Note: Descriptions are shown in the official language in which they were submitted.
--1--
ORTHO SVBSTITUTE~ DIHYDROXY-2(1H)QUINAZOLIMONE-l-ALKANOIC
ACIDS
The present invention relates to substituted quinazoli-
nones having functionality at Nl. The substituted
q~inazolinones which are the subject of this invention
have the following formula
~ = -R5
z~O
R~X
R4
wherein Rl is hydrogen, amino or nitro; R2 is hydrogen,
alkyl having 1-20 carbon atoms, cycloalkyl having 4-8
carbon atoms, cycloalkylalkyl wherein the cycloalkyl group
has 4-8 carbon atoms and the alkyl group has 1-3 carbon
atoms, haloalkyl having 1-3 halogen atoms and 1-4 carbon
atoms and the halogen is chloro, bromo or fluoro, and
bicycloalkyl such as norbornyl and norbornylmethyl; R3 and
R4 may be the same or different and are hydrogen, lower
alkyl having 1-6 carbon atoms, aryl and substituted aryl
such as phenyl, 2-, 3-, and 4-pyridyl, o~, m~, and E~
hydroxyphenyl, halophenyl such as ~-chlorophenyl, p-
fluorophenyl, o-chlorophenyl, 2,4-difluorophenyl, lower
alkoxyphenyl such as methoxy, ethoxy, and butoxyphenyl,
alkylphenyl wherein the alkyl group contains 1-6 carbon
atoms; X is benzyl, carboxy, carboalkoxy wherein the
alkoxy group has 1-3 carbon ato~s, cyano, carboxamido,
methanesulfonyl, formyl, aroyl, such as benzoyl, substitu-
ted benzoyl wherein the substituent is an alkyl group
having 1-4 carbon atoms, heteroaryl such as 2-, 3-, and 4-
pyridyl, and 2-thienyl; heteroaroyl, such as 2-, 3-, and
4-pyridoyl, 2-thienoyl, 2-furoyl and 3~(1,2,5-) thiadia-
zolyl; R5 is hydrogen, lower alkyl having 1-6 carbons;
~1$~
` ORTH-388
benzyl or substituted benzyl wherein the substituent is
Eluoro, chloro, bromo, alkyl or alkoxy wherein the alkyl
group has 1-6 carbon atoms; provided that when R5 is other
than hydrogen the compound is a quaternary salt when the
3,4-imine linkage is unsaturated; (the presence of an
unsat~rated imine linkage between N3 and C4 is optional
and N3 may or may not be substituted); Y and Z are
hydrogen or hydroxy, provided that at least one of Y and Z
is hydroxy (when Y and Z are both hydroxy the hydroxyl
groups are positioned adjacent to each other at ei~her the
5,6- or the 6,7- position); and including the alkali metal
and alkaline earth metal salts of the phenolic hydroxyls
and the carboxy group at N-l and selected amine salts such
as the salts of meglumine, piperazine, ~I-methylpiperazine,
morpholine and aliphatic amines having 1-5 carbon atoms;
a~inoalcohols such as ethanolamine, 2-amino-1,3-propane-
diol and bis(hydroxymethyl)methylamine; and amino acids
such as arginine, lysine and ornithine.
The preferred compounds of the present invention are those
wherein Rl is hydrogen; R2 is hydrogen, alkyl, cycloalkyl,
bicycloalkyl and haloalkyl; R3 and R4 are hydrogen, lower
alkyl, aryl and substituted aryl; X is carboxy, carbo-
alkoxy, cyano, carboxamido and formyl; R5 is hydrogen,
lower alkyl, benzyl, substi~uted benzyl, provided that
when R5 is other than hydrogen ~he compound is a quater-
nary salt when the 3,4-imine linkage is unsaturated (the
unsaturated imine linkage between N3 and C4 is optional
and N3 may or may not be substituted); Y and Z are hydro-
gen or hydroxy, provided that at least one of Y and Z ishydroxy; and including the alkali metal and alkaline
earth metal salts of the phenolic hydroxyls and the
carboxy group at Nl and selected amine salts such as the
salts of meglumine, piperazine, N-methylpiperazi~e, mor
pholine and aliphatic amines having 1-5 carbon atoms,
aminoalcohols such as ethanolamine, 2-amino-1,3-
propanediol and bis(hydroxymethyl)methylamine; and amino
ORTH-388
--3--
acids such as arginine, lysine and ornithine. When Y and
Z are both hydroxy, the hydroxyl groups are positioned
adjacent to each other and are located at either the 5,6-
or the 6,7-position.
Several 6,7-dialkoxy-~-alkyl 2(1H)quinazolinones have been
reported in the literature [Budesinsky et al., _oll.
Czech. Chem. Commun., 37, 2779 (1972); Belgian Patent No.
765947 (1971)]. None of the reported substituted quinazo-
linones have hydroxy groups substitu~ed on the benzenering. In addition, the known quinazolinones are not simi-
larly substituted at Nl.
The novel quinazolinones of this invention are renal
vasodilators. As such they increase renal blood flow and
are therefore useful as cardiovascular agents. In
addition, some of the compounds and some of the
inter~ediates used to prepare the novel quinazolinones
possess cardiotonic activity.
The substituted quinazolinones can be synthesized
according to the following schematic diagram.
ORTH-388
~2~ 61~
R?~
R~ H~O
¦ X~ R3
¦, R4
0~ ~ ~ Aci~ Roj~
HS~ ~R3 R4 2 R~4 X
a, R5I
Rl R2 ~ ~. H~
HHO~X
6 R4 3 R3
j~ N-RX ~ R4
Or'~TH 3 8 8
wherein Rl, R2, R3, R4, R5 and X are as defined above and
R is lower alkyl having 1-S carbon atoms.
As can be seen from the diagram, the Nl substituted quin-
azolinone (2) is prepared by reacting a substituted quina-
zolinone with an appropriately substituted olefin, such as
methyl cinnamate, methyl acrylate, methyl crotonate,
acrylonitrile and methyl methacrylate, for example. The
particular olefin employed will depend upon the type of
substitution desired in the end product. The reaction is
carried out in the presence of a basic catalyst such as
sodium carbonate, potassium carbonate, potassium fluoride,
sodium fluoride, potassium hydroxide, sodium hydroxide,
alkali metal alkoxides such as potassium ethoxide, and
sodium methoxide, quaternary ammonium hydroxides such as
benzyltrimethylammonium hydroxide, quaternary ammonium
fluorides such as tetraethylammonium fluoride and tertiary
amines such as triethylamine. The reaction temperature
employed can vary between -10C and 100C; the preferred
reaction temperature is about 65C.
The Nl substituted quinazolinone (2) can be used to pre-
pare the other Nl substituted quinazolinones by the routes
shown in the diagram. For example, the Nl substituted
quinazolinone (2) can be conveniently alkylated with an
alkyl iodide such as methyl or ethyl iodide or a benzyl
iodide such as o , m-, or E~ ~luorobenzyl, o-, m~, or
methylbenzyl and Q-, m-, or p- methoxybenzyl iodide to
give the corresponding quaternary salt. The salt in ~urn
can be hydrolyzed with an acid such as hydrobromic acid or
hydriodic acid, for example, to give the corresponding
dihydroxy compound (33. The Nl substituted ~uinazolinone
(2) can be converted directl~ to the corresponding
dihydroxy compound (5) by reaction with an acid such as
hydrobromic or hydriodic acid. The dihydroxy compounds
ORTH-38~
--6--
(3 and 5) can then be partially saturated (4 and 6) by
reaction with hydrogen in the presence of a catalyst such
as platinum, palladi~m, rhodium or nickel. Ammonium
formate, boranes and metallic hydrides such as sodium
borohydride may also be employed as reagents in the
reduction step.
The starting material (1) used in the preparation of the
substituted hydroxyquinazolinones wherein the substituents
on the benzene ring are in the 6,7-position can be pre-
pared by two main routes. For the first, an appropriately
substituted alkoxyaniline is converted to the correspond-
ing isocyanate. The conversion is carried out with
phosgene in a suitable solvent such as, for example,
benzene, toluene or xylene. The isocyanate is then con-
densed with the appropriate carboxamide to form the cor-
responding adduct. The condensation can be carried out
either neat or in an inert solvent such as xylene or
toluene. It is preferred to carry out the reaction at a
temperature between 100-150C. The adduct is then
cyclized to form a quinazolinone. Suitable cyclizing
agents which can be employed include polyphosphoric acid,
polyphosphoric ester and a mixture of phosphorous pent-
oxide and methanesulfonic acid. ~he ratio of the
cyclizing agent to the adduct may vary between 1:1 and
25:1; however, the preferred ratio is 5:I. The reaction
is preferably carried out at a temperature between 100-
130C in an inert atmosphere such as nitrogen. In the
second route, an appropriately substituted acetophenone is
nitrated. After separation of the isomers the substituted
o-nitroacetophenone is reduced to the corresponding amine.
This in turn is acylated with an alkylhaloformate to give
the corresponding urethane. Cyclization of the urethane
so obtained with ammonia gives the corresponding quinazo-
linone. Examples of these transformations are illustratedbelow.
ORTH-383
~2~
Pharmaceutical compositions containing a compound of the
present invention as the active ingredient in in~imate
admixture with a pharmaceutical carrier can be prepared
accocding to conventional pharmaceutical compounding tech-
ni~ues. The carrier may take a wide variety of formsclepending on the for~ of preparation desired for adminis-
tration, e.g., intravenous, oral or parenteral. In pre-
paring the compositions in oral dosage form, any of the
usual pharmaceutical media may be employed, such as, for
example, water, glycols, oils, alcohols, flavoring agents,
preservatives, coloring agents and the like in the case of
oral liquid preparations such as, for example, suspen-
sions, elixirs and solutions; or carriers such as
starches, sugars, diluents, granulating agents, lubri-
cants, binders, disintegrating agents and the like in thecase of oral solid preparations such as, for example,
powders, caps~lles and tablets. Because of their ease in
administration, tablets and capsules represent the most
advantageous oral dosage unit form, in which case solid
pharmaceutical carriers are obviously employed. If
desired, tablets may be sugar coated or enteric coated by
standard techniques. For parenterals, the carrier will
usually comprise sterile water, though other ingredien~s,
for example, to aid solubility or for preservatlve pur-
poses, may be included. Injectable suspensions may also
be prepared, in which case appropriate liquid carriers,
suspending agents and the like may be employed. The
pharmaceutical compositions will generally con~ain, dosage
unit, e.g., tablet, capsule, powder, injection, teaspoon-
ful and the like, from about 15 to about 300 mg/kg and
preferably fro~ about 30 to about 200 mg/kg of the active
ingredient.
The following examples describe the invention in greater
particularity and are intended to be a way of illustrating
but not limiting the invention.
ORTH-388
--8--
Example 1
6,7-Dihydroxy-4-methyl-2(1H)quinazolinone-1-(3'-methyl)
propionic acid Monohydrobromide Monohydrate
A solution of methyl 6,7-dimethoxy-4-methyl-2(1H)quinazo-
linone-1-(3'-methyl)propionate (1.0 g, 3~2 mM) in acetic
acid (10 ml) and 48% aqueous hydrogen bromide (10 ml) is
refluxed for 66 hours. The reaction mixture is cooled. A
green precipitate results which is isolated by filtration,
washed with cold ether (20 ml) and dried under vacuum to
afford the product (300 mg, 25~),
mp 220-222C; ~TMA 1.71-1.95 (d, 3H, 3'-CH3), 3.04
(s, 3H, 4-CH3) 3.18-3.53 (m, lH, -C-CH3), 5.21-5.82 (m, 2H,
-CH2-), 7.62 (s, lH, C5-H), 7.79 (s, lH, C8-H); M~ 273.
Example 2
6,7-Dihydroxy-3,4-dimethyl-2(1H)quinazolinonium-l-
propionic acid Bromide
A solution of methyl 6,7-dimethoxy-3,4-dimethyl-2(1H)-
quinazolinonium-l-propionate iodide (1.5 g, 33 mM) in
acetic acid (10.5 ml) and 48% aqueous hydrobromic acid
(10.5 ml) is refluxed with stirring for 48 hours. The
brown reaction mixture is cooled to room temperature and a
yellow precipitate is isolated by filtration. After
washing with cold ether (25 ml) and drying under vacuum,
the product (650 mg, 55~) is isolated.
mp 270-272C; ~TMS 3.22 (s, 3H, 4 CH3), 3.01-3.42
(m, 2H, 2'-CH2), 4.12 (s, 3H, =~CH3), 4.67-5.11 (t, 2H,
2'=CH2), 7.47 (s, lH, C5-H), 7.93 (s, lH, C8-H); M+ 278
(M-80).
ORTH-388
Exam~le 3
6,7-Dihvdroxv-4-methyl-2(1H)quina7Olinone-1-(2'-methyl)
propionic acid
A solution of methyl 6,7-dimethoxy-4-methyl-2(1H)quinazo-
linone-1-(2'-methyl)propionate (2.40 g, 7.5 mM), acetic
acid (25 ml) and 48% aqueous hydrogen bromide (25 ml) is
refl~xed for 48 hours under nitrogen. The reaction mixture
is cooled in an ice bath, concentrated in vacuo to half
volume and basified to pH 12 with lN sodium hydroxide
(25 ml). The reaction is chilled again and acidified with
glacial acetic acid to pH 5. A yellow precipitate results
which is isolated by filtration, washed with cold ether and
dried under vacuum to afford the product. (1.60 g, 7609%);
mp 266-268C; ~TMS 1.38-1.65 (d, 3H, 2'-CH3), 2.99 (s, 3H-
H N-
4-CH3), 3.10-3.49 (m, lH, -C-), 3.91-5.09 (m, 2H, CH2 C),
7.37 (s, lH, C5-H), 7.72 (s, lH, C8-H); M+ 278.
When in the above procedure methyl 6-methoxy-4-methyl-
2(1H)quinazolinone-l-propionate, methyl 7-methoxy-4-
methyl-2(1H)quinazolinone-l-propionate, methyl 6-methoxy-
2(1H)quinazolinone-l-propionate, methyl 7-~ethoxy-2(1H)-
quinazolinone-l-propionate, methyl 6-~ethoxy-4-trifluoro-
methyl-2~1H)quinazolinone-l-propionate and methyl 7-
methoxy-4-trifluoromethyl-2(1H)quinazolinone-l-propionate
are employed in place of methyl 6,7-dimethoxy-4-methyl-
2(1H)quinazolinone-1-(2'-methyl)propionate the corres-
ponding 6-hydroxy-4-methyl-2(1H)quinaæolinone~l-propionic
acid, 7-hydroxy-4-methyl-2(1H)quinazolinone-l-propionic
acid, 6-hydroxy-2(1H)quinazolinone-l-propionic acid, 7-
3S hydroxy 2(lH)quinazolinone-l-propionate~ 6-hydroxy-4-
trifluoromethyl-2(1H)quinaæolinone-l-propionic acid and 7-
hydroxy-4-trifluoromethyl-2(1H)quinazolinone-l propionic
acid are obtained.
ORTH-388
:~2~
--10--
Example 4
6,7-Dihydroxy-4--methy1-2(1H)quinazolinone-1-(2'-methyl)
propionic acld tripotassium salt monohydrate
S A suspension of 6,7 dihydroxy-4-methyl-2(1H)quinazolinone-
1-(2'-methyl)propionic acid (1.5 9, 5.39 mM) in methanol
(100 ml) is treated with 1.0~ methanolic ~OH (16.17 ml,
16.1 mM) with good stirring ~nder nitrogen. The resulting
dark solution is filtered under nitrogen and concentrated
in vacuo to a yellow solid. The solid is triturated with
acetone (40 ml) and isolated by filtrationO After washing
with ether (20 ml), the solid is dried in a dessicator
under vacuum for 16 hours at room temperature to afford
6,7-dihydroxy-4-methyl-2(1H)quinazolinone-1-(2'-methyl)
propionic acid tripotassium salt monohydrate (2.2 9,
100%); mp >300C.
ExamE~
6,7-Dihydroxy-4-methyl-1-(3'-phenylpropyl)-2(_H ~ -
linone Monohydrate
A mixture of 6,7-dimethoxy-4-methyl-1-(3' phenylpropyl)-
2(1H)quinazolinone (1.25 g, 3.6 mM) and 43% aqueous
hydrogen bromide (10 ml) in glacial acetic acid (10 ml) is
refl~xed with stirring for 24 hours. After cooling to
room temperature, the reaction mix~ure is quenched on ice
~100 9). A yellow-brown solid deposits which is isolated,
washed with water (2x20 ml) and then with ether (3x40 ml).
After drying in air, 1.21 9 (100~) of the product is
obtained.
mp >275C dec.; ~ TMS 2.00-2.70 (m, 2H, -CH~-), 2.75-3.30
(m, 2H, -CH~-0), 3.00 (s, 3Hr CH3), 4.30-5000 (t, 2H,
35 -CH,N), 7.07 and 7.65 (2s, 2H, C5H, C~H), 7.25 (s, 5H,0-);
~I+ 310.
ORTH-388
.
4~
~hen in the above procedure 6,7-dimethoxy-4-methyl-2(1H)-
quinazolinone-1-(2-methanesulfonyl)ethane, 6,7-dimethoxy-
4-methyl-2(1H)quinazolinone-1-(2-benzoyl)ethane, and 6,7-
dimethoxy-~-methyl-2(lH)quinazolinone-l-2-(2~-pyridyl)-
ethane, are employed in place of 6,7-dimethoxy-4-methyl-1-
(3-phenylpropyl)-2(1H)quinazolinone the corresponding 6,7-
dihydroxy-4-methyl-.1-(2-methanesulfonyl)ethane-2(lH)-
quinazolinone monohydrate, 6,7-dihydroxy-4-methyl-1-
2(benzoyl)ethane-2(1H)quinazolinone monohydrate, and 6,7-
dihydroxy-4-methyl-1-2(2'-pyridyl)ethane-2(1H)quinazoli-
none monohydrate are obtained.
When in the above procedure 6,7-dimethoxy-4-methyl-2(1H)-
quinazolinone-l-propionaldehyde, 6,7-dimethoxy-4-methyl-
2(1H)quinazolinone-l-propionitrile and methyl 6,7-
dimethoxy-4-methyl-2(1H)quinazolinone-l-(l-phenyl)propio-
nate are employed in place of 6,7-dimethoxy-~-methyl-1-(3-
phenylpropyl)-2(lH)quinazolinone the corresponding 6,7-
~ dihydroxy-4-methyl-2(lH)quinazolinone-l-propionaldehyde,
- -~ 20 6,7-dihydroxy-4-methyl-2(1H)quinazolinone-l-propionic acid
and 6,7-dihydroxy-4-methyl-2(1H)quinazolinone~l-(l-phenyl)
propionic acid are obtained.
The following compounds are prepared by the procedure of
Examples 3, 4 or S using an appropriately substi.t~ted
quinazolinone as the starting materialO
R6O ~ ~
CH2CH2C02R6
wherein R6 is potassium or hydrogen and R2 is as
de~ined.
ORTH-388
-12-
R2 Hydrobromide Salt Free Acid Tripotassium Salt
_ _p/Yield % mp/Yield ~ mp/Yield %
H 231~232C/57.8
CH~ 257-259C/82.5 >300C/96.9
CF3 125-130C/22.2 >310C/76.6
ethyl 308-310C/84~5 305-306C/73.3
propyl 264-266C/42.8 328-329C/71.4 310-312C/97.2
isopropyl 310-312C/73.3 Dec.>300C/74.0
n-pentyl 222-224C/79.2 275-277C/72.3
n-hexyl 242-246C/64.3 Dec. 220C/68.2
n-heptyl 248-250C/91.6
n-octyl 238-240C/55.1 302~304C/80.0
n-decyl 164-166C/71.6 259-261C/100.0
CH2-CH2 276-278C/88.0 228-230C/8.9
CH2-CH-
fH2 CH~cH_ 276-278C/74.6 298-300C/91.5
CH2-CH~
CH -CH
1 ~ 2~ CH-CH2~ 262-264C/79.0
CH 2 -CH 2
Example 6
Ethyl 6,7-dihydroxy-4-methyl-2(1H)quinazolinone-1-
propionate
A suspension of 6,7-dihydroxy-4-methyl-211H)quina~olinone
-l-propionic acid (2.0 g, 6.5 mM) in absolute ethanol
(35 ml) containing methanesulfonic acid (1.0 ml) is
refluxed with stirring for 3 days. The reaction mixture
is cooled to room temperature and quenched on ice (200 g3.
A yellow-green precipitate forms which is isolated, washed
with water, acetone, and ether and then dried in vacuo to
afford the product. (1.75 g, 92.2%); mp >308C (dec.);
IOl
~TTFA 1.35-1.60 (t, 3H, CH2CH3), 2.g5-3.30 (m, 2H, CH~C-),
3.10 (s, 3H, CH3), 4.20-4.60 (q, 2H, CH2-O), 4.65-5.00
(t, 2H, CH2-N), 7.35 (s, lH, C5-H), 7.75 (s, lH, C8-H); M+ 292.
ORTH-388
g6~
-13-
Example ?
-
6,7-Dihydroxy-3,4-dimethyl-3,4-dihydro-2(1H)~uinazolinone
-l-propion_ acid
A solution of the quaternary salt 6,7-dihydroxy-3,4-di-
methyl-2(lH)quinazolinonium-l-propionic acid bro~ide
(1 meq) in glacial acetic acid (15 ml) is treated with
5~ Pd/C (0.1 9) and the reaction mixture is hydrogenated
at 45 psi for 12 hours. The catalyst is filtered and the
mother liquor is poured into water (100 ml). The precipi-
tate of 6,7-dihydroxy-3,4-di~ethyl-3,4-dihydro 2(1H)quin-
azolinone-l-propionic acid is filtered, washed with water
and dried _ vacuo.
Example 8
6,7-Dlhydroxy-3,4-dihy~ro-4-methyl-2(lH)quinazolinone-l-
propionic acid monohydrate
A slurry of 6,7-dihydroxy-4-methyl-2(1H)quinazolinone-1-
20 propionic acid monohydrate (5.0 g, 17.7 mM) in methanol
(270 ml) is treated with Pd/C (10%, 2.5 9) and the mixture
hydrogenated at 45 psi for 16 hours. Filtration, removal
of the solvent in vacuo and titration of the residue with
acetone gives the product as a tan solid (4.3 g, 91.4%);
25 mp 202-204C; ~TTMAs 6.86 (s, lH, 5-H), 6.83 (s, lH, 8-H),
4.78 (d, lH, J=7.0 Hz, 4-H), 4.36 (t, 2HI J=10 Hz, 2'-H),
3.03 (t, 2H, J=10 H~ H), 1.55 (d, 3H, J=7 Hz, 4-CH3);
30 M+ 266.
Example 9
6,7-Dihydroxy~3-benzyl 4-methyl-2(1H)~uinaz_linonium-l-
~ropionic ac d bromide
A solution of methyl 6,7-dimethoxy-4-methyl-2(1H)
quinazolinone-l-propionate (10 9) in acetone (100 ml) is
treated with benzyl bromide (10 eq) and the solution aged
ORTH-338
68
-14-
overnight at room temperature. The resulting crystalline
precipitate is isolated and dried in vacuo. The crude
quaternary salt is then dissolved in a mixture of glacial
acetic acid (70 ml) and 48% aqueous Hsr (70 ml) and the
reaction mixture refluxed Wit}l stirring for three days.
Upon cooling to room temperature 6,7-dihydroxy-3-benzyl-4-
methyl-2(1H)quinazolinonium-l-propionic acid bromide is
isolated as a crystalline precipitate.
Identical conditions are utilized employing ~-fluorobenzyl
bromide and E-chlorobenzyl bromide to give the correspond-
ing substituted benzyl quaternary salts.
Example 10
15 6,7-Dih~drox~4-norbornylmethyl-2(lH~quinazolinone-1-
propionic acicl hydrobrom _ e
A mixture of methyl 6,7-dimethoxy-4-norbornylmethyl-2(1H)-
quinazolinone-l-propionate (5 g), 48% aqueous HBr (40 ml)
and glacial acetic acid (40 ml) is refluxed with stirring
for three days. The solu~ion is then cooled and the
resulting gold precipitate isolated by filtration, washed
with acetone (25 ml) and dried in vacuo to afford the
title compound.
When in the above procedure methyl 6,7-dimethoxy-5-amino-
4-methyl-2(lH)quinazolinone-l-proplonate and methyl 6,7-
dimethoxy-5-nitro-4-methyl-2(1H~uinazolinone-l-propionate
are employed in place of methyl 6,7-dimethoxy-4-nor-
bornylmethyl-2(lH)quinazolinone-l-propionate, the corres-
ponding hydrobromides 6,7-dihydroxy-5-amino-4-methyl-
2(1H)quinazolinone-l-propionic acid dihydrobromide and
6,7~dimethoxy-5-nitro-4-methyl-2(1H)quinazolinone-l-
propionic acid hydrobromide are obtained. The propionate
3S starting materials are prepared according to the procedure
outlined in Example G.
ORTH-38~
~2~
-15-
Exa~ple 11
6,7-Dih~_roxy-4-methyl-2(1H)quinazolinone-l-propionic acid
monopotassium salt
5 A suspension of 6,7-dihydroxy-4-methyl-2(1H)quina2Olinone-
l-propionic acid (9.97 g, 37.10 mM) in methanol (30 ml)
under nitrogen, is treated with lN KOH in methanol
(37.10 ml, 37.10 mM). The resulting yellow slurry is
stirred at room temperature, under nitrogen, for 22 hours.
The reaction mixture is cooled in an ice-water bath and
filtered. The resulting yellow solid is washed with cold
methanol (3x17 ml) and dried in vacuo at 120C for 336
hours (14 days). The product (10.41 9) is obtained as a
yellow solid, mp = 303-305C.
Example 12
6,7-Dihydroxy-4-methyl-~(lH)quinazolinone-l-~ropionic acid
dipotassium salt
20 A suspensiorl of 6,7-dihydroxy-4-methyl-2(1H)quinazolinone-
1-propionic acid (45.0 g 167.47 mM) in methanol (600 ml)
is treated with lN KOH in methanol (334~94 ml, 334.94 mM)
at room temperature under nitrogen; a large a~ount of
yellow solid is present after addition of the KOH. Addi-
tional methanol (200 ml) is added. Water is then added
until the solid dissolves. The total amount of water
added is 300 ml. The reaction mixture is then stirred at
room temperature, under nitrogen for 30 minutes. The
slightly cloudy solution is then filtered and concentrated
to dryness in vacuo to give a yellowish-brown semi-solid.
This is triturated with acetone (300 ml) and the resulting
yellow solid filtered and dried to afford the dipotassium
salt (54.26 g, mp >325C).
ORTH-383
~22~
-16-
6,7-Dihydroxy-4-methyl-2(lH)quinazolinone-l-propionic acid
monoarginine salt monohydrate
A mixture of 6,7-dihydroxy-4-methyl-2(1H)quinazolinone-l-
propionic acid (4.0 9, 14.6 mM) and L-arginine (2.34 9,
14.6 mM) in water (150 ml) is aged at room temperature for
3 ho~rs. After 15 minutes the initial solution clears and
then a yellow precipitate begins ~o form. ~fter 3 hours,
this precipitate is isolated, washed with wa~er (15 ml),
acetone (20 ml), and then ether (2 x 20 ml). The precipi-
tate is dried in vacuo at 60C. for 3 hours to give the
-
amino acid salt (5.81 9, 93.8%).
Example 14
6,7-Dihydrox~-4 methyl-2(1H)quinazolinone-l-propionic acid
N-methylglucamine salt
A mixture of 6,7-dihydroxy-4-methyl-2(1H)quinazolinone-l-
propionic acid (0.79 9, 3 mM), meglumine (0.59 g, 3 mM),
methanol (40 ml) and water (4 ml) is aged at ambient
temperature overnight. The resulting slurry is filtered
and the precipitate washed with ether (2 x 20 ml). After
drying in air for 3 hours, the amine salt is isolated as a
yellow solid, (0.88 9, 62.51%, mp = dec. 197-8C).
The salts from monoethanolamine, piperazine, N-methylpi-
perazine and morpholine are prepared in a similar fashion.
Example 15
6,7-Dihydroxy~4~methyl-2(1H)quinaxolinone-l-pro~ionic acid
mono~2-methyl-~2-amino-1,3-propandiol) salt monohydrate
A suspension of 6,7-dihydroxy-4 methyl-2(1H)quinazolinone-
l-propionic acid (1.0 9, 3.6 mM) in methanol (40 ml) and
ORTH-388
~2Z~
-17-
water (10 ml) is treated with mono(2-methyl-2-amino-1,3-
propandiol) (0.38 9, 3.6 mM) and the mixture aged at
ambient temperature for 16 hours. The resulting pale-
yellow precipitate is isolated, washed with methanol
(10 ml) and ether (2 x 10 ml). After drying in vacuo for
6 hours at 60C, the amine salt (1.18 g, 85.5%) is
isolated, mp = 212-13C.
Example 16
6,7-Dihyd~oxy-4-methyl-2(1H)quinazolinone-l-propionic aci_
mono(l-amino-2,3-propandiol) salt hemihydrate
A mixture of 6,7-dihydroxy-4-methyl-2(1H)quinazolinone-l-
propionic acid (0.84 g, 3 mM), mono (l-amino-2,3-propan-
diol) (0.27 g, 3 mM), methanol (40 ml) and water (10 ml)
is aged overnight at room temperature. The resulting
precipitate is isolated and washed with methanol (10 ml)
and ether (1 x 20 ml). After drying under a stream of
nitrogen for 3 hours, the amine salt (0.94 g, 84.73) is
obtained.
Example 175,6-Dihydroxy-4-methyl-2(1H)~uinazolinone-l-propionic
acid Monohydroiodide
Methyl 5,6-dimethoxy-4-methyl-2(1H)quinazolinone-l-
propionate (1.173g, 3.83mM) is treated with 50% aq HI
(13 ml) at room temperature to give a clear orange
solution which is refluxed under nitrogen for 11 hr. and
then allowed to stir at room temperature overnight. The
orange crystalline solid which precipitates is collected
by filtration, washed with acetone and dried to give the
product; yield 0.972 g, (65%), mp. 240-241C(d) IR
(KBr)~, 3.23 (broad, OH), 5.78 (C=O).
ORTH-388
-18-
When in the above procedure methyl 5,6-dimethoxy-4-tri-
Eluoromethyl-2~1H)quinazolinone-l-propionate, methyl 5,6-
dimethoxy-~-isopropyl-2(1H)quinazolinone-l-propionate
methyl 4-cyclopentyl-5,6-dimethoxy-2(1H)quinazolinone
l-propionate, and methyl 4-cyclohexylmethyl-5,6-dimethoxy-
2(1H)quinazolinone-1-propionate are employed in place of
methyl 5,6-dimethoxy-4-methyl-2(1H)quinazolinone-l-pro-
pionate the correspondiny 5,6-dihydroxy-4-trifluoromethyl-
2(1H)quinazolinone-l-propionic acid monohydroiodide, 5,6-
dihydroxy-4-isopropyl-2(1H)quinazolinone-l-propionic acid
monohydroiodide, 4-cyclopentyl-5,6-dihydroxy-2(1H)quina-
zolinone-l-propionic acid monohydroiodide and ~-cyclo-
hexylmethyl-5,6-dihydroxy-2(lH)quinazolinone-l-propionic
acid monohydroiodide are obtained. The ester starting
materials are prepared accordiny to the method outlined in
Example G.
Example 18
6,7-Dihydroxy-4-methyl-2(1H)quinazolinone-l-propionic acid
Monoh~drate
A suspension of methyl 6,7-dimethoxy-4-methyl-2(1H)quina-
zolinone-l-propionate (1.53 g, 5 mM), acetic acid (20
; ml) and 48% aqueous HBr (15 ml) is refluxed for 120 hours
under nitrogen. The solvent is removed ln vacuo to yield
a greenish hydrobromide salt Iyield 1.5 9, 88.2%); mp 292-
295C. A solution o~ the salt in methanol (5 ml) is
treated with saturated aqueous NaHCO3 until the pH is
neutral. The precipitated free base is collected by
filtration and washed with acetone to obtain the product
; (yield 1.0 g, 76.9%) as a pale green solid, mp 308-310C;
NMR: ~TMS 7.80 (s, lH, 5-H), 7.46 (s, lH, 8-H), ~.66-5.08
(m, 2H, 2'-H), 3.13 (m, 5H, l'-H, 4-CH31 M+ 264.
ORTH-388
.
~19--
The various other substituted mono- and dihydroxy-2(1H)-
quinazolinones encompassed by the present invention can be
prepared b~ any of the above methods using an appropriate-
ly substituted mono- or dialkoxy-2(1H)~uinazolinone pre-
S pared according to the examples utilizing the variousstarting materials described below.
The biological activity of the novel quinazolinones was
determined according to the method of Goldberg, L.I.,
Sonneville, P. F. and McNay, J. L. (1968). An investiga-
tion of the structural requirements for dopamine-like
renal vasodilation; phenethylamines and apomorphine, J.
Pharmacol. Exp. Ther. 163.
Adult mongrel dogs are anesthetized and surgically pre-
pared for electromagnetic measurements of renal artery
blood flow. A carotid artery is cannulated for measuring
arterial blood pressure and drugs are administered intra-
venously. Heart rate is monitored by a cardiotachometer.
~0 Renal vascular resistance is calculated as the ratio of
mean arterial blood pressure/renal artery blood flow.
Dopamine is infused intravenously at 3 ~g/kg/min for ten
minutes (1 ~l/min) to determine responsiveness of each dog
to renal dopamine receptor stimulation. Cumulative dose-
response data are obtained by infusing the test drug atprogressively increasing (usually three fold) infusion
rates, each dose being infused five ~inutes. The maximum
percent increase from pre-drug control in renal artery
blood flow (or decrease in renal vascular resistance) is
quantitated for each infusion dose.
ORTH-388
6~
-20-
Preparation of Startin~ Materials
Example A
3,4-Dimethoxyphenylisocyanate
s
Phosgene (4 eq) is bubbled at a moderate rate into a 3-
neck flask containing a solution of 3,4-dimethoxyaniline
(1 eq.), in benzene (2 liters). The flask is cooled in an
ice bath for 15 minutes and then the solution is refluxed
for 1 3/4 hours while excess phosgene is added. The reac-
tion mixture is then refluxed overnight and the solvent
removed under vacuum. Acetone is added and the solvent is
again removed under vacu~m leaving a dark brown oily resi-
due which is distilled at 132-134C/0.6 mm. Yield: 22.5 g.
~ `
N-(3,4-Dimethox~henyl)-N'-propionylurea
A mixture of 3,4-dimethoxyphenylisocyanate (26.0 g,
145 mM) and propionamide (10.61 g, 145 mM) is heated at
160-165C for 1 1/2 hours. A homogeneous pale yellow
solution forms which after 15 minutes solidifies. The
heating is discontinued and the flask is allowed to cool
slowly. The mixture is triturated with acetone and this
resulting white solid is filtered and dried. Yield:
32.45 9, mp 193-197C.
Example C
6,7-Dimethox~-4-ethyl-2(1H)~uinazolinone
A suspension of N-(3,4 dimethoxyphenyl)-N'-propionylurea
(32~45 9, 128 mM) in polyphosphoric acid (375.12 g,
1109 mM) is heated at 130-135C under nitrogen with
vigorous stirring for 3.5 hours. The mixture is then
poured onto 500 g ice H2O and stirred. The solution is
brought to pH 5.5 with concentra~ed NH40H and allowed to
stand at room temperature overnight. ~ brown precipitate
ORTH-388
~2~
-21-
forms. The resultir,g solid is filtered and dried to yield
7.40 g of a white solid. This filtrate is extracted with
CHCl3 (5x 250 ml), the organic extract is dried (MgS04)
and the solvent removed in vacuo to give a tan solid. The
solid is triturated with acetone and filtered to give a
tan solid (4.98 g). A sample is slurried in water and
redried for additional purification, m.p. 263-265C.
10 ~TMS 7 50 (s, lH, 5-H), 7.23 (s, lH, 8-H), 4.30 (s, 3H, 6
or 7-OCH3) 4.17 (s, 3H, 6 or 7-OCH3), 3.50 (q, 2H,
J=8.0Hz, CH~CH3), 1.70 (t, 3H, J-8.0Hz, CH~3).
Tabulated below are selected examples of 2(1H)~uinazoli-
nones prepared by the route described above~
C 3
3 H
ORTH~388
-22-
R2 M.P./C % Yield
H 247-248 67.5
CH3 269-271 65.0
CF3 280-282 46.3
propyl 208-210 53.8
isopropyl 233-240 86.0
n-pentyl 152-154 21.9
-CH2-CH 199-202 14.4
~ H3
n-hexyl 120-123 8.0
n-heptyl 184-186 78.2
n-octyl 130-132 24.4
n-decyl 166~167 37.4
-CH2 ~ 262-264 79.0
fH~-7H2 253-255 12.6
CH2-CH
CH~-ÇH2
I C 196-197 37 0
C\2/ H
CH~
~ CH2- 298-302 16.6
Example D
3,4-Dimethoxy-6-nitroacetophenone
3,4-Dimethoxyacetophenone (1.8 eq) is added during 0.5
hour to nitric acid (18 eq), at 0O After a further 1
hour at 20C., the dark brown solution is poured onto ice
water. The crude product is collected by filtration.
: Recrystallization from ethyl alcohol affords the purified
product, mp = 124-126C; ~CDC13 2.50 (s, 3H, CH3), 4.00
(s, 6H, OCH3's), 6.80, 7.59 (2s, lH ea., C2H, C5H).
ORTH-388
.
-23-
Example E
6-Amino-3,4-dimet_oxyacetophenone
A slurry of 1 equivalent of 3,4-dimethoxy-6-nitroaceto-
phenone in methanol is treated with Pd/C (10%) and the
mixture is hydrogenated at 45 psi for 24 hours. The resi-
due after filtration and removal of solvent is crystal-
lized from ethyl alcohol to afford purified product, mp =
98-100C; ~TMS 3 2.50 (s, 3H, CH3), 3.80-3.85 12s, 3H ea.,
OCH3); 6.05, 7.05 (2s, lH ea., C2H, C5H).
Example F
2-(N-Carbethoxyamino)-4,5-dimethoxyacetophenone
Ethyl chloroformate (1 eq) is added cautiously with stir-
ring to 6-amino-3,4-dimethoxyacetophenone (0.3 eq) at room
temperature. The dark brown reaction mixture is stirred
at room temperature for 1/2 hour. Aqueous sodium hydrox-
ide is added and the reaction mixture stirred at room
temperature for an additional hour. The reaction mixture
is extracted with chloroform. Removal of chloroform gives
an oily residue. Recrystallization from ether affords the
product, mp = 97-99C; ~TDsc 3 1.10-1.50 (t, 3H, CH3), 2.60
(s, 3H, CH3), 3.~5 and 3.95 (2s, 3H ea., OCH3's), 4.0~4.4
(q, 2H, CH2), 7.15 and 8.20 (2s, lH ea., C2H, C5H).
General Preparation of me~hyl 2(1~)quinazolinone-1-
propionates
R2
CH30
~ N ~
CH30 CH2CH2COOCH3
ORTH-388
~2~6~
-24-
An appropriately substituted 2(1H)quinazolinone (S g) is
placed in a mixture of methanol (75 mol), chloroform
(100 ml), methyl acrylate (125 ml) and excess Triton a
(40% methanol) and the mixture is refluxed with stirring
for 4-16 hours. The solution is then cooled and after
evaporation of the solvent, the ester is obtained by
chromatography on silica gel.
The following compounds are made by the above general
procedure:
R2 M.P/C
H 186-188
CH3 155~157
CF3 140-143
ethyl 132-134
propyl 120-122
isopropyl 112-114
n-pentyl oil
n-hexyl 122-124
n-heptyl 107-110
n-octyl 100-104
n-decyl oil
fH 2-CH2 140-142
CH2- ~
CH2-~H2 103-105
\ /
CH~
f 2 2 CH-CH2- 92-95
CH2--CH2/
When in the above procedure 6-methoxy-4-methyl-2(1H)quina-
zolinone, 4-methyl-7-methoxy-2(1H)quinazolinone, 6-
methoxy-2(lH)quinazolinone, 7~methoxy-2(lH3quinazolinone,
6 methoxy-4-trifluoromethyl-2(1H)quinazolinone and
ORTH-388
.
~z~
7-methoxy-4-trifluoromethyl-2(1H)quinazolinone are
employed as the starting materials, the corresponding 1-
propionic acid esters are ob~ained.
S When in the above procedure 3,4-dihydro-5,6-dimethoxy-4-
methyl-2(1H)quinazolinone, 5,6-dimethoxy-4-methyl-2(1H)-
quinazolinone, 5,6-dimethoxy-4-trifluoromethyl-2(1H)-quin-
azolinone are employed as the substituted quinazolinone
the corresponding l-propionic acid esters are obtained.
Example H
6,7-Dimethoxy-4-methyl-2(lH)quinazolinone-1-(2-methane-
sulfonyl)ethane
A solution of 6,7-dimethoxy-4-methyl-2(1H)quinazolinone
(10 g) in chloroform (100 ml), methanol (100 ml) and
methylvinyl sulfone (40 eq) is treated with Triton B
(benzyltrimethylammonium hydroxide, 40% in methanol,
1.1 eq) and the solution refluxed, with stirring, for 24
hours. The solution is then cooled to room temperature
and the solvent removed by concentration in vacuo. The
residue is chromatographed on silica gel to afford puri-
fied 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1-(2-
methanesulfonyl) ethane.
Exam~e I
6,7-Dimethoxy-4-methyl-2(1H)~uina~olinone-1-(2-benzoyl)
ethane
A solution of 6,7-dimethoxy-6-methyl-2(1H3quinazolinone
(10 y) in chloroform (100 ml), methanol 1100 ml) and
phenylvinyl ketone (40 eq) is treated with Triton B (40%
in methanol, 1.1 eq~ and the solution refluxed with stir-
ring for 24 hours. Af~er cooling to room temperature, the
solvent is removed in vacuo and the residue chromato-
graphed on silica gelO Purified 6,7-dimethoxy-4-methyl-
2(1H)quinazolinone-1-(2-benzoyl) ethane is obtained.
ORTH-388
* Trademark
46~3
-26-
Example J
6,7-Dimethoxy-4-methyl-2(lH)quinazolinone-1-[2-(2'-
~ )ethane]
A solution of 6,7-dimethoxy-4-methyl-2(1H)quinazolinone
(10 g) in chloroform (100 ml), methanol (100 ml and 2-
vinylpyridine (25 eq) is treated with Triton B (40~ in
methanol, 1.1 eq), and the solution refluxed with stirring
for 24 hours. The resulting solution is cooled to roo~
temperature and the solvent removed by concentration
in vacuo. The residue is chromatographed on silica gel to
give purified 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-l-
[2-(2'-pyridyl)ethane].
When in the above procedure 4-vinylpyridine is employed in
place of 2-vinylpyridine the corresponding 4'-pyridyl
derivative is obtainedO
Example K
6,7-Dimethoxy-4-methyl-2(1H)quinazolinone-l-propionaldehy~
A solution of 6,7-dimethoxy-4-methyl-2(1H)qulnazolinone
(10 g) in methanol (100 ml), chloroform (100 ml) and acro-
lein (40 eq) is treated with Triton B (40% in methanol,
1.1 eq). The resulting mixture is concentrated in vacuo
and the residue is chromatographed on silica gel to afford
purified 6,7-dimethoxy-4-methyl-2 (lH~quinazolinone-l-
propionaldehyde.
Exam~le L
6,7-Dimethoxv-4-methYl-2(lH)quinazolinon~ propionitrile
A solution of 6,7-dimethoxy-4-methyl-2(1H)quinazolinone
(10 g) in chloroform (100 ml), methanol (100 ml) and
acrylonitrile (excess) is treated with Triton B (40% in
` methanol, x's). The solution is refluxed with stirring
for 24 hours. The resulting solution is cooled to room
ORTH-388
~Z~ 8
-27-
temperature and the solvent is removed by evaporation
_ vacuo. The resulting residue is chromatographed on
silica gel to give purified 6,7-dimethoxy-4-methyl-2(1H)
quinazolinone-l-propionitrile.
Methyl 6,7-dimethoxy-4-methyl-2(1H)qulnazolinone-l-(l-
phenyl)_propionate
A solution of 6,7-dimethoxy-4-methyl-2(1H)quinazolinone
(10 9) in chloroform (100 ml), methanol (100 ml) anc3
methyl -phenylacrylate (excess) is treated with
Triton B (40% in methanol, 1.1 eq) and the resulting
solution refluxed with stirring for 24 hours. After
cooling to room temperature, the solvent is removed
in vacuo and the residue purified by chromatography on
silica gel to give purified methyl 6,7-dimethoxy-4-methyl-
2(lH)quinazolinone-l-(l-phenyl)propionate.
When in the above procedure methyl (2,4~difluorophenyl)
acrylate, methyl (4-chlorophenyl)acrylate and methyl (4-
methoxyphenyl acrylate are employed in place of methyl
a-phenylacrylate, the corresponding quinazolinones methyl
6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1-~1-(2,4-
difluorophenyl)propionate]; methyl 6l7-dimethoxy-4-~ethyl-
2(1H)quinazolinone-1-[1-(4-chlorophenyl) propionate~; and
methyl 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1-[1-(4-
methoxyphenyl) propiona~e] are obtained.
Exam~le N
Methyl 6,7-dimethoxy-4-methyl-2(1H)~Llnazollnone-1-(2-
~henyl pro~ nate)
A solution of 6,7-dimethoxy-4-methyl-2(1H)quinazolinone
3S (10 9) in chloroform tlOO ml), methanol (100 ml), and
methyl cinnamate (excess) is treated with Triton B (50% in
methanol, 1.1 eq) and the resulting solution refluxed with
ORTH-388
~2~46~3
-28-
stirring for 24 hours. The solution is concentrated in
vacuo to remove the solvent and the residue is purified by
chromatography on silica gel. In this manner, purified
methyl 6,7-dimethoxy-~-methyl-2(1H)quinazolinone-1-(2-
phenyl propionate) is obtained.
When in the above procedure methyl 2,4-difluorocinnamate,
methyl 4-chlorocinnamate and methyl 4-methoxycinnamate are
employed in place of methyl cinnamate, the corresponding
quinazolinones methyl 6,7-dimethoxy~4-methyl-2(lH)quinazo-
linone-1-[2-(2,4-difluorophenyl)propionate]; methyl 6,7-
dimethoxy-4-methyl-2-(lH)quinazolinone-1-[2-(4-chloro-
phenyl) propionate] and methyl 6,7-dimethoxy-4-methyl-
2(lH)quinazolinone-1-[2-(4-methoxyphenyl)propionate] are
obtained.
Example O
6,7-Dimethoxy-4-(2-norbornylmethyl)-2(1H)quinazolinone
A solution of norbornyl-2-acetic acid (25.0 gl 0.16 m) in
benzene (SO ml) is treated with thionyl chloride (75 ml)
and the mixture refluxed with stirring ~or 12 hours. The
volatiles are removed on a rotary evaporator at about
50C. The resulting acid chloride is dissolved in
tetrahydrofuran (150 ml) and then aqueous concentrated
ammonia (200 ml) i5 slowly introduced with stirring. A
precipitate forms during the subsequent 30 minute aging
period. It is isolated by filtration and washed well with
cold water. After drying, 15.3 9 (62.5%), mp = 1~4-6C,
of norbornyl-2-acetamide are ob~ained.
A mixture of 3,4-dimethoxyphenylisocyanate (8.95 9,
O.OS m) and norbornyl-2-acetamide (6.12 9, 0.04 m) is
fused under nitrogen at 130-140C with stirring for one
hour. A~ter cooling, acetone tlOO ml) is introduced and
the mixture broken-up manually. A~ter one hour aging at
room temperature, the precipitate is isolated and dried
ORTH-388
-29-
in vacuo. A sol~tion of the adduct (9.0 g, 0.027 m) in
polyphosphoric acid (200 g) is heated at 130-140C for
three hours wlth stirring. After cooling, the reaction
mixture is quenched on ice (1500 9) and stirred well.
This pale green solution is brought to pH~ 8.0 with
concentrated ammonia. The resulting precipitate is
isolated, washed with distilled water (2x50 ml) and dried
to yield 6,7-dimethoxy-4-(2-norbornylmethyl)-2-(lH)-
quinazoline as a tan solid. After recrystallization from
95% ethanol, pale yellow crystals are obtained, 2.0 g,
M.P. 231-2C.
Example P
Methyl 6,7-dimethoxy-4-methyl-2(lH)quinazolinone-1-(3'-
m_ b ~ ~n~e
Triton B (26.0 ml, 40~ in methanol) is added as a slow
stream with stirring to a solution of 6,7-dimethoxy-4-
methyl-2(1H)quinazolinone (20.0 g, 91 mM) in methyl
20 crotonate t90.0 9, 900 mM); methanol (80 ml), and
chloroform (126 ml) precooled to 0C. The reaction is
stirred at reflux for 18 hours. The reaction mixture is
then cooled to room temperature and the suspension is
isolated by filtration. The filtrate is concentrated in
vacuo to give a fluffy solid which is chromatographed on
*
SilicAR CC-7 (125 9) prepared in 1:1 C~2Cl2/ethyl acetate.
Elution with 5-20% methanol/CH2C12 aEords the prod~ct as
an orange solid (560 mg, 1.9~); mp 55-56C.
Exam~le Q
Methyl 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-l-
(2'-methyl)propionate
Triton B (26.0 ml, 40% in methanol) is added as a slow
stream with stirring to a solution of 6,7-dimethoxy-4-
methyl-2(1H)quinazolinone (20.0 g, 91 mM) in methyl
methacrylate (206 ml), methanol (79 ml), and chloroform
ORTH-388
* Trademark
-30-
(127.5 ml) precooled to 0C. The reaction is stirred at
room temperature for 1~ hours and then heated at 50C for
66 hours. The suspension is cooled in an ice bath and the
resulting precipitate is isolated by filtration. Water
~75 ml) is added to the filtrate and this solution is
extracted with methylene chloride (4x100 ml). The extract
is dried (MgSO4), filtered and concentrated in vacuo to
give a reddish oil which is chromatographed on SilicAR CC-
7 prepared in ethyl acetate. Elution with 5-10% ethyl
acetate/ethanol gives an oil. Trituration of this oil
with cold ethyl acetate/ether (1:1) deposits white
crystals which àre filtered, washed with ether ~25 ml),
and dried in vacuo to afford methyl 6,7-dimethoxy-4-
methyl-2(1~)-quinazolinone-1-(2'-methyl)propionate.
1~
Example R
Methyl 6,7-dimethoxy-4-norbornylmethyl-2(1H)quinazolinone-
1-(2l-m~ElcLLb3ca~L~
A solution of 6,7-dimethoxy-4-norbornylmethyl-2(1E~)quin-
azolinone (10 g) in chloroform (50 ml), methan~l (50 ml)
and methylacrylate (50 ml) is treated with Triton B
(benzyltrimethylammonium hydroxide, 40% in methanol,
20 ml, excess) and the reaction is refluxed with stirring
for 24 hours. After work-up and purification via chroma-
tography, the purified product is obtained.
Example S
Methyl 6,7-dimethoxy-3,4-dihydro-3,4-dimethyl-2[1H)
~uinazolinone l-propionate
A solution of methyl 6,7-dimethoxy-3,4-dimethyl-2(lH)quin-
azolinonium-l-propionate bromide (1 eq) in ethanol
(700 ml) is treated with 10 9 10~ Pd/Co The mixture is
hydrogenated at ~45 psi for 16 hours until uptake ceases.
The solution is filtered free of catalys~ and ~he filtrate
is concentrated in vacuo. The resulting solid is
ORTH-388
-31-
recrystallized from acetone to give a 60-70~ yield of
purified methyl-6,7-dimethoxy-3,4-dihydro-3,4-dimethyl-
2(lH)quinazolinone-l-propionate.
S ~
6,7-Dimethoxy--5-nitro-4-methyl-2(1H)quinazolinone
One equivalent of 6,7-dimethoxy-4-methyl-2(1H)quinazoli-
none is added during 3/4 hr. to a mixture (5:1) of 6 equi-
valents of concentrated nitric acid (70%) and concentratedH2SO4 at 0 ~ 3C. After one hour at the same temperature
the solution is poured onto crushed ice (1000 ml). ~he
crude product is collected by filtration, digested with
boiling alcohol and the suspension is filtered. Crystal-
lization from ethyl alcohol affords 6,7-dimethoxy-5-nitro-
4-methyl-2(1H)quinazolinone.
Example U
6,7-Dimethoxy-5-amino-4-methyl-2(1H)quinazolinone
A solution of 13 equivalents of FeS04~7H20 in water
(6 parts) is heated to 95C. A slurry of 1 equivalent of
6,7-dimethoxy-5-nitro-4-methyl-2(1H)quinazolinone in water
(800 ml) at 80C. is added and the resulting yellow
mixture is heated at 98-100C. for 15 minutes. Ammonium
hydroxide (13 eq) is added to the mixture dropwise over a
15 minute period, maintaining the temperature at 98-100C.
The resulting black reaction mixture is stirred at 98-
100C. for 30 minutes, ~he hot mixture is filtered and the
insoluble black residue is washed with hot water. The
brownish filtrate is extracted with chloroform. The
solvent is removed in vacuo to give a dark brown semi~
solid crude product, which is chromatographed on a silica
gel column. Recrystallization of the crude product from
ethyl alcohol affords purified product.
ORTH-388
-32-
Example V
6,7-Dimethoxy-3,4-dimethyl-2(lH)quinazolinonium propionic
acid methyl_ester Iodide Hemihydrate
A large excess of CH3I (20 ml) is added to a solution of
methyl 6,7-dimethoxy-4-methyl-2(1H)quinazolinone propionate
(2.0 g, 6.53 mM) in acetone (300 ml) and the mixture is
refluxed for 3 days. Removal of the solvent in vacuo and
subsequent trituration with ether yields a dark brownish
solid (2.4 9). Crystallization from isopropyl alcohol and
then from methanol affords the product as a yellow solid;
yield 1.2 g (41.3%).
The starting materials for those compounds wherein the
lS hydroxyl groups on the aromatic ring are in the 5-, 6- or
7-positions are prepared according to the following
examples.
Example W
2-Hydroxy-3-methoxybenzaldehyde-2-benze_esulfonate
A slurry of 3-methoxysalicylaldehyde (45.6 g, 299 mM) in
NaOH (138 ml, 15% aqueous solution) is treated with
benzenesulfonyl chloride (66 g, 373 mM) and the mixture
vigorously stirred for 1 hour. The reaction mixture is
then poured into ice-water (500 ml) and the resulting
white solid filtered, washed with cold water, and then
recrystallized from acetic acid to afford the product as a
white solid; yield 72.2 g (85%); m.p. 119-120C.
Example X
2-Hydroxy-3-methoxy-6-nitrobenzald~y~
benzenesulfonate
2-Hydroxy-3-methoxybenzaldehyde-2-benzenesulfona~e (50 g,
171 mM) is added to nitric acid (500 ml) at 0C - 5C.
:
.
;` oRTH-388
~L22~
-33-
The solution is kept five minutes at 5C and then poured
into ice-water (1.5 L). The crude product, a tan solid,
is filtered, washed with cold water, alcohol, and then
recr~stallized from acetic acid (650 ml) to afford the
product as a white solid; yield 30.3 g (52.6%); m.p. 152-
154C.
Example Y
2-H~droxy-3-methoxy-6-nitrobenzaldehxde
A slurry of 2-hydroxy-3-methoxy-6-nitrobenzaldehyde-2-
benzenesulfonate (10.12 g, 30 mr~) in methanol (12Q ml) is
heated to reflux. A solution of KOH (6 g) in water
(2~ ml) and methanol (1~ ml) is added and the two phase
mixture refluxed for 30 minutes. The light reddish preci-
pitate which forms is filtered and then dissolved in
boiling water (120 ml). Acidification of the hot aqueous
solution with 10% aqueous HCl to pH~ 4 gives a yellow
precipitate (5.0 g). Recrystallization from isopropyl
alcohol affords the product as a yellow solid; yield 4.5 g
(76.2%); m.p. 102-104~.
Example Z
2,3-Dimethoxy-6-nitrobenzaldehyde
A slurry of NaH (16.0 g, 50% oily dispersion, 337 mM) in
dimethylformamide (200 ml) was treated dropwise with a
solution of 2-hydroxy 3-methoxy-6-nitrobenzaldehyde
~49.0 g, 248 mM) in DMF (300 ml) at such a rate that the
temperature did not exceed 35C. The mixture is aged at
room temperature for 1 hour and then a large excess of
methyl iodide (100 ml) is added dropwise. A slight
exothermic reaction occurs. The mixture is then stirred
vigorously for 19 hours at room ~emperature. After the
removal of excess methyl iodide, the reaction mixture is
poured into ice-wa~er (1 1). The crude product, a brown
ORTH-388
~2~6~
solid, is filtered, washed with cold water, and then
recrystallized from isopropyl alcohol (700 ml) to a~ford
the product as a tan solid; yield 27.9 g (53.3%);
m.p. 106-108~C.
2,3-Dimethoxy~6-nitrobenzaldehyde-ethyleneketal
A mixture of 2,3-dimethoxy-6-nitrobenzaldehyde (16~0 g,
10 75 mM), ethylene glycol (64 g, 103 mM), and ~-toluenesul-
fonic acid monohydrate (0.2 g) in benzene (750 ml) is
refluxed in a Dean-Stark apparatus for 4S hours. The
solution is then poured into water (1 1.). The organic
phase is washed with saturated aqueous NaHCO3 (2x20 ml),
dried over Na2SO4, filtere~, and the solvent removed
in vacuo. The crude product is recrystallized from n-
-
hexane (2 1.); yield 15.2 9 (78.2%); m.p. 74-76C.
Example BB
2-A~ino-5,6-dimethoxybenzaldehyde ethyleneketal
A solution of 2,3-dimethoxy-6-nitrobenzaldehyde-ethylene-
ketal (12.1 9, 62.7 mM) in ethyl ace~ate (350 ml) con~ain-
ing sodium acetate (0.5 g) is treated with platinum oxide
(1.0 g) and the mixture hydrogenated for 24 hours at
~50 psi. The solvent is removed in vacuo af~er filtering
off the catalyst to give a pale brown oil. A~ter crystal-
lization from n-hexane, the product is obtained as a tan
solid; yield 12.8 g (85.1%); m.p. 78-80C.
Example CC
2-(N-Carbethoxyamino)-5,6-dimethoxy~ zaldehyde
ethyleneketal
35 Ethylchloroformate (1.9 g, 17.5 mM) is added with stirring
to 2-amino-5,6-dimethoxybenzaldehyde-ethyleneketal
ORTH-388
(1.6 g, 7.1 mM) dissolved in tetrahydrofuran ~50 ml). A
solution of sodium hydroxide in H2O (0.72 9 in 3.5 ml H2O)
is added and the resulting solution is stirred for 2 hours
at room te~perature. The ~etrahydrofuran is removed
in vacuo and the residue extracted with CHC13 (2x100 ml).
The extracts are dried over ~la2SO4, filtered, and the
solvent removed in vacuo. The crude product is recrystal-
-
lized from n-hexane; yield 1.2 g (57.1%); m.p. gS-96C.
-
Example DD
2-(N-Carbethox~amino)-5,6-dimethox~benzaldehyde
2-(N-Carbethoxyamino)-5,6-dimethoxybenzaldehyde-ethylene-
ketal (5.0 g, 16.8 mM) is dissolved in acetone {36 ml) and
aqueous HCl (3 ml of lN solution). The mixture is stirred
at room temperature for 4 hours. The solvent is removed
ln _acuo to give a yellow solid (3.9 g). Recrystalliza-
tion from n-hexane gives the pure product as a yellow
solid; yield 3.6 9 (84.7%); m.p. 86-88C.
Example EE
5,6-Dimethoxy-2(lH)-quinazolinone
A stream of dry ammonia gas is passed through a solution
of 2-(N-carbethoxyamino)-5,6-dimethoxybenzaldehyde
(12.4 g, 48.9 mM) and ammonium acetate (95 g) maintained
at 155-160C for 3 hours~ The reaction mixture is cooled
and poured into an ice-water mixture. A tan solid formsO
The aqueous mixture is treated with NaCl (50 g) and then
extracted with CHC13 (3x200 ml). The organic extracts are
combined and the solvent is removed in vacuo to yield
9.2 9 of a pale brown oil~ Trituration of the oil with
hot acetone gives the product as a yellow solid; yield
2.1 9 (20.8%); ~.p. 242-244C.
; ORTH-388
~2~Z~
-36-
~xam~le FF
3,4-Dihydro-5!6-dimethoxy-4-met_~1-2(1H)quinazolinone
To a partial solution of 5,6-dimethoxy-2(1H)quinazolinone
S (10.0 g, 48.5 mM) in dry tetrahydrofuran (1100 ml) under
nitrogen, is added at 0C over 20 minutes, an excess of
methyl magnesium bromide in ether (62.60 ml of a 3.1 M
solution in ether, 194.06 mM). The reaction mixture is
then removed from the cooling bath, allowed to reach room
temperature and is stirred at room temperature for 16
hours. Additional methyl magnesium bro~ide is added
(15.65 ~1 of a 3.1 M solution ln ether; 48.52 mM) and the
reaction mixture is heated at reflux for 2 hours, cooled
in an ice-water bath and an aqueous solution of NH4Cl
(100 ml of saturated NH4Cl and 100 ml H~O) is added with
stirring. After the addition is complete, 10% aqueous HCl
is added until a pH of ~6.0 is reached. The layers are
separated and the aqueous layer is extracted with CHCl3
(3x250 ml). The CHC13 extract is combined with the pre-
viously separated tetrahydrofuran layer, and the combined
organic layers are washed with a saturated aqueous solu-
tion of NaCl (200 ml) and dried (Na2SO4). Filtration
followed by concentration to ~250 ml affords an off-white
precipitate which is filtered and recrystallized from
isopropanol (200 ml) to give the product as a colorless
solid; yield 9.7 9 (~7.8%), m.p. 210-212C.
Eample GG
5,6-Dimethoxy-4-meth~1-2(lH)~uinazolinone
Potassium permanganate (25.6 ~, 162.38 mM) is added to a
solution of 3,4-dihydro-5,6-dimethoxy-4-methyl-2(1H)quina-
zolinone (18.04 9, 81.19 mM) in acetone (5.0 liters) and
the mixture is stirred at room temperature (under nitro-
gen, protected from light with aluminum foil) for 96hours. The brown precipitate which forms is filtered and
washed with acetone (500 ml) and is partially dissolved in
ORTH-388
2~
boiling water (1000 ml). The hot, aqueous solution (after
filtration) is neutraliæed with 10~ aqueous HCl and then
extracted with CHC13 (4x250 ml) and 10% isopropyl
alcohol/ethyl acetate (4x250 ml). The CHC13 extracts are
5 dried (MYSOL,), filtered, and concentrated to 500 ml at
which point a solid forms. The solid is filtered off and
the filtrate is further concentrated in vacuo to give
3.25 9 of a tan solid which is chromatographed on a 350 g
SilicAR column that has been prepared in CHC13 (500 ml
10 fractions). ~lution with 1/2% methanol/chloroform affords
a yellow solid (1.92 9) which upon recrystallization from
isopropanol (75 ml) affords the product as a yellow solid;
yield 0.940 g (5.3%); mp 230-232C.
15 When in the above procedure 3,4-dihydro-5,6-dimethoxy-4-
trifluoromethyl-2(lH)quinazolinone, 3,4-dihydro-5,6-
dimethoxy-4-isopropyl-2(1H)quinazolinone and 3,4-dihydro-
4-cyclohexyl-5,6-dimethoxy-2(1H)quinazolinone are e~ployed
in place of 3,4-dihydro-5,6-dimethoxy-4-methyl-2(1H)quina-
20 zolinone the corresponding 5,6-dimethoxy-4-trifluoro-
methyl-2(lH)quinazolinone, 5,6-dimethoxy-4-isopropyl-
2(lH)quinazolinone and 4-cyclohexyl-5,6-dimethoxy 2(lH)-
quinazolinone are obtained.
25 Example HH
2-(N-Carbethoxyamino)-5-methoxy-acetophenone
Ethyl chloroformate (8.6 9, 080 m) is added cautiously
with stirring to 2-amino-5-methoxyacetophenone (8.0 g,
30 0.0479 ~ while cooling the reaction mixture~ A solution
of sodium hydroxide in H20 (3.2 g in 15 ml) is added
slowly. The reaction becomes exothermic and all of the
solids dissolve~ The yellow reaction mixture is removed
from the ice bath and allowed to stir a~ room temperature
35 for 2 hours. The reaction mixture is then extracted with
CHC13 (3X100 ml) dried over Na2SO4, filtered, and the
solvent is removed in vaGuo to give a yellow solid.
ORTH-388
~2~
-38-
Crystallization from hexane affords the product as a
yellow solid; yield 7.4 g (65~); mp 90-92C.
Example II
S 6-Methoxy-4-methyl-2(lH)quinazolinone
A stream of dry ammonia gas is passed for 3 hours through
a solution of 2-tN-carbethoxyamino)-5-methoxy-acetophenone
(14.0 g, 0.058 m) and ammonium acetate maintained at 155-
160C. The reaction mixture is cooled and poured intoice-water ~750 ml) to give a dark orange solution. The
solution is extracted with CH~C12 (3X500 ml) followed by
ethyl acetate (2X500 ml) and n-butanol (2XS00 ml); the
combined organic extracts are dried over Na2SO4 and the
solvent is removed to give a brownish residue. The
residue is slurried in acetone and the insoluble portion
is filtered to give the product as a pale yellow solid;
yield 3.25 g, (25~); mp 232-236C dec.
Example JJ
4-Methyl-7-methoxy-2(lH~quinazolinone
A mixture of l-acetyl-3~3-methoxyphenyl)urea (3205 g,
0.156 m) and polyphosphoric acid (912.5 g) is heated at
25 120-130C for 2 hours. Ater cooling to 50C the melt is
poured on ice-water (2 liters), and ~he solution is made
weakly basic with ammonia and left standing overnight.
The brownish-red precipitate which forms is filtered off,
washed with cold water followed by hot aeetone, and
crystallized from ethanol (after treatment with charcoal)
to give the product as a p~le yellow solid; yield 11.5 g
(39.1%); mp ~51-254C.
The 5,6-2(1H)quina~olinones having a substituent other
than the methoxy group at C6 and C7 and a substituent
other than lower alkyl at C4 are prepared according to the
methods described for the preparation of the corresponding
ORTH-388 6,7-2(1H)quinazolinones.
