Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
1997-12-15
2001-02-06
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C544S233000, C544S247000, C544S250000, C544S251000, C544S284000, C544S285000, C544S287000, C544S289000
Reexamination Certificate
active
06184377
ABSTRACT:
1. FIELD OF THE INVENTION
The present invention relates to N-hydroxy- and N-amino-quinazolinones and methods for preparing such compounds.
2. BACKGROUND OF THE INVENTION
There is a great interest in synthetic methods directed toward the creation of large collections of small organic compounds, or libraries, which could be screened for pharmacological, biological or other activity. Often referred to as combinatorial chemistry, the synthetic methods applied to create vast combinatorial libraries are performed in solution or in the solid phase, i.e., on a solid support. Further, solid-phase synthesis makes it easier to conduct multi-step reactions and to drive reactions to completion with high yields because excess reagents can be easily added and washed away after each reaction step. Solid-phase combinatorial synthesis also tends to improve isolation, purification and screening. However, the more traditional solution phase chemistry supports a wider variety of organic reactions than solid-phase chemistry.
Typically, combinatorial methods involve the addition of various structural components sequentially, either in a controlled or random manner to a core chemical structure in order to produce all or a substantial portion of the possible combinations that can result from the different possible reactions at each stage. The efficient use of this technique can create thousands of compounds for pharmacological screening in a rapid fashion.
Methods for screening libraries of compounds for binding properties to a receptor include methods wherein each member of the library is tagged with a unique identifier to facilitate identification of compounds having binding properties, or where the library comprises a plurality of compounds synthesized at particular locations on the surface of a solid substrate. The receptor may be appropriately labelled with a radioactive or fluorescent label that enables one to ascertain whether binding to the receptor of interest has occurred. Correlation of the labelled receptor bound to the substrate, which has its location on the substrate, identifies the binding ligand as disclosed in U.S. Pat. No. 5,143,854.
In contrast to the standard combinatorial chemistry approach which results in libraries with maximum diversity, there is a trend toward the design of more targeted libraries, particularly of small compounds, which minimize redundancy and improve screening efficiency.
One particular class of compounds that would be useful for inclusion in targeted libraries is quinazolinone compounds such as N-hydroxy-quinazolinones and derivatives thereof. Quinazolinone compounds possess a diverse array of beneficial pharmaceutical and chemical properties. For example, certain quinazolinones are known to possess antipyretic, hypotensive, antibacterial, antifungal or central nervous system (CNS) activity, as well as the ability to inhibit enzymes of biological importance, such as metalloenzymes.
C. Schapira and S. Lamdan (
J. Heterocyclic Chem.,
9:569-576 (1972)) disclose the action of various simple acylating agents on 2-aminobenzohydroxamic acid, which afforded 3-hydroxy-4(3H)-quinazolinones (hydroxamic acids), as well as several ethers and esters derived therefrom.
H. Kohl and E. Wolf (
Liebigs Ann. Chem.,
766:106-115 (1972)) disclose that O-alkyl N-acylaminobenzhydroxamates are readily cyclized to 2-substituted-3-alkoxyquinazolinones.
M. Ghelardoni and V. Pestellini (
Annali di Chimica,
64:445-453 (1974)) disclose the synthesis of fused-ring systems containing the 4-quinazolone nucleus. These compounds are obtained by condensation of o-aminobenzoylhydrazine or o-aminobenzohydroxamic acid with compounds containing both carbonyl and carboxyl groups, such as phthalaldehydic acid or levulinic acid, or with cyclic anhydrides, such as phthalic anhydride or succinic anhydride.
K. Tanaka et al. (
Chem. Pharm. Bull.,
36(7):2323-2330 (1988)) disclose the synthesis of 3-Hydroxy-4-oxo-3,4 dihydroquinazolinones, which exhibited metal chelating abilities, analgesic activities, and inhibition of the growth of microorganisms. The 3-hydroxy-4-oxo-3,4-dihydroquinazolinones were prepared, for example, by reacting a 2-aminobenzohydroxamic acid with acetic anhydride or formic acid.
Although, a variety of syntheses of quinazolinones using solution-phase techniques have been reported, there is a need for a general method of synthesis of such compounds, especially in the solid phase. In other words, there is a need for a solid-phase synthesis that allows one to synthesize a multiplicity of quinazolinones on a variety of solid supports, as well as a need for preparing and screening a library of quinazolinones for pharmacological or biological activities.
Accordingly, there is a need in the art for an efficient method for obtaining a library of N-hydroxy- and N-amino quinazolinones, particularly 3-hydroxy-quinazolinones and 3-amino-quinazolinones, wherein the starting materials are amenable to large scale synthesis.
Citation or identification of any reference in this section of this application shall not be construed as an admission that such reference is available as prior art to the application.
3. SUMMARY OF THE INVENTION
The present invention is directed to synthesis of N-amino and N-hydroxy-quinazolinone compounds on solid supports. The use of solid support in the present invention both allows for protection of the N-moiety and facilitates purification and/or isolation. The synthesis of the instant invention is particularly useful since mild conditions are involved.
In general terms, the invention involves the coupling of a substituted or unsubstituted isatoic anhydride to a solid support, preferably a solid support containing a hydrazino or hydroxylamine moiety that is available for reaction. This coupling reaction forms a 2-aminobenzamide which is bound to the solid support via the amide-nitrogen, thereby both protecting and anchoring the 2-aminobenzamide. The bound 2-aminobenzamide is subsequently reacted with a compound of the formula
R
2
—CHY—CO—X
or
W—CO—X
wherein X is OH, Cl, F, Br or a carboxylic acid activating group; Y is NR
3
R
4
where NR
3
R
4
is an N-protected-amino acid, or Cl, Br, or F and R
2
is a substituted or unsubstituted alkyl, aryl, alkylaryl group and W is a heterocyclic group to form a cyclized compound, i.e., a quinazolinone. It should be recognized that a variety of quinazolinone can be prepared depending upon the compound chosen for coupling. Further, the resulting solid-phase bound product can either be further modified or simply cleaved, or both. Thus, a vast number of quinazolinone compounds can be prepared and screened for potential biological activity. In certain embodiments, the resin-bound 2-aminobenzamide is reacted with a carboxylic acid or activated form thereof which is represented by the formula:
R
2
—CHY—CO—X
or
W—CO—X
wherein X is OH, Cl, F, Br or a carboxylic acid activating group; Y is NR
3
R
4
, Cl, Br, F or I; R
2
is a substituted or unsubstituted alkyl, aryl, heteroarylalkyl or aralkyl group; R
3
and R
4
are suitable NH protecting groups; and W is a heterocyclic group.
The present invention is directed, in one of its aspects, to general synthetic methods for incorporating a N-amino or N-hydroxy-4(1H)-quinazolinone of the formula (I) onto a solid support.
wherein R
1
is an independently selected mono-, di-, tri-, or quad-substitutent on the phenyl ring, and where R
1
is independently hydrogen, halogen, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl optionally substituted with halogen, hydroxy, C
1
-C
6
alkoxy and aryl, or hydroxy, C
1
-C
6
alkoxy, NO
2
, SO
2
Ph, phenyl SO
2
NR
3
R
4
, OCOR
5
, SR
5
, CO
2
R
5
; NHCOR
5
; or R
1
, when disubstituted, can be taken together to form a 5, 6 or 7-membered carbocyclic aromatic group or heterocyclic aromatic group wherein the heterocyclic aromatic group is selected from the group consisting of furo, thieno, pyrido, pyrrolo, oxazolo, thiazolo, imidazolo, pyrazolo, isoxazolo, isothiazolo, pyridazino, pyrimidino, pyrazino, and indolo;
R
2
is branched or straight chain C
1
-C
6
a
Foley Hoag & Eliot LLP
Gordon Dana M.
Raymond Richard L.
Sepracor Inc.
Vincent Matthew P.
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