Note: Descriptions are shown in the official language in which they were submitted.
AZOLE ~IDES
(SY-1502-A)
~(38~22i~3
This invention relates to new nitrogenous containing
heterocyclic carbonyl plperazinyl quinazolines which are
potent antihypertensive drugs having generally less ~-adrener-
gic blocking activlty than does 2-[4-(2-furoyl)-piperazin~
yl]-4-amino-6,7~dimethoxyquinazoline which is a known potent
antihypertensive drug.
More particular~y, this invention relates to
compounds having the formula ~ ;
NH2
CH30~;~N~~ C-Z
CH30 ~
~rherein Z is a substituted or unsubstituted oxazole, isoxazole,
thiazole, isot~liazole or alkylthio substituted l,3,4-oxadiazole
group, pharmaceutically acceptable acid addition salts thereof
and to the processes ~or the preparation thereo~,
,,
United States Patent Nos. 3,511,386; 3,635,979 and
3J663~706 disclose several 4-amino-6,7-dimethoxy-~-~L~-(hetero-
cyclic-2-carbon~l)-piperazin-1-yl] quinazolines. One of these
compoundsj i.e., 2-[4-(2-furoyl)-piperàzin-1-yl]-4-amino-6J7-
dimethoxyquinazoline described in Example LXXII of these
patents is a clinically useful antihypertensive agent and is
marketed as such in many countries of the world under the
generic name prazosin. It is well established that the
antihypertensive efficacy o~ prazosin results from a dual
mechanism of action:
(i) a direct peripheral vasodilatation effect on
vascular smooth muscle; and,
(ii) a functional peripheral ~-adrenergic receptor
blockade,
~ 2 ~ ~
H. Adrlaensen, The Practit~onerJ 21~, 268 (1975);
Mroczek, et al., Current Therapeutic Research, 16,769 (1974); ?
Scriabine, et al., ~xperientia, 2L~, 1150 (1968);
Gonstantine, et al., "~Iypertension: Mechanisms and Management",
ed. by Onesti, Klm and Moyer,
Grune and Stratton, 1973 pp. 429-44; and
Zacest, Med. J, of AustraI. Special Supplement, 1,4 (1975)~
Although initial clinical a~sessments on prazosin indicated an
almost complete absence of side effects, recent reports have
revealed severe adverse reactions of postural hypotension in
some patients, Bendall, et al,, Brit. Med. J,, 727 (June 28,
1975); Rees, Brit. Med. J., 593 (Sept. 6, 1975); Gabriel, et
al , The Lancet, 1095 (May 10, 1975); and, Bloom, et al.
Current Therapeutic Research, _, 14l~ (1975). It is generally
felt that this type of side effect results from the ~-blockade
component of prazosin. IndeedJ it has been stated by Ro Zacest
in the Med. J. of Austral., Special Supplement, 1, 4 ( 1975)
that "if the alpha adrenergic 'blocking' activity does prove to
be significant with high doses it may lead to postural hypo-
tension','
United States Patents Nos. 3J 669~ 968 and 3,769,286
cover trialkoxyquinazolines~ such as those having the formula:
~2
CH30
C-R
~I30 CH30 ~
wherein R may be a number of different groups including furyl
and thienyl. These patents claim to have certain advantages
over the corresponding 6,7-dialkoxy compounds such as those
disclosed in the patents previously discussed. ThusJ it is
stated that such compounds "have a more favorable pharmacolo-
gical profile (e.g, 3 they are non-adrenolytic in dogs) and
-- 2 --
L2'~8
possess greatly improved solubility characteristics
(particularly ln water) as contrasted to the corresponding
6,7-dialkoxy compounds reported in the prior artl'. One of
the compounds disclosed in these patents is known by the
generic name trimazosln and has the formula:
NH2
CH30
~1N N-C-O-CH2-~ CH3
CH30 C~30 ~
Trimazosin is reported to be active in humans as an antihy-
pertensive agent, DeGuia, et al., Current Therapeutic Research,
15J 339 (1973); Vlachakis, et al., Current Therapeutic Research,
17, 564 (1975). However, it is a much weaker drug than
prazosin, the respective clinical daily dose ranges being
approximately 150 to 500 mg. ~or trimazosin as compared to
1.5 to 15 mg. ~or prazosin. Trimazosin is there~ore 100-fold
weaker than prazosin at the lower end of the dosage range.
U. S. Patent Nos. 3,517,005; 3,594,480; and 3,812,127
describe certain piperazinyl quinazolines having both broncho-
dilator and antihypertensive activity, e.g., a compound having
the rormula~
~ N ~ ~ ~ R "
wherein A and B may each be alkoxy, etc~, R~ may be hydrogen
or alkyl and R " may be hydrogen or a radical such as alkyl, -
benzoyl, etc.
U. S. Patent No. 3,920,636 describes homopiperazino
quinazolines as antihypertensive agents, e.g.~ the compound:
NH2
C~130 ~N~ CR~ ?
~H30 ~ ~I2~3
U. S. Patent No. 3~780,040 discloses compounds
useful as antihypertensive agents such as the compound:
CH30
~ ~N ~ N ~ ~
3 S
Netherlands application 72 o6,06 (CA, 78, 72180s) .
describes a process ~or preparing aminoquinazolines, such
as prazosin, by treating the corresponding o-aminobenzoni-
trile in the presence of phenyl lithium according to the
following mechanism: .
NH2
CH30 CN CH30
~ + PyNCN PhL1 >
CH30 CH30
wherein R2N may be the group 4-(2-furoyl)-l~piperazin~l.
The present invention provides compounds having
the formula ~ :
NH2
CH30
~ N ~ N ~ 11 z
CH30 ~ ;~
wherein Z is
Z8
Rl Rl
N ~ N ~ .-
R2
in which X is either oxygen or sulfur, Rl and R2 may be
the same or different and are selected from the group
consisting of hydrogen, (lower)alkyl having from 1 to 6
carbon atoms, (lower)alkoxy ha~ng from 1 to 6 carbon atoms `.
and (lower)alkylthio having from 1 to 6 carbon atoms, and
R3 is (lower?alkyl having from 1 to 6 carbon atoms and
pharmaceutically acceptable acid addition salts thereof,
possessing antihypertensive potency comparab.le to proazosin
but having generally less of the peripheral ~-adrenergic
blocking properties shown by prazosin. Embodiments of this
invention are compounds having the formula:
~ ~ N ~ ~ G-~
in which R is (lower)alkyl having from 1 to 6 carbon atoms
and pharmaceutlcally acceptable acid addition salts thereof.
m ese compounds posse~ss antihypertensive potency comparable
to prazosin but have little or none of.the peripheral a -
adrenergic blocking properties shown by prazosin. m ese
compounds are potent antihypertensive agents which ha~e
little or no potential for side effect as reflected by their
lack of adrenolytic activity~
The most preferred compound of this invention is
4-amino-6,7-dimethyloxy-2-~4-(5-methylthio-1,3,4-oxidiazole-
2-carbonyl)piperazin-1-yl~-quinazoline having the
formula:
Cii30 ~ N l N ~ N-C ~ ~I CH3
and acid addition salts -thereof, in particular~ the hydro-
chloride salt.
m e term "pharmaceutically acceptable" used herein
to describe an acid addition salt of a compound of Formula I
refers to those salts having anionic species of a variety
of relatively non-toxic inorganic or organic acids. The
anion does not contribute appreciably to the toxicity of
the salt or to its pharmacological activity. Illustrative
of such salts are those formed with acetic, lactic, succinic,
maleic, tartaric, citric, gluconic, ascorbic, benzoicJ
cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydro-
bromic, hydroiodic, sulfamic, sul~inic acids such as methane-
sulfonic, benzenesulfonic, ~-toluenesulfonic, and related
acids~ Preparation of the mono-acid addition salts may be
carried out in conventional manner by treating a solution or
suspension of the free base in a reaction inert organic ~ ~;
solvent wi-th one chemical equivalent of the acid or, if the
di-acid addi-tion salt is desired, at least two chemical
equivalents of the acid. Conventional concentration or
crystallization techniques are employed in isolating the salts~ ~ `
This invention also provides process for the
preparation of compounds having the formula
NH2
CH30
j - 6 -
wherein Z is a substituted or unsubstituted oxazole,
lsoxazole, thiazole, isothiazole or alkylthio substituted ?
l,3,4-oxadiazole group and non-toxic pharmaceutically
acceptable acid addition salts thereof,
According to the present invention, compounds of
Formula I are prepared by a process which comprises
reacting a quinazoline derivative of Formula II
CH30 ~ N~ ~ B II
in which substituent "A" is NH2 or NR'2, wherein R~2 is a
conventional amine protecting group, and substituent "B"
is chlorine, piperaæino or OR" wherein R11 is the radical
F3CC(o) ~, CH3SO2 -, F3CSO2 -, or alkyl SO2 - wlth a reactant
of the group consisting of 9 and 8
~ Y b z z C piperazine
wherein "Y" is a carbonyl activating group of the type
typically used in amidation reactions3 e.g., halo, azido,
ethoxy, carbonyloxy, l-imidazo and the like; and æ is
Rl Rl :`
N ~ N - N
~ ~ x2 , ~ ~ R Or ~ ~ S-R3
in which X is either oxygen or sulfur, Rl and R2 may be
the same or different and are selected ~rom the group
consisting of hydrogen, (lower)alkyl haying from`l to 6
carbon atoms, (lower)alkoxy having from l to 6 carbon atoms
and (lower)alkylthio having from l to 6 carbon atoms, and
R3 is (lower)alkyl having from l to 6 carbon atoms; when
necessary, removing the amine protecting group R'2 by
conventional means and, if desired, converting the product to
a non-toxic, pharmaceutically acceptable acid addition salt by
methods known, ~
The following reaction schemes of Equations 1-5
illustrate the various synthetic routes embodied in the
preparation of the compounds of the instant invention according
to the process discussed above.
Equation 1
30~ 2 \~ O
C 3 N J\ 2~ NH CH30/~ J~ ~_C_Z
,
In a preferred embodiment of this process, Z is .
N N
SR where R is a (lower)alkyl group and the reaction
O
is conducted in an ine~ solvent such as dioxane, chloroform,
methylene chloride, glyme and the like at room temperature,
and/or with heating at reflux to insure completion of the
reaction.
In a more preerred embodiment, Y is chlorine, Z is
N - N
~S-cH and the reaction is conducted in dioxane. .
O~ ;
Equation 2
CH~ + HN -C--Z ~ ~ O
N 7 N N/~ 1 - Z
CH30 Cl CH30 \J
- 8 -
Equation 3
~ ~2N
CH30 Cl CH30
~N + R 2NH ~
C~3O N'l Cl ¦ N~NH
R 2N
CH30~ ~~ CH30~
C~30 N 1N,_~C Z 3 N~N-H
I~a)
The amine protecting group R'2 may then be removed from
compound I(a) by conventional means to provide the product
compound I.
Equation 4
R' N--
Cl CH30 ~ N 1 Cl
CH30~1 + ~'2NH~ 1 HNOI-C-Z
R'2N
CH30 ~ 1~N-C-Z
I (a)
2~
As in the reaction of Equation 3, the amine protecting group
R'2 may be removed from compound Ia by conventional means to
provide the product compound I.
Equation 5 CH30 ~ N ::
CH30 ~ ~ R~ 0 (or R~Cl)--~ ~ N~l OR "
CH30 4N'l 0 / ~
:, ,
MH2
CH30 ~ N ~ ~ N~ z CH30 ~ N
CH3 0 N 1N~N-C-Z CH3 O 10R "
The compounds of the instant invention may also be prepared
by the following reaction sequence~
CH30 ~02CH3 CH30 C2CH3 CH30 C02CH3
~ ~ NaSCN ~ / CH3I \ ~
CH30 / ~ A~2 3 ~ ~k CH30 / C~35 ~H~HI
.
O ~. ~
N N-C-Z
O
CH30 ~ ~ ~ ~ ~ O 0 ~ ;
- 10 -
. ~ : . . . . .. . ~ . . . .
28
EXAMPLES
Example 1 J
4-Amino-6l7-dimethoxy-2-l4-~5-methylthio-l~3~ oxadiazole-2-car
bonyl)-piperazin-l-yl]-quinazoline hyd ochloride - ~ solution
of 5-methylthio-1,3,4-oxadiazole-2-carbonyl chloride (0.601 9.,
3.36 mmole) in dioxane (10 ml.) was added to a solution of 4-
amino-6,7-dimethoxy-2-(1-piperazinyl)~uinazoline (0.972 g.,
3.36 mmole) in dioxane (100 ml.). The resultant mixture was
stirred at room temperature for 65 hours, then was heated at re-
flu~ for 30 minutesO Eiltration gave the title compound (1.56 g.).
Recrystallization from methanol gave a product having a M.P. of
280-285C. with decomposition.
Anal. Calcd ~or C H N O S-HCl: C, 46.20; H, 4.74; Cl, 7.58;
--- 18 21 7 ~
N; 20.96; S, 6.85
Found: C, 46.34; ~I, 4.89; Cl, 7.59;
N, 20.38; S, 6.58.
Example 2
4--Amino-6,7-dimethoxy-2-[4-(5-ethylthio-1,3,4-oxadiazole-2-car-
bonyl)-piperazin-I-ylI-quinazoline hydrochloride - The title
compound was prepared from 5-ethylthio-1,3,4-oxadiazole-2-car-
bonyl chloride (0.79 g., 4.1 mmole) and 4-amino-6,7-dimethoxy-
2-~1-piperazinyl)quinazoline (1.19 g~, 4.1 mmole) following
the procedure described in Example 1. The product had a M.P.
o~ 2~6-248.5C.
Anal. Calcd for C H N O S.~ICl: C, 47.34; ~I, 5.02, N, 20.34;
19 23 7 4
S, 6.65
Found: C, 47.37; H~ 4.76; N, 20.15;
S, 6.71.
(corrected for 4.11% H2O)
~L~8~
Example 3
~-~mino-6,7-dilTI~t~loxy-2-~4-(5-isopropylthio-l~3~4-oy~a(liazo~c-2
carbonyl)-piperazin-l_yl]-qUlna7oline hyc~rochlori(le - The title
compound was prepared from 5-isopropylthio-l~3~4-oxadiazole-2-car
bonyl chloride (1.54 g., 705 mmole) and 4-amino-6,7-dimethoxy-2
piperazinyl)quinazoline (2.1 9., 7.5 mmole) follo~ing the procedure
of Example 1. The product had a M.P. of 260-263C. with decomposi-
tion.
20H25N7Q4S HCI: C, 48.43; H, 5 28; N 19 77
~ound: C, 48.05; ~I, 5.~0; N, 19.61.
Example 4
4-Amino-6,7-dimethoxy-2-E4-(5-n-propylthio-1,3,4-oxadiazole-2-
.
carbonyl)-piperazin-l-yl]-quinazoline hydrochloride - The title
compound was prepared from 5-n-propylthio-1,3,4-oxadiazole-2-car-
bonyl chloride (1.68 g., 8.16 mmole) and 4-amino-6,7-dimethoxy-
2-(1-piperazinyl)quinazoline (2.36 g., 8.16 mmole) following the
procedure of Example lo The product had a Pl.P. of 230-245C.
with decomposition~
Anal. Calcd for C H N 0 S~HCl: C, 48.43; H, 5.25; N, 19.77
20 25 7 4Found: C, 48.11; Il, 5.35; N, 19.65.
j`.:,
Example 5
4-Amino~6~7-dimethoxy-2~[4~(5~n~butylthio-1,3,4-oxadiazole-2~
carbonyl)-piperazin-l-yl]-quinazoli'ne hydrochloride - The title
compound was prepared from 5-n-butylthio-1,3,4-oxadiazole-2-
carbonyl chloride and 4-amino-6,7-dimethoxy-2-(l-piperazinyl)
quinazoline following the procedure o~ Example 1.
- 12
22~
Example 6 ~ ?
4-~rnino-6,7-dirn~thyo~y-2-[~-(iso~:a201e-5-carbonyl)-piperazin-l-
yl~quinazoline llyclrochloride - A solution oE isoxazDle-5-carbonyl
chloride (1.33 9., 0.0l molc) in dioxane was added to a solu-
tion at 30C. of ~-alnino-6,7-dimethoxy-2-~1-piperazinyl]quin-
azoline (2.94 9., 0.01 mole) in dioxane. The mixture was
stirred at reflux for three minutes, then at room temperatULe
for 16 hours. Filtration qave the title compound ~.02 ~.,
94% ~ield). Recrystallization ~rom aqueous methanol gave a
product having a m.p. of 270C. with decomposition.
H2o~l6o~llcl: C 51 37; ~I, 5.03; Cl 8 42;
Found: C, 50.86; 11, 4.65; Cl, 8.52;
N, 19.~1
(corrected for 4.30~ ~l20)
Example 7
. ~
4-~mino-6,7-dimethoxy-2-[4-(isoxazole-3-carbonyl)-piperazin-1-
... . . .
ylJquinazoline llydrochloride ~ A solution of isoxazole-3-carbonyl
chloride (0.753 9., 0.0057 mole~ in dioxane (20 ml.) was added
to a solution of 4-amino-6,~-diimethoxy~2-(l-pipera2inyl)quin-
azoline (1.66 g., 0.0057 mole~ in dioxane (60 ml.). The mix-
ture was stirred at reflux for 30 minutes, t~en at room tempera-
ture for 6q hours. Filtration gave the title compound whic~h was
recrystallized from methanol (-1.81 g., 75~ yield). Tl~ product
had a m.p. o~ 26~-273C. with decomposition.
C18~120N60~1Cl: C, 51 37; ~, 5.03; Cl 8 42;
Found: C, 50.04; ~, ~.86; Cl, 8.66;
N, 19.57
(corrected for 3.11~ H20)
- 13 -
Example 8
4-~mino-6,7-dimethox~-2-[~-(lsoxazole-4~ iperazin-l-
yl]quin~zoline ~yd~ochlotide - ~ solution of isoxazole-~-carbonyl
chloride ~1~06 g., 8.08 mmole)~ in dioxane (8 ml.) was adcled to
a solution of 4-amino-6,7-dimethoxy-2-(1-pipelazinyl)~uinazoline
(2.34 9., 8.08 mmole) in dioxane (200 ml.). The mixture was
stirred at room tempeLature for 20 hours. Piltration gave the
title compound, which, after recrystallization ~rom methanol,
had a m.p. of 255-260C. with decomposition.
Anal. Calcd. for C18H~0~6O4~1Cl: C, Sl.37; H, 5.03; Cl, 8.42;
N, 19.97
Found: C, 51.37; H, 4.95; Cl, 8.34;
N, 19.95
~corrected for 1.63% ~12)
Example 9
. .
4-Amino-h,7-dimethoxy-2-14-~S-methyliso~zole-3-carbonyl)piper-
,
azin-l-yll~uinazoline HydrochloLide - A solu~ion of 5-methyliso-
xazole-3-carbon~l chloride ~0.41 ~., 2.83 ~mole) in dioxane was
addecl to a solution of 4-amino-~,7-dimethoxy-2-~1-piperaæinyl)
quinazoline ~0.82 g., 2.83 mmole) in dioxane. ~he mixture was
treated as described in the previous éxample to give the title
compound havin~ a m.p. of 271-273C. with decomposition.
~nal Calcd- for C19H22N64HC1 ~12 ~1 0, 3.92
Found: C, 50.58; H, 5.4Q; N, 18.86;
~l2' 3.72
2~3
Exa~ple 10
J
~5-Amino-6~7-dirncthoxy-2-~ (3-methylisoxazole-~-c~rbonyl)piDer
~zin-l-ylJ~uinazoline llyclrochloride - ~ solution oE 3-methyl-
____ .
isoxazole-4-calbonyl chloride (1.01 g., 6.9 mmole) in dio~ane
and 4-amino-6,7-dimethoxy-2-(1-pipera~inyl)quinazoline (2.00 g.,
6.9 mmole) in dioxane was stirred under reflux or 15 hours,
then worked up as described in Example 6. The titlc compound
after recrystallization from methanol had a m.p. of 300-301C.
with decomposition.
Anal. Calcd. for C19E~22N604~3Cl: C, 52.47; El, 5.3~; N, 19.3~
Found~ C, 52.62; El, 5031; N, 19.12
(corrected for 1~13~o ~2)
Fxample 11
4-Amino-6,7-dimethoxy-2-i~-(3-methylisoxazole-5-carbonyl)piper-
_ _ _
azin-l-yl~uinazoline Hydrochloride - ~ solution of 3-methyl-
isoxazole-5-carbonyl chloride (0.73 g., 5.02 m~ole) in dioxane
was added to a solution of 4-amino-6,~-dimethoxy-2-~1-piper~zinyl~
quinazoline (1.45 g., 5.02 mmole) in dioxane. The mixture was
heated briefly, then was stirred at %0C. for 2.5 hours. ~ork-
up as in Example 6 gave the title compound having a m.p. of
263-264C. with decomposition.
Anal. Calcd. for ClgEI22N6C~EICl: C, 52.47; ~1, 5.33; Cl, 8.15;
N, 19.33
Found: C, 51.82; ~1, 5.04; Cl, 8.36;
N, 19.46
(corrected for 4.82~ ~l2)
- 15 -
2Z8
Example 12
.
4-Amino-6,7-dimethox~-2-~4-(oxazole-4-carbonyl)plperazin-1-yl]
quinazoline Hydrochloride - A solution of oxazole-4-carbonyl
chloride (O.73 g., 5,53 mmole) in dioxane was added to a solu-
tion o~ 4-amino-6,7-dimethoxy-2-(l-plpera~inyl)quinazoline
(1.60 g,, 5.53 mmole) in dioxane. m e misture wa~ heated at
reflux ~or O.5 hour, ~hen was stirred at 20C ~or:64 hours.
Filtration g~ve the title compound having a m.p. o~ 291-294C,
with decomposition a~ter rec~y~tallization from aqueous
ethanol. ..
18 20N64HCl ~l2 Ci 49 26 tl, 5.28;
Found: C, 48.92; tl, ~.83;
Cl, 8.33; N, 18.94
Example 13
.
4-Amino-6,7-dimetho~y-2-~ (2-methylo~:azole-4-ca~bonyl)~ peL~
azin-l-yl~quinazoline tlydrochlo~ide - A sol~tion of 2-methyl-
oxazole-4-carbonyl chloride (1.01 g., 6,9 ~ole) in dioxane
was added to a solution of 4-amino-6~7-dime~hoxy-2-(l-pipera~ `
zinyl)quinazoline (2.00 g., 6.9 mmole) in d~oxane. The mix- .
tule was heated at reflux for 2 hours. Fil~ra~ion ~ave the
title compound having a m.p. of 278-280C. ~ith decomposition
after recrystallization from methanol.
~al. Calcd. for C19~122N6O~HCl: C, 52.47; H, 5.33; N, 19.33
~ound: C, 52.08; ~, 5.~3; N, 18.89 ~
~correcte~ for moisture) .
,.
~.
- 16 -
.-J
z~
Example 14 ?
4-~mino-6,-7-clillleth_xy~2-~4-(4~ et}lyloxazo.lc-5-caL~onyl)pipec-
azin-l-yl~quinazoline llydrochloride - The title compound was
prepar~d frorn ~-rnethyloxazolc-5~carbonyl chloride (0.85 ~.)
and 4-amino-6,7-dimethoxy-2-~1-piPerazinyl)q-linazoline
(1.68 g.) followin~ the procedure of Example 6. Tlie produc~
had a m.p. of 283.5-288C. with decomposition.
H22N6O4HCl: C 52 48; H,. 5.33; Cl 8 i5
Found: C, 52.~9; H, 4.94; Cl" 8.13;
N, 19.05
~corrected for 1.59~ H2O)
Example 15
4-Amino-6,7-dimethoxy-2-[4-~isothiazole-~-carbonyl)pipcrazin-
:
l-yl~auinazoline ~ydrochloridc - The title compound was pre- -
.
pared from isothiazole-4-carbonyl chloride ~1.01 ~.) and
4-amino-6,7-dimethoxy-2-(1-pipeLazinyl)qulnazoline (1.99 g.)
~o~lowing previously clescribed proc~dures. The product had
a m.p. of 286-287C. with decomposition.
1 Calcd for C18~l20N6O3S N 19 23, S, 7 34
Found: C, 49.20; ~I, 4.81; Cl, 8.19;
N, 19.27; S, 7.23
(corrected for 0.93 % H2O)
- 17 -
Example 16
~-~mil-o-fi,7 dil_etho_y-2~ ( tt)~ zol-e-2-cclLbonyl)pi~erazin-t-
yl]quirla~olln~ _yclrochloride - The title compouncl was prepaLed
from thia%ole 2-c~Lbonyl clllolide (0.79 cJ.) and 4-amino-6,7-
dimethoY.y-2-(1-pipeLa~inyl)quinazoline (1.5~ g.) ollowing
previously described proceclures. The product had a m.p. of
273-276C. with decomposition.
nal. Calcd. for C18~120N6O3S HCl: C, 49.~8; ~I, 4.84; N, 19.23
Found: C, 48.6~; ~1, 4.62; N, 18.87
~corrected foc 4.19 ~ ~12O)
Example 17
4-Amino-6,7-dimethoxy-?-[4-(thiazole-4-carb3nyl)piper~z n-l-
yl~quinazoline ~!ydrochloride - The title compound was prepared
from thiazole-4~carbonyl chloride (1~02 ~.) and 4-amino--6,7-
dimethoxy-2-~1-piper~%inyl)quinazoline (2.00 g.) following
previously described procedures. The product had a m.p. of
274-277C. with decomposition.
C18~12o~6O3S ~ICl: C, 49.48; E3, 4.84; N 19 24
Found: C, 49.11; H, 4.69; N, 19.31
~corrected for 4.47% H2O)
Example 18
4-~mino-6,7~dimethoxy-2-[4-(2-methylthiazole 4-calbonyl)piper-
azin~l-yl~quinazoline 33ydrochloride - The title compound was
,
pre~ared rom 2-methylthiazole-4-carbonyl chloride (0.49 g.)
and 4-amino 6,7-dimethoxy-2-~1-piperazinyl)quinazoline (0.87 g.)
following previously described procedures. The product had a
m.p. of 260-263C. with decomposltion
~nal- Calcd. for C19~122N6O3S ~ICl: C, S0.60; ~1, 5.1~; N, 1~ 6~
Found: C, S0.88; Il, 4.96; N, 18.67
~corrected for 2.88 ~ H2O)
- 18 -
Example 19
~I-Amino-6~7~ rle~llO:~y-~ 14--(thia~ole-s-carL)onyl)piperazi~
yl]quinazoline l_ydrochlori(1e - The title com~oun~ was p~epared
from thiazole-5-carbonyl chloride (0.77 g.) and 4-arnino-6,7-
dimethoxy-2-~1-piperazinyl)q-linazoline ~1.51 9.) following
previously desc~ib~d proc~dur~s. The product had ~ m.p. of
280-281C. with decomposition.
Anal. Calcd. for C H N O S IICl: C, 49.48; ~1, 4.84; Cl, 8.11
18 20 6 3 N, 19.23; S, 7.34
Found: C, 49.22; H, 5.19; Cl, 8,31;
N~ 19.49; S, 6.79
(corrected for 2.63~ H2O)
Example 20
... .
4-Amino-6,7-dimethoxy-2-[4-(2-m_ hylthiazole-5-carbonyl)piper-
azin-l-yl]quinazoline Hydrochlorlde - The title compound ~las
prepared from 2-methylthiazole-5-carbonyl chloride (0.42 g.)
and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (0.75 g.)
following previously described procedures. The product had a
.p. of 294-297C. with decomposition.
Anal~ Calcd. for C19H22N6O3S HCl: C, 50.6~; H, 5 l4; N, 18.64
~ound; C, 50.60; ~1, 4.95; N, 18.50
~corrected for 1.96 ~ ~12O)
~.
Example 21
4-Amino-6,7-dimethoxy-2-[4-(4-nlethylthiazole-5-c~bonyl)piper-
azin-l-yl]quinazoline Hydrochloride - The title co~pound was
prepared from 4-methylthiazole-5-carbonyl chloride (1.1 g.)
and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline ~2.0 g.)
following previously described procedures. The product had a
m.p~ of 293-295C. with decomposition.
- 19 22 6 3
~ound: C, 50.47; H, 4.78; N, 18.43
tcorrected for 4.72~ H2O)
- 19 -
8~22~
To determine the efficacy of the compounds of this ?
invention as antihypertensive agents, tests were conducted
comparing these products to prazosin.
Table 1 below sets forth the comparison of the
product of Example 1 to prazosin, As shown in Table 1,
the product obtained in Example 1, above (hereinafter referred
to as BL-5111) is o~ comparable antihypertensive potency to
prazosin, but has little or none of the peripheral ~-adrenergic
blocking properties shown by prazosin. This compound thus
represents a significant and unexpected advance in the
continuin~ quest for potent antihypertensive drugs which have
little or no potential ~or side effects as re~lected by their
lack o~ a-adrenergic blocking activity,
In Table 1, antihypertensive activity was
determined by oral administration to spontaneous hypertensive
rats, and the in vitro and in vivo ~-adrenergic receptor
blocking e~ect was determined by tests described following
Table 1. ln the in itro test, the inhibition by BL-5111 o~
norepinephrine induced contractions of rat seminal vesicles
was measured; and in the in vivo test, the inhibition by BL-5111
o~ norepinephrine induced pressor responses in anesthetized
dogs was measured. The in vivo tests were conducted using intra-
venous administration, each compound bèing assayed in 4 dogs with
2 dose response results in each dog.
- 20 -
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I l¢
.
j
P~ :~o ~
,~ O .
~ ~Y ~ r i O
~ ¢ 0~ ~1 ~ ,: :
~i ~ ~ ~ ~\J CJ
~ ta~,a.) :
>~ h O ~ bD C~J ~ ~ ~1 ~O
~ \~ Q) O CO ~ ~ C~ J r~l
OtY~ ~ ~i 1 ~ . ?i
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,"
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- 21 ~
ISOLI\T~:D l~/~T SEMII`~I\L VESICI.E I~SSI~Y J
Dangan ct al, Int. J. Ncuropl)~rmacol., 4:219 (1965)
have shown th~t the seminal vesicle of the rat is a tissue
which is notably responsive to compounds which activate a-re-
ceptors but is relatively insensitive to compounds which activate
~-receptors. Lietch et al, Brit. J~ Pharmacol., 9:236 ~1954),
have employed the isolated rat seminal vesicle in the comparative
assay of a-receptor blocking drugs and the present studies were
carried out using a modification of their procedure.
Male l,ong Evans rats weighing approximately 300 g. were
sacrificed by a sharp blow on the head. Seminal vesicles were
removed and transfered to a shallow dish containing modified
Tyrode's solution. The vesicles were emptied of their cantents
by squeezing them gently with a pair of Eorceps. Silk thread
(4-0) was attached to both ends of the vesicle and it was sus-
pended in a 20 ml. muscle chamber containing modi~ied oxygenated .
Tyrode's solution (g./liter: ~aCl 8, KCl 0.2, CaC12 0.26, NaHCO~
ll Ma2HP0~ 0.0575, glucose 0.5 and MgC12 0.02). The bathing fluid
was maintained at 37C. with a thermostatically controlled iso-
lated organ tiss~e bath. Contractions were recorded isometrically
by means of a force displacement transd~cer and recordings
were made with a Beckman RP Dynograph. Norepinephrine ~NE)
was added to the muscle chamber in volumes ranging from 0.1
to 0.4 ml. with a one ml. syringe attached to a 3 inch 20 gauge
needle. NE and test compounds were dissolved in deionized
water.
-- 22 -
2'~8
NE dose resporlse curves were obtained alone and in the
preserlce of test compoullds. Nl~ was allowed to remain in contact
with the strip until a maximal contraction was obtaincd~ The strip
was then washed with the perfusion fluid for 15-30 seconds and
the preparation was allowed to return to base line before a sub-
sequent dose of NE was given. Increasing amounts of ME were in-
jected into the bath in the same manner until a co~nplete dose
response was obtainedO
The seminal vesicles used to obtain the control NE dose
response were discarded and new preparations were placed in the
tissue bath for evalllation of the test compound. The test com-
pound was added directly to the perfusion fluid ~10 nanograms/ml.)
and the strips were allowed to remain in contact with the bathing
media for at least 1~ minutes before the NE dose response was
determined.
ED50 values for NE were obtained by regression analysis
as described by Finneyl Probit. Analysis, 2d Ed., Cambridge (1964).
A minimum of ~ strips and at least 4 doses were employed to cal-
culate the regression lines. The ED50 value is defined as the
concentration oE NE which produces a contraction equal to 50% of
the ~aximal contraction.
The ratio of the a-adrenergic blocking activity of BL-
5111 relative to that of prazosin was calculated as follows:
% Change~from NE = ED50 NE -~ Drug - ED50 NE Alone X 100
ED50 NE Alone
The value obtained for BL-5111 was then expressed as a
ratio of the value obtained for prazosin.
Activity Ratio = ~ Change for NE - BL-5111
~ Change from NE - Prazosin
- 23 -
The results o~tainecl ~ith NE, prazosin and BL 511~ are
summarized in Table II.
Table _I
Effect of Prazosin and BL-5111 on NE Response
in Isolated Rat Seminal Vesicles
NE Activity
ED50 with 95~ - Ratio
No. of Conf. Li~its Percent Change Relative to
Treatment Strips (,ug/ml)From Control Prazosin
Control 32 0.89 (0.84-0.94) - -
Prazosin, ~ 6.03 ~5.30-6.81)578 1.0
10 nano/ml.
BL-5111 7 n~s3 (0.80-1008)4.5 0.008
10 nano/ml.
These data indicate rather clearly that at a concentra-
tion of 10 nanograms/ml., prazosin caused nearly a six fold de-
crease in the sensitivity of isolated rat seminal vesicles to
the stimulant activity of NE while BL--5111 was essentially in-
active in this respect. It was concludéd that BL-Slll possesses
less than one percent of the a-adrenergic ~locking activity of
prazosin.
., ~' '
ANESTHETIZED DOG ASSAY FOR a-ADRENERGIC BLOCKIMG ~GENTS
Nashl C.B., Pharmacological Research Communications,
4:423 (1969~ and Maxwell, R.A., Drill's_Pharmacology in Medicine,
(1971) p. 683 have shown that in anesthetized dogs a-adrenergic
blocking agents antagonize the blood pressure elevating effects
of intravenous norepinephr-ine. Thus, blood pressure responses
to norepinephrine (~E) in anesthetized dogs was used ~s a com-
parative assay for a-adrenergic receptor blocking properties of
drugs.
- 24 -
3~3~ Z8
Experim~nts ~ler~ done on mongrel ~lo~Js anes~hetized with
sodium pentoharbital, 30 mcJ./kg. iv. The le[t femoral artery was ?
cannulat~d to recoL-d aortic bloo(l pressure ancl a femoral vein was
cannul~ted foc cldministration of drugs. All anim~ls underwent a
bilat~ral vagotorny. A norepinephrin~ dose-respons~ curve was ob-
tained by administeriny increasin~ doses of iv. norepinephrine
(0.01 - 1 ,ug/kg). The test drug (prazosin, BL-5111) was then ad-
ministered iv. at 3 mg/kg. Approximately 30 minutes later a dose-
response curve was again established for iv. norepinephrine (0.01-
10 ~g/kg). The dose of norepinephrine (with 95% confidence limits)
that increased blood pressure by 50 mm of Hg was obtained from dose-
re,sponse curve analysis before and after vrazosin and BL-5111~
The ratio of the a-adrenergic blocking activity of BL-Slll rela- ~`
tive to that of prazosin was obtained as follows:
EDS0 mm llg ED50 mm Elg
~ctivity R~tio = BL-5111 - NE
ED50 mm ~g ~D5Q mm E~g
Prazosin NE
The results obtained with norepinephrine, prazosin and
BL-5111 are summarized in Table III. The results indicate that
BL-Slll was approximately 30 times less active than prazosin in
causing ~-adrenergic blockade at 3 mg/kg iv. !',
Table III
Effect of Prazosin and BL-5111 on the Blood Pressure
Response to Intravenous ~orepinephrine
NE ED50 mm Elg Activity Ratio
Treatment Nw/ 95% Conf. Limits Rela~ive to Prazosin
.
Control 200.23 (0.19-Q.28)
Prazosin, ~ 6.90 (4.R0-lQ.7) 1.00
3 mg/kg
BL-5111 ~ 0.47~0.40-0.55) 0.036
A 25 -
Table IV below sets forth -the comparison test
data for the products of Examples 6-21 and prazosin. As ? -
shown in thls table, the products obtained in the foregoing
Examples 6-21 are of comparable antihypertensive potency
to prazosin, but have generally less o~ the peripheral ~-
-adrenergic blocking properties shown by prazosin. These
compounds thus represent a significant and unexpected advance
in the continuing quest ~or potent antihypertensive drugs.
- 26 -
~8~
TABLE IY
Antihypertensive Activlty ~-Adrenergic Recéptor Blocking Effect
Dose % Blood Pressure In Vitro In Vivo
Examplemg/kg ChangeActlvity Ratio: Activity Ratio
Prazosin 10 -42 1.0 1.0
(Reference 3 -29
Drug) 1 -14
6 lO -35 0.11 0.18
3 -26
1 -15
7 10 -32
3 -26 ::
1 -12
8 10 -35 0.92
3 -23
1 -13
9 10 -41 0 0.24
3 -18
1 -14
-33 0.30 0.18
3 -29
1 -17
11 10 -37 0.25
3 -21 ~ `
1 -18
12 10 -45 0.6 1.22
3 -29
1 -15 `
13 10 -35 0.17
3 -31
1 -13
14 10 -41 0.19 -:
3 -26
1 -14
-25
3 -23
1 -14
16 10 -33
3 -27
1 -14 -~
. .: . .
- 27 -
z~ :
TABLE IV ~Cont'd.)
Antihypertensive Activity ~ -Adrenergic Receptor Blocking Effect
Dose % Blood Pressure In Vitro In Vivo :
Example mg/kg Change Activity Ratio Activity Ratio
17 10 -32 0.12
3 -24 .
l -20
18 10 -28 0.02
3 -28
1 0 1 -19
19 10 -33 0.10
3 -22
l -12
-37 0.19 0.09
3 -25
1 -20
21 10 -28 0.35
3 -22 : :
1 ~4
- 28 -
-. , :
