Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
'5~'7~
Description of the Invention
The present invention relates to the use in the treat-
ment of hypertension and bradycardia and as a card10tonic
agent, of a compound of the formula
X CH2Rl
~ y~O
H
I
`
wherein Rl is hydrogen; alkyl having 4-20 carbons; cyclo-
alkyl, heterocycloalkyl; halo; COO loweralkyl; CN; COOH;
CH20H; CH(O-loweralkyl)2 or nitro; and X and Y are each
hydrogen; halo; nitro; loweralkyl; loweralkoxy; aryl;
arylalkyloxy; hydroxy; acyloxy; aryloxy; amino; loweralkyl-
amino; diloweralkylamino; amido; loweralkylamido; diloweralkyl-
amido; cyano; COOH; COO loweralkyl; CHO; CH20H; CH20
acyl; or CH20 aryl; and pharmaceutically-acceptable acid
.
r
.,
w~ ~
addition salts thereof; providecl that when X and Y are
loweralkoxy Rl is not hydrogen.
As used herein, the terms ~loweralkyl~ and ~loweralkoxy"
mean straight or branched chain aliphatic hydrocarbons having
from 1 to about 6 carbon atoms, such as for example methyl,
ethyl, ~sopropyl, pentyl, and the like loweralkyls, and
respectively, methoxy, ethoxy, isopropoxy, pentoxy, and the
like loweralkoxys. The term "halo" includes fluoro, chloro,
bromo, and iodo. The term ~aryl~ includes aromatic hydro-
carbons such as naphthyl, phenyl and the l~ke and subst~tuted
aromatic hydrocarbons such as phenyl substituted with from
one to three members each selected from the group consisting
of loweralkyl, loweralkoxy, halo and methylenedioxy, prov~ded
that only one such member is methylenedioxy (called herein
"substituted phenyl"); and the like. The term "acyl"
includes loweralkanoyl and aroyl radicals derived from
carboxylic acids having the formula HCOOH, loweralkyl-COOH,
and aryl-COOH. Examples of the acyl groups included herein
are acetyl, propionyl, n-butyryl, and the like loweralkanoyls
and benzoyl, naphthoyl, 3,5-dichlorobenzoyl, and the like
aroyls.
The quinazolines of this invention having the formula
I, possess cardiovascular activity and are also useful
in the treatment of hypertension and bradycardia and as
cartiotonic agents.
Some of the instant compounds are novel and as such are
included as part of this invention. The novel substituted
quinazolinones include those compounds having the following
formula:
CH2Rl
~ N ~ 0
Y
H I'
wherein Rl is alkyl having 4-20 carbons or cycloalkyl; and
X and Y are each hydrogen; halo; nitro; loweralkyl; lower-
alkoxy; aryl; arylalkyloxy; hydroxy; acyloxy; aryloxy;
amino; loweralkylamino; diloweralkylamino; amido, loweralkyl-
amido; diloweralkylam~do; cyano; COOH; C00 loweralkyl; CH0;
CH20H; CH20 acyl; or CH20 aryl; and pharmaceutically-
acceptable acid addition salts thereof.
The compounds of the invent~on possess cardiovascular
activities and are useful ~n the treatment of hypertension
and bradycardia and as cardiotonic agents, as shown by the,r
activity in the spontaneous hypertensive rat test at dosages
from about 50 mg/kg to about 100 mg/kg body weight. They
have also been found to inhibit cyclic AMP phosphodiesterase
at dosages from about 10 to about 900 mg/kg/day, thereby
providing an increase in the intracellular concentration of
adenosine-3',5'-cyclic monophosphate, and are, therefore,
useful as antiasthmatic agents. A preferred dosage range is
from about 200 to about 250 mg/kg/day. The compounds of
the invention are also useful for treatment of cardiac arrythmia
as shown by their activ1ty in eliminating chloroform-
~nduced arrythmia in the mouse at dosages from about 30
to about 150 mg/kg.
In view of the activities of the subject compounds of
formula I, they are suitable for use in a method for
treating a patient or subject having an ailment selected
-3-
;
from hypertension, bradycardia, and cardiac arrythmia whichmethod comprises systematically administering to said
patient or subject an effective amount of said compounds
for treatment of said ailment in base or acid addition
salt form, preferably in admixture with a pharmaceutically-
acceptable carrier. The present compounds are particularly
suitable for use in treating warm-blooded animals.
To prepare the pharmaceutical compositions of this
invention, a compound of formula I or salt thereof is combined
as the active ingredient in intimate admixture with a
pharmaceutical carrier according to conventional pharmaceutical
compounding techniques, which carrier may take a wide
variety of forms depending on the form of preparation desired
for administration, e.g., oral or parenteral. In preparing
the compositions in oral dosage form, any of the usual phar-
maceutical media may be employed, such as, for example,
water, glycols, oils, alcohols, flavoring agents, preservatlves,
coloring agents and the like in the case of oral liquid
preparations such as for example, suspensions, elixirs and
solutions; or carriers such as starches, sugars, diluents,
granulating agents, lubricants, binders, disintegrating
agents and the ltke in the case of oral solid preparations
such as, for example, powders, capsules and tablets. 8ecause
of their ease in administration, tablets and capsules
represent the most atvantageous 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 ingre-
dients, for example, to aid solubil1ty or for preservatlve
,:
purposes 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 herein will generally
contain, per dosage unit, e.g., tablet, capsule,
powder, iniections, teaspoonful and the like, from
about 5 to about 500 mg and preferably from about 10
to about 250 mg.
The instant compounds may be isolated as the free
base or in the form of an acid addition salt by the
synthetic process normally employed. These compounds,
in base form, are convertible to therapeutically active acid
addition salts by treatment w1th an appropriate acid,
such as, for example, an inorganic acid, such as, a
hydrohalic acid, e.g., hydrochloric, hydrobromic, hydro-
iodic acid; sulfuric or nitric acid; a phosphoric acid;
an organlc acid, such as acetic, propionic, glycolic, lactic,
pyruvic, malonic, succinic, maleic, fumaric, malic,
tartaric, citric, benzoic, cinnamic, mandelic, methane-
sulfonic, p-toluenesulfonic, cyclohexanesulfamic,
salicylic, p-aminosalicylic, 2-phenoxybenzoic, or 2-acetoxy-
benzoic acid. Conversely, the salt form can be
converted in the usual manner into the free base.
Most of the substituted quinazolines of the invention,
with the exception of those wherein Rl is C4-20 alkyl or
cycloalkyl, are generally known per se or can be
prepared by known procedures, as taught in the following
articles and book: Schoefield, J. Chem. Soc., 1927 tl952);
Albert, J. Chem. Soc., 505 (1954); Armarego, J. Chem. Soc.,
(C) 234 (1966); and "Part I-Quinazolines" by W. L. F.
Armarego in "Fused Pyrimidines," D. J. Brown, ed.,
_5_
;
~1
~ 5
Interscience, 1967.
The novel compounds of formula I' may be prepared
by cyclizing a compound of the formula
X
NH - C - NH - C - CH2-~
O O
in the presence of a polyphosphoric acid. Preferably,
said reactlon is carr~ed out by heat~ng compound II in
polyphosphiric acit under nitrogen to about 135C., the
suspension being maintained at this temperature for about
;~ 3 hours. After cooling, the product ~s neutralized
with a suitable base, preferably ammonium hydroxide. Im-
proved yields have also been obtained by preheating
the polyphosphoric acid to about 100-120C. before
adding compound II.
An alternative method of preparing novel
compounds of formula I' consists in reacting a compound
of the formula
O
X
~ ~ C -- CH2-
; - ~ NHC02Et
Y
I I I
^6-
.,
with ammonia in the presence of ammonium acetate.
Preferably, dry ammonia gas is passed for about3 hours through a solutlon of compound III with ammonium
acetate in a suitable solvent such as dimethyl formamide.
: The temperature is preferably maintained at about
155-160C.
The intermediate used in the preparation of compound
II may be prepared as indicated in the following chart:
O
; ~ Phosgene ~ ~ ~ 2 ~ :l
,~ IY Y
Preferably, compound Y together with the compound
O
RlC-NH2 in a suitable solvent such as xylene or benzene
are heated under nitrogen at about 140C.
The intermediate used in the preparation of compound
III may be prepared as indicated in the following chart:
CT.~O ~Et > III
NH2
VI
--7--
~ 5~
Preferably, the above reaction is carried out at room
temperature in a suitable solvent such as tetrahydrofuran.
The present invention is lllustrated by the following
examples.
EXAMPLE 1
7-Ethoxy-6-methoxy-4-methyl-2(lH)quinazolinone hemihydrate
Dry ammonia gas is passed for three hours through a sol-
ution of 2-(N-carbethoxyamino)-4-ethoxy-5-methoxy acetophenone
(12.0 g, 42.6 mM) and ammonium acetate (118.9 g) maintained at
155-160C. The reaction mixture is cooled and poured into an
ice-water mixture (500 ml). The crude product is collected
and washed well with acetone to give 7-ethoxy-6-methoxy-4-
methyl-2(1H)quinazolinone hemihydrate as a tan solid; 8.5 g
TFA
(85.2%); m.p. 262-264C;~ TMS 7.46 (s,lH,5-H), 7.15 (s,lH,8-H),
4.56 (q,2H, J= 7.0Hz,7-0-CH~-CH3), 4.16 (s,3H,6-OCH3), 3.13
(s,3H,4-CH3~, 1.65 (t,3H,J = 7.OHz,7-0-CH2-CH3); M+ 234.
EXAMPLE 2
7-Benzyloxy-6-methoxy-4-methyl-2(lH)quinazolinone
A stream of dry ammonia gas is passed for 3 hours through
a solution of 4-benzyloxy-2-(N-carbethoxyamino)-5-methoxy
acetophenone (16.7 g, 0.0486 m) and ammonium acetate (140g)
in dimethylformamide (75 ml) maintained at 155-160C. The
reaction mixture is cooled and poured into an ice water mix-
ture (1000 ml). The greyish precipitate is filtered and
crystallized from methanol (after treatment with charcoal) to
give 7-benzyloxy-6-methoxy-4-methyl-2(1H)qu-inazolinone as an
off-white solid; 11.4 g (80.0%); m.p. 250-252C; CF-COOH
TMS
7.46 (s,5H, 2', 3', 4', 5'~ 6~-H), 7.43 (s, lH/ 5-H), 7.23
(s, lH, 8-H~, 5.46 (s,2H, 7-0-CH2-), 4.11 (s,3H, 6-OCH3),
3.13 (s,3H, 4-CH3~.
_ g
-
"
,,
.,
v~ ~
EXAMPLE 3
7-n-Butoxy-6-methoxy-4-methyl-2(lH)quinazolinone hydrate
A stream of dry ammonia gas is passed for three hours
through a solution of 4-_-butoxy-2-(N-carbethoxyamino)-5-
methoxy acetophenone (21.97 g, 71 mM) and ammonia acetate(196 g) maintained at 155-160C. The reaction mixture is
cooled and poured into an ice-water mixture (500 ml). A tan
solid forms. Filtration, washing with water (50 ml), and
drying affords 7-_-Butoxy-6-methoxy-4-methyl-2(lH)quinazolinone
hydrate as a tan solid, 15.77 g (79.2~); m.p. 138-140C,
CF3COOH 7.40 (s,lH,5-H), 7.10 (s,lH,8-H), 4.40 (t,2H,J=
6.0Hz,l'-H), 4.13 (s,3H~6-OCH3), 3.10 (s,3H,4-CH3), 0.80-2.38
(m,7H2'-H~3'-H,4'-H); M+ 262.
EXAMPLE 4
7-(2',6'-Dichlorobenzyloxy)-6-methoxy-4-methyl-2(lH)
quinazolinone
A stream of dry ammonia gas is passed for three hours
through a solution of 2-(N-carbethoxyamino-4-(2',6'-dichloro-
benzyloxy)-5-methoxy acetophenone and ammonium acetate (200 g)
2Q in dimethylformamide (125 ml) maintained at 160-165C. The
reaction mixture is cooled and poured into methanol-water (500
ml). The tan precipitate which forms is filtered, washed with
cold water (50 ml) and triturated with acetone (250 ml) to give
7-(2',6'-dichlorobenzyloxy)-6-methoxy-4-methyl-2(lH)quinazoli-
none as a tan solid; 15.33 g (76.3%); m.p.= 286-288 C.
CF COOH
53 7.55 (s,lH,5-H), 7.30-7.65 (M,4H,8-H,3'H,4'H,5'H),
TMS
5.80 (s,2H,C_2-0-), 4.15 (s,3H,6 OCH3), 3.15 (s,3H,4-CH3)
M 365.
-- 1 0
~,
~ 52 ~ ~
EXAMPLE 5
4-n-Decyl-6,7-dimethoxy-2(:LH)quinazolinone
A suspension of N-(3,4-dimethoxyphenyl)-N'-undecanoyl
urea (10.0 g, 0.024 m) in excess polyphosphoric acid (80 g)
is heated under nitrogen to 135C. The suspension is main-
tained at 135C for three hours with stirring~ The reaction
mixture is cooled and quenched on ice water (200 g) and the
resulting gummy mixture is warmed and neutralized with conc.
ammonium hydroxide to ~ pH 8Ø The resulting precipitate is
isolated, washed with water and dried in air to give 4-n-decyl-
6,7-dimethoxy-2(1H)quinazolinone (6.1 g; 63.2%). Upon re-
crystallization from ethanol (200 ml) yellow flakes are
obtained (M.P. 166-167C).
EXAMPLE 6
6,7-Dimethoxy-4-n-hexyl-2(lH)quinazolinone
A mixture of N-(3,4-dimethoxyphenyl)-N'-heptanoyl urea
(21.1 g, 68.8 mM) and polyphosphdric acid (254.4 g, 753 mM)
is heated to 130C for three hours under nitrogen. After
cooling, ice water ( -200 ml) is added followed by the addi-
tion of conc. ammonium hydroxide until the pH is ~ 7Ø Theprecipitate is isolated, washed with water, and dried to give
a light green solid (4.4 g). Recrystallization from ethyl
acetate/isopropanol (1:1) gives 6,7-dimethoxy-4-n-hexyl-2(lH)-
TMS
quinazolinone (1.6 g, 8.0%); m.p. 120-123 C; NMR DMSO-6 ~ 0.60-
2.00 (m,llH-(CH2)4-CH3), 2.80-3.20 (m,2H-CH2-C=N-), 3.87
(s,6H,-OCH3s), 6.80 and 7.30 (2-s, 2H, C5-C8-H's); M~290.
5~ ~
EXAMPLE 7
4-Cyclopentylmethyl-6,7-dimethoxy-2(1H)quinazolinone
A suspension of N-(3,4-dimethoxyphenyl)-N'-cyclopentyl-
acetyl urea (6.95 g,0.024 m) in polyphosphoric acid (200 g) is
heated for 3 hours under nitrogen at 130-140C. After cooling,
the reaction mixture is quenched on 1000 g ice and brought to
~ pH 10 with conc. ammonium hydroxide~ The precipitate
which forms is isolated, washed with water and dried to give
4-cyclopentylmethyl-6,7-dimethoxy-2(lH)quinazolinone (0.97 g,
15.4~) as a dark solid, m.p.~ 240C. dec.
EXAMPLE 8
4-n-Butoxy-3-methoxyacetophenone
.
A solution of acetovanillone (40.0 g, 241 mM), sodium
hydroxide (10.12 g, 253 mM) and iodobutane (56.60 g, 308 mr~)
in ethanol (800 ml) is heated at reflux for 16 hours. The
reaction mixture is cooled and the solvent removed in vacuo
to give a brown syrup. Crystallization from methanol/water
affords 4-_-butoxy-3-methoxy-acetophenone as an off-white
solidi (47.61 g, 88.9~); m.p.= 46-47 C; ~TMS 7.58 (dd,lH,
2Q J6 5 =9; Hz, J6 2 =2 Hz,6-H), 7.50 (d,lH,J2 6=2 Hz,2-H),
6.85 (d,lH,J5 6 =9 Hz,5-H), 4.10 (t,2H,J =6 Hz,l'-H), 3.95
(s,3H,3-OCH3), 2.55 (s,3H,-C-CH3), 0.75-2.10 (m,7H,2'-H,
3'-H, 4'-H), M+222.
,:
.,
- 12 -
,,
EXAMPLE 9
6-Amino-3-methoxy-4-benzyloxyacetophenone
A solution of 4-benzyloxy-3-methoxy-6-nitroacetophenone
(24.5 g, 0.0183 m) in glacial acetic acid (140 ml) and water
(140 ml) is treated at 90-95C with iron powder (19.5 g),
added in portions during 1 hour; water is added at the start
of the reaction and at successive quarter hour intervals
(total of 5 times/ml each). After a further 30 minutes, the
mixture is diluted with water and the precipitated solid is
filtered. Crystallization from ethanol (150 ml) and subse-
quent recrystallization from methanol (200 ml~ gives 6-amino-
3-methoxy-4-benzyloxy-acetophenone as a light brown solid;
DMSO
(L5.5 g, 70.8%); m.p. 124-126C; TMS 6.6-7.6 (m, 9H, 2, 5,
2~, 3~, 4~, 5'r 61-H and N_2), 5.06 (s, 2H~ ~-C_2-0-),
3.73 (s, 3H, -OCH3), 2.46 (s, 3H, -Cl-C_3).
,!,.~ EXAMPLE 10
` 4-Benz lox -2-(N-carbethoxyamino)-5-methoxyacetophenone
~, Y Y
Ethyl chloroformate (18.5 g, 0.125 m) is added cautiously
with stirring to 6-amino-3-methoxy-4-benzyloxy-acetophenone
(20.5 g, 0.0755 m) in tetrahydrofuran (200 ml). A solution
of sodium hydroxide in water (5.0 g in 25 ml) is added slowly.
Removal of the solvent in vacuo yields a light brown semi-solid.
The crude product is extracted with chloroform (3X200 ml),
dried (sodium sulfate), filtered, and the solvent removed in
vacuo to give a pale brown residue (19.2 g). Recrystalliza-
; tion from isopropanol affords 4-benzyloxy-2-(N-carbethoxyamino)-
5-methoxyacetophenone as an off-white solid, (18.1 g, 70.0%)
m.p88-90 C; ~ TMS 3 11.33 (broad s, lH, NH), 8.23 (s, lH, 6H),
- 13 -
~i
.
.,
"
s
7.20-7.40 (m, 6H, 2', 3', 4', 5', 6', 3-H), 5.16 (s, 2H,
4-O-CH2), 4.16 (q, 2H, J=7.0 Hz, -O-C_2-CH3), 3.83 (s, 3H,
5-OCH3), 2.53 (s, 3H, -,C,-C_3), 1.32 (t, 3H, J=7.0 Hz,
-O-CH -CH ).
EXAMPLE 11
Undecanoylamide
A mixture of undecanoic acid (150 g), thionyl chloride
(100 g) and benzene (150 ml) is refluxed with stirring for 6
hours. The reaction mixture is eoncentrated ln vacuo to a
dark oil. The oil is dissolved in tetrahydrofuran (150 ml),
eooled to 0 C and coneentrated ammonium hydroxide (150 ml) is
added dropwise with stirring. After aging for 1 hour at 0 C,
the precipitate whieh forms is isolated, washed with water
and dried in air to give undeeanoylamide (61.0 g, 61%) m.p.
88-89C.
EXAMPLE 12
N-3,4-Dimethoxyphenyl-N'--undeeanoyl urea
A mixture of 3,4-dimethoxyphenylisoeyanate (19.69 g,
0.11 m) and undeeanoylamide (18.5 g, 0.1 m) in xylene (15 ml)
is heated to 140C under nitrogen. After 2.5 hours, the
reaction mixture is cooled to 70C and aeetone is added (50 ml).
; After eooling to about 10C, the erystalline produet whieh
forms is isolated and dried in vaeuo to give N-3,4-dimethoxy-
phenyl-N'-undeeanoyl urea (22.5 g, 55.2%), m.p. 112-113 C.
- 14 -
,.~i
u'
EXAMPLE 13
4-n-Decyl-6,7-dimethoxy-2(lH)quinazolinone
_
A suspension of N-3,4-dimethoxyphenyl-N'-undecanoyl
urea (10.0 g, 0.024 m) in polyphosphoric acid (80 g, x's)
is heated under nitrogen for 3 hours at 135C. The reaction
is quenched on ice water (200 g) and adjusted to ~JpH 8 with
conc. ammonium hydroxide. The yellow precipitate is isolated,
washed with water and air dried to give 4-n-decyl-6,7-di-
methoxy-2(lH)quinazolinone (6.1 g, 64%). The product is re-
crystallized from ethanol (m.p. 166-67C).
When in the above procedure heptadecanamide is employed
in place of undecanoylamide, 4-hexadecyl-6,7-dimethoxy-2-
(lH)quinazolinone is obtained.
When in the above procedures 3-piperidylpropionamide
is employed in place of undecanoylamide, 4-(3-piperidylethyl)-
6,7-dimethoxy-2(1H)quinazolinone is obtained.
When in the above procedures 2-chloroacetamide is
employed in place of undecanoylamide, 4-chloromethyl-6,-
7-dimethoxy-2(1H)quinazolinone is obtained.
2Q
1`
~ 25
.
:
~; - 15 -
,: . j.,
.; ", I
.`. .
;~ .
:;
:~
~ ~2~7~
EXAMPLE 14
-
Heptanamide
A mixture of heptanoyl chloride (52 g, 0.3514 m) and
tetrahydrofuran (100 ml) is cooled to 0C and stirred under
nitrogen. After cooling, the reaction mixture is made basic
by adding conc. ammonium hydroxide dropwise. A tan solid
precipitates and is collected by filtration and dried ln
vacuo over phosphorus pentoxide to give heptanamide (13.68 g,
30.1~), m.p. 87-110 C, M 129.
EXAMPLE 15
N-(3,4-Dimethoxylphenyl)-N'-heptanoyl urea
A mixture of 3,4-dimethoxyphenyl isocyanate (18.98 g,
0.106 m) and heptanamide (13.68 g, 0.106 m) is fused under
nitrogen at 125 C for 3 hours. After cooling to room tem-
perature, acetone is added and the solid which forms is
filtered, washed with acetone and dried ln vacuo over phos-
phorus pentoxide to give N-(3,4-dimethoxy-phenyl)-N'-
heptanoyl urea (31.2 g, 95.5~); m.p. 168-172C, M 308.
EXAMPLE 16
Cyclopentylacetamide
A solution of cyclopentyl acetic acid (50 g, 0.38 m)
in benzene (100 ml) is treated with thionyl chloride (100 ml)
and the resulting mixture is reflxued with stirring for 16
hours. The reaction mixture is then concentrated ln vacuo
to a tan oil. The oil is dissolved in tetrahydrofuran (200 ml)
and cooled to 0C.
- 16 -
-, .
~-p~
concentrated ammonium hydroxide (200 ml) is added over 1 hour
with stirring. After aging at room temperature overnight,
the réaction mixture is concentrated ln vacuo to 100 ml and
chilled at 0C for 12 hours. The resulting precipitate is
isolated, washed with water and dried in vacuo to give cyclo-
pentylacetamide (21.7 g, 28%) as a colorless solid (m.p.
137-39C).
EXAMPLE 17
N-(3,4-dimethoxyphenyl)-N'-cyclopentylacetyl urea
A mixture of 3,4-dimethoxyphenyl-isocyanate (5.0 g,
0.028 m) and cyclopentylacetamide (3.81 g, 0.028 m) is fused
neat at 130-140C for 3 hours. The solid mass is cooled and
triturated with acetone (30 ml) to give N-(3,4-dimethoxy-
phenyl)-N'-cyclopentylacetyl urea (6.95 g, 78.9%), m.p.
180-210C dec.
EXAMPLE 18
-
3-Methoxy-4-n-bu*oxynitrobenzene
Sodium hydride (mineral oil) (50~, 1.44 g, 0.03 m) is
added to a solution of 3-methoxy-4-hydroxynitrobenzene
(3.78 g; 0.02 m) in anhydrous dimethylformamide (25 ml) at
5 C. After aging for 15 minutes at room temperature, n-butyl-
bromide (4.11 g) is added all at once and the mixture is aged
for 2 hours at room temperature and then 2.5 hours at 80C.
After cooling, the reaction is ~uenched on ice (100 g) and
extracted with either (3X100 ml). The ether is washed with
water (2X75 ml) and dried over magnesium sulfate. Evaporation
of the ether yields a tan oil which is crystallized from hot
hexane to give 3-methoxy-4-n-butoxynitrobenzene (1.72 g, 38.5%),
m.p. 53-54C.
~,'2~~
EXA~IPLE 19
3-Methoxy-4-n-butoxyaniline hydrochloride
A solution of 3-methoxy-4-n-butoxynitrobenzene (1.1 g,
0.004 m) in ethanol (50 ml) and conc. aqueous hydrochloric
acid (2 ml) is treated with 10% Pd/C (0.2 g). The mixture
is shaken with hydrogen for 2 hours at about 45 psi., filtered
through celite and conc. in vacuo to give 3-methoxy-4-_-
butoxyaniline hydrochloride (1.0 g, 88%) as a gray solid,
(m.p. dec 250C~.
EXAMPLE 20
4-Ethoxy-3-methoxy-2-nitroacetophenone
Nitric acid (180 ml) is cooled in ice water. 4-Ethoxy-
3-methoxy-acetophenone (30 g, 0.154 m) is added portion wise
and a light brown solution forms. After standing for 10
minutes, the reaction mixture is poured over ice water. The
solid yellow product which forms is filtered and crystallized
from isopropyl alcohol to yield 4-ethoxy-3-methoxy-2-nitro-
acetophenone (30.1 g, 81.9~), m.p. 105-109C.
,/, 20
- 18 -
!.
5~'^L''V
EXAMPLE 21
2-Amino-4-ethoxy-5-methoxyacetophenone
A mixture of 4-ethoxy-5-methoxy-2-nitroacetophenone
(20.1 g, 84 mM) in glacial acetic acid (144.2 ml) and water
(144.2 ml) is treated at 90-95C with iron powder (20.1 g)
(added in portions over one hour). Water is added at the
start of the reaction and at successive auarter hour intervals
(five times/5 ml each). After two hours, the mixture is di-
luted with water and the light green precipitate which forms
is filtered. Recrystallization from isopropanol gives 2-amino-
4-ethoxy-5-methoxyacetophenone as a yellow solid (13.5 g,
76.8%), m.p. 154-156C.
EXAMPLE 22
2-(N-Carbethoxyamino)-4-ethoxy-5-methoxyacetophenone
Ethyl chloroformate (12 g, 117 mM) is added with stirring
to 2-amino-4-ethoxy-5-methoxyacetophenone (11.4 g, 59.5 mM)
dissolved in tetrahydrofuran (200 ml). A solution of sodium
hydroxide in water (3.7 g in 10 ml water) is added and the
solution is refluxed for two hours and then concentrated ln
2~ vacuo. The light brown residue which forms is extracted with
chloroform (2 x 125 ml), dried over sodium sulfate, filtered,
and the solvent removed in vacuo. The crude product is re-
crystallized from _-hexane (200 ml) to afford 2-(N-carbethoxy-
amino)-4-ethoxy-5-methoxyacetophenone (14.5 g, 94.7%),(m.p.
` 25 91-93C).
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EXAMPLE 23
_
4-n-Butoxy-5-methoxy-2-nitroacetophenone
4-n-Butoxy-5-methoxyacetophenone (45.33 g, 204 mM) is
added during five minutes to nitric acid (280 ml, specific
gravity 1.42) at 0. After an additional ten minutes at the
same temperature, the dark brown solution is poured into ice
water (1 liter). The crude product is collected by filtra-
tion. Recrystallization from methanol (200 ml) affords 4-n-
butoxy-5-methoxy-2-nitroacetophenone as a yellow solid, (32.76
g, 60.1~); m.p. 76-77C.
EXAMPLE 24
2-Amino-4-n-butoxy-5-methoxyacetophenone
A mixture of 4-_-butoxy-5-methoxy-2-nitroacetophenone
(30.66 g, 115 mM) in glacial acetic acid (205 ml) and water
(205 ml) is treated at 90-95C with iron powder (64.4 g, 40
mesh), added in portions over one hour; water is added at the
start of the reaction and at successive quarter hour intervals
(total of five times/5 ml each). After two hours at 90-95C,
the mixture is diluted with water (1000 ml) and the precipi-
tate filtered. The dark brown solid which forms is washedwith chloroform (2 liters). The chloroform is dried (Na2SO4),
filtered, and the solvent removed in vacuo to give the product
` as a light brown syrup that crystallizes on standing. Re-
crystallization of a portion (3.10 g) from isopropanol (30 ml)
affords 2-amino-4-n-butoxy-5-methoxy-acetophenone as a yellow
solid (1.90 gl~ m.p. 88-89C.
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EXAMPLE 25
4-n-sutoxy-2-(N-carbethoxyamino)-5-methoxyacetophenone
Ethyl chloroformate (23.6 ml, 0.247 m) is added cautious-
ly with stirring to 2-amino-4-_-butoxy-5-methoxy-acetophenone
(23.10 g, 0.097 m) dissolved in tetrahydrofuran (500 ml). A
solution of sodium hydroxide (7.84 g, 0.196 m) in water (24 ml)
is added slowly and the resulting solution is heated at reflux
for two hours. The tetrahydrofuran is removed ln vacuo from
the reaction mixture and the resulting brown aqueous mixture
is extracted with chloroform (4 x 150 ml), dried (Na2SO4) and
the chloroform is removed in vacuo to give a brown syrup that
crystallizes on standing. Recrystallization from hexane yields
4-n-butoxy-2-(N~carbethoxyamino)-5-methoxyacetophenone as a
pale yellow solid (m.p. 64-66C).
EXAMPLE 26
4-(2',6'-Dichlorobenzyloxy)-5-methoxy-2-nitroacetophenone
To HNO3 (specific gravity 1.42, 285 ml) cooled in ice
water is added portion wise 4-(2',6'-dichlorobenzyloxy)-5-
methoxyacetophenone (56.27 g, 0.173 m). A red solid forms.
The reaction mixture is removed from the ice bath and heated
to 30 C in an oil bath. The temperature is maintained at 30 C
~.:
i~ for ten minutes. During this time, the red solid turns yellow.
The reaction mixture is then poured over ice water (1 liter)
and the resulting yellow solid is filtered, washed with water
(100 ml), and dried to give 4-(2',6'-dichlorobenzyloxy)-5-
methoxy 2-nitroacetophenone as a yellow solid (m.p. 148-151C).
- 21 -
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EXAMPLE 27
2-Amino-4-(2~,6'-dichlorobenzyloxy)-5-methoxyacetophenone
A mixture of 4-(2',6'-dichlorobenzyloxy)-5-methoxy-2-
nitroacetophenone (60.98 g, 0.165 m) in glacial acetic acid
(428.5 ml) and water (428.5 ml) at 90-95C is treated with
iron powder (134.4 g) added in 10-12 portions over 0.5 hours
with vigorous stirring. When the addition is complete, the
suspension is heated at 90-95C for two hours. The reaction
mixture is then heated at 90-95C for an additional four hours
and then cooled. Water (1 liter) is added and the dark brown
solid material is filtered and washed with chloroform (2
liters). The chloroform is dried (Na2SO4), filtered, and the
solvent removed in vacuo to give a brown solid. Recrystal-
lization from methanol (500 ml) treated with charcoal gives
15 2-amino-4-(2~,6~-dichlorobenzyloxy)-5-methoxyacetophenone as
a yellow solid (22.71 g); m.p. 86-88C.
EXAMPLE 28
2-(N-Carbethoxyamino)-4-(2',6'-dichlorobenzyloxy)-5-methoxy-
acetophenone
Ethyl chloroformate (16.28 g, 0.150 m) is added cautious-
ly with stirring to 2-amino-4-(2',6'-dichlorobenzyloxy)-5-
methoxyacetophenone (20.41 g, 0.058 m) dissolved in tetra-
hydrofuran (500 ml). A solution of sodium hydroxide (4.84 g,
0.121 m) in water (20 ml) is added slowly and the resulting
solution is heated at reflux for two and one half hours. The
tetrahydrofuran is removed m vacuo from the reaction mixture
- 22 -
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to give a light brown solid. Water (50 ml) is added and the
resulting mixture is extracted with chloroform (3 x 150 ml)
and dried (Na2SO4). The chloroform is then removed in vacuo
to give a yellow solid. Recrystallization from isopropanol
gives 2-(N-carbethoxyamino)-4-(2',6'-dichlorobenzyloxy)-5-
methoxyacetophenone as an off-white solid (m.p. 160-162 C),
7.80 g.
EXAMPLE 29
4-Benzyloxy-3-methoxy-6-nitroacetophenone
4-Benzyloxy-3-methoxyacetophenone (61.0 g, 0.234 m) is
added to nitric acid (110 ml, specific gravity 1.42)at 0-
20C. After 2-5 minutes, a vigorous reaction occurs dis-
solving all solids. The dark brown solution which forms is
poured onto ice water (1 liter) and the crude product is col-
lected by filtration. Two recrystallizations from methanol
give 4-benzyloxy-3-methoxy-6-nitroacetophenone as a pale
yellow solid (40.0 g, 57.3%); m.p. 141-143C.
EXAMPLE 30
6,7-Dihydroxy-4-methyl-2-(lH)quinazolinone hydrate
,,
A solution of 6,7-dimethoxy-4-methyl-2(1H~quinazolinone
(12.4 g, 0.057 M) in acetic acid (300 ml) and hydrobromic acid
(240 ml, 48% aqueous) is refluxed for 19 hours. The solution
is cooled in an ice-water bath and the precipitated hydro-
bromide salt (8.Q g) is collected by filtration and then
washed with excess acetone. The salt is dissolved in water
' (75 ml) and saturated aqueous sodium bicarbonate is added
' until the pH is neutral. The precipitated free base is
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collected by filtration and washed with acetone to yield 6,7-
dihydroxy-4-methyl-2(1H)quinazolinone hydrate (4.5 g, 41.0%)
as a pale yellow solid; m.p. 320C dec.
EXAMPLE 31
7-Hydroxy-6-methoxy-4-methyl-2(1H)quinazolinone hydrobromide
A solution of 7-benzyloxy-6-methoxy-4-methyl-2(lH)
quinazolinone (20.0 g, 0.0675 m) in acetic acid (350 ml) and
hydrobromic acid (325 ml, 48% aqueous) is refluxed for 4 hours.
The solution is cooled in an ice-water bath and the solid
(10.1 g) which precipitates is~ collected by filtration, washed
with hot methanol and then recrystallized from water (150 ml)
to afford pure 7-hydroxy-6-methoxy-4-methyl-2(1H)quinazolinone
- hydrobromide as a yellowish-green solid (9.0 g, 46.4~); m.p.
303-305C.
EXAMP~E 32
6 Hyd ox 7 methox -4-meth 1-2(1H) inazolinone hydrobromide
- r y- - y y qu
hemihydrate
6,7-Dimethoxy-4-methyl-2(1H)quinazolinone (6.2 g, 0.0285
m~ in acetic acid (150 ml) and hydrobromic acid (120 ml, 48%
aqueous) is refluxed for 19 hours. The solution is cooled
in an ice-water bath and the solid (5.1 g) which precipitates
is collected by filtration. Removal of the solvent from the
filtrate gives an oily residue (1.95 g) which is crystallized
from water and then tw-ice from methanol to afford pure 6-hy-
droxy-7-methoxy-4-2(lH)quinazolinone hydrobromide hemihydrate
as a yellowish-green solid (0.6 g, 7.1~); m.p. 230-232 C.
- 24 ~
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The following pharmacological data is provided:
TABLE I
R' ~ ~ O
H
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R R' ~" I ORF I lowcring (mm)Dose (!/
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n-ClOH21 CH3 CH3 15757 12 100
6 13 CH3 CH3 15643 18 100
.
CH3 . C2H5 CH3 15710 27.5 40
CH3 n-C4HgCH3 15724 17 10
CH3 H CH3 15417 6 100
:
.^ CH3 H H 15615 12 100
I
CH3 CH3 H 15403 1 12 100
. I
TABLE II
Increase in -
; ~RF RBF (%) Dose (MPK)
: 15757 NA 13.9
. 15643 +44 13.9
: 15710 NA 13.9
15724 +26 13.9
15417 +16 13.9
. 15615 +49 13.9
5403 +29 13.9
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exa e ~
The following procedure of the SHR (spontaneously hypertensive
rats) is as follows: Groups of 4 male SHR rats with
systolic pressures greater than 170 mm. mercury were used
to evaluate compounds for antihypertensive activity.
Systolic blood pressure is recorded Vid the tail-cuff
method (which is indirect). Compounds are administered
by various routes in graded doses. Blood pressure is
recorded at various time intervals following each dose.
There are two references regarding this procedure--Okamoto
and his co-author Aoki. Japanese Circulation Journal
Volume 27, Page 282 (1963).
Roper Laboratory of Animal Science, Volume 26, 305 (1976).
The Renal Vasodilator Procedure
Adult mongrel dogs are anesthesized and surgically
prepared for electromagnetic measurement of renal artery
blood flow.
A carotid artery is cannulated for measuring arterial
blood pressure and drugs are administered intravenously.
Heart rate is monitored by a cardio tachometer. Renal
vascular resistance is calculated as the ratio of the
mean-arterial blood pressure over renal artery blood
flow. Cumulative dose response data is obtained by
infusing the test drug at progressively increasing
infusion rates, each dose being infused for five minutes.
The maximum percentage increase from pre-drug control in
renal artery blood flow (or decrease in renal vascular
resistance) is quantitated for each infusion dose.
Reference Goldberg and coworkers, Journal of Pharmacology
and Experimental Therapeutics, Vol. 163 (1968).
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