Methods for synthesizing libraries of dihydro-quinazolinones

Details Methods for synthesizing libraries of dihydro-quinazolinones Methods for synthesizing libraries of dihydro-quinazolinones

1997-12-15

2001-08-14

Venkat, Jyothsna (Department: 1627)

Chemistry: analytical and immunological testing

Involving an insoluble carrier for immobilizing immunochemicals

C544S283000, C544S284000, C544S286000, C544S287000, C544S289000, C436S536000, C436S518000

Reexamination Certificate

active

06274383

ABSTRACT:

1. FIELD OF THE INVENTION
The present invention is directed to solution and solid phase syntheses of dihydro-quinazolinones.
2. BACKGROUND OF THE INVENTION
There is a great interest in synthetic methods directed toward the creation of large collections (libraries) of small organic compounds which could be screened for pharmacological activity. Often referred to as combinatorial chemistry, the synthetic methods applied to create vast combinatorial libraries are performed in solution or on the solid phase. Solid-phase synthesis makes it easier to conduct multistep reactions and to drive reactions to completion, because excess reagents can be added and easily washed away after each reaction step. Solid-phase combinatorial synthesis also makes isolation, purification or screening more manageable. However, more traditional solution phase chemistry supports a wider variety of organic reactions than the solid-phase. Typically, combinatorial methods involve selection of various structural components which are used to modify a core chemical structure. One adds individual structural components as part of a chemical synthesis sequentially, either in a controlled or random manner, to produce all or a substantial portion of the possible compounds that can result from the different choices possible at each sequential stage in the synthesis. Efficient use of this technique can create thousands of compounds for pharmacological screening in a short period of time.
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, and methods wherein 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 with its location on the substrate identifies the binding ligand as described 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 which minimize redundancy and improve screening efficiency.
One particular class of compounds that would be useful for inclusion in targeted libraries is quinazolinone compounds, including dihydro-quinazolinones and derivatives thereof. This class of compounds possesses a diverse array of pharmaceutical and chemical properties. For example, dihydro-quinazolinones are known to possess antipyretic, hypotensive, antibacterial, antifungal or Central Nervous System (“CNS”) depressant activity as well as the ability to inhibit enzymes of biological importance, for example, metalloenzymes.
Bonola et al. (J. Med. Chem., 13, 329-332 (1970)) describe the synthesis of 2,3-dihydro-4(1H)-quinazolinone derivatives of the following formula:
where R is hydrogen, hydroxy, phenyl, substituted phenyl, and furyl and R
1
is hydroxy, alkoxy, anilino, alkylamino, and alkyl (dialkylamino). These compounds are made by condensation of an appropriately substituted amine with isatoic anhydride. The corresponding aminobenzamide is then condensed with the appropriate aldehyde or ketone to yield a dihydro-quinazolinone. Alternatively, the condensation of 2-aminobenzohydroxamic acid with the appropriate aldehyde or ketone leads to the corresponding N-hydroxy-dihydroquinazolinone. Notably, all of the dihydroquinazolinones described above are prepared under neutral or basic conditions in alcoholic solvents or alcoholic solvents containing an alkoxide or amine base.
Christie et al. (J. Chem. Soc. Perkin Trans. I, 2779-2783 (1985)) describe the synthesis of dihydro-quinazolinones and N-hydroxy-quinazolinones by the reaction of the appropriate aminobenzamide or aminobenzohydroxamic acid with the appropriate corresponding aldehyde or ketone in an alcoholic solvent.
However, a simple procedure for synthesizing a multiplicity of quinazolinones on a variety of solid supports would create a combinatorial library, enhance the structural variation of the pharmacophore and provide the opportunity to evaluate the library through pharmacological screening to obtain important structure-activity information and potential drug candidates.
Accordingly, there is a clear need in the art for an efficient method for obtaining a library of 2,3-dihydro-quinazolinones, wherein the starting materials are amenable to large scale synthesis, and wherein the desired products can be obtained under relatively mild conditions employing readily available reagents.
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 present application.
3. SUMMARY OF THE INVENTION
It has now been surprisingly found that combinatorial libraries of 3-alkoxy and 3-hydroxy-2,3-dihydro-4(1H)-quinazolinones can be synthesized from the corresponding 2-amino-benzamides bound to a solid support by treatment with a Lewis acid catalyst such as zinc chloride or triflates of the lanthanide series, such as scandium triflate or ytterbium triflate. Previously, dihydro-quinazolinones were formed from 2-aminobenzamides under neutral or basic conditions, and not on a solid support.
The present invention is directed towards methods for synthesizing libraries of dihydro-quinazolinones, particularly 2,3-dihydro-3-alkoxy-4(1H)-quinazolinones or 2,3-dihydro-3-hydroxy-4(1H)quinazolinones via the Lewis-acid catalyzed cyclization of the appropriate 2-aminobenzamide with aldehydes at ambient temperatures. In another aspect, the present invention relates to a method for preparing 2,3-dihydro-3-hydroxy-4(1H)-quinazolinones by the Lewis-acid catalyzed reaction of aldehydes with a 2-amino-3-alkoxybenzamide on a solid support, either in a parallel manner or in a combinatorial fashion followed by the cleavage of the desired products from the solid support.
This invention also provides, in one of its aspects, to general synthetic methods for incorporating a 2,3-dihydro-3-alkoxy-4(1H)-quinazolinone of the following formula (I) onto a solid support.
wherein R
1
, R
2
, R
3
and R
4
are independently hydrogen, halogen, C
1
-C
6
alkyl, C
1
-C
6
alkenyl, hydroxy, C
1
-C
6
alkoxy, NO
2
, SO
2
Ph, phenyl, SO
2
NR
6
R
7
, NR
6
R
7
, OCOR
8
, SR
8
, CO
2
R
8
, NHCOR
8
; or R
1
and R
2
, R
2
and R
3
, or R
3
and R
4
can be taken together to form a 5-7 membered carbocyclic aromatic group or heterocyclic aromatic group wherein the heterocyclic aromatic group is selected from the group consisting of furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, or indolyl;
R
5
is hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkenyl, benzyl, phenyl, CH
2
-furyl, CH
2
-pyridyl wherein the alkyl, alkenyl, benzyl, phenyl, furyl and pyridyl groups may be further substituted with substituents independently selected from the group consisting of C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogen, NO
2
CF
3
or CN;
R
6
and R
7
are independently H, C
1
-C
6
alkyl or, taken together are (CH
2
)
f
where f is 3-6;
R
8
is hydrogen, C
1
-C
6
alkyl, benzyl, phenyl, or substituted phenyl with 1-3 substituents independently selected from the group consisting of C
1
-C
6
alkyl, C.-C
6
alkoxy, NO
2
, CF
31
or CN;
R
9
is hydrogen, C
1
-C
6
branched or straight alkyl, C
1
-C
6
branched or straight alkenyl, C
1
-C
6
aralkyl, C
1
-C
6
aralkenyl, C
1
-C
10
cycloalkenyl, C
1
-C
10
bicycloalkenyl, C
1
-C
6
cycloalkyl, phenyl, phenyl substituted with 1-3 substituents independently selected from the group consisting of halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, SR
8
, OR
8
, CF
3
, OCF
3
or NO
2
, a 5-10 membered carbocyclic aromatic group or heterocyclic aromatic group wherein the heterocyclic group is select

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