981), Chpt. 1).
Assays for determining the concentration of guanidine and its derivatives in blood serum, urine and hemodialysate are useful in detecting certain metabolic disorders such as hyperargininemia and argininosuccinic acidurea; (Kobayashi, et al., Anal. Chem., 58, 1380-1383 (1986)).
Small molecules designed to bind urea, guanidine and their derivatives and signal this event can be applied for determination of analyte concentration in bodily fluids. Previously, a hexagonal lattice approach for urea receptors was developed by Bell's research group (Bell et al., in
Inclusion Phenomena and Molecular Recognition,
Atwood, J. L., Ed. (Plenum, New York, 1990) pp. 49-56). For example, fused pyridine rings in 1 and 2 form a rigid backbone for hydrogen bond donor/acceptor atoms (FIG.
1
). The complexes of 1 and 2 with urea are stabilized by four and six hydrogen bonds, respectively. The dissociation constants (K
d
) of these complexes were measured in organic solvents with low polarity. Thus, the K
d
for complex 1 in water-saturated chloroform was calculated as 0.33 mM and for complex 2 in 1:1 CDCl
3
/DMSO mixture as 0.07 mM (Bell et al.
J. Am. Chem. Soc.
1988, 110, 3673; Bell et al., in
Inclusion Phenomena and Molecular Recognition,
Atwood, J. L., Ed. (Plenum, New York, 1990) pp. 49-56; Bell et al.
Pure & Appl. Chem.
1998, 70, 2371-2377; Bell et al.,
Angew. Chem. Int. Ed. Engl.
1997, 36, 1536-1538). Although the stability of complexes 1 and 2 in relatively non-polar solvents is significant, it is well known that corresponding complexes stability in aqueous solutions is generally weaker by several orders of magnitude. Lack of solubility of 1 and 2 in aqueous medium, due to lipophilicity of these molecules, precludes the use of these receptors in water-based solutions, such as serum and urine.
Since the 1970's almost all designed receptors for guanidinium have been crown ether derivatives which lack chromogenic or fluorescence signaling (e.g., Lehn et al.,
J. Chem. Soc., Chem. Commun.
1979, 296-298). In 1990 Bell et al. (
Angew. Chem. Int. Ed. Eng.
1990, 29, 923-925) reported an alternative to flexible crown ethers—also cyclic, but rigid and preorganized, a torand which forms a highly stable complex with unsubstituted guanidinium ion in methanol/dichloromethane mixture. However, the reported torand lacks signaling mechanism and is not soluble in water. Another type of partially flexible receptors for guanidinium ion, called molecular “tweezer”, which incorporate two carboxylate groups (Eliseev et al.,
J. Am. Chem. Soc.
1997, 119, 1147-1148) and two phosphonate groups (Schrader,
Chem. Eur. J.
1997, 3, 1537-1541), only weakly bind guanidinium ions in methanol.
Recently reported water-soluble receptor for guanidinium ion, the “arginine cork” (3) strongly binds alkylguanidinium ions in water (Bell et al.,
Angew. Chem., Int. Ed. Engl.,
1999, 38, 2543-2547). The dissociation constant of the complex of 3 with methylguanidinium ion in water was found as 4.3 mM. The two negatively-charged carboxylate groups make receptor 3 soluble in water. Electrostatic attraction between negatively charged carboxylate groups of 3 and the positive charge of guanidinium ion together with the preorganized network of the hydrogen-bond acceptor sites of the receptor make the complex of 3 with guanidinium ion to be highly stable even in water. However, receptor 3 does not change any optical properties upon binding guanidinium ions.
A rigid U-shaped guanidinium receptor (4) undergoes a small change in absorption spectrum upon complexation to unsubstituted guanidinium ion (Bell et al.,
Angew. Chem. Int. Ed. Eng.
1990, 29, 923-925). The mechanism of this absorption change apparently comes from partial flexibility of the naphthyridine arms in 4. Without guanidinium these arms can flip up and down from the plane of the molecule. Complexation of guanidinium ion partially restricts this motion, resulting rigidification of the chromophore with consequent change in optical properties. However, receptor 4 is restricted by design to bind only to unsubstituted guanidinium ion. In addition, the molecules it is not soluble in water due to lipophilicity of the molecule.
From the above examples of urea and guanidinium receptors, it will be readily apparent that currently available compounds lack one or more of the useful properties required for utilization as chemosensors. These properties include aqueous solubility, strong binding to analyte in aqueous solutions and optical signaling of the binding event. In view of these deficiencies, there is a need for compounds that can provide a suitable balance of these properties.
Accordingly, it is an object of the present invention to provide compounds that exhibit these required properties.
SUMMARY OF THE INVENTION
The present invention provides multicyclic aromatic compounds having the formula set forth below:
where R
1
, R
2
and R
3
are the same or different and at least one is selected from the group consisting of a hydrophillic substituent, a directly or indirectly linked quencher molecule, a substituted or unsubstituted heterocyclic ring structure, and a combination thereof, with the remainder being hydrogen,
where R
1
′, R
2
′ and R
3
′ are the same or different and at least one is selected from the group consisting of a hydrophillic substituent, a substituted or unsubstituted heterocyclic ring structure, a directly or indirectly linked fluorophore, R
1
′ and R
2
′ together form a five- or six-membered cyclic ring fused to a substituted or unsubstituted heterocyclic ring structure, and a combination thereof, with the remainder being hydrogen;
where R4 and R4′ are the same or different and are selected from the group consisting of hydrogen, a hydrophillic substituent, a substituted or unsubstituted heterocyclic ring structure, a directly or indirectly linked quencher molecule, a directly or indirectly linked fluorophore and a combination thereof, or R4 and R4′ together form a five- or six-membered cyclic ring fused to a substituted or unsubstituted heterocyclic ring structure;
where A and A′ are the same or different and are selected from the group consisting of carbon, nitrogen, oxygen, sulfur and a combination thereof,
where X and X′ are the same and different and are a substituted or unsubstituted chain of 0 to 10 atoms selected from the group consisting of carbon, nitrogen, oxygen, sulfur, and a combination thereof;
where R
1
and R
1
′ are not both selected from the group consisting of a carboxy group, a carboxylate and a combination thereof, when R
2
, R
2
′, R
3
, R
3
′, R
4
, and R
4
′ are hydrogen, A and A′ are methylene, and X and X′ are methylene; and
where R
1
is not selected from the group consisting of a carboxy group and a carboxylate, when R
1
′ is a substituted heterocyclic ring structure being a pyridine with substituents other than amines or alcohols.
The present invention also advantageously provides methods of forming complexes with urea, guanidine, mono- or di-substituted alkyl guanidines, derivatives thereof and acid addition salts thereof, which includes:
(a) providing a multicylic aromatic compound having the formula:
where R
1
, R
2
and R
3
are the same or different and at least one is selected from the group consisting of a hydrophillic substituent, a directly or indirectly linked quencher molecule

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