Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~ 3~2;~3
Case 500-5494
BENZOXADIAZOLES AND BENZOTHIADIAZOLES, THEIR PREPARA-
4 TION AND PHA~CEUTICAL COMPOSITIONS CONTAINING THEM
The present invention relates to benzoxadia-
zoles and benzothiadiazoles having a 4-dihydropyridine
moiety.
The present invention provides in particular
compounds of formula I,
.. ~ N
R ~ ~=N
Il 11
R5 ~ ¦ R2
R
wherein : .
R1 is hydrogen, alkyl(Cl ~), hydroxyalkyl(C2 ~), alkoxy-
alkyl(C3 6)~ alkenyl(C3_6), a].kinyl(C3 6)~ cyclo-
L.~
'~
'
~3~Z8 s00-5494
r
alkyl(C3_7), cycloalkylalkyl(C4 8)~ phenylalkyl (C7 9
or phenylalkenyl(Cg 12)~ the phenyl ring heing un-
substituted or mono-, di- or trisubstituted indepen-
dently by halogen, hydroxy, alkyl(Cl 4) or alkoxy
( 1-4)'
R2 and R5, independently, are hydrogen, alkyl(Cl 6)'
PhenYlalkYl(c7_l0)~ cycloalkyl(C3 7) or cycloalkyl-
yl(C4_3),
R3 and R4, independently are CN, COR7, COOR7, SIO)nR7
or COO-A-N ~ 8, where-n
n is 0, 1 or 2,
R7 is alkyl(Cl_6), alkenyl(C3_6), alkinyl(c3 6)' cyclo-
alkyl(C3 7), cycloalkylalkyl(C4 83~ hydroxyalkyl
(C2 6)~ alkoxyalkyl(C3 6)~ hydroxyalkoxyalkyl(C4 g),
y (C2_6), alkYl(Cl_4)aminoalkYl(C2 6~ di[al-
kyl(C1 4)~aminoalkyl, phenyl, phenylalkyl~C7 10)~ a
5- or 6-membered heterocyclic ring containing one
heteroatom selected from nitrogen, oxygen or suIphur
and may contain additionally 1, 2 or 3 ring nitrogen
atoms, or alkyl(C1_~) substituted by a 5- or 6-mem-
bered heterocyclic ring containing one heteroatom
selëcted from nit:rogen, oxygen or suIp~ur and may
contain additionally 1, 2 or 3 ring nitrogen atoms,
A is alkylene(~ 6)~
.
,,., ,. ,,,, ... ~ ~ :
~; _ 3 ~3~Z~
. 500-5494
( -
R8 and Rg, independently, are alkyl(Cl 6)~ alkenyl or
alkinyl(C3 6)' cycloalkyl(C3 7), cycloallcylalkyl
(C4 8)~ hydroxyalkyl(C2 6)~ alkoxyalkyl(C3 6)~ hy-
droxyalkoxyalkyl(C4 8)' aminoalkyl(C2 6)' alkyl-
(Cl_4)aminoalkyl(C2_6), di[alkyl(Cl_4)]aminoalkyl,
phenyl, phenylalkyl(C7_10), or
R8 and Rg together with the nitrogen atom form a 5-,
6- or 7-membered heterocyclic ring, which may con-
tain a further heteromember selected from oxygen,
sulphur and a group --N-Rlo, wherein Rlo is alkyl
(Cl_4), and
R6 is hydrogen, haloaen, alkyl(Cl 4), alkoxy(Cl_4),
alkylthio(Cl 4), alkylsulfonyl(Cl 4), trifluoro-
methyl, nitro, hydroxy, azido, amino, alkyl(Cl 4)-
amino, di[alkyl(Cl ~)~amino, alkanoyl(Cl_5)amino,
carbalkoxy(C2 5), aminocarbonyl, trifluoromethoxy,
cyano, sulfamyl, alkyl(Cl 4)sulfamyl or di[alkyl
(Cl_4)]sulfamyl, and
X is oxy~en or sulphur, with the proviso that when Rl -
is hydrogen, alkyl(Cl ~), alkenyl~C3 6)' alkinyl
(C3 6)~ cycloalkyl(C3_7), cycloalkylalkyl(C4 8)~
phenylalkyl~C7 9) or phenylalkenyl(Cg 12)' the phe-
nylring being unsubstituted or mono-, di- or tri-
substituted independently by halogen, hydroxy,
alkyl(Cl_4) or alkoxy(Cl_4),
R2.and R5, independently, ~re hyd~ogen or alkyl(Cl ~),
Z;i~8
_ ~ _ 500-5494
(~ .
R6 is hydrogen, halogen, alkyl(Cl ~), alkoxy(Cl 4),
alkylthio(Cl 4), alkylsulfonyl(Cl ~), trifluoro-
methyl, nitro or hydroxy, and
X is oxygen or sulphur, then at least one o~ the sub-
.stituents R3 and R4 is other than COR7I, wherein
R7I is alkyl(Cl 6)~ alkenyl(C3 6j, alkinyl(C3_6),
cycloalkyl~C3 7), cycloalkylalkyl(C4 8)' and is other
than COOR7II, wherein R7II is alkyl(Cl 6)~ alkenyl
(C3_6), alkinyl(C3_6),cycloalkyl(C3 7), cycloalkyl-
allcyl(C4 8)' hydroxyalkyl(C2 6)' alkoxyalkyl(C3 6) or
hydroxyalkoxyalkyl(C~ 8)
In any of the above radicals alkyl of 1 to 6
carbon atoms is preferably of 1 to 4 carbon atoms,
especially of 1 to 2 carbon atoms. Any alkyl, alkoxy,
alkylthio or alkylsulfonyl radical of 1 to 4 carbon
atoms is preferably of 1 to 2 carbon atoms. The hy-
droxy, alkoxy, hydroxyalkoxy, amino or alkylamino group
of the hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl,
aminoalkyl or alkylaminoalkyl moiety in COOR7 is pre
ferably not attached to the a-carbon atom and is pre-
ferably attached to the distal terminal carbon atom.
Any hydroxyalkyl, alkoxyalkyl,hydroxyalkoxyalkyl,
aminoalkyl or alkylaminoalkyl radical preferably has an
ethylene or propylene moiety substituted by hydroxy,
alkoxy, hydroxyalkoxy, amino or alkylamino respectively.
The alkyl moiety of cycloalkylalkyl is conveniently
'~
3~2~8
_ 5 _ 500-5494
(
methyl. Halogen means fluorine, chlorine or bromine
and is especially chlorine. Cycloalkyl or the cyclo-
alkyl moiety oE cycloalkylalkyl is conveniently cyclo-
propyl or cyclopen~yl or cyclohexyl. The multiple bond
of alkenyl, alkinyl or phenylalkenyl in Rl or COOR7 is
preferably not in the a,~ position. Alkenyl or alkinyl
preferably has 3 to 5 carbon atoms. Alkenyl is conve-
niently allyl or 2-methylallyl. Alkinyl is convenient]y
propinyl. Phenylalkenyl preferably has the trans-confi-
guration and is for example cinnamyl. When Rl is optio-
nally substituted phenylalkyl, the phenyl group is pre-
ferably unsubstituted. When the phenyl group is di- or
tri-substituted, preferably the substituents are the
same.
When R7 is alkyl, this is preferably branched.
When R7 contains a heterocyclic ring this may be for
example furyl, thienyl, pyrrolyl, thiazolyl, isothia-
æolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,
imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl,
pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, mor-
pholinyl or triazinyl.
When R8 and Rg together with the nitrogen atom
to which they are bound, form a heterocyclic ring, this
is preferably saturated and may be for example pyrroli-
dine, piperidine, piperazine, N-alkylpiperazine, morpho-
line, -azepane, di~ze~ane or M-alkyl-diazepane.
. . ,
,
' - 6 - ~ ~3~Z~ 500-5494
Rl is conveniently hydrogen. R2 is convenien'ly
identical to R5. R2 is conveniently alkyl. R3 and/or
R4 is conveniently COOR7 or COO-A-N 8. R7 is con-
venientl~ alkyl, preferably branched or alkoxyalkyl,
where the alkoxy moiety is preferably branched. A is
conveniently ethylene~ R8 and Rg are conveniently
alkyl or phenylalkyl.
The present invention also provides a process
.~ -
for the production of a compound of formula I as de-
fined above, comprising replacing the moiety -HC=Y in
a compound of formula II,
R6 _N\
~X II
~IC=Y
wherein R6 and ~ are as defined a~ove, and
--~C-Y is i~ for~
ii) a radical of forJnula -~C-C-C(=Z)R2
R3
R3
- ~ Hc-c(=~)x2
lii) a xadical of formula -HC
`~HC-C(=Z')R5
R~
wherein ~ and Z' are independently oxy-
~en or I~Rl, and
Rl to ~5 are as define~ above,
by a moiety of ~ormula III,
,, . .. . _ ... ..
::
,: : . ,
.:
~3~28 500_5494
-R4 ~ 3
~ ~ III
5 ~ R2
~1 ..
erein ~1 to R5 are as defined above.
The process may be efected in conventional
manner for analogous dihydrop~ridine syntheses, e.s.
according to Hantzsch. ~hen the moiety ~I~C=Y is formyl
and when it is desired to produce a compound of f,ormula
~, wherein R2 is identical to R5 and ~3 is identical to
R~, it is convenient to react a compowld of rormula II
with a compound o~ fo~mula IV,
R5CO-CH2-R4- IV
~herein R4 and R5 are as define~ above,
in the presence of a compound of formala V,
H2NRl V
~ ~herein Rl is as de~lne~ a)~ove.
Preferably at least 2 moles of a compound of
formula IV per mole of a compound of fo~mula II are
present. Alternatively a compound of formula II may
be reacted with a compound o~ formula VI,
R5-C(NH-Rl)=CH-~4 VI
~7herein Rl, P~ and ~5 are as defined above.
Preerabl~ at least 2 moles of a corp~und o~ for-
mula VI per mole of a compound o~ for~ula II are present.
Pre~erably also ~1 is hydrG.~en.
;~ .
. _, .. _ ,.. .... .. .. ..
,
.
~ _- 8 ~3~ZZ8 5~0-549~--
l~hen he moiet~- -HC=Y is for~yl and ~refer2~1y
when it is desired to produce a com~o~d of Lormula I
wherein ~2 is dif erent to R5 and/or R3 is difLeren~ to
R~, it is also possible to xeact such a co~pound of formula
II with a compound of ~orrula IV and a compound of fol~ula
VII,
R -C(NH-R 1=CH~R ~ VII
wherein R2, Rl and R3 are as de~ined above.
It will be appreciated that a compound of formula
VI may be formed as an intermediate during the reaction of
a compound of for~ula IV and a compound of formula V. A
compound of formula II, ~herein -HC-~ is a radical ii)
or iii), may be formed as an inte~lediate in the above
reactions. They may however ~e produced by dif erent pro-
cesses.
Alternatively or particularly for the prcd~ctio~
of a compound o~ formula I, t7herein R2 is different to K5
and/or R3 is different to R4, it is convenient to react a
compound o~ fonm~la II, wherein the moiety -HC=Y is a ra-
dical ii) ~7ith a compound of formula IV or VI~
and t~here appropriate, wlth a compound of fGrmula V. A
co~.pound of ol-mula II, wherein ~he moiety -HC=Y is a
radical iii) ma~ be an intermediate.
'~J: .
~: ,
:
~3~Z~3
_ _~ 9 _ 500-5~94
In tl~ abo~e reac'~ions it is possi~le in certa-n
installCes ~I;en ~2~ R3~ R~ and R5 are not identical that
more than one isomer of formula ~ may be formed. If so
the3~ may be separated in conventional m2nner, e.g. by
.. . , ~ ... ... .. . ... . . . .. .
column or thin layer chromatography~
~ en ti~e starting material is a ccmpound cf formu-
la II, wherein -~C=Y is a radical iii), the reaction is a
ring cyclisation. ~'hen Z and Z' are both oxygen~ then an
amine of formula V should be present.
However, all the abo~!e reactions may be effected
under the same conditions.
The reaction may be effected conveniently in solu-
tion. ~ suitable sol~ent is water, ethanol, dioxane, di-
methyl ormamide, dimethyl sulphoxide, pyridine or glacial
acetic acid. Suitable reaction tempexa~ures may be from
20 to 160~ C, preferably from 60 to 120 C.
Insofar as the production of starting ~aterials
is not particularly described these compounds are kno.in
or may be ~roduced in analoqous manner to kno~m
compounds,
The basic compounds of formula I may be con-
verted into acid addition salt forms in conventional
manner and vlce versa. Suitable acids are e.g. maleic
'
:
1 3~
- 10 - 500_54~4
acid, oxalic acid, methanesulphonic acid, hydrochloric
acid and hydrobromic acid.
In the following Examples the temperatures
given are in degrees Centigrade and are uncorrected.
- - :- ,-
. : ,
~j
~ ~ 500-549~
~'
Example 1: ~-(2,1,3-Benzoxadiaz~1-4-Yl)-2,6-dimethyl-
1,4-dihydro-3-methoxyearbonyl-pyridine-5-
carboxylic acid benzyl ester
3,0 g of 2,1,3-benzoxadiazol-4-aldehyde, 3,9 g
of aeetoacetic acid benzyl ester, 2,3 g of 3-amino cro-
tonie aeid methyl ester and 10 ml of ethanol are re-
fluxed for 6 hours. The mixture is subsequently evapo-
rated and the residual oil is ehromatographed on silica
gel with ehloroform/aeetie aeid ethyl ester (8:1) to
yield the title compound. The product is reerystallised
from cyeiohëxane/diisopropylether, m.p. 131-136.
By using the process described in Example 1,
ard corresponding starting compounds, e.g. a eompound
of formula II, wherein -HC-Y is a radieal i~ and eom-
pounds of formula IV and V, and for Examplec 2-9 and
12-16 a eompound of formula II, wherein HC=Y is a
radieal ii), wherein Z is oxygen and a eompound of
formula VI, the following eompounds of formula I may
ke obtained, wherein y indieates the position of the
dihydropyridine moiety:
.... .
:, ,. ~,
~L~3~28 500-5494
U) ~ *
~ ,nr~ o ,~ ~ ~r In ~ ~ O~ ~ ~ a) ~
N O t~ O C~ 1` a~ 111 ~ (~) 1` tJI ~15
~I N ~I -1 ~I N ~/ ~ 1 ~1 0 ~1
I I I I I I I I I ~ I h 1
N O ~) OD E~ ~D F
N O
X: O O OU~ U~ O O U~ O U~ O U~
:
n ~ C X X m :~ ~c x
U
: :
N N
--~
. ~ O ~)
~ z æ
. ~ N N
m ntn o u~ Lr) ~ N IS )
. I ~ ~ ~ ~ ~ m m
. ~1 ~ N N ~ X N N U U N N
. I U U~ ) U ~D U ~ U C )
O N o o o C_) o o o o o o
~r O O o o o O o o o o o o
u u~ u ~ u u u u ~ u ~
.
u~
~ ~ $
. ~D ~O
N t`') N N N N N
\ / \ /
Z Z :Z æ Z Z
N N N ~`3 N t~l
_ ^~ --~ ~ N
C X
U ~ U U U ~ U U
O O O O O O O O
Z o æ Z Z o o o o o o
~; u u u u u c~ ~ u u ~ ~) u
:C x m ~ u C~ ~u m ~ u[ ~ a
I ~
X N ~ ~ o~ o ~t ~ ~7
~ . ~
'~ .
,
.' .
.
c ~ ~ 3~2%~
- 13 - 500-5494
~.
'n r~ o ~
a~ ID N~1
,_~
. I ~ ~ I I
~ 4 ~I r l t~ I O OC~ O ~D
E; o o
In In ~ ~r ~ ~r ' ~ ~r
X U~ O O O O O O O
~D
~'~ ~ ~ <
n ~: X m x :~ / / ~:
~; ~ o \ \
In n n n
m ~ m ~ ~ :~
m ~ x
~ U
o o o o o o o o
~ O O Q O O O O O
P;' C~ V U ~ C~ U
Ln n In
~ s :c
~) ~ ~) t~l ~ N
m m m ~ m x
~ U C) O ~ C~ In
\ I \ / . \/ ~
Z Z Z
^ ^ ~ ~3
~ ~ ~ U~ In ~
~ :~ m :~ ~ ~ m
X ~ O
_ _ ~ U ~ ~ ~ ~
o o o o o o o o
o o o o o o o o
V V
~ a
O ~
c~ m <1<1<1<1 ~ ~
o
o
:~ m 5: ~ m u ~
X ~r In ~ ~ O -I
W
: .
.
~ 4 _ ~ ~3~ 500-54~4
C
The compounds of formula I exhibit pharmacolo-
: gical activity. In particular, they lead to a dilation
of the coronary vessels as 2emonstrated by the results
of tests measuring the blood flow to the myocardi~m of
S an anaesthetised cat by means of the microsphere me~hod
(Rudolph A.~l. and l~eymann M.S.: Circulation Research 21,
163, 1967) upon administration of from 30 to 50 ,ug/kg
i.v. or of from 50 to 150 ~ug~k~ i.d. of the active sub-
stance.
The compounds of formula I also possess a fa-
vourable effect against angina pectoris, as shown by
the increase of the coronary flow of an anaesthetised
cat upon administration of the ~ctive substance.
- The compounds of formula I are thereore indi-
cated for use in the treatment of coronary insuffi-
: ciency.
The compounds of formula I increase the blood
flow to limbs, e~g. leg musculature, as can be shown
b~ means of the microsphere method on the anaesthetise~
cat upon administration of from 30 to 50 ~gJkg i.v. or
from 50 to 150 ~g/~g i.d. of the compounds.
The compounds of formula I are therefore indi-
cated for use in the treatment of interm1ttent claudi-
cation and other peripheral disturbances of blood
- 25 flow to limb muscles.
,",~
. ~ , . . :
,. ~ , , , , , ~
.
~L~.3~%~
- lS - 500-5494
.
The compounds of formula I increase cerebral
blood flo~ t as can be sllown by means of the microsphere
method on the anaesthetised cat upon adminis~ration of
from 30 ~o 50 ~g/kg i.v. or from S0 to 150 ~g/kg i.d.
of the compounds.
The compounds of formula I are therefore indi-
.- cate~ ~or use in the treatment of cerebxovascular in-
sults.
The compounds of formula I possess calcium-
antagonistic activity as indicated in standard tests,for example by an inhibition of a calci~m induced con-
traction of isolated dog coronary arteries suspended
in a depolarizing solution at concentration o lO 10
to lO 8 ~ of the compounds according to the pri~ci-
lS ples of Godfraind and Kaba, Brit, J. Pharm. 36, 54~-560,
1969.
The compounds of formula I are thereCore indi-
cated for use as spasmolytic agents for the treatment
of spasms of muscles. For the above indicatio~ an inai-
cated daily dose is from about 5 to lO0 mg, conve-
n~ently administered in divided doses 2 to 4 times a
day in unit dosage form con~aining from abo~t 1.25 mg
to about 50 mg, or in sustained release form.
Ad~itionally, the compounds of formula I ex-
hibit antihypertensive activity, as indica~ed in s~an-
dard tests, e.g. in the C.rollman rat test ~see ~. Groll-
, ~
- 16 - ~ ~ ~ ~ ~ ~ 500-5494
man, Proc. Soc. Expt. Biol. and Med~ 57, 104 ~1944)] on
s.c. administration of from 0.1 to 10 mg/kg animal
body weight of the compounds.
The compounds of formula I are therefore fur-
ther indicated for use as antihypertensive asents. For
this use an indicated daily dose is from about 5 to
about lO00 mg, conveniently given in divided doses 2
to 4 times a day in unit dosa~e form containing about
1.25 mg to about 500 mg, or in sustained release form.
,
A compound of formula I may be administered in
ree base form. ~lternatively any sufficiently basic
compound of formula I, e.g. those compounds wherein R3
or R4 contain an amino moiety, may be administered in
pharmaceutically acceptable acid addition salt form.
Such acid addition salt forms exhibit the same order
of activity as the free base forms. The present inven-
tion also provides a pharmaceutical composition com-
prising a compound of formula I in association with a
pharmaceutical carrier or diluent. Such compositions
may be prepared by conventional techniaues to be in
conventional forms, for example capsules or tablets.
The compounds of Examples l, 8 and 16 are the
preferred compounds. The coronary insufficiency, the
intermittent claudication, the cerebrovascular in-
sufficiency and the spasmolytic activities are thepreferred utilities for compounds of formula I.
., .
'
'
- 17 - ~ ~3~ 500-54g4
(
In one group of compounds
Rl is hydrogen, alkyl(Cl 6)~ hydroxyalkyl(C2 6~' alkoxy-
alkyl(C3 6)~ alkenyl(C3 6)~ alkinyl(C3 6)~ cyclo-
alkyl(C3 7), cycloalkylalkyl(C4 8)' phenylalkyl(C7 9)
or phenylalkenyl(C9 12)~ the phenyl ring being un-
substituted or mono-, di- or trisubstituted indepen-
dently by halogen, hydroxy, alkyl(Cl 4) or alkoxy
(Cl_4~,
R2 and R5, independently, are hydrogen, alkyl(Cl 6) or
phen~lalkyl(C7_10)t
R3 and R4, independently are CN, COP~7, COOR7 or S(O)nR7,
wherein
n is 0, l or 2,
R~ is alkyl(Cl 6)' alkenyl(C3 6)' alkinyl(C3_~), cyclo-
alkyl(C3 7), cycloalkylalkyl(C4 8)' hydroxyalkyl
(C2 6)~ alkoxyalkyl(C3 6), hydroxyalkoxyalkyl(C4 8)~
aminoalkyl(C2_6), alkyl(Cl_4)aminoa1kyl(C2 6),
phenyl, phenylalkyl(C7 10)~ a 5- or 6-membered
heterocyc~ c ring containing one heteroatom se-
lected from nitrogen, oxygen or sulphur, or alkyl
(Cl 4) substi~uted by a 5- or 6-membered hetero-
cyclic ring containing one heteroatom selected
from nitrogen,oxygen or sulphur,
R6 is hydrogen, halogen, alkyl(Cl ~), alkoxy(Cl 4),
alkylthio(Cl 4), alkylsulfonyl(Cl_4), trifluoro-
methyl, nitro, hydro~y, azido,amino, alkyl(C1 4)-
~a .
. .
,
~ 18 - ~3~%~ 500-5494
ami.no, alkanoyl(Cl 5)amino/ carbalkoxy(C2 4), amino-
carbonyl, trifluoromethoxy, cyano, sulfamyl, alkyl-
tCl 4)sulfamyl or di[alkyl(Cl 4)]sulfamyl, and
X is oxy~en or sulphur, with the proviso tllat when R
is hydrogen, alkyl(C1_6), alkenyl(C3_6), alkinyl
(C3 ~), cycloalkyl(C3 7), cycloalkylalkyl(C4 8)'
phenylalkyl(C7 9) or phenylalkenyl(C9 12)~ the phe-
nylrin~ being unsubstituted or mono-, di- or tri-
substituted independently by halogenr hydroxy,
alkyl(Cl_4) or alkoxy(C]_4)~
R2.and R5, indepenclently, are hydrogen or alkyl(Cl 4),
R6 is hydrogen, halogen, alkyl(Cl_4), alkoxy(Cl_4) f
alkylthio(Cl 4), alkylsulfonyl(Cl 4), trifluoro-
methyl, nitro or hydroxy, and
X is oxygen or sulphur, then at least one of the sub-
stituents R3 and R4 is other than COR7I, wherein
R I is alkyl(Cl_6), alkenYl(C3_6~ 3 6
cycloalkyl(C3 7), cycloalkylalkyl(C4 8)~ and is other
than COO~7II, wherein R7II is alkyl(Cl 6)~ alkenyl
(C3_6), alkinyl(C3_6),cycloalkyl(C3 7), cycloalkyl-
alkyl(C4_8), hydroxyalkyl(C2 6)~ alkoxyalkyl(C3 6) or
hydroxyalkoxyalkyl(C4 8)
In another group of compounds
Rl is hydrogen, alkyl(Cl 6)~ hydroxyalkyl(C2 6)/ alkoxy-
alkyl(C3 6) ~ alkenyl(C3 6) f alkinyl(C3 6)' cyclo-
alkyl(C3 7)~ cycloalkylalkyl(C~ 8)~ phenylalkyl(C7 9)
,,, ., ~ .. ,, . .. . :
'
- 19 - ~3~22~ ~00-5494
(
or phenylalkenyl(Cg 12)~ the phenyl ring being un-
substituted or mono-, di- or trisubstituted indepen-
dently by halogen, hydroxy, alkyl(Cl ~) or alkoxy
(Cl_4) ~
R2 and R5, independently, are hydrogen, alkyl(Cl 6) or
phenylalkyl (C7_10),
~R8
R is COO-A-N , and ~R
R4 is CN, COR7, COOR7, S(O)nR7 or COO-A-N ~ 8,
wherein
n is 2,
R is alkyl(Cl_6), alkenyl(C3_6), 3 6
cycloalkyl(C3 7), cycloalkylalkyl(C4 8)' hydroxy-
alkyl(C2 6)~ alkoxyalkyl(C3_6), hydroxyalkoxy-
alkyl(C4 8)~ aminoalkyl(C2 6)~ alkyl(Cl 4)amino-
alkyl(C2_6), phenyl or phenylalkyl(C7_10),
A is alkylene(Cl_6),
R8 and Rg, independently, are alkyl(Cl 6)~ alkenyl or
alkinyl(C3 6)' cycloalkyl(C3 7), cycloalkylalkyl
(C4 8)~ hydroxyal}cyl(C~ 6)~ alkoxyal~yl(C3 6~' hy-
droxyalkoxyalkyl(C4 ~), aminoalkyl(C2 6)' alkyl-
(Cl_4)aminoal.kyl(c2_6)~ phenyl, phenylalkyl(C7_1 n
or
R8 and Rg together with the ni~rogen atom form a 5-,
6- or 7-membered heterocyclic ring, which may con-
tain a further heterome~er selected from oxygen,
~ulphur and a group -N-Rl~, wherein Rlo is alkyl
(Cl_4~, and
...... .... .. . . . .
:
_ 20 ~ ~ ~ ~ ~ 500~5494
(
R6 is hydrogen, halogen, alkyl(Cl ~), alkoxy(C~
alkylthio(Cl 4), alkylsulLonyl(Cl 4), trifiuoro-
methyl, nitro, hydroxy, azido, amino, alkyl(Cl 4)-
amino, alkanoyl(Cl 5)amino, carbalkoxy(C2 5), amino-
carbonyl, trifluoromethoxy, cyano or sulfamyl, and
X is oxygen or sulphur.
In another group o~ compounds
Rl is hydrogen, alkyl(Cl_6), alkenyl(C3_6), alkinyl
(C3 6)~ cycloalkyl(C3 7), cycloalkylalkyl(C4 8)~
phenylalkyl(C7 9~ or ~henylalkenyl(Cg 12)' the
phenyl ring being unsubstituted or mono-, di-or
trisubstituted independently by halogen, hydroxy,
alkyl(Cl_4) or alkoxy~Cl_4),
R2 and R5, independently, are hydrogen, alkyl~Cl 6)~
phenylalkyl(c7_10), cycloalkyl(C3_7) or cycloalkyl-
alkyl (C~_8),
R3 and Ra~ independently, are COR7I or COOR7II, wherein
R7I is alkyl(Cl_6), alkenyl(C3_6), alkinyl(~3_6),
cycloalkyl(C3_7), cycloalkylalkyl(C4_8~, and ~7II
is alkyl(Cl 6)~ alkenyl(C3_6), alkinyl(C3_6)r
cycloalkyl(C3 7~, cycloalkylalkyl(C4_8), hydroxy-
alkyl(C2 6)~ alkoxyalkyl(C3 6j or hydroxyalkoxyalkyl
(C4~
R6 is hydrogen, halogen, alkyl(Cl ~), alkoxy(Cl 4),
alkylthio(Cl 4), alkylsulfonyl(Cl 4), trifluoro-
methyl, nitro or hydroxy, and
.
ZZ~
_ 21 _ 500-5494
X is oxygen or sulphur, with the proviso, that at least
one of the substituents R2 and R5 is phenylalkyl
(C7 10)~ cycloalkyl.(C3 7) or cycloalkylal~yl(C4 8)
A group of compounds are compounds of formula
I,
wherein
Rl is alkyl(Cl 6)' alkoxyalkyl(C3 6)' alkenyl(C3 6)'
alkinyl(C3 6)~ cycloalkyl(C3 7),
R2 and R5, independently, are hydrogen or alkyl~Cl 6)'
R3 and R4, independently, are COOR7, wherein R7 is
other than phenylalkyl.
These compounds show surprisingly benefic al
pharmacological activity than is expected for co~-
pounds of this type, e.g. long lasting coronary
lS suffic-ency activity in the tests mentioned above
and good tolerability.
- In another group
Rl lS alkyl(Cl 6)~ hydroxyalkyl(C2 6)~ alkoxy-
alkyl(C3 6)' alkenyl(C3 6)' alkinyl(C3 6)' cyclo-
alkyl(C3 7?, cycloalk~rlalkyl(C4 8~' phenylalkyl (~7 9)
or phenylalkenyl(Cg 12~ the phenyL ring beins un-
substituted or mono~, di- or trisubstituted indepen~
dently by halogen, hydroxy, alkyl(Cl 4) or alkoxy
( Cl_ 4 ~ ,
R2 and R5, independently, are hydrogen, alkyl(Cl 6)~
Y ( 7-10)~ cycloalkyl(C3~7) or cycloalkyl-
alkyl(c4-8)~ ~
. ~ ~
.~i .
:: : : .
- 22 - ~ ~3~ 500-54g~
(
R3 and R4, independently are CN, COR7, COOR7, S(O)nR7
or COO-A-N 8, wherein n, R7, ~, R8 and Rg and
subject to the proviso as defined above, provided
that R3 and R4 are not both COOR7, wherein R7 is
alkyl(Cl 6)
In another group of compounds
Rl is alkyl(Cl_6), alkenyl(C3_6), alkinyl(C3 6)' cyclo~
alkyl(C3 7),
R2 and R5, independently, are hydrogen or alkyl(Cl_6),
R3 and R4, independently, are C~, COR7, COOR7, S(O)nR7
/R~
or COO-A-N , wherein n, R7, A, R8 and Rg and
subject to the proviso as defined above and pro-
vided that R3 and R4 are not both COOR7, wherein
R7 is alkYl(C1-6)
In a sub-group R6 is alkylsulfonyl~Cl 4),
hydroxy, azido, amino, a~kyl(Cl 4)amino, ai ~alkyl~Cl ~)]
amino, alkanoyl(Cl 5)amino, aminocarbonyl, tri-fluoro-
methoxy, sulfamyl, alkyl(Cl ~)sulfamyl or di[alkyl
(cl-4)]sulfamyl.
In another group of compounds
Rl is hydrogen, alkyl(Cl 6)~ hydroxyalkyl(C2 6)~ alkoxy-
alkyl(C3 6~' alkenyl(C3 6)' alkinyl(C3 6)' cyclo-
, ~
-- 2 3 ~ 2~B 5 ~ 0 5 4 9 4
alkyl (C3 7?, ycloalkylall;yl (C4_~), phenylall;yl (C.~ _3)
or phenylal~enyJ.(C9 12)~ the phenyl ring bci.n~ un-
substi.~u~ed or mono-, di- or trisubstituted indepen-
dently by halogen, hydroxy, alkyl(Cl 4~ or zlkoxy
S (C
R2 and R5, independently, are hydrosen, alkyl(Cl 6)~
phen~l21kyl(c7_l0), cYcloalkyl(c3-7) or cycloalkyl-
allcyl (C4_8 ) ~
R3 and R4, independently are C~, COR7, COOR7, S (O) nX7
lQ or COO-~-N ~ 8, wherei.n n, R7, A, R3 and Rg ~ sub-
ject to the proviso as defined above, provi.ded thzt
R3 and R4 are not independently COR7, wherein R7 is
alkyl(Cl 6)~ alkenyl(C3 6)~ al]cinyl(C3 6) or CGOR7,
wherein R7 is other than phenyl or phenylalkyl as
defined above.
