Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-02-03
2001-07-17
Stockton, Laura L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S165000, C546S167000, C546S171000, C546S173000
Reexamination Certificate
active
06262269
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the synthesis of heterocyclic compounds based on the 4-substituted quinoline ring. More specifically, the invention provides novel 4-substituted quinolines as well as novel libraries comprised of such compounds.
2. Background Information
The process of discovering new therapeutically active compounds for a given indication involves the screening of all compounds from available compound collections. From the compounds tested one or more structure(s) is selected as a promising lead. A large number of related analogs are then synthesized in order to develop a structure-activity relationship and select one or more optimal compounds. With traditional one-at-a-time synthesis and biological testing of analogs, this optimization process is long and labor intensive. Adding significant numbers of new structures to the compound collections used in the initial screening step of the discovery and optimization process cannot be accomplished with traditional one-at-a-time synthesis methods, except over a time frame of months or even years. Faster methods are needed that allow for the preparation of up to thousands of related compounds in a matter of days or a few weeks. This need is particularly evident when it comes to synthesizing more complex compounds, such as 4-substituted quinolines.
Solid-phase techniques for the synthesis of peptides have been extensively developed and combinatorial libraries of peptides have been generated with great success. During the past four years there has been substantial development of chemically synthesized combinatorial libraries (SCLs) made up of peptides. The preparation and use of synthetic peptide combinatorial libraries has been described, for example, by Dooley in U.S. Pat. No. 5,367,053, Huebner in U.S. Pat. No. 5,182,366, Appel et al. in WO PCT 92/09300, Geysen in published European Patent Application 0 138 855 and Pirrung in U.S. Pat. No. 5,143,854. Such SCLs provide the efficient synthesis of an extraordinary number of various peptides in such libraries and the rapid screening of the library which identifies lead pharmaceutical peptides.
Combinatorial approaches have recently been extended to “organic,” or non-peptide, libraries. The organic libraries to the present, however, are of limited diversity and generally relate to peptidomimetic compounds; in other words, organic molecules that retain peptide chain pharmacophore groups similar to those present in the corresponding peptide.
Combinatorial chemical methods have been applied to a limited number of heterocyclic compounds, as described, for example, in U.S. Pat. No. 5,288,514 to Ellman, U.S. Pat. No. 5,324,483 to Cody et al. and Goff and Zuckermann, J. Org. Chem., 60:5748-5749 (1995)). Additionally, there is U.S. Pat. No. 5,549,974 to Holmes and U.S. Pat. No. 5,506,337 to Summerton and Weller. The patent application WO 94/08051 discloses the reaction of ether-linked aldehyde-derived imines with dihydrofuran under Lewis acid catalysis. The library, however, was limited to 108 compounds. However, the heterocyclic libraries to date contain compounds of limited diversity and complexity.
Leeson et al.,
J. Med. Chem.,
35:1954 (1992), reported related tetrahydroquinolines as N-methyl-D-aspartate (NMDA) receptor site antagonists wherein the 2-position was by necessity a carboxy group, the 4position an acylated amine and two chlorine atoms present in the aromatic ring. In the one example employing N-vinylpyrrolidinone, Leeson et al. were limited to a stepwise procedure that required boron trifluoride as condensation agent. Mellor et al.,
Tetrahedron Letters
32:7103 (1991), described the use of 300 mole percent styrenes and formaldehyde with electron deficient anilines to prepare tetrahydroquinolines in modest yield but not free of the uncyclized adduct. This was modestly extended in Mellor and Merriman,
Tetrahedron,
51:6115 (1995) but could not be halted at the single adduct stage except for electron withdrawn anilines.
Substituent limitations have been overcome for mixtures of peptides and peptidomimetics through the use of solid phase techniques versus solution-phase. An important step in the development of solid-phase techniques was the discovery of methods to identify active individual compounds from soluble mixtures of large numbers of compounds, as described, for example, by Rutter in U.S. Pat. No. 5,010,175 and Simon in WO PCT 91/19735. These soluble mixture methods, however, have rarely been applied to the syntheses of complex heterocyclic structures. There exists a need to develop more complex “organic” libraries based on heterocyclic medicinal compounds which would require less time and effort in the synthesis and testing needed to bring an organic pharmaceutical product to fruition. In short, improved methods for generating therapeutically useful heterocyclic compounds, such as -4-substituted quinoline derivatives, are desired.
This invention satisfies these needs and provides related advantages as well. The present invention overcomes the known limitations to classical organic synthesis of -4-substituted quinolines and as well as the shortcomings of combinatorial chemistry with heterocycles. The present invention combines the techniques of solid-phase synthesis of heterocycles and the general techniques of synthesis of combinatorial libraries to prepare new 4-substituted quinoline compounds.
SUMMARY OF THE INVENTION
The present invention relates to novel 4-substituted quinoline compounds of the following formula, libraries containing at least two or more such compounds, and to the generation of such combinatorial libraries composed of such compounds:
wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
9
, and Y have the meanings provided below.
REFERENCES:
patent: 3262906 (1966-07-01), Perry
patent: 3910918 (1975-10-01), Monroy
patent: 5767129 (1998-06-01), Yuen
patent: 5856503 (1999-01-01), Aebi et al.
patent: 5962200 (1999-10-01), Taniguchi et al.
patent: 462761 (1991-12-01), None
patent: 0 634 169 (1995-01-01), None
patent: 95/11592 (1995-05-01), None
patent: 96/33717 (1996-10-01), None
Bortolotti et al., “DDQ-Mediated Formation of Carbon-Carbon Bonds: Oxidation of Imines,”Tetrahedron, 49(44) :10157-10174 (1993).
Gallop et al., “Applications of combinatorial technologies to drug discovery. 1. Background and peptide combinatorial libraries,”J. of Med. Chem., 37(9) :1233-1251 (April 29, 1994).
Gordon et al., “Applications of combinatorial technologies to drug discovery. 2. Combinatorial organic synthesis, library screening strategies, and future directions,”J. of Med. Chem., 37(10) :1385-1401 (May 13, 1994).
Leardini et al., “Annulation Reactions with Iron(III) Chloride: Oxidation of Imines,”J. Org. Chem., 57:1842-1848 (1992).
Leeson et al., “4-Amido-2-carboxytetrahydroquinolines, Structure Activity Relationships for Antagonism at the Glycine Site of the NMDA Receptor,”J. Med. Chem., 35:1954-1968 (1992).
Makioka et al., “Ytterbium (III) Triflate Catalyzed Synthesis of Quinoline Derivatives from N-Arylaldimines and Vinyl Ethers,”Synthesis, 801-804 (1995).
Mellor and Merriman, “Reaction of Electron Rich Alkenes with Anilines and Formaldehyde: Syntheses of Tetrahydroquinolines,”Tetrahedron, 51(21) :6115-6132 (1995).
Mellor et al., “Synthesis of Tetrahydroquinolines From Aromatic Amines, Formaldehyde and Electron Rich Alkenes: Evidence For Nonconcertedness,”Tetrahedron Letters, 32(48) :7103-7106 (1991).
Nefzi et al., “The Current Status of Heterocyclic Combinatorial Libraries,”Chem. Rev., 97(2) :449-472 (1997).
Case et al., CA 57:9825g, 1962.*
Yamada, CA 58:4515f, 1963.*
Yun et al., CA 122:56707, 1995.*
Ryu et al., CA 118:233411, 1993.*
Ali et al., CA 118:102287, 1993.*
Rim et al., CA 119:181340, 1993.*
Spector et al., CA 123:218394, 1995.*
Dunn et al., CA 119:117598, 1993.*
Leardini et al., CA 117:26286, 1992.*
Friesen et al., CA 123:198641, 1995.*
Uchida et al., CA 112:198213, 1990.*
Atwell et al., CA 108:167271, 1988.*
Asaks et al., CA 94:15526, 1981.*
Echavarren et al., CA 109:55027,
Forood Behrouz
Hayes Thomas K.
Kiely John S.
Law Office of David Spolter
Stockton Laura L.
Trega Biosciences, Inc.
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