Dye labeled imidazoquinoline compounds

Details Dye labeled imidazoquinoline compounds Dye labeled imidazoquinoline compounds

2002-02-19

2003-10-07

Huang, Evelyn Mei (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S013000, C546S118000, C544S229000, C548S110000, C548S405000, C549S224000, C549S225000, C549S226000, C549S227000

Reexamination Certificate

active

06630588

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to imidazonaphthyridine, imidazopyridine and imidazoquinoline compounds that have immune response modulating activity and that contain a dye moiety, in particular, a fluorescent dye moiety. The invention also relates to methods of preparing the dye labeled compounds.
BACKGROUND OF THE INVENTION
Compounds that are labeled or tagged have long been used in the chemical and biological sciences. Such compounds can be used in a variety of ways. For example, by labeling a compound that is known to be biologically active, one can more readily identify metabolites of the compound, one can determine the binding and/or receptor sites for the molecule, one can determine how long the compound remains in the body or other system, and so on.
One known way to label compounds is by attaching a dye marker to the compound. This is typically done by grafting a dye moiety onto the biologically active molecule or by incorporating the dye moiety into the biologically active molecule during its synthesis. It is important that the labeled compound retain the critical properties of the unlabeled compound such as selective binding to a receptor or nucleic acid, activation or inhibition of a particular enzyme, or ability to incorporate into a biological membrane. There are a wide variety of dye moieties available, including for example, dipyrrometheneboron difluoride dyes, fluorescein, fluorescein derivatives, rhodamine, rhodamine derivatives and Texas Red.
The imidazonaphthyridines, imidazopyridines and imidazoquinolines are part of a unique class of immune response modifier compounds that have the ability to induce the biosynthesis of interferon and other cytokines. See, for example, Gerster, U.S. Pat. No. 4,689,338; Gerster et al., U.S. Pat. No. 4,929,624; Gerster, U.S. Pat. No. 5,268,376; Gerster et al., U.S. Pat. No. 5,389,640; Nikolaides et al., U.S. Pat. No. 5,352,784; Lindstrom et al., U.S. Pat. No. 5,494,916.; and International Publication WO 99/29693. Dyes, particularly fluorescent dyes, are typically relatively large, bulky molecules and it is possible that such a large substituent may impair the compound's ability to bind or otherwise interact with the subject cells in a manner that causes biologic response.
SUMMARY OF THE INVENTION
We have discovered a class of dye labeled imidazonaphthyridine, imidazopyridine or imidazoquinoline compounds that retain their ability to induce cytokines. These compounds employ a spacer group to separate the dye moiety from the active core of the compound so that the bulky dye group does not interfere with the biological activity of the molecule. The compounds of the invention have the generic formula (I):
wherein:
R
1
is a spacer group;
R
2
is hydrogen, alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amidoalkyl, alkylamidoalkyl, dialkylamidoalkyl, alkanoylalkyl, azidoalkyl, carbamoylalkyl, alkyl optionally interrupted by a heteroatom; alkenyl, alkenyloxyalkyl; cycloalkylalkyl, heterocycloalkyl; aryl, aralkyl, aralkenyl, heteroarylalkyl, in which aryl is optionally substituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo, amino, alkylamino or dialkylamino; aroylalkyl, or heteroaroylalkyl;
R
3
and R
4
are each independently hydrogen, alkyl, alkoxy of 1 to 4 carbon atoms, halo, amino, alkylamino, dialkylamino, or when taken together, R
3
and R
4
form a fused aryl or heteroaryl group that is optionally substituted by one or more substituents selected from alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo, amino, alkylamino, dialkylamino, hydroxy and alkoxymethyl; or
R
3
and R
4
form a fused 5- to 7-membered saturated ring, optionally containing one or more heteroatoms and optionally substituted by one or more substituents selected from alkyl of 1 to 4 carbon atoms, amino, halo and haloalkyl of 1 to 4 carbon atoms; and
DYE is a dye moiety, with the proviso that the dye moiety is not dansyl; or a pharmaceutically acceptable acid addition salt thereof.
The invention additionally provides methods of preparing the dye labeled imidazonaphthyridine, imidazopyridine and imidazoquinoline compounds.


REFERENCES:
patent: 3314941 (1967-04-01), Littell et al.
patent: 4689338 (1987-08-01), Gerster
patent: 4698348 (1987-10-01), Gerster
patent: 4774339 (1988-09-01), Haugland et al.
patent: 4929624 (1990-05-01), Gerster et al.
patent: 4988815 (1991-01-01), Andre et al.
patent: 5037986 (1991-08-01), Gerster
patent: 5175296 (1992-12-01), Gerster
patent: 5187288 (1993-02-01), Kang et al.
patent: 5238944 (1993-08-01), Wick et al.
patent: 5248782 (1993-09-01), Haugland et al.
patent: 5266575 (1993-11-01), Gerster
patent: 5268376 (1993-12-01), Gerster
patent: 5274113 (1993-12-01), Kang et al.
patent: 5346905 (1994-09-01), Gerster
patent: 5352784 (1994-10-01), Nikolaides et al.
patent: 5367076 (1994-11-01), Gerster
patent: 5389640 (1995-02-01), Gerster et al.
patent: 5395937 (1995-03-01), Nikolaides et al.
patent: 5444065 (1995-08-01), Nikolaides et al.
patent: 5446153 (1995-08-01), Lindstrom et al.
patent: 5482936 (1996-01-01), Lindstrom
patent: 5494916 (1996-02-01), Lindstrom et al.
patent: 5525612 (1996-06-01), Gerster
patent: 5605899 (1997-02-01), Gerster et al.
patent: 5627281 (1997-05-01), Nikolaides et al.
patent: 5644063 (1997-07-01), Lindstrom et al.
patent: 5648516 (1997-07-01), Nikolaides et al.
patent: 5693811 (1997-12-01), Lindstrom
patent: 5714608 (1998-02-01), Gerster
patent: 5741908 (1998-04-01), Gerster et al.
patent: 5741909 (1998-04-01), Gerster et al.
patent: 5756747 (1998-05-01), Gerster et al.
patent: 5886006 (1999-03-01), Nikolaides et al.
patent: 5939090 (1999-08-01), Beaurline et al.
patent: 5977366 (1999-11-01), Gerster et al.
patent: 6039969 (2000-03-01), Tomai et al.
patent: 6069149 (2000-05-01), Nanba et al.
patent: 6083505 (2000-07-01), Miller et al.
patent: 6110929 (2000-08-01), Gerster et al.
patent: 6194425 (2001-02-01), Gerster et al.
patent: 6323200 (2001-11-01), Gerster et al.
patent: 6331539 (2001-12-01), Crooks et al.
patent: 6348462 (2002-02-01), Gerster et al.
patent: 6365166 (2002-04-01), Beaurline et al.
patent: 9-208584 (1997-08-01), None
patent: 9-255926 (1999-03-01), None
patent: WO 93/09119 (1993-05-01), None
patent: WO 00/09506 (2000-02-01), None
patent: WO 00/76505 (2000-12-01), None
patent: WO 00/76518 (2000-12-01), None
Gregory P. ‘Dyes and dye intermediates’ in Kirk-Othmer Encyclopedia of Chemical Technology. 1993.*
Wozniak, et al, “The Amination of 3-nitro-1, 5-naphthyridines by Liquid Ammonia/Potassium Permanganate1,2. A New and Convenient Amination Method.”,Journal of the Royal Netherlands Chemical Society, 102, pp 511-513, Dec. 12, 1983.
Brennan, et al, “Automated Bioassay of Interferons in Micro-Test Plates”,Biotechniques, Jun./Jul., 78, 1983.
Testerman, et al, “Cytokine Induction by the Immunomodulators Imiquimod and S-27609”,Journal of Leukocyte Biology, vol. 58, pp. 365-372, Sep. 1995.
Bachman, et al, “Synthesis of Substituted Quinolylamines. Derivatives of 4-Amino-7-Chloroquinoline”,J. Org. Chem, 15, pp 1278-1284 (1950).
Jain, et al, “Chemical and Pharmacological Investigations of Some &ohgr;-Substituted Alkylamino-3-aminopyridines”,J. Med. Chem., 11, pp 87-92 (1968).
Baranov, et al.,Chem. Abs. 85, 94371, (1976).
Berényi, et al, “Ring Transformation of Condensed Dihydro-as-triazines”,J. Heterocyclic Chem., 18, pp 1537-1540 (1981).
Gibson, et al. “Molecular Requirements for Cytokine Production Response to the Immunomodulators Imiquimod and S-27609”,Journal of Interferon and Cytokine Research, 15, 537-545-(1995).

Affiliated with

Also associated with

Rating

Dye labeled imidazoquinoline compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Dye labeled imidazoquinoline compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Dye labeled imidazoquinoline compounds will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3165705