Note: Descriptions are shown in the official language in which they were submitted.
BACKGROUND OF THE INYENTION..
Field of the Invention
This invention celates to certain substituted -3-(4-phenyl
-l-pipecazinyl)alkylquinazolin -2,4-(lH,3H) diones. These
compounds are antihypertensive and cardiovasrular agents
and are therefore useful in male and ~emale mammals. Thi6
invention also relates to a process ~oe preparing these
compounds, to composi~ions thereof and to methods of use.
Rgl--L~~
Several quinazolin-2~4-(~H,3H) diones having vasodilator,
alpha~-blocking or antihypertensive activity have been
reported in the literatu~e. Examples thereo~ are U.S.
Patent No. 3,879,393; European Patent No. 89065-A; U.S.
Pa~ent No. 3,91g,425 and J. Med. Chem. 8, 807 (1965);
German Patent No. 2,258,403 (June 7, 1973); and U.S.
Patent No. 4,405,623. None of the above reported
quinazolinediones contain all of the specific substituents
presently claimed.
Summary of the Inven~ion
The substituted quinazolin-2,4-(lH,3H) diones which are
- ~ the subject o this invention have the following yeneral
formula:
,'~
~
33~31
- 2 -
R ~ ~ CH2)n-N ~ R5 Z
R ~ N 0
H
wherein X is hydrogen, amino, nitro, acetamido or halo:
Rl and R3 are the same or diffeeent and are hydrogen,
hydroxy or alkoxy:
R2 is hydroxy or alkoxy;
lS or when Rl and R2 or Rz and R3 are taken together
they are lower alkylenedioxy;
n is an integer ~rom 2 to 6;
R4 and R5 are the same or different and are hydrogen,
hydroxy, alkyl, alkoxy, halo, or tri~luoromethyl; or when
R4 and R5 are taken together they are lowee alkylene-
dioxy; or the pharmaceutically acceptable acid addition
salts ~hereof.
~ Also included in this invention is a process for preparing
- the compounds of foemula I Which comprises reacting a
compound of the formula
H-N ~ ~
~5
7~t~
-- 3
with a compound o~ the-fsrmula
~, O
R~ N,CH2CH2CI
R3~1 ~0
X H IV
Rl, R2i R3, ~4, R5 and X are as defined
above in connection with the produc~.
Also part of the present invention are cer~ain
intermediates and the processe6 for the prepara~ion
~hereof.
.,
Preferred compounds of the present invention are:
3-{2-[4-(2-methoxyphenyl)-1-piperazinyl~ethyl}-5,6-
dimethoxy-guinazolin-2,4(1H,3H)-dione;
8-chlo~o-3-12-[4-(2-methoxyphenyl)-1-piperazinyl~ethyl)-
5,6-dimethoxyquinazolin-2,4-(lH,3H)-dione:
25 6,7-dimethoxy-3-l2-t4-t2-methoxyphenyl)-1-piperazinyl~
ethyl)-quinazolin-2,4-(lH,3H)dione;
5,6-dihydroxy-3-{2-~4 (2-methoxyphenyl)-1-piperazinyl3
ethyl}-quinazolin-2,4-(lH,3H~dione.
The compounds of this invention possess oral hypotensive
activity in spontaneously hypertensive ~ats and peripheral
- vasodilator activity in dogs th~ough, at least in part, an
al-adrene~gic antagonist mechanis~. When compared to
the pri.~r art, such as a representative compound o~ the
~.~7~
a~ove-mentioned European Paten~ No. 89065-A, (set forth in
Table 1 herein~, the present compounds show less
inhibition o~ the tilt ~e~lex r~sponse suggesting that the
compounds will be be~ter tolerated in human~ due to a
S lesser potential ~oe oethostatic hypotension. In
addition, they show an unexpected ~uperior bioavailability
profile o~er prior art when the oral/i.v. ratios are
compared.
The compounds, compositions and methods for making the
various aspects of the present invention noted above will
become more readily apparent from the following descrip-
tion.
. . .
DescliPtion and Peeerred Embodiments
Various ~erms used herein should be understood to signi~y
the following.
. .
The ~erm "lower alkyl" r2~ers to a straight or branched
chain substituent consisting solely o~ carbon and hydrogen
with no unsaturation and con~aining ~rom 1 to 6 carbon
atoms. The te~m "lower alkoxy~' reers to a lower alkyl
chain as described above having no more than 4 carbons.
The term "halo" means ~luoro chloro, bromo and iodo.
?
The phease "pharmaceutically acceptable salts" denotes
salts of the ~cee base which posses~ the desired
pharmacological activity of the free base and which are
neither biologically nor o~herwise undesirable. These
salts may be derived from inorganic or organic acids.
Examples o~ inorganic acids are hydrochloric acid, nitric
~ acid, hydrobromic acid, sulfuric acid or phosphoric acid.
Examples o~ organic acids are acetic acid, propionic acid,
glycolic acid, lactic acid, pyruvic acid, oxalic ~cid,
- ~7~
malonic acid, succinic acid, malic acid, maleic acid,
fumaric acid, tartaric acid, citric acid, benzoic acid,
cinnamic acid, mandelic aaid, methane sulfonic acid,
ethane sulfonic acid, p-toluene sul~onic acid, ~alicylic
acid and the like.
Pharmaceutical compo~ition~ containing a compsund of ~he
presen~ invention as the active ingredient in intimate
admixture wi~h a pharmaceutical carrier can be prepared
according to conventional pharmaceutical compounding
techniques. The carrier may take a wide variety of form~
depending on the form of preparation desired for
administration, e.g., intravenous, oral or topical. In
preparing ~he compositions in oral dosage ~orm, any of the
usual pharmaceutical media may be employed, such as, for
example, water, glycolsO oils, alcohols, ~lavoring agent~,
preservativefi, coloring agents and the like in the case of
oral liquid preparations such as, ~or example,
suspensions, elixies and solutions; or carriers such as
s~arches, sugars, diluent~, granulating agents,
lubricants, binders, disintegrating agents and the lika in
the ca~e or oral ~olid prepacations such as, for example,
powders, capsules and tablets. Because of ~heir ease in
admini~tration, ~ablets and capsules represent the most
advantageous oral dosage unit form, in which case solid
pharmaceutical carrier~ are ob~iously e~ployed. I
desired, tablets may be sugar coated or enteric coated by
standard techniques. For parenterals, the carrier will
usually compeise sterile water, though other ingredients,
~or example, ~o aid solubility or for preservative
purposes, may be included. Injectable suspensions may
also be prepared, in which ca~e appropeiate liquid
carriers, suspending agen~s and the like may be employed.
The pharmaceutical composition6 will generally contain per
dosage u~it, e.g., tablet, capsule, powder, injection~
.. . ..
3~
tea~poonful and the like. from about 0.05 to about 100
mg~kg and pref erably f rom about 0.1 to abou~ 20 mg/kg of
the active ingredient.
The novel quinazoline dione~ of the presen~ invention may
be synthesized according to the following reaction scheme
1~ R2~ R3. R4, R~...R6, and X are as
defined above and Q i6 a leaving group which is most
preferably ethoxy.
--7--
m m
~ o Z; ~ '~
O =~ H =~
~X
P; ~ +
~Z~ ~
0~ ~ ~
~ L~t
C~ P~
~;~ ~
,cl m O
1~ H r~ ;, H
~; Pi
~.~7~ 13
Compound II, in the reaction scheme above, may be
initially prepared by reacting a cooled solution of an
appropria~ely substituted ethyl 2-amino-benzoate with
ethyl chloroformate and a suitable base such a6 triethyl-
amine in a ~ hl ~ ~olvent such as tetrahydrofuran,dioxane oe no additional solvent.
The resultant appropriately substituted ethyl
N-~2-carbe~oxy phenyl]carbamate i8 then reacted with
ethanolamine a~ approximately 160 - 170C ~or between
30 minutes and 60 minutes.
The resultant product of ~ormula I r I is then treated with
a suitable chlorinating agent such as thionyl chloside.
The chlorination reaction takes place in a suitable
solvent such as chloroform or methylene chloride,
preferably under re~lux ~or between 1 and 5 hours under
nitrogan. The resultant compound IV is a novel compound,
as is also compound III.
Compound IV is then reacted with compound ~ in order to
produce compound I. The eeaction prefecably takes place
in the presence of sodium iodide and potassium carbonate
in a solYent such as dimethylfoemamide SDMF) or
4-methyl-2-pentanone at a temperature of between about
and 85 C under nitrogen for about 1-36 hours.
In the instance wherein sub6tituents Rl, R2, and R3
are loweralkoxy, such substituents may be hydrolyzed to
the corresponding hydroxyl groups by reacting the
appropriately substituted compound of ormula I under
reflux for about 24 hours in an acidic medium, pre~erably
a mixture of hydcobromic acid and acetic acid. However,
other acidic media such as HI, B~3r3, pyeidine bydro-
chlocide or 47~ HBr, may also be used. When thi~
~2~
g
procedure is carried out any lower alkoxy group onthe phenyl ring attached to the piperazine riny,
remains unaffected.
The following specific preparations and examples are
illustrative of -the present invention and should not
be considered as limitative thereof in any manner.
Preparation 1
Ethyl N-[2-carbethoxy-4~5-dimethoxyphenyl]carbamate
The following preparation illustrates the conversion
of 2-amino-4,5-dimethoxybenzoate to compound II, in
the instance wherein Q is ethoxy.
Ethyl chloroformate (10.4 g, 0.096 mole) was added to
a cooled solution containing 6.5 g (0.028 mole) of
ethyl 2-amino-4, 5-dimethoxybenzoate, 6.6 g (0.065
mole) of triethylamine and 90 ml of tetrahydrofuran.
The resultant reaction mixture was allowed to warm to
room temperature and stirred for 2.5 hours. The
reaction mixture was filtered and the filtrate was
evaporated to give a yellow gum which was crystalliz-
20 ed from hexane giving 4.0 g (46.6~) of desired
product, mp 59 -61 C.
EXAMPLE 1
3-(2-Hydroxyethyl)5,6-dimethoxyquinazolin-2,4-(lH,3H)
dione
This example illustrates the preparation of compounds
of formula III.
A mixture of ethyl N-[2-carbethoxy-3,4 dimethoxy-
phenyl)-carbamate (2.2 g, 0.006 mole) and ethanol-
amine (0.8 g,
'~
~ ~7~
-- 10 --
0.013 mole) was heated at 160-170C in an oil bath
~or 0.5 hours. The semisolid which formed was triturated
wi~h 2-propanol and ~he insolubie solid was collected to
give Che dPsired product, mp 2Z2-224~C.
EX~MPLE 2
3-t2-chloroethyl)-5~6-dlmethox~fquinazolin-2.4-(lH~3H)~dione
This example illustrates the preparation oE compounds o~
formula IV.
A mixture of 3-(2-hydroxyethyl)-5, 6-dimethoxyquina-
zolin-2,4- (1~,3H)dione (2.0 g, 0.0075 mole) and thionyl
15 chloride (1.24 g, 0.010 mole) in 20 ml of chloroform was
heated at reflux for 4 hours ~nder nitrogen. The solid
which formed was washed with chloroform and collected to
give ~he crude product which was recrystallized from
methanol to give 1.3B g ~64.5~ yield) o~ the desired
20 product, mp 110-113C.
EXAMPLE 3
3-{2-[4-(2-Methoxyphenyl)-l-piperazinyl]ethyl} -5,6-
dimethoxyquinazolin-2,4-(lH 3H)dione monohYdrobromide
A mixture of 3-~Z-chloroethyl)-5,6-dimethoxyquinazolin-
2,4-(lH,3H)dione 15.0 y, 0.018 mole), 1-(2-methoxyphenyl)
piperazine (3.4 g, 0.018 mole), sodium iodide (2.64 9,
30 0.018 mole) and potassium carbonate (1.23 g, 0.009 mole)
in 28 ml of dry DMF (dimethylformamide) was heated at
80 - 85C under nitrogen for 23 hours. Ice-water (75
ml) was then added to the solution and the resultant
mixture extracted with chloroform (400 ml). The organics
were dried with magnesium sulfate and evaporated in vacuo
~7f~
-- 11 --
to give a yellow-brown gummy residue which yielded 4.979
of an off-white solid upon tritura~ion with ether.
Treatment o~ the crude product with one equivalen~ of
hyd~og~n bromide in teSrahydro~uran gave the monohydro-
bromide salt which was puri~ied by washing with hot
2-propanol to give a white solid; yield, 3.72 g, ~40~) mp
168-lil . Treatmen~ of the free base with excess
hydrogen bromide ga~e the dihydrobromide salt, mp
184-189C.
EXAMPLE 4
5,6-Dihydroxy-3-~2-~4-(2-methoxyphenyl~-l-piperazinyl~ethy
l}-quinazolin-2,4(1H,3H)-dione monohydrobromide
monohYdrate.
This example illustrates the hydrolysis of the
5,6~dimethoxy substituted compound to the corresponding
5,6-dihydroxy substituted compound.
A solu~ion of 3-{2-t4-(2-methoxyphenyl)-l-piperazinyl
ethyl)-5,6-dimethoxyquinazolin-2,4-(lH,3~)dione (1.6 g,
2.66 M) in hydrobromic acid (4~% aqueous, 9.6 ml) and
glacial acetic acid (26.2 ml) was heated at reflux for 18
hours. The reaction mixture was cooled and the resulting
solid wa ~iltered, washed with ether (30 ml), hexane (30
ml) and dried under high vacuum at 62C overnight to
give a crude product as a white ~olid. The crude p~oduct
was recrystallized from methanol (75 ml). The product was
dried under high vaauum at 6ZC for 2 days to afford
5,6-dihydroxy-3-2-t~-(2-methoxyphenyl)- l-piperazinyl~
ethyl quinazolin-2, 4(1H,3H)-dione (dihydrobromide) as a
~ white solid~ (A); 0.72 g (yield 47.~%) mp,283-286C.
A second crop precipitated out of the filtrate. I~ was
8~
- 12 -
filtered and dried under high vacuum at 62C for 6 days
to afford additional 5,6-dihydroxy-3- 2-t4-~2-methoxy-
phanyl)-l-piperazinyl] ethyl quinazolin-Z,~(lH,3~I)-dione
(monohydrobromide monohydrate) as a white solid; (B) 0.54
S g, yield 39.7~, mp , 223-227C. The total yield o~
product was 86.~%.
. .
The compounds set forth in Table l are prepared by ~he
procedures of Examples l through 4 using appropriately
substituted starting comp~unds. The last column of Table
l indicates the speci~ic example, the procadure o~ which
is utilized to prepare the indicated compound. In Table l,
the final compounds are designated as A through E
respectively.
The prior art compound Z set forth at the bottom o
Table l is that disclosed in the Chugai European Patent
No. 89065-A.
. ,
--13--
z
x
~1 ~ ~ O 1
r ~ r ~ N ~ 0
o\o
~r ~1 ~1 ~) ^ O Ll') O O ^
N ~1 1-- ~ CO 5~ 0
C:) N ~ ~, ~, ~ m N ~ ~I N V N N N
o I I I m I ~ I I I I :c I I I
N O a~ o . ~ t~
N ~ ~ ~ D 00 Ll~
N ~1 ~-- r~ N ~ l N ~I N N N
N
N
0 ~X~
O V I O V I O V
X X ::C X V V U ~ ~ ::C
~
:C ~
Vo V
:C ~ ~ X ~ X
N V V V V V U V U V
P~ O O O O O O O O O
~; ~ ~ 5~ ~ 5 '~
V V V U V ")
O O O O O O
o
~ ~ m v
o
v
r~
~7~
--13a-
o
z
X r~
.,1 O O ~D
~ co ~r ~
o\o
,-- ~
~r ~ co
t~ l l l
O O rl o
~ ~ ~ 00
,_ r~ :C
~ Co)
O ~ ~ xro
zl) (j
X ;~
~; ~ ~ x
K O O O
~1
~ ~C O
O O O :C
~ ra
o n ~ ~ o
~ o 1, ~
O h Ll 0
O ~ ~
~7~
The compounds of the pEeSent invention were evaluated f OL
their biological properties. The biological data indicate
that certain of the compounds desceibed herein are potent
an~ effective antihypertensivs agen~s. In addition, the
data 5UppOL ~ cept o~ unexpected ~indings regarding
side ef~ect liability. For example, Compound ~
demonstrate6 ~ignificantly 1~8 (p 0.05) inhibitio~ of
the tilt reflex recovery respon e than the prior art
Chugai compound Z (Compound A: 37% ~ 12 vs. Chugai
compound Z: 83~ ~ a). Furthermore, a direct comparison in
autonomic tests between Compound A and the Chugai compound
Z shows that Compound A possesses almost no antihistaminic
or anticholinergic effect, suggesting less sids effects
such as dryness of mouth, drowsiness or sedation. In
contrast, Compound Z inhibits histamine and acetylcholine
blood pressure Lesponses in dogs indicating antihistamine
and anticholinergic properties . ~hese ~indings taken
together support the contention that Compound A possesses
an orally efEective antihypertensive pro~ile with the
unexpected finding6 of a mor6 tolerable ~ide ef~ect
profile. In addition, the biological data also support
Che finding of unexpected superior bioavailability, as
with compound A when compared with the prior art compound
Z, by means of the oral~i.v. ratio (Table 3).
The tilt reElex recovery response i6 determined as ~ollows:
Adult mongrel dogs of either sex are anesthetized with
pentobarbital sodium, secured Co a tilt table and
surgically prepared for measurement o~ blood pressure and
heart rate. Animals are tilted and the percent recovery
of the tilt response in the blood pressure is quantitated.
- 15 ~
The percent recovery i~ calculated by dividing the maximum
decrease in mean arterial blood pres6ure (mm ~g) caused by
tilt into the amoun~ o~ eise in blood pre~su~e at 15
seconds after initia~ing tilt. The antihypectensive as
well as the alpnal-aarenergic blocking propeLties of the
no~el guinazolinedione piperazines were evaluated and set
~orth in Tabl~ 2.
The antihypertensive evaluation followed the following
procedure:
Adult male spontaneously hypertensive rats (SHR) were
placed in restrainers in a chamber warmed tO 32C. A
s~andard indirect method employing a pneumatic pulse
lS transducer and inflatable tail cuf was used to measure
systolic blood pressuee (SBP) in the conscious state.
After baseline SBP were recorded, groups o~ 4 SHR received
a single oral dose of drug or vehicle (0.5% methylcellu-
lose) administered with a gavage tube. SBP's were
obtained at 1/2, 1, 2, 3 and 4 hours post treatment.
Changes in SBP ' 5 were stat~stically compared to ~he
vehicle effec~ usin~ Students t test. at p c.05.
The al-adrenergic blockade: inhibition of phenyl-
ephrine-induced increases in diastolic blood pressure in
the anesthetized dog was determined according to the
method set ~orth in the following literature reference:
Arunlakshana, 0. and Schild, HØ (1959). Same
Quantitative Uses of Drug Antagonists. ~r. J. Pharmac.
Chemothee., 14:48-58.
The procedure is as follows:
Dogs are anesthetized and bilaterally vagotomized.
"
~ ~74~
- 16 -
~emoral artery and vein.are cannulated for detection of
diastolic blood pressure and drug admini6~ration,
respecti~ely. Percent inhibition o~ alpha adrenergic
recep~or ancagoni~m 18 quan~lta~ed by det~rmining the
dose-re6ponse (increase in diastolic pressure)
relationship of phenylephrine be~ore and a~ter variou
doses o~ the antagonist. Statistical analysis of percent
inhibition is calculated by use o~ the variance component
estimation test. In addition, the Dose Ratio (DR20) may
be calculated for potency compari60ns an~ is deined as
the dose of antagonist required to produce an agonist dose
ratio o~ 20.
The biological activity as determin~d by the above tests,
is set forth in Table 2. The ~ested compounds were the
same as those described in detail in Table 1 and referred
to as compounds A through E, respectively. The prior art
compound set forth at the bottom of ~able 2 i6 that
disclosed in the Chugai Eueopean Patent No. 89065-A.
The bioavailability comparison was determined in conscious
direct cannulated spontaneously hypertensive ~ats.
Brie~ly, the SH~s were anesthetized with ether and a
carotid arterial cat~eter was inserted foe measurement of
Z5 arterial blood pressure while a jugular catheter was
inserted ~or i.v. drug administration. Por oral dosing, a
catheter was also passed via the e60phagus into the
stomach. All caSheters were exteriorized at the nape of
the neck and animals were placed in restrainers and
allowed to recover from surgery. Blood pres6ure was
continuou&ly recorded. Drugs were dissolved in 5%
dextrose in water and administered as a bolus at time
- zero. Bioavailability results are presented in Table 3.
~7~ 3
-
--17--
V
O ~ aJ
.,~
-1-) H ~
-rl I O
O 0~' Q ~: ~
~ ~ ~ o o o r~ ~ oo
m a ~ ~ ~; O ~ ~O
~1 H Q. ~1 ,_1
d ~ ~
rn h ,~ h
~ a
.~
s~ _~ ^o
O H ~
h Q
P~ ., _,
~ ~ ~7
~ U~ O~ O O O
Y ~ Q ~ O 0 1~1 ~1 0 0 0
O N ~_ O O O OO _I O
1 ~ 'a)
a) ~ ~ ~
O ,~ ~ X ~~ X X 5 X
X ~ ~
E~ ~ ~ ~ a~ o o o
. a) >
ro P~ U~
~ N
~ 0
rl O ~;
O _, O
~1 ~ ~4 11
.~~ ~ ~ ,~ o
~ ~ ~, X O O OO O O O O
.~, ,, . Q ~ ,~ ~
r:l ~ ~;
.,,
~n
.~, ~
~ o m ~ o
~ o~ ~ 's~ o
~: m ~ Q
.~ ,
.
. :
.. . .
~-~7~
'- -- 1~ --
Table_3
Bioavailabilitv COmDari60n of Quinazoline dione
Piperazines in SPontaneo-u6ly H~Pertensive Rats
I.V. . P.O. Ratio
CompoundE.D.-lO~_(a) E.D -10% tb~(P.o./I.V. (cl
(mg/kg) (mg~kg)
A 1.8 70 38.9
Z ~prior art) 0.5 370 740
(a) I.V. bolus dose that lowers MABP in conscious SHR by 10%.
(b~ Oral gavage dose that lowers ~ABP in conscious
cannulated SHR by 10%.
(c) Bioavailability ratio with small numbers (close to
unity) indicating good bioavailability.
THIS APPLICATION IS A DIVISION OF
Application No. 519,319 filed on September 29, 1986
