Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-11-10
2003-02-25
Raymond, Richard L. (Department: 1627)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S267000, C544S249000, C544S287000
Reexamination Certificate
active
06525061
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to substituted 2-amino-1,4-dihydroquinazolin-4-one derivatives having pharmacological activity, to processes for their preparation, to combinatorial and solid phase methods for preparing libraries of the compounds, to utilizing libraries of the compounds for drug discovery, and to pharmaceutical compositions thereof.
BACKGROUND OF THE INVENTION
Quinazolinone derivatives are important class of molecules with physiological significance and pharmaceutical utility. Substituted quinazolinones are a useful class of compounds. DeRuiter, et al. (
J. Med. Chem.
1986, 29, 627-629) describe 2-(arylamino)-4(3H)-quinazolinones as inhibitor of enzyme aldose reductase that prevents or delays the onset of diabetic complications. Hussain, et al. (
Pharmaceuticals Research,
1988, 5, 242-244) and Hess, et al. (
J. Med. Chem.
1968, 11, 130-136) describe antihypertensive activity of 2-amino-4(3H)-quinazolinone.
Combinatorial chemistry is becoming an important tool for drug discovery and lead optimization (Borman, S.
Chemical and Engineering News
1997, 75 (8), 43-62). A combinatorial synthesis requires that at least two components of the product molecules be independently variable, so that all of the combinations of these components can be prepared. Thus, to prepare a combinatorial library of quinazolinones with a high degree of potential diversity and wide utility for drug discovery using solid phase techniques, it is important to identify a synthesis in which all the components can be independently varied. The solution phase synthesis of 2-aminoquinazolinones by condensation of thiopseudoureas and isotoic anhydrides is known (Coopla, G. M.
J. Org. Chem.
1976, 41, 825). For a solid phase combinatorial synthesis it is necessary to modify this syntheses to allow for the independent introduction of variables and to adapt the solution phase synthesis to a solid supported synthesis. The solid phase 2-aminoquinazolinone synthesis of this invention is achieved by using a variety of amino acids as starting material which can be attached to a solid support through the carboxylic acid group.
Multiple compounds can be prepared simultaneously by the solid phase process. The simultaneous solid phase synthesis of a library of trisubstituted quinazolinones of the present invention is not known. The preparation of libraries of compounds of the present invention is useful because it provides rapid structural variation and structure-activity information.
The libraries of substituted quinazolinones synthesized according to the present invention are useful for drug discovery.
Accordingly, the present invention provides compounds of the formula (I):
wherein:
R
1
is phenyl optionally substituted with chloro, bromo, fluoro, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 2 to 6 carbon atoms, or alkoxy of 1 to 6 carbon atoms,
straight chain alkyl of 1 to 6 carbon atoms optionally substituted with hydroxyl, amino, guanidino, thiol, phenyl, substituted phenyl, COOH, or CONH2,
branched chain alkyl of 3 to 7 carbon atoms, optionally substituted with optionally substituted with hydroxyl, amino, guanidino, thiol, phenyl, substituted phenyl, COOH, or CONH2;
R
2
is hydrogen, fluoro, chloro, bromo, nitro, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or phenyl substituted with fluoro, chloro, bromo, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, or methylenedioxy;
R
3
is hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, straight chain alkenyl of 2 to 6 carbon atoms, branched chain alkenyl of 3 to 9 carbon atoms, straight chain alkynyl of 3 to 9 carbon atoms, branched chain alkynyl of 4 to 9 carbon atoms, phenylalkyl of 7 to 12 carbon atoms, phenyl or acyl; and
R
4
is hydroxy, alkoxy of 1 to 6 carbon atoms or amino; and pharmaceutical salts thereof.
In some preferred embodiments of the present invention R1 is phenyl and R4 is hydroxy.
Most preferred compounds of the present invention are:
4-[(4-oxo-1,4-dihydroquinazolin-2-yl)amino]benzoic acid,
4-[(1-methyl-4-oxo-1,4-dihydroquinazolin-2-yl)amino]benzoic acid,
4-[(1-allyl-4-oxo-1,4-dihydroquinazolin-2-yl)amino]benzoic acid,
4-[(1-benzyl-4-oxo-1,4-dihydroquinazolin-2-yl)amino]benzoic acid,
4-[(6-chloro-4-oxo-1,4-dihydroquinazolin-2-yl)amino]benzoic acid,
4-[(6-bromo-4-oxo-1,4-dihydroquinazolin-2-yl)amino]benzoic acid,
4-[(6-nitro-4-oxo-1,4-dihydroquinazolin-2-yl)amino]benzoic acid,
3-[(4-oxo-1,4-dihydroquinazolin-2-yl)amino]benzoic acid,
3-[(1-methyl-4-oxo-1,4-dihydroquinazolin-2-yl)amino]benzoic acid,
3-[(1-allyl-4-oxo-1,4-dihydroquinazolin-2-yl)amino]benzoic acid,
3-[(1-benzyl-4-oxo-1,4-dihydroquinazolin-2-yl)amino]benzoic acid,
3-[(6-chloro-4-oxo-1,4-dihydroquinazolin-2-yl)amino]benzoic acid,
3-[(6-bromo-4-oxo-1,4-dihydroquinazolin-2-yl)amino]benzoic acid,
3-[(6-nitro-4-oxo-1,4-dihydroquinazolin-2-yl)amino]benzoic acid,
N-(4-oxo-1,4-dihydroquinazolin-2-yl)-beta-alanine,
N-(1-methyl-4-oxo-1,4-dihydroquinazolin-2-yl)-beta-alanine,
N-(1-allyl-4-oxo-1,4-dihydroquinazolin-2-yl)-beta-alanine,
N-(1-benzyl-4-oxo-1,4-dihydroquinazolin-2-yl)-beta-alanine,
N-(6-chloro-4-oxo-1,4-dihydroquinazolin-2-yl)-beta-alanine,
N-(6-bromo-4-oxo-1,4-dihydroquinazolin-2-yl)-beta-alanine,
N-(6-nitro-4-oxo-1,4-dihydroquinazolin-2-yl)-beta-alanine,
4-[(1-allyl-4-oxo-1,4-dihydroquinazolin-2-yl)amino]-2-chlorobenzoic acid, and
5-[(1-allyl-4-oxo-1,4-dihydroquinazolin-2-yl)amino]-2-chlorobenzoic acid.
Compounds of the present invention are expected to be useful to delay the onset of diabetic complications such as cataract formation, retinopathy and neuropathy.
Compounds of Formula I may be prepared via solid phase synthesis which comprises the steps of:
a) attaching a Fmoc protected amino acid of the formula:
to a solid support to produce compounds of formula (1):
wherein P is a solid support;
b) Deprotecting said compounds of formula (1) with piperidine to produce compounds of formula (2):
c) reacting said compounds of formula (2) with Fmoc-isothiocyanate to produce compounds of formula (3):
d) deprotecting said compounds of formula (3) with piperidine to produce compounds of formula (4):
e) reacting said compounds of formula (4) with methyl iodide to produce compounds of formula (5):
f) reacting said compounds of formula (5) with isotoic anhydrides of formula (6):
in polar aprotic solvent at ambient temperature to produce compounds of formula (7):
and
g) reacting said compounds of formula (7) with a cleaving reagent such as trifluoroacetic acid to produce compounds of formula (I).
Libraries of compounds of Formula I can thus be prepared. Such libraries are useful for drug discovery by providing a group of quinazolinones with a high degree of diversity, thus allowing for structure-activity information against a given drug discovery target.
In accordance with the present invention, the solid support P is preferably a polystyrene resin crosslinked with divinylbenzene and functionalized with a linker such as a hydroxymethylphenoxy group. More preferably the solid support P is Wang's resin.
In some preferred embodiments of the present invention a substituted phenyl group has 1 to 3 substituents. More preferably, a substituted phenyl group has one substituent.
Substituted alkyl groups can have from 1 to three substituents. Substituted alkyl groups preferably have no more than one substitutent per carbon atom. Substituted alkyl groups preferably contains a total of from 1 to three substituents in some preferred embodiments of the invention.
Fmoc, as used herein refers to the protecting group, fluorenylmethoxycarbonyl.
It is understood that the definition of the compounds of formula (I),
Gopalsamy Ariamala
Yang Hui Y.
Barrett Rebecca R.
Raymond Richard L.
Wyeth
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